################################################################################ # Metadata ################################################################################ SET DOCUMENT Name = "Epilepsy Knowledge Assembly" SET DOCUMENT Description = "A knowledge assembly of the genes, proteins, biological processes, pathologies, and other biological entities found within the epilepsy litearture. The edges have been assigned NeuroMMSig signatures according to the procedure from Domingo-Fernandez et al. (2017)." SET DOCUMENT Version = "1.0.0" SET DOCUMENT Authors = "Nora Filep, Anka Gueldenpfennig, Charles Tapley Hoyt, Daniel Domingo-Fernandez" SET DOCUMENT ContactInfo = "nora.filep@gmail.com" SET DOCUMENT Copyright = "Copyright © 2012-2018 Fraunhofer SCAI, All rights reserved." SET DOCUMENT Licenses = "CC BY 4.0" ################################################################################ # Author Credits ################################################################################ # Nora Filep - main curation # Anka Gueldenpfennig - main curation # Charles Tapley Hoyt - revision and evaluation # Daniel Domingo-Fernandez - revision, evaluation, and supervision ################################################################################ # Namespaces ################################################################################ # BEL Framework Namespaces, distributed by SCAI DEFINE NAMESPACE UBERON AS URL "https://arty.scai.fraunhofer.de/artifactory/bel/namespace/uberon/uberon-20170724.belns" DEFINE NAMESPACE GOCC AS URL "https://arty.scai.fraunhofer.de/artifactory/bel/namespace/go-cellular-component/go-cellular-component-20170511.belns" DEFINE NAMESPACE CHEBI AS URL "https://arty.scai.fraunhofer.de/artifactory/bel/namespace/chebi/chebi-20170511.belns" DEFINE NAMESPACE DO AS URL "https://arty.scai.fraunhofer.de/artifactory/bel/namespace/disease-ontology/disease-ontology-20170511.belns" DEFINE NAMESPACE GOBP AS URL "https://arty.scai.fraunhofer.de/artifactory/bel/namespace/go-biological-process/go-biological-process-20170511.belns" DEFINE NAMESPACE GO AS URL "https://arty.scai.fraunhofer.de/artifactory/bel/namespace/go/go-20180109.belns" DEFINE NAMESPACE HGNC AS URL "https://arty.scai.fraunhofer.de/artifactory/bel/namespace/hgnc-human-genes/hgnc-human-genes-20170511.belns" DEFINE NAMESPACE MESHC AS URL "https://arty.scai.fraunhofer.de/artifactory/bel/namespace/mesh-chemicals/mesh-chemicals-20170511.belns" DEFINE NAMESPACE MESHCS AS URL "https://arty.scai.fraunhofer.de/artifactory/bel/namespace/mesh-cell-structures/mesh-cell-structures-20170511.belns" DEFINE NAMESPACE MESHD AS URL "https://arty.scai.fraunhofer.de/artifactory/bel/namespace/mesh-diseases/mesh-diseases-20170511.belns" DEFINE NAMESPACE MESHPP AS URL "https://arty.scai.fraunhofer.de/artifactory/bel/namespace/mesh-processes/mesh-processes-20170511.belns" DEFINE NAMESPACE MGI AS URL "https://arty.scai.fraunhofer.de/artifactory/bel/namespace/mgi-mouse-genes/mgi-mouse-genes-20170511.belns" DEFINE NAMESPACE RGD AS URL "https://arty.scai.fraunhofer.de/artifactory/bel/namespace/rgd-rat-genes/rgd-rat-genes-20170511.belns" DEFINE NAMESPACE SCOMP AS URL "https://arty.scai.fraunhofer.de/artifactory/bel/namespace/selventa-named-complexes/selventa-named-complexes-20170511.belns" DEFINE NAMESPACE EPT AS URL "https://arty.scai.fraunhofer.de/artifactory/bel/namespace/epilepsy-terminology/epilepsy-terminology-1.0.3.belns" # BELIEF Namespaces #DEFINE NAMESPACE ADO AS URL "https://arty.scai.fraunhofer.de/artifactory/bel/namespace/alzheimer-disease-ontology/alzheimer-disease-ontology-1.0.2.belns" #DEFINE NAMESPACE PDO AS URL "http://belief.scai.fraunhofer.de/openbel/repository/namespaces/PDO.belns" DEFINE NAMESPACE PTS AS URL "https://arty.scai.fraunhofer.de/artifactory/bel/namespace/neurodegeneration-pathways/neurodegeneration-pathways-1.0.0.belns" DEFINE NAMESPACE NIFT AS URL "https://arty.scai.fraunhofer.de/artifactory/bel/namespace/imaging-ontology/imaging-ontology-1.0.0.belns" DEFINE NAMESPACE BRCO AS URL "https://arty.scai.fraunhofer.de/artifactory/bel/namespace/brain-region-ontology/brain-region-ontology-1.0.0.belns" DEFINE NAMESPACE dbSNP AS PATTERN "rs[0-9]+" DEFINE NAMESPACE InChI AS PATTERN "InChI=1S\/([^\/]+)(?:\/[^\/]+)*" ################################################################################ # Annotations ################################################################################ # BEL Framework Annotations DEFINE ANNOTATION Anatomy AS URL "https://arty.scai.fraunhofer.de/artifactory/bel/annotation/anatomy/anatomy-20170511.belanno" #DEFINE ANNOTATION CellLine AS URL "https://arty.scai.fraunhofer.de/artifactory/bel/annotation/cell-line/cell-line-20170511.belanno" DEFINE ANNOTATION CellStructure AS URL "https://arty.scai.fraunhofer.de/artifactory/bel/annotation/cell-structure/cell-structure-20170511.belanno" DEFINE ANNOTATION Cell AS URL "https://arty.scai.fraunhofer.de/artifactory/bel/annotation/cell/cell-20170511.belanno" # Use MeshAnatomy from 2015 release instead of 1.0 annotations that were seperated by system DEFINE ANNOTATION MeSHAnatomy AS URL "https://arty.scai.fraunhofer.de/artifactory/bel/annotation/mesh-anatomy/mesh-anatomy-20170511.belanno" DEFINE ANNOTATION MeSHDisease AS URL "https://arty.scai.fraunhofer.de/artifactory/bel/annotation/mesh-diseases/mesh-diseases-20170511.belanno" DEFINE ANNOTATION Species AS URL "https://arty.scai.fraunhofer.de/artifactory/bel/annotation/species-taxonomy-id/species-taxonomy-id-20170511.belanno" DEFINE ANNOTATION Subgraph AS URL "https://arty.scai.fraunhofer.de/artifactory/bel/annotation/neurommsig/neurommsig-1.0.3.belanno" DEFINE ANNOTATION TextLocation AS URL "https://arty.scai.fraunhofer.de/artifactory/bel/annotation/text-location/text-location-1.0.1.belanno" DEFINE ANNOTATION Published AS LIST {"Epilepsy comorbidity paper"} # Other Annotations DEFINE ANNOTATION Gender AS URL "https://arty.scai.fraunhofer.de/artifactory/bel/annotation/gender/gender-1.0.0.belanno" DEFINE ANNOTATION Confidence AS URL "https://arty.scai.fraunhofer.de/artifactory/bel/annotation/confidence/confidence-1.0.0.belanno" # List Annotations DEFINE ANNOTATION Drug AS LIST {"cisplatin", "cancer drugs", "Bromides", "benzodiazepine", "phenobarbital", "phenytoin", "ethosuximide", "carbamazepine", "valproate", "primidone", "gabapentin", "lamotrigine", "topiramate", "tiagabine", "oxcarbazepine", "zonisamide", "levetiracetam", "felbamate", "pregabalin", "rufinamide", "lacosamide", "brivaracetam", "ezogabine", "vigabatrin", "clobazam", "barbiturate"} DEFINE ANNOTATION Cohort AS LIST {"Argentinean", "Indians", "European"} ############################################################################### # Conventions ############################################################################### # All unknown mutations that are associated with the disease of that lead to the disease are now coded in BEL 2.0 (p:HGNC:X, var("?")) # Deletion of the genes are coded for now as: var("del") # Gene(HGNC:xxx) hasVariant gene(dbsnp:rsYYY) # gene(dbsnp:rsYYY) positiveCorrelation path(MESHD:XXX) # gene(HGNC:rsYYY, var("?")) positiveCorrelation path(MESHD:XXX) unknown mutations of this gene increase the risk of the disease # Duplications are represented using "c.(?_-1)_(*1_?)dup" (taken from HGVS) ############################################################################### # Confidence annotations ############################################################################### # Confidence annotations start around line 5000. Before that, statements were checked by Daniel. We decided to start adding confidence annotations depending on whether the statements were carefully expected ("High") or just checked that the entities were in the evidence ("Medium") ############################################################################### # Structure of the BEL Script ############################################################################### # # Line aprox 100 -> 1000: Normal statements about gene associated with Epilepsy # line 1040 -> 2100 (Tag: "Drug annotations") Drugs associated to Epilepsy # # line 7547 "Paper on Ras...": can be applicable to other context since it is a general paper about the role of this pathway in the other processes. Might be interesting to add to AD/PD # line 8000 medication (drug stuffs) ############################################################################### # Statements ############################################################################### SET STATEMENT_GROUP = "Group 1" SET Citation = {"PubMed", "Genomics. 2015 Apr;105(4):229-36. doi: 10.1016/j.ygeno.2015.02.001. Epub 2015 Feb 7.", "25668517"} SET Evidence = "Evidence has shown an association of RORA and RORB polymorphisms with susceptibility to autism and depression." SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} g(HGNC:RORA, var("?")) -- path(MESHD:"Depression, Postpartum") g(HGNC:RORA, var("?")) -- path(DO:"autism spectrum disorder") UNSET Subgraph g(HGNC:RORB, var("?")) -- path(MESHD:"Depression, Postpartum") g(HGNC:RORB, var("?")) -- path(DO:"autism spectrum disorder") SET Evidence = "Significant association was obtained for rs12912233 in Malaysian Chinese (p=0.003)." SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} g(HGNC:RORA) -- path(MESHD:Epilepsy) g(dbSNP:rs12912233) pos path(MESHD:Epilepsy) g(dbSNP:rs12912233) hasMember g(HGNC:RORA) UNSET Subgraph SET Evidence = "Interaction between rs12912233-rs880626 and rs3812718 was associated with the epilepsy risk in the subjects overall (p=0.001)." # rs12912233, rs880626 are related to RORA protein, rs3812718 to SCN1A SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} composite(g(dbSNP:rs12912233), g(dbSNP:rs880626)) pos path(MESHD:Epilepsy) UNSET Subgraph ##################################################### SET Citation = {"PubMed", "PLoS One. 2014 Feb 21;9(2):e89253. doi: 10.1371/journal.pone.0089253. eCollection 2014.", "24586633"} SET Evidence = "However, a significant association was observed between ABCB1 (C3435T) rs1045642 and risk of having epilepsy" g(HGNC:ABCB1) hasVariant g(dbSNP:rs1045642) g(dbSNP:rs1045642) pos path(MESHD:Epilepsy) ##################################################### SET Citation = {"PubMed", "Psychiatry Res. 2015 Sep 30;229(1-2):580-2. doi: 10.1016/j.psychres.2015.07.077. Epub 2015 Jul 28.", "26239769"} SET Evidence = "Haplotype analysis: rs1912960 (GABRA4) and rs211037 (GABRG2) overrepresented in cases. Rs1912960 has been associated with ASD and rs211037 with epilepsy. GABRA4 is associated with autism in the Argentinean dataset independently or in combination with GABRG2." SET Confidence = "High" g(HGNC:GABRA4) hasVariant g(dbSNP:rs1912960) g(HGNC:GABRG2) hasVariant g(dbSNP:rs1912960) SET Evidence = "Rs1912960 has been associated with ASD and rs211037 with epilepsy." SET Confidence = "High" g(dbSNP:rs1912960) pos path(DO:"autism spectrum disorder") g(dbSNP:rs211037) pos path(MESHD:Epilepsy) SET Evidence = "GABRA4 is associated with autism in the Argentinean dataset independently or in combination with GABRG2." SET Subgraph = {"GABA subgraph", "Neurotransmitter release subgraph"} SET Cohort = "Argentinean" composite(p(HGNC:GABRA4), p(HGNC:GABRG2)) -- path(DO:"autism spectrum disorder") p(HGNC:GABRA4) -- path(DO:"autism spectrum disorder") UNSET Subgraph UNSET Cohort #################################################### SET Citation = {"PubMed", "Hum Genet. 2014 May;133(5):651-9. doi: 10.1007/s00439-013-1405-1. Epub 2013 Dec 13.", "24337656"} SET Evidence = "These play a key role in epilepsy, with the most commonly mutated gene in epilepsy being SCN1A." SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} g(HGNC:SCN1A, var("?")) pos path(MESHD:Epilepsy) SET Evidence = "SCN1A rs2298771 was associated in Indians (OR = 0.56, p = 0.005) and SCN2B rs602594 with idiopathic epilepsy (OR = 0.62, p = 0.002)." SET Confidence = "High" SET Cohort = "Indians" g(dbSNP:rs602594) pos path(DO:"idiopathic generalized epilepsy") g(HGNC:SCN2B) hasVariant g(dbSNP:rs602594) g(dbSNP:rs2298771) pos path(DO:"idiopathic generalized epilepsy") g(HGNC:SCN1A) hasVariant g(dbSNP:rs2298771) path(DO:"idiopathic generalized epilepsy") isA path(MESHD:Epilepsy) UNSET Subgraph UNSET Cohort #################################################### SET Citation = {"PubMed", "Epilepsy Res. 2016 Jan;119:20-3. doi: 10.1016/j.eplepsyres.2015.11.016. Epub 2015 Dec 1.", "26656780"} SET Evidence = "Together these results demonstrate that Hlf is a genetic modifier of epilepsy caused by voltage-gated sodium channel mutations and that modulation of the pyridoxine pathway can also influence phenotype severity." SET Subgraph = "Neurotransmitter release subgraph" SET Species = "10090" p(MGI:Hlf) -- path(MESHD:Epilepsy) p(MGI:Hlf) -- bp(GOBP:"regulation of voltage-gated sodium channel activity") UNSET Subgraph ################################################### SET Citation = {"PubMed", "In Vivo. 2014 Nov-Dec;28(6):1193-6.", "25398822"} SET Evidence = "These results seem to exclude the DRPLA gene as a major candidate gene for JME in this European population." # DRPLA is ATN1 SET Subgraph = "Apoptosis signaling subgraph" SET Cohort = "European" SET Confidence = "High" p(HGNC:ATN1) causesNoChange path(MESHD:"Myoclonic Epilepsy, Juvenile") path(MESHD:"Myoclonic Epilepsy, Juvenile") isA path(MESHD:Epilepsy) UNSET Cohort UNSET Subgraph ################################################### SET Citation = {"PubMed", "Am J Med Genet A. 2015 Oct;167A(10):2314-8. doi: 10.1002/ajmg.a.37152. Epub 2015 May 10.", "25959266"} SET Evidence = "Mutations in the KCNQ2 gene, encoding a potassium channel subunit, were reported in patients presenting epileptic phenotypes of varying severity." SET Subgraph = "Calcium dependent subgraph" g(HGNC:KCNQ2, var("?")) pos path(MESHD:Epilepsy) p(HGNC:KCNQ2, var("?")) -- bp(GOBP:"regulation of voltage-gated calcium channel activity") UNSET Subgraph ################################################### SET Citation = {"PubMed", "J Neurosci. 2016 Jan 13;36(2):405-18. doi: 10.1523/JNEUROSCI.2555-15.2016.", "26758833"} SET Evidence = "Inborn errors of Cacna1a, the P/Q-type voltage-gated calcium channel α subunit gene, expressed throughout the brain destabilize corticothalamic rhythmicity and produce this phenotype. To determine the minimal cellular lesion required for this network disturbance, we used neurotensin receptor 1 (Ntsr1) cre-driver mice to ablate floxed Cacna1a in layer VI pyramidal neurons, which supply the sole descending cortical synaptic input to thalamocortical relay cells and reticular interneurons and activate intrathalamic circuits." SET Subgraph = "Calcium dependent subgraph" g(HGNC:CACNA1A, var("del")) pos path(MESHD:"Epilepsy, Generalized") g(HGNC:CACNA1A, var("del")) -- bp(GOBP:"regulation of voltage-gated calcium channel activity") UNSET Subgraph path(MESHD:"Epilepsy, Generalized") isA path(MESHD:Epilepsy) ################################################### SET Citation = {"PubMed", "Epilepsy Res. 2016 Feb;120:73-8. doi: 10.1016/j.eplepsyres.2015.12.006. Epub 2015 Dec 12.", "26773249"} SET Evidence = "Heterozygous mutations in LGI1 account for up to 50% of ADLTE families and only rarely observed in IPEAF cases." g(HGNC:LGI1, var("?")) pos path(MESHD:"Epilepsy, Temporal Lobe") g(HGNC:LGI1, var("?")) causesNoChange path(MESHD:"Epilepsies, Partial") path(MESHD:"Epilepsy, Temporal Lobe") isA path(MESHD:Epilepsy) ################################################### SET Citation = {"PubMed", "Neuropharmacology. 2016 Feb;101:320-9. doi: 10.1016/j.neuropharm.2015.09.032. Epub 2015 Oct 9.", "26456350"} SET Evidence = "T-type (Cav3) calcium channels play important roles in neuronal excitability, both in normal and pathological activities of the brain. In particular, they contribute to hyper-excitability disorders such as epilepsy." SET Subgraph = "Calcium dependent subgraph" p(HGNC:CAV3) -- path(MESHD:Epilepsy) bp(GOBP:"neuronal action potential") -- p(HGNC:CAV3) UNSET Subgraph ################################################### SET Citation = {"PubMed", "Neuro Oncol. 2015 Dec;17(12):1550-9. doi: 10.1093/neuonc/nov152. Epub 2015 Aug 19.", "26289591"} SET Evidence = "TSC is caused by mutations within the TSC1 or TSC2 genes that inactivate the genes' tumor-suppressive function and drive hamartomatous cell growth." SET Subgraph = "mTOR signaling subgraph" g(HGNC:TSC1, var("?")) pos path(MESHD:"Tuberous Sclerosis") g(HGNC:TSC2, var("?")) pos path(MESHD:"Tuberous Sclerosis") g(HGNC:TSC1, var("?")) pos path(MESHD:Hamartoma) g(HGNC:TSC2, var("?")) pos path(MESHD:Hamartoma) SET Evidence = "Tuberous sclerosis complex (TSC) is a genetic autosomal dominant disorder characterized by benign tumor-like lesions, called hamartomas, in multiple organ systems, including the brain, skin, heart, kidneys, and lung. These hamartomas cause a diverse set of clinical problems based on their location and often result in epilepsy." SET Confidence = "High" path(MESHD:"Tuberous Sclerosis") -- path(MESHD:Hamartoma) path(MESHD:Hamartoma) pos path(MESHD:Epilepsy) UNSET Subgraph ################################################### SET Citation = {"PubMed", "Nature. 2015 Dec 3;528(7580):123-6. doi: 10.1038/nature16159. Epub 2015 Nov 25.", "26605526"} SET Evidence = "MECP2 duplication syndrome is one of the most common genomic rearrangements in males and is characterized by autism, intellectual disability, motor dysfunction, anxiety, epilepsy, recurrent respiratory tract infections and early death." SET Subgraph = "brain_derived neurotrophic factor signaling subgraph" g(HGNC:MECP2, var("c.(?_-1)_(*1_?)dup")) pos path(DO:"autism spectrum disorder") g(HGNC:MECP2, var("c.(?_-1)_(*1_?)dup")) pos path(MESHD:Epilepsy) g(HGNC:MECP2, var("c.(?_-1)_(*1_?)dup")) pos path(DO:"anxiety disorder") UNSET Subgraph ################################################### SET Citation = {"PubMed", "Neurobiol Dis. 2016 Feb;86:52-61. doi: 10.1016/j.nbd.2015.11.014. Epub 2015 Dec 1.", "26607785"} SET Evidence = "This translationally designed study in a clinically relevant model of epilepsy suggests that simultaneous overexpression of NPY and Y2 receptors unilaterally in the seizure focus is a relevant and promising approach that can be further validated in more extensive preclinical studies to develop a future treatment strategy for severe, often pharmacoresistant focal epilepsy cases that cannot be offered alternative therapeutic options." SET Subgraph = "Long term synaptic potentiation" p(HGNC:NPY) neg path(MESHD:Epilepsy) p(HGNC:NPY2R) neg path(MESHD:Epilepsy) UNSET Subgraph ################################################### SET Citation = {"PubMed", "J Mol Biol. 2015 Jul 31;427(15):2418-34. doi: 10.1016/j.jmb.2015.05.014. Epub 2015 May 22.", "26004542"} SET Evidence = "Cystatin C amyloids cause a hereditary form of cerebral amyloid angiopathy whilst cystatin B aggregates are found in cases of Unverricht-Lundborg Syndrome, a progressive form of myoclonic epilepsy" SET Subgraph = {"GABA subgraph", "Apoptosis signaling subgraph", "Neurotransmitter release subgraph"} g(HGNC:CSTB) -- path(MESHD:"Myoclonic Epilepsies, Progressive") path(MESHD:"Myoclonic Epilepsies, Progressive") isA path(MESHD:Epilepsy) UNSET Subgraph ################################################## SET Citation = {"PubMed", "Epilepsia. 2015 Apr;56(4):e40-3. doi: 10.1111/epi.12944. Epub 2015 Mar 6.", "25752200"} SET Evidence = "Our study did not support a role for the CSTB gene in patients with familial or sporadic JME." SET Subgraph = "Apoptosis signaling subgraph" g(HGNC:CSTB) causesNoChange path(MESHD:"Myoclonic Epilepsy, Juvenile") UNSET Subgraph ################################################## SET Citation = {"PubMed", "Clin Genet. 2016 Jan;89(1):104-8. doi: 10.1111/cge.12570. Epub 2015 Mar 19.", "25683376"} SET Evidence = "LD is caused by mutations either in the EPM2A or in NHLRC1 genes." SET Subgraph = "Energy metabolic subgraph" g(HGNC:EPM2A, var("?")) pos path(MESHD:"Lafora Disease") g(HGNC:NHLRC1, var("?")) pos path(MESHD:"Lafora Disease") path(MESHD:"Lafora Disease") isA path(MESHD:Epilepsy) UNSET Subgraph ################################################# SET Citation = {"PubMed", "Semin Neurol. 2015 Jun;35(3):288-92. doi: 10.1055/s-0035-1552922. Epub 2015 Jun 10.", "26060908"} SET Evidence = "The first decade of the 21st century was marked by progress in understanding the basic biology of generalized epilepsies including generalized/genetic epilepsies with febrile seizures plus (GEFS+) and GGE through studies of large families, discovering causative mutations in SCN1A, SCN1B, GABRG2, and GABRA1" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} g(HGNC:SCN1A, var("?")) pos path(MESHD:"Epilepsy, Generalized") g(HGNC:SCN1B, var("?")) pos path(MESHD:"Epilepsy, Generalized") UNSET Subgraph SET Subgraph = {"GABA subgraph", "Neurotransmitter release subgraph"} g(HGNC:GABRG2, var("?")) pos path(MESHD:"Epilepsy, Generalized") g(HGNC:GABRA1, var("?")) pos path(MESHD:"Epilepsy, Generalized") UNSET Subgraph SET Evidence = "However, after discovery of these three genes, discovery of other genes for GEFS+ stagnated for more than a decade until the recent discovery of STX1B mutations in GEFS+." SET Subgraph = "Neurotransmitter release subgraph" g(HGNC:STX1B, var("?")) pos path(MESHD:"Seizures, Febrile") g(HGNC:STX1B, var("?")) pos path(MESHD:"Epilepsy, Generalized") UNSET Subgraph SET Evidence = " Genetic studies in large families with GGE identified mutations in GABRG2 in families with absence epilepsy as the predominant phenotype and GABRA1 in families with juvenile myoclonic epilepsy." SET Subgraph = {"GABA subgraph", "Neurotransmitter release subgraph"} g(HGNC:GABRG2, var("?")) pos path(MESHD:"Epilepsy, Absence") path(MESHD:"Epilepsy, Absence") isA path(MESHD:Epilepsy) g(HGNC:GABRA1, var("?")) pos path(MESHD:"Myoclonic Epilepsy, Juvenile") UNSET Subgraph SET Evidence = "More recently, mutations in SLC2A1 were identified in patients with rare generalized epilepsies including frequencies of up to 10% in early-onset absence epilepsy (EOAE) and myoclonic astatic epilepsy (MAE)" SET Subgraph = "Energy metabolic subgraph" g(HGNC:SLC2A1, var("?")) pos path(MESHD:"Epilepsy, Absence") g(HGNC:SLC2A1, var("?")) pos path(MESHD:"Epilepsies, Myoclonic") path(MESHD:"Epilepsies, Myoclonic") isA path(MESHD:Epilepsy) UNSET Subgraph ################################################# SET Citation = {"PubMed", "Nat Genet. 2004 Aug;36(8):842-9. Epub 2004 Jul 18.", "15258581"} SET Evidence = "Mutation analyses identified five missense mutations in EFHC1 that cosegregated with epilepsy or EEG polyspike wave in affected members of six unrelated families with JME and did not occur in 382 control individuals." g(HGNC:EFHC1, var("?")) pos path(MESHD:"Myoclonic Epilepsy, Juvenile") ################################################## SET Citation = {"PubMed", "Nat Rev Neurol. 2014 May;10(5):283-92. doi: 10.1038/nrneurol.2014.62. Epub 2014 Apr 15.", "24733163"} SET Evidence = "The majority (around 80%) of cases of Dravet syndrome are caused by mutations in SCN1A, which encodes the α-subunit of the type 1 voltage-gated sodium channel" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} g(HGNC:SCN1A, var("?")) pos path(DO:"Dravet syndrome") path(DO:"Dravet syndrome") isA path(MESHD:Epilepsy) UNSET Subgraph SET Evidence = "Dravet syndrome also illustrates another key feature of inherited epilepsy, in that novel mutations are also reported in other seemingly unconnected genes. Occasionally, de novo mutations in GABRG2 and PCDH19 cause a Dravet-like presentation" SET Subgraph = {"GABA subgraph", "Neurotransmitter release subgraph"} g(HGNC:GABRG2, var("?")) pos path(DO:"Dravet syndrome") UNSET Subgraph g(HGNC:PCDH19, var("?")) pos path(DO:"Dravet syndrome") SET Evidence = "Although any gene mutation that explains an individual’s epilepsy is impor- tant, some genes (such as STXBP1,60 PCDH19,59,61 SCN2A62 and CDKL548,49,63) are recurrently mutated. Recognition of these more-common disorders permits the identification of their characteristic clinical features, such as movement disorders and head stereotypies with STXBP1 mutations,64 or clustered focal seizures with affective symptoms in female patients with PCDH19 mutations.6" SET Subgraph = "Neurotransmitter release subgraph" g(HGNC:STXBP1, var("?")) pos path(MESHD:Epilepsy) g(HGNC:SCN2A, var("?")) pos path(MESHD:Epilepsy) UNSET Subgraph SET Subgraph = "mTOR signaling subgraph" g(HGNC:CDKL5, var("?")) pos path(MESHD:Epilepsy) SET Evidence = "Surprisingly, however, the first crop of gene discoveries in Mendelian epilepsies included mutations in CHRNA4 (which encodes the nicotinic receptor subunit) causing an autosomal dominant nocturnal frontal lobe epilepsy and mutations in LGI1 causing autosomal dominant epilepsy with auditory features." g(HGNC:CHRNA4, var("?")) pos path(MESHD:"Epilepsy, Frontal Lobe") path(MESHD:"Epilepsy, Frontal Lobe") isA path(MESHD:Epilepsy) g(HGNC:LGI1, var("?")) pos path(MESHD:Epilepsy) SET Evidence = "Nonsense and missense mutations in DEPDC5 are responsible for familial focal epilepsy with variable foci in seven of the eight published large pedigrees, but DEPDC5 mutations also explain around 12% of focal epilepsies in 10 smaller families." g(HGNC:DEPDC5, var("?")) pos path(DO:"focal epilepsy") path(DO:"focal epilepsy") isA path(MESHD:Epilepsy) SET Evidence = "Surprisingly, the protein encoded by DEPDC5 is involved in the mammalian target of rapamycin (mTOR) pathway, which is also implicated in tuberous sclerosis." SET Subgraph = "mTOR signaling subgraph" p(HGNC:DEPDC5) -- path(MESHD:"Tuberous Sclerosis") p(HGNC:DEPDC5) -- bp(PTS:"mTOR signaling pathway") UNSET Subgraph SET Evidence = "The NMDA-type glutamate receptor subunit ε1, encoded by GRIN2A, has major importance in the epilepsy–aphasia spectrum, including patients with mild focal epilepsy but no intellectual disability." SET Subgraph = "Long term synaptic potentiation" p(HGNC:GRIN2A) -- path(DO:"focal epilepsy") UNSET Subgraph SET Evidence = "Importantly, however, altered ε1 subunit function has also been connected to severe pres- entations of epilepsy–aphasia spectrum disorders, such as Landau–Kleffner syndrome and epilepsy with continuous spike-and-wave in slow-wave sleep.73–75 The proportion of patients with typical or atypical benign epilepsy with centrotemporal spikes who harbour a GRIN2A mutation (0–5%) is much lower than the corresponding proportion of patients with Landau–Kleffner syndrome (12–20%)" SET Subgraph = "Long term synaptic potentiation" g(HGNC:GRIN2A, var("?")) pos path(MESHD:"Landau-Kleffner Syndrome") UNSET Subgraph #code SET Evidence = "the sodium-activated potassium channel subunit encoded by KCNT1 is widely expressed in the brain, partic- ularly in the neurons of the frontal cortex, in keeping with its association with autosomal dominant nocturnal frontal lobe epilepsy." SET Subgraph = "mTOR signaling subgraph" g(HGNC:KCNT1, var("?")) pos path(MESHD:"Epilepsy, Frontal Lobe") SET Evidence = "KCNT1 mutations can also cause a quite different epilepsy phenotype: epilepsy in infancy with migrating focal seizures, which was previously known as malignant migrating partial seizures of infancy." g(HGNC:KCNT1, var("?")) pos path(DO:"focal epilepsy") UNSET Subgraph ############################################## SET Citation = {"PubMed", "Nat Genet. 2013 Jul;45(7):825-30. doi: 10.1038/ng.2646. Epub 2013 May 26.", "23708187"} SET Evidence = "We show that de novo CHD2 and SYNGAP1 mutations are new causes of epileptic encephalopathies, accounting for 1.2% and 1% of cases, respectively." g(HGNC:CHD2, var("?")) pos path(DO:"early myoclonic encephalopathy") g(HGNC:SYNGAP1, var("?")) pos path(DO:"early myoclonic encephalopathy") SET Evidence = "Furthermore, in vivo studies of human CHD7 showed that mutations affecting the helicase domain, which cause CHARGE (coloboma, heart defects, atresia of the choanae, retardation of growth and/or development, genital and/or urinary abnormalities and ear abnormalities and deafness) syndrome, resulted in decreased remodeling ability." g(HGNC:CHD7, var("?")) pos path(MESHD:"CHARGE Syndrome") SET Evidence = "Notably, recent studies have implicated de novo mutations in CHD8 in individuals with ASD." g(HGNC:CHD8, var("?")) pos path(DO:"autism spectrum disorder") SET Evidence = "SYNGAP1 mutations have been associated with intellectual disability, and, although most cases also have epilepsy, seizures are typically well controlled." g(HGNC:SYNGAP1, var("?")) pos path(DO:"intellectual disability") g(HGNC:SYNGAP1, var("?")) pos path(MESHD:Epilepsy) SET Evidence = "Variants were identified in three additional epilepsy-associated genes. There were two de novo variants in MEF2C (NM_002397.4;NP_002388.2), a missense variant (p.Cys39Arg) and a stop-loss variant (p.*464SerExt*?)." p(HGNC:MEF2C, var("p.*464SerExt*?")) pos path(MESHD:Epilepsy) p(HGNC:MEF2C, var("p.Cys39Arg")) pos path(MESHD:Epilepsy) SET Evidence = "Furthermore, we found de novo pathogenic variants in MBD5 (NM_018328.4; NP_060798.2) (p.Thr157Glnfs*4) and GABRG2 (NM_000816.3; NP_000807.2) (p.Arg323Gln)." g(HGNC:MBD5, var("p.Thr157Glnfs*4")) pos path(MESHD:Epilepsy) g(HGNC:GABRG2, var("p.Arg323Gln)")) pos path(MESHD:Epilepsy) SET Evidence = "Collectively these data suggest that haploinsufficiency for HNRNPU is associated with ? epileptic encephalopathy as well as with intellectual disability" # Haploinsufficiency means that there is only one functional copy of the protein p(HGNC:HNRNPU) neg path(DO:"intellectual disability") p(HGNC:HNRNPU) neg path(DO:"infantile epileptic encephalopathy") SET Evidence = "We also identified a pathogenic missense mutation (encoding p.Leu1290Val) in SCN8A." g(HGNC:SCN8A, var("p.Leu1290Val")) pos path(MESHD:Epilepsy) SET Evidence = "Notably, mutations in SYNGAP1 and CHD2 have now been described in probands with epileptic encephalopathy, intellectual disability and ASD phenotypes, highlighting the shared genetic basis of neurodevelopmental disorders." SET Subgraph = {"Glutamatergic subgraph", "Neurotransmitter release subgraph"} g(HGNC:SYNGAP1, var("?")) pos path(DO:"autism spectrum disorder") g(HGNC:CHD2, var("?")) pos path(DO:"intellectual disability") g(HGNC:CHD2, var("?")) pos path(DO:"autism spectrum disorder") UNSET Subgraph ################################################# SET Citation = {"PubMed", "Epilepsy Behav. 2011 May;21(1):20-2. doi: 10.1016/j.yebeh.2011.03.022. Epub 2011 Apr 17.", "21501974"} SET Evidence = "Mutations in the presenilin-1 gene (PSEN1) on chromosome 14 are the most common cause of autosomal dominant Alzheimer's disease (AD), with around 180 mutations described to date." SET Subgraph = "Long term synaptic potentiation" g(HGNC:PSEN1, var("?")) pos path(MESHD:"Alzheimer Disease") SET Evidence = "Epileptic seizures have been reported as part of the phenotype of 37 different PSEN1 mutations (Table 1), which represents around 20% (37/180) of described pathogenic mutations." g(HGNC:PSEN1, var("?")) pos path(MESHD:Epilepsy) UNSET Subgraph ################################################# SET Citation = {"PubMed", "J Alzheimers Dis. 2015;46(4):863-76. doi: 10.3233/JAD-143162.", "25854934"} SET Evidence = "Lamotrigine (LTG), a broad-spectrum anti-epileptic drug widely used in treatment for seizures, shows potential efficacy in Alzheimer's disease (AD) therapy. Chronic LTG treatment rescues the suppressed long-term potentiation, loss of spines and cognitive deficits in Abeta mice, known to overexpress a chimeric mouse/human mutant amyloid-beta protein precursor and a mutant human presenilin 1 (PS1)." SET Subgraph = "Long term synaptic potentiation" g(HGNC:PSEN1) -| bp(PTS:"Long_Term Potentiation") bp(PTS:"Long_Term Potentiation") -| path(MESHD:Epilepsy) a(CHEBI:lamotrigine) -> bp(PTS:"Long_Term Potentiation") a(CHEBI:lamotrigine) -| path(MESHD:"Alzheimer Disease") SET Evidence = "These results suggest LTG treatment reduces A‚beta production, possibly through modulation of cleavage of A‚beta-secretase" a(CHEBI:lamotrigine) -| p(HGNC:APP, frag(672_713)) a(CHEBI:lamotrigine) reg p(HGNC:BACE1) p(HGNC:BACE1) -| p(HGNC:APP) UNSET Subgraph ############################################### SET Citation = {"PubMed", "Arch Pediatr. 2013 Dec;20 Suppl 4:S117-26. doi: 10.1016/S0929-693X(13)71425-8.", "24360362"} SET Evidence = "Permanent neonatal diabetes mellitus requires lifelong therapy, whereas transient form resolves early in life but may relapse later on. Two main physiopathological mechanisms may explain this disease: cell functional impairment or absence (pancreas agenesis or ‚cells destruction). The main genetic causes of ‚beta cells impairment are 6q24 abnormalities and mutations in ABCC8 or KCNJ11 potassium channel (KATP channel) genes." SET Subgraph = "Energy metabolic subgraph" g(HGNC:ABCC8, var("?")) pos path(DO:"neonatal diabetes mellitus") g(HGNC:KCNJ11, var("?")) pos path(DO:"neonatal diabetes mellitus") SET Evidence = " Patients with mutations in ABCC8 or KCNJ11 genes had developmental delay with or without epilepsy but also developmental coordination disorder (particularly visual-spatial dyspraxia) or attention deficits in all of those who underwent in-depth neuropsychomotor investigations." g(HGNC:ABCC8, var("?")) pos path(MESHD:Epilepsy) g(HGNC:ABCC8, var("?")) pos path(DO:"specific developmental disorder") g(HGNC:ABCC8, var("?")) pos path(DO:"developmental coordination disorder") g(HGNC:ABCC8, var("?")) pos path(DO:"attention deficit hyperactivity disorder") g(HGNC:KCNJ11, var("?")) pos path(MESHD:Epilepsy) g(HGNC:KCNJ11, var("?")) pos path(DO:"specific developmental disorder") g(HGNC:KCNJ11, var("?")) pos path(DO:"developmental coordination disorder") g(HGNC:KCNJ11, var("?")) pos path(DO:"attention deficit hyperactivity disorder") UNSET Subgraph ################################################# SET Citation = {"PubMed", "Cephalalgia. 2014 Jan;34(1):68-72. doi: 10.1177/0333102413498941. Epub 2013 Aug 5.", "23918834"} SET Evidence = "Mutations in the ion transportation coding genes CACNA1A , ATP1A2 and SCN1A are responsible for the FHM phenotype." SET Subgraph = "Calcium dependent subgraph" g(HGNC:CACNA1A, var("?")) pos path(MESHD:"Migraine with Aura") g(HGNC:ATP1A2, var("?")) pos path(MESHD:"Migraine with Aura") g(HGNC:SCN1A, var("?")) pos path(MESHD:"Migraine with Aura") SET Evidence = "Moreover, some mutations in ATP1A2 or SCN1A also may lead to epilepsy." g(HGNC:ATP1A2, var("?")) pos path(MESHD:Epilepsy) g(HGNC:SCN1A, var("?")) pos path(MESHD:Epilepsy) UNSET Subgraph ##################################################### SET Citation = {"PubMed", "Neurology. 2012 Nov 20;79(21):2122-4. doi: 10.1212/WNL.0b013e3182752cb8. Epub 2012 Oct 17.", "23077016"} SET Evidence = "PRRT2 mutations have recently been shown to cause various childhood-onset episodic syndromes including paroxysmal kinesigenic dyskinesia, infantile convulsions with choreoathetosis syndrome, and benign familial infantile epilepsy." SET Subgraph = "Neurotransmitter release subgraph" g(HGNC:PRRT2, var("?")) pos path(MESHD:Epilepsy) g(HGNC:PRRT2, var("?")) pos path(DO:"benign familial infantile epilepsy") path(DO:"benign familial infantile epilepsy") isA path(MESHD:Epilepsy) SET Evidence = "PRRT2 mutations can occasionally cause HM." g(HGNC:PRRT2, var("?")) pos path(MESHD:"Migraine with Aura") UNSET Subgraph ####################################################### SET Citation = {"PubMed", "Exp Mol Med. 2011 May 31;43(5):231-74. doi:10.3858/emm.2011.43.5.032.", "21467839"} SET TextLocation = "Review" SET Evidence = " In these studies, kainate or pilocarpine was injected into rats to induce status epilepticus (SE) and the animals went on to develop spontaneous seizures. It has been shown that S6, a ribosomal protein involved in translation initiation, and a downstream molecule in the mTOR signaling pathway, became phosphorylated (activated)." SET Species = "10116" SET Subgraph = "mTOR signaling subgraph" a(CHEBI:"kainic acid") -> path(MESHD:"Status Epilepticus") a(CHEBI:pilocarpine) -> path(MESHD:"Status Epilepticus") p(HGNC:RPS6KA1, pmod(P)) -- bp(GOBP:"translational initiation") p(HGNC:RPS6KA1, pmod(P)) -- bp(PTS:"mTOR signaling pathway") a(CHEBI:sirolimus) -| bp(PTS:"mTOR signaling pathway") a(CHEBI:sirolimus) -| path(MESHD:Seizures) a(CHEBI:sirolimus) isA a(CHEBI:"mTOR inhibitor") UNSET Species SET Evidence = "Treatment with rapamycin reduced the seizure frequency in TSC patients and mouse models of TSC." SET MeSHDisease = "Tuberous Sclerosis" SET Species = "10090" a(CHEBI:sirolimus) -| path(MESHD:Seizures) UNSET MeSHDisease SET Evidence = "Similarly, PTEN (phosphatase and tensin homolog) is a molecule found mutated in autosomal dominant harmatoma and epilepsy-associated glioblastoma, and the conditional knockout mice showed cortical dysplasia, ataxia, and seizures." SET Species = "10090" SET Subgraph = "mTOR signaling subgraph" g(RGD:Pten, var("?")) pos path(MESHD:Epilepsy) UNSET Subgraph SET Evidence = "PTEN is a negative regulator of phosphoinositide 3-kinase (PI3K) which is located at upstream of mTOR." SET Species = "10090" SET Subgraph = "mTOR signaling subgraph" p(RGD:Pten) -| p(RGD:Pik3c2a) p(RGD:Pik3c2a) -- bp(PTS:"mTOR signaling pathway") UNSET Species UNSET Subgraph SET Evidence = "Lafora Disease is an autosomal recessive epilepsy which is caused by defective laforin or malin proteins. This neurodegenerative disease has lafora bodies, which are polyglucosans masses, are found in neurons, myocytes, and hepatocytes." path(MESHD:"Lafora Disease") isA path(DO:"autosomal recessive disease") # Mutations in the EPM2A gene or the NHLRC1 gene interfere with the production of functional proteins, leading to the formation of Lafora bodies p(HGNC:EPM2A, var("?")) -- path(MESHD:"Lafora Disease") p(HGNC:NHLRC1, var("?")) -- path(MESHD:"Lafora Disease") SET Evidence = "Laforin (encoded by EPM2A gene) dephosphorylates GSK3‚ thus controlling GS." p(HGNC:EPM2A) -| p(HGNC:GSK3B,pmod(P)) SET Evidence = "GSK3 is phosphorylated by AKT and S6K1, and it phosphorylates TSC1, TSC2, and REDD1 which all are on the mTOR pathway." kin(p(HGNC:AKT1)) -> p(HGNC:GSK3B, pmod(P)) kin(p(HGNC:RPS6KB1)) -> p(HGNC:GSK3B, pmod(P)) kin(p(HGNC:GSK3B)) -> p(HGNC:TSC1, pmod(P)) kin(p(HGNC:GSK3B)) -> p(HGNC:TSC2, pmod(P)) kin(p(HGNC:GSK3B)) -> p(HGNC:DDIT4, pmod(P)) p(HGNC:TSC1) -- bp(PTS:"mTOR signaling pathway") p(HGNC:TSC2) -- bp(PTS:"mTOR signaling pathway") p(HGNC:DDIT4) -- bp(PTS:"mTOR signaling pathway") p(HGNC:AKT1) -- bp(PTS:"mTOR signaling pathway") p(HGNC:RPS6KB1) -- bp(PTS:"mTOR signaling pathway") SET Evidence = "PMSE (Polyhydramnios, megalencephaly and symptomatic epilepsy) has been recently found having gene deletion in STRAD" # deletion of this gene pos pathologies despite the bad evidence (is a review) g(HGNC:STRADA, var("del")) pos path(MESHD:Polyhydramnios) g(HGNC:STRADA, var("del")) pos path(MESHD:Megalencephaly) g(HGNC:STRADA, var("del")) pos path(MESHD:Epilepsy) g(HGNC:STRADA, var("del")) =| r(HGNC:STRADA) SET Evidence = "STRAD forms a complex with LKB1 and MO25‚ and this complex regulates AMPK which controls mTORC1 and TSC2, an upstream regulator of mTORC1." complex(p(HGNC:STRADA), p(HGNC:STK11), p(HGNC:CAB39)) -> bp(GOBP:"regulation of cAMP-dependent protein kinase activity") complex(p(HGNC:STRADA), p(HGNC:STK11), p(HGNC:CAB39)) -> bp(GOBP:"regulation of cAMP-dependent protein kinase activity") SET Subgraph = "mTOR signaling subgraph" bp(GOBP:"regulation of cAMP-dependent protein kinase activity") -- p(HGNC:MTOR) bp(GOBP:"regulation of cAMP-dependent protein kinase activity") -- g(HGNC:TSC2) g(HGNC:TSC2) -> p(HGNC:MTOR) SET Evidence = "When the ligand such as insulin-like growth factor (IGF) binds to its receptor (e.g., IGF receptor) on the plasma membrane, the activated signal (phosphorylation) transduces to PI3K either directly or indirectly via mediator proteins such as Insulin receptor substrate-1 (IRS-1)." complex(p(HGNC:IGF1R),p(HGNC:IGF1)) -> p(HGNC:PIK3CA, pmod(P)) SET Evidence = "PI3K makes phosphatidylinositol 3, 4, 5 trisphosphate (PIP3) from phosphatidylinositol 4, 5 bisphosphate (PIP2), PIP3 activates PDK1, and PDK1 phosphorylates and activates AKT/PKB at Thr308. " p(HGNC:PIK3CA, pmod(P)) -> a(CHEBI:"phosphatidylinositol trisphosphate") a(CHEBI:"phosphatidylinositol trisphosphate") -> p(HGNC:PDK1, pmod(P)) kin(p(HGNC:PDK1, pmod(P))) -> p(HGNC:AKT1, pmod(P, T, 308)) SET Evidence = "Activated AKT inhibits TSC2 by phosphorylation, subsequently disinhibits Rheb to activate mTORC1." kin(p(HGNC:AKT1, pmod(P))) -| p(HGNC:TSC2, pmod(P)) kin(p(HGNC:TSC2, pmod(P))) -> p(HGNC:MTOR, pmod(P)) SET Evidence = "AKT can be fully activated by phosphorylation at Ser473 by mTORC2, inhibiting mTORC2-regulating molecules such as FOXO and BAD." kin(complex(SCOMP:"TORC2 Complex")) -> p(HGNC:AKT1, pmod(P, S, 473)) p(HGNC:AKT1, pmod(P, S, 473)) -| p(HGNC:FOXO1) p(HGNC:AKT1, pmod(P, S, 473)) -| p(HGNC:BAD) SET Evidence = "TSC2 forms a complex with TSC1 inhibiting Rheb by keeping it GDP bound form (Rheb-GDP), and Rheb-GTP activates mTORC1" complex(p(HGNC:TSC1), p(HGNC:TSC2)) -> complex(p(HGNC:RHEB), a(CHEBI:GDP)) complex(p(HGNC:RHEB), a(CHEBI:GDP)) -| complex(p(HGNC:RHEB), a(CHEBI:GTP)) #kin(complex(p(HGNC:RHEB), a(CHEBI:GTP))) -> complex(SCOMP:"TORC1 Complex", pmod(P)) kin(complex(p(HGNC:RHEB), a(CHEBI:GTP))) -> complex(p(HGNC:MTOR, pmod(P)), p(HGNC:MLST8), p(HGNC:DEPTOR), p(HGNC:RPTOR), p(HGNC:AKT1S1)) SET Evidence = "Signaling through mTORC1 promotes protein synthesis via phosphorylation which causes the inactivation of translation repressor 4E-BPs and the activation of S6 Kinases and ribosomal protein S6." kin(complex(p(HGNC:MTOR, pmod(P)), p(HGNC:MLST8), p(HGNC:DEPTOR), p(HGNC:RPTOR), p(HGNC:AKT1S1))) -> p(HGNC:RPS6KA1, pmod(P)) SET Evidence = "mTORC1 comprises five different components: 3 common proteins that it shares with mTORC2 (mTOR, mLST8, and DEPTOR), and 2 mTORC1-specific proteins (RAPTOR and PRAS40)." complex(SCOMP:"TORC1 Complex") hasComponents list(p(HGNC:MTOR), p(HGNC:MLST8), p(HGNC:DEPTOR), p(HGNC:RPTOR), p(HGNC:AKT1S1)) SET Evidence = "mTORC1 plays a major role in controlling cell growth in response to amino acids, energy status, stress, oxygen levels, hormones, growth factors and cytokines by regulating several cellular processes, including translation, transcription, ribosome biogenesis, nutrients transport and autophagy." complex(SCOMP:"TORC1 Complex") -- bp(GOBP:"regulation of cell growth") complex(SCOMP:"TORC1 Complex") -- bp(GOBP:"regulation of translation") complex(SCOMP:"TORC1 Complex") -- bp(GOBP:"regulation of transcription, DNA-templated") complex(SCOMP:"TORC1 Complex") -- bp(GOBP:"regulation of ribosome biogenesis") complex(SCOMP:"TORC1 Complex") -- bp(GOBP:"regulation of autophagy") SET Evidence = "mTORC1 is known to be rapamycin-sensitive via its FKBP12 interaction." a(CHEBI:sirolimus) -- complex(SCOMP:"TORC1 Complex") SET Evidence = "Identified downstream targets of mTORC1 for regulating these processes at the translational level are S6K1, 4E-BP1, eEF2K, eIF3F, and eIF4G" complex(SCOMP:"TORC1 Complex") -- p(HGNC:RPS6KB1) complex(SCOMP:"TORC1 Complex") -- p(HGNC:EIF4EBP1) complex(SCOMP:"TORC1 Complex") -- p(HGNC:EEF2K) complex(SCOMP:"TORC1 Complex") -- p(HGNC:EIF3F) complex(SCOMP:"TORC1 Complex") -- p(HGNC:EIF4G1) SET Evidence = "At the transcriptional level, SREBP1, Lipin-1, c-Myc and STAT3 interact with mTORC1 to control expression of their specific target genes" complex(SCOMP:"TORC1 Complex") -- p(HGNC:SREBF1) complex(SCOMP:"TORC1 Complex") -- p(HGNC:LPIN1) complex(SCOMP:"TORC1 Complex") -- p(HGNC:MYC) complex(SCOMP:"TORC1 Complex") -- p(HGNC:STAT3) SET Evidence = "mTORC1 phosphorylates CLIP-170 to reorganize microtubule, and ULK1 (ATG1)/ATG13 to inhibit autophagy." kin(complex(SCOMP:"TORC1 Complex")) -> p(HGNC:CLIP3, pmod(P)) p(HGNC:CLIP3, pmod(P)) -> bp(GOBP:"cytoplasmic microtubule organization") kin(complex(SCOMP:"TORC1 Complex")) -> p(HGNC:ULK1, pmod(P)) p(HGNC:ULK1, pmod(P)) -| bp(GOBP:autophagy) SET Evidence = "PP2A, PIM-1, and 14-3-3 interact closely with mTORC1." complex(SCOMP:"TORC1 Complex") -- p(HGNC:PPP2R5B) complex(SCOMP:"TORC1 Complex") -- p(HGNC:PIM1) complex(SCOMP:"TORC1 Complex") -- p(HGNC:SFN) SET Evidence = "The upstream regulators of mTORC2 are less clearly defined- it is TSC1/2-dependent, possibly via direct TSC2-RICTOR interaction" p(HGNC:TSC1) -- complex(SCOMP:"TORC2 Complex") p(HGNC:TSC2) -- complex(SCOMP:"TORC2 Complex") SET Evidence = "mTORC2 is generally known as rapamycin-insensitive, and it seems to be regulated only by growth factors." a(CHEBI:sirolimus) causesNoChange complex(SCOMP:"TORC2 Complex") a(CHEBI:sirolimus) causesNoChange complex(SCOMP:"TORC2 Complex") complex(GOCC:"growth factor complex") reg complex(SCOMP:"TORC2 Complex") SET Evidence = "AKT/PKB, PKC‚ and SGK1 are known downstream targets of mTORC2." complex(SCOMP:"TORC2 Complex") -- p(HGNC:AKT1) complex(SCOMP:"TORC2 Complex") -- p(HGNC:PRKCA) complex(SCOMP:"TORC2 Complex") -- p(HGNC:SGK1) SET Evidence = "By releasing the inhibitory action of TSC via AKT, mTORC2 controls the upstream of mTORC1 activity." kin(complex(SCOMP:"TORC2 Complex")) -> p(HGNC:AKT1, pmod(P)) kin(p(HGNC:AKT1, pmod(P))) -> p(HGNC:TSC1, pmod(P)) p(HGNC:TSC1, pmod(P)) -| complex(SCOMP:"TORC1 Complex") SET Evidence = "Through AKT activation, mTORC2 controls the expression of transcription factors such as FOXO, and an apoptosis regulator, BAD." p(HGNC:AKT1, pmod(P)) -- p(HGNC:FOXO1) p(HGNC:AKT1, pmod(P)) -- p(HGNC:BAD) SET Evidence = "mTORC2 also reorganizes actin cytoskeleton through Rho-associated kinase (ROCK1) and PKC‚beta¬±." kin(complex(SCOMP:"TORC2 Complex")) -> p(HGNC:ROCK1, pmod(P)) kin(complex(SCOMP:"TORC2 Complex")) -> p(HGNC:PRKCA, pmod(P)) p(HGNC:ROCK1, pmod(P)) -> bp(GOBP:"actin cytoskeleton reorganization") p(HGNC:PRKCA, pmod(P)) -> bp(GOBP:"actin cytoskeleton reorganization") SET Evidence = "P-REX1, HSP70, and 14-3-3 interact closely with mTORC2." complex(SCOMP:"TORC2 Complex") -- p(HGNC:REXO1) complex(SCOMP:"TORC2 Complex") -- p(HGNC:HSPA1A) complex(SCOMP:"TORC2 Complex") -- p(HGNC:SFN) SET Evidence = "mTOR participates in signaling pathways associated with human diseases including tuberous sclerosis complex, lymphangioleiomyomatosis, Cowden disease, Peutz-Jeghers syndrome, neurofibromatosis, familial cardiac hypertrophy, and cancers characterized by hyperactivation of PI3K/AKT." p(HGNC:MTOR) -- path(MESHD:"Tuberous Sclerosis") p(HGNC:MTOR) -- path(MESHD:Lymphangioleiomyomatosis) p(HGNC:MTOR) -- path(DO:"Cowden disease") p(HGNC:MTOR) -- path(MESHD:"Peutz-Jeghers Syndrome") p(HGNC:MTOR) -- path(MESHD:Neurofibromatoses) p(HGNC:MTOR) -- path(MESHD:"Cardiomyopathy, Hypertrophic, Familial") SET Evidence = "There are three phosphorylation sites (Thr2446, Ser2448, and Ser2481) on mTOR: Thr2446 has been shown to be phosphorylated by AMPK and S6K1, Thr2448 by AKT and S6K1, and Ser2481 has been reported to be autophosphorylated by mTOR itself." kin(p(HGNC:PRKAA1)) -> p(HGNC:MTOR, pmod(P, Y, 2446)) kin(p(HGNC:RPS6KB1)) -> p(HGNC:MTOR, pmod(P, Y, 2446)) kin(p(HGNC:AKT1)) -> p(HGNC:MTOR, pmod(P, S, 2448)) kin(p(HGNC:RPS6KB1)) -> p(HGNC:MTOR, pmod(P, S, 2448)) kin(p(HGNC:MTOR)) -> p(HGNC:MTOR, pmod(P, S, 2481)) SET Evidence = "mLST8 (mammalian lethal with Sec13 protein 8) is a positive regulator of mTORC1 and mTORC2." p(HGNC:MLST8) -> complex(SCOMP:"TORC1 Complex") p(HGNC:MLST8) -> complex(SCOMP:"TORC2 Complex") SET Evidence = "DEPTOR (DEP-domain containing mTOR-interacting protein) is a negative regulator of mTOR complexes." p(HGNC:DEPTOR) -| complex(SCOMP:"TORC1 Complex") p(HGNC:DEPTOR) -| complex(SCOMP:"TORC2 Complex") SET Evidence = "RAPTOR (regulatory-associated protein of mTOR) is a positive regulator of mTORC1, and recruits mTOR substrates." p(HGNC:RPTOR) -> complex(SCOMP:"TORC1 Complex") SET Evidence = "RAPTOR is phosphorylated at Ser792 by AMPK, inducing 14-3-3 binding to AMPK-ULK1-mTORC1 complex to inhibit mTORC1 activity." kin(p(HGNC:PRKAA1)) -> p(HGNC:RPTOR, pmod(P, S, 792)) p(HGNC:RPTOR, pmod(P, S, 792)) -> complex(p(HGNC:SFN), p(HGNC:PRKAA2), p(HGNC:ULK1), complex(SCOMP:"TORC1 Complex")) complex(p(HGNC:SFN), p(HGNC:PRKAA2), p(HGNC:ULK1), complex(SCOMP:"TORC1 Complex")) -| complex(SCOMP:"TORC1 Complex") UNSET Subgraph SET Evidence = "It is also phosphorylated by ERK1/2 at Ser8, Ser696, and Ser863 and by RSK at Ser719, Ser721 and Ser722, activating mTORC1 activity" SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph"} kin(p(HGNC:MAPK3)) -> p(HGNC:RPTOR, pmod(P, S, 8)) kin(p(HGNC:MAPK3)) -> p(HGNC:RPTOR, pmod(P, S, 696)) kin(p(HGNC:MAPK3)) -> p(HGNC:RPTOR, pmod(P, S, 863)) kin(p(HGNC:RPS6KA1)) -> p(HGNC:RPTOR, pmod(P, S, 719)) kin(p(HGNC:RPS6KA1)) -> p(HGNC:RPTOR, pmod(P, S, 721)) kin(p(HGNC:RPS6KA1)) -> p(HGNC:RPTOR, pmod(P, S, 722)) UNSET Subgraph SET Subgraph = "mTOR signaling subgraph" p(HGNC:RPTOR, pmod(P, S)) -> complex(SCOMP:"TORC1 Complex") SET Evidence = "PRAS40 (Proline-rich AKT substrate of 40 KDa; also known as AKT1 substrate 1 (AKTS1)) is phosphorylated at Thr246 by AKT and this promotes its binding with 14-3-3, relieving from mTORC1, thus disinhibits mTORC1." kin(p(HGNC:AKT1)) -> p(HGNC:AKT1S1, pmod(P, Thr, 246)) p(HGNC:AKT1S1, pmod(P, Thr, 246)) -> complex(SCOMP:"TORC1 Complex") UNSET Subgraph ################################################################ SET Citation = {"PubMed", "PLoS One. 2012;7(1):e28268. doi: 10.1371/journal.pone.0028268. Epub 2012 Jan 25.", "22295056"} SET Evidence = "Functional evaluation of these replicated SNPs revealed rs471931 on 11q13.3 to exert a cis-regulatory effect on mRNA expression in the PPFIA1 gene (0.0021)." #g(dbSNP:rs471931) pos g(HGNC:PPFIA1) #regulatory sequence snp, so there is no gene for it SET Evidence = "PPFIA1 encodes liprin alpha, a protein involved in cell adhesion, integrin expression, and cell-matrix interactions." p(HGNC:PPFIA1) -- bp(GOBP:"cell adhesion") p(HGNC:PPFIA1) -- p(HGNC:ITGA1) p(HGNC:PPFIA1) -- bp(GOBP:"cell-matrix adhesion") SET Evidence = "This study supports the feasibility of future multi-center GWA investigations of ALI risk, and identifies PPFIA1 as a potential functional candidate ALI risk gene for future research." p(HGNC:PPFIA1) pos path(MESHD:"Acute Lung Injury") SET Evidence = "Acute lung injury (ALI) is a syndrome characterized by diffuse pulmonary edema and severe hypoxemia in the absence of clinical evidence of left atrial hypertension" path(MESHD:"Acute Lung Injury") pos path(MESHD:"Pulmonary Edema") SET Evidence = "Notably, the IL10 SNP (rs1800896 at 1082 in the promoter region) showed a similar effect on ALI risk as in prior reports." g(dbSNP:rs1800896) pos path(MESHD:"Acute Lung Injury") #belongs to IL10, already annotated below SET Evidence = "Several of these candidate genes contained additional loci associated with ALI risk including IL10, FAS, MYLK, and ANGTP2" # unknown risk loci pos the pathology g(HGNC:IL10, var("?")) pos path(MESHD:"Acute Lung Injury") g(HGNC:FAS, var("?")) pos path(MESHD:"Acute Lung Injury") g(HGNC:MYLK, var("?")) pos path(MESHD:"Acute Lung Injury") g(HGNC:ANGPT2, var("?")) pos path(MESHD:"Acute Lung Injury") SET Evidence = "however, liprin alpha binds to the intracellular membrane-distal phosphatase domain of tyrosine phosphatase ‚leukocyte antigen related' (LAR), and may regulate the disassembly of focal cell adhesion, influencing cell-matrix interactions [47]." complex(p(HGNC:PPFIA1), p(HGNC:PTPRF)) -> bp(GOBP:"regulation of focal adhesion assembly") SET Evidence = "CD161 has recently been implicated in regulating the tissue-homing and inflammatory effects of T-cells, including IL-17 producing cells" SET Cell = "T cell" #p(HGNC:KLRB1) -- bp("tissue-homing") p(HGNC:KLRB1) -- bp(PTS:"inflammatory response pathway") UNSET Cell SET Evidence = "ARGAP26 encodes Rho GTPase activating protein 26; and Rho family GTPases may regulate endothelial barrier integrity through interactions with the actin cytoskeleton" p(HGNC:ARHGAP26) -- bp(GOBP:"actin cytoskeleton reorganization") p(HGNC:ARHGAP26) -- bp(GOBP:"establishment of endothelial barrier") SET Evidence = "Replicated SNPS with putative functional roles in ALI pathogenesis: rs2398611, rs1468674, rs248244, rs2838659, rs1321106, rs2701129, rs847301, rs4546368, rs7778918, rs1948837, rs12547884, rs2302006, rs3820145, rs7922288, rs237012, rs1317790, rs4553956, rs8178179, rs10520676. (Table 2)" g(dbSNP:rs2398611) pos path(MESHD:"Acute Lung Injury") g(dbSNP:rs2838659) pos path(MESHD:"Acute Lung Injury") g(dbSNP:rs1321106) pos path(MESHD:"Acute Lung Injury") g(dbSNP:rs2701129) pos path(MESHD:"Acute Lung Injury") g(dbSNP:rs847301) pos path(MESHD:"Acute Lung Injury") g(dbSNP:rs4546368) pos path(MESHD:"Acute Lung Injury") g(dbSNP:rs7778918) pos path(MESHD:"Acute Lung Injury") g(dbSNP:rs1948837) pos path(MESHD:"Acute Lung Injury") g(dbSNP:rs12547884) pos path(MESHD:"Acute Lung Injury") g(dbSNP:rs2302006) pos path(MESHD:"Acute Lung Injury") g(dbSNP:rs3820145) pos path(MESHD:"Acute Lung Injury") g(dbSNP:rs7922288) pos path(MESHD:"Acute Lung Injury") g(dbSNP:rs237012) pos path(MESHD:"Acute Lung Injury") g(dbSNP:rs1317790) pos path(MESHD:"Acute Lung Injury") g(dbSNP:rs4553956) pos path(MESHD:"Acute Lung Injury") g(dbSNP:rs8178179) pos path(MESHD:"Acute Lung Injury") g(dbSNP:rs10520676) pos path(MESHD:"Acute Lung Injury") ###################################################### SET Citation = {"PubMed", "Pharmacogenomics. 2012 Mar;13(4):399-405. doi: 10.2217/pgs.11.165.", "22379998"} SET Evidence = "Table S3: Genome-wide analysis of total lamotrigine and phenytoin-induced hypersensitivity subjects vs controls (Supplementary Material)" SET Drug = {"lamotrigine", "phenytoin"} SET Confidence = "High" g(dbSNP:rs1250560) pos path(MESHD:"Drug-Related Side Effects and Adverse Reactions") g(HGNC:ZMIZ1) hasVariant g(dbSNP:rs1250560) UNSET Drug SET Evidence = "Carbamazepine (CBZ), lamotrigine (LTG) and phenytoin (PHT), among a class of antiepileptic drugs (AEDs) involved in sodium-channel modulation, are three of the leading first-line treatments for epilepsy" SET Confidence = "High" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} SET Published = "Epilepsy comorbidity paper" a(CHEBI:carbamazepine) -| path(MESHD:Epilepsy) a(CHEBI:carbamazepine) -- bp(GOBP:"regulation of voltage-gated sodium channel activity") UNSET Published SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph", "Calcium dependent subgraph", "Long term synaptic potentiation"} a(CHEBI:lamotrigine) -| path(MESHD:Epilepsy) a(CHEBI:lamotrigine) -- bp(GOBP:"regulation of voltage-gated sodium channel activity") SET Drug = "phenytoin" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} a(CHEBI:phenytoin) -| path(MESHD:Epilepsy) a(CHEBI:phenytoin) -- bp(GOBP:"regulation of voltage-gated sodium channel activity") UNSET {Subgraph, Drug, Confidence} ###################################################### SET Citation = {"PubMed", "Alcohol Clin Exp Res. 2010 May;34(5):840-52. doi: 10.1111/j.1530-0277.2010.01156.x. Epub 2010 Mar 1.", "20201924"} SET Evidence = "Supplementary Table 1: SNPs associated with alcohol dependence in European Americans (p≤10−3 rs2475335)" g(dbSNP:rs2475335) pos path(MESHD:Alcoholism) g(HGNC:PTPRD) hasVariant g(dbSNP:rs2475335) UNSET Evidence UNSET Citation ##################################################### # Gene correlated epilepsy drug resistance SET Citation = {"PubMed", "Epilepsia. 2001 Dec;42(12):1501-6.", "11879359"} SET Evidence = "Drug resistance is thought primarily to involve the MDR1 gene that encodes for P-glycoprotein (PgP1 or MDR1), an adenosine triphosphate (ATP)-dependent transport protein that exports planar, hydrophobic, amphipathic drugs out of cells and helps to protect normal and tumor cells against the influx of certain xenobiotics (2,3)." # MDR1 is ABCB1 SET Drug="cisplatin" p(HGNC:ABCB1) -- bp(GOBP:"regulation of response to drug") p(HGNC:ABCB1) -> bp(GOBP:"drug export") UNSET Drug SET Evidence = "Based on the preliminary results linking MDR1-mediated resistance to AEDs, it is not clear whether other MDR genes or proteins also are overexpressed in epileptic brain." path(MESHD:Epilepsy) -- p(HGNC:ABCB1) SET Evidence = "hCRA is believed to be involved in resistance to common antineoplastic treatment." SET Drug="cisplatin" p(HGNC:MTMR11) -- bp(GOBP:"regulation of response to drug") UNSET Drug SET Evidence = "Thus it is possible that overexpression of hCRA may occur in the presence of AEDs or antineoplastic agents." a(CHEBI:"antineoplastic agent") -> p(HGNC:MTMR11) a(CHEBI:anticonvulsant) -> p(HGNC:MTMR11) ###################################################### SET Citation = {"PubMed", "Brain. 2002 Jan;125(Pt 1):22-31.", "11834590"} SET Evidence = "MDR1 can transport phenytoin (Tishleretal.,1995) and phenobarbitone (Schuetzetal.,1996) and is known to be able to transport other planar lipophilic molecular structures: most current AEDs are planar and lipophilic" tport(p(HGNC:ABCB1)) -- tloc(a(CHEBI:phenytoin), fromLoc(GOCC:"extracellular space"), toLoc(GOCC:"intracellular")) tport(p(HGNC:ABCB1)) -- tloc(a(CHEBI:phenobarbital), fromLoc(GOCC:"extracellular space"), toLoc(GOCC:"intracellular")) tport(p(HGNC:ABCB1)) -- tloc(a(CHEBI:anticonvulsant), fromLoc(GOCC:"extracellular space"), toLoc(GOCC:"intracellular")) SET Evidence = "MRP1 may be able to transport other AEDs, and is known to transport drug epoxides and glucuronides, into which the conjugates carbamazepine and lamotrigine are metabolized" tport(p(HGNC:ABCC1)) -- tloc(a(CHEBI:anticonvulsant), fromLoc(GOCC:"extracellular space"), toLoc(GOCC:"intracellular")) tport(p(HGNC:ABCC1)) -- tloc(a(CHEBI:carbamazepine), fromLoc(GOCC:"extracellular space"), toLoc(GOCC:"intracellular")) SET Evidence = "It is possible, therefore, that MDR1 and MRP1 overexpressed in the pattern observed in our cases might lower local interstitial AED concentration and thereby reduce their antiepileptic effects." p(HGNC:ABCB1) -| act(a(CHEBI:anticonvulsant)) p(HGNC:ABCC1) -| act(a(CHEBI:anticonvulsant)) act(a(CHEBI:anticonvulsant)) -| path(MESHD:Epilepsy) ######################### ### Drug annotations ## ######################### ############################################### SET Citation = {"PubMed", "Antiepileptic treatment in patients with epilepsy and other comorbidities", "20554455"} SET Evidence = "Comorbidities can be a direct cause of epilepsy, as with stroke, be in complex relationship with epilepsy, as with psychiatric disorders, or be associated with no apparent relationship as, for example, with heart disease." path(MESHD:Stroke) pos path(MESHD:Epilepsy) SET Evidence = "In the acute management of an epileptic seizure, intravenous phenytoin (PHT) can cause arrhythmias and hypotension." SET Drug = "phenytoin" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} a(CHEBI:phenytoin) -> path(MESHD:"Arrhythmias, Cardiac") a(CHEBI:phenytoin) -> path(MESHD:Hypotension) a(CHEBI:phenytoin) -> path(MESHD:"Cardiovascular Diseases") a(CHEBI:phenytoin) -| path(MESHD:Seizures) a(CHEBI:phenytoin) isA a(CHEBI:anticonvulsant) UNSET Subgraph UNSET Drug SET Evidence = " Valproic acid (VPA) is a good alternative to PHT in these patients because no abnormalities have been observed in heart rate or in blood pressure, even when a fast intravenous infusion rate is used." SET Drug = "valproate" SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph", "Notch signaling subgraph", "thyroid hormone signaling subgraph", "hormone signaling subgraph", "Neurotransmitter release subgraph", "GABA subgraph", "Calcium dependent subgraph", "Protein Metabolism", "Metabolism"} a(CHEBI:valproate) causesNoChange path(MESHD:"Cardiovascular Diseases") a(CHEBI:valproate) -| path(MESHD:Seizures) a(CHEBI:valproate) isA a(CHEBI:anticonvulsant) UNSET Subgraph UNSET Drug SET Evidence = " Levetiracetam (LEV) also appears safe, although few studies on its use in emergency situations are available." SET Drug = "levetiracetam" SET Subgraph = {"Neurotransmitter release subgraph", "GABA subgraph", "Calcium dependent subgraph", "Serotonergic subgraph"} a(CHEBI:levetiracetam) causesNoChange path(MESHD:"Cardiovascular Diseases") a(CHEBI:levetiracetam) -| path(MESHD:Seizures) a(CHEBI:levetiracetam) isA a(CHEBI:anticonvulsant) UNSET Subgraph UNSET Drug SET Evidence = " Benzodiazepines (BZD) can be used with careful monitoring of respiratory function." SET Drug = "benzodiazepine" a(CHEBI:benzodiazepine) causesNoChange path(MESHD:"Cardiovascular Diseases") a(CHEBI:benzodiazepine) -| path(MESHD:Seizures) a(CHEBI:benzodiazepine) isA a(CHEBI:anticonvulsant) UNSET Drug SET Evidence = "In chronic antiepileptic treatment, carbamazepine (CBZ), oxcarbazepine (OXC) and PHT should be used with caution in patients with heart disease, and they should be avoided in the event of atrioventricular conduction dysfunction" SET Drug = "carbamazepine" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} a(CHEBI:carbamazepine) -- path(DO:"heart disease") a(CHEBI:carbamazepine) isA a(CHEBI:anticonvulsant) UNSET Subgraph UNSET Drug SET Drug = "oxcarbazepine" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph", "Calcium dependent subgraph"} a(CHEBI:oxcarbazepine) -- path(DO:"heart disease") a(CHEBI:oxcarbazepine) -| path(MESHD:Epilepsy) a(CHEBI:oxcarbazepine) isA a(CHEBI:anticonvulsant) UNSET Subgraph UNSET Drug SET Drug = "phenytoin" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} a(CHEBI:phenytoin) -- path(DO:"heart disease") UNSET Subgraph UNSET Drug SET Evidence = " Pregabalin (PGB) should be used with care in cases of heart failure due to left ventricular systolic dysfunction" SET Drug = "pregabalin" SET Subgraph = {"Calcium dependent subgraph", "MAPK-ERK subgraph", "protein kinase signaling subgraph"} a(CHEBI:pregabalin) -- path(DO:"systolic heart failure") a(CHEBI:pregabalin) -| path(MESHD:Epilepsy) a(CHEBI:pregabalin) isA a(CHEBI:anticonvulsant) UNSET Subgraph UNSET Drug SET Evidence = "The most recommended AEDs are LEV, lamotrigine (LTG), topiramate (TPM), VPA and zonisamide (ZNS)." SET Drug = "levetiracetam" SET Subgraph = {"Neurotransmitter release subgraph", "GABA subgraph", "Calcium dependent subgraph", "Serotonergic subgraph"} a(CHEBI:levetiracetam) causesNoChange path(MESHD:"Cardiovascular Diseases") a(CHEBI:levetiracetam) -| path(MESHD:Epilepsy) UNSET Subgraph UNSET Drug SET Drug = "lamotrigine" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph", "Calcium dependent subgraph", "Long term synaptic potentiation"} a(CHEBI:lamotrigine) causesNoChange path(MESHD:"Cardiovascular Diseases") a(CHEBI:lamotrigine) isA a(CHEBI:anticonvulsant) UNSET Subgraph UNSET Drug SET Drug = "topiramate" SET Subgraph = {"GABA subgraph", "Neurotransmitter release subgraph", "Calcium dependent subgraph", "thyroid hormone signaling subgraph", "hormone signaling subgraph", "Glutamatergic subgraph", "Long term synaptic potentiation", "Long term synaptic depression", "Serotonergic subgraph"} a(CHEBI:topiramate) causesNoChange path(MESHD:"Cardiovascular Diseases") a(CHEBI:topiramate) -| path(MESHD:Epilepsy) a(CHEBI:topiramate) isA a(CHEBI:anticonvulsant) UNSET Subgraph UNSET Drug SET Drug = "valproate" SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph", "Notch signaling subgraph", "thyroid hormone signaling subgraph", "hormone signaling subgraph", "Neurotransmitter release subgraph", "GABA subgraph", "Calcium dependent subgraph", "Protein Metabolism", "Metabolism"} a(CHEBI:valproate) -| path(MESHD:Epilepsy) UNSET Subgraph UNSET Drug SET Drug = "zonisamide" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph", "Glutamatergic subgraph", "MAPK-ERK subgraph", "protein kinase signaling subgraph", "Calcium dependent subgraph"} a(CHEBI:zonisamide) causesNoChange path(MESHD:"Cardiovascular Diseases") a(CHEBI:zonisamide) isA a(CHEBI:anticonvulsant) a(CHEBI:zonisamide) -| path(MESHD:Epilepsy) UNSET Subgraph UNSET Drug SET Evidence = " Gabapentin (GBP) can also be useful as an add-on therapy." SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph", "Calcium dependent subgraph"} a(CHEBI:gabapentin) causesNoChange path(MESHD:"Cardiovascular Diseases") a(CHEBI:gabapentin) -| path(MESHD:Epilepsy) a(CHEBI:gabapentin) isA a(CHEBI:anticonvulsant) UNSET Subgraph SET Evidence = "Table 1. Precautions in the management of AEDs together with other commonly used drugs in heart disease: Salicylates increase the free fraction of VPA." a(CHEBI:salicylate) -| path(DO:"heart disease") a(CHEBI:salicylate) -> a(CHEBI:valproate) SET Evidence = "Ticlopidine increases the levels of PHT and CBZ." a(CHEBI:ticlopidine) -| path(DO:"heart disease") a(CHEBI:ticlopidine) -> a(CHEBI:phenytoin) a(CHEBI:ticlopidine) -> a(CHEBI:carbamazepine) SET Evidence = "Enzyme-inducing AEDs (CBZ, PB, PHT, PRM) increase the metabolism of antiarrhythmics and so it may be necessary to increase the doses of the latter." SET Drug = "carbamazepine" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} a(CHEBI:carbamazepine) -| a(CHEBI:"anti-arrhythmia drug") UNSET Subgraph UNSET Drug SET Drug = "phenobarbital" SET Subgraph = {"GABA subgraph", "Neurotransmitter release subgraph"} a(CHEBI:phenobarbital) -| a(CHEBI:"anti-arrhythmia drug") UNSET Subgraph UNSET Drug SET Drug = "phenytoin" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} a(CHEBI:phenytoin) -| a(CHEBI:"anti-arrhythmia drug") UNSET Subgraph UNSET Drug SET Drug = "primidone" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} a(CHEBI:primidone) -| a(CHEBI:"anti-arrhythmia drug") UNSET Subgraph UNSET Drug a(CHEBI:"anti-arrhythmia drug") -| path(DO:"heart disease") SET Evidence = "Dilthiazem and verapamil increase the levels of CBZ." a(CHEBI:diltiazem) -> a(CHEBI:carbamazepine) a(CHEBI:diltiazem) -| path(DO:"heart disease") a(CHEBI:verapamil) -> a(CHEBI:carbamazepine) a(CHEBI:verapamil) -| path(DO:"heart disease") SET Evidence = "Amiodarone increases the levels of PHT." a(CHEBI:amiodarone) -> a(CHEBI:phenytoin) a(CHEBI:amiodarone) -| path(DO:"heart disease") SET Evidence = " Enzyme-inducing AEDs increase the metabolism of beta-blockers and dihydropyridine calcium antagonists" SET Drug = "carbamazepine" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} a(CHEBI:carbamazepine) -| a(CHEBI:"beta-adrenergic drug") a(CHEBI:carbamazepine) -| a(CHEBI:"calcium channel blocker") UNSET Subgraph UNSET Drug SET Drug = "phenobarbital" SET Subgraph = {"GABA subgraph", "Neurotransmitter release subgraph"} a(CHEBI:phenobarbital) -| a(CHEBI:"beta-adrenergic drug") a(CHEBI:phenobarbital) -| a(CHEBI:"calcium channel blocker") UNSET Subgraph UNSET Drug SET Drug = "phenytoin" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} a(CHEBI:phenytoin) -| a(CHEBI:"beta-adrenergic drug") a(CHEBI:phenytoin) -| a(CHEBI:"calcium channel blocker") UNSET Subgraph UNSET Drug SET Drug = "primidone" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} a(CHEBI:primidone) -| a(CHEBI:"beta-adrenergic drug") a(CHEBI:primidone) -| a(CHEBI:"calcium channel blocker") UNSET Subgraph UNSET Drug a(CHEBI:"beta-adrenergic drug") -| path(DO:"heart disease") a(CHEBI:"calcium channel blocker") -| path(DO:"heart disease") SET Evidence = " PHT reduces the active metabolite of losartan by up to 63%." SET Drug = "phenytoin" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} a(CHEBI:phenytoin) -| a(CHEBI:losartan) UNSET Subgraph UNSET Drug a(CHEBI:losartan) -| path(DO:"heart disease") SET Evidence = " VPA increases levels of nimodipine by 50%." SET Drug = "valproate" SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph", "Notch signaling subgraph", "thyroid hormone signaling subgraph", "hormone signaling subgraph", "Neurotransmitter release subgraph", "GABA subgraph", "Calcium dependent subgraph", "Protein Metabolism", "Metabolism"} a(CHEBI:valproate) -> a(CHEBI:nimodipine) UNSET Subgraph UNSET Drug a(CHEBI:nimodipine) -| path(DO:"heart disease") SET Evidence = "Enzyme-inducing AEDs reduce the anticoagulant effect of OACs" SET Drug = "carbamazepine" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} a(CHEBI:carbamazepine) -| a(CHEBI:anticoagulant) UNSET Subgraph UNSET Drug SET Drug = "phenobarbital" SET Subgraph = {"GABA subgraph", "Neurotransmitter release subgraph"} a(CHEBI:phenobarbital) -| a(CHEBI:anticoagulant) UNSET Subgraph UNSET Drug SET Drug = "phenytoin" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} a(CHEBI:phenytoin) -| a(CHEBI:anticoagulant) UNSET Subgraph UNSET Drug SET Drug = "primidone" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} a(CHEBI:primidone) -| a(CHEBI:anticoagulant) UNSET Subgraph UNSET Drug a(CHEBI:anticoagulant) -| path(DO:"heart disease") SET Evidence = "Complex interaction with PHT: PHT increases the initial effect of the OAC and then reduces it. OACs can increase the levels of PHT. The dose of both drugs must be adjusted if used together." SET Drug = "phenytoin" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} a(CHEBI:phenytoin) -| a(CHEBI:anticoagulant) UNSET Subgraph UNSET Drug a(CHEBI:anticoagulant) -> a(CHEBI:phenytoin) SET Evidence = "PHT reduces the diuretic response to furosemide." SET Drug = "phenytoin" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} a(CHEBI:phenytoin) -| a(CHEBI:furosemide) UNSET Subgraph UNSET Drug a(CHEBI:furosemide) -| path(DO:"heart disease") SET Evidence = " PHT significantly reduces digoxin levels." SET Drug = "phenytoin" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} a(CHEBI:phenytoin) -| a(CHEBI:digoxin) UNSET Subgraph UNSET Drug a(CHEBI:digoxin) -| path(DO:"heart disease") SET Evidence = "Parenteral use of barbiturates, BZD and PHT can cause respiratory depression." SET Drug = "barbiturate" a(CHEBI:barbiturate) -> path(MESHD:Hypoventilation) a(CHEBI:barbiturate) -| path(MESHD:Epilepsy) a(CHEBI:barbiturate) isA a(CHEBI:anticonvulsant) UNSET Drug SET Drug = "benzodiazepine" a(CHEBI:benzodiazepine) -> path(MESHD:Hypoventilation) UNSET Drug SET Drug = "phenytoin" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} a(CHEBI:phenytoin) -> path(MESHD:Hypoventilation) UNSET Subgraph UNSET Drug SET Evidence = "Enzyme-inducing AEDs reduce theophyline concentration and theophyline can lower the levels of CBZ and PHT." SET Drug = "carbamazepine" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} a(CHEBI:carbamazepine) -| a(CHEBI:theophylline) UNSET Subgraph UNSET Drug SET Drug = "phenobarbital" SET Subgraph = {"GABA subgraph", "Neurotransmitter release subgraph"} a(CHEBI:phenobarbital) -| a(CHEBI:theophylline) UNSET Subgraph UNSET Drug SET Drug = "phenytoin" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} a(CHEBI:phenytoin) -| a(CHEBI:theophylline) UNSET Subgraph UNSET Drug SET Drug = "primidone" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} a(CHEBI:primidone) -| a(CHEBI:theophylline) UNSET Subgraph UNSET Drug a(CHEBI:theophylline) -| path(MESHD:"Lung Diseases") a(CHEBI:theophylline) -| a(CHEBI:carbamazepine) a(CHEBI:theophylline) -| a(CHEBI:phenytoin) SET Evidence = "PB should be avoided in the acute management of epileptic seizures in patients with liver disease because it can trigger or aggravate hepatic encephalopathy." SET Subgraph = {"GABA subgraph", "Neurotransmitter release subgraph"} a(CHEBI:phenobarbital) -| path(MESHD:Epilepsy) a(CHEBI:phenobarbital) isA a(CHEBI:anticonvulsant) a(CHEBI:phenobarbital) -> path(MESHD:"Hepatic Encephalopathy") UNSET Subgraph path(MESHD:"Hepatic Encephalopathy") -- path(MESHD:"Liver Diseases") SET Evidence = " BZDs are metabolised in the liver and can also cause hepatic encephalopathy." a(CHEBI:benzodiazepine) -> path(MESHD:"Hepatic Encephalopathy") a(CHEBI:benzodiazepine) -| path(MESHD:Epilepsy) SET Evidence = "VPA is contraindicated because of its hepatotoxic capacity in patients with underlying liver disease." a(CHEBI:valproate) -> path(MESHD:"Liver Diseases") SET Evidence = " PHT should be used with caution because, due to its high protein binding, the free fraction is increased in the presence of hypoalbuminaemia with the possibility of intoxication." SET Drug = "phenytoin" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} a(CHEBI:phenytoin) -> path(MESHD:"Liver Diseases") UNSET Subgraph UNSET Drug SET Evidence = "LEV is the most recommended therapeutic alternative in the acute phase of epileptic seizures in patients with liver disease" SET Drug = "levetiracetam" SET Subgraph = {"Neurotransmitter release subgraph", "GABA subgraph", "Calcium dependent subgraph", "Serotonergic subgraph"} a(CHEBI:levetiracetam) causesNoChange path(MESHD:"Liver Diseases") UNSET Subgraph UNSET Drug SET Evidence = "In chronic treatment, the most suitable AEDs are those with a low level of protein binding and limited hepatic metabolism: GBP, LEV, OXC, PGB and TPM." SET Drug = "gabapentin" SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph", "Calcium dependent subgraph"} a(CHEBI:gabapentin) causesNoChange path(MESHD:"Liver Diseases") UNSET Subgraph UNSET Drug SET Drug = "oxcarbazepine" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph", "Calcium dependent subgraph"} a(CHEBI:oxcarbazepine) causesNoChange path(MESHD:"Liver Diseases") UNSET Subgraph UNSET Drug SET Drug = "pregabalin" SET Subgraph = {"Calcium dependent subgraph", "MAPK-ERK subgraph", "protein kinase signaling subgraph"} a(CHEBI:pregabalin) causesNoChange path(MESHD:"Liver Diseases") UNSET Subgraph UNSET Drug SET Drug = "topiramate" SET Subgraph = {"GABA subgraph", "Neurotransmitter release subgraph", "Calcium dependent subgraph", "thyroid hormone signaling subgraph", "hormone signaling subgraph", "Glutamatergic subgraph", "Long term synaptic potentiation", "Long term synaptic depression", "Serotonergic subgraph"} a(CHEBI:topiramate) causesNoChange path(MESHD:"Liver Diseases") UNSET Subgraph UNSET Drug SET Evidence = "The use of LTG and VPA is not recommended." SET Drug = "lamotrigine" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph", "Calcium dependent subgraph", "Long term synaptic potentiation"} a(CHEBI:lamotrigine) -- path(MESHD:"Liver Diseases") UNSET Subgraph UNSET Drug SET Drug = "valproate" SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph", "Notch signaling subgraph", "thyroid hormone signaling subgraph", "hormone signaling subgraph", "Neurotransmitter release subgraph", "GABA subgraph", "Calcium dependent subgraph", "Protein Metabolism", "Metabolism"} a(CHEBI:valproate) -- path(MESHD:"Liver Diseases") UNSET Subgraph UNSET Drug SET Evidence = " For this reason, LEV is not recommended in acute management" SET Drug = "levetiracetam" SET Subgraph = {"Neurotransmitter release subgraph", "GABA subgraph", "Calcium dependent subgraph", "Serotonergic subgraph"} a(CHEBI:levetiracetam) -- path(DO:"kidney disease") UNSET Subgraph UNSET Drug SET Evidence = "Furthermore, TPM and ZNS should be avoided in the event of nephrolithiasis or when there is a possibility of developing it." SET Drug = "topiramate" SET Subgraph = {"GABA subgraph", "Neurotransmitter release subgraph", "Calcium dependent subgraph", "thyroid hormone signaling subgraph", "hormone signaling subgraph", "Glutamatergic subgraph", "Long term synaptic potentiation", "Long term synaptic depression", "Serotonergic subgraph"} a(CHEBI:topiramate) -- path(MESHD:Nephrolithiasis) UNSET Subgraph UNSET Drug SET Drug = "zonisamide" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph", "Glutamatergic subgraph", "MAPK-ERK subgraph", "protein kinase signaling subgraph", "Calcium dependent subgraph"} a(CHEBI:zonisamide) -- path(MESHD:Nephrolithiasis) UNSET Subgraph UNSET Drug SET Evidence = "The most recommended AEDs in renal impairment and haemodialysis are those that are mainly eliminated by the liver, such as BZD, CBZ, ESM, PHT, TGB and VPA." SET Drug = "benzodiazepine" a(CHEBI:benzodiazepine) causesNoChange path(DO:"kidney disease") UNSET Drug SET Drug = "carbamazepine" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} a(CHEBI:carbamazepine) causesNoChange path(DO:"kidney disease") UNSET Subgraph UNSET Drug SET Drug = "ethosuximide" SET Subgraph = {"Calcium dependent subgraph", "MAPK-ERK subgraph", "protein kinase signaling subgraph", "Serotonergic subgraph", "Neurotransmitter release subgraph"} a(CHEBI:ethosuximide) causesNoChange path(DO:"kidney disease") a(CHEBI:ethosuximide) isA a(CHEBI:anticonvulsant) a(CHEBI:ethosuximide) -| path(MESHD:Epilepsy) UNSET Subgraph UNSET Drug SET Drug = "phenytoin" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} a(CHEBI:phenytoin) causesNoChange path(DO:"kidney disease") UNSET Subgraph UNSET Drug SET Drug = "tiagabine" SET Subgraph = {"GABA subgraph", "Neurotransmitter release subgraph"} a(CHEBI:tiagabine) causesNoChange path(DO:"kidney disease") UNSET Subgraph UNSET Drug SET Drug = "valproate" SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph", "Notch signaling subgraph", "thyroid hormone signaling subgraph", "hormone signaling subgraph", "Neurotransmitter release subgraph", "GABA subgraph", "Calcium dependent subgraph", "Protein Metabolism", "Metabolism"} a(CHEBI:valproate) causesNoChange path(DO:"kidney disease") UNSET Subgraph UNSET Drug a(CHEBI:tiagabine) isA a(CHEBI:anticonvulsant) a(CHEBI:tiagabine) -| path(MESHD:Epilepsy) SET Evidence = "The induction of hepatic haemosynthesis on the part of enzyme-inducing AEDs can exacerbate the symptoms of porphyria. " SET Drug = "carbamazepine" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} a(CHEBI:carbamazepine) -> path(MESHD:Porphyrias) UNSET Subgraph UNSET Drug SET Drug = "phenobarbital" SET Subgraph = {"GABA subgraph", "Neurotransmitter release subgraph"} a(CHEBI:phenobarbital) -> path(MESHD:Porphyrias) UNSET Subgraph UNSET Drug SET Drug = "phenytoin" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} a(CHEBI:phenytoin) -> path(MESHD:Porphyrias) UNSET Subgraph UNSET Drug SET Drug = "primidone" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} a(CHEBI:primidone) -> path(MESHD:Porphyrias) UNSET Subgraph UNSET Drug SET Evidence = "Treatment with CBZ, PB, PHT, PRM, TPM, VPA and ZNS should be avoided." SET Drug = "topiramate" SET Subgraph = {"GABA subgraph", "Neurotransmitter release subgraph", "Calcium dependent subgraph", "thyroid hormone signaling subgraph", "hormone signaling subgraph", "Glutamatergic subgraph", "Long term synaptic potentiation", "Long term synaptic depression", "Serotonergic subgraph"} a(CHEBI:topiramate) -- path(MESHD:Porphyrias) UNSET Subgraph UNSET Drug SET Drug = "valproate" SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph", "Notch signaling subgraph", "thyroid hormone signaling subgraph", "hormone signaling subgraph", "Neurotransmitter release subgraph", "GABA subgraph", "Calcium dependent subgraph", "Protein Metabolism", "Metabolism"} a(CHEBI:valproate) -- path(MESHD:Porphyrias) UNSET Subgraph UNSET Drug SET Drug = "zonisamide" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph", "Glutamatergic subgraph", "MAPK-ERK subgraph", "protein kinase signaling subgraph", "Calcium dependent subgraph"} a(CHEBI:zonisamide) -- path(MESHD:Porphyrias) UNSET Subgraph UNSET Drug a(CHEBI:primidone) isA a(CHEBI:anticonvulsant) a(CHEBI:primidone) -| path(MESHD:Epilepsy) SET Evidence = "The use of non-enzyme-inducing AEDs such as GBP, LEV and PGB is recommended" SET Drug = "gabapentin" SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph", "Calcium dependent subgraph"} a(CHEBI:gabapentin) causesNoChange path(MESHD:Porphyrias) UNSET Subgraph UNSET Drug SET Drug = "levetiracetam" SET Subgraph = {"Neurotransmitter release subgraph", "GABA subgraph", "Calcium dependent subgraph", "Serotonergic subgraph"} a(CHEBI:levetiracetam) causesNoChange path(MESHD:Porphyrias) UNSET Subgraph UNSET Drug SET Drug = "pregabalin" SET Subgraph = {"Calcium dependent subgraph", "MAPK-ERK subgraph", "protein kinase signaling subgraph"} a(CHEBI:pregabalin) causesNoChange path(MESHD:Porphyrias) UNSET Subgraph UNSET Drug SET Evidence = " OXC has been used successfully in an isolated case of porphyria cutanea tarda and also in another case of intermittent acute porphyria." SET Drug = "oxcarbazepine" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph", "Calcium dependent subgraph"} a(CHEBI:oxcarbazepine) causesNoChange path(MESHD:Porphyrias) UNSET Subgraph UNSET Drug SET Evidence = " Enzyme-inducing AEDs (CBZ, PB, PHT, PRM) can reduce plasma levels of cyclosporine, tacrolimus, sirolimus and corticosteroids and so it may be necessary to increase the dose of these drugs." SET Drug = "carbamazepine" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} a(CHEBI:carbamazepine) -| a(CHEBI:"cyclosporin A") a(CHEBI:carbamazepine) -| a(CHEBI:"tacrolimus (anhydrous)") a(CHEBI:carbamazepine) -| a(CHEBI:sirolimus) a(CHEBI:carbamazepine) -| a(CHEBI:corticosteroid) UNSET Subgraph UNSET Drug SET Drug = "phenobarbital" SET Subgraph = {"GABA subgraph", "Neurotransmitter release subgraph"} a(CHEBI:phenobarbital) -| a(CHEBI:"cyclosporin A") a(CHEBI:phenobarbital) -| a(CHEBI:"tacrolimus (anhydrous)") a(CHEBI:phenobarbital) -| a(CHEBI:sirolimus) a(CHEBI:phenobarbital) -| a(CHEBI:corticosteroid) UNSET Subgraph UNSET Drug SET Drug = "phenytoin" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} a(CHEBI:phenytoin) -| a(CHEBI:"cyclosporin A") a(CHEBI:phenytoin) -| a(CHEBI:"tacrolimus (anhydrous)") a(CHEBI:phenytoin) -| a(CHEBI:sirolimus) a(CHEBI:phenytoin) -| a(CHEBI:corticosteroid) UNSET Subgraph UNSET Drug SET Drug = "primidone" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} a(CHEBI:primidone) -| a(CHEBI:"cyclosporin A") a(CHEBI:primidone) -| a(CHEBI:"tacrolimus (anhydrous)") a(CHEBI:primidone) -| a(CHEBI:sirolimus) a(CHEBI:primidone) -| a(CHEBI:corticosteroid) UNSET Subgraph UNSET Drug a(CHEBI:"cyclosporin A") isA a(CHEBI:"immunosuppressive agent") a(CHEBI:"tacrolimus (anhydrous)") isA a(CHEBI:"immunosuppressive agent") a(CHEBI:sirolimus) isA a(CHEBI:"immunosuppressive agent") a(CHEBI:"corticosteroid") isA a(CHEBI:"immunosuppressive agent") SET Evidence = " VPA only causes a minimal reduction of cyclosporine and tacrolimus levels." SET Drug = "valproate" SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph", "Notch signaling subgraph", "thyroid hormone signaling subgraph", "hormone signaling subgraph", "Neurotransmitter release subgraph", "GABA subgraph", "Calcium dependent subgraph", "Protein Metabolism", "Metabolism"} a(CHEBI:valproate) -| a(CHEBI:"cyclosporin A") a(CHEBI:valproate) -| a(CHEBI:"tacrolimus (anhydrous)") UNSET Subgraph UNSET Drug SET Evidence = "Cyclosporine binds largely to plasma proteins, and this can significantly increase the free fraction of AEDs that have a high percentage of protein binding." a(CHEBI:"cyclosporin A") -> a(CHEBI:anticonvulsant) SET Evidence = "Azathioprine, mycophenolate and muromonab-CD3 (OKT3) are not significantly affected by AEDs." a(CHEBI:anticonvulsant) causesNoChange a(CHEBI:azathioprine) a(CHEBI:azathioprine) isA a(CHEBI:"immunosuppressive agent") a(CHEBI:anticonvulsant) causesNoChange a(CHEBI:mycophenolate) a(CHEBI:mycophenolate) isA a(CHEBI:"immunosuppressive agent") a(CHEBI:anticonvulsant) causesNoChange a(MESHC:"Muromonab-CD3") a(MESHC:"Muromonab-CD3") isA a(CHEBI:"immunosuppressive agent") SET Evidence = "Enzyme-inducing AEDs (CBZ, PB, PHT, PRM) influence thyroid hormone metabolism, causing a decrease in total and free thyroxin levels." SET Drug = "carbamazepine" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} a(CHEBI:carbamazepine) -| a(CHEBI:"L-thyroxine") UNSET Subgraph UNSET Drug SET Drug = "phenobarbital" SET Subgraph = {"GABA subgraph", "Neurotransmitter release subgraph"} a(CHEBI:phenobarbital) -| a(CHEBI:"L-thyroxine") UNSET Subgraph UNSET Drug SET Drug = "phenytoin" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} a(CHEBI:phenytoin) -| a(CHEBI:"L-thyroxine") UNSET Subgraph UNSET Drug SET Drug = "primidone" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} a(CHEBI:primidone) -| a(CHEBI:"L-thyroxine") UNSET Subgraph UNSET Drug SET Evidence = "However, it may be clinically significant in patients with hypothyroidism who are on replacement therapy." SET Drug = "carbamazepine" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} a(CHEBI:carbamazepine) -- path(MESHD:Hypothyroidism) UNSET Subgraph UNSET Drug SET Drug = "phenobarbital" SET Subgraph = {"GABA subgraph", "Neurotransmitter release subgraph"} a(CHEBI:phenobarbital) -- path(MESHD:Hypothyroidism) UNSET Subgraph UNSET Drug SET Drug = "phenytoin" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} a(CHEBI:phenytoin) -- path(MESHD:Hypothyroidism) UNSET Subgraph UNSET Drug SET Drug = "primidone" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} a(CHEBI:primidone) -- path(MESHD:Hypothyroidism) UNSET Subgraph UNSET Drug SET Evidence = "Likewise, VPA can cause a subclinical, reversible increase in TSH." SET Drug = "valproate" SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph", "Notch signaling subgraph", "thyroid hormone signaling subgraph", "hormone signaling subgraph", "Neurotransmitter release subgraph", "GABA subgraph", "Calcium dependent subgraph", "Protein Metabolism", "Metabolism"} a(CHEBI:valproate) -> a(CHEBI:"thyroid hormone") UNSET Subgraph UNSET Drug SET Evidence = "Although data on the effect of second-generation AEDs are currently insufficient, it is likely that the AEDs with a moderate enzyme-inducing effect (OXC, TPM) will also affect thyroid hormones, while the non-enzyme-inducing AEDs will not affect them." SET Drug = {"oxcarbazepine", "topiramate"} SET Subgraph = {"thyroid hormone signaling subgraph", "hormone signaling subgraph"} a(CHEBI:oxcarbazepine) -- a(CHEBI:"thyroid hormone") a(CHEBI:topiramate) -- a(CHEBI:"thyroid hormone") UNSET Subgraph UNSET Drug SET Evidence = "Enzyme-inducing AEDs and PHT in particular accelerate vitamin D catabolism and increase bone turnover." SET Drug = "carbamazepine" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} a(CHEBI:carbamazepine) -| a(CHEBI:"vitamin D") a(CHEBI:carbamazepine) -> path(MESHD:Osteoporosis) UNSET Subgraph UNSET Drug SET Drug = "phenobarbital" SET Subgraph = {"GABA subgraph", "Neurotransmitter release subgraph"} a(CHEBI:phenobarbital) -| a(CHEBI:"vitamin D") a(CHEBI:phenobarbital) -> path(MESHD:Osteoporosis) UNSET Subgraph UNSET Drug SET Drug = "phenytoin" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} a(CHEBI:phenytoin) -| a(CHEBI:"vitamin D") a(CHEBI:phenytoin) -> path(MESHD:Osteoporosis) UNSET Subgraph UNSET Drug SET Drug = "primidone" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} a(CHEBI:primidone) -| a(CHEBI:"vitamin D") a(CHEBI:primidone) -> path(MESHD:Osteoporosis) UNSET Subgraph UNSET Drug SET Evidence = " VPA interferes with osteoblast function" SET Drug = "valproate" SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph", "Notch signaling subgraph", "thyroid hormone signaling subgraph", "hormone signaling subgraph", "Neurotransmitter release subgraph", "GABA subgraph", "Calcium dependent subgraph", "Protein Metabolism", "Metabolism"} a(CHEBI:valproate) -- bp(GOBP:"osteoblast development") UNSET Subgraph UNSET Drug SET Evidence = "Although LEV and LTG do not appear to have a significant effect in this respect, a case‚control study revealed that enzyme-inducing and non-enzyme-inducing AEDs alike are an independent risk factor for osteoporosis.45" a(CHEBI:anticonvulsant) -- path(MESHD:Osteoporosis) SET Evidence = "Some AEDs are associated with weight gain (CBZ, CLB, GBP, PGB and VPA) and others with weight loss (TPM and ZNS)." SET Drug = "carbamazepine" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} a(CHEBI:carbamazepine) -> path(MESHD:"Weight Gain") UNSET Subgraph UNSET Drug SET Drug = "clobazam" a(CHEBI:clobazam) -> path(MESHD:"Weight Gain") UNSET Drug SET Drug = "gabapentin" SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph", "Calcium dependent subgraph"} a(CHEBI:gabapentin) -> path(MESHD:"Weight Gain") UNSET Subgraph UNSET Drug SET Drug = "pregabalin" SET Subgraph = {"Calcium dependent subgraph", "MAPK-ERK subgraph", "protein kinase signaling subgraph"} a(CHEBI:pregabalin) -> path(MESHD:"Weight Gain") UNSET Subgraph UNSET Drug SET Drug = "valproate" SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph", "Notch signaling subgraph", "thyroid hormone signaling subgraph", "hormone signaling subgraph", "Neurotransmitter release subgraph", "GABA subgraph", "Calcium dependent subgraph", "Protein Metabolism", "Metabolism"} a(CHEBI:valproate) -> path(MESHD:"Weight Gain") UNSET Subgraph UNSET Drug SET Drug = "clobazam" a(CHEBI:clobazam) isA a(CHEBI:anticonvulsant) a(CHEBI:clobazam) -| path(MESHD:Epilepsy) UNSET Drug SET Drug = "topiramate" SET Subgraph = {"GABA subgraph", "Neurotransmitter release subgraph", "Calcium dependent subgraph", "thyroid hormone signaling subgraph", "hormone signaling subgraph", "Glutamatergic subgraph", "Long term synaptic potentiation", "Long term synaptic depression", "Serotonergic subgraph"} a(CHEBI:topiramate) -> path(MESHD:"Weight Loss") UNSET Subgraph UNSET Drug SET Drug = "zonisamide" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph", "Glutamatergic subgraph", "MAPK-ERK subgraph", "protein kinase signaling subgraph", "Calcium dependent subgraph"} a(CHEBI:zonisamide) -> path(MESHD:"Weight Loss") UNSET Subgraph UNSET Drug SET Evidence = "Some studies with small sample size found that patients on VPA treatment who gained weight showed insulin resistance that was reversible on withdrawal of VPA." SET Drug = "valproate" SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph", "Notch signaling subgraph", "thyroid hormone signaling subgraph", "hormone signaling subgraph", "Neurotransmitter release subgraph", "GABA subgraph", "Calcium dependent subgraph", "Protein Metabolism", "Metabolism"} a(CHEBI:valproate) positiveCorrelation path(MESHD:"Insulin Resistance") UNSET Subgraph UNSET Drug SET Evidence = "In the treatment of neurocysticercosis, enzyme-inducing AEDs reduce the concentration of praziquantel and albendazole by over 50%." SET Drug = "carbamazepine" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} a(CHEBI:carbamazepine) -| a(CHEBI:praziquantel) a(CHEBI:carbamazepine) -| a(CHEBI:albendazole) UNSET Subgraph UNSET Drug SET Drug = "phenobarbital" SET Subgraph = {"GABA subgraph", "Neurotransmitter release subgraph"} a(CHEBI:phenobarbital) -| a(CHEBI:praziquantel) a(CHEBI:phenobarbital) -| a(CHEBI:albendazole) UNSET Subgraph UNSET Drug SET Drug = "phenytoin" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} a(CHEBI:phenytoin) -| a(CHEBI:praziquantel) a(CHEBI:phenytoin) -| a(CHEBI:albendazole) UNSET Subgraph UNSET Drug SET Drug = "primidone" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} a(CHEBI:primidone) -| a(CHEBI:praziquantel) a(CHEBI:primidone) -| a(CHEBI:albendazole) UNSET Subgraph UNSET Drug a(CHEBI:praziquantel) -| path(MESHD:Neurocysticercosis) a(CHEBI:albendazole) -| path(MESHD:Neurocysticercosis) SET Evidence = "n the treatment of tuberculosis, isoniazid inhibits the metabolism of CBZ, PHT and VPA, and can cause toxicity." a(CHEBI:isoniazide) -| a(CHEBI:carbamazepine) a(CHEBI:isoniazide) -| a(CHEBI:phenytoin) a(CHEBI:isoniazide) -| a(CHEBI:valproate) a(CHEBI:isoniazide) -| path(MESHD:Tuberculosis) SET Evidence = "Conversely, rifampicin reduces the plasma concentration of CBZ, LTG, PB, PHT and VPA." a(CHEBI:rifampicin) -| a(CHEBI:carbamazepine) a(CHEBI:rifampicin) -| a(CHEBI:lamotrigine) a(CHEBI:rifampicin) -| a(CHEBI:phenobarbital) a(CHEBI:rifampicin) -| a(CHEBI:phenytoin) a(CHEBI:rifampicin) -| a(CHEBI:valproate) a(CHEBI:rifampicin) -| path(MESHD:Tuberculosis) SET Evidence = " However, the use of Diazepam (oral or rectal route) or Midazolam (buccal or intranasal route) is recommended for acute treatment of prolonged and cluster seizures." a(CHEBI:diazepam) isA a(CHEBI:anticonvulsant) a(CHEBI:diazepam) -| path(MESHD:Seizures) SET Evidence = " Table 4. Optimisation of treatment in patients with epilepsy with psychiatric comorbidity." SET Drug = "gabapentin" SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph", "Calcium dependent subgraph"} a(CHEBI:gabapentin) causesNoChange path(DO:"major depressive disorder") a(CHEBI:gabapentin) causesNoChange path(DO:"anxiety disorder") UNSET Subgraph UNSET Drug SET Drug = "lamotrigine" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph", "Calcium dependent subgraph", "Long term synaptic potentiation"} a(CHEBI:lamotrigine) causesNoChange path(DO:"major depressive disorder") UNSET Subgraph UNSET Drug SET Drug = "oxcarbazepine" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph", "Calcium dependent subgraph"} a(CHEBI:oxcarbazepine) causesNoChange path(DO:"major depressive disorder") UNSET Subgraph UNSET Drug SET Drug = "pregabalin" SET Subgraph = {"Calcium dependent subgraph", "MAPK-ERK subgraph", "protein kinase signaling subgraph"} a(CHEBI:pregabalin) causesNoChange path(DO:"major depressive disorder") a(CHEBI:pregabalin) causesNoChange path(DO:"anxiety disorder") UNSET Subgraph UNSET Drug SET Drug = "valproate" SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph", "Notch signaling subgraph", "thyroid hormone signaling subgraph", "hormone signaling subgraph", "Neurotransmitter release subgraph", "GABA subgraph", "Calcium dependent subgraph", "Protein Metabolism", "Metabolism"} a(CHEBI:valproate) causesNoChange path(DO:"major depressive disorder") a(CHEBI:valproate) causesNoChange path(DO:"anxiety disorder") UNSET Subgraph UNSET Drug SET Drug = "phenobarbital" SET Subgraph = {"GABA subgraph", "Neurotransmitter release subgraph"} a(CHEBI:phenobarbital) -- path(DO:"major depressive disorder") UNSET Subgraph UNSET Drug SET Drug = "phenytoin" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} a(CHEBI:phenytoin) -- path(DO:"major depressive disorder") UNSET Subgraph UNSET Drug SET Drug = "primidone" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} a(CHEBI:primidone) -- path(DO:"major depressive disorder") UNSET Subgraph UNSET Drug SET Drug = "tiagabine" SET Subgraph = {"GABA subgraph", "Neurotransmitter release subgraph"} a(CHEBI:tiagabine) -- path(DO:"major depressive disorder") UNSET Subgraph UNSET Drug SET Drug = "topiramate" SET Subgraph = {"GABA subgraph", "Neurotransmitter release subgraph", "Calcium dependent subgraph", "thyroid hormone signaling subgraph", "hormone signaling subgraph", "Glutamatergic subgraph", "Long term synaptic potentiation", "Long term synaptic depression", "Serotonergic subgraph"} a(CHEBI:topiramate) -- path(DO:"major depressive disorder") UNSET Subgraph UNSET Drug a(CHEBI:citalopram) causesNoChange path(MESHD:Epilepsy) a(CHEBI:citalopram) -| path(DO:"major depressive disorder") a(CHEBI:escitalopram) causesNoChange path(MESHD:Epilepsy) a(CHEBI:escitalopram) -| path(DO:"major depressive disorder") a(CHEBI:sertraline) causesNoChange path(MESHD:Epilepsy) a(CHEBI:sertraline) -| path(DO:"major depressive disorder") a(CHEBI:trazodone) causesNoChange path(MESHD:Epilepsy) a(CHEBI:trazodone) -| path(DO:"major depressive disorder") a(CHEBI:venlafaxine) causesNoChange path(MESHD:Epilepsy) a(CHEBI:venlafaxine) -| path(DO:"major depressive disorder") a(CHEBI:amoxapine) -- path(MESHD:Epilepsy) a(CHEBI:amoxapine) -| path(DO:"major depressive disorder") a(CHEBI:Maprotiline) -- path(MESHD:Epilepsy) a(CHEBI:Maprotiline) -| path(DO:"major depressive disorder") a(CHEBI:bupropion) -- path(MESHD:Epilepsy) a(CHEBI:bupropion) -| path(DO:"major depressive disorder") SET Drug = "levetiracetam" SET Subgraph = {"Neurotransmitter release subgraph", "GABA subgraph", "Calcium dependent subgraph", "Serotonergic subgraph"} a(CHEBI:levetiracetam) -- path(DO:"anxiety disorder") UNSET Subgraph UNSET Drug SET Drug = "benzodiazepine" a(CHEBI:benzodiazepine) -| path(DO:"anxiety disorder") UNSET Drug SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} a(CHEBI:"serotonin uptake inhibitor") causesNoChange path(MESHD:Epilepsy) a(CHEBI:"serotonin uptake inhibitor") -| path(DO:"anxiety disorder") UNSET Subgraph SET Drug = "lamotrigine" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph", "Calcium dependent subgraph", "Long term synaptic potentiation"} a(CHEBI:lamotrigine) causesNoChange path(DO:"drug psychosis") UNSET Subgraph UNSET Drug SET Drug = "oxcarbazepine" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph", "Calcium dependent subgraph"} a(CHEBI:oxcarbazepine) causesNoChange path(DO:"drug psychosis") UNSET Subgraph UNSET Drug SET Drug = "valproate" SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph", "Notch signaling subgraph", "thyroid hormone signaling subgraph", "hormone signaling subgraph", "Neurotransmitter release subgraph", "GABA subgraph", "Calcium dependent subgraph", "Protein Metabolism", "Metabolism"} a(CHEBI:valproate) causesNoChange path(DO:"drug psychosis") UNSET Subgraph UNSET Drug SET Drug = "ethosuximide" SET Subgraph = {"Calcium dependent subgraph", "MAPK-ERK subgraph", "protein kinase signaling subgraph", "Serotonergic subgraph", "Neurotransmitter release subgraph"} a(CHEBI:ethosuximide) -- path(DO:"drug psychosis") UNSET Subgraph UNSET Drug SET Drug = "levetiracetam" SET Subgraph = {"Neurotransmitter release subgraph", "GABA subgraph", "Calcium dependent subgraph", "Serotonergic subgraph"} a(CHEBI:levetiracetam) -- path(DO:"drug psychosis") UNSET Subgraph UNSET Drug SET Drug = "topiramate" SET Subgraph = {"GABA subgraph", "Neurotransmitter release subgraph", "Calcium dependent subgraph", "thyroid hormone signaling subgraph", "hormone signaling subgraph", "Glutamatergic subgraph", "Long term synaptic potentiation", "Long term synaptic depression", "Serotonergic subgraph"} a(CHEBI:topiramate) -- path(DO:"drug psychosis") UNSET Subgraph UNSET Drug a(CHEBI:olanzapine) causesNoChange path(MESHD:Epilepsy) a(CHEBI:olanzapine) -| path(DO:"drug psychosis") a(CHEBI:quetiapine) causesNoChange path(MESHD:Epilepsy) a(CHEBI:quetiapine) -| path(DO:"drug psychosis") a(CHEBI:risperidone) causesNoChange path(MESHD:Epilepsy) a(CHEBI:risperidone) -| path(DO:"drug psychosis") a(CHEBI:chlorpromazine) -- path(MESHD:Epilepsy) a(CHEBI:chlorpromazine) -| path(DO:"drug psychosis") a(CHEBI:clozapine) -- path(MESHD:Epilepsy) a(CHEBI:clozapine) -| path(DO:"drug psychosis") SET Evidence = "Enzyme-inducing AEDs can lower the plasma levels of other psychotropic drugs (neuroleptics, tricyclic and selective serotonin reuptake inhibitor antidepressants), hindering the control of psychiatric symptoms." SET Drug = "carbamazepine" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} a(CHEBI:carbamazepine) -| a(CHEBI:"antipsychotic agent") a(CHEBI:carbamazepine) -| a(MESHC:"Antidepressive Agents, Tricyclic") UNSET Subgraph UNSET Drug SET Drug = "phenobarbital" SET Subgraph = {"GABA subgraph", "Neurotransmitter release subgraph"} a(CHEBI:phenobarbital) -| a(CHEBI:"antipsychotic agent") a(CHEBI:phenobarbital) -| a(MESHC:"Antidepressive Agents, Tricyclic") UNSET Subgraph UNSET Drug SET Drug = "phenytoin" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} a(CHEBI:phenytoin) -| a(CHEBI:"antipsychotic agent") a(CHEBI:phenytoin) -| a(MESHC:"Antidepressive Agents, Tricyclic") UNSET Subgraph UNSET Drug SET Drug = "primidone" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} a(CHEBI:primidone) -| a(CHEBI:"antipsychotic agent") a(CHEBI:primidone) -| a(MESHC:"Antidepressive Agents, Tricyclic") UNSET Subgraph UNSET Drug a(CHEBI:"antipsychotic agent") -| path(DO:"psychotic disorder") a(MESHC:"Antidepressive Agents, Tricyclic") isA a(CHEBI:antidepressant) a(CHEBI:antidepressant) -| path(DO:"major depressive disorder") a(MESHC:"Antidepressive Agents, Tricyclic") -| path(DO:"major depressive disorder") SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} a(CHEBI:carbamazepine) -| a(CHEBI:"serotonin uptake inhibitor") a(CHEBI:phenobarbital) -| a(CHEBI:"serotonin uptake inhibitor") a(CHEBI:phenytoin) -| a(CHEBI:"serotonin uptake inhibitor") a(CHEBI:primidone) -| a(CHEBI:"serotonin uptake inhibitor") a(CHEBI:"serotonin uptake inhibitor") isA a(CHEBI:antidepressant) a(CHEBI:"serotonin uptake inhibitor") -| path(DO:"major depressive disorder") UNSET Subgraph SET Evidence = ". The interaction between VPA and amitriptyline or nortriptyline can cause an increase of up to 60% in the plasma levels of these drugs, causing intoxication." SET Drug = "valproate" SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph", "Notch signaling subgraph", "thyroid hormone signaling subgraph", "hormone signaling subgraph", "Neurotransmitter release subgraph", "GABA subgraph", "Calcium dependent subgraph", "Protein Metabolism", "Metabolism"} a(CHEBI:valproate) -> a(CHEBI:amitriptyline) a(CHEBI:valproate) -> a(CHEBI:nortriptyline) UNSET Subgraph UNSET Drug SET Evidence = "There are no significant interactions between AEDs and lithium." a(CHEBI:anticonvulsant) causesNoChange a(CHEBI:"lithium atom") a(CHEBI:"lithium atom") causesNoChange a(CHEBI:anticonvulsant) SET Evidence = "Tricyclic antidepressants (TCAs) can inhibit AED metabolism, causing toxicity symptoms." ###a(EPT:"tricyclic antidepressant") -> path(MESHD:"Drug Toxicity") SET Evidence = " Clozapine should be avoided in patients with epilepsy, while olanzapine, quetiapine and risperidone do not usually require dose adjustment, even when used in combination with enzyme-inducing AEDs" a(CHEBI:olanzapine) causesNoChange path(MESHD:Epilepsy) a(CHEBI:quetiapine) causesNoChange path(MESHD:Epilepsy) a(CHEBI:risperidone) causesNoChange path(MESHD:Epilepsy) SET Evidence = "Among the AEDs with the most severe impact on cognitive function are BZD, PB and PRM, and to a lesser degree PHT and TPM." SET Drug = "benzodiazepine" a(CHEBI:benzodiazepine) -- path(DO:"cognitive disorder") UNSET Drug SET Drug = "phenobarbital" SET Subgraph = {"GABA subgraph", "Neurotransmitter release subgraph"} a(CHEBI:phenobarbital) -- path(DO:"cognitive disorder") UNSET Subgraph UNSET Drug SET Drug = "primidone" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} a(CHEBI:primidone) -- path(DO:"cognitive disorder") UNSET Subgraph UNSET Drug SET Drug = "phenytoin" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} a(CHEBI:phenytoin) -- path(DO:"cognitive disorder") UNSET Subgraph UNSET Drug SET Drug = "topiramate" SET Subgraph = {"GABA subgraph", "Neurotransmitter release subgraph", "Calcium dependent subgraph", "thyroid hormone signaling subgraph", "hormone signaling subgraph", "Glutamatergic subgraph", "Long term synaptic potentiation", "Long term synaptic depression", "Serotonergic subgraph"} a(CHEBI:topiramate) -- path(DO:"cognitive disorder") UNSET Subgraph UNSET Drug SET Evidence = "The AEDs with the least impact on cognitive function are GBP, LEV, LTG and PGB" SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph", "Calcium dependent subgraph"} a(CHEBI:gabapentin) causesNoChange path(DO:"cognitive disorder") UNSET Subgraph SET Drug = "levetiracetam" SET Subgraph = {"Neurotransmitter release subgraph", "GABA subgraph", "Calcium dependent subgraph", "Serotonergic subgraph"} a(CHEBI:levetiracetam) causesNoChange path(DO:"cognitive disorder") UNSET Subgraph UNSET Drug SET Drug = "lamotrigine" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph", "Calcium dependent subgraph", "Long term synaptic potentiation"} a(CHEBI:lamotrigine) causesNoChange path(DO:"cognitive disorder") UNSET Subgraph UNSET Drug SET Drug = "pregabalin" SET Subgraph = {"Calcium dependent subgraph", "MAPK-ERK subgraph", "protein kinase signaling subgraph"} a(CHEBI:pregabalin) causesNoChange path(DO:"cognitive disorder") UNSET Subgraph UNSET Drug SET Evidence = "For different reasons conventional AEDs such as BZD, CBZ, PHT, PB and VPA are in general less recommended in patients with stroke." SET Drug = "benzodiazepine" a(CHEBI:benzodiazepine) -- path(MESHD:Stroke) UNSET Drug SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} a(CHEBI:carbamazepine) -- path(MESHD:Stroke) UNSET Subgraph SET Drug = "phenobarbital" SET Subgraph = {"GABA subgraph", "Neurotransmitter release subgraph"} a(CHEBI:phenobarbital) -- path(MESHD:Stroke) UNSET Subgraph UNSET Drug SET Drug = "valproate" SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph", "Notch signaling subgraph", "thyroid hormone signaling subgraph", "hormone signaling subgraph", "Neurotransmitter release subgraph", "GABA subgraph", "Calcium dependent subgraph", "Protein Metabolism", "Metabolism"} a(CHEBI:valproate) -- path(MESHD:Stroke) UNSET Subgraph UNSET Drug SET Drug = "phenytoin" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} a(CHEBI:phenytoin) -- path(MESHD:Stroke) UNSET Subgraph UNSET Drug SET Evidence = "Some recent AEDs such as GBP, LEV, LTG, OXC and TPM do not seem to have interactions with antiplatelets or anticoagulants or to affect functional prognosis following a stroke." SET Drug = "gabapentin" SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph", "Calcium dependent subgraph"} a(CHEBI:gabapentin) causesNoChange path(MESHD:Stroke) UNSET Subgraph UNSET Drug SET Drug = "levetiracetam" SET Subgraph = {"Neurotransmitter release subgraph", "GABA subgraph", "Calcium dependent subgraph", "Serotonergic subgraph"} a(CHEBI:levetiracetam) causesNoChange path(MESHD:Stroke) UNSET Subgraph UNSET Drug SET Drug = "lamotrigine" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph", "Calcium dependent subgraph", "Long term synaptic potentiation"} a(CHEBI:lamotrigine) causesNoChange path(MESHD:Stroke) UNSET Subgraph UNSET Drug SET Drug = "oxcarbazepine" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph", "Calcium dependent subgraph"} a(CHEBI:oxcarbazepine) causesNoChange path(MESHD:Stroke) UNSET Subgraph UNSET Drug SET Drug = "topiramate" SET Subgraph = {"GABA subgraph", "Neurotransmitter release subgraph", "Calcium dependent subgraph", "thyroid hormone signaling subgraph", "hormone signaling subgraph", "Glutamatergic subgraph", "Long term synaptic potentiation", "Long term synaptic depression", "Serotonergic subgraph"} a(CHEBI:topiramate) causesNoChange path(MESHD:Stroke) UNSET Subgraph UNSET Drug SET Evidence = "This suggests that VPA could be the conventional AED of choice in patients with brain tumours." SET Drug = "valproate" SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph", "Notch signaling subgraph", "thyroid hormone signaling subgraph", "hormone signaling subgraph", "Neurotransmitter release subgraph", "GABA subgraph", "Calcium dependent subgraph", "Protein Metabolism", "Metabolism"} a(CHEBI:valproate) causesNoChange path(DO:"brain cancer") UNSET Subgraph UNSET Drug SET Evidence = " LEV has shown good efficacy and tolerability in monotherapy in prospective studies in patients with brain tumours" SET Drug = "levetiracetam" SET Subgraph = {"Neurotransmitter release subgraph", "GABA subgraph", "Calcium dependent subgraph", "Serotonergic subgraph"} a(CHEBI:levetiracetam) causesNoChange path(DO:"brain cancer") UNSET Subgraph UNSET Drug ############################# ### End Drug annotations ## ############################# ######################################################## SET Citation = {"PubMed", "Single-Gene Determinants of Epilepsy Comorbidity", "26525453"} SET Evidence = "An interesting example is presented by two genes for the childhood syndrome of autosomal dominant frontal lobe epilepsy (ADNFLE), the nicotinic cholinergic receptor nAchR4 (Steinlein et al. 1995), and the sodium-sensitive potassium channel KCNT1, where human mutations are associated with epilepsy and severe intellectual disability and developmental delay" SET Subgraph = "mTOR signaling subgraph" g(HGNC:KCNT1, var("?")) -- path(MESHD:"Epilepsy, Frontal Lobe") g(HGNC:KCNT1, var("?")) -- path(DO:"intellectual disability") g(HGNC:KCNT1, var("?")) -- path(DO:"specific developmental disorder") UNSET Subgraph SET Evidence = "Examples include individuals with multiple seizure types, such as infantile spasms followed by convulsive epilepsy in ARX mutations or staring spells followed by the onset of convulsive seizures, a common occurrence in childhood absence epilepsy." g(HGNC:ARX, var("?")) pos path(MESHD:"Spasms, Infantile") SET Evidence = "Various GLUT1 mutations are found in individuals with childhood absence epilepsy, generalized seizures, and movement disorders, sometimes even without accompanying seizures." SET Subgraph = "Energy metabolic subgraph" g(HGNC:SLC2A1, var("?")) pos path(MESHD:"Epilepsy, Generalized") g(HGNC:SLC2A1, var("?")) pos path(MESHD:"Movement Disorders") SET Evidence = "This membrane transporter mediates glucose uptake across the blood‚brain barrier, is present throughout the brain, and loss-of-function mutations give rise to diverse neurological syndromes with multiple seizure types in children" SET Anatomy = "brain" tport(p(HGNC:SLC2A1)) -> a(CHEBI:glucose) g(HGNC:SLC2A1, var("?")) pos path(MESHD:Seizures) UNSET Subgraph SET Evidence = "Benign neonatal familial seizures as a result of missense mutations in the KCNQ2 potassium channel gene (Singh et al. 1998) were modeled in mice and found to leave little trace of hippocampal reorganization (Singh et al. 2008). Subsequently, it was recognized that dominant negative mutations in the same gene gave rise to the far more severe cognitive deficits of Ohtahara syndrome" SET Species = "10090" SET Subgraph = "Calcium dependent subgraph" g(HGNC:KCNQ2, var("?")) pos path(MESHD:"Epilepsy, Benign Neonatal") g(HGNC:KCNQ2, var("?")) pos path(DO:"Ohtahara syndrome") UNSET Subgraph UNSET Species SET Evidence = "Of these six, CHD8, DYRK1A, ANK2, GRIN2B, DSCAM, and CHD2 were identified in three or more people with autism. A second study (De Rubeis et al. 2014) added ADNP, SCN2A, SYNGAP1, and TBR1. Still other candidates include NRX1, CNTN4, DCLK2, CNTNAP2, CATNAP4, TRIM32, MBD5, ASTN2, CNTN5, GABRG1, SYN1, and CHRNA7." p(HGNC:CHD8) -- path(DO:"autism spectrum disorder") p(HGNC:DYRK1A) -- path(DO:"autism spectrum disorder") p(HGNC:ANK2) -- path(DO:"autism spectrum disorder") p(HGNC:GRIN2B) -- path(DO:"autism spectrum disorder") p(HGNC:DSCAM) -- path(DO:"autism spectrum disorder") p(HGNC:CHD2) -- path(DO:"autism spectrum disorder") p(HGNC:ADNP) -- path(DO:"autism spectrum disorder") p(HGNC:SCN2A) -- path(DO:"autism spectrum disorder") p(HGNC:SYNGAP1) -- path(DO:"autism spectrum disorder") p(HGNC:TBR1) -- path(DO:"autism spectrum disorder") p(HGNC:NRXN1) -- path(DO:"autism spectrum disorder") p(HGNC:CNTN4) -- path(DO:"autism spectrum disorder") p(HGNC:DCLK2) -- path(DO:"autism spectrum disorder") p(HGNC:CNTNAP2) -- path(DO:"autism spectrum disorder") p(HGNC:TRIM32) -- path(DO:"autism spectrum disorder") p(HGNC:MBD5) -- path(DO:"autism spectrum disorder") p(HGNC:ASTN2) -- path(DO:"autism spectrum disorder") p(HGNC:CNTN5) -- path(DO:"autism spectrum disorder") p(HGNC:GABRG1) -- path(DO:"autism spectrum disorder") p(HGNC:SYN1) -- path(DO:"autism spectrum disorder") p(HGNC:CHRNA7) -- path(DO:"autism spectrum disorder") SET Evidence = "CNTNAP2 and family members are membrane proteins involved in ion channel localization that lead to autism and epilepsy (Penagarikano et al. 2011)." SET Confidence = "High" SET Subgraph = "Neurotransmitter release subgraph" bp(GOBP:"ion channel regulator activity") -- path(MESHD:Epilepsy) p(HGNC:CNTNAP2) -- bp(GOBP:"ion channel regulator activity") SET Evidence = "Recent work with the gene PRICKLE1, which contributes to both autism and epilepsy phenotypes, reveals an interaction of Prickle protein with synapsin 1, a second exocytosis-related protein linked to epilepsy" p(HGNC:PRICKLE1) -- path(MESHD:Epilepsy) p(HGNC:PRICKLE1) -- path(DO:"autism spectrum disorder") p(HGNC:PRICKLE1) -- p(HGNC:SYN1) p(HGNC:SYN1) -- bp(GOBP:exocytosis) p(HGNC:SYN1) -- path(MESHD:Epilepsy) UNSET Subgraph SET Evidence = "Tuberous sclerosis is one of the largest identifiable causes of epilepsy and autism" SET Confidence = "High" path(MESHD:"Tuberous Sclerosis") -> path(MESHD:Epilepsy) path(MESHD:"Tuberous Sclerosis") -> path(DO:"autism spectrum disorder") SET Evidence = "Mammalian target of rapamycin (mTOR) signaling is directly involved in TS cellular pathology, autism, and epilepsy, and represents a potential key molecular pathway joining these phenotypes" SET Subgraph = "mTOR signaling subgraph" bp(PTS:"mTOR signaling pathway") -- path(MESHD:"Tuberous Sclerosis") bp(PTS:"mTOR signaling pathway") -- path(MESHD:Epilepsy) bp(PTS:"mTOR signaling pathway") -- path(DO:"autism spectrum disorder") UNSET Subgraph SET Evidence = "ADHD genes, with the exception of CHRNA7, GRIN2A, and SNAP25 show little overlap with known epilepsy loci (Li et al. 2014). " SET Subgraph = "Calcium dependent subgraph" p(HGNC:CHRNA7) -- path(DO:"attention deficit hyperactivity disorder") p(HGNC:CHRNA7) -- path(MESHD:Epilepsy) p(HGNC:GRIN2A) -- path(DO:"attention deficit hyperactivity disorder") p(HGNC:SNAP25) -- path(DO:"attention deficit hyperactivity disorder") p(HGNC:SNAP25) -- path(MESHD:Epilepsy) UNSET Subgraph SET Evidence = "For example, deletion of the glial glutamate uptake transporter GLT1 (Rothstein et al. 1996; Tanaka et al. 1997), a candidate gene for depression, produces epilepsy in mice with a very specific pattern of excitotoxic hippocampal pyramidal cell death." p(HGNC:GLT1D1) -- path(DO:"major depressive disorder") SET Species = "10090" p(HGNC:GLT1D1) -- path(MESHD:Epilepsy) UNSET Species SET Evidence = "Individuals with mutations in three known genes for Alzheimer's disease (AD) (PSEN1, PSEN2, and APP) show a dramatic elevation of epilepsy risk" SET Subgraph = {"Protein Metabolism", "Metabolism"} g(HGNC:PSEN2, var("?")) -- path(MESHD:Epilepsy) g(HGNC:PSEN2, var("?")) -- path(MESHD:"Alzheimer Disease") g(HGNC:APP, var("?")) -- path(MESHD:Epilepsy) g(HGNC:APP, var("?")) -- path(MESHD:"Alzheimer Disease") UNSET Subgraph SET Evidence = "Early evidence has emerged that antiepileptic treatment in AD may slow the progression of the disorder" a(CHEBI:anticonvulsant) -| path(MESHD:"Alzheimer Disease") SET Evidence = "Interestingly, genes that suppress the pathophysiology of A‚beta overexpression and protect against cognitive decline, such as MAPT1 (tau) (Roberson et al. 2011), also prevent epilepsy in ion channel mutant models of epilepsy (Holth et al. 2013; Gheyara et al. 2014). " SET Subgraph = "Metabolism" p(HGNC:MAPT) -| p(HGNC:APP) p(HGNC:MAPT) -| path(MESHD:Epilepsy) UNSET Subgraph SET Evidence = "SRPX2, a human language and epilepsy-associated gene promoting synaptogenesis in language regions of the cerebral cortex is the target of the transcription factor FOXP2" p(HGNC:SRPX2) -- path(MESHD:Epilepsy) p(HGNC:SRPX2) -- path(MESHD:"Language Development Disorders") p(HGNC:FOXP2) -> p(HGNC:SRPX2) SET Evidence = "Interactors with SRXP2 have been identified by yeast 2-hybrid analysis of a human brain cDNA library including two other known epilepsy genes, urokinase-type plasminogen activator receptor (UPAR or PLAUR) (Powell et al. 2003) and cathepsin B (CTSB)" p(HGNC:PLAUR) -- path(MESHD:Epilepsy) p(HGNC:CTSB) -- path(MESHD:Epilepsy) p(HGNC:PLAUR) -- p(HGNC:SRPX2) p(HGNC:CTSB) -- p(HGNC:SRPX2) SET Evidence = "A clinical relationship between migraine and epilepsy is well established" path(MESHD:Epilepsy) pos path(MESHD:"Migraine Disorders") SET Evidence = "Beginning with the finding that SCN5A, a cardiac long QT interval syndrome (LQTS) sodium channel gene linked to sudden death is expressed in the amygdala (Hartmann et al. 1999), the limbic nucleus regulating cardiac representation in the forebrain, human mutations in the KCNQ1 potassium channel (the most common cause of human LQTS and sudden death) were evaluated in mouse models and shown to replicate the SUDEP phenotype (Goldman et al. 2009), pointing to other LQT genes as candidates for shared epilepsy-cardiac arrhythmia phenotypes" SET Subgraph = "Neurotransmitter release subgraph" g(HGNC:KCNQ1, var("?")) -- path(MESHD:Epilepsy) g(HGNC:KCNQ1, var("?")) -- path(MESHD:"Arrhythmias, Cardiac") SET Evidence = "KCNA1 is a second, non-LQTS potassium channel linked to brainstem and vagal nerve-driven cardiac arrhythmias, severe seizures, and early mortality" p(HGNC:KCNA1) -- path(MESHD:"Arrhythmias, Cardiac") p(HGNC:KCNA1) -- path(MESHD:Seizures) UNSET Subgraph ###################################################### SET Citation = {"PubMed", "Biol Res. 2016 Jan 7;49(1):3. doi: 10.1186/s40659-015-0060-5.", "26742644"} SET Evidence = "Total 214 up-regulated genes and 206 down-regulated DEGs between epilepsy and control group were screened out. According to PPI network analysis, top ten DEGs with high node degrees were all down-regulated. Among them, FN1 showed the highest degree, which was closely associated with cell transport activity.Among them, FN1 showed the highest degree, which was closely associated with cell transport activity." SET Subgraph = "Long term synaptic potentiation" SET MeSHDisease = "Epilepsy" p(HGNC:FN1) -- bp(GOBP:"regulation of transporter activity") UNSET {Subgraph, MeSHDisease} SET Evidence = "These DEGs included C1QB, C1S, CFI, PTPRC, HLA-DRA and B2M." p(HGNC:C1QB) -- path(MESHD:Epilepsy) p(HGNC:C1S) -- path(MESHD:Epilepsy) p(HGNC:CFI) -- path(MESHD:Epilepsy) p(HGNC:PTPRC) -- path(MESHD:Epilepsy) p(HGNC:"HLA-DRA") -- path(MESHD:Epilepsy) SET Subgraph = "Innate immune system subgraph" g(HGNC:B2M) -- path(MESHD:Epilepsy) UNSET Subgraph SET Evidence = "Among these DEGs in the co-expression module, C1QB and C1S encoded the subunits of human complement component C1 and play roles in the complement activation pathway." p(HGNC:C1QB) -- bp(GOBP:"complement activation, classical pathway") p(HGNC:C1S) -- bp(GOBP:"complement activation, classical pathway") complex(SCOMP:"C1 Complex") hasComponent p(HGNC:C1QB) complex(SCOMP:"C1 Complex") hasComponent p(HGNC:C1S) SET Evidence = "C1 deficiency and impaired activation of the complement classical pathway generally leads to severe immune complex disease" complex(SCOMP:"C1 Complex") -| path(MESHD:"Immune Complex Diseases") SET Evidence = "In addition to down-co-expression module, in the up-co-expression module, SCN3B was found enriched in GO terms related to sodium ion transport." SET Subgraph = "Neurotransmitter release subgraph" p(HGNC:SCN3B) -- bp(GOBP:"positive regulation of sodium ion transport") p(HGNC:SCN3B) -- bp(GOBP:"sodium ion transport") SET Evidence = "The rapid and selective transport of sodium ion through sodium channels is essential for initiating action potentials within excitable cells" bp(GOBP:"sodium ion transport") -> bp(GOBP:"positive regulation of action potential") SET Evidence = "Therefore, we speculated that SCN3B might play an important role in the progression of epilepsy through sodium channels." p(HGNC:SCN3B) -- path(MESHD:Epilepsy) UNSET Subgraph ############################################################ SET Citation = {"PubMed", "Epilepsy Res. 2016 Jan;119:13-9. doi:10.1016/j.eplepsyres.2015.11.001. Epub 2015 Nov 10.", "26656779"} SET Evidence = "A major cause of mortality in epilepsy patients is sudden unexpected death in epilepsy (SUDEP)" path(MESHD:Epilepsy) -- path(MESHD:"Death, Sudden") SET Evidence = "Post-ictal respiratory dysfunction following generalized convulsive seizures is most commonly observed in witnessed cases of human SUDEP" path(MESHD: Seizures) pos path(MESHD:"Respiratory Insufficiency") SET Evidence = " Adenosine is released extensively during seizures and depresses respiration, which may contribute to seizure-induced death." SET Subgraph = {"Neurotransmitter release subgraph", "adenosine signaling subgraph"} path(MESHD:Seizures) -> a(CHEBI:adenosine) a(CHEBI:adenosine) -| bp(GOBP:"aerobic respiration") UNSET Subgraph SET Evidence = " Systemic administration of adenosine metabolism inhibitors, erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA, 30mg/kg) with 5-Iodotubericidin (5-ITU, 3mg/kg) in GEPR-9s resulted insignificant changes in the duration of AGSz-induced PID as compared to vehicle in both genders." SET Subgraph = {"Metabolism", "adenosine signaling subgraph", "Neurotransmitter release subgraph"} SET Species= "10116" a(CHEBI:EHNA) -| bp(GOBP:"adenosine metabolic process") a(CHEBI:EHNA) -> a(CHEBI:adenosine) a(CHEBI:"5-iodotubercidin") -| bp(GOBP:"adenosine metabolic process") a(CHEBI:"5-iodotubercidin") -> a(CHEBI:adenosine) a(CHEBI:EHNA) -- path(MESHD:"Respiratory Insufficiency") a(CHEBI:"5-iodotubercidin") -- path(MESHD:"Respiratory Insufficiency") UNSET Subgraph SET Evidence = " These agents also significantly increased the duration of post-seizure RD and significantly decreased the mean% SpO2 after AGSz, as compared to vehicle but only in females." SET Gender = "Female" a(CHEBI:EHNA) -> path(MESHD:"Respiratory Insufficiency") a(CHEBI:"5-iodotubercidin") -> path(MESHD:"Respiratory Insufficiency") UNSET Gender SET Evidence = "Subsequently, we observed that the incidences of death in both genders 12-48h post-seizure were significantly greater in drug vs. vehicle treatment." a(CHEBI:EHNA) -> path(MESHD:"Death, Sudden") a(CHEBI:"5-iodotubercidin") -> path(MESHD:"Death, Sudden") UNSET Species SET Evidence = "Several neurotransmitters are known to be released during seizures, including serotonin, GABA, opioid peptides, and adenosine (Fisher and Schachter, 2000, Lado and Moshe, 2008), and it has been proposed that these neurotransmitters affect post-ictal respiratory depression and the susceptibility to SUDEP" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} path(MESHD:Seizures) -> a(CHEBI:serotonin) a(CHEBI:serotonin) pos path(MESHD:"Death, Sudden") UNSET Subgraph SET Subgraph = {"Neurotransmitter release subgraph", "adenosine signaling subgraph"} path(MESHD:Seizures) pos a(CHEBI:adenosine) a(CHEBI:adenosine) pos path(MESHD:"Death, Sudden") UNSET Subgraph SET Subgraph = {"GABA subgraph", "Neurotransmitter release subgraph"} path(MESHD:Seizures) -> a(CHEBI:"GABA agent") path(MESHD:Seizures) -> a(CHEBI:"opioid agent") a(CHEBI:"GABA agent") pos path(MESHD:"Death, Sudden") a(CHEBI:"opioid agent") pos path(MESHD:"Death, Sudden") UNSET Subgraph SET Evidence = "Adenosine is implicated as an important causative factor in the induction of sleep, since adenosine levels are highest as sleep is initiated and increase greatly during sleep deprivation" SET Subgraph = {"Neurotransmitter release subgraph", "adenosine signaling subgraph"} a(CHEBI:adenosine) -> bp(GOBP:"positive regulation of circadian sleep/wake cycle, sleep") UNSET Subgraph ######################################### SET Citation = {"PubMed", "Brain Dev. 2016 Jan;38(1):142-4. doi:10.1016/j.braindev.2015.04.012. Epub 2015 May 14.", "25982940"} SET Evidence = "l-2-Hydroxyglutaric aciduria (l-2-HGA) is a rare inborn error of metabolism." path(DO:"2-hydroxyglutaric aciduria") isA path(MESHD:"Metabolic Diseases") SET Evidence = " Mainly, patients with this disorder exhibit neurological symptoms and characteristic neuroradiological findings, such as subcortical white matter abnormalities, which are believed to be caused by the toxicity of the accumulation of l-2-hydroxyglutaric acid." SET Anatomy = "cerebral subcortex" SET MeSHAnatomy = "White Matter" path(DO:"2-hydroxyglutaric aciduria") -> a(CHEBI:"(S)-2-hydroxyglutaric acid") a(CHEBI:"(S)-2-hydroxyglutaric acid") -> path(MESHD:"Brain Damage, Chronic") UNSET MeSHAnatomy UNSET Anatomy SET Evidence = " A genotype-first approach of the whole exome sequence was used to identify compound heterozygous mutations, c.584A>G (p.Y195C) and c.772T>C (p.C258R), in L2HGDH, the gene responsible for this disorder, in an adult patient with intellectual disability and intractable epilepsy." SET MeSHDisease = {"Epilepsy","Intellectual Disability"} g(HGNC:L2HGDH, var("p.Y195C")) -- path(DO:"2-hydroxyglutaric aciduria") g(HGNC:L2HGDH, var("p.C258R")) -- path(DO:"2-hydroxyglutaric aciduria") UNSET MeSHDisease SET Evidence = " The c.772T>C mutation is registered in the dbSNP137 SNP database as rs145390085, and it has a frequency of 0.007% in the National Heart, Lung, and Blood Institute Exome Sequencing Project (NHLBI-ESP) 6500" g(HGNC:L2HGDH, var("p.Y195C")) eq g(dbSNP:rs145390085) g(dbSNP:rs145390085) pos path(DO:"2-hydroxyglutaric aciduria") #snp isn't in dbSNP and is linked to L2HGDH (see above) ############################################################ SET Citation = {"PubMed", "Trends Neurosci. 2013 Jan;36(1):32-40. doi: 10.1016/j.tins.2012.11.005. Epub 2012 Dec 8.", "23228828"} SET Evidence = "Neuronal excitability is intertwined with Energy metabolic subgraph in multiple ways" SET Subgraph = {"Energy metabolic subgraph", "Metabolism"} bp(PTS:"Energy Metabolism") -- path(MESHD:Epilepsy) bp(GOBP:"metabolic process") -- path(MESHD:Epilepsy) SET Evidence = "At the most basic level, maintenance of neuronal function incurs a substantial energy demand, and this demand must be met by active cellular metabolism" bp(GOBP:"cellular metabolic process") -- bp("maintenance of neuronal function") SET Evidence = "This drastic decrease in carbohydrates reduces the amount of glucose utilization. Instead, fatty acids are used by the liver to produce the ketone bodies, beta-hydroxybutyrate (BHB) and acetoacetate, which fuel cellular metabolism in lieu of glucose" a(CHEBI:carbohydrate) -| path(MESHD:Ketosis) a(CHEBI:carbohydrate) -> bp(GOBP:"glucose catabolic process") path(MESHD:Ketosis) -| bp(GOBP:"glucose catabolic process") path(MESHD:Ketosis) -> a(CHEBI:ketone) a(CHEBI:"fatty acid") -- a(CHEBI:ketone) a(CHEBI:"3-hydroxybutyrate") isA a(CHEBI:ketone) a(CHEBI:acetoacetate) isA a(CHEBI:ketone) path(MESHD:Ketosis) -> a(CHEBI:"3-hydroxybutyrate") path(MESHD:Ketosis) -> a(CHEBI:acetoacetate) a(CHEBI:glucose) -- bp(GOBP:"cellular metabolic process") a(CHEBI:"3-hydroxybutyrate") -- bp(GOBP:"cellular metabolic process") a(CHEBI:acetoacetate) -- bp(GOBP:"cellular metabolic process") SET Evidence = "Recently, glutamate transport into synaptic vesicles by the vesicular glutamate transporter, VGLUT2, was found to be inhibited by the ketone body acetoacetate [14] at concentrations that are expected during the ketogenic diet" a(CHEBI:acetoacetate) -- bp(GOBP:"negative regulation of L-glutamate transport") a(CHEBI:acetoacetate) -| p(HGNC:SLC17A6) p(HGNC:SLC17A6) => bp(GOBP:"L-glutamate transport") SET CellStructure = "Synaptic Vesicles" a(CHEBI:acetoacetate) -| a(MESHC:Glutamates) UNSET CellStructure UNSET Subgraph SET Evidence = "Furthermore, in these experiments (although not in an earlier study [15] ), acetoacetate reduced excitatory glutamatergic synaptic transmission at hippocampal CA1 neurons" SET MeSHAnatomy="CA1 Region, Hippocampal" SET Subgraph = "Neurotransmitter release subgraph" a(CHEBI:acetoacetate) -| bp(GOBP:"synaptic transmission, glutamatergic") UNSET Subgraph UNSET MeSHAnatomy SET Evidence = "There was no effect on inhibitory synaptic input, consistent with the lack of inhibition of the vesicular GABA transporter by acetoacetate." SET Subgraph = {"Neurotransmitter release subgraph", "GABA subgraph"} a(CHEBI:acetoacetate) causesNoChange p(HGNC:SLC32A1) p(HGNC:SLC32A1) -| a(CHEBI:"GABA agent") p(HGNC:SLC32A1) -| bp(PTS:"gamma_aminobutyric acid signaling pathway") UNSET Subgraph SET Evidence = "Inhibition of glutamate signaling by acetoacetate would be expected to reduce neuronal excitability" SET Subgraph = {"Neurotransmitter release subgraph", "Glutamatergic subgraph"} a(CHEBI:acetoacetate) -| bp(GOBP:"glutamate secretion, neurotransmission") bp(GOBP:"glutamate secretion, neurotransmission") -> bp(GOBP:"neuron development") a(MESHC:Glutamates) isA a(CHEBI:neurotransmitter) a(CHEBI:acetoacetate) -| bp(GOBP:"neuron development") UNSET Subgraph SET Evidence = "Earlier work suggested that increased production of the inhibitory neurotransmitter GABA might result from changes in brain metabolism produced by a ketogenic diet" SET Subgraph = {"Neurotransmitter release subgraph", "GABA subgraph"} a(CHEBI:"GABA agent") isA a(CHEBI:neurotransmitter) path(MESHD:Ketosis) -> a(CHEBI:"GABA agent") UNSET Subgraph SET Evidence = "It is hypothesized that glutamate recycling via gluta- mine becomes more efficient when ketone bodies are avail-able, and that this may improve GABA resynthesis for inhibitory neurotransmission even more than it affects glutamate repackaging for excitatory neurotransmission" SET Subgraph = {"Neurotransmitter release subgraph", "GABA subgraph", "Glutamatergic subgraph"} a(CHEBI:ketone) -> bp(GOBP:"glutamate biosynthetic process") bp(GOBP:"glutamate biosynthetic process") -> a(CHEBI:"GABA agent") UNSET Subgraph SET Evidence = "Because ketone bodies are directly metabolized by mito- chondria, glycolysis is bypassed and even inhibited by the increase in mitochondrial metabolism" SET Subgraph = {"Energy metabolic subgraph", "Metabolism"} a(CHEBI:ketone) -- bp(GOBP:"mitochondrial DNA metabolic process") bp(GOBP:"mitochondrial DNA metabolic process") -| bp(GOBP:"canonical glycolysis") SET Evidence = "This metabolic shift is expected to increase mitochondrial ATP production and decrease production" SET CellStructure = "Mitochondria" bp(GOBP:"mitochondrial DNA metabolic process") -> a(CHEBI:ATP) UNSET CellStructure bp(GOBP:"canonical glycolysis") -> a(CHEBI:ATP) bp(GOBP:"mitochondrial DNA metabolic process") -| a(CHEBI:ATP) SET Evidence = "Indeed, it is believed that the pumps maintaining the ntracellular ionic concentrations utilize glycolytic ATP" a(MESHC:"Ion Channels") -- a(CHEBI:ATP) SET Evidence = "The submembrane consumption of ATP by pumps may activate nearby ATP-sensitive potassium (K ATP ) channels [26,27] , which are candidates for the link between metabolism and neuronal excitability." a(CHEBI:ATP) -> p(HGNC:KCNJ1) SET Evidence = "Increases in blood glucose levels lead to inhibition of KATP channels by ATP, which then permits membrane depolarization and triggers insulin release" a(CHEBI:glucose) -> a(CHEBI:ATP) a(CHEBI:ATP) -| p(HGNC:KCNJ1) p(HGNC:KCNJ1) -- bp(GOBP:"membrane depolarization") p(HGNC:KCNJ1) -- bp(GOBP:"insulin secretion") p(HGNC:KCNJ1) -- bp(PTS:"Regulation of Insulin Secretion") bp(GOBP:"insulin secretion") -> a(CHEBI:"insulin (human)") SET Evidence = "K ATP hannels are widely expressed in the brain [32‚34] and may play a role in the anticonvulsant action of the ketogenic diet, possibly via a use-dependent mechanism" path(MESHD:Ketosis) -- p(HGNC:KCNJ1) SET Evidence = "Increased activity of the channel has been observed with bursts of action potentials in respiratory neurons [26] and hippocampal dentate granule neurons" p(HGNC:KCNJ1) -> bp(GOBP:"membrane depolarization during action potential") UNSET Subgraph SET Evidence = "Adenosine signaling via A1 receptors can reduce neuronal excitability [41] , and an increased level of adenosine in the brain has been hypothesized as a mechanism for the anticonvulsant effect of the ketogenic diet" SET Subgraph = {"Neurotransmitter release subgraph", "adenosine signaling subgraph"} SET Anatomy = "brain" path(MESHD:Ketosis) -> a(CHEBI:adenosine) a(CHEBI:adenosine) -> bp(GOBP:"adenosine receptor signaling pathway") bp(GOBP:"adenosine receptor signaling pathway") -- p(HGNC:ADORA1) UNSET Anatomy SET Evidence = "The effectiveness of the ketogenic diet in reducing the seizures was reversed by injection of glucose or DPCPX, a blocker of the adenosine A 1 receptor." a(CHEBI:DPCPX) -| p(HGNC:ADORA1) path(MESHD:Ketosis) -- p(HGNC:ADORA1) UNSET Subgraph SET Evidence = "Thus, a reduction in glucose usage might be more important than ketone bodies" SET Subgraph = {"Energy metabolic subgraph", "Metabolism"} a(CHEBI:glucose) -- path(MESHD:Seizures) SET Evidence = "The reduction in glucose levels and increase in ketone body metabolism observed during the ketogenic diet are consis- tent with a decrease in lycolysis" a(CHEBI:glucose) -> bp(GOBP:"canonical glycolysis") a(CHEBI:ketone) -| bp(GOBP:"canonical glycolysis") bp(GOBP:"cellular ketone body metabolic process") -| bp(GOBP:"canonical glycolysis") SET Evidence = "The glucose analog, 2-deoxyglucose (2DG), inhibits glycolysis by decreasing glucose uptake [54] and competing for phosphoglucose isomerase" a(CHEBI:deoxyglucose) -| bp(GOBP:"canonical glycolysis") a(CHEBI:deoxyglucose) -| bp(GOBP:"glucose import") a(CHEBI:deoxyglucose) -- p(HGNC:GPI) a(CHEBI:glucose) -- p(HGNC:GPI) bp(GOBP:"canonical glycolysis") -- p(HGNC:GPI) SET Evidence = "2DG is able to slow seizure progression in the rodent kindling seizure model" SET Species = "10090" a(CHEBI:deoxyglucose) -| path(MESHD:Seizures) SET Evidence = "Glycolytic inhibition is anticonvulsant" bp(GOBP:"canonical glycolysis") -> path(MESHD:Seizures) SET Evidence = "Reduced oxidative stress may be involved in the seizure protection of the ketogenic diet" bp(GOBP:"response to oxidative stress") -> path(MESHD:Seizures) path(MESHD:Ketosis) -| bp(GOBP:"response to oxidative stress") SET Evidence = "Because the pentose phosphate pathway produces NADPH, which is used to reduce intracellular ROS, it is hypothesized that the improved antioxidant function might be important for seizure protection" bp(PTS:"Pentose phosphate pathway") -> a(CHEBI:NADPH) a(CHEBI:NADPH) -| a(CHEBI:"reactive oxygen species") a(CHEBI:"reactive oxygen species") -> path(MESHD:Seizures) bp(PTS:"Pentose phosphate pathway") -| path(MESHD:Seizures) SET Evidence = "Several studies have presented evidence that the ketogenic diet augments mechanisms, that attenuate ROS" path(MESHD:Ketosis) -| a(CHEBI:"reactive oxygen species") SET Evidence = "Dietary treatment for epilepsy may reverse these changes by block- ing seizure activity itself" path(MESHD:Ketosis) -| path(MESHD:Seizures) UNSET Subgraph ################################################## SET Citation = {"PubMed", "Epilepsy Res. 2015 Aug;114:23-31. doi: 10.1016/j.eplepsyres.2015.04.004. Epub 2015 Apr 17.", "26088882"} SET Evidence = "The Tau-protein level is a parameter for neurodegeneration and axonal damage and is usually investigated under special questions" SET Subgraph = "Metabolism" p(HGNC:MAPT) -- path(MESHD:"Neurodegenerative Diseases") p(HGNC:MAPT) -- bp(GOBP:"axonal defasciculation") SET Evidence = "In this large retrospective study it has been shown that CSF parameters such as albumin quotient, lactate and Tau- protein are changed in a considerable percentage of patients with epileptic seizures whereascell counts remain largely unaffected" p(HGNC:ALB) -- path(MESHD:Epilepsy) a(CHEBI:lactate) -- path(MESHD:Epilepsy) p(HGNC:MAPT) -- path(MESHD:Epilepsy) SET Evidence = "The albumin quotient is a parameter which reflects blood CSF barrier function" p(HGNC:ALB) -- bp(GOBP:"regulation of establishment of blood-brain barrier") SET Evidence = "It has already been described that epileptic seizures can be accompanied by blood-brain barrier dysfunction" bp(GOBP:"regulation of establishment of blood-brain barrier") -- path(MESHD:Epilepsy) SET Evidence = "An influence of epileptic seizures on lactate levels has been reported by" path(MESHD:Seizures) pos a(CHEBI:lactate) SET Evidence = "As neurons have increased, sySCOMPronized activity during an epileptic seizure, elevated lactate levels may hint to an increase in glucose metabolism." bp(GOBP:"glucose catabolic process") -> a(CHEBI:lactate) bp(GOBP:"glucose catabolic process") -- path(MESHD:Seizures) SET Evidence = "In our study, 36% of patients had an elevated Tau- protein level in the CSF." path(MESHD:Seizures) pos p(HGNC:MAPT) UNSET Subgraph ################################################# SET Citation = {"PubMed", "Seizure. 2015 Sep;31:155-64. doi: 10.1016/j.seizure.2015.07.021. Epub 2015 Aug 4.", "26362394"} SET Evidence = "Thyroid hormones (THs) L -thyroxine and L -triiodothyronine, primarily known as metabolism regulators, are tyrosine-derived hormones produced by the thyroid gland" SET Subgraph = {"thyroid hormone signaling subgraph", "hormone signaling subgraph", "Metabolism"} a(CHEBI:"L-thyroxine") isA a(CHEBI:"thyroid hormone") a(CHEBI:"3,3',5'-triiodothyronine") isA a(CHEBI:"thyroid hormone") a(CHEBI:"L-thyroxine") -- bp(GOBP:"metabolic process") a(CHEBI:"3,3',5'-triiodothyronine") -- bp(GOBP:"metabolic process") SET Evidence = "They play an essential role in normal central nervous system development and physiological function." a(CHEBI:"L-thyroxine") -> bp(GOBP:"central nervous system development") a(CHEBI:"3,3',5'-triiodothyronine") -> bp(GOBP:"central nervous system development") SET Evidence = "By binding to nuclear receptors and modulating gene expression, THs influence neuronal migration, differentiation, myelination, synapto- genesis and neurogenesis in developing and adult brains" a(CHEBI:"L-thyroxine") -- bp(GOBP:"neuron differentiation") a(CHEBI:"3,3',5'-triiodothyronine") -- bp(GOBP:"neuron differentiation") a(CHEBI:"L-thyroxine") -- bp(GOBP:"neuron migration") a(CHEBI:"3,3',5'-triiodothyronine") -- bp(GOBP:"neuron migration") a(CHEBI:"L-thyroxine") -- bp(GOBP:myelination) a(CHEBI:"3,3',5'-triiodothyronine") -- bp(GOBP:myelination) a(CHEBI:"L-thyroxine") -- bp(GOBP:neurogenesis) a(CHEBI:"3,3',5'-triiodothyronine") -- bp(GOBP:neurogenesis) UNSET Subgraph SET Evidence = "The development and function of GABAergic neurons as well as glutamatergic transmission are also affected by THs." SET Subgraph = {"GABA subgraph", "Neurotransmitter release subgraph", "thyroid hormone signaling subgraph", "hormone signaling subgraph"} a(CHEBI:"L-thyroxine") -- bp(GOBP:"GABAergic neuron differentiation") a(CHEBI:"3,3',5'-triiodothyronine") -- bp(GOBP:"GABAergic neuron differentiation") UNSET Subgraph SET Subgraph = {"Glutamatergic subgraph", "Neurotransmitter release subgraph"} a(CHEBI:"L-thyroxine") -- bp(GOBP:"synaptic transmission, glutamatergic") a(CHEBI:"3,3',5'-triiodothyronine") -- bp(GOBP:"synaptic transmission, glutamatergic") UNSET Subgraph SET Evidence = "Though the underlying molecular mechanisms still remain unknown, the effects of THs on inhibitory and excitatory neurons may affect brain seizure activity" SET Subgraph = {"thyroid hormone signaling subgraph", "hormone signaling subgraph"} a(CHEBI:"L-thyroxine") -- bp(GOBP:"regulation of membrane potential") a(CHEBI:"3,3',5'-triiodothyronine") -- bp(GOBP:"regulation of postsynaptic membrane potential") a(CHEBI:"L-thyroxine") -- bp(GOBP:"regulation of postsynaptic membrane potential") a(CHEBI:"3,3',5'-triiodothyronine") -- bp(GOBP:"regulation of postsynaptic membrane potential") bp(GOBP:"regulation of postsynaptic membrane potential") -- path(MESHD:Seizures) bp(GOBP:"regulation of postsynaptic membrane potential") -- path(MESHD:Seizures) UNSET Subgraph SET Evidence = "Pathologically, epilepsy may be accompanied by mitochondrial dysfunction, oxidative stress and eventually dysregulation of excitatory glutamatergic and inhibitory GABAergic neurotransmission" path(MESHD:Epilepsy) -- path(MESHD:"Mitochondrial Diseases") path(MESHD:Epilepsy) -- bp(GOBP:"response to oxidative stress") SET Subgraph = {"Glutamatergic subgraph", "Neurotransmitter release subgraph"} path(MESHD:Epilepsy) -- bp(GOBP:"regulation of synaptic transmission, glutamatergic") UNSET Subgraph SET Subgraph = {"GABA subgraph", "Neurotransmitter release subgraph"} path(MESHD:Epilepsy) -- bp(GOBP:"regulation of synaptic transmission, GABAergic") UNSET Subgraph SET Evidence = "Based on the latest evidence on the association between THs and epilepsy, we hypothesize that THs abnormalities may contribute to the pathogenesis of epilepsy." SET Subgraph = {"thyroid hormone signaling subgraph", "hormone signaling subgraph", "Metabolism"} a(CHEBI:"L-thyroxine") -- path(MESHD:Epilepsy) a(CHEBI:"3,3',5'-triiodothyronine") -- path(MESHD:Epilepsy) SET Evidence = "Through interaction with thyroid hormone receptors (TRs), THs regulate cell development, homeostasis, differentiation, growth and metabolism" a(CHEBI:"thyroid hormone") -- bp(GOBP:"cell development") a(CHEBI:"thyroid hormone") -- bp(GOBP:"cell differentiation") a(CHEBI:"thyroid hormone") -- bp(GOBP:"cell growth") a(CHEBI:"thyroid hormone") -- bp(GOBP:"homeostasis of number of cells") SET Evidence = "Thyroid hormones act in the brain where they play an essential role in fetal and post-natal brain development as well as the maintenance of adult brain function" SET Anatomy = "brain" a(CHEBI:"thyroid hormone") -- bp(GOBP:"brain development") UNSET Anatomy SET Evidence = "In addition, THs promotes CNS repair, as it has been demonstrated that CNS re-myelination is dependent on these hormones" a(CHEBI:"thyroid hormone") -- bp(GOBP:"central nervous system myelin maintenance") SET Evidence = "Furthermore, THs abnormalities including both hypothyroidism and hyperthy- roidism, have been shown to induce the production of reactive oxygen species (ROS) and affect the oxidative capacity of the adult brain by modulating antioxidant enzymes" path(MESHD:Hypothyroidism) -> a(CHEBI:"reactive oxygen species") path(MESHD:Hyperthyroidism) -> a(CHEBI:"reactive oxygen species") SET Evidence = "The hypothalamus releases thyrotropin-releasing hor- mone (TRH) which stimulates the pituitary gland to release thyroid stimulating hormone (TSH)" a(BRCO:Hypothalamus) -> p(HGNC:TRH) p(HGNC:TRH) -> p(HGNC:CGA) SET Evidence = "TSH binds to its receptor on the thyroid gland and activates the synthesis and release of THs" p(HGNC:CGA) -> a(CHEBI:"thyroid hormone") SET Evidence = "Head injury is one of the causative factors of adult epilepsy and on the other hand, patients with brain injuries have been shown to have lower levels of THs." path(MESHD:"Brain Injuries") -> path(MESHD:Epilepsy) path(MESHD:"Brain Injuries") neg a(CHEBI:"thyroid hormone") SET Evidence = "In patients with traumatic brain injury THs metabolism is defected, and conversion of T4 to the active form T3 catalyzed by deiodinase enzyme becomes impaired" path(MESHD:"Brain Injuries") neg bp(GOBP:"thyroid hormone metabolic process") path(MESHD:"Brain Injuries") neg a(CHEBI:"3,3',5'-triiodothyronine") SET Evidence = "Furthermore, in the early phases of brain injury, TSH level is decreased and this might be another causative factor for THs decreased levels" path(MESHD:"Brain Injuries") neg p(HGNC:CGA) path(MESHD:"Brain Injuries") neg a(CHEBI:"thyroid hormone") SET Evidence = "THs exert regenerative effects on nerves cells" a(CHEBI:"thyroid hormone") -> bp(GOBP:"axon regeneration") SET Evidence = "Among the genes affected by THs, neurotrophic factors are of special significance," a(CHEBI:"thyroid hormone") -> p(HGNC:BDNF) UNSET Subgraph SET Evidence = "Neurotrophic factors exert a variety of effects on neural differentiation, survival and growth, and also influence neurotransmitter synthesis, synaptic plasticity and neural excitability" p(HGNC:FGF2) -- bp(GOBP:"neuron differentiation") p(HGNC:FGF2) -- bp(GOBP:"neuron development") p(HGNC:FGF2) -- bp(GOBP:"neurotransmitter biosynthetic process") p(HGNC:FGF2) -- bp(GOBP:"regulation of neuronal synaptic plasticity") SET Subgraph = {"brain_derived neurotrophic factor signaling subgraph", "Mossy Fiber Subgraph"} p(HGNC:BDNF) -- bp(GOBP:"neuron differentiation") p(HGNC:BDNF) -- bp(GOBP:"neuron development") p(HGNC:BDNF) -- bp(GOBP:"neurotransmitter biosynthetic process") p(HGNC:BDNF) -- bp(GOBP:"regulation of neuronal synaptic plasticity") UNSET Subgraph p(HGNC:NTF3) -- bp(GOBP:"neuron differentiation") p(HGNC:NTF3) -- bp(GOBP:"neuron development") p(HGNC:NTF3) -- bp(GOBP:"neurotransmitter biosynthetic process") p(HGNC:NTF3) -- bp(GOBP:"regulation of neuronal synaptic plasticity") p(HGNC:NGF) -- bp(GOBP:"neuron differentiation") p(HGNC:NGF) -- bp(GOBP:"neuron development") p(HGNC:NGF) -- bp(GOBP:"neurotransmitter biosynthetic process") p(HGNC:NGF) -- bp(GOBP:"regulation of neuronal synaptic plasticity") p(HGNC:GDNF) -- bp(GOBP:"neuron differentiation") p(HGNC:GDNF) -- bp(GOBP:"neuron development") p(HGNC:GDNF) -- bp(GOBP:"neurotransmitter biosynthetic process") p(HGNC:GDNF) -- bp(GOBP:"regulation of neuronal synaptic plasticity") p(HGNC:VEGFA) -- bp(GOBP:"neuron differentiation") p(HGNC:VEGFA) -- bp(GOBP:"neuron development") p(HGNC:VEGFA) -- bp(GOBP:"neurotransmitter biosynthetic process") p(HGNC:VEGFA) -- bp(GOBP:"regulation of neuronal synaptic plasticity") SET Evidence = "Neurotrophic factors that are shown to influence epileptic conditions and seizures include fibroblast growth factor-2 (FGF-2), brain derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), nerve growth factor (NGF), glial cell line derived neurotrophic factor(GDNF), and the vascular endothelial growth factor (VEGF)" p(HGNC:FGF2) reg path(MESHD:Seizures) p(HGNC:BDNF) reg path(MESHD:Seizures) p(HGNC:NTF3) reg path(MESHD:Seizures) p(HGNC:NGF) reg path(MESHD:Seizures) p(HGNC:GDNF) reg path(MESHD:Seizures) p(HGNC:VEGFA) reg path(MESHD:Seizures) p(HGNC:FGF2) reg path(MESHD:Epilepsy) p(HGNC:BDNF) reg path(MESHD:Epilepsy) p(HGNC:NTF3) reg path(MESHD:Epilepsy) p(HGNC:NGF) reg path(MESHD:Epilepsy) p(HGNC:GDNF) reg path(MESHD:Epilepsy) p(HGNC:VEGFA) reg path(MESHD:Epilepsy) SET Evidence = "It is well known that epileptogenic insults increase the synthesis of BDNF" SET Subgraph = {"brain_derived neurotrophic factor signaling subgraph", "Mossy Fiber Subgraph"} path(MESHD:Epilepsy) -> p(HGNC:BDNF) UNSET Subgraph SET Evidence = "Consequently, it has been reported that the over-expression of P43 in vivo nd in cell culture contexts increases protein synthesis and mitochondrial transcription" SET Subgraph = {"thyroid hormone signaling subgraph", "hormone signaling subgraph", "Protein Metabolism"} a(CHEBI:"3,3',5'-triiodothyronine") -> p(HGNC:AIMP1) p(HGNC:AIMP1) -> bp(GOBP:"mitochondrial translation") p(HGNC:AIMP1) -> bp(GOBP:"protein metabolic process") UNSET Subgraph SET Evidence = "T3 attaches o nuclear-localized TRs and TREs to control gene expression of nuclear-encoded proteins that are destined to the mitochondria and in this way affect mitochondrial biogenesis" SET Subgraph = {"thyroid hormone signaling subgraph", "hormone signaling subgraph"} a(CHEBI:"3,3',5'-triiodothyronine") -- bp(GOBP:"mitochondrion morphogenesis") SET Evidence = "T3 strongly increases oxygen consumption and the rate of ATP hydrolysis." a(CHEBI:"3,3',5'-triiodothyronine") -> bp(GOBP:"oxygen metabolic process") a(CHEBI:"3,3',5'-triiodothyronine") -> bp(GOBP:"ATP hydrolysis coupled transmembrane transport") SET Evidence = "Therefore, it seems that by controlling mitochondrial gene expression, THs modulates mitochondrial biogenesis and oxidative phosphorylation capacity in certain areas of the brain such as the striatum and cerebral cortex" SET Anatomy = "striatum" a(CHEBI:"thyroid hormone") -- bp(GOBP:"oxidative phosphorylation") UNSET Anatomy SET MeSHAnatomy = "Cerebral Cortex" a(CHEBI:"thyroid hormone") -- bp(GOBP:"oxidative phosphorylation") UNSET MeSHAnatomy SET Evidence = "While hypothyroidism increases protein carbonyl and lipid peroxidation products as oxidative stress indices in the mitochondrial fraction of the brain, replacement of T3 restores hese parameters" SET MeSHDisease = "Hypothyroidism" a(CHEBI:"3,3',5'-triiodothyronine") -| a(CHEBI:"reactive oxygen species") UNSET MeSHDisease SET Evidence = "that the proper function of THs in the brain might prevent or slow down the development of epileptic seizures." a(CHEBI:"thyroid hormone") -| path(MESHD:Seizures) a(CHEBI:"thyroid hormone") -| path(MESHD:Epilepsy) UNSET Subgraph SET Evidence = "Generally, GABA inhibits thyroid function at all three levels of the hypothalamus, pituitary, and thyroid axes" SET Subgraph = {"GABA subgraph", "Neurotransmitter release subgraph", "thyroid hormone signaling subgraph", "hormone signaling subgraph"} a(CHEBI:"GABA agent") -| a(CHEBI:"thyroid hormone") SET Evidence = "GABA also plays an important role in seizure suppression as an inhibitory neurotransmitter" a(CHEBI:"GABA agent") -| path(MESHD:Seizures) SET Evidence = "t can be presumed that THs inhibits seizures by increasing GABAergic system during brain development" a(CHEBI:"thyroid hormone") -> a(CHEBI:"GABA agent") UNSET Subgraph SET Evidence = "gene expression of thyrotropin-releasing hormone (TRH) and its receptor are affected by seizures suggesting that TRH ight play a role in the pathogenesis of epilepsy" SET Subgraph = {"thyroid hormone signaling subgraph", "hormone signaling subgraph"} path(MESHD:Seizures) -- p(HGNC:TRH) path(MESHD:Seizures) -- p(HGNC:TRHR) p(HGNC:TRH) -- path(MESHD:Epilepsy) UNSET Subgraph SET Evidence = "On one hand, NPY is shown to negatively modulate TSH/T4 concentration [101] and on the other hand, it has been shown that seizure induction alters the expression of NPY and different NPY receptor subtypes" SET Subgraph = "brain_derived neurotrophic factor signaling subgraph" p(HGNC:NPY) -| p(HGNC:CGA) path(MESHD:Seizures) -- p(HGNC:NPY) UNSET Subgraph SET Evidence = "Another set of genes that participate in the process of epileptogenesis and are also affected by THs are some of the immediate early genes (IEGs) like Homer1, early growth response 1 (egr1) and activity-rp(egulated cytoskeleton-associated protein (Arc)" SET Subgraph = {"thyroid hormone signaling subgraph", "hormone signaling subgraph"} p(HGNC:HOMER1) -> path(MESHD:Epilepsy) p(HGNC:HOMER1) -- a(CHEBI:"thyroid hormone") p(HGNC:EGR1) -> path(MESHD:Epilepsy) p(HGNC:EGR1) -- a(CHEBI:"thyroid hormone") p(HGNC:ARC) -> path(MESHD:Epilepsy) p(HGNC:ARC) -- a(CHEBI:"thyroid hormone") SET Evidence = "it is conceivable to assume that sex hormones and THs interact with each other during brain development." a(CHEBI:"thyroid hormone") -- a(CHEBI:"sex hormone") SET Evidence = "In other words, TRAP220 enhances the function of TRs, steroid hormone receptors, retinoic acid receptor a and vitamin D receptor" p(HGNC:MED1) -> p(HGNC:THRA) p(HGNC:MED1) -> p(HGNC:THRB) p(HGNC:MED1) -> a(CHEBI:"steroid hormone") p(HGNC:MED1) -> p(HGNC:RARA) p(HGNC:MED1) -> p(HGNC:VDR) SET Evidence = "Decreased TRAP220 mRNA levels in epileptic tissue can be an indicator of the role that TRAP220 plays in the neuropathology of epileptic seizures" path(MESHD:Epilepsy) negativeCorrelation p(HGNC:MED1) SET Evidence = "Type 3 deiodinase or D3, which is necessary for the maturation and function of the brain." p(HGNC:DIO3) -> bp(GOBP:"hindbrain maturation") #p(HGNC:DIO3) -> bp("brain function") SET Evidence = "D3 protects the brain from high doses of T3 by reducing its effects." p(HGNC:DIO3) -| a(CHEBI:"3,3',5'-triiodothyronine") SET Evidence = "Several lines of evidence show that antiepileptic drugs (AEDs) affect different aspects of THs hemostasis such as biosynthesis, release and transport as well as metabolism in both children and adults" a(CHEBI:anticonvulsant) -- bp(GOBP:"regulation of thyroid hormone generation") a(CHEBI:anticonvulsant) -- bp(GOBP:"thyroid hormone metabolic process") a(CHEBI:anticonvulsant) -- bp(GOBP:"thyroid hormone transport") SET Evidence = "all AEDs except levetiracetam increased TSH level and decreased fT4 concentration" a(CHEBI:anticonvulsant) -> p(HGNC:CGA) a(CHEBI:anticonvulsant) -| a(CHEBI:"3,3',5'-triiodothyronine") UNSET Subgraph SET Drug = "lamotrigine" SET Subgraph = {"Neurotransmitter release subgraph", "GABA subgraph", "Calcium dependent subgraph", "Serotonergic subgraph"} a(CHEBI:levetiracetam) causesNoChange p(HGNC:CGA) a(CHEBI:levetiracetam) causesNoChange a(CHEBI:"3,3',5'-triiodothyronine") UNSET Subgraph UNSET Drug SET Evidence = "t was reported that carbamazepine monotherapy in epileptic children and adult patients impaired thyroid function" SET Drug = "carbamazepine" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph", "thyroid hormone signaling subgraph", "hormone signaling subgraph"} a(CHEBI:carbamazepine) -| a(CHEBI:"thyroid hormone") UNSET Subgraph UNSET Drug SET Evidence = "THs also modulate in vivo and in vitro binding of benzodiazepines on their specific membrane receptors" SET Subgraph = {"thyroid hormone signaling subgraph", "hormone signaling subgraph"} a(CHEBI:"thyroid hormone") -- a(CHEBI:benzodiazepine) UNSET Subgraph #################################################### SET Citation = {"PubMed", "J Child Neurol. 2007 May;22(5):606-16.", "17690069"} SET Evidence = "gamma-amino butyric acid (GABA) metabolism is associated with several disorders, including glutamic acid decarboxylase deficiency with nonsyndromic cleft lip/ palate, GABA-transaminase deficiency, and succinic semialdehyde dehydrogenase deficiency. The latter is characterized by elevated gamma-hydroxybutyric acid and includes a wide range of neuropsychiatric symptoms as well as epilepsy" SET Subgraph = {"GABA subgraph", "Neurotransmitter release subgraph"} bp(PTS:"gamma_aminobutyric acid metabolic pathway") pos path(MESHD:Epilepsy) bp(PTS:"gamma_aminobutyric acid metabolic pathway") pos a(CHEBI:"GABA agent") UNSET Subgraph #################################################### SET Citation = {"PubMed", "Bioorg Med Chem. 2012 Oct 1;20(19):5763-73. doi: 10.1016/j.bmc.2012.08.009. Epub 2012 Aug 16.", "22944334"} SET Evidence = "Because of GABA's poor ability to cross the blood-brain barrier (BBB), a successful strategy to raise brain GABA concentrations is the use of a compound that does cross the BBB and inhibits or inactivates GABA aminotransferase (GABA-AT), the enzyme responsible for GABA catabolism" SET Subgraph = {"GABA subgraph", "Neurotransmitter release subgraph"} p(HGNC:ABAT) -| a(CHEBI:"GABA agent") p(HGNC:ABAT) -> bp(PTS:"gamma_aminobutyric acid metabolic pathway") bp(PTS:"gamma_aminobutyric acid metabolic pathway") -| a(CHEBI:"GABA agent") SET Evidence = "Vigabatrin, a mechanism-based inactivator of GABA-AT, is currently a successful therapeutic for epilepsy" SET Drug = "vigabatrin" a(CHEBI:vigabatrin) -| p(HGNC:ABAT) a(CHEBI:vigabatrin) -> a(CHEBI:"GABA agent") a(CHEBI:vigabatrin) -| path(MESHD:Epilepsy) a(CHEBI:vigabatrin) isA a(CHEBI:anticonvulsant) a(CHEBI:vigabatrin) -| bp(PTS:"gamma_aminobutyric acid signaling pathway") p(HGNC:ABAT) -> path(MESHD:Epilepsy) a(CHEBI:"GABA agent") -| path(MESHD:Epilepsy) UNSET Subgraph UNSET Drug #################################################### SET Citation = {"PubMed", "Neurochem Res. 1999 Nov;24(11):1387-95.", "10555779"} SET Evidence = "Concentrations of glutamate, aspartate and glycine are significantly increased in epileptogenic cerebral cortex" SET Subgraph = {"Glutamatergic subgraph", "Neurotransmitter release subgraph", "Metabolism"} a(CHEBI:"glutamate(1-)") -- path(MESHD:Epilepsy) a(CHEBI:"aspartate(1-)") -- path(MESHD:Epilepsy) a(CHEBI:glycine) -- path(MESHD:Epilepsy) SET Evidence = "The activities of the enzymes, glutamate dehydrogenase and aspartate aminotransferase, involved in glutamate and aspartate metabolism are also increased" p(HGNC:GLUD1) -- bp(PTS:"Glutamate metabolism") bp(PTS:"Glutamate metabolism") -> a(CHEBI:"glutamate(1-)") bp(PTS:"Glutamate metabolism") -- path(MESHD:Epilepsy) UNSET Subgraph SET Subgraph = "Neurotransmitter release subgraph" p(HGNC:GOT1) -- bp(PTS:"aspartate metabolic pathway") bp(PTS:"aspartate metabolic pathway") -> a(CHEBI:"aspartate(1-)") bp(PTS:"aspartate metabolic pathway") -- path(MESHD:Epilepsy) SET Evidence = "Polyamine synthesis is enhanced in epileptogenic cortex" bp(PTS:"aspartate metabolic pathway") -- path(MESHD:Epilepsy) UNSET Subgraph ################################################## SET Citation = {"PubMed", "Neural Plast. 2014;2014:310146. doi: 10.1155/2014/310146. Epub 2014 Mar 13.", "24757570"} SET Evidence = " In addition, both BDNF and its receptor TrkB were also decreased in hippocampus of the chronic CTZ seizure rats" SET Subgraph = {"brain_derived neurotrophic factor signaling subgraph", "Mossy Fiber Subgraph"} SET Species = "10116" p(HGNC:BDNF) -- path(MESHD:Epilepsy) path(MESHD:Epilepsy) negativeCorrelation p(HGNC:BDNF) p(HGNC:NTRK2) -- path(MESHD:Epilepsy) path(MESHD:Epilepsy) negativeCorrelation p(HGNC:NTRK2) UNSET Subgraph SET Evidence = "the decreased GABA synthesis and transport as well as the impaired BDNF-TrkB signaling pathway may contribute to the development of the recurrent seizure" SET Subgraph = {"brain_derived neurotrophic factor signaling subgraph", "GABA subgraph", "Neurotransmitter release subgraph"} p(HGNC:BDNF) -> bp(PTS:"brain_derived neurotrophic factor signaling pathway") bp(PTS:"brain_derived neurotrophic factor signaling pathway") -- path(MESHD:Epilepsy) UNSET Subgraph UNSET Species ##################################################### SET Citation = {"PubMed", "Ann Indian Acad Neurol. 2014 Jul;17(3):259-66. doi: 10.4103/0972-2327.138475.", "25221392"} SET Evidence = "AEDs are mostly metabolized by Cyp2C9, Cyp2C19 and Cyp3A4 and transported by ABCB1" a(CHEBI:anticonvulsant) -- p(HGNC:CYP2C9) a(CHEBI:anticonvulsant) -- p(HGNC:CYP2C19) a(CHEBI:anticonvulsant) -- p(HGNC:CYP3A4) a(CHEBI:anticonvulsant) -- p(HGNC:ABCB1) p(HGNC:CYP2C9) -> bp(PTS:"drug pathway") p(HGNC:CYP2C19) -> bp(PTS:"drug pathway") p(HGNC:CYP3A4) -> bp(PTS:"drug pathway") p(HGNC:ABCB1) -> bp(PTS:"drug pathway") bp(PTS:"drug pathway") -- path(MESHD:Epilepsy) #################################################### SET Citation = {"PubMed", "Mol Neurobiol. 2014 Apr;49(2):633-44. doi: 10.1007/s12035-013-8545-0. Epub 2013 Sep 3.", "23999872"} SET Evidence = "we found that Notch signaling was activated in the kainic acid (KA)-induced epilepsy model and in human epileptogenic tissues" SET Subgraph = "Notch signaling subgraph" a(CHEBI:"kainic acid") -> path(MESHD:"Status Epilepticus") a(CHEBI:"kainic acid") -- bp(PTS:"Notch signaling pathway") UNSET Subgraph ################################################## SET Citation = {"PubMed", "J Inherit Metab Dis. 2015 Mar;38(2):231-42. doi: 10.1007/s10545-014-9755-y. Epub 2014 Aug 12.", "25112391"} SET Evidence = " Adenylosuccinate lyase (ADSL) deficience is a defect of purine metabolism" SET Subgraph = "Metabolism" p(HGNC:ADSL) -> bp(PTS:"Purine metabolism") bp(PTS:"Purine metabolism") -- path(MESHD:Epilepsy) UNSET Subgraph #################################################### SET Citation = {"PubMed", "Brain Dev. 2011 Oct;33(9):796-805. doi: 10.1016/j.braindev.2011.04.013. Epub 2011 Jun 12.", "21664777"} SET Evidence = "Succinic semialdehyde dehydrogenase (SSADH) deficiency is a gamma-aminobutyric acid (GABA) degradative defect." SET Subgraph = {"GABA subgraph", "Neurotransmitter release subgraph"} p(HGNC:ALDH5A1) -> bp(PTS:"gamma_aminobutyric acid metabolic pathway") UNSET Subgraph ################################################### SET Citation = {"PubMed", "Clin Biochem. 2005 Dec;38(12):1051-8. Epub 2005 Nov 18.", "16298354"} SET Evidence = "Inherited disorders of neurotransmitters are a group of neurometabolic syndromes attributable to a primary disturbance of neurotransmitter metabolism or transport. This is an enlarging group of recognized disorders requiring specialized diagnostic procedures for detection. This review considers clinical disorders of biopterin, catecholamines, serotonin, glycine, pyridoxine, and GABA metabolism." SET Subgraph = {"Neurotransmitter release subgraph", "GABA subgraph"} bp(PTS:"gamma_aminobutyric acid metabolic pathway") isA bp(PTS:"Neurotransmitter secretion") UNSET Subgraph ################################################ SET Citation = {"PubMed", "Mol Genet Metab. 2015 Sep-Oct;116(1-2):35-43. doi: 10.1016/j.ymgme.2015.05.011. Epub 2015 May 23.", "26026794"} SET Evidence = " PDE is caused by deficiency of aminoadipic semialdehyde dehydrogenase resulting in impaired lysine degradation and subsequent accumulation of aminoadipic semialdehyde." SET Subgraph = {"Protein Metabolism", "Metabolism"} p(HGNC:ALDH7A1) -> bp(PTS:"Lysine degradation") bp(PTS:"Lysine degradation") -| path(MESHD:Epilepsy) UNSET Subgraph ################################################ SET Citation = {"PubMed", "J Child Neurol. 2014 May;29(5):704-7. doi: 10.1177/0883073813505354. Epub 2013 Oct 10.", "24114605"} SET Evidence = "ALDH7A1 and PNPO deficiencies are rare inborn errors of vitamin B6 metabolism causing perinatal seizure disorders." SET Subgraph = "Metabolism" p(HGNC:ALDH7A1) -> bp(PTS:"Vitamin B6 metabolism") p(HGNC:PNPO) -> bp(PTS:"Vitamin B6 metabolism") bp(PTS:"Vitamin B6 metabolism") -- path(MESHD:Epilepsy) UNSET Subgraph ################################################ SET Citation = {"PubMed", "Brain Dev. 2013 Jun;35(6):586-9. doi: 10.1016/j.braindev.2012.09.003. Epub 2012 Oct 6.", "23044053"} SET Evidence = "Congenital disorders of glycosylation (CDG) are inherited metabolic diseases affecting N-linked glycosylation pathways " bp(PTS:"N_linked glycosylation") -- path(MESHD:"Congenital Disorders of Glycosylation") SET Evidence = "CDG-Ic is caused by mutation in the ALG6 gene encoding alpha-1,3-glucosyltransferase" g(HGNC:ALG6, var("?")) pos path(MESHD:"Congenital Disorders of Glycosylation") SET Evidence = "She developed severe psychomotor retardation, epileptic seizures," path(MESHD:"Congenital Disorders of Glycosylation") -> path(MESHD:Epilepsy) bp(PTS:"N_linked glycosylation") -- p(HGNC:ALG6) bp(PTS:"N_linked glycosylation") -- path(MESHD:Epilepsy) ########################################### SET Citation = {"PubMed", "Am J Hum Genet. 2004 Jul;75(1):146-50. Epub 2004 May 17.", "15148656"} SET Evidence = "Using this approach, we have found, in a patient with CDG, a deficiency of the ALG9 mannosyltransferase enzyme, which causes an accumulation of lipid-linked-GlcNAc2Man6 and -GlcNAc2Man8 structures," g(HGNC:ALG6, var("?")) -- path(MESHD:"Congenital Disorders of Glycosylation") SET Evidence = "The N-linked glycosylation pathway bears the hallmark of first assembling the GlcNAc2Man9Glc3 oligosaccharide core on the lipid carrier dolichylpyrophosphate (DolPP) and then of transferring it en bloc to nascent polypeptides" p(HGNC:ALG9) -> bp(PTS:"N_linked glycosylation") ############################################# SET Citation = {"PubMed", "Subcell Biochem. 2008;49:241-68. doi: 10.1007/978-1-4020-8831-5_9.", "18751914"} SET Evidence = "Deregulated lipid metabolism may be of particular importance for CNS injuries and disorders, as this organ has the highest lipid concentration next to adipose tissue" SET Subgraph = "Metabolism" bp(PTS:"Lipid Metabolism") -> path(MESHD:"Central Nervous System Diseases") path(MESHD:Epilepsy) isA path(MESHD:"Central Nervous System Diseases") SET Evidence = "Apolipoprotein E is the principal cholesterol carrier protein in the brain" p(HGNC:APOE) -> bp(PTS:"Lipid Metabolism") SET Evidence = "Phenytoin (Dilantin, Phenytek) is a widely used anti-seizure medicine (LaRoche, 2007). The primary site of action appears to be the motor cortex where spread of seizure activity is inhibited, possibly by promoting sodium efflux from neurons." SET Drug = "phenytoin" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} a(CHEBI:phenytoin) -| path(MESHD:"Seizures") a(CHEBI:phenytoin) -> bp(GOBP:"positive regulation of sodium ion transport") SET Evidence = "Phenytoin tends to stabilize the threshold against hyper-excitability caused by excessive stimulation." #a(CHEBI:phenytoin) -| ehyper excitability") UNSET Subgraph UNSET Drug ################################################# SET Citation = {"PubMed", "Toxicol Lett. 2013 Feb 27;217(2):162-9. doi: 10.1016/j.toxlet.2012.12.010. Epub 2012 Dec 21.", "23266720"} SET Evidence = " The results of the present study suggest that E-64d, an elective inhibitor of calpain and autophagy, is potentially useful in the treatment of developmental seizure-induced brain damage both by regulating abnormal zinc signal transduction and through the modulation of altered lipid metabolism via ApoE/clusterin pathway in hippocampus." SET Subgraph = "Metabolism" a(CHEBI:E64) -| bp(GOBP:autophagy) a(CHEBI:E64) isA a(CHEBI:"calpain inhibitor") a(CHEBI:E64) -| p(HGNC:CAPN1) a(CHEBI:E64) -- bp(PTS:"Lipid Metabolism") UNSET Subgraph ################################################ SET Citation = {"PubMed", "CNS Neurosci Ther. 2014 May;20(5):385-90. doi: 10.1111/cns.12267. Epub 2014 Apr 8.", "24712483"} SET Evidence = "Aquaporin 4 (AQP4) is the main water channel in the central nervous system (CNS) and specifically localized to astrocyte processes" SET Subgraph = "Calcium dependent subgraph" SET Anatomy = "central nervous system" p(HGNC:AQP4) -> bp(GOBP:"water transport") p(HGNC:AQP4) -- bp(GOBP:"astrocyte activation") UNSET Anatomy SET Evidence = "Recent studies indicate that AQP4 regulates various biological functions of astrocytes, including maintaining CNS water balance, spatial buffering of extracellular potassium, calcium signal transduction, regulation of neurotransmission, synaptic plasticity, and adult neurogenesis" p(HGNC:AQP4) -> bp(GOBP:"calcium-mediated signaling") p(HGNC:AQP4) -> bp(PTS:"Calcium signaling pathway") p(HGNC:AQP4) -> bp(GOBP:"regulation of neuronal synaptic plasticity") p(HGNC:AQP4) -> bp(GOBP:neurogenesis) SET Evidence = "In addition, accumulating evidence suggests that, besides cerebral edema, neuromyelitis optica and epilepsy, AQP4 participates in the onset and progression of Alzheimer disease, Parkinson disease, depression, and drug addiction" p(HGNC:AQP4) -- path(MESHD:Epilepsy) bp(PTS:"Calcium signaling pathway") -- path(MESHD:Epilepsy) p(HGNC:AQP4) -- path(MESHD:"Neuromyelitis Optica") p(HGNC:AQP4) -- path(MESHD:"Alzheimer Disease") p(HGNC:AQP4) -- path(MESHD:"Parkinson Disease") p(HGNC:AQP4) -- path(MESHD:Edema) p(HGNC:AQP4) -- path(DO:"drug dependence") p(HGNC:AQP4) -- path(DO:"major depressive disorder") UNSET Subgraph ################################################# SET Citation = {"PubMed", "Epilepsia. 2012 Nov;53 Suppl 6:53-9. doi: 10.1111/j.1528-1167.2012.03703.x.", "23134496"} SET Evidence = "Blood-brain barrier (BBB) opening during status epilepticus has short-term proepileptic effects, as the ionic composition of serum interferes with neuronal excitability" bp(GOBP:"maintenance of permeability of blood-brain barrier") -- path(MESHD:Epilepsy) SET Evidence = "Although many of the astrocytic mechanisms involving spatial K(+) buffering, nitric oxide, adenosine, and metabotropic glutamate receptor (mGluR)-mediated signalling are altered in epilepsy" SET Subgraph = {"Glutamatergic subgraph", "Neurotransmitter release subgraph"} bp(PTS:"Nitric Oxide Signaling Pathway") -- path(MESHD:Epilepsy) bp(GOBP:"nitric oxide mediated signal transduction") isA bp(PTS:"Nitric Oxide Signaling Pathway") bp(PTS:"cAMP mediated signaling") -- path(MESHD:Epilepsy) bp(GOBP:"adenosine receptor signaling pathway") isA bp(PTS:"cAMP mediated signaling") bp(PTS:"glutamate signaling pathway") -- path(MESHD:Epilepsy) bp(GOBP:"glutamate receptor signaling pathway") isA bp(PTS:"glutamate signaling pathway") UNSET Subgraph ############################################## SET Citation = {"PubMed", "Eur J Hum Genet. 2016 Jan;24(1):59-65. doi: 10.1038/ejhg.2015.69. Epub 2015 Apr 22.", "25898924"} SET Evidence = "Protein synthesis regulation via mammalian target of rapamycin complex 1 (mTORC1) signaling pathway has key roles in neural development and function, and its dysregulation is involved in neurodevelopmental disorders associated with autism and intellectual disability" SET Subgraph = "mTOR signaling subgraph" bp(PTS:"mTOR signaling pathway") -> bp(GOBP:"regulation of protein metabolic process") bp(PTS:"mTOR signaling pathway") -> bp(GOBP:"neuron development") bp(PTS:"mTOR signaling pathway") -- path(DO:"autism spectrum disorder") bp(PTS:"mTOR signaling pathway") -- path(DO:"intellectual disability") SET Evidence = "mTOR regulates assembly of the translation initiation machinery by interacting with the eukaryotic initiation factor eIF3 complex and by controlling phosphorylation of key translational regulators." p(HGNC:MTOR) -> bp(GOBP:"eukaryotic translation initiation factor 3 complex assembly") p(HGNC:MTOR) -- bp(GOBP:translation) UNSET Subgraph ################################################### SET Citation = {"PubMed", "J Hum Genet. 2011 Aug;56(8):561-5. doi: 10.1038/jhg.2011.58. Epub 2011 Jun 2.", "21633362"} SET Evidence = "cell division cycle 42 guanine nucleotide exchange factor (GEF)-9 gene (ARHGEF9), encoding collybistin, which has a pivotal role in formation of postsynaptic glycine and gamma-aminobutyric acid receptor clusters" SET Subgraph = "Neurotransmitter release subgraph" p(HGNC:ARHGEF9) -> bp(GOBP:"glycine receptor clustering") p(HGNC:ARHGEF9) -> bp(GOBP:"gamma-aminobutyric acid receptor clustering") bp(GOBP:"gamma-aminobutyric acid receptor clustering") -> bp(PTS:"gamma_aminobutyric acid signaling pathway") UNSET Subgraph SET Evidence = "A cohort study of ARHGEF9 nucleotide sequence identified a nonsense mutation in another male patient with severe mental retardation and epilepsy." p(HGNC:ARHGEF9) -> path(MESHD:Epilepsy) ################################################## SET Citation = {"PubMed", "Hum Mol Genet. 2008 Dec 1;17(23):3740-60. doi: 10.1093/hmg/ddn271. Epub 2008 Sep 16.", "18799476"} SET Evidence = "Studies in mice indicate Arx plays a role in neuronal progenitor proliferation and development of the cerebral cortex, thalamus, hippocampus, striatum, and olfactory bulbs" SET Confidence = "High" SET Species = "10090" p(HGNC:ARX) -- bp(GOBP:"common myeloid progenitor cell proliferation") p(HGNC:ARX) -- bp(GOBP:"cerebral cortex development") p(HGNC:ARX) -- bp(GOBP:"thalamus development") p(HGNC:ARX) -- bp(GOBP:"hippocampus development") p(HGNC:ARX) -- bp(GOBP:"striatum development") p(HGNC:ARX) -- bp(GOBP:"olfactory bulb development") UNSET Species SET Evidence = "This population was enriched in genes involved in cell migration, axonal guidance, neurogenesis, and regulation of transcription and includes genes implicated in autism, epilepsy, and mental retardation; all features recognized in patients with ARX mutations" SET Confidence = "High" p(HGNC:ARX) -> bp(GOBP:"regulation of cell migration") p(HGNC:ARX) -> bp(GOBP:"axon guidance") p(HGNC:ARX) -> bp(GOBP:"neurogenesis") p(HGNC:ARX) -> bp(GOBP:"regulation of transcription, DNA-templated") p(HGNC:ARX) -> bp(PTS:"Regulation of transcription") g(HGNC:ARX, var("?")) pos path(DO:"autism spectrum disorder") g(HGNC:ARX, var("?")) pos path(MESHD:Epilepsy) SET Evidence = "Additionally, we found Arx directly repressed three of the identified transcription factors: Lmo1, Ebf3 and Shox2." p(HGNC:ARX) -| p(HGNC:LMO1) p(HGNC:ARX) -| p(HGNC:EBF3) p(HGNC:ARX) -| p(HGNC:SHOX2) ###################################################### SET Citation = {"PubMed", "Ann N Y Acad Sci. 2009 Jan;1151:133-56. doi: 10.1111/j.1749-6632.2008.03572.x.", "19154521"} SET Evidence = "The calcium ion is one of the most versatile, ancient, and universal of biological signaling molecules, known to regulate physiological systems at every level from membrane potential and ion transporters to kinases and transcription factors." SET Subgraph = "Calcium dependent subgraph" a(CHEBI:"calcium(2+)") isA a(CHEBI:"signalling molecule") a(CHEBI:"calcium(2+)") -> bp(GOBP:"regulation of system process") a(CHEBI:"calcium(2+)") -> bp(GOBP:"regulation of membrane potential") a(CHEBI:"calcium(2+)") -> bp(GOBP:"regulation of ion transmembrane transport") a(CHEBI:"calcium(2+)") -> bp(GOBP:"regulation of ion transmembrane transporter activity") a(CHEBI:"calcium(2+)") -> bp(GOBP:"regulation of kinase activity") SET Evidence = "Disruptions of intracellular calcium homeostasis underlie a host of emerging diseases, the calciumopathies" a(CHEBI:"calcium(2+)") -> bp(GOBP:"calcium-mediated signaling using intracellular calcium source") a(CHEBI:"calcium(2+)") -- bp(GOBP:"calcium ion homeostasis") bp(GOBP:"calcium ion homeostasis") -| path(MESHD:Channelopathies) UNSET Subgraph SET Evidence = "Furthermore, the mitochondria have long been recognized to represent the major intracellular calcium repository, but only more recently have they been shown to dynamically participate with the ER stores in calcium signaling,8,9 thereby integrating cellular Energy metabolic subgraph into these pathways, a process of emerging importance in the analysis of the neurodegenerative and neuropsychiatric diseases." SET Subgraph = {"Energy metabolic subgraph", "Metabolism", "Calcium dependent subgraph"} a(CHEBI:"calcium(2+)") -> bp(GOBP:"mitochondrial calcium ion homeostasis") bp(GOBP:"mitochondrial calcium ion homeostasis") -- bp(GOBP:"endoplasmic reticulum calcium ion homeostasis") bp(GOBP:"mitochondrial calcium ion homeostasis") -> bp(GOBP:"cellular metabolic process") bp(GOBP:"mitochondrial calcium ion homeostasis") -> bp(PTS:"Energy Metabolism") a(CHEBI:"calcium(2+)") -> bp(GOBP:"cellular metabolic process") a(CHEBI:"calcium(2+)") -> bp(PTS:"Energy Metabolism") bp(PTS:"Energy Metabolism") -- path(DO:"neurodegenerative disease") bp(GOBP:"cellular metabolic process") -- path(DO:"neurodegenerative disease") UNSET Subgraph SET Evidence = "The cardinal feature of ion channel disease of excitable tissue is a periodic disturbance of rhythmic function. In the heart this disturbance produces a fatal arrhythmia" path(MESHD:Channelopathies) -- bp(GOBP:"regulation of circadian rhythm") path(MESHD:"Arrhythmias, Cardiac") isA path(MESHD:Channelopathies) SET Evidence = "In skeletal muscle abnormal ion channel function produces periodic alterations in contractility, ranging from paralysis to the inability to relax, myotonia, and the allelic, but illusorily distinct phenotype of malignant hyperthermia mentioned above" bp(GOBP:"regulation of ion transmembrane transporter activity") -- bp(GOBP:"regulation of skeletal muscle contraction") bp(GOBP:"regulation of skeletal muscle contraction") -> path(MESHD:Myotonia) bp(GOBP:"regulation of skeletal muscle contraction") -> path(MESHD:"Malignant Hyperthermia") path(MESHD:Myotonia) isA path(MESHD:Channelopathies) path(MESHD:"Malignant Hyperthermia") isA path(MESHD:Channelopathies) SET Evidence = "In the central nervous system (CNS) the same range of rhythmic disturbances are produced, and the best documented to date are those that cause an episodic, abnormally synchronous electrical discharge—a seizure, and the syndrome of recurrent seizures—epilepsy." path(MESHD:Epilepsy) isA path(MESHD:Channelopathies) SET Evidence = "Typically, activation is initiated across a synapse; then neuroreceptors and their endogenous or coupled channels are activated, and as a patch of membrane begins to depolarize because of the activation of ligand-gated channels, the local voltage-gated Na+ and Ca++ channels begin to respond to the voltage change by undergoing a conformational change from the closed into the open conformation." #bp("neuroreceptor activation") -> bp(GOBP:"membrane depolarization") bp(GOBP:"membrane depolarization") -> bp(GOBP:"positive regulation of high voltage-gated calcium channel activity") bp(GOBP:"membrane depolarization") -> bp(GOBP:"regulation of voltage-gated sodium channel activity") SET Evidence = "This increases the membrane's permeability to sodium and calcium and hence further drives the membrane potential toward its inside-positive Nernst potential, a depolarization that serves to further activate more channels in surrounding patches of membrane" SET Subgraph = "Calcium dependent subgraph" bp(GOBP:"positive regulation of high voltage-gated calcium channel activity") -> bp(GOBP:"membrane depolarization") bp(GOBP:"regulation of voltage-gated sodium channel activity") -> bp(GOBP:"membrane depolarization") SET Evidence = "Should this reach the critical threshold for channel activation, an explosive self-reinforcing cycle would be set off that would, in turn, be recognized as a propagating AP, a depolarizing wave that rapidly spreads through an excitable tissue until all of its channels have been activated" bp(GOBP:"membrane depolarization") -> bp(GOBP:"neuronal action potential propagation") SET Evidence = "The voltage-gated channels next spontaneously enter an inactive, nonconducting conformation that is distinct from the closed state, since while it is inactive, a channel cannot be opened and the tissue is therefore rendered nonexcitable." bp(GOBP:"neuronal action potential propagation") -> bp(GOBP:"membrane repolarization") bp(GOBP:"membrane repolarization") -> bp(GOBP:"negative regulation of membrane potential") SET Evidence = "The resetting of the membrane potential that restores excitability is carried out by the more slowly activating voltage-gated K+ channels that hyperpolarize the membrane" bp(GOBP:"positive regulation of voltage-gated potassium channel activity") -> bp(GOBP:"membrane repolarization") SET Evidence = "The AP couples to biochemical effector pathways through the rise it produces in the cytosolic calcium concentration" bp(GOBP:"neuronal action potential propagation") -> a(CHEBI:"calcium(2+)") bp(GOBP:"neuronal action potential propagation") -- bp(GOBP:"calcium ion homeostasis") UNSET Subgraph SET Evidence = "The gene CHRNA4 was the first ion channel gene demonstrated to contribute pathogenic alleles to an epilepsy syndrome" g(HGNC:CHRNA4, var("?")) pos path(MESHD:Epilepsy) p(HGNC:CHRNA4) -- a(MESHC:"Ion Channels") SET Evidence = "It encodes the most abundant neuronal isoform of the major subunit of the nicotinic acetylcholine receptor (nAChR), a heteropentameric, ligand-gated, nonselective cation channel, the activation of which directly depolarizes the neuronal membrane" p(HGNC:CHRNA4) -> bp(GOBP:"membrane depolarization") SET Evidence = "The EBN genes are KCNQ2 and KCNQ3" g(HGNC:KCNQ3) -- path(MESHD:"Epilepsy, Benign Neonatal") g(HGNC:KCNQ2) -- path(MESHD:"Epilepsy, Benign Neonatal") SET Evidence = "Calcium has been well established to play an almost unparalleled role in physiology, and increasingly, pathogenesis, and seems to naturally connect into the signaling pathway of channelopathy pathogenesis" SET Subgraph = {"Energy metabolic subgraph", "Metabolism", "Calcium dependent subgraph"} a(CHEBI:"calcium(2+)") -- path(MESHD:Channelopathies) g(HGNC:ATP1A2) -> bp(PTS:"Calcium signaling pathway") g(HGNC:ATP1A2) -> bp(PTS:"Energy Metabolism") bp(PTS:"Energy Metabolism") -- path(MESHD:Epilepsy) g(HGNC:ATP1A2) -- path(MESHD:Epilepsy) UNSET Subgraph SET Evidence = "The gene families and genetic lesions underlying familial hemiplegic migraine, FHM1/CACNA1A, FHM2/ATP1A2, and FHM3/SCN1A," SET Subgraph = "Calcium dependent subgraph" g(HGNC:CACNA1A) -> bp(PTS:"Calcium signaling pathway") UNSET Subgraph ###################################### SET Citation = {"PubMed", "J Neuroimmunol. 2015 Feb 15;279:33-8. doi: 10.1016/j.jneuroim.2014.12.003. Epub 2014 Dec 4.", "25669997"} SET Evidence = "Lack of microglial phagocytosis and decreased levels of BDNF appear to distinguish Rett syndrome from ASDs, in which there is instead microglia activation and/or proliferation and possibly defective BDNF signaling." SET Confidence = "High" SET Subgraph = {"brain_derived neurotrophic factor signaling subgraph", "Mossy Fiber Subgraph"} p(HGNC:BDNF) neg path(MESHD:"Rett Syndrome") path(MESHD:"Rett Syndrome") isA path(MESHD:Epilepsy) bp(GOBP:"microglial cell activation") -> path(DO:"autism spectrum disorder") bp(GOBP:"microglial cell proliferation") -> path(DO:"autism spectrum disorder") bp(PTS:"brain_derived neurotrophic factor signaling pathway") -> path(DO:"autism spectrum disorder") p(HGNC:BDNF) -- bp(PTS:"brain_derived neurotrophic factor signaling pathway") bp(PTS:"brain_derived neurotrophic factor signaling pathway") -- path(MESHD:Epilepsy) UNSET Subgraph ########################################## SET Citation = {"PubMed", "Neuroscientist. 2005 Aug;11(4):282-7.", "16061515"} SET Evidence = "On the other hand, several reports demonstrate that intrahippocampal infusion of BDNF can attenuate (or retard) the development of epilepsy. This antiepileptogenic effect seems to be mediated mainly by an increase in the expression of neuropeptide Y." SET Subgraph = {"brain_derived neurotrophic factor signaling subgraph", "Mossy Fiber Subgraph"} p(HGNC:BDNF) -> p(HGNC:NPY) p(HGNC:NPY) -| path(MESHD:Epilepsy) p(HGNC:NPY) -| bp(EPT:"epileptogenesis") SET Evidence = "These contrasting effects of BDNF have prevented us from concluding whether inhibition or enhancement of BDNF signaling finally achieves the prevention of TLE" bp(PTS:"brain_derived neurotrophic factor signaling pathway") -- path(MESHD:"Epilepsy, Temporal Lobe") SET Evidence = "One of the well-established effects of BDNF on the hip- pocampus is a rapid modulation of excitatory and inhibitory synaptic transmission" p(HGNC:BDNF) -> bp(GOBP:"chemical synaptic transmission") SET Evidence = "In cultured hippocam- pal neurons, BDNF increases spontaneous firing rates more than twofold, leading to an increase in both the amplitude and frequency of excitatory postsynaptic cur- rents (EPSCs) within two to three minutes of application" SET MeSHAnatomy = "Hippocampus" p(HGNC:BDNF) -> bp(GOBP:"neuronal action potential propagation") UNSET MeSHAnatomy UNSET Subgraph SET Evidence = "Results from our laboratory showed that BDNF increases neural excitability of CA1 cells by inhibiting GABA A receptor- mediated inhibitory postsynaptic currents (IPSCs)" SET MeSHAnatomy="CA1 Region, Hippocampal" SET Cell = "pyramidal neuron" SET Subgraph = {"Mossy Fiber Subgraph", "Neurotransmitter release subgraph", "GABA subgraph", "brain_derived neurotrophic factor signaling subgraph"} p(HGNC:BDNF) -| bp(GOBP:"regulation of membrane potential") p(HGNC:BDNF) -> bp(GOBP:"rhythmic excitation") p(HGNC:BDNF) -| bp(GOBP:"inhibitory postsynaptic potential") p(HGNC:BDNF) -| p(HGNC:GABRA1) UNSET Cell UNSET Subgraph UNSET MeSHAnatomy SET Evidence = "We therefore conclude that BDNF induces the brachingn-out of hilar axonal shafts." SET Subgraph = {"brain_derived neurotrophic factor signaling subgraph", "Mossy Fiber Subgraph"} p(HGNC:BDNF) -> bp(GOBP:"regulation of branching morphogenesis of a nerve") SET Evidence = "These results indicate that BDNF plays a causal role in triggering MF sprouting, and they provide morphological evi- dence for the idea that BDNF contributes to hyperex- citability of the dentate gyrus." SET Anatomy = "mossy fiber" SET MeSHAnatomy = "Dentate Gyrus" p(HGNC:BDNF) -> bp(GOBP:"rhythmic excitation") UNSET MeSHAnatomy UNSET Anatomy UNSET Subgraph SET Evidence = "there is also a report sug- gesting that BDNF potentiates GABAergic inhibition in human epileptic brai" SET Subgraph = {"brain_derived neurotrophic factor signaling subgraph", "GABA subgraph"} p(HGNC:BDNF) -> bp(GOBP:"negative regulation of synaptic transmission, GABAergic") UNSET Subgraph SET Evidence = "BDNF is reported to increase the density of inhibitory synapses in hippocampal slice cul- tures (Marty and others 2000), enlarge the body size of GABAergic neurons, and enhance the expression of glu- tamic acid decarboxylase (GAD), a GABA-synthesizing enzyme, in cultured hippocampal neuron" SET Subgraph = {"brain_derived neurotrophic factor signaling subgraph", "GABA subgraph", "Neurotransmitter release subgraph"} p(HGNC:BDNF) -> p(HGNC:GAD1) p(HGNC:GAD1) -> a(CHEBI:"GABA agent") SET Evidence = " the link of BDNF to the GABAergic system in the epileptic brain." p(HGNC:BDNF) -- bp(PTS:"gamma_aminobutyric acid signaling pathway") UNSET Subgraph SET Evidence = "he level of NPY is increased in the neocortex of TLE patients and positively correlated with the BDNF level" SET Subgraph = {"brain_derived neurotrophic factor signaling subgraph"} p(HGNC:BDNF) -> p(HGNC:NPY) SET Evidence = "Taken together, inhibiting BDNF-TrkB signaling and reinforcing the NPY system in the adult hippocampus seem to be potential therapeutic strategies for TLE" bp(PTS:"brain_derived neurotrophic factor signaling pathway") -> path(MESHD:Epilepsy) UNSET Subgraph ################################################ SET Citation = {"PubMed", "Med Hypotheses. 2005;65(1):79-82.", "15893122"} SET Evidence = "Brain-derived neurotrophic factor (BDNF) is important for normal neuronal development" SET Subgraph = "brain_derived neurotrophic factor signaling subgraph" p(HGNC:BDNF) -> bp(GOBP:"neuron development") SET Evidence = "Early BDNF hyperactivity may play an etiological role in autism early in life" SET Confidence = "High" act(p(HGNC:BDNF)) -- path(DO:"autism spectrum disorder") UNSET Subgraph ############################################## SET Citation = {"PubMed", "Eur J Neurosci. 2015 Apr;41(7):976-88. doi: 10.1111/ejn.12835. Epub 2015 Jan 21.", "25605420"} SET Evidence = "Recent studies in animal models have suggested that the mammalian target of rapamycin (mTOR) signaling pathway is involved in several features of mesio-temporal lobe epilepsy (MTLE)" SET Subgraph = "mTOR signaling subgraph" bp(PTS:"mTOR signaling pathway") -> path(MESHD:"Epilepsy, Temporal Lobe") UNSET Subgraph ################################################ SET Citation = {"PubMed", "J Neurosci. 2009 May 27;29(21):6964-72. doi: 10.1523/JNEUROSCI.0066-09.2009.", "19474323"} SET Evidence = "mTOR inhibitors prevent epilepsy in a mouse model" a(CHEBI:sirolimus) -| p(HGNC:MTOR) a(CHEBI:sirolimus) -| bp(PTS:"mTOR signaling pathway") SET Species = "10090" a(CHEBI:sirolimus) -| path(MESHD:Epilepsy) UNSET Species ############################################## SET Citation = {"PubMed", "BMC Dev Biol. 2008 Apr 10;8:39. doi: 10.1186/1471-213X-8-39.", "18402692"} SET Evidence = "Brd2 facilitates expression of genes promoting proliferation and is implicated in apoptosis and in egg maturation and meiotic competence in mammals; it is also a susceptibility gene for juvenile myoclonic epilepsy (JME) in humans" SET Subgraph = "Innate immune system subgraph" p(HGNC:BRD2) -- path(MESHD:"Myoclonic Epilepsy, Juvenile") p(HGNC:BRD2) -> bp(GOBP:"cell proliferation") p(HGNC:BRD2) -> bp(GOBP:"execution phase of apoptosis") UNSET Subgraph ############################################### SET Citation = {"PubMed", "J Inherit Metab Dis. 2008 Dec;31 Suppl 2:S375-9. doi: 10.1007/s10545-008-0934-6. Epub 2008 Sep 13.", "18780161"} SET Evidence = "Molecular study identified a novel homozygous c.185C>A, p.A62D mutation on the L2HGDH gene in families 1 and 3; they share some clinical signs of the patients of family 1 (MESHD:Epilepsy, pyramidal and extrapyramidal syndromes)" SET Subgraph = "Metabolism" g(HGNC:L2HGDH, var("p.A62D")) pos path(MESHD:Epilepsy) SET Evidence = "Disturbance of other unknown Metabolic pathways related to L2HGA may contribute to this phenomenon." p(HGNC:L2HGDH) -- bp(PTS:"Metabolic pathway") p(HGNC:L2HGDH) -- path(MESHD:Epilepsy) UNSET Subgraph ################################################# SET Citation = {"PubMed", "Am J Hum Genet. 2008 Mar;82(3):623-30. doi: 10.1016/j.ajhg.2007.12.022.", "18319072"} SET Evidence = "The CABC1 gene, also called COQ8 or ADCK3, is the human homolog of the yeast ABC1/COQ8 gene, one of the numerous genes involved in the ubiquinone biosynthesis pathway" p(HGNC:COQ8A) -> bp(PTS:"Ubiquinone biosynthesis") SET Evidence = "We report here CABC1 gene mutations in four ubiquinone-deficient patients in three distinct families. These patients presented a similar progressive neurological disorder with cerebellar atrophy and seizures." g(HGNC:COQ8A, var("?")) pos path(MESHD:Seizures) ################################################## SET Citation = {"PubMed", "Eur J Neurosci. 2005 Mar;21(6):1617-25.", "15845089"} SET Evidence = "E-type channels trigger exocytosis and are also involved in long-term potentiation." SET Subgraph = "Long term synaptic potentiation" p(HGNC:CACNA1E) -> bp(GOBP:exocytosis) p(HGNC:CACNA1E) -> bp(GOBP:"long-term synaptic potentiation") p(HGNC:CACNA1E) -> bp(PTS:"Long_Term Potentiation") SET Evidence = " Recently, it was shown that the interaction of Ca(v)2.3 with the EF-hand motif containing protein EFHC1 is involved in the aetiology and pathogenesis of juvenile myoclonic epilepsy." p(HGNC:CACNA1E) -- p(HGNC:EFHC1) p(HGNC:CACNA1E) -- path(MESHD:"Myoclonic Epilepsy, Juvenile") UNSET Subgraph ################################################## SET Citation = {"PubMed", "Proc Natl Acad Sci U S A. 2015 Nov 3;112(44):13705-10. doi: 10.1073/pnas.1511740112. Epub 2015 Oct 19.", "26483470"} SET Evidence = "These channels are low voltage-activated calcium channels that play a key role in cellular excitability and various physiological functions. Their dysfunction has been linked to several neurological disorders, including absence epilepsy and neuropathic pain." act(p(HGNC:CACNA1G), ma(GO:"voltage-gated channel activity")) neg path(MESHD:"Epilepsy, Absence") act(p(HGNC:CACNA1G), ma(GO:"voltage-gated channel activity")) neg path(DO:neuropathy) act(p(HGNC:CACNA1H), ma(GO:"voltage-gated channel activity")) neg path(MESHD:"Epilepsy, Absence") act(p(HGNC:CACNA1H), ma(GO:"voltage-gated channel activity")) neg path(DO:neuropathy) #################################################### SET Citation = {"PubMed", "Channels (Austin). 2013 Mar-Apr;7(2):119-25. doi: 10.4161/chan.23895. Epub 2013 Mar 1.", "23511121"} SET Evidence = "In a recent study, we demonstrated that the Cacnb4 (beta4) isoform is at the center of a new signaling pathway that connects neuronal excitability and gene transcription." p(HGNC:CACNB4) -- bp(GOBP:"regulation of membrane potential") p(HGNC:CACNB4) -- bp(GOBP:"regulation of gene expression") ############################################# SET Citation = {"PubMed", "EMBO J. 2012 Sep 12;31(18):3730-44. doi: 10.1038/emboj.2012.226. Epub 2012 Aug 14.", "22892567"} SET Evidence = "Calcium current through voltage-gated calcium channels (VGCC) controls gene expression" SET Subgraph = "Calcium dependent subgraph" a(CHEBI:"calcium(2+)") -> bp(GOBP:"regulation of gene expression") SET Evidence = " In humans, a mutation of CACNB4 , leading to a 38 amino acid truncation of b 4 C-terminus, has been associated to juvenile myoclonic epilepsy" g(HGNC:CACNB4, var("?")) pos path(MESHD:"Myoclonic Epilepsy, Juvenile") UNSET Subgraph SET Evidence = "We show that in-vitro TR a acts as a transcription factor capable to interact with b4 and repress TH gene expression" SET Subgraph = {"thyroid hormone signaling subgraph", "hormone signaling subgraph", "Calcium dependent subgraph"} p(HGNC:TRA) -- p(HGNC:CACNB4) p(HGNC:TRA) -| a(CHEBI:"thyroid hormone") p(HGNC:CACNB4) -| a(CHEBI:"thyroid hormone") SET Evidence = "The human R482X CACNB4 mutation, responsible for a form of juvenile myoclonic epilepsy, prevents association with Ppp2r5 and nuclear targeting of the complex by altering Cacnb4 conformation. These findings demonstrate that an intact VGCC subunit acts as a repressor recruiting platform to control neuronal gene expression" # mutated form of this gene, could not find a snp p(HGNC:CACNB4) -| p(HGNC:PPP2R5A) UNSET Subgraph #################################################### SET Citation = {"PubMed", "Mol Membr Biol. 2008 May;25(4):353-62. doi: 10.1080/09687680801986480.", "18446621"} SET Evidence = "AMPA receptors (AMPAR) mediate the majority of fast excitatory neurotransmission in the central nervous system" p(HGNC:CACNG2) -> bp(GOBP:"positive regulation of synaptic transmission") SET Evidence = "he trafficking of AMPARs to regulate the number of receptors at the synapse plays a key role in various forms of synaptic plasticity, including long-term potentiation (LTP) and long-term depression (LTD)." SET Subgraph = "Long term synaptic potentiation" p(HGNC:CACNG2) -> bp(GOBP:"regulation of neuronal synaptic plasticity") p(HGNC:CACNG2) -> bp(PTS:"Long_Term Potentiation") UNSET Subgraph SET Subgraph = "Long term synaptic depression" p(HGNC:CACNG2) -> bp(PTS:"long term depression") UNSET Subgraph SET Evidence = "Expression of the prototypical TARP, stargazin/TARPgamma2, is ablated in the stargazer mutant mouse, an animal model of absence epilepsy and cerebellar ataxia" p(HGNC:CACNG2) -- path(MESHD:"Epilepsy, Absence") ################################################# SET Citation = {"PubMed", "Prog Mol Biol Transl Sci. 2009;89:31-95. doi: 10.1016/S1877-1173(09)89003-0. Epub 2009 Oct 7.", "20374733"} SET Evidence = ". The activated CASR modulates intracellular signaling pathways altering PTH secretion and renal cation and water handling" SET Subgraph = "Calcium dependent subgraph" p(HGNC:CASR) -- bp(PTS:"Calcium signaling pathway") p(HGNC:CASR) -- p(HGNC:PTH) p(HGNC:CASR) -- bp(GOBP:"parathyroid hormone secretion") SET Evidence = "Inherited abnormalities of the CASR gene give rise to a variety of disorders of mineral ion homeostasis." p(HGNC:CASR) -> bp(GOBP:"ion homeostasis") SET Evidence = "Heterozygous activating mutations of the CASR cause autosomal dominant hypocalcemia (ADH) that may be asymptomatic or present with seizures" g(HGNC:CASR, var("?")) pos path(MESHD:Seizures) UNSET Subgraph ############################################# SET Citation = {"PubMed", "Cell Physiol Biochem. 2010;26(3):363-74. doi: 10.1159/000320560. Epub 2010 Aug 24.", "20798521"} SET Evidence = "Mutation(s) identified in chronic pancreatitis and idiopathic epilepsy syndrome therefore increase plasma membrane targeting of CaSR, likely contributing to the altered Ca(2+) signaling characteristic of these diseases." SET Subgraph = "Calcium dependent subgraph" g(HGNC:CASR, var("?")) -- path(MESHD:Epilepsy) g(HGNC:CASR, var("?")) -- path(MESHD:"Pancreatitis, Chronic") p(HGNC:CASR) reg act(a(CHEBI:"calcium(2+)"), ma(tport)) UNSET Subgraph ############################################# SET Citation = {"PubMed", "Pharmacology. 2015;95(1-2):10-21. doi: 10.1159/000369627. Epub 2015 Jan 8.", "25572699"} SET Evidence = "Our results suggest that CaSR promotes cardiac apoptosis and fibrosis in TRM rat through the induction of mitochondrial and MAPK pathways as well as the activation of TGF-beta-1 and CTGF." SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph"} SET Species = "10116" p(HGNC:CASR) -> bp(GOBP:"cardiac muscle cell apoptotic process") p(HGNC:CASR) -> path(MESHD:Fibrosis) p(HGNC:CASR) -> bp(PTS:"mitogen activated protein kinase signaling pathway") UNSET {Subgraph, Species} ############################################ SET Citation = {"PubMed", "Cerebrovasc Dis. 2014;38(6):433-40. doi: 10.1159/000369200. Epub 2014 Dec 3.", "25472749"} SET Evidence = "Familial cerebral cavernous malformation type 1 (CCM1) is an autosomal dominant disease caused by mutations in the Krev Interaction Trapped 1 (KRIT1/CCM1) gene, and characterized by multiple brain lesions that often result in intracerebral hemorrhage (ICH), seizures, and neurological deficits" SET Subgraph = "Innate immune system subgraph" g(HGNC:KRIT1, var("?")) pos path(MESHD:Seizures) g(HGNC:KRIT1, var("?")) pos path(MESHD:Epilepsy) SET Evidence = "Evidence is emerging that inflammation and immune response play a role in the pathogenesis of CCM." p(HGNC:KRIT1) -> bp(PTS:"Immune response") bp(PTS:"Immune response") -- path(MESHD:Epilepsy) UNSET Subgraph ############################################### SET Citation = {"PubMed", "Am J Hum Genet. 2003 Dec;73(6):1459-64. Epub 2003 Nov 17.", "14624391"} SET Evidence = "MGC4607, similar to the KRIT1 binding partner ICAP1alpha, encodes a protein with a phosphotyrosine-binding domain. This protein may be part of the complex pathway of integrin signaling that, when perturbed, causes abnormal vascular morphogenesis in the brain, leading to CCM formation." SET Subgraph = "Innate immune system subgraph" p(HGNC:CCM2) -- p(HGNC:KRIT1) p(HGNC:CCM2) -> bp(PTS:"integrin mediated signaling pathway") SET MeSHAnatomy = "Cerebellum" SET MeSHAnatomy = "Caveolae" bp(PTS:"integrin mediated signaling pathway") -- path(MESHD:"Nervous System Malformations") p(HGNC:CCM2) -- path(MESHD:"Nervous System Malformations") UNSET MeSHAnatomy UNSET Subgraph ################################################## SET Citation = {"PubMed", "Hum Mol Genet. 2005 Sep 1;14(17):2521-31.Epub 2005 Jul 21.", "16037064"} SET Evidence = "Familial CCM is caused by mutations in KRIT1 (CCM1) or in malcavernin (CCM2)" SET Confidence = "High" SET Subgraph = "Innate immune system subgraph" g(HGNC:CCM2, var("?")) pos path(MESHD:Seizures) SET MeSHAnatomy = "Cerebellum" SET MeSHAnatomy = "Caveolae" g(HGNC:KRIT1, var("?")) pos path(MESHD:"Nervous System Malformations") UNSET MeSHAnatomy UNSET Subgraph SET Evidence = "Furthermore, we expand upon the established involvement of CCM2 in the p38 mitogen-activated protein kinase signaling module by demonstrating that CCM1 associates with CCM2 and MEKK3 in a ternary complex." SET Subgraph = {"Innate immune system subgraph", "MAPK-ERK subgraph", "protein kinase signaling subgraph"} p(HGNC:KRIT1) -- p(HGNC:CCM2) p(HGNC:KRIT1) -- p(HGNC:MAP3K2) p(HGNC:KRIT1) -> bp(PTS:"mitogen activated protein kinase signaling pathway") p(HGNC:CCM2) -> bp(PTS:"mitogen activated protein kinase signaling pathway") p(HGNC:MAP3K2) -> bp(PTS:"mitogen activated protein kinase signaling pathway") UNSET Subgraph ############################################### SET Citation = {"PubMed", "J Neuropathol Exp Neurol. 2006Jan;65(1):55-66.", "16410749"} SET Evidence = "Cyclin-dependent kinase 5 (cdk5), known to be crucial in development of the normal cerebral cortex, has now been shown as pivotal in several cell death paradigms, including apoptosis and necrosis." SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph", "Apoptosis signaling subgraph", "Reelin signaling subgraph"} p(HGNC:CDK5) -> bp(GOBP:"cerebral cortex development") p(HGNC:CDK5) -- bp(GOBP:"apoptotic process") p(HGNC:CDK5) -- bp(PTS:"necrosis pathway") UNSET Subgraph SET Evidence = "Deregulation of cdk5 by p25 causes hyperphosphorylation of tau" p(HGNC:DCTN5) -> p(HGNC:CDK5) kin(p(HGNC:CDK5)) -> p(HGNC:MAPT, pmod(P)) SET Evidence = "Because apoptosis, necrosis, and excitotoxicity are all thought to contribute to neuronal loss in HS, we hypothesized that abnormalities of the cdk5 pathway would accompany this disorder" SET Confidence = "High" SET Subgraph = "Apoptosis signaling subgraph" bp(GOBP:"apoptotic process") -> path(MESHD:Epilepsy) bp(PTS:"necrosis pathway") -> path(MESHD:Epilepsy) UNSET Subgraph ################################################## SET Citation = {"PubMed", "Acta Neuropathol. 2002 Oct;104(4):403-8. Epub2002 Jun 19.", "12200628"} SET Evidence = "Gangliogliomas represent highly differentiated glioneuronal tumors frequently occurring in young patients with focal epilepsies" path(MESHD:Ganglioglioma) -- path(DO:"focal epilepsy") SET Evidence = "Here, we have analyzed two major components of the Reelin signaling pathway associated with neuronal migration and cortical cytoarchitecture in gangliogliomas, i.e., cyclin-dependent kinase 5 (CDK5) and doublecortin (DCX). " SET Subgraph = "Reelin signaling subgraph" bp(PTS:"Reelin signaling pathway") -> bp(GOBP:"neuron migration") bp(PTS:"Reelin signaling pathway") -> path(MESHD:Ganglioglioma) p(HGNC:CDK5) -> bp(PTS:"Reelin signaling pathway") p(HGNC:DCX) -> bp(PTS:"Reelin signaling pathway") UNSET Subgraph ################################################## SET Citation = {"PubMed", "Mol Neurobiol. 2006 Jun;33(3):215-36.", "16954597"} SET Evidence = "By selective cleavage of synaptically localized molecules, calpains may play pivotal roles in the regulation of synaptic processes" SET Subgraph = "Calcium dependent subgraph" p(HGNC:CAPN1) -> bp(GOBP:"regulation of synaptic activity") SET Evidence = "Activation of calpains during sustained synaptic activity is crucial for Ca2+-dependent neuronal functions, such as neurotransmitter release, synaptic plasticity, vesicular trafficking, and structural stabilization" SET Subgraph = "Calcium dependent subgraph" p(HGNC:CAPN1) -- bp(PTS:"Calcium signaling pathway") p(HGNC:CAPN1) -> bp(GOBP:"neurotransmitter secretion") p(HGNC:CAPN1) -> bp(GOBP:"regulation of neuronal synaptic plasticity") p(HGNC:CAPN1) -> bp(GOBP:"synaptic vesicle transport") SET Evidence = "Overactivation of calpain following dysregulation of Ca2+ homeostasis can lead to neuronal damage in response to events such as epilepsy, stroke, and brain trauma" SET Subgraph = "Calcium dependent subgraph" p(HGNC:CAPN1) -| bp(GOBP:"calcium ion homeostasis") bp(GOBP:"calcium ion homeostasis") -> bp(PTS:"Calcium signaling pathway") bp(GOBP:"calcium ion homeostasis") -- path(MESHD:Epilepsy) bp(GOBP:"calcium ion homeostasis") -- path(MESHD:Stroke) act(p(HGNC:CAPN1)) pos path(MESHD:Epilepsy) act(p(HGNC:CAPN1)) pos path(MESHD:Stroke) UNSET Subgraph ############################################### SET Citation = {"PubMed", "J Neurosci. 2010 Sep 22;30(38):12777-86. doi:10.1523/JNEUROSCI.1102-10.2010.", "20861382"} SET Evidence = "Mutations in cyclin-dependent kinase-like 5 (CDKL5), also known as serine/threonine kinase 9 (STK9), have been identified in patients with Rett syndrome (RTT) and X-linked infantile spasm" SET Subgraph = {"mTOR signaling subgraph","brain_derived neurotrophic factor signaling subgraph","Metabolism"} g(HGNC:CDKL5, var("?")) pos path(MESHD:"Rett Syndrome") g(HGNC:CDKL5, var("?")) pos path(MESHD:"Spasms, Infantile") SET Evidence = "Here, we report that CDKL5 is a critical regulator of neuronal morphogenesis" p(HGNC:CDKL5) reg bp(GOBP:"neuron development") SET Evidence = "Downregulating CDKL5 by RNA interference (RNAi) in cultured cortical neurons inhibited neurite growth and dendritic arborization" #: Add cell culture annotation SET Subgraph = {"mTOR signaling subgraph","brain_derived neurotrophic factor signaling subgraph","Metabolism"} p(HGNC:CDKL5) -> bp(GOBP:"dendrite development") SET Evidence = "Moreover, CDKL5 was required for brain-derived neurotrophic factor (BDNF)-induced activation of Rac1." SET Subgraph = {"mTOR signaling subgraph","brain_derived neurotrophic factor signaling subgraph","Metabolism"} p(HGNC:CDKL5) -- p(HGNC:BDNF) p(HGNC:CDKL5) -- bp(PTS:"brain_derived neurotrophic factor signaling pathway") p(HGNC:CDKL5) -> p(HGNC:RAC1) p(HGNC:BDNF) -> p(HGNC:RAC1) p(HGNC:CDKL5) -- bp(PTS:"RAC1 signaling pathway") ##################################### SET Citation = {"PubMed", "Neurobiol Dis. 2014 Oct;70:53-68. doi:10.1016/j.nbd.2014.06.006. Epub 2014 Jun 18.", "24952363"} SET Evidence = "Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene have been identified in a neurodevelopmental disorder characterized by early-onset intractable seizures, severe developmental delay, intellectual disability" SET Subgraph = {"mTOR signaling subgraph","brain_derived neurotrophic factor signaling subgraph","Metabolism"} g(HGNC:CDKL5, var("?")) pos path(MESHD:Seizures) g(HGNC:CDKL5, var("?")) pos path(DO:"intellectual disability") SET Evidence = "Looking at the mechanisms whereby CDKL5 exerts its functions, we identified a central role of the AKT/GSK-3-beta signaling pathway" SET Subgraph = {"mTOR signaling subgraph","brain_derived neurotrophic factor signaling subgraph","Metabolism"} p(HGNC:CDKL5) reg bp(PTS:"Akt/GSK3 pathway") bp(PTS:"Akt/GSK3 pathway") -- path(MESHD:Epilepsy) SET Evidence = "Overall our findings highlight a critical role of CDKL5 in the fundamental processes of brain development, namely neuronal precursor proliferation, survival and maturation." SET Subgraph = {"mTOR signaling subgraph","brain_derived neurotrophic factor signaling subgraph","Metabolism"} p(HGNC:CDKL5) -> bp(GOBP:"brain development") p(HGNC:CDKL5) -> bp(GOBP:"rostral hindbrain neuronal precursor cell proliferation") UNSET Subgraph ###################################### SET Citation = {"PubMed", "Neurobiol Dis. 2010 Jun;38(3):414-24. doi:10.1016/j.nbd.2010.02.014. Epub 2010 Mar 6.", "20211261"} SET Evidence = "In contrast, Cdkl5 was induced by siRNA-mediated knockdown of Mecp2 and by DNA-methyltransferase inhibitors, demonstrating its regulation by MeCP2 and by DNA methylation" SET Subgraph = {"mTOR signaling subgraph","brain_derived neurotrophic factor signaling subgraph","Metabolism"} p(HGNC:MECP2) -> p(HGNC:CDKL5) bp(GOBP:"DNA methylation") -> p(HGNC:CDKL5) UNSET Subgraph ###################################### SET Citation = {"PubMed", "Proc Natl Acad Sci U S A. 2012 Dec26;109(52):21516-21. doi: 10.1073/pnas.1216988110. Epub 2012 Dec 10.", "23236174"} SET Evidence = "Moreover, kinome profiling uncovers disruption of multiple signal transduction pathways, including the AKT-mammalian target of rapamycin (mTOR) cascade, upon Cdkl5 loss-of-function" SET Subgraph = {"mTOR signaling subgraph","brain_derived neurotrophic factor signaling subgraph","Metabolism"} p(HGNC:CDKL5) -> bp(PTS:"mTOR signaling pathway") UNSET Subgraph ########################################## SET Citation = {"PubMed", "Ann Surg. 2008 Jun;247(6):1036-40. doi:10.1097/SLA.0b013e3181758d0e.", "18520232"} SET Evidence = "VPA activates Notch1 signaling in MTC cells and inhibits their growth by inducing apoptosis" SET Subgraph = "Notch signaling subgraph" a(CHEBI:valproate) -> bp(PTS:"Notch signaling pathway") a(CHEBI:valproate) -> p(HGNC:NOTCH1) p(HGNC:NOTCH1) -> bp(PTS:"Notch signaling pathway") bp(PTS:"Notch signaling pathway") -| bp(GOBP:"cell growth") bp(PTS:"Notch signaling pathway") -> bp(GOBP:"apoptotic process") a(CHEBI:valproate) -| bp(GOBP:"cell growth") UNSET Subgraph ###################################### SET Citation = {"PubMed", "Biochem Pharmacol. 2007 Oct 15;74(8):1308-14.Epub 2007 Jun 23.", "17662253"} SET Evidence = "The role of neuronal acetylcholine receptors (nAChRs) in epilepsy has been clearly established by the finding of mutations in a subset of genes coding for subunits of the nAChRs in a form of sleep-related epilepsy" SET Subgraph = {"GABA subgraph","Neurotransmitter release subgraph"} g(HGNC:CHRNA2, var("?")) pos path(MESHD:Epilepsy) g(HGNC:CHRNB2, var("?")) pos path(MESHD:Epilepsy) ########################################## SET Citation = {"PubMed", "Neuroscience. 2010 Apr 28;167(1):154-62. doi:10.1016/j.neuroscience.2010.01.042. Epub 2010 Jan 29.", "20116415"} SET Evidence = "Initially, it was hypothesized that mutations in ClC-2 may be associated with epilepsy due to a direct role for ClC-2 in the modification of hippocampal neuronal excitability" SET Subgraph = "Calcium dependent subgraph" g(HGNC:CLCN2, var("?")) pos path(MESHD:Epilepsy) SET Evidence = "A recent study of older ClC-2 KO mice (>6 months) revealed abnormalities in the myelin of central axons and a subtle defect in the neuronal function in the central auditory pathway" SET Species = "10090" SET Subgraph = "Calcium dependent subgraph" p(HGNC:CLCN2) -- bp(GOBP:"regulation of myelination") UNSET Species UNSET Subgraph ########################################## SET Citation = {"PubMed", "J Cell Physiol. 2008 Jan;214(1):273-80.", "17620322"} SET Evidence = "In particular, ClC-2 has been implicated in the regulation of neuronal chloride ion homeostasis and mutations in ClC-2 are associated with idiopathic generalized epilepsy." SET Subgraph = "Calcium dependent subgraph" p(HGNC:CLCN2) -> bp(GOBP:"chloride ion homeostasis") p(HGNC:CLCN2) -> bp(PTS:"Calcium signaling pathway") SET Evidence = "The functional expression of ClC-2 at the cell surface has been shown to be enhanced by depletion of cellular ATP, implicating its possible role in cellular energy sensing" SET Subgraph = "Calcium dependent subgraph" a(CHEBI:ATP) negativeCorrelation p(HGNC:CLCN2) SET Evidence = "biochemical assays of cell surface expression suggest that this gain of function reflects, in part, an increase in channel number due to the reduction in ClC-2 internalization by endocytosis." SET Subgraph = "Calcium dependent subgraph" p(HGNC:CLCN2) -> bp(PTS:Endocytosis) UNSET Subgraph ############################################ SET Citation = {"PubMed", "Ned Tijdschr Geneeskd. 2005 Feb5;149(6):300-3.", "15730038"} SET Evidence = "Most NCL cases are caused by mutations in the CLN1, CLN2 and CLN3 genes, which play an essential role in lysosomal protein degradation" SET Subgraph = "Innate immune system subgraph" g(HGNC:PPT1, var("?")) pos path(MESHD:"Neuronal Ceroid-Lipofuscinoses") g(HGNC:TPP1, var("?")) pos path(MESHD:"Neuronal Ceroid-Lipofuscinoses") UNSET Subgraph SET Subgraph = "Apoptosis signaling subgraph" g(HGNC:CLN3, var("?")) pos path(MESHD:"Neuronal Ceroid-Lipofuscinoses") path(MESHD:"Neuronal Ceroid-Lipofuscinoses") pos path(MESHD:Seizures) UNSET Subgraph SET Subgraph = {"Protein Metabolism", "Metabolism"} g(HGNC:PPT1, var("?")) pos bp(PTS:"protein degradation pathway") g(HGNC:TPP1, var("?")) pos bp(PTS:"protein degradation pathway") g(HGNC:CLN3, var("?")) pos bp(PTS:"protein degradation pathway") UNSET Subgraph ############################################## SET Citation = {"PubMed", "Gene. 2013 May 1;519(2):245-50. doi:10.1016/j.gene.2013.02.022. Epub 2013 Feb 28.", "23458879"} SET Evidence = "Although apoptotic cell death is one of the pathological hallmarks of Batten disease" SET Subgraph = "Apoptosis signaling subgraph" bp(GOBP:"apoptotic process") -- path(MESHD:"Neuronal Ceroid-Lipofuscinoses") SET Evidence = "Since the CLN3 gene is suggested to be involved in the cell cycle in" SET Subgraph = "Apoptosis signaling subgraph" p(HGNC:CLN3) -- bp(PTS:"Cell cycle") bp(PTS:"Cell cycle") -- bp(GOBP:"apoptotic process") UNSET Subgraph ################################################# SET Citation = {"PubMed", "Yi Chuan. 2009 Aug;31(8):779-84.", "19689937"} SET Evidence = "The pathogenesis, summarized in this review, include apoptosis, autophagy, dysfunction in the structure associated with plasmalemma, oxidative stress and disruption of nitric oxide signaling, dysfunction of the mitochondrial and lysosome, unbalanced intracellular pH, and other relative mechanisms" #: No reference to the pathology, check the article if it exists SET Subgraph = "Apoptosis signaling subgraph" bp(GOBP:"apoptotic process") -> path(MESHD:"Neuronal Ceroid-Lipofuscinoses") bp(GOBP:autophagy) -> path(MESHD:"Neuronal Ceroid-Lipofuscinoses") bp(GOBP:"response to oxidative stress") -> path(MESHD:"Neuronal Ceroid-Lipofuscinoses") SET Evidence = "In apoptosis, the defects in CLN3 result in ceramide accumulation and upstream of mitochondrial membrane per-meabilization, which eventually induce caspase-dependent and caspase-independent cell death." SET Subgraph = "Apoptosis signaling subgraph" g(HGNC:CLN3, var("?")) -> bp(GOBP:"apoptotic process") g(HGNC:CLN3, var("?")) -> a(CHEBI:ceramide) a(CHEBI:ceramide) -> bp(GOBP:"cell death") UNSET Subgraph ############################################# SET Citation = {"PubMed", "Dis Model Mech. 2013 Mar;6(2):342-57. doi:10.1242/dmm.010140. Epub 2012 Oct 12.", "23065637"} SET Evidence = "Both CLN1 and CLN5 deficiencies lead to severe neurodegenerative diseases of childhood, known as neuronal ceroid lipofuscinoses (NCLs)" # CLN1 is PPT1 SET Subgraph = "Innate immune system subgraph" g(HGNC:CLN5, var("?")) pos path(MESHD:"Neuronal Ceroid-Lipofuscinoses") g(HGNC:PPT1, var("?")) pos path(MESHD:"Neuronal Ceroid-Lipofuscinoses") SET Evidence = "Finally, gene expression profiling of Cln1/5 dko cortex revealed defects in myelination and immune response pathways" SET Subgraph = "Innate immune system subgraph" p(HGNC:CLN5) -| bp(PTS:"Immune response") p(HGNC:CLN5) -| bp(GOBP:myelination) UNSET Subgraph ############################################# SET Citation = {"PubMed", "PLoS One. 2013;8(3):e58644. doi:10.1371/journal.pone.0058644. Epub 2013 Mar 14.", "23516525"} SET Evidence = "Mutations in the CLN6 gene cause a variant late infantile form of neuronal ceroid lipofuscinosis " SET Subgraph = {"protein kinase signaling subgraph","MAPK-ERK subgraph"} g(HGNC:CLN6, var("?")) pos path(MESHD:"Neuronal Ceroid-Lipofuscinoses") SET Evidence = "Analyses revealed increased zinc and manganese concentrations" a(CHEBI:"zinc ion") -- path(MESHD:"Neuronal Ceroid-Lipofuscinoses") a(CHEBI:"manganese atom") -- path(MESHD:"Neuronal Ceroid-Lipofuscinoses") SET Evidence = "Synaptic proteins, the metal-binding protein metallothionein, and the Akt/GSK3 and ERK/MAPK cellular signaling pathways were also altered" SET Subgraph = "mTOR signaling subgraph" bp(PTS:"Akt/GSK3 pathway") -- path(MESHD:"Neuronal Ceroid-Lipofuscinoses") UNSET Subgraph bp(PTS:"mitogen activated protein kinase signaling pathway") -- path(MESHD:"Neuronal Ceroid-Lipofuscinoses") p(HGNC:MT1A) -- path(MESHD:"Neuronal Ceroid-Lipofuscinoses") SET Evidence = "These results demonstrate that altered metal concentrations, synaptic protein changes, and aberrant modulation of cellular signaling pathways are characteristic features in the CLN6 ovine form of NCL." SET Species = "9940" SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph"} p(HGNC:CLN6) -- bp(PTS:"Akt/GSK3 pathway") p(HGNC:CLN6) -- bp(PTS:"mitogen activated protein kinase signaling pathway") UNSET Subgraph ############################################ SET Citation = {"PubMed", "Neurosci Lett. 2011 Jan 25;488(3):258-62.doi: 10.1016/j.neulet.2010.11.041. Epub 2010 Nov 19.", "21094208"} SET Evidence = "Neuronal ceroid lipofuscinoses (NCLs) are a group of inherited neurodegenerative disorders characterized by epilepsy" path(MESHD:"Neuronal Ceroid-Lipofuscinoses") -- path(MESHD:Epilepsy) SET Evidence = "Late-infantile onset forms (LINCL) include those linked to mutations in CLN8 gene" SET Subgraph = "Apoptosis signaling subgraph" g(HGNC:CLN8, var("?")) pos path(MESHD:"Neuronal Ceroid-Lipofuscinoses") ###################################### SET Citation = {"PubMed", "Epilepsy Res. 2012 Mar;99(1-2):64-8. doi:10.1016/j.eplepsyres.2011.10.020. Epub 2011 Nov 10.", "22079489"} SET Evidence = "It has been known for centuries that exogenous cannabinoids, such as tetrahydrocannabinol have anticonvulsant activity." SET Subgraph = "G-protein-mediated signaling" a(CHEBI:"Delta(9)-tetrahydrocannabinol") isA a(CHEBI:anticonvulsant) a(CHEBI:"Delta(9)-tetrahydrocannabinol") -| path(MESHD:Seizures) SET Evidence = "The endogenous cannabinoid system is rapidly activated after seizure activity" path(MESHD:Seizures) -> bp(PTS:"Retrograde endocannabinoid signaling") UNSET Subgraph ##################################### SET Citation = {"PubMed", "Mol Syndromol. 