Dermato-protective properties of ergothioneine through induction of Nrf2/ARE-mediated antioxidant genes in UVA-irradiated Human keratinocytes |
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| Affiliation: | 1. Department of Cosmeceutics, College of Pharmacy, China Medical University, Taichung 40402, Taiwan;2. Department of Health and Nutrition Biotechnology, Asia University, Taichung 41354, Taiwan;3. Institute of Nutrition, China Medical University, Taichung 40402, Taiwan;1. Dipartimento di Biochimica, Biofisica e Patologia Generale, Seconda Università degli Studi di Napoli, 7-80138 Napoli, Italy;2. Stazione Sperimentale per le Industrie delle Essenze e dei Derivati dagli Agrumi, Azienda Speciale della Camera di Commercio di Reggio Calabria, 12-89125 Reggio Calabria, Italy;1. Department of Biochemistry, National University of Singapore, Singapore;2. Cardiovascular Research Institute, National University Health System, Singapore;3. Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore;4. Translational Laboratory in Genetic Medicine, 8A Biomedical Grove, Immunos, Level 5, 138648, Singapore;1. Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-1192, Japan;2. School of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-1192, Japan;3. Life Science Institute Co. Ltd., Chuo-ku, Tokyo 103-0012, Japan;4. Customer Support Division, L·S Corporation Co. Ltd., Chuo-ku, Tokyo 103-0013, Japan;1. Department of Biochemistry, Biophysics and General Pathology, Università degli Studi della Campania “Luigi Vanvitelli”, Naples, Italy;2. Stazione Sperimentale per le Industrie delle Essenze e dei derivati dagli Agrumi, Azienda Speciale della Camera di Commercio di Reggio Calabria, Reggio Calabria, Italy;3. Ministero dello Sviluppo Economico, MiSE, Roma, Italy |
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| Abstract: | UVA irradiation-induced skin damage and redox imbalance have been shown to be ameliorated by ergothioneine (EGT), a naturally occurring sulfur-containing amino acid. However, the responsible molecular mechanism with nanomolar concentrations of EGT remains unclear. We investigated the dermato protective efficacies of EGT (125–500 nM) against UVA irradiation (15 J/cm2), and elucidated the underlying molecular mechanism in human keratinocyte-derived HaCaT cells. We found that EGT treatment prior to UVA exposure significantly increased the cell viability and prevented lactate dehydrogenase release into the medium. UVA-induced ROS and comet-like DNA formation were remarkably suppressed by EGT with a parallel inhibition of apoptosis, as evidenced by reduced DNA fragmentation (TUNEL), caspase-9/-3 activation, and Bcl-2/Bax dysregulation. Furthermore, EGT alleviated UVA-induced mitochondrial dysfunction. Dose-dependent increases of antioxidant genes, HO-1, NQO-1, and γ-GCLC and glutathione by EGT were associated with upregulated Nrf2 and downregulated Keap-1 expressions. This was confirmed by increased nuclear accumulation of Nrf2 and inhibition of Nrf2 degradation. Notably, augmented luciferase activity of ARE may explain Nrf2/ARE-mediated signaling pathways behind EGT dermato-protective properties. We further demonstrated that Nrf2 translocation was mediated by PI3K/AKT, PKC, or ROS signaling cascades. This phenomenon was confirmed with suppressed nuclear Nrf2 activation, and consequently diminished antioxidant genes in cells treated with respective pharmacological inhibitors (LY294002, GF109203X, and N-acetylcysteine). Besides, increased basal ROS by EGT appears to be crucial for triggering the Nrf2/ARE signaling pathways. Silencing of Nrf2 or OCTN1 (EGT carrier protein) signaling with siRNA showed no such protective effects of EGT against UVA-induced cell death, ROS, and apoptosis, which is evidence of the vitality of Nrf2 translocation and protective efficacy of EGT in keratinocytes. Our findings conclude that EGT at nanomolar concentrations effectively ameliorated UVA-induced skin damage, and may be considered as a desirable food supplement for skin protection and/or preparation of skin care products. |
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| Keywords: | Ergothioneine Ultraviolet A Free radicals Apoptosis Heme oxygenase-1 Nrf2 Skin damage |
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