biomedicines
Re iew
Res e a ol: A Double-Edged Swo d in Heal h Bene i s
Baha e Salehi 1,2 , Abhay P akash Mish a 3, Manisha Nigam 4, Bilge Sene 5, Meh ap Kilic 5,
Mehdi Sha i i-Rad 6,*, Pa ick Vale e Tsouh Fokou 7,* , Na ália Ma ins 8,9,* and
Ja ad Sha i i-Rad 10,11,*
1Medical E hics and Law Resea ch Cen e , Shahid Behesh i Uni e si y o Medical Sciences,
Teh an 88777539, I an; baha [email p o ec ed]
2S uden Resea ch Commi ee, Shahid Behesh i Uni e si y o Medical Sciences, Teh an 22439789, I an
3Depa men o Pha maceu ical Chemis y, H. N. B. Ga hwal (A Cen al) Uni e si y, S inaga Ga hwal
246174, U a akhand, India; [email p o ec ed]
4Depa men o Biochemis y, H. N. B. Ga hwal (A Cen al) Uni e si y,
S inaga Ga hwal 246174, U a akhand, India; [email p o ec ed]
5Gazi Uni e si y Facul y o Pha macy Depa men o Pha macognosy, Anka a 06330, Tu key;
[email p o ec ed] (B.S.); [email p o ec ed] (M.K.)
6Depa men o Medical Pa asi ology, Zabol Uni e si y o Medical Sciences, Zabol 61663335, I an
7An imic obial and Biocon ol Agen s Uni , Depa men o Biochemis y, Facul y o Science,
Uni e si y o Yaounde 1, Ngoa Ekelle, Annex Fac. Sci, P.O. Box. 812, Yaounde-Came oon
8Facul y o Medicine, Uni e si y o Po o, Alameda P o . He nâni Mon ei o, Po o 4200-319, Po ugal
9Ins i u e o Resea ch and Inno a ion in Heal h (i3S), Uni e si y o Po o, Po o 4200-135, Po ugal
10 Phy ochemis y Resea ch Cen e , Shahid Behesh i Uni e si y o Medical Sciences, Teh an 11369, I an
11 Depa men o Chemis y, Richa dson College o he En i onmen al Science Complex,
The Uni e si y o Winnipeg, Winnipeg, MB R3B 2G3, Canada
*Co espondence: [email p o ec ed] (M.S.-R.); [email p o ec ed] (P.V.T.S.);
[email p o ec ed] (N.M.); [email p o ec ed] (J.S.-R.); Tel.: +98-54-322-51-790 (M.S.-R.);
+237-676620503 (P.V.T.F.); +35-12-2551-2100 (N.M.); +98-21-8820-0104 (J.S.-R.)
Recei ed: 14 Augus 2018; Accep ed: 7 Sep embe 2018; Published: 9 Sep embe 2018


Abs ac :
Res e a ol (3,5,4
0
- ihyd oxy- ans-s ilbene) belongs o polyphenols’ s ilbenoids g oup,
possessing wo phenol ings linked o each o he by an e hylene b idge. This na u al polyphenol has been
de ec ed in mo e han 70 plan species, especially in g apes’ skin and seeds, and was ound in disc e e
amoun s in ed wines and a ious human oods. I is a phy oalexin ha ac s agains pa hogens, including
bac e ia and ungi. As a na u al ood ing edien , nume ous s udies ha e demons a ed ha es e a ol
possesses a e y high an ioxidan po en ial. Res e a ol also exhibi an i umo ac i i y, and is conside ed a
po en ial candida e o p e en ion and ea men o se e al ypes o cance . Indeed, es e a ol an icance
p ope ies ha e been con i med by many
in i o
and
in i o
s udies, which shows ha es e a ol is able
o inhibi all ca cinogenesis s ages (e.g., ini ia ion, p omo ion and p og ession). E en mo e, o he bioac i e
e ec s, namely as an i-in lamma o y, an ica cinogenic, ca diop o ec i e, aso elaxan , phy oes ogenic
and neu op o ec i e ha e also been epo ed. None heless, es e a ol applica ion is s ill being a majo
challenge o pha maceu ical indus y, due o i s poo solubili y and bioa ailabili y, as well as ad e se
e ec s. In his sense, his e iew summa ized cu en da a on es e a ol pha macological e ec s.
Keywo ds:
es e a ol; physiological e ec s; pha macological ac i i y; an ioxidan ;
an icance ; an imic obial
1. In oduc ion
Among many phy ochemicals, phy oes ogens ha e been epo ed o con ain se e al bioac i e
molecules, mos ly ound in soy, ege ables and ui s. These compounds can be classi ied in o ou main
Biomedicines 2018,6, 91; doi:10.3390/biomedicines6030091 www.mdpi.com/jou nal/biomedicines
Biomedicines 2018,6, 91 2 o 20
g oups, such as iso la onoids, la onoids, s ilbenes and lignans. F om hem, s ilbenes, in pa icula
ans- es e a ol and i s glucoside, a e widely epo ed o be bene icial o human heal h, ha ing e en
shown o possess an ioxidan , an ica cinogenic, an i umo and es ogenic/an ies ogenic ac i i y [1].
Speci ically, es e a ol is well known biologically ac i e compound syn hesized by plan s
unde going in ec ious o ionizing adia ion. Renaud and De Lo ge il we e he i s o ela e wine
polyphenols such as es e a ol, o he po en ial heal h bene i s a ibu ed o egula and mode a e
wine consump ion ( he so called “F ench Pa adox”) [
2
]. Res e a ol has since ecei ed an inc easing
scien i ic a en ion, leading o in es iga ion on i s biological ac i i y, and o nume ous publica ions [
3
].
Res e a ol was i s isola ed om whi e hellebo e (Ve a um g andi lo um O. Loes) oo s in 1940, hen
om Polygonum cuspida um oo s in 1963, a plan used in adi ional Chinese and Japanese Medicine
as an i-in lamma o y and an i-pla ele agen . This na u al polyphenol has been de ec ed in mo e
han 70 plan species, and is also ound in disc e e amoun s in ed wines and a ious human oods.
High concen a ions a e p esen in g apes, possibly because o Vi is ini e a esponse o ungal in ec ion.
In plan s, es e a ol ac s as a phy oalexin ha is syn hesized in esponse o mechanical inju y, UV
i adia ion and ungal a acks. Fo indus ial pu poses, es e a ol is gene ally ob ained by chemical
o bio echnological syn hesis om yeas s Saccha omyces ce e isiae [4–8].
