Quercetin, Epigallocatechin Gallate, Curcumin, and Resveratrol: From Dietary Sources to Human MicroRNA Modulation

Abstract

Epidemiologic studies suggest that dietary polyphenol intake is associated with a lower incidence of several non-communicable diseases. Although several foods contain complex mixtures of polyphenols, numerous factors can affect their content. Besides the well-known capability of these molecules to act as antioxidants, they are able to interact with cell-signaling pathways, modulating gene expression, influencing the activity of transcription factors, and modulating microRNAs. Here we deeply describe four polyphenols used as nutritional supplements: quercetin, resveratrol, epigallocatechin gallate (ECGC), and curcumin, summarizing the current knowledge about them, spanning from dietary sources to the epigenetic capabilities of these compounds on microRNA modulation.

Full text

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Molecules2020,25,63;doi:10.3390/molecules25010063www.mdpi.com/journal/molecules
Review
Quercetin,EpigallocatechinGallate,Curcumin,
andResveratrol:FromDietarySourcestoHuman
MicroRNAModulation
ErikaCione
1
,ChiaraLaTorre
1
,RobertoCannataro
1,2
,MariaCristinaCaroleo
1
,
PierluigiPlastina
1
andLucaGallelli
2,
*
1
DepartmentofPharmacy,HealthandNutritionalSciences,DepartmentofExcellence2018–2022,
UniversityofCalabria,EdificioPolifunzionale,87036Rende(CS),Italy;erika.cione@unical.it(E.C.);
latorre.chiara@libero.it(C.L.T.);r.cannataro@gmail.com(R.C.);mariacristinacaroleo@virgilio.it(M.C.C.);
pierluigi.plastina@unical.it(P.P.)
2
DepartmentofHealthScience,SchoolofMedicine,UniversityofMagnaGraecia,ClinicalPharmacology
Unit,MaterDominiHospital,88100Catanzaro,Italy
*Correspondence:gallelli@unicz.it;Tel.:+39‐0961‐712322
Received:30November2019;Accepted:20December2019;Published:23December2019
AcademicEditor:SusanaM.Cardoso;AlessiaFazio
Abstract:Epidemiologicstudiessuggestthatdietarypolyphenolintakeisassociatedwithalower
incidenceofseveralnon‐communicablediseases.Althoughseveralfoodscontaincomplexmixtures
ofpolyphenols,numerousfactorscanaffecttheircontent.Besidesthewell‐knowncapabilityofthese
moleculestoactasantioxidants,theyareabletointeractwithcell‐signalingpathways,modulating
geneexpression,influencingtheactivityoftranscriptionfactors,andmodulatingmicroRNAs.Here
wedeeplydescribefourpolyphenolsusedasnutritionalsupplements:quercetin,resveratrol,
epigallocatechingallate(ECGC),andcurcumin,summarizingthecurrentknowledgeaboutthem,
spanningfromdietarysourcestotheepigeneticcapabilitiesofthesecompoundsonmicroRNA
modulation.
Keywords:nutrients;antioxidants;commonuse;phenoliccompounds

1.Introduction
Epidemiologicstudiessuggestthatdietarypolyphenolintakeisassociatedwithalower
incidenceofseveralnon‐communicablediseasesincludingtype2diabetesandcardiovascular
disease(CVD)[1].Theyareoftenlinkedtoexcessiveproductionofreactiveoxygenspecies(ROS)
[2,3].Polyphenolsarethemostabundantantioxidantsinourdietandarecommonlypresentinfruits
[4],vegetables,cereals,olives[5],drylegumes[6],licorice[7],chocolateandbeverages,suchastea,
coffee,andwine.Dividedintodifferentclasses,accordingtotheirchemicalstructure,polyphenols
describeessentiallyphenolicacids,stilbenes,flavonoids,lignans,andcurcuminoids(seeFigure1).
Besidesthewell‐knowncapabilityofthesemoleculestoactasantioxidants,theyareabletointeract
withcell‐signalingpathways,modulatinggeneexpressionintwodifferentways:i)influencingthe
activityoftranscriptionfactorsandii)epigenetically,modulatingmicroRNAs.Herewedeeply
describefourpolyphenolsusedasnutritionalsupplements:quercetin,epigallocatechingallate
(ECGC),curcumin,andresveratrol,summarizingthecurrentknowledgeaboutthem,spanningfrom
dietarysourcestotheirepigeneticcapabilities.

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Figure1.Contentofphenolicacids,stilbenes,flavonoids,lignans,andcurcuminoids(expressedas
mg/100goffood)inthemainfoodsourcesofthesepolyphenolicclasses,accordingtothedatabase
Phenol‐Explore(http://phenol‐explorer.eu/).
2.Polyphenols
2.1.DietarySources
Polyphenols,mainlyflavonoids,aresecondaryplantmetabolitescontainedinfruitsand
vegetables[8].Someofthemarespecificofparticularfoods,suchasflavanonesincitrusfruits[9],
isoflavonesinsoy,andphloridzininapples.Ontheotherhand,otherpolyphenols,suchasquercetin,
arefoundinaplethoraofvegetableproducts[10].Biochemicalandchemicalactivitiesofpolyphenols
havebeentestedwithdifferentanti‐inflammatoryandantioxidantmethods[9,11].Although,several
foodscontaincomplexmixturesofpolyphenols,numerousfactorssuchclimate(sunexposure,
precipitation)and/oragronomyandstorageaswellasmaturityatthetimeofharvest,canaffecttheir
contentinplants.Furthermore,simplypeelingfruitsorvegetablescansignificantlyreduce
polyphenoliccontent,sincethesesubstancesareoftenpresentinhighconcentrationsintheexternal
parts.
2.1.1.PhenolicAcids
Phenolicacidsarederivedfromtwomainphenoliccompounds:benzoicandcinnamicacids.
Examplesofhydroxybenzoicderivativesaregallic,vanillic,andsyringicacids,whereascaffeic,
ferulic,sinapic,andp‐coumaricacidsbelongtohydroxycinnamicacids[12,13].Fruitsandvegetables
arecharacterizedmainlybythepresenceoffreephenolicacids,whereasgrainsandderivativesby
boundphenolicacids[14].Hydroxycinnamicacidsarepresentathighconcentrationsinfruits,
vegetables,tea,cocoa,wine,coffee,andwholegrains[15].Theyexisteitherinfreeorconjugatedform

