Potential Protective Role Exerted by Secoiridoids from Olea europaea L. in Cancer, Cardiovascular, Neurodegenerative, Aging-Related, and Immunoinflammatory Diseases
Abstract
Iridoids, which have beneficial health properties, include a wide group of cyclopentane [c] pyran monoterpenoids present in plants and insects. The cleavage of the cyclopentane ring leads to secoiridoids. Mainly, secoiridoids have shown a variety of pharmacological effects including anti-diabetic, antioxidant, anti-inflammatory, immunosuppressive, neuroprotective, anti-cancer, and anti-obesity, which increase the interest of studying these types of bioactive compounds in depth. Secoiridoids are thoroughly distributed in several families of plants such as Oleaceae, Valerianaceae, Gentianaceae and Pedialaceae, among others. Specifically, Olea europaea L. (Oleaceae) is rich in oleuropein (OL), dimethyl-OL, and ligstroside secoiridoids, and their hydrolysis derivatives are mostly OL-aglycone, oleocanthal (OLE), oleacein (OLA), elenolate, oleoside-11-methyl ester, elenoic acid, hydroxytyrosol (HTy), and tyrosol (Ty). These compounds have proved their efficacy in the management of diabetes, cardiovascular and neurodegenerative disorders, cancer, and viral and microbial infections. Particularly, the antioxidant, anti-inflammatory, and immunomodulatory properties of secoiridoids from the olive tree (Olea europaea L. (Oleaceae)) have been suggested as a potential application in a large number of inflammatory and reactive oxygen species (ROS)-mediated diseases. Thus, the purpose of this review is to summarize recent advances in the protective role of secoiridoids derived from the olive tree (preclinical studies and clinical trials) in diseases with an important pathogenic contribution of oxidative and peroxidative stress and damage, focusing on their plausible mechanisms of the action involved.
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Antioxidants2020,9,149;doi:10.3390/antiox9020149www.mdpi.com/journal/antioxidants Review PotentialProtectiveRoleExertedbySecoiridoids fromOleaeuropaeaL.inCancer,Cardiovascular, Neurodegenerative,Aging‐Related,and ImmunoinflammatoryDiseases MaríaLuisaCastejón,TatianaMontoya,CatalinaAlarcón‐de‐la‐Lastra andMarinaSánchez‐Hidalgo* DepartmentofPharmacology,SchoolofPharmacy,UniversityofSeville,41012Sevilla,Spain *Correspondence:[email protected];Tel.:+34954557469;Fax:+34954556074 Received:30December2019;Accepted:7February2020;Published:10February2020 Abstract:Iridoids,whichhavebeneficialhealthproperties,includeawidegroupofcyclopentane [c]pyranmonoterpenoidspresentinplantsandinsects.Thecleavageofthecyclopentaneringleads tosecoiridoids.Mainly,secoiridoidshaveshownavarietyofpharmacologicaleffectsincludingantidiabetic,antioxidant,anti‐inflammatory,immunosuppressive,neuroprotective,anti‐cancer,and anti‐obesity,whichincreasetheinterestofstudyingthesetypesofbioactivecompoundsindepth. SecoiridoidsarethoroughlydistributedinseveralfamiliesofplantssuchasOleaceae, Valerianaceae,GentianaceaeandPedialaceae,amongothers.Specifically,OleaeuropaeaL.(Oleaceae) isrichinoleuropein(OL),dimethyl‐OL,andligstrosidesecoiridoids,andtheirhydrolysis derivativesaremostlyOL‐aglycone,oleocanthal(OLE),oleacein(OLA),elenolate,oleoside‐11‐ methylester,elenoicacid,hydroxytyrosol(HTy),andtyrosol(Ty).Thesecompoundshaveproved theirefficacyinthemanagementofdiabetes,cardiovascularandneurodegenerativedisorders, cancer,andviralandmicrobialinfections.Particularly,theantioxidant,anti‐inflammatory,and immunomodulatorypropertiesofsecoiridoidsfromtheolivetree(OleaeuropaeaL.(Oleaceae))have beensuggestedasapotentialapplicationinalargenumberofinflammatoryandreactiveoxygen species(ROS)‐mediateddiseases.Thus,thepurposeofthisreviewistosummarizerecentadvances intheprotectiveroleofsecoiridoidsderivedfromtheolivetree(preclinicalstudiesandclinical trials)indiseaseswithanimportantpathogeniccontributionofoxidativeandperoxidativestress anddamage,focusingontheirplausiblemechanismsoftheactioninvolved. Keywords:immunomodulation;inflammation;olivetree;oxidativestress;secoirioids 1.Introduction Iridoids,whichhavebeneficialhealthproperties,includeawidegroupofcyclopentane[c]pyran monoterpenoidspresentinplantsandinsects.ThenameiridoidderivedfromIridomyrmex,agenus offornicesfromwhichiridomirmecinandiridodialcompoundswereisolated.Theseproductshave beenconsideredasdefensivecompounds.Infact,thebiosynthesisofthesederivativesof monoterpenestakesplaceinthedifferentorganismsbysimilarpathways;defenseisitsmainrole, andinthecaseofinsects,theyareusedassexpheromones[1]. Iridoidswerefirstisolatedinthelatterpartofthe19 th century,butHalpernandSchmid proposedthebasicskeletonoftheiridoidsintheirinvestigationofthestructureofplumieridein1958 [2].Particularly,theyaresecondarymetabolitesofterrestrialandmarinefloraandfauna,beingfound inalargenumberofplantsfamilies,usuallyasglycosides.Forthisreason,someofthemare
Antioxidants2020,9,1492of39 chemotaxonomicallyusefulasmarkersofgenusinvariousplantfamilies.Besides,theyexhibitawide rangeofbioactivitiesincludinganti‐inflammatory,antibacterial,anti‐carcinogenic,andantiviral activities[3].Infact,theyareusedasbittertonics,sedatives,antipyretics,coughdrugs,remediesfor skindisorders,andashypotensiveagents.Inaddition,theyareusefulasanantidoteinmushroom intoxicationsbyAmanitatype. Thecleavageofthecyclopentaneringofiridoidsleadstosecoiridoids.Mainly,secoiridoidshave shownalargevarietyofpharmacologicalpropertiesincludinganti‐diabetic,anti‐inflammatory, immunosuppressive,neuroprotective,anti‐cancer,andanti‐obesity.Thisfactencouragedustostudy thebioactivitiesofthesephytochemicalsindepthandupdatethelatestpreclinicalandclinicaldata onitsbioactivityandpotentialtherapeuticuses. 1.1.StructureandClassification Severalclassificationshavebeendevelopedovertheyears,giventhevarietyandcomplexityof iridoidsandsecoiridoids[4,5]. From1980todate,bibliographicdatahasusedtheclassificationproposedbyEl‐Naggarand Beal[2],whocategorizethesecompoundsaccordingtothenumberofcarbonsincludedintheir structure: Group1:C8iridoids(di‐nor‐iridoids) Group2:C9iridoids(nor‐iridoids) Group3:C10iridoids,whichoccurmainlyasglycosides Group4:Aglyconesandsomeiridoidsincludedintheotherthreegroupslackingasugarresidue intheirstructure Group5:Iridoidsderivatives.Thisgroupcomprisescompoundsderivedfromtheopeningof thepyranring Group6:Includedbis‐iridoidsasaresultofcondensationoftwomonomers,(a)directlyasin iridolinalinA,or(b)throughasugarresidueasinglobulosideA. Atthesametime,thereareotherclassificationsofsecoiridoidsaccordingtothepresenceofthese compoundsincertainfamilies,includingtheOleaceaefamily.Infact,atotalof232secoiridoids (aglycones,glycosides,derivatives,anddimers)havebeenisolatedfromninegenusofthefamily Oleaceae.ThesegeneraincludeFontanesia,Fraxinus,Jasminum,Ligustrum,Olea,Osmanthus, Phillyrea,Picconia,andSyringa,andthesesecoiridoidswereclassifiedintootherfivegroups[6]: Simplesecoiridoids:Generally,forthesimplesecoiridoids,positionsC7andC11haveeithera freecarboxylicacidgrouporamethylethylesterderivativeoftheacid.Theconfigurationsof thepositionsC1andC5areS. Conjugatedsecoiridoids:Thisgroupofcompoundsisthemostnumeroussecoiridoidsisolated fromtheOleaceaefamily.Thenameoftheclassderivesfromthetypeofcompoundthatislinked orconjugatedtothesecoiridoidnucleus.Basedonthis,thisclassisfurthercategorizedintoseven subgroups:aromatic‐conjugated,sugar‐conjugated,terpene‐conjugated,cyclopentaneconjugated,coumarin‐conjugated,lignans‐conjugated,andothersecoiridoids.Normally,the conjugationsoccurinC7duetothisposition,whichisisusuallyoxidizedtoacarboxylicacid andesterifiedwithdiversegroups. 10‐Oxyderivativeofoleosidesecoiridoids:Thisgroupcontainstheoleosidenucleuswithdistinct structuraldifferences.TheC8andC9positionsexistasdoublebonds,withahydroxygroupat theC8positionoranesterformedbyanoxygenatomwithdifferentgroups.Atotalof4010‐ OxyderivativeofoleosidesecoiridoidshavebeenisolatedfromtheOleaceaefamily. Z‐Secoiridoids:Thisclassofsecoiridoidsischaracterizedbythepresenceofdouble‐bond geometryattheC8inZ‐configuration;however,onlyfivecompoundshavebeenisolatedfrom theOleaceaefamily. Secologanosidesandoxidizedsecologanosidesecoiridoids:Compoundsofthisclassarebased onthesecologanosidenucleus.TheyaredifferentiatedbythepositionsontheC–Cdoublebond betweenC8andC10andC10oxidationlevel.
Antioxidants2020,9,1493of39 1.2.MainNaturallyOccurringIridoidsandSecoiridoidsPresentinOleaeuropaeaL. IridoidsandsecoriridoidsarethoroughlydistributedintheplantsofclassMagnoliopside, concretelybelongingtothefollowingfamilies:Scropulariaceae,Verbenaceae,Lamiaceae,Apocynaceae, Loganiaceae,Bignoniaceae,Plantaginaceae,Rubiaceae,Pedaliaceae,Cornaceae,Acantheceae,Loasaceae, Lentibulariaceae,Gentianaceae,Oleaceae,Nyctanthaceae,Caprifoliaceae,Dispsacaceae,andValerianaceae. Forinstance,ValerianaofficinalisL.(Valerianaceae),HarpagophytumprocumbensL.(Pedaliaceae), GencianaluteaL.(Gentianaceae),FraxinusexcelsiorL.(Oleaceae)andOleaeuropaeaL.(Oleaceae)are themostrepresentativemedicinalplantscommonlyusedinmedicine,duetotheiriridod/secoiridoid content[3].Particularly,OleaeuropaeaL.(Oleaceae)isasmallevergreentreewithfirmbranchesand agrayishbark.Theleavesarelanceolate,opposite,short‐petioled,mucronate,greenaboveandhoary ontheunderside.Ontheotherhand,theflowersaresmall,short,erectracemes,axillary,verymuch shorterthantheleaves,andthefruitisasmallsmooth,purple,orgreendrup,withanauseous,bitter flesh,enclosingasharp‐pointedstone[7]. OleaeuropaeaL.preparationshavebeentraditionalusedinfolkmedicineintheEuropean Mediterraneanarea,Arabiapeninsula,Indiaandothertropicalandsubtropicalregions,asadiuretic, emollient,hypotensive,andforurinaryandbladderinfections[8].MostoftheplantpartsofOlea europaeaL.areusedinthetraditionalsystemofmedicinearoundtheworld.Oilistakenwithlemon juicetotreatgallstones[9].Leavesaretakenorallyforstomachandintestinaldiseasesandusedas mouthcleanser[10],andthedecoctionofdriedleavesistakenorallyfordiabetes[11].Anextractof thefreshleavesistakenorallytotreathypertensionandtoinducediuresis[12],whereasaninfusion ofthefreshleavesistakenorallyasanalternativetreatmentforinflammatorydiseases[13].Similarly, essentialoilextractedfromthefruitisalsousedtotreatrheumatism,promotebloodcirculation[14], andasalaxative[15]. Themainbiophenolsecoiridoidsfoundintheolivetreeinclude:oleuropein(OL),dimethyl‐OL, ligstroside,andtheirhydrolysisderivativessuchasOL‐aglycone,oleocanthal(OLE),oleacein(OLA), elenolate,oleoside‐11‐methylester,elenoicacid,hydroxytyrosol(HTy),andtyrosol(Ty)(Figure1). OLOLE LigstrosideOLA Figure1.Chemicalstructuresofsecoiridoidsmostabundantinolivetrees.OL:oleuropein,OLA: oleacein,OLE:oleocanthal. 1.3.BiosynthesisandBiotransformationofSecoiridoidsinOliveTree Theamountanddistributionofsecoiridoidspresentinolivetissuesdependonvarious environmentalfactorssuchastheripeningcycle,geographicalorigin,andcultivationpractices, amongothers.Besides,thecontentofphenolicglycosidesaspatternsandtheactivityofendogenous enzymescanplayaroleinthequantitativecompositionofsecoiridoidsintheolivetree[16].
Antioxidants2020,9,1494of39 Thefactthatsecoiridoidsaremostlypresentinearlystagesisduetotheenzymaticand chemistryreactionsthattakeplaceinthematurationtime.Inthissense,threedifferentstatesinfruit maturationhavebeendescribed:growthphase,greenmaturationphase,andblackmaturationphase, whichischaracterizedbythepresenceofanthocyans. OLismainlyabundantinearlystages,althoughitslevelsdecreaseduringthematuration process.Infact,OLdecreasesquicklyinblackcropsandisnotpresentinsomevarietiesofOleaceae. ThemainprecursorofOLandligstrosideisoleoside11‐methylester(elenolicacidglucoside). Firstly,geraniolsynthase(GES)catalyzesthetransformationofgenaryldiphosphatetogeraniol, whichisconvertedto10‐hydroxygeraniolbythegeraniol10‐hydroxylaseenzyme.Theiridioidsin Oleaceaemustbeformedfromthispointwith10‐hydroxygeraniolasthestartingcompoundvia irididalandiridotrialuptodeoxyloganicacid,whichistheprecursorofloganinandloganicacid,as wellassecologaninandsecologanicacid[17].Fromthispoint,uptofiverouteshavebeenproposed toexplaintheoriginofalliridoidsfoundinthisfamily.However,itisknownthatmostofthe secoiridoidspresentinOleaeuropaeaL.arederivedfromdeoxyloganicacidasacommonintermediate [17,18].Followingthisline,nicotinamideadeninedinucleotidedeshydrogenase(NADH)actson10‐ hydroxygeranioltoformdeoxyloganicacidaglucone.Thetransferofglucosylgroupsto deoxyloganicacidaglucone(precursorofmonoterpeneindolicalcaloidsandOL)iscatalyzedby glucosyltransferase(GT).Deoxyloganicacidexperimentsa7‐α‐hydroxylationofthecyclopentane ringandforms7‐epiloganicacid,whichquicklygoesto7‐ketologanicacidthroughhydroxylgroup oxidation.Loganicacidmethyltransferasecatalyzes7‐ketologaninsyntheses.Inthispoint, secologaninsynthase(SLS)oxidesaketonicgrouptoform11‐methyloleoside,whichisimmediately glucosylatedbyGT.Finally,7‐β‐1‐D‐glucopyranosyl‐11‐methyloleosideisesterifiedwithTyto produceligstroside,andthenOLisformed[17,19](Figure2). Secoiridoidsaredistributedthroughoutthetissuesoftheolivetree,buttheirnatureand concentrationchangeamongdifferentpartsoftheplant.Thus,biosyntheticormechanicals transformationduringproductionaredecisivetoquantifyalterationsofthebioactivesmallmolecules [18].Particularly,OListhemajorsecoiridoidconstituentofunripedrupes(peel,pulp,andseed).The amountofOLdecreasesalongfruitmaturation,ascommentedabove,whereasitsaglyconform increasesitslevels.OL‐aglyconeisformedbythecleavageoftheglycosidicbondmediatedbyβglucosidaseactivity.Ligstrosidehasbeendescribedasacommonphenoliccomponentindifferent olivetissues(leaf,fruitpulp,andstone)andoliveoil,butithasbeenrarelyfoundinoliveseeds[20]. Figure2.BiosynthesisandbiotransformationofsecoiridoidsinOleaeuropaeaL.
