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WorldJTraditChinMed|Volume3|Issue3|JulySeptember201746ReviewArticleIntroductionXiaoChaiHuTang(XCHT,MinorBupleurumDecoction),alsoknownasShosaikotoinJapan,isapopularChineseherbalformulaappliedinAsia,containingsevenmedicinalplants:bupleurumroot,pinelliaternata,scutellariaroot,jujubaefructus,panaxginseng,licorice,andginger.
Table1liststheprincipalconstituentsofeachherbcomponent.
ThisformulaisderivedfromthebookTreatiseonColdDamageDiseases,writtenbyZhangZhongjing(afamousphysicianofthelateEasternHanDynasty,about200A.
D.
),andnow,manyexperimentalandclinicalresearchesincludingprospective,randomized,andplacebocontrolledtrialshaveinvolvedtheclinicefficacyofXCHT.
Althoughithasbeenwidelyusedbypatientswithdifferentkindsofhepaticdiseases,suchashepatitisandliverfibrosis,itsbenefitsclaimedneedanaccurateassessment.
ThisreviewsumsuptheavailablescientificfindingsaboutXCHTandhepaticdiseases,pointingoutthedirectionforfurtherstudies.
MechanismsofActionHepatoprotectiveeffectsXCHThelpstomaintainthebalanceamongtheimmunologicalcytokines,whichmayhaveimmunologicalbenefitstochronicviralhepatitis.
[1]Forexample,scutellariarootandlicoriceinXCHTcouldinducetheproductionofcytokinessuchasinterleukin(IL)1β,tumornecrosisfactor(TNF)α,andgranulocytecolonystimulatingfactor(GCSF)frommonocytes/macrophages.
[2]Kakumuetal.
[3]foundXCHTincreasedinterferonγ(IFNγ)andantibodyagainstHBV,strengtheningcellularandhumoralimmuneresponses.
ToXiaoChaiHuTangforLiverDiseases:ALiteratureReviewYiWanga,LiLib,YanMeiChenga,ShengLiangZhuaaDepartmentofGastroenterology,YueyangHospitalofIntegratedTraditionalChineseandWesternMedicine,ShanghaiUniversityofTraditionalChineseMedicine,bClinicalResearchInstituteofIntegratedTraditionalChineseandWesternMedicine,YueyangHospitalofIntegratedTraditionalChineseandWesternMedicine,ShanghaiUniversityofTraditionalChineseMedicine,Shanghai200437,ChinaTheobjectiveofthisstudyistosummarizethepharmacologicaleffectsandthemechanismsofactionofXiaoChaiHuTang(XCHT,MinorBupleurumDecoction)onliverdiseases,soastogiverelevantresearchersavaluableinsightandbenefitpatientswithhepatopathy.
PubMedwasusedtosearchforandcollectscientificpublicationsrelatedtoXCHTandliverdiseasesfrom1986to2016.
Theavailablescientificresultsorevidencewereread,classified,andanalyzed.
XCHTshowedclinicalefficacyinpatientswithhepaticdiseasesincludinghepatitis,hepaticfibrosis,andhepatoma.
Themechanismsinvolvedtheproductionofcytokines,theregulationofimmunefunction,thesuppressionoflipidperoxidation,etc.
,XCHTmightworkonthemetabolismofsomemedicationssuchastolbutamidebytheregulationofgastricemptyingandintragastricpH.
XCHTexhibitedaverylowtoxicityprofile,suchasinterstitialpneumoniaduetodurationofmedication,patients'age,anddrugcombination.
XCHThasbeenaeutherapeuticsupplementalremedyforliverdiseases.
However,manymechanismsofactionandeffectsofXCHTonnewtypesofliverdiseasesstillremainunclear,somoreandmoreanimalexperimentsandhumanclinicaltrialsareneededtoobtainenoughproofsfortheclinicaluseofXCHTinnewtypesofhepatosissuchasnonalcoholicfattyliverdiseaseandautoimmuneliverdisease.
Keywords:Hepaticfibrosis,hepatitis,hepatoma,interstitialpneumonia,tolbutamide,XiaoChaiHuTang(minorbupleurumdecoction)AccessthisarticleonlineQuickResponseCode:Website:www.
wjtcm.
netDOI:10.
4103/wjtcm.
wjtcm_4_17AbstractDownloadfreefromwww.
wjtcm.
netAddressforcorrespondence:Prof.
