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Free Radic Biol Med. 2016 Oct;99:608-622. doi: 10.1016/j.freeradbiomed.2016.08.006. Epub 2016 Aug 8.

Hormetic shifting of redox environment by pro-oxidative resveratrol protects cells against stress.

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Otto Warburg Laboratory, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
Unilever R&D, Colworth Science Park, Sharnbrook, Bedfordshire MK44 1LQ, UK.
Otto Warburg Laboratory, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany; CU Systems Medicine, University of Würzburg, Josef-Schneider-Straße 2, Building D15, 97080 Würzburg, Germany; Laboratory of Functional Genomics, Nutrigenomics and Systems Biology, BIMSB and BIH Genomics Platforms, Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Straße 10, 13125 Berlin, Germany. Electronic address:


Resveratrol has gained tremendous interest owing to multiple reported health-beneficial effects. However, the underlying key mechanism of action of this natural product remained largely controversial. Here, we demonstrate that under physiologically relevant conditions major biological effects of resveratrol can be attributed to its generation of oxidation products such as reactive oxygen species (ROS). At low nontoxic concentrations (in general <50µM), treatment with resveratrol increased viability in a set of representative cell models, whereas application of quenchers of ROS completely truncated these beneficial effects. Notably, resveratrol treatment led to mild, Nrf2-specific gene expression reprogramming. For example, in primary epidermal keratinocytes derived from human skin this coordinated process resulted in a 1.3-fold increase of endogenously generated glutathione (GSH) and subsequently in a quantitative reduction of the cellular redox environment by 2.61mVmmol GSH per g protein. After induction of oxidative stress by using 0.78% (v/v) ethanol, endogenous generation of ROS was consequently reduced by 24% in resveratrol pre-treated cells. In contrast to the common perception that resveratrol acts mainly as a chemical antioxidant or as a target protein-specific ligand, we propose that the cellular response to resveratrol treatment is essentially based on oxidative triggering. In physiological microenvironments this molecular training can lead to hormetic shifting of cellular defense towards a more reductive state to improve physiological resilience to oxidative stress.


Epidermis; Nrf2; Oxidative stress; Polyphenols; ROS; Redox environment; Skin

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