14aCatechinsandTheirTherapeu

molecules Review CatechinsandTheirTherapeuticBenefitsto InflammatoryBowelDisease Fei-YanFan1,Li-XuanSang2,*andMinJiang1,* 1 2 *DepartmentofGastroenterology,FirstAffiliatedHospitalofChinaMedicalUniversity,155NanjingNorthStreet,HepingDistrict,Shenyang110001,China;feiyanfan7212@163.comDepartmentofGeriatrics,FirstAffiliatedHospitalofChinaMedicalUniversity,155NanjingNorthStreet,HepingDistrict,Shenyang110001,ChinaCorrespondence:sanglixuan2008@163.com(L.-X.S.);fendou1957@163.com(M.J.); Tel.:+86-24-8328-3720(L.-X.S.);Fax:+86-24-8328-2563(M.J.) AcademicEditor:DerekJ.McPhee Received:6January2017;Accepted:28February2017;Published:19March2017 Abstract:Catechinsarenaturalpolyphenolicphytochemicalsthatexistinfoodandmedicinalplants,suchastea,legumeandrubiaceae.Anincreasingnumberofstudieshaveassociatedtheintakeofcatechins-richfoodswiththepreventionandtreatmentofchronicdiseasesinhumans,suchasinflammatoryboweldisease(IBD).Somestudieshavedemonstratedthatcatechinscouldsignificantlyinhibittheexcessiveoxidativestressthroughdirectorindirectantioxidanteffectsandpromotetheactivationoftheantioxidativesubstancessuchasglutathioneperoxidases(GPO)andglutathione(GSH),reducingtheoxidativedamagestothecolon.Inaddition,catechinscanalsoregulatetheinfiltrationandproliferationofimmunerelated-cells,suchasneutrophils,colonicepithelialcells,macrophages,andTlymphocytes,helpingreducetheinflammatoryrelationsandprovidebenefitstoIBD.Perhapscatechinscanfurtherinhibitthedeteriorationofintestinallesionsthroughregulatingthecellgapjunctions.Furthermore,catechinscanexerttheirsignificantanti-inflammatorypropertiesbyregulatingtheactivationordeactivationofinflammation-relatedoxidativestress-relatedcellsignalingpathways,suchasnuclearfactor-kappaB(NF-κB),mitogenactivatedproteinkinases(MAPKs),transcriptionfactornuclearfactor(erythroid-derived2)-like2(Nrf2),signaltransducerandtheactivatoroftranscription1/3(STAT1/3)pathways.Finally,catechinscanalsostabilizethestructureofthegastrointestinalmicro-ecologicalenvironmentviapromotingtheproliferationofbeneficialintestinalbacteriaandregulatingthebalanceofintestinalflora,soastorelievetheIBD.Furthermore,catechinsmayregulatethetightjunctions(TJ)intheepithelium.ThispaperelaboratesthecurrentlyknownpossiblemolecularmechanismsofcatechinsinfavorofIBD. Keywords:catechins;inflammatoryboweldisease;oxidativestress;mechanisms;tightjunctionfunctionality 1.Introduction 1.1.InflammatoryBowelDisease(IBD) IBD,whichcontainstwomajormanifestations,namelyulcerativecolitis(UC)andCrohn’sdisease(CD)[1],referstoidiopathicgutchronicinflammatorydisease.Itischaracterizedbytheremissionandexacerbationofclinicalsyndromeswhicharecharacterizedbyintestinalbleedinganddiarrhea,leadingtothedisruptionoftheepithelialbarrierandtheformationofepithelialulceration[2],withextensiveareasofstructuraldamagetotheintestine[3].TheclinicalmanifestationsofIBDthatdependontheintestinalsegmentinvolvedgenerallyincludehaematochezia,diarrhea,abdominalpain,passageofpus,mucus,blood,obstruction,fever,weightloss,wasting,andultimatedevelopmentintocancer[4,5].Molecules2017,22,484;doi:10.3390/molecules22030484www.mdpi.com/journal/molecules Molecules2017,22,4842of29Inaddition,morethan25%ofIBDpatientsarealsosufferingfromextra-intestinalcomplications,includingperipheralarthritis,axialarthropathies,erythemanodosum,pyodermagangrenosum,episcleritis,iridocyclitis,anemia,etc.[3,4]. WiththeriseofitsincidenceandprevalenceinEasternEuropeandAsia,especiallyinwesterncountries(beingashighas1%),IBDhasgraduallybecomemoreprevalentworldwide[5].Eventoday,itsaetiologyandpathogenesishavenotbeencompletelyelucidated.However,ithasbeenmadeclearthatIBDisacomplexmultifactorialdiseasewhichinvolvestheinteractionbetweenthehostgenecomponent,theintestinalimmunesystem,environmentalfactors,the“in-vironment”,andthecomplexintestinemicrobiome[6].Enormousmolecular-andgenome-wide-relatedstudieshaverevealedtheexistenceofdistinctchangesinthegutmicrobiotaofIBDandalsohaveelucidatedtheimportanceof“dysbiosis”ofthegutmicrobiomeintheaetiopathogenesisofIBD[6].Forexample,theinvadingpathogensandtheentericcommensalbacteriawhichhavebeentransformedfromasymbiotictoaputativepathogenicone,oritsproduction,caninitiatetheimmuneresponseofIBDingenetically-susceptibleindividuals[6].Afterreactingwiththeantigens,suchasformyl-Met-Leu-Phe(fMLP)andlipopolysaccharide(LPS),theintestinalepitheliaorthemacrophages,neutrophilcellswillbestimulated[7,8].Then,theactivatedcellscaninfiltrate,proliferate,differentiate,andproducedifferentkindsofinflammatorycytokinesandchemokines,pro-inflammatorycytokines,andreactiveoxygenspecies(ROS),thusinitiatingandexpandingtheinflammation,whileresultinginwidespreadlesionstocellsandtissues[3,9,10].Onthecontrary,therearealsomeaningfulstudieswhichhavedemonstratedthattheneutrophilsandmacrophageswouldplayaprotectiveroleincolitisbysecretingimmunosuppressivefactorsorotherfactors[11–13]. IBDischaracterizedbyexcessiveTh1orTh2cellresponses,whichhave,respectively,becomemorecommoninCDorUC[14].Th1cells,thechiefmediatorsintype1immunity,cansecreteinterferon-γ(IFN-γ)(theiconicproductofTh1cells),interleukin12(IL-12),andtumornecrosisfactor-α(TNF-α)which,inturn,induceTNF-α,IL-6,andIL-1βtoreleasefrommacrophages.Wangetal.havefoundthattheclinicalcourseofCD-likemousecolitishasbeenimprovedbyinhibitingtheactivationofTh1/Th17cells[15].TheactivatedTh2cellsandthecytokinessecretedbyTh2cells,suchasIL-4,IL-5,IL-9,IL-10,IL-23,andIL-25,haveincreasedininflamedmucosaofUCpatientsthaninCDones[3].InadistinctactivationpathwayfromTh1andTh2cells,theincreasednumberofactivatedTh17cellsandsecretedcytokines,suchasIL-17AandIL-17F,inIBDpatientsandanimalsinstudieshavesuggestedthatTh17cellsplayanimportantroleinthedevelopmentofIBD[16,17].Additionally,manyauthorshavereportedthatT-regulatory(Treg)cells,characterizedbytheexpressionoffork-headboxP3(FOXP3),IL-10,andTGFβ1,playafundamentalroleinmaintainingthegutimmune-regulatorypropertiesandinhibitingtheactivationofTh1,Th2,andTh17cells[16,18,19]. ThemainproblemsfacedbythecurrenttherapeuticstrategiesforIBDincludelimitedbenefits,numeroussideeffects,andtheweakresponsivenesstopatientswhotakeanti-inflammatorydrugs[20–23].Apopulation-basedstudyhasindicatedthatthewidely-usedfirst-linetherapies,corticosteroids(CSs),canmerelyhelpapartofIBDpatientswhoneededCSstoachieveremission,comparedwith16%whofailedtorespondtoCSs.However,overtime,aprolongedresponseorsteroiddependencewillappear[24].Thesemotivatedtheimminentrequirementofalternativetreatmentwithhighefficacybutlesstoxicsideeffects.Dietarypolyphenolshavebeenconsideredasnoveltherapies[5,25].Onlyafewhumanstudies,whichmadeuseofpurepolyphenolornaturalplantextracts,havedemonstratedtheeffectsofplantpolyphenols,suchascurcuminandpycnogenol,onIBD[14,26,27].Arandomized,double-blind,multicenterhumantrialindicatedthatcurcuminseemedtobeapromisingandsafechoiceforkeepingremissioninpatientswithquiescentUC[27].Pycnogenolhasbeenprovedtosignificantlyreducethemarkersofoxidativestress,butnotmarkersofinflammation,indicatingthepositiveeffectsofmid-long-termadministrationofhydrophilicpolyphenolsinCDpatients[26].FurtherhumantrialsemployingpolyphenolsareneededtoconfirmthebeneficialeffectsofpolyphenolsinthemanagementofIBD.Atthesametime,catechins,includingsomekindsofpolyphenols,havealsogainedincreasingattentionoverthepastfewyears[8,9,14,28]. Molecules2017,22,4843of29Owingtotheirpotentialforanti-inflammation,anti-oxidation,andanti-bacterialactivities,theycontributetotheremissionofIBD.AhumanstudyabouttheeffectsofpolyphenonE(astandardizedgreenteapreparationconsistingof65%epigallocatechingallate(EGCG)and22%othercatechins)onIBDshowedtheimprovementinresponseandintheremissionrateinmildtomoderate,butrefractory,UCpatients[14].Howthesecatechinsexpresstheirpoweristhefocusofthisreview(Figure1 ). Figure1.ThemaintargetsofactionofcatechinsinIBDaccordingtothisarticle.Figure 1. The main targets of action of catechins in IBD according to this article. 1.2. Overview of Catechins Activity 1.2.OverviewofCatechinsActivity Catechins are known as a type of polyphenols naturally occurring in certain foods and Catechinsareknownasatypeofpolyphenolsnaturallyoccurringincertainfoodsandmedicinalmedicinal plants, such as legumes, Rubiaceaefabaceae species, including the plants,suchaslegumes,Rubiaceae,stembark, stem bark of the ofthefabaceaespecies,includingtheMimosoideaeMimosoideae subfamily, such as Abarema cochliacarpossubfamily,suchasAbaremacochliacarpos,teas(greentea,, teas (green tea, pu-erh tea, pu-erh green pu-erhtea,pu-erhgreentea),Mouriripusatea), Mouriri pusa Gardn, buckwheat, grapes, cocoa beans, litchis, and apples [29–36]. Catechins Gardn,buckwheat,grapes,cocoabeans,litchis,andapples[29–36].Catechinshavebeenregardedashave been regarded as the characteristic compounds in green tea for daily beverage and crude thecharacteristiccompoundsingreenteafordailybeverageandcrudemedicineinAsia,especiallyinmedicine in Asia, especially in China and Japan, for thousands of years. In general, catechins ChinaandJapan,forthousandsofyears.Ingeneral,catechinsmainlyincludecatechin,epicatechinmainly include catechin, epicatechin (EC), epicatechin gallate (ECG), epigallocatechin (EGC) (EC),epicatechingallate(ECG),epigallocatechin(EGC)anditsstereoisomergallocatechin(GC),and its stereoisomer gallocatechin (GC), EGCG and its stereoisomer gallocatechin gallate (GCG), EGCGanditsstereoisomergallocatechingallate(GCG),withtheircompositionsbeingsimilarforwith their compositions being similar for each other [36–39] (Figure 2). Catechins are the most eachother[36–39](Figure2).Catechinsarethemostactiveconstituentpolyphenolsinthegreenactive constituent polyphenols in the green tea (tea(Cameliasinensis)[3].EGCG,whichaccountsCamelia sinensisforalmost50%) [3]. EGCG, which accounts for ofthetotalcatechinscontentofalmost 50% of the total catechins content of green tea extracts, makes up to 30% of the dry weight greenteaextracts,makesupto30%ofthedryweightofgreentealeaves[40],andhasthestrongestof green tea leaves [40], and has the strongest chemopreventive