内毒素血症是一种由脂多糖（LPS）感染引起的全身炎症反应和器官损伤的疾病，病死率高。尼卡拉韦（AVS）是一种高效的羟自由基清除剂，已被证明能调节肿瘤炎症反应。为了研究AVS在内毒素血症中的保护效应和机制，我们向小鼠腹腔注射LPS，诱导内毒素血症。AVS治疗显著降低了血清中前炎症细胞因子水平，减少了中性粒细胞浸润，减轻了多器官损伤，并提高了LPS挑战小鼠的生存率。在LPS诱导的巨噬细胞炎症模型中，AVS抑制了巨噬细胞活化，抑制了一氧化氮（NO）的产生，抑制了前炎症细胞因子的表达和分泌。在机制上，AVS治疗以时间和剂量依赖的方式上调了沉默信息调节因子转录本1（Sirt1）的表达。AVS治疗激活了AMP依赖的蛋白激酶（AMPK）/Sirt1信号通路，在暴露于LPS的巨噬细胞中抑制了核因子κB（NF-κB）的活化。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通过在巨噬细胞中激活AMPK/Sirt1信号通路缓解内毒素血症。版权所有©2023 Elsevier B.V.发表。

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.Copyright © 2023. Published by Elsevier B.V.