Unknown,Transcriptomics,Genomics,Proteomics

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Hormetic shifting of redox environment by the ROS-producing polyphenol resveratrol protects cells from oxidative stress

ABSTRACT: Resveratrol is a natural product that has gained tremendous interest due to multiple reported health-beneficial effects. However, the underlying mechanisms of action of this compound remained largely controversial. Here, we demonstrate that major biological effects of resveratrol might be attributed to its bicarbonate-induced production of phenolic radicals and reactive oxygen species (ROS) such as superoxide and hydrogen peroxide under physiologically relevant conditions. These products derived from low hormetic micromolar concentrations of resveratrol led to gene expression reprogramming, which was mainly controlled by the redox-sensitive transcription factor nuclear factor (erythroid-derived 2) like 2 (Nrf2), whereas too high concentrations of resveratrol became detrimental for cells. Gentle but significant activation of Nrf2-controlled gene expression resulted in a metabolic switch and reduced cellular redox environment. Thereby cells could be preconditioned against stress, for example to protect primary keratinocytes of the human epidermis from oxidative stress that was induced by metabolization of ethanol. Hormetic shifting of cells by chemical triggers such as resveratrol towards a more reductive state might represent a powerful conceptual framework to improve cellular fitness at low nontoxic concentrations. Total RNA obtained from cultured primary neonatal normal human epidermal keratinocytes (NHEK) subjected to 16 hours treatment with 50 ÂµM resveratrol (trans-3,5,4â-trihydroxystilbene, RSV) compared to vehicle-treated control NHEKs.

ORGANISM(S): Homo sapiens

SUBMITTER: Annabell Plauth

PROVIDER: E-GEOD-72119 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:OBJECTIVE: The liver X receptor M-NM-1 (LXRM-NM-1) is a ligand-dependent nuclear receptor and the major regulator of reverse cholesterol transport in macrophages. This makes it an interesting target for mechanistic study and treatment of atherosclerosis. METHODS AND RESULTS: We optimized a promising stilbenoid structure (STX4) in order to reach nanomolar effective concentrations in LXRM-NM-1 reporter-gene assays. STX4 displayed the unique property to activate LXRM-NM-1 effectively but not its subtype LXRM-NM-2. The potential of STX4 to increase transcriptional activity as an LXRM-NM-1 ligand was tested with gene expression analyses in THP1-derived human macrophages and oxLDL-loaded human foam cells. Only in foam cells but not in macrophage cells STX4 treatment showed athero-protective effects with similar potency as the synthetic LXR ligand T0901317 (T09). Surprisingly, combinatorial treatment with STX4 and T09 resulted in an additive effect on reporter-gene activation and target gene expression. In physiological tests the cellular content of total and esterified cholesterol was significantly reduced by STX4 without the undesirable increase in triglyceride levels as observed for T09. CONCLUSIONS: STX4 is a new LXRM-NM-1-ligand to study transcriptional regulation of anti-atherogenic processes in cell or ex vivo models, and provides a promising lead structure for pharmaceutical development. 2 treatment groups (STX4 vs. DMSO in foam cells), 3 biological replicates per treatment (6 samples in total), each representing one well from cell culture plate 2 treatment groups (STX4 vs. DMSO in macrophages), 4 biological replicates per treatment (8 samples in total), each representing one well from cell culture plate 2 treatment groups (T0901317 vs. DMSO in foam cells), 3-4 biological replicates per treatment (7 samples in total), each representing one well from cell culture plate 2 treatment groups (T0901317 vs. DMSO in macrophages), 4 biological replicates per treatment (8 samples in total), each representing one well from cell culture plate

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Hormetic shifting of redox environment by the ROS-producing polyphenol resveratrol protects cells from oxidative stress

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