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Resveratrol
Resveratrol, a natural
stilbene in grapes and wine, enhances intraphagocytosis
in human promonocytes: a co-factor in antiinflammatory
and anticancer chemopreventive activity.
Bertelli AA, Ferrara F, Diana G, Fulgenzi A, Corsi
M, Ponti W, Ferrero ME, Bertelli A
Institute of Human Anatomy, Faculty of Medicine, University
of Milan, Italy. MariaElena.Ferrero@unimi.it
Trans-resveratrol, a natural stilbene present in wine
and grapes, has been studied mainly for its antiinflammatory
and anticancer activities. In this study the activity
of resveratrol on proliferative immunological parameters
(differentiation, apoptosis, phagocytosis and intracellular
killing) was studied using a U937 human promonocytic
cell line in comparison with another polyphenol, quercetin.
After incubation of the pathogen, Candida albicans,
intracellular killing by macrophage-like cells was
decreased by quercetin and resveratrol 10 microM but
was enhanced by resveratrol 1 microM after 20 h of
treatment. Phagocytosis rate, expressed as phagocytosis
frequency, (i.e., percentage number of phagocytosing
cells/total cells) at 20 h was highest with resveratrol
10 microM and was higher with quercetin 10 microM
than with resveratrol 1 microM. The phagocytosis index
exhibited the same trend. While both polyphenols demonstrated
cytostatic activity on U937 growth, a prointraphagocytic
effect for resveratrol 10 microM-treated cells at
10 min, resveratrol 1 microM-treated cells at 20 h
and resveratrol 10 microM-treated cells at 48 h was
observed. Morphological examination with optic microscopy
demonstrated both apoptotic and differentiating cells,
even after 10 min treatment. Resveratrol-induced apoptosis
(following 4 h treatment) was confirmed by flow cytometry
at concentrations as low as 1 microM and 100 nM in
the assay for detection of membrane phosphatidylserine.
Resveratrol- or quercetin-treated, but unstimulated
cells, did not produce tumor necrosis factor-alpha
protein. As phosphatidylserine externalization triggers
specific recognition by monocytes and macrophages,
removal of intact apoptotic cells is important a)
in cell population selection and differentiation for
antiblastic therapy, and b) in preventing the release
of toxic inflammatory substances such as reactive
oxygen substances and proteolytic enzymes by dying
cells. This observation suggests that wine polyphenols,
at the same concentrations as those found in plasma
after moderate wine consumption, are important cofactors
in antiinfective, antiinflammatory and anticancer
nonspecific immune reactions.
PMID: 10761539, UI: 20224605
Resveratrol Reverses
Tumor-Promoter-Induced Inhibition of Gap-Junctional
Intercellular Communication.
Nielsen M, Ruch RJ, Vang O
Department of Chemistry and Life Sciences, Roskilde
University, Roskilde, DK-4000, Denmark
[Record supplied by publisher]
The naturally occurring stilbene/alexin trans-resveratrol
(trans-3,5,4'-trihydroxystilbene) is a promising agent
for the prevention of cancer. We investigated the
effect of resveratrol on gap-junctional intercellular
communication (GJIC) in WB-F344 rat liver epithelial
cells because inhibition of GJIC is an important mechanism
of tumor promotion. Seventeen to 50 muM resveratrol
increased GJIC significantly by a factor of 1.3 compared
with solvent vehicle controls, when the WB-F344 cells
were exposed to resveratrol for 6 h. Most tumor promoters,
including the phorbol ester TPA and the insecticide
DDT, block GJIC. Resveratrol at 17-50 muM also significantly
prevented down-regulation of GJIC by TPA and DDT,
by a factor of 2.7 and 1.8, respectively. This recovery
of GJIC from TPA inhibition was partly correlated
with hindered hyperphosphorylation of Cx43. In conclusion,
resveratrol was found to enhance GJIC and counteract
the effects of tumor promoters on GJIC, and this is
likely a mechanism that contributes to the antipromotional
and anticarcinogenic properties of resveratrol. Copyright
2000 Academic Press.
PMID: 10973802
Cardioprotective
effect of resveratrol, a natural antioxidant derived
from grapes.
