RESVERATROLO: Certezze e prospettive di un...

RESVERATROLO Certezze e prospettive di RESVERATROLO Certezze e prospettive di un un polifenolopolifenolo per lrsquoalimentazione dellrsquoanzianoper lrsquoalimentazione dellrsquoanziano

--Proprietagrave Proprietagrave farmacologichefarmacologiche--Impieghi terapeutici e nutrizionaliImpieghi terapeutici e nutrizionali

--Sinergie NutrizionaliSinergie Nutrizionali

Andrea Andrea FratterFratterPharmPharm D D PhPh D D CosmeticCosmetic SciencesSciences

Scienze Scienze dermodermo--cosmetichecosmetiche e nutrizione funzionalee nutrizione funzionaleMaster in Medicina Estetica Universitagrave di PaviaMaster in Medicina Estetica Universitagrave di Pavia

POLIFENOLIPOLIFENOLI

I I PolifenoliPolifenoli sono sostanze sono sostanze ubiquitarieubiquitarie nel nel mondo vegetale e rivestono un ruolo mondo vegetale e rivestono un ruolo fondamentale nella difesa della pianta contro fondamentale nella difesa della pianta contro gli agenti patogeni esterni come i gli agenti patogeni esterni come i microrganismimicrorganismi

Sono sostanze con un nucleo di base fenolico Sono sostanze con un nucleo di base fenolico a cui sono legati diversi gruppi chimici che li a cui sono legati diversi gruppi chimici che li rendono una classe molecolare molto rendono una classe molecolare molto eterogenea e variegataeterogenea e variegata

Hanno in comune la caratteristica di essere Hanno in comune la caratteristica di essere riducenti e di riducenti e di chelarechelare ioni metalliciioni metallici

Vengono da tempo impiegati come sostanze Vengono da tempo impiegati come sostanze ad attivitagrave antiossidante e protettiva degli ad attivitagrave antiossidante e protettiva degli endoteli per via sistemica e topicaendoteli per via sistemica e topica

A questa categoria sono annoverati i A questa categoria sono annoverati i FLAVONOIDI e gli ANTOCIANIFLAVONOIDI e gli ANTOCIANI

DANNI BIOLOGICI DA ROSDANNI BIOLOGICI DA ROS

PRINCIPALI ROSPRINCIPALI ROS

RESVERATROLO UN POrsquo DI RESVERATROLO UN POrsquo DI CHIAREZZAhellipCHIAREZZAhellip

Questa molecola si estrae fondamentalmente Questa molecola si estrae fondamentalmente dalle dalle spermatofitespermatofite (uva rossa) e rappresenta una (uva rossa) e rappresenta una ldquomolecola segnalerdquo che viene sintetizzata dalla ldquomolecola segnalerdquo che viene sintetizzata dalla pianta in caso di danni come stress infezioni ed pianta in caso di danni come stress infezioni ed eccessiva irradiazione UVeccessiva irradiazione UV

Il Resveratrolo manifesta notevoli proprietagrave Il Resveratrolo manifesta notevoli proprietagrave antiossidanti e antiossidanti e scavengerscavenger dei ROS (pubblicazioni dei ROS (pubblicazioni su Nature su Nature LancetLancet ScienceScience) e le sue proprietagrave ) e le sue proprietagrave furono scoperte quando dai risultati di uno studio furono scoperte quando dai risultati di uno studio epidemiologico condotto in Francia (Clinica epidemiologico condotto in Francia (Clinica ChimChimActaActa 237 155 1995 237 155 1995 AnnAnn InternIntern Med 117 Med 117 646 1992 646 1992 LancetLancet 338 464 1991) si scoprigrave che 338 464 1991) si scoprigrave che la bassa incidenza di patologie cardiovascolari la bassa incidenza di patologie cardiovascolari nella popolazione francese (che notoriamente nella popolazione francese (che notoriamente consuma forti quantitagrave di grassi) era legata al consuma forti quantitagrave di grassi) era legata al consumo di vino rossoconsumo di vino rosso

MECCANISMO MECCANISMO DrsquoAZIONEDrsquoAZIONE ONCOONCO--PREVENTIVAPREVENTIVA

AZIONE ONCOAZIONE ONCO--PREVENTIVAPREVENTIVAInduzione dellrsquoInduzione dellrsquoApoptosiApoptosi cellulare (cellulare (CaspasiCaspasi))

Inibizione della Inibizione della CiclossigenasiCiclossigenasi (COX) I II e LOX(COX) I II e LOX

Inibizione dei tre principali eventi Inibizione dei tre principali eventi oncogeneticioncogenetici (iniziazione promozione (iniziazione promozione progressione)progressione)

Inibizione delle proteine Inibizione delle proteine kinasikinasi

Soppressione dellrsquoespressione di Soppressione dellrsquoespressione di GrowGrow FactorFactor

Attivazione del gene Attivazione del gene oncosoppressoreoncosoppressore p53p53

Inibizione dellrsquoespressione dei citocromi P450Inibizione dellrsquoespressione dei citocromi P450

QuenchingQuenching delle forme delle forme radicalicheradicaliche ossigenate piugrave aggressive (riduzione ossigenate piugrave aggressive (riduzione del danno del danno tissutaletissutale))

AZIONE ESTROGENO MODULATRICEAZIONE ESTROGENO MODULATRICE

Il Il TransTrans--ResveratroloResveratrolo si lega ai recettori si lega ai recettori ERERαα ed ed ERERββ agendo in senso agonistaagendo in senso agonista--antagonistaantagonista

Puograve essere di fatto considerato un Puograve essere di fatto considerato un fitofito--estrogenoestrogeno

Agisce come Agisce come cardiocardio e e oncoonco--protettivoprotettivo grazie grazie allrsquointerazione con ERallrsquointerazione con ER