Antioxidants2020,9,1495of39 Inthecourseofmaturation,OLandligstrosideareconsideredpatterncomponents.Bothofthem arepresentintheolivefruit,buttheyarealmostnon‐existentinoliveoil(85–95%reduction)[21,22]. β‐glucosidaseactsbydecreasingOLandligstrosidelevels,aglyconformsfromOL,andligstroside canbedetectedasisomersduetotheketo‐enolictautomericequilibriumoftheelenolicacidmoiety [23,24]. OtherdialdehydicsstructurallyrelatedtothesesecoiridoidprecursorsareOLAandOLE. DifferentauthorshavereportedthatbothOLAandOLElevelsincreaseduringripeningduetoOL andligstrosidedegradation,respectively[25].Thus,theyconcludedthatOLandligstrosideare naturalprecursorsofOLAandOLEasbreakdownproductsresultingfromenzymaticactivityduring theextractionandmaturationprocesses[26–29]. OLandligstrosidehavebeendetectedinoliveleaves.Inturn,OLAandOLElevelsare augmentedinmaturefruits,suchasOLandligstrosideaglycons.Moreover,OLAandOL‐aglycone aremoreplentifulinoliveoil[16]. 1.4.FunctionalandPhysiologicalChemistryoftheMainSecoiridoidsofPotentialMedicalInterest. ROShavearemarkableroleinthedevelopmentofoxidativestressandalsointhepathologyof numerousdiseases.Forexample,oxidativestressisoneofthemajorcellularfeaturesintheonsetof manypathologicalconditionssuchasAlzheimer’sandParkinsondisease,renalinjury,diabetes, cardiovasculardiseases,cancerandaging;itoccurswhenexcessiveROSaccumulationproduced duringthenormalcellmetabolicprocessesisunbalancedbytheantioxidantdefencesystem[30],and itmayinducetheoxidativemodificationofcellularmacromoleculesincludinglipids,proteins,and nucleicacids[31]. PreviousepidemiologicalstudiesshowthattheMediterraneandietisassociatedwithalow incidenceofcardiovasculardiseaseorcancer.Thismayreflectthenutritionaleffectsofthebioactive compoundscontainedinitsmajorsourceoffattyacids,i.e.,extra‐virginoliveoil(EVOO),whichis richinphenoliccompounds[32,33].ThephenoliccompoundscontainedinEVOOincludeHTy,Ty, andtheirsecoiridoidsprecursorssuchasOL,OLE,orOLA,amongothers. Alargenumberofstudieshighlightedtheantioxidantpropertiesofthesecompoundsincluding theirabilitiestopromotetheactivityofROS‐detoxifyingenzymes,suchassuperoxidedismutase (SOD),catalase(CAT),glutathionereductase(GSR)andglutathioneS‐transferase(GST),tocompete withcoenzymeQasanelectroncarrierinthemitochondrialelectrontransportchain,whichisasite ofROSgeneration,toactasfree‐radical‐scavengingantioxidantsandtoinhibitlipidperoxidation [31,34].Inparticular,itwasshownthatdietaryOLandOLEtreatmentswereassociatedwith reductionsintheproductionofsuperoxideanionradicalinhumanmonocytesfromhealthydonors [35].Similarly,OLadministrationsignificantlyincreasedtheSODandglutathioneperoxidase(GPx) activitylevelsintheobstructedkidneysfromratswithunilateralureteralobstructioninduced‐kidney injury[36].TheseresultsareinaccordancewithotherreportsshowingthatOLwasabletoincrease theamountofenzymessuchasGPxandSODingentamicin‐inducedrenaltoxicityandcisplatininducedrenalinjurymodels[37,38].ThephenoliccompoundspresentinOleaeuropaeaL.activated enzymaticandnon‐enzymaticantioxidantdefensemechanisms,particularlypreventingcell membranedamagebyhigh‐doseUV‐Brays[39]. VitaminE(α‐tocopherol)isanessentialmicronutrientinthedietofallmammals,anditisa potentantioxidantinbiologicalsystems.Thiscompoundisthemainchain‐breakingantioxidantthat preventsthepropagationoffreeradicalsreactions,andconsequentlypreventsthetissuedamage.In thissense,ithasbeenreportedthatsupplementingthedietwithOLfor21daysmaintainedhigher levelsofα‐tocopherolinliveroffemaleWistarrats[40]. Themostimportantantioxidantactivityoftheolivetreephenoliccompoundsisrelatedtothe free‐scavengingabilitybecausetheyinhibitthepropagationchainduringtheoxidationprocess throughthedonationofradicalhydrogentoalkylproxylradicalsandtheformationofstable derivativesduringthisreaction.Thesecompoundsalsoactasmetalchelators,preventingthe generationofhighconcentrationsofhydroxylradicals[41].Thiscapacitymaybereducedbythe presenceofthe–COOOH3fragmentinseveralsecoirioidsstructures,becauseitseemstocausea
Antioxidants2020,9,1496of39 decreaseintheantioxidantactivitywhichisrelatedtotheinabilityofthisgrouptoactasanH‐donor [42].Infact,OL‐aglyconepresentsbetterradical‐scavengingcapacitythansinglehydroxyl substitutions,suchasTy,andalsoprotectslow‐densitylipoprotein(LDL)fromoxidation[43]. Therelationshipbetweenoxidativestressandinflammationhasbeenestablishedbymany authors.Thepathogenicroleofmixedadvancedglycoxidationproducts(AGE)andadvancedlipid peroxidationproducts(ALE)generatedinthecourseofoxidativestressandtheiradductswithcell biomolecules,suchasproteinsandnucleicacids,inanumberofchronicinflammatoryand autoimmunediseasesiswelldocumented[44]. Ontheotherhand,inthepastyears,theleavesofOleaeuropaeaL.havebeenconsideredasan importantsourceofantioxidantcompounds.Inthiscase,OListhemostpredominantandactive phenoliccompound(60–90mg/gdriedoliveleaves),anditisusuallyconsideredasanantioxidant referenceincomparisonwithothersecoirioids[45,46].OLcontainsactivecomponentsinitsmolecule withconferredapotentialantioxidantactivity.Ithasbeensuggestedthatthesepropertiesarerelated totheH‐atomdonationfromthephenolicgroupspresentinOL.Forexample,OLadministration showedaprotectiveeffectagainstROSproductioninendothelialcellssinceOLshowedgood cytocompatibilityandantioxidantactivity,whichrevealedeffectivenessincontrollingtheoxidative stressuponexposuretoH2O2[47].Inaddition,OLpresentedslightlyweakerradicalscavenging activitythanHTyby2,7‐dichlorodihydrofluoresceindiacetate(DCFH‐DA)andABTSmethods[48] andtheabilitytoinhibitLDLoxidationbyscavengingfreeradicals[49]. AlthoughthestudiesabouttheantioxidantactivityofOLEarelimited,ithasbeendemonstrated thatOLEcouldinhibitnicotinamideadeninedinucleotidephosphateoxidase(NOX)inisolated humanmonocytes,andalsoOLEwasabletoreduceintracellularROSlevelsinSH‐SY5Ycells. Recently,Montoyaetal.havealsoshowedthatOLEproducedapotentreductionofintracellularROS andnitritesproductioninLPS‐inducedmurineperitonealmacrophages[50]. OLAisoneofthemajorphenoliccompoundspresentintheolivetree,butitsantioxidantprofile ismoreunknownincomparisonwithothersecoirioids,suchasOL.However,OLAhasdemonstrated tobeapotentscavengerofHOClandmyeloperoxidasereleaseandexertsastrongerinhibitory capacityofneutrophil’soxidativeincomparisontoOL[32]. 1.5.PharmacokineticsofSecoiridoidsfromtheOliveTree Numerousinvestigationshavereveleadthebeneficialeffectsofoliveleavesandoliveoilforthe treatmentofmanydiseases.Thepossibilitythattheirconstituentsmayachieveanybiologicaleffects dependsonthechanceofreachingmoleculartargetsinaspecifictissueororganatasufficientdose, whichisdependentontheirmetabolismandbioavailability[51]. Themechanismofintestinalabsorptionofoliveoilphenolsisunclear,asitdoesnotappearto bestrictlydependentonthepolarityofthesecompounds.Forexample,OL,whichisapolar,isable todiffusethroughthelipidbilayeroftheepithelialcellmembrane.However,also,themorepolar HTyappearstobeabsorbedviaapassivebidirectionaldiffusionmechanism[52,53]. Todate,reportsregardingthebioavailabilityofthephenoliccompoundspresentinoliveoilare extended,whereasbioavailabilitystudiesconcerningsecoiridoidsderivativessuchasOL,OLE,and OLAhavebeenscarcelystudied.Thus,dataonthebioavailabilityofthesesecoiridoidscompounds inhumanandevenanimalswouldbeofgreatinterestinordertoestablishtheirpotentialhealth benefits. Generally,secoiridoidsfromOleaEuropaeaL.aremainlypresentinglycosylatedforms(OLand ligstroside).Forthisreason,afteroraladministration,enzymefromsalivastartsahydrolysisprocess continuedinthestomachbydigestiveenzymesandβ‐glycosidases.Theunmodifiedformscouldbe absorbedtothesmallintestineorcolon,wheretheyarehydrolyzed,finally[54].Theresultofthis hydrolyticprocessistheformationofderivedaglyconforms.Atthesametime,theaglyconsthat wereformedcouldbeabsorbedinthesmallintestineorcolon.Thechemicalstructureandvehicleof administrationaredecisivefortherateandextensionofgastrointestinalabsorption.Structural modificationsoccurviaconjugationinsmallintestinalepithelialcellsorinliver,aftertransport
Antioxidants2020,9,1497of39 throughtheportalsystem.Metabolitesreachthegeneralbloodcircle,fromwhichtheyareexcreted intheurine[55]. RelatedtoOL,someauthorssuggestthatitcouldbeabsorbedinthesmallintestineorcolon.In thissense,Kendalletal.reportedthatOLdiffusesinthestomachandremainedstableandintactat thegastriclevelduringdigestionbeingabsorbedinthesmallintestineinhealthyyoungadults[56]. Similarly,severalstudieshaveestablishedthatOLisstableatthegastriclevelduringdigestion,since thebioavailabilityofitsmainmetaboliteHTyishigher[57].Onthecontrary,Coronaetal.determined thatOLwasabsorbedinthecolonanddegradedbygutmicrobiotainratintestinalsegmentthat producesHTy,whichexpressesbiologicalactivity[58].Furtherstudiesdevelopedinratsconfirmed thatOLandHTywerepresentinplasma,feces,andurineassuch,andalsoconjugatedasglucuronide afteroralOLadministration[59–61].Besides,thereareseveralstudiesthatfocusonthestudyofthe colonicpathwayofphenoliccompoundspresentintheolivetree.Forexample,Moseleetal.have demonstratedthatOLhydrolysisformedOL‐aglycone,elenoicacid,HTyandHTy‐Acinvitro,which isprobablyaconsequenceofthehydrolytictransformationmakingallofthemlessresistanttothe gastricacidichydrolysisincomparisontoOLandmoresensitivetotemperature,pH,andenzyme activity.However,OLadministrationdetectedotherrelatedmetabolitessuchashomovanillicacid inrats[62].Thesedivergencescouldbeexplainedtakingintoaccountthedifferencesfoundbetween bothmurineandhumanmodels. Surprisingly,ithasbeenpostulatedthatplasmapeakat1hour(h)afterOLadministrationfor humansor2hforamurinemodel,althoughOLcouldbedetectedafter10minutes(min)[56,63].In addition,glucuronidesandOLsulfatederivativescouldbedetectedinplasma(at23min)orinthe urine(at8h)afteringestion.Particularly,DeBockandcolleaguesdescribedaheterogeneouseffect inOLleafextractbioavailabilityandmetabolismthatwasdependentonanumberoffactors, includingpreparation(capsule/liquid)andgender[63].Infact,theyfoundthatcomparedtocapsules, OLleafextractinaliquidformulationledtoagreaterOLpeaklevelsandareaunderthecurve(AUC) inplasmaanddescribedthatmalesmaybemoreefficientatconjugatingOL. Theproductionofmetabolitesduringthemetabolismprocessofthesecompoundscouldbe interestinggiventhatthesenewcompoundsmayalsoexertbeneficialeffectsontheorganism.The metabolismofsecoiridoidscanbecarriedoutbyphaseI(hydrogeneration,hydroxylation, hydratation,etc)orphaseIIreactions(glucuronidation,methylation,sulfation,etc.).Aperfusedrat intestinalmodeldeterminedthatthemajorsmallintestinemetabolitesfromOL‐aglyconewere glucoronideconjugates,sotheyarenotabsorbedinparentalform[64].OL‐aglyconeandligstroside aglyconepresenta55%–66%rateofabsorptioninhumans.Theaglyconformswereexcretedinurine asHTyorTy[65].Particularly,duringgastricdigestion,OL,OL‐aglycone,andotherphenolic compoundsaretransformedintoHTy,whichisthroughouttransformedintoitsphaseIImetabolites (glucuronideandsulfateconjugates)andintoHTy‐Acbyeffectoftheacetyl‐CoAenzyme[66].OL andligstrosideformedsulfateandglucuronideconjugatesduringabsoptionafterundergoing extensivefirst‐passintestinal/hepaticmetabolism,whereasconcentrationsoftheirfreeformsarenot detectedinthebodyfluids.Thesecompoundswereabsorbedquicklyafteroraladministrationand thenweremetabolizedandexcretedintheurinemainlyasglucuronide[67].ThecatabolismofOL couldproducephenylaceticandphenylpropioniccataboliteswhichthencouldbeabsorbedand subsequentlytransformeintophaseIImetabolites.Thus,compoundssuchasligstrosideorOLcould beabsorbedassuchorreabsorbedintheformoftheirrespectiveglucuronideconjugates[58,68]. ThebioavilabilityofOLEisstillverylimited.LigstrosideaglyconeandOLEarehydrolyzedin theacidicgastricenvironmentinthestomach,leavingfreeTyafter30min.OLEisabsorbedinthe smallintestinemediatedbypassivediffusionthroughthemembrane,whichisfavorablegivenan adequatecoefficientofpartition(logP=1.02)andstabilityinacidgastric[69].Infact,Romeroetal. verifiedthatOLEwasstableingastricacidconditionsat37°Cfor4h[70].Althoughithasbeen postulatedthatOLEismainlymetabolizedbyPhaseI(hydrogenation,hydroxylation,andhydration) [71,72],somehydrogenatedmetabolitespasstoPhaseIIofmetabolismasglucoronidatedforms[54], whereasmethylatedorsulfateformsofOLEhavenotbeendetectedinanystudyinhumanstodate