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inplants[16].Thegreatinterestinphenolicacidsisassociatedwiththeiruseinfoodtechnologydue
totheirhighpotentialinfoodpreservation[17].
2.1.2.Lignans
Lignansarepresentinawidevarietyofplantfoods,includingseeds(flax,pumpkin,sunflower,
poppy,sesame),wholegrains(rye,oats,barley),bran(wheat,oat,rye),beans,fruit(berriesin
particular),andvegetables[18–20].Amongedibleplantcomponents,themostconcentratedlignan
sourcesaresesameandflaxseeds.Sesameseedsexhibitthesecondhighestconcentrationof
sesaminolfollowedbycashewnuts(seeFigure2).Regardingvegetables,theBrassicafamilycontains
pinoresinol,whilespinach,whitepotatoes,andmushroomscontainlowamountsoflignin[21–23].
Secoisolariciresinolandmatairesinolwerethefirstlignansidentifiedinfoods[24,25].Avarietyof
factorscouldaffectlignancontentsinplants,includinggeographiclocation,climate,maturity,and
storageconditions.

Figure2.Mainfoodscontaininglignans,mostlysesaminol,accordingtothedatabasePhenol‐Explore
(http://phenol‐explorer.eu/).
2.1.3.Flavonoids
Amongseveralflavonoidspresentinfoods,quercetin(aflavonol)andepigallocatechin‐3‐gallate
(aflavanol)gainedourscientificinterest.Quercetinprimarilyentersintothedietasquercetin‐3‐
glucoside(isoquercetin).Thisishydrolyzedinthesmallintestineandisrapidlyabsorbed.Foodsrich
inquercetinincludeprincipallyapples,berries,grapes,butalsoredonions,broccoli,blacktea,green
tea,pepper,redwine,tomatoes,andsomefruitjuices(seeFigure3).Theamountofquercetinreceived
fromfoodisprimarilydependentonanindividual’sdietaryhabits[26,27].Itisalsoimportanttonote
thatthefoodcontentofquercetinreflectsvariationsinsoilquality,timeofharvest,andstorage
conditions.Thewayofcookingfoodalsohasanoticeableeffectonquercetincontent:forexample,
onionsloseabout75%oftheirinitialquercetincontentafterboilingfor15min,65%after
microwavingand30%afterfrying.Recentworksdescribetheroleofthismoleculeagainstchronic
diseases,suchastype2diabetesbystimulatinginsulinsecretion[28–31].

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
Figure3.Foodsthatcontainsquercetin,accordingtothedatabasePhenol‐Explore(http://phenol‐
explorer.eu/).
Epigallocatechin‐3‐gallate(EGCG)isthemoststudiedmoleculeoftheflavanolclass.Itisa
catechinconjugatedwithgallicacidandisabundantingreentea(seeFigure4)[32]andcocoabased
products[33].Themaindietarysourcesofcatechins,determiningtheintake,inEuropeandUSAare
cocoaproducts,tea,andpomefruits[34].Cocoahasthehighestcontentofcatechins,followedby
prunejuiceandbroadbeanpod.Moreover,açaíoil,obtainedfromthefruitoftheaçaípalminthe
formof(−)‐epicatechinand(+)‐catechin,ispresentinarganoil[35].Itwasreportedthatgreentea
consumptionhasbeencorrelatedwithalowincidenceofchroniccardiovasculardisease[36].Inany
case,comparedtoothercatechinsfoundintea,EGCGpossessesthemostimportantbiological
activitiesoninhibitionofangiogenesisand,therefore,cancerprogressionlikelyduetoitsgalloyl
moiety[37,38].

Figure4.Epigallocatechin‐3‐gallate(EGCG)fromgreentea,accordingtothedatabasePhenol‐
Explore(http://phenol‐explorer.eu/).
2.1.4.Stilbenes
Lowquantitiesofstilbenesarepresentinthehumandiet,andthemainrepresentativeis
resveratrol.ThiscompoundwasfirstisolatedfromtherootsofVeratrumgrandiflorumO.Loesin1940
andlaterfromtherootsofPolygonumcuspidatum[39].Itisproducedbyplantsinresponsetoinfection
bypathogens[40–42]ortoavarietyofstressconditions.Ithasbeendetectedinmorethan70plant
species,includinggrapes,berries,andpeanuts(seeFigure5).Severalstudieshighlightedthatthis
compoundhasawiderangeofbiologicalactivities[43,44].

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
Figure5.Structureofresveratrolanditscontentinmainfoods,accordingtothedatabasePhenol‐
Explore.
2.1.5.Curcumin
Curcuministhemostwidelystudiedamongcurcuminoids.Itisanaturalphenolicthatis
responsiblefortheyellowcolorofturmeric(Curcumalonga),amemberofthegingerfamily,
Zingiberaceae.Themostcommonapplicationsareasaningredientindietarysupplements,in
cosmetics,andasflavoringforfoods,suchasturmeric‐flavoredbeveragesinSouthandSoutheast
Asia.Asafoodadditivefororange–yellowcoloringinpreparedfoods,itsEnumberisE100inthe
EuropeanUnion.Curcuminisnotverywidespreadinfood,infactthefoodsrichestincurcuminare
onlyturmericplantandcurrypowder(Figure6)[45].

