{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T14:30:42Z","timestamp":1786113042328,"version":"build-2736575974"},"reference-count":81,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T00:00:00Z","timestamp":1785888000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Ethanol (EtOH)-induced gastric ulcer (GU) is a common model used to investigate mechanisms of mucosal injury and repair. Omeprazole (OMP) is a conventional anti-ulcer drug that effectively suppresses gastric acid secretion, but its efficacy may be enhanced by combining it with bioactive phytochemicals derived from a Glycyrrhiza glabra L. (licorice; LIQ) extract that possess potent antioxidant and anti-inflammatory properties. The aim of the present study was to evaluate the gastroprotective effects of OMP, LIQ extract, and their combined treatment against EtOH-induced GU in rats, focusing on modulation of TLR4\/NF-\u03baB\/NLRP3 signaling and PI3K\/AKT\/mTOR gene expression. The ethanolic extract of LIQ was chemically characterized by LC-ESI-QTOF-MS\/MS, and molecular docking was performed to evaluate the potential binding interactions of its major constituents with H+\/K+-ATPase and COX-2. Thirty male Wistar rats were randomly allocated into control, ulcer (ULC), OMP-treated, LIQ-treated, and combined treatment groups. GU was induced by absolute EtOH. Subsequently, gastric pH, stomach coefficient, oxidative stress, inflammatory mediators, and PI3K, AKT, and mTOR gene expression were assessed. Histopathological and immunohistochemical analyses of mucosal architecture and the expression of TNF-\u03b1, caspase-3, and PCNA were performed. Coadministration of OMP and LIQ demonstrated the greatest gastroprotective activity, marked by a significant increase in gastric pH, restoration of antioxidant status, and substantial reduction in ROS, TLR4, NF-\u03baB, and NLRP3 levels. The combined therapy significantly upregulated the expression of PI3K, AKT, and mTOR genes in comparison to ULC. Histopathological and immunohistochemical findings further demonstrated preservation of gastric mucosal integrity, reduced inflammatory cell infiltration, and decreased TNF-\u03b1, caspase-3, and PCNA immunoreactivity, indicating attenuation of mucosal injury. In conclusion, LIQ extract enhanced the gastroprotective effect of OMP against EtOH-induced GU, supporting its potential as an adjunct to OMP. Further studies are warranted to confirm the underlying molecular mechanisms.<\/jats:p>","DOI":"10.3390\/ijms27157037","type":"journal-article","created":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T16:48:08Z","timestamp":1785948488000},"page":"7037","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Combined Omeprazole and Glycyrrhiza glabra L. Extract Attenuate Ethanol-Induced Gastric Ulceration Through Modulation of TLR4\/NF-\u03baB\/NLRP3 Signaling and Upregulation of PI3K\/AKT\/mTOR Gene Expression"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1524-7247","authenticated-orcid":false,"given":"Sahar","family":"Khateeb","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Faculty of Science, University of Tabuk, Tabuk 71491, Saudi Arabia"},{"name":"Biochemistry Division, Department of Chemistry, Faculty of Science, Fayoum University, Fayoum 63514, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-4955-5705","authenticated-orcid":false,"given":"Mody","family":"Albalawi","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Science, University of Tabuk, Tabuk 71491, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-9249-3649","authenticated-orcid":false,"given":"Amnah","family":"Obidan","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Science, University of Tabuk, Tabuk 71491, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fahad M.","family":"Almutairi","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Science, University of Tabuk, Tabuk 71491, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2613-7553","authenticated-orcid":false,"given":"Hanan Abdulrahman","family":"Sagini","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, College of Sciences, University of Jeddah, Jeddah 21959, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eman F. S.","family":"Taha","sequence":"additional","affiliation":[{"name":"Health Radiation Research Department, National Center for Radiation Research and Technology, Egyptian Atomic Energy Authority (EAEA), Cairo 11787, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"13619","DOI":"10.1038\/s41598-020-70312-7","article-title":"Metabolites profiling and pharmacokinetics of troxipide and its pharmacodynamics in rats with gastric ulcer","volume":"10","author":"Guo","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2862706","DOI":"10.1155\/2018\/2862706","article-title":"Gastroprotective mechanism and ulcer resolution effect of Cyrtocarpa procera methanolic extract on ethanol-induced gastric injury","volume":"2018","author":"Romero","year":"2018","journal-title":"Evid.-Based Complement. Altern. 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