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Open AccessArticle

Formononetin Upregulates Nrf2/HO-1 Signaling and Prevents Oxidative Stress, Inflammation, and Kidney Injury in Methotrexate-Induced Rats

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Department of Medical Analysis, Princess Aisha Bint Al-Hussein Faculty of Nursing and Health Sciences, Al-Hussein Bin Talal University, Ma`an 71111, Jordan
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Department of Biology, Faculty of Science, Al-Hussein Bin Talal University, Ma`an 71111, Jordan
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Physiology Division, Department of Zoology, Faculty of Science, Beni-Suef University, Beni-Suef 62514, Egypt
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Department of Biology, College of Science, Princess Nourah bint Abdulrahman University, Riyadh 84428, Saudi Arabia
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Department of Biology, Faculty of Science, King Faisal University, Al-Ahsa 31982, Saudi Arabia
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Department of Biology, College of Science, Jouf University, Sakaka 2014, Saudi Arabia
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Department of Applied Medical Sciences, Community College of Unaizah, Qassim University, Buraydah 51431, Saudi Arabia
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Authors to whom correspondence should be addressed.
Antioxidants 2019, 8(10), 430; https://doi.org/10.3390/antiox8100430
Received: 2 September 2019 / Revised: 24 September 2019 / Accepted: 25 September 2019 / Published: 26 September 2019
Acute kidney injury (AKI) is a serious complication of methotrexate (MTX). This study explored the protective effect of the isoflavone formononetin (FN) against MTX nephrotoxicity with an emphasis on oxidative stress, inflammation, and nuclear factor (erythroid-derived 2)-like 2/heme oxygenase 1 (Nrf2/HO-1) signaling. Rats received FN (10, 20, and 40 mg/kg) for 10 days and a single dose of MTX on day 7. MTX induced kidney injury was characterized by increased serum creatinine and urea, kidney injury molecule-1 (Kim-1), and several histological alterations. FN ameliorated kidney function and inhibited the renal tissue injury induced by MTX. Reactive oxygen species (ROS), lipid peroxidation (LPO), nitric oxide, and 8-Oxo-2′-deoxyguanosine were increased, whereas antioxidant defenses were diminished in the kidney of MTX-administered rats. In addition, MTX upregulated renal iNOS, COX-2, TNF-α, IL-1β, Bax, caspase-9, and caspase-3, and decreased Bcl-2, Nrf2, and HO-1. FN suppressed oxidative stress, LPO, DNA damage, iNOS, COX-2, proinflammatory cytokines, and apoptosis, and boosted Bcl-2, antioxidants, and Nrf2/HO-1 signaling in MTX-administered rats. In conclusion, FN prevents MTX-induced AKI by activating Nrf2/HO-1 signaling and attenuates oxidative damage and inflammation. Thus, FN may represent an effective adjuvant that can prevent MTX nephrotoxicity, pending further mechanistic studies. View Full-Text
Keywords: formononetin; methotrexate; ROS; Nrf2; nephrotoxicity formononetin; methotrexate; ROS; Nrf2; nephrotoxicity
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Aladaileh, S.H.; Hussein, O.E.; Abukhalil, M.H.; Saghir, S.A.M.; Bin-Jumah, M.; Alfwuaires, M.A.; Germoush, M.O.; Almaiman, A.A.; Mahmoud, A.M. Formononetin Upregulates Nrf2/HO-1 Signaling and Prevents Oxidative Stress, Inflammation, and Kidney Injury in Methotrexate-Induced Rats. Antioxidants 2019, 8, 430.

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