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PubMed2006

Oncogenicity evaluation of resveratrol in p53(+/-) (p53 knockout) mice.

A six-month study was conducted in p53(+/-) mice to evaluate the possible oncogenicity of resveratrol (3,5,4'-trihydroxy-trans-stilbene), a cancer chemopreventive agent present in grapes and other foods. p53(+/-) mice (25/sex/group) received daily gavage exposure to vehicle only (negative control), resveratrol doses of 1000, 2000, or 4000 mg/kg/day, or p-cresidine (400 mg/kg/day; positive control). No mortality was seen in mice receiving the low dose of resveratrol. However, the mid and high doses induced mortality associated with impaction of the test article in the gastrointestinal tract. Resveratrol had no effect on body weight, food consumption, or clinical signs in surviving mice in any dose group, but induced dose-related increases in liver weight and serum cholesterol in both sexes. Mild anemia was seen in male mice at the high dose only; hematologic effects were not seen in females. Histopathology identified the kidney (hydronephrosis) and urinary bladder (epithelial hyperplasia) as target tissues for resveratrol toxicity. The incidences of both benign and malignant tumors in mice exposed to resveratrol were comparable to those in vehicle controls. By contrast, the positive control article, p-cresidine, induced urinary bladder cancer in both sexes. When administered to p53(+/-) mice at its maximum tolerated dose, resveratrol demonstrates no evidence of oncogenicity.

Administration, Oral↗
PubMed2004

Production of highly 13C-labeled polyphenols in Vitis vinifera cell bioreactor cultures.

The use of Vitis vinifera cells grown in a 2 l-stirred tank bioreactor for producing isotopically 13C-labeled phenolic substances is presented. Several culture parameters were optimized to achieve characteristics of growth and polyphenol metabolism similar to that recorded in shake flasks. Administration of [1-13C]L-phenylalanine (3 mM) to grape cell suspension cultures led to the production of 13C-labeled stilbenes (trans- and cis-piceids), catechins (catechin and epicatechin) and anthocyanins (delphinidin-, cyanidin-, petunidin-, peonidin- and malvidin-3-O-beta-glucosides). Incorporation of [1-13C]L-phenylalanine into polyphenols was measured by means of 13C satellites in the proton NMR spectrum and EA-IRMS. The enrichment of labeling obtained for all the compounds (between 40 and 65%) is sufficient to investigate their absorption and metabolism in humans.

Bioreactors↗
PubMed2006

The rolB gene-induced overproduction of resveratrol in Vitis amurensis transformed cells.

Resveratrol is a stilbene, which prevents carcinogenesis at stages of tumor initiation, promotion and progression. In the present investigation, we developed cell cultures of wild-growing grape (Vitis amurensis Rupr.). The cultures produced low levels of resveratrol, up to 0.026% dry wt., i.e., comparable to levels reported for other plant cell cultures previously established. Different methods commonly used to increase secondary metabolite production (cell selection, elicitor treatments and addition of a biosynthetic precursor) only slightly enhanced cell productivity. Transformation of V. amurensis V2 callus culture by the rolB gene of Agrobacterium rhizogenes resulted in more than a 100-fold increase in resveratrol production in transformed calli. The rolB-transformed calli are capable of producing up to 3.15% dry wt. of resveratrol. We show that the capability to resveratrol biosynthesis is tightly correlated with the abundance of rolB mRNA transcripts. Tyrosine phosphatase inhibitors abolished the rolB-gene-mediated stimulatory effect, thus documenting for the first time the involvement of tyrosine phosphorylation in plant secondary metabolism.

Bacterial Proteins↗
PubMed2004

Phytoalexin resveratrol attenuates the mutagenicity of the heterocyclic amines 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline.

Resveratrol is a phytoalexin, that belongs to a family of naturally occurring stilbenes. It has been reported that resveratrol can inhibit chemical carcinogenesis in experimental animals and although the mechanisms involved are unknown, an anti-mutagen mechanism has been proposed. We have explored this hypothesis using mutagenicity assays based on bacterial (Salmonella typhimurium) and eukaryotic cells (Chinese hamster V79 cells). We found resveratrol to be potent in both systems, blocking the mutagenicity of the food-derived heterocyclic amines (HA) 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) at micromolar concentrations. Furthermore, in cells capable of activating 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine to cytotoxic derivatives, resveratrol was able to attenuate cytotoxicity. Paradoxically, in cells lacking the ability to activate PhIP, resveratrol itself was toxic and co-incubation with PhIP reduced this toxicity. Our data confirm the potent anti-mutagenic activity of resveratrol and support its potential as a chemopreventative.

