Curcumin | Linus Pauling Institute | Oregon State University

However, it is important to note that the effect of curcumin on biotransformation enzymes may vary depending on the route of administration, the dose, and the ... 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Curcuminisabiologicallyactivepolyphenoliccompoundfoundinturmeric,aspicederivedfromtherhizomesoftheplantCurcumalongaLinn.CommonlyconsumedinAsiancountries,turmerichasbeenusedformedicinalpurposesforcenturies.(Moreinformation) Mountingevidencefrompreclinicalstudiesshowsthatcurcuminmodulatesnumerousmoleculartargetsandexertsantioxidant,anti-inflammatory,anticancer,andneuroprotectiveactivities.(Moreinformation) Inhumans,curcumintakenorallyispoorlyabsorbedandrapidlymetabolizedandeliminated.Therefore,thepotentialofcurcuminasatherapeuticagentislimitedbyitspoorbioavailability.(Moreinformation) Currentevidencesuggestingthatcurcuminmayhelppreventand/ortreatcolorectalcancerandtype2diabetesmellitusisverylimited.Yet,severalclinicaltrialsdesignedtoassessthesafetyandefficacyofcurcuminaloneorwithfirst-linetreatmentinpatientswithbreast,prostate,pancreatic,lung,orcolorectalcancerareunderway.(Moreinformation) Whileafewpreliminarytrialssuggestedthatcurcuminmayhaveanti-inflammatoryactivitiesinhumans,largerrandomizedcontrolledtrialsarestillneededtoestablishtheefficacyofcurcuminasananti-inflammatoryagentagainstrheumatoidarthritis,ulcerativecolitis,andradiotherapy-induceddermatitis.(Moreinformation) Thereiscurrentlynosubstantialevidenceshowingthatcurcuminmayimprovecognitiveperformanceinolderadultswithorwithoutcognitiveimpairments.Yet,somepreclinicalstudieshavefoundcurcuminpreventedorreversedcertainpathologicalfeaturesofAlzheimer’sdisease(AD).AnumberofclinicaltrialsdesignedtoassesswhethercurcuminmighthelppreventortreatADareunderway.(Moreinformation) Long-termclinicaltrialsarerequiredtoconfirmwhethercurcumincouldexhibitlong-lastingantidepressanteffectsinpatientssufferingfrommajordepressivedisorder.(Moreinformation) Oralsupplementationwithcurcuminisgenerallyregardedassafe,especiallybecauseofitslowbioavailability.However,useofcurcuminsupplementsmayaffecttheefficacyorincreasethetoxicityofawiderangeofdrugswhentakenconcurrently.(Moreinformation) Introduction TurmericisaspicederivedfromtherhizomesofthetropicalplantCurcumalongaLinn,whichisamemberofthegingerfamily(Zingiberaceae).Rhizomesarehorizontalundergroundstemsthatsendoutshoots,aswellasroots.Thebrightyellow-orangecolorofturmericcomesmainlyfromfat-soluble,polyphenolicpigmentsknownascurcuminoids.Curcumin,theprincipalcurcuminoidfoundinturmeric,isgenerallyconsidereditsmostactiveconstituent(1).Othercurcuminoidsfoundinturmericincludedemethoxycurcuminandbisdemethoxycurcumin(Figure1).Inadditiontoitsuseasaspiceandpigment,turmerichasbeenusedinIndiaformedicinalpurposesforcenturies(2).Morerecently,evidencethatcurcuminmayhaveanti-inflammatoryandanticanceractivitieshasrenewedscientificinterestinitspotentialtopreventandtreatdisease.   MetabolismandBioavailability Clinicaltrialsinhumansindicatethatthesystemicbioavailabilityoforallyadministeredcurcuminisrelativelylow(3-5)andthatmostlymetabolitesofcurcumin,insteadofcurcuminitself,aredetectedinplasmaorserumfollowingoralconsumption(6,7).Intheintestineandliver,curcuminisreadilyconjugatedtoformcurcuminglucuronideandcurcuminsulfateor,alternately,reducedtotetrahydrocurcumin,hexahydrocurcumin,andoctahydrocurcumin(Figure2)(4).AnearlyclinicaltrialconductedinTaiwanindicatedthatserumcurcuminconcentrationspeakedat0.41to1.75micromoles/liter(μM)onehourafteroraldosesof4to8gofcurcumin(8).AnotherclinicaltrialconductedintheUKfoundthatplasmaconcentrationsofcurcumin,curcuminsulfate,andcurcuminglucuronidewereintherangeof0.01μMonehouraftera3.6goraldoseofcurcumin(9).Curcuminanditsmetabolitescouldnotbedetectedinplasmaatdoseslowerthan3.6g/day.Thereissomeevidencethatorallyadministeredcurcuminaccumulatesingastrointestinaltissues.Forinstance,whencolorectalcancerpatientstook3.6g/dayofcurcuminorallyforsevendayspriortosurgery,curcuminwasdetectedinbothmalignantandnormalcolorectaltissue(10).Incontrast,curcuminwasnotdetectedinthelivertissueofpatientswithlivermetastasesofcolorectalcancerafterthesameoraldoseofcurcumin(11),suggestingthatoralcurcuminadministrationmaynoteffectivelydelivercurcumintotissuesoutsidethegastrointestinaltract. Thesafetyandefficacyofseveralcurcuminformulationsarecurrentlybeingexploredin(pre)clinicalsettingswiththeaimofincreasingtheabsorption,bioavailability,andtissue-targeteddeliveryofcurcumin(12-16).Examplesofapproachesincludeconjugationtopeptidecarriers(e.g.,topolylactic-co-glycolicacid[PLGA]);complexationwithessentialoils;coadministrationwithpiperine;andencapsulationintonanoparticles,liposomes,phytosomes,polymericmicelles,andcyclodextrins(reviewedin17). BiologicalActivities