{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T15:36:57Z","timestamp":1791992217338,"version":"4.4.0"},"reference-count":29,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2023,6,5]],"date-time":"2023-06-05T00:00:00Z","timestamp":1685923200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Trade, Industry, and Energy (MOTIE) at the Korea Institute for Advancement of Technology (KIAT)","award":["P0017663"],"award-info":[{"award-number":["P0017663"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>We investigated the effects of four coumarin derivatives, namely, 6-methylcoumarin, 7-methylcoumarin, 4-hydroxy-6-methylcoumarin, and 4-hydroxy-7-methylcoumarin, which have similar structures on melanogenesis in a murine melanoma cell line from a C57BL\/6J mouse called B16F10. Our results showed that only 6-methylcoumarin significantly increased the melanin synthesis in a concentration-dependent manner. In addition, the tyrosinase, TRP-1, TRP-2, and MITF protein levels were found to significantly increase in response to 6-methylcoumarin in a concentration-dependent manner. To elucidate the molecular mechanism whereby 6-methylcoumarin-induced melanogenesis influences the melanogenesis-related protein expression and melanogenesis-regulating protein activation, we further assessed the B16F10 cells. The inhibition of the ERK, Akt, and CREB phosphorylation, and conversely, the increased p38, JNK, and PKA phosphorylation activated the melanin synthesis via MITF upregulation, which ultimately led to increased melanin synthesis. Accordingly, 6-methylcoumarin increased the p38, JNK, and PKA phosphorylation in the B16F10 cells, whereas it decreased the phosphorylated ERK, Akt, and CREB expressions. In addition, the 6-methylcoumarin activated GSK3\u03b2 and \u03b2-catenin phosphorylation and reduced the \u03b2-catenin protein level. These results suggest that 6-methylcoumarin stimulates melanogenesis through the GSK3\u03b2\/\u03b2-catenin signal pathway, thereby affecting the pigmentation process. Finally, we tested the safety of 6-methylcoumarin for topical applications using a primary human skin irritation test on the normal skin of 31 healthy volunteers. We found that 6-methylcoumarin did not cause any adverse effects at concentrations of 125 and 250 \u03bcM. Our findings indicate that 6-methylcoumarin may be an effective pigmentation stimulator for use in cosmetics and the medical treatment of photoprotection and hypopigmentation disorders.<\/jats:p>","DOI":"10.3390\/molecules28114551","type":"journal-article","created":{"date-parts":[[2023,6,6]],"date-time":"2023-06-06T02:08:15Z","timestamp":1686017295000},"page":"4551","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["6-Methylcoumarin Promotes Melanogenesis through the PKA\/CREB, MAPK, AKT\/PI3K, and GSK3\u03b2\/\u03b2-Catenin Signaling Pathways"],"prefix":"10.3390","volume":"28","author":[{"given":"Taejin","family":"Kim","sequence":"first","affiliation":[{"name":"Jeju Inside Agency and Cosmetic Science Center, Department of Chemistry and Cosmetics, Jeju National University, Jeju-si 63243, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin-Kyu","family":"Kang","sequence":"additional","affiliation":[{"name":"Jeju Inside Agency and Cosmetic Science Center, Department of Chemistry and Cosmetics, Jeju National University, Jeju-si 63243, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3000-7989","authenticated-orcid":false,"given":"Chang-Gu","family":"Hyun","sequence":"additional","affiliation":[{"name":"Jeju Inside Agency and Cosmetic Science Center, Department of Chemistry and Cosmetics, Jeju National University, Jeju-si 63243, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,6,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1401","DOI":"10.1007\/s11010-020-04000-5","article-title":"Involvement of adenylate cyclase\/cAMP\/CREB and SOX9\/MITF in melanogenesis to prevent vitiligo","volume":"476","author":"Arora","year":"2021","journal-title":"Mol. 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