Review
Role
of
natural
antioxidants
and
potential
use
of
bergamot
in
treating
rheumatoid
arthritis
A.
Marino
a,
I.
Paterniti
a,
M.
Cordaro
a,
R.
Morabito
a,
M.
Campolo
a,
M.
Navarra
b,
E.
Esposito
a,
S.
Cuzzocrea
a,*
a
DepartmentofBiologicalandEnvironmentalSciences,UniversityofMessina,V.leF.StagnoD’Alcontres31,Messina98166,Italy
b
DepartmentofDrugSciencesandProductsforHealth,UniversityofMessina,SS.Annunziata,Messina98168,Italy
ARTICLE INFO
Articlehistory: Received19March2015
Receivedinrevisedform23March2015 Accepted23March2015
Chemicalcompoundsstudiedinthisarticle: Limonene(PubMedCID:22311) Bergapten(PubMedCID:2355) Luteolin(PubMedCID:5280445) Quercetin(PubMedCID:5280343) Genistein(PubMedCID:5280961) Oleuropein(PubMedCID:5281544) Epigallocatechin-3-gallate(PubMedCID: 65064)
Resveratrol(PubMedCID:445154) Curcumin(PubMedCID:969516)
Keywords: Naturalantioxidants Flavonoids Bergamot Oxidativestress Rheumatoidarthritis ABSTRACT
Theaimofthepresentreviewistoreportabouttheeffectofnaturalcompounds,withprovedantioxidant activity and mainly introducedwithdiet, on rheumatoid arthritis(RA). RA is a chronic, systemic inflammatory disorderleading tocartilage damage,bone erosions, joint destructionand impaired movement.ThepathophysiologyofRA includesreactiveoxygenspecies(ROS)production,whichis concomitantwithinflammationandprovokesawiderangeoftoxicreactions,likelipidperoxidation, inhibition of mitochondrial respiratory chain enzymes and modifications of membrane transport proteins.SincethedevelopmentofeffectivetherapeuticstrategiestocounteractRAisstillinprogress,the presentreviewis intendedtoaddmoreinformationaboutthepossiblerole ofnaturalantioxidant compoundsintreatingRAwithagoodbalancebetweenefficacyandtoxicity.Naturalproductswith proved anti-inflammatoryand antioxidant actionssuchas ()-epigallocatechingallate,resveratrol, oleuropein,quercetinandtheflavonoidfractionofbergamotjuiceareherebeingreviewed,withspecific regardtotheirpossibleantioxidanttherapeuticactionagainstRA.
ã2015ElsevierB.V.Allrightsreserved.
Contents
1. Introduction ... 54
2. Pathophysiologyofrheumatoidarthritisandtherapeuticstrategies... 54
3. Naturalantioxidantsandrheumatoidarthritis ... 55
3.1. Flavonoids ... 55
3.1.1. Bergamot ... 55
3.1.2. Otherflavonoids ... 56
3.2. Othernaturalantioxidantcompounds ... 56
3.2.1. Oleuropein ... 56 3.2.2. Epigallocatechin-3-gallate ... 57 3.2.3. Resveratrol ... 57 3.2.4. Curcumin ... 57 4. Conclusion ... 57 References ... 57
* Correspondingauthor.Tel.:+39906765208. E-mailaddress:[email protected](S. Cuzzocrea).
http://dx.doi.org/10.1016/j.phanu.2015.03.002
2213-4344/ã2015ElsevierB.V.Allrightsreserved.
ContentslistsavailableatScienceDirect
PharmaNutrition
1.Introduction
Rheumatoid arthritis (RA)is a chronic inflammatorydisease characterized by the activation of synovial tissue in the joint capsule,invasionofthecartilageandbone,withprogressivejoint dysfunction[1].InRA,cartilageextracellularmatrixcomponents are degradedby matrix metalloproteinases (MMPs) as well as aggrecanasesandlargeamountsoffreeradicals,suchasreactive oxygen species (ROS), are produced by macrophages [2]. This disease occurs in approximately 1% of the adult population worldwide, often implying personal, family and financial con-sequences[3].
