One of the many harmful factors faced by the skin is solar UV radiation, which damages skin by inducing chronic low-grade inflammation through increased expression of proinflammatory cytokines, metalloproteinases (MMPs) and cyclooxygenase-2 (COX-2). Estrogen receptors (ERs) ␣ and  are ligand-dependent transcription factors that are expressed in skin, and an ER agonist has previously shown efficacy in vivo in models of pain and inflammation. Because ER does not carry the breast and uterine proliferation liabilities of ER␣, we decided to explore the possibility of using ER as a target for photoaging. We show that ER-selective compounds suppressed the expression of cytokines and MMPs in activated keratinocytes and fibroblast-based in vitro models of photoaging. Furthermore, in activated dermal fibroblasts, ER-selective compounds also inhibited COX-2. These activities of ER ligands in skin cells correlated with the expression levels of ER and showed reversal by treatment with a potent synthetic ER antagonist. Furthermore, the pharmacology of ER-selective compound was observed in wild-type but not in skin cells obtained from ER knockout mice. Finally, we demonstrate that a synthetic ER agonist inhibited UV-induced photodamage and skin wrinkle formation in a murine model of photoaging. Therefore, the potential of an ER ligand to regulate multiple pathways underlying the cause of photoaging suggests ER to be a novel therapeutic target for the prevention and treatment of photoaging.Photoaging results from the repetitive exposure of skin to damaging effects of solar UV radiation and is characterized by wrinkles, laxity, dryness, and mottled pigmentation. In recent years, some of the molecular mechanisms underlying the cause of photoaging have been described. The process of photoaging involves three cell types, namely keratinocytes, fibroblasts, and infiltrating neutrophils (Fisher et al., 2002;Rijken et al., 2005;Makrantonaki and Zouboulis, 2007). Within minutes of UVB radiation exposure, epidermal keratinocytes show an increased activation of transcription factors, activator protein 1 (AP-1), and nuclear factor-B (NF-B), resulting in high expression of matrix metalloproteinases (MMPs) and proinflammatory cytokines (Fisher et al., 1996). These cytokines and a UVA component of the UV radiation in turn activate dermal fibroblasts to secrete MMPs, which damage the collagen component of the dermal extracellular matrix (Fagot et al., 2004). Cytokines and chemotactic factors that are secreted by skin cells also recruit neutrophilic granulocytes to the dermis. These neutrophils further degrade dermal extracellular matrix by secreting MMPs and elastases, thus contributing to UV-mediated dermal collagen and elastin degradation (Rijken et al., 2005). Repetitive UV exposure leads to the accumulation of partially degraded extracellular matrix components in the dermis, resulting in wrinkle appearance. Therefore, a number of pathways and processes involved in photoaging could be targeted by potential therapeutic a...
Liver X receptors (LXRalpha and -beta) are liposensors that exert their metabolic effects by orchestrating the expression of macrophage genes involved in lipid metabolism and inflammation. LXRs are also expressed in other tissues, including skin, where their natural oxysterol ligands induce keratinocyte differentiation and improve epidermal barrier function. To extend the potential use of LXR ligands to dermatological indications, we explored the possibility of using LXR as a target for skin aging. We demonstrate that LXR signaling is down-regulated in cell-based models of photoaging, i.e. UV-activated keratinocytes and TNFalpha-activated dermal fibroblasts. We show that a synthetic LXR ligand inhibits the expression of cytokines and metalloproteinases in these in vitro models, thus indicating its potential in decreasing cutaneous inflammation associated with the etiology of photoaging. Furthermore, a synthetic LXR ligand induces the expression of differentiation markers, ceramide biosynthesis enzymes, and lipid synthesis and transport genes in keratinocytes. Remarkably, LXRbeta-null mouse skin showed some of the molecular defects that are observed in chronologically aged human skin. Finally, we demonstrate that a synthetic LXR agonist inhibits UV-induced photodamage and skin wrinkle formation in a murine model of photoaging. Therefore, the ability of an LXR ligand to modulate multiple pathways underlying the etiology of skin aging suggests that LXR is a novel target for developing potential therapeutics for photoaging and chronological skin aging indications.
Aim:To investigate the effect of [6]-shogaol, an active ingredient in ginger, on melanogenesis and the underlying mechanisms. Methods: B16F10 mouse melanoma cells were tested. Cell viability was determined with the MTT assay. Melanin content and tyrosinase activity were analyzed with a spectrophotometer. The protein expression of tyrosinase and microphthalmia associated transcription factor (MITF), as well as phosphorylated or total ERK1/2 and Akt were measured using Western blot.
Melanin protects the skin against ultraviolet radiation by scattering incoming light and absorbing diverse free radicals. Agents that increase melanin synthesis in melanocytes may reduce the risk of photodamage and skin cancer. The present study investigated the effect of a methanol extract of Ardisia crenata (AC) on melanogenesis in B16F10 cells. Treatment of cultured B16F10 cells with AC extract (10, 20 and 40 µg/ml) stimulated an increase in melanin levels in a concentration-dependent manner, without cytotoxicity. Tyrosinase is key in the regulation of melanin production, thus the effect of AC extract on tyrosinase activity and protein expression was analyzed. AC extract was observed to significantly increase tyrosinase activity and protein expression in B16F10 cells. Furthermore, AC extract was found to markedly increase the protein expression of microphthalmia-associated transcription factor, which is an important transcription factor involved in tyrosinase gene expression. In addition, AC extract (40 µg/ml) was observed to suppress the activation of extracellular signal-regulated kinase (ERK) and Akt, which negatively regulate melanin synthesis in B16F10 cells. In conclusion, to the best of our knowledge, the present study is the first to show that a methanol extract of AC stimulates melanogenesis by increasing tyrosinase expression via the inhibition of ERK and Akt. Thus, methanol extract of AC may be a potential treatment for hypopigmentation diseases and may be a candidate for skin-tanning cosmetic products.
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