Back to Search
Start Over
Inhibition of Histone Deacetylation by MS-275 Alleviates Colitis by Activating the Vitamin D Receptor
- Source :
- Journal of Crohn'scolitis. 14(8)
- Publication Year :
- 2020
-
Abstract
- Background Ulcerative colitis [UC] is a common chronic inflammatory bowel disease without curative treatment. Methods We conducted gene set enrichment analysis to explore potential therapeutic agents for UC. Human colon tissue samples were collected to test H3 acetylation in UC. Both in vivo and in vitro colitis models were constructed to verify the role and mechanism of H3 acetylation modification in UC. Intestine-specific vitamin D receptor [VDR]-/- mice and VD [vitamin D]-deficient diet-fed mice were used to explore downstream molecular mechanisms accordingly. Results According to the Connectivity Map database, MS-275 [class I histone deacetylase inhibitor] was the top-ranked agent, indicating the potential importance of histone acetylation in the pathogenesis of UC. We then found that histone H3 acetylation was significantly lower in the colon epithelium of UC patients and negatively associated with disease severity. MS-275 treatment inhibited histone H3 deacetylation, subsequently attenuating nuclear factor kappa B [NF-κB]-induced inflammation, reducing cellular apoptosis, maintaining epithelial barrier function, and thereby reducing colitis activity in a mouse model of colitis. We also identified VDR as be a downstream effector of MS-275. The curative effect of MS-275 on colitis was abolished in VDR-/- mice and in VD-deficient diet-fed mice and VDR directly targeted p65. In UC patients, histone H3 acetylation, VDR and zonulin-1 expression showed similar downregulation patterns and were negatively associated with disease severity. Conclusions We demonstrate that MS-275 inhibits histone deacetylation and alleviates colitis by ameliorating inflammation, reducing apoptosis, and maintaining intestinal epithelial barrier via VDR, providing new strategies for UC treatment.
- Subjects :
- medicine.drug_class
Pyridines
Apoptosis
Calcitriol receptor
Inflammatory bowel disease
Severity of Illness Index
Histone Deacetylases
Histones
Histone H3
Mice
medicine
Animals
Humans
Colitis
Intestinal Mucosa
Histone H3 acetylation
Cells, Cultured
business.industry
Histone deacetylase inhibitor
Gastroenterology
Acetylation
General Medicine
medicine.disease
Vitamin D Deficiency
Histone H3 deacetylation
Histone Deacetylase Inhibitors
Disease Models, Animal
Vitamin D3 Receptor
Benzamides
Cancer research
Receptors, Calcitriol
Colitis, Ulcerative
business
Signal Transduction
Subjects
Details
- ISSN :
- 18764479
- Volume :
- 14
- Issue :
- 8
- Database :
- OpenAIRE
- Journal :
- Journal of Crohn'scolitis
- Accession number :
- edsair.doi.dedup.....fb12e4d24ec708c791599e211921f006