Molecular Inflammation Research Center for Aging Intervention, College of Pharmacy, Pusan National University, Busan 609-735, Republic of Korea.
J Dermatol Sci. 2012 Dec;68(3):164-71. doi: 10.1016/j.jdermsci.2012.09.014. Epub 2012 Oct 3.
Ultraviolet B (UVB) radiation is the main physiological stimulus for skin pigmentation. Nitric oxide (NO) and the NO/PKG signaling pathway play an important role in UVB-induced melanogenesis, which is related to the induction of expression of tyrosinase. In an attempt to find a novel anti-melanogenic agent, we synthesized a new compound, 2-bromo-4-(5-chloro-benzo[d]thiazol-2-yl) phenol (MHY966).
The purpose of this study was to investigate the action of MHY966 on NO and the NO-mediated signaling pathway using in vitro and in vivo models of melanogenesis.
NO generation, melanin synthesis, and the expression of tyrosinase and PKG were measured in B16F10 melanoma cells to verify the anti-melanogenic effect of MHY966 in vitro. Next, melanin-possessing hairless mice were pre-treated with MHY966 and then irradiated with UVB repeatedly. Morphological, histological, and biochemical analyses including the expressions of PKG, tryosinase and nuclear MITF, and productions of nitric oxide, peroxynitrite and ROS were conducted.
MHY966 effectively inhibited NO generation and subsequent melanin synthesis induced by sodium nitroprusside, an NO donor, and suppressed the expression of tyrosinase and PKG. Topical application of MHY966 dose-dependently attenuated UVB-induced pigmentation in a mouse model. This hypopigmentation effect induced by MHY966 treatment was mediated by the down-regulation of tyrosinase, PKG, and nuclear MITF, which was accompanied by decreased NO and NO-related oxidative stress.
The novel compound, MHY966 had an inhibitory effect on NO generation and the NO-mediated signaling pathway leading to the down-regulation of tyrosinase. The significance of the present study is the finding of a promising anti-melanogenic agent targeting the NO/PKG signaling pathway.
中波紫外线（UVB）辐射是皮肤色素沉着的主要生理刺激因素。一氧化氮（NO）和 NO/PKG 信号通路在 UVB 诱导的黑色素生成中发挥重要作用，这与诱导酪氨酸酶的表达有关。为了寻找一种新型的抗黑色素生成剂，我们合成了一种新化合物 2-溴-4-（5-氯-苯并[d]噻唑-2-基）苯酚（MHY966）。
本研究旨在通过体外和体内黑色素生成模型研究 MHY966 对 NO 和 NO 介导的信号通路的作用。
在 B16F10 黑色素瘤细胞中测量 NO 的产生、黑色素的合成以及酪氨酸酶和 PKG 的表达，以验证 MHY966 的体外抗黑色素生成作用。然后，用 MHY966 预处理具有黑色素的无毛小鼠，然后反复用 UVB 照射。进行形态学、组织学和生化分析，包括 PKG、tryosinase 和核 MITF 的表达以及一氧化氮、过氧亚硝酸盐和 ROS 的产生。
MHY966 有效抑制了一氧化氮供体硝普钠诱导的 NO 生成和随后的黑色素合成，并抑制了酪氨酸酶和 PKG 的表达。MHY966 的局部应用可剂量依赖性地减轻小鼠模型中 UVB 诱导的色素沉着。MHY966 处理诱导的这种色素减退作用是通过下调酪氨酸酶、PKG 和核 MITF 介导的，伴随着 NO 和与 NO 相关的氧化应激的减少。
新型化合物 MHY966 对 NO 的产生及其介导的信号通路具有抑制作用，导致酪氨酸酶下调。本研究的意义在于发现了一种针对 NO/PKG 信号通路的有前途的抗黑色素生成剂。