Animals↗
PubMed2005

Metabolites and the pharmacokinetics of kobophenol A from Caragana sinica in rats.

This research aims to study the metabolism and pharmacokinetics of phytoestrogen kobophenol A (1), the main active compound of Caragana sinica (Buc'hoz) Rehd. (Fabaceae), in rats. Metabolites of 1 in rats' feces were isolated and purified by multi-chromatograph techniques; three new metabolites of 1, named koboquinone A (M1), koboquinone B (M2) and koboquinone C (M3), were isolated, purified from rats' feces after they being orally administered with 1. Structure identification of the metabolites was fulfilled by spectroscopic analysis. M1 and M2 are structurally different to those natural occurring stilbene tetramers, which also have para-quinone structure. M1 also showed the activity of stimulating the proliferation of cultured osteoblasts. The pharmacokinetics of 1 in rats could be described by a two-compartmental model (P<0.05). The half-life was 0.68 h for i.v. administration and 5.78 h for oral administration. The oral bioavailability of 1 was calculated to be 2.0%; rats tissue distribution experiments show that 1 was prominently concentrated in livers. Both of the low oral bioavailability and the rapid reduction of 1 in blood indicated a suitable formulation is needed while it is developed as a new drug.

Animals↗
PubMed2005

Divergent effects of resveratrol, a polyphenolic phytostilbene, on free radical levels and type of cell death induced by the histone deacetylase inhibitors butyrate and trichostatin A.

We investigated the effects of the polyphenolic phytostilbene resveratrol on the steady-state free radical (FR) concentration and mode of cell death induced by the histone deacetylase inhibitors butyrate and trichostatin A. (i) There was no correlation between cell death induction by butyrate or trichostatin A (TSA) and FR levels. (ii) Treatment with resveratrol or N-acetyl-l-cystein (NAC) of cells, in which the FR concentration was high, resulted in an almost complete reduction of FR levels. (iii) When, however, the cellular FR concentration was marginal, resveratrol caused a minor, and NAC a marked increase of FRs as well as of the extent of cell death. Thus, resveratrol and NAC acted as antioxidants only when the cellular FR levels were high, and acted as pro-oxidants when facing a low FR concentration. (iv) Since resveratrol and the antioxidant NAC exhibited analogous effects, it is concluded that the observed actions of resveratrol are due to polyphenolic redox reactions and not related to the stilbene moiety of the molecule. (v) The results indicate that the redox status of a given cell type plays an important role in determining whether resveratrol and other antioxidants promote cell death or protect cells from it.

Acetylcysteine↗
PubMed2004

Inhibition of inducible nitric oxide synthase expression by yuccaol C from Yucca schidigera roezl.

Yucca schidigera extract finds wide commercial application in foods, cosmetics and pharmaceuticals. In a previous paper we have found as the main constituents of yucca bark, yuccaol A, B and C, new and very unusual spiro-derivatives made up of a C15 unit and a stilbenic portion closely related to resveratrol. This study was performed to examine whether yuccaol A, B or C (0.01-100 microM) could affect cytosolic inducible nitric oxide synthase (iNOS) protein expression and nitric oxide (NO) generation in vitro in Escherichia coli lipopolysaccharide (LPS)-activated J774.A1 macrophage cell line. NO production, detected as NO2-, increased significantly in LPS treated J774.A1 cells from 0.05 +/- 0.03 microM to 16.64 +/- 0.58 microM (P < 0.001). Yuccaol C (0.01-100 microM), added to the culture medium 1 h before LPS-stimulation, significantly (P < 0.001) and in a concentration related manner reduced NO release (P < 0.001) and iNOS protein expression (P < 0.05). In contrast, no inhibitory effect either on iNOS protein expression or on NO release was observed when yuccaol C was added after LPS stimulation. In contrast yuccaol A inhibited significantly (P < 0.001) only NO release at the highest concentration tested (100 microM) while yuccaol B did not reduce either NO release or iNOS expression. Yuccaol C was demonstrated to reduce iNOS protein expression via the transcription factor NF-kappaB. These results indicated that the empirical use of Y. schidigera as anti-inflammatory remedy could be addressed not only to the resveratrol content but also to the presence of yuccaol C.

Analysis of Variance↗
PubMed2005

A blend of polyphenolic compounds explains the stimulatory effect of red wine on human endothelial NO synthase.

