Numerous beneficial effects of resveratrol were reported; however, its pharmacological profile is contradictious. Previously, we have demonstrated that resveratrol has a dose-dependent cytoprotective effect and the essential role of autophagy induction was demonstrated. Resveratrol suffers from unfavorable pharmacokinetics, hindering its clinical use. Our aim was to study the cytoprotective effect of resveratrol derivatives to better understand structure–activity relationships that may facilitate the development of compounds with better druglike characteristics. Serum-deprivation-induced caspase activation, free radical generation, mitochondrial membrane depolarization and autophagy were detected in the presence of resveratrol analogs with different oxidation states on mouse embryonal fibroblasts. Distinct cytoprotective mechanisms of the examined compounds were revealed. Monomethyl resveratrol had similar potency to resveratrol (EC₅₀: 85.3 vs. 84.2 μM); however, autophagy induction was not essential for its cytoprotective effect. Oxyresveratrol was found to be a strong antioxidant that can induce direct cytoprotection rather than autophagy. Trimethyl-resveratrol, lacking free hydroxyl groups, induced damage that was too significant and hardly compensated by the activation of cytoprotective machineries, and caspase activation was reduced by only 24.5%. Based on our results, methylation of resveratrol reduces its antioxidant activity, while autophagy induction can still contribute to its cytoprotective effect. The introduction of an additional hydroxyl group, however, augments the antioxidant properties, inducing cytoprotection without autophagy induction.

Background and Objectives: Expansion of white adipose tissue causes systemic inflammation and increased risk of metabolic diseases due to its endocrine function. Resveratrol was suggested to be able to prevent obesity-related disorders by mimicking caloric restriction; however, its structure–activity relationships and molecular targets are still unknown. We aimed to compare the effects of resveratrol and its analogues on adipocyte metabolism and lipid accumulation in vitro. Methods: Mouse embryonic fibroblasts were differentiated to adipocytes in the absence or presence of resveratrol or its derivatives (oxyresveratrol, monomethylated resveratrol, or trimethylated resveratrol). Intracellular lipid content was assessed by Oil Red O staining. Glucose uptake and its response to insulin were estimated by 2-NBDG, and mitochondrial activity was assayed via resazurin reduction. Involvement of potential molecular pathways was investigated by concurrent treatment with their inhibitors. Results: Although lipid accumulation was significantly reduced by all analogues without altering protein content, oxyresveratrol was the most potent (IC50 = 4.2 μM), while the lowest potency was observed with trimethylated resveratrol (IC50 = 27.4 μM). Increased insulin-stimulated glucose uptake was restored by each analogue with comparable efficiency. The enhanced mitochondrial activity was normalized by resveratrol and its methylated derivatives, while oxyresveratrol had a minor impact on it. Among the examined pathways, inhibition of SIRT1, PGC-1α, and JNK diminished the lipid-reducing effect of the compounds. Autophagy appeared to play a key role in the effect of all compounds but oxyresveratrol. Conclusions: Resveratrol and its analogues can mimic caloric restriction with complex mechanisms, including activation of SIRT1, PGC-1α, and JNK, making them possible drug candidates to treat obesity-related diseases.