As o oday, 92 new es e a ol compounds, including 39 dime s, 23 ime s, 13 e ame s,
6 es e a ol monome s, 6 hexame s, 4 pen ame s, and 1 oc ame ha e been epo ed om he
Dip e oca paceae,Paeoniaceae,Vi aceae,Leguminosae,Gne aceae,Cype aceae,Polygonaceae G amineae,
and Poaceae amilies [
9
]. Among hese amilies, Dip e oca paceae, con aining 50 es e a ol’s, accoun s
o he majo i y, being in ol ed 7 Dip e oca paceae gene a, including Va ica,Va e ia,Sho ea,Hopea,
Neobalanoca pus,Dip e oca pus and D yobalanops [
9
]. Cu en ly, es e a ol is sold as a nu i ional
supplemen wi h a wide ange o pha macological e ec s, including cellula de ensi e ac ion
agains oxida i e s ess [
10
–
12
]. In his sense, he p esen e iew summa izes es e a ol’ bene icial
heal h e ec s, including an icance , an imic obial, neu op o ec i e, an iaging, an i-in lamma o y,
ca diop o ec i e and blood-suga lowe ing p ope ies, as also li e-p olonging e ec s.
2. Chemis y o Res e a ol
Res e a ol is a s ilbenoid polyphenol, possessing wo phenol ings linked o each o he by an
e hylene b idge. The chemical s uc u e o es e a ol ( ans-3,5,4
0
- ihyd oxys ilbene) is iden i ied
in wo isome ic o ms, cis- and ans- es e a ol (Figu e 1). ans o m is dominan in e ms o i s
p e alence and di e en biological ac i i ies a e a ibu ed, namely in inducing cellula esponses such
as cell cycle a es , di e en ia ion, apop osis, and o enhance cance cells an i-p oli e a ion [13–15].
Biomedicines 2018, 6, x FOR PEER REVIEW 2 o 19
1. In oduc ion
Among many phy ochemicals, phy oes ogens ha e been epo ed o con ain se e al bioac i e
molecules, mos ly ound in soy, ege ables and ui s. These compounds can be classi ied in o ou main
g oups, such as iso la onoids, la onoids, s ilbenes and lignans. F om hem, s ilbenes, in pa icula
ans- es e a ol and i s glucoside, a e widely epo ed o be bene icial o human heal h, ha ing e en
shown o possess an ioxidan , an ica cinogenic, an i umo and es ogenic/an ies ogenic ac i i y [1].
Speci ically, es e a ol is well known biologically ac i e compound syn hesized by plan s
unde going in ec ious o ionizing adia ion. Renaud and De Lo ge il we e he i s o ela e wine
polyphenols such as es e a ol, o he po en ial heal h bene i s a ibu ed o egula and mode a e
wine consump ion ( he so called “F ench Pa adox”) [2]. Res e a ol has since ecei ed an inc easing
scien i ic a en ion, leading o in es iga ion on i s biological ac i i y, and o nume ous publica ions
[3]. Res e a ol was i s isola ed om whi e hellebo e (Ve a um g andi lo um O. Loes) oo s in 1940,
hen om Polygonum cuspida um oo s in 1963, a plan used in adi ional Chinese and Japanese
Medicine as an i-in lamma o y and an i-pla ele agen . This na u al polyphenol has been de ec ed in
mo e han 70 plan species, and is also ound in disc e e amoun s in ed wines and a ious human
oods. High concen a ions a e p esen in g apes, possibly because o Vi is ini e a esponse o ungal
in ec ion. In plan s, es e a ol ac s as a phy oalexin ha is syn hesized in esponse o mechanical
inju y, UV i adia ion and ungal a acks. Fo indus ial pu poses, es e a ol is gene ally ob ained
by chemical o bio echnological syn hesis om yeas s Saccha omyces ce e isiae [4–8].
As o oday, 92 new es e a ol compounds, including 39 dime s, 23 ime s, 13 e ame s, 6
es e a ol monome s, 6 hexame s, 4 pen ame s, and 1 oc ame ha e been epo ed om he
Dip e oca paceae, Paeoniaceae, Vi aceae, Leguminosae, Gne aceae, Cype aceae, Polygonaceae G amineae, and
Poaceae amilies [9]. Among hese amilies, Dip e oca paceae, con aining 50 es e a ol’s, accoun s o
he majo i y, being in ol ed 7 Dip e oca paceae gene a, including Va ica, Va e ia, Sho ea, Hopea,
Neobalanoca pus, Dip e oca pus and D yobalanops [9]. Cu en ly, es e a ol is sold as a nu i ional
supplemen wi h a wide ange o pha macological e ec s, including cellula de ensi e ac ion agains
oxida i e s ess [10–12]. In his sense, he p esen e iew summa izes es e a ol’ bene icial heal h
e ec s, including an icance , an imic obial, neu op o ec i e, an iaging, an i-in lamma o y,
ca diop o ec i e and blood-suga lowe ing p ope ies, as also li e-p olonging e ec s.
2. Chemis y o Res e a ol
Res e a ol is a s ilbenoid polyphenol, possessing wo phenol ings linked o each o he by an
e hylene b idge. The chemical s uc u e o es e a ol ( ans-3,5,4′- ihyd oxys ilbene) is iden i ied in
wo isome ic o ms, cis- and ans- es e a ol (Figu e 1). ans o m is dominan in e ms o i s
p e alence and di e en biological ac i i ies a e a ibu ed, namely in inducing cellula esponses such
as cell cycle a es , di e en ia ion, apop osis, and o enhance cance cells an i-p oli e a ion [13–15].
Figu e 1. Res e a ol chemical s uc u e (cis and ans o ms).
Fo mal chemical name (IUPAC name) o es e a ol is E-5-(4-hyd oxys y yl)benzene-1,3-diol.
Va ious aspec s on es e a ol chemis y a e cu en ly being s udied. I exis s as wo geome ic
isome s: cis-(Z) and ans-(E). ans o m can unde go o cis o m isome iza ion when exposed o UV
Figu e 1. Res e a ol chemical s uc u e (cis and ans o ms).
Fo mal chemical name (IUPAC name) o es e a ol is E-5-(4-hyd oxys y yl)benzene-1,3-diol.