Antioxidantactivity Curcuminisaneffectivescavengerofreactiveoxygenspecies(ROS)andreactivenitrogenspeciesinthetesttube(18,19).However,itisnotclearwhethercurcuminactsasadirectantioxidantinvivo.Duetoitslimitedoralbioavailabilityinhumans(seeMetabolismandBioavailability),plasmaandtissuecurcuminconcentrationsarelikelytobemuchlowerthanthoseofotherfat-solubleantioxidantslikeα-tocopherol(vitaminE).Yet,curcumintakenorallymayreachsufficientconcentrationsinthegastrointestinaltractandprotecttheintestinalmucosaagainstoxidativeDNAdamage(11).Inadditiontoapotentiallydirectantioxidantactivity,curcumincaninducetheexpressionofphaseIIantioxidantenzymes,includingglutamate-cysteineligase(GCL),therate-limitingenzymeinglutathionesynthesis.Glutathione(GSH)isanimportantintracellularantioxidantthatplaysacriticalroleincellularadaptationtostress(20).CurcuminwasfoundtoupregulatetheexpressionofGCLthroughtheactivationofdifferentsignalingpathways(21).Inparticular,curcuminincreasestheexpressionofGCLandotherdetoxifyingenzymesviatheactivationofthenuclearfactorE2-relatedfactor2(Nrf2)-dependentpathway. Nrf2-dependentantioxidantpathway Briefly,Nrf2isatranscriptionfactorthatisboundtotheproteinKelch-likeECH-associatedprotein1(Keap1)inthecytosol.Keap1respondstooxidativestresssignalsbyfreeingNrf2.Uponrelease,Nrf2translocatestothenucleusandbindstotheantioxidantresponseelement(ARE)locatedinthepromoterofgenescodingforantioxidant/detoxifyingenzymesandscavengers.Nrf2/ARE-dependentgenescodefornumerousmediatorsoftheantioxidantresponse,includingGCL,glutathioneS-transferases(GSTs),thioredoxin,NAD(P)Hquinoneoxidoreductase1(NQO-1),andhemeoxygenase1(HO-1)(22).Nrf2-dependentupregulationofHO-1incurcumin-treatedrenaltubularepithelialcellschallengedwithhighglucoseconcentrationswasshowntopreventphenotypechangesresemblingfibrosisandknowntooccuratanearlystageofdiabeticrenalinjury(23).Curcuminalsoinhibitedtheprogressionoffibrosisinliverandlunginanimalmodelsofchronicinflammatorydiseases(24,25).Curcuminmitigatedtheeffectofchronicethanolintakeonmouseliver,partlybyupregulatingNrf2targetgenescodingforNQO-1,HO-1,glutathioneperoxidase(GSH-Px),andsuperoxidedismutase(SOD)(26).CurcumintreatmentalsocounteractedoxidativedamageinducedbyheavyionirradiationbyupregulatingNrf2downstreamgenesforGCL,HO-1,NQO-1,andSODinthebrainofrats(27).AdditionalstudieshavedemonstratedtheabilityofcurcumintoreduceoxidativestressindifferentexperimentalsettingsviatheinductionofNrf2/AREpathway(reviewedin22). Anti-inflammatoryactivity Curcuminhasbeenshowntoinhibitmediatorsoftheinflammatoryresponse,includingcytokines,chemokines,adhesionmolecules,growthfactors,andenzymeslikecyclooxygenase(COX),lipoxygenase(LOX),andinduciblenitricoxidesynthase(iNOS).Nuclearfactor-kappaB(NF-κB)isatranscriptionfactorthatbindsDNAandinducesthetranscriptionoftheCOX-2gene,otherpro-inflammatorygenes,andgenesinvolvedincellproliferation,adhesion,survival,anddifferentiation.Theanti-inflammatoryeffectsofcurcuminresultfromitsabilitytoinhibittheNF-κBpathway,aswellasotherpro-inflammatorypathwayslikethemitogen-activatedproteinkinase(MAPK)-andtheJanuskinase(JAK)/Signaltransducerandactivatoroftranscription(STAT)-dependentsignalingpathways(28).Inhibitionofdextransulfatesodium(DSS)-inducedcolitisbycurcumininmicehasbeenassociatedwithadownregulationoftheexpressionofp38-MAPKandpro-inflammatorycytokineTNF-αandareductionofmyeloperoxidase(MPO)activity,amarkerofneutrophilinfiltrationinintestinalmucosa(29).CurcuminhasalsobeenshowntoimprovecolitisbypreventingSTAT3activationandSTAT3-dependentinductionofcellproliferationinmousecolon(30).Moreover,curcuminwasshowntoattenuatetheimmuneresponsetriggeredbycollageninjectionsinamousemodelofrheumatoidarthritis,partlybyblockingtheproliferationofTlymphocytesinmousesplenocytes(31).Inaddition,curcuminhasbeenfoundtoreducethesecretionofTNF-αandIL-1βandtheproductionofCOX-2-inducedprostaglandinG2.Inonestudy,curcumininhibitedthesecretionofmatrixmetalloproteins(MMPs)—responsibleforthedegradationofthesynovialjoints —inhumanfibroblast-likesynoviocytes(31)andinhumanarticularchondrocytes(32).Curcuminhasalsobeenfoundtoalleviateneuro-inflammationinamousemodeloftraumaticbraininjury,reducingmacrophageandmicroglialactivationandincreasingneuronalsurvival(33). Anticanceractivity Effectsonbiotransformationenzymes SomecompoundsarenotcarcinogenicuntiltheyaremetabolizedinthebodybyphaseIbiotransformationenzymes,suchasenzymesofthecytochromeP450(CYP)family(34).Primarilybasedonevidencefromrodentstudies,itisthoughtthatcurcuminmayinhibitprocarcinogenbioactivationandhelppreventcancerbyinhibitingtheactivityofmultipleCYPenzymesinhumans(35-37).CurcuminmayalsoincreasetheactivityofphaseIIdetoxificationenzymes,suchasGSTsandquinonereductase(QR)(seealsoNrf2-dependentantioxidantpathway)(35,38,39).However,itisimportanttonotethattheeffectofcurcuminonbiotransformationenzymesmayvarydependingontherouteofadministration,thedose,andtheanimalmodel.Inaddition,curcuminintakesrangingfrom0.45to3.6g/dayforuptofourmonthsdidnotincreaseleukocyteGSTactivityinhumans(9). Inhibitionofproliferationandinductionofapoptosis FollowingDNAdamage,thecellcyclecanbetransientlyarrestedtoallowforDNArepairorforactivationofpathwaysleadingtoprogrammedcelldeath(apoptosis)ifthedamageisirreparable(40).Defectivecell-cycleregulationmayresultinthepropagationofmutationsthatcontributetothedevelopmentofcancer.Unlikenormalcells,cancercellsproliferaterapidlyandareunabletorespondtocelldeathsignalsthatinitiateapoptosis.Curcuminhasbeenfoundtoinducecell-cyclearrestandapoptosisbyregulatingavarietyofcell-signalingpathways(3,41-45).Forexample,theinhibitionofcellproliferationbycurcuminhasbeenassociatedwiththeNrf2-dependentdownregulationofDNArepair-specificflapendonuclease1(Fen1)inbreastcancercellsinculture(46).Curcuminhasbeenshowntoinducep53-dependentor-independentapoptosisdependingonthecancercelltype(47).Inapanelofcancercelllines,p53-independentapoptosisinducedbycurcuminwasmediatedbytherapidincreaseofROSandtheactivationofMAPKandc-junkinase(JNK)signalingcascades(48).InhibitionofNF-κBsignalingbycurcuminalsosuppressesproliferationandinducesapoptosisincancercells(47). Inhibitionoftumorinvasionandangiogenesis Malignantandaggressiveformsofcancercaninvadesurroundingtissuesandspreadtodistanttissuesoncecancercellshaveacquiredtheabilitytoleavetheprimarysite(reducedcell-to-celladhesionandlossofpolarity),migrate,anddisseminate.Epithelial-mesenchymaltransition(EMT)istheprocessbywhichepithelialcellsacquiretheabilitytomigrateandinvadethroughdownregulatingproteinslikeE-cadherinandγ-cateninandexpressingmesenchymalmarkerslikeMMPs,N-cadherin,andvimentin.Inbreastcancercells,curcuminpreventedEMT-associatedmorphologicalchangesinducedbylipopolysaccharide(LPS)whileupregulatingE-cadherinanddownregulatingvimentin.ItwasfurthershownthatcurcumininhibitedNF-κB/SnailsignalinginvolvedinLPS-inducedEMT(49).Inanotherstudy,curcuminincreasedtheexpressionofthesmallnon-codingRNAmiR181b,whichthendownregulatedproinflammatorycytokines,CXCL1andCXCL2,aswellasMMPs,therebyreducingthemetastaticpotentialofbreastcancercells.CurcumininhibitedIL-6-inducedproliferation,migration,andinvasivenessofhumansmallcelllungcancer(SCLC)cellsbyreducingJAK/STAT3phosphorylation(i.e.,activation)anddownstreamgenescodingforcyclinB1,survivin,Bcl-XL,MMPs,intercellularadhesionmolecule1(ICAM-1),andvascularendothelialgrowthfactor(VEGF)(30). Curcuminwasfoundtoexertitsanticanceractivitiesinmanydifferenttypesofcancercellsbyregulatingavarietyofsignalingpathways(reviewedin2,47). Neuroprotectiveactivity