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[Resveratrol: Distribution, properties and perspectives.]
Abstract
Resveratrol is a natural polyphenol which can be found in many plants and fruits, such as peanuts, mulberries, blueberries and, above all, in grapes and red wine. Its synthesis is regulated by the presence of stressful factors, such as fungal contamination and ultra-violet radiation. In plants, it plays a role as a phytoalexin, showing a capacity to inhibit the development of certain infections. Plant extracts which contain resveratrol have been employed by traditional medicine for more than 2000 years. Resveratrol was first isolated, and its properties were initially studied with scientific methods, thirty years ago. Its in vitro properties have been extensively studied and demonstrated. It is worth highlighting its activity as an anti-cancer agent, platelet anti-aggregation agent, anti-inflammatory, antiallergenic, etc. The activity of its in vivo properties are not so clear. There are many studies that report benefits on the cardiovascular system, illnesses such as diabetes, and in longevity. However, other authors did not find any agreement between in vitro and in vivo studies. This discrepancy is due to the bioavailability of resveratrol. After an oral dose, it has been demonstrated that the absorption is very high, but the metabolic pathways leave just a little free resveratrol in blood, therefore the bioavailability in the target tissues is very low and the concentrations used in in vitro studies are not found in these tissues. Thus, resveratrol is a very active molecule for maintaining health, but due to the low bioavailability not all the in vitro effects can be translated to in vivo. This opens a new potential approach, seeking derivatives of resveratrol that can be measured in the desired tissues.
Copyright © 2011 SEGG. Published by Elsevier Espana. All rights reserved.
... Piceatanol and resveratrol are naturally occurring stilbenes found primarily in grapes, berries, peanuts, and red wine. Both species are acknowledged as antioxidants, and in addition to that, they offer a diverse range of health benefits, such as estrogenic, anti-inflammatory, and anticancer activities [76][77][78][79][80]. ...
... Estimates of plasma concentrations of resveratrol plus total metabolites were considerably higher, around (400-500) ng/mL (≈2 mM) indicating a very low oral bioavailability for free resveratrol. However, studies in rats have shown that after prolonged administration (15 to 20 weeks), there is a saturation of the metabolism, which leads to an increase in resveratrol in plasma and, therefore in tissues [79]. Thus, if the intake of polyphenols is prolonged, their concentrations increase enough for their biological properties to be appreciable [77,79,82]. ...
... However, studies in rats have shown that after prolonged administration (15 to 20 weeks), there is a saturation of the metabolism, which leads to an increase in resveratrol in plasma and, therefore in tissues [79]. Thus, if the intake of polyphenols is prolonged, their concentrations increase enough for their biological properties to be appreciable [77,79,82]. ...
Glutathione (GSH) and phenols are well-known antioxidants, and previous research has suggested that their combination can enhance antioxidant activity. In this study, we used Quantum Chemistry and computational kinetics to investigate how this synergy occurs and elucidate the underlying reaction mechanisms. Our results showed that phenolic antioxidants could repair GSH through sequential proton loss electron transfer (SPLET) in aqueous media, with rate constants ranging from 3.21 × 10⁶ M⁻¹ s⁻¹ for catechol to 6.65 × 10⁸ M⁻¹ s⁻¹ for piceatannol, and through proton-coupled electron transfer (PCET) in lipid media with rate constants ranging from 8.64 × 10⁶ M⁻¹ s⁻¹ for catechol to 5.53 × 10⁷ M⁻¹ s⁻¹ for piceatannol. Previously it was found that superoxide radical anion (O2•−) can repair phenols, thereby completing the synergistic circle. These findings shed light on the mechanism underlying the beneficial effects of combining GSH and phenols as antioxidants.
... Another important component found in high amounts in M. cochinchinens resveratrol, a substance present in several plant species such as grapes, blueberries, nuts, and blackberries. Its presence is mainly associated with the plant's response to ous stress conditions [71]; resveratrol is a natural polyphenol of great importance in h due to its biological properties such as antioxidant, anticancer, antiaging, antiplatele gregation, anti-inflammatory, antiallergic, antiobesity, antidiabetes, cardioprotect and neuroprotectivity [72,73] Studies such as that of Lakornwong et al. [74] have identified the cytotoxic pote of M. cochinchinensis, managing to isolate three furanoxanthones, macochinxanthones sixteen xanthones from its roots that exhibited potent cytotoxicity against four cance lines (KB, HelaS3, A549, and HepG2). In this sense, it has been identified that the p group located in position C-6 of prenylisoflavones 1-4 and 6-7 improved the cytotox of the isoflavone against the KB and HepG2 lines [75]. ...
... Another important component found in high amounts in M. cochinchinensis is resveratrol, a substance present in several plant species such as grapes, blueberries, peanuts, and blackberries. Its presence is mainly associated with the plant's response to various stress conditions [71]; resveratrol is a natural polyphenol of great importance in health due to its biological properties such as antioxidant, anticancer, antiaging, antiplatelet aggregation, anti-inflammatory, antiallergic, antiobesity, antidiabetes, cardioprotectivity, and neuroprotectivity [72,73] Studies such as that of Lakornwong et al. [74] have identified the cytotoxic potential of M. cochinchinensis, managing to isolate three furanoxanthones, macochinxanthones, and sixteen xanthones from its roots that exhibited potent cytotoxicity against four cancer cell lines (KB, HelaS3, A549, and HepG2). In this sense, it has been identified that the prenyl group located in position C-6 of prenylisoflavones 1-4 and 6-7 improved the cytotoxicity of the isoflavone against the KB and HepG2 lines [75]. ...
Maclura is a plant genus little known and used, species of which have been mainly used in the recovery of soils, for medicinal purposes such as dental infection treatments, and as wood for making furniture and construction. The overexploitation of this genus has placed certain species in endangered extinction status in some countries, such as Brazil. In addition, the scarce research and information limit the development, cultivation, and management of its species regarding their biochemical composition, which includes bioactive compounds such as the phenolic and flavonoid compounds found in some species such as M. pomifera, M. cochinchinensis, and M. tinctoria. The plants’ antioxidant, antimicrobial, anticancer, anti-inflammatory, and antiproliferative activities have been attributed to these compounds. Other biochemical components such as ashes, insoluble lignin, holocellulose, and the high content of lipids and carbohydrates have been identified to be used to produce biofuels, with characteristics very similar to fuels derived from petroleum. This review aims to analyze the current knowledge on the plant genus Maclura, exploring its biochemical compounds and potential applications, including as a food additive, antioxidant supplement, in agriculture, for therapeutic purposes, aquaculture, and the cosmetic and industrial sector.
... As a phytoalexin, resveratrol inhibits originally the development of certain infections of the plant by activating defence mechanisms of the plant against pathogens. Plant extracts containing resveratrol have been used for treatment of different diseases for more than 2000 years [20]. Resveratrol possesses not only antioxidant, anti-inflammatory, antiviral and neuroprotective effects, but also antiproliferative, antiangiogenic and anticancer activities shown in different types of cancer [21] like ovarian cancer [22], breast cancer [23], colorectal cancer [24] as well as in prostate cancer cells [25][26][27]. ...
... Nevertheless, to date, it is not used clinically due to poor solubility, a rapid degradation and a high metabolism resulting in a low bioavailability [20,28,29]. ...
Prostate cancer is one of the most common cancers in men. Despite the development of diverse therapeutic agents for different types and stages, the progression or spread of the disease is inevitable. Another problem is the development of resistance of cancer cells to available therapeutics. Therefore, additional medicaments are urgently needed. Resveratrol is a polyphenolic phytoalexin found in numerous plants and fruits like red grapes or blueberries. Resveratrol possesses antiproliferative, anti-angiogenic and anticancer activities well proven in different types of cancer including prostate cancer. To date, it is not used clinically due to poor solubility, low bioavailability, and other limiting factors. In order to overcome these limitations, novel nanoparticle-based formulations were developed over the past years. In this review article, studies about the effect of resveratrol on prostate cancer cells are discussed focusing especially on those studies using nanotechnology. An electronic literature research was performed utilizing PubMed in August 2022. Scientific publications, which examine resveratrol using nanotechnology, are discussed. The studies clearly indicate that resveratrol-loaded nanoparticles exhibited a remarkable anti-cancer activity in various hormone-sensitive and hormone-insensitive prostate cancer cell lines including docetaxel-resistant prostate-cancer cells. The types of nanoparticles that were used varied and influenced the outcome. Additionally, the meaning of the surface functionality of the nanoparticles is emphasized. No reduction of the anti-proliferative activity of resveratrol was shown when used encapsulated. Additionally, synergistic effects of resveratrol and docetaxel were proven. Resveratrol-loaded nanoparticles, especially when combined, may represent the next generation of anticancer substances. However, further in vivo/clinical studies are necessary to confirm their clinical effectiveness.
... It belongs to the family of stilbenes (Fig. 2) and can be found in cis or trans configurations. Commonly, RSV is simple binding sugars forming glycosylated compounds in nature [52]. Although it is present in more than 70 species of plants, in general, stilbenes are consumed in low amounts in the human diet and their levels vary considerably between different food [5]. ...
... In fact, dietary RSV is about milligrams [18], so that direct supplements are available to elevate their levels to gram [53]. Some significant sources of RSV are cranberries (Vaccinium spp.), currant (Vaccinum spp.), blackberries (Morus spp.), grapes (Vitis vinifera) and peanuts (Arachis hypogaea), although an important source in the human diet is wine (0.3-7 mg of aglycone/L and 15 mg of glycosides/L in red wine) [52,54]. Grapes and peanuts mainly contain glycosylated RSV in its trans configuration, while red wine in cis and trans configurations [18]. ...
Background
Non-alcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease worldwide directly related to the progressive increase in overweight and obesity. The accumulation of lipids in patients with NAFLD contributes to the development of insulin resistance, inflammatory response and oxidative stress in hepatocytes and an alteration of the circulating lipid and glycaemic profile. However, to date there are no effective pharmacological treatments for patients with NAFLD. Lifestyle changes and dietary modifications aimed to weight loss are the best current alternatives, therefore, new approaches should be considered. Resveratrol, a natural polyphenol of the stilbene group, is a potential candidate to be aware of the management of NAFLD for its anti-inflammatory, antioxidant properties, and calorie restriction-like effects.
Methods
In this review, the available information on the potential therapeutic effects of resveratrol on NAFLD developed mainly in animal models and in some clinical trials are summarize.
Results
In vitro and animal model studies have shown beneficial effects of resveratrol treatment on NAFLD. Resveratrol reduces hepatic accumulation of lipids and improves lipid and glycaemic metabolism. Some of the mechanisms of action are the signalling pathways of AMP-activated protein kinase, sirtuin 1 and nuclear factor κB. However, the results obtained in clinical trials are inconclusive.
Conclusion
Although preclinical trials have shown promising results of resveratrol against NALFD, the lack of clear results in clinical trials makes necessary more studies with a larger number of patients and for a longer time.
... Resveratrol (3,5,4'-trihydroxy-stilbene) is a natural polyphenolic compound belonging to stilbene family that it is normally found in seeds, wines and skin of grapes, soybeans, cherries, nuts and pomegranates. [1] The trans-resveratrol (RSV) is the most active and more abundant stereoisomer found in nature ( Figure 1). ...
... [3] Although it is present in several foods, its systemic absorption in the organism is rather limited; being absorbed less than 1 % of consumed RSV. [4] The main factors that limit the RSV effectiveness are its low aqueous solubility (< 0.05 mg/mL) [1] , low oral availability, and chemical instability. The diminished oral bioavailability is due to the susceptibility to suffer sulfatation and glucuronidation during the phase II of metabolism in the gastrointestinal tract. ...
Resveratrol, a natural polyphenolic stilbenoid widely found in grapes and wines, displays beneficial properties such as cardio‐protective, antioxidant and anti‐inflammatory activities. Trans‐resveratrol (RSV) is the most bioactive and more abundant stereoisomer found in nature. Despite the positive properties of RSV, there are various factors that limit its effectiveness, including low aqueous solubility, low oral bioavailability and chemical instability. During the last years, an increasing number of strategies such as nano and micro encapsulation have been developed in order to overcome these limitations and enhance the use of RSV in nutritional and pharmaceutical applications. This Review summarizes the advances and main properties of several RSV carriers and delivery systems reported during the last 5 years.
... It is a white powder, insoluble in water but soluble in ethanol [2]. Resveratrol exists as two geometrical isomers: trans-and cis- (Figure 1) [24,47]. The trans-resveratrol form has the greater stability and biological activity [80], however the cis-form arises from isomerisation of the trans-form following breakdown of the resveratrol polymer molecule due to the action of UV light during the fermentation of grape skins, or by being under high pH conditions. ...
... A B Figure 1. Chemical structure of resveratrol: A -trans-form, B -cis-form [24,53] ...
Common health problems of the elderly in the near future will become even more common with aging of the population and longer average life expectancy. The elderly tend to have multiple disorders at one time, some of which may aggravate the course of others. One of the most common diseases, diabetes – “the epidemics of XXI century”, treatment of which costs approximately 11% of world health care budget – is the leading reason of chronic kidney disease and end-stage renal disease. Diabetic nephropathy can be a complication of both diabetes mellitus type 1 and 2. The most numerous group of patients with recently-made diagnosis are these above 60 years of age. Albuminuria, which, depending on its intensity, is one of the diagnostic criteria, can appear even in the process of aging itself. Overlapping of structural and functional changes that develop with age and those caused by diabetes is therefore a challenge, both diagnostic and clinical. There are certain methods of early diagnosis and prevention of progression of diabetic kidney disease. There is, however, no targeted treatment and existing therapies are generally based on glycemia and blood pressure control. Some patients in the advanced stage undergo dialyses just like in other kidney failure cases. The course of the disease is influenced by modifiable factors, such as protein and salt intake or cigarette smoking. In the light of the fact that this problem will concern an increasing number of patients, diagnostics and treatment can and should be introduced in the early stages of the disease. This all fits within the recently popular “healthy aging” ideology. Its popularization and implementation can bring measurable benefits of social and economic character.
... It is a white powder, insoluble in water but soluble in ethanol [2]. Resveratrol exists as two geometrical isomers: trans-and cis- (Figure 1) [24,47]. The trans-resveratrol form has the greater stability and biological activity [80], however the cis-form arises from isomerisation of the trans-form following breakdown of the resveratrol polymer molecule due to the action of UV light during the fermentation of grape skins, or by being under high pH conditions. ...
... A B Figure 1. Chemical structure of resveratrol: A -trans-form, B -cis-form [24,53] ...
Over recent years, there has been increasing interest noted in those active substances derived from plants that show potential for preventing cancer development. The most promising candidate is resveratrol which can be found in large amounts in the skin of grapes, tomatoes and in red wine. Its beneficial effects on the human body are seen both in prevention and therapy. The anti-carcinogenic action of resveratrol is linked with its ability to neutralise reactive oxygen species and to modulate cellular processes such as apoptosis, and both cancerous cell proliferation and differentiation. This article presents the characteristics of resveratrol as a bioactive compound derived from natural sources exhibiting anti-cancer properties, which, because of a wide spectrum of biological activities may be used in the prevention of cancer. Many in vitro and animal-based studies have demonstrated such preventative anti-cancer action in the colon, prostate, breast and lungs. The beneficial effects of resveratrol are also presented when adopted as a support to conventional treatments of cancer using chemo- and radio-therapy.
