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Morin ameliorates methotrexate-induced hepatotoxicity via targeting Nrf2/HO-1 and Bax/Bcl2/Caspase-3 signaling pathways

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Abstract

Background

Organ toxicity limits the therapeutic efficacy of methotrexate (MTX), an anti-metabolite therapeutic that is frequently used as an anti-cancer and immunosuppressive medicine. Hepatocellular toxicity is among the most severe side effects of long-term MTX use. The present study unveils new confirmations as regards the remedial effects of morin on MTX-induced hepatocellular injury through regulation of oxidative stress, apoptosis and MAPK signaling.

Methods and results

Rats were subjected to oral treatment of morin (50 and 100 mg/kg body weight) for 10 days. Hepatotoxicity was induced by single intraperitoneal injection of MTX (20 mg/kg body weight) on the 5th day. MTX related hepatic injury was associated with increased MDA while decreased GSH levels, the activities of endogen antioxidants (glutathione peroxidase, superoxide dismutase and catalase) and mRNA levels of HO-1 and Nrf2 in the hepatic tissue. MTX treatment also resulted in apoptosis in the liver tissue via increasing mRNA transcript levels of Bax, caspase-3, Apaf-1 and downregulation of Bcl-2. Conversely, treatment with morin at different doses (50 and 100 mg/kg) considerably mitigated MTX-induced oxidative stress and apoptosis in the liver tissue. Morin also mitigated MTX-induced increases of ALT, ALP and AST levels, downregulated mRNA expressions of matrix metalloproteinases (MMP-2 and MMP-9), MAPK14 and MAPK15, JNK, Akt2 and FOXO1 genes.

Conclusion

According to the findings of this study, morin may be a potential way to shield the liver tissue from the oxidative damage and apoptosis.

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Data Availability

All the data are available with the corresponding author. The data will be provided on request.

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Funding

Part of this study was supported by the Bingol University Scientific Research Project (BAP-FEF.2021.006) and another part was supported by the authors.

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Authors and Affiliations

  1. Vocational School of Health Sevices, Bayburt University, Bayburt, Turkey

    Hamit Emre Kızıl

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

    Cuneyt Caglayan

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

    Ekrem Darendelioğlu

  4. Department of Chemistry, Faculty of Science and Literature, Bingol University, Bingol, Turkey

    Adnan Ayna

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

    Cihan Gür & Sefa Küçükler

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

    Fatih Mehmet Kandemir

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  1. Hamit Emre Kızıl
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  2. Cuneyt Caglayan
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  4. Adnan Ayna
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  7. Sefa Küçükler
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Contributions

All authors contributed to the study conception and design. HEK, CG and SK performed the experiments. CC and ED designed the present study. FMK, AA and CG analyzed the data. HEK and CC drafted the manuscript. CC, AA and FMK revised the manuscript.

Corresponding authors

Correspondence to Cuneyt Caglayan or Fatih Mehmet Kandemir.

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Ethical approval

Experimental and animal-care protocols were approved by the Animal Experimentation Ethics Committee of Bingol University (Protocol No: 2022-E.66052).

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Kızıl, H.E., Caglayan, C., Darendelioğlu, E. et al. Morin ameliorates methotrexate-induced hepatotoxicity via targeting Nrf2/HO-1 and Bax/Bcl2/Caspase-3 signaling pathways. Mol Biol Rep 50, 3479–3488 (2023). https://doi.org/10.1007/s11033-023-08286-8

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