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Sirtuin 1 alleviates endoplasmic reticulum stress-mediated apoptosis of intestinal epithelial cells in ulcerative colitis
- Source :
- World Journal of Gastroenterology
- Publication Year :
- 2019
- Publisher :
- Baishideng Publishing Group Inc., 2019.
-
Abstract
- BACKGROUND Sirtuin 1 (SIRT1) is a nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylase that is involved in various diseases, including cancers, metabolic diseases, and inflammation-associated diseases. However, the role of SIRT1 in ulcerative colitis (UC) is still confusing. AIM To investigate the role of SIRT1 in intestinal epithelial cells (IECs) in UC and further explore the underlying mechanisms. METHODS We developed a coculture model using macrophages and Caco-2 cells. After treatment with the SIRT1 activator SRT1720 or inhibitor nicotinamide (NAM), the expression of occludin and zona occludens 1 (ZO-1) was assessed by Western blot analysis. Annexin V-APC/7-AAD assays were performed to evaluate Caco-2 apoptosis. Dextran sodium sulfate (DSS)-induced colitis mice were exposed to SRT1720 or NAM for 7 d. Transferase-mediated dUTP nick-end labeling (TUNEL) assays were conducted to assess apoptosis in colon tissues. The expression levels of glucose-regulated protein 78 (GRP78), CCAAT/enhancer-binding protein homologous protein (CHOP), caspase-12, caspase-9, and caspase-3 in Caco-2 cells and the colon tissues of treated mice were examined by quantitative real-time PCR and Western blot. RESULTS SRT1720 treatment increased the protein levels of occludin and ZO-1 and inhibited Caco-2 apoptosis, whereas NAM administration caused the opposite effects. DSS-induced colitis mice treated with SRT1720 had a lower disease activity index (P < 0.01), histological score (P < 0.001), inflammatory cytokine levels (P < 0.01), and apoptotic cell rate (P < 0.01), while exposure to NAM caused the opposite effects. Moreover, SIRT1 activation reduced the expression levels of GRP78, CHOP, cleaved caspase-12, cleaved caspase-9, and cleaved caspase-3 in Caco-2 cells and the colon tissues of treated mice. CONCLUSION SIRT1 activation reduces apoptosis of IECs via the suppression of endoplasmic reticulum stress-mediated apoptosis-associated molecules CHOP and caspase-12. SIRT1 activation may be a potential therapeutic strategy for UC.
- Subjects :
- Niacinamide
Apoptosis
CHOP
Occludin
Heterocyclic Compounds, 4 or More Rings
Mice
03 medical and health sciences
0302 clinical medicine
SRT1720
Sirtuin 1
Annexin
medicine
Animals
Humans
Intestinal Mucosa
Colitis
Endoplasmic Reticulum Chaperone BiP
Intestinal barrier
Caspase 12
biology
Chemistry
Macrophages
Endoplasmic reticulum
Dextran Sulfate
Gastroenterology
Epithelial Cells
General Medicine
Basic Study
Endoplasmic Reticulum Stress
medicine.disease
Molecular biology
Coculture Techniques
Disease Models, Animal
Ulcerative colitis
030220 oncology & carcinogenesis
biology.protein
Colitis, Ulcerative
Female
030211 gastroenterology & hepatology
Caco-2 Cells
Transcription Factor CHOP
Subjects
Details
- ISSN :
- 10079327
- Volume :
- 25
- Database :
- OpenAIRE
- Journal :
- World Journal of Gastroenterology
- Accession number :
- edsair.doi.dedup.....baef38d34c8b34ee6143899533f08d3d