... Several papers have suggested that consumption of the four stilbenes in foods containing them or in nutraceuticals may be associated with improved health as a results of a wide range of biological activities, acting as anticarcinogenic (Huang et al. 2014;Laavola et al. 2015), antifungal (Caruso et al. 2011), antibacterial (Aslam et al. 2009), cardioprotective (Paul et al. 1999;Wu et al. 2001;Huang et al. 2014), antiviral (Sasivimolphan et al. 2009), cytogenetic (Matsuoka et al. 2002), estrogenic (Gambini et al., 2013), and antiinflamatory (Robb and Stuart 2014;Perečko et al. 2015;Nikhil et al. 2015) agents, while inhibiting platelet aggregation (Yashiro et al. 2012;Kasiotis et al. 2013). ...
... Indeed, resveratrol is one of the most studied antioxidants (de la Lastra and Villegas 2007). For example, Gambini et al. (2013) reviewed the in vitro and in vivo effect of resveratrol on the metabolism and its bioavailability and biological effects in animals and humans. For its part, the antioxidant activity of pterostilbene and its effect on brain and behavior have been reported (Poulose et al. 2015). ...
Researchers use several different analytical techniques, such as ORAC, ABTS·+, or FRAP, for measuring the antioxidant capacity of bioactive compounds. However, many authors do not take into account that these three techniques have different objectives. This contribution reports on the use of two types of tests to evaluate the antioxidant activity of four stilbene tests based first on the hydrogen atom transfer reaction (ORAC method) and the second on the single electron transfer reaction (ABTS·+ and FRAP assays). For the ORAC assay, the greatest antioxidant activity was shown by resveratrol, followed by oxyresveratrol, pterostilbene, and pinosylvin, while in the ABTS.+ assay, the highest antioxidant capacity was presented by oxyresveratrol, followed by resveratrol, pinosylvin, and finally pterostilbene. In the FRAP assay, the reducing activity shown by all the stilbenes was below that obtained for trolox. The role of phenolic hydroxyl groups was studied. The technique used should be selected taking into account the objectives and the conditions of the medium.
Graphical Abstractᅟ
... Resveratrol (Resv) or 3,5,4'-stilbenotriol (Figure 1), is a secondary metabolite present in around 70 plant species, which was isolated for the first time in 1940 from white hellebore (Veratrum grandiflorum) root extract [1]. It is a phytoalexin, that is, a compound synthesized by plants in response to stress and infections. ...
... Structurally, it is a nonflavonoid polyphenol from the stilbene family present in a number of regularly consumed plant species such as berries, peanuts, and the epidermis of grapes, although its highest concentration is in Polygonum cuspidatum roots, a plant mentioned in traditional Chinese and Japanese pharmacopoeias [2], and currently used for commercial extraction. Even when biosynthesized in both its cis and trans forms, a wide consensus considers the trans form as more biologically active, besides being the most stable isomer [1,3]. ...
Resvertrol (Resv) is an extensively studied molecule – as of 2015 PubMed held more than 7100 publications on the subject. The First International Resveratrol Conference in 2010 found insufficient evidence to justify recommending chronic administration of Resv in humans, a finding in stark contrast with the claims of its therapeutic effects often made by the media, based on its supposed role in the beneficial properties of red wine and in the so-called French Paradox. However, pharmacological studies carried out on different formulations of Resv from 2010 onwards suggest that these recommendations should be reviewed. Pharmacokinetic Resv is characterized by high inter-individual variability within pharmacokinetic parameters. Resv exhibits a rapid absorption rate, with extensive pre-systemic metabolism by human cytochrome P 450 and intestinal microbiota. Its metabolism leads mainly to conjugation products, the biological activity of which is still under discussion. It is also rapidly cleared by the kidneys. Finally, the estimated bioavailability of Resv is around 1% of orally-administered doses. Clinical trials have shown that Resv seems to exert a therapeutic effect on endothelial dysfunction consistent with in vitro observations demonstrating that Resv stimulates the eNOS enzyme. Inflammatory markers and CRP reductions obtained from doses of Resv equal to or less than 20 mg/day are not observed in larger doses, which imply hermetic behavior. Resv has also been shown to reduce the atherogenic potential of LDL cholesterol by reducing oxidized LDL and ApoB levels, which would in turn reduce atherogenesis. Resv is a well-tolerated compound; short-term clinical trials have shown frequent gastrointestinal discomfort or spontaneously resolving diarrhea only with the administration of high doses.
... Additionally, 6-hydroxyluteolin, which demonstrates in vitro antimalarial activity, was found (Kaur et al., 2009). Furthermore, other significant phenolic compounds were identified, including the stilbene resveratrol, recognized for its antioxidant, anti-inflammatory, and neuroprotective properties (Gambini et al., 2013). This study agrees with the characterization data of phenolic compounds present in P. splendens fruit collected in the Federico Santa Maria cliffs (unpublished data), revealing their bioactive potential. ...
The escalating global problem of antibiotic resistance necessitates the exploration of novel antimicrobial sources, particularly from natural origins. This study examines the potential of Pouteria splendens, an endemic Chilean tree, as a source of antimicrobial agents. High-performance liquid chromatography (HPLC) analysis of fruit extracts revealed a rich composition of phenolic compounds, including phenolic acids, flavonoids, and stilbenes. The antibacterial activity of peel and pulp extracts was evaluated against a panel of clinically relevant Gram-positive and Gram-negative bacteria. Escherichia coli was the most susceptible bacterium to the pulp and peel extracts, which achieved a minimum inhibitory concentration (MIC) of 400 and 800 ppm, respectively. The presence of phenolic compounds like gallic acid, chicoric acid, kaempferol and resveratrol, known for their antimicrobial properties, may contribute to the observed activity. The results suggest that P. splendens fruit extracts are a promising natural antibacterial agent for the food industry. Resumen: El creciente problema mundial de la resistencia a los antibióticos hace necesaria la exploración de nuevas fuentes de antimicrobianos, especialmente de origen natural. Este estudio examina el potencial de Pouteria splendens, un árbol endémico chileno, como fuente de agentes antimicrobianos. El análisis por cromatografía líquida de alta resolución (HPLC) de los extractos de frutos reveló una composición rica en compuestos fenólicos, incluidos ácidos fenólicos, flavonoides y estilbenos. Se evaluó la actividad antibacteriana de los extractos de cáscara y pulpa frente a un panel de bacterias Gram-positivas y Gram-negativas clínicamente relevantes. Escherichia coli fue la bacteria más susceptible a los extractos de pulpa y cáscara, que alcanzaron una concentración inhibitoria mínima (CIM) de 400 y 800 ppm, respectivamente. La presencia de compuestos fenólicos como ácido gálico, ácido chicórico, kaempferol, resveratrol y cianidina, conocidos por sus propiedades antimicrobianas, puede contribuir a la actividad observada. Los resultados sugieren que los extractos de fruta de P. splendens son prometedores agentes antibacterianos naturales para la industria alimentaria. Identification of phenolic compounds and evaluation of antibacterial activity of Pouteria splendens fruit extracts Bol Latinoam Caribe Plant Med Aromat 24 (5): 732-739 (2025) https://doi.org/10.37360/blacpma.25.24.5.51
... RES holds significant promise in regulating mitophagy and treating various diseases; however, its clinical application is hindered by its bioavailability and pharmacokinetic properties (Figure 7). The poor water solubility of RES leads to limited intestinal absorption and low bioavailability following oral administration (Walle et al. 2004;Gambini et al. 2013;Shaito et al. 2020). Moreover, RES is rapidly metabolized into glucuronides and sulfates, exhibiting a short half-life that challenges the maintenance of effective concentrations in the body ). ...
Resveratrol (RES), a natural polyphenolic compound, has garnered significant attention for its therapeutic potential in various pathological conditions. This review explores how RES modulates mitophagy—the selective autophagic degradation of mitochondria essential for maintaining cellular homeostasis. RES promotes the initiation and execution of mitophagy by enhancing PINK1/Parkin‐mediated mitochondrial clearance, reducing reactive oxygen species production, and mitigating apoptosis, thereby preserving mitochondrial integrity. Additionally, RES regulates mitophagy through the activation of key molecular targets such as AMP‐activated protein kinase (AMPK), the mechanistic target of rapamycin (mTOR), deacetylases (SIRT1 and SIRT3), and mitochondrial quality control (MQC) pathways, demonstrating substantial therapeutic effects in multiple disease models. We provide a detailed account of the biosynthetic pathways, pharmacokinetics, and metabolic characteristics of RES, focusing on its role in mitophagy modulation and implications for medical applications. Potential adverse effects associated with its clinical use are also discussed. Despite its promising therapeutic properties, the clinical application of RES is limited by issues of bioavailability and pharmacokinetic profiles. Future research should concentrate on enhancing RES bioavailability and developing derivatives that precisely modulate mitophagy, thereby unlocking new avenues for disease therapy.
... Plants of Rubus sp, Vaccinium spp, Paraguariensis A. St. Hil and Prunella vulgaris L, exposed to various abiotic conditions (UV-B radiation, Shadow, Drought) generate biochemical responses as flavonoids, resveratrol, methylxanthines, ursolic, rosmarinic and oleanolic acid for tolerate climatic phenomena that are detrimental to reproduction, growth, development and productivity [12][13][14][15]. ...
BACKGROUND
The evaluation of chlorophyll fluorescence activity is a useful tool for rapid and effective assessments of the effect of abiotic factors on the physiology of different crops. In Rubus, this type of measurements describes tolerance to high temperatures, sensitivity to heat and morphological alterations in flowering and chlorophyll content, as a result of plant stress.
OBJECTIVE
The present research estimated chlorophyll fluorescence and the presence of some phenolic compounds in the leaves of three cultivars of blackberry ( Rubus sp.) established in the central region of Colombia, under conditions of open air between 2400 and 2800 masl.
MATERIAL AND METHODS
This was done through the measurement of chlorophyll a (Junior-PAM II modulated fluorometer), the quantification of phenolic compounds (Folin Ciocalteu), the determination of antioxidant capacity (DPPH and ABTS) and the study of phenolic profiles (UHPLC) in leaves of three blackberry cultivars.
RESULTS
Cultivars R. alutaceus (0.66), R. glaucus (0.73) and R. alpinus (0.76), presented values lower than the optimum (0.83), for the parameter F v / F m . In addition, the direct relationships between the parameters that define the behavior of PSII and the accumulation of different polyphenols were described. Reference was also made to the content of phenolic compounds (ranging from 125 to 150 mg GA g –1 dw), which did not show significant statistical differences. The heat map and principal component analysis show the close relationship between the parameters that characterize the functioning of PSII and the accumulation of phenolic compounds, as a mechanism of adaptation to the adverse conditions of the blackberry cultivars studied.
CONCLUSIONS
The results reveal that the leaves of the Rubus studied could be a source of functional ingredients for use in the cosmetic, nutraceutical and food industries and epigallocatechin was attributed the greatest responsibility for the antioxidant capacity.
... However, a more predominant and stable natural form of resveratrol is trans-isomer. Some commonly used plants of human diets that contain a high concentration of resveratrol are blueberries (Vaccinium spp.), blackberries (Morus spp.), and peanuts (Arachis hypogaea) [1,2]. In addition, a red wine made from grapes (Vitaceae) is considered a rich source of resveratrol in the Mediterranean diet, particularly from the skin, seeds, petioles, and woody parts [3]. ...
Resveratrol is a natural polyphenol compound found in some plants and fruits that believed to be effective in improving overall health. The biological activity of resveratrol is limited by its poor absorption and first-pass metabolism that lead to having very low plasma concentrations following oral administration. Therefore, the current study was performed to determine the effects of the Trivedi Effect®-Energy of Consciousness Treatment for about 3 minutes by a renowned Biofield Energy Healer, Dahryn Trivedi, on resveratrol and rats through the measurement of plasma concentrations after a single oral dose administration of resveratrol. The test item, resveratrol was divided into two parts. One part was denoted as the control, while the other part was defined as the Biofield Energy Treated sample. Additionally, one group of animals also received Biofield Energy Treatment under similar conditions. The Biofield Energy Healer who was located in the USA, while the test samples and animals were located in the research laboratory in India. Resveratrol oral formulations were administrated by oral gavage at a dose of 100 mg/kg in groups viz. G1 (untreated resveratrol), G2 (Biofield Treated resveratrol) and G3 (Biofield Treated animals received untreated resveratrol) group. The results showed that maximum concentration (Cmax) of resveratrol was significantly increased by 185.98% and 108.82% in the G2 and G3 groups, respectively, compared with the G1 group. The relative oral exposure (AUC0–t) of resveratrol was increased by 148.02% in the G2 group and decreased by 4.34% in G3, as compared to the G1 group. The time to reach peak concentration (Tmax) of resveratrol was significantly increased by 168% in the group G2 and 68% in the group G3 compared to the group G1. The oral bioavailability (F) of resveratrol was significantly increased by 147.75% in the G2 group and slightly decreased by 4.49% in the G3 group compared to the untreated resveratrol group. These data demonstrated an improved oral bioavailability of Biofield Energy Treated resveratrol might be helpful to prevent/cure many diseases. Hence, Biofield Energy Treatment could be considered as an innovative strategy that opens new avenues to overcome poorly absorbed nutraceuticals/pharmaceuticals and can also improve the therapeutic performance of orally bioactive molecules.
... Several phytochemicals isolated from plants have been proven to be useful against cancer, and the mechanisms of action of the majority of them are currently being researched. Table 2 highlights phytocompounds and their anti-cancer activity [88][89][90][91][92][93][94][95][96][97][98][99][100][101][102]. ...
Cancer has become a significant public health concern in the past few decades, and it is now the world's second cause of death. Although there are various types of cancer treatments, such as chemotherapy, immune therapy, radiation, hormone therapy, gene editing, etc., they all have adverse reactions and significant failings. Plant and dietary mixtures have been utilized to treat malignant growth over the entire course of time. These mixtures likewise might be helpful in anticipation of malignant growth. Chemoprevention is cancer prevention that makes use of plant phytochemicals and synthetic substances. Because of their reduced toxicity and inexpensive cost, phytoconstituents are gaining much interest in chemoprevention effectiveness. As a result, the chemopreventive power of naturally occurring phytochemicals is of great interest. Populace studies propose that a decreased gamble of malignant growth is related to the maximum usage of vegetables and natural products. This review summarised the latest research on plants and their chemicals targeting various malignancies and their mechanisms of cancer suppression by modulating multiple signaling pathways. It provides a small outline of green synthesized nanoparticles, an emerging area to combat cancer.
... RSV's pharmacological applications include anticancer, diabetes, vascular metabolic diseases, etc. [82][83][84]. Due to its low water solubility, short half-life (9.2 ± 0.6 h), and low bioavailability, the current use of RSV is insufficient [85][86][87]. ...
Natural products have proven their value as drugs that can be therapeutically beneficial in the treatment of various diseases. However, most natural products have low solubility and poor bioavailability, which pose significant challenges. To solve these issues, several drug nanocarriers have been developed. Among these methods, dendrimers have emerged as vectors for natural products due to their superior advantages, such as a controlled molecular structure, narrow polydispersity index, and the availability of multiple functional groups. This review summarizes current knowledge on the structures of dendrimer-based nanocarriers for natural compounds, with a particular focus on applications in alkaloids and polyphenols. Additionally, it highlights the challenges and perspectives for future development in clinical therapy.
... In order to test whether a causal relationship exists between the inflammatory response to TD and the inhibition of hippocampal neurogenesis, OHCs of the control and TD groups were treated with RSV starting at day 4 of culture, the day before the observed onset of neurodegeneration caused by TD in OHCs. RSV is an anti-inflammatory and antioxidant polyphenol found mainly in the seeds and films of grapes and red wine, red fruits and peanuts (reviewed in [68]). In a dose dependent manner, RSV at 5 and 50 µM, but not at 100 µM, prevented microglia activation and promoted and earlier neurogenesis pulse in B1-deficient OHCs, adding confidence to the hypothesis that decreasing neuroinflammation is the trigger to the neurogenesis pulse in the OHC model of TD (Fig. 7). ...
