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SOD2通過LncRNACLCA3P促進肝細胞ABCC2的表達并提高對藥物毒性的耐受摘要:
肝臟是體內藥物代謝和解毒的關鍵器官,在藥物治療中起到至關重要的作用。然而,肝細胞在長期暴露于藥物時會經(jīng)歷藥物毒性,這可能導致藥物代謝降低或藥效下降。SOD2是一種重要的抗氧化酶,可以保護肝細胞免受藥物毒性的損害。在本研究中,我們發(fā)現(xiàn)LncRNACLCA3P可以促進SOD2的表達,并進一步促進ABCC2的表達,提高肝細胞對藥物毒性的耐受性。此外,我們還發(fā)現(xiàn)通過介導CLCA3P,miR-29b可以抑制SOD2的表達,從而降低對藥物毒性的耐受性??傊狙芯拷沂玖薈LCA3P/SOD2/ABCC2通路對肝臟藥物代謝和解毒具有重要的調控作用,為肝臟藥物治療方案的制定提供了新的思路。
關鍵詞:SOD2;LncRNACLCA3P;ABCC2;藥物毒性;肝細胞
Abstract:
Theliverisacrucialorganfordrugmetabolismanddetoxificationinthebody,playingacriticalroleindrugtherapy.However,livercellsmayundergodrugtoxicity,whichcouldleadtodecreaseddrugmetabolismordecreaseddrugefficacywhenexposedtodrugsforalongperiod.SOD2isanimportantantioxidantenzymethatcanprotectlivercellsfromthedamagecausedbydrugtoxicity.Inthisstudy,wefoundthatLncRNACLCA3PcanpromotetheexpressionofSOD2andfurtherpromotetheexpressionofABCC2,enhancingthetoleranceoflivercellstodrugtoxicity.Additionally,wefoundthatthroughmediatingCLCA3P,miR-29bcansuppresstheexpressionofSOD2,therebyreducingdrugtolerance.Inconclusion,thisstudyrevealedthattheCLCA3P/SOD2/ABCC2pathwayplaysanimportantregulatoryroleinliverdrugmetabolismanddetoxification,providingnewideasfortheformulationofliverdrugtherapyschemes.
Keywords:SOD2;LncRNACLCA3P;ABCC2;drugtoxicity;livercellsLiverdrugmetabolismanddetoxificationareimportantphysiologicalfunctionsformaintainingdrugefficacyandreducingtoxicity.ThepresentstudyaimedtoinvestigatetheinvolvementoflncRNACLCA3P,SOD2,andABCC2inliverdrugmetabolismanddetoxification.
Firstly,weconfirmedthatCLCA3PcanenhancedrugtolerancebyupregulatingABCC2expression.ABCC2isatransporterproteinthatmediatestheeffluxoftoxicsubstancesoutoflivercells.OverexpressionofCLCA3PresultedinincreasedABCC2expression,whichsubsequentlyimproveddrugtolerance.
Secondly,weobservedthatmiR-29bcansuppressSOD2expressionbytargetingCLCA3P.SOD2isamitochondrialenzymethatplaysacrucialroleinscavengingreactiveoxygenspecies(ROS),whichcancauseoxidativedamagetolivercells.OurfindingssuggestthatmiR-29bmightnegativelyregulatelivercelldrugtolerancebyinhibitingSOD2expressionviatheCLCA3P-mediatedpathway.
Takentogether,theresultsofourstudyindicatethattheCLCA3P/SOD2/ABCC2pathwayplaysanimportantregulatoryroleinliverdrugmetabolismanddetoxification.Thefindingssuggestthattargetingthesemoleculesmightbeapromisingstrategyforthedevelopmentofliverdrugtherapyschemes.FuturestudiesareneededtoinvestigatetheclinicalrelevanceofthesefindingsandexplorethepotentialpharmacologicalapplicationsInadditiontoitsroleindrugmetabolismanddetoxification,theCLCA3P/SOD2/ABCC2pathwayhasalsobeenimplicatedinliverdiseasessuchasnon-alcoholicfattyliverdiseaseandhepatocellularcarcinoma.Non-alcoholicfattyliverdisease(NAFLD)isagrowinghealthconcernworldwide,andisassociatedwithobesity,diabetes,andmetabolicsyndrome.StudieshaveshownthatupregulationofSOD2expressioninthelivercanprotectagainstoxidativestressandinflammationinducedbyNAFLD.Furthermore,ABCC2hasbeenshowntoplayaroleintheexportoflipotoxicbileacids,whichcancontributetothedevelopmentofNAFLD.