InAlzheimer’sdisease(AD),apeptidecalledβ-amyloid(Aβpeptide)aggregatesintooligomersandfibrilsandformsdepositsknownasamyloid(orsenile)plaquesoutsideneuronsinthehippocampusandcerebralcortexofpatients.AnotherfeatureofADistheaccumulationofintracellularneurofibrillarytanglesformedbyphosphorylatedTauprotein(50).Abnormalmicroglialactivation,oxidativestress,andneuronaldeatharealsoassociatedwiththeprogressionofthedisease.CurcuminhasbeenfoundtoinhibitAβfibrilformationandextensionandtodestabilizepreformedfibrilsinvitro(51-53).Metalchelationbycurcuminmightinterferewithmetalion(Cu2+/Zn2+)-inducedAβaggregation.CurcuminmightalsoaffectthetraffickingofAβpeptideprecursor(APP)andthegenerationofAβpeptidesfromAPP(54,55).AbnormallyactivatedmicrogliaandhypertrophicastrocytesaroundamyloidplaquesinADbrainsreleasecytotoxicmolecules,suchasproinflammatorycytokinesandROS,whichenhanceAβformationanddepositionandfurtherdamageneurons.CurcuminwasfoundtoreducetheinflammatoryresponsetriggeredbyAβpeptide-inducedmicroglialactivationandincreaseneuronalcellsurvival(56).WheninjectedintothecarotidarteryofatransgenicmousemodelofAD,curcuminwasfoundtocrosstheblood-brainbarrier,bindtoamyloidplaques,andblocktheformationofAβoligomersandfibrils(53).InotheranimalmodelsofAD,dietarycurcumindecreasedbiomarkersofinflammationandoxidativedamage,increasedAβpeptideclearancebymacrophages,dismantledamyloidplaquesinthebrain,stimulatedneuronalcellgrowthinthehippocampus,andimprovedAβ-inducedmemorydeficits(reviewedin57). Note:Itisimportanttokeepinmindthatsomeofthebiologicalactivitiesdiscussedabovewereobservedinculturedcellsandanimalmodelsexposedtocurcuminatconcentrationsunlikelytobeachievedincellsofhumansconsumingcurcuminorally(seeMetabolismandBioavailability). DiseasePrevention Cancer Oralcurcuminadministrationhasbeenfoundtoinhibitthedevelopmentofchemically-inducedcancerinanimalmodelsoforal(58,59),stomach(60,61),liver(62),andcolon(63-65)cancer.ApcMin/+micehaveamutationintheApc(adenomatouspolyposiscoli)genesimilartothatinhumanswithfamilialadenomatouspolyposis,ageneticconditioncharacterizedbythedevelopmentofnumerouscolorectaladenomas(polyps)andahighriskforcolorectalcancer.OralcurcuminadministrationhasbeenfoundtoinhibitthedevelopmentofintestinaladenomasinApcMin/+mice(66,67).Despitepromisingresultsinanimalstudies,thereispresentlylittleevidencethathighintakesofcurcuminorturmericareassociatedwithdecreasedcancerriskinhumans.A30-dayphaseIIclinicaltrialin40smokerswithatleasteightrectalaberrantcryptfoci(ACF;precancerouslesions)foundthatthenumberofACFwassignificantlylowerwithadailysupplementationwith4g/dayofcurcumincomparedto2g/day(68).Severalcontrolledclinicaltrialsinhumansdesignedtoevaluatetheeffectoforalcurcuminsupplementationonprecancerouscolorectallesions,suchasadenomas,areunderway(69). Type2diabetesmellitus Oxidativestressandinflammationhavebeenimplicatedinthepathogenesisoftype2diabetesmellitusandrelatedvascularcomplications.Alargebodyofpreclinicalevidencesuggeststhattheantioxidant,anti-inflammatory,andglucose-loweringactivitiesofcurcuminanditsanalogsmaybeusefulinthepreventionand/ortreatmentoftype2diabetes(70).Inanine-month,randomized,double-blind,placebo-controlledstudyin237subjectswithimpairedglucosetolerance(pre-diabetes),noprogressiontoovertdiabeteswasreportedwithadailyingestionofamixtureofcurcuminoids(0.5g),while16.4%ofplacebo-treatedparticipantsdevelopeddiabetes(71).Inaddition,curcuminsupplementationwasshowntoreduceinsulinresistanceandimprovemeasuresofpancreaticβ-cellfunctionandglucosetolerance.Inaneight-week,randomized,placebo-controlledstudyin67individualswithtype2diabetes,oralcurcumin(amixtureofallthreemajorcurcuminoids;0.6g/day)failedtosignificantlylowerthelevelofglycatedhemoglobinA1c(HbA1c;ameasureofglycemiccontrol),plasmafastingglucose,totalserumcholesterol,LDL-cholesterol,andserumtriglycerides(72).Yet,supplementalcurcuminwasfoundtobeaseffectiveaslipid-loweringdrugatorvastatin(10mg/day)inreducingcirculatingmarkersofoxidativestress(malondialdehyde)andinflammation(endothelin-1,TNFα,IL-6)andinimprovingendothelialfunction.Anotherrandomizedcontrolledtrialalsoreportedthatoralcurcuminsupplementation(1.5g/day)forsixmonthsimprovedendothelialfunction,insulinsensitivity,andmetabolicmarkersassociatedwithatherogenesis(plasmatriglycerides,visceralfat,totalbodyfat)inparticipantswithtype2diabetes(73).Finally,inatwo-monthrandomized,double-blind,placebo-controlledstudyin40individualswithtype2diabeticnephropathy(kidneydisease),dailycurcuminingestion(66.3mg)significantlyreducedurinaryconcentrationsofproteinsandinflammationmarkers(TGF-β,IL-8),suggestingthatcurcuminmightbehelpfulwithslowingtheprogressionofkidneydamageandpreventingkidneyfailure(74).Largertrialsareneededtoassesswhethercurcumincouldbeusefulinthepreventionormanagementoftype2diabetesandvascularcomplications. DiseaseTreatment