Source :

http://en.wikipedia.org/wiki/Resveratrol

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Res"eratro
#rom Wikipedia, t!e free enc$c opedia

Resveratrol

Other names[hide] trans-3,5,4'-Trihydroxystilbene; 3,4',5-Stilbenetriol; trans-Resveratrol; (E)-5-(p-Hydroxystyryl)resorcinol (E)-5-(4-hydroxystyryl)ben!ene-",3-diol

Identifiers

#$S n%&ber

5'"-3(-'

)%b#he&

445"54

#he&S*ider

3+,-.5

/011

23(+3-+,(4

5r%67an8

57',.'+

9:;;

#'35-,

#h:71

#H:71<45."3

#h:=74

#H:=74"(5

>&ol-35 i&a6es

1&a6e "

SMILES
[sho?]

InChI
[sho?]

Properties

=olec%lar @or&%la

#"4H",33

=olar &ass

,,-A,4 6 &olB"

:xact &ass

,,-A'.-(44

$**earance

?hite *o?der ?ith sli6ht yello? cast

Sol%bility in ?ater

'A'3 6C4

Sol%bility in 5=S3

"( 6C4

Sol%bility in ethanol

5' 6C4

(veri@y) (?hat is<

C D)

:xce*t ?here noted other?ise, data are 6iven @or &aterials in their standard state (at ,5 E#, "'' 8)a)

1n@obox re@erences

Resveratrol %&,',()*tri!$dro+$*trans*sti bene, is a sti benoid, a t$pe of natura p!eno , and a p!$toa e+in produced natura $ b$ se"era p ants w!en under attack b$ pat!ogens suc! as bacteria orfungi. -!e effects of res"eratro are current $ a topic of numerous anima and !uman studies. Its effects on t!e ifespan of man$ mode organisms remain contro"ersia , wit! uncertain effects in fruit f ies,nematode worms,.1/ and s!ort* i"ed fis!. In mouse and rat e+periments, anticancer, anti*inf ammator$, b ood sugar* owering and ot!er beneficia cardio"ascu ar effects of res"eratro !a"e been reported. -!ese resu ts !a"e $et to be rep icated in !umans. In one positi"e !uman tria , e+treme $ !ig! doses %&0' g, of res"eratro , in a proprietar$ formu ation designed to en!ance its bioa"ai abi it$, significant $ owered b ood sugar. .2/ -!is 21*da$ 2!ase 1b stud$ was conducted pri"ate $ in India b$ p!armaceutica compan$ Sirtris, and was announced at an in"estors conference in 2001..&/ 3owe"er, a t!oug! it !as been a uded to in re"iew artic es, t!e stud$ itse f !as ne"er been pub is!ed in a peer*re"iewed scientific pub ication. 4espite t!e mainstream press a eging res"eratro )s anti*aging effects,.(/ t!ere are no accepted data to form a scientific basis for t!e app ication of t!ese c aims to mamma s %see ife e+tension section be ow,. 5t t!e present time, researc! on res"eratro is in its infanc$ and t!e ong*term effects of supp ementation in !umans are not known. .'/.6/ Res"eratro is found in t!e skin of red grapes and in ot!er fruits. 3owe"er, red wine contains "er$ itt e of it, in t!e order of one mi igram per g ass. Res"eratro !as a so been produced b$ c!emica s$nt!esis .7/ and b$ biotec!no ogica s$nt!esis %metabo ic engineered microorganisms, .1/ and is so d as a nutritiona supp ement deri"ed primari $ from 8apanese knotweed.
Contents
[hide]

" 5iscovery and na&e , Recent st%dies

o o

,A" 4i@e extension ,A, #ancer *revention

,A3 3ther a**lications 3 )har&aco8inetics

3A" $dverse e@@ects and %n8no?ns 3A"A" )ossible carcino6enicity 4 =echanis&s o@ action 5 #he&ical and *hysical *ro*erties ( )lants and @oods

o o

(A" #ontent in ?ines and 6ra*e F%ice (A, #ontent in selected @oods . S%**le&entation

.A" Testosterone - Related co&*o%nds + See also "' Re@erences "" G%rther readin6 ", :xternal lin8s

.edit/4isco"er$

and name

Res"eratro was initia $ mentioned in a 8apanese artic e in 19&9 b$ M. -akaoka, w!o iso ated it from t!e poisonous but medicina Veratrum album, "ariet$ grandiflorum. -!e name presumab $ comes from t!e fact t!at it is a resorcino deri"ati"e coming from a Veratrum species..9/

.edit/Recent .edit/Life

studies

extension

-!e groups of 3owit: and Sinc air reported in 200& in t!e ;ourna Nature t!at res"eratro significant $ e+tends t!e ifespan of t!e $east Saccharomyces cerevisiae..10/ <ater studies conducted b$ Sinc air s!owed t!at res"eratro a so pro ongs t!e ifespan of t!e worm Caenorhabditis elegans and t!e fruit f $ Drosophila melanogaster..11/ In 2007, a different group of researc!ers were ab e to reproduce Sinc air)s resu ts wit! C.

elegans,.12/ but a t!ird group cou d not ac!ie"e consistent increases in ifespan of eit!er D. melanogaster or C. elegans..1/ In 2006, Ita ian scientists obtained t!e first positi"e resu t of res"eratro supp ementation in a "ertebrate. =sing a s!ort* i"ed fis!, Nothobranchius furzeri, wit! a median ife span of nine weeks, t!e$ found a ma+ima dose of res"eratro increased t!e median ifespan b$ '6>. Compared wit! t!e contro fis! at nine weeks, t!at is b$ t!e end of contro fis!)s ife, t!e fis! supp emented wit! res"eratro s!owed significant $ !ig!er genera swimming acti"it$ and better earning to a"oid an unp easant stimu us. -!e aut!ors noted a s ig!t increase of morta it$ in $oung fis! caused b$ res"eratro , and !$pot!esi:ed its weak to+ic action stimu ated t!e defense mec!anisms and resu ted in t!e ife span e+tension. .1&/ <ater t!e same $ear, Sinc air reported res"eratro counteracted t!e detrimenta effects of a !ig!*fat diet in mice. -!e !ig!*fat diet was compounded b$ adding !$drogenated coconut oi to t!e standard diet? it pro"ided 60> of energ$ from fat, and t!e mice on it consumed about &0> more ca ories t!an t!e mice on standard diet and became obese and diabetic. Mice on t!e !ig!*fat diet e+!ibited a !ig! morta it$ rate compared to mice fed t!e standard diet? mice fed t!e !ig!*fat diet p us 22 mg@kg res"eratro !ad a &0> ower risk of deat! t!an t!e mice on t!e !ig!*fat diet a one, making t!eir deat! rates simi ar to t!ose on t!e standard diet. -!e supp ement a so partia $ corrected a subset of t!e abnorma gene e+pressionprofi e and abnorma insu in and g ucose metabo ism. 3owe"er, res"eratro supp ements did not c!ange t!e e"e s of free fatt$ acids and c!o estero , w!ic! were muc! !ig!er t!an in t!e mice on standard diet. .1(/ 5 furt!er stud$ b$ a group of scientists, w!ic! inc uded Sinc air, indicated res"eratro treatment !ad a range of beneficia effects in e der $ mice, but did not increase t!e onge"it$ of ad libitum0fed mice w!en started mid ife..1'/ <ater, t!eAationa Institute on 5ging)s Inter"entions -esting 2rogram %I-2, a so tested t!ree different doses of res"eratro in mice on a norma diet beginning in $oung adu t!ood, and again found no effect on ifespan, e"en at doses roug! $ eig!t times !ig!er t!an t!ose t!at !ad norma i:ed t!e ifespan of t!e !ig!*fat*fed, obese mice in t!e ear ier stud$..16/ 3owe"er, a 2011 stud$ pub is!ed in Aature s!owed t!at t!e benefits demonstrated in pre"ious studies stemmed from errors in contro s..17/

.edit/Cancer

prevention

In 1997, 8ang reported t!at topica res"eratro app ications pre"ented skin cancer de"e opment in mice treated wit! a carcinogen..11/ -!ere !a"e since been man$ studies of t!e anti*cancer acti"it$ of res"eratro in anima mode s..19/ Ao resu ts of !uman c inica tria s for cancer !a"e been reported. .20/ C inica tria s to in"estigate t!e effects on co on cancer and me anoma %skin cancer, are current $ recruiting patients..21/ 3owe"er, t!e stud$ of p!armacokinetics of res"eratro in !umans conc uded e"en !ig! doses of res"eratro mig!t be insufficient to ac!ie"e res"eratro concentrations reBuired for t!e s$stemic pre"ention of cancer..22/ -!is is consistent wit! t!e resu ts from t!e anima cancer mode s, w!ic! indicate t!e in vivo effecti"eness of res"eratro is imited b$ its poor s$stemic bioa"ai abi it$..20/.2&/.2(/ -!e strongest e"idence of anticancer action

of res"eratro e+ists for tumors it can contact direct $, suc! as skin and gastrointestina tract tumors. #or ot!er cancers, t!e e"idence is uncertain, e"en if massi"e doses of res"eratro are used. .20/ -!us, res"eratro %1 mg@kg ora $, reduced t!e number and si:e of t!e esop!agea tumors in rats treated wit! a carcinogen.?.2'/ and in se"era studies, sma doses %0.0201 mg@kg, of res"eratro , gi"en prop!$ actica $, reduced or pre"ented t!e de"e opment of intestina and co on tumors in rats gi"en different carcinogens..20/ Simi ar $, topica app ication of res"eratro in mice, bot! before and after t!e =CD e+posure, in!ibited t!e skin damage and decreased skin cancer incidence. 3owe"er, ora res"eratro was ineffecti"e in treating mice inocu ated wit! me anoma ce s. Res"eratro gi"en ora $ a so !ad no effect on eukemia and ung cancer?.20/.26/ !owe"er, in;ected intraperitonea $, 2.' or 10 mg@kg of res"eratro s owed t!e growt! of metastatic <ewis ung carcinomas in mice..20/.27/ Res"eratro treatment appeared to pre"ent t!e de"e opment of mammar$ tumors in anima mode s? !owe"er, it !ad no effect on t!e growt! of e+isting tumors. 2arado+ica $, treatment of prepuberta mice wit! !ig! doses of res"eratro en!anced formation of tumors. In;ected in !ig! doses into mice, res"eratro s owed t!e growt! of neurob astomas..20/ 5 of t!e aforementioned in vivo studies !a"e been in anima mode s in w!ic! t!e cancer !as been artificia $ induced b$ some e+perimenta means. -!ree ot!er studies !a"e in"estigated t!e effect of res"eratro on t!e risk of cancer in norma mice i"ing out a norma ifespan? a of t!em !a"e found res"eratro supp ementation !as no significant effect on t!e burden of tumors, nor on t!e rate of cancer deat!..1'/.16/.21/

