{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T01:55:54Z","timestamp":1791251754867,"version":"4.1.0"},"reference-count":61,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2025,12,10]],"date-time":"2025-12-10T00:00:00Z","timestamp":1765324800000},"content-version":"vor","delay-in-days":9,"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":[[2025,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Drug\u2010induced nephrotoxicity is a significant clinical complication associated with several chemotherapeutic agents, including 5\u2010fluorouracil (5\u2010FU). This study was aimed to investigate the nephroprotective potential of boldine, an aporphine alkaloid, against 5\u2010FU\u2010induced renal toxicity using in vitro (HEK293 cells) and in vivo (Wistar rats) models. In vitro cytotoxicity was evaluated using the MTT assay, AO\/EB and DAPI staining was performed to identify apoptotic alterations. The expression of apoptotic and antioxidant genes was analyzed by quantitative and semi\u2010quantitative PCR. For the in vivo study, rats were divided into five groups. One group received a single intraperitoneal dose of 5\u2010FU (150\u2009mg\/kg) to induce nephrotoxicity. In the remaining groups, 5\u2010FU was administered followed by oral treatment with boldine (10 or 20\u2009mg\/kg) or silymarin (100\u2009mg\/kg) for 7 days. Biochemical markers including creatinine, urea, blood urea nitrogen, uric acid in serum and oxidative stress indicators in kidney tissue were analyzed. MAPK pathway\u2010related gene expression and histopathological changes were assessed. Treatment of HEK cells with 5\u2010FU markedly reduced cell viability and induced apoptosis, while co\u2010treatment with boldine restored viability and normal cell morphology. Boldine modulated the 5\u2010FU\u2010induced downregulation of SOD, CAT, GPx, and Bcl\u20102 and upregulation of Bax and caspase\u20103. In vivo, boldine treatment normalized elevated nephrotoxic markers in serum, enhanced antioxidant enzyme activities, and inhibited activation of ASK1, ERK1, c\u2010Jun, and NF\u2010\u03baB1. Histopathological findings further confirmed that boldine preserved renal tissue integrity and prevented tubular and glomerular damage. Overall, boldine significantly protected against 5\u2010FU\u2010induced renal injury via anti\u2010apoptotic, antioxidant, and anti\u2010inflammatory mechanisms.<\/jats:p>","DOI":"10.1002\/jbt.70636","type":"journal-article","created":{"date-parts":[[2025,12,11]],"date-time":"2025-12-11T07:07:31Z","timestamp":1765436851000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Protective Role of Boldine Against 5\u2010Fluorouracil\u2010Induced Nephrotoxicity: In Vitro and In Vivo Approach"],"prefix":"10.1002","volume":"39","author":[{"given":"Rayar","family":"Arthina","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Hepatology and Molecular Medicine Lab, Saveetha Dental College and Hospitals Saveetha Institute of Medical and Technical Sciences (SIMATS) Chennai Tamil Nadu India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5845-4932","authenticated-orcid":false,"given":"Munusamy","family":"Karthick","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Hepatology and Molecular Medicine Lab, Saveetha Dental College and Hospitals Saveetha Institute of Medical and Technical Sciences (SIMATS) Chennai Tamil Nadu India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muthusethupathi","family":"Sharmila","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Hepatology and Molecular Medicine Lab, Saveetha Dental College and Hospitals Saveetha Institute of Medical and Technical Sciences (SIMATS) Chennai Tamil Nadu India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Somasundaram","family":"Sanjay","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Hepatology and Molecular Medicine Lab, Saveetha Dental College and Hospitals Saveetha Institute of Medical and Technical Sciences (SIMATS) Chennai Tamil Nadu India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karthik","family":"Shree Harini","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Hepatology and Molecular Medicine Lab, Saveetha Dental College and Hospitals Saveetha Institute of Medical and Technical Sciences (SIMATS) Chennai Tamil Nadu India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kulanthaivel","family":"Langeswaran","sequence":"additional","affiliation":[{"name":"Department of Biomedical Science, Science Campus Alagappa University Karaikudi Tamil Nadu India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5068-2383","authenticated-orcid":false,"given":"Devaraj","family":"Ezhilarasan","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Hepatology and Molecular Medicine Lab, Saveetha Dental College and Hospitals Saveetha Institute of Medical and Technical Sciences (SIMATS) Chennai Tamil Nadu India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,12,10]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.4103\/japtr.JAPTR_336_18"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.2215\/CJN.11290821"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.3390\/life12010060"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.2174\/1389200218666171108154419"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.3390\/life13020325"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1590\/1806-9282.66.s1.82"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12882-017-0536-3"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.etp.2017.01.012"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc1074"},{"key":"e_1_2_9_11_1","first-page":"152","article-title":"Severe Adverse Effects of 5\u2010fluorouracil in S\u20101 Were Lessened by Haemodialysis Due to Elimination of the Drug","volume":"18","author":"Isaka Y.","year":"2009","journal-title":"NDT Plus Advance Access"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics11060288"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.3390\/antiox12051005"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jsps.2023.05.021"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2024.1427147"},{"issue":"11","key":"e_1_2_9_16_1","article-title":"Boldine