Experiment Center for Science and Technology, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
J Ethnopharmacol. 2015 Jul 1;169:210-8. doi: 10.1016/j.jep.2015.04.030. Epub 2015 Apr 25.
Astragaloside IV and cycloastragenol are present together in Astragalus membranaceus Moench (Fabaceae) and this study aims to simultaneously investigate their regulation of endothelial homeostasis in the setting of endoplasmic reticulum stress (ER stress).
We stimulated endothelial cells with palmitate (PA 100μM) to evoked ROS-associated ER stress and observed the effects of astragaloside IV and cycloastragenol on thioredoxin-interacting protein (TXNIP) expression, NLRP3 inflammasome activation and mitochondrion-dependent apoptosis.
Astragaloside IV and cycloastragenol inhibited ROS generation and attenuated ER stress inducer IRE1α phosphorylation, indicating the inhibition of ROS-associated ER stress. In response to ER stress, TXNIP expression increased, accompanied with NLRP3 induction and increased IL-1β and IL-6 production, but these alternations were reversed by treatment with astragaloside IV and cycloastragenol, demonstrating the inhibitory effects of astragaloside IV and cycloastragenol on TXNIP/NLRP3 inflammasome activation. Inflammasome activation led to mitochondrial cell death in endothelial cells, whereas astragaloside IV and cycloastragenol restored the loss of the mitochondrial membrane potential with inhibition of caspase-3 activity, and thereby protected cells from ER stress-induced apoptosis. Astragaloside IV and cycloastragenol enhanced AMPK phosphorylation and AMPK inhibitor compound C diminished their beneficial effects, indicative of the potential role of AMPK in their regulation.
Astragaloside IV and cycloastragenol suppressed ROS-associated ER stress and then inhibited TXNIP/NLRP3 inflammasome activation with regulation of AMPK activity, and thereby ameliorated endothelial dysfunction by inhibiting inflammation and reducing cell apoptosis. Simultaneous investigations further showed that astragaloside IV and cycloastragenol were equally effective in regulation of endothelial homeostasis.
黄芪甲苷和环黄芪醇共同存在于黄芪（豆科）中，本研究旨在同时研究它们对内质网应激（ER 应激）条件下内皮细胞稳态的调节作用。
我们用棕榈酸（PA 100μM）刺激内皮细胞，引起 ROS 相关的 ER 应激，并观察黄芪甲苷和环黄芪醇对硫氧还蛋白相互作用蛋白（TXNIP）表达、NLRP3 炎性体激活和线粒体依赖性细胞凋亡的影响。
黄芪甲苷和环黄芪醇抑制 ROS 的产生，并减弱 ER 应激诱导剂 IRE1α 的磷酸化，表明其抑制 ROS 相关的 ER 应激。在 ER 应激下，TXNIP 的表达增加，伴随着 NLRP3 的诱导和 IL-1β 和 IL-6 的产生增加，但这些改变被黄芪甲苷和环黄芪醇的处理所逆转，表明黄芪甲苷和环黄芪醇对 TXNIP/NLRP3 炎性体激活的抑制作用。炎性体激活导致内皮细胞中线粒体细胞死亡，而黄芪甲苷和环黄芪醇通过抑制 caspase-3 活性恢复线粒体膜电位的丧失，从而保护细胞免受 ER 应激诱导的凋亡。黄芪甲苷和环黄芪醇增强 AMPK 的磷酸化，而 AMPK 抑制剂化合物 C 削弱了它们的有益作用，表明 AMPK 在它们的调节中可能起作用。
黄芪甲苷和环黄芪醇抑制 ROS 相关的 ER 应激，然后抑制 TXNIP/NLRP3 炎性体激活，调节 AMPK 活性，从而通过抑制炎症和减少细胞凋亡来改善内皮功能障碍。同时的研究进一步表明，黄芪甲苷和环黄芪醇在调节内皮细胞稳态方面同样有效。
