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Ferulic acid prevents oxidative stress, inflammation, and liver injury via upregulation of Nrf2/HO-1 signaling in methotrexate-induced rats

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Abstract

Liver injury is one of the adverse effects of methotrexate (MTX). Ferulic acid (FA) is an antioxidant phytochemical that confers hepatoprotective efficacy; however, its effect against MTX hepatotoxicity remains unexplored. This study investigated the role of FA in modulating oxidative stress, inflammation, Nrf2/HO-1 signaling, and PPARγ in MTX-administered rats. Following oral FA supplementation for 15 days, rats received a single dose of MTX at day 16 and samples were collected at day 19. MTX provoked multiple histological manifestations, including degenerative changes, steatosis, inflammatory cells infiltration and hemorrhage, and altered serum transaminases, bilirubin, and albumin. Reactive oxygen species, lipid peroxidation, and nitric oxide were increased in the liver of rats that received MTX. FA prevented all histological alterations, ameliorated liver function markers, suppressed oxidative stress, and boosted antioxidants in MTX-induced rats. FA reduced serum TNF-α and IL-1β, and hepatic NF-κB p65, Bax, and caspase-3, whereas increased Bcl-2, Nrf2, NQO1, HO-1, and PPARγ. In conclusion, FA prevented MTX hepatotoxicity by activating Nrf2/HO-1 signaling and PPARγ, and attenuating oxidative stress, inflammation, and cell death.

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Acknowledgments

The authors extend their appreciation to the Deanship of Scientific Research at Princess Nourah bint Abdulrahman University for supporting this research through the Fast-track Research Funding Program.

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Authors and Affiliations

  1. Physiology Division, Department of Zoology, Faculty of Science, Beni-Suef University, Beni-Suef, 62514, Egypt

    Ayman M. Mahmoud, Omnia E. Hussein & Sanaa M. Abd El-Twab

  2. Biochemistry Department, Faculty of Science, Beni-Suef University, Beni-Suef, Egypt

    Walaa G. Hozayen

  3. Department of Biology, College of Science, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia

    May Bin-Jumah

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  1. Ayman M. Mahmoud
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  2. Omnia E. Hussein
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  3. Walaa G. Hozayen
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  4. May Bin-Jumah
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  5. Sanaa M. Abd El-Twab
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Correspondence to Ayman M. Mahmoud.

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Mahmoud, A.M., Hussein, O.E., Hozayen, W.G. et al. Ferulic acid prevents oxidative stress, inflammation, and liver injury via upregulation of Nrf2/HO-1 signaling in methotrexate-induced rats. Environ Sci Pollut Res 27, 7910–7921 (2020). https://doi.org/10.1007/s11356-019-07532-6

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  • DOI: https://doi.org/10.1007/s11356-019-07532-6

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