Moustafa Passant E, Farouk Hadir, Khattab Marwa S, El-Marasy Salma A
Department of Pharmacology, Medical Research and Clinical Studies Institute, National Research Centre, Giza, Egypt.
Department of Pathology, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt.
Toxicol Mech Methods. 2025 Sep;35(7):787-799. doi: 10.1080/15376516.2025.2499024. Epub 2025 May 7.
This study investigates the protective effects of diacerein (DCN) against amiodarone (AMIO)-induced hepatotoxicity in a rat model. AMIO administration resulted in significant elevations of liver enzymes, ALT and AST, indicating hepatocellular membrane disruption and oxidative stress, as demonstrated by elevated levels of malondialdehyde (MDA) and decreased glutathione (GSH). Additionally, pro-inflammatory cytokines including TNF-α and IL-1β were expressed more when AMIO triggered the Toll-like receptor 4/nuclear factor kappa B/inflammasome 3 (TLR4/NF-κB/NLRP3) inflammatory pathway, along with elevated caspase-1 (CASP1) levels, which promoted apoptosis. In contrast, oral administration of DCN for two weeks effectively mitigated these effects by reducing liver enzyme levels and improving histopathological alterations. DCN also demonstrated anti-oxidant properties by decreasing MDA levels and increasing nuclear factor erythroid 2-related factor 2 (Nrf2) and GSH content. Furthermore, DCN downregulated the hepatic content of TLR4, NF-κB p65, NLRP3, CASP1, and pro-inflammatory cytokines, thereby inhibiting the activation of the inflammatory cascade. Moreover, DCN reduced protein expression of caspase 3. Those findings suggest that DCN exerts its hepatoprotective effects through its anti-oxidant activity, modulation of TLR4/NF-κB/NLRP3 inflammatory pathways, and reduction of apoptosis. These results provide new insights into potential therapeutic strategies for managing AMIO-induced hepatotoxicity, warranting further investigation into the underlying molecular mechanisms of DCN's protective effects.
本研究在大鼠模型中探究了双醋瑞因（DCN）对胺碘酮（AMIO）诱导的肝毒性的保护作用。给予AMIO导致肝酶谷丙转氨酶（ALT）和谷草转氨酶（AST）显著升高，表明肝细胞膜受到破坏且存在氧化应激，这可通过丙二醛（MDA）水平升高和谷胱甘肽（GSH）降低得以证明。此外，当AMIO触发Toll样受体4/核因子κB/炎性小体3（TLR4/NF-κB/NLRP3）炎症通路时，包括肿瘤坏死因子-α（TNF-α）和白细胞介素-1β（IL-1β）在内的促炎细胞因子表达增加，同时半胱天冬酶-1（CASP1）水平升高，进而促进细胞凋亡。相比之下，连续两周口服DCN可通过降低肝酶水平和改善组织病理学改变有效减轻这些影响。DCN还通过降低MDA水平以及增加核因子红细胞2相关因子2（Nrf2）和GSH含量表现出抗氧化特性。此外，DCN下调了肝脏中TLR4、NF-κB p65、NLRP3、CASP1和促炎细胞因子的含量，从而抑制炎症级联反应的激活。此外，DCN降低了半胱天冬酶3的蛋白表达。这些发现表明，DCN通过其抗氧化活性、调节TLR4/NF-κB/NLRP3炎症通路以及减少细胞凋亡发挥其肝保护作用。这些结果为管理AMIO诱导的肝毒性的潜在治疗策略提供了新的见解，有必要进一步研究DCN保护作用的潜在分子机制。