Va ious aspec s on es e a ol chemis y a e cu en ly being s udied. I exis s as wo geome ic
isome s: cis-(Z) and ans-(E). ans o m can unde go o cis o m isome iza ion when exposed
o UV i adia ion. ans- es e a ol powde was ound o be s able unde “accele a ed s abili y”
condi ions o 75% humidi y and 40
◦
C in he p esence o ai . The low es e a ol bioa ailabili y
was encumbe ed i s he apeu ic applica ion. The e o e, modi ica ion o es e a ol s uc u e has
ecei ed special a en ion om esea che s and many es e a ol de i a i es ha e been syn hesized
Biomedicines 2018,6, 91 3 o 20
such as me hoxyla ed, hyd oxyla ed and halogena ed de i a i es, all o hem exhibi ing a o able
he apeu ic po en ial [
3
,
16
,
17
]. Res e a ol is p esen in die a y p oduc s as glycosyla ed o ms, known
as piceid. Though, plan s and pa hogens, and e en human diges i e ac possess enzymes able o
igge s polyphenols oxida ion (and subsequen inac i a ion), he glycosyla ion p e en s enzyma ic
oxida ion o es e a ol, he eby p ese ing i s biological e ec s and inc easing i s o e all s abili y
and bioa ailabili y [
18
]. Fu he mo e, since in es inal cells can abso b only es e a ol aglycone o m,
abso p ion p ocess equi es glycosidases. The e o e, he ela i e aglycone and glycosyla ed es e a ol
amoun s in oods and be e ages may modula e i s abso p ion a e [19].
Th ee glycosyla ed es e a ol analogues, piceid, picea annol glucoside, and es e a oloside
isola ed om he in asi e plan species Polygonum cuspida um [
19
] we e iden i ied as he majo
an ibac e ial compounds [
20
]. Glycosyla ed es e a ol analogues ha e compa able biological e ec s
a e ansepi elial passage, as hey can be hyd olyzed in o deglycosyla ed o ms, es e a ol in he
in es ine [
21
]. Howe e ,
in i o
s udies ha e shown ha he glycosyla ed analogues e en show
mo e powe ul bioac i i ies. Fo example, es e a ol and piceid ha e simila an ioxidan capaci y,
bu piceid appea s o be mo e e icacious han es e a ol due o i s eac ion wi h i s adical o m [
22
,
23
].
Indeed, es e a ol-glycoside was mo e e ec i e han es e a ol agains hepa i is B i us [
24
,
25
].
Picea annol, wi h one mo e hyd oxyl g oup, was al eady epo ed as ha ing s onge an i-in lamma o y,
immunomodula o y, an i-p oli e a i e, an i-leishmanial, an i-leukemic, and p o ein- y osine kinase
inhibi o y e ec s [19].
P e os ilbene, a na u al me hoxyla ed es e a ol analogue, was i s isola ed om P e oca pus
san alinus ( ed sandalwood), a plan used in adi ional medicine o diabe es ea men [
26
].
This P e oca pus ma supium ac i e cons i uen is mainly ound in bluebe ies, g apes, and se e al
plan woods. [
26
,
27
]. P e os ilbene has a simila s uc u e o es e a ol excep ha in A ing 3 and
5 posi ion was eplaced by a me hoxyl g oup [
26
]. This compound p o-lipophilici y, g ea e han
ha o es e a ol, inc eases i s bioa ailabili y [
28
–
30
] esul ing in s onge bioac i i ies, including
an icance , an i-lipidemic, an idiabe ic, and ca diop o ec i e e ec s han hose o es e a ol [
26
,
31
,
32
].
In he same line, es e a ol nano o mula ion ha e been concei ed as a p omising app oach
o biological unc ion e aining, whe e polycap olac one o m he hyd ophobic co e, whe eas
polye hylene glycol o m he hyd ophilic shell o he encapsula ed es e a ol micelles [
33
,
34
].
Solid lipid nanopa icles and nanos uc u ed lipid ca ie s a e wo unique es e a ol nanodeli e y
sys ems ha we e de eloped o enhance es e a ol’ o al bioa ailabili y o nu aceu ical pu poses [
35
].
Indeed, es e a ol nanopa icles led o an imp o emen in i s solubili y and enhances i s an ioxidan
po en ial han ee o m [
35
,
36
]. Fo example, es e a ol nano o mula ion exhibi ed an
in i o
abso p ion aise, leng h o ac ion ex ension and bioa ailabili y imp o emen by 3.516 imes mo e,
when compa ed wi h aw o m [
37
]. In addi ion, he hyd ophobic na u e o es e a ol conside ably
con ibu es o i s limi ed bioa ailabili y, which esul s om i s poo wa e solubili y. Thus, es e a ol
encapsula ed in me hyla ed-
β
-cyclodex ins (in a a io 1:1) imp o ed i s wa e solubili y (abou
400- old), and consequen ly i s bioa ailabili y, main aining i s an ioxidan and an ibac e ial e ec s
(agains Campylobac e ) [
38
], a same ime ha encou ages i s u he applica ion in ood indus y,
aiming a oodbo ne pa hogens con ol, as well as o nu aceu icals pu poses.
3. Biological Ac i i ies o Res e a ol
Res e a ol possesses a wide ange o biological p ope ies, among hem an ioxidan ,
ca diop o ec i e, neu op o ec i e, an i-in lamma o y and an icance ac i i ies [19,38].
3.1. F ee Radical Sca enging and An ioxidan E ec s
Res e a ol possess many biological p ope ies, bu he bes desc ibed es e a ol p ope y is hei
capaci y o ac as a po en an ioxidan [
39
]. Res e a ol an ioxidan ac i i y depends upon he a angemen
o unc ional g oups on nuclea s uc u e. The e o e, con igu a ion, subs i u ion, and o al hyd oxyl g oups
numbe subs an ially in luence se e al mechanisms o an ioxidan ac i i y, such as adical sca enging and
Biomedicines 2018,6, 91 4 o 20
me al ion chela ion abili ies. P e ious s udies showed ha hyd oxyl g oup in 4
0
posi ion is no he sole
de e minan o an ioxidan ac i i y, bu also he 3- and 5-OH g oups [
40
,
41
]. The s udy o an ioxidan e ec
agains hyd oxyl (
•
OH) and hyd ope oxyl (
•
OOH) adicals in aqueous simula ed media using densi y
unc ional quan um chemis y and compu a ional kine ics me hods e ealed ha ans- es e a ol may ac
as an e icien
•
OOH, and also p esumably
•
OOR, adical sca enge [
42
]. Res e a ol can also be used in
minimizing o p e en ing lipid oxida ion in pha maceu ical p oduc s, delaying oxic oxida ion p oduc s
o ma ion, and main aining bo h nu i ional quali y and p olonging pha maceu icals shel -li e [
43
–
45
].