IntheUnitedStates,RAandosteoarthritis(OA)affectmorethan 40millionpeople,withhealthcarehugecostsandtheurgentneed formore effectivetherapeutic treatments.In this regard, treat-mentstargetingcytokines,likeanti-tumornecrosisfactor(TNF)-
a
antibodies,soluble TNFreceptor,anti-interleukin(IL)-6receptor antibodyand IL-1 receptor antagonist, are currentlyused as a therapeutic approach for RA, in addition to anti-inflammatory agentsanddisease-modifyinganti-rheumaticdrugs,likein flime-thotrexate. These treatments are not without risks though, especiallyintermsofcostsandincreasedsusceptibilityofpatients toinfection.TNF-a
blockersareveryefficient,but,astheotherside ofthecoin,onethirdoftheRApatientsareunresponsiveoreven exhibitadversesideeffects[4].Because of the limited success of disease-modifying anti-rheumatic drugs, the exploration of new anti-rheumatic agentswithhighefficacyandlesstoxicityisstillinprogress,and therapiesrelyingontheuseofnaturalsubstances havebecome increasinglymarked.Inthis regard,an exampleisgivenbythe anti-arthritic action of herbal extracts protecting cartilage destructioninarthriticdiseases,asreportedbyKeisukeetal.[5]. Since ROS generationis concomitantwithinflammation[6], leadingtooxidationofproteinsandlipidsandfurthersustaining theinflammatoryprocess,increasinginteresthasbeenaddressed totheuseofantioxidantcompoundsintreatingRA.Inparticular, compoundsextractedfromplants,suchas flavonoids,terpenes, quinones,catechins,alkaloids, anthocyaninsandanthoxanthins, allofwhichareknowntoelicitantioxidanteffects,canmodulate theexpressionofpro-inflammatorysignalsandexhibitpotential againstarthritis[7].Theuseofnaturalantioxidantsispromising, thoughrequiringmoreextensiveinvestigationsinpreclinicaland clinicalprocedures to prove theirusefulness and, as stated by Khannaetal.[7],mayserveasagoldminefortreatmentofRA.
In the present review, the effect of antioxidant natural substancesandtheirpossibleuseagainstRAhavebeenconsidered, withspecific regard to()-epigallocatechingallate, resveratrol, oleuropein,quercetinandtheflavonoidfractionofbergamotjuice. 2.Pathophysiologyofrheumatoidarthritisandtherapeutic strategies
The understanding of RA pathogenesis and, hence, the development of opportune therapeutic strategies include the useofanimalmodels,likeratormousemodelsofautoimmune erosivearthritis[1].Inthisregard,Adipueetal.[8]discoveredthat miceintheirbreedingcolonyspontaneouslydevelopedinflamed jointsreminiscentofRAandmay,therefore,provideanewmodel toexaminepathogenicmechanismsandtestnewtreatmentsfor thishumaninflammatorydisease.
Type II collagen-induced arthritis (CIA) in the mouse is recognized as a useful model of RA, being cell and humoral immunitycharacteristicshallmarksofthepathogenesiscommon tohumanRA[9],likerecruitmentandactivationofneutrophils, macrophagesandlymphocytesinjointtissuesandtheformation ofthepannus.RAfinallyimpliesthedestructionofaffectedjoints.
The inflamed synovium consists of diverse cell populations, including Bcells, Tcells, macrophages and synovial fibroblasts (SF),leadingtoabnormalimmunephenomenainthejoint,chronic inflammation and synovial hyperplasia and contributing tothe progressionofthedisease.