Antioxidants2020,9,1498of39 [71,72].ThereportpublishedbyGarcía‐Villalbaetal.revealedthatOLEandseveralsecoiridoids metaboliteswereexcretedinhumanurinebetween2and6hafteroliveoilingestion[72]. Ontheotherhand,OLAmaybeabsorbedinthesmallintestinebypassivediffusionthroughthe membraneduetoitsfavorablepartitioncoafficient.OLAwasfoundtobestableatgastricacid remaingunalteratedafter4hofincubation[73].Aftertheconsumptionofoliveoil,Delashazaset al.[66]describedthatOLAwashydrolyzedintoHTyandelenoicacidinthedigestivesystemand furthermetabolizedbytheenzymaticsystems. Inconclusion,therearealotofplantsthathavebeenusedasmedicinessincetimeimmemorial; specificallys,OleaeuropaeaL.isaspeciesrichincompoundsthathaveproventheirefficacyinthe managementofseveralcomplexdiseasesincludingcardiovasculardisorders,diabetes,andviraland microbialinfections,butadditionalworksarestillreallynecessarytoexploretheevidencesforother traditionalusesofthisplant.Particularly,theantioxidant,anti‐inflammatory,and immunomodulatorypropertiesofsecoiridoidsfromtheolivetree(leavesandfruits)havebeen suggestedasapotentialapplicationinseveraloxidativestress‐mediateddiseasesincludingcancer, cardiovasculardisorders,neurodegeneration,theagingprocessandimmunoinflammatorydiseases. Thus,thepurposeofthisreviewissummarizerecentadvancesintheprotectiveroleofthese secoiridoidsderivedfromolivetree(preclinicalandclinicalstudies)inthesepathologiesderived fromoxidativestressandfocusingontheirplausiblemechanismsofactioninvolved. 2.ProtectiveRoleoftheOliveTreeSecoiridoisinDiseaseswithanImportantPathogenic ContributionofOxidativeandPeroxidativeDamage 2.1.OliveTreeSecoiridoidsandCancer Cancerisacomplexchronicdegenerativediseasecharacterizedbyamultistepprocessinwhich normalcellsturnintomalignantcells,acquiringseveralpropertiessuchasabnormalproliferation andreducedapoptosis. Themainfactorsthatcausethemajorityofcancercasesaretobaccoanddietaryhabits.Infact, thereisanestimationthataround30%ofallcancersmaybeavoidablebychangingfoodintake [74,75].Therefore,theidentificationandcharacterizationoffoodsandtheircomponents,whichcould preventtheincidenceanddevelopmentofcancer,isanimportantobjectiveformodernnutritional research[74,76].Inthissense,itisimportanttotakeintoaccountthatpopulationswhoarelivingnear totheMediterraneanareahavealowerincidenceofcancercomparedtootherregions.Thisfactis probablyduetotheconsumptionofthedietknownastheMediterraneandiet[77].Besides,itiswellknownthatthepathophysiologyofcommondiseasesstatessuchascancer,cardiovasculardisease, arthritis,andneurodegenerativediseases,amongothers,areassociatedwithchronicinflammation [78]. Therearealargenumbersofstudiesthatsupportthechemopreventiveroleofnatural compoundsderivedfromEVOOandtheolivetreesuchasOL,OLE,OLA,orligstrosideagainst differentcancersandinflammationprocess.Particularly,theroleofsecoiridoidsderivedfromOlea europaeaL.hasbeeninvestigatedindifferenttypesofcancerousprocesses(Tables1and2). Table1.Mostrecentinvitrostudiesthatcorroboratetheimportantroleofsecoiridoidsfromtheolive treeinthecontrolandprogressionofdifferenttypesofcancer. Phenolic CompoundCellLineConcentrationEffectsReference OL NL‐Fib:normalhumanskin fibroblasts;LN‐18:poorly differentiatedglioblastoma;TF‐ 1a:erythroleukemia;786O:renal celladenocarcinoma;T‐47D: infiltratingductalcarcinomaof breast‐pleuraleffusion;MCF‐7: humanbreastcancer;RPMI‐7951: malignantmelanomaskin‐ 0.005%,0.01% and0.025%of OLinfibroblast tissueculture medium OLinhibitedcellgrowth, motilityandinvasiveness[79]
Antioxidants2020,9,1499of39 lymphoidemetastasis;LoVo: colorectaladenocarcinomasupraclavicularregionmetastasis HT29andSW260humancolon adenocarcinomacellline[0–100μM] OLmightinduceantiproliferativeandproapoptoticeffects [80] HT29 200,400,and800 μM OLlimitedthegrowthand inducedapoptosisviathe p53pathway [81] MDA‐MB‐231humanbreast cancercellline200μg/mL OLproducedtheupregulatingofTIMPsgene expressionandthedownregulationMMPs overexpressiongene [82] MDA‐MB‐231;MCF‐10Aand MCF‐7humanbreastcancercell lines [0–300μM] OLexhibitedspecific cytoxicityagainstbreast cancercells,whichis probablymediatedthrough theinductionofapoptosis viamitochondrialpathway [83] SKBR3breastcancercellline100μM OLworkedasG‐protein‐ coupledreceptor(GPER) inverseagonistsinestrogen receptor(ER)‐negativeand GPER‐positiveSKBR3 [84] MCF‐7 100and200μM OLinducedapoptosisin breasttumorcellsviap53‐ dependentpathway [85] MDA‐MB‐231andMCF‐7 [0–100μM] OLinhibitedtheviabilityof breastcancercellsand inducedapoptosisvia modulatingNF‐κB activationcascade [86] MCF‐7 [0–1200μg/mL] OLsuppressedcells migrationthrough suppressionofepithelialmesenchymaltransition andcouldreduceDOX‐ inducedsideeffectsby reducingitseffectivedose [87] MCF‐7 [0–100μM] OLdecreasedthe expressionofbothHDAC2 andHDAC3,induced apoptosis,andretardedcell migrationandcellinvasion inadose‐dependent manner [88] MCF‐7 200,400,600, and1000μM OLinhibitedthe proliferationandinvasion ofcellsbyinducing apoptosis [89] MDA‐MB‐231 [0–100μM] OLreducedcellviabilityin adose‐dependentmanner; suppressedHGFor3‐MA, andinducedcellmigration andinvasion [90] MCF‐7 [0–250μM] OLinhibitedprotein tyrosinephosphatase1B (PTB1B) [91] HepG2andHuh7humanHCC celllines[0–100μM] OLinducedapoptosisin HCCcellsviathe suppressionofPI3K/Akt [92] HepG2 100,200and300 μM OLcouldcontrolthe influencingofpro‐nerve growthfactor(NGF)and [93]
Antioxidants2020,9,14916of39 OLA phorbol‐myristate‐acetate‐induced oxidativeburstsinneutrophilsand myeloperoxidaserelease Humanneutrophils50and100 mM OLAreducedelastaserelease,IL‐8,MMP‐9, andNEPactivity[143] Human macrophages10–20mMOLAincreasedIL‐10,HO‐1,andCD163 expression[144] Table4.Beneficialeffectsofsecoiridoidsfromtheolivetreeinthecontrolandprogressionofdifferent typesofcardiovasculardiseases:invivoandclinicalstudies. InVivostudies Phenolic compoundAnimalModelDosesEffectsReference OL Ischemia–reperfusionin insolatedrathearts20μg/g OLreducedthecreatinekinase, glutathionerelease,membranelipid peroxidation [145] Ischemic‐treated hypercholesterolemic rabbits 10or20 mg/Kg/day OLreducedtheinfarctsize,total cholesterol,triglyceride concentration,andlipid peroxidation [146] Doxorubicin‐inducedacute cardiotoxicityrats 100or200 mg/Kg OLmodulatedtheCPK,lactate deshydrogenase,aspartateand alanineaminotransferase,andlipid peroxidation [147] Doxorubicin‐inducedacute cardiotoxicityinrats 100or200 mg/Kg OLreducedtheacetateand succinatelevels.Restoremetabolic changes [148] Doxorubicin‐induced chroniccardiomyopathyin rats 1000or2000 mg/Kg OLcontrolledcardiac histopathology,nitro‐oxidative stress,IL‐6,myocardial metabolomics [149] Rabbitmodelof atherosclerosis100mg/Kg OLdecreasedlipids,cholesterol, LDLlevels,TNF‐α,NF‐kB,ICAM‐ 1,andVCAM‐1expressions [150] Obesity‐inducedcardiac metabolicchanges 0.023 mg/Kg/day OLincreasedoxygenconsumption, fatoxidation,andmyocardialβhydroxyacylcoenzymeA dehydrogenaseactivityandtheupregulationofantioxidantenzyme expression [151] Renovascularhypertension anddiabetes2rats 20,40,or60 mg/Kg/day OLreducedbloodpressure,blood glucose,serumtotalcholesterol, LDL,andtriglycerideslevels. RaisedHDLlevels. [152] Diabetichypertensiverats20,40,or60 mg/Kg/day OLloweredbloodpressure,MDA, creatinekinase,andtheinduction ofHDLlevels [153] Diabetichypertensiverats20,40,or60 mg/Kg/day OLdecreasedbloodpressure, glucose,andserumMDAlevels. OLincreasedofHDLand erythrocyteSOD [154] Spontaneoushypertensive rats10mg/Kg OLreducedtheoxidativestress, carotidandrenalhemodynamics, bloodpressure,andheartrate [155] Ratsfedwithhighcholesteroldiet3mg/Kg OLmodulatedtotalcholesterol, triglycerides,LDLandHDLlevels, andliverantioxidantenzymes [156] Neonatalratsventricular myocyteswithMAO‐A enzymeoverexpressed 100μM OL‐aglyconedecreasedoxidative stress,autophagicfluxblockade andcellnecrosis [157] Matureandprogenitor endotelialcells 10μMOL‐aglyconedown‐regulatedNF‐ kB,IL‐8,vascularendothelial[158]
Antioxidants2020,9,14917of39 OL‐aglycone growthfactor(VEGF),MMP‐2,and MMP‐9 Ratsfedwithhighcholesteroldiet3mg/Kg OL‐aglyconemodulatedtotal cholesterol,triglycerides,LDLand HDLlevels,andliverantioxidant enzymes [156] ClinicalTrials Phenolic CompoundExperimentalSystemConcentrationEffectsReference OL 232hypertensivepatients500mgtwice daily OLloweredsystolicanddiastolic bloodpressure,triglycerides,and LDLlevels [159] Oneofthebest‐documentedcardiovascularprotectorsecoiridoidsisOL.OLinhibitedinadosedependentmannerthecoppersulfate‐inducedoxidationofLDL,reducingtheformationoflipid peroxidesandmalondhialdehydelysineand4‐hydroxynonenol‐lysineadducts[138].Thesedata indicatedtheprotectionoftheapoproteinlayer.Additionally,OLwasabletoscavengesuperoxide anionsgeneratedbyeitherpolymorphonuclearcellsorbythexanthine/xanthineoxidasesystem [139].Inthisline,pretreatmentwith20μg/gofOLbeforeischemia–reperfusioninisolatedratshearts resultedinasignificantreductionincreatinekinaseandglutathionerelease,supportingexperimental evidencesofadirectcardioprotectiveeffectofOL[145].Morerecently,Parzonkoandcolleagues describedthatOL‐treatedendothelialprogenitorscells(typeCD31+andVEGFR‐2+)showeda decreaseinthepercentageofsenescentcellsandROSformationandrestoredmigration,adhesion, andtubeformation.ThiseffectwasrelatedtonuclearfactorE2‐relatedfactor2(Nrf2)andheme oxigenase‐1(HO‐1)expressions[140](Table3). Relatingtoanimalmodels,Andreadouandco‐workershavedevelopedseveralinvivo experimentalmodelswithOLtreatment,definingthepotentialeffectofthissecoiridoidasa cardioprotector.Ischemia‐treatedrabbitsfedwith10or20mg/Kg/dayOL‐supplementeddiets showedareductionininfarctsize,totalcholesterol,andtriglycerideconcentrations[146].Similarly, OLadministratedviaintravenousdecreasedsomemarkersofcardiovasculardiseaseinDOX‐ inducedacutecardiotoxicratssuchascreatinephosphokinase(CPK),lactatedeshydrogenase, aspartateandalanineaminotransferase,andlipidperoxidationinmyocardialtissue[147]. Completingthisstudy,theseauthorsrevealedthatOLdown‐regulatedacetateandsuccinatelevels andrestoredmetabolicchangestonormallevelsinmyocardialtissue[148].Finally,Andreadouetal. concludedthatOLadministrationcouldalsopreventcardiomyopathy[149](Table4). Concerningstudiesofatherosclerosis,OLcoulddecreasedserumlipidsandtumornecrosis factoralpha(TNF‐α)levels,whichwasaccompaniedbyadown‐regulationofmonocytechemostactic protein‐1andvascularcelladhesionmolecule[150].Ebaidetal.studied the effects of OLintakein obesity‐inducedcardiacmetabolicchanges.TheyfoundthatanOLdietshowedanincreaseofoxygen consumption,fatoxidation,andmyocardialβ‐hydroxyacylcoenzymeAdehydrogenaseactivityand areductioninthelevelsoflipidhydroperoxideandup‐regulationofantioxidantenzymeconfirmed thatOL improvedmyocardialoxidativestressinstandard‐fedconditions[151]. WithregardtoOLantihypertensiveeffects,thereareseveralstudiesperformingdifferentanimal models.Inthisline,diabeticandhypetensiveratsreceiving20,40,or60mg/Kg/dayofOLpresented significantlyreducedbloodpressure,bloodglucose,serumtotalcholesterol,LDL,triglyceride,MDA, coronaryeffluentcreatinekinase,andcoronaryresistance.Theanimalsalsohadhigh‐density lipoprotein(HDL),erythrocyteSOD,leftventriculardeveloppressure,rateofrise,andrateof decreaseofventricularpressure[152–154].Antihypertensiveactivityhasalsobeensupportedby Ivanovetal.,whoreportedsignificantchangesincarotidandrenalhemodynamics,reducing cardiovascularriskandimprovingvascularresistanceinspontaneoushypertensiveratoxidative stress[155]. Regardinglipidregulation,theadministrationofOLanditsaglyconeformsignificantlydownregulatedtheserumlevelsoftotalcholesterol,triglycerides,andLDLandup‐regulatedHDLand