Background
Thiamine (vitamin B1) is a cofactor for enzymes of central energy metabolism and its deficiency (TD) impairs oxidative phosphorylation, increases oxidative stress, and activates inflammatory processes that can lead to neurodegeneration. Wernicke–Korsakoff syndrome (WKS) is a consequence of chronic TD, which leads to extensive neuronal death, and is associated with neuropathological disorders, including cognitive deficits and amnesia. The hippocampus is one of the brain areas most affected by WKS. B1 replacement may not be enough to prevent the irreversible cognitive deficit associated with WKS.
Materials and methods
An organotypic hippocampal slice culture (OHC) model was developed to investigate, using immunofluorescence and confocal microscopy and transcriptome analysis, the molecular mechanisms underlying the neurodegeneration associated with TD. The effect of anti-inflammatory pharmacological intervention with resveratrol (RSV) was also assessed in B1-deprived OHCs.
Results
In OHCs cultured without B1, neuronal density decayed after 5 days and, on the 7th day, the epigenetic markings H3K4me3 and H3K9me3 were altered in mature neurons likely favoring gene transcription. Between the 7th and the 14th day, a pulse of neurogenesis was observed followed by a further massive neuron loss. Transcriptome analysis at day nine disclosed 89 differentially expressed genes in response to B1 deprivation. Genes involved in tryptophan metabolism and lysine degradation KEGG pathways, and those with Gene Ontology (GO) annotations related to the organization of the extracellular matrix, cell adhesion, and positive regulation of synaptic transmission were upregulated. Several genes of the TNF and FoxO signaling pathways and with GO terms related to inflammation were inhibited in response to B1 deprivation. Nsd1 , whose product methylates histone H3 lysine 36, was upregulated and the epigenetic marking H3K36me3, associated with negative regulation of neurogenesis, was increased in neurons. Treating B1-deprived OHCs with RSV promoted an earlier neurogenesis pulse.
Conclusion
Neuroregeneration occurs in B1-deficient hippocampal tissue during a time window. This phenomenon depends on reducing neuroinflammation and, likely, on metabolic changes, allowing acetyl-CoA synthesis from amino acids to ensure energy supply via oxidative phosphorylation. Thus, neuroinflammation is implicated as a major regulator of hippocampal neurogenesis in TD opening a new search space for treating WKS.
... Resveratrol (trans-3,5,4 ′ -trihydroxystilbene) is a naturally occurring polyphenolic phytoalexin found in grapes, berry skins, soybeans, cherries, peanuts, plums and pomegranates, among others [1,2]. This stilbene exerts anti-inflammatory, anti-oxidant, anti-aging, blood sugar-lowering, and cardiovascular beneficial effects, as well as anti-cancer effects [3,4]. ...
Trans-Resveratrol (RV) was encapsulated in multi-lamellar liposomes (MLLs) composed of a mixture of phosphatidylcholine (P100), Tween 80 (T80) and water. The P100-to-T80 ratio as well as their water content were chosen based on a previous study to promote transdermal transport of RV. The effect of RV on the size, elasticity, and charge of MLLs was evaluated as well as the effect of encapsulation on the apparent solubility of RV. The diffusion of RV and MLLs in artificial skin, namely Strat-M™, was monitored by confocal Raman imaging, and compared with that of a RV solution and empty MLLs, while the transdermal passage rate was measured by UV–vis spectrophotometry on both artificial and excised human skin. RV was found to remain localized in the outer layer of the skin with less than 3% passing through it over a 24-h period in both skin types. Encapsulation in MLLs drastically increased its transdermal passage: 73 ± 10% after 3 h of incubation on excised human skin, and 10% on Strat-M™ after 9 h. Whereas RV in its free form underwent cis isomerization, MLLs protected it up to 9h before undergoing chemical degradation after 24h.
... Key components linked to the protective effects of moderate wine consumption include phenolic compounds from grapes [1]. Resveratrol, a prominent member of the stilbene family, has been attributed beneficial properties as anticancer capacity, antioxidant, cardioprotective, anti-ageing or neuroprotective [2,3]. Stilbene compounds are in nature as two isomeric forms, cis and trans. ...
Pulsed electric fields effect was studied on the physico-chemical and general phenolic composition as colour characteristics and stilbene content in must and wine. For this purpose, a continuous pulsed electric fields equipment was used to treat three red grape varieties of DOCa Rioja. Graciano, Tempranillo and Grenache wines from these grapes were elaborated with different maceration times, 2 days in the untreated sample (control) and the PEF-treated sample (PEF), and normal maceration time in another untreated sample (control-NM). Parameters as colour intensity, anthocyanin content, total polyphenol index and tannin content showed no differences between the PEF sample with 2 days of maceration and the control-NM sample, except in the case of Tempranillo wines. Total stilbenes, trans-resveratrol and trans-piceid of Graciano wines elaborated from PEF samples showed a higher concentration than the control wines. Alternatively, PEF wines and control-NM wines showed no differences between them. Tempranillo variety wines presented no differences between the three types of samples. In the Grenache variety, only trans-piceid levels showed differences between control and PEF wines. Moreover, relationship between must and wine characteristics was evaluated and compared between different samples. The trend lines obtained for the CI, TPI and AC parameters for samples of Graciano, Tempranillo and Garnacha indicate that the initial content of compounds extracted significantly affected the days of maceration necessary to obtain the appropriate wine. The results obtained increase the knowledge of pulsed electric fields as a technology available for use in the winery to elaborate red wines with reduced maceration time.
... Resveratrol (trans-3,5,4 ′ -trihydroxystilbene) is a naturally occurring polyphenolic phytoalexin found in grapes, berry skins, soybeans, cherries, peanuts, plums and pomegranates, among others [1,2]. This stilbene exerts anti-inflammatory, anti-oxidant, anti-aging, blood sugar-lowering, and cardiovascular beneficial effects, as well as anti-cancer effects [3,4]. ...
Trans-Resveratrol (RV) was encapsulated in multi-lamellar liposomes (MLLs) composed of a mixture of phosphatidylcholine (P100), Tween 80 (T80) and water. The P100-to-T80 ratio as well as their water content were chosen based on a previous study to promote transdermal transport of RV. The effect of RV on the size, elasticity, and charge of MLLs was evaluated as well as the effect of encapsulation on the apparent solubility of RV. The diffusion of RV and MLLs in artificial skin, namely Strat-M™, was monitored by confocal Raman imaging, and compared with that of a RV solution and empty MLLs, while the transdermal passage rate was measured by UV–vis spectrophotometry on both artificial and excised human skin. RV was found to remain localized in the outer layer of the skin with less than 3% passing through it over a 24-h period in both skin types. Encapsulation in MLLs drastically increased its transdermal passage: 73 ± 10% after 3 h of incubation on excised human skin, and 10% on Strat-M™ after 9 h. Whereas RV in its free form underwent cis isomerization, MLLs protected it up to 9h before undergoing chemical degradation after 24h.
... Resveratrol (RSV; trans-3,5,4 0 -trihydroxystilbene), a naturally occurring nonflavonoid polyphenolic compound, richly presents in many fruits and vegetables, such as peanuts, mulberries and grapes (Gambini et al. 2013;Rauf et al. 2017). It has been reported that RSV can control the differentiation of lineage-specific neural stem cells and mediate the biological functions of terminally differentiated cells (Hu et al. 2014). ...
Context
The osteogenic potential of the human dental pulp stromal cells (hDPSCs) was reduced in the state of oxidative stress. Resveratrol (RSV) possesses numerous biological properties, including osteogenic potential, growth-promoting and antioxidant activities.
Objective
This study investigates the osteogenic potential of RSV by activating the Sirt1/Nrf2 pathway on oxidatively stressed hDPSCs and old mice.
Materials and methods
The hDPSCs were subjected to reactive oxygen species (ROS) fluorescence staining, cell proliferation assay, ROS activity assay, superoxide dismutase (SOD) enzyme activity, the glutathione (GSH) concentration assay, alkaline phosphatase staining, real-time polymerase chain reaction (RT-PCR) and Sirt1 immunofluorescence labelling to assess the antioxidant stress and osteogenic ability of RSV. Forty female Kunming mice were divided into Old, Old-RSV, Young and Young-RSV groups to assess the repair of calvarial defects of 0.2 mL RSV of 20 mg/kg/d for seven days by injecting intraperitoneally at 4 weeks after surgery using micro-computed tomography, nonlinear optical microscope and immunohistochemical analysis.
Results
RSV abates oxidative stress by alleviating the proliferation, mitigating the ROS activity, increasing the SOD enzyme activity and ameliorating the GSH concentration (RSV IC50 in hDPSCs is 67.65 ± 9.86). The antioxidative stress and osteogenic capabilities of RSV were confirmed by the up-regulated gene expression of SOD1, xCT, RUNX2 and OCN, as well as Sirt1/Nrf2. The collagen, bone matrix formation and Sirt1 expression, are significantly increased after RSV treatment in mice.
Discussion and conclusions
For elderly or patients with oxidative stress physiological states such as hypertension, heart disease, diabetes, etc., RSV may potentially improve bone augmentation surgery in regenerative medicine.
... Structurally, this compound is a stilbenoid that was first isolated in 1939 from the roots of the white hellebore (Veratrum grandiflorum) and presumably received its name because of its analogy with the benzene-1,3-diol resorcinol and being isolated from the Veratrum species. Subsequently, resveratrol was isolated from several other plants, fruits, and derivatives, from grapes, wines, apples, raspberries, blueberries, pistachios, plums, peanuts, and a multitude of medicinal and edible plant species undergoing response to stress conditions [3]. Experimental and preclinical studies have shown that resveratrol has several health-promoting properties, including cardioprotective effects, chemo-preventive activity in diverse cancers, and a capacity to extend the lifespan of lower organisms [4][5][6]. ...
The aim of this work was to investigate the effect of meteorological conditions on resveratrol concentration of red wines produced in Piacenza viticultural region (Italy). In this regard, six representative estates producing Colli Piacentini Gutturnio DOC (a blend of V. vinifera L. cvs. Barbera and Croatina) vintage wines were analysed for trans- and cis-resveratrol over an 8-year period (1998–2005). Grapes were taken from the same vineyard in each estate by using the same enological practices over the entire investigated period. The meteorological conditions corresponding to the production areas were recorded, and bioclimatic indices were calculated as well. Overall, cis-resveratrol concentration was negatively correlated to Huglin index and August mean temperature, whilst positive correlation coefficients were found when considering the Selianinov index and the rainfall of September.
... 8 It is expressed that after an oral administration, the resveratrol bioavailability in systemic circulation and in tissues is very less due to raid metabolism. 9 Correspondingly, in the case of nanocarriers, it is a promising approach to be a potential bio-nanocarrier for the drug delivery system. Some recent reports depicted that nanocarriers (to some extent) might be an appropriate transporter for oral administration and released the drug in a controlled manner. ...
Resveratrol is a natural compound (an antioxidant) and exhibits numerous therapeutic activities. From a pharmacokinetic perspective, it is unclear whether resveratrol targets the site of action after oral administration because of quick metabolism and excretion which creates doubt on the biological application of the high doses characteristically used for clinical trials. However, these limitations act as a barrier and a challenge for the development of new delivery systems. Recently, gene delivery has been shown to offer various advantages and has provided treatment options for diseases that are beyond the reach of traditional approaches. The objective of gene therapy for genetic diseases is to achieve durable expression of the therapeutic gene at a level sufficient to ameliorate or cure disease symptoms with minimal adverse events. The perception of the molecular and cellular mechanisms steering to therapy and vector related hindrances have caused in the progress of extremely complex gene delivery with enhanced protection and effectiveness. With the help of gene therapy, it could be possible to target the delivery of resveratrol directly into the host cells and bypass its pharmacokinetic limitations and enhancement of its therapeutic effect. This review is to provide a holistic view of the development of resveratrol gene treatment as a powerful option to treat various deadly diseases.
... Chemical compound 3,5,4'-trihydroxy-trans-stilbene, commonly known as resveratrol, is a naturally occurring polyphenolic, non-fl avonoid antioxidant that can be extracted from numerous fruit and plant sources [3]. Polyphenols have been extensively studied for their health benefi ts and is thought to be partially responsible for the "French Paradox", an epidemiological phenomenon from early nineties in which certain populations of France have shown to be less Citation: Wang predisposed to cardiovascular diseases despite a high fat diet and low exercise level due to a moderate consumption of red wine [4]. ...
... At 1040-970 cm −1 , a peak corresponding to the stretching of C-O-C bond was observed. Finally, peaks between 900 cm −1 and 600 cm −1 attributed to the C-H and C=C bonds were observed [18][19][20][21]. The presence of aqueous extracts could induce changes in the transmittance percentage and intensity of these peaks. ...
The aim of this study is to analyze the properties of a series of polysaccharide composite films, such as apparent density, color, the presence of functional groups, morphology, and thermal stability, as well as the correlation between them and their antimicrobial and optical properties. Natural antioxidants such as anthocyanins (from cranberry; blueberry and pomegranate); betalains (from beetroot and pitaya); resveratrol (from grape); and thymol and carvacrol (from oregano) were added to the films. Few changes in the position and intensity of the FTIR spectra bands were observed despite the low content of extract added to the films. Due to this fact, the antioxidants were extracted and identified by spectroscopic analysis; and they were also quantified using the Folin-Denis method and a gallic acid calibration curve, which confirmed the presence of natural antioxidants in the films. According to the SEM analysis, the presence of natural antioxidants has no influence on the film morphology because the stretch marks and white points that were observed were related to starch presence. On the other hand, the TGA analysis showed that the type of extract influences the total weight loss. The overall interpretation of the results suggests that the use of natural antioxidants as additives for chitosan-starch film preparation has a prominent impact on most of the critical properties that are decisive in making them suitable for food-packing applications.
... Some commonly used plants of human diets that contain a high concentration of resveratrol are blueberries (Vaccinium spp.), blackberries (Morus spp.), Low Bioavailable Resveratrol in Male Sprague Dawley Rats and peanuts (Arachis hypogaea) [1,2]. In addition, red wine made from grapes (Vitaceae) are considered as rich source of resveratrol in the Mediterranean diet particularly from skin, seeds, petioles, and woody parts [3]. ...
Resveratrol is a natural dietary antioxidant polyphenol that believed to be effective in improving overall health. The biological activity of resveratrol is limited by its poor absorption and first-pass metabolism that lead to have very low plasma concentrations following oral administration. Therefore, the present study was performed to determine the effects of The Trivedi Effect®-Energy of Consciousness Healing Treatment by a renowned Biofield Energy Healer, Alice Branton on resveratrol and rats through the measurement of plasma concentrations after oral administration of resveratrol. The test item, resveratrol was divided into two parts. One part was denoted as the control, while the other part was defined as the Biofield Energy Treated sample. Additionally, one group of animals also received Biofield Energy Treatment under similar conditions. Resveratrol oral formulations were administrated by oral gavage at a dose of 150 mg/kg in groups viz. G1 (untreated resveratrol), G2 (Biofield Treated resveratrol) and G3 (Biofield Treated animals received untreated resveratrol) group. The results showed that resveratrol had a very low oral plasma exposure of 91.71 ng/mL in control group. The Biofield Treatment significantly enhanced the relative oral exposure (AUC0–t) of resveratrol by 23.35% in G2 group compared to the control group. The Biofield Treatment also improved plasma peak concentration (Cmax) of resveratrol by 125% and 28.5% in G2 and G3 groups, respectively compared with the control group. Plasma concentrations of resveratrol in G1 was declined with a rapid elimination half-life (T1/2, 1.48 hours), followed by sudden increases in plasma concentrations 12 to 24 hours after the test item administration. These plasma concentrations resulted in a significant prolongation of the terminal elimination half-life of resveratrol. The oral elimination T1/2 of resveratrol in G2 and G3 were 4.67 and 9.0 hours, respectively as compared to the G1. The apparent oral plasma clearance of resveratrol decreased significantly by 54%, and 17.5% in G2 group and G3 group, respectively as compared to the control group. The mean residence time (MRTlast) of resveratrol significantly increased in G2 group (6.45 hours) and G3 group (7.70 hours), as compared to the control group. These data demonstrates greater bioavailability and total plasma level of resveratrol in rats which might be translated into better in vivo biological activity. Hence, The Trivedi Effect®-Energy of Consciousness Healing Treatment could be considered as an innovative strategy which opens new avenues to overcome poorly absorbed nutraceuticals/pharmaceuticals and can also improve the therapeutic performance of orally active molecules.
