Abstract

This study evaluates the protective effects of Thymoquinone (Tq) and Curcumin (Cur) in models of cisplatin-induced renal toxicity. Proliferation studies were carried out in HEK-293 cells. Cisplatin(ip) 5 mg/kg BW was used to induce renal injury in Sprague–Dawley rats. 50 mg/kg BW Tq + 100 mg/kg BW Cur, with or without cisplatin-treatment were administered for 5 days. Tq + Cur combination synergistically reduced the proliferation inhibition of HEK-293 cells resulted from cisplatin treatment and brought down cisplatin-induced apoptosis in these cells. In vitro studies revealed serum levels of BUN, creatinine, CK and pro-inflammatory cytokines like TNF-α, IL-6 and MRP-1 to be elevated in the cisplatin-treated group while reducing glomerular filtration rate. Tq + Cur treatment significantly improved these conditions. The antioxidant enzyme levels and mitochondrial ATPases were restored upon treatment, which were lessened in the cisplatin-treated group. Cisplatin induced the expression of KIM-1, which was brought down by the combination treatment. Tq + Cur treatment increased the expressions of phosphorylated Akt, Nrf2 and HO-1 proteins while decreasing the levels of cleaved caspase 3 and NFκB in kidney homogenates. In summary, Tq + Cur had protective effects on cisplatin-induced nephrotoxicity and renal injury, which could be mediated by up-regulation of survival signals like Akt, Nrf2/HO-1 and attenuation of KIM-1, NFκB.

摘要

本研究评估了百里醌 (Tq) 和姜黄素 (Cur) 在顺铂诱导的肾毒性模型中的保护作用。在 HEK-293 细胞中进行增殖研究。顺铂 (ip) 5 mg/kg BW 用于诱导 Sprague-Dawley 大鼠的肾损伤。50 mg/kg BW Tq + 100 mg/kg BW Cur，有或没有顺铂治疗，给药 5 天。Tq + Cur 组合协同降低顺铂处理导致的 HEK-293 细胞增殖抑制，并降低这些细胞中顺铂诱导的细胞凋亡。体外研究表明，顺铂治疗组中 BUN、肌酐、CK 和促炎细胞因子（如 TNF-α、IL-6 和 MRP-1）的血清水平升高，同时降低了肾小球滤过率。Tq + Cur 处理显着改善了这些条件。抗氧化酶水平和线粒体ATP酶在治疗后恢复，顺铂治疗组减少。顺铂诱导了 KIM-1 的表达，这被联合治疗降低了。Tq + Cur 处理增加了磷酸化 Akt、Nrf2 和 HO-1 蛋白的表达，同时降低了肾匀浆中裂解的 caspase 3 和 NFκB 的水平。总之，Tq+Cur对顺铂诱导的肾毒性和肾损伤具有保护作用，这可能是通过上调Akt等存活信号介导的。