.edit/Other

applications

8o!an 5uwer+ %at t!e Institute of Eenetics and Mo ecu ar and Ce Dio og$ in I kirc!, #rance, and coaut!ors pub is!ed an on ine artic e in t!e ;ourna Cell in Ao"ember, 2006. Mice fed res"eratro for fifteen weeks !ad better treadmi endurance t!an contro s. -!e stud$ supported Sinc air)s !$pot!esis t!at t!e effects of res"eratro are indeed due to t!e acti"ation of t!e Sirtuin 1 gene. Aic!o as Wade)s inter"iew*artic e wit! 4r. 5uwer+ .29/ stated t!e dose was (00 mg@kg of bod$ weig!t %muc! !ig!er t!an t!e 22 mg@kg of t!e Sinc air stud$,. #or an 10 kg %17' b, person, t!e (00 mg@kg of bod$ weig!t amount used in 5uwer+)s mouse stud$ wou d tota &0,000 mg@da$. Compensating for t!e fact t!at !umans !a"e s ower metabo ic rates t!an mice wou d c!ange t!e eBui"a ent !uman dose to roug! $ (000 mg@da$. 5gain, t!ere is no pub is!ed e"idence an$w!ere in t!e scientific iterature of an$ c inica tria for efficac$ in !umans. -!ere are imited !uman safet$ data. <ong*term safet$ !as not been e"a uated in !umans. In a stud$ of 12& #innis! adu ts, t!ose born wit! certain increased "ariations of t!e SIR-1 gene !ad faster metabo isms, !e ping t!em to burn more energ$, indicating t!e same pat!wa$ s!own in t!e ab mice works in !umans..&0/ Aeuroprotecti"e effects: In Ao"ember 2001, researc!ers at t!e Wei Medica Co ege of Corne =ni"ersit$ reported dietar$ supp ementation wit! res"eratro significant $ reduced p aBue formation in anima brains, a component of 5 :!eimer)s disease and ot!er neurodegenerati"e diseases..&1/ In mice, ora res"eratro

produced arge reductions in brain p aBue in t!e !$pot!a amus %*90>,, striatum %*19>,, and media corte+ %*(1>, sections of t!e brain. In !umans, ora doses of res"eratro t!oretica $ ma$ reduce beta am$ oid p aBue associated wit! aging c!anges in t!e brain. Researc!ers t!eori:e t!at one mec!anism for p aBue eradication is t!e abi it$ of res"eratro to c!e ate %bind, copper. -!e neuroprotecti"e effects !a"e been confirmed in se"era anima mode studies..&2/.&&/.&(/.&'/.&6/ 5nti*inf ammator$ effects: -!e anti*inf ammator$ effects of res"eratro !a"e been demonstrated in se"era anima mode studies. In a rat mode of carrageenan*induced paw edema, res"eratro in!ibited bot! acute and c!ronic p!ases of t!e inf ammator$ process..&7/ Simi ar $, preincubation wit! res"eratro decreased arac!idonic acid re ease and CFG*2 induction in mouse peritonea macrop!ages stimu ated wit! tumor promoter 2M5, RFI, or ipopo $sacc!arides %<2S,. .&1/ In an e+perimenta rabbit inf ammator$ art!ritis mode , res"eratro s!owed promise as a potentia t!erap$ for art!ritis. W!en administered to rabbits wit! induced inf ammator$ art!ritis, res"eratro protected carti age against t!e progression of inf ammator$ art!ritis. .&9/ Cardioprotecti"e effects: Moderate drinking of red wine !as ong been known to reduce t!e risk of !eart disease..(0/ -!is is best known as Ht!e #renc! parado+I..(1/.(2/.(&/ Studies suggest res"eratro in red wine ma$ p a$ an important ro e in t!is p!enomenon..((/ It ac!ie"es t!e effects b$ t!e fo owing functions: %1, In!ibition of "ascu ar ce ad!esion mo ecu e e+pression?.('/.(6/ %2, In!ibition of "ascu ar smoot! musc e ce pro iferation?.(7/.(1/.(9/ %&, Stimu ation of endo et!e ia nitric o+ide s$nt!ase %eAFS, 5cti"it$? .'0/.'1/.'2/ %(, In!ibition of p ate et aggregation?.'&/.'(/.''/ %', In!ibition of <4< pero+idation?.'6/.'7/ -!e cardioprotecti"e effects of res"eratro are a so t!eori:ed to be a form of preconditioningJt!e best met!od of cardioprotection, rat!er t!an direct t!erap$..'1/ 5 2011 stud$ .'9/ conc udes, HFur data demonstrate t!at bot! me atonin and res"eratro , as found in red wine, protect t!e !eart in an e+perimenta mode of m$ocardia infarction "ia t!e S5#K pat!wa$.I 5ntidiabetic effects: Studies !a"e s!own res"eratro possesses !$pog $cemic and !$po ipidemic effects in bot! strepto:otocin %S-L,*induced diabetes rats and S-L*nicotinamide*induced diabetes rats. Res"eratro ame iorates common diabetes s$mptoms, suc! as po $p!agia, po $dipsia, and bod$ weig!t oss..60/ Ft!er diabetic anima mode studies b$ different researc!ers !a"e a so demonstrated t!e antidiabetic effects of res"eratro ..&0/.61/.62/.6&/.6(/.6'/.66/ In !uman c inica tria s, res"eratro !as owered b ood sugar e"e s in bot! 2!ase Ib and 2!ase IIa, conducted b$ Sirtris 2!armaceutica s, Inc..67/.61/ 5nti"ira effects: Studies s!ow res"eratro in!ibits !erpes simp e+ "irus %3SC, t$pes 1 and 2 rep ication b$ in!ibition of an ear $ step in t!e "irus rep ication c$c e. In vivo studies in mice found res"eratro in!ibits or reduces 3SC rep ication in t!e "agina and imits e+tra"agina disease. -!e skin of res"eratro *treated anima s s!owed no apparent derma to+icit$, suc! as er$t!ema, sca ing, crusting, ic!enification, or e+coriation..69/.70/.71/ Studies a so s!ow res"eratro in!ibits"arice a*:oster "irus, certain inf uen:a "iruses, respirator$ "iruses, and !uman c$tomega o"irus. #urt!ermore, res"eratro s$nergistica $ en!ances t!e anti*3IC*1 acti"it$ of se"era anti*3IC drugs..72/.7&/.7(/.7'/.76/.77/

.edit/2!armacokinetics

This section has multiple issuesA )lease hel* improve it or disc%ss these iss%es on the talk pageA 1t may contain original researchA Ta66ed since =ay ,'"'A 1ts neutrality is disputedA Ta66ed since =ay ,'"'A

Fne wa$ of administering res"eratro in !umans ma$ be bucca de i"er$, t!at is wit!out swa owing, b$ direct absorption t!roug! t!e inside of t!e mout!. W!en one mi igram of res"eratro in '0 m< '0> a co!o @ water so ution was retained in t!e mout! for one minute before swa owing, &7 ng@m of free res"eratro were measured in p asma two minutes ater. -!is e"e of unc!anged res"eratro in b ood can on $ be ac!ie"ed wit! 2'0 mg of res"eratro taken in a pi form..71/ 3owe"er, t!e "iabi it$ of a bucca de i"er$ met!od is ca ed into Buestion due to t!e ow aBueous so ubi it$ of t!e mo ecu e. #or a drug to be absorbed "ia t!e transmucosa membrane, t!e drug must be in free*form@disso "ed. .79/.10/ Res"eratro fits t!e criteria for ora transmucosa dosing, e+cept for t!is ca"eat. -!e ow aBueous so ubi it$ great $ imits t!e amount t!at can be absorbed t!roug! t!e bucca mucosa , and is w!$ t!e met!od !as not been serious $ e+p ored furt!er. 5 res"eratro t!at is attempted to be taken bucca $ wi fai to pass t!roug! t!e mucous membrane of t!e mout! and be absorbed as an ora dose. .11/ 3owe"er, a need to e+p ore bucca de i"er$ in future p!armasutica formu ations !as been e+pressed..10/.12/ 5bout 70> of t!e res"eratro dose gi"en ora $ as a pi is absorbed? ne"ert!e ess, ora bioa"ai abi it$ of res"eratro is ow because it is rapid $ metabo i:ed in intestines and i"er into con;ugated forms: g ucuronate and su fonate..1&/ Fn $ trace amounts %be ow ' ng@m<, of unc!anged res"eratro cou d be detected in t!e b ood after 2' mg ora dose..1&/ K"en w!en a "er$ arge dose %2.' and ' g, was gi"en as an uncoated pi , t!e concentration of res"eratro in b ood fai ed to reac! t!e e"e c aimed to be necessar$ for t!e s$stemic cancer pre"ention. .22/ 5 formu ation of res"eratro in a c!ewing gum form is now in production, and t!is wou d be e+pected to ac!ie"e muc! !ig!er b ood e"e s t!an ora formu ations. Res"eratro gi"en in a proprietar$ formu ation SR-*'01 %& or ' g,, de"e oped b$ Sirtris 2!armaceutica s, reac!ed fi"e to eig!t times !ig!er b ood e"e s. -!ese e"e s did approac! t!e concentration necessar$ to e+ert t!e effects s!own in anima mode s and in vitro e+periments..2/ 3owe"er, on Ma$ ', 2010, E a+oSmit!M ine %ESM, said it !ad suspended a sma c inica tria of SR-'01, a proprietar$ form of res"eratro , due to safet$ concerns, and terminated t!e stud$ on 4ecember 2, 2010 .C inica -ria s.go" Identifier: AC-00920''6/. Sirtris 2!armaceutica s, w!ic! =.M.*based E a+oSmit!M ine boug!t for N720 mi ion in 2001, was de"e oping t!e drug. E a+oSmit!M ine is now focusing its efforts on more potent and se ecti"e SIR-1 acti"atorsJSR-210( and SR-2&79Jbot! of w!ic! are in"o "ed in se"era e+p orator$ c inica tria s. #u forma p!armacokinetics of ora res"eratro 2000 mg twice dai $ in !umans, stud$ing interaction wit! concurrent et!ano , Buercetin and fat mea !as been pub is!ed. .1(/ Mean peak serum res"eratro concentration was 127( ng@m< at stead$*state, w!ic! was reduced (6> b$ a fat mea at dosing. -!ere was no effect of concurrent ora Buercetin or et!ano . 3ea t!$ "o unteers !ad freBuent $ reported minor diarr!ea, and aborator$ measures identified s ig!t c!anges in i"er function tests, and serum potassium. Ao ad"erse

effect on rena function was identified, a t!oug! on $ eig!t !ea t!$ adu ts were obser"ed in t!e two*week stud$. In !umans.22/.1&/ and rats,.1'/.16/.17/ ess t!an '> of t!e ora dose is being obser"ed as free res"eratro in b ood p asma. -!e most abundant res"eratro metabo ites in !umans, rats, and mice are trans*res"eratro *&*F* g ucuronide and trans*res"eratro *&*su fate. .11/ Wa e suggests su fate con;ugates are t!e primar$ source of acti"it$,.1&/ Wang et a . suggests t!e g ucuronides, .19/ and Doocock et a . a so emp!asi:ed t!e need for furt!er stud$ of t!e effects of t!e metabo ites, inc uding t!e possibi it$ of decon;ugation to free res"eratro inside ce s. Eo dberd, w!o studied t!e p!armacokinetics of res"eratro , catec!in and Buercetin in !umans, conc uded Oit seems t!at t!e potentia !ea t! benefits of t!ese compounds based upon t!e in "itro acti"ities of t!e uncon;ugated compounds are unrea istic and !a"e been great $ e+aggerated. Indeed, t!e profusion of papers describing suc! acti"ities can egitimate $ be described as irre e"ant and mis eading. 3encefort!, in"estigations of t!is nature s!ou d focus upon t!e potentia !ea t! benefits of t!eir g ucuronide and su fate con;ugates.O.90/ -!e !$pot!esis t!at res"eratro from wine cou d !a"e !ig!er bioa"ai abi it$ t!an res"eratro from a pi
.91/ .19/

!as been refuted b$ e+perimenta data..90/.92/ #or e+amp e, after fi"e men took 600 m< of red wine wit!

t!e res"eratro content of &.2 mg@< %tota dose about 2 mg, before breakfast, unc!anged res"eratro was detected in t!e b ood of on $ two of t!em, and on $ in trace amounts %be ow 2.' ng@m<,. Res"eratro e"e s appeared to be s ig!t $ !ig!er if red wine %600 m< of red wine containing 0.6 mg@m< res"eratro ? tota dose about 0.' mg, was taken wit! mea : trace amounts %106 ng@m<, were found in four out of ten sub;ects..92/ In anot!er stud$, t!e p!armacokinetics of res"eratro %2' mg, did not c!ange w!et!er it was taken wit! "egetab e ;uice, w!ite wine or w!ite grape ;uice. -!e !ig!est e"e of unc!anged res"eratro in t!e serum %709 ng@m<, was ac!ie"ed after &0 minutes, and it comp ete $ disappeared from b ood after four !ours..90/ -!e aut!ors of bot! studies conc uded t!e trace amounts of res"eratro reac!ed in t!e b ood are insufficient to e+p ain t!e #renc! parado+. -!e beneficia effects of wine apparent $ cou d be e+p ained b$ t!e effects of a co!o .90/ or t!e w!o e comp e+ of substances wine contains? .92/ for e+amp e, t!e cardio"ascu ar benefits of wine appear to corre ate wit! t!e content of proc$anidins..9&/

