Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, Zagazig University, Zagazig 44511, Egypt.
Laboratories Technology Department, Turabah University College, Taif University, Turabah 21995, Saudi Arabia.
Toxins (Basel). 2019 Nov 4;11(11):642. doi: 10.3390/toxins11110642.
This study explored the probable in vivo cardiac and renal toxicities together with in silico approaches for predicting the apoptogenic potential of methanolic extract (EPME) in rats. Cardiac and renal injury biomarkers were estimated with histopathological and immunohistochemical evaluations of both kidney and heart. The probable underlying mechanism of compounds to potentiate p53 activity is examined using Molecular Operating Environment (MOE) docking software and validated experimentally by immunohistochemical localization of p53 protein in the kidney and heart tissues. The gas chromatography/mass spectrometry analysis of revealed the presence of nine different compounds dominated by di-(2-ethylhexyl) phthalate (DEHP). Significant elevations of troponin, creatine phosphokinase, creatine kinase-myocardium bound, lactate dehydrogenase, aspartate transaminase, alkaline phosphatase, urea, creatinine, and uric acid were evident in the EPME treated rats. The EPME treated rats showed strong renal and cardiac p53 expression and moderate cardiac TNF-α expression. Further, our in silico results predicted the higher affinity and good inhibition of DEHP, glyceryl linolenate, and lucenin 2 to the MDM2-p53 interface compared to the standard reference 15 a compound. Conclusively, EPME long-term exposure could adversely affect the cardiac and renal tissues probably due to their inflammatory and apoptotic activity. Moreover, the in silico study hypothesizes that EPME inhibits MDM2-mediated degradation of p53 suggesting possible anticancer potentials which confirmed experimental by strong p53 expression in renal and cardiac tissues.
本研究探讨了甲醇提取物（EPME）在大鼠体内可能的心脏和肾脏毒性，并结合计算方法预测其诱导细胞凋亡的潜力。通过对肾脏和心脏的组织病理学和免疫组织化学评估来评估心脏和肾脏损伤生物标志物。使用分子操作环境（MOE）对接软件来检查化合物增强 p53 活性的可能潜在机制，并通过免疫组织化学定位肾脏和心脏组织中的 p53 蛋白来验证实验。气相色谱/质谱分析显示存在九种不同的化合物，其中邻苯二甲酸二（2-乙基己基）酯（DEHP）占主导地位。EPME 处理的大鼠中肌钙蛋白、肌酸磷酸激酶、肌酸激酶-心肌结合物、乳酸脱氢酶、天门冬氨酸氨基转移酶、碱性磷酸酶、尿素、肌酐和尿酸明显升高。EPME 处理的大鼠表现出强烈的肾脏和心脏 p53 表达以及中度的心脏 TNF-α 表达。此外，我们的计算结果预测，与标准参考 15a 化合物相比，DEHP、亚麻酸甘油酯和藜芦醇 2 对 MDM2-p53 界面具有更高的亲和力和良好的抑制作用。总之，EPME 的长期暴露可能会对心脏和肾脏组织产生不利影响，可能是由于它们的炎症和凋亡活性。此外，计算研究假设 EPME 抑制了 MDM2 介导的 p53 降解，这表明可能具有抗癌潜力，这在肾脏和心脏组织中强烈的 p53 表达得到了实验证实。
