Department of Pharmaceutics and Pharmaceutical Technology, College of Pharmacy, Mutah University, Al-Karak, Jordan.
Department of Biochemistry, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt.
J Biochem Mol Toxicol. 2021 Sep;35(9):e22856. doi: 10.1002/jbt.22856. Epub 2021 Jul 28.
Cisplatin-induced nephrotoxicity limits its wide application as a chemotherapeutic drug. Betaine is a natural trimethylglycine compound involved in several biological reactions. In this study, the protective effect of betaine against cisplatin-induced nephrotoxicity through modulating the expression of microRNA 34a (miRNA 34a), p53, apoptosis, and inflammation was investigated. Adult Wistar rats were divided into normal group (received vehicle); betaine group (received 250 mg betaine/kg BW/day via oral gavage from Day 1 to Day 25); cisplatin group (received a single intraperitoneal dose of cisplatin at 5 mg/kg BW on Day 21) and betaine + cisplatin group (received the same doses of betaine and cisplatin). The results demonstrated that the cisplatin group exhibited severe kidney tissue damage and an increase in blood creatinine and urea levels. Furthermore, the cisplatin group showed a significant upregulation of miRNA 34a and higher levels of phospho-p53, caspase 3, cytochrome c, NF B, and IL-1β compared to the normal group. Remarkably, the betaine + cisplatin group showed significantly decreased blood creatinine and urea concentrations, decreased levels of miRNA 34a, phospho-p53, caspase 3, cytochrome c, NF B, and IL-1β as well as improved kidney tissue integrity compared to the cisplatin group. In conclusion, cisplatin-induced nephrotoxicity in rats was associated with upregulation of miRNA 34a expression, apoptosis, and inflammation in p53-dependent manner. These effects were reversed by betaine administration that ultimately improved the kidney function and tissue integrity.
顺铂诱导的肾毒性限制了其作为化疗药物的广泛应用。甜菜碱是一种参与多种生物反应的天然三甲基甘氨酸化合物。在这项研究中，研究了甜菜碱通过调节 microRNA 34a (miRNA 34a)、p53、细胞凋亡和炎症的表达来对抗顺铂诱导的肾毒性的保护作用。成年 Wistar 大鼠分为正常组（给予载体）；甜菜碱组（第 1 天至第 25 天每天通过口服灌胃给予 250mg/kg BW 甜菜碱）；顺铂组（第 21 天给予顺铂 5mg/kg BW 单次腹腔注射）和甜菜碱+顺铂组（给予相同剂量的甜菜碱和顺铂）。结果表明，顺铂组表现出严重的肾组织损伤和血肌酐和尿素水平升高。此外，与正常组相比，顺铂组 miRNA 34a 显著上调，磷酸化 p53、caspase 3、细胞色素 c、NF B 和 IL-1β 水平更高。值得注意的是，与顺铂组相比，甜菜碱+顺铂组血肌酐和尿素浓度显著降低，miRNA 34a、磷酸化 p53、caspase 3、细胞色素 c、NF B 和 IL-1β 水平降低，肾组织完整性得到改善。总之，顺铂诱导的大鼠肾毒性与 miRNA 34a 表达上调、p53 依赖性细胞凋亡和炎症有关。甜菜碱的给药逆转了这些影响，最终改善了肾功能和组织完整性。
