Grape Constituents Research Articles

Inhibition of cell transformation by resveratrol and its derivatives: differential effects and mechanisms involved.

Resveratrol, a constituent of grapes and other foods, has been reported to be a potential cancer chemopreventive agent. Our previous study showed that the antitumor activity of resveratrol occurs through mitogen-activated protein kinases-mediated p53 activation and induction of apoptosis. To develop more effective agents with fewer side effects for the chemoprevention of cancer, we investigated the effect of resveratrol and its structurally related derivatives on epidermal growth factor (EGF)-induced cell transformation. Our results provided the first evidence that one of the resveratrol derivatives exerted a more potent inhibitory effect than resveratrol on EGF-induced cell transformation, but had less cytotoxic effects on normal nontransformed cells. Compared to resveratrol, this compound also caused cell cycle arrest in the G1 phase, but did not induce p53 activation and apoptosis. Furthermore, this compound, but not resveratrol, markedly inhibited EGF-induced phosphatidylinositol-3 kinase (PI-3K) and Akt activation. Collectively, these data suggested that the higher antitumor effect of the compound compared to resveratrol, may act through a different mechanism by mainly targeting PI-3K/Akt signaling pathways.

Involvement of c-jun NH(2)-terminal kinases in resveratrol-induced activation of p53 and apoptosis.

Resveratrol, a constituent of grapes and other foods, is one of the most promising agents for cancer prevention. In a previous study, we showed that the antitumor activity of resveratrol occurs through extracellular signal-regulated protein kinases (ERKs) and p38 kinase-mediated p53 activation. In this study, we also determined that c-jun NH(2)-terminal kinases (JNKs) are involved in resveratrol-induced p53 activation and induction of apoptosis. In the JB6 mouse epidermal cell line, resveratrol activated JNKs dose-dependently within a dose range of 10-40 microM, the same dosage responsible for the inhibition of tumor promoter-induced cell transformation. Stable expression of a dominant negative mutant of JNK1 or disruption of the Jnk1 or Jnk2 gene markedly inhibited resveratrol-induced p53-dependent transcription activity and induction of apoptosis. Furthermore, resveratrol-activated JNKs were shown to phosphorylate p53 in vitro, but this activity was repressed in the cells expressing a dominant negative mutant of JNK1 or in Jnk1 or Jnk2 knockout (Jnk1(-/-) or Jnk2(-/-)) cells. These data suggested that JNKs act as mediators of resveratrol-induced activation of p53 and apoptosis, which may occur partially through p53 phosphorylation.

Enhancement of red wine colour by pre-fermentation addition of copigments

Abstract The effects of pre-fermentation additions of catechin and caffeic acid to musts were investigated. The cultivar Listan negro, a major red grape grown in the Canary Islands, was used for these studies. The addition of catechin at 120 mg/l resulted in only 10% enhancement in wine colour (AU at 520 nm) after fermentation, while caffeic acid, at the same level, enhanced the wine colour by 60%. These results appear to be the first report of such a significant increase in wine colour achieved by pre-fermentation treatments with natural grape constituents, supporting the view that red wine colour is generally limited by the levels of cofactors for copigmentation rather than by the level of anthocyanins alone. This demonstrates the importance of non-pigment composition in establishing red wine colour and the influence of initial must composition.

Resveratrol Inhibits Intestinal Tumorigenesis and Modulates Host-Defense-Related Gene Expression in an Animal Model of Human Familial Adenomatous Polyposis

We studied the effect of oral administration of resveratrol, a natural constituent of grapes, on tumorigenesis in Min mice. Min mice are congenic mice genetically predisposed to develop intestinal tumors as a result of a mutation of the Apc gene. Resveratrol (0.01% in the drinking water containing 0.4% ethanol) was administered for seven weeks to Min mice starting at five weeks of age. The control group was fed the same diet and received water containing 0.4% ethanol. Resveratrol prevented the formation of colon tumors and reduced the formation of small intestinal tumors by 70%. Comparison of the expression of 588 genes in the small intestinal mucosa showed that resveratrol downregulated genes that are directly involved in cell cycle progression or cell proliferation (cyclins D1 and D2, DP-1 transcription factor, and Y-box binding protein). In addition, resveratrol upregulated several genes that are involved in the recruitment and activation of immune cells (cytotoxic T lymphocyte Ag-4, leukemia inhibitory factor receptor, and monocyte chemotactic protein 3) and in the inhibition of the carcinogenic process and tumor expansion (tumor susceptibility protein TSG101, transforming growth factor-β, inhibin-β A subunit, and desmocollin 2). Our data highlight the complexity of the events associated with intestinal tumorigenesis and the multiplicity of the molecular targets of resveratrol. The high potency and efficacy of resveratrol support its use as a chemopreventive agent in the management of intestinal carcinogenesis.

