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IntroductionHesperetinisanaturalcompoundbelongingtotheavanoneclassofavonoids.Itistheaglyconeofhesperidin(-7-rutinosideofhesperetin),apredominantavonoidcompo-nentofcitrusfruits(Figure1).Itisnowwellacceptedthatlowconsumptionofhighfatfoodsandanincreasedintakeoffruitandvegetableswillreducetheriskofsomelife-threateningdiseasesandmaintainagoodhealthstatus(ParrandBolwell,2000).Worldwide,thedietaryintakeofcitrusfruitproducts,andhenceavanones,isincreasingeveryyearetal.,2014).InWesterncountries,theintakeofhesperetinislargelydependentondietaryhabits(Knektetal.,2002),whereashesperetinisalsoknownasamajorac-tiveingredientintheChinesetraditionalmedicinalherbChenpi(Lietal.,2008).Becauseofthereportedbioactivities,extensiveresearchhasbeenperformedonhesperidinandhesperetininvariousexperimentalmodels.Thesebioactiv-itiesincludeantioxidant,anti-inammatoryandanti-carcinogeniceffects(Iranshahietal.,2015;Parhizetal.,2015).Mostliverdiseasesareaccompaniedbyinammationandoxidativestress,regardlessoftheaetiologyoftheunderlyingdisorder.Mildandtime-restrictedhepaticinammationcouldbeconsideredbenecialintherestorationoftissueho-meostasis,forexample,byeliminatinginvadingpathogenicorganismsanddamagedordeadcells.However,excessiveanduncontrolledinammationleadstomassivelossofhepa-tocytesasaresultofapoptosisand/ornecrosis(GuicciardiandGores,2005)irreversibledamagetotheliverparenchymaandlossofliverfunction(Brenneretal.,2013).Lossofhepa-tocytesandlossofliverfunctionoccursinmanyformsofliverpathology,includingfulminanthepatitis,reperfusioninjury,(non-)alcoholicliverdiseases,cholestasisandviralhepatitis.Alltheseconditionsdemonstratehighmorbidityandmortalityandlivertransplantationisoftentheonlylife-savingtreatment(Malhietal.,2010;Protzeretal.,2012).Themanagementofacuteandchronicinammatoryliverdiseaseisstillachallengetomoderndrugdevelopment,be-causetherearecurrentlynoeffectivetreatmentsthatimproveliverfunctionand/orregenerateorprotecthepaticcells(NamdeoandSyed,2014).Therefore,thereisanurgentneedfornoveltherapeuticapproachesthatpreventliverinjuryviaprotectionagainsthepatocytecelldeath.Inparticular,thepotentialofherbalanddietarysupplements,likehesperetin,hasbeenlargelyunexploredinthisregard.Althoughhesperidinexhibitsawiderangeofbiologicalactivities,includinghepatoprotectivepropertiesinliverin-jury(Kauretal.,2006;Chenetal.,2010;Lietal.,2014),itsaglycone,hesperetin,hasgreaterbioactivityasaresultofmoreefcientabsorptionfromtheintestinethanhesperidin(Jungetal.,2003;Kimetal.,2004;Kanazeetal.,2007;Kobayashietal.,2008).Existingstudiesaremainlyfocusedononespeciinvivoinvitromodel(Chaetal.,2001;PariandShagirtha,2012),butcomprehensivereportsontheef-fectivenessofdifferentdosesoforallyadministeredhesperetininmultiplemodelsoffulminanthepatitisarelack-ing.Inviralandautoimmunehepatitis,activationofT-cellsandmacrophagesistheinitialevent(Wolfetal.,2005).Ex-perimentalliverinjurymodelswereestablishedthatresemblefulminanthumanhepatitis,includingTNF-andIFN-dependentinammatoryliverinjurymodels,thatallowtheevaluationofhepatoprotectiveinterventions,includingme-dicinalplantcomponents.Inourstudy,immune-mediatedliverinjurywasinducedbytheT-cellmitogenicplantlectinconcanavalinA(ConA).Liverinjuryinthismodelisdepen-dentonbothmacrophage-derivedTNFandT-cell-derivedIFN-.Inthismodel,theexpressionofvariouscytokinesisstronglyinduced,includingIFN-,IL-4andIL-2(Sassetal.,2002).Asasecondmodel,weusedaninammation-inducedmodeloffulminanthepatitis.EndotoxinssuchasLPSareknownasstrongstimulatorsofmacrophages,includingKupffercells.TNFalonedoesnotinducehepatocytecelldeath.However,whenhepatocytesaresimultaneouslysensi-tizedwithD-galactosamine(D-GalN),preventinghepatocytetranscription,LPS-inducedTNFbecomesextremelyhepato-toxic,becauseofextensiveapoptosisofhepatocytes(Schoemakeretal.,2002). Figure1Structuresofhesperetinandhesperidin. TablesofLinksTARGETSEnzymesJNKsubfamilyCaspase3PARPfamilyCatalyticreceptorsiNOS,inducibleNOsynthaseTLR-4LIGANDSIFN-IL-6IL-1IL-10IL-4TNF-TheseTableslistkeyproteintargetsandligandsinthisarticlethatarehyperlinkedtocorrespondingentriesinhttp://www.guidetopharmacology.org,thecommonportalfordatafromtheIUPHAR/BPSGuidetoPHARMACOLOGY(Southanetal.,2016),andarepermanentlyarchivedintheConciseGuidetoPHARMACOLOGY2015/16(etal.,2015a,b). BJP XBaietal.42BritishJournalofPharmacology(2017)174 Theaimofthepresentstudywastoinvestigatethehepa-toprotectiveandanti-inammatorypropertiesofhesperetininacuteliverinjury.Wehavedemonstratedthathesperetinisanti-inammatoryandcytoprotective,inpartbyrepres-sionofIFN-expressioninT-cell-mediatedhepatitisandbyrepressionofTNFexpressionintheTNF-dependentD-GalN/LPSmodelofliverinjury.MethodsAllanimalcarecompliedwiththelegalrequirementsandguidelinesapprovedbytheethicscommitteefortheanimalfacilityofShantouUniversityMedicalCollegeortheguide-linesofInstitutionalAnimalCareandUseCommitteeofLaboratoryAnimalsoftheUniversityofGroningen(DEC-RUG).ExperimentalprocedureswereapprovedbytheappropriateAnimalethicsCommittee.AllstudiesinvolvinganimalsarereportedinaccordancewiththeARRIVEguide-linesforreportingexperimentsinvolvinganimals(Kilkennyetal.,2010;McGrathandLilley,2015).MaleWistarrats(220250g;68weeks;specipathogenfree(SPF))werepurchasedfromHarlan(Zeist,TheNetherlands)andkeptincagescontainingstandardbedding,withatleasttworatspercage.6week-oldmaleBALB/cmice22g)wereobtainedfromHunanSJALaboratoryAnimalCo.Ltd(Changsha,Chinano.43004700009427).Allanimalswerehousedinaspecicpathogen-freefacilitywith12hlight/darkcycle[07to19h,temperature(222