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

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.

BRCC36 promotes intestinal mucosal barrier injury caused by BMP2 after ischemia-reperfusion via inhibiting PPARγ signaling

As one of the most common pathological changes in trauma and surgery practice, intestinal ischemia-reperfusion (I/R) injury is regarded as a major precipitating factor in the occurrence and development of fatal diseases. BRCA1-BRCA2-containing complex subunit 36 (BRCC36), a deubiquitinase, has been proved important in a variety of pathophysiological processes such as DNA repair, cell cycle regulation, tumorigenesis and inflammatory response. However, the effect of BRCC36 on intestinal mucosal barrier injury after I/R has not been fully elucidated. Our research found that BRCC36 aggravated intestinal mucosal barrier injury caused by BMP2 (Bone morphogenetic protein 2) after I/R by downregulating PPARγ (Peroxisome proliferator-activated receptor-γ) signaling. These results suggested that BRCC36/PPARγ axis might serve as a potential therapeutic target for preventing intestinal mucosal barrier injury after I/R.

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

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.

Anterior Gradient Protein 2 Promotes Mucosal Repair in Pediatric Ulcerative Colitis

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.

Interleukin-9 promotes intestinal barrier injury of sepsis: a translational research

Background Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. Intestinal mucosal barrier injury is one of the important manifestations of sepsis. Interleukin-9 (IL-9) and IL-9-producing CD4(+) T cells were emerging pro-inflammatory mediators with development of intestinal injury. However, it is unclear whether IL-9 is related to the intestinal barrier injury of sepsis. Methods To investigate the roles of IL-9-producing CD4(+) T cells and IL-9 in the process of barrier injury in sepsis, serum IL-9-producing CD4(+) T cell percentages, IL-9, and D-lactate levels were measured in septic patients and controls. The markers of barrier function in serum and intestinal tissue were also collected in septic rats. Moreover, the barrier injury degree and survival rate of septic rats were also investigated after increasing or interfering with IL-9 expression. Results The serum IL-9-producing CD4(+) T cell percentages, IL-9, and D-lactate levels were significantly higher in septic patients or rats than those in controls. IL-9-producing CD4(+) T cells and IL-9 levels were positively correlated with D-lactate levels and had a high predictive value of 28-day mortality in septic patients. The non-survivors had significantly higher serum T cell percentages, IL-9, and D-lactate levels compared with survivors. In septic rats, IL-9 increased the expression levels of D-lactate, whereas that decreased the expression levels of zonula occludens 1. Moreover, the barrier injury was aggravated or alleviated by increasing or interfering with IL-9 expression, respectively. Survival rate analysis also showed that IL-9 decreased the 14-day survival rate of septic rats. Conclusion IL-9 is closely related to intestinal mucosal barrier injury and mortality in sepsis. IL-9 blockade has the potential to improve the barrier injury in sepsis. Trial registration The study was registered at ClinicalTrials.gov (ID: NCT03791866, Date: December 2018).

REGULATION OF THE INTESTINAL INFLAMMATORY RESPONSE THROUGH THE INGESTION OF MAILLARD COMPOUNDS AND THEIR INTERACTION WITH RAGE AND GPR43 RECEPTORS

Molecular damage signals attract neutrophils to sites of infection or inflammation. The G-protein coupled receptor (GPR43) and the receptor for advanced glicosilation compounds (RAGE) recognize short-chain fatty acids (propionate and butyrate) and AGEs (advanced glycosylation compounds) respectively, both receptors being abundantly expressed in neutrophils and intestinal epithelial cells. The functional role that activation of these receptors plays in the in vivo orchestration of the immune response is unclear. Our work examines the effect of the ingestion of AGEs on the immune response, both in healthy mice and in mice that were induced to colitis, using transgenic mice deficient in GPR43 or RAGE receptors. One of the main findings is that both the GPR43 receptor and RAGE are necessary for the recruitment of neutrophils in a model of intestinal inflammation due to mucosal barrier injury. We have also verified that the AGEs ingested with the diet promote the appearance of an imbalance in the inflammatory balance at the intestinal level, giving rise to a pro-inflammatory status. We have also show that carboxymethylisine (CML), a specific type of AGE, is capable of stimulating the GPR43 receptor and acting as a neutrophil chemoattraction factor. Finally, we have tested the treatment with sRAGE, a protein capable of capturing free AGEs. This procedure could be a promising therapy for the treatment of inflammatory bowel disease.

Specificity Influences in (1→3)-β-d-Glucan-Supported Diagnosis of Invasive Fungal Disease

(1→3)-β-glucan (BDG) testing as an adjunct in the diagnosis of invasive fungal disease (IFD) has been in use for nearly three decades. While BDG has a very high negative predictive value in this setting, diagnostic false positives may occur, limiting specificity and positive predictive value. Although results may be diagnostically false positive, they are analytically correct, due to the presence of BDG in the circulation. This review surveys the non-IFD causes of elevated circulating BDG. These are in the main, iatrogenic patient contamination through the use of BDG-containing medical devices and parenterally-delivered materials as well as translocation of intestinal luminal BDG due to mucosal barrier injury. Additionally, infection with Nocardia sp. may also contribute to elevated circulating BDG. Knowledge of the factors which may contribute to such non-IFD-related test results can improve the planning and interpretation of BDG assays and permit investigational strategies, such as serial sampling and BDG clearance evaluation, to assess the likelihood of contamination and improve patient care.