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Oridonin Attenuates TNBS-induced Post-inflammatory Irritable Bowel Syndrome via PXR/NF-κB Signaling

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Abstract

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-κBp65 as well as its downstream gene (iNOS, COX-2, IL-1β, 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-κB 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-κB 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-κB signaling pathway. Oridonin may serve as a PXR ligand for the development of drugs in the therapy for PI-IBS.

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Abbreviations

PI-IBS:

post-inflammatory irritable bowel syndrome

IBD:

inflammation bowel diseases

L/M:

lactulose/mannitol; NF-κB: Nuclear factor-κB

PXR:

pregnane X receptor

TNBS:

2,4,6-trinitrobenzenesulfonic acid

RFP:

rifampicin

KCZ:

ketoconazole

AWR:

abdominal withdrawal reflex

DAI:

disease activity index

LPS:

lipopolysaccharide;

HPLC-MS/MS:

high-performance liquid chromatography electrospray ionization tandem mass spectrometry;

LBD:

ligand binding domain

TJ:

tight junction

TLR4:

toll-like receptor 4

MPO:

myeloperoxidase

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Funding

We thank the Youth fund of the second affiliated hospital of Shanxi medical university (grant: 201802-1 and 201902-2) and Shanxi Basic Applied Research Program (201901D111389).

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Authors and Affiliations

  1. School of Pharmaceutical, Shanxi Medical University, Taiyuan, 030000, Shanxi, China

    Yun-yun Shao, Yao Guo, Xiao-juan Feng, Jun-jin Liu, Zhuang-peng Chang, Gui-feng Deng, Ding Xu, Jian-ping Gao & Rui-gang Hou

  2. Department of Pharmacy, Second Hospital of Shanxi Medical University, No.382 Wuyi Road, Xinghualing District, Taiyuan City, 030000, Shanxi Province, China

    Yun-yun Shao, Yao Guo, Xiao-juan Feng, Jun-jin Liu, Zhuang-peng Chang, Gui-feng Deng, Ding Xu & Rui-gang Hou

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  1. Yun-yun Shao
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Contributions

Y.S designed the study. R.H. and J.G conceived the experimental protocol. X.F., Z.C., G.D., and D.X. performed the experiments. Y.G. interpreted the results and wrote the manuscript. J.L. reviewed and approved the final manuscript.

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Correspondence to Jun-jin Liu, Jian-ping Gao or Rui-gang Hou.

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Shao, Yy., Guo, Y., Feng, Xj. et al. Oridonin Attenuates TNBS-induced Post-inflammatory Irritable Bowel Syndrome via PXR/NF-κB Signaling. Inflammation 44, 645–658 (2021). https://doi.org/10.1007/s10753-020-01364-0

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