基于HMGB1-TLR4介导的NF-κB信号通路探讨毛蕊异黄酮在脑缺血再灌注损伤中的保护机制

脑缺血再灌注损伤是一种复杂的病理生理过程，针对关键靶点对其进行有效防治是国内外研究的热点。有研究表明，NF-κB信号通路的激活在缺血再灌注炎性损伤中发挥着重要作用。我们研究发现，植物雌激素毛蕊异黄酮可降低HMGB1、TLR4、NF-κB表达，减轻炎性反应和抗凋亡，对大鼠脑缺血再灌注损伤具有保护作用。毛蕊异黄酮的这一作用是否与其对HMGB1-TLR4介导的NF-κB信号通路的调控有关，值得深入探讨。故提出假设：脑缺血再灌注后由缺血性损伤向炎症性损伤转变的过程中，与炎症相关的HMGB1-TLR4-NF-κB信号通路的激活可促进脑组织免疫炎性反应和细胞凋亡，毛蕊异黄酮可能通过抑制该信号通路而发挥作用。本课题拟通过在神经细胞和动物脑内过表达或沉默HMGB1-TLR4-NF-κB通路中的关键信号分子，探讨其在脑缺血再灌注损伤中的作用及毛蕊异黄酮的治疗机制，为缺血性脑卒中的防治开拓新思路。

The pathophysiological mechanisms underlying cerebral ischemia/reperfusion (I/R) injury have been proved to be complex, and a hotspot of current researches is searching for the promising targets in the prevention and treatment of stroke. It has reported that NF-κB signaling pathway plays a pivotal role in the pathological inflammatory damage process of I/R injury. We have found that calycosin, a typical phytoestrogen, exhibited anti-inflammatory and anti-apoptosis effects by decreasing the expression of HMGB1, TLR4 and NF-κB, subsequently improving the brain function in cerebral I/R rats. However, it deserves further research whether the neuroprotective effect of calycosin is related to the modulation of HMGB1-TLR4-NF-κB signaling pathway in cerebral I/R injury. Therefore, we proposed the following assumption: in the process of transition from focal ischemia to inflammatory injury, the activation of HMGB1-TLR4-NF-κB signaling pathway can lead to immune inflammatory reaction and apoptosis in brain tissue, and the neuroprotective effect of calycosin probably related to inhibiting this signaling pathway. The projects aims to, through overexpressing and silencing the key molecules in the HMGB1-TLR4-NF-κB signaling pathway, explore its roles in cerebral I/R injury and the therapeutical mechanism of calycosin, which provide theoretical basis and new ideas on the application of calycosin in the treatment of ischemic stroke.