| Summary: | Different species belonging to the genus <i>Nephthea</i> (Acyonaceae) are a rich resource for bioactive secondary metabolites. The literature reveals that the gastroprotective effects of marine secondary metabolites have not been comprehensively studied in vivo. Hence, the present investigation aimed to examine and determine the anti-ulcer activity of 4<i>α</i>,24-dimethyl-5<i>α</i>-cholest-8<i>β</i>,18-dihydroxy,22<i>E</i>-en-3<i>β</i>-ol (<b>ST-1</b>) isolated from samples of a <i>Nephthea</i> species. This in vivo study was supported by in silico molecular docking and protein–protein interaction techniques. Oral administration of <b>ST-1</b> reduced rat stomach ulcers with a concurrent increase in gastric mucosa. Molecular docking calculations against the H<sup>+</sup>/K<sup>+</sup>-ATPase transporter showed a higher binding affinity of <b>ST-1</b>, with a docking score value of −9.9 kcal/mol and a p<i>K</i><sub>i</sub> value of 59.7 nM, compared to ranitidine (a commercial proton pump inhibitor, which gave values of −6.2 kcal/mol and 27.9 µM, respectively). The combined PEA-reactome analysis results revealed promising evidence of <b>ST-1</b> potency as an anti-ulcer compound through significant modulation of the gene set controlling the PI3K signaling pathway, which subsequently plays a crucial role in signaling regarding epithelialization and tissue regeneration, tissue repairing and tissue remodeling. These results indicate a probable protective role for <b>ST-1</b> against ethanol-induced gastric ulcers.
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