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The GS-nitroxide JP4-039 improves intestinal barrier and stem cell recovery in irradiated mice

Total body irradiation (TBI) leads to dose- and tissue-specific lethality. In the current study, we demonstrate that a mitochondrion-targeted nitroxide JP4-039 given once 24 hours after 9–10 Gy TBI significantly improves mouse survival, and the recovery of intestinal barrier, differentiation and ste...

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Autores principales: Wei, Liang, Leibowitz, Brian J., Epperly, Michael, Bi, Cheng, Li, Allen, Steinman, Justin, Wipf, Peter, Li, Song, Zhang, Lin, Greenberger, Joel, Yu, Jian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5794877/
https://www.ncbi.nlm.nih.gov/pubmed/29391546
http://dx.doi.org/10.1038/s41598-018-20370-9
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author Wei, Liang
Leibowitz, Brian J.
Epperly, Michael
Bi, Cheng
Li, Allen
Steinman, Justin
Wipf, Peter
Li, Song
Zhang, Lin
Greenberger, Joel
Yu, Jian
author_facet Wei, Liang
Leibowitz, Brian J.
Epperly, Michael
Bi, Cheng
Li, Allen
Steinman, Justin
Wipf, Peter
Li, Song
Zhang, Lin
Greenberger, Joel
Yu, Jian
author_sort Wei, Liang
collection PubMed
description Total body irradiation (TBI) leads to dose- and tissue-specific lethality. In the current study, we demonstrate that a mitochondrion-targeted nitroxide JP4-039 given once 24 hours after 9–10 Gy TBI significantly improves mouse survival, and the recovery of intestinal barrier, differentiation and stem cell functions. The GI-protective effects are associated with rapid and selective induction of tight junction proteins and cytokines including TGF-β, IL-10, IL-17a, IL-22 and Notch signaling long before bone marrow depletion. However, no change was observed in crypt death or the expression of prototypic pro-inflammatory cytokines such as TNF-α, IL-6 or IL-1β. Surprisingly, bone marrow transplantation (BMT) performed 24 hours after TBI improves intestinal barrier and stem cell recovery with induction of IL-10, IL-17a, IL-22, and Notch signaling. Further, BMT-rescued TBI survivors display increased intestinal permeability, impaired ISC function and proliferation, but not obvious intestinal inflammation or increased epithelial death. These findings identify intestinal epithelium as a novel target of radiation mitigation, and potential strategies to enhance ISC recovery and regeneration after accidental or medical exposures.
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spelling pubmed-57948772018-02-12 The GS-nitroxide JP4-039 improves intestinal barrier and stem cell recovery in irradiated mice Wei, Liang Leibowitz, Brian J. Epperly, Michael Bi, Cheng Li, Allen Steinman, Justin Wipf, Peter Li, Song Zhang, Lin Greenberger, Joel Yu, Jian Sci Rep Article Total body irradiation (TBI) leads to dose- and tissue-specific lethality. In the current study, we demonstrate that a mitochondrion-targeted nitroxide JP4-039 given once 24 hours after 9–10 Gy TBI significantly improves mouse survival, and the recovery of intestinal barrier, differentiation and stem cell functions. The GI-protective effects are associated with rapid and selective induction of tight junction proteins and cytokines including TGF-β, IL-10, IL-17a, IL-22 and Notch signaling long before bone marrow depletion. However, no change was observed in crypt death or the expression of prototypic pro-inflammatory cytokines such as TNF-α, IL-6 or IL-1β. Surprisingly, bone marrow transplantation (BMT) performed 24 hours after TBI improves intestinal barrier and stem cell recovery with induction of IL-10, IL-17a, IL-22, and Notch signaling. Further, BMT-rescued TBI survivors display increased intestinal permeability, impaired ISC function and proliferation, but not obvious intestinal inflammation or increased epithelial death. These findings identify intestinal epithelium as a novel target of radiation mitigation, and potential strategies to enhance ISC recovery and regeneration after accidental or medical exposures. Nature Publishing Group UK 2018-02-01 /pmc/articles/PMC5794877/ /pubmed/29391546 http://dx.doi.org/10.1038/s41598-018-20370-9 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Wei, Liang
Leibowitz, Brian J.
Epperly, Michael
Bi, Cheng
Li, Allen
Steinman, Justin
Wipf, Peter
Li, Song
Zhang, Lin
Greenberger, Joel
Yu, Jian
The GS-nitroxide JP4-039 improves intestinal barrier and stem cell recovery in irradiated mice
title The GS-nitroxide JP4-039 improves intestinal barrier and stem cell recovery in irradiated mice
title_full The GS-nitroxide JP4-039 improves intestinal barrier and stem cell recovery in irradiated mice
title_fullStr The GS-nitroxide JP4-039 improves intestinal barrier and stem cell recovery in irradiated mice
title_full_unstemmed The GS-nitroxide JP4-039 improves intestinal barrier and stem cell recovery in irradiated mice
title_short The GS-nitroxide JP4-039 improves intestinal barrier and stem cell recovery in irradiated mice
title_sort gs-nitroxide jp4-039 improves intestinal barrier and stem cell recovery in irradiated mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5794877/
https://www.ncbi.nlm.nih.gov/pubmed/29391546
http://dx.doi.org/10.1038/s41598-018-20370-9
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