Antiproliferative and Anti-Invasive Effect of Piceatannol, a Polyphenol Present in Grapes and Wine, against Hepatoma AH109A Cells
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Piceatannol is a stilbenoid, a metabolite of resveratrol found in red wine. Piceatannol and sera from rats orally given piceatannol were found to dose-dependently suppress both the proliferation and invasion of AH109A hepatoma cells in culture. Its antiproliferative effect was based on cell cycle arrest at lower concentration (25~50 μM) and on apoptosis induction at higher concentration (100 μM). Piceatannol suppressed reactive oxygen species-potentiated invasive capacity by scavenging the intracellular reactive oxygen species. These results suggest that piceatannol, unlike resveratrol, has a potential to suppress the hepatoma proliferation by inducing cell cycle arrest and apoptosis induction. They also suggest that the antioxidative property of piceatannol, like resveratrol, may be involved in its anti-invasive action. Subsequently, piceatannol was found to suppress the growth of solid tumor and metastasis in hepatoma-bearing rats. Thus, piceatannol may be a useful anticancer natural product.Keywords:
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Abstract Resveratrol and its analogs are promising cancer chemoprevention agents, currently under investigation in clinical trials. However, patients administered other plant polyphenols experienced severe diarrhea, likely due to an increase in intracellular cyclic AMP (cAMP). Resveratrol itself raises intracellular cAMP levels in breast cancer cells in vitro. Its future use as a cancer chemopreventive agent could therefore be compromised by its severe side effects. The aim of the study was (a) to define the influence of resveratrol on intestinal Cl− secretion and (b) to elucidate possible intracellular transduction pathways involved. Resveratrol caused a dose- and time-dependent increase in ΔIsc in T84 cells. The specificity of resveratrol was confirmed by using piceatannol 100 μmol/L, the hydroxylated resveratrol analog, which did not alter ΔIsc. A significant elevation of [cAMP]i by resveratrol was assessed in T84 cells. In mouse jejunum, resveratrol induced a time- and dose-dependent increase in ΔIsc as well. In bilateral Cl−-free medium, as well as after inhibition of protein kinase A, resveratrol-induced ΔIsc was reduced significantly. Preincubation of T84 cells with butyrate 2 mmol/L (24 and 48 hours) significantly inhibited resveratrol as well as forskolin-induced Cl− secretion. In summary, the main mechanism of action of resveratrol in intestinal epithelia is cAMP-induced chloride secretion which can be suppressed by butyrate. It can therefore be suggested that in cancer chemoprevention, both agents should be combined to reduce an undesired side effect such as diarrhea and to benefit from the known agonistic effect of both agents on differentiation of colon cancer cells.
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Background Resveratrol has been unanimously recognized as an cardiovascular protective substance in red wine. It has been speculated that the anti-atherosclerosis effect of resveratrol is ascribed to its powerful anti-inflammatory effect. Objective To investigate the effects of resveratrol on injured human umbilical veno-endothelial cells (HUVEC) and the reactive oxygen species(ROS) production induced by TNF-α or soluble CD40L (sCD40L). Methods Cultured HUVEC were pre-incubated with resveratrol(1-50 μmol/L) for 2 hours and then treated with TNF-α(10 μg/L) or sCD40Lα(10 μg/L) for another 4 hours. MTT assay was used to detect proliterative activity of HUVEC. Immunofluorescence microscopy was used for determination of ROS expression. Results Both TNF-α and sCD40L impaired HUVEC proliferation (-32.7% and -26% vs control,P0.05) which was associated with increases in ROS expression by 3.4 and 4.9 folds respectively (P0.05). Resveratrol (10 μmol/L,50 μmol/L) dose-dependently prevented the cells from being injured by TNF-α and sCD40L (P0.01),and decreased the expression of ROS(P0.01). Conclusion Resveratrol protect TNF-α or sCD40L-induced injury in HUVEC might be ascribed to inhibition of generation of ROS.
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Resveratrol, a stilbenoid compound present in various berries, has been associated with reduced risk of chronic diseases such as cancer, obesity and diabetes. Accumulated evidence indicates that biotransformation plays important roles in the biological activities of dietary compounds. We investigated the gastrointestinal biotransformation of resveratrol in mice fed with resveratrol for 5 weeks. LC‐MS analysis revealed that the major site of biotransformation for resveratrol was the small intestine, although there was a low degree of biotransformation occurring in the stomach. In the small intestine, resveratrol underwent phase I metabolism to produce dihydroresveratrol and piceatannol. Subsequently, resveratrol, dihydroresveratrol and piceatannol all underwent phase II metabolism to yield their corresponding sulfate and glucuronide conjugates. However, in the colon, resveratrol, dihydroresveratrol and piceatannol mainly existed in the non‐conjugated forms, presumably due to the deconjugation by colonic microbiota. Moreover, the level of dihydroresveratrol in the colon was much higher that of resveratrol, suggesting that dihydroresveratrol may be essential for potential beneficial biological effects in the colon, such as anti‐inflammation and anti‐carcinogenesis. In summary, our results provided detailed information on the metabolic fate of resveratrol in the gastrointestinal tract, which is important for better understanding of the health benefits of resveratrol. Support or Funding Information This study was supported by funding from USDA.
