trans-3,5,4'-Trihydroxystilbene (trans-resveratrol) is a phytochemical present in peanuts, grapes and wine with beneficial effects such as protection against cardiovascular disease and cancer prevention. The purpose of this study was to evaluate whether high doses of trans-resveratrol have harmful effects on Sprague-Dawley rats. trans-Resveratrol was administered orally to male rats for 28 d at a dose of 20 mg/(kg x d), 1000 times the amount consumed by a 70-kg person taking 1.4 g of trans-resveratrol/d. Body weight, and food and water consumption did not differ between rats treated with trans-resveratrol and the control group. Hematologic and biochemical variables were not affected by the treatment. Histopathologic examination of the organs obtained at autopsy did not reveal any alterations. These results support the view that repeated consumption of trans-resveratrol at 20 mg/(kg x d) does not adversely affect the variables tested in rats.
trans-Resveratrol was reported to have health benefits including anticarcinogenic effects and protection against cardiovascular disease. One of the mechanisms by which it exerts its action is through modulating the estrogen response systems. Because estrogen is involved in male reproductive biology, we investigated the effect of trans-resveratrol on testis and spermatogenesis. Adult male rats were divided into 2 groups. The treated group was administered by gavage 20 mg/(kg . d) of trans-resveratrol suspended in 10 g/L of carboxymethylcellulose for 90 d, whereas the control group received only carboxymethylcellulose during the same period. The relative weight of testes did not differ between the groups. However, the diameter of the seminiferous tubules was significantly reduced from 437.5 +/- 0.1 mum in the controls to 310.9 +/- 0.1 mum in the resveratrol-treated rats. This decrease was accompanied by a significant increase in tubular density, from 3.20 +/- 0.18 in controls to 6.58 +/- 0.18 tubules/mm(2) in the treated group. Moreover, sperm counts were significantly greater in the resveratrol-treated rats (24.8 +/- 3.30 x 10(7)) than in the control group (14.1 +/- 0.80 x 10(7)), but sperm quality did not differ. Serum concentrations of gonadotrophins and testosterone were significantly higher in the resveratrol-treated group. We identified a novel activity of trans-resveratrol. The daily oral administration of this phytochemical to adult male rats enhanced sperm production by stimulating the hypothalamic-pituitary-gonadal axis, without inducing adverse effects.
trans-Resveratrol is a polyphenol found in blueberries, grapes, and wine with cancer chemopreventive properties. The low bioavailability of this compound enhances its concentration in the luminal content and becomes a potential chemopreventive agent against colon cancer. In the present study, the antiproliferative and pro-apoptotic effects on the human colorectal carcinoma HT-29 cells as well as the mechanisms underlying these effects were examined. Proliferation, cytotoxicity, and apoptosis were measured by fluorescence-based techniques. Studies of dose-dependent effects of trans-resveratrol showed antiproliferative activity with an EC 50 value of 78.9 +/- 5.4 microM. Caspase-3 was activated in a dose-dependent manner after incubation for 24 h giving an EC 50 value of 276.1 +/- 1.7 microM. Apoptosis was also confirmed with microscopic observation of changes in membrane permeability and detection of DNA fragmentation. The activity of trans-resveratrol on the mitochondria apoptosis pathway was evidenced by the production of superoxide anions in the mitochondria of cells undergoing apoptosis. In conclusion, trans-resveratrol inhibits cell proliferation without cytotoxicity and induces apoptosis in HT-29. Results of the present study provide evidence demonstrating the antitumor effect of trans-resveratrol via a ROS-dependent apoptosis pathway in colorectal carcinoma.
We have previously reported the anticarcinogenic effects of an olive fruit extract composed of pentacyclic triterpenes, the main components of which are maslinic acid (73·25 %) and oleanolic acid (25·75 %). Here we examined the effects of the individual components on proliferation, necrosis and apoptosis rates by fluorescence-based techniques in human HT-29 colon cancer cells. Oleanolic acid showed moderate antiproliferative activity, with an EC 50 of 160·6 (SE 10·6) mmol/l, and moderate cytotoxicity at high concentrations ($ 250 mmol/l). On the other hand, maslinic acid inhibited cell growth with an EC 50 of 101·2 (SE 7·8) mmol/l, without necrotic effects. Oleanolic acid, which lacks a hydroxyl group at the carbon 2 position, failed to activate caspase-3 as a prime apoptosis protease. In contrast, maslinic acid increased caspase-3-like activity at 10, 25 and 50 mmol/l by 3-, 3·5-and 5-fold over control cells, respectively. The detection of ROS in the mitochondria, which serve as pro-apoptotic signal, evidenced the different bioactivity of the two triterpenes. Confocal microscopy analysis revealed that maslinic acid generated superoxide anions while oleanolic acid-treated cells did not differ from the control. Completion of apoptosis by maslinic acid was confirmed microscopically by the increase in plasma membrane permeability, and detection of DNA fragmentation. In conclusion, the anticancer activity observed for olive fruit extracts seems to originate from maslinic acid but not from oleanolic acid. Maslinic acid therefore is a promising new compound for the chemoprevention of colon cancers.
Maslinic acid is a pentacyclic triterpene found in a variety of natural sources, ranging from herbal remedies used in traditional Asian medicine to edible vegetables and fruits present in the Mediterranean diet. In recent years, several studies have proved that maslinic acid exerts a wide range of biological activities, i.e. antitumor, antidiabetic, antioxidant, cardioprotective, neuroprotective, antiparasitic and growth-stimulating. Experimental models used for the assessment of maslinic acid effects include established cell lines, which have been often used to elucidate the underlying mechanisms of action, and also animal models of different disorders, which have confirmed the effects of the triterpene in vivo. Overall, and supported by the lack of adverse effects in mice, the results provide evidence of the potential of maslinic acid as a nutraceutical, not only for health promotion, but also as a therapeutic adjuvant in the treatment of several disorders.
Olives and their derivatives represent an important component of the Mediterranean diet that has been considered to be protective against cancer. We investigated the effect on cell proliferation and apoptosis in HT-29 cells of an extract from the skin of olives composed of pentacyclic triterpenes with the main components maslinic acid (73.25%) and oleanolic acid (25.75%). Studies of the dose-dependent effects showed antiproliferative activity at an EC50 value of 73.96 +/- 3.19 micromol/L of maslinic acid and 26.56 +/- 2.55 micromol/L of oleanolic acid without displaying necrosis. Apoptosis was confirmed by the microscopic observation of changes in membrane permeability in 40.9 +/- 3.9% and detection of DNA fragmentation in 24.5 +/- 1.5% of HT-29 cells incubated for 24 h with olive fruit extract containing 150 and 55.5 micromol/L of maslinic and oleanolic acids, respectively. Caspase-3 was activated in a dose-dependent manner after incubation for 24 h. The extract containing 200 micromol/L maslinic acid and 74 micromol/L oleanolic acid increased caspase-3-like activity to 6-fold that of control cells. Programmed cell death was induced by the intrinsic pathway, as evidenced by the production of superoxide anions in the mitochondria of cells treated with olive fruit extracts containing 150 and 55.5 micromol/L of maslinic and oleanolic acids, respectively. Our results report for the first time, to our knowledge, the inhibition of cell proliferation without cytotoxicity and the restoration of apoptosis in colon cancer cells by maslinic and oleanolic acids present in olive fruit extracts.
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