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We conducted large‐scale screening test on drugs that were already approved for other diseases to find pigmentation‐modulating agents. Among drugs with potential for pigmentation control, we selected sorafenib and further investigated the effect on pigmentation using HM3KO melanoma cells. As a result of treating melanoma cells with sorafenib, pigmentation was promoted in terms of melanin content and tyrosinase activity. Sorafenib increased mRNA and protein levels of pigmentation‐related genes such as MITF, tyrosinase and TRP1. To uncover the action mechanism, we investigated the effect of sorafenib on the intracellular signalling pathways. Sorafenib reduced phosphorylation of AKT and ERK, suggesting that sorafenib induces pigmentation through inhibition of the AKT and ERK pathways. In addition, sorafenib significantly increased the level of active β‐catenin, together with activation of β‐catenin signalling. Mechanistic study revealed that sorafenib decreased phosphorylation of serine 9 (S9) of GSK3β, while it increased phosphorylation of tyrosine 216 (Y216) of GSK3β. These results suggest that sorafenib activates the β‐catenin signalling through the regulation of GSK3β phosphorylation, thereby affecting the pigmentation process. [ABSTRACT FROM AUTHOR]

Drug repurposing and/or repositioning is an alternative method to develop new treatment for certain diseases. Albendazole was originally developed as an anthelmintic medication, and it has been used to treat a variety of parasitic infestations. In this study, we investigated the antitumor effect of albendazole and putative action mechanism. Results showed that albendazole dramatically decreased the cell viability of SCC cell lines (SCC12 and SCC13 cells). Albendazole increased apoptosis-related signals, including cleaved caspase-3 and PARP-1 in a dose-dependent fashion. The mechanistic study showed that albendazole induced endoplasmic reticulum (ER) stress, evidenced by increase of CHOP, ATF-4, caspase-4, and caspase-12. Pretreatment with ER stress inhibitor 4-PBA attenuated albendazole-induced apoptosis of SCC cells. In addition, albendazole decreased the colony-forming ability of SCC cells, together with inhibition of Wnt/β-catenin signaling. These results indicate that albendazole shows an antitumor effect via regulation of ER stress and cancer stemness, suggesting that albendazole could be repositioned for cutaneous SCC treatment. [ABSTRACT FROM AUTHOR]

Adiponectin plays important roles in metabolic function, inflammation and multiple biological activities in various tissues. However, evidence for adiponectin signaling in sebaceous glands is lacking, and its role remains to be clarified. This study investigated the role of adiponectin in lipid production in sebaceous glands in an experimental study of human sebocytes. We demonstrated that human sebaceous glands in vivo and sebocytes in vitro express adiponectin receptor and that adiponectin increased cell proliferation. Moreover, based on a lipogenesis study using Oil Red O, Nile red staining and thin layer chromatography, adiponectin strongly upregulated lipid production in sebocytes. In three-dimensional culture of sebocytes, lipid synthesis was markedly enhanced in sebocytes treated with adiponectin. This study suggested that adiponectin plays a significant role in human sebaceous gland biology. Adiponectin signaling is a promising target in the clinical management of barrier disorders in which sebum production is decreased, such as in atopic dermatitis and aged skin. [ABSTRACT FROM AUTHOR]

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]

Psoriasis is a common skin disease, of which pathogenesis involves the increase of inflammatory reaction in epidermal cells. In an attempt to find therapeutics for psoriasis, we found that cucurbitacin B has an inhibitory potential on imiquimod-induced inflammation of keratinocytes. Cucurbitacin B significantly inhibited imiquimod-induced expression of crucial psoriatic cytokines, such as IL-8 and CCL20, via down-regulation of NF-κB and STAT3 signaling pathway in human keratinocytes. In addition, keratinocyte proliferation was markedly inhibited by cucurbitacin B. The potential beneficial effect of cucurbitacin B on psoriasis was further validated in imiquimod-induced psoriasiform dermatitis of experimental animal. Topical application of cucurbitacin B resulted in significant reduction of epidermal hyperplasia and inflammatory cytokines production, and ameliorated the psoriatic symptom. Taken together, these results suggest that cucurbitacin B may be a potential candidate for the treatment of psoriasis. [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]

Imiquimod is known to exert its effects through Toll-like receptor 7 (TLR7) and/or TLR8, resulting in expression of proinflammatory cytokines and chemokines. Keratinocytes have not been reported to constitutively express TLR7 and TLR8, and the action of imiquimod is thought to be mediated by the adenine receptor, not TLR7 or TLR8. In this study, we revealed the expression of TLR7 in keratinocytes after calcium-induced differentiation. After addition of calcium to cultured keratinocytes, the immunological responses induced by imiquimod, such as activation of NF-κB and induction of TNF-α and IL-8, were more rapid and stronger. In addition, imiquimod induced the expression TLR7, and acted synergistically with calcium to induce proinflammatory cytokines. We confirmed that the responses induced by imiquimod were significantly inhibited by microRNAs suppressing TLR7 expression. These results suggest that TLR7 expressed in keratinocytes play key roles in the activation of NF-κB signaling by imiquimod, and that their modulation in keratinocytes could provide therapeutic potential for many inflammatory skin diseases. [ABSTRACT FROM AUTHOR]