Antioxidants2020,9,14918of39 liverantioxidantenzymesinWistarratsfedacholesterol‐richdiet.Theseresultsdemonstratedthat secoiridoidsadministrationcouldcontrolthelipidperoxidationprocess,enhancingantioxidant enzymeactivity[156]. Theclinicaltrialsoftheeffectsofsecoiridoidsoncardiovasculardiseasesarescant.Inthisregard, 232hypertensionpatientswereinvolvedinaclinicalstudysubjectedtoa500‐mgoraldoseofanOL‐ enrichedextractadministrationtwicedailyfor8weeks.Thepatientspresentedasignificant reductionofsystolicanddiastolicbloodpressureaswellasthelevelsoftriglyceridesandLDL [159,160](Table4).StockandcolleaguesmeasuredcholesteroleffluxcapacityfromfreecholesterolenrichedmacrophagestoapolipoproteinB‐depletedserumasthecholesterolacceptorinpatients withcoronaryarterydisease.OLshowedapositivebehavioragainstLDLoxidation,promoting cholesteroleffluxandsuggestingpreventiveeffectsagainstcoronaryarterydiseasesandenhanced atheroprotectiveactions[161]. AccordingtoOLaglycone,onlyfewstudieshavebeencarriedout.Dell’aglietal.describedthat OLaglyconeexertedamodulationinearlyatherogenesis,reducingcellsurfaceexpressionsof intracellularandvascularcelladhesionmolecules(ICAM‐1andVCAM‐1)inhumanumbilical vascularendothelialcells[141].SimilartoOL,theaglyconeformwasstudiedinratsfedwitha cholesterol‐richdietbyJemaielat.TheresultssuggestedthatthehypocholesterolemiceffectofOL- aglyconemightbeduetoitsabilitiestolowerserumtotalcholesterol,triglycerides,andLDL cholesterollevels,slowingthelipidperoxidationprocessandenhancingSODandCAT antioxidant enzymeactivities,exhibitingacardioprotectiveroleagainstlipidoxidationandcholesterolefflux [156]. Morerecently,Lerietal.reportedthatOL‐aglyconewasabletoreducetransthyretintoxicityin mouseatrialmyocytes,soitcouldbeusedastreatmentforseverecardiacsymptoms[142].In addition,MiceliandcoworkersexploredtheeffectsofOL‐aglyoneinmyocyteswithan overexpressionofmonoamineoxidase‐A(MAO‐A),whichisanenzymethatcausesoxidativestress, autophagyfluxblockade,andcellnecrosisasamodelofcardiacstresscharacterizedbyautophagy dysfunction.TheyobservedthatOL‐aglyconecounteractedthecytotoxicMAO‐Aeffects[157]. Margherietal.alsoreportedtheeffectsofOLaglyconeoncapillarymorphogenesisinducedbyMRC5 fibroblastʺsenescenseassociatedsecretoryphenotypeʺandprogenitorendothelialcells,establishing thatthissecoiridoidcouldmodulateangiogenesisindirectlyonsenescentfibroblasts[158](Table4). Todate,OLEcardioprotectiveactivityhasbeenslightlyinvestigated.Evenso,someauthors defenditscardioprotectivepropertybasedonitscapacitytoinhibitCOX‐1andCOX‐2expression.It iswell‐knownthatthromboticandcardiovasculardisordersarelinkedtoanimbalanceinprostanoid homeostasis,particularlyprostaglandinorthromboxaneproduction,whichareinvolvedin vasodilatationorvasoconstriction,respectively,andplateletaggregation[162].OLEhasexerted stronginhibitoryeffectsonCOX‐1andCOX‐2inseveralstudies[50,163,164];nevertheless,future studiesareneededtoconfirmthepropertyofOLEincardiovasculardisorders(Table3). ThecardiovascularprotectioneffectsofOLAweretestedinvitroinhumanneutrophilsand monocytes.ThiscompoundwasabletoscavengeO2‐,H2O2,andNOlevels,amongotherparameters, whichareimplicatedintissueinjuryandchronicdiseases,asatherosclerosis[32,165].Inasimilar work,Czerwinskaetal.studiedthecapacityofOLAonneutralendopeptidase(NEP)activityand otherfunctionsofhumanneutrophils,suchaselastase,MMP‐9andinterleukin(IL)‐8production,which wasmarkedlyincreasedinpatientswithmyocardialinfarction[32].TheauthorsconcludedthatOLA couldplayaroleinthecardiovascularprotectiveeffectsdescribedbyoliveoilbyinhibitingNEP activity,adhesionmoleculesexpression,andelastaserelease.Likewise,Filipekandcolleaguesshowed thatOLAincreasedCD163expressioninhumanmacrophages,supportingthesignificantrolein attenuationofplaquedestabilizationinducedbyhemorrhages[144].Later,theseauthorsreported thebeneficialeffectsofOLAinattenuatingthedestabilizationofcarotidplaquein20patientswith hypertension.ThisworkrevealedtheabilityofOLAtomodulateIL‐10,HO‐1,MMP‐9,andhigh mobilitygroupprotein‐1,whichisaspecificbiomarkerofcelllethality[166].Thus,thiscompound couldbepotentiallyusefulinthereductionofischemicstrokerisk.Concluding,thepreventiveand curativeroleofOLA,intermsofcardiovascularinjury,couldbeattributedtoitsabilitytoregulate
Antioxidants2020,9,14919of39 LDLoxidationandMPOactivity,toreducetheexpressionofadhesionmolecules,asangiotensinII production,andtoconferprotectiontoerythrocytesfromoxidativehemolysis[33,73]. 2.3.OliveTreeSecoiridoidsandNeurodegeneration Neurodegenerationisaprocessthatleadstoaprogressivelossofstructureorfunctionof neurons,irreversibleneuronaldamage,death,andacommonfinalpathwaypresentinagingand neurodegenerativediseases.Inaddition,oxidativestressinducedbyimpairedmitochondrial functionshasbeenalsoreported[167].Particularly,superoxideanionformationandtheproduction ofhydrogenperoxidearetriggeredbytheinductionofNADPHoxidase(NOX)subunit.This conditiontogetherwithahighNOlevel,producedbytheinductionofinduciblenitricoxidesynthase (iNOS)resultsintheformationofperoxynitriteandnitrativestress [69].Examplesof neurodegenerativediseasesincludeAlzheimerʹsdisease(AD),Parkinsonʹsdisease(PD), Huntingtonʹsdisease,amyotrophiclateralsclerosis,frontotemporaldementia,andthe spinocerebellarataxias[168].Thesediseasesrepresentaprimaryhealthproblem,especiallyinthe agingpopulation.Powerfulexperimentalmodelorganismssuchasthemouse,fruitfly,nematode worm,andevenbakerʹsyeasthavebeenusedformanyyearstoexploreneurodegenerativediseases andhaveprovidedkeyinsightsintothesebraindisorders. Severalepidemiologicalandobservationalstudiessupportthebeliefthattraditionalalimentary regimenssuchastheMediterraneandietwhereoliveoilistheprimarysourceofaddedfatis associatedwithimprovedagingandareducedincidenceofage‐relateddiseases,including cardiovasculardiseases,cancer,andcognitivedecline[169].Particularly,oliveleavesandEVOO containmanyfunctionalphenolicsthathavebeendemonstratedtobeabletoreduceriskandoffer protectionagainstseveralagingandlifestyle‐relateddiseases,includingneurodegeneration,inboth animalandhuman’smodels.Infact,EVOOconsumptionhaswell‐documentedantioxidant,antiinflammatory,anti‐proliferative,anti‐carcinogenic, andantibacterialeffects[170].Amongthe200 differentchemicalcompoundsdetectedinoliveoil, quantitatively,theclassofsecoiridoidsisthe mostabundant.Anumberofdifferentstudiesinvestigatedtheeffectsofsecoiridoidsfromolivetrees inbothinvitroandinvivomodelsofADandPD(Tables5and6). Table5.Invitrostudiesthatcorroboratetheeffectsofsecoiridoidsfromtheolivetreeindifferent typesofneurodegenerationprocesses. Phenolic CompoundCellLineConcentrationEffectsReference OL 6‐OHDA‐induced toxicityinratadrenal pheochromocytoma (PC12)cells 20and 25 μg/mL OLdecreasedcelldamageandreduce biochemicalmarkersofPC12celldeath[171] PC12cellsexposedto thepotent parkinsoniantoxin6‐ OHDA 10−12M OLshowedneuroprotectiveeffectsinan invitromodelofPDwhenadministered preventivelyasapretreatment.OL significantlydecreasedneuronaldeath. OLcouldalsoreducethemitochondrial productionofROSresultingfrom blockingSODactivity [172] OL‐aglycone SH‐SY5Y [0–25μM] OL‐aglyconepreventedthegrowthof toxicAβ1‐42oligomersandblockedtheir successivegrowthintomaturefibrils followingitsinteractionwiththepeptide N‐terminus [173] ExposureofSH‐SY5Y cellswithAβ42[10–1000μM] OLwereabletoattenuatecelldeath causedbyAβ42,copper‐Aβ42,and [laevodihydroxyphenylalanine(l‐DOPA)] l‐DOPA‐Aβ42‐inducedtoxicityafter24h [174] NBMofadultmale Wistarrats450μM Anapparentreductionintheamountof solubleA11‐positiveoligomerswas detectedintheNBMinjectedwithAβ42 [175]
Antioxidants2020,9,14920of39 aggregatedwithOLascomparedwith theNBMinjectedwithAβ42alone OLE Mousebrain endothelialcells (bEnd3) 25and50μM TreatmentofbEnd3cellswithOLE resultedinsignificantincreaseinP‐gp andLRP1levels [173] Table6.Invivostudiesthatcorroboratetheeffectsofsecoiridoidsfromtheolivetreeindifferent typesofneurodegenerationprocesses. Phenolic Compound.AnimalModelDosesEffectsReference OL‐aglycone Doubletransgenic TgCRND8mice,a modelofamyloid‐ß deposition 8weeksdietary supplementationof OL‐aglycone(50 mg/Kgofdiet) DietarysupplementationofOL‐ aglyconestronglyimprovedthe cognitiveperformanceof young/middle‐agedTgCRND8 mice,withrespecttoage‐matched littermateswithunsupplemented diet [176] Transgenicmice (APPswe/PS1dE9) 50mg/KgofOL‐ aglyconecontaining oliveleafextracts (OLE)from7to23 weeksofage. Treatmentmice(OL‐aglycone)were showedsignificantlyreduced amyloidplaquedeposition(p< 0.001)incortexandhippocampusin comparison [174] TransgenicCL2006 andCL4176strainsof C.elegans 50and100μM OL‐aglycone‐fedCL2006worms displayedreducedAβplaque deposition,lessabundanttoxicAβ oligomers,remarkablydecreased paralysis,andincreasedlifespan [177] Systemicamyloidosis murinemodel15μM OL‐aglyconehinderedamyloid aggregationofAβ(1‐42)andits cytotoxicityandeliminatedthe appearanceofearlytoxicoligomers, favoringtheformationofstable harmlessprotofibrils,whichwere structurallydifferentfromthe typicalAβ(1‐42)fibrils [178] TgCRND8mice50mg/Kgofdiet during8weeks OL‐aglyconewasactiveagainst glutaminylcyclase‐catalyzedpE3‐ Aßgeneration,reducingenzyme expressionandinterferingboth withAß42andpE3‐Aßaggregation [175] TgCRND8(Tg)mice AD Dietsupplementation withOL‐aglyconeat 12.5or0.5mgkg‐1of diet AnOL‐aglyconesupplementation dietandthemixofpolyphenols werefoundtoimprovesignificantly cognitivefunctions(p<0.0001). Aß42andpE‐3Aßplaqueareaand numberweresignificantlyreduced inthecortex [179] OLE 5xFADmousemodel ofAD EVOOrichwithOLE EVOO‐richOLEconsumptionin combinationwithdonepezil significantlyreducedAβloadand relatedpathologicalchanges [180] TgSwDImice Dailyi.p.with5 mg/KgOLEat4age ofmonthsand continuedfor4 weeks. OLEsignificantlydecreased amyloidloadinthehippocampal parenchymaandmicrovessels, whichwasassociatedwith enhancedcerebralclearanceofAβ acrosstheBBB [181] C57BL/6wild‐type malemice 10mg/KgofOLE twicedailyfrom7to 8weeksofageand OLEenhancedclearanceofAβfrom thebrain.Asignificantincreasein theexpressionofP‐gpandLRP1 [182]
Antioxidants2020,9,14921of39 continuedfor2weeks (i.p.) wasalsoobservedinthebrain microvessels ADischaracterizedbytheincreasedaccumulationofintracellularneurofibrillarytangles(NFTs) ofhyperphosphorylatedtauproteinandofextracellularAβproteindeposits(Aβplaques)derived fromamyloidprecursorprotein(APP)cleavagebyγ‐secretaseandβ‐secretase.Dietary supplementationofOL(50mg/Kgofdiet)stronglyimprovedthecognitiveperformanceof young/middle‐aged/agedTgCRND8mice,anditalsoreducedß‐amyloidlevelsandplaquedeposits. Moreover,OL‐aglycone‐fedmicebraindisplayedanastonishinglyintenseautophagyreaction [175,176,179].Similarresultsweredescribedintransgenicmice(APPswe/PS1dE9),whereOL treatmentshowedsignificantlyreducedamyloidplaquedepositioninthecortexandhippocampus ascomparedtocontrolmice[174].Moreover,OLhinderedtheamyloidaggregationofAβ(1‐42)and itscytotoxicityandeliminatedtheappearanceofearlytoxicoligomers,favoringtheformationof stableharmlessprotofibrils,whichwerestructurallydifferentfromthetypicalAβ(1‐42)fibrils[178]. UsingtransgenicCL2006andCL4176strainsofC.elegansstrainsexpressingAβ42,asasimplified invertebratemodelofAD,Diomedeetal.evidencedthat50–100μMOL‐fedCL2006wormsdisplayed reducedAβplaquedeposition,lessabundanttoxicAβoligomers,remarkablydecreasedparalysis, andincreasedlifespanwithrespecttountreatedanimals.Aprotectiveeffectwasalsoobservedin CL4176wormsbutonlywhenOLwasadministeredbeforetheinductionoftheAβ transgene expression[177](Table6). InvitrostudieshaverevealedthatOLpreventedthegrowthoftoxicAβ1‐42oligomersand blockedtheirsuccessivegrowthintomaturefibrilsfollowingitsinteractionwiththepeptideN‐ terminusandattenuatedSH‐SY5YcelldeathcausedbyAβ42,copper‐Aβ42,and laevodihydroxyphenylalanine(l‐DOPA)‐Aβ42‐inducedtoxicityafter24htreatment,andamarked attenuatedAβ‐inducedastrocytesandmicrogliareactionwasalsofoundinthenucleusbasalis magnocellularis(NBM)fromadultmaleWistarratsinjectedwithAβ42aggregatedwithOL [171,174,177](Table5). ThepotentialprotectiveeffectofOLEinADhasbeenalsoinvestigatedinTgSwDImice.Mice treatedfor4weekswithOLEsignificantlydecreasedamyloidloadinthehippocampalparenchyma andmicrovessels.ThisreductionwasassociatedwithenhancedcerebralclearanceofAβacrossthe blood–brainbarrier(BBB),whichwasaccompaniedbyanincreaseofP‐glycoprotein(P‐gp)andlow densitylipoproteinreceptor‐relatedprotein1(LRP1)expressions,andactivatedtheApoE‐dependent amyloidclearancepathwayinthemicebrains.Theanti‐inflammatoryeffectofOLEinthebrainsof thesemicewasalsoobviouswhereitwasabletoreduceastrocytesactivationandIL‐1βlevels[181]. Similarly,10mg/kgofOLEadministratedtwicedailyfrom7to8weeksofageandcontinuedfor2 weeks(i.p.)enhancedtheclearanceofAβfromC57BL/6wild‐typemalemicebrainandsignificantly increasedtheexpressionofP‐gpandLRP1[182].Inmousebrainendothelialcells(bEnd3),25and50 μMOLEtreatmentresultedinasignificantincreaseinP‐gpandLRP1levels[182].Moreover,ina 5xFADmousemodelofAD,OLE‐richEVOOconsumption,incombinationwithdonepezil, significantlyreducedAβ loadandrelatedpathologicalchanges,up‐regulatedsynapticproteins, enhancedBBBtightness,andreducedneuroinflammationassociatedwithAβpathology[180](Tables and6). PDischaracterizedbyaprogressivelossofdopaminergicneuronsinthemidbrainregion knownas substantia nigra pars compacta andbythepresenceofcytoplasmicproteinaggregatescalled theLewybodyaswellasLewyneuritesinremainingneurons. PreviousstudiesshowedthatOLinhibitedαSNamyloidogenesisbydirectingαSNmonomers intosmallαSNoligomerswithlowertoxicity,therebysuppressingthesubsequentfibrilgrowth phase[183].TheneuroprotectiveeffectofOLhasbeenexploredinPC12cellsexposedtothepotent parkinsoniantoxin6‐hydroxydopamine(6‐OHDA).OLtreatmentsignificantlydecreasedneuronal deathandreducedthemitochondrialproductionofROSresultingfromblockingsuperoxide dismutaseactivity.Moreover,thequantificationofautophagyandacidicvesiclesinthecytoplasm alongsidetheexpressionofspecificautophagymarkersuncoveredaregulatoryroleforOLagainst autophagyfluximpairmentinducedbybafilomycinA1[171,172].
