Panax notoginseng Saponins for Treating Coronary Artery ...

Panax notoginseng is a medicinal plant that was first used by ethnic minorities in China. It has been one of the most acclaimed herbs in China ... DownloadArticle DownloadPDF ReadCube EPUB XML(NLM) Supplementary Material Supplementaldata totalviews ViewArticleImpact SHAREON AipingLu HongKongBaptistUniversity,HongKong,SARChina ThomasHeinbockel HowardUniversity,UnitedStates ZhenhuaDai GuangdongProvincialAcademyofChineseMedicalSciences,China Theeditorandreviewer'saffiliationsarethelatestprovidedontheirLoopresearchprofilesandmaynotreflecttheirsituationatthetimeofreview. Abstract Introduction Methodology BiologicalCharacteristicsofPanaxnotoginseng TheTherapeuticEffectsofPNSonCAD AdverseEvents TheMechanismsofPNSonCAD Discussion Conclusion AuthorContributions Funding ConflictofInterestStatement Acknowledgments Footnotes References Opensupplementaldata Exportcitation EndNote ReferenceManager SimpleTEXTfile BibTex Checkforupdates Peoplealsolookedat REVIEWarticle Front.Pharmacol.,17October2017Sec.Ethnopharmacology https://doi.org/10.3389/fphar.2017.00702 PanaxnotoginsengSaponinsforTreatingCoronaryArteryDisease:AFunctionalandMechanisticOverview LianDuan1,2†,XingjiangXiong1†,JunyuanHu1,2,YongmeiLiu1,JunLi1andJieWang1* 1DepartmentofCardiology,Guang'anmenHospital,ChinaAcademyofChineseMedicalScience,Beijing,China 2GraduateSchool,BeijingUniversityofTraditionalChineseMedicine,Beijing,China Coronaryarterydisease(CAD)isamajorpublichealthproblemandthechiefcauseofmorbidityandmortalityworldwide.Panaxnotoginseng,avaluableherbintraditionalChinesemedicine(TCM)withobviousefficacyandfavorablesafety,showsagreatpromiseasanoveloptionforCADandisincreasinglyrecognizedclinically.Firstly,thisreviewintroducedrecentclinicaltrialsontreatmentwithPNSeitheraloneorincombinationwithconventionaldrugsasnoveltreatmentstrategies.ThenwediscussedthemechanismsofP.notoginsengandPanaxnotoginsengsaponins(PNS),whichcanregulatesignalingpathwaysassociatedwithinflammation,lipidmetabolism,thecoagulationsystem,apoptosis,angiogenesis,atherosclerosis,andmyocardialischaemia. Introduction Coronaryarterydisease(CAD)isamajorpublichealthproblemandachiefcauseofmorbidityandmortalityworldwide.ThenumberofdeathsduetoCADwas56millionpeoplegloballyduringadecadefrom2000(WHO,2014).Thesumofhospitalizedcardiovascularoperationsrisedby28%,fromabout6to7.5million(Mozaffarianetal.,2016).Theeconomicloadofcaringforpatientsalsorepresentsahugecostforsociety.RevascularizationrepresentsinnovativeprogressinthetreatmentforsymptomaticCAD.However,bytargetingoneortwovascularlesions,itfailstocompletelysolvetheproblemofplaqueprogress.AtrulyadvanceinthetreatmentofCADwillrequiremoreeffectiveprevention.Attheendofthenineteenthcentury,drugresistancetoorganicnitrateswasobserved(Dilidar,2009;Münzeletal.,2011),whileaspirinresistancewasobservedin1994(Helgasonetal.,1994).Clopidogrelhasbeenwidelyusedinvariousthromboticdiseases,especiallyinCADpatientswithpercutaneouscoronaryintervention(PCI;O'Garaetal.,2013).Aboutaquarterofpatientsadministeringstandardloadingofclopidogrelexhibitpoorresponsiveness(Serebruanyetal.,2005).DuetothecomplexityofCAD,mostpatientsrequirelifelongmedication.Moreover,oralaspirinmaydirectlystimulatethegastricmucosaandinitiateabdominaldiscomfort,nauseaandvomiting.Thelong-termuseofaspirincaneasilycausegastricmucosaldamage(Hirshetal.,1995).Theriskofdiabetesgreatlyincreaseswithlargedosesofstatins.Inaddition,statinscancauseabnormalliverenzymesandmyopathy(Thompsonetal.,2016).Varyingdegreesofdrugresistanceandadversereactionsincreasethedifficultyanddissatisfactionwithtreatment. Inrecentyears,TraditionalChineseMedicine(TCM)hasgainedwidespreadpopularity.Furthermore,anincreasingnumberofstudieshaveconfirmedtheefficacyofTCMfortreatingCAD.In2007,nearly4outof10adultshadusedTCMtherapyinthepast12months,withnaturalproductsasthemostcommonlyusedtherapies(Barnesetal.,2008).Ofthevariousnaturalproducts,Panaxnotoginsengisoneofthemostcommonlyappliedproductsbecauseithasbeenevaluatedwithvariousbeneficialeffects,suchaspromotionofbloodcirculation,cerebrovascularprotection(LiuL.etal.,2014;Zhangetal.,2016),improvementofneurologicalfunction(Gaoetal.,2012),reductionofoxidativestress(Dingetal.,2015),andmitigationofboneloss(Fanetal.,2015). PanaxnotoginsengisparticularlypopularamongpatientswithCADbecausemanystudieshavebeenassociatedtheconsumptionofP.notoginsengwithCADtreatment.Panaxnotoginsengsaponin(PNS)isthemainactiveingredientofP.notoginseng.Overthepastover40years,greatenergyhasbeendevotedtoconfirmingtheeffectivenessofthecompoundsofP.notoginsengonCAD.ManyanimalexperimentshaveshownthatPNScanimprovetheenergymetabolismofmyocardialcells,reducemyocardialdamage,andinhibitischaemia-inducedcardiomyocyteapoptosisinacuteMIrats(Chenetal.,2011;Yueetal.,2012).NowthecompoundofPNSisavailableasanover-the-counterdruginbothChinaandworldwide.InChinaalone,5,000tonsofP.notoginsengproductsareproducedannually(LiuJ.etal.,2014).TheroleofP.notoginsengincardiovasculardiseaseshasbeensummarized(LiuJ.etal.,2014;Yangetal.,2014),butnoarticleshavefocusedontheeffectsofP.notoginsengagainstCAD.ThisreviewsummarizesextensivelyrecentevidenceontheuseofP.notoginsenginCADtherapy,itstherapeuticeffectsandadverseevents.OurcurrentunderstandingofP.notoginsengcardioprotectiveeffectsandmechanismsagainstCADwillalsobediscussedindetail. Methodology Theterms“P.notoginseng”or“Sanqi”or“P.notoginsengsaponins”weresearchedas“Title/Abstract”andMeSHtermsinPubMed,ChinaNationalKnowledgeInfrastructure(CNKI)andSinoMeddatabase.Articlesrelatedtotherapeuticeffectsincoronaryarterydisease(CAD)werepickedoutmanually.Allarticleswithabstractwereincludedandnolanguagerestrictionswasapplied. BiologicalCharacteristicsofPanaxnotoginseng BriefHistory PanaxnotoginsengisamedicinalplantthatwasfirstusedbyethnicminoritiesinChina.IthasbeenoneofthemostacclaimedherbsinChinafor400years.Panaxnotoginsengistraditionallyappliedasananodyneandahemorheologic-alteringdrug.ThemainmedicalcomponentistheradixofP.notoginseng,alsoknownasSanqi,Tianqi,andShanqiinEastAsiancountries(WangT.etal.,2016).