Department of Rheumatology and Immunology, Zhongnan Hospital, Wuhan University, China; Department of Integrated Chinese Traditional and Western Medicine, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, China.
Department of Endocrinology, Zhongnan Hospital, Wuhan University, China.
Int Immunopharmacol. 2024 Jul 30;136:112296. doi: 10.1016/j.intimp.2024.112296. Epub 2024 May 28.
Acetaminophen (APAP) is a widely used antipyretic and analgesic medication, but its overdose can induce acute liver failure with lack of effective therapies. Icariin is a bioactive compound derived from the herb Epimedium that displays hepatoprotective activities. Here, we explored the protective effects and mechanism of icariin on APAP-induced hepatotoxicity. Icariin (25/50 mg/kg) or N-Acetylcysteine (NAC, 300 mg/kg) were orally administered in wild-type C57BL/6 mice for 7 consecutive days before the APAP administration. Icariin attenuated APAP-induced acute liver injury in mice, as measured by alleviated serum enzymes activities and hepatic apoptosis. In vitro, icariin pretreatment significantly inhibited hepatocellular damage and apoptosis by reducing the BAX/Bcl-2 ratio as well as the expression of cleaved-caspase 3 and cleaved-PARP depended on the p53 pathway. Moreover, icariin attenuated APAP-mediated inflammatory response and oxidative stress via the Nrf2 and NF-κB pathways. Importantly, icariin reduced the expression of S100A9, icariin interacts with S100A9 as a direct cellular target, which was supported by molecular dynamics simulation and surface plasmon resonance assay (equilibrium dissociation constant, K = 1.14 μM). In addition, the genetic deletion and inhibition of S100A9 not only alleviated APAP-induced injury but also reduced the icariin's protective activity in APAP-mediated liver injury. These data indicated that icariin targeted S100A9 to alleviate APAP-induced liver damage via the following signaling pathways NF-κB, p53, and Nrf2.
对乙酰氨基酚（APAP）是一种广泛使用的解热镇痛药，但过量会导致缺乏有效治疗方法的急性肝衰竭。淫羊藿素是一种从草药淫羊藿中提取的生物活性化合物，具有保肝作用。在这里，我们探讨了淫羊藿素对 APAP 诱导的肝毒性的保护作用及其机制。淫羊藿素（25/50mg/kg）或 N-乙酰半胱氨酸（NAC，300mg/kg）在 APAP 给药前连续 7 天每天口服给予野生型 C57BL/6 小鼠。淫羊藿素减轻了 APAP 诱导的小鼠急性肝损伤，表现为血清酶活性和肝凋亡减轻。在体外，淫羊藿素预处理通过降低 BAX/Bcl-2 比值以及减少 cleaved-caspase 3 和 cleaved-PARP 的表达来显著抑制肝细胞损伤和凋亡，这依赖于 p53 途径。此外，淫羊藿素通过 Nrf2 和 NF-κB 途径减轻了 APAP 介导的炎症反应和氧化应激。重要的是，淫羊藿素降低了 S100A9 的表达，淫羊藿素与 S100A9 相互作用作为直接的细胞靶标，这得到了分子动力学模拟和表面等离子体共振分析（平衡解离常数，K=1.14μM）的支持。此外，S100A9 的基因缺失和抑制不仅减轻了 APAP 诱导的损伤，而且降低了淫羊藿素在 APAP 介导的肝损伤中的保护活性。这些数据表明，淫羊藿素通过以下信号通路 NF-κB、p53 和 Nrf2 靶向 S100A9 来减轻 APAP 诱导的肝损伤。