DrugsDrugs ExpExp ClinClin ResRes 199925(2199925(2--3)1113)111--44NonalcoholicNonalcoholic compounds of wine the compounds of wine the phytoestrogenphytoestrogenresveratrolresveratrol and moderate red wine consumption during and moderate red wine consumption during menopausemenopause

Calabrese GCalabrese G

DepartmentDepartment of of HumanHuman NutritionNutrition UniversitaUniversita Cattolica S Cuore Cattolica S Cuore Piacenza Piacenza ItalyItaly

The literature on the natural sources of The literature on the natural sources of resveratrolresveratrol a a phytochemicalphytochemical substance found in grapes and wine is reviewed substance found in grapes and wine is reviewed herein Its structure is similar to that of diethylstilbestrol aherein Its structure is similar to that of diethylstilbestrol and nd like other authors we consider that like other authors we consider that resveratrolresveratrol might be a might be a phytoestrogenphytoestrogen We analyzed the populations who ingest this We analyzed the populations who ingest this substance as well as the known biological effects of substance as well as the known biological effects of phytoestrogensphytoestrogens in humans The literature on the effects of in humans The literature on the effects of resveratrolresveratrol on female reproduction osteoporosis and cancer on female reproduction osteoporosis and cancer was assessed using relevant case reports and cohort studies as was assessed using relevant case reports and cohort studies as well as randomized trials and review articles We conclude that well as randomized trials and review articles We conclude that phytoestrogensphytoestrogens exhibit physiological effects in humans and that exhibit physiological effects in humans and that these estrogenic actions increase the biological reactions these estrogenic actions increase the biological reactions produced by moderate red wine consumption with mealsproduced by moderate red wine consumption with meals

Cancer ResCancer Res 2001 Oct 1561(20)74562001 Oct 1561(20)7456--63 63 Estrogenic and Estrogenic and antiestrogenicantiestrogenic properties of properties of resveratrolresveratrol in mammary in mammary tumortumor modelsmodelsBhat KPBhat KP Lantvit DLantvit D Christov KChristov K Mehta RGMehta RG Moon RCMoon RC PezzutoPezzuto JMJM Program for Collaborative Research in the Pharmaceutical ScienceProgram for Collaborative Research in the Pharmaceutical Sciences Department of Medicinal Chemistry and s Department of Medicinal Chemistry and PharmacognosyPharmacognosy College of Pharmacy University of Illinois at Chicago Chicag College of Pharmacy University of Illinois at Chicago Chicago Illinois 60612 USAo Illinois 60612 USATransTrans--345345--trihydroxystilbene (trihydroxystilbene (resveratrolresveratrol) a ) a phytoalexinphytoalexin present in grapes and grape products such as wine present in grapes and grape products such as wine has been identified as a has been identified as a chemopreventivechemopreventive agent Recent studies performed with MCFagent Recent studies performed with MCF--7 human breast cancer 7 human breast cancer cells have demonstrated cells have demonstrated superestrogenicsuperestrogenic effects with effects with resveratrolresveratrol In contrast studies performed using In contrast studies performed using estrogenestrogenreceptorreceptor--transfectedtransfected cell lines have shown that cell lines have shown that resveratrolresveratrol acts as a mixed agonistantagonist The major acts as a mixed agonistantagonist The major objective of this study was to characterize the objective of this study was to characterize the estrogenestrogen--modulatorymodulatory effects of effects of resveratrolresveratrol in a variety of in vitro in a variety of in vitro and in vivo mammary models Thus the effect of and in vivo mammary models Thus the effect of resveratrolresveratrol alone and in combination with 17betaalone and in combination with 17beta--estradiol estradiol (E2) was assessed with MCF(E2) was assessed with MCF--7 T47D LY2 and S30 mammary cancer cell lines With cells 7 T47D LY2 and S30 mammary cancer cell lines With cells transfectedtransfected with with reporter gene systems the activation of reporter gene systems the activation of estrogenestrogen response elementresponse element--luciferaseluciferase was studied and using Western was studied and using Western blot analysis the expression of E2blot analysis the expression of E2--responsive progesterone receptor (PR) and responsive progesterone receptor (PR) and presnelinpresnelin 2 protein was 2 protein was monitored Furthermore the effect of monitored Furthermore the effect of resveratrolresveratrol on formation of on formation of preneoplasticpreneoplastic lesions (induced by 712lesions (induced by 712--dimethylbenz(a)anthracene) and PR expression (with or without E2dimethylbenz(a)anthracene) and PR expression (with or without E2) was evaluated with mammary glands of ) was evaluated with mammary glands of BALBc mice placed in organ culture Finally the effect of BALBc mice placed in organ culture Finally the effect of popo administered administered resveratrolresveratrol on Non N--methylmethyl--NN--nitrosoureanitrosourea--induced mammary induced mammary tumorstumors was studied in female Sprague was studied in female Sprague DawleyDawley rats As a result in transient rats As a result in transient transfectiontransfection studies with MCFstudies with MCF--7 cells 7 cells resveratrolresveratrol showed a weak estrogenic response but when showed a weak estrogenic response but when resveratrolresveratrol was was combined with E2 (1 combined with E2 (1 nMnM) a clear dose) a clear dose--dependent antagonism was observed Similar mixed dependent antagonism was observed Similar mixed estrogenicestrogenicantiestrogenicantiestrogenic effects were noted with S30 cells whereas effects were noted with S30 cells whereas resveratrolresveratrol functioned as a pure functioned as a pure estrogenestrogenantagonist with T47D and LY2 cells Furthermore in MCFantagonist with T47D and LY2 cells Furthermore in MCF--7 cells 7 cells resveratrolresveratrol induced PR protein expression but induced PR protein expression but when when resveratrolresveratrol was combined with E2 expression of PR was suppressed With T47was combined with E2 expression of PR was suppressed With T47D cells D cells resveratrolresveratrolsignificantly downsignificantly down--regulated steadyregulated steady--state and E2state and E2--induced protein levels of PR With LY2 and S30 cells induced protein levels of PR With LY2 and S30 cells resveratrolresveratrol downdown--regulated regulated presnelinpresnelin 2 protein expression Using the mouse mammary organ culture mod2 protein expression Using the mouse mammary organ culture model el resveratrolresveratrol induced PR when administered alone but expression was suppressinduced PR when administered alone but expression was suppressed in the presence of E2 (1 ed in the presence of E2 (1 nMnM) ) Furthermore Furthermore resveratrolresveratrol inhibited the formation of inhibited the formation of estrogenestrogen--dependent dependent preneoplasticpreneoplastic ductalductal lesions induced by lesions induced by 712712--dimethylbenz(a)anthracene in these mammary glands (IC50 = 32 dimethylbenz(a)anthracene in these mammary glands (IC50 = 32 microMmicroM) and reduced N) and reduced N--methylmethyl--NN--nitrosoureanitrosourea--induced mammary induced mammary tumorigenesistumorigenesis when administered to female Sprague when administered to female Sprague DawleyDawley rats by rats by gavagegavage Therefore in the absence of E2 Therefore in the absence of E2 resveratrolresveratrol exerts mixed exerts mixed estrogenestrogen agonistantagonist activities in agonistantagonist activities in some mammary cancer cell lines but in the presence of E2 some mammary cancer cell lines but in the presence of E2 resveratrolresveratrol functions as an functions as an antiestrogenantiestrogen In rodent models carcinogen In rodent models carcinogen--induced induced preneoplasticpreneoplastic lesions and mammary lesions and mammary tumorstumorsare inhibitedare inhibited These data suggest thatThese data suggest that resveratrolresveratrol may have beneficial effects if used as amay have beneficial effects if used as a

