SIRT1和MAPKs在新型白黎芦醇防治皮肤光损伤机制中的作用

JNK and p38 MAPKs via upregulation MMPs play important roles in UV-induced photodamage. Previous studies focused on NF-κB, p53 acetylation, TGF-β2 and ROS to elaborate the mechanism of resveratrol's photoprovention effects. Recently, a novel resveratrol was developed and found to have advantages over traditonal one owing to its' special molecular structure. Our preliminarily studies have showed the protective effects of the novel resveratrol on UV-induced photodamages including sunburning, pigmenataion, immunosuppression, et al. The mechanism needs to be further determined. The present study will expose normal and SIRT1-silenced human skin fibroblast to UVA, the novel resveratrol, and MAPKs inhibitors, to elaborate whether the mechanism of resveratol on UVA-induced photodamage is through SIRT1 inhibiton of MAPKs pathways. Furthermore, wildtype and SIRT1 inhibitor-dealed C57BL/6 mice will be treated with UVA, the novel resveratrol, and MAPKs inhibitors, to verify above mechinism and to found optimal modality for UV-induced photodamage on mice skin. The study will provide theory evidence for the application and a new strategy of resveratrol on photodamage.

MAPKs信号通路中的JNK及p38在UV所致皮肤光损伤机制中发挥重要作用。以往关于白黎芦醇防护皮肤光损伤机制方面的研究着眼于NF-κB、p53乙酰化、TGF-β2、ROS等角度。最近问世一种新型白藜芦醇因分子结构特殊而具有不同于传统白藜芦醇的药理特点。本课题组前期研究发现这种新型白藜芦醇可防治UV诱导的皮肤晒红、黑素沉积、免疫抑制等光损伤表现。其具体作用机制需进一步明确。本研究拟采用UVA、新型白黎芦醇、MAPKs抑制剂作用于正常及沉默SIRT1基因的人皮肤成纤维细胞，阐明新型白黎芦醇防治UVA诱导的皮肤光损伤的分子机制是否通过SIRT1 抑制MAPKs通路实现的。另外，以UVA、新型白藜芦醇、MAPKs抑制剂处理野生型及SIRT1抑制剂干预的C57BL/6小鼠，动物水平证实上述机制并据此找到防治小鼠皮肤光损伤的最佳方案。本研究将为新型白藜芦醇防治光损伤提供理论依据及新的防治策略。

MAPKs信号通路中的JNK及p38在UV所致皮肤光损伤机制中发挥重要作用。本研究拟采用UVA、新型白黎芦醇、MAPKs抑制剂作用于正常及沉默SIRT1基因的人皮肤成纤维细胞，阐明新型白黎芦醇防治UVA诱导的皮肤光损伤的分子机制是否通过SIRT1 抑制MAPKs通路实现的。另外，处理野生型及SIRT1抑制剂干预的C57BL/6小鼠，动物水平证实上述机制并据此找到防治小鼠皮肤光损伤的最佳方案．.研究过程中发现，0.01mmol/L白藜芦醇可逆转UVA照射对细胞增殖活性的抑制作用并且降低细胞上清液中IL-1β蛋白的高表达，还可下调细胞NF-κB、MMP-1和MMP-3的mRNA表达并且对正常人成纤维细胞的细胞增值活性无影响。0.01 mmol/L白藜芦醇可下调细胞MMP-9的表达。此外动物实验部分，确定像素激光可以辅助白藜芦醇溶液传输，且可防治小鼠皮肤的急性光损伤。另外，抗氧化剂如硫辛酸可以在得宝松+NB-UVB的联合疗法治疗白癜风中加快白斑复色，但并不能影响最终的复色程度。Meta分析表明高水平的超氧化物歧化酶或丙二醛和白癜风有明显相干性。.本项目整个过程中，共发表论文3篇。其中2篇被SCI收录。分别为：.1..雷卫, 陈凰, 吴严等. 白藜芦醇对UVA照射人成纤维细胞的光保护作用. 中国麻风皮肤病杂志. 2015; 31(7): 387-391. 通讯作者.2..Li Li, Lu Li, Yan Wu, et al. Triple combination treatment with oral α-lipoic acid, betamethasone injection, and NB-UVB for non-segmental active vitiligo. J Cos Laser Ther. 2016 Jun;18(3):182-5. Co-Correspondence author. Epub 2016 Mar 8..3..Meihui Shi, Yan Wu, et al. Meta-Analysis of the association between level of SOD or MDA and vitiligo. Clin Exp Dermatol. Equal first author. Epub 2016 Oct 13.