2024
Glutathione synthesis in the mouse liver supports lipid abundance through NRF2 repression
Asantewaa G, Tuttle E, Ward N, Kang Y, Kim Y, Kavanagh M, Girnius N, Chen Y, Rodriguez K, Hecht F, Zocchi M, Smorodintsev-Schiller L, Scales T, Taylor K, Alimohammadi F, Duncan R, Sechrist Z, Agostini-Vulaj D, Schafer X, Chang H, Smith Z, O’Connor T, Whelan S, Selfors L, Crowdis J, Gray G, Bronson R, Brenner D, Rufini A, Dirksen R, Hezel A, Huber A, Munger J, Cravatt B, Vasiliou V, Cole C, DeNicola G, Harris I. Glutathione synthesis in the mouse liver supports lipid abundance through NRF2 repression. Nature Communications 2024, 15: 6152. PMID: 39034312, PMCID: PMC11271484, DOI: 10.1038/s41467-024-50454-2.Peer-Reviewed Original ResearchConceptsGlutamate-cysteine ligase catalytic subunitLipid abundanceLipogenic enzyme expressionAbundance in vivoLipid productionCatalytic subunitRepress Nrf2Transcription factorsNrf2 repressionAdult tissuesSynthesis of GSHEnzyme expressionNon-redundantRedox bufferMouse liverLoss of GSHTriglyceride productionIn vivo modelsAbundanceGlutathione synthesisLiver balanceFat storesOxidative stressLipidDeletion
2022
Oxidative stress induces inflammation of lens cells and triggers immune surveillance of ocular tissues
Thompson B, Davidson EA, Chen Y, Orlicky DJ, Thompson DC, Vasiliou V. Oxidative stress induces inflammation of lens cells and triggers immune surveillance of ocular tissues. Chemico-Biological Interactions 2022, 355: 109804. PMID: 35123994, PMCID: PMC9136680, DOI: 10.1016/j.cbi.2022.109804.Peer-Reviewed Original ResearchMeSH KeywordsAcetylcysteineAnimalsButhionine SulfoximineCell LineChemokine CCL7CytokinesDown-RegulationEpithelial CellsEpithelial-Mesenchymal TransitionEyeGlutamate-Cysteine LigaseImmunity, InnateLens, CrystallineLeukocytesMiceMice, Inbred C57BLMice, KnockoutOxidative StressReactive Oxygen SpeciesUp-RegulationConceptsPosterior capsule opacificationCytokine expressionKO miceImmune surveillanceOxidative stressLens epithelial cellsOcular structuresLens cellsDevelopment of PCOEpithelial cellsInnate immune cellsExpression of cytokinesEx vivo inductionOcular surface tissuesExpression of markersImmune response genesCON miceControl miceCapsule opacificationImmune cellsPostnatal dayΑ-SMAMouse modelOcular tissuesVivo induction
2021
Oxidative stress and genotoxicity in 1,4-dioxane liver toxicity as evidenced in a mouse model of glutathione deficiency
Chen Y, Wang Y, Charkoftaki G, Orlicky DJ, Davidson E, Wan F, Ginsberg G, Thompson DC, Vasiliou V. Oxidative stress and genotoxicity in 1,4-dioxane liver toxicity as evidenced in a mouse model of glutathione deficiency. The Science Of The Total Environment 2021, 806: 150703. PMID: 34600989, PMCID: PMC8633123, DOI: 10.1016/j.scitotenv.2021.150703.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsDioxanesDNA DamageFollow-Up StudiesGlutathioneLiverMiceMice, KnockoutOxidative StressConceptsOxidative stressLiver cytotoxicityGlutamate-cysteine ligase modifier subunitWild-type micePrimary target organRecent mouse studiesCYP2E1 inductionLiver toxicitySubchronic exposureNrf2 inductionOxidative DNA damageCancer riskMouse modelAnti-oxidative responseDNA damageTarget organsAnimal studiesLiver carcinogenicityRedox dysregulationEarly changesHealth CanadaNull miceMouse studiesNuclear factorCarcinogenic mechanisms