AZIONE ANTIAZIONE ANTI--AGEAGE

Riduzione delle forme Riduzione delle forme radicalicheradicalicheossigenate (NO)ossigenate (NO)

Aumento della Aumento della perfusioneperfusione tissutaletissutale

Riduzione della degenerazione delle Riduzione della degenerazione delle membrane membrane mitocondrialimitocondriali

J J NutrNutr 2005 Aug135(8)19112005 Aug135(8)1911--7 7 Grape Grape polyphenolspolyphenols exert a exert a cardioprotectivecardioprotective effect in preeffect in pre-- and postmenopausal and postmenopausal

women by lowering plasma lipids and reducing oxidative stresswomen by lowering plasma lipids and reducing oxidative stressZern TLZern TL Wood RJWood RJ GreeneGreene CC West KLWest KL Liu YLiu Y Aggarwal DAggarwal D Shachter NSShachter NS FernandezFernandez MLML Department of Nutritional Sciences University of Connecticut SDepartment of Nutritional Sciences University of Connecticut Storrs 06269 USAtorrs 06269 USA

To evaluate the effects of grape To evaluate the effects of grape polyphenolspolyphenols on plasma lipids inflammatory cytokines and on plasma lipids inflammatory cytokines and oxidative stress 24 preoxidative stress 24 pre-- and 20 postmenopausal women were randomly assigned to and 20 postmenopausal women were randomly assigned to consume 36 g of a lyophilized grape powder (LGP) or a placebo foconsume 36 g of a lyophilized grape powder (LGP) or a placebo for 4 wk The LGP r 4 wk The LGP consisted of 92 carbohydrate and was rich in consisted of 92 carbohydrate and was rich in flavansflavans anthocyaninsanthocyanins quercetinquercetin myricetinmyricetin kaempferolkaempferol and and resveratrolresveratrol After a 3 After a 3--wk washout period subjects were wk washout period subjects were assigned to the alternate treatment for an additional 4 wk The assigned to the alternate treatment for an additional 4 wk The placebo consisted of an placebo consisted of an equal ratio of fructose and dextrose and was similar in appearanequal ratio of fructose and dextrose and was similar in appearance and energy content ce and energy content (554 kJ) to LGP Plasma triglyceride concentrations were reduced(554 kJ) to LGP Plasma triglyceride concentrations were reduced by 15 and 6 in preby 15 and 6 in pre--and postmenopausal women respectively (P lt 001) after LGP suppand postmenopausal women respectively (P lt 001) after LGP supplementation In lementation In addition plasma LDL cholesterol and addition plasma LDL cholesterol and apolipoproteinsapolipoproteins B and E were lower due to LGP B and E were lower due to LGP treatment (P lt 005) Further cholesterol ester transfer proteitreatment (P lt 005) Further cholesterol ester transfer protein activity was decreased by n activity was decreased by approximately 15 with intake of LGP (P lt 005) In contrast to approximately 15 with intake of LGP (P lt 005) In contrast to these beneficial effects these beneficial effects on plasma lipids LDL oxidation was not modified by LGP treatmenon plasma lipids LDL oxidation was not modified by LGP treatment However wholet However whole--body body oxidative stress as measured by urinary F(2)oxidative stress as measured by urinary F(2)--isoprostanes was significantly reduced after isoprostanes was significantly reduced after LGP supplementation LGP supplementation LGP also decreased the levels of plasma LGP also decreased the levels of plasma tumortumor necrosis necrosis factorfactor--alpha which plays a major role in the inflammation process Thralpha which plays a major role in the inflammation process Through ough alterations in lipoprotein metabolism oxidative stress and infalterations in lipoprotein metabolism oxidative stress and inflammatory lammatory markers LGP intake beneficially affected key risk factors for cmarkers LGP intake beneficially affected key risk factors for coronary heart oronary heart disease in both predisease in both pre-- and postmenopausal womenand postmenopausal women

Cell Cycle 2006 May 155(10) [Cell Cycle 2006 May 155(10) [EpubEpub ahead of print] Related Articlesahead of print] Related ArticlesLinksLinks

ResveratrolResveratrol and The Pharmacology of Aging A New Vertebrate Model toand The Pharmacology of Aging A New Vertebrate Model toValidate an Old MoleculeValidate an Old Molecule

