Trans-cinnamic acid attenuates UVA-induced photoaging through inhibition of AP-1 activation and induction of Nrf2-mediated antioxidant genes in human skin fibroblasts

Background: UVA irradiation-induced skin damage/photoaging is associated with redox imbalance and collagen degradation. Objective: Dermato-protective efficacies of trans-cinnamic acid (t-CA), a naturally occurring aromatic compound have been investigated against UVA irradiation, and elucidated underlying molecular mechanism. Methods: Human foreskin fibroblast-derived (Hs68) cells and nude mice were treated with t-CA prior to UVA exposure, and assayed the anti-photoaging effects of t-CA. Results: We found t-CA (20-100 mu M) pretreatment substantially ameliorated UVA (3J/cm(2))-induced cytotoxicity, and inhibited intracellular ROS production in Hs68 cells. UVA-induced profound upregulation of metalloproteinase (MMP)-1/-3 and degradation of type I procollagen in dermal fibroblasts were remarkably reversed by t-CA, possibly through inhibition of AP-1 (c-Fos, but not c-Jun) translocation. The t-CA-mediated anti-photoaging properties are associated with increased nuclear translocation of Nrf2. Activation of Nrf2 signaling is accompanied with induction of HO-1 and gamma-GCLC expressions in t-CA-treated fibroblasts. Furthermore t-CA-induced Nrf2 translocation is mediated through PKC, AMPK, CKII or ROS signaling cascades. This phenomenon was confirmed with respective pharmacological inhibitors, GF109203X, Compound C, CKII inhibitor or NAC, which blockade t-CA-induced Nrf2 activation. Silencing of Nrf2 signaling with siRNA showed no anti-photoaging effects of t-CA against UVA-induced ROS production, loss of HO-1 and type I collagen degradation in fibroblasts. In vivo evidence on nude mice revealed that t-CA pretreatment (20 or 100 mM/day) significantly suppressed MMP-1/-3 activation and maintained sufficient type I procollagen levels in biopsied skin tissue against UVA irradiation (3J/cm(2)/day for 10-day). Conclusion: t-CA treatment diminished UVA-induced photoaging/collagen degradation, and protected structural integrity of the skin. (C) 2018 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.