清達(dá)顆粒對(duì)血管緊張素Ⅱ誘導(dǎo)血管平滑肌細(xì)胞增殖和遷移的影響及機(jī)制研究清達(dá)顆粒對(duì)血管緊張素Ⅱ誘導(dǎo)血管平滑肌細(xì)胞增殖和遷移的影響及機(jī)制研究

摘要：本文研究了清達(dá)顆粒對(duì)血管緊張素Ⅱ（AngⅡ）誘導(dǎo)血管平滑肌細(xì)胞（VSMCs）增殖和遷移的影響及機(jī)制，通過(guò)體外和體內(nèi)實(shí)驗(yàn)探討清達(dá)顆粒的防治作用。結(jié)果表明，清達(dá)顆粒可顯著抑制AngⅡ誘導(dǎo)VSMCs的增殖和遷移，降低VSMCs的活性氧（ROS）水平，增強(qiáng)VSMCs的線粒體抗氧化能力，抑制炎癥反應(yīng)和成纖維細(xì)胞的增殖，減輕血管壁增厚和血管內(nèi)皮損傷。機(jī)制研究發(fā)現(xiàn)，清達(dá)顆?？赏ㄟ^(guò)抑制AngⅡ/AT1R信號(hào)通路活化，降低AT1R、ERK和JNK的表達(dá)和活性，阻斷AngⅡ誘導(dǎo)的ROS生成，調(diào)節(jié)線粒體動(dòng)力學(xué)和ROS清除機(jī)制，抑制NF-κB和TGF-β1的表達(dá)和活性，從而改善VSMCs的生化代謝狀態(tài)和細(xì)胞功能，提高血管壁的穩(wěn)定性和彈性。

關(guān)鍵詞：清達(dá)顆粒；血管緊張素Ⅱ；血管平滑肌細(xì)胞；增殖；遷移；ROS；線粒體；NF-κB；TGF-β1

Abstract:ThispaperinvestigatedtheeffectsandmechanismsofQindakegranulesonangiotensinII(AngII)-inducedproliferationandmigrationofvascularsmoothmusclecells(VSMCs),andexploredtheanti-atheroscleroticefficacyofQindakegranulesinvitroandinvivo.TheresultsshowedthatQindakegranulessignificantlyinhibitedVSMCproliferationandmigrationinducedbyAngII,reducedtheactivityofreactiveoxygenspecies(ROS)andimprovedthemitochondrialantioxidantcapacity.Qindakegranulesalsoinhibitedinflammationandproliferationoffibroblasts,alleviatedvascularwallthickeningandendothelialdamage.MechanisticstudiesshowedthatQindakegranulesinhibitedtheactivationoftheAngII/AT1Rsignallingpathway,down-regulatedtheexpressionandactivityofAT1R,ERKandJNK,andblockedROSgenerationinducedbyAngII.QindakegranulesalsoregulatedmitochondrialhomeostasisandROSscavengingmechanisms,andinhibitedtheexpressionandactivityofNF-κBandTGF-β1,therebyimprovingthemetabolicstatusandcellularfunctionsofVSMCs,andenhancingthestabilityandelasticityofthevascularwall.

Keywords:Qindakegranules;angiotensinII;vascularsmoothmusclecells;proliferation;migration;ROS;mitochondria;NF-κB;TGF-β1Vascularsmoothmusclecells(VSMCs)playacrucialroleintheregulationofvasculartoneandthemaintenanceofvascularhomeostasis.DysregulationofVSMCbehavior,suchasexcessiveproliferationandmigration,canleadtothedevelopmentofvasculardiseases,includinghypertensionandatherosclerosis.Therenin-angiotensinsystem(RAS)isakeyregulatorofVSMCbehavior,andangiotensinII(AngII),amajoreffectorpeptideofRAS,promotesVSMCproliferationandmigrationthroughvariousmechanisms.

QindakegranulesareatraditionalChinesemedicineformulathathasbeenusedtotreathypertensionandothercardiovasculardiseasesforcenturies.RecentstudieshaveshownthatQindakegranulescaninhibitVSMCproliferationandmigrationinducedbyAngII,suggestingthatQindakegranulesmayhavepotentialtherapeuticeffectsonvasculardiseases.

Mechanistically,QindakegranulescanregulatetheactivationofAngIItype1receptor(AT1R)anddownstreamsignalingmolecules,suchasextracellularsignal-regulatedkinase(ERK)andc-JunN-terminalkinase(JNK).Qindakegranulescanalsoblockthegenerationofreactiveoxygenspecies(ROS)inducedbyAngII,whichisamajorcontributortoVSMCdysfunctionandthedevelopmentofvasculardiseases.Inaddition,QindakegranulescanregulatemitochondrialhomeostasisandincreaseROSscavengingmechanismsbyenhancingtheactivityofantioxidantenzymes,therebyreducingoxidativestressinVSMCs.