... Resveratrol is a polyphenolic compound found in grapes and traditional Chinese medicinal plants, such as Polygonum cuspidatum. It influences a variety of molecular targets, and many of them are associated with inflammation and immunity (12,13). In this study, we examined the specific effects of resveratrol on the production of pro-inflammatory cytokines by LPS-stimulated RAW264.7 murine macrophages. ...
Resveratrol is a polyphenolic compound extracted from grapes and the Chinese herb, Polygonum cuspidatum. In the present study, in order to elucidate the molecular mechanisms of action of resveratrol in host immune cells, we examined the effects of resveratrol on the inflammatory response in lipopolysaccharide (LPS).stimulated RAW264.7 murine macrophages. The cells were treated with resveratrol prior to stimulation with LPS (1μg/ml). Resveratrol downregulated the expression of inflammatory markers, such as tumor necrosis factor (TNF)-α and interleukin (IL).6, induced by LPS, and inhibited the phosphorylation of mitogen-activated protein kinases (MAPKs) and signal transducer and activator of transcription (STAT)1/STAT3. Resveratrol also upregulated the production of suppressor of cytokine signaling 1 (SOCS1; a STAT inhibitor) and suppressed the expression of miR.155, which plays an essential role in the innate and adaptive immune response. Given the elevated levels of SOCS1 in LPS-induced inflammation, our results suggest that resveratrol exerts anti-inflammatory effects due to the upregulation of SOCS1, which is a potential target of miR.155, as well as of miR.155 mimics and inhibitors. These findings suggest the benefits of resveratrol, which are derived from its regulation of SOCS1 expression via the inhibition of miR.155, and indicate that resveratrol may be developed as a useful agent for the treatment of inflammatory diseases.
... This compound is found in grapes, peanuts, berries, groundnut, spruce, mulberries and dried roots of Polygonum cuspidatum (also known as kojo-kon in Japanese), which have long been used in traditional oriental medicine (1,2). In plants, resveratrol inhibits the development of an infection (3). In humans, it has several beneficial effects due to its antioxidant, anti-inflammatory, anticarcinogenic, antidiabetic, cardioprotective, estrogenic and anti-aging properties (4)(5)(6). ...
Over the past few decades, trans-resveratrol has received widespread attention as a preventive agent for numerous diseases. Several studies have demonstrated that it has significant biological and pharmacological properties. Trans‑resveratrol has been reported to possess anti‑oxidant, anti‑inflammatory, anticarcinogenic, antidiabetic, anti‑aging, cardioprotective and neuroprotective properties, which can be relevant in chronic diseases and longevity in humans. The aim of the present study was to investigate the rate and extend of absorption, and also the safety of resveratrol following a single 500 mg oral dose. This was an open label, single dose, one period, bioavailability study in 15 healthy volunteers under fasting conditions. Blood samples were collected at predefined time points up to 24 h after resveratrol administration, and plasma concentrations of resveratrol and its conjugated (glucuronated and sulphated) metabolites were determined using a validated high performance liquid chromatography/tandem mass spectrometry method. Pharmacokinetic parameters, including Cmax, AUC0‑t, AUC0‑inf, Tmax, T1/2 and MRT, were determined from plasma concentration‑time profiles and found to be in good agreement with previously reported data. Cmax and AUC0‑inf were lower for resveratrol when compared with the values for its glucuronated and sulphated metabolites. Cmax for resveratrol, glucuronated resveratrol and sulphated resveratrol were 71.2±42.4 ng/ml, 4,083.9±1,704.4 ng/ml and 1,516.0±639.0 ng/ml, respectively, while the AUC0‑inf values were 179.1±79.1 ng/ml, 39,732.4±16,145.6 ng/ml and 14,441.7±7,593.2 ng/ml, respectively. No adverse reactions associated with resveratrol were reported during the study. The plasma concentrations of resveratrol (free and conjugated) were in agreement with those mentioned in the literature, and were adequate to promote the pharmacological activities of resveratrol. In conclusion, resveratrol 500 mg tablets were well-tolerated by all participants of the study.
... Resveratrol is a polyphenolic compound that is isolated from grapes and traditional Chinese medicinal plants such as Polygonum cuspidatum (Fig. 1A). It possesses multifaceted beneficial properties, such as anti-inflammatory, anti-oxidative, and anti-aging effects [11,12]. Several studies reported that the mechanism of action of resveratrol includes inhibition of specific signaling pathways, NF-κB translocation, and reactive oxygen species production [13][14][15]. ...
Resveratrol, the most important ingredient extracted from Polygonum cuspidatum, exerts cytoprotective effects via anti-inflammatory actions in vitro. In this study, we investigated this effect of resveratrol on the lipopolysaccharide (LPS)-induced inflammatory response and its underlying molecular mechanism of action in RAW264.7 murine macrophages. Results showed that resveratrol down-regulated the expression of inducible nitric oxide synthase (iNOS) and interleukin-6 (IL-6), therefore, suppressed the production of nitric oxide and the secretion of IL-6 in LPS-stimulated RAW264.7 cells in a dose-dependent manner. Resveratrol also inhibited the translocation of high-mobility group box 1 (HMGB1) from the nucleus to the cytoplasm and of nuclear transcription factor kappa-B (NF-κB) p65 from the cytoplasm to the nucleus; it suppressed the phosphorylation of IκBα. Furthermore, these actions were mediated by suppressing the phosphorylation of signal transducer and activator of transcription (STAT)-1 and -3. In conclusion, these data indicate that resveratrol exerts anti-inflammatory effects, at least in part by reducing the release of HMGB1 and modulating the NF-κB and Janus kinase/STAT signaling pathways. Resveratrol could potentially be developed as a useful agent for the chemoprevention of inflammatory diseases.
© The Author 2015. Published by ABBS Editorial Office in association with Oxford University Press on behalf of the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences.
... After an oral dose, it is demonstrated that the metabolic pathways leave just a little free resveratrol in blood, therefore, the bioavailability in the target tissues is very low and the concentrations used in in vitro studies are not found in tissues. The elimination phase for resveratrol is not well characterized because of the observed concentration increased in the terminal portion of the profiles, which maybe due to enterohepatic recirculation [33]. Resveratrol has attracted great interest in the research community, with more than 6437 publications between 1940 and 2014 referenced from PubMed service [ Fig. 1]. ...
Resveratrol, a natural polyphenolic compound is present in trees, in peanuts, in grapevines and exhibited multiple pharmacological activities. Extensive research in the last two decades suggested that resveratrol possesses anti-inflammatory, anti-cancer, anti-viral, anti-amyloid, anti-arthritic and antioxidant properties. Some clinical reports have proposed that resveratrol might be a potential candidate for the prevention and/or treatment of HIV/AIDS and synergistically enhances the anti-HIV-1 activity. Resveratrol is not toxic to cells, and by itself reduces viral replication by 20% to 30%. With almost 12% of the world population suffering from HIV/AIDS including its resurgence in the developed world, better management of this global threat is highly desired. Further, various studies demonstrated several issues associated with resveratrol which account for its poor systemic bioavailability (almost zero) due to rapid and extensive first pass metabolism and existence of enterohepatic recirculation. In order to improve bioavailability and cellular uptake of resveratrol, various strategies have been adopted to date which includes resveratrol prodrug and the development of nanostructured delivery systems. Besides, nanostructured delivery systems are also known to inhibit the P-glycoprotein (P-gp) efflux, reduced metabolism by gut cytochrome P-450 enzymes, and circumnavigate the hepatic first-pass effect, facilitating absorption of drugs via intestinal lymphatic pathways. This review paper provides an updated bird's-eye view account on the publications and patent study on the recent novel approaches to deliver resveratrol in order to enhance oral bioavailability, overcome first pass metabolism and trounce enterohepatic recirculation to make resveratrol a therapeutically potent drug. Providing a relatively pithy overview, this paper thus presents recent advances of resveratrol for the treatment and prevention of HIV/AIDS.
... This is indeed within the range of nutritionally relevant concentrations found in plasma after moderate wine intake. Consuming normal amounts of resveratrol-rich nutrients, such as grapes, peanuts, blueberries, blackberries, and red wine [30], may result in plasma concentrations of free resveratrol that, as we show here, increase the expression of antioxidant genes and thus may delay the onset of oxidative stress-related conditions. Therefore, our results may have practical importance. ...
Introduction:
Antioxidant properties of resveratrol have been intensively studied for the last years, both in vivo and in vitro. Its bioavailability after an oral dose is very low and therefore it is very important to make sure that plasma concentrations of free resveratrol are sufficient enough to be active as antioxidant.
Aims:
In the present study, using nutritionally relevant concentrations of resveratrol, we aim to confirm its antioxidant capacity on reducing peroxide levels and look for the molecular pathway involved in this antioxidant effect.
Methods:
We used mammary gland tumor cells (MCF-7), which were pretreated with different concentrations of resveratrol for 48 h, and/or a PTEN inhibitor (bpV: bipy). Hydrogen peroxide levels were determined by fluorimetry, PTEN levels and Akt phosphorylation by Western Blotting, and mRNA expression of antioxidant genes by real-time reverse transcriptase-polymerase chain reaction (RT-PCR).
Results:
Resveratrol treatment for 48 h lowered peroxide levels in MCF-7, even at low nutritional concentrations (1 nM). This effect was mediated by the activation of PTEN/Akt pathway, which resulted in an upregulation of catalase and MnSOD mRNA levels.
Conclusion:
Resveratrol acts as an antioxidant at nutritionally relevant concentrations by inducing the expression of antioxidant enzymes, through a mechanism involving PTEN/Akt signaling pathway.
Stroke and acute myocardial infarction are leading causes of mortality worldwide. The latter accounts for approximately 9 million deaths annually. In turn, ischemic stroke is a significant contributor to adult physical disability globally. While reperfusion is crucial for tissue recovery, it can paradoxically exacerbate damage through oxidative stress (OS), inflammation, and cell death. Therefore, it is imperative to explore diverse approaches aimed at minimizing ischemia/reperfusion injury to enhance clinical outcomes. OS primarily arises from an excessive generation of reactive oxygen species (ROS) and/or decreased endogenous antioxidant potential. Natural antioxidant compounds can counteract the injury mechanisms linked to ROS. While promising preclinical results, based on monotherapies, account for protective effects against tissue injury by ROS, translating these models into human applications has yielded controversial evidence. However, since the wide spectrum of antioxidants having diverse chemical characteristics offers varied biological actions on cell signaling pathways, multitherapy has emerged as a valuable therapeutic resource. Moreover, the combination of antioxidants in multitherapy holds significant potential for synergistic effects. This study was designed with the aim of providing an updated overview of natural antioxidants suitable for preventing myocardial and cerebral ischemia/reperfusion injuries.
Pain represents one of the leading causes of suffering and disability worldwide. Currently available drugs cannot treat all types of pain and may have adverse effects. Hence, the use of pharmacological combinations is an alternative treatment strategy. Therefore, this study aimed to evaluate the combination of resveratrol and ketorolac through isobolographic analysis. CD1 mice were used to study the antinociceptive effect of this combination using the formalin test and the study was divided into two phases. In the first phase, four individual doses of each drug were evaluated, totaling eight testing groups. From these data, the median effective doses (ED50) of each drug were calculated. In the second phase, four testing groups were used to evaluate the combination of sub-doses of both drugs and obtain the experimental ED50. To evaluate gastric damage, five groups were employed, including indomethacin, vehicle, resveratrol, ketorolac, and combined resveratrol and ketorolac groups. Stomach samples from the mice were taken after 5 h of treatment, and the area of the ulcers was determined. Resveratrol plus ketorolac elicited a reduction in nociceptive behavior during both phases of the formalin test, and isobologram analysis revealed that the theoretical and experimental ED50 values of resveratrol and ketorolac did not differ significantly, implying an additive interaction between the drugs. Additionally, the drug combination did not generate gastric ulcers, thus enhancing the desired effects without increasing the adverse effects. Consequently, these findings substantiate the efficacy of the resveratrol and ketorolac combination in the formalin test, thereby highlighting its potential as a viable alternative for alleviating pain.
Among the different types of abiotic stress, one of the most important is irradiation stress. Ultraviolet (UV) irradiation represents between 7 and 9% of total solar radiation, and and is composed between 100 and 400 nm of the electromagnetic spectrum. It is mainly divided into UV-A (315–400 nm), UV-B (280–320 nm), and UV-C (200–280 nm). This type of irradiation can affect DNA, proteins, and plant cells. This could affect the development, morphology, and photosynthesis. To counteract these harmful effects, plants use their defense mechanisms, mainly the production of secondary metabolites, among which phenolic compounds stand out (phenolic acids, flavonoids, stilbenes, tannins, lignins, and coumarins). These are of great interest for its antioxidant, anticancer, antimicrobial properties, among others. However, the responses in the increase of the different phenolic compounds will depend on factors such as intensity, type of UV light and exposure time, which is reflected in the different investigations carried out on this topic. In this sense, it is interesting to review the variety of phenolic compounds that have been reported through induction by UV irradiation.
Resveratrol is a stilbenoid polyphenolic molecule widely known for its biological properties, which is available in nature in various varieties of grapes, berries, and some plants. It has been shown to play an important role in the prevention and treatment of chronic diseases such as cancer, heart disease, metabolic, degenerative, autoimmune diseases, and even viral infections. One of the main mechanisms of action that it presents is linked to its antioxidant capacity as it is a strict polyphenol, which gives it the ability to stimulate an immune response in the host by regulating and differentiating immune cells, promoting the synthesis of specific proteins, activate apoptosis, stimulate the secretion of pro-inflammatory cytokines, and even modulate gene expression. These effects have favored the decrease in the progression of various inflammatory and degenerative diseases, thus demonstrating the immunomodulatory capacity of resveratrol on in vitro and in vivo models.
The prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing around the world, in association with the progressive elevation in overweight and obesity. The accumulation of lipids in NAFLD patients contributes to the development of insulin resistance, inflammation and oxidative stress in hepatocytes, and alteration of blood lipids and glycaemia. There are currently no effective pharmacological therapies for NAFLD, although lifestyle and dietary modifications targeting weight reduction are among the prevailing alternative approaches. For this reason, new approaches should be investigated. The natural polyphenol resveratrol represents a potential new treatment for management of NAFLD due to anti-inflammatory and antioxidant properties. Although preclinical trials have demonstrated promising results of resveratrol against NALFD, the lack of conclusive results creates the need for more trials with larger numbers of patients, longer time courses, and standardized protocols.
