Guest guest Posted February 25, 2006 Report Share Posted February 25, 2006 Fungicidal effect of resveratrol on human infectious fungi. Arch Pharm Res. 2005 May;28(5):557-60. Resveratrol, a phenolic antioxidant found in grapes, has been known to mediate various biological activities on the human body. In the present study, we tested the antifungal activity of resveratrol against human pathogenic fungi before carrying out further studies to elucidate the antifungal mechanism(s) of resveratrol. Resveratrol displayed potent antifungal activity against human pathogenic fungi at concentration levels of 10-20 microg/mL. Furthermore, time-kill curve exhibited fungicidal effect of resveratrol on Candida albicans, but the compound had no hemolytic activity against human erythrocytes. The destruction of C. albicans cells by resveratrol was confirmed by scanning electron microscopy. These results suggest that resveratrol could be employed as a therapeutic agent to treat fungal infections of humans. Resveratrol, a chemical found in red grapes, blocks replication of the influenza virus in cell culture and in animals. In cell culture experiments, resveratrol prevented influenza from replicating. Resveratrol treatment had the greatest effect when administered 3 hours after exposure to influenza. Smaller but significant effects were seen when treatment began 6 hours after infection, but at 9 hours after infection resveratrol treatment had no effect. Pre- treatment also did not change susceptibility to infection. Studies in a mouse model of influenza showed that injections of resveratrol after inoculation of influenza increased survival by 40% compared with placebo injections. The amount of virus present in the lung 6 days after infection was 98% lower in the resveratrol -treated mice. Resveratrol's anti-influenza activity seems to center on its ability to interfere with key " host-cell functions " that are essential for virus replication, the authors explain in The Journal of Infectious Diseases, May 15, 2005. ------------------------------ Resveratrol reduces oxidation and proliferation of human retinal pigment epithelial cells via extracellular signal-regulated kinase inhibition. Chem Biol Interact. 2005 Jan 15;151(2):143-9. King RE, Kent KD, Bomser JA. Department of Food Science and Technology, Ohio State University, Columbus, OH Epidemiological evidence suggests that moderate wine consumption and antioxidant-rich diets may protect against age-related macular degeneration, the leading cause of vision loss among the elderly. Development of age-related macular degeneration and other retinal diseases, such as proliferative vitreoretinopathy (PVR), is associated with oxidative stress in the retinal pigment epithelium (RPE), a cell layer responsible for maintaining the health of the retina by providing structural and nutritional support. We hypothesize that resveratrol, a red wine polyphenol, may be responsible, in part, for the health benefits of moderate red wine consumption on retinal disease. To test this hypothesis, the antioxidant and antiproliferative effects of resveratrol were examined in a human RPE cell line (designated ARPE-19). These results suggest that resveratrol can reduce oxidative stress and hyperproliferation of the RPE. ----------------------------------- Role of resveratrol in prevention and therapy of cancer: preclinical and clinical studies. Anticancer Res. 2004 Sep-Oct;24(5A):2783-840. Aggarwal BB, Bhardwaj A, Aggarwal RS, Seeram NP, Shishodia S, Takada Y. Cytokine Research Laboratory, Department of Bioimmunotherapy, The University of Texas M. D. Besides cardioprotective effects, resveratrol exhibits anticancer properties, as suggested by its ability to suppress proliferation of a wide variety of tumor cells, including lymphoid and myeloid cancers; multiple myeloma; cancers of the breast, prostate, stomach, colon, pancreas, and thyroid; melanoma; head and neck squamous cell carcinoma; ovarian carcinoma; and cervical carcinoma. The growth- inhibitory effects of resveratrol are mediated through cell-cycle arrest; upregulation of p21Cip1/WAF1, p53 and Bax; down-regulation of survivin, cyclin D1, cyclin E, Bcl-2, Bcl-xL and clAPs; and activation of caspases. Resveratrol has been shown to suppress the activation of several transcription factors, including NF-kappaB, AP- 1 and Egr-1; to inhibit protein kinases including IkappaBalpha kinase, JNK, MAPK, Akt, PKC, PKD and casein kinase II; and to down- regulate products of genes such as COX-2, 5-LOX, VEGF, IL-1, IL-6, IL- 8, AR and PSA. These activities account for the suppression of angiogenesis by this stilbene. Resveratrol also has been shown to potentiate the apoptotic effects of cytokines (e.g., TRAIL), chemotherapeutic agents and gamma-radiation. Phamacokinetic studies revealed that the target organs of resveratrol are liver and kidney, where it is concentrated after