Hung L, Chen J, Huang S, Lee R, Su M
Institute of Pharmacology, College of Medicine, National
Taiwan University, No. 1, Sec. 1, Jen-Ai Road, Taipei,
Taiwan.
[Medline record in process]
Background: The major objective of the present study
was to examine the cardioprotective effect of resveratrol,
an antioxidant presents in red wines, in the rat after
ischemia and ischemia-reperfusion (I-R). Methods:
The left main coronary artery was occluded for 30
or 5 min followed by a 30-min reperfusion in anesthetized
rats. Animals were preinfused with and without resveratrol
before occlusion and the severity of ischemia- and
I-R-induced arrhythmias and mortality were compared.
Results: Resveratrol pretreatment had no effect on
ischemia-induced arrhythmias nor on mortality. In
contrast, a dramatic protective effects were observed
against I-R-induced arrhythmias and mortality. Resveratrol
pretreatment both reduced the incidence and duration
of ventricular tachycardia (VT) and ventricular fibrillation
(VF). During the same period, resveratrol pretreatment
also increased nitric oxide (NO) and decreased lactate
dehydrogenase levels in the carotid blood. Conclusions:
Resveratrol is a potent antiarrhythmic agent with
cardioprotective properties in I-R rats. The cardioprotective
effects of resveratrol in the I-R rats may be correlated
with its antioxidant activity and upregulation of
NO production.
PMID: 10963727, UI: 20419793
Anti-proliferative
effect of resveratrol, a natural component of grapes
and wine, on human colonic cancer cells.
Schneider Y, Vincent F, Duranton B, Badolo L, Gosse
F, Bergmann C, Seiler N, Raul F
ULP/CJF INSERM 95-09, Laboratory of Metabolic and
Nutritional Control in Digestive Oncology, IRCAD,
1 Place de l'Hopital, 67091, Strasbourg, France
[Record supplied by publisher]
Resveratrol, a natural polyphenolic phytoalexine present
in grapes and wines, has been reported to exert a
variety of important pharmacological effects. We investigated
the effects of resveratrol on the growth and polyamine
metabolism of CaCo-2 human colon cancer cells. Treatment
of the CaCo-2 cells with 25 muM resveratrol caused
a 70% growth inhibition. The cells accumulated at
the S/G2 phase transition of the cell cycle. No signs
of cytotoxicity or apoptosis were detected. Resveratrol
caused a significant decrease of ornithine decarboxylase
(ODC) activity, a key enzyme of polyamine biosynthesis,
which is enhanced in cancer growth. ODC inhibition
resulted in the reduction of the intracellular putrescine
content, indicating that polyamines might represent
one of several targets involved in the anti-proliferative
effects of resveratrol.
PMID: 10940513
Dose-dependent effect
of resveratrol on proliferation and apoptosis in endothelial
and tumor cell cultures.
Szende B, Tyihak E, Kiraly-Veghely Z
1st Institute of Pathology and Experimental Cancer
Research, Semmelweis University, Budapest, Hungary.
bszende@korb1.sote.hu
[Medline record in process]
Experimental data suggest that Resveratrol, a compound
found in grapes and other fruits may influence cell
proliferation and apoptosis. The aim of our experiments
was to study the effect of Resveratrol on tumor cell
cultures and an endothelial cell culture in order
to examine the effect of various doses of this compound
on active cell death and cell proliferation. Human
tumor (HT-29, SW-620, HT-1080) and endothelial (HUV-EC-C)
cells were treated with various doses of (0.1 to 100.0
microg/ml) Resveratrol in vitro. Cell number, apoptotic
and mitotic index was measured 24, 48 and 72 h after
treatment. Low doses (0.1-1.0 microg/ml) of Resveratrol
enhance cell proliferation, higher doses (10.0-100.0
microg/ml) induce apoptosis and decrease mitotic activity,
which is reflected in changes of cell number. Resveratrol
influences dose dependently the proliferative and
apoptotic activity of human tumor and endothelial
cells. The possible role of formaldehyde in the mechanism
of action of Resveratrol is discussed.
