scholarly journals The Protective Mechanism of CAY10683 on Intestinal Mucosal Barrier in Acute Liver Failure through LPS/TLR4/MyD88 Pathway

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Yao Wang ◽  
Hui Chen ◽  
Qian Chen ◽  
Fang-Zhou Jiao ◽  
Wen-Bin Zhang ◽  
...  
Keyword(s):  
Liver Failure ◽  
Acute Liver Failure ◽  
Mucosal Barrier ◽  
Protective Mechanism ◽  
Epithelial Tissue ◽  
Intestinal Epithelial ◽  
Model Group ◽  
Intestinal Mucosal Barrier ◽  
Protein Levels ◽  
Myd88 Pathway

The purpose of this study was to investigate the protective mechanism of HDAC2 inhibitor CAY10683 on intestinal mucosal barrier in acute liver failure (ALF). In order to establish ALF-induced intestinal epithelial barrier disruption models, D-galactosamine/LPS and LPS were, respectively, used with rats and NCM460 cell and then administrated with CAY10683. Transepithelial electrical resistance (TEER) was measured to detect the permeability of cells. Real-time PCR and Western blotting were employed to detect the key mRNA and protein levels. The intestinal epithelial tissue pathology was detected. After interfering with CAY10683, the mRNA and protein levels of TLR4, MyD88, TRIF, and TRAF6 were decreased compared with model group (P<0.05), whereas the levels of ZO-1 and occluding were elevated (P<0.05). The permeability was elevated in CAY10683-interfered groups, when compared with model group (P<0.05). And the degree of intestinal epithelial tissue pathological damage in CAY10683 group was significantly reduced. Moreover, CAY10683 significantly decreased the TLR4 staining in animal tissue. The HDAC2 inhibitor CAY10683 could promote the damage of intestinal mucosal barrier in ALF through inhibiting LPS/TLR4/MyD88 pathway.

scholarly journals Betaine ameliorates intestinal injury by targeting the LPS/TLR4/MyD88 pathway and microbial communities of intestinal tract in acute liver failure

2019 ◽  
Author(s):  
Qian Chen ◽  
Yao Wang ◽  
Fang-Zhou Jiao ◽  
Chun-Xia Shi ◽  
Mao-Hua Pei ◽  
...  
Keyword(s):  
Liver Failure ◽  
Acute Liver Failure ◽  
Relative Abundance ◽  
Normal Group ◽  
Mucosal Barrier ◽  
Mrna Levels ◽  
Intestinal Epithelial ◽  
Model Group ◽  
Intestinal Epithelial Barrier ◽  
Gut Microbiota Composition

Abstract Background: A growing body of evidence revealed that the gut microbiome has a marked impact in acute liver failure (ALF). Microbes and their products will translocate into enterocoelia and enter into circulation system from the damaged intestinal lumen. It will further aggravate liver injury by enhancing the spread of inflammation, tissue damage and sepsis. Betaine is a hepatoprotective drug which has anti-inflammatory and anti-oxidant effects. Here, we evaluated the impact of betaine on gut microbiota composition in ALF animal experiment. The potential protective effect of betaine by inhibiting Toll-like receptor 4 (TLR4) responses was explored as well.Results: Eighteen mice were randomly divided into normal, model, and betaine groups. The ALF-induced intestinal epithelial barrier disruption internal models were induced by D-galactosamine（D-Gal）and lpopolysaccharide (LPS). Betaine was administered intragastrically 1 week before exposure of D-Gal/LPS. LPS were solely applied with a rat small intestinal cell line IEC-18 to establish ALF-induced intestinal epithelial barrier disruption external model. Mice in the model group developed severe intestinal epithelial tissue injury than normal group, increased significantly in the protein levels of TLR4, MyD88, TRAF6 and TNF-a and the mRNA levels of TLR4 and MyD88, and decreased significantly in the protein and mRNA levels of (ZO)-1 and occludin. Whereas, all above indicators were improved significantly by administration of betaine than that in model. The degree of liver tissue pathological damage, liver function and serum inflammatory cytokines in betaine group were significantly reduced than that in model group. The permeability of mice intestinal epithelial and IEC-18 cell in models was improved in betaine group than models. A total of 509 Operational Taxonomic Units (OTUs) were produced from mice fecal samples according to 16s rRNA gene sequence analysis. There were 156 core microbiomes in fecal samples. There existed a total of 24 species contained 11 species at the genus level which had a significant difference between groups. The increased relative abundance of g-Enterorhabdus in the model group was detected compared with normal group. Betaine down-regulated the relative abundance of g-Enterorhabdus in model. The relative abundance of g-Bacteroides was the highest in normal group and the least in model group. The relative abundance of g-Prevotella was almost identical in normal and betaine group, and it was decreased in model group.Conclusion: Betaine effectively improved the intestinal mucosal barrier in acute liver failure. The mechanism was probably related to inhibit the LPS/TLR4/MyD88 signaling pathways, improved the intestinal mucosal barrier and then maintained the gut microbiota composition.

