Department of Infectious Diseases, Affiliated Zhoushan Hospital, Wenzhou Medicine University, Zhoushan, Zhejiang 316004, China.
Department of Cardiology, Shanghai Tenth People's Hospital, Tongji University, School of Medicine, Shanghai, China.
Biomed Pharmacother. 2024 Oct;179:117280. doi: 10.1016/j.biopha.2024.117280. Epub 2024 Sep 4.
Acetaminophen (APAP) overdose is a prevalent cause of clinical pharmacological liver injury worldwide. Artemether (ART), a first-line antimalarial drug, has demonstrated hepatoprotective activity. However, its effect on APAP-induced acute liver injury (AILI) remains unclear. In this study, we investigated whether ART can protect against AILI and examined its underlying mechanisms. In vivo, ART mitigated APAP-induced liver histological changes, including mitochondrial damage, hepatocyte necrosis, hepatocyte apoptosis, and inflammatory infiltration. Additionally, ART reduced serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in APAP-induced mice. ART also activated the Nrf2-HO-1/GPX4 signaling pathway, exerting antioxidant effects in both in vitro and in vivo models of AILI. To confirm Nrf2 as a target of ART in vivo, we pretreated C57BL/6 mice with the Nrf2 inhibitor, ML385. The results indicated that inhibiting Nrf2 diminishes the protective effect of ART against AILI. Overall, our findings suggest that ART's protective effect against AILI is mediated through the Nrf2-related antioxidant pathway.
对乙酰氨基酚（APAP）过量是全球范围内临床药物性肝损伤的常见原因。青蒿素（ART）作为一线抗疟药物，已显示出肝保护活性。然而，其对 APAP 诱导的急性肝损伤（AILI）的影响尚不清楚。在这项研究中，我们研究了 ART 是否可以预防 AILI，并探讨了其潜在的机制。在体内，ART 减轻了 APAP 诱导的肝组织学变化，包括线粒体损伤、肝细胞坏死、肝细胞凋亡和炎症浸润。此外，ART 降低了 APAP 诱导的小鼠血清丙氨酸氨基转移酶（ALT）和天冬氨酸氨基转移酶（AST）水平。ART 还在 AILI 的体外和体内模型中激活了 Nrf2-HO-1/GPX4 信号通路，发挥了抗氧化作用。为了确认 Nrf2 是 ART 在体内的靶点，我们用 Nrf2 抑制剂 ML385 预处理 C57BL/6 小鼠。结果表明，抑制 Nrf2 会降低 ART 对 AILI 的保护作用。总的来说，我们的研究结果表明，ART 对 AILI 的保护作用是通过 Nrf2 相关的抗氧化途径介导的。
