Polyphenols, historically known as "vegetable tannins", feature health- beneficial effects [14]. The phytoalexin trans-resveratrol (RSV) was originally isolated from Veratrum grandiflorum O. Loes [30] and is ascertained to naturally occur in approximately 72 plant species [19]. The "French paradox" [16] and early reports of cancer chemo-preventive properties [19] contributed to the growing popularity of RSV [24, 388, 389]. The human skin is the largest organ of our body [2] and challenged by

more »

... dative and environmental stressors on a daily basis [390–392]. The use of RSV in a skin context is a cutting-edge topic [19, 329] as epidermal keratinocytes are a prime target for RSV-based lotions and emollients. However, the mechanism of action of RSV remains largely elusive and controversially discussed. In this study, neonatal normal human epidermal keratinocyte (NHEK) cells are used as a primary cellular model to investigate the mechanism of action of RSV. We demonstrate that RSV is unstable under physiologically relevant conditions, resulting in the generation of oxidation products and reactive oxygen species (ROS). In addition, RSV increases the cellular viability at "low", hormetic doses (≤ 50 μM) in representative cell models. The application of ROS scavengers truncates these beneficial effects. Moreover, Nrf2-dependent gene expression is initiated by RSV. A 1.3-fold increase of endogenous glutathione (GSH) is sufficient to cause a quantitative reduction of the cellular redox environment. Consequently, RSV pre-treated cells are more resistant to ethanol-induced oxidative stress and generate 24% less ROS. We propose that the major effect of RSV is to induce a mild oxidative stress resulting in hormetic shifting of cellular metabolism towards a more reductive state.