scholarly journals Anterior Gradient Protein 2 Promotes Mucosal Repair in Pediatric Ulcerative Colitis

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Xiaolin Ye ◽  
Jie Wu ◽  
Jing Li ◽  
Hongyu Wang
Keyword(s):  
Ulcerative Colitis ◽  
Mucosal Injury ◽  
Mucosal Healing ◽  
Mucosal Barrier ◽  
Control Group ◽  
Intestinal Epithelial ◽  
Intestinal Mucosal Barrier ◽  
Mucosal Barrier Injury ◽  
Tnf Α

Mucosal healing comprises a key goal of ulcerative colitis (UC) treatment. Anterior gradient protein 2 (AGR2) plays an important role in maintaining intestinal homeostasis in UC. However, the role of AGR2 in the repair of mucosal injury is not yet clear. This study is aimed at investigating the expression of AGR2 in the intestinal tissues of children with UC and its role in repairing mucosal injury. Forty UC patients who were hospitalized in the Pediatric Gastroenterology Ward of Shengjing Hospital affiliated with China Medical University between July 1, 2013, and May 31, 2020, and 20 children who had normal colonoscopy results during the same period (control group) made up the study sample. The disease activity of UC was evaluated based on the pediatric ulcerative colitis activity index, and the ulcerative colitis endoscopic index was evaluated according to the Rachmilewitz score. Immunohistochemical staining was employed to examine the differences in AGR2 expression in the intestinal mucosa between groups. The protective effect of AGR2 in a model of tumor necrosis factor-alpha- (TNF-α-) induced intestinal mucosal barrier injury and the underlying molecular mechanism were explored through in vitro experiments. The results showed that compared with the normal control group, UC patients in the remission or active period had significantly higher expression of AGR2 in the intestine. AGR2 expression was positively correlated with Ki67, an intestinal epithelial cell proliferation marker, but negatively correlated with the degree of endoscopic mucosal injury. In an in vitro model, AGR2 overexpression promoted cell proliferation and migration and inhibited TNF-α-induced intestinal epithelial barrier damage by activating yes-associated protein (YAP). Collectively, our study suggests that AGR2 might serve as a valuable biomarker to help assess the condition and mucosal healing status of UC patients. In vitro, AGR2 promoted the repair of intestinal mucosal barrier injury by activating YAP.

Intestinal mucosal barrier dysfunction in SAP patients with MODS ameliorated by continuous blood purification

2017 ◽  
Vol 41 (1) ◽  
pp. 43-51
Author(s):  
Qing Shen ◽  
Zhengrong Li ◽  
Shanshan Huang ◽  
Liman Li ◽  
Hua Gan ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Mucosal Barrier ◽  
Intestinal Epithelial ◽  
Barrier Dysfunction ◽  
Intestinal Mucosal Barrier ◽  
Epithelial Monolayer ◽  
Tnf Α ◽  
Monolayer Permeability ◽  
Α Level ◽  
Junction Proteins

Background: Dysfunction of the intestinal mucosal barrier plays an important role in the pathophysiology of severe acute pancreatitis (SAP). Continuous blood purification (CBP) has been shown to improve the prognosis of SAP patients. In order to investigate the effect of CBP on intestinal mucosal barrier dysfunction in SAP patients with MODS, we conducted in vivo and in vitro experiments to explore the underlying mechanisms. Methods: The markers for the assessment of intestinal mucosal barrier function including serum diamine oxidase (DAO), endotoxin and intestinal epithelial monolayer permeability were detected during CBP therapy. The distribution and expression of cytoskeleton protein F-actin and tight junction proteins claudin-1 were observed. In addition, Rho kinase (ROCK) mRNA expression and serum tumor necrosis factor-alpha (TNF-α) levels during CBP were determined. Results: SAP patients with MODS had increased levels of serum DAO, endotoxin and intestinal epithelial monolayer permeability when compared with normal controls. While the distribution of F-actin and claudin-1 was rearranged, and the expression of claudin-1 significantly decreased, but F-actin had no change. Meanwhile, ROCK mRNA expression and serum TNF-α level were increased. However, after CBP treatment, levels of serum DAO, endotoxin and intestinal epithelial monolayer permeability decreased. The F-actin and claudin-1 reorganization attenuated and the expression of claudin-1 increased. At the same time, ROCK mRNA expression and serum TNF-α level were decreased. Conclusions: CBP can effectively improve intestinal mucosal barrier dysfunction. The beneficial effect is associated with the improvement of cytoskeleton and tight junction proteins in stability by downregulation of ROCK mRNA expression through the removal of excess proinflammatory factors.

