黄芩素激活Nrf2/HO-1通路在改善线粒体功能增强白癜风黑素细胞抗氧化应激能力中的作用机制研究

Patients with vitiligo have been enduring great suffering due to its poorly understood etiology and limited effective therapies. Studies reported that oxidative stress closely associates with vitiligo. Mitochondria dysfunction produces excess ROS, therefore mitochondria dysfunction in epithelial cells may play an important role in the pathogenesis of vitiligo. Nrf2/HO-1 is a critical signaling pathway that can protect against oxidative damage and alleviate mitochondria dysfunction. We reported earlier that HO-1 was found a critical molecule in protecting melanocytes against oxidative damage, and Nrf2 activation disorder was identified as a main cause of oxidative damage to VMC in vitiligo. Baicalein functions as an antioxidant, which protects melanocytes against oxidative stress by inhibiting mitochondria apoptosis and activating Nrf2/HO-1 signaling pathway. We therefore infer that baicalein may activate the Nrf2/HO-1 signaling pathway and thereby improves mitochondria functions along with the oxidation resistance of melanocytes. The present study aims to explore the functions and mechanism of baicalein activation to Nrf2/HO-1 pathway in the improvement of mitochondria functions and VMC oxidation resistance, therefore identify the correlation between melanocyte mitochondria dysfunction and vitiligo. This study provides a theoretical foundation to Nrf2/HO-1 as a therapeutic target in the treatment of baicalein to vitiligo.

白癜风多发、难治。研究表明，氧化应激与白癜风发病密切相关。线粒体功能发生障碍时将产生过量的ROS。白癜风表皮细胞线粒体功能障碍与白癜风发病相关。Nrf2/HO-1是细胞抗氧化损伤的主要通路，在改善线粒体功能障碍中发挥重要作用。我们前期研究发现HO-1是保护黑素细胞抗氧化损伤的关键分子，Nrf2转录活性降低是白癜风患者黑素细胞(VMC)易发生氧化损伤的主要原因之一。黄芩素具有抗氧化作用，可通过抑制线粒体凋亡途径及激活Nrf2/HO-1信号通路对抗氧化应激对黑素细胞的损伤。我们推测黄芩素可能通过激活Nrf2/HO-1通路改善线粒体功能，增强黑素细胞抗氧化能力。本项目拟以VMC 为研究对象，研究黄芩素激活Nrf2/HO-1通路在改善线粒体功能障碍、增强VMC抗氧化能力中的作用和机制，阐明黑素细胞线粒体功能障碍与白癜风发病的关系，为以Nrf2/HO-1为靶点应用黄芩素治疗白癜风奠定基础。

白癜风是一种常见的以黑素细胞被破坏而引起的色素脱失性皮肤病，该病治疗棘手且发病率呈逐年上升趋势。已有研究表明，氧化应激诱导的黑素细胞损伤与白癜风发病密切相关。Nrf2通路是细胞抗氧化损伤的重要通路，具有改善线粒体功能障碍的作用。我们的前期研究发现Nrf2通路的靶基因HO-1 是保护黑素细胞抗氧化损伤的关键分子，同时我们发现黄芩素具有增强黑素细胞抗氧化的作用。因此我们推测黄芩素可能通过激活Nrf2通路改善线粒体功能，从而增强白癜风黑素细胞抗氧化的能力。本项目研究了黄芩素激活Nrf2通路在改善线粒体功能障碍、增强白癜风黑素细胞抗氧化能力中的作用和机制，研究发现：1、白癜风黑素细胞Nrf2通路异常受损，对过氧化氢更敏感；2、过表达Nrf2促进白癜风黑素细胞线粒体生物合成和功能；3、黄芩素减轻氧化应激对白癜风黑素细胞线粒体超微结构和功能的损害，增强白癜风黑素细胞抗氧化能力；4、黄芩素上调Nrf2通路，促进线粒体合成相关基因（NRF1、TFAM）的表达；5、在白癜风黑素细胞中干涉Nrf2蛋白抑制细胞增殖、增加细胞对H2O2的敏感性；6、在氧化应激下黄芩素通过激活Nrf2 信号通路改善白癜风黑素细胞线粒体的功能障碍增强细胞抗氧化能力。本研究为临床上以Nrf2通路为靶点应用黄芩素治疗白癜风提供了理论和实验基础。