2019
Glutathione deficiency-elicited reprogramming of hepatic metabolism protects against alcohol-induced steatosis
Chen Y, Manna SK, Golla S, Krausz KW, Cai Y, Garcia-Milian R, Chakraborty T, Chakraborty J, Chatterjee R, Thompson DC, Gonzalez FJ, Vasiliou V. Glutathione deficiency-elicited reprogramming of hepatic metabolism protects against alcohol-induced steatosis. Free Radical Biology And Medicine 2019, 143: 127-139. PMID: 31351176, PMCID: PMC6848780, DOI: 10.1016/j.freeradbiomed.2019.07.025.Peer-Reviewed Original ResearchMeSH KeywordsAcetyl Coenzyme AAlcohol DrinkingAMP-Activated Protein KinasesAnimalsEthanolFatty AcidsFatty LiverGlucuronic AcidGlutamate-Cysteine LigaseGlutamatesGlutathioneHomeostasisLipogenesisLiverMaleMiceMice, Inbred C57BLMice, KnockoutOligonucleotide Array Sequence AnalysisOxidation-ReductionOxidative StressPentose Phosphate PathwayProtective AgentsTranscription, GeneticConceptsGlutamate-cysteine ligase modifier subunit geneProtein kinase pathwayAcetyl-CoA fluxMultiple cellular pathwaysAlcohol-induced steatosisCellular stressNucleotide biosynthesisLiver microarray analysisGlobal profilingSubunit geneCellular pathwaysMetabolic reprogrammingKinase pathwayMicroarray analysisMolecular mechanismsGSH poolCellular responsesMetabolic pathwaysLower GSHMolecular pathwaysMetabolic homeostasisAmino acidsDepletion of glutathioneCritical pathogenic eventGlucuronate pathway
2018
Glutathione de novo synthesis but not recycling process coordinates with glutamine catabolism to control redox homeostasis and directs murine T cell differentiation
Lian G, Gnanaprakasam JR, Wang T, Wu R, Chen X, Liu L, Shen Y, Yang M, Yang J, Chen Y, Vasiliou V, Cassel TA, Green DR, Liu Y, Fan TW, Wang R. Glutathione de novo synthesis but not recycling process coordinates with glutamine catabolism to control redox homeostasis and directs murine T cell differentiation. ELife 2018, 7: e36158. PMID: 30198844, PMCID: PMC6152796, DOI: 10.7554/elife.36158.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell DifferentiationCell ProliferationDimethyl FumarateGlutamate-Cysteine LigaseGlutamineGlutathioneGlutathione DisulfideHomeostasisLymphocyte ActivationMice, Inbred C57BLOxidation-ReductionOxidative StressReactive Oxygen SpeciesReceptors, Antigen, T-CellTh17 CellsT-LymphocytesT-Lymphocytes, RegulatoryConceptsCell fateDe novo synthesisNovo synthesisCell differentiationT cell differentiationMurine T cell differentiationT cell fateGlutamate-cysteine ligaseLineage choiceRedox demandsGlutathione de novo synthesisRecycling pathwayInhibition of GSHRedox homeostasisGSH biosynthesisGlutamine catabolismRedox balanceModifier subunitEssential precursorIntracellular GSHEssential roleGlutathione disulfideDifferentiationGSH contentGSH
2012
Aldehyde dehydrogenases in cellular responses to oxidative/electrophilicstress
Singh S, Brocker C, Koppaka V, Chen Y, Jackson BC, Matsumoto A, Thompson DC, Vasiliou V. Aldehyde dehydrogenases in cellular responses to oxidative/electrophilicstress. Free Radical Biology And Medicine 2012, 56: 89-101. PMID: 23195683, PMCID: PMC3631350, DOI: 10.1016/j.freeradbiomed.2012.11.010.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsReactive oxygen speciesOxidative stressMulticellular speciesEukaryotic organismsElectrophilic stressExogenous aldehydesCancer stem cellsLiving systemsStress responseCellular responsesEnvironmental stressorsSimilar functionsAldehyde scavengerSpeciesStem cellsLipid peroxidationROS loadOxygen speciesElevated oxidative stressLipid membranesALDHALDH expressionOrganismsPathological processesPathological conditionsEffect of chronic glutathione deficiency on the behavioral phenotype of Gclm(−/−) knockout mice