Fecal Microbiota Transplantation Repairs Intestinal Mucosal Barrier Injury in Mice with Ulcerative Colitis

2021 ◽  
Vol 15 (5) ◽  
pp. 679-684
Author(s):  
Yijuan Lin ◽  
Jian Ding ◽  
Xunru Huang ◽  
Jintong Chen ◽  
Chengdang Wang
Keyword(s):  
Structural Changes ◽  
Fecal Microbiota Transplantation ◽  
Intestinal Barrier ◽  
Fecal Microbiota ◽  
Mucosal Barrier ◽  
Control Group ◽  
Model Group ◽  
Intestinal Mucosal Barrier ◽  
Mucosal Barrier Injury ◽  
Group A

This study aimed to explore the effects of fecal microbiota transplantation (FMT) on intestinal mucosal barrier injury in mice with ulcerative colitis (UC) and to elucidate the underlying mechanisms. Dextran sodium sulfate (DSS) was administered to develop the UC mouse model. Next, the experiment was divided into a normal control group, a DSS model group, a DSS+5-amino acid salicylic acid (5-ASA) group, and a DSS+FMT group. Hematoxylin–eosin staining was used to detect pathological changes; transmission electron microscopy was used to evaluate structural changes of intestinal mucosa; enzyme-linked immunosorbent assay (ELSIA) was used to detect endotoxins; and western blotting was used to detect the expression of zonula occludens-1 (ZO-1). In the control group, the intestinal mucosa and microvilli were intact, epithelial cells were closely connected, and the intercellular space was narrow. By contrast, focal intestinal barrier defects, including shallow ulcer, local inflammatory cell infiltration, hyperplasia of connective tissue, and loss of gland structure were observed in the model group. These abnormal morphological and structural changes were ameliorated by 5-ASA and FMT. Compared with the control group, the endotoxin content increased significantly, and the ZO-1 protein expression decreased significantly in the model group (P < 0.05). By contrast, the endotoxin level decreased significantly, and the ZO-1 protein expression increased significantly in the 5-ASA group and FMT group compared with that of the model group (P < 0.05). FMT ameliorates UC by repairing the intestinal barrier function, which is likely involved in upregulating ZO-1 expression.

scholarly journals The Effect of Peritoneal Air Exposure on Intestinal Mucosal Barrier

2014 ◽  
Vol 2014 ◽  
pp. 1-6 ◽  
Author(s):  
Jun Bao ◽  
Shanjun Tan ◽  
Wenkui Yu ◽  
Zhiliang Lin ◽  
Yi Dong ◽  
...  
Keyword(s):  
Terminal Ileum ◽  
Inflammatory Cells ◽  
Mucosal Injury ◽  
Mucosal Barrier ◽  
Control Group ◽  
Sprague Dawley ◽  
Air Exposure ◽  
Intestinal Mucosal Barrier ◽  
Group A ◽  
Lactate Levels

Background. Damage of the intestinal mucosa barrier may result in intestinal bacterial and endotoxin translocation, leading to local and systemic inflammation. The present study was designed to investigate whether peritoneal air exposure induces damage of intestinal mucosal barrier.Methods. Sprague-Dawley rats (weighing 210 to 230 g) were randomized into five groups (6/group): a control group, a sham group, and three exposure groups with peritoneal air exposure for 1, 2, and 3 h, respectively. At 24 h after surgery, blood and terminal ileum were sampled. The serum D-lactate levels were determined using an ELISA kit. The intestinal permeability was determined by measuring the intestinal clearance of FITC-dextran (FD4). The histopathological changes in terminal ileum were also assessed.Results. Compared with the controls, peritoneal air exposure caused an increase in both serum D-lactate level and intestinal FD4 clearance, which were proportional to the length of peritoneal air exposure and correlated to Chiu’s scores, indices for intestinal mucosal injury. Edema and inflammatory cells were also observed in mucosa and submucosa of ileum in three exposure groups.Conclusions. Peritoneal air exposure could induce damage to the intestinal mucosal barrier, which is proportional to the time length of peritoneal air exposure.

scholarly journals Small molecule FAK activator promotes human intestinal epithelial monolayer wound closure and mouse ulcer healing

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Qinggang Wang ◽  
Shyam K. More ◽  
Emilie E. Vomhof-DeKrey ◽  
Mikhail Y. Golovko ◽  
Marc D. Basson
Keyword(s):  
Wound Healing ◽  
Small Molecule ◽  
Wound Closure ◽  
Mucosal Injury ◽  
Mucosal Healing ◽  
Jejunal Mucosa ◽  
Intestinal Epithelial ◽  
Ki 67 ◽  
Injury Models

