Zang Deng, Niu Chao, Aisa Haji Akber
Key Laboratory of Plant Resources and Chemistry in Arid Regions, State Key Laboratory Basis of Xinjiang Indigenous Medicinal Plants Resource Utilization, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi 830011, China,
University of Chinese Academy of Sciences, Beijing 100049, China.
Drug Des Devel Ther. 2019 Feb 12;13:623-632. doi: 10.2147/DDDT.S180960. eCollection 2019.
Melanogenesis, or the biosynthesis of melanin, plays a critical role in the pigmentation of skin, hair, and eyes. Reduced melanogenesis may lead to depigmentation conditions such as vitiligo. Psoralen, a furocoumarin derivative, is closely associated with melanogenesis, and its derivative 8-methoxypsoralen is used in psoralen and ultraviolet A therapy for pigmentation disorders. In a previous study, we synthesized a new series of amine derivatives of furocoumarin, of which 5-(morpholinomethyl)-3-phenyl-7-furo[3,2-]chromen-7-one (encoded as D206008) showed a remarkable melanogenic effect in B16 murine cells.
In this study, we examined the effects of D206008 on the melanogenesis-related pathways in B16 cells. D206008 increased melanin production and tyrosinase (TYR) activity, as well as the mRNA and protein expression levels of the melanogenic enzymes TYR, TRP-1 and TRP-2, and the melanogenesis-related transcription factor microphthalmia-associated transcription factor (MITF) in a dose-dependent (0-100 µM) and time-dependent (0-48 hours) manner.
Mechanistically, D206008 inhibited β-catenin degradation by enhancing the phosphorylation of Akt and glycogen synthase kinase-3β (GSK-3β), which increased the accumulation of β-catenin in the cytoplasm. Nuclear translocation of β-catenin also increased in response to D206008 treatment.
Taken together, these data indicate that D206008 promotes melanin synthesis by stimulating the nuclear translocation of β-catenin, which activates MITF transcription and eventually melanogenesis.
黑色素生成，即黑色素的生物合成，在皮肤、毛发和眼睛的色素沉着过程中起着关键作用。黑色素生成减少可能导致诸如白癜风等色素脱失病症。补骨脂素，一种呋喃香豆素衍生物，与黑色素生成密切相关，其衍生物8-甲氧基补骨脂素用于治疗色素沉着紊乱的补骨脂素加紫外线A疗法。在先前的一项研究中，我们合成了一系列新的呋喃香豆素胺衍生物，其中5-(吗啉甲基)-3-苯基-7-呋喃并[3,2-]色原酮（编码为D206008）在B16小鼠细胞中显示出显著的促黑色素生成作用。
在本研究中，我们检测了D206008对B16细胞中黑色素生成相关信号通路的影响。D206008以剂量依赖性（0-100μM）和时间依赖性（0-48小时）的方式增加黑色素生成、酪氨酸酶（TYR）活性，以及黑色素生成酶TYR、TRP-1和TRP-2的mRNA和蛋白质表达水平，还有黑色素生成相关转录因子小眼相关转录因子（MITF）。
从机制上来说，D206008通过增强Akt和糖原合酶激酶-3β（GSK-3β）的磷酸化来抑制β-连环蛋白的降解，这增加了β-连环蛋白在细胞质中的积累。响应D206008处理，β-连环蛋白的核转位也增加。
综上所述，这些数据表明D206008通过刺激β-连环蛋白的核转位来促进黑色素合成，β-连环蛋白激活MITF转录并最终促进黑色素生成。
