Wei Shichao, Xiao Junshen, Ju Feng, Li Jiaxue, Liu Ting, Hu Zhaoyang
Department of Anesthesiology (S.W., J.X., F.J., J.L.) and Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology (S.W., J.X., F.J., J.L., T.L., Z.H.), West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Department of Anesthesiology (S.W., J.X., F.J., J.L.) and Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology (S.W., J.X., F.J., J.L., T.L., Z.H.), West China Hospital, Sichuan University, Chengdu, Sichuan, China
J Pharmacol Exp Ther. 2024 Sep 18;391(1):51-63. doi: 10.1124/jpet.123.001992.
Hepatic ischemia/reperfusion (I/R) damage is one of the most common side effects of liver surgery. This pathophysiological process may lead to excessive hepatic damage. Aloperine is an active ingredient isolated from Linn and has a variety of therapeutic effects, including organ protection. However, the hepatoprotective effect of aloperine against hepatic I/R damage has not yet been determined. C57BL/6 mice were allocated to the sham-operated (sham), hepatic ischemia/reperfusion (I/R), and aloperine groups. The mice were exposed to 30 min of hepatic hilum occlusion. Then a 3-h reperfusion was performed. Mice in the sham group underwent sham surgery. Hepatic injury was evaluated by plasma aspartate aminotransferase (AST) and transaminase alanine aminotransferase (ALT) levels, histological evaluation, cell apoptosis, the number of activated inflammatory cells, and the expression levels of inflammatory cytokines, including tumor necrosis factor- and interleukin-6. The protein phosphorylation status of the reperfusion-associated survival pathways was evaluated. Mice with hepatic I/R injury presented increased plasma ALT and AST levels, increased hepatic apoptosis, abnormal histological structure, and elevated inflammatory responses. However, aloperine ameliorated hepatic I/R-induced injury. Moreover, aloperine enhanced the level of signal transducer and activator of transcription (STAT)-3 phosphorylation after I/R. Ag490, an agent that inhibits STAT-3 activity, abolished aloperine-induced STAT-3 phosphorylation and liver protection. Aloperine ameliorates hepatic I/R-induced liver injury via a STAT-3-mediated protective mechanism. Patients with hepatic I/R injury may benefit from aloperine treatment. SIGNIFICANCE STATEMENT: Hepatic I/R can cause excessive liver damage. This study revealed that aloperine, an active component isolated from Linn, ameliorates hepatic I/R injury and related liver damage in vivo. The underlying protective mechanism may involve the STAT-3 signaling pathway. These findings may lead to the development of a novel approach for treating hepatic I/R damage in clinical practice.
肝缺血/再灌注（I/R）损伤是肝脏手术最常见的副作用之一。这一病理生理过程可能导致肝脏过度损伤。苦豆碱是从苦豆子中分离出的一种活性成分，具有多种治疗作用，包括器官保护作用。然而，苦豆碱对肝缺血/再灌注损伤的肝脏保护作用尚未确定。将C57BL/6小鼠分为假手术组（sham）、肝缺血/再灌注组（I/R）和苦豆碱组。对小鼠进行30分钟的肝门阻断。然后进行3小时的再灌注。假手术组小鼠进行假手术。通过血浆天冬氨酸氨基转移酶（AST）和丙氨酸氨基转移酶（ALT）水平、组织学评估、细胞凋亡、活化炎症细胞数量以及包括肿瘤坏死因子-α和白细胞介素-6在内的炎症细胞因子表达水平来评估肝损伤。评估再灌注相关生存通路的蛋白磷酸化状态。肝缺血/再灌注损伤小鼠的血浆ALT和AST水平升高、肝脏凋亡增加、组织结构异常以及炎症反应增强。然而，苦豆碱改善了肝缺血/再灌注诱导的损伤。此外，苦豆碱增强了再灌注后信号转导和转录激活因子（STAT）-3的磷酸化水平。Ag490是一种抑制STAT-3活性的药物，它消除了苦豆碱诱导的STAT-3磷酸化和肝脏保护作用。苦豆碱通过STAT-3介导的保护机制改善肝缺血/再灌注诱导的肝损伤。肝缺血/再灌注损伤患者可能从苦豆碱治疗中获益。意义声明：肝缺血/再灌注可导致肝脏过度损伤。本研究表明，从苦豆子中分离出的活性成分苦豆碱可改善体内肝缺血/再灌注损伤及相关肝损伤。潜在的保护机制可能涉及STAT-3信号通路。这些发现可能会在临床实践中促成一种治疗肝缺血/再灌注损伤的新方法的开发。