A high intake of polyphenolic compounds is likely to have beneficial effects on the cardiovascular system. Especially red wine is a rich source of polyphenols, and we have previously shown that French red wine upregulates eNOS, a protective enzyme in the cardiovascular system. The current study tested (poly)phenolic constituents of red wine for their ability to enhance eNOS expression (and the activity of a 3.5-kb human eNOS promoter) in human EA.hy 926 endothelial cells. Of the compounds tested, we found 3,4',5-trihydroxy-trans-stilbene (trans-resveratrol) to be the most efficacious stimulator of eNOS expression (and eNOS transcription), but this compound alone could not explain the total stimulatory effect of red wine. The flavanols catechin and epicatechin, the flavonols fisetin, myricetin, isoquercitrin and hyperoside, the anthocyanins delphinidin, malvidin, and paeonidin, gallic acid, and the hydroxycinnamic acids ferulic acid and sinapinic acid did not change eNOS expression or eNOS promoter activity in any substantial way. The flavonol quercetin inhibited eNOS expression (with no effect on eNOS promoter activity). Cinnamic acid was a rather potent enhancer of eNOS expression, however with an efficacy of only 170%. Surprisingly, it reduced eNOS promoter activity. The anthocyanins cyanidin, the hydroxycinnamic acids p-coumaric acid and caffeic acid, and the phenolic acids benzoic acid and vanillic acid also enhanced eNOS expression moderately (with no effect on eNOS promoter activity). Thus, the increase in eNOS in response to red wine involves several polyphenolic compounds with a major contribution from trans-resveratrol and lesser contributions from cinnamic and hydroxycinnamic acids, cyanidin, and some phenolic acids.

Anthocyanins↗
PubMed2004

Dietary phytoestrogens and health.

The interest in the potential health effects of dietary phytoestrogens has increased with the findings that hormone replacement therapy is not as safe or effective as previously thought. This review summarizes the dietary sources of the phytoestrogens; isoflavonoids, stilbenes, coumestans and lignans. It also examines 105 clinical studies related to effects of phytoestrogens on bone density, cardiovascular health, cancer prevention, cognitive ability and menopausal symptoms.

Animals↗
PubMed2006

Stilbenoids from Tragopogon orientalis.

A phytochemical investigation of Tragopogon orientalis L. (Asteraceae, Cichorieae) yielded the natural products 6''-O-(7,8-dihydrocaffeoyl)-alpha,beta-dihydrorhaponticin, 3'-O-methyl-alpha,beta-dihydrorhaponticin, and (S)-3-(4-beta-glucopyranosyloxybenzyl)-7-hydroxy-5-methoxyphtalide as well as known compounds alpha,beta-dihydrorhaponticin, 3-(4-methoxybenzyl)-5,7-dimethoxyphthalide, p-dihydrocoumaric acid methyl ester, and 1-hydroxypinoresinol-1-O-beta-glucopyranoside. The structures were established by HR mass spectrometry, extensive 1D and 2D NMR spectroscopy, and CD spectroscopy. Moreover, the radical scavenging activities of the major compounds were measured using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay. The chemosystematic impact of the occurrence of stilbene derivatives in T. orientalis is discussed.

Antioxidants↗
PubMed1997

Self-association of Band 3, the human erythrocyte anion exchanger, in detergent solution.

Dimeric Band 3 purified in n-dodecyl octaethyleneglycol (C12E8) underwent an irreversible, temperature-dependent association, resulting in a complex with a Stokes radius slightly larger than a native tetramer, before forming a higher molecular weight aggregate. Self-association occurred with a half-time of about 1 h at 37 degrees C but did not occur at 0 degrees C after several days. No change in the secondary structure of Band 3, as observed by circular dichroism, occurred during the association process. However, self-association of Band 3 was accompanied by loss of the stilbene disulfonate inhibitor binding site. No association or loss of inhibitor binding occurred with the dimeric membrane domain under similar incubation conditions. The membrane domain dimer was also stable over a wide range of pH (5.5-9.5) and buffer conditions, while Band 3 aggregated below pH 6.5. Inhibitors of anion transport, which stabilize the membrane domain, slowed the association. Band 3, depleted of phospholipids by extensive washing of resin-bound protein with detergent or, incubated with excess detergent, was more prone to aggregation. The membrane domain also showed some aggregation when depleted of lipids. Preparations could be stabilized by adding dimyristoylphosphatidylcholine (DMPC) prior to the 37 degrees C incubation. The effect of inhibitors and DMPC was additive, with a combination of 1 mM 4,4'-dinitrostilbene-2,2'-disulfonate (DNDS) and 1:1 (wt/wt) DMPC:Band 3 stabilizing 90% of the protein to a 24-h incubation at 37 degrees C. The results suggest that self-association of Band 3 dimers is promoted by the cytoplasmic domain but results in alterations to the membrane domain involving the loss of essential phospholipids. Addition of phospholipid or inhibitors to Band 3 results in a stable preparation of the intact protein that may be suitable for crystallization studies.

