Sepsis is one of the most severe complications and causes of mortality in the clinic. It remains a great challenge with no effective treatment for clinicians worldwide. Inhibiting the release of proinflammatory cytokines during sepsis is considered as an important strategy for treating sepsis and improving survival. In the present study, we have observed the effect of dimethyl fumarate (DMF) on lipopolysaccharide- (LPS-) induced sepsis and investigated the possible mechanism. By screening a subset of the Johns Hopkins Drug Library, we identified DMF as a novel inhibitor of nitric oxide synthesis in LPS-stimulated RAW264.7 cells, suggesting that DMF could be a potential drug to treat sepsis. To further characterize the effect of DMF on LPS signaling, TNF-α, MCP-1, G-CMF, and IL-6 expression levels were determined by using cytokine array panels. In addition, an endotoxemia model with C57BL/6 mice was used to assess the in vivo efficacy of DMF on sepsis. The survival rate was assessed, and HE staining was performed to investigate histopathological damage to the organs. DMF was found to increase the survival of septic mice by 50% and attenuate organ damage, consistent with the reduction in IL-10, IL-6, and TNF-α (inflammatory cytokines) in serum. In vitro experiments revealed DMF’s inhibitory effect on the phosphorylation of p65, IκB, and IKK, suggesting that the primary inhibitory effects of DMF can be attributed, at least in part, to the inhibition of phosphorylation of IκBα, IKK as well as nuclear factor-κB (NF-κB) upon LPS stimulation. The findings demonstrate that DMF dramatically inhibits NO and proinflammatory cytokine production in response to LPS and improves survival in septic mice, raising the possibility that DMF has the potential to be repurposed as a new treatment of sepsis.

中文翻译：

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富马酸二甲酯通过抑制 NF-κB 通路预防小鼠脂多糖 (LPS-) 诱导的脓毒症

脓毒症是临床上最严重的并发症和死亡原因之一。对于全世界的临床医生来说，目前还没有有效的治疗方法，这仍然是一个巨大的挑战。抑制脓毒症期间促炎细胞因子的释放被认为是治疗脓毒症和提高生存率的重要策略。在本研究中，我们观察了富马酸二甲酯（DMF）对脂多糖（LPS）诱导的败血症的作用，并研究了可能的机制。通过筛选约翰霍普金斯大学药物库的一个子集，我们确定 DMF 是 LPS 刺激的 RAW264.7 细胞中一氧化氮合成的新型抑制剂，这表明 DMF 可能是治疗脓毒症的潜在药物。为了进一步表征 DMF 对 LPS 信号传导的影响，使用细胞因子阵列组测定了TNF- α 、MCP-1、G-CMF 和 IL-6 表达水平。此外，使用 C57BL/6 小鼠的内毒素血症模型来评估 DMF 对脓毒症的体内功效。评估存活率，并进行HE染色以研究器官的组织病理学损伤。研究发现 DMF 可使脓毒症小鼠的存活率提高 50%，并减轻器官损伤，这与血清中IL-10、IL-6 和 TNF- α （炎症细胞因子）的减少一致。体外实验揭示了 DMF 对 p65、 IκB和 IKK磷酸化的抑制作用，表明 DMF 的主要抑制作用至少部分归因于对 IκBα、IKK 磷酸化的抑制以及 LPS 刺激后的核因子-κ B (NF -κ B)。研究结果表明，DMF 可显着抑制 LPS 反应中 NO 和促炎细胞因子的产生，并提高脓毒症小鼠的存活率，这提高了 DMF 有可能重新用作脓毒症新治疗方法的可能性。