absorption and is mainly converted to a sulfated form and a glucuronide conjugate. In vivo, resveratrol blocks the multistep process of carcinogenesis at various stages: it blocks carcinogen activation by inhibiting aryl hydrocarbon-induced CYP1A1 expression and activity, and suppresses tumor initiation, promotion and progression. Besides chemopreventive effects, resveratrol appears to exhibit therapeutic effects against cancer. Limited data in humans have revealed that resveratrol is pharmacologically quite safe. Currently, structural analogues of resveratrol with improved bioavailability are being pursued as potential therapeutic agents for cancer. Consumption of red wine is associated with a slight but statistically significant reduction in the development of lung cancer, as reported in the journal Thorax. Red wine contains tannins and resveratrol, substances which could explain the drink's anti-cancer properties. Tannins act as antioxidants, which mop up free radicals — particles harmful to cells. Resveratrol is known to fight cancer tumor growth. ------------------- Resveratrol-induced cellular apoptosis and cell cycle arrest in neuroblastoma cells and antitumor effects on neuroblastoma in mice. Surgery. 2004 Jul;136(1):57-66. The prognosis of neuroblastoma patients remains unsatisfactory. Therefore, developing an effective treatment strategy is important. Resveratrol, a natural polyphenol, possesses chemopreventive and antitumor effects. We investigated the effects of resveratrol on the proliferation, apoptosis, and cell cycle alteration of neuroblastoma cells and determined its effects on neuroblastoma tumors in mice. METHODS: Cytotoxic effects, cellular apoptosis, and alterations in the cell cycle were determined in neuro-2a neuroblastoma cells exposed for varying lengths of time to a series of resveratrol concentrations. Expression of associated cell cycle regulatory proteins, cyclin E and p21, was detected by Western blot analysis, and the antitumor effects of resveratrol were investigated by treating subcutaneous neuroblastoma tumors with intraperitoneal injections of 40 mg/kg resveratrol daily for 28 days. RESULTS: Resveratrol exerted cytotoxic effects on neuroblastoma cells. After resveratrol treatment, the apoptosis rate of the neuroblastoma cells significantly increased, a significant accumulation of cells occurred at the S phase of the cell cycle, p21 was downregulated, and cyclin E was upregulated. In addition, resveratrol treatment suppressed the growth rate of subcutaneous neuroblastomas, resulting in 70% long- term survival. CONCLUSION: Resveratrol caused significant cytotoxicity and increased apoptosis and S-phase accumulation of neuroblastoma cells. S-phase accumulation was related to the down- regulation of p21 and up-regulation of cyclin E. In addition, resveratrol exerted antitumor effects on neuroblastomas in mice. Thus, resveratrol shows promise for the treatment of neuroblastoma. ------------------ Anti-inflammatory Effects of Resveratrol in Lung Epithelial Cells: Molecular Mechanisms. Am J Physiol Lung Cell Mol Physiol. 2004 Jun 4 Resveratrol is a polyphenolic stilbene found in the skins of red fruits including grapes that may be responsible for some of the health benefits ascribed to the consumption of red wine. Resveratrol has previously been shown to have anti-oxidant properties and can act as an estrogen agonist. This study examined the anti-inflammatory effects of resveratrol on human airway epithelial cells. Resveratrol and the related molecule quercetin, but not deoxyrhapontin, inhibited both interleukin (IL)-8 and granulocyte-macrophage colony stimulating factor (GM-CSF) release from A549 cells. Neither the estrogen receptor antagonist, tamoxifen, nor the glucocorticoid antagonist, mifepristone, altered the inhibitory effect of resveratrol. The mechanism of resveratrol action was investigated further using luciferase reporter genes stably transfected into A549 cells. Both resveratrol and quercetin inhibited NF-kappaB-, AP-1- and CREB- dependent transcription to a greater extent than the glucocorticosteroid, dexamethasone. These compounds also had no significant effect on acetylation or deacetylation of core histones. Resveratrol, but not estradiol or N-acetyl cysteine, inhibited cytokine-stimulated inducible nitric oxide synthase expression and nitrite production in human primary airway epithelial cells. Resveratrol also inhibited GM-CSF release, IL-8 release and cyclo- oxygenase-2 expression in these cells. This study demonstrates that resveratrol and quercetin have novel non-steroidal anti-inflammatory activity that may have applications for the treatment of inflammatory diseases. ---------------------- Identification of a p53-dependent pathway in the induction of apoptosis of human breast cancer cells by the natural product, resveratrol. Laux MT, Aregullin M, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA. J Altern Complement Med. 2004 Apr;10(2):235-9. Resveratrol, a constituent found in grapes and various other plants, has been shown to have chemo-preventive activity against cancer, and specifically demonstrated to induce apoptosis by p53-dependent pathways in murine cells. DESIGN: A number of human breast cancer cell lines, as well as a control of a wild-type line (astrocytoma N 1321N1), were investigated for induction of apoptosis by resveratrol using both microscopic evaluation and DNA fragmentation assays. RESULTS: Apoptosis induced by resveratrol was found to occur only in breast cancer cells expressing wild-type p53 but not in mutant p53- expressing cells. CONCLUSIONS: We therefore conclude that the natural product, resveratrol, induces apoptosis in breast cancer cells via p53-dependent pathways. -------------------- Curcumin and resveratrol induce apoptosis and nuclear translocation and activation of p53 in human neuroblastoma. Anticancer Res. 2004 Mar-Apr;24(2B):987-98. BACKGROUND: Neuroblastoma (NB) is an aggressive childhood cancer of the peripheral nervous system arising from neural crest sympathoadrenal progenitor cells. Despite current rigorous treatment protocols, prognosis for high stage NB patients is poor and so there remains a need for more effective, less cytotoxic treatments. Curcumin and resveratrol possess anti-tumor properties in adult cancer models and negligible toxicity in normal cells, but little is known about the effect of these agents on pediatric cancers. MATERIALS AND METHODS: Stage 4 MYCN-amplified NB cell lines, with wild-type or mutant p53, were treated with curcumin and resveratrol and analyzed for effects on proliferation, cell cycle, induction of apoptosis and p53 function. RESULTS: Treatment with resveratrol and curcumin induced a dose- and time-dependent decrease in cell viability, cell cycle arrest and induction of apoptosis. CONCLUSION: Observations suggest that the cytotoxicity, cell cycle arrest and apoptosis induced by curcumin and resveratrol in NB cells may be mediated via functionally activated p53 and merit further study. ----------------------- Resveratrol in raw and baked blueberries and bilberries. J Agric Food Chem. 2003 Sep 24;51(20):5867-70. Lyons MM, Yu C, Toma RB, Cho SY, Reiboldt W, Lee J, van Breemen RB. Food and Nutritional Science Division, California State University- Long Beach, CA 90840 Resveratrol in the fruits of bilberry (Vaccinium myrtillus L.), the lowbush " wild " blueberry (Vaccinium angustifolium Aiton), the rabbiteye blueberry (Vaccinium ashei Reade), and the highbush blueberry (Vaccinium corymbosum L.) were measured using a new assay based on high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). The LC-MS/MS assay provided lower limits of detection than previous methods for resveratrol measurement, 90 fmol of trans-resveratrol injected on-column, and a linear standard curve spanning >3 orders of magnitude. The recoveries of resveratrol from blueberries spiked with 1.8, 3.6, or 36 ng/g were 91.5 +/- 4.5, 95.6 +/- 6.5, and 88.0 +/- 3.6%, respectively. trans-Resveratrol but not cis-resveratrol was detected in both blueberry and bilberry samples. The highest levels of trans-resvertatrol in these specimens were 140.0 +/- 29.9 pmol/g in highbush blueberries from Michigan and 71.0 +/- 15.0 pmol/g in bilberries from Poland. However, considerable regional variation was observed; highbush blueberries from British Columbia contained no detectable resveratrol. Because blueberries and bilberries are often consumed after cooking, the effect of baking on resveratrol content was investigated. After 18 min of heating at 190 degrees C, between 17 and 46% of the resveratrol had degraded in the various Vaccinium species. Therefore, the resveratrol content of baked or heat-processed blueberries or bilberries should be expected to be lower than in the raw fruit. Although blueberries and bilberries were found to contain resveratrol, the level of this chemoprotective compound in these fruits was <10% that reported for grapes. Furthermore, cooking or heat processing of these berries will contribute to the degradation of resveratrol. -------------------- Wine and tumors: study of resveratrol. Drugs Exp Clin Res. 2003;29(5-6):257-61. In modern industrial societies the attention to public health, especially in relation to food habits, is increasing day by day. Considering this, it's no wonder that wine, the voluptuary drink that best represents human history, is the most interesting compound. The main and best known wine effects on the human body are caused by alcohol, but several other active compounds are present in wine. Above all, resveratrol is able to neutralize free radicals, which can damage DNA and may lead to cancer onset. In this study, we have indagated resveratrol anticancer action, analyzing its effects on both cell cycle and growing of human lymphoma B (DHL-4) cells. MTT colorimetric test, tripan blue dye exclusion assay, and cell cycle analysis showed that resveratrol has a dose-dependent antiproliferative and antiapoptotic action on DHL-4 cells. These results confirm resveratrol's potential therapeutic role on tumors. --------------------------- Potent induction of cellular antioxidants and phase 2 enzymes by resveratrol in cardiomyocytes: protection against oxidative and electrophilic injury. Cao Z, Li Y. St. 