Cancer Theabilityofcurcumintoregulateavarietyofsignalingpathwaysinvolvedincellgrowth,apoptosis,invasion,metastasis,andangiogenesisinpreclinicalstudieselicitedscientificinterestinitspotentialasananticanceragentintumortherapy(75).Todate,mostofthecontrolledclinicaltrialsofcurcuminsupplementationincancerpatientshavebeenphaseItrials,whichareaimedatdeterminingfeasibility,tolerability,safety,andprovidingearlyevidenceofefficacy(76).AphaseIclinicaltrialinpatientswithadvancedcolorectalcancerfoundthatdosesupto3.6g/dayforfourmonthswerewelltolerated,althoughthesystemicbioavailabilityoforalcurcuminwaslow(77).Whencolorectalcancerpatientswithlivermetastasestook3.6g/dayofcurcuminorallyforsevendays,tracelevelsofcurcuminmetabolitesweremeasuredinlivertissue,butcurcuminitselfwasnotdetected(11).Incontrast,curcuminwasmeasurableinnormalandmalignantcolorectaltissueafterpatientswithadvancedcolorectalcancertook3.6g/dayofcurcuminorallyforsevendays(10).Inapilottrialinpatientsawaitinggastrointestinalendoscopyorcolorectalcancerresection,theadministrationofamixtureofthreemajorcurcuminoids(2.35g/dayfor14days)resultedindetectableamountsofcurcuminincolonicmucosa(meanconcentration,48.4μg/goftissue),demethoxycurcumin(7.1μg/g),andbisdemethoxycurcumin(0.7μg/g)(78). Whilethesefindingssuggestedthatoralcurcuminmaylikelybemoreeffectiveasatherapeuticagentincancersofthegastrointestinaltractthanofothertissues,somephaseI/IItrialshavealsoexaminedwhethersupplementalcurcuminmayconferadditionalbenefitstoconventionaldrugsagainstdifferenttypesofcancer.Combiningcurcuminwithanticancerdrugslikegemcitabineinpancreaticcancer(79,80),docetaxelinbreastcancer(81),andimatinibinchronicmyeloidleukemia(82)maybesafeandwelltolerated.Arecentsingle-arm,phaseIItrialcombiningthreecyclesofdocetaxel/prednisoneandcurcumin(6g/day)wascarriedoutin26patientswithcastration-resistantprostatecancer(83).Thelevelofprostate-specificantigen(PSA)wasdecreasedinmostpatientsandwasnormalizedin36%ofthem,andtheco-administrationofcurcuminwithdrugsshowednotoxicitybeyondadverseeffectsalreadyrelatedtodocetaxelmonotherapy.ManyregisteredphaseI/IIclinicaltrialsdesignedtoinvestigatetheeffectivenessofcurcuminaloneorwithfirst-linetreatmentinpatientswithbreast,prostate,pancreatic,lung,orcolorectalcancerareunderway(69). Inflammatorydiseases Althoughcurcuminhasbeendemonstratedtohaveanti-inflammatoryandantioxidantactivitiesincellcultureandanimalstudies,fewrandomizedcontrolledtrialshaveexaminedtheefficacyofcurcumininthetreatmentofinflammatoryconditions.Aplacebo-controlledtrialin40menwhohadsurgerytorepairaninguinalherniaorhydrocelefoundthatoralcurcuminsupplementation(1.2g/day)forfivedayswasmoreeffectivethanplaceboinreducingpost-surgicaledema,tendernessandpain,andwascomparabletophenylbutazonetherapy(300mg/day)(84). Rheumatoidarthritis Apreliminaryinterventiontrialthatcomparedcurcuminwithanonsteroidalanti-inflammatorydrug(NSAID)in18patientswithrheumatoidarthritis(RA)foundthatimprovementsinmorningstiffness,walkingtime,andjointswellingaftertwoweeksofcurcuminsupplementation(1.2g/day)werecomparabletothoseexperiencedaftertwoweeksofphenylbutazone(NSAID)therapy(300mg/day)(85).Inamorerecentrandomized,open-labelstudyin45RApatients,supplementationwithamixtureofallthreemajorcurcuminoids(0.5g/dayforeightweeks)wasfoundtobeaseffectiveasdiclofenac(NSAID;50mg/day)inreducingmeasuresofdiseaseactivity,tenderness,andswellingjoints(86).LargerrandomizedcontrolledtrialsareneededtodeterminewhetheroralcurcuminsupplementationiseffectiveinthetreatmentofRA. Radiationdermatitis Radiation-inducedskininflammationoccursinmostpatientsreceivingradiationtherapyforsarcoma,lung,breast,orheadandneckcancer.Onerandomized,double-blind,placebo-controlledtrialin30womenprescribedradiationtherapyforbreastcarcinomainsitureportedareductionofradiation-induceddermatitisseverityandmoistdesquamationwithasupplementalcurcuminoidmixture(6g/dayforfourtosevenweeks).Curcuminfailedtoreduceskinrednessandradiation-inducedpainatthesiteoftreatment(87). Ulcerativecolitis