In addi ion, es e a ol’s an ioxidan p ope ies ha e been success ully employed o p o ec cells agains
hyd ogen pe oxide-induced oxida i e s ess, whe e he p e- ea men wi h es e a ol p omo ed cell
su i al and p o ec ion agains UV-i adia ion-induced cell dea h. Res e a ol cellula de ense could be
achie ed, a leas in pa , by i s abili y o ac as a di ec an ioxidan and an indi ec cellula an ioxidan
sys em induce h ough modula ion o se e al cellula an ioxidan pa hways, he eby balancing cellula
edox s a us [10,46,47].
As al eady highligh ed, es e a ol is a powe ul an ioxidan ha bene icial e ec is hampe ed
by i s low bioa ailabili y. Many a emp s ha e been made o gene a e es e a ol de i a i es
by es e i ica ion p ocess o imp o e hei lipophilici y and applica ion in lipid-based oods and
biological en i onmen s. Abou 12 di e en es e i ied acyl chlo ides ha e been syn hesized including
bu y yl chlo ide, cap oyl chlo ide, cap yloyl chlo ide, cap yl chlo ide, docosahexaenoyl chlo ide,
eicosapen aenoyl chlo ide, lau oyl chlo ide, my is oyl chlo ide, oleoyl chlo ide, palmi oyl chlo ide,
p opionyl chlo ide, and s ea oyl chlo ide. These de i a i es we e able o e ec i ely inhibi coppe
ion-induced low-densi y lipop o ein (LDL) oxida ion and inhibi ed hyd oxyl adical-induced DNA
scission [
33
]. These esul s clea ly demons a ed ha es e a ol de i a i es migh se e as po en ial
an ioxidan s in oods and biological sys ems.
3.2. An icance E ec s
Nume ous s udies ha e demons a ed ha es e a ol possesses an i umo ac ion and is a likely
candida e o ea men and p e en ion se e al ypes o cance [
31
,
48
]. The an icance p ope ies o
es e a ol ha e been con i med by many
in i o
and
in i o
s udies, which show ha es e a ol
is able o inhibi all ca cinogenesis s ages (e.g., ini ia ion, p omo ion and p og ession) [
49
–
51
].
Many s udies also p o ided e idence ha es e a ol no only ac s a chemop e en i e agen , bu also
display chemo he apeu ic p ope ies linked o i s an i-in lamma o y, an ioxidan , p o-apop osis and
an i-p oli e a i e ac ions [
50
,
52
]. Indeed, Res e a ol is belie ed o a ge in acellula signaling
pa hway componen s such as egula o s o cell su i al and apop osis, p o-in lamma o y media o s,
and umo angiogenic and me as a ic swi ches by modula ing a dis inc se o ansc ip ion ac o s,
ups eam kinases, and hei egula o s [
53
]. Fo ins ance, es e a ol ha e demons a ed apop o ic
and an i-p oli e a i e e ec s on human ce ical ca cinoma by inducing cell sh inkage in HeLa cells
and apop osis h ough he ac i a ion o caspase-3 and -9, up egula ion o he exp ession o he
p o-apop o ic B-cell lymphoma (Bcl)-2-associa ed X p o ein and down egula ion o he exp ession o
he an i-apop o ic p o eins Bcl-2 and Bcl-ex a-la ge in HeLa cells, and inc eased exp ession o he p53,
a p o ein ha is essen ial o cell su i al and cell cycle p og ession [
54
]. Cheng e al. demons a e ha
es e a ol exe i s an icance ac ion in in panc ea ic cance cells by supp essing he exp ession o
NAF-1 h ough ac i a ion o N 2 signaling and inducing cellula eac i e oxygen species accumula ion
ha lead o apop osis ac i a ion and p e en p oli e a ion o panc ea ic cance cells [
55
]. Res e a ol is
also an His one deace ylase inhibi o s ha display i s an ip oli e a i e ac ion by ac i a ing cell cycle
a es , inducing apop osis and au ophagy, angiogenesis inhibi ion, inc easing eac i e oxygen species
gene a ion causing oxida i e s ess, and mi o ic cell dea h in cance cells [
56
]. The p esence o 4
0
-OH
oge he wi h he s e eoisome in ans-con o ma ion (4
0
-hyd oxys y yl moie y) is absolu ely equi ed
o cell p oli e a ion inhibi ion [
40
]. Enzyma ic assays demons a ed ha DNA syn hesis inhibi ion
was induced by a di ec in e ac ion o es e a ol wi h DNA polyme ases [
40
]. Ano he
in i o
wo k has shown ha es e a ol enhances chemo he apy e ec i eness h ough inac i a ing NF-
κ
B
Biomedicines 2018,6, 91 5 o 20
p o ein (a ansc ip ion ac o ) o med by cance cells and which con ols ce ain genes exp ession.
When his ac o is p esen , cance cells become chemo he apy- esis an , which hen allows hem o
mul iply. Res e a ol ac s blocking his ansc ip ion ac o , he eby enabling chemo he apeu ics o ac
a hei a ge ed si es [
57
–
59
]. Res e a ol also a enua es he ace yla ion, phospho yla ion, and nuclea
ansloca ion o NF-
κ
B [
60
] and inhibi iNOS exp ession in colon cance cells (a key enzyme in
colon umo igenesis induced by p o-in lamma o y and cy okines agen s) and he IGF-1R/Ak /Wn
pa hways, and ac i a es p53 o hampe ed cell and umo de elopmen [
60
]. These e ec s all in o wo
classes: (i) Well-documen ed an i-p oli e a i e and p o-apop o ic e ec s on cance cell lines; and (ii)
sligh ly mo e hypo he ical chemop e en i e e ec s ha co esponds o es e a ol e ec s on cance
ini ia ion [57–59].
