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.

Sishen Pill Maintained Colonic Mucosal Barrier Integrity to Treat Ulcerative Colitis via Rho/ROCK Signaling Pathway

Sishen Pill (SSP) is a classical prescription of traditional Chinese medicine and often used to treat gastrointestinal diseases, including ulcerative colitis (UC). However, its mechanism is still unclear. We aimed to determine the mechanism of SSP in the treatment of UC by investigating if it maintains the integrity of the intestinal mucosal barrier via the Rho A/Rho kinase (ROCK) signaling pathway. Administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS) successfully induced chronic UC in rats, while the treatment effect of SSP was evaluated by body weight change, colonic length, colonic weight, colonic weight index, histological injury score, and pathological injury score after colitis rats were treated for 7 days. TNF-α and IL-1β levels were analyzed by ELISA, and the proteins of PI3K/Akt and RhoA/ROCK signaling pathway and junction proteins expression were measured by western blotting assay, and the distribution of Claudin 5 was shown by immunofluorescence. SSP significantly improved the clinical symptoms of colitis in rats and reduced the expression of p-RhoA, ROCK1, PI3K, and Akt in the colon mucosa, while it increased the expression of p-Rac and related proteins (Claudin-5, JAM1, VE-cadherin, and Connexin 43). In addition, SSP increased p-AMPKα and PTEN proteins expression, decreased Notch1 level, and hinted that activation of the PI3K/Akt signaling pathway was inhibited. In conclusion, SSP effectively treated chronic colitis induced by TNBS, which may have been achieved by inhibiting PI3K/Akt signal to suppress activation of the Rho/ROCK signaling pathway to finally maintain the integrity of the intestinal mucosal barrier.

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.

Protective effect of dexmedetomidine on intestinal mucosal barrier function in rats after cardiopulmonary bypass

Cardiopulmonary bypass can result in damage to the intestines, leading to the occurrence of systemic inflammatory response syndrome. Dexmedetomidine is reported to confer anti-inflammatory properties. Here, the purpose of this study is to investigate the effect of dexmedetomidine on the intestinal mucosa barrier damage in a rat model of cardiopulmonary bypass. It was observed that cardiopulmonary bypass greatly decreased the levels of hemodynamic parameters than SHAM group, whereas dexmedetomidine pretreatment in a cardiopulmonary bypass model rat prevented this reduction. Also, it showed that compared with control animals, cardiopulmonary bypass caused obvious mucosal damage, which was attenuated in dexmedetomidine + cardiopulmonary bypass group. The above findings were in line with that of dexmedetomidine pretreatment, which increased the expression of tight junction proteins, but it decreased the levels of DAO, D-LA, FABP2, and endotoxin. Moreover, the results demonstrated that due to pre-administration of dexmedetomidine, the level of pro-inflammatory factors was decreased, while the level of anti-inflammatory cytokine was increased. Also, it showed that dexmedetomidine suppressed TLR4/JAK2/STAT3 pathway that was activated by cardiopulmonary bypass. Together, these results revealed that dexmedetomidine pretreatment relieves intestinal microcirculation, attenuates intestinal damage, and inhibits the inflammatory response of cardiopulmonary bypass model rats, demonstrating that in CPB-induced damage of intestinal mucosal barrier function, dexmedetomidine pretreatment plays a protective role by inactivating TLR4/JAK2/STAT3-mediated inflammatory pathway.

From the intestinal mucosal barrier to the enteric neuromuscular compartment: an integrated overview on the morphological changes in Parkinson’s disease

Gastrointestinal dysfunctions represent the most common non-motor symptoms in Parkinson’s disease (PD). Of note, changes in gut microbiota, impairments of intestinal epithelial barrier (IEB), bowel inflammation and neuroplastic rearrangements of the enteric nervous system (ENS) could be involved in the pathophysiology of the intestinal disturbances in PD. In this context, although several review articles have pooled together evidence on the alterations of enteric bacteria-neuro-immune network in PD, a revision of the literature on the specific morphological changes occurring in the intestinal mucosal barrier, the ENS and enteric muscular layers in PD, is lacking. The present review provides a complete appraisal of the available knowledge on the morphological alterations of intestinal mucosal barrier, with particular focus on IEB, ENS and enteric muscular layers in PD. In particular, our intent was to critically discuss whether, based on evidence from translational studies and pre-clinical models, morphological changes in the intestinal barrier and enteric neuromuscular compartment contribute to the pathophysiology of intestinal dysfunctions occurring in PD.

Emodin Improves Intestinal Health and Immunity through Modulation of Gut Microbiota in Mice Infected by Pathogenic Escherichia coli O1

The effect of emodin on the intestinal mucosal barrier of a mouse E. coli O1-induced diarrhea model was observed. Following successful establishment of a diarrhea model, the mice were treated with drugs for seven days. Intestinal lesions and the shape and the number of goblet cells were assessed via hematoxylin-eosin and periodic-acid-Schiff staining, while changes in inflammatory factors, ultrastructure of the small intestine, expression of MUC-2, and changes in the intestinal microbiota were analyzed via RT-PCR, electron microscopy, immunofluorescence, and 16S rRNA sequencing. Examination showed that emodin ameliorated pathological damage to the intestines of diarrheic mice. RT-PCR indicated that emodin reduced TNF-α, IL-β, IL-6, MPO, and COX-2 mRNA levels in duodenal tissues and increased the levels of sIgA and MUC-2 and the number of goblet cells. Microbiome analysis revealed that Escherichia coli O1 reduced bacterial richness and altered the distribution pattern of bacterial communities at the phylum and order levels in cecum contents. Notably, pathogenic Clostridiales and Enterobacteriales were significantly increased in diarrheic mice. However, emodin reversed the trend. Thus, emodin protected against intestinal damage induced by E. coli O1 and improved intestinal mucosal barrier function in mice by increasing the abundance of beneficial intestinal microbiota and inhibiting the abundance of harmful bacteria, thereby alleviating diarrhea.