Carvedilol alleviates the detrimental effects of azathioprine on hepatic tissues in experimental rats: Focusing on redox system, inflammatory and apoptosis pathways.

Abdel-Gawad S Shalkami, Ehab A M El-Shoura, Mohammed I A Hassan
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Abstract

Purpose: Drug-induced liver injury is becoming an increasingly important topic in drug research and clinical practice. Due to a lack of experimental animal models, predicting drug-induced liver injury in humans is challenging. Azathioprine (AZA) is a classical immunosuppressant with hepatotoxic adverse effects. The present study aimed to address the hepatoprotective effect of carvedilol (CAR) against AZA-induced hepatocellular injury via assessing redox-sensitive signals.

Method: To achieve this purpose, rats were allocated into four groups: control, CAR only, AZA only, and CAR plus AZA groups. The induction of hepatic injury was induced by a single intraperitoneal injection of AZA at a dose of 50 mg/kg on the 6th day of the experiment. Each experimental protocol was approved and supervised by the Ethics Committee for Animal Experiments.

Results: The results of the present study revealed that CAR administration significantly diminished AZA-induced hepatic dysfunction, as evidenced by relief of hepatic function biomarkers and histopathological aberration induced by AZA injection. Besides, CAR restored oxidant/antioxidant balance as well as NRF2 expression. In addition, CAR suppressed inflammatory response induced by AZA challenge as evidenced by downregulation of TLR4, TNF-α, MPO, and eNOS/iNOS levels in hepatic tissue. Moreover, CAR recovered apoptotic/anti-apoptotic status by modulation of caspase-3/Bcl2 expression.

Conclusion: Taken together, CAR protects against AZA-induced hepatic injury via antioxidant, anti-inflammatory, and anti-apoptotic activities. These findings revealed that CAR could be a good candidate for hepatic injury protection and can be added to AZA therapeutic regimen to reduce their adverse effect.

卡维地洛减轻硫唑嘌呤对实验大鼠肝组织的有害影响关注氧化还原系统、炎症和细胞凋亡途径
目的:药物引起的肝损伤正成为药物研究和临床实践中一个日益重要的课题。由于缺乏实验动物模型,预测药物诱导的人体肝损伤具有挑战性。硫唑嘌呤(AZA)是一种经典的免疫抑制剂,具有肝毒性不良反应。本研究旨在通过评估氧化还原敏感信号,探讨卡维地洛(CAR)对 AZA 诱导的肝细胞损伤的保肝作用:为此,将大鼠分为四组:对照组、仅 CAR 组、仅 AZA 组和 CAR 加 AZA 组。在实验的第 6 天,大鼠腹腔注射一次剂量为 50 毫克/千克的 AZA,诱导肝损伤。每个实验方案都经过了动物实验伦理委员会的批准和监督:本研究结果显示,CAR能显著减轻AZA诱导的肝功能障碍,这体现在AZA注射诱导的肝功能生物标志物和组织病理学畸变得到缓解。此外,CAR还能恢复氧化剂/抗氧化剂平衡以及NRF2的表达。此外,CAR 还抑制了 AZA 挑战引起的炎症反应,肝组织中 TLR4、TNF-α、MPO 和 eNOS/iNOS 水平的下调就是证明。此外,CAR 还通过调节 caspase-3/Bcl2 的表达来恢复凋亡/抗凋亡状态:综上所述,CAR 可通过抗氧化、抗炎和抗凋亡活性保护 AZA 诱导的肝损伤。这些研究结果表明,CAR 是保护肝损伤的良好候选药物,可添加到 AZA 治疗方案中以减少其不良反应。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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