Besides, he phy oes ogen, es e a ol has ecei ed g ea a en ion as an upcoming p e en i e
and he apeu ic agen agains b eas cance [
61
]. Res e a ol has also shown p omise as pa o
combina ion he apy, pa icula ly in b eas cance [
62
]. This compound has been shown o e e se
d ug esis ance in a wide a ie y o
in i o
cell sys ems by sensi izing umo cells o d ug-media ed
e ec s in combina ion wi h o he chemo he apeu ic agen s [
50
]. Res e a ol demons a es abili y o
enhance he sensi i i y o panc ea ic cance cells o gemci abine he apy [
55
]. Cispla in, a cance
chemo he apy agen agains o a ian, bladde , es icula , and many o he cance s, high isk o
neph o oxici y is educe by Res e a ol [
63
]. Globally, many
in i o
and animal-based s udies
ha e demons a ed such p e en i e an icance ac i i y in colon, ce ical, p os a e, b eas and
lungs [
50
,
64
–
69
]. Res e a ol-loaded nanopa icles ha e also demons a ed an ioxidan po en ial
in cance cells [
37
]. In addi ion, es e a ol bene icial e ec s a e also p esen when adop ed as a
con en ional ea men suppo o cance , using chemo he apy and adio he apy [
70
–
72
]. Based on
p e ious expe imen al and clinical ials, and on molecula cha ac e is ics o es e a ol, i could be
used as: (i) A neoadju an chemo he apy agen be o e su ge y o dec ease umo olume, owing o
i s abili y o inhibi cance cell p oli e a ion and o induce apop osis; (ii) an adju an chemo he apy
d ug o inhibi ea ly cance in asion and me as asis a e su ge y; (iii) a adio he apy o chemo he apy
sensi iza ion agen in combina ion wi h chemo he apy agen s, like capsaicin, doce axel, doxo ubicin,
gemci abine and emozolomide, since es e a ol may imp o e hei an icance e ec s; (i ) in cance
p e en ion o people unde high isk o cance ; ( ) a adiop o ec i e agen o educe ea men ad e se
e ec s, including adio he apy-induced xe os omia and mucosi is.
3.3. Ca diop o ec i e E ec s
Res e a ol p o ec i e e ec was shown o imp o e ca dio ascula unc ion in diabe ic a s [
73
,
74
]
by p ese ing he unc ional abili ies o ca diac s em/p ogeni o cell compa men s and ma u e
ca diac cells, imp o ed ca diac en i onmen by educing in lamma o y s a e and dec eased
un a o able en icula emodeling o he diabe ic hea , leading o a ma ked eco e y o en icula
unc ion [
74
]. Res e a ol showed bene icial e ec in hea ailu e by imp o ing le en icle unc ion,
dec eased ca diac hype ophy, con ac ile dys unc ion and emodeling, in e s i ial ib osis, and he
le el o plasma BNP [
75
]. Some molecula mechanism o es e a ol ac ion include inhibi ion o
p ohype ophic signaling molecules, imp o emen o myoca dial Ca
2+
handling, phospho yla ion o
p osu i al (Ak -1, GSK-3
β
) and s ess signaling (MKP-1) pa hways and he educ ion o oxida i e
s ess and in lamma ion (iNOS, COX-2 ac i i y, and ROS o ma ion) [
75
]. Yan e al. sugges
ha es e a ol ac by p e en ing he exp essions o endo helial ni ic oxide syn hase, ascula
endo helial g ow h ac o , and supp essing phospho yla ion o p38 in a s wi h diabe es- ela ed
myoca dial in a c ion [
73
]. Besides, es e a ol adminis a ion in myoca dial in a c ion- ela ed diabe ic
a s signi ican ly educed blood glucose, body weigh , plasma iglyce ide le els, hea a e and
aspa a e ansaminase (AST)/alanine ansaminase (ALT) a io, a same ime ha ma kedly inc eased
o al plasma insulin le els [
73
,
76
]. In addi ion, es e a ol signi ican ly educed in lamma ion
ac o s and malondialdehyde le els, which is a ma ke o oxida i e s ess [
77
]. These esul s
showed ha es e a ol ea men can imp o e ca dio ascula unc ion by educing myoca dial

Biomedicines 2018,6, 91 6 o 20
ischemia- epe usion inju y, asodila ion and a he oscle osis [
78
]. Con a ily, a physiological
concen a ions, es e a ol induces asodila ion, and consequen ly dec eases hype ension and
ca dio ascula diseases isk [
79
]. On he o he hand, hese esul s ha e also con i med he uses o
Polygonum cuspida um as a es e a ol sou ce o ea and o p e en hype lipidemia and a e ioscle osis
in adi ional chinese medicine [
80
–
82
]. O e all, he ca dio ascula p o ec i e e ec o es e a ol ha e
been linked o mul iple molecula a ge s and migh be use ul o he de elopmen o no el he apy o
a he oscle osis, me abolic synd ome, ischemia/ epe usion, and hea ailu e [83].
3.4. Neu op o ec i e E ec s
Res e a ol has se e al neu op o ec i e oles in a ious neu odegene a i e impai men s, such as
Alzheime
0
s, Hun ing on
0
s and Pa kinson
0
s diseases, amyo ophic la e al scle osis and alcohol-induced
neu odegene a i e diso de s [
84
,
85
]. I has been shown ha es e a ol p o ec i e e ec s a e no limi ed o
he an i-in lamma o y and an ioxidan ac i i y bu also imp o ed mi ochond ial unc ions and biogenesis
h ough SIRT1(si uin 1)/AMPK/PGC1
α
pa hway and i agenes, which p e en he dele e ious e ec s
igge ed by oxida i e s ess [
85
–
87
]. Res e a ol dec eases choline gic neu o ansmission, b ain-de i ed
neu o ophic ac o exp ession, and oxida i e s ess, p omo es
β
-amyloid pep ides clea ance and
an i-amyloidogenic clea age o APP, and educes neu onal apop osis [
88
]. A me a-analysis showed
ha es e a ol signi ican ly dec eased P o ile o Mood S a es (POMS) including igo and a igue bu had
no signi ican e ec on memo y and cogni i e pe o mance [
89
]. Among he isola ed es e a ol oligome s,
i isinAandheyneanolA ha ebeen epo ed o be e dose-dependen inhibi o ypo en ialcompa ed wi h
s anda d inhibi o (galan amine) on bo h ace ylcholines e ase (AChE) and bu y ylcholines e ase (BChE)
ac i i y [
17
,
37
]. Res e a ol is also able o imp o e a mo o abili ies and o deac i a e neu oin lamma o y
esponse ollowing in ace eb al hemo hage. I may be used as a no el he apeu ic agen o ea
in ace eb al hemo hage [90,91].