's University College of Pharmacy and Allied Health Professions, Jamaica, NY Eur J Pharmacol. 2004 Apr 5;489(1-2):39-48. Resveratrol is known to be protective against oxidative cardiovascular disorders. However, the underlying mechanisms remain unclear. This study was undertaken to determine if resveratrol could increase endogenous antioxidants and phase 2 enzymes in cardiomyocytes, and if such increased cellular defenses could provide protection against oxidative and electrophilic cell injury. Incubation of cardiac H9C2 cells with low micromolar resveratrol resulted in a significant induction of a scope of cellular antioxidants and phase 2 enzymes in a concentration- and/or time- dependent fashion. To investigate the protective effects of the resveratrol-induced cellular defenses on oxidative and electrophilic cell injury, H9C2 cells were first incubated with resveratrol, and then exposed to xanthine oxidase (XO)/xanthine, 4-hydroxy-2-nonenal or doxorubicin. We observed that resveratrol pretreatment afforded a marked protection against the above agent-mediated cytotoxicity in H9C2 cells. Moreover, the resveratrol pretreatment led to a great reduction in XO/xanthine-induced intracellular accumulation of ROS. Taken together, this study demonstrates that resveratrol induces antioxidants and phase 2 enzymes in cardiomyocytes, which is accompanied by increased resistance to oxidative and electrophilic cell injury. --------------------- Modulation of androgen receptor-dependent transcription by resveratrol and genistein in prostate cancer cells. Gao S, Liu GZ, Wang Z. The University of Texas M. D. Cancer Center, Houston, Texas. Prostate. 2004 May 1;59(2):214-25. BACKGROUND: The androgen receptor (AR) is a ligand-activated transcription factor that mediates the biological responses of androgens in the prostate gland. This study focuses on the chemopreventive agents, resveratrol and genistein, on AR-mediated transcription in prostate cancer cells. RESULTS: We found that resveratrol and genistein activated AR-driven gene expression at low concentrations, whereas they repressed the AR-dependent reporter gene activity at high concentrations. We determined that resveratrol and genistein induced AR-driven gene expression by activating the Raf-MEK- ERK kinase pathway. The ERK1 kinase phosphorylated the AR on multiple sites in vitro, but this phosphorylation event did not contribute to the resveratrol-induced AR transactivation. CONCLUSIONS: In vitro and in vivo studies have indicated that resveratrol and genistein are promising chemopreventive agents. Given the clear evidence that AR pathways are involved in the development and progression of prostate cancer, these data showed that the ability to modulate AR function would contribute the observed chemopreventive activity of resveratrol and genistein. ------------------- Resveratrol suppresses the angiogenesis and tumor growth of gliomas in rats. Clin Cancer Res. 2004 Mar 15;10(6):2190-202. PURPOSE: We wanted to investigate the antitumor effects and effect on angiogenesis of resveratrol in rat RT-2 gliomas. RT-2 glioma cells were treated with resveratrol, and then cytotoxicity was assayed, apoptosis was measured by flow-activated cell sorter flow cytometry, and expression of vascular endothelial growth factor was measured by reverse transcription-PCR. Tumor size, animal survival time, and survival rate were followed in resveratrol-treated rats with s.c. or intracerebral gliomas. Furthermore, in vitro proliferation was assayed to explore the effect of resveratrol on the proliferation of ECV304 human umbilical vein endothelial cells. Expression of CD31 in resveratrol-treated gliomas was followed immunohistochemically to study the effect of resveratrol on the glioma-induced angiogenesis. RESULTS: Resveratrol was demonstrated to exert cytotoxic effects and induce glioma cell apoptosis in a concentration- and time-dependent manner. Resveratrol (40 mg/kg/day) exerted significant antitumor effects on s.c. tumors, including slower tumor growth rate, longer animal survival time, and higher animal survival rate (P < 0.05). In contrast, resveratrol affected intracerebral tumors at only an increased dose (100 mg/kg/day), prolonging animal survival (P < 0.05) without affecting survival rate. The expression of vascular endothelial growth factor in the glioma cells and the proliferation of ECV304 cells were inhibited by resveratrol in a concentration- dependent manner. Immunohistochemical analyses showed that the s.c. gliomas from resveratrol-treated rats had fewer microvessel densities than did control rats. CONCLUSIONS: Resveratrol caused significant glioma cell cytotoxicity and apoptosis, exerted antitumor effects on the s.c. and intracerebral gliomas, and inhibited angiogenesis in s.c. gliomas. Thus, resveratrol might be considered a possible treatment strategy for gliomas. ------------------ Neuroprotective effects of resveratrol against beta-amyloid-induced neurotoxicity in rat hippocampal neurons: involvement of protein kinase C. Br J Pharmacol. 