Correlation of Intestinal Mucosal Healing and Tight Junction Protein Expression in Ulcerative Colitis Patients

Tan, Yue; Guan, Yadi; Sun, Yan; Cheng, Zheng

doi:10.1016/j.amjms.2018.11.011

Cited by 60 publications

(26 citation statements)

References 40 publications

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“…Low mucus PC content is due to disturbed tight-junction barrier [37][38][39][40] and causes insufficient translocation of PC from systemic lipoproteins to the luminal side of mucosal cells. The reduced surface hydrophobicity allows attack of microbiota to induce mucosal inflammation [53,54].…”

Section: Discussionmentioning

confidence: 99%

“…NEC exhibits severe tight-junction defects as shown in rodent models and human neonates [33][34][35]. As defective tight junctions are also reported in humans with ulcerative colitis (UC) [36][37][38], we became interested in the potential therapeutic usefulness of milk exosomes for the treatment of UC. For this purpose, we investigated the effects of oral exposure of bovine milk exosomes in an established genetic mouse model of UC [39].…”

Section: Introductionmentioning

confidence: 99%

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Milk Exosomes Prevent Intestinal Inflammation in a Genetic Mouse Model of Ulcerative Colitis: A Pilot Experiment

Stremmel¹,

Weiskirchen

Melnik

2020

Inflamm Intest Dis

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Background: Milk is rich in nutrients and anabolic mediators rendering it essential for postnatal growth and metabolic programming. However, in adults, excessive consumption of milk is controversial as civilization disorders such as diabetes or prostate cancer may be promoted. A cytoprotective effect of milk could be utilized in inflammatory conditions, that is, chronic colitis. Objective: To evaluate the effect of bovine milk exosomes on intestinal inflammation in a genetic mouse model of ulcerative colitis. Methods: Intestinal-specific kindlin 2 knockout (KO) mice were exposed for 4 days to tamoxifen for induction of an ulcerative colitis phenotype. At the same time 4 other kindlin 2 KO mice were exposed to 33 μg/g cow milk derived exosomes in PBS by oral gavage. Both groups were compared to untreated wild-type controls. Results: Milk exosomes prevented the appearance of a severe ulcerative phenotype. The macroscopic colitis score dropped from a mean of 3.33 in untreated mice to 0.75 index points (p < 0.01) in exosome-treated mice, which included significant improvement of the subscores of stool improvement and colon weight and length. Treated mice featured a noninflamed appearance of the intestinal mucosa. Key Message: Milk exosomes have cytoprotective/anti-inflammatory activity in a genetic mouse model of ulcerative colitis. The mechanisms behind this need to be elucidated. This pilot study needs verification before a therapeutic strategy is developed.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Milk Exosomes Prevent Intestinal Inflammation in a Genetic Mouse Model of Ulcerative Colitis: A Pilot Experiment

Stremmel¹,

Weiskirchen

Melnik

2020

Inflamm Intest Dis

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“…ZO-1, a peripheral membrane protein forms narrow junction together with transmembrane proteins, is essential for maintenancing the intestinal mucosal barrier integrity (Turner, 2009). A recent study revealed that the expression of ZO-1 in UC patients was not only reduced as compared to that of healthy controls but also positively related to the intestinal mucosal healing (Tan et al, 2019). In this study, M10 by oral administration increased the expression of ZO-1, consequently resulting in the contribution to the restore of intestinal barrier.…”

Section: Discussionmentioning

confidence: 99%

M10, a Myricetin-3-O-b-D-Lactose Sodium Salt, Prevents Ulcerative Colitis Through Inhibiting Necroptosis in Mice

Zhou¹,

Yang²,

Qu³

et al. 2020

Front. Pharmacol.

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Background: M10 is a derivative of Myricetin by adding a hydrophilic glycosylation group. Our previous study revealed that M10 by oral administration prevented colitis-associated colonic cancer (CAC) through attenuating endoplasmic reticulum stress in mice. In current study, we evaluated the inhibitory effects of M10 on ulcerative colitis in mice model, the mechanism of M10 in preventing colitis was further investigated. Methods: Mice model of ulcerative colitis was induced by continuous oral dextran sodium sulfate (DSS). M10 was given gavage once a day for 12 consecutive weeks. Disease activity index (DAI) was recorded by analyzing the symptoms of colitis. Intestinal barrier was analyzed by the Immunofluorescence staining assay. The structure of microvilli of intestinal epithelial cells was analyzed under Transmission electron microscopy (TEM). TEM assay was also performed to determine the formation of necroptosis in the colonic epithelium with ulcerative colitis. We performed Western blotting assay to analyze the IL-6 and NF-kB pathways, as well as the cytokine cascades related to TNF-a signaling pathway during necroptosis. Results: M10 by oral administration demonstrated a prevention of ulcerative colitis, showing a significant decrease of DAI as compared to the model mice. Pathological analysis indicated that M10 attenuated the degree of colonic inflammation in colonic tissues. M10 restored the structures of intestinal barrier damaged by DSS. M10 prevented the activation of the IL-6 and NF-kB signaling pathways in the inflamed colonic epithelium. Further, M10 prevented necroptosis in the inflamed colonic mucosal cells through downregulating the TNF-a pathway. Importantly, M10 demonstrated higher activities in preventing ulcerative colitis than Myricetin and control drug Mesalazine. Conclusions: Myricetin derivative M10 prevents chronic ulcerative colitis through inhibiting necroptosis. M10 could be developed as a promising drug for the treatment of chronic ulcerative colitis.

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“…ZO-1 is a peripheral membrane protein that is essential for TJ assembly and maintenance[29]. A recent study revealed that occludin and ZO-1 expression in UC patients was not only significantly decreased compared with that of healthy controls but also positively related to intestinal mucosal healing[30]. Moreover, previous studies have demonstrated that SIRT1 enhances TJs in other physical barriers[31,32].…”

Section: Discussionmentioning

confidence: 99%

Sirtuin 1 alleviates endoplasmic reticulum stress-mediated apoptosis of intestinal epithelial cells in ulcerative colitis

Ren

Zhou

et al. 2019

WJG

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BACKGROUNDSirtuin 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.AIMTo investigate the role of SIRT1 in intestinal epithelial cells (IECs) in UC and further explore the underlying mechanisms.METHODSWe 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.RESULTSSRT1720 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.CONCLUSIONSIRT1 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.

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Correlation of Intestinal Mucosal Healing and Tight Junction Protein Expression in Ulcerative Colitis Patients

Cited by 60 publications

References 40 publications

Milk Exosomes Prevent Intestinal Inflammation in a Genetic Mouse Model of Ulcerative Colitis: A Pilot Experiment

Milk Exosomes Prevent Intestinal Inflammation in a Genetic Mouse Model of Ulcerative Colitis: A Pilot Experiment

M10, a Myricetin-3-O-b-D-Lactose Sodium Salt, Prevents Ulcerative Colitis Through Inhibiting Necroptosis in Mice

Sirtuin 1 alleviates endoplasmic reticulum stress-mediated apoptosis of intestinal epithelial cells in ulcerative colitis

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