Silicosis remains one of the most serious diseases worldwide, with no effective drug for its treatment. Our research results have indicated that arctiin and arctigenin could increase the mitochondrial membrane potential, which in turn reduces the production of reactive oxygen species (ROS), blocks the polarization of macrophages, and inhibits the differentiation of myofibroblasts to reduce oxidative stress, inflammation, and fibrosis. Further, our study revealed that arctiin and arctigenin suppressed the activation of NLRP3 inflammasome through the TLR-4/Myd88/NF-κB pathway and the silica-induced secretion of TNF-α, IL-1β, TGF-β, and α-SMA. Besides, the silica-induced increase in the levels of serum ceruloplasmin and HYP was also inhibited. Results of metabolomics indicated that arctiin and arctigenin could regulate the abnormal metabolic pathways associated with the development of silicosis, which involve pantothenate and CoA biosynthesis, cysteine and methionine metabolism, linoleic acid metabolism, and arginine and proline metabolism successively. Furthermore, the analysis of metabolomics, together with network topological analysis in different phases of silicosis, revealed that urine myristic acid, serum 4-hydroxyproline, and L-arginine could be regarded as diagnosis biomarkers in the early phase and formation of pulmonary fibrosis in the latter phases of silicosis. Arctiin and arctigenin could downregulate the increased levels of myristic acid in the early phase and serum 4-hydroxyproline in the latter phase of silicosis. Interestingly, the integration of TLR-4/NLRP3/TGF-β signaling and metabolomics verified the importance of macrophage polarization in the silicosis fibrosis process. To the best of our knowledge, this is the first study reporting that arctiin and arctigenin both can ameliorate silicosis effectively, and the former is a little stronger than its aglycone arctigenin because of its high oral bioavailability, low toxicity, and multimolecular active metabolites as determined by AdmetSAR and molecular docking analysis.

中文翻译：

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牛蒡苷和牛蒡甙元通过TLR-4/NLRP3/TGF-β信号通路改善二氧化硅诱导的肺氧化损伤

矽肺仍然是世界上最严重的疾病之一，目前尚无有效的药物治疗。我们的研究结果表明，牛蒡苷和牛蒡甙元可以增加线粒体膜电位，进而减少活性氧（ROS）的产生，阻断巨噬细胞的极化，并抑制肌成纤维细胞的分化，从而减少氧化应激、炎症和炎症。纤维化。此外，我们的研究表明，牛蒡苷和牛蒡甙元通过 TLR-4/Myd88/NF- κ B 途径抑制 NLRP3 炎症小体的激活，以及二氧化硅诱导的 TNF- α、IL-1 β、TGF- β和α的分泌。 -SMA。此外，二氧化硅引起的血清铜蓝蛋白和HYP水平的升高也受到抑制。代谢组学结果表明，牛蒡苷和牛蒡甙元可调节与矽肺发生相关的异常代谢途径，依次涉及泛酸和辅酶A生物合成、半胱氨酸和蛋氨酸代谢、亚油酸代谢、精氨酸和脯氨酸代谢。此外，代谢组学分析结合矽肺不同时期的网络拓扑分析发现，尿液肉豆蔻酸、血清4-羟脯氨酸和L-精氨酸可作为矽肺早期和肺纤维化形成的诊断生物标志物。矽肺后期。牛蒡苷和牛蒡甙元可下调矽肺早期升高的肉豆蔻酸和后期升高的血清4-羟脯氨酸水平。有趣的是，TLR-4/NLRP3/TGF- β信号传导和代谢组学的整合证实了巨噬细胞极化在矽肺纤维化过程中的重要性。据我们所知，这是第一个研究报告牛蒡子苷和牛蒡子苷元都可以有效改善矽肺病，并且前者比其苷元牛蒡子苷元稍强，因为其口服生物利用度高，毒性低，并且确定其具有多分子活性代谢物。通过 AdmetSAR 和分子对接分析。