{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,19]],"date-time":"2026-01-19T09:14:32Z","timestamp":1768814072247,"version":"3.49.0"},"reference-count":37,"publisher":"Public Library of Science (PLoS)","issue":"2","license":[{"start":{"date-parts":[[2025,2,6]],"date-time":"2025-02-06T00:00:00Z","timestamp":1738800000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100006545","name":"National Institute on Minority Health and Health Disparities","doi-asserted-by":"publisher","award":["U54MD007598"],"award-info":[{"award-number":["U54MD007598"]}],"id":[{"id":"10.13039\/100006545","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Peter A. Morton Foundation"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>The nutraceutical COMP-4 \u2013consisting of L-citrulline, ginger extract, and herbal components <jats:italic>Paullinia cupana<\/jats:italic> and muira puama\u2013has been shown previously to stimulate the production of nitric oxide (NO) in a variety of tissue types. We hypothesized that COMP-4 may have a protective, stimulatory effect on the vascular endothelial cell. Human umbilical arterial endothelial cells were incubated for 24 hours with or without COMP-4 and, to replicate impairment of endothelial function, co-incubated with or without H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub>. NO intracellular content, nitrite formation and cGMP content in culture media, nitric oxide synthase (NOS) isoforms and mRNA content, pro-inflammatory cytokines, and PAI-1 expression and activity were measured. COMP-4 increased endothelial cell production of NO and cGMP and the expression of both endothelial NOS (eNOS) and inducible NOS (iNOS), in tandem with a reduction in cytokine expression and activity of PAI-1. Co-incubation of COMP-4 with H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub> reversed detrimental effects of H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub> on endothelial function, evidenced by improvement in NO availability and abrogation of the pro-inflammatory milieu. These results suggest that COMP-4 exerts a stimulatory effect on endothelial cell eNOS and iNOS to increase NO bioavailability, leading to a reduction in pro-inflammatory cytokines, particularly the prothrombotic PAI-1.<\/jats:p>","DOI":"10.1371\/journal.pone.0316798","type":"journal-article","created":{"date-parts":[[2025,2,6]],"date-time":"2025-02-06T18:33:34Z","timestamp":1738866814000},"page":"e0316798","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Nutraceutical COMP-4 confers protection against endothelial dysfunction through the eNOS\/iNOS-NO-cGMP pathway"],"prefix":"10.1371","volume":"20","author":[{"given":"Monica 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