2015 Feb;6(1):7-22. doi:10.1159/000371594. Epub 2015 Feb 3.", "25852443"} SET Evidence = "the contactin-associated protein-like 2 gene (CNTNAP2) has been implicated in neurodevelopmental disorders such as Gilles de la Tourette syndrome, intellectual disability, obsessive compulsive disorder, cortical dysplasia-focal epilepsy syndrome, autism, schizophrenia, Pitt-Hopkins syndrome, and attention deficit hyperactivity disorder" g(HGNC:CNTNAP2, var("?")) pos path(DO:"intellectual disability") g(HGNC:CNTNAP2, var("?")) pos path(DO:"Gilles de la Tourette syndrome") g(HGNC:CNTNAP2, var("?")) pos path(DO:"obsessive-compulsive disorder") g(HGNC:CNTNAP2, var("?")) pos path(MESHD:Epilepsy) g(HGNC:CNTNAP2, var("?")) pos path(DO:"autism spectrum disorder") g(HGNC:CNTNAP2, var("?")) pos path(DO:schizophrenia) g(HGNC:CNTNAP2, var("?")) pos path(DO:"attention deficit hyperactivity disorder") SET Evidence = "Those include gene disruption, loss of a gene copy by a heterozygous deletion, altered regulation of gene expression due to loss of transcription factor binding and DNA methylation sites, and mutations in the amino acid sequence of the encoded protein which may provoke altered interactions of the CNTNAP2-encoded protein, Caspr2, with other proteins" g(HGNC:CNTNAP2, var("?")) pos bp(GOBP:"DNA methylation") ###################################### SET Citation = {"PubMed", "Biochem Biophys Res Commun. 2011 Feb11;405(2):180-5. doi: 10.1016/j.bbrc.2010.12.137. Epub 2011 Jan 7.","21216226"} SET Evidence = "Calsenilin, a neuronal calcium binding protein that has been shown to have multiple functions in the cell, interacts with presenilin 1 (PS1) and presenilin 2 (PS2), represses gene transcription and binds to A-type voltage-gated potassium channels" SET Subgraph = "Calcium dependent subgraph" p(HGNC:KCNIP3) -- a(CHEBI:"calcium(2+)") p(HGNC:KCNIP3) -- bp(PTS:"Calcium signaling pathway") p(HGNC:KCNIP3) -- p(HGNC:PSEN1) p(HGNC:KCNIP3) -- p(HGNC:PSEN2) p(HGNC:KCNIP3) -- p(HGNC:KCNA1) #p(HGNC:KCNIP3) -| bp(GOBP:transcription) SET Evidence = "In addition, increased levels of calsenilin are observed in the brains of Alzheimer's disease and epilepsy patients" p(HGNC:KCNIP3) pos path(MESHD:Epilepsy) p(HGNC:KCNIP3) pos path(MESHD:"Alzheimer Disease") UNSET Subgraph SET Evidence = "Here, we demonstrate that inhibition of the ubiquitin-proteasomal pathway (UPP) but not lysosomal pathway markedly increased the expression levels of calsenilin." SET Subgraph = {"Protein Metabolism", "Metabolism"} bp(PTS:"ubiquitin proteasomal pathway") -| p(HGNC:KCNIP3) bp(PTS:"lysosomal degradation pathway") causesNoChange p(HGNC:KCNIP3) SET Evidence = "that impairment in the UPP may contribute to the involvement of calsenilin in disease-associated neurodegeneration." bp(PTS:"ubiquitin proteasomal pathway") -> path(MESHD:Epilepsy) bp(PTS:"ubiquitin proteasomal pathway") -> path(MESHD:"Alzheimer Disease") UNSET Subgraph ################################### SET Citation = {"PubMed", "Neurosci Lett. 2003 Apr 3;340(1):33-6.", "12648752"} SET Evidence = "Calsenilin is a neuronal calcium binding protein that may function in calcium signaling and cell death" SET Subgraph = "Calcium dependent subgraph" p(HGNC:KCNIP3) -> bp(PTS:"Calcium signaling pathway") p(HGNC:KCNIP3) -> bp(GOBP:"cell death") UNSET Subgraph ################################ SET Citation = {"PubMed", "Biochim Biophys Acta. 2014Sep;1843(9):2089-99. doi: 10.1016/j.bbamcr.2014.05.018. Epub 2014 Jun5.", "24909779"} SET Evidence = "EPM1 is a rare progressive myoclonus epilepsy accompanied by apoptosis in the cerebellum of patients" SET Subgraph = "Apoptosis signaling subgraph" SET MeSHAnatomy = "Cerebellum" bp(GOBP:"apoptotic process") -- path(MESHD:"Myoclonic Epilepsies, Progressive") bp(GOBP:"apoptotic process") -- path(MESHD:"Myoclonic Epilepsies, Progressive") UNSET MeSHAnatomy SET Evidence = "Mutations in the gene of stefin B (cystatin B) are responsible for the primary defect underlying EPM1" g(HGNC:CSTB, var("?")) pos path(MESHD:"Myoclonic Epilepsies, Progressive") SET Evidence = "the EPM1 mutants produce lower expression of the stefin B protein, whose most well-known function is inhibition of the cysteine proteases‚ cathepsins B, H, K, L and S " SET Subgraph = "Apoptosis signaling subgraph" path(MESHD:"Myoclonic Epilepsies, Progressive") -| p(HGNC:CSTB) p(HGNC:CSTB, var("?")) -| p(HGNC:CTSB) p(HGNC:CSTB, var("?")) -| p(HGNC:CTSH) p(HGNC:CSTB, var("?")) -| p(HGNC:CTSK) p(HGNC:CSTB, var("?")) -| p(HGNC:CTSL) p(HGNC:CSTB, var("?")) -| p(HGNC:CTSS) SET Evidence = "Although the protective role of stefin B against apoptosis was suggested" SET Subgraph = "Apoptosis signaling subgraph" p(HGNC:CSTB) -| bp(GOBP:"apoptotic process") p(HGNC:CSTB) -| bp(GOBP:"apoptotic process") SET Evidence = "however, a consensus was reached in the last years that excess ROS generation appears in most neurodegenerative diseases before cell death" SET Subgraph = "Apoptosis signaling subgraph" a(CHEBI:"reactive oxygen species") -> bp(GOBP:"response to oxidative stress") bp(GOBP:"response to oxidative stress") -> bp(GOBP:"cell death") a(CHEBI:"reactive oxygen species") -> bp(GOBP:"cell death") SET Evidence = "Furthermore, sensitivity to oxidative stress has been connected to stefin B deficiency in" SET Subgraph = "Apoptosis signaling subgraph" p(HGNC:CSTB) -| bp(GOBP:"response to oxidative stress") UNSET Subgraph ################################ SET Citation = {"PubMed", "Epilepsia. 2005;46 Suppl 5:49-51.", "15987253"} SET Evidence = "The present study demonstrates that tryptophan metabolism along 5-HT and KYN pathways are disrupted in EPM1" SET Confidence = "High" SET Subgraph = {"Protein Metabolism", "Metabolism"} bp(PTS:"Tryptophan metabolism") -- path(MESHD:"Myoclonic Epilepsies, Progressive") UNSET Subgraph ################################## SET Citation = {"PubMed", "Biol Chem. 2013 Jun;394(6):783-90. doi:10.1515/hsz-2012-0278.", "23362198"} SET Evidence = "Human stefins and cystatins are physiologically important cysteine proteinase inhibitors, acting as a first line of defense against undesirable proteolysis." SET Subgraph = {"Protein Metabolism", "Metabolism"} p(HGNC:CSTB) -| bp(PTS:"ubiquitin proteasomal pathway") p(HGNC:CTSB) -> bp(PTS:"ubiquitin proteasomal pathway") p(HGNC:CTSH) -> bp(PTS:"ubiquitin proteasomal pathway") p(HGNC:CTSK) -> bp(PTS:"ubiquitin proteasomal pathway") p(HGNC:CTSL) -> bp(PTS:"ubiquitin proteasomal pathway") p(HGNC:CTSS) -> bp(PTS:"ubiquitin proteasomal pathway") UNSET Subgraph ################################# SET Citation = {"PubMed", "PLoS One. 2014 Feb 27;9(2):e89321. doi:10.1371/journal.pone.0089321. eCollection 2014.", "24586687"} SET Evidence = "In particular, the gene expression data pinpointed alterations in GABAergic pathway. " SET Subgraph = {"GABA subgraph", "Neurotransmitter release subgraph"} p(HGNC:CSTB) -> bp(PTS:"gamma_aminobutyric acid signaling pathway") UNSET Subgraph ################################## SET Citation = {"PubMed", "Ann Indian Acad Neurol. 2014Jul;17(3):259-66. doi: 10.4103/0972-2327.138475.", "25221392"} SET Evidence = "AEDs are mostly metabolized by Cyp2C9, Cyp2C19 and Cyp3A4 and transported by ABCB1." SET Subgraph = "Metabolism" p(HGNC:CYP2C9) -> bp(PTS:"drug pathway") p(HGNC:CYP2C19) -> bp(PTS:"drug pathway") p(HGNC:CYP3A4) -> bp(PTS:"drug pathway") ################################# SET Citation = {"PubMed", "J Neurochem. 2003 Sep;86(5):1260-70.", "12911633"} SET Evidence = "Death-associated protein (DAP) kinase is calcium-regulated and known to function downstream of death receptors, prompting us to examine its role in the mechanism of seizure-induced neuronal death" SET Subgraph = {"Calcium dependent subgraph","Apoptosis signaling subgraph"} bp(PTS:"Calcium signaling pathway") -> p(HGNC:DAPK1) a(CHEBI:"calcium(2+)") -- p(HGNC:DAPK1) UNSET Subgraph SET Evidence = "hese data suggest DAP kinase is involved in the molecular pathways activated during seizure-induced neuronal death." SET Subgraph = {"Calcium dependent subgraph","Apoptosis signaling subgraph"} p(HGNC:DAPK1) -> bp(GOBP:"neuron death") p(HGNC:DAPK1) -> bp(GOBP:"apoptotic process") path(MESHD:Seizures) -> bp(GOBP:"neuron death") p(HGNC:DAPK1) -- path(MESHD:Seizures) UNSET Subgraph ################################### SET Citation = {"PubMed", "Hippocampus. 2004;14(3):326-36.", "15132432"} SET Evidence = "Since DAP kinase has been implicated in p53-mediated apoptosis, a pathway activated following epileptic brain injury, we examined the relationship between DAP kinase and p53 following seizures. " SET Subgraph = "Apoptosis signaling subgraph" p(HGNC:DAPK1) -> bp(GOBP:"apoptotic process") p(HGNC:DAPK1) -> bp(PTS:"p53 dependent apoptotic pathway") path(MESHD:"Brain Injuries") -> bp(PTS:"p53 dependent apoptotic pathway") SET Evidence = "seizures triggered a significant increase in numbers of DAP kinase-expressing cells" path(MESHD:Seizures) -> p(HGNC:DAPK1) UNSET Subgraph ################################### SET Citation = {"PubMed", "Acta Neuropathol Commun. 2014 Jul 8;2:71.doi: 10.1186/2051-5960-2-71.", "25005575"} SET Evidence = "Activation of the mTOR pathway has been linked to the cytopathology and epileptogenicity of malformations, specifically Focal Cortical Dysplasia (FCD) and Tuberous Sclerosis (TSC)." SET Confidence = "High" SET Subgraph = "mTOR signaling subgraph" bp(PTS:"mTOR signaling pathway") -> path(MESHD:Epilepsy) bp(PTS:"mTOR signaling pathway") -> path(MESHD:"Tuberous Sclerosis") SET Evidence = "Experimental and clinical trials have shown than mTOR inhibitors have anti-epileptogenic effects in" a(CHEBI:"mTOR inhibitor") -| bp(PTS:"mTOR signaling pathway") a(CHEBI:"mTOR inhibitor") isA a(CHEBI:anticonvulsant) a(CHEBI:"mTOR inhibitor") -| path(MESHD:Seizures) a(CHEBI:"mTOR inhibitor") -| path(MESHD:Epilepsy) a(CHEBI:"mTOR inhibitor") -| path(MESHD:"Tuberous Sclerosis") UNSET Subgraph ################################ SET Citation = {"PubMed", "Epilepsia. 2010 Jul;51 Suppl 3:56-60. doi:10.1111/j.1528-1167.2010.02611.x.", "20618402"} SET Evidence = "Distinct caspase pathways mediate necrosis and apoptosis in subpopulations of hippocampal neurons after status epilepticus." SET Subgraph = "Apoptosis signaling subgraph" bp(PTS:"caspase pathway") -> bp(PTS:"necrosis pathway") bp(PTS:"caspase pathway") -> bp(GOBP:"apoptotic process") bp(PTS:"caspase pathway") -> bp(GOBP:"apoptotic process") UNSET Subgraph ###################################### SET Citation = {"PubMed", "Eur J Hum Genet. 2013 Aug;21(8):844-9. doi:10.1038/ejhg.2012.257. Epub 2012 Dec 19.", "23249953"} SET Evidence = "The CDG-I subgroup is characterized by protein N-glycosylation defects originating in the endoplasmic reticulum" bp(PTS:"N_linked glycosylation") -- path(MESHD:"Congenital Disorders of Glycosylation") SET Evidence = "Patients in the few reported DPAGT1-CDG families exhibit severe intellectual disability (ID), epilepsy, microcephaly, severe hypotonia, facial dysmorphism and structural brain anomalies" path(MESHD:"Congenital Disorders of Glycosylation") -- path(MESHD:Epilepsy) path(MESHD:"Congenital Disorders of Glycosylation") -- path(MESHD:Microcephaly) ################################## SET Citation = {"PubMed", "Mol Genet Metab. 2012 Apr;105(4):634-41. doi:10.1016/j.ymgme.2012.01.001. Epub 2012 Jan 9.", "22304930"} SET Evidence = "CDG-Ij (DPAGT1-CDG) is caused by a defect of the human DPAGT1, catalyzing the first step of N-linked glycosylation" SET Confidence = "High" g(HGNC:DPAGT1, var("?")) pos path(MESHD:"Congenital Disorders of Glycosylation") p(HGNC:DPAGT1) -> bp(PTS:"N_linked glycosylation") ##################################### SET Citation = {"PubMed", "Cell Death Differ. 2010 Oct;17(10):1577-87.doi: 10.1038/cdd.2010.31. Epub 2010 Mar 26.", "20339376"} SET Evidence = "Dentatorubral-pallidoluysian Atrophy (DRPLA) is one of these disorders caused by mutations in the Atrophin-1 protein" SET Confidence = "High" SET Subgraph = "Apoptosis signaling subgraph" g(HGNC:ATN1, var("?")) pos path(DO:"dentatorubral-pallidoluysian atrophy") UNSET Subgraph ################################### SET Citation = {"PubMed", "Epilepsy Res. 2001 Aug;46(2):139-44.", "11463515"} SET Evidence = "Among them, a subtype persisting with tonic-clonic seizures has been mapped to 8q24 (ECA1" SET Confidence = "High" g(HGNC:ECA1, var("?")) pos path(DO:"childhood absence epilepsy") #################################### SET Citation = {"PubMed", "Cell Calcium. 2012 Feb;51(2):179-85. doi:10.1016/j.ceca.2011.12.011. Epub 2012 Jan 4.", "22226147"} SET Evidence = "We report here a molecular and functional interaction between the TRPM2 channel and EF-hand motif-containing protein EFHC1, whose mutation causes juvenile myoclonic epilepsy (JME) via mechanisms including neuronal apoptosis." SET Subgraph = "Apoptosis signaling subgraph" p(HGNC:TRPM2) -- p(HGNC:EFHC1) p(HGNC:EFHC1) -> bp(GOBP:"neuron death") p(HGNC:EFHC1) -> bp(GOBP:"apoptotic process") bp(GOBP:"neuron death") -> path(MESHD:"Myoclonic Epilepsy, Juvenile") bp(GOBP:"apoptotic process") -> path(MESHD:"Myoclonic Epilepsy, Juvenile") SET Evidence = "These results reveal a positive regulatory action of EFHC1 on TRPM2 activity, suggesting that TRPM2 contributes to the expression of JME phenotypes by mediating disruptive effects of JME mutations of EFHC1 on biological processes including cell death." p(HGNC:EFHC1) -> p(HGNC:TRPM2) p(HGNC:TRPM2) -> bp(GOBP:"neuron death") p(HGNC:TRPM2) -> bp(GOBP:"apoptotic process") p(HGNC:TRPM2) -> path(MESHD:"Myoclonic Epilepsy, Juvenile") UNSET Subgraph ###################################### SET Citation = {"PubMed", "Eur J Neurosci. 2005 Mar;21(6):1617-25.", "15845089"} SET Evidence = "Ca2+ influx into excitable cells is a prerequisite for neurotransmitter release and regulated exocytosis" SET Subgraph = {"Calcium dependent subgraph", "Neurotransmitter release subgraph"} a(CHEBI:"calcium(2+)") -> bp(GOBP:"regulation of calcium ion-dependent exocytosis of neurotransmitter") a(CHEBI:"calcium(2+)") -> bp(GOBP:"neurotransmitter secretion") a(CHEBI:"calcium(2+)") -> bp(GOBP:"regulation of calcium ion-dependent exocytosis") SET Evidence = "the Ca(v)2.3-containing E-type Ca2+ channels are involved in various physiological processes, such as neurotransmitter release and exocytosis" p(HGNC:EFHC1) -> bp(GOBP:"regulation of calcium ion-dependent exocytosis of neurotransmitter") p(HGNC:EFHC1) -> bp(GOBP:"regulation of calcium ion-dependent exocytosis") p(HGNC:EFHC1) -- bp(PTS:"Calcium signaling pathway") SET Evidence = "E-type channels trigger exocytosis and are also involved in long-term potentiation" p(HGNC:EFHC1) -> bp(PTS:"Long_Term Potentiation") p(HGNC:EFHC1) -> bp(GOBP:"long-term synaptic potentiation") UNSET Subgraph ##################################### SET Citation = {"PubMed", "Neurosci Lett. 2015 Jan 12;585:126-31. doi:10.1016/j.neulet.2014.11.040. Epub 2014 Nov 27.", "25434873"} SET Evidence = "Carbon monoxide (CO) is neuroprotective in various models of brain injury" SET Subgraph = "Apoptosis signaling subgraph" a(CHEBI:"carbon monoxide") isA a(CHEBI:"neuroprotective agent") a(CHEBI:"neuroprotective agent") -| path(MESHD:"Neurodegenerative Diseases") path(MESHD:Epilepsy) isA path(MESHD:"Neurodegenerative Diseases") a(CHEBI:"neuroprotective agent") -| path(MESHD:Epilepsy) a(CHEBI:"carbon monoxide") -| path(MESHD:"Neurodegenerative Diseases") a(CHEBI:"carbon monoxide") -| path(MESHD:Epilepsy) SET Evidence = "In contrast, treating FS rats with ZnPP-IX (a CO synthase inhibitor) aggravated the neuronal damage, enhanced neuronal apoptosis, downregulated GRP78 expression, increased CHOP, and decreased p-PERK and p-eIF2a expression" SET Species = "10116" a(CHEBI:"carbon monoxide") -| bp(GOBP:"neuron death") a(CHEBI:"carbon monoxide") -| bp(GOBP:"neuron death") a(CHEBI:"carbon monoxide") -> p(RGD:Hspa5) a(CHEBI:"carbon monoxide") -> p(RGD:Ddit3) SET Evidence = "These results suggest that endogenous CO limits the neuronal damage induced by recurrent FSs, through the PERK-activated ERS pathway." a(CHEBI:"carbon monoxide") -> bp(PTS:"Unfolded Protein Response") bp(PTS:"Unfolded Protein Response") -> path(MESHD:"Neurodegenerative Diseases") bp(PTS:"Unfolded Protein Response") -> path(MESHD:Epilepsy) UNSET Subgraph ######################################## SET Citation = {"PubMed", "Antioxid Redox Signal. 2014 Jun20;20(18):2907-22. doi: 10.1089/ars.2013.5455. Epub 2014 Feb 6.","24219064"} SET Evidence = "Phosphoinositide 3-kinases (PI3Ks) relay growth factor signaling and mediate cytoprotection and cell growth" SET Subgraph = "protein kinase signaling subgraph" p(HGNC:PIK3CA) -> bp(PTS:"growth factor signaling pathway") p(HGNC:PIK3CA) -> bp(GOBP:"cell growth") p(HGNC:PIK3CA) -> bp(PTS:"phosphatidylinositol 3_kinase signaling pathway") SET Evidence = "PI3Ks induce system xc(-) through glycogen synthase kinase 3 beta (GSK-3-beta) inhibition, general control non-derepressible-2-mediated eukaryotic initiation factor 2a phosphorylation, and the subsequent translational up-regulation of activating transcription factor 4." p(HGNC:PIK3CA) -| p(HGNC:GSK3B) p(HGNC:GSK3B) -- bp(GOBP:"response to oxidative stress") kin(p(HGNC:PIK3CA)) -> p(HGNC:EIF2S1, pmod(P)) p(HGNC:EIF2S1, pmod(P)) -- bp(GOBP:"response to oxidative stress") p(HGNC:EIF2S1, pmod(P)) -> p(HGNC:ATF4) p(HGNC:ATF4) -- bp(GOBP:"response to oxidative stress") SET Evidence = "This pathway is essential for PI3Ks to modulate oxidative stress resistance of nerve cells and insulin-induced growth in fibroblasts." p(HGNC:PIK3CA) -> bp(GOBP:"response to oxidative stress") bp(PTS:"phosphatidylinositol 3_kinase signaling pathway") -> bp(GOBP:"response to oxidative stress") SET Evidence = "Importantly, the induction of this pathway by neuronal activity and in epileptic hippocampi points to a potential role in epilepsy." bp(PTS:"phosphatidylinositol 3_kinase signaling pathway") -- path(MESHD:Epilepsy) UNSET Subgraph ######################################## SET Citation = {"PubMed", "Free Radic Biol Med. 2015 Nov;88(Pt A):30-41.doi: 10.1016/j.freeradbiomed.2015.01.034. Epub 2015 Feb 10.","25680286"} SET Evidence = "Thus, it has been reported that laforin and malin form a functional complex that acts as a key regulator of glycogen metabolism and that also plays a crucial role in protein homeostasis (proteostasis)" SET Subgraph = {"Energy metabolic subgraph", "Metabolism"} p(HGNC:EPM2A) -- p(HGNC:EPM2A) p(HGNC:EPM2A) -> complex(p(HGNC:EPM2A), p(HGNC:EPM2A)) p(HGNC:EPM2A) -> complex(p(HGNC:EPM2A), p(HGNC:EPM2A)) complex(p(HGNC:EPM2A), p(HGNC:EPM2A)) -> bp(PTS:"glycogen metabolic pathway") SET Evidence = "Regarding this last function, it has been shown that cells are more sensitive to ER stress and show defects in proteasome and autophagy activities in the absence of a functional laforin-malin complex" complex(p(HGNC:EPM2A), p(HGNC:EPM2A)) -> bp(GOBP:"response to endoplasmic reticulum stress") complex(p(HGNC:EPM2A), p(HGNC:EPM2A)) -> bp(PTS:"ubiquitin proteasomal pathway") complex(p(HGNC:EPM2A), p(HGNC:EPM2A)) -> bp(PTS:"autophagy pathway") UNSET Subgraph ############################################ SET Citation = {"PubMed", "Neuroscience. 1999;91(4):1315-9.", "10391438"} SET Evidence = "Some of the neurotrophic factors induced by brief seizures such as basic fibroblast growth factor and nerve growth factor have been shown to have neuroprotective action; against apoptotic hippocampal cell death " p(HGNC:FGF2) isA a(CHEBI:"neuroprotective agent") p(HGNC:NGF) isA a(CHEBI:"neuroprotective agent") p(HGNC:FGF2) -| path(MESHD:"Neurodegenerative Diseases") p(HGNC:NGF) -| path(MESHD:"Neurodegenerative Diseases") p(HGNC:FGF2) -| bp(GOBP:"neuron death") p(HGNC:FGF2) -| bp(GOBP:"apoptotic process") p(HGNC:NGF) -| bp(GOBP:"neuron death") p(HGNC:NGF) -| bp(GOBP:"apoptotic process") ############################################# SET Citation = {"PubMed", "Neurochem Res. 2004 Nov;29(11):2037-42.", "15662837"} SET Evidence = "In the CNS, extracellular ATP can function as an excitatory neurotransmitter as well as a trophic factor" SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph"} a(CHEBI:ATP) isA a(CHEBI:neurotransmitter) SET Evidence = "Cellular proliferation, differentiation and survival are regulated by signaling cascades composed of protein kinases, including extracellular signal regulated protein kinase (ERK) and protein kinase B (also called Akt)" bp(PTS:"mitogen activated protein kinase signaling pathway") -> bp(GOBP:"cell proliferation") bp(PTS:"mitogen activated protein kinase signaling pathway") -> bp(GOBP:"cell differentiation") UNSET Subgraph SET Subgraph = "mTOR signaling subgraph" bp(PTS:"Akt/GSK3 pathway") -> bp(GOBP:"cell proliferation") bp(PTS:"Akt/GSK3 pathway") -> bp(GOBP:"cell differentiation") UNSET Subgraph SET Evidence = "the role of protein kinase cascades in mediating the trophic actions of extracellular ATP, alone or together with FGF2. " SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph"} bp(PTS:"mitogen activated protein kinase signaling pathway") -- a(CHEBI:ATP) bp(PTS:"mitogen activated protein kinase signaling pathway") -- p(HGNC:FGF2) UNSET Subgraph SET Subgraph = "mTOR signaling subgraph" bp(PTS:"Akt/GSK3 pathway") -- a(CHEBI:ATP) bp(PTS:"Akt/GSK3 pathway") -- p(HGNC:FGF2) SET Evidence = "extracellular ATP and FGF2 contribute to the hyperplastic and hypertrophic response of astrocytes to CNS injuries," SET MeSHAnatomy = "Central Nervous System" SET MeSHAnatomy = "Astrocytes" bp(GOBP:"response to axon injury") -> bp(MESHPP:"Cell Plasticity") bp(GOBP:"response to axon injury") -> bp(MESHPP:"Tropism") a(CHEBI:ATP) -> bp(MESHPP:"Cell Plasticity") a(CHEBI:ATP) -> bp(MESHPP:"Tropism") p(HGNC:FGF2) -> bp(MESHPP:"Cell Plasticity") p(HGNC:FGF2) -> bp(MESHPP:"Tropism") SET Evidence = "neurological conditions that involve gliosis and the generation of reactive astrocytes, such as trauma, stroke, seizure and neurodegenerativeand demyelinating disorders." SET MeSHAnatomy = "Astrocytes" bp(MESHPP:"Cell Plasticity") -> path(MESHD:Seizures) bp(MESHPP:"Tropism") -> path(MESHD:Seizures) bp(MESHPP:"Cell Plasticity") -> path(MESHD:Stroke) bp(MESHPP:"Tropism") -> path(MESHD:Stroke) UNSET MeSHAnatomy UNSET Subgraph ######################################### SET Citation = {"PubMed", "Neurobiol Dis. 2013 Nov;59:1-17. doi:10.1016/j.nbd.2013.06.013. Epub 2013 Jul 2.", "23831253"} SET Evidence = "Outside of Fragile X syndrome (FXS), the role of Fragile-X Mental Retardation Protein (FMRP) in mediating neuropsychological abnormalities is not clear. FMRP, p70-S6 kinase (S6K) and protein phosphatase 2A (PP2A) are thought to cooperate as a dynamic signaling complex. " SET Subgraph = "Long term synaptic depression" complex(p(HGNC:FMR1), p(HGNC:RPS6KA3), p(HGNC:PPP2R1A)) SET Evidence = "adult rats have enhanced CA1 hippocampal long-term depression (LTD) following an early life seizure (ELS)" SET Species = "10116" SET MeSHAnatomy="CA1 Region, Hippocampal" path(MESHD:"Fragile X Syndrome") -- path(MESHD:Seizures) path(MESHD:Seizures) -- bp(PTS:"long term depression") path(MESHD:"Fragile X Syndrome") -- bp(PTS:"long term depression") UNSET MeSHAnatomy SET Evidence = "Total FMRP expression is uSCOMPanged but S6K is hyperphosphorylated, consistent with S6K overactivation" p(HGNC:RPS6KA3) -> path(MESHD:"Fragile X Syndrome") SET Evidence = "Consistent with this, striatal-enriched protein tyrosine phosphatase (STEP), an FMRP target which regulates mLTD expression, is specifically increased in the synaptosomal compartment following ELS" p(HGNC:FMR1) -> p(HGNC:PTPN5) p(HGNC:FMR1) -> bp(PTS:"long term depression") p(HGNC:PTPN5) -> bp(PTS:"long term depression") p(HGNC:PTPN5) -> bp(GOBP:"regulation of long term synaptic depression") UNSET Subgraph ######################################## SET Citation = {"PubMed", "Mol Cell Neurosci. 2011 Mar;46(3):563-72.doi: 10.1016/j.mcn.2010.12.005. Epub 2011 Jan 6.", "21215802"} SET Evidence = "Fragile X syndrome (FXS), the most common cause of inherited mental retardation, is caused by the loss of the mRNA binding protein, FMRP" SET Confidence = "High" SET Subgraph = {"G-protein-mediated signaling", "Long term synaptic depression"} g(HGNC:FMR1, var("?")) pos path(MESHD:"Fragile X Syndrome") SET Evidence = "Persons with FXS also display epileptic seizures, social anxiety, hyperactivity, and autistic behaviors" path(MESHD:"Fragile X Syndrome") pos path(MESHD:Epilepsy) SET Evidence = "in the absence of FMRP, enhanced signaling though G-protein coupled group I metabotropic glutamate receptors in the brain contributes to many of the abnormalities observed in the disorder." p(HGNC:FMR1) -- bp(PTS:"GPCR signaling pathway") bp(PTS:"GPCR signaling pathway") -> path(MESHD:"Fragile X Syndrome") UNSET Subgraph SET Evidence = "Notably, RGS4 is highly expressed in brain and has been shown to negatively regulate signaling through Group I mGluRs and GABA(B) receptors" SET Subgraph = {"G-protein-mediated signaling", "GABA subgraph", "Neurotransmitter release subgraph"} p(HGNC:RGS4) pos path(MESHD:"Fragile X Syndrome") p(HGNC:RGS4) -| bp(PTS:"GPCR signaling pathway") p(HGNC:RGS4) -| bp(PTS:"gamma_aminobutyric acid signaling pathway") UNSET Subgraph ######################################## SET Citation = {"PubMed", "Mol Pharmacol. 2009 Jul;76(1):18-24. doi:10.1124/mol.109.056127. Epub 2009 Apr 7.", "19351745"} SET Evidence = "Indeed, administration of the GABA(B) receptor agonist baclofen to FMR1 mice inhibited seizures, whereas the GABA(B) receptor antagonist (3-aminopropyl)(cyclohexylmethyl)phosphinic acid (CGP 46381) increased seizure incidence in double-knockout mice but not in wild-type mice." SET Confidence = "High" SET Species = "10090" SET Subgraph = {"GABA subgraph", "Neurotransmitter release subgraph"} a(CHEBI:baclofen) -> bp(PTS:"gamma_aminobutyric acid signaling pathway") a(CHEBI:baclofen) -| path(MESHD:"Fragile X Syndrome") bp(PTS:"gamma_aminobutyric acid signaling pathway") -| path(MESHD:"Fragile X Syndrome") a(InChI:"InChI=1S/C10H22NO2P/c11-7-4-8-14(12,13)9-10-5-2-1-3-6-10/h10H,1-9,11H2,(H,12,13)") -| bp(PTS:"gamma_aminobutyric acid signaling pathway") a(InChI:"InChI=1S/C10H22NO2P/c11-7-4-8-14(12,13)9-10-5-2-1-3-6-10/h10H,1-9,11H2,(H,12,13)") -> path(MESHD:"Fragile X Syndrome") a(InChI:"InChI=1S/C10H22NO2P/c11-7-4-8-14(12,13)9-10-5-2-1-3-6-10/h10H,1-9,11H2,(H,12,13)") -> path(MESHD:Seizures) UNSET {Subgraph, Species } ##################################### SET Citation = {"PubMed", "Nat Med. 2013 May;19(5):603-7. doi:10.1038/nm.3127. Epub 2013 Mar 31.", "23542787"} SET Evidence = "Uncontrolled activity of metabotropic glutamate receptor 5 (mGluR5) and mammalian target of rapamycin (mTOR) signaling seem crucial in th pathology of this disease" SET Subgraph = {"mTOR signaling subgraph", "Long term synaptic depression"} act(p(HGNC:GRM5)) -- path(MESHD:"Fragile X Syndrome") bp(PTS:"mTOR signaling pathway") -- path(MESHD:"Fragile X Syndrome") UNSET Subgraph ###################################### SET Citation = {"PubMed", "Neurobiol Dis. 2014 Feb;62:73-85. doi:10.1016/j.nbd.2013.09.003. Epub 2013 Sep 16.", "24051278"} SET Evidence = "Pilocarpine-induced status epilepticus (SE), which results in temporal lobe epilepsy (TLE) in rodents, activates the JAK/STAT pathway" SET Species = "10090" path(MESHD:"Status Epilepticus") -> path(MESHD:"Epilepsy, Temporal Lobe") UNSET Species SET Evidence = "Protein and/or mRNA levels for pSTAT3, and STAT3-regulated genes including: ICER, Gabra1, c-myc, mcl-1, cyclin D1, and bcl-xl were evaluated" p(HGNC:STAT3) -> p(HGNC:CREM) p(HGNC:STAT3) -> p(HGNC:GABRA1) p(HGNC:STAT3) -> p(HGNC:MYC) p(HGNC:STAT3) -> p(HGNC:MCL1) p(HGNC:STAT3) -> p(HGNC:CCND1) p(HGNC:STAT3) -> p(HGNC:BCL2L1) SET Evidence = "WP1066 (two 50mg/kg doses) administered within the first hour after onset of SE results in transient inhibition of pSTAT3. Early WP1066 administration reduces known downstream targets of STAT3 transcription 24h after SE including cyclin D1 and mcl-1 levels, known for their roles in cell-cycle progression and cell survival, respectively" a(CHEBI:"STAT3 inhibitor") -| p(HGNC:STAT3) a(CHEBI:"STAT3 inhibitor") -| p(HGNC:CCND1) p(HGNC:CCND1) -> bp(PTS:"Cell cycle") a(CHEBI:"STAT3 inhibitor") -| p(HGNC:MCL1) p(HGNC:MCL1) -| bp(GOBP:"cell death") #################################### SET Citation = {"PubMed", "Proc Natl Acad Sci U S A. 2013 Nov26;110(48):19603-8. doi: 10.1073/pnas.1312791110. Epub 2013 Nov 11.","24218551"} SET Evidence = "ErbB4 signaling in the central nervous system is implicated in neuropsychiatric disorders and epilepsy." SET Subgraph = {"GABA subgraph", "Neurotransmitter release subgraph", "Notch signaling subgraph"} bp(PTS:"ErbB4 signaling events") -> path(MESHD:Epilepsy) p(HGNC:ERBB4) -> bp(PTS:"ErbB4 signaling events") SET Evidence = "We show that ErbB4 and GABAR a1 are robustly coexpressed in hippocampal interneurons, and that ErbB4-null mice have diminished cortical GABAR a1 expression" SET Confidence = "High" p(HGNC:ERBB4) pos p(HGNC:GABRA1) SET Evidence = "Consistent with an evolving understanding of GABAR trafficking, this pathway requires both clathrin-mediated endocytosis and protein kinase C to reduce GABAR inhibitory currents, surface GABAR a1 expression, and colocalization with the inhibitory postsynaptic protein gephyrin" bp(PTS:Endocytosis) -> bp(PTS:"ErbB4 signaling events") p(HGNC:GABRA1) -> bp(PTS:"ErbB4 signaling events") UNSET Subgraph #################################### SET Citation = {"PubMed", "Nihon Rinsho. 2014 May;72(5):790-5.", "24912277"} SET Evidence = "GABA(A) synaptic inhibition decreased in the hippocampal CA1 area of patients with intractable temporal lobe epilepsy (TLE)." SET MeSHAnatomy="CA1 Region, Hippocampal" SET Subgraph = {"GABA subgraph", "Neurotransmitter release subgraph"} path(MESHD:"Epilepsy, Temporal Lobe") -- bp(PTS:"gamma_aminobutyric acid signaling pathway") SET Evidence = "The reduction of GABAergic inhibition was accompanied by a decrease in the expression of gephyrin, a scaffolding protein, and GABA(A) receptor gamma2 subunit" path(MESHD:"Epilepsy, Temporal Lobe") negativeCorrelation p(HGNC:GPHN) path(MESHD:"Epilepsy, Temporal Lobe") negativeCorrelation p(HGNC:GABRG2) p(HGNC:GABRG2) -> bp(PTS:"gamma_aminobutyric acid signaling pathway") SET Evidence = "These findings indicate that the reduction of gephyrin impairs the clustering and fixation of GABA(A) receptors in postsynaptic membranes, leading to a decrease in number of GABA(A) receptor subunits and GABA(A) synaptic inhibition" p(HGNC:GPHN) -> p(HGNC:GABRG2) p(HGNC:GPHN) -> bp(PTS:"gamma_aminobutyric acid signaling pathway") SET Evidence = "the hippocampal GABA(A) receptor beta3 subunits were significantly disphosphorylated, resulting in a facilitation of the endocytosis of GABA(A) receptors" p(HGNC:GABRB3) -> bp(PTS:"gamma_aminobutyric acid signaling pathway") UNSET Subgraph UNSET MeSHAnatomy ##################################### SET Citation = {"PubMed", "J Biol Chem. 2012 Apr 6;287(15):12083-97.doi: 10.1074/jbc.M111.332528. Epub 2012 Feb 2.", "22303015"} SET Evidence = "A GABA(A) receptor β3 subunit mutation, G32R, has been associated with childhood absence epilepsy." SET Subgraph = {"GABA subgraph", "Neurotransmitter release subgraph"} g(HGNC:GABRB3, var("?")) pos path(DO:"childhood absence epilepsy") p(HGNC:GABRB3, sub(G, 32, R)) pos path(DO:"childhood absence epilepsy") SET Evidence = "We evaluated the possibility that this mutation, which is located adjacent to the most N-terminal of three beta3 subunit N-glycosylation sites, might reduce GABAergic inhibition by increasing glycosylation of beta3 subunits." p(HGNC:GABRB3) -- bp(PTS:"N_linked glycosylation") p(HGNC:GABRB3, sub(G, 32, R)) -- bp(PTS:"N_linked glycosylation") g(HGNC:GABRB3) -| bp(GOBP:"negative regulation of synaptic transmission, GABAergic") p(HGNC:GABRB3, sub(G, 32, R)) -| bp(GOBP:"negative regulation of synaptic transmission, GABAergic") UNSET Subgraph ###################################### SET Citation = {"PubMed", "Front Neural Circuits. 2013 Sep 17;7:146.doi: 10.3389/fncir.2013.00146. eCollection 2013.", "24062648"} SET Evidence = "Drugs that increase dGABA(A) receptor activity have been proposed as treatments for a variety of disorders including insomnia, epilepsy and chronic pain. " SET Subgraph = {"Long term synaptic potentiation", "GABA subgraph", "Neurotransmitter release subgraph"} p(HGNC:GABRD) -| path(MESHD:Epilepsy) SET Evidence = "Furthermore, THIP inhibited LTP in hippocampal slices" p(HGNC:GABRD) -| bp(PTS:"Long_Term Potentiation") SET Evidence = "Thus, acutely increasing dGABA(A) receptor activity impairs memory behaviors and inhibits synaptic plasticity" p(HGNC:GABRD) -> bp(GOBP:"negative regulation of synaptic plasticity") UNSET Subgraph ###################################### SET Citation = {"PubMed", "Exp Neurol. 2007 Jan;203(1):72-81. Epub 2006Sep 26.", "17005180"} SET Evidence = "Estrogen has been suggested to be pro-epileptic by reducing GABA synthesis" SET Subgraph = {"GABA subgraph", "Neurotransmitter release subgraph"} # I would leave estrogn -> pathology since it is proepileptic a(CHEBI:estrogen) -> path(MESHD:Epilepsy) a(CHEBI:estrogen) -| bp(PTS:"gamma_aminobutyric acid metabolic pathway") a(CHEBI:estrogen) -| a(CHEBI:"GABA agent") SET Evidence = "in this study we focused on aromatase, the rate-limiting enzyme in estrogen synthesis " p(HGNC:CYP19A1) -> a(CHEBI:estrogen) SET Evidence = "To this end, we first examined the effects of letrozole, a potent aromatase inhibitor" a(CHEBI:letrozole) -| p(HGNC:CYP19A1) a(CHEBI:letrozole) -| a(CHEBI:estrogen) SET Evidence = "Letrozole downregulated estradiol release into the medium, as well as glutamate decarboxylase (GAD) expression and GABA synthesis, and decreased the number of GAD positive cells in the cultures" a(CHEBI:letrozole) -| bp(GOBP:"estradiol secretion") a(CHEBI:estrogen) -> bp(GOBP:"estradiol secretion") a(CHEBI:letrozole) -| p(HGNC:GAD1) a(CHEBI:estrogen) -> p(HGNC:GAD1) a(CHEBI:letrozole) -| a(CHEBI:"GABA agent") SET Evidence = " points to a neuroprotective role of aromatase in epilepsy. Re" p(HGNC:CYP19A1) -| path(MESHD:Epilepsy) SET Evidence = "Re-filling of estradiol stores after their depletion due to overexcitation may therefore add to therapeutical strategies in epilepsy." bp(MESHPP:"Cortical Excitability") -| a(CHEBI:estradiol) a(CHEBI:estradiol) -| path(MESHD:Epilepsy) UNSET Subgraph ###################################### SET Citation = {"PubMed", "Neuropeptides. 2005 Jun;39(3):249-51. Epub2005 Mar 19.", "15944018"} SET Evidence = "The impairment of cognitive performance by galanin administration in rodents indicates a possible modulating effect of this neuropeptide on long-term potentiation (LTP) induction" SET Species = "10090" SET Subgraph = "Long term synaptic potentiation" p(HGNC:GAL) -- bp(PTS:"Long_Term Potentiation") SET Evidence = "Similarly to galanin (1-29) (i.c.v.), galnon (i.p.) has exhibited anticonvulsant effects" p(HGNC:GAL) -| path(MESHD:Seizures) p(HGNC:GAL) isA a(CHEBI:anticonvulsant) SET Evidence = "This result was very similar to the effect of galanin (1-29) and galmic" p(HGNC:GAL) -| bp(PTS:"Long_Term Potentiation") UNSET Subgraph ##################################### SET Citation = {"PubMed", "Epilepsia. 2012 Dec;53 Suppl 9:41-58. doi:10.1111/epi.12034.", "23216578"} SET Evidence = "Sustaining synaptic transmission depends on the continuing cycle of synaptic vesicle formation, release, and endocytosis, which requires proteins such as dynamin, syndapin, synapsin, and synaptic vesicle protein 2A." SET Subgraph = "Neurotransmitter release subgraph" bp(GOBP:"synaptic vesicle maturation") -> bp(GOBP:"chemical synaptic transmission") bp(GOBP:"synaptic vesicle exocytosis") -> bp(GOBP:"chemical synaptic transmission") bp(GOBP:"synaptic vesicle endocytosis") -> bp(GOBP:"chemical synaptic transmission") p(HGNC:DNM1) -> bp(GOBP:"chemical synaptic transmission") p(HGNC:PACSIN1) -> bp(GOBP:"chemical synaptic transmission") p(HGNC:SYN1) -> bp(GOBP:"chemical synaptic transmission") p(HGNC:SV2A) -> bp(GOBP:"chemical synaptic transmission") UNSET Subgraph SET Evidence = "Moreover, different neuropeptides such as neuropeptide Y, brain-derived neurotrophic factor (BDNF), somatostatin, ghrelin, and galanin, act as regulators of diverse synaptic functions " SET Subgraph = {"brain_derived neurotrophic factor signaling subgraph", "Mossy Fiber Subgraph"} p(HGNC:NPY) -> bp(GOBP:"regulation of synaptic activity") p(HGNC:BDNF) -> bp(GOBP:"regulation of synaptic activity") UNSET Subgraph SET Subgraph = "Neurotransmitter release subgraph" p(HGNC:SST) -> bp(GOBP:"regulation of synaptic activity") p(HGNC:GHRL) -> bp(GOBP:"regulation of synaptic activity") p(HGNC:GAL) -> bp(GOBP:"regulation of synaptic activity") SET Evidence = "Abnormalities in the regulation of synaptic transmission play a critical role in the pathogenesis of numerous brain diseases, including epilepsy" bp(GOBP:"negative regulation of synaptic transmission") -- path(MESHD:Epilepsy) # Full Text ###################################### SET Citation = {"PubMed", "Peptides. 2009 Jan;30(1):16-25. doi:10.1016/j.peptides.2008.07.023. Epub 2008 Aug 13.", "18765263"} SET Evidence = " have found that activation of GPR54 with kisspeptin-10 causes a rapid and large increase in the amplitude of excitatory synaptic responses in granule cells" p(HGNC:KISS1) -> p(HGNC:KISS1R) p(HGNC:KISS1R) -> bp(GOBP:"chemical synaptic transmission") SET Evidence = "The effect was suppressed by the G-protein inhibitor GDP-beta-S and the calcium chelator BAPTA, increases synaptic transmission in dentate granule cells through signaling cascades possibly linked to the MAP kinase system" SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph"} a(CHEBI:"GDP-beta-S") -| p(HGNC:KISS1R) a(CHEBI:BAPTA) -| p(HGNC:KISS1R) p(HGNC:KISS1R) -- bp(PTS:"mitogen activated protein kinase signaling pathway") p(HGNC:KISS1) -- bp(PTS:"mitogen activated protein kinase signaling pathway") SET Evidence = "This novel peptide system may play a role in cognition and in the pathogenesis of epilepsy." p(HGNC:KISS1R) -- path(MESHD:Epilepsy) p(HGNC:KISS1) -- path(MESHD:Epilepsy) UNSET Subgraph ########################################## SET Citation = {"PubMed", "J Neurosci. 2000 Jun 1;20(11):4037-49.", "10818139"} SET Evidence = " Grin1(D481N) mice exhibited deficits in hippocampal theta burst-induced long-term potentiation (LTP)" SET Species = "10090" SET Subgraph = "Long term synaptic potentiation" p(HGNC:GRIN1) -- bp(PTS:"Long_Term Potentiation") UNSET {Subgraph, Species} ######################################## SET Citation = {"PubMed", "Neurobiol Dis. 2013 Jun;54:183-93. doi:10.1016/j.nbd.2012.12.011. Epub 2013 Jan 8.", "23313317"} SET Evidence = "Impairment of synaptic plasticity such as long-term potentiation (LTP) is a common finding in various animal models of a number of neurodegenerative disorders. " SET Subgraph = "Long term synaptic potentiation" bp(PTS:"Long_Term Potentiation") -- path(MESHD:"Neurodegenerative Diseases") bp(GOBP:"regulation of neuronal synaptic plasticity") -- bp(PTS:"Long_Term Potentiation") UNSET Subgraph ################################## SET Citation = {"PubMed", "J Pharmacol Exp Ther. 2011 Sep;338(3):897-905. doi: 10.1124/jpet.111.183327. Epub 2011 Jun 2.","21636656"} SET Evidence = "In the absence of FMRP, signaling through group I metabotropic glutamate receptors (mGluRs) is enhanced" SET Subgraph = {"G-protein-mediated signaling", "Long term synaptic depression"} p(HGNC:FMR1) -- p(HGNC:GRM1) p(HGNC:GRM1) -- bp(PTS:"GPCR signaling pathway") UNSET Subgraph ################################# SET Citation = {"PubMed", "J Neurosci. 2010 Apr 21;30(16):5724-9. doi:10.1523/JNEUROSCI.0795-10.2010.", "20410124"} SET Evidence = "Many protein-synthesis-dependent functions of group I metabotropic glutamate receptors (Gp1 mGluRs) are exaggerated in FXS." SET Subgraph = {"Protein Metabolism", "Metabolism", "Long term synaptic depression"} p(HGNC:GRM1) pos path(MESHD:"Fragile X Syndrome") p(HGNC:GRM1) -- bp(PTS:"pathway of protein biosynthesis") bp(PTS:"pathway of protein biosynthesis") -- path(MESHD:"Fragile X Syndrome") UNSET Subgraph SET Evidence = "Gp1 mGluR activation can mobilize endocannabinoids (eCBs) in the hippocampus and thereby increase excitability" SET Subgraph = {"G-protein-mediated signaling", "Long term synaptic depression"} p(HGNC:GRM1) -> bp(PTS:"Retrograde endocannabinoid signaling") bp(PTS:"Retrograde endocannabinoid signaling") -> bp(GOBP:"chemical synaptic transmission") p(HGNC:GRM1) -> bp(GOBP:"chemical synaptic transmission") SET Evidence = "The increased susceptibility of Fmr1 KO slices to eCB-iLTD was physiologically relevant, since long-term potentiation of EPSP-spike (E-S) coupling induced by the mGluR agonist was markedly larger in Fmr1 KO mice than in WT animals" SET Species = "10090" bp(PTS:"Retrograde endocannabinoid signaling") -- bp(PTS:"Long_Term Potentiation") UNSET Species SET Evidence = "Alterations in eCB signaling could contribute to the cognitive dysfunction associated with FXS." bp(PTS:"Retrograde endocannabinoid signaling") -> path(MESHD:"Fragile X Syndrome") UNSET Subgraph ################################# SET Citation = {"PubMed", "Neurochem Res. 2012 Jan;37(1):116-25. doi:10.1007/s11064-011-0589-9. Epub 2011 Sep 11.", "21909957"} SET Evidence = "It has been reported that HAX-1 may act as antiapoptotic protein " SET Subgraph = "Apoptosis signaling subgraph" p(HGNC:HAX1) -| bp(GOBP:"apoptotic process") p(HGNC:HAX1) -| bp(GOBP:"apoptotic process") SET Evidence = "the role of HAX-1 in neuronal death induced by status epilepticus in the immature brain has not been reported" SET Subgraph = "Apoptosis signaling subgraph" path(MESHD:"Status Epilepticus") -> bp(GOBP:"neuron death") SET Evidence = "In this study, we performed a status epilepticus in rats and investigated the dynamic changes of HAX-1 expression, HtrA2 distribution and caspase-3 activation in the hippocampus. Western blot and immunohistochemistry analysis revealed that HAX-1 was expressed at very low levels in the hippocampus" SET MeSHAnatomy = "Hippocampus" SET Subgraph = "Apoptosis signaling subgraph" path(MESHD:"Status Epilepticus") neg p(HGNC:HAX1) p(HGNC:HAX1) -| bp(GOBP:"neuron death") ################################# SET Citation = {"PubMed", "Neurobiol Dis. 2008 Feb;29(2):297-305. Epub2007 Sep 22.", "17964174"} SET Evidence = "The mechanisms for HCN1 reduction involved Ca(2+)-permeable AMPA receptor-mediated Ca(2+) influx, and subsequent activation of Ca (2+)/calmodulin-dependent protein kinase II. " SET Subgraph = "Calcium dependent subgraph" p(HGNC:HCN1) -- a(CHEBI:"calcium(2+)") p(HGNC:HCN1) -- bp(PTS:"Calcium signaling pathway") SET Evidence = "involving the HCN channels that may contribute to certain epilepsies." g(HGNC:HCN1) -- path(MESHD:Epilepsy) g(HGNC:HCN2) -- path(MESHD:Epilepsy) UNSET Subgraph #################################### SET Citation = {"PubMed", "Eur J Neurol. 2013 Jun;20(6):872-8. doi:10.1111/ene.12104. Epub 2013 Feb 9.", "23398397"} SET Evidence = "The pathogenesis may be caused by PRRT2 loss of function, which may induce synaptic deregulation and neuronal hyperexcitability" p(HGNC:PRRT2) -- bp(GOBP:"regulation of synaptic activity") ##################################### SET Citation = {"PubMed", "Neurobiol Dis. 2013 Nov;59:183-93. doi:10.1016/j.nbd.2013.07.015. Epub 2013 Aug 9.", "23938763"} SET Evidence = "pharmacological blockade of the IL-1-beta mediated signaling, rapidly activated in forebrain by epileptogenic injuries," SET Anatomy = "forebrain" SET Subgraph = "Interleukin signaling subgraph" path(MESHD:"Brain Injuries") -| bp(PTS:"IL_1beta pathway") p(HGNC:IL1B) -> bp(PTS:"IL_1beta pathway") bp(PTS:"IL_1beta pathway") -- path(MESHD:Epilepsy) UNSET {Subgraph, Anatomy} ##################################### SET Citation = {"PubMed", "Mol Med Rep. 2015 Aug;12(2):1877-83. doi:10.3892/mmr.2015.3641. Epub 2015 Apr 17.", "25891824"} SET Evidence = "Peroxisome proliferator-activated receptor gamma has a protective role in several neurological diseases" p(HGNC:PPARG) -| path(MESHD:"Neurodegenerative Diseases") SET Evidence = "Therefore, the mTOR signaling pathway was activated in the PTZ-induced SE rat model, and the PPAR-gamma agonist, pioglitazone, had a neuroprotective effect, by inhibiting activation of the mTOR pathway and preventing the increase in the levels of IL-1beta and IL-6." SET Species = "10116" SET Subgraph = "mTOR signaling subgraph" bp(PTS:"mTOR signaling pathway") -> path(MESHD:Epilepsy) bp(PTS:"mTOR signaling pathway") -> path(MESHD:Seizures) p(HGNC:PPARG) -| bp(PTS:"mTOR signaling pathway") a(CHEBI:pioglitazone) -> p(HGNC:PPARG) a(CHEBI:pioglitazone) -| bp(PTS:"mTOR signaling pathway") UNSET Subgraph SET Subgraph = {"mTOR signaling subgraph", "Interleukin signaling subgraph"} a(CHEBI:pioglitazone) -| p(HGNC:IL1B) a(CHEBI:pioglitazone) -| p(HGNC:IL6) p(HGNC:IL1B) -> bp(PTS:"mTOR signaling pathway") # p(HGNC:IL1B) -> path(MESHD:Epilepsy) p(HGNC:IL6) -> bp(PTS:"mTOR signaling pathway") # p(HGNC:IL6) -> path(MESHD:Epilepsy) p(HGNC:IL6) -> bp(PTS:"IL_1beta pathway") UNSET Species UNSET Subgraph # full text also available ####################################### SET Citation = {"PubMed", "Neurobiol Dis. 2015 Jan;73:96-105. doi:10.1016/j.nbd.2014.09.011. Epub 2014 Sep 28.", "25270294"} SET Evidence = "The mechanistic/mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase that mediates activity-dependent protein synthesis in neurons." SET Subgraph = "mTOR signaling subgraph" p(HGNC:MTOR) -> bp(PTS:"mTOR signaling pathway") SET Subgraph = {"mTOR signaling subgraph", "Protein Metabolism", "Metabolism"} p(HGNC:MTOR) -> bp(PTS:"pathway of protein biosynthesis") SET Evidence = "mTOR is overactive in epilepsy, suggesting that excessive protein synthesis may contribute to the neuronal pathology" bp(PTS:"pathway of protein biosynthesis") -> path(MESHD:Epilepsy) SET Evidence = "When mTOR activity is low, Kv1.1 expression is high and the frequency of behavioral seizures is low" p(HGNC:MTOR) -| p(HGNC:KCNA1) p(HGNC:KCNA1) -| path(MESHD:Seizures) SET Evidence = "Interestingly, blocking mTOR activity with rapamycin reduces behavioral seizures and temporarily keeps Kv1.1 levels elevated" a(CHEBI:sirolimus) -| p(HGNC:MTOR) a(CHEBI:sirolimus) -| path(MESHD:Seizures) a(CHEBI:sirolimus) -> p(HGNC:KCNA1) UNSET Subgraph ######################################## SET Citation = {"PubMed", "Glia. 2014 Mar;62(3):411-27. doi:10.1002/glia.22613. Epub 2014 Jan 10.", "24415225"} SET Evidence = "Kir4.1, a glial-specific K+ channel, is critical for normal CNS development." p(HGNC:KCNJ10) -> bp(GOBP:"central nervous system development") SET Evidence = "Notably, decreased Kir4.1 protein expression occurs in several human CNS pathologies including CNS ischemic injury, spinal cord injury, epilepsy, ALS, and Alzheimer's disease" p(HGNC:KCNJ10) neg path(MESHD:Epilepsy) p(HGNC:KCNJ10) neg path(MESHD:"Alzheimer Disease") p(HGNC:KCNJ10) neg path(MESHD:"Spinal Cord Injuries") p(HGNC:KCNJ10) neg path(MESHD:"Amyotrophic Lateral Sclerosis") SET Evidence = "Robust developmental upregulation of Kir4.1 expression in rats is coincident with reductions in DNA methylation of the Kir4.1 gene, KCNJ10" SET Species = "10116" #: When this gene is metylated, there is a developmental upregulation. Seems interesting to code p(HGNC:KCNJ10) -| bp(GOBP:"DNA methylation") # full text available UNSET Species ################################## SET Citation = {"PubMed", "J Pediatr Endocrinol Metab. 2012;25(3-4):367-70.", "22768671"} SET Evidence = "Heterozygous activation mutations in KCNJ11, encoding the Kir6.2 subunit of the ATP-sensitive potassium (K(ATP)) channel, which acts as a key role in insulin secretion regulation, account for about half of the cases of PNDM" SET Subgraph = "hormone signaling subgraph" p(HGNC:KCNJ11, var("?")) pos bp(PTS:"Regulation of Insulin Secretion") g(HGNC:KCNJ11, var("?")) pos path(DO:"neonatal diabetes mellitus") SET Evidence = "Approximately 20% have associated neurologic features: the most severe form, which includes epilepsy and developmental delay," g(HGNC:KCNJ11) -- path(MESHD:Epilepsy) UNSET Subgraph ##################################### SET Citation = {"PubMed", "Mol Pharmacol. 2009 Feb;75(2):281-95. doi: 10.1124/mol.108.051425. Epub 2008 Oct 27.", "18955585"} SET Evidence = "Small-conductance (KCa2.1-2.3) and intermediate-conductance (KCa3.1) calcium-activated K(+) channels are critically involved in modulating calcium-signaling cascades and membrane potential in both excitable and nonexcitable cells" SET Subgraph = "Calcium dependent subgraph" p(HGNC:KCNN2) -> bp(PTS:"Calcium signaling pathway") p(HGNC:KCNN2) -> bp(GOBP:"regulation of resting membrane potential") p(HGNC:KCNN4) -> bp(PTS:"Calcium signaling pathway") p(HGNC:KCNN4) -> bp(GOBP:"regulation of resting membrane potential") SET Evidence = "Activators of these channels constitute useful pharmacological tools and potential new drugs for the treatment of ataxia, epilepsy, and hypertension. Here" p(HGNC:KCNN2) -| path(MESHD:Epilepsy) p(HGNC:KCNN4) -| path(MESHD:Epilepsy) UNSET Subgraph ###################################### SET Citation = {"PubMed", "Sci Signal. 2014 Mar 4;7(315):ra22. doi: 10.1126/scisignal.2005025.", "24595108"} SET Evidence = "Na(+)-coupled solute transport is crucial for the uptake of nutrients and metabolic precursors, such as myo-inositol, an important osmolyte and precursor for various cell signaling molecules. " a(CHEBI:"sodium(1+)") -> bp(GOBP:"myo-inositol import into cell") bp(GOBP:"myo-inositol import into cell") -> a(CHEBI:"myo-inositol") a(CHEBI:"myo-inositol") -> bp(PTS:"Signaling pathway") SET Evidence = "Global metabolite profiling revealed that mice lacking KCNE2, a K(+) channel beta subunit, showed a reduction in myo-inositol concentration in cerebrospinal fluid (CSF) but not in serum" SET Confidence = "High" SET Species = "10090" SET Anatomy = "cerebrospinal fluid" p(HGNC:KCNE2) -> bp(GOBP:"myo-inositol import into cell") p(HGNC:KCNE2) -> a(CHEBI:"myo-inositol") SET Anatomy = "serum" p(HGNC:KCNE2) causesNoChange bp(GOBP:"myo-inositol import into cell") p(HGNC:KCNE2) causesNoChange a(CHEBI:"myo-inositol") SET Evidence = "Increased behavioral responsiveness to stress and seizure susceptibility in Kcne2(-/-) mice were alleviated by injections of myo-inositol" SET Confidence = "High" SET Species = "10090" g(HGNC:KCNE2, var("del")) pos path(MESHD:Seizures) a(CHEBI:"myo-inositol") -| path(MESHD:Seizures) SET Evidence = "Heterologous coexpression demonstrated that myo-inositol transport by SMIT1 was augmented by coexpression of KCNQ1 " SET Species = "10090" p(HGNC:SLC5A3) -> bp(GOBP:"myo-inositol import into cell") p(HGNC:KCNQ1) -> p(HGNC:SLC5A3) p(HGNC:KCNQ1) -> bp(GOBP:"myo-inositol import into cell") # full text available ######################################### SET Citation = {"PubMed", "PLoS One. 2012;7(11):e50279. doi: 10.1371/journal.pone.0050279. Epub 2012 Nov 29.", "23209695"} SET Evidence = "In humans, KCNQ2/3 channels form an M-current that regulates neuronal excitability, with mutations in these channels causing benign neonatal familial convulsions." SET Subgraph = "Calcium dependent subgraph" p(HGNC:KCNQ2) -> bp(GOBP:"positive regulation of synaptic transmission") p(HGNC:KCNQ3) -> bp(GOBP:"positive regulation of synaptic transmission") SET Evidence = "The M-current is important in mechanisms of neural plasticity" p(HGNC:KCNQ2) -> bp(GOBP:"positive regulation of synaptic plasticity") p(HGNC:KCNQ3) -> bp(GOBP:"positive regulation of synaptic plasticity") SET Evidence = "KCNQ overexpression decreasing excitability and calcium signalling, consistent with KCNQ regulating the resting membrane potential and neural release as in mammalian neurons" p(HGNC:KCNQ2) -| bp(PTS:"Calcium signaling pathway") p(HGNC:KCNQ3) -| bp(PTS:"Calcium signaling pathway") p(HGNC:KCNQ2) -> bp(GOBP:"regulation of resting membrane potential") p(HGNC:KCNQ3) -> bp(GOBP:"regulation of resting membrane potential") UNSET Subgraph ########################################### SET Citation = {"PubMed", "Postepy Hig Med Dosw (Online). 2013 Sep 12;67:973-81. doi: 10.5604/17322693.1066537.", "24088541"} SET Evidence = "Retigabine opens potassium channels of subfamily Kv 7, especially Kv 7.2 and Kv 7.3" SET Subgraph = {"GABA subgraph", "Neurotransmitter release subgraph"} a(CHEBI:ezogabine) -> p(HGNC:KCNQ2) a(CHEBI:ezogabine) -> p(HGNC:KCNQ3) a(CHEBI:ezogabine) -> p(HGNC:KCNQ4) a(CHEBI:ezogabine) -> p(HGNC:KCNQ5) SET Evidence = "The drug enhances GABA-ergic transmission" a(CHEBI:ezogabine) -> bp(PTS:"gamma_aminobutyric acid signaling pathway") a(CHEBI:ezogabine) -> bp(GOBP:"synaptic transmission, GABAergic") SET Evidence = "The drug has been registered as treatment of partial onset seizures with" a(CHEBI:ezogabine) -| path(MESHD:Seizures) a(CHEBI:ezogabine) isA a(CHEBI:anticonvulsant) UNSET Subgraph ############################################## SET Citation = {"PubMed", "Genomics. 2010 Feb;95(2):93-100. doi: 10.1016/j.ygeno.2009.10.001. Epub 2009 Oct 14.", "19835947"} SET Evidence = "In a gene expression array comparison between parental cells and T98G cell clones forced to express LGI1, we demonstrate that the canonical axon guidance pathway is the most significantly affected" p(HGNC:LGI1) -> bp(GOBP:"axon guidance") SET Evidence = " In particular, aspects of axon guidance that involve reorganization of the actin cytoskeleton, which is also involved in cell movement and invasion, were affected." bp(GOBP:"axon guidance") -> bp(GOBP:"actin cytoskeleton reorganization") bp(GOBP:"actin cytoskeleton reorganization") -> bp(GOBP:"cell motility") p(HGNC:LGI1) -> bp(GOBP:"actin cytoskeleton reorganization") p(HGNC:LGI1) -> bp(GOBP:"cell motility") ############################################ SET Citation = {"PubMed", "Sci Rep. 2015 Jan 16;5:7827. doi: 10.1038/srep07827.", "25591666"} SET Evidence = "Enhanced Jagged1-Notch1 signaling in KO mice via reduced alpha-secretase proteolysis suggests that altered phenotype of RGCs is due to abnormal Notch1 signaling." SET Species = "10090" SET Subgraph = "Notch signaling subgraph" p(HGNC:LGI1) -- bp(PTS:"Notch signaling pathway") p(HGNC:LGI1) -> p(HGNC:NOTCH1) SET Evidence = "Together, our results demonstrate that LGI1 is an essential player in the cerebellar development. " p(HGNC:LGI1) -> bp(GOBP:"cerebellum development") UNSET Subgraph ######################################## SET Citation = {"PubMed", "Pediatr Neurol. 2007 Sep;37(3):157-64.", "17765802"} # full text annotated SET Evidence = "Many of these genes encode for some important central nervous system ion channels (KCNJ10, KCNJ3, KCNQ2/KCNQ3, CLCN2, GABRG2, GABRA1, SCN1B, and SCN1A), while many others encode for ubiquitary enzymes that play crucial roles in various Metabolic pathways (HP, ACP1, ME2, LGI4, OPRM1, GRIK1, BRD2, EFHC1, and EFHC2)." SET Subgraph = "Metabolism" p(HGNC:HP) -> bp(PTS:"Metabolic pathway") p(HGNC:ACP1) -> bp(PTS:"Metabolic pathway") p(HGNC:ME2) -> bp(PTS:"Metabolic pathway") p(HGNC:LGI4) -> bp(PTS:"Metabolic pathway") p(HGNC:OPRM1) -> bp(PTS:"Metabolic pathway") p(HGNC:EFHC2) -> bp(PTS:"Metabolic pathway") SET Evidence = "Haptoglobin is a polymorphic protein that is well-known for its hemoglobin-binding property" p(HGNC:HP) -| a(CHEBI:hemoglobin) SET Evidence = "Free hemoglobin mediates hydroxyl free-radical formation, which produces brain lipid peroxidation, increased neuronal excitability, and cellular damage." a(CHEBI:hemoglobin) -> a(CHEBI:"reactive oxygen species") a(CHEBI:"reactive oxygen species") -> bp(GOBP:"chemical synaptic transmission") a(CHEBI:"reactive oxygen species") -> bp(GOBP:"cell death") SET Evidence = "The association between the haptoglobin 2-2 genotype and idiopathic generalized epilepsy may be explained at a functional level, because the haptoglobin phenotype 2-2 is less efficient at protecting nervous cells against free hemoglobin oxidative damage [48], [49] and [50]." #: The second statement should be replace by the HP2-2 polymorphism which is a weaker binding p(HGNC:HP) -- bp(GOBP:"response to oxidative stress") g(HGNC:HP, var("?")) -| bp(GOBP:"response to oxidative stress") UNSET Subgraph SET Evidence = "Because BRD2 is a putative nuclear transcriptional regulator from a family of genes that are expressed during development, these findings also suggested that abnormalities of neural development may be a cause of common idiopathic generalized epilepsy" SET Subgraph = "Innate immune system subgraph" p(HGNC:BRD2) -> bp(GOBP:"central nervous system development") UNSET Subgraph bp(GOBP:"central nervous system development") -- path(MESHD:Epilepsy) SET Evidence = "EFHC1 messenger RNA. The helix E and helix F-hand motif [81] is the most common calcium-binding motif found in proteins" SET Subgraph = "Calcium dependent subgraph" p(HGNC:EFHC1) -- a(CHEBI:"calcium(2+)") SET Evidence = "The proapoptotic effects of EFHC1 were assigned to its enhancement of Ca2+ influx through the R-type voltage-dependent Ca2+ channel" p(HGNC:EFHC1) -> bp(GOBP:"calcium ion import into cell") p(HGNC:EFHC1) -> a(CHEBI:"calcium(2+)") SET Subgraph = {"Apoptosis signaling subgraph", "Calcium dependent subgraph"} p(HGNC:EFHC1) -> bp(GOBP:"apoptotic process") p(HGNC:EFHC1) -> bp(GOBP:"apoptotic process") SET Evidence = "A molecular and functional interaction of EFHC1 with the redox-sensitive transient receptor potential M2 channel, which is a Ca2+-permeable action channel that mediates susceptibility to cell death, was reported" p(HGNC:EFHC1) -- p(HGNC:TRPM2) p(HGNC:TRPM2) -> bp(GOBP:"cell death") p(HGNC:TRPM2) -> bp(GOBP:"apoptotic process") UNSET Subgraph ################################ SET Citation = {"PubMed", "Neuroscience. 2014 May 30;268:276-83. doi: 10.1016/j.neuroscience.2014.03.030. Epub 2014 Mar 25.", "24680936"} SET Evidence = "Nuclear distribution factor E homolog like 1 (NDEL1) plays an important role in mitosis, neuronal migration, and microtubule organization during brain development by binding to disrupted-in-schizophrenia-1 (DISC1) or lissencephaly (LIS1)." SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph"} p(HGNC:NDEL1) -> bp(GOBP:"cell division") p(HGNC:NDEL1) -> bp(GOBP:"neuron migration") p(HGNC:NDEL1) -> bp(GOBP:"cortical microtubule organization") p(HGNC:NDEL1) -- p(HGNC:DISC1) p(HGNC:NDEL1) -- p(HGNC:PAFAH1B1) SET Evidence = "Although some evidence has suggested that DISC1 expression is altered in epilepsy, few studies have reported the relationship between NDEL1 and the etiology of epilepsy. In" p(HGNC:DISC1) -- path(MESHD:Epilepsy) SET Evidence = "Based on these results, we hypothesize that NDEL1 might interact with DISC1 to activate ERK signaling and function as a potential protective factor during the spontaneous seizure period after pilocarpine-induced SE." a(CHEBI:pilocarpine) -> path(MESHD:"Status Epilepticus") composite(p(HGNC:NDEL1),p(HGNC:DISC1)) -| path(MESHD:"Status Epilepticus") composite(p(HGNC:NDEL1),p(HGNC:DISC1)) -> bp(PTS:"mitogen activated protein kinase signaling pathway") p(HGNC:DISC1) -- p(HGNC:NDEL1) UNSET Subgraph ################################# SET Citation = {"PubMed", "Pediatr Res. 2013 Dec;74(6):658-67. doi: 10.1038/pr.2013.155. Epub 2013 Sep 3.", "24108187"} SET Evidence = " Brain injury from preterm birth causes white matter injury (WMI), and it leads to chronic neurological deficits including cerebral palsy, epilepsy, " SET MeSHDisease = "Premature Birth" path(MESHD:"Brain Injuries") -> a(NIFT:"White matter atrophy") a(NIFT:"White matter atrophy") -- path(MESHD:Epilepsy) SET Evidence = "Previously, we found that recombinant EPO (rEPO) treatment enhances myelin basic protein (MBP) expression" SET Subgraph = "hormone signaling subgraph" p(HGNC:EPO) -> p(HGNC:MBP) SET Evidence = "Together, these studies demonstrate that EPO signaling promotes critical stages of oligodendroglial lineage development and recovery after prenatal TSHI injury." SET MeSHDisease = "Hypoxia-Ischemia, Brain" SET Subgraph = "hormone signaling subgraph" p(HGNC:EPO) -> bp(PTS:"EPO signaling pathway") bp(PTS:"EPO signaling pathway") -> bp(GOBP:"oligodendrocyte development") bp(PTS:"EPO signaling pathway") -| path(MESHD:Epilepsy) UNSET {Subgraph, MeSHDisease} ###################################### SET Citation = {"PubMed", "Proc Natl Acad Sci U S A. 2010 Apr 13;107(15):7042-7. doi: 10.1073/pnas.0912041107. Epub 2010 Mar 26.", "20348416"} SET Evidence = "Mutations of leukemia-associated AF9/MLLT3 are implicated in neurodevelopmental diseases, such as epilepsy and ataxia" SET Subgraph = {"Wnt signaling subgraph","protein kinase signaling subgraph"} g(HGNC:MLLT3, var("?")) pos path(MESHD:Epilepsy) g(HGNC:MLLT3, var("?")) pos path(MESHD:Ataxia) SET Evidence = "We show that the molecular mechanism of TBR1 suppression is based on the interaction of AF9 with DOT1L, a" SET Subgraph = {"Wnt signaling subgraph","protein kinase signaling subgraph"} composite(p(HGNC:MLLT3), p(HGNC:DOT1L)) -| p(HGNC:TBR1) ################################## SET Citation = {"PubMed", "Curr Opin Pharmacol. 2008 Apr;8(2):127-32. doi: 10.1016/j.coph.2007.12.009. Epub 2008 Feb 19.", "18243793"} SET Evidence = "The receptor acts as co-factor for renin and prorenin by increasing their enzymatic activity on the cell-surface and it activates the mitogen activated protein kinases ERK1/2 cascade leading to cell proliferation and to up-regulation of profibrotic genes expression." SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph"} p(HGNC:ATP6AP2) -> p(HGNC:REN) p(HGNC:ATP6AP2) -> bp(PTS:"mitogen activated protein kinase signaling pathway") bp(PTS:"mitogen activated protein kinase signaling pathway") -> bp(GOBP:"cell proliferation") p(HGNC:ATP6AP2) -> bp(GOBP:"cell proliferation") SET Evidence = " (P)RR is necessary to cell survival and proliferation and a mutation of (P)RR is associated with mental retardation and epilepsy, pointing to an essential role of (P)RR in brain development." p(HGNC:ATP6AP2) -> bp(GOBP:"cell proliferation") g(HGNC:ATP6AP2, var("?")) pos path(MESHD:Epilepsy) p(HGNC:ATP6AP2) -> bp(GOBP:"brain development") UNSET Subgraph ################################### SET Citation = {"PubMed", "Mol Cell Neurosci. 2012 Jan;49(1):13-22. doi: 10.1016/j.mcn.2011.08.008. Epub 2011 Aug 26.", "21903164"} SET Evidence = "Children with the neurofibromatosis-1 (NF1) cancer predisposition syndrome exhibit numerous clinical problems that reflect defective central nervous system (CNS) neuronal function, including learning disabilities, attention deficit disorder, and seizures. These clinical features result from reduced NF1 protein (neurofibromin) expression in NF1+/- (NF1 heterozygosity) brain neurons. " SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph"} SET Anatomy = "brain" p(HGNC:NF1) neg path(MESHD:"Neurofibromatosis 1") path(MESHD:Seizures) pos path(MESHD:"Neurofibromatosis 1") path(MESHD:"Attention Deficit and Disruptive Behavior Disorders") pos path(MESHD:"Neurofibromatosis 1") SET Evidence = "To gain insights into the differential responses of CNS and PNS neurons to reduced neurofibromin function, we designed a series of experiments to define the molecular mechanism(s) underlying the unique CNS neuronal sensitivity to Nf1 heterozygosity. First, Nf1 heterozygosity decreases cAMP levels in CNS, but not in PNS, neurons. " #: Heterozygous NF1 ... SET MeSHAnatomy = "Central Nervous System" g(HGNC:NF1) -| a(MESHC:"Cyclic AMP") UNSET MeSHAnatomy SET MeSHAnatomy = "Peripheral Nervous System" g(HGNC:NF1) causesNoChange a(MESHC:"Cyclic AMP") UNSET MeSHAnatomy SET Evidence = "Second, CNS neurons exhibit Nf1 gene-dependent increases in RAS pathway signaling, but no further decreases in cAMP levels were observed in Nf1-/- CNS neurons relative to their Nf1+/- counterparts. " SET MeSHAnatomy = "Central Nervous System" p(HGNC:NF1) -> bp(PTS:"Ras mediated signaling") p(HGNC:NF1) -> bp(PTS:"mitogen activated protein kinase signaling pathway") UNSET Subgraph ######################################## SET Citation = {"PubMed", "Epilepsia. 2012 Jul;53(7):1119-30. doi: 10.1111/j.1528-1167.2012.03506.x. Epub 2012 May 11.", "22578218"} SET Evidence = "The mammalian target of rapamycin (mTOR) signaling pathway regulates cell growth, differentiation, proliferation, and metabolism" SET Subgraph = "mTOR signaling subgraph" bp(PTS:"mTOR signaling pathway") reg bp(GOBP:"regulation of cell growth") bp(PTS:"mTOR signaling pathway") reg bp(GOBP:"regulation of cell differentiation") bp(PTS:"mTOR signaling pathway") reg bp(GOBP:"regulation of cell proliferation") bp(PTS:"mTOR signaling pathway") reg bp(GOBP:"regulation of metabolic process") SET Evidence = "Loss-of-function mutations in upstream regulators of mTOR have been highly associated with dysplasias, epilepsy, and neurodevelopmental disorders. These include tuberous sclerosis, which is due to mutations in TSC1 or TSC2 genes; mutations in phosphatase and tensin homolog (PTEN) as in Cowden syndrome, polyhydramnios, megalencephaly, symptomatic epilepsy syndrome (PMSE) due to mutations in the STE20-related kinase adaptor alpha (STRADalpha); and neurofibromatosis type 1 attributed to neurofibromin 1 mutations" SET Subgraph = "mTOR signaling subgraph" p(HGNC:TSC1) -- p(HGNC:MTOR) p(HGNC:TSC1) -> bp(PTS:"mTOR signaling pathway") SET Subgraph = {"mTOR signaling subgraph", "Reelin signaling subgraph"} p(HGNC:TSC2) -- p(HGNC:MTOR) p(HGNC:TSC2) -> bp(PTS:"mTOR signaling pathway") p(HGNC:PTEN) -- p(HGNC:MTOR) p(HGNC:PTEN) -> bp(PTS:"mTOR signaling pathway") SET Subgraph = "mTOR signaling subgraph" p(HGNC:STRADA) -- p(HGNC:MTOR) p(HGNC:STRADA) -> bp(PTS:"mTOR signaling pathway") p(HGNC:NF1) -- p(HGNC:MTOR) p(HGNC:NF1) -> bp(PTS:"mTOR signaling pathway") UNSET Subgraph ################################## SET Citation = {"PubMed", "Biochem Biophys Res Commun. 2015 Aug 14;464(1):106-11. doi: 10.1016/j.bbrc.2015.06.018. Epub 2015 Jun 21.", "26102034"} SET Evidence = "Laforin and malin were shown play key roles in proteolytic processes, unfolded stress response, and glycogen metabolism." SET Subgraph = {"Protein Metabolism", "Metabolism", "Energy metabolic subgraph"} p(HGNC:EPM2A) -> bp(GOBP:proteolysis) p(HGNC:EPM2A) -> bp(PTS:"protein degradation pathway") p(HGNC:EPM2A) -> bp(PTS:"glycogen metabolic pathway") p(HGNC:EPM2A) -> bp(GOBP:"endoplasmic reticulum unfolded protein response") p(HGNC:NHLRC1) -> bp(GOBP:proteolysis) p(HGNC:NHLRC1) -> bp(PTS:"protein degradation pathway") p(HGNC:NHLRC1) -> bp(GOBP:"endoplasmic reticulum unfolded protein response") p(HGNC:NHLRC1) -> bp(PTS:"glycogen metabolic pathway") UNSET Subgraph SET Evidence = "Therefore, the LD proteins laforin and malin are thought to function as pro-survival factors" SET Subgraph = "Apoptosis signaling subgraph" p(HGNC:EPM2A) -| bp(GOBP:"cell death") p(HGNC:EPM2A) -| bp(GOBP:"apoptotic process") p(HGNC:NHLRC1) -| bp(GOBP:"cell death") p(HGNC:NHLRC1) -| bp(GOBP:"apoptotic process") SET Evidence = "We show that loss of laforin or malin results in the increased level and activity of p53, both in cellular and animal models of LD, and that this is primarily due to the increased levels of Hipk2, a proapoptotic activator of p53. " p(HGNC:EPM2A) -| p(HGNC:HIPK2) p(HGNC:NHLRC1) -| p(HGNC:HIPK2) p(HGNC:HIPK2) -> p(HGNC:TP53) p(HGNC:TP53) -> bp(GOBP:"apoptotic process") p(HGNC:TP53) -> bp(PTS:"p53 dependent apoptotic pathway") p(HGNC:HIPK2) -> bp(GOBP:"apoptotic process") p(HGNC:HIPK2) -> bp(PTS:"p53 dependent apoptotic pathway") UNSET Subgraph ################################## SET Citation = {"PubMed", "Hippocampus. 2008;18(6):564-74. doi: 10.1002/hipo.20415.", "18306304"} SET Evidence = "We found that long-term potentiation (LTP) in the CA1 area is partially impaired and have a slower rate of hippocampal-based spatial discrimination learning" SET MeSHAnatomy="CA1 Region, Hippocampal" SET Subgraph = "Long term synaptic potentiation" p(HGNC:NPY) -| bp(PTS:"Long_Term Potentiation") bp(PTS:"Long_Term Potentiation") -| bp(GOBP:"learning or memory") UNSET Subgraph UNSET MeSHAnatomy ################################ SET Citation = {"PubMed", "Neuroscience. 2002;114(1):13-7.", "12207950"} SET Evidence = "Furthermore we observed a significant increase in mRNA levels of PAK3 and IL1RAPL following LTP induction." SET Subgraph = "Long term synaptic potentiation" bp(PTS:"Long_Term Potentiation") -> p(HGNC:IL1RAPL1) bp(PTS:"Long_Term Potentiation") -> p(HGNC:PAK3) UNSET Subgraph ################################ SET Citation = {"PubMed", "Prog Brain Res. 2007;163:245-63.", "17765723"} SET Evidence = "Opiate drugs alter cognitive performance and influence hippocampal excitability, including long-term potentiation (LTP) and seizure activity" SET Subgraph = "Long term synaptic potentiation" a(CHEBI:"opioid agent") -- bp(PTS:"Long_Term Potentiation") a(CHEBI:"opioid agent") -- path(MESHD:Seizures) SET Evidence = "Enkephalins preferentially bind to delta- and mu-opioid receptors (DORs and MORs) while dynorphins preferentially bind to kappa-opioid receptors (KORs" p(HGNC:PENK) -- p(HGNC:OPRM1) p(HGNC:PENK) -- p(HGNC:OPRD1) p(HGNC:PDYN) -- p(HGNC:OPRK1) a(CHEBI:morphine) -- p(HGNC:OPRK1) SET Evidence =" MOR and DOR agonists increase excitability and facilitate LTP in the molecular layer. " p(HGNC:PENK) isA a(CHEBI:"opioid agent") p(HGNC:PENK) -> bp(PTS:"Long_Term Potentiation") p(HGNC:OPRM1) -> bp(PTS:"Long_Term Potentiation") p(HGNC:OPRD1) -> bp(PTS:"Long_Term Potentiation") SET Evidence = "KOR agonists, including endogenous dynorphins, diminish the induction of LTP." p(HGNC:PDYN) isA a(CHEBI:"opioid agent") p(HGNC:PDYN) -| bp(PTS:"Long_Term Potentiation") a(CHEBI:morphine) isA a(CHEBI:"opioid agent") a(CHEBI:morphine) -| bp(PTS:"Long_Term Potentiation") p(HGNC:OPRK1) -| bp(PTS:"Long_Term Potentiation") UNSET Subgraph ############################### SET Citation = {"PubMed", "Hippocampus. 2012 Feb;22(2):122-7. doi: 10.1002/hipo.20891. Epub 2010 Nov 3.", "21049484"} SET Evidence = "Mu opioid receptors (MOR) are known to be involved in seizure activity. " SET Confidence = "High" p(HGNC:OPRM1) -- path(MESHD:Seizures) ############################### SET Citation = {"PubMed", "Biochem Biophys Res Commun. 2008 Jun 20;371(1):22-7. doi: 10.1016/j.bbrc.2008.03.109. Epub 2008 Mar 31.", "18381200"} SET Evidence = " PIMT deficient mice exhibit accumulation of l-isoAsp in several tissues and die, on average, 12 days after birth from progressive epileptic seizures " SET Confidence = "High" SET Species = "10090" SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph"} p(HGNC:PCMT1) -| path(MESHD:Epilepsy) SET Evidence = "These results suggest that PIMT repair of abnormal proteins is necessary to maintain normal MAPK signaling." p(HGNC:PCMT1) -> bp(PTS:"mitogen activated protein kinase signaling pathway") UNSET Subgraph ############################### SET Citation = {"PubMed", "Neurobiol Learn Mem. 2009 Oct;92(3):301-9. doi: 10.1016/j.nlm.2009.03.010. Epub 2009 May 4.", "19410009"} SET Evidence = "Serine proteases such as tissue plasminogen activator (tPA), thrombin and neuropsin influence hippocampal plasticity involved in learning and memory by facilitating both synaptic remodelling and long-term potentiation." SET Subgraph = "Long term synaptic potentiation" p(HGNC:PLAT) -- bp(GOBP:"learning or memory") p(HGNC:PLAT) -> bp(PTS:"Long_Term Potentiation") p(HGNC:F2) -- bp(GOBP:"learning or memory") p(HGNC:F2) -> bp(PTS:"Long_Term Potentiation") p(HGNC:KLK8) -- bp(GOBP:"learning or memory") p(HGNC:KLK8) -> bp(PTS:"Long_Term Potentiation") SET Evidence = "activation of PAR2 attenuates 'pathogenic' plasticity related to epilepsy," p(HGNC:F2RL1) -- path(MESHD:Epilepsy) SET Evidence = "These results suggest that activation of central PAR2 with brain accessible peptide agonists causes a temporary deficit in the formation and/or recollection of experience-dependent learning and memory." p(HGNC:F2RL1) -| bp(GOBP:"learning or memory") UNSET Subgraph ################################ SET Citation = {"PubMed", "Semin Pediatr Neurol. 2013 Sep;20(3):176-87.doi: 10.1016/j.spen.2013.10.001. Epub 2013 Oct 9.", "24331359"} SET Evidence = "Oxidative stress is one of the possible mechanisms in the pathogenesis of epilepsy resulting from mt dysfunction gradually disrupting the intracellular Ca(2+) homeostasis, which modulates neuronal excitability and synaptic transmission, making neurons more vulnerable to additional stress,and leading to energy failure and neuronal loss in epilepsy." SET Subgraph = "Calcium dependent subgraph" bp(GOBP:"response to oxidative stress") -| bp(GOBP:"calcium ion homeostasis") bp(GOBP:"response to oxidative stress") -> a(CHEBI:"calcium(2+)") bp(GOBP:"calcium ion homeostasis") -- bp(GOBP:"chemical synaptic transmission") bp(GOBP:"response to oxidative stress") -> bp(GOBP:"neuron death in response to oxidative stress") bp(GOBP:"response to oxidative stress") -> path(MESHD:Epilepsy) UNSET Subgraph ############################################# SET Citation = {"PubMed", "Dis Model Mech. 2013 Mar;6(2):342-57. doi:10.1242/dmm.010140. Epub 2012 Oct 12.", "23065637"} SET Evidence = "Both CLN1 and CLN5 deficiencies lead to severe neurodegenerative diseases of childhood, known as neuronal ceroid lipofuscinoses (NCLs)" SET Subgraph = "Innate immune system subgraph" g(HGNC:CLN5, var("?")) pos path(MESHD:"Neuronal Ceroid-Lipofuscinoses") g(HGNC:PPT1, var("?")) pos path(MESHD:"Neuronal Ceroid-Lipofuscinoses") SET Evidence = "Finally, gene expression profiling of Cln1/5 dko cortex revealed defects in myelination and immune response pathways" SET Species = "10090" SET MeSHAnatomy = "Cerebral Cortex" g(MGI:Cln5, var("?"))-| bp(PTS:"Immune response") g(MGI:Cln5, var("?")) -| bp(GOBP:myelination) UNSET Subgraph ################################# SET Citation = {"PubMed", "Am J Hum Genet. 2008 Nov;83(5):572-81. doi:10.1016/j.ajhg.2008.10.003. Epub 2008 Oct 30.", "18976727"} SET Evidence = "PRICKLE1 is expressed in brain regions implicated in epilepsy and ataxia in mice and humans, and, to our knowledge, is the first molecule in the noncanonical WNT signaling pathway to be directly implicated in human epilepsy." SET Species = "10090" SET Anatomy = "brain" SET Subgraph = "Wnt signaling subgraph" p(HGNC:PRICKLE1) -- bp(PTS:"Wnt signaling pathway") bp(PTS:"Wnt signaling pathway") -- path(MESHD:Epilepsy) p(HGNC:PRICKLE1) -- path(MESHD:Epilepsy) #################################### SET Citation = {"PubMed", "Brain Res. 2008 Nov 19;1241:148-56. doi:10.1016/j.brainres.2008.08.097. Epub 2008 Sep 24.", "18840415"} SET Evidence = "The cellular prion protein (PrP(C)) has been implicated with the modulation of neuronal apoptosis, adhesion, neurite outgrowth and maintenance which are processes involved in the neocortical development" SET Subgraph = "Apoptosis signaling subgraph" p(HGNC:PRPF8) -- bp(GOBP:"apoptotic process") p(HGNC:PRPF8) -- bp(GOBP:"neuron death") p(HGNC:PRPF8) -- bp(GOBP:"cerebral cortex development") SET Evidence = "Malformations of cortical development (MCD) arefrequently associated with neurological conditions including mental retardation, autism, and epilepsy" bp(GOBP:"cerebral cortex development") -| path(MESHD:"Malformations of Cortical Development") g(HGNC:PRPF8) -> path(MESHD:"Malformations of Cortical Development") path(MESHD:"Malformations of Cortical Development") -> path(MESHD:Epilepsy) UNSET Subgraph ##################################### SET Citation = {"PubMed", "Neuropharmacology. 2008 Apr;54(5):874-84.doi: 10.1016/j.neuropharm.2008.01.008. Epub 2008 Feb 3.", "18329054"} SET Evidence = "The neuromodulatory peptide somatostatin-14 (SRIF) plays an important inhibitory role in epilepsy," p(HGNC:SST) -| path(MESHD:Epilepsy) SET Evidence = "Both the expression of COX-2 (mRNA and protein) and the endogenous release of PGE(2) increased in concomitance with epileptiform bursting." SET Subgraph = "Interleukin signaling subgraph" path(MESHD:Epilepsy) pos p(HGNC:PTGS2) path(MESHD:Epilepsy) pos a(CHEBI:"prostaglandin E2(1-)") SET Evidence = " In addition, the selective inhibition of COX-2 by NS-398 markedly decreased endogenous PGE(2) release " p(HGNC:PTGS2) -> a(CHEBI:"prostaglandin E2(1-)") UNSET Subgraph SET Evidence = "hese results demonstrate that: i) the COX-2/PGE(2) pathway facilitates epileptiform bursting; and ii) SRIF exerts an anti-epileptic role by coupling to the COX-2/PGE(2) pathway." a(CHEBI:somatostatin) -| path(MESHD:Epilepsy) a(CHEBI:somatostatin) isA a(CHEBI:anticonvulsant) composite(a(CHEBI:"prostaglandin E2(1-)"),p(HGNC:"MT-CO2")) -| path(MESHD:Epilepsy) ##################################### SET Citation = {"PubMed", "Neurobiol Dis. 2012 Jan;45(1):234-42. doi:10.1016/j.nbd.2011.08.007. Epub 2011 Aug 10.", "21856425"} SET Evidence = "Together, these results suggest that endogenous IL-1 beta possesses anticonvulsive properties that may be mediated by arachidonic acid metabolites derived from the catalytic action of COX-2." SET Subgraph = "Interleukin signaling subgraph" p(HGNC:PTGS2) -- p(HGNC:IL1B) p(HGNC:IL1B) -| path(MESHD:Seizures) p(HGNC:PTGS2) -> bp(PTS:"IL_1beta pathway") UNSET Subgraph ##################################### SET Citation = {"PubMed", "Hippocampus. 2011 Sep;21(9):935-44. doi:10.1002/hipo.20793. Epub 2010 May 17.", "20865728"} SET Evidence = "Alterations of reelin signaling or expression have been involved in major neurological disorders, and they underlie granule cell dispersion (GCD) in mesial temporal lobe epilepsy (TLE)." SET Confidence = "High" SET Subgraph = {"Reelin signaling subgraph", "brain_derived neurotrophic factor signaling subgraph"} p(HGNC:RELN) -> bp(PTS:"Reelin signaling pathway") g(HGNC:RELN, var("?")) pos path(MESHD:"Epilepsy, Temporal Lobe") bp(PTS:"Reelin signaling pathway") -> path(MESHD:"Epilepsy, Temporal Lobe") SET Evidence = "Altogether, these data reveal that GCD results from abnormal reelin processing in Cajal-Retzius cells under the control of BDNF." #: Cajal-Retzius cell annotation missing. Another statement with granule cell dispersion (GCD) # p(HGNC:BDNF) -- p(HGNC:RELN) UNSET Subgraph #################################### SET Citation = {"PubMed", "Hum Mol Genet. 2008 Feb 1;17(3):440-57. Epub 2007 Nov 5.", "17984171"} SET Evidence = "Network analyses suggested that upregulated expression of chromosome 21 genes such as S100B and amyloid precursor protein activated the stress response kinase pathways, and furthermore, could be linked to upregulation of the water channel aquaporin 4 (AQP4)." SET Subgraph = "protein kinase signaling subgraph" p(HGNC:S100B) -> bp(PTS:"stress_activated protein kinase _sapk_ pathway") p(HGNC:APP) -> bp(PTS:"stress_activated protein kinase _sapk_ pathway") p(HGNC:AQP4) pos p(HGNC:S100B) p(HGNC:AQP4) pos p(HGNC:APP) SET Evidence = "In addition, AQP4 expression could be induced by direct exposure to ROS" a(CHEBI:"reactive oxygen species") -> p(HGNC:AQP4) UNSET Subgraph #################################### SET Citation = {"PubMed", "Neurology. 2011 Sep 13;77(11):1055-60. doi:10.1212/WNL.0b013e31822e5627. Epub 2011 Aug 31.", "21880993"} SET Evidence = "Infantile spasms may be associated with interactions between ATXN2 and the postsynaptic structural proteins MAGI2 and SPTAN1." composite(p(HGNC:ATXN2), p(HGNC:MAGI2), p(HGNC:SPTAN1)) -- path(MESHD:"Spasms, Infantile") SET Evidence = "Severe phenotype in children with massive expansion of SCA2 may be due to a functional deficit in protein networks in the postsynapse, specifically involving vesicle endocytosis." # SCA2 is ATXN2 SET Subgraph = "Neurotransmitter release subgraph" p(HGNC:ATXN2) -- path(MESHD:"Spasms, Infantile") p(HGNC:ATXN2) -- bp(PTS:Endocytosis) UNSET Subgraph #################################### SET Citation = {"PubMed", "Am J Physiol Renal Physiol. 2011 Jun;300(6):F1437-47. doi: 10.1152/ajprenal.00015.2011. Epub 2011 Mar 23.", "21429972"} SET Evidence = "Deficiency of the intrinsic lysosomal protein human scavenger receptor class B, member 2 (SCARB2; Limp-2 in mice) causes collapsing focal and segmental glomerular sclerosis (FSGS) and myoclonic epilepsy in humans," p(HGNC:SCARB2, var("?")) pos path(MESHD:"Epilepsies, Myoclonic") ##################################### SET Citation = {"PubMed", "J Neurophysiol. 2014 Aug 15;112(4):903-12.doi: 10.1152/jn.00135.2014. Epub 2014 May 7.", "24805083"} SET Evidence = "The mutation-specific effects of 5-HTP on heat-induced seizures suggest the serotonin pathway as a potential therapeutic target for DS." SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} bp(PTS:"serotonin signaling pathway") -- path(DO:"Dravet syndrome") g(HGNC:HTR2A, var("?")) pos path(MESHD:Seizures) UNSET Subgraph #: no idea where this comes from g(HGNC:SCN1A) -- bp(PTS:"serotonin signaling pathway") ################################## SET Citation = {"PubMed", "J Neurophysiol. 2013 Nov;110(9):2090-8. doi:10.1152/jn.00921.2012. Epub 2013 Aug 14.", "23945787"} SET Evidence = "These results indicate that altered responses of the mutant channels to PKA signaling may impair the delicate balances between chemical and electrical harmony and lead to abnormal neuronal excitability." #: no idea where this comes from SET Confidence = "Low" SET Subgraph = "protein kinase signaling subgraph" p(HGNC:SCN1A) -- bp(PTS:"protein kinase A _PKA_ signaling pathway") bp(PTS:"protein kinase A _PKA_ signaling pathway") -- bp(GOBP:"chemical synaptic transmission") UNSET Subgraph #################################### SET Citation = {"PubMed", "Acta Neuropathol. 2003 May;105(5):515-23.Epub 2003 Feb 20.", "12677453"} SET Evidence = "The growth factor-induced overexpression of beta1 protein was abrogated by PD98059, which inhibits the mitogen-activated protein kinase pathway." SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph"} a(CHEBI:"2-(2-amino-3-methoxyphenyl)chromen-4-one") -| p(HGNC:SCN1B) a(CHEBI:"2-(2-amino-3-methoxyphenyl)chromen-4-one") -| bp(PTS:"mitogen activated protein kinase signaling pathway") p(HGNC:SCN1B) -- bp(PTS:"mitogen activated protein kinase signaling pathway") UNSET Subgraph #################################### SET Citation = {"PubMed", "J Neurosci. 2002 Aug 1;22(15):6372-9.", "12151515"} SET Evidence = " The predominant neuronal glutamate transporter, EAAC1 (for excitatory amino acid carrier-1), is localized to the dendrites and somata of many neurons. " # EAAC1 is SLC1A1 SET Subgraph = {"GABA subgraph", "Neurotransmitter release subgraph"} p(HGNC:SLC1A1) -> a(CHEBI:"glutamate(1-)") SET Evidence = "Because glutamate is a precursor for GABA synthesis" a(CHEBI:"glutamate(1-)") -> a(CHEBI:"GABA agent") a(CHEBI:"glutamate(1-)") -> bp(PTS:"gamma_aminobutyric acid metabolic pathway") SET Evidence = "Reduced expression of EAAC1 by antisense treatment led to behavioral abnormalities, including staring-freezing episodes and electrographic (EEG) seizures." p(HGNC:SLC1A1) -| path(MESHD:Seizures) p(HGNC:SLC1A1) -| path(MESHD:Epilepsy) SET Evidence = " EAAC1 may participate in normal GABA neurosynthesis and limbic hyperexcitability, whereas epilepsy can result from a disruption of the interaction between EAAC1 and GABA metabolism." p(HGNC:SLC1A1) -> bp(PTS:"gamma_aminobutyric acid metabolic pathway") UNSET Subgraph #full text available ################################## SET Citation = {"PubMed", "Exp Neurol. 2015 Nov;273:288-300. doi:10.1016/j.expneurol.2015.09.009. Epub 2015 Sep 21.", "26391563"} SET Evidence = "Astrocyte glutamate transporters GLAST and GLT1 play a key role in regulating neuronal excitation and their levels are altered in patients with epilepsy, and after traumatic brain injury." SET Confidence = "High" SET MeSHDisease = "Brain Injuries" SET MeSHAnatomy = "Astrocytes" g(HGNC:SLC1A3) pos path(MESHD:Epilepsy) g(HGNC:SLC1A2) pos path(MESHD:Epilepsy) p(HGNC:SLC1A2) -- tport(a(CHEBI:"glutamate(1-)")) p(HGNC:SLC1A3) -- tport(a(CHEBI:"glutamate(1-)")) SET Evidence = "We tested the hypothesis that exposure of astrocytes to high levels of thrombin, as may occur after a compromise of the blood-brain barrier, would reduce astrocyte glutamate transporter levels." path(MESHD:"Brain Injuries") -| bp(GOBP:"regulation of maintenance of permeability of blood-brain barrier") bp(GOBP:"regulation of maintenance of permeability of blood-brain barrier") negativeCorrelation p(HGNC:F2) SET Evidence = "Thrombin induced a selective decrease in the expression of GLAST but not GLT1, with a corresponding decrease in the capacity of astrocytes to take up glutamate" SET MeSHAnatomy = "Astrocytes" p(HGNC:F2) -| p(HGNC:SLC1A3) p(HGNC:F2) causesNoChange p(HGNC:SLC1A2) p(HGNC:F2) -| a(CHEBI:"glutamate(1-)") SET Evidence = "In contrast, inhibition of the Rho kinase pathway using the specific inhibitor, Y27632, suppressed both the decrease in the expression of GLAST and the decrease in glutamate uptake induced by thrombin. " SET Confidence = "High" SET Subgraph = {"Glutamatergic subgraph", "Neurotransmitter release subgraph"} a(CHEBI:"Y-27632") -| bp(PTS:"Rho GTPase cycle") p(HGNC:F2) -> bp(PTS:"Rho GTPase cycle") bp(PTS:"Rho GTPase cycle") -> p(HGNC:SLC1A3) bp(PTS:"Rho GTPase cycle") -> a(CHEBI:"glutamate(1-)") p(HGNC:F2) -| a(CHEBI:"glutamate(1-)") UNSET {Subgraph, MeSHAnatomy, Confidence} ###################################### SET Citation = {"PubMed", "JAMA Neurol. 2014 Oct;71(10):1255-65. doi:10.1001/jamaneurol.2014.1584.", "25110966"} SET Evidence = "Glucose transporter type I deficiency (G1D) is commonly associated with seizures and with electrographic spike-waves." SET Confidence = "High" SET Subgraph = "Energy metabolic subgraph" path(EPT:"Glucose transporter type 1 deficiency") -- path(MESHD:Seizures) SET Evidence = "The G1D syndrome has long been attributed to energy (ie, adenosine triphosphate synthetic) failure such as that consequent to tricarboxylic acid (TCA) cycle intermediate depletion." path(EPT:"Glucose transporter type 1 deficiency") -- bp(PTS:"Energy Metabolism") path(EPT:"Glucose transporter type 1 deficiency") -| bp(PTS:"Citrate cycle _TCA cycle_") UNSET Subgraph ######################################## SET Citation = {"PubMed", "J Med Chem. 2014 Aug 14;57(15):6809-21. doi:10.1021/jm5008566. Epub 2014 Jul 25.", "25025595"} SET Evidence = "Inhibition of mGAT1, the most abundant GABA transporter in the brain, enhances GABA signaling and alleviates symptoms of CNS disorders such as epilepsy assumed to be associated with low GABA levels" # mGAT1 is SLC6A1. It seems that the evidence for nipecotic acid as inhibitor of GAT1 is not in the paper but is true SET Subgraph = {"GABA subgraph", "Neurotransmitter release subgraph"} a(CHEBI:"nipecotic acid") -| p(HGNC:SLC6A1) a(CHEBI:"nipecotic acid") -> bp(PTS:"gamma_aminobutyric acid signaling pathway") a(CHEBI:"nipecotic acid") -> a(CHEBI:"GABA agent") a(CHEBI:"nipecotic acid") -| path(MESHD:Epilepsy) p(HGNC:SLC6A1) -| a(CHEBI:"GABA agent") p(HGNC:SLC6A1) -| bp(PTS:"gamma_aminobutyric acid signaling pathway") p(HGNC:SLC6A1) -> path(MESHD:Epilepsy) UNSET Subgraph ####################################### SET Citation = {"PubMed", "Curr Drug Targets. 2011 Jun;12(7):1037-55.", "21291385"} SET Evidence = "Proteins of glutamatergic NMDA receptor signaling pathways have been studied as targets for intervention in a variety of neuropathological conditions, including neurodegenerations, epilepsy, neuropathic pain, drug addiction, and schizophrenia. High activity NMDA-blocking agents have been designed to treat some of these disorders" SET Confidence = "High" a(CHEBI:"NMDA receptor antagonist") -| path(MESHD:Epilepsy) ###################################### SET Citation = {"PubMed", "Brain Res. 2015 Nov 2;1625:314-23. doi:10.1016/j.brainres.2015.08.023. Epub 2015 Aug 28.", "26320550"} SET Evidence = "Extracellular signal-regulated kinase 1/2 (ERK1/2) plays diverse roles in the central nervous system. Activation of ERK1/2 has been observed in various types of neuronal excitation, including seizure activity" SET Confidence = "Medium" SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph"} p(HGNC:MAPK3) -- path(MESHD:Seizures) p(HGNC:MAPK1) -- path(MESHD:Seizures) p(HGNC:MAPK3) -- bp(PTS:"mitogen activated protein kinase signaling pathway") p(HGNC:MAPK1) -- bp(PTS:"mitogen activated protein kinase signaling pathway") SET Evidence = "showed that ERK1/2-dependent phosphorylation of synapsin I was indeed under control of ERK1/2 activity in vivo." SET Confidence = "High" kin(p(HGNC:MAPK3)) -> p(HGNC:SYN1, pmod(P)) kin(p(HGNC:MAPK1)) -> p(HGNC:SYN1, pmod(P)) SET Evidence = "In KA-SE, robust ERK1/2 activation was observed in the hippocampus" SET MeSHAnatomy = "Hippocampus" path(MESHD:"Status Epilepticus") -> bp(PTS:"mitogen activated protein kinase signaling pathway") path(MESHD:"Status Epilepticus") -> p(HGNC:MAPK3) path(MESHD:"Status Epilepticus") -> p(HGNC:MAPK1) UNSET {Subgraph, Confidence, MeSHAnatomy} ######################################### SET Citation = {"PubMed", "Brain Res. 2013 Apr 24;1507:1-10. doi:10.1016/j.brainres.2013.02.015. Epub 2013 Feb 16.", "23419897"} SET Evidence = " Activation of ERK1/2 has been observed in various types of neuronal excitation, including seizure activity in vivo and in vitro, as well as in NMDA-receptor (NMDA-R)-dependent long-term potentiation in the hippocampu" # ERK1 is MAPK3 SET Confidence = "High" SET Subgraph = {"Long term synaptic potentiation", "MAPK-ERK subgraph", "protein kinase signaling subgraph"} path(MESHD:"Seizures") -> p(HGNC:MAPK1) path(MESHD:"Seizures") -> p(HGNC:MAPK3) SET MeSHAnatomy = "Hippocampus" path(MESHD:"Seizures") -> bp(PTS:"Long_Term Potentiation") UNSET Subgraph # full text available ################################### SET Citation = {"PubMed", "Mol Cell Neurosci. 2010 Jun;44(2):190-200.doi: 10.1016/j.mcn.2010.03.007. Epub 2010 Mar 23.", "20338242"} SET Evidence = "epileptic-like seizures typical for synapsin II gene deleted animals (Syn II(-)). " g(HGNC:SYN2, var("del")) pos path(MESHD:Epilepsy) SET Evidence ="Taken together, our results suggest that synapsin II and Rab3a have separate roles in maintaining the total store of synaptic vesicles and cooperate in promoting the latest steps of neuronal secretion" SET Subgraph = "Neurotransmitter release subgraph" p(HGNC:SYN2) -> bp(GOBP:"synaptic vesicle exocytosis") p(HGNC:SYN2) -> bp(PTS:"Synaptic vesicle cycle") p(HGNC:RAB3A) -> bp(GOBP:"synaptic vesicle exocytosis") p(HGNC:RAB3A) -> bp(PTS:"Synaptic vesicle cycle") UNSET Subgraph ################################## SET Citation = {"PubMed", "Synapse. 2015 Jul;69(7):375-83. doi:10.1002/syn.21825. Epub 2015 May 20.", "25967571"} SET Evidence = "A higher expression of TRPV1 protein in the hippocampus as well as a higher distribution of this channel in CA1 and CA3 areas in both acute and chronic phases of pilocarpine-induced SE was observed. " SET MeSHAnatomy = {"CA1 Region, Hippocampal", "CA3 Region, Hippocampal"} path(MESHD:"Status Epilepticus") pos p(HGNC:TRPV1) SET Evidence = "Activation of TRPV1 using capsaicin (1 mM) enhanced LTP induction in CA1 region in non-epileptic rats" SET Confidence = "High" SET MeSHAnatomy = "CA1 Region, Hippocampal" SET Species = "10116" SET Subgraph = "Long term synaptic potentiation" p(HGNC:TRPV1) -> bp(PTS:"Long_Term Potentiation") UNSET {Subgraph, MeSHAnatomy, Species, Confidence} ################################### SET Citation = {"PubMed", "Med Hypotheses. 2009 Jul;73(1):100-2. doi:10.1016/j.mehy.2009.01.005. Epub 2009 Mar 27.", "19328632"} SET Evidence = " TRPV1 activation modulates activity-dependent synaptic efficacy: (i) facilitating long-term potentiation (LTP) and suppressing long-term depression (LTD) of hippocampal neurons" SET Subgraph = "Long term synaptic depression" p(HGNC:TRPV1) -| bp(PTS:"long term depression") UNSET Subgraph SET Evidence = "Nerve growth factor (NGF) can acutely and chronically upregulates TRPV1 expression, suggesting that TRPV1 channels would play an important role in the course of NGF regulated epileptogenesis" SET Confidence = "High" SET Subgraph = "brain_derived neurotrophic factor signaling subgraph" p(HGNC:NGF) -> p(HGNC:TRPV1) UNSET Subgraph SET Evidence = "Moreover, TRPV1 activation triggers apoptotic neuronaldeath of rat cortical cultures, which may be responsible, at least in part, for the volume loss of neocortex in chronic epilepsy. Our" SET Species = "10116" SET Confidence = "Medium" SET Subgraph = "Apoptosis signaling subgraph" p(HGNC:TRPV1) -> bp(GOBP:"apoptotic process") p(HGNC:TRPV1) -> bp(GOBP:"neuron death") UNSET Subgraph ##################################### SET Citation = {"PubMed", "Neuro Oncol. 2015 Dec;17(12):1550-9. doi:10.1093/neuonc/nov152. Epub 2015 Aug 19.", "26289591"} SET Evidence = "TSC is caused by mutations within the TSC1 or TSC2 genes" SET Confidence = "High" SET Subgraph = "mTOR signaling subgraph" g(HGNC:TSC1, var("?")) pos path(MESHD:"Tuberous Sclerosis") g(HGNC:TSC2, var("?")) pos path(MESHD:"Tuberous Sclerosis") SET Evidence = "The molecular connection between TSC and mTOR led to the clinical use of allosteric mTOR inhibitors (sirolimus and everolimus) for the treatment of TSC." bp(PTS:"mTOR signaling pathway") -- path(MESHD:"Tuberous Sclerosis") a(CHEBI:everolimus) -| bp(PTS:"mTOR signaling pathway") a(CHEBI:everolimus) -| p(HGNC:MTOR) a(CHEBI:everolimus) -| path(MESHD:"Tuberous Sclerosis") a(CHEBI:sirolimus) -| bp(PTS:"mTOR signaling pathway") a(CHEBI:sirolimus) -| p(HGNC:MTOR) a(CHEBI:sirolimus) -| path(MESHD:"Tuberous Sclerosis") UNSET Subgraph #################################### SET Citation = {"PubMed", "Biol Psychiatry. 2012 Aug 1;72(3):182-90.doi: 10.1016/j.biopsych.2012.01.021. Epub 2012 Mar 3.", "22381732"} SET Evidence = " Angelman syndrome (AS) is a human neuropsychiatric disorder associated with autism, mental retardation, motor abnormalities, and epilepsy. In most cases, AS is caused by the deletion of the maternal copy of UBE3A gene," #: path(MESHD:"Autism Spectrum Disorder") or path(DO:"Autism Spectrum Disorder") Needs normalization SET Confidence = "High" path(MESHD:"Angelman Syndrome") -- path(MESHD:Epilepsy) path(MESHD:"Angelman Syndrome") -- path(MESHD:"Autism Spectrum Disorder") g(HGNC:UBE3A, var("del")) pos path(MESHD:"Angelman Syndrome") ################################### SET Citation = {"PubMed", "Mol Cell Biol. 1999 Feb;19(2):1182-9.", "9891052"} SET Evidence = "This finding suggests that the AS phenotype results from a defect in the ubiquitin-proteosome protein degradation pathway." SET Subgraph = {"Protein Metabolism", "Metabolism"} SET Confidence = "High" bp(PTS:"ubiquitin proteasomal pathway") -- path(MESHD:"Angelman Syndrome") p(HGNC:UBE3A) -> bp(PTS:"ubiquitin proteasomal pathway") deg(p(HGNC:UBE3A)) -| bp(PTS:"ubiquitin proteasomal pathway") UNSET Subgraph ################################### SET Citation = {"PubMed", "J Neuroinflammation. 2012 Jul 31;9:184.", "22849356"} SET Evidence = "Activation of PPAR gamma upregulated mitochondrial UCP2 expression, which decreased overproduction of reactive oxygen species, improved mitochondrial Complex I dysfunction, inhibited mitochondrial translocation of Bax and prevented cytosolic release of cytochrome c by stabilizing the mitochondrial transmembrane potential, leading to amelioration of apoptotic neuronal cell death in the hippocampus following status epilepticus." SET Confidence = "High" SET MeSHAnatomy="Hippocampus" SET Subgraph = "Apoptosis signaling subgraph" p(HGNC:PPARG) -> p(HGNC:UCP2) p(HGNC:UCP2) -| a(CHEBI:"reactive oxygen species") p(HGNC:UCP2) -| bp(GOBP:"neuron death") p(HGNC:UCP2) -| bp(GOBP:"apoptotic process") UNSET {Subgraph, Confidence, MeSHAnatomy} ################################### SET Citation = {"PubMed", "Neurotherapeutics. 