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Protective effect of quercetin against 5-fluorouracil-induced cardiac impairments through activating Nrf2 and inhibiting NF-κB and caspase-3 activities

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Abstract

5-Fluorouracil (5-FU) is a chemotherapy used to treat many types of cancer. Cardiotoxicity is one of the common drawbacks of 5-FU therapy. Quercetin (Qu) is a bioflavonoid with striking biological activities. This research aimed to assess the ameliorative effect of Qu against 5-FU-mediated cardiotoxicity. Thirty-five rats were allocated into five groups: control group (normal saline), 5-FU group (30 mg/kg, intraperitoneally), Qu group (50 mg/kg, oral), 25 mg/kg Qu+5-FU group, and 50 mg/kg Qu+5-FU. The experimental animals were received the above-mentioned drugs for 21 days. Results showed that 5-FU significantly elevated creatine kinase, lactate dehydrogenase, serum cholesterol and triglyceride, and upregulated troponin and renin mRNA expression. Additionally, cardiac oxidant/antioxidant imbalance was evident in elevated oxidants (malondialdehyde and nitric oxide) and depleted antioxidants (superoxide dismutase, catalase, glutathione peroxidase, and glutathione). 5-FU also downregulated the gene expression of nuclear factor erythroid 2-related factor 2. Furthermore, 5-FU significantly increased cardiac pro-inflammatory cytokines (tumor necrosis factor-alpha and interleukin-1 beta) and upregulated gene expression of nuclear factor kappa-B. 5-FU significantly enhanced cardiac apoptosis through upregulating caspase-3 expression and downregulating B-cell lymphoma 2. Immunohistochemical and histopathological examinations verified the above-mentioned findings. However, all these changes were significantly ameliorated in Qu pre-administered rats. Conclusively, Qu counteracted 5-FU-mediated cardiotoxicity through potent antioxidant, anti-inflammatory, and anti-apoptotic effects.

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Acknowledgements

The authors appreciate and thank the Taif University Researchers Supporting Program (Project number: TURSP-2020/151), Taif University, Saudi Arabia, for supporting this study.

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Authors and Affiliations

  1. Department of Biology, College of Science and Humanities in Al-Kharj, Prince Sattam Bin Abdulaziz University, Al-kharj, 11942, Saudi Arabia

    Maha S. Lokman

  2. Department of Zoology and Entomology, Faculty of Science, Helwan University, Cairo, 11795, Egypt

    Maha S. Lokman & Rami B. Kassab

  3. Department of Biology, Faculty of Science and Arts, Al-Baha University, Almakhwah, Al-Baha, Saudi Arabia

    Hussam A. Althagafi & Rami B. Kassab

  4. Department of Biology, College of Science, Taif University, Taif, Saudi Arabia

    Fahad Alharthi

  5. Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, Mansoura University, Mansoura, 35516, Egypt

    Ola A. Habotta

  6. Department of Pharmacology and Toxicology, Faculty of Pharmacy and Pharmaceutical Industries, Sinai University, El Arish, Egypt

    Arwa A. Hassan

  7. Department of Cancer and Molecular Biology, National Cancer Institute, Cairo University, Cairo, Egypt

    Mohamed A. Elhefny

  8. Department of Medical Genetics, Faculty of Medicine, Umm Al-Qura University, Alqunfudah, Saudi Arabia

    Mohamed A. Elhefny

  9. Basic Medical Science, Histopathology Department, National Organization for Drug Control and Research, Giza, Egypt

    Hassan Al Sberi

  10. Department of Biology, Faculty of Science, Taif University, Taif, Saudi Arabia

    Hassan Al Sberi

  11. Department of Laboratory & Blood Bank, Security Forces Hospital, P.O. Box 14799, Mecca, 21955, Saudi Arabia

    Abdulrahman Theyab

  12. Medical Genetics Department, Faculty of Medicine, Umm Al-Qura University, Mecca, Saudi Arabia

    Ahmad Hasan Mufti

  13. Medical Laboratory Technology Department, Jazan University, Jazan, Saudi Arabia

    Alaa Alhazmi

  14. SMIRES for Consultation in Specialized Medical Laboratories, Jazan University, Jazan, Saudi Arabia

    Alaa Alhazmi

  15. Research Center, King Faisal Specialist Hospital and Research Center, MBC-J04, PO Box 40047, Jeddah, 21499, Saudi Arabia

    Yousef M. Hawsawi

  16. Department of Pathology, Faculty of Veterinary Medicine, Alexandria University, Edfina, 22758, Egypt

    Asmaa F. Khafaga

  17. Department of Anatomy and Embryology, Faculty of Veterinary Medicine, Kafrelsheikh University, Kafrelsheikh, 33516, Egypt

    Mahmoud S. Gewaily

  18. Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, PO Box 11099, Taif, 21944, Saudi Arabia

    Khalaf F. Alsharif

  19. Department of Human Anatomy, College of Medicine, Taif University, PO Box 11099, Taif, 21944, Saudi Arabia

    Ashraf Albrakati

  20. College of Medicine, Al-Faisal University, P.O. Box 50927, Riyadh, 11533, Saudi Arabia

    Abdulrahman Theyab

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  1. Maha S. Lokman
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  2. Hussam A. Althagafi
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Contributions

Conceptualization and supervision were performed by RBK; animal treatments, molecular and biochemical methodologies were performed by MSL, HAA, RBK, FA, and OAH; histological methodology and investigation were performed by AH, MAE, and HA; data analysis, software, data curation, and visualization were performed by OAH, AT, AHM, AA, and YMH; writing–reviewing and editing manuscript were performed by RBK, AFK, MSG, KFA, and AA. All authors participated in the design and interpretation of the study and approved the final manuscript.

Corresponding author

Correspondence to Maha S. Lokman.

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All of the research protocols were performed in accordance with the European Community Directive (86/609/EEC) and the national rules on animal care that were conducted consistently with the NIH Guidelines for the Care and Use of Laboratory Animals 8th edition and were given their approval by the Institutional Animal Ethics Committee guidelines for animal care and use at Faculty of Veterinary Medicine, Mansoura University (Approval Number: R/58).

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Lokman, M.S., Althagafi, H.A., Alharthi, F. et al. Protective effect of quercetin against 5-fluorouracil-induced cardiac impairments through activating Nrf2 and inhibiting NF-κB and caspase-3 activities. Environ Sci Pollut Res 30, 17657–17669 (2023). https://doi.org/10.1007/s11356-022-23314-z

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