{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:49:43Z","timestamp":1792788583348,"version":"4.5.0"},"reference-count":103,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2023,4,22]],"date-time":"2023-04-22T00:00:00Z","timestamp":1682121600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007614","name":"Deanship of Scientific Research at Jouf University","doi-asserted-by":"publisher","award":["DSR-2021-01-03138"],"award-info":[{"award-number":["DSR-2021-01-03138"]}],"id":[{"id":"10.13039\/501100007614","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxics"],"abstract":"<jats:p>Background: the nephrotoxicity of methotrexate (MTX) is observed in high-dose therapy. Moreover, low-dose MTX therapy for rheumatic diseases is debatable and claimed to cause renal impairment. This study aimed at studying the effect of methotrexate in repeated low doses on rat kidneys and assessing the efficacy of adipose-derived mesenchymal stem cells (AD-MSCs) and platelet rich plasma (PRP) for attenuating this effect. Methods: Forty-two male Wistar rats were used, 10 rats were donors of AD-MSCs and PRP, 8 rats served as control, and the remaining rats were subjected to induction of nephrotoxicity by MTX intraperitoneal injection once weekly for successive 8 weeks and then assigned into 3 groups of 8 animals each: Group II: received MTX only. Group III: received MTX + PRP. Group IV: received MTX + AD-MSCs. After one month, rats were anaesthetized, serum-sampled, and renal tissue removed for biochemical, histological, and ultrastructural evaluation. Results: there was significant tubular degeneration, glomerulosclerosis, fibrosis, decreased renal index, along with increased levels of urea and creatinine in the MTX group compared to the control group. Immunohistochemical expression of caspase-3 and iNOS in the renal tissue was significantly increased in group II compared to groups III and IV. Biochemical results revealed higher tissue malondialdehyde (MDA) concentration in the MTX-injected group which decreased significantly in co-treatment with either AD-MSC or PRP + MTX. MSC promoted the activation of the Nrf2\/PPAR\u03b3\/HO-1 and NF-\u03baB\/Keap1\/caspase-3 pathways, increased antioxidant enzyme activities, reduced lipid peroxidation levels, and alleviated oxidative damage and apoptosis. PRP showed therapeutic effects and molecular mechanisms similar to MSC. Furthermore, MSC and PRP treatment significantly reduced MTX-induced upregulation of the pro-inflammatory (NF-\u03baB, interleukin-1\u00df, and TNF-\u03b1), oxidative stress (Nrf-2, hemoxygenase-1, glutathione, and malondialdehyde), and nitrosative stress (iNOS) markers in the kidney. Conclusion: repeated administration of low-dose MTX resulted in massive renal tissue toxicity and deterioration of renal function in rats which proved to be attenuated by PRP and AD-MSCs through their anti-inflammatory, anti-apoptotic and anti-fibrotic properties.<\/jats:p>","DOI":"10.3390\/toxics11050398","type":"journal-article","created":{"date-parts":[[2023,4,24]],"date-time":"2023-04-24T02:31:05Z","timestamp":1682303465000},"page":"398","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Platelet Rich Plasma and Adipose-Derived Mesenchymal Stem Cells Mitigate Methotrexate-Induced Nephrotoxicity in Rat via Nrf2\/Ppar\u03b3\/HO-1 and NF-\u039ab\/Keap1\/Caspase-3 Signaling Pathways: Oxidative Stress and Apoptosis Interplay"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8614-3293","authenticated-orcid":false,"given":"Farooq A.","family":"Wani","sequence":"first","affiliation":[{"name":"Pathology Department, College of Medicine, Jouf University, Sakaka 72388, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahrous A.","family":"Ibrahim","sequence":"additional","affiliation":[{"name":"Forensic Medicine and Clinical Toxicology, College of Medicine, Jouf University, Sakaka 41412, Saudi Arabia"},{"name":"Forensic Medicine and Clinical Toxicology Department, Faculty of Medicine, Suez Canal University (SCU), Ismailia 41522, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shimaa H.","family":"Ameen","sequence":"additional","affiliation":[{"name":"Forensic Medicine and Clinical Toxicology Department, Faculty of Medicine, Zagazig University, Alsharqia 44519, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amira E.","family":"Farage","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Faculty of Medicine, Kafrelsheikh University, Kafrelsheikh 33516, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zinab Abd-Elhady","family":"Ali","sequence":"additional","affiliation":[{"name":"Vice Deanship for Academic Affairs, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam 31441, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6736-6379","authenticated-orcid":false,"given":"Khaldoon","family":"Saleh","sequence":"additional","affiliation":[{"name":"Vice Deanship for Academic Affairs, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam 31441, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Medhat M.","family":"Farag","sequence":"additional","affiliation":[{"name":"Medical Biochemistry Department, College of Medicine, Shaqra University, Shaqra 11961, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed U.","family":"Sayeed","sequence":"additional","affiliation":[{"name":"Pathology Department, College of Medicine, Jouf University, Sakaka 72388, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhannad A. Y.","family":"Alruwaili","sequence":"additional","affiliation":[{"name":"College of Medicine, Jouf University, Sakaka 72388, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdulsalam H. F.","family":"Alruwaili","sequence":"additional","affiliation":[{"name":"College of Medicine, Jouf University, Sakaka 72388, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmad Z. A.","family":"Aljared","sequence":"additional","affiliation":[{"name":"College of Medicine, Jouf University, Sakaka 72388, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rania A.","family":"Galhom","sequence":"additional","affiliation":[{"name":"Human Anatomy and Embryology Department, Faculty of Medicine, Suez Canal University (SCU), Ismailia 41522, Egypt"},{"name":"Center of Excellence in Molecular and Cellular Medicine (CEMCM), Faculty of Medicine, Suez Canal University (SCU), Ismailia 41522, Egypt"},{"name":"Human Anatomy and Embryology Department, Faculty of Medicine, Badr University in Cairo (BUC), Cairo 11829, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,22]]},"reference":[{"key":"ref_1","first-page":"CD000957","article-title":"Methotrexate for treating rheumatoid arthritis","volume":"2014","author":"Siddhanamatha","year":"2014","journal-title":"Cochrane Database Syst. 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