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transcript
Subhendu Mukherjee, Jocelyn I Dudley, Dipak K Das
Cardiovascular Research Center, University of Connecticut HealthCenter, School of Medicine, 263 Farmington Avenue, Farmington, CT
06030-1110, USA
Resveratrol, a Polyphenolic Antioxidant, Present in Grape Skin, is Dose Dependent in Providing Health
Benefits
cis - resveratrol
trans - resveratrol
Source Resveratrol concentration
100% Natural peanut butterBilberries Blueberries Boiled peanuts Cranberry raw juice Dry grape skin Grapes Peanut butter Peanuts Pistachios Ports and sherries Ref grape juice Red winesRoasted peanuts White grape juiceWhite wines
~0.65 μg/g~16 ng/g~32 ng/g~5.1 μg/g~0.2 mg/L~24.06 μg/g0.16–3.54 μg/g0.3–1.4 μg/g0.02–1.92 μg/g0.09–1.67 μg/g<0.1 mg/L ~0.50 mg/L0.1–14.3 mg/L~0.055 μg/g~0.05 mg/L<0.1–2.1 mg/L
The French paradox
Infa
rct s
ize
(%)
10
20
30
40
**
*
*
*
Control-IR
White Wine-I
R
Tyrosol-IR
Hydroxytyrosol-IR
Red Wine-I
R
Resvera
trol-IR
Ethanol-IR
Effect of white wine, its components tyrosol and hydroxytyrosol, red wine, and resveratrol on the infarct size.
Dudley et al., J Agric Food Chem. 2008
0
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45 *
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0
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45 *
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Control White wine Tyrosol Hydroxytyrosol
Red wine ResveratrolI/R
A
C
Car
diom
yocy
te a
popt
osis
(%)
Effect of white wine, its components tyrosol and hydroxytyrosol, red wine, and resveratrol on the infarct size.
Dud
ley
et a
l., J
Agr
ic F
ood
Che
m. 2
008
B
Bcl2Akt
p-Akt
GAPDH
Bax
HO-1
COX-1
COX-2
e-NOS
i-NOS
GAPDH
Control-B
L
White Wine-I
R
Tyrosol-IR
Hydroxytyrosol-IR
Red Wine-I
R
Resvera
trol-IR
Control-IR
Control-B
L
White Wine-I
R
Tyrosol-IR
Hydroxytyrosol-IR
Red Wine-I
R
Resvera
trol-IR
Control-IR
Trx1
Trx2
GAPDH
Control-B
L
White Wine-I
R
Tyrosol-IR
Hydroxytyrosol-IR
Red Wine-I
R
Resvera
trol-IR
Control-IR
Dudley et al., J Agric Food Chem. 2008
RESVERATROL
Antitumor activity, ChemopreventionInhibits NF-κB activation, Proliferation,Causes S-phase arrest, Induces apoptosisof myeloid leukomia cells
Reduces platelet adhesion,Monocyte adhesion(anti-inflammatory response)
Prevents LDL oxidation
Protects lung from DNADamage and apoptosis
Neuroprotection
Reversible inhibition of herpessimplex virus types 1 & 2 replication
Anti-Aging
Cardioprotection
Protects from UVRadiation injury
Prevents prostate andPancreatic, gastricand thyroid cancer
Protects cerebralischemic injury
Inhibited growth ofH. pylori
Resveratrol
COX / LOX
PKC/PKD
ERK 1/2, JNK, p38 MAPK
PI3K/PKB
AMPKSirt1
PBEFeNOSiNOS
Bax/Bcl2
DNA polymerases α and δ
Quinone reductase 2
Aromatase
Adenylyl cyclase
Src
AktNFκB
p53
Ribonucleotidereductase
STAT3
NO
p56lck
FoxOPGE2
TNF
Molecular targets of Resveratrol
Myocardial injury and ageing related diseases
RESVERATROL
Cancer prevention
RESVERATROL
ApoptosisApoptosis
Anti-apoptoticresveratrol
Pro-apoptoticresveratrol? ? ?
Myocardial injury and ageing related diseases Cancer prevention
Low dose of resveratrol was used
High dose of resveratrol was used
Health beneficiary effects of resveratrol are dose dependent or not?
Panel A Panel B
Sudan-IV stained rabbit aortas with atherosclerotic lesions appearing as darkened areas on a white aortic surface. Panel A) Arteries from control rabbits. Panel B) Arteries from resveratrol-treated rabbits.
