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Granulomatous rosacea (GR) is a variant of rosacea. Ultraviolet radiation (UVR) is considered to be etiologically related to GR, but its pathogenesis still remains unclear. Although, recent studies suggested that transient receptor potential vanilloid (TRPV) and mast cells are involved in the pathogenesis of rosacea, their role in each variants of rosacea such as GR has not been reported. In this respect, this study was conducted to investigate immunohistochemical expression of MMP-1, -9, TRPV, and CD117 in the GR compared with the non-granulomatous rosacea (NGR) and to test the hypothesis that immunohistochemical expressions of GR would relate with UVR. Biopsy samples were obtained from 11 patients of GR and 11 patients of NGR. For the analysis, subjects in two groups were age-matched. The sections were stained using hematoxylin and eosin, and antibodies MMP-1, -9, TRPV, and CD117. And expression of antibodies was evaluated with a semi-quantitative scale. The expression of MMP-1, -9, and TRPV was significantly increased in GR lesions compared with NGR lesions (p < 0.05), especially at the center of granulomas. CD117 expression was increased in GR lesions, although difference between the two groups was not statistically significant. We suggest that, in GR lesions, TRPV is associated significantly with granuloma formation as well as MMP-1, -9 in relation to UVR exposure, and mast cells may play an important role in this process. 724Protection against photo-aging by targeting the transient receptor potential channel, TRPV1 2 The Estee Lauder Companies, Melville, NY and 3 The Estee Lauder Companies and Clinique Laboratories, Melville, NY Photo-aging, due to repetitive exposure to solar radiation, is linked to the premature development of wrinkles and skin sagging. Solar radiation is composed of a spectrum of electromagnetic radiation that is divided into three categories based on wavelength: ultraviolet (UV), visible, and infrared (IR). It is established that prolonged exposure to UV radiation has deleterious effects on skin; however, recent evidence suggests that precipitous aging of the skin is also influenced by IR radiation that comprises w54% of solar radiation. It has been demonstrated, in vivo that IR-induced heating and UV radiation up-regulate and activate TRPV1 channels, which has been shown to induce collagen degradation via the up-regulation of the matrix metalloprotease, MMP-1, contributing to photo-aging. We sought to investigate if an antagonist of TRPV1, 4-t-butylcyclohexanol, would protect against IR and UV radiation. To address this, reconstructed human skins were irradiated with IR or UV light once a day for 2 days in the presence or absence of the TRPV1 antagonist. Transepithelial Electrical Resistance (TEER) measurements, immunochemical assays, and histological analysis were used to determine modifications in skin barrier, cytokine release, and protein expression, respectively. TEER data revealed that modulating TRPV1 activation markedly improved barrier integrity. The pro-inflammatory cytokines...

During skin wound healing, fibroblasts differentiate into myofibroblasts (MF) that assist in wound contraction and repair. Neoexpression of a-smooth muscle actin (a-SMA), an established marker for MF differentiation, is driven by TGFb receptor (TGFbR)-mediated signaling. Hyaluronan (HA) and its receptor CD44 on cell surface can also participate in this process. To further understand how HA, CD44, and TGFbR pathways interact, primary mouse skin fibroblasts were isolated and treated in vitro with recombinant TGF-b1 (rTGF-b1) and the expression of a-SMA and CD44 were increased. Paradoxically, CD44 knockdown by RNA interference (RNAi) led to increased a-SMA expression and a-SMA-containing stress fibers. Reduction of extracellular HA or HA synthesis had no effect on a-SMA levels, suggesting that CD44-mediated effect on a-SMA is HA-independent. Exploration of mechanisms linking CD44 knockdown to a-SMA induction using RNAi and chemical inhibitors revealed a requirement for non-canonical TGFbR signaling through p38MAPK activity. A decrease in monomeric G-actin via conversion to filamentous F-actin following CD44 RNAi suggested a possible role for Myocardin-related Transcription Factor (MRTF), a known regulator of a-SMA transcription and itself being regulated by G-actin binding. CD44 RNAi led to increased nuclear MRTF and to increased binding to its transcriptional cofactor, SRF. MRTF knockdown suppressed a-SMA expression and abrogated its increase caused by CD44 RNAi, suggesting that MRTF is required for CD44-mediated regulation of a-SMA. Finally, pretreatment with a p38MAPK inhibitor reversed nuclear MRTF accumulation after rTGF-b1 addition or CD44RNAi, revealing a central requirement for p38MAPK in both cases. Thus, CD44 regulates a-SMA gene expression via cooperation between two intersecting pathways, one mediated via G-actin/MRTF and the other via TGFbR/p38MAPK.

PCE-DP (D-pantothenyl alcohol) is an active ingredient in pharmaceuticals and cosmetics that prevents inflammation and promotes hair growth. In our previous randomized doubleblind placebo-controlled UVB irradiation-induced pigmentation study using healthy Japanese men and women, we found that topical PCE-DP has brightening effects when used for 4 weeks. In this study, we examined four studies to clarify the molecular mechanism of PCE-DP activity: (i) epidermal turnover, (ii) melanosomal uptake of keratinocytes, (iii) melanocyte activation by keratinocytes, or (iv) melanin production in melanocytes. When PCE-DP was added to normal human epidermal keratinocytes (NHEK), the intracellular CoA and ATP concentrations significantly increased, and cell growth was significantly induced. Furthermore, epidermal turnover was enhanced by PCE-DP because the average projected area of corneocytes (APAc) significantly decreased after 4 weeks of daily topical application of PCE-DP to the skin of the medial upper arm. The mRNA expression level of adrenomedullin, a key factor for dendrite elongation in melanocytes, significantly decreased, and melanin uptake was inhibited by adding PCE-DP to the NHEK. The induction of endothelin-1 mRNA, which increases melanin synthesis in melanocytes, was significantly decreased by the addition of PCE-DP after UVB irradiation to the NHEK. On the other hand, when PCE-DP was added to melanocytes, no effects on cell growth or melanin synthesis were observed. This suggested that PCE-DP improves skin pigmentation by inducing epidermal turnover through the activation of ATP production in NHEK. This improvement mechanism may involve activation of the tricarboxylic acid cycle by increasing the intracellular CoA level. In addition, PCE-DP prevents skin pigmentation by inhibiting melanin uptake and inflammation after UVB irradiation in NHEK.

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