Ergothioneine mitigates cisplatin-evoked nephrotoxicity via targeting Nrf2, NF-κB, and apoptotic signaling and inhibiting γ-glutamyl transpeptidase
| Autor: | Hesham S. Gad, Gamil M. Abd-Allah, Ahmed M. Mohamadin, Samir A. Salama, Mostafa M. Elshafey |
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| Rok vydání: | 2021 |
| Předmět: |
Male
0301 basic medicine Antioxidant NF-E2-Related Factor 2 medicine.medical_treatment Antineoplastic Agents Apoptosis DNA Fragmentation Pharmacology Kidney medicine.disease_cause 030226 pharmacology & pharmacy Antioxidants General Biochemistry Genetics and Molecular Biology Nephrotoxicity 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine medicine Animals Rats Wistar General Pharmacology Toxicology and Pharmaceutics Blood urea nitrogen Cisplatin Caspase 3 NF-kappa B Ergothioneine NF-κB gamma-Glutamyltransferase General Medicine Rats Up-Regulation Oxidative Stress 030104 developmental biology chemistry Tumor Suppressor Protein p53 Oxidative stress Signal Transduction medicine.drug |
| Zdroj: | Life Sciences. 278:119572 |
| ISSN: | 0024-3205 |
| DOI: | 10.1016/j.lfs.2021.119572 |
| Popis: | Aim 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. Main methods 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. Key findings 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. Significance 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. |
| Databáze: | OpenAIRE |
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