Polymeric nano-micelle of carbon monoxide donor SMA/CORM2 ameliorates acetaminophen-induced liver injury via suppressing HMGB1/TLR4 signaling pathway

作者：Yanni Xue, Daoxu Zhang, Yanyan Wei, Chunyu Guo, Bingdong Song, Yingying Cui, Cheng Zhang, De‐Xiang Xu, Shichen Zhang, Jun Fang · 发表于：European Journal of Pharmaceutical Sciences · 年份：2023 · DOI：10.1016/j.ejps.2023.106413 · 被引用次数：11 · 研究领域：Heme Oxygenase-1 and Carbon Monoxide、Drug-Induced Hepatotoxicity and Protection、Alcohol Consumption and Health Effects

Acetaminophen (APAP) overdose-induced hepatotoxicity is the most common cause of acute liver failure. Excessive generation of reactive oxygen species (ROS) and inflammatory responses are the major causes of necrosis and/or necroptosis of the liver cells. Currently, the treatment options for APAP-induced liver injury are very limited, N-acetylcysteine (NAC) is the only approved drug to treat APAP overdose patients. It is of great necessity to develop new therapeutic strategies. In a previous study, we focused on the anti-oxidative, anti-inflammatory signal molecule carbon monoxide (CO), and developed a nano-micelle encapsulating CO donor, i.e., SMA/CORM2. Administration of SMA/CORM2 to the mice exposed to APAP significantly ameliorated the liver injury and inflammatory process, in which modulating macrophage reprogramming plays a critical role. Along this line, in this study, we investigated the potential effect of SMA/CORM2 on toll-like receptor 4 (TLR4) and high mobility group protein B1 (HMGB1) signaling pathways that are known to be closely involved in many inflammatory responses and necroptosis. In a mouse APAP-induced liver injury model, similar to the previous study, SMA/CORM2 at 10 mg/kg remarkably improved the condition of the liver after injury as evidenced by histological examination and liver function. During the process of liver injury triggered by APAP, TLR4 expression gradually increased over time, and it was significantly upregulated as early as 4 h after APAP ...