基于Nrf2/HO-1参与调控线粒体受损—NLRP3炎症小体—焦亡信号通路探讨黄芩苷治疗NASH的机制研究

国内外最新研究指出焦亡是NASH发生的重要机制。当线粒体损伤时，可诱发NLRP3炎症小体活化，导致肝细胞焦亡和肝脏炎症的扩散。.前期研究发现黄芩对湿热证NASH有较好的临床疗效，其主要及有效成分为黄芩苷。预实验证实其可降低ROS-NLRP3炎症小体-焦亡信号通路的表达，但上游机制不清楚。经基因测序分析发现变化的基因主要聚焦于NLRs signal，Nrf2 signal，同时发现Nrf2/HO-1为氧化应激通道，可调控线粒体和ROS。因此，我们提出假说：黄芩苷可通过Nrf2/HO-1调控线粒体受损，改善NLRP3炎症小体诱发的细胞焦亡，达到治疗NASH的目的。.本研究将聚焦于肝细胞焦亡，首次将氧化应激系统和线粒体功能损伤、炎症小体-焦亡联系起来，拟采用siRNA干扰及基因敲除技术，透射电镜、Tunel、Wb及Rt-PCR等手段证明假说，明确黄芩苷的作用靶点，为NASH的防治提供新的思路。

Recent studies show that pyroptosis is the main mechanism for the development of NASH. Damaged mitochondria activate the NLRP3 inflammasomes,thus inducing pyroptosis and the spread of inflammation..Previous studies have found that Scutellaria baicalensis, the main component of which is baicalin, has good clinical effects on the treatment of NASH. Our preliminary research confirmed that baicalin could reduce the expression of ROS-NLRP3 inflammasomes-pyroptosis signaling pathway. However, the mechanism was unclear. By using the technology of Genetic sequencing, we verified that these changed genes were mainly focused on NLRs and Nrf2 signals. We also found that Nrf2/HO-1 was an oxidative stress channel to regulate mitochondria and the release of ROS. Therefore, our hypothesis is that baicalin, regulating the function of mitochondrion through Nrf2/HO-1, can reduce the pyroptosis induced by NLRP3 inflammasomes -pyroptosis signaling pathway ..This study will focus on the pyroptosis of hepatocytes, linking the oxidative stress system to mitochondrial dysfunction and pyroptosis for the first time.We intend to clarify our hypothesis by using siRNA interference and gene knockout techniques. It will help us to further study the pharmacological effects of baicalin and the treatment of NASH in a new light.