{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T01:13:00Z","timestamp":1787015580448,"version":"build-2736575974"},"reference-count":40,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2022,10,7]],"date-time":"2022-10-07T00:00:00Z","timestamp":1665100800000},"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 of Periodontal Research"],"published-print":{"date-parts":[[2022,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective and Background<\/jats:title>\n                    <jats:p>Gingival overgrowth (GO) is a common side effect of some drugs such as anticonvulsants, immunosuppressant, and calcium channel blockers. Among them, the antiepileptic agent phenytoin is the most common agent related to this condition due to its high incidence. Transforming growth factor \u03b2 (TGF\u03b2) importantly contributes to the pathogenesis of GO. Connective tissue growth factor (CTGF or CCN2) is a key mediator of tissue fibrosis and is positively associated with the degree of fibrosis in GO. We previously showed that Src, c\u2010jun N\u2010terminal kinase, and Smad3 mediate TGF\u03b21\u2010induced CCN2 protein expression in human gingival fibroblasts (HGFs). This study investigates whether phenytoin can induce CCN2 synthesis through activated latent TGF\u03b2 in HGFs and its mechanisms.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>CCN2 synthesis, latent TGF\u03b21 activation, and cellular reactive oxygen species (ROS) generation in HGFs were studied using western blot analysis, a TGF\u03b21 Emax\u00ae ImmunoAssay System, and 2\u2032,7\u2032\u2010dichlorodihydrofluorescein diacetate (an oxidation\u2010sensitive fluorescent probe), respectively.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Phenytoin significantly stimulated CCN2 synthesis, latent TGF\u03b21 activation, and ROS generation in HGFs. Addition of an TGF\u03b2\u2010neutralizing antibody, TGF\u03b2 receptor kinase inhibitor SB431542, and Smad3 inhibitor SIS3 completely inhibited phenytoin\u2010induced CCN2 synthesis. General antioxidant N\n                      <jats:italic>\u2010<\/jats:italic>\n                      acetylcysteine, NADPH oxidase (NOX) inhibitor diphenylene iodonium, and specific NOX4 inhibitor plumbagin almost completely suppressed phenytoin\u2010induced total cellular ROS and latent TGF\u03b21 activation. Curcumin dose\u2010dependently decreased phenytoin\u2010induced TGF\u03b21 activation and CCN2 synthesis in HGFs.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our findings indicated that NOX4\u2010derived ROS play pivotal roles in phenytoin\u2010induced latent TGF\u03b21 activation. Molecular targeting the phenytoin\/NOX4\/ROS\/TGF\u03b21 pathway may provide promising strategies for the prevention and treatment of GO. Curcumin\u2010inhibited phenytoin\u2010induced CCN2 synthesis is caused by the suppression of latent TGF\u03b21 activation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/jre.13058","type":"journal-article","created":{"date-parts":[[2022,10,7]],"date-time":"2022-10-07T03:49:44Z","timestamp":1665114584000},"page":"1219-1226","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Phenytoin induces connective tissue growth factor (\n                    <scp>CTGF<\/scp>\n                    \/\n                    <scp>CCN2<\/scp>\n                    ) production through\n                    <scp>NADPH<\/scp>\n                    oxidase 4\u2010\n                    <scp>mediated latent TGF\u03b21<\/scp>\n                    activation in human gingiva fibroblasts: Suppression by curcumin"],"prefix":"10.1111","volume":"57","author":[{"given":"Yi\u2010Ting","family":"Deng","sequence":"first","affiliation":[{"name":"School of Dentistry, College of Medicine National Taiwan University  Taipei Taiwan"},{"name":"Department of Dentistry National Taiwan University Hospital Hsin\u2010Chu Branch  Hsin\u2010Chu Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"King\u2010Jean","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Dentistry National Taiwan University Hospital Hsin\u2010Chu Branch  Hsin\u2010Chu Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark Yen\u2010Ping","family":"Kuo","sequence":"additional","affiliation":[{"name":"School of Dentistry, College of Medicine National Taiwan University  Taipei Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,10,7]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1177\/154411130401500305"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1177\/0022034515571265"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1902\/jop.2005.76.1.3"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1902\/jop.2001.72.7.921"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/path.2277"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1902\/jop.2006.050379"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0765.1996.tb00519.x"},{"issue":"12","key":"e_1_2_10_9_1","first-page":"1287","article-title":"Phenytoin activates Smad3 phosphorylation and periostin expression in drug\u2010induced gingival enlargement","volume":"33","author":"Kim 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