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Role of Nrf2/HO-1, PPAR-γ, and cytoglobin signals in the pathogenesis of methotrexate-induced testicular intoxication in rats and the protective effect of diacerein

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Abstract

Methotrexate (MTX) is an inhibitor of folic acid reductase used in managing a variety of malignancies. Testicular injury by MTX is one of its serious adverse effects. The current investigation aims to assess the protective effects of diacerein (DIA) on testicular injury by MTX and clarify the possible underlying mechanisms. Testicular injury in rats was induced by a single injection of 20 mg/kg body weight of MTX. DIA was given in 25 mg/kg body weight/day and 50 mg/kg body weight/day doses for 10 days. Compared to the MTX group, DIA attenuated testicular intoxication as evidenced by improvement of testicular histopathological abnormalities and increased serum testosterone and luteinizing hormone. DIA attenuated testicular oxidative stress changes by lowering testicular MDA and boosting GSH content and SOD activity. Moreover, administration of DIA attenuated MTX-induced testicular inflammation, as proved by decreased TNF-α and IL-6. At the molecular level, DIA induced significant upregulation in Nrf2, HO-1, PPAR-γ, and cytoglobin protein expression. The present results proved that DIA, in a dose-dependent manner, exhibited notable amelioration of testicular toxicity induced by MTX through augmentation of anti-inflammatory and antioxidant effects combined by upregulating Nrf2/HO-1, PPAR-γ, and cytoglobin signaling.

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Acknowledgements

The authors would like to thank the Deanship of Scientific Research at Shaqra University for supporting this work and to Dr. Mai A. Elhemely, School of Medical Sciences, Faculty of Biology, Medicine, and Health, The University of Manchester, United Kingdom, for her generous assistance in language editing. In addition, we thank Dr. Mohamed A. Khattab, Faculty of Veterinary Medicine, Cairo University, Egypt for his assistance in histopathology examination and Dr. Fares E.M. Ali, Lecturer of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University for western blot analysis of the samples.

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  1. Department of Pharmaceutical Sciences, College of Pharmacy, Shaqra University, 11961, Shaqra, Saudi Arabia

    Mustafa Ahmed Abdel-Reheim

  2. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, 62514, Egypt

    Mustafa Ahmed Abdel-Reheim, Gaber F. Ali & Wafaa R. Mohamed

  3. Department of Pharmacology & Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut, 71524, Egypt

    Emad H. M. Hassanein

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MAA-R: resources, conceptualization, methodology, validation, writing—original draft. GFA: resources, methodology, investigation, data curation, investigation, formal analysis, writing—original draft. EHMH: conceptualization, methodology, data curation, investigation, formal analysis, supervision, writing—original draft, writing—review and editing. WRM: conceptualization, methodology, data curation, investigation, formal analysis, general supervision, writing—original draft, writing—review and editing. The authors declare that all data were generated in-house and that no paper mill was used.

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Correspondence to Wafaa R. Mohamed.

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Abdel-Reheim, M.A., Ali, G.F., Hassanein, E.H.M. et al. Role of Nrf2/HO-1, PPAR-γ, and cytoglobin signals in the pathogenesis of methotrexate-induced testicular intoxication in rats and the protective effect of diacerein. Naunyn-Schmiedeberg's Arch Pharmacol 397, 4235–4246 (2024). https://doi.org/10.1007/s00210-023-02876-w

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