Figure6.Structureofcurcuminanditscontentinmainfoods,accordingtothedatabasePhenol‐
Explore.
2.2.Chemistry
Polyphenolsrepresentthemostabundantcompoundsamongthesecondarymetabolites
producedbyplants,withmorethan8000identifiedcompounds,rangingfromsmallmoleculessuch
asphenolicacidstohighlypolymerizedsubstancessuchastannins[46].Theyareproducedviathe
phenylpropanoidpathwayinwhichphenylalaninerepresentsthestartingcompound[47].Froma
chemicalpointofview,polyphenolsarecharacterizedbythepresenceofoneormorearomaticrings
bearingoneormorehydroxylgroups.AnearlyclassificationwasfirstsuggestedbyManachand

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colleagues[48],whodistinguishedfourclassesofpolyphenols,namely:1)phenolicacids,2)
flavonoids,3)stilbenes,and4)lignans.Phenolicacidscanbefurthersub‐dividedintotwoclasses:
hydroxybenzoicandhydroxycinnamicacids(seeTable1).Thesecompoundsexistinthefreeformas
wellasintheesterifiedform.Caffeicacidismostoftenconjugatedwithquinicacidtoform
chlorogenicacid,whichisthemajorphenoliccompoundincoffee,whileferulicacidisabundantly
presentincerealswhereitisesterifiedtohemicellulosesinthecellwall[49].
Table1.Structureandclassificationofphenolicacids.

Hydroxybenzoicacids
NameR1R2R3
p‐HydroxybenzoicacidHOHH
ProtocatechuicacidOHOHH
VanillicacidOCH3OHH
GallicacidOHOHOH
SyringicacidOCH3OHOCH3


Hydroxycinnamicacids
AcidR1R2R3
p‐CoumaricacidHOHH
CaffeicacidOHOHH
FerulicacidOCH3OHH
SinapicacidOCH3OHOCH3

Theflavonoidfamilyrepresentsthelargestclassofpolyphenols.Thebasicflavonoidstructure
containstwoaromaticrings(labeledAandB)connectedbyaC3linkagewhichisnormally
incorporatedintoanotherring(labeledC)[50].Flavonoidsaresub‐dividedintosixmainsubgroups:
flavones,isoflavones,flavonols,flavanones,anthocyanins,andflavan‐3‐ols,accordingtothe
oxidationstateofthecentralCring.Structuralvariationineachsubgroupdependsonthenumber
andpositionofhydroxylandmethoxylgroups.Moreover,thesecompoundsexistintheirfreeform,
aswellasintheesterified,prenylated,andglycosylatedforms(seeFigure7)[51,52].

FlavoneIsoflavoneFlavonol
FlavanoneAnthocyaninFlavan‐3‐ol
Figure7.Basicstructureandclassificationofthemostimportantflavonoids.
Quercetinusuallyoccursinplantsasglycosides,linkedwithvarioussugarmoieties,mostly
glucose,butalsogalactose,rhamnose,andothers.Flavan‐3‐olscanbefoundintheiresterifiedforms,
linkedtoagallatemoiety,asinthecaseofepigallocatechin‐3‐gallate(EGCG).Anthocyanins(from
theGreek‘anthos’,flower)areresponsiblefortheorange,red,blue,andpurplecolorsofflowersand
fruitsofmanyplants.Theyaretheglycosylatedformofthecorrespondinganthocyanidins
(aglycones)[52].

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Tanninsrepresentanimportantgroupofpolymericphenoliccompoundsandareusually
dividedintotwosubgroups:hydrolyzabletanninsandcondensedtannins.Hydrolyzabletannins
containacentralcoreofglucoseesterifiedwithgallicacidmoieties(gallotannins),orwith
hexahydroxydiphenicacid(ellagitannins).Thesecompoundshaveamolecularweightrangingfrom
2000to5000Daltons.Condensedtannins,alsoreferredtoasproanthocyanidins,areoligomersor
polymersofflavan‐3‐olslinkedthroughaninterflavancarbonbond[49].
Stilbenesandlignansarelesscommonplantphenolics.Resveratrol(3,4′,5‐trihydroxystilbene,
seeFigure8)isthemostinvestigatedcompoundbelongingtothestilbeneclassexistingincisand
transforms.Itispredominantlyfoundingrapesandgrapejuiceastrans‐resveratrolglucoside(trans‐
piceid).

Figure8.Structureofresveratrol(R=H)andresveratrolglucoside(R=glucose).
Curcumin[1,7‐bis(4‐hydroxy‐3‐methoxyphenyl)‐1,6heptadiene‐3,5‐dione]isanon‐polar
polyphenol.Itisabis‐α,β‐unsaturatedβ‐diketoneandexistsindifferenttautomericforms(seeFigure
9).Theβ‐diketoneformprevailsinacidicandneutralaqueoussolutions,whiletheenolform
predominatesinmorealkalinemedia[53].Inthecaseofcurcumin,thearomaticringsare
functionalizedwithhydroxyandmethoxygroups,whereastheothercurcuminoidslackoneorboth
methoxygroups(desmethoxycurcuminandbisdesmethoxycurcumin,respectively).