.edit/Adverse

effects and unknowns

<ong*term effects of using res"eratro are as of $et unknown. .'/ Fne stud$ !as t!eori:ed it ma$ stimu ate t!e growt! of !uman breast cancer ce s, possib $ because of res"eratro )s c!emica structure, w!ic! is simi ar to a p!$toestrogen..6/.9(/3owe"er, ot!er studies !a"e found res"eratro intake is in"erse $ associated wit! breast cancer risk, and acts to s ow t!e progression of breast cancer t!at !as been transp anted into mice..9'/.96/ Some studies suggest res"eratro s ows t!e de"e opment of b ood "esse s, w!ic! suppresses tumors, but a so s ows !ea ing..97/ Citing t!e e"idence t!at res"eratro is estrogen antagonistic, some retai ers of res"eratro ad"ise t!at t!e compound ma$ interfere wit! ora contracepti"es and t!at women w!o are pregnant or intending to become pregnant s!ou d not use t!e product, w!i e ot!ers ad"ise t!at res"eratro s!ou d not be taken b$ c!i dren or $oung adu ts under 11, as no studies !a"e s!own !ow it

affects t!eir natura de"e opment. 5 sma stud$ found a sing e dose of up to ' g of trans*res"eratro caused no serious ad"erse effects in !ea t!$ "o unteers. .22/

.edit/Possible carcinogenicity
Res"eratro in common wit! ot!er po $p!eno s, was found to be a strong topoisomerase in!ibitor, s!aring simi arities to c!emot!erapeutic anticancer drugs, suc! as etoposide and do+orubicin..91/.99/ -!is ma$ simu taneous $ contribute to bot! t!e potentia anticarcinogenic and carcinogenic properties of t!e substance in gi"en circumstances. 3armfu properties of res"eratro ma$ be pronounced in t!e !uman fetus, as it !as diminis!ed deto+ification s$stems. -!erefore, res"eratro as common $ so d combined wit! ot!er Obiof a"onoidsO, s!ou d be not used b$ pregnant women..100/

.edit/Mec!anisms

of action

See Calorie restriction#Sir2.2 SI!"# and resveratrol for the details of the debate on resveratrol$ calorie restriction and life e%tension. -!e mec!anisms of res"eratro )s apparent effects on ife e+tension are not fu $ understood, but t!e$ appear to mimic se"era of t!e bioc!emica effects of ca orie restriction. Some studies indicates res"eratro acti"ates Sirtuin 1 %SIR-1,.101/and 2EC*1P and impro"es t!e functioning of t!e mitoc!ondria..&0/ Ft!er researc! ca s into Buestion t!e t!eor$ connecting res"eratro , SIR-1, and ca orie restriction. .102/.10&/ In addition res"eratro )s abi it$ to direct $ acti"ate sirtuin 1 !as been ca ed into Buestion. .10&/.10(/.10'/ 5 paper b$ Robb et al. discusses res"eratro action in ce s. It reports a fourteen*fo d increase in t!e action of MnSF4 %SF42,..106/ MnSF4 reduces supero+ide to !$drogen pero+ide %32F2,, but 32F2 is not increased due to ot!er ce u ar acti"it$. Supero+ide F2* is a b$product of respiration in comp e+es 1 and & of t!e e ectron transport c!ain. It is Onot !ig! $ to+ic, .but/ can e+tract an e ectron from bio ogica membrane and ot!er ce components, causing free radica c!ain reactions. -!erefore it is essentia for t!e ce to keep supero+ide anions in c!eck.O.107/ MnSF4 reduces supero+ide and t!ereb$ confers resistance to mitoc!ondria d$sfunction, permeabi it$ transition, and apoptotic deat! in "arious diseases..101/ It !as been imp icated in ifespan e+tension, in!ibits cancer, %e.g. pancreatic cancer .109/.110/, and pro"ides resistance to reperfusion in;ur$ and irradiation damage..111/.112/.11&/ -!ese effects !a"e a so been obser"ed wit! res"eratro . Robb et a . propose MnSF4 is increased b$ t!e pat!wa$ RKSC Q SIR-1 @ A54R Q #FGF&a Q MnSF4. Res"eratro !as been s!own to cause SIR-1 to cause migration of #FGF transcription factors to t!e nuc eus.11(/ w!ic! stimu ates #FGF&a transcriptiona acti"it$ .11'/ and it !as been s!own to en!ance t!e sirtuin*cata $:ed deacet$ ation %acti"it$, of #FGF&a. MnSF4 is known to be a target of #FGF&a, and MnSF4 e+pression is strong $ induced in ce s o"ere+pressing #FGF&a. .116/ Res"eratro interferes wit! a t!ree stages of carcinogenesisJinitiation, promotion and progression. K+periments in ce cu tures of "aried t$pes and iso ated subce u ar s$stems in vitro imp $ man$ mec!anisms in t!e p!armaco ogica acti"it$ of res"eratro . -!ese mec!anisms inc ude modu ation of t!e transcription factor A#*SD,.117/ in!ibition of t!e c$toc!rome 2('0 isoen:$me CT2151.111/ %a t!oug! t!is ma$ not be re e"ant to t!e CT2151*mediated bioacti"ation of t!e procarcinogen ben:o%a,p$rene.119/,,

a terations in androgenic.120/ actions and e+pression and acti"it$ of c$c oo+$genase %CFG, en:$mes. In "itro, res"eratro Oin!ibited t!e pro iferation of !uman pancreatic cancer ce ines.O In some ineages of cancer ce cu ture, res"eratro !as been s!own to induce apoptosis, w!ic! means it ki s ce s and ma$ ki cancer ce s..120/.121/.122/.12&/.12(/.12'/ Res"eratro !as been s!own to induce #as@#as igand mediated apoptosis, p'& and c$c ins5, D1 and c$c in*dependent kinases cdk 1 and 2. Res"eratro a so possesses antio+idant and anti*angiogenic properties..97/.126/.127/ Res"eratro was reported to be effecti"e against neurona ce d$sfunction and ce deat!, and, in t!eor$, cou d be effecti"e against diseases suc! as 3untington)s disease and 5 :!eimer)s disease..121/.129/ 5gain, t!is !as not $et been tested in !umans for an$ disease. Researc! at t!e Aort!eastern F!io =ni"ersities Co ege of Medicine and F!io State =ni"ersit$ indicated res"eratro !as direct in!ibitor$ action on cardiac fibrob asts, and ma$ in!ibit t!e progression of cardiac fibrosis..1&0/ Res"eratro a so significant $ increases natura testosterone production from being bot! a se ecti"e estrogen receptor modu ator.1&1/.1&2/ and an aromatase in!ibitor..1&&/.1&(/ In 4ecember 2007, work from Irfan Ra!man)s aborator$ at t!e =ni"ersit$ of Roc!ester demonstrated res"eratro increased intrace u ar g utat!ione e"e s "ia Arf2*dependent upregu ation of gamma* g utam$ c$steine igase in ung epit!e ia ce s, w!ic! protected t!em against cigarette smoke e+tract* induced o+idati"e stress..1&'/ 5not!er potentia $ important mec!anism common to bot! res"eratro supp ementation and ca oric restriction is t!e modu ation of autop!ag$.1&6/ SIR-1 is a !$pot!esi:ed target of bot! res"eratro and ca oric restriction, and !as been s!own to faci itate autop!ag$ t!roug! t!e in!ibition of m-FR, w!ic! itse f negati"e $ regu ates autop!ag$..1&7/

.edit/C!emica

and p!$sica properties

Res"eratro %&,',()*tri!$dro+$sti bene, is a sti benoid, a deri"ate of sti bene. It e+ists as two geometric isomers: cis& %', and trans& %(,, wit! t!e trans*isomer s!own in t!e top image. -!e trans* and cis*res"eratro can be eit!er free or bound to g ucose. .1&1/ -!e trans& form can undergo isomerisation to t!e cis& form w!en e+posed to u tra"io et irradiation..1&9/ "rans*res"eratro in t!e powder form was found to be stab e under Oacce erated stabi it$O conditions of 7'> !umidit$ and (0UC in t!e presence of air..1(0/ Res"eratro content a so was stab e in t!e skins of grapes and pomace taken after fermentation and stored for a ong period..1(1/ 3* and 1&C*AMR data for t!e four most common forms of res"eratro s are reported in iterature..1&1/

.edit/2

ants and foods

Res"eratro is produced in p ants wit! t!e !e p of t!e en:$me res"eratro s$nt!ase.

Res"eratro was origina $ iso ated b$ -akaoka from t!e roots of !e ebore in 19(0, and ater, in 196&, from t!e roots of 8apanese knotweed. 3owe"er, it attracted wider attention on $ in 1992, w!en its presence in wine was suggested as t!e e+p anation for cardioprotecti"e effects of wine. .19/ In grape, trans*res"eratro is a p!$toa e+in produced against t!e growt! of funga pat!ogens suc! as )otrytis cinerea..1(2/ Its presence in Vitis vinifera grapes can a so be constituti"e, wit! accumu ation in ripe berries of different e"e s of bound and free res"eratro s, according to t!e genot$pe. .1(&/ In grapes, res"eratro is found primari $ in t!e skin,.1((/ and, in muscadine grapes, a so in t!e seeds..1('/ -!e amount found in grape skins a so "aries wit! t!e grape cu ti"ar, its geograp!ic origin, and e+posure to funga infection. -!e amount of fermentation time a wine spends in contact wit! grape skins is an important determinant of its res"eratro content..1&1/.1((/ -!e e"e s of res"eratro found in food "aries great $. Red wine contains between 0.2 and '.1 mg@<,
.1(6/

depending on t!e grape "ariet$, w!i e w!ite wine !as muc! ess, because red wine is fermented wit!

t!e skins, a owing t!e wine to e+tract t!e res"eratro , w!ereas w!ite wine is fermented after t!e skin !as been remo"ed..1((/.1(7/ -!e composition of wine is different from t!at of grape since t!e e+traction of res"eratro s from grape depends on t!e duration of t!e skin contact, and t!e res"eratro &*g ucosides are in part !$dro ised, $ie ding bot! trans* and cis*res"eratro ..1&1/ 5 number of reports !a"e indicated muscadine grapes ma$ contain !ig! concentrations of res"eratro , and t!at wines produced from t!ese grapes, bot! red and w!ite, ma$ contain more t!an (0 mg@<..1('/.1(1/ 3owe"er, subseBuent studies !a"e found itt e or no res"eratro in different "arieties of muscadine grapes. .1(9/.1'0/ -!e fruit of t!e mu berr$ %esp. t!e skin,.1'1/ is a source, and so d as a nutritiona supp ement. Cocoa powder, baking c!oco ate and dark c!oco ate a so !a"e ow e"e s of res"eratro in norma consumption Buantities %0.&' to 1.1' mg@kg,..1'2/

.edit/Content everage

in wines and grape juice

Total resveratrol !mg"L#["44]["45] Total resveratrol !mg"$%&mL#["44]["45]

Red ?ine (6lobal)

"A+- - .A"3

'A3' - "A'.

Red ?ine (S*anish)

"A+, - ",A5+

'A,+ - "A-+

Red 6ra*e F%ice (S*anish) "A"4 - -A(+

'A". - "A3'

Rose ?ine (S*anish)

'A43 - 3A5,

'A'( - 'A53

)inot noir

'A4' - ,A'

'A'( - 'A3'

Hhite ?ine (S*anish)

'A'5 - "A-'

'A'" - 'A,.