Treatment Induces Cytotoxicity in Human Colorectal Carcinoma and Osteosarcoma Cells","volume":"15","author":"Chandan P.","year":"2023","journal-title":"Cureus"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbt.22697"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms25010510"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms19071864"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/0022-1759(83)90303-4"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1101\/pdb.prot4493"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.3390\/nu10060718"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.2147\/JIR.S389017"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/cbf.3839"},{"key":"e_1_2_9_25_1","first-page":"1862","article-title":"Determination of Uric Acid","volume":"31","author":"Collin P. F.","year":"1959","journal-title":"Justus Liebigs Annalen der Chemie"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1093\/ajcp\/60.5.691"},{"issue":"1","key":"e_1_2_9_27_1","first-page":"15","article-title":"A New Photometric Method for Serum Urea Nitrogen Determination","volume":"33","author":"Searcy R. L.","year":"1967","journal-title":"American Journal of Medical Technology"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0009-9120(79)90032-8"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(19)52451-6"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/0003-2697(79)90738-3"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/0076-6879(90)86141-H"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1432-1033.1974.tb03714.x"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/0003-2697(72)90132-7"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/0003-9861(59)90090-6"},{"key":"e_1_2_9_35_1","first-page":"882","article-title":"Improved Method for the Determination of Blood Glutathione","volume":"61","author":"Beutler E.","year":"1963","journal-title":"Journal of Laboratory and Clinical Medicine"},{"key":"e_1_2_9_36_1","first-page":"317","article-title":"Quantification and Location of Disulfide Bonds in Proteins","volume":"64","author":"Aitken A.","year":"1997","journal-title":"Methods in Molecular Biology"},{"key":"e_1_2_9_37_1","volume-title":"Manual of Histological Techniques","author":"Bancroft J. D.","year":"1984"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1186\/1756-9966-31-60"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.3892\/ijo.2015.2904"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.3164\/jcbn.21-23"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.3390\/biom12101490"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tox.2022.153113"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00143359"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1002\/1099-1573(200008)14:5<339::AID-PTR585>3.0.CO;2-T"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2018.08.077"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.3390\/antiox10020203"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.toxrep.2024.101778"},{"issue":"10","key":"e_1_2_9_48_1","article-title":"Tangeretin's Anti\u2010Apoptoticsignaling Mechanisms in Oral Cancer Cells: In Vitro Anti\u2010Cancer Activity","volume":"15","author":"Gv V.","year":"2023","journal-title":"Cureus"},{"issue":"4","key":"e_1_2_9_49_1","first-page":"404","article-title":"The Protective Effects of Naringin Against 5\u2010fluorouracil\u2010induced Hepatotoxicity and Nephrotoxicity in Rats","volume":"21","author":"Gelen V.","year":"2018","journal-title":"Iranian Journal of Basic Medical Sciences"},{"key":"e_1_2_9_50_1","doi-asserted-by":"publisher","DOI":"10.4103\/BMRJ.BMRJ_19_19"},{"key":"e_1_2_9_51_1","doi-asserted-by":"publisher","DOI":"10.21608\/amj.2020.82575"},{"key":"e_1_2_9_52_1","first-page":"9","article-title":"Boldine Provides Protective Effect Against Nephrotoxicity Induced by Cisplatin in Wistar Rats: Role of Oxidative Stress, Inflammation and Caspase\u20103","volume":"46","author":"Turgut N.","year":"2022","journal-title":"Biocell"},{"key":"e_1_2_9_53_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbt.22404"},{"key":"e_1_2_9_54_1","doi-asserted-by":"publisher","DOI":"10.1002\/jbt.23691"},{"issue":"3","key":"e_1_2_9_55_1","first-page":"103","article-title":"The Protective Effects of Silymarin in 5\u2010fluorouracil\u2010\u0131nduced Hepatotoxicity and Nephrotoxicity in Rats","volume":"18","author":"Noorbakhsh M. F.","year":"2022","journal-title":"Iranian Veterinary Journal"},{"key":"e_1_2_9_56_1","doi-asserted-by":"publisher","DOI":"10.1111\/jgh.16087"},{"key":"e_1_2_9_57_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.taap.2015.03.019"},{"key":"e_1_2_9_58_1","doi-asserted-by":"publisher","DOI":"10.2147\/JIR.S396604"},{"key":"e_1_2_9_59_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2025.114092"},{"key":"e_1_2_9_60_1","doi-asserted-by":"publisher","DOI":"10.1016\/0165-1218(94)90038-8"},{"key":"e_1_2_9_61_1","doi-asserted-by":"publisher","DOI":"10.1016\/1043-6618(94)80093-6"},{"key":"e_1_2_9_62_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1099-1573(200003)14:2<99::AID-PTR600>3.0.CO;2-4"}],"container-title":["Journal of Biochemical and Molecular Toxicology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jbt.70636","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,22]],"date-time":"2025-12-22T06:50:51Z","timestamp":1766386251000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/jbt.70636"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12]]},"references-count":61,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2025,12]]}},"alternative-id":["10.1002\/jbt.70636"],"URL":"https:\/\/doi.org\/10.1002\/jbt.70636","archive":["Portico"],"relation":{},"ISSN":["1095-6670","1099-0461"],"issn-type":[{"value":"1095-6670","type":"print"},{"value":"1099-0461","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12]]},"assertion":[{"value":"2025-10-14","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-12-01","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-12-10","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70636"}}