{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T13:56:10Z","timestamp":1782827770091,"version":"3.54.5"},"reference-count":42,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2024,11,6]],"date-time":"2024-11-06T00:00:00Z","timestamp":1730851200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100020884","name":"Agencia Nacional de Investigaci\u00f3n y Desarrollo","doi-asserted-by":"publisher","award":["1200098"],"award-info":[{"award-number":["1200098"]}],"id":[{"id":"10.13039\/501100020884","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Int Endodontic J"],"published-print":{"date-parts":[[2025,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Aim<\/jats:title><jats:p>Epigenetic regulation of the key inflammatory genes plays a crucial role in controlling monocyte\/macrophage\u2010mediated local and systemic responses to bacterial challenges. However, it has not been addressed in apical periodontitis (AP). We aimed to explore the methylation pattern of the TNF\u2010\u03b1 gene promoter and its association with the inflammatory phenotype of peripheral blood monocytes from individuals with AP and controls.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A cross\u2010sectional study was conducted, including otherwise healthy individuals with AP (<jats:italic>n<\/jats:italic>\u2009=\u200925) and controls (<jats:italic>n<\/jats:italic>\u2009=\u200929). Monocytes were isolated from the volunteer\u2019s blood samples using a Ficoll gradient followed by negative immunoselection. RNA and DNA were extracted. The DNA methylation profiles of the TNF\u2010\u03b1 gene promoter region were analyzed using bisulfite sequencing PCR. The mRNA expression levels of DNA methyltransferases 3a (DNMT3a) and Ten Eleven Translocation enzymes 1(TET1) were assessed by qPCR. A fraction of primary monocytes was also cultured for 24 h, and the supernatant was collected to measure cytokine levels through a Luminex assay. Generalized structural equation models (GSEM) evaluated the association between AP, DNA methylation, and TNF\u2010\u03b1 protein expression controlled for potential covariates. Models included the effect of the methylation of TNF\u2010\u03b1 gene promoter as a mediator of the association between AP and TNF\u2010\u03b1 protein expression levels.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Monocytes from AP individuals exhibited a heightened secretion of TNF\u2010\u03b1 and IL\u20101\u03b2 and hypomethylation of the TNF gene promoter (<jats:italic>p<\/jats:italic>\u2009&lt;\u2009.05). AP diagnosis was associated with the TNF\u2010\u03b1 gene promoter\u00b4s hypomethylated profile and enhanced pro\u2010inflammatory cytokine levels, while lower methylation of the gene promoter region and \u2010163 CpG single site mediated TNF\u2010\u03b1 overexpression (<jats:italic>p<\/jats:italic>\u2009&lt;\u2009.05).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>DNA hypomethylation at the TNF\u2010\u03b1 gene mediates a proinflammatory phenotype in monocytes from AP patients, supporting a role in the systemic response.<\/jats:p><\/jats:sec>","DOI":"10.1111\/iej.14162","type":"journal-article","created":{"date-parts":[[2024,11,6]],"date-time":"2024-11-06T14:30:17Z","timestamp":1730903417000},"page":"284-294","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["TNF\u2010alpha gene promoter's hypomethylation mediates a pro\u2010inflammatory phenotype in peripheral blood monocytes from apical periodontitis individuals"],"prefix":"10.1111","volume":"58","author":[{"given":"Alejandra","family":"Fern\u00e1ndez","sequence":"first","affiliation":[{"name":"Faculty of Dentistry Universidad Andres Bello  Santiago Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1046-6045","authenticated-orcid":false,"given":"Mar\u00eda Jos\u00e9","family":"Bordagaray","sequence":"additional","affiliation":[{"name":"Laboratory of Periodontal Biology, Faculty of Dentistry Universidad de Chile  Santiago Chile"},{"name":"Conservative Dentistry Department, Faculty of Dentistry Universidad de Chile  Santiago Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mauricio","family":"Garrido","sequence":"additional","affiliation":[{"name":"Laboratory of Periodontal Biology, Faculty of Dentistry Universidad de Chile  Santiago 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