ShengLiangZhu,DepartmentofGastroenterology,YueyangHospitalofIntegratedTraditionalChineseandWesternMedicine,ShanghaiUniversityofTraditionalChineseMedicine,Shanghai200437,China.
Email:zhushengliang999@126.
comHowtocitethisarticle:WangY,LiL,ChengYM,ZhuSL.
Xiaochaihutangforliverdiseases:Aliteraturereview.
WorldJTraditChinMed2017;3:46-50.
1ThisisanopenaccessarticledistributedunderthetermsoftheCreativeCommonsAttributionNonCommercialShareAlike3.
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com2017WorldJournalofTraditionalChineseMedicine|PublishedbyWoltersKluwerMedknowReceived:01092016,Accepted:03052017WorldJTraditChinMed|Volume3|Issue3|JulySeptember201747patientswithchronichepatitisC,Yamashikietal.
[4]pointedoutthatXCHTcouldmediatethelevelsofIL4,IL5,andIL10topreventthediseaseprogression.
Inimprintingcontrolregion(ICR)micewithliverinjuryinducedbyDgalactosamine,oraladministrationofXCHTfor14daysresultedinasignificantdecreaseofIL6andTNFαlevelsintheserum,asimilarreductionofFasmRNA,FasLmRNA,andBaxproteinexpression,butanincreaseoftheBcl2mRNAexpressioninthelivertissues,andfinally,XCHTrelievedthiskindofliverinjurythroughthemechanismabove.
[5]HowXCHTanditscomponentsworkonthecountandproliferationofTcellsubsetsinspleniccellsandhepatocytesinvitrohasalsobeenexamined.
ThedataindicatedthatXCHTselectivelyinhibitedtheproliferationofCD8+TcelltoregulatetheCD4/CD8ratioduetotheconstituentwogonin7Oglucuronideanditsmetabolin,whichmighttakeanessentialroleinthetreatmentofchronichepatitis.
[6]Inotherwords,thetherapeuticeffectofXCHTmightbeimprovingbodyresistance,removingevilpathogen,andstrengtheningorregulatingimmunefunction.
[7]ThepotentsynergisticeffectofXCHTonopsonicintracavitaryofHBVcarrierhasalsobeenconfirmedinamousemodel,whichinspiresawidespreaduseofXCHTinimmunetherapies.
[8]Changetal.
[9]testedtheantiHBVactivityofXCHTinHepG(2)2.
2.
15cellmodelandfoundXCHTcouldbesupplementarytonucleotideanalogstominimizetherecurrenceofviremiaafteritsdiscontinuation;however,thiseffectmightnotbemediatedbysaikosaponinA.
Nonalcoholicfattyliverdisease(NAFLD)referstotheaccumulationofexcessivefatintheliverofapatientwhohasnohistoryofalcoholabuse.
Db/dbmicefedonamethionineandcholinedeficientdiet,asanimalmodelsofnonalcoholicsteatohepatitis(NASH),andweretreatedwithXCHTfor4weeks.
Afterbiochemical,pathological,andmolecularanalyses,itwasrevealedthatthevalueofserumalanineaminotransferase(ALT)andthedegreeoflivernecroinflammationandfibrosis,weredramaticallyimprovedbyXCHTandmeanwhilemalondialdehydelevelsinlivertissueswereloweraftertreatment.
AllthesesuggestedXCHTmightinhibithepaticnecroinflammationandfibrosisinpatientswithNASH.
[10]StudiesofNammi'slaboratoryreportedtheunderlyingmechanismsofgingerasonecomponentofXCHTformulainregulatinghepaticcholesterolandlipidmetabolismofhighfatdiet(HFD)fedrats,[11,12]whosehypercholesterolemiaweremainlyregulatedbyincreasedhepaticlowdensitylipoproteinreceptorandreduced3hydroxy3methylglutarylCoAreductase.
HFDinducedhepaticinflammationwasprovedtoattenuatebecauseofgingerextractthroughinhibitionofnuclearfactorkB(NFkB).
[13]Gaoetal.
verifiedthatethanolicextractofginger(50mg/kg)significantlyreduceddyslipidemiaandhepaticlipidaccumulationinfructoseinducedNASHbymodulationofthehepaticcarbohydrateresponseelementbindingproteinmediatedpathway.