Figure9.Structureandketo–enoltautomerismofcurcumin(R1=R2=OMe),desmethoxycurcumin(R1
=OMe,R2=H),andbisdesmethoxycurcumin(R1=R2=H).
2.3.NutritionalSupplements
Followingthepromisingresultfrominvivoandinvitrostudies,overthelastdecade,therewas
astrongdevelopmentofnutritionalsupplementsbasedonpolyphenols.However,strongandsolid
studiesonhumanefficacyarestilllacking.Despitethat,quercetin,EGCG,curcumin,andresveratrol
aremarketedasdietarysupplements.ThesemoleculeshavebeenrecognizedasGRAS(generally
recognizedassafe)bytheFoodandDrugAdministration(FDA)aswellasbytheEuropeanFood
SafetyAuthority(EFSA)forthebeneficialeffectsontheprotectionofDNA,proteins,andlipidsfrom
oxidativedamage,highlightingtheirantioxidantpower.
Quercetinisusedasanergogenicsupplement(asupplementthatcouldimprovesports
performance)buttheresultsonthiscapabilityarecontroversial.Forexample,Neimanandcoworkers
supplementedquercetintocyclistsfortwoweeks(1gperday)andanalyzedmuscularbiopsyfinding

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aslightlysignificantimprovementinmitochondrialdensity[54].Ontheotherhands,meta‐regression
analysisrelativetosubjects’fitnesslevelandplasmaquercetinconcentrationachievedby
supplementationwasnotsignificant[55].ThepointofviewofKerksickandtheInternationalSociety
ofSportNutritionisthatquercetinissafeandisagoodantioxidant,butitneedsmorestudiesto
evaluateitsergogenicpower[56].
EGCGfromgreenteaandgreenteaextractsiswidelyusedintraditionalChinesemedicine,so
itisconsideredsafeeveninhugedosages(>1–3gperday)itcanbeapro‐oxidantbringingnegative
effectssuchreactiveoxygenspecies(ROS)production[54,57].Despitethisdichotomiceffect,todate
nostudiesconfirmedthenegativeeffectofEGCGinhumans.Incontrast,aninterestingstudy
performedbyPervinandcoworkersshowedthatgreenteaconsumptionleadstoanimprovementin
cognitivefunction[58].Recently,Xicotaandco‐workersshowedthatEGCGhasmodestbeneficial
effectonweightmanagementinDownsyndromesubjectsandcognitivefunction[59].Furthermore,
EGCGhasalsobeenseentohaveasex‐dependenteffectonlipidprofilethatwasrelatedtochanges
inbodymassandcomposition.
CurcuminiswidespreadinmanyAsiancuisinesaswellasinAyurvedicmedicine[60].Besides
that,theantioxidantandanti‐inflammatorypropertiesofcurcuminarewellknown[61],dealingwith
variouspathologiessucharthritisandosteoarthritis[62–67],obesityanddiabetes[68,69].Inaddition
toitsverylowbioavailability,therealmechanismofactionofcurcuminisstilluncertain.Itwas
speculatedthatitprobablyactsviathe“sanitation”ofthegutandtheconsequenthealingof
inflammation.Therefore,itwassupposedthatthemicrobiomecouldyieldactivemetabolitesfrom
curcumin.However,themechanismsofactionremainunclear;itprobablypossessesanepigenetic
modulatingpowerbuttodateonlyinvitrostudiesareinsupportoftheseimportanteffects[70].
Inthe1992,Renaudandco‐workerspublishedaninterestingstudy,pointingoutwhatisknown
asthe“Frenchparadox”[71].ThelowsusceptibilityofFrenchpeopletoCVDlinkedtotheuseofred
wine.Redwineandobviouslygrapeareasourceofresveratrol,apowerfulantioxidantwithbenefits
formusclestrengthwithanti‐inflammatoryeffects[72,73].Resveratrolisabletoregulatemetabolism
[74],anditisusefulinthetreatmentofneurodegenerativediseases[75],diabetes[76],cardiovascular
diseases[77–79],andcancer[80].Inhumans,adoseof450mgperdayisconsideredsafe[81].
2.4.MicroRNAs
Usedasnutritionalsupplements,polyphenolsareabletoinfluencetheactivityoftranscription
factorsortomodulatemicroRNAs(miRNAs).miRNAsaredefinedassmallnoncodingRNA
molecules,havingfrom21to22nucleotides.Theirsynthesisproceedsthroughwell‐defined
biochemicalsteps:theprimarytranscriptsalsocalledhairpin‐shaped(knownaspre‐miRNAs)are
derivedfrom:i)intronsoftheircorrespondingtranscriptionpartsandii)intergenicregionsofDNA,
catalyzedbyRNaseII;thecatalyticcleavageofthepre‐miRNAsgeneratessmallertranscripts,called
pre‐miRNAsabout70nucleotideslong[82].ThisbiochemicalstepiscatalyzedbythepolymeraseIII
Drosha.Then,DGCR8aproteinasadsRNA(doublestrand‐RNA)bindingmoleculemakesa
complexwithDrosha,forminga“microprocessor”abletocuttheinitialtranscripttoa70‐nucleotide
lengthwithanincompletestem‐loopstructure,calledpre‐miRNA.Thepre‐miRNAsareasubstrate
thateasilyproceedtothecytoplasmthroughthecarrierExportin5[83].Then,aspecifichelicase,
knownasDicerRNase,togetherwithaseconddsRNAbindingprotein,calledTAR‐RNAbinding
protein(TRBP)performsthelastcleavageprocessofpre‐miRNAsintheirhairpinsiteandconverts
themtosmalldouble‐strandedRNAs,containingthematuremiRNAanditscomplementarystrand.
TRBPisabletorecruittheargonaute(AGO)proteinasthemainfactorforRNA‐induced
silencingcomplex(RISC)loading[83].Finally,maturemiRNAsarepackagedintoexosomesfor
extracellularandbloodstreamtransport[84].
Theireffectisrecognizedafterspecificbindingtocomplementarynucleotidesoftheseedregion
(about2–8nucleotideslong)oftargetmRNAsuppressingitstranslationandstability[85].Recently,
theroleofnutritionand
microRNAs
aspowerfulregulators
meta
bolicfunctionsandthe
maintenanceofoxidativestressisemerging[86–88].Sincedietary
factors
mayhaveaninfluenceon