Abstract GI mucosal healing requires epithelial sheet migration. The non-receptor tyrosine kinase focal adhesion kinase (FAK) stimulates epithelial motility. A virtual screen identified the small drug-like FAK mimic ZINC40099027, which activates FAK. We assessed whether ZINC40099027 promotes FAK-Tyr-397 phosphorylation and wound healing in Caco-2 monolayers and two mouse intestinal injury models. Murine small bowel ulcers were generated by topical serosal acetic acid or subcutaneous indomethacin in C57BL/6J mice. One day later, we began treatment with ZINC40099027 or DMSO, staining the mucosa for phosphorylated FAK and Ki-67 and measuring mucosal ulcer area, serum creatinine, ALT, and body weight at day 4. ZINC40099027 (10–1000 nM) dose-dependently activated FAK phosphorylation, without activating Pyk2-Tyr-402 or Src-Tyr-419. ZINC40099027 did not stimulate proliferation, and stimulated wound closure independently of proliferation. The FAK inhibitor PF-573228 prevented ZINC40099027-stimulated wound closure. In both mouse ulcer models, ZINC40099027accelerated mucosal wound healing. FAK phosphorylation was increased in jejunal epithelium at the ulcer edge, and Ki-67 staining was unchanged in jejunal mucosa. ZINC40099027 serum concentration at sacrifice resembled the effective concentration in vitro. Weight, creatinine and ALT did not differ between groups. Small molecule FAK activators can specifically promote epithelial restitution and mucosal healing and may be useful to treat gut mucosal injury.

scholarly journals Hyaluronan Accelerates Intestinal Mucosal Healing through Interaction with TSG-6

Cells ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 1074 ◽  
Author(s):  
Giusy Sammarco ◽  
Mohammad Shalaby ◽  
Sudharshan Elangovan ◽  
Luciana Petti ◽  
Giulia Roda ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Wound Repair ◽  
Mucosal Healing ◽  
Mucosal Inflammation ◽  
Intestinal Epithelial ◽  
Beneficial Effects ◽  
Distal Ulcerative Colitis ◽  
Epithelial Regeneration

Hyaluronan (HA) has proven to be beneficial in the treatment of several diseases. Recently, it has been shown that the local application of HA (IBD98E) improves endoscopic and clinical outcomes in subjects with active distal ulcerative colitis (UC). However, the mechanisms by which this polysaccharide exerts its beneficial effects are unclear. Here, we demonstrated that HA treatment in vitro and in vivo improved mucosal healing by accelerating intestinal epithelial regeneration. Indeed, mice treated with HA showed a faster recovery from colitis and reduced endoscopic signs of mucosal inflammation compared to those receiving saline. Furthermore, histological analysis revealed less ulcerated mucosa in mice treated with HA, characterized by re-epithelialized areas. TSG-6, the secreted product of TNF-stimulated gene-6, is an HA-binding protein shown previously to have tissue-protective properties and promote wound healing. Mucosal levels of TSG-6 increased in UC patients compared to the healthy controls and also after wounding in mice. TSG-6 deletion prevented the beneficial properties of HA in mucosal wound repair, suggesting that the interaction of HA with TSG-6 is crucial for intestinal epithelial regeneration. Overall these results are consistent with HA having a therapeutic effect via the promotion of mucosal healing in patients with ulcerative colitis.

scholarly journals ILK mediates the effects of strain on intestinal epithelial wound closure

2011 ◽  
Vol 300 (2) ◽  
pp. C356-C367 ◽  
Author(s):  
Lisi Yuan ◽  
Matthew A. Sanders ◽  
Marc D. Basson
Keyword(s):  
Wound Closure ◽  
Mucosal Injury ◽  
Mucosal Barrier ◽  
Intestinal Epithelial ◽  
Cell Monolayers ◽  
Epithelial Migration ◽  
Gut Function ◽  
Integrin Linked Kinase ◽  
Interfering Rna