“CompendiumofMateriaMedica”(BencaoGangmu本草纲目)recordedtheofficialdetailedmedicalapplicationsofP.notoginsengin1758,inwhichP.notoginsengiscalled“morepreciousthangold”(jinbuhuan金不换)andwrittenas“三七”inChinese(redboxinFigure1).Asonespeciesofginseng,itwasunrecognizedworldwideuntilAmericanginsengwasdiscoveredin1716.In1843,theRussianbotanistCarlMeyernominateAsianginsengthebotanicalname“Panax,”whichimplies“all-healing”inGreek(Wongetal.,2015).“Noto”means“back,spine,”and“ginseng”represents“essenceofmen.” FIGURE1 Figure1.TheimportantpersonandclassicmedicalbooksinwhichPanaxnotoginsengwasrecorded.ZhangSiweirecordedfirstPanaxnotoginseng.ThecompendiumofMateriaMedicadescribedthefunctionofPanaxnotogingsengindetail.AndthenPanaxnotoginsengiscapturedinfoursignificantancientmedicalbooksandChinesePharmacopoeia. BotanicalCharacteristics PanaxnotoginsengF.H.Chenisahemitropousperennialherbwithashortrhizome,abamboowhip,and2toseveralfleshyroots(EditorialBoardofFloraofChina,1978).Thetaprootlooksconicalorcylindricalwithalengthof1–6cmandadiameterof1–4cm.Thesurfaceisgrayishbrownorgrayishyellowwithintermittentverticalwrinklesandbranchmarks.Therearestemscarsontopwithsurroundingtumor-likebulges.Thecharacteristicsincludedense,solidgraygreen,yellowgreen,orgraysections(Figure2). FIGURE2 Figure2.Radix(A)andplantspictures(B)forPanaxnotoginsengF.H.Chen.Thewholeplantlookslike(B).Themainpartusedformedicalpurposeistheprincipalrootwhichlookslike(A)aftercleaningandpruning. PNS:TheMajorTherapeuticConstituentsofPanaxnotoginseng Panaxnotoginsengcontainsthreekeyconstituents,includingsaponins,polysaccharides,anddencichine(Kim,2012).Polysaccharideshavemanyphysiologicalfunctions,suchasanti-tumorandimmuneregulationactivity(Guetal.,2015).Aspecialtypeofaminoacid,dencichine,isanactivesubstanceofP.notoginseng.Itsstructureisβ-NoXalo-L-α,βdiaminopropionicacidandcanbeartificiallysynthetized(WeiandWang,1987).SaponinsconstituteoneofthemostimportanteffectivecomponentsofP.notoginseng.Sofar,morethan80kindsofmonomersaponinshavebeenisolatedfromP.notoginsengparts(radix,stem,leaf,alabastrum,seed,etc.)sincetheirfirstseparationandidentificationin1979(Wu,1979).However,themostimportantcomponentsofPNSareginsenosideRg1,Rb1,Re,andnotoginsenosideR1(NR1;Figure3).TheamountsofthesefourcomponentsinPNSare30,2.5,20,and2.5%,respectively.TheradixofP.notoginsengisthemainpartforextraction.Accordingtothedifferentaglyconestructures,saponinsaredividedintotwocategories:dammaranetetracyclictriterpeneandoleananetypepentacyclictriterpene.BasedonwhetherthemothermolecularnucleusstructureofC6displacesahydroxylgroup,dammarane-typesaponinscanbedividedintoprotopanaxadiol(PPD),protopanaxatriol(PPT),oroctotillol(Wongetal.,2015).GinsenosideRb1isoneofthemajorprotopanaxadiol-typesaponins.GinsenosideRe,Rg1,andNR1arethemainrawginsengtriolsaponins(Wongetal.,2015). FIGURE3 Figure3.ThechemicalstructureofthemainactiveingredientsofPNS.(A)NotoginsenosideR1.(B)GinsenosideRg1.(C)GinsenosideRe.(D)GinsenosideRd.(E)GinsenosideRb11. QualityControl ManyplantspeciesarenamedSanqi(P.notoginseng).Accordingtothestatisticsofthereferenceliterature,exceptforAraliaceaeP.notoginseng,medicinalplantsnamedSanqi(P.notoginseng)includeasmanyas20speciesbelongingto11families,whichcausesdifficultyindistinguishingrealP.notoginseng.PharmacologicalstudiesindicatedthatginsenosideRg1,ginsenosideRb1,andNR1arethemainactiveconstituentsofP.notoginseng.ThequalitycontrolofP.notoginsengalsofocusesonthesethreecomponents.Accordingtothe“ChinesePharmacopoeia,”thedistinctionprocessisasfollows:preciselyextractthecontrolsolutionandthetestsolution,pourintoaliquidchromatograph,anddeterminethespecies.ThetotalamountsofginsenosideRg1(C42H72O14),ginsenosideRb1(C54H92O23),andNR1(C47H80O18)shouldnotbe<5%.InstandardChineseMedicinalMaterialsinHongkong(HKCMMS,2017),P.notoginsengcanbeidentifiedbythinlayerchromatography.ThechromatographicresultsindicatethattheRb1,Rg1,andNR1havethesamecolorsandRfvalues.Inaddition,therelativeretentiontimeofP.notoginsengandthecharacteristicpeaksofthesixextractionliquidsshouldbeinaccordancewiththestandardbyHPLCfingerprintidentification. TheTherapeuticEffectsofPNSonCAD SearchStrategy WeconductedasystematicsearchoforalPNSforover4weeksagainstCADonfourEnglishdatabasesandfourChinesedatabases:MEDLINE,theCochraneCentralRegisterofControlledTrials(CENTRAL),EMBASEDatabase,WHOClinicalTrialsRegistrationPlatform,ChineseNationalKnowledgeInfrastructure(CNKI),ChineseScientificJournalDatabase(VIP),WANFANG,andSinoMed.Thesearchtimeframerangedfromthedatabases'inceptionuntil20Feb2017.Wealsosearchedreferencelistsforfurtherpublications.ThesearchexpressionusedinMEDLINEwas((“coronaryheartdisease”[MeSHTerms]OR(“coronaryarterydisease”[MeSHTerms]AND(“P.notoginseng”[MeSHTerms]ORsanqi[TextWord]ORsanchi[TextWord]))ORXuesaitong[TextWord]ORXueshuantong[TextWord]))AND“RandomizedControlledTrial”[PublicationType:NoExp].Similarexpressionswereusedintheotherdatabases.Outcomemeasuresmeettheprimaryorsecondaryoutcomes. StudyQuality