-!e trans*res"eratro concentration in (0 -uscan wines ranged from 0.& to 2.1 mg@< in t!e &2 red wines tested and !ad a ma+imum of 0.1 mg@< in t!e 1 w!ite wines in t!e test. Dot! t!e cis* and trans*isomers of res"eratro were detected in a tested samp es. cis*Res"eratro e"e s were comparab e to t!ose of t!e trans*isomer. -!e$ ranged from 0.' mg@< to 1.9 mg@< in red wines and !ad a ma+imum of 0.2 mg@< in w!ite wines..1'&/ In a re"iew of pub is!ed res"eratro concentrations, t!e a"erage in red wines is 1.9 V 1.7 mg trans* res"eratro @< %1.2 V 7.' WM,, ranging from nondetectab e e"e s to 1(.& mg@< %62.7 WM, trans*res"eratro . <e"e s of cis*res"eratro fo ow t!e same trend as trans*res"eratro ..1'(/ Reports suggest some aspect of t!e wine making process con"erts piceid to res"eratro in wine, as wine seems to !a"e twice t!e a"erage res"eratro concentration of t!e eBui"a ent commercia ;uices. .1('/ In genera , wines made from grapes of t!e 2inot Aoir and St. <aurent "arieties s!owed t!e !ig!est e"e of trans*res"eratro , t!oug! no wine or region can $et be said to produce wines wit! significant $ !ig!er concentrations t!an an$ ot!er wine or region. .1'(/

.edit/Content 'ood

in selected foods
Serving Total resveratrol !mg#["5,]["55]

)ean%ts (ra?)

" c ("4( 6) 'A'" - 'A,(

)ean%ts (boiled) " c ("-' 6) 'A3, - "A,-

)ean%t b%tter

" c (,5- 6) 'A'4 - 'A"3

Red 6ra*es

" c ("(' 6) 'A,4 - "A,5

#ocoa *o?der

" c (,'' 6) 'A,- - 'A4(

Funce for ounce, peanuts !a"e about !a f as muc! res"eratro as red wine. -!e a"erage amount in peanuts in t!e marketp ace is 79.( Xg@ounce. In comparison, some red wines contain appro+imate $ 160 Xg@f uid ounce..1'6/ Res"eratro was detected in grape, cranberr$, and wine samp es. Concentrations ranged from 1.'6 to 10(2 nmo @g in Concord grape products, and from 1.6& to 2(.1( Xmo @< in Ita ian red wine. -!e concentrations of res"eratro were simi ar in cranberr$ and grape ;uice at 1.07 and 1.'6 nmo @g, respecti"e $. .1'7/

D ueberries !a"e about twice as muc! res"eratro as bi berries, but t!ere is great regiona "ariation. -!ese fruits !a"e ess t!an 10> of t!e res"eratro of grapes. Cooking or !eat processing of t!ese berries wi contribute to t!e degradation of res"eratro , reducing it b$ up to !a f. .1'1/

.edit/Supp

ementation

5s a resu t of e+tensi"e news co"erage,.1'9/.160/ sa es of supp ements great $ increased in 2006. .161/ -!is was despite t!e e+istence of studies cautioning t!at benefits to !umans are unpro"en. .161/.162/.16&/ Supp ements "ar$ in purit$, and can contain an$w!ere from '0 percent to 99 percent res"eratro . Man$ brands consist of an unpurified e+tract of 8apanese knotweed? t!ese contain about '0 percent res"eratro b$ weig!t, as we as emodin, w!ic!, w!i e considered safe in moderate Buantities, can !a"e a a+ati"e effect in !ig! amounts..16(/ 3ar"ard =ni"ersit$ scientist 2rofessor 4a"id Sinc air is often Buoted in on ine ads. Sinc air, w!o !as studied res"eratro e+tensi"e $, !as gone on record in )loomberg )usiness*ee+ to sa$ !e ne"er uttered man$ of t!e statements attributed to !im on t!ese sites..16'/

.edit/Testosterone
5 Morean stud$ s!owed t!at trans*res"eratro supp ementation increased testosterone e"e s in men in vivo,.166/ w!ic! !as ed to its marketing as a bod$bui ding supp ement. 5 Spanis! stud$ !as a so s!own t!e antio+idant to increase sperm production in rats..167/

.edit/Re

ated compounds

Kpsi on*"iniferin and 2a ido , two different res"eratro dimers -rans*diptoindonesin D, a res"eratro trimer 3opeap!eno , a res"eratro tetramer 2iceatanno , an acti"e metabo ite of res"eratro found in red wine 2iceid, a res"eratro g ucoside 2terosti bene, a doub $ met!$ ated res"eratro

.edit/See

a so

Pharmacy and Pharmacology portal

8apanese knotweed <ist of grape "arieties Mu berr$

 .edit/References

Muscadine 2terosti bene, a sti benoid c!emica $ re ated to res"eratro 2!eno ic compounds in wine 2roant!oc$anidin 2o $p!eno antio+idant Wine and !ea t!

1. Y a b Dass -M, Weinko"e 4, 3out!oofd M, Eems 4, 2artridge < %Fctober

2007,. OKffects of res"eratro on ifespan in 4rosop!i a me anogaster and Caenor!abditis e egansO. ,echanisms of -geing and Development !"%10,: '(60 '2. doi:10.1016@;.mad.2007.07.007. 2MI4 1717'&1'. 2. Y a b K iott 28, 8irousek M %5pri 2001,. OSirtuins: no"e targets for metabo ic diseaseO. Current .pinion in Investigational Drugs # %(,: &710 1.2MI4 11&9&10(. &. $ Sirtris 5nnounces 2ositi"e Resu ts wit! 2roprietar$ Cersion of Res"eratro , SR-'01, in a 2!ase 1b -$pe 2 4iabetes C inica Stud$, Dusiness Wire, 8an 7, 2001

4. $ O2!arma seeks genetic c ues to !ea t!$ agingO. !euters. 6 5pri 2010. 5. Y a b -!e Connecticut 2ost, OSe ing res"eratro : Wonder drug or snake
oi Z,O 01@0(@2009, b$ Me issa 3ea $ for t!e <os 5nge es -imes news ser"ice 6. Y a b Ee!m D4, Mc5ndrews 8M, C!ien 2T, 8ameson 8< %4ecember 1997,.ORes"eratro , a po $p!eno ic compound found in grapes and wine, is an agonist for t!e estrogen receptorO. /roceedings of the National -cademy of Sciences of the 0nited States of -merica #% %2',: 1(1&10 (&.doi:10.107&@pnas.9(.2'.1(1&1. 2MC 21((6. 2MI4 9&91166. 7. $ #arina 5, #erranti C, Marra C %2006,. O5n impro"ed s$nt!esis of res"eratro O.Nat. /rod. !es. !& %&,: 2(70 '2. doi:10.1010@1(716(10'000'9'&2.2MI4 16(01'''.

1.

$ -rantas K, 2anopou os A, Cer"eridis # %2009,. OMetabo ic engineering of t!e comp ete pat!wa$ eading to !etero ogous bios$nt!esis of "arious f a"onoids and sti benoids in Saccharomyces cerevisiaeO. ,etab. (ng. %6,: &''0

&66. doi:10.1016@;.$mben.2009.07.00(. 2MI4 196&1271. 9. $ Sc!r[der, 8oac!im %Marc! 6, 2010,. O4isco"er$ of res"eratro O.!esveratrol..self&published source1/ 10. $ 3owit: M-, Ditterman M8, Co!en 3T, et al. %September 200&,. OSma mo ecu e acti"ators of sirtuins e+tend Sacc!arom$ces cere"isiae ifespanO. Nature %!' %69'(,: 1910 6. doi:10.10&1@nature01960.2MI4 129&9617. 11. $ Wood 8E, Rogina D, <a"u S, et al. %5ugust 200(,. OSirtuin acti"ators mimic ca oric restriction and de a$ ageing in meta:oansO. Nature %(& %7000,: 6160 9. doi:10.10&1@nature02719. 2MI4 1'2'(''0. 12. $ Eruber 8, -ang ST, 3a iwe D %5pri 2007,. OK"idence for a trade*off between sur"i"a and fitness caused b$ res"eratro treatment of Caenor!abditis e egansO. -nnals of the Ne* 2or+ -cademy of Sciences &&: '&00(2. doi:10.1196@anna s.1&9'.0'9. 2MI4 17(60219.

1&. $ Ca en:ano 4R, -er:ibasi K, Eenade -, Cattaneo 5, 4omenici <, Ce erino 5 %#ebruar$ 2006,. ORes"eratro pro ongs ifespan and retards t!e onset of age*re ated markers in a s!ort* i"ed "ertebrateO. Current )iology ) %&,: 2960 &00. doi:10.1016@;.cub.200'.12.0&1. 2MI4 16(6121&.

14. $ Daur 85, 2earson M8, 2rice A<, et al. %Ao"ember 2006,. ORes"eratro
impro"es !ea t! and sur"i"a of mice on a !ig!*ca orie dietO. Nature %%%%7117,: &&70 (2. doi:10.10&1@nature0'&'(. 2MI4 17016191.

15. Y a b 2earson M8, Daur 85, <ewis MA, et al. %5ugust 2001,. ORes"eratro
de a$s age*re ated deterioration and mimics transcriptiona aspects of dietar$ restriction wit!out e+tending ife spanO. Cell ,etabolism " %2,: 1'7061. doi:10.1016@;.cmet.2001.06.011. 2MC 2'&161'. 2MI4 11'99&6 &.

16. Y a b Mi er R5, 3arrison 4K, 5st e CM, et al. %Fctober 2' 2010,. ORapam$cin, Dut Aot Res"eratro or Sim"astatin, K+tends <ife Span of Eenetica $ 3eterogeneous Mice.O. 3 4erontol a )iol Sci ,ed Sci. )) %2,: 1910 201.doi:10.109&@gerona@g B171. 2MC &021&72. 2MI4 2097(7&2. 17. $ !ttp:@@news.$a!oo.com@ onge"it$*gene*ma$*dead*end*stud$* 22'72'611.!tm

18. $ 8ang M, Cai <, =deani EF, S owing MC, -!omas C#, Deec!er CW,
#ong 33, #arnswort! AR, Ming!orn 54, Me!ta RE, Moon RC, 2e::uto 8M %1997,. OCancer c!emopre"enti"e acti"it$ of res"eratro , a natura product deri"ed from grapesO. Science !*' %'297,: 2110 20.doi:10.1126@science.27'.'297.211. 2MI4 191'016.

19. Y a b c Daur 85, Sinc air 45 %2006,. O-!erapeutic potentia of res"eratro :

t!e in "i"o e"idenceO. Nat !ev Drug Discov ' %6,: (9&0 '06. doi:10.10&1@nrd2060.2MI4 167&2220. 20. Y a b c d e f g 5t!ar M, Dack 83, -ang G, et al. %Ao"ember 2007,. ORes"eratro : a re"iew of prec inica studies for !uman cancer pre"entionO. "o%icology and -pplied /harmacology !!% %&,: 27(0 1&.doi:10.1016@;.taap.2006.12.02'. 2MC 201&12&. 2MI4 17&06&16.

21. $ Res"eratro . #rom C inica tria s.go". Retrie"ed 5ugust 1', 2001.
22. Y a b c d Doocock 48, #aust EK, 2ate MR, et al. %8une 2007,. O2!ase I dose esca ation p!armacokinetic stud$ in !ea t!$ "o unteers of res"eratro , a potentia cancer c!emopre"enti"e agentO. Cancer (pidemiology$ )iomar+ers 5 /revention ) %6,: 12(60 '2. doi:10.11'1@10''*996'.K2I*07*0022.2MI4 17'(1692. 2&. $ Ai es RM, Cook C2, Meadows EE, #u TM, Mc<aug! in 8<, Rankin EF %Fctober 2006,. ORes"eratro is rapid $ metabo i:ed in at!$mic %nu@nu, mice and does not in!ibit !uman me anoma +enograft tumor growt!O. "he 3ournal of Nutrition () %10,: 2'(20 6. 2MC 1612'12. 2MI4 1691112&. 2(. $ Wen:e K, So do -, Krbersdob er 3, Somo:a C %Ma$ 200',. ODioacti"it$ and metabo ism of trans*res"eratro ora $ administered to Wistar ratsO. ,ol Nutr ood !es %# %',: (120 9(. doi:10.1002@mnfr.200'0000&.2MI4 1'779067.