Cardioprotective Effects of Grape Seed Proanthocyanidin Against Ischemic Reperfusion Injury

There is increasing evidence to indicate cardioprotective effects of red wine consumption. Such cardioprotective properties of wine have been attributed to certain polyphenolic constituents of grapes. The purpose of this investigation was to examine whether proanthocyanidins derived from grape seeds possess cardioprotective properties. Rats were randomly divided into two groups: grape-seed proanthocyanidin was administered orally to one group of rats (100 mg/kg/day) for 3 weeks while the other group served as control. After 3 weeks, rats were killed, hearts excised, mounted on the perfusion apparatus and perfused with Krebs–Henseleit bicarbonate (KHB) buffer. After stabilization hearts were perfused in the working mode for baseline measurements of contractile functions. Hearts were then subjected to 30 min of global ischemia followed by 2 h of reperfusion. Coronary perfusates were collected to monitor malonaldehyde formation, a presumptive marker for oxidative stress development. At the end of each experiment, the heart was processed for infarct size determination. Peroxyl radical scavenging activity of proanthocyanidin was determined by examining its ability to remove peroxyl radical generated by 2,2′-azobis (2-amidinopropane) dihydrochloride while hydroxyl radical scavenging activity was tested with its ability to reduce 7-OH·-coumarin-3-carboxylic acid. The results of our study demonstrated that proanthocyanidin-fed animals were resistant to myocardial ischemia reperfusion injury as evidenced by improved recovery of post-ischemic contractile functions. The proanthocyanidin-fed group revealed reduced extent of myocardial infarction compared to the control group. Fluorimetric study demonstrated the antioxidant property of proanthocyanidin as judged by its ability to directly scavenge peroxyl radicals. Taken together, the results of this study showed that grape seed-proanthocyanidins possess a cardioprotective effect against ischemia reperfusion injury. Such cardioprotective property, at least in part, may be attributed to its ability to directly scavenge peroxyl and hydroxyl radicals and to reduce oxidative stress developed during ischemia and reperfusion.

Grape catechins—natural antioxidants

Catechin monomers and procyanidin dimers of group B are constituents of grapes, with grape seeds the natural reservoir of these polyphenols. The antioxidant properties of these natural compounds is well established. In this research the mass fractions of catechin monomers (+)‐catechin and (‐ )‐epicatechin, and of procyanidin dimers B1, B2, B3 and B4, were determined in the grape skin extracts of 10 different grape cultivars. Fractionation of neutral phenolics was carried out on Sep Pak C18 cartridges. Separation and quantification of catechin monomers and procyanidin B dimers were undertaken using the high‐performance liquid chromatography reversed‐phase technique. The results confirmed the presence of catechin monomers in almost all the grape skin extracts analysed from the 1990, 1991 and 1992 vintages. The dominating catechin monomer was (+)‐catechin, except for grape skin extracts of Cabernet Sauvignon cv. (vintage 1992). The dominating procyanidin dimer was procyanidin dimer B1. According to the results obtained, the amounts of catechin monomers and procyanidin dimers of group B in the grape skin extracts are not sufficiently high to consider the grape skin a rich source of these polyphenolic compounds.

The polyphenol constituents of grape pomace

Chemical investigation of Chardonnay grape pomace has resulted in the isolation of 17 polyphenols which were identified by NMR spectroscopy as gallic acid, its 3- and 4-β-glucopyranosides, trans-caftaric acid, cis- and trans-coutaric acid, 2-hydroxy-5-(2-hydroxyethyl)phenyl-β-glucopyranoside, catechin, epicatechin, procyanidin B1, quercetin 3-glucoside, quercetin 3-glucuronide, kaempferol 3-glucoside, kaempferol 3-galactoside, eucryphin, astilbin and engeletin. Gallic acid 3-β-glucopyranoside, gallic acid 4-β-glucopyranoside and 2-hydroxy-5-(2-hydroxyethyl)phenyl-β-glucopyranoside are reported here as natural grape constituents for the first time. ©

Chemopreventive Agent Resveratrol, a Natural Product Derived From Grapes, Triggers CD95 Signaling-Dependent Apoptosis in Human Tumor Cells

AbstractResveratrol, a constituent of grapes and other food products, has been shown to prevent carcinogenesis in murine models. We report here that resveratrol induces apoptotic cell death in HL60 human leukemia cell line. Resveratrol-treated tumor cells exhibit a dose-dependent increase in externalization of inner membrane phosphatidylserine and in cellular content of subdiploid DNA, indicating loss of membrane phospholipid asymmetry and DNA fragmentation. Resveratrol-induced cell death is mediated by intracellular caspases as observed by the dose-dependent increase in proteolytic cleavage of caspase substrate poly (ADP-ribose) polymerase (PARP) and the ability of caspase inhibitors to block resveratrol cytotoxicity. We also show that resveratrol treatment enhances CD95L expression on HL60 cells, as well as T47D breast carcinoma cells, and that resveratrol-mediated cell death is specifically CD95-signaling dependent. On the contrary, resveratrol treatment of normal human peripheral blood lymphocytes (PBLs) does not affect cell survival for up to 72 hours, which correlates with the absence of a significant change in either CD95 or CD95L expression on treated PBLs. These data show specific involvement of the CD95-CD95L system in the anti-cancer activity of resveratrol and highlight the chemotherapeutic potential of this natural product, in addition to its recently reported chemopreventive activity.© 1998 by The American Society of Hematology.

