Absorption of trans-resveratrol in rats

The long-term sequelae and serious side effects of conventional breast cancer chemotherapy due to ubiquitous biodistribution and systemic toxicity remain the main obstacle to success in clinic. Recent anticancer research rely on tailoring smart carriers to overcome these drawbacks. In this regard, numerous stimuli-responsive polymers have been assembled and successfully employed as smart carriers various chemotherpeutic agents due to their intrinsic tumor targeting properties. Among which, poly(N-isopropylacrylamide (PNIPAM) has gained increasing attention being amenable to various chemical modifications for tuning its intrinsic thermoresponsivity or endowing additional stimulus responsiveness. This work aims to develop PNIPAM-maltodextrin nanohydrogels (PNIPAM-MD NGs) decorated with folic acid (FA) as smart breast cancer-targeted stimuli-responsive delivery system to the natural polyphenol resveratrol (RSV) suffering from low bioavailaibity.

PNIPAM-MD was synthesized by graft copolymerization, characterized and evaluated for its modulated stimuli-responsivity. The PNIPAM-based copolymer was coupled with FA, the breast cancer active targeting ligand. The FA-PNIPAM-MD NGs core was loaded RSV, then subjected to in vitro and in vivo evaluation. Results showed that the developed RSV-loaded FA-PNIPAM-MD (F3) NGs displayed dual thermo- and pH-responsivities, high drug-loading capacity (8.31 wt%,) and excellent physical and serum stability. The targeted formula F3 exhibited enhanced in vitro anti-breast cancer potency as evident by 7.4 folds reduction in the IC₅₀ of free RSV and significant MCF-7 cellular uptake. In breast cancer-bearing mice, F3 suppressed the tumor growth, lowered VEGF-1 and Ki-67 expression levels, and induced apoptosis via upregulating caspase-3.

Overall, the PNIPAM-MD NGs as well as its FA-decorated breast cancer-targted NGs could serve as promising smart nanocarrier for efficient RSV brest cancer delivery. It could be safely deduced that the assembled FA-PNIPAM-MD F3 NGs enabled sequestering the therapeutic cargo (RSV) in normal tissue and released it in tumor site, thus guarding against its rapid metabolism and maximizing its accumulation in the cancer tissue as evidenced by the remarkable tumor growth suppression noticed in the targeted RSV/FA-PNIPAM-MD F3 NGs-treated mice compared to that in the free RSV-treated group. Hence, The fabricated nanohydrogels may be further employed for smart delivery of various anti-breast cancer agents.

Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is a polyphenol obtained from diverse groups of plants, especially in the muscadine grape, red wine, lingonberry, cranberry and redcurrant. Resveratrol's health benefits were first highlighted in the study of the French paradox, which opened up an expansive research endeavor into this compound. Ever since, an array of pharmacological activities, including antioxidant, antiaging, anti-inflammatory, anti-cancer and antidiabetic have been attributed to resveratrol. For many polyphenols, low solubility in biological fluids, as well as by rapid in vivo metabolization, limits their bioavailability. However, improving resveratrol formulation could enhance oral bioavailability and have other beneficial properties. The development of innovative methodological approaches, such as the utilization of innovative formulations has been developed to overcome these limitations and provide a considerable therapeutic amount of resveratrol.

In this narrative review, a brief outline of historical perspectives of resveratrol is provided, together with an extensive and inclusive overview of various approaches and contemporary developments on the bioavailability, pharmacodynamics and pharmacokinetics of this nutraceutical, along with its biotechnological applications and drug formulations.

Accumulating evidences of research suggest that resveratrol (dietary polyphenolic compound) has gained immense attention and growing interest among the biomedical scientific community due to its vast number of biological activities and properties involved in human health and disease. Resveratrol has a very broad spectrum of beneficial properties ranging from neurological, hepatic, cardiovascular systems, antitumor, antioxidant, antimicrobial, and phytoestrogenic properties. Resveratrol is rapidly absorbed orally but the extensive metabolism leads to very low bioavailability resulting in its low plasma concentrations. In general, resveratrol is well tolerated in humans, with fewer nonserious adverse events reported in animal studies. Moreover, various cell-based in vitro and in vivo studies have been performed to evaluate the protective effects of resveratrol in several diseases including cancer. At molecular level, resveratrol has multifaceted beneficial effects including antioxidant and antiinflammatory pathways, along with epigenetic regulation particularly sirtuin activation. This chapter focuses on the several aspects of resveratrol, particularly its sources, isolation/characterization, chemistry, mechanism of action, bioavailability, stability, safety/toxicology, and applications.

