Lian Wenwen, Yuan Xiaotang, Zhou Fulin, Tong Zhuohang, Cheng Yungchi, Zhang Weiku, He Jun, Xu Jiekun
School of Life Science, Beijing University of Chinese Medicine, Beijing, 100029, People's Republic of China; Institute of Clinical Medical Sciences & Department of Pharmacy, China-Japan Friendship Hospital, Beijing, 100029, People's Republic of China.
School of Life Science, Beijing University of Chinese Medicine, Beijing, 100029, People's Republic of China.
J Ethnopharmacol. 2025 Sep 15;355(Pt A):120615. doi: 10.1016/j.jep.2025.120615.
Corni fructus are the fruits of Cornus officinalis Sieb. et Zucc. and is widely used in traditional Chinese Medicine for the treatment of dementia. Cornuside, derived from Corni fructus, has been shown to be effective in improving cognition of AD mouse.
In the present study, we investigated the effect of cornuside on cognitive dysfunction and microglial NLRP3 inflammasome activation, as well as explored the underlying mechanism with respect to Sirt1 and autophagy.
AD mice were established and then treated with cornuside (3, 10, and 30 mg/kg) for 2 weeks. A series of behavioral tests were performed to assess cognition, including the Morris water maze, Y maze, nest building, step-down and step-through tests. Nissl staining was used to evaluate neuronal structural damage. LPS-stimulated BV2 cells were used for in vitro experiments. The anti-inflammatory effects of cornuside on cytokines and NLRP3 inflammasome activation were assessed using ELISA, RT-PCR, immunohistochemistry, western blotting, and immunofluorescence assays. To further elucidate the relationship between Sirt1, autophagy, and NLRP3 inflammasome activation, EX527 and 3-MA were used to inhibit Sirt1 and block autophagy flux in vitro, respectively.
Cornuside significantly improved various behavioral performance and inhibited NLRP3 inflammasome activation in LPS-induced mice, as evidenced by decreased levels of NLRP3, ASC, pro-caspase1, caspase1, pro-IL-1β, IL-1β, GSDMD, GSDMD-NT and IL-18. Similar inhibitory effects of cornuside on NLRP3 inflammasome activation was also detected in LPS stimulated BV2 cells. The involvement of Sirt1 and autophagy were further explored in-vivo and in-vitro, revealing that cornuside increased the expression of Sirt1 and enhanced autophagy, with decreased SQSTM1/p62 and increased LC3BII. However, the inhibitory effect of cornuside on NLRP3 inflammasome activation was abrogated by 3-MA, and the effects of cornuside on promoting autophagy and inhibiting NLRP3 inflammasome activation was abolished by EX527.
Cornuside exerts therapeutic effects on LPS induced AD mice by inhibiting microglial activation and NLRP3 inflammasome overactivation. And Sirt1 mediated autophagy activation is a vital mechanism by which cornuside degrades NLRP3 inflammasome, thereby alleviating neuroinflammation and improving cognitive function.
山茱萸为山茱萸科植物山茱萸的果实，在传统中药中广泛用于治疗痴呆症。从山茱萸中提取的山茱萸苷已被证明可有效改善阿尔茨海默病小鼠的认知能力。
在本研究中，我们研究了山茱萸苷对认知功能障碍和小胶质细胞NLRP3炎性小体激活的影响，并探讨了其与Sirt1和自噬相关的潜在机制。
建立阿尔茨海默病小鼠模型，然后用山茱萸苷（3、10和30mg/kg）治疗2周。进行了一系列行为测试以评估认知能力，包括莫里斯水迷宫、Y迷宫、筑巢、跳台和穿梭箱测试。尼氏染色用于评估神经元结构损伤。用脂多糖刺激的BV2细胞进行体外实验。使用酶联免疫吸附测定、逆转录-聚合酶链反应、免疫组织化学、蛋白质免疫印迹和免疫荧光分析评估山茱萸苷对细胞因子和NLRP3炎性小体激活的抗炎作用。为了进一步阐明Sirt1、自噬和NLRP3炎性小体激活之间的关系，分别使用EX527和3-甲基腺嘌呤在体外抑制Sirt1并阻断自噬通量。
山茱萸苷显著改善了各种行为表现，并抑制了脂多糖诱导的小鼠中NLRP3炎性小体的激活，NLRP3、凋亡相关斑点样蛋白、前半胱天冬酶1、半胱天冬酶1、前白细胞介素-1β、白细胞介素-1β、Gasdermin D、Gasdermin D-N端和白细胞介素-18水平降低证明了这一点。在脂多糖刺激的BV2细胞中也检测到山茱萸苷对NLRP3炎性小体激活的类似抑制作用。在体内和体外进一步探讨了Sirt1和自噬的参与情况，结果表明山茱萸苷增加了Sirt1的表达并增强了自噬，p62/sequestosome 1水平降低，微管相关蛋白1轻链3-II水平升高。然而，3-甲基腺嘌呤消除了山茱萸苷对NLRP3炎性小体激活的抑制作用，EX527消除了山茱萸苷促进自噬和抑制NLRP3炎性小体激活的作用。
山茱萸苷通过抑制小胶质细胞激活和NLRP3炎性小体过度激活对脂多糖诱导的阿尔茨海默病小鼠发挥治疗作用。Sirt1介导的自噬激活是山茱萸苷降解NLRP3炎性小体从而减轻神经炎症和改善认知功能的重要机制。
