Yoko Funasaka

Background: Hyperpigmentation is a common acquired disorder that can be a cosmetic concern for many individuals. To reduce and prevent hyperpigmentation, numerous skin lightening agents have been developed. Potassium 4‐methoxysalicylate (4MSK) is a skin lightening agent that was approved as an active skin lightening ingredient of quasi‐drugs by the Ministry of Health, Labour and Welfare of Japan in 2003. For over 20 years, 4MSK has been widely used in quasi‐drug and cosmetic products. However, the mechanism of action and efficacy of 4MSK on skin pigmentation and skin lightness have not been publicly reported.Aims: This study aimed to assess the mechanism of action and the efficacy of 4MSK on facial pigmentation.Methods: The mechanism of action of 4MSK on epidermal cells was investigated using human melanocytes, human keratinocytes, and human 3D epidermal equivalents. The efficacy of 4MSK on facial pigmentation was evaluated by a human clinical study, which is a double‐blind, split‐face, placebo‐controlled, paired‐design study.Results: 4MSK significantly suppressed melanin content in cultured human melanocytes and a 3D epidermal equivalent. It also promoted gene expression of differentiation markers of human keratinocytes. In the clinical study, a 4MSK formulation significantly increased skin lightness values in both pigmented and non‐pigmented areas of cheek skin. In addition, it reduced the desquamation area ratio of the cheek.Conclusions: 4MSK reduces skin pigmentation and contributes to brighter skin by acting on both melanocytes and keratinocytes.

Background: Both ultraviolet B (UVB) phototherapy with 308-nm excimer light and excimer laser devices are widely used to treat vitiligo. While the devices share the 308-nm wavelength, they have distinct characteristics. Notably, the excimer laser exhibits laser properties (monochromatic coherent light) and unique device specifications (a high frequency of 400 Hz and a remarkably high irradiance of 83 million mW/cm2). This study compared excimer light and laser irradiation, focusing on the depth of penetration into hair follicles and the effects on activation of melanocyte lineage cells, including melanocyte stem cells (McSCs) and melanoblasts. Methods: We irradiated the dorsal skin of mice with both devices at 1,000 mJ/cm2. Samples taken at 15 min and 3, 24, and 72 h after irradiation were used for immunostaining analysis. We evaluated penetration depth by using the staining pattern of cyclobutane pyrimidine dimers (CPDs), induction of apoptosis by using a terminal deoxynucleotidyl transferase-mediated deoxy-uridine triphosphate nick end-labeling (TUNEL) assay, and activation of melanocyte lineage cells by using fluorescent double immunostaining for TRP2 and β-catenin. Results: The excimer laser induced significantly more CPDs in the deeper regions of hair follicles while causing significantly faster removal of CPDs and less apoptosis in the epidermis. Moreover, the percentage of TRP2-positive cells with nuclear β-catenin in the follicles was significantly higher with the excimer laser. Conclusions: As compared with excimer light, the excimer laser penetrated more deeply into hair follicles, resulted in fewer epidermal side effects, and activated significantly more melanocyte-lineage cells.

Psoriasis is a chronic skin disease with interleukin (IL)-17-dominated inflammation and hyperproliferation of epidermis. Dietary fiber is fermented by the gut microbiome into short-chain fatty acids (SCFAs) that manifest anti-inflammatory effects. We examined if feeding with an inulin-enriched high-fiber diet (HFD) might improve topical imiquimod-induced psoriasis-like dermatitis in mice. HFD reduced thickening and total severity scores of imiquimod-induced dermatitis and reduced epidermal thickness, inflammatory infiltrates, including Ly6G+ neutrophils, and epidermal Ki67+ proliferating cells. HFD reduced mRNA levels of IL-17A, IL-17F, IL-22, IL-1β, tumor necrosis factor (TNF)-α, CXCL1, CXCL2, and keratin 16 and increased those of transforming growth factor (TGF)-β1 and cyclin-dependent kinase inhibitor 1A in imiquimod-induced dermatitis. In 16S rRNA sequencing of the gut microbiome, imiquimod increased relative abundance of phylum Firmicutes, while HFD increased that of phylum Bacteroidota and genus Bacteroides. HFD increased serum and fecal concentrations of SCFA propionate. Oral propionate reduced inflammatory infiltrates and epidermal Ki67+ cells and reduced mRNA levels of IL-17A, IL-17F, IL-17C, IL-22, IL-1β, IL-6, TNF-α, CXCL1, CCL20 and increased those of TGF-β1and IL-10 in imiquimod-indued dermatitis. Dietary inulin supplementation improves imiquimod-induced psoriasis-like dermatitis partially via propionate, and may be a promising adjunctive therapy for psoriasis.

Background: We previously reported that pre-irradiation with infrared radiation A (IRA) eliminated ultraviolet B (UVB) -induced cyclobutane pyrimidine dimers (CPDs). Accelerated elimination of CPDs could have resulted from enhanced DNA repair and/or enhanced induction of apoptosis. In this study, we examined whether IRA accelerated the elimination of CPDs by enhancing DNA repair, using Xpa knockout (KO) mice, which were deficient in DNA repair. Methods: We have already generated mice harboring epidermal melanocytes that produce only eumelanin and dominant pheomelanin, and no melanin. To obtain such mice but with impaired DNA repair ability, we backcrossed these mice with Xpa KO mice. Three hours before UVB irradiation, the mice were irradiated with IRA, and CPDs and apoptotic cells were examined. Results: Pre-irradiation of Xpa KO mice with IRA before UVB irradiation could accelerate the removal of CPDs and enhance apoptotic changes. Conclusion: These results indicate that the enhancement of UVB-induced apoptosis and acceleration of removal of CPDs by pre-irradiation with IRA does not depend on DNA damage repair.

Background Pembrolizumab, an anti-programmed cell death-1 protein monoclonal antibody, is effective for patients with advanced non-small-cell lung cancer. However, immune checkpoint inhibitors such as pembrolizumab induce various immune-related adverse events, involving the lung, liver, gastrointestinal, endocrine system, and skin. Intralymphatic histiocytosis (ILH) is a rare, chronic cutaneous disorder with a reactive inflammatory component, which often occurs in patients with rheumatoid arthritis. Case presentation We present a 67-year-old man with lung adenocarcinoma who developed ILH associated with pembrolizumab treatment. He was treated with palliative thoracic radiotherapy for superior vena cava syndrome. Subsequently, he received four cycles of pembrolizumab. Approximately 2.5 months after the initiation of pembrolizumab, he developed erythema on the trunk of his body. Based on findings of skin biopsies, he was diagnosed with pembrolizumab-induced ILH. Moreover, the upregulation of tumor necrosis factor-α was observed during pembrolizumab therapy. Conclusions This is the first report of ILH induced by pembrolizumab in a patient with lung adenocarcinoma.

Background: For laser therapy, darker skin types should be carefully treated, however, the precise role of melanin content, subspecies, and the heat effect of the laser has not been well studied in vivo. Methods: We generated three groups of mice that have epidermal melanocytes producing only eumelanin, dominant pheomelanin, and no melanin. Using these mice, the effect of a frequency-doubled Nd:YAG laser was studied. Results: The mouse epidermis that contained eumelanin underwent heat degeneration at a lower fluence when compared with the mouse epidermis with dominant pheomelanin. The mouse skin with no melanin did not show any degeneration of the epidermis. Conclusion: The effect of the Nd:YAG laser on the cells containing different melanin subspecies was shown to be different in an in vivo irradiation system.