2014 Apr;11(2):385-400. doi: 10.1007/s13311-014-0266-1.", "24671870"} # medication SET Evidence = "While the precise way in which valproate protects against seizures is still obscure, the drug has a variety of actions, including effects on Na+ and T-type Ca2+ channels, and also on gamma-aminobutyric acid (GABA) metabolism [8]." SET Confidence = "High" SET Drug = "valproate" SET Subgraph = {"GABA subgraph", "Neurotransmitter release subgraph"} a(CHEBI:valproate) -- bp(PTS:"gamma_aminobutyric acid metabolic pathway") UNSET Subgraph UNSET Drug SET Evidence = "ethosuximide was introduced nearly 5 decades ago and continues to constitute a first-line treatment for the symptomatic treatment of absence seizures. Its primary mechanism relates to inhibition of T-type Ca2+ channels" SET Confidence = "High" SET Subgraph = {"Calcium dependent subgraph", "MAPK-ERK subgraph", "protein kinase signaling subgraph", "Serotonergic subgraph", "Neurotransmitter release subgraph"} a(CHEBI:ethosuximide) -| p(HGNC:CACNA1G) SET Evidence = "The number, but not duration, of the SWDs was found to be markedly suppressed during 3 months of sequential recordings performed after termination of treatment, revealing an antiepileptogenic potential of ethosuximide. " SET Confidence = "High" a(CHEBI:ethosuximide) -| bp(EPT:epileptogenesis) bp(EPT:epileptogenesis) -> path(MESHD:Epilepsy) SET Evidence = "Furthermore, ethosuximide also seems to prevent comorbid anxiety [32] and depression [31, 33] in the genetic absence epilepsy models," SET Confidence = "High" a(CHEBI:ethosuximide) -| path(DO:"anxiety disorder") a(CHEBI:ethosuximide) -| path(DO:"major depressive disorder") SET Evidence = "Indeed, T-type Ca2+ channels seem to play a critical role in the epileptogenic process in the mouse pilocarpine SE model" # CACNA1G is Calcium Channel, Voltage-Dependent, T Type, Alpha 1G Subunit SET Confidence = "High" SET Species = "10090" p(HGNC:CACNA1G) -> bp(EPT:epileptogenesis) SET Evidence = "In this model, increased T-type Ca2+ current and intrinsic burst firing in hippocampal CA1 pyramidal neurons was associated with later spontaneous seizure expression." #: Check this one SET MeSHAnatomy="CA1 Region, Hippocampal" SET Cell = "pyramidal neuron" # p(HGNC:CACNA1G) -> path(MESHD:Seizures) UNSET MeSHAnatomy UNSET Cell SET Evidence = "It has also been observed that antiepileptogenic treatment with ethosuximide in the WAG/Rij rat prevented activity-dependent changes in the expression of Nav 1.1, Nav 1.6, and HCN1 ion channels, which may reduce excitability and contributed to the reduced emergence of seizures " SET Species = "10116" a(CHEBI:ethosuximide) -| p(HGNC:SCN1A) a(CHEBI:ethosuximide) -| p(HGNC:SCN8A) a(CHEBI:ethosuximide) -| p(HGNC:HCN1) p(HGNC:SCN1A) -> bp(EPT:epileptogenesis) p(HGNC:SCN8A) -> bp(EPT:epileptogenesis) p(HGNC:HCN1) -> bp(EPT:epileptogenesis) UNSET {Species, Subgraph} SET Evidence = "Topiramate is a newer, structurally novel ASD with multiple pharmacological actions that could contribute to its ability to protect against seizures. These include modulatory effects on Na+ and Ca2+ channels, GABAA receptors, and ionotropic glutamate receptors." SET Drug = "topiramate" SET Subgraph = {"GABA subgraph", "Neurotransmitter release subgraph", "Calcium dependent subgraph", "thyroid hormone signaling subgraph", "hormone signaling subgraph", "Glutamatergic subgraph", "Long term synaptic potentiation", "Long term synaptic depression", "Serotonergic subgraph"} SET Confidence = "High" a(CHEBI:topiramate) -- p(HGNC:CACNA1A) a(CHEBI:topiramate) -- p(HGNC:SCN1A) a(CHEBI:topiramate) -- p(HGNC:GABRA1) a(CHEBI:topiramate) -- p(HGNC:GRIN1) SET Evidence = "An initial preliminary study in the rat pilocarpine model of SE found topiramate to be both neuroprotective and antiepileptogenic" SET Confidence = "High" SET Species = "10116" a(CHEBI:topiramate) isA a(CHEBI:"neuroprotective agent") a(CHEBI:topiramate) -| bp(EPT:epileptogenesis) UNSET Species UNSET Subgraph UNSET Drug SET Evidence = "Levetiracetam is another newer ASD which, like topiramate, possesses a novel chemical structure and has diverse pharmacological actions [51]. For example, the drug reduces high voltage-activated Ca2+ currents, inhibits intracellular Ca2+ release through the IP3 and ryanodine receptors associated with the endoplasmatic reticulum, reverses the inhibitory effects of zinc on both GABAA- and glycine receptor-mediated currents, and inhibits AMPA." SET Drug = "levetiracetam" SET Subgraph = {"Neurotransmitter release subgraph", "GABA subgraph", "Calcium dependent subgraph", "Serotonergic subgraph"} SET Confidence = "Low" a(CHEBI:levetiracetam) -|tloc(a(CHEBI:"calcium(2+)"), fromLoc(GOCC:"intracellular"), toLoc(GOCC:"extracellular space")) #: Check these statements a(CHEBI:levetiracetam) -- bp(PTS:"Calcium signaling pathway") a(CHEBI:levetiracetam) -| p(HGNC:ITPR1) p(HGNC:ITPR1) -- a(CHEBI:"calcium(2+)") p(HGNC:ITPR1) -> bp(PTS:"Calcium signaling pathway") a(CHEBI:"1D-myo-inositol 1,4,5-trisphosphate") -> p(HGNC:ITPR1) a(CHEBI:levetiracetam) -| p(HGNC:RYR1) a(CHEBI:levetiracetam) -> p(HGNC:GABRA1) a(CHEBI:levetiracetam) -> p(HGNC:GLRA1) a(CHEBI:levetiracetam) -| a(CHEBI:"AMPA receptor agonist") SET Evidence = "However, the most likely target of relevance to the antiseizure actions of levetiracetam is synaptic vesicle protein 2A (SV2A), a ubiquitous presynaptic protein. SV2A-deficient mice show a marked reduction in the anticonvulsant activity of levetiracetam, confirming the role of SV2A in the seizure protection conferred by the drug" SET Confidence = "High" SET Species = "10090" composite(a(CHEBI:levetiracetam),p(HGNC:SV2A)) -| path(MESHD:Seizures) p(HGNC:SV2A) -| a(CHEBI:levetiracetam) p(HGNC:SV2A) -- path(MESHD:Epilepsy) SET Evidence = "levetiracetam has also exhibited neuroprotective properties in SE studies [28, 63] and an ability to suppress seizure-induced neurogenesis [62], whereas cognitive impairment induced by SE was not prevented" SET Confidence = "High" a(CHEBI:levetiracetam) isA a(CHEBI:"neuroprotective agent") UNSET {Subgraph, Confidence, Drug} SET Evidence = " In this context it is noteworthy that the selective, high-affinity SV2A ligand brivaracetam shows more pronounced antiepileptogenic effects than levetiracetam in the kindling model" SET Subgraph = {"Neurotransmitter release subgraph", "Serotonergic subgraph"} ###a(CHEBI:brivaracetam) isA a(CHEBI:anticonvulsant) ###a(CHEBI:brivaracetam) -> p(HGNC:SV2A) ###a(CHEBI:brivaracetam) -| bp(EPT:epileptogenesis) UNSET Subgraph SET Evidence = "Rapidly mounting evidence indicates a potential role of inflammation in the pathophysiology of epilepsy and epileptogenesis" SET Confidence = "High" path(MESHD:Inflammation) -- path(MESHD:Epilepsy) path(MESHD:Inflammation) -- bp(EPT:epileptogenesis) SET Evidence = "The interleukin 1 beta pathway is one of the best characterized inflammatory pathways in epilepsy." SET Confidence = "High" SET Subgraph = "Interleukin signaling subgraph" bp(PTS:"IL_1beta pathway") -- path(MESHD:Inflammation) bp(PTS:"IL_1beta pathway") -- path(MESHD:Epilepsy) SET Evidence = "Seminal work performed by Dr. Annamaria Vezzani and her collaborators has provided compelling evidence for a pathophysiological role of IL1-beta in epilepsy" SET Confidence = "High" bp(PTS:"IL_1beta pathway") -- path(MESHD:Epilepsy) SET Evidence = "For example, VX-765 is an orally active IL-converting enzyme/caspase-1 inhibitor that blocks IL1 beta secretion and produces a strong anti-inflammatory effect" SET Confidence = "High" a(MESHC:"1-(2-((1-(4-amino-3-chlorophenyl)methanoyl)amino)-3,3-dimethylbutanoyl)pyrrolidine-2-carboxylic acid") -| sec(p(HGNC:IL1B)) a(MESHC:"1-(2-((1-(4-amino-3-chlorophenyl)methanoyl)amino)-3,3-dimethylbutanoyl)pyrrolidine-2-carboxylic acid") -| path(MESHD:Inflammation) SET Evidence = "ubchronic treatment (4 days) with VX-765 before acute kainate injection reduces the duration and number of seizures during SE" a(MESHC:"1-(2-((1-(4-amino-3-chlorophenyl)methanoyl)amino)-3,3-dimethylbutanoyl)pyrrolidine-2-carboxylic acid") -| bp(EPT:epileptogenesis) SET Evidence = "The drug combination significantly decreased IL1‚beta‚⧠expression and exerted a neuroprotective effect" a(MESHC:"1-(2-((1-(4-amino-3-chlorophenyl)methanoyl)amino)-3,3-dimethylbutanoyl)pyrrolidine-2-carboxylic acid") isA a(CHEBI:"neuroprotective agent") UNSET Subgraph SET Evidence = "Experimental data from a mouse model of TLE indicate that seizures cause increased expression of vascular cell adhesion molecules, and enhance leukocyte rolling and arrest in brain vessels " SET Confidence = "High" SET Species = "10090" path(MESHD:Seizures) -> bp(GOBP:"leukocyte tethering or rolling") UNSET Species SET Evidence = "These effects could be mediated by specific leukocyte integrins, such as‚beta1 integrin [very late antigen-4 " SET Confidence = "High" p(HGNC:ITGA4) reg bp(GOBP:"leukocyte tethering or rolling") p(HGNC:ITGA4) reg bp(GOBP:"leukocyte migration") SET Evidence = "Nevertheless, these observations suggest that inhibition of leukocyte migration into the brain could be a promising therapeutic strategy in epilepsy." SET Anatomy = "brain" bp(GOBP:"leukocyte migration") -> bp(EPT:epileptogenesis) bp(GOBP:"leukocyte migration") -> path(MESHD:Epilepsy) UNSET Anatomy SET Evidence = "This is particularly attractive as the VLA-4 blocking antibody natalizumab is already approved for the treatment of multiple sclerosis" SET Confidence = "High" a(MESHC:Natalizumab) -| p(HGNC:ITGA4) a(MESHC:Natalizumab) -| path(MESHD:"Multiple Sclerosis") a(MESHC:Natalizumab) -| bp(GOBP:"leukocyte migration") SET Evidence = "There are several reports from experimental epilepsy models suggesting that COX-2 inhibitors may have potential disease-modifying properties; however, the results have not been consistent [84]. Jung et al. [85] reported that celecoxib has antiepileptic and neuroprotective effects in the lithium-pilocarpine model in rats." SET Species = "10116" SET Subgraph = "Interleukin signaling subgraph" p(HGNC:PTGS2) -- path(MESHD:Inflammation) a(CHEBI:celecoxib) -| p(HGNC:PTGS2) a(CHEBI:celecoxib) -| bp(EPT:epileptogenesis) p(HGNC:PTGS2) -> bp(EPT:epileptogenesis) a(CHEBI:celecoxib) isA a(CHEBI:"neuroprotective agent") UNSET Species SET Evidence = "Unfortunately, clinical use of selective COX-2 inhibitors has been associated with significantly increased risk of cardiovascular diseases " SET Confidence = "High" a(CHEBI:celecoxib) pos path(MESHD:"Cardiovascular Diseases") UNSET Subgraph SET Evidence = "Indeed, recent data indicate that small molecule inhibitors of prostaglandin E2 receptor subtype EP2 are neuroprotective when administered after SE" p(HGNC:PTGER2) -> bp(EPT:epileptogenesis) SET Evidence = "Fingolimod (FTY720), a sphingosine analog that acts as a sphingosine 1-phosphate receptor modulator, is an approved oral treatment for relapsing forms of multiple sclerosis" a(CHEBI:fingolimod) -| path(MESHD:"Multiple Sclerosis") a(CHEBI:fingolimod) -- p(HGNC:S1PR1) SET Evidence = "Fingolimod inhibits lymphocyte egress, selectively retaining lymphocytes within the lymph nodes, but, in addition, it acts on a number of neuronal and non-neuronal cells to exert neuroprotective and anti-inflammatory effects in the brain" a(CHEBI:fingolimod) -| path(MESHD:Inflammation) a(CHEBI:fingolimod) isA a(CHEBI:"neuroprotective agent") SET Evidence = "Interestingly, fingolimod produced a clear-cut neuroprotective effect, inhibiting pathological mossy fiber sprouting, decreasing activation of microglia and restoring abnormal expression of IL1beta in the hippocampus" a(CHEBI:fingolimod) -| bp(EPT:epileptogenesis) SET MeSHAnatomy = "Hippocampus" SET Subgraph = {"Mossy Fiber Subgraph", "Interleukin signaling subgraph"} a(CHEBI:fingolimod) -| bp(GOBP:"microglial cell activation") a(CHEBI:fingolimod) -| p(HGNC:IL1B) UNSET Subgraph UNSET MeSHAnatomy SET Evidence = "A plethora of largely preclinical studies has found broad therapeutic potential of resveratrol in the treatment of diverse conditions, including metabolic syndromes, cancer, and cardiovascular diseases. " SET Confidence = "High" a(CHEBI:resveratrol) -| path(DO:cancer) a(CHEBI:resveratrol) -| path(MESHD:"Metabolic Diseases") a(CHEBI:resveratrol) -| path(MESHD:"Cardiovascular Diseases") SET Evidence = "The incidence and rate of spontaneous seizures was markedly reduced in the resveratrol treatment group. The effect on seizures was associated with neuroprotection in the hippocampus, as well as a reduction in mossy fiber sprouting" SET Confidence = "High" SET Subgraph = "Mossy Fiber Subgraph" a(CHEBI:resveratrol) -| bp(EPT:epileptogenesis) UNSET Subgraph SET Evidence = "Overall, Nrf2 coordinates the expression of numerous genes encoding detoxification, antioxidant, and anti-inflammatory mediators, and calcium homeostasis and signaling proteins resulting in an orchestrated protective response." SET Subgraph = "Calcium dependent subgraph" p(HGNC:NFE2L2) -> bp(PTS:"inflammatory response pathway") p(HGNC:NFE2L2) -> bp(GOBP:"calcium ion homeostasis") p(HGNC:NFE2L2) -> bp(PTS:"Calcium signaling pathway") p(HGNC:NFE2L2) -- a(CHEBI:"reactive oxygen species") UNSET Subgraph SET Evidence = "Indeed, Nrf2 exerts a protective role in a number of neurodegenerative disease models" SET Confidence = "High" p(HGNC:NFE2L2) isA a(CHEBI:"neuroprotective agent") SET Evidence = "Together, these recent results provide a strong rationale for the investigation of small molecule activators the Nrf2 pathway to treat epilepsy" p(HGNC:NFE2L2) -> bp(PTS:"nuclear factor erythroid 2_related factor 2 _Nrf2_ signaling pathway") bp(PTS:"nuclear factor erythroid 2_related factor 2 _Nrf2_ signaling pathway") -| path(MESHD:Epilepsy) bp(PTS:"nuclear factor erythroid 2_related factor 2 _Nrf2_ signaling pathway") -| bp(EPT:epileptogenesis) SET Evidence = "For example, dimethyl fumarate (BG-12) has recently been licensed for the treatment of relapsing remitting multiple sclerosis [109]." a(MESHC:"Dimethyl Fumarate") -| path(MESHD:"Multiple Sclerosis") a(MESHC:"Dimethyl Fumarate") -> p(HGNC:NFE2L2) a(MESHC:"Dimethyl Fumarate") -> bp(PTS:"nuclear factor erythroid 2_related factor 2 _Nrf2_ signaling pathway") SET Evidence = "Recent studies have indicated that mTOR plays a role in the epileptogenic process in TS inasmuch as early treatment with the mTOR inhibitor rapamycin can prevent the development of epilepsy" SET Subgraph = "mTOR signaling subgraph" p(HGNC:MTOR) -> bp(EPT:epileptogenesis) bp(PTS:"mTOR signaling pathway") -> bp(EPT:epileptogenesis) a(CHEBI:sirolimus) -| bp(EPT:epileptogenesis) UNSET Subgraph SET Evidence = "The peroxisome proliferator-activated receptors (PPARs) constitute a group of three nuclear receptor isoforms: PPAR-gamma alpha and delta. They operate as ligand-regulated transcription factors, which heterodimerize with retinoid X receptor and upon agonist binding interact with various cofactors to initiate gene transcription. Fatty acids are the natural ligands for PPARs, which thereby serve as lipid sensors and regulators of lipid metabolism." SET Subgraph = "Metabolism" p(HGNC:PPARG) -- bp(PTS:"Lipid Metabolism") p(HGNC:PPARA) -- bp(PTS:"Lipid Metabolism") p(HGNC:PPARD) -- bp(PTS:"Lipid Metabolism") UNSET Subgraph SET Evidence = "Consequently, synthetic PPAR ligands have been developed for the treatment of dyslipidemias and diabetes. However, emerging research indicates broader potential of these ligands as therapies for atherosclerosis, inflammation, cancer, demyelination, and several neurological diseases" p(HGNC:PPARG) -- path(MESHD:"Diabetes Mellitus") p(HGNC:PPARA) -- path(MESHD:"Diabetes Mellitus") p(HGNC:PPARD) -- path(MESHD:"Diabetes Mellitus") p(HGNC:PPARG) -- path(MESHD:"Neurodegenerative Diseases") p(HGNC:PPARA) -- path(MESHD:"Neurodegenerative Diseases") p(HGNC:PPARD) -- path(MESHD:"Neurodegenerative Diseases") SET Evidence = "Many PPARgamma agonists have been tested in various models of epilepsy and it has generally been found that these agents protect against seizures" a(CHEBI:"PPARgamma agonist") -> p(HGNC:PPARG) a(CHEBI:"PPARgamma agonist") -| path(MESHD:Seizures) a(CHEBI:"PPARgamma agonist") isA a(CHEBI:anticonvulsant) SET Evidence = "For example, pioglitazone delayed the development of seizures in genetically epileptic EL mice, which was associated with overall reduction in several neuroinflammation biomarkers" SET Confidence = "High" a(CHEBI:pioglitazone) isA a(CHEBI:"PPARgamma agonist") a(CHEBI:pioglitazone) -> p(HGNC:PPARG) SET Species = "10090" a(CHEBI:pioglitazone) -| path(MESHD:Seizures) a(CHEBI:pioglitazone) isA a(CHEBI:anticonvulsant) UNSET Species SET Evidence = "Fenofibrate displayed anticonvulsant effects in the lithium pilocarpine SE model and against pentylentetrazol-induced seizures" a(CHEBI:fenofibrate) isA a(CHEBI:"PPARgamma agonist") a(CHEBI:fenofibrate) -> p(HGNC:PPARG) SET Species="10090" a(CHEBI:fenofibrate) -| path(MESHD:Seizures) a(CHEBI:fenofibrate) isA a(CHEBI:anticonvulsant) UNSET Species SET Evidence = "Another PPAR‚beta agonist, rosiglitazone, consistently displayed significant neuroprotective effects and attenuated inflammatory responses after induction of SE " SET Confidence = "High" SET MeSHDisease = "Status Epilepticus" a(CHEBI:rosiglitazone) isA a(CHEBI:"PPARgamma agonist") a(CHEBI:rosiglitazone) -> p(HGNC:PPARG) a(CHEBI:rosiglitazone) -| path(MESHD:Seizures) a(CHEBI:rosiglitazone) isA a(CHEBI:anticonvulsant) a(CHEBI:rosiglitazone) -| bp(PTS:"inflammatory response pathway") UNSET {MeSHDisease, Confidence} SET Evidence = "Importantly, intracerebroventricular rosiglitazone administered prior to the administration of lithium‚pilocarpine also decreased the number of spontaneous recurrent seizures in the chronic phase beginning 2 weeks after SE, although it did not affect the severity of SE in the acute phase; some of its protective effects were indirectly mediated by TrkB signaling" SET Subgraph = "brain_derived neurotrophic factor signaling subgraph" a(CHEBI:rosiglitazone) -| bp(EPT:epileptogenesis) p(HGNC:PPARG) -| bp(EPT:epileptogenesis) a(CHEBI:rosiglitazone) -> bp(PTS:"brain_derived neurotrophic factor signaling pathway") p(HGNC:PPARG) -> bp(PTS:"brain_derived neurotrophic factor signaling pathway") UNSET Subgraph SET Evidence = "Ordinarily, tPA is expressed at low levels in the brain, but its synthesis is increased by seizures" SET Confidence = "High" SET Anatomy = "brain" SET Subgraph = "Mossy Fiber Subgraph" path(MESHD:Seizures) -> p(HGNC:PLAT) UNSET {Subgraph, Anatomy, Confidence} SET Evidence = "Mutation of the neuroserpin gene, which is a serine proteinase inhibitor of tPA, has been associated with progressive myoclonic epilepsy raising the possibility that epileptogenesis occurs when tPA activity in brain is unrestrained by neuroserpin" SET Confidence = "High" SET Subgraph = "Apoptosis signaling subgraph" p(HGNC:SERPINI1) -| p(HGNC:PLAT) g(HGNC:SERPINI1, var("?")) pos path(MESHD:"Myoclonic Epilepsies, Progressive") p(HGNC:PLAT) -> bp(EPT:epileptogenesis) SET Evidence = "Collectively, the data raise the possibility that strategies to reduce the activity of brain tPA or increase the activity of neuroserpin could be antiepileptogenic" SET Confidence = "High" SET Anatomy = "brain" p(HGNC:SERPINI1) -| bp(EPT:epileptogenesis) UNSET {Subgraph, Anatomy, Confidence} SET Evidence = "In particular, there is evidence that exogenous EPO administration can protect against seizures" SET Confidence = "High" SET Subgraph = "hormone signaling subgraph" p(HGNC:EPO) -| path(MESHD:Seizures) p(HGNC:EPO) isA a(CHEBI:anticonvulsant) UNSET {Confidence, Subgraph} SET Evidence = "More importantly, EPO treatment reduced the risk for the development of spontaneous recurrent seizures and led to a reduction in the seizure duration" SET Confidence = "High" SET Subgraph = "hormone signaling subgraph" p(HGNC:EPO) -| bp(EPT:epileptogenesis) UNSET {Confidence, Subgraph} SET Evidence = "This may occur because SE increases transcript levels of hypoxia-inducible factor-1‚ the regulatory subunit of hypoxia-inducible factor-1, which regulates the gene for EPO and vascular endothelial growth factor (VEGF; see below)." SET Confidence = "High" path(MESHD:"Status Epilepticus") -> p(HGNC:HIF1A) p(HGNC:HIF1A) -> p(HGNC:EPO) p(HGNC:HIF1A) -> p(HGNC:VEGFA) SET Evidence = "However, in humans and rodents, ongoing angiogenesis and BBB disruption are still evident in the epileptic focus during the chronic phase of the disease, probably as a result of ongoing recurrent seizures " bp(GOBP:"establishment of blood-brain barrier") -- path(MESHD:Epilepsy) bp(GOBP:angiogenesis) -- path(MESHD:Epilepsy) path(MESHD:Seizures) -> bp(GOBP:angiogenesis) SET Evidence = "VEGF is a key signal promoting angiogenesis, but it also alters BBB permeability and enhances monocyte infiltration into brain pareSCOMPyma" SET Confidence = "High" p(HGNC:VEGFA) -> bp(GOBP:angiogenesis) p(HGNC:VEGFA) -- bp(GOBP:"establishment of blood-brain barrier") SET Evidence = "If VEGF is involved in the maintenance of the epileptic state, anti-VGEF therapies such as Bevacizumab and ranibizumab that are marketed for several cancer indications and for ophthalmic diseases could be beneficial in therapy of epilepsy or epileptogenesis" SET Confidence = "High" a(MESHC:Bevacizumab) -| p(HGNC:VEGFA) a(MESHC:Bevacizumab) -| p(HGNC:VEGFA) p(HGNC:VEGFA) -> path(MESHD:Epilepsy) p(HGNC:VEGFA) -> bp(EPT:epileptogenesis) a(MESHC:Bevacizumab) -| path(MESHD:Epilepsy) a(MESHC:Bevacizumab) -| bp(EPT:epileptogenesis) a(MESHC:Bevacizumab) -| path(DO:cancer) a(MESHC:Ranibizumab) -| path(MESHD:Epilepsy) a(MESHC:Ranibizumab) -| bp(EPT:epileptogenesis) a(MESHC:Ranibizumab) -| path(DO:cancer) SET Evidence = "Unfortunately, VEGF plays an important neuroprotective role so that aproaches aiming at diminution of VEGF signaling could be problematic" SET Confidence = "High" p(HGNC:VEGFA) isA a(CHEBI:"neuroprotective agent") SET Evidence = "VEGF-R2, a receptor tyrosine kinase, mediates most of the cellular responses to VEGF, including its neuroprotective actions" SET Confidence = "High" p(HGNC:VEGFA) -> p(HGNC:KDR) p(HGNC:KDR) isA a(CHEBI:"neuroprotective agent") p(HGNC:KDR) -| path(MESHD:"Neurodegenerative Diseases") SET Evidence = "Moreover, VEGF-R2 overexpression in mice exerted an antiseizure effect, but failed to affect kindling epileptogenesis" SET Confidence = "High" SET Species = "10090" p(HGNC:KDR) neg path(MESHD:Seizures) p(HGNC:KDR) causesNoChange bp(EPT:epileptogenesis) UNSET Species SET Evidence = "Statins are a class of drugs used to lower cholesterol levels by inhibiting the enzyme HMG-CoA reductase, which plays a central role in the production of cholesterol in the liver" SET Confidence = "High" a(CHEBI:statin) -| p(HGNC:HMGCR) p(HGNC:HMGCR) -> a(CHEBI:cholesterol) SET Evidence = "For example, treatment with atorvastatin and simvastatin produced clear-cut neuroprotective and anti-inflammatory effects in the kainate model of TLE [" SET Confidence = "High" a(CHEBI:atorvastatin) isA a(CHEBI:statin) a(CHEBI:simvastatin) isA a(CHEBI:statin) a(CHEBI:atorvastatin) isA a(CHEBI:"neuroprotective agent") a(CHEBI:atorvastatin) -| bp(EPT:epileptogenesis) a(CHEBI:atorvastatin) -| path(MESHD:Inflammation) a(CHEBI:simvastatin) isA a(CHEBI:"neuroprotective agent") a(CHEBI:simvastatin) -| bp(EPT:epileptogenesis) a(CHEBI:simvastatin) -| path(MESHD:Inflammation) SET Evidence = "Emerging evidence suggests that activation of BDNF receptor TrkB promotes epileptogenesis caused by SE" SET Confidence = "High" SET Subgraph = "brain_derived neurotrophic factor signaling subgraph" p(HGNC:NTRK2) -> bp(EPT:epileptogenesis) path(MESHD:"Status Epilepticus") -> bp(EPT:epileptogenesis) UNSET {Confidence, Subgraph} SET Evidence = "Indeed, animal models of TLE are associated with a strong increase in BDNF expression and enhanced activation of TrkB, while infusion of BDNF and transgenic overexpression of BDNF or TrkB increase seizure susceptibility or severity" SET Confidence = "High" SET Subgraph = "brain_derived neurotrophic factor signaling subgraph" bp(PTS:"brain_derived neurotrophic factor signaling pathway") -> bp(EPT:epileptogenesis) p(HGNC:NTRK2) -> bp(PTS:"brain_derived neurotrophic factor signaling pathway") UNSET {Confidence, Subgraph} SET Evidence = "Combined augmentation of fibroblast growth factor-2 (FGF-2) and BDNF increased neurogenesis, reduced neuronal loss, and, most importantly, reduced the occurrence of spontaneous seizures in a model of TLE" SET Confidence = "High" SET Subgraph = "brain_derived neurotrophic factor signaling subgraph" composite(p(HGNC:FGF2), p(HGNC:BDNF)) -> bp(GOBP:neurogenesis) composite(p(HGNC:FGF2), p(HGNC:BDNF)) -| bp(GOBP:"neuron death") composite(p(HGNC:FGF2), p(HGNC:BDNF)) -| path(MESHD:Seizures) composite(p(HGNC:FGF2), p(HGNC:BDNF)) -> bp(PTS:"brain_derived neurotrophic factor signaling pathway") UNSET {Confidence, Subgraph} SET Evidence = "Interestingly, antiepileptogenic effects of FGF-2 and BDNF might involve inhibition of neuroinflammatory mechanisms" SET Confidence = "Medium" SET Subgraph = "brain_derived neurotrophic factor signaling subgraph" p(HGNC:FGF2) -| path(MESHD:Inflammation) p(HGNC:BDNF) -| path(MESHD:Inflammation) path(MESHD:Inflammation) -> bp(EPT:epileptogenesis) p(HGNC:FGF2) -| bp(EPT:epileptogenesis) p(HGNC:BDNF) -| bp(EPT:epileptogenesis) UNSET Subgraph SET Evidence = "Adrenergic receptors are a family of G protein-coupled receptors that serve as the targets of the neurotransmitter norepinephrine" SET Confidence = "High" SET Subgraph = "G-protein-mediated signaling" a(MESHC:Norepinephrine) -> p(HGNC:ADRA2A) a(MESHC:Norepinephrine) isA a(CHEBI:neurotransmitter) UNSET {Confidence, Subgraph} SET Evidence = "Specifically, stimulation of a2 adrenergic receptors is generally anticonvulsant, while blockade of these receptors is proconvulsant" SET Confidence = "High" SET Subgraph = "G-protein-mediated signaling" p(HGNC:ADRA2A) -| path(MESHD:Seizures) UNSET {Confidence, Subgraph} SET Evidence = "the observation of Pitk/E4nen et al. [167] that inhibition of a2 adrenergic receptors may have disease-modifying and neuroprotective effects in a model of TLE is intriguing. atipamezole, a selective a2 adrenergic receptor antagonist, was started 1 week after the induction of SE by electrical stimulation of the amygdala" SET Subgraph = "G-protein-mediated signaling" SET Confidence = "High" a(MESHC:atipamezole) -| p(HGNC:ADRA2A) a(MESHC:atipamezole) isA a(CHEBI:"neuroprotective agent") UNSET {Confidence, Subgraph} SET Evidence = "Inasmuch as atipamezole, like other a2 adrenergic receptor blockers, has proconvulsant activity [168], this study clearly rebuts the conventional view that assumes antiseizure treatments will lead to antepileptogenesis. " SET Confidence = "High" SET Subgraph = "G-protein-mediated signaling" a(MESHC:atipamezole) -> path(MESHD:Seizures) a(MESHC:atipamezole) -> path(MESHD:Epilepsy) a(MESHC:atipamezole) -| bp(EPT:epileptogenesis) UNSET {Confidence, Subgraph} SET Evidence = "Studies have demonstrated that cannabinoid agonists are acutely anticonvulsant, whereas cannabinoid antagonists, including the selective CB1 antagonist SR141716A (rimonabant), are acutely proconvulsant" SET Subgraph = "G-protein-mediated signaling" SET Confidence = "High" a(CHEBI:"cannabinoid receptor agonist") isA a(CHEBI:anticonvulsant) a(CHEBI:"cannabinoid receptor antagonist") -> path(MESHD:Seizures) p(HGNC:CNR1) -| path(MESHD:Seizures) p(HGNC:CNR1) -| path(MESHD:Epilepsy) a(MESHC:rimonabant) -| p(HGNC:CNR1) a(MESHC:rimonabant) -> path(MESHD:Seizures) a(MESHC:rimonabant) -> path(MESHD:Epilepsy) SET Evidence = "SR141716A treatment prevents the development of increased seizure susceptibility when administered during or shortly after a brain insult in models of prolonged febrile seizures" SET Confidence = "High" a(MESHC:rimonabant) -| bp(EPT:epileptogenesis) UNSET Subgraph SET Evidence = "Bumetanide, an inhibitor of NKCC1, prevents the outward flow of Cl-, opposing the shift in Cl- equilibrium potential and the depolarizing action of GABA, which leads to an anticonvulsant action" SET Confidence = "High" SET Subgraph = {"GABA subgraph", "Neurotransmitter release subgraph"} a(MESHC:Bumetanide) -| p(HGNC:SLC12A2) p(HGNC:SLC12A2) -> bp(GOBP:"chloride transmembrane transport") a(MESHC:Bumetanide) -| bp(GOBP:"chloride transmembrane transport") p(HGNC:SLC12A2) -- a(CHEBI:"GABA agent") a(MESHC:Bumetanide) -- a(CHEBI:"GABA agent") a(MESHC:Bumetanide) -| path(MESHD:Seizures) a(MESHC:Bumetanide) isA a(CHEBI:anticonvulsant) UNSET Subgraph ##################################### # MAPK Signaling ##################################### SET Citation = {"PubMed", "EMBO J. 2007 Nov 28;26(23):4891-901. Epub 2007 Nov 1.", "17972914"} SET Evidence = "ERK kinases are the only known substrates of MEK1 and MEK2" SET Confidence = "High" SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph"} kin(p(HGNC:MAP2K1)) -> p(HGNC:MAPK1, pmod(P)) kin(p(HGNC:MAP2K1)) -> p(HGNC:MAPK3, pmod(P)) kin(p(HGNC:MAP2K2)) -> p(HGNC:MAPK1, pmod(P)) kin(p(HGNC:MAP2K2)) -> p(HGNC:MAPK3, pmod(P)) SET Evidence = "The ERK kinases are abundantly expressed in the central nervous system and are activated in response to various physiological stimuli associated with synaptic activity and plasticity, most notably calcium influx and neurotrophins, but also during pathological events such as brain ischaemia and epilepsy" SET Confidence = "High" a(MESHC:neurotropin) -> act(p(HGNC:MAPK1)) a(MESHC:neurotropin) -> act(p(HGNC:MAPK3)) SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph", "Calcium dependent subgraph"} bp(GOBP:"calcium ion import") -> act(p(HGNC:MAPK1)) bp(GOBP:"calcium ion import") -> act(p(HGNC:MAPK3)) SET Subgraph = "brain_derived neurotrophic factor signaling subgraph" p(HGNC:BDNF) isA a(MESHC:neurotropin) UNSET Subgraph SET Evidence = "ERK can activate several classes of kinases, including the ribosomal S6 kinase (RSK) and MAPK-interacting kinase (Mnk) protein families" SET Confidence = "High" SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph"} p(HGNC:MAPK1) -> act(p(HGNC:RPS6KA1)) p(HGNC:MAPK1) -> act(p(HGNC:RPS6KA2)) p(HGNC:MAPK1) -> act(p(HGNC:RPS6KA3)) p(HGNC:MAPK3) -> act(p(HGNC:RPS6KA1)) p(HGNC:MAPK3) -> act(p(HGNC:RPS6KA2)) p(HGNC:MAPK3) -> act(p(HGNC:RPS6KA3)) p(HGNC:MAPK1) -> act(p(HGNC:MKNK1)) p(HGNC:MAPK1) -> act(p(HGNC:MKNK2)) p(HGNC:MAPK3) -> act(p(HGNC:MKNK1)) p(HGNC:MAPK3) -> act(p(HGNC:MKNK2)) SET Evidence = "ERK signalling plays an important role in transcriptional regulation by phosphorylating and thereby modulating the activity of transcription factors " SET Confidence = "High" SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph"} kin(p(HGNC:MAPK1)) -> p(HGNC:GTF2A1, pmod(P)) kin(p(HGNC:MAPK3)) -> p(HGNC:GTF2A1, pmod(P)) p(HGNC:GTF2A1, pmod(P)) -> bp(GOBP:"regulation of transcription, DNA-templated") bp(PTS:"mitogen activated protein kinase signaling pathway") -> bp(GOBP:"regulation of transcription, DNA-templated") SET Evidence = "ERK can also alter transcription indirectly, for example through activation of RSKs which phosphorylate, among other substrates, the cAMP response element-binding protein (CREB) at serine 133" SET Confidence = "High" kin(p(HGNC:RPS6KA1, pmod(P))) -> p(HGNC:CREB1, pmod(P, S, 133)) kin(p(HGNC:RPS6KA2, pmod(P))) -> p(HGNC:CREB1, pmod(P, S, 133)) kin(p(HGNC:RPS6KA3, pmod(P))) -> p(HGNC:CREB1, pmod(P, S, 133)) p(HGNC:CREB1, pmod(P, S, 133)) -> bp(GOBP:"regulation of transcription, DNA-templated") SET Evidence = "Moreover, ERK also positively regulates translational efficiency by controlling the phosphorylation of translational initiation factors" SET Confidence = "High" kin(p(HGNC:MAPK1)) -> p(HGNC:EIF1, pmod(P)) p(HGNC:EIF1, pmod(P)) -> bp(GOBP:translation) SET Evidence = "Recent evidence has shown that neuronal activity-dependent modulation of translation initiation factor activity by the ERK MAPK signalling pathway plays an important role in long-lasting forms of synaptic plasticity and memory" SET Confidence = "High" SET MeSHAnatomy = "Neurons" bp(PTS:"mitogen activated protein kinase signaling pathway") -> bp(GOBP:"translation initiation") bp(GOBP:"translational initiation") -- bp(GOBP:"learning or memory") bp(GOBP:"translation initiation") -- bp(GOBP:"regulation of neuronal synaptic plasticity") UNSET {Confidence, MeSHAnatomy} SET Evidence = "To investigate the consequences of ERK activation in neurons, we employed conditional brain-specific expression of a caMEK1 to show that ERK activation causes spontaneous epileptic seizures" SET Confidence = "High" SET MeSHAnatomy = "Neurons" bp(PTS:"mitogen activated protein kinase signaling pathway") -> path(MESHD:Seizures) UNSET {Confidence, MeSHAnatomy} SET Evidence = "Mechanistically, our study identifies NMDA receptor 2B (NR2B) as a novel target for both translational and for transcriptional regulation by ERK" SET Subgraph = "MAPK-ERK subgraph" SET Confidence = "High" p(HGNC:MAP2K1) -- p(HGNC:GRIN2B) UNSET Confidence SET Evidence = "However, caMEK1?N mice showed a reactive gliosis, an activation of astrocytes characterized by increased GFAP expression, which is commonly seen in response to epileptic seizures" SET Species = "10090" SET Confidence = "High" p(HGNC:MAP2K1) -> path(MESHD:Gliosis) SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph", "Interleukin signaling subgraph"} p(HGNC:MAP2K1) -> p(HGNC:GFAP) p(HGNC:GFAP) -> path(MESHD:Gliosis) path(MESHD:Seizures) -> path(MESHD:Gliosis) UNSET {Subgraph, Species } SET Evidence = "Thus, ERK activation triggers epilepsy without causing widespread neuronal death." SET Confidence = "High" SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph"} act(p(HGNC:MAP2K1)) causesNoChange bp(GOBP:"neuron death") act(p(HGNC:MAP2K1)) -> path(MESHD:Epilepsy) bp(PTS:"mitogen activated protein kinase signaling pathway") causesNoChange bp(GOBP:"neuron death") UNSET {Subgraph, Confidence} SET Evidence = "NMDARs are heteromeric complexes containing both NR1 and NR2 subunits located at the postsynaptic side of excitatory synapses and regulate the influx of Ca2+ ions" SET Confidence = "High" SET Subgraph = "Calcium dependent subgraph" p(HGNC:GRIN1) reg bp(GOBP:"calcium ion import") p(HGNC:GRIN1) reg a(CHEBI:"calcium(2+)") p(HGNC:GRIN2B) reg bp(GOBP:"calcium ion import") p(HGNC:GRIN2B) reg a(CHEBI:"calcium(2+)") SET Evidence = "NMDARs have been strongly implicated in epileptogenesis and have been suggested as therapeutic targets for anti-epileptic treatment" g(HGNC:GRIN1) -- bp(EPT:epileptogenesis) g(HGNC:GRIN1) -- path(MESHD:Epilepsy) g(HGNC:GRIN2B) -- bp(EPT:epileptogenesis) g(HGNC:GRIN2B) -- path(MESHD:Epilepsy) UNSET {Subgraph, Confidence} SET Evidence = "uSCOMPanged in the hippocampi of caMEK1?N mice (Figure 4A), there was a significant increase in NR2B, but not NR1 or NR2A, protein levels (Figure 4B). This suggested that NR2B is regulated by ERK signalling through a post-transcriptional mechanism." SET Species = "10090" SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph"} SET Confidence = "High" p(HGNC:MAP2K1) -> g(HGNC:GRIN2B) p(HGNC:MAP2K1) causesNoChange p(HGNC:GRIN1) p(HGNC:MAP2K1) causesNoChange p(HGNC:GRIN2A) SET Evidence = "The eukaryotic translation initiation factor 4E (eIF4E) is a well-characterized substrate of the MEK signalling pathway, and phosphorylation of eIF4E positively regulates translation efficiency. Whereas total eIF4E protein levels were unaltered, eIF4E phosphorylation was augmented in hippocampal protein extracts from caMEK1?N mice" SET Species = "10090" SET Confidence = "High" p(HGNC:MAP2K1) -> p(HGNC:EIF4E, pmod(P)) p(HGNC:MAP2K1) causesNoChange p(HGNC:EIF4E) p(HGNC:EIF4E, pmod(P)) -> p(HGNC:GRIN2B) bp(PTS:"mitogen activated protein kinase signaling pathway") -> p(HGNC:EIF4E, pmod(P)) SET Evidence = "Ifenprodil is representative of a class of NMDA receptor antagonists (phenylethanolamines) with high selectivity for NR2B-containing receptors" SET Subgraph = "Calcium dependent subgraph" a(MESHC:ifenprodil) -| p(HGNC:GRIN2B) a(CHEBI:phenylethanolamines) -| p(HGNC:GRIN2B) a(MESHC:ifenprodil) isA a(CHEBI:phenylethanolamines) SET Evidence = " NR2B function was pharmacologically inhibited in caMEK1?N mice. Strikingly, a single injection of ifenprodil almost completely abrogated the epileptic seizures caused by overexpression of caMEK1" SET Subgraph = "MAPK-ERK subgraph" p(HGNC:MAP2K1) pos path(MESHD:Seizures) SET Confidence = "High" SET Subgraph = "Calcium dependent subgraph" SET Species = "10090" a(MESHC:ifenprodil) -| path(MESHD:Seizures) UNSET Subgraph SET Evidence = "Western blot analysis of caMEK1?N hippocampi revealed increased phosphorylation of the transcription factor CREB, a known mediator of ERK signalling" SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph", "brain_derived neurotrophic factor signaling subgraph"} p(HGNC:CREB1) -> bp(PTS:"mitogen activated protein kinase signaling pathway") UNSET Subgraph SET Evidence = "CREB has recently been shown to bind the ephrinB2 promoter in a genome-wide approach to characterize CREB target genes, suggesting that ephrinB2 may be a direct target of CREB" SET Confidence = "High" SET Subgraph = {"Reelin signaling subgraph", "MAPK-ERK subgraph", "protein kinase signaling subgraph"} p(HGNC:CREB1) => p(HGNC:EFNB2) SET Evidence = "We were especially interested in ephrinB2 as a target for ERK signalling because previous work had linked ephrinB2 function to NMDA receptor signalling at synapses" SET Confidence = "High" p(HGNC:EFNB2) -> p(HGNC:GRIN2B) p(HGNC:EFNB2) -> p(HGNC:GRIN1) UNSET Subgraph SET Evidence = "Trans-synaptic interactions between postsynaptic EphB receptors and presynaptic B-ephrins are necessary for the induction of mossy fibre long-term potentiation (LTP)" SET Confidence = "High" SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph", "Long term synaptic potentiation", "Reelin signaling subgraph"} SET Confidence = "High" p(HGNC:EFNB2) -> bp(PTS:"Long_Term Potentiation") p(HGNC:EPHB2) -> bp(PTS:"Long_Term Potentiation") UNSET Subgraph SET Evidence = "Treatment of cultured neurons with ephrinB2 led to tyrosine phosphorylation specifically of the NR2B subunit" SET Confidence = "High" SET MeSHAnatomy = "Neurons" SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph", "Reelin signaling subgraph"} kin(p(HGNC:EFNB2)) -> p(HGNC:GRIN2B, pmod(P, Y)) UNSET {Subgraph, MeSHAnatomy} SET Evidence = "NR2B tyrosine phosphorylation was greatly augmented in caMEK1?N mutant mice (Figure 5E), suggesting that stimulation of NR2B phosphorylation, in addition to increasing NR2B protein levels, is a second mechanism by which ERK signalling augments NR2B activity." SET Confidence = "High" SET Species = "10090" SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph"} p(HGNC:MAP2K1) -> p(HGNC:GRIN2B, pmod(P, Y)) bp(PTS:"mitogen activated protein kinase signaling pathway") -> p(HGNC:GRIN2B, pmod(P, Y)) UNSET Subgraph SET Evidence = "Quantification revealed that the absence of ephrinB2 reduced the frequencies of seizures by 80% (Figure 6A). Probably as a consequence, astrocytic gliosis was not observed in caMEK1?fb; ephrinB2?fb mice" SET Species = "10090" SET Subgraph = "Reelin signaling subgraph" p(HGNC:EFNB2) -> path(MESHD:Seizures) p(HGNC:EFNB2) -> path(MESHD:Gliosis) SET Evidence = "EphrinB2 is thus essential for NR2B phosphorylation and epileptogenesis triggered by caMEK1 in vivo." p(HGNC:EFNB2) -> bp(EPT:epileptogenesis) SET Evidence = "Thus, presynaptic ephrinB2 transcription induced by ERK signalling may signal across the mossy fibre synapse to activate postsynaptic Eph receptors" p(HGNC:EFNB2) -> p(HGNC:EPHB2) UNSET {Subgraph, Species} #################################### SET Citation = {"PubMed", "Neurochem Res. 2015 Jul;40(7):1546-53. doi: 10.1007/s11064-015-1617-y. Epub 2015 Jun 20.", "26092535"} # medication resistance SET Evidence = "Increased expression of multidrug-resistance associated protein 1 in brain tissue has been reported which lead to multidrug resistance of refractory epilepsy." SET Confidence = "High" SET MeSHAnatomy="Brain" p(HGNC:ABCC1) -- path(MESHD:Epilepsy) UNSET MeSHAnatomy SET Evidence = "In our previous study, we have found that the MAPK signaling pathway mediated the expression of P-glycoprotein. The expression of MRP1 and p38 MAPK was detected by immunofluorescence, Western-blot and real time-PCR, while the concentration of AEDs was measured by microdialysis and HPLC. The result showed that SB202190, the specific inhibitor of p38 MAPK, could down-regulate the expression of MRP1, while increase the concentrations of valproate and lamotrigine in hippocampus extracellular fluid of refractory epileptic rat. " SET Species = "10116" SET Confidence = "High" SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph"} bp(PTS:"mitogen activated protein kinase signaling pathway") reg p(HGNC:ABCB1) SET Evidence = "The result showed that SB202190, the specific inhibitor of p38 MAPK, could down-regulate the expression of MRP1, while increase the concentrations of valproate and lamotrigine in hippocampus extracellular fluid of refractory epileptic rat." SET Confidence = "High" SET Species="10116" a(CHEBI:"SB-202190") -| p(HGNC:MAPK14) a(CHEBI:"SB-202190") -| p(HGNC:ABCC1) p(HGNC:MAPK14) -> p(HGNC:ABCC1) a(CHEBI:"SB-202190") -> a(CHEBI:valproate) a(CHEBI:"SB-202190") -> a(CHEBI:lamotrigine) p(HGNC:ABCC1) -| a(CHEBI:valproate) p(HGNC:ABCC1) -| a(CHEBI:lamotrigine) p(HGNC:ABCC1) -> bp(PTS:"drug pathway") SET Evidence = "We demonstrate that p38 MAPK signaling pathway may be involved in drug resistance of refractory epilepsy by regulating MRP1." SET Confidence = "High" p(HGNC:MAPK14) -> bp(PTS:"mitogen activated protein kinase signaling pathway") bp(PTS:"mitogen activated protein kinase signaling pathway") -> p(HGNC:ABCC1) bp(PTS:"mitogen activated protein kinase signaling pathway") -> bp(GOBP:"negative regulation of response to drug") bp(PTS:"mitogen activated protein kinase signaling pathway") -> bp(GOBP:"drug export") bp(GOBP:"drug export") -| a(CHEBI:valproate) bp(GOBP:"drug export") -| a(CHEBI:lamotrigine) bp(PTS:"mitogen activated protein kinase signaling pathway") -| a(CHEBI:valproate) bp(PTS:"mitogen activated protein kinase signaling pathway") -| a(CHEBI:lamotrigine) bp(PTS:"mitogen activated protein kinase signaling pathway") -| a(CHEBI:anticonvulsant) SET Evidence = "The MRP1 and p38 MAPK-positive cells were significantly higher in both cortex and hippocampus CA1 region in epilepsy group than those in control group" SET Confidence = "High" SET MeSHAnatomy= {"CA1 Region, Hippocampal", "Cerebral Cortex"} path(MESHD:Epilepsy) pos p(HGNC:ABCC1) path(MESHD:Epilepsy) pos p(HGNC:MAPK14) UNSET MeSHAnatomy SET Evidence = "Finally, quantitative real time-PCR (qPCR) analysis revealed that the mRNA expression of MRP1 was significantly higher in the hippocampus and cortex in epilepsy group than that in control group " SET Confidence = "High" SET MeSHAnatomy={"CA1 Region, Hippocampal", "Cerebral Cortex"} path(MESHD:Epilepsy) pos r(HGNC:ABCC1) UNSET {MeSHAnatomy, Confidence} SET Evidence = "For the SB202190 group, the mRNA expression of MRP1 and p38 was lower than that in the epilepsy group (p < 0.05; Fig. 3)." #: Check this one a(CHEBI:"SB-202190") -| r(HGNC:ABCC1) a(CHEBI:"SB-202190") -| r(HGNC:MAPK14) SET Evidence = "It showed that seizures level and frequency in the SB202190 group were decreased than that in the epilepsy group " a(CHEBI:"SB-202190") -| path(MESHD:Seizures) a(CHEBI:"SB-202190") -| path(MESHD:Epilepsy) UNSET Subgraph SET Evidence = "However, the concentrations of VPA in the hippocampal extracellular fluid in the epilepsy group were significantly lower at each time point (p = 0.000, 0.023, 0.000, 0.000 and 0.002, respectively) compared with those in the control group" SET Confidence = "High" SET MeSHAnatomy="Hippocampus" path(MESHD:Epilepsy) negativeCorrelation a(CHEBI:valproate) UNSET MeSHAnatomy SET Evidence = "The LTG level found in the hippocampal extracellular fluid in the epilepsy group was much lower than those in the control group at each time point over 30/96150 min" SET Confidence = "High" SET MeSHAnatomy="Hippocampus" path(MESHD:Epilepsy) negativeCorrelation a(CHEBI:lamotrigine) UNSET MeSHAnatomy UNSET Species SET Evidence = "MRP2, another transporter of AEDs in the brain, found mainly in the luminal surface of brain capillary endothelium, whereas other MRPs, such as MRP3 and MRP5, are located basolaterally " SET Confidence = "High" SET MeSHAnatomy="Brain" SET MeSHAnatomy="Endothelium" p(HGNC:ABCC2) -> bp(GOBP:"drug export") p(HGNC:ABCC2) -| a(CHEBI:anticonvulsant) UNSET MeSHAnatomy SET MeSHAnatomy="Basement Membrane" p(HGNC:ABCC3) -> bp(GOBP:"drug export") p(HGNC:ABCC3) -| a(CHEBI:anticonvulsant) p(HGNC:ABCC5) -> bp(GOBP:"drug export") p(HGNC:ABCC5) -| a(CHEBI:anticonvulsant) UNSET MeSHAnatomy SET Evidence = "Subsequently, it was shown by other groups that, the concentration of PHT in the brain of MRP2-deficient rats was significantly higher than in the wild-type rats [29], indicating that MRP2 substantially contributes to BBB function" SET Species = "10116" p(RGD:Abcc2) -| a(CHEBI:phenytoin) p(RGD:Abcc2) -> bp(GOBP:"regulation of maintenance of permeability of blood-brain barrier") SET Evidence = "In our early studies, we had found that probenecid, MRP inhibitor, significantly increased the concentration of LTG in the extracellular fluid of the hippocampus" SET Confidence = "High" a(MESHC:Probenecid) -| p(RGD:Abcc1) a(MESHC:Probenecid) -| p(RGD:Abcc2) SET MeSHAnatomy="Hippocampus" a(MESHC:Probenecid) -> a(CHEBI:lamotrigine) UNSET MeSHAnatomy SET Evidence = "MAPK cascade reaction system is involved in cell proliferation, differentiation, apoptosis, migration, invasion and inflammation" SET Confidence = "High" SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph"} bp(PTS:"mitogen activated protein kinase signaling pathway") -> bp(GOBP:"cell differentiation") bp(PTS:"mitogen activated protein kinase signaling pathway") -> bp(GOBP:"apoptotic process") bp(PTS:"mitogen activated protein kinase signaling pathway") -> bp(GOBP:"cell migration") bp(PTS:"mitogen activated protein kinase signaling pathway") -> path(MESHD:Inflammation) SET Evidence = "And it was shown by other groups that the p38 MAPK and ERK pathway were involved in the resistance of cells to mercury by regulation the expression of MRP1" SET Confidence = "High" p(HGNC:MAPK1) reg p(RGD:Abcc1) p(HGNC:MAPK3) reg p(RGD:Abcc1) p(HGNC:ABCC1) -- bp(GOBP:"response to mercury ion") UNSET Subgraph ################################### SET Citation = {"PubMed", "Neurology. 2013 Apr 23;80(17):1571-6. doi: 10.1212/WNL.0b013e31828f18d8. Epub 2013 Mar 27.", "23535492"} SET Evidence = "AA diplotype of ADORA2A is associated with AESD and may alter the intracellular adenosine/cAMP cascade, thereby promoting seizures and excitotoxic brain damage in patients." SET Confidence = "High" SET Subgraph = {"adenosine signaling subgraph", "Neurotransmitter release subgraph"} g(HGNC:ADORA2A) pos path(MESHD:Seizures) g(HGNC:ADORA2A) -- bp(PTS:"cAMP mediated signaling") bp(PTS:"cAMP mediated signaling") -- bp(PTS:"cAMP mediated signaling") bp(PTS:"cAMP mediated signaling") -- path(MESHD:Seizures) a(MESHC:"Cyclic AMP") -> bp(PTS:"cAMP mediated signaling") UNSET Subgraph SET Evidence = "Recently, polymorphism of a gene encoding a mitochondrial enzyme, carnitine palmitoyltransferase II (CPT2), was identified as a genetic predisposition for AESD7" SET Confidence = "High" g(HGNC:CPT2, var("?")) pos path(MESHD:Seizures) SET Evidence = "We hypothesized that the adenosine-mediated signal pathway is altered in AESD because theophylline, a nonselective adenosine receptor antagonist, aggravates AESD." SET Confidence = "High" SET Subgraph = {"adenosine signaling subgraph", "Neurotransmitter release subgraph"} a(CHEBI:theophylline) -| p(HGNC:ADORA1) a(CHEBI:theophylline) -| p(HGNC:ADORA2A) a(CHEBI:theophylline) -| bp(PTS:"cAMP mediated signaling") bp(PTS:"cAMP mediated signaling") -| path(MESHD:Seizures) SET Evidence = "For synaptic transmission, ADORA2A enhances excitatory neurotransmitter release, whereas ADORA1 exerts an inhibitory effect" SET Confidence = "High" p(HGNC:ADORA2A) -> bp(GOBP:"neurotransmitter secretion") p(HGNC:ADORA1) -| bp(GOBP:"neurotransmitter secretion") SET Evidence = "The role of adenosine as an endogenous anticonvulsant is mediated via ADORA1" SET Published = "Epilepsy comorbidity paper" SET Confidence = "High" a(CHEBI:adenosine) -| path(MESHD:Seizures) a(CHEBI:adenosine) isA a(CHEBI:anticonvulsant) p(HGNC:ADORA1) -> a(CHEBI:adenosine) SET Evidence = "Inhibition of ADORA1 function has been shown to cause status epilepticus" p(HGNC:ADORA1) -| path(MESHD:"Status Epilepticus") UNSET {Confidence, Published} SET Evidence = "In a rat model of seizure kindling, ADORA1 in the hippocampal CA1 region reduces seizures, whereas ADORA2A promotes them." SET Published = "Epilepsy comorbidity paper" SET Confidence = "High" SET MeSHAnatomy="CA1 Region, Hippocampal" SET Species = "10116" p(HGNC:ADORA1) -| path(MESHD:Seizures) p(HGNC:ADORA2A) -> path(MESHD:Seizures) UNSET Species, MeSHAnatomy, Published SET Evidence = "ADORA2A, together with coupled Gs proteins, activates adenylate cyclase and increases the cellular cAMP level." SET Confidence = "High" p(HGNC:ADORA2A) -> a(MESHC:"Cyclic AMP") UNSET Subgraph SET Evidence = "cAMP promotes protein kinase A, which in turn enhances Ca2+ influx through the l-type Ca2+ channel in the basal ganglia, hippocampus, and striatum. " SET Subgraph = {"Calcium dependent subgraph", "adenosine signaling subgraph", "Neurotransmitter release subgraph", "protein kinase signaling subgraph"} a(MESHC:"Cyclic AMP") -> p(HGNC:PRKACA) bp(PTS:"cAMP mediated signaling") -> p(HGNC:PRKACA) SET MeSHAnatomy="Hippocampus" p(HGNC:PRKACA) -> bp(GOBP:"calcium ion import") SET Evidence = "Ca2+ then enhances glutamate efflux from the endoplasmic reticulum to the extracellular space, leading to excitotoxicity" SET Confidence = "High" bp(GOBP:"calcium ion import") -> tloc(a(MESHC:Glutamates), fromLoc(GOCC:"endoplasmic reticulum"), toLoc(GOCC:"intracellular")) tloc(a(MESHC:Glutamates), fromLoc(GOCC:"endoplasmic reticulum"), toLoc(GOCC:"intracellular")) -> bp(GOBP:"regulation of postsynaptic membrane potential") UNSET Subgraph ############################## SET Citation = {"PubMed", "Cell Signal. 2013 Dec;25(12):2848-55. doi: 10.1016/j.cellsig.2013.09.007. Epub 2013 Sep 14.", "24041654"} SET Evidence = "Regulator of G-protein signaling (RGS) proteins potently suppress G-protein coupled receptor (GPCR) signal transduction by accelerating GTP hydrolysis on activated heterotrimeric G-protein a subunits." SET Confidence = "High" p(HGNC:RGS1) -| p(HGNC:GPBAR1) SET Evidence = "RGS4 is enriched in the CNS and is proposed as a therapeutic target for treatment of neuropathological states including epilepsy and Parkinson/92s disease" SET Confidence = "High" SET Subgraph = "G-protein-mediated signaling" p(HGNC:RGS4) -- path(MESHD:"Parkinson Disease") p(HGNC:RGS4) -- path(MESHD:Epilepsy) SET Evidence = "An HEK293-FlpIn cell-line stably expressing M3-muscarinic receptor with Doxycycline-regulated RGS4 expression was employed to identify compounds that inhibit RGS4-mediated suppression of M3-muscarinic receptor signaling." #: Missing cell line annotation and wrong annotation SET Confidence = "Low" p(HGNC:RGS4) -| p(HGNC:CHRM3) UNSET Subgraph SET Evidence = "RGS4 is highly expressed in cortex, thalamus, and other brain regions [11], and potentially affects numerous centrally-acting G protein mediated pathways" SET Subgraph = "G-protein-mediated signaling" SET MeSHAnatomy = "Cerebral Cortex" p(HGNC:RGS4) -- bp(PTS:"GPCR signaling pathway") UNSET MeSHAnatomy SET MeSHAnatomy = "Thalamus" p(HGNC:RGS4) -- bp(PTS:"GPCR signaling pathway") UNSET MeSHAnatomy UNSET Subgraph SET Evidence = "Within the dorsolateral striatum, RGS4 serves as a bridge between D2-dopamine and A2-adenosine receptors and the endocannabinoid mobilization driving the striatal plasticity associated with normal motor behavior." ###SET Anatomy="Striatum" SET Subgraph = {"G-protein-mediated signaling", "adenosine signaling subgraph", "Neurotransmitter release subgraph"} p(HGNC:RGS4) -- p(HGNC:DRD2) p(HGNC:RGS4) -- p(HGNC:ADORA2A) p(HGNC:DRD2) -- p(HGNC:ADORA2A) ###UNSET Anatomy SET Evidence = "As a result, RGS4 knockout mice are more resistant than WT animals to motor behavior deficits occurring from 6-OHDA depletion of dopamine" SET Confidence = "Medium" SET Species = "10090" p(HGNC:RGS4) pos path(MESHD:"Motor Disorders") a(CHEBI:oxidopamine) -| a(CHEBI:dopamine) UNSET Species UNSET Subgraph SET Evidence = "Additionally, formation of an RGS4-A1-adenosine receptor complex via the neurabin scaffolding protein can negatively regulate the neuroprotective effects of adenosine signaling in a kainate-induced seizure model" SET Species = "10090" SET Subgraph = {"Neurotransmitter release subgraph", "G-protein-mediated signaling", "adenosine signaling subgraph"} p(HGNC:PPP1R9B) -> complex(p(HGNC:RGS4), p(HGNC:ADORA1)) complex(p(HGNC:RGS4), p(HGNC:ADORA1)) -| a(CHEBI:"neuroprotective agent") complex(p(HGNC:RGS4), p(HGNC:ADORA1)) -| a(CHEBI:adenosine) complex(p(HGNC:RGS4), p(HGNC:ADORA1)) -| bp(PTS:"cAMP mediated signaling") UNSET Subgraph SET Evidence = "Genetic knockout of neurabin or small molecule antagonism of RGS4 reduces seizure severity in this model" SET Species = "10090" SET Confidence = "High" p(HGNC:PPP1R9B) pos path(MESHD:Seizures) SET Subgraph = "G-protein-mediated signaling" p(HGNC:RGS4) pos path(MESHD:Seizures) UNSET {Subgraph, Species} SET Evidence = "In the primary screen (PubChem AID: 463165), 305,721 compounds were tested for their ability to increase carbachol-stimulated calcium transient in RGS4-expressing cells" SET Confidence = "High" SET Subgraph = "Calcium dependent subgraph" a(CHEBI:carbachol) -> bp(PTS:"Calcium signaling pathway") p(HGNC:RGS4) -- a(CHEBI:carbachol) UNSET Subgraph SET Evidence = "Inhibition of Ga binding to RGS4 (-Cys) or RGS8 occurred with only two of the 58 compounds tested ( 11957531 and 10069059, supplemental table 1)," SET Subgraph = "G-protein-mediated signaling" SET Confidence = "High" a(InChI:"InChI=1S/C17H17NO3.BrH/c1-18-5-4-10-6-11(19)8-12-15(10)13(18)7-9-2-3-14(20)17(21)16(9)12;/h2-3,6,8,13,19-21H,4-5,7H2,1H3;1H/t13-;/m1./s1") -| complex(p(HGNC:GNAQ), p(HGNC:RGS4)) a(InChI:"InChI=1S/C17H17NO3.BrH/c1-18-5-4-10-6-11(19)8-12-15(10)13(18)7-9-2-3-14(20)17(21)16(9)12;/h2-3,6,8,13,19-21H,4-5,7H2,1H3;1H/t13-;/m1./s1") -| complex(p(HGNC:GNAQ), p(HGNC:RGS8)) a(InChI:"InChI=1S/C19H21NO3.BrH/c1-2-6-20-7-5-12-8-13(21)10-14-17(12)15(20)9-11-3-4-16(22)19(23)18(11)14;/h3-4,8,10,15,21-23H,2,5-7,9H2,1H3;1H/t15-;/m1./s1") -| complex(p(HGNC:GNAQ), p(HGNC:RGS4)) a(InChI:"InChI=1S/C19H21NO3.BrH/c1-2-6-20-7-5-12-8-13(21)10-14-17(12)15(20)9-11-3-4-16(22)19(23)18(11)14;/h3-4,8,10,15,21-23H,2,5-7,9H2,1H3;1H/t15-;/m1./s1") -| complex(p(HGNC:GNAQ), p(HGNC:RGS8)) SET Evidence = "One compound in particular stood out with high potency in both assays ( 1472216)" a(InChI:"InChI=1S/C16H14Cl2N2O3S/c1-23-13-8-7-12(9-19-13)20-16(21)14(17)15(18)24(22)10-11-5-3-2-4-6-11/h2-9H,10H2,1H3,(H,20,21)/b15-14+") -| p(HGNC:RGS4) ############################# SET Citation = {"PubMed", "Bioinformation. 2012;8(4):170-4. doi: 10.6026/97320630008170. Epub 2012 Feb 28.", "22419835"} SET Evidence = "There are a variety of ligands that can activate these receptors like hormones, pheromones, neurotransmitters and many others" SET Confidence = "High" SET Subgraph = {"Neurotransmitter release subgraph", "G-protein-mediated signaling"} a(CHEBI:neurotransmitter) -> bp(PTS:"GPCR signaling pathway") a(CHEBI:hormone) -> bp(PTS:"GPCR signaling pathway") a(CHEBI:pheromone) -> bp(PTS:"GPCR signaling pathway") SET Evidence = "GPCRs play important role in causing many diseases like neuronal dysfunction including seizures, Parkinson's disease, night blindness and epilepsy" SET Confidence = "High" bp(PTS:"GPCR signaling pathway") -- path(MESHD:Seizures) bp(PTS:"GPCR signaling pathway") -- path(MESHD:"Parkinson Disease") bp(PTS:"GPCR signaling pathway") -- path(MESHD:Epilepsy) SET Evidence = "mGluRs are a member of GPCR super family" SET Confidence = "High" p(HGNC:GRM1) -> bp(PTS:"GPCR signaling pathway") a(MESHC:Glutamates) -> p(HGNC:GRM1) SET Evidence = "Glutamate which is an amino acid acts as a neurotransmitter" SET Confidence = "High" a(MESHC:Glutamates) isA a(CHEBI:neurotransmitter) UNSET Subgraph ################################ SET Citation = {"PubMed", "Int J Dev Neurosci. 2011 Apr;29(2):121-9. doi: 10.1016/j.ijdevneu.2010.12.006. Epub 2011 Jan 14.", "21238565"} # medication ? SET Evidence = "cytosolic calcium concentrations ([Ca2+]c) were measured by cell imaging. [Ca2+]c increases were evoked upon cell stimulation with high K+ (KCl 75 mM), glutamate (500 B5M) or bicuculline (100 B5M)." SET Confidence = "High" SET Subgraph = "Calcium dependent subgraph" a(CHEBI:"potassium(1+)") -> bp(GOBP:"calcium ion transport into cytosol") a(MESHC:Glutamates) -> bp(GOBP:"calcium ion transport into cytosol") a(CHEBI:bicuculline) -> bp(GOBP:"calcium ion transport into cytosol") SET CellStructure = "Cytosol" bp(GOBP:"calcium ion transport into cytosol") -> a(CHEBI:"calcium(2+)") UNSET CellStructure SET Evidence = "Ca2+ has been described to play an important role in epileptogenesis and seizure mechanisms and also in long-term plasticity changes related to epileptogenesis" SET Confidence = "High" SET Subgraph = "Calcium dependent subgraph" a(CHEBI:"calcium(2+)") -- bp(EPT:epileptogenesis) bp(PTS:"Calcium signaling pathway") -- bp(EPT:epileptogenesis) a(CHEBI:"calcium(2+)") -> bp(GOBP:"regulation of long-term neuronal synaptic plasticity") bp(PTS:"Calcium signaling pathway") -> bp(GOBP:"regulation of long-term neuronal synaptic plasticity") bp(GOBP:"regulation of long-term neuronal synaptic plasticity") -- bp(EPT:epileptogenesis) SET Evidence = "Some studies on different epileptic animal models demonstrated that epileptogenesis produced a disruption of Ca2+ homeostasis (" bp(EPT:epileptogenesis) -| bp(GOBP:"calcium ion homeostasis") SET Evidence = "This prolonged increase in [Ca2+]c may initiate the long-term plasticity changes that underlie the development and maintenance of epilepsy" SET Confidence = "High" SET CellStructure="Cytosol" a(CHEBI:"calcium(2+)") -> bp(GOBP:"regulation of long-term neuronal synaptic plasticity") a(CHEBI:"calcium(2+)") -- path(MESHD:Epilepsy) UNSET {CellStructure, Confidence} SET Evidence = "Astrocytes cultured from a seizure focus, tissue present more depolarized membrane potential and much larger tetrodotoxin-sensitive Na+ currents, compared to cortical or non-seizure focus hippocampal astrocytes" SET Confidence = "High" SET MeSHAnatomy = "Astrocytes" path(MESHD:Seizures) -> bp(GOBP:"positive regulation of membrane depolarization") a(CHEBI:tetrodotoxin) -> a(CHEBI:"sodium(1+)") UNSET MeSHAnatomy UNSET Subgraph ###################################### SET Citation = {"PubMed", "Glia. 2012 Aug;60(8):1227-33. doi: 10.1002/glia.22318. Epub 2012 Mar 2.", "22389222"} SET Evidence = "More recent studies, however, reappraised the role of neurons in epileptogenesis and suggested that Ca2+-dependent gliotransmission directly contributes to the excessive neuronal sySCOMPronization that predisposes the brain network to seizures" SET Confidence = "High" SET Subgraph = "Calcium dependent subgraph" SET MeSHAnatomy = "Neuroglia" a(CHEBI:"calcium(2+)") -> bp(MESHPP:"Cell Communication") bp(MESHPP:"Cell Communication") -- bp(EPT:epileptogenesis) UNSET MeSHAnatomy SET Evidence = "Significant support for this view comes from the finding that astrocytes from hyperexcitable networks respond to neuronal signals with massive Ca2+ elevations and generate a recurrent excitatory loop with neurons that has the potential to promote a focal seizure." SET Confidence = "High" SET MeSHAnatomy = "Astrocytes" bp(GOBP:"chemical synaptic transmission") -> a(CHEBI:"calcium(2+)") a(CHEBI:"calcium(2+)") -> path(MESHD:Seizures) UNSET MeSHAnatomy SET Evidence = "The extracellular concentration of K+ ions ([K+]o) is an important factor that regulates the neuronal excitability in the brain network" SET CellStructure="Extracellular Space" a(CHEBI:"potassium(1+)") reg bp(GOBP:"regulation of neuronal signal transduction") SET Evidence = "An increased [K+]o deriving from intense neuronal firing discharges tends, indeed, to depolarize neuronal cells and facilitate the development of epileptiform discharges" a(CHEBI:"potassium(1+)") -> bp(EPT:epileptogenesis) UNSET CellStructure UNSET Subgraph SET Evidence = "Unlike other K+ channels that allow large K+ efflux from depolarized cells, Kir channels have the peculiarity to mediate small K+ efflux from depolarized cells and large influx at hyperpolarized potentials. Importantly, Kir4.1 channels have a high open probability at resting potential (Ransom and Sontheimer 1995) and a channel conductance that is proportional to [K+]o (Newman 1993; Sakmann and Trube 1984). These features allow astrocytes to remove large amounts of K+ from the extracellular space" SET Confidence = "High" p(HGNC:KCNJ10) -- a(CHEBI:"potassium(1+)") SET Evidence = "The discovery that through a Ca2+-dependent glutamate release astrocytes can directly excite groups of neighbouring neurons (Parpura et al. 1994) and favour sySCOMPronised activities mediated by extrasynaptic N-methyl-D-aspartate (NMDA) receptor activation (Fellin et al. 2004) were the initial observations that hinted at a more direct role of Ca2+-dependent gliotransmission in the generation of epileptiform activities" SET Confidence = "High" SET Published = "Epilepsy comorbidity paper" SET MeSHAnatomy = "Astrocytes" SET Subgraph = {"Glutamatergic subgraph", "Neurotransmitter release subgraph"} a(CHEBI:"calcium(2+)") -> bp(GOBP:"glutamate secretion, neurotransmission") UNSET Published bp(GOBP:"glutamate secretion, neurotransmission") -> bp(GOBP:"chemical synaptic transmission") bp(GOBP:"glutamate secretion, neurotransmission") -> p(HGNC:GRIN2B) bp(GOBP:"glutamate secretion, neurotransmission") -> p(HGNC:GRIN1) UNSET {Subgraph, MeSHAnatomy, Confidence} SET Evidence = "In animals models of temporal lobe epilepsy, the astrocytic expression of mGluRs that mediates Ca2+ oscillations was also found to be increased" SET Confidence = "High" SET MeSHAnatomy = "Astrocytes" path(MESHD:"Epilepsy, Temporal Lobe") pos p(HGNC:GRM1) p(HGNC:GRM1) reg a(CHEBI:"calcium(2+)") UNSET Confidence SET Evidence = "it has been reported that the paroxysmal depolarising shifts (PDSs), i.e., the cellular correlate of interictal events recorded between seizures, are tetrodotoxin (TTX)-resistant and mediated by glutamate released from astrocytes" #: Check this a(CHEBI:"calcium(2+)") -> bp(GOBP:"membrane depolarization") bp(GOBP:"membrane depolarization") -> p(HGNC:SCN1A) p(HGNC:SCN1A) -> bp(GOBP:"neuronal action potential") bp(GOBP:"neuronal action potential") -> p(HGNC:KCNN1) p(HGNC:KCNN1) -> bp(EPT:hyperpolarization) bp(EPT:hyperpolarization) -> path(MESHD:Seizures) a(CHEBI:tetrodotoxin) causesNoChange bp(EPT:hyperpolarization) a(MESHC:Glutamates) -> bp(EPT:hyperpolarization) bp(GOBP:"glutamate secretion, neurotransmission") -> bp(EPT:hyperpolarization) SET Evidence = "We found that after a double, but not a single NMDA stimulation, a high number of astrocytes exhibited a large, TTX-sensitive Ca2+ elevation just prior to the onset of the ictal discharge" SET Confidence = "High" act(p(HGNC:GRIN2B)) -> a(CHEBI:"calcium(2+)") act(p(HGNC:GRIN1)) -> a(CHEBI:"calcium(2+)") SET Evidence = "astrocytes by TFLLR (Gomez-Gonzalo et al. 2010). This peptide has been reported to trigger in astrocytes both Ca2+ elevations and glutamate release by activating the thrombin protease activated receptor-1 (PAR-1) " SET Confidence = "High" SET MeSHAnatomy = "Astrocytes" a(MESHC:"PAR-1-activating peptide") -> p(HGNC:F2R) p(HGNC:F2R) -> a(CHEBI:"calcium(2+)") p(HGNC:F2R) -> bp(GOBP:"glutamate secretion, neurotransmission") UNSET {MeSHAnatomy, Confidence} SET Evidence = "Most interestingly, this astrocytic ATP enhances inhibitory transmission by acting on the P2Y1 receptors expressed in a subset of hippocampal interneurons" #: second statement is not well represented SET Confidence = "High" SET MeSHAnatomy = "Astrocytes" a(CHEBI:ATP) -> p(HGNC:P2RY1) p(HGNC:P2RY1) -> bp(GOBP:"regulation of membrane potential") SET Evidence = "Given that during the epileptic discharges the extracellular Ca2+ is markedly reduced, the consequent release of astrocytic ATP may potentiate inhibitory transmission thereby working as an anticonvulsant feedback mechanism that opposes seizure propagation." SET Confidence = "High" SET MeSHAnatomy = "Astrocytes" a(CHEBI:ATP) -| path(MESHD:Seizures) UNSET MeSHAnatomy SET Evidence = "Consistent with this conclusion, in aquoporin-4 knock-out mice the LTP evoked by theta-burst stimulation was found to be significantly reduced, while that evoked by high frequency stimulation was unaffected" SET Confidence = "High" SET Species = "10090" SET Subgraph = "Long term synaptic potentiation" p(HGNC:AQP4) -> bp(PTS:"Long_Term Potentiation") UNSET Subgraph UNSET Species SET Evidence = "ATP which is released from astrocytes through different mechanisms, including a Ca2+-dependent mechanism" SET MeSHAnatomy = "Astrocytes" SET Subgraph = "Calcium dependent subgraph" a(CHEBI:"calcium(2+)") -- a(CHEBI:ATP) a(CHEBI:ATP) -> bp(PTS:"Calcium signaling pathway") UNSET {Subgraph, MeSHAnatomy} ##################################### SET Citation = {"PubMed", "J Cereb Blood Flow Metab. 2005 Dec;25(12):1557-72.", "15889042"} SET Evidence = "Expression and cleavage of caspase-3 is significantly elevated in the temporal cortex of epilepsy patients compared with control " SET Confidence = "High" SET MeSHAnatomy="Temporal Lobe" SET Subgraph = "Apoptosis signaling subgraph" p(HGNC:CASP3) positiveCorrelation path(MESHD:Epilepsy) UNSET {MeSHAnatomy, Subgraph, Confidence} SET Evidence = "Caspase-1, an inflammatory caspase, is also activated in the epilepsy brain " SET Subgraph = {"Apoptosis signaling subgraph", "Interleukin signaling subgraph"} SET Confidence = "High" p(HGNC:CASP1) positiveCorrelation path(MESHD:Epilepsy) SET Evidence = "Because experimental modeling has showed that caspase inhibition reduces seizure-induced neuronal death, it is tempting to speculate that caspases may be contributing to damage progression in refractory epilepsy patients" SET Subgraph = {"Apoptosis signaling subgraph", "Interleukin signaling subgraph"} SET Confidence = "High" p(HGNC:CASP1) positiveCorrelation bp(GOBP:"neuron death") p(HGNC:CASP1) positiveCorrelation bp(GOBP:"apoptotic process") SET Subgraph = "Apoptosis signaling subgraph" p(HGNC:CASP3) positiveCorrelation bp(GOBP:"neuron death") p(HGNC:CASP3) positiveCorrelation bp(GOBP:"apoptotic process") SET Evidence = "Qualitative descriptions of increased Bax expression have been reported for the hippocampus (Nagy and Esiri, 1998; Uysal et al, 2003), but not the neocortex" SET Subgraph = {"Apoptosis signaling subgraph", "Interleukin signaling subgraph"} SET Confidence = "High" SET MeSHAnatomy="Hippocampus" p(HGNC:BAX) pos path(MESHD:Epilepsy) SET MeSHAnatomy="Neocortex" p(HGNC:BAX) causesNoChange path(MESHD:Epilepsy) UNSET MeSHAnatomy UNSET Subgraph SET Evidence = "Bid cleavage is detected in the hippocampus (Henshall et al, 2004) but expression of Bid (p22) and Bad is unaltered" SET MeSHAnatomy="Hippocampus" path(MESHD:Epilepsy) causesNoChange p(HGNC:BID) path(MESHD:Epilepsy) causesNoChange p(HGNC:BAD) SET Evidence = "Surprisingly, expression of Bim is significantly lower in patient brain than control" SET Confidence = "High" p(HGNC:BCL2L11) negativeCorrelation path(MESHD:Epilepsy) SET Evidence = "Antiapoptotic Akt is phosphorylated (activated) in the human TLE brain compared with control " SET Confidence = "High" SET Species="9606" SET Subgraph = "Apoptosis signaling subgraph" p(HGNC:AKT1, pmod(P)) -| bp(GOBP:"apoptotic process") path(MESHD:"Epilepsy, Temporal Lobe") pos p(HGNC:AKT1, pmod(P)) UNSET {Species, Subgraph, Confidence} SET Evidence = "In the same samples, elevated phosphorylation of the Akt target FKHR was found suggesting Akt may be functionally active in epilepsy brain " SET Confidence = "High" SET Species="9606" SET MeSHDisease = "Epilepsy" SET MeSHAnatomy = "Brain" kin(p(HGNC:AKT1, pmod(P))) -> p(HGNC:FOXO1, pmod(P)) SET Evidence = "While mitochondrial pathways have been the major focus so far, significant elevations in ER levels of DAP kinase and its E3 ligase DAP kinase interacting protein 1 are found in the human epilepsy brain" SET CellStructure="Endoplasmic Reticulum" p(HGNC:DAPK1) pos path(MESHD:Epilepsy) SET Subgraph = "Notch signaling subgraph" p(HGNC:MIB1) pos path(MESHD:Epilepsy) UNSET {Subgraph, CellStructure, MeSHDisease, Species, MeSHAnatomy} ################################# # Paper on MAPK/ERK pathway (also known as the Ras-Raf-MEK-ERK pathway) that can be generally applicable to other contexts ################################# SET Citation = {"PubMed", "Biochim Biophys Acta. 2007 Aug;1773(8):1263-84. Epub 2006 Oct 7.", "17126425"} # MAPK Signaling (+ apoptosis) # medication SET Evidence = "Growth factors and mitogens use the Ras/Raf/MEK/ERK signaling cascade to transmit signals from their receptors to regulate gene expression and prevent apoptosis" SET Confidence = "High" SET Subgraph = {"Apoptosis signaling subgraph", "MAPK-ERK subgraph", "protein kinase signaling subgraph"} bp(PTS:"mitogen activated protein kinase signaling pathway") -| bp(GOBP:"apoptotic process") bp(PTS:"mitogen activated protein kinase signaling pathway") -> bp(GOBP:"regulation of gene expression") bp(PTS:"Ras mediated signaling") -| bp(GOBP:"apoptotic process") bp(PTS:"Ras mediated signaling") -> bp(GOBP:"regulation of gene expression") bp(PTS:"RAF activation") -| bp(GOBP:"apoptotic process") bp(PTS:"RAF activation") -> bp(GOBP:"regulation of gene expression") a(CHEBI:mitogen) -| bp(GOBP:"apoptotic process") a(CHEBI:mitogen) reg bp(PTS:"mitogen activated protein kinase signaling pathway") UNSET Subgraph SET Evidence = "Some components of these pathways are mutated or aberrantly expressed in human cancer (e.g., Ras, B-Raf)." SET Confidence = "High" SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph"} p(HGNC:HRAS) pos path(DO:cancer) p(HGNC:NRAS) pos path(DO:cancer) p(HGNC:KRAS) pos path(DO:cancer) p(HGNC:BRAF) pos path(DO:cancer) SET Evidence = "Even in the absence of obvious genetic mutations, this pathway has been reported to be activated in over 50% of acute myelogenous leukemia and acute lymphocytic leukemia and is also frequently activated in other cancer types" SET Confidence = "High" bp(PTS:"mitogen activated protein kinase signaling pathway") pos path(DO:cancer) bp(PTS:"mitogen activated protein kinase signaling pathway") pos path(DO:"acute leukemia") bp(PTS:"mitogen activated protein kinase signaling pathway") pos path(DO:"acute lymphocytic leukemia") UNSET Subgraph SET Evidence = "The Raf/MEK/ERK pathway also has profound effects on the regulation of apoptosis by the post-translational phosphorylation of apoptotic regulatory molecules including Bad, Bim, Mcl-1, caspase 9 and more controversially Bcl-2." SET Confidence = "High" SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph", "Apoptosis signaling subgraph"} bp(PTS:"mitogen activated protein kinase signaling pathway") -> p(HGNC:BAD, pmod(P)) p(HGNC:BAD, pmod(P)) -- bp(GOBP:"apoptotic process") bp(PTS:"mitogen activated protein kinase signaling pathway") -> p(HGNC:BCL2L11, pmod(P)) p(HGNC:BCL2L11, pmod(P)) -- bp(GOBP:"apoptotic process") bp(PTS:"mitogen activated protein kinase signaling pathway") -> p(HGNC:MCL1, pmod(P)) p(HGNC:MCL1, pmod(P)) -- bp(GOBP:"apoptotic process") bp(PTS:"mitogen activated protein kinase signaling pathway") -> p(HGNC:CASP9, pmod(P)) p(HGNC:CASP9, pmod(P)) -- bp(GOBP:"apoptotic process") bp(PTS:"mitogen activated protein kinase signaling pathway") -> p(HGNC:BCL2, pmod(P)) p(HGNC:BCL2, pmod(P)) -- bp(GOBP:"apoptotic process") UNSET Subgraph SET Evidence = "For Ras to be targeted to the cell membrane, it must be farnesylated by farnesyl transferase [...] on the same cysteine residue " SET Confidence = "High" SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph"} p(HGNC:FNTA) -> p(HGNC:HRAS, pmod(F, C)) p(HGNC:FNTA) -> p(HGNC:NRAS, pmod(F, C)) p(HGNC:FNTA) -> p(HGNC:KRAS, pmod(F, C)) SET Evidence = "Ras is a small GTP-binding protein, which is the common upstream molecule of several signaling pathways including Raf/MEK/ERK, PI3K/Akt and RalEGF/Ral [3]. Four Ras proteins have been identified, namely Ha-Ras, N-Ras, Ki-Ras 4A and Ki-Ras 4B" SET Confidence = "High" SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph"} p(HGNC:HRAS, pmod(F, C)) -> bp(PTS:"Ras mediated signaling") p(HGNC:NRAS, pmod(F, C)) -> bp(PTS:"Ras mediated signaling") p(HGNC:KRAS, pmod(F, C)) -> bp(PTS:"Ras mediated signaling") bp(PTS:"Ras mediated signaling") -> bp(PTS:"RAF activation") SET Evidence = "The GTP bound active Ras can then recruit Raf to cell membrane [...] The mammalian Raf gene family consists of A-Raf, B-Raf and Raf-1 " SET Confidence = "High" p(HGNC:HRAS, pmod(F, C)) -> p(HGNC:RAF1) p(HGNC:HRAS, pmod(F, C)) -> p(HGNC:BRAF) p(HGNC:HRAS, pmod(F, C)) -> p(HGNC:ARAF) p(HGNC:NRAS, pmod(F, C)) -> p(HGNC:RAF1) p(HGNC:NRAS, pmod(F, C)) -> p(HGNC:ARAF) p(HGNC:NRAS, pmod(F, C)) -> p(HGNC:BRAF) p(HGNC:KRAS, pmod(F, C)) -> p(HGNC:RAF1) p(HGNC:KRAS, pmod(F, C)) -> p(HGNC:ARAF) p(HGNC:KRAS, pmod(F, C)) -> p(HGNC:BRAF) SET Evidence = "Raf activity is further modulated by chaperonin proteins including Bag1, 14-3-3 [12] and heat shock protein 90 (Hsp90)" SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph"} SET Confidence = "High" p(HGNC:BAG1) -- p(HGNC:RAF1) p(HGNC:BAG1) -- p(HGNC:RAF1) p(HGNC:BAG1) -- p(HGNC:ARAF) p(HGNC:YWHAQ) -- p(HGNC:BRAF) p(HGNC:YWHAQ) -- p(HGNC:RAF1) p(HGNC:YWHAQ) -- p(HGNC:ARAF) p(HGNC:HSP90AA1) -- p(HGNC:BRAF) p(HGNC:HSP90AA1) -- p(HGNC:ARAF) p(HGNC:HSP90AA1) -- p(HGNC:BRAF) SET Evidence = "Some of these sites [e.g., S43, S259 and S621] are phosphorylated when Raf-1 is inactive." SET Confidence = "High" p(HGNC:RAF1, pmod(P, S, 43)) -| bp(PTS:"RAF activation") p(HGNC:RAF1, pmod(P, S, 259)) -| bp(PTS:"RAF activation") p(HGNC:RAF1, pmod(P, S, 621)) -| bp(PTS:"RAF activation") SET Evidence = "This allows 14-3-3 to bind Raf-1 and confer a configuration which is inactive" SET Confidence = "High" p(HGNC:YWHAQ) -| bp(PTS:"RAF activation") UNSET Subgraph SET Evidence = "Phosphatases such as protein phosphatase 2A (PP2A) dephosphorylate S259" SET Confidence = "High" SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph", "Long term synaptic depression"} p(HGNC:PPP2R1A) -| p(HGNC:RAF1, pmod(P, S, 259)) UNSET Subgraph SET Evidence = "This allows Raf-1 to be phosphorylated at S338, Y340, and Y341, rendering Raf-1 active" SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph"} SET Confidence = "High" p(HGNC:RAF1, pmod(P, S, 338)) -> bp(PTS:"RAF activation") p(HGNC:RAF1, pmod(P, Y, 340)) -> bp(PTS:"RAF activation") p(HGNC:RAF1, pmod(P, Y, 341)) -> bp(PTS:"RAF activation") SET Evidence = "A Src family kinase is likely responsible for phosphorylation at Y340 and Y341" SET Confidence = "High" kin(p(HGNC:BLK)) -> p(HGNC:RAF1, pmod(P, Y, 340)) kin(p(HGNC:BLK)) -> p(HGNC:RAF1, pmod(P, Y, 341)) SET Evidence = "Thus a side effect of Src family kinase inhibitors such as Dasatinib, which is being used to treat certain Imatinib resistant chronic myeloid leukemia (CML) patients and other cancer patients who overexpresses mutant c-Kit [15] and [16] would be suppression of Raf-1/MEK/ERK signaling in certain cells." SET Confidence = "High" a(MESHC:Dasatinib) -| p(HGNC:BLK) a(MESHC:Dasatinib) -| bp(PTS:"RAF activation") SET Evidence = "Y340 and Y341, the phosphorylation targets of Src family kinases, are conserved in A-Raf (Y299 and Y300), but are replaced with aspartic acid (D) at the corresponding positions in B-Raf (D492 and D493)" SET Confidence = "High" kin(p(HGNC:BLK)) -> p(HGNC:ARAF, pmod(P, Y, 299)) kin(p(HGNC:BLK)) -> p(HGNC:ARAF, pmod(P, Y, 300)) p(HGNC:ARAF, pmod(P, Y, 299)) -> bp(PTS:"RAF activation") p(HGNC:ARAF, pmod(P, Y, 300)) -> bp(PTS:"RAF activation") kin(p(HGNC:BLK)) -> p(HGNC:BRAF, pmod(P, Asp, 492)) kin(p(HGNC:BLK)) -> p(HGNC:ARAF, pmod(P, Asp, 493)) p(HGNC:BRAF, pmod(P, Asp, 492)) -> bp(PTS:"RAF activation") p(HGNC:BRAF, pmod(P, Asp, 493)) -> bp(PTS:"RAF activation") SET Evidence = "Maximal activation of Raf-1 and A-Raf requires both Ras and Src activity while B-Raf activation is Src-independent" SET Confidence = "High" p(HGNC:BRAF) -> bp(PTS:"RAF activation") SET Evidence = "Dasatinib would be predicted to not inhibit B-Raf signaling" SET Confidence = "High" a(MESHC:Dasatinib) causesNoChange p(HGNC:BRAF) SET Evidence = "S338 phosphorylation on Raf-1 is stimulated by Ras and is dependent on p21-activated protein kinase (PAK)" SET Confidence = "High" kin(p(HGNC:HRAS)) -> p(HGNC:RAF1, pmod(P, S, 338)) kin(p(HGNC:NRAS)) -> p(HGNC:RAF1, pmod(P, S, 338)) kin(p(HGNC:KRAS)) -> p(HGNC:RAF1, pmod(P, S, 338)) kin(p(HGNC:PAK1)) -> p(HGNC:RAF1, pmod(P, S, 338)) SET Evidence = "Protein kinase C (PKC) has been shown to activate Raf and induce cross-talk between PKC and Raf/MEK/ERK signaling pathways" SET Confidence = "High" p(HGNC:PRKACA) -> p(HGNC:RAF1) p(HGNC:PRKACA) -- bp(PTS:"RAF activation") p(HGNC:PRKACA) -- bp(PTS:"mitogen activated protein kinase signaling pathway") SET Evidence = "Akt and protein kinase A (PKA) phosphorylate S259 on Raf-1 and inhibit its activity " SET Confidence = "High" kin(p(HGNC:AKT1)) -> p(HGNC:RAF1, pmod(P, S, 259)) kin(p(HGNC:PRKACA)) -> p(HGNC:RAF1, pmod(P, S, 259)) p(HGNC:RAF1, pmod(P, S, 259)) -| bp(PTS:"RAF activation") SET Evidence = "The scaffolding protein RKIP has been shown to inhibit Raf-1 activation and downstream signaling" SET Confidence = "High" p(HGNC:PEBP1) -| p(HGNC:RAF1) p(HGNC:PEBP1) -| bp(PTS:"RAF activation") SET Evidence = "Various isoforms of PKC have been shown to phosphorylate RKIP on S153 which results in the disassociation of Raf and RKIP" SET Confidence = "High" kin(p(HGNC:PRKACA)) -> p(HGNC:PEBP1, pmod(P, S, 153)) p(HGNC:PEBP1, pmod(P, S, 153)) causesNoChange p(HGNC:RAF1) p(HGNC:PEBP1, pmod(P, S, 153)) causesNoChange bp(PTS:"RAF activation") SET Evidence = "Drugs such as geldanamycin inhibit Hsp90 and result in the rapid degradation of Raf " SET Confidence = "High" a(CHEBI:geldanamycin) -| p(HGNC:HSP90AA1) a(CHEBI:geldanamycin) -| p(HGNC:RAF1) p(HGNC:HSP90AA1) positiveCorrelation p(HGNC:RAF1) SET Evidence = "Interestingly and controversially it was recently proposed that B-Raf is not only the major activator of MEK1, but B-Raf is also involved in Raf-1 activation" p(HGNC:BRAF) -> p(HGNC:MAP2K1) p(HGNC:BRAF) -> p(HGNC:RAF1) SET Evidence = "the discovery that B-Raf was a much more potent activator of MEK compared to Raf-1 and A-Raf" p(HGNC:ARAF) -> p(HGNC:MAP2K1) p(HGNC:RAF1) -> p(HGNC:MAP2K1) SET Evidence = "Its activity is positively regulated by Raf phosphorylation on S residues in the catalytic domain" kin(p(HGNC:RAF1)) -> p(HGNC:MAP2K1, pmod(P, S)) kin(p(HGNC:ARAF)) -> p(HGNC:MAP2K1, pmod(P, S)) kin(p(HGNC:BRAF)) -> p(HGNC:MAP2K1, pmod(P, S)) p(HGNC:MAP2K1, pmod(P, S)) -> bp(PTS:"mitogen activated protein kinase signaling pathway") UNSET Subgraph SET Evidence = "Another interesting aspect regarding MEK1 is that its predominate downstream target is ERK" SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph"} kin(p(HGNC:MAP2K1, pmod(P, S))) -> p(HGNC:MAPK1, pmod(P)) kin(p(HGNC:MAP2K1, pmod(P, S))) -> p(HGNC:MAPK3, pmod(P)) SET Evidence = "Extracellular-signal-regulated kinases 1,2 (ERK), are S/T kinases and their activities are positively regulated by phosphorylation mediated by MEK1 and MEK2" kin(p(HGNC:MAP2K2, pmod(P))) -> p(HGNC:MAPK1, pmod(P)) kin(p(HGNC:MAP2K2, pmod(P))) -> p(HGNC:MAPK3, pmod(P)) SET Evidence = "ERKs can directly phosphorylate many transcription factors including Ets-1, c-Jun and c-Myc" kin(p(HGNC:MAPK1)) -> p(HGNC:ETS1, pmod(P)) kin(p(HGNC:MAPK3)) -> p(HGNC:ETS1, pmod(P)) p(HGNC:ETS1, pmod(P)) -> bp(GOBP:"regulation of gene expression") kin(p(HGNC:MAPK1)) -> p(HGNC:JUN, pmod(P)) kin(p(HGNC:MAPK3)) -> p(HGNC:JUN, pmod(P)) p(HGNC:JUN, pmod(P)) -> bp(GOBP:"regulation of gene expression") kin(p(HGNC:MAPK1)) -> p(HGNC:MYC, pmod(P)) kin(p(HGNC:MAPK3)) -> p(HGNC:MYC, pmod(P)) p(HGNC:MYC, pmod(P)) -> bp(GOBP:"regulation of gene expression") SET Evidence = "Moreover, through an indirect mechanism, ERK can lead to activation of the NF-?B transcription factor (nuclear factor immunoglobulin ? chain enhancer-B cell) by phosphorylating and activating inhibitor ?B kinase (IKK" kin(p(HGNC:MAPK1)) -> p(HGNC:CHUK, pmod(P)) SET Subgraph = "Interleukin signaling subgraph" p(HGNC:CHUK, pmod(P)) -> p(HGNC:NFKB1) UNSET Subgraph SET Evidence = "Reactive oxygen species (ROS) are well known to induce the activation of the Raf/MEK/ERK signaling pathways" SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph"} a(CHEBI:"reactive oxygen species") -> bp(PTS:"RAF activation") a(CHEBI:"reactive oxygen species") -> bp(PTS:"mitogen activated protein kinase signaling pathway") SET Evidence = "Oxidative stress-induced ERK1/2 activation is reported in a variety of cell types" a(CHEBI:"reactive oxygen species") -> p(HGNC:MAPK1) a(CHEBI:"reactive oxygen species") -> p(HGNC:MAPK3) SET Evidence = "In some cases reactive oxygen intermediates act directly on growth receptors, such as the EGFR, in a ligand-independent fashion and induce the activation of Ras and ERK1/2 signaling" complex(p(HGNC:EGFR), a(CHEBI:"reactive oxygen species")) -> bp(PTS:"Ras mediated signaling") complex(p(HGNC:EGFR), a(CHEBI:"reactive oxygen species")) -> p(HGNC:MAPK1) complex(p(HGNC:EGFR), a(CHEBI:"reactive oxygen species")) -> p(HGNC:MAPK3) complex(p(HGNC:EGFR), a(CHEBI:"reactive oxygen species")) -> bp(PTS:"mitogen activated protein kinase signaling pathway") SET Evidence = "This type of responsiveness does not appear to be limited to the EGFR as ROS will also induce the ligand-independent activation of the platelet derived growth factor (PDGF) receptor and a subsequent increase in both Ras and ERK1/2 activity" complex(p(HGNC:PDGFRA), a(CHEBI:"reactive oxygen species")) -> p(HGNC:HRAS) complex(p(HGNC:PDGFRA), a(CHEBI:"reactive oxygen species")) -> p(HGNC:NRAS) complex(p(HGNC:PDGFRA), a(CHEBI:"reactive oxygen species")) -> p(HGNC:KRAS) complex(p(HGNC:PDGFRA), a(CHEBI:"reactive oxygen species")) -> p(HGNC:MAPK1) complex(p(HGNC:PDGFRA), a(CHEBI:"reactive oxygen species")) -> p(HGNC:MAPK3) complex(p(HGNC:PDGFRA), a(CHEBI:"reactive oxygen species")) -> bp(PTS:"mitogen activated protein kinase signaling pathway") SET Evidence = "t should be noted, however, that the MEK1 and 2 inhibitors U0126 and PD98059 both block oxidative stress-induced ERK1/2 activation [51] and [52] indicating that activating actions of oxidative stress do not occur directly on ERK1/2 but instead are localized at upstream targets." #a(CHEBI:"(2Z,3Z)-bis\{amino[(2-aminophenyl)sulfanyl]methylidene\}butanedinitrile") -| p(HGNC:MAP2K1) #a(CHEBI:"(2Z,3Z)-bis\{amino[(2-aminophenyl)sulfanyl]methylidene\}butanedinitrile") -| p(HGNC:MAP2K2) #a(CHEBI:"(2Z,3Z)-bis\{amino[(2-aminophenyl)sulfanyl]methylidene\}butanedinitrile") -| p(HGNC:MAPK1) #a(CHEBI:"(2Z,3Z)-bis\{amino[(2-aminophenyl)sulfanyl]methylidene\}butanedinitrile") -| p(HGNC:MAPK3) a(CHEBI:"2-(2-amino-3-methoxyphenyl)chromen-4-one") -| p(HGNC:MAP2K1) a(CHEBI:"2-(2-amino-3-methoxyphenyl)chromen-4-one") -| p(HGNC:MAP2K2) a(CHEBI:"2-(2-amino-3-methoxyphenyl)chromen-4-one") -| p(HGNC:MAP2K1) a(CHEBI:"2-(2-amino-3-methoxyphenyl)chromen-4-one") -| p(HGNC:MAP2K2) a(CHEBI:"reactive oxygen species") -> p(HGNC:MAP2K1) a(CHEBI:"reactive oxygen species") -> p(HGNC:MAP2K2) SET Evidence = "ROS such as, singlet oxygen [55], [56] and [57], hydrogen peroxide [58], nitric oxide [44] and [59], and peroxynitrite [60] induce the activation of the stress activated or JNK and p38 pathways" a(CHEBI:"singlet dioxygen") isA a(CHEBI:"reactive oxygen species") a(CHEBI:"hydrogen peroxide") isA a(CHEBI:"reactive oxygen species") a(CHEBI:"nitric oxide") isA a(CHEBI:"reactive oxygen species") a(CHEBI:peroxynitrite) isA a(CHEBI:"reactive oxygen species") a(CHEBI:"singlet dioxygen") -> bp(PTS:"mitogen activated protein kinase signaling pathway") a(CHEBI:"hydrogen peroxide") -> bp(PTS:"mitogen activated protein kinase signaling pathway") a(CHEBI:"nitric oxide") -> bp(PTS:"mitogen activated protein kinase signaling pathway") a(CHEBI:peroxynitrite) -> bp(PTS:"mitogen activated protein kinase signaling pathway") a(CHEBI:"singlet dioxygen") -> bp(PTS:"stress_activated protein kinase _sapk_ pathway") a(CHEBI:"hydrogen peroxide") -> bp(PTS:"stress_activated protein kinase _sapk_ pathway") a(CHEBI:"nitric oxide") -> bp(PTS:"stress_activated protein kinase _sapk_ pathway") a(CHEBI:peroxynitrite) -> bp(PTS:"stress_activated protein kinase _sapk_ pathway") SET Evidence = "Ras and its downstream effectors alter the expression of many molecules which regulate cell cycle including p16Ink4a, p15Ink4b and p21Cip1, and can lead to premature cell cycle arrest at the G1 phase" p(HGNC:NRAS) -- p(HGNC:CDKN2A) p(HGNC:KRAS) -- p(HGNC:CDKN2A) p(HGNC:HRAS) -- p(HGNC:CDKN2A) p(HGNC:NRAS) -- p(HGNC:CDKN2B) p(HGNC:KRAS) -- p(HGNC:CDKN2B) p(HGNC:HRAS) -- p(HGNC:CDKN2B) p(HGNC:NRAS) -- p(HGNC:CDKN1A) p(HGNC:KRAS) -- p(HGNC:CDKN1A) p(HGNC:HRAS) -- p(HGNC:CDKN1A) p(HGNC:CDKN2A) -> bp(GOBP:"regulation of cell cycle") p(HGNC:CDKN2B) -> bp(GOBP:"regulation of cell cycle") p(HGNC:CDKN1A) -> bp(GOBP:"regulation of cell cycle") p(HGNC:CDKN2A) -> bp(GOBP:"regulation of cell cycle arrest") p(HGNC:CDKN2B) -> bp(GOBP:"regulation of cell cycle arrest") p(HGNC:CDKN1A) -> bp(GOBP:"regulation of cell cycle arrest") SET Evidence = "This p15Ink4b/p16Ink4a or p21Cip1-mediated premature G1 arrest and subsequent senescence is dependent on the Raf/MEK/ERK pathway" bp(PTS:"mitogen activated protein kinase signaling pathway") -> bp(GOBP:"regulation of cell cycle arrest") bp(GOBP:"cell cycle arrest") -> bp(GOBP:"cellular senescence") SET Evidence = "Overexpression of activated Raf proteins is associated with such divergent responses as cell growth, cell cycle arrest" g(HGNC:RAF1) -> bp(GOBP:"cell growth") g(HGNC:ARAF) -> bp(GOBP:"cell growth") g(HGNC:BRAF) -> bp(GOBP:"cell growth") g(HGNC:RAF1) -> bp(GOBP:"cell cycle arrest") g(HGNC:ARAF) -> bp(GOBP:"cell cycle arrest") g(HGNC:BRAF) -> bp(GOBP:"cell cycle arrest") SET Evidence = "For many years now, it has been known that the Raf/MEK/ERK pathway can phosphorylate Bad on S112 which contributes to its inactivation and subsequent sequestration by 14-3-3 proteins" bp(PTS:"mitogen activated protein kinase signaling pathway") -> p(HGNC:BAD, pmod(P, S, 112)) p(HGNC:BAD, pmod(P, S, 112)) causesNoChange bp(GOBP:"apoptotic process") p(HGNC:BAD) -> bp(GOBP:"apoptotic process") p(HGNC:YWHAQ) -| p(HGNC:BAD, pmod(P, S, 112)) SET Evidence = "Activation of the Raf/MEK/ERK cascade can also result in the phosphorylation of the anti-apoptotic Mcl-1 protein and the pro-apoptotic Bim protein" bp(PTS:"mitogen activated protein kinase signaling pathway") -> p(HGNC:MCL1, pmod(P)) p(HGNC:MCL1, pmod(P)) -| bp(GOBP:"apoptotic process") bp(PTS:"mitogen activated protein kinase signaling pathway") -> p(HGNC:BCL2L11, pmod(P)) SET Evidence = "Phosphorylation of Bim results in its disassociation from Bcl-2, Bcl-XL, and Mcl-1 and Bim becomes ubiquitionated and targeted to the proteosome" p(HGNC:BCL2L11, pmod(P)) causesNoChange bp(GOBP:"apoptotic process") p(HGNC:BCL2L11) -> bp(GOBP:"apoptotic process") SET Evidence = " allows Bcl-2, Bcl-XL and Mcl-1 to bind Bax and prevent Bax activation and the formation of Bax:Bax homodimers. Thus apoptosis is inhibited" complex(p(HGNC:BCL2), p(HGNC:BCL2L1), p(HGNC:MCL1), p(HGNC:BAX)) -| bp(GOBP:"apoptotic process") p(HGNC:BAX) -> bp(GOBP:"apoptotic process") SET Evidence = "ERK phosphorylation of Bim on S69 can result in ubiquitination of Bim and subsequent proteosomal degradation" kin(p(HGNC:MAPK1)) -> p(HGNC:BCL2L11, pmod(P, S, 69)) kin(p(HGNC:MAPK3)) -> p(HGNC:BCL2L11, pmod(P, S, 69)) p(HGNC:BCL2L11, pmod(P, S, 69)) causesNoChange bp(GOBP:"apoptotic process") SET Evidence = "Bim can also be phosphorylated by Akt at S87 and this also attenuates Bim's apoptotic potential" kin(p(HGNC:AKT1)) -> p(HGNC:BCL2L11, pmod(P, S, 87)) p(HGNC:BCL2L11, pmod(P, S, 87)) causesNoChange bp(GOBP:"apoptotic process") UNSET Subgraph SET Evidence = "In contrast, phosphorylation of Bim at S65 by JNK can result in apoptosis due to stimulation of Bax:Bax interactions" SET Subgraph = {"Apoptosis signaling subgraph", "protein kinase signaling subgraph", "MAPK-ERK subgraph"} kin(p(HGNC:MAPK8)) -> p(HGNC:MAPK8, pmod(P, S, 65)) p(HGNC:MAPK8, pmod(P, S, 65)) -> bp(GOBP:"apoptotic process") UNSET Subgraph ################################# # END Paper on MAPK/ERK pathway ################################# ################################### # Epilepsy paper "Potential roles of the RGMa-FAK-Ras pathway in hippocampal mossy fiber sprouting in the pentylenetetrazole kindling model." ################################### SET Citation = {"PubMed", "Mol Med Rep. 2015 Mar;11(3):1738-44. doi: 10.3892/mmr.2014.2993. Epub 2014 Nov 21.", "25420768"} SET Evidence = "The repulsive guidance molecule A (RGMa) appears to contribute to axon growth and axonal guidance, and may exert its biological effects by dephosphorylating focal adhesion kinase (FAK) at Tyr397, then regulating the activation of Ras. " SET Confidence = "High" p(HGNC:RGMA) -> bp(GOBP:"axon guidance") p(HGNC:RGMA) -> bp(GOBP:"axon extension") p(HGNC:RGMA) -| p(HGNC:PTK2, pmod(P, Y, 397)) p(HGNC:RGMA) -> p(HGNC:PTK2) p(HGNC:RGMA) -- p(HGNC:HRAS) p(HGNC:RGMA) -- p(HGNC:KRAS) p(HGNC:RGMA) -- p(HGNC:NRAS) SET Evidence = "Compared with the control (saline-injected) group, the expression of RGMa in the CA3 area was significantly downregulated " SET Confidence = "High" SET MeSHAnatomy="CA3 Region, Hippocampal" SET Subgraph = "Mossy Fiber Subgraph" p(HGNC:RGMA) negativeCorrelation path(MESHD:Epilepsy) UNSET Subgraph UNSET MeSHAnatomy SET Evidence = "The expression of FAK (Tyr397) and Ras was upregulated (P<0.05) in the PTZ groups" SET Confidence = "High" SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph"} p(HGNC:PTK2, pmod(P, Y, 397)) positiveCorrelation path(MESHD:Epilepsy) p(HGNC:HRAS) positiveCorrelation path(MESHD:Epilepsy) p(HGNC:KRAS) positiveCorrelation path(MESHD:Epilepsy) p(HGNC:NRAS) positiveCorrelation path(MESHD:Epilepsy) SET Evidence = "To the best of our knowledge, these are the first results to indicate that the RGMa-FAK-Ras pathway may be involved in MFS and the development of temporal lobe epilepsy." SET Confidence = "High" bp(PTS:"Ras mediated signaling") -> path(MESHD:"Epilepsy, Temporal Lobe") SET Evidence = "Ras, one of the GTPase proteins that is abundantly distributed in neuronal axons and growth cones, promotes axonal extension during development" SET Confidence = "High" p(HGNC:HRAS) -> bp(GOBP:"axon extension") p(HGNC:KRAS) -> bp(GOBP:"axon extension") p(HGNC:NRAS) -> bp(GOBP:"axon extension") SET Evidence = "Studies have shown that RGMa induces cytoskeletal rearrangement by regulating the activation of Ras and RhoA" p(HGNC:RGMA) -- p(HGNC:RHOA) p(HGNC:HRAS) -> bp(GOBP:"regulation of actin cytoskeleton reorganization") p(HGNC:KRAS) -> bp(GOBP:"regulation of actin cytoskeleton reorganization") p(HGNC:NRAS) -> bp(GOBP:"regulation of actin cytoskeleton reorganization") p(HGNC:RHOA) -> bp(GOBP:"regulation of actin cytoskeleton reorganization") SET Evidence = "RhoA has been demonstrated to be associated with epilepsy" SET Confidence = "High" p(HGNC:RHOA) -- path(MESHD:Epilepsy) SET Evidence = "A previous study has revealed that RGMa could inactivate Ras via FAK dephosphorylation to induce growth cone collapse" SET Confidence = "High" p(HGNC:PTK2, pmod(P, Y, 397)) -> p(HGNC:HRAS) p(HGNC:PTK2, pmod(P, Y, 397)) -> p(HGNC:KRAS) p(HGNC:PTK2, pmod(P, Y, 397)) -> p(HGNC:NRAS) p(HGNC:RGMA) -| p(HGNC:HRAS) p(HGNC:RGMA) -| p(HGNC:KRAS) p(HGNC:RGMA) -| p(HGNC:NRAS) UNSET Subgraph ################################ # Epilepsy paper about interluekin 1 beta ################################ SET Citation = {"PubMed", "J Neuroimmunol. 2015 May 15;282:110-7. doi: 10.1016/j.jneuroim.2015.04.003. Epub 2015 Apr 2.", "25903737"} SET Evidence = "Increasing evidence indicated that interleukin-1/DF (IL-1/DF) plays a critical role in the pathogenesis of MTLE" SET Confidence = "High" SET Subgraph = "Interleukin signaling subgraph" p(HGNC:IL1B) -- path(MESHD:"Epilepsy, Temporal Lobe") SET Evidence = "In this study, we cultured primary hippocampal neurons, using IL-1/DF to mimic the process of inflammatory reaction in neurons, then inhibited the inflammation using inhibitors of the PI3K/Akt/mTOR signaling pathway." #: Add cell culture annotation for hippocampal neurons SET Confidence = "High" SET MeSHAnatomy = "Hippocampus" SET Subgraph = "Interleukin signaling subgraph" p(HGNC:IL1B) -> bp(PTS:"IL_1beta pathway") p(HGNC:IL1B) -> path(MESHD:Inflammation) bp(PTS:"IL_1beta pathway") -> path(MESHD:Inflammation) bp(PTS:"phosphatidylinositol 3_kinase signaling pathway") -> path(MESHD:Inflammation) SET Subgraph = {"mTOR signaling subgraph", "Interleukin signaling subgraph"} bp(PTS:"mTOR signaling pathway") -> path(MESHD:Inflammation) bp(PTS:"Akt/GSK3 pathway") -> path(MESHD:Inflammation) SET Evidence = "We observed that stimulation with IL-1/DF in neuron led to the up-regulation of p-Akt and p70S6K and promoted the growth of cell somatic size and dendritic length via the PI3K/Akt/mTOR signaling pathway" SET MeSHAnatomy = "Neurons" SET Subgraph = "Interleukin signaling subgraph" p(HGNC:IL1B) -> bp(PTS:"phosphatidylinositol 3_kinase signaling pathway") p(HGNC:IL1B) -> bp(PTS:"mTOR signaling pathway") p(HGNC:IL1B) -> bp(PTS:"Akt/GSK3 pathway") p(HGNC:IL1B) -> p(HGNC:AKT1, pmod(P, S, 473)) p(HGNC:IL1B) -> p(HGNC:RPS6KB1) p(HGNC:IL1B) -> bp(GOBP:"cell growth") p(HGNC:IL1B) -> bp(GOBP:"dendrite extension") SET Evidence = "Pre-treatment with inhibitors of the pathway, LY294002 and rapamycin, decreased the expression of p-Akt and p70S6K" SET Confidence = "High" a(CHEBI:LY294002) -| bp(PTS:"phosphatidylinositol 3_kinase signaling pathway") a(CHEBI:LY294002) -| bp(PTS:"mTOR signaling pathway") a(CHEBI:LY294002) -| bp(PTS:"Akt/GSK3 pathway") a(CHEBI:LY294002) -| p(HGNC:AKT1, pmod(P, S, 473)) a(CHEBI:LY294002) -| p(HGNC:RPS6KB1) bp(PTS:"phosphatidylinositol 3_kinase signaling pathway") -> p(HGNC:AKT1, pmod(P, S, 473)) bp(PTS:"mTOR signaling pathway") -> p(HGNC:AKT1, pmod(P, S, 473)) bp(PTS:"Akt/GSK3 pathway") -> p(HGNC:AKT1, pmod(P, S, 473)) bp(PTS:"phosphatidylinositol 3_kinase signaling pathway") -> p(HGNC:RPS6KB1) bp(PTS:"mTOR signaling pathway") -> p(HGNC:RPS6KB1) bp(PTS:"Akt/GSK3 pathway") -> p(HGNC:RPS6KB1) UNSET MeSHAnatomy SET Evidence = "We further verified the increasement of P-Akt and p70S6K in the hippocampi of children with MTLE." SET MeSHAnatomy = "Hippocampus" p(HGNC:AKT1, pmod(P, S, 473)) positiveCorrelation path(MESHD:"Epilepsy, Temporal Lobe") p(HGNC:RPS6KB1) positiveCorrelation path(MESHD:"Epilepsy, Temporal Lobe") UNSET MeSHAnatomy SET Evidence = "These data are the first to demonstrate that the inflammatory response induced by IL-1/DF promotes seizures and plays an important role in the pathogenesis of MTLE via the PI3K/Akt/mTOR signaling pathway. Therefore, modulation of the PI3K/Akt/mTOR signaling pathway may be a novel therapeutic target for the treatment of MTLE." bp(PTS:"phosphatidylinositol 3_kinase signaling pathway") -- path(MESHD:"Epilepsy, Temporal Lobe") bp(PTS:"Akt/GSK3 pathway") -- path(MESHD:"Epilepsy, Temporal Lobe") UNSET Subgraph ####################################################### # Drug part medication ####################################################### #: Not checked SET Citation = {"PubMed", "Ther Adv Drug Saf. 2011 Aug;2(4):141-58. doi: 10.1177/2042098611411127.", "25083209"} SET Evidence = "Bromides Unknown; potentially stabilize neuronal membranes via hyperpolarization" SET Drug = "Bromides" a(MESHC:Bromides) -| path(MESHD:Epilepsy) a(MESHC:Bromides) isA a(CHEBI:anticonvulsant) a(MESHC:Bromides) -> bp(GOBP:"membrane hyperpolarization") UNSET Drug SET Evidence = "Phenobarbital (PB) Enhance -aminobutyric acid (GABA) inhibition" SET Subgraph = {"GABA subgraph", "Neurotransmitter release subgraph"} SET Drug = "phenobarbital" a(CHEBI:phenobarbital) -> p(HGNC:GABRA1) p(HGNC:GABRA1) -| path(MESHD:Epilepsy) a(CHEBI:phenobarbital) -> p(HGNC:GABRA2) p(HGNC:GABRA2) -| path(MESHD:Epilepsy) a(CHEBI:phenobarbital) -> p(HGNC:GABRA3) p(HGNC:GABRA3) -| path(MESHD:Epilepsy) a(CHEBI:phenobarbital) -> p(HGNC:GABRA4) p(HGNC:GABRA4) -| path(MESHD:Epilepsy) a(CHEBI:phenobarbital) -> p(HGNC:GABRA5) p(HGNC:GABRA5) -| path(MESHD:Epilepsy) a(CHEBI:phenobarbital) -> p(HGNC:GABRA6) p(HGNC:GABRA6) -| path(MESHD:Epilepsy) a(CHEBI:phenobarbital) -> p(HGNC:GABRB1) p(HGNC:GABRB1) -| path(MESHD:Epilepsy) a(CHEBI:phenobarbital) -> p(HGNC:GABRB2) p(HGNC:GABRB2) -| path(MESHD:Epilepsy) a(CHEBI:phenobarbital) -> p(HGNC:GABRB3) p(HGNC:GABRB3) -| path(MESHD:Epilepsy) a(CHEBI:phenobarbital) -> p(HGNC:GABRD) p(HGNC:GABRD) -| path(MESHD:Epilepsy) a(CHEBI:phenobarbital) -> p(HGNC:GABRE) p(HGNC:GABRE) -| path(MESHD:Epilepsy) a(CHEBI:phenobarbital) -> p(HGNC:GABRG1) p(HGNC:GABRG1) -| path(MESHD:Epilepsy) a(CHEBI:phenobarbital) -> p(HGNC:GABRG2) p(HGNC:GABRG2) -| path(MESHD:Epilepsy) a(CHEBI:phenobarbital) -> p(HGNC:GABRG3) p(HGNC:GABRG3) -| path(MESHD:Epilepsy) a(CHEBI:phenobarbital) -> p(HGNC:GABRP) p(HGNC:GABRP) -| path(MESHD:Epilepsy) a(CHEBI:phenobarbital) -> p(HGNC:GABRQ) p(HGNC:GABRQ) -| path(MESHD:Epilepsy) a(CHEBI:phenobarbital) -> bp(GOBP:"synaptic transmission, GABAergic") UNSET Drug UNSET Subgraph SET Evidence = "Primidone (PRM) May act synergistically with potassium bromide to reduce high-frequency repetitive neuronal firing " SET Drug = "primidone" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} complex(a(CHEBI:primidone), a(CHEBI:"potassium bromide")) -| bp(GOBP:"neuronal action potential propagation") a(CHEBI:primidone) -> a(CHEBI:phenobarbital) UNSET Subgraph UNSET Drug SET Evidence = "Phenytoin (PHT) Use-dependent inhibition of sodium channels, thus blocking repetitive firing of action potential" SET Drug = "phenytoin" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} a(CHEBI:phenytoin) -| bp(GOBP:"neuronal action potential propagation") a(CHEBI:phenytoin) -| p(HGNC:SCN1A) a(CHEBI:phenytoin) -| p(HGNC:SCN2A) a(CHEBI:phenytoin) -| p(HGNC:SCN3A) p(HGNC:SCN3A) -> path(MESHD:Epilepsy) a(CHEBI:phenytoin) -| p(HGNC:SCN4A) p(HGNC:SCN4A) -> path(MESHD:Epilepsy) a(CHEBI:phenytoin) -| p(HGNC:SCN5A) p(HGNC:SCN5A) -> path(MESHD:Epilepsy) a(CHEBI:phenytoin) -| p(HGNC:SCN8A) p(HGNC:SCN8A) -> path(MESHD:Epilepsy) a(CHEBI:phenytoin) -| p(HGNC:SCN9A) p(HGNC:SCN9A) -> path(MESHD:Epilepsy) UNSET Subgraph UNSET Drug SET Evidence = "Ethosuximide (ESM) Reduction of low-threshold T-type calcium currents in thalamic neurons" SET Drug = "ethosuximide" SET Subgraph = "Calcium dependent subgraph" a(CHEBI:ethosuximide) -| bp(PTS:"Calcium signaling pathway") a(CHEBI:ethosuximide) -| p(HGNC:CACNA1A) p(HGNC:CACNA1A) -> path(MESHD:Epilepsy) a(CHEBI:ethosuximide) -| p(HGNC:CACNA1H) p(HGNC:CACNA1H) -> path(MESHD:Epilepsy) a(CHEBI:ethosuximide) -| p(HGNC:CACNA1G) p(HGNC:CACNA1G) -> path(MESHD:Epilepsy) UNSET Subgraph SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph"} a(CHEBI:ethosuximide) -| bp(PTS:"mitogen activated protein kinase signaling pathway") UNSET Subgraph SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} a(CHEBI:ethosuximide) -| p(HGNC:SCN1A) a(CHEBI:ethosuximide) -| p(HGNC:SCN8A) UNSET Subgraph UNSET Drug SET Evidence = "Carbamazepine (CBZ) Use-dependent inhibition of sodium channels, thus blocking repetitive firing of action potentials" SET Drug = "carbamazepine" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} a(CHEBI:carbamazepine) -| bp(GOBP:"neuronal action potential propagation") a(CHEBI:carbamazepine) -| p(HGNC:SCN1A) a(CHEBI:carbamazepine) -| p(HGNC:SCN2A) a(CHEBI:carbamazepine) -| p(HGNC:SCN3A) a(CHEBI:carbamazepine) -| p(HGNC:SCN4A) a(CHEBI:carbamazepine) -| p(HGNC:SCN5A) a(CHEBI:carbamazepine) -| p(HGNC:SCN8A) a(CHEBI:carbamazepine) -| p(HGNC:SCN9A) UNSET Subgraph UNSET Drug SET Evidence = "valproate (VPA) Precise mechanism unknown; multiple GABA-related actions, N-methyl D-aspartate (NMDA) receptor antagonist, and histone deacetylase inhibitor " SET Drug = "valproate" SET Subgraph = "Calcium dependent subgraph" a(CHEBI:valproate) -| p(HGNC:CACNA1G) a(CHEBI:valproate) -| p(HGNC:CACNA1H) a(CHEBI:valproate) -| p(HGNC:CACNA1I) p(HGNC:CACNA1I) -> path(MESHD:Epilepsy) a(CHEBI:valproate) -- bp(PTS:"Calcium signaling pathway") UNSET Subgraph a(CHEBI:valproate) -| p(HGNC:CDY2B) p(HGNC:CDY2B) -> path(MESHD:Epilepsy) a(CHEBI:valproate) -| p(HGNC:CDY1B) p(HGNC:CDY1B) -> path(MESHD:Epilepsy) a(CHEBI:valproate) -| p(HGNC:CDY1) p(HGNC:CDY1) -> path(MESHD:Epilepsy) a(CHEBI:valproate) -| p(HGNC:CDY2A) p(HGNC:CDY2A) -> path(MESHD:Epilepsy) SET Subgraph = {"Protein Metabolism", "Metabolism"} a(CHEBI:valproate) -| p(HGNC:HDAC1) p(HGNC:HDAC1) -> path(MESHD:Epilepsy) a(CHEBI:valproate) -| p(HGNC:HDAC2) p(HGNC:HDAC2) -> path(MESHD:Epilepsy) a(CHEBI:valproate) -| p(HGNC:HDAC3) p(HGNC:HDAC3) -> path(MESHD:Epilepsy) a(CHEBI:valproate) -| p(HGNC:HDAC4) p(HGNC:HDAC4) -> path(MESHD:Epilepsy) a(CHEBI:valproate) -| p(HGNC:HDAC5) p(HGNC:HDAC5) -> path(MESHD:Epilepsy) a(CHEBI:valproate) -| p(HGNC:HDAC6) p(HGNC:HDAC6) -> path(MESHD:Epilepsy) a(CHEBI:valproate) -| p(HGNC:HDAC7) p(HGNC:HDAC7) -> path(MESHD:Epilepsy) a(CHEBI:valproate) -| p(HGNC:HDAC8) p(HGNC:HDAC8) -> path(MESHD:Epilepsy) a(CHEBI:valproate) -| p(HGNC:HDAC9) p(HGNC:HDAC9) -> path(MESHD:Epilepsy) a(CHEBI:valproate) -| p(HGNC:HDAC10) p(HGNC:HDAC10) -> path(MESHD:Epilepsy) UNSET Subgraph SET Subgraph = {"Neurotransmitter release subgraph", "GABA subgraph"} a(CHEBI:valproate) -| p(HGNC:ABAT) p(HGNC:ABAT) -| a(CHEBI:"GABA agent") p(HGNC:ABAT) -| bp(PTS:"gamma_aminobutyric acid signaling pathway") a(CHEBI:valproate) -> bp(GOBP:"synaptic transmission, GABAergic") a(CHEBI:valproate) -> bp(PTS:"gamma_aminobutyric acid signaling pathway") a(CHEBI:valproate) -> p(HGNC:ALDH5A1) p(HGNC:ALDH5A1) -> a(CHEBI:"GABA agent") p(HGNC:ALDH5A1) -> bp(PTS:"gamma_aminobutyric acid signaling pathway") UNSET Subgraph SET Subgraph = {"thyroid hormone signaling subgraph", "hormone signaling subgraph"} a(CHEBI:valproate) -> a(CHEBI:"thyroid hormone") UNSET Subgraph SET Subgraph = "Notch signaling subgraph" a(CHEBI:valproate) -> bp(PTS:"Notch signaling pathway") UNSET Subgraph a(CHEBI:valproate) -| bp(GOBP:"cell growth") SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph"} a(CHEBI:valproate) -- bp(PTS:"mitogen activated protein kinase signaling pathway") UNSET Subgraph UNSET Drug SET Evidence = "Vigabatrin (VGB) Specifically and irreversibly inhibits GABA-T; may also stimulate GABA release Felbamate (FBM) Binds to open channels of the NMDA subtype glutamate receptor (thus, blocking sodium and calcium conduction); also possesses other properties, such as inhibition of voltage-gated sodium channels" # vigabatrin already annotated elsewhere SET Drug = "felbamate" SET Subgraph = {"Calcium dependent subgraph", "Long term synaptic potentiation", "Glutamatergic subgraph", "Neurotransmitter release subgraph"} a(CHEBI:felbamate) -| p(HGNC:GRIN2A) p(HGNC:GRIN2A) -> path(MESHD:Epilepsy) a(CHEBI:felbamate) -| p(HGNC:GRIN3A) p(HGNC:GRIN3A) -> path(MESHD:Epilepsy) a(CHEBI:felbamate) -| p(HGNC:GRIN2B) p(HGNC:GRIN2B) -> path(MESHD:Epilepsy) a(CHEBI:felbamate) -| bp(PTS:"Calcium signaling pathway") UNSET Subgraph SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} a(CHEBI:felbamate) -| p(HGNC:SCN1A) a(CHEBI:felbamate) -| p(HGNC:SCN2A) a(CHEBI:felbamate) -| p(HGNC:SCN3A) a(CHEBI:felbamate) -| p(HGNC:SCN4A) a(CHEBI:felbamate) -| p(HGNC:SCN5A) a(CHEBI:felbamate) -| p(HGNC:SCN8A) a(CHEBI:felbamate) -| p(HGNC:SCN9A) UNSET Subgraph UNSET Drug SET Evidence = "Gabapentin (GBP) and pregabalin (PGB) Precise mechanism unknown; bind to the ‚àö√â‚àÜ√≠‚àö√ñ¬¨Œ©‚àö√â‚Äö√Ñ√∂‚àö√ᬨ¬±2‚àö√â‚àÜ√≠‚àö√ñ¬¨Œ©‚àö√â‚Äö√Ñ√∂‚àö√ᬨ¬• modulatory subunit of voltage-sensitive calcium channels" SET Drug = {"gabapentin", "pregabalin"} SET Subgraph = "Calcium dependent subgraph" a(CHEBI:gabapentin) -| p(HGNC:CACNA2D1) p(HGNC:CACNA2D1) -> path(MESHD:Epilepsy) a(CHEBI:gabapentin) -| p(HGNC:CACNA2D2) p(HGNC:CACNA2D2) -> path(MESHD:Epilepsy) a(CHEBI:gabapentin) -| p(HGNC:CACNA2D3) p(HGNC:CACNA2D3) -> path(MESHD:Epilepsy) a(CHEBI:gabapentin) -| p(HGNC:CACNA2D4) p(HGNC:CACNA2D4) -> path(MESHD:Epilepsy) a(CHEBI:pregabalin) -| p(HGNC:CACNA2D1) a(CHEBI:pregabalin) -| p(HGNC:CACNA2D2) a(CHEBI:pregabalin) -| p(HGNC:CACNA2D3) a(CHEBI:pregabalin) -| p(HGNC:CACNA2D4) UNSET Subgraph SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph"} a(CHEBI:gabapentin) -- bp(PTS:"mitogen activated protein kinase signaling pathway") a(CHEBI:pregabalin) -- bp(PTS:"mitogen activated protein kinase signaling pathway") UNSET Subgraph UNSET Drug SET Evidence = "Lamotrigine (LTG) Blocks sodium channels; inhibits high-voltage-activated calcium currents" SET Drug = "lamotrigine" SET Subgraph = "Calcium dependent subgraph" a(CHEBI:lamotrigine) -| bp(PTS:"Calcium signaling pathway") UNSET Subgraph SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} a(CHEBI:lamotrigine) -| p(HGNC:SCN1A) a(CHEBI:lamotrigine) -| p(HGNC:SCN2A) a(CHEBI:lamotrigine) -| p(HGNC:SCN3A) a(CHEBI:lamotrigine) -| p(HGNC:SCN4A) a(CHEBI:lamotrigine) -| p(HGNC:SCN5A) a(CHEBI:lamotrigine) -| p(HGNC:SCN8A) a(CHEBI:lamotrigine) -| p(HGNC:SCN9A) UNSET Subgraph UNSET Drug SET Evidence = "Tiagabine (TGB) Enhances GABA-mediated inhibition by blocking GABA reuptake" SET Drug = "tiagabine" SET Subgraph = {"GABA subgraph", "Neurotransmitter release subgraph"} a(CHEBI:tiagabine) -> p(HGNC:SLC6A1) a(CHEBI:tiagabine) -> p(HGNC:SLC6A12) p(HGNC:SLC6A1) -| path(MESHD:Epilepsy) p(HGNC:SLC6A1) -> a(CHEBI:"GABA agent") p(HGNC:SLC6A1) -> bp(PTS:"gamma_aminobutyric acid signaling pathway") p(HGNC:SLC6A12) -> a(CHEBI:"GABA agent") p(HGNC:SLC6A12) -> bp(PTS:"gamma_aminobutyric acid signaling pathway") a(CHEBI:tiagabine) -> a(CHEBI:"GABA agent") a(CHEBI:tiagabine) -> bp(PTS:"gamma_aminobutyric acid signaling pathway") UNSET Drug SET Evidence = "Topiramate (TPM) Multiple mechanisms: blocks the kainate/‚àö√â‚àÜ√≠‚àö√ñ¬¨Œ©‚àö√â‚Äö√Ñ√∂‚àö√ᬨ¬±-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid (AMPA) glutamate receptor subtype; blocks voltage-activated sodium channels; enhances GABA-mediated chloride flux at GABAA receptors; reduces amplitude of high-voltage-activated calcium currents; and activates potassium conduction " SET Drug = "topiramate" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} a(CHEBI:topiramate) -| p(HGNC:SCN1A) a(CHEBI:topiramate) -| p(HGNC:SCN2A) a(CHEBI:topiramate) -| p(HGNC:SCN3A) a(CHEBI:topiramate) -| p(HGNC:SCN4A) a(CHEBI:topiramate) -| p(HGNC:SCN5A) a(CHEBI:topiramate) -| p(HGNC:SCN8A) a(CHEBI:topiramate) -| p(HGNC:SCN9A) UNSET Subgraph SET Subgraph = {"Glutamatergic subgraph", "Neurotransmitter release subgraph", "Long term synaptic potentiation", "Long term synaptic depression"} a(CHEBI:topiramate) -- bp(PTS:"glutamate signaling pathway") a(CHEBI:topiramate) -- bp(PTS:"Long_Term Potentiation") a(CHEBI:topiramate) -- bp(PTS:"long term depression") a(CHEBI:topiramate) -| p(HGNC:GRIA1) p(HGNC:GRIA1) -> path(MESHD:Epilepsy) a(CHEBI:topiramate) -| p(HGNC:GRIA2) p(HGNC:GRIA2) -> path(MESHD:Epilepsy) a(CHEBI:topiramate) -| p(HGNC:GRIA3) p(HGNC:GRIA3) -> path(MESHD:Epilepsy) a(CHEBI:topiramate) -| p(HGNC:GRIA4) p(HGNC:GRIA4) -> path(MESHD:Epilepsy) a(CHEBI:topiramate) -| p(HGNC:GRIK1) p(HGNC:GRIK1) -> path(MESHD:Epilepsy) a(CHEBI:topiramate) -| p(HGNC:GRIK2) p(HGNC:GRIK2) -> path(MESHD:Epilepsy) a(CHEBI:topiramate) -| p(HGNC:GRIK3) p(HGNC:GRIK3) -> path(MESHD:Epilepsy) a(CHEBI:topiramate) -| p(HGNC:GRIK4) p(HGNC:GRIK4) -> path(MESHD:Epilepsy) a(CHEBI:topiramate) -| p(HGNC:GRIK5) p(HGNC:GRIK5) -> path(MESHD:Epilepsy) UNSET Subgraph SET Subgraph = "Calcium dependent subgraph" a(CHEBI:topiramate) -| p(HGNC:CACNA1C) p(HGNC:CACNA1C) -> path(MESHD:Epilepsy) a(CHEBI:topiramate) -| p(HGNC:CACNA1D) p(HGNC:CACNA1D) -> path(MESHD:Epilepsy) a(CHEBI:topiramate) -| p(HGNC:CACNA1F) p(HGNC:CACNA1F) -> path(MESHD:Epilepsy) a(CHEBI:topiramate) -| p(HGNC:CACNA1S) p(HGNC:CACNA1S) -> path(MESHD:Epilepsy) a(CHEBI:topiramate) -| bp(PTS:"Calcium signaling pathway") UNSET Subgraph SET Subgraph = {"GABA subgraph", "Neurotransmitter release subgraph"} a(CHEBI:topiramate) -- bp(PTS:"gamma_aminobutyric acid signaling pathway") UNSET Subgraph SET Subgraph = {"thyroid hormone signaling subgraph", "hormone signaling subgraph"} a(CHEBI:topiramate) -> a(CHEBI:"thyroid hormone") UNSET Subgraph UNSET Drug SET Evidence = "Levetiracetam (LEV) Precise mechanism unknown; binds SV2A, a presynaptic protein, on synaptic vesicles" SET Drug = "levetiracetam" SET Subgraph = "Neurotransmitter release subgraph" a(CHEBI:levetiracetam) -> p(HGNC:SV2A) p(HGNC:SV2A) -| path(MESHD:Epilepsy) p(HGNC:SV2A) -> bp(PTS:"Synaptic vesicle cycle") UNSET Subgraph SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} a(CHEBI:levetiracetam) -| p(HGNC:SCN1A) UNSET Subgraph SET Subgraph = "Calcium dependent subgraph" a(CHEBI:levetiracetam) -| bp(PTS:"Calcium signaling pathway") a(CHEBI:levetiracetam) -| p(HGNC:CACNA1A) a(CHEBI:levetiracetam) -| p(HGNC:ITPR1) p(HGNC:ITPR1) -> a(CHEBI:"calcium(2+)") p(HGNC:ITPR1) -> bp(PTS:"Calcium signaling pathway") p(HGNC:ITPR1) -> path(MESHD:Epilepsy) a(CHEBI:levetiracetam) -| p(HGNC:RYR1) p(HGNC:RYR1) -> a(CHEBI:"calcium(2+)") p(HGNC:RYR1) -> bp(PTS:"Calcium signaling pathway") p(HGNC:RYR1) -> path(MESHD:Epilepsy) UNSET Subgraph SET Subgraph = {"GABA subgraph", "Neurotransmitter release subgraph"} a(CHEBI:levetiracetam) -> p(HGNC:GABRA1) UNSET Subgraph SET Subgraph = "Neurotransmitter release subgraph" a(CHEBI:levetiracetam) -> p(HGNC:GLRA1) p(HGNC:GLRA1) -| path(MESHD:Epilepsy) UNSET Subgraph UNSET Drug SET Evidence = "Oxcarbazepine (OXC) Blocks voltage-dependent ionic membrane conduction (particularly sodium, potassium, and calcium) thereby stabilizing membranes and reducing synaptic impulse propagation; acts on N-type calcium channels" SET Drug = "oxcarbazepine" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} a(CHEBI:oxcarbazepine) -| p(HGNC:SCN1A) a(CHEBI:oxcarbazepine) -| p(HGNC:SCN2A) a(CHEBI:oxcarbazepine) -| p(HGNC:SCN3A) a(CHEBI:oxcarbazepine) -| p(HGNC:SCN4A) a(CHEBI:oxcarbazepine) -| p(HGNC:SCN5A) a(CHEBI:oxcarbazepine) -| p(HGNC:SCN8A) a(CHEBI:oxcarbazepine) -| p(HGNC:SCN9A) UNSET Subgraph SET Subgraph = "Calcium dependent subgraph" a(CHEBI:oxcarbazepine) -| p(HGNC:CACNA1B) p(HGNC:CACNA1B) -> path(MESHD:Epilepsy) a(CHEBI:oxcarbazepine) -> bp(GOBP:"membrane hyperpolarization") a(CHEBI:oxcarbazepine) -| bp(GOBP:"neuronal action potential propagation") UNSET Subgraph UNSET Drug SET Evidence = "Zonisamide (ZNS) Blocks T-type calcium channels, inhibits slow sodium channels, and inhibits glutamate release" SET Drug = "zonisamide" SET Subgraph = "Calcium dependent subgraph" a(CHEBI:zonisamide) -| p(HGNC:CACNA1I) a(CHEBI:zonisamide) -| p(HGNC:CACNA1H) a(CHEBI:zonisamide) -| p(HGNC:CACNA1G) a(CHEBI:zonisamide) -| bp(PTS:"Calcium signaling pathway") UNSET Subgraph SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} a(CHEBI:zonisamide) -| p(HGNC:SCN1A) a(CHEBI:zonisamide) -| p(HGNC:SCN2A) a(CHEBI:zonisamide) -| p(HGNC:SCN3A) a(CHEBI:zonisamide) -| p(HGNC:SCN4A) a(CHEBI:zonisamide) -| p(HGNC:SCN5A) a(CHEBI:zonisamide) -| p(HGNC:SCN8A) a(CHEBI:zonisamide) -| p(HGNC:SCN9A) UNSET Subgraph SET Subgraph = {"Glutamatergic subgraph", "Neurotransmitter release subgraph"} a(CHEBI:zonisamide) -| bp(PTS:"glutamate signaling pathway") UNSET Subgraph SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph"} a(CHEBI:zonisamide) -- bp(PTS:"mitogen activated protein kinase signaling pathway") UNSET Subgraph UNSET Drug SET Evidence = "Rufinamide (RFN) Exact mechanism of action unknown; prolongs inactivation of voltage-dependent sodium channels" SET Drug = "rufinamide" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} a(MESHC:rufinamide) -| p(HGNC:SCN1A) a(MESHC:rufinamide) -| p(HGNC:SCN2A) a(MESHC:rufinamide) -| p(HGNC:SCN3A) a(MESHC:rufinamide) -| p(HGNC:SCN4A) a(MESHC:rufinamide) -| p(HGNC:SCN5A) a(MESHC:rufinamide) -| p(HGNC:SCN8A) a(MESHC:rufinamide) -| p(HGNC:SCN9A) UNSET Subgraph UNSET Drug SET Evidence = "Lacosamide (LCM) Selectively enhances the slow inactivation of voltage-gated sodium channels; inhibits the collapsing response mediator protein 2 (CRMP-2) thereby possibly inhibiting neuronal growth that may occur in chronic epilepsy" SET Drug = "lacosamide" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} a(MESHC:lacosamide) -| p(HGNC:SCN9A) a(MESHC:lacosamide) -| p(HGNC:SCN10A) p(HGNC:SCN10A) -> path(MESHD:Epilepsy) a(MESHC:lacosamide) -| p(HGNC:SCN3A) UNSET Subgraph SET Subgraph = "Calcium dependent subgraph" a(MESHC:lacosamide) -| p(HGNC:DPYSL2) p(HGNC:DPYSL2) -> path(MESHD:Epilepsy) UNSET Subgraph UNSET Drug SET Evidence = "Patients treated with bromides often remained on the drug for long periods of time, and many developed side effects including but not limited to dose-related drowsiness, restlessness, headache, delirium, acneiform rashes, granulomatous skin lesions, loss of appetite, and psychosis" SET Drug = "Bromides" a(MESHC:Bromides) -> path(MESHD:"Drug-Related Side Effects and Adverse Reactions") path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(MESHD:Delirium) a(MESHC:Bromides) -> path(MESHD:Delirium) path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(MESHD:"Acneiform Eruptions") a(MESHC:Bromides) -> path(MESHD:"Acneiform Eruptions") path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(DO:"substance-induced psychosis") a(MESHC:Bromides) -> path(DO:"substance-induced psychosis") path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(DO:"granulomatous dermatitis") a(MESHC:Bromides) -> path(DO:"granulomatous dermatitis") path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(MESHD:Headache) a(MESHC:Bromides) -> path(MESHD:Headache) UNSET Drug SET Evidence = "Phenobarbital became widely used as a sedative and hypnotic agent" SET Drug = "phenobarbital" SET Subgraph = {"GABA subgraph", "Neurotransmitter release subgraph"} a(CHEBI:phenobarbital) isA a(CHEBI:sedative) a(CHEBI:phenobarbital) isA a(MESHC:"Hypnotics and Sedatives") SET Evidence = "Although phenobarbital continues to be an effective AED and has less toxicity than bromides [Krall et al. 1978] it is not without side effects, the more common being sedation, depression, and paradoxical hyperactivity in children" a(CHEBI:phenobarbital) -> path(MESHD:"Drug-Related Side Effects and Adverse Reactions") path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(DO:"major