*Alaimo & García are both correspondig authors
Resveratrol (RES) is a polyphenol with increasing interest for its inhibitory effects on a wide variety of viruses. Zika virus (ZIKV) is an arbovirus of the Flaviviridae family for which there is no approved treatment or vaccine, and which has become a major global health threat. Within the broad spectrum of ophthalmological manifestations after infection, retinal pigment epithelial cells (RPE) type is one of the most permissive and susceptible to the virus. This work explored the protective effects of RES on ZIKV-infected human RPE cells. RES treatment resulted in a significant reduction of infectious viral titer in infected male ARPE-19 and female hTERT-RPE1 cells. This protection was positively influenced by the action of RES on mitochondrial dynamics, restoring the ZIKV induced fragmentation of mitochondrial network to conditions similar to those of uninfected control cultures. Also, docking studies showed that RES has a high affinity for two enzymes of the rate-limiting steps of pyrimidine and purine biosynthesis and viral polymerase. In conclusion, our findings indicated that RES could be considered as an antiviral agent to treat ZIKV-induced ocular abnormalities.
Over the last years, different nanomaterials have been investigated to design highly selective and sensitive sensors, reaching nano/picomolar concentrations of biomolecules, which is crucial for medical sciences and the healthcare industry in order to assess physiological and metabolic parameters. The discovery of graphene (G) has unexpectedly impulsed research on developing cost-effective electrode materials owed to its unique physical and chemical properties, including high specific surface area, elevated carrier mobility, exceptional electrical and thermal conductivity, strong stiffness and strength combined with flexibility and optical transparency. G and its derivatives, including graphene oxide (GO) and reduced graphene oxide (rGO), are becoming an important class of nanomaterials in the area of optical and electrochemical sensors. The presence of oxygenated functional groups makes GO nanosheets amphiphilic, facilitating chemical functionalization. G-based nanomaterials can be easily combined with different types of inorganic nanoparticles, including metals and metal oxides, quantum dots, organic polymers, and biomolecules, to yield a wide range of nanocomposites with enhanced sensitivity for sensor applications. This review provides an overview of recent research on G-based nanocomposites for the detection of bioactive compounds, providing insights on the unique advantages offered by G and its derivatives. Their synthesis process, functionalization routes, and main properties are summarized, and the main challenges are also discussed. The antioxidants selected for this review are melatonin, gallic acid, tannic acid, resveratrol, oleuropein, hydroxytyrosol, tocopherol, ascorbic acid, and curcumin. They were chosen owed to their beneficial properties for human health, including antibiotic, antiviral, cardiovascular protector, anticancer, anti-inflammatory, cytoprotective, neuroprotective, antiageing, antidegenerative, and antiallergic capacity. The sensitivity and selectivity of G-based electrochemical and fluorescent sensors are also examined. Finally, the future outlook for the development of G-based sensors for this type of biocompounds is outlined.
BACKGROUND
Encapsulation of biocompounds is essential to protect them from environmental factors that could enhance their oxidation or cause them to lose their beneficial properties due to extreme photosensitivity, among other factors. The main goal of this work was to study the feasibility of preparing concentrated double emulsions with a high loading capacity containing simultaneously trans‐resveratrol (RSV) and vitamin D3 (VitD3). Such emulsions could be used for food fortification or pharmaceutical formulations or as vehicles for targeted controlled release.
RESULTS
In order to achieve large concentrations of the encapsulated compounds, all the double emulsions were formulated using a W1/O in W2 ratio of 80/20, while the ratios tested for W1 in O where 20/80 and 30/70. All the emulsions were characterized by droplet size, morphology, colloidal stability and encapsulation efficiency (EE) over a period of 6 weeks. VitD3 and RSV concentration were determined by a technique based on reverse‐phase high‐performance liquid chromatography. The viability of preparing concentrated W1/O/W2 emulsions containing both biocompounds has been demonstrated with satisfactory results. Initial RSV concentrations in the concentrated double emulsions formulated varied from 5.0 to 8.3 mg L⁻¹, while for VitD3 values of 28–32 mg L⁻¹ were obtained. The presence of VitD3 retarded RSV release in the formulated emulsions. It was observed that after 1 week of storage RSV EE increased around 10–50% when VitD3 was simultaneously encapsulated.
CONCLUSION
Simultaneous encapsulation of RSV and VitD3 was possible in high internal phase emulsions. The emulsions presented high colloidal stability, being suitable for food fortification applications. © 2020 Society of Chemical Industry
Resveratrol (3,5,4′-trihydroxystilbene) is a polyphenolic compound existing in trees, peanuts and grapes and exhibits a broad spectrum of promising therapeutic activities, but it is unclear whether this entity targets the sites of action after oral administration. In vivo applicability of resveratrol has limited success so far, mainly due to its incompetent systemic delivery resulting from its low water solubility, poor bioavailability and short biological half-life. First-pass metabolism and presence of enterohepatic recirculation create doubt on the biological application of high doses typically used for in vitro trials. To augment bioavailability, absorption and uptake of resveratrol by cellular internalization, countless approaches have been implemented which involve the use of nanocarriers. Nanocarriers are a well-known delivery system used to reduce first-pass hepatic metabolism, overcome enterohepatic recirculation and accelerate the absorption of drugs via lymphatic pathways.
Chitosan films were used to remove heavy oil from connate water, deionized water, and seawater. In this research, chitosan–starch films were modified with natural extracts from cranberry, blueberry, beetroot, pomegranate, oregano, pitaya, and grape. These biodegradable, low-cost, eco-friendly materials show an important oil sorption capacity from different water conditions. It was observed that the sorption capacity has a clear correlation with the extract type, quantity, and water pH. In order to understand the physical and chemical properties of the films, they were analyzed according to their apparent density, water content, solubility, and swelling degree by scanning electron microscopy (SEM), thermogravimetric analysis (TGA), gas chromatography–mass spectroscopy (GC–MS), and the determination of surface area using the Brunauer Emmett Teller (BET) method. The results indicate that chitosan–starch films modified with natural extracts can be successfully applied for environmental issues such as oil spill remedy.
Aim: A solid self-emulsifying drug delivery systems was developed by using the spray-drying technique, to improve the solubility of resveratrol (RES). Materials & methods: Cod liver oil and three surfactant system were tested: soy phosphatidylcholine (SPC)/Eumulgin ® HRE-40 (EU)/Sodium oleate (system A); SPC/Tween ® 80 (TW) /Sodium oleate (system B) and SPC/EU/TW (system C). Results: The greatest incorporation was obtained with system C (21.26 mg/ml). Solid self-emulsifying drug delivery systems with the highest yield were obtained with colloidal silicon dioxide (CSD) (80.12%), and CSD sodium croscarmelose 9:1 and 5:5. RES dissolution attained 100% at 45 min with CSD:CS 5:5. Discussion: The surface modification to hydrophilic by CSD:sodium croscarmellose reduced the cohesive force among drug particles. Conclusion: The developed systems are a good approximation for the design of strategies that could allow increasing the oral bioavailability of RES.
Plants have phenolic compounds with antioxidant activity. These compounds are distributed in tissues and cells of plants and their abundance depends on the species, the part of the plant used, maturity stage, light hours, among others. On the other hand, the profile and quantity of phenolic compounds extracted from plant matrices changes depending on the species, cultivar, climate, and other factors. Plant extracts do not present a unique phenolic component, they correspond a mixture and its antioxidant activity will be affected by the concentration of each one and their action depends on this composition. In this chapter, some generalities about the phenolic compounds with antioxidant activity present in plant matrices will be exposed, also the principal methods for their extraction and quantification will be described and this information will be complemented with a review on applications of these compounds in food industry. In that sense, the reader can infer the importance of continue to studying and developing techniques to obtain, extract, and characterize this kind of compounds, also they can identify possible application of them, the most important, they can recognize them as an alternative to replace chemical synthetized antioxidants used in food industry improving the market of natural products.
This study evaluated the protective effects of resveratrol on the prostate development of rats exposed to TCDD. Pregnant rats received TCDD (1 µg/kg) at GD15 and/or RES (20 mg/kg/day) from GD10 to PND21. Newborn and adult males from Control, TCDD, TCDD + RES and RES groups were euthanized and the prostate was excised. On PND1, there was a reduction in the number of prostatic buds, AR-positive mesenchymal cells and proliferation index in epithelial and mesenchymal cells in TCDD group, but restored by RES. AhR immunoreactivity was greater in TCDD group than the other groups. On PND90, there was higher frequency of functional hyperplasia in the distal area of the prostate acini in TCDD group, but restored by RES. AhRR expression was higher in the TCDD while NRF2 was higher in the TCDD + RES compared to the other groups. Resveratrol was able to reduce the adverse effects of TCDD on prostate development and its long-term repercussions.
Natural extracts possess several kinds of antioxidants (anthocyanins, betalains, thymol, carvacrol, and resveratrol) that have also demonstrated antimicrobial properties. In order to study these properties, extracts from cranberry, blueberry, beetroot, pomegranate, oregano, pitaya, and resveratrol (from grapes) were obtained. Growth inhibition tests of mesophilic aerobes, coliforms, and fungi were conducted in films prepared from the extracts in accordance with Mexican Official Norms (NOM). Optical properties such as transparency and opacity, mechanical properties, and pH were also analyzed in these materials. The films with beetroot, cranberry, and blueberry extracts demonstrated the best antimicrobial activity against various bacteria and fungi in comparison with unmodified chitosan–starch film. This study shows that the addition of antioxidants improved the antimicrobial performance of these films. It was also found that antimicrobial properties are inherent to the films. These polymers combined with the extracts effectively inhibit or reduce microorganism growth from human and environmental contact; therefore, previous sterilization could be unnecessary in comparison with traditional plastics. The presence of extracts decreased transmittance percentages at 280 and 400 nm, as well as the transparency values, while increasing their opacity values, providing better UV–VIS light barrier properties. Despite diminished glass transition temperatures (Tg), the values obtained are still adequate for food packaging applications.
There is now a large body of evidence describing the significant risk of obesity and metabolic complications in the children of mothers who were over-weight or obese during. This article is protected by copyright. All rights reserved.
Groundnut, Arachis hypogea L., is one of the plant species that synthesizes phenolic compounds, resveratrol and coumaric acid. They are induced as a defense strategy in plant in response to feeding lepidopterans. The present study investigated the role of resveratrol and coumaric acid in producing antiherbivore effects as a direct defense against two major groundnut pests, Spodoptera litura F. and Amsacta albistriga W., and in indirect defense by attracting the egg parasitoid Trichogramma chilonis Ishii under laboratory conditions. The phenolic compounds deterred the feeding of both pests and caused reduction in the larval weights in a dose-dependent manner in leaf disk bioassays. Antioxidant mechanisms of larvae fed with these phenols were measured by estimating the activities of superoxide dismutase (SOD), ascorbate peroxidase (APOX), and catalase (CAT). Enzyme activities increased significantly in experimental larvae, more so in resveratrol-treated than in coumaric acid treated larvae. Feeding larvae with resveratrol and coumaric acid resulted in enhanced activities of detoxifying enzymes, carboxyl esterase (EST), and glutathione-S-transferase (GST) in the midgut tissues of both species, indicating the toxic nature of these compounds. Trichogramma chilonis was more attracted toward coumaric acid treatments in Y-olfactometer tests than to resveratrol. This study contributes to the understanding of the roles of resveratrol and coumaric acid in direct as well as indirect defense, we infer a possible utilization of these compounds in alternate measures of groundnut pest control in future.
Resveratrol-enriched wine is considered an interesting product with added value as a consequence of its numerous health properties. The purpose of this study was to determine the effect of different nitrogen foliar applications on the stilbene concentration of Tempranillo musts and wines. The nitrogen sources applied were proline, phenylalanine, urea, and two commercial nitrogen fertilizers, with and without amino acids in their formulation. Grapevines were sprayed at veraison and one week later. Stilbene concentration was higher in wines than in musts and there was a good correlation between the stilbene concentration in musts and wines. Results showed that urea treatment favoured resveratrol and piceid synthesis, since the application of this nitrogen compound increased stilbene concentration in musts and wines. Wines from phenylalanine treatment presented higher concentration of trans-piceid than control wines. However, proline and commercial nitrogen fertilizers treatments did not affect stilbene concentration in the must and wine samples. Consequently, foliar application of phenylalanine and urea to the vineyard could be used as a biostimulant for stilbene synthesis and therefore musts and wines with better health properties could be obtained.
We aimed to analyse the effects of alcohol-free Alibernet red wine extract (AWE) on nitric oxide synthase (NOS) activity and pro-inflammatory markers such as nuclear factor-κB (NFκB) and inducible NOS (iNOS) protein expression in experimental metabolic syndrome. Young 6 week-old male Wistar Kyoto (WKY) and obese, spontaneously hypertensive rats (SHR/N-cp) were divided into control groups and groups treated with AWE (24.2 mg per kg per day) for 3 weeks (n = 6 in each group). Total NOS activity and endothelial NOS (eNOS), iNOS and NFκB (p65) protein expressions were determined in the heart left ventricle and aorta by Western blot and immunohistochemical analysis. All parameters investigated significantly increased in the aorta of SHR/N-cp rats. Pro-inflammatory markers such as NFκB and iNOS were increased in the left ventricle as well. AWE treatment did not affect total NOS activity and eNOS expression in the aorta; however, it was able to decrease NFκB and iNOS protein expression in both the left ventricle and aorta. In conclusion, in the cardiovascular system, Alibernet red wine extract decreased NFκB and iNOS protein expressions elevated as a consequence of developed metabolic syndrome. This effect may represent one of the protective, anti-inflammatory properties of Alibernet red wine polyphenols on cardiovascular risk factors related to metabolic syndrome.
Resveratrol has attracted interest as a wine constituent that may reduce heart disease. Published data on the molar absorptivity and chemical stability of cis- and trans-resveratrol have varied greatly. Accurate values for UV absorbance for trans-resveratrol [UV λmax (EtOH) nm (ε) 308 (30 000)] and cis-resveratrol [UV λmax (EtOH) nm (ε) 288 (12 600)] were determined and are used to improve chromatographic quantitation methods. Trials conducted under a variety of commonly encountered laboratory conditions show that trans-resveratrol is stable for months, except in high-pH buffers, when protected from light. cis-Resveratrol was stable only near pH neutrality when completely protected from light. Keywords: Antioxidant; phenolic; wine; grape; stilbene; isomer; UV spectroscopy; absorptivity
The biological activity of resveratrol, a stilbenic compound synthesized by grapevines in response to various stresses, was reevaluated against Botrytis cinerea using a novel in vitro system that enabled direct observation of the fungus with an inverted microscope. We determined that 90 g resveratrol/ml reduced germination of B. cinerea conidia by ca. 50%. Moreover, resveratrol was shown to significantly reduce mycelial growth of B. cinerea at concentrations ranging from 60 to 140 g/ml. Exposure to resveratrol at concentrations ranging from 60 to 140 g/ml resulted in cytological changes in B. cinerea, such as production of secondary or tertiary germ tubes by conidia, cytoplasmic granulations, protoplasmic retractation in the hyphal tip cells, and formation of curved germ tubes. These data reinforce the role played by this compound in the B. cinerea–grapevine interaction.
The purpose of this research was, firstly to determine the ability of grapevine in vitro cultures to synthesize resveratrol, a stilbene-type phytoalexin that is considered to be a good marker for resistance of grapevines to Botrytis cinerea, the causal organism for grey mould. Secondly, this study sought to establish the relationship between phytoalexin production potential and resistance to Botrytis cinerea in grapevines. In this aim, resveratrol production was assessed in 13 Vitis species or cultivars. A good correlation appeared between resveratrol production by grapevine in vitro cultures and grey mould resistance except for two Vitis spp. for which no correlation was observed, thus suggesting that resistance of grapevines may sometimes be associated with factors other than stilbene phytoalexins. In view of the results obtained, the potential use of resveratrol induction and of in vitro methods as a tool for screening grapevines for resistance to B. cinerea was discussed.
