Inflammation and an increase in antioxidant responses mediated by oxidative stress play an important role in the pathogenesis of acute liver injury (ALI). We utilized in silico prediction of biological activity spectra for substances (PASS) analysis to estimate the potential biological activity profile of deethylated ethoxyquin (DEQ) and hypothesized that DEQ exhibits antioxidant and anti-inflammatory effects in a rat model of carbon tetrachloride (CCl₄)-induced ALI. Our results demonstrate that DEQ improved liver function which was indicated by the reduction of histopathological liver changes. Treatment with DEQ reduced CCl₄-induced elevation of gene expression, and the activity of antioxidant enzymes (AEs), as well as the expression of transcription factors Nfe2l2 and Nfkb2. Furthermore, DEQ treatment inhibited apoptosis, downregulated gene expression of pro-inflammatory cytokines (Tnf and Il6), cyclooxygenase 2 (Ptgs2), decreased glutathione (GSH) level and myeloperoxidase (MPO) activity in rats with ALI. Notably, DEQ treatment led to an inhibition of CCl₄-induced NLRP3-inflammasome activation which was indicated by the reduced protein expression of IL-1β, caspase-1, and NLRP3 in the liver. Our data suggest that DEQ has a hepatoprotective effect mediated by redox-homeostasis regulation, NLRP3 inflammasome, and apoptosis inhibition, which makes that compound a promising candidate for future clinical studies.

中文翻译：

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新型抗氧化剂，去乙基乙氧基喹，通过抑制NLRP3炎性体激活和凋亡，防止四氯化碳诱导的大鼠肝毒性。

炎症和氧化应激介导的抗氧化反应的增强在急性肝损伤（ALI）的发病机理中起着重要作用。我们利用计算机对物质的生物活性谱的计算机模拟（PASS）分析来估计脱乙基乙氧基喹啉（DEQ）的潜在生物活性谱，并假设DEQ在四氯化碳（CCl ₄）大鼠模型中表现出抗氧化和抗炎作用诱导的ALI。我们的结果表明DEQ改善了肝功能，这是由组织病理学肝脏改变的减少所表明的。DEQ处理可降低CCl ₄诱导的基因表达升高，抗氧化酶（AEs）活性以及转录因子Nfe2l2的表达和Nfkb2。此外，DEQ处理可抑制ALI大鼠的凋亡，促炎性细胞因子（Tnf和Il6），环氧合酶2（Ptgs2）的基因表达下调，谷胱甘肽（GSH）水平降低和髓过氧化物酶（MPO）活性降低。值得注意的是，DEQ处理可抑制CCl ₄诱导的NLRP3-炎症小体活化，这可通过肝脏中IL-1β，caspase-1和NLRP3的蛋白表达降低来表明。我们的数据表明DEQ具有由氧化还原稳态调节，NLRP3炎性体和凋亡抑制介导的肝保护作用，这使该化合物成为未来临床研究的有希望的候选者。