Synovialfibroblastsareresponsibleforthedestructionofthe joint, by secreting matrix degrading enzymes, and maintain inflammation by inducing pro-inflammatory cytokines produc-tion.Macrophages are alsoinvolved inTNF-
a
and IL-1 release, whenincontactwithTcellsintheinflamedsynovium.Hence,the roleofcytokines,alongwithotherinflammatorymediatorsinRA pathogenesis, hasbeen ascertainedand is a majorissue under debatetodevelopeffectivetargetedtherapiesagainstRA[10].Cytokinesactivatethenuclearfactor(NF)-
k
B, thep38stress activatedMAPkinases(MAPK)andPI-3kinase[11,12],contributing to the maintenance of a chronical pro-inflammatory cytokine milieuinthesynoviumandtriggeringcatabolicenzymes produc-tion.Monoclonalantibodiessuchasinfliximabandadalimumab, as well as eternacept that inhibit TNF-a
, have been used successfully in the treatment of RA [13]. On the other hand, targeting MAPK pathways, including the extracellular signal-regulatedkinase(ERK),c-Junaminoterminalkinase(JNK)andp38 [14]totreatRAmaybenotafullyeffectivetherapeutictool,asall inhibitorsofp38MAPKdoaffecteachisoform.TheTNFfamilymemberFasligand(FasL)hasbeenalsoreported totriggerapoptosisinfibroblast-likesynoviocytes(FLS)ofarthritic jointsbybindingtoitsreceptorFas.Therefore,itissuggestedasa promisingcandidatefortargetingthehyperplasticsynovialtissue. ThisisthequestionunderscoredbyCalmon-Hamatyetal.[15].
Since it has been demonstrated that in RA some kinases participateinthegenerationofpathogenicsignalingcascades,the pharmacologicalinhibitionofkinasesmaybealsoconsideredasan effectivetherapeuticstrategyagainstRA.OralinhibitorsofJAKs, Syk,PI3Ks,MAPKsandBtkareactuallyunderdevelopmentorin clinicaltrialsinpatientswithRA,aspointedoutbyChakravarty etal.[16].
Moreover, Toll-likereceptors (TLRs) are alsoinvolved in RA pathogenesis,astheiractivationinducestheexpressionofmany inflammatory cytokines, chemokines and co-stimulatory mole-culesfromantigenpresentingcells.Therefore,a deregulationin theactivationofTLRscanmodulatethedevelopmentof autoim-munediseases.InRA,TLRligandshavebeendetectedinthejointof thepatients[17].
The discovery of key intracellular pathways, particularly kinases which modulate cytokines function and immune cell receptorsimplicated in RA pathogenesis, is promising for drug development.Thus, a range of kinase inhibitorshas effectively enteredclinicaltrials,asrecentlyreportedbyMeierandMcInnes [18].
Painandswellingreduction,delayofdiseaseprogressionand improvement quality of life in RA patients are also goals of therapeuticinterventionagainstRA.Forpaincontrolandswelling, treatmentincludesanalgesics,suchasacetaminophenandopioids, non steroidal anti-inflammatory drugs (NSAIDs), and intra-articulartherapies, suchas glucocorticoids.In addition, disease modifyinganti-rheumaticdrugs(DMARDs)areusedtomodifythe clinical and radiological course of RA. Examples are given by methotrexate(MTX), sulfasalazine, leflunomide, hydroxychloro-quine andnewer therapies,suchas TNF-
a
therapy(etanercept, infliximabandadalimumab),anti-CD20therapy(rituximab)and abatacept.Nevertheless,theseagentsareassociatedwithseveral sideeffects[7].AnotherapproachtothetreatmentofRAisaimedtocounteract ROS production occurring in RA. Free radicals are chemical species possessingan unpairedelectron.The synovialfluidand peripheral blood of RA patients have high levels of ROS and
ROS-generated molecules, including superoxide, peroxide, hydroxyl radicals and reactive nitrogen species (RNS), like peroxynitrite[2,19].
InvivoexperimentscarriedoutinFreund’scompleteadjuvant (FCA)–inducedratsshowedthatneutrophils,macrophagesand dendritic cells generate ROS in large amounts in response to inflammation[20].TheactivatedO2intermediates,togetherwith secondarilyformedradicalslikehydroxylradicals,areinfactable todestroymembranelipids,proteins,DNAandcartilage[21].O2, the 1-electron reduction product of oxygen, perpetuates the chronicinflammatorystateassociatedwithRAandasuperoxide dismutasemimetic(SODm),likeM40403,hasbeendemonstrated toexertabeneficialeffectinthecollagen-inducedarthritis(CIA) model[22].