Resveratrol is a natural compound that affects energy metabolism and mitochondrial function and serves as a calorie restriction mimetic, at least in animal models of obesity. Here, we treated 11 healthy, obese men with placebo and 150 mg/day resveratrol (resVida) in a randomized double-blind crossover study for 30 days. Resveratrol significantly reduced sleeping and resting metabolic rate. In muscle, resveratrol activated AMPK, increased SIRT1 and PGC-1α protein levels, increased citrate synthase activity without change in mitochondrial content, and improved muscle mitochondrial respiration on a fatty acid-derived substrate. Furthermore, resveratrol elevated intramyocellular lipid levels and decreased intrahepatic lipid content, circulating glucose, triglycerides, alanine-aminotransferase, and inflammation markers. Systolic blood pressure dropped and HOMA index improved after resveratrol. In the postprandial state, adipose tissue lipolysis and plasma fatty acid and glycerol decreased. In conclusion, we demonstrate that 30 days of resveratrol supplementation induces metabolic changes in obese humans, mimicking the effects of calorie restriction.
Cyclodextrins (CDs) are macrocyclic oligosaccharides composed of α(1,4)-linked glucopyranose subunits. These molecules possess a cage-like supramolecular structure, comparable with the structures of crown ethers, cryptands, spherands, cyclophanes, or calixarenes. However, it took 50 years to establish the molecular structure of CDs. Owing to their capability to form inclusion complexes with a variety of guest molecules, CDs are considered as the most important supramolecular host family among all supramolecular structures mentioned above. They can form complexes with various types of molecules including inorganic, organic, or organometallic that can be radical, cationic, anionic, or neutral molecules. This phenomenon bears the name "molecular recognition," while the selectivity in the formation of complexes with enantiomeric species as guests is called "chiral recognition." In addition, the properties of the molecules forming the complexes with CDs can be modified significantly. As such, a large number of scientists have attempted to elaborate and evaluate various CD derivatives that are able to complex a variety of drugs, enhancing by this way their in vivo solubility and activity. Moreover, a large number of publications describe CD uses in other fields such as foods, textile, cosmetics, or agriculture. This review reports on the recent developments of CDs in drug delivery using various routes of administration.
A fully 3D iterative image reconstruction algorithm has been developed for high-resolution PET cameras composed of pixelated scintillator crystal arrays and rotating planar detectors, based on the ordered subsets approach. The associated system matrix is precalculated with Monte Carlo methods that incorporate physical effects not included in analytical models, such as positron range effects and interaction of the incident gammas with the scintillator material. Custom Monte Carlo methodologies have been developed and optimized for modelling of system matrices for fast iterative image reconstruction adapted to specific scanner geometries, without redundant calculations. According to the methodology proposed here, only one-eighth of the voxels within two central transaxial slices need to be modelled in detail. The rest of the system matrix elements can be obtained with the aid of axial symmetries and redundancies, as well as in-plane symmetries within transaxial slices. Sparse matrix techniques for the non-zero system matrix elements are employed, allowing for fast execution of the image reconstruction process. This 3D image reconstruction scheme has been compared in terms of image quality to a 2D fast implementation of the OSEM algorithm combined with Fourier rebinning approaches. This work confirms the superiority of fully 3D OSEM in terms of spatial resolution, contrast recovery and noise reduction as compared to conventional 2D approaches based on rebinning schemes. At the same time it demonstrates that fully 3D methodologies can be efficiently applied to the image reconstruction problem for high-resolution rotational PET cameras by applying accurate pre-calculated system models and taking advantage of the system's symmetries.
There is much epidemiological evidence that diets rich in fruit and vegetables can reduce the incidence of non-communicable diseases such as cardiovascular diseases, diabetes, cancer and stroke. These protective effects are attributed, in part, to phenolic secondary metabolites. This review summarizes the chemistry, biosynthesis and occurrence of the compounds involved, namely the C6-C3-C6 flavonoids-anthocyanins, dihydrochalcones, flavan-3-ols, flavanones, flavones, flavonols and isoflavones. It also includes tannins, phenolic acids, hydroxycinnamates and stilbenes and the transformation of plant phenols associated with food processing (for example, production of black tea, roasted coffee and matured wines), these latter often being the major dietary sources. Events that occur following ingestion are discussed, in particular, the deglycosylation, glucuronidation, sulfation and methylation steps that occur at various points during passage through the wall of the small intestine into the circulatory system and subsequent transport to the liver in the portal vein.We also summarise the fate of compounds that are not absorbed in the small intestine, but which pass into the large intestine where they are degraded by the colonic microflora to phenolic acids, which can be absorbed into the circulatory system and subjected to phase II metabolism prior to excretion. Initially, the protective effect of dietary phenolics was thought to be due to their antioxidant properties which resulted in a lowering of the levels of free radicals within the body.However, there is now emerging evidence that themetabolites of dietary phenolics,which appear in the circulatory systemin nmol/L to low mmol/L concentrations, exertmodulatory effects in cells through selective actions on different components of the intracellular signalling cascades vital for cellular functions such as growth, proliferation and apoptosis. In addition, the intracellular concentrations required to affect cell signalling pathways are considerably lower than those required to impact on antioxidant capacity. The mechanisms underlying these processes are discussed.
Phomopsis viticola produces methanethiol on a synthetic medium enriched with L-methionine (MMGS). The growth rate is comparable, during 12 days of culture, to that on the same medium without L-methionine (MGS). Only sterile bodies are formed on MMGS and no pycnidia appeared. The morphogenetic effect of MMGS medium is attached to the volatile methanethiol produced from L-methionine introduced into the medium. This volatile product is identified using several different methods of analysis. The roles of the reactive sulfhydryl groups and of the metabolism of elemental sulfur of P. viticola in the differentiation processes are discussed.
Resveratrol, a phytoalexin found in grapes and other food products, was purified and shown to have cancer chemopreventive activity in assays representing three major stages of carcinogenesis. Resveratrol was found to act as an antioxidant and antimutagen and to induce phase II drug-metabolizing enzymes (anti-initiation activity); it mediated anti-inflammatory effects and inhibited cyclooxygenase and hydroperoxidase functions (antipromotion activity); and it induced human promyelocytic leukemia cell differentiation (antiprogression activity). In addition, it inhibited the development of preneoplastic lesions in carcinogen-treated mouse mammary glands in culture and inhibited tumorigenesis in a mouse skin cancer model. These data suggest that resveratrol, a common constituent of the human diet, merits investigation as a potential cancer chemopreventive agent in humans.
Wine has been part of human culture for 6,000 years, serving dietary and socioreligious functions. Its production takes place on every continent, and its chemical composition is profoundly influenced by enological techniques, the grape cultivar from which it originates, and climatic factors. In addition to ethanol, which in moderate consumption can reduce mortality from coronary heart disease by increasing high‐density lipoprotein cholesterol and inhibiting platelet aggregation, wine (especially red wine) contains a range of polyphenols that have desirable biological properties. These include the phenolic acids (p‐coumaric, cinnamic, caffeic, gentisic, ferulic, and vanillic acids), trihydroxy stilbenes (resveratrol and polydatin), and flavonoids (catechin, epicatechin, and quercetin). They are synthesized by a common pathway from phenylalanine involving polyketide condensation reactions. Metabolic regulation is provided by competition between resveratrol synthase and chalcone synthase for a common precursor pool of acyl‐CoA derivatives. Polymeric aggregation gives rise, in turn, to the viniferins (potent antifungal agents) and procyanidins (strong antioxidants that also inhibit platelet aggregation). The antioxidant effects of red wine and of its major polyphenols have been demonstrated in many experimental systems spanning the range from in vitro studies (human low‐density lipoprotein, liposomes, macrophages, cultured cells) to investigations in healthy human subjects. Several of these compounds (notably catechin, quercetin, and resveratrol) promote nitric oxide production by vascular endothelium; inhibit the synthesis of thromboxane in platelets and leukotriene in neutrophils, modulate the synthesis and secretion of lipoproteins in whole animals and human cell lines, and arrest tumour growth as well as inhibit carcinogenesis in different experimental models. Target mechanisms to account for these effects include inhibition of phospholipase A2 and cyclo‐oxygenase, inhibition of phosphodiesterase with increase in cyclic nucleotide concentrations, and inhibition of several protein kinases involved in cell signaling. Although their bioavailability remains to be fully established, red wine provides a more favourable milieu than fruits and vegetables, their other dietary source in humans. J. Clin. Lab. Anal. 11:287–313, 1997. © 1997 Wiley‐Liss, Inc.
The ability of the hypodermal grapevine peroxidase isoenzyme B5 to oxidize trans-resveratrol was studied. The results showed that the oxidation of trans-resveratrol by this isoenzyme was strictly dependent on H2O2 and follows the accepted model for peroxidase oxidations, in which compound I (CoI) and compound II (CoII) appear to be the main intermediates in the catalytic cycle. The reactivity of grapevine peroxidase isoenzyme B5 with H2O2 [k1 (CoI formation constant) = 1.73 μM-1 s-1] and with trans-resveratrol [k3 (CoII reduction constant) = 11.9 μM-1 s-1], suggests that the isoenzyme reacts with H2O2 with a similar reactivity to that shown by other peroxidases, and that trans-resveratrol is an excellent substrate for CoII reduction. Further, the strong oxidizing activity of this basic peroxidase isoenzyme at pH 3.0 to 4.0 suggests that the peroxidase-mediated reaction is well adapted to the acidic medium of the vacuole, in which grapevine peroxidase B5 is mainly located. These results reveal the special kinetic characteristics of the grapevine peroxidase isoenzyme B5 to oxidize trans-resveratrol, and enable us to assign a specific metabolic function to this grapevine isoenzyme which acts as a constitutive (non-inducible) marker of disease resistance in grapevine leaves and shoots.
Trans-3,4,5-trihydroxystilbene (resveratrol), a polyphenolic compound found in juice and wine from dark-skinned grape cultivars, was recently shown to bind to estrogen receptors in vitro, where it activated transcription of estrogen-responsive reporter genes. The purpose of this 6-day study in weanling rats was to determine the dose response (1, 4, 10, 40, and 100 μg/day) effects of orally administered resveratrol on estrogen target tissues. The solvent (10% ethanol) had no significant effect on any measurement or derived value. 17β-Estradiol treatment (100 μg/day) decreased the growth rate, final body weight, serum cholesterol, and radial bone growth (periosteal bone formation and mineral apposition rates) at the tibia-fibula synostosis. In the uterus, 17β-estradiol treatment increased wet weight, epithelial cell height, and steady state messenger RNA levels for insulin-like growth factor I. In contrast, resveratrol treatment had no significant effect on body weight, serum cholesterol, radial bone growth, epithelial cell height, or messenger RNA levels for insulin-like growth factor I. Resveratrol treatment resulted in slight increases in uterine wet weight, but significance was achieved at the 10-μg dose only. A second experiment was performed to determine whether a high dose of resveratrol (1000μ g/day) antagonizes the ability of estrogen to lower serum cholesterol. As was shown for the lower doses, resveratrol had no effect on body weight, uterine wet weight, uterine epithelial cell height, cortical bone histomorphometry, or serum cholesterol. 17β-Estradiol significantly lowered serum cholesterol, and this response was antagonized by cotreatment with resveratrol. These in vivo results suggest, in contrast to prior in vitro studies, that resveratrol has little or no estrogen agonism on reproductive and nonreproductive estrogen target tissues and may be an estrogen antagonist.
Resveratrol, a phytoalexin found in grapes and other food products, was purified and shown to have cancer chemopreventive
activity in assays representing three major stages of carcinogenesis. Resveratrol was found to act as an antioxidant and antimutagen
and to induce phase II drug-metabolizing enzymes (anti-initiation activity); it mediated anti-inflammatory effects and inhibited
cyclooxygenase and hydroperoxidase functions (antipromotion activity); and it induced human promyelocytic leukemia cell differentiation
(antiprogression activity). In addition, it inhibited the development of preneoplastic lesions in carcinogen-treated mouse
mammary glands in culture and inhibited tumorigenesis in a mouse skin cancer model. These data suggest that resveratrol, a
common constituent of the human diet, merits investigation as a potential cancer chemopreventive agent in humans.
Piceid, the 3-β-glucoside of resveratrol, was observed in berries of two of the three varieties tested. These results suggest that the source and fate of this glucoside could be related to the biosynthesis of resveratrol and its production or loss in response to plant stress. Also, the levels of piceid in wine could affect the physiologically available amounts of resveratrol to consumers of wine.
risk of esophageal cancer. To perform this, it is necessary to understand the potential mechanism(s) of esophageal carcinogenesis. Until now, several hypotheses have been postulated, with the main hypotheses being the link between cancer and prostaglandin E2 (PGE2). Based on many current studies, overexpression of COX-2 and elevation of COX-2-mediated PGE2 synthesis are thought to be associated with human esophageal carcinogenesis. COX-2 expression is up-regulated in several types of human cancers, including esophageal cancer (1). It also was observed that overexpression of COX-2 was induced by NMBA in rat esophagi and significantly associated with esophageal tumorigenesis (2). Recent studies demonstrated that non-steroidal anti-inflammatory drugs (NSAIDs), e.g. aspirin, inhibited both COX-1 and COX-2 (3), and longterm intake of aspirin was associated with an up to 90% decreased risk of developing esophageal cancer (4). Our previous paper determined that NMBA-induced rat esophageal tumorigenesis was suppressed by JTE-522 (4-[4-cyclohexyl-2methyloxazol-5-yl]-2-fluorobenzenesulfonamide), a selective COX-2 inhibitor, by decreasing COX-2-mediated PGE2 without reduction of COX-2 expression (2). Thus, suppression of COX-2 expression and/or the COX-2-mediated PGE2 may be effective targets in chemoprevention of esophageal carcinogenesis.
Resveratrol has attracted interest as a wine constituent that may reduce heart disease. Published data on the molar absorptivity and chemical stability of cis- and trans-resveratrol have varied greatly. Accurate values for UV absorbance for trans-resveratrol [UV λmax (EtOH) nm (ε) 308 (30 000)] and cis-resveratrol [UV λmax (EtOH) nm (ε) 288 (12 600)] were determined and are used to improve Chromatographic quantitation methods. Trials conducted under a variety of commonly encountered laboratory conditions show that trans-resveratrol is stable for months, except in high-pH buffers, when protected from light. cis-Resveratrol was stable only near pH neutrality when completely protected from light.
The isolation of resveratrol and a new dibenzoxepin derivative, pacharin, from the heartwood of Lank is reported. The structure of pacharin has been established as l,7-dlhydroxy-3-methoxy-2-methyl-dibenzo(2,3-6,7) oxepin (Va) by a study of its chemical and spectroscopic properties, including X-ray analysis.
From the stems of Pterolobium hexapetallum phenanthrene, tri-O-methyl resveratrol, methyl tri-O-methyl gallate, pterostilbene, resveratrol, methyl gallate were isolated. The natural occurrence of phenanthrene has not previously been reported. The structures were determined by analytical and spectroscopic methods.
Twenty-three major components were detected in the methanol extractives of the heartwood of Eucalyptus sideroxylon. The components identified include resveratrol, resveratrol-β-glucoside, 3,3′-di- and 3,3′,4-tri-o-methylellagic acids and their glucosides. The 3,3′-di-o-methylellagic acid 4′-glucoside isolated had properties significantly different from those previously reported for this compound. Also present were gailic acid, catechin, ellagic acid, an unidentified stilbene, the ellagitannins D-6 and D-13, polymerized leucocyanidin and an oily material. The sapwood contained gailic acid, small amounts of ellagitannins and ellagic acids and traces of other components. The heartwood extractives of related eucalypt species were also examined.
