Formononetin Upregulates Nrf2/HO-1 Signaling and Prevents Oxidative Stress, Inflammation, and Kidney Injury in Methotrexate-Induced Rats
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 (Nr...
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| Format: | Article |
| Language: | English |
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MDPI AG
2019-09-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/8/10/430 |
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| author | Saleem H. Aladaileh Omnia E. Hussein Mohammad H. Abukhalil Sultan A. M. Saghir May Bin-Jumah Manal A. Alfwuaires Mousa O. Germoush Amer A. Almaiman Ayman M. Mahmoud |
| author_facet | Saleem H. Aladaileh Omnia E. Hussein Mohammad H. Abukhalil Sultan A. M. Saghir May Bin-Jumah Manal A. Alfwuaires Mousa O. Germoush Amer A. Almaiman Ayman M. Mahmoud |
| author_sort | Saleem H. Aladaileh |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-12T05:49:53Z |
| format | Article |
| id | doaj.art-c32721e33f9a45398f48eaec32153089 |
| institution | Directory Open Access Journal |
| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-12T05:49:53Z |
| publishDate | 2019-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antioxidants |
| spelling | doaj.art-c32721e33f9a45398f48eaec321530892023-09-03T05:19:06ZengMDPI AGAntioxidants2076-39212019-09-0181043010.3390/antiox8100430antiox8100430Formononetin Upregulates Nrf2/HO-1 Signaling and Prevents Oxidative Stress, Inflammation, and Kidney Injury in Methotrexate-Induced RatsSaleem H. Aladaileh0Omnia E. Hussein1Mohammad H. Abukhalil2Sultan A. M. Saghir3May Bin-Jumah4Manal A. Alfwuaires5Mousa O. Germoush6Amer A. Almaiman7Ayman M. Mahmoud8Department of Medical Analysis, Princess Aisha Bint Al-Hussein Faculty of Nursing and Health Sciences, Al-Hussein Bin Talal University, Ma`an 71111, JordanPhysiology Division, Department of Zoology, Faculty of Science, Beni-Suef University, Beni-Suef 62514, EgyptDepartment of Medical Analysis, Princess Aisha Bint Al-Hussein Faculty of Nursing and Health Sciences, Al-Hussein Bin Talal University, Ma`an 71111, JordanDepartment of Medical Analysis, Princess Aisha Bint Al-Hussein Faculty of Nursing and Health Sciences, Al-Hussein Bin Talal University, Ma`an 71111, JordanDepartment of Biology, College of Science, Princess Nourah bint Abdulrahman University, Riyadh 84428, Saudi ArabiaDepartment of Biology, Faculty of Science, King Faisal University, Al-Ahsa 31982, Saudi ArabiaDepartment of Biology, College of Science, Jouf University, Sakaka 2014, Saudi ArabiaDepartment of Applied Medical Sciences, Community College of Unaizah, Qassim University, Buraydah 51431, Saudi ArabiaPhysiology Division, Department of Zoology, Faculty of Science, Beni-Suef University, Beni-Suef 62514, EgyptAcute 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.https://www.mdpi.com/2076-3921/8/10/430formononetinmethotrexaterosnrf2nephrotoxicity |
| spellingShingle | Saleem H. Aladaileh Omnia E. Hussein Mohammad H. Abukhalil Sultan A. M. Saghir May Bin-Jumah Manal A. Alfwuaires Mousa O. Germoush Amer A. Almaiman Ayman M. Mahmoud Formononetin Upregulates Nrf2/HO-1 Signaling and Prevents Oxidative Stress, Inflammation, and Kidney Injury in Methotrexate-Induced Rats Antioxidants formononetin methotrexate ros nrf2 nephrotoxicity |
| title | Formononetin Upregulates Nrf2/HO-1 Signaling and Prevents Oxidative Stress, Inflammation, and Kidney Injury in Methotrexate-Induced Rats |
| title_full | Formononetin Upregulates Nrf2/HO-1 Signaling and Prevents Oxidative Stress, Inflammation, and Kidney Injury in Methotrexate-Induced Rats |
| title_fullStr | Formononetin Upregulates Nrf2/HO-1 Signaling and Prevents Oxidative Stress, Inflammation, and Kidney Injury in Methotrexate-Induced Rats |
| title_full_unstemmed | Formononetin Upregulates Nrf2/HO-1 Signaling and Prevents Oxidative Stress, Inflammation, and Kidney Injury in Methotrexate-Induced Rats |
| title_short | Formononetin Upregulates Nrf2/HO-1 Signaling and Prevents Oxidative Stress, Inflammation, and Kidney Injury in Methotrexate-Induced Rats |
| title_sort | formononetin upregulates nrf2 ho 1 signaling and prevents oxidative stress inflammation and kidney injury in methotrexate induced rats |
| topic | formononetin methotrexate ros nrf2 nephrotoxicity |
| url | https://www.mdpi.com/2076-3921/8/10/430 |
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