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Background Wnt/β-catenin signaling is important in development and differentiation of melanocytes. Objective The object of this study was to evaluate the effects of several Wnt/β-catenin signaling inhibitors on pigmentation using melanoma cells. Methods Melanoma cells were treated with Wnt/β-catenin signaling inhibitors, and then melanin content and tyrosinase activity were checked. Results Although some inhibitors showed slight inhibition of pigmentation, we failed to observe potential inhibitory effect of those chemicals on pigmentation of HM3KO melanoma cells. Rather, one of powerful Wnt/β-catenin signaling inhibitors, ICG-001, increased the pigmentation of HM3KO melanoma cells. Pigmentation-enhancing effect of ICG-001 was reproducible in other melanoma cell line MNT-1. Consistent with these results. ICG-001 increased the expression of pigmentation-related genes, such as MITF, tyrosinase and TRP1. When ICG-001 was treated, the phosphorylation of CREB was significantly increased. In addition, ICG-001 treatment led to quick increase of intracellular cAMP level, suggesting that ICG-001 activated PKA signaling. The blockage of PKA signaling with pharmaceutical inhibitor H89 inhibited the ICG-001-induced pigmentation significantly. Conclusions These results suggest that PKA signaling is pivotal in pigmentation process itself, while the importance of Wnt/β-catenin signaling should be emphasized in the context of development and differentiation. [ABSTRACT FROM AUTHOR]

Abstract: Background: The extraneuronal cholinergic system has been implicated in numerous functions in the skin, such as terminal differentiation, barrier formation, sweat secretion and the microcirculation. However, the evidence for cholinergic signalling in sebaceous glands is lacking, and its role needs to be clarified. Objective: We investigated the role of acetylcholine signalling in sebaceous glands using human sebocytes and a clinical study using botulinum toxin. Methods: Immunohistochemistry and immunocytofluorescence were performed to evaluate cholinergic receptor levels in sebaceous glands. Lipid levels were assessed by Oil Red O staining and signalling pathways by Western blotting. To evaluate the clinical relevance, we also assessed the effect of botulinum toxin on sebum production in healthy volunteers. Results: We demonstrated that human skin sebaceous glands in vivo and sebocytes in vitro express nicotinic acetylcholine receptor α7 (nAchRα7), and that acetylcholine increased lipid synthesis in a dose-dependent manner. When sebocytes were incubated with α-bungarotoxin, a competitive nAchR antagonist, acetylcholine failed to up-regulate lipid synthesis. Twenty healthy volunteers were enrolled in a double-blind, placebo-controlled, split-face study. A marked decrease in sebum production on the botulinum-treated side was found in volunteers with oily skin. Conclusion: These results provide evidence that acetylcholine signalling plays a significant role in human sebaceous gland biology and identify acetylcholine signalling as a promising target in the clinical management of disorders in which sebum production is increased, such as acne vulgaris. [Copyright &y& Elsevier]