depressive disorder") a(CHEBI:phenobarbital) -> path(DO:"major depressive disorder") path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(DO:"attention deficit hyperactivity disorder") a(CHEBI:phenobarbital) -> path(DO:"attention deficit hyperactivity disorder") SET Evidence = "Neurologic toxicity (such as ataxia, nystagmus, dysarthria) can occur with increased doses [Bourgeois, 2011]. More extreme respiratory and circulatory collapse can also occur, particularly when toxic amounts of the drug have been ingested" path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(MESHD:Ataxia) a(CHEBI:phenobarbital) -> path(MESHD:Ataxia) path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(MESHD:"Nystagmus, Pathologic") a(CHEBI:phenobarbital) -> path(MESHD:"Nystagmus, Pathologic") path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(MESHD:Dysarthria) a(CHEBI:phenobarbital) -> path(MESHD:Dysarthria) UNSET Subgraph UNSET Drug SET Evidence = "Phenytoin is known for its various side effects affecting the CNS and other organ systems, including but not limited to nystagmus, ataxia, diplopia, drowsiness, impaired concentration, gingival hyperplasia, hirsutism, acne, hepatotoxicity, and idiosyncratic reactions including lupus-like reactions and aplastic anemia" SET Drug = "phenytoin" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} a(CHEBI:phenytoin) -> path(MESHD:"Drug-Related Side Effects and Adverse Reactions") path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(MESHD:"Nystagmus, Pathologic") a(CHEBI:phenytoin) -> path(MESHD:"Nystagmus, Pathologic") path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(MESHD:Ataxia) a(CHEBI:phenytoin) -> path(MESHD:Ataxia) path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(MESHD:Diplopia) a(CHEBI:phenytoin) -> path(MESHD:Diplopia) path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(MESHD:"Gingival Hyperplasia") a(CHEBI:phenytoin) -> path(MESHD:"Gingival Hyperplasia") path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(MESHD:Hirsutism) a(CHEBI:phenytoin) -> path(MESHD:Hirsutism) path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(DO:acne) a(CHEBI:phenytoin) -> path(DO:acne) path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(MESHD:"Anemia, Aplastic") a(CHEBI:phenytoin) -> path(MESHD:"Anemia, Aplastic") UNSET Subgraph UNSET Drug SET Evidence = "Ethosuximide was marketed in 1960, and possesses a fairly narrow therapeutic indication for absence epilepsy. Its AE profile includes but is not limited to nausea, abdominal discomfort, anorexia, drowsiness, dizziness, and numerous idiosyncratic reactions" SET Drug = "ethosuximide" SET Subgraph = {"Calcium dependent subgraph", "MAPK-ERK subgraph", "protein kinase signaling subgraph", "Serotonergic subgraph", "Neurotransmitter release subgraph"} a(CHEBI:ethosuximide) -| path(MESHD:"Epilepsy, Absence") a(CHEBI:ethosuximide) -> path(MESHD:"Drug-Related Side Effects and Adverse Reactions") path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(DO:"anorexia nervosa") a(CHEBI:ethosuximide) -> path(DO:"anorexia nervosa") path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(MESHD:Nausea) a(CHEBI:ethosuximide) -> path(MESHD:Nausea) UNSET Subgraph UNSET Drug SET Evidence = "Carbamazepine was introduced in 1974. Common AEs include drowsiness, loss of coordination, vertigo, and weight gain [Hogan et al. 2000; Pellock, 1987]. Rash, hyponatremia, leucopenia, rare cases of hepatotoxicity, and other idiosyncratic reactions have also been reported " SET Drug = "carbamazepine" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} a(CHEBI:carbamazepine) -> path(MESHD:"Drug-Related Side Effects and Adverse Reactions") path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(MESHD:"Weight Gain") a(CHEBI:carbamazepine) -> path(MESHD:"Weight Gain") path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(MESHD:Hyponatremia) a(CHEBI:carbamazepine) -> path(MESHD:Hyponatremia) path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(DO:leukopenia) a(CHEBI:carbamazepine) -> path(DO:leukopenia) UNSET Subgraph UNSET Drug SET Evidence = "Valproate came to the market in 1978 and has since been associated with various side effects, some of the more common and/or formidable being dose-related tremor (less with controlled-release formulations), hair loss, weight gain, nausea, vomiting, hepatotoxicity, acute hemorrhagic pancreatitis, thrombocytopenia, and hyperammonemia; lethargy is also reported, but less commonly [Gerstner et al. 2008; Rinnerthaler et al. 2005; Davis et al. 1994]. Valproate is also associated with the greatest risk for major congenital malformations (MCMs) among the existing AEDs " SET Drug = "valproate" SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph", "Notch signaling subgraph", "thyroid hormone signaling subgraph", "hormone signaling subgraph", "Neurotransmitter release subgraph", "GABA subgraph", "Calcium dependent subgraph"} a(CHEBI:valproate) -> path(MESHD:"Drug-Related Side Effects and Adverse Reactions") path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(MESHD:Tremor) a(CHEBI:valproate) -> path(MESHD:Tremor) path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(MESHD:"Weight Gain") a(CHEBI:valproate) -> path(MESHD:"Weight Gain") path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(MESHD:Nausea) a(CHEBI:valproate) -> path(MESHD:Nausea) path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(DO:pancreatitis) a(CHEBI:valproate) -> path(DO:pancreatitis) path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(MESHD:Thrombocytopenia) a(CHEBI:valproate) -> path(MESHD:Thrombocytopenia) path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(MESHD:Hyperammonemia) a(CHEBI:valproate) -> path(MESHD:Hyperammonemia) path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(MESHD:"Nervous System Malformations") a(CHEBI:valproate) -> path(MESHD:"Nervous System Malformations") path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(MESHD:Lethargy) a(CHEBI:valproate) -> path(MESHD:Lethargy) UNSET Subgraph UNSET Drug SET Evidence = "primidone caused a higher incidence of intolerable side effects such as nausea, vomiting, dizziness, and sedation compared with the other agents " SET Drug = "primidone" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} a(CHEBI:primidone) -> path(MESHD:"Drug-Related Side Effects and Adverse Reactions") path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(MESHD:Nausea) a(CHEBI:primidone) -> path(MESHD:Nausea) a(CHEBI:primidone) isA a(CHEBI:sedative) UNSET Subgraph UNSET Drug SET Evidence = "Phenobarbital was associated with the lowest incidence of motor disturbance and gastrointestinal (GI) side effects compared to the other AEDs, but with more sedation and hyperactivity, while phenytoin caused more dysmorphic side effects and rash" SET Drug = "phenobarbital" SET Subgraph = {"GABA subgraph", "Neurotransmitter release subgraph"} a(CHEBI:phenobarbital) causesNoChange path(MESHD:"Gastrointestinal Diseases") a(CHEBI:phenobarbital) causesNoChange path(MESHD:"Motor Neuron Disease") UNSET Subgraph UNSET Drug SET Evidence = "Gabapentin: Again, the most frequent AEs were somnolence, dizziness, and fatigue [FreSCOMP et al. 2004]. Reports of serious idiosyncratic reactions to gabapentin have been few. Gabapentin is not known to cause blood dyscrasias, hepatic toxicity, Stevens Johnson syndrome or serious hypersensitivity syndromes." SET Drug = "gabapentin" SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph", "Calcium dependent subgraph"} a(CHEBI:gabapentin) -> path(MESHD:"Drug-Related Side Effects and Adverse Reactions") path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(MESHD:Fatigue) a(CHEBI:gabapentin) -> path(MESHD:Fatigue) path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(MESHD:"Disorders of Excessive Somnolence") a(CHEBI:gabapentin) -> path(MESHD:"Disorders of Excessive Somnolence") a(CHEBI:gabapentin) causesNoChange path(MESHD:"Stevens-Johnson Syndrome") a(CHEBI:gabapentin) causesNoChange path(MESHD:Hypersensitivity) UNSET Subgraph UNSET Drug SET Evidence = "Lamotrigine is not known to cause hepatotoxicity. However, it is associated with serious hypersensitivity reactions that increase in frequency with rapidity of titration, with decreasing age, and with concomitant valproate use" SET Drug = "lamotrigine" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph", "Calcium dependent subgraph"} a(CHEBI:lamotrigine) -> path(MESHD:"Drug-Related Side Effects and Adverse Reactions") path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(MESHD:Hypersensitivity) a(CHEBI:lamotrigine) -> path(MESHD:Hypersensitivity) complex(a(CHEBI:lamotrigine), a(CHEBI:valproate)) -> path(MESHD:Hypersensitivity) SET Evidence = "Nonetheless, Stevens Johnson syndrome, toxic epidermal necrolysis and other hypersensitivity reactions occur at a frequency of between 1 and 10 per 10,000 new users [Mockenhaupt et al. 2005]. Other neurologic AEs include dizziness, nausea, and headache most commonly, particularly when administered in combination with valproate" path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(MESHD:"Stevens-Johnson Syndrome") a(CHEBI:lamotrigine) -> path(MESHD:"Stevens-Johnson Syndrome") path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(MESHD:Hypersensitivity) a(CHEBI:lamotrigine) -> path(MESHD:Hypersensitivity) path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(MESHD:Nausea) a(CHEBI:lamotrigine) -> path(MESHD:Nausea) path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(MESHD:Headache) a(CHEBI:lamotrigine) -> path(MESHD:Headache) UNSET Subgraph UNSET Drug SET Evidence = "The most common idiosyncratic adverse event associated with topiramate use is renal calculi, which may occur in 1.5% of patients with chronic use [Shorvon, 1996]. Other side effects include paresthesias, hypohydrosis (especially in children), and metabolic acidosis." SET Drug = "topiramate" SET Subgraph = {"GABA subgraph", "Neurotransmitter release subgraph", "Calcium dependent subgraph", "thyroid hormone signaling subgraph", "hormone signaling subgraph", "Glutamatergic subgraph", "Long term synaptic potentiation", "Long term synaptic depression", "Serotonergic subgraph"} a(CHEBI:topiramate) -> path(MESHD:"Drug-Related Side Effects and Adverse Reactions") path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(MESHD:Calculi) a(CHEBI:topiramate) -> path(MESHD:Calculi) path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(MESHD:Paresthesia) a(CHEBI:topiramate) -> path(MESHD:Paresthesia) path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(MESHD:Hypohidrosis) a(CHEBI:topiramate) -> path(MESHD:Hypohidrosis) path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(MESHD:Acidosis) a(CHEBI:topiramate) -> path(MESHD:Acidosis) UNSET Subgraph UNSET Drug SET Evidence = "Tiagabine:Overall, it is a well-tolerated medication, the most common AEs being dizziness, asthenia, amnesia, nervousness, and abdominal pain" SET Drug = "tiagabine" SET Subgraph = {"GABA subgraph", "Neurotransmitter release subgraph"} a(CHEBI:tiagabine) -> path(MESHD:"Drug-Related Side Effects and Adverse Reactions") path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(MESHD:Asthenia) a(CHEBI:tiagabine) -> path(MESHD:Asthenia) path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(MESHD:Amnesia) a(CHEBI:tiagabine) -> path(MESHD:Amnesia) path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(MESHD:"Abdominal Pain") a(CHEBI:tiagabine) -> path(MESHD:"Abdominal Pain") SET Evidence = "Tiagabine: The five most frequent AEs were dizziness, tremor, abnormal thinking, nervousness, and abdominal pain " path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(MESHD:Tremor) a(CHEBI:tiagabine) -> path(MESHD:Tremor) UNSET Subgraph UNSET Drug SET Evidence = "Some of the more common AEs associated with oxcarbazepine include fatigue, headache, dizziness, ataxia, diplopia, nausea, vomiting, rash, and others. Oxcarbazepine use has also been associated with several safety issues, including hyponatremia (with 2.7% of patients having a serum sodium of <125 mmol/L) [Harden, 2000], allergic rash, and Stevens Johnson syndrome" SET Drug = "oxcarbazepine" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph", "Calcium dependent subgraph"} a(CHEBI:oxcarbazepine) -> path(MESHD:"Drug-Related Side Effects and Adverse Reactions") path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(MESHD:Nausea) a(CHEBI:oxcarbazepine) -> path(MESHD:Nausea) path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(MESHD:Diplopia) a(CHEBI:oxcarbazepine) -> path(MESHD:Diplopia) path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(MESHD:Ataxia) a(CHEBI:oxcarbazepine) -> path(MESHD:Ataxia) path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(MESHD:Hyponatremia) a(CHEBI:oxcarbazepine) -> path(MESHD:Hyponatremia) path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(MESHD:"Stevens-Johnson Syndrome") a(CHEBI:oxcarbazepine) -> path(MESHD:"Stevens-Johnson Syndrome") path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(MESHD:Headache) a(CHEBI:oxcarbazepine) -> path(MESHD:Headache) UNSET Subgraph UNSET Drug SET Evidence = "Zonisamide: Fatigue, dizziness, somnolence, anorexia, and abnormal thinking were the five most common AEs reported; others included renal calculi, rash, and depression" SET Drug = "zonisamide" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph", "Glutamatergic subgraph", "MAPK-ERK subgraph", "protein kinase signaling subgraph", "Calcium dependent subgraph"} a(CHEBI:zonisamide) -> path(MESHD:"Drug-Related Side Effects and Adverse Reactions") path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(MESHD:Fatigue) a(CHEBI:zonisamide) -> path(MESHD:Fatigue) path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(DO:"anorexia nervosa") a(CHEBI:zonisamide) -> path(DO:"anorexia nervosa") path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(DO:"major depressive disorder") a(CHEBI:zonisamide) -> path(DO:"major depressive disorder") path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(MESHD:Calculi) a(CHEBI:zonisamide) -> path(MESHD:Calculi) UNSET Subgraph UNSET Drug SET Evidence = "Levetiracetam: Overall, dizziness, somnolence, asthenia, headache, and infection were the most frequently reported AEs [FreSCOMP et al. 2004], with behavioral problems, depression, and psychosis also noted" SET Drug = "levetiracetam" SET Subgraph = {"Neurotransmitter release subgraph", "GABA subgraph", "Calcium dependent subgraph", "Serotonergic subgraph"} a(CHEBI:levetiracetam) -> path(MESHD:"Drug-Related Side Effects and Adverse Reactions") path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(MESHD:Asthenia) a(CHEBI:levetiracetam) -> path(MESHD:Asthenia) path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(DO:"major depressive disorder") a(CHEBI:levetiracetam) -> path(DO:"major depressive disorder") path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(DO:"substance-induced psychosis") a(CHEBI:levetiracetam) -> path(DO:"substance-induced psychosis") path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(MESHD:Infection) a(CHEBI:levetiracetam) -> path(MESHD:Infection) path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(MESHD:Headache) a(CHEBI:levetiracetam) -> path(MESHD:Headache) SET Evidence = "Levetiracetam has not been associated with idiosyncratic AEs such as hepatic failure, Stevens Johnson syndrome, organ failure" a(CHEBI:levetiracetam) causesNoChange path(MESHD:"Stevens-Johnson Syndrome") a(CHEBI:levetiracetam) causesNoChange path(MESHD:"Multiple Organ Failure") UNSET Subgraph UNSET Drug SET Evidence = "Vigabatrin has seen relatively restricted use in patients with infantile spasms and cortical dysplasia who remain refractory to other medications, namely due to the now well-established risk of visual field deficits incurred through retinal nerve fiber layer toxicity" SET Drug = "vigabatrin" SET Subgraph = {"GABA subgraph", "Neurotransmitter release subgraph"} a(CHEBI:vigabatrin) -| path(MESHD:"Spasms, Infantile") a(CHEBI:vigabatrin) -> path(MESHD:"Drug-Related Side Effects and Adverse Reactions") path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(MESHD:"Vision Disorders") a(CHEBI:vigabatrin) -> path(MESHD:"Vision Disorders") SET Evidence = "The most common AEs were headache, fatigue, dizziness, and drowsiness " path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(MESHD:Headache) a(CHEBI:vigabatrin) -> path(MESHD:Headache) path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(MESHD:Fatigue) a(CHEBI:vigabatrin) -> path(MESHD:Fatigue) UNSET Subgraph UNSET Drug SET Evidence = "Felbamate was approved for use in the US in 1993 but was withdrawn from the market following its implication in the development of fulminant hepatic failure and aplastic anemia. The drug was later re-introduced to the market with strict blood monitoring parameters and is currently used as an add-on agent in cases of refractory epilepsy" SET Drug = "felbamate" SET Subgraph = {"Calcium dependent subgraph", "Long term synaptic potentiation", "Glutamatergic subgraph", "Neurotransmitter release subgraph", "Serotonergic subgraph"} a(CHEBI:felbamate) -> path(MESHD:"Drug-Related Side Effects and Adverse Reactions") path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(MESHD:"Anemia, Aplastic") a(CHEBI:felbamate) -> path(MESHD:"Anemia, Aplastic") SET Evidence = "the main AEs noted across the three trials (with felbamate doses of were headache, nausea, and dizziness" path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(MESHD:Nausea) a(CHEBI:felbamate) -> path(MESHD:Nausea) path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(MESHD:Headache) a(CHEBI:felbamate) -> path(MESHD:Headache) UNSET Subgraph UNSET Drug SET Evidence = "Across pivotal clinical trials (which administered pregabalin at doses of 50 mg/day), the most common AEs experienced were dizziness, somnolence, asthenia, ataxia, blurred vision, and weight gain" SET Drug = "pregabalin" SET Subgraph = {"Calcium dependent subgraph", "MAPK-ERK subgraph", "protein kinase signaling subgraph"} a(CHEBI:pregabalin) -> path(MESHD:"Drug-Related Side Effects and Adverse Reactions") path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(MESHD:Ataxia) a(CHEBI:pregabalin) -> path(MESHD:Ataxia) path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(MESHD:Asthenia) a(CHEBI:pregabalin) -> path(MESHD:Asthenia) path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(MESHD:"Weight Gain") a(CHEBI:pregabalin) -> path(MESHD:"Weight Gain") path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(MESHD:"Vision Disorders") a(CHEBI:pregabalin) -> path(MESHD:"Vision Disorders") SET Evidence = "To date, pregabalin use, like its predecessor gabapentin, has been relatively devoid of serious idiosyncratic adverse events such as hepatotoxicity, Stevens Johnson syndrome and blood dyscrasias" a(CHEBI:pregabalin) causesNoChange path(MESHD:"Stevens-Johnson Syndrome") UNSET Subgraph UNSET Drug SET Evidence = "Rufinaminde came to the US market in 2008 and is primarily indicated for use as adjunctive treatment of seizures in Lennox-Gastaut syndrome" SET Drug = "rufinamide" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} a(MESHC:rufinamide) -| path(MESHD:"Lennox Gastaut Syndrome") SET Evidence = "In the double-blind plus open-label extension population, the most common serious AEs were aggravated seizures, status epilepticus, and pneumonia" a(MESHC:rufinamide) -> path(MESHD:"Drug-Related Side Effects and Adverse Reactions") path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(MESHD:Seizures) a(MESHC:rufinamide) -> path(MESHD:Seizures) path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(MESHD:"Status Epilepticus") a(MESHC:rufinamide) -> path(MESHD:"Status Epilepticus") path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(MESHD:Pneumonia) a(MESHC:rufinamide) -> path(MESHD:Pneumonia) UNSET Subgraph UNSET Drug SET Evidence = "Doses of 200, 400, and 600‚mg/day of lacosamide were administered to patients and the most common AEs were: dizziness (31%), headache (13%), nausea (11%), and diplopia " SET Drug = "lacosamide" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph", "Calcium dependent subgraph"} a(MESHC:lacosamide) -> path(MESHD:"Drug-Related Side Effects and Adverse Reactions") path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(MESHD:Headache) a(MESHC:lacosamide) -> path(MESHD:Headache) path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(MESHD:Nausea) a(MESHC:lacosamide) -> path(MESHD:Nausea) path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(MESHD:Diplopia) a(MESHC:lacosamide) -> path(MESHD:Diplopia) SET Evidence = "Three serious AEs were noted: dizziness (1.5% in the lacosamide 600mg/day group); nystagmus (1.0% in the lacosamide 600mg/day group); and convulsion" path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(MESHD:"Nystagmus, Pathologic") a(MESHC:lacosamide) -> path(MESHD:"Nystagmus, Pathologic") path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(MESHD:Seizures) a(MESHC:lacosamide) -> path(MESHD:Seizures) UNSET Subgraph UNSET Drug SET Evidence = "Four of the major older AEDs (phenytoin, carbamazepine, phenobarbital, and primidone) are hepatic enzyme inducers, and one (valproate) is a hepatic enzyme inhibitor. Recent evidence has supported the concept that these effects have safety implications, as body homeostasis is altered" a(CHEBI:phenytoin) -| bp(GOBP:"homeostatic process") a(CHEBI:carbamazepine) -| bp(GOBP:"homeostatic process") a(CHEBI:phenobarbital) -| bp(GOBP:"homeostatic process") a(CHEBI:primidone) -| bp(GOBP:"homeostatic process") a(CHEBI:valproate) -| bp(GOBP:"homeostatic process") SET Evidence = "In the case of the inducing AEDs, this may result in an increase in cardiovascular risk (increase in serum lipids and C-reactive protein), and alteration of sex steroids. " a(CHEBI:phenytoin) -> path(MESHD:"Cardiovascular Abnormalities") a(CHEBI:carbamazepine) -> path(MESHD:"Cardiovascular Abnormalities") a(CHEBI:phenobarbital) -> path(MESHD:"Cardiovascular Abnormalities") a(CHEBI:primidone) -> path(MESHD:"Cardiovascular Abnormalities") SET Subgraph = "hormone signaling subgraph" a(CHEBI:phenytoin) -- a(CHEBI:"steroid hormone") a(CHEBI:carbamazepine) -- a(CHEBI:"steroid hormone") a(CHEBI:phenobarbital) -- a(CHEBI:"steroid hormone") a(CHEBI:primidone) -- a(CHEBI:"steroid hormone") UNSET Subgraph SET Evidence = "Valproate inhibition of hepatic enzymes may contribute to polycystic ovarian syndrome" a(CHEBI:valproate) -> path(MESHD:"Polycystic Ovary Syndrome") SET Evidence = "binds to the synaptic vesicle protein 2A, but with higher affinity; brivaracetam also inhibits sodium channels" SET Drug = "brivaracetam" SET Subgraph = {"Neurotransmitter release subgraph", "Serotonergic subgraph"} a(CHEBI:brivaracetam) -| p(HGNC:SCN1A) a(CHEBI:brivaracetam) -| p(HGNC:SCN2A) a(CHEBI:brivaracetam) -| p(HGNC:SCN3A) a(CHEBI:brivaracetam) -| p(HGNC:SCN4A) a(CHEBI:brivaracetam) -| p(HGNC:SCN5A) a(CHEBI:brivaracetam) -| p(HGNC:SCN8A) a(CHEBI:brivaracetam) -| p(HGNC:SCN9A) SET Evidence = "The most common AEs were mild to moderate in intensity, and included headache, somnolence, influenza, dizziness, neutropenia, and fatigue" a(CHEBI:brivaracetam) -> path(MESHD:"Drug-Related Side Effects and Adverse Reactions") path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(MESHD:Headache) a(CHEBI:brivaracetam) -> path(MESHD:Headache) path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(MESHD:"Influenza, Human") a(CHEBI:brivaracetam) -> path(MESHD:"Influenza, Human") path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(MESHD:Fatigue) a(CHEBI:brivaracetam) -> path(MESHD:Fatigue) path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(MESHD:Neutropenia) a(CHEBI:brivaracetam) -> path(MESHD:Neutropenia) UNSET Subgraph UNSET Drug SET Evidence = "In both studies, AEs leading to discontinuation (which occurred in 27%, 26%, 17% versus 6% of patients on retigabine 1200, 900, 600mg, versus placebo, respectively) included dizziness, somnolence, headache, and fatigue" SET Drug = "ezogabine" SET Subgraph = {"GABA subgraph", "Neurotransmitter release subgraph"} a(CHEBI:ezogabine) -> path(MESHD:"Drug-Related Side Effects and Adverse Reactions") path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(MESHD:Headache) a(CHEBI:ezogabine) -> path(MESHD:Headache) path(MESHD:"Drug-Related Side Effects and Adverse Reactions") -> path(MESHD:Fatigue) a(CHEBI:ezogabine) -> path(MESHD:Fatigue) UNSET Subgraph UNSET Drug ################################################## SET Citation = {"PubMed", "Mol Pharmacol. 1995 Jun;47(6):1189-96.", "7603459"} SET Evidence = "We report here that carbamazepine and phenytoin, two widely used antiepileptic drugs, potentiate gamma-aminobutyric acid (GABA)-induced Cl- currents" SET Subgraph = {"GABA subgraph", "Neurotransmitter release subgraph"} a(CHEBI:carbamazepine) -> bp(PTS:"gamma_aminobutyric acid signaling pathway") a(CHEBI:phenytoin) -> bp(PTS:"gamma_aminobutyric acid signaling pathway") UNSET Subgraph ################################################### SET Evidence = "Bernasconi et al . [3] reported that CBZ as well as valproic acid, propranolol and lithium decreased GABA turnover and this effect is more prominent in hippocampus ." SET MeSHAnatomy = "Hippocampus" SET Subgraph = {"GABA subgraph", "Neurotransmitter release subgraph"} a(CHEBI:carbamazepine) -| bp(PTS:"gamma_aminobutyric acid metabolic pathway") a(CHEBI:carbamazepine) -> a(CHEBI:"GABA agent") a(CHEBI:valproate) -| bp(PTS:"gamma_aminobutyric acid metabolic pathway") a(CHEBI:valproate) -> a(CHEBI:"GABA agent") a(MESHC:Lithium) -| bp(PTS:"gamma_aminobutyric acid metabolic pathway") a(MESHC:Lithium) -> a(CHEBI:"GABA agent") a(CHEBI:propranolol) -| bp(PTS:"gamma_aminobutyric acid metabolic pathway") a(CHEBI:propranolol) -> a(CHEBI:"GABA agent") UNSET MeSHAnatomy SET Evidence = "The present study was aimed to assess whether or not GABA-ergic agents might influence the antidepressant-like effect of CBZ ." a(CHEBI:carbamazepine) -| path(DO:"major depressive disorder") a(CHEBI:carbamazepine) isA a(CHEBI:antidepressant) SET Evidence = "The effect of two GABA-antagonists picrotoxin and bicuculline on the reduction of immobility caused by CBZ in behavioral despair test are shown in Fig .2 . Both of them significantly counteracted the reduction of immobility in rats treated chronicaly with CBZ " a(MESHC:picrotin) -| a(CHEBI:"GABA agent") complex(a(MESHC:picrotin), a(CHEBI:carbamazepine)) causesNoChange path(DO:"major depressive disorder") a(CHEBI:bicuculline) -| a(CHEBI:"GABA agent") complex(a(CHEBI:bicuculline), a(CHEBI:carbamazepine)) causesNoChange path(DO:"major depressive disorder") SET Citation = {"PubMed", "2553432"} SET Evidence = "Potentialisation by muscimol the effect of CBZ may suggest that the reduction of immobility by CBZ in the behavioral despair test is mediated through the activation of GABA-a receptors, linked to the chloride ionophore" SET Confidence = "High" SET Subgraph = {"GABA subgraph", "Neurotransmitter release subgraph"} SET Published = "Epilepsy comorbidity paper" a(CHEBI:carbamazepine) -> p(HGNC:GABRA1) a(CHEBI:carbamazepine) -> p(HGNC:GABRA2) a(CHEBI:carbamazepine) -> p(HGNC:GABRA3) a(CHEBI:carbamazepine) -> p(HGNC:GABRA4) a(CHEBI:carbamazepine) -> p(HGNC:GABRA5) a(CHEBI:carbamazepine) -> p(HGNC:GABRA6) a(CHEBI:carbamazepine) -> p(HGNC:GABRB1) a(CHEBI:carbamazepine) -> p(HGNC:GABRB2) a(CHEBI:carbamazepine) -> p(HGNC:GABRB3) a(CHEBI:carbamazepine) -> p(HGNC:GABRD) a(CHEBI:carbamazepine) -> p(HGNC:GABRE) a(CHEBI:carbamazepine) -> p(HGNC:GABRG1) a(CHEBI:carbamazepine) -> p(HGNC:GABRG2) a(CHEBI:carbamazepine) -> p(HGNC:GABRG3) a(CHEBI:carbamazepine) -> p(HGNC:GABRP) a(CHEBI:carbamazepine) -> p(HGNC:GABRQ) UNSET {Published, Confidence} p(HGNC:GABRA1) -| path(DO:"major depressive disorder") p(HGNC:GABRA2) -| path(DO:"major depressive disorder") p(HGNC:GABRA3) -| path(DO:"major depressive disorder") p(HGNC:GABRA4) -| path(DO:"major depressive disorder") p(HGNC:GABRA5) -| path(DO:"major depressive disorder") p(HGNC:GABRA6) -| path(DO:"major depressive disorder") p(HGNC:GABRB1) -| path(DO:"major depressive disorder") p(HGNC:GABRB2) -| path(DO:"major depressive disorder") p(HGNC:GABRB3) -| path(DO:"major depressive disorder") p(HGNC:GABRD) -| path(DO:"major depressive disorder") p(HGNC:GABRE) -| path(DO:"major depressive disorder") p(HGNC:GABRG1) -| path(DO:"major depressive disorder") p(HGNC:GABRG2) -| path(DO:"major depressive disorder") p(HGNC:GABRG3) -| path(DO:"major depressive disorder") p(HGNC:GABRP) -| path(DO:"major depressive disorder") p(HGNC:GABRQ) -| path(DO:"major depressive disorder") SET Evidence = "Baclofen GABA-b agonist counteracted the antiimmobility effect of CBZ in our study . It did not block the anticonvulsant effect of CBZ on amygdala-kindled model in rats [1] . Therefore the GABA-b mechanism is also involved in antidepressant-like effect of CBZ and probably it is not joint with anticonvulsant properties of CBZ ." SET Species = "10116" a(CHEBI:baclofen) -| p(HGNC:GABBR1) a(CHEBI:baclofen) -| p(HGNC:GABBR2) a(CHEBI:carbamazepine) -> p(HGNC:GABBR1) a(CHEBI:carbamazepine) -> p(HGNC:GABBR2) p(HGNC:GABBR1) -| path(DO:"major depressive disorder") p(HGNC:GABBR2) -| path(DO:"major depressive disorder") UNSET Subgraph ########################################### SET Citation = {"PubMed", "J Affect Disord. 2008 Jul;109(1-2):91-7. Epub 2008 Feb 21.", "18093662"} SET Evidence = "Nevertheless, they [anticonvulsants] also have been found to have diverse psychotropic profiles, especially mood-stabilizing effects" a(CHEBI:anticonvulsant) -| path(DO:"mood disorder") SET Evidence = "carbamazepine (CBZ) began to be studied in a systematic fashion in 1970s and became more widely used in the treatment of bipolar disorder" SET Subgraph = {"GABA subgraph", "Neurotransmitter release subgraph"} a(CHEBI:carbamazepine) -| path(DO:"bipolar disorder") UNSET Subgraph SET Evidence = "Unlike conventional antidepressant drugs, of which mechanisms underlying the therapeutic actions are largely derived from enhancement of central catecholaminergic or indoleaminergic systems by inhibiting relevant metabolic enzymes or reuptake process, psychotrophic effects of anticonvulsants are thought to be mainly associated with the facilitation of central gamma-aminobutyric acid (GABA) neurotransmission or blockade of glutaminergic hyperexcitabilit" SET Subgraph = "Neurotransmitter release subgraph" a(CHEBI:antidepressant) -> a(CHEBI:catecholamine) a(CHEBI:dopamine) isA a(CHEBI:catecholamine) a(CHEBI:adrenaline) isA a(CHEBI:catecholamine) a(CHEBI:noradrenaline) isA a(CHEBI:catecholamine) a(CHEBI:catecholamine) isA a(CHEBI:neurotransmitter) a(CHEBI:catecholamine) -| path(DO:"major depressive disorder") a(CHEBI:antidepressant) -> a(CHEBI:indolamine) a(CHEBI:indolamine) isA a(CHEBI:neurotransmitter) a(CHEBI:indolamine) -| path(DO:"major depressive disorder") UNSET Subgraph SET Published = "Epilepsy comorbidity paper" SET Confidence = "High" SET Subgraph = {"Neurotransmitter release subgraph", "Glutamatergic subgraph"} a(CHEBI:anticonvulsant) -| bp(GOBP:"synaptic transmission, glutamatergic") a(CHEBI:carbamazepine) -| bp(GOBP:"synaptic transmission, glutamatergic") UNSET {Subgraph, Published, Confidence} ########################################### SET Citation = {"PubMed", "Eur J Pharmacol. 2006 Dec 28;553(1-3):104-8. Epub 2006 Sep 23.", "17054941"} SET Evidence = "It is likely that several of the pharmacological effects of antiepileptic drugs contribute in different ways to a decrease in neuronal excitability, leading to therapeutically evident neuro protection and relief of chronic pain." a(CHEBI:anticonvulsant) -| path(MESHD:"Chronic Pain") a(CHEBI:anticonvulsant) isA a(CHEBI:"neuroprotective agent") a(CHEBI:carbamazepine) isA a(CHEBI:"neuroprotective agent") SET Evidence = "Recently, several antiepileptic drugs have been used successfully in the treatment of diseases related to neuronal hyperexcitability, including neuropathic and inflammatory pain (Pappagallo, 2003) and neurodegeneration after cerebral ischemia and brain injury" a(CHEBI:anticonvulsant) -| path(MESHD:"Neurodegenerative Diseases") SET Evidence = "For instance, after introduction of metabolic stress such as oxygen/glucose deprivation (OGD) in the CA1 pyramidal region of the hippocampus, the excitatory synaptic transmission and population spike are depressed due to an increase in the extracellular concentration of adenosine, which is considered to be an endogenous neuroprotective mechanism" SET MeSHAnatomy = "CA1 Region, Hippocampal" SET Subgraph = "adenosine signaling subgraph" bp(GOBP:"cellular response to glucose starvation") -> a(CHEBI:adenosine) bp(GOBP:"cellular response to decreased oxygen levels") -> a(CHEBI:adenosine) a(CHEBI:adenosine) -| bp(GOBP:"chemical synaptic transmission") bp(GOBP:"cellular response to glucose starvation") -| bp(GOBP:"chemical synaptic transmission") bp(GOBP:"cellular response to decreased oxygen levels") -| bp(GOBP:"chemical synaptic transmission") a(CHEBI:adenosine) isA a(CHEBI:"neuroprotective agent") UNSET Subgraph UNSET MeSHAnatomy SET Evidence = "The major finding of this study was the slowed time course of electrically detectable changes in the PS and PV during OGD in hippocampal slices treated with phenytoin and carbamazepine." a(CHEBI:carbamazepine) -| bp(GOBP:"excitatory postsynaptic potential") a(CHEBI:phenytoin) -| bp(GOBP:"excitatory postsynaptic potential") SET Evidence = "It has been demonstrated that the initial depression of excitatory synaptic transmission and PS during energy deprivation is caused primarily by an increase of extracellular adenosine (Fowler, 1989, 1990; Cassar et al., 1998; Latini et al., 1998, 1999; Dale et al., 2000; Gervitz et al., 2001; Pearson et al., 2003). This increase in extracellular adenosine constitutes an endogenous neuroprotective process that is mediated by adenosine A1-receptors (Fowler, 1989, 1990; Latini et al., 1999), leading to reduced neuronal activity with lowered energy consumption, hampering the excitotoxic effects of glutamate" SET Confidence = "High" SET Published = "Epilepsy comorbidity paper" SET Subgraph = {"Neurotransmitter release subgraph", "Glutamatergic subgraph", "adenosine signaling subgraph"} a(CHEBI:carbamazepine) -> a(CHEBI:adenosine) UNSET Published a(CHEBI:phenytoin) -> a(CHEBI:adenosine) a(CHEBI:carbamazepine) -- p(HGNC:ADORA1) a(CHEBI:phenytoin) -- p(HGNC:ADORA1) SET Published = "Epilepsy comorbidity paper" complex(p(HGNC:ADORA1), a(CHEBI:adenosine)) -| bp(GOBP:"synaptic transmission, glutamatergic") UNSET Published SET Evidence = " Recently, Pearson and Frenguelli have shown that noradrenaline facilitates the hypoxic depression of excitatory synaptic transmission partly by increasing extracellular adenosine via ‚adrenergic receptors in the CA1 hippocampal region" SET MeSHAnatomy="CA1 Region, Hippocampal" a(CHEBI:carbamazepine) -> a(CHEBI:noradrenaline) a(CHEBI:noradrenaline) -| bp(GOBP:"synaptic transmission, glutamatergic") a(CHEBI:noradrenaline) -> a(CHEBI:adenosine) complex(p(HGNC:ADRB1), a(CHEBI:noradrenaline)) -> a(CHEBI:adenosine) UNSET MeSHAnatomy UNSET Subgraph SET Evidence = "reduction of extracellular Ca2+ concentration during hypoxia increases adenosine release and hastens the hypoxic depression of excitatory synaptic transmission" SET Subgraph = {"Neurotransmitter release subgraph", "Calcium dependent subgraph", "Glutamatergic subgraph", "adenosine signaling subgraph"} SET Confidence = "High" SET MeSHDisease = "Hypoxia, Brain" path(MESHD:"Hypoxia, Brain") -| a(CHEBI:"calcium(2+)") a(CHEBI:"calcium(2+)") -> a(CHEBI:adenosine) path(MESHD:"Hypoxia, Brain") -| bp(GOBP:"synaptic transmission, glutamatergic") UNSET {Subgraph, MeSHDisease, Confidence } SET Evidence = "Importantly, Pugliese et al. (2003, 2006) have shown that A3-adenosine receptors have a harmful influence on the post-ischemic recovery of synaptic transmission. Indeed, blockade of A3-adenosine receptors results in delayed initial ischemic depression and facilitated restoration of excitatory synaptic transmission in the hippocampus" SET Confidence = "High" SET Published = "Epilepsy comorbidity paper" SET Subgraph = {"Neurotransmitter release subgraph", "Glutamatergic subgraph", "adenosine signaling subgraph"} p(HGNC:ADORA3) -| bp(GOBP:"synaptic transmission, glutamatergic") UNSET {Confidence, Published} SET Evidence = "The Na+ channel-blocking effect of phenytoin and carbamazepine (Anderson and Raines, 1974; Hershkowitz and Raines, 1978) is likely to be an important factor, and may lead to reduced release of non-synaptic glutamate" p(HGNC:SCN1A) -> a(MESHC:Glutamates) a(MESHC:Glutamates) -> bp(GOBP:"synaptic transmission, glutamatergic") UNSET Subgraph ##################################### SET Citation = {"PubMed", "Biol Psychiatry. 1996 Nov 1;40(9):935-7.", "8896785"} SET Evidence = "Antidepressants may have pernicious effects on persons with BPD" a(CHEBI:antidepressant) -> path(DO:"bipolar disorder") SET Evidence = "Bupropion may be useful in the treatment of rapidly cycling patients (Haykel and Akiska 1989) and persons with depressive mania From the Department of Psychiatry and Behavioral Sciences, The University of Health Sciences Center at Houston, Harris County Psychiatric Center, Houston, Texas. Address reprint requests to Dr. Steven C. Dilsaver, 707 South Orange Grove Blvd., Unit E, Pasadena, CA 91105. Received December 7, 1995; revised June 18, 1996. whose depression lingers following the remission of mania " a(CHEBI:bupropion) -| path(DO:"bipolar disorder") SET Evidence = "Results of a well-designed study suggest that tranylcypromine is superior to imipramine in the treatment of BPD" a(CHEBI:tranylcypromine) -| path(DO:"bipolar disorder") a(CHEBI:imipramine) -| path(DO:"bipolar disorder") SET Evidence = "Patients with refractory BPD can do well when treated with the combination of lithium and carbamazepine" a(MESHC:Lithium) -| path(DO:"bipolar disorder") ############################################ SET Citation = {"PubMed", "J Affect Disord. 2006 Oct;95(1-3):69-78. Epub 2006 Jun 15.", "16780960"} SET Evidence = "Maintenance treatment with lithium was more effective than CBZ in patients with bipolar disorder (bipolar I disorder with no mood-incongruent delusions or comorbidity), while maintenance treatment with CBZ tended to be more effective in patients with bipolar disorder, which includes bipolar II disorder, bipolar not otherwise specified (NOS), bipolar disorder with mood incongruent delusions or comorbidity, and mixed states." SET Subgraph = {"GABA subgraph", "Neurotransmitter release subgraph"} a(CHEBI:carbamazepine) -| path(DO:"bipolar disorder") a(CHEBI:carbamazepine) -| path(DO:"mood disorder") UNSET Subgraph ############################################ SET Citation = {"PubMed", "Eur Neuropsychopharmacol. 2002 Jun;12(3):255-60.", "12007677"} SET Evidence = "The enantiomer S-CIT, escitalopram, is more potent than the R enantiomer in inhibiting the reuptake of serotonin (Hyttel et al., 1992), and it was recently introduced as an antidepressant" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} a(CHEBI:citalopram) -> bp(GOBP:"inhibition of serotonin uptake") a(CHEBI:escitalopram) -> bp(GOBP:"inhibition of serotonin uptake") a(CHEBI:citalopram) isA a(CHEBI:"serotonin uptake inhibitor") a(CHEBI:escitalopram) isA a(CHEBI:"serotonin uptake inhibitor") a(CHEBI:citalopram) -| bp(GOBP:"serotonin uptake") a(CHEBI:escitalopram) -| bp(GOBP:"serotonin uptake") bp(GOBP:"serotonin uptake") -| a(CHEBI:serotonin) bp(GOBP:"serotonin uptake") -> path(DO:"major depressive disorder") a(CHEBI:citalopram) -| path(DO:"major depressive disorder") a(CHEBI:escitalopram) -| path(DO:"major depressive disorder") a(CHEBI:citalopram) isA a(CHEBI:antidepressant) a(CHEBI:escitalopram) isA a(CHEBI:antidepressant) UNSET Subgraph SET Evidence = ". In vitro studies have shown that CYP2C19, CYP3A4 and CYP2D6 contribute to the stereoselective formation of S- and R-de- methylcitalopram from racemic citalopram" p(HGNC:CYP3A4) -| a(CHEBI:escitalopram) p(HGNC:CYP3A4) -| a(CHEBI:citalopram) SET Evidence = ". As a matter of fact, a carbamazepine treatment leads to a release of serotonin in rat hippocampus" SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} SET Species = "10116" SET MeSHAnatomy = "Hippocampus" a(CHEBI:carbamazepine) -> a(CHEBI:serotonin) UNSET Species UNSET MeSHAnatomy SET Evidence = "On the other hand, carbamazepine not only induces its own metabolism (Kudriakova et al., 1992), but also that of other drugs which are metabolised by CYP3A4" p(HGNC:CYP3A4) -| a(CHEBI:carbamazepine) SET Evidence = ". Carbamazepine induces CYP3A4 (Bertilsson et al., 1997), but it does not seem to induce CYP2C19 significantly and there is no evidence in the literature about inducibility of CYP2D6 by any drug" a(CHEBI:carbamazepine) -> p(HGNC:CYP3A4) a(CHEBI:carbamazepine) -| a(CHEBI:citalopram) a(CHEBI:carbamazepine) causesNoChange a(CHEBI:escitalopram) UNSET Subgraph ############################################## SET Citation = {"PubMed", "Eur J Pharmacol. 1995 Feb 24;275(1):23-9.", "7774659"} SET Evidence = "Since the combination of an arteriole-constricting compound 48/80 and hypotension-inducing clonidine injected prior to NMDA results in a significant protection against seizures, and since acute stimulation of adenosine A3 receptor causes both arteriolar constriction and severe hypotension, there is a possibility that the protection obtained by the acutely administered drug may result from inadequate delivery of chemoconvulsants to the brain" SET Subgraph = {"adenosine signaling subgraph", "Neurotransmitter release subgraph"} p(HGNC:ADORA3) -| path(MESHD:Seizures) a(CHEBI:adenosine) -> act(p(HGNC:ADORA3)) UNSET Subgraph ############################################### SET Citation = {"PubMed", "Rinsho Shinkeigaku. 2001 Dec;41(12):1064-6.", "12235796"} SET Evidence = "Expression of truncated DRPLA proteins in cultured cell has been shown to result in aggregate body formation and apoptosis." SET Subgraph = "Apoptosis signaling subgraph" g(HGNC:ATN1) -> bp(GOBP:"cell aggregation") g(HGNC:ATN1) -> bp(GOBP:"apoptotic process") UNSET Subgraph ########################################### SET Citation = {"PubMed", "Eur J Pharmacol. 2016 Jun 15;781:139-47. doi: 10.1016/j.ejphar.2016.04.012. Epub 2016 Apr 9.", "27068147"} SET Evidence = "HCPT induced apoptosis of fibroblasts, according to CCK-8 assays, Hoechst staining and Western blot analysis. As the concentration of HCPT increased, the expressions of glucose-regulated protein 78 (GRP78), inositol-requiring kinase1 (IRE-1), C/EBP homologous protein (CHOP) and Bax were all increased" SET Subgraph = "Apoptosis signaling subgraph" a(CHEBI:"10-Hydroxycamptothecin") -> p(HGNC:DDIT3) a(CHEBI:"10-Hydroxycamptothecin") -> p(HGNC:ERN1) a(CHEBI:"10-Hydroxycamptothecin") -> p(HGNC:BAX) a(CHEBI:"10-Hydroxycamptothecin") -> p(HGNC:HSPA5) a(CHEBI:"10-Hydroxycamptothecin") -> bp(GOBP:"apoptotic process") p(HGNC:DDIT3) -> bp(GOBP:"apoptotic process") p(HGNC:ERN1) -> bp(GOBP:"apoptotic process") p(HGNC:BAX) -> bp(GOBP:"apoptotic process") p(HGNC:HSPA5) -> bp(GOBP:"apoptotic process") UNSET Subgraph ############################################ SET Citation = {"PubMed", "Drugs. 2016 Mar;76(3):301-13. doi: 10.1007/s40265-015-0529-0.", "26729186"} SET Evidence = "The article aims to develop the current concept of the involvement of tau in the neurodegenerative triad of synaptic loss, cell death and dendritic simplification" p(HGNC:MAPT) -> bp(GOBP:"neuron death") p(HGNC:MAPT) -> bp(GOBP:"apoptotic process") ######################################### SET Citation = {"PubMed", "Eur J Pharmacol. 2015 Oct 5;764:55-62. doi: 10.1016/j.ejphar.2015.06.043. Epub 2015 Jun 27.", "26123846"} SET Evidence = "A combination of PC+tPA reduced BBB leakage, brain edema, apoptosis and reactive oxygen species levels. " SET Subgraph = "Apoptosis signaling subgraph" p(HGNC:PLAT) -| bp(GOBP:"apoptotic process") p(HGNC:PLAT) -| a(CHEBI:"reactive oxygen species") p(HGNC:PLAT) -| path(MESHD:"Brain Edema") UNSET Subgraph ########################################## SET Citation = {"PubMed", "PLoS One. 2015 Jul 15;10(7):e0130440. doi: 10.1371/journal.pone.0130440. eCollection 2015.", "26176694"} SET Evidence = "SP increased ischemic tolerance in the retina at least partially by inhibiting the intrinsic cell death signaling pathway of caspase-3." SET Subgraph = "Apoptosis signaling subgraph" p(HGNC:SERPINI1) -| p(HGNC:CASP3) p(HGNC:SERPINI1) -| bp(GOBP:"apoptotic process") UNSET Subgraph ########################################## SET Citation = {"PubMed", "J Clin Invest. 2015 Aug 3;125(8):3163-77. doi: 10.1172/JCI80323. Epub 2015 Jul 27.", "26214522"} SET Evidence = "Therefore, the elevated PTP1B that accompanies disruption of MECP2 function in RTT represents a barrier to BDNF signaling. " p(HGNC:PTPN1) -| p(HGNC:MECP2) p(HGNC:PTPN1) -| bp(PTS:"brain_derived neurotrophic factor signaling pathway") p(HGNC:MECP2) -> bp(PTS:"brain_derived neurotrophic factor signaling pathway") ########################################## SET Citation = {"PubMed", "Mol Neurobiol. 2015 Aug;52(1):256-69. doi: 10.1007/s12035-014-8856-9. Epub 2014 Aug 23.", "25146846"} SET Evidence = "upregulated transcriptional and translational levels of BDNF and increased phosphorylation of the cyclic adenosine monophosphate (cAMP) response element-binding protein, CREB, a downstream target of the BDNF signaling pathway," SET Subgraph = "brain_derived neurotrophic factor signaling subgraph" bp(PTS:"brain_derived neurotrophic factor signaling pathway") -> p(HGNC:CREB1) UNSET Subgraph ########################################## SET Citation = {"PubMed", "Curr Opin Neurobiol. 2016 Feb;36:1-6. doi: 10.1016/j.conb.2015.07.002. Epub 2015 Jul 25.", "26210959"} SET Evidence = "implicating genes such as CACNA1C and ANK3. The genes highlight several pathways, notably calcium signalling," SET Subgraph = "Calcium dependent subgraph" p(HGNC:CACNA1C) -> bp(PTS:"Calcium signaling pathway") UNSET Subgraph ########################################## # Mutations in epilepsy ########################################## SET Citation = {"PubMed", "Epilepsia. 2010 Sep;51(9):1650-8. doi: 10.1111/j.1528-1167.2010.02640.x.", "20831750"} SET Evidence = "However, results from mouse models suggest that the primary effect of both GEFS+ and DS mutations is to decrease the activity of GABAergic inhibitory neurons. Decreased activity of the inhibitory circuitry is thus likely to be a major factor contributing to seizure generation in patients with GEFS+ and DS, and may be a general consequence of SCN1A mutations." SET Species = "10090" SET Confidence = "High" SET Subgraph = "GABA subgraph" g(HGNC:SCN1A, var("?")) -| bp(PTS:"gamma_aminobutyric acid signaling pathway") bp(PTS:"gamma_aminobutyric acid signaling pathway") -| path(MESHD:Epilepsy) bp(PTS:"gamma_aminobutyric acid signaling pathway") -| path(MESHD:"Epilepsy, Generalized") UNSET Subgraph SET Evidence = "Mutations in SCN1A (Nav1.1) and SCN2A (Nav1.2) cause several subtypes of dominant idiopathic generalized epilepsy. Mutations in both genes lead to genetic epilepsy with febrile seizures plus" SET Confidence = "High" g(HGNC:SCN1A, var("?")) pos path(DO:"idiopathic generalized epilepsy") g(HGNC:SCN2A, var("?")) pos path(DO:"idiopathic generalized epilepsy") g(HGNC:SCN1A, var("?")) pos path(DO:"generalized epilepsy with febrile seizures plus") g(HGNC:SCN2A, var("?")) pos path(DO:"generalized epilepsy with febrile seizures plus") UNSET Confidence SET Evidence = "This syndrome is also caused by mutations in the SCN1B gene encoding the sodium channel subunit (Wallace et al., 1998; Wallace et al., 2002) and two GABAA receptor genes: GABRG2 encoding the subunit (Baulac et al., 2001; Wallace et al., 2001a; Harkin et al., 2002) and GABRD encoding the ‚ subunit" SET Confidence = "High" g(HGNC:SCN1B, var("?")) pos path(DO:"generalized epilepsy with febrile seizures plus") g(HGNC:GABRG2, var("?")) pos path(DO:"generalized epilepsy with febrile seizures plus") g(HGNC:GABRD, var("?")) pos path(DO:"generalized epilepsy with febrile seizures plus") UNSET Confidence SET Evidence = "SCN1A mutations are the main cause of both Dravet syndrome (DS, MIM 607208) and intractable childhood epilepsy with generalized tonic-clonic seizures, also known as severe idiopathic generalized epilepsy of infancy" SET Confidence = "High" g(HGNC:SCN1A, var("?")) pos path(DO:"epilepsy with generalized tonic-clonic seizures") UNSET Confidence SET Evidence = "SCN2A mutations cause benign familial neonatal-infantile seizures (BFNIS; MIM 607745) and some cases of DS" SET Confidence = "High" g(HGNC:SCN2A, var("?")) pos path(DO:"benign familial neonatal epilepsy") g(HGNC:SCN2A, var("?")) pos path(DO:"benign familial infantile epilepsy") g(HGNC:SCN2A, var("?")) pos path(DO:"Dravet syndrome") UNSET Confidence SET Evidence = "and a mutation in SCN1B has also been identified in a patient with DS" SET Confidence = "High" g(HGNC:SCN1B, var("?")) -> path(DO:"Dravet syndrome") UNSET Confidence SET Evidence = "One mutation in SCN3A (Nav1.3) has been reported in a patient with partial epilepsy" g(HGNC:SCN3A, var("?")) pos path(MESHD:"Epilepsies, Partial") SET Evidence = "Interestingly, mutations in SCN9A, which is considered to be expressed predominantly in the peripheral nervous system, were recently identified in patients with febrile seizures" SET Confidence = "High" SET MeSHAnatomy = "Peripheral Nervous System" g(HGNC:SCN9A, var("?")) pos path(MESHD:"Seizures, Febrile") UNSET MeSHAnatomy UNSET Confidence SET Evidence = "Febrile seizures occur in approximately 5% of all children under the age of six years and typically are not associated with increased risk of epilepsy in adolescence and adulthood" SET Confidence = "High" path(MESHD:"Seizures, Febrile") causesNoChange path(MESHD:Epilepsy) UNSET Confidence SET Evidence = "In contrast, patients with GEFS+ demonstrate febrile seizures that persist beyond six years of age and are associated with generalized or partial epilepsies, such as absence epilepsy, myoclonic seizures, atonic seizures, and myoclonic-astatic epilepsy" SET Confidence = "High" path(DO:"generalized epilepsy with febrile seizures plus") -> path(MESHD:"Epilepsy, Absence") path(DO:"generalized epilepsy with febrile seizures plus") -> path(MESHD:"Epilepsies, Myoclonic") path(DO:"generalized epilepsy with febrile seizures plus") -> path(MESHD:"Epilepsy, Generalized") path(DO:"generalized epilepsy with febrile seizures plus") -> path(MESHD:"Epilepsies, Partial") UNSET Confidence SET Evidence = "The amino acid substitution R468Q in CACNB4, the voltage-gated calcium channel ‚ subunit, was identified in one individual [of DS patients]. Increased calcium currents were seen when R468Q mutant channels were examined in BHK cells" SET Confidence = "High" SET Subgraph = "Calcium dependent subgraph" p(HGNC:CACNB4, sub(R, 468, Q)) pos path(DO:"Dravet syndrome") p(HGNC:CACNB4, sub(R, 468, Q)) pos bp(PTS:"Calcium signaling pathway") UNSET {Subgraph, Confidence} SET Evidence = "This mutation may therefore result in increased neurotransmitter release from excitatory cells, which when combined with reduced inhibition as a result of the SCN1A mutation, may cause a more severe clinical presentation." SET Confidence = "High" SET Subgraph = "Neurotransmitter release subgraph" p(HGNC:CACNB4, sub(R, 468, Q)) pos bp(PTS:"Neurotransmitter secretion") UNSET {Subgraph, Confidence} SET Evidence = "Recently, Singh et al. (2009) proposed a role for SCN9A as a genetic modifier of DS. In that study, six DS patients who harbored missense or splice site mutations in SCN1A were also found to carry SCN9A variants" #: specify missense or splice mutation SET Confidence = "High" g(HGNC:SCN9A, var("?")) -> path(DO:"Dravet syndrome") UNSET Confidence SET Evidence = "Electrophysiological analysis of hippocampal pyramidal neurons from homozygous Scn1a knockout mice revealed normal levels of sodium currents, indicating that Nav1.1 does not contribute significantly to sodium currents in these neurons" SET Confidence = "High" SET Species = "10090" SET Subgraph = "GABA subgraph" SET MeSHAnatomy = "Hippocampus" SET Cell = "pyramidal neuron" p(HGNC:SCN1A) causesNoChange bp(GOBP:"sodium ion transport") UNSET {Cell, Confidence} SET Evidence = "In contrast, sodium currents were significantly reduced in hippocampal interneurons that are critical for GABA-mediated neuronal inhibition" SET Confidence = "High" SET MeSHAnatomy= "Interneurons" SET Published = "Epilepsy comorbidity paper" p(HGNC:SCN1A) -> bp(GOBP:"sodium ion transport") bp(GOBP:"sodium ion transport") -> bp(PTS:"gamma_aminobutyric acid signaling pathway") UNSET {MeSHAnatomy, Published, Confidence} SET Evidence = "In addition, GABAergic cerebellar Purkinje neurons demonstrated significantly decreased peak, persistent and resurgent sodium currents, which is a likely explanation for the severe ataxia in these mice" SET Species = "10090" SET MeSHAnatomy = "Cerebellum" #purkinje cell was only in the 2015 version #SET Cell = "Purkinje Cells" bp(GOBP:"sodium ion transport") -> bp(PTS:"gamma_aminobutyric acid signaling pathway") bp(PTS:"gamma_aminobutyric acid signaling pathway") -| path(MESHD:Ataxia) #UNSET Cell UNSET MeSHAnatomy UNSET Subgraph SET Evidence = "The results from both the BAC transgenic and knock-in mouse models suggest that the primary effect of the R1648H GEFS+ mutation is to cause cell-specific impairment of interneuron sodium channel activity, leading to decreased inhibition" # GEFS = SCN1A #: Check if there is something more specific than regulation of membrane potential SET Confidence = "High" SET MeSHAnatomy= "Interneurons" SET Subgraph = "GABA subgraph" p(HGNC:SCN1A, sub (R, 1648, H)) -| bp(GOBP:"regulation of membrane potential") bp(GOBP:"regulation of membrane potential") -| path(MESHD:Seizures) bp(GOBP:"regulation of membrane potential") -> bp(PTS:"gamma_aminobutyric acid signaling pathway") UNSET {Subgraph, Confidence} SET Evidence = "and possibly other GABAergic interneurons, contributes to seizure generation in the Scn1aR1648H mouse models. This model is consistent with the fact that mutations of GABAA receptor genes GABRG2, GABRD, GABRA1 and GABRB3 cause GEFS+, DS and childhood absence epilepsy by decreasing either the function or number of GABAA receptors " #: Check this one SET Subgraph = "GABA subgraph" p(HGNC:GABRG2) -> bp(PTS:"gamma_aminobutyric acid signaling pathway") p(HGNC:GABRD) -> bp(PTS:"gamma_aminobutyric acid signaling pathway") p(HGNC:GABRA1) -> bp(PTS:"gamma_aminobutyric acid signaling pathway") p(HGNC:GABRB3) -> bp(PTS:"gamma_aminobutyric acid signaling pathway") UNSET Subgraph ################################################## SET Citation = {"PubMed", "Cell Signal. 2013 Dec;25(12):2848-55. doi: 10.1016/j.cellsig.2013.09.007. Epub 2013 Sep 14.", "24041654"} SET Evidence = "Over 300,000 compounds were screened for an ability to enhance G‚ -mediated calcium signaling in the presence of RGS4. " SET Subgraph = {"Calcium dependent subgraph", "G-protein-mediated signaling"} p(HGNC:GNAQ) -> bp(PTS:"Calcium signaling pathway") p(HGNC:GNAQ) -> bp(PTS:"G protein mediated signaling pathway") p(HGNC:RGS4) -| p(HGNC:GNAQ) p(HGNC:RGS4) -| bp(PTS:"Calcium signaling pathway") p(HGNC:RGS4) -| bp(PTS:"G protein mediated signaling pathway") SET Evidence = "Regulators of G-protein Signaling (RGS) suppress GPCR signal transduction by selectively interacting with GTP-bound (activated) heterotrimeric G‚àö√©¬¨¬± subunits to enhance their intrinsic rate of nucleotide hydrolysis" SET Subgraph = {"Calcium dependent subgraph", "G-protein-mediated signaling"} complex(p(HGNC:GNAQ), a(CHEBI:GTP)) -> bp(PTS:"G protein mediated signaling pathway") complex(p(HGNC:GNAQ), a(CHEBI:GTP)) -> bp(PTS:"Calcium signaling pathway") complex(p(HGNC:GNAQ), a(CHEBI:GTP), p(HGNC:RGS4)) causesNoChange bp(PTS:"G protein mediated signaling pathway") complex(p(HGNC:GNAQ), a(CHEBI:GTP), p(HGNC:RGS4)) causesNoChange bp(PTS:"Calcium signaling pathway") complex(p(HGNC:GNAQ), p(HGNC:RGS4)) causesNoChange bp(PTS:"G protein mediated signaling pathway") complex(p(HGNC:GNAQ), p(HGNC:RGS4)) causesNoChange bp(PTS:"Calcium signaling pathway") SET Evidence = "Additionally, formation of an RGS4-A1-adenosine receptor complex via the neurabin scaffolding protein can negatively regulate the neuroprotective effects of adenosine signaling in a kainate-induced seizure model" SET Subgraph = {"Calcium dependent subgraph", "G-protein-mediated signaling"} complex(p(HGNC:ADORA1), p(HGNC:RGS4)) -> path(MESHD:"Neurodegenerative Diseases") complex(p(HGNC:ADORA1), p(HGNC:RGS4)) -> path(MESHD:Seizures) SET Evidence = "Supplemental Table 1: thirteen inhibitors directly targeting the RGS-G-protein interaction. CID 1911669,5428579,1905297,6010977,6018993,6383479,1389577,6866727,52210,1472216,11957531,10069059,1777233" #pubchem cids https://pubchem.ncbi.nlm.nih.gov/compound/1911669#section=Top ###a(1911669) =| complex(p(HGNC:GNAQ), p(HGNC:RGS4)) ###a(5428579) =| complex(p(HGNC:GNAQ), p(HGNC:RGS4)) ###a(1905297) =| complex(p(HGNC:GNAQ), p(HGNC:RGS4)) ###a(6010977) =| complex(p(HGNC:GNAQ), p(HGNC:RGS4)) ###a(6018993) =| complex(p(HGNC:GNAQ), p(HGNC:RGS4)) ###a(6383479) =| complex(p(HGNC:GNAQ), p(HGNC:RGS4)) ###a(1389577) =| complex(p(HGNC:GNAQ), p(HGNC:RGS4)) ###a(6866727) =| complex(p(HGNC:GNAQ), p(HGNC:RGS4)) ###a(52210) =| complex(p(HGNC:GNAQ), p(HGNC:RGS4)) ###a(1472216) =| complex(p(HGNC:GNAQ), p(HGNC:RGS4)) ###a(11957531) =| complex(p(HGNC:GNAQ), p(HGNC:RGS4)) ###a(10069059) =| complex(p(HGNC:GNAQ), p(HGNC:RGS4)) ###a(1777233) =| complex(p(HGNC:GNAQ), p(HGNC:RGS4)) SET Evidence = "Like all previously reported RGS4 inhibitors, these compounds are dependent on covalent modification of cysteine residues for activity" ###a(1911669) -> p(HGNC:RGS4, pmod(C)) ###a(5428579) -> p(HGNC:RGS4, pmod(C)) ###a(1905297) -> p(HGNC:RGS4, pmod(C)) ###a(6010977) -> p(HGNC:RGS4, pmod(C)) ###a(6018993) -> p(HGNC:RGS4, pmod(C)) ###a(6383479) -> p(HGNC:RGS4, pmod(C)) ###a(1389577) -> p(HGNC:RGS4, pmod(C)) ###a(6866727) -> p(HGNC:RGS4, pmod(C)) ###a(52210) -> p(HGNC:RGS4, pmod(C)) ###a(1472216) -> p(HGNC:RGS4, pmod(C)) ###a(11957531) -> p(HGNC:RGS4, pmod(C)) ###a(10069059) -> p(HGNC:RGS4, pmod(C)) ###a(1777233) -> p(HGNC:RGS4, pmod(C)) #p(HGNC:RGS4,pmod(C)) -| complex(p(HGNC:GNAQ), p(HGNC:RSG4)) UNSET Subgraph ############################################# # General paper about Cdk5 modulation of MAPK regulating neuronal survival ############################################# SET Citation = {"PubMed", "Mol Biol Cell. 2007 Feb;18(2):404-13. Epub 2006 Nov 15.", "17108320"} SET Evidence = "Cdk5, a cyclin-dependent kinase, is critical for neuronal development, neuronal migration, cortical lamination, and survival" SET Confidence = "High" SET Subgraph = "protein kinase signaling subgraph" p(HGNC:CDK5) -> bp(GOBP:"neuron development") p(HGNC:CDK5) -> bp(GOBP:"neuron migration") UNSET {Subgraph, Confidence} SET Evidence = "Previously, we showed that Cdk5 phosphorylation of mitogen-activated protein kinase kinase (MEK)1 inhibits transient activation induced by nerve growth factor (NGF) in PC12 cells" SET Confidence = "High" SET Subgraph = {"protein kinase signaling subgraph", "MAPK-ERK subgraph"} SET MeSHAnatomy = "PC12 Cells" kin(p(HGNC:CDK5)) -> p(HGNC:MAP2K1, pmod(P)) p(HGNC:MAP2K1, pmod(P)) -| bp(PTS:"mitogen activated protein kinase signaling pathway") UNSET MeSHAnatomy SET Evidence = "NGF alone induced an Erk1/2-transient activation that peaked in 15 min and declined rapidly to baseline. " SET Confidence = "High" p(HGNC:NGF) -> p(HGNC:MAP2K1) p(HGNC:NGF) -> p(HGNC:MAP2K2) SET Evidence = "Roscovitine, alone or with NGF, reached peak Erk1/2 activation in 30 min that was sustained for 48 h" SET Confidence = "High" a(MESHC:roscovitine) -> p(HGNC:MAP2K1) a(MESHC:roscovitine) -> p(HGNC:MAP2K2) UNSET Subgraph SET Evidence = "Moreover, the sustained Erk1/2 activation induced apoptosis in cortical neurons" SET Confidence = "High" SET Subgraph = {"Apoptosis signaling subgraph", "MAPK-ERK subgraph", "protein kinase signaling subgraph"} SET MeSHAnatomy = "Cerebellar Cortex" SET MeSHAnatomy = "Neurons" p(HGNC:MAP2K1) -> bp(GOBP:"apoptotic process") p(HGNC:MAP2K2) -> bp(GOBP:"apoptotic process") SET Evidence = "Significantly, pharmacological application of the MEK1 inhibitor PD98095 to roscovitine-treated cortical neurons prevented apoptosis" SET Confidence = "High" a(CHEBI:"2-(2-amino-3-methoxyphenyl)chromen-4-one") -| p(HGNC:MAP2K1) a(CHEBI:"2-(2-amino-3-methoxyphenyl)chromen-4-one") -| bp(GOBP:"apoptotic process") SET Evidence = "These results suggest that survival of cortical neurons is also dependent on tight Cdk5 modulation of the mitogen-activated protein kinase signaling pathway." SET Confidence = "High" p(HGNC:CDK5) -- bp(PTS:"mitogen activated protein kinase signaling pathway") p(HGNC:CDK5) -| bp(GOBP:"apoptotic process") p(HGNC:CDK5) -| bp(GOBP:"neuron death") UNSET MeSHAnatomy SET Evidence = "Cdk5, a cyclin-dependent kinase, regulated by its neuron-specific activators, p35 and p39" SET Confidence = "High" p(HGNC:CDK5R1) reg p(HGNC:CDK5) p(HGNC:CDK5R2) reg p(HGNC:CDK5) UNSET {Subgraph, Confidence} SET Evidence = "Cdk5 promotes neuronal survival by phosphorylation and inactivation of the c-Jun NH2-terminal kinase (JNK) 3 kinase, a key player in an apoptotic pathway (Li et al., 2002 blue right-pointing triangle) and activation of the neuregulin/phosphatidylinositol 3-kinase (PI3K)/Akt survival pathway" SET Confidence = "High" SET Subgraph = {"protein kinase signaling subgraph", "Apoptosis signaling subgraph"} kin(p(HGNC:CDK5)) -> p(HGNC:MAPK10, pmod(P)) p(HGNC:MAPK10, pmod(P)) causesNoChange bp(GOBP:"apoptotic process") p(HGNC:MAPK10) -> bp(GOBP:"apoptotic process") p(HGNC:CDK5) -> bp(PTS:"phosphatidylinositol 3_kinase signaling pathway") bp(PTS:"phosphatidylinositol 3_kinase signaling pathway") -| bp(GOBP:"apoptotic process") UNSET Subgraph SET Evidence = "Cdk5 also has a darker side; when deregulated, it has been implicated in apoptosis in several cell systems, including neurons, and it may play a key role in the pathology of several neurodegenerative disorders" SET Confidence = "High" SET Subgraph = "Apoptosis signaling subgraph" p(HGNC:CDK5) -- bp(GOBP:"apoptotic process") p(HGNC:CDK5) -- path(MESHD:"Neurodegenerative Diseases") SET Evidence = "We propose that neurons may uniquely possess a tightly regulated mechanism in which Cdk5/p35 prevents apoptosis induced by sustained activation of the MAPK pathway" p(HGNC:CDK5) -| bp(PTS:"mitogen activated protein kinase signaling pathway") p(HGNC:CDK5R1) -| bp(PTS:"mitogen activated protein kinase signaling pathway") p(HGNC:CDK5R1) -| bp(GOBP:"apoptotic process") UNSET {Subgraph, Confidence} SET Evidence = "Although proliferating PC12 cells express Cdk5, its activity is low and only after NGF stimulation is p35 synthesized, activating Cdk5" #: PC12 cell annotation missing p(HGNC:NGF) -> p(HGNC:CDK5R1) SET Evidence = "Finally, although GSK3 is activated in roscovitine-treated cortical neurons, that neurons are rescued from apoptosis by the MEK1 inhibitor PD98095 also argues against a role for GSK3 in apoptosis." #: Probably code GSK3 as a complex with these two a(MESHC:roscovitine) -> act(p(HGNC:GSK3A)) a(MESHC:roscovitine) -> act(p(HGNC:GSK3B)) p(HGNC:GSK3A) causesNoChange bp(GOBP:"apoptotic process") p(HGNC:GSK3B) causesNoChange bp(GOBP:"apoptotic process") SET Evidence = "An altered cytoskeleton or scaffolding proteins may be involved because these are essential in localizing the activated Erk1/2 to cytosol, membrane, or nucleus" bp(GOBP:"cytoskeleton organization") -> p(HGNC:MAPK1) bp(GOBP:"cytoskeleton organization") -> p(HGNC:MAPK3) bp(GOBP:"cytoskeleton organization") -- bp(GOBP:"apoptotic process") SET Evidence = " In stress-induced neurons undergoing apoptosis (Zhang and Johnson, 2000 blue right-pointing triangle) and in abnormal accumulation of hyperphosphorylated tau and NF proteins occur in cell bodies" SET Subgraph = {"Apoptosis signaling subgraph", "protein kinase signaling subgraph", "MAPK-ERK subgraph"} bp(GOBP:"apoptotic process") -> p(HGNC:MAPT, pmod(P)) bp(GOBP:"apoptotic process") -> p(HGNC:NFKB1, pmod(P)) path(MESHD:"Neurodegenerative Diseases") -> p(HGNC:MAPT, pmod(P)) path(MESHD:"Neurodegenerative Diseases") -> p(HGNC:NFKB1, pmod(P)) SET Evidence = "Cell death could have been caused by aberrant phosphorylation of the neuronal cytoskeleton, which altered cellular trafficking and transport, inducing neuronal dysfunction (Smith and Tsai, 2002 blue right-pointing triangle). This is consistent with pathological accumulations of phosphorylated NF proteins in the soma of Cdk5 knockout brain stem neurons" p(HGNC:CDK5) negativeCorrelation p(HGNC:NFKB1) p(HGNC:NFKB1) -- bp(GOBP:"cytoskeleton organization") UNSET Subgraph SET Evidence = "Cdk5/p35 is implicated in the exocytotic and endocytotic events of transmitter release at the synapse " SET Subgraph = "Neurotransmitter release subgraph" p(HGNC:CDK5) -> bp(PTS:"Neurotransmitter secretion") p(HGNC:CDK5R1) -> bp(PTS:"Neurotransmitter secretion") p(HGNC:CDK5) -> bp(GOBP:"neurotransmitter uptake") p(HGNC:CDK5R1) -> bp(GOBP:"neurotransmitter uptake") p(HGNC:CDK5) -> bp(GOBP:"neurotransmitter transport") p(HGNC:CDK5R1) -> bp(GOBP:"neurotransmitter transport") UNSET Subgraph SET Evidence = "For example, roscovitine induced a rapid transmitter release in hippocampal slices and synaptosomes that was coupled to enhanced Ca2+ influx from P/Q-type voltage-dependent calcium channels" SET Subgraph = "Calcium dependent subgraph" a(MESHC:roscovitine) -> bp(PTS:"Neurotransmitter secretion") a(MESHC:roscovitine) -> bp(GOBP:"calcium ion import") p(HGNC:CACNA1A) -> bp(GOBP:"calcium ion import") p(HGNC:CACNA1G) -> bp(GOBP:"calcium ion import") p(HGNC:CACNA1H) -> bp(GOBP:"calcium ion import") p(HGNC:CACNA1I) -> bp(GOBP:"calcium ion import") p(HGNC:CACNA1A) -> bp(PTS:"Calcium signaling pathway") p(HGNC:CACNA1G) -> bp(PTS:"Calcium signaling pathway") p(HGNC:CACNA1H) -> bp(PTS:"Calcium signaling pathway") p(HGNC:CACNA1I) -> bp(PTS:"Calcium signaling pathway") SET Evidence = "Evidently, Cdk5/p35 modulates transmitter release through phosphorylation of a P/Q-type Ca2+ channel subunit and down-regulation of channel activity" kin(p(HGNC:CDK5)) -> p(HGNC:CACNA1A, pmod(P)) kin(p(HGNC:CDK5)) -> p(HGNC:CACNA1G, pmod(P)) kin(p(HGNC:CDK5)) -> p(HGNC:CACNA1H, pmod(P)) kin(p(HGNC:CDK5)) -> p(HGNC:CACNA1I, pmod(P)) kin(p(HGNC:CDK5R1)) -> p(HGNC:CACNA1A, pmod(P)) kin(p(HGNC:CDK5R1)) -> p(HGNC:CACNA1G, pmod(P)) kin(p(HGNC:CDK5R1)) -> p(HGNC:CACNA1H, pmod(P)) kin(p(HGNC:CDK5R1)) -> p(HGNC:CACNA1I, pmod(P)) p(HGNC:CACNA1A, pmod(P)) causesNoChange bp(GOBP:"calcium ion import") p(HGNC:CACNA1G, pmod(P)) causesNoChange bp(GOBP:"calcium ion import") p(HGNC:CACNA1H, pmod(P)) causesNoChange bp(GOBP:"calcium ion import") p(HGNC:CACNA1I, pmod(P)) causesNoChange bp(GOBP:"calcium ion import") bp(GOBP:"calcium ion import") -> bp(PTS:"Neurotransmitter secretion") UNSET Subgraph SET Evidence = "It is well documented that in neuronal cultures subjected to NMDA-meditated toxicity, okadaic acid, and oxidative stress, Erk activity is elevated and cell death follows, an effect inhibited by MEK1 inhibitors" a(CHEBI:"reactive oxygen species") -> bp(PTS:"mitogen activated protein kinase signaling pathway") a(CHEBI:"reactive oxygen species") -> p(HGNC:MAPK1) a(CHEBI:"reactive oxygen species") -> p(HGNC:MAPK3) a(CHEBI:"okadaic acid") -> bp(PTS:"mitogen activated protein kinase signaling pathway") a(CHEBI:"okadaic acid") -> p(HGNC:MAPK1) a(CHEBI:"okadaic acid") -> p(HGNC:MAPK3) #p(HGNC:GRIN1) -> -> bp(PTS:"mitogen activated protein kinase signaling pathway") #p(HGNC:GRIN1) -> p(HGNC:MAPK1) #p(HGNC:GRIN1) -> p(HGNC:MAPK3) p(HGNC:MAPK1) -> bp(GOBP:"apoptotic process") p(HGNC:MAPK3) -> bp(GOBP:"apoptotic process") SET Evidence = "Stress induced ischemia evoke similar excitotoxic effects in neurons correlated with activated sustained Erk1/2 and cell death rescued by MEK1 inhibitors " path(MESHD:Ischemia) -> bp(PTS:"mitogen activated protein kinase signaling pathway") path(MESHD:Ischemia) -> p(HGNC:MAPK1) path(MESHD:Ischemia) -> p(HGNC:MAPK3) ######################################################### # Neurodegeneration apoptosis paper ########################################################## SET Citation = {"PubMed", "Bioinformation. 2014 Apr 23;10(4):191-5. doi:10.6026/97320630010191. eCollection 2014.", "24966519"} SET Evidence = "Neurodegenerative disorders are often associated with excessive neuronal apoptosis" SET Subgraph = "Apoptosis signaling subgraph" bp(GOBP:"apoptotic process") -> path(MESHD:"Neurodegenerative Diseases") bp(GOBP:"neuron death") -> path(MESHD:"Neurodegenerative Diseases") SET Evidence = "In fact, Caspase-8 which is an initiator caspase, has been identified as a key mediator of neuronal apoptosis" p(HGNC:CASP8) -> bp(GOBP:"neuron death") p(HGNC:CASP8) -> bp(GOBP:"apoptotic process") SET Evidence = "Caspase-8 inhibition may provide an effective means of treatment for multiple neurodegenerative disorders. rosmarinic acid and curcumin proved to be the most potent inhibitors of Caspase-8" p(HGNC:CASP8) pos path(MESHD:Epilepsy) p(HGNC:CASP8) pos path(MESHD:"Neurodegenerative Diseases") a(CHEBI:"rosmarinic acid") -| p(HGNC:CASP8) a(CHEBI:"rosmarinic acid") -| bp(GOBP:"apoptotic process") a(CHEBI:"rosmarinic acid") -| bp(GOBP:"neuron death") a(CHEBI:"rosmarinic acid") -| path(MESHD:"Neurodegenerative Diseases") a(CHEBI:"rosmarinic acid") -| path(MESHD:Epilepsy) a(CHEBI:curcumin) -| p(HGNC:CASP8) a(CHEBI:curcumin) -| bp(GOBP:"apoptotic process") a(CHEBI:curcumin) -| bp(GOBP:"neuron death") a(CHEBI:curcumin) -| path(MESHD:"Neurodegenerative Diseases") a(CHEBI:curcumin) -| path(MESHD:Epilepsy) UNSET Subgraph SET Evidence = "Caspases are proteolytic in nature and key executioners of apoptosis" SET Subgraph = {"Protein Metabolism", "Apoptosis signaling subgraph"} p(HGNC:CASP8) -> bp(PTS:"protein degradation pathway") SET Evidence = "Caspases can be classified into two broad categories firstly, initiator caspases (caspase-2, caspase-8, caspase-9, and caspase- 10) and secondly effector caspases (caspase-3, caspase-6, and caspase-7). Initiator caspases generally act in early stages of a proteolytic cascade whereas effector caspases act downstream and are involved in the cleavage of specific cellular proteins" p(HGNC:CASP2) -> bp(GOBP:"apoptotic process") p(HGNC:CASP2) -> bp(PTS:"protein degradation pathway") p(HGNC:CASP9) -> bp(GOBP:"apoptotic process") p(HGNC:CASP9) -> bp(PTS:"protein degradation pathway") p(HGNC:CASP10) -> bp(GOBP:"apoptotic process") p(HGNC:CASP10) -> bp(PTS:"protein degradation pathway") p(HGNC:CASP3) -> bp(GOBP:"apoptotic process") p(HGNC:CASP3) -> bp(PTS:"protein degradation pathway") p(HGNC:CASP6) -> bp(GOBP:"apoptotic process") p(HGNC:CASP6) -> bp(PTS:"protein degradation pathway") p(HGNC:CASP7) -> bp(GOBP:"apoptotic process") p(HGNC:CASP7) -> bp(PTS:"protein degradation pathway") UNSET Subgraph SET Evidence = "In such a caspase cascade, initiator caspases (such as caspase 8) activate so-called effector caspases (such as caspase 3 or 6), which are responsible for the cleavage of various cellular proteins, leading to apoptotic death " p(HGNC:CASP2) -> p(HGNC:CASP3) p(HGNC:CASP2) -> p(HGNC:CASP6) p(HGNC:CASP2) -> p(HGNC:CASP7) p(HGNC:CASP8) -> p(HGNC:CASP3) p(HGNC:CASP8) -> p(HGNC:CASP6) p(HGNC:CASP8) -> p(HGNC:CASP7) p(HGNC:CASP9) -> p(HGNC:CASP3) p(HGNC:CASP9) -> p(HGNC:CASP6) p(HGNC:CASP9) -> p(HGNC:CASP7) p(HGNC:CASP10) -> p(HGNC:CASP3) p(HGNC:CASP10) -> p(HGNC:CASP6) p(HGNC:CASP10) -> p(HGNC:CASP7) ############################################## SET Citation = {"PubMed", "Neurochem Res. 2016 Jun;41(6):1335-42. doi: 10.1007/s11064-016-1835-y. Epub 2016 Jan 22.", "26801176"} SET Evidence = "Mitochondrial division inhibitor 1 (mdivi-1), a selective inhibitor of the mitochondrial fission protein dynamin-related protein 1, has been proposed to have a neuroprotective effect on hippocampal neurons in animal models of epilepsy" SET Subgraph = "Apoptosis signaling subgraph" a(MESHC:"3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3H)-quinazolinone") -| p(HGNC:DNM1L) p(HGNC:DNM1L) -> bp(GOBP:"apoptotic process") a(MESHC:"3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3H)-quinazolinone") -| path(MESHD:Epilepsy) a(MESHC:"3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3H)-quinazolinone") isA a(CHEBI:"neuroprotective agent") SET Evidence = "We found that mitochondrial fission was increased in the HNC model of AE and inhibition of mitochondrial fission by mdivi-1 significantly decreased neuronal apoptosis induced by AE." p(HGNC:DNM1L) -> bp(GOBP:"mitochondrial fission") bp(GOBP:"mitochondrial fission") -> bp(GOBP:"apoptotic process") path(MESHD:Epilepsy) -> bp(GOBP:"mitochondrial fission") a(MESHC:"3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3H)-quinazolinone") -| bp(GOBP:"mitochondrial fission") SET Evidence = "In addition, mdivi-1 pretreatment significantly attenuated oxidative stress induced by AE characterized by decrease of reactive oxygen species (ROS) production and malondialdehyde level and by increase of superoxide dismutase activity" path(MESHD:Epilepsy) -> a(CHEBI:"reactive oxygen species") path(MESHD:Epilepsy) -> bp(GOBP:"response to oxidative stress") bp(GOBP:"response to oxidative stress") -> a(CHEBI:"reactive oxygen species") bp(GOBP:"response to oxidative stress") -> a(MESHC:Malondialdehyde) a(MESHC:"3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3H)-quinazolinone") -| bp(GOBP:"mitochondrial fission") a(MESHC:"3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3H)-quinazolinone") -| a(MESHC:Malondialdehyde) a(MESHC:"3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3H)-quinazolinone") -> p(HGNC:SOD1) p(HGNC:SOD1) -> degradation(a(CHEBI:"reactive oxygen species")) SET Evidence = "Moreover, mdivi-1 pretreatment significantly decreased endoplasmic reticulum (ER) stress markers glucose-regulated protein 78, C/EBP homologous protein expression and caspase-3 activation" a(MESHC:"3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3H)-quinazolinone") -| bp(GOBP:"response to endoplasmic reticulum stress") bp(GOBP:"response to endoplasmic reticulum stress") -> bp(GOBP:"apoptotic process") bp(GOBP:"response to endoplasmic reticulum stress") -> bp(GOBP:"neuron death") bp(GOBP:"response to endoplasmic reticulum stress") -> p(HGNC:HSPA5) bp(GOBP:"response to endoplasmic reticulum stress") -> p(HGNC:DDIT3) bp(GOBP:"response to endoplasmic reticulum stress") -> p(HGNC:CASP3) SET Evidence = "Altogether, our findings suggest that mdivi-1 protected against AE-induced hippocampal neuronal apoptosis in vitro via decreasing ROS-mediated oxidative stress and ER stress" a(MESHC:"3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3H)-quinazolinone") -| bp(GOBP:"neuron death") a(MESHC:"3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3H)-quinazolinone") -| bp(GOBP:"apoptotic process") UNSET Subgraph ############################################### SET Citation = {"PubMed", "Epilepsia. 2015 Dec;56(12):1899-909. doi: 10.1111/epi.13223. Epub 2015 Oct 30.", "26515103"} SET Evidence = "BRV, similar to LEV, entered into recycling synaptic vesicles and produced a frequency-dependent decrement of synaptic transmission at 100-fold lower concentrations than LEV. In addition, BRV slowed synaptic vesicle mobilization more effectively than LEV, suggesting that these drugs may modify multiple functions of the synaptic vesicle protein SV2A to curb synaptic transmission and limit epileptic activity." SET Subgraph = "Neurotransmitter release subgraph" a(CHEBI:brivaracetam) -> bp(PTS:"Synaptic vesicle cycle") a(CHEBI:levetiracetam) -> bp(PTS:"Synaptic vesicle cycle") a(CHEBI:brivaracetam) -| bp(PTS:"Neurotransmitter secretion") a(CHEBI:levetiracetam) -| bp(PTS:"Neurotransmitter secretion") # full text not available, but would be interesting ############################################## SET Citation = {"PubMed", "Mol Neurobiol. 2014 Apr;49(2):633-44. doi: 10.1007/s12035-013-8545-0. Epub 2013 Sep 3.", "23999872"} SET Evidence = "Here, focusing on temporal lobe epilepsy, we found that Notch signaling was activated in the kainic acid (KA)-induced epilepsy model and in human epileptogenic tissues" SET Subgraph = "Notch signaling subgraph" a(CHEBI:"kainic acid") -> path(MESHD:"Status Epilepticus") a(CHEBI:"kainic acid") -> bp(PTS:"Notch signaling pathway") SET Evidence = "Using an acute model of seizures, we showed that DAPT, an inhibitor of Notch, inhibited ictal activity" a(MESHC:"N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester") -| p(HGNC:NOTCH1) a(MESHC:"N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester") -| bp(PTS:"Notch signaling pathway") a(MESHC:"N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester") -| path(MESHD:Seizures) bp(PTS:"Notch signaling pathway") positiveCorrelation path(MESHD:Epilepsy) SET Evidence = "In vitro, we found that DAPT treatment impaired synaptic vesicle endocytosis in cultured hippocampal neurons" SET MeSHAnatomy = "Hippocampus" SET MeSHAnatomy = "Neurons" a(MESHC:"N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester") -| bp(PTS:"Synaptic vesicle cycle") UNSET MeSHAnatomy SET Evidence = "Notch signaling is up-regulated in response to seizure activity, and its activation further promotes neuronal excitation of CA1 pyramidal neurons in acute seizures." SET Cell = "pyramidal neuron" path(MESHD:Seizures) -> bp(PTS:"Notch signaling pathway") bp(PTS:"Notch signaling pathway") -> bp(GOBP:"rhythmic excitation") UNSET Subgraph ################################################# SET Citation = {"PubMed", "Neural Regen Res. 2014 Mar 1;9(5):526-33. doi: 10.4103/1673-5374.130083.", "25206850"} SET Evidence = "Temporal lobe epilepsy is associated with astrogliosis" SET Subgraph = "Notch signaling subgraph" path(MESHD:"Epilepsy, Temporal Lobe") positiveCorrelation bp(GOBP:"astrocyte activation") SET Evidence = "Notch1 signaling can induce astrogliosis in glioma." bp(PTS:"Notch signaling pathway") -> bp(GOBP:"astrocyte activation") p(HGNC:NOTCH1) -> bp(GOBP:"astrocyte activation") SET Evidence = "Results revealed that the presence of Notch1, hairy and enhancer of split-1, and glial fibrillary acidic protein were enhanced in status epilepticus" path(MESHD:"Status Epilepticus") positiveCorrelation p(HGNC:NOTCH1) path(MESHD:"Status Epilepticus") positiveCorrelation p(HGNC:HES1) path(MESHD:"Status Epilepticus") positiveCorrelation p(HGNC:GFAP) SET Evidence = "Therefore, these results suggest that Notch1 signaling may play an important role in the onset of temporal lobe epilepsy via astrogliosis" bp(GOBP:"astrocyte activation") -> bp(EPT:epileptogenesis) bp(GOBP:"astrocyte activation") -> path(MESHD:"Epilepsy, Temporal Lobe") SET Evidence = "Furthermore, zileuton may be a potential therapeutic strategy for temporal lobe epilepsy by blocking Notch1 signaling." a(CHEBI:zileuton) -| bp(PTS:"Notch signaling pathway") a(CHEBI:zileuton) -| p(HGNC:NOTCH1) a(CHEBI:zileuton) -| path(MESHD:"Epilepsy, Temporal Lobe") SET Evidence = "Notch signaling coordinates a wide range of fundamental processes and cellular programs, including proliferation, apoptosis, migration, growth, and differentiation in a context-dependent manner" bp(PTS:"Notch signaling pathway") -> bp(GOBP:"regulation of apoptotic process") bp(PTS:"Notch signaling pathway") -- bp(GOBP:"cell proliferation") bp(PTS:"Notch signaling pathway") -> bp(GOBP:"neuron migration") bp(PTS:"Notch signaling pathway") -> bp(GOBP:"neuron differentiation") bp(PTS:"Notch signaling pathway") -> bp(GOBP:"neuron development") SET Evidence = "The four mammalian Notch receptors are single-pass type-1 trans-membrane proteins that are expressed on the cell surface[15]. The Notch pathway is activated when a signal-sending cell expressing a membrane-bound ligand physically interacts with a signal-receiving cell expressing a Notch receptor" p(HGNC:NOTCH2) -> bp(PTS:"Notch signaling pathway") p(HGNC:NOTCH3) -> bp(PTS:"Notch signaling pathway") p(HGNC:NOTCH4) -> bp(PTS:"Notch signaling pathway") SET Evidence = "The most prominent targets of the Notch pathway include a set of basic helix-loop-helix factors of the hairy and enhancer-of-split and hairy and enhancer-of-split-related repressor protein transcription factor families" p(HGNC:NOTCH1) -> p(HGNC:HES1) p(HGNC:NOTCH2) -> p(HGNC:HES1) p(HGNC:NOTCH3) -> p(HGNC:HES1) p(HGNC:NOTCH4) -> p(HGNC:HES1) p(HGNC:NOTCH1) -> p(HGNC:HES2) p(HGNC:NOTCH2) -> p(HGNC:HES2) p(HGNC:NOTCH3) -> p(HGNC:HES2) p(HGNC:NOTCH4) -> p(HGNC:HES2) p(HGNC:NOTCH1) -> p(HGNC:HES3) p(HGNC:NOTCH2) -> p(HGNC:HES3) p(HGNC:NOTCH3) -> p(HGNC:HES3) p(HGNC:NOTCH4) -> p(HGNC:HES3) p(HGNC:NOTCH1) -> p(HGNC:HES4) p(HGNC:NOTCH2) -> p(HGNC:HES4) p(HGNC:NOTCH3) -> p(HGNC:HES4) p(HGNC:NOTCH4) -> p(HGNC:HES4) p(HGNC:NOTCH1) -> p(HGNC:HES6) p(HGNC:NOTCH2) -> p(HGNC:HES6) p(HGNC:NOTCH3) -> p(HGNC:HES6) p(HGNC:NOTCH4) -> p(HGNC:HES6) SET Evidence = "These transcription factors execute Notch signaling functions" p(HGNC:HES1) -> bp(PTS:"Notch signaling pathway") p(HGNC:HES2) -> bp(PTS:"Notch signaling pathway") p(HGNC:HES3) -> bp(PTS:"Notch signaling pathway") p(HGNC:HES4) -> bp(PTS:"Notch signaling pathway") p(HGNC:HES6) -> bp(PTS:"Notch signaling pathway") SET Evidence = "The dysregulation of Notch signaling is associated with diseases with functional mutations in the key components of this pathway, such as Allagile[23], cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy[24] and Hajdu-Cheney syndromes" #: Positive correlation between dysregulation of pathway and disease bp(PTS:"Notch signaling pathway") -> path(MESHD:"Alagille Syndrome") bp(PTS:"Notch signaling pathway") -> path(MESHD:CADASIL) bp(PTS:"Notch signaling pathway") -> path(MESHD:"Hajdu-Cheney Syndrome") SET Evidence = "Moreover, abnormal levels of Notch are found in Down's syndrome[26] and Alzheimer's disease[27] patients" bp(PTS:"Notch signaling pathway") positiveCorrelation path(MESHD:"Alzheimer Disease") p(HGNC:NOTCH1) positiveCorrelation path(MESHD:"Alzheimer Disease") bp(PTS:"Notch signaling pathway") positiveCorrelation path(MESHD:"Down Syndrome") p(HGNC:NOTCH1) positiveCorrelation path(MESHD:"Down Syndrome") SET Evidence = "Recent in vitro evidence indicates that the preferential formation of astrocytes occurs after Notch is activated" bp(PTS:"Notch signaling pathway") -> bp(GOBP:"astrocyte differentiation") p(HGNC:NOTCH1) -> bp(GOBP:"astrocyte differentiation") SET Evidence = "Zileuton may modulate the expression levels of gamma-secretase to regulate the activity of Notch1 signaling" a(CHEBI:zileuton) -| p(HGNC:APH1A) SET Evidence = "Rapid astrocytic activation occurs in the hippocampus of temporal lobe epilepsy models[41,42]. Such changes cause neuronal damage and are related to abnormal neurotransmission" bp(GOBP:"astrocyte activation") -> path(MESHD:"Epilepsy, Temporal Lobe") bp(GOBP:"astrocyte activation") -| bp(GOBP:"regulation of neurotransmitter secretion") bp(GOBP:"astrocyte activation") -> bp(GOBP:"neuron death") SET Evidence = "With the changes in both glutamate transporters and receptors, and other neurotransmitters of glial cells, astrocytic proliferation has been hypothesized to play an important role in hyperexcitability and spontaneous seizures" # glutamate transporter 1, there are others bp(GOBP:"astrocyte activation") -- p(HGNC:SLC1A1) # first subunit of all three types of glutamate receptors, there are other subunits bp(GOBP:"astrocyte activation") -- p(HGNC:GRIN1) bp(GOBP:"astrocyte activation") -- p(HGNC:GRIA1) bp(GOBP:"astrocyte activation") -- p(HGNC:GRIK1) SET Evidence = "With the changes in both glutamate transporters and receptors, and other neurotransmitters of glial cells, astrocytic proliferation has been hypothesized to play an important role in hyperexcitability and spontaneous seizures" bp(GOBP:"astrocyte activation") -> path(MESHD:Seizures) SET Evidence = "Activation of Notch signaling requires the binding of Jagged and Delta like ligands followed by the release of the Notch intracellular domain by gamma-secretase and its translocation to the nucleus" complex(p(HGNC:NOTCH1), p(HGNC:JAG1), p(HGNC:JAG2), p(HGNC:DLL1)) -> bp(PTS:"Notch signaling pathway") p(HGNC:APH1A) -> p(HGNC:NOTCH1) p(HGNC:APH1A) -> bp(PTS:"Notch signaling pathway") a(CHEBI:zileuton) -| bp(PTS:"Notch signaling pathway") a(CHEBI:zileuton) -| p(HGNC:NOTCH1) SET Evidence = "Notch intracellular domain interacts with CSL transcription factors (CBF1/RBP-Jk, Su(H), Lag-1) and converts them from repressors to activators, promoting the transcription of downstream genes involved in various differentiation programs" p(HGNC:NOTCH1) -> p(HGNC:RBPJ) p(HGNC:RBPJ) -> bp(GOBP:"transcription, DNA-templated") p(HGNC:RBPJ) -> bp(GOBP:"cell differentiation") SET Evidence = "Interestingly, glioma and epilepsy share a feature of astrogliosis" bp(GOBP:"astrocyte activation") -> path(MESHD:Epilepsy) bp(GOBP:"astrocyte activation") -> path(MESHD:Glioma) SET Evidence = "The blood brain barrier plays an important role in the homeostasis of the central nervous system, and its breakdown is known to be associated with epileptic seizures" bp(GOBP:"establishment of blood-brain barrier") -| path(MESHD:Epilepsy) bp(GOBP:"establishment of blood-brain barrier") -| path(MESHD:Seizures) SET Evidence = "In summary, increased presence of Notch was observed in intractable temporal lobe epilepsy patients and experimental animals." path(MESHD:"Epilepsy, Temporal Lobe") positiveCorrelation p(HGNC:NOTCH1) SET Evidence = "Therefore, Notch signaling may play a role in the pathogenesis of epilepsy in temporal lobe epilepsy and its suppression may provide a new treatment to promote remission in epilepsy." bp(PTS:"Notch signaling pathway") -> bp(EPT:epileptogenesis) UNSET Subgraph ############################################## SET Citation = {"PubMed", "J Pharmacol Exp Ther. 2006 Nov;319(2):790-8. Epub 2006 Aug 8.", "16895979"} SET Evidence = "Carbamazepine (CBZ) aggravates many generalized seizures types, particularly absence seizures, but the mechanisms underlying this are poorly understood" a(CHEBI:carbamazepine) -> path(MESHD:"Epilepsy, Generalized") a(CHEBI:carbamazepine) -> path(MESHD:"Epilepsy, Absence") SET Evidence = "GABA signaling within the reticular nucleus (Rt) and the ventrobasal complex (VB) of the thalamus is critical to the neurophysiology of absence seizures." SET MeSHAnatomy = "Ventral Thalamic Nuclei" SET Subgraph = "GABA subgraph" bp(PTS:"gamma_aminobutyric acid signaling pathway") -- path(MESHD:"Epilepsy, Absence") SET Evidence = "These data demonstrate that CBZ acts at the VB thalamus to aggravate absence seizures in GAERS and that activation of GABAA receptors is critical to this effect." SET Published = "Epilepsy comorbidity paper" a(CHEBI:carbamazepine) -> act(p(HGNC:GABRA1)) a(CHEBI:carbamazepine) -> act(p(HGNC:GABRA2)) a(CHEBI:carbamazepine) -> act(p(HGNC:GABRA3)) a(CHEBI:carbamazepine) -> act(p(HGNC:GABRA4)) a(CHEBI:carbamazepine) -> act(p(HGNC:GABRA5)) a(CHEBI:carbamazepine) -> act(p(HGNC:GABRA6)) a(CHEBI:carbamazepine) -> act(p(HGNC:GABRB1)) a(CHEBI:carbamazepine) -> act(p(HGNC:GABRB2)) a(CHEBI:carbamazepine) -> act(p(HGNC:GABRB3)) a(CHEBI:carbamazepine) -> act(p(HGNC:GABRG1)) a(CHEBI:carbamazepine) -> act(p(HGNC:GABRG2)) a(CHEBI:carbamazepine) -> act(p(HGNC:GABRG3)) a(CHEBI:carbamazepine) -> act(p(HGNC:GABRD)) a(CHEBI:carbamazepine) -> act(p(HGNC:GABRE)) a(CHEBI:carbamazepine) -> act(p(HGNC:GABRP)) a(CHEBI:carbamazepine) -> act(p(HGNC:GABRQ)) UNSET Published p(HGNC:GABRA1) -> path(MESHD:"Epilepsy, Absence") # contradicting because all other evidence suggests that GABA signaling is lowered in Epilepsy, and drugs targeting GABA receptors increase their activity to alleviate the condition ################################################### SET Citation = {"PubMed", "Exp Neurol. 2009 Apr;216(2):390-7. doi: 10.1016/j.expneurol.2008.12.029. Epub 2009 Jan 13.", "19185570"} SET Evidence = "Temporal lobe epilepsy (TLE) is often accompanied by granule cell dispersion (GCD), a migration defect of granule cells in the dentate gyrus." SET Subgraph = "Reelin signaling subgraph" SET Anatomy = "cerebellum internal granule cell layer" path(MESHD:"Epilepsy, Temporal Lobe") -- bp(EPT:"granule cell dispersion") path(MESHD:"Epilepsy, Temporal Lobe") -- bp(PTS:"Reelin signaling pathway") bp(EPT:"granule cell dispersion") -| bp(GOBP:"cerebellar granular layer formation") SET Evidence = "We have previously shown that a decrease in the expression of reelin, an extracellular matrix protein important for neuronal positioning, is associated with the development of GCD in TLE patients" p(HGNC:RELN) -- bp(EPT:"granule cell dispersion") bp(PTS:"Reelin signaling pathway") -- bp(EPT:"granule cell dispersion") p(HGNC:RELN) -> bp(GOBP:"neuron migration") bp(PTS:"Reelin signaling pathway") -> bp(GOBP:"neuron migration") SET Evidence = "As a prerequisite we analyzed whether the reelin signaling transduction cascade was preserved in the KA-injected hippocampus. Using in situ hybridization and Western blot analysis we found that the expression of the reelin signaling components, apolipoprotein E receptor 2, the very-low-density lipoprotein receptor and the intracellular adaptor protein disabled 1, was maintained in dentate granule cells after KA injection" p(HGNC:LRP8) -> bp(PTS:"Reelin signaling pathway") p(HGNC:VLDLR) -> bp(PTS:"Reelin signaling pathway") p(HGNC:DAB1) -> bp(PTS:"Reelin signaling pathway") path(MESHD:"Epilepsy, Temporal Lobe") causesNoChange p(HGNC:LRP8) path(MESHD:"Epilepsy, Temporal Lobe") causesNoChange p(HGNC:VLDLR) path(MESHD:"Epilepsy, Temporal Lobe") causesNoChange p(HGNC:DAB1) SET Evidence = "Next, recombinant reelin was infused into the KA-injected hippocampus by osmotic minipumps over a period of 2 weeks. Quantitative analysis of granule cell layer width revealed a significant reduction of GCD in reelin-treated" p(HGNC:RELN) -| bp(EPT:"granule cell dispersion") bp(PTS:"Reelin signaling pathway") -| bp(EPT:"granule cell dispersion") p(HGNC:RELN) -| path(MESHD:"Epilepsy, Temporal Lobe") bp(PTS:"Reelin signaling pathway") -| path(MESHD:"Epilepsy, Temporal Lobe") SET Evidence = "Cortical neuronal migration defects are often associated with the occurrence of epilepsy" bp(GOBP:"neuron migration") -- path(MESHD:Epilepsy) SET Evidence = "During normal brain development reelin is synthesized and secreted by Cajal‚àö¬¢‚Äö√ᬮ‚Äö√Ñ√∫Retzius cells in the marginal zones of the neocortex and hippocampus where it provides a positional cue for migrating neurons, thus regulating layer formation" p(HGNC:RELN) -> bp(GOBP:"layer formation in cerebral cortex") bp(PTS:"Reelin signaling pathway") -> bp(GOBP:"layer formation in cerebral cortex") SET Evidence = "The Reelin signaling pathway involves two reelin receptors, apolipoprotein E receptor 2 (ApoER2), the very-low-density lipoprotein receptor (VLDLR), and the intracellular adaptor protein disabled 1 (dab1; Howell et al., 1997, Sheldon et al., 1997, Trommsdorff et al., 1999 and D'Arcangelo et al., 1995). Mouse mutants deficient in these molecules also show granule cell migration defects. " SET Species = "10090" p(HGNC:LRP8) -- bp(EPT:"granule cell dispersion") p(HGNC:VLDLR) -- bp(EPT:"granule cell dispersion") p(HGNC:DAB1) -- bp(EPT:"granule cell dispersion") bp(PTS:"Reelin signaling pathway") -- bp(EPT:"granule cell dispersion") UNSET Species SET Evidence = "Recent evidence suggests that reelin is not only important during development, but also in the adult hippocampus for the maintenance of lamination" p(HGNC:RELN) -> bp(GOBP:"brain development") p(HGNC:RELN) -| bp(GOBP:delamination) ########################################### SET Citation = {"PubMed", "Neurotherapeutics. 