Alleviation of Gut Inflammation by Cdx2/Pxr Pathway in a Mouse Model of Chemical Colitis

被引：79

作者：

Dou, Wei ^{[1
,2
,3
,4
]}

Mukherjee, Subhajit ^{[1
,2
]}

Li, Hao ^{[1
,2
]}

Venkatesh, Madhukumar ^{[1
,2
]}

Wang, Hongwei ^{[1
,2
]}

Kortagere, Sandhya ^{[5
]}

Peleg, Ariel ^{[1
,2
]}

Chilimuri, Sridhar S. ^{[6
]}

Wang, Zheng-Tao ^{[3
,4
]}

Feng, Ying ^{[7
]}

Fearon, Eric R. ^{[8
]}

Mani, Sridhar ^{[1
,2
]}

机构：

[1] Albert Einstein Coll Med, Dept Med, New York, NY USA

[2] Albert Einstein Coll Med, Dept Genet, New York, NY USA

[3] Shanghai Univ TCM, Inst Chinese Mat Med, Shanghai Key Lab Formulated Chinese Med, Shanghai, Peoples R China

[4] Shanghai Univ TCM, Inst Chinese Mat Med, MOE Key Lab Standardizat Chinese Med, Shanghai, Peoples R China

[5] Drexel Univ, Coll Med, Dept Microbiol & Immunol, Philadelphia, PA 19104 USA

[6] Bronx Lebanon Hosp Ctr, Dept Med, Bronx, NY 10457 USA

[7] Univ Michigan, Sch Med, Dept Internal Med, Div Mol Med & Genet, Ann Arbor, MI USA

[8] Univ Michigan, Sch Med, Dept Internal Med Human Genet & Pathol, Div Mol Med & Genet, Ann Arbor, MI 48109 USA

来源：

PLOS ONE | 2012年 / 7卷 / 07期

基金：

美国国家卫生研究院;

关键词：

PREGNANE-X-RECEPTOR; NUCLEAR RECEPTOR; SCUTELLARIA-BAICALENSIS; DRUG DEVELOPMENT; GENE-EXPRESSION; BINDING-SITES; KAPPA-B; RATS; BAICALIN; PXR;

D O I：

10.1371/journal.pone.0036075

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

Pregnane X Receptor (PXR), a master regulator of drug metabolism and inflammation, is abundantly expressed in the gastrointestinal tract. Baicalein and its O-glucuronide baicalin are potent anti-inflammatory and anti-cancer herbal flavonoids that undergo a complex cycle of interconversion in the liver and gut. We sought to investigate the role these flavonoids play in inhibiting gut inflammation by an axis involving PXR and other potential factors. The consequences of PXR regulation and activation by the herbal flavonoids, baicalein and baicalin were evaluated in vitro in human colon carcinoma cells and in vivo using wild-type, Pxr-null, and humanized (hPXR) PXR mice. Baicalein, but not its glucuronidated metabolite baicalin, activates PXR in a Cdx2-dependent manner in vitro, in human colon carcinoma LS174T cells, and in the murine colon in vivo. While both flavonoids abrogate dextran sodium sulfate (DSS)-mediated colon inflammation in vivo, oral delivery of a potent bacterial beta-glucuronidase inhibitor eliminates baicalin's effect on gastrointestinal inflammation by preventing the microbial conversion of baicalin to baicalien. Finally, reduction of gastrointestinal inflammation requires the binding of Cdx2 to a specific proximal site on the PXR promoter. Pharmacological targeting of intestinal PXR using natural metabolically labile ligands could serve as effective and potent therapeutics for gut inflammation that avert systemic drug interactions.

引用

页数：13

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