{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T14:37:42Z","timestamp":1793457462633,"version":"4.5.0"},"reference-count":76,"publisher":"Springer Science and Business Media LLC","issue":"5","license":[{"start":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T00:00:00Z","timestamp":1765756800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T00:00:00Z","timestamp":1765756800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Deraya University"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Naunyn-Schmiedeberg's Arch Pharmacol"],"published-print":{"date-parts":[[2026,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>This study aimed to assess the preventive potential of apremilast (APRE) against methotrexate (MTX)-induced renal damage in rats through modulation of nuclear factor erythroid 2-related factor 2\/heme oxygenase-1 (Nrf2\/HO-1) signaling and toll-like receptor 4\/nuclear factor-kappa B\/p38 mitogen-activated protein kinase\/caspase-3 (TLR4\/NF-\u03baB\/p38 MAPK\/Caspase-3) signaling pathways. Four groups of male Wistar albino rats were assigned: control, APRE, MTX, MTX\u2009+\u2009APRE. Histopathological investigation and biochemical analysis of the serum renal damage indicators (urea and creatinine) were used to evaluate the renal toxicity of MTX. Testing for renal malondialdehyde (MDA) and reduced glutathione (GSH) was conducted. The levels of renal tumor necrosis factor-alpha (TNF-\u03b1), interleukin-6 (IL-6), Nrf2, HO-1, and cleaved caspase-3 were measured using the ELISA method. Using an immunohistochemistry method, the expression of NF-\u03baB p65 in the kidney was investigated. Western blotting was used to examine the expression of TLR4 and p38 MAPK proteins. MTX administration resulted in significant renal injury, as evidenced by elevated serum urea and creatinine levels. The kidneys were significantly affected as evidenced by histopathological alterations and increased levels of renal MDA, TNF-\u03b1, IL-6, Bcl-2-associated x (Bax), and cleaved caspase-3, alongside decreased levels of GSH and B-cell lymphoma 2 (Bcl-2) expression. These outcomes were linked to inhibition of Nrf2\/HO-1 signaling and activation of the TLR4\/NF-\u03baB\/p38 MAPK\/Caspase-3 pathway. Co-treatment with APRE at 20\u00a0mg\/kg\/day for 21\u00a0days markedly improved all biochemical and pathological alterations evoked by MTX, demonstrating significant nephroprotective effects. Apremilast inhibits methotrexate\u2019s harmful effects on the kidneys by activating signaling cascades that include Nrf2\/HO-1, while simultaneously downregulating TLR4\/NF-\u03baB\/p38 MAPK\/Caspase-3.<\/jats:p>","DOI":"10.1007\/s00210-025-04846-w","type":"journal-article","created":{"date-parts":[[2025,12,15]],"date-time":"2025-12-15T05:34:45Z","timestamp":1765776885000},"page":"7615-7629","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Apremilast ameliorates methotrexate-induced renal injury in rats: role of TLR4\/NF-\u03baB\/P38 MAPK\/caspase-3 and Nrf2\/HO-1 signaling pathways"],"prefix":"10.1007","volume":"399","author":[{"given":"Reham H.","family":"Mohyeldin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ehab E.","family":"Sharata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahmoud","family":"Abdelnaser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mina Ezzat","family":"Attya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Al Shaimaa Mahmoud","family":"Kotb","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Remon Roshdy","family":"Rofaeil","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,12,15]]},"reference":[{"issue":"1","key":"4846_CR1","doi-asserted-by":"publisher","first-page":"3281670","DOI":"10.1155\/2017\/3281670","volume":"2017","author":"MM Abdel-Daim","year":"2017","unstructured":"Abdel-Daim MM et al (2017) Diosmin attenuates methotrexate-induced hepatic, renal, and cardiac injury: a biochemical and histopathological study in mice. Oxid Med Cell Longev 2017(1):3281670","journal-title":"Oxid Med Cell Longev"},{"key":"4846_CR2","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2024.113764","volume":"146","author":"IA Abdelmawgood","year":"2025","unstructured":"Abdelmawgood IA et al (2025) Gentisic acid attenuates ovalbumin-induced airway inflammation, oxidative stress, and ferroptosis through the modulation of Nrf2\/HO-1 and NF-\u03baB signaling