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

Abstract

Resveratrol has gained tremendous interest owing to multiple reported health-beneficial effects. However, the underlying key mechanism of action of resveratrol remained largely controversial. Here, we demonstrate that under physiologically relevant conditions major biological effects of resveratrol can be attributed to the generation of oxidation products such as reactive oxygen species (ROS). At low hormetic concentrations (< 50 µM), treatment with resveratrol increased cell viability in a set of representative cell models, whereas application of quenchers of ROS completely truncated these beneficial effects. Notably, application of resveratrol led to mild, Nrf2-specific cellular gene expression reprogramming. For example, in 2 primary human epidermal keratinocytes this resulted in a 1.3-fold increase of endogenous metabolites such as glutathione (GSH) and subsequently in a quantitative reduction of the cellular redox environment by 2.61 mV mmol GSH per g protein. After external application of oxidative stress by using 0.8% (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 effects from resveratrol treatment are essentially based on oxidative triggering of cells. In relevant physiological microenvironments this effect can lead to hormetic shifting of cellular defence towards a more reductive state to improve resilience to oxidative stress in a manner that can be exactly defined by the redox-environment of the cell.

A combination of pyridine‐2, 4‐dicarboxylic acid diethyl ester and resveratrol stabilizes hypoxia‐inducible factor 1‐alpha and improves hair density in female volunteers

“…In this study, pyridine‐2, 4‐dicarboxylic acid diethyl ester has been associated with the natural antioxidant resveratrol to improve its efficacy to stabilize HIF‐1α protein and to protect the epithelial hair matrix cells from deleterious oxidative stress . This combination was also studied through a clinical study to confirm that these in vitro properties were linked to a significant efficacy on human hair density.…”

Thai herbal antipyretic 22 formula (APF22) inhibits UVA‐mediated melanogenesis through activation of Nrf2‐regulated antioxidant defense

“…Nuclear factor E2‐related factor 2 (Nrf2), a crucial transcription factor regulating the expression of various cytoprotective genes including antioxidant and detoxification genes, has been shown to play a beneficial role in maintaining redox balance and cellular homeostasis supporting physiological function and integrity of a series of skin cells including melanocytes and keratinocytes (Chaiprasongsuk et al, ; Janjetovic et al, ; Jian et al, ; Kim et al, ; Plauth et al, ).…”

Glutathione levels influence chronological life span of Saccharomyces cerevisiae in a glucose‐dependent manner

“…Restriction of certain nutrients such as glucose and supplementation with resveratrol improve the longevity of a wide range of species and have also been related to the amelioration of some chronic degenerative diseases (Huffman, Schafer, & LeBrasseur, ). Resveratrol and dietary restriction affect mitochondrial function and the antioxidant systems, which directly impact ROS generation (Barros et al, ; Madrigal‐Perez et al, ; Plauth et al, ). Nonetheless, it is unclear whether the molecular mechanism by which dietary restriction counteracts oxidative stress also modulates mitochondrial function and the aging process.…”