{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T14:45:38Z","timestamp":1786977938743,"version":"build-2736575974"},"reference-count":107,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2025,8,5]],"date-time":"2025-08-05T00:00:00Z","timestamp":1754352000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2025,8,5]],"date-time":"2025-08-05T00:00:00Z","timestamp":1754352000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["analyticalsciencejournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Applied Toxicology"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Oral submucous fibrosis (OSMF) is an oral potentially malignant disorder associated with a high risk of malignant transformation, characterized by the excessive accumulation of extracellular matrix (ECM). The primary etiological factors contributing to OSMF include betel nut chewing, smoking, and tobacco use, with or without alcohol consumption. Exposure to betel nut, smokeless tobacco extracts, and cigarette smoke induces cytotoxicity in oral epithelial cells through apoptosis and oxidative stress, while simultaneously promoting fibroblast proliferation and ECM synthesis. Arecoline, a major alkaloid in betel nut, contributes to epithelial atrophy, senescence, and apoptosis. It also activates the JNK\/ATF2\/Jun pathway, leading to the activation of transforming growth factor (TGF)\u2010\u03b2 signaling in epithelial cells. TGF\u2010\u03b21 signaling, initiated by epithelial cells, activates fibroblasts in a paracrine manner, facilitating their transition to myofibroblasts and resulting in excessive ECM deposition within the OSMF microenvironment. Furthermore, arecoline stimulates fibroblast proliferation and activates the TGF\u2010\u03b21\/SMAD signaling pathway, thereby promoting ECM synthesis. From a therapeutic perspective, intralesional administration of corticosteroids (such as dexamethasone, betamethasone, hydrocortisone, or triamcinolone) combined with hyaluronidase and antioxidants has shown improvements in mouth opening, burning sensations, and overall quality of life in OSMF patients. Additionally, herbal medicines such as curcumin and\n                    <jats:styled-content style=\"fixed-case\">\n                      <jats:italic>aloe vera<\/jats:italic>\n                    <\/jats:styled-content>\n                    have demonstrated efficacy, particularly in enhancing tongue protrusion and alleviating burning sensations, respectively. Lycopene and salvianolic acid B have also proven beneficial in relieving clinical symptoms and contributing to the long\u2010term management of OSMF.\n                  <\/jats:p>","DOI":"10.1002\/jat.4877","type":"journal-article","created":{"date-parts":[[2025,8,6]],"date-time":"2025-08-06T00:09:47Z","timestamp":1754438987000},"page":"2498-2511","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Toxicological Impacts of Arecoline and Tobacco in Oral Submucous Fibrosis: Mechanisms and Therapeutic Insights"],"prefix":"10.1002","volume":"45","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5068-2383","authenticated-orcid":false,"given":"Devaraj","family":"Ezhilarasan","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Saveetha Dental College and Hospital, Saveetha Institute of Medical and Technical Sciences (SIMATS) Saveetha University  Chennai Tamil Nadu India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1959-3419","authenticated-orcid":false,"given":"Vadivel","family":"Jayanth\u00a0Kumar","sequence":"additional","affiliation":[{"name":"Department of Oral Medicine, Saveetha Dental College and Hospital, Saveetha Institute of Medical and Technical Sciences (SIMATS) Saveetha University  Chennai Tamil Nadu India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,8,5]]},"reference":[{"issue":"2","key":"e_1_2_13_2_1","article-title":"Evaluation of Hematological Profile in Oral Submucous Fibrosis","volume":"14","author":"Abidullah