ID | 62435 |
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Matsumoto, Ryohtaroh
Division of Biochemistry, Graduate School of Pharmaceutical Science and Faculty of Pharmacy, Keio University
Takahashi, Daisuke
Division of Biochemistry, Graduate School of Pharmaceutical Science and Faculty of Pharmacy, Keio University
Watanabe, Masaki
Division of Pharmaceutical Sciences, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University
Nakatani, Shunsuke
Division of Pharmaceutical Sciences, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University
Takamura, Yuta
Division of Pharmaceutical Sciences, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University
Kurosaki, Yuji
Division of Pharmaceutical Sciences, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University
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Kakuta, Hiroki
Division of Pharmaceutical Sciences, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University
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Hase, Koji
Division of Biochemistry, Graduate School of Pharmaceutical Science and Faculty of Pharmacy, Keio University
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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(high)CD4(+) 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-gamma-producing Th1 cell expansion in the colon. In conclusion, NEt-3IB, a large intestine-directed RXR agonist, is a promising drug candidate for IBDs.
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Keywords | RXR
NEt-3IB
inflammatory bowel disease
colitis
Th1 cells
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Published Date | 2021-08-12
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Publication Title |
Frontiers In Pharmacology
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Volume | volume12
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Publisher | Frontiers Media SA
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Start Page | 715752
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ISSN | 1663-9812
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Content Type |
Journal Article
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language |
English
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OAI-PMH Set |
岡山大学
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Copyright Holders | © 2021 Matsumoto, Takahashi, Watanabe, Nakatani, Takamura,Kurosaki, Kakuta and Hase.
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File Version | publisher
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Related Url | isVersionOf https://doi.org/10.3389/fphar.2021.715752
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License | https://creativecommons.org/licenses/by/4.0/
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助成番号 | Matsumoto R, Takahashi D, Watanabe M, Nakatani S, Takamura Y, Kurosaki Y, Kakuta H and Hase K (2021) A Retinoid X Receptor Agonist Directed to the Large Intestine Ameliorates T-Cell-Mediated Colitis in Mice. Front. Pharmacol. 12:715752. doi: 10.3389/fphar.2021.715752
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Open Access (Publisher) |
OA
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