pathways. Int Immunopharmacol 146:113764","journal-title":"Int Immunopharmacol"},{"key":"4846_CR3","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2023.121562","volume":"320","author":"M Abdelnaser","year":"2023","unstructured":"Abdelnaser M et al (2023) Hepatoprotective potential of gabapentin in cecal ligation and puncture-induced sepsis; targeting oxidative stress, apoptosis, and NF-kB\/MAPK signaling pathways. Life Sci 320:121562","journal-title":"Life Sci"},{"issue":"2","key":"4846_CR4","doi-asserted-by":"publisher","first-page":"947","DOI":"10.1007\/s00210-023-02650-y","volume":"397","author":"M Abdelnaser","year":"2024","unstructured":"Abdelnaser M et al (2024) Modulating Nrf-2\/HO-1, apoptosis and oxidative stress signaling pathways by gabapentin ameliorates sepsis-induced acute kidney injury. Naunyn-Schmiedeberg\u2019s Arch Pharmacol 397(2):947\u2013958","journal-title":"Naunyn-Schmiedeberg\u2019s Arch Pharmacol"},{"key":"4846_CR5","doi-asserted-by":"publisher","DOI":"10.1016\/j.abb.2024.110229","volume":"763","author":"M Abdelnaser","year":"2025","unstructured":"Abdelnaser M et al (2025a) Clemastine mitigates sepsis-induced acute kidney injury in rats; the role of \u03b1-Klotho\/TLR-4\/MYD-88\/NF-\u03baB\/Caspase-3\/p-P38 MAPK signaling pathways. Arch Biochem Biophys 763:110229","journal-title":"Arch Biochem Biophys"},{"issue":"1","key":"4846_CR6","doi-asserted-by":"publisher","first-page":"715","DOI":"10.1186\/s40001-025-02982-w","volume":"30","author":"M Abdelnaser","year":"2025","unstructured":"Abdelnaser M et al (2025b) Mitigation of sepsis-induced liver injury by Clemastine via modulating GSDMD\/NLRP-3\/Caspase-1\/NF-\u03baB signalling pathways. Eur J Med Res 30(1):715","journal-title":"Eur J Med Res"},{"issue":"5","key":"4846_CR7","doi-asserted-by":"publisher","first-page":"426","DOI":"10.1002\/cbf.1676","volume":"28","author":"P Abraham","year":"2010","unstructured":"Abraham P, Kolli VK, Rabi S (2010) Melatonin attenuates methotrexate-induced oxidative stress and renal damage in rats. Cell Biochem Funct 28(5):426\u2013433","journal-title":"Cell Biochem Funct"},{"issue":"10","key":"4846_CR8","doi-asserted-by":"publisher","DOI":"10.3390\/antiox8100430","volume":"8","author":"SH Aladaileh","year":"2019","unstructured":"Aladaileh SH et al (2019) Formononetin upregulates Nrf2\/HO-1 signaling and prevents oxidative stress, inflammation, and kidney injury in methotrexate-induced rats. Antioxidants 8(10):430","journal-title":"Antioxidants"},{"issue":"5","key":"4846_CR9","doi-asserted-by":"publisher","first-page":"3414","DOI":"10.1016\/j.sjbs.2022.02.023","volume":"29","author":"NO Al-Harbi","year":"2022","unstructured":"Al-Harbi NO et al (2022) Protective effect of Apremilast against LPS-induced acute lung injury via modulation of oxidative stress and inflammation. Saudi J Biol Sci 29(5):3414\u20133424","journal-title":"Saudi J Biol Sci"},{"issue":"7","key":"4846_CR10","doi-asserted-by":"publisher","first-page":"1327","DOI":"10.1016\/j.jsps.2023.05.022","volume":"31","author":"NO Al-Harbi","year":"2023","unstructured":"Al-Harbi NO et al (2023) Effect of Apremilast on LPS-induced immunomodulation and inflammation via activation of Nrf2\/HO-1 pathways in rat lungs. Saudi Pharm J 31(7):1327\u20131338","journal-title":"Saudi Pharm J"},{"key":"4846_CR11","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1016\/j.cbi.2017.05.002","volume":"272","author":"N Ali","year":"2017","unstructured":"Ali N et al (2017) Protective effect of chlorogenic acid against methotrexate induced oxidative stress, inflammation and apoptosis in rat liver: an experimental approach. Chem Biol Interact 272:80\u201391","journal-title":"Chem Biol Interact"},{"issue":"5","key":"4846_CR12","doi-asserted-by":"publisher","first-page":"779","DOI":"10.1096\/fasebj.14.5.779","volume":"14","author":"O Almeida","year":"2000","unstructured":"Almeida O et al (2000) Subtle shifts in the ratio between pro-and antiapoptotic molecules after activation of corticosteroid receptors decide neuronal fate. FASEB J 14(5):779\u2013790","journal-title":"FASEB J"},{"key":"4846_CR13","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2021.108284","volume":"103","author":"HH Arab","year":"2022","unstructured":"Arab HH et al (2022) Targeting inflammation, autophagy, and apoptosis by troxerutin attenuates methotrexate-induced