3.5. An i-In lamma o y Ac i i y
S ilbenoids including es e a ol a e non-ni ogenous polyphenols wi h acidic and amphiphilic
cha ac e s wi h an i-in lamma o y ac i i y. Many o hei a ge s a e occu ing on cyclooxygenase
(COX), 5-lipoxygenase (5-LOX) and p o ein kinase B [
92
], which is associa ed wi h i s abili y o
inhibi COX-1 and COX-2 ac i i y along wi h ansc ip ion ac o s ac i i y inhibi ion, di ec ly
in ol ed in COX ac i i y egula ion [
93
]. S udies epo ed he abili y o es e a ol o educe he
sec e ion and exp ession o in lamma o y ac o s [
94
]. The an i-in lamma o y ac i i y o es e a ol
p e en s acu e pha yngi is-induced in lamma ion by inhibi ing NF-
κ
B, umo nec osis ac o -
α
and
in e leukin-6 se um le els, mac ophage in lamma o y p o ein-2 and cyclooxygenase-2 ac i i y le els,
eac i e oxygen species p oduc ion and caspase-3/9 in abbi models [
94
]. Res e a ol inhibi he ea
oedema o mice, WBC and pleu isy exuda es, dec ease he p oduc ion o NO, and ele a e he ac i i y
o SOD in se um in ace ic acid-induced pleu isy es , educe he con en o MDA and ele a e he T-SOD
ac i i y in se um; RSV could inhibi he exp essions o TP, PGE2, NO, and MDA in ca ageenan-induced
syno i is es suppo ing i s analgesic and an i-in lamma o y ac i i ies [
95
]. Res e a ol inhibi he
ac i a ion o mic oglia ha lead o he elease o a ious p o-in lamma o y ac o s, he p oduc ion o
eac i e oxygen species, and he ac i a ion o signal pa hways leading o neu oin lamma ion [
96
] in
in i o
es e a ol modula es he in lamma o y esponse a mode a e o high concen a ions wi hin
in es inal cells by down- egula ing NF-
κ
B ac i a ion and p e en ing mi ochond ial dys unc ion.
This esul was con i med
in i o
whe e es e a ol inhibi s TNF-
α
p oduc ion and NF-
κ
B ac i a ion,
dec eases neu ophil in il a ion in he in es inal mucosa, and ep esses in es inal umo igenesis by
egula ing an i-in lamma o y miRNA [
97
,
98
]. Chen e al. demons a ed ha es e a ol signi ican ly
supp essed he TLR-4/MyD88/NF-
κ
B signaling pa hway in lysophospha idylcholine-induced damage
and in lamma ion ha migh be use ul o ea men o a e ioscle osis [
99
]. Taken oge he , hese
s udies sugges ha es e a ol can p e en in lamma ion and oxida i e s ess, educe he isk o
ca cinogenesis and de eloped as an i-in lamma o y agen o imp o e he quali y o li e o pa ien s.
Biomedicines 2018,6, 91 7 o 20
3.6. An imic obial Ac i i y
Res e a ol, in addi ion o he abo e desc ibed biological ac i i ies, has been s udied o i s abili y
o inhibi he g ow h o some pa hogenic mic oo ganisms, such as G am-posi i e and G am-nega i e
bac e ia and ungi [
100
]. Indeed, es e a ol has been shown o e icien ly inhibi Candida albicans
g ow h [
101
]. Dime hoxy es e a ol de i a i es exhibi ed an i ungal ac i i y agains C. albicans wi h
minimum inhibi o y concen a ion (MIC) alues o 29–37
µ
g/mL, including agains 11 o he Candida
species [
102
]. Howe e , he pu a i e candidacidal ac i i y o es e a ol is a ma e o con o e sy.
In ac , a s udy indica es ha es e a ol is no e ec i e agains bo h C. albicans and non-C. albicans
species [
101
]. In ano he s udy, es e a ol an i ungal ac i i y agains C. albicans could be eached a 400
µ
g/mL, he eby minimizing he an i ungal ole o es e a ol agains C. albicans-caused in ec ions [
103
].
Campylobac e jejuni and Campylobac e coli a e he majo causes o bac e ial
gas oen e i is, while A cobac e species a e also known o be human and animal pa hogens.
Res e a ol-hyd oxyp opyl-
γ
-cyclodex in inclusion complexes imp o ed es e a ol solubili y and
showed an i-Campylobac e and an i-A cobac e e ec s. Fu he mo e, i inhibi ed bio ilm o ma ion and
p omo ed bio ilm dispe sion e en a sub-MIC concen a ions and he e o e could be de eloped as a
new an i-bio ilm agen o enhance oods shel -li e and sa e y [104].
Res e a ol showed an ibac e ial ac i i y agains G am-posi i e bac e ia and ime-kill assays
showed ha i s e ec s we e due o i s bac e ios a ic ac ion [
105
]. Howe e , he mechanism unde lying
i s an ibac e ial ac i i y is no clea ly unde s ood [
106
]. Res e a ol was also able o a ec cells wi h
changes in cell mo phology and DNA con en s [
105
]. Hwang and Lim [
106
] demons a ed ha
es e a ol led o DNA agmen a ion in Esche ichia coli, inducing an SOS esponse; ne e heless,
es e a ol also induced cell elonga ion wi hou an SOS esponse and he eby inhibi s bac e ial cell
g ow h by supp essing F sZ (c ucial o Z- ing o ma ion) exp ession and Z- ing o ma ion in E. coli.
F om ano he poin o iew, eac i e oxygen species (ROS), supe oxide, pe oxide, and hyd oxyl
adicals a e hough o con ibu e o he apid bac e icidal ac i i y o di e se an imic obial agen s.
E. coli and S aphylococcus au eus cul u e supplemen ed wi h es e a ol and ea ed wi h an imic obials
educed ROS concen a ions o suble hal le els, ha a e mu agenic, while he absence o es e a ol
allows ROS o high enough o kill mu agenized cells. An imic obial le hali y supp ession and mu an
eco e y p omo ion abili ies e idenced by es e a ol sugges s ha his an ioxidan may con ibu e
o he eme gence o se e al an imic obials- esis an species, especially i new de i a i es and/o
es e a ol o mula ions ma kedly inc ease i s bioa ailabili y [107].
Pseudo abies i us is one o he de as a ing pa hogen o swine o which he e is no ea men
and ha o en esul in economic losses. Res e a ol showed an i i al ac i i y by inhibi ing he
Pseudo abies i us eplica ion and e ec i ely inc ease he g ow h pe o mance and educe he
mo ali y o Pseudo abies i us-in ec ed pigle s [108].
P e os ilbene is a me hoxyla ed de i a i e o es e a ol ha showed an ibac e ial ac i i y
agains d ug- esis an S aphylococcus au eus (MRSA) wi h minimum inhibi o y concen a ion (MIC)
supe io o p e os ilbene compa ed o es e a ol (8~16- old). P e os ilbene an i-MRSA po ency was
ela ed o bac e ial memb ane leakage, chape one p o ein down egula ion, and ibosomal p o ein
up egula ion and can be opically applied o ea men o skin MRSA in ec ion bea ing i less oxici y
o mammalian cells [
32
]. Res e a ol is a po en ially use ul agen on S aphylococcus au eus pneumonia
and S. au eus-induced in ec ious diseases ea men [
109
]. Also, es e a ol could alle ia e o a i us
in ec ion-induced dia hea [109].