Withregardtoclinicalstudies,increasedlipidperoxidationand malondialehyde(MDA)levelsanddecreasedenzymaticand non-enzymaticantioxidantsarefoundinRApatients,but glutathione-peroxidase (GSH-peroxidase) and superoxide dismutase (SOD) activitiesarelower,suggestingthatanincreaseinoxidativestress andalowantioxidantstatusoccurinRApatients[23].Therefore oxidantstressplaysacriticalroleinthepathogenesisofRAdisease. Defense mechanisms against oxidative stress, SOD, GSH-peroxidase, catalase (CAT) and glutathione S-transferase (GST), compensateforthetoxicityresultingfromROS.ROSproducedby severeorchronicinflammationmayexceedthecapabilityofthe corresponding anti-oxidant enzymes, which seems to cause imbalanceintheredoxstate[24].AnexcessinROSproduction disruptsthisredoxbalanceandamplifiesinflammatoryresponses viaNF-
k
B,which,assaidabove,isacentralregulatorofcellular inflammatoryresponse,asitcontrolsmanyofthegenesinvolved ininflammation[25,26].ROSalsohavedirect effectsasthey oxidizeand degradethe majorcomponentsofcartilageandbone,includingcollagenand hyaluronicacid(HA)[2].Thedegradationofhyaluronicacid(HA) is,atleastinpart,theresultoffragmentationbyhydroxylradical [2,27]andseemstoberesponsibleforthedecreasedviscosityof jointfluidobservedinRApatients.Thepositivefeedbackresulting from the accumulation of oxidized products could further exacerbate the cartilage and bone erosion, and lead to joint destruction.Therefore, protectionofthejointcomponentsfrom thedirectdegradationbyROSrepresentsanotherpotentialtarget ofRAtherapy.
Whatismore,oxidativestressmayparticipateintheetiologyof RAthroughdirectinteractionwithDNA.Anexampleisgivenby 8-OHdG,producedbytheoxidationofguaninebasesofDNA[28], whoselevelsareelevatedinRApatients[29].Itishighlymutagenic since it pairs with adenine as well as cytosine, provoking transversion mutations during DNA replication. Therefore ROS, by inducing somatic mutations, alter protein function and/or immunogenicity, contributing to further activate the immune system[30].
3.Naturalantioxidantsandrheumatoidarthritis
Since ROS production is a hallmark for RA,one therapeutic approachtotreatRAistoremoveROS.Forthisreason,theuseof antioxidantstotreatRAhasbeenconsideredbymanyresearchers [31], with specific regard to natural compounds with proven antioxidanteffect[7,32,33].
Somestudieshaveprovidedevidenceofalinkbetweendietary antioxidantintakeandthelikelihoodofdevelopinginflammatory arthritis,albeitthepathwaysunderlyingantioxidantcompounds actionarenotcompletelyunderstood.Nevertheless,thepotential therapeuticroleofdietaryantioxidantsininflammatoryarthritisis anissuerisingmuchinterest[34].Amongstnaturalantioxidants, flavonoidsand inparticular the flavonoid fractionof bergamot
juice,areworthyofnoteandarebeingconsideredinthisreviewfor theirpossiblebenefitintreatingRA.