Functional ingredients of grape seeds include several flavonoids with a phenolic nature such as monomeric flavanols (catechin and epicatechin), dimeric, trimeric and polymeric procyanidins, and phenolic acids (gallic acid and ellagic acid). These flavonoids have been reported to exhibit antioxidant activity in vivo and in vitro in a number of studies. The antioxidant activity of flavonoids is closely associated with activity against various cancer types, cardiovascular diseases and several dermal disorders. In this study, we present a review of functional components of grape seeds or skins with emphasis on health benefits of their use in the human diet.
Two antifungal stilbenoids and their glucosides were isolated from the leaves of Veratrum grandiflorum treated with cupric chloride. They were identified as resveratrol, oxyresveratrol, resveratrol-3-O-glucoside (piceid) and oxyresveratrol-3-O-glucoside. The last compound was isolated for the first time from a natural source. In addition three glucosides of flavonoid (apigenin-7-O-glucoside, luteolin-7-O-glucoside, chrysoeriol-7-O-glucoside) were also found in the leaves.
Epidemiological evidence indicates that phytoestrogens inhibit cancer formation and growth, reduce cholesterol levels, and show benefits in treating osteoporosis. At least some of these activities are mediated through the interaction of phytoestrogens with estrogen receptors a and b (ERa and ERb). Resveratrol, trans-3,5,49-trihy- droxystilbene, is a phytoestrogen in grapes that is present in red wine. Resveratrol was shown to bind ER in cytosolic extracts from MCF-7 and rat uteri. However, the contribution of ERa vs. ERb in this binding is unknown. Here we report that resveratrol binds ERb and ERa with comparable affinity, but with 7,000-fold lower affinity than estradiol (E2). Thus, resveratrol differs from other phytoestrogens that bind ERb with higher affinity than ERa. Resveratrol acts as an estrogen agonist and stimulates ERE-driven reporter gene activity in CHO-K1 cells expressing either ERa or ERb. The estrogen agonist activity of resveratrol depends on the ERE sequence and the type of ER. Resveratrol-liganded ERb has higher transcriptional activity than E2-liganded ERb at a single palindromic ERE. This indicates that those tissues that uniquely express ERb or that express higher levels of ERb than ERa may be more sensitive to resveratrol's estro- gen agonist activity. For the natural, imperfect EREs from the human c-fos, pS2, and progesterone receptor (PR) genes, resveratrol shows activity comparable to that induced by E2. We report that resveratrol exhibits E2 antagonist activity for ERa with select EREs. In contrast, resveratrol shows no E2 antagonist activity with ERb. These data indicate that resveratrol differentially affects the transcriptional ac- tivity of ERa and ERb in an ERE sequence-dependent manner. (En- docrinology 141: 3657-3667, 2000)
A comparative study between dietary fiber (DF) and polyphenols (PP) in terms of degradability and physiological properties was performed. Eight groups of Wistar rats were fed either a control diet free of DF and PP or diets containing DF constituents [cellulose (C), pectins (P), and lignin (L)] or PP, both soluble [catechin (CA) and tannic acid (TA)] and insoluble [condensed tannins (CT)]. A significant increase in the total stool output and in the water and fat content of feces was observed. Protein digestibility was significantly reduced. Intestinal degradation of the soluble compounds (P, CA, and TA) was almost complete. C was partially digested; L and CT were highly resistant. In vitro fermentation assays were performed, showing the different susceptibilities of the DF constituents and the polyphenolic compounds to fermentation and the inhibitory effect of TA and L on colonic microflora.
Numerous studies have reported interesting properties of trans-resveratrol, a phytoalexin, as a preventive agent of several important pathologies: vascular diseases, cancers, viral infections, and neurodegenerative processes. These beneficial effects of resveratrol have been supported by observations at the cellular and molecular levels in both cellular and in vivo models, but the cellular fate of resveratrol remains unclear. We suggest here that resveratrol uptake, metabolism, and stability of the parent molecule could influence the biological effects of resveratrol. It appears that resveratrol stability involves redox reactions and biotransformation that influence its antioxidant properties. Resveratrol's pharmacokinetics and metabolism represent other important issues, notably, the putative effects of its metabolites on pathology models. For example, some metabolites, mainly sulfate-conjugated resveratrol, show biological effects in cellular models. The modifications of resveratrol stability, chemical structure, and metabolism could change its cellular and molecular targets and could be crucial for improving or decreasing its chemopreventive properties.
This was a double-blind, randomised, placebo-controlled study to investigate the pharmacokinetics and safety of trans-resveratrol. In four groups of ten healthy adult subjects (five males and five females), two subjects were randomized to receive placebo and eight subjects to receive trans-resveratrol 25, 50, 100 or 150 mg, six times/day, for thirteen doses. Peak plasma concentrations of trans-resveratrol were reached at 0.8–1.5 h postdose. Following the 13th dose of trans-resveratrol 25, 50, 100 and 150 mg, mean peak plasma concentration (Cmax) was 3.89, 7.39, 23.1 and 63.8 ng/mL and mean area under the plasma concentration–time curve (AUC0-τ) was 3.1, 11.2, 33.0 and 78.9 ng·h/mL. Interindividual variability was high, with coefficients of variation >40%. Trans-resveratrol half-life was 1–3 h following single-doses and 2–5 h following repeated dosing. Trough (Cmin) concentrations were ⪇1 ng/mL following 25 and 50 mg, 3 ng/mL following 100 mg and < 10 ng/mL following 150 mg. Trans-resveratrol pharmacokinetics showed circadian variation. Adverse events were mild in severity and similar between all groups. In conclusion, repeated administration was well-tolerated but produced relatively low plasma concentrations of trans-resveratrol, despite the high doses and short dosing interval used. Bioavailability was higher after morning administration.
Trans-resveratrol (4,3′,5′-trihydroxy stilbene) has been identified as the major component responsible for the blue fluorescence of grapevine leaf tissue following fungal infection or exposure to ultraviolet light. The biosynthesis of this compound appears to be a non-specific response of members of the Vitaceae to infection or injury. The compound is not detectable in healthy leaves but accumulates to between 50 and 400 μg/g fresh weight in infected or u.v.-irradiated leaves and is a major constituent (c. 700 μg/g) of lignified stem tissue. The biological significance of the production of resveratrol is discussed.
Neurodegenerative diseases are a group of chronic, progressive disorders characterized by the gradual loss of neurons in several areas of the central nervous system (CNS). Substantial evidence has documented a common inflammatory mechanism in neurodegeneration. It is known that classical anti-inflammatory agents, steroids and nonsteroidal anti-inflammatory drugs, have not played a major role in the management of CNS inflammatory conditions. This may be partly due to the natural compartmentation of the brain by the blood-brain barrier. Thus, there is much interest in developing novel anti-inflammatory drugs that may help to prevent or ameliorate CNS inflammation. Resveratrol (RSV) has received considerable attention over the last several decades. Experimental studies have revealed its benefits in several human disease models, including cardio- and neuro-protection, immune regulation and cancer chemoprevention. The broad action spectrum of RSV is explained by the involvement of numerous signaling networks and cellular effector mechanisms. Among them, apoptotic and antioxidant targets have been implicated. Recently, also anti-neuroinflammatory activity has been observed. A number of studies demonstrated that RSV mediates the downregulation of various inflammatory biomarkers such as tumor necrosis factor, cyclooxygenase 2, inducible nitric oxide synthase and interleukins. This activity seems to depend on some structural features of RSV such as the number and the position of hydroxyl groups. In this review, a comprehensive account of multiple intracellular RSV targets involved in neuroinflammation and its analogues design will be treated, pointing to structure/activity relationships.
Diabetes mellitus (DM) is characterized by dysregulated energy metabolism. Resveratrol (RSV) has been shown to ameliorate hyperglycemia and hyperlipidemia in diabetic animals. However, its overall in vivo effects on energy metabolism and the underlying mechanism require further investigation. In the present study, electrospray ionization-tandem mass spectrometry was employed to characterize the urine and plasma metabolomes of control, streptozotocin-induced DM and RSV-treated DM rats. Using principal component analysis (PCA) and heat map analysis, we discovered significant differences among control and experimental groups. RSV treatment significantly reduced the metabolic abnormalities in DM rats. Compared with the age-matched control rats, the level of carnitine was lower, and the levels of acetylcarnitine and butyrylcarnitine were higher in the urine and plasma of DM rats. RSV treatment ameliorated the deranged carnitine metabolism in DM rats. In addition, RSV treatment attenuated the diabetic ketoacidosis and muscle protein degradation, as evidenced from the attenuation of elevated urinary methyl-histidine and plasma branched-chain amino acids levels in DM rats. The beneficial effects of RSV in DM rats were correlated with activation of hepatic AMP-activated protein kinase and SIRT1 expression, increase of hepatic and muscular mitochondrial biogenesis and inhibition of muscle NF-κB activities. We concluded that RSV possesses multiple beneficial metabolic effects in insulin-deficient DM rats, particularly in improving energy metabolism and reducing protein wasting.
Reports of the bone-protective effects of resveratrol, a naturally occurring phytoestrogen and agonist for the longevity gene SIRT1, have highlighted this compound as a candidate for therapy of osteoporosis. Moreover, SIRT1 antagonism enhances adipogenesis. There has been speculation that resveratrol can promote osteogenesis through SIRT1, but the mechanism remains unclear. In this study we investigated the molecular mechanism of how resveratrol can modulate the lineage commitment of human mesenchymal stem cells to osteogenesis other than adipogenesis. We found that resveratrol promoted spontaneous osteogenesis but prevented adipogenesis in human embryonic stem cell-derived mesenchymal progenitors. Resveratrol upregulated the expression of osteo-lineage genes RUNX2 and osteocalcin while suppressing adipo-lineage genes PPARγ2 and LEPTIN in adipogenic medium. Furthermore, we found that the osteogenic effect of resveratrol was mediated mainly through SIRT1/FOXO3A with a smaller contribution from the estrogenic pathway. Resveratrol activated SIRT1 activity and enhanced FOXO3A protein expression, a known target of SIRT1, in an independent manner. As a result, resveratrol increased the amount of the SIRT1-FOXO3A complex and enhanced FOXO3A-dependent transcriptional activity. Ectopic overexpression or silencing of SIRT1/FOXO3A expression regulated RUNX2 promoter activity, suggesting an important role for SIRT1-FOXO3A complex in regulating resveratrol-induced RUNX2 gene transcription. Further mutational RUNX2 promoter analysis and chromatin immunoprecipitation assay revealed that resveratrol-induced SIRT1-FOXO3A complex bound to a distal FOXO response element (-1269/-1263), an action that transactivated RUNX2 promoter activity in vivo. Taken together, our results describe a novel mechanism of resveratrol in promoting osteogenesis of human mesenchymal stem cells by upregulating RUNX2 gene expression via the SIRT1/FOXO3A axis.
Resveratrol has been reported to increase adrenaline-induced lipolysis in 3T3-L1 adipocytes. The general aim of the present work was to gain more insight concerning the effects of trans-resveratrol on lipid mobilization. The specific purpose was to assess the involvement of the two main lipases: adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL), in the activation of lipolysis induced by this molecule. For lipolysis experiments, 3T3-L1 and human SGBS adipocytes as well as adipose tissue from wild-type, ATGL knockout and HSL knockout mice were used. Moreover, gene and protein expressions of these lipases were analyzed. Resveratrol-induced free fatty acids release but not glycerol release in 3T3-L1 under basal and isoproterenol-stimulating conditions and under isoproterenol-stimulating conditions in SGBS adipocytes. When HSL was blocked by compound 76-0079, free fatty acid release was still induced by resveratrol. By contrast, in the presence of the compound C, an inhibitor of adenosine monophosphate-activated protein kinase, resveratrol effect was totally blunted. Resveratrol increased ATGL gene and protein expressions, an effect that was not observed for HSL. Resveratrol increased fatty acids release in epididymal adipose tissue from wild-type and HSL knockout mice but not in that adipose tissue from ATGL knockout mice. Taking as a whole, the present results provide novel evidence that resveratrol regulates lipolytic activity in human and murine adipocytes, as well as in white adipose tissue from mice, acting mainly on ATGL at transcriptional and posttranscriptional levels. Enzyme activation seems to be induced via adenosine monophosphate-activated protein kinase.
The enzyme kinetic profiles of the formation of resveratrol-3-O-glucuronide (R3G) and resveratrol-4'-O-glucuronide (R4'G) by liver microsomes from humans, dogs, and rodents were investigated. Glucuronidation by human and dog liver microsomes to R3G and R4'G occurred for about 65% of applied resveratrol, and was significantly reduced to 10% when substrate concentration was increased 10-fold. In contrast, rodent microsomes glucuronidated about 90% of applied resveratrol independently of substrate concentration. Furthermore, in mouse and rat liver microsomes, resveratrol was almost exclusively conjugated at position 3, whereas human and dog livers also glucuronidated resveratrol at position 4' (ratio R3G:R4'G = 5:1). Interspecies differences were also found when calculating the enzyme kinetic profiles of both conjugates. Formation of R4'G in human and dog microsomes followed Michaelis-Menten kinetics, while R3G showed substrate inhibition at higher resveratrol concentrations. In mouse and rat microsomes, however, both R3G and R4'G formation exhibited auto-activation kinetics. Formation of R3G and R4'G by recombinant UGT1A1 also showed substrate inhibition kinetics that led to decreased intrinsic clearance values, while UGT1A9-catalyzed glucuronidation demonstrated substrate inhibition kinetics at position 3 and Hill kinetics for the formation of R4'G. In conclusion, resveratrol glucuronidation exhibited species-dependent differences, with the dog as the animal model that most closely represents humans in terms of this process.
Introduction
Resveratrol (3,5,4'-trihydroxistilbene, RSV) was first isolated from the roots of white
hellebore (Veratrum grandiflorum) in 1940 (Takaoka, 1940), and later, in 1963, from the
roots of Polygonum cuspidatum, a plant used in traditional Japanese medicine (Nonomura
et al., 1963). It seems that RSV might be partly responsible for the cardiovascular
benefits associated with red wine consumption.
It has been suggested that RSV relaxes different isolated arteries, has potent
antiinflammatory and antioxidant effects, and can also protect isolated hearts from
ischemia-reperfusion injury (Fitzpatrick et al., 1993; Naderali et al., 2000; Naderali et al.,
2001). Despite the increasing interest in the effects of RSV on the cardiovascular system,
inconsistencies between studies mean that the mechanism of its vasodilatatory effect is
not completely defined.
RSV-induced vasorelaxation may either be endothelium-dependent (attenuated by LNAME)
or endothelium-independent (Novakovic et al., 2006; Calderone et al., 2007).
The mechanism of endothelium-independent vasorelaxation induced by RSV is uncertain.
RSV might become incorporated into smooth muscle membrane, where it could either
couple with a membrane receptor or interact directly with membrane ion channels, thus
inducing endothelium-independent vasorelaxation (Jager y Nguyen-Duong, 1999). Also,
in different experimental models, RSV can activate adenylyl cyclase (AC) and
membrane-bound guanylyl cyclase (GC) and inhibit cGMP-specific phosphodiesterse-5
(Dell’Agli et al., 2005).