2'. $ <i LE, 3ong -, S!imada T, Momoto I, Mawabe 5, 4ing T, Maganoi 8, 3as!imoto T, Imamura M %2002,. OSuppression of A* nitrosomet!$ ben:$ amine %AMD5,*induced esop!agea tumorigenesis in #&(( rats b$ res"eratro O. Carcinogenesis !( %9,: 1'&10 6.doi:10.109&@carcin@2&.9.1'&1. 2MI4 12119197. 26. $ Eao G, Gu TG, 4i"ine E, 8anakiraman A, C!apman R5, Eautam SC %8u $ 2002,. O4isparate in "itro and in "i"o anti eukemic effects of res"eratro , a natura po $p!eno ic compound found in grapesO. "he 3ournal of Nutrition (! %7,: 2076011. 2MI4 12097696. 27. $ Mimura T, Fkuda 3 %8une 2001,. ORes"eratro iso ated from 2o $gonum cuspidatum root pre"ents tumor growt! and metastasis to ung and tumor*induced neo"ascu ari:ation in <ewis ung carcinoma*bearing miceO. "he 3ournal of Nutrition ( %6,: 11((09. 2MI4 11&1'077. 21. $ Darger 8<, Ma$o -, Cann 8M, et al. %8une 2001,. -om\, 4anie . ed. O5 ow dose of dietar$ res"eratro partia $ mimics ca oric restriction and retards aging parameters in miceO. /6oS .ne ( %6,: e226(.doi:10.1&71@;ourna .pone.000226(. 2MC 2&16967. 2MI4 11'2&'7 7.

29. $ Wade, Aic!o as %Ao"ember 16, 2006,. ORed Wine Ingredient Increases
Kndurance, Stud$ S!owsO. Ne* 2or+ "imes. &0. Y a b c <agouge M, 5rgmann C, Eer!art*3ines L, et al. %4ecember 2006,. ORes"eratro impro"es mitoc!ondria function and protects against metabo ic disease b$ acti"ating SIR-1 and 2EC*1a p!aO. Cell !* %6,: 1109022.doi:10.1016@;.ce .2006.11.01&. 2MI4 17112'76. &1. $ Maruppagounder SS, 2into 8-, Gu 3, C!en 3<, Dea M#, Eibson EK %#ebruar$ 2009,. O4ietar$ supp ementation wit! res"eratro reduces p aBue pat!o og$ in a transgenic mode of 5 :!eimer)s diseaseO. Neurochemistry International '% %2,: 1110 1. doi:10.1016@;.neuint.2001.10.001.2MC 2192907. 2MI4 190(1676. &2. $ 5nekonda -S %September 2006,. ORes"eratro **a boon for treating 5 :!eimer)s diseaseZO. )rain !esearch !evie*s '! %2,: &160 26.doi:10.1016@;.brainresre".2006.0(.00(. 2MI4 167660&7. &&. $ S!arma M, Eupta TM %Fctober 2002,. OC!ronic treatment wit! trans res"eratro pre"ents intracerebro"entricu ar strepto:otocin induced

cogniti"e impairment and o+idati"e stress in ratsO. 6ife Sciences * %21,: 2(19091.doi:10.1016@S002(*&20'%02,0201&*0. 2MI4 122707'(. &(. $ Mumar 2, 2adi SS, Aaidu 2S, Mumar 5 %September 2006,. OKffect of res"eratro on &*nitropropionic acid*induced bioc!emica and be!a"ioura c!anges: possib e neuroprotecti"e mec!anismsO. )ehavioural /harmacology * %'06,: (1'092. doi:10.1097@00001177*200609000* 0001(. 2MI4 169(0769. &'. $ Tang TD, 2iao T8 %8u $ 200&,. OKffects of res"eratro on secondar$ damages after acute spina cord in;ur$ in ratsO. -cta /harmacologica Sinica!% %7,: 70&010. 2MI4 121'21&9. &6. $ Sin!a M, C!aud!ar$ E, Eupta TM %8une 2002,. O2rotecti"e effect of res"eratro against o+idati"e stress in midd e cerebra arter$ occ usion mode of stroke in ratsO. 6ife Sciences * %6,: 6''0 6'. doi:10.1016@S002(*&20'%02,01691*0. 2MI4 120721'(. &7. $ Eenti i M, Ma:oit 8G, Doua:i: 3, et al. %#ebruar$ 2001,. ORes"eratro decreases !$pera gesia induced b$ carrageenan in t!e rat !ind pawO. 6ife Sciences )" %11,: 1&17021. doi:10.1016@S002(* &20'%00,01011*&.2MI4 112&&991. &1. $ -sai S3, <in*S!iau ST, <in 8M %#ebruar$ 1999,. OSuppression of nitric o+ide s$nt!ase and t!e down*regu ation of t!e acti"ation of A#kappaD in macrop!ages b$ res"eratro O. )ritish 3ournal of /harmacology !) %&,: 67&010. doi:10.10&1@s;.b;p.0702&'7. 2MC 1'6'162. 2MI4 10111971. &9. $ K ma i A, Da$sa F, 3arma 5, Ksenka$a I, Mi:rak D %5pri 2007,. OKffects of res"eratro in inf ammator$ art!ritisO. Inflammation (& %102,: 10 6.doi:10.1007@s107'&*006*9012*0. 2MI4 1711'116. (0. $ S:mitko, 2. K.? Cerma, S %200',. ORed Wine and Tour 3eartO. Circulation %2,:

e10. doi:10.1161@01.CIR.00001'1601.29217.62.2MI4 1'6'7&77. (1. $ #erri]res 8 %8anuar$ 200(,. O-!e #renc! parado+: essons for ot!er countriesO. 7eart #& %1,: 1070 11. doi:10.11&6@!eart.90.1.107.2MC 176101&. 2MI4 1(676260.

(2. $ Simini, D %2000,. OSerge Renaud: from #renc! parado+ to Cretan mirac eO."he 6ancet ('' %9197,: (1. doi:10.1016@S01(0*67&6%0',71990* '.2MI4 1061'191. (&. $ Renaud S, de <orgeri M %8une 1992,. OWine, a co!o , p ate ets, and t!e #renc! parado+ for coronar$ !eart diseaseO. 6ancet ((# %1101,: 1'2&0 6.doi:10.1016@01(0*67&6%92,91277*#. 2MI4 1&'1191. ((. $ Mopp 2 %8une 1991,. ORes"eratro , a p!$toestrogen found in red wine. 5 possib e e+p anation for t!e conundrum of t!e )#renc! parado+)ZO. (uropean 3ournal of (ndocrinology (" %6,: 6190 20. doi:10.1'&0@e;e.0.1&10619.2MI4 9671'2'. ('. $ #errero MK, Derte i 5K, #u gen:i 5, et al. %4ecember 1991,. O5cti"it$ in "itro of res"eratro on granu oc$te and monoc$te ad!esion to endot!e iumO. "he -merican 3ournal of Clinical Nutrition )" %6,: 12010 1(. 2MI4 91(61(1. (6. $ Rotondo S, Ra;tar E, Manarini S, et al. %5pri 1991,. OKffect of trans* res"eratro , a natura po $p!eno ic compound, on !uman po $morp!onuc ear eukoc$te functionO. )ritish 3ournal of /harmacology !( %1,: 16910 9.doi:10.10&1@s;.b;p.070171(. 2MC 1'6'&&1. 2MI4 960''77. (7. $ 3aider =E, Roos -=, Montaridis MI, et al. %8u $ 200',. ORes"eratro in!ibits angiotensin II* and epiderma growt! factor*mediated 5kt acti"ation: ro e of Eab1 and S!p2O. ,olecular /harmacology )" %1,: (10 1.doi:10.112(@mo .10(.00'(21. 2MI4 1'1(9&''. (1. $ Wang L, C!en T, <abinsk$$ A, 3sie! -C, =ng"ari L, Wu 8M %8u $ 2006,. ORegu ation of pro iferation and gene e+pression in cu tured !uman aortic smoot! musc e ce s b$ res"eratro and standardi:ed grape e+tractsO.)iochemical and )iophysical !esearch Communications (%) %1,: &670 76.doi:10.1016@;.bbrc.2006.0'.1'6. 2MI4 167'96(0. (9. $ 2oussier D, Cordo"a 5C, DecBuemin 82, Sumpio DK %4ecember 200',. ORes"eratro in!ibits "ascu ar smoot! musc e ce pro iferation and induces apoptosisO. 3ournal of Vascular Surgery %! %6,: 11900 7.doi:10.1016@;.;"s.200'.01.01(. 2MI4 16&7621&.

'0. $ 4uff$ S8, Cita 85 %#ebruar$ 200&,. OKffects of p!eno ics on "ascu ar endot!e ia functionO. Current .pinion in 6ipidology % %1,: 210 7.doi:10.1097@01.mo .00000'21'7.262&6.f2 %inacti"e 2010*01* 10,.2MI4 12'((6'7. '1. $ Wa erat!, -.? 4eckert, E? -ernes, -? 5nderson, 3? <i, 3? Witte, M? #[rstermann, = %2002,. ORes"eratro , a 2o $p!eno ic 2!$toa e+in 2resent in Red Wine, Kn!ances K+pression and 5cti"it$ of Kndot!e ia Aitric F+ide S$nt!aseO. Circulation &) %1&,: 16'20 1.doi:10.1161@01.CIR.000002992'.11'9&.'C. 2MI4 122701'1. '2. $ C!en CM, 2ace*5sciak CR %Marc! 1996,. OCasore a+ing acti"it$ of res"eratro and Buercetin in iso ated rat aortaO. 4eneral /harmacology !* %2,: &6&06. doi:10.1016@0&06*&62&%9',02001* 2. 2MI4 19196'7. '&. $ F as D, Wac!owic: D %5ugust 200',. ORes"eratro , a p!eno ic antio+idant wit! effects on b ood p ate et functionsO. /latelets ) %',: 2'10 60.doi:10.1010@09'&7100(00020'91. 2MI4 1601197'. '(. $ Stef E, Csis:ar 5, <erea M, =ng"ari L, Ceress E %5ugust 2006,. ORes"eratro in!ibits aggregation of p ate ets from !ig!*risk cardiac patients wit! aspirin resistanceO. 3ournal of Cardiovascular /harmacology %" %2,: 10 '.doi:10.1097@01.f;c.00002&1'92.67191.ab. 2MI4 169'(11(. ''. $ Wang L, Lou 8, 3uang T, Cao M, Gu T, Wu 8M %Marc! 2002,. OKffect of res"eratro on p ate et aggregation in "i"o and in "itroO. Chinese ,edical 3ournal ' %&,: &71010. 2MI4 119(0&69.

'6. $ #r\mont <, De guendou: <, 4e pa S %1999,. O5ntio+idant acti"it$ of res"eratro and a co!o *free wine po $p!eno s re ated to <4< o+idation and po $unsaturated fatt$ acidsO. 6ife Sciences )% %26,: 2'110 21.doi:10.1016@S002(*&20'%99,00209*G. 2MI4 10(0&'11. '7. $ =ng"ari L, Fros: L, Ri"era 5, et al. %Ma$ 2007,. ORes"eratro increases "ascu ar o+idati"e stress resistanceO. -merican 3ournal of /hysiology. 7eart and Circulatory /hysiology !#! %',: 32(170 2(.doi:10.11'2@a;p!eart.012'1.2006. 2MI4 17220179.

