{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T11:28:33Z","timestamp":1781177313796,"version":"3.54.1"},"reference-count":60,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2025,11,12]],"date-time":"2025-11-12T00:00:00Z","timestamp":1762905600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000072","name":"National Institute of Dental and Craniofacial Research (NIDCR), USA","doi-asserted-by":"publisher","award":["U01DE033241"],"award-info":[{"award-number":["U01DE033241"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences (NIGMS), USA","doi-asserted-by":"publisher","award":["R16GM149440"],"award-info":[{"award-number":["R16GM149440"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Institute on Minority Health and Health Disparities (NIMHD), USA","award":["UC2MD019626"],"award-info":[{"award-number":["UC2MD019626"]}]},{"name":"NIH","award":["MD007586"],"award-info":[{"award-number":["MD007586"]}]},{"name":"NIH","award":["CA163069"],"award-info":[{"award-number":["CA163069"]}]},{"name":"NIH","award":["S10RR025497"],"award-info":[{"award-number":["S10RR025497"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Background: Polybacterial infections associated with periodontitis are increasingly linked to systemic vascular complications, yet the underlying endothelial mechanisms remain unclear. This study investigated how a consortium of red-complex bacteria (Porphyromonas gingivalis, Tannerella forsythia, Treponema denticola) and orange complex (Fusobacterium nucleatum) affects oxidative stress, inflammation, metabolism, and apoptosis in endothelial cells, and whether L-Sepiapterin [a tetrahydrobiopterin (BH4) precursor via salvage pathway] or bardoxolone methyl (CDDO-Me) [a potent nuclear factor erythroid 2-related factor 2 (Nrf2) activator)] could provide protection. Methods: Human umbilical vein endothelial cells (HUVECs) were infected for 12\u201372 h and treated with L-Sepiapterin or CDDO-Me. Nitric oxide (NO), BH4, and reactive oxygen species (ROS) levels were quantified, and mRNA expression of key genes regulating nitric oxide synthase activity, antioxidant defense, inflammation (TLR4\/NF-\u03baB, cytokines), metabolism (PI3K-AKT-PEA-15), and apoptosis (FAS\u2013caspase pathway) was analyzed. Results: Infection markedly reduced NO and BH4, elevated ROS, activated TLR4\/NF-\u03baB and proinflammatory cytokines, disrupted PI3K\/AKT signaling, and triggered endothelial apoptosis. Treatments with L-Sepiapterin and CDDO-Me restored NO bioavailability, reduced oxidative and inflammatory responses, normalized metabolic gene expression, and attenuated apoptosis, with CDDO-Me showing more promising effects. This study provides the mechanistic insight linking periodontal polybacterial infection to endothelial dysfunction and metabolic impairment such as diabetes, suggesting that redox-modulating strategies such as L-Sepiapterin and CDDO-Me may help prevent vascular damage associated with periodontal disease.<\/jats:p>","DOI":"10.3390\/cells14221777","type":"journal-article","created":{"date-parts":[[2025,11,13]],"date-time":"2025-11-13T09:10:45Z","timestamp":1763025045000},"page":"1777","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Role of Nitric Oxide and Nrf2 to Counteract Vascular Endothelial Dysfunction Induced by Periodontal Pathogens Using HUVECs"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8828-6020","authenticated-orcid":false,"given":"Gunaraj","family":"Dhungana","sequence":"first","affiliation":[{"name":"Department of Oral Diagnostic Sciences & Research, School of Dentistry, Meharry Medical College, Nashville, TN 37208, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6396-227X","authenticated-orcid":false,"given":"Chethan","family":"Sampath","sequence":"additional","affiliation":[{"name":"Department of Oral Diagnostic Sciences & Research, School of Dentistry, Meharry Medical College, Nashville, TN 37208, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vineeta","family":"Sharma","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Cancer Biology, Neuroscience and Pharmacology, Meharry Medical College, Nashville, TN 37208, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga","family":"Korolkova","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Cancer Biology, Neuroscience and Pharmacology, 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 Oral Diagnostic Sciences & Research, School of Dentistry, Meharry Medical College, Nashville, TN 37208, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Wang, Y., Zhuo, L., Yang, S., Dong, C., and Shu, P. 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