吴茱萸碱

文献讲解•Title：EvodiamineAbolishesConstitutiveandInducibleNF-κBActivationbyInhibitingIκBαKinaseActivation,TherebySuppressingNF-κB-regulatedAntiapoptoticandMetastaticGeneExpression,Up-regulatingApoptosis,andInhibitingInvasion.•Author：YasunariTakadaYoshinoriKobayashiBharatB.AggarwalKeywords：Evodiamine(吴茱萸碱)NF-κBTNFAbstract：Evodiamine,analkaloidalcomponentextractedfromthefruitofEvodiaefructus.Inthepresentstudy,evodiaminewasahighlypotentinhibitorofNF-κBactivation.Evodiaminealsoinhibitedtumornecrosisfactor(TNF)-inducedAktactivationanditsassociationwithIKK.weinvestigatedtheeffectofevodiamineonNF-κBandNF-κB-regulatedgeneexpressionactivatedbyvariouscarcinogens.WedemonstratethatevodiaminewasahighlypotentinhibitorofNF-κBactivation,anditabrogatedbothinducibleandconstitutiveNF-κBactivation.TheinhibitioncorrespondedwiththesequentialsuppressionofIκBαkinaseactivity,IκBαphosphorylation,IκBαdegradation,p65phosphorylation,p65nucleartranslocation,andp65acetylation.Evodiaminealsoinhibitedtumornecrosisfactor(TNF)-inducedAktactivationanditsassociationwithIKK.MATERIALSANDMETHODSCelllines--KBM-5,H1299,Jurkat,A293,FaDu,andU266.Methods--EMSA,KinaseAssay,WesternBlotAnalysis,NF-κB-dependent,ReporterGeneExpressionAssay,Immunoprecipitationofp65forp65Acetylationandsoon.Result•Result•EvodiamineactsatastepintheNF-κBactivationpathwaythatiscommontoallsixagents.•InhibitionofNF-κBActivationbyEvodiamineIsNotCellType-specific.EvodiamineInhibitsTNF-inducedNF-κBActivationinaDose-andTime-dependentManner--TheEMSAresultsshowedthatevodiaminebyitselfdidnotactivateNF-κB,butTNF-inducedNF-κBactivationwasinhibitedbyevodiamineinadose-dependentmannerandTNF-inducedNF-κBactivationwascompletelyabolishedat24h.•ResultsshowedthatevodiamineisapotentinhibitorofTNF-inducedNF-κBactivation.•EvodiaminedidnotmodifytheDNA-bindingabilityoftheNF-κBcomplex.WeconcludedthatevodiamineinhibitsNF-κBactivationindirectly.•TheseresultsindicatedthatevodiamineinhibitsbothTNF-inducedNF-κBactivationandIκBαdegradation.•EffectofevodiamineonIκBαphosphorylationanddegradationinducedbyTNF.•ResultsfromtheimmunocomplexkinaseassayshowedthatTNFactivatedIKKasearlyas10minafterTNFtreatmentandthatevodiaminecompletelysuppressedthisactivation.NeitherTNFnorevodiamineaffectedtheexpressionofIKK-αorIKK-β.•ThisfindingsuggeststhatevodiaminemodulatesTNF-inducedIKKactivation.•EvodiamineinhibitionoftheTNF-inducedexpressionofNF-κB-dependentgenes.•Theseresultssuggestedthattheeffectofevodiamineoccursatastepupstreamfromp65.•EvodiamineinhibitionoftheTNF-inducedexpressionofNF-κB-dependentproliferative,metastatic,andantiapoptoticgenes.•TheresultsprovidefurtherevidenceoftheroleofevodiamineinblockingtheexpressionofTNF-inducedNF-κB-regulatedgeneproducts.•EvodiamineenhancementofTNF-inducedcytotoxicity.•EvodiaminebyitselfhadlittlecytotoxiceffectatthisConcentration.•EvodiamineenhancestheapoptoticeffectsofTNFandchemotherapeuticagents.•EvodiaminesuppressionofTNF-inducedinvasionactivity.•TNFinduced2.6-foldgreaterinvasiveactivity,andevodiaminesuppressedit.summaryOverall,ourresultsindicatedthatevodiamineinhibitsbothconstitutiveandinducedNF-κBactivationandNF-κB-regulatedgeneexpressionandthatthisinhibitionmayprovideamolecularbasisfortheabilityofevodiaminetosuppressproliferation,induceapoptosis,andinhibitmetastasis.Thanks.