renal injury in rats. Int Immunopharmacol 103:108284","journal-title":"Int Immunopharmacol"},{"issue":"4","key":"4846_CR14","doi-asserted-by":"publisher","first-page":"890","DOI":"10.1016\/j.jfda.2017.05.001","volume":"25","author":"H Asci","year":"2017","unstructured":"Asci H et al (2017) The impact of gallic acid on the methotrexate-induced kidney damage in rats. J Food Drug Anal 25(4):890\u2013897","journal-title":"J Food Drug Anal"},{"key":"4846_CR15","doi-asserted-by":"publisher","DOI":"10.1016\/j.tox.2024.153879","volume":"506","author":"H Badreldin","year":"2024","unstructured":"Badreldin H et al (2024) Targeting Nrf2\/HO-1 and NF-\u03baB\/TNF-\u03b1 signaling pathways with empagliflozin protects against atrial fibrillation-induced acute kidney injury in rats. Toxicology 506:153879","journal-title":"Toxicology"},{"key":"4846_CR16","doi-asserted-by":"crossref","unstructured":"Caetano, Nilce N, et al\u00a0(1997) Effect of methotrexate (MTX) on NAD (P)+ dehydrogenases of HeLa cells: malic enzyme, 2\u2010oxoglutarate and isocitrate dehydrogenases. Cell biochemistry and function: cellular biochemistry and its modulation by active agents or disease 15. 4:259\u2013264","DOI":"10.1002\/(SICI)1099-0844(199712)15:4<259::AID-CBF749>3.0.CO;2-D"},{"issue":"5","key":"4846_CR17","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0155748","volume":"11","author":"C-Y Cheng","year":"2016","unstructured":"Cheng C-Y et al (2016) Ferulic acid administered at various time points protects against cerebral infarction by activating p38 MAPK\/p90RSK\/CREB\/Bcl-2 anti-apoptotic signaling in the subacute phase of cerebral ischemia-reperfusion injury in rats. PLoS ONE 11(5):e0155748","journal-title":"PLoS ONE"},{"issue":"7","key":"4846_CR18","doi-asserted-by":"publisher","first-page":"1194","DOI":"10.1177\/0960327121991905","volume":"40","author":"A Dar","year":"2021","unstructured":"Dar A et al (2021) The protective role of luteolin against the methotrexate-induced hepato-renal toxicity via its antioxidative, anti-inflammatory, and anti-apoptotic effects in rats. Hum Exp Toxicol 40(7):1194\u20131207","journal-title":"Hum Exp Toxicol"},{"issue":"12","key":"4846_CR19","first-page":"1281","volume":"21","author":"FN Eki\u0307nci\u0307-Akdemi\u0307r","year":"2018","unstructured":"Eki\u0307nci\u0307-Akdemi\u0307r FN et al (2018) The effects of casticin and myricetin on liver damage induced by methotrexate in rats. Iran J Basic Med Sci 21(12):1281","journal-title":"Iran J Basic Med Sci"},{"issue":"15","key":"4846_CR20","doi-asserted-by":"publisher","first-page":"7156","DOI":"10.1039\/D2FO03212K","volume":"14","author":"AH Elmaidomy","year":"2023","unstructured":"Elmaidomy AH et al (2023) Vitis vinifera leaf extract liposomal Carbopol gel preparation\u2019s potential wound healing and antibacterial benefits: in vivo, phytochemical, and computational investigation. Food Funct 14(15):7156\u20137175","journal-title":"Food Funct"},{"issue":"1","key":"4846_CR21","doi-asserted-by":"publisher","DOI":"10.1155\/2015\/859383","volume":"2015","author":"AA El-Sheikh","year":"2015","unstructured":"El-Sheikh AA et al (2015) Mechanisms of thymoquinone hepatorenal protection in methotrexate-induced toxicity in rats. Mediators Inflamm 2015(1):859383","journal-title":"Mediators Inflamm"},{"issue":"9","key":"4846_CR22","doi-asserted-by":"publisher","first-page":"1492","DOI":"10.3109\/0886022X.2015.1074521","volume":"37","author":"M Erboga","year":"2015","unstructured":"Erboga M et al (2015) Quercetin ameliorates methotrexate-induced renal damage, apoptosis and oxidative stress in rats. Ren Fail 37(9):1492\u20131497","journal-title":"Ren Fail"},{"key":"4846_CR23","doi-asserted-by":"publisher","DOI":"10.1155\/2018\/3140983","volume":"2018","author":"M Fiore","year":"2018","unstructured":"Fiore M et al (2018) Liver illness and psoriatic patients. Biomed Res Int 2018:3140983","journal-title":"Biomed Res Int"},{"issue":"6","key":"4846_CR24","doi-asserted-by":"publisher","first-page":"e2841","DOI":"10.1038\/cddis.2017.236","volume":"8","author":"M Ge","year":"2017","unstructured":"Ge M et al (2017) Brg1-mediated Nrf2\/HO-1 pathway activation alleviates hepatic ischemia\u2013reperfusion injury. Cell Death Dis 8(6):e2841\u2013e2841","journal-title":"Cell Death Dis"},{"issue":"3","key":"4846_CR25","doi-asserted-by":"publisher","first-page":"248","DOI":"10.4103\/0976-500X.99426","volume":"3","author":"NR