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The impact of Nrf2/HO-1, caspase-3/Bax/Bcl2 and ATF6/IRE1/PERK/GRP78 signaling pathways in the ameliorative effects of morin against methotrexate-induced testicular toxicity in rats

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Abstract

Background

Methotrexate (MT) is a broadly used chemotherapeutic drug however its clinical use is confronted with several forms of toxicities containing testicular damage. The current study assessed the ameliorative effects of morin on MT-induced testicular damage with the investigation of its mechanism and the potential involvement of oxidative stress, inflammation, apoptosis and endoplasmic reticulum stress in such protection.

Methods

The animals were divided into 5 distinct groups (7 rats in each group). Group 1 was control group, group 2 received MT-only (20 mg/kg bw), group 3 received orally morin-only (100 mg/kg bw), group 4 received MT (20 mg/kg bw) + morin (50 mg/kg bw) and group 5 received MT (20 mg/kg bw) + morin (100 mg/kg). In this study, morin was administered orally for 10 days, while MT was administered intraperitoneally on the 5th day.

Results

MT intoxication was linked with augmented MDA while decreased GSH levels, the enzyme activities of glutathione peroxidase, superoxide dismutase, and catalase and mRNA levels of HO-1 and Nrf2 in the testis tissues. MT injection caused inflammation in the testicular tissue via up-regulation of MAPK14, NFκB, TNF-α and IL-1β. MT application also caused apoptosis and endoplasmic reticulum stress in the testis tissue via increasing mRNA transcript levels of Bax, caspase-3, PERK, IRE1, ATF-6, GRP78 and down-regulation of Bcl-2.

Conclusion

Treatment with morin at a dose of 50 and 100 mg/kg considerably mitigated oxidative stress, inflammation, apoptosis and endoplasmic reticulum stress in the testicular tissue indicating that testicular damage related to MT toxicity could be modulated by morin administration.

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Data availability

The data that support the findings of this study are available from the corresponding author, [Cuneyt Caglayan], upon reasonable request.

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Acknowledgements

The authors thank Assoc. Prof. Ekrem Darendelioğlu and Assoc. Prof. Adnan Ayna for their valuable contributions to this study.

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Authors and Affiliations

  1. Vocational School of Health Sevices, Final International University, Kazafani, Cyprus

    Behçet Varışlı

  2. Department of Medical Biochemistry, Faculty of Medicine, Bilecik Seyh Edebali University, Bilecik, Turkey

    Cuneyt Caglayan

  3. Department of Medical Biochemistry, Faculty of Medicine, Aksaray University, Aksaray, Turkey

    Fatih Mehmet Kandemir

  4. Department of Biochemistry, Faculty of Veterinary Medicine, Atatürk University, Erzurum, Turkey

    Cihan Gür

  5. Department of Molecular Biology and Genetics, Faculty of Science and Literature, Bingol University, 12000, Bingol, Turkey

    İbrahim Bayav

  6. Department of Biochemistry, Faculty of Veterinary Medicine, Bingol University, 12000, Bingol, Turkey

    Aydın Genç

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All authors contributed equally to this work.

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Correspondence to Cuneyt Caglayan.

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Experimental and animal-care protocols were approved by the Animal Experimentation Ethics Committee of Bingol University (Protocol No: 2022-E.53634).

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Varışlı, B., Caglayan, C., Kandemir, F.M. et al. The impact of Nrf2/HO-1, caspase-3/Bax/Bcl2 and ATF6/IRE1/PERK/GRP78 signaling pathways in the ameliorative effects of morin against methotrexate-induced testicular toxicity in rats. Mol Biol Rep 49, 9641–9649 (2022). https://doi.org/10.1007/s11033-022-07873-5

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