3.1.Flavonoids
Flavonoids are organic molecules, secondary metabolites of plant cells, including many edible plants, where they exert a protectiveactionagainstultravioletradiationandoxidativestress [35].Theyrepresentanotablepartofhumansupplyandseveral studies have shown that high regular intake of somephenolic compoundsinthedietprovidesapreventiveactionagainstseveral humandiseases,suchascardiovascularpathologies, atherosclero-sis, osteoporosis,allergies,diabetes, neurodegenerativediseases andcancer[3].Althoughthemechanismsbywhichthesenatural compoundsexerttheirbenefitsarenotcompletelyclarified, anti-inflammatoryeffectsofflavonoidshavebeenattributedprimarily totheirantioxidantactivity,becausetheyareknowntoscavenge and prevent the formation of ROS and RNS [36]. Moreover, flavonoidscouldinfluencecellularfunctionbydirectinteraction withreceptors,modulationofintracellularsignalingand inhibit theactivitiesofmanyinflammatoryproteinssuchasNF-
k
Band theexpressionofgenesassociatedinchronicinflammatorydisease [37].Themainsourcesofflavonoidsarethedailyintakeofteaand Citrus fruits and juices. Amongst theCitrus, bergamot (juice or essentialoil)hasbeenrisingtheinterestofmanyresearchersin therecentyears,duetoitsrecognizedbeneficialproperties,sothat itis nowconsideredanewchallengeinthefieldoftherapeutic strategiesdevelopment,namelyagainstinflammatorydiseases. 3.1.1.Bergamot
Citrus bergamiaRisso et Poiteau(Rutaceae)is a fruit typical of a limited coastal area of the province of Reggio Calabria, Italy, where both climate and environmental conditions are favorable for its cultivation. Bergamot fruit is mainly used to extract the essential oil (BEO) obtained from the peel, much employed in perfumery, cosmetic, pharmaceutical and food industries [38]. BEO, obtained by cold pressing of the epicarp and, in part, of the mesocarp of the fresh fruit of bergamot, comprises a volatile fraction(93–96% of total) containing both monoterpeneandsesquiterpenehydrocarbons(suchaslimonene, c-terpinene, a- and
b
-pinene,b
-myrcene, sabinene andb
-bisabolene)andoxygenatedderivatives(suchaslinalool,linalyl acetate,neral,geranial,nerylacetateandgeranylacetate),anda nonvolatile fraction(4–7%of total)characterized bycoumarins and furocoumarins, such as bergapten (5-methoxypsoralen) [38,39].InItalianfolkmedicineBEOhasbeenlongusedasantiseptic and to facilitate wound healing due its antifungal [40] and antimicrobial[41]properties.
Theuseofthisessentialoilhasbeenconsideredin aromather-apy[38],forthereliefofpainandanxiety/depressionsymptoms andhasbeenshowntomodulatethereleaseofneurotransmitters in discrete brain regions under both basal and pathological conditions[42].Inthislatterregard,theintraperitoneal adminis-tration of BEO has been reported to significantly increase the extracellularlevelsoftheinhibitoryaminoacidneurotransmitter gamma-aminobutyricacid(GABA)inrathippocampus[42].This effectontheGABAergicsystemmayaccountforanxiolyticrelated behavioraleffects,comparabletobenzodiazepineanxiolyticdrugs, whichareknowntoactbyincreasingGABAfunctioninthebrain [43]. Moreover, in vitro experiments suggested the potential neuroprotectiveactivityofBEO[44].
In the cardiovascular field, it has been shown that the non-volatilefractionofBEOreducedtheneointimaproliferation inanexperimentalmodelofratangioplasty,inhibitingbothfree
radical production and lectin-like oxyLDL receptor-1 (LOX-1) expression [45]. Moreover, BEO induces vasorelaxation in the mouseaortabyactivatingK+channelsandinhibitingCa2+influx [46].
Finally,thebiologicalpropertiesoftheBEOhavebeenexplored eveninexperimentaloncology.Ursinoetal.werethefirsttoreport theantiproliferativeactivityofBEOintheSH-SY5Yneuroblastoma cells,suggestingapotentialroleagainstcancerinacontextofa multitargetpharmacologicalstrategy[47].Veryrecentlytheyhave addednewfindingsonthepharmaco-toxicologicalprofileofBEO, revealing the activation of multiple pathways leading to both necroticandapoptoticSH-SY5Ycelldeath[48].Finally,toimprove thewatersolubilityof thephytocomplex,they formulated BEO liposomes,thusincreasingtheinvitroanticanceractivityofBEO anditsfractions[49].
Despitebergamotjuice(BJ),obtainedfromtheendocarpofthe fruit,isoftenconsideredasecondaryproductoftheessentialoil industry,ithasbeenactuallyrecognizedasasourceofbeneficial effects.Inthisregard,BJchronicadministrationhasbeenshownto preventthediet-inducedhyperlipidemiainrats[50].Moreover,a significant reduction of serum cholesterol, triglycerides and glycemiahasbeendescribedinpatientssufferingfrommetabolic syndrome and treated with bergamot-derived polyphenolic fraction[51].