2007 Jan;4(1):18-61.", "17199015"} SET Evidence = "Thus, seizures occur in animals and humans if GABA synthesis is impaired (as in pyridoxine deficiency or by exposure to isoniazid, a pyridoxine antagonist) or if GABAA receptors are inhibited by any one of a diverse group of compounds such as bicuculline, PTZ, picrotoxin, penicillin, convulsant barbiturates, and inverse benzodiazepine-site ligands" SET Subgraph = {"GABA subgraph", "Neurotransmitter release subgraph"} bp(GOBP:"gamma-aminobutyric acid biosynthetic process") negativeCorrelation path(MESHD:Seizures) a(CHEBI:pyridoxine) -> bp(GOBP:"gamma-aminobutyric acid biosynthetic process") a(CHEBI:pyridoxine) -| path(MESHD:Seizures) a(CHEBI:isoniazide) -| bp(GOBP:"gamma-aminobutyric acid biosynthetic process") a(CHEBI:isoniazide) -> path(MESHD:Seizures) a(CHEBI:bicuculline) -| bp(PTS:"gamma_aminobutyric acid signaling pathway") a(CHEBI:bicuculline) -> path(MESHD:Seizures) complex(a(CHEBI:picrotoxinin), a(MESHC:picrotin)) -| bp(PTS:"gamma_aminobutyric acid signaling pathway") complex(a(CHEBI:picrotoxinin), a(MESHC:picrotin)) -> path(MESHD:Seizures) a(CHEBI:penicillin) -| bp(PTS:"gamma_aminobutyric acid signaling pathway") a(CHEBI:penicillin) -> path(MESHD:Seizures) UNSET Subgraph SET Evidence = "Toxins that slow inactivation of voltage-gated Na+ channels and broaden action potentials, such as scorpion ‚àö√©¬¨¬±-toxins, also are convulsant" a(MESHC:"scorpion toxin AaH III") -> path(MESHD:Seizures) a(MESHC:"scorpion toxin AaH III") -> bp(GOBP:"neuronal action potential") a(MESHC:"scorpion toxin AaH III") -- p(HGNC:SCN1A) SET Evidence = "In addition, the activator of voltage-activated Ca2+ channels Bay K 8644 is a potent convulsant. It is L-type channels that are activated by Bay K 8644" SET Subgraph = "Calcium dependent subgraph" a(MESHC:"3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester") -> path(MESHD:Seizures) a(MESHC:"3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester") -> p(HGNC:CACNA1S) a(MESHC:"3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester") -> p(HGNC:CACNA1C) a(MESHC:"3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester") -> p(HGNC:CACNA1D) a(MESHC:"3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester") -> p(HGNC:CACNA1F) UNSET Subgraph SET Evidence = "Blockers of voltage-gated K+ channels are powerful convulsants. Such agents include antagonists of delayed rectifier and A-type channels such as 4-aminopyridine, dendrotoxin I, tityustoxin-K‚àö√©¬¨¬±, and pandinustoxin-K‚àö√©¬¨¬±" a(MESHC:"4-Aminopyridine") -| p(HGNC:KCNA4) a(MESHC:"4-Aminopyridine") -> path(MESHD:Seizures) a(MESHC:"dendrotoxin I") -| p(HGNC:KCNA4) a(MESHC:"dendrotoxin I") -> path(MESHD:Seizures) a(MESHC:tityustoxin) -| p(HGNC:KCNA4) a(MESHC:tityustoxin) -> path(MESHD:Seizures) a(MESHC:"Pandinus toxin K-alpha") -| p(HGNC:KCNA4) a(MESHC:"Pandinus toxin K-alpha") -> path(MESHD:Seizures) SET Evidence = "n addition, linopirdine, a blocker of M-type (KCNQ) K+ channels, also has convulsant actions, at least in the immature brain" a(MESHC:linopirdine) -| p(HGNC:KCNQ1) a(MESHC:linopirdine) -> path(MESHD:Seizures) SET Evidence = "Thus, progressive understanding of the role of gap junctions in neuronal sySCOMPronization and in the generation of epileptic discharges has led to the identification of connexins as potential targets" bp(GOBP:"gap junction assembly") -- path(MESHD:Epilepsy) bp(GOBP:"gap junction assembly") -- bp(GOBP:"neuronal action potential propagation") p(HGNC:GJA1) -- path(MESHD:Epilepsy) SET Evidence = "Voltage-gated-like ion channels not only control excitability in the central nervous system, but also in the peripheral autonomic nervous system, the cardiovascular system, and the digestive system. They also control all secretory functions including the release of hormones" a(MESHC:"Ion Channels") -> bp(GOBP:"regulation of secretion") a(MESHC:"Ion Channels") -> bp(GOBP:"regulation of hormone secretion") SET Evidence = "In the mammalian brain, the fast, transient Na+ currents that generate action potentials are mediated by Nav1.1 and Nav1.2 isoforms (predominant in the rostral brain, globus pallidus, hippocampus, thalamus, and cerebellum) and by the Nav1.6 isoform" p(HGNC:SCN1A) -> bp(EPT:"generation of fast sodium current") p(HGNC:SCN2A) -> bp(EPT:"generation of fast sodium current") p(HGNC:SCN8A) -> bp(EPT:"generation of fast sodium current") bp(EPT:"generation of fast natrium current") -- path(MESHD:Epilepsy) bp(EPT:"generation of fast natrium current") -- a(CHEBI:anticonvulsant) SET Evidence = "These channels also mediate the persistent, resurgent, or late Na+ current, which (although much smaller than the fast inactivating Na+ current) may play a significant role in epilepsy and in the action of AED" p(HGNC:SCN1A) -> bp(EPT:"generation of late sodium current") p(HGNC:SCN2A) -> bp(EPT:"generation of late sodium current") p(HGNC:SCN8A) -> bp(EPT:"generation of late sodium current") bp(EPT:"generation of late sodium current") -- path(MESHD:Epilepsy) bp(EPT:"generation of late sodium current") -- a(CHEBI:anticonvulsant) SET Evidence = "One group has reported that phenytoin and lamotrigine actually increase the spontaneous release of GABA, which they have proposed as contributing to the anticonvulsant actions of the drugs" SET Subgraph = {"GABA subgraph", "Neurotransmitter release subgraph"} a(CHEBI:phenytoin) -> bp(GOBP:"gamma-aminobutyric acid secretion, neurotransmission") a(CHEBI:lamotrigine) -> bp(GOBP:"gamma-aminobutyric acid secretion, neurotransmission") bp(GOBP:"gamma-aminobutyric acid secretion, neurotransmission") -| path(MESHD:Epilepsy) UNSET Subgraph SET Evidence = "In vivo microdialysis studies have confirmed that carbamazepine, oxcarbazepine, and lamotrigine inhibit glutamate release, but those studies are not entirely consistent with the view that this constitutes the primary anticonvulsant mechanism" SET Subgraph = "Neurotransmitter release subgraph" a(CHEBI:carbamazepine) -| bp(GOBP:"glutamate secretion, neurotransmission") a(CHEBI:oxcarbazepine) -| bp(GOBP:"glutamate secretion, neurotransmission") a(CHEBI:lamotrigine) -| bp(GOBP:"glutamate secretion, neurotransmission") SET Evidence = "Thus, tetrodotoxin shows exquisite selectivity, blocking Na+ channel isoforms with an aromatic residue in the first intracellular linker (phenylalanine 383 in Nav1.1, tyrosine 401 in Nav1.4, cysteine 374 in Nav1.5), but not channels in which a polar residue is present at this site(as in Nav1.8 and Nav1.9)" a(CHEBI:tetrodotoxin) -| p(HGNC:SCN1A) a(CHEBI:tetrodotoxin) -| p(HGNC:SCN4A) a(CHEBI:tetrodotoxin) -| p(HGNC:SCN5A) a(CHEBI:tetrodotoxin) causesNoChange p(HGNC:SCN10A) a(CHEBI:tetrodotoxin) causesNoChange p(HGNC:SCN11A) UNSET Subgraph SET Evidence = "Because Ca2+ serves as a messenger, Ca2+ channels have the unique ability among ion channels to couple membrane electrical events to diverse cellular functions, including exocytosis of neurotransmitters." SET Subgraph = "Calcium dependent subgraph" a(CHEBI:"calcium(2+)") -> bp(GOBP:exocytosis) a(CHEBI:"calcium(2+)") -> bp(GOBP:"regulation of calcium ion-dependent exocytosis of neurotransmitter") p(HGNC:CACNA1A) -> bp(GOBP:"regulation of calcium ion-dependent exocytosis of neurotransmitter") SET Evidence = "L-type channels have not been associated with epilepsy syndromes in mice or humans and are not considered to be targets for AEDs." SET Species = "10090" p(HGNC:CACNA1S) causesNoChange path(MESHD:Epilepsy) p(HGNC:CACNA1C) causesNoChange path(MESHD:Epilepsy) p(HGNC:CACNA1D) causesNoChange path(MESHD:Epilepsy) p(HGNC:CACNA1F) causesNoChange path(MESHD:Epilepsy) a(CHEBI:anticonvulsant) causesNoChange p(HGNC:CACNA1S) a(CHEBI:anticonvulsant) causesNoChange p(HGNC:CACNA1C) a(CHEBI:anticonvulsant) causesNoChange p(HGNC:CACNA1D) a(CHEBI:anticonvulsant) causesNoChange p(HGNC:CACNA1F) p(HGNC:CACNA1S) -> a(MESHC:"Calcium Channels, L-Type") p(HGNC:CACNA1C) -> a(MESHC:"Calcium Channels, L-Type") p(HGNC:CACNA1D) -> a(MESHC:"Calcium Channels, L-Type") p(HGNC:CACNA1F) -> a(MESHC:"Calcium Channels, L-Type") a(MESHC:"Calcium Channels, L-Type") causesNoChange path(MESHD:Epilepsy) a(CHEBI:anticonvulsant) causesNoChange a(MESHC:"Calcium Channels, L-Type") SET Evidence = "T-type Ca2+ channels are believed to be the targets of antiabsence agents such as ethosuximide, which weakly block native and recombinant T-type Ca2+ channel currents" p(HGNC:CACNA1G) -> bp(EPT:"generation of T-type calcium current") p(HGNC:CACNA1H) -> bp(EPT:"generation of T-type calcium current") p(HGNC:CACNA1I) -> bp(EPT:"generation of T-type calcium current") bp(EPT:"generation of T-type calcium current") -> path(MESHD:Epilepsy) a(CHEBI:ethosuximide) -| bp(EPT:"generation of T-type calcium current") SET Evidence = "The three recessive mutations in Cacna1a (Cav2.1) that produce absence-like syndromes in tottering, leaner and rocker mice all impair channel function, reducing P/Q-type Ca2+ currents" SET Species = "10090" g(HGNC:CACNA1A, var("?")) -> bp(EPT:"generation of P/Q-type calcium current") bp(EPT:"generation of P/Q-type calcium current") -> path(MESHD:Epilepsy) bp(EPT:"generation of P/Q-type calcium current") -> path(MESHD:"Epilepsy, Absence") SET Evidence = "In sum, a common factor in these six very different mouse syndromes expressing absence-like seizures is impaired function in presynaptic Ca2+ channels (P/Q-type) controlling neurotransmitter release" bp(GOBP:"regulation of calcium ion-dependent exocytosis of neurotransmitter") -- path(MESHD:"Epilepsy, Absence") SET Evidence = "Proteins involved in the SNARE complex that link P/Q-type Ca2+ channels to synaptic vesicle release (SNAP-25, syntaxin, synaptotagmin)82 play an essential role in neurotransmitter release." complex(p(HGNC:SNAP25), p(HGNC:CACNA1A)) -> bp(GOBP:"neurotransmitter secretion") complex(p(HGNC:STX1A), p(HGNC:CACNA1A)) -> bp(GOBP:"neurotransmitter secretion") complex(p(HGNC:SYT1), p(HGNC:CACNA1A)) -> bp(GOBP:"neurotransmitter secretion") SET Evidence = "In childhood absence epilepsy (CAE), 12 mutations involving CACNA1H (encoding the ‚ subunit Cav3.2) have been reported" SET Confidence = "High" g(HGNC:CACNA1H, var("?")) pos path(DO:"childhood absence epilepsy") UNSET Confidence SET Evidence = "Five mutations in EFHC1, a gene encoding a protein with an EF-hand motif, have been found in families with juvenile myoclonic epilepsy (JME).34 This protein associates with the R-type Ca2+ channel Cav2.3. EFHC1 increases R-type Ca2+ currents, but this activity is lost when the protein bears the mutations associated with JME." p(HGNC:EFHC1) -> bp(EPT:"generation of R-type calcium current") UNSET Subgraph SET Evidence = "A-currents and M-currents play important roles in regulating the excitability of neurons in brain regions relevant to epilepsy, such as the neocortex and the hippocampus" bp(EPT:"generation of A-type potassium current") -- path(MESHD:Epilepsy) bp(EPT:"generation of M-type potassium current") -- path(MESHD:Epilepsy) SET Confidence = "High" SET Evidence = "TABLE3" p(HGNC:LGI1) -- bp(EPT:"generation of potassium current") p(HGNC:KCNAB2) -- bp(EPT:"generation of potassium current") p(HGNC:KCNAB2) -- path(MESHD:Epilepsy) p(HGNC:KCNJ6) -- bp(EPT:"generation of potassium current") p(HGNC:KCNJ6) -- path(MESHD:Epilepsy) p(HGNC:KCNMA1) -- bp(EPT:"generation of potassium current") p(HGNC:KCNMA1) -- path(MESHD:Epilepsy) p(HGNC:KCNK9) -- bp(EPT:"generation of potassium current") p(HGNC:KCNK9) -- path(MESHD:Epilepsy) SET Evidence = "A second example of a mutation in a Kv subunit associated with epilepsy is in a developmental syndrome associated with a deletion on chromosome segment 1p36 that includes the auxiliary ‚àö√©¬¨‚â§2 subunit KCNAB2. Many of the individuals with this syndrome exhibit partial or generalized seizures and infantile spasms" SET Confidence = "High" g(HGNC:KCNAB2, var("?")) pos path(MESHD:"Epilepsies, Partial") g(HGNC:KCNAB2, var("?")) pos path(MESHD:"Epilepsy, Generalized") g(HGNC:KCNAB2, var("?")) pos path(MESHD:"Spasms, Infantile") UNSET Confidence SET Evidence = "The combination of KCNQ2 and KCNQ3 underlies the bulk of the M-current in neurons,121 although KCNQ5 alone or in combination with KCNQ3 can also contribute to M-current" complex(p(HGNC:KCNQ2), p(HGNC:KCNQ3)) -> bp(EPT:"generation of M-type potassium current") p(HGNC:KCNQ5) -> bp(EPT:"generation of M-type potassium current") complex(p(HGNC:KCNQ3), p(HGNC:KCNQ5)) -> bp(EPT:"generation of M-type potassium current") SET Evidence = "Blockade of SK channels with apamin can lead to epileptiform activity, at least in in vitro hippocampal slice preparations" a(MESHC:Apamin) -| p(HGNC:KCNN1) a(MESHC:Apamin) -| p(HGNC:KCNN2) a(MESHC:Apamin) -| p(HGNC:KCNN3) a(MESHC:Apamin) -> path(MESHD:Epilepsy) SET Evidence = "Conversely, enhancing SK channel activity with 1-ethyl-2-benzimidazolinone (EBIO), which activates all three SK channels, inhibits epileptiform activity in the hippocampal sl" a(CHEBI:"1-Ethyl-2-benzimidazolinone") -> p(HGNC:KCNN1) a(CHEBI:"1-Ethyl-2-benzimidazolinone") -> p(HGNC:KCNN2) a(CHEBI:"1-Ethyl-2-benzimidazolinone") -> p(HGNC:KCNN3) a(CHEBI:"1-Ethyl-2-benzimidazolinone") -| path(MESHD:Epilepsy) p(HGNC:KCNN1) -| path(MESHD:Epilepsy) p(HGNC:KCNN2) -| path(MESHD:Epilepsy) p(HGNC:KCNN3) -| path(MESHD:Epilepsy) SET Evidence = " For example, an association study linked a polymorphism in KCNJ3 with absence seizures" SET Confidence = "High" g(HGNC:KCNJ3, var("?")) -> path(MESHD:"Epilepsy, Absence") SET Evidence = "Classical pharmacological antagonists of Kv channels include 4-aminopyridine (4-AP), which is commonly used to induce seizures in rodent models23 and brain slices132 and is a blocker of Kv1, Kv3, and Kv4 channels." SET Species = "10090" a(CHEBI:"4-aminopyridine") -| p(HGNC:KCNA1) a(CHEBI:"4-aminopyridine") -| p(HGNC:KCNC1) a(CHEBI:"4-aminopyridine") -| p(HGNC:KCND1) a(CHEBI:"4-aminopyridine") -> path(MESHD:Seizures) SET Evidence = "The second class of K+ channel opener to be described is one that acts selectively on neuronal KCNQ (M-current) channels." p(HGNC:KCNQ1) -> bp(EPT:"generation of M-type potassium current") p(HGNC:KCNQ2) -> bp(EPT:"generation of M-type potassium current") p(HGNC:KCNQ3) -> bp(EPT:"generation of M-type potassium current") p(HGNC:KCNQ4) -> bp(EPT:"generation of M-type potassium current") p(HGNC:KCNQ5) -> bp(EPT:"generation of M-type potassium current") SET Evidence = "retigabine ... three research groups independently demonstrated that the current affected was the M-current carried by Kv7.2 or Kv7.3 (whose channels are encoded by KCNQ2 and KCNQ3, respectively)" a(CHEBI:ezogabine) -- bp(EPT:"generation of M-type potassium current") SET Evidence = " confirming that opening of KCNQ channels per se is an anticonvulsant mechanism." p(HGNC:KCNQ1) -| path(MESHD:Epilepsy) p(HGNC:KCNQ2) -| path(MESHD:Epilepsy) p(HGNC:KCNQ3) -| path(MESHD:Epilepsy) p(HGNC:KCNQ4) -| path(MESHD:Epilepsy) p(HGNC:KCNQ5) -| path(MESHD:Epilepsy) SET Evidence = "The hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channels are Na+-permeable and K+ -permeable channels that participate in pacemaker currents in cardiac cells and neurons" p(HGNC:HCN1) -- a(CHEBI:"sodium(1+)") p(HGNC:HCN2) -- a(CHEBI:"sodium(1+)") p(HGNC:HCN3) -- a(CHEBI:"sodium(1+)") p(HGNC:HCN4) -- a(CHEBI:"sodium(1+)") p(HGNC:HCN1) -- a(CHEBI:"potassium(1+)") p(HGNC:HCN2) -- a(CHEBI:"potassium(1+)") p(HGNC:HCN3) -- a(CHEBI:"potassium(1+)") p(HGNC:HCN4) -- a(CHEBI:"potassium(1+)") SET Evidence = "The channels are opened by hyperpolarization to negative membrane potentials" bp(GOBP:"membrane hyperpolarization") -> p(HGNC:HCN1) bp(GOBP:"membrane hyperpolarization") -> p(HGNC:HCN2) bp(GOBP:"membrane hyperpolarization") -> p(HGNC:HCN3) bp(GOBP:"membrane hyperpolarization") -> p(HGNC:HCN4) SET Evidence = "In addition, they are also modulated by cAMP binding to a consensus cyclic nucleotide binding domain in the carboxy terminus. Binding of cAMP shifts the voltage dependence of activation to more positive potentials; it can also directly open the channels." a(MESHC:"Cyclic AMP") -> p(HGNC:HCN1) a(MESHC:"Cyclic AMP") -> p(HGNC:HCN2) a(MESHC:"Cyclic AMP") -> p(HGNC:HCN3) a(MESHC:"Cyclic AMP") -> p(HGNC:HCN4) SET Evidence = "A role for HCN channels in epilepsy has been widely proposed, but the evidence is complex." p(HGNC:HCN1) -- path(MESHD:Epilepsy) p(HGNC:HCN2) -- path(MESHD:Epilepsy) p(HGNC:HCN3) -- path(MESHD:Epilepsy) p(HGNC:HCN4) -- path(MESHD:Epilepsy) SET Evidence = "In mice, deletion of the HCN2 subunit produces animals with 5-Hz spike-and-wave discharges and absence-like seizures" SET Confidence = "High" SET Species = "10090" g(HGNC:HCN2, var("del")) pos path(MESHD:"Epilepsy, Absence") UNSET Species SET Evidence = "In recordings from hippocampal or cortical neurons, the current produced by opening of the HCN channels is referred to as Ih" p(HGNC:HCN1) -> bp(EPT:"generation of Ih current") p(HGNC:HCN2) -> bp(EPT:"generation of Ih current") p(HGNC:HCN3) -> bp(EPT:"generation of Ih current") p(HGNC:HCN4) -> bp(EPT:"generation of Ih current") SET Evidence = "In addition, changes in Ih and in HCN subunit expression have been observed in epileptogenesis." g(HGNC:HCN1) -> bp(EPT:epileptogenesis) g(HGNC:HCN2) -> bp(EPT:epileptogenesis) g(HGNC:HCN3) -> bp(EPT:epileptogenesis) g(HGNC:HCN4) -> bp(EPT:epileptogenesis) SET Evidence = "ZD-7288, a blocker of HCN channels, inhibits spontaneous epileptiform bursting in the hippocampal slice, confirming the potential of Ih inhibition as an anticonvulsant approach" a(MESHC:"ICI D2788") -| p(HGNC:HCN1) a(MESHC:"ICI D2788") -| p(HGNC:HCN2) a(MESHC:"ICI D2788") -| p(HGNC:HCN3) a(MESHC:"ICI D2788") -| p(HGNC:HCN4) a(MESHC:"ICI D2788") -| path(MESHD:Epilepsy) SET Evidence = "rugs targeting HCN1 might be relevant for limbic seizures, whereas those affecting HCN2 may be more relevant to absence epilepsy" p(HGNC:HCN1) -- path(MESHD:"Epilepsy, Temporal Lobe") SET Evidence = "In rat hippocampal pyramidal neurons, lamotrigine has been reported to decrease dendritic excitability by increasing Ih" SET Species = "10116" SET MeSHAnatomy = "Hippocampus" SET Cell = "pyramidal neuron" a(CHEBI:lamotrigine) -> bp(EPT:"generation of Ih current") bp(EPT:"generation of Ih current") -| path(MESHD:Seizures) UNSET Cell UNSET MeSHAnatomy UNSET Species SET Evidence = "ClC-2 is a plasma membrane channel activated by hyperpolarization, cell swelling and extracellular acidification" bp(GOBP:"membrane hyperpolarization") -> p(HGNC:CLCN2) SET Evidence = "ClC-2 knockout mice do not have epilepsy" SET Species = "10090" p(HGNC:CLCN2) causesNoChange path(MESHD:Epilepsy) UNSET Species SET Evidence = "n humans, however, ClC-2 mutations cosegregated in three families with various idiopathic generalized epilepsy syndromes, including JME, juvenile absence epilepsy, CAE, and epilepsy with grand mal seizures on awakening (EGMA)." SET Confidence = "High" g(HGNC:CLCN2, var("?")) pos path(MESHD:"Epilepsy, Generalized") g(HGNC:CLCN2, var("?")) pos path(DO:"juvenile absence epilepsy") g(HGNC:CLCN2, var("?")) pos path(DO:"childhood absence epilepsy") UNSET Confidence SET Evidence = "In any case, it has been proposed that the epilepsy-associated ClC-2 mutations may lead to alterations in the Cl‚àö¬¢√Ä√ú‚Äö√Ñ√¥ gradient in neurons such that GABAA-mediated inhibition is impaired or may even become excitatory." SET Subgraph = {"GABA subgraph", "Neurotransmitter release subgraph"} p(HGNC:CLCN2) -- bp(PTS:"gamma_aminobutyric acid signaling pathway") p(HGNC:CLCN2) -- a(CHEBI:"GABA agent") SET Evidence = "The importance of these transporters in the regulation of seizure susceptibility is highlighted by the seizure phenotypes of mice deficient in KCC2, a neuronal electroneutral K+ and Cl‚àö¬¢√Ä√ú‚Äö√Ñ√¥ cotransporter that drives intracellular Cl‚àö¬¢√Ä√ú‚Äö√Ñ√¥ to low concentrations and shifts the reversal potential for GABAA and glycine receptors so that the channels are hyperpolarizing. Mice lacking KCC2 exhibit severe seizures and die shortly after birth whereas those in which KCC2 has been reduced by 80‚àö¬¢‚Äö√ᬮ‚Äö√Ñ√∫85% show enhanced susceptibility to PTZ seizures." SET Species = "10090" p(HGNC:SLC12A5) -- bp(PTS:"gamma_aminobutyric acid signaling pathway") p(HGNC:SLC12A5) -- a(CHEBI:"GABA agent") p(HGNC:SLC12A5) -| path(MESHD:Seizures) UNSET Species SET Evidence = "TABLE 4: GABRA1, GABRA2, GABRA3, GABRA5 ‚àö√©¬¨¬±1, ‚àö√©¬¨¬±2, ‚, ‚àö√©¬¨¬±5 JME (‚àö√©¬¨¬±1 A322D), GABRG2 GEFS+, CAE GABRD GEFS+" g(HGNC:GABRA1) -> path(MESHD:"Myoclonic Epilepsy, Juvenile") g(HGNC:GABRA2) -> path(MESHD:"Myoclonic Epilepsy, Juvenile") g(HGNC:GABRA3) -> path(MESHD:"Myoclonic Epilepsy, Juvenile") g(HGNC:GABRA5) -> path(MESHD:"Myoclonic Epilepsy, Juvenile") g(HGNC:GABRA4) -> path(MESHD:Epilepsy) g(HGNC:GABRA6) -> path(MESHD:Epilepsy) g(HGNC:GABRG2) -> path(DO:"generalized epilepsy with febrile seizures plus") g(HGNC:GABRG2) -> path(DO:"childhood absence epilepsy") g(HGNC:GABRD) -> path(DO:"generalized epilepsy with febrile seizures plus") SET Evidence = "Benzodiazepines act as positive allosteric modulators of sensitive isoforms. High concentrations of barbiturates, propofol, etomidate, neurosteroids and topiramate directly activate GABAA receptors, whereas benzodiazepines and felbamate do not." a(CHEBI:barbiturate) => p(HGNC:GABRA1) a(CHEBI:propofol) => p(HGNC:GABRA1) a(CHEBI:etomidate) => p(HGNC:GABRA1) a(CHEBI:topiramate) => p(HGNC:GABRA1) a(MESHC:Benzodiazepines) -> p(HGNC:GABRA1) a(CHEBI:felbamate) -> p(HGNC:GABRA1) SET Evidence = "Therefore, drugs that selectively target GABAA receptors containing ‚àö√©¬¨¬±2 or ‚ can be expected to avoid sedative side effects." p(HGNC:GABRA2) -| path(MESHD:Seizures) p(HGNC:GABRA2) causesNoChange a(CHEBI:sedative) p(HGNC:GABRA3) -| path(MESHD:Seizures) p(HGNC:GABRA3) causesNoChange a(CHEBI:sedative) SET Evidence = "Those that block the action of GABA or allosterically inhibit receptor function (as with benzodiazepine site inverse agonists such as DMCM [methyl-6,7-dimethoxy-4-ethyl-‚àö√©¬¨‚â§-carboline-3-carboxylate]) are proconvulsant" a(MESHC:"methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate") -| p(HGNC:GABRA1) a(MESHC:"methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate") -| bp(PTS:"gamma_aminobutyric acid signaling pathway") a(MESHC:"methyl 6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate") -> path(MESHD:Seizures) SET Evidence = "Substantial effort has been devoted to obtaining GABAA receptor positive allosteric modulators that have reduced activity on GABA receptors containing ‚àö√©¬¨¬±1 subunits, to avoid the sedation that is believed to be mediated by these receptors." a(CHEBI:sedative) -> p(HGNC:GABRA1) SET Evidence = "For example, TPA023 [7-(1,1-dimeth-ylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3- (2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine], which selectively modulates ‚àö√©¬¨¬±2- or ‚-containing receptors, is anxiolytic yet not sedating in rodents" SET Species = "10116" a(MESHC:"TPA-023-B") -| path(DO:"anxiety disorder") a(MESHC:"TPA-023-B") isA a(CHEBI:"anxiolytic drug") a(MESHC:"TPA-023-B") causesNoChange a(CHEBI:sedative) a(MESHC:"TPA-023-B") -> p(HGNC:GABRA2) a(MESHC:"TPA-023-B") -> p(HGNC:GABRA3) SET Evidence = "ELB139 [1-(4-chlorophenyl)-4-piperidin-1-yl-1,5-dihydro-imidazol-2-on], which is selective for -containing receptors, also has anxiolytic and anticonvulsant properties but is non-sedating in rodents." SET Species = "10090" a(MESHC:"1-(4-chlorophenyl)-4-piperidin-1-yl-1,5-dihydroimidazol-2-one") -> p(HGNC:GABRA3) a(MESHC:"1-(4-chlorophenyl)-4-piperidin-1-yl-1,5-dihydroimidazol-2-one") -| path(DO:"anxiety disorder") a(MESHC:"1-(4-chlorophenyl)-4-piperidin-1-yl-1,5-dihydroimidazol-2-one") -| path(MESHD:Epilepsy) a(MESHC:"1-(4-chlorophenyl)-4-piperidin-1-yl-1,5-dihydroimidazol-2-one") isA a(CHEBI:"anxiolytic drug") a(MESHC:"1-(4-chlorophenyl)-4-piperidin-1-yl-1,5-dihydroimidazol-2-one") isA a(CHEBI:anticonvulsant) a(MESHC:"1-(4-chlorophenyl)-4-piperidin-1-yl-1,5-dihydroimidazol-2-one") causesNoChange a(CHEBI:sedative) UNSET Species UNSET Subgraph SET Evidence = "Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), characterized by partial seizures that occur predominantly during sleep,211 has been associated in some families with mutations involving either the beta or ≈í‚⧠subunit in beta4≈í‚â§2 nicotinic acetylcholine receptors" SET Confidence = "High" g(HGNC:CHRNA4, var("?")) pos path(MESHD:"Epilepsy, Frontal Lobe") g(HGNC:CHRNB2, var("?")) pos path(MESHD:"Epilepsy, Frontal Lobe") UNSET Confidence SET Evidence = "A common feature of the ADNFLE mutations is that they reduce Ca2+ potentiation of the beta nicotinic receptor response to acetylcholine" p(HGNC:CHRNA4) -- a(CHEBI:"calcium(2+)") p(HGNC:CHRNB2) -- a(CHEBI:"calcium(2+)") p(HGNC:CHRNA4) -> bp(GOBP:"calcium ion homeostasis") p(HGNC:CHRNB2) -> bp(GOBP:"calcium ion homeostasis") SET Evidence = "Whatever the underlying mechanism, the clinical syndrome of ADNFLE is known to respond well to carbamazepine and topiramate" a(CHEBI:carbamazepine) -| path(MESHD:"Epilepsy, Frontal Lobe") a(CHEBI:topiramate) -| path(MESHD:"Epilepsy, Frontal Lobe") SET Evidence = "Carbamazepine is a noncompetitive inhibitor of nicotinic receptors that blocks acetylcholine-evoked currents at concentrations in the therapeutic rang" a(CHEBI:carbamazepine) -| bp(GOBP:"acetylcholine secretion, neurotransmission") a(CHEBI:carbamazepine) -| p(HGNC:CHRNA1) SET Evidence = "Several endogenous ligands including glycine, taurine, or betaine are able to open glycine receptors" a(CHEBI:glycine) -> p(HGNC:GLRA1) a(CHEBI:taurine) -> p(HGNC:GLRA1) a(MESHC:Betaine) -> p(HGNC:GLRA1) SET Evidence = "Glycine receptors are positively modulated by volatile anesthetics, n-alcohols (including ethanol), and chloral derivatives" a(MESHC:Anesthetics) -> p(HGNC:GLRA1) a(CHEBI:alcohol) -> p(HGNC:GLRA1) SET Evidence = "Strychnine is a powerful selective antagonist of glycine receptors that binds selectively to glycinergic synapses" a(CHEBI:strychnine) -| p(HGNC:GLRA1) SET Evidence = "Strychnine induces convulsions with fierce contractions of skeletal musculature" a(CHEBI:strychnine) -> path(MESHD:Seizures) SET Evidence = "no human epilepsy syndromes have been associated with glycine receptors." SET Species = "9606" g(HGNC:GLRA1) causesNoChange path(MESHD:Epilepsy) UNSET Species SET Evidence = "The ionotropic glutamate receptors are a superfamily of ligand-gated cation channels that encompass three receptor families identified by the agonists that selectively activate them: AMPA, kainate, and NMDA." a(MESHC:"aminomethylphosphonic acid") -> p(HGNC:GRIA1) a(MESHC:"Kainic Acid") -> p(HGNC:GRIK1) a(CHEBI:"N-methyl-D-aspartic acid") -> p(HGNC:GRIN1) SET Evidence = "Neurotransmitter glutamate serves to activate all ionotropic glutamate receptors at synapses. However, NMDA receptors require the presence of a coagonist, either glycine or D-serine." a(MESHC:Glutamates) -> p(HGNC:GRIA1) a(MESHC:Glutamates) -> p(HGNC:GRIK1) complex(a(MESHC:Glutamates), a(CHEBI:glycine), a(CHEBI:"D-serine")) -> p(HGNC:GRIN1) SET Evidence = "An important special functional property of NMDA receptors is that they are blocked in a voltage-dependent fashion by Mg2+, such that the open channels are largely impermeable to ion flow at negative membrane potentials near the resting potential " a(CHEBI:"magnesium(2+)") -| p(HGNC:GRIN1) bp(GOBP:"regulation of resting membrane potential") -| p(HGNC:GRIN1) SET Evidence = "The requirement for membrane depolarization in addition to glutamate signaling is considered to be the coincidence detector of Hebbian learning; it may also be important in epileptogenesis." p(HGNC:GRIN1) -| bp(EPT:epileptogenesis) p(HGNC:GRIN1) -| path(MESHD:Seizures) SET Evidence = "Systemic or intracerebroventricular administration of AMPA elicits robust seizure activity, demonstrating a role for AMPA receptors in triggering or mediating seizures" a(MESHC:"aminomethylphosphonic acid") -> path(MESHD:Seizures) p(HGNC:GRIA1) -- path(MESHD:Seizures) SET Evidence = "ilarly, pharmacological antagonists of AMPA receptors are protective in diverse animal seizure models, raising the possibility that AMPA receptor antagonists could be useful in epilepsy therap" a(CHEBI:"AMPA receptor antagonist") -| p(HGNC:GRIA1) a(CHEBI:"AMPA receptor antagonist") -| path(MESHD:Seizures) a(CHEBI:"AMPA receptor antagonist") isA a(CHEBI:anticonvulsant) SET Evidence = "n epileptogenesis models in which a susceptibility to spontaneous seizures is triggered by status epilepticus, however, AMPA receptor antagonists can have antiepileptogenic activity, if only by virtue of their ability to powerfully suppress the seizures" a(CHEBI:"AMPA receptor antagonist") -| bp(EPT:epileptogenesis) a(CHEBI:"AMPA receptor antagonist") -| path(MESHD:"Status Epilepticus") SET Evidence = "equently, noncompetitive NMDA antagonists such as MK-801 (dizocilpine), glycine site antagonists (such as HA-966) and NR2B site antagonists (such as ifenprodil) were all shown to possess protective activity in some rodent models" SET Species = "10090" a(CHEBI:Dizocilpine) isA a(CHEBI:"NMDA receptor antagonist") a(CHEBI:Dizocilpine) -| path(MESHD:Seizures) #a(1232) isA a(CHEBI:"NMDA receptor antagonist") #a(1232) -| path(MESHD:Seizures) SET Evidence = "The first selective AMPA receptor antagonists to be identified were quinoxalinedione derivatives (such as NBQX)" a(CHEBI:"2,3-Dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline") isA a(CHEBI:"AMPA receptor antagonist") a(CHEBI:"2,3-Dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline") -| path(MESHD:Seizures) SET Evidence = "The high-affinity, water-soluble competitive antagonist NS1209 (which blocks AMPA and GluR5 kainate receptors)255 is effective in animal models of status epilepticus and prevents the development of spontaneous seizure" ############################################################ # Reelin signaling SET Citation = {"PubMed", "J Neurosci. 2007 Feb 21;27(8):1803-11.", "17314278"} SET Evidence = "Dentate granule cell (DGC) neurogenesis persists throughout life in the mammalian hippocampal dentate gyrus and increases after epileptogenic insults" a(BRCO:"Dentate_gyrus_granule_cell") -- bp(EPT:epileptogenesis) a(BRCO:"Dentate_gyrus_granule_cell") -- path(MESHD:Epilepsy) SET Evidence = "Reelin is a secreted migration guidance cue that persists in the adult rodent and human hippocampus. We tested the hypothesis that loss of Reelin in the epileptic dentate gyrus leads to aberrant chain migration of DGC precursors" SET Species = "10090" SET Subgraph = "Reelin signaling subgraph" p(HGNC:RELN) -- a(BRCO:"Dentate_gyrus_granule_cell") p(HGNC:RELN) -| bp(EPT:epileptogenesis) SET Evidence = "We found that interneuron subsets typically lost in human and experimental mTLE express Reelin, and DGC progenitors express the downstream Reelin signaling molecule Disabled 1 (Dab1)." path(MESHD:"Epilepsy, Temporal Lobe") -| a(BRCO:"Dentate_gyrus_trilaminar_interneuron") a(BRCO:"Dentate_gyrus_trilaminar_interneuron") -> p(HGNC:RELN) bp(PTS:"Reelin signaling pathway") -> p(HGNC:DAB1) p(HGNC:RELN) -- p(HGNC:DAB1) SET Evidence = "Prolonged seizures decreased Reelin immunoreactivity in the adult rat dentate gyrus and increased Dab1 expression in hilar-ectopic neuroblasts" SET Species = "10116" path(MESHD:Seizures) -| act(p(HGNC:RELN)) path(MESHD:Seizures) -> p(HGNC:DAB1) SET Evidence = "Reelin binds to the apolipoprotein E receptor 2 (ApoER2) and very low density lipoprotein receptor (VLDLR) expressed on neurons or radial glia (D'Arcangelo et al., 1999; Hiesberger et al., 1999; Trommsdorff et al., 1999; Luque et al., 2003). Binding and internalization leads to phosphorylation, downstream signaling, and subsequent degradation of the adaptor protein Disabled 1 (Dab1)" complex(p(HGNC:RELN), p(HGNC:LRP8), p(HGNC:VLDLR)) -> bp(PTS:"Reelin signaling pathway") complex(p(HGNC:RELN), p(HGNC:LRP8), p(HGNC:VLDLR)) -> p(HGNC:DAB1, pmod(P)) p(HGNC:DAB1, pmod(P)) -| p(HGNC:DAB1) complex(p(HGNC:RELN), p(HGNC:LRP8), p(HGNC:VLDLR)) -> deg(p(HGNC:DAB1)) UNSET Subgraph ##################################################### # Reelin signaling SET Citation = {"PubMed", "Neuropathol Appl Neurobiol. 2004 Jun;30(3):225-32.", "15175076"} SET Evidence = "Here, we have analysed two major components of the reelin pathway involved in neuronal migration and cortical development, that is, p35 and disabled-1 (dab1), in gangliogliomas." SET Subgraph = "Reelin signaling subgraph" p(HGNC:DAB1) -> bp(GOBP:"neuron migration") p(HGNC:DAB1) -> bp(GOBP:"cerebral cortex development") p(HGNC:CDK5R1) -> bp(PTS:"Reelin signaling pathway") p(HGNC:CDK5R1) -> bp(GOBP:"neuron migration") p(HGNC:CDK5R1) -> bp(GOBP:"cerebral cortex development") SET Evidence = "However, significantly lower levels of dab1 and p35 gene transcripts were detected in gangliogliomas compared to controls " path(MESHD:Ganglioglioma) negativeCorrelation p(HGNC:DAB1) path(MESHD:Ganglioglioma) negativeCorrelation p(HGNC:CDK5R1) SET Evidence = "A growing body of experimental studies suggests an involvement of developmental mechanisms in the pathogenesis of focal epilepsies [1]. The reelin signal transduction pathway represents an interesting candidate." bp(PTS:"Reelin signaling pathway") -- path(DO:"focal epilepsy") SET Evidence = "It has been associated with neuronal development, cellular morphology, cytoskeletal formation, synaptic plasticity and neurodegeneration" bp(PTS:"Reelin signaling pathway") -- bp(GOBP:"neuron development") bp(PTS:"Reelin signaling pathway") -- bp(GOBP:"cell morphogenesis") bp(PTS:"Reelin signaling pathway") -- bp(GOBP:"regulation of neuronal synaptic plasticity") bp(PTS:"Reelin signaling pathway") -- bp(GOBP:"cytoskeleton organization") bp(PTS:"Reelin signaling pathway") -- path(MESHD:"Neurodegenerative Diseases") UNSET Subgraph SET Evidence = "Moleculargenetic studies have provided first hints for an involvement of developmentally regulated genes such as TSC1/2, CDK5 and doublecortin in the molecular pathogenesis of focal cortical dysplasias as well as gangliogliomas" p(HGNC:TSC1) -- path(DO:"focal epilepsy") p(HGNC:TSC1) -- path(MESHD:Ganglioglioma) p(HGNC:TSC2) -- path(DO:"focal epilepsy") p(HGNC:TSC2) -- path(MESHD:Ganglioglioma) p(HGNC:CDK5) -- path(DO:"focal epilepsy") p(HGNC:CDK5) -- path(MESHD:Ganglioglioma) p(HGNC:DCX) -- path(DO:"focal epilepsy") p(HGNC:DCX) -- path(MESHD:Ganglioglioma) SET Evidence = "The cdk5 kinase and its neuronal activator p35 are intracellular downstream components of the reelin signalling cascade." SET Subgraph = "Reelin signaling subgraph" bp(PTS:"Reelin signaling pathway") -> p(HGNC:CDK5) bp(PTS:"Reelin signaling pathway") -> p(HGNC:CDK5R1) SET Evidence = "In mice lacking p35, severe cortical dyslamination can be observed" SET Species = "10090" p(HGNC:CDK5R1) -| bp(GOBP:delamination) SET Evidence = "Signals for cdk5/ p35 are transduced by disabled-1 (dab1), a cytoplasmic kinase. Binding of reelin to the plasma membrane Apolipoprotein E receptor results in dab1 phosphorylation" p(HGNC:DAB1, pmod(P)) -> act(p(HGNC:CDK5)) p(HGNC:DAB1, pmod(P)) -> act(p(HGNC:CDK5R1)) SET Evidence = "This hypothesis is further substantiated by the previously reported finding that the reelin pathway components doublecortin and CDK5 also show reduced expression levels in gangliogliomas compared to unaffected brain tissue [2]." path(MESHD:Ganglioglioma) negativeCorrelation p(HGNC:CDK5) path(MESHD:Ganglioglioma) negativeCorrelation p(HGNC:DCX) UNSET Subgraph ####################################################### # Reelin signaling SET Citation = {"PubMed", "Acta Neuropathol. 2002 Oct;104(4):403-8. Epub 2002 Jun 19.", "12200628"} SET Evidence = "Here, we have analyzed two major components of the reelin pathway associated with neuronal migration and cortical cytoarchitecture in gangliogliomas, i.e., cyclin-dependent kinase 5 (CDK5) and doublecortin (DCX)" SET Subgraph = "Reelin signaling subgraph" p(HGNC:CDK5) -> bp(PTS:"Reelin signaling pathway") p(HGNC:DCX) -> bp(PTS:"Reelin signaling pathway") p(HGNC:CDK5) -> bp(GOBP:"neuron migration") p(HGNC:DCX) -> bp(GOBP:"neuron migration") SET Evidence = "While the mutational analysis of CDK5 and DCX did not reveal any sequence alterations in gangliogliomas, a lower expression was observed for both genes in tumor compared to control tissue samples." SET MeSHDisease = "Neoplasms" path(MESHD:Ganglioglioma) negativeCorrelation p(HGNC:CDK5) path(MESHD:Ganglioglioma) negativeCorrelation p(HGNC:DCX) SET Evidence = "Functional loss of CDK5 results in impairment not only of neuronal movement but also differentiation" p(HGNC:CDK5) -> bp(GOBP:"neuron differentiation") p(HGNC:CDK5) -> bp(GOBP:"neuron migration") SET Evidence = "CDK5 interaction with its activatorprotein p35 is essential for proper microtubulus assembly" p(HGNC:CDK5R1) -> act(p(HGNC:CDK5)) UNSET Subgraph SET Evidence = "By complex formation with p25, the active form of p35, CDK5 induces cytoskeletal interruption and apoptosis" SET Subgraph = {"Apoptosis signaling subgraph", "Reelin signaling subgraph"} complex(p(HGNC:CDK5R1), p(HGNC:CDK5)) -> bp(GOBP:"apoptotic process") UNSET Subgraph SET Evidence = "At this point, it remains unclear whether down-regulation of DCX and CDK5 mRNA underlies the observed lower expression of both genes in gangliogliomas compared to controls" SET Subgraph = "Reelin signaling subgraph" path(MESHD:Ganglioglioma) negativeCorrelation r(HGNC:CDK5) path(MESHD:Ganglioglioma) negativeCorrelation r(HGNC:DCX) SET Evidence = "A second potential mechanism for reduction of CDK5 and DCX transcript levels in gangliogliomas would involve lack of reelin pathway signaling. A recent study shows that impaired function of more than a single component in the reelin signaling cascade results in a synergistically negative effect on positioning of cortical neurons in the developing mouse brain" path(MESHD:Ganglioglioma) -| bp(PTS:"Reelin signaling pathway") UNSET Subgraph ####################################### # Reelin signaling SET Citation = {"PubMed", "Annu Rev Neurosci. 2001;24:1005-39.", "11520926"} SET Evidence = "Several neuronal populations throughout the brain secrete Reelin, which binds to transmembrane receptors located on adjacent cells triggering a tyrosine kinase cascade." SET Subgraph = {"Reelin signaling subgraph", "protein kinase signaling subgraph"} p(HGNC:RELN) -> bp(PTS:"protein kinase signaling pathway") UNSET Subgraph SET Evidence = "Recent studies have also suggested a role for the Reelin pathway in axonal braSCOMPing, synaptogenesis, and pathology underlying neurodegeneration" SET Subgraph = "Reelin signaling subgraph" bp(PTS:"Reelin signaling pathway") -> bp(GOBP:"axon development") bp(PTS:"Reelin signaling pathway") -> bp(GOBP:"synapse assembly") SET Evidence = "Binding of Reelin to lipoprotein receptors induces tyrosine phosphorylation of Dab1 (Howell et al 1999a), triggering an intracellular signaling cascade that instructs neurons to occupy their proper locations in the developing central nervous system (CNS)." complex(p(HGNC:RELN), p(HGNC:LRP8), p(HGNC:VLDLR)) -> p(HGNC:DAB1, pmod(P, T)) p(HGNC:DAB1, pmod(P,T)) -> bp(GOBP:"neuron migration") SET Evidence = "TABLE 1 Mouse genes implicated, genetically or biochemically, in the Reelin signaling pathway: ApoE ApolipoproteinE Bdnf Brain-derived neurotrophic factor Reln Reelin ApoER2 Apolipoprotein E receptor 2 CNR Cadherin-related neuronal receptor itga3 ¬¨√Ü3 integrin PS-1 Presenilin-1 Vldlr Very low‚Äö√Ñ√¨density lipoprotein receptor Abl Abelson proto-oncogene CASK Membrane-associated guanylate kinase Cdk5 Cyclin-dependent kinase 5 Cdk5r p35 Dab-1 Disabled 1 Src Src proto-oncogene Emx2 Related to empty spiracles P73 Transformation-related protein 73 Tbr-1 T-box brain-1" SET Species = "10090" p(RGD:Apoe) -> bp(PTS:"Reelin signaling pathway") p(RGD:Bdnf) -> bp(PTS:"Reelin signaling pathway") p(RGD:Reln) -> bp(PTS:"Reelin signaling pathway") p(RGD:Lrp8) -> bp(PTS:"Reelin signaling pathway") p(RGD:Cdhr1) -> bp(PTS:"Reelin signaling pathway") p(RGD:Itga3) -> bp(PTS:"Reelin signaling pathway") p(RGD:Psen1) -> bp(PTS:"Reelin signaling pathway") p(RGD:Vldlr) -> bp(PTS:"Reelin signaling pathway") p(RGD:Abl1) -> bp(PTS:"Reelin signaling pathway") p(RGD:Cask) -> bp(PTS:"Reelin signaling pathway") p(RGD:Cdk5) -> bp(PTS:"Reelin signaling pathway") p(RGD:Cdk5r1) -> bp(PTS:"Reelin signaling pathway") p(RGD:Dab1) -> bp(PTS:"Reelin signaling pathway") p(RGD:Src) -> bp(PTS:"Reelin signaling pathway") p(RGD:Emx1) -> bp(PTS:"Reelin signaling pathway") p(RGD:Tp73) -> bp(PTS:"Reelin signaling pathway") p(RGD:Tbr1) -> bp(PTS:"Reelin signaling pathway") UNSET Subgraph SET Evidence = "Tyrosine phosphorylation of Dab1 promotes an interaction with several nonreceptor tyrosine kinases, including Src, Fyn, and Abl through their SH2 domains, implying Dab1 functions in kinase signaling cascades during development" SET Subgraph = {"Reelin signaling subgraph", "protein kinase signaling subgraph"} complex(p(RGD:Dab1, pmod(P, T)), p(RGD:Src)) -> bp(PTS:"protein kinase signaling pathway") complex(p(RGD:Dab1, pmod(P, T)), p(RGD:Fyn)) -> bp(PTS:"protein kinase signaling pathway") complex(p(RGD:Dab1, pmod(P, T)), p(RGD:Abl1)) -> bp(PTS:"protein kinase signaling pathway") UNSET Subgraph SET Evidence = "However, the cell plate does not form in mice lacking reelin or Dab1" SET Species = "10090" SET Subgraph = "Reelin signaling subgraph" p(RGD:Dab1) -> a(BRCO:"Purkinje_cell_layer_of_cerebellar_cortex") p(RGD:Reln) -> a(BRCO:"Purkinje_cell_layer_of_cerebellar_cortex") bp(PTS:"Reelin signaling pathway") -- a(BRCO:"Purkinje_cell_layer_of_cerebellar_cortex") UNSET Species SET Evidence = "Reelin is produced by cells in the ntz and egl, implying that one or both sources could provide a signal to Purkinje cells. Recent genetic evidence suggests that both sources of Reelin are required for the proper positioning of Purkinje cells." a(BRCO:"Dentate_gyrus_granule_cell_layer_outer_blade") -> p(HGNC:RELN) a(BRCO:"Dentate_gyrus_granule_cell_layer_outer_blade") -- a(BRCO:"Purkinje_cell_layer_of_cerebellar_cortex") SET Evidence = "Mice with a targeted disruption of Math-1 fail to form an egl, and consequently the cerebellum lacks granule cells" SET Species = "10090" p(RGD:Atoh1) -> a(BRCO:"Dentate_gyrus_granule_cell_layer_outer_blade") a(BRCO:"Dentate_gyrus_granule_cell_layer_outer_blade") -> a(BRCO:"Cerebellum_granule_cell") SET Evidence = "Moreover, Dab1 levels are elevated in mice that lack both Vldlr and ApoER2, implying that signaling through Reelin and the lipoprotein receptors results in increased turnover of Dab1." p(RGD:Vldlr) negativeCorrelation p(RGD:Dab1) p(RGD:Lrp8) negativeCorrelation p(RGD:Dab1) UNSET Species SET Evidence = "Recently, Reelin was suggested to bind alpha3beta1 integrin, resulting in an alteration in neuronal migration in vitro" complex(p(HGNC:RELN), p(HGNC:ITGA3), p(HGNC:ITGB1)) -> bp(GOBP:"neuron migration") SET Evidence = "Interestingly, alpha3 integrin does not appear to be required for the Reelin-induced tyrosine phosphorylation of Dab1 in primary neurons (Dulabon et al 2000). This implies that the kinase activity associated with Reelin binding to the lipoprotein receptors on neurons is independent of integrin signaling." p(HGNC:ITGA3) causesNoChange p(HGNC:DAB1, pmod(P, T)) bp(PTS:"integrin mediated signaling pathway") causesNoChange p(HGNC:DAB1, pmod(P, T)) p(HGNC:ITGA3) causesNoChange complex(p(HGNC:RELN), p(HGNC:VLDLR), p(HGNC:LRP8)) SET Evidence = "A recent study has indicated that increased levels of tau phosphorylation can be detected in mice deficient in reelin or both Vldlr and ApoER2" SET Species = "10090" SET Confidence = "High" p(HGNC:RELN) negativeCorrelation p(HGNC:MAPT, pmod(P)) complex(p(HGNC:LRP8), p(HGNC:VLDLR)) negativeCorrelation p(HGNC:MAPT, pmod(P)) p(HGNC:MAPT, pmod(P)) -> path(MESHD:"Neurodegenerative Diseases") UNSET Species SET Evidence = "Several protein kinases have been implicated in tau hyperphosphorylation, including Cdk5." SET Confidence = "High" p(HGNC:CDK5) -> p(HGNC:MAPT, pmod(P)) SET Evidence = "Dab1 was reported to be an in vitro substrate of Cdk5, and it is tempting to speculate that Cdk5 activity may be modulated by the Reelin signaling pathway (Homayouni et al 1999). Dab1 may affect Cdk5 kinase activity directly or indirectly by interacting with its binding partners such as Abl" SET Confidence = "High" bp(PTS:"Reelin signaling pathway") -- p(HGNC:MAPT, pmod(P)) p(HGNC:DAB1) -- act(p(HGNC:CDK5)) complex(p(HGNC:DAB1), p(HGNC:ABL1)) -- act(p(HGNC:CDK5)) bp(PTS:"Reelin signaling pathway") -- act(p(HGNC:CDK5)) UNSET Subgraph ####################################################### # Reelin signaling SET Citation = {"PubMed", "Nat Genet. 2003 Nov;35(3):270-6. Epub 2003 Oct 26.", "14578885"} SET Evidence = "Dab1 and Lis1 bound in a reelin-induced phosphorylation-dependent manner. These data indicate genetic and biochemical interaction between the reelin signaling pathway and Lis1." SET Species = "10090" SET Subgraph = "Reelin signaling subgraph" p(RGD:Reln) -> p(RGD:Pafah1b1, pmod(P)) p(RGD:Reln) -> complex(p(RGD:Pafah1b1, pmod(P)), p(RGD:Dab1, pmod(P))) bp(PTS:"Reelin signaling pathway") -- p(RGD:Pafah1b1) UNSET Subgraph UNSET Species ######################################################### # Reelin signaling SET Citation = {"PubMed", "Biol Psychiatry. 2005 Apr 1;57(7):777-87.", "15820235"} SET Evidence = "Reductions in Reelin protein and mRNA and Dab 1 mRNA and elevations in Reln receptor VLDLR mRNA demonstrate impairments in the Reelin signaling system in autism, accounting for some of the brain structural and cognitive deficits observed in the disorder." SET Subgraph = "Reelin signaling subgraph" p(HGNC:RELN) negativeCorrelation path(DO:"autism spectrum disorder") r(HGNC:RELN) negativeCorrelation path(DO:"autism spectrum disorder") p(HGNC:DAB1) negativeCorrelation path(DO:"autism spectrum disorder") r(HGNC:DAB1) negativeCorrelation path(DO:"autism spectrum disorder") r(HGNC:VLDLR) positiveCorrelation path(DO:"autism spectrum disorder") bp(PTS:"Reelin signaling pathway") -- path(DO:"autism spectrum disorder") SET Evidence = "Interestingly, reductions in levels of Reelin mRNAs caused significant increases in levels of Reelin receptor, VLDLR messages in frontal and cerebellar cortices of autistic subjects." r(HGNC:RELN) -> p(HGNC:VLDLR) SET Evidence = "Reelin activates a Src kinase nonreceptor family member Fyn, which then phosphorylates and downregulates Dab-1 during brain development" p(HGNC:RELN) -> act(p(HGNC:FYN)) act(p(HGNC:FYN)) -> p(HGNC:DAB1, pmod(P)) act(p(HGNC:FYN)) -| p(HGNC:DAB1) UNSET Subgraph SET Evidence = "Additionally, Reelin activates a phosphatidylinositol (PI) 3-kinase dependent cascade in embryonic neurons, which results in activation of protein kinase B (or Akt) and inhibition of glycogen synthase kinase-3 (GSK-3) leading to reduction in levels of phosphorylated protein Tau" SET Subgraph = {"Reelin signaling subgraph", "protein kinase signaling subgraph"} p(HGNC:RELN) -> act(p(HGNC:PIK3CA)) p(HGNC:RELN) -> bp(PTS:"phosphatidylinositol 3_kinase signaling pathway") bp(PTS:"phosphatidylinositol 3_kinase signaling pathway") -> act(p(HGNC:AKT1)) bp(PTS:"phosphatidylinositol 3_kinase signaling pathway") -| act(p(HGNC:GSK3A)) bp(PTS:"phosphatidylinositol 3_kinase signaling pathway") -| act(p(HGNC:GSK3B)) complex(p(HGNC:GSK3A), p(HGNC:GSK3B)) -> p(HGNC:MAPT, pmod(P)) UNSET Subgraph SET Evidence = "Activation of downstream PI3-K/PKB system and inhibition of GSK-3 affect and modulate neuroprotective and antiapoptotic pathways of cell survival and growth, which may become dysfunctional in autism, because of Reelin deficiency." SET Subgraph = {"Reelin signaling subgraph", "protein kinase signaling subgraph", "Apoptosis signaling subgraph"} p(HGNC:GSK3B) -| bp(GOBP:"apoptotic process") p(HGNC:GSK3B) -- bp(GOBP:"cell growth") p(HGNC:GSK3B) -- bp(GOBP:"cell proliferation") bp(PTS:"phosphatidylinositol 3_kinase signaling pathway") -> bp(GOBP:"apoptotic process") bp(PTS:"phosphatidylinositol 3_kinase signaling pathway") -- bp(GOBP:"cell growth") bp(PTS:"phosphatidylinositol 3_kinase signaling pathway") -- bp(GOBP:"cell proliferation") bp(GOBP:"apoptotic process") -- path(DO:"autism spectrum disorder") p(HGNC:RELN) -| bp(GOBP:"apoptotic process") UNSET Subgraph SET Evidence = "It is, however, possible that levels of phorphorylated GSK3 is altered in autism similar to the same phenomenon reported in schizophrenia" SET Subgraph = "Reelin signaling subgraph" p(HGNC:GSK3A, pmod(P)) -- path(DO:"autism spectrum disorder") p(HGNC:GSK3B, pmod(P)) -- path(DO:"autism spectrum disorder") SET Evidence = "Reduction in Reelin was associated with significant decreases in GAD67kDa protein expression in the same postmortem brains" p(HGNC:RELN) positiveCorrelation p(HGNC:GAD1) p(HGNC:RELN) positiveCorrelation p(HGNC:GAD2) UNSET Subgraph SET Evidence = "Moreover, mice that lack the Reelin receptors ApoER2 or VLDL-R have pronounced defects in memory formation and LTP" SET Subgraph = {"Reelin signaling subgraph", "Long term synaptic potentiation"} SET Species = "10090" p(RGD:Lrp8) -> bp(GOBP:"learning or memory") p(RGD:Lrp8) -> bp(PTS:"Long_Term Potentiation") p(RGD:Vldlr) -> bp(GOBP:"learning or memory") p(RGD:Vldlr) -> bp(PTS:"Long_Term Potentiation") UNSET Species SET Evidence = "In a supportive vein, Re (2004) proposed that Reelin may act as an intracrine peptide affecting production of short- and long-term synaptic potentiation." p(HGNC:RELN) -> bp(PTS:"Long_Term Potentiation") UNSET Subgraph ############################################### # Glycine signaling ############################################### SET Citation = {"PubMed", "Neuropharmacology. 2015 Dec;99:554-65. doi: 10.1016/j.neuropharm.2015.08.031. Epub 2015 Aug 21.", "26302655"} SET Evidence = "Glycine is the major inhibitory neurotransmitter in brainstem" SET Subgraph = "Neurotransmitter release subgraph" # Glycine transporter 1/GlyT1 = SLC6A9 a(CHEBI:glycine) isA a(CHEBI:neurotransmitter) SET Evidence = "In hippocampus, the synaptic availability of glycine is largely under control of glycine transporter 1 (GlyT1)." p(HGNC:SLC6A9) -> tport(a(CHEBI:glycine)) SET Evidence = "Since epilepsy is a disorder of disrupted network homeostasis affecting the equilibrium of various neurotransmitters and neuromodulators, we hypothesized that changes in hippocampal GlyT1 expression and resulting disruption of glycine homeostasis might be implicated in the pathophysiology of epilepsy." SET Confidence = "High" p(HGNC:SLC6A9) -- path(MESHD:Epilepsy) SET Evidence = "Using two different rodent models of temporal lobe epilepsy (TLE) e the intrahippocampal kainic acid model of TLE in mice, and the rat model of tetanic stimulation-induced TLE e we first demonstrated robust overexpression of GlyT1 in the hippocampal formation, suggesting dysfunctional glycine signaling in epilepsy" SET Species = "10116" p(HGNC:SLC6A9) -> path(MESHD:"Epilepsy, Temporal Lobe") SET Evidence = "In support of a role of dysfunctional glycine signaling in the pathophysiology of epilepsy, both the genetic deletion of GlyT1 in hippocampus and the GlyT1 inhibitor LY2365109 increased seizure thresholds in mice." SET Species = "10090" SET Confidence = "High" g(HGNC:SLC6A9, var("del")) pos path(MESHD:Seizures) a(MESHC:LY2365109) -| act(p(HGNC:SLC6A9)) a(MESHC:LY2365109) -| path(MESHD:Seizures) SET Evidence = "The indirect modulation of NMDAR function via glycine is a promising strategy to improve cognition (" a(CHEBI:glycine) -> act(p(HGNC:GRIN1)) complex(a(CHEBI:glycine), p(HGNC:GRIN1)) -> bp(GOBP:"learning or memory") SET Evidence = "Low concentrations of extracellular glycine (10 mM) activate presynaptic glycine receptors (GlyRs) and thereby promote pro-convulsant mechanisms" a(CHEBI:glycine) -> act(p(HGNC:GLRA1)) a(CHEBI:glycine) -> act(p(HGNC:GLRA2)) a(CHEBI:glycine) -> act(p(HGNC:GLRA3)) a(CHEBI:glycine) -> act(p(HGNC:GLRA4)) a(CHEBI:glycine) -> act(p(HGNC:GLRB)) complex(p(HGNC:GLRA1), p(HGNC:GLRA2), p(HGNC:GLRA3), p(HGNC:GLRA4), p(HGNC:GLRB), a(CHEBI:glycine)) -> path(MESHD:Seizures) SET Evidence = "Accordingly, in vitro studies demonstrated that exogenous glycine suppressed neuronal excitation in the dentate gyrus (Chattipakorn and McMahon, 2003) and reduced the firing of action potentials in hippocampal neurons (Song et al., 2006), whereas blockade of glycine-reuptake depressed excitatory postsynaptic potentials" # glycine reuptake: glycine tport by SLC6A9 tport(a(CHEBI:glycine)) -> bp(GOBP:"regulation of postsynaptic membrane potential") p(HGNC:SLC6A9) -> bp(GOBP:"regulation of postsynaptic membrane potential") SET Evidence = "Because glycine homeostasis in the hippocampus is largely under the control of GlyT1 (Pinto et al., 2015; Yee et al., 2006), we predicted that GlyT1 dysregulation might be associated with chronic epilepsy." p(HGNC:SLC6A9) -> bp(EPT:"glycine homeostasis") p(HGNC:SLC6A9) positiveCorrelation path(MESHD:Epilepsy) ################################################## # glycine signaling ############################################### SET Citation = {"PubMed", "Prog Neurobiol. 2010 Aug;91(4):349-61. doi: 10.1016/j.pneurobio.2010.04.008. Epub 2010 May 7.", "20438799"} SET Evidence = "On the other hand, besides D-serine, glycine has also been shown to modulate NMDAR function in the hippocampus." SET Confidence = "High" SET MeSHAnatomy = "Hippocampus" SET Subgraph = "Neurotransmitter release subgraph" a(CHEBI:"D-serine") reg act(p(HGNC:GRIN1)) a(CHEBI:glycine) reg act(p(HGNC:GRIN1)) UNSET {MeSHAnatomy, Subgraph, Confidence} SET Evidence = "Furthermore, glycine can regulate hippocampal neuronal activity through GlyR-mediated cross-inhibition of GABAergic inhibition; Furthermore, glycine can regulate hippocampal inhibition through GlyR-mediated downregulation of another major inhibitory receptor, the GABAA receptors (GABAARs)" SET MeSHAnatomy = "Hippocampus" complex(a(CHEBI:glycine), p(HGNC:GLRA1)) -> bp(GOBP:"synaptic transmission, glycinergic") bp(GOBP:"synaptic transmission, glycinergic") -| a(CHEBI:"GABA agent") bp(GOBP:"synaptic transmission, glycinergic") -| p(HGNC:GABRA1) bp(GOBP:"synaptic transmission, glycinergic") -| bp(GOBP:"synaptic transmission, GABAergic") SET Evidence = "Therefore, hippocampal glycine and its receptors may operate in concert to finely regulate hippocampusdependent high brain function such as learning and memory." SET MeSHAnatomy = "Hippocampus" SET Confidence = "High" SET Subgraph = "Neurotransmitter release subgraph" composite(p(HGNC:GLRA1),a(CHEBI:glycine)) reg bp(GOBP:"learning or memory") UNSET {MeSHAnatomy, Subgraph, Confidence} SET Evidence = "Glycine is a major inhibitory neurotransmitter in the spinal cord and brain stem," SET Subgraph = "Neurotransmitter release subgraph" SET MeSHAnatomy = {"Spinal Cord", "Brain Stem"} a(CHEBI:glycine) -> bp(PTS:"Inhibitory synaptic transmission pathway") UNSET {MeSHAnatomy, Subgraph} SET Evidence = "GlyT1 is widely expressed in astrocytic glial cells and is thought to control extracellular glycine concentration and regulate excitatory neurotransmission mediated by glycine binding to NMDARs" SET Subgraph = "Neurotransmitter release subgraph" # SLC6A9 = GlyT1 p(HGNC:SLC6A9) reg a(CHEBI:glycine) p(HGNC:SLC6A9) -> tport(a(CHEBI:glycine)) p(HGNC:SLC6A9) -- bp(PTS:"excitatory synaptic transmission pathway") SET Evidence = "However, recent studies also indicate the neuronal expression of GlyT1 at glutamatergic synapses" SET Subgraph = "Neurotransmitter release subgraph" p(HGNC:SLC6A9) -- bp(GOBP:"synaptic transmission, glutamatergic") a(CHEBI:glycine) -- bp(GOBP:"synaptic transmission, glutamatergic") SET Evidence = "GlyT2 is largely localized to the presynaptic terminals of glycinergic neurons in the brain stem and spinal cord (Zafra et al., 1995), and is thought to provide the principal glycine uptake mechanism at glycinergic synapses." SET Subgraph = "Neurotransmitter release subgraph" SET MeSHAnatomy = {"Spinal Cord", "Brain Stem"} # SLC6A5 = GlyT2 p(HGNC:SLC6A5) -> tport(a(CHEBI:glycine)) p(HGNC:SLC6A5) -> bp(GOBP:"neurotransmitter uptake") UNSET MeSHAnatomy SET Evidence = "GlyT1 is essential for regulating the level of ambient glycine and thus controlling the functions of both NMDARs and GlyRs." SET Subgraph = "Neurotransmitter release subgraph" SET Confidence = "High" p(HGNC:SLC6A9) reg a(CHEBI:glycine) a(CHEBI:glycine) --bp(GOBP:"regulation of synaptic transmission, glutamatergic") a(CHEBI:glycine) -- bp(GOBP:"regulation of synaptic transmission, glycinergic") SET Evidence = "Certain factors can suppress the function of GlyT1, including Zn2+ (Ju et al., 2004) and protons, which are both stored in transmitter vesicles and transient changes in extracellular pH or Zn2+ occur during synaptic transmission" SET Confidence = "Medium" a(CHEBI:"zinc(2+)") -| act(p(HGNC:SLC6A9)) a(CHEBI:proton) -| act(p(HGNC:SLC6A9)) bp(GOBP:"chemical synaptic transmission") -- a(CHEBI:"zinc(2+)") bp(GOBP:"chemical synaptic transmission") -- a(CHEBI:proton) SET Evidence = "Although serine hydroxymethyltransferase (SHMT) and the glycine cleavage system (GCS) have been shown to be able to synthesize and degrade glycine in the central nervous system (Verleysdonk et al., 1999), little is known about the relationship between SHMT and glycine levels." SET Confidence = "High" SET Subgraph = "Neurotransmitter release subgraph" p(HGNC:SHMT1) reg a(CHEBI:glycine) p(HGNC:SHMT2) reg a(CHEBI:glycine) p(HGNC:SHMT1) -> bp(PTS:"Biosynthesis of Glycine") p(HGNC:SHMT2) -> bp(PTS:"Biosynthesis of Glycine") p(HGNC:GCSH) -> deg(a(CHEBI:glycine)) p(HGNC:GCSH) -> bp(PTS:"glycine degradative pathway") SET Evidence = "Thus, GlyT1 and GlyT2 enable the accumulation of glycine in astrocytes and neurons, respectively." SET Confidence = "High" SET Subgraph = "Neurotransmitter release subgraph" SET MeSHAnatomy = "Astrocytes" p(HGNC:SLC6A9) -> a(CHEBI:glycine) SET MeSHAnatomy = "Neurons" p(HGNC:SLC6A5) -> a(CHEBI:glycine) UNSET MeSHAnatomy SET Evidence = "Third, taurine activates GlyRs with a higher affinity than it activates GABAARs in acutely dissociated hippocampal neurons" SET MeSHAnatomy = "Hippocampus" SET Confidence = "High" SET Subgraph = "Neurotransmitter release subgraph" a(CHEBI:taurine) -> act(p(HGNC:GLRA1)) a(CHEBI:taurine) -> act(p(HGNC:GLRA2)) a(CHEBI:taurine) -> act(p(HGNC:GLRA3)) a(CHEBI:taurine) -> act(p(HGNC:GLRA4)) a(CHEBI:taurine) -> act(p(HGNC:GLRB)) UNSET {Subgraph, MeSHAnatomy, Confidence} SET Evidence = "However, several other studies have shown that blockade of GlyT1 facilitated the induction of NMDAR-dependent long-term potentiation (LTP) in the hippocampus" SET Subgraph = {"Neurotransmitter release subgraph", "Long term synaptic potentiation"} SET MeSHAnatomy = "Hippocampus" p(HGNC:SLC6A9) negativeCorrelation bp(PTS:"Long_Term Potentiation") p(HGNC:GRIN1) -> bp(PTS:"Long_Term Potentiation") UNSET MeSHAnatomy UNSET Subgraph SET Evidence = "The rapid potentiation of GlyRs by cytoplasmic Ca2+ is an important characteristic of GlyRs" SET Confidence = "Medium" SET Subgraph = "Neurotransmitter release subgraph" a(CHEBI:"calcium(2+)") -- act(p(HGNC:GLRA1)) a(CHEBI:"calcium(2+)") -- act(p(HGNC:GLRA2)) a(CHEBI:"calcium(2+)") -- act(p(HGNC:GLRA3)) a(CHEBI:"calcium(2+)") -- act(p(HGNC:GLRA4)) a(CHEBI:"calcium(2+)") -- act(p(HGNC:GLRB)) SET Evidence = "At a low potentiating concentration, Zn2+ enhances the tonic inhibitory effects of GlyRs in mouse hippocampal neurons" SET Species = "10090" SET MeSHAnatomy = "Hippocampus" SET Confidence = "High" a(CHEBI:"zinc(2+)") -> act(p(HGNC:GLRA1)) a(CHEBI:"zinc(2+)") -> act(p(HGNC:GLRA2)) a(CHEBI:"zinc(2+)") -> act(p(HGNC:GLRA3)) a(CHEBI:"zinc(2+)") -> act(p(HGNC:GLRA4)) a(CHEBI:"zinc(2+)") -> act(p(HGNC:GLRB)) UNSET {Species, MeSHAnatomy, Confidence} SET Evidence = "Proton (H+), which is a monovalent cation, dose-dependently suppresses the GlyR currents as well as glycinergic miniature IPSCs (mIPSCs) in spinal dorsal horn neurons" SET MeSHAnatomy = "Spinal Nerves" a(CHEBI:proton) -| act(p(HGNC:GLRA1)) a(CHEBI:proton) -| act(p(HGNC:GLRA2)) a(CHEBI:proton) -| act(p(HGNC:GLRA3)) a(CHEBI:proton) -| act(p(HGNC:GLRA4)) a(CHEBI:proton) -| act(p(HGNC:GLRB)) UNSET MeSHAnatomy SET Evidence = "Several lines of evidence show that ethanol potentiates hippocampal GlyR currents (Aguayo and Pancetti, 1994), while cocaine, sevoflurane and benzodiazepines exert inhibitory effects" SET MeSHAnatomy = "Hippocampus" a(CHEBI:ethanol) -> act(p(HGNC:GLRA1)) a(CHEBI:ethanol) -> act(p(HGNC:GLRA2)) a(CHEBI:ethanol) -> act(p(HGNC:GLRA3)) a(CHEBI:ethanol) -> act(p(HGNC:GLRA4)) a(CHEBI:ethanol) -> act(p(HGNC:GLRB)) a(CHEBI:cocaine) -> act(p(HGNC:GLRA1)) a(CHEBI:cocaine) -> act(p(HGNC:GLRA2)) a(CHEBI:cocaine) -> act(p(HGNC:GLRA3)) a(CHEBI:cocaine) -> act(p(HGNC:GLRA4)) a(CHEBI:cocaine) -> act(p(HGNC:GLRB)) a(CHEBI:sevoflurane) -> act(p(HGNC:GLRA1)) a(CHEBI:sevoflurane) -> act(p(HGNC:GLRA2)) a(CHEBI:sevoflurane) -> act(p(HGNC:GLRA3)) a(CHEBI:sevoflurane) -> act(p(HGNC:GLRA4)) a(CHEBI:sevoflurane) -> act(p(HGNC:GLRB)) a(CHEBI:benzodiazepine) -> act(p(HGNC:GLRA1)) a(CHEBI:benzodiazepine) -> act(p(HGNC:GLRA2)) a(CHEBI:benzodiazepine) -> act(p(HGNC:GLRA3)) a(CHEBI:benzodiazepine) -> act(p(HGNC:GLRA4)) a(CHEBI:benzodiazepine) -> act(p(HGNC:GLRB)) UNSET MeSHAnatomy SET Evidence = "Interestingly, progesterone, a neurosteroid, specifically inhibits a2-containing GlyRs" a(CHEBI:progesterone) isA a(CHEBI:steroid) a(CHEBI:progesterone) -| act(p(HGNC:GLRA2)) SET Evidence = "Given the predominant expression of the a2 subunit in hippocampus, it is not surprising that estrogen, which selectively inhibits a2-containing GlyR currents, also reduces glycine-evoked currents in hippocampal neurons" SET MeSHAnatomy = "Hippocampus" a(CHEBI:estrogen) -| act(p(HGNC:GLRA2)) UNSET MeSHAnatomy UNSET Subgraph SET Evidence = "At many central synapses, endocannabinoids released by postsynaptic cells act retrogradely at presynaptic G-protein coupled cannabinoid receptors to inhibit neurotransmitter release." SET Subgraph = {"Neurotransmitter release subgraph", "G-protein-mediated signaling"} SET MeSHAnatomy = "Synapses" a(CHEBI:endocannabinoid) -> bp(PTS:"Retrograde endocannabinoid signaling") a(CHEBI:endocannabinoid) -> bp(PTS:"GPCR signaling pathway") a(CHEBI:endocannabinoid) -| bp(PTS:"Neurotransmitter secretion") bp(PTS:"Retrograde endocannabinoid signaling") -| bp(PTS:"Neurotransmitter secretion") UNSET MeSHAnatomy UNSET Subgraph SET Evidence = "It was reported that cannabinoids directly inhibited the function of hippocampal GlyRs independent of the G-protein-coupled cannabinoid CB1 receptors" SET MeSHAnatomy = "Hippocampus" SET Subgraph = "Neurotransmitter release subgraph" a(CHEBI:cannabinoid) =| act(p(HGNC:GLRA1)) a(CHEBI:cannabinoid) =| act(p(HGNC:GLRA2)) a(CHEBI:cannabinoid) =| act(p(HGNC:GLRA3)) a(CHEBI:cannabinoid) =| act(p(HGNC:GLRA4)) a(CHEBI:cannabinoid) =| act(p(HGNC:GLRB)) complex(p(HGNC:CNR1), a(CHEBI:cannabinoid)) -| act(p(HGNC:GLRA1)) complex(p(HGNC:CNR1), a(CHEBI:cannabinoid)) -| act(p(HGNC:GLRA2)) complex(p(HGNC:CNR1), a(CHEBI:cannabinoid)) -| act(p(HGNC:GLRA3)) complex(p(HGNC:CNR1), a(CHEBI:cannabinoid)) -| act(p(HGNC:GLRA4)) complex(p(HGNC:CNR1), a(CHEBI:cannabinoid)) -| act(p(HGNC:GLRB)) UNSET MeSHAnatomy SET Evidence = "Ginkgolide B is a selective antagonist of platelet activating factor-activated receptor (Braquet and Hosford, 1991). Recently, it has been shown that ginkgolide B is also an efficient blocker of GlyRs, especially for the b subunit-containing heteromeric GlyRs" a(CHEBI:"Ginkgolide B") =| p(HGNC:PTAFR) a(CHEBI:"Ginkgolide B") -| act(p(HGNC:GLRA1)) a(CHEBI:"Ginkgolide B") -| act(p(HGNC:GLRA2)) a(CHEBI:"Ginkgolide B") -| act(p(HGNC:GLRA3)) a(CHEBI:"Ginkgolide B") -| act(p(HGNC:GLRA4)) a(CHEBI:"Ginkgolide B") =| act(p(HGNC:GLRB)) SET Evidence = "On the other hand, picrotoxin is known to be effective only at inhibiting a subunit homomeric GlyRs" a(MESHC:picrotin) -| act(p(HGNC:GLRA1)) a(MESHC:picrotin) -| act(p(HGNC:GLRA2)) a(MESHC:picrotin) -| act(p(HGNC:GLRA3)) a(MESHC:picrotin) -| act(p(HGNC:GLRA4)) SET Evidence = "More recently, we found that cyclothiazide, an epileptogenic agent, potently inhibited hippocampal GlyR currents with a specificity for the a2-containing GlyRs" a(CHEBI:cyclothiazide) -> bp(EPT:epileptogenesis) a(CHEBI:cyclothiazide) -> path(MESHD:Epilepsy) a(CHEBI:cyclothiazide) -| act(p(HGNC:GLRA2)) SET Evidence = "Quercetin selectively inhibits a2 or a3 subunitcontaining GlyRs (Sun et al., 2007), which are the major components of hippocampal GlyRs." SET Confidence = "High" SET MeSHAnatomy = "Hippocampus" a(CHEBI:quercetin) -| act(p(HGNC:GLRA2)) a(CHEBI:quercetin) -| act(p(HGNC:GLRA3)) UNSET {MeSHAnatomy, Subgraph, Confidence} SET Evidence = "During whole-cell recordings from rat hippocampal neurons, a time-dependent facilitation of GlyR current could be observed, and tamoxifen, an inhibitor of PKC diminished this phenomenon (Schonrock and Bormann, 1995), suggesting the involvement of PKC cascade in the modulation of GlyRs." SET Species = "10116" SET MeSHAnatomy = "Hippocampus" SET Subgraph = {"Neurotransmitter release subgraph", "protein kinase signaling subgraph"} a(CHEBI:tamoxifen) -| act(p(HGNC:GLRA1)) a(CHEBI:tamoxifen) -| act(p(HGNC:GLRA2)) a(CHEBI:tamoxifen) -| act(p(HGNC:GLRA3)) a(CHEBI:tamoxifen) -| act(p(HGNC:GLRA4)) a(CHEBI:tamoxifen) -| act(p(HGNC:GLRB)) a(CHEBI:tamoxifen) -| act(p(HGNC:PRKCA)) p(HGNC:PRKCA) -> bp(PTS:"protein kinase C _PKC_ signaling pathway") bp(PTS:"protein kinase C _PKC_ signaling pathway") -- p(HGNC:GLRA1) bp(PTS:"protein kinase C _PKC_ signaling pathway") -- p(HGNC:GLRA2) bp(PTS:"protein kinase C _PKC_ signaling pathway") -- p(HGNC:GLRA3) bp(PTS:"protein kinase C _PKC_ signaling pathway") -- p(HGNC:GLRA4) bp(PTS:"protein kinase C _PKC_ signaling pathway") -- p(HGNC:GLRB) UNSET {MeSHAnatomy, Subgraph, Species} SET Evidence = "Another protein kinase, protein tyrosine kinase (PTK), has also been found to enhance the function of GlyR in rat hippocampal neurons through tyrosine phosphorylation at position 413 of the b subunit" SET Confidence = "High" SET Species = "10116" SET Subgraph = {"Neurotransmitter release subgraph", "protein kinase signaling subgraph"} SET MeSHAnatomy = "Hippocampus" p(HGNC:PTK2) -> bp(PTS:"protein tyrosine kinase pathway") bp(PTS:"protein tyrosine kinase pathway") -> p(HGNC:GLRB, pmod(P, T, 413)) kin(p(HGNC:PTK2)) -> p(HGNC:GLRB, pmod(P, T, 413)) p(HGNC:GLRB, pmod(P, T, 413)) -> act(p(HGNC:GLRA1)) p(HGNC:GLRB, pmod(P, T, 413)) -> act(p(HGNC:GLRA2)) p(HGNC:GLRB, pmod(P, T, 413)) -> act(p(HGNC:GLRA3)) p(HGNC:GLRB, pmod(P, T, 413)) -> act(p(HGNC:GLRA4)) p(HGNC:GLRB, pmod(P, T, 413)) -> act(p(HGNC:GLRB)) UNSET {MeSHAnatomy, Subgraph, Confidence} SET Evidence = "Prostaglandin E2 (PGE2) has been shown to inhibit glycinergic neurotransmission in the spinal dorsal horn through a postsynaptic protein kinase A (PKA)-mediated pathway" a(CHEBI:"prostaglandin E2") -> bp(PTS:"protein kinase A _PKA_ signaling pathway") bp(PTS:"protein kinase A _PKA_ signaling pathway") -| bp(GOBP:"synaptic transmission, glycinergic") SET Evidence = "Interestingly, this PGE2-induced modulation was abolished in mice lacking GlyR a3 subunit (Harvey et al., 2004), suggesting that the hippocampal GlyR a3 subunit may be also subject to the PKA-dependent phosphorylation and regulation." SET Subgraph = {"Neurotransmitter release subgraph", "protein kinase signaling subgraph"} bp(PTS:"protein kinase A _PKA_ signaling pathway") -> p(HGNC:GLRA3, pmod(P)) p(HGNC:GLRA3, pmod(P)) -| bp(GOBP:"synaptic transmission, glycinergic") UNSET Subgraph SET Evidence = "As the primary GlyR subunit in the hippocampus, a2 subunit is highly expressed in the embryonic brain and it declines with development (Malosio et al., 1991; Sato et al., 1992), indicating a possible role in early brain development. Furthermore, the GlyR activation induced increase of intracellular Ca2+ has been observed in the developing neocortex (Flint et al., 1998), where GlyRs are activated nonsynaptically." SET Confidence = "High" SET Subgraph = {"Neurotransmitter release subgraph", "Calcium dependent subgraph"} p(HGNC:GLRA2) pos bp(GOBP:"brain development") SET Anatomy = "neocortex" act(p(HGNC:GLRA2)) -> tloc(a(CHEBI:"calcium(2+)"), fromLoc(GOCC:"extracellular space"), toLoc(GOCC:"intracellular")) UNSET {Subgraph, Anatomy, Confidence} SET Evidence = "In the hippocampal CA1 area, taurine significantly depressed epileptiform activity induced by Mg2+ removal (Kirchner et al., 2003). This antiepileptic effect of taurine was blocked by the specific GlyR antagonist strychnine." SET Confidence = "High" SET MeSHAnatomy = "CA1 Region, Hippocampal" SET Subgraph = "Neurotransmitter release subgraph" a(CHEBI:taurine) -| bp(EPT:epileptogenesis) a(CHEBI:taurine) -| path(MESHD:Epilepsy) a(CHEBI:strychnine) -| bp(EPT:epileptogenesis) a(CHEBI:strychnine) -| path(MESHD:Epilepsy) a(CHEBI:strychnine) isA a(CHEBI:"glycine receptor antagonist") SET Evidence = "First, activation of GlyR reduces the driving force of Cl by shifting the Cl reversal potential towards membrane potential, thus depressing GABAAR-mediated responses (" SET Confidence = "High" act(p(HGNC:GLRA1)) -| bp(GOBP:"synaptic transmission, GABAergic") act(p(HGNC:GLRA2)) -| bp(GOBP:"synaptic transmission, GABAergic") act(p(HGNC:GLRA3)) -| bp(GOBP:"synaptic transmission, GABAergic") act(p(HGNC:GLRA4)) -| bp(GOBP:"synaptic transmission, GABAergic") act(p(HGNC:GLRB)) -| bp(GOBP:"synaptic transmission, GABAergic") UNSET {Subgraph, Confidence} SET Evidence = "Furthermore, during LTP, the levels of GlyR agonists, such as glycine and taurine, and the GlyR modulators, such as Ca2+, Zn2+, PKC, PTK, and endocannabinoid, may be elevated, facilitating GlyR signaling." a(CHEBI:glycine) isA a(CHEBI:"glycine receptor antagonist") a(CHEBI:taurine) isA a(CHEBI:"glycine receptor antagonist") SET Confidence = "High" SET Subgraph = {"Long term synaptic potentiation", "protein kinase signaling subgraph"} bp(PTS:"Long_Term Potentiation") pos a(CHEBI:glycine) bp(PTS:"Long_Term Potentiation") pos a(CHEBI:taurine) bp(PTS:"Long_Term Potentiation") pos a(CHEBI:"calcium(2+)") bp(PTS:"Long_Term Potentiation") pos a(CHEBI:"zinc(2+)") bp(PTS:"Long_Term Potentiation") pos a(CHEBI:endocannabinoid) bp(PTS:"Long_Term Potentiation") pos bp(PTS:"protein kinase A _PKA_ signaling pathway") bp(PTS:"Long_Term Potentiation") pos bp(PTS:"protein tyrosine kinase pathway") bp(PTS:"Long_Term Potentiation") -> act(p(HGNC:GLRA1)) bp(PTS:"Long_Term Potentiation") -> act(p(HGNC:GLRA2)) bp(PTS:"Long_Term Potentiation") -> act(p(HGNC:GLRA3)) bp(PTS:"Long_Term Potentiation") -> act(p(HGNC:GLRA4)) bp(PTS:"Long_Term Potentiation") -> act(p(HGNC:GLRB)) UNSET {Subgraph, Confidence} SET Evidence = "Strychnine blocked the effect of glycine on the paired-pulse ratio PPR, indicating that hippocampal GlyRs are involved in short-term synaptic plasticity" SET Subgraph = "Neurotransmitter release subgraph" SET MeSHAnatomy = "Hippocampus" SET Confidence = "High" p(HGNC:GLRA1) -- bp(GOBP:"regulation of short-term neuronal synaptic plasticity") p(HGNC:GLRA2) -- bp(GOBP:"regulation of short-term neuronal synaptic plasticity") p(HGNC:GLRA3) -- bp(GOBP:"regulation of short-term neuronal synaptic plasticity") p(HGNC:GLRA4) -- bp(GOBP:"regulation of short-term neuronal synaptic plasticity") p(HGNC:GLRB) -- bp(GOBP:"regulation of short-term neuronal synaptic plasticity") UNSET MeSHAnatomy SET Evidence = "Furthermore, the GlyR a3 subunit knockout mice have increased susceptibility to pharmacologically induced seizures;" SET Species = "10090" SET Confidence = "High" SET Subgraph = "Neurotransmitter release subgraph" p(HGNC:GLRA3) -| path(MESHD:Seizures) UNSET {Species, Confidence, Subgraph} SET Evidence = "High-affinity isoforms of GlyRs (a2P192L and a3P185L) have been found in the hippocampus from patients with temporal lope epilepsy, which further cause the epileptic hippocampal damage due to the concurrent downregulation of KCC2 expression and the subsequent disinhibition of GABAergic and glycinergic transmission" SET Subgraph = "Neurotransmitter release subgraph" SET MeSHAnatomy = "Hippocampus" p(HGNC:GLRA2, sub(P, 192, L)) positiveCorrelation path(MESHD:"Epilepsy, Temporal Lobe") p(HGNC:GLRA3, sub(P, 185, L)) positiveCorrelation path(MESHD:"Epilepsy, Temporal Lobe") p(HGNC:GLRA2, sub(P, 192, L)) -| p(HGNC:SLC12A5) p(HGNC:GLRA3, sub(P, 185, L)) -| p(HGNC:SLC12A5) p(HGNC:SLC12A5) -> bp(GOBP:"synaptic transmission, GABAergic") p(HGNC:SLC12A5) -> bp(GOBP:"synaptic transmission, glycinergic") UNSET {Subgraph, MeSHAnatomy} SET Evidence = "For example, a recent study has reported that glycine can activate G-protein-coupled pathways through a metabotropic GlyR in" SET Subgraph = {"G-protein-mediated signaling", "Neurotransmitter release subgraph"} SET Confidence = "High" a(CHEBI:glycine) -> bp(PTS:"GPCR signaling pathway") UNSET {Subgraph, Confidence} SET Evidence = "the blockade of GlyT1 (thus elevating extracellular glycine level) rescued the impaired longterm depression (LTD) due to the depletion of D-serine (Zhang et al., 2008c), indicating that endogenous glycine overcomes the loss of D-serine and restores NMDAR activation." SET Subgraph = {"Neurotransmitter release subgraph", "Long term synaptic depression"} a(CHEBI:"D-serine") -> bp(PTS:"long term depression") a(CHEBI:glycine) -> bp(PTS:"long term depression") act(p(HGNC:GLRA1)) -> bp(PTS:"long term depression") a(CHEBI:glycine) -> act(p(HGNC:GLRA1)) UNSET Subgraph ################################################################### # adenosine signaling ############################################### SET Citation = {"PubMed", "Neuropharmacology. 2015 Oct;97:18-34. doi: 10.1016/j.neuropharm.2015.04.031. Epub 2015 May 13.", "25979489"} SET Evidence = "e. Here we will specifically focus on the adenosine hypothesis of comorbidities‚implying that astrocyte activation, via overexpression of adenosine kinase (ADK), induces a deficiency in the homeostatic tone of adenosine" SET Subgraph = {"adenosine signaling subgraph", "Neurotransmitter release subgraph", "protein kinase signaling subgraph"} bp(GOBP:"astrocyte activation") -> p(HGNC:ADK) p(HGNC:ADK) -- bp(GOBP:"adenosine catabolic process") p(HGNC:ADK) -- bp(GOBP:"adenosine metabolic process") p(HGNC:ADK) -| a(CHEBI:adenosine) SET Evidence = "We present evidence from patient-derived samples showing astrogliosis and overexpression of ADK as common pathological hallmark of epilepsy, AD, PD, and ALS" bp(GOBP:"astrocyte activation") positiveCorrelation path(MESHD:Epilepsy) bp(GOBP:"astrocyte activation") positiveCorrelation path(MESHD:"Alzheimer Disease") bp(GOBP:"astrocyte activation") positiveCorrelation path(MESHD:"Parkinson Disease") bp(GOBP:"astrocyte activation") positiveCorrelation path(MESHD:"Amyotrophic Lateral Sclerosis") p(HGNC:ADK) positiveCorrelation path(MESHD:Epilepsy) p(HGNC:ADK) positiveCorrelation path(MESHD:"Alzheimer Disease") p(HGNC:ADK) positiveCorrelation path(MESHD:"Parkinson Disease") p(HGNC:ADK) positiveCorrelation path(MESHD:"Amyotrophic Lateral Sclerosis") UNSET Subgraph SET Evidence = "We discuss a transgenic comorbidity model in which brain-wide overexpression of ADK and resulting adenosine deficiency produces a comorbid spectrum of seizures, altered dopaminergic function, attentional impairment, and deficits in cognitive domains and sleep regulation." SET Subgraph = {"adenosine signaling subgraph", "Neurotransmitter release subgraph"} a(CHEBI:adenosine) negativeCorrelation path(MESHD:Seizures) a(CHEBI:adenosine) -- bp(GOBP:"synaptic transmission, dopaminergic") a(CHEBI:adenosine) negativeCorrelation path(MESHD:"Neurocognitive Disorders") a(CHEBI:adenosine) negativeCorrelation path(MESHD:"Sleep Disorders, Intrinsic") SET Evidence = "Because physiological adenosine levels are about 100,000 times lower than ATP levels, fluctuations in adenosine tone will not affect the availability of ATP, " a(CHEBI:adenosine) causesNoChange a(CHEBI:ATP) SET Evidence = "As a homeostatic regulator and retaliatory metabolite adenosine sets the inhibitory and general neuroprotective tone via activation of widespread inhibitory A1Rs" a(CHEBI:adenosine) -> act(p(HGNC:ADORA1)) act(p(HGNC:ADORA1)) -> bp(PTS:"Inhibitory synaptic transmission pathway") SET Evidence = "On the synaptic level however, adenosine facilitates synaptic function via activation of stimulatory A2ARs " SET MeSHAnatomy = "Synapses" a(CHEBI:adenosine) -> act(p(HGNC:ADORA2A)) act(p(HGNC:ADORA2A)) -> bp(GOBP:"chemical synaptic transmission") UNSET MeSHAnatomy SET Evidence = "For example, the ADK hypothesis of epileptogenesis suggests that a precipitating injury triggers an acute surge in adenosine, which facilitates inflammatory processes and glial activation, resulting in astrogliosis, overexpression of ADK and adenosine deficiency, which in turn drives hypermethylation of DNA" path(MESHD:"Brain Injuries") -> a(CHEBI:adenosine) a(CHEBI:adenosine) -> bp(GOBP:"inflammatory response") a(CHEBI:adenosine) -> act(a(BRCO:"CNS_glial_cell")) a(CHEBI:adenosine) -> bp(GOBP:"DNA hypermethylation") bp(GOBP:"DNA hypermethylation") -> bp(EPT:epileptogenesis) bp(GOBP:"DNA hypermethylation") -> path(MESHD:Epilepsy) UNSET Subgraph SET Evidence = "Histopathologically, HS is defined by specific features, including a characteristic pattern of neuronal cell loss associated with astrogliosis" SET Subgraph = {"adenosine signaling subgraph", "Neurotransmitter release subgraph"} bp(GOBP:"apoptotic process") -- bp(GOBP:"astrocyte activation") bp(GOBP:"neuron death") -- bp(GOBP:"astrocyte activation") bp(GOBP:"apoptotic process") -> path(MESHD:Sclerosis) SET Evidence = " Because the reorganization of excitatory and inhibitory networks in the dentate gyrus appears to be a characteristic of HS associated with chronic epilepsy, " path(MESHD:Sclerosis) -- path(MESHD:Epilepsy) UNSET Subgraph SET Evidence = "Astrocytes initiate, regulate and amplify immune-mediated mechanisms involved in different neurological disorders, including epilep" SET Subgraph = {"adenosine signaling subgraph", "Neurotransmitter release subgraph", "Innate immune system subgraph"} a(BRCO:Astrocyte) -> bp(GOBP:"immune response") ########################################################### ############################################################ # Annotation for the genes in Nora's subsets for NeuroMMSig SET Citation = {"PubMed", "Atheroscler Suppl. 2010 Jun;11(1):5-9. doi: 10.1016/j.atherosclerosissup.2010.03.005.", "20434963"} SET Evidence = "ATP binding cassette proteins G5/G8 regulate cholesterol re-excretion in the intestine and in the liver, cholesterol excretion into the bile" SET Subgraph = {"Transport related subgraph", "Metabolism"} p(HGNC:ABCB5) -> bp(PTS:"transport pathway") p(HGNC:ABCB5) -> bp(PTS:"cholesterol transport pathway") p(HGNC:ABCB5) -- bp(PTS:"Cholesterol Metabolism") SET Evidence = "Diabetes is associated with reduced ATP binding cassette protein G5/G8 expression in both the liver and intestine in animal models" g(HGNC:ABCB5) -- path(DO:"neonatal diabetes mellitus") ############################## SET Citation = {"PubMed", "Biochem Soc Trans. 2015 Oct;43(5):943-51. doi: 10.1042/BST20150118.", "26517908"} SET Evidence = "Previous studies suggested a role of ABCB6 in transport of porphyrins for haem biosynthesis " SET Subgraph = "Transport related subgraph" p(HGNC:ABCB6) -> bp(PTS:"transport pathway") ############################# SET Citation = {"PubMed", "Comp Biochem Physiol C Toxicol Pharmacol. 2016 Jul-Aug;185-186:45-56. doi: 10.1016/j.cbpc.2016.02.006. Epub 2016 Mar 2.", "26945521"} SET Evidence = "We therefore studied the mRNA profiles of eight ABC transporters (abcb1a, abcb1b, abcc1, abcc2, abcc3, abcc4, abcc5, abcg2) " SET Subgraph = "Transport related subgraph" p(HGNC:ABCC1) -> bp(PTS:"transport pathway") p(HGNC:ABCC2) -> bp(PTS:"transport pathway") p(HGNC:ABCC3) -> bp(PTS:"transport pathway") p(HGNC:ABCC4) -> bp(PTS:"transport pathway") p(HGNC:ABCC5) -> bp(PTS:"transport pathway") p(HGNC:ABCG2) -> bp(PTS:"transport pathway") ################################ SET Citation = {"PubMed", "J Leukoc Biol. 2016 Jun;99(6):857-62. doi: 10.1189/jlb.2MR0915-441R. Epub 2015 Dec 9.", "26657511"} SET Evidence = "Many studies, including those coming from our lab, have shown that only a limited number of chemokines are key drivers of inflammation. We have referred to them as driver chemokines. They include the CXCR3 ligands CXCL9 and CXCL10, the CCR2 ligand CCL2, all 3 CCR5 ligands, and the CCR9 ligand CCL25." SET Subgraph = "Inflammatory response subgraph" p(HGNC:CXCL9) -> bp(PTS:"inflammatory response pathway") p(HGNC:CXCL10) -> bp(PTS:"inflammatory response pathway") p(HGNC:CCL2) -> bp(PTS:"inflammatory response pathway") p(HGNC:CCL25) -> bp(PTS:"inflammatory response pathway") SET Evidence = " This provides new evidence for the role of biased signaling in regulating biologic activities, in which CXCL11 induces ligand bias at CXCR3 and receptor-biased signaling via atypical chemokine receptor 3." p(HGNC:ACKR3) -> bp(PTS:"inflammatory response pathway") ################################## SET Citation = {"PubMed", "Stem Cells. 2015 Aug;33(8):2574-85. doi: 10.1002/stem.2022. Epub 2015 May 13.", "25833331"} SET Evidence = "Both CXCR7 and Rac1 are required for extracellular signal-regulated kinases (ERK) 1/2 activation and subsequent NPC migration, indicating that CXCR7 could serve as a functional receptor in CXCL12-mediated NPC migration independent of CXCR4." # CXCR7 = ACKR3 SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph"} p(HGNC:ACKR3) -> act(p(HGNC:MAPK1)) p(HGNC:ACKR3) -> act(p(HGNC:MAPK3)) p(HGNC:ACKR3) -> bp(PTS:"mitogen activated protein kinase signaling pathway") ################################## SET Citation = {"PubMed", "Eur J Immunol. 2006 Jul;36(7):1659-61.", "16791884"} SET Evidence = " In this issue of the European Journal of Immunology, the biochemical properties of a third silent chemokine receptor, CCX-CKR, have been characterized and it is suggested that it may act as a scavenger for homeostatic chemokines, pointing to a broad and significant role for this group of chemokine binding molecules in chemokine biology." SET Subgraph = "Inflammatory response subgraph" # CCX-CKR p(HGNC:ACKR4) -> bp(PTS:"inflammatory response pathway") ############################# SET Citation = {"PubMed", "J Mol Med (Berl). 2013 Dec;91(12):1399-406. doi: 10.1007/s00109-013-1075-4. Epub 2013 Aug 20.", "23955123"} SET Evidence = "Due to the previous association of ACMSD deficiency with the development of epileptic seizures, we concluded that the identified nonsense mutation in the ACMSD gene, which encodes for a critical enzyme of the kynurenine pathway of the tryptophan metabolism, is the disease-segregating mutation most likely to be responsible for the phenotype described in our family" SET Subgraph = {"Metabolism", "Protein Metabolism"} g(HGNC:ACMSD, var("?")) pos path(MESHD:Epilepsy) g(HGNC:ACMSD, var("?")) -> bp(PTS:"Tryptophan metabolism") g(HGNC:ACMSD, var("?")) -> bp(PTS:"Tryptophan metabolism") g(HGNC:ACMSD, var("?")) -> bp(PTS:"tryptophan _TRY_ _ kynurenine _KYN_ pathway") g(HGNC:ACMSD, var("?")) -> bp(PTS:"Metabolic pathway") SET Evidence = "The kynurenine pathway as a potential drug target for the treatment of epilepsy." bp(PTS:"tryptophan _TRY_ _ kynurenine _KYN_ pathway") -> path(MESHD:Epilepsy) ################################# SET Citation = {"PubMed", "Biochim Biophys Acta. 2014 Feb;1841(2):227-39.", "24201376"} SET Evidence = "The acyl-CoA synthetase 4 (ACSL4) has been implicated in carcinogenesis and neuronal development. Acyl-CoA synthetases are essential enzymes of lipid metabolism, and ACSL4 is distinguished by its preference for arachidonic acid" SET Subgraph = "Metabolism" p(HGNC:ACSL4) -> bp(PTS:"Lipid Metabolism") p(HGNC:ACSL4) -- path(DO:cancer) p(HGNC:ACSL4) -> a(MESHC:"Arachidonic Acid") SET Evidence = "Remarkably, phospholipid metabolism was changed by ACSL4 expression" p(HGNC:ACSL4) -> bp(PTS:"phospholipid metabolic pathway") ############################### SET Citation = {"PubMed", "Dev Growth Differ. 2013 Apr;55(3):368-76. doi: 10.1111/dgd.12051. Epub 2013 Mar 18.", "23496030"} SET Evidence = "Members of the ADAM (a disintegrin and metalloprotease) family are type I transmembrane proteins involved in biological processes of proteolysis, cell adhesion, cell-matrix interaction, as well as in the intracellular signaling transduction." SET Subgraph = {"Metabolism", "Protein Metabolism"} p(HGNC:ADAM22) -> bp(PTS:"Cell adhesion") p(HGNC:ADAM22) -> bp(PTS:"Ubiquitin mediated proteolysis") ######################################## SET Citation = {"PubMed", "Reprod Biol Endocrinol. 2010 Apr 12;8:34. doi: 10.1186/1477-7827-8-34.", "20385004"} SET Evidence = "s part of the innate immune response during infection, a number of cytokines such as tumor necrosis factor alpha (TNF alpha) and other immune factors, are produced and act on the reproductive syste" SET Subgraph = "Innate immune system subgraph" p(HGNC:TNF) -> bp(PTS:"innate immune response pathway") ####################################### SET Citation = {"PubMed", "Basic Clin Pharmacol Toxicol. 2006 Jan;98(1):61-7.", "16433893"} SET Evidence = " Our results suggest that the up-regulation of alpha1A-adrenoceptors involves transcription and intracellular signal transduction via the protein kinase C and the ERK 1/2 pathways." SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph"} p(HGNC:ADRA1A) -> bp(PTS:"mitogen activated protein kinase signaling pathway") p(HGNC:ADRA1A) -> bp(PTS:"protein kinase C _PKC_ signaling pathway") ####################################### SET Citation = {"PubMed", "Am J Physiol Heart Circ Physiol. 2010 Jun;298(6):H1797-806. doi: 10.1152/ajpheart.00112.2010. Epub 2010 Mar 26.", "20348219"} SET Evidence = " In conclusion, in the fetal CA, alpha(1B)-AR and alpha(1D)-AR subtypes play a key role in contractile response as well as in ERK activation" SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph"} p(HGNC:ADRA1D) -> bp(PTS:"mitogen activated protein kinase signaling pathway") ######################################## SET Citation = {"PubMed", "Mol Cell Biol. 2016 Jan 25;36(7):1152-63. doi: 10.1128/MCB.00009-16.", "26811329"} SET Evidence = "surface expression of newly synthesized beta2B-AR without altering overall receptor synthesis and internalization. The receptors were arrested in the TGN. Furthermore, GGA3 knockdown attenuated beta2B-AR-mediated signaling, including extracellular signal-regulated kinase 1/2 (ERK1/2) activation and cyclic AMP (cAMP) inhibition" SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph"} p(HGNC:ADRA2B) -> bp(PTS:"mitogen activated protein kinase signaling pathway") p(HGNC:ADRA2B) -| a(MESHC:"Cyclic AMP") p(HGNC:GGA3) -> p(HGNC:ADRA2B) ######################################## SET Citation = {"PubMed", "Tumour Biol. 2016 Mar;37(3):3987-96. doi: 10.1007/s13277-015-4165-9. Epub 2015 Oct 19.", "26482618"} SET Evidence = "Overexpreesion of miR‚Äö√Ñ√´29a obviously decreased AKT3 expression, thereby suppressing phosphatidylinositol 3-kinase (PI3K)/AKT pathway activation. " SET Subgraph = "protein kinase signaling subgraph" r(HGNC:MIR29A) -| p(HGNC:AKT3) r(HGNC:MIR29A) -| bp(PTS:"Akt/GSK3 pathway") p(HGNC:AKT3) -> bp(PTS:"Akt/GSK3 pathway") ######################################## SET Citation = {"PubMed", "Free Radic Biol Med. 2016 Apr;93:165-76. doi: 10.1016/j.freeradbiomed.2016.02.001. Epub 2016 Feb 5.", "26855420"} SET Evidence = " Mitochondrial aldehyde dehydrogenase 2 (ALDH2) is a member of the aldehyde dehydrogenase superfamily and is involved with the metabolic processing of aldehydes. ALDH2 plays a cytoprotective role by removing aldehydes produced during normal metabolism. " SET Subgraph = "Metabolism" p(HGNC:ALDH2) -> bp(PTS:"Metabolic pathway") ######################################## SET Citation = {"PubMed", "Biochim Biophys Acta. 2015 Dec;1850(12):2485-96. doi: 10.1016/j.bbagen.2015.09.014. Epub 2015 Sep 21.", "26391843"} SET Evidence = " We suggest that AP-TNAP activity is involved in lipid and Energy metabolic subgraph of fat cells, and it might regulate glucose metabolism and insulin sensitivity via adipokine synthesis and secretion. GENERAL SIGNIFICANCE: The activity of AP-TNAP might have a critical role in the energy balance of the adipocyte, probably participating in obesity and metabolic syndrome." # AP-TNAP = ALPL SET Subgraph = {"Energy metabolic subgraph", "Metabolism"} p(HGNC:ALPL) -> bp(PTS:"Metabolic pathway") p(HGNC:ALPL) -> bp(PTS:"Energy Metabolism") p(HGNC:ALPL) -- path(MESHD:Obesity) ######################################## SET Citation = {"PubMed", "Int J Food Microbiol. 2013 Mar 1;162(1):105-13. doi: 10.1016/j.ijfoodmicro.2012.12.023. Epub 2013 Jan 7.", "23376784"} SET Evidence = "The group of proteins whose expression was visible only during biofilm growth included proteins involved in global regulation and stress response (ArcA, BtuE, Dps, OsmY, SspA, TrxA, YbbN and YhbO), nutrient transport (Crr, DppA, Fur and SufC), degradation and Energy metabolic subgraph (GcvT, GpmA, RibB), detoxification (SseA and YibF), DNA metabolism (SSB), curli production (CsgF), and murein synthesis (MipA)" # GcvT = AMT SET Subgraph = {"Energy metabolic subgraph", "Metabolism"} p(HGNC:AMT) -> bp(PTS:"Metabolic pathway") p(HGNC:AMT) -> bp(PTS:"Energy Metabolism") ######################################## SET Citation = {"PubMed", "Mol Interv. 2003 May;3(3):131-6.", "14993420"} SET Evidence = " Calcium signalling is altered, and the functions of several channels and pumps that normally interact with wild-type ankyrin-B are impaired in the presence of mutant ankyrin-B." SET Subgraph = "Calcium dependent subgraph" p(HGNC:ANK2) -> bp(PTS:"Calcium signaling pathway") ######################################## SET Citation = {"PubMed", "Med Sci (Paris). 2015 Apr;31(4):432-8. doi: 10.1051/medsci/20153104018. Epub 2015 May 8.", "25958762"} SET Evidence = "Finally, DRD2 and ANKK1 genes, involved in the dopaminergic pathway, and which were initially associated with AD" SET Subgraph = "Neurotransmitter release subgraph" p(HGNC:ANKK1) -> bp(PTS:"dopamine signaling pathway") ######################################## SET Citation = {"PubMed", "Histochem Cell Biol. 2003 Jan;119(1):1-13. Epub 2002 Dec 21.", "12548400"} SET Evidence = "Interestingly, coexpression of PTP-SL and beta4-adaptin leads to an altered subcellular localisation for PTP-SL" # beta4-adaptin = AP4B1 SET Subgraph = "Transport related subgraph" p(HGNC:AP4B1) -> bp(PTS:"transport pathway") ######################################## SET Citation = {"PubMed", "J Clin Oncol. 2004 Nov 15;22(22):4584-94.", "15542810"} SET Evidence = "Activating mutations of BRAF and KRAS were identified and correlated with promoter methylation of 11 loci, including MINT1, MINT2, MINT31, CACNA1G, p16(INK4a), p14(ARF), COX2, DAPK, MGMT, and the two regions in hMLH1 in 468 CRCs and matched normal mucosa." SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph"} p(HGNC:APBA2) -> bp(PTS:"mitogen activated protein kinase signaling pathway") ######################################## SET Citation = {"PubMed", "Mol Cell Endocrinol. 2016 Aug 15;431:12-23. doi: 10.1016/j.mce.2016.04.024. Epub 2016 Apr 28.", "27132804"} SET Evidence = " Notable synergistic effects of Q+C combination in re-sensitizing androgen refractory CaP cells to AR-mediated apoptosis," SET Subgraph = "Apoptosis signaling subgraph" p(HGNC:AR) -> bp(GOBP:"apoptotic process") ######################################## SET Citation = {"PubMed", "Mol Biol Cell. 2016 May 1;27(9):1420-30. doi: 10.1091/mbc.E15-12-0833. Epub 2016 Mar 16.", "26985018"} SET Evidence = "Activation of RhoA in this system depends on PI3K-mediated activation of GEF-H1 and p115 RhoGEF. These two GEFs are further regulated by FAK/ERK and Src family kinases, respectively" # GEF-H1 = ARHGEF2 SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph"} bp(PTS:"PI3K/AKT signaling") -- p(HGNC:ARHGEF2) bp(PTS:"mitogen activated protein kinase signaling pathway") -- p(HGNC:ARHGEF2) ######################################## SET Citation = {"PubMed", "J Cell Sci. 2011 Jul 15;124(Pt 14):2375-88. doi: 10.1242/jcs.080630. Epub 2011 Jun 21.", "21693584"} SET Evidence = "including the Rac1 activator ≈í‚â§-Pix (also known as Rho guanine-nucleotide-exchange factor 7) " SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph"} p(HGNC:ARHGEF7) -> act(p(HGNC:RAC1)) p(HGNC:ARHGEF7) -> bp(PTS:"mitogen activated protein kinase signaling pathway") ######################################## SET Citation = {"PubMed", "Cancer Biomark. 2011-2012;11(1):15-28. doi: 10.3233/CBM-2012-0259.", "22820137"} SET Evidence = " In addition, this study identified ARSD, a gene belonging to the sphingolipid metabolism, as a new gene significantly overexpressed in UMZAP70(+)" SET Subgraph = {"Energy metabolic subgraph", "Metabolism"} p(HGNC:ARSD) -> bp(PTS:"Lipid Metabolism") p(HGNC:ARSD) -> bp(PTS:"Metabolic pathway") ######################################## SET Citation = {"PubMed", "Can J Neurol Sci. 2013 Jan;40(1):10-6.", "23250121"} SET Evidence = "The etiologies vary and include; structural brain malformations, acquired brain insults, and inborn errors of metabolism in the majority of the affected patients. The recently described genes include; Cyclin-Dependent Kinase-Like 5 gene (CDKL5), Protocadherin 19 (PCDH19), Sodium channel neuronal type 1a subunit gene (SCN1A), Aristaless-Related Homeobox Gene (ARX), and Syntaxin binding protein 1 gene (STXBP1)" SET Subgraph = "Metabolism" p(HGNC:PCDH19) -> bp(PTS:"Metabolic pathway") p(HGNC:CDKL5) -> bp(PTS:"Metabolic pathway") p(HGNC:SCN1A) -> bp(PTS:"Metabolic pathway") p(HGNC:ARX) -> bp(PTS:"Metabolic pathway") p(HGNC:STXBP1) -> bp(PTS:"Metabolic pathway") ######################################## SET Citation = {"PubMed", "J Biol Chem. 2016 Jan 29;291(5):2422-34. doi: 10.1074/jbc.M115.666909. Epub 2015 Nov 9.", "26553872"} SET Evidence = " The results suggest that AC-controlled sphingolipid metabolism may play an important role in the control of melanoma proliferation." # AC = ASAH1 SET Subgraph = {"Energy metabolic subgraph", "Metabolism"} p(HGNC:ASAH1) -> bp(PTS:"Lipid Metabolism") p(HGNC:ASAH1) -> bp(PTS:"Metabolic pathway") ######################################## SET Citation = {"PubMed", "Hum Mol Genet. 2015 Mar 1;24(5):1441-56. doi: 10.1093/hmg/ddu561. Epub 2014 Dec 5.", "25480889"} SET Evidence = " the Notch signaling genes hairy and enhancer of split 4 (HES4) and JAGGED2," SET Subgraph = "Notch signaling subgraph" p(HGNC:HES4) -> bp(PTS:"Notch signaling pathway") p(HGNC:JAG2) -> bp(PTS:"Notch signaling pathway") SET Evidence = "Lastly, shRNA knockdown of HES4 in human neuroblastoma cells altered MASH1 and P21 mRNA expression and markedly increased mutated HTT-induced aggregates and cell death." # MASH1 = ASCL1 p(HGNC:HES4) -- p(HGNC:ASCL1) ######################################## SET Citation = {"PubMed", "Am J Physiol. 1995 Oct;269(4 Pt 1):C992-7.", "7485470"} SET Evidence = "These data argue that ATP1AL1 is the catalytic alpha-subunit of a human nongastric P-type ATPase capable of exchanging extracellular potassium for intracellular protons." SET Subgraph = "Transport related subgraph" # ATP1AL1 = ATP12A p(HGNC:ATP12A) -> bp(PTS:"transport pathway") p(HGNC:ATP12A) -> bp(PTS:"proton transfer pathway") p(HGNC:ATP12A) -- a(CHEBI:proton) p(HGNC:ATP12A) -- a(CHEBI:"potassium(1+)") ######################################## SET Citation = {"PubMed", "Am J Physiol Renal Physiol. 2002 Aug;283(2):F335-43.", "12110518"} SET Evidence = "Therefore, PKC-mediated phosphorylation is a potential regulatory mechanism for apical nongastric H+-K+-ATPase plasma membrane expression." SET Subgraph = "protein kinase signaling subgraph" bp(PTS:"protein kinase C _PKC_ signaling pathway") -> p(HGNC:ATP12A) ######################################## SET Citation = {"PubMed", "Biol Psychiatry. 2015 Jun 1;77(11):959-68. doi: 10.1016/j.biopsych.2014.09.006. Epub 2014 Nov 26.", "25433904"} SET Evidence = "Proteins with evidence for altered expression in schizophrenia were significantly enriched for glutamate signaling pathway proteins (GRIA4, GRIA3, ATP1A3, and GNAQ)." SET Subgraph = {"Glutamatergic subgraph", "Neurotransmitter release subgraph"} p(HGNC:ATP1A3) -> bp(PTS:"glutamate signaling pathway") p(HGNC:GNAQ) -> bp(PTS:"glutamate signaling pathway") p(HGNC:ATP1A3) -- path(DO:schizophrenia) p(HGNC:GNAQ) -- path(DO:schizophrenia) ######################################## SET Citation = {"PubMed", "Eur J Immunol. 2001 Mar;31(3):687-91.", "11241271"} SET Evidence = "These data indicate that RTF is expressed by the tissues most intimately involved at the maternal-fetal interface, and its biological activity is capable of producing the necessary immune response for initiating and maintaining the maternal-fetal relationship." SET Subgraph = "Innate immune system subgraph" p(HGNC:ATP6V0A2) -> bp(PTS:"Immune response") ######################################## SET Citation = {"PubMed", "Mol Genet Metab Rep. 2015 Jun 9;4:25-9. doi: 10.1016/j.ymgmr.2015.05.005. eCollection 2015.", "26937406"} SET Evidence = "Menkes kinky hair disease is an X-linked neurodegenerative disease of impaired copper transport, resulting from a mutation of the Menkes disease gene, a transmembrane copper-transporting p-type ATPase gene (ATP7A). " SET Confidence = "High" SET Subgraph = "Transport related subgraph" p(HGNC:ATP7A) -- bp(PTS:"transport pathway") p(HGNC:ATP7A) -- a(CHEBI:"copper(2+)") path(MESHD:"Menkes Kinky Hair Syndrome") pos g(HGNC:ATP7A, var("?")) ######################################## SET Citation = {"PubMed", "J Trace Elem Med Biol. 2016 May;35:1-6. doi: 10.1016/j.jtemb.2016.01.006. Epub 2016 Jan 15.", "27049121"} SET Evidence = "genes involved in Cu metabolism (Ctr1, Atox1, SOD1, ATP7A, CCS, CP" SET Subgraph = "Metabolism" p(HGNC:ATP7A) -> bp(PTS:"Metabolic pathway") ######################################## SET Citation = {"PubMed", "Physiol Rep. 2015 Nov;3(11). pii: e12615. doi: 10.14814/phy2.12615.", "26564067"} SET Evidence = " At Ca concentrations of 1.2 mmol L(-1) on both sides of the tissues, Jms were higher than Jsm resulting under some conditions in significant Ca net flux rates (Jnet), indicating the presence of active Ca transport" # Jsm = ATRX SET Subgraph = "Transport related subgraph" p(HGNC:ATRX) -> bp(PTS:"transport pathway") ######################################## SET Citation = {"PubMed", "Sci Rep. 2015 Feb 10;5:8360. doi: 10.1038/srep08360.", "25666058"} SET Evidence = "Previous investigations have identified that depletion of Ataxin-10, the gene product, leads to cellular apoptosis and cytokinesis failure" SET Subgraph = "Apoptosis signaling subgraph" p(HGNC:ATXN10) -| bp(GOBP:"apoptotic process") p(HGNC:ATXN10) -> bp(GOBP:cytokinesis) ######################################## SET Citation = {"PubMed", "J Nat Prod. 2014 May 23;77(5):1130-4. doi: 10.1021/np4010085. Epub 2014 May 14.", "24828199"} SET Evidence = "Plumbagin (1) was found to downregulate Wnt signaling when assessed by a TOPFlash/FOPFlash reporter activity assay and also decreased the expression of several coactivators and downstream targets of Wnt signaling such as ≈í‚â§-catenin, TCF7L2, p300, Bcl9l, c-Myc, vimentin, and cyclinD1" SET Subgraph = "Wnt signaling subgraph" #bp(PTS:"Wnt signaling pathway") -> p(HGNC:BLC9L) a(CHEBI:plumbagin) -| bp(PTS:"Wnt signaling pathway") bp(PTS:"Wnt signaling pathway") -> p(HGNC:VIM) bp(PTS:"Wnt signaling pathway") -> p(HGNC:CCND1) ######################################## SET Citation = {"PubMed", "Cancer Res. 2016 Mar 1;76(5):1237-44. doi: 10.1158/0008-5472.CAN-15-1542. Epub 2015 Dec 16.", "26676745"} SET Evidence = "urthermore, we demonstrate that BMP4 is a direct thyroid hormone target and is involved in a positive autoregulatory feedback loop that modulates thyroid hormone signaling." SET Subgraph = {"thyroid hormone signaling subgraph", "hormone signaling subgraph"} p(HGNC:BMP4) -> bp(PTS:"thyroid hormone signaling pathway") ######################################## SET Citation = {"PubMed", "Mol Med Rep. 2016 Jan;13(1):720-30. doi: 10.3892/mmr.2015.4586. Epub 2015 Nov 19.", "26648540"} SET Evidence = "inhibiting the Wnt/≈í‚⧂Äö√Ñ√´catenin signaling pathway using dickkopf Wnt signaling pathway inhibitor 1 (DKK1) ; Reduced expression levels of NeuroD and bone morphogenetic protein 4 were observed in the DKK1‚Äö√Ñ√´treated ESCs" SET Subgraph = "Wnt signaling subgraph" # bone morphogenic protein 4 = BMP4 bp(PTS:"Wnt signaling pathway") -> p(HGNC:BMP4) ######################################## SET Citation = {"PubMed", "J Mol Neurosci. 2012 Jan;46(1):88-99. doi: 10.1007/s12031-011-9675-3. Epub 2011 Nov 30.", "22127929"} SET Evidence = " BRS-3 was also detected in normal human pancreatic islet cells suggesting a critical role of BRS-3 in regulating Energy metabolic subgraph" SET Subgraph = {"Energy metabolic subgraph", "Metabolism"} p(HGNC:BRS3) -- bp(PTS:"Energy Metabolism") ######################################## SET Citation = {"PubMed", "Cerebellum. 2009 Sep;8(3):312-22. doi: 10.1007/s12311-009-0097-5. Epub 2009 Feb 24.", "19238500"} SET Evidence = "Developmentally regulated Ca2+-dependent activator protein for secretion 2 (CAPS2) is involved in BDNF secretion" SET Subgraph = "brain_derived neurotrophic factor signaling subgraph" p(HGNC:CAPS2) -> tport(p(HGNC:BDNF)) p(HGNC:CAPS2) -> bp(PTS:"brain_derived neurotrophic factor signaling pathway") SET Evidence = "CAPS2-deficient (CAPS2(-/-)) mice show reduced secretion of BDNF and NT-3; consequently, the cerebella of these mice exhibit developmental deficits, such as delayed development and increased cell death" SET Species = "10090" SET Subgraph = "Apoptosis signaling subgraph" p(HGNC:CAPS2) -| bp(GOBP:"apoptotic process") ######################################## SET Citation = {"PubMed", "Neurosci Lett. 2016 Aug 3;627:77-83. doi: 10.1016/j.neulet.2016.05.055. Epub 2016 May 26.", "27238748"} SET Evidence = "The nociceptin/orphanin FQ peptide (NOP) opioid receptors regulate neurotransmitter release via inhibition of voltage-gated Ca(2+) channels (CaV2.2) in sympathetic and sensory neurons" SET Subgraph = {"Calcium dependent subgraph", "Neurotransmitter release subgraph"} p(HGNC:CAV2) -- bp(PTS:"Calcium signaling pathway") p(HGNC:CAV2) -- bp(PTS:"Neurotransmitter secretion") ######################################## SET Citation = {"PubMed", "Enzymes. 2013;33 Pt A:117-46. doi: 10.1016/B978-0-12-416749-0.00006-3. Epub 2013 Aug 8.", "25033803"} SET Evidence = "inhibits the related Rho GTPase Cdc42, but not Rho" SET Subgraph = "G-protein-mediated signaling" p(HGNC:CDC42) -- bp(PTS:"Rho GTPases signaling pathway") ######################################## SET Citation = {"PubMed", "Brain Res. 2012 Jan 9;1430:25-34. doi: 10.1016/j.brainres.2011.10.054. Epub 2011 Nov 6.", "22119396"} SET Evidence = "Inhibition of Rac/cdc42, which lies upstream of JNK, modestly enhanced BDNF induced formation of neurites" SET Subgraph = "brain_derived neurotrophic factor signaling subgraph" p(HGNC:CDC42) -> bp(PTS:"brain_derived neurotrophic factor signaling pathway") ######################################## SET Citation = {"PubMed", "Mol Cancer Ther. 2016 Jun;15(6):1332-43. doi: 10.1158/1535-7163.MCT-15-0692-T. Epub 2016 May 17.", "27196784"} SET Evidence = "Wee1 inhibition led to decreased CDK1 Y15 phosphorylation and increased DNA damage and apoptosis in each line" SET Subgraph = "Apoptosis signaling subgraph" p(HGNC:CDK1) -- bp(GOBP:"apoptotic process") ######################################## SET Citation = {"PubMed", "Dis Model Mech. 2016 May 1;9(5):573-83. doi: 10.1242/dmm.023515. Epub 2016 Mar 24.", "27013528"} SET Evidence = "Only diabetic IRS2(-/-) mice showed increased cell death and activation of caspase-8 and -3 in the hypothalamus. Regulators of apoptosis such as FADD, Bcl-2, Bcl-xL and p53 were also increased, whereas p-IB and c-FLIPL were decreased. " SET Confidence = "High" SET Species = "10090" SET Anatomy = "hypothalamus" SET Subgraph = "Apoptosis signaling subgraph" p(HGNC:IRS2) -> act(p(HGNC:CASP8)) p(HGNC:IRS2) -> act(p(HGNC:CASP3)) p(HGNC:FADD) neg p(HGNC:IRS2) p(HGNC:BCL2) neg p(HGNC:IRS2) p(HGNC:BCL2L1) neg p(HGNC:IRS2) p(HGNC:ATP7A) pos p(HGNC:IRS2) p(HGNC:CFLAR) pos p(HGNC:IRS2) UNSET {Species, Anatomy} p(HGNC:FADD) reg bp(GOBP:"apoptotic process") p(HGNC:BCL2) reg bp(GOBP:"apoptotic process") p(HGNC:BCL2L1) reg bp(GOBP:"apoptotic process") p(HGNC:ATP7A) reg bp(GOBP:"apoptotic process") p(HGNC:CFLAR) reg bp(GOBP:"apoptotic process") UNSET {Subgraph, Confidence} ######################################## SET Citation = {"PubMed", "Pflugers Arch. 2014 Aug;466(8):1571-9. doi: 10.1007/s00424-013-1385-y. Epub 2013 Nov 1.", "24177919"} SET Evidence = "The beta7 neuronal nicotinic acetylcholine receptor (nAChR) displays the highest calcium permeability among the different subtypes of nAChRs expressed in the mammalian brain and can impact cellular events including neurotransmitter release, second messenger cascades, cell survival, and apoptosis." SET Subgraph = {"Apoptosis signaling subgraph", "Neurotransmitter release subgraph"} p(HGNC:CHRFAM7A) -- a(CHEBI:"calcium(2+)") p(HGNC:CHRFAM7A) -> bp(GOBP:"apoptotic process") p(HGNC:CHRFAM7A) -> bp(PTS:"Neurotransmitter secretion") ######################################## SET Citation = {"PubMed", "Biochem Pharmacol. 2007 Oct 15;74(8):1308-14. Epub 2007 Jun 23.", "17662253"} SET Evidence = " (CHRNA4, CHRNA2, and CHRNB2) subunits of the nAChRs; In vitro and in vivo studies have shown high density of nAChRs in the thalamus, over activated brainstem ascending cholinergic pathway and enhanced GABAergic function" SET Subgraph = {"GABA subgraph", "Neurotransmitter release subgraph"} p(HGNC:CHRNA2) -- bp(PTS:"gamma_aminobutyric acid signaling pathway") p(HGNC:CHRNA4) -- bp(PTS:"gamma_aminobutyric acid signaling pathway") p(HGNC:CHRNB2) -- bp(PTS:"gamma_aminobutyric acid signaling pathway") ######################################## SET Citation = {"PubMed", "Cell Mol Life Sci. 2016 Jul;73(13):2511-30. doi: 10.1007/s00018-016-2175-4. Epub 2016 Mar 15.", "26979166"} SET Evidence = ". Activation of beta7 nAChRs leads to an anti-inflammatory effect." SET Subgraph = "Inflammatory response subgraph" p(HGNC:CHRNA7) -| bp(PTS:"inflammatory response pathway") ######################################## SET Citation = {"PubMed", "Neurosci Lett. 2016 Aug 3;627:1-6. doi: 10.1016/j.neulet.2016.05.043. Epub 2016 May 24.", "27233215"} SET Evidence = "Genetic knockout of the beta7 nicotinic acetylcholine receptor gene alters hippocampal long-term potentiation" SET Subgraph = "Long term synaptic potentiation" p(HGNC:CHRNA7) -> bp(PTS:"Long_Term Potentiation") ######################################## SET Citation = {"PubMed", "Am J Physiol Renal Physiol. 2015 Apr 1;308(7):F697-705. doi: 10.1152/ajprenal.00270.2014. Epub 2015 Jan 13.", "25587116"} SET Evidence = "Here, we show for the first time that PRL activates sodium and chloride transport in renal epithelial cells via ENaC and ClC4. " SET Subgraph = "Transport related subgraph" p(HGNC:CLCN4) -- bp(PTS:"transport pathway") ######################################## SET Citation = {"PubMed", "Hum Mutat. 2009 Jul;30(7):1104-16. doi: 10.1002/humu.21012.", "19431184"} SET Evidence = "Our results, validated through a gene silencing approach, indicate that CLN8 plays a role in cell proliferation during neuronal differentiation and in protection against cell death." SET Subgraph = "Apoptosis signaling subgraph" p(HGNC:CLN8) -| bp(GOBP:"apoptotic process") ######################################## SET Citation = {"PubMed", "Oncotarget. 2016 Apr 5;7(14):18541-57. doi: 10.18632/oncotarget.8105.", "26988917"} SET Evidence = " the overexpression of eIF3f suppressed Akt and ERK signaling and subsequently depleted CLU expression" SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph"} p(HGNC:EIF3F) -| bp(PTS:"mitogen activated protein kinase signaling pathway") bp(PTS:"mitogen activated protein kinase signaling pathway") -> p(HGNC:CLU) SET Evidence = "Clusterin is a secretory heterodimeric glycoprotein and the overexpression of secretory clusterin (sCLU) promotes cancer cell proliferation and reduces chemosensitivity" SET Subgraph = "Apoptosis signaling subgraph" p(HGNC:CLU) -| bp(GOBP:"apoptotic process") ######################################## SET Citation = {"PubMed", "Front Neuroanat. 2014 Dec 18;8:158. doi: 10.3389/fnana.2014.00158. eCollection 2014.", "25565981"} SET Evidence = "We show that Tagln3 is an early marker for post-mitotic neurons whereas Chga and Cntn2 are expressed in mature neurons. We demonstrate that inhibition of Notch signaling during spinal cord neurogenesis enhances expression of these markers." SET Subgraph = "Notch signaling subgraph" bp(PTS:"Notch signaling pathway") -| p(HGNC:CNTN2) bp(PTS:"Notch signaling pathway") -| p(HGNC:CHGA) ######################################## SET Citation = {"PubMed", "Tumour Biol. 2016 Apr;37(4):4679-88. doi: 10.1007/s13277-015-4284-3. Epub 2015 Oct 28.", "26511968"} SET Evidence = "Our findings suggested that rh-Endo inhibited the metastasis of esophageal cancer and the activation of AKT pathway, " # rh-Endo = COL18A1 SET Subgraph = "protein kinase signaling subgraph" p(HGNC:COL18A1) -| bp(PTS:"Akt_dependent signaling pathway") ######################################## SET Citation = {"PubMed", "Clin Transl Oncol. 2016 Jan;18(1):18-26. doi: 10.1007/s12094-015-1319-6. Epub 2015 Nov 5.", "26542176"} SET Evidence = " Endostatin enhanced the radiosensitivity of Calu-1 cells to SER = 1.38 and induced apoptosis (P < 0.01)" SET Subgraph = "Apoptosis signaling subgraph" p(HGNC:COL18A1) -> bp(GOBP:"apoptotic process") ######################################## SET Citation = {"PubMed", "J Clin Invest. 2005 Oct;115(10):2801-10. Epub 2005 Sep 8.", "16151532"} SET Evidence = " Also, alpha1(IV)NC1 pretreatment inhibited FAK/c-Raf/MEK/ERK1/2/p38 MAPK activation in ECs but had no effect on the PI3K/Akt pathway." SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph"} p(HGNC:COL4A1) -| bp(PTS:"mitogen activated protein kinase signaling pathway") p(HGNC:COL4A1) causesNoChange bp(PTS:"Akt_dependent signaling pathway") SET Evidence = "Human noncollagenous domain 1 of the alpha1 chain of type IV collagen [alpha1(IV)NC1], or arresten, is derived from the carboxy terminal of type IV collagen. It was shown to inhibit angiogenesis and tumor growth in vivo" SET Subgraph = "Apoptosis signaling subgraph" p(HGNC:COL4A1) -> bp(GOBP:"apoptotic process") ######################################## SET Citation = {"PubMed", "J Biol Chem. 2002 Mar 1;277(9):7619-25. Epub 2001 Dec 18.", "11751872"} SET Evidence = "Schwann cell adhesion to alpha4(V)-NTD induced actin cytoskeleton assembly, tyrosine phosphorylation, and activation of the Erk1/Erk2 protein kinases" # alpha4(V)-NTD = COL4A5 SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph"} p(HGNC:COL4A5) -> bp(PTS:"mitogen activated protein kinase signaling pathway") ######################################## SET Citation = {"PubMed", "Fertil Steril. 2016 Jan;105(1):134-43.e1-3. doi: 10.1016/j.fertnstert.2015.09.019. Epub 2015 Oct 9.", "26450530"} SET Evidence = "Homocysteine levels were higher in women with preeclampsia than in normal pregnancies, and were inversely correlated with 2-ME plasma levels, indicating that its altered metabolism may lower COMT activity in vivo." SET Subgraph = "Metabolism" bp(PTS:"Metabolic pathway") -- p(HGNC:COMT) ######################################## SET Citation = {"PubMed", "J Biosci. 2015 Sep;40(3):477-85.", "26333394"} SET Evidence = "However, the molecular mechanisms of ORF4 protein regulation of apoptosis remain unclear, especially given there is no information regarding any cellular partners of the ORF4 protein. Here, we have utilized the yeast two-hybrid assay and identified four host proteins (FHC, SNRPN, COX8A and Lamin C) interacting with the ORF4 protein" SET Subgraph = "Apoptosis signaling subgraph" p(HGNC:COX8A) -- bp(GOBP:"apoptotic process") ######################################## SET Citation = {"PubMed", "PLoS One. 2016 Jan 4;11(1):e0145460. doi: 10.1371/journal.pone.0145460. eCollection 2016.", "26727221"} SET Evidence = " activation of caspase-2 and caspase-8 before mitochondrial apoptosis. Furthermore, cathepsin D caused the activation of caspase-8 but not caspase-2. I" SET Subgraph = "Apoptosis signaling subgraph" p(HGNC:CTSD) -> act(p(HGNC:CASP8)) act(p(HGNC:CASP8)) -> bp(GOBP:"apoptotic process") ######################################## SET Citation = {"PubMed", "PLoS One. 2015 May 13;10(5):e0123581. doi: 10.1371/journal.pone.0123581. eCollection 2015.", "25970626"} SET Evidence = "Using a genomic siRNA screening approach, we identified a novel E3 ligase complex containing cullin 4B (CUL4B), DNA damage binding protein 1 (DDB1) and F-box protein 44 (FBXO44) that mediates RGS2 protein degradation." SET Subgraph = {"Metabolism", "Protein Metabolism"} complex(p(HGNC:CUL4B), p(HGNC:DDB1), p(HGNC:FBXO44)) -> bp(PTS:"protein degradation pathway") complex(p(HGNC:CUL4B), p(HGNC:DDB1), p(HGNC:FBXO44)) -> deg(p(HGNC:RGS2)) ######################################## SET Citation = {"PubMed", "J Immunol. 2015 Sep 1;195(5):2335-42. doi: 10.4049/jimmunol.1500935. Epub 2015 Jul 24.", "26209621"} SET Evidence = "We found that exaggerated skin inflammation was absent in CXCR6(-/-) mice." SET Species = "10090" SET Subgraph = "Inflammatory response subgraph" p(HGNC:CXCR6) reg bp(PTS:"inflammatory response pathway") ######################################## SET Citation = {"PubMed", "Chemosphere. 2016 Sep;159:113-25. doi: 10.1016/j.chemosphere.2016.05.049. Epub 2016 Jun 7.", "27281544"} SET Evidence = " CYP2B6, a member of CYP450, is well known for being a highly inducible and polymorphic enzyme and for its important role in the oxidative metabolism of environmental pollutants," SET Subgraph = "Metabolism" p(HGNC:CYP2B6) -> bp(PTS:"Metabolic pathway") ######################################## SET Citation = {"PubMed", "Zhonghua Kou Qiang Yi Xue Za Zhi. 2012 Dec;47(12):743-7. doi: 10.3760/cma.j.issn.1002-0098.2012.12.012.", "23328101"} SET Evidence = "There were eight genes [CYP2B6, CYP2C18, CYP2F1, CYP3A5, microsomal glutathione S-transferase 2 (MGST2), alcohol dehydrogenase (ADH), UDP glucuronosyl transferase 2B15 (UGT2B15), ADH1C] which were related to the pathway of CYP metabolism. " SET Subgraph = "Metabolism" p(HGNC:CYP2C18) -> bp(PTS:"Metabolic pathway") p(HGNC:CYP3A5) -> bp(PTS:"Metabolic pathway") ######################################## SET Citation = {"PubMed", "Xenobiotica. 2016 Nov;46(11):967-76. doi: 10.3109/00498254.2016.1144896. Epub 2016 Feb 22.", "26899628"} SET Evidence = "In conclusion, CYP2C19, CYP3A4/5, UGT1A9 and ADH4 were the primary drug metabolizing enzymes involved in the in vitro metabolism of tivantinib and its metabolites" SET Subgraph = "Metabolism" p(HGNC:CYP2C19) -> bp(PTS:"Metabolic pathway") p(HGNC:CYP2C19) -> bp(PTS:"Drug metabolism _ cytochrome P450") ######################################## SET Citation = {"PubMed", "Int J Clin Pharmacol Ther. 2016 Aug;54(8):587-96. doi: 10.5414/CP202490.", "27191765"} SET Evidence = "Genetic polymorphisms of the P450 2C9 enzyme (CYP2C9), CYP2C19 and CYP3A5 gene are known to affect the metabolism of many drugs " SET Subgraph = "Metabolism" p(HGNC:CYP2C9) -> bp(PTS:"Metabolic pathway") p(HGNC:CYP2C9) -> bp(PTS:"Drug metabolism _ cytochrome P450") ######################################## SET Citation = {"PubMed", "Eur J Clin Pharmacol. 2016 Jun;72(6):689-95. doi: 10.1007/s00228-016-2048-7. Epub 2016 Mar 29.", "27023460"} SET Evidence = "These data demonstrated that administration of Zuojin Pill inhibited moderately CYP2D6-mediated metabolism of dextromethorphan in healthy volunteers. " SET Subgraph = "Metabolism" p(HGNC:CYP2D6) -> bp(PTS:"Metabolic pathway") p(HGNC:CYP2D6) -> bp(PTS:"Drug metabolism _ cytochrome P450") ######################################## SET Citation = {"PubMed", "Neuroscience. 2015 Apr 16;291:53-69. doi: 10.1016/j.neuroscience.2015.02.002. Epub 2015 Feb 11.", "25681271"} SET Evidence = "Cysteinyl leukotrienes (CysLTs) induce inflammatory responses by activating their receptors, CysLT1R and CysLT2R." SET Subgraph = "Inflammatory response subgraph" p(HGNC:CYSLTR1) -> bp(PTS:"inflammatory response pathway") p(HGNC:CYSLTR2) -> bp(PTS:"inflammatory response pathway") ######################################## SET Citation = {"PubMed", "Arterioscler Thromb Vasc Biol. 2003 Aug 1;23(8):e37-41. Epub 2003 Jun 19.", "12816881"} SET Evidence = "2. Dominant expression of the CysLT2 receptor accounts for calcium signaling by cysteinyl leukotrienes in human umbilical vein endothelial cells." SET Subgraph = "Calcium dependent subgraph" p(HGNC:CYSLTR2) -> bp(PTS:"Calcium signaling pathway") ######################################## SET Citation = {"PubMed", "Infect Immun. 2014 Nov;82(11):4899-908. doi: 10.1128/IAI.02213-14. Epub 2014 Sep 2.", "25183729"} SET Evidence = " DAP1, a negative regulator of autophagy, controls SubAB-mediated apoptosis These results show that DAP1 is a key regulator, through PERK-eIF2beta-dependent pathways, of the induction of apoptosis and reduction of autophagy by SubAB. " SET Subgraph = "Apoptosis signaling subgraph" p(HGNC:DAP) -> bp(GOBP:"apoptotic process") p(HGNC:DAP) -| bp(GOBP:autophagy) ######################################## SET Citation = {"PubMed", "Neuroscience. 2008 Sep 22;156(1):129-42. doi: 10.1016/j.neuroscience.2008.06.063. Epub 2008 Jul 8.", "18674600"} SET Evidence = " Dopamine beta-hydroxylase (DBH) and norepinephrine transporter (NET) were present in all cholinergic somata, indicating a wider capability for dopamine metabolism and catecholamine uptake." SET Subgraph = "Metabolism" p(HGNC:DBH) -- bp(PTS:"Metabolic pathway") p(HGNC:DBH) -- bp(PTS:"dopamine metabolic pathway") ######################################## SET Citation = {"PubMed", "J Neurosci Methods. 2016 Feb 15;260:132-43. doi: 10.1016/j.jneumeth.2015.06.003. Epub 2015 Jun 11.", "26072248"} SET Evidence = "While earlier genetic studies suggested a strong contribution of ion channel and neurotransmitter receptor genes, later work has revealed alternative pathways, among which the mammalian target of rapamycin (mTOR) signal transduction pathway with DEPDC5." SET Subgraph = "mTOR signaling subgraph" p(HGNC:DEPDC5) -> bp(PTS:"mTOR signaling pathway") ######################################## SET Citation = {"PubMed", "Nat Genet. 2013 May;45(5):552-5. doi: 10.1038/ng.2601. Epub 2013 Mar 31.", "23542701"} SET Evidence = "Mutations of DEPDC5 cause autosomal dominant focal epilepsies. The implication of a DEP (Dishevelled, Egl-10 and Pleckstrin) domain-containing protein that may be involved in membrane trafficking and/or G protein signaling opens new avenues for research." SET Subgraph = "G-protein-mediated signaling" p(HGNC:DEPDC5) -- bp(PTS:"GPCR signaling pathway") g(HGNC:DEPDC5, var("?")) pos path(MESHD:Epilepsy) ######################################## SET Citation = {"PubMed", "Mol Cell Endocrinol. 2013 May 6;370(1-2):130-7. doi: 10.1016/j.mce.2013.02.017. Epub 2013 Mar 7.", "23480967"} SET Evidence = "androgen metabolism (Srda1 and Dhrs9)," SET Subgraph = "Metabolism" p(HGNC:DHRS9) -> bp(PTS:"Metabolic pathway") ######################################## SET Citation = {"PubMed", "J Neurosci. 2016 May 18;36(20):5437-47. doi: 10.1523/JNEUROSCI.3124-15.2016.", "27194325"} SET Evidence = " Pin1 has been detected in dendritic spines and shafts where it regulates protein synthesis required to sustain the late phase of long-term potentiation (LTP). Here, we demonstrate that Pin1 residing in postsynaptic structures can interact with postsynaptic density protein-95 (PSD-95)" SET Subgraph = {"Long term synaptic potentiation", "Metabolism", "Protein Metabolism"} complex(p(HGNC:DLG4), p(HGNC:PIN1)) -> bp(PTS:"Long_Term Potentiation") complex(p(HGNC:DLG4), p(HGNC:PIN1)) -> bp(PTS:"pathway of protein biosynthesis") ######################################## SET Citation = {"PubMed", "Stem Cells. 