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Dexamethasone and Tofacitinib suppress NADPH oxidase expression and alleviate very-early-onset ileocolitis in mice deficient in GSH peroxidase 1 and 2.

Authors
  • Chu, Fong-Fong1
  • Esworthy, R Steven2
  • Shen, Binghui3
  • Gao, Qiang4
  • Doroshow, James H5
  • 1 Department of Gastroenterology and Hepatology, The First Affiliated Hospital and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, Henan, 471003, China; Department of Cancer Genetics and Epigenetics, Beckman Research Institute of the City of Hope, Duarte, CA, 91010, USA. Electronic address: [email protected] , (China)
  • 2 Department of Cancer Genetics and Epigenetics, Beckman Research Institute of the City of Hope, Duarte, CA, 91010, USA. Electronic address: [email protected]
  • 3 Department of Cancer Genetics and Epigenetics, Beckman Research Institute of the City of Hope, Duarte, CA, 91010, USA. Electronic address: [email protected]
  • 4 Department of Gastroenterology and Hepatology, The First Affiliated Hospital and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, Henan, 471003, China; Department of Gastroenterology and Hepatology, Beijing Rehabilitation Hospital, Capital Medical University, Beijing, 100144, China. Electronic address: [email protected] , (China)
  • 5 Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, NIH, Bethesda, MD, USA. Electronic address: [email protected]
Type
Published Article
Journal
Life sciences
Publication Date
Dec 15, 2019
Volume
239
Pages
116884–116884
Identifiers
DOI: 10.1016/j.lfs.2019.116884
PMID: 31689440
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

C57BL6/J (B6) mice lacking Se-dependent GSH peroxidase 1 and 2 (GPx1/2-DKO) develop mild to moderate ileocolitis around weaning. These DKO mice have a disease resembling human very-early-onset inflammatory bowel disease (VEOIBD), which is associated with mutations in NADPH oxidase genes. Drugs including dexamethasone (Dex), Tofacitinib (Tofa; a Janus kinase/JAK inhibitor) and anti-TNF antibody are effective to treat adult, but not pediatric IBD. To test the efficacy of hydrophobic Dex and hydrophilic Dex phosphate (Dex phos), Tofa, anti-Tnf Ab, Noxa1ds-TAT and gp91ds-TAT peptides (inhibiting NOX1 and NOX2 assembly respectively), antioxidant MJ33 and ML090, and pifithrin-α (p53 inhibitor) on alleviation of gut inflammation in DKO weanlings. All treatments began on 22-day-old GPx1/2-DKO mice. The mouse intestine pathology was compared between the drug- and vehicle-treated groups after six or thirteen days of treatment. Among all drugs tested, Dex, Dex phos and Tofa were the strongest to suppress ileocolitis in the DKO weanlings. Dex, Dex phos and Tofa inhibited crypt apoptosis and increased crypt density. Dex or Dex phos alone also inhibited cell proliferation, exfoliation and crypt abscess in the ileum. Dex, but not Tofa, retarded mouse growth. Both Dex and Tofa inhibited ileum Nox1, Nox4 and Duox2, but not Nox2 gene expression. Noxa1ds-TAT and gp91ds-TAT peptides as well as MJ33 had subtle effect on suppressing pathology, while others had negligible effect. These findings suggest that NADPH oxidases can be novel drug targets for pediatric IBD therapy, and Tofa may be considered for treating VEOIBD. Copyright © 2019 Elsevier Inc. All rights reserved.

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