{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T20:28:59Z","timestamp":1790368139899,"version":"4.1.0"},"reference-count":33,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2015,9,28]],"date-time":"2015-09-28T00:00:00Z","timestamp":1443398400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"James Paget Foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J Oral Pathology Medicine"],"published-print":{"date-parts":[[2016,5]]},"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Oral submucous fibrosis (<jats:styled-content style=\"fixed-case\">OSMF<\/jats:styled-content>) is a pre\u2010malignant condition that is strongly associated with the areca nut alkaloids, arecoline (<jats:styled-content style=\"fixed-case\">ARC<\/jats:styled-content>) and arecaidine (<jats:styled-content style=\"fixed-case\">ARD<\/jats:styled-content>). The condition is characterised by the presence of senescent fibroblasts in the subepithelial mesenchyme which have the potential to promote malignancy in the neighbouring epithelial cells. We tested the hypothesis that areca nut alkaloids induce senescence in oral fibroblasts and promote the secretion of invasion\u2010promoting transforming growth factor \u03b2 (<jats:styled-content style=\"fixed-case\">TGF<\/jats:styled-content>\u2010\u03b2) and matrix metalloproteinase\u20102 (<jats:styled-content style=\"fixed-case\">MMP<\/jats:styled-content>\u20102).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Two oral fibroblast lines were treated for 48h with ARC and <jats:styled-content style=\"fixed-case\">ARD<\/jats:styled-content>. Senescence\u2010associated \u03b2\u2010galactosidase (<jats:styled-content style=\"fixed-case\">SA<\/jats:styled-content>\u2010\u03b2Gal) activity, Ki67 (cycling cells), large 53<jats:styled-content style=\"fixed-case\">BP<\/jats:styled-content>1 foci (irreparable <jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content> strand breaks) and p16<jats:styled-content style=\"fixed-case\"><jats:sup>INK<\/jats:sup><\/jats:styled-content><jats:sup>4A<\/jats:sup> (late senescence) were used as markers of cellular senescence and were quantified using indirect immunofluorescence and the ImageJ program. <jats:styled-content style=\"fixed-case\">TGF<\/jats:styled-content>\u2010\u03b2 and <jats:styled-content style=\"fixed-case\">MMP<\/jats:styled-content>\u20102 levels were measured using <jats:styled-content style=\"fixed-case\">ELISA<\/jats:styled-content>. Statistical analyses were performed with the two\u2010tailed unpaired <jats:italic>t<\/jats:italic>\u2010test where <jats:italic>n<\/jats:italic> = 3 and the Wilcoxon\u2013Mann\u2013Whitney test where <jats:italic>n<\/jats:italic> = 6.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p><jats:styled-content style=\"fixed-case\">ARC<\/jats:styled-content> (100 and 300 \u03bcM) and <jats:styled-content style=\"fixed-case\">ARD<\/jats:styled-content> (30 and 100 \u03bcM) significantly (<jats:italic>P<\/jats:italic> &lt; 0.05) induced fibroblast senescence, as determined by the increased expression of <jats:styled-content style=\"fixed-case\">SA<\/jats:styled-content>\u2010\u03b2Gal, 53<jats:styled-content style=\"fixed-case\">BP<\/jats:styled-content>1 staining and <jats:italic><jats:styled-content style=\"fixed-case\">CDKN<\/jats:styled-content>2A<\/jats:italic>\/p16<jats:styled-content style=\"fixed-case\"><jats:sup>INK<\/jats:sup><\/jats:styled-content><jats:sup>4A<\/jats:sup>; there was also a non\u2010significant reduction in Ki67 staining. Treated cells also showed a three\u2010 fivefold increase in <jats:styled-content style=\"fixed-case\">TGF<\/jats:styled-content>\u2010\u03b2 and a small non\u2010significant increase in <jats:styled-content style=\"fixed-case\">MMP<\/jats:styled-content>\u20102.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Areca nut alkaloids induce senescence in oral fibroblasts and promote increased secretion of <jats:styled-content style=\"fixed-case\">TGF<\/jats:styled-content>\u2010\u03b2 and perhaps <jats:styled-content style=\"fixed-case\">MMP<\/jats:styled-content>\u20102 that may create a tissue environment thought to be critical in the progression of <jats:styled-content style=\"fixed-case\">OSMF<\/jats:styled-content> to malignancy.<\/jats:p><\/jats:sec>","DOI":"10.1111\/jop.12370","type":"journal-article","created":{"date-parts":[[2015,9,28]],"date-time":"2015-09-28T13:15:59Z","timestamp":1443446159000},"page":"365-372","source":"Crossref","is-referenced-by-count":40,"title":["Areca nut alkaloids induce irreparable <scp>DNA<\/scp> damage and senescence in fibroblasts and may create a favourable environment for tumour progression"],"prefix":"10.1111","volume":"45","author":[{"given":"Ambreen","family":"Rehman","sequence":"first","affiliation":[{"name":"Centre for Clinical &amp; Diagnostic Oral Sciences Institute of Dentistry Barts and the London School of Medicine and Dentistry Queen Mary University of London London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sitara","family":"Ali","sequence":"additional","affiliation":[{"name":"Centre for Clinical &amp; Diagnostic Oral Sciences Institute of Dentistry Barts and the London School of Medicine and Dentistry Queen Mary University of London London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohid Abrar","family":"Lone","sequence":"additional","affiliation":[{"name":"Centre for Clinical &amp; Diagnostic Oral Sciences Institute of Dentistry Barts and the London School of Medicine and Dentistry Queen Mary University of London London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad","family":"Atif","sequence":"additional","affiliation":[{"name":"Centre for Clinical &amp; Diagnostic Oral Sciences Institute of Dentistry Barts and the London School of Medicine and Dentistry Queen Mary University of London London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yazan","family":"Hassona","sequence":"additional","affiliation":[{"name":"Department of Dentistry University of Jordan Amman Jordan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen Stewart","family":"Prime","sequence":"additional","affiliation":[{"name":"Centre for Clinical &amp; 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