Chen Y, Curran CP, Nebert DW, Patel KV, Williams MT, Vorhees CV. Effect of chronic glutathione deficiency on the behavioral phenotype of Gclm(−/−) knockout mice. Neurotoxicology And Teratology 2012, 34: 450-457. PMID: 22580179, PMCID: PMC3404268, DOI: 10.1016/j.ntt.2012.04.009.Peer-Reviewed Original ResearchConceptsGlutamate-cysteine ligase modifier subunitMorris water mazeKO miceKnockout miceWater mazeOxidative stressChronic glutathione deficiencyPostnatal day 60Novel object recognitionWild-type littermatesTime of conceptionChronic GSH depletionChronic oxidative stressOpen-field activityKnockout mouse lineNormal spatial learningControl brain regionsAcoustic startleBehavioral abnormalitiesPostnatal lifeBrain regionsNeurodegenerative disordersDay 60Phenotyping testsMiceMolecular mechanisms of ALDH3A1-mediated cellular protection against 4-hydroxy-2-nonenal
Black W, Chen Y, Matsumoto A, Thompson DC, Lassen N, Pappa A, Vasiliou V. Molecular mechanisms of ALDH3A1-mediated cellular protection against 4-hydroxy-2-nonenal. Free Radical Biology And Medicine 2012, 52: 1937-1944. PMID: 22406320, PMCID: PMC3457646, DOI: 10.1016/j.freeradbiomed.2012.02.050.Peer-Reviewed Original ResearchMeSH KeywordsAldehyde DehydrogenaseAldehydesAnimalsApoptosisCell LineCorneaHumansOxidative StressProteasome Endopeptidase ComplexRabbitsConceptsAldehyde dehydrogenasesOxidative stress responseCellular defense mechanismsOxidative stressHuman ALDH3A1Proteasome functionMolecular mechanismsPrevents apoptosisStress responseCellular protectionLipid peroxidationAdverse effectsWestern blot analysisAldehydic moleculesGlutathione homeostasisALDH3A1 expressionCell viability assaysMetabolic functionsALDH3A1Blot analysisDefense mechanismsProtein adduct formationCell linesCell viabilityViability assays
2011
Lipid metabolism and body composition in Gclm(−/−) mice
Kendig EL, Chen Y, Krishan M, Johansson E, Schneider SN, Genter MB, Nebert DW, Shertzer HG. Lipid metabolism and body composition in Gclm(−/−) mice. Toxicology And Applied Pharmacology 2011, 257: 338-348. PMID: 21967773, PMCID: PMC3226854, DOI: 10.1016/j.taap.2011.09.017.Peer-Reviewed Original ResearchConceptsHigh-fat dietExcessive weight gainInsulin resistanceWeight gainFatty liverBasal metabolic rateGlutamate-cysteine ligase modifier subunit geneDecreased respiratory quotientExcess body weightIntestinal lipid absorptionHepatic oxidative stress responseDietary energy consumptionWild-type controlsGlucose intoleranceOxidative stress responseFat dietNormal dietRisk factorsBody compositionBody weightMetabolic rateDietary lipidsLipid absorptionMetabolic diseasesExperimental animalsUltraviolet Radiation: Cellular Antioxidant Response and the Role of Ocular Aldehyde Dehydrogenase Enzymes
