MHY884, a newly synthesized tyrosinase inhibitor, suppresses UVB-induced activation of NF-κB signaling pathway through the downregulation of oxidative stress
MHY884, a newly synthesized tyrosinase inhibitor, suppresses UVB-induced activation of NF-κB signaling pathway through the downregulation of oxidative stress
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DOI：
10.1016/j.bmcl.2014.01.040
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发表时间：
2014-03-01
影响因子：
2.7
通讯作者：
Chung, Hae Young
中科院分区：
文献类型：
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作者：
Choi, Yeon Ja;Uehara, Yohei;Chung, Hae Young
皮肤是长时间和重复紫外线（UVB）照射的主要目标，其诱导皮肤炎症和色素沉着。核因子κ B（NF-κ B B）是介导UVB诱导的炎症反应的主要因子，通过表达多种促炎蛋白如诱导型一氧化氮合酶（iNOS）和环氧合酶-2（考克斯-2）。我们先前已经报道了合成的新化合物4-（5-氯-2，3-二氢苯并[d]噻唑-2-基）-2，6-二甲氧基苯酚（MHY 884）强烈抑制B16 F10黑素瘤细胞中的酪氨酸酶活性和黑色素合成。在本研究中，我们研究了MHY 884对UVB诱导的NF-κ B B活化及其促炎下游蛋白的抑制作用，通过抑制体内光老化模型中的氧化应激。在体外和在B16 F10黑素瘤细胞中测量活性氧物质（ROS）和过氧亚硝酸盐的产生，以验证MHY 884的清除活性。MHY 884在体外和黑素瘤细胞中以剂量依赖性方式抑制氧化应激。接下来，用MHY 884预处理具有黑色素的无毛小鼠，然后用UVB重复照射。局部应用MHY 884减弱UVB诱导的氧化应激，导致NF-κ B活性降低。用MHY 884预处理抑制Akt和I κ B激酶α/β信号通路，导致NF-κ B亚基p65的易位和磷酸化减少。该结果与MHY 884处理小鼠皮肤中iNOS和考克斯-2的表达水平相关。因此，新型酪氨酸酶抑制剂MHY 884通过清除UVB诱导的氧化应激抑制NF-κ B活化信号通路。MHY 884是一种靶向NF-κ B信号传导的新型酪氨酸酶抑制剂，其发现具有重要意义，因为该化合物是一种有前途的抗UVB诱导的皮肤损伤的保护剂。(C)2014爱思唯尔有限公司版权所有。
The skin is the primary target of prolonged and repeated ultraviolet (UVB) irradiation which induces cutaneous inflammation and pigmentation. Nuclear factor kappa B (NF-kappa B) is the major factor mediating UVB-induced inflammatory responses through the expression of various proinflammatory proteins such as inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). We have previously reported that the synthetic novel compound 4-(5-chloro-2,3-dihydrobenzo[d] thiazol-2-yl)-2,6-dimethoxyphenol (MHY884) strongly suppressed tyrosinase activity and melanin synthesis in B16F10 melanoma cells. In the present study, we investigated the effect of MHY884 on the inhibition of UVB-induced NF-kappa B activation and its proinflammatory downstream proteins through the suppression of oxidative stress in an in vivo model of photoaging. Generation of reactive oxygen species (ROS) and peroxynitrite was measured in vitro and in B16F10 melanoma cells to verify the scavenging activity of MHY884. MHY884 suppressed oxidative stress both in vitro and in the melanoma cells in a dose-dependent manner. Next, melanin-possessing hairless mice were pre-treated with MHY884 and then irradiated with UVB repeatedly. Topical application of MHY884 attenuated UVB-induced oxidative stress, resulting in reduced NF-kappa B activity. Pre-treatment with MHY884 inhibited Akt and I kappa B kinase alpha/beta signaling pathways, leading to decreased translocation and phosphorylation of p65, a subunit of NF-kappa B. This result correlated with the expression levels of iNOS and COX-2 in the skin of MHY884-treated mice. Thus, the novel tyrosinase inhibitor MHY884 suppressed NF-kappa B activation signaling pathway by scavenging UVB-induced oxidative stress. The discovery of MHY884, a novel tyrosinase inhibitor that targets NF-kappa B signaling, is significant, because this compound is a promising protective agent against UVB-induced skin damage. (C) 2014 Elsevier Ltd. All rights reserved.