'1. $ 4as 4M, Mau ik A %#ebruar$ 2006,. ORes"eratro in cardioprotection: a t!erapeutic promise of a ternati"e medicineO. ,olecular Interventions ) %1,: &60(7. doi:10.112(@mi.6.1.7. 2MI4 16'077(9. '9. $ <amont, Mim -.? Sarin Somers, <$dia <acerda, <ione 3. Fpie, Sandrine <ecour %2011,. OIs red wine a S5#K sip awa$ from cardioprotectionZ Mec!anisms in"o "ed in res"eratro * and me atonin* induced cardioprotectionO. 3ournal of /ineal !esearch '& %(,: &7(0 &10.doi:10.1111@;.1600*079G.2010.001'&.+. ISSA 07(2*&091.2MI4 21&( 22(7. 60. $ Su, 3.*C.? 3ung, <M? C!en, 8M %2006,. ORes"eratro , a red wine antio+idant, possesses an insu in* ike effect in strepto:otocin*induced diabetic ratsO.-3/8 (ndocrinology and ,etabolism !#& %6,: K1&&9.doi:10.11'2@a;pendo.00(17.200'. 2MI4 16(&(''&. 61. $ Daur, 8osep! 5.? 2earson, Me"in 8.? 2rice, Aat!an <.? 8amieson, 3amis! 5.? <erin, Car es? Ma ra, 5"as!? 2rab!u, Cina$akumar C.? 5 ard, 8oanne S. et a . %2006,. ORes"eratro impro"es !ea t! and sur"i"a of mice on a !ig!*ca orie dietO. Nature %%% %7117,: &&70 (2. doi:10.10&1@nature0'&'(.2MI4 17016191. 62. $ 4eng, 8.*T.? 3sie!, 2.*S.? 3uang, 8.*2.? <u, <.*S.? 3ung, <.*M. %2001,.O5cti"ation of Kstrogen Receptor Is Crucia for Res"eratro * Stimu ating Muscu ar E ucose =ptake "ia Dot! Insu in*4ependent and *Independent 2at!wa$sO. Diabetes '* %7,: 111(02&. doi:10.2&&7@db07* 17'0.2MC 2('&6&6. 2MI4 11(2616'. 6&. $ 2a sam$, 2? Subramanian, S %2001,. ORes"eratro , a natura p!$toa e+in, norma i:es !$perg $cemia in strepto:otocin*nicotinamide induced e+perimenta diabetic ratsO. )iomedicine 5 /harmacotherapy )! %9,: '910 60'. doi:10.1016@;.biop!a.2001.06.0&7. 2MI4 1167''&2. 6(. $ S!arma S, 5n;ane$u u M, Mu karni SM, C!opra M %2006,. ORes"eratro , a po $p!eno ic p!$toa e+in, attenuates diabetic nep!ropat!$ in ratsO./harmacology *) %2,: 690 7'. doi:10.11'9@000019720. 2MI4 16216109. 6'. $ Sc!mat: R, Ma::anti CM, Spane"e o R, et al. %Ma$ 2009,. ORes"eratro pre"ents memor$ deficits and t!e increase in

acet$ c!o inesterase acti"it$ in strepto:otocin*induced diabetic ratsO. (uropean 3ournal of /harmacology) & %10&,: (20 1. doi:10.1016@;.e;p!ar.2009.0&.0&2. 2MI4 19&0&(06. 66. $ 2enumat!sa SC, -!iruna"ukkarasu M, L!an <, et al. %4ecember 2001,. ORes"eratro en!ances E<=-*( trans ocation to t!e ca"eo ar ipid raft fractions t!roug! 5M2M@5kt@eAFS signa ing pat!wa$ in diabetic m$ocardiumO. 3ournal of Cellular and ,olecular ,edicine ! %65,: 2&'00 61.doi:10.1111@;.1'12*(9&(.2001.002'1.+. 2MI4 11266911. 67. $ OSirtris 5nnounces SR-'01 <owers E ucose in -wice*4ai $ 4osing C inica -ria ? Stud$ Suggests 4ose Response for 2roprietar$ #ormu ation of Res"eratro in -$pe 2 4iabeticsO %2ress re ease,. Sirtris 2!armaceutica s. 5pri 17, 2001. Retrie"ed 5ugust 9, 2010. 61. $ OSirtris Continues to <ead -!e Wa$ In Res"eratro Dased Researc!O. M$ Res"eratro K+perience. 2009*0(*10. Retrie"ed 2011*01*22. 69. $ 4oc!ert$ 88, #u MM, Stiff er DS, <imperos R8, 2okab a CM, 4e<ucia 5< %Fctober 1999,. ORes"eratro in!ibition of !erpes simp e+ "irus rep icationO.-ntiviral !esearch %( %&,: 1('0''. 2MI4 10''1&7&. 70. $ 4oc!ert$ 88, #u MM, 3a! 8M, Sweet -8, #ait! S5, Doot! - %September 200',. OKffect of res"eratro on !erpes simp e+ "irus "agina infection in t!e mouseO. -ntiviral !esearch )* %&,: 1''0 62.doi:10.1016@;.anti"ira .200'.06.001. 2MI4 1612'2'1. 71. $ 4oc!ert$ 88, Smit! 8S, #u MM, Stoner -, Doot! - %8anuar$ 200(,. OKffect of topica $ app ied res"eratro on cutaneous !erpes simp e+ "irus infections in !air ess miceO. -ntiviral !esearch ) %1,: 190 26.doi:10.1016@;.anti"ira .200&.07.001. 2MI4 1(670'90. 72. $ 4oc!ert$ 88, Sweet -8, Dai e$ K, #ait! S5, Doot! - %4ecember 2006,. ORes"eratro in!ibition of "arice a*:oster "irus rep ication in "itroO. -ntiviral !esearch *! %&,: 1710 7. doi:10.1016@;.anti"ira .2006.07.00(.2MI4 16199&06. 7&. $ Euan W4, Tang L#, <iu A, ^in S, L!ang #G, L!u T- %September 2001,. O.In "itro e+perimenta stud$ on t!e effect of res"eratro against se"era kinds of respiro"iruses/O %in C!inese,. 'hong 2ao Cai ( %9,: 1&11090.2MI4 19110966.

7(. $ 2a amara 5-, Aencioni <, 5Bui ano M, et al. %Ma$ 200',. OIn!ibition of inf uen:a 5 "irus rep ication b$ res"eratro O. "he 3ournal of Infectious Diseases # %10,: 1719029. doi:10.1016@(2969(. 2MI4 1'1&1100. 7'. $ <i T^, <i L<, L!ao W8, Wen RG, Meng ^W, Leng T %September 2006,. OS$nt!esis of sti bene deri"ati"es wit! in!ibition of S5RS corona"irus rep icationO. (uropean 3ournal of ,edicinal Chemistry % %9,: 101(0 9.doi:10.1016@;.e;mec!.2006.0&.02(. 2MI4 1617'760. 76. $ K"ers 4<, Wang G, 3uong SM, 3uang 4T, 3uang KS %5ugust 200(,. O&,(),'*-ri!$dro+$*trans*sti bene %res"eratro , in!ibits !uman c$tomega o"irus rep ication and "irus*induced ce u ar signa ingO. -ntiviral !esearch )( %2,: 1'0 9'. doi:10.1016@;.anti"ira .200(.0&.002. 2MI4 1'&021&7. 77. $ 3eredia 5, 4a"is C, Redfie d R %Ao"ember 2000,. OS$nergistic in!ibition of 3IC*1 in acti"ated and resting perip!era b ood mononuc ear ce s, monoc$te*deri"ed macrop!ages, and se ected drug*resistant iso ates wit! nuc eoside ana ogues combined wit! a natura product, res"eratro O. 3ournal of -c9uired Immune Deficiency Syndromes !' %&,: 2(60''.doi:10.1097@00126&&(*200011010*00006. 2MI4 1111'9''. 71. $ 5sensi M, Medina I, Frtega 5, et al. %5ugust 2002,. OIn!ibition of cancer growt! b$ res"eratro is re ated to its ow bioa"ai abi it$O. ree !adical )iology 5 ,edicine (( %&,: &17091. doi:10.1016@S0191*'1(9%02,00911* '.2MI4 12126761.

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82. $ Aew de i"er$ s$stems to impro"e t!e bioa"ai abi it... .K+pert Fpin 4rug
4e i". 2011/ * 2ubMed resu t 1&. Y a b c d Wa e -, 3sie! #, 4e<egge M3, Fatis 8K, Wa e =M %4ecember 200(,. O3ig! absorption but "er$ ow bioa"ai abi it$ of ora res"eratro in

!umansO. Drug ,etabolism and Disposition (! %12,: 1&770 12.doi:10.112(@dmd.10(.00011'. 2MI4 1'&&&'1(. 1(. $ Stead$*State 2!armacokinetics and -o erabi it$ of -rans*Res"eratro 2000 mg -wice 4ai $ wit! #ood, ^uercetin and 5 co!o %Kt!ano , in 3ea t!$ 3uman Sub;ects. C inica 2!armacokinetics: 1 8u $ 2010 * Co ume (9 * Issue 7 * pp ((9*('( doi: 10.216'@11'&1120*000000000* 00000_!ttp:@@www.ncbi.n m.ni!.go"@pubmed@20'2100' 1'. $ Marier 8#, Cac!on 2, Eritsas 5, L!ang 8, Moreau 82, 4uc!arme M2 %8u $ 2002,. OMetabo ism and disposition of res"eratro in rats: e+tent of absorption, g ucuronidation, and entero!epatic recircu ation e"idenced b$ a inked*rat mode O. "he 3ournal of /harmacology and (%perimental "herapeutics (&! %1,: &690 7&. doi:10.112(@;pet.102.0&&&(0.2MI4 1206'7&9. 16. $ 5bd K *Mo!sen M, Da$e e 3, Mu!n e E, et al. %8u $ 2006,. O4istribution of .&3/trans*res"eratro in rat tissues fo owing ora administrationO. "he )ritish 3ournal of Nutrition #) %1,: 620 70. doi:10.1079@D8A20061110.2MI4 16169992. 17. $ Wen:e K, So do -, Krbersdob er 3, Somo:a C %Ma$ 200',. ODioacti"it$ and metabo ism of trans*res"eratro ora $ administered to Wistar ratsO. ,olecular Nutrition 5 ood !esearch %# %',: (120 9(. doi:10.1002@mnfr.200'0000&.2MI4 1'779067. 11. $ Tu C, S!in TE, C!ow 5, et al. %4ecember 2002,. O3uman, rat, and mouse metabo ism of res"eratro O. /harmaceutical !esearch # %12,: 190701(.doi:10.102&@5:1021(1(129210. 2MI4 12'2&67&.

89. $ Wang <G, 3eredia 5, Song 3, et al. %Fctober 200(,. ORes"eratro

g ucuronides as t!e metabo ites of res"eratro in !umans: c!aracteri:ation, s$nt!esis, and anti*3IC acti"it$O. 3ournal of /harmaceutical Sciences #( %10,: 2((10 '7. doi:10.1002@;ps.201'6. 2MI4 1'&(99''. 90. Y a b c d Eo dberg 4M, Tan 8, So eas E8 %#ebruar$ 200&,. O5bsorption of t!ree wine*re ated po $p!eno s in t!ree different matrices b$ !ea t!$ sub;ectsO.Clinical )iochemistry () %1,: 79017. doi:10.1016@S0009* 9120%02,00&97*1.2MI4 12''(06'.

91. $ Wen:e K, Somo:a C %Ma$ 200',. OMetabo ism and bioa"ai abi it$ of
trans*res"eratro O. ,olecular Nutrition 5 ood !esearch %# %',: (720 11.doi:10.1002@mnfr.200'00010. 2MI4 1'779070. 92. Y a b c Citag ione 2, Sfor:a S, Ea a"erna E, et al. %Ma$ 200',. ODioa"ai abi it$ of trans*res"eratro from red wine in !umansO. ,olecular Nutrition 5 ood !esearch %# %',: (9'0 '0(. doi:10.1002@mnfr.200'00002.2MI4 1'1&0&&6. 9&. $ Corder R, Mu en W, M!an A^, et al. %Ao"ember 2006,. OFeno og$: red wine proc$anidins and "ascu ar !ea t!O. Nature %%% %7119,: '66.doi:10.10&1@((('66a. 2MI4 171&601'. 9(. $ Dowers 8<, -$u menko" CC, 8ernigan SC, M inge CM %Fctober 2000,. ORes"eratro acts as a mi+ed agonist@antagonist for estrogen receptors a p!a and betaO. (ndocrinology % %10,: &6'70 67. doi:10.1210@en.1(1.10.&6'7.2MI4 1101(220. 9'. $ <e"i #, 2asc!e C, <ucc!ini #, E!idoni R, #erraroni M, <a Cecc!ia C %5pri 200',. ORes"eratro and breast cancer riskO. (uropean 3ournal of Cancer /revention % %2,: 1&90(2. doi:10.1097@00001(69*200'0(000* 00009.2MI4 1'71'&17.