Marchitti SA, Chen Y, Thompson DC, Vasiliou V. Ultraviolet Radiation: Cellular Antioxidant Response and the Role of Ocular Aldehyde Dehydrogenase Enzymes. Eye & Contact Lens Science & Clinical Practice 2011, 37: 206-213. PMID: 21670692, PMCID: PMC3356694, DOI: 10.1097/icl.0b013e3182212642.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsMeSH KeywordsAldehyde DehydrogenaseAntioxidantsEyeHumansOxidative StressReactive Oxygen SpeciesUltraviolet RaysConceptsReactive oxygen speciesCombat reactive oxygen speciesImportant enzymatic antioxidantsAldehyde dehydrogenaseReduction-oxidation homeostasisOxidative damageConstant oxidative stressAldehyde dehydrogenase enzymeCellular antioxidant responseOxidative stressUnique roleCellular membranesCellular responsesAntioxidant defense systemSuperoxide dismutasesAntioxidant responseEnvironmental insultsDownstream effectsDefense systemGlutathione reductaseEnzymatic antioxidantsOxygen speciesDehydrogenase enzymeNicotinamide adenine dinucleotide phosphateNonenzymatic antioxidants
2010
Structural and Functional Modifications of Corneal Crystallin ALDH3A1 by UVB Light
Estey T, Chen Y, Carpenter JF, Vasiliou V. Structural and Functional Modifications of Corneal Crystallin ALDH3A1 by UVB Light. PLOS ONE 2010, 5: e15218. PMID: 21203538, PMCID: PMC3006428, DOI: 10.1371/journal.pone.0015218.Peer-Reviewed Original ResearchConceptsActive site CysNon-native aggregationNon-covalent interactionsAldehyde dehydrogenase 3A1MALDI-TOF mass spectrometryMammalian corneal epitheliumCorneal crystallinsSpectroscopic studiesChemical modificationUV-induced damageCys residuesGlucose-6-phosphate dehydrogenaseTertiary structureMass spectrometryMultifaceted roleResult of aggregationALDH3A1Enzymatic activityCorneal proteinsUV-induced inactivationOxidative stressProteinFunctional modificationsResiduesDirect absorptionOral N-acetylcysteine rescues lethality of hepatocyte-specific Gclc-knockout mice, providing a model for hepatic cirrhosis
Chen Y, Johansson E, Yang Y, Miller ML, Shen D, Orlicky DJ, Shertzer HG, Vasiliou V, Nebert DW, Dalton TP. Oral N-acetylcysteine rescues lethality of hepatocyte-specific Gclc-knockout mice, providing a model for hepatic cirrhosis. Journal Of Hepatology 2010, 53: 1085-1094. PMID: 20810184, PMCID: PMC2970663, DOI: 10.1016/j.jhep.2010.05.028.Peer-Reviewed Original ResearchAcetylcysteineAdministration, OralAnimalsAntioxidantsBase SequenceCytokinesDisease Models, AnimalDNA PrimersGene Expression ProfilingGlutamate-Cysteine LigaseGlutathioneHepatocytesLiverLiver CirrhosisMiceMice, KnockoutMicroscopy, Electron, TransmissionMitochondria, LiverOxidative StressRNA, MessengerRedox Dysregulation Affects the Ventral But Not Dorsal Hippocampus: Impairment of Parvalbumin Neurons, Gamma Oscillations, and Related Behaviors
Steullet P, Cabungcal JH, Kulak A, Kraftsik R, Chen Y, Dalton TP, Cuenod M, Q. K. Redox Dysregulation Affects the Ventral But Not Dorsal Hippocampus: Impairment of Parvalbumin Neurons, Gamma Oscillations, and Related Behaviors. Journal Of Neuroscience 2010, 30: 2547-2558. PMID: 20164340, PMCID: PMC6634545, DOI: 10.1523/jneurosci.3857-09.2010.Peer-Reviewed Original Research8-Hydroxy-2'-DeoxyguanosineAdaptation, OcularAnalysis of VarianceAnimalsAnimals, NewbornBehavior, AnimalBiological ClocksCalbindin 2CalbindinsConditioning, ClassicalDeoxyguanosineElectric StimulationElectroencephalographyExcitatory Amino Acid AgonistsExploratory BehaviorFearFeeding BehaviorGene Expression RegulationGene Expression Regulation, DevelopmentalGlutamate-Cysteine LigaseGlutathioneHippocampusInterneuronsKainic AcidMaleMaze LearningMiceMice, Inbred C57BLMice, KnockoutNeural PathwaysOxidation-ReductionOxidative StressParvalbuminsPattern Recognition, VisualRewardS100 Calcium Binding Protein GSpatial Behavior