potential containing chemopreventivepotentialcontaininganti-inflammatory,anti-mutagenic,andanti-carcinogeniceffectsanti-inflammatory, anti-mutagenic, and anti-carcinogenic effects among the green tea catechins amongthegreenteacatechinswhichcontainEC,EGC,andEGCG[3,41,42].Overthepastfewyears,which contain EC, EGC, and EGCG [3,41,42]. Over the past few years, catechins have attracted catechinshaveattractedinterestduetotheirpresumedrolesinvariousphysiologicalaccommodativeinterest due to their presumed roles in various physiological accommodative activities, such as activities,suchasanti-hypertensive[9],antibacterial[36],anti-inflammatory[29,43],andantioxidativeanti-hypertensive [9], antibacterial [36], anti-inflammatory [29,43], and antioxidative activities activities[34,40,44,45],andasaprotectiveeffectfromatherosclerosis.Moreover,increasingnumbers [34,40,44,45], and as a protective effect from atherosclerosis. Moreover, increasing numbers of ofstudieshavedemonstratedthatcatechinscouldalsopossesstheanti-carcinogenicactivityinmanystudies have demonstrated that catechins could also possess the anti-carcinogenic activity in experimentalsystemsandinmanykindsoforgans,includingtheoralcavity,esophagus,stomach,many experimental systems and in many kinds of organs, including the oral cavity, esophagus, smallintestine,colon,lung,liver,pancreas,skin,prostate,mammarygland,andbladder[46–50].Ithasstomach, small intestine, colon, lung, liver, pancreas, skin, prostate, mammary gland, and beenprovedthatcatechinscouldinhibitcarcinogenesis,tumorgrowth,cancercellinvasion,andtumorbladder [46–50]. It has been proved that catechins could inhibit carcinogenesis, tumor growth, angiogenesis,bysuppressingtheinductionofproangiogenicfactors,suchasvascularendothelialcancer cell invasion, and tumor angiogenesis, by suppressing the induction of proangiogenic growthfactor(VEGF)[51].ItwasestablishedthatEGCG,relyingonitsverystrongreducingproperty, Molecules2017,22,4844of29cansuppresstheactivityofurokinase,anenzymeusedbytumorcellstoinvadeandmetastasize,andthecatechinscanbesaferthanthesyntheticinhibitorofurokinaseactivity[52]. Atthesametime,someresearchershavefocusedonthefactthatcatechinshavebeenproventobeeffectiveinanti-tumoractivityandforthesuppressionofinflammationwhichresultsincellinjuryanddeath,contributingtomanydiseases,suchasIBD,lunginjury,andinflammation-inducedcarcinogenesisinvariouskindsofmodels[14,41,53].Thus,catechinsmaybeeffectivetherapiestorelieveIBDwithoutobvioussideeffectsinvariouscell,animal,andhumanexperiments[53],whichmayconcentrateonthecatechin,EC,ECG,EGCG,orplantextracts.Studieshaveshowedthatthedietarypolyphenollevelsof0.12%and0.24%decreasedtheazoxymethane(AOM)-inducedaberrantcryptfoci(ACF)formationinaratmodel[49],whichwasalsoobservedwithEGCG(0.01%and0.1%indrinkingwater)inrats,too[54].ItwasdescribedthatEGCGappliedintraperitoneallyat50mg/kgbodyweightwasshowntoinhibitcoloninflammationincolitisinratmodels,resultinginthedecreaseofweightlossandshorteninginthelengthofthecolon[40].InanotherstudybyVasconcelosetal.,EC(10mg/kg)hasalsobeenapprovedtobenefitcolitisinducedby2,4,6-trinitrobenzenesulfonicacid(TNBS)inacuteandchronicratmodels[30].InCaco2cells,ECGhasshowncomparableantioxidantcapacitieswithadoseresponsebetween10and100µM[55].However,thebeneficialeffectsofcatechinsontheintestinallesionshavedisappearedinhigherdosesinpreviousstudies.Forexample,dietarygreenteapolyphenols(GTP,includingEC,EGC,ECGandEGCG.Amongthem,greaterthan40%isEGCG[56]),atdoselevelsof0.5%and1%,profoundlyenhancedthedextransodiumsulfate(DSS)-inducedacutecolitis,butthe0.1%and0.25%levelsofGTPinthediethadatendencytodecreasein1,2-dimethylhydrazine(DMH)-inducedmaleICRmice[57].AhighdoseofEGCGwasalsodemonstratedtoactasaprooxidant[57,58],insteadofantioxidant[59],bygeneratingROSandevencausingdamagetocellularDNAinvariouskindsofcells.Guanetal.suggestedthat0.5%dietaryEGCGcouldexacerbateDSS-inducedcolitisininflamedcolonsofmicemodelsascomparedwiththoseontheAIN93Mdiet[50].Inaddition,thedoseof0.3%EGCGintherodentdietcorrespondstoadailyingestionof1.5gEGCGforindividualswithdailyrequirementsof2000kcal[50].However,thedetailedmechanismsbywhichEGCGpromotesinflammationinanimalmodelsarenotclearyet,anditisprobablyrelatedtotheantiplateletandantithromboticactivitiesofEGCG[60].ThisphenomenoncouldalsobeobservedinTNBS-inducedrats’colitis,sothattheanti-inflammatoryeffectof10mg/kgdoseofECwilldisappearwithhigherdoses[30].AstudyinvitroofhumanneutrophilsshowedthatEGCGconcentrationsrangingfrom0to30µMwerenottoxictothecells.However,whentreatedwith100and400µMofEGCG,cellmembraneintegritydecreased[61].Additionally,10µMofEGCcouldcauseanobviouslossofcellmembraneintegrity,whichwillhappeninECGlevelsof3and10µM,too.ECalsocausedcelldeathataconcentrationof2µMormore[61].However,30µMofEGCG,3µMofEGC,2µMofECG,and1.4µMofEC,eitheraloneorincombination,presentmarkedimmunomodulatoryactionsbyregulationofinflammatorycytokines,reductionofROSproduction,andmigrationofneutrophils[61],andrelevantevidencehasindicatedthatthepro-inflammatorycapacitymayexceedthebenefitsongutinflammationintheapplicationofhighconcentrationofcatechins[30].Thus,theconcentrationsofcatechinsplayanimportantrolewhentheyareappliedtointestinalinflammation.However,mostoftoday’strialsforcatechinsinIBDarerelatedtotheanti-inflammationcapacity.Ontheotherhand,duetovariousreasons,likethelackofspecificobservationalandepidemiologicalanimalsandhumanstudiesaimingtodefinethequantitativeeffectiveconcentrations,aswellasduetothefactthatthematerialsforstudiesarealwaysamixtureextractofvariouskindsofplants,itisstillunabletoprovideexact,orevenequivalent,effectivedoserangesofcatechinsinvivoandinvitroindetail.Nowadayssuggesteddosagesofvariousmarketedsupplementsoftenhavenoscientificbasis[62].ApilotstudysuggestedthattheoralconcentrationofEGCG,upto400mgtwicedaily,achievedtheimmunocompetenceeffectinUCpatients[14].However,theupperlimitofthedoseofEGCGisnotstillfullyindicated[2,14].Thecatechins,andthecorrespondingplants’optimaldoses,needtobefurtherdefined;forexample, Molecules2017,22,4845of29Kimetal.demonstratedthatthedailyoralintakeof6gofteawouldinduceacorrespondingadversereaction[57],withthreecupsofteagenerallycontainingabout500mgofgreentea[40]. 1.2.1.Catechins:ChemicalStructures Catechinsarecomposedoftypesofplantpolyphenols,whichubiquitouslyexistinfoodsandmedicalplants,suchasgreentea.Intermsofchemicalstructures,polyphenolsarecompoundswhichhavedifferentamountsofphenolicringsattachedbytwoormorehydroxylgroups[3],resultinginmorethan8000dietarypolyphenols[44],whichhavethousandsofchemicalstructures,varyingfromsimplemoleculestohighlypolymerizedcompounds[10].Actingashydrogenorelectrondonors,thecommonphenolgroupscanscavengefreeradicals[3].Amongthem,flavonoidslinktwoaromaticrings(AandB)viaathree-carbonchainforminganoxygenatedheterocycle(Cring),endinginacommonC6-C3-C6structure,byreactingwithdifferentgroupsofhydroxylandglycosidicgroupsandbindingwithothermolecules[10,44].Flavonoidsaredividedintovarioussubfamilies.Flavanolsareonekindofthesubfamilywhichhasahydroxylinposition4attachedtoasaturatedCring.Catechin,anditsstereoisomersincisortransconfiguration,withrespecttocarbons2and3,((–)-EC(cis)(6.4%approximatelyoftotalgreenteacatechins)and(+)-catechin(trans))areflavan-3-olcompounds[10,44](Figure2).Throughesterificationwithgallategroups,flavanolscanformEGCG,thegallicacidesterofEGCatposition3,approximatelyhalfoftotalgreenteacatechins[63],andECG(approximately13.6%oftotalgreenteacatechins)[9](Figure2).Thecatechinsmainlycomprisecatechin,EC,ECG,EGC,andEGCG[9,10].Monomericcatechinscanfurtherreactandsynthesizethecondensedcatechinswhichareproducedbyrandompolymerization[10,44,64].Then,thechemicalstructuresoftheresultingdimericcondensedcatechinsaredefinedbynotonlythemonomericcatechins,butalsothepathwayoflinkamongmonomers[44].Forexample,themostcommonoligomersderivedfromEC(i.e.,procyanidins)areclassifiedintoA-typeandB-type,dependingontheplant,respectively,andgenerallypresentinpeanutsandcoca(Theobromacacao).Chemically,inA-typedimers,themonomersarelinkedbybotha4→8carbon–carbonanda2→O7etherbond,andthemonomersoftheB-typedimersarelinkedthrough4→8carbon–carbonbonds[10].Theisomerization,thearrangementofgroupsadheredtothearomaticring,monomerbondingstyles,andlevelsallhaveanimportantimpactonthebiochemicalfunction.Moreover,catechinswilldecomposeorproducesecondarycompounds,liketheformationofglucuronide,sulfate,andmethylmetabolites,acetylateconjugatesandquinonetypemetabolites,andevenmicrobialmetabolitesincludingphenolicacidsandtheirglycineconjugatesetc.[10,39,40,65–67].Theproductionofcondensationreactionsofcatechins,ortheirderivatives,willhaveaneffectontheirbiologicaleffects[40].Forexample,theintracellularEGCG-3󰀅󰀅-glucuronidecanbedecreasedbypiperine,resultinginhigherfreeEGCG[40].Thus,maintainingthestabilityofthechemicalstructureisessentialtothebiochemicalfunctionsofcatechins. unctions of catechins. (a) catechin Figure2.Cont.(b) EC Molecules2017,22,4846of 29 (c) ECG (d ) EGC (e) GC (f) EGCG (g) GCG theirmetabolites,are(mainly)formedintheacidicenvironmentofthestomach,enterohepaticrecirculation,themucosaofthesmallintestine,andthemicrobialmetabolitesinthecolon[35,66]1.2.2. The Bioavailability of Catechins (Figure3).Allcatechinsmayundergothreetypesofmetabolicpathways:methylation,glucuronidation,Catechins can be absorbed by the gastrointestinal tract (GIT), as catechins themselves, and their metabolites, are (mainly) formed in the acidic environment of the stomach, enterohepatic Figure 2. The chemical structures of major kinds of catechins. (a)) catechin: (2R,3,3SS)-(+)-catechin; Figure2.Thechemicalstructuresofmajorkindsofcatechins.