(+)-Magnolin Enhances Melanogenesis in Melanoma Cells and Three-Dimensional Human Skin Equivalent; Involvement of PKA and p38 MAPK Signaling Pathways
(+)-Magnolin Enhances Melanogenesis in Melanoma Cells and Three-Dimensional Human Skin Equivalent; Involvement of PKA and p38 MAPK Signaling Pathways
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( )-Magnolin 增强黑色素瘤细胞和三维人体皮肤等效物中的黑色素生成；
DOI：
10.1055/a-1740-7325
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发表时间：
2022
期刊：
影响因子：
2.7
通讯作者：
Shoyama Yukihiro
中科院分区：
文献类型：
--
作者：
Uto Takuhiro;Tung Nguyen Huu;Ohta Tomoe;Shoyama Yukihiro
木兰花是一种传统的草药，用于治疗与头痛，脓胸和过敏性鼻炎相关的鼻塞。在我们初步筛选的原料药中， 日本汉方黑色素合成公式，木兰花的甲醇提取物被发现表现出很强的黑色素合成活性。然而，没有研究评估 木兰花及其成分对黑素生成的影响。本研究旨在从木兰花中分离激活黑色素瘤黑色素合成的活性化合物 细胞和三维人体皮肤等效物，并研究黑色素诱导的分子机制。木兰花甲醇提取物能诱导细胞凋亡， B16-F1和HMV-II细胞中的黑色素含量。通过比较从提取物制备的三个级分的黑色素诱导，表明乙酸乙酯级分显著诱导黑色素生成， 黑色素合成乙酸乙酯级分的生物测定引导的分离导致七种木脂素（1-7）的分离。其中，（+）-木兰脂素（5）强烈地 诱导黑色素合成和细胞内酪氨酸酶活性。此外，乙酸乙酯级分和5明显诱导三维人体皮肤中的黑色素含量 相当于分子分析显示，5触发酪氨酸酶、酪氨酸酶相关蛋白-1和酪氨酸酶相关蛋白-2的蛋白表达。进一步分析 转录因子和信号通路表明，5诱导酪氨酸酶、酪氨酸酶相关蛋白-1和酪氨酸酶相关蛋白-2的蛋白表达 通过蛋白激酶A和p38丝裂原活化蛋白激酶依赖性途径激活，导致cAMP反应元件结合蛋白磷酸化， 小眼症相关转录因子表达。这些发现证明了5作为色素减退症的有效治疗剂的潜力。
Magnoliae Flos is a traditional herbal medicine used to treat nasal congestion associated with headache, empyema, and allergic rhinitis. In our preliminary screening of crude drugs used in Japanese Kampo formulas for melanin synthesis, the methanol extract of Magnoliae Flos was found to exhibit strong melanin synthesis activity. However, there have been no studies evaluating the effects of Magnoliae Flos or its constituents on melanogenesis. The present study aimed to isolate the active compounds from Magnoliae Flos that activate melanin synthesis in melanoma cells and three-dimensional human skin equivalent, and to investigate the molecular mechanism underlying melanin induction. The methanol extract of Magnoliae Flos induced an increase of melanin content in both B16-F1 and HMV-II cells. A comparison of melanin induction by three fractions prepared from the extract showed that the ethyl acetate fraction markedly induced melanin synthesis. Bioassay-guided separation of the ethyl acetate fraction resulted in the isolation of seven lignans (1–7). Among them, (+)-magnolin (5) strongly induced melanin synthesis and intracellular tyrosinase activity. Furthermore, the ethyl acetate fraction and5clearly induced melanin content in a three-dimensional human skin equivalent. Molecular analysis revealed that5triggered the protein expression of tyrosinase, tyrosinase-related protein-1, and tyrosinase-related protein-2. Further analysis of transcriptional factors and signaling pathways demonstrated that5induces the protein expression of tyrosinase, tyrosinase-related protein-1, and tyrosinase-related protein-2 activated by the protein kinase A- and p38 mitogen-activated protein kinase-dependent pathways, leading to cAMP-responsive element-binding protein phosphorylation and microphthalmia-associated transcription factor expression. These findings demonstrate the potential of5as a potent therapeutic agent for hypopigmentation.