PMID: 10926121, UI: 20380109
Resveratrol inhibits
AGEs-induced proliferation and collagen synthesis
activity in vascular smooth muscle cells from stroke-prone
spontaneously hypertensive rats.
Mizutani K, Ikeda K, Yamori Y
Life Science, Environmental Conservation and Development,
Graduate School of Human and Environmental Studies,
Kyoto University, Yosida, Nihonmatu-cho, Sakyo-ku,
Kyoto, 6068501, Japan.
Advanced glycation end-products (AGEs) of plasma proteins
and/or matrix proteins are candidate mediators for
various vascular complications such as atherosclerosis.
We previously reported a significantly larger accumulation
of AGEs of the aorta in stroke-prone spontaneously
hypertensive rats (SHRSP) than in age-matched Wistar-Kyoto
rats (WKY). In this study, we examined the effects
of AGEs on vascular smooth muscle cells (VSMC) from
SHRSP and WKY rats. We also studied the in vitro effects
of resveratrol (3, 4',5-trihydroxystilbene), a natural
phytestrogen, on VSMC proliferation, DNA synthesis,
and collagen synthesis activity in SHRSP-VSMC. AGEs
accelerated the proliferation of SHRSP- or WKY-VSMC
in a time- and dose-dependent manner. VSMC from SHRSP
were more sensitive to AGEs than VSMC from normotensive
WKY. AGEs also significantly increased DNA synthesis
and prolyl hydroxylase activity, a marker for collagen
synthesis, in SHRSP-VSMC. AGEs-induced increases in
TGF-beta1 mRNA in SHRSP-VSMC were significantly greater
than in WKY-VSMC. Resveratrol inhibited AGEs-stimulated
proliferation, DNA synthesis, and prolyl hydroxylase
activity in SHRSP-VSMC in a dose-dependent manner.
ICI 182780, a specific estrogen receptor antagonist,
partly blocked the inhibitory effects of resveratrol
on AGEs-stimulated proliferation, DNA synthesis, and
prolyl hydroxylase activity. Resveratrol significantly
inhibited AGEs-induced TGF-beta1 mRNA increases in
a dose-dependent manner. Thus, resveratrol may confer
protective effects on the cardiovascular system by
attenuating vascular remodeling and may be clinically
useful as a safer substitute for feminizing estrogens
in preventing cardiovascular disease. Copyright 2000
Academic Press.
PMID: 10903896, UI: 20365828
Resveratrol depresses
the growth of colorectal aberrant crypt foci by affecting
bax and p21(CIP) expression.
Tessitore L, Davit A, Sarotto I, Caderni G
Dipartimento di Scienze Chimiche Alimentari Farmaceutiche
e Farmacologiche, Universita del Piemonte Orientale
'Amedeo Avogadro', Vercelli, Italy. tessitor@pasteur.sluigi.unito.it
We investigated whether resveratrol (RV) affects azoxymethane
(AOM)-induced colon carcinogenesis, by administering
RV (200 microg/kg/day in drinking water) to male F344
rats for 100 days, beginning 10 days before carcinogen
treatment (two weekly doses of 15 mg/kg AOM). Aberrant
crypt foci (ACF) were isolated and proliferation,
apoptosis and expression of the cell cycle genes bax
and p21 were determined. RV significantly reduced
the number of ACF/colon [25.7 +/- 3.6 (mean +/- SEM)
versus 39.4 +/- 3.3 in controls; P < 0.01] and
their multiplicity (2.7 +/- 0.3 versus 4.9 +/- 0.6
in controls; P < 0.01), and also abolished large
ACF. In RV-treated rats, bax expression was enhanced
in ACF but not in the surrounding mucosa. In both
controls and RV-treated rats, proliferation was higher
in ACF than in normal mucosa. p21 was expressed in
ACF of controls and of RV-treated rats and in normal
mucosa of controls, but was lost in normal mucosa
of RV-treated animals. In conclusion, the results
suggest a protective role of RV in colon carcinogenesis
with a mechanism involving changes in bax and p21
expression.
