Department of Psychiatry, Renmin Hospital of Wuhan University, Wuhan 430060, China.
Department of Psychiatry, Renmin Hospital of Wuhan University, Wuhan 430060, China.
Int Immunopharmacol. 2021 Feb;91:107298. doi: 10.1016/j.intimp.2020.107298. Epub 2020 Dec 31.
Oridonin (Ori) has multiple biological properties, especially anti-inflammatory. However, its effects on chronic unpredictable mild stress (CUMS)-induced insulin resistance are still unclear. In this study, we explored the regulatory role of Ori in CUMS-triggered insulin resistance, and the underlying molecular mechanisms; Methods: SD rats were subjected to CUMS for 4 weeks, some of which were injected with Ori or fluoxetine (FLX) in durations of CUMS. After CUMS procedure, the behavioral and metabolic tests were performed. Elisa, immunofluorescence and western blotting were used to determine the inflammatory response and NLRP3 inflammasome activation. We investigated the interaction between NLRP3 and NEK7 using immunoprecipitation. Finally, we detected the proinflammatory cytokines in Lipopolysaccharide (LPS)-activated RAW264.7 cells treated with Ori; RESULTS: In this study, we found that chronic stress resulted in depressive-like behavior comorbid with insulin resistance. Ori was discovered to ameliorate insulin resistance as well as insulin signaling disturbance in the hippocampus. In addition, CUMS caused the infiltration of macrophages into the islets. And IL-1β, IL-18 and caspase-1 were elevated in pancreases of CUMS rats, which could also be reversed by Ori treatment via reducing the interaction between NLRP3 and NEK7. Furthermore, Ori dose-dependently inhibited the levels of IL-1β and IL-18 in LPS-activated RAW264.7 cells; CONCLUSIONS: All these results supported our hypothesis that Ori possesses potent anti-insulin resistant actions, which is partially correlated with inhibiting infiltration of macrophages into the islets and NLRP3 activation induced by CUMS. Therefore, our results highlighted the protective role of Ori against CUMS-elicited insulin resistance.
冬凌草甲素（Ori）具有多种生物学特性，尤其具有抗炎作用。然而，其对慢性不可预测轻度应激（CUMS）诱导的胰岛素抵抗的影响尚不清楚。在这项研究中，我们探讨了 Ori 在 CUMS 触发的胰岛素抵抗中的调节作用及其潜在的分子机制；方法：SD 大鼠接受 CUMS 处理 4 周，其中一些在 CUMS 期间注射 Ori 或氟西汀（FLX）。CUMS 程序后，进行行为和代谢测试。使用 Elisa、免疫荧光和 Western blot 来确定炎症反应和 NLRP3 炎性体激活。我们使用免疫沉淀来研究 NLRP3 和 NEK7 之间的相互作用。最后，我们检测了 Ori 处理的脂多糖（LPS）激活的 RAW264.7 细胞中的促炎细胞因子；结果：在这项研究中，我们发现慢性应激导致抑郁样行为伴胰岛素抵抗。发现 Ori 可改善海马胰岛素抵抗和胰岛素信号紊乱。此外，CUMS 导致巨噬细胞浸润胰岛。CUMS 大鼠胰腺中 IL-1β、IL-18 和 caspase-1 升高，Ori 治疗可通过减少 NLRP3 和 NEK7 之间的相互作用来逆转这种升高。此外，Ori 呈剂量依赖性抑制 LPS 激活的 RAW264.7 细胞中 IL-1β 和 IL-18 的水平；结论：所有这些结果都支持我们的假设，即 Ori 具有强大的抗胰岛素抵抗作用，这部分与抑制 CUMS 诱导的巨噬细胞浸润胰岛和 NLRP3 激活有关。因此，我们的结果强调了 Ori 对 CUMS 引起的胰岛素抵抗的保护作用。