Hadi","year":"2012","unstructured":"Hadi NR, Al-Amran FG, Swadi A (2012) Metformin ameliorates methotrexate-induced hepatotoxicity. J Pharmacol Pharmacother 3(3):248\u2013253","journal-title":"J Pharmacol Pharmacother"},{"key":"4846_CR26","doi-asserted-by":"publisher","first-page":"152","DOI":"10.1016\/j.fct.2018.03.041","volume":"116","author":"EH Hassanein","year":"2018","unstructured":"Hassanein EH et al (2018) Renoprotective effects of umbelliferone on methotrexate-induced renal injury through regulation of Nrf-2\/Keap-1, P38MAPK\/NF-\u03baB, and apoptosis signaling pathways. Food Chem Toxicol 116:152\u2013160","journal-title":"Food Chem Toxicol"},{"issue":"4","key":"4846_CR27","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1007\/s12272-023-01436-3","volume":"46","author":"EHM Hassanein","year":"2023","unstructured":"Hassanein EHM et al (2023) Apocynin abrogates methotrexate-induced nephrotoxicity: role of TLR4\/NF-\u03baB-p65\/p38-MAPK, IL-6\/STAT-3, PPAR-\u03b3, and SIRT1\/FOXO3 signaling pathways. Arch Pharm Res 46(4):339\u2013359","journal-title":"Arch Pharm Res"},{"issue":"1","key":"4846_CR28","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1186\/s13075-015-0814-z","volume":"17","author":"AF Hawwa","year":"2015","unstructured":"Hawwa AF et al (2015) Methotrexate polyglutamates as a potential marker of adherence to long-term therapy in children with juvenile idiopathic arthritis and juvenile dermatomyositis: an observational, cross-sectional study. Arthritis Res Ther 17(1):295","journal-title":"Arthritis Res Ther"},{"issue":"12","key":"4846_CR29","doi-asserted-by":"publisher","first-page":"1471","DOI":"10.1634\/theoncologist.2015-0164","volume":"21","author":"SC Howard","year":"2016","unstructured":"Howard SC et al (2016) Preventing and managing toxicities of high-dose methotrexate. Oncologist 21(12):1471\u20131482","journal-title":"Oncologist"},{"issue":"1","key":"4846_CR30","doi-asserted-by":"publisher","first-page":"19207","DOI":"10.1038\/s41598-025-03387-9","volume":"15","author":"AM Ibrahim","year":"2025","unstructured":"Ibrahim AM et al (2025) Design and synthesis of a novel quinoline thiazolidinedione hybrid as a potential antidiabetic PPAR\u03b3 modulator. Sci Rep 15(1):19207","journal-title":"Sci Rep"},{"issue":"9","key":"4846_CR31","doi-asserted-by":"publisher","first-page":"700","DOI":"10.1080\/15376516.2016.1236425","volume":"26","author":"F Imam","year":"2016","unstructured":"Imam F et al (2016) Apremilast reversed carfilzomib-induced cardiotoxicity through inhibition of oxidative stress, NF-\u03baB and MAPK signaling in rats. Toxicol Mech Methods 26(9):700\u2013708","journal-title":"Toxicol Mech Methods"},{"key":"4846_CR32","doi-asserted-by":"publisher","first-page":"993","DOI":"10.1016\/j.pharep.2018.03.009","volume":"70","author":"F Imam","year":"2018","unstructured":"Imam F et al (2018a) Apremilast prevent doxorubicin-induced apoptosis and inflammation in heart through inhibition of oxidative stress mediated activation of NF-\u03baB signaling pathways. Pharmacol Rep 70:993\u20131000","journal-title":"Pharmacol Rep"},{"issue":"5","key":"4846_CR33","doi-asserted-by":"publisher","first-page":"993","DOI":"10.1016\/j.pharep.2018.03.009","volume":"70","author":"F Imam","year":"2018","unstructured":"Imam F et al (2018b) Apremilast prevent doxorubicin-induced apoptosis and inflammation in heart through inhibition of oxidative stress mediated activation of NF-\u03baB signaling pathways. Pharmacol Rep 70(5):993\u20131000","journal-title":"Pharmacol Rep"},{"key":"4846_CR34","doi-asserted-by":"publisher","first-page":"260","DOI":"10.1016\/j.intimp.2018.11.023","volume":"66","author":"F Imam","year":"2019","unstructured":"Imam F et al (2019) Apremilast ameliorates carfilzomib-induced pulmonary inflammation and vascular injuries. Int Immunopharmacol 66:260\u2013266","journal-title":"Int Immunopharmacol"},{"key":"4846_CR35","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2023.115953","volume":"170","author":"E Kalantari","year":"2024","unstructured":"Kalantari E, Zolbanin NM, Ghasemnejad-Berenji M (2024) Protective effects of empagliflozin on methotrexate induced hepatotoxicity in rats. Biomed Pharmacother 170:115953","journal-title":"Biomed