Department of Pharmaceutical Engineering & Biotechnology, Sun Moon University, Asan 31460, Korea.
Microorganism Resources Division, National Institute of Biological Resources, Incheon 17058, Korea.
Molecules. 2022 Jun 29;27(13):4183. doi: 10.3390/molecules27134183.
Dimethyl itaconate (DMI) exhibits an anti-inflammatory effect. Activation of nuclear factor erythroid 2-related factor 2 (NRF2) is implicated in the inhibition of melanogenesis. Therefore, DMI and itaconic acid (ITA), classified as NRF2 activators, have potential uses in hyperpigmentation reduction. The activity of cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB), an important transcription factor for MITF gene promoter, is regulated by glycogen synthase kinase 3β (GSK3β) and protein kinase A (PKA). Here, we investigated the inhibitory effect of ITA and DMI on alpha-melanocyte-stimulating hormone (α-MSH)-induced MITF expression and the modulatory role of protein kinase B (AKT) and GSK3β in melanogenesis in B16F10 mouse melanoma cells. These cells were incubated with α-MSH alone or in combination with ITA or DMI. Proteins were visualized and quantified using immunoblotting and densitometry. Compared to ITA, DMI treatment exhibited a better inhibitory effect on the α-MSH-induced expression of melanogenic proteins such as MITF. Our data indicate that DMI exerts its anti-melanogenic effect via modulation of the p38 mitogen-activated protein kinase (MAPK) and AKT signaling pathways. In conclusion, DMI may be an effective therapeutic agent for both inflammation and hyperpigmentation.
丁烯酸二甲酯（DMI）具有抗炎作用。核因子红细胞 2 相关因子 2（NRF2）的激活与黑色素生成的抑制有关。因此，被归类为 NRF2 激活剂的 DMI 和衣康酸（ITA）在减少色素沉着方面具有潜在用途。环磷酸腺苷（cAMP）反应元件结合蛋白（CREB）的活性，MITF 基因启动子的重要转录因子，受糖原合成酶激酶 3β（GSK3β）和蛋白激酶 A（PKA）调节。在这里，我们研究了 ITA 和 DMI 对α-黑色素细胞刺激激素（α-MSH）诱导的 MITF 表达的抑制作用，以及蛋白激酶 B（AKT）和 GSK3β在 B16F10 小鼠黑色素瘤细胞中黑色素生成中的调节作用。这些细胞单独用α-MSH 或与 ITA 或 DMI 一起孵育。使用免疫印迹和密度测定法观察和定量蛋白质。与 ITA 相比，DMI 处理对 α-MSH 诱导的黑色素生成蛋白（如 MITF）的表达表现出更好的抑制作用。我们的数据表明，DMI 通过调节 p38 丝裂原活化蛋白激酶（MAPK）和 AKT 信号通路发挥其抗黑色素生成作用。总之，DMI 可能是炎症和色素沉着过度的有效治疗剂。
