Objective: To investigate the mechanism by which swertiamarin (STM) ameliorates CD-like colitis in mice.
Methods: A Caco-2 cell model of TNF--stimulated apoptosis was established and divided into three groups: Con, TNF- and STM, and the effects of STM on apoptosis and barrier function were assessed by Tunel staining, western blotting, immunofluorescence, and transepithelial electric resistance (TEER). A mouse model of 2, 4, 6-trinitrobenzenesulfonic acid (TNBS) -induced CD-like colitis was established to assess the effects of STM on colitis, intestinal barrier function and epithelial cell apoptosis. The regulatory role of the PI3K/AKT pathway in STM-induced resistance to intestinal epithelial cell apoptosis was investigated in both the cell model and mouse models.
Results: TUNEL staining showed that in Caco-2 cells with TNF- stimulation, STM treatment significantly reduced the percentage of TUNEL-stained cells (<0.05). STM obviously reduced TNF--induced enhancement of cleaved-caspase 3 and Bax expressions (<0.05), increased Bcl-2 expression (<0.05), protected intestinal barrier integrity and function by restoring transepithelial electrical resistance (TEER) of the cells, promoted normal localization and expressions of the tight junction proteins (ZO1 and claudin 1) (<0.05), and inhibited the expression of pro-inflammatory factors (IL-6 and CCL3) (<0.05) in TNF--stimulated Caco-2 cells. In the mouse models, STM significantly alleviated TNBS-induced CD-like colitis and intestinal barrier dysfunction (<0.05) as shown by improved weight loss, lowered Disease Activity Index (DAI) score and inflammation score, reduction of IL-6 and CCL3 release, and restoration of intestinal barrier permeability, colonic TEER, bacterial translocation, and localization and expressions of the tight junction proteins. Mechanistically, STM inhibited the expressions of p-PI3K and p-AKT in both the cell model and mouse model(<0.05), and treatment with 740Y-P (a PI3K/AKT pathway activator) significantly attenuated the inhibitory effect of STM on TNF--induced apoptosis in Caco-2 cells (<0.05).
Conclusion: STM inhibits intestinal epithelial cell apoptosis at least in part by suppressing activation of the PI3K/AKT pathway to ameliorate intestinal barrier dysfunction and colitis in mice.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11378047 | PMC |
http://dx.doi.org/10.12122/j.issn.1673-4254.2024.08.13 | DOI Listing |
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