High dose resveratrol promotes atherosclerosis in case ofhypercholesterolemic rabbits
Wilson et al., Life Sciences. 1996
Effect of High Dose Resveratrol on Proliferation and Apoptosis in Endothelial and Tumer Cell Culture
Effect of resveratrol on the apoptotic and mitotic index of HT-1080 human fibrosarcoma cell culture
Szende et al., Experimental And Molecular Medicine 2000
Effect of resveratrol on the apoptotic and mitotic index of HT-29 cell culture
Effect of resveratrol on the apoptotic and mitotic index of HUVEC Endothelial cell culture
-2
-1
0
1
2
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4
5
6
7
8
0
0.5
1
1.5
2
2.5
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3.5
Control 100 μg/ml 10 μg/ml 1 μg/ml
Control 100 μg/ml 10 μg/ml 1 μg/ml 0.1 μg/ml
Effect of resveratrol on theproliferation of HUVEChuman endothelial cells
Resveratrol
Effect of Reserveratol on the proliferation of HT-29human colon carcinoma cells
Resveratrol
24h treatment48h treatment
Szende et al., Experimental And Molecular Medicine 2000
Resveratrol Associated Renal Toxicity is Dose Dependent
Crowell et al., Toxicological Sciences. 2004
Influence of resveratrol (RSV) concentration on the viability of HEK 293 cells before and after UV irradiation
Caddeo et al., International Journal of Pharmaceutics. 2008
Dumazet et al. (2002) showed that at higher dose resveratrol inhibits the growth and induces apoptosis in case of both normal and leukemic hematopoietic cells
Signorelli et al., (2005) showed that in androgen – sensitive prostatecancer cells, resveratrol had a proliferative activity at a low dose(5 µM), whereas it had a pro-apoptotic activity at a high dose (15 µM or higher)
Zhou et al., (2003) showed that in human esophageal carcinoma cells,resveratrol induces apoptosis when used in high concentration(100 mM) and this high dose of resveratrol also downregulatedBcl2 protein expression and upregulated Bax protein expression
Jang et al., (2006) showed that low concentration (5µM), resveratrolappears to increase cell proliferation, whereas apoptosis is induced invarious cancer cells at 15 µM or higher concentration.
Kyungmin et al. (2006) showed that 100 µM resveratrol induced apoptosis by cleavage of caspase 3 and resveratrol has an inhibitoryeffect on cell migration.
Howitz et al. (2003) showed that the photoprotective effect of resveratrolfrom radiation induced apoptosis in HEK 293 cells was reversed at concentrations greater than 50 µM.
Dose-response curve of the effects of resveratrol on myocardial performance
Control3.7 μM
7.4 μM10 μM
25 μM
Das et al., J Pharmacol Exp Ther. 2006
Dose-response curve of the effects of resveratrol on myocardial performance
Control3.7 μM
7.4 μM10 μM
25 μM
Das et al., J Pharmacol Exp Ther. 2006
Con
trol
3.7 μM
7.4 μM
10 μ
M
25 μ
M
Con
trol
3.7 μM
7.4 μM
10 μ
M
25 μ
M
Dose-response curve of the effects of resveratrol onmyocardial infarction and cardiomyocyte apoptosis.
Das et al., J Pharmacol Exp Ther. 2006
2 h 45 min Perfusion with KHB
15’
15’
30’ Ischemia 2 h Reperfusion
30’ Ischemia 2 h Reperfusion
I/R
Infarct size Apoptosis Biochemical and Molecular Biological Studies
Control
Resveratrol Treated
Isolated Working Heart Model of Ischemia-Reperfusion
Dudley et al., Journal of Nutritional Biochemistry. 2008
Dudley et al., Journal of Nutritional Biochemistry. 2008
Dudley et al., Journal of Nutritional Biochemistry. 2008
0
10
20
30
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50
Myo
card
ial i
nfar
ct s
ize
(%)
Con
trol I
/R
2.5m
g/kg
5 m
g/ k
g
25 m
g/kg
50 m
g/kg
* *
*
Resveratrol
Dudley et al., Journal of Nutritional Biochemistry. 2008
Effects of high and low doses of resveratrol on the myocardial infarct size
0
5
10
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25
30C
ardi
omyo
cyte
apo
ptos
is(%
)
Con
trol I
/R
2.5m
g/kg
5 m
g/ k
g
25 m
g/kg
50 m
g/kg
* *
*
Resveratrol
Dudley et al., Journal of Nutritional Biochemistry. 2008
Effects of high and low doses of resveratrol on the myocardial infarct size
TRX-2
TRX-1
GRX-1
GRX2
Cont
rol
I/R 2.5
mg/
kg
5mg/
kg
25m
g/kg
50m
g/kg
GAPDH
Resveratrol
Dudley et al., Journal of Nutritional Biochemistry. 2008
Effects of high and low doses of resveratrol on mRNA transcript of some redox genes
0
0.2
0.4
0.6
0.8
1
0.2
0.4
0.6
0.8
1
Control I/R 2.5mg/kg 5mg/kg 25mg/kg 50mg/kg
Rel
ativ
e ba
nd in
tens
ity(A
rbitr
ary
units
)
Resveratrol
Ref 1
GAPDH
Contro
l
I/R2.5
mg/kg
5mg/k
g25
mg/kg
50m
g/kg
Resveratrol
Dudley et al., Journal of Nutritional Biochemistry. 2008
Effects of high and low doses of resveratrol on Ref1 protein induction
Control I/R 2.5mg/kg 5mg/kg 25mg/kg 50mg/kg0
0.5
1
1.5
2
2.5
3p-AktBcl 2
*
* †
* † * †
*
***
†
Rel
ativ
e ba
nd in
tens
ity(A
rbitr
ary
units
)
GAPDH
Bcl 2Akt
P-Akt
Contro
l
I/R2.5
mg/kg
5mg/k
g25
mg/kg
50m
g/kg
Resveratrol
ResveratrolDudley et al., Journal of Nutritional Biochemistry. 2008
Effects of high and low doses of resveratrol on survival signal
•Resveratrol is good for health but the health benefit of resveratrol is dose dependent.
•Low doses resveratrol protects from different types of diseases such as cardiovascular, ageing etc.
• High doses resveratrol can be detrimental for normal tissue but it can be used in cancer prevention.