scholarly journals Effects and Mechanism of Oxymatrine Combined with Compound Yinchen Granules on the Apoptosis of Hepatocytes through the Akt/FoxO3a/Bim Pathway

2022 ◽  
Vol 2022 ◽  
pp. 1-11
Author(s):  
Xian Zhang ◽  
Jiajia Ge ◽  
Xuejuan Zhu ◽  
Haifeng Zhang ◽  
Yuanzi Wang ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Western Blot ◽  
Liver Failure ◽  
Acute Liver Failure ◽  
Rat Liver ◽  
Caspase 3 ◽  
Normal Group ◽  
Model Group ◽  
Apoptosis Rate ◽  
Liver Tissues

The aim of the present study was to investigate the effects and mechanism of oxymatrine (OMT) combined with compound yinchen granules (CYG) on the apoptosis of hepatocytes through the Akt/FoxO3a/Bim pathway in rats with acute liver failure. The rat model of acute liver failure was established using lipopolysaccharide/D-galactosamine (LPS/D-GalN). The expression of proteins in rat liver tissues was detected by western blot analysis. The mRNA expression of FoxO3a, Bim, Bax, Bcl-2, and caspase-3 in rat liver tissues was detected by RT-qPCR. The apoptosis rate of rat hepatocytes was determined by flow cytometry. Western blots showed that when compared with the normal group, the expression of p-Akt and p-FoxO3a in the model group was decreased ( P < 0.05 ), while the expression of Bim was increased ( P < 0.01 ). Compared with the model group, the expression of p-Akt and p-FoxO3a in the OMT group and the OMT combined with CYG groups was increased ( P < 0.05 or P < 0.01 ), while the expression of Bim was decreased ( P < 0.05 ). The Bax/Bcl-2 ratio and caspase-3 protein expression in the model group were significantly higher than those in the normal group ( P < 0.01 ). The Bax/Bcl-2 ratio and the expression of caspase-3 protein in the OMT group and the OMT combined with CYG groups were significantly lower than those in the model group ( P < 0.01 ). The results of RT-qPCR were consistent with those of western blot. The results of flow cytometry showed that the apoptosis rate of hepatocytes in the OMT group and the OMT combined with CYG groups was significantly lower than that in the model group ( P < 0.05 or P < 0.01 ). We concluded that LPS/D-GalN can induce apoptosis of hepatocytes in rats with acute liver failure through the Akt/FoxO3a/Bim pathway. OMT combined with CYG inhibits apoptosis of hepatocytes in rats with acute liver failure via the Akt/FoxO3a/Bim pathway.

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.

scholarly journals Simvastatin Ameliorates PAK4 Inhibitor-Induced Gut and Lung Injury

2017 ◽  
Vol 2017 ◽  
pp. 1-9
Author(s):  
Shuming Pan ◽  
Zengbin Wu ◽  
Xuan Liu ◽  
Jiameng Chen ◽  
Huiqi Wang ◽  
...  
Keyword(s):  
Lung Injury ◽  
Mitogen Activated Protein Kinase ◽  
Mucosal Barrier ◽  
Protective Effects ◽  
Sprague Dawley ◽  
Intestinal Mucosal Barrier ◽  
Protein Levels ◽  
Mitogen Activated Protein ◽  
P21 Activated Kinase ◽  
D Values

P21 activated kinase 4 (PAK4), a key regulator of cytoskeletal rearrangement and endothelial microparticles (EMPs), is released after lipopolysaccharide (LPS) stimulation. In addition, it participates in LPS-induced lung injury. In this study, forty-eight Sprague Dawley (SD) rats were divided into two groups, including PAK4 inhibitor (P) and PAK4 inhibitor + simvastatin (P + S) treatment groups. All rats were given PAK4 inhibitor (15 mg/kg/d) orally. Immediately after PAK4 inhibitor administration, simvastatin was injected intraperitoneally to P + S group animals at 20 mg/kg/day. Then, treatment effects on the intestinal mucosal barrier and lung injury caused by PAK4 inhibitor and simvastatin were assessed. The results showed that gut Zonula Occludens- (ZO-) 1, PAK4, mitogen-activated protein kinase 4 (MPAK4), and CD11c protein levels were reduced, while plasma endotoxin levels were increased after administration of PAK4 inhibitor. Furthermore, compared with normal rats, wet-to-dry (W/D) values of lung tissues and circulating EMP levels were increased in the treatment group, while PAK4 and CD11c protein amounts were reduced. Therefore, in this lung injury process induced by PAK4 inhibitor, the protective effects of simvastatin were reflected by intestinal mucosal barrier protection, inflammatory response regulation via CD11c+ cells, and cytoskeleton stabilization. In summary, PAK4 is a key regulator in the pathophysiological process of acute lung injury (ALI) and can be a useful target for ALI treatment.

scholarly journals Analysis of