The intestinal epithelium is subjected to repetitive deformation during normal gut function by peristalsis and villous motility. Such repetitive strain promotes intestinal epithelial migration across fibronectin in vitro, but signaling mediators for this are poorly understood. We hypothesized that integrin-linked kinase (ILK) mediates strain-stimulated migration in intestinal epithelial cells cultured on fibronectin. ILK kinase activity increased rapidly 5 min after strain induction in both Caco-2 and intestinal epithelial cell-6 (IEC-6) cells. Wound closure in response to strain was reduced in ILK small interfering RNA (siRNA)-transfected Caco-2 cell monolayers when compared with control siRNA-transfected Caco-2 cells. Pharmacological blockade of phosphatidylinositol-3 kinase (PI3K) or Src or reducing Src by siRNA prevented strain activation of ILK. ILK coimmunoprecipitated with focal adhesion kinase (FAK), and this association was decreased by mutation of FAK Tyr925 but not FAK Tyr397. Strain induction of FAK Tyr925 phosphorylation but not FAK Tyr397 or FAK Tyr576 phosphorylation was blocked in ILK siRNA-transfected cells. ILK-Src association was stimulated by strain and was blocked by the Src inhibitor PP2. Finally, ILK reduction by siRNA inhibited strain-induced phosphorylation of myosin light chain and Akt. These results suggest a strain-dependent signaling pathway in which ILK association with FAK and Src mediates the subsequent downstream strain-induced motogenic response and suggest that ILK induction by repetitive deformation may contribute to recovery from mucosal injury and restoration of the mucosal barrier in patients with prolonged ileus. ILK may therefore be an important target for intervention to maintain the mucosa in such patients.

scholarly journals Emodin Protects Sepsis Associated Damage to the Intestinal Mucosal Barrier Through the VDR/ Nrf2 /HO-1 Pathway

2021 ◽  
Vol 12 ◽  
Author(s):  
Luorui Shang ◽  
Yuhan Liu ◽  
Jinxiao Li ◽  
Guangtao Pan ◽  
Fangyuan Zhou ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Protective Effect ◽  
Cecal Ligation ◽  
Mucosal Barrier ◽  
Protective Mechanism ◽  
Cecal Ligation And Puncture ◽  
Polygonum Multiflorum ◽  
Intestinal Mucosal Barrier ◽  
Mucosal Barrier Injury ◽  
Tnf Α

Aims: Emodin is an anthraquinone extracted from Polygonum multiflorum, which has potential anti-inflammatory and anti-oxidative stress effects. However, the possible protective mechanism of emodin is unclear. The purpose of this study was to investigate the protective mechanism of emodin against cecal ligation and puncture and LPS-induced intestinal mucosal barrier injury through the VDR/ Nrf2 /HO-1 signaling pathway.Methods: We established a mouse model of sepsis by cecal ligation and puncture (CLP), and stimulated normal intestinal epithelial cells with lipopolysaccharide (LPS). VDR in cellswas down-regulated by small interfering ribonucleic acid (siRNA) technology.Mice were perfused with VDR antagonists ZK168281 to reduce VDR expression and mRNA and protein levels of VDR and downstream molecules were detected in cells and tissue. Inflammation markers (tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6)) and oxidative stress markers (superoxide dismutase (SOD), malondialdehyde (MDA) and glutathione (GSH)) were measured in serum and intestinal tissueby enzym-linked immunosorbent assay. The expression of VDR in intestinal tissue was detected by immunofluorescence. Histopathological changes were assessed by hematoxylin and eosin staining.Results: In NCM460 cells and animal models, emodin increased mRNA and protein expression of VDR and its downstream molecules. In addition, emodin could inhibit the expressions of TNF-α, IL-6 and MDA in serum and tissue, and increase the levels of SOD and GSH. The protective effect of emodin was confirmed in NCM460 cells and mice, where VDR was suppressed. In addition, emodin could alleviate the histopathological damage of intestinal mucosal barrier caused by cecal ligation and puncture.Conclusion: Emodin has a good protective effect against sepsis related intestinal mucosal barrier injury, possibly through the VDR/ Nrf2 /HO-1 pathway.

The Promise of Patient-Derived Colon Organoids to Model Ulcerative Colitis

2021 ◽  
Author(s):  
Babajide A Ojo ◽  
Kelli L VanDussen ◽  
Michael J Rosen
Keyword(s):  
Ulcerative Colitis ◽  
Self Organization ◽  
Great Promise ◽  
Preclinical Model ◽  
Intestinal Epithelial ◽  
Epigenetic Changes ◽  
Nutrient Delivery ◽  
3 Dimensional ◽  
Tissue Systems

