Resveratrol

Resveratrol, a stilbenoid, is commonly found in peanuts, grapes and red wine. It has been identified to possess antioxidant, chemopreventive and anti-inflammatory activities. However, upon digestion and absorption, resveratrol is metabolized by phase II enzymes, resulting mainly in the formation of sulfated and glucuronated metabolites. In human intervention studies, the following metabolites have been identified in the human plasma and urine: resveratrol-3-sulfate (Res-3-sulf, R3S), resveratrol-3,5-disulfate, resveratrol-3,4’-disulfate (Res-disulfates, RDS), resveratrol-4’-sulfate, resveratrol-3-glucuronide (Res-3-gluc, R3G) and resveratrol-4’-glucuronide (Res-4’-gluc, R4’G). After intake of a bolus dose of 85.5 mg per 70 kg body weight of piceid, a resveratrol glucoside, the in 3-position monosulfated metabolite and the disulfated metabolites were the predominant metabolites detected after 6 h in the plasma of the volunteers, reaching a maximum concentration of 1 mM. In addition, after consumption of a high bolus of 5 g resveratrol, resveratrol-3-sulfate was detected as the most abundant metabolite with a concentration of up to 14 mM in the plasma. In the same study, resveratrol sulfates and glucuronides were analyzed in the plasma with half-lives between 3.2 and 11.5 h, and 2.9 to 10.6 h, respectively. Moreover, an uptake of repeated doses of up to 5 g resveratrol per day for 21 days resulted in a maximal plasma concentration of about 13 mM resveratrol-3-sulfate. ncubation times and the concentrations used in in vitro studies focusing on the biological effects of these metabolites should, therefore, not exceed 14 μM.

Resveratrol (3,5,4’-trihydroxy-stilbene) is a phenolic phytochemical that accumulates in many plants, such as peanuts, grapes, blueberries, mulberries and cranberries. The natural phenol has been found to interfere with a variety of signaling pathways in mammal cells to exhibit anti-carcinogenic, anti-aging, anti-inflammatory, anti-diabetic and antioxidant actions. The study of the metabolic fate of resveratrol has determined its ability to be glycosylated into glucuronides in human cells, glucopyranosides in plant cells, or diglucosides by cyclodextrin glucanotransferase and sucrose phosphorylase from Thermoanaerobacter sp. In addition, resveratrol functions as a phytoalexin in response to microbial stresses. The engineering of resveratrol synthaseencoding genes in heterogenous plants such as Solanum lycopersicum and Oryza sativa can increase their resistance against fungal pathogens. These observations, along with the reported fungal glycosylation of stilbenoids, prompted us to use resveratrol as a xenochemical tool to investigate the glycosylating capacity of D. eschscholzii with an intention to obtain unprecedented fungal glycosides. Here, resveratrol is demonstrated to increase the ribosylation capacity of D. eschscholzii through the activation (or up-regulation) of silent (or less active) ribosyltransferase and p-glycoprotein genes, and the rare fungal ribosylation takes place uniquely through an undescribed mechanism using nicotinamide mononucleotide (NMN) as the ribosyl donor. As detailed below, the work reveals a conventionally undetectable ribosylation process that provides direct evidence for the fungal detoxification of phenolic chemicals and access to new ribosides with biological and/or biomedical significance.

Over the past decades, considerable efforts have been devoted to study the antioxidative activity of resveratrol. The phenolic OH groups, especially 4’-OH, and the trans conformation, are believed to be responsible for the excellent anti-oxidative activity of resveratrol. Owing to its structural simplicity, resveratrol has aroused great interest in developing novel analogues with improved antioxidative activity. Various resveratrol-oriented analogues have been designed by introducing different substituent groups to aromatic rings of resveratrol, and electron-donating groups were found to be more effective than other substituent groups. Mikulski et al. found that the oligomers, glucosides of resveratrol, and trans-resveratrol-3-O-glucuronide exhibited more excellent anti-oxidative activity than resveratrol. Incorporation of chroman moiety of vitamin E into resveratrol scaffold, replacement of 4’-OH by mercapto group have also been reported to improve the antioxidative activity. In addition, several structural modifications in the stilbene scaffold have also been performed, such as elongation of conjugated chain, N-substituent of carbon–carbon double bond, and development of novel resveratrol analogues with cis-restricted conformation, to enhance the antioxidative capacity significantly.