M.","year":"2022","journal-title":"Cureus"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.31557\/APJCP.2022.23.9.3125"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.oraloncology.2020.104799"},{"key":"e_1_2_13_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/jop.12463"},{"key":"e_1_2_13_6_1","doi-asserted-by":"publisher","DOI":"10.1111\/jop.12581"},{"key":"e_1_2_13_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.archoralbio.2013.11.003"},{"key":"e_1_2_13_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tiv.2014.01.004"},{"key":"e_1_2_13_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/5584_2014_91"},{"key":"e_1_2_13_10_1","doi-asserted-by":"publisher","DOI":"10.5005\/jp-journals-10024-3259"},{"key":"e_1_2_13_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.10200"},{"key":"e_1_2_13_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12603-015-0578-9"},{"key":"e_1_2_13_13_1","doi-asserted-by":"publisher","DOI":"10.31557\/APJCP.2021.22.12.3941"},{"key":"e_1_2_13_14_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.00847"},{"key":"e_1_2_13_15_1","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.12219"},{"key":"e_1_2_13_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jfma.2021.04.012"},{"key":"e_1_2_13_17_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12903-023-03488-9"},{"key":"e_1_2_13_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.oraloncology.2011.11.021"},{"key":"e_1_2_13_19_1","doi-asserted-by":"publisher","DOI":"10.1158\/1541-7786.MCR-08-0062"},{"key":"e_1_2_13_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.archoralbio.2019.03.021"},{"key":"e_1_2_13_21_1","volume-title":"Holland\u2010Frei Cancer Medicine","author":"Engstrom P. F.","year":"2003"},{"key":"e_1_2_13_22_1","doi-asserted-by":"publisher","DOI":"10.1080\/00498254.2025.2505066"},{"key":"e_1_2_13_23_1","doi-asserted-by":"publisher","DOI":"10.12669\/pjms.294.3696"},{"key":"e_1_2_13_24_1","doi-asserted-by":"publisher","DOI":"10.3390\/app12073464"},{"key":"e_1_2_13_25_1","doi-asserted-by":"publisher","DOI":"10.1111\/jop.13009"},{"key":"e_1_2_13_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/0278-2391(88)90043-2"},{"key":"e_1_2_13_27_1","doi-asserted-by":"publisher","DOI":"10.25259\/IJDVL_371_20"},{"key":"e_1_2_13_28_1","doi-asserted-by":"publisher","DOI":"10.4103\/0975-962X.135266"},{"key":"e_1_2_13_29_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.26344"},{"key":"e_1_2_13_30_1","doi-asserted-by":"publisher","DOI":"10.1034\/j.1600-0714.2000.290304.x"},{"key":"e_1_2_13_31_1","doi-asserted-by":"publisher","DOI":"10.1034\/j.1600-0714.2001.300103.x"},{"key":"e_1_2_13_32_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1013991025848"},{"key":"e_1_2_13_33_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M115.641670"},{"key":"e_1_2_13_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jfma.2017.07.003"},{"key":"e_1_2_13_35_1","first-page":"82","article-title":"Management of Oral Submucous Fibrosis With Injection of Hyaluronidase and Dexamethasone in Grade III Oral Submucous Fibrosis: A Retrospective Study","volume":"8","author":"James L.","year":"2015","journal-title":"Journal of International Oral Health"},{"key":"e_1_2_13_36_1","first-page":"160","article-title":"Risk for Oral Cancer From Smokeless Tobacco","volume":"18","author":"Janbaz K. H.","year":"2014","journal-title":"Contemporary Oncology"},{"key":"e_1_2_13_37_1","doi-asserted-by":"publisher","DOI":"10.4103\/JPBS.JPBS_6_19"},{"key":"e_1_2_13_38_1","doi-asserted-by":"publisher","DOI":"10.1017\/S0022215100096286"},{"key":"e_1_2_13_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jobcr.2024.12.007"},{"key":"e_1_2_13_40_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1601-0825.2011.01791.x"},{"key":"e_1_2_13_41_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0051806"},{"key":"e_1_2_13_42_1","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.12622"},{"key":"e_1_2_13_43_1","doi-asserted-by":"publisher","DOI":"10.1186\/1746-160X-2-33"},{"key":"e_1_2_13_44_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12015-024-10744-0"},{"key":"e_1_2_13_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tripleo.2006.07.011"},{"key":"e_1_2_13_46_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjc.6600727"},{"key":"e_1_2_13_47_1","doi-asserted-by":"publisher","DOI":"10.1080\/13880209.2020.1851729"},{"key":"e_1_2_13_48_1","first-page":"5066","article-title":"Smokeless