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miRNAbiogenesis,itseemsreasonabletoassumethatsome
bioactive
compounds
presentin
different
foods
may
modulatethe
development
and
progressionof
certain
diseases
.Therefore,
bioactivecompoundspresentinfoodsmayaffectendogenousmiRNAsynthesis.
Itwasdemonstratedthatnaturalcompoundssuchaspolyphenolscanstimulatetumor
suppressorgenes,alteringmiRNAexpressions.Inthisregard,s
everalinvitrostudiesshowthe
effectofquercetin,EGCG,curcumin,andresveratrolonmiRNAexpressioninmodelsystems.
Currently,manyinvestigationshavefocusedonmodifyingthemiRNAfunctionsincancercellsto
achievetherapeuticapproaches.Inaddition,inthecaseofresveratrol,ahumanstudyhasalsobeen
carriedout.Atthemomentofthewritingofthisarticle,2675humanmaturemiRNAsequencehave
beendescribedinmiRBase22(http://www.mirbase.org/).
2.4.1.QuercetinandMicroRNAs
Theprotectiveeffectsofquercetinonhumanhealtharemediatedbymultifaceted,pleiotropic
actionevenfromanepigeneticpointofview.Currently,muchresearchhasfocusedonmodulating
themiRNAexpressionincancercellsinordertoachievetherapeuticapproaches.Quercetinperse,
wasabletoincreasetheexpressionofmiR‐146ainhumanbreastcancercells[89].Similarresultswere
achievedbyquercetinderivativesonmiR‐146ainlipopolysaccharide(LPS)‐treatednormalcolon
cells,aswellasinmurinemacrophagesinwhichmiR‐155expressionwasdecreased[90].The
upregulationofmiR‐146ainducedToll‐likereceptor4(TLR4)stimulationwhichregulatesnuclear
factorkappa‐light‐chain‐enhancerofactivatedBcells(NF‐κB)andotherTLRmediatorsof
inflammation[91].
Theinfluenceofquercetinwasalsostudiedinseveraltypesofhumancancercelllinespointing
outtheupregulationoflet‐7a,let‐7c,miR‐200b‐3p,andmiR‐142‐3pinpancreaticductal
adenocarcinoma[92–95].Theupregulationofmir‐let‐7familyfunctionasinhibitormoleculesableto
targetK‐Rasgeneandthereforeaffectsproliferationfunctioningasbiomarkersforbothprognosis
andtherapyforprecisionmedicineincancer[92,96];whilemiR‐200b‐3pandmiR‐142‐3pregulates
themodeofself‐renewingdivisionsandtheheatshockprotein70,respectively[92–95].
Furthermore,miR‐16,miR‐217,andmiR‐145weremodulatedbyquercetininlung
adenocarcinoma,osteosarcoma,andovariancancercells,respectively[97–99].Inthelung,miR‐16
wasabletodownregulateClaudin‐2whichisalsoamediatorofleakygutbarrierduringintestinal
inflammation[97,100].Ontheotherhand,miR‐217enhancescisplatinsensitivityinterferingwithK‐
Raspathways[98]andmiR‐145inhibitsandcontroltargetinggenesthathavesimilarbehaviorin
apoptosisandindifferentGeneExpressionOmnibus(GEO)databases[99,101].
2.4.2.EGCGandMicroRNAs
Similartootherpolyphenols,EGCGwasextensivelystudiedininflammation.Inparticular,
whenEGCGisusedininterleukin‐1‐beta(IL‐1β)‐stimulatedhumanosteoarthritischondrocytescell
line,itwasabletoupregulateanddownregulateaplethoraofmiRNAs.Especially,let‐7family(let‐
7a‐5p,let‐7b‐5p,let‐7c,let‐7d‐5p,let‐7f‐5p,let‐7i‐5p),miR‐140‐3p,miR‐193a‐3p,miR‐199a‐3p,miR‐
27b‐3p,miR‐29a‐3p,miR‐320b,miR‐34a‐5p,miR‐3960,miR‐4284,miR‐4454,miR‐497‐5p,miR‐5100,
andmiR‐100‐5pwereupregulated[102].ItisofnotethatmiRsexosomecargoistodayproposedin
theosteoarthritismanagement[103].Withregardtothis,recentstudiesshowedthattheexosomes
derivedfrommesenchymalstemcellsmaintainchondrocytehomeostasis,amelioratingthe
pathologicalseverityofthediseasethisisduetothemiR‐100‐5pwhichinturnsinhibitsthemTOR‐
autophagypathway[104].Inthesamesetofexperiments,researcherdocumentedthatEGCGwas
abletodecreaselet‐7e‐5p,miR‐103a‐3p,miR‐151a‐5p,miR‐195‐5p,miR‐222‐3p,miR‐23a‐3p,miR‐23b‐
3p,miR‐26a‐5p,miR‐27a‐3p,miR‐29b‐3p,miR‐3195,miR‐3651,miR‐4281,miR‐4459,miR‐4516,miR‐
762,andmiR‐125b‐5pexpression[102].ThedecreaseofthislattermiRisnotpositiveforthe
preventionofcartilagebreakdowninosteoarthritis[105].
SincemodulationofmiRNAexpressionincancercellscouldbeatherapeuticstrategy,EGCG’s
biochemicaleffectswerealsostudiedincancer.EGCGwasabletoupregulatemiR‐140‐3pandmiR‐