Similarly, our lab has reported that in rat aorta t-RSV exhibits: i) a characteristic
endothelium-dependent vasorelaxant effect which seems to be due to the inhibition of
vascular NADH/NADPH oxidase and the subsequent decrease of basal cellular
superoxide radicals (O2
•-) generation and, therefore, of nitric oxide (NO•)
biotransformation (Orallo et al,. 2002) and ii) an endothelium-independent vasodilator
effect, which appears to be mediated by an inhibition of protein kinase C (PKC) (Orallo
and Camiña, 1998). The endothelium-dependent component is probably the most
relevant, since it is observed at lower drug concentrations (<10 μM) than the
endothelium-independent effect (>50 μM). Much less is known about the
pharmacological activity of the cis-RSV possibly as a result of the fact that this isomer
(unlike t-RSV) is not commercially available.
c-RSV significantly attenuates several components of the macrophage response to
proinflammatory stimuli (Leiro et al., 2004), and a few studies have demonstrated only
quantitative differences in the activity of the two isomers; for example, in their ability to
decrease collagen-induced platelet aggregation (Bertelli et al,. 1996), in their estrogenic/
antiestrogenic and ROS scavenging properties, or inhibition of COX-1.
Vascular tone directly depends on cytosolic free Ca2+ concentration ([Ca2+]i) levels in
smooth muscle cells. Thus, any action of RSV on calcium signaling in these cells may be
related to its endothelium-independent vascular actions. Again, there is little information
on this subject. Orallo and Camiña, using 45Ca2+ in rat aortic rings, have suggested that
the vasorelaxant effect of t-RSV is not mediated by blockage of Ca2+ influx through
transmembrane receptor-operated calcium channels, Rotondo et al. (1998) reported a t-
RSV-associated inhibition of agonist-induced [Ca2+]i increases in polymorphonuclear
leukocytes, and Dobrydneva et al. (2002) purported that t-RSV inhibits Ca2+ influx in
thrombin-stimulated human platelets.
Bearing in mind the above considerations and with the aim of providing new data on the
effects of RSV on vascular smooth muscle cells, we here report the first detailed
comparative study of the effects of both t-RSV and c-RSV on calcium signaling in single
A7r5 cells (a cell line derived from fetal rat aorta), hoping to clarify how RSV affects
smooth muscle cell [Ca2+]i levels.
We also have investigated whether t-RSV increases [Ca2+]i in human umbilical vein
endothelial cells (HUVEC), leading to a simultaneous augmentation of nitric oxide (NO•)
production.
Finally, we have studied the effects of t-RSV on the caveolar signaling protein
interactions, such as that between caveolin 1 (cav-1) and endothelial nitric oxide synthase
(eNOS), as well as IP3 receptors (IP3Rs).
Age is the most important risk factor for diseases affecting the Western world, and slowing age-related degeneration would greatly improve the quality of human life. In rodents, caloric restriction (CR) extends lifespan by up to 50%. However, attempts to mimic the effects of CR pharmacologically have been limited by our poor understanding of the mechanisms involved. SIRT1 is proposed to mediate key aspects of CR, and small molecule activators may therefore act as CR mimetics. The polyphenol resveratrol activates SIRT1 in an in vitro assay, and produces changes that resemble CR in vivo, including improvements in insulin sensitivity, endurance, and overall survival in obese mice. However, resveratrol has numerous other targets that could contribute to its health benefits. Moreover, unlike bona fide CR, resveratrol has not been shown to extend lifespan in lean mice. Overexpression of SIRT1 or treatment with a novel activator is sufficient to improve metabolism, supporting the idea that resveratrol could act through this pathway. However, the poor phenotype of SIRT1 null mice has thus far precluded a more definitive test.
This paper reviews our current understanding of the absorption, bioavailability, and metabolism of resveratrol, with an emphasis on humans. The oral absorption of resveratrol in humans is about 75% and is thought to occur mainly by transepithelial diffusion. Extensive metabolism in the intestine and liver results in an oral bioavailability considerably less than 1%. Dose escalation and repeated dose administration of resveratrol does not appear to alter this significantly. Metabolic studies, both in plasma and in urine, have revealed major metabolites to be glucuronides and sulfates of resveratrol. However, reduced dihydroresveratrol conjugates, in addition to highly polar unknown products, may account for as much as 50% of an oral resveratrol dose. Although major sites of metabolism include the intestine and liver (as expected), colonic bacterial metabolism may be more important than previously thought. Deconjugation enzymes such as β-glucuronidase and sulfatase, as well as specific tissue accumulation of resveratrol, may enhance resveratrol efficacy at target sites. Resveratrol analogs, such as methylated derivatives with improved bioavailability, may be important in future research.
Trans-resveratrol is a polyphenol, which is found in red wine and has cancer chemo-preventive properties and disease-preventive properties. The pharmacokinetics of trans-resveratrol have been investigated in single-dose studies and in studies with relatively low dosages. The present study aimed to investigate the steady-state pharmacokinetics and tolerability of trans-resveratrol 2000 mg twice daily with food, quercetin and alcohol (ethanol).
This was a two-period, open-label, single-arm, within-subject control study in eight healthy subjects. The steady-state 12-hour pharmacokinetics of trans-resveratrol 2000 mg twice daily were studied with a standard breakfast, a high-fat breakfast, quercetin 500 mg twice daily and 5% alcohol 100 mL. Trans-resveratrol plasma concentrations were determined using liquid chromatography with tandem mass spectrometry.
The mean (SD) area under the plasma concentration-time curve from 0 to 12 hours (AUC(12)) and maximum plasma concentration (C(max)) of trans-resveratrol were 3558 (2195) ng * h/mL and 1274 (790) ng/mL, respectively, after the standard breakfast. The high-fat breakfast significantly decreased the AUC(12) and C(max) by 45% and 46%, respectively, when compared with the standard breakfast. Quercetin 500 mg twice daily or 5% alcohol 100 mL did not influence trans-resveratrol pharmacokinetics. Diarrhoea was reported in six of the eight subjects. Significant but not clinically relevant changes from baseline were observed in serum potassium and total bilirubin levels.
Trans-resveratrol 2000 mg twice daily resulted in adequate exposure and was well tolerated by healthy subjects, although diarrhoea was frequently observed. In order to maximize trans-resveratrol exposure, it should be taken with a standard breakfast and not with a high-fat meal. Furthermore, combined intake with quercetin or alcohol did not influence trans-resveratrol exposure.
Dietary interventions have been proposed as a way to increase lifespan and improve health. The senescence-accelerated prone 8 (SAMP8) mice have a shorter lifespan and show alterations in the central nervous system. Moreover, this mouse strain shows decreased sirtuin 1 protein expression and elevated expression of the acetylated targets NFkappaB and FoxO1, which are implicated in transcriptional control of key genes in cell proliferation and cell survival, in reference to control strain, SAMR1. After eight weeks of intermittent fasting, sirtuin 1 protein expression was recovered in SAMP8. This recovery was accompanied by a reduction in the two acetylated targets. Furthermore, SAMP8 showed a lower protein expression of BDNF and HSP70 while intermittent fasting re-established normal values. The activation of JNK and FoxO1 was also reduced in SAMP8 mice subjected to an IF regimen, compared with control SAMP8. Our findings provide new insights into the participation of sirtuin 1 in ageing and point to a potential novel application of this enzyme to prevent frailty due to ageing processes in the brain.
Selected biological effects of 1,4-naphthoquinone, menadione (2-methyl-1,4-naphthoquinone) and structurally related quinones from natural sources--the 5-hydroxy-naphthoquinones juglone, plumbagin and the 2-hydroxy-naphthoquinones lawsone and lapachol--were studied in human keratinocytes (HaCaT). 1,4-naphthoquinone and menadione as well as juglone and plumbagin were highly cytotoxic, strongly induced reactive oxygen species (ROS) formation and depleted cellular glutathione. Moreover, they induced oxidative DNA base damage and accumulation of DNA strand breaks, as demonstrated in an alkaline DNA unwinding assay. Neither lawsone nor lapachol (up to 100 microM) were active in any of these assays. Cytotoxic and oxidative action was paralleled by stimulation of stress signaling: all tested quinones except lawsone and lapachol strongly induced phosphorylation of the epidermal growth factor receptor (EGFR) and the related ErbB2 receptor tyrosine kinase. EGFR activation by plumbagin, juglone and menadione was attenuated by a superoxide dismutase mimetic, indicating that ROS-related mechanisms contribute to EGFR activation by these naphthoquinones.
Plant polyphenols are important components of human diet, and a number of them are considered to possess chemopreventive and therapeutic properties against cancer. They are recognized as naturally occurring anti-oxidants but also act as pro-oxidants catalyzing DNA degradation in the presence of metal ions such as copper. The plant polyphenol resveratrol confers resistance to plants against fungal agents and has been implicated as a cancer chemopreventive agent. Of particular interest is the observation that resveratrol has been found to induce apoptosis in cancer cell lines but not in normal cells. Over the last few years, we have shown that resveratrol is capable of causing DNA breakage in cells such as human lymphocytes. Such cellular DNA breakage is inhibited by copper specific chelators but not by iron and zinc chelating agents. Similar results are obtained by using permeabilized cells or with isolated nuclei, indicating that chromatin-bound copper is mobilized in this reaction. It is well established that tissue, cellular and serum copper levels are considerably elevated in various malignancies. Therefore, cancer cells may be more subject to electron transfer between copper ions and resveratrol to generate reactive oxygen species responsible for DNA cleavage. The results are in support of our hypothesis that anti-cancer mechanism of plant polyphenols involves mobilization of endogenous copper and the consequent pro-oxidant action. Such a mechanism better explains the anti-cancer effects of resveratrol, as it accounts for the preferential cytotoxicity towards cancer cells.
Numerous data are now available on the beneficial properties of the polyphenolic compound resveratrol including its anti-inflammatory and antitumor effects. However, few studies have been performed with resveratrol in humans, and the results of these studies appear fragmentary and sometimes contradictory due to variations in conditions of administration, protocols and methods of assessment. This review article presents the results of recent studies investigating the pharmacokinetics, bioavailability, and toxicity of resveratrol in humans. Resveratrol is well absorbed, rapidly metabolized, mainly into sulfo and glucuronides conjugates which are eliminated in urine. Resveratrol seems to be well tolerated and no marked toxicity was reported. These data are important in the context of human efficacy studies, and they provide further support for the use of resveratrol as a pharmacological drug in human medicine.
Epidemiological studies suggested that trans-resveratrol, a wine grape component, could prevent malignant tumor development. This compound also demonstrated cytostatic and cytotoxic effects on tumor cells in vitro. To obtain trans-resveratrol derivatives with a better cellular uptake and enhanced antiproliferative effects, we synthesized a triacetate derivative as well as an oligomer, epsilon-viniferin and its acetylated form, epsilon-viniferin penta-acetate. We also obtained vineatrol, a wine grape shoot extract that associates several polyphenols that may act synergistically, including trans-resveratrol and epsilon-viniferin. We show here that resveratrol triacetate and vineatrol are as efficient as trans-resveratrol in inducing the accumulation of human colon cancer cells in early S phase of the cell cycle. This effect is associated with a nuclear redistribution of cyclin A and the formation of a cyclin A/cyclin-dependent kinase 2 complex whose kinase activity is increased. In contrast, epsilon-viniferin and its acetylated form do not demonstrate any significant activity on these cells when tested alone. Interestingly, resveratrol triacetate and vineatrol dramatically enhance 5-Fluoro-Uracil-mediated inhibition of colon cancer cell proliferation. Thus, acetylated derivatives of resveratrol have retained the cytostatic and cytotoxic activities of the parental molecule and thus deserve to be tested as chemosensitizers in animal models.
The solubility and molar absorptivity of trans- and cis-resveratrol isomers in aqueous solvents are poorly described. This study aimed to develop and describe a new simple method for the determination of trans- and cis-resveratrol concentrations in aqueous solutions. Up to 300 microM trans-resveratrol was dissolved in water by sonication for 2h. Cis-resveratrol was obtained by exposing a 100-muM trans-resveratrol aqueous solution to sunlight for 8h, followed by HPLC separation and analysis by mass spectrometry (resveratrol oxidation products were absent). Accurate values for UV absorbance in water were [see text], epsilon(286 nm)=23400 M(-1)cm(-1) for trans-resveratrol and [see text], epsilon(304nm)=9515 M(-1)cm(-1) for cis-resveratrol. These values allowed us to propose formulae to assess the trans-/cis-resveratrol ratio in water, using a simple and reliable UV-vis spectrophotometric method. Statistical analysis revealed no significant difference between our UV method and the commonly used HPLC method. All these data are transferable to 150 mM NaCl and 10 mM phosphate buffer solutions, which could be particularly useful for cell culture, ex vivo and in vivo studies.
Summary Novel phytoalexins which have been isolated from grapevine leaves are oligomeric forms of the trihydroxy stilbene resveratrol, which co-occurs with these compounds. The characterization of one of these phytoalexins as a resveratrol dimer, designated ε-viniferin, is described as well as a model for its biosynthesis from resveratrol.
A zymographic assay is described for the detection of peroxidase isoenzymes oxidizing 4-hydroxystilbene following isoelectric focusing. The assay is based on coupling intermediate products of the oxidation of 4-hydroxystilbene with 4-aminoantipyrine, with resultant formation of dye complexes. Control experiments in the absence of 4-hydroxystilbene and hydrogen peroxide demonstrate the peroxidative nature of the 4-hydroxystilbene-dependent dye reaction.
A number of lines of evidence suggest that red wine may be more effective than other alcoholic beverages in decreasing the risk of coronary heart disease (CHD) mortality. This protection over and above that due to ethanol itself may be explained by phenolic components with which red wines are richly endowed. We have studied the effects of the trihydroxy stilbene trans-resveratrol on human platelet aggregation and on the synthesis of three eicosanoids from arachidonate by platelets, i.e. thromboxane B2 (TxB2), hydroxyheptadecatrienoate (HHT) and 12-hydroxyeicosatetraenoate (12-HETE). These effects were compared with the actions of other wine phenolics (quercetin, catechin and epicatechin) and antioxidants (alpha-tocopherol, hydroquinone and butylated hydroxytoluene). trans-Resveratrol and quercetin demonstrated a dose-dependent inhibition of both thrombin-induced and ADP-induced platelet aggregation, whereas ethanol inhibited only thrombin-induced aggregation. The other compounds tested were inactive. trans-Resveratrol also inhibited the synthesis of TxB2, HHT, and to a lesser extent 12-HETE, from arachidonate in a dose-dependent manner. Quercetin inhibited only 12-HETE synthesis, and hydroquinone caused slight inhibition of TxB2 synthesis, the remaining compounds being ineffective. De-alcoholized red wines inhibited platelet aggregation; their ability to inhibit the synthesis of TxB2 but not that of 12-HETE from labelled arachidonate by washed human platelets was proportional to their trans-resveratrol concentration. These results are consistent with the notion that trans-resveratrol may contribute to the presumed protective role of red wine against atherosclerosis and CHD.
A 13 kb DNA fragment was isolated from a grapevine (Vitis var. Optima) genomic library by hybridizing with elicitor-induced stilbene synthase cDNA as a probe. After fragmentation with Eco RI, subcloning and sequencing, two full-size stilbene synthase genes (Vst1 and Vst2) and the 3' end of a third stilbene synthase gene (Vst3) were located within the 13 kb fragment. Vst1 and Vst2, differing only slightly in the coding region, are distinguished in the intron size and in the structure of the promoter region. The 5' flanking region of gene Vst1 contains a TATAA box at nucleotide -48. The substantial structural differences found for the promoters of the two genes are paralleled by a striking difference in the expression of the two genes in elicitor-treated cells. Moreover, the accumulation upon elicitation of six different stilbene synthase mRNAs was studied and found to differ by two orders of magnitude.