{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T22:28:43Z","timestamp":1774391323081,"version":"3.50.1"},"reference-count":107,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2023,9,18]],"date-time":"2023-09-18T00:00:00Z","timestamp":1694995200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Acute respiratory distress syndrome (ARDS) is a highly morbid inflammatory lung disease with limited pharmacological interventions. The present study aims to evaluate and compare the potential pulmonoprotective effects of natural prolyl oligopeptidase (POP) inhibitors namely rosmarinic acid (RA), chicoric acid (CA), epigallocatechin-3-gallate (EGCG) and gallic acid (GA), against lipopolysaccharide (LPS)-induced ARDS. Cell viability and expression of pro-inflammatory mediators were measured in RAW264.7 cells and in primary murine lung epithelial and bone marrow cells. Nitric oxide (NO) production was also assessed in unstimulated and LPS-stimulated RAW264.7 cells. For subsequent in vivo experiments, the two natural products (NPs) with the most favorable effects, RA and GA, were selected. Protein, cell content and lipid peroxidation levels in bronchoalveolar lavage fluid (BALF), as well as histopathological changes and respiratory parameters were evaluated in LPS-challenged mice. Expression of key mediators involved in ARDS pathophysiology was detected by Western blotting. RA and GA favorably reduced gene expression of pro-inflammatory mediators in vitro, while GA decreased NO production in macrophages. In LPS-challenged mice, RA and GA co-administration improved respiratory parameters, reduced cell and protein content and malondialdehyde (MDA) levels in BALF, decreased vascular cell adhesion molecule-1 (VCAM-1) and the inducible nitric oxide synthase (iNOS) protein expression, activated anti-apoptotic mechanisms and down-regulated POP in the lung. Conclusively, these synergistic pulmonoprotective effects of RA and GA co-administration could render them a promising prophylactic\/therapeutic pharmacological intervention against ARDS.<\/jats:p>","DOI":"10.3390\/ijms241814235","type":"journal-article","created":{"date-parts":[[2023,9,19]],"date-time":"2023-09-19T02:26:17Z","timestamp":1695090377000},"page":"14235","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Synergistic Pulmonoprotective Effect of Natural Prolyl Oligopeptidase Inhibitors in In Vitro and In Vivo Models of Acute Respiratory Distress Syndrome"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0745-3224","authenticated-orcid":false,"given":"Stelios","family":"Zerikiotis","sequence":"first","affiliation":[{"name":"Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, 157 71 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Panagiotis","family":"Efentakis","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, 157 71 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Danai","family":"Dapola","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, 157 71 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Agapaki","sequence":"additional","affiliation":[{"name":"Histochemistry Facility, Biomedical Research Foundation of the Academy of Athens, 115 27 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Georgios","family":"Seiradakis","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, 157 71 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4787-5106","authenticated-orcid":false,"given":"Nikolaos","family":"Kostomitsopoulos","sequence":"additional","affiliation":[{"name":"Laboratory Animal Facility, Centre of Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, 115 27 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexios-Leandros","family":"Skaltsounis","sequence":"additional","affiliation":[{"name":"Section of Pharmacognosy and Natural Product Chemistry Faculty of Pharmacy, National and Kapodistrian University of Athens, 157 71 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ioulia","family":"Tseti","sequence":"additional","affiliation":[{"name":"Uni-Pharma S.A., 145 64 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6433-4016","authenticated-orcid":false,"given":"Filippos","family":"Triposkiadis","sequence":"additional","affiliation":[{"name":"Department of Cardiology, University General Hospital of Larissa, 413 34 Larissa, Greece"},{"name":"Faculty of Health Sciences, University of Thessaly, 413 34 Larissa, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ioanna","family":"Andreadou","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacology, Faculty of Pharmacy, National and Kapodistrian University of Athens, 157 71 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,9,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1038\/s41572-019-0069-0","article-title":"Acute respiratory distress syndrome","volume":"5","author":"Matthay","year":"2019","journal-title":"Nat. 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