3.7. O he Biological Ac i i ies
Besides he ca diop o ec i e, an ioxidan , an icance , neu op o ec i e, an i-in lamma o y,
an i-dyslipidemia, and an idiabe ic e ec s o es e a ol, i also exhibi s an ip oli e a i e and
and ogen-lowe ing e ec s on heca-in e s i ial cells o o a y. Mo eo e , i exe s a cy os a ic bu
no cy o oxic e ec in g anulosa cells, while inhibi ing a oma iza ion and ascula endo helial g ow h
ac o (VEGF) exp ession. These ac ions may be o clinical ele ance in condi ions associa ed wi h
Biomedicines 2018,6, 91 8 o 20
heca-in e s i ial cell hype plasia, and ogen excess, and abno mal angiogenesis, such as polycys ic
o a y synd ome. In addi ion, es e a ol may inc ease o a ian ollicula ese e and p olong o a ian
li e span, se ing as a po en ial an i-aging agen [110].
Res e a ol is also able o dec ease his opa hological and biochemical damages and o exe
p o ec i e e ec s on ischemia- epe usion inju y induced o a ian damages. Res e a ol has become
o con inue a ho spo in many ields, including espi a o y sys em diseases. Indeed, esea ch has
demons a ed ha es e a ol is help ul in elie ing pulmona y unc ion in gene al popula ion and
plays a p o ec i e ole in espi a o y sys em diseases. The main p o ec i e e ec s o es e a ol in
espi a o y sys em diseases, including i s an i-in lamma o y, an iapop o ic, an ioxidan , an i ib o ic,
an ihype ensi e, and an icance ac i i ies we e also examined. In es e a ol- ea ed pa ien s,
se um le els o ce ain biochemical ma ke s (i.e., C- eac i e p o ein, e y h ocy e sedimen a ion
a e, unde ca boxyla ed os eocalcin, ma ix me allop o einase-3, umo nec osis ac o alpha,
and in e leukin-6) we e also signi ican ly dec eased [
111
]. The e o e, he use o es e a ol as an
adju an o con en ional an i heuma ic agen s seems o be an op imum app oach. Res e a ol can
also be used as a p o ec i e and/o he apeu ic agen , pa icula ly in male in e ili y cases caused
by es icula oxici y. On he o he hand, es e a ol could be use ul o p o ec heal h agains
se e al pa hologies and ageing p oblems [
84
]. Howe e , he compa a i e e alua ion o animal and
human s udies shows ha es e a ol canno p o ec agains me abolic diseases and hei ele an
complica ions. None heless, i is impo an o poin ou ha he clinical indings a e in luenced by many
ac o s, such as sample size and s udy objec i es. Till now, small sample size and high dosage le els
we e used o conduc mos o clinical ials o assess es e a ol signi icance in ch onic diseases [
84
].
Consequen ly, i is no easy o de e mine he exac sa e y ange and he apeu ic e ec i eness o speci ic
es e a ol doses on speci ic popula ions. In his sense, be o e p esc ibing es e a ol, pa ien s should
be p ope ly ad ised o e ec i e ea men wi h minimum side e ec s. Fu he e alua ions a e needed
be o e decla ing es e a ol as a bene icial compound o human heal h.
4. Nega i e E ec s o Res e a ol
Res e a ol is widely known o i s enowned bene icial biological e ec s, namely in ol ing i s
chemop e en i e and an ioxidan p ope ies. Howe e , some s udies ha e documen ed ha i may
beha e as a p o-oxidizing agen [
112
]; hus, pa adoxically, i may also ha e implica ion in pa hology
o se e al diseases.
Res e a ol an ioxidan po en ial has been a ibu ed o i s ROS-sca enging capaci y [
112
,
113
] and o
an up egula ion capaci y on cells an ioxidan de ense [
114
]. S udies ha e epo ed ha es e a ol could
ac as a signaling molecule wi hin issues and cells in modula ing genes and p o eins exp ession h ough
edox-sensi i e in acellula pa hways ac i a ion. Thus, cell ole ance agains oxida i e en i onmen could
be a ibu ed o gene exp ession changes and o a aise in an ioxidan de ense sys ems ac ion and syn hesis,
which e en ually esul s in cell su i al and adap a ion [
115
–
117
]. Mo eo e , depending on enzyma ic
eac ions condi ions, es e a ol can be (au o-)oxidized o gene a e semiquinones and ela i ely s able
4
0
-phenoxyl adical, inally leading o ROS p oduc ion [
118
,
119
]. Such polyphenols’ oxida i e eac ions a e
in luenced by pH and p esence o hyd oxyl anions o o ganic bases [120,121].
A s udy ca ied ou by Ma ins e al. e ealed ha es e a ol can modula e di e en pa hways a
a ime, which can esul in dis inc and e en opposi e biological e ec s, depending on i s concen a ion
o ea men ime de ined. The au ho s documen ed ha , al hough a dose-dependen es e a ol
p o-oxida i e e ec leads o cells oxida i e s ess o e lesse ime exposu e, a same dose bu wi h an
inc ease in exposu e ime, less exp essi e cy o oxici y was ound. This sugges ha su i ing cells
seemed o be mo e esis an o es e a ol-induced damages, being i s e ec s a enua ed o e ea men
ime [
114
]. Addi ionally, low es e a ol doses (0.1–1.0
µ
g/mL) has been documen ed o enhance cell
p oli e a ion, whe eas highe doses (10.0–100.0
µ
g/mL) induces apop osis (Figu e 2) and dec eases
mi o ic ac i i y on human umo s and endo helial cells [
122
]. Recen ly, dual es e a ol pa e n e ec s
on HT-29 colon cance cells dea h and p oli e a ion we e obse ed, whe e a low concen a ions (1 and
Biomedicines 2018,6, 91 9 o 20
10
µ
mol/L), es e a ol inc eased cells numbe , while a highe doses (50 o 100
µ
mol/L) es e a ol
educed cells numbe and inc eased apop o ic o nec o ic cells pe cen age [123].