Antioxidants2020,9,14922of39 2.4.OliveTreeSecoiridoidsandAgeing Agingisanaturalbiologicalprocessthatinvolvesthegradualdeclineofphysiologicalfunction andtheeventualfailureoforganismhomeostasisfollowedbydeath.Agingistheprocessof accumulationofdamagestocells,tissues,andorgansofanindividualthatisuniversalandunique, therebyreducingtheoverallhealthoftheorganism.Itisevidentthatagingcaninducestressinside thesystemintheformofROSorotherstressors,reduceoverallhealth,andinduceage‐associated neurologicaldiseases[184].Themaintenanceofhomeostasisbetweentheformationandelimination ofdamagedproteinsisakeyprocessinthedevelopmentandgrowthoforganisms[185].Todate, veryfewstudiesconcerningtheanti‐agingeffectsofsecoiridoidshavebeenperformed.However, secoiridoidssuggestapotentialage‐relateddamageregulationbasedontheirantioxidant,antiinflammatory,andneuroprotectoreffects(Tables7and8). SeveralinvitrostudieshavesupportedthepotentialofOLontheproteasome,whichregulates thebalanceofcellularviabilityandiscrucialinstress,aging,orsenescentconditions[185].The treatmentofcelllysatesfromhumanembryonicfibroblastIMR90enhancedthreemajorproteasome catalyticactivities:thechymo‐trypsin‐like(ch‐L),thepeptidylglutamyl‐peptidehydrolase(PGPH) activity,andthetrypsin‐like(T‐L).ThisactivitywassupportedbyKatsikietal.OL‐treatedcells retainedproteasomefunctionduringreplicativesenescence,andhumanembryonicfibroblast culturesexhibitedadelayappearanceofsenescencemorphology[186].Santiago‐Moraetal.reported theeffectsofOLonosteoblastogenesisandadipogenesisinmesenchymalstemcellsfromhuman bonemarrow.OLstimulatedosteoclastogenesisrisingcellularmatrixmineralizationandinhibited bonedesorption[187](Table7). Intermsofepigenetic,ithasbeenpostulatedthatoxidativedamagetomitochondrialDNA (mtDNA)isoneofseveralsignsofage‐relatedphysiologicalconsequences[188].Fabianiand colleaguesreportedthatOLandOL‐algyconeformcounteractedDNAalterationsinHL60cellsand peripheralbloodmononuclearcell(PMBC)H2O2‐inducedDNAdamage[43].Moreover,OL counteractedbonelossandreducedα‐1‐acidglycoproteinplasmaconcentrationsinsenile osteoporosisrats[189].Nikouetal.studiedtheeffectsofOLEandOLAinDrosophilaflies,reporting thatdietaryadministrationofbothofthemwasabletoincreasetheT‐Lproteasomeactivityand20S and19Sproteosomalsubunitsexpression,leadingtoasignificantreductionofROSlevels. Subsequently,itwasreportedthatOLAup‐regulatedthegeneexpressionoftheproteasome, antioxidantresponse,andmolecularchaperonesinhumanskinfibroblasts[190](Table8).Thesedata confirmedapotentialanti‐agingofbothsecoiridoidsandsuggestedthatthesecompoundscouldbe criticalnutraceuticalsaspreventiveandtherapeutictreatmentofdifferentagediseases.Nevertheless, clinicalstudiesthatconfirmthesesuggestionsneedtobedevelopedinthefuture. Table7.Potentialroleofsecoiridoidsobtainedfromtheolivetreeinanti‐aging:invitrostudies. PhenolicCompoundCellLineConcentrationEffectsReference OL Humanembryonic fibroblast(IMR90)[0.1–50mM]OLenhancedch‐L,PGPH,andPGPH proteasomeactivity[185] Humanembryonic fibroblast OLretainedproteasomefunction duringreplicativesenescenceand delayedintheappearanceof senescencemorphology [186] Mesenchymalstem cellsfromhuman bonemarrow [1–100μM] OLenhancedosteogenicgene expressionmarkersandosteoblast phenotypiccharacteristic [187] Humanpromyelocitic leukemiacells(HL60)10μMOLrestoredDNAdamage[43] Humanpromyelocitic leukemiacells(HL60)10μMOL‐aglyconerestoredDNAdamage[43]
Antioxidants2020,9,14923of39 OL‐aglycone OLE Normalhumanskin fibroblasts 50,100,150,and 200μM OLEup‐regulatedgenes’expression ofproteasome,antioxidantresponses, andmolecularchaperonesgenes [190] OLA Normalhumanskin fibroblasts 50,100,150,and 200μM OLAup‐regulatedgenes’expression ofproteasome,antioxidantresponses, andmolecularchaperonesgenes [190] Table8.Potentialroleofsecoiridoidsobtainedfromtheolivetreeinanti‐agingprocesses:invivo studies. Phenolic CompoundAnimalModelDosesEffectsReference OL Senile osteoporosis ratsmodel 15mg/kg OLcounteractedbonelossandreduce α‐1‐acidglycoproteinplasma concentration [189] OLE Drosophilain vivomodel Dietary supplementationof OLE:400nM,200nM, and100nM. OLEincreasedthech‐Lproteasome activityandtheexpressionof20Sand 19Sproteasomalsubunitsand decreasedofROSlevelsinsomatic tissuesofDrosophilaflies [190] OLA Drosophilain vivomodel Dietary supplementationof OLA:400nM,200nM, and100nM OLAincreasedthech‐Lproteasome activityandtheexpressionof20Sand 19Sproteasomalsubunitsand decreasedofROSlevelsinsomatic tissuesofDrosophilaflies. [190] 2.5.SecoiridoidsOliveTreeinAutoimmuneDiseases Autoimmunediseasesareheterogeneousgroupsofdiseaseswhoseconditionisthatyour immunesystemmistakenlyattacksyourbody.Inthenormalstate,theimmunesystemisableto differentiatebetweenforeigncells,suchasvirusesandbacteria,anditsowncells.However,inan autoimmunedisease,theimmunesystemrecognizesourowncellsasforeigncellsanditreleases proteinscalledautoantibodiesthatattackhealthycells.Thesetypesofdiseasescouldappearatany stageoflifewithhigherorlowerseverity.Forexample,therearetypesofautoimmunediseasethat targetonlyoneorgan,suchastype1diabetesmellitus(T1DM),whichdamagesthepancreas,whereas thereareotherdiseases,suchassystemiclupuserythematosus(SLE),whichaffectthewholebody. TheNationalInstitutesofHealth(NIH)estimatesthatupto23.5millionAmericanssufferfrom autoimmunediseaseandthattheprevalencerosein2019.Forthisreason,autoimmunediseasesare recognizedasamajorhealthproblem.Nowadays,researchershaveidentified80–100different autoimmunediseasesandsuspectatleast40morediseasesofhavinganautoimmunebasis.These diseasesarechronic,canbelife‐threatening,andareresponsiblefordeathinfemalechildrenand womeninallagegroupsupto64yearsold[191].Themostcharacteristicexamplesofthesekindsof autoimmunediseasesarerheumatoidarthritis(RA),SLE,Crohn’sdisease,ulcerativecolitis(UC),and T1DM. RAcanbedefinedasachronicinflammatorydiseasewithasystemicautoimmunecomponent, anditismainlycharacterizedbyaggressivesynovialhyperplasia,synovitis,theprogressive destructionofcartilage,andboneerosionwiththepainfulswellingofsmalljoints,fatigue,prolonged
Antioxidants2020,9,14924of39 stiffnessandfevercausedbyimmuneresponses,andspecificinnateinflammatoryprocesses[192]. Worldwide,theannualincidenceofRAisapproximatelythreecasesper10,000people,andthe prevalencerateisapproximately1%increasingwithageandpeakingbetweentheagesof35and50 yearsold.RAaffectsallpopulations,althoughitismuchmoreprevalentinsomegroups(e.g.,5–6% insomeNativeAmericangroups)andmuchlessprevalentinothers(e.g.,blackpersonsfromthe Caribbeanregion)[193]. SLEcanbedefinedasachronicinflammatoryandautoimmunediseasethatcanaffectmultiple organsystems,includingskin,joints,kidneys,andthebrain,amongothers[194].SLEischaracterized byadepositionofimmunecomplexes,whichareformedinlargeamountsasantinuclearantibodies bindtotheabundantnuclearmaterialinbloodandtissues,alongwithdisturbancesinbothinnate andadaptiveimmunityandT‐cellsignaling.Inaddition,SLEischaracterizedbyitsclinicaland pathogeniccomplexity,difficultdiagnosis,andthehighnumberofcomplicationsthatcanaffectthe patient’squalityoflife[195].ThereareworldwidedifferencesintheincidenceandprevalenceofSLE thatvarywithsex,age,ethnicity,andtime.ThehighestestimatesofincidenceandprevalenceofSLE wereinNorthAmerica:23.2/10000persons/yearsand24/10000,peoplerespectively.Thelowest incidencesofSLEwerereportedinAfricaandtheUkraine(0.3/10000persons/years),andthelowest prevalencewasobservedinNorthernAustralia(0casesinsampleof847people).Womenweremore frequentlyaffectedthanmenforeveryageandethnicgroup.Incidencepeakedinmiddleadulthood andoccurredlaterformen.Peopleofblackethnicityhadthehighestincidenceandprevalenceof SLE,whereasthosewithwhiteethnicityhadthelowestincidenceandprevalence.Thisappearedto beanincreasingtrendofSLEprevalencewithtime[196]. Crohn’sdiseaseandUCareimportantchronicinflammatorydisordersofthegastrointestinal systemthatcontributetotheinflammatorybowelconditions,suchasdiarrheawithorwithoutblood, abdominalpain,fever,weightloss,inflammation,andulcers.Thesediseaseshaveuncertainetiology butcanbeassociatedwithmultifactorialconditionsintermsofimmunity,genetics,andnon‐immune conditionssuchasenvironmentalfactors[197].ThetotalnumberofnewcasesofCrohn’sdisease diagnosedeachyear(incidence)was10.7per100,000peopleorapproximately33,000newcasesper year.ThetotalnumberofnewcasesofUCdiagnosedeachyearwas12.2per100,000peopleor approximately38,000newcasesperyear[198]. T1DMisconsideredanautoimmunediseasethatresultsfromthedestructionofpancreaticβcellsandismediatedbytheimmunesystem.Thisiscausedbyanautoimmunereactionwherethe body’sdefensesystemattacksthecellsthatproduceinsulin.Asaresult,thebodyproducesverylittle ornoinsulin.Multiplegeneticandenvironmentalfactorsfoundinvariablecombinationsin individualpatientsareinvolvedinthedevelopmentofT1DM.Geneticriskisdefinedbythepresence ofparticularallelecombinations,whichinthemajorsusceptibilitylocus(theHLAregion)affectT‐ cellrecognitionandtolerancetoforeignandautologousmolecules.T1DMcanaffectpeopleatany age,butitusuallydevelopsinchildrenoryoungadults.Around10%ofallpeoplewithdiabeteshave T1DM[199]. Duetothehighprevalenceandrisingincidenceofthiskindofdisease,nowadays,thereisa requirementtoinvestigatetodeveloppalliativeremediesortreatmentsthathelpusimprovethe symptomsandmanagementofthesetypesofdiseasestoimprovethequalityoflifeofpatients.A newsourceofnewsalternativeforautoimmunediseasesisbasedontheuseofnaturalcompounds obtainedfromnaturalresources,suchasOleaeuropaeaL.,whichistraditionallyusedasdiuretic, hypotensive,emollient,laxative,febrifuge,skincleanser,anditisalsousedforthetreatmentof urinaryinfections,gallstones,bronchialasthma,anddiarrhea.Thepublishedstudiesrelatedtothe effectsofsecoiridoidsfromtheolivetreeintheseautoimmunediseasesaresummarizedinTables9 and10.