Seventeenrandomizedclinicaltrialswith1,747participantswascollectedwhichrandomlyassignedtoaconventionaltreatmentvs.aPNpreparationevaluatedcardiovascularoutcomes(Table1).Thequalityofthe17RCTswasevaluatedfromsevenaspectsusingtheROBscaleintheCochranehandbook(Table2).ThreeRCTsindicatedtherandomwayasrandomnumbers.However,theotherstudiesdidn'tdescribetherandommethod.TwoRCT(Han,2008;Teng,2014)referstorandomconcealmentandblindness. TABLE1 Table1.Thebasicinformationofthe17RCTsofPNSonCAD. TABLE2 Table2.Riskofbiasinthe17RCTsofPNSonCAD. PrimaryOutcome TheprimaryoutcomeofCADistheprimaryendpointwhichwasdefinedasthecompositeofall-causemortality,myocardialinfarction(MI),revascularization,andrehospitalizationforunstableangina.PNShasbeenobservedtohaveseveralbeneficialeffectsinpatientswithdifferentstagesofCAD.SeveralRCTsreportedoralPNScouldreducetheprimaryoutcome.In2008,ateamunderwentaRCTof60patientswithCADafterPCI.ThepatientswhohadPNS(120mgeverytime,threetimeseveryday)oraplacebowasprescribeddailyincombinationwiththeirconventionaltherapyfor3months.Theendpoint,rehospitalization,wasfocusedon.TherehospitalizationrateofpatientswithPNSwasbetterthaninthecontrolgroup(1/30and3/30;Han,2008)(Table3).In2013,furthermore,anotherteamconducteda1-yearRCTwith~1,200CADpatents,600patientsintheexperimentalgroupweregivenPNS(300mgeverytime,threetimeseveryday).PNSincreasedtheinhibitoryeffectofclopidogrelonplateletaggregationandreducedtheprimaryendpoints.Thistrialcomparedtheincidenceoftheprimaryendpointsintheexperimentandcontrolgroups,whichwas3.3%(20cases)and7.8%(47cases;Mengetal.,2013),resepctively.Theprimaryendpointsincludedcardiacdeath,myocardialinfarction,revascularization,stentthrombosis,ofwhichmostwererelatedtorevascularization. TABLE3 Table3.TheendpointwithPNS+conventionaldrugsandconventionaldrugsalone. SecondaryOutcomes Secondaryoutcomesincludeelectrocardiogram(ECG),attackofanginapectoris,suchasfrequencyofanginapectoris,durationofanginapectorisanddosageofnitroglycerin,qualityoflife.TwosystematicreviewsestimatedcurrentevidenceforthebenefitofsecondaryoutcomesandadverseeventsofPNSforCAD.Onesystematicreviewincluded17randomizedclinicaltrials.OralPNcouldalleviateanginapectoris(Shangetal.,2013).AnothersystematicreviewincludingatotalofsixRCTswith716participantsonunstableanginapectoris(UA)studiedPNSaloneorcombinedwithconventionaldrugsvs.conventionaldrugsalone.TheresultsillustratedthatPNScombinedwithconventionaldrugsdisplayedalsoasignificanteffectonrelievinganginasymptomsandimprovingECGcomparedwithconventionaldrugsalone(Yangetal.,2013). AttackofAnginaPectoris AnginapectorisisthesymptomsforchestpainordiscomfortduetoCAD(Xiongetal.,2015).Thepatientsmayalsofeelthediscomfortinyourneck,jaw,shoulder,back,orarm.Conventionaldrugsincludeanti-ischemicagentsandvascularprotectiveagents,suchasnitroglycerin,aspirin,clopidogrel,beta-blockers,andstatin(Smithetal.,2011). Inthisoverview,nineRCTsreviewedthetherapeuticeffectsofPNSonanginapectoriscomparedPNS+conventionaldrugswithconventionaldrugs.It'sdemonstratedPNSisoneeffectiveagentstodecreasefrequencyanddurationofanginapectoris.PNScoulddecreasesignificantlyfrequencyanddurationofanginapectoris.180patientsofunstableanginawererandomlydividedintotreatmentgroupandcontrolgroupof,respectively90patients.ThetreatmentgroupaddedPNS(2times/dfor4weeks)onthebasisofconventionaltreatmentofanginapectoris.Thecontrolgroupadministeredconventionaltreatmentofanginapectoris.Theresultsshowedthatthefrequencyofunstableanginapectoris,painintensityanddurationweresignificantlyreduced(Kuangetal.,2011). IschemicChangesonECG ECGistheotherimportantsecondaryoutcomeonevaluatingtheclinicalefficacyagainstanginapectoris.AtotalofeightRCTsobservedECGchangeswithPNSonCADpatients.PositivecorrelationsofPNSandimprovementsofECGwerereportedthatischaemicchangesonECGwereattenuatedsignificantly.ARCTdivided100patientsrandomlyintotreatmentgroupandcontrolgroup.Thetwogroupsweregivenconventionaldrugs,treatmentgroupplusPNSfor4weeks.It'selucidatedthatECGinthetreatmentgroupwerebetterthanthoseinthecontrolgroup,incompanywiththecurativeeffectofanginapectoris,FAA,therateofstoppingandthedosageofnitroglycerin(Songetal.,2005).AnotherRCTreportedthatwithPNStreatment,ECGof92%CADpatientsreturnedtonormalstateorrisemorethan0.05MvofSTsegmentdepression,differentsignificantlywithconventionaldrugsalone(Hou,2016). LipidMetabolism LipiddisorderisoneofthemainriskfactorsforCAD.A20%reductioninmajorcoronaryeventswithin5yearswascausedbyadecreaseof1mmol/LinLDLlevel(Baigentetal.,2005).AllthreeRCTsreportedeffectivenessofPNSonlipidsofCADpatients.PNScoulddecreasesignificantlyTC,TG,LDL.PNScombinedwithconventionaldrugswasmoreeffectivethanconventionaldrugsalone.Inaddition,someresearchesweretryingtoevaluatePNSalonewithatorvastatin.Seventy-onepatientswithCADwererandomlydividedintotwogroups:PNSgroup(36cases)andatorvastatingroup(n=35).PNSwasgiven100mgorally,whileatorvastatingroupreceivedatorvastatin20mgorally.TheresultsshowedthattherewasnosignificantdifferenceinthelevelsofTG,TC,CIMT,andplaquebetweentwogroupsbeforeandaftertreatment.TherewasnosignificantdifferenceinLDL-CbeforeandaftertreatmentinPNSgroup,whiletheLDL-Cdescendedsignificantlyinatorvastatingroup.Theincidenceofabnormalliverfunction,gastrointestinalreaction,andrecurrentcardiovasculareventsinpatientswithatorvastatinwassignificantlyhigherthanPNS(Fengetal.,2016). Inthisoverview,15RCTsobservetheeffectofPNSasalternativeandcomplementarymedicineonsecondaryoutcomes,suchasfrequencyofanginaattack,durationofanginaattack,ECGandlipidmetabolism.AndtheresultsillustratedPNScombinedwithconventionaldrugshadalsosignificanteffectsonchangingthesecondaryoutcomes. AdverseEvents AsystematicreviewevaluatedthesafetyofPNSforUA,includingsixRCTswith716participants.Fouroftheincludedtrials(66.7%)reportedadverseeffectsrelatedtotreatmentwithPNScombinedwithconventionaldrugs.Theonlyreportedadverseeffectwasrashat0.27%(1/363).Nosevereadverseeventswerereported(Yangetal.,2013).AnothersystematicreviewevaluatedanoralP.notoginsengpreparationforCADandincluded17randomizedclinicaltrialswith1,747participants.Ninetrialsreportedadverseevents.Onetrialreportedreducedbloodpressureandincreasedheartrates.Onetrialreportednausea,dizziness,andvomiting.Onetrialreportederythra,andsixtrialsindicatednoadverseeventsthroughoutthedurationoftreatment(Shangetal.,2013). FocusingonPNSforCAD,nineRCTsreportedadverseeventsinall17RCTs.Noobservabletoxicityinliverorkidneyfunctionwasmeasuredbyserummarkers.SeveralRCTsdescribedadverseeventsthatindicatedthatoralPNSforCADisnotrelatedtoadversereactions(Table4).Fengetal.