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Intestinal epithelial barrier dysfunction is crucial in the pathogenesis of intestinal and systemic diseases. In this study, we sought to elucidate the protective role of cinnamaldehyde (CNM, an activator of Nrf2) against P. gingivalis (W83) and Pg-derived lipopolysaccharide (Pg-LPS) induced intestinal epithelial barrier dysfunction via antioxidative mechanisms in IEC-6 cells. IEC-6 (ATCC, CRL-1592) cells were pretreated with or without CNM (100 \u00b5M), in the presence or absence of P. gingivalis (strain W83, 109 MOI) or Pg-LPS (1, 10, and 100 \u00b5g\/mL), respectively, between 0\u201372 h time points by adopting a co-culture method. Intestinal barrier function, cytokine secretion, and intestinal oxidative stress protein markers were analyzed. P. gingivalis or Pg-LPS significantly (p &lt; 0.05) increased reactive oxygen species (ROS) and malondialdehyde (MDA) levels expressing oxidative stress damage. Pg-LPS, as well as Pg alone, induces inflammatory cytokines via TLR-4 signaling. Furthermore, infection reduced Nrf2 and NAD(P)H quinone dehydrogenase 1 (NQO1). Interestingly, inducible nitric oxide synthase (iNOS) protein expression significantly (p &lt; 0.05) increased with Pg-LPS or Pg infection, with elevated levels of nitric oxide (NO). CNM treatment suppressed both Pg- and Pg-LPS-induced intestinal oxidative stress damage by reducing ROS, MDA, and NO production. Furthermore, CNM treatment significantly upregulated the expression of tight junction proteins via increasing the phosphorylation levels of PI3K\/Akt\/Nrf2 suppressing inflammatory cytokines. CNM protected against Pg infection-induced intestinal epithelial barrier dysfunction by activating the PI3K\/Akt-mediated Nrf2 signaling pathway in IEC-6 cells.<\/jats:p>","DOI":"10.3390\/ijms25094734","type":"journal-article","created":{"date-parts":[[2024,4,26]],"date-time":"2024-04-26T08:18:27Z","timestamp":1714119507000},"page":"4734","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Cinnamaldehyde Protects against P. gingivalis Induced Intestinal Epithelial Barrier Dysfunction in IEC-6 Cells via the PI3K\/Akt-Mediated NO\/Nrf2 Signaling Pathway"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6396-227X","authenticated-orcid":false,"given":"Chethan","family":"Sampath","sequence":"first","affiliation":[{"name":"Department of Diabetes, Metabolism and Endocrinology, Vanderbilt University Medical Center, Nashville, TN 37232, USA"},{"name":"Department of ODS & Research, School of Dentistry, Meharry Medical College, Nashville, TN 37208, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sasanka S.","family":"Chukkapalli","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Texas A&M University, College Station, TX 77843, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abhinav V.","family":"Raju","sequence":"additional","affiliation":[{"name":"College of Osteopathic Medicine, Kansas City University, Kansas City, MO 64106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1280-4367","authenticated-orcid":false,"given":"Leela Subhashini C.","family":"Alluri","sequence":"additional","affiliation":[{"name":"Department of Periodontics, School of Dentistry, Meharry Medical College, Nashville, TN 37208, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dollada","family":"Srisai","sequence":"additional","affiliation":[{"name":"Department of ODS & Research, School of Dentistry, Meharry Medical College, Nashville, TN 37208, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7259-570X","authenticated-orcid":false,"given":"Pandu R.","family":"Gangula","sequence":"additional","affiliation":[{"name":"Department of ODS & Research, School of Dentistry, Meharry Medical College, Nashville, TN 37208, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,4,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3492","DOI":"10.4103\/jfmpc.jfmpc_866_19","article-title":"Metabolic syndrome and periodontal disease: An overview for physicians","volume":"8","author":"Srivastava","year":"2019","journal-title":"J. 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