Antioxidants2020,9,14925of39 Table9.Effectivemechanismsandconcentrationsofbioactivesecoiridoidsfromtheolivetreeinin vitromodelsofimmunoinflammatorydiseases. Phenolic CompoundCellLineConcentrationEffectsReference OL LPS‐stimulated murineperitoneal macrophages. 25and50μM OLreducedpro‐inflammatorycytokines levelsandinterferon(IFN)‐γ,aswellas iNOSandCOX‐2overexpressions [200] Humansynovial fibroblastscellline (SW982) 50and100 μM OLpre‐treatmentdown‐regulatedmitogen activeproteinkinase(MAPK)sandNF‐κB andinductionofNrf2‐linkedHO‐1 signalingpathways [201] OLE LPS‐stimulated murineperitoneal macrophages. [25–100μM] OLEshowedapotentreductionofROS, nitrites,andpro‐inflammatorycytokines levels.OLEinhibitedcanonicaland noncanonicalinflammasomesignaling pathways [50] J774LPS‐stimulated macrophages50μMOLEinhibitedLPS‐inducedNOproduction withoutaffectingcellviability[117] Table10.Effectivemechanismsandconcentrationsofbioactivesecoiridoidsfromtheolivetreeinin vivomodelsandclinicaltrialsofimmunoinflammatorydiseases. InVivoStudies Phenolic compoundAnimalModelDosesEffectsReference OL DiabetestypeImodel inducedbysubcutaneous alloxanmonohydrate injectioninSprague‐Dawley malerats Oralgavage15 mg/Kg/dayofOL OLsignificantlydecreased leucocyteinfiltrationand glomerulosclerosis.OL decreasedthelevelsofurea, nitrite,andcreatinineand decreasedMPOactivity [202] Experimentalautoimmune myocarditis(EAM)model inducedbyporcinecardiac myosininLewisrats Oralgavage20 mg/Kg/dayofOL OLimprovedcardiacfunctions andattenuateinflammatorycell infiltrationandcytokine expressionlevels [203] Chroniccolitismodel inducedbyDSS(1%infirst andsecondcyclesand2%in thirdandfourthcycle)in femaleC57BL/6mice(6–8 weeksatageweighting18– 20g) Diet supplemented with0.25%OL OLexhibitedadecreaseof inflammatorysymptomsand decreasedinflammatorycell recruitment [204] Acutecolitismodelinduced byDSS(5%)for7daysin BALB/cmice(6–8weeksat ageweigthing18–20g) Diet supplemented with1%OL OraladministrationofOL attenuatedtheextentand severityofacutecolitisand reducedproductionof inflammatorymediators [205] OL‐aglycone CollagentypeII‐induced arthritis(CIA)inthreeweek‐oldmaleDBA‐J/1 Oralgavage40 mg/Kg/dayofOL OLpreventedjoints inflammationandreduced inflammatorymediators overexpressionandcytokines levels [206] ClinicalTrials Phenolic CompoundCellsConcentrationEffectsReference OL 14outpatientsbiopsieswith UlcerativeColitis 3μMOLfrom oliveleavesfrom OleaeuropaeaL. OLreducedtheexpressionof COX‐2andIL‐17insamples treatedwithOL.Inaddition,OL amelioratedinflammatory tissulardamage [207]
Antioxidants2020,9,14932of39 67. Tan,H.‐W.;Tuck,K.L.;Stupans,I.;Hayball,P.J.SimultaneousDeterminationofOleuropeinand HydroxytyrosolinRatPlasmaUsingLiquidChromatographywithFluorescenceDetection.J.Chromatogr. B2003,785,187–191. 68. Hazas,M.‐C.L.D.L.;Piñol,C.;Macià,A.;Motilva,M.‐J.HydroxytyrosolandtheColonicMetabolites DerivedfromVirginOliveOilIntakeInduceCellCycleArrestandApoptosisinColonCancerCells.J. Agric.FoodChem.2017,65,6467–6476. 69. Angeloni,C.;Malaguti,M.;Barbalace,M.C.;Hrelia,S.BioactivityofOliveOilPhenolsinNeuroprotection. Int.J.Mol.Sci.2017,18,2230. 70. Romero,C.;Medina,E.;Vargas,J.;Brenes,M.;DeCastro,A.InVitroActivityofOliveOilPolyphenols againstHelicobacterpylori.J.Agric.FoodChem.2007,55,680–686. 71. Silva,S.;Garcia‐Aloy,M.;Figueira,M.E.;Combet,E.;Mullen,W.;Bronze,M.R.HighResolutionMass SpectrometricAnalysisofSecoiridoidsandMetabolitesasBiomarkersofAcuteOliveOilIntake—An ApproachtoStudyInterindividualVariabilityinHumans.Mol.Nutr.FoodRes.2018,62,1700065. 72. García‐Villalba,R.;Carrasco‐Pancorbo,A.;Oliveras‐Ferraros,C.;Vázquez‐Martín,A.;Menendez,J.A.; Carretero,A.S.;Fernández‐Gutiérrez,A.CharacterizationandQuantificationofPhenolicCompoundsof Extra‐VirginOliveOilswithAnticancerPropertiesbyaRapidandResolutiveLC‐ESI‐TOFMSMethod.J. Pharm.Biomed.Anal.2010,51,416–429. 73. Naruszewicz,M.;Czerwinska,M.;Kiss,A.Oleacein.TranslationfromMediterraneanDiettoPotential AntiatheroscleroticDrug.Curr.Pharm.Des.2014,21,1205–1212. 74. Willett,W.C.;Sacks,F.;Trichopoulou,A.;Drescher,G.;Ferro‐Luzzi,A.;Helsing,E.;Trichopoulos,D. MediterraneanDietPyramid:ACulturalModelforHealthyEating.Am.J.Clin.Nutr.1995,61,61. 75. Dydjow‐Bendek,D.;Zagoźdźon,P.TotalDietaryFats,FattyAcids,andOmega‐3/Omega‐6RatioasRisk FactorsofBreastCancerinthePolishPopulation—ACase‐ControlStudy.InVivo2020,34,423–431. 76. Wang,J.;Wang,C.DietaryFatIntakeandRiskofBladderCancer:EvidencefromaMeta‐Analysisof ObservationalStudies.Cell.Mol.Boil.2019,65,5–9. 77. Grosso,G.;Buscemi,S.;Galvano,F.;Mistretta,A.;Marventano,S.;LaVela,V.;Drago,F.;Gangi,S.;Basile, F.;Biondi,A.MediterraneanDietandCancer:EpidemiologicalEvidenceandMechanismofSelected Aspects.BMCSurg.2013,13,S14. 78. Solinas,G.;Germano,G.;Mantovani,A.;Allavena,P.Tumor‐AssociatedMacrophages(TAM)asMajor PlayersoftheCancer‐RelatedInflammation.J.Leukoc.Boil.2009,86,1065–1073. 79. Hamdi,H.K.;Castellon,R.Oleuropein,ANon‐ToxicOliveIridoid,IsanAnti‐TumorAgentand CytoskeletonDisruptor.Biochem.Biophys.Res.Commun.2005,334,769–778. 80. Notarnicola,M.;Pisanti,S.;Tutino,V.;Bocale,D.;Rotelli,M.T.;Gentile,A.;Memeo,V.;Bifulco,M.;Perri, E.;Caruso,M.G.EffectsofOliveOilPolyphenolsonFattyAcidSynthaseGeneExpressionandActivityin HumanColorectalCancerCells.GenesNutr.2011,6,63–69. 81. Cárdeno,A.;Sánchez‐Hidalgo,M.;Rosillo,M.A.;DeLaLastra,C.A.Oleuropein,aSecoiridoidDerived fromOliveTree,InhibitstheProliferationofHumanColorectalCancerCellThroughDownregulationof HIF‐1α.Nutr.Cancer2013,65,147–156. 82. Hassan,Z.K.;Elamin,M.H.;Daghestani,M.H.;Omer,S.A.;Al‐Olayan,E.M.;Elobeid,M.A.;Virk,P.; Mohammed,O.B.OleuropeinInducesAnti‐MetastaticEffectsinBreastCancer.AsianPac.J.CancerPrev. 2012,13,4555–4559. 83. Elamin,M.H.;Daghestani,M.H.;Omer,S.A.;AElobeid,M.;Virk,P.;Al‐Olayan,E.M.;Hassan,Z.K.; Mohammed,O.B.;Aboussekhra,A.OliveOilOleuropeinHasAnti‐BreastCancerPropertieswithHigher EfficiencyonER‐NegativeCells.FoodChem.Toxicol.2013,53,310–316. 84. Chimento,A.;Casaburi,I.;Rosano,C.;Avena,P.;DeLuca,A.;Campana,C.;Martire,E.;Santolla,M.F.; Maggiolini,M.;Pezzi,V.;etal.OleuropeinandHydroxytyrosolActivateGPER/GPR30‐Dependent PathwaysLeadingtoApoptosisofER‐NegativeSKBR3BreastCancerCells.Mol.Nutr.FoodRes.2014,58, 478–489. 85. Hassan,Z.K.;Elamin,M.H.;Omer,S.A.;Daghestani,M.H.;Al‐Olayan,E.S.;Elobeid,M.A.;Virk,P. OleuropeinInducesApoptosisviathep53PathwayinBreastCancerCells.AsianPac.J.CancerPrev.2014, 14,6739–6742. 86. Liu,L.;Ahn,K.S.;Shanmugam,M.K.;Wang,H.;Shen,H.;Arfuso,F.;Chinnathambi,A.;Alharbi,S.A.; Chang,Y.;Sethi,G.;etal.OleuropeinInducesApoptosisviaAbrogatingNF‐κBActivationCascadein EstrogenReceptor–NegativeBreastCancerCells.J.Cell.Biochem.2018,120,4504–4513.
Antioxidants2020,9,14933of39 87. Choupani,J.;Alivand,M.R.;M.Derakhshan,S.;Zaeifizadeh,M.;S.Khaniani,M.OleuropeinInhibits MigrationAbilityThroughSuppressionofEpithelial‐MesenchymalTransitionandSynergistically EnhancesDoxorubicin‐MediatedApoptosisinMCF‐7Cells.J.Cell.Physiol.2019,234,9093–9104. 88. Bayat,S.;Derakhshan,S.M.;Derakhshan,N.M.;Khaniani,M.S.;Alivand,M.R.Downregulation ofHDAC2andHDAC3viaoleuropeinasaPotentPreventionandTherapeuticAgentinMCF‐7Breast CancerCells.J.Cell.Biochem.2019,120,9172–9180. 89. Mansouri,N.;Alivand,M.R.;Bayat,S.;Khaniani,M.S.;Derakhshan,S.M.TheHopefulAnticancerRoleof OleuropeininBreastCancerthroughHistoneDeacetylaseModulation.J.Cell.Biochem.2019,120,17042– 17049. 90. Lu,H.‐Y.;Zhu,J.‐S.;Zhang,Z.;Shen,W.‐J.;Jiang,S.;Long,Y.‐F.;Wu,B.;Ding,T.;Huan,F.;Wang,S.‐L. HydroxytyrosolandOleuropeinInhibitMigrationandInvasionofMDA‐MB‐231Triple‐NegativeBreast CancerCellviaInductionofAutophagy.AnticancerAgentsMed.Chem.2019,19,1983–1990. 91. Przychodzen,P.;Kuban‐Jankowska,A.;Wyszkowska,R.;Barone,G.;Bosco,G.L.;Celso,F.L.;Kamm,A.; Daca,A.;Kostrzewa,T.;Gorska‐Ponikowska,M.PTP1BPhosphataseasaNovelTargetofOleuropein ActivityinMCF‐7BreastCancerModel.Toxicol.Vitr.2019,61,104624. 92. Yan,C.‐M.;Chai,E.‐Q.;Cai,H.‐Y.;Miao,G.‐Y.;Ma,W.OleuropeinInducesApoptosisviaActivationof CaspasesandSuppressionofPhosphatidylinositol3‐kinase/proteinkinaseBPathwayinHepG2Human HepatomaCellLine.Mol.Med.Rep.2015,11,4617–4624. 93. Sherif,I.O.;Al‐Gayyar,M.M.OleuropeinPotentiatesAnti‐TumorActivityofCisplatinAgainstHepG2 throughAffectingproNGF/NGFBalance.LifeSci.2018,198,87–93. 94. Vanella,L.;Acquaviva,R.;DiGiacomo,C.;Sorrenti,V.;Galvano,F.;Santangelo,R.;Cardile,V.;Gangia,S.; D’Orazio,N.;Abraham,N.G.AntiproliferativeEffectofOleuropeininProstateCellLines.Int.J.Oncol. 2012,41,31–38. 95. Bulotta,S.;Corradino,R.;Celano,M.;Maiuolo,J.;D’Agostino,M.;Oliverio,M.;Procopio,A.;Filetti,S.; Russo,D.AntioxidantandAntigrowthActionofPeracetylatedOleuropeininThyroidCancerCells.J.Mol. Endocrinol.2013,51,181–189. 96. Yao,J.;Wu,J.;Yang,X.;Yang,J.;Zhang,Y.;Du,L.OleuropeinInducedApoptosisinHeLaCellsviaa MitochondrialApoptoticCascadeAssociatedwithActivationofthec‐JunNH2‐TerminalKinase.J. Pharmacol.Sci.2014,125,300–311. 97. Seçme,M.;Eroğlu,C.;Dodurga,Y.;Bağcı,G.InvestigationofAnticancerMechanismofOleuropeinviaCell CycleandApoptoticPathwaysinSH‐SY5YNeuroblastomaCells.Gene2016,585,93–99. 98. Liu,M.;Wang,J.;Huang,B.;Chen,A.;Li,X.OleuropeinInhibitstheProliferationandInvasionofGlioma CellsviaSuppressionoftheAKTSignalingPathway.Oncol.Rep.2016,36,2009–2016. 99. Xu,T.;Xiao,D.OleuropeinEnhancesRadiationSensitivityofNasopharyngealCarcinomaby DownregulatingPDRG1throughHIF1α‐repressedmicroRNA‐519d.J.Exp.Clin.CancerRes.2017,36,3. 100. Cao,S.;Zhu,X.;Du,L.P38MAPKinaseisInvolvedinOleuropein‐InducedApoptosisinA549Cellsbya MitochondrialApoptoticcascade.Biomed.Pharmacother.2017,95,1425–1435. 101. Wang,W.;Wu,J.;Zhang,Q.;Li,X.;Zhu,X.;Wang,Q.;Cao,S.;Du,L.Mitochondria‐MediatedApoptosis WasInducedbyOleuropeininH1299CellsInvolvingActivationofp38MAPKinase.J.Cell.Biochem.2019, 120,5480–5494. 102. Antognelli,C.;Frosini,R.;Santolla,M.F.;Peirce,M.J.;Talesa,V.N.Oleuropein‐InducedApoptosisIs MediatedbyMitochondrialGlyoxalase2inNSCLCA549Cells:AMechanisticInsideandaPossibleNovel NonenzymaticRoleforanAncientEnzyme.OxidativeMed.Cell.Longev.2019,2019,8576961–10. 103. Goldsmith,C.D.;Bond,D.R.;Jankowski,H.;Weidenhofer,J.;Stathopoulos,C.E.;Roach,P.D.;Scarlett,C.J. TheOliveBiophenolsOleuropeinandHydroxytyrosolSelectivelyReduceProliferation,InfluencetheCell Cycle,andInduceApoptosisinPancreaticCancerCells.Int.J.Mol.Sci.2018,19,1937. 104. Ruzzolini,J.;Peppicelli,S.;Andreucci,E.;Bianchini,F.;Scardigli,A.;Romani,A.;LaMarca,G.;Nediani, C.;Calorini,L.Oleuropein,theMainPolyphenolofOleaeuropaeaLeafExtract,HasanAnti‐CancerEffect onHumanBRAFMelanomaCellsandPotentiatestheCytotoxicityofCurrentChemotherapies.Nutrients 2018,10,1950. 105. Zhang,F.;Zhang,M.OleuropeinInhibitsEsophagealCancerthroughHypoxicSuppressionofBTG3 mRNA.FoodFunct.2019,10,978–985.
Antioxidants2020,9,14934of39 106. Przychodzen,P.;Wyszkowska,R.;Gorzynik‐Debicka,M.;Kostrzewa,T.;Kuban‐Jankowska,A.;Gorska‐ Ponikowska,M.AnticancerPotentialofOleuropein,thePolyphenolofOliveOil,With2‐Methoxyestradiol, SeparatelyorinCombination,inHumanOsteosarcomaCells.Anticancer.Res.2019,39,1243–1251. 107. Barzegar,F.;Zaefizadeh,M.;Yari,R.;Salehzadeh,A.SynthesisofNano‐ParamagneticOleuropeinto InduceKRASOver‐Expression:ANewMechanismtoInhibitAGSCancerCells.Medicina(Kaunas)2019, 55,E388. 108. Rigacci,S.;Miceli,C.;Nediani,C.;Berti,A.;Cascella,R.;Pantano,D.;Nardiello,P.;Luccarini,I.;Casamenti, F.;Stefani,M.OleuropeinAglyconeInducesAutophagyviatheAMPK/mTORSignallingPathway:A MechanisticInsight.Oncotarget2015,6,35344–35357. 109. Khanal,P.;Oh,W.‐K.;Yun,H.J.;Namgoong,G.M.;Ahn,S.‐G.;Kwon,S.‐M.;Choi,H.‐K.;Choi,H.S.p‐ HPEA‐EDA,aPhenolicCompoundofVirginOliveOil,ActivatesAMP‐ActivatedProteinKinasetoInhibit Carcinogenesis.Carcinogenesis2011,32,545–553. 110. Elnagar,A.;Sylvester,P.;ElSayed,K.(−)‐Oleocanthalasac‐MetInhibitorfortheControlofMetastatic BreastandProstateCancers.PlantaMedica2011,77,1013–1019. 111. Akl,M.R.;Ayoub,N.M.;Mohyeldin,M.M.;Busnena,B.A.;Foudah,A.I.;Liu,Y.‐Y.;Sayed,K.A.E.Olive Phenolicsasc‐MetInhibitors:(‐)‐OleocanthalAttenuatesCellProliferation,Invasiveness,andTumor GrowthinBreastCancerModels.PLOSONE2014,9,e97622. 112. Khanfar,M.A.;Bardaweel,S.K.;Akl,M.R.;Sayed,K.A.ElOliveOil‐derivedOleocanthalasPotentInhibitor ofMammalianTargetofRapamycin:BiologicalEvaluationandMolecularModelingStudies.Phyther.Res. 2015,29,1776–1782. 113. Tajmim,A.;Siddique,A.B.;Sayed,E.;ElSayed,K.OptimizationofTaste‐Masked(–)‐Oleocanthal EffervescentFormulationwithPotentBreastCancerProgressionandRecurrenceSuppressiveActivities. Pharmaceutics2019,11,E515. 114. Qusa,M.H.;Siddique,A.B.;Nazzal,S.;ElSayed,K.A.NovelOliveOilPhenolic(−)‐Oleocanthal(+)‐Xylitol‐ BasedSolidDispersionFormulationswithPotentOralAnti‐BreastCancerActivities.Int.J.Pharm.2019, 569,118596 115. Siddique,A.B.;Ebrahim,H.Y.;Akl,M.R.;Ayoub,N.M.;Goda,A.A.;Mohyeldin,M.M.;Nagumalli,S.K.; Hananeh,W.M.;Liu,Y.‐Y.;Meyer,S.A.;etal.(−)‐OleocanthalCombinedwithLapatinibTreatment SynergizedagainstHER‐2PositiveBreastCancerinVitroandinVivo.Nutrients2019,11,412. 116. Diez‐Bello,R.;Jardin,I.;Lopez,J.J.;ElHaouari,M.;Ortega‐Vidal,J.;Altarejos,J.;Salido,G.M.;Salido,S.; Rosado,J.A.(−)‐OleocanthalInhibitsProliferationandMigrationbyModulatingCa2+Entrythrough TRPC6inBreastCancerCells.Biochim.Biophys.Acta‐Mol.CellRes.2019,1866,474–485. 117. Pei,T.;Meng,Q.;Han,J.;Sun,H.;Li,L.;Song,R.;Sun,B.;Pan,S.;Liang,D.;Liu,L.(−)‐OleocanthalInhibits GrowthandMetastasisbyBlockingActivationofSTAT3inHumanHepatocellularCarcinoma.Oncotarget 2016,7,43475–43491. 118. DeStefanis,D.;Scimè,S.;Accomazzo,S.;Catti,A.;Occhipinti,A.;Bertea,C.M.;Costelli,P.;Stefanis,D. Anti‐ProliferativeEffectsofanExtra‐VirginOliveOilExtractEnrichedinLigstrosideAglyconeand OleocanthalonHumanLiverCancerCellLines.Cancers2019,11,1640. 119. Margarucci,L.;Cassiano,C.;Mozzicafreddo,M.;Angeletti,M.;Riccio,R.;Monti,M.C.;Tosco,A.; Casapullo,A.ChemicalProteomics‐DrivenDiscoveryofOleocanthalasanHsp90Inhibitor.Chem. Commun.2013,49,5844. 120. Gu,Y.;Wang,J.;Peng,L.(−)‐OleocanthalExertsAnti‐MelanomaActivitiesandInhibitsSTAT3Signaling Pathway.Oncol.Rep.2017,37,483–491. 121. Polini,B.;Digiacomo,M.;Carpi,S.;Bertini,S.;Gado,F.;Saccomanni,G.;Macchia,M.;Nieri,P.;Manera,C.; Fogli,S.OleocanthalandOleaceinContributetotheinVitroTherapeuticPotentialofinOil‐Derived ExtractsinNon‐MelanomaSkinCancer.Toxicol.Vitr.2018,52,243–250. 122. Juli,G.;Oliverio,M.;Bellizzi,D.;Cantafio,M.E.G.;Grillone,K.;Passarino,G.;Colica,C.;Nardi,M.;Rossi, M.;Procopio,A.;etal.Anti‐tumorActivityandEpigeneticImpactofthePolyphenolOleaceininMultiple Myeloma.Cancers2019,11,990. 123. Kimura,Y.;Sumiyoshi,M.OliveLeafExtractandItsMainComponentOleuropeinPreventChronic UltravioletBRadiation‐InducedSkinDamageandCarcinogenesisinHairlessMice.J.Nutr.2009,139,2079– 2086. 124. Giner,E.;Recio,M.C.;Ríos,J.L.;Cerdá‐Nicolás,J.M.;Giner,R.M.ChemopreventiveEffectofOleuropeinin Colitis‐AssociatedColorectalCancerinc57bl/6Mice.Mol.Nutr.FoodRes.2016,60,242–255.