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Resveratrol (3,4',5 tri-hydroxystilbene) is a phytoalexin produced in hudge amount in grapevine skin in response to infection by Bothrytis cinerea. This production of resveratrol blocks the proliferation of the pathogen, thereby acting as a natural antibiotic. Numerous studies have reported interesting properties of trans-resveratrol as a preventive agent against important pathologies i.e. vascular diseases, cancers, viral infection or neurodegenerative processes. Moreover, several epidemiological studies have revealed that resveratrol is probably one of the main microcomponents of wine responsible for its health benefits such as prevention of vaso-coronary diseases and cancer. Resveratrol acts on the process of carcinogenesis by affecting the three phases: tumor initiation, promotion and progression phases and suppresses the final steps of carcinogenesis, i.e. angiogenesis and metastasis. It is also able to activate apoptosis, to arrest the cell cycle or to inhibit kinase pathways. Interestingly, resveratrol does not present any cytotoxicity in animal models. Moreover, concentrations of resveratrol in blood seem to be sufficient for anti-invasive activity. The enterohepatic recirculation may contribute to a delayed elimination of the drug from the body and bring about a prolonged effect. By its binding to plasmatic proteins, resveratrol also exhibits a prolonged effect. Interestingly, low doses of resveratrol can sensitize to low doses of cytotoxic drugs and so provide an innovative strategy to enhance the efficacy of anticancer therapy in various human cancers. By these properties, resveratrol appears to be a good candidate in chemopreventive or chemotherapeutic strategies and is believed to be a novel weapon for new therapeutic strategies.
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Resveratrol, a nontoxic polyphenol, has been shown to inhibit tumor growth in a xenograft mouse model of neuroblasoma. However, resveratrol is rapidly metabolized, mainly to its glucuronidated and sulfated derivatives. This study demonstrates that resveratrol alone, and not the glucuronidated or sulfated metabolites, is taken up into tumor cells, induces a rise in [Ca(2+)](i), and ultimately leads to a decrease in tumor cell viability. A new water-soluble resveratrol formulation was delivered directly at the site of the tumor in a neuroblastoma mouse model. The amount of unmodified resveratrol associated with the tumor increased more than 1000-fold. The increase of unmodified resveratrol associated with the tumor resulted in tumor regression. The number of residual tumor cells that remained viable also decreased as the ratio of the metabolites relative to unmodified resveratrol declined.
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Trans-resveratrol (3,5,4'-trihydroxy-trans-stilbene), a naturalpolyphenol, displays diversified bioactivities that are crucial in chemoprevention of cancer and cardiovascular diseases. Equally promising action is exerted by resveratrol analogues, mainly pterostilbene (3,5-dimethoxy-4'-hydroxy-trans-stilbene) and piceatannol (3,5,3', 4'-tetrahydroxy-trans-stilbene). Although fruits and their products are the main natural source of resveratrol and their analogues, recently these polyphenols have been commercially available in numerous pharmaceutical preparations and diet supplements. The aim of this review is to present the status of clinical studies on chemopreventive/chemotherapeutic effect of resveratrol and its analogues.
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Several series of natural polyphenols are described for their biological and therapeutic potential. Natural stilbenoid polyphenols, such as trans-resveratrol, pterostilbene and piceatannol are well-known for their numerous biological activities. However, their moderate bio-availabilities, especially for trans-resveratrol, prompted numerous research groups to investigate innovative and relevant synthetic resveratrol derivatives. This review is focused on isosteric resveratrol analogs aza-stilbenes and azo-stilbenes in which the C=C bond between both aromatic rings was replaced with C=N or N=N bonds, respectively. In each series, synthetic ways will be displayed, and structural sights will be highlighted and compared with those of resveratrol. The biological activities of some of these molecules will be presented as well as their potential therapeutic applications. In some cases, structure-activity relationships will be discussed.
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The polyphenol compounds can be responsible for the beneficial physiological effects of the wine, specially of the red wine. The supposed mechanism in health protecting effect due to the polyphenol components in the wine can be grouped to several biochemical reactions. One of the most important and mostly examined characteristics is their antioxidant and radical scavenging effect.Examination of the antioxidant characteristics of a newly developed vermouth wine.Antioxidant characteristics of a newly developed vermouth wine (marked with FB) till now not in the market were studied comparing with those of three red and three white wines as well as of one rose wine. The total polyphenol content, the hydrogen donor activity, the reduction capacity and the complex building activity were determined.Hundred ml of the vermouth wine involves 18.8 mg alcohol, as well as 220 mg polyphenol compounds, comparing to the mean polyphenol content of white wine with 10.5 mg alcohol and 35 mg polyphenol contents.Usual consumption of one unit from the vermouth wine examined in this paper is medically acceptable, furthermore the organism can have those polyphenol compounds which play substantial role in the protection against oxidative stress.
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