METHODS: Rats were orally administered with ARB (ARB1 = 50 mg/kg; ARB2 = 100 mg/kg) for 14 consecutive days against hepatotoxicity induced by a single dose of cisplatin (10 mg/kg) on day 15. Three days after the intraperitoneal cisplatin injection, serum and liver tissue were collected for subsequent analyses.
RESULTS: Cisplatin triggered marked increases in serum AST, ALT, and ALP activities, hepatic malondialdehyde (MDA) and reactive oxygen species (ROS) coupled with a considerable diminution in hepatic activities of superoxide dismutase (SOD), catalase (CAT) and the concentration of reduced glutathione (GSH). The gene expressions of interleukin-1β (IL-1β), tumor necrosis factor (TNF-α), and IL-6 were notably increased. The pre-administration of ARB1 and ARB2 reduced AST, ALT and ALP in serum and restored SOD, CAT, GSH, ROS, MDA and cytokine levels which was also evidenced by alleviated hepatic lesions. Further, cisplatin-induced prominent alterations in the gene expressions of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), iNOS, NF-κB, Bax, Bcl-2, caspase-3 and 8-OHdG in the liver. Interestingly, ARB protected the liver and mitigated the cisplatin-induced alterations in serum AST, ALT, ALP, and reduced hepatic redox markers, 8-OdG, inflammatory markers and gene expressions.
CONCLUSIONS: The findings demonstrate that ARB is a potential protective adjuvant against cisplatin-induced hepatotoxicity via inhibition of hepatic oxidative stress, inflammation, and apoptosis.
方法:在第15天对大鼠口服ARB(ARB1=50mg/kg;ARB2=100mg/kg)以对抗单剂量顺铂(10mg/kg)诱导的肝毒性。腹膜内注射顺铂后三天,收集血清和肝组织用于后续分析.
结果:顺铂导致血清AST显著升高,ALT,和ALP活动,肝脏丙二醛(MDA)和活性氧(ROS)以及超氧化物歧化酶(SOD)的肝脏活性显着降低,过氧化氢酶(CAT)和还原型谷胱甘肽(GSH)的浓度。白细胞介素-1β(IL-1β)的基因表达,肿瘤坏死因子(TNF-α),IL-6显著升高。预先给药ARB1和ARB2降低AST,ALT和ALP在血清和恢复SOD,CAT,GSH,ROS,MDA和细胞因子水平也通过减轻肝脏病变得到证实。Further,顺铂诱导的核因子红细胞2相关因子2(Nrf2)基因表达的显著改变,血红素加氧酶-1(HO-1),iNOS,NF-κB,Bax,Bcl-2、caspase-3和8-OHdG在肝脏中的表达。有趣的是,ARB保护肝脏,减轻顺铂诱导的血清AST变化,ALT,ALP,和减少肝脏氧化还原标志物,8-OdG,炎症标记和基因表达。
结论:研究结果表明,ARB是一种潜在的保护性佐剂,可以通过抑制肝脏氧化应激来对抗顺铂诱导的肝毒性,炎症,和凋亡。