National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang, 330031, China.
Department of Stem Cell Biology, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan.
Eur J Pharmacol. 2023 May 5;946:175666. doi: 10.1016/j.ejphar.2023.175666. Epub 2023 Mar 20.
Endotoxemia is a disease characterized by systemic inflammatory responses and organ injury caused by lipopolysaccharide (LPS) infection, with high mortality. Nicaraven (AVS), a potent hydroxyl radical scavenger, has been proven to regulate the inflammatory response in tumors. To investigate the protective effects and mechanisms of AVS in endotoxemia, mice were injected intraperitoneally with LPS to induce endotoxemia. AVS treatment significantly decreased the levels of pro-inflammatory cytokines in the serum, reduced neutrophil infiltration, attenuated multiple organ injury, and increased the survival rate in LPS-challenged mice. In the LPS-induced inflammatory model of macrophages, AVS inhibited macrophage activation, suppressed nitric oxide (NO) production, and inhibited the expression and secretion of pro-inflammatory cytokines. Mechanistically, AVS treatment up-regulated silence information regulator transcript-1 (Sirt1) expression in a time- and dose-dependent manner. AVS treatment activated the AMP-dependent protein kinase (AMPK)/Sirt1 signaling pathway and suppressed the activation of nuclear factor kappa B (NF-κB) in macrophages exposed to LPS. However, the anti-inflammatory effects of AVS could be reversed by the AMPK, the Sirt1 inhibitor, or the histone deacetylase inhibitor. We confirmed that the AMPK inhibitor inhibited AVS-mediated AMPK/Sirt1 activation and NF-κB p65 acetylation. These results suggested that AVS alleviated endotoxemia by activating the AMPK/Sirt1 signaling pathway in macrophages.
内毒素血症是一种由脂多糖（LPS）感染引起的全身性炎症反应和器官损伤的疾病，死亡率很高。Nicaraven（AVS）是一种有效的羟自由基清除剂，已被证明可调节肿瘤中的炎症反应。为了研究 AVS 在内毒素血症中的保护作用和机制，我们用 LPS 腹腔注射诱导内毒素血症小鼠模型。AVS 治疗显著降低了血清中促炎细胞因子的水平，减少了中性粒细胞浸润，减轻了多器官损伤，并提高了 LPS 攻击小鼠的存活率。在 LPS 诱导的巨噬细胞炎症模型中，AVS 抑制了巨噬细胞的激活，抑制了一氧化氮（NO）的产生，并抑制了促炎细胞因子的表达和分泌。机制上，AVS 治疗以时间和剂量依赖的方式上调沉默信息调节转录物 1（Sirt1）的表达。AVS 治疗激活了 LPS 暴露的巨噬细胞中 AMP 依赖的蛋白激酶（AMPK）/Sirt1 信号通路，并抑制了核因子 kappa B（NF-κB）的激活。然而，AVS 的抗炎作用可以被 AMPK、Sirt1 抑制剂或组蛋白去乙酰化酶抑制剂逆转。我们证实，AMPK 抑制剂抑制了 AVS 介导的 AMPK/Sirt1 激活和 NF-κB p65 乙酰化。这些结果表明，AVS 通过激活巨噬细胞中的 AMPK/Sirt1 信号通路缓解内毒素血症。