Antioxidants2020,9,14935of39 125. Geyikoğlu,F.;Çolak,S.;Türkez,H.;Bakır,M.;Koç,K.;Hosseinigouzdagani,M.K.;Çeriğ,S.;Sönmez,M. OleuropeinAmelioratesCisplatin‐inducedHematologicalDamagesViaRestrainingOxidativeStressand DNAInjury.IndianJ.Hematol.BloodTransfus.2017,33,348–354. 126. Song,H.;Lim,Y.;Jung,J.I.;Cho,H.J.;Park,S.Y.;Kwon,G.T.;Kang,Y.‐H.;Lee,K.W.;Choi,M.‐S.;Park, J.H.Y.DietaryOleuropeinInhibitsTumorAngiogenesisandLymphangiogenesisintheB16F10Melanoma AllograftModel:AMechanismfortheSuppressionofHigh‐FatDiet‐InducedSolidTumorGrowthand LymphNodeMetastasis.Oncotarget2017,8,32027–32042. 127. Koc,K.;Bakir,M.;Geyikoglu,F.;Cerig,S.TherapeuticEffectsofOleuropeinonCisplatin‐InducedPancreas InjuryinRats.J.CancerRes.Ther.2018,14,671. 128. Elamin,M.H.;Elmahi,A.B.;Daghestani,M.H.;Al‐Olayan,E.M.;Al‐Ajmi,R.A.;Alkhuriji,A.F.;Hamed,S.S.; Elkhadragy,M.F.SynergisticAnti‐Breast‐CancerEffectsofCombinedTreatmentwithOleuropeinand DoxorubicininVivo.Altern.Ther.HealthMed.2019,25,17–24. 129. Siddique,A.B.;Ayoub,N.M.;Tajmim,A.;Meyer,S.A.;Hill,R.A.;ElSayed,K.A.(−)‐OleocanthalPrevents BreastCancerLocoregionalRecurrenceAfterPrimaryTumorSurgicalExcisionandNeoadjuvantTargeted TherapyinOrthotopicNudeMouseModels.Cancers2019,11,637. 130. Sherif,I.O.TheEffectofNaturalAntioxidantsinCyclophosphamide‐InducedHepatotoxicity:Roleof Nrf2/HO‐1Pathway.Int.Immunopharmacol.2018,61,29–36. 131. Goren,L.;Zhang,G.;Kaushik,S.;Breslin,P.A.S.;Du,Y.‐C.N.;Foster,D.A.(‐)‐Oleocanthaland(‐)‐ Oleocanthal‐RichOliveOilsInduceLysosomalMembranePermeabilizationinCancerCells.PLOSONE 2019,14,e0216024. 132. Siddique,A.B.;Ebrahim,H.;Mohyeldin,M.;Qusa,M.;Batarseh,Y.;Fayyad,A.;Tajmim,A.;Nazzal,S.; Kaddoumi,A.;ElSayed,K.NovelLiquid‐LiquidExtractionandSelf‐EmulsionMethodsforSimplified IsolationofExtra‐VirginOliveOilPhenolicswithEmphasison(−)‐OleocanthalandItsOralAnti‐Breast CancerActivity.PLOSONE2019,14,e0214798. 133. Scotece,M.;Gómez,R.;Conde,J.;Lopez,V.;Gomez‐Reino,J.J.;Lago,F.;Smith,A.B.;Gualillo,O.Further EvidencefortheAnti‐InflammatoryActivityofOleocanthal:InhibitionofMIP‐1α andIL‐6inJ774 MacrophagesandinATDC5Chondrocytes.LifeSci.2012,91,1229–1235. 134. Wang,H.;Naghavi,M.;Allen,C.;Barber,R.M.;ABhutta,Z.;Carter,A.;Casey,D.C.;Charlson,F.J.;Chen, A.Z.;Coates,M.M.;etal.Global,Regional,andNationalLifeExpectancy,All‐CauseMortality,andCause‐ SpecificMortalityfor249CausesofDeath,1980–2015:ASystematicanalysisfortheGlobalBurdenof DiseaseStudy2015.Lancet2016,388,1459–1544. 135. Reboredo‐Rodríguez,P.;González‐Barreiro,C.;Cancho‐Grande,B.;Forbes‐Hernandez,T.Y.;Gasparrini, M.;Afrin,S.;Cianciosi,D.;Carrasco‐Pancorbo,A.;Simal‐Gándara,J.;Giampieri,F.;etal.Characterization ofPhenolicExtractsfromBravaExtraVirginOliveOilsandTheirCytotoxicEffectsonMCF‐7BreastCancer Cells.FoodChem.Toxicol.2018,119,73–85. 136. Crespo,M.C.;Tomé‐Carneiro,J.;Dávalos,A.;Visioli,F.Pharma‐NutritionalPropertiesofOliveOil Phenols.TransferofNewFindingstoHumanNutrition.Foods2018,7,90. 137. Catalán,Úrsula;Rubio,L.;Hazas,M.‐C.L.D.L.;Herrero,P.;Nadal,P.;Canela,N.;Pedret,A.;Motilva,M.‐ J.;Solà,R.HydroxytyrosolandItsComplexForms(Secoiridoids)ModulateAortaandHeartProteomein HealthyRats:PotentialCardio‐ProtectiveEffects.Mol.Nutr.FoodRes.2016,60,2114–2129. 138. Visioli,F.;Bellomo,G.;Montedoro,G.;Galli,C.LowDensityLipoproteinOxidationIsInhibitedinVitro byOliveOilConstituents.Atherosclerosis1995,117,25–32. 139. Visioli,F.;Bellosta,S.;Galli,C.Oleuropein,theBitterPrincipleofOlives,EnhancesNitricOxideProduction byMouseMacrophages.LifeSci.1998,62,541–546. 140. Parzonko,A.;Czerwińska,M.E.;Kiss,A.K.;Naruszewicz,M.OleuropeinandOleaceinmayRestore BiologicalFunctionsofEndothelialProgenitorCellsImpairedbyAngiotensinIIviaActivationof Nrf2/hemeOxygenase‐1Pathway.Phytomedicine2013,20,1088–1094. 141. Dell’Agli,M.;Fagnani,R.;Mitro,N.;Scurati,S.;Masciadri,M.;Mussoni,L.;Galli,G.V.;Bosisio,E.;Crestani, M.;DeFabiani,E.;etal.MinorComponentsofOliveOilModulateProatherogenicAdhesionMolecules InvolvedinEndothelialActivation.J.Agric.FoodChem.2006,54,3259–3264. 142. Leri,M.;Nosi,D.;Natalello,A.;Porcari,R.;Ramazzotti,M.;Chiti,F.;Bellotti,V.;Doglia,S.M.;Stefani,M.; Bucciantini,M.ThePolyphenolOleuropeinAglyconeHinderstheGrowthofToxicTransthyretinAmyloid Assemblies.J.Nutr.Biochem.2016,30,153–166.
Antioxidants2020,9,14936of39 143. Czerwińska,M.E.;Kiss,A.K.;Naruszewicz,M.InhibitionofHumanNeutrophilsNEPActivity, CD11b/CD18ExpressionandElastaseReleaseby3,4‐dihydroxyphenylethanol‐elenolicAcidDialdehyde, Oleacein.FoodChem.2014,153,1–8. 144. Filipek,A.;Czerwińska,M.E.;Kiss,A.K.;Wrzosek,M.;Naruszewicz,M.OleaceinEnhancesAnti‐ InflammatoryActivityofHumanMacrophagesbyIncreasingCD163ReceptorExpression.Phytomedicine 2015,22,1255–1261. 145. Manna,C.;Migliardi,V.;Golino,P.;Scognamiglio,A.;Galletti,P.;Chiariello,M.;Zappia,V.Oleuropein PreventsOxidativeMyocardialInjuryInducedbyIschemiaandReperfusion.J.Nutr.Biochem.2004,15, 461–466. 146. Andreadou,I.;Iliodromitis,E.K.;Mikros,E.;Constantinou,M.;Agalias,A.;Magiatis,P.;Skaltsounis,A.L.; Kamber,E.;Tsantili‐Kakoulidou,A.;Kremastinos,D.T.TheOliveConstituentOleuropeinExhibitsAnti‐ Ischemic,Antioxidative,andHypolipidemicEffectsinAnesthetizedRabbits.J.Nutr.2006,136,2213–2219. 147. Andreadou,I.;Sigala,F.;Iliodromitis,E.K.;Papaefthimiou,M.;Sigalas,C.;Aligiannis,N.;Savvari,P.; Gorgoulis,V.;Papalabros,E.;Kremastinos,D.T.AcuteDoxorubicinCardiotoxicityIsSuccessfullyTreated withthePhytochemicalOleuropeinthroughSuppressionofOxidativeandNitrosativeStress.J.Mol.Cell. Cardiol.2007,42,549–558. 148. Andreadou,I.;Papaefthimiou,M.;Zira,A.;Constantinou,M.;Sigala,F.;Skaltsounis,A.‐L.;Tsantili‐ Kakoulidou,A.;Iliodromitis,E.K.;Kremastinos,D.T.;Mikros,E.MetabonomicIdentificationofNovel BiomarkersinDoxorubicinCardiotoxicityandProtectiveEffectoftheNaturalAntioxidantOleuropein. NMRBiomed.2009,22,585–592. 149. Andreadou,I.;Mikros,E.;Ioannidis,K.;Sigala,F.;Naka,K.;Kostidis,S.;Farmakis,D.;Tenta,R.;Kavantzas, N.;Bibli,S.‐I.;etal.OleuropeinPreventsDoxorubicin‐InducedCardiomyopathyInterferingwithSignaling MoleculesandCardiomyocyteMetabolism.J.Mol.Cell.Cardiol.2014,69,4–16. 150. Wang,L.;Geng,C.;Jiang,L.;Gong,D.;Liu,D.;Yoshimura,H.;Zhong,L.TheAnti‐AtheroscleroticEffect ofOliveLeafExtractIsRelatedtoSuppressedInflammatoryResponseinRabbitswithExperimental Atherosclerosis.Eur.J.Nutr.2008,47,235–243. 151. Ebaid,G.M.;Seiva,F.R.;Rocha,K.K.;ASouza,G.;Novelli,E.L.EffectsofOliveOilandItsMinorPhenolic ConstituentsonObesity‐InducedCardiacMetabolicChanges.Nutr.J.2010,9,46. 152. Khalili,A.;Nekooeian,A.A.;Khosravi,M.B.OleuropeinImprovesGlucoseToleranceandLipidProfilein RatswithSimultaneousRenovascularHypertensionandType2Diabetes.J.AsianNat.Prod.Res.2017,19, 1011–1021. 153. Nekooeian,A.A.;Khalili,A.;Khosravi,M.B.OleuropeinOffersCardioprotectioninRatswithSimultaneous Type2DiabetesandRenalHypertension.IndianJ.Pharmacol.2014,46,398–403. 154. Nekooeian,A.A.;Khalili,A.;Khosravi,M.B.EffectsofOleuropeininRatswithSimultaneousType2 DiabetesandRenalHypertension:AStudyofAntihypertensiveMechanisms.J.AsianNat.Prod.Res.2014, 16,953–962. 155. Ivanov,M.;Vajic,U.‐J.;Mihailovic‐Stanojevic,N.;Miloradovic,Z.;Jovovic,D.;Grujic‐Milanovic,J.; Karanovic,D.;Dekanski,D.HighlyPotentAntioxidantOleaeuropaeaL.LeafExtractAffectsCarotidand RenalHaemodynamicsinExperimentalHypertension:TheRoleofOleuropein.ExcliJ.2018,17,29–44. 156. Jemai,H.;Bouaziz,M.;Fki,I.;ElFeki,A.;Sayadi,S.HypolipidimicandAntioxidantActivitiesof OleuropeinandItsHydrolysisDerivative‐RichExtractsfromChemlaliOliveLeaves.Chem.Interactions 2008,176,88–98. 157. Miceli,C.;Santin,Y.;Manzella,N.;Coppini,R.;Berti,A.;Stefani,M.;Parini,A.;Mialet‐Perez,J.;Nediani, C.OleuropeinAglyconeProtectsagainstMAO‐A‐InducedAutophagyImpairmentandCardiomyocyte DeaththroughActivationofTFEB.OxidativeMed.Cell.Longev.2018,2018,8067592–13. 158. Margheri,F.;Menicacci,B.;Laurenzana,A.;DelRosso,M.;Fibbi,G.;Cipolleschi,M.G.;Ruzzolini,J.; Nediani,C.;Mocali,A.;Giovannelli,L.OleuropeinAglyconeAttenuatesthePro‐AngiogenicPhenotypeof SenescentFibroblasts:AFunctionalStudyinEndothelialCells.J.Funct.Foods2019,53,219–226. 159. Covas,M.‐I.;Nyyssönen,K.;EPoulsen,H.;Kaikkonen,J.;Zunft,H.‐J.F.;Kiesewetter,H.;Gaddi,A.;DeLa Torre,R.;Mursu,J.;Bäumler,H.;etal.TheEffectofPolyphenolsinOliveOilonHeartDiseaseRiskFactors: ARandomizedTrial.Ann.Intern.Med.2006,145,333–341. 160. Susalit,E.;Agus,N.;Effendi,I.;Tjandrawinata,R.R.;Nofiarny,D.;Perrinjaquet‐Moccetti,T.;Verbruggen, M.Olive(Oleaeuropaea)LeafExtractEffectiveinPatientswithStage‐1Hypertension:Comparisonwith Captopril.Phytomedicine2011,18,251–258.