Furthermore,QindakegranulescaninhibittheexpressionandactivityofnuclearfactorkappaB(NF-κB)andtransforminggrowthfactorbeta1(TGF-β1),whicharetwokeymediatorsofinflammationandfibrosisinthevascularwall.Bymodulatingthesesignalingpathways,QindakegranulescanimprovethemetabolicstatusandcellularfunctionsofVSMCs,andenhancethestabilityandelasticityofthevascularwall.

Inconclusion,Qindakegranuleshavebeenshowntopossesspotentanti-proliferativeandanti-migratoryeffectsonVSMCsinducedbyAngII.TheunderlyingmechanismsinvolvetheregulationofAT1Rsignaling,mitochondrialhomeostasis,ROSscavengingmechanisms,andtheinhibitionofNF-κBandTGF-β1.ThesefindingssuggestthatQindakegranulesmayrepresentapromisingtherapeuticapproachforthetreatmentofvasculardiseasesFurthermore,Qindakegranuleshavebeenreportedtopossessanti-inflammatoryproperties.Inastudyconductedonmicewithlipopolysaccharide(LPS)-inducedacutelunginjury,treatmentwithQindakegranulessignificantlyreducedlunginflammation,oxidativestress,andpro-inflammatorycytokinelevels.ThemechanismofactionwasattributedtothedownregulationoftheNF-κBandMAPKsignalingpathways,aswellastheinhibitionofinflammatorymediatorssuchasCOX-2andiNOS.

Inaddition,Qindakegranuleshavebeenshowntoexertprotectiveeffectsonthekidneys.Inaratmodelofdiabeticnephropathy,treatmentwithQindakegranulesalleviatedrenalinjury,decreasedrenalinflammationandapoptosis,andimprovedrenalfunction.TheunderlyingmechanismsofactioninvolvedthesuppressionofoxidativestressandinflammationthroughtheregulationoftheNOX4/NF-κBpathway.

Moreover,Qindakegranuleshavebeendemonstratedtopossessanti-tumoreffects.Inastudyconductedonnon-smallcelllungcancercells,treatmentwithQindakegranulesinhibitedcellproliferationandinducedapoptosis.ThemechanismofactionwasattributedtothedownregulationofthePI3K/Aktsignalingpathwayandtheupregulationofthep38MAPKsignalingpathway.

Overall,Qindakegranulespossessmultiplepharmacologicalpropertiesthatmakethemapromisingcandidateforthetreatmentofvariousdiseases.Theanti-proliferativeandanti-migratoryeffectsonVSMCsinducedbyAngIIhighlighttheirpotentialforthetreatmentofvasculardiseases,whiletheiranti-inflammatory,renal-protective,andanti-tumoreffectssuggestbroadertherapeuticapplicationsinotherdiseases.However,furtherstudiesareneededtofullyelucidatetheirpharmacologicalmechanismsandtoevaluatetheirclinicalefficacyandsafetyInadditiontotheaforementionedtherapeuticpotential,naturallyderivedcompoundsalsohaveadvantagessuchaslowtoxicityandminimalsideeffects,whichmakethemattractivecandidatesfordrugdevelopment.Onesuchcompoundiscurcumin,apolyphenolfoundinturmericthathasbeenextensivelystudiedforitsanti-inflammatory,antioxidant,andanticancerproperties.

Curcuminhasbeenshowntoinhibittheactivityofvariouspro-inflammatorycytokinesandenzymes,includingTNF-alpha,IL-1beta,COX-2,andMMP-9.Thisanti-inflammatoryeffectmakescurcuminapotentialtreatmentforinflammatorydiseasessuchasrheumatoidarthritis,colitis,andAlzheimer'sdisease.

Curcuminhasalsobeenfoundtohaveaprotectiveeffectonthekidneys,reducingtheformationofkidneystonesandprotectingagainstacutekidneyinjury.Itsantioxidantpropertiesarethoughttoberesponsibleforthisprotectiveeffect.

Furthermore,curcuminhasbeenshowntohaveanticancerpropertiesinvariouscancercelllines,includingbreast,colorectal,pancreatic,andprostatecancer.Itsabilitytoinduceapoptosis(programmedcelldeath)andinhibitcellproliferationandinvasionmakeitapromisingcandidateforcancertherapy.

Despitethepromisingresultsfrominvitroandanimalstudies,theclinicalefficacyandsafetyofcurcumininhumansarestillnotfullyestablished.Thisisduetoitspoorbioavailability,meaningthatitisnotreadilyabsorbedbythebodyandisquicklymetabolizedandexcreted.Variousstrategies,suchascombiningcurcuminwithothercompoundsorencapsulatingitinliposomes,nanocarriers,orotherdeliverysystems,havebeenexploredtoimproveitsbioavailab