In a e y in e es ing s udy, dose- ime dependency o acu e es e a ol adminis a ion on
lipope oxida ion le els (in hea , li e and kidney o male a s synch onized wi h a 12-h da k-ligh
cycle) was in es iga ed. I was documen ed ha es e a ol beha ed as an an ioxidan du ing da k
span and as a p o-oxidan du ing ligh span, possibly e lec ing he pu a i e changing a io be ween
p o- and an ioxidan ac i i ies in a ious o gans du ing 24-h cycle o pos p andial oxida i e bu s
ha occu ed a e a meal [
124
]. The e is an in e es ing co ela ion among die a y polyphenols
p o-oxidan and cy o oxic ac i i ies, such as o es e a ol. In ac , since e e y an ioxidan is a edox
agen i migh become a p o-oxidan , accele a ing lipid pe oxida ion and/o inducing DNA damages
unde special condi ions. In his way, i has been p oposed ha such p o-oxidan ac ion could be an
impo an mechanism o ac ion o es e a ol an i-cance and apop o ic-inducing p ope ies [
112
].
I has al eady been epo ed ha es e a ol can lead o DNA damages, as well as o a e e sible o
i e e sible cell cycle in e up ion media ed by i s p o-oxidan e ec [
117
]. Recen ly, Plau h e al. [
125
]
p oposed ha cellula esponse o es e a ol ea men is based on oxida i e igge ing ac ion, ha
can lead o cell i ness ho me ic induc ion owa ds a mo e educ i e s a e, so as o physiological
esilience aising in igh oxida i e s ess. Also, i has been epo ed ea lie ha a c i ical balance
be ween in acellula hyd ogen pe oxide (H
2
O
2
) and O
2–
decides cells a e o apop o ic s imuli.
Thus, a shi owa ds H
2
O
2
a o s apop osis, whe eas inclina ion owa ds O
2-
obs uc s apop osis.
Indeed, H
2
O
2
p omo es apop osis by educing in acellula O
2-
concen a ion and igge ing cy osolic
pH d op. Ahmad e al. [
126
] epo ed ha es e a ol inhibi o y e ec on H
2
O
2
-induced apop osis is
no due o i s an ioxidan ac i i y, bu a he , h ough a p o-oxidan e ec e idenced by he p ominen
aise in in acellula O
2-
p oduc ion, which c ea es a non-conduci e in acellula en i onmen o
apop o ic execu ion.
Biomedicines 2018, 6, x FOR PEER REVIEW 9 o 19
In a e y in e es ing s udy, dose- ime dependency o acu e es e a ol adminis a ion on
lipope oxida ion le els (in hea , li e and kidney o male a s synch onized wi h a 12-h da k-ligh cycle)
was in es iga ed. I was documen ed ha es e a ol beha ed as an an ioxidan du ing da k span and
as a p o-oxidan du ing ligh span, possibly e lec ing he pu a i e changing a io be ween p o- and
an ioxidan ac i i ies in a ious o gans du ing 24-h cycle o pos p andial oxida i e bu s ha occu ed
a e a meal [124]. The e is an in e es ing co ela ion among die a y polyphenols p o-oxidan and
cy o oxic ac i i ies, such as o es e a ol. In ac , since e e y an ioxidan is a edox agen i migh
become a p o-oxidan , accele a ing lipid pe oxida ion and/o inducing DNA damages unde special
condi ions. In his way, i has been p oposed ha such p o-oxidan ac ion could be an impo an
mechanism o ac ion o es e a ol an i-cance and apop o ic-inducing p ope ies [112]. I has al eady
been epo ed ha es e a ol can lead o DNA damages, as well as o a e e sible o i e e sible cell
cycle in e up ion media ed by i s p o-oxidan e ec [117]. Recen ly, Plau h e al. [125] p oposed ha
cellula esponse o es e a ol ea men is based on oxida i e igge ing ac ion, ha can lead o cell
i ness ho me ic induc ion owa ds a mo e educ i e s a e, so as o physiological esilience aising in
igh oxida i e s ess. Also, i has been epo ed ea lie ha a c i ical balance be ween in acellula
hyd ogen pe oxide (H
2
O
2
) and O
2–
decides cells a e o apop o ic s imuli. Thus, a shi owa ds H
2
O
2
a o s apop osis, whe eas inclina ion owa ds O
2-
obs uc s apop osis. Indeed, H
2
O
2
p omo es apop osis
by educing in acellula O
2-
concen a ion and igge ing cy osolic pH d op. Ahmad e al. [126]
epo ed ha es e a ol inhibi o y e ec on H
2
O
2
-induced apop osis is no due o i s an ioxidan
ac i i y, bu a he , h ough a p o-oxidan e ec e idenced by he p ominen aise in in acellula O
2-
p oduc ion, which c ea es a non-conduci e in acellula en i onmen o apop o ic execu ion.
Figu e 2. Diag amma ic ep esen a ion o es e a ol biphasic ac i i y and gene exp ession
modula ion. A nanomola [124] doses, es e a ol ac s as a po en an ioxidan , while a mic omola
(μM) ange, i in e ac s as agonis o an agonis exhibi ing cell p oli e a ion/cy op o ec i e esponses
o cy os a ic/apop o ic e ec s, espec i ely.
Rega ding an ioxidan /p o-oxidan hyd oxys ilbenes ( es e a ol) ac i i ies, a ious s udies we e
pe o med in he pas aiming o de ine i s s uc u e–ac i i y ela ionship, using cell- ee sys ems
[127,128]. Thus, Rüwele e al. [117] ound ha nei he cy o oxic o cy os a ic ac i i ies no
cy op o ec i e and an ioxidan ac i i ies in cul u ed (C6 glioma) cells a e indica i e o a s uc u e–
ac i i y ela ionship s essing he need o explo e mechanisms a molecula le el. Fukuha a and Miya a,
i s ly epo ed es e a ol p o-oxidan ac i i y in a plasmid-based DNA clea age assay, in he p esence
o ansi ion me al ions, such as coppe , he mos edox-ac i e me al ions p esen in nucleus, se um and
Figu e 2.
Diag amma ic ep esen a ion o es e a ol biphasic ac i i y and gene exp ession modula ion.
A nanomola [
124
] doses, es e a ol ac s as a po en an ioxidan , while a mic omola (
µ
M)
ange, i in e ac s as agonis o an agonis exhibi ing cell p oli e a ion/cy op o ec i e esponses o
cy os a ic/apop o ic e ec s, espec i ely.
Rega ding an ioxidan /p o-oxidan hyd oxys ilbenes ( es e a ol) ac i i ies, a ious s udies
we e pe o med in he pas aiming o de ine i s s uc u e–ac i i y ela ionship, using cell- ee
sys ems
[127,128]
. Thus, Rüwele e al. [
117
] ound ha nei he cy o oxic o cy os a ic ac i i ies
no cy op o ec i e and an ioxidan ac i i ies in cul u ed (C6 glioma) cells a e indica i e o
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