{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,21]],"date-time":"2026-02-21T11:38:57Z","timestamp":1771673937805,"version":"3.50.1"},"reference-count":69,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2025,2,23]],"date-time":"2025-02-23T00:00:00Z","timestamp":1740268800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J Biochem &amp;amp; Molecular Tox"],"published-print":{"date-parts":[[2025,3]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>Carbon tetrachloride (CCl<jats:sub>4<\/jats:sub>), a volatile organic compound, is harmful to multi\u2010organs, including the liver, lungs, muscles, and kidneys. Methyl donors, such as methionine, choline, betaine, and folic acid, are vital to one\u2010carbon metabolism and have great potential to\u00a0alleviate oxidative stress and inflammation, thus mitigating disease onset. Hence, the current study aims to examine the therapeutic effect of methyl donors against CCl<jats:sub>4<\/jats:sub>\u2010induced nephrotoxicity. Nephrotoxicity was developed in male Sprague Dawley rats using CCl<jats:sub>4<\/jats:sub> at a dose of 1\u2009mL\/kg (4\u2010week model induction) twice a week via the intraperitoneal route. Thereafter, methyl donor treatments through oral gavage were given for the next 6 weeks with a continuation of CCl<jats:sub>4<\/jats:sub> administration. Biochemical, oxidative stress parameters, histopathological, and qRT\u2010PCR analyses were done at the completion of the 10\u2010week. Biochemical analyses revealed that CCl<jats:sub>4<\/jats:sub> induces nephrotoxicity, as evidenced by increased urea and creatinine levels and decreased albumin levels. These detrimental effects were significantly ameliorated by methyl donor treatment. Moreover, CCl<jats:sub>4<\/jats:sub> decreased the antioxidant enzyme activity (superoxide dismutase; SOD and catalase; CAT) while increasing oxidative stress markers (malondialdehyde; MDA and nitrite). Methyl donor treatment effectively mitigated these oxidative changes. Histopathological analysis demonstrated the nephroprotective effect of methyl donors against CCl<jats:sub>4<\/jats:sub>\u2010induced nephrotoxicity, showing reduced tissue damage and protection of renal architecture. At the molecular level, methyl donor treatment alleviated the CCl<jats:sub>4<\/jats:sub>\u2010induced increase in kidney injury biomarkers (Kidney injury molecule 1; KIM\u20101 and Neutrophil gelatinase\u2010associated lipocalin; NGAL), as well as inflammatory (IL\u20106 and TNF\u2010\u03b1) and fibrosis\u2010related genes (Acta\u20102 and TGF\u2010\u03b2). In conclusion, our findings suggest that methyl donors possess anti\u2010inflammatory and anti\u2010fibrotic properties. They protect against CCl<jats:sub>4<\/jats:sub>\u2010induced oxidative damage to renal cells, likely due to their reactive oxygen species scavenging capabilities and their ability to restore key early renal injury biomarkers (KIM\u20101 and NGAL). Methyl donors hold great promise as a cutting\u2010edge therapy approach for preventing CCl<jats:sub>4<\/jats:sub>\u2010induced nephrotoxicity.<\/jats:p>","DOI":"10.1002\/jbt.70188","type":"journal-article","created":{"date-parts":[[2025,2,23]],"date-time":"2025-02-23T23:13:56Z","timestamp":1740352436000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Methyl Donor Ameliorates CCl<sub>4<\/sub>\u2010Induced Nephrotoxicity by Inhibiting Oxidative Stress, Inflammation, and Fibrosis Through the Attenuation of Kidney Injury Molecule 1 and Neutrophil Gelatinase\u2010Associated Lipocalin Expression"],"prefix":"10.1002","volume":"39","author":[{"given":"Nirmal","family":"Manhar","sequence":"first","affiliation":[{"name":"Department of Pharmacology Central University of Punjab Bathinda India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sumeet Kumar","family":"Singh","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Central University of Punjab Bathinda India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Poonam","family":"Yadav","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Central University of Punjab Bathinda India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manish","family":"Bishnolia","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Central University of Punjab Bathinda India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amit","family":"Khurana","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Central University of Punjab Bathinda India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jasvinder Singh","family":"Bhatti","sequence":"additional","affiliation":[{"name":"Department of Human Genetics and Molecular Medicine School of Health Sciences, Central University of Punjab Bathinda India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7498-5680","authenticated-orcid":false,"given":"Umashanker","family":"Navik","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Central University of Punjab Bathinda India"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,2,23]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.4062\/biomolther.2012.20.3.268"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.4103\/japtr.JAPTR_336_18"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ekir.2023.08.031"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1042\/bj2220001"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.2174\/0115665240257603230919103539"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11356-021-16524-4"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1080\/15376516.2018.1519864"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1021\/tx200169n"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2010.3790"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.3934\/genet.2017.2.103"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1186\/1472-6882-11-17"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1139\/cjpp-2018-0641"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