(2016)reported2caseswithelevatedtransaminase,1casewithmusclepain,and1casewithgastrointestinaldiscomfortinthecontrolgroup.Noobviousadversereactionswereobservedinthetreatmentgroup(Fengetal.,2016).IntheexperimentalgroupofYanetal.(2015),1caseofsubcutaneoushemorrhageand1caseofpositivefecaloccultbloodoccurred.Onecaseofnauseaand1caseofpositivefecaloccultbloodoccurredinthecontrolgroup(Yanetal.,2015).InYu2010,1caseintheexperimentalgroupshowedasmallamountofrashafter3doftreatment,whichwasnotcausedbythetreatment(Yu,2010).Nosignificantdifferencewasobservedintheincidenceofadversereactions.Furthermore,PNSwasnotrelatedtoanyobviousabnormalitiesinliverandkidneyfunction. TABLE4 Table4.TheincidenceofadversereactionswithPNSforCAD. TheMechanismsofPNSonCAD CADoccurswhenatheroscleroticlesionsimpedebloodflowinthecoronaryartery.Theplaqueactivationcausesischaemiaandinfarction.Rupturestendtohappennearthethinandeasydestroyedfibrouscapwhereactivatedimmunecells,inflammatorymolecules,andproteolyticenzymesareabundant(Santos-Gallegoetal.,2014).Theycanweakenthecapandtransformstableplaquetoanunstablevulnerableplaquethatismorelikelytorupture.ThepathomechanismofatherosclerosisinCADisrelatedtoinflammation,lipidmetabolism,endothelialerosion,coagulationsystemdysfunction,andapoptosis(Hopkins,2013).PlaqueruptureisthemajortriggerofCAD(Hansson,2005),whilehypoxiaandischaemiaarethepathologicalmanifestationsofthedisease.Inaddition,angiogenesiscanimprovebloodflowinthepresenceofmicrovascularblockageinCAD. Saponinsareagroupofnaturalcompoundsinplantsandfoods.PNSisthemostimportantcompoundamongP.notoginseng'seffectivecomponents.Inthepast10years,ithadreceivedextensiveattentioninthetreatmentofCADathomeandabroad.Manystudiesshowedthatithadanti-inflammatory,anti-apoptotic,anti-hypoxic,loweringlipids,anti-coagulation,andpro-angiogenesisproperties(Table5,Figure4). TABLE5 Table5.SummaryofanimalandcellexperimentsofPanaxnotoginsengsaponinsonCAD. FIGURE4 Figure4.SummaryofsevenmainfunctionsofPNSinCAD. Anti-inflammation InflammationdominatesinCADandatherosclerosis.Immunecellsgatherintheearlyatheroscleroticlesions,whereeffectormoleculespromotetheprogressofinflammationwhichcaninduceacutecoronarysyndrome(ACS;Han,2008).Invulnerableplaques,themaincharacteristicisthatinflammationexistswidespread.SeveralstudiesshowedthatdifferentsystemsofinflammationmarkerssuchasC-reactiveproteininpatientsarerelatedtoanincreasedriskofACS(CreaandLiuzzo,2013;Mannetal.,2014).AndinflammationassociatedwithCADincludesMAPKactivation,theroleofNF-κB,TNF-α,ROSforsignaling,modifiedlipoproteinonendothelialcellsandothercellactivation,leukocyteadhesion,formationoffoamcells,macrophages(Figure5A),andvascularsmoothmusclecells(VSMCs). FIGURE5 Figure5.IllustrationofthemechanismofPNSon(A)macrophage,(B)endothelialcell,(C)cardiomyocyte,and(D)plateletaggregation.Intheprocessofinflammationamongmacrophages(A),pro-inflammatoryfactorssuchasIL-6,MCP-1,VCAM-1,ICAM-1,MCR-1,andTNF-alphaareregulatedbyROSandSOD.ProstaglandinsproducedbyCOX-2isnegativelyrelatedtophagocytosis.PNScanregulatepro-inflammatoryfactorsbyinhibitingROSandpromotingSOD.Inaddition,PNSalsoinhibitTNAalphadirectly.TheactivatedNF-κBregulatestheexpressionofmanyatherogenicgenes,creatingalocalinflammatoryconditionandinducingchemotacticfactorsandadhesionmoleculesonthesurfaceofECs(B).PNScanincreaseSODactivitybydecreasingTNFalpha,IL-6andROSgeneration.NotoginsenosideR1cansuppressinflammatorycytokinesproductionbyactivatingPPARgammaandbysuppressingERKandPKB,inhibitingTNF-alpha.Inaddition,NR1caninhibitNF-κB,MAPK,IL-1betaandreducecardiomyocyteapoptosisandinflammationthroughtheactivationofERalphaandPI3K/Aktsignaling(C).GinsenosideRg1reducedintracellularROSandLDHandsuppressedtheintracellularCa2+levelbyincreasingtheactivityofendogenousantioxidants,includingT-SOD,CATandGSH.About(D),NGhaveaninhibitoryeffectonplateletaggregation.TheeffectofPNSinanti-plateletaggregationisrelatedtothesuppressionofintracellularcalciummobilizationandERK2/p38activation.Threemainginsenosides(Rg1,Re,andR1)thatexistinPNSalsoshowedanti-plateletactivity.Ft1induceddose-dependentplateletaggregationmediatedthroughP2Y12receptors.NR1significantlydecreasedTNFalpha-inducedPAI-1. First,NF-κBiscriticalforthetriggeranddevelopmentofatherosclerosis(Hopkins,2013).TheelevatedNF-κBactivatorssuchasosteoprotegerinwererelatedtoincreasedmortality,especiallyofcardiovasculardiseases(Venurajuetal.,2010).ActivationofNF-κBledtoregulationofmanyatherogenicgenes,facilitationofinflammation,inductionofchemokines,andadhesionmoleculesonthesurfaceofendothelialcell(ECs)(Figure5B).Chemokinesandadhesionmoleculesattractedthemonocytestothelocationpronetoatheroma(Geritsetal.,2007;Marksetal.,2009;Bakeretal.,2011).PNSinhibitedNF-κBDNAbindingactivity(SunX.etal.,2013)andsecretingpro-inflammatoryfactors,interleukin(IL)-6andMCP-1inmacrophages(Fanetal.,2012).ThesizeofatheroscleroticlesionsandthenumberofmacrophagesinapolipoproteinE(apoE;−/−)micewerereducedbyPNS.Inaddition,PNSreducedtheexpressionofproinflammatorycytokinesVCAM-1,ICAM-1,andMCP-1withinhibitionofNF-κB,JNK,p38(MAPK),andERK1/2activationandRAGE(Douetal.,2012).Phagocytosisinducedtheexpressionofthepro-inflammatoryfactorCOX-2andtheproductionbyCOX-2regulatedthefunctionsofmacrophage(Aronoffetal.,2004).Inthemodelofinflammation,theexpressionofCOX-2reachedapeak.However,inthelaterstageCOX-2descendedwhichleadstoactivationofPPARγandinhibitionofinflammationbyNF-κB.Interestingly,PNSsuppressedtheexpressionofCOX-2atanearlystagewithpromotionofphagocytosis,whilePNSalsoelevatedCOX-2expressionatalaterstage(Yuanetal.,2009). Second,oxidationisgenerallyconsideredasafacilitatororamodulatorofinflammatorysignaling(Oliveira-Marquesetal.,2009),andalsoamajorendothelial-derivedhyperpolarizingfactor(EDHF)mediator(Capettinietal.,2010).Oxidativestressinvolvestheinflammationofvesselsandtheprogressionofatherosclerosis.Excessivereactiveoxygenspecies(ROS)generationhasbeensuggestedtoup-regulatepro-inflammatorycytokinesandadhesionmoleculeswhichcanresultinatherosclerosisinitiationconsequently(Zhangetal.,2009).ROSfacilitatedtheactivationofROS/Akt/IKKpathwaysthatinteractwithNF-κB(Qietal.,2012).Inaddition,MDA(malondialdehyde)isaproductofafree-radicalperoxidaticreactiononlipids,andSuperoxidedismutase(SOD)isafree-radicalscavenger(VanRaamsdonkandHekimi,2012).Myeloperoxidase(MPO),aperoxidaseenzyme,couldaccuratelypredictedthemortalityriskinpatientswithcoronaryangiography.TheimprovementofMPOandCRPamelioratedthelong-termriskassessmentofoutcomesinCADpatients(Heslopetal.,2010). PNSalsoareconsideredasfreeradical-scavengerswithantioxidantproperties.PNScouldimpedethedevelopmentofatheroscleroticlesionsthroughtheantioxidantandanti-inflammatoryeffects(Aronoffetal.,2004).PNSprotectedarathaemorrhagicshockmodelviaantioxidativestressandanti-inflammatorypathways.PNSalsoincreasedSODactivity,decreaseMDA,endotoxin,MPO,TNFalpha,andIL-6(LiuH.Z.etal.,2014).PNScouldreduceoxidativestressandinhibitplaqueprogression.SODandglutathioneactivitieswereelevatedandROSgenerationisimpairedinapoE(−/−)micetreatedwithPNS(Aronoffetal.,2004). TreatmentwithNotoginsengnosides(NG)coulddecreasetheROSlevelinplatelets(Shangetal.,2013).Ginsenoside-RdsignificantlypromotedH2O2-inducedcellapoptosiswithaconcentration-dependentmanner(Lietal.,2012).NR1withtheeffectofphytoestrogen,wasillustratedasacomponentwithanti-inflammatory,antioxidativeandanti-apoptoticproperties.NR1canrestrictoxidizedlow-densitylipoprotein(ox-LDL)-inducedinflammatorycytokinesincludingNF-κB,MAPK,TNF-alpha,andIL-1beta(Suetal.,2016).ItalsoinhibitsPAI-1overexpressionbyTNF-alphainhumanaorticsmoothmusclecells(HASMCs)andtheERK/PKBpathways(ZhangandWang,2006).NR1canprotecttheheartfromsepticshock,probablythroughtheactivationofERalphaandPI3K/Aktpathway.ThismechanismblockedNF-κBactivationandattenuatedinflammationandapoptosisinthemyocardium(SunB.etal.,2013;Zhongetal.,2015).Inaddition,thepretreatmentwithginsenosideRg1decreasedthereleaseoflactatedehydrogenase(LDH)andincreasedcellviabilitydose-dependently.GinsenosideRg1suppressedROSandCa2+levelintracellularlybyraisingtheactivityofendogenousantioxidantsasT-SOD,CAT,GSH(Zhuetal.,2009). RegulationofLipidMetabolism LipoproteindisorderisoneofthemainriskfactorsofCAD.Ameta-analysisof14randomizedtrialsshowedthatadecreaseof1mmol/LinplasmaLDLlevelsgeneratesa20%reductioninmajorcoronaryeventsincludingcoronaryrevascularizationandstrokewithin5years(Baigentetal.,2005).CADiscloselyrelatedtolipidmetabolicdisorders,specificallyincreasedtriglycerides(TG),low-densitylipoproteincholesterol(LDL-C),ox-LDL,andtotalcholesterol(TC;Labreucheetal.,2010;Nyyssonenetal.,2012).PNScanreduceremarkablythelevelofcholesterolesterinfoamcellsbyup-regulationofABCA1.ThisbioactivitymayberelatedtothespecialchemicalstructuresofPNSthatarelikethenaturalagonistofliverXreceptoralpha(LXRalpha;Jiaetal.,2010).LXRαasakeyregulatorofmacrophagefunction,controlstranscriptionalprogrammesinvolvedinlipidmetabolismandinflammation(Christoffoleteetal.,2010).PNScouldregulatelipidsbyactivationoftheLXRalphagenepromoterwhichincreasedABCA1andABCG1subsequentlyandsuppressedNF-κBDNAbindingactivity(Fanetal.,2012). PNScouldmarkedlyreduceTC,TG,andLDL-C(Zhangetal.,2008)andincreasehigh-densitylipoproteincholesterol(HDL-C)significantly(Liuetal.,2010).CPT-1Aisakeyenzymeintheprocessoffattyacidoxidation.Whilethefattyacidtransporterprotein4(FATP4)isassociatedwithlongandverylongchainfattyaciduptakeandpromotingsynthesisofacyl-CoA(Halletal.,2005).Fattyacidbindingprotein4(FABP4)andCPT-1A,weredownregulatedinischemiczoneoftheheart.PNScouldregulatelipidmetabolismbyincreasingtheexpressionofFABP4andCPT-1A(WangQ.etal.,2016). Lipidmetabolicdisordercanbecausedbyinflammationandcanexasperatetheinflammation(Hotamisligil,2006).Dyslipidemiaandinflammationaccelerateeachothertoformadetrimentalcycle.Regulationoflipidmetabolismdisordersisconducivetoinflammationalleviationandanti-inflammatoryeffectsbenefitsthemaintenanceofbalancedlipidmetabolism.PNScouldregulatelipidmetabolism.Meanwhile,PNSdecreasedsignificantlytheexpressionsofsomeinflammatorycytokinesincludingintegrins,IL-18,IL-1beta,andmatrixmetalloproteinases2(MMP2)and9(Zhangetal.,2008). Inconclusion,CADiscloselyrelatedtolipidmetabolicdisorders,specificallyincludingincreasedTG,LDL-C,ox-LDL,andTC.PNScoulddepressthelevelofTCbyelevatingLXRalpha,ABCA1,andABCG1andreducingNF-κB.Inaddition,PNScanregulatelipidmetabolismbyinhibitingLPLandincreasingFABP4andCPT-1A.Furthermore,lipidosisiscloselyrelatedtoinflammation,whichPNShavediverseeffectson. RegulationofCoagulationSystem