Chemopreventive Agent Resveratrol, a Natural Product Derived From Grapes, Triggers CD95 Signaling-Dependent Apoptosis in Human Tumor Cells

Resveratrol, a constituent of grapes and other food products, has been shown to prevent carcinogenesis in murine models. We report here that resveratrol induces apoptotic cell death in HL60 human leukemia cell line. Resveratrol-treated tumor cells exhibit a dose-dependent increase in externalization of inner membrane phosphatidylserine and in cellular content of subdiploid DNA, indicating loss of membrane phospholipid asymmetry and DNA fragmentation. Resveratrol-induced cell death is mediated by intracellular caspases as observed by the dose-dependent increase in proteolytic cleavage of caspase substrate poly (ADP-ribose) polymerase (PARP) and the ability of caspase inhibitors to block resveratrol cytotoxicity. We also show that resveratrol treatment enhances CD95L expression on HL60 cells, as well as T47D breast carcinoma cells, and that resveratrol-mediated cell death is specifically CD95-signaling dependent. On the contrary, resveratrol treatment of normal human peripheral blood lymphocytes (PBLs) does not affect cell survival for up to 72 hours, which correlates with the absence of a significant change in either CD95 or CD95L expression on treated PBLs. These data show specific involvement of the CD95-CD95L system in the anti-cancer activity of resveratrol and highlight the chemotherapeutic potential of this natural product, in addition to its recently reported chemopreventive activity.© 1998 by The American Society of Hematology.

Effect of Flavour Extraction on the Phenolic Constituents of Grape Leaves

AbstractExtraction of phenolic compounds of grape leaves after flavour extraction has been studied. Fractionation of these compounds was done using thin‐layer and column chromatography and the compounds were identified by NMR analysis. A remarkable variation in the concentration of these phenolic compounds of all the varieties was observed. when subjected to flavour extraction.

Considerations of the Biological Significance of Some Volatile Constituents of Grape (Vitis spp)

The intensity and diversity of volatile constituents in the fruit of grape (Vitis spp.) cultivars assume importance to humans as sources of aroma and flavour of wine. These volatile constituents include hydrocarbons, esters, aldehydes, ketones, alcohols and compounds of miscellaneous structure (Schreier 1979). Their determination has been based invariably on juice expressed by maceration of the fruit or its parts and usually by chromatographic analysis of headspace or solvent extracts. Many of these constituents are common to most cultivars, and many are probably the products of hydrolytic andlor oxidative reactions resulting from the disruption of the internal compartmentation of the plant cells. For example, six carbon aldehydes form readily from unsaturated fatty acids under such conditions (Schreier 1979). While some of the volatile constituents of grape juice can therefore be considered products of cellular disorganisation, others are clearly products under genetic control, particularly those compounds associated with specific cultivars. In other biotic systems compounds of this latter group are now known to have important functions not associated directly with primary metabolism and have thus become known as secondary metabolites. Their adaptive value seems to rest with a role in ecological interactions with other plants, animals andlor the physical environment.

Sucrose Breakdown and Synthesis in the Ripening Grape Berry

Sucrose is the major translocated sugar in the grapevine (Swanson and EIShishiny 1958), but in the berry glucose and fructose together make up the bulk of the sugar content at all stages of development (Kliewer 1965a). The inversion of sucrose to glucose and fructose in ripening berries is suggested by the presence of invertase (Arnold 1965) and by the occurrence of approximately equal amounts of glucose and fructose (Kliewer 1965a). During the early stages of berry development, glucose and fructose concentrations are low, but at the onset of ripening there begins a phase of rapid glucose and fructose accumulation (Kliewer 1965a). Besides sugar, the other major soluble constituents of grapes are malate and tartrate. The concentrations of both substances increase rapidly in the immature berry, but when ripening commences sharp decreases occur, particularly in the concentration of malate (Kliewer 1965b). Some workers believe that malate and tartrate are translocated from the leaves (Amerine 1956; Peynaud and Maurie 1958) but there is evidence that some at least of the malate and tartrate is synthesized in the berry (Hale 1962). The mechanisms of the syntheses of malate and tartrate in the berry are not known.