[14]AntifibrogeniceffectsInratswhosebileductswereligated,XCHTwasfoundtoreducecholestasissignificantly,cutdownthecollagencontentby50%,andexertantifibrogeniceffectbydownregulatinghepaticmRNAexpressionofprocollagenalpha1typeI,typeIII,andtissueinhibitorsofmetalloproteinase(TIMP)1.
[15]Thebalanceofmatrixmetalloproteinases(MMPs)andTIMPswasthefurtherbreakthroughpointofresearchonXCHT.
MMPhaddegradativeactivityagainstcollagen,whereasTIMPcontrolledtheactiveformsofMMPbyblockingtheactivesiteofit.
Sakaidaetal.
[16]claimedXCHTraisedMMP2,13activitiesandinhibitedTIMP1,2activitiesofhepaticstellatecells(HSCs)probablybyP38pathway.
Inaninvitrostudy,[17]XCHTsignificantlyaccumulatedthestellatecells,transformingmorphologicallytomyofibroblastlikecellsintheG0/G1phase,anddecreasedcellnumbersubsequentlyinG2/Mphase.
FromfurtherinsightintoXCHT,baicalinandbaicaleinbelongingtoflavonoidshadtheabilitytoinhibittheactivationofHSCsagainstfibrosis.
[18,19]XCHTalsosuppressedfibrogenesisbyreductionoflipidperoxides,andthispreventiveeffectwasshownininhibitingbothlipidperoxidationinculturedrathepaticcellswhichwereinthestateofoxidativestress,andgenerationofalphasmoothmuscleactin,typeIcollagenexpression,cellmultiplication,andoxidativeburstinculturedratHSCsconsideredasthemaincollagenproducingcells.
[19,20]Inaddition,XCHTshoweditsdosedependentsuppressiontoFe2+/adenosine5'diphosphateinducedlipidperoxidationinrathepaticmitochondriaanditsabilityoffreeradicalelimination.
[19]Onoetal.
[21]holdedthatadministrationofXCHTbroughtaboutanincreaseinretinoidlevelandadecreaseinhydroxyprolinelevelofliver,inhibitingactivationofItocells,andthen,causinginhibitionofcollagenproductionandpreventionofliverfibrosis.
However,whenactiveconstituentsofXCHTweretakenalone,liverretinoidlevelsremainedlow,implyingthatitwasinteractionamongactiveconstituentsofXCHTthatsuppressedactivationofItocell.
[22]Table1:ComponentsandconstituentsofXiaoChaiHuTangComponentsConstituentsBupleurumrootSaikosides,quercetin,αchondrillasterol,polysaccharide,naphthasPinelliaternataβsitosterol,glucosides,aminoacids,proteins,naphthas,saponin,alkaloidsScutellariarootBaicalins,chrysin,wogonoside,neobaicalein,naphthas,aminoacidsJujubaefructusBetulinicacid,oleanolicacid,crategolicacid,triterpenoid,alkaloids,flavonoids,saccharides,vitaminsPanaxginsengGinsenosides,polysaccharide,αpanacene,panaxacid,panasenosideLicoriceGlycyrrhizinGingerNaphthas(includinggingerolandzingiberene),gingerolWorldJTraditChinMed|Volume3|Issue3|JulySeptember201748AntihepatomaeffectsXCHTinducedTNFαandGCSFinvitroinperipheralbloodmononuclearcellsofpatientswithhepatocellularcarcinoma(HCC),whichmightbethesourceofbenefitsforpatientstakingadministrationofXCHTtodealwithhepatoma.
[23]AsubsequentstudysuggestedthatXCHTpreventedhepatocarcinogenesiswithinhibitionof8hydroxy2'-deoxyguanosine(8OHdG)formation,whichplayedanimportantroleinoxidativestress.
[24]Meanwhile,theviciouscirclebetweentheoxidativestressandthealkalinephosphataseinactivationthroughlipopolysaccharides(LPS)catecholaminesinteractionsinthegut,liver,andbraincouldbeattenuatedbyXCHTduringCCI4+ethanolinducedmouseHCC.
[25]Besides,XCHTwasprovedtosuppresstheproliferationofthecarcinomacelllinesinmorphological,DNA,andcellcycleanalyses,inducingapoptosisintheearlyperiodofexposureandarrestattheG0/G1phaseinthelateperiodofexposure.