2009
Antioxidant Defenses in the ocular surface
Chen Y, Mehta G, Vasiliou V. Antioxidant Defenses in the ocular surface. The Ocular Surface 2009, 7: 176-185. PMID: 19948101, PMCID: PMC4104792, DOI: 10.1016/s1542-0124(12)70185-4.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsMeSH KeywordsAnimalsAntioxidantsCorneaEye DiseasesHumansOxidative StressReactive Oxygen SpeciesTears
2007
Oxidative and electrophilic stress induces multidrug resistance–associated protein transporters via the nuclear factor‐E2–related factor‐2 transcriptional pathway
Maher JM, Dieter MZ, Aleksunes LM, Slitt AL, Guo G, Tanaka Y, Scheffer GL, Chan JY, Manautou JE, Chen Y, Dalton TP, Yamamoto M, Klaassen CD. Oxidative and electrophilic stress induces multidrug resistance–associated protein transporters via the nuclear factor‐E2–related factor‐2 transcriptional pathway. Hepatology 2007, 46: 1597-1610. PMID: 17668877, DOI: 10.1002/hep.21831.Peer-Reviewed Original ResearchMeSH Keywords5' Flanking RegionAnimalsAntioxidantsButylated HydroxyanisoleCell Line, TumorFluorescent Antibody Technique, IndirectGene Expression RegulationGlutamate-Cysteine LigaseGlutathioneHepatocytesLiverMiceMice, Inbred C57BLMice, KnockoutMultidrug Resistance-Associated ProteinsNF-E2-Related Factor 2Oxidative StressPromoter Regions, GeneticPyrazinesReverse Transcriptase InhibitorsThionesThiophenesConceptsTranscriptional pathwaysBinding of Nrf2Nrf2 transcriptional pathwayNrf2 target genesMarked geneAdenosine triphosphate-dependent transportersChromatin immunoprecipitationElectrophilic stressNuclear Nrf2 levelsTarget genesRegulatory pathwaysCoordinated inductionPromoter regionProtein transportersMultidrug resistance-associated proteinNrf2-null miceResponse elementResistance-associated proteinHepa1c1c7 cellsProtein inductionFactor 2 (Nrf2) activatorQuinone oxidoreductase 1MRP transportersTransportersNrf2 levelsHepatocyte‐specific Gclc deletion leads to rapid onset of steatosis with mitochondrial injury and liver failure
Chen Y, Yang Y, Miller ML, Shen D, Shertzer HG, Stringer KF, Wang B, Schneider SN, Nebert DW, Dalton TP. Hepatocyte‐specific Gclc deletion leads to rapid onset of steatosis with mitochondrial injury and liver failure. Hepatology 2007, 45: 1118-1128. PMID: 17464988, DOI: 10.1002/hep.21635.Peer-Reviewed Original ResearchConceptsLiver failureMitochondrial injuryLiver biochemistry testsSevere parenchymal damageNumerous liver diseasesMonths of ageGCLC geneHepatic failureLiver injuryParenchymal damageLiver diseaseDepletion of glutathioneHepatic steatosisHistological featuresGSH synthesisHepatic functionPostnatal dayHepatocyte deathKnockout miceRapid onsetBiochemistry testsHepatic GSHSteatosisUltrastructural examinationOxidative stress
2005
Butylhydroquinone Protects Cells Genetically Deficient in Glutathione Biosynthesis from Arsenite-Induced Apoptosis Without Significantly Changing Their Prooxidant Status