Pharmacother"},{"key":"4846_CR36","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/j.lfs.2018.01.010","volume":"196","author":"AF Khafaga","year":"2018","unstructured":"Khafaga AF, El-Sayed YS (2018) Spirulina ameliorates methotrexate hepatotoxicity via antioxidant, immune stimulation, and proinflammatory cytokines and apoptotic proteins modulation. Life Sci 196:9\u201317","journal-title":"Life Sci"},{"key":"4846_CR37","doi-asserted-by":"publisher","DOI":"10.1016\/j.taap.2025.117373","author":"WA Khallaf","year":"2025","unstructured":"Khallaf WA et al (2025) Buspirone ameliorates premature ovarian insufficiency evoked by cyclophosphamide in female rats; attention to AMPK\/Nrf2\/HO-1, \u03b1-Klotho\/NLRP3\/Caspase-1, and Caspase-3-mediated apoptosis interplay. Toxicol Appl Pharmacol. https:\/\/doi.org\/10.1016\/j.taap.2025.117373","journal-title":"Toxicol Appl Pharmacol"},{"issue":"2","key":"4846_CR38","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1517\/17425247.2012.642362","volume":"9","author":"ZA Khan","year":"2012","unstructured":"Khan ZA, Tripathi R, Mishra B (2012) Methotrexate: a detailed review on drug delivery and clinical aspects. Expert Opin Drug Deliv 9(2):151\u2013169","journal-title":"Expert Opin Drug Deliv"},{"issue":"4","key":"4846_CR39","first-page":"278","volume":"63","author":"WB Kim","year":"2017","unstructured":"Kim WB, Jerome D, Yeung J (2017) Diagnosis and management of psoriasis. Can Fam Physician 63(4):278\u2013285","journal-title":"Can Fam Physician"},{"issue":"32","key":"4846_CR40","doi-asserted-by":"publisher","first-page":"1354","DOI":"10.4254\/wjh.v8.i32.1354","volume":"8","author":"S Kiziltas","year":"2016","unstructured":"Kiziltas S (2016) Toll-like receptors in pathophysiology of liver diseases. World J Hepatol 8(32):1354","journal-title":"World J Hepatol"},{"key":"4846_CR41","doi-asserted-by":"publisher","first-page":"847","DOI":"10.1016\/j.biopha.2017.10.065","volume":"96","author":"J Li","year":"2017","unstructured":"Li J et al (2017) Xiaochaihutang attenuates liver fibrosis by activation of Nrf2 pathway in rats. Biomed Pharmacother 96:847\u2013853","journal-title":"Biomed Pharmacother"},{"issue":"1","key":"4846_CR42","doi-asserted-by":"publisher","first-page":"8583","DOI":"10.1080\/21655979.2021.1987818","volume":"12","author":"J Liang","year":"2021","unstructured":"Liang J et al (2021) Apremilast mitigates interleukin (IL)-13-induced inflammatory response and mucin production in human nasal epithelial cells (hNECs). Bioengineered 12(1):8583\u20138593","journal-title":"Bioengineered"},{"key":"4846_CR43","doi-asserted-by":"publisher","first-page":"280","DOI":"10.1016\/j.biopha.2017.07.101","volume":"94","author":"AM Mahmoud","year":"2017","unstructured":"Mahmoud AM, Hozayen WG, Ramadan SM (2017) Berberine ameliorates methotrexate-induced liver injury by activating Nrf2\/HO-1 pathway and PPAR\u03b3, and suppressing oxidative stress and apoptosis in rats. Biomed Pharmacother 94:280\u2013291","journal-title":"Biomed Pharmacother"},{"issue":"8","key":"4846_CR44","doi-asserted-by":"publisher","first-page":"4593","DOI":"10.1039\/C9FO00114J","volume":"10","author":"AM Mahmoud","year":"2019","unstructured":"Mahmoud AM et al (2019) Ferulic acid protects against methotrexate nephrotoxicity via activation of Nrf2\/ARE\/HO-1 signaling and PPAR\u03b3, and suppression of NF-\u03baB\/NLRP3 inflammasome axis. Food Funct 10(8):4593\u20134607","journal-title":"Food Funct"},{"issue":"4","key":"4846_CR45","doi-asserted-by":"publisher","first-page":"1029","DOI":"10.1016\/j.jaad.2018.11.057","volume":"80","author":"A Menter","year":"2019","unstructured":"Menter A et al (2019) Joint AAD-NPF guidelines of care for the management and treatment of psoriasis with biologics. J Am Acad Dermatol 80(4):1029\u20131072","journal-title":"J Am Acad Dermatol"},{"key":"4846_CR46","doi-asserted-by":"crossref","unstructured":"Mohyeldin RH et al\u00a0(2025) Modulating platelet-activating factor by rupatadine attenuates gentamicin-induced nephrotoxicity in rats via NF-\u03baB\/caspase-3 and Nrf2\/HO-1 signaling cascades.