2016 Apr;34(4):902-12. doi: 10.1002/stem.2262. Epub 2016 Jan 6.", "26732848"} SET Evidence = "Transcriptomic analysis identified cyclin-dependent kinase (CDK) cell cycle inhibiting genes (p16, p21, and p57), the Notch signaling pathway (dll1, dll4, hes1, and hey1), and the endothelial cytokine il33 as highly expressed in CD34‚Äö√Ñ√¢+‚Äö√Ñ√¢ECFC" SET Subgraph = "Notch signaling subgraph" p(HGNC:DLL4) -> bp(PTS:"Notch signaling pathway") p(HGNC:DLL1) -> bp(PTS:"Notch signaling pathway") p(HGNC:HES1) -> bp(PTS:"Notch signaling pathway") p(HGNC:HEY1) -> bp(PTS:"Notch signaling pathway") ######################################## SET Citation = {"PubMed", "Development. 2002 Nov;129(21):5029-40.", "12397111"} SET Evidence = " We provide evidence that the Mash1 (bHLH) and Dlx1 and Dlx2 (homeobox) transcription factors have complementary roles in regulating Notch signaling," SET Subgraph = "Notch signaling subgraph" p(HGNC:DLX1) -- bp(PTS:"Notch signaling pathway") p(HGNC:DLX2) -- bp(PTS:"Notch signaling pathway") p(HGNC:ASCL1) -- bp(PTS:"Notch signaling pathway") SET Evidence = " Dlx1 and Dlx2 are required to downregulate Notch signaling during specification and differentiation steps of 'late' progenitors (P3). " p(HGNC:DLX1) -| bp(PTS:"Notch signaling pathway") p(HGNC:DLX2) -| bp(PTS:"Notch signaling pathway") ######################################## SET Citation = {"PubMed", "Rare Dis. 2016 Feb 18;4(1):e1153777. doi: 10.1080/21675511.2016.1153777. eCollection 2016.", "27141413"} SET Evidence = "wever, we discuss here the evidence that, already in myogenic cells, DMD mutations produce a plethora of abnormalities, including in cell proliferation, differentiation, Energy metabolic subgraph, Ca(2+) homeostasis and death" SET Confidence = "High" SET Subgraph = {"Energy metabolic subgraph", "Metabolism", "Calcium dependent subgraph", "Apoptosis signaling subgraph"} p(HGNC:DMD) -- bp(PTS:"Energy Metabolism") p(HGNC:DMD) -- a(CHEBI:"calcium(2+)") p(HGNC:DMD) -- bp(GOBP:"apoptotic process") ######################################## SET Citation = {"PubMed", "PLoS One. 2011 Mar 23;6(3):e18259. doi: 10.1371/journal.pone.0018259.", "21448287"} SET Evidence = "Thus, the main role of auxilin in Notch signaling is not to produce uncoated ligand-containing vesicles, but to maintain the pool of free clathrin" SET Subgraph = "Notch signaling subgraph" # auxilin = DNAJC6 p(HGNC:DNAJC6) -> bp(PTS:"Notch signaling pathway") ######################################## SET Citation = {"PubMed", "Biochem Biophys Res Commun. 2016 Apr 22;473(1):342-8. doi: 10.1016/j.bbrc.2016.03.116. Epub 2016 Mar 26.", "27021683"} SET Evidence = " In addition, we further investigated whether miR-140-5p and Dnmt1 regulate HPASMC proliferation, apoptosis and differentiation by regulating SOD2 expression, and the results confirmed our speculation" SET Subgraph = "Apoptosis signaling subgraph" p(HGNC:DNMT1) -- bp(GOBP:"apoptotic process") ######################################## SET Citation = {"PubMed", "Biochem Biophys Res Commun. 2013 Sep 6;438(4):673-9. doi: 10.1016/j.bbrc.2013.07.123. Epub 2013 Aug 9.", "23939044"} SET Evidence = " The miR-29 family (miR-29a, -29b, and -29c), which negatively regulates DNMT3A and DNMT3B, was examined in association with the Wnt/≈í‚â§-catenin signaling pathway. Taken together, our findings show that miR-29s suppress the Wnt signaling pathway through demethylation of WIF-1 in NSCLC. " SET Subgraph = "Wnt signaling subgraph" p(HGNC:DNMT3A) -- bp(PTS:"Wnt signaling pathway") ######################################## SET Citation = {"PubMed", "BMC Struct Biol. 2012 Jun 21;12:14. doi: 10.1186/1472-6807-12-14.", "22720794"} SET Evidence = " DNPEP has implicated roles in protein and peptide metabolism, as well as the renin-angiotensin system in blood pressure regulation" SET Subgraph = {"Metabolism", "Protein Metabolism"} p(HGNC:DNPEP) -> bp(PTS:"Metabolic pathway") ######################################## SET Citation = {"PubMed", "Insect Mol Biol. 2016 Aug;25(4):413-21. doi: 10.1111/imb.12226. Epub 2016 Mar 14.", "26991800"} SET Evidence = "The arthropod Down syndrome cell adhesion molecule (Dscam) mediates pathogen-specific recognition via an extensive protein isoform repertoire produced by alternative splicing. To date, most studies have focused on the subsequent pathogen-specific immune response, " SET Subgraph = "Adaptive immune system subgraph" p(HGNC:DSCAM) -> bp(PTS:"immune response pathway") p(HGNC:DSCAM) -> bp(PTS:"adaptive immune response pathway") ######################################## SET Citation = {"PubMed", "Mol Cell Proteomics. 2006 Dec;5(12):2244-51. Epub 2006 Sep 13.", "16971385"} SET Evidence = "The model network implicated several kinases of known relevance to myogenesis including AKT, GSK3, CDK5, p38, DYRK, and MAPKAPK2 kinases" SET Subgraph = "protein kinase signaling subgraph" p(HGNC:DYRK1A) -> bp(PTS:"protein kinase signaling pathway") ######################################## SET Citation = {"PubMed", "Oncotarget. 2016 Jan 26;7(4):4009-23. doi: 10.18632/oncotarget.6546.", "26675258"} SET Evidence = "miR-30a was found to specifically bind to the 3'UTR of ETAR mRNA, indicating that ETAR is a direct target of miR-30a. Overexpression of miR-30a decreased Akt and mitogen activated protein kinase signaling pathway activation," SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph"} p(HGNC:EDNRA) -- bp(PTS:"mitogen activated protein kinase signaling pathway") ######################################## SET Citation = {"PubMed", "J Cancer Res Clin Oncol. 2015 Jul;141(7):1265-75. doi: 10.1007/s00432-014-1897-7. Epub 2015 Jan 20.", "25601347"} SET Evidence = " Eukaryotic elongation factor 1 alpha-2 (eEF1A2) is a protein translation factor involved in protein synthesis. It is overexpressed in various cancers, " SET Confidence = "High" SET Subgraph = {"Metabolism", "Protein Metabolism"} p(HGNC:EEF1A2) -> bp(PTS:"pathway of protein biosynthesis") p(HGNC:EEF1A2) pos path(DO:cancer) ######################################## SET Citation = {"PubMed", "Parkinsons Dis. 2016;2016:8716016. doi: 10.1155/2016/8716016. Epub 2016 Feb 14.", "26981313"} SET Evidence = "The possible role of eEF1A isoforms in the regulation of the PI3K/Akt/mTOR pathway in PD is discussed. " SET Subgraph = "mTOR signaling subgraph" p(HGNC:EEF1A2) -- bp(PTS:"mTOR signaling pathway") SET Evidence = " eEF1A2 is proposed to contribute protection against apoptotic death, likely through activation of the PI3K/Akt pathway." SET Subgraph = {"Apoptosis signaling subgraph", "protein kinase signaling subgraph"} p(HGNC:EEF1A2) -| bp(GOBP:"apoptotic process") p(HGNC:EEF1A2) -> bp(PTS:"PI3K/AKT signaling") bp(PTS:"PI3K/AKT signaling") -| bp(GOBP:"apoptotic process") ######################################## SET Citation = {"PubMed", "Reprod Toxicol. 2014 Dec;50:60-7. doi: 10.1016/j.reprotox.2014.10.010. Epub 2014 Oct 18.", "25461906"} SET Evidence = " early growth response 1 (Egr1), a zinc finger transcription factor that regulates cell growth, differentiation and apoptosis in the uterus" SET Subgraph = "Apoptosis signaling subgraph" p(HGNC:EGR1) -- bp(GOBP:"apoptotic process") p(HGNC:EGR1) -> bp(GOBP:"regulation of cell growth") p(HGNC:EGR1) -> bp(GOBP:"cell differentiation") SET Evidence = "Collectively, our results show that through nuclear ER-dependent ERK1/2 phosphorylation, not only E2 but also endocrine disruptors with estrogenic activity such as BPA rapidly and transiently induce Egr1 which may be important for embryo implantation and decidualization in mouse uterus. " SET Subgraph = "MAPK-ERK subgraph" bp(PTS:"mitogen activated protein kinase signaling pathway") -> p(HGNC:EGR1) ######################################## SET Citation = {"PubMed", "Cell Cycle. 2015;14(10):1540-7. doi: 10.1080/15384101.2015.1026492.", "25785348"} SET Evidence = "This includes several translation initiation factors (eIF2C2, eIF2B4, eIF3I, eIF3L, eIF4A1) " SET Subgraph = {"Metabolism", "Protein Metabolism"} p(HGNC:EIF2B4) -> bp(PTS:"pathway of protein biosynthesis") ######################################## SET Citation = {"PubMed", "Indian J Biochem Biophys. 2014 Apr;51(2):115-20.", "24980014"} SET Evidence = "eIF2B plays a crucial role in protein translation and its regulation under different conditions" SET Subgraph = {"Metabolism", "Protein Metabolism"} p(HGNC:EIF2B5) -> bp(PTS:"pathway of protein biosynthesis") ######################################## SET Citation = {"PubMed", "Mol Cell Pediatr. 2016 Dec;3(1):25. doi: 10.1186/s40348-016-0053-7. Epub 2016 Jul 25.", "27456476"} SET Evidence = "These studies demonstrated that NE is implicated in several key features of CF lung disease such as neutrophilic airway inflammation," #NE = ELANE SET Subgraph = "Inflammatory response subgraph" p(HGNC:ELANE) -> bp(PTS:"inflammatory response pathway") ######################################## SET Citation = {"PubMed", "Cell Rep. 2016 Feb 23;14(7):1761-73. doi: 10.1016/j.celrep.2016.01.053. Epub 2016 Feb 11.", "26876177"} SET Evidence = "Furthermore, we show that the serine proteases neutrophil elastase and proteinase 3 can also cleave the IL-11R." SET Subgraph = {"Metabolism", "Protein Metabolism"} p(HGNC:ELANE) -> bp(PTS:"Protein cleavage") ######################################## SET Citation = {"PubMed", "Pathol Biol (Paris). 2014 Apr;62(2):91-5. doi: 10.1016/j.patbio.2014.02.007. Epub 2014 Mar 18.", "24650524"} SET Evidence = " Many recent data, however, have shown that extracellular matrix macromolecules (collagens, elastin, glycosaminoglycans, proteoglycans and connective tissue glycoproteins) are able to regulate many important cell functions, such as proliferation, migration, protein synthesis or degradation, apoptosis, etc." SET Subgraph = {"Apoptosis signaling subgraph", "Metabolism", "Protein Metabolism"} p(HGNC:ELN) -- bp(GOBP:"apoptotic process") p(HGNC:ELN) -- bp(PTS:"pathway of protein biosynthesis") p(HGNC:ELN) -- bp(PTS:"protein degradation pathway") ######################################## SET Citation = {"PubMed", "Nat Methods. 2008 May;5(5):397-9. doi: 10.1038/nmeth.1206. Epub 2008 Apr 20.", "18425138"} SET Evidence = "The small size improved access of QD-labeled glutamate receptors to neuronal synapses, and monovalency prevented EphA3 tyrosine kinase activation." SET Subgraph = "protein kinase signaling subgraph" p(HGNC:EPHA3) -> bp(PTS:"protein kinase signaling pathway") ######################################## SET Citation = {"PubMed", "Toxicol Lett. 2016 Mar 30;246:35-41. doi: 10.1016/j.toxlet.2016.01.019. Epub 2016 Feb 1.", "26840748"} SET Evidence = "indicating that the metabolites associated with mEH-mediated metabolism could be partially responsible for cytotoxicity at this site" # mEH = EPHX1 SET Subgraph = "Metabolism" p(HGNC:EPHX1) -> bp(PTS:"Metabolic pathway") ######################################## SET Citation = {"PubMed", "J Dent Res. 2016 Jun;95(6):689-96. doi: 10.1177/0022034516633154. Epub 2016 Feb 25.", "26917440"} SET Evidence = " ERbeta is required to maintain the microarchitecture of maxillary alveolar bone. This process is linked to bone cell differentiation and apoptosis, as well as local production of inflammatory molecules such as IL-33, TNF-beta, and IL-1≈í‚â§. " SET Subgraph = {"Apoptosis signaling subgraph", "Inflammatory response subgraph"} p(HGNC:ESR1) -> bp(GOBP:"apoptotic process") p(HGNC:ESR1) -> bp(PTS:"inflammatory response pathway") p(HGNC:ESR1) -> p(HGNC:IL33) p(HGNC:ESR1) -> p(HGNC:TNF) p(HGNC:ESR1) -> p(HGNC:IL1B) p(HGNC:IL33) -> bp(PTS:"inflammatory response pathway") p(HGNC:IL1B) -> bp(PTS:"inflammatory response pathway") p(HGNC:TNF) -> bp(PTS:"inflammatory response pathway") ######################################## SET Citation = {"PubMed", "Mol Endocrinol. 2015 Nov;29(11):1634-45. doi: 10.1210/me.2015-1153. Epub 2015 Oct 1.", "26426411"} SET Evidence = "Estrogen receptor (ER)beta-positive tumors are commonly treated with ERbeta antagonists or inhibitors of estrogen synthesis, " SET Subgraph = "hormone signaling subgraph" p(HGNC:ESR1) -> bp(PTS:"estrogen signaling pathway") ######################################## SET Citation = {"PubMed", "Stud Hist Philos Biol Biomed Sci. 2014 Sep;47 Pt A:23-34. doi: 10.1016/j.shpsc.2014.03.007. Epub 2014 May 20.", "24853975"} SET Evidence = "Since its initial discovery in the 1940s, factor V has long been viewed as an important procoagulant protein in the coagulation cascade. " SET Subgraph = "Inflammatory response subgraph" p(HGNC:F5) -> bp(PTS:"coagulation cascade pathway") p(HGNC:F5) -- bp(PTS:"inflammatory response pathway") ######################################## SET Citation = {"PubMed", "PLoS One. 2016 Jan 25;11(1):e0147717. doi: 10.1371/journal.pone.0147717. eCollection 2016.", "26808816"} SET Evidence = "Cellular metabolic changes, especially to lipid metabolism, have recently been recognized as a hallmark of various cancer cells." SET Subgraph = "Metabolism" SET Confidence = "High" bp(PTS:"Lipid Metabolism") -- path(DO:cancer) SET Evidence = "d fatty acid binding protein (FABP7), markers of GCSs, decreased while that of glial fibrillary acidic protein (GFAP) expression increased. Taken together, our results indicate that FASN plays a pivotal role in the maintenance of GSC stemness, and FASN-mediated de novo lipid biosynthesis is closely associated with tumor growth and invasion in glioblastoma." p(HGNC:FABP7) -- bp(PTS:"Lipid Metabolism") ######################################## SET Citation = {"PubMed", "Nat Commun. 2014 Nov 27;5:5650. doi: 10.1038/ncomms6650.", "25427601"} SET Evidence = "Aminoacyl-tRNA synthetases (aaRSs) constitute a family of ubiquitously expressed essential enzymes that ligate amino acids to their cognate tRNAs for protein synthesis." SET Subgraph = "Protein Metabolism" p(HGNC:FARS2) -> bp(PTS:"pathway of protein biosynthesis") SET Evidence = " phenylalanyl-tRNA synthetase (PheRS). Double-sieving-defective mutations dramatically misacylate non-cognate Tyr, induce protein mistranslation and cause endoplasmic reticulum stress in flies. Mutant adults exhibit many defects, including loss of neuronal cells, impaired locomotive performance, shortened lifespan and smaller organ size. At the cellular level, the mutations reduce cell proliferation and promote cell death." SET Confidence = "High" SET Subgraph = "Apoptosis signaling subgraph" g(HGNC:FARS2, var("?")) -> bp(GOBP:"apoptotic process") ######################################## SET Citation = {"PubMed", "J Biol Chem. 2012 Jun 15;287(25):21450-60. doi: 10.1074/jbc.M111.331249. Epub 2012 May 3.", "22556421"} SET Evidence = " Loss of FBLP-1 significantly impaired the growth and survival of BMSCs" SET Confidence = "High" SET Cell = "stromal cell of bone marrow" SET Subgraph = "Apoptosis signaling subgraph" p(HGNC:FBLIM1) -| bp(GOBP:"apoptotic process") p(HGNC:FBLIM1) -> bp(GOBP:"cell growth") UNSET {Cell, Confidence} SET Evidence = ". The level of receptor activator of nuclear factor ≈í‚à´B ligand (RANKL), a key regulator of OCL differentiation, was markedly increased in FBLP-1 null BMSCs" p(HGNC:FBLIM1) -| p(HGNC:TNFSF11) ######################################## SET Citation = {"PubMed", "J Mol Histol. 2016 Apr;47(2):105-16. doi: 10.1007/s10735-016-9654-7. Epub 2016 Jan 12.", "26759260"} SET Evidence = "FHL2 is one transcriptional cofactor that can interact with many different proteins, such as AP-1, BRCA1, IGFBP, and integrin, and involved in organ differentiation, development, cell apoptosis, and carcinogenesis." SET Subgraph = "Apoptosis signaling subgraph" p(HGNC:FHL2) -- bp(GOBP:"apoptotic process") p(HGNC:FHL2) -- bp(GOBP:"cell development") ######################################## SET Citation = {"PubMed", "J Neurol. 2013 Nov;260(11):2917-27. doi: 10.1007/s00415-013-7112-y. Epub 2013 Oct 2.", "24085347"} SET Evidence = "and physiological functions of some molecules, including VCP, UBQLN2, OPTN, FIG4 and SQSTM1, are involved in a protein degradation system." SET Subgraph = {"Metabolism", "Protein Metabolism"} p(HGNC:FIG4) -> bp(PTS:"protein degradation pathway") p(HGNC:VCP) -> bp(PTS:"protein degradation pathway") p(HGNC:UBQLN2) -> bp(PTS:"protein degradation pathway") p(HGNC:OPTN) -> bp(PTS:"protein degradation pathway") p(HGNC:SQSTM1) -> bp(PTS:"protein degradation pathway") ######################################## SET Citation = {"PubMed", "FEBS Lett. 2006 Mar 20;580(7):1795-800. Epub 2006 Feb 24.", "16513120"} SET Evidence = "Filamin plays an important role in actin cytoskeleton organization, " SET Subgraph = "Regulation of actin cytoskeleton subgraph" p(HGNC:FLNA) -> bp(PTS:"Actin cytoskeleton organization and biogenesis") p(HGNC:FLNA) -> bp(PTS:"Cytoskeleton organization") SET Evidence = "This work defines filamin A involvement in GPCR signaling " SET Subgraph = "G-protein-mediated signaling" p(HGNC:FLNA) -> bp(PTS:"GPCR signaling pathway") SET Evidence = "Silencing of filamin A gene expression inhibits Ca2+ -sensing receptor signaling." SET Subgraph = "Calcium dependent subgraph" p(HGNC:FLNA) -- bp(PTS:"Calcium signaling pathway") ######################################## SET Citation = {"PubMed", "Cell Rep. 2015 Sep 1;12(9):1414-29. doi: 10.1016/j.celrep.2015.07.061. Epub 2015 Aug 20.", "26299970"} SET Evidence = "These gene expression changes are rescued by antagonizing Wnt signaling in a critical developmental window, supporting the hypothesis that DISC1-dependent suppression of basal Wnt signaling influences the distribution of cell types generated during cortical development." SET Subgraph = "Wnt signaling subgraph" p(HGNC:DISC1) -| bp(PTS:"Signaling with Wnt") SET Evidence = "This results in an increased level of canonical Wnt signaling in neural progenitor cells and altered expression of fate markers such as Foxg1 and Tbr2." p(HGNC:FOXG1) -- p(HGNC:DISC1) p(HGNC:FOXG1) -- bp(PTS:"Signaling with Wnt") ######################################## SET Citation = {"PubMed", "J Neurosci. 2012 Feb 29;32(9):2931-49. doi: 10.1523/JNEUROSCI.5240-11.2012.", "22378868"} SET Evidence = "that Foxg1 may be involved in Reelin signaling in regulating postnatal DG development." SET Subgraph = "Reelin signaling subgraph" p(HGNC:FOXG1) -- bp(PTS:"Reelin signaling pathway") ######################################## SET Citation = {"PubMed", "J Mol Neurosci. 2015 Feb;55(2):437-48. doi: 10.1007/s12031-014-0359-7. Epub 2014 Jul 16.", "25027557"} SET Evidence = " FOXP2 regulates the expression of many genes important in embryonic development, including WNT and Notch signaling pathways. " SET Subgraph = {"Notch signaling subgraph", "Wnt signaling subgraph"} p(HGNC:FOXP2) -> bp(PTS:"Wnt signaling pathway") p(HGNC:FOXP2) -> bp(PTS:"Notch signaling pathway") ######################################## SET Citation = {"PubMed", "Arq Neuropsiquiatr. 2003 Jun;61(2A):176-80. Epub 2003 Jun 9.", "12806492"} SET Evidence = "The protocol included chromosomal analysis, screening for inborn errors of metabolism, cytogenetic and molecular study of the FRAXA, FRAXE, and FRAXF mutations," SET Confidence = "High" SET Subgraph = "Metabolism" g(HGNC:FRAXA, var("?")) -- bp(PTS:"Metabolic pathway") ######################################## SET Citation = {"PubMed", "Rev Neurol. 2006 Jan 7;42 Suppl 1:S77-83.", "16506138"} SET Evidence = "regulating transcription (ZNF41, ZNF81, PQBP1) translation (FTSJ1), and fatty acid metabolism (FACL4), etc." SET Subgraph = {"Metabolism", "Protein Metabolism"} g(HGNC:FTSJ1) -- bp(PTS:"Regulation of translation") ######################################## SET Citation = {"PubMed", "Mol Cell Oncol. 2015 Apr 14;3(1):e1027440. doi: 10.1080/23723556.2015.1027440. eCollection 2016.", "27308540"} SET Evidence = "Recent work has uncovered a novel role of gamma-aminobutyric acid receptor-associated proteins (GABARAPs), a subfamily of human ATG8 ubiquitin-like modifiers, in providing a scaffold for recruitment of an ubiquitin E3 ligase complex to its substrate, T-lymphoma invasion and metastasis-inducing protein 1 (TIAM1), to enable ubiquitylation and thereby local control of RAC1 activity. " SET Subgraph = {"GABA subgraph", "MAPK-ERK subgraph", "Neurotransmitter release subgraph"} p(HGNC:GABARAP) -- a(CHEBI:"GABA agent") p(HGNC:GABARAP) -- bp(PTS:"gamma_aminobutyric acid signaling pathway") p(HGNC:GABARAP) -- bp(PTS:"RAC1 signaling pathway") ######################################## SET Citation = {"PubMed", "Mol Pharmacol. 2015 Feb;87(2):240-50. doi: 10.1124/mol.114.096156. Epub 2014 Nov 25.", "25425625"} SET Evidence = "We propose a novel mechanism by which Vc1.1 activates GABA(B)R and requires the GABA(B)(1a) proximal carboxyl terminus domain to inhibit Cav2.2 channels. These findings provide important insights into how GABA(B)Rs mediate Cav2.2 channel inhibition and alter nociceptive transmission." SET Subgraph = {"Calcium dependent subgraph", "GABA subgraph", "Neurotransmitter release subgraph"} p(HGNC:GABBR1) -- a(CHEBI:"GABA agent") p(HGNC:GABRR1) -- bp(PTS:"gamma_aminobutyric acid signaling pathway") p(HGNC:GABRR1) -- p(HGNC:CACNA1B) ######################################## SET Citation = {"PubMed", "Am J Med Genet B Neuropsychiatr Genet. 2010 Mar 5;153B(2):418-27. doi: 10.1002/ajmg.b.30995.", "19536785"} SET Evidence = "herefore, as part of a comprehensive evaluation of the GABA receptor genes, we evaluated the potential association of GABRR1 and GABRR2, which encode the rho1 and rho2 subunits of the pentameric GABA-A/GABA-C receptors. " SET Subgraph = {"GABA subgraph", "Neurotransmitter release subgraph"} p(HGNC:GABRR2) -- bp(PTS:"gamma_aminobutyric acid signaling pathway") p(HGNC:GABRR2) -- a(CHEBI:"GABA agent") ######################################## SET Citation = {"PubMed", "Biochim Biophys Acta. 2009 Sep;1792(9):862-73.", "19899223"} SET Evidence = " LUNATIC FRINGE encodes for a fucose-specific beta1,3-N-acetylglucosaminyltransferase, which modifies Notch receptors and alters Notch signaling activity." SET Subgraph = "Notch signaling subgraph" p(HGNC:GCNT2) -- p(HGNC:NOTCH1) p(HGNC:GCNT2) -- p(HGNC:NOTCH2) p(HGNC:GCNT2) -- p(HGNC:NOTCH3) p(HGNC:GCNT2) -- p(HGNC:NOTCH4) p(HGNC:GCNT2) -- bp(PTS:"Notch signaling pathway") ######################################## SET Citation = {"PubMed", "Glia. 2012 Feb;60(2):239-52. doi: 10.1002/glia.21259. Epub 2011 Oct 24.", "22025386"} SET Evidence = " Cx30/Cx43-mediated sodium diffusion between astrocytes could represent a signal indicating increased metabolic needs," SET Subgraph = "Metabolism" #Cx43 = GJA1 p(HGNC:GJA1) -- bp(PTS:"Metabolic pathway") ######################################## SET Citation = {"PubMed", "Food Chem Toxicol. 2011 Jan;49(1):309-18. doi: 10.1016/j.fct.2010.10.034. Epub 2010 Nov 4.", "21056074"} SET Evidence = "The results suggest that CAE can prevent photo-damage in skin through inhibiting MMP expression and MAP kinase pathway." SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph"} # CAE = GJA8 p(HGNC:GJA8) -| bp(PTS:"mitogen activated protein kinase signaling pathway") ######################################## SET Citation = {"PubMed", "Front Mol Neurosci. 2009 Nov 4;2:14. doi: 10.3389/neuro.02.014.2009. eCollection 2009.", "19915732"} SET Evidence = "GlyR alpha3 has previously been found to play a critical role in pain hypersensitivity following spinal PGE(2) injection, complete Freund's adjuvant (CFA) and zymosan induced peripheral inflammation." SET Subgraph = {"Inflammatory response subgraph", "Neurotransmitter release subgraph"} p(HGNC:GLRA3) -> bp(PTS:"inflammatory response pathway") ######################################## SET Citation = {"PubMed", "Elife. 2016 Jan 11;5:e10727. doi: 10.7554/eLife.10727.", "26751560"} SET Evidence = "Glutaminase (GLS) isoenzymes GLS1 and GLS2 are key enzymes for glutamine metabolism." SET Subgraph = "Metabolism" p(HGNC:GLS) -> bp(PTS:"Metabolic pathway") p(HGNC:GLS) -> bp(PTS:"D_glutamine metabolic pathway") p(HGNC:GLS2) -> bp(PTS:"Metabolic pathway") p(HGNC:GLS2) -> bp(PTS:"D_glutamine metabolic pathway") ######################################## SET Citation = {"PubMed", "J Neural Transm (Vienna). 2015 Apr;122(4):541-50. doi: 10.1007/s00702-015-1387-3. Epub 2015 Mar 6.", "25742870"} SET Evidence = " Since GS is an ATP-dependent enzyme, mitochondrial dysfunction might contribute to reduced activity, which might also account for the increased metabolism of glutamate via the GABA shunt, a metabolic pathway to bypass intra-mitochondrial beta-ketoglutarate-dehydrogenase, resulting in elevated GABA levels." SET Subgraph = {"Metabolism", "GABA subgraph"} p(HGNC:GLUL) -> bp(PTS:"Metabolic pathway") p(HGNC:GLUL) -> bp(PTS:"Glutamate metabolism") p(HGNC:GLUL) -- a(CHEBI:"GABA agent") ######################################## SET Citation = {"PubMed", "J Biol Chem. 2015 Mar 6;290(10):6120-9. doi: 10.1074/jbc.M114.605725. Epub 2015 Jan 22.", "25614626"} SET Evidence = "to the effect that overexpressed PIST reduces activation of the MAPK pathway by ≈í‚â§1-adrenergic receptor (≈í‚â§1AR) agonists" SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph"} # PIST = GOPC p(HGNC:GOPC) -| bp(PTS:"mitogen activated protein kinase signaling pathway") ######################################## SET Citation = {"PubMed", "Proc Natl Acad Sci U S A. 2015 May 12;112(19):6194-9. doi: 10.1073/pnas.1421785112. Epub 2015 Apr 27.", "25918380"} SET Evidence = "We examined aGPCR activation using two prototypical aGPCRs, GPR56 and GPR110. " SET Subgraph = "G-protein-mediated signaling" p(HGNC:ADGRG1) -- bp(PTS:"G protein mediated signaling pathway") p(HGNC:ADGRV1) -- bp(PTS:"G protein mediated signaling pathway") ######################################## SET Citation = {"PubMed", "Environ Int. 2016 Jul-Aug;92-93:220-31. doi: 10.1016/j.envint.2016.03.033. Epub 2016 Apr 22.", "27107227"} SET Evidence = "Genetic susceptibility might play a role, especially for genes encoding for the Cytochrome P450 (CYP2E1) and Glutathione S-Transferase (GST) enzymes, involved in metabolism and activation of DBPs" SET Subgraph = "Metabolism" # GST = GSTM1 + GSTM2 p(HGNC:GSTM1) -- bp(PTS:"Metabolic pathway") p(HGNC:GSTM2) -- bp(PTS:"Metabolic pathway") ######################################## SET Citation = {"PubMed", "Comput Biol Chem. 2016 Jun;62:70-4. doi: 10.1016/j.compbiolchem.2016.04.003. Epub 2016 Apr 11.", "27107179"} SET Evidence = "Besides, miR-339-3p targets many apoptosis related genes (ZNF346, TAOK2, PIM2, HIP1, BBC3, TNFRSF25, CLCF1, IHPK2, NOL3)" SET Subgraph = "Apoptosis signaling subgraph" p(HGNC:HIP1) -- bp(GOBP:"apoptotic process") ######################################## SET Citation = {"PubMed", "J Cell Physiol. 2016 Nov;231(11):2319-26. doi: 10.1002/jcp.25352. Epub 2016 Mar 9.", "26909509"} SET Evidence = " High mobility group box 1 (HMGB1) is a nuclear protein that can be released from activated or dead cells. Extracellular HMGB1 can serve as a danger signal and novel cytokine that mediates sterile inflammation." SET Subgraph = "Inflammatory response subgraph" p(HGNC:HMGB1) -- bp(PTS:"inflammatory response pathway") ######################################## SET Citation = {"PubMed", "PLoS One. 2016 Mar 24;11(3):e0152097. doi: 10.1371/journal.pone.0152097. eCollection 2016.", "27011261"} SET Evidence = "The effect of BBR on hepatic gluconeogenesis and lipid metabolism is mediated through HNF-4beta and is regulated downstream of miR122" SET Subgraph = "Metabolism" p(HGNC:HNF4A) -- bp(PTS:"Lipid Metabolism") ######################################## SET Citation = {"PubMed", "J Allergy Clin Immunol. 2016 Mar;137(3):919-21. doi: 10.1016/j.jaci.2015.11.032.", "26947983"} SET Evidence = "2. Hematopoietic prostaglandin D synthase: Linking pathogenic effector CD4(+) T(H)2 cells to proeosinophilic inflammation in patients with gastrointestinal allergic disorders." SET Subgraph = "Inflammatory response subgraph" p(HGNC:HPGDS) -> bp(PTS:"inflammatory response pathway") ######################################## SET Citation = {"PubMed", "Biochemistry. 2015 Nov 10;54(44):6704-11. doi: 10.1021/acs.biochem.5b00567. Epub 2015 Oct 30.", "26407043"} SET Evidence = "The hormone human islet amyloid polypeptide (hIAPP or amylin) plays a role in glucose metabolism," SET Subgraph = {"Energy metabolic subgraph", "Metabolism", "hormone signaling subgraph"} p(HGNC:IAPP) -- bp(PTS:"Glucose metabolism") ######################################## SET Citation = {"PubMed", "Nature. 2016 Apr 14;532(7598):255-8. doi: 10.1038/nature17393. Epub 2016 Apr 6.", "27049945"} SET Evidence = "Reductive glutamine metabolism was highly dependent on cytosolic isocitrate dehydrogenase-1 (IDH1), because" SET Subgraph = "Metabolism" p(HGNC:IDH1) -- bp(PTS:"D_glutamine metabolic pathway") ######################################## SET Citation = {"PubMed", "Magnes Res. 2013 Apr-Jun;26(2):56-66. doi: 10.1684/mrh.2013.0339.", "23823179"} SET Evidence = "Other polytons (interactors appearing in the screen more than once) included: IER3IP1, PPIB, UPF0480 protein C15orf24, SPINT2, C14orf1/PEBP28, NIFIE14, YIPF6, and KCP2. In total, 20 polytons and 38 singletons (interactors appearing in the screen only once) were identified. The polytons identified were mostly endoplasmic reticulum-located, integral proteins involved in protein maturation, N-glycosylation, protein folding, anterograde transport of proteins, protein secretion, and the regulation of apoptosis." SET Subgraph = "Apoptosis signaling subgraph" p(HGNC:IER3IP1) -- bp(GOBP:"apoptotic process") ######################################## SET Citation = {"PubMed", "Open Rheumatol J. 2014 Sep 29;8:29-42. doi: 10.2174/1874312901408010029. eCollection 2014.", "25328554"} SET Evidence = " NOTCH4, RHOB, KIAA0319, PSD3 and PSOR1C1. These genes encode proteins mainly involved in immune regulation and inflammation," SET Subgraph = "Inflammatory response subgraph" p(HGNC:KIAA0319) -> bp(PTS:"inflammatory response pathway") p(HGNC:NOTCH4) -> bp(PTS:"inflammatory response pathway") p(HGNC:RHOB) -> bp(PTS:"inflammatory response pathway") ######################################## SET Citation = {"PubMed", "Dev Cell. 2016 Jul 25;38(2):171-85. doi: 10.1016/j.devcel.2016.06.012. Epub 2016 Jul 7.", "27396362"} SET Evidence = "KIF1A/UNC-104 Transports ATG-9 to Regulate Neurodevelopment and Autophagy at Synapses." SET Subgraph = {"Neurotransmitter release subgraph", "Transport related subgraph"} p(HGNC:KIF1A) -- bp(PTS:Translocation) ######################################## SET Citation = {"PubMed", "Acta Histochem. 2014 Oct;116(8):1270-5. doi: 10.1016/j.acthis.2014.07.011. Epub 2014 Aug 15.", "25131155"} SET Evidence = "The wide distribution of the Ob-R suggests that leptin might exert diverse biological functions, not only by regulating Energy metabolic subgraph and appetite" SET Subgraph = {"Energy metabolic subgraph", "Metabolism"} # Ob-R = LEPR p(HGNC:LEPR) -> bp(PTS:"Energy Metabolism") p(HGNC:LEPR) -- a(CHEBI:Leptin) ######################################## SET Citation = {"PubMed", "Breast Cancer Res Treat. 2014 Sep;147(2):381-7. doi: 10.1007/s10549-014-3081-9. Epub 2014 Aug 10.", "25108739"} SET Evidence = "that single nucleotide polymorphisms (SNPs) in candidate genes in the PI3 K-AKT-mTOR signaling pathway may act as genetic modifiers of breast cancer DFS. We analyzed the association of 106 tagging SNPs in 13 genes (ADIPOQ, IGF1, INS, IRS1, LEP, LEPR, LEPROT, PIK3CA, PIK3R5, PTEN, TSC1, TSC2, and AKT1) in the P13K-AKT-mTOR pathway " SET Subgraph = "mTOR signaling subgraph" p(HGNC:LEPR) -> bp(PTS:"mTOR signaling pathway") p(HGNC:LEPROT) -> bp(PTS:"mTOR signaling pathway") p(HGNC:INS) -> bp(PTS:"mTOR signaling pathway") ######################################## SET Citation = {"PubMed", "Sci China Life Sci. 2011 Aug;54(8):763-9. doi: 10.1007/s11427-011-4203-9. Epub 2011 Jul 24.", "21786199"} SET Evidence = " mitochondrial uncoupling proteins, LETM1 (Ca(2+)/H(+) exchanger)" SET Subgraph = "Transport related subgraph" p(HGNC:LETM1) -- bp(PTS:Translocation) ######################################## SET Citation = {"PubMed", "Int J Mol Med. 2013 Aug;32(2):439-47. doi: 10.3892/ijmm.2013.1411. Epub 2013 Jun 7.", "23754155"} SET Evidence = "Our results demonstrated that MAGI2 enhanced STS-induced apoptosis by increasing the protein expression of cytoplasmic phosphatase and tensin homologue deleted on chromosome 10 (PTEN) and decreasing its protein degradation. The" SET Subgraph = {"Metabolism", "Protein Metabolism"} p(HGNC:MAGI2) -> bp(PTS:"PTEN signaling pathway") bp(PTS:"PTEN signaling pathway") -> bp(GOBP:"apoptotic process") p(HGNC:MAGI2) -| bp(PTS:"protein degradation pathway") ######################################## SET Citation = {"PubMed", "Cell Biol Int. 2016 Jul;40(7):803-11. doi: 10.1002/cbin.10621. Epub 2016 May 17.", "27145383"} SET Evidence = "Our data suggest that MANF inhibits apoptosis induced by 6-OHDA and overexpressed beta-synuclein in SH-SY5Y cells via upregulating GRP78 in the transcriptional pattern. " SET Subgraph = "Apoptosis signaling subgraph" p(HGNC:MANF) -| bp(GOBP:"apoptotic process") ######################################## SET Citation = {"PubMed", "Elife. 2016 Mar 21;5. pii: e11414. doi: 10.7554/eLife.11414.", "26999821"} SET Evidence = " MAP3K8 (COT/TPL2) directly regulated MEK/ERK phosphorylation, " p(HGNC:MAP3K8) -> bp(PTS:"mitogen activated protein kinase signaling pathway") p(HGNC:MAP3K8) -> p(HGNC:MAP2K1, pmod(P)) p(HGNC:MAP3K8) -> p(HGNC:MAP2K2, pmod(P)) ######################################## SET Citation = {"PubMed", "Eur J Hum Genet. 2015 Jun;23(6):781-9. doi: 10.1038/ejhg.2014.200. Epub 2014 Oct 1.", "25271084"} SET Evidence = "Circadian and mTOR signaling pathways, both associated with sleep disturbance, were altered in both MBD5 and RAI1 knockdown microarray data, overlapping with findings associated with FMR1. " SET Subgraph = "mTOR signaling subgraph" p(HGNC:MBD5) -- bp(PTS:"mTOR signaling pathway") ######################################## SET Citation = {"PubMed", "Cancer Res. 2015 Nov 1;75(21):4560-72. doi: 10.1158/0008-5472.CAN-15-0439. Epub 2015 Sep 10.", "26359458"} SET Evidence = "6. Targeting the MDM2/MDM4 interaction interface as a promising approach for p53 reactivation therapy. This peptide induces p53-dependent apoptosis" SET Subgraph = "Apoptosis signaling subgraph" p(HGNC:MDM4) -> p(HGNC:TP53) p(HGNC:TP53) -> bp(GOBP:"apoptotic process") ######################################## SET Citation = {"PubMed", "Development. 2013 Jan 1;140(1):31-42. doi: 10.1242/dev.081851. Epub 2012 Nov 15.", "23154418"} SET Evidence = "Thus, miRNA-mediated modulation of WNT signaling by MEF2A is a requisite step for proper muscle regeneration," SET Subgraph = "Wnt signaling subgraph" p(HGNC:MEF2A) -- bp(PTS:"Wnt signaling pathway") ######################################## SET Citation = {"PubMed", "Eur J Immunol. 2012 May;42(5):1327-36. doi: 10.1002/eji.201142226.", "22311635"} SET Evidence = " Forced expression of MEF2C in transitional B cells promoted cell survival, proliferation, and upregulation of pro-survival genes" SET Subgraph = "Apoptosis signaling subgraph" p(HGNC:MEF2C) -| bp(GOBP:"apoptotic process") ######################################## SET Citation = {"PubMed", "Biochem Biophys Res Commun. 2009 Sep 11;387(1):212-7. doi: 10.1016/j.bbrc.2009.07.012. Epub 2009 Jul 8.", "19591803"} SET Evidence = "Both Diversin and AF9 block canonical Wnt signaling; however, this occurs independently of each other, and does not require nuclear Diversin." SET Subgraph = "Wnt signaling subgraph" # AF9 = MLLT3 p(HGNC:MLLT3) -| bp(PTS:"Wnt signaling pathway") p(HGNC:ANKRD6) -| bp(PTS:"Wnt signaling pathway") SET Evidence = "In contrast, AF9 strongly augments the Diversin-driven activation of c-Jun N-terminal kinase (JNK)-dependent gene expression in the nucleus" SET Subgraph = "protein kinase signaling subgraph" p(HGNC:MLLT3) -> bp(PTS:"ASK1/JNK pathway") ######################################## SET Citation = {"PubMed", "J Mol Cell Cardiol. 2014 Oct;75:76-87. doi: 10.1016/j.yjmcc.2014.07.008. Epub 2014 Jul 24.", "25066696"} SET Evidence = "Inhibition of malonyl-coenzyme A decarboxylase (MCD) shifts metabolism from fatty acid towards glucose oxidation" SET Subgraph = "Metabolism" # MCD = MLYCD p(HGNC:MLYCD) -- bp(PTS:"Metabolic pathway") p(HGNC:MLYCD) -- bp(PTS:"Fatty acid metabolism") ######################################## SET Citation = {"PubMed", "Cell Death Differ. 2012 Jun;19(6):915-25. doi: 10.1038/cdd.2011.210. Epub 2012 Jan 27.", "22281706"} SET Evidence = "BOK/MTD was discovered as a protein that binds to the anti-apoptotic Bcl-2 family member MCL-1 and shares extensive amino-acid sequence similarity to BAX and BAK, which are essential for the effector phase of apoptosis. " SET Subgraph = "Apoptosis signaling subgraph" # MTD = MT1E p(HGNC:MT1E) -- bp(GOBP:"apoptotic process") ######################################## SET Citation = {"PubMed", "Cancer Genet Cytogenet. 2007 May;175(1):73-6.", "17498563"} SET Evidence = " In this region three putative oncogenes or tumor suppressor genes have been mapped: SF3B4 (splicing factor 3b, subunit 4), OTUD7B (OTU domain containing 7B), and MTMR11 (myotubularin related protein 11)." SET Subgraph = "Apoptosis signaling subgraph" p(HGNC:MTMR11) -| path(MESHD:"Carcinoid Tumor") p(HGNC:MTMR11) -> bp(GOBP:"apoptotic process") bp(GOBP:"apoptotic process") -| path(MESHD:"Carcinoid Tumor") ######################################## SET Citation = {"PubMed", "Sci Rep. 2016 Jul 26;6:28019. doi: 10.1038/srep28019.", "27456431"} SET Evidence = "The single nucleotide polymorphisms (SNPs) and their interactions of genes in the one-carbon metabolism (OCM) pathway, including Methylenetetrahydrofolate reductase (MTHFR), Methionine synthase reductase (MTRR), Methionine synthase (MTR)" SET Subgraph = "Metabolism" p(HGNC:MTRR) -> bp(PTS:"Metabolic pathway") p(HGNC:MTHFR) -> bp(PTS:"Metabolic pathway") ######################################## SET Citation = {"PubMed", "Hepatology. 2012 Jul;56(1):57-66. doi: 10.1002/hep.25642. Epub 2012 Jun 1.", "22318991"} SET Evidence = " Major vault protein (MVP) is the major constituent of vaults and is involved in multidrug resistance, nucleocytoplasmic transport, and cell signaling" SET Subgraph = "Transport related subgraph" p(HGNC:MVP) -- bp(PTS:Translocation) ######################################## SET Citation = {"PubMed", "Arthritis Care Res (Hoboken). 2014 Jul;66(7):1048-56. doi: 10.1002/acr.22282.", "24470392"} SET Evidence = " N-acetyltransferase 2 (NAT2) is involved in the metabolism of various environmental substances," SET Subgraph = "Metabolism" p(HGNC:NAT2) -- bp(PTS:"Metabolic pathway") ######################################## SET Citation = {"PubMed", "Am J Physiol Renal Physiol. 2016 May 1;310(9):F821-31. doi: 10.1152/ajprenal.00522.2015. Epub 2016 Jan 28.", "26823285"} SET Evidence = " overexpression of Nedd4-1 or Nedd4-2 enhanced hOAT1 ubiquitination, reduced the hOAT1 amount at the cell surface, and suppressed hOAT1 transport activity." SET Subgraph = {"Metabolism", "Protein Metabolism"} p(HGNC:NEDD4L) -- p(HGNC:SLC22A6) p(HGNC:NEDD4L) -> bp(PTS:"protein degradation pathway") ######################################## SET Citation = {"PubMed", "J Biol Chem. 2007 Mar 16;282(11):8060-8. Epub 2006 Dec 13.", "17166836"} SET Evidence = "Here, we show that reduced magnesium concentration enhances expression of NIPA1 suggesting a role in cellular magnesium metabolism." SET Subgraph = "Metabolism" p(HGNC:NIPA1) -- bp(PTS:"Metabolic pathway") ######################################## SET Citation = {"PubMed", "FASEB J. 2002 May;16(7):712-4. Epub 2002 Mar 12.", "11978737"} SET Evidence = "3. The neuropeptide Y Y1 receptor regulates leptin-mediated control of energy homeostasis and reproductive functions." SET Subgraph = {"Energy metabolic subgraph", "Metabolism"} p(HGNC:NPY1R) -- bp(PTS:"Energy Metabolism") ######################################## SET Citation = {"PubMed", "Biochem Soc Trans. 2015 Aug;43(4):752-7. doi: 10.1042/BST20150112. Epub 2015 Aug 3.", "26551724"} SET Evidence = "The liver X receptors (LXRs), LXRbeta and LXR≈í‚â§, are transcription factors with well-established roles in the regulation of lipid metabolism and cholesterol homeostasis." SET Subgraph = "Metabolism" # LXRbeta = NR1H2 p(HGNC:NR1H2) -- bp(PTS:"Lipid Metabolism") p(HGNC:NR1H2) -- bp(PTS:"Cholesterol Metabolism") ######################################## SET Citation = {"PubMed", "J Huazhong Univ Sci Technolog Med Sci. 2016 Jun;36(3):463-8. doi: 10.1007/s11596-016-1609-4. Epub 2016 Jul 5.", "27376821"} SET Evidence = "The human pregnane X receptor (hPXR) plays a critical role in the metabolism, transport and clearance of xenobiotics in the liver and intestine." SET Subgraph = "Metabolism" #hPXR = NR1I2 p(HGNC:NR1I2) -- bp(PTS:"Metabolic pathway") ######################################## SET Citation = {"PubMed", "J Diabetes Res. 2016;2016:6375804. doi: 10.1155/2016/6375804. Epub 2015 Dec 14.", "26788519"} SET Evidence = "Using expression analysis to define Nkx6.1-independent mechanisms by which Nr4a1 and Nr4a3 induce ≈í‚â§-cell proliferation, we demonstrated that cyclin-dependent kinase 5 regulatory subunit 1 (Cdk5r1) is upregulated by Nr4a1 and Nr4a3 but not by Nkx6.1. " SET Subgraph = "Apoptosis signaling subgraph" p(HGNC:NR4A1) -| bp(GOBP:"apoptotic process") p(HGNC:NR4A3) -| bp(GOBP:"apoptotic process") p(HGNC:NR4A1) -> p(HGNC:CDK5R1) p(HGNC:NR4A3) -> p(HGNC:CDK5R1) ######################################## SET Citation = {"PubMed", "Mol Med Rep. 2015 Oct;12(4):6098-104. doi: 10.3892/mmr.2015.4155. Epub 2015 Jul 30.", "26239564"} SET Evidence = " Overexpression of neuron‚Äö√Ñ√´derived orphan nuclear receptor‚Äö√Ñ√´1 (NOR‚Äö√Ñ√´1) in macrophages reduces the synthesis of inflammatory cytokines and chemokines" SET Subgraph = "Inflammatory response subgraph" p(HGNC:NR4A3) -| bp(PTS:"inflammatory response pathway") ######################################## SET Citation = {"PubMed", "Histopathology. 2013 May;62(6):908-15. doi: 10.1111/his.12098. Epub 2013 Mar 28.", "23551578"} SET Evidence = " Neuropilin-1 (NRP1) and neuropilin-2 (NRP2) are transmembrane glycoproteins which interact with vascular endothelial growth factor (VEGF) to prevent tumour cell apoptosis and regulate angiogenesis" SET Subgraph = "Apoptosis signaling subgraph" p(HGNC:NRP1) -| bp(GOBP:"apoptotic process") p(HGNC:NRP2) -| bp(GOBP:"apoptotic process") ######################################## SET Citation = {"PubMed", "Cell Stem Cell. 2015 Sep 3;17(3):316-28. doi: 10.1016/j.stem.2015.07.017. Epub 2015 Aug 13.", "26279266"} SET Evidence = "Both heterozygous NRXN1 mutations selectively impaired neurotransmitter release in human neurons without changing neuronal differentiation or synapse formation" SET Confidence = "High" SET Subgraph = "Neurotransmitter release subgraph" g(HGNC:NRXN1, var("?")) -- bp(PTS:"Neurotransmitter secretion") ######################################## SET Citation = {"PubMed", "PLoS One. 2012;7(11):e49229. doi: 10.1371/journal.pone.0049229. Epub 2012 Nov 14.", "23155469"} SET Evidence = "It was shown that RASIP1 dose-dependently potentiated bFGF induced expression of the MAPK responsive SBE reporter providing further support for a link between NSD1 and the MAPK/ERK signaling pathway." SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph"} p(HGNC:NSD1) -- bp(PTS:"mitogen activated protein kinase signaling pathway") ######################################## SET Citation = {"PubMed", "Dev Biol. 2016 Feb 15;410(2):190-201. doi: 10.1016/j.ydbio.2015.12.023. Epub 2015 Dec 31.", "26746789"} SET Evidence = "Homozygous knockout of NgBR in ESC results in cell apoptosis." SET Subgraph = "Apoptosis signaling subgraph" # NUS1 = NgBR p(HGNC:NUS1) -| bp(GOBP:"apoptotic process") ######################################## SET Citation = {"PubMed", "Development. 2001 Jun;128(11):2019-30.", "11493524"} SET Evidence = "Furthermore, in Otx1(-/-); Otx2(+/-) mice neural retina cell proliferation, cell differentiation and apoptotic cell death were also severely affected." SET Species = "10090" SET Subgraph = "Apoptosis signaling subgraph" p(HGNC:OTX1) -- bp(GOBP:"apoptotic process") ######################################## SET Citation = {"PubMed", "BMC Biol. 2015 Nov 30;13:103. doi: 10.1186/s12915-015-0210-9.", "26621269"} SET Evidence = "This was accompanied by reduced expression of midbrain markers, including Pax3 and Pax7, as a consequence of decreased Wnt/≈í‚â§-catenin signaling." SET Subgraph = "Wnt signaling subgraph" p(HGNC:PAX3) -- bp(PTS:"Wnt signaling pathway") ######################################## SET Citation = {"PubMed", "ACS Nano. 2014 Jan 28;8(1):76-103. doi: 10.1021/nn405077y. Epub 2013 Dec 10.", "24467380"} SET Evidence = "Cur-PLGA-NPs significantly increase expression of genes involved in cell proliferation (reelin, nestin, and Pax6" SET Subgraph = "Apoptosis signaling subgraph" p(HGNC:PAX6) -| bp(GOBP:"apoptotic process") ######################################## SET Citation = {"PubMed", "Oncol Rep. 2016 Jul;36(1):383-9. doi: 10.3892/or.2016.4793. Epub 2016 May 9.", "27176920"} SET Evidence = "Overexpression of PCDH10 can inhibit the proliferation, migration, invasion ability of pancreatic cancer cells and induce apoptosis." SET Subgraph = "Apoptosis signaling subgraph" p(HGNC:PCDH10) -> bp(GOBP:"apoptotic process") ######################################## SET Citation = {"PubMed", "Br J Cancer. 2013 Nov 12;109(10):2696-704. doi: 10.1038/bjc.2013.635. Epub 2013 Oct 15.", "24129240"} SET Evidence = "apoptosis-associated genes such as APOL6, PENK, PCDH7 and MST4" SET Subgraph = "Apoptosis signaling subgraph" p(HGNC:PCDH7) -- bp(GOBP:"apoptotic process") ######################################## SET Citation = {"PubMed", "J Biol Chem. 2014 Jun 20;289(25):17699-708. doi: 10.1074/jbc.M113.546622. Epub 2014 May 7.", "24808173"} SET Evidence = "resulting in prolonged activation of PDGF receptor ≈í‚⧠and the subsequent Ras/mitogen-activated protein kinase pathway in a PDGF-dependent manner" SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph"} p(HGNC:PDGFRB) -- bp(PTS:"mitogen activated protein kinase signaling pathway") ######################################## SET Citation = {"PubMed", "PLoS One. 2014 Apr 7;9(4):e93840. doi: 10.1371/journal.pone.0093840. eCollection 2014.", "24710520"} SET Evidence = "Osteocytes express multiple genes involved in mineral metabolism including PHEX, FGF23, DMP1 and FAM20C." SET Subgraph = "Metabolism" p(HGNC:PHEX) -- bp(PTS:"Metabolic pathway") ######################################## SET Citation = {"PubMed", "Exp Cell Res. 2008 Feb 15;314(4):707-19. doi: 10.1016/j.yexcr.2007.12.008. Epub 2008 Jan 16.", "18201699"} SET Evidence = "1. The MSX1 homeobox transcription factor is a downstream target of PHOX2B and activates the Delta-Notch pathway in neuroblastoma. " SET Subgraph = "Notch signaling subgraph" p(HGNC:PHOX2B) -> act(p(HGNC:MSX1)) act(p(HGNC:MSX1)) -> bp(PTS:"Notch signaling pathway") ######################################## SET Citation = {"PubMed", "Hematology Am Soc Hematol Educ Program. 2008:111-5. doi: 10.1182/asheducation-2008.1.111.", "19074067"} SET Evidence = "The PIG-A mutation confers an intrinsic resistance to apoptosis that becomes more conspicuous when the marrow is under immune attack;" SET Subgraph = {"Adaptive immune system subgraph", "Apoptosis signaling subgraph"} g(HGNC:PIGA, var("?")) -- bp(GOBP:"apoptotic process") ######################################## SET Citation = {"PubMed", "Biol Reprod. 2015 May;92(5):132. doi: 10.1095/biolreprod.114.126136. Epub 2015 Apr 1.", "25833159"} SET Evidence = "expression of multiple genes related to inflammation, including mediators of lipoxygenase and prostaglandin production and signaling (Alox5, Pla2g1b, Ptgfr)," SET Subgraph = "Inflammatory response subgraph" p(HGNC:PLA2G1B) -- bp(PTS:"inflammatory response pathway") ######################################## SET Citation = {"PubMed", "IUBMB Life. 2002 Nov;54(5):253-60.", "12587975"} SET Evidence = "Phosphatidic acid regulates PLC-beta1 activity and stimulation of PLC-beta1 activity by G proteins." SET Subgraph = "G-protein-mediated signaling" p(HGNC:PLCB1) -- bp(PTS:"G protein mediated signaling pathway") ######################################## SET Citation = {"PubMed", "Biochem Cell Biol. 1989 Sep;67(9):612-31.", "2679804"} SET Evidence = ", six structural genes (ura2, ura4, ura1, ura5, ura10, and ura3) and one regulatory gene (PPR1) are involved in this metabolic pathway." SET Subgraph = "Metabolism" p(HGNC:ACKR4) -- bp(PTS:"Metabolic pathway") ######################################## SET Citation = {"PubMed", "Hum Mol Genet. 1999 Jun;8(6):977-87.", "10332029"} SET Evidence = ". PQBP-1 has several functional domains, including hepta- and di-amino acid repeat sequences rich in polar residues essential for its interaction with the polyglutamine tract, a WWP/WW domain which binds to proline-rich motifs in other proteins, a putative nuclear localization signal sequence and a C2domain implicated in Ca2+-dependent phospholipid signaling." SET Subgraph = "Calcium dependent subgraph" p(HGNC:PQBP1) -- bp(PTS:"calcium dependent signaling pathway") ######################################## SET Citation = {"PubMed", "Nephrology (Carlton). 2015 Nov;20(11):832-42. doi: 10.1111/nep.12515.", "25989822"} SET Evidence = "7. Peroxiredoxin 1 inhibits the oxidative stress induced apoptosis in renal tubulointerstitial fibrosis." SET Subgraph = "Apoptosis signaling subgraph" p(HGNC:PRDX1) -| bp(GOBP:"apoptotic process") ######################################## SET Citation = {"PubMed", "Prion. 2016 Mar 3;10(2):143-52. doi: 10.1080/19336896.2016.1163457.", "27216988"} SET Evidence = "The cellular prion protein PrP(c) plays important roles in proliferation, cell death and survival, differentiation and adhesion." SET Subgraph = "Apoptosis signaling subgraph" p(HGNC:PRNP) -- bp(GOBP:"apoptotic process") p(HGNC:PRNP) -- bp(GOBP:"cell proliferation") ######################################## SET Citation = {"PubMed", "PLoS One. 2011;6(7):e21876. doi: 10.1371/journal.pone.0021876. Epub 2011 Jul 5.", "21750738"} SET Evidence = "Polypyrimidine Tract Binding (PTB) protein is a regulator of mRNA processing and translation. How PTB regulates the Notch pathway is unknown. " SET Subgraph = {"Metabolism", "Notch signaling subgraph", "Protein Metabolism"} p(HGNC:PTBP1) -- bp(PTS:"translation pathway") ######################################## SET Citation = {"PubMed", "J Pineal Res. 2012 Nov;53(4):358-65. doi: 10.1111/j.1600-079X.2012.01005.x. Epub 2012 May 28.", "22639951"} SET Evidence = "Calcium-buffering proteins including parvalbumin and hippocalcin are involved in neuronal differentiation and maturation through calcium signaling. " SET Subgraph = "Calcium dependent subgraph" p(HGNC:PVALB) -- bp(PTS:"calcium dependent signaling pathway") ######################################## SET Citation = {"PubMed", "PLoS One. 2015 May 20;10(5):e0125661. doi: 10.1371/journal.pone.0125661. eCollection 2015.", "25993541"} SET Evidence = " RLIP76 knockdown in IOMM-Lee and CH157-MN cells inhibited cell proliferation and induced apoptosis." SET Subgraph = "Apoptosis signaling subgraph" p(HGNC:RALBP1) -| bp(GOBP:"apoptotic process") ######################################## SET Citation = {"PubMed", "Leuk Lymphoma. 2014 Dec;55(12):2907-16. doi: 10.3109/10428194.2014.898759. Epub 2014 Apr 2.", "24597981"} SET Evidence = "Knockdown of Rasgrf-1 in CLL specimens inhibited active GTP-bound Ras and the Ras/Erk/mitogen-activated protein kinase (MAPK) pathway." SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph"} p(HGNC:RASGRF1) -- bp(PTS:"mitogen activated protein kinase signaling pathway") ######################################## SET Citation = {"PubMed", "Am J Hypertens. 2014 Nov;27(11):1387-95. doi: 10.1093/ajh/hpu049. Epub 2014 Mar 31.", "24688000"} SET Evidence = "Second, in 61 candidate SNPs involved in vitamin D metabolism and signaling, rs1507023 (in RBFOX1) and rs2296241 (in CYP24A1) showed significant associations with SBP" SET Subgraph = "Metabolism" p(HGNC:RBFOX1) -- bp(PTS:"vitamin D pathway") ######################################## SET Citation = {"PubMed", "PLoS One. 2012;7(9):e44636. doi: 10.1371/journal.pone.0044636. Epub 2012 Sep 5.", "22957092"} SET Evidence = "1. RBMS3 at 3p24 inhibits nasopharyngeal carcinoma development via inhibiting cell proliferation, angiogenesis, and inducing apoptosis. " SET Subgraph = "Apoptosis signaling subgraph" p(HGNC:RBMS3) -> bp(GOBP:"apoptotic process") ######################################## SET Citation = {"PubMed", "PLoS One. 2015 Dec 21;10(12):e0145280. doi: 10.1371/journal.pone.0145280. eCollection 2015.", "26690059"} SET Evidence = "During differentiation, REST knockdown resulted in increased MAPK/ERK and WNT signaling and increased expression of mesendoderm differentiation markers" SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph", "Wnt signaling subgraph"} p(HGNC:REST) -| bp(PTS:"Wnt signaling pathway") p(HGNC:REST) -| bp(PTS:"mitogen activated protein kinase signaling pathway") ######################################## SET Citation = {"PubMed", "Neurogastroenterol Motil. 2015 Jan;27(1):82-91. doi: 10.1111/nmo.12473. Epub 2014 Nov 27.", "25428414"} SET Evidence = "TPH1 gene polymorphisms and S100A10 expression, which correlate with 5-HT signaling were associated with ramosetron effectiveness in IBS-D, and may" SET Subgraph = {"Neurotransmitter release subgraph", "Serotonergic subgraph"} p(HGNC:S100A10) -- bp(PTS:"serotonin signaling pathway") ######################################## SET Citation = {"PubMed", "Am J Physiol Renal Physiol. 2011 Jun;300(6):F1437-47. doi: 10.1152/ajprenal.00015.2011. Epub 2011 Mar 23.", "21429972"} SET Evidence = "There was a defect in proteolysis of reabsorbed proteins in the Limp-2(-/-) mice" SET Subgraph = {"Metabolism", "Protein Metabolism"} # Limp-2 = SCARB2 p(HGNC:SCARB2) -- bp(PTS:"Ubiquitin mediated proteolysis") ######################################## SET Citation = {"PubMed", "Free Radic Biol Med. 2016 Mar;92:61-77. doi: 10.1016/j.freeradbiomed.2016.01.014. Epub 2016 Jan 21.", "26802903"} SET Evidence = "Here, we reported that 2-methoxy-6-acetyl-7-methyl juglone (MAM), a natural naphthoquinone isolated from Polygonum cuspidatum Sieb. et Zucc, caused hydrogen peroxide (H2O2) dependent activation of JNK In summary, a natural product MAM induced NO-dependent multiple forms of cell death in cancer cells" SET Subgraph = {"Apoptosis signaling subgraph", "protein kinase signaling subgraph"} # MAM = SGCG p(HGNC:SGCG) -> bp(PTS:"JNK _c_Jun kinases_ activation") ######################################## SET Citation = {"PubMed", "Dev Cell. 2015 May 26;33(4):373-87. doi: 10.1016/j.devcel.2015.03.005. Epub 2015 Apr 30.", "25936505"} SET Evidence = "We demonstrate that Notch signaling plays an essential role in this process, enabling neural progenitors to attain sufficiently high levels of Shh pathway activity needed to direct the ventral-most cell fates" SET Subgraph = "Notch signaling subgraph" p(HGNC:SHH) -> bp(PTS:"Notch signaling pathway") ######################################## SET Citation = {"PubMed", "Oncotarget. 2016 Jan 26;7(4):4570-83. doi: 10.18632/oncotarget.6726.", "26717037"} SET Evidence = " Moreover, SHMT1 is required to maintain DNA integrity. Depletion in lung cancer cell lines causes cell cycle arrest and uracil accumulation and ultimately leads to apoptosis." #: Add the context SET Subgraph = "Apoptosis signaling subgraph" g(HGNC:SHMT1, var("del")) -| bp(GOBP:"apoptotic process") ######################################## SET Citation = {"PubMed", "Bioinformatics. 2006 Apr 1;22(7):775-8. Epub 2006 Jan 20.", "16428264"} SET Evidence = "More specifically, we propose that they are members of a novel mitogen-activated protein kinase pathway with DYRK1A, SNF1LK and RIPK4 gene products being elements of the kinase cascade " SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph"} # SNF1KL = SIK1 p(HGNC:SIK1) -- bp(PTS:"mitogen activated protein kinase signaling pathway") ######################################## SET Citation = {"PubMed", "Cell Commun Signal. 2014 Apr 7;12:25. doi: 10.1186/1478-811X-12-25.", "24708522"} SET Evidence = "We found that pretreatment with Slit2N, an active fragment of Slit2, inhibited VEGF-C-mediated lung-derived lymphatic endothelial cell (L-LEC) proliferation, migration, and in vitro tube formation. Slit2N induced the internalization of VEGFR-3, which blocked its activation, and inhibited the activation of the PI3K/Akt pathway by VEGF-C in L-LECs" SET Subgraph = {"Apoptosis signaling subgraph", "protein kinase signaling subgraph"} p(HGNC:SLIT2) -| bp(GOBP:"apoptotic process") p(HGNC:SLIT2) -| bp(PTS:"PI3K/AKT signaling") ######################################## SET Citation = {"PubMed", "Oncol Rep. 2005 Nov;14(5):1351-5.", "16211308"} SET Evidence = "SLIT1 gene at human chromosome 10q24.1, SLIT2 gene at 4p15.31, and SLIT3 gene at 5q34-q35.1 encode large secreted proteins functioning as ligands for Roundabout (Robo) receptors. SLIT-ROBO signaling pathway is implicated in neurogenesis, angiogenesis, and immune response " SET Subgraph = "Innate immune system subgraph" p(HGNC:SLIT3) -- bp(PTS:"Immune response") ######################################## SET Citation = {"PubMed", "Zhongguo Ying Yong Sheng Li Xue Za Zhi. 2012 Jan;28(1):53-6.", "22493896"} SET Evidence = "Influence of SRS on some related indexes of free radical and Energy metabolic subgraph is one of the mechanisms of anti-exercise-induced fatigue of SRS." SET Subgraph = {"Energy metabolic subgraph", "Metabolism"} #p(HGNC:SRS) -- bp(PTS:"Energy Metabolism") ######################################## SET Citation = {"PubMed", "Breast Cancer Res Treat. 2013 Dec;142(3):515-27. doi: 10.1007/s10549-013-2769-6. Epub 2013 Nov 20.", "24253812"} SET Evidence = " For mechanistic insights, SMUG1 was correlated to biomarkers of aggressive phenotype, DNA repair, cell cycle and apoptosis. " SET Subgraph = "Apoptosis signaling subgraph" p(HGNC:SMUG1) -- bp(GOBP:"cell cycle") p(HGNC:SMUG1) -- bp(GOBP:"DNA repair") ######################################## SET Citation = {"PubMed", "BMC Cancer. 2016 Jul 18;16:493. doi: 10.1186/s12885-016-2550-4.", "27430213"} SET Evidence = "However, recent data show that the neural transcription factor SOX11 is a disease defining antigen and several involved signaling pathways have been pin-pointed, among others the Wnt/≈í‚â§-catenin pathway that is of importance for proliferation in MCL." SET Subgraph = {"Adaptive immune system subgraph", "Wnt signaling subgraph"} p(HGNC:SOX11) -- bp(PTS:"Wnt signaling pathway") ######################################## SET Citation = {"PubMed", "Pigment Cell Melanoma Res. 2016 Jul;29(4):453-8. doi: 10.1111/pcmr.12483.", "27105574"} SET Evidence = "This phenotype switch can be explained by SOX2-mediated cross talk between TGF-≈í‚⧠and non-canonical Wnt signaling." SET Subgraph = "Wnt signaling subgraph" p(HGNC:SOX2) -- bp(PTS:"Wnt signaling pathway") ######################################## SET Citation = {"PubMed", "Mol Cell Endocrinol. 2016 Aug 15;431:71-87. doi: 10.1016/j.mce.2016.05.010. Epub 2016 May 12.", "27179757"} SET Evidence = " Moreover, we showed that the up-regulation of Hsp27 by ERbeta/Sp1 facilitates proliferation and confers resistance to apoptosis through interaction with procaspase-3." SET Subgraph = "Apoptosis signaling subgraph" p(HGNC:SP1) -| bp(GOBP:"apoptotic process") p(HGNC:SP1) -- p(HGNC:CASP3) ######################################## SET Citation = {"PubMed", "Parkinsonism Relat Disord. 2014 Feb;20(2):256-9. doi: 10.1016/j.parkreldis.2013.11.004. Epub 2013 Nov 14.", "24315199"} SET Evidence = "Our results suggest that SPATACSIN may be involved in cerebella metabolism, " SET Subgraph = "Metabolism" # SPATACSIN = SPG11 p(HGNC:SPG11) -- bp(PTS:"Metabolic pathway") ######################################## SET Citation = {"PubMed", "Prostate. 2010 Sep 15;70(13):1422-8. doi: 10.1002/pros.21177.", "20687215"} SET Evidence = "These data suggest that the loss of HAI-2 may be actively involved in prostate cancer progression by causing a reduced inhibitory capacity of proteolysis possibly of the physiological target for HAI-2 matriptase." SET Subgraph = {"Metabolism", "Protein Metabolism"} # HAI-2 = SPINT2 p(HGNC:SPINT2) -| bp(PTS:"Ubiquitin mediated proteolysis") ######################################## SET Citation = {"PubMed", "Cell Mol Neurobiol. 2016 Oct;36(7):1067-76. doi: 10.1007/s10571-015-0300-9. Epub 2015 Dec 7.", "26643178"} SET Evidence = "Our results indicate that SRPX2 facilitates GBM metastasis by enhancing the EMT process via the MAPK signaling pathway." SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph"} p(HGNC:SRPX2) -> bp(PTS:"mitogen activated protein kinase signaling pathway") ######################################## SET Citation = {"PubMed", "Biochemistry. 2006 Dec 26;45(51):15529-40. Epub 2006 Dec 19.", "17176074"} SET Evidence = "including RNA binding proteins SRRM2, SFRS1, SFRS9, and SFRS10, by siRNAs reduced the rate of migration of ErbB2-overexpressing ovarian cancer cells." SET Subgraph = {"Metabolism", "Protein Metabolism"} p(HGNC:SRRM2) -- bp(PTS:"pathway of protein biosynthesis") ######################################## SET Citation = {"PubMed", "J Cancer. 2015 Feb 23;6(4):360-6. doi: 10.7150/jca.11308. eCollection 2015.", "25767606"} SET Evidence = "Our results indicated that depending on the drug, somatostatin treatment before or after chemotherapeutic drugs increased apoptosis in small cell lung cancer cells" SET Subgraph = "Apoptosis signaling subgraph" p(HGNC:SSTR1) -- bp(GOBP:"apoptotic process") p(HGNC:SSTR2) -- bp(GOBP:"apoptotic process") p(HGNC:SSTR4) -- bp(GOBP:"apoptotic process") ######################################## SET Citation = {"PubMed", "Mol Cells. 2014 Feb;37(2):161-71. doi: 10.14348/molcells.2014.2347. Epub 2014 Feb 19.", "24599001"} SET Evidence = "1. Inhibition of GM3 synthase attenuates neuropathology of Niemann-Pick disease Type C. by affecting sphingolipid metabolism." SET Subgraph = "Metabolism" p(HGNC:ST3GAL5) -- bp(PTS:"Sphingolipid metabolism") ######################################## SET Citation = {"PubMed", "Curr Mol Med. 2014;14(7):814-32.", "25109799"} SET Evidence = "1) valproic acid and advanced AMD-associated genes with the capacity to alter GABA-succinate signaling (ALDH5A1, CACNA1C, SUCLA2, and GABBR2) " SET Subgraph = {"GABA subgraph", "Neurotransmitter release subgraph"} p(HGNC:SUCLA2) -- a(CHEBI:"GABA agent") p(HGNC:SUCLA2) -- bp(PTS:"gamma_aminobutyric acid signaling pathway") ######################################## SET Citation = {"PubMed", "Chem Pharm Bull (Tokyo). 2016;64(5):399-409. doi: 10.1248/cpb.c15-00958.", "27150472"} SET Evidence = "The compound CH-1 was found to induce apoptosis as evidenced by phase contrast microscopy" SET Subgraph = "Apoptosis signaling subgraph" # CH-1 = SUCO p(HGNC:SUCO) -> bp(GOBP:"apoptotic process") ######################################## SET Citation = {"PubMed", "Eur J Endocrinol. 2015 Oct;173(4):447-54. doi: 10.1530/EJE-15-0460. Epub 2015 Jul 20.", "26194504"} SET Evidence = "We aimed to determine mRNA expressions of genes associated with local androgen synthesis and metabolism (CYP11A1, STS, CYP19A1, SRD5A1, SRD5A2, HSD3B1, AR, COMT, ESR1, ESR2, HSD3B2, CYP17A1, SULT2A1, SULT1E1, HSD17B2, IL6, TGFB1, TNFA)" SET Subgraph = "Metabolism" p(HGNC:SULT1E1) -- bp(PTS:"Metabolic pathway") ######################################## SET Citation = {"PubMed", "Elife. 2016 Apr 15;5. pii: e14211. doi: 10.7554/eLife.14211.", "27083046"} SET Evidence = "Synaptotagmin-1 (Syt1) acts as a Ca(2+) sensor for neurotransmitter release through its C2 domains." SET Subgraph = {"Calcium dependent subgraph", "Neurotransmitter release subgraph"} p(HGNC:SYT1) -- a(CHEBI:"calcium(2+)") p(HGNC:SYT1) -- bp(PTS:"Calcium signaling pathway") ######################################## SET Citation = {"PubMed", "Eur J Neurosci. 2012 Feb;35(3):402-10. doi: 10.1111/j.1460-9568.2011.07963.x. Epub 2012 Jan 12.", "22239345"} SET Evidence = "1. Cerebellar long-term depression requires dephosphorylation of TARP in Purkinje cells." SET Subgraph = "Long term synaptic depression" #p(HGNC:TARP) -- bp(PTS:"long term depression") ######################################## SET Citation = {"PubMed", "J Orthop Res. 2010 Jul;28(7):965-70. doi: 10.1002/jor.21089.", "20108324"} SET Evidence = "Other genes, including ISG, ApoB, MGAT4, and TBC1D9, showed a significantly different expression between groups. These genes may play a role in high carbohydrate diet, abnormal insulin metabolism, or inflammation, mechanisms suspected to be involved in OC" SET Subgraph = {"Inflammatory response subgraph", "Metabolism"} p(HGNC:TBC1D9) -- bp(PTS:"inflammatory response pathway") p(HGNC:TBC1D9) -- bp(PTS:"Metabolic pathway") ######################################## SET Citation = {"PubMed", "Exp Cell Res. 2010 Apr 15;316(7):1254-62. doi: 10.1016/j.yexcr.2010.01.007. Epub 2010 Jan 11.", "20060826"} SET Evidence = " Both up- and downregulation of tescalcin require activation of the MEK/ERK cascade. " SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph"} bp(PTS:"mitogen activated protein kinase signaling pathway") -> p(HGNC:TESC) ######################################## SET Citation = {"PubMed", "Lab Invest. 2015 Nov;95(11):1246-57. doi: 10.1038/labinvest.2015.106. Epub 2015 Aug 24.", "26302185"} SET Evidence = " Our data also show, for the first time, that TFPI has an anti-proliferative role" SET Subgraph = "Apoptosis signaling subgraph" p(HGNC:TFPI) -> bp(GOBP:"apoptotic process") ######################################## SET Citation = {"PubMed", "Br J Pharmacol. 2014 Jul;171(14):3432-47. doi: 10.1111/bph.12691.", "24641279"} SET Evidence = " It also indicates that modulation of the NCX is an effective method to disrupt Ca(2+) homeostasis and suppress human glioblastoma cells." SET Subgraph = "Calcium dependent subgraph" p(HGNC:TLX2) -- a(CHEBI:"calcium(2+)") ######################################## SET Citation = {"PubMed", "Oncotarget. 2016 Nov 25. doi: 10.18632/oncotarget.13579.", "27902967"} SET Evidence = " In the current study, we show that high expression of TNK2 in breast cancer cell lines correlates with high proliferation, invasion and colony forming ability. We demonstrate that knockdown of TNK2 expression can substantially suppress the invasiveness and proliferation advantage of TNBC cells " SET Subgraph = "Apoptosis signaling subgraph" p(HGNC:TNK2) -| bp(GOBP:"apoptotic process") ######################################## SET Citation = {"PubMed", "Int J Clin Exp Pathol. 2015 Oct 1;8(10):12577-82. eCollection 2015.", "26722447"} SET Evidence = "Isoliquiritigenin had a reversible inhibitory effect on TOP I activity, reduced the rate of single strand DNA unwinding in tumor cells, and thus played an important role in inducing the apoptosis of U87 glioma cells." SET Subgraph = "Apoptosis signaling subgraph" p(HGNC:TOP1) -- bp(GOBP:"apoptotic process") ######################################## SET Citation = {"PubMed", "Biomol NMR Assign. 2016 Apr;10(1):49-51. doi: 10.1007/s12104-015-9635-x. Epub 2015 Aug 21.", "26294377"} SET Evidence = "p53, p63, p73 family of proteins are transcription factors with crucial roles in regulating cellular processes such apoptosis, proliferation, differentiation, and DNA damage response" SET Subgraph = "Apoptosis signaling subgraph" p(HGNC:TP63) -- bp(GOBP:"apoptotic process") p(HGNC:TP73) -- bp(GOBP:"apoptotic process") ######################################## SET Citation = {"PubMed", "Exp Biol Med (Maywood). 2016 Jun;241(11):1250-7. doi: 10.1177/1535370216636719. Epub 2016 Mar 3.", "26941058"} SET Evidence = " Either curative or prophylactic silibinin and vitamin E groups significantly decreased ASK1 and p38 MAPK levels through increasing the gene expression of Trx1, TrxR1," SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph"} p(HGNC:TXNRD1) -| bp(PTS:"mitogen activated protein kinase signaling pathway") ######################################## SET Citation = {"PubMed", "Drug Metab Rev. 2016;48(1):47-69. doi: 10.3109/03602532.2015.1131292. Epub 2016 Feb 1.", "26828111"} SET Evidence = "Glucuronidation plays an important role in the metabolism and clearance of endogenous and exogenous carcinogenic compounds, and this reaction is primarily catalyzed by the UGT1A and UGT2B enzymes." SET Subgraph = "Metabolism" p(HGNC:UGT1A) -> bp(PTS:Glucuronidation) ######################################## SET Citation = {"PubMed", "Int J Mol Sci. 2016 Mar 9;17(3):205. doi: 10.3390/ijms17030205.", "27005621"} SET Evidence = "that the PPD glucuronidation was mainly catalyzed by UGT1A4 " SET Subgraph = "Metabolism" p(HGNC:UGT1A4) -> bp(PTS:Glucuronidation) ######################################## SET Citation = {"PubMed", "J Steroid Biochem Mol Biol. 2015 Nov;154:104-11. doi: 10.1016/j.jsbmb.2015.07.013. Epub 2015 Jul 26.", "26220143"} SET Evidence = "8. Glucuronidation of estrone and 16beta-hydroxyestrone by human UGT enzymes: The key roles of UGT1A10 and UGT2B7." SET Subgraph = "Metabolism" p(HGNC:UGT2B7) -> bp(PTS:Glucuronidation) p(HGNC:UGT8) -> bp(PTS:Glucuronidation) p(HGNC:UGT1A6) -> bp(PTS:Glucuronidation) ######################################## SET Citation = {"PubMed", "Mol Microbiol. 2006 Aug;61(3):704-22. Epub 2006 Jun 27.", "16803598"} SET Evidence = "their roles include transport (e.g. QDR2, YBT1), lipid metabolism (ATF2, ARE1), cell stress (HSP12, CTA1), DNA repair (YIM1, MEC3) and cell wall function" SET Subgraph = "Metabolism" # ARE1 = VPS52 p(HGNC:VPS52) -- bp(PTS:"Lipid Metabolism") ######################################## SET Citation = {"PubMed", "Cell Mol Life Sci. 2012 Nov;69(22):3881-93. doi: 10.1007/s00018-012-1056-8. Epub 2012 Jul 4.", "22752157"} SET Evidence = "1. VRK2 anchors KSR1-MEK1 to endoplasmic reticulum forming a macromolecular complex that compartmentalizes MAPK signaling." SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph"} p(HGNC:VRK2) -- bp(PTS:"mitogen activated protein kinase signaling pathway") ######################################## SET Citation = {"PubMed", "Trends Biochem Sci. 2006 Jan;31(1):7-10. Epub 2005 Nov 16.", "16297628"} SET Evidence = "Human tyrosyl- and tryptophanyl-tRNA synthetases (TyrRS and TrpRS, respectively) link protein synthesis to signal-transduction pathways," SET Subgraph = {"Metabolism", "Protein Metabolism"} p(HGNC:WARS) -- bp(PTS:"pathway of protein biosynthesis") ######################################## ############################################# # Nora 30.3. SET Citation = {"PubMed", "Lancet Neurol. 2014 Sep;13(9):893-903. doi: 10.1016/S1474-4422(14)70171-1. Epub 2014 Jul 30.", "25087078"} SET Evidence = "Results from the focal meta-analysis suggested an inflation factor of 1¬∑014 (appendix). We observed one notable subthreshold signal (rs12987787, p=1¬∑45‚Äà√ó‚Äà10‚àí7) from 2q24.3, the region containing SCN1A" g(dbSNP:rs12987787) pos path(MESHD:Epilepsy) g(HGNC:SCN1A) hasMember g(dbSNP:rs12987787) ############################################## SET Citation = {"PubMed", "J Neurosci. 2014 Nov 5;34(45):14874-89. doi: 10.1523/JNEUROSCI.0721-14.2014.", "25378155"} SET Evidence = "Here, we present a multisystem analysis of an SCN1A mouse model carrying the NaV1.1-R1648H mutation, which causes febrile seizures and epilepsy in humans." SET Confidence = "High" g(dbSNP:rs121918622) pos path(MESHD:Seizures) g(HGNC:SCN1A) hasMember g(dbSNP:rs121918622) ############################################## SET Citation = {"PubMed", "Epilepsia. 2013 May;54(5):927-35. doi: 10.1111/epi.12123. Epub 2013 Feb 8", "23398611"} SET Evidence = "Divergent effects of the T1174S SCN1A mutation associated with seizures and hemiplegic migraine." SET Confidence = "High" g(dbSNP:rs121918799) pos path(MESHD:Seizures) g(HGNC:SCN1A) hasMember g(dbSNP:rs121918799) ############################################## SET Citation = {"PubMed", "Hum Mol Genet. 2012 Dec 15;21(24):5359-72. doi: 10.1093/hmg/dds373. Epub 2012 Sep 4.", "22949513"} SET Evidence = "Suggestive evidence for an association with GGEs was found in the region 2q24.3 (rs11890028, P(meta) = 4.0 √ó 10(-6)) nearby the SCN1A gene, which is currently the gene with the largest number of known epilepsy-related mutations. " SET Confidence = "High" g(dbSNP:rs11890028) pos path(MESHD:Epilepsy) g(HGNC:SCN1A) hasMember g(dbSNP:rs11890028) ############################################## SET Citation = {"PubMed", "Gene. 2014 Jan 1;533(1):26-31. doi: 10.1016/j.gene.2013.09.071. Epub 2013 Sep 27.", "24076350"} SET Evidence = "The present meta-analysis suggests that SCN1A IVS5N+5G>A polymorphism is a risk factor of EFS and epilepsy, especially in Caucasian." SET Confidence = "High" g(dbSNP:rs3812718) pos path(MESHD:Epilepsy) ############################################## SET Citation = {"PubMed", "Genomics. 2015 Apr;105(4):229-36. doi: 10.1016/j.ygeno.2015.02.001. Epub 2015 Feb 7.", "25668517"} SET Evidence = "Results show that RORA rs12912233 alone might be a possible risk variant for epilepsy in Malaysian Chinese, but that, together with RORA rs880626 and SCN1A rs3812718, this polymorphism may have a synergistic effect in the epilepsy risk in Malaysians." SET Confidence = "High" g(dbSNP:rs12912233) -> path(MESHD:Epilepsy) g(dbSNP:rs880626) -> path(MESHD:Epilepsy) g(dbSNP:rs3812718) -> path(MESHD:Epilepsy) g(HGNC:RORA) hasMember g(dbSNP:rs880626) g(HGNC:RORA) hasMember g(dbSNP:rs12912233) ############################################## SET Citation = {"PubMed", "Pharmacogenet Genomics. 2013 Nov;23(11):605-10. doi: 10.1097/FPC.0000000000000000", "24061200"} SET Evidence = "A significant allelic (P=0.0006, odds ratio=1.6, 95% confidence interval=1.22-2.08) and genotypic (P=0.001) association of a synonymous variant in GABRG2, rs211037 (Asn196Asn) was observed with epilepsy irrespective of its phenotype" SET Confidence = "High" g(dbSNP:rs211037) -> path(MESHD:Epilepsy) g(HGNC:GABRG2) hasMembers list (g(dbSNP:rs211037), g(dbSNP:rs1045642), g(dbSNP:rs121909674)) ############################################## SET Citation = {"PubMed", "J Clin Pharm Ther. 2015 Jun;40(3):315-9. doi: 10.1111/jcpt.12263. Epub 2015 Apr 4.", "25846690"} SET Evidence = "Thai patients of ABCB1 3435CC genotype and with focal epilepsy were more often PB resistant." SET Confidence = "High" g(dbSNP:rs1045642) pos path(MESHD:Epilepsy) g(dbSNP:rs1045642) neg a(CHEBI:phenobarbital) ############################################## SET Citation = {"PubMed", "Nat Neurosci. 2015 Jul;18(7):988-96. doi: 10.1038/nn.4024. Epub 2015 May 25.", "26005849"} SET Evidence = "These findings suggest that the fundamental protein metabolism and cellular consequences of the epilepsy-associated mutant Œ≥2(Q390X) ion channel subunit are not fundamentally different from those associated with neurodegeneration." SET Confidence = "High" g(dbSNP:rs121909674) pos path(MESHD:Epilepsy) ############################################# SET Citation = {"PubMed", "Eur J Hum Genet. 2009 Sep;17(9):1171-81. doi: 10.1038/ejhg.2008.267. Epub 2009 Jan 28", "19172991"} SET Evidence = "Rolandic epilepsy (RE) is the most common human epilepsy, affecting children between 3 and 12 years of age, boys more often than girls (3:2). Focal sharp waves in the centrotemporal area define the electroencephalographic (EEG) trait for the syndrome, are a feature of several related childhood epilepsies and are frequently observed in common developmental disorders (eg, speech dyspraxia, attention deficit hyperactivity disorder and developmental coordination disorder)." SET Subgraph = "Chromatin organization subgraph" path(MESHD:"Epilepsy, Rolandic") -> a(EPT:"EEG, centrotemporal focal sharp waves") a(EPT:"EEG, centrotemporal focal sharp waves") -> path(MESHD:"Speech Disorders") a(EPT:"EEG, centrotemporal focal sharp waves") -> path(MESHD:"Attention Deficit Disorder with Hyperactivity") SET Evidence = "the strongest evidence was with rs986527 in intron 9 of ELP4, providing a likelihood ratio of 629:1 (P=0.0002) in favor of an association. We hypothesize that a non-coding mutation in ELP4 impairs brain-specific Elongator-mediated interaction of genes implicated in brain development, resulting in susceptibility to seizures and neurodevelopmental disorders." SET Confidence = "High" g(dbSNP:rs986527) -> a(EPT:"EEG, centrotemporal focal sharp waves") g(HGNC:ELP4) hasMember g(dbSNP:rs986527) g(dbSNP:rs986527) pos path(MESHD:"Epilepsy, Rolandic") ############################################## SET Citation = {"PubMed", "Neurology. 2010 Mar 16;74(11):909-12. doi: 10.1212/WNL.0b013e3181d6b852.", "20231667"} SET Evidence = " MECP2 mutations most frequently associated with epilepsy were T158M (74%) and R106W (78%), and less frequently R255X and R306C (both 49%). " SET Confidence = "High" g(dbSNP:rs28934906) pos path(MESHD:Epilepsy) g(dbSNP:rs28934907) pos path(MESHD:Epilepsy) ############################################## SET Citation = {"PubMed", "Hum Genet. 2014 May;133(5):651-9. doi: 10.1007/s00439-013-1405-1. Epub 2013 Dec 13.", "24337656"} SET Evidence = "SCN1A rs2298771 was associated in Indians (OR = 0.56, p = 0.005) and SCN2B rs602594 with idiopathic epilepsy (OR = 0.62, p = 0.002)." SET Confidence = "High" g(dbSNP:rs2298771) pos path(MESHD:Epilepsy) g(HGNC:SCN1A) hasMember g(dbSNP:rs2298771) g(dbSNP:rs602594) pos path(MESHD:Epilepsy) g(HGNC:SCN2B) hasMember g(dbSNP:rs602594) ############################################## # Nora 31.3. SET Citation = {"PubMed", "2011-05 Journal: Indian journal of human genetics Affiliation: R. Madhavan Nayar Center for Comprehensive Epilepsy Care, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, Kerala, India.", "21747587"} SET Evidence = "We compared five single nucleotide polymorphisms in the ABCB1 gene Ex06+139C/T (rs1202168), Ex 12 C1236T (rs1128503), Ex 17-76T/A (rs1922242), Ex 21 G2677T/A (rs2032582), Ex26 C3435T (rs1045642) among 46 MTLE-HS patients of south Indian ancestry with and without CoA accumulation. RESULTS: We found that subjects carrying the Ex-76T/A polymorphism (TA genotype) had a five-times higher risk of developing CoA accumulation than subjects without this genotype" SET Confidence = "High" g(HGNC:ABCB1) hasMembers list(g(dbSNP:rs1202168), g(dbSNP:rs1128503), g(dbSNP:rs1922242), g(dbSNP:rs2032582), g(dbSNP:rs1045642)) g(dbSNP:rs1922242) -> a(CHEBI:"coenzyme A") ############################################## # SNP Annotation SET Citation = {"PubMed", "Lenzen, K P; Heils, A; Lorenz, S; Hempelmann, A; H√∂fels, S; Lohoff, F W; Schmitz, B; Sander, T Date: 2005-02 Journal: Epilepsy research Affiliation: Gene Mapping Center, Max-Delbr√ºck-Center for Molecular Medicine, Robert-R√∂ssle-Str. 10, 13125 Berlin, Germany.", "15725393"} SET Evidence = "Replication analysis revealed a significant decrease of the Cys271 allele frequency in 446 IGE patients compared to controls (chi2 = 3.52, d.f. = 1, P = 0.030, one-sided; OR(Cys271+) = 0.69; 95% CI: 0.50-0.95). Among the IGE subgroups, lack of the Cys271 allele was accentuated in the JME group (chi2 = 5.20, d.f. = 1, P = 0.011, one-sided)." SET Confidence = "High" g(dbSNP:rs1130183) positiveCorrelation path(MESHD:"Myoclonic Epilepsy, Juvenile") ############################################## SET Citation = {"PubMed", "Mol Neurobiol. 2016 Jul;53(5):2869-77. doi: 10.1007/s12035-015-9150-1. Epub 2015 Apr 16.", "25876511"} SET Evidence = "Results showed significant association between rs6265 T, rs7103411 C, and rs7127507 T and cryptgenic epilepsy risk (p=0.00003, p=0.0002, and p=0.002, respectively) or between rs6265 and rs7103411 and symptomatic epilepsy risk in Malaysian Indians (TT vs. CC, p=0.004 and T vs. C, p=0.0002, respectively) as well as between rs6265 T and risk of cryptogenic epilepsy in Malaysian Chinese (p=0.005). The Trs6265-Crs7103411-Trs7127507 was significantly associated with cryptogenic epilepsy in Malaysian Indians (p=0.00005)." SET Confidence = "High" SET Subgraph = {"brain_derived neurotrophic factor signaling subgraph", "GABA subgraph", "Neurotransmitter release subgraph", "Mossy Fiber Subgraph", "Reelin signaling subgraph"} g(dbSNP:rs6265) positiveCorrelation path(MESHD:Epilepsy) g(dbSNP:rs7103411) positiveCorrelation path(MESHD:Epilepsy) g(dbSNP:rs7127507) positiveCorrelation path(MESHD:Epilepsy) g(HGNC:BDNF) hasMembers list(g(dbSNP:rs6265), g(dbSNP:rs7103411), g(dbSNP:rs7127507)) ############################################## SET Citation = {"PubMed", "Zhongguo Dang Dai Er Ke Za Zhi. 2016 Jun;18(6):492-5.", "27324535"} SET Evidence = "In the Han population in Central China, the polymorphisms of SNP rs9390754 in the GRIK2 gene may be associated with EP susceptibility, and the C allele of SNP rs4840200 may be a genetic risk factor for the development of drug resistance in children with EP." SET Subgraph = {"Glutamatergic subgraph", "Neurotransmitter release subgraph", "Long term synaptic depression", "Long term synaptic potentiation"} g(HGNC:GRIK2) hasMembers list(g(dbSNP:rs9390754), g(dbSNP:rs4840200)) g(dbSNP:rs9390754) positiveCorrelation path(MESHD:Epilepsy) g(dbSNP:rs4840200) -| a(CHEBI:anticonvulsant) ############################################## SET Citation = {"PubMed", "J Child Neurol. 2016 Mar;31(3):271-6. doi: 10.1177/0883073815589757. Epub 2015 Jun 12.", "26071373"} SET Evidence = "These data indicate that rs35753505 of NRG1 plays an important role in conferring susceptibility to the temporal lobe epilepsy in a Chinese Han population." SET Subgraph = "Inflammatory response subgraph" g(HGNC:NRG1) hasMember g(dbSNP:rs35753505) g(dbSNP:rs35753505) pos path(MESHD:"Epilepsy, Temporal Lobe") ############################################## SET Citation = {"PubMed", "Behav Brain Funct. 2016 Jul 8;12(1):21. doi: 10.1186/s12993-016-0106-z.", "27391700"} SET Evidence = "Following the obtained results, C3435T polymorphism of MDR1 gene may be connected with the incidence of drug-resistant epilepsy in the population of Polish children." # TODO find gene SET Confidence = "High" g(HGNC:ABCB1) hasMember g(dbSNP:rs1045642) g(dbSNP:rs1045642) positiveCorrelation path(MESHD:Epilepsy) g(dbSNP:rs1045642) -| a(CHEBI:anticonvulsant) ############################################## SET Citation = {"PubMed", "J Neuroimmunol. 2015 Jan 15;278:137-43. doi: 10.1016/j.jneuroim.2014.12.016. Epub 2014 Dec 20.", "25595263"} SET Evidence = "Evidence has shown linkage disequilibrium between rs3755724 (-55C/T) of this gene with synapsin 2 (SYN2) rs3773364 and peroxisome proliferator-activated G receptor (PPARG) rs2920502 loci, which contribute to epilepsy in Caucasians." SET Confidence = "High" SET Subgraph = "Neurotransmitter release subgraph" g(HGNC:SYN2) hasMembers list(g(dbSNP:rs3755724), g(dbSNP:rs3773364)) UNSET Subgraph SET Subgraph = {"brain_derived neurotrophic factor signaling subgraph", "Metabolism", "mTOR signaling subgraph", "Apoptosis signaling subgraph"} g(HGNC:PPARG) hasMember g(dbSNP:rs2920502) g(dbSNP:rs3773364) pos path(MESHD:Epilepsy) g(dbSNP:rs2920502) pos path(MESHD:Epilepsy) UNSET Subgraph SET Evidence = "Allele and genotype association of rs3755724 with susceptibility to epilepsy was significant in the Malaysian Chinese with focal epilepsy under codominant and dominant models (C vs. T: 1.5 (1.1-2.0), p=0.02; CT vs. TT: 1.8 (1.2-2.8), p=0.007 and 1.8 (1.2-2.7), p=0.006, respectively)" g(dbSNP:rs3755724) positiveCorrelation path(MESHD:Epilepsy) SET Evidence = "This study provides evidence that the promoter TIMP4 rs3755724 is a new focal epilepsy susceptibility variant that is plausibly involved in inflammation-induced seizures in Malaysian Chinese." SET Confidence = "High" g(HGNC:TIMP4) hasMember g(dbSNP:rs3755724) g(dbSNP:rs3755724) -> bp(GOBP:"inflammatory response") ############################################## SET Citation = {"PubMed", "Pharmacogenomics. 2014 Mar;15(4):459-66. doi: 10.2217/pgs.13.239.", "24624913"} SET Evidence = "Significant allele association of rs2273697 was observed in Chinese females with epilepsy, Malaysian Chinese patients with generalized seizure and Japanese patients with partial seizure for the AA versus GG genotype model and Malaysian Chinese patients with generalized seizure for the GA versus GG and autosomal dominant models. Significant association of the rs3740066 allele was observed in Malaysian females of Malay origin with cryptogenic epilepsy and Chinese patients with partial seizure and for genotypes in Malay patients with cryptogenic epilepsy for the CT versus CC and autosomal dominant genotype models. " SET Confidence = "High" SET Subgraph = "Transport related subgraph" g(HGNC:ABCC2) hasMembers list(g(dbSNP:rs2273697), g(dbSNP:rs3740066)) g(dbSNP:rs2273697) positiveCorrelation path(MESHD:Epilepsy) g(dbSNP:rs3740066) positiveCorrelation path(MESHD:Epilepsy) ############################################## SET Citation = {"PubMed", "CNS Neurosci Ther. 2012 Aug;18(8):647-51. doi: 10.1111/j.1755-5949.2012.00336.x. Epub 2012 May 28.", "22630058"} SET Evidence = "ABCC2-24C>T, 3972C>T polymorphisms and one ABCC2 haplotype is associated with AED resistance" SET Subgraph = "Transport related subgraph" SET Confidence = "High" g(HGNC:ABCC2) hasMembers list(g(dbSNP:rs717620), g(dbSNP:rs3740066)) g(dbSNP:rs717620) -| a(CHEBI:anticonvulsant) g(dbSNP:rs3740066) -| a(CHEBI:anticonvulsant) ############################################## SET Citation = {"PubMed", "Brain. 2014 May;137(Pt 5):1350-60. doi: 10.1093/brain/awu051. Epub 2014 Mar 18.", "24645144"} SET Evidence = " This sequence change has been reported in the 1000 Genomes project suggesting it could be a polymorphism but alternatively it could be a common mutation, perhaps responsible for the susceptibility locus for genetic generalized epilepsy on 17q21.32 (close to rs72823592). We believe the reduction in PNPO activity and B6-responsive epilepsy in the patients reported here indicates that it contributes to the pathogenesis of epilepsy." SET Confidence = "High" g(dbSNP:rs72823592) positiveCorrelation path(MESHD:Epilepsy) ############################################## SET Citation = {"PubMed", "Hum Genet. 2014 May;133(5):651-9. doi: 10.1007/s00439-013-1405-1. Epub 2013 Dec 13.", "24337656"} SET Evidence = "he strongest association with epilepsy was rs3812718, or SCN1A IVS5N+5G>A. Allele G affects splicing and speeds recovery from inactivation. Since SCN1A is preferentially expressed in inhibitory neurons, G may decrease epilepsy risk. SCN1A rs10188577 displayed OR = 1.20 for allele C (p = 0.003); SCN2A rs12467383 had OR = 1.16 for allele A (p = 0.01), and displayed linkage disequilibrium with rs2082366 (r (2) = 0.67), whose genotypes tended toward association with SCN2A brain expression (p = 0.10). SCN1A rs2298771 was associated in Indians (OR = 0.56, p = 0.005) and SCN2B rs602594 with idiopathic epilepsy (OR = 0.62, p = 0.002). Therefore, sodium channel polymorphisms are associated with epilepsy." SET Confidence = "High" SET Subgraph = {"Calcium dependent subgraph", "Glutamatergic subgraph", "Neurotransmitter release subgraph", "Serotonergic subgraph", "Metabolism", "Protein Metabolism"} g(HGNC:SCN1A) hasMembers list(g(dbSNP:rs3812718), g(dbSNP:rs10188577), g(dbSNP:rs2298771)) g(dbSNP:rs3812718) positiveCorrelation path(MESHD:Epilepsy) g(dbSNP:rs10188577) positiveCorrelation path(MESHD:Epilepsy) g(dbSNP:rs2298771) positiveCorrelation path(MESHD:Epilepsy) UNSET Subgraph SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} g(HGNC:SCN2B) hasMember g(dbSNP:rs602594) g(dbSNP:rs602594) positiveCorrelation path(MESHD:Epilepsy) UNSET Subgraph SET Subgraph = {"Serotonergic subgraph", "Neurotransmitter release subgraph"} g(HGNC:SCN2A) hasMember g(dbSNP:rs12467383) g(dbSNP:rs12467383) positiveCorrelation path(MESHD:Epilepsy) ############################################## SET Citation = {"PubMed", "Epilepsy Behav. 2014 Mar;32:59-63. doi: 10.1016/j.yebeh.2014.01.007. Epub 2014 Feb 1.", "24491795"} SET Evidence = " Tryptophan hydroxylase 2 gene allele variants might be risk factors for psychiatric conditions in TLE. More specifically, we observed that the T allele in the rs4570625 polymorphism was associated with psychotic disorders, and the A allele in the rs17110747 TPH2 polymorphism was associated with alcohol abuse in patients with TLE." SET Confidence = "High" # TODO find gene g(HGNC:TPH2) hasMembers list(g(dbSNP:rs4570625), g(dbSNP:rs17110747)) g(dbSNP:rs4570625) positiveCorrelation path(MESHD:"Psychotic Disorders") g(dbSNP:rs17110747) positiveCorrelation path(MESHD:Alcoholism) g(dbSNP:rs17110747) -- path(MESHD:"Epilepsy, Temporal Lobe") ############################################## SET Citation = {"PubMed", "J Recept Signal Transduct Res. 2014 Feb;34(1):38-43. doi: 10.3109/10799893.2013.848893. Epub 2013 Oct 29.", "24164654"} SET Evidence = "In the haplotype analysis, the frequency of the T alleles of rs1569061 and of the C alleles of the 33-bp promoter region of Synaptotagmin XI was found to be significantly higher in patients with IGE as compared with the healthy subjects" SET Confidence = "High" # TODO find gene g(dbSNP:rs1569061) positiveCorrelation path(DO:"selective IgE deficiency disease") g(HGNC:STX1A) hasMember g(dbSNP:rs1569061) ############################################## SET Citation = {"PubMed", "Epilepsia. 2014 Feb;55(2):362-9. doi: 10.1111/epi.12515. Epub 2014 Jan 13.", "24417206"} SET Evidence = "This provides evidence that rs3812718 affects the pharmacoresponse to carbamazepine via an effect on GABAergic cortical interneurons" SET Confidence = "High" SET Subgraph = {"Calcium dependent subgraph", "Glutamatergic subgraph", "Neurotransmitter release subgraph", "Serotonergic subgraph", "Metabolism", "Protein Metabolism"} g(dbSNP:rs3812718) -| a(CHEBI:carbamazepine) g(HGNC:SCN1A) hasMember g(dbSNP:rs3812718) ############################################## SET Citation = {"PubMed", "PLoS One. 2014 Feb 21;9(2):e89253. doi: 10.1371/journal.pone.0089253. eCollection 2014.", "24586633"} SET Evidence = "However, a significant association was observed between ABCB1 (C3435T) rs1045642 and risk of having epilepsy (MTLE-HS and JME pooled cohort; genotypic p-value = 0.0002; allelic p-value = 0.004)." SET Confidence = "High" SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph"} g(dbSNP:rs1045642) positiveCorrelation path(MESHD:Epilepsy) g(HGNC:ABCB1) hasMember g(dbSNP:rs1045642) ############################################## SET Citation = {"PubMed", "Front Neurol. 2014 Oct 9;5:184. doi: 10.3389/fneur.2014.00184. eCollection 2014.", "25346718"} SET Evidence = " Of six SNPs associated with the ABCC2 that were found in the study population, rs3740066 (TT) and 66744T>A (TG) were found only in the ADR. The strongest risk factor in the ABCB1 gene was identified as the TA genotype of rs2032582, whereas for the ABCC2 gene the strongest risk factor was the T allele of rs3740066. The screening of SNPs in ACBC1 and ABCC2 indicates that the Mexican patients with epilepsy in this study display frequently reported ABCC1 polymorphisms; however, in the study subjects with a higher risk factor for drug resistance, new nucleotide changes were found in the ABCC2 gene. Thus, the population of Mexican patients with AED-resistant epilepsy (ADR) used in this study exhibits genetic variability with respect to those reported in other study populations; however, it is necessary to explore this polymorphism in a larger population of patients with ADR." SET Confidence = "High" SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph"} g(HGNC:ABCB1) hasMember g(dbSNP:rs2032582) g(dbSNP:rs2032582) -| a(CHEBI:anticonvulsant) UNSET Subgraph SET Subgraph = "Transport related subgraph" g(HGNC:ABCC2) hasMember g(dbSNP:rs3740066) g(dbSNP:rs3740066) -| a(CHEBI:anticonvulsant) ############################################## SET Citation = {"PubMed", "PLoS One. 2014 Oct 14;9(10):e109634. doi: 10.1371/journal.pone.0109634. eCollection 2014.", "25313998"} SET Evidence = "Our results suggest that the ALDH2 rs671 polymorphism is associated with PSE susceptibility and affects the 4-HNE levels. " SET Confidence = "High" SET Subgraph = "Metabolism" g(dbSNP:rs671) positiveCorrelation path(DO:"photosensitive epilepsy") g(dbSNP:rs671) -- a(CHEBI:"4-hydroxynon-2-enal") g(HGNC:ALDH2) hasMember g(dbSNP:rs671) ############################################## SET Citation = {"PubMed", "Pharmacogenomics. 2013 Nov;14(15):1849-56. doi: 10.2217/pgs.13.158.", "24236484"} SET Evidence = "Further multivariate logistic regression and multifactor dimensionality reduction analyses of interactions between these genes showed that under adjustment of clinical factors, the epilepsy treatment outcomes were significantly associated with the genotype combinations of GABRA1 rs6883877, GABRA2 rs511310 and GABRA3 rs4828696 (p < 0.0001; adjusted r(2) = 0.149). CONCLUSION: Our results indicated that genetic variants in the Œ± subunits of GABA(A) receptors may interactively affect the treatment responses of antiepileptic drugs." SET Confidence = "High" SET Subgraph = {"brain_derived neurotrophic factor signaling subgraph", "GABA subgraph", "Neurotransmitter release subgraph", "hormone signaling subgraph", "Mossy Fiber Subgraph", "Notch signaling subgraph"} g(HGNC:GABRA1) hasMember g(dbSNP:rs6883877) UNSET Subgraph SET Subgraph = {"GABA subgraph", "Neurotransmitter release subgraph"} g(HGNC:GABRA2) hasMember g(dbSNP:rs511310) g(HGNC:GABRA3) hasMember g(dbSNP:rs4828696) g(dbSNP:rs6883877) -| a(CHEBI:anticonvulsant) g(dbSNP:rs511310) -| a(CHEBI:anticonvulsant) g(dbSNP:rs4828696) -| a(CHEBI:anticonvulsant) ############################################## SET Citation = {"PubMed", "DNA Cell Biol. 2013 Nov;32(11):640-7. doi: 10.1089/dna.2012.1880. Epub 2013 Sep 11.", "24024466"} SET Evidence = " Moreover, it has been demonstrated that this polymorphic variant is associated with the c.524-12_524-11insGTT variation (rs10649395) in intron 7 of CHRFAM7A. Our study substantiates the involvement of the Œ±7 subunit of nAChR in the pathophysiology of IGEs and indicates that the CHRFAM7A c.497-498TG deletion or a nearby polymorphism may play a role in the pathogenesis of IGE.c.497-498delTG; rs67158670" SET Confidence = "High" SET Subgraph = {"Apoptosis signaling subgraph", "Neurotransmitter release subgraph"} g(HGNC:CHRFAM7A) hasMember g(dbSNP:rs10649395) g(dbSNP:rs10649395) -- path(DO:"selective IgE deficiency disease") g(dbSNP:rs67158670) -- path(DO:"selective IgE deficiency disease") ############################################## SET Citation = {"PubMed", "Epileptic Disord. 2013 Sep;15(3):272-7. doi: 10.1684/epd.2013.0603.", "23996681"} SET Evidence = "The rs1024611 was genotyped by PCR-RPLP. The rs1024611 AA genotype was associated with a greater susceptibility to drug-resistant epilepsy (p=0.008; OR=2.51, 95% CI: 1.33-4.72), adjusted for age, sex, and seizure type, and the association remained significant after Bonferroni correction for multiple testing (p<0.05). Our results demonstrate that the CCL2 genetic polymorphism is associated with drug-resistant epilepsy in Chinese paediatric patients." SET Confidence = "High" SET Subgraph = "Inflammatory response subgraph" g(dbSNP:rs1024611) positiveCorrelation path(MESHD:Epilepsy) g(dbSNP:rs1024611) -| a(CHEBI:anticonvulsant) g(HGNC:CCL2) hasMember g(dbSNP:rs1024611) ############################################## SET Citation = {"PubMed", "Brain Res. 2013 Mar 7;1499:136-44. doi: 10.1016/j.brainres.2012.12.045. Epub 2013 Jan 16.", "23333373"} SET Evidence = " In order to address a potential role of rs6295 variants in human brain tissue, we have isolated DNA and mRNA from fresh frozen hippocampal tissue of pharmacoresistant temporal lobe epilepsy (TLE) patients (n=140) after epilepsy surgery for seizure control. We carried out SNP genotyping studies and mRNA analyses in order to determine HTR1a mRNA expression in human hippocampal samples stratified according to the rs6295 allelic variant. The mRNA expression of HTR1a was significantly more abundant in hippocampal mRNA of TLE patients homozygous for the rs6295 C-allele as compared to those with the GG-genotype. These data may point to a novel, i.e., rs6295 allelic variant and c-Jun dependent transcriptional 5HT1AR 'receptoropathy" SET Confidence = "High" # TODO find gene g(HGNC:HTR1A) hasMember g(dbSNP:rs6295) g(dbSNP:rs6295) -- path(MESHD:"Epilepsy, Temporal Lobe") ############################################## SET Citation = {"PubMed", "Ann Hum Genet. 2012 Jul;76(4):277-82. doi: 10.1111/j.1469-1809.2012.00713.x.", "22681516"} SET Evidence = "The distribution of 1354C>T did not differ between these two TLE groups, both in the comparison of genotype distribution (P= 0.177) and allele frequencies (P = 0.065). Nonetheless, patients with the T allele had a significantly earlier age at onset of the disease (P= 0.006). This effect was even stronger in patients with impaired memory (P= 0.00015). A second independent sample of 86 individuals with TLE satisfactorily confirmed the relationship between T allele and age at epilepsy onset. The results of this study have demonstrated that the T variant of 5-HTR2A may influence an earlier age of onset of TLE, especially in those with impaired memory." SET Confidence = "High" SET Subgraph = "G-protein-mediated signaling" g(dbSNP:rs6314) positiveCorrelation path(MESHD:"Epilepsy, Temporal Lobe") g(dbSNP:rs6314) positiveCorrelation path(MESHD:"Memory Disorders") g(HGNC:HTR2A) hasMember g(dbSNP:rs6314) ############################################## SET Citation = {"PubMed", "Seizure. 2013 Jan;22(1):53-8. doi: 10.1016/j.seizure.2012.10.007. Epub 2012 Nov 7.", "23140995"} SET Evidence = "This study showed significant association of GABRG2 rs211037 with susceptibility to FS(focal seizure), caused by two studies with small sample sizes, however the possibility of false positive results due to the effect of significant studies for FS cannot be excluded." SET Confidence = "High" SET Subgraph = {"GABA subgraph", "Neurotransmitter release subgraph"} g(HGNC:GABRG2) hasMember g(dbSNP:rs211037) g(dbSNP:rs211037) positiveCorrelation path(DO:"focal epilepsy") ############################################## SET Citation = {"PubMed", "Epilepsia. 2013 Jan;54(1):36-44. doi: 10.1111/j.1528-1167.2012.03603.x. Epub 2012 Aug 6.", "22881836"} SET Evidence = "Stage 1 analysis included 290 patients with epilepsy and revealed a higher load of adverse psychotropic side effects of LEV in patients carrying genetic variants associated with decreased dopaminergic activity: rs1611115 (dopamine-Œ≤-hydroxylase, DBH), rs4680 (catechol-O-methyltransferase, COMT), and rs1800497 (dopamine receptor D2-associated ANKK1 TAQ-1A). Stage II analysis including 100 patients with epilepsy, and joint meta-analysis confirmed the effect of the rs1800497 polymorphism (Bonferroni corrected significance of the joint meta-analysis, p = 0.0096)." SET Confidence = "High" SET Subgraph = "Metabolism" g(HGNC:DBH) hasMember g(dbSNP:rs1611115) SET Drug="levetiracetam" g(dbSNP:rs1611115) pos path(MESHD:"Drug-Related Side Effects and Adverse Reactions") a(CHEBI:levetiracetam) -> path(MESHD:"Drug-Related Side Effects and Adverse Reactions") g(HGNC:COMT) hasMember g(dbSNP:rs4680) g(dbSNP:rs4680) pos path(MESHD:"Drug-Related Side Effects and Adverse Reactions") a(CHEBI:levetiracetam) -> path(MESHD:"Drug-Related Side Effects and Adverse Reactions") UNSET Subgraph SET Subgraph = "Neurotransmitter release subgraph" g(HGNC:ANKK1) hasMember g(dbSNP:rs1800497) SET Drug="levetiracetam" g(dbSNP:rs1800497) pos path(MESHD:"Drug-Related Side Effects and Adverse Reactions") a(CHEBI:levetiracetam) -> path(MESHD:"Drug-Related Side Effects and Adverse Reactions") ############################################## SET Citation = {"PubMed", "ISRN Neurol. 2013 Aug 7;2013:261497. doi: 10.1155/2013/261497. eCollection 2013.", "23997965"} SET Evidence = "The results of this study support a notion that in the Caucasian patients with epilepsy undergoing VPA therapy, a T1405N (4217C > A, rs1047891) nonsynonymous variant was a significant risk factor for the occurrence of HA, even in patients with normal plasma levels of VPA." # TODO find gene SET Confidence = "High" g(HGNC:CPS1) hasMember g(dbSNP:rs1047891) SET Drug="valproate" g(dbSNP:rs1047891) pos path(MESHD:Hyperammonemia) a(CHEBI:valproate) -> path(MESHD:Hyperammonemia) ############################################## SET Citation = {"PubMed", "Epilepsy Res. 2012 Sep;101(3):261-7. doi: 10.1016/j.eplepsyres.2012.04.013. Epub 2012 May 11.", "22578659"} SET Evidence = "The genotype and allelic frequency of rs1800795 showed a significant association (p<0.05) in seizure frequency (number of seizures/6-months) and drug refractory epilepsy" SET Subgraph = {"Interleukin signaling subgraph", "mTOR signaling subgraph"} SET Confidence = "High" g(HGNC:IL6) hasMember g(dbSNP:rs1800795) g(dbSNP:rs1800795) positiveCorrelation path(MESHD:Seizures) g(dbSNP:rs1800795) -| a(CHEBI:anticonvulsant) UNSET Subgraph SET Evidence = "ABCC2 rs717620 -24TT genotype was significantly associated with drug resistant epilepsy (odds ratio [OR]= 4.06 [1.79-9.20], P= 0.001). The OR values of ABCC2 rs717620 -24 CT+TT genotypes and ABCC2 rs3740066 (3972C>T) CT+TT genotypes were markedly higher in drug resistant patients (OR = 1.57 [1.08-2.29], P= 0.018; OR = 1.49 [1.02-2.18], P= 0.038, respectively) compared with responsive patients. ABCC2 rs2273697 (1249G>A) and ABCB1 rs1045642 (3435C>T) polymorphisms were not associated with drug resistant epilepsy. Linkage disequilibrium (LD) test showed that the ABCC2 rs717620 were in strong LD with rs2273697 (D'= 0.694) and rs3740066 (D'= 0.699). The frequencies of haplotypes TGT (ABCC2 -24C>T/ABCC2 1249G>A/ABCC2 3972C>T) in resistant patients was significantly higher than those in responsive patients (21.0% vs. 14.2%, P < 0.05)." SET Confidence = "High" SET Subgraph = "Transport related subgraph" g(HGNC:ABCC2) hasMembers list(g(dbSNP:rs717620), g(dbSNP:rs3740066), g(dbSNP:rs2273697)) g(dbSNP:rs2273697) causesNoChange a(CHEBI:anticonvulsant) g(dbSNP:rs717620) -| a(CHEBI:anticonvulsant) g(dbSNP:rs3740066) -| a(CHEBI:anticonvulsant) UNSET Subgraph SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph"} g(HGNC:ABCB1) hasMember g(dbSNP:rs1045642) g(dbSNP:rs1045642) causesNoChange a(CHEBI:anticonvulsant) ############################################## SET Citation = {"PubMed", "Nat Genet. 2012 Apr 15;44(5):552-61. doi: 10.1038/ng.2250.", "22504417"} SET Evidence = "The intergenic variant rs7294919 was associated with hippocampal volume (12q24.22; N = 21,151; P = 6.70 √ó 10(-16)) and the expression levels of the positional candidate gene TESC in brain tissue. Additionally, rs10784502, located within HMGA2, was associated with intracranial volume (12q14.3; N = 15,782; P = 1.12 √ó 10(-12)). We also identified a suggestive association with total brain volume at rs10494373 within DDR2 (1q23.3; N = 6,500; P = 5.81 √ó 10(-7))." SET Confidence = "High" SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph"} g(dbSNP:rs7294919) -- p(HGNC:TESC) p(HGNC:TESC) -- path(MESHD:Epilepsy) g(dbSNP:rs7294919) -- a(NIFT:"Hippocampal Formation") UNSET Subgraph # TODO find gene g(HGNC:HMGA2) hasMember g(dbSNP:rs10784502) g(dbSNP:rs10784502) -- a(NIFT:"Intracranial volume") # TODO find gene g(HGNC:DDR2) hasMember g(dbSNP:rs10494373) g(dbSNP:rs10494373) -- a(NIFT:"Brain volume") ############################################## SET Citation = {"PubMed", "Epilepsia. 2011 May;52(5):975-83. doi: 10.1111/j.1528-1167.2010.02970.x. Epub 2011 Feb 14.", "21320115"} SET Evidence = "An association was found between the G allele of rs7588807 located in the INHA gene and juvenile absence epilepsy (JAE) syndrome and patients having generalized tonic-clonic seizures (GTCS) with p-values of 0.003 and 0.0002, respectively (uncorrected for multiple comparisons). DNA sequence analysis of the INHA gene in 110 JAE/GTCS patients revealed three point mutations with possible damaging effects on inhibin function in three patients and the presence of a common ACTC haplotype (H1) with a possible dominant protective role conferred by the T allele of rs7588807 with respective p-values of 0.0005 and 0.0014." SET Confidence = "High" SET Subgraph = "Chromatin organization subgraph" g(HGNC:INHA) hasMember g(dbSNP:rs7588807) g(dbSNP:rs7588807) positiveCorrelation path(DO:"juvenile absence epilepsy") g(dbSNP:rs7588807) positiveCorrelation path(MESHD:"Epilepsy, Tonic-Clonic") ############################################## SET Citation = {"PubMed", "Epilepsy Behav. 