PMID: 10910967, UI: 20372603
Resveratrol attenuates
ovariectomy-induced hypertension and bone loss in
stroke-prone spontaneously hypertensive rats.
Mizutani K, Ikeda K, Kawai Y, Yamori Y
Life Science, Environmental Conservation and Development,
Graduate School of Human and Environmental Studies,
Kyoto University, Japan.
[Medline record in process]
We examined the effect of resveratrol (3,4',5-trihydroxy
stilbene), a phenolic compound found in the skins
of most grapes, on blood pressure and bone loss in
ovariectomized (OVX), stroke-prone spontaneously hypertensive
rats (SHRSP). Nineteen-week-old female SHRSP were
divided into a sham-ovariectomized (sham) group fed
a control diet and two OVX groups fed either a control
diet (OVX-Cont) or a diet supplemented with resveratrol
(5 mg/kg per d; OVX-Resv). Ovariectomy induced significant
increases in systolic blood pressure (SBP). Resveratrol
lowered the SBP by 15%) by the third week of administration,
and this effect was maintained throughout the study.
Resveratrol treatment also significantly enhanced
endothelium-dependent vascular relaxation in response
to acetylcholine (ACh) in OVX rats. Finally, femur
breaking energies measured for the resveratrol-treated
(OVX-Resv) group were significantly higher than those
of the resveratrol-untreated (OVX-Cont) group. While
no significant differences in calcium, magnesium and
phosphorus content were found between the femurs of
OVX-Cont and OVX-Resv rats, the femur hydroxyproline
content in the OVX-Resv group was significantly higher
than of the OVX-Cont group. We conclude that, in OVX-SHRSP,
resveratrol acts by a similar mechanism to mammalian
estrogens, lowering blood pressure by increasing dilatory
responses to ACh. The present study also demonstrated
that resveratrol was able to prevent ovariectomy-induced
decreases in femoral bone strength.
PMID: 10885794, UI: 20340320
Resveratrol induces
Fas signalling-independent apoptosis in THP-1 human
monocytic leukaemia cells.
Tsan MF, White JE, Maheshwari JG, Bremner TA, Sacco
J
Research and Medical Services, Stratton VA Medical
Center, Albany, NY 12208, USA.
Resveratrol, a natural product present in wine, has
recently been shown to inhibit the growth of a number
of cancer cell lines in vitro. In the current study,
we have demonstrated that resveratrol inhibits the
growth of THP-1 human monocytic leukaemia cells in
a dose-dependent manner with a median effective dose
of 12 microM. It did not induce differentiation of
THP-1 cells and had no toxic effect on THP-1 cells
that had been induced to differentiate into monocytes/macrophages
by phorbol myristate acetate. A significant fraction
of resveratrol-treated cells underwent apoptosis as
judged by flow cytometric analysis of DNA content,
DNA fragmentation and caspase-specific cleavage of
poly(ADP-ribosyl) polymerase. Resveratrol treatment
had no effect on the expression of Fas receptor or
Fas ligand (FasL) in THP-1 cells, nor did it induce
clustering of Fas receptors. In addition, THP-1 cells
were resistant to activating anti-Fas antibody, and
neutralizing anti-Fas and/or anti-FasL antibodies
had no protective effect against resveratrol-induced
inhibition of THP-1 cell growth. The effect of resveratrol
on THP-1 cells was reversible after its removal from
the culture medium. These results suggest that (1)
resveratrol inhibits the growth of THP-1 cells, at
least in part, by inducing apoptosis, (2) resveratrol-induced
apoptosis of THP-1 cells is independent of the Fas/FasL
signalling pathway and (3) resveratrol does not induce
differentation of THP-1 cells and has no toxic effect
on differentiated THP-1 cells. Thus, resveratrol may
be a potential chemotherapeutic agent for the control
of acute monocytic leukaemia.
PMID: 10848832, UI: 20308123
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