Anion Exchange Protein 1, Erythrocyte↗
PubMed1978

Effects of ammonium and bicarbonate-CO2 on intracellular chloride levels in Aplysia neurons.

The level of intracellular free chloride in Aplysia giant neurons can be made to decline by pretreatment with 50 mM NH4+ solution followed by washing with 10 mM HCO3-/0.4% CO2-containing fluids. This effect can be completely blocked by the anion flux inhibitor, 4-acetamido-4'-isothiocyano-stilbene-2,2'-disulfonic acid (SITS). The net change of free chloride in the cell cannot be explained by changes in the electrochemical gradient of chloride. These results support the hypothesis that at least one mechanism for intracellular pH regulation involves a Cl-/HCO-3 exchange process.

Animals↗
PubMed1999

Hydrodynamic properties of human erythrocyte band 3 solubilized in reduced Triton X-100.

The oligomeric state and function of band 3, purified by sulfhydryl affinity chromatography in reduced Triton X-100, was investigated. Size exclusion high-performance liquid chromatography showed that a homogeneous population of band 3 dimers could be purified from whole erythrocyte membranes. The elution profile of band 3 purified from membranes that had been stripped of its cytoskeleton before solubilization was a broad single peak describing a heterogeneous population of oligomers with a mean Stokes radius of 100 A. Sedimentation velocity ultracentrifugation analysis confirmed particle heterogeneity and further showed monomer/dimer/tetramer equilibrium self-association. Whether the conversion of dimer to the form described by a Stokes radius of 100 A was initiated by removal of cytoskeletal components, alkali-induced changes in band 3 conformation, or alkali-induced loss of copurifying ligands remains unclear. After incubation at 20 degrees C for 24 h, both preparations of band 3 converted to a common form characterized by a mean Stokes radius of 114 A. This form of the protein, examined by equilibrium sedimentation ultracentrifugation, is able to self-associate reversibly, and the self-association can be described by a dimer/tetramer/hexamer model, although the presence of higher oligomers cannot be discounted. The ability of the different forms of the protein to bind stilbene disulfonates revealed that the dimer had the highest inhibitor binding affinity, and the form characterized by a mean Stokes radius of 114 A to have the lowest.

Anion Exchange Protein 1, Erythrocyte↗
PubMed1985

Subcellular distribution, catalytic properties and partial purification of epoxide hydrolase in the human adrenal gland.

Epoxide hydrolase in human adrenal gland was characterized with respect to catalytic properties and subcellular distribution. With human adrenal microsomes and the substrates styrene-7,8-oxide, cis-stilbene oxide, estroxide and androstene oxide the specific activities were between 1.9 and 19.0 nmol/min/mg protein. With styrene-7,8-oxide as substrate the apparent Km-value was 0.98 mM and the pH optimum was 9.2. Subcellular fractionation revealed that the bulk of the activity was confined to the endoplasmic reticulum. Different compounds known to influence rodent microsomal epoxide hydrolase activity were also tested on the human adrenal enzyme. 1,1,1-Trichloropropene-2,3-oxide (TCPO) and cyclohexene oxide (CHO) inhibited the activity while benzil and clotrimazole stimulated the activity. Partial purification of human adrenal epoxide hydrolase indicates that its molecular weight is about 51 000 and that its concentration relative total protein in the human adrenal microsomes is about 10%.

Adrenal Glands↗
PubMed2002

A comparison of the anticarcinogenic properties of four red wine polyphenols.

BACKGROUND: There has been growing interest in the analysis of certain polyphenols in wine, especially flavonoids, trihydroxystilbenes and phenolic acids, stimulated by intense research into their potential benefits to human health. One of their main properties in this regard is their antioxidant activity, which enables them to attenuate the development of atherosclerosis, inflammatory diseases, and cancer. METHODS: A two stage CD-1 mouse skin cancer model using 9,10-dimethyl-1,2-benzanthracene (DMBA) as initiator and phorbol 12-myristate 13-acetate (TPA) as promoter was employed to compare the antitumorigenic activities of one polyphenol from each of four different classes: flavanols [(+)-catechin], stilbenes (trans-resveratrol), flavonols (quercetin) and hydroxybenzoic acids (gallic acid). Animals were treated with specific polyphenols at doses ranging from 0 to 25 micromoles (dissolved in 200 microL acetone), twice a week for eighteen weeks. The solution was applied topically to the shaved dorsal region of each animal. The relative potencies of the polyphenols were compared by evaluating the percentage inhibition of tumor formation in individual mice and the number of mice developing one or more tumors with the different dose schedules. RESULTS: Probit analysis revealed that quercetin was the most (ED(50)<1 micromole) and gallic acid the least effective (ED(50) 5-10 micromoles). (+)-Catechin and trans-resveratrol were intermediate, with ED(50) values of 5 and 6 micromoles, respectively. CONCLUSION: We have shown recently that trans-resveratrol is absorbed much more efficiently than (+)-catechin and quercetin in humans after oral consumption. Taking this and the relative concentrations in red wine into account, together with the present results, we conclude that trans-resveratrol may be the most effective anticancer polyphenol present in red wine as consumed po by healthy human subjects.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed2002