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221inmelanomaandhepatomacelllines,respectively[106,107]inhibitingosteopontinininduced
liverfibrosis[107].SimilarresultsformiR‐140‐3pwereobtainedunderEGCGtreatmentin
chondrocyte[102].Furthermore,EGCGinducedtheincreaseofmiR‐3663‐3p,miR‐1181,miR‐3613‐
3p,miR1281,andmiR‐1539andthedecreaseofmiR‐221‐5p,miR‐374b,miR‐4306,miR‐500a‐5p,and
miR590‐5pinhumandermalpapillacells[108]fromscalphair.Thesensitivityofthescalpisalso
higherinmigraine,andthislattermiRwasfounddownregulatedinhumanssufferingfrompain‐
migraine.ThelevelofthismiR‐590‐5pwasrestoredwithdiet[109].Interestingly,greenteais
recommendedtorelievemigraineattackfrequency[110].
2.4.3.CurcuminandMicroRNAs
Curcumin treatmentonschwannomacellsbymiRsarrayrevealedthatmiR‐350,miR‐17‐2‐3p,
let7e‐3p,miR‐1224,miR‐466b‐1‐3p,miR‐18a‐5p,andmiR‐322‐5pweredownregulatedwhilemiR‐
122‐5p,miR‐3473,miR‐182,andmiR‐344a‐3pwereupregulated.ThislattermiRshavearoleinthe
controlofapoptosisinschwannomacells[111].Inaddition,inseveraltypesofcancer,curcuminhas
beenshowntoplayaroleinthemodulationofmiRscontrollingapoptosis,i.e.,miR‐33bandmiR‐
205‐5pareupregulatedinmelanomacancercellswhilemiR‐21wasdownregulated.Onthecontrary,
incolorectalcancer,upontreatmentwithcurcumin,miR‐21,miR‐3a/c,andmiR‐27awere
upregulated,andmiR‐200b/c,miR‐141,miR‐101,miR‐429,andmiR‐34adisplayedlowerexpression
withrespecttotheuntreatedcells[112].
UpregulationoftheclustermiR‐192‐5p/215wasreportedinlungcanceruponcurcumin
treatmentaswellasmiR‐9,miR‐205,miR‐200a/b,miR‐15a/16‐1,andmiR‐203inovarian,prostate,
hepatocellular,leukemia,andbladdercancercells,respectively.Inbreastcancercells,miR‐19and
miR‐15a/16‐1werefoundupregulated,whereasmiR‐34aandmiR‐181bweredownregulated.In
thyroidcarcinomasmiR‐21andmiRNA‐200cwerefoundupregulatedwhilelet7c,miR‐26a,miR‐215,
miR‐192‐5p,andmiR‐125bweredownregulated[112].Thelatterwasalsofounddownregulated
uponcurcumintreatmentinnasopharyngealcarcinoma[112].
Furthermore,curcumininducedapoptosisincisplatin‐resistanthumanovariancancercells
throughcaspase‐3activationandpoly(ADP‐ribose)polymerase(PARP)cleavage,viaupregulation
ofmiR‐9[113].
AltogetherthemiRsmodulatedbythepolyphenolsdiscussedhereresultedtoinfluenceseveral
pathwaysincludingWntandmitogen‐activatedproteinkinase(MAPK)signaling,pathwaysin
cancerandbasalcellcarcinoma,aswellasinadherencejunction,neurotrophinsignaling,andaxon
guidance,and,lastbutnotleast,cytokine–cytokinereceptorinteractionasitispresentinKEGG
(KyotoEncyclopediaofGenesandGenomes)database
(https://www.genome.jp/kegg/pathway.html).
2.4.4.ResveratrolandMicroRNAs
Currently,morethanahundredscientificdocumentshaveconfirmedthattheeffectof
resveratrolinthepreventionortreatmentofvariousdiseases,includingcancer,ismediatedbymiRs.
Thebiologicaleffectsofresveratrolwerestudiedinhumancoloncancerinwhichitsignificantly
decreasedthelevelsofmiR‐17,miR‐21,miR‐25,miR‐92a‐2,miR‐103‐1,andmiR‐103‐2.ThosemiRsin
certaincontextshavebeenshowntoactasoncomiRs[114].Inprostatecancer[115]andinmelanoma,
resveratroldecreasedmiR‐221levels[116].Whileinlungtumors,resveratrolledtoanupregulation
ofmiR‐200c[117].Inaddition,itactstodecreasemiR‐542‐3pandincreasemiR‐122‐5pinestrogen‐
responsiveandtriple‐negativebreastcancercells,whileonlymir‐122‐5pisincreasedinthetriple‐
negativecells[118].ResveratrolshowedeffectivenessviamiRsnotonlyinaberrantpathophysiology
suchascancer,butinphysiologicalcellsystemssuchaswhiteadiposecelllinesalsoresveratrol
inducedtheexpressionofmiR‐539‐5pinhibitingdenovolipogenesis[119].
Inprimaryhumanfibroblasts,resveratrolwasabledecreasemiR‐566andmiR‐23a,restoring
mitochondrialfattyacidβ‐oxidationratesinprimaryhumanfibroblastsformpatientsharboring
carnitinepalmitoyltransferase‐2mutationassociatedwithtwodifferentphenotypes(neonatal