BJhasbeenalsodemonstratedtoreducetheproliferationof severaltumorcelllinessuchasSH-SY5Y,PC12,PC3and MDA-MB-231cellsshowingthestrongestgrowthrateinhibitioninSH-SY5Y cells.Inthiscellline,theantiproliferativeeffectofBJwasnotdue to a cytotoxic action, but to a marked reduction of cell adhesiveness together with a block of the cell cycle in the G1-phase,causedbyareducedexpression ofcyclinD1[52].In this regards, the cell cycle modulation by Citrus flavonoids exhibiting antiproliferative effects has been already described [53].Moreover,theabilityofBJtointerferewiththecytoskeleton reorganization and the actin remodeling impair the migratory machineryandmayberesponsiblefortheanti-metastaticeffectof BJ observed in a spontaneous metastatic neuroblastoma SCID mousemodel[54].Interestingly,theinvitroantiproliferativeand anti-mestastaticeffectsoccurwithoutcytotoxiceffectsneitherin tumornorinnormalcells.Moreover,noapparentsignofsystemic toxicitieswasdetectedwheninvivoexperimentswereperformed, suggesting thus a potential role of BJ in oncologic field. More recently, it has been demonstrated that the antiproliferative propertiesofBJarereferabletoitsflavonoids,sincetheflavonoid fractionofBJ(BJe)reducedthegrowthrateofcoloncancercells [55].
Another setof experiments, carried out byNavarra and co-workers,demonstratedthatBJeisabletosignificantlyreduceboth transcription profile and protein levels of pro-inflammatory cytokinesinLPS-stimulatedTHP-1monocytes,ahumanleukemia monocytic cell line widely used as a model to study the inflammatorycellresponse[56].Inparticular,theauthorsreported that BJe modulates NF-
k
B pathway, likely via SIRT1 activation, demonstratinganinvitroanti-inflammatoryactivityofflavonoid fractionfromBJ.Thus, it isreasonabletoproposethatBJemay representsanovelpharmacologicalstrategytopreventin flamma-toryresponses.Finally,veryrecentlythetreatmentwithBJehas beendemonstratedtoexertbothantioxidantandanti-in flamma-toryactivity in an experimental model of inflammatory bowel disease,suggestingthatBJecouldrepresentatargetfortherapeutic intervention in autoimmune/inflammatory disorders, such as colitis[57].3.1.2.Otherflavonoids
Many studies contributedtoverify theantioxidanteffect of other flavonoids and their potential use against inflammatory
diseases, like RA. Luteolin, a common flavonoid found in plantssuchasApiumgraveolensL.var.dulce,Petroseliumcrispum, and Capsicum annuum L. var. grossum, possesses antioxidant andanticanceractionsandhasbeenconsideredforitsprotective effect against oxidative stress-induced inflammation and cell damage [58]. In this regard, Impellizzeri et al. [59] interestingly proposed the use of a combined treatment with theendocannabinoidPEAandtheflavonoidluteolintocounteract the inflammatory process associated with RA in a mouse model. These authors showed that a co-ultramicronized PEA+luteolin formulation(PEA-LUT)isprotectivein amodelof collagen-inducedarthritis.Furthermore,theydemonstratedthat the formation of highly reactive nitrogen derivatives and chondrocyte lipid peroxidation, responsible for cartilage oxidation/degradation[1], aresignificantlyreduced byPEA-LUT formulation and that the effect of PEA alone in reducing the inflammatoryresponseispotentiatedbythecombinationwiththe flavonoidluteolin.
