Background

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.

中文翻译：

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冬凌草甲素通过抑制慢性不可预测的温和应激大鼠的炎症反应来部分改善胰岛素抵抗

 背景

冬凌草甲素 (Ori) 具有多种生物学特性，尤其是抗炎特性。然而，其对慢性不可预测温和应激（CUMS）引起的胰岛素抵抗的影响仍不清楚。在本研究中，我们探讨了Ori在CUMS引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治疗4周，其中部分大鼠在CUMS期间注射Ori或氟西汀（FLX）。 CUMS 程序后，进行行为和代谢测试。采用Elisa、免疫荧光和蛋白质印迹法测定炎症反应和NLRP3炎性体激活。我们使用免疫沉淀研究了 NLRP3 和 NEK7 之间的相互作用。最后，我们检测了用 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，我们发现慢性压力会导致抑郁样行为，并伴有胰岛素抵抗。人们发现 Ori 可以改善胰岛素抵抗以及海马体中的胰岛素信号传导紊乱。此外，CUMS 导致巨噬细胞浸润到胰岛中。 CUMS 大鼠胰腺中 IL-1β、IL-18 和 caspase-1 升高，Ori 治疗也可以通过减少 NLRP3 和 NEK7 之间的相互作用来逆转这种情况。此外，Ori 剂量依赖性地抑制 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 具有有效的抗胰岛素抵抗作用，这部分与抑制巨噬细胞向胰岛的浸润和 CUMS 诱导的 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。