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lethalityormyopathyinmildforms)[120].Therefore,resveratrol,independentlyofthedisease,led
tomiR‐566andmiR‐23amodulationspecifically[120].MicroarrayanalysisshowedthathumanTHP‐
1monocyticcellstreatedwithresveratrolincreasedtheexpressionofmiR‐663decreasingmiR‐155
[121].Ontheotherhand,thereductionofproliferationanddifferentiationofpre‐adipocytesdueto
resveratroltreatment,ledtotheoverexpressionofmiR‐155[122].
Althoughofinterest,theinvitrostudiesconductedsofarhavenotbeentranslatedtohumans
yet.Onlyresveratrolhasbeenstudiedinhumansubjects[81].Thedailyintakeusedwasone
capsule/dayofgrapeextract(139mg)containingresveratrol(8.1mg)bymenwithT2D,hypertension,
andBMI>30kg/m2forsixmonthsandtwocapsules/dayforfurthersixmonths.Thistreatment
yieldedtheupregulationofmiR‐21,miR‐181b,miR‐663,andmiR‐30candtheconcomitantlower
levelsofinflammatorycytokinessuchasIL‐6,chemokine(C‐Cmotif)ligand3(CCL3),IL‐1β,and
tumornecrosisfactorα(TNF‐α).Additionally,miR‐155increasedaswellinperipheralblood
mononuclearcells.TheincreaseinthesemiRNAswasassociatedwithareductionofinflammation
mediatedbytheregulationoftheTLRandNF‐kBpathwaysandinflammatorycytokinegene
expression[81].
2.5.PharmacokineticProfile
Variousreportsunveiledpolyphenolsaspromisingtherapeuticagentsowingtotheirbroad
spectrumofbiologicalactivities.Thesecompoundshavelongbeenrecognizedtopossessfreeradical
scavengingproperties,however,thepresenceofbothhydrophobicandhydrophilicdomainswithin
thechemicalstructureenablespolyphenolstoaffectmembranedynamicsthroughthearrangement
ofmembraneproteinsandtheformationoffunctionalcomplexesresponsibleforcellsignal
transductionandtheregulationofthemetabolism[123].Thismechanismofactionunderliesmostof
thebeneficialeffectsofpolyphenols,howevertheeffectivenessofthesecompoundsindisease
preventionandhumanhealthimprovementistightlyrelatedandlimitedtotheirbioavailability[48].
Theconceptofbioavailabilityencompassesseveralvariablessuchasintestinalabsorption,
metabolismbygutmicrobiota,intestinalandlivermetabolism,biologicalpropertiesofmetabolites,
distributionattissueslevel,andexcretion,whichinturndependuponthechemicalstructureof
xenobiotics.
Thevariouschemicalformsofpolyphenolsleadtohighvariabilityintheirrateandextentof
intestinalabsorptionaswellasinthenatureofcirculatingmetabolites[48].Mostofthesecompounds
areintheglycosylatedformresultinginalowgradeofabsorptionoftheirnativemolecule.
Commonlyflavonoidsshowassugarmoietyglucoseorrhamnose,andfollowingtheiringestion,
thesecompoundsundergodeglycosylationpriortobeingabsorbed[124].Hydrolysisofsaccharide
moietyoccursatthelevelofgastrointestinalcells,anditiscarriedoutbyintracellularcytoplasmicβ‐
glucosidase(CBG)[125],ofnote,theexpressionpatternistissuespecificandoftenregulatedduring
development.Inhumans,differentglycosidaseshavebeendocumented:i)lactasephlorizin
hydrolase(LPH)andCBGatthelevelofredbloodcellsandcytosol,respectively.Bothenzymes
hydrolyzedglycosylatedflavonoidsinthemorehydrophobicaglycones,thuspromotingpassive
diffusionthroughenterocytes[126–128].However,determinedglycosylatedflavonoids,suchas
quercetin‐4′‐glucoside,werefoundtobealsoactivelytransportedintoenterocytesthroughtheactive
sodium‐dependentglucosetransport(SGLT1)[128].Itisworthmentioningthatflavonoidswith
rhamnosemoietyarenotsubstratesforhumanβ‐glycosylasesbeingcleavedbycolonmicrofloraα‐
rhamnosidasesbeforetheabsorptionprocess[129].Alargeproportionofpolyphenolsisconstituted
byflavan‐3‐olssuchas(−)‐epicatechins.Thesecompoundsareneverglycosylatedbutoften
acetylatedbygallicacid.Asrevealedbypharmacokineticstudies,catechins,andparticularlyEGCG,
arepredominantlyabsorbedinthejejunumandtheileum,viaaparacellulardiffusionthrough
epithelialcellswithoutanyde‐conjugationorhydrolysis[130].
Animportantsteplimitingtheabsorptionofthedeterminedflavonoidsisrepresentedby
intestinalefflux[131].Thisprocessisaffectedbymembranetransportersand,amongthese,members
oftheadenosinetriphosphate(ATP)‐bindingcassette(ABC)superfamilysuchasmultidrug‐

