Department of Dermatology, College of Medicine, The Catholic University of Korea, 505 Banpo-dong, Seocho-gu, Seoul 06591, Republic of Korea.
Department of Dermatology, College of Medicine, The Catholic University of Korea, 505 Banpo-dong, Seocho-gu, Seoul 06591, Republic of Korea.
Life Sci. 2018 Oct 1;210:201-208. doi: 10.1016/j.lfs.2018.08.056. Epub 2018 Aug 24.
Several anti-melanogenic molecules have been developed or identified, but their uses are limited due to either adverse effects or instability during the treatment. We aimed to evaluate the effects of extracellular superoxide dismutase (SOD3), a powerful antioxidant, as a candidate anti-melanogenic molecule.
UVB-induced reactive oxygen species (ROS) production and proliferation in melan-a cells was evaluated by 6-carboxy-2',7'-dichlorodihydrofluorescein diacetate staining and bromodeoxyuridine incorporation assay, respectively. Quantitative real-time polymerase chain reaction and western blot were performed to detect the melanogenesis-related gene expression and downstream signaling. Anti-melanogenic effects of SOD3 were also evaluated using SOD3 transgenic mice under UVB exposure in-vivo condition.
SOD3 inhibited UVB-induced proliferation, ROS production and melanogenesis in melanocytes. Measurement of melanin content and tyrosinase activity assays showed that SOD3 significantly inhibited melanin synthesis. Moreover, these suppressive effects of SOD3 were dependent on the endothelin-1 (ET-1)/endothelin B receptor, protein kinase C, melanocortin 1 receptor/protein kinase A, Wnt7a/β-catenin, and mitogen-activated protein kinase pathways, with concomitant downregulation of microphthalmia-associated transcription factor, tyrosinase, and tyrosinase-related proteins 1, dopachrome tautomerse. Interestingly, SOD3 was found to inhibit transforming growth factor-beta 1 (TGF-β1) to inactivate the ET-1 signaling pathway, and finally prevents the production of melanin.
Our results provide novel insights into the role of SOD3 in melanocyte homeostasis and its uses as a potential biomedicine to treat hyperpigmentary conditions of the skin.
已经开发或鉴定了几种抗黑色素生成分子，但由于治疗过程中的不良反应或不稳定性，其应用受到限制。我们旨在评估细胞外超氧化物歧化酶（SOD3）作为候选抗黑色素生成分子的作用。
通过 6-羧基-2'，7'-二氯二氢荧光素二乙酸酯染色和溴脱氧尿苷掺入试验分别评估 UVB 诱导的活性氧（ROS）产生和黑色素瘤细胞增殖。进行定量实时聚合酶链反应和蛋白质印迹以检测黑色素生成相关基因表达和下游信号转导。还通过 SOD3 转基因小鼠在体内暴露于 UVB 条件下评估 SOD3 的抗黑色素生成作用。
SOD3 抑制黑色素细胞中 UVB 诱导的增殖、ROS 产生和黑色素生成。黑色素含量和酪氨酸酶活性测定表明 SOD3 显著抑制黑色素合成。此外，SOD3 的这些抑制作用依赖于内皮素-1（ET-1）/内皮素 B 受体、蛋白激酶 C、黑色素皮质素 1 受体/蛋白激酶 A、Wnt7a/β-catenin 和丝裂原激活蛋白激酶途径，同时下调小眼相关转录因子、酪氨酸酶和酪氨酸酶相关蛋白 1、多巴色素互变异构酶。有趣的是，发现 SOD3 抑制转化生长因子-β1（TGF-β1）使 ET-1 信号通路失活，最终阻止黑色素的产生。
我们的结果为 SOD3 在黑素细胞动态平衡中的作用及其作为治疗皮肤色素沉着过度的潜在生物医学用途提供了新的见解。