InCAD,antiplatelettherapyhasbecomeanimportanttreatmentaccordingtoseveralimportantguidelines(Chewetal.,2016;Levineetal.,2016).Nearwound,plateletsarerecruitedtorestoreendothelialintegritytoinitiatethrombusformation(Nordingetal.,2015).Thrombosisisassociatedwithplateletaggregation.ThromboxaneA2(TXA2),derivedfromplatelets,inducespowerfullyreleaseandaggregationofplatelets. PNSinhibitedplateletactivationbymultipleingredientsandpathways.PNScoulddecreaseplateletactivation,inhibitadhesionandaggregationofplatelet,preventthrombosis,andimprovemicrocirculation(Wangetal.,2004).PNSprotectedECsfrominjurybysuppressingplateletadhesion,inwhichPNSwassuperiortoaspirin.TheunderlyingmechanismisrelatedtotheCOXpathwayinbothECsandplatelets(Figures5B,D;WangM.M.etal.,2016).NGcouldsuppressplateletaggregationinvitro.Furthermore,invivoNGcouldalsosignificantlyinhibitplateletaggregationofplateletrichplasma(PRP;Yaoetal.,2008b).TheeffectofPNSinanti-plateletaggregationisassociatedwithinhibitionofintracellularcalciummobilizationandactivationofERK2/p38.Threemainginsenosides(Rg1,Re,andNR1)existinginPNSalsodemonstratedanti-plateletactivity,buttheircombinationdidnotexhibitanysynergisticeffectonrabbitplateletaggregation(Qietal.,2016).Rg1andRg2cansignificantlyprolongtheclottingtime.ComparedwithRg1,Rg2showedastrongeranticoagulanteffect(Lietal.,2013). However,inPNS,notoginsenosideFt1asthepotentprocoagulantcomponentinducedplateletaggregationdose-dependently.TheP2Y12receptorservesasacrucialregulatorofhaemostasisandthrombosisontheplatelet.WhenconditionedbyADP,theP2Y12receptoractivatedaseriesofdownstreameventsthatresultinplateletaggregation,shapechange,densegranulesecretion(DorsamandKunapuli,2004;Gaoetal.,2014).Ft1deceasedplasmacoagulationindexesandtailbleedingtimeandincreasedthrombogenesisandcytosolicCa2+accumulation. Fibrinolysisispartofthecoagulationcascade,whichisadjustedbyplasminogenactivator(PA)andPAinhibitor(PAI-1).AbnormalfibrinolysisandhighplasmaconcentrationsofPAI-1arerelatedtoanincreasedriskofCAD(McBaneetal.,2010).Whenhumanumbilicalveinendothelialcells(HUVECs)wereconditionedwithpurifiedNR1,tissue-typePA(TPA)synthesisincreaseinadose-(0.01–100mgofNR1/mL)andtime-dependentmanner.NR1significantlydecreasedPAI-1mRNA,proteinandsecretioninHASMCsinadose-dependentmanner(ZhangandWang,2006).TPAactivityandTPA-PAI-1complexesreachedgreaterthantwo-foldandthreefoldmaximalstimulation,respectivelyNR1.Incontrast,NR1inducedfive-folddecreaseinPAI-1activity(Zhangetal.,1994). Anti-apoptosis Myocardialischaemiacanleadtowidespreadcellapoptosis(Ohnoetal.,1998).PI3K/Aktpathwayisanimportantregulatorincludingproliferation,apoptosisandnitricoxide(NO)synthesis(Blanesetal.,2007).PI3Kalsostrengthenstheoxidativecapacityofcardiacfattyacid.ThePI3Ksignalingcascadediminishesmyocardialdamagebyischaemiaviarecruitingseveralendogenouscardioprotectivepathways(Hausenloyetal.,2005). PNScouldprotectmyocardialcellsfromapoptosisinducedbyischaemiabothinvitroandinvivobyactivatingthePI3K/Aktsignalingpathway(Tello-Montoliuetal.,2006).PNSsignificantlyup-regulatedp-AktinH9c2cellsandischaemicmyocardialtissues.PNSattenuatedcellapoptosisviachromatinconcentrationandcondensationbyup-regulatingtheantioxidativeabilitiesofSODandMDA(Lietal.,2014).PNSalsoimprovedcardiacfunctionintheleftventricularejectionfractions(EF)ofrats(Chenetal.,2011;Wangetal.,2015). ThepathologicalproliferationofVSMCsisacrucialfactorinvolvedinthepathogenesisofatherosclerosis,associatedwithinflammation,apoptosis,andmatrixalterations(ZakarandKen,2003).PNSsuppressedproliferationandinducedapoptosisinVSMCs(Wangetal.,2009)byup-regulatingp53,Bax,andcaspase-3anddown-regulatingBcl-2(Xuetal.,2011).Inaddition,bothatorvastatinandPNShavebeenobservedtosuppressVSMCproliferationbyinhibitingtheactivationoftheERKsignalingpathway(Zhangetal.,2012). Pro-angiogenesis Angiogenesisisthestimulationoftheendotheliumtoshapenewbloodvessels,whichisimplicatedinthepathophysiologyofCAD(Tello-Montoliuetal.,2006).InCAD,inflammationrelatedtoatherogenesiscontributestotheinteractionofangiogenicfactors(Pateletal.,2006),whichleadtovascularrepair(Chongetal.,2004).Variousangiogenicgrowthfactorsandprogenitorcellscanpromotetheformationofnewbloodvessels(Mitsosetal.,2012).AngiogenesisisapotentialtreatmentinmanyphysiologicalprocessessuchasMI,chroniccardiacischaemia,andstroke(GiaccaandZacchigna,2012). PNScouldenhanceangiogenesisandtheproangiogeniceffectsincludingtheVEGF-KDR/Flk-1andPI3K-Akt-eNOSsignalingpathwaysinvivoandinvitro(Hongetal.,2009).NR1,similartoRg1andRe,hadbeenshowntohavepro-angiogeniceffect,possiblybyactivationoftheVEGF-KDR/Flk-1andPI3K-Akt-eNOSsignalingpathwaysinvivoandinvitro(Yangetal.,2016). Ft1canstimulateangiogenesis.Ft1ledtoproliferation,migrationandtubeformationinHUVECsbyactivationofthePI3K/AktandERK1/2pathwaysinratmesentericarteries.ThisleadstothephosphorylationofeNOSandreleaseofNO,whichtriggerssolubleguanylylcyclaseintheVSMCs(Shenetal.,2014). Anti-atherosclerosis