ThesuppressiveeffectofXCHTwasstrongerthaneachofitsmajoringredients,andalmostnoinhibitionwasobservedinnormalhumanperipheralbloodlymphocytesornormalrathepaticcells.
[26]Otherresearchesdemonstratedthatbaicalein,baicalin,andsaikosaponinAsuppressedculturedhumanhepatomacellproliferationinadosedependentmannerbutirrelevanttothecellcycle.
Furthermore,itwasreportedthatsaikosaponinApossessedstrongcellkillingability,butsaikosaponinC,ginsenosideRb1,andginsenosideRg1didnotworkoncellproliferation.
[27]Afterward,XCHTwasshowntoimprovetheimmunefunctionoftumorbearingmicetoinhibitthegrowthofsolidlivercancer.
[28]However,Watanabeetal.
[29]foundthenumberofGlutathioneStransferaseplacentalformpositiveareaswithintheHCClesionswassmallerinboththecontrolandthelycopenegroupthanthatintheXCHTgroup(P=0.
024andP=0.
012,respectively),whichmeantlongtermadministrationofXCHTdidnotreducetheriskofhepatocarcinogenesisinLong–Evanscinnamonrats.
HumanClinicalTrialsHepatitisInaninvivostudy,[30]XCHTseemedtohelpeliminateHBeAginchildren.
Amongthe24chronichepatitisCpatientswhowerenotcandidatesforIFNbasedtherapyandreceivedXCHTatthedoseof2.
5gthreetimesdailyfor12months,aspartateaminotransferaseof67%ofparticipants,ALTof75%ofparticipants,viralloadresponseof29%ofparticipantsandhistologyactivityindexscoresof38%ofparticipantswereimprovedaccordingtotheassay.
ThedatasupportedthenotionthatXCHTcouldimproveliverpathologyinselectedhepatitisCpatientswhowerenotcandidatesforIFNbasedtreatment.
[31]Anothertrial,inwhich26healthyparticipantsreceivedXCHTatthedoseof2.
5gtwicedailyfor5daysandunderwentthecaffeinetestonday1andday5,[32]showedthatthemeanactivityofcytochromeP450enzymes1A2(CYP1A2)reducedby16%onboth1stdayand5thdaycomparedwiththebaseline;themeanactivityofxanthineoxidase(XO)alsodramaticallyreducedby25%on1stdayand20%on5thdaycomparedwiththebaseline;theactivityofcytochromeP450enzymes3Atendedtobeloweron5thdaythanthebaseline.
Inbrief,XCHTreducedCYP1A2andXOactivityinhuman.
HepaticfibrosisTheherbalmedicineXCHThasbeenadministeredtoahugenumberofpatientswithchronicliverdiseases.
InpatientswithHCVpositivelivercirrhosis,thelifeextendingeffectofXCHTwasattributedtotwoofitssevenherbcomponents,thatwas,scutellariarootandlicorice.
ThemechanismmightincludethepromotionofIL12production.
[33]HepatomaXCHTisknowntodramaticallyinhibitdevelopmentofhepatomaandplaysaroleinlifeprolongation.
Okaetal.
[34]performedaprospective,randomized,nonblindcontrolledstudythatrevealedXCHTcouldhelptopreventtheprogressionofHCCinpatientswithcirrhosis,especiallyinpatientswithoutHBsantigen.
PotentialDrugInteractionBecauseofcurrentpopularityofXCHTinhepaticdisease,cancer,andotherdiseases,itisessentialtodeterminewhetherithasaneffectoncytochromeP450,thehepaticenzymesysteminchargeofmetabolismofmanymedications.
Nishimuraetal.
[35]tooktheattitudethatXCHTcutdownthebioavailabilityoftolbutamide(asulfonylureahypoglycemicagent)inratsafteroraladministration,butitmadenoeffectontheintravenousadministrationoftolbutamide.
Thatwastosay,theabovechangewasnotrelatedtohepaticmetabolism.
Simultaneously,theyclaimedthatXCHThadaninhibitiononthegastricemptyingandanincreaseontheintragastricpH,leadingtothelowerplasmaconcentrationoftolbutamideafteroraladministration,butitaffectedneithertheintragastricdissolutionnorthegastricabsorptionoftolbutamide.