ValenzanoValenzano DR DR CellerinoCellerino AA

ScuolaScuola NormaleNormale SuperioreSuperiore Pisa Italy Pisa Italy

The natural The natural phytoalexinphytoalexin resveratrolresveratrol found in grapes and red wine found in grapes and red winerecently rose to public fame for its positive effects on longevirecently rose to public fame for its positive effects on longevity inty inyeasts worms and flies yeasts worms and flies ResveratrolResveratrol antianti--cancer and anticancer and anti--inflammatoryinflammatoryin vitro action on mammalian cell cultures also suggest a possibin vitro action on mammalian cell cultures also suggest a possiblelepositive effect on human health and lifepositive effect on human health and life--expectancy To study theexpectancy To study theeffects of effects of resveratrolresveratrol on vertebrate aging is obviously a particularlyon vertebrate aging is obviously a particularlyrelevant question We have studied relevant question We have studied resveratrolresveratrol effects in a veryeffects in a veryshortshort--lived vertebrate the annual fish lived vertebrate the annual fish NothobranchiusNothobranchius furzerifurzeriResveratrolResveratrol treatment prolonged lifespan and delayed the onset oftreatment prolonged lifespan and delayed the onset ofageage--related dysfunctions in this fish This result identifiesrelated dysfunctions in this fish This result identifiesresveratrolresveratrol as the first molecule which consistently retards aging inas the first molecule which consistently retards aging inorganisms as diverse as yeast worm fly and fish but it also rorganisms as diverse as yeast worm fly and fish but it also revealsevealsthe potential of this shortthe potential of this short--lived fish as an animal model forlived fish as an animal model forpharmacological research Moreover being related to sticklebackpharmacological research Moreover being related to stickleback((GasterosteusGasterosteus aculeatusaculeatus) the ) the pufferfishespufferfishes TakifuguTakifugu and and TetraodonTetraodon and andeven more closely related to even more closely related to medakamedaka ((OryziasOryzias latipeslatipes) it can greatly) it can greatlybeneficiate from the recent development of genomic resources forbeneficiate from the recent development of genomic resources for thesethesefish models and in the future become a complete model system forfish models and in the future become a complete model system for thetheaging research communityaging research community

FARMACOCINETICAFARMACOCINETICAIn seguito ad assunzione orale il In seguito ad assunzione orale il TransTrans--ResveratroloResveratroloda luogo ad assorbimento entericoda luogo ad assorbimento enterico

Vasta Vasta metabolizzazionemetabolizzazione nei nei microsomimicrosomi epaticiepatici

Reazioni di fase II (Reazioni di fase II (GlucuronidazioneGlucuronidazione e e solfatazionesolfatazione))

Lrsquoassorbimento e la distribuzione Lrsquoassorbimento e la distribuzione tissutaletissutale aumentano aumentano se lrsquoassunzione egrave simultanea a se lrsquoassunzione egrave simultanea a PolifenoliPolifenoli ((flavonoidiflavonoidi))

Il Il TransTrans--ResveratroloResveratrolo si accumula si accumula preferenzialmentepreferenzialmentein intestino stomaco reni vasiin intestino stomaco reni vasi

Escrezione principale con lrsquoemuntorio renaleEscrezione principale con lrsquoemuntorio renale

RESVERATROLO RESVERATROLO FONTI NATURALIFONTI NATURALI

VITIS VINIFERA ESTRATTO SECCOVITIS VINIFERA ESTRATTO SECCO

POLIFENOLI TOTALI POLIFENOLI TOTALI 95 pp95 ppANTOCIANOSIDI ANTOCIANOSIDI 20 pp20 ppRESVERATROLO RESVERATROLO 88--10 pp10 pp

IlIl contenuto medio di contenuto medio di ResveratroloResveratrolo in un litro di vino rosso egrave di in un litro di vino rosso egrave di circa 5 mg circa 5 mg

ORAC (ORAC (OxigenOxigen RadicalRadical AbosrbanceAbosrbance CapacityCapacity) gt10000) gt10000

POLYGONUM CUSPIDATUM ESTRATTO SECCOPOLYGONUM CUSPIDATUM ESTRATTO SECCO

ATTIVITArsquoATTIVITArsquoSCAVENGER DEI ROSSCAVENGER DEI ROSANTINFIAMMATORIAANTINFIAMMATORIAVASODILATATRICEVASODILATATRICETROFICA DEGLI ENDOTELI VASALITROFICA DEGLI ENDOTELI VASALIANTIALLERGICAANTIALLERGICARIDUCE IL RISCHIO DELLE MALATTIE CARDIORIDUCE IL RISCHIO DELLE MALATTIE CARDIO--VASCOLARI E NEUROLOGICHEVASCOLARI E NEUROLOGICHERIDUCE IL RISCHIO DI CONTRARRE ALCUNE RIDUCE IL RISCHIO DI CONTRARRE ALCUNE FORME NEOPLASTICHEFORME NEOPLASTICHEAGISCE COME MODULATORE DEL RECETTORE AGISCE COME MODULATORE DEL RECETTORE DEGLI ESTROGENIDEGLI ESTROGENI

FORMULAZIONE NUTRICEUTICAFORMULAZIONE NUTRICEUTICA

LL--CARNITINACARNITINA 100 mg100 mgLL--CARNOSINACARNOSINA 500 mg500 mgVITIS VINIFERA ESVITIS VINIFERA ES 300 mg300 mg

TIT PROANTOCIANIDINEgt90TIT PROANTOCIANIDINEgt90TITTIT TRANSTRANS--RESVERATROLOgt5RESVERATROLOgt5

Forme liquide da applicare sotto la lingua e Forme liquide da applicare sotto la lingua e transtrans--mucosalemucosaleForme solide (capsule compresse granulati)Forme solide (capsule compresse granulati)