Piceatannol, a Syk-selective tyrosine kinase inhibitor, attenuated antigen challenge of guinea pig airways in vitro.

Activation of nontransmembrane protein tyrosine kinases, such as Lyn and Syk, has been shown to be the earliest detectable signaling response to Fc receptor (Fc epsilon RI) cross-linking on mast cells leading to mast cell degranulation. The present study examined the effects of piceatannol (3,4,3',5'-tetrahydroxy-trans-stilbene, 10-100 microM), a Syk-selective tyrosine kinase inhibitor, on ovalbumin-induced anaphylactic contraction of isolated guinea pig bronchi and release of histamine and peptidoleukotrienes from chopped lung preparations. Pretreatment with piceatannol slightly suppressed ovalbumin-induced peak anaphylactic bronchial contraction but markedly (P<0.05) facilitated relaxation of the anaphylactically contracted bronchi. Piceatannol did not inhibit direct histamine-, leukotriene D(4)- or KCl-induced bronchial contraction, nor revert an existing anaphylactic bronchial contraction. Piceatannol, at 30 microM and above, significantly (P<0.05) prevented ovalbumin-induced release of both histamine and peptidoleukotrienes from lung fragments. Piceatannol did not inhibit exogenous arachidonic acid-induced release of peptidoleukotrienes from lung fragments. Our data show for the first time that inhibition of Syk tyrosine kinase can attenuate anaphylactic bronchial contraction in vitro, probably via inhibition of mast cell degranulation.

Airway Obstruction↗
PubMed2003

Oral administration of trans-resveratrol to guinea pigs increases cardiac DT-diaphorase and catalase activities, and protects isolated atria from menadione toxicity.

Resveratrol (3,4',5-trihydroxy-trans-stilbene) is a natural phytoalexin found in grapes and wine. It has antioxidant and antiproliferative activities, and has been shown to induce NAD(P)H:quinone oxidoreductase, also known as DT-diaphorase, in cultured mouse hepatoma cells. DT-diaphorase is a detoxifying enzyme for quinone-containing substances, due to its ability to prevent their one-electron reduction and the consequent generation of reactive oxygen species (ROS). The aim of the present study was to investigate whether oral administration of trans-resveratrol to guinea pigs (60 mg/l in tap water for 16 days, ad libitum) increases cardiac DT-diaphorase and, consequently, reduces the response of isolated atria to 2-methyl-1,4-naphthoquinone (menadione), the positive inotropic effect of which is related to the amount of ROS generated by its cardiac metabolism. In the cardiac tissue of resveratrol-treated animals, DT-diaphorase activity was significantly higher than that measured in control animals, the V(max) of the enzyme reaction being 75.47 +/- 3.87 and 50.73 +/- 0.63 nmoles/mg protein/min, respectively (p < 0.05). Resveratrol administration also significantly increased the activity of cardiac catalase (32.20 +/- 2.39 vs. 25.14 +/- 3.85 units/mg protein in treated and control animals, respectively; p < 0.001). As a consequence, menadione metabolism by the cardiac homogenate obtained from resveratrol-treated animals generated a smaller amount of ROS and, in electrically driven left atria, menadione produced a significantly lower increase in the force of contraction than in atria isolated from control animals. These results indicate that oral administration of resveratrol exerts cardioprotection against ROS-mediated menadione toxicity.

Animals↗
PubMed2002

Stilbenoids from the stem of Gnetum latifolium (Gnetaceae).

An acetone extract of the stem of Gnetum latifolium Blume afforded the stilbene trimer (latifolol) together with five known stilbenoids (gnetin E, gnetin D, gnetin C, (-)epsilon -viniferin and resveratrol). Their structures were elucidated on the basis of spectral evidence, in particular by using 2D NMR methods.

Gnetum↗