AtherosclerosisisthepathologicalbasisofCAD.Furthermore,thedevelopmentofchronicatherosclerosistoformthrombosisisthepathogenesisofACS(Mannetal.,2014).ApoEisaligandforcleansingreceptorsofchylomicronsandverylowdensitylipoproteinresidues.ThelackofapoEcanleadtotheaccumulationofcholesterol-richresiduesinplasma,andlong-timeaccumulationcangenerateatherosclerosis(Heerenetal.,2006)withhypercholesterolemiaandspontaneousarteriallesions(MeirandLeitersdorf,2004).PNSwasabletodecreaselipids,ox-LDLinserumandtheexpressionsofCD40andMMP-9inapoE(−/−)mice(Liuetal.,2009).Meanwhile,PNSlessenedthesizeofatheroscleroticplaques,partlybyprogenitorcellmobilization.PNSalsoaugmentedendothelializationandreducedtheVSMCcontentofthelesions(Liuetal.,2013). Ahigh-fatdiettogetherwithZymosan(Zym)inducesatherogenesisinrats.PNSreducedthelevelsofTC,TG,LDL-C,IL-6,andC-reactiveproteinandincreasedtheHDL-ClevelsignificantlyinserumofatherosclerosisrabbitsbyinhibitingFAKphosphorylation,integrinsexpressionandNF-κBtranslocation(Yuanetal.,2011).AndPNSsignificantlydown-regulatedMCP-1andNF-κB/p65with8weeksoftreatment(Liuetal.,2010). GinsenosideRd,isolatedfromPNS,isavoltagedependentCa2+channelblocker.GinsenosideRddecreasedremarkablythesizeofatheroscleroticplaqueandox-LDLofmacrophageintheapoE(−/−)rats.Invitro,ginsenosideRdsuppressedtheformationoffoamcellsinducedbyox-LDLandcholesterolaccumulationinmacrophages(Lietal.,2011). ProtectionagainstMyocardialIschaemia PNSexertedacertaindegreeofimprovementonmyocardialischaemia(Tangetal.,2010).Infact,theearlieststudytodemonstratetheeffectsofP.notoginsengonCADwasastudypublishedin1972,inwhichtheoraladministrationofP.notoginsengreducedthedosagerequirementofnitroglycerinandimprovedECGinclinic.AndP.notoginsengsignificantlyincreasedcoronarybloodflowindogs(DepartmentofCardiologyinSecondAffiliatedHospitalofWuhanMedicalCollege,1972).PNSwasshowntoobviouslyalleviatethedegreeofmyocardialischaemiaandnarrowtheischaemicareasubjectedtomyocardialischaemiaandinfarction(Fuetal.,2006).PNScouldenhanceleftventricularsystolicanddiastolicfunctions,decreaseperipheralresistance,andimprovethecardiacfunctionofratswithpost-myocardialinfarctionleftventricularremodeling(Guoetal.,2009).Theendotheliumwasdenudatedcompletelyafterballoonendothelialdenudation(BED).PNScouldsustaineanti-restenoticeffectsafterBEDinjury.PNSpromotedendothelialregenerationandreducedECMthickening(Chenetal.,2004).Invitro,PNSexhibitedananti-apoptoticeffectbothinoxygen-deprivedH9c2cellsandinischaemicmyocardialtissues(Chenetal.,2011).Inaddition,PNScoulddecreasethepathologicalinjurytocardiacmyocyteswithischaemiaandimproveventricularremodeling(Guoetal.,2010). ThePPARfamily,aseriesoftranscriptionfactors,regulatescardiacenergymetabolismandimpactsmetabolismofcardiacfattyacidandglucose(MadrazoandKelly,2008).PGC-1αisatranscriptionalcoactivatorofthePPARsandacriticalfactorinmyocardialmetabolism(Hussetal.,2004).Inischaemicrats,transcriptionalfactorsweredownregulatedsuchasPPARs,RXRA,andPGC-1alpha(WangQ.etal.,2016).PNScouldup-regulateexpressionsofthesefactors. Inaddition,salvianolicacids'compatibilitywithPNScouldprotectcardiomyocytes(Figure5C)duringhypoxiaandreoxygenationinjurybyinhibitingapoptosisandimprovingenergymetabolismcomparedtoanysingledrug(Gongetal.,2013).Inthemodelofischaemia/reperfusion,salvianolicacids(SA),NG,andacombinationofSAandNGexhibitedthecardioprotectiveeffects.SAandNGdisplayedbothsimilaritiesanddifferencesinpathwayssuchasenergymetabolism,lipidmetabolism,cellproliferation,andapoptosis(Yueetal.,2012).ThecombinationofSalBandRg1,insteadofSalBandRb1,advancedcardiaccontractilityinratswithMI(Dengetal.,2015). Discussion SummaryofCurrentEvidence Inthepasttwodecades,abreakthroughhasbeenachievedinthepharmacologyofPNS.TheknowledgeofPNSfunctionsoffersanewopportunityforthepreventionandtreatmentofCAD.PNShasbeenobservedtohavemultiplepositiveeffectsinthekeyprocessesofCAD,includinganti-inflammation,theregulationoflipidmetabolismandthecoagulationsystem,anti-apoptosis,pro-angiogenesis,anti-atherosclerosis,andanti-myocardialischaemia(Figure6).SeveralRCTshaveshownthatthelong-termuseofPNScaneffectivelyreducetheend-pointofCAD(Mengetal.,2013;Yanetal.,2015).Inaddition,manyRCTsfoundthatPNScanalsosignificantlyimproveperformanceontheECGandreducethefrequencyandthedurationofanginaattacks,greatlyregulatingthelipids(Songetal.,2005;Han,2008;Liuetal.,2008;DuandChen,2009;ZhouandBai,2009;Wei,2010;Yu,2010;Kuangetal.,2011;Wan,2011;Mengetal.,2013;Teng,2014;Zhang,2014;Zheng,2014;Yanetal.,2015;Hou,2016). FIGURE6 Figure6.PNSontheevolutionofatheroscleroticplaque.Intheevolutionofatherosclerosisplaque,PNShaseffectsontheoxidationofLDL,theaccumulationoflipoprotein,chemoattractantcytokinesrelatedtomacrophages,modifiedlipoproteinparticles,plateletaggregation,themigrationofsmoothmusclecells(SMCs),apoptosisofSMCsandthedevelopmentoffoamcells. ThefunctionofPNSonplateletaggregationresemblesaspirin.Forthepatientswithaspirinresistance(Arachidonicacidinhibitoryrate<50%)andclopidogrelresistance(Adenosinediphosphateinhibitionrate<30%),Ticagreloran,anoralreversiblybindingP2Y12inhibitor,iscommonlyusedalternativedrug(NylanderandSchulz,2016).However,Ticagrelorisunsuitableforpatientswithbleedingtendency,meanwhileitmeansabigfinancialburdenonpatientsorthegovernment.Forthosepatients,PNSisrecommendforanti-plateletaggregation.SeveralstudiesinvitroandinvivoPNSmayinhibittheactivationofplateletthroughmultiplecomponentsandmultiplepathways.InaRCT,PNSaloneisillustratedtodecreaseplateletaggregationandlessadverseevents(Yu,2010). StatinsasamaindrugbymanyguidelineshaveshowngoodeffectsintheprimaryandsecondarypreventionofCAD(Harrisetal.,2015;Jellingeretal.,2017).However,statinshavesideeffectsincludingelevatedlivertransaminase,myopathy,myalgia,myositis,andevenrhabdomyolysis.PNScouldregulatelipidmetabolism,notsostronglyasstatins,butwithahighersafety.MeanwhilePNShastherolesofanti-inflammationandanti-plateletaggregation.So,forpatientswithliverdamage,ortheelderlywithouthighTC,TG,LDL,werecommendPNSforlipid-loweringandanti-inflammation. Inaddition,nitroglycerinisoneoftheoldestofcardiovasculardrugsinclinics.Nitroglycerinexertsanti-ischemiceffectmainlybyexpandingcapacityvein,reducingpreloadandreleasingcoronaryarteryspasm.PNScouldreducemyocardialischemiaandrelieveanginapectoris.InclinicPNShassimilareffectsanddifferentmechanismswithnitroglycerin.PNSwasrecommendedwhenpatientscan'ttoleratethesideeffectsofnitroglycerinsuchasheadache,dizziness,tachycardia.PatientswithnitrateresistancewerealsorecommendedtoadministratePNS. Inflammationrunsthroughtheinitiation,formationandonsetofCAD.Thewidespreadpresenceofinflammationgeneratesthemajorfeatureofvulnerableplaques(CreaandLiuzzo,2013).PNSexertsanti-inflammationbyseveralsignalingpathways.PNScanregulatepro-inflammatoryfactorsbyinhibitingROS,TNAalpha,NF-κB,andpromotingSOD.Interestingly,PNShasdualfunctionsonCOX-2atdifferentperiods.AnindividualPNS,NR1cansuppressinflammatorycytokinesproductionbyactivatingPPARgammaandbysuppressingERKandPKB,inhibitingTNF-alphainvitroandinvivo.InflammationplaysanimportantroleinthewholeprocessofCAD,PNSwithlesssideeffectscouldbeadministeredforalongtime.Meanwhile,long-termapplicationofPNScouldreducetheendpointofCAD. Differentwithwesternmedicines,TCMactsonseveraltargetstoplayavarietyofrolesonthemechanismsofthedisease.PNShaseffectssimultaneouslyonanti-inflammation,theregulationoflipidmetabolismandthecoagulationsystem,anti-apoptosis,pro-angiogenesis,anti-atherosclerosis,andanti-myocardialischaemia.IntheentirepathologicalprocessofCAD,atdifferentpathologicalstages,PNScaneffectivelyreducetheoccurrenceandthedevelopmentofCAD.InseveralRCTs,PNSeffectivelyreducetheend-pointofCAD,greatlyregulatethelipids,improveperformanceontheECGandreducethefrequencyandthedurationofanginaattacks.Thus,PNSisapotentialagentagainstCAD. Recently,themedicalcommunityhasgraduallyassignedimportancetotheprimarypreventionofCADwithPNSduetotheiruniqueadvantages.Inprimaryprevention,PNScanregulatelipidmetabolismandhypertension(Panetal.,2012)andinhibitplateletaggregation.Aspirinhassideeffectssuchasgastrointestinalreactionsandstatinscancauseliverinjury.Especiallyinpreventivetreatment,long-termadministrationwillincreasetherateofsideeffects.AndPNSappeartobesafer.PNShavemultipletargets,awiderangeoftherapeuticeffectsandhighsafety.Therefore,webelievethatithasgreatpotentialinthetreatmentofCAD. LimitationsandPerspectives Currently,increasingresearchisfocusingonindividualPNS.However,thesestudiesarestillrarecomparedtothoseontotalPNS.IndividualPNScouldhavecontradictoryfunctions,especiallyonplatelets.Fourmainginsenosides(Rg1,Re,NR1,andRg2)thatexistinPNSalsoshowedanti-plateletandanticoagulationactivity.BothRg1andRg2couldsignificantlyextendbloodclottingtime.However,notoginsenosideFt1wasprocoagulantandinduceddose-dependentplateletaggregation.Therefore,PNScouldbefurtherseparatedinordertothoroughlyinvestigatethefunctionofP.notoginseng.Inaddition,themechanismofPNSinCADiscomplicated,sotheworkofindividualPNSmulti-targetnetworkswillfurtherraisethepotentialofP.notoginsengfortheeffectivetreatmentofCAD. Inaddition,weneedtofurtherimprovethedrugpurityandscreenconcentrationstorevealandenhancethemedicinalvalueofPNSasanindividuallipid-loweringdrugoranantiplateletagglutinationdrug.WehavefoundsomeresearchthatfocusesoncomparingPNSandaspirinorPNSandstatins.TheinhibitoryeffectofPNSonplateletactivationwassimilartoaspirin,buttheinhibitoryeffectofPNSonplateletadhesiontoECswassuperiortoaspirin(WangM.M.etal.,2016).InaRCTOFPNSgroup,aspiringroupandPNSplusaspiringroup,theresultsshoweddecreasedD-dimer,plateletaggregationtime,increasedinternationalstandardizationratioofprothrombintimeandprolongedprothrombintimeinthreegroups.ComparedwithPNS,aspirinwasmoreeffectivethanPNSinimprovingplateletaggregation(Yanetal.,2015).ThepurityandconcentrateincreaseprobablygeneratestrongereffectsonCAD. However,themedicaltechnologyandtherelatedanimalexperimentsandRCTsarelimited.Moreover,onlyone1-yearRCThasreportedtheeffectofPNSontheend-pointofCAD.However,wehopethatsomemulti-center,large-sampleRCTswillprovidehigh-levelevidencefortheeffectivenessofPNSinCAD. Conclusion PNShavemultiplepositiveeffectsinthekeyprocessesofCAD,includinganti-inflammation,theregulationoflipidmetabolismandthecoagulationsystem,anti-apoptosis,pro-angiogenesis,anti-atherosclerosis,andanti-myocardialischaemia.Long-termuseofPNScaneffectivelyreducetheendpointofCADandimproveanginapectoris,ECGandlipidmetabolismwhichillustratesthatPNSispotentialagentonCAD.However,morehigh-levelRCTsareexpectedtoprovideevidencefortheefficacyofPNSinCAD. AuthorContributions JWandLDdesignedtheworkofreview;LD,XX,andJHreviewedtheliteratureavailableonthistopicandwrotethepaper;XX,YL,andJLcontributedinthescientificwritingofthemanuscript;JWandXXrevisedthemanuscript. Funding ThisworkwassupportedbytheNationalNaturalScienceFoundationofChina(No.81473561). ConflictofInterestStatement Theauthorsdeclarethattheresearchwasconductedintheabsenceofanycommercialorfinancialrelationshipsthatcouldbeconstruedasapotentialconflictofinterest. Acknowledgments Theauthorsapologizetocolleagueswhoseworkwasnotcitedduetospacelimitationsorouroversight. 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Editedby:AipingLu,HongKongBaptistUniversity,HongKong Reviewedby:ZhenhuaDai,GuangdongProvincialAcademyofChineseMedicalSciences,ChinaThomasHeinbockel,HowardUniversity,UnitedStates Copyright©2017Duan,Xiong,Hu,Liu,LiandWang.Thisisanopen-accessarticledistributedunderthetermsoftheCreativeCommonsAttributionLicense(CCBY).Theuse,distributionorreproductioninotherforumsispermitted,providedtheoriginalauthor(s)orlicensorarecreditedandthattheoriginalpublicationinthisjournaliscited,inaccordancewithacceptedacademicpractice.Nouse,distributionorreproductionispermittedwhichdoesnotcomplywiththeseterms. *Correspondence:JieWang,[email protected] †Theseauthorshavecontributedequallytothiswork. Peoplealsolookedat Download