(acatechin:(2R)-(+)-catechin;(2S)-2-(3,4-dihydroxyphenyl)-3,4-dihydro-2H-chromene-3,5,7-triol; (b) EC: (2RR,3,3S)-2-(3,4-dihydroxyphenyl)-3,4-dihydro-2H-chromene-3,5,7-triol;(b)EC:(2R,3S)-(–)-epicatechin;(2R,3S)-(–)-epicatechin; 2-(3,4-Dihydroxyphenyl)-3,4-dihydro-2c) 2-(3,4-Dihydroxyphenyl)-3,4-dihydro-2H-1-benzopyran-3,5,7-triol;(Hc)-1-benzopyran-3,5,7-triol; (ECG:(2R,3R)-(–)-epicatechinECG: (2R,3R)-(–)-epicatechin gallate; gallate;(2R,3R)-2-(3,4-dihydroxyphenyl)-3,4-dihydro-1(2H)-benzopyran-3,5,7-triol3-(3,4,5-(2R,3R)-2-(3,4-dihydroxyphenyl)-3,4-dihydro-1(2H)-benzopyran-3,5,7-triol trihydroxybenzoate);(d)EGC:(2R,3R)-(–)-epigallocatechin;(2R,3R)-2-(3,4,5-trihydroxyphenyl)-3,4-3-(3,4,5-trihydroxybenzoate); (d) EGC: (2R,3R)-(–)-epigallocatechin; dihydro-1(2H)-benzopyran-3,5,7-triol;(e)GC:(2S,3R-(–)-gallocatechin;(2S,3R)-2-(3,4,5-trihydroxyphenyl)-(2R,3R)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-1(2HR)-benzopyran-3,5,7-triol; (e) GC: 3,4-dihydro-1(2H)-benzopyran-3,5,7-triol;(f)EGCG:(2R,3)-(–)-epigallocatechingallate;(2R,3R)-2-(3,4,5-(2S,3R-(–)-gallocatechin; trihydroxyphenyl)-3,4-dihydro-1(2H)-benzopyran-3,5,7-triol3-(3,4,5-trihydroxybenzoate);(g)GCG:(2S,3R)-(2S,3R)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-1(2H)-benzopyran-3,5,7-triol; (f) EGCG: (–)-gallocatechingallate;(2S,3R)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-1(2H)-benzopyran-3,5,7-triol(2R,3R)-(–)-epigallocatechin gallate; 3-(3,4,5-trihydroxybenzoate).(2R,3R)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-1(2H)-benzopyran-3,5,7-triol 3-(3,4,5-trihydroxybenzoate); (1.2.2.TheBioavailabilityofCatechinsg) GCG: (2S,3R)-(–)-gallocatechin gallate; (2S,3R)-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-1(2H)-benzopyran-3,5,7-triol Catechinscanbeabsorbedbythegastrointestinaltract(GIT),ascatechinsthemselves,and3-(3,4,5-trihydroxybenzoate). Molecules2017,22,4847of29andsulfationintheliverandintestinaltissuesinhumans[67],like(epi)catechintransferingintoplasmaitself,orthecorrespondingglucuronide,sulfate,andmethylatedmetabolitesproducedbyuridine-5󰀅-diphosphateglucuronytransferase,sulfotransferase,andcate-chol-O-methyltransferaseenzymes[66].Stalmachetal.haverevealedthatsomeflavan-3-olmonomersareabsorbedintheupperpartoftheGITinahumanstudy[68].Then,mostoftheingestedflavan-3-olsandtheirmetabolites,formedintheupperGITandtransportedbackintotheintestinallumen,willreachthelargeintestine.Onthedeglucosidationfunctionofmammalianβ-hydrolaseslikelactase-phlorizinhydrolase(LPH)intheintestinalepithelialcells,andsomehydrolasesfromtheintestinalmicrofloralikeglucuronidase,catechins,andtypesofflavonoids,willfinallyformthecorrespondingaglycones,thenbeabsorbedintohumancirculationandundergofurthertransformationandmetabolism,whichisbelievedtobethefirstandimportantstepintheabsorptionofflavonoids[69,70].Underthefunctionofgutmicrobiota,theywillalsoturnintophenolicacidsandlactonederivatives,whichwillbeabsorbedorpassinthefeces[65].Themicrobialmetabolitesandtheirhepaticconjugatesaredistributedtotissuesandareexcretedbyurine[71].Investigationsinhumanshaveunderlinedthatmoreoftheflavan-3-olmetaboliteswerederivedfromgutflora-associatedcatabolitescomingfromthecolonratherthanfromtheupperGITinthebody[66].Asshowninahumanstudy,colonicflora-derivedflavan-3-olcatabolites(polyhydroxyphenyl-γ-valerolactones)werethemainsubstanceinurine,withhigherconcentrationsthanflavan-3-olconjugates[72]. Intheplasmafollowingtheadministrationofdecaffeinatedgreentea(DGT)orpurecatechins,morethan80%ofgreenteacatechinswerefoundtoexistintheirconjugateforms[67].Similarly,EGCwasmostlyintheglucuronideform(57%–71%),thesulfateform(23%–36%),andthefreeform(3%–13%).Afteroraladministration,theurinaryexcretionlevelsoffourcatechins:(+)-catechin,ECG,EGC,andEGCG,rangedfrom0%to9.8%,exceptfor(+)-catechinwith23.6%–28.2%inhumanvolunteers[67].Urinaryexcretionofmetabolitesduringa24hperiodaftergreenteaconsumptioncorrespondedto28.5%oftheingested(epi)catechinand11.4%of(epi)gallocatechin.Humanstudyhasrevealedthatafterabsorptioninthesmallintestine,thepeakplasmaconcentrations(nmol/L)of(epi)catechinand(epi)gallocatechinglucuronideandtheirconjugatedmetaboliteswouldbereached,varyingfrom1.6to2.3h[66].Then,theplasmaconcentrationrapidlydecreasesduetotheshortapparenthalf-life,whilefewdietarycatechinsandrelatedphenoliccompoundsarenotchanged,exceptforECGandEGCGinplasma[66]. Thebioavailabilityofcatechinsmaybeinfluencedbyflavan-3-olstereochemistry,enterohepaticrecirculation,andtheimpactofdoseandotherfoodcomponentsonit[35,40,66,67,71].Ottavianietal.investigatedinhumanstheadministrationofequalquantitiesof(–)-EC,(–)-catechin,(+)-EC,and(+)-catechin.Thebioavailabilityofthesestereoisomerswererankedas(–)-EC>(+)-EC=(+)-catechin>(–)-catechinonthebasisofplasmaconcentrationsandurinaryexcretionoftheaglycones[73].Studiesdemonstratedthatenterohepaticrecyclingcouldimprovethebioavailabilityofpolyphenols.Hepaticmetaboliteswillbeexcretedinthebileandenterthesmallintestine[74],thenaftertheenzymes,likeglucuronidase,comingfromgutmicrobes,theformedaglyconesofcatechinscanbereabsorbedagain[35].Thebioavailabilitycanbeinfluencedbythedoseofcatechins.Inileostomists,0–24hurinaryexcretionofthe(epi)gallocatechinmetabolitesdidnotincreasesignificantlywithintakesof22µmol,55µmol,and165µmol.However,urinaryexcretionincreasedsignificantlyto107µmoland262µmolfrom36µmol,whentheingestionof77µmol(epi)catechinsareincreasedtodosesof192µmoland577µmol[66].Whencombinedwithdifferentpolyphenols,catechinsmayshowverydifferentbioaccessibilities,too.Owingtotheexistenceofmaterial,suchassucroseandascorbicacidwhichcanmaintainstabilityandprotectfromdegradationinalkalineconditions,thebioaccessibilityofcatechinshasbeenup-regulated.Thismayexplainthat,inrats,chocolateincludinghighersucroselevelsenhancedtheplasmaconcentrationofcatechinsmetabolitesthanmilkanddarkchocolates[75].IthasbeenfoundthatECG,EGCG,andsomemetabolitesofEGCGcanstronglyinhibitthemethylationofEGC[67]. Molecules2017,22,4848of29 Aswecansee,afterGITapplication,catechinsshowalowabsorptionandbioavailability,leadingtoareductionoftheeffectonthetissues.However,mostofcatechinsandtheirmetabolitesreachhighconcentrationsintheGIT[3].Therefore,somesupposethatthepotentialbenefitfromcatechinswouldbemoreusefulforgastrointestinaldisease[2,40,55 ]. Figure 3. Supposed metabolism of green tea catechins in humans. Figure3.Supposedmetabolismofgreenteacatechinsinhumans. 2. Therapeutic Benefits of Catechins to IBD 2.TherapeuticBenefitsofCatechinstoIBD It has not yet been entirely made clear that the mechanisms by which catechins benefit Ithasnotyetbeenentirelymadeclearthatthemechanismsbywhichcatechinsbenefitinflammatory diseases, such as IBD, while human experiments demonstrating that catechins can inflammatorydiseases,suchasIBD,whilehumanexperimentsdemonstratingthatcatechinscanimprove IBD are still scarce so far. However, there is abundant evidence showing that catechins improveIBDarestillscarcesofar.However,thereisabundantevidenceshowingthatcatechinsmaymay work through a combination of oxidation inhibition, alteration of cellular signaling, and workthroughacombinationofoxidationinhibition,alterationofcellularsignaling,andregulationofregulation of intestinal flora [29,53,76]. intestinalflora[29,53,76]. 2.1. Effect of Catechins on Oxidative Stress 2.1.EffectofCatechinsonOxidativeStress The imbalance between the oxidative reactions and antioxidative defenses plays an Theimbalancebetweentheoxidativereactionsandantioxidativedefensesplaysanimportantroleimportant role in the pathogenesis of IBD [3,30,77]. IBD is considered as one of the major inthepathogenesisofIBD[3,30,77].IBDisconsideredasoneofthemajoroxyradical-overloaddiseases,oxyradical-overload diseases, with a cancer-prone phenotype [7]. Kruidenier et al. have also withacancer-pronephenotype[7].Kruidenieretal.havealsoshowntheexcessiveproductionofshown the excessive production of ROS and radical nitrogen metabolites can be observed in the ROSandradicalnitrogenmetabolitescanbeobservedinthegutofIBDpatients[78].Ingeneral,gut of IBD patients [78]. In general, oxidant species are referred to as ROS [10], including oxygen oxidantspeciesarereferredtoasROS[10],includingoxygenasasuperoxideanion(O2−),hydroxyl1O2) [36,40]. ROS as a superoxide anion (O2−), hydroxyl radical (OH·), and singlet oxygen (radical(OH·),andsingletoxygen(1O2)[36,40].ROSactivationisessentialinthenormalregulationofactivation is essential in the normal regulation of cell signaling [79,80]. When different ROS cellsignaling[79,80].WhendifferentROSoverwhelmtheantioxidantdefensesoftissue,theylikelyoverwhelm the antioxidant defenses of tissue, they likely contribute to the functional disruption contributetothefunctionaldisruptionoftheintestinalmucosa[3],bycausingdamagetocellularof the intestinal mucosa [3], by causing damage to cellular lipids, proteins, cytoskeleton, even lipids,proteins,cytoskeleton,evenDNA,andultimatelyincreasethegutpermeability,thendestroyDNA, and ultimately increase the gut permeability, then destroy the gastrointestinal barrier thegastrointestinalbarrierintegrity[40].Furthermore,theimbalancecanstimulateaninflammatoryintegrity [40]. Furthermore, the imbalance can stimulate an inflammatory cascade by enhancing cascadebyenhancingtheexpressionofsignalingpathways,suchasnuclearfactor-kappaB(NF-κB)the expression of signaling pathways, such as nuclear factor-kappa B (NF-κB) and andmitogen-activatedproteinkinases(MAPKs),enlargingtheinflammatoryevents,evencolonmitogen-activated protein kinases (MAPKs), enlarging the inflammatory events, even colon cancers,inaccordancewiththenotionofBrückneretal.