Salama Samir A, Abd-Allah Gamil M, Mohamadin Ahmed M, Elshafey Mostafa M, Gad Hesham S
Division of Biochemistry, Department of Pharmacology, College of Pharmacy, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia.
Department of Biochemistry, Faculty of Pharmacy, Al-Azhar University, Cairo 11751, Egypt; Department of Biochemistry, Faculty of Pharmacy, Egyptian Russian University, Badr city, Cairo 11829, Egypt.
Life Sci. 2021 Aug 1;278:119572. doi: 10.1016/j.lfs.2021.119572. Epub 2021 May 6.
Cisplatin is a potent chemotherapeutic agent whose therapeutic application is hindered by the associated nephrotoxicity. Cisplatin-evoked nephrotoxicity has been largely attributed to the induction of oxidative stress and inflammatory responses. The current study aimed at investigating the ability of ergothioneine to mitigate cisplatin-evoked nephrotoxicity and to elucidate the underlining molecular mechanisms.
Wistar rats were treated with a daily dose of ergothioneine (70 mg/kg, po) for fourteen days and a single dose of cisplatin (5 mg/kg, ip) on day ten. On day fifteen, kidneys and blood specimens were collected and subjected to Western blotting, ELISA, histopathological, and spectrophotometric analysis.
Ergothioneine significantly enhanced renal function in cisplatin-treated rats as manifested by increased GFR and decreased serum creatinine and blood urea nitrogen. Ergothioneine effectively reduced the cisplatin-induced oxidative stress and mitigated apoptosis and the histopathological changes. Mechanistically, ergothioneine induced the expression of the antioxidant transcription factor Nrf2 and up-regulated its downstream targets NQO1 and HO-1. Equally important, ergothioneine inhibited γ-glutamyl transpeptidase that plays crucial roles in biotransformation of cisplatin into a toxic metabolite. Additionally, it reduced the pro-apoptotic protein p53 and the inflammatory transcription factor NF-κB along with its downstream pro-inflammatory cytokines TNF-α and IL-1β.
The results of the current work shed the light on the ameliorating effect of ergothioneine on cisplatin-evoked nephrotoxicity that is potentially mediated through modulation of Nrf2, p53, and NF-κB signaling and inhibition of γ-glutamyl transpeptidase. This findings support the potential application of ergothioneine in controlling cisplatin-associated nephrotoxicity although clinical investigations are warranted.
顺铂是一种有效的化疗药物，但其治疗应用因相关的肾毒性而受到阻碍。顺铂诱发的肾毒性在很大程度上归因于氧化应激和炎症反应的诱导。本研究旨在探讨麦角硫因减轻顺铂诱发的肾毒性的能力，并阐明其潜在的分子机制。
将Wistar大鼠每日给予麦角硫因剂量（70mg/kg，口服），持续14天，并在第10天给予单次剂量的顺铂（5mg/kg，腹腔注射）。在第15天，收集肾脏和血液标本，并进行蛋白质免疫印迹法、酶联免疫吸附测定、组织病理学和分光光度分析。
麦角硫因显著增强了顺铂处理大鼠的肾功能，表现为肾小球滤过率增加、血清肌酐和血尿素氮降低。麦角硫因有效降低了顺铂诱导的氧化应激，减轻了细胞凋亡和组织病理学变化。机制上，麦角硫因诱导抗氧化转录因子Nrf2的表达并上调其下游靶点NQO1和HO-1。同样重要的是，麦角硫因抑制了γ-谷氨酰转肽酶，该酶在顺铂生物转化为有毒代谢物中起关键作用。此外，它还降低了促凋亡蛋白p53和炎症转录因子NF-κB及其下游促炎细胞因子TNF-α和IL-1β。
当前工作的结果揭示了麦角硫因对顺铂诱发的肾毒性的改善作用，这可能是通过调节Nrf2、p53和NF-κB信号通路以及抑制γ-谷氨酰转肽酶介导的。这一发现支持了麦角硫因在控制顺铂相关肾毒性方面的潜在应用，尽管仍需进行临床研究。
