Department of Biochemistry, Faculty of Veterinary Medicine, Atatürk University, Erzurum, Turkey.
Department of Medical Biochemistry, Faculty of Medicine, Aksaray University, Aksaray, Turkey.
Chem Biol Interact. 2022 Sep 25;365:110073. doi: 10.1016/j.cbi.2022.110073. Epub 2022 Jul 31.
Paclitaxel (PTX) is a widely used chemotherapeutic drug particularly effective against lung, breast, and ovarian cancer, though its usefulness is limited due to its multi-organ toxicity. The mechanisms underlying PTX toxicity are currently not yet known and there are no approved treatments for its control or prevention. This study aimed to investigate whether hesperidin (HSP) had a protective effect on paclitaxel-induced hepatotoxicity and nephrotoxicity from biochemical, and molecular perspectives. The rats were administered PTX 2 mg/kg, b.w. intraperitoneally for the first 5 consecutive days, then 100 or 200 mg/kg b.w. HSP orally for 10 consecutive days. Our results demonstrated that HSP decreased the PTX induced lipid peroxidation, improved the serum hepatic and renal functions (by decreasing the levels of AST, ALT, ALP, urea, and creatinine), and restored the liver and kidney antioxidant armory (SOD, CAT, GPx, and GSH). HSP also significantly reduced mRNA expression levels of NF-κB, TNF-α, IL-1β, IL-6, MAPK 14, Caspase-3, Bax, LC3A, LC3B, MMP2, and MMP9 whereas caused an increase in levels of Nrf2, HO-1, and Bcl-2 in the kidney and liver of PTX-induced rats. In addition, caspase-3, Bax, and Bcl-2 protein levels were examined by Western blot analysis, and it was determined that HSP decreased caspase-3 and Bax protein levels, but increased Bcl-2 protein levels. The findings of the study suggest that HSP has chemopreventive potential against PTX-induced hepatorenal toxicity plausibly through the attenuation of oxidative stress, inflammation, apoptosis, and autophagy.
紫杉醇（PTX）是一种广泛使用的化疗药物，对肺癌、乳腺癌和卵巢癌尤其有效，但由于其多器官毒性，其用途有限。PTX 毒性的机制目前尚不清楚，也没有批准的治疗方法来控制或预防其毒性。本研究旨在从生化和分子角度探讨橙皮苷（HSP）是否对紫杉醇诱导的肝毒性和肾毒性具有保护作用。大鼠腹腔内连续 5 天每天给予 PTX 2mg/kg，体重，然后连续 10 天每天给予 HSP100 或 200mg/kg，体重。我们的结果表明，HSP 降低了 PTX 诱导的脂质过氧化，改善了血清肝肾功能（通过降低 AST、ALT、ALP、尿素和肌酐水平），并恢复了肝和肾的抗氧化剂军备（SOD、CAT、GPx 和 GSH）。HSP 还显著降低了 NF-κB、TNF-α、IL-1β、IL-6、MAPK14、Caspase-3、Bax、LC3A、LC3B、MMP2 和 MMP9 的 mRNA 表达水平，同时增加了 Nrf2、HO-1 和 Bcl-2 的水平在 PTX 诱导的大鼠的肾脏和肝脏中。此外，通过 Western blot 分析检查了 caspase-3、Bax 和 Bcl-2 蛋白水平，结果表明 HSP 降低了 caspase-3 和 Bax 蛋白水平，但增加了 Bcl-2 蛋白水平。研究结果表明，HSP 具有预防 PTX 诱导的肝肾毒性的化学预防潜力，可能是通过减轻氧化应激、炎症、细胞凋亡和自噬。