[3,29,40].cancers, in accordance with the notion of Brückner et al. [3,29,40]. Najafzadehetal.havealsoprovedthatinvitrolymphocytesfromIBDpatients,whentreatedbyEC,showedaprotectiveeffectagainstoxidativestressinducedby2-amino-3-methylimidazo Molecules2017,22,4849of29 [4,5-f]-quinolone(IQ),reliablyprotectingcellsfromthedamagingeffectsofROSinIBDwherelevelsofROSarehighlyincreased[81].Renatoetalhaveshownthat(+)-catechinhastheantioxidantcapacityinadose-dependentwaybetween0and100µM[82].ThestudyofantioxidanteffectsofcatechinshasshownthatEGCG,ECG,andperacetylated(–)-epigallocatechin-3-gallate(AcEGCG)cansignificantlylowertheROSlevelsinducedbyLPSinRAW264.7cells[58].IthasalsobeenproposedthatthehighdosesofEGCGcanproduceROStobeaprooxidant,inducingtheactivationofthetranscriptionfactornuclearfactor(erythroid-derived2)-like2(Nrf2)pathway[58]. Asantioxidativeagents,catechinspossessboth“directantioxidanteffects”and“indirectantioxidanteffects”.Thecatechinscanscavengefreeradicalsandchelateredox-activemetals,makingthemdirectantioxidants.Atthesametime,asindirectantioxidants,catechinsregulateproteinsynthesisactivitiesandsignalingstrategies,suchasmediatingthepropertyofprooxidantenzymes.Bothcapacitiesaredependentonconcentrations,respectively,inhighorlowdose,inwhichthehighdosecandemonstratemoreadequateantioxidantcapacityinthedigestivetract[10,44,62]. Catechinscanexertdirectantioxidanteffectswithfreeradicalscavengingandredox-activemetalsequestrationinthedigestivetract(Figure4).CatechinshavedifferenttypesofdiastereoisomerslikeEC,ECG,EGC,andEGCG,buttheyallcomposeasimilarchemicalstructuretostabilizethefreeradicals,whicharerelatedtothephenolicgroups[43,44].Additionally,catechinsaresuccessfulinachievinghighconcentrationsinthedigestivetract[10].Catechins,askindsofpolyphenols,havethecommoncharacteristicoffreeradicalscavengersbecauseofthecommonchemicalstructureofphenolichydroxylgroupsinpolyphenols[44],inwhichcatechinhasshownthemostpowerfulcapacityoffreeingtheradicalscavenger[36].Astudytoassesstheeffectof(+)-catechinontheLPS-inducedmurineperitonealmacrophagessuggestedthat(+)-catechiniscapableofsignificantlyinhibitingtheintracellularROSbyremovingfreeradicalsandNOproduction,showingantioxidantability,confirmingthatpropertyagainsttheROSandreactivenitrogenspecies(RNS)activityinRAW264.7macrophagesorinvitro[29]. Asfreeradicalscavengers(Figure4),catechinsareabletoreactwithfreeradicalstodisruptfreeradicalchainreactions,likethecommonoxidativereactionoflipidoxidation.Theexactmechanismssharedbypolyphenolsare(i)catechinscandonateaone-electronofphenolicOHgroupstoreducefreeradicals(forexample:LOO·+EC=LOOH+EC·)[44];(ii)thearomaticgroupcanmaintainstabilitythroughtheresonanceoftheresultantaroxylradicals[83].Forexample,thefreeradical(LOO·)withahigherE◦’willgettheelectronofthecatechinswithalowerE◦’,resultinginbreakingthefreeradicalchainreaction(e.g.,LOO·+POH=LOOH+PO·).ThepotencyoftheparentpolyphenoltodisruptthefreeradicalchainreactionisdependentonthestabilityoftheproducedPO·.ThemorestablethePO·is,thegreaterpotencytheparentpolyphenolhas[44].Inaddition,thereisnoconvincingexperimenttocomparethereducibilitybetweencatechinsthatshowextensiveantioxidantactivityinvitroandGSH,whichbelongstoanendogenousantioxidantsystemand,generally,isinbothreduced(GSH)andoxidized(GSSG)forms.Whereas,whenpretreatedwithAβ,theGSHcontentisreduced,butafteradditionofEGCG,thecontentofGSHwillberestoredagaininBV2cells[84],indicatingthatthereductionofEGCGisgreaterthanthatofGSH.However,generally,catechinsincreasetheactivityofGSHbyformingtypesofcomplexeswithgreaterreductionintheBring.However,itisneededtocomparethereducibilitybetweencatechinsandGSHbyusingfurthermorepreciseandspecificexperiments,likeapplyingchromogeniccompoundstoassesstheabilityoftheantioxidanttotrapfreeradicals[82].Asanothermechanismofdirectantioxidanteffectofhighdosesofcatechins,catechinshavethecommonstructuretochelateredox-activemetals(Figure4).Byreactingwith(freeorpoorlyliganded)Fe2+intheFentonreaction,hydrogenperoxide(H2O2)canproduceFe3+,andbyreactingwithFe3+intheHaber–Weissreaction,superoxideproducesFe2+,therebyresultinginredoxcycling.Whenoccurringinpathologicalchanges,theimbalanceofironandROSlikeover-productionofROSmayfreeironfromchelators,likeferritin,producingmoreROS[85,86].Asatypeofflavonoids,catechinscanbindiron,likeinflavonoid-metalchelation,whichoccurspreferentiallyatthe3-hydroxyl-4-carbonylgroup,firstly,thenthe4-carbonyl-5-hydroxyl Molecules2017,22,48410of29group,andthe3󰀅-4󰀅hydroxyl(ifpresent)[87],thusinhibitingtheactivityofredox-sensitivemetalanddecreasingtheproductionreactionoffreeradicals[44].Finally,thebasicformofthiskindofantioxidanteffectdependsontheE◦’ofeachpolyphenol-metalcomplex.Forbeinganantioxidant,thepolyphenol-metalcomplexshouldhavealowerpowerinradicalformation,ascomparedwiththephysiologicalmetal-complexes[44 ]. Figure 4. Catechins can exert direct antioxidant effects by reacting with free radicals to disrupt Figure4.Catechinscanexertdirectantioxidanteffectsbyreactingwithfreeradicalstodisruptthefree the free radical chain reaction and chelating redox-active metals. radicalchainreactionandchelatingredox-activemetals. Catechins in low concentrations have indirect antioxidant capability for inhibiting the Catechinsinlowconcentrationshaveindirectantioxidantcapabilityforinhibitingthemodulationmodulation of enzymes that generate oxidants, like NADPH-oxidase (NOX), and change the ofenzymesthatgenerateoxidants,likeNADPH-oxidase(NOX),andchangetheoxidantproductionoxidant production by inhibiting the combination of ligands with receptors, such as TNF-α to byinhibitingthecombinationofligandswithreceptors,suchasTNF-αtoTNF-αR,ingutcells[10].TNF-αR, in gut cells [10]. Biasi et al. have shown that EGCG could inhibit NOX and the Biasietal.haveshownthatEGCGcouldinhibitNOXandthefollowingenhancedROS[3].Ithasfollowing enhanced ROS [3]. It has been proposed that EC and its metabolites could inhibit beenproposedthatECanditsmetabolitescouldinhibitNOX,resultinginthedecreaseofsuperoxideNOX, resulting in the decrease of superoxide production. One of EC metabolites, O-metabolite, production.OneofECmetabolites,O-metabolite,hasasimilarstructuretoapocynin,aclassicalNOXhas a similar structure to apocynin, a classical NOX inhibitor [10,44]. EC may inhibit NOX by the inhibitor[10,44].ECmayinhibitNOXbythefollowmethod:(i)ECwillcombinewithNOXdirectly;follow method: (i) EC will combine with NOX directly; (ii) EC will change the calcium influx, (ii)ECwillchangethecalciuminflux,theninhibittheactivationofNOX;and(iii)ECcanregulatethethen inhibit the activation of NOX; and (iii) EC can regulate the upstream signaling of NOX, for upstreamsignalingofNOX,forexample,byblockingthecombinationofligandswithreceptorswhichexample, by blocking the combination of ligands with receptors which can promote NOX [10]. canpromoteNOX[10]. 2.2. Effect of Catechins on GSH and Enzymatic Antioxidants 2.2.EffectofCatechinsonGSHandEnzymaticAntioxidants Synthetized by mucosal cells, GSH is an antioxidant acting as a cellular defense component. Synthetizedbymucosalcells,GSHisanantioxidantactingasacellulardefensecomponent.ItcanIt can scavenge free radicals and peroxides [82], and maintain the function of protein sulfhydryl scavengefreeradicalsandperoxides[82],andmaintainthefunctionofproteinsulfhydrylgroupsgroups facing oxidative stress [30]. The presence of a catechol group in the B ring is essential for facingoxidativestress[30].ThepresenceofacatecholgroupintheBringisessentialforcatechinstocatechins to show synergistic effects with GSH in an antioxidant capacity [82]. showsynergisticeffectswithGSHinanantioxidantcapacity[82]. Theoverproductionofreactiveoxygennitrogenspecies(RONS)depletesintracellularGSH.ThedecreasecanstimulatetheNrf2signalingactivationtoinducetheenhancementofHO-1andGSH,itself,forthemaintenanceofhomeostasis.However,whenthedamagefromRONSoverwhelmsthe Molecules2017,22,48411of29benefitfromtheactivatedantioxidant,diseasesareinduced[58].Byusingflowcytometry,Chiouetal.demonstratedthatthecatechinanalogs(ECG,EGCG,AcEGCG)couldelevatetheamountofGSHinLPS-inducedRAW264.7cells,butnotinadose-dependentmanner[58].However,theyfoundthatthelowdoseofcatechinshadahighlypotentabilitycomparedtothehighdose.TheresearchersproposedthatperhapsthelowdoseofcatechinscouldinducetheexpressionofNrf2-relatedGSH-relatedenzymes,likeGPO,resultinginregulatingGSHexpression.AnotherexperimentprovedthatECat10mg/kgcouldinduceahigherdoseofGSHbothinacuteandchroniccolitis,withrelapseinratmodels.TheresearchersinferredthatthehighlevelsofGSHwerecausedbytheincreaseofexpressionand/orthedecreaseofdepletioninducedbyEC[30]. Ontheotherhand,inresponsetothebenignoxidativestress,thedefensemechanismswillbecarriedoutwithanincreaseinenzymaticantioxidantsandotherlowmolecularweightantioxidants[40].Whenthebodyisexposedtotheoxidativestresscomingfromtheover-productionofROSforalongtime,thedefensemechanismscannotinduceenoughproductionofantioxidantenzymes,suchascatalase(anH2O2-specificcatalyst),GPO,whichcancatalysethereductionofperoxidesandactasabarrieragainsthydroperoxideattack[55],andsuperoxidedismutases(SOD)[88],whichareessentialasthesturdyantioxidantdefensesystembycatalysingperoxyanions.IthasbeendemonstratedthatthismaybetheresultfromtheROSwhichcaninactivateonetoseveralantioxidantenzymes[40].Additonally,ithasbeennoticedthatthedeficiencyofGPOgenescancontributetotheoccurrenceofIBDinmice[89]. Catechinshavebeenshowntoenhancetheactivityofanumberofprotectiveenzymes,resultinginaprotectiveeffect[55].TheeffectofEGCGintragastricallyadministeredforcolitishasbeenevaluatedinthemurinemodelinducedbyoraladministrationofDSS.Brückneretal.haverevealedthatthecombinationofEGCGandpiperine,whichwasusedtoraisethebioavailabilityofEGCG,showapositiveantioxidativepotentialconsecutivelyontheantioxidantenzymesGPOandSODinimmunohistochemicalanalysis,confirmingthenotionwithonlyEGCG[40].TheactivitiesofcatalasecanalsobeincreasedbyEGCG,ECthroughdecreasingROS,malonedialdehyde(MDA),andproteincarbonyls[61,84],buttheexactmechanismsofEGCGonantioxidantenzymesarestillunknown[40].InhumanHepG2cellstreatedwithacocoapolyphenolicextract,whichcontainedEC,ECG,procyanidinB2andotherflavanols,researchersreportedthattheactivitiesofGPOandglutathionereductase(GR),whichcanrecycleoxidizedglutathionebacktoreducedglutathione,wouldbeenhanced[90]. 