Journal
INFLAMMATION
Volume 44, Issue 2, Pages 645-658Publisher
SPRINGER/PLENUM PUBLISHERS
DOI: 10.1007/s10753-020-01364-0
Keywords
oridonin; post-inflammatory irritable bowel syndrome; intestinal barrier function; chronic low-grade inflammation; PXR/NF-kappa B
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Funding
- Youth fund of the second affiliated hospital of Shanxi medical university [201802-1, 201902-2]
- Shanxi Basic Applied Research Program [201901D111389]
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Oridonin showed therapeutic effects in experimental PI-IBS by repairing intestinal barrier function, potentially through the regulatory role of PXR/NF-κB signaling pathway. Oridonin may serve as a PXR ligand for the development of drugs in the therapy for PI-IBS.
To investigate the beneficial effects of oridonin, a diterpenoid compound isolated from Rabdosia rubescens, on the inflammatory response in TNBS-induced post-inflammatory irritable bowel syndrome (PI-IBS) model and the underlying mechanism. Using the PI-IBS rat model and Caco-2 cell lines, we found that intestinal barrier function reflected by lactulose/mannitol (L/M) ratio and tight junction protein level was significantly ameliorated by oridonin. We also demonstrated that oridonin abrogated inflammation through inhibiting the phosphorylation of NF-kappa Bp65 as well as its downstream gene (iNOS, COX-2, IL-1 beta, and IL-6) level. Molecular docking studies confirmed the good binding activity between oridonin and PXR. In Caco-2 cell lines, oridonin markedly inhibited LPS-induced NF-kappa B activation in a PXR-dependent manner. Meanwhile, PXR and its target genes CYP3A4 and P-gp were induced by oridonin, which was associated with the decreased expression of NF-kappa B and the recovery of intestinal barrier. This study indicated that the therapeutic effect of oridonin on experimental PI-IBS through repairing intestinal barrier function may be closely associated with the regulatory role of PXR/NF-kappa B signaling pathway. Oridonin may serve as a PXR ligand for the development of drugs in the therapy for PI-IBS.
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