1155\/2018\/2474831"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/jat.1249"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00253-014-6156-y"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00726-017-2494-2"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1097\/SHK.0b013e318160f417"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-230064"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.etap.2016.05.033"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbt.23559"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0090-4295(03)00255-3"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1002\/tox.24291"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1753-4887.2009.00246.x"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1093\/ajcn\/86.4.1073"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-0037-1614438"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI10588"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.3945\/an.114.007955"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1093\/jn\/nxz315"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1017\/jns.2019.34"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2019.01386"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.7150\/ijbs.5976"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.3945\/an.111.000992"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1186\/1743-7075-10-20"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12576-024-00900-z"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.fct.2024.115230"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1002\/mnfr.201801401"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jnutbio.2018.05.010"},{"issue":"7","key":"e_1_2_9_39_1","first-page":"897","article-title":"Betaine Inhibits Toll\u2010Like Receptor 4 Expression in Rats With Ethanol\u2010Induced Liver Injury","volume":"16","author":"Shi Q. Z.","year":"2010","journal-title":"World Journal of Gastroenterology"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2019.01.039"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.acthis.2021.151820"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(19)52451-6"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/0003-2697(79)90738-3"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1002\/cber.187901201117"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/0003-9861(78)90479-4"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-395630-9.50159-6"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.4103\/ijp.IJP_850_16"},{"key":"e_1_2_9_48_1","first-page":"1","article-title":"What Are the Toxicological Effects of Carbon Tetrachloride U.S","author":"Carbon Tetrachloride Poisoning","year":"2019","journal-title":"Department of Health & Human Services: AGENCY FOR TOXIC SUBSTANCES AND DISEASE REGISTRY"},{"key":"e_1_2_9_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-824315-2.01082-4"},{"key":"e_1_2_9_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2021.09.008"},{"key":"e_1_2_9_51_1","doi-asserted-by":"publisher","DOI":"10.3390\/healthcare10010061"},{"key":"e_1_2_9_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejcb.2016.06.003"},{"issue":"10","key":"e_1_2_9_53_1","article-title":"Assessment and Correlation of Urea and Creatinine Levels in Saliva and Serum of Patients With Chronic Kidney Disease, Diabetes and Hypertension\u2010 A Research Study","volume":"10","author":"Pandya D.","year":"2016","journal-title":"Journal of Clinical and Diagnostic Research"},{"key":"e_1_2_9_54_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-022-25254-7"},{"key":"e_1_2_9_55_1","doi-asserted-by":"publisher","DOI":"10.1248\/bpb.25.1494"},{"key":"e_1_2_9_56_1","doi-asserted-by":"publisher","DOI":"10.1248\/bpb.b16-00078"},{"key":"e_1_2_9_57_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1440-1681.1993.tb00579.x"},{"key":"e_1_2_9_58_1","doi-asserted-by":"publisher","DOI":"10.1002\/cbf.1166"},{"key":"e_1_2_9_59_1","doi-asserted-by":"publisher","DOI":"10.3109\/13880209.2015.1035794"},{"key":"e_1_2_9_60_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-023-35228-y"},{"key":"e_1_2_9_61_1","doi-asserted-by":"publisher","DOI":"10.1002\/cbf.1166"},{"key":"e_1_2_9_62_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2024.116340"},{"key":"e_1_2_9_63_1","doi-asserted-by":"publisher","DOI":"10.1080\/0886022X.2024.2319330"},{"key":"e_1_2_9_64_1","doi-asserted-by":"publisher","DOI":"10.1039\/D0FO00711K"},{"key":"e_1_2_9_65_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2020.107117"},{"key":"e_1_2_9_66_1","doi-asserted-by":"publisher","DOI":"10.1002\/path.2277"},{"key":"e_1_2_9_67_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-662-46943-9_13"},{"key":"e_1_2_9_68_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11010-014-2171-7"},{"key":"e_1_2_9_69_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11255-009-9608-z"},{"key":"e_1_2_9_70_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.medine.2013.09.003"}],"container-title":["Journal of Biochemical and Molecular Toxicology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jbt.70188","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T12:51:56Z","timestamp":1748350316000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/jbt.70188"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,23]]},"references-count":69,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2025,3]]}},"alternative-id":["10.1002\/jbt.70188"],"URL":"https:\/\/doi.org\/10.1002\/jbt.70188","archive":["Portico"],"relation":{},"ISSN":["1095-6670","1099-0461"],"issn-type":[{"value":"1095-6670","type":"print"},{"value":"1099-0461","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,23]]},"assertion":[{"value":"2024-08-21","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-02-08","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-02-23","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70188"}}