Iskusnykh Igor Y, Kryl'skii Evgenii D, Brazhnikova Darya A, Popova Tatyana N, Shikhaliev Khidmet S, Shulgin Konstantin K, Matasova Larisa V, Popov Sergey S, Zhaglin Dmitry A, Zakharova Anastasia A, Popova Nelli R, Fattakhov Nikolai
Department of Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Department of Medical Biochemistry and Microbiology, Voronezh State University, Universitetskaya sq. 1, Voronezh 394018, Russia.
Antioxidants (Basel). 2021 Jan 15;10(1):122. doi: 10.3390/antiox10010122.
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 (CCl)-induced ALI. Our results demonstrate that DEQ improved liver function which was indicated by the reduction of histopathological liver changes. Treatment with DEQ reduced CCl-induced elevation of gene expression, and the activity of antioxidant enzymes (AEs), as well as the expression of transcription factors and . Furthermore, DEQ treatment inhibited apoptosis, downregulated gene expression of pro-inflammatory cytokines ( and ), cyclooxygenase 2 (), decreased glutathione (GSH) level and myeloperoxidase (MPO) activity in rats with ALI. Notably, DEQ treatment led to an inhibition of CCl-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.
炎症以及由氧化应激介导的抗氧化反应增加在急性肝损伤（ALI）的发病机制中起重要作用。我们利用物质生物活性谱的计算机预测（PASS）分析来评估脱乙基乙氧喹（DEQ）的潜在生物活性概况，并假设DEQ在四氯化碳（CCl）诱导的ALI大鼠模型中具有抗氧化和抗炎作用。我们的结果表明，DEQ改善了肝功能，这通过肝组织病理学变化的减轻得以体现。DEQ处理降低了CCl诱导的基因表达升高、抗氧化酶（AE）活性以及转录因子的表达。此外，DEQ处理抑制了凋亡，下调了ALI大鼠促炎细胞因子（和）、环氧化酶2（）的基因表达，降低了谷胱甘肽（GSH）水平和髓过氧化物酶（MPO）活性。值得注意的是，DEQ处理导致对CCl诱导的NLRP3炎性小体激活的抑制，这通过肝脏中IL-1β、半胱天冬酶-1和NLRP3蛋白表达的降低得以体现。我们的数据表明，DEQ具有通过氧化还原稳态调节、NLRP3炎性小体和凋亡抑制介导的肝保护作用，这使得该化合物成为未来临床研究的有希望的候选物。