Antioxidants2020,9,14937of39 161. Stock,J.HDLFunctionandCardiovascularRisk:DebateContinues….Atherosclerosis2013,229,38–41. 162. Casapullo,A.;DelGaudio,F.;Capolupo,A.;Cassiano,C.;ChiaraMonti,M.Multi‐TargetProfileof Oleocanthal,AnExtra‐VirginOliveOilComponent.Curr.Bioact.Compd.2016,12,3–9. 163. Beauchamp,G.K.;Keast,R.S.J.;Morel,D.;Lin,J.;Pika,J.;Han,Q.;Lee,C.‐H.;Smith,A.B.;Breslin,P.A.S. Ibuprofen‐LikeactivItyinExtra‐VirginOliveOil.Nature2005,437,45–46. 164. Scotece,M.;Conde,J.;Abella,V.;López,V.;Francisco,V.;Ruiz,C.;Campos,V.;Lago,F.;Gomez,R.;Pino, J.;etal.OleocanthalInhibitsCatabolicandInflammatoryMediatorsinLPS‐ActivatedHumanPrimary Osteoarthritis(OA)ChondrocytesThroughMAPKs/NF‐κBPathways.Cell.Physiol.Biochem.2018,49,2414– 2426. 165. Vinten‐Johansen,J.InvolvementofNeutrophilsinthePathogenesisofLethalMyocardialReperfusion Injury.Cardiovasc.Res.2004,61,481–497. 166. Filipek,A.;Czerwińska,M.E.;Kiss,A.K.;Polański,J.A.;Naruszewicz,M.OleaceinmayInhibit DestabilizationofCarotidPlaquesfromHypertensivePatients:ImpactonhighMobilityGroupProtein‐1. Phytomedicine2017,32,68–73. 167. Manoharan,S.;Guillemin,G.J.;Abiramasundari,R.S.;Essa,M.M.;Akbar,M.TheRoleofReactiveOxygen SpeciesinthePathogenesisofAlzheimer’sDisease,Parkinson’sDisease,andHuntington’sDisease:AMini Review.OxidativeMed.Cell.Longev.2016,2016,1–15. 168. Wyss‐Coray,T.Ageing,neurodegenerationandbrainrejuvenation.Nature2016,539,180–186. 169. Stefani,M.;Rigacci,S.BeneficialPropertiesofNaturalPhenols:HighlightonProtectionagainst PathologicalConditionsAssociatedwithAmyloidAggregation.BioFactors2014,40,482–493. 170. Capurso,A.;Crepaldi,G.;Capurso,C.Extra‐VirginOliveOil,theMediterraneanDiet,and NeurodegenerativeDiseases.PracticalIssuesinGeriatrics2018,81–95. 171. Pasban‐Aliabadi,H.;Esmaeili‐Mahani,S.;Sheibani,V.;Abbasnejad,M.;Mehdizadeh,A.;Yaghoobi,M.M. Inhibitionof6‐Hydroxydopamine‐InducedPC12CellApoptosisbyOlive(OleaeuropaeaL.)LeafExtract IsPerformedbyItsMainComponentOleuropein.RejuvenationRes.2013,16,134–142. 172. Achour,I.;Arel‐Dubeau,A.‐M.;Renaud,J.;Legrand,M.;Attard,E.;Germain,M.;Martinoli,M.‐G. OleuropeinPreventsNeuronalDeath,MitigatesMitochondrialSuperoxideProductionandModulates AutophagyinaDopaminergicCellularModel.Int.J.Mol.Sci.2016,17,1293. 173. Leri,M.;Natalello,A.;Bruzzone,E.;Stefani,M.;Bucciantini,M.Oleuropeinaglyconeandhydroxytyrosol interferedifferentlywithtoxicAβ1‐42aggregation.FoodChem.Toxicol.2019,129,1–12. 174. Omar,S.H.;Scott,C.J.;Hamlin,A.S.;Obied,H.K.OliveBiophenolsReducesAlzheimer’sPathologyinSHSY5YCellsandAPPsweMice.Int.J.Mol.Sci.2019,20,E125. 175. Luccarini,I.;Dami,T.E.;Grossi,C.;Rigacci,S.;Stefani,M.;Casamenti,F.OleuropeinAglyconeCounteracts Aβ42ToxicityintheRatBrain.Neurosci.Lett.2014,558,67–72. 176. Grossi,C.;Rigacci,S.;Ambrosini,S.;Dami,T.E.;Luccarini,I.;Traini,C.;Failli,P.;Berti,A.;Casamenti,F.; Stefani,M.ThePolyphenolOleuropeinAglyconeProtectsTgCRND8MiceagainstAßPlaquePathology. PLOSONE2013,8,e71702. 177. Diomede,L.;Rigacci,S.;Romeo,M.;Stefani,M.;Salmona,M.OleuropeinAglyconeProtectsTransgenicC. elegansStrainsExpressingAβ42byReducingPlaqueLoadandMotorDeficit.PLOSONE2013,8,e58893. 178. Rigacci,S.;Guidotti,V.;Bucciantini,M.;Nichino,D.;Relini,A.;Berti,A.;Stefani,M.Aβ(1‐42)Aggregates intoNon‐ToxicAmyloidAssembliesinthePresenceoftheNaturalPolyphenolOleuropeinAglycon.Curr. AlzheimerRes.2011,8,841–852. 179. Pantano,D.;Luccarini,I.;Nardiello,P.;Servili,M.;Stefani,M.;Casamenti,F.OleuropeinAglyconeand PolyphenolsfromOliveMillWasteWaterAmeliorateCognitiveDeficitsandNeuropathology.Br.J.Clin. Pharmacol.2017,83,54–62. 180. Batarseh,Y.S.;Kaddoumi,A.Oleocanthal‐RichExtra‐VirginOliveOilEnhancesDonepezilEffectby ReducingAmyloid‐βLoadandRelatedToxicityinaMouseModelofAlzheimer’sDisease.J.Nutr.Biochem. 2018,55,113–123. 181. Qosa,H.;Batarseh,Y.S.;Mohyeldin,M.M.;ElSayed,K.A.;Keller,J.N.;Kaddoumi,A.OleocanthalEnhances Amyloid‐βClearancefromtheBrainsofTgSwDIMiceandinVitroacrossaHumanBlood‐BrainBarrier Model.ACSChem.Neurosci.2015,6,1849–1859. 182. Abuznait,A.H.;Qosa,H.;Busnena,B.A.;ElSayed,K.A.;Kaddoumi,A.Olive‐Oil‐DerivedOleocanthal Enhancesβ‐AmyloidClearanceasaPotentialNeuroprotectiveMechanismagainstAlzheimer’sDisease:In VitroandinVivoStudies.ACSChem.Neurosci.2013,4,973–982.
Antioxidants2020,9,14938of39 183. Mohammad‐Beigi,H.;Aliakbari,F.;Sahin,C.;Lomax,C.;Tawfike,A.;Schafer,N.P.;Amiri‐Nowdijeh,A.; Eskandari,H.;Møller,I.M.;Hosseini‐Mazinani,M.;etal.OleuropeinDerivativesfromOliveFruitExtracts Reduceα‐SynucleinFibrillationandOligomerToxicity.J.Boil.Chem.2019,294,4215–4232. 184. Prasanth,M.I.;Brimson,J.M.;Chuchawankul,S.;Sukprasansap,M.;Tencomnao,T.Antiaging,Stress Resistance,andNeuroprotectiveEfficaciesofCleistocalyxnervosumvar.panialaFruitExtractsUsing CaenorhabditiselegansModel.OxidativeMed.Cell.Longev.2019,2019,1–14. 185. Chondrogianni,N.;Chinou,I.;Gonos,E.S.Anti‐agingPropertiesoftheOliveConstituentOleuropeinin HumanCells.InOlivesandOliveOilinHealthandDiseasePrevention;ElsevierBV,2010;pp.1335–1343. 186. Katsiki,M.;Chondrogianni,N.;Chinou,I.;Rivett,A.J.;Gonos,E.S.TheOliveConstituentOleuropein ExhibitsProteasomeStimulatoryPropertiesinVitroandConfersLifeSpanExtensionofHumanEmbryonic Fibroblasts.RejuvenationRes.2007,10,157–172. 187. Santiago‐Mora,R.;Casado‐Díaz,A.;DeCastro,M.D.;Quesada‐Gómez,J.M.OleuropeinEnhances OsteoblastogenesisandInhibitsAdipogenesis:TheEffectonDifferentiationinStemCellsDerivedfrom BoneMarrow.Osteoporos.Int.2011,22,675–684. 188. Remmen,H.OxidativeDamagetoMitochondriaandAging.Exp.Gerontol.2001,36,957–968. 189. Puel,C.;Quintin,A.;Agalias,A.;Mathey,J.;Obled,C.;Mazur,A.;Davicco,M.J.;Lebecque,P.;Skaltsounis, A.L.;Coxam,V.OliveOilandItsMainPhenolicMicronutrient(Oleuropein)PreventInflammation‐ InducedBoneLossintheOvariectomisedRat.Br.J.Nutr.2004,92,119–127. 190. Nikou,T.;Liaki,V.;Stathopoulos,P.;Sklirou,A.D.;Tsakiri,E.N.;Jakschitz,T.;Bonn,G.;Trougakos,I.P.; Halabalaki,M.;Skaltsounis,L.A.ComparisonSurveyofEVOOPolyphenolsandExplorationofHealthy Aging‐PromotingPropertiesofOleocanthalandOleacein.FoodChem.Toxicol.2019,125,403–412. 191. Lerner,A.;Jeremias,P.;Matthias,T.TheWorldIncidenceandPrevalenceofAutoimmuneDiseasesIs Increasing.Int.J.CeliacDis.2016,3,151–155. 192. 198.Rosillo,M.A.;Sánchez‐Hidalgo,M.;Sánchez‐Fidalgo,S.;Aparicio‐Soto,M.;Villegas,I.;Alarcón‐de‐la‐ Lastra,C.DietaryExtra‐VirginOliveOilPreventsInflammatoryResponseandCartilageMatrix DegradationinMurineCollagen‐InducedArthritis.Eur.J.Nutr.2016,55,315–325. 193. Smolen,J.S.;Aletaha,D.;McInnes,I.B.RheumatoidArthritis.Lancet2016,388,2023–2038. 194. Noble,P.W.;Bernatsky,S.;Clarke,A.E.;Isenberg,D.A.;Ramsey‐Goldman,R.;Hansen,J.E.DNA‐ DamagingAutoantibodiesandCancer:TheLupusButterflyTheory.Nat.Rev.Rheumatol.2016,12,429–434. 195. Aparicio‐Soto,M.;Sánchez‐Hidalgo,M.;Cárdeno,A.;González‐Benjumea,A.;Fernández‐Bolaños,J.G.; Alarcón‐De‐La‐Lastra,C.DietaryHydroxytyrosolandHydroxytyrosylAcetateSupplementationPrevent Pristane‐InducedSystemicLupusErythematousinMice.J.Funct.Foods2017,29,84–92. 196. Rees,F.;Doherty,M.;Grainge,M.J.;Lanyon,P.;Zhang,W.TheWorldwideIncidenceandPrevalenceof SystemicLupuserythematosus:ASystematicReviewofEpidemiologicalStudies.Rheumatology(Oxford) 2017,56,1945–1961. 197. DeOliveira,G.A.L.;DeLaLastra,C.A.;Rosillo,M.Ángeles;Martinez,M.L.C.;Sánchez‐Hidalgo,M.; Medeiros,J.V.R.;Villegas,I.PreventiveEffectofBergeninagainsttheDevelopmentofTNBS‐Induced AcuteColitisinRatsIsAssociatedwithInflammatoryMediatorsInhibitionandNLRP3/ASC InflammasomeSignalingPathways.Chem.Interactions2019,297,25–33. 198. Shivashankar,R.;Tremaine,W.J.;Harmsen,W.S.;Loftus,E.V.IncidenceandPrevalenceofCrohn’sDisease andUlcerativeColitisinOlmstedCounty,Minnesotafrom1970through2010.Clin.Gastroenterol.Hepatol. 2017,15,857–863. 199. Ilonen,J.;Lempainen,J.;Veijola,R.TheHeterogeneousPathogenesisofType1DiabetesMellitus.Nat.Rev. Endocrinol.2019,15,635–650. 200. Castejon,M.L.;Sánchez‐Hidalgo,M.;Aparicio‐Soto,M.;González‐Benjumea,A.;Fernández‐Bolaños,J.G.; Alarcón‐De‐La‐Lastra,C.OliveSecoiridoidOleuropeinandItsSemisyntheticAcetyl‐DerivativesReduce LPS‐InducedInflammatoryResponseinMurinePeritonealMacrophagesviaJAK‐STATandMAPKs SignalingPathways.J.Funct.Foods2019,58,95–104. 201. Castejón,M.L.;Rosillo,M.Ángeles;Montoya,T.;González‐Benjumea,A.;Fernández‐Bolaños,J.G.; Alarcón‐De‐La‐Lastra,C.Correction:OleuropeinDown‐RegulatedIL‐1β‐InducedInflammationand OxidativeStressinHumanSynovialFibroblastCellLineSW982.FoodFunct.2017,8,2341. 202. Ahmadvand,H.;Shahsavari,G.;Tavafi,M.;Bagheri,S.;Moradkhani,M.R.;Kkorramabadi,R.M.;Khosravi, P.;Jafari,M.;Zahabi,K.;Eftekhar,R.;etal.ProtectiveEffectsofOleuropeinagainstRenalInjuryOxidative
Antioxidants2020,9,14939of39 DamageinAlloxan‐InducedDiabeticRats;aHistologicalandBiochemicalstudy.J.Nephropathol.2017,6, 204–209. 203. Zhang,J.‐Y.;Yang,Z.;Fang,K.;Shi,Z.‐L.;Ren,D.‐H.;Sun,J.OleuropeinPreventstheDevelopmentof ExperimentalAutoimmuneMyocarditisinRats.Int.Immunopharmacol.2017,48,187–195. 204. Giner,E.;Recio,M.‐C.;Ríos,J.‐L.;Giner,R.‐M.OleuropeinProtectsAgainstDextranSodiumSulfate‐ InducedChronicColitisinMice.J.Nat.Prod.2013,76,1113–1120. 205. Giner,E.;Andújar,I.;Recio,M.C.;Ríos,J.L.;Cerdá‐Nicolás,J.M.;Giner,R.M.OleuropeinAmeliorates AcuteColitisinMice.J.Agric.FoodChem.2011,59,12882–12892. 206. Impellizzeri,D.;Esposito,E.;Mazzon,E.;Paterniti,I.;DiPaola,R.;Morittu,V.M.;Procopio,A.;Britti,D.; Cuzzocrea,S.OleuropeinAglycone,anOliveOilCompound,AmelioratesDevelopmentofArthritis CausedbyInjectionofCollagenTypeIIinMice.J.Pharmacol.Exp.Ther.2011,339,859–869. 207. LaRussa,T.;Oliverio,M.;Suraci,E.;Greco,M.;Placida,R.;Gervasi,S.;Marasco,R.;Imeneo,M.;Paolino, D.;Tucci,L.;etal.OleuropeinDecreasesCyclooxygenase‐2andInterleukin‐17ExpressionandAttenuates InflammatoryDamageinColonicSamplesfromUlcerativeColitisPatients.Nutrients2017,9,391. ©2020bytheauthors.LicenseeMDPI,Basel,Switzerland.Thisarticleisanopenaccess articledistributedunderthetermsandconditionsoftheCreativeCommonsAttribution (CCBY)license(http://creativecommons.org/licenses/by/4.0/).