CARNOSINACARNOSINADipeptideDipeptide composto da composto da ll--alaninaalanina e e ββ--IstidinaIstidinapresente fisiologicamente in diversi tessuti e presente fisiologicamente in diversi tessuti e cellule (cellule (cellulecellule neuronalineuronali muscolo muscolo scleletricoscleletrico rene) e capace di agire da ldquotamponerdquo del rene) e capace di agire da ldquotamponerdquo del pHpH ma soprattutto di reagire con grande affinitagrave ma soprattutto di reagire con grande affinitagrave con gli zuccheri circolanti e stoccati nei tessuti con gli zuccheri circolanti e stoccati nei tessuti impedendo che questi reagiscano con le impedendo che questi reagiscano con le proteine strutturali del connettivo alterandone proteine strutturali del connettivo alterandone la struttura e quindi le funzioni fisiologiche la struttura e quindi le funzioni fisiologiche (cataratta in corso di diabete (cataratta in corso di diabete agingaging cutaneo)cutaneo)

Manifesta un ottimo profilo di assorbimento Manifesta un ottimo profilo di assorbimento transtrans--mucosalemucosale e attraversa la BEE e la BERe attraversa la BEE e la BER

Sotto forma di gocce oculari e di Sotto forma di gocce oculari e di integratore nutrizionale rappresenta una integratore nutrizionale rappresenta una efficace terapia per la prevenzione e efficace terapia per la prevenzione e lrsquoarresto della progressione della cataratta lrsquoarresto della progressione della cataratta e della e della retinopatiaretinopatia del diabetico (giagrave del diabetico (giagrave farmaco USA)farmaco USA)

50 mgltDose efficace50 mgltDose efficacediedielt150 mglt150 mg

ArchArch BiochemBiochem BiophysBiophys 2004 2004 JulJul 1427(1)1101427(1)110--55CarnosineCarnosine disaggregates disaggregates glycatedglycated alphaalpha--crystallincrystallin an in vitro study an in vitro study

SeidlerSeidler NWNW YeargansYeargans GSGS Morgan TGMorgan TG

University of Health Sciences Department of Biochemistry 1750 University of Health Sciences Department of Biochemistry 1750 Independence Avenue Kansas City MO 64106Independence Avenue Kansas City MO 64106--1453 USA 1453 USA nseidleruhsedunseidleruhsedu

Protein Protein glycationglycation which promotes aggregation involves the unwanted which promotes aggregation involves the unwanted reaction of carbohydrate oxidation products with proteins reaction of carbohydrate oxidation products with proteins GlycationGlycation of lens of lens alphaalpha--crystallincrystallin occurs in vivo and may contribute to occurs in vivo and may contribute to cataractogenesiscataractogenesis Anti Anti--glycationglycation compounds such as compounds such as carnosinecarnosine may be preventive but interestingly may be preventive but interestingly carnosinecarnosine reverses lens opacity in human trials The mechanism for this reverses lens opacity in human trials The mechanism for this observation may involve observation may involve carnosinescarnosines ability to disaggregate ability to disaggregate glycatedglycatedprotein We investigated this hypothesis using protein We investigated this hypothesis using glycatedglycated alphaalpha--crystallincrystallin as as our in vitro model our in vitro model MethylglyoxalMethylglyoxal--induced induced glycationglycation of alphaof alpha--crystallincrystallincaused aggregation as evidenced by increased 90 degrees light sccaused aggregation as evidenced by increased 90 degrees light scattering attering After addition of After addition of carnosinecarnosine light scattering returned to baseline levels light scattering returned to baseline levels suggesting that the size of the suggesting that the size of the glycationglycation--induced aggregates decreased induced aggregates decreased Additionally Additionally carnosinecarnosine decreased decreased tryptophantryptophan fluorescence polarization of fluorescence polarization of glycatedglycated alphaalpha--crystallincrystallin suggesting that suggesting that carnosinecarnosine increased peptide chain increased peptide chain mobility which may contribute to the controlled unfolding of mobility which may contribute to the controlled unfolding of glycatedglycatedprotein Comparatively guanidineprotein Comparatively guanidine--HClHCl and urea had no effect Our data and urea had no effect Our data support the hypothesis that support the hypothesis that carnosinecarnosine disaggregates disaggregates glycatedglycated alphaalpha--crystallincrystallin

PeptidesPeptides 2001 2001 JunJun22(6)97922(6)979--9494NN--AcetylcarnosineAcetylcarnosine a natural a natural histidinehistidine--containing containing dipeptidedipeptide as a potent as a potent ophthalmic drug in treatment of human cataractsophthalmic drug in treatment of human cataractsBabizhayevBabizhayev MAMA DeyevDeyev AIAI YermakovaYermakova VNVN SemiletovSemiletov YAYA DavydovaDavydova NGNG KuryshevaKurysheva NINI ZhukotskiiZhukotskii AVAV GoldmanGoldman IMIM

Innovative Vision Products Inc County of New Castle DE 19810Innovative Vision Products Inc County of New Castle DE 19810 USA USA markbabizhayevmailrumarkbabizhayevmailru