2011 Apr;20(4):681-5. doi: 10.1016/j.yebeh.2011.02.007. Epub 2011 Mar 24.", "21439911"} SET Evidence = "We found a positive association between rs11191692 and TLE, but a negative result between rs2986017 and TLE. The rs11191692-A allele frequency was found in 32.4% of the patients and in 26.2% of control subjects (OR=1.35, 95% CI=1.10-1.65, uncorrected P=0.003, corrected P=0.015). Furthermore, the positive association between rs11191692 and TLE independent of apolipoprotein E Œµ4 was supported by five SNPs haplotype analysis. The results of this study provide the first evidence that the SNP rs11191692 in CALHM1 confers highly increased susceptibility to TLE." # TODO find gene SET Confidence = "High" g(HGNC:CALHM1) hasMembers list(g(dbSNP:rs11191692), g(dbSNP:rs2986017)) g(dbSNP:rs11191692) positiveCorrelation path(MESHD:"Epilepsy, Temporal Lobe") g(dbSNP:rs2986017) causesNoChange path(MESHD:"Epilepsy, Temporal Lobe") ############################################## SET Citation = {"PubMed", "Epilepsy Res. 2011 Mar;94(1-2):110-6. doi: 10.1016/j.eplepsyres.2011.01.010. Epub 2011 Feb 18.", "21333500"} SET Evidence = "The KCNAB1 gene is a candidate susceptibility factor for lateral temporal epilepsy (LTE) because of its functional interaction with LGI1, the gene responsible for the autosomal dominant form of LTE. We investigated association between polymorphic variants across the KCNAB1 gene and LTE. The allele and genotype frequencies of 14 KCNAB1 intronic SNPs were determined in 142 Italian LTE patients and 104 healthy controls and statistically evaluated. Single SNP analysis revealed one SNP (rs992353) located near the 3'end of KCNAB1 slightly associated with LTE after multiple testing correction (odds ratio=2.25; 95% confidence interval 1.26-4.04; P=0.0058). Haplotype analysis revealed two haplotypes with frequencies higher in cases than in controls, and these differences were statistically significant after permutation tests (Psim=0.047 and 0.034). One of these haplotypes was shown to confer a high risk for the syndrome (odds ratio=12.24; 95% confidence interval 1.32-113.05) by logistic regression analysis. These results support KCNAB1 as a susceptibility gene for LTE, in agreement with previous studies showing that this gene may alter susceptibility to focal epilepsy." # TODO find gene SET Confidence = "High" g(HGNC:KCNAB1) -- path(MESHD:Epilepsy) g(HGNC:KCNAB1) hasMember g(dbSNP:rs992353) g(dbSNP:rs992353) positiveCorrelation path(MESHD:Epilepsy) g(dbSNP:rs992353) positiveCorrelation path(EPT:"lateral temporal epilepsy") ############################################## SET Citation = {"PubMed", "Cell Mol Neurobiol. 2011 Jan;31(1):45-56. doi: 10.1007/s10571-010-9551-7. Epub 2010 Aug 10.", "20697953"} SET Evidence = "Case-control analysis revealed significant over-representation of G/C and (G/C+C/C) genotypes, and C allele of exon 22 G/C marker (rs362691) in cases as compared to controls. Pair-wise linkage disequilibrium analysis demonstrated two separate LD blocks with moderately high D' values in epileptic cases. Based on these data, we have carried out haplotype case-control analysis. Even though we found over-representation of A-C haplotype of intron 12 A/C/exon 22 G/C markers and haplotype combination involving G-allele of exon 22 marker in cases and controls, respectively, the overall test was not significant. LD in this region involving this marker was also more robust in epileptic cases. Taken together, the results provide possible evidences for association of exon 22 G/C marker or any marker in the vicinity, which is in LD with this marker with epilepsy in the West Bengal population. Further investigations involving higher sample sizes are warranted to validate the present finding." SET Confidence = "High" SET Subgraph = {"brain_derived neurotrophic factor signaling subgraph", "Reelin signaling subgraph"} g(HGNC:RELN) hasMember g(dbSNP:rs362691) g(dbSNP:rs362691) positiveCorrelation path(MESHD:Epilepsy) ############################################## SET Citation = {"PubMed", "Pharmacogenomics. 2010 Nov;11(11):1525-34. doi: 10.2217/pgs.10.120.", "21121773"} SET Evidence = " An alteration in estradiol:progesterone ratio is believed to play a role in seizure occurrence in women. CYP1A1 is a key enzyme involved in the metabolism of estradiol, with variants of the CYP1A1 gene having been reported to play a role in the alteration of sex hormone metabolism in women." SET Confidence = "High" SET Subgraph = "estradiol metabolism" SET Gender = "Female" a(EPT:"estradiol-progesterone ratio") -- path(MESHD:Seizures) g(HGNC:CYP1A1) -> bp(GOBP:"response to estradiol") SET Evidence = "Results: A significant association of an intronic SNP, IVS1 +606C>A (rs2606345), with respect to seizure recurrence (genotypic: p = 3.3 × 10-4; allelic: p = 7.2 × 10-4; OR: 2.86; 95% CI: 1.5–5.3) in women with epilepsy from North India was observed. Conclusion: Since CYP1A1 is not involved in the metabolism of any of the first-line antiepileptic drugs, these results imply that variants from genes encoding sex hormone metabolizing enzymes might act as markers for predicting response to antiepileptic drug therapy in women with epilepsy." g(HGNC:CYP1A1) hasMember g(dbSNP:rs2606345) g(dbSNP:rs2606345) positiveCorrelation path(MESHD:Seizures) g(dbSNP:rs2606345) -> a(CHEBI:progesterone) g(dbSNP:rs2606345) -- path(MESHD:"Drug Resistant Epilepsy") ############################################## SET Citation = {"PubMed", "Ann Neurol. 2009 Jun;65(6):748-53. doi: 10.1002/ana.21625.", "19557857"} SET Evidence = "We sequenced genes coding for components of the SNARE complex (STX1A, VAMP2, SNAP25) and their regulatory proteins (STXBP1/Munc18-1, SYT1), which are essential for neurotransmission, in 95 patients with idiopathic mental retardation. We identified de novo mutations in STXBP1 (nonsense, p.R388X; splicing, c.169+1G>A) in two patients with severe mental retardation and nonsyndromic epilepsy. Reverse transcriptase polymerase chain reaction and sequencing showed that the splicing mutation creates a stop codon downstream of exon-3. No de novo or deleterious mutations in STXBP1 were found in 190 control subjects, or in 142 autistic patients. These results suggest that STXBP1 disruption is associated with autosomal dominant mental retardation and nonsyndromic epilepsy." SET Confidence = "High" SET Subgraph = {"Metabolism", "Neurotransmitter release subgraph"} g(HGNC:STXBP1) hasMember g(dbSNP:rs1318074) g(dbSNP:rs1318074) positiveCorrelation path(MESHD:Epilepsy) g(dbSNP:rs1318074) positiveCorrelation path(MESHD:"Mental Retardation, X-Linked") ############################################## SET Citation = {"PubMed", "Brain Dev. 2009 Jan;31(1):27-33. doi: 10.1016/j.braindev.2008.05.010. Epub 2008 Jul 21.", "18640800"} SET Evidence = "A novel heterozygous mutation (c.910-2delTTC or TTT, Phe304del) of KCNQ2 was identified in the patient. The mutation was de novo verified by parentage analysis. The mutation was associated with impaired functions of KCNQ K(+) channel. The mutant channels were expressed on the cell surface. CONCLUSION: The mutant Phe304del of KCNQ2 leads to null function of the KCNQ K(+) channel but the mutation does not alter proper channel sorting onto the cell membrane. Our findings indicate that the genes responsible for rare inherited forms of idiopathic epilepsy could be also involved in sporadic forms of idiopathic epilepsy and expand our notion of the involvement of molecular mechanisms in the more common forms of idiopathic epilepsy." SET Confidence = "High" SET Subgraph = {"Calcium dependent subgraph", "GABA subgraph", "Neurotransmitter release subgraph"} g(HGNC:KCNQ2) hasMember g(dbSNP:rs2297385) g(dbSNP:rs2297385) positiveCorrelation path(MESHD:Epilepsy) g(dbSNP:rs2297385) -| act(p(HGNC:KCNQ2)) ############################################## SET Citation = {"PubMed", "Neurology. 2008 Jul 15;71(3):177-83. doi: 10.1212/01.wnl.0000317090.92185.ec.", "18625963"} SET Evidence = "An in-frame deletion of codon 116 in KCNQ2 (p.Lys116del) and a missense mutation in KCNQ3 (p.Glu299Lys) were detected in two index cases exhibiting rolandic epilepsy and benign neonatal convulsions. Both mutations resulted in reduced potassium current amplitude in Xenopus oocytes. Mutation analysis of families with rolandic epilepsy without neonatal seizures discovered three novel missense variations (KCNQ2 p.Ile592Met, KCNQ3 p.Ala381Val, KCNQ3 p.Pro574Ser). The KCNQ2 p.Ile592Met variant displayed a significant reduction of potassium current amplitude in Xenopus oocytes and was present only once in 552 controls. Both missense variants identified in KCNQ3 (p.Ala381Val and p.Pro574Ser) were present in all affected family members and did not occur in controls, but did not show obvious functional abnormalities. The KCNQ3 missense variant p.Pro574Ser was also detected in 8 of 455 IGE patients but not in 454 controls (p = 0.008). In KCNQ2, a silent single nucleotide polymorphism (rs1801545) was found overrepresented in both epilepsy samples (IGE, p = 0.004)." SET Confidence = "High" SET Subgraph = {"Calcium dependent subgraph", "GABA subgraph", "Neurotransmitter release subgraph"} g(HGNC:KCNQ2) hasMember g(dbSNP:rs1801545) g(dbSNP:rs1801545) positiveCorrelation path(MESHD:Epilepsy) ############################################## SET Citation = {"PubMed", "Epilepsy Res. 2007 Jul;75(2-3):145-53. Epub 2007 Jun 18.", "17580110"} SET Evidence = "In order to assess the chloride channel gene CLCN2 as a candidate susceptibility gene for childhood absence epilepsy, parametric and non-parametric linkage analysis was performed in 65 nuclear pedigrees. This provided suggestive evidence for linkage with heterogeneity: NPL score=2.3, p<0.009; HLOD=1.5, alpha=0.44. Mutational analysis of the entire genomic sequence of CLCN2 was performed in 24 unrelated patients from pedigrees consistent with linkage, identifying 45 sequence variants including the known non-synonymous polymorphism rs2228292 (G2154C, Glu718Asp) and a novel variant IVS4+12G>A. Intra-familial association analysis using the pedigrees and a further 308 parent-child trios showed suggestive evidence for transmission disequilibrium of the G2154C minor allele: AVE-PDT chi(1)2 = 5.17, p<0.03. Case-control analysis provided evidence for a protective effect of the IVS4+12G>A minor allele: chi(1)2 = 7.27, p<0.008. The 65 nuclear pedigrees were screened for three previously identified mutations shown to segregate with a variety of idiopathic generalised epilepsy phenotypes (597insG, IVS2-14del11 and G2144A) but none were found. We conclude that CLCN2 may be a susceptibility locus in a subset of cases of childhood absence epilepsy." SET Confidence = "High" SET Subgraph = "Calcium dependent subgraph" g(HGNC:CLCN2) hasMember g(dbSNP:rs2228292) g(dbSNP:rs2228292) positiveCorrelation path(DO:"childhood absence epilepsy") g(HGNC:CLCN2) -- path(DO:"childhood absence epilepsy") ############################################## SET Citation = {"PubMed", "Neurosci Lett. 2007 Jun 21;421(1):1-4. Epub 2006 Nov 7.", "17092648"} SET Evidence = "Specific variations in the prion protein gene (PRNP) are associated with, and prevalent in patients with intractable temporal lobe epilepsy (TLE) and influence the surgical outcome. We investigated whether or not the PRNP gene is a susceptibility gene in temporal lobe epileptic patients with mild epilepsy. We systematically screened the entire open reading frame of the PRNP gene and evaluated the genetic contribution of the functional PRNP M129V polymorphism in 289 patients with mild TLE compared with a neurologically unaffected age and sex matched control group (n=272). Statistical analysis revealed a moderate difference in the distribution at codon 129 of the PRNP gene between sporadic mild TLE patients and healthy controls (p=0.036; OR=1.30; 95% CI=1.01-1.68). Although, there was no statistically significant difference in the genotype distribution within the study groups (p=0.101), a further analysis showed that the 129V allele was highly represented only in women with TLE compared with control group (p=0.006, OR=1.632; 95%CI=1.15-2.31). This is the first publication of data that support the hypothesis that the common methionine/valine polymorphism at codon 129 of the PRNP gene may modify the susceptibility of women to mild TLE." SET Confidence = "High" SET Gender = "Female" SET Subgraph = "Apoptosis signaling subgraph" g(HGNC:PRNP) hasMember g(dbSNP:rs1799990) g(dbSNP:rs1799990) positiveCorrelation path(MESHD:"Epilepsy, Temporal Lobe") ############################################## SET Citation = {"PubMed", "Seizure. 2016 Aug;40:21-6. doi: 10.1016/j.seizure.2016.04.011. Epub 2016 May 4.", "27310665"} SET Evidence = "miR-146a rs57095329 polymorphism might be involved in the genetic susceptibility to drug-resistance and seizure severity in childhood epilepsy patients." SET Confidence = "High" g(dbSNP:rs57095329) positiveCorrelation path(MESHD:Seizures) g(dbSNP:rs57095329) pos path(MESHD:Epilepsy) g(dbSNP:rs57095329) -| a(CHEBI:anticonvulsant) ############################################## SET Citation = {"PubMed", "Ann Clin Transl Neurol. 2016 Jun 2;3(7):512-22. doi: 10.1002/acn3.320. eCollection 2016.", "27386500"} SET Evidence = "The minor T allele of SNP rs662702 disrupts regulation by microRNA-328, which is known to result in increased PAX6 expression in vitro. This study provides, for the first time, evidence of a noncoding genomic variant contributing to the etiology of a common human epilepsy via a posttranscriptional regulatory mechanism." SET Confidence = "High" SET Subgraph = "Apoptosis signaling subgraph" g(dbSNP:rs662702) -> p(HGNC:PAX6) g(dbSNP:rs662702) positiveCorrelation path(MESHD:Epilepsy) g(dbSNP:rs662702) -| bp(GOBP:"posttranscriptional regulation of gene expression") bp(GOBP:"posttranscriptional regulation of gene expression") -- path(MESHD:Epilepsy) ############################## # Neuroimaging features annotation SET Citation = {"PubMed", "Brain Res. 2016 May 15;1639:99-107. doi: 10.1016/j.brainres.2016.02.045. Epub 2016 Mar 3.", "26947618"} SET Evidence = "Biochemical measures revealed activation of phospholipase Cγ1 (PLCγ1), extracellular signal-regulated kinase1/2 (ERK1/2) and cAMP response-element binding protein (CREB) signaling molecules in the Mg(2+)-free model in hippocampal neurons, of which ERK1/2-CREB but not PLCγ1 signaling pathway was able to be inhibited by miR-204. Epileptiform discharges assessed using whole-cell current-clamp techniques were suppressed by miR-204 in cultured Hippocampus neurons of SE (status epilepicus)." SET Confidence = "High" SET Subgraph = "Adaptive immune system subgraph" p(HGNC:PLCG1) -> a(NIFT:Hippocampus) a(NIFT:Hippocampus) -- path(MESHD:Epilepsy) ######################################## SET Citation = {"PubMed", "Hippocampus. 2004;14(3):337-44.", "15132433"} SET Evidence = " These results suggest that NRG1 may contribute to the reduction in GABAergic synaptic activity in hippocampal CA1 pyramidal neurons that normally occurs during early postnatal development, and that alterations in NRG1 signaling in the Hippocampus may contribute to schizophrenia and epilepsy." SET Confidence = "High" SET Subgraph = "Inflammatory response subgraph" p(HGNC:NRG1) -> a(NIFT:"CA1 of the hippocampus") p(HGNC:NRG1) -> a(NIFT:"Synaptic activity") ######################################## SET Citation = {"PubMed", "Cell Mol Neurobiol. 2005 Nov;25(7):1107-22.", "16392040"} SET Evidence = "The distribution of sPLA2-IB seems to be mainly neuronal, with the highest abundance occurring in the cerebral cortex and Hippocampus. We also find that genes encoding sPLA2-IB are induced by kainic acid and by electroshock-induced convulsions." SET Confidence = "High" SET Subgraph = "Inflammatory response subgraph" p(HGNC:PLA2G1B) -> a(NIFT:Hippocampus) p(HGNC:PLA2G1B) -> a(NIFT:"Cerebral Cortex") ######################################## SET Citation = {"PubMed", "J Pediatr. 2013 Sep;163(3):828-34.e1. doi: 10.1016/j.jpeds.2013.03.014. Epub 2013 Apr 13.", "23587436"} SET Evidence = "Receiver operator characteristic curve analysis indicated that the most accurate single factor for predicting unfavorable outcome was CSF β2-m >7.9 mg/L" SET Confidence = "High" SET Anatomy = "cerebrospinal fluid" SET Subgraph = "Innate immune system subgraph" p(HGNC:B2M) pos path(MESHD:"Cytomegalovirus Infections") ######################################## SET Citation = {"PubMed", "J Cell Biochem. 2011 Oct;112(10):2784-93. doi: 10.1002/jcb.23192.", "21608014"} SET Evidence = "In situ hybridization and immunohistochemical studies showed that although Brd2 mRNA is expressed in both the hippocampus and cerebellum, Brd2 protein only can be detected in the cerebellar Purkinje cells and not in hippocampal cells. These multiple levels of regulation would likely affect the production of functional BRD2 protein during neural development and hence, its role in the etiology of seizure susceptibility." SET Confidence = "High" SET Subgraph = "Innate immune system subgraph" p(HGNC:BRD2) -> a(NIFT:Hindbrain) p(HGNC:BRD2) -> bp(GOBP:"cerebellar Purkinje cell layer development") ######################################## SET Citation = {"PubMed", "J Proteomics. 2015 Jun 18;123:42-53. doi: 10.1016/j.jprot.2015.03.038. Epub 2015 Apr 10.", "25865307"} SET Evidence = "Moreover, the PPT1 IP implicate the enzyme in novel roles including: involvement in neuronal migration and dopamine receptor mediated signalling pathway." SET Subgraph = {"Innate immune system subgraph", "Metabolism", "Protein Metabolism"} p(HGNC:PPT1) -> a(NIFT:Dopamine) ######################################## SET Citation = {"PubMed", "Epilepsia. 2013 Sep;54(9):e142-5. doi: 10.1111/epi.12337. Epub 2013 Aug 14.", "23944193"} SET Evidence = "Postictal IL-17A levels in the CSF were significantly elevated compared to interictal patients and patients with IIDDs. Our results suggest that interictal IL-17A levels correlated highly with seizure severity." SET Anatomy = "cerebrospinal fluid" SET Subgraph = "Interleukin signaling subgraph" p(HGNC:IL17A) pos path(MESHD:Seizures) p(HGNC:IL17A) pos path(MESHD:Epilepsy) ######################################## SET Citation = {"PubMed", "Neurobiol Dis. 1997;3(4):263-9.", "9173924"} SET Evidence = "Compared to control animals, IL-1alpha transcripts were elevated 6 to 8 h postseizure in the hypothalamus, but not Hippocampus, by a dexamethasone-sensitive pathway. " SET Subgraph = "Interleukin signaling subgraph" SET Anatomy = "hypothalamus" path(MESHD:Seizures) positiveCorrelation p(HGNC:IL1A) path(MESHD:Seizures) -- path(MESHD:Epilepsy) UNSET Anatomy ######################################## SET Citation = {"PubMed", "Neurobiol Dis. 2015 Apr;76:126-36. doi: 10.1016/j.nbd.2014.12.032. Epub 2015 Jan 17.", "25600211"} SET Evidence = "A large number of inflammatory mediators were upregulated in Hippocampus after SE with COX-2 and IL-1β temporally leading many others." SET Subgraph = "Interleukin signaling subgraph" p(HGNC:PTGS2) -> a(NIFT:Hippocampus) ######################################## SET Citation = {"PubMed", "Chin Med Sci J. 2012 Mar;27(1):7-10.", "22734207"} SET Evidence = "The activation of p70S6k is mainly located in the dentate gyrus in KA-induced mouse model of temporal lobe epilepsy," SET Subgraph = {"Interleukin signaling subgraph", "mTOR signaling subgraph"} SET Anatomy = "dentate gyrus granule cell layer" p(HGNC:RPS6KB1) -- path(MESHD:"Epilepsy, Temporal Lobe") UNSET Anatomy ######################################## SET Citation = {"PubMed", "Brain Res. 2014 Feb 10;1546:53-62. doi: 10.1016/j.brainres.2013.12.027. Epub 2013 Dec 28.", "24380676"} SET Evidence = " Stargazin is abundantly expressed in the cerebellum and its loss results in severe deficits in AMPAR trafficking to cerebellar synapses" SET Subgraph = {"Long term synaptic depression", "Long term synaptic potentiation"} p(HGNC:CACNG2) -> a(NIFT:Hindbrain) ######################################## SET Citation = {"PubMed", "Neurobiol Aging. 2016 Aug;44:96-107. doi: 10.1016/j.neurobiolaging.2016.04.016. Epub 2016 Apr 29.", "27318137"} SET Evidence = " Amyloid precursor protein mice exhibited reduced activity marker expression in the reticular thalamic nucleus, a key inhibitory regulatory nucleus," SET Species = "10090" SET Subgraph = {"Long term synaptic potentiation", "Metabolism", "Protein Metabolism", "protein kinase signaling subgraph"} p(HGNC:APP) -> a(NIFT:"Left Thalamus Proper") ######################################## SET Citation = {"PubMed", "J Biol Chem. 2011 Mar 11;286(10):8106-16. doi: 10.1074/jbc.M110.134692. Epub 2010 Dec 29.", "21190943"} SET Evidence = " We have previously identified the contribution of elevated BACE1 activity to voltage-gated sodium channel Na(v)1.1 density and neuronal function." SET Subgraph = "Long term synaptic potentiation" p(HGNC:BACE1) -> a(NIFT:"Neuronal function") ######################################## SET Citation = {"PubMed", "Epilepsy Behav. 2015 Jul;48:66-9. doi: 10.1016/j.yebeh.2015.03.030. Epub 2015 Jun 8.", "26057352"} SET Evidence = "Serum- and CSF-FN levels constitute a potential clinical diagnostic biomarker for epilepsy and could also be used for differential diagnosis." SET Subgraph = "Long term synaptic potentiation" SET Anatomy = {"cerebrospinal fluid","serum"} p(HGNC:FN1) pos path(MESHD:Epilepsy) ######################################## SET Citation = {"PubMed", "Kaibogaku Zasshi. 2003 Sep;78(3):77-82.", "14531278"} SET Evidence = " Neuropsin is expressed by the neurons of the hippocampal subfields CA1 and CA3 and shown to cleave extracellular proteins such as fibronectin and L1. This protease plays essential roles in synaptic plasticity such as long-term potentiation (LTP) and kindling. " SET MeSHAnatomy = {"CA3 Region, Hippocampal", "CA1 Region, Hippocampal"} SET Subgraph = "Long term synaptic potentiation" p(HGNC:KLK8) -> a(NIFT:"CA1 of the hippocampus") p(HGNC:KLK8) -> bp(GOBP:"regulation of neuronal synaptic plasticity") UNSET MeSHAnatomy ######################################## SET Citation = {"PubMed", "Hippocampus. 2012 Feb;22(2):122-7. doi: 10.1002/hipo.20891. Epub 2010 Nov 3.", "21049484"} SET Evidence = "In conclusion, our present data provide strong evidence that the epileptic Hippocampus of patients with pharmacoresistant mesial TLE presents significant alterations in MOR." SET Subgraph = {"Long term synaptic potentiation", "Metabolism"} p(HGNC:OPRM1) -> a(NIFT:Hippocampus) ######################################## SET Citation = {"PubMed", "Neurol Sci. 2014 Aug;35(8):1203-8. doi: 10.1007/s10072-014-1681-0. Epub 2014 Mar 4.", "24590840"} SET Evidence = "These results demonstrated the overexpression of HIF-1α and MDR1/Pgp in Hippocampus and MTL/entorhinal cortex of mTLE patients and the pharmacoresistant TLE rat model" SET Species = "10116" SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph"} p(HGNC:ABCB1) -> a(NIFT:Hippocampus) p(HGNC:ABCB1) -> a(NIFT:"Entorhinal Cortex") ######################################## SET Citation = {"PubMed", "Iran J Child Neurol. 2016 Winter;10(1):53-60.", "27057189"} SET Evidence = "The simple febrile seizure markedly disturbed the hippocampal expression of both Bcl2 and Bax proteins, resulting in apoptosis promotion in hippocampi of juvenile rats, which were measurable for at least 15 days." SET Subgraph = {"Apoptosis signaling subgraph", "MAPK-ERK subgraph", "protein kinase signaling subgraph"} p(HGNC:BCL2) -> a(NIFT:Hippocampus) ######################################## SET Citation = {"PubMed", "Neurosci Lett. 2009 May 15;455(2):134-9. doi: 10.1016/j.neulet.2009.03.051. Epub 2009 Mar 20.", "19368862"} SET Evidence = "We found that extended amygdala kindling (i.e., 99-electrical stimulations) significantly decreased DISC1 labeling in the dentate granule cell layer and subgranular zone" SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph", "Wnt signaling subgraph"} p(HGNC:DISC1) -> a(NIFT:Amygdala) ######################################## SET Citation = {"PubMed", "Evid Based Complement Alternat Med. 2013;2013:961289. doi: 10.1155/2013/961289. Epub 2013 Dec 4.", "24381640"} SET Evidence = "The results indicate that pretreatment with UR (1.0 g/kg), RP (0.25 mg/kg), and valproic acid (VA, 250 mg/kg) for 3 d could reduce epileptic seizures and could also reduce the expression of c-Jun aminoterminal kinase phosphorylation (JNKp) of MAPK signal pathways in the cerebral cortex and Hippocampus brain tissues" SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph"} p(HGNC:JUN) -> a(NIFT:Hippocampus) p(HGNC:JUN) -> a(NIFT:"Cerebral Cortex") ######################################## SET Citation = {"PubMed", "Peptides. 2009 Jan;30(1):16-25. doi: 10.1016/j.peptides.2008.07.023. Epub 2008 Aug 13.", "18765263"} SET Evidence = "The granule cells of the dentate gyrus form the input stage of the hippocampal trisynaptic circuit and their function is strongly influenced by peptidergic systems. GPR54 is highly and discretely expressed in these cells" SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph"} p(HGNC:KISS1R) -> a(NIFT:Hippocampus) p(HGNC:KISS1R) -> a(EPT:"dentate gyrus") ######################################## SET Citation = {"PubMed", "Neural Regen Res. 2013 Jun 15;8(17):1597-605. doi: 10.3969/j.issn.1673-5374.2013.17.008.", "25206456"} SET Evidence = "After transfection of neuropeptide Y gene, mossy fiber sprouting in the hippocampal CA3 region of epileptic rats was significantly suppressed, hippocampal synaptophysin (p38) mRNA and protein expression were inhibited, and epileptic seizures were reduced" SET Species = "10116" SET Subgraph = {"Mossy Fiber Subgraph", "brain_derived neurotrophic factor signaling subgraph", "Long term synaptic potentiation"} p(HGNC:NPY) -> a(GOCC:"mossy fiber rosette") p(HGNC:NPY) -> a(UBERON:"CA3 field of hippocampus") UNSET Subgraph SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph"} p(HGNC:MAPK14) -> a(NIFT:Hippocampus) ######################################## SET Citation = {"PubMed", "Neuroscience. 2014 May 30;268:276-83. doi: 10.1016/j.neuroscience.2014.03.030. Epub 2014 Mar 25.", "24680936"} SET Evidence = "Data revealed that the mRNA and protein expression of NDEL1 and DISC1 in the whole Hippocampus increased during the spontaneous seizure period after status epilepticus (SE)" SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph"} p(HGNC:NDEL1) -> a(NIFT:Hippocampus) UNSET Subgraph SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph", "Wnt signaling subgraph"} p(HGNC:DISC1) -> a(NIFT:Hippocampus) ######################################## SET Citation = {"PubMed", "Mol Cell Neurosci. 2001 Dec;18(6):691-701.", "11749043"} SET Evidence = "Mice lacking Ras-GRF1 (-/-) are severely impaired in amygdala-dependent long-term synaptic plasticity and show higher basal synaptic activity at both amygdala and hippocampal synapses" SET Species = "10090" SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph"} p(HGNC:RASGRF1) -> a(NIFT:Amygdala) p(HGNC:RASGRF1) -> bp(GOBP:"regulation of neuronal synaptic plasticity") p(HGNC:RASGRF1) -> a(NIFT:Hippocampus) p(HGNC:RASGRF1) -> a(NIFT:"Synaptic activity") ######################################## SET Citation = {"PubMed", "Mol Med Rep. 2015 Mar;11(3):1738-44. doi: 10.3892/mmr.2014.2993. Epub 2014 Nov 21.", "25420768"} SET Evidence = "The protein levels of RGMa, FAK (Tyr397) and Ras were analyzed at different time points in the CA3 region of the Hippocampus using immunofluorescence, immunohistochemistry and western blot analysis. Compared with the control (saline‑injected) group, the expression of RGMa in the CA3 area was significantly downregulated" SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph", "Mossy Fiber Subgraph"} p(HGNC:RGMA) -> a(UBERON:"CA3 field of hippocampus") ######################################## SET Citation = {"PubMed", "Clin Lab. 2014;60(2):175-84.", "24660528"} SET Evidence = "We hypothesized that Rac1 and RhoA are involved in aberrant mossy fiber sprouting (MFS). RhoGTPases play a role in MFS but fasudil is not sufficient to inhibit RhoGTPases and MFS in the PTZ kindling model." SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph"} SET Anatomy = "mossy fiber" path(MESHD:Epilepsy) -> p(HGNC:RHOA) ######################################## SET Citation = {"PubMed", "Exp Mol Med. 2003 Oct 31;35(5):365-70.", "14646589"} SET Evidence = "Our results demonstrate that chronic activation CREB and p90RSK in the epileptic Hippocampus may be closely associated with the histopathological changes of AHS." SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph", "brain_derived neurotrophic factor signaling subgraph", "Reelin signaling subgraph"} p(HGNC:CREB1) -> a(NIFT:Hippocampus) UNSET Subgraph SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph", "mTOR signaling subgraph"} p(HGNC:RPS6KA1) -> a(NIFT:Hippocampus) ######################################## SET Citation = {"PubMed", "Science. 2013 Nov 22;342(6161):987-91. doi: 10.1126/science.1245079. Epub 2013 Oct 31.", "24179158"} SET Evidence = "Here, we show that the sushi repeat-containing protein X-linked 2 (SRPX2) gene encodes a protein that promotes synaptogenesis in the cerebral cortex." SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph"} p(HGNC:SRPX2) -> a(NIFT:"Cerebral Cortex") ######################################### SET Citation = {"PubMed", "Anat Cell Biol. 2016 Mar;49(1):21-33. doi: 10.5115/acb.2016.49.1.21. Epub 2016 Mar 28.", "27051565"} SET Evidence = " The increased density of synapsin I immunoreactivity in the outer molecular layer of the dentate gyrus of untreated epileptic rats showed a profound decrease following melatonin treatment." SET Subgraph = {"MAPK-ERK subgraph", "Neurotransmitter release subgraph", "protein kinase signaling subgraph"} SET Species = "10116" p(HGNC:SYN1) -> a(EPT:"dentate gyrus") ########################################## SET Citation = {"PubMed", "Nat Genet. 2012 Apr 15;44(5):552-61. doi: 10.1038/ng.2250.", "22504417"} SET Evidence = " The intergenic variant rs7294919 was associated with hippocampal volume (12q24.22; N = 21,151; P = 6.70 × 10(-16)) and the expression levels of the positional candidate gene TESC in brain tissue" SET Subgraph = {"MAPK-ERK subgraph", "protein kinase signaling subgraph"} p(HGNC:TESC) -> a(NIFT:"Hippocampus volume") ########################################## SET Citation = {"PubMed", "Folia Neuropathol. 2009;47(4):314-20.", "20054783"} SET Evidence = "Adenylosuccinate lyase (ADSL) deficiency is an autosomal recessive disorder caused by mutation in the ADSL gene. Affected children revealed encephalopathy with epilepsy. We present brain MR examinations of seven patients with ADSL deficiency in the correlation with their clinical findings. In all cases lack of myelination or of delayed myelination of cerebral white matter was seen" SET Subgraph = "Metabolism" p(HGNC:ADSL) -> a(NIFT:"Cerebral Cortex") p(HGNC:ADSL) -> a(NIFT:"White matter") ########################################## SET Citation = {"PubMed", "J Neurol. 2013 May;260(5):1263-71. doi: 10.1007/s00415-012-6787-9. Epub 2012 Dec 23.", "23263592"} SET Evidence = " Immunohistochemistry revealed albumin-containing monocytes and astrocytes in the perivascular areas of the cerebral white matter. " SET Subgraph = "Metabolism" p(HGNC:ALB) -> a(NIFT:"Cerebral Cortex") p(HGNC:ALB) -> a(NIFT:"White matter") ########################################## SET Citation = {"PubMed", "Ann N Y Acad Sci. 2014 May;1314:15-23. doi: 10.1111/nyas.12378. Epub 2014 Mar 4.", "24593825"} SET Evidence = " Cu and ATP7A are present at synapses, in key positions to respond to and influence synaptic activity." SET Subgraph = {"Metabolism", "Transport related subgraph"} p(HGNC:ATP7A) -> a(NIFT:"Synaptic activity") ########################################## SET Citation = {"PubMed", "Neurochem Res. 2007 Apr-May;32(4-5):905-15. Epub 2007 Mar 7.", "17342413"} SET Evidence = "The COMT and DRD2 genes may influence dopamine dependent cognitive processes such as executive/frontal lobe functions" SET Subgraph = "Metabolism" p(HGNC:COMT) -> a(NIFT:Dopamine) p(HGNC:COMT) -> a(NIFT:"Frontal lobe") UNSET Subgraph SET Subgraph = {"adenosine signaling subgraph", "Neurotransmitter release subgraph", "G-protein-mediated signaling"} p(HGNC:DRD2) -> a(NIFT:Dopamine) p(HGNC:DRD2) -> a(NIFT:"Frontal lobe") ########################################### SET Citation = {"PubMed", "Acta Neuropathol. 2007 Feb;113(2):137-52. Epub 2006 Nov 18.", "17115168"} SET Evidence = " Thus, the MTLE hippocampal formation contains an increased concentration and activity of PAG per neuron compared to non-MTLE." SET Subgraph = "Metabolism" p(HGNC:GLS) -> a(NIFT:"Hippocampal Formation") ########################################### SET Citation = {"PubMed", "Epilepsia. 2014 May;55(5):e44-9. doi: 10.1111/epi.12603. Epub 2014 Apr 4.", "24702645"} SET Evidence = "We have reported that hippocampal CA3 regions of epileptic Kv1.1α knockout (KO) mice generate pathologic sharp waves (SPWs) and high-frequency oscillations (HFOs) that have higher incidence, longer duration, and fast ripples compared to wild-type (WT)." SET Subgraph = {"Metabolism", "mTOR signaling subgraph", "Protein Metabolism", "Neurotransmitter release subgraph"} SET Species = "10090" p(HGNC:KCNA1) -> a(UBERON:"CA3 field of hippocampus") ############################################ SET Citation = {"PubMed", "Cold Spring Harb Mol Case Stud. 2015 Oct;1(1):a000356. doi: 10.1101/mcs.a000356.", "27148565"} SET Evidence = "Mutations in PURA may alter normal brain development and impair neuronal function, leading to developmental delay and the seizures observed in patients with mutations in PURA." SET Confidence = "High" g(HGNC:PURA, var("?")) pos path(MESHD:Seizures) ########################################## SET Citation = {"PubMed", "Neurology. 2006 Apr 25;66(8):1230-4.", "16636240"} SET Evidence = "At least 22 genetic loci have been linked to HSP, 8 of which are autosomal recessive (ARHSP). HSP complicated with the presence of thin corpus callosum (HSP-TCC) is a common subtype of HSP. One genetic locus has been identified on chromosome 15q13-q15 (SPG11) for HSP-TCC, but some HSP-TCC families have not been linked to this locus" SET Subgraph = "Metabolism" p(HGNC:SPG11) -> a(NIFT:"Corpus Callosum") ########################################### SET Citation = {"PubMed", "Curr Opin Neurol. 2014 Apr;27(2):199-205. doi: 10.1097/WCO.0000000000000079.", "24553459"} SET Evidence = "A series of studies in experimental and human epilepsy have undertaken large-scale expression profiling of miRNAs, key regulatory molecules in cells controlling protein levels. Levels of over 100 different miRNAs were found to either increase or decrease in the Hippocampus, of which more than 20 were identified in more than one study, including higher levels of miR-23a, miR-34a, miR-132 and miR-146a" SET Subgraph = {"miRNA subgraph", "Innate immune system subgraph", "Inflammatory response subgraph"} m(HGNC:MIR132) -> a(NIFT:Hippocampus) m(HGNC:MIR146A) -> a(NIFT:Hippocampus) ########################################### SET Citation = {"PubMed", "Brain Struct Funct. 2015 Jul;220(4):2387-99. doi: 10.1007/s00429-014-0798-5. Epub 2014 May 30.", "24874920"} SET Evidence = " Status epilepticus induced by pilocarpine was associated with upregulation of miR-134 within the Hippocampus of mice" SET Subgraph = "miRNA subgraph" m(HGNC:MIR134) -> a(NIFT:Hippocampus) ########################################### SET Citation = {"PubMed", "Brain Res. 2011 Nov 18;1424:53-9. doi: 10.1016/j.brainres.2011.09.039. Epub 2011 Sep 24.", "22019057"} SET Evidence = " MiR21 is a candidate for regulating neurotrophin-3 signaling in the Hippocampus following status epilepticus." SET Subgraph = "miRNA subgraph" m(HGNC:MIR21) -> a(NIFT:Hippocampus) ########################################### SET Citation = {"PubMed", "J Clin Invest. 2004 Apr;113(7):1059-68.", "15057313"} SET Evidence = " Blocking of FKHR/FKHRL-1 dephosphorylation after seizures improved hippocampal neuronal survival in vivo, and Bim antisense oligonucleotides were neuroprotective against seizures in vitro" SET Subgraph = "mTOR signaling subgraph" p(HGNC:FOXO1) -> a(NIFT:Hippocampus) ########################################### SET Citation = {"PubMed", "Neurobiol Dis. 2015 Oct;82:298-310. doi: 10.1016/j.nbd.2015.06.018. Epub 2015 Jul 2.", "26143616"} SET Evidence = "2. Inhibition of GSK3β rescues hippocampal development and learning in a mouse model of CDKL5 disorder." SET Species = "10090" SET Subgraph = {"mTOR signaling subgraph", "protein kinase signaling subgraph"} p(HGNC:GSK3B) -> a(NIFT:Hippocampus) ########################################### SET Citation = {"PubMed", "Epilepsia. 2012 May;53(5):922-7. doi: 10.1111/j.1528-1167.2012.03459.x. Epub 2012 Apr 17.", "22509781"} SET Evidence = " Patients with SE (p < 0.001) and RS (p < 0.05) had significantly higher NfH(SMI35) levels than controls, and SE was associated with increased concentrations when compared with SS (p < 0.001). NfH(SMI35) levels in SS did not differ from controls. Patients with SE had significantly raised HSP-70 levels compared to RS (p < 0.05), SS (p < 0.05), and controls (p < 0.001). SS and RS did not differ from each or from controls. Levels of NfH(SMI35) and HSP-70 showed a significant correlation (r = 0.34; p = 0.007) in the group of all study subjects, which was not apparent when controls and patients with seizures were considered separately. The correlation between NfH(SMI35) and HSP-70 tended to be inverse in patients with SE, but it did not reach statistical significance (r = -0.3; p > 0.05).." SET Anatomy = "cerebrospinal fluid" SET Subgraph = "mTOR signaling subgraph" p(HGNC:HSPA1A) pos path(MESHD:"Status Epilepticus") p(HGNC:NEFH) pos path(MESHD:"Status Epilepticus") ########################################### SET Citation = {"PubMed", "J Neurosci Res. 1998 Aug 15;53(4):502-9.", "9710271"} SET Evidence = " Systemic kainic acid administration to adult rats induces PIM-1 expression in the dentate gyrus region of the Hippocampus." SET Species = "10116" SET Anatomy = "dentate gyrus of hippocampal formation" SET Subgraph = "mTOR signaling subgraph" bp(GOBP:"response to kainic acid") -> p(HGNC:PIM1) ########################################### SET Citation = {"PubMed", "PLoS One. 2014 Dec 12;9(12):e114554. doi: 10.1371/journal.pone.0114554. eCollection 2014.", "25501575"} SET Evidence = " We have demonstrated that inhibition of PTEN by bpv(pic) rescues neuronal death and decreases the reactive astrogliosis in the CA3 area of the Hippocampus caused by systemic administration of kainate." SET Subgraph = {"mTOR signaling subgraph", "Reelin signaling subgraph"} p(HGNC:PTEN) -> a(UBERON:"CA3 field of hippocampus") ########################################### SET Citation = {"PubMed", "Clin Lab. 2014;60(2):175-84.", "24660528"} SET Evidence = " Rac1 and RhoA were significantly up-regulated in the PTZ group, and as predicted, the degree of aberrant MFS was correspondingly increased. " SET Subgraph = "mTOR signaling subgraph" SET Anatomy = "mossy fiber" path(MESHD:Epilepsy) -> p(HGNC:RAC1) ########################################### SET Citation = {"PubMed", "Hum Mol Genet. 2013 Jan 1;22(1):140-52. doi: 10.1093/hmg/dds414. Epub 2012 Oct 9.", "23049074"} SET Evidence = "Rictor CKO mice are hyperactive and have reduced anxiety-like behavior. Finally, there is decreased white matter and increased levels of monoamine neurotransmitters in the cerebral cortex. " SET Species = "10090" SET Subgraph = "mTOR signaling subgraph" p(HGNC:RICTOR) -> a(NIFT:"White matter") p(HGNC:RICTOR) -> a(NIFT:"Cerebral Cortex") ########################################### SET Citation = {"PubMed", "Neuroscience. 2011 Dec 29;199:64-73. doi: 10.1016/j.neuroscience.2011.10.014. Epub 2011 Oct 19.", "22033457"} SET Evidence = " The mechanism of inhibition is different from the long-lasting depression of evoked potentials, which is partly mediated via ROCK." SET Subgraph = "mTOR signaling subgraph" p(HGNC:ROCK1) -> bp(GOBP:"long term synaptic depression") ########################################### SET Citation = {"PubMed", "Neurochem Int. 2010 Dec;57(8):899-905. doi: 10.1016/j.neuint.2010.09.009. Epub 2010 Oct 7.", "20933037"} SET Evidence = " SGK1 expression was enhanced in the temporal neocortex of patients with drug-refractory epilepsy" SET Subgraph = "mTOR signaling subgraph" p(HGNC:SGK1) -> a(NIFT:Neocortex) ########################################### SET Citation = {"PubMed", "J Mol Neurosci. 2013 Jan;49(1):172-81. doi: 10.1007/s12031-012-9854-x. Epub 2012 Jul 8.", "22772901"} SET Evidence = "Through microarray analysis, we found that signal transducer and activator of transcription-3 (Stat3) gene expression was upregulated in the hippocampal CA3 region, 24 h after KA injection (15 mg/kg), and that CBZ further elevated Stat3 expression in KA-treated mice" SET Species = "10090" SET Subgraph = {"Innate immune system subgraph", "mTOR signaling subgraph"} p(HGNC:STAT3) -> a(UBERON:"CA3 field of hippocampus") ########################################### SET Citation = {"PubMed", "Trends Mol Med. 2011 Dec;17(12):734-42. doi: 10.1016/j.molmed.2011.07.008. Epub 2011 Sep 2.", "21890410"} SET Evidence = "The mTOR signaling network functions as a pivotal regulatory cascade during the development of the cerebral cortexf" SET Subgraph = {"mTOR signaling subgraph", "Metabolism", "Protein Metabolism"} p(HGNC:MTOR) -> a(NIFT:"Cerebral Cortex") ########################################### SET Citation = {"PubMed", "Adv Pharm Bull. 2013;3(2):265-71. doi: 10.5681/apb.2013.043. Epub 2013 Aug 20.", "24312846"} SET Evidence = "Therefore, it is possible to speculate that ghrelin acts in the Hippocampus to modulate seizures via NPY." SET Subgraph = "Neurotransmitter release subgraph" p(HGNC:GHRL) -> a(NIFT:Hippocampus) ########################################### SET Citation = {"PubMed", "Brain Res Dev Brain Res. 2004 Sep 17;152(2):137-42.", "15351501"} SET Evidence = "of the recurrent-seizure group was significantly decreased, but NR2C protein expression in the cerebral cortex and Hippocampus significantly increased" SET Subgraph = {"Glutamatergic subgraph", "Neurotransmitter release subgraph"} p(HGNC:GRIN2C) -> a(NIFT:"Cerebral Cortex") p(HGNC:GRIN2C) -> a(NIFT:Hippocampus) ########################################### SET Citation = {"PubMed", "Genes Brain Behav. 2013 Aug;12(6):615-25. doi: 10.1111/gbb.12052. Epub 2013 Jun 20.", "23714430"} SET Evidence = "Here, we examined mGluR4 knockout mice for types of behavior and synaptic plasticity that depend on either the Hippocampus or the prefrontal cortex (PFC). We found improved spatial short- and long-term memory in the radial arm maze, which was accompanied by enhanced long-term potentiation (LTP) in hippocampal CA1 region" SET Subgraph = {"Glutamatergic subgraph", "Neurotransmitter release subgraph"} SET Species = "10090" p(HGNC:GRM4) -> a(NIFT:"CA1 of the hippocampus") ########################################### SET Citation = {"PubMed", "Neurochem Res. 2008 Sep;33(9):1663-71. Epub 2007 Oct 18.", "17940877"} SET Evidence = "We investigated the role of metabotropic glutamate-8 receptor (mGluR8) gene expression in cerebellum during epilepsy and neuroprotective role of Bacopa monnieri extract in epilepsy." SET Subgraph = {"Glutamatergic subgraph", "Neurotransmitter release subgraph"} p(HGNC:GRM8) -> a(NIFT:Hindbrain) ########################################### SET Citation = {"PubMed", "Hum Mutat. 2015 Jan;36(1):69-78. doi: 10.1002/humu.22709. Epub 2014 Nov 27.", "25265257"} SET Evidence = "Individuals with de novo mutations in KIF1A display a phenotype characterized by cognitive impairment and variable presence of cerebellar atrophy, spastic paraparesis, optic nerve atrophy, peripheral neuropathy, and epilepsy. " SET Subgraph = {"Transport related subgraph", "Neurotransmitter release subgraph"} p(HGNC:KIF1A) -> a(NIFT:Hindbrain) p(HGNC:KIF1A) -> a(NIFT:"Cerebellar atrophy") ########################################### SET Citation = {"PubMed", "J Neurosci. 2013 Nov 13;33(46):18319-30. doi: 10.1523/JNEUROSCI.5293-12.2013.", "24227741"} SET Evidence = "1. Synapsin II and Rab3a cooperate in the regulation of epileptic and synaptic activity in the CA1 region of the Hippocampus." SET Subgraph = "Neurotransmitter release subgraph" p(HGNC:RAB3A) -> a(NIFT:"Synaptic activity") p(HGNC:SYN2) -> a(NIFT:"Synaptic activity") p(HGNC:RAB3A) -> a(NIFT:"CA1 of the hippocampus") p(HGNC:SYN2) -> a(NIFT:"CA1 of the hippocampus") ########################################### SET Citation = {"PubMed", "Biochim Biophys Acta. 2015 Jan;1849(1):1-9. doi: 10.1016/j.bbagrm.2014.11.004. Epub 2014 Nov 18.", "25459751"} SET Evidence = " In the Hippocampus of seizure mice, the expressions of Scn3a and Mbd2 were upregulated after 10-day KA treatment" SET Species = "10090" SET Subgraph = {"Neurotransmitter release subgraph", "Serotonergic subgraph"} p(HGNC:SCN3A) -> a(NIFT:Hippocampus) ########################################### SET Citation = {"PubMed", "Epilepsia. 2016 Jun;57(6):977-83. doi: 10.1111/epi.13376. Epub 2016 Mar 31.", "27030321"} SET Evidence = " Somatostatin interneurons are a major subpopulation of inhibitory neurons in the dentate gyrus, and many are lost in patients and animal models" SET Subgraph = "Neurotransmitter release subgraph" p(HGNC:SST) -> a(EPT:"dentate gyrus") ########################################### SET Citation = {"PubMed", "Neural Regen Res. 2014 Mar 1;9(5):526-33. doi: 10.4103/1673-5374.130083.", "25206850"} SET Evidence = "Compared with patient control cases, the presences of Notch1 and hairy and enhancer of split-1 were upregulated in the temporal neocortex of patients with intractable temporal lobe epilepsy." SET Subgraph = "Notch signaling subgraph" p(HGNC:NOTCH1) -> a(NIFT:Neocortex) p(HGNC:HES1) -> a(NIFT:Neocortex) ########################################### SET Citation = {"PubMed", "Proc Natl Acad Sci U S A. 2010 Apr 13;107(15):7042-7. doi: 10.1073/pnas.0912041107. Epub 2010 Mar 26.", "20348416"} SET Evidence = "Furthermore, in postmitotic neurons of the developing cortical plate, AF9 is implicated in the formation of the six-layered cerebral cortex by suppressing a TBR1-positive cell fate mainly in upper layer neurons." SET Subgraph = {"protein kinase signaling subgraph", "Transport related subgraph"} p(HGNC:MLLT3) -> a(NIFT:"Cerebral Cortex") ########################################### SET Citation = {"PubMed", "Am J Med Genet A. 2015 Dec;167A(12):3096-102. doi: 10.1002/ajmg.a.37353. Epub 2015 Sep 14.", "26364767"} SET Evidence = "FOXG1-related disorders are caused by heterozygous mutations in FOXG1 and result in a spectrum of neurodevelopmental phenotypes including postnatal microcephaly, intellectual disability with absent speech, epilepsy, chorea, and corpus callosum abnormalities" SET Subgraph = {"Transport related subgraph", "Reelin signaling subgraph"} p(HGNC:FOXG1) -> a(NIFT:"Corpus Callosum") ########################################### SET Citation = {"PubMed", "J Neurosci. 2015 Jun 10;35(23):8866-81. doi: 10.1523/JNEUROSCI.3470-14.2015.", "26063919"} SET Evidence = " Anatomic studies revealed expression of Fgf13 mRNA in both excitatory and inhibitory neurons of Hippocampus. " SET Subgraph = "Regulation of actin cytoskeleton subgraph" p(HGNC:FGF13) -> a(NIFT:Hippocampus) ########################################### SET Citation = {"PubMed", "Neurol Res. 2012 Jun;34(5):430-8. doi: 10.1179/1743132811Y.0000000055. Epub 2012 May 30.", "22643638"} SET Evidence = "Rats after SE exhibited a significant upregulation of Mrp2 in the capillary endothelial cells of the cerebral cortex, piriform cortex, and Hippocampus, compared with those in control at 24 hours after the end of SE." SET Confidence = "High" SET MeSHAnatomy = "Hippocampus" SET Anatomy = {"piriform cortex","cerebral cortex"} SET Species = "10116" SET Subgraph = "Transport related subgraph" p(HGNC:ABCC2) pos path(MESHD:"Status Epilepticus") ########################################### SET Citation = {"PubMed", "Biol Open. 2014 Nov 13;3(12):1158-63. doi: 10.1242/bio.20148730.", "25395668"} SET Evidence = " Here, we show that Cre-mediated inactivation of Atrx in the embryonic mouse (Mus musculus) brain results in expansion of cerebral cortical layer VI, and a concurrent thinning of layers II-IV. We conclude that ATRX is required for correct lamination of the mouse neocortex by regulating the timing of neuroprogenitor cell differentiation." SET Species = "10090" SET Subgraph = "Transport related subgraph" p(HGNC:ATRX) -> a(NIFT:"Cerebral Cortex") p(HGNC:ATRX) -> a(NIFT:Neocortex) ########################################### SET Citation = {"PubMed", "J Neurol Sci. 2011 Sep 15;308(1-2):88-93. doi: 10.1016/j.jns.2011.05.047. Epub 2011 Jun 17.", "21683962"} SET Evidence = "We detected MVP expression in tissue samples from the refractory frontal cortex of 30 patients who had been surgically treated for refractory epilepsy. We compared these tissues with twelve histologically normal frontal lobe samples from controls. In the control group, the expression of MVP was faint in the cortex. The expression of MVP protein increased dramatically in the refractory epilepsy group;" SET Subgraph = "Transport related subgraph" p(HGNC:MVP) -> a(NIFT:"Frontal lobe") ########################################### SET Citation = {"PubMed", "Cell Mol Life Sci. 2015 Sep;72(18):3489-506. doi: 10.1007/s00018-015-1937-8. Epub 2015 Jun 2.", "26033496"} SET Evidence = "EAAT2 plays a critical role in regulation of synaptic activity and plasticity." SET Subgraph = "Transport related subgraph" p(HGNC:SLC1A2) -> a(NIFT:"Synaptic activity") p(HGNC:SLC1A2) -> bp(GOBP:"regulation of neuronal synaptic plasticity") ########################################### SET Citation = {"PubMed", "Arch Neurol. 2008 Apr;65(4):550-3. doi: 10.1001/archneur.65.4.550.", "18413482"} SET Evidence = " SLC4A10 (OMIM 605556), a sodium bicarbonate transporter gene with high expression in the cerebral cortex and Hippocampus, was disrupted by the translocation breakpoint on chromosome 2q24." SET Subgraph = "Transport related subgraph" p(HGNC:SLC4A10) -> a(NIFT:"Cerebral Cortex") p(HGNC:SLC4A10) -> a(NIFT:Hippocampus) ########################################### SET Citation = {"PubMed", "Mol Cell Biol. 2006 Jan;26(1):182-91.", "16354689"} SET Evidence = " In the pyramidal cell layer of the hippocampal CA3 region, where AE3 is strongly expressed, disruption of AE3 abolished sodium-independent chloride-bicarbonate exchange. These findings strongly support the hypothesis that AE3 modulates seizure susceptibility and, therefore, are of significance for understanding the role of intracellular pH in epilepsy." SET Subgraph = "Transport related subgraph" p(HGNC:SLC4A3) -> a(UBERON:"CA3 field of hippocampus") ######################################## SET Citation = {"PubMed", "Neuron. 2016 Apr 6;90(1):56-69. doi: 10.1016/j.neuron.2016.02.040. Epub 2016 Mar 24.", "27021170"} SET Evidence = "Here we investigate consequences of selective Ube3a loss from either GABAergic or glutamatergic neurons, focusing on the development of hyperexcitability within L2/3 neocortex and in broader circuit and behavioral contexts. We find that GABAergic Ube3a loss causes AS-like increases in neocortical EEG delta power, enhances seizure susceptibility, and leads to presynaptic accumulation of clathrin-coated vesicles (CCVs)-all without decreasing GABAergic inhibition onto L2/3 pyramidal neurons." SET Subgraph = {"adenosine signaling subgraph", "Metabolism", "Protein Metabolism"} p(HGNC:UBE3A) -> a(NIFT:Neocortex) a(NIFT:Neocortex) -- path(MESHD:Epilepsy) ######################################## SET Citation = {"PubMed", "Neuroradiology. 2016 Jul;58(7):697-703. doi: 10.1007/s00234-016-1676-z. Epub 2016 Mar 18.", "26993811"} SET Evidence = "Adenosine kinase deficiency (ADK deficiency) is a recently described disorder of methionine and adenosine metabolism resulting in a neurological phenotype with developmental delay, muscular hypotonia, and epilepsy as well as variable systemic manifestations. White matter changes occurring in five of eight patients were discrete, periventricular, and unspecific (4/5), or diffuse with sparing of optic radiation, corona radiata, and pyramidal tracts." SET Subgraph = {"adenosine signaling subgraph", "protein kinase signaling subgraph", "Neurotransmitter release subgraph"} p(HGNC:ADK) -> a(NIFT:"White matter") a(NIFT:"White matter") -- path(MESHD:Epilepsy) ######################################## SET Citation = {"PubMed", "Mol Neurobiol. 2013 Dec;48(3):921-30. doi: 10.1007/s12035-013-8480-0. Epub 2013 Jun 20.", "23783558"} SET Evidence = "Dynamic changes in adenosine A1 receptors (A1Rs) and A2a receptors (A2aRs) were investigated in a kindling model of epilepsy. RT-PCR, Western blotting, and immunofluorescence results indicated that expression of A1Rs was increased in the Hippocampus 24 h after kindling, but progressively decreased 1 and 6 months after kindling" SET Subgraph = {"adenosine signaling subgraph", "Glutamatergic subgraph", "Neurotransmitter release subgraph"} p(HGNC:ADORA1) -> a(NIFT:Hippocampus) ######################################## SET Citation = {"PubMed", "Front Cell Neurosci. 2015 Jan 21;8:472. doi: 10.3389/fncel.2014.00472. eCollection 2014.", "25653593"} SET Evidence = "We report that fractalkine/CX3CL1 protects hippocampal neurons from NMDA-induced cell death with a mechanism requiring the adenosine receptors type 2A (A2AR)." SET Subgraph = {"adenosine signaling subgraph", "G-protein-mediated signaling", "Neurotransmitter release subgraph"} p(HGNC:ADORA2A) -> a(NIFT:Hippocampus) ######################################## SET Citation = {"PubMed", "Pharmacol Res. 2007 Aug;56(2):110-7. Epub 2007 May 1.", "17548208"} SET Evidence = "These results suggest that activation of A1 receptors of the entorhinal cortex has an anticonvulsant, but activation of A2A receptors of this region has a proconvulsive effect on piriform cortex kindled seizures" SET Subgraph = {"adenosine signaling subgraph", "G-protein-mediated signaling", "Neurotransmitter release subgraph"} p(HGNC:ADORA2A) -> a(NIFT:"Entorhinal Cortex") UNSET Subgraph SET Subgraph = {"adenosine signaling subgraph", "Glutamatergic subgraph", "Neurotransmitter release subgraph"} p(HGNC:ADORA1) -> a(NIFT:"Entorhinal Cortex") a(NIFT:"Entorhinal Cortex") -- path(MESHD:Epilepsy) ######################################## SET Citation = {"PubMed", "J Mol Neurosci. 2013 Jan;49(1):202-10. doi: 10.1007/s12031-012-9927-x. Epub 2012 Nov 29.", "23188702"} SET Evidence = "Dopamine D2 receptor (D2R) signalling has been shown to modulate seizure-induced hippocampal cell death" SET Subgraph = {"adenosine signaling subgraph", "G-protein-mediated signaling", "Neurotransmitter release subgraph"} p(HGNC:DRD2) -> a(NIFT:Hippocampus) ######################################## SET Citation = {"PubMed", "J Biol Chem. 2005 Mar 25;280(12):11361-8. Epub 2005 Jan 4.", "15632197"} SET Evidence = "Mutations in the human Doublecortin (DCX) gene cause X-linked lissencephaly, a neuronal migration disorder affecting the neocortex and characterized by mental retardation and epilepsy" SET Subgraph = "Reelin signaling subgraph" p(HGNC:DCX) -> a(NIFT:Neocortex) ######################################## SET Citation = {"PubMed", "J Neurosci. 1997 Oct 15;17(20):8024-37.", "9315921"} SET Evidence = " RGS4 mRNA is notable for its dense expression in neocortex, piriform cortex, caudoputamen, and ventrobasal thalamus." SET Subgraph = {"adenosine signaling subgraph", "Neurotransmitter release subgraph", "Calcium dependent subgraph", "G-protein-mediated signaling", "GABA subgraph"} p(HGNC:RGS4) -> a(NIFT:Neocortex) SET Anatomy = "piriform cortex" p(HGNC:ABCC2) -- path(MESHD:Epilepsy) UNSET Anatomy #p(HGNC:RGS4) -> a("caudoputamen") #p(HGNC:RGS4) -> a("ventrobasal thalamus") ######################################## SET Citation = {"PubMed", "Epilepsia. 2009 Aug;50(8):1875-90. doi: 10.1111/j.1528-1167.2009.02161.x. Epub 2009 Jun 1.", "19490052"} SET Evidence = "In the present study, we analyzed expression of androgen receptor (AR), estrogen receptor alpha (ERalpha), and CYP3A in the Hippocampus of TLE patients and in murine hippocampal cell line HN25.1." SET Subgraph = "Apoptosis signaling subgraph" p(HGNC:AR) -> a(NIFT:Hippocampus) ######################################## SET Citation = {"PubMed", "Iran J Child Neurol. 2016 Winter;10(1):53-60.", "27057189"} SET Evidence = "The simple febrile seizure markedly disturbed the hippocampal expression of both Bcl2 and Bax proteins, resulting in apoptosis promotion in hippocampi of juvenile rats, which were measurable for at least 15 days." SET Subgraph = {"Apoptosis signaling subgraph", "MAPK-ERK subgraph", "protein kinase signaling subgraph"} p(HGNC:BAX) -> a(NIFT:Hippocampus) p(HGNC:BCL2) -> a(NIFT:Hippocampus) ######################################## SET Citation = {"PubMed", "Cell Death Differ. 2010 Mar;17(3):459-68. doi: 10.1038/cdd.2009.134. Epub 2009 Sep 25.", "19779495"} SET Evidence = "In this study, we examined Bim expression in mice and compared seizure damage between wild-type and Bim-deficient animals. Status epilepticus induced by intra-amygdala kainic acid (KA) caused extensive neuronal death within the ipsilateral hippocampal CA3 region. In contrast, neocortical Bim expression declined after status epilepticus, and neocortex damage in Bim-deficient mice was comparable with that in wild-type animals." SET Species = "10090" SET Subgraph = {"Apoptosis signaling subgraph", "MAPK-ERK subgraph", "protein kinase signaling subgraph"} p(HGNC:BCL2L11) -> a(NIFT:"CA1 of the hippocampus") ######################################## SET Citation = {"PubMed", "J Neuroinflammation. 2014 Dec 17;11:212. doi: 10.1186/s12974-014-0212-5.", "25516224"} SET Evidence = "Meanwhile, knock down of NLRP3 or caspase-1 led to a remarkable reduction of hippocampal neuronal loss in the CA1 and CA3 area of the Hippocampus at 6 weeks after SE." SET Species = "10116" SET MeSHDisease = "Status Epilepticus" SET Confidence = "High" #: Add the context annotation SET Subgraph = {"Apoptosis signaling subgraph", "Interleukin signaling subgraph"} p(HGNC:CASP1) pos path(MESHD:"Status Epilepticus") p(HGNC:NLRP3) pos path(MESHD:"Status Epilepticus") ######################################## SET Citation = {"PubMed", "Neuroscience. 2015 Jul 9;298:161-70. doi: 10.1016/j.neuroscience.2015.04.033. Epub 2015 Apr 20.", "25907443"} SET Evidence = "In addition, a higher number of apoptotic cells as well as a higher expression of caspase-3 was observed in the hippocampal CA1 and CA3 regions, the laterodorsal thalamic nucleus, and the somatosensory cortex of 6-month-old WAG/Rij rats compared to other animal groups" SET Species = "10116" SET Subgraph = "Apoptosis signaling subgraph" p(HGNC:CASP3) -> a(NIFT:"CA1 of the hippocampus") p(HGNC:CASP3) -> a(UBERON:"CA3 field of hippocampus") p(HGNC:CASP3) -> a(NIFT:"Left Thalamus Proper") ######################################## SET Citation = {"PubMed", "J Neurosci. 1993 Jul;13(7):2930-8.", "8331381"} SET Evidence = "Expression of the cell cycle regulatory proteins RB and p34cdc2 was examined in the adult rat brain, with special emphasis on proliferation and neuronal differentiation in the hippocampal formation and olfactory bulb" SET Species = "10116" SET Subgraph = "Apoptosis signaling subgraph" p(HGNC:CDK1) -> a(NIFT:"Hippocampal Formation") ######################################## SET Citation = {"PubMed", "Exp Mol Pathol. 2014 Dec;97(3):484-91. doi: 10.1016/j.yexmp.2014.10.003. Epub 2014 Oct 7.", "25303899"} SET Evidence = "To obtain understanding of the development of the cell types that are mostly affected by defective function of CLN proteins, timing of expression of CLN2, CLN3 and CLN5 genes was investigated in developing mouse brain. Throughout the development strong expression of the three mRNAs was detected in germinal epithelium and in ventricle regions, Hippocampus and cerebellum" SET Species = "10090" SET Subgraph = {"Apoptosis signaling subgraph", "Metabolism", "Protein Metabolism"} p(HGNC:CLN3) -> a(NIFT:Hippocampus) p(HGNC:CLN3) -> a(NIFT:Hindbrain) a(NIFT:Hindbrain) -- path(MESHD:Epilepsy) ######################################## SET Citation = {"PubMed", "J Mol Neurosci. 2014 Sep;54(1):1-9. doi: 10.1007/s12031-014-0237-3. Epub 2014 Feb 2.", "24488574"} SET Evidence = "Our previous study on proteomic analysis has shown that clusterin (CLU) is significantly decreased in the cerebrospinal fluid (CSF) of patients with epilepsy." SET Confidence = "High" SET Anatomy = "cerebrospinal fluid" SET Subgraph = {"Apoptosis signaling subgraph", "MAPK-ERK subgraph", "protein kinase signaling subgraph"} p(HGNC:CLU) pos path(MESHD:Epilepsy) ######################################## SET Citation = {"PubMed", "Dev Med Child Neurol. 2012 Jun;54(6):569-74. doi: 10.1111/j.1469-8749.2011.04198.x. Epub 2012 Jan 16.", "22574627"} SET Evidence = " To describe the clinical and radiological features of four new families with a childhood presentation of COL4A1 mutation. Magnetic resonance imaging (MRI) showed bilateral white matter change in all cases, except in one mutation-positive family member." SET Subgraph = {"Apoptosis signaling subgraph", "MAPK-ERK subgraph"} p(HGNC:COL4A1) -> a(NIFT:"White matter") ######################################## SET Citation = {"PubMed", "PLoS One. 2016 Jun 29;11(6):e0158195. doi: 10.1371/journal.pone.0158195. eCollection 2016.", "27355630"} SET Evidence = "The deficiency of CSTB in mice (Cstb-/- mice) generates a phenotype resembling the symptoms of EPM1 patients and is accompanied by microglial activation at two weeks of age and an upregulation of immune system-associated genes in the cerebellum at one month of age" SET Subgraph = {"Apoptosis signaling subgraph", "GABA subgraph", "Neurotransmitter release subgraph", "Protein Metabolism", "Metabolism"} p(HGNC:CSTB) -> a(NIFT:Hindbrain) ######################################## SET Citation = {"PubMed", "Neurosci Lett. 2007 Dec 18;429(2-3):136-41. Epub 2007 Oct 18.", "17997037"} SET Evidence = "Immunohistochemistry using cell type-specific markers showed that cathepsin S was induced in microglia, especially those surrounding degenerating pyramidal neurons, but not in neurons themselves or astroglia, in the hippocampal CA1 region of kainate-injected mice" SET Species = "10090" SET Subgraph = {"Apoptosis signaling subgraph", "Metabolism", "Protein Metabolism"} p(HGNC:CTSS) -> a(NIFT:"CA1 of the hippocampus") p(HGNC:CTSS) -> a(BRCO:Microglia) ######################################## SET Citation = {"PubMed", "Zhen Ci Yan Jiu. 2014 Aug;39(4):267-71.", "25219120"} SET Evidence = " The expression levels of Grp 78 and CHOP proteins in the hippocampal CA 1 region were detected by immunohistochemistry.RESULTS: Compared with the normal group, the expression levels of Grp 78 protein at time-points of 2 h and 12 h, and those of CHOP protein at 2 h, 12 h and 48 h after epilpeptic seizure were significantly increased in the model group (P < 0.01)" SET Subgraph = "Apoptosis signaling subgraph" p(HGNC:DDIT3) -> a(NIFT:"CA1 of the hippocampus") ######################################## SET Citation = {"PubMed", "Front Cell Neurosci. 2016 Jul 8;10:174. doi: 10.3389/fncel.2016.00174. eCollection 2016.", "27458343"} SET Evidence = "Dystrophin is part of a protein complex that connects the cytoskeleton to the extracellular matrix. In addition to its role in muscle tissue, it functions as an anchoring protein within the central nervous system such as in Hippocampus and cerebellum." SET Subgraph = {"Apoptosis signaling subgraph", "Energy metabolic subgraph", "Metabolism"} p(HGNC:DMD) -> a(NIFT:Hippocampus) p(HGNC:DMD) -> a(NIFT:Hindbrain) ######################################## SET Citation = {"PubMed", "Epilepsy Res. 2010 Feb;88(2-3):196-207. doi: 10.1016/j.eplepsyres.2009.11.009. Epub 2009 Dec 16.", "20015616"} SET Evidence = " we studied the neuroanatomical distribution of EFHC1 in mature and developing mouse brain. In the adult, low mRNA expression was detected in several brain structures such as cortex, striatum, Hippocampus and cerebellum." SET Subgraph = {"Apoptosis signaling subgraph", "Calcium dependent subgraph", "Long term synaptic potentiation", "Neurotransmitter release subgraph"} SET Species = "10090" p(HGNC:EFHC1) -> a(NIFT:"Hippocampal Formation") p(HGNC:EFHC1) -> a(NIFT:Hindbrain) p(HGNC:EFHC1) -> a(NIFT:Striatum) a(NIFT:Striatum) -- path(MESHD:Epilepsy) ######################################## SET Citation = {"PubMed", "Mol Cell Neurosci. 2008 Nov;39(3):356-71. doi: 10.1016/j.mcn.2008.07.016. Epub 2008 Jul 30.", "18718866"} SET Evidence = "After status epilepticus, Manf mRNA expression was transiently increased in the dentate granule cell layer of Hippocampus, thalamic reticular nucleus and in several cortical areas." #: Add the region annotation SET Confidence = "High" SET Subgraph = "Apoptosis signaling subgraph" p(HGNC:MANF) pos path(MESHD:"Status Epilepticus") ######################################## SET Citation = {"PubMed", "Epilepsy Res. 2015 Aug;114:23-31. doi: 10.1016/j.eplepsyres.2015.04.004. Epub 2015 Apr 17.", "26088882"} SET Evidence = "Pathological findings were only observed in patients with epileptic but not with psychogenic seizures. The lactate concentration was elevated in 14%, the albumin quotient in 34%, and the Tau protein level in 36% of CSF samples" SET Confidence = "High" SET Anatomy = "cerebrospinal fluid" SET Subgraph = {"Apoptosis signaling subgraph", "MAPK-ERK subgraph", "protein kinase signaling subgraph", "Metabolism"} p(HGNC:MAPT) pos path(MESHD:Epilepsy) p(HGNC:ALB) pos path(MESHD:Epilepsy) ######################################## SET Citation = {"PubMed", "Front Cell Neurosci. 2013 Jul 16;7:110. doi: 10.3389/fncel.2013.00110. eCollection 2013.", "23882182"} SET Evidence = "Loss of certain pro-apoptotic members, including Puma, protected against seizure-induced neuronal death whereas loss of anti-apoptotic Mcl-1 and Bcl-w enhanced hippocampal damage." SET Subgraph = {"Apoptosis signaling subgraph", "MAPK-ERK subgraph", "protein kinase signaling subgraph"} p(HGNC:MCL1) -> a(NIFT:Hippocampus) p(HGNC:MCL1) -> bp(MESHPP:"Cell Death") ######################################## SET Citation = {"PubMed", "Brain Res. 2002 Nov 22;956(1):67-73.", "12426047"} SET Evidence = "Accordingly, neuropilin-2 might regulate remodeling after seizures as it does during the development of the hippocampal formation." SET Confidence = "High" SET Subgraph = "Apoptosis signaling subgraph" p(HGNC:NRP2) -> a(NIFT:"Hippocampal Formation") p(HGNC:NRP2) -- path(MESHD:Seizures) ######################################## SET Citation = {"PubMed", "Neuroscience. 2015 Jan 29;285:139-54. doi: 10.1016/j.neuroscience.2014.11.019. Epub 2014 Nov 20.", "25446351"} SET Evidence = "The transcription factor Otx1 is specifically expressed in layer V pyramidal cells (L5PCs) in the cerebral cortex." SET Subgraph = "Apoptosis signaling subgraph" p(HGNC:OTX1) -> a(NIFT:"Cerebral Cortex") #p(HGNC:OTX1) -> a("Cerebral Cortex, layer V pyramidal cells") ######################################## SET Citation = {"PubMed", "Orphanet J Rare Dis. 2015 Feb 27;10:23. doi: 10.1186/s13023-015-0243-8.", "25885527"} SET Evidence = "In severe PIGA deficiency, as described in our patient, patients also present with dysmorphic facial features, multiple CNS abnormalities, such as thin corpus callosum and delayed myelination" SET Subgraph = {"Adaptive immune system subgraph", "Apoptosis signaling subgraph"} p(HGNC:PIGA) -> a(NIFT:"Corpus Callosum") a(NIFT:"Corpus Callosum") -- path(MESHD:Epilepsy) ######################################## SET Citation = {"PubMed", "J Neuropathol Exp Neurol. 2000 Dec;59(12):1070-86.", "11138927"} SET Evidence = "Neuropathologically, eosinophilic bodies, which were positive for periodic acid-Schiff and immunoreactive with antibodies against human neuroserpin (=SERPINI1), were present in the perikarya and cell processes of the neurons. They were found in large numbers in the cerebral cortex and substantia nigra" SET Subgraph = "Apoptosis signaling subgraph" p(HGNC:SERPINI1) -> a(NIFT:"Cerebral Cortex") p(HGNC:SERPINI1) -> a(NIFT:"Substantia Nigra") a(NIFT:"Substantia Nigra") -- path(MESHD:Epilepsy) ######################################## SET Citation = {"PubMed", "Epilepsia. 2012 Jun;53(6):e106-10. doi: 10.1111/j.1528-1167.2012.03437.x. Epub 2012 Mar 16.", "22429196"} SET Evidence = "This report supports the causative relationship between SPTAN1 mutations and early onset intractable seizures with severe hypomyelination and widespread brain volume reduction" SET Subgraph = "Apoptosis signaling subgraph" p(HGNC:SPTAN1) -> a(NIFT:"Brain volume") a(NIFT:"Brain volume") -- path(MESHD:Epilepsy) ######################################## SET Citation = {"PubMed", "Neuropeptides. 2008 Oct-Dec;42(5-6):569-83. doi: 10.1016/j.npep.2008.09.002. Epub 2008 Oct 31.", "18951627"} SET Evidence = " SSTR1 and SSTR4 immunoreactivities were increased in the Hippocampus at 1 week after SE." SET Subgraph = "Apoptosis signaling subgraph" p(HGNC:SSTR1) -> a(NIFT:Hippocampus) p(HGNC:SSTR4) -> a(NIFT:Hippocampus) ######################################## SET Citation = {"PubMed", "J Biol Chem. 2005 Jan 7;280(1):660-8. Epub 2004 Nov 10.", "15537634"} SET Evidence = "In the Hippocampus, extracellular signal-regulated kinase (ERK) and the non-receptor protein proline-rich tyrosine kinase 2 (PYK2) are activated by depolarization and involved in synaptic plasticity." SET Subgraph = "Apoptosis signaling subgraph" p(HGNC:TNK2) -> a(NIFT:Hippocampus) p(HGNC:TNK2) -> bp(GOBP:"regulation of neuronal synaptic plasticity") bp(GOBP:"regulation of neuronal synaptic plasticity") -- path(MESHD:Epilepsy) ######################################## SET Citation = {"PubMed", "Front Cell Neurosci. 2015 Feb 10;9:20. doi: 10.3389/fncel.2015.00020. eCollection 2015.", "25713512"} SET Evidence = "Transient receptor potential vanilloid 1 (TRPV1) is widely distributed in the central nervous system (CNS) including Hippocampus, and regulates the balance of excitation and inhibition in CNS, which imply its important role in epilepsy." SET Subgraph = {"Apoptosis signaling subgraph", "brain_derived neurotrophic factor signaling subgraph", "Long term synaptic depression", "Long term synaptic potentiation"} p(HGNC:TRPV1) -> a(NIFT:Hippocampus) ######################################## SET Citation = {"PubMed", "Epilepsy Behav. 2016 Jun;59:147-54. doi: 10.1016/j.yebeh.2016.02.029. Epub 2016 May 3.", "27152461"} SET Evidence = " Serum BDNF levels reflected longer epilepsy duration, impaired white matter integrity, and poor cognitive function in patients with chronic TLE." SET Subgraph = {"brain_derived neurotrophic factor signaling subgraph", "GABA subgraph", "Mossy Fiber Subgraph", "Neurotransmitter release subgraph", "Reelin signaling subgraph"} p(HGNC:BDNF) -> a(NIFT:"White matter") ######################################## SET Citation = {"PubMed", "Epilepsia. 2011 Mar;52(3):572-8. doi: 10.1111/j.1528-1167.2010.02930.x. Epub 2011 Jan 26.", "21269288"} SET Evidence = "These data suggest that the supplementation of FGF-2 and BDNF in an epileptogenic Hippocampus may prevent epileptogenesis by decreasing neuronal loss and mossy fiber sprouting, that is, reducing some forms of circuit reorganization." SET Subgraph = {"brain_derived neurotrophic factor signaling subgraph", "thyroid hormone signaling subgraph", "MAPK-ERK subgraph", "protein kinase signaling subgraph"} p(HGNC:FGF2) -> a(NIFT:Hippocampus) SET Anatomy = "mossy fiber" path(MESHD:Epilepsy) -> p(HGNC:FGF2) UNSET Subgraph SET Subgraph = {"brain_derived neurotrophic factor signaling subgraph", "GABA subgraph", "Mossy Fiber Subgraph", "Neurotransmitter release subgraph", "Reelin signaling subgraph"} p(HGNC:BDNF) -> a(NIFT:Hippocampus) p(HGNC:BDNF) -> a(GOCC:"cerebellar mossy fiber") a(GOCC:"cerebellar mossy fiber") -- path(MESHD:Epilepsy) ######################################## SET Citation = {"PubMed", "Neuroscience. 2015 Oct 15;306:28-38. doi: 10.1016/j.neuroscience.2015.08.021. Epub 2015 Aug 20.", "26297893"} SET Evidence = "Recently, we demonstrated region-specific alterations in the tissue expression level of GABAA receptors (GABA(A)Rs) α1 and β2 subunits within the thalamus of the stargazer mouse model of absence epilepsy." SET Subgraph = {"brain_derived neurotrophic factor signaling subgraph", "GABA subgraph", "Neurotransmitter release subgraph", "hormone signaling subgraph", "Mossy Fiber Subgraph", "Notch signaling subgraph"} p(HGNC:GABRA1) -> a(NIFT:"Left Thalamus Proper") ######################################## SET Citation = {"PubMed", "J Exerc Rehabil. 2015 Apr 30;11(2):80-6. doi: 10.12965/jer.150193. eCollection 2015.", "25960980"} SET Evidence = " Glutamic acid decarboxylase (GAD67) expression in the hippocampal CA1 region was reduced by pilocarpine-induced seizure." SET Subgraph = {"brain_derived neurotrophic factor signaling subgraph", "GABA subgraph", "Neurotransmitter release subgraph"} p(HGNC:GAD1) -> a(NIFT:"CA1 of the hippocampus") ######################################## SET Citation = {"PubMed", "Oncotarget. 2016 Mar 29;7(13):15329-38. doi: 10.18632/oncotarget.7855.", "26943580"} SET Evidence = " Increased expression of NPY and its receptors has been identified in the Hippocampus of patients with mesial temporal lobe epilepsy, presumed to act as an endogenous anticonvulsant mechanism." SET Subgraph = {"brain_derived neurotrophic factor signaling subgraph", "Energy metabolic subgraph", "Long term synaptic potentiation", "Metabolism", "Mossy Fiber Subgraph"} p(HGNC:NPY) -> a(NIFT:Hippocampus) ######################################## SET Citation = {"PubMed", "Front Integr Neurosci. 2016 Feb 24;10:8. doi: 10.3389/fnint.2016.00008. eCollection 2016.", "26941623"} SET Evidence = "The regulation of AQP4 has been extensively investigated in various neuropathological conditions such as cerebral edema, epilepsy, and ischemia." SET Subgraph = {"Calcium dependent subgraph", "Long term synaptic potentiation", "Notch signaling subgraph"} p(HGNC:AQP4) -> a(NIFT:"Cerebral edema") ######################################## SET Citation = {"PubMed", "J Neurol Neurosurg Psychiatry. 2015 Mar;86(3):344-53. doi: 10.1136/jnnp-2014-307731. Epub 2014 Jun 30.", "25411546"} SET Evidence = "To report biphasic changes in cerebral blood flow (CBF) in the acute phase of hemiplegic migraine with prolonged aura (HMPA), in which aura symptoms lasted longer than 24 h, in three patients with familial hemiplegic migraine (FHM) carrying a p.H916L mutation in ATP1A2 gene." SET Subgraph = {"Calcium dependent subgraph", "Energy metabolic subgraph", "Metabolism"} p(HGNC:ATP1A2) -> a(NIFT:"Change in cerebral blood flow") ######################################## SET Citation = {"PubMed", "Am J Med Genet A. 2016 Aug;170(8):2173-6. doi: 10.1002/ajmg.a.37678. Epub 2016 Jun 2.", "27250579"} SET Evidence = "Compound heterozygous mutations in the CACNA1A gene presumably cause early onset epileptic encephalopathy, and progressive cerebral, cerebellar and optic nerve atrophy with reduced lifespan." SET Subgraph = {"Calcium dependent subgraph", "Neurotransmitter release subgraph"} p(HGNC:CACNA1A) -> a(NIFT:Atrophy) a(NIFT:Atrophy) -- path(MESHD:Epilepsy) ######################################## SET Citation = {"PubMed", "Mol Med Rep. 2015 Nov;12(5):6663-71. doi: 10.3892/mmr.2015.4227. Epub 2015 Aug 18.", "26299765"} SET Evidence = "A significant increase in the expression of CaM and decrease in the expression of CaV1.2 (CACNA1C) were observed in the TRM cerebellum." SET Subgraph = "Calcium dependent subgraph" p(HGNC:CACNA1C) -> a(NIFT:Hindbrain) ######################################## SET Citation = {"PubMed", "PLoS One. 2015 Aug 14;10(8):e0130012. doi: 10.1371/journal.pone.0130012. eCollection 2015.", "26274319"} SET Evidence = "At the completion of drug treatment, CaV3.1, CaV3.2 and CaV3.3 mRNA expression levels were assessed in the Hippocampus and amygdala using qPCR. Our results show that selectively targeting T-type Ca2+ channels with Z944 inhibits the progression of amygdala kindling." SET Subgraph = {"Calcium dependent subgraph", "Neurotransmitter release subgraph"} p(HGNC:CACNA1G) -> a(NIFT:Amygdala) UNSET Subgraph SET Subgraph = "Calcium dependent subgraph" p(HGNC:CACNA1H) -> a(NIFT:Amygdala) p(HGNC:CACNA1I) -> a(NIFT:Amygdala) a(NIFT:Amygdala) -- path(MESHD:Epilepsy) ######################################## SET Citation = {"PubMed", "PLoS One. 2013 Dec 16;8(12):e82154. doi: 10.1371/journal.pone.0082154. eCollection 2013.", "24358150"} SET Evidence = "In a patient with epilepsy, dyskinesia, cerebellar atrophy, psychomotor delay and dysmorphic features, offspring to consanguineous parents, we performed whole exome sequencing (WES) for homozygosity mapping and mutation detection. WES identified extended autozygosity on chromosome 3, containing two novel homozygous candidate mutations: c.1295delA (p.Asn432fs) in CACNA2D2 and c.G6407A (p.Gly2136Asp) in CELSR3." SET Subgraph = "Calcium dependent subgraph" p(HGNC:CACNA2D2) -> a(NIFT:"Cerebellar atrophy") a(NIFT:"Cerebellar atrophy") -- path(MESHD:Epilepsy) ######################################## SET Citation = {"PubMed", "J Neurophysiol. 1999 May;81(5):2066-74.", "10322048"} SET Evidence = "Excitatory but not inhibitory synaptic transmission is reduced in lethargic (Cacnb4(lh)) and tottering (Cacna1atg) mouse thalami." SET Species = "10090" SET Subgraph = {"Calcium dependent subgraph", "hormone signaling subgraph", "thyroid hormone signaling subgraph"} p(HGNC:CACNB4) -> a(NIFT:"Left Thalamus Proper") ######################################## SET Citation = {"PubMed", "Ann Neurol. 2008 Aug;64(2):158-67. doi: 10.1002/ana.21428.", "18756473"} SET Evidence = " CASR expression was detected in the temporal lobe, frontal lobe, parietal lobe, cerebellum, and Hippocampus. Four additional, potentially pathogenic, missense CASR variants, Glu354Ala, Ile686Val, Ala988Val, and Ala988Gly, were observed in five individuals affected with idiopathic generalized epilepsy." SET Subgraph = {"Calcium dependent subgraph", "MAPK-ERK subgraph", "protein kinase signaling subgraph"} p(HGNC:CASR) -> a(NIFT:"Frontal lobe") p(HGNC:CASR) -> a(NIFT:Hindbrain) p(HGNC:CASR) -> a(NIFT:Hippocampus) SET Anatomy = "temporal lobe" path(MESHD:Epilepsy) -> p(HGNC:CASR) SET Anatomy = "parietal lobe" path(MESHD:Epilepsy) -> p(HGNC:CASR) ######################################## SET Citation = {"PubMed", "J Neurosci. 2007 Jun 13;27(24):6581-9.", "17567819"} SET Evidence = "We now show that the white matter of the brain and spinal cord of ClC-2 knock-out mice developed widespread vacuolation that progressed with age." SET Species = "10090" SET Subgraph = "Calcium dependent subgraph" p(HGNC:CLCN2) -> a(NIFT:"White matter") ######################################## SET Citation = {"PubMed", "Mol Brain. 2013 Feb 14;6:9. doi: 10.1186/1756-6606-6-9.", "23406666"} SET Evidence = " In addition to functioning as neurotransmitter receptors to modulate synaptic activity,pathological mGluR5 signaling has been implicated in a number of disease processes including Fragile X, amyotrophic lateral sclerosis, multiple sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, epilepsy," SET Subgraph = {"Long term synaptic depression", "mTOR signaling subgraph"} p(HGNC:GRM5) -> a(NIFT:"Synaptic activity") a(NIFT:"Synaptic activity") -- path(MESHD:Epilepsy) ######################################## SET Citation = {"PubMed", "Gen Hosp Psychiatry. 2014 Jul-Aug;36(4):388-91. doi: 10.1016/j.genhosppsych.2014.02.010. Epub 2014 Mar 5.", "24731834"} SET Evidence = " Presence of antibodies against the GluN1 subunit of the NMDAR in the CSF and serum confirm the diagnosis of NMDAR encephalitis, " SET Subgraph = {"Calcium dependent subgraph", "Glutamatergic subgraph", "Long term synaptic potentiation", "Neurotransmitter release subgraph"} SET Anatomy = {"cerebrospinal fluid","serum"} p(HGNC:GRIN1) pos path(MESHD:"Anti-N-Methyl-D-Aspartate Receptor Encephalitis") ######################################## SET Citation = {"PubMed", "Neurotox Res. 2015 May;27(4):441-52. doi: 10.1007/s12640-014-9515-7. Epub 2015 Jan 10.", "25576253"} SET Evidence = " Effects of repetitive seizures on ionotropic glutamate receptors (iGluRs) were investigated in rat entorhinal cortex slices. While there was a marked decrease in the level of GluA1-4, GluA2 and GluK5 receptor subunits, GluA1 and GluN2A protein levels moderately increased. The results indicate that brief convulsions, repeated daily for 10 days can increase overall entorhinal cortex excitability." SET Subgraph = {"Glutamatergic subgraph", "Neurotransmitter release subgraph", "Long term synaptic depression", "Long term synaptic potentiation"} SET Species = "10116" p(HGNC:GRIA1) -> a(NIFT:"Entorhinal Cortex") p(HGNC:GRIA2) -> a(NIFT:"Entorhinal Cortex") p(HGNC:GRIK5) -> a(NIFT:"Entorhinal Cortex") UNSET Subgraph SET Subgraph = {"Glutamatergic subgraph", "Neurotransmitter release subgraph", "Long term synaptic potentiation", "Calcium dependent subgraph"} p(HGNC:GRIN2A) -> a(NIFT:"Entorhinal Cortex") ######################################## SET Citation = {"PubMed", "Zh Evol Biokhim Fiziol. 2015 May-Jun;51(3):204-13.", "26281223"} SET Evidence = "Indeed, the expression of vesicular glutamate transporter type 2 (VGlut2) and NR2B subunit of NMDA receptor was increased in the striatum of KM rats (Krushinsky-Molodkina (KM) rats prone to audiogenic seizures)." SET Subgraph = {"Calcium dependent subgraph", "Glutamatergic subgraph", "Neurotransmitter release subgraph", "Long term synaptic potentiation", "MAPK-ERK subgraph", "protein kinase signaling subgraph", "Reelin signaling subgraph"} SET Species = "10116" p(HGNC:GRIN2B) -> a(NIFT:Striatum) UNSET Subgraph SET Subgraph = {"Energy metabolic subgraph", "Metabolism"} p(HGNC:SLC17A6) -> a(NIFT:Striatum) UNSET Subgraph SET Evidence = " at the same time, in KM rats an increased ERK1/2 activity has been detected both in striatum and substantia nigra." SET Subgraph = {"Calcium dependent subgraph", "Interleukin signaling subgraph", "MAPK-ERK subgraph", "protein kinase signaling subgraph"} SET Species = "10116" p(HGNC:MAPK1) -> a(NIFT:Striatum) p(HGNC:MAPK1) -> a(NIFT:"Substantia Nigra") UNSET Subgraph SET Subgraph = {"Calcium dependent subgraph", "Interleukin signaling subgraph", "MAPK-ERK subgraph", "protein kinase signaling subgraph", "Long term synaptic potentiation"} p(HGNC:MAPK3) -> a(NIFT:Striatum) p(HGNC:MAPK3) -> a(NIFT:"Substantia Nigra") ######################################## SET Citation = {"PubMed", "Pflugers Arch. 2015 Jun;467(6):1367-82. doi: 10.1007/s00424-014-1549-4. Epub 2014 Jun 24.", "24953239"} SET Evidence = " In support, levels of HCN-1 and HCN-3 isoform channel proteins were increased in GAERS VB thalamic tissue. (absence epilepsy)" SET Subgraph = {"Calcium dependent subgraph"} p(HGNC:HCN1) -> a(NIFT:"Left Thalamus Proper") ######################################## SET Citation = {"PubMed", "Trends Neurosci. 2010 May;33(5):211-9. doi: 10.1016/j.tins.2010.02.005. Epub 2010 Mar 11.", "20226542"} SET Evidence = "We argue that the unifying feature of many genes involved in cerebellar ataxias is their impact on the signaling protein ITPR1 (inositiol 1,4,5-triphosphate receptor type 1), that underlies coincidence detection in Purkinje cells and could play an important role in cerebellar coordination" SET Subgraph = {"Calcium dependent subgraph", "Neurotransmitter release subgraph"} p(HGNC:ITPR1) -> a(NIFT:Hindbrain) ######################################## SET Citation = {"PubMed", "Brain Res. 2014 Jan 28;1544:54-61. doi: 10.1016/j.brainres.2013.12.004. Epub 2013 Dec 10.", "24333359"} SET Evidence = "This study evaluated the role of Nrf2-ARE signal pathway in protecting the brain from seizure-mediated damage. Wistar rats and Nrf2-deficient or control mice were chronic kindled in the amygdala." SET Species = {"10116","10090"} SET Subgraph = "Calcium dependent subgraph" p(HGNC:NFE2L2) -> a(NIFT:Amygdala) ######################################## SET Citation = {"PubMed", "Brain Res Bull. 2002 Oct 15;59(1):53-8.", "12372549"} SET Evidence = " RyR1 was decreased in the flocculus of the cerebellum in both the tg/tg-N and tg/tg-P groups compared to wild type (p = 0.0174, ANOVA). " SET Subgraph = {"Calcium dependent subgraph", "Neurotransmitter release subgraph"} p(HGNC:RYR1) -> a(NIFT:Hindbrain) ######################################## SET Citation = {"PubMed", "J Hum Genet. 2016 Jun;61(6):565-9. doi: 10.1038/jhg.2016.5. Epub 2016 Feb 4.", "26841829"} SET Evidence = " Our findings suggest that SCN1A mutation leads to changes in the dopamine system that may contribute to the behavioral abnormalities in DS." SET Confidence = "High" SET Subgraph = {"Calcium dependent subgraph", "Glutamatergic subgraph", "Neurotransmitter release subgraph", "Serotonergic subgraph", "Metabolism", "protein kinase signaling subgraph"} g(HGNC:SCN1A, var("?")) -- a(NIFT:Dopamine) ######################################## SET Citation = {"PubMed", "Front Pharmacol. 2016 Jul 14;7:210. doi: 10.3389/fphar.2016.00210. eCollection 2016.", "27471467"} SET Evidence = "In vivo microdialysis study showed that the Sv2a(L174Q) mutation preferentially reduced high K(+) (depolarization)-evoked GABA release, but not glutamate release, in the amygdala. The present results suggest that dysfunction of SV2A by the missense mutation elevates seizure susceptibility in rats by preferentially disrupting synaptic GABA release in the amygdala," SET Species = "10116" SET Subgraph = {"Calcium dependent subgraph", "Neurotransmitter release subgraph", "Serotonergic subgraph"} p(HGNC:SV2A) -> a(NIFT:Amygdala) ######################################## SET Citation = {"PubMed", "Brain Res. 2013 Jun 23;1517:141-9. doi: 10.1016/j.brainres.2013.04.009. Epub 2013 Apr 17.", "23603404"} SET Evidence = "hereditary animal model for generalized tonic-clonic (GTC) seizures. Western blot analysis showed that Kir4.1 expression in NERs was significantly reduced in the occipito-temporal cortical region and thalamus." SET Confidence = "High" SET Subgraph = {"Energy metabolic subgraph", "Metabolism"} SET Anatomy = "occipitotemporal sulcus" path(MESHD:Epilepsy) pos p(HGNC:KCNJ10) ######################################## SET Citation = {"PubMed", "Diabetes Care. 2013 Aug;36(8):2311-6. doi: 10.2337/dc12-2166. Epub 2013 Mar 5.", "23462667"} SET Evidence = "Significant changes in single-photon emission computed tomography signal intensity after transfer to SU therapy were restricted to the cerebellum, consistent with previous data showing high Kir6.2 expression in this brain region." SET Subgraph = {"Energy metabolic subgraph", "hormone signaling subgraph"} p(HGNC:KCNJ11) -> a(NIFT:Hindbrain) ######################################## SET Citation = {"PubMed", "Acta Neurol Scand. 2015 Dec;132(6):371-80. doi: 10.1111/ane.12411. Epub 2015 Apr 15.", "25880465"} SET Evidence = " Leptin receptors are widely expressed throughout the brain, especially in the Hippocampus, basal ganglia, cortex and cerebellum" SET Subgraph = {"Energy metabolic subgraph", "Metabolism", "mTOR signaling subgraph"} p(HGNC:LEPR) -> a(NIFT:Hippocampus) p(HGNC:LEPR) -> a(NIFT:Hindbrain) p(HGNC:LEPR) -> a(UBERON:"collection of basal ganglia") ######################################## SET Citation = {"PubMed", "Mol Pharmacol. 2007 Jun;71(6):1572-81. Epub 2007 Mar 6.", "17341653"} SET Evidence = "These results suggest that, under conditions of impaired GABAergic inhibition, activation of alpha(2A)ARs is primarily responsible for the antiepileptic actions of norepinephrine in the rat hippocampal CA3 region" SET Species = "10116" SET Subgraph = "G-protein-mediated signaling" p(HGNC:ADRA2A) -> a(UBERON:"CA3 field of hippocampus") ######################################## SET Citation = {"PubMed", "Eur J Med Genet. 2013 Feb;56(2):118-22. doi: 10.1016/j.ejmg.2012.11.003. Epub 2012 Dec 16.", "23253743"} SET Evidence = "The M3 muscarinic receptor influences a multitude of central and peripheral nervous system processes via its interaction with acetylcholine and may be an important modulator of behavior, learning and memory." SET Subgraph = "G-protein-mediated signaling" p(HGNC:CHRM3) -> a(NIFT:Acetylcholine) ######################################## SET Citation = {"PubMed", "Neurobiol Dis. 2016 May;89:23-35. doi: 10.1016/j.nbd.2016.01.013. Epub 2016 Jan 21.", "26804027"} SET Evidence = " Hippocampal pyramidal cells and dentate granule cells show specific reduction in cannabinoid receptor type 1 (CB1R)-sensitive GABAergic inputs in experimental epilepsy." SET MeSHAnatomy="Hippocampus" SET Confidence = "High" SET Subgraph = "G-protein-mediated signaling" p(HGNC:CNR1) neg path(MESHD:Epilepsy) ######################################## SET Citation = {"PubMed", "Neuropsychopharmacology. 2014 Dec;39(13):3100-11. doi: 10.1038/npp.2014.167. Epub 2014 Jul 7.", "24998620"} SET Evidence = "Western blotting and immunocytochemical analyses of AAV-FMRP-injected mice revealed FMRP expression in the striatum, Hippocampus, retrosplenial cortex, and cingulate cortex." SET Species = "10090" SET Confidence = "High" SET Subgraph = {"G-protein-mediated signaling", "Long term synaptic depression"} #: TODO add the MESH anataomy annotation p(HGNC:FMR1) pos path(MESHD:"Fragile X Syndrome") ######################################## SET Citation = {"PubMed", "Brain. 2010 Nov;133(11):3194-209. doi: 10.1093/brain/awq259. Epub 2010 Oct 7.", "20929962"} SET Evidence = "GPR56 mutations cause an autosomal recessive polymicrogyria syndrome that has distinctive radiological features combining bilateral frontoparietal polymicrogyria, white matter abnormalities and cerebellar hypoplasia." # GPR56 is ADGRG1 SET Confidence = "High" SET Subgraph = "G-protein-mediated signaling" g(HGNC:ADGRG1, var("?")) -- a(NIFT:"White matter") g(HGNC:ADGRG1, var("?")) -- a(NIFT:Hindbrain) g(HGNC:ADGRG1, var("?")) -- path(MESHD:Polymicrogyria) ######################################## SET Citation = {"PubMed", "Epilepsy Res. 2014 Dec;108(10):1853-63. doi: 10.1016/j.eplepsyres.2014.09.013. Epub 2014 Sep 22.", "25304920"} SET Evidence = "The 5-hydroxytryptamine-1A (5-HT1A) receptors are known to be involved in the inhibition of seizures in epilepsy. Moreover, studies propose a role for the 5-HT1A receptor in memory function; it is believed that the higher density of this receptor in the Hippocampus plays an important role in its regulation." SET Subgraph = "G-protein-mediated signaling" SET Confidence = "High" p(HGNC:HTR1A) -- path(MESHD:Epilepsy) bp(GOBP:"learning or memory") -- p(HGNC:HTR1A) ######################################## SET Citation = {"PubMed", "Brain. 2010 Oct;133(10):2964-70. doi: 10.1093/brain/awq238. Epub 2010 Sep 9.", "20833646"} SET Evidence = " Phospholipase C-β 1 has important functions in both hippocampal muscarinic acetylcholine receptor signalling and in cortical development. Thus, the discovery of a phospholipase C-β 1 mutation allows us to propose a novel potential underlying mechanism in early-onset epileptic encephalopathy." SET Confidence = "High" SET Subgraph = "G-protein-mediated signaling" g(HGNC:PLCB1, var("?")) pos path(MESHD:Epilepsy) ######################################## SET Citation = {"PubMed", "Brain Res. 2010 Feb 22;1315:41-52. doi: 10.1016/j.brainres.2009.09.111. Epub 2009 Oct 6.", "19815003"} SET Evidence = "Aromatase is a key enzyme in estrogen biosynthesis that is involved in neuronal plasticity in the rodent Hippocampus. Although aromatase mRNA expression has been detected in the human Hippocampus, its cellular distribution has yet to be determined" SET MeSHAnatomy="Hippocampus" SET Species = "10090" SET Confidence = "High" SET Subgraph = {"GABA subgraph", "Neurotransmitter release subgraph"} p(HGNC:CYP19A1) reg a(CHEBI:estrogen) a(CHEBI:estrogen) -- bp(GOBP:"regulation of neuronal synaptic plasticity") ######################################## SET Citation = {"PubMed", "Proc Natl Acad Sci U S A. 2013 Nov 26;110(48):19603-8. doi: 10.1073/pnas.1312791110. Epub 2013 Nov 11.", "24218551"} SET Evidence = "We show that ErbB4 and GABAR α1 are robustly coexpressed in hippocampal interneuron" SET Confidence = "High" SET Subgraph = {"GABA subgraph", "Neurotransmitter release subgraph", "Notch signaling subgraph"} SET Cell = interneuron p(HGNC:GABRA1) pos p(HGNC:ERBB4) ######################################## SET Citation = {"PubMed", "Cerebellum. 2009 Mar;8(1):64-9. doi: 10.1007/s12311-008-0075-3.", "19002745"} SET Evidence = " Expression of GABA(B) receptors is altered in brains of subjects with autism.. Levels of GABBR1 were significantly decreased in BA9, BA40, and cerebellum, while GABBR2 was significantly reduced in the cerebellum." SET Confidence = "High" SET MeSHAnatomy="Cerebellum" SET Subgraph = {"GABA subgraph", "Neurotransmitter release subgraph"} p(HGNC:GABBR1) pos path(MESHD:"Autism Spectrum Disorder") p(HGNC:GABBR2) pos path(MESHD:"Autism Spectrum Disorder") ######################################## SET Citation = {"PubMed", "Epilepsia. 2013 Apr;54(4):616-24. doi: 10.1111/epi.12063. Epub 2013 Jan 7.", "23294024"} SET Evidence = "Down-regulation of gephyrin and GABAA receptor subunits during epileptogenesis in the CA1 region of Hippocampus." SET Confidence = "High" SET MeSHAnatomy="CA1 Region, Hippocampal" SET Subgraph = {"GABA subgraph", "Neurotransmitter release subgraph"} p(HGNC:GPHN) neg path(MESHD:Epilepsy) ######################################## SET Citation = {"PubMed", "Fluids Barriers CNS. 2015 Apr 29;12:11. doi: 10.1186/s12987-015-0006-x.", "25925580"} SET Evidence = " It is suggested that EAAT1 in ependymal cells and EAAT3 in choroid plexus epithelial cells participate in L-Glu elimination from the CSF." SET Confidence = "High" SET Anatomy = {"cerebrospinal fluid","ependyma"} SET Subgraph = {"GABA subgraph", "Neurotransmitter release subgraph", "Glutamatergic subgraph"} act(p(HGNC:SLC1A1)) -| a(CHEBI:"L-glutamine") SET Subgraph = {"Glutamatergic subgraph", "Neurotransmitter release subgraph"} act(p(HGNC:SLC1A3)) -| a(CHEBI:"L-glutamine") ######################################## SET Citation = {"PubMed", "Neurochem Res. 2015 Mar;40(3):621-7. doi: 10.1007/s11064-014-1504-y. Epub 2015 Feb 24.", "25708016"} SET Evidence = "Our results show that IL-1β, IL-6 and TNF-α were significantly increased in the parietal cortex, Hippocampus and amygdala of KA-rats as compared with sham control animals" SET Confidence = "High" SET MeSHAnatomy = "Hippocampus" SET Anatomy = {"parietal cortex","amygdala"} SET Species = "10116" SET Subgraph = {"Interleukin signaling subgraph", "Mossy Fiber Subgraph", "mTOR signaling subgraph"} p(HGNC:IL1B) neg path(MESHD:Epilepsy) SET Subgraph = {"Interleukin signaling subgraph", "mTOR signaling subgraph"} p(HGNC:IL6) neg path(MESHD:Epilepsy) SET Subgraph = "Innate immune system subgraph" p(HGNC:TNF) neg path(MESHD:Epilepsy) ######################################## SET Citation = {"PubMed", "Cell Physiol Biochem. 2015;37(5):2023-31. doi: 10.1159/000438562. Epub 2015 Nov 20.", "26584300"} SET Evidence = "middle cerebral artery occlusion MCAO significantly increased IL-1beta, IL-6 and TNF-alpha in the parietal cortex, Hippocampus and amygdala as compared with sham control animals (P<0.05 vs. control rats). Also, in these specific brain regions expression of GAT-1 and GAT-3 was amplified;" SET Confidence = "High" SET Species = "10116" SET MeSHAnatomy = "Hippocampus" SET Anatomy = {"parietal cortex","amygdala"} SET Subgraph = {"GABA subgraph", "Neurotransmitter release subgraph"} p(HGNC:TNF) pos path(DO:"cerebral artery occlusion") p(HGNC:IL1B) pos path(DO:"cerebral artery occlusion") p(HGNC:IL6) pos path(DO:"cerebral artery occlusion") p(HGNC:SLC6A1) pos path(DO:"cerebral artery occlusion") p(HGNC:SLC6A12) pos path(DO:"cerebral artery occlusion") UNSET {Anatomy, MeSHAnatomy, Species, Subgraph, Confidence} ######################################## SET Citation = {"PubMed", "Neural Regen Res. 2012 Sep 15;7(26):2036-42. doi: 10.3969/j.issn.1673-5374.2012.26.005.", "25624835"} SET Evidence = "Results demonstrated that glutamate transporter 2 and γ-aminobutyric acid transporter 1 expression levels were significantly increased in the cerebral cortex and Hippocampus of the developing rat brain following recurrent seizures" SET Species = "10116" SET MeSHAnatomy = {"Hippocampus", "Cerebral Cortex"} SET Confidence = "High" SET Subgraph = {"GABA subgraph", "Neurotransmitter release subgraph"} p(HGNC:SLC1A2) pos path(MESHD:Seizures) p(HGNC:SLC6A12) pos path(MESHD:Seizures) ######################################## SET Citation = {"PubMed", "Hum Mol Genet. 2008 Jun 15;17(12):1738-49. doi: 10.1093/hmg/ddn064. Epub 2008 Mar 3.", "18316356"} SET Evidence = " Gria3 and Gria4 encode the predominant AMPA receptor subunits in the reticular thalamus, which is thought to play a central role in seizure " SET Subgraph = {"Glutamatergic subgraph", "Neurotransmitter release subgraph", "Long term synaptic depression", "Long term synaptic potentiation"} SET Anatomy = "reticular formation" SET Confidence = "High" p(HGNC:GRIA3) -- path(MESHD:Seizures) p(HGNC:GRIA4) -- path(MESHD:Seizures) UNSET Anatomy # TODO continue subgraph annotation ######################################## SET Citation = {"PubMed", "J Neurosci. 2014 Apr 23;34(17):5765-75. doi: 10.1523/JNEUROSCI.5307-13.2014.", "24760837"} SET Evidence = "Kainate receptors containing the GluK1 subunit have an impact on excitatory and inhibitory neurotransmission in brain regions, such as the amygdala and Hippocampus, which are relevant to seizures and epilepsy." #: Change to inhibitory neurotransmission SET Subgraph = {"Glutamatergic subgraph", "Neurotransmitter release subgraph", "Long term synaptic depression", "Long term synaptic potentiation"} p(HGNC:GRIK1) -- a(NIFT:Hippocampus) p(HGNC:GRIK1) -- a(NIFT:Amygdala) ######################################## SET Citation = {"PubMed", "Cereb Cortex. 2013 Feb;23(2):323-31. doi: 10.1093/cercor/bhs022. Epub 2012 Feb 17.", "22345355"} SET Evidence = "We have found that UBP310 and related willardiine derivatives, previously characterized as selective GluK1 and GluK3 KAR antagonists, block postsynaptic KARs at hippocampal mossy fiber (MF) CA3 synapses while sparing AMPA and NMDA receptors." #: TO check SET Subgraph = {"Glutamatergic subgraph", "Neurotransmitter release subgraph", "Long term synaptic depression", "Long term synaptic potentiation"} p(HGNC:GRIK1) -> a(UBERON:"CA3 field of hippocampus") SET Anatomy = "mossy fiber" path(MESHD:Epilepsy) -> p(HGNC:GRIK1) UNSET Anatomy p(HGNC:GRIK3) -> a(UBERON:"CA3 field of hippocampus") SET Anatomy = "mossy fiber" path(MESHD:Epilepsy) -> p(HGNC:GRIK3) UNSET Anatomy ######################################## SET Citation = {"PubMed", "Life Sci. 1993;53(10):857-64.", "8394966"} SET Evidence = "The amount of KA receptor mRNA detected with the KA-1 probe increased (25%) on both the left and right sides of the hippocampal CA3 region in the kindled rats, but in no other brain areas (hippocampal CA1, dentate gyrus, amygdala nuclei and pyriform cortex" SET Confidence = "High" SET Subgraph = {"Glutamatergic subgraph", "Neurotransmitter release subgraph", "Long term synaptic depression", "Long term synaptic potentiation"} p(HGNC:GRIK4) pos path(MESHD:Seizures) ######################################## # Paper comparing rat with seizures and controls ######################################## SET Citation = {"PubMed", "Brain Res Dev Brain Res. 2004 Sep 17;152(2):137-42.", "15351501"} SET Evidence = "Compared with the control rats, the protein expressions of NR1, NR2A and NR2B in the cerebral cortex and NR2A in the Hippocampus of the recurrent-seizure group was significantly decreased, but NR2C protein expression in the cerebral cortex and Hippocampus significantly increased." # NR1 is GRIN1 # NR2A is GRIN2A SET Species = "10116" SET MeSHAnatomy = {"Hippocampus", "Cerebral Cortex"} SET Confidence = "High" SET Subgraph = {"Glutamatergic subgraph", "Neurotransmitter release subgraph"} p(HGNC:GRIN1) neg path(MESHD:Epilepsy) p(HGNC:GRIN2A) neg path(MESHD:Epilepsy) p(HGNC:GRIN2B) neg path(MESHD:Epilepsy) p(HGNC:GRIN2C) pos path(MESHD:Epilepsy) ######################################## SET Citation = {"PubMed", "Neuropharmacology. 2012 Mar;62(4):1867-73. doi: 10.1016/j.neuropharm.2011.12.012. Epub 2011 Dec 17.", "22202905"} SET Evidence = "Moreover, we also found that this significantly enhanced DCG-IV effect in the medial perforant path recorded in slices from pilocarpine-treated rats was due to a significant increase of mGluR2, but not mGluR3 transcripts in the entorhinal cortex using quantitative real-time reverse transcriptase-PCR. Immunohistochemistry confirmed the increased expression of group II mGluRs in the epileptic medial molecular layer. These results demonstrate that chronic epilepsy not only causes downregulation of mGluRs in the Hippocampus, but may also lead to enhanced expression of these receptors - at least in the medial perforant path." #: Probably more statements can be takenf rom the evidence SET Species = "10116" SET Subgraph = {"Glutamatergic subgraph", "Neurotransmitter release subgraph"} SET Confidence = "High" SET MeSHAnatomy = "Hippocampus" p(HGNC:GRM1) neg path(MESHD:Epilepsy) p(HGNC:GRM2) neg path(MESHD:Epilepsy) p(HGNC:GRM3) neg path(MESHD:Epilepsy) p(HGNC:GRM4) neg path(MESHD:Epilepsy) p(HGNC:GRM5) neg path(MESHD:Epilepsy) p(HGNC:GRM6) neg path(MESHD:Epilepsy) p(HGNC:GRM7) neg path(MESHD:Epilepsy) p(HGNC:GRM8) neg path(MESHD:Epilepsy) ######################################## SET Citation = {"PubMed", "Neurosci Lett. 2004 Nov 16;371(1):73-8.", "15500970"} SET Evidence = "Synaptic Ras-GTPase activating protein (SynGAP) has important roles in RAS/MAPK-dependent synaptic plasticity and mammalian learning." SET Confidence = "High" SET Subgraph = {"Glutamatergic subgraph", "Neurotransmitter release subgraph"} p(HGNC:SYNGAP1) -- bp(GOBP:"regulation of neuronal synaptic plasticity") p(HGNC:SYNGAP1) -- bp(GOBP:"learning or memory") ######################################## SET Citation = {"PubMed", "Brain Res. 2014 Nov 24;1590:20-30. doi: 10.1016/j.brainres.2014.09.028. Epub 2014 Sep 19.", "25242614"} SET Evidence = "These results indicate that the HIF-1α expression is associated with hippocampal apoptosis, and suggest that HIF-1α is an important factor during epileptogenesis." SET Confidence = "High" SET Subgraph = {"Apoptosis signaling subgraph","hormone signaling subgraph"} SET MeSHAnatomy = "Hippocampus" p(HGNC:HIF1A) -- bp(GOBP:"apoptotic process") UNSET {Confidence, Subgraph, MeSHAnatomy} ######################################## SET Citation = {"PubMed", "Pediatr Neurol. 2013 Dec;49(6):431-8. doi: 10.1016/j.pediatrneurol.2013.08.020. Epub 2013 Oct 15.", "24138949"} SET Evidence = "Kernicterus is an irreversible brain damage caused by bilirubin deposition in selective brain regions. Sick and preterm infants with hyperbilirubinemia are particularly susceptible to the condition.. in the corpus striatum and Hippocampus. These two regions exhibited increased expression of vascular endothelial growth factor," SET Confidence = "High" SET Subgraph = "hormone signaling subgraph" p(HGNC:VEGFA) pos path(MESHD:Kernicterus) ######################################## SET Citation = {"PubMed", "Pharmacol Rep. 2013;65(2):368-78.", "23744421"} SET Evidence = "The most prominent increase in Arc expression during kindling was present in the entorhinal cortex, the dentate gyrus, and the basolateral nucleus of the amygdala." #: Missing anatomy annotation SET Confidence = "High" SET Subgraph = {"hormone signaling subgraph", "thyroid hormone signaling subgraph"} a(CHEBI:pentetrazol) -> p(HGNC:ARC) SET Evidence = "The fastest and most potent increase in Egr1 expression during PTZ-induced kindling was found in the piriform and entorhinal cortices" SET Subgraph = {"hormone signaling subgraph", "thyroid hormone signaling subgraph"} SET Confidence = "High" SET Anatomy = "piriform cortex" a(CHEBI:pentetrazol) -> p(HGNC:EGR1) a(CHEBI:pentetrazol) -> path(MESHD:Epilepsy) UNSET {Confidence, Subgraph, Anatomy} ######################################## SET Citation = {"PubMed", "Eur J Neurosci. 2009 Sep;30(6):1077-91. doi: 10.1111/j.1460-9568.2009.06903.x. Epub 2009 Sep 1.", "19723286"} SET Evidence = "Glycine receptor (GlyR) alpha3 is involved in vision, and processing of acoustic and nociceptive signals, and RNA editing of GLRA3 transcripts was associated with hippocampal pathophysiology of mesial temporal lobe epilepsy (TLE)." SET Confidence = "High" SET Subgraph = {"Inflammatory response subgraph", "Neurotransmitter release subgraph"} g(HGNC:GLRA3) -- path(MESHD:"Epilepsy, Temporal Lobe") UNSET {Confidence, Subgraph} ######################################## SET Citation = {"PubMed", "6617734"} SET Evidence = "The action of various doses of intraperitoneally administered carbamazepine, ethosuximide, Na-valproate, phenobarbital and diphenylhydantoin on the neuronal firing rate of presumed noradrenergic neurons of the locus coeruleus was investigated in the anaesthetized rat. Carbamazepine was the only compound which produced a statistically significant, dose-dependent activation of these neurons. The other anticonvulsant drugs caused a small but non significant reduction in locus coeruleus cell firing. It is concluded that this brain nucleus is not a main target of anticonvulsant drugs." SET Confidence = "High" SET Published = "Epilepsy comorbidity paper" SET Species = "10116" SET Anatomy = "locus ceruleus" a(CHEBI:carbamazepine) -> act(a(UBERON:"noradrenergic system")) UNSET {Published, Species, Anatomy, Confidence} ######################################## SET Citation = {"PubMed", "3280560"} SET Evidence = "Biochemical and pharmacological data suggest that the anticonvulsant effects of carbamazepine are related to "peripheral-type" benzodiazepine and alpha 2-noradrenergic receptor systems and to its ability to stabilize sodium channels. " SET Confidence = "High" SET Published = "Epilepsy comorbidity paper" a(CHEBI:carbamazepine) -- bp(GOBP:"regulation of voltage-gated sodium channel activity") UNSET {Published, Confidence} ######################################## SET Citation = {"PubMed", "23535492"} SET Evidence = "The role of adenosine as an endogenous anticonvulsant is mediated via ADORA1.12 Inhibition of ADORA1 function has been shown to cause status epilepticus. In a rat model of seizure kindling, ADORA1 in the hippocampal CA1 region reduces seizures, whereas ADORA2A promotes them.14 " SET Confidence = "High" SET Published = "Epilepsy comorbidity paper" a(CHEBI:adenosine) -| path(MESHD:Seizures) a(CHEBI:adenosine) -- p(HGNC:ADORA1) p(HGNC:ADORA1) neg path(MESHD:Seizures) p(HGNC:ADORA1) neg path(MESHD:"Status Epilepticus") SET Species = "10116" SET MeSHAnatomy="CA1 Region, Hippocampal" act(p(HGNC:ADORA2A)) -> path(MESHD:Seizures) act(p(HGNC:ADORA1)) -| path(MESHD:Seizures) UNSET {Published, Confidence, Species, MeSHAnatomy} UNSET STATEMENT_GROUP