Alpha-Arbutin Promotes Wound Healing by Lowering ROS and Upregulating Insulin/IGF-1 Pathway in Human Dermal Fibroblast
概要
1. Introduction
Skin is the body’s largest organ, representing the interface between self and nonself. Skin aging is most prominently caused by extrinsic factors, mainly the permanent exposure of this organ to oxidative environmental stimuli, such as solar radiation, cigarette smoke, and other pollutants.The second most important contributor to skin aging is an intrinsic factor: the age- related mitochondrial enzyme dysfunction that inhibits epidermal regeneration. Skin aging is clinically characterized by water loss, reduced skin thickness, sagging, and wrinkle formation. At the molecular level, skin aging is characterized by reduced procollagen synthesis and degradation of the extracellular matrix, which mainly comprises collagen, glycosaminoglycan, and elastin. Aged skin fibroblasts become detached from the destabilized extracellular matrix, leading to a rounded and collapsed appearance. This in turn upregulates matrix metalloproteinase expression, activating a positive-feedback loop that further accelerates collagen matrix degradation. Based on evidence that oxidative stress plays pivotal roles in both intrinsic and extrinsic aging, it has been suggested that antioxidants may be an efficient means of defense against aging processes. Numerous studies have examined compounds derived from marine and botanical organisms that show cosmetically useful antioxidant and antiaging activities.
2. Methods
Alpha-arbutin (4-hydroxyphenyl alpha-glucopyranoside) is a known inhibitor of tyrosinase in keratinocytes; however, its effect on other genes and pathways in other skin cells has not been thoroughly investigated. In this study, we investigate the mechanism of alpha-arbutin activity in human dermal fibroblast cultures for 48 hours.
3. Results
Results showed that the oxidative stress pathway was activated as alpha-arbutin reduced reactive oxygen species (ROS). In addition, we found a high possibility of wound healing and the upregulation of the insulin-like growth factor 1 receptor (IFG1R) pathway. We also investigated the role of the NRF2 gene in mediating the alpha-arbutin response. In silico comparative genomics analysis conducted using our original tool, SHOE, suggested transcription factors with a role in tumor suppression and toxicity response as candidates for regulating the alpha-arbutin mediated pathway.
4. Conclusions
Our study determined the anti-oxidative activity of alpha-arbutin to the human dermal fibroblast in 48 hours after supplementation. Our study showed that alpha-arbutin enhances the wound healing process in human dermal fibroblasts via activation of the MMP3, EGFR, and COL1A1 genes and suppression of the FOXO1 and SIRT1 genes. We also found that a decrease in ROS activates the Ins/IGF-1 signaling pathway, which is indispensable for the skin autophagic process. Further, thirty-four genes of the oxidative stress pathway undergo significant change upon alpha-arbutin supplementation, and NFE2L2 (Nrf2) gene is a candidate for mediating its external signal. We believe that the positive effect of alpha-arbutin will offer insights into healthy skin maintenance, which, together with oral supplementation, may be crucial in the treatment and prevention of age-susceptible diseases.