Kann S, Estes C, Reichard JF, Huang MY, Sartor MA, Schwemberger S, Chen Y, Dalton TP, Shertzer HG, Xia Y, Puga A. Butylhydroquinone Protects Cells Genetically Deficient in Glutathione Biosynthesis from Arsenite-Induced Apoptosis Without Significantly Changing Their Prooxidant Status. Toxicological Sciences 2005, 87: 365-384. PMID: 16014739, DOI: 10.1093/toxsci/kfi253.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsApoptosisArsenitesBlotting, WesternCell SurvivalCells, CulturedDNA, ComplementaryElectrophoretic Mobility Shift AssayFibroblastsGene Expression RegulationGlutamate-Cysteine LigaseGlutathioneHydroquinonesMiceMice, KnockoutNF-kappa BOligonucleotide Array Sequence AnalysisOxidantsOxidative StressRNATetrazolium SaltsThiazolesConceptsMouse embryo fibroblastsGlutathione biosynthesisGlobal gene expression profilesAntioxidant responseCell cycle regulationArsenite-induced apoptosisEffective antioxidant responseArsenic-induced apoptosisGene expression profilesExpression of genesGlutamate-cysteine ligaseOxidative stressProtein biosynthesisRole of glutathioneCycle regulationRate-limiting enzymeGene deregulationExpression profilesArsenic-induced oxidative stressEmbryo fibroblastsInduces oxidative stressModifier subunitApoptotic deathDNA damageToxicity of arsenic
2004
Genetically altered mice to evaluate glutathione homeostasis in health and disease
Dalton TP, Chen Y, Schneider SN, Nebert DW, Shertzer HG. Genetically altered mice to evaluate glutathione homeostasis in health and disease. Free Radical Biology And Medicine 2004, 37: 1511-1526. PMID: 15477003, DOI: 10.1016/j.freeradbiomed.2004.06.040.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsRole of GSHGSH biosynthetic pathwayCell model systemBiosynthetic pathwayExogenous electrophilesGSH homeostasisCellular GSHHuman diseasesGlutathione homeostasisMouse modelGSH synthesisTripeptide glutathioneAntioxidant systemOxidative damageGenetic deficiencyModel systemOxidative stressHomeostasisSuch chemicalsGSHDisease processNonspecific effects
2002
Initial Characterization of the Glutamate-Cysteine Ligase Modifier Subunit Gclm(−/−) Knockout Mouse NOVEL MODEL SYSTEM FOR A SEVERELY COMPROMISED OXIDATIVE STRESS RESPONSE*
Yang Y, Dieter MZ, Chen Y, Shertzer HG, Nebert DW, Dalton TP. Initial Characterization of the Glutamate-Cysteine Ligase Modifier Subunit Gclm(−/−) Knockout Mouse NOVEL MODEL SYSTEM FOR A SEVERELY COMPROMISED OXIDATIVE STRESS RESPONSE*. Journal Of Biological Chemistry 2002, 277: 49446-49452. PMID: 12384496, DOI: 10.1074/jbc.m209372200.Peer-Reviewed Original ResearchMeSH KeywordsAge FactorsAllelesAnimalsBlotting, NorthernBlotting, SouthernBody WeightCell DeathChromatography, GelCysteineDose-Response Relationship, DrugFibroblastsGenotypeGlutamate-Cysteine LigaseGlutamic AcidGlutathioneHomozygoteHydrogen PeroxideImmunoblottingKidneyKineticsLiverMiceMice, KnockoutModels, GeneticMutagenesis, Site-DirectedOxidative StressOxygenPhenotypePolymerase Chain ReactionProtein Structure, TertiaryTime FactorsTissue DistributionConceptsGlutamate-cysteine ligaseModifier subunitGSH biosynthesis pathwayGlutamate-cysteine ligase modifier subunitOxidative stress responseGCL holoenzymeHigher eukaryotesBiosynthesis pathwayCellular functionsCatalytic subunitNovel model systemRate-limiting enzymeNumerous pathophysiological conditionsNull allelesStress responseOvert phenotypeGCL activityOxidant insultSubunitsFetal fibroblastsChronic GSH depletionInitial characterizationHoloenzymeGSH inhibitionGSH depletion