Abstract Physiologic, molecular, and genetic findings all point to impaired intestinal epithelial function as a key element in the multifactorial pathogenesis of ulcerative colitis (UC). The lack of epithelial-directed therapies is a conspicuous weakness of our UC therapeutic armamentarium. However, a critical barrier to new drug discovery is the lack of preclinical human models of UC. Patient tissue–derived colon epithelial organoids (colonoids) are primary epithelial stem cell–derived in vitro structures capable of self-organization and self-renewal that hold great promise as a human preclinical model for UC drug development. Several single and multi-tissue systems for colonoid culture have been developed, including 3-dimensional colonoids grown in a gelatinous extracellular matrix, 2-dimensional polarized monolayers, and colonoids on a chip that model luminal and blood flow and nutrient delivery. A small number of pioneering studies suggest that colonoids derived from UC patients retain some disease-related transcriptional and epigenetic changes, but they also raise questions regarding the persistence of inflammatory transcriptional programs in culture over time. Additional research is needed to fully characterize the extent to which and under what conditions colonoids accurately model disease-associated epithelial molecular and functional aberrations. With further advancement and standardization of colonoid culture methodology, colonoids will likely become an important tool for realizing precision medicine in UC.

scholarly journals P187 The significance of netrin-1 level in the clinical activity of ulcerative colitis, its association between TNF-α and IL-6

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S232-S232
Author(s):  
H Korkmaz ◽  
K Fidan
Keyword(s):  
Ulcerative Colitis ◽  
Proinflammatory Cytokines ◽  
Activity Index ◽  
Enzyme Linked Immunosorbent Assay ◽  
Control Group ◽  
Clinical Activity ◽  
Tnf Α ◽  
Significant Difference ◽  
And Control ◽  
Control Study

Abstract Background In this study, we investigated the importance of netrin-1 levels in ulcerative colitis (UC) in clinical activity of the disease, and its association with other proinflammatory cytokines IL-6 and TNF-α. Methods This study is a type of case–control study. Sixty-seven patients with UC (36 of them activation, 31 of remission) and 50 healthy controls were included in the study. UC patients; ‘Truelove Witts clinical activity index by remission (n = 31), mild activation (n = 21), moderate activation (n = 6) and severe activation (n = 9) were divided into groups. Netrin, IL-6 and TNF-α measurements in plasma samples were performed using enzyme-linked immunosorbent assay kit. Results Between the patient group and the control group; there was a statistically significant difference between netrin-1, IL-6, TNF-α, neutrophil, platelet (p &lt; 0.05 for all). The plasma netrin-1 mean of UC with severe activation group (139.21 ± 48.09 pg/ml) was statistically significantly higher than that of the mild activation (p = 0,037), remission group (p = 0,001) and control group(p = 0,011). The plasma netrin-1 mean of UC with moderate activation group was statistically significantly higher than that of the mild activation(p = 0,045) and remission group(p = 0,004). Conclusion Our results reveal that plasma netrin-1 levels have been shown to be associated with UC activation, similar to proinflammatory cytokines such as TNF-α and IL-6, in UC.

scholarly journals RETRACTED ARTICLE:Deficiency in intestinal epithelial Reg4 ameliorates intestinal inflammation and alters the colonic bacterial composition

2019 ◽  
Vol 12 (4) ◽  
pp. 919-929 ◽  
Author(s):  
Yongtao Xiao ◽  
Ying Lu ◽  
Ying Wang ◽  
Weihui Yan ◽  
Wei Cai
Keyword(s):  
Intestinal Inflammation ◽  
Elevated Serum ◽  
Intestinal Failure ◽  
Experimental Colitis ◽  
Mucosal Injury ◽  
Intestinal Epithelial ◽  
Bacterial Composition ◽  
Novel Target

AbstractThe regenerating islet-derived family member 4 (Reg4) in the gastrointestinal tract is up-regulated during intestinal inflammation. However, the physiological function of Reg4 in the inflammation is largely unknown. In the current study, the functional roles and involved mechanisms of intestinal epithelial Reg4 in intestinal inflammation were studied in healthy and inflamed states using human intestinal specimens, an intestinal conditional Reg4 knockout mouse (Reg4ΔIEC) model and dextran sulfate sodium (DSS)-induced colitis model. We showed that the elevated serum Reg4 in pediatric intestinal failure (IF) patients were positively correlated with the serum concentrations of proinflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). In inflamed intestine of IF patients, the crypt base Reg4 protein was increased and highly expressed towards the luminal face. The Reg4 was indicated as a novel target of activating transcription factor 2 (ATF2) that enhanced Reg4 expression during the intestinal inflammation. In vivo, the DSS-induced colitis was significantly ameliorated in Reg4ΔIEC mice. Reg4ΔIEC mice altered the colonic bacterial composition and reduced the bacteria adhere to the colonic epithelium. In vitro, Reg4 was showed to promote the growth of colonic organoids, and that this occurs through a mechanism involving activation of signal transducer and activator of transcription 3 (STAT3). In conclusion, our findings demonstrated intestinal-epithelial Reg4 deficiency protects against experimental colitis and mucosal injury via a mechanism involving alteration of bacterial homeostasis and STAT3 activation.

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