ThisviewcontradictsthepreviousconclusionthatXCHTslightlyhastenedthegastrointestinalabsorptionoftolbutamide,whichmightenhancethehypoglycemiceffectofthesulfonylureaintheearlyperiodafteroraladministration.
[36,37]SideEffectsSomecasereportshaveshownthesideeffectsofXCHT,mostofwhichareinterstitialpneumoniaandacuterespiratoryfailureinJapan.
[38]Patientsoftenmanifestedwithcoughing,dyspnea,andacuteepisodesoffever.
Chestradiographsrevealeddiffusefrostedglassshadowsandinfiltration.
ThereweresignificantincreasesabovenormalinbothserumCreactiveproteinandlactatedehydrogenaselevel.
Hypoxiawascommon.
AnalysisofbronchoalveolarlavagefluidshowedabnormallyhighWorldJTraditChinMed|Volume3|Issue3|JulySeptember201749proportionsoflymphocytesandneutrophilsandalowCD4/CD8ratio.
[39]Asreportwent,theyoungestsufferingfrominterstitialpneumoniaattributedtoXCHTinJapanwasa7yearoldboywithacutelymphoblasticleukemiacomplicatedbytypeChepatitis.
[40]Atthesametime,druginducedpneumoniaduetoXCHToccurredina71yearoldwomanwithautoimmunehepatitis.
[41]Inanotherautopsycase,[42]itwasinferredthatthedevelopmentofinterstitialpneumoniawascausedbyHCVincombinationwithXCHTinducedlunginjury.
TherewasalsosomeonegettinghepaticinjuryandpneumonitissimultaneouslyafterintakeofXCHT.
[43]Asthesecasereportsshow,themorbidityandriskofXCHTinducedinterstitialpneumoniaareincreasedbycoadministrationofIFN,[44,45]durationofmedication,andhighinanelderlypopulation.
[38]Murakamietal.
[46]madeitclearthatinterstitialpneumoniawasasideeffectoftreatmentwithIFN,andXCHTmightpotentiatethissideeffect.
ApossiblemechanismwasthatXCHTcouldoverstimulatetheneutrophilswhichwascausedbyIFNtoaccumulateinthelung.
Activatedneutrophilsreleasedgranulocyteselastaseandoxygenradicalsthatmightdamagelungtissue.
Whenthefibroblastsrepairedthedamagedtissue,pulmonaryfibrosismightoccur.
Therefore,itissaferforXCHTtobeusedinpatientswithhepaticdiseasewhocontraindicateIFN.
AccordingtoSato,[39]themeantreatmentcourseofXCHTbeforetheoccurrenceofpneumonitiswas50.
2±42.
1daysandthemeanagewas63.
7yearold.
Nevertheless,Ohtakeetal.
[47]arguedthatglycyrrhizin,ametaboliteoflicoriceasoneoftheprimarycomponentsinXCHT,raisedinvitroIL6inantiCD3monoclonalantibody(antiCD3mAb)stimulatedlungmononuclearcellsinacelltypespecificanddosedependentmanner,soXCHTalleviatedLPSinducedlunginjuryatthelaterphasewhenlungleakwasobvious,butwasineffectiveonearlyneutrophilsequestrationtothelunginBALB/cmice.
ConclusionsandOtherPotentialUsesXCHT,atraditionalcommonlyappliedChineseherbalmedicineformula,haslongbeenusedtopatientswithhepaticdiseasesinAsia.
[48]Infact,XCHTstillhasmanyothereffectsthathavenotbeenexerted.
Inliverdiseases,moreandmorehumanclinicaltrialsareneededtoobtainenoughproofsfortheclinicaluseofXCHTinmoreaspects,suchasNAFLDandautoimmuneliverdisease.
XCHTexhibitsaverylowtoxicityprofileandappearstobesafeforclinicaluseandconsumption.
AcknowledgmentWewouldliketothankallthosewhohavecontributedtheirtimeandknowledgetothismanuscript.
WealsowishtothanktwoanonymousrefereesandtheacademiceditorsofWJTCMfortheirveryconstructivefeedback.
FinancialsupportandsponsorshipThisworkwassupportedbygrantsfromtheScienceandTechnologyCommissionFoundationofShanghaiMunicipality;China(grants13401902801).
ConflictsofinterestTherearenoconflictsofinterest.
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