Ulcerativecolitis(UC)isalong-termconditioncharacterizedbydiffuseandsuperficialinflammationofthecolonicmucosa.Diseaseactivitymayfluctuatebetweenperiodsofremissionandperiodsofrelapse.Preliminaryevidencesuggeststhatcurcuminmightbeusefulasanadd-ontherapytocontroldiseaseactivity.Onemulticenter,randomized,double-blind,placebo-controlledstudyhasexaminedtheefficacyofcurcuminenema(2g/day)inthepreventionofrelapsein82patientswithquiescentUC(88).Six-monthtreatmentwithcurcuminsignificantlyreducedmeasuresofdiseaseactivityandseverityandresultedinalowerrelapseratethanwithplaceboinsubjectsonstandard-of-caremedication(sulfasalazineormesalamine);yet,therewasnodifferenceintheproportionofpatientswhoexperiencedrelapsesixmonthsaftercurcuminwasdiscontinued(88).InanotherrandomizedcontrolledtrialinactiveUCpatientstreatedwithmesalamine,thepercentageofpatientsinclinicalremissionwassignificantlyhigherafteraone-monthtreatmentwithoralcurcumin(3g/day)thanwithplacebo(89).LargertrialsareneededtoensurethatcurcumincanbesafelyusedwithconventionalUCtreatmentsandtofurthersupportitspotentialtherapeuticbenefitsforrelapsing-remittingUC. Oralhealth Emergingevidencesuggeststhatcurcuminhasanti-inflammatoryandantimicrobialpropertiesthatcouldbebeneficialinthetreatmentofcertaindiseasesoftheoralcavity.Forexample,thetopicalapplicationofacurcumingelwasfoundtoreducegingivalbleedingandperiodontalbacteriaafterconventionalperiodontaltherapy(scalingandrootplaning)(90-92).Amouthwashcontainingcurcuminwasalsofoundtobeaseffectiveaschlorhexidineinreducinginflammationinindividualswhounderwentperiodontaltherapyforgingivitis(93). Oralsubmucousfibrosis Anypartoftheoralcavitymaybeaffectedbyoralsubmucousfibrosis(OSMF),acurrentlyincurableconditionespeciallyprevalentinSoutheastAsiaandIndia.OSMFischaracterizedbytheformationofexcessfibroustissue(fibrosis)thatleadstostiffnessofthemucosaandrestrictedmouthopening.Afewrecentinterventionstudiesshowedthatcurcumincouldimprovesomesymptoms,suchasburningsensationsandreducedmouthopening(reviewedin94).Inanopen-labelinterventionstudyin40OSMFpatientsrandomizedtoreceiveeithertheconventionaltreatment(weeklyintra-lesionalinjectionsofsteroids)ordailyoraladministrationofaCurcumalongaLinnextract(600mg/day)forthreemonths,theburningsensationsignificantlyimprovedinthecurcumin-treatedgroup,whiletongueprotrusionwasreducedwithconventionaltherapy.Nodifferencesbetweenthetwotreatmentgroupswereseenwithrespecttomouthopening(95).Asix-monthfollow-upoftheeffectoforalcurcumin(2g/day)inOSMFpatientstreatedforthreemonthsfoundthatcurcuminoutperformedsteroidointmentinitsabilitytoincreasemaximummouthopeningandtoreduceself-reportedburningsensation(96).Furtherstudiesshouldassesstheappropriatedoseofcurcumintoachievethegreatestbenefitsanddeterminewhethercurcumincanenhancetheeffectofstandard-of-caretreatmentinlimitingOSMFdiseaseprogression. CognitivedeclineandAlzheimer’sdisease Alzheimer’sdisease(AD)isaformofdementiacharacterizedbyextracellulardepositionofβ-amyloidplaques,intracellularformationofneurofibrillarytangles,andneuronalloss,eventuallyleadingtobrainatrophyandcognitiveimpairmentinaffectedindividuals(57).Wheninjectedintothecarotidartery,curcuminwasfoundtocrosstheblood-brainbarrierinananimalmodelofAD(53),thoughitisnotknownwhethercurcumintakenorallycanreachtheblood-brainbarrieratsufficientconcentrationsandimpedecognitivedeclineinhumans.Asaresultofpromisingfindingsinanimalmodels(seeNeuroprotectiveactivity),afewrecentclinicaltrialshaveexaminedtheeffectoforalcurcuminsupplementationoncognitioninhealthyolderadultsandADpatients(57).Arandomized,double-blind,placebo-controlledtrialin60healthyolderadults(meanage,68.5years)investigatedwhetheracute(80mg)orchronic(80mg/dayfor4weeks)oralintakeofcurcumincouldimprovetheirabilitytocopewiththementalstressandchangeinmoodusuallyassociatedwithundergoingabatteryofcognitivetests(97).Asignificantreductioninmentalfatigueandhigherlevelsofcalmnessandcontentednessfollowingcognitivetestsessionswereobservedinindividualswhoconsumedcurcumin(eitheracutelyorchronically)comparedtotheplacebogroup.Additionally,theresultsofcognitiveabilitytestssuggestedthatcurcumintreatmenthadlimitedbenefitsoncognitivefunction,asshownbybetterscoresinmeasuresofsustainedattentionandworkingmemorycomparedtoplacebo(97). Theresultsofasix-monthtrialin27patientswithADfoundthatoralsupplementationwithupto4g/dayofcurcumin —containingallthreemajorcurcuminoids—wassafe(6).Yet,measuresofcognitiveperformance(usingtheMiniMentalStateExamination[MMSE]scoringscale)andlevelsofF2-isoprostanes(oxidativestressmarkers)andantioxidantsinbloodwerenotfoundtobesignificantlydifferentbetweencurcumin-andplacebo-treatedsubjectsattheendoftheinterventionperiod.Inanothersix-month,randomized,double-blind,placebo-controlledstudyofsubjectswithmild-to-moderateAD,curcuminfailedtoimprovecognitivetestscoresandtoreducebloodandcerebrospinalfluid(CSF)concentrationsofβ-amyloidpeptide,CSFconcentrationsoftotalandphosphorylatedTauprotein,andCSFconcentrationsofF2-isoprostanes(98). Despitethelackofencouragingresultsfromcompletedtrials,severalrandomizedcontrolledstudiesareunderwaytodeterminewhethersupplementalcurcuminhastheabilitytoreverseorpreventcognitivedeficitsinbothhealthyandcognitivelyimpairedindividuals(57). Majordepressivedisorder Majordepressivedisorder(MDD)isaneuropsychiatricdisorderassociatedwithabnormalneurotransmission;itisprimarilytreatedwithdrugsthatimprovethebioavailabilityofneurotransmitterslikeserotonin,noradrenaline,anddopamineinthebrain(99).CharacteristicsofMDDalsoincludealterationsinthehypothalamus-pituitary-adrenalaxis,increasedneuroinflammation,defectiveneurogenesis,andneuronaldeath. AfewclinicalstudieshaveexaminedtheeffectofcurcuminaloneorwithconventionalantidepressantdrugsinMDDpatients.Arecentmeta-analysisofsixrandomizedcontrolledtrialsfoundthatsupplementationwithcurcuminsignificantlyreduceddepressionsymptoms(100).However,inoneofthestudiesincludedinthismeta-analysis —adouble-blind,controlledstudyin56adultsdiagnosedwithMDD —curcumintreatment(~880mg/dayofcurcuminoids)foreightweekswasnomoreeffectivethanplaceboinreducingself-reporteddepression-andanxiety-relatedsymptoms(101).Significantimprovementsintheseverityandfrequencyofspecificdepression-relatedsymptomsonlyoccurredafterfourweeksoftreatment,suggestingthatalongertreatmentperiodmightbeneededtouncovertheantidepressanteffectsofcurcumin(100,101).Inanotherrandomized,placebo-controlledtrial,supplementalcurcumin(330mg/day)forfiveweeksfailedtorelievedepressivesymptomsinpatientstreatedwithconventionalantidepressants(102).Incontrast,inasix-week,randomized,single-blinded,placebo-controlledstudyin60MDDpatients,supplementalcurcumin(~880mg/dayofcurcuminoids)aloneyieldedasimilarresponseratetotheantidepressant,fluoxetine(aserotoninreuptakeinhibitor[Prozac];20mg/day)intermsofdepressivesymptoms;noadditionaleffectwasobservedwhenbothcurcuminandfluoxetinetreatmentswerecombined(103).Moreover,inarandomizedcontrolledstudyin100participantstakingescitalopram(aserotoninreuptakeinhibitor[Lexapro];5to15mg/week),supplementalcurcumin(1,000mg/day)forsixweeksincreasedtheantidepressanteffectofthemedication(104).Curcuminalsoinducedareductioninplasmaconcentrationsofinflammatorymarkersandanincreaseinplasmaconcentrationsofbrain-derivedneurotrophicfactorcomparedtoplacebo(antidepressantdrugalone)(104). Largerclinicaltrialsareneededtoaddressthelong-termeffectofcurcumininsubjectswithmajordepression. Premenstrualsyndrome Premenstrualsyndrome(PMS)referstoarangeofemotional(e.g.,irritability,anxiety),behavioral(e.g.,fatigue,insomnia),andphysicalsymptoms(e.g.,breasttenderness,headache)occurringpriortothemonthlymenstrualperiodinupto90%ofpremenopausalwomen.Inarecentrandomized,double-blind,placebo-controlledtrialin70womenwithPMS,thedailysupplementationwith0.2gofcurcuminfor10daysduringthreeconsecutivemenstrualcyclessignificantlyreducedoverallPMSseverity,asassessedbyacompositemeasureofallemotional,behavioral,andphysicalsymptoms(105).AdditionaltrialsarenecessarytoevaluatetheefficacyofcurcumininthemanagementofPMS. Sources Foodsources TurmericisthedriedgroundrhizomeofCurcumalongaLinn(106).ItisusedasaspiceinIndian,SoutheastAsian,andMiddleEasterncuisines.Curcuminoidscompriseabout2%-9%ofturmeric(107).Curcuministhemostabundantcurcuminoidinturmeric,providingabout75%ofthetotalcurcuminoids,whiledemethoxycurcuminandbisdemethoxycurcumingenerallyrepresent10%-20%andlessthan5%ofthetotalcurcuminoids,respectively(108).Currypowdercontainsturmericalongwithotherspices,buttheamountofcurcuminincurrypowdersisvariableandoftenrelativelylow(109).Curcuminextractsarealsousedasfood-coloringagents(110). Supplements