datasheet1_FGIN-1-27 Inhibits Melanogenesis by Regulating Protein Kinase A/cAMP-Responsive Element-Binding, Protein Kinase C-β, and Mitogen-Activated Protein Kinase Pathways.pdf

FGIN-1-27 is a synthetic mitochondrial diazepam binding inhibitor receptor (MDR) agonist that has demonstrated pro-apoptotic, anti-anxiety, and steroidogenic activity in various studies. Here we report, for the first time, the anti-melanogenic efficacy of FGIN-1-27 in vitro and in vivo. FGIN-1-27 significantly inhibited basal and α-melanocyte-stimulating hormone (α-MSH)-, 1-Oleoyl-2-acetyl-sn-glycerol (OAG)- and Endothelin-1 (ET-1)-induced melanogenesis without cellular toxicity. Mushroom tyrosinase activity assay showed that FGIN-1-27 did not directly inhibit tyrosinase activity, which suggested that FGIN-1-27 was not a direct inhibitor of tyrosinase. Although it was not capable of modulating the catalytic activity of mushroom tyrosinase in vitro, FGIN-1-27 downregulated the expression levels of key proteins that function in melanogenesis. FGIN-1-27 played these functions mainly by suppressing the PKA/CREB, PKC-β, and MAPK pathways. Once inactivated, it decreased the expression of MITF, tyrosinase, TRP-1, TRP-2, and inhibited the tyrosinase activity, finally inhibiting melanogenesis. During in vivo experiments, FGIN-1-27 inhibited the body pigmentation of zebrafish and reduced UVB-induced hyperpigmentation in guinea pig skin, but not a reduction of numbers of melanocytes. Our findings indicated that FGIN-1-27 exhibited no cytotoxicity and inhibited melanogenesis in both in vitro and in vivo models. It may prove quite useful as a safer skin-whitening agent.

FGIN-1-27是一种合成的线粒体苯二氮䓬结合抑制剂受体（mitochondrial diazepam binding inhibitor receptor, MDR）激动剂，多项研究已证实其具备促凋亡、抗焦虑及类固醇生成活性。本研究首次报道了FGIN-1-27在体外（in vitro）和体内（in vivo）中的抗黑素生成活性。FGIN-1-27可显著抑制基础状态以及α-黑素细胞刺激素（α-melanocyte-stimulating hormone, α-MSH）、1-油酰-2-乙酰基-sn-甘油（1-Oleoyl-2-acetyl-sn-glycerol, OAG）和内皮素-1（Endothelin-1, ET-1）诱导的黑素生成，且无细胞毒性。蘑菇酪氨酸酶（mushroom tyrosinase）活性实验结果显示，FGIN-1-27并未直接抑制酪氨酸酶活性，这表明FGIN-1-27并非酪氨酸酶的直接抑制剂。尽管FGIN-1-27无法在体外调节蘑菇酪氨酸酶的催化活性，但它可下调黑素生成通路中关键蛋白的表达水平。FGIN-1-27主要通过抑制PKA/CREB、蛋白激酶C-β（PKC-β）以及丝裂原活化蛋白激酶（MAPK）通路发挥上述作用。这些通路被抑制失活后，可下调小眼畸形相关转录因子（microphthalmia-associated transcription factor, MITF）、酪氨酸酶、酪氨酸酶相关蛋白1（TRP-1）、酪氨酸酶相关蛋白2（TRP-2）的表达，并抑制酪氨酸酶活性，最终阻断黑素生成。体内实验中，FGIN-1-27可抑制斑马鱼（zebrafish）的体色素沉着，并减轻紫外线B（UVB）诱导的豚鼠皮肤色素过度沉着，但并未减少黑素细胞数量。本研究结果表明，FGIN-1-27无细胞毒性，可在体外及体内模型中均抑制黑素生成，有望成为更安全的皮肤美白剂。