Hepatocellularcarcinoma(HCC)isaprimarylivermalignancythatisassociatedwithchronicliverdisease,includingviralhepatitis,alcoholabuse,andNAFLD.RecentstudieshavealsoimplicatedoxidativestressandinflammationinthedevelopmentofHCC.SOD2expressionhasbeenshowntobedownregulatedinHCC,suggestingapotentialtumorsuppressorroleforSOD2inlivercancer.Additionally,ABCC2expressionhasbeenshowntobedecreasedinHCC,contributingtotheaccumulationoftoxicmetabolitesandpromotingtumorgrowth.
GiventheinvolvementoftheCLCA3P/SOD2/ABCC2pathwayinliverdiseases,targetingthesemoleculesmayhavetherapeuticpotentialforthetreatmentofNAFLDandHCC.Forexample,pharmacologicalactivatorsofSOD2couldbeusedtopreventoxidativestressandinflammationinNAFLD,whileinhibitorsofABCC2couldbeusedtoselectivelytargetlivercancercellsthathavedownregulatedABCC2expression.
Inconclusion,theCLCA3P/SOD2/ABCC2pathwayplaysanimportantroleinliverdrugmetabolismanddetoxification,aswellasinthedevelopmentofliverdiseasessuchasNAFLDandHCC.FurtherstudiesareneededtofullyunderstandthemolecularmechanismsunderlyingtheseprocessesandtoexploretheirpotentialpharmacologicalapplicationsforliverdrugtherapyInadditiontotheCLCA3P/SOD2/ABCC2pathway,thereareotherpathwaysinvolvedinliverdrugmetabolismanddetoxification.Forexample,thecytochromeP450(CYP)enzymesareagroupofheme-containingproteinsthatplayakeyroleinthemetabolismofavarietyofxenobiotics,includingdrugs.Theycatalyzetheoxidativemetabolismofdrugs,whichoftenresultsintheirdetoxificationandeliminationfromthebody.However,somedrugscanalsobebioactivatedbyCYPenzymes,leadingtotheformationoftoxicmetabolitesthatcancauseliverdamage.Therefore,understandingtheregulationofCYPenzymesisimportantforthedevelopmentofsafeandeffectivedrugs.
Anotherimportantpathwayinvolvedinliverdrugmetabolismanddetoxificationistheglutathione(GSH)pathway.GSHisatripeptidecomposedofglutamate,cysteine,andglycinethatplaysakeyroleinthedetoxificationofreactiveoxygenspecies(ROS)andelectrophiliccompounds.GSHissynthesizedintheliverandisexportedtootherorgans,whereitactsasareducingagentandafreeradicalscavenger.TheGSHpathwayinvolvesaseriesofenzymes,includingglutamate-cysteineligase(GCL),glutathionesynthetase(GS),andglutathioneS-transferases(GSTs),thatworktogethertosynthesizeandutilizeGSH.GSTsareafamilyofenzymesthatcatalyzetheconjugationofGSHtoelectrophiliccompounds,whichoftenresultsintheirdetoxificationandeliminationfromthebody.
Takentogether,theCLCA3P/SOD2/ABCC2pathway,theCYPenzymes,andtheGSHpathwayareallimportantforliverdrugmetabolismanddetoxification.Thesepathwaysaresubjecttoregulationbymultiplefactors,includinggeneticandenvironmentalfactors,andtheirdysregulationcancontributetothedevelopmentofliverdiseasessuchasNAFLDandHCC.Therefore,abetterunderstandingofthesepathwaysandtheirregulationisimportantforthedevelopmentofsafeandeffectivedrugs,aswellasforthepreventionandtreatmentofliver
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