96. $ Ear"in S, F inger M, 4abrosin C %8anuar$ 2006,. ORes"eratro induces

apoptosis and in!ibits angiogenesis in !uman breast cancer +enografts in "i"oO. Cancer 6etters !( %1,: 11&0 22. doi:10.1016@;.can et.200'.01.0&1.2MI4 16&'61&6. 97. Y a b Dr`ken!ie m K, Cao R, Cao T %5ugust 2001,. OSuppression of angiogenesis, tumor growt!, and wound !ea ing b$ res"eratro , a natura compound in red wine and grapesO. "he -S() 3ournal ' %10,: 17910 100.doi:10.1096@f;.01*0021f;e. 2MI4 11(112&(. 91. $ <eone, S.? Cornetta, -.? Dasso, K.? Co::i, R. %Sep 2010,. ORes"eratro induces 4A5 doub e*strand breaks t!roug! !uman topoisomerase II interactionO. Cancer 6ett !#' %2,: 1670 72.doi:10.1016@;.can et.2010.02.022. 2MI4 20&0(''&. 99. $ 8o, 8T.? Eon:a e: de Me;ia, K.? <i a, M5. %Mar 2006,. OCata $tic in!ibition of !uman 4A5 topoisomerase II b$ interactions of grape ce cu ture po $p!eno sO. 3 -gric ood Chem '% %6,: 201&0 7. doi:10.1021@;f0'2700:.2MI4 16'&6'79.

100. $ 2ao ini, M.? Sapone, 5.? Ca gimig i, <. %8un 200&,. O5"oidance of biof a"onoid supp ements during pregnanc$: a pat!wa$ to infant eukemiaZO. ,utat !es'!* %102,: 990101. 2MI4 12717911. 101. $ 5 caan #8, Ci a ba 8M %5pri 2009,. OSirtuin acti"atorsO. (%pert .pinion on "herapeutic /atents # %(,: (0&0 1(. doi:10.1'17@1&'(&77090276219&.2MI4 19((192&.

102.

$ Maeber ein M, Mirk and M-, #ie ds S, Menned$ DM %September

200(,. OSir2*independent ife span e+tension b$ ca orie restriction in $eastO. /los )iology ! %9,: K296. doi:10.1&71@;ourna .pbio.0020296. 2MC '1((91.2MI4 1'&21'(0. 10&.Y a b Maeber ein M, Mc4onag! -, 3e tweg D, et al. %5pri 200',. OSubstrate*specific acti"ation of sirtuins b$ res"eratro O. "he 3ournal of )iological Chemistry !"& %17,: 170&10 ('. doi:10.107(@;bc.M'006''200.2MI4 1'61((1&. 10(. $ De!er 4, Wu 8, Cumine S, et al. %4ecember 2009,. ORes"eratro is not a direct acti"ator of SIR-1 en:$me acti"it$O. Chemical )iology 5 Drug Design *%%6,: 61902(. doi:10.1111@;.17(7* 021'.2009.00901.+. 2MI4 191(&076. 10'. $ 2ac!o ec M, D easda e 8K, C!run$k D, et al. %Marc! 2010,. OSR-1720, SR-211&, SR-1(60, and res"eratro are not direct acti"ators of SIR-1O."he 3ournal of )iological Chemistry !"' %11,: 1&(00 '1.doi:10.107(@;bc.M109.011612. 2MC 21&291(. 2MI4 20061&71. 106. $ Robb K<, 2age MM, Wiens DK, Stuart 85 %Marc! 2001,. OMo ecu ar mec!anisms of o+idati"e stress resistance induced b$ res"eratro : Specific and progressi"e induction of MnSF4O. )iochemical and )iophysical !esearch Communications ()* %2,: (060 12.doi:10.1016@;.bbrc.2007.12.1&1. 2MI4 11167&10. 107. $ Radbk, Lso t %2000,. ree radicals in e%ercise and aging. C!ampaign, I<: 3uman Minetics. p. &9. ISDA 971*0*11011*111*1. 101. $ Macmi an*Crow <5, Crut!irds 4< %5pri 2001,. OIn"ited re"iew: manganese supero+ide dismutase in diseaseO. ree !adical !esearch (% %(,: &2'0 &6.doi:10.1010@1071'760100&00211. 2MI4 11&21670.

109. $ Cu en 88, We$dert C, 3ink!ouse MM, et al. %Marc! 200&,. O-!e ro e of manganese supero+ide dismutase in t!e growt! of pancreatic adenocarcinomaO. Cancer !esearch )( %6,: 12970&0&. 2MI4 126(9190. 110. $ OMounting e"idence s!ows red wine antio+idant ki s cancerO %2ress re ease,. =ni"ersit$ of Roc!ester Medica Center. Marc! 26, 2001. Retrie"ed 5ugust 10, 2010. 111. $ Sun 8, #o k 4, Drad e$ -8, -ower 8 %8une 2002,. OInduced o"ere+pression of mitoc!ondria Mn*supero+ide dismutase e+tends t!e ife span of adu t 4rosop!i a me anogasterO. 4enetics ) %2,: 6610 72. 2MC 1(621&'.2MI4 12072(6&. 112. $ 3u 4, Cao 2, -!ie s K, et al. %Marc! 2007,. O3ippocampa ong*term potentiation, memor$, and onge"it$ in mice t!at o"ere+press mitoc!ondria supero+ide dismutaseO. Neurobiology of 6earning and ,emory "* %&,: &720 1(. doi:10.1016@;.n m.2006.10.00&. 2MC 11(7&21.2MI4 171297&9. 11&. $ Wong E3 %Ma$ 199',. O2rotecti"e ro es of c$tokines against radiation: induction of mitoc!ondria MnSF4O. )iochimica et )iophysica -cta !* %1,: 20'09. 2MI4 7'99209. 11(. $ Stefani M, Markus M5, <in RC, 2inese M, 4awes IW, Morris D8 %Fctober 2007,. O-!e effect of res"eratro on a ce mode of !uman agingO. -nnals of the Ne* 2or+ -cademy of Sciences 11.doi:10.1196@anna s.1&96.001. 2MI4 1710('21. 11'. $ Drunet 5, Sweene$ <D, Sturgi 8#, et al. %Marc! 200(,. OStress* dependent regu ation of #FGF transcription factors b$ t!e SIR-1 deacet$ aseO. Science(&( %'666,: 20110 '. doi:10.1126@science.109(6&7. 2MI4 1(97626(. 116. $ Mops E8, 4ansen -D, 2o derman 2K, et al. %September 2002,. O#ork!ead transcription factor #FGF&a protects Buiescent ce s from o+idati"e stressO.Nature % # %690(,: &160 21. doi:10.10&1@nature010&6. 2MI4 122&9'72. 117. $ <eiro 8, 5rran: 85, #rai: A, Sanmartan M<, ^ue:ada K, Fra o # %#ebruar$ 200',. OKffect of cis*res"eratro on genes in"o "ed in nuc ear factor kappa D signa ingO. International Immunopharmacology ' %2,: &9&0 (06.doi:10.1016@;.intimp.200(.10.006. 2MI4 1'6'2761. %: (070

111. $ C!un T8, Mim MT, Euengeric! #2 %5ugust 1999,. ORes"eratro is a se ecti"e !uman c$toc!rome 2('0 151 in!ibitorO. )iochemical and )iophysical !esearch Communications !)! %1,: 200 (. doi:10.1006@bbrc.1999.11'2.2MI4 10((1061.

119.

$ Sc!war: 4, Roots I %5pri 200&,. OIn "itro assessment of in!ibition

b$ natura po $p!eno s of metabo ic acti"ation of procarcinogens b$ !uman CT2151O.)iochemical and )iophysical !esearch Communications (&( %&,: 90207.doi:10.1016@S0006*291G%0&,00(&'* 2. 2MI4 12670(96. 120.Y a b Denite: 45, 2o:o*Euisado K, 5 "are:*Darrientos 5, #ernande:* Sa guero 2M, Caste cn K5 %2007,. OMec!anisms in"o "ed in res"eratro * induced apoptosis and ce c$c e arrest in prostate cancer*deri"ed ce inesO. 3ournal of -ndrology !" %2,: 2120 9&. doi:10.216(@;andro .106.000961.2MI4 170'0717. 121. $ #aber 5C, C!i es -C %4ecember 2006,. ORes"eratro induces apoptosis in transformed fo icu ar $mp!oma FCI*<T1 ce s: e"idence for a no"e mec!anism in"o "ing in!ibition of DC<6 signa ingO. International 3ournal of .ncology !# %6,: 1'6106. 2MI4 17011997. 122. $ Ri es W<, Krickson 8, Aa$$ar S, 5tten M8, 5ttar DM, 3o ian F %September 2006,. ORes"eratro engages se ecti"e apoptotic signa s in gastric adenocarcinoma ce sO. :orld 3ournal of 4astroenterology ! %&',: '6210&(. 2MI4 1700701(. 12&. $ Sareen 4, "an Einke 2R, -akac! 8C, et al. %September 2006,. OMitoc!ondria as t!e primar$ target of res"eratro *induced apoptosis in !uman retinob astoma ce sO. Investigative .phthalmology 5 Visual Science%* %9,: &701016. doi:10.1167@io"s.06*0119. 2MI4 169&6077. 12(. $ -ang 3T, S!i! 5, Cao 38, 4a"is #D, 4a"is 28, <in 3T %5ugust 2006,. ORes"eratro *induced c$c oo+$genase*2 faci itates p'&*dependent apoptosis in !uman breast cancer ce sO. ,olecular Cancer "herapeutics ' %1,: 20&(0(2. doi:10.11'1@1'&'*716&.MC-*06* 0216. 2MI4 1692112(. 12'. $ 5:i: M3, Ai!a M, #u CG, 8arrard 4#, 5!mad A %Ma$ 2006,. ORes"eratro *caused apoptosis of !uman prostate carcinoma <ACa2 ce s is mediated "ia modu ation of p!osp!atid$ inosito &)*kinase@5kt

pat!wa$ and Dc *2 fami $ proteinsO. ,olecular Cancer "herapeutics ' %',: 1&&'0(1. doi:10.11'1@1'&'*716&.MC-*0'*0'26. 2MI4 167&1767. 126. $ Cao T, #u L4, Wang #, <iu 3T, 3an R %8une 200',. O5nti*angiogenic acti"it$ of res"eratro , a natura compound from medicina p antsO. 3ournal of -sian Natural /roducts !esearch * %&,: 20'0 1&.doi:10.1010@10216020(10001690190. 2MI4 1'621621. 127. $ 3ung <M, C!en 8M, 3uang SS, <ee RS, Su M8 %5ugust 2000,. OCardioprotecti"e effect of res"eratro , a natura antio+idant deri"ed from grapesO. Cardiovascular !esearch %* %&,: '(90''. doi:10.1016@S0001* 6&6&%00,00102*(. 2MI4 1096&727. 121. $ 2arker 85, 5rango M, 5bderra!mane S, et al. %5pri 200',. ORes"eratro rescues mutant po $g utamine c$toto+icit$ in nematode and mamma ian neuronsO. Nature 4enetics (* %(,: &(90 '0. doi:10.10&1@ng1'&(.2MI4 1'79&'19. 129. $ Marambaud 2, L!ao 3, 4a"ies 2 %Ao"ember 200',. ORes"eratro promotes c earance of 5 :!eimer)s disease am$ oid*beta peptidesO. "he 3ournal of )iological Chemistry !"& %(',: &7&770 12. doi:10.107(@;bc.M'012(6200.2MI4 16162'02. 1&0. $ F son KR, Aaug e 8K, L!ang G, Domser 85, Mes:aros 8E %Marc! 200',. OIn!ibition of cardiac fibrob ast pro iferation and m$ofibrob ast differentiation b$ res"eratro O. -merican 3ournal of /hysiology. 7eart and Circulatory /hysiology !"" %&,: 311&10 1. doi:10.11'2@a;p!eart.0076&.200(.2MI4 1'(9112(. 1&1. $ 8uan MK, Eon:b e:*2ons K, Munuera -, Da ester 8, Rodrague:*Ei 8K, 2 anas 8M %5pri 200',. Otrans*Res"eratro , a natura antio+idant from grapes, increases sperm output in !ea t!$ ratsO. "he 3ournal of Nutrition (' %(,: 7'7060. 2MI4 1'79'(&0. 1&2. $ D!at M2, <ant"it 4, C!risto" M, Me!ta RE, Moon RC, 2e::uto 8M %Fctober 2001,. OKstrogenic and antiestrogenic properties of res"eratro in mammar$ tumor mode sO. Cancer !esearch ) %20,: 7('60 6&. 2MI4 11606&10. 1&&. $ Wang T, <ee MW, C!an #<, C!en S, <eung <M %8u $ 2006,. O-!e red wine po $p!eno res"eratro disp a$s bi e"e in!ibition on aromatase in