Tobacco Extract Inhibits Proliferation and Promotes Apoptosis in Oral Mucous Fibroblasts","volume":"16","author":"Li L.","year":"2018","journal-title":"Oncology Letters"},{"key":"e_1_2_13_49_1","doi-asserted-by":"publisher","DOI":"10.3892\/or.2014.3091"},{"key":"e_1_2_13_50_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12903-023-02887-2"},{"key":"e_1_2_13_51_1","doi-asserted-by":"crossref","first-page":"812","DOI":"10.55519\/JAMC-04-10841","article-title":"Comparison of Efficacy of Steroids Alone and Combination of Steroids With Hyaluronidase on Mouth Opening in Oral Submucous Fibrosis Patients","volume":"34","author":"Liaqat S.","year":"2022","journal-title":"Journal of Ayub Medical College, Abbottabad: JAMC"},{"key":"e_1_2_13_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.oooo.2015.04.013"},{"key":"e_1_2_13_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.archoralbio.2019.104646"},{"key":"e_1_2_13_54_1","first-page":"801","article-title":"Zhong Nan Da Xue Xue Bao. Yi Xue Ban = Journal of Central South University","volume":"44","author":"Lu C.","year":"2019","journal-title":"Medical Science"},{"key":"e_1_2_13_55_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jfma.2016.03.011"},{"key":"e_1_2_13_56_1","doi-asserted-by":"publisher","DOI":"10.1080\/01635589709514499"},{"key":"e_1_2_13_57_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13065-015-0132-1"},{"key":"e_1_2_13_58_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10787-023-01212-1"},{"key":"e_1_2_13_59_1","doi-asserted-by":"publisher","DOI":"10.1111\/jop.12222"},{"key":"e_1_2_13_60_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jobcr.2012.10.008"},{"key":"e_1_2_13_61_1","doi-asserted-by":"publisher","DOI":"10.5005\/jp-journals-10024-1406"},{"key":"e_1_2_13_62_1","doi-asserted-by":"publisher","DOI":"10.1111\/jop.12017"},{"key":"e_1_2_13_63_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12105-023-01591-5"},{"key":"e_1_2_13_64_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0129252"},{"key":"e_1_2_13_65_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep34314"},{"key":"e_1_2_13_66_1","doi-asserted-by":"publisher","DOI":"10.4103\/jomfp.JOMFP_65_20"},{"key":"e_1_2_13_67_1","doi-asserted-by":"publisher","DOI":"10.1111\/jop.12924"},{"key":"e_1_2_13_68_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.157.4.1339"},{"key":"e_1_2_13_69_1","first-page":"ZC43\u2013ZC46","article-title":"Impact of Alcohol Dependency on Oral Health\u2014A Cross\u2010Sectional Comparative Study","volume":"11","author":"Priyanka K.","year":"2017","journal-title":"Journal of Clinical and Diagnostic Research: JCDR"},{"key":"e_1_2_13_70_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jormas.2023.101423"},{"key":"e_1_2_13_71_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10534-006-9013-3"},{"key":"e_1_2_13_72_1","doi-asserted-by":"publisher","DOI":"10.31557\/APJCP.2025.26.5.1483"},{"issue":"1","key":"e_1_2_13_73_1","article-title":"Assessment of Oral Lesions With Tobacco Usage: A Cross\u2010Sectional Clinicopathological Study in Sri Ganganagar, Rajasthan, India","volume":"15","author":"Ramalingam K.","year":"2023","journal-title":"Cureus"},{"key":"e_1_2_13_74_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jobcr.2020.10.008"},{"key":"e_1_2_13_75_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12070-020-01965-z"},{"key":"e_1_2_13_76_1","doi-asserted-by":"publisher","DOI":"10.4103\/0970-9290.49064"},{"key":"e_1_2_13_77_1","doi-asserted-by":"publisher","DOI":"10.4103\/jcrt.JCRT_719_19"},{"key":"e_1_2_13_78_1","doi-asserted-by":"publisher","DOI":"10.1155\/2018\/3472087"},{"key":"e_1_2_13_79_1","doi-asserted-by":"publisher","DOI":"10.3109\/15376516.2014.943441"},{"key":"e_1_2_13_80_1","doi-asserted-by":"publisher","DOI":"10.1177\/20503121231200757"},{"key":"e_1_2_13_81_1","doi-asserted-by":"publisher","DOI":"10.1186\/1475-2867-13-51"},{"key":"e_1_2_13_82_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