他莫昔芬（TAM）是一种广泛用于治疗乳腺癌的化疗药物。另一方面，它在临床应用中作为抗肿瘤剂发挥有害的细胞作用，例如肝损伤和肝硬化。 TAM 引起的肝毒性主要归因于氧化应激和炎症。吡格列酮 (PIO) 是一种过氧化物酶体增殖物激活受体-γ (PPAR-γ) 激动剂，用于治疗 2 型糖尿病。据报道，PIO 在不同组织中发挥抗炎和抗氧化作用。本研究评估了 PIO 对 TAM 诱导的肝中毒的影响。大鼠口服 PIO (10 mg/kg) 和 TAM (45 mg/kg) 10 天。TAM 增加了天冬氨酸转氨酶 (AST) 和丙氨酸转氨酶 (ALT)，引发多种组织病理学改变、NF-κB p65、肝脏氧化应激增加和促炎细胞因子。 PIO 可防止 TAM 诱导的肝功能障碍、减少丙二醛 (MDA) 和促炎标记物，并改善肝脏抗氧化剂。此外，PIO 增加肝脏 Bcl-2 表达，同时降低 Bax 表达和 caspase-3 水平。此外，PIO 降低 Keap-1、Notch1 和 Hes-1，同时上调 HO-1、Nrf2 和 SIRT1。分子对接显示 PIO 与 Keap-1、NF-κB 和 SIRT1 的结合亲和力。PIO 通过减少细胞凋亡、炎症和氧化应激来减轻 TAM 肝毒性。 PIO的保护能力伴随着减少Keap-1和NF-κB以及调节Keap1/Nrf2/HO-1和Sirt1/Notch1信号传导。示意图说明 PIO 对 TAM 肝毒性的保护作用。 PIO 通过调节 Nrf2/HO-1 和 SIRT1/Notch1 信号传导并减轻氧化应激、炎症和细胞凋亡来预防 TAM 诱导的肝损伤。© 2023。作者。

Tamoxifen (TAM) is a chemotherapeutic drug widely utilized to treat breast cancer. On the other hand, it exerts deleterious cellular effects in clinical applications as an antineoplastic agent, such as liver damage and cirrhosis. TAM-induced hepatic toxicity is mainly attributed to oxidative stress and inflammation. Pioglitazone (PIO), a peroxisome proliferator-activated receptor-gamma (PPAR-γ) agonist, is utilized to treat diabetes mellitus type-2. PIO has been reported to exert anti-inflammatory and antioxidant effects in different tissues. This research assessed the impact of PIO against TAM-induced hepatic intoxication.Rats received PIO (10 mg/kg) and TAM (45 mg/kg) orally for 10 days.TAM increased aspartate aminotransferase (AST) and alanine aminotransferase (ALT), triggered several histopathological alterations, NF-κB p65, increased hepatic oxidative stress, and pro-inflammatory cytokines. PIO protects against TAM-induced liver dysfunction, reduced malondialdehyde (MDA), and pro-inflammatory markers along with improved hepatic antioxidants. Moreover, PIO, increased hepatic Bcl-2 expression while reducing Bax expression and caspase-3 levels. In addition, PIO decreased Keap-1, Notch1, and Hes-1 while upregulated HO-1, Nrf2, and SIRT1. Molecular docking showed the binding affinity of PIO for Keap-1, NF-κB, and SIRT1.PIO mitigated TAM hepatotoxicity by decreasing apoptosis, inflammation, and oxidative stress. The protecting ability of PIO was accompanied by reducing Keap-1 and NF-κB and regulating Keap1/Nrf2/HO-1 and Sirt1/Notch1 signaling. A schematic diagram illustrating the protective effect of PIO against TAM hepatotoxicity. PIO prevented TAM-induced liver injury by regulating Nrf2/HO-1 and SIRT1/Notch1 signaling and mitigating oxidative stress, inflammation, and apoptosis.© 2023. The Author(s).