Dataset Information

A Retinoid X Receptor Agonist Directed to the Large Intestine Ameliorates T-Cell-Mediated Colitis in Mice.

ABSTRACT: Retinoid X receptor (RXR) is a nuclear receptor that heterodimerizes with several nuclear receptors, integrating ligand-mediated signals across the heterodimers. Synthetic RXR agonists have been developed to cure certain inflammatory diseases, including inflammatory bowel diseases (IBDs). However, pre-existing RXR agonists, which are lipophilic and readily absorbed in the upper intestine, cause considerable adverse effects such as hepatomegaly, hyperlipidemia, and hypothyroidism. To minimize these adverse effects, we have developed an RXR agonist, NEt-3IB, which has lipophilic and thus poorly absorptive properties. In this study, we evaluated the effects of NEt-3IB in an experimental murine colitis model induced through the adoptive transfer of CD45RB^highCD4⁺ T cells. Pharmacokinetic studies demonstrated that the major portion of NEt-3IB was successfully delivered to the large intestine after oral administration. Notably, NEt-3IB treatment suppressed the development of T cell-mediated chronic colitis, as indicated by improvement of wasting symptoms, inflammatory infiltration, and mucosal hyperplasia. The protective effect of NEt-3IB was mediated by the suppression of IFN-γ-producing Th1 cell expansion in the colon. In conclusion, NEt-3IB, a large intestine-directed RXR agonist, is a promising drug candidate for IBDs.

SUBMITTER: Matsumoto R

PROVIDER: S-EPMC8406631 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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A Retinoid X Receptor Agonist Directed to the Large Intestine Ameliorates T-Cell-Mediated Colitis in Mice.

Matsumoto Ryohtaroh R Takahashi Daisuke D Watanabe Masaki M Nakatani Shunsuke S Takamura Yuta Y Kurosaki Yuji Y Kakuta Hiroki H Hase Koji K

Frontiers in pharmacology 20210812

Retinoid X receptor (RXR) is a nuclear receptor that heterodimerizes with several nuclear receptors, integrating ligand-mediated signals across the heterodimers. Synthetic RXR agonists have been developed to cure certain inflammatory diseases, including inflammatory bowel diseases (IBDs). However, pre-existing RXR agonists, which are lipophilic and readily absorbed in the upper intestine, cause considerable adverse effects such as hepatomegaly, hyperlipidemia, and hypothyroidism. To minimize the ...[more]

PMID: 34475823

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Project description:Bergenin, isolated from the herb of Saxifraga stolonifera Curt. (Hu-Er-Cao), has anti-inflammatory, antitussive and wound healing activities. The aim of the present study was to identify the effect of bergenin on experimental colitis, and explored the related mechanisms. Our results showed that oral administration of bergenin remarkably alleviated disease symptoms of mice with dextran sulfate sodium (DSS)-induced colitis, evidenced by reduced DAI scores, shortening of colon length, MPO activity and pathologic abnormalities in colons. Bergenin obviously inhibited the mRNA and protein expressions of IL-6 and TNF-α in colon tissues, but not that of mucosal barrier-associated proteins occludin, E-cadherin and MUC-2. In vitro, bergenin significantly inhibited the expressions of IL-6 and TNF-α as well as nuclear translocation and DNA binding activity of NF-κB-p65 in lipopolysaccharide (LPS)-stimulated peritoneal macrophages and RAW264.7 cells, which was almost reversed by addition of PPARγ antagonist GW9662 and siPPARγ. Subsequently, bergenin was identified as a PPARγ agonist. It could enter into macrophages, bind with PPARγ, promote nuclear translocation and transcriptional activity of PPARγ, and increase mRNA expressions of CD36, LPL and ap2. In addition, bergenin significantly up-regulated expression of SIRT1, inhibited acetylation of NF-κB-p65 and increased association NF-κB-p65 and IκBα. Finally, the correlation between activation of PPARγ and attenuation of colitis, inhibition of IL-6 and TNF-α expressions, NF-κB-p65 acetylation and nuclear translocation, and up-regulation of SIRT1 expression by bergenin was validated in mice with DSS-induced colitis and/or LPS-stimulated macrophages. In summary, bergenin could ameliorate colitis in mice through inhibiting the activation of macrophages via regulating PPARγ/SIRT1/NF-κB-p65 pathway. The findings can provide evidence for the further development of bergenin as an anti-UC drug, and offer a paradigm for the recognization of anti-UC mechanisms of compound with similar structure occurring in traditional Chinese medicines.

Dataset Information

A Retinoid X Receptor Agonist Directed to the Large Intestine Ameliorates T-Cell-Mediated Colitis in Mice.

Publications

A Retinoid X Receptor Agonist Directed to the Large Intestine Ameliorates T-Cell-Mediated Colitis in Mice.

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