Liver fibrosis is a common pathological consequence of liver injury, which increases liver failure-related morbidity and mortality. Hence, anti-fibrotic treatment is urgently needed. Oxidative stress plays a pivotal role in the progression of liver fibrosis. Thus, targeting ROS may be an effective strategy for liver fibrosis treatment. In this study, we investigated four benzoquinones derivatives, including 5-isopropyl-2-methyl-1,4-benzoquinone (TQ), 2-tert-butyl-1,4-benzoquinone (tBu-Q) 2,5-dimethyl-p-benzoquinone (Dime-Q) and p-benzoquinone (Ph-Q), as well as the evaluation of their antioxidant activity and anti-fibrotic effects on activated hepatic stellate cells and TAA-induced mice. Electrochemical analysis showed that all compounds possessed antioxidant property. The result was first confirmed by in vitro experiments, which revealed potential anti-fibrotic activity of all four compounds at the cellular level. Benzoquinone derivatives act as ROS-scavenging molecules, which modulated the TLR4-CD14 signaling pathway to inhibit the expression of procaspase-1 and IL-1β in cells, induced apoptosis via a mitochondrial pathway by upregulating the ratio of Bax/Bcl-2 and by activating caspase-3, as well as inhibited the expression of the anti-apoptotic proteins FLIP and XIAP in activated LX-2 cells. In addition, a TAA (Thioacetamide)-induced mouse model was used to further validate the results. Treatment with benzoquinone derivatives significantly decreased the levels of liver injury markers and lipid peroxidation caused by excessive ROS, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), and malondialdehyde (MDA). Moreover, treatment with benzoquinone derivatives significantly inhibited extracellular matrix (ECM) deposition and downregulated the mRNA and protein expression of liver fibrosis markers, such as collagen I, alpha-smooth muscle actin (α-SMA), and TIMP-1. In summary, these results indicate that benzoquinone derivatives may act as potential therapeutic drugs against liver fibrosis.

中文翻译：

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具有抗氧化活性的苯醌衍生物可抑制TAA诱导的小鼠肝星状细胞活化并减轻肝纤维化。

肝纤维化是肝损伤的常见病理结果，它会增加与肝衰竭相关的发病率和死亡率。因此，迫切需要抗纤维化治疗。氧化应激在肝纤维化的进展中起关键作用。因此，靶向ROS可能是治疗肝纤维化的有效策略。在这项研究中，我们研究了四种苯醌衍生物，包括5-异丙基-2-甲基-1,4-苯醌（TQ），2-叔丁基-1,4-苯醌（tBu-Q）2,5-二甲基-对苯醌（Dime-Q）和对苯醌（Ph-Q），以及它们对活化的肝星状细胞和TAA诱导的小鼠的抗氧化活性和抗纤维化作用的评估。电化学分析表明，所有化合物均具有抗氧化性能。该结果首先通过体外实验得到证实，揭示了这四种化合物在细胞水平上潜在的抗纤维化活性。苯醌衍生物作为ROS清除分子，通过调节TLR4-CD14信号通路来抑制细胞中procaspase-1和IL-1β的表达，并通过线粒体途径上调Bax / Bcl-2的比例并诱导线粒体凋亡。激活caspase-3，并抑制激活的LX-2细胞中抗凋亡蛋白FLIP和XIAP的表达。此外，TAA（硫代乙酰胺）诱导的小鼠模型用于进一步验证结果。用苯醌衍生物治疗可显着降低由过量ROS（包括天冬氨酸转氨酶（AST），丙氨酸转氨酶（ALT）和丙二醛（MDA））引起的肝损伤标志物和脂质过氧化的水平。此外，苯醌衍生物治疗显着抑制了细胞外基质（ECM）沉积，并下调了肝纤维化标记物（如胶原蛋白I，α平滑肌肌动蛋白（α-SMA）和TIMP-1）的mRNA和蛋白质表达。总之，这些结果表明，苯醌衍生物可以作为抗肝纤维化的潜在治疗药物。