Quercetin(QU)(3,30,40,5,7-pentahydroxyflavone)isanatural flavonoid, found in herbs, vegetables and fruits (broccoli, tea, onionsandapples),exhibitingdifferentbiologicalactivities.Ithas been shown to prevent or reduce inflammatory reactions by regulating NF-
k
Bactivation and inhibiting the transcription of joint synovial inflammatory factors.Nevertheless, QU hasbeen reportedtoinhibittheactivityofVEGF,bFGF,MMP-2andother cytokines, inhibit angiogenesis and synovialpannus formation, thus suggesting that QU, playing a role in counteracting RA inflammation,maybereasonablyproposedasanadjuvantdrugfor RAtreatment[60].Genistein, the major active compound from soybean, has attracted the attentionof many researchers,due to its proven antioxidant,anti-inflammatory,antiangiogenesis, immunomodu-latory,painreliefandjointprotectionproperties.Lietal.[61],on thebasisofthesepropertiesassayedonbothinvitroandinvivo models,proposegenisteinasapromisingagentforRAtreatment. Genisteinpossess strongcytoprotectiveactivity,inhibiting cyto-kine-mediatedtoxicity,breastcancerandpromoting chemothera-peutic efficacy. Genistein’s mechanisms of action include inhibition of tyrosine kinases, activation of PPAR-gamma and bindingofestrogenreceptors[35].
3.2.Othernaturalantioxidantcompounds 3.2.1.Oleuropein
Olive oil with its unique characteristics is an ingredient comprisedinthetraditionalMediterraneandiet,whosebeneficial effectsarerecognized[62].Themajorconstituentoftheleavesand unprocessedolivedrupesofOleaeuropaeaisoleuropeinandthe majority of polyphenols found in olive oil derives from its hydrolysis. Oleuropein elicits high antioxidant activity in vitro, comparabletothatofahydrosolubleanalogoftocopherol[63], scavengessuperoxideanionsandhydroxylradicalsandinhibitsthe respiratory burst of neutrophils and hypochlorous acid-derived radicals[64].
Impellizzeri et al. [65] have proposed a mouse model of arthritis,inducedbyinjectionofcollagentypeII(CII),tostudythe inflammatory response and its possible amelioration under oleuropein treatment. These authors observed that oleuropein aglycone,a hydrolysis productobtainedfromoleuropeinbythe actionofbeta-glucosidase[66],amelioratesarthritisprogression by reducing the activation of the nuclear enzyme poly(ADP-ribosyl)polymerase(PARP)involvedininflammation[67],witha decreaseinPARexpressionintheinflamedjoint.Itislikelythat oleuropeinaglycone,givenattheonsetofthedisease,mayreduce pawswellingandthehistologicaldamageduetoRA.Otherauthors supportthesedata,withspecificregardtothereductionofROS
levels,demonstratingtheantioxidanteffectofoliveoilphenolsand theirbeneficialeffectsagainstinflammation[68].
3.2.2.Epigallocatechin-3-gallate
Green tea (Camellia sinensis) is one of the most commonly consumed beverages in the world and is a rich source of polyphenolsknownascatechins(30–36%ofdryweight)including epigallocatechin-3-gallate(EGCG),whichconstitutesupto63%of total catechins [69]. A cup of green tea typically provides 60–125mgcatechins,includingEGCG,whichhasbeenshownto be25–100timesmorepotentthanvitaminsCandEintermsof antioxidantactivity [70].In thepastEGCGhasbeenextensively evaluatedforitspotentialanti-rheumaticactivityusinginvitroand in vivo arthritis models, providing evidences to consider this compoundacandidatefortherapyagainstRA.