\u00a0Naunyn-Schmiedeberg's Arch Pharmacol\u00a0p 1\u201312","DOI":"10.1007\/s00210-025-04327-0"},{"key":"4846_CR47","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2024.116020","volume":"221","author":"RH Mohyeldin","year":"2024","unstructured":"Mohyeldin RH et al (2024) Aprepitant boasted a protective effect against olanzapine-induced metabolic syndrome and its subsequent hepatic, renal, and ovarian dysfunction; role of IGF(1)\/p-AKT\/FOXO(1) and NF\u03baB\/IL-1\u03b2\/TNF-\u03b1 signaling pathways in female Wistar albino rats. Biochem Pharmacol 221:116020","journal-title":"Biochem Pharmacol"},{"key":"4846_CR48","doi-asserted-by":"crossref","unstructured":"Mohyeldin RH, Sharata EE, Fawzy MA, Attya ME, Welson NN, Rofaeil RR (2025) Memantine abrogates testicular dysfunction induced by risperidone in rats with a potential role of ERK1\/2-Nrf2-caspase-3 signaling pathway. Sci Rep 15(1):12914","DOI":"10.1038\/s41598-025-94760-1"},{"issue":"1","key":"4846_CR49","first-page":"6978936","volume":"2016","author":"M Molteni","year":"2016","unstructured":"Molteni M, Gemma S, Rossetti C (2016) The role of toll-like receptor 4 in infectious and noninfectious inflammation. Mediators Inflamm 2016(1):6978936","journal-title":"Mediators Inflamm"},{"issue":"6","key":"4846_CR50","doi-asserted-by":"publisher","first-page":"3589","DOI":"10.4049\/jimmunol.173.6.3589","volume":"173","author":"HS Park","year":"2004","unstructured":"Park HS et al (2004) Cutting edge: direct interaction of TLR4 with NAD (P) H oxidase 4 isozyme is essential for lipopolysaccharide-induced production of reactive oxygen species and activation of NF-\u03baB. J Immunol 173(6):3589\u20133593","journal-title":"J Immunol"},{"key":"4846_CR51","doi-asserted-by":"publisher","first-page":"758","DOI":"10.1016\/j.biopha.2018.03.147","volume":"102","author":"N P\u0131nar","year":"2018","unstructured":"P\u0131nar N et al (2018) Ameliorating effects of tempol on methotrexate-induced liver injury in rats. Biomed Pharmacother 102:758\u2013764","journal-title":"Biomed Pharmacother"},{"issue":"11","key":"4846_CR52","doi-asserted-by":"publisher","first-page":"1667","DOI":"10.1002\/jat.4503","volume":"43","author":"SM Radwan","year":"2023","unstructured":"Radwan SM et al (2023) L-carnitine reverses methotrexate-induced nephrotoxicity in experimental rat model: insight on SIRT1\/PGC-1\u03b1\/Nrf2\/HO-1 axis. J Appl Toxicol 43(11):1667\u20131675","journal-title":"J Appl Toxicol"},{"issue":"3","key":"4846_CR53","doi-asserted-by":"publisher","first-page":"170","DOI":"10.7861\/clinmed.2021-0257","volume":"21","author":"A Raharja","year":"2021","unstructured":"Raharja A, Mahil SK, Barker JN (2021) Psoriasis: a brief overview. Clin Med (Lond) 21(3):170\u2013173","journal-title":"Clin Med (Lond)"},{"issue":"5","key":"4846_CR54","doi-asserted-by":"publisher","first-page":"511","DOI":"10.1080\/08923973.2023.2181684","volume":"45","author":"RR Rofaeil","year":"2023","unstructured":"Rofaeil RR et al (2023) Role of EGF\/ERK1\/2\/HO-1 axis in mediating methotrexate induced testicular damage in rats and the ameliorative effect of xanthine oxidase inhibitors. Immunopharmacol Immunotoxicol 45(5):511\u2013520","journal-title":"Immunopharmacol Immunotoxicol"},{"key":"4846_CR55","doi-asserted-by":"publisher","DOI":"10.1016\/j.fct.2025.115406","volume":"200","author":"RR Rofaeil","year":"2025","unstructured":"Rofaeil RR et al (2025) Repurposing levomilnacipran to attenuate premature ovarian insufficiency induced by cyclophosphamide in female Wistar albino rats through modulation of TLR4\/p38-MAPK\/NF-\u03baB p65, caspase-3-driven apoptosis, and Klotho protein expression. Food Chem Toxicol 200:115406","journal-title":"Food Chem Toxicol"},{"key":"4846_CR56","doi-asserted-by":"publisher","DOI":"10.2147\/DDDT.S237107","author":"M Roghani","year":"2020","unstructured":"Roghani M et al (2020) Alleviation of liver dysfunction, oxidative stress and inflammation underlies the protective effect of ferulic acid in methotrexate-induced hepatotoxicity. Drug des Devel Ther. https:\/\/doi.org\/10.2147\/DDDT.S237107","journal-title":"Drug des Devel Ther"},{"issue":"3","key":"4846_CR57","doi-asserted-by":"publisher","first-page":"626","DOI":"10.1038\/leu.2017.283","volume":"32","author":"T Sakura","year":"2018","unstructured":"Sakura T et al (2018) High-dose methotrexate therapy significantly improved survival of adult acute lymphoblastic leukemia: a phase III study by JALSG. Leukemia 32(3):626\u2013632","journal-title":"Leukemia"},{"key":"4846_CR58","doi-asserted-by":"publisher","DOI":"10.1016\/j.tox.2020.152439","volume":"437","author":"RM Salama","year":"2020","unstructured":"Salama RM et al (2020) LCZ696 (sacubitril\/valsartan) protects against cyclophosphamide-induced testicular toxicity in rats: role of neprilysin inhibition and lncRNA TUG1 in ameliorating apoptosis. Toxicology 437:152439","journal-title":"Toxicology"},{"issue":"1","key":"4846_CR59","doi-asserted-by":"publisher","first-page":"32706","DOI":"10.1038\/s41598-025-90710-z","volume":"15","author":"AM Sayed","year":"2025","unstructured":"Sayed AM et al (2025) Sparstolonin B attenuates MRSA-induced wound and peritonitis infection: in vivo, phytochemical, and computational investigation. Sci Rep 15(1):32706","journal-title":"Sci Rep"},{"key":"4846_CR60","doi-asserted-by":"crossref","unstructured":"Sharata EE, Attya ME, Khalaf MM, Rofaeil RR, Hemeida RAM, Abo-Youssef\u00a0AM\u00a0(2025) Unraveling chemotherapy-evoked hepatic dysfunction: a deep dive into cyclophosphamide-related liver injury.\u00a0Naunyn-Schmiedeberg's Arch Pharmacol 1\u201316","DOI":"10.1007\/s00210-025-04583-0"},{"key":"4846_CR61","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2025.114384","volume":"152","author":"EE Sharata","year":"2025","unstructured":"Sharata EE et al (2025a) Levomilnacipran alleviates cyclophosphamide-induced hepatic dysfunction in male Wistar albino rats; emerging role of \u03b1-Klotho\/TLR4\/p38-MAPK\/NF-\u03baB p65 and caspase-3-driven apoptosis trajectories. Int Immunopharmacol 152:114384","journal-title":"Int Immunopharmacol"},{"key":"4846_CR62","doi-asserted-by":"crossref","unstructured":"Sharata EE, Attya ME, Khalaf MM, Rofaeil RR, Abo-Youssef AM, Hemeida RA (2025b) Decoding premature ovarian insufficiency: a full spectrum review from epidemiology to management with emphasis on cyclophosphamide-evoked ovarian injury. Food Chem Toxicol 115719","DOI":"10.1016\/j.fct.2025.115719"},{"issue":"11","key":"4846_CR63","doi-asserted-by":"publisher","first-page":"691","DOI":"10.3390\/biom9110691","volume":"9","author":"IO Sherif","year":"2019","unstructured":"Sherif IO, Al-Shaalan NH, Sabry D (2019) Ginkgo biloba extract alleviates methotrexate-induced renal injury: new impact on PI3K\/Akt\/mTOR signaling and MALAT1 expression. Biomolecules 9(11):691","journal-title":"Biomolecules"},{"key":"4846_CR64","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2020.110259","volume":"128","author":"MM Soliman","year":"2020","unstructured":"Soliman MM et al (2020) The ameliorative impacts of Moringa oleifera leaf extract against oxidative stress and methotrexate-induced hepato-renal dysfunction. Biomed Pharmacother 128:110259","journal-title":"Biomed Pharmacother"},{"issue":"12","key":"4846_CR65","doi-asserted-by":"publisher","first-page":"3197","DOI":"10.1681\/ASN.2021050598","volume":"32","author":"JA Sparks","year":"2021","unstructured":"Sparks JA et al (2021) Effect of low-dose methotrexate on eGFR and kidney adverse events: a randomized clinical trial. J Am Soc Nephrol 32(12):3197\u20133207","journal-title":"J Am Soc Nephrol"},{"key":"4846_CR66","unstructured":"Suvarna S, Layton C, Bancroft J (2013) The hematoxylins and eosin. Bancroft\u2019s theory and practice of histological techniques, 7th ed., Churchill Livingstone: London, UK, 172\u2013186"},{"key":"4846_CR67","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1007\/s12016-008-8091-0","volume":"36","author":"F Tacke","year":"2009","unstructured":"Tacke F, Luedde T, Trautwein C (2009) Inflammatory pathways in liver homeostasis and liver injury. Clin Rev Allergy Immunol 36:4\u201312","journal-title":"Clin Rev Allergy Immunol"},{"issue":"3","key":"4846_CR68","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1016\/j.jaad.2016.07.064","volume":"76","author":"J Takeshita","year":"2017","unstructured":"Takeshita J et al (2017) Psoriasis and comorbid diseases: epidemiology. J Am Acad Dermatol 76(3):377\u2013390","journal-title":"J Am Acad Dermatol"},{"issue":"3","key":"4846_CR69","first-page":"44","volume":"2","author":"E Tousson","year":"2014","unstructured":"Tousson E et al (2014) Abrogation by Ginkgo Byloba leaf extract on hepatic and renal toxicity induced by methotrexate in rats. J Cancer Res Treat 2(3):44\u201351","journal-title":"J Cancer Res Treat"},{"issue":"5","key":"4846_CR70","doi-asserted-by":"publisher","first-page":"744","DOI":"10.3109\/0886022X.2016.1158070","volume":"38","author":"HB Ulusoy","year":"2016","unstructured":"Ulusoy HB, \u00d6zt\u00fcrk \u0130, S\u00f6nmez MF (2016) Protective effect of propolis on methotrexate-induced kidney injury in the rat. Ren Fail 38(5):744\u2013750","journal-title":"Ren Fail"},{"key":"4846_CR71","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1016\/0006-291X(63)90275-4","volume":"10","author":"WH Vogel","year":"1963","unstructured":"Vogel WH, Snyder R, Schulman MP (1963) The inhibition of dehydrogenases by folic acid and several of its analogs. Biochem Biophys Res Commun 10:97\u2013101","journal-title":"Biochem Biophys Res Commun"},{"issue":"10","key":"4846_CR72","doi-asserted-by":"publisher","first-page":"2222","DOI":"10.1002\/cncr.20255","volume":"100","author":"BC Widemann","year":"2004","unstructured":"Widemann BC et al (2004) High-dose methotrexate-induced nephrotoxicity in patients with osteosarcoma: incidence, treatment, and outcome. Cancer 100(10):2222\u20132232","journal-title":"Cancer"},{"issue":"5303","key":"4846_CR73","doi-asserted-by":"publisher","first-page":"1129","DOI":"10.1126\/science.275.5303.1129","volume":"275","author":"J Yang","year":"1997","unstructured":"Yang J et al (1997) Prevention of apoptosis by Bcl-2: release of cytochrome c from mitochondria blocked. Science 275(5303):1129\u20131132","journal-title":"Science"},{"issue":"3","key":"4846_CR74","doi-asserted-by":"publisher","first-page":"754","DOI":"10.1007\/s12640-021-00340-2","volume":"39","author":"H Yin","year":"2021","unstructured":"Yin H et al (2021) The protective effects of apremilast against oxygen\u2013glucose deprivation\/reperfusion (OGD\/R)-induced inflammation and apoptosis in astroglia mediated by CREB\/BDNF. Neurotox Res 39(3):754\u2013763","journal-title":"Neurotox Res"},{"issue":"3","key":"4846_CR75","doi-asserted-by":"publisher","first-page":"1741","DOI":"10.3390\/cimb43030123","volume":"43","author":"NS Younis","year":"2021","unstructured":"Younis NS et al (2021) Geraniol averts methotrexate-induced acute kidney injury via Keap1\/Nrf2\/HO-1 and MAPK\/NF-\u03baB pathways. Curr Issues Mol Biol 43(3):1741\u20131755","journal-title":"Curr Issues Mol Biol"},{"issue":"1","key":"4846_CR76","doi-asserted-by":"publisher","DOI":"10.1002\/ardp.202400684","volume":"358","author":"EM Zahran","year":"2025","unstructured":"Zahran EM et al (2025) Sumac liposomes\/mesenchymal stem cells fight methotrexate-induced nephrotoxicity in rats via regulating Nrf-2\/Keap-1\/HO-1 and apoptotic signaling pathways. Arch Pharm (Weinheim) 358(1):e2400684","journal-title":"Arch Pharm (Weinheim)"}],"container-title":["Naunyn-Schmiedeberg's Archives of Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00210-025-04846-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00210-025-04846-w","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00210-025-04846-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T05:16:27Z","timestamp":1776316587000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00210-025-04846-w"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,15]]},"references-count":76,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2026,3]]}},"alternative-id":["4846"],"URL":"https:\/\/doi.org\/10.1007\/s00210-025-04846-w","relation":{},"ISSN":["0028-1298","1432-1912"],"issn-type":[{"value":"0028-1298","type":"print"},{"value":"1432-1912","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,15]]},"assertion":[{"value":"2 September 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 November 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 December 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Compliance with the ARRIVE (Animal Research: Reporting of In Vivo Experiments) standards was maintained during all animal experiments included in this study. Furthermore, the animal protocols in this work adhered to the NIH Guide (8th edition, National Research Council, 2010) for the Care and Use of Laboratory Animals and were approved by the Institutional Ethical Committee of Deraya Center for Scientific Research, Deraya University, Egypt (permission number: DCSR-04025\u201351).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participate"}},{"value":"Not applicable.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"Not applicable.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Clinical trial number"}},{"value":"The authors declare no competing interests.","order":6,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}