2.3.EffectofCatechinsonCellInfiltration ThemainprotagonistsinIBDincludeneutrophils,lymphocytes,monocytes,andmacrophages.Themigrationandactivationofthemintotheinflamedtissuedependonthecytokines,chemokines,andadhesionmolecules[18].Thecytokinesandchemokinesareextracellularsignalingmoleculeswhichmediatecell–cellcommunication.Theycanmediatecellproliferation,differentiation,geneexpression,migration,immunity,andinflammation.TheinflammatoryprocessofIBDincludesalargeamountofinfiltrationofTcells,polymorpho-andmononuclearphagocyticleukocytes,whichwillpromotelocalinflammationandoxidativestressandextendthedamagetothemucosathroughproductionofabundantamountsofpro-inflammatorycytokines,chemokines,andreactiveoxygenintermediates[3,8,18,40,81],whichmayfurtherpromotecellinfiltrationtoenlargeinflammationinaloop[7].Mochizukietal.showedthatthemigrationofneutrophilsdependedoncytokinessecretedbymacrophagesandmastcells[8].Theyalsodemonstratedthatincreasedlevelsofnewly-recruitedmonocyteswouldgathertotheinflamedintestinalmucosafromthebloodandderiveintomacrophagesanddendriticcells,insteadofsuccumbingtoapoptosisaftercirculationinthebloodforseveraldayswithoutspecificsignals[8,29,63].Inaddition,someresearchersfoundthatEGCGhadaninhibitoryeffectonendothelialVACM-1,resultinginadecreaseofmonocyteadhesiontoendothelialcellsandmovementintotheinflamedtissue.ItwasshownthattreatmentwithEGCGinTHP-1decreasedgene Molecules2017,22,48412of29andproteinexpressionofthemonocytechemotacticprotein1(MCP-1)andoftheMCP-1receptor(CCR2),inhibitingexcessiveTHP-1migrationtothedamagedtissue[9]. Thequantitiesofneutrophilinfiltrationcouldbeindicatedbytheactivationofmyeloperoxidase(MPO),alysosomalperoxidaseenzymeexistingmostabundantlyinneutrophilgranulocytes[40].However,itwaspreviouslyreportedthatEGCGcouldreduceMPOactivity,indicatingthereductionofneutrophilinfiltration[91]. Inastudytoevaluatetheanti-inflammatoryandantioxidativeeffectsofEGCGonaDSS-inducedmurinecolitismodelbyintragastricapplication,whichcorrespondedtoapplicableformsforhumans,theMPOwastestedtoassesstheleukocyteinfiltration.ItwasobservedthattheMPOwasreducedinpiperineplusEGCGincolontissue.Thepiperinecouldnotinhibittheneutrophilinfiltrationalone.However,theEGCGpurelyfailedtoeliminatetheMPO[40],maybeowingtothelowbioavailability.InanotherexperimentregardingtheeffectofEConTNBS-inducedcolitisratmodels,ECcouldnotdecreasetheneutrophilinfiltrationthroughanychangeintheenzymeMPO.IthasbeenimplicatedbythesubjectsthattheinabilitymaybeduetothesustainedandextensivedamageresultingfromsohighaconcentrationofMPOthatitisdifficulttotakeeffectwithanytreatment[30]. ThestudyintheTNBS-inducedratcolitisbyMochizukiandHasegawashowedthatEGCGcouldsignificantlydecreasetheenzymeMPOandhistamineinthedistalgutmucosa[8].ItisimportantthatEGCGcansuppressthemacrophagemigration,causingtheinhibitionofneutrophilmigration.Theexperimentexhibitedtheincreasingmastcellsandthehighconcentrationofhistamine,bothofwhichcouldbefoundinthemucosaofIBD,andwerealsoamelioratedbyEGCGinadose-dependentmanner.Thus,theneutrophilinfiltrationcouldbeinhibitedbyEGCG,owingtohistaminebeingakindofchemoattractantofneutrophils[8,9]. 2.4.EffectofCatechinsonCellProliferationandApoptosis Afterbeingstimulatedbyvariousfactors,suchascytokines,bacterialcomponents,andROS,Tcellswillproliferateanddifferentiateintokindsofsubsets,likeTh1cells,Th2cells,Th17cells,andTregcells,respectively,exhibitingdistincteffectstoregulatetheprogressofinflammationinIBD[14,16,92].Themonocyteswhichcantransformtomacrophagesanddendriticcellsplayanimportantroleintheinflamedtissueasthemaineffectorcellsintheinitiation,development,andresultoftheimmune-relatedresponse[29,63].Activatedmacrophagesplayimportantrolesininflammatorydiseasesviaexcessiveproductionofinflammatorymediators,suchasnitricoxide(NO),andpro-inflammatorycytokines,promotinginflammatoryresponses[29].Andtheanti-inflammatorycytokines,suchasIL-4andIL-10,willpromotethemonocytestowardapoptosis. AbundantevidenceshowsthatcatechinscouldbenefittheinflamedmucosaofIBDbydecreasingtheexcessivenumbersofharmfulcells,suchasmonocytes,andbyrecoveringthephysicalbarrier,suchasepithelia,tobalancethehomeostasisbetweencellproliferationandcelldeath[30]. AstudyconductedbyWuetal.assessedtheeffectofEGCGonCD4+Tcells[93].WiththeadministrationofEGCGandIFN-γinCD4+Tcells(i.e.,primaryCD4+TcellsfromC57Bl/6miceandahumanleukemicCD4+TcelllineofHut78cells)andnon-CD4+Tcells(i.e.,HepG2cells),thestudyindicatedthatEGCGalternativelyenhancedthesignaltransducerandactivatoroftranscription(STAT)1phosphorylation,butinhibitedtheSTAT1homodimerformationviatheSrcpathway,butnottheJanuskinase(JAK)1/2pathway,ultimatelypromotingtheapoptosisofIFN-γ-inducedCD4+TcellsandbenefitingtheTcell-relatedcolitis[93].TheresearchofKawaietal.revealedthatEGCGspecificallyinducedtheapoptosisofmonocytes[63],administeringperipheralbloodextractionofmononuclearcellswithcatechinsasthecontrolgroup.Additionally,EGCGandECGcouldsignificantlypromotetheapoptosisofmononuclearcells;however,ECandEGCdidnot.Theimportantagent,whichissupposedtobeessentialinapoptosis,isthecommonstructureofthegalloylgroupinEGCGandECG,butnotthepyrogallolgroup,whichispresentinEGCandEGCGbutnotinECandECG[63].Itsinhibitiontomononuclearcells,unliketheglucocorticoid,thefunctionofcatechinsisnotaffectedbygranulocyte-macrophagecolonystimulatingfactor(GM-CSF)andLPS.Kawaietal.alsofoundthatCD4+ Molecules2017,22,48413of29EGCGwouldenhancethecomponentofcaspases3,8,and9contentinadose-dependentmanner,whichinvolvedtwomajorpathwaysofapoptosis—thedeathreceptorpathwayandthemitochondrialpathwaytopromotemonocytestodie[63]. Epithelialcellsbelongtotheinnatephysicalbarrierspreventingtheattachmentofantigens.Afterbeingstimulated,epithelialcellscanpresentantigensandsecreteanabundanceofcytokinestomaintainthebalancebetweenpro-inflammatoryandanti-inflammatoryevents.DefectsinthemucosalbarriercontributetothepathogenesisofIBD[3].Oligonol,aformulationconsistingof17.6%ofcatechin-typemonomersand18.6%ofproanthocyanidindimersandtrimers,wasprovedtopreventoxidativestress-inducedapoptosisofcolonicepithelialcells[7].InastudytoassesstheeffectofEConthepreventionandtreatmentofintenseinflammationinacuteandchronicmodelsofcolitisinducedbyTNBS,theratswerefedwithdifferentdosesofEC.TheresearchersfoundthattherewasasignificantincreaseofProliferatingCellNuclearAntigen(PA)andEpidermalGrowthFactor(EGF)inthechronicandacutecolitismodelwhichwasadministratedwithadoseof10mg/kgEC(EC10).ThePArepresentthecellswhichareintheSphaseofthecellcycle.WhiletheEGFcanstimulateepithelialcellstoproliferate,thestudyindicatedthatECcouldinducetheproliferationofepithelialcells,torecovertheintestinalmucosaofcolitis,andreducetherelapselesion.However,whentheyincreasedtheconcentrationoftheEC,theeffectofEC10woulddisappearforthepro-inflammatoryfunctionofEC[30]. 2.5.EffectofCatechinsonGapJunctions Gapjunctions,themembranechannelspermittingthedirectexchangeofsmallwater-solublemoleculesbetweenadjacently-coupledcells,areimportantincellulargrowthcontrol,differentiation,andapoptosis[42,80,94,95].Whenthegapjunctionalintercellularcommunication(GJIC)amongeachcellisdown-regulated,thepropertiestodevelopintomalignantlesionsareincreased[94,96]. CatechinshaveshownprotectivefunctionstotheGJICwhichcanbedown-regulatedbyvariousstimuli,suchasinflammatorymediators,cytokines,andoxidativestressinvariouskindsofcells[97].GTPhavetheabilitytopreventthedown-regulationofGJICinpentachlorophenol-inducedmousehepatocarcinogenesis[97].ECexhibitedpositiveeffectsonGJICinWB-F344cellstreatedwith12-O-tetradecanoylphorbol-13-acetate(TPA),whichhasinhibitoryeffectsonGJICbyphosphorylationofthegapjunctionproteinconnexin43(CX43)[98].ECGcouldalsoenhanceGJICinp,p󰀅-dichlorodiphenyltrichloroethane(DDT)-treatedWB-F344cellsindose-relatedways[99].Hydrogenperoxide-inducedinhibitionofGJICwasalsoblockedbytreatmentwithEGCGinliverepithelialcelllines[100],contrarytotheviewofLeeetal.,whichbroughtforwardthatEGCGcouldinhibitGJICandinducephosphorylationofCx43[42].Additionally,EGCGwasshowntoactivateERK-MAPK,resultinginthedown-regulationofCX43andGJICinendothelialcells[101].Furthermore,EGCGcouldgreatlyimprovetheGJIC-inhibitoryeffectsofdimethylnitrosamineinkidneycells[101]. MostinvestigatorsbelievethatcatechinshaveaprotectiveeffectonGJIC.Recentstudiesabouttherolesofcatechinsingapjunctionshavemainlyfocusedoncardiomyocytes[102],vascularendothelialcellstopreventcardiovasculardiseases,lungcells,livercells[42],andkidneycells[101]etc.,abouttheiranti-cancereffect,withlessemphasisinintestinaltumorsandevenIBD.However,studiesalsoshowedthatcatechinsatleastpreventedintestinaldamage.IthasbeenproposedECwasshowntoup-regulateGJICbetweenepithelialcells,helpingpreventtheprogressionofgastrointestinallesionsfromworseningintocancer[30]. 2.6.EffectofCatechinsonCellSignalingPathways 2.6.1.EffectofCatechinsonNF-κB AbundantevidenceisavailabletosupportthenotionthattheactivationandnucleartranslocationofNF-κBplayanimportantroleinthepathogenisisanddevelopmentofIBD[3,14,91].Underthephysiologicalcondition,theNF-κBmemberp65/p50heterodimerremainsaninactiveforminthe Molecules2017,22,48414of29cytoplasmwhereitformsacomplexbybondingtoinhibitors,likeIκBα[3].Uponactivationbydistinctpro-inflammatorystimuli,theNF-κBbecomesfreethroughthephosphorylationanddegradationofIκBαbyIκBkinase(IKK),thentranslocatestothenucleusandinducestranscriptionofawiderangeofgenes[3,7,10,18,29,103]indifferenttypesofcells,suchasmacrophagesanddendriticcells(Figure5).Someofthesegenesencodeforseveralkindsofcytokines,likeTNF-α,chemokines,likeIL-8,pro-inflammatoryenzymes,likecyclooxygenase-2(COX-2)andinduciblenitricoxidesynthase(iNOS),celladhesionmolecules,andgrowthfactors[14,104].TheproteinproductofthegenescanbeobservedathighlevelsinpatientswithIBD,too[14].Generally,NF-κBisusedtomaintainguthomeostasis.Itcanhelptheepithelialcellsandimmunecellstoresistthedamagefrompathogenicagents,buttheexcessiveactivationofNF-κBcanamplifytheintestinalinflammationthendamagethetissue[3].HighlevelsofNF-κBcouldbeobservedinthemucosalcellsofIBDpatients[18].Inaddition,oncetheNF-κBandrelatedmaterialwereinhibited,wefoundthattheprogressionofIBDwasalleviated[104,105 ]. Figure5. Catechins regulate the activation of NF-CatechinsregulatetheactivationofNF-κBatmultiplelevels.CatechinsdemonstratedirectFigure 5.