EGCG suppresses IL-1-induced glycosaminoglycan release from cartilage by blocking NF-
k
B activity in chondrocytes and inhibitsthoseprocessesresponsibleforcartilagedegradation,like IL-1-stimulatedinduciblenitricoxidesynthase(iNOS).Bothinvitro and in vivo studies suggest that EGCG could reduce synovial hyperplasia, cartilage degradation and bone resorption by modulatingmultipletargetsinjoints[71].Nevertheless, preclini-calstudies arestill neededtobettersupport theefficacyofits antioxidantpowerintreatingpatientswithjointdiseases[72]. 3.2.3.ResveratrolResveratrol(Vitisvinifera,ortrans-3,5,40-trihydroxystibene)isa constituentoftherootsofwhitehellebore(Veratrumgrandiflorum O.Loes), but it is also foundin plants like grapes,berries and peanuts[73].Somestudies indicatethat this stilbene could be involved in the prevention and treatment of arthritis by suppressingROSproduction,IL-1synthesis,p53-induced apopto-sisandprostaglandinE2synthesis[74].Inparticular,ithasbeen shownthatintra-articularresveratroltreatmentreducedcartilage lossinrabbitarthritismodelsandRA-relatedpannusformation, usefulin treatingRA.It hasbeenalreadydemonstrated[7]that resveratrol can suppressNF-
k
B activation. This issue has been morerecentlyfurtherinvestigated[75],inanattempttounravel the mechanisms by which resveratrol elicits antiapoptotic and anti-inflammatoryeffects.Inthisregard,theauthorsdescribeda modulationofinvitrotumorpromotionbyresveratrol,actingvia inhibition of the NF-k
B signaling pathway. Moreover, in vivo investigationsfurtherconfirmedtheanti-inflammatoryproperties ofresveratrol,showingthatitreducesTNFa
,IL-1b
andIL-6levels inaratmodelofHepatocellularcarcinoma(HCC)[76].Hence,the anti-inflammatoryeffectofresveratrolinducedmanyresearchers toverifyitspossiblebeneficialactionsinrheumatoidarthritis(RA). In particular, Tian et al. [77] demonstrated that resveratrol attenuatesTNF-a
-inducedproductionofIL-1b
andmatrix metal-loproteinase(MMP-3)viainhibitionofPI3K-Aktsignalingpathway inrheumatoidarthritisfibroblast-likesynoviocytes(FLS).Inadditiontoinvitrostudies,clearlyshowingthebeneficial effectsofresveratrol,clinicaltrialsarecertainlyneededtoconfirm itsefficacyinthepreventionandtreatmentofarthritis,takinginto account that, despite these anti-inflammatory and antioxidant activities,resveratroloralconsumptionandtissuebioavailability areproblematic[7,35].
3.2.4.Curcumin
Curcumin(diferuloylmethane),anorange-yellowcomponentof turmericorcurrypowder,isapolyphenolnaturalproductisolated from the rhizome of the plant Curcuma longa. For centuries, curcuminhasbeenusedinmedicinalpreparationsorusedasa food-coloringagentanditsrecognizedcytoprotectiveeffectsmay beattributedtoitspotentantioxidantactivity[35].Recently, in vitro and in vivo studies indicated that curcumin exhibits
anticancer, antiviral,antiarthritic, anti-amyloid,antioxidant and anti-inflammatory properties. On this basis it has received considerable interest as a potential therapeutic agent for the prevention and/or treatment of various malignant diseases, arthritis, allergies, Alzheimer’s disease and other inflammatory illnesses.Curcuminmitigatesinflammatoryresponsesby inhibit-ingcyclooxygenase-2(COX-2),lipoxygenase,NF
k
B,induciblenitric oxidesynthase,andNOproduction[78,79].Theanti-inflammatory effects of curcumin are partly mediated via inhibition of the transcriptionfactorNF-kBandactivatorprotein(AP)-1,inhibition ofpro-inflammatorycytokinesexpressioninmanycelltypes[35]. Othertargetswithwhichcurcumininteractsinclude phosphory-lase-3 kinase, xanthine oxidase, N-aminopeptidase, amyloid protein, autophosphorylation activated protein kinase, DNA polymerase, glutathione,albumin,tubulin,topoisomeraseIIand toll-like receptor (TLR)4. Because most chronic diseases are mediated through dysregulated inflammation, curcumin has potential use in the prevention of these diseases. Enhanced bioavailabilityofcurcumininthenearfuturemakesthisnatural productpromisingforthetreatmentofhumandiseases[80,81]. However more clinical trials are needed to fully realize its potential.4.Conclusion
Various dietary components like natural antioxidant and, namely, flavonoids could modulate predisposition to chronic inflammatoryconditions and mayhave a role in theirtherapy. Thesecomponentsactthroughavarietyofmechanismsincluding thereductionofbothinflammatorymediatorsproduction,viacell signalingandgeneexpressionmodulation,anddamagingoxidants production.However,reallystrongevidenceofbenefittohuman health throughanti-inflammatoryactionsislackingfor mostof thesedietarycomponents.Thus,furtherstudiesontheefficacyin humansandonunderstandingtheinvolvedmechanismsofaction arerequired[81].
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