A study was designed to document and quantify the changes in lenA study was designed to document and quantify the changes in lens clarity over 6 and 24 months in 2 s clarity over 6 and 24 months in 2 groups of 49 volunteers (76 eyes) with an average age of 653 +groups of 49 volunteers (76 eyes) with an average age of 653 +-- 70 enrolled at the time of diagnosis of 70 enrolled at the time of diagnosis of senile cataracts of minimal to advanced senile cataracts of minimal to advanced opacificationTheopacificationThe patients received Npatients received N--acetylcarnosineacetylcarnosine 1 sol 1 sol (NAC) (26 patients 41 eyes = Group II) placebo composition (13(NAC) (26 patients 41 eyes = Group II) placebo composition (13 patients 21 eyes) topically (two drops patients 21 eyes) topically (two drops twice daily) to the twice daily) to the conjunctivalconjunctival sac or were untreated (10 patients 14 eyes) the placebo and sac or were untreated (10 patients 14 eyes) the placebo and untreated untreated groups were combined into the control (reference) Group I Patiegroups were combined into the control (reference) Group I Patients were evaluated upon entry at 2nts were evaluated upon entry at 2--month (Trial 1) and 6month (Trial 1) and 6--month (Trial 2)month (Trial 2)--intervals for best corrected visual acuity (intervals for best corrected visual acuity (bcbc VA) by VA) by ophthalmoscopyophthalmoscopy and the original techniques of glare test (for Trial 1) and the original techniques of glare test (for Trial 1) stereocinematographicstereocinematographic slitslit--image image and retroand retro--illumination photography with subsequent scanning of the lens Tillumination photography with subsequent scanning of the lens The computerized interactive he computerized interactive digital analysis of obtained images displayed the light scatteridigital analysis of obtained images displayed the light scatteringabsorbing ngabsorbing centerscenters of the lens into 2of the lens into 2--D and D and 33--D D scalesThescalesThe intraintra--reader reproducibility of measuring techniques for reader reproducibility of measuring techniques for cataractouscataractous changes was good changes was good with the overall average of correlation coefficients for the imawith the overall average of correlation coefficients for the image analytical data 0830 and the glare test ge analytical data 0830 and the glare test readings 0998 Compared with the baseline examination over 6 mreadings 0998 Compared with the baseline examination over 6 months 415 of the eyes treated with onths 415 of the eyes treated with NAC presented a significant improvement of the gross NAC presented a significant improvement of the gross transmissivitytransmissivity degree of lenses computed from the degree of lenses computed from the images 900 of the eyes showed a gradual improvement in images 900 of the eyes showed a gradual improvement in bcbc VA to 7VA to 7--100 and 889 of the eyes 100 and 889 of the eyes ranged a 27ranged a 27--100 improvement in glare sensitivity Topographic studies demon100 improvement in glare sensitivity Topographic studies demonstrated less density and strated less density and corresponding areas of corresponding areas of opacificationopacification in posterior in posterior subcapsularsubcapsular and cortical morphological regions of the lens and cortical morphological regions of the lens consistent with VA up to 03 The total study period over 24 monconsistent with VA up to 03 The total study period over 24 months revealed that the beneficial effect of ths revealed that the beneficial effect of NAC is sustainable No cases resulted in a worsening of VA and iNAC is sustainable No cases resulted in a worsening of VA and image analytical readings of lenses in the mage analytical readings of lenses in the NACNAC--treated group of patients In most of the patients drug toleranctreated group of patients In most of the patients drug tolerance was good Group I of patients e was good Group I of patients demonstrated the variability in the demonstrated the variability in the densitometricdensitometric readings of the lens readings of the lens cloudingscloudings negative advance in glare negative advance in glare sensitivity over 6 months and gradual deterioration of VA and grsensitivity over 6 months and gradual deterioration of VA and gross oss transmissivitytransmissivity of lenses over 24 of lenses over 24 months compared with the baseline and 6months compared with the baseline and 6--month followmonth follow--up examinations Statistical analysis revealed the up examinations Statistical analysis revealed the significant differences over 6 and 24 months in cumulative positsignificant differences over 6 and 24 months in cumulative positive changes of overall characteristics of ive changes of overall characteristics of cataracts in the NACcataracts in the NAC--treated Group II from the control Group treated Group II from the control Group ITheIThe NN--acetylated form of natural acetylated form of natural dipeptidedipeptideLL--carnosinecarnosine appears to be suitable and physiologically acceptable for appears to be suitable and physiologically acceptable for nonsurgicalnonsurgical treatment for senile treatment for senile cataractscataracts

ExpExp EyeEye ResRes 2004 2004 AprApr78(4)81578(4)815--2222Mechanism of a model Mechanism of a model dipeptidedipeptide transport across bloodtransport across blood--ocular barriers ocular barriers following systemic administrationfollowing systemic administration

AtluriAtluri HH AnandAnand BSBS Patel JPatel J MitraMitra AKAK

Division of Pharmaceutical Sciences School of Pharmacy UniversDivision of Pharmaceutical Sciences School of Pharmacy University of Missouriity of Missouri--Kansas City 5005 Kansas City 5005 RockhillRockhill Road Kansas City MO 64112Road Kansas City MO 64112--2499 USA2499 USA

The purposes of this study were to provide functional evidence fThe purposes of this study were to provide functional evidence for the presence of a or the presence of a peptide peptide transportertransporter on bloodon blood--ocular barriers and to elucidate the mechanism of a ocular barriers and to elucidate the mechanism of a dipeptidedipeptide transport across these barriers following systemic administratitransport across these barriers following systemic administration on GlycylsarcosineGlycylsarcosine was chosen as a model was chosen as a model dipeptidedipeptide and [(3)H] and [(3)H] glycylsarcosineglycylsarcosine was was administered through the marginal ear vein of New Zealand white administered through the marginal ear vein of New Zealand white rabbits At the end rabbits At the end of an experimental period vitreous of an experimental period vitreous humorhumor retina and aqueous retina and aqueous humorhumor were were collected Time dependent uptake of collected Time dependent uptake of glycylsarcosineglycylsarcosine into ocular tissues was studied into ocular tissues was studied at 5 10 15 and 30 min Competitive inhibition studies were perat 5 10 15 and 30 min Competitive inhibition studies were performed by formed by intravenous administration of [(3)H] intravenous administration of [(3)H] glycylsarcosineglycylsarcosine with and without various with and without various inhibitors Concentrationinhibitors Concentration--dependent ocular uptake of dependent ocular uptake of glycylsarcosineglycylsarcosine was carried out was carried out by administration of various concentrations of unlabelled by administration of various concentrations of unlabelled glycylsarcosineglycylsarcosine spiked with spiked with a fixed amount of [(3)H] a fixed amount of [(3)H] glycylsarcosineglycylsarcosine Time Time--dependent uptake of dependent uptake of glycylsarcosineglycylsarcosineinto vitreous into vitreous humorhumor retina and aqueous retina and aqueous humorhumor for a period of 30 min following for a period of 30 min following systemic administration was linear Ocular uptake of systemic administration was linear Ocular uptake of glycylsarcosineglycylsarcosine was inhibited by was inhibited by peptide peptide transportertransporter substrates such as substrates such as dipeptidesdipeptides ((glycylprolineglycylproline and and carnosinecarnosine) and ) and captoprilcaptopril but not by nonbut not by non--substrates such as amino acids Concentrationsubstrates such as amino acids Concentration--dependent dependent selfself--inhibition of inhibition of glycylsarcosineglycylsarcosine ocular uptake was also observed The results ocular uptake was also observed The results indicate that model indicate that model dipeptidedipeptide is transported across bloodis transported across blood--ocular barriers via a ocular barriers via a carriercarrier--mediated process In conclusion an mediated process In conclusion an oligopeptideoligopeptide transport system is involved transport system is involved in the transport of in the transport of glycylsarcosineglycylsarcosine across bloodacross blood--ocular barriers This information may ocular barriers This information may be utilized to design be utilized to design transportertransporterreceptor targeted drug delivery systems for efficient receptor targeted drug delivery systems for efficient ocular uptake from systemic administrationocular uptake from systemic administration