Trans-resveratrol (RES) is a naturally occurring stilbene found in numerous plants and foods. Due to its widespread human exposure and lack of toxicity and carcinogenicity data, RES was nominated to the National Toxicology Program for testing. To aid the toxicology studies, the dose, sex, and species differences in RES toxicokinetics was investigated in Harlan Sprague Dawley rats and B6C3F1/N mice following single intravenous (IV) (10 mg/kg) or oral gavage administration (312.5, 625, and 1250 mg/kg and 625, 1250, and 2500 mg/kg in rats and mice, respectively).

Following IV and gavage administration, systemic exposure of RES based on AUC was trans-resveratrol-3-O-β-D-glucuronide (R3G)> > trans-resveratrol-3-sulfate (R3S) > RES in both species. Following gavage administration T_{max_predicted} values were ≤ 263 min for both species and sexes. RES elimination half-life was longer in rats than mice, and shortest in male mice. Clearance was slower in mice with no apparent sex difference in both species. In both rats and mice, following gavage administration AUC increased proportionally to the dose. After gavage administration, enterohepatic recirculation of RES was observed in both rats and mice with secondary peaks occurring around 640 min in the concentration-time profiles. RES was rapidly metabolized to R3S and R3G in both species. Extensive first pass conjugation and metabolism resulted in low levels of the parent compound RES which was confirmed by the low estimates for bioavailability. The bioavailability of RES was low, ~12–31% and ~2–6% for rats and mice, respectively, with no apparent difference between sexes.

This study aims to investigate the ameliorative effects of resveratrol (RSV) in a high-fat diet (HFD)-induced non-alcoholic steatohepatitis (NASH) rat model, focusing on the gut endocannabinoid system (ECS), regulated by RSV, in the maintenance of gut barrier integrity and inhibition of gut inflammation.

Male Sprague–Dawley (SD) rats were fed HFD with or without RSV for 6 weeks. The HFD caused increase in body weight, liver index, hepatic lipid accumulation, and inflammation, which was inhibited by RSV. RSV also attenuated gut microbial dysbiosis, with an increase in Akkermansia muciniphila, Ruminococcaceae, and Lachnospiraceae, and a decrease in Desulfovibrio. Moreover, RSV led to a reduction of metabolic endotoxemia and colon inflammation in HFD-fed rats. This was indicated by a decrease in bacterial invasion and translocation along with up-regulation of the mRNA levels of occludin, ZO1, claudin1, and down-regulation of FAK, MyD88, and IRAK4 in the distal colon. Furthermore, RSV inhibited HFD-induced elevation in the expression of cannabinoid receptor type 1 (CB1) mRNA and suppressed CB2 mRNA levels in the colon. The RSV-induced benefits regarding enhanced gut barrier integrity and reduced intestinal permeability were abrogated with a CB1 agonist, ACEA, whereas the inhibitory effect of RSV on the intestinal inflammation was abolished by a CB2 antagonist, AM630. Moreover, microbiota depletion using a cocktail of antibiotics was sufficient to block RSV-induced reduction in intestinal permeability and gut inflammation, as well as the altered mRNA expressions of CB1 and CB2 in the distal colon.

These data indicate that the ECS, particularly the expressions of CB1 and CB2, appears to play a crucial role in the RSV induced anti-NASH effect by maintaining the gut barrier integrity and inhibiting gut inflammation.

Resveratrol is a naturally occurring phytochemical present in wine, grapes, berries, chocolate, and peanuts and exhibits numerous pharmacological properties to treat a variety of ailments. It demonstrates beneficial and protective effects in Alzheimer’s disease (AD) models and thus proves to be a promising therapeutic alternative to existing treatments, with excellent potential and minimal side effects. Resveratrol inhibits the disaggregation of Aβ-peptides, reduces the level of proinflammatory factors (the NF-kB pathway), restores the level of CREB protein, activates the Sirt1 pathway, and regulates other autophagy mechanisms. Thus, resveratrol appears to mitigate the pathophysiological aspects of AD. This chapter compiles the documented data from various research studies and peer reviews regarding the use of resveratrol in AD.