Commercialcurcuminisusuallyamixtureofcurcumin,demethoxycurcumin,andbisdemethoxycurcumin(seeFigure1above).CurcuminoidextractsareavailableasdietarysupplementswithoutaprescriptionintheUS.Thelabelsofanumberoftheseextractsstatethattheyarestandardizedtocontain95%curcuminoids,althoughsuchclaimsarenotstrictlyregulatedbytheUSFoodandDrugAdministration(FDA).Somecurcuminpreparationsalsocontainpiperine,whichmayincreasethebioavailabilityofcurcuminbyinhibitingitsmetabolism(108).However,piperinemayalsoaffectthemetabolismofdrugs(seeDruginteractions).Optimaldosesofcurcuminforcancerchemopreventionortherapeuticuseshavenotbeenestablished.Itisunclearwhetherdoseslessthan3.6g/dayarebiologicallyactiveinhumans(seeMetabolismandBioavailability).Curcuminoid-containingsupplementstakenonanemptystomachmaycausegastritisandpepticulcerdisease(108). Safety Adverseeffects IntheUnitedStates,turmericisgenerallyrecognizedassafe(GRAS)bytheFDAasafoodadditive(110).Anincreaseingallbladdercontractionswasobservedin12healthypeoplesupplementedwithsingledosesof20to40mgofcurcumin(111,112).Yet,seriousadverseeffectshavenotbeenreportedinhumanstakinghighdosesofcurcumin.Adoseescalationtrialin24adultsfoundthatsingleoraldosagesupto12gweresafe,andadverseeffects,includingdiarrhea,headache,rash,yellowstool,werenotrelatedtodose(7).InaphaseItrialinTaiwan,curcuminsupplementationupto8g/dayforthreemonthswasreportedtobewelltoleratedinpatientswithprecancerousconditionsornoninvasivecancer(8).AnotherclinicaltrialintheUKfoundthatcurcuminsupplementationrangingfrom0.45to3.6g/dayforfourmonthswasgenerallywelltoleratedbypeoplewithadvancedcolorectalcancer,althoughtwoparticipantsexperienceddiarrheaandanotherreportednausea(9).Increasesinserumalkalinephosphataseandlactatedehydrogenasewerealsoobservedinseveralparticipants,butitwasnotclearwhethertheseincreaseswererelatedtocurcuminsupplementationorcancerprogression(3).Inanopen-labelphaseIItrial,curcumintreatment(8g/day)incombinationwiththeanticancerdruggemcitabinewasassociatedwithsevereabdominalpainin7outof17patientswithadvancedpancreaticcancer,leadingtothetreatmentbeingdiscontinuedinfivepatientswhilecurcumindosagewasreducedto4g/dayintwopatients(79). Pregnancyandlactation Althoughthereisnoevidencethatdietaryconsumptionofturmericasaspiceadverselyaffectspregnancyorlactation,thesafetyofcurcuminsupplementsinpregnancyandlactationhasnotbeenestablished. Druginteractions Curcuminhasbeenfoundtoinhibitplateletaggregationinvitro(113,114),suggestingapotentialforcurcuminsupplementationtoincreasetheriskofbleedinginpeopletakinganticoagulantorantiplateletmedications,suchasaspirin,clopidogrel(Plavix),dalteparin(Fragmin),enoxaparin(Lovenox),heparin,ticlopidine(Ticlid),andwarfarin(Coumadin).Inculturedbreastcancercells,curcumininhibitedapoptosisinducedbythechemotherapeuticagents,camptothecin,mechlorethamine,anddoxorubicinatconcentrationsof1to10μM(115).Inananimalmodelofbreastcancer,dietarycurcumininhibitedcyclophosphamide-inducedtumorregression.Yet,itisnotknownwhetheroralcurcuminadministrationwillresultinbreasttissueconcentrationsthatarehighenoughtoinhibitcancerchemotherapeuticagentsinhumans(11).CurcuminoidsmayinterferewiththeactivityofeffluxdrugtransportersoftheATP-bindingcassette(ABC)family,includingP-glycoprotein,multidrugresistanceprotein(MRP),andbreastcancer-resistantprotein(BCRP),whichfunctionasATP-dependenteffluxpumpsthatactivelyregulatetheexcretionofanumberofdrugslimitingtheirsystemicbioavailability(116,117).CurcuminwasalsofoundtoaffecttheactivityofphaseIbiotransformationenzymeslikecytochromeP450(CYP)3A4(CYP3A4)(118),whichcatalyzesthemetabolismofaboutone-halfofallmarketeddrugsintheUS(119).InhealthyJapanesevolunteers,curcumin(2g)wasfoundtoincreaseplasmasulfasalazineconcentrationfollowingtheadministrationofatherapeuticdose(2g)oftheanti-rheumaticdrugsulfasalazine(Salazopyrin,Azulfidine)(120). Somecurcuminsupplementsalsocontainpiperinetoincreasethebioavailabilityofcurcumin.PiperinemayalsointerferewitheffluxdrugtransportersandphaseIcytochromeP450enzymesandincreasethebioavailabilityandslowtheeliminationofanumberofdrugs,includingphenytoin(Dilantin),propranolol(Inderal),theophylline,andcarbamazepine(Tegretol)(121-123). 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