DrugsDrugs R D 20023(2)87R D 20023(2)87--103 103 Efficacy of NEfficacy of N--acetylcarnosineacetylcarnosine in the treatment of cataractsin the treatment of cataracts

BabizhayevBabizhayev MA MA DeyevDeyev AI AI YermakovaYermakova VN VN SemiletovSemiletov YA YA DavydovaDavydova NG NG DoroshenkoDoroshenkoVS VS ZhukotskiiZhukotskii AV Goldman IMAV Goldman IM

Innovative Vision Products Inc County of Newcastle DelawareInnovative Vision Products Inc County of Newcastle Delaware USA USA markbabizhayevyahoocommarkbabizhayevyahoocom

PURPOSE To evaluate the effects of 1 NPURPOSE To evaluate the effects of 1 N--acetylcarnosineacetylcarnosine (NAC) solution on lens clarity over 6 (NAC) solution on lens clarity over 6 and 24 months in patients with and 24 months in patients with cataractscataracts TRIAL DESIGN Randomised placebo TRIAL DESIGN Randomised placebo--controlled study controlled study PARTICIPANTS 49 subjects (76 affected eyes) with an average agePARTICIPANTS 49 subjects (76 affected eyes) with an average age of 653 +of 653 +-- 70 years with a 70 years with a diagnosis of senile cataract with minimum to advanced diagnosis of senile cataract with minimum to advanced opacificationopacification in various lens layers in various lens layers METHODS 26 patients (41 eyes) were allocated to topical NAC 1 METHODS 26 patients (41 eyes) were allocated to topical NAC 1 eyedropseyedrops twice daily The twice daily The control group consisted of 13 patients (21 eyes) who received plcontrol group consisted of 13 patients (21 eyes) who received placebo acebo eyedropseyedrops and 10 patients and 10 patients (14 eyes) who did not receive (14 eyes) who did not receive eyedropseyedrops MAIN OUTCOME MEASURES All patients were evaluated MAIN OUTCOME MEASURES All patients were evaluated at entry and followed up every 2 months for a 6at entry and followed up every 2 months for a 6--month period (trial 1) or at 6month period (trial 1) or at 6--month intervals month intervals for a 2for a 2--year period (trial 2) for bestyear period (trial 2) for best--corrected visual acuity and glare corrected visual acuity and glare testingtesting In addition In addition cataract was measured using cataract was measured using stereocinematographicstereocinematographic slitslit--images and retroimages and retro--illumination illumination examination of the lens Digital analysis of lens images displayexamination of the lens Digital analysis of lens images displayed light scattering and absorbing ed light scattering and absorbing centres in twocentres in two-- and threeand three--dimensional dimensional scalesscales RESULTS The overall intra RESULTS The overall intra--reader reproducibility of reader reproducibility of cataract measurements (cataract measurements (image analysisimage analysis) was 0830 and glare testing 0998 After 6 months ) was 0830 and glare testing 0998 After 6 months 90 of NAC90 of NAC--treated eyes showed improvement in best corrected visual acuity treated eyes showed improvement in best corrected visual acuity (7 to 100) and (7 to 100) and 889 showed a 27 to 100 improvement in glare sensitivity Topo889 showed a 27 to 100 improvement in glare sensitivity Topographic studies indicated graphic studies indicated fewer areas of posterior fewer areas of posterior subcapsularsubcapsular lens opacity and 415 of treated eyes had improvement in lens opacity and 415 of treated eyes had improvement in image analysis characteristics The overall ratios of image analimage analysis characteristics The overall ratios of image analysis characteristics at 6 months ysis characteristics at 6 months compared with baseline measures were 104 and 086 for the contrcompared with baseline measures were 104 and 086 for the control and NACol and NAC--treated group treated group respectively (p lt 0001) The apparent benefits of treatment werrespectively (p lt 0001) The apparent benefits of treatment were sustained after 24 months e sustained after 24 months treatment No treated eyes demonstrated worsening of vision Thetreatment No treated eyes demonstrated worsening of vision The overall visual outcome in the overall visual outcome in the control group showed significant worsening after 24 months in cocontrol group showed significant worsening after 24 months in comparison with both baseline and mparison with both baseline and the 6the 6--month followmonth follow--up examination The overall clinical results observed in the NACup examination The overall clinical results observed in the NAC--treated group treated group by the 24by the 24--month period of examination differed significantly (p lt 0001) fmonth period of examination differed significantly (p lt 0001) from the control group rom the control group in the eyes with cortical posterior in the eyes with cortical posterior subcapsularsubcapsular nuclear or combined lens opacities Tolerability of nuclear or combined lens opacities Tolerability of NAC NAC eyedropseyedrops was good in almost all patients with no reports of ocular or swas good in almost all patients with no reports of ocular or systemic adverse ystemic adverse effects CONCLUSION Topical NAC shows potential for the treatmeeffects CONCLUSION Topical NAC shows potential for the treatment and prevention of nt and prevention of cataractscataracts