2004 Mar;141(6):997-1005. Resveratrol, an active ingredient of red wine extracts, has been shown to exhibit neuroprotective effects in several experimental models. The present study evaluated the neuroprotective effects of resveratrol against amyloid beta(Abeta)-induced toxicity in cultured rat hippocampal cells and examined the role of the protein kinase C (PKC) pathway in this effect. Pre-, co- and post-treatment with resveratrol significantly attenuated Abeta-induced cell death in a concentration-dependent manner. Taken together, the present results indicate that PKC is involved in the neuroprotective action of resveratrol against Abeta-induced toxicity. ----------------- Resveratrol in raw and baked blueberries and bilberries. J Agric Food Chem. 2003 Sep 24;51(20):5867-70. Lyons MM, Yu C, Toma RB, Cho SY, Reiboldt W, Lee J, van Breemen RB. Food and Nutritional Science Division, California State University- Long Beach, CA 90840 Resveratrol in the fruits of bilberry (Vaccinium myrtillus L.), the lowbush " wild " blueberry (Vaccinium angustifolium Aiton), the rabbiteye blueberry (Vaccinium ashei Reade), and the highbush blueberry (Vaccinium corymbosum L.) were measured using a new assay based on high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). The LC-MS/MS assay provided lower limits of detection than previous methods for resveratrol measurement, 90 fmol of trans-resveratrol injected on-column, and a linear standard curve spanning >3 orders of magnitude. The recoveries of resveratrol from blueberries spiked with 1.8, 3.6, or 36 ng/g were 91.5, 95.6 +/- 6.5, and 88.0, respectively. trans-Resveratrol but not cis-resveratrol was detected in both blueberry and bilberry samples. The highest levels of trans-resvertatrol in these specimens were 140.0 +/- 29.9 pmol/g in highbush blueberries from Michigan and 71.0 +/- 15.0 pmol/g in bilberries from Poland. However, considerable regional variation was observed; highbush blueberries from British Columbia contained no detectable resveratrol. Because blueberries and bilberries are often consumed after cooking, the effect of baking on resveratrol content was investigated. After 18 min of heating at 190 degrees C, between 17 and 46% of the resveratrol had degraded in the various Vaccinium species. Therefore, the resveratrol content of baked or heat- processed blueberries or bilberries should be expected to be lower than in the raw fruit. Although blueberries and bilberries were found to contain resveratrol, the level of this chemoprotective compound in these fruits was <10% that reported for grapes. Furthermore, cooking or heat processing of these berries will contribute to the degradation of resveratrol. ---------------- Resveratrol protects myocardial ischemia-reperfusion injury through both NO-dependent and NO-independent mechanisms. Free Radic Biol Med. 2004 Mar 15;36(6):774-81. We previously showed that resveratrol (3,4',5-trihydroxystilbene) stimulates NO production and is cardioprotective in rat heart subjected to ischemia-reperfusion (I/R rat heart). We now show that in I/R rat heart, inducible nitric oxide synthase (iNOS) expression is markedly induced, while expression of endothelial nitric oxide synthase (eNOS) and nueronal nitric oxide synthase (nNOS) is unchanged. In animals preconditioned with resveratrol (0.5 to 1 mg/kg body wt), I/R-induced iNOS induction is abrogated; however, expression of eNOS and nNOS is greatly upregulated. The protective effects of resveratrol on I/R rat heart include reduced rhythm disturbances, reduced cardiac infarct size, and decreased plasma levels of lactate dehydrogenase (LDH) and creatine kinase (CK). Among these, the reductions in LDH/CK levels and infarct size are NO- dependent as the coadministration of N(omega)-nitro-L-arginine methyl ester (L-NAME, 1 mg/kg body wt) with resveratrol abolishes the resveratrol effect. In contrast, the reductions in the severity of ventricular arrhythmia and mortality rate are not affected by L-NAME coadministration, suggesting that a NO-independent mechanism is involved. (From: http://www.raysahelian.com/resveratrol.html) Quote Link to comment Share on other sites More sharing options...
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