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resistanceprotein(MRP),P‐glycoprotein(P‐gp),andbreastcancerresistanceprotein(BCRP)have
beenreportedtobeinvolvedintheregulationofsomeflavonoidsintestinaleffluxandultimatelyto
influencethenetamountthatisabsorbedintosystemiccirculation[132,133].Theeffluxofquercetin
andepicatechinmetabolitesisthoughttooccurbyMRP2,locatedontheluminalsideofepithelial
cells[131]whilethemonocarboxylatetransporterP‐gp,MRP1,andMPR2playsignificantrolesinthe
cellularaccumulationandpossibleeffectsof(−)‐epicatechingallate[134].SinceABCtransportersare
ubiquitouslypresentinmosttissues,theinterplaybetweenflavonoidsandABCtransporterscould
notonlymodulatetheextentofintestinaleffluxandbioavailabilitybutalsothedistributionof
flavonoidconjugatestothetargetsitesandtheirelimination.Moreover,bioavailabilityofthese
compoundsmaybeamplifiedorreducedbyaselectiveinteractionwithABCtransporters[135]when
co‐administered.
BothquercetinandEGCGundergotoextensivemetabolismatbothenterocytesandliverlevels
byglucuronidation,sulfation,andmethylationreactions[136–138].Someoftheliverconjugatesare
excretedasbilecomponentsandundergoenterohepaticrecirculation.Thede‐conjugatedcompounds
arethenregeneratedbygutmicrobialenzymesbeforebeingreabsorbedagain[139–142]whilethe
unabsorbedmetabolitesareeliminatedviafeces.Alltheconjugationmechanismsarehighlyefficient,
thereforeconsiderableamountsofmetabolitesreachthebloodstream[143].Theseproductsretainthe
biologicalactivityproducingsimilar,stronger,orweakereffectscomparedwithparentcompounds
[144,145].Anexceptionisgreenteacatechins,whoseaglyconesconstituteasubstantialproportionof
thetotalamountinplasma,astheyaredevoidofthesugarmoietyand,hence,quicklyabsorbedat
thesmallintestinewithoutfurthermodifications[146].
Thepoorsystemicbioavailabilityalsoaffectsthemechanismofactionacrossconditionsand
dosesofresveratrolasdemonstratedbytheinvivonon‐reproducibilityofinvitroeffects[147,148].
Inhumans,resveratrolishighlyabsorbedorally.However,arapidandextensivebiotransformation
ofthepolyphenoloccursaftertheabsorptionphaseintotheenterocytes.Specifically,resveratrol
undergoessulfationandglucuronidationmediatedbysulfotransferase1A1(SULT1A1)andUDP
glucuronosyltransferase1family,polypeptideA1(UGT1A1)andUDPglucuronosyltransferase1
family,polypeptideA9(UGT1A9)enzymes,respectively.Themetabolismtakesplaceinmultiple
organsandcelltypes,andtheobservedbiotransformationdiffersinmetabolitelevels[149],according
totissueexpressionofthespecificenzymesinvolvedinthebiotransformation[150].Ofnote,thereis
aninter‐speciesvariationofphaseIImetabolismand,inthisrespect,resveratrolsulfatesarethemain
conjugatesinhumans,whileglucuronidesconjugatesaredominantinpigsandrats[151].Itisworth
mentioningthat,drugmetabolismisawell‐documentedcauseofinter‐individualvariabilityandfor
bothSULTsandUGTsgeneticpolymorphismshavebeenreported[152,153].Afterabsorptionand
conjugation,resveratrolsulfatesandglucuronidesthroughtheABCtransportersexpressedatboth
apicalandbasolateralportionsofenterocytemembranecanbetransportedeitherintheintestinal
lumenorinthebloodstreamwheretheybindtolipoproteinsoralbuminbeforedistributingto
peripheraltissues[154].Ofnote,transportersarenotlimitedtoparticipatingintheabsorptionand
distributionofresveratrolandmetabolitesintheduodenumandjejunum,astheyarealsoexpressed
inothertissues,suchaskidneys[155–158],thuscontributingtoexcretionprocesses.Unlike
resveratrol,thelowavailabilityofcurcumininhumansafteroralintakeisprimarilyduetoalow
gradeofabsorptionbythesmallintestinecoupledwithfastmetabolismandelimination.
Thepoorbioavailabilityisalsointensifiedbythecurcumin’scapabilitytobindtoenterocyte
proteinsthatcanmodifyitsstructure[159–161].TheliveristheprimarysiteofphaseIandII
curcuminbiotransformationalongwithintestineandgutmicrobiota[162].Extensivemetabolic
reductionalsooccursatenterocyteandhepatocytelevelsleadingtotheformationof
dihydrocurcumin,tetrahydrocurcumin,hexa‐hydrocurcumin,andoctahydrocurcuminwhichinturn
areconvertedthroughconjugationintophysiologicallyinactiveconstituents[163].Ofnote,these
reducedcompoundscanexistbothinfreeformorasglucuronides[162].PhaseIImetabolismtakes
placeintheintestinalandhepaticcytosolonbothcurcuminanditsphaseIproductsbyconjugation
withglucuronicacidorsulfationatphenolicsite.CurcuminissulfatedbySULT1A1,SULT1A3inthe
cytosolicfractionwhileUGTscatalyzetheglucuronidationatthelevelofhepaticmicrosomes.Gut

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microfloraalsocontributetocurcuminmetabolismmainlythroughsulfationordemethylation
reactionsleadingtotetrahydrocurcumin[164]anddemethylcurcuminandbis‐demethylcurcumin
[165],respectively.Ofnote,curcuminmetabolitesretainallpharmacologicalpropertiesoftheparent
compoundshowinganti‐oxidant,anti‐inflammatory,antitumor,cardioprotective,andanti‐diabetic
effects[5,19,20].Gendercanalsosignificantlyaffectcurcuminpharmacokinetics.Thedifferencesare
relatedtogender‐specificfactors,amongthese,ahigheractivityofhepaticdrugeffluxtransporters
inmenandthepresenceofhigherbodyfatinwomen[166,167].
3.Methods
PubMed,Embase,Cochranelibrary,andreferencelistsweresearchedforarticlespublisheduntil
1November2019,usingthekeywords“polyphenols”,“radicaloxygenspeciesandantioxidant
activity”,“inflammatorybiomarkers”,“epidemiology”,“foodsource”,“geneexpression”,
“microRNAs”,“microRNAsandinflammatorybiomarkers”.Secondarysearchesincludedarticles
citedinsourcesidentifiedbytheprevioussearch.
4.Conclusions
Understandingpolyphenolconsumptionisessentialtodeterminethenatureandthe
distributionofthesecompoundsinourdiet.Despitetheirpoorbioavailability,quercetin,EGCG,
curcumin,andresveratrolaremarketedassupplements.Onlyforthelatterone,studieswere
conductedinhumansubjectspointingoutitscapabilitytoinfluencemiRNAexpressionpattern
relatedtoinflammation.Inthisview,asafuturedirection,wesuggestusingthemicroRNAslinked
toinflammatory,antioxidant,orimmunestatusasmarker(s)formonitoringnutraceuticaleffectsof
polyphenols.Atthemoment,polyphenolsarebecomingprotagonistsinthenutraceuticalscenario
withoutstudiesonhumansubjects.Themainfactorresponsibleforthisdelayisthevarietyandthe
complexityoftheirchemicalstructureandtosomeextenttheirgutmicroflorametabolite.
AuthorContributions:E.C.coordinatedandrevisedtheworkandwrotethesectiononmicroRNAs;C.L.T.
wrotethesectionondietarysources;R.C.wrotethesectionondietarysupplements,P.P.wrotethesectionon
chemistry;M.C.C.wrotethesectiononpharmacology;L.G.facilitatedtheworkandwrotetheconclusions.All
authorshavereadandagreedtothepublishedversionofthemanuscript.
Funding: Thisresearchreceivednoexternalfunding
ConflictsofInterest:Theauthorsdeclarenoconflictofinterest.
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