breast cancer ce sO. "o%icological Sciences #! %1,: 710 7.doi:10.109&@to+sci@kf;190. 2MI4 16611627. 1&(. $ <eder DL, Ro!rer 8<, Rubin S4, Ea o 8, <ongcope C %Marc! 200(,. OKffects of aromatase in!ibition in e der $ men wit! ow or border ine* ow serum testosterone e"e sO. "he 3ournal of Clinical (ndocrinology and ,etabolism"# %&,: 117(010. doi:10.1210@;c.200&* 0&1(67. 2MI4 1'00160'. 1&'. $ Mode 5, Ra;endraso:!an S, Caito S, Tang SR, Megson I<, Ra!man I %Marc! 2001,. ORes"eratro induces g utat!ione s$nt!esis b$ acti"ation of Arf2 and protects against cigarette smoke*mediated o+idati"e stress in !uman ung epit!e ia ce sO. -merican 3ournal of /hysiology. 6ung Cellular and ,olecular /hysiology !#% %&,: <(710 11.doi:10.11'2@a;p ung.00&61.2007. 2MI4 11162601. 1&6. $ E!os! 3S, McDurne$ M, Robbins 24, Robbins 2au 4. %2010,. D agosk onn$, Mik!ai C.. ed. OSIR-1 Aegati"e $ Regu ates t!e Mamma ian -arget of Rapam$cinO. /6oS .N( ' %2,: e9199.doi:10.1&71@;ourna .pone.0009199. 2MC 2121(10. 2MI4 2016916 '.

137.

$ Kugenia Morse i, <oren:o Ea u::i, F i"er Mepp, 5 fredo Crio o,

Maria C!iara Maiuri, Aektarios -a"ernarakis(, #rank Madeo', and Euido Mroemer %2009, 5utop!ag$ mediates p!armaco ogica ifespan e+tension b$ spermidine and res"eratro . 5ging %1,12 1&1.Y a b c d Matti"i #., Reniero #., Mor!ammer S. %199',. OIso ation, c!aracteri:ation, and e"o ution in red wine "inification of res"eratro monomersO. 3 -gric ood Chem. %( %7,: 11200 &.doi:10.1021@;f000''a01&. 1&9. $ <amue a*Ra"entos, Rosa M.? Romero*2ere:, 5na I.? Water!ouse, 5ndrew <.? 4e <a -orre*Doronat, M. Carmen %199',. O4irect 32<C 5na $sis of cis* and trans*Res"eratro and 2iceid Isomers in Spanis! Red Citis "inifera WinesO. 3ournal of -gricultural and ood Chemistry %( %2,: 211.doi:10.1021@;f000'0a00&. 1(0. $ 2rokop 8, 5brman 2, Se igson 5<, So"ak M %2006,. ORes"eratro and its g $con piceid are stab e po $p!eno sO. 3ournal of ,edicinal ood # %1,: 110(.doi:10.1019@;mf.2006.9.11. 2MI4 16'79722.

1(1. $ Derte i 55, Eo::ini 5, Stradi R, Ste a S, Derte i 5 %1991,. OStabi it$ of res"eratro o"er time and in t!e "arious stages of grape transformationO.Drugs under (%perimental and Clinical !esearch !% %(,: 207011.2MI4 100'1967. 1(2. $ O-!e ro e of grape po $p!eno s on trans*res"eratro acti"it$ against Dotr$tis cinerea and of funga accase on t!e so ubi it$ of putati"e grape 2R proteins, #. #a"aron, M. <ucc!etta, S. Fdori::i, 5.-. 2ais da Cun!a and <. Se a, 8ourna of 2 ant 2at!o og$ %2009,, 91 %&,, '79*'11, 2009 '79O %24#,. Retrie"ed 2011*01*22.

143.

$ Eatto 2., Cr!o"sek =., Mut! 8., Sega a C., Romua di C., #ontana

2., 2ruefer 4., Stefanini M., Moser C., Matti"i #. and Ce asco R. %2001,. ORipening and genot$pe contro sti bene accumu ation in !ea t!$ grapesO. 3 -gric ood Chem. ') %2(,: 1177&0 1'. doi:10.1021@;f1017707. 2MI4 190&2022.

144.

Y a b c d e Ro$, 3., <und$, S., Res"eratro , 2ennington Autrition

Series, 200' Ao. 7 1('.Y a b c d e <eD anc, Mark Rene %1& 4ecember 200',. OCu ti"ar, 8uice K+traction, = tra Cio et Irradiation and Storage Inf uence t!e Sti bene Content of Muscadine Erapes %Citis Rotundifo ia Mic!+.,O. Retrie"ed 2007*01*1'. 1(6. $ Eu G, Creas$ <, Mester 5, Leece M %5ugust 1999,. OCapi ar$ e ectrop!oretic determination of res"eratro in winesO. 3 -gric ood Chem. %* %1,: &22&07.doi:10.1021@;f911211e. 2MI4 10''26&'. 1(7. $ Matti"i #. %199&,. OSo id p!ase e+traction of trans*res"eratro from wines for 32<C ana $sisO. 'eitschrift f;r 6ebensmittel& 0ntersuchung und orschung #) %6,: '220'. doi:10.1007@D#01201&&1. 2MI4 1&21217. 1(1. $ Kctor D8, Magee 8D, 3egwood C2, Coign M8., Res"eratro Concentration in Muscadine Derries, 8uice, 2omace, 2urees, Seeds, and Wines. 1(9. $ 2astrana*Doni a K, 5ko! CC, Se appan S, Mrewer E %5ugust 200&,. O2!eno ic content and antio+idant capacit$ of muscadine grapesO. 3. -gric. ood Chem. ' %11,: '(970 '0&. doi:10.1021@;f0&011&c.2MI4 1292690(. OContrar$ to pre"ious resu ts, e agic acid and not res"eratro was t!e ma;or p!eno ic in

muscadine grapes. -!e 32<C so "ent s$stem used coup ed wit! f uorescence detection a owed separation of e agic acid from res"eratro and detection of res"eratro .O O.-/rans*res"eratro !ad t!e owest concentrations of t!e detected p!eno ics, ranging from not detected in two "arieties to 0.2 mg@ 100 g of #W %-ab es 1 and 2,. Fur resu t for res"eratro differed from pre"ious resu ts .Kctor et a ., 1996/ indicating !ig! concentrations. -!ese researc!ers apparent $ were not ab e to separate e agic acid from res"eratro wit! =C detection a one.O 1'0. $ 3udson -S, 3art e 4M, 3ursting S4, et al. %September 2007,. OIn!ibition of prostate cancer growt! b$ muscadine grape skin e+tract and res"eratro t!roug! distinct mec!anismsO. Cancer !es. )* %17,: 1&960 (0'.doi:10.11'1@0001*'(72.C5A*06*(069. 2MI4 1710(7'6. OMSMK .muscadine grape skin e+tract/ does not contain significant Buantities of res"eratro and differs from MSKK. -o determine w!et!er MSMK contains significant e"e s of res"eratro and to compare t!e c!emica content of MSMK %skin, wit! MSKK %seed,, 32<C ana $ses were done. 5s depicted in Supp ementar$ #ig. S15 and D, MSMK does not contain significant amounts of res"eratro %d1 Zg@g b$ imit of detection,.O

151.

$ Stewart 8R, 5rtime MC, F)Drian C5 %1 8u $ 200&,. ORes"eratro : a

candidate nutritiona substance for prostate cancer pre"entionO. 3 Nutr. (( %7 Supp ,: 2((0S02((&S. 2MI4 121(0221. 1'2.Y a b W. 8effre$ 3urst, 8an 5. E inski, Mennet! D. Mi er, 8oan 5pgar, Matt!ew 3. 4a"e$ and 4a"id 5. Stuart %2001,. OSur"e$ of t!e trans* Res"eratro and trans*2iceid Content of Cocoa*Containing and C!oco ate 2roductsO. 3. -gric. ood Chem. ') %11,: 1&7(0 1&71. doi:10.1021@;f101297w.2MI4 117'9((&.

153.

$ Mo::on, M. %1996,. ORes"eratro content in some -uscan

winesO. Ital. 3. ood sci. %C!iriotti, 2inero o, I-5<IK, " %2,: 1('0'2. Retrie"ed 2007*06*11. 1'(.Y a b Ster"bo, =.? Cang, F.? Donnesen, C. %2007,. O5 re"iew of t!e content of t!e putati"e c!emopre"enti"e p!$toa e+in res"eratro in red wineO. ood Chemistry & %2,: ((90 '7. doi:10.1016@;.foodc!em.2006.01.0(7.

1''. $ 3igdon, 8ane? 4rake, Cictoria 8.? Steward, Wi iam 2. %Ma$ 2001,.ORes"eratro O. ,icronutrient Information Center. <inus 2au ing Institute. 1'6. $ ORes"eratro In 2eanutsO. <ids ood for "hought %-!e 2eanut Institute, %(,. 1999. 5rc!i"ed from t!e origina on 5ugust 2(, 2000.
.unreliable source1/

1'7. $ Wang T, Catana #, Tang T, Roderick R, "an Dreemen RD %8anuar$ 2002,. O5n <C*MS met!od for ana $:ing tota res"eratro in grape ;uice, cranberr$ ;uice, and in wineO. 3ournal of -gricultural and ood Chemistry '& %&,: (&10'.doi:10.1021@;f010112u. 2MI4 1110('01. 1'1. $ <$ons MM, Tu C, -oma RD, et al. %September 200&,. ORes"eratro in raw and baked b ueberries and bi berriesO. 3ournal of -gricultural and ood Chemistry ' %20,: '1670 70. doi:10.1021@;f0&(1'0f. 2MI4 1&129216. 1'9. $ Rimas, 5ndrew %4ecember 11, 2006,. O3is researc! targets t!e aging processO. "he )oston 4lobe.

160.

$ Stipp, 4a"id %8anuar$ 19, 2007,. OCan red wine !e p $ou i"e

fore"erZO. ortune magazine %CAA,. 161.Y a b Seward, Lac!ar$ M. %Ao"ember &0, 2006,. O^uest for $out! dri"es cra:e for )wine) pi sO. /ittsburgh /ost&4azette %-!e Wa Street 8ourna ,. 162. $ OCaution urged wit! res"eratro O. =nited 2ress Internationa . Ao"ember &0, 2006. 16&. $ 5 eccia, 8oAe %5pri 22, 2001,. O<onge"it$ Buest mo"es s ow $ from ab to ifeO. MSADC. 16(. $ Eoc:e, -om %September 1, 2001,. O8apanese Mnotweed a Resi ient In"aderO. )angor Daily Ne*s. 16'. $ Weintraub, 5r ene %8u $ 29, 2009,. ORes"eratro : -!e 3ard Se on 5nti* 5gingO. )loomberg )usiness*ee+. 166. $ trans*Res"eratro re a+es t!e corpus ca"ernosum e+... .5rc! 2!arm Res. 2001/ * 2ubMed resu t 167. $ trans*Res"eratro , a Aatura 5ntio+idant from Erapes, Increases Sperm Futput in 3ea t!$ Rats

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Eesc!er 58, Steward W2 %1 Fctober 200&,. ORe ations!ip between mec!anisms, bioa"ai ibi it$, and prec inica c!emopre"enti"e efficac$ of res"eratro : a conundrumO. Cancer (pidemiol )iomar+ers /rev. ! %10,: 9'&07.2MI4 1('71121.

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#\ icien Dreton %2001,. ORes"eratro and po $p!eno s in winesO. C-4)s Res"eratro page from t!e Comparati"e -o+icogenomics 4atabase =.S. Aationa <ibrar$ of Medicine: 4rug Information 2orta * Res"eratro 4etai ed Micro*Autrient information on Res"eratro from t!e <inus 2au ing Institute

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