POSOLOGIAPOSOLOGIA

Dosaggio consigliato Dosaggio consigliato 2 capsule al giorno2 capsule al giorno(attivitagrave fisica intensa patologie cardiovascolari dieta (attivitagrave fisica intensa patologie cardiovascolari dieta ricca di grassi convalescenza infezioni in corso ricca di grassi convalescenza infezioni in corso gestione coadiuvante nei sintomi da climaterio)gestione coadiuvante nei sintomi da climaterio)

Per la protezione quotidiana e il supplemento Per la protezione quotidiana e il supplemento antiagingantiaging 1 capsula al giorno1 capsula al giorno

BIBLIOGRAFIABIBLIOGRAFIA1 Omenn G S Chemoprevention of lung cancer the rise and demise of beta-carotene Ann Rev Public Health 19 73ndash99 19982 Jang M S Cai E N Udeani G O Slowing K V Thomas C F BeecherC W W Fong H H S Farnsworth N R Kinghorn A D Mehta R GMoon R C and Pezzuto J M Cancer chemopreventive activity of resveratrola natural product derived from grapes Science (Wash DC) 275 218ndash220 19973 Gusman J Malonne H and Atassi G A A re-appraisal of the potentialchemopreventive and chemotherapeutic properties of resveratrol Carcinogenesis(Lond) 22 1111ndash1117 20014 Fremont L MinireviewndashBiological effects of resveratrol Life Sci 66 663ndash673 20005 Roemer K and Mahyar-Roemer M The basis for the chemopreventiveaction of resveratrol Drugs Today 38 571ndash580 20026 Savouret J F and Quesne M Resveratrol and cancer a review BiomedPharmacother 56 84ndash87 20027 Bhat K P L and Pezzuto J M Cancer chemopreventive activity of resveratrolAnn N Y Acad Sci 957 210ndash229 20028 Chang T K Lee W B and Ko H H Trans-resveratrol modulates thecatalytic activity and mRNA expression of the procarcinogen-activating humancytochrome P450 1B1 Can J Physiol Pharmacol 78 874ndash881 20009 Basly J P Marre-Fournier F LeBail J C Habrioux G and Chulia A JEstrogenicantiestrogenic and scavanging properties of (E)- and (Z)-resveratrolLife Sci 66 769ndash777 200010 Goldberg D M Yan J and Soleas G J Absorption of three wine-relatedpolyphenols in three different matrices by healthy subjects Clin Biochem 3679ndash87 200311 Juan M E Buenafuente J Casals I and Planas J M Plasmatic levels oftrans-resveratrol in rats Food Res Int 35 195ndash199 2002

GRAZIE PER GRAZIE PER LrsquoATTENZIONELrsquoATTENZIONE

RESVERATROLO Certezze e prospettive di un polifenolo per lrsquoalimentazione dellrsquoanziano -Proprietagrave farmacologiche-Impiegh

POLIFENOLI

DANNI BIOLOGICI DA ROS

PRINCIPALI ROS

RESVERATROLO UN POrsquo DI CHIAREZZAhellip

MECCANISMO DrsquoAZIONE ONCO-PREVENTIVA

AZIONE ONCO-PREVENTIVA

AZIONE ESTROGENO MODULATRICE

AZIONE ANTI-AGE

FARMACOCINETICA

RESVERATROLO FONTI NATURALI

ATTIVITArsquo

FORMULAZIONE NUTRICEUTICA

CARNOSINA

POSOLOGIA

BIBLIOGRAFIA

GRAZIE PER LrsquoATTENZIONE

POLIFENOLIPOLIFENOLI

I I PolifenoliPolifenoli sono sostanze sono sostanze ubiquitarieubiquitarie nel nel mondo vegetale e rivestono un ruolo mondo vegetale e rivestono un ruolo fondamentale nella difesa della pianta contro fondamentale nella difesa della pianta contro gli agenti patogeni esterni come i gli agenti patogeni esterni come i microrganismimicrorganismi

Sono sostanze con un nucleo di base fenolico Sono sostanze con un nucleo di base fenolico a cui sono legati diversi gruppi chimici che li a cui sono legati diversi gruppi chimici che li rendono una classe molecolare molto rendono una classe molecolare molto eterogenea e variegataeterogenea e variegata

Hanno in comune la caratteristica di essere Hanno in comune la caratteristica di essere riducenti e di riducenti e di chelarechelare ioni metalliciioni metallici

Vengono da tempo impiegati come sostanze Vengono da tempo impiegati come sostanze ad attivitagrave antiossidante e protettiva degli ad attivitagrave antiossidante e protettiva degli endoteli per via sistemica e topicaendoteli per via sistemica e topica

A questa categoria sono annoverati i A questa categoria sono annoverati i FLAVONOIDI e gli ANTOCIANIFLAVONOIDI e gli ANTOCIANI








































































POSOLOGIAPOSOLOGIA






POLIFENOLI


PRINCIPALI ROS





AZIONE ANTI-AGE

FARMACOCINETICA


ATTIVITArsquo


CARNOSINA

POSOLOGIA

BIBLIOGRAFIA









































































POSOLOGIAPOSOLOGIA






POLIFENOLI


PRINCIPALI ROS





AZIONE ANTI-AGE

FARMACOCINETICA


ATTIVITArsquo


CARNOSINA

POSOLOGIA

BIBLIOGRAFIA





POLIFENOLI


PRINCIPALI ROS





AZIONE ANTI-AGE

FARMACOCINETICA


ATTIVITArsquo


CARNOSINA

POSOLOGIA

BIBLIOGRAFIA


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