1: Int J Tissue React 1999;21(4):93-104

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.

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


1: Biochem Biophys Res Commun 2000 Sep 7;275(3):804-809

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


1: Cardiovasc Res 2000 Aug 18;47(3):549-55

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


1: Cancer Lett 2000 Sep 29;158(1):85-91

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


1: Exp Mol Med 2000 Jun 30;32(2):88-92

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.

[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


1: Biochem Biophys Res Commun 2000 Jul 21;274(1):61-7

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


1: Carcinogenesis 2000 Aug;21(8):1619-22

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.

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


1: J Nutr Sci Vitaminol (Tokyo) 2000 Apr;46(2):78-83

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


1: Br J Haematol 2000 May;109(2):405-12

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


1: Cancer Detect Prev 1997;21(1):71-7

Effect of Krestin as adjuvant treatment following radical radiotherapy in non-small cell lung cancer patients.

Hayakawa K, Mitsuhashi N, Saito Y, Nakayama Y, Furuta M, Nakamoto S, Kawashima M, Niibe H

Department of Radiology and Radiation Oncology, Gunma University School of Medicine, Japan.

To evaluate the efficacy of Krestin (PSK) as adjuvant treatment after radical radiation therapy (RT) for non-small cell lung cancer (NSCLC), treatment results of 225 patients with NSCLC treated with RT followed by adjuvant administration of PSK between 1976 and 1989 were analyzed. Of these patients, 170 (76%) had squamous cell carcinoma. In the patients with squamous cell carcinoma of the lung, PSK was given only when the tumor showed satisfactory shrinkage (complete or partial response) after completion of RT. The treatment outcomes were compared with those of the responders to RT not receiving PSK. The 5-year survival rates of patients with stages I-II and stage III disease were 39 and 26%, respectively, while the non-administered responder group's were 17 and 8%. These differences are statistically significant. An improvement in the treatment results with combined use of appropriate immuno-modulating drugs is anticipated in the future. When clinical trials of the efficacy of these drugs are conducted, the agents should be given to the patients with satisfactory tumor regression after RT, although they still take much time and cost.

Publication Types:

      Clinical trial

PMID: 9043766, UI: 97196677





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