21197231"},{"key":"e_1_2_13_83_1","doi-asserted-by":"publisher","DOI":"10.3126\/kumj.v11i4.12521"},{"key":"e_1_2_13_84_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0765.2012.01472.x"},{"key":"e_1_2_13_85_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phytochem.2016.02.002"},{"key":"e_1_2_13_86_1","doi-asserted-by":"publisher","DOI":"10.5005\/jp-journals-10024-3144"},{"key":"e_1_2_13_87_1","doi-asserted-by":"publisher","DOI":"10.4317\/medoral.17083"},{"key":"e_1_2_13_88_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2006.12.001"},{"key":"e_1_2_13_89_1","doi-asserted-by":"crossref","first-page":"30","DOI":"10.4103\/jomfp.JOMFP_131_15","article-title":"Estimation of Hemoglobin, Serum Iron, Total Iron\u2010Binding Capacity and Serum Ferritin Levels in Oral Submucous Fibrosis: A Clinicopathological Study","volume":"21","author":"Thakur M.","year":"2017","journal-title":"Journal of Oral and Maxillofacial Pathology: JOMFP"},{"key":"e_1_2_13_90_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0765.2008.01185.x"},{"key":"e_1_2_13_91_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.oooo.2015.11.023"},{"key":"e_1_2_13_92_1","doi-asserted-by":"publisher","DOI":"10.1034\/j.1600-0714.2003.00004.x"},{"key":"e_1_2_13_93_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.oraloncology.2005.05.006"},{"key":"e_1_2_13_94_1","doi-asserted-by":"publisher","DOI":"10.4103\/0973-029X.40936"},{"key":"e_1_2_13_95_1","doi-asserted-by":"publisher","DOI":"10.1111\/jop.12965"},{"key":"e_1_2_13_96_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jfma.2015.05.011"},{"key":"e_1_2_13_97_1","doi-asserted-by":"publisher","DOI":"10.7717\/peerj.15158"},{"key":"e_1_2_13_98_1","doi-asserted-by":"publisher","DOI":"10.1177\/00220345221092751"},{"key":"e_1_2_13_99_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.apjtm.2017.10.026"},{"key":"e_1_2_13_100_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jds.2022.10.023"},{"key":"e_1_2_13_101_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0714.2009.00758.x"},{"key":"e_1_2_13_102_1","first-page":"188","article-title":"Methods and Effects of Injection of Salvianolic Acid B Combined With Triamcinolone Acetonide in the Treatment of Oral Submucous Fibrosis","volume":"26","author":"Xiao Y. C.","year":"2017","journal-title":"Shanghai Kou Qiang Yi Xue"},{"issue":"3","key":"e_1_2_13_103_1","first-page":"260","article-title":"Rat Model With Oral Submucous Fibrosis Induced by Arecoline and Mechanical Stimulation","volume":"37","author":"Yang B.","year":"2019","journal-title":"Hua Xi Kou Qiang Yi Xue Za Zhi"},{"key":"e_1_2_13_104_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0714.2007.00633.x"},{"key":"e_1_2_13_105_1","doi-asserted-by":"publisher","DOI":"10.1111\/jop.12945"},{"key":"e_1_2_13_106_1","doi-asserted-by":"publisher","DOI":"10.1111\/odi.14235"},{"key":"e_1_2_13_107_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxres\/tfab046"},{"key":"e_1_2_13_108_1","doi-asserted-by":"publisher","DOI":"10.2334\/josnusd.19-0170"}],"container-title":["Journal of Applied Toxicology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jat.4877","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/jat.4877","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jat.4877","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T06:41:19Z","timestamp":1776062479000},"score":1,"resource":{"primary":{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/10.1002\/jat.4877"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,5]]},"references-count":107,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2025,12]]}},"alternative-id":["10.1002\/jat.4877"],"URL":"https:\/\/doi.org\/10.1002\/jat.4877","archive":["Portico"],"relation":{},"ISSN":["0260-437X","1099-1263"],"issn-type":[{"value":"0260-437X","type":"print"},{"value":"1099-1263","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,5]]},"assertion":[{"value":"2025-05-13","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-07-22","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-08-05","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}