青蒿烯的抗氧化分子机理及其保护作用

Keap1-Nrf2 signaling pathway is the most important antioxidant defense responses system. Keap1-Nrf2 signaling pathway targeted therapies have important application prospects for the prevention, delay and treatment of oxidative stress-associated diseases such as cancer, inflammation, neurodegenerative diseases, cardiovascular diseases, diabetes and so on. Recently, we screened a chemical library and selected a novel small molecule chemical inducer for Nrf2 ,annua ene, that can activate Nrf2, and protect cells from oxidative stress. In this study, We will take a step forward to reveal the antioxidant molecular mechanism of annua ene targeting Keap1-Nrf2 signaling pathway. Based on this,, we will further investigate the antioxidant protective effect of annua ene in bleomycin-induced lung injury mouse model. We assume that annua ene targets Keap1 or induces modification of Keap1, thus contributing to the stability of Nrf2, enhancing antioxidant capacity and function of cells. As a chemical molecules with potential medicinal value, it is very significant to reveal its antioxidant molecular mechanism and validate its antioxidant protective effect in mouse.

Keap1-Nrf2信号通路是高等生物最重要的抗氧化防卫反应 (anti-oxidant defense response)系统. Keap1-Nrf2信号通路的靶向疗法，对于预防、延缓和治疗与氧化应激相关的疾病如癌症、炎症、神经退行性疾病、心血管疾病、糖尿病等，有着非常重要的应用前景。最近，我们定向筛选到一个新的Nrf2的小分子化学诱导子青蒿烯，能有效激活Nrf2,抵抗氧化应激。本研究将近一步揭示青蒿烯靶向激活Keap1-Nrf2信号通路的分子机理，在此基础上，进一步验证青蒿烯在个体水平上的抗氧化保护效应，如对博莱霉素（Bleomycin）诱导的肺损伤的阻抑作用。我们假设青蒿烯打靶Keap1或诱导Keap1的修饰，从而促进Nrf2的稳定，增强细胞的抗氧化能力和功能。青蒿稀作为一个潜在的具有药用价值的化学分子，有关它的抗氧化分子机理的研究及鼠模型的试验具有非常重要的意义。

Nrf2是人体抗氧化防卫反应的主要调节子，Nrf2的激活已经被证实能够预防环境有毒物质对人体组织的损害，预防和抑制氧化应急相关的疾病。青蒿烯是我们先前鉴定出的一个新的Nrf2化学激活剂。在这项研究中，我们探索了青蒿烯激活Nrf2的分子机制，并且在细胞和老鼠模型上证实了其抗氧化保护作用。青蒿烯以Keap1Cys151依赖的方式，抑制Nrf2的多聚泛素化修饰，增强Nrf2的稳定性，从而激活Nrf2介导的抗氧化下游效应。在老鼠模型中，青蒿烯能有效地抑制帕莱霉素（BLM）诱导的肺组织损伤，炎性反应和肺纤维化。这项研究表明，青蒿烯有可能被用作人体预防和抑制与氧化应激相关的各种疾病。