Hanieh Hamza, Alfwuaires Manal A
Department of Basic Humanities and Sciences, Faculty of Medicine, Aqaba Medical Sciences University, Aqaba, 77110, Jordan.
Biological Sciences Department, College of Science, King Faisal University, Hofuf, 31982, Saudi Arabia.
Inflammation. 2025 Apr 26. doi: 10.1007/s10753-025-02292-7.
Sepsis is a severe systemic inflammatory syndrome and one of the leading causes of global morbidity and mortality. Preclinical studies have identified several quinoxaline-based compounds with anti-inflammatory properties, but their effects in sepsis have not been investigated. This study aimed to identify a quinoxaline derivative with anti-inflammatory properties in sepsis. Examining the inflammatory response of primary mouse macrophages to Lipopolysaccharides (LPS) revealed that 2-methoxy-N-(3-quinoxalin-2-ylphenyl)benzamide (2-MQB) is a promising molecule. It suppressed the production of several inflammatory cytokines, including Interleukin-1β (IL-1β), IL-6, IL-12p70, Interferon-γ (IFN-γ), IFN-β, and Tumor necrosis factor-α (TNF-α). Importantly, 2-MQB inhibited the transcriptional activities of Toll-like receptor 4 (TLR4) signaling pathways, including Nuclear factor-κB (NF-κB) and Interferon regulatory factor 3 (IRF3). This was accompanied by lower expression of TLR4, Myeloid differentiation primary response 88 (MyD88), TIR Domain-containing adaptor molecule 1 (Trif), and TNF Receptor-associated factor 3 (Traf3). Additionally, 2-MQB selectively reduced the expression of genes encoding CD80, CD86, and Programmed death-ligand 1 (PD-L1). In vivo, 2-MQB improved mice survival, mitigated tissue damage in the spleen, kidney, and lung, and reduced pro-inflammatory cytokine levels in both LPS-induced endotoxin shock and Cecal ligation and puncture (CLP) models. Notably, 2-MQB decreased the numbers of CD4 and CD8 T cells in the spleen and inhibited TLR4 signaling pathways in LPS-induced endotoxemia. In conclusion, these results introduce the quinoxaline derivative 2-MQB as a potential therapeutic agent for sepsis by inhibiting TLR4 signaling pathways, paving the way for future clinical applications.
脓毒症是一种严重的全身性炎症综合征，也是全球发病和死亡的主要原因之一。临床前研究已鉴定出几种具有抗炎特性的喹喔啉类化合物，但尚未研究它们在脓毒症中的作用。本研究旨在鉴定一种在脓毒症中具有抗炎特性的喹喔啉衍生物。检测原代小鼠巨噬细胞对脂多糖（LPS）的炎症反应发现，2-甲氧基-N-(3-喹喔啉-2-基苯基)苯甲酰胺（2-MQB）是一种有前景的分子。它抑制了几种炎性细胞因子的产生，包括白细胞介素-1β（IL-1β）、IL-6、IL-12p70、干扰素-γ（IFN-γ）、IFN-β和肿瘤坏死因子-α（TNF-α）。重要的是，2-MQB抑制了Toll样受体4（TLR4）信号通路的转录活性，包括核因子-κB（NF-κB）和干扰素调节因子3（IRF3）。这伴随着TLR4、髓样分化初级反应88（MyD88）、含TIR结构域的接头分子1（Trif）和肿瘤坏死因子受体相关因子3（Traf3）表达的降低。此外，2-MQB选择性降低了编码CD80、CD86和程序性死亡配体1（PD-L1）的基因的表达。在体内，2-MQB提高了小鼠的存活率，减轻了脾脏、肾脏和肺部的组织损伤，并降低了LPS诱导的内毒素休克和盲肠结扎穿刺（CLP）模型中的促炎细胞因子水平。值得注意的是，2-MQB减少了脾脏中CD4和CD8 T细胞的数量，并抑制了LPS诱导的内毒素血症中的TLR4信号通路。总之，这些结果表明喹喔啉衍生物通过抑制TLR4信号通路，2-MQB作为脓毒症的潜在治疗药物，为未来的临床应用铺平了道路。