κB at multiple levels. Catechins demonstrate inhibitoryeffectontheoxidantorinhibittheNF-κB-relatedupstreamNOX[10].Alsocatechinsdirect inhibitory effect on the oxidant or inhibit the NF-κB-related upstream NOX [10]. Also caninhibitNF-κBactivationthroughIKKinactivationbyseveralmechanismssuchasup-regulatingcatechins can inhibit NF-κB activation through IKK inactivation by several mechanisms such as SOCS1expression,whichcouldimpairinflammation.CatechinscaninhibittheactivationofNF-κBbyup-regulating SOCS1 expression, which could impair inflammation. Catechins can inhibit the regulatingtheupstreamproteinkinasesJNK1/2,p38,andPI3K/Aktetc.Insidethenucleus,catechinsactivation of NF-κB by regulating the upstream protein kinases JNK1/2, p38, and PI3K/Akt etc. caninteractwiththeDNA-bindingsiteintheNF-κBproteins,thuspreventinggeneInside the nucleus, catechins can interact with the DNA-binding site in the NF-κtranscription.B proteins, thus preventing gene transcription. AnincreasingnumberofstudiesdemonstratedthatcatechinscouldinteractwithNF-κBinAn increasing number of studies demonstrated that catechins could interact with NF-κB in multiplestepsintheactivationprocess(Figure5).Catechinscandisrupttheactivationandmultiple steps in the activation process (Figure 5). Catechins can disrupt the activation and translocationofNF-κB[14,106].EGCGcaninhibitIκBdegradationinadose-dependentmannertranslocation of NF-κB [14,106]. EGCG can inhibit IκB degradation in a dose-dependent manner byinhibitingAKTphosphorylation,anecessaryupstreamstep,andinhibitor-kkinaseactivationforNF-κBactivation[3,14].Inaddition,EGCGcanfinallyinducethedegradationofTLR-4co-factorMyD88adaptor-like(MAL)protein,whichlinksTLR-4signalingtoNF-κBactivation,byenhancingtheactivationofthesuppressorofcytokinesignaling1(SOCS1),whichdampensinflammatoryresponsesasakindofcompensatoryanti-inflammatorypathway[14](Figure5).Chiouetal.revealed,forthefirsttime,thatECGcouldsignificantlyinhibitthep-p65inthenucleus,whichrepresentedtheactivationofNF-κB,inLPS-inducedRAW264.7macrophagesbyinhibitingtheupstreamprotein Molecules2017,22,48415of29kinasesc-Junamino-terminalkinases(JNK)1/2,p38,andphosphatidylinositol3-kinase/proteinkinaseB(PI3K/Akt),oractivatingtheNrf2pathway[58].Inthepreviousstudy,asFragaetal.demonstrated,ECcouldinhibitNF-κBindistinctlevelsintheactivationpathways[10].ECcanactonboththecellmembraneandtheintracellulartargets.Forexample,ECcansuppresstheactivationofNF-κBbyinhibitingNOXandthesubsequentsuperoxideproductionthroughreactingdirectlywiththeenzymeorinhibitingthecombinationfromligandstoreceptors,likeTNF-αtotheirreceptors(Figure5),whichtriggersNOXactivity,andtheninducesNF-κB.Additionally,ECcandirectlyscavengefreeradicalsandoxidants,andenterthedownstreamofNOXtoreducetheactivationofNF-κB.EvenECcanprotectNF-κBtranscriptionfrominteractionofNF-κBwithDNA-bindingsitesinthegenepromoters[10](Figure5).ExperimentsshowedthatintheDSS-inducedmouse,theeffectofECand(+)-catechinonNF-κBactivationdidnotperformobviously,becausethecontentofnuclearNF-κBp65hadnosignificantchangeafterpolyphenol-enrichedcocoaextract(PCE)-treatment,extractedfromcocoa,includingECand(+)-catechin[105].Therefore,catechins,asubsetofpolyphenolsrichintea,cansignificantlysuppresstheinflammationofIBDbyinhibitingtheactivationofNF-κBthroughdifferentlevels(Figure5). 2.6.2.EffectofCatechinsonMAPKs IncreasingstudiesprovedthatMAPKpathwaysplayedanimportantroleinthepathogenesisprocessofIBD.TheinhibitionofMAPKactivationcanbeausefultreatmenttobenefitIBD[107].MAPKsconsistofaredox-sensitivefamilyofserine–threoninekinasesthatmediatefundamentalbiologicalprocessesandcellularresponsestoexternalstresssignals[29].MAPKscanberegulatedbytheMAPKkinasesandtheMAPKphosphatasesthroughphosphorylationanddephosphorylation,respectively,toactiveandinactivestates.TheMAPKs,knownasbeingabletoactivateNF-κB[28],containsthreegroups:extracellularsignal-regulatedkinase(ERK),JNK,andp38MAPkinases[53](Figure6).TheinactivationofMAPKphosphatasescanleadtopersistentactivationofJNKandp38,constitutingoneregulatorypointofwell-knownsensitivitytooxidativestress. ItwasestablishedthatMAPKscouldregulatetheexpressionofpro-inflammatorymediators[29].Uponvariousactivation,likeLPS,MAPKscouldbephosphorylatedandthenup-regulatetheexpressionofiNOSandCOX-2topromotetheinflammation[29].Thep38MAPKcanalsobedemonstratedtoenhancetheproductionofpro-inflammatorycytokines,thus,inturn,stimulatingthephosphorylationofp38MAPKandexpandingtheinflammation[28].Additionally,afterstimulatedbystress,growthfactors[108],activatedJNKcanpromotetheactivationanddifferentiationofTcellsandtheexpressionofpro-inflammatorycytokines[53].Thus,MAPK’sinhibitiononJNKcanprovideaneffectivetherapyagainstinflammation,suchasIBD[53]. ItwasprovedthatECcouldreducetheactiveMAPKsthroughreductionofoxidantconcentration[10].EGCGcanattenuatetheERKoftheMAPKpathwayinhumanmastcelllines(HMC-1)[40].InLPS-inducedperitonealmacrophages,itwasobservedthat(+)-catechinwouldinhibitthephosphorylationofMAPKs[29].InactivatedTHP-1humanmonocytecelllines,catechinsexertdifferentinhibitingabilitiesonMAPKpathwaysthroughregulatingp38,JNK,andtheirphosphorylatedforms,reducingoxidativestressandinhibitingawiderangeofpro-inflammatorygenes[29,109](Figure6).OtherstudiesinvivomodelsofUCshowedthat(+)-catechincouldinhibittheMAPKpathwaybydepressingJNKandp38activationand,thus,contributetotheremissionofUC[29].EGCGcouldinhibitthereceptoractivatorofNF-κBligand(RANKL)-inducedactivationoftheJNKpathway[110].EGCGalsoshowedaninhibitionofLPS-inducedphosphorylationofp38,JNK,andERK1/2(Figure6),inbonemarrow-derivedmacrophages[29].AllcouldshowthattheMAPKcascadepathwayinhibitionbycatechinscouldbecriticaltotheestablishmentofbothanti-inflammatoryandprotectiveeffects(Figure6). ThecatechineffectontheLPS-inducedinflammationinRAW264.7cellswasexaminedbyLiuetal.byusingtheextractofthelotusleaf[53].Theyinvestigatedtheanti-inflammatoryeffectofcatechinoniNOS,COX-2,andinflammatorycytokines,suchasIL-6andTNF-α.Furthermore,theyrevealedthat Molecules2017,22,48416of29thecatechincouldblockthephosphorylationofJNK,butnotERKandp38.Further,theyfoundthattheuseofthephospho-JNKinhibitor(SP600125)andcatechincouldbothinhibittheactivationofNF-κB.Thus,theresultsindicatedthatinflammationcouldbepreventedbycatechin,whichreactedastheMAPK-inhibitortoinhibittheLPS-inducedphospho-JNK,combiningwithdecreasingtheNF-κB[53].EGCGcouldattenuatetheERKoftheMAPKpathwayandNF-κB,thusinhibitingthesecretionofTNF-α,IL-6,andIL-8inHMC-1[40].AsimilarresultwasdescribedbyDanesietal.,wherethecross-talkbetweenMAPKsandNF-κBplayedanimportantroleintheinhibitionofTNF-αmRNAexpressionbyEGCGinTNF-αover-expressionduetoIL-23inkit225cells[111].Moonetal.alsoreportedthatEGCGcouldblockboththeMAPKsandNF-κBpathwaysinHT29cells[112].Thus,wecanconcludethatcatechinscanattenuatetheinflammationbyinhibitingthecascadeofMAPKsandNF-κB.Thus,catechinsmayactasatherapeuticagentforpreventinginflammation[53 ]. Figure 6. Catechins show an inhibition of the MAPK cascade pathway through the inhibition of Figure6.CatechinsshowaninhibitionoftheMAPKcascadepathwaythroughtheinhibitionofthe the phosphorylation of ERK1/2, JNK, and p38. phosphorylationofERK1/2,JNK,andp38. 2.6.3. Effect of Catechins on Nrf2 2.6.3.EffectofCatechinsonNrf2 Nrf2 activation seems to play a promising strategy in maintaining active antioxidant Nrf2activationseemstoplayapromisingstrategyinmaintainingactiveantioxidantpathwayspathways in response to oxidative stress-induced inflammation [10,58]. Numerous studies in inresponsetooxidativestress-inducedinflammation[10,58].Numerousstudiesinvivoshowedvivo showed that Nrf2-deficient mice exhibited increased DSS or AOM/DSS-mediated intestinal thatNrf2-deficientmiceexhibitedincreasedDSSorAOM/DSS-mediatedintestinalinflammationinflammation and ACF formation and tumors, as compared with Nrf2 wild-type mice [76]. Some andACFformationandtumors,ascomparedwithNrf2wild-typemice[76].Somecellandanimalcell and animal experiments supported the proposition that Nrf2 could be a novel epigenetic experimentssupportedthepropositionthatNrf2couldbeanovelepigenetictherapeuticinterventionusedtocontrolvariousformsofinflammatorydisorders,likeIBD,andeveninflammatory-drivencoloncancer[76]. Nrf2isatranscriptionfactorcentraltotheprotectionofcellsagainsttheadverseeffectsofoxidativeandelectrophilicstress[10,113].Usually,Nrf2remainsinaninactivestateinthecytosol,bindingtotheproteinkelch-likeECH-associatedprotein1(Keap1),formingacomplex[10].Afterstimulatedbyvariousoxidativestresses,likeROS,thiscomplexwouldbedisruptedtoformactiveNrf2,leadingNrf2totranslocatetothenucleusandbindtoantioxidantresponseelement(ARE)genes, Molecules2017,22,48417of29whichcanencodeproteinswithcytoprotectivefunctions,likeNADPHregeneratingenzymes[10,35](Figure7). VariousstudiesprovedthatactivationofNrf2couldup-regulateNAD(P)H,GSH,andHO-1expression,whichcouldsuppressoxidativestressandinflammatoryresponses[34,58,76].Previously,itwasrevealedthatcatechinshadasignificanteffectonneurologicdamage.Forexample,ECstimulatedtheNrf2signalingpathwayinprimaryculturesofastrocytes[114]. OtherstudieswithknockdownofNrf2mediatorsandtestingvariousrelatedagentsinLPS-activatedRAW264.7murinemacrophagesshowedthesimilarconclusion.ResearchersalsoproposedthatHO-1inductionwasregulatedbythecomplexcross-talkofMAPKs,NF-κB,andNrf2.TheresultsprovidednewevidencethatHO-1inductionwasinvolvedinERK1/2signal-mediatedcross-talkbetweenNF-κBandNrf2/AREtranscriptionalactivity,suggestingthatNF-κB-regulatedpro-inflammatorysignalingwasrelatedtoupstreamp38,JNK,andPI3k/Aktpathways,whichoccurredearlierthanNrf2/ARE-regulatedantioxidantsignalingunderLPS-stimulatedoxidativestressbyenhancingNF-κBanddisruptingthekeap1-Nrf2[58].ItwasalsoprovedthatECGmightinhibittheNF-κBbysuppressingtheLPS-inducedactivationofthep38,JNK,andPI3k/Aktpathways.Atthesametime,ECGcanenhancethephosphorylationofERK1/2,thenregulatetheactivationofNrf2,resultinginthesignificantincreaseofGSHandHO-1expression[58],protectingcellsfromoxidativestressandothertoxicagents[7](Figure7).Additionally,actingasthedirectKeap1-Nrf2interactioninhibitor,ECGisabetteroptiontoactivateNrf2forinflammatorydiseasethanROS,whichcancontributeseriousdamagetotissuebynotonlyenhancingtheHO-1expression[58](Figure7).Furthermore,thedecreaseofNF-κBisabenefittoNrf2expression.ThestudyalsopointedoutthattheERK1/2oftheMAPKpathwaymightplayadualroleinthemediationofNF-κBandNrf2signalingwithpro-inflammatoryandantioxidantgeneregulation[58].Therefore,catechinscancontributetoinhibitingtheinflammationandoxidativestressbyactingasapotentialNrf2activatortoimproveantioxidantagents,likeHO-1expressionandNF-κBrepressors(Figure7).ThestudysupportedtheideathatenhancingNrf2expressioncouldcontributetoapotentialtreatmenttopreventinflammationandoxidativedamageintheintestinalepitheliumduringIBD[76]. Increasingevidenceshowsthatthereisacross-talkbetweenNF-κB,MAPKs,andNrf2pathwaystoantioxidants[58,76].ItwasreportedthatNF-κBcoulddirectlyrepressNrf2signalingatthetranscriptionlevelbyenhancingtheconcentrationofco-repressorsorcompetingagainstNrf2forcoactivatorslikeCREBbindingprotein(CBP)[115,116],whichwasessentialfortranscriptionandlocalizationofNrf2[76].Nrf2couldattenuateNF-κBtranscriptionalactivityininflammatoryresponses[58].Catechinsmayinhibittheoxidativestressdamageandinflammationthroughthecross-talkbetweenthem.AstudyconductedbyChiouetal.evaluatedthechemopreventiveandmolecularmechanismofdietaryadministrationwithAcEGCG,whichactedasaprodrugofEGCGtoimprovethebiologicalactivityandbioavailabilityofEGCG,andEGCGinDSS-inducedcolitisinmice[76].TheresultsindicatedthatAcEGCGadministrationwasmoreeffectivethanEGCGinsuppressingDSS-inducedsymptomsofcolitisandcoloncancerassociatedcoloncolitis[76].TheresultsindicatedthatAcEGCGreducedp65phosphorylationandNF-κB-DNA-bindingactivity,butdidnotaffectCBPactivity.TheproteinlevelofNrf2wassignificantlyescalatedintheAcEGCG-treatedmucosadose-dependentlythanthecontrol,dependingonhistoneacetyltransferase(CBP/p300)activity,owingtotheNF-κBinactivationandERK(p44/42)MAPKphosphorylation.TheincreaseofNrf2resultedinenhancingantioxidantenzyme(HO-1)expression,whichcontributedtoantioxidant,anti-apoptotic,andanti-inflammatoryproperties[58]. Molecules2017,22,48418of 29 Figure 7.Figure7. Catechins can activate Nrf2 by enhancing the phosphorylation of ERK1/2, then regulate CatechinscanactivateNrf2byenhancingthephosphorylationofERK1/2,thenregulate the activation of Nrf2 by directly inhibiting Keap1-Nrf2 interaction or enhancing ERK1/2 theactivationofNrf2bydirectlyinhibitingKeap1-Nrf2interactionorenhancingERK1/2expression. expression. Catechins can regulate the Nrf2 by acting on NF-κB. CatechinscanregulatetheNrf2byactingonNF-κB. 2.6.4. Effect of Catechins on STAT1 and STAT3 2.6.4.EffectofCatechinsonSTAT1andSTAT3 It was noted that transcription factors—STAT1 and STAT3 were implicated in the Itwasnotedthattranscriptionfactors—STAT1andSTAT3wereimplicatedinthepathogenesisofpathogenesis of IBD [105]. In the neutrophils and monocytes of the intestinal lamina propria of IBD[105].IntheneutrophilsandmonocytesoftheintestinallaminapropriaofIBDpatients,itwasIBD patients, it was observed that there was an increased expression and activation of STAT1, observedthattherewasanincreasedexpressionandactivationofSTAT1,whichwasgreaterinUCwhich was greater in UC than in CD [105,117]. The STAT3 in IBD was proved to be important thaninCD[105,117].TheSTAT3inIBDwasprovedtobeimportantaccordingtoanimalandhumanaccording to animal and human IBD studies. It takes on a different role in the immune system, IBDstudies.Ittakesonadifferentroleintheimmunesystem,connectingwiththepathogenesisofconnecting with the pathogenesis of IBD [118]. After stimulation, the active STAT1 can form IBD[118].Afterstimulation,theactiveSTAT1canformhomodimers,whicharetranslatedintothehomodimers, which are translated into the nucleus and bind to gamma activated sequence (GAS) nucleusandbindtogammaactivatedsequence(GAS)toregulatetheexpressionofgenes[14,93].Afterto regulate the expression of genes [14,93]. After stimulation by cytokines, such as IL-6, TNF-α, stimulationbycytokines,suchasIL-6,TNF-α,andgrowthfactors,thetyrosineresidue705intheand growth factors, the tyrosine residue 705 in the C-terminal transactivation domain (TAD) can C-terminaltransactivationdomain(TAD)canbephosphorylated,formingtheactivateddimerizationbe phosphorylated, forming the activated dimerization of STAT3, and then the active ones will ofSTAT3,andthentheactiveoneswilltranslateintothenucleusandup-regulatevariousgenes,suchtranslate into the nucleus and up-regulate various genes, such as the pro-inflammatory enzymes asthepro-inflammatoryenzymesandmediators[7,14,118].and mediators [7,14,118]. EGCGcaninhibitJAK1/2,resultinginsuppressingtheactivationofSTAT1andSTAT3fromEGCG can inhibit JAK1/2, resulting in suppressing the activation of STAT1 and STAT3 from formingtheSTAT1–STAT1,STAT1–STAT3,andSTAT3–STAT3homodimers,respectivelyinducedforming the STAT1–STAT1, STAT1–STAT3, and STAT3–STAT3 homodimers, respectively byIFN-γ,IL-27,andIL-6[14].ItwasprovedthatEGCGinhibitedSTAT1activationinmanycellinduced by IFN-γ, IL-27, and IL-6 [14]. It was proved that EGCG inhibited STAT1 activation in lineslikeHePG2cells.Forexample,EGCGcouldsuppresstheJAK/STAT1pathway,thensuppressmany cell lines like HePG2 cells. For example, EGCG could suppress the JAK/STAT1 pathway, indoleamine2,3-dioxygenaseexpressioninIFN-γ-inducedmurinedendriticcells[93].However,onthen suppress indoleamine 2,3-dioxygenase expression in IFN-γ-induced murine dendritic cells thecontrary,EGCGcouldincreasetheactivationofSTAT1inIFN-γ-inducedCD4+Tcells,suchas[93]. However, on the contrary, EGCG could increase the activation of STAT1 in IFN-γ-induced splenicCD4+TcellsandHut78cells,butitstillsuppressedtheSTAT1homodimerformationand++CD4 T cells, such as splenic CD4inhibitedthedownstreamsignaling: T cells and Hut 78 cells, but it still suppressed the STAT1 themRNAexpressionoftheIFN-γ-inducedpro-inflammatoryhomodimer formation and inhibited the downstream signaling: the mRNA expression of the gene,chemokine(C–X–Cmotif)ligand9(CXCL9)[93].EGCGcouldstillinhibitJAK1/2,resultinginIFN-γ-induced pro-inflammatory gene, chemokine (C–X–C motif) ligand 9 (CXCL9) [93]. EGCG thedecreaseofSTAT3,theninhibitthepro-inflammatorysignalinginCD4+Tcells[93].could still inhibit JAK1/2, resulting in the decrease of STAT3, then inhibit the pro-inflammatory Increasingstudiessupportthattheregulationinlevelsofover-activationofNF-κBandSTAT3+ T cells [93]. signaling in CD4bydietaryormedicinalplants,likelychee,iseffectiveininhibitingIBD[7,119].Justlikeoligonol,itmainlyconsistsofcatechin-typeoligomersderivedfromlycheefruitextract,andcouldinhibitSTAT3, Molecules2017,22,48419of29NF-κB,andthecross-talkbetweenthem,benefitingDSS-inducedcolitisinmice[7].CurcumincouldalsoinhibitinflammationbyblockingNF-κBandSTAT3pathways,too[59].Inaddition,puregallicacidexertsanti-inflammatoryeffectsthroughthesuppressionofbothp65-NF-κBandIL-6/p-STAT3tyrosine705activationinDSS-inducedUCinmurinemodels,reducingthecolonicMPOactivityandexpressionofinflammatorymediators,likeiNOS,COX-2,andpro-inflammatorycytokines,andthereductionofthedisruptionofthecolonicarchitecture[119].However,inastudyofDSS-inducedacuteUCinmice,oraladministrationofPCE,whichcontainsEC,procyanidinB2,catechin,andprocyanidinB1,coulddecreasebothSTAT1andSTAT3phosphorylationlevelswithaslighteffectonNF-κB,resultinginreducedcytokineproductionofIL-6andCOX-2,reducedtissuedamageandneutrophilinfiltrationinvivo[105]. 2.7.EffectofCatechinsonIntestinalFlora Thehumangutbacteriacommunitiescanbedividedintodifferententerocytes(Bacteroides,Prevotella,orRuminococcus)bymetagenomicsanalysis[6].Themajorityofhumangutmicrobiotacontain:theBacteroidetesphylum,theFirmicutesphylum[120],theActinobacteriaphylum,theProteobacteriaphylum,andtheVerrucomicrobiaphylum[121].Whilethetwoformerphylacontributeto90%oftheclassesofthenormalmicrobiome[6],thecompositionofmicrobiotainadultsisstableandhasalargeinter-individualvariation[121],whichcanbeinfluencedbydiet,BMI,age,intestinaldiseasesandmedication,particularlyantibiotics[65,121,122]. Accompaniedbytheenrichmentofmoleculartechniques,suchastheadventofculture-independent,enormousstudies,includingtheNIHsponsoredHumanMicrobiomeProjectforthehumanmicrobiomechangeinhealthordisease,indicatedthattheimbalanceofintestinalmicroflora,itsmetabolites,andhostsusceptibilitygenes,aswellasthehostintestinalmucosainnateoracquiredimmuneresponseplayedanimportantroleintheaetiopathogenesisofIBD[5,6]. ThegutmicrobiotaisalteredintheIBDpatientasawhole.Inrecentyears,researcherssuggestedthatthebreakdownofthegutmicrobiomeandthecoordinationofhost-microbialmutualismbecamethekeyprogressinthedevelopmentofIBD[6].Amongthediversificationofmicrobiota,thedecreaseintheamountanddiversityoftheFirmicutesphylum,likeobligateanaerobes,isthemostobvious,especiallyFaecalibacteriumprausnitzii.FortheBacteroidetesphylum,therearedifferentviewsabouttheirincreaseordecrease[123,124].WhiletheincreasingProteobacteriaphylum,includingfacultativeanaerobes,isshowntoinducetheinitiationofchronicinflammatoryIBD[6].EvenEscherichiacoli,consistingofapathogenicsubsetfoundinilealCD,makessenseinthepathogenesisofCD[6].However,bacteroidescaninteractwithTregcellsandmacrophages,stimulatingtheproductionofanti-inflammatorycytokineIL-10[5].Theseindicatethatthechangesincompositionofthegutmicrobiomeconstitutingthehost-microbiomeecologyarethecoreinfluenceinIBD,andtheadjustmentofinterventiontothemicrobiomecomponentmaybeanapproachtoIBD. Severalhumantrialsrevealedthatbysuppressionofthegrowthofpathogenicgutbacteriaandregulationofinflammationofthebowel,flavonoid(whichcontainsofcatechins)intakebenefitsguthealth[125].Increasingstudiesindicatedthatthecatechinsbelongingtopolyphenolspossessedantimicrobialability[63,120],inaccordancewiththeconclusionproposedbyArchanaetal.[126].Catechinscouldsignificantlykillcertainpathogenicbacteria,likeClostridiumperfringens,Erwinia,Pseudomonas,Clavibacter,Xanthomonas,Agrobacteriumspp.[38],Staphylococcusspp.,Vibrioparahaemolyticus,Bacilluscereus,andPlesiomonasshigelloides,buthavelesseffectinpromotingthebeneficialbacteria,likeBifidobacteriumspp.inhumanstudies[36,120].Xueetal.revealedthatcatechinscouldsignificantlyrepressthegrowthofBacteroidetesandFirmicutesanddown-regulatedtherateofBacteroidetestoFirmicutesinvitro[120].DifferenttothephenomenonobservedbyXueetal.,Rastmaneshetal.arguedthatpolyphenolshadabiasedpromotingeffectonBacteroidetes,butabiasedinhibitingpropertyonFirmicutes[127].Tosomeextent,catechinswerecapableofenhancingseveralgeneraofbacteria,includingBifidobacteriumspp.,Enterococcusspp.,Streptococcusspp.,andCollinsellaspp.[120].InvestigationsbyAmarowiczetal.indicatedthatthe Molecules2017,22,48420of29antibacterialfunctionsofcatechinsaredose-dependent[38].TheECandEGChadnoantimicrobialpropertyagainstE.coliK12atlowdoses,beingconsistentwith(+)-catechinby1000µM[128].EventheantibacterialpropertyofEGCGagainstphytopathogenicbacteriawasstrongerthanECby10–20times,butitexertedslightpoweratlowdoses[38]. Thetoxicityofcatechin,whichhasmanydiastereoisomerslikeECandECG,tobacteriamembranes,extracellularproteins,DNA,andmorphologywasanalyzedbyFathimaetal.,usingGram-positivebacteria(B.subtilis)andGram-negativebacteria(E.coli).Itwasdemonstratedthatcatechincouldbenefitbacteriainadoseofabout10µMinB.subtilisandabout12µMinE.coli.Iftheconcentrationwashigherthanthat,catechinpossessedanegativefunctiononbacteriathroughtheoxidativedamageresultinginthechangeinmembranepermeabilizationandmembraneliposomes[36].Thisconclusionshowsthatcatechinhasadualfunctionthatbothbenefitsandharmstobacteriainadose-dependentmanner,whichisconsistentwithapreviousstudy.TheauthorsalsorevealedthattheinhibitionofcatechinagainstbacteriawasmoreobviousintheGram-positivebacteria(B.subtilis)thanGram-negativebacteria(E.coli)inallofthepermeabilizationchanges,DNAdamage,andstressproteinexpression[36].CatechinshaveastrongeraffinitytothepeptidoglycanofGram-positivebacteriathanthenegatively-chargedliopolysaccharidesinthemembraneofGram-negativebacteria,resultingingreaterpermeation,absorptionofcatechins,andmoreinjurytothecellmembraneinGram-positivebacteria[129,130].Additionally,catechinscancutthesupercoiledDNAintoopenlinearorcircularDNA,actinglikerestrictionenzymesinB.subtilisDNA,butnotinE.coliDNA.TheextracellularproteinscanalsobeelevatedinB.subtilisthanE.coliwhenbotharetreatedwithcatechin[36].Inaddition,polyphenolscaninfluencegutmicrobiota,andthegutmicrobiotacanalsohaveaninfluenceonthepolyphenols(Figure8),suchascleavingittobeakindofenergyfoundation,especiallyforbacteroidetes.Thismaybeoneofthereasonsforthechangeinintestinalmicrobiota[35]. Indeed,thereissignificantevidencetoprovethatpolyphenolscouldnotonlyinfluencegutmicrobiotatomaintainbodyhealth,butalsothatgutmicrobialmetabolitesofpolyphenols,likecatechins,hadanimportantinfluenceonhumanhealth,whichmightbenefitIBD,too[35,119](Figure8).Itwasdemonstratedthattheexistenceoftheenterohepaticrecyclingscenario,andtheglycosidaseandglucuronidaseactivityofgutmicrobes,madeitpossibleforgutbacteriatoenhancethebioavailabilityofpolyphenols[35,70,131].MicrobialglycosidasesexcretedbyEnterococcusavium(LY1)areabletocatalyzethehydrolysisoftheflavonoidglycosidesintoaglycones,whicharethenrapidlyabsorbedandfurthermetabolizedintheliver,whicharethenexcretedbackintothelumen[70],whichmightapplytocatechins,too.AgeneralroleapplicabletothegeneralmicrobialmetabolismofGTCs(greenteacatechins)isthefollowing:1.Underthecleavageofanetherbond–O–,TheC-ringisgoingthroughring-fission.Additionally,gallatedcatechinsarebrokendown;2.OntheB-ring,lactonesconformtopartialdehydroxylation;3.Theycanconformtophenolicacidsandsomeoftheirconjugatederivatives,andbenzoicacidsandsomeoftheirconjugates[67].Themaingutmicrobialmetabolitesofcatechinsappeartobe3-hydroxyphenylaceticacid,3-hydroxyphenylpropionicacid,3,4-dihydroxyphenylaceticacid,and3-hydroxyphenyl-γ-valerolactone[35,132].Invitroandinvivoanimalandhumansystems,thirteenmicrobialmetabolitesof(+)-catechinand(–)-EChavebeenrevealed:1-(3󰀅,4󰀅-dihydroxyphenyl)-3-(2󰀅󰀅,4󰀅󰀅,6󰀅󰀅-trihydroxyphenyl)-propan-2-ol,1-(3󰀅-hydroxyphenyl)-3-(2󰀅󰀅,4󰀅󰀅,6󰀅󰀅-trihydroxyphenyl)-propan-2-ol,5-(3󰀅,4󰀅-dihydroxyphenyl)-γ-valericacid,δ-(3󰀅,4󰀅-dihydroxyphenyl)-γ-valerolactone,δ-(3󰀅-hydroxyphenyl)-γ-valerolactone,5-(3󰀅,-hydroxyphenyl)-γ-valericacid,δ-(4󰀅-hydroxy-3󰀅-methoxyphenyl)-γ-valerolactone,3󰀅,4󰀅-dihydroxybenzoicacid,m-hydroxyphenylpropionicacid,4󰀅-hydroxy-3󰀅-methoxybenzoicacid(vanillicacid),m-hydroxyphenylhydracrylicacid,m-hydroxybenzoicacid,andm-hydroxyhippuricacid[65,67].Afterhydrolysisbyintestinalflora,ECGwillformgallicacidand(–)-EC.Bothgallicacidand(–)-ECwillundergofurthermicrobialmetabolism.Actually,gallicacidwillbecomepyrogallolandpyrogallolconjugates.AsforEGCG,itwillformEGCandgallicacid,thenundergofurthermicrobialmetabolism;Usually,EGCcanform1-(3󰀅,4󰀅,5󰀅-trihydroxyphenyl)-3-(2󰀅󰀅,4󰀅󰀅,6󰀅󰀅-trihydroxyphenyl)-propan-2-ol,δ-(3󰀅,4,5󰀅󰀅-trihydroxyphenyl)-r-valerolactone,δ-(3󰀅,4󰀅-dihydroxyphenyl)-r-valerolactone,δ-(3󰀅,5󰀅- Molecules2017,22,48421of29dihydroxyphenyl)-r-valerolactone,andδ-(3󰀅,5󰀅-dihydroxyphenyl)-r-valerolactone-3󰀅-glucuronide[67].Atthesametime,anabundanceofpapersrevealedtheexactenzymesandmicrobespeciesbreakingdownfromcatechinstometabolites,tryingtomakesure“whattheydo”and“whoarethere”,whatbacteriaaredoingwithrespecttocatechins[35,133].Forexample,Gordonibacterfaecihominissp.Nov.,anovelactinobacterialstrainbelongingtothegenusGordonibacter,isolatedfromhumanfeces,iscapableofdehydroxylating(+)-catechinderivatives[133].AnotherhumanintestinalbacteriumEggerthellasp.CAT-1cancleavetheC-ringanddehydroxylatetheB-ringofboth(+)-catechinand(–)-EC[134].Wangetal.provedthatahumanintestinalbacteriumEubacteriumsp.StrainSDG-2wouldcleavetheC-ringof(3R)-isomers,like(–)-catechinand(–)-EC,GCandEGC,and(3S)-isomers,like(+)-catechin(2R,3S)and(+)-EC(2S,3S),togive1󰀅,3󰀅-diphenylpropan-2-olderivatives,andhad(3S) isomers [135]. Bacterial enzymes, including the enterohepatic circulation-related ones, can theabilityofp-dehydroxylationintheB-ringof(3 R )isomers,butnotof(3S)isomers[135].Bacterialinduce many enzymatic reactions including hydrolysis, hydrogenation, dehydroxylation, enzymes,includingtheenterohepaticcirculation-relatedones,caninducemanyenzymaticreactionsoxidation, ring cleavage, decarboxylation, and rapid deconjugation, resulting in the microbial includinghydrolysis,hydrogenation,dehydroxylation,oxidation,ringcleavage,decarboxylation,andmetabolites of catechins [67]. For example, through the reaction with a complex with peroxyl rapiddeconjugation,resultinginthemicrobialmetabolitesofcatechins[67].Forexample,throughiron of dioxygenase, catechin can finally convert into 3, 4-dihydroxyphenyl acetic acid [136], and thereactionwithacomplexwithperoxylironofdioxygenase,catechincanfinallyconvertinto3,β-glucosidase, isolated from sp., revealed transglycosylation activity toward 4-dihydroxyphenylaceticacidNovosphingobium[136],andβ-glucosidase,isolatedfromNovosphingobiumsp.,revealed(+)-catechin, synthesizing catechin glycosides [137]. However, the species of microorganisms transglycosylationactivitytoward(+)-catechin,synthesizingcatechinglycosides[137].However,thethat take effect, the corresponding enzymes, and the specific mechanisms, even the exact speciesofmicroorganismsthattakeeffect,thecorrespondingenzymes,andthespecificmechanisms,relationships require further exploration. eventheexactrelationshipsrequirefurtherexploration. Figure 8. The interaction between catechins and intestinal microflora. Figure8.Theinteractionbetweencatechinsandintestinalmicroflora. 2.8.EffectofCatechinsonTightJunctions(TJ) TJ,adynamicmultifunctionalcomplexthatformsasealbetweenadjacentepithelialcells,inwhichzonulaoccludens-(ZO-)1proteinplaysacentralroleinTJfunctionsconnectingtheoccludinandclaudintootherproteins,playinganimportantroleintheintestinalbarrier[5,138,139].ThechangeofTJregulatorsandcomponents,andtherelatedbarrierpermeability,willexacerbatetissuedamagein Molecules2017,22,48422of29IBD[140].SeveralcellstudiesshowedthatcatechinsmightbenefitIBDbyimprovingTJstabilityinepitheliumcells[5,139,141]. Contrerasetal.provedthatECcouldinhibitTNF-α-inducedpermeabilizationofCaco-2cellmonolayersthroughinhibitingthedecreaseandredistributionofZO-1protein,preventingIBDfrombecomingworse[139].Additionally,Carrasco-Pozoetal.provedthatseveralpolyphenols,includingEGCG,hadasimilarfunction,inhibitingtheredistributionoftheZO-1proteinandthedecreasedexpressionofZO-1andoccludininducedbyindomethacininaCaco-2-basedmodel[5,141]. 3.Conclusions Insummary,weproposethatcatechinshavetheslightpotentialforuseinamelioratingIBDandrelatedabnormalconditions,withitsknownanti-inflammatory,antioxidative,andanti-bacteriaactivation.Importantly,asantioxidants,catechinscansuppressthedamagetocellsandtissuesoriginatingfromtheimbalancebetweentheoxidationsystemandantioxidantsystembytheenhancementoftheantioxidant,therelatedenzymes,andthedirectorindirectantioxidativeeffects,whichdependontheconcentration.Catechinscanalsoinhibittheinfiltrationandproliferationofimmune-relatedcellsandregulateinflammationandoxidativereactionsbyinteractionwithapluralityofinflammation-relatedoxidativestress-relatedpathways,suchasNF-κB,MAPKs,Nrf2,andSTAT1/3pathways,contributingtothedecreaseoftheproduction,secretion,andreactionofcytokines,chemokines,pro-inflammatorycytokines,adhesionmolecules,andinflammatory-relatedenzymes,likeiNOSandCOX-2.CatechinsmaypreventgastrointestinallesionsfromworseningintocancerthroughtheregulationofcellgapjunctionsandtheimprovementoftheexpressionofTJintheepithelium.TheregulationofinflammationmayhelpbenefitinflammationinIBD.Finally,catechinsmaybealsostabilizeintestinalflora,helpingtherecoveryofIBD. However,thereisaverylimitednumberofstudies,eitherintheanimalmodelsofIBDorinIBDpatients,whichmayhelpprovethebiologicalactivities.Morestudiesareneededtofurtherexploretheexactactivitiesandpossiblemechanisms,evendowntothemolecularlevel.Additionally,morelaboratoryandclinicaltrialsareneededtoinvestigatetheappropriateclinicalapplication,theoptimaldosesinthecaseoflowbioavailability,buthighdosesexposedinthegut,andthebalanceofanti-inflammatoryandpro-inflammatoryproperties. Acknowledgments:ThisstudywasfundedbytheNaturalScienceFoundationofLiaoNingProvince(No.2015020515). AuthorContributions:Fei-YanFanandLi-XuanSangtheliterature,modifiedthelanguage,anddraftedthemanuscript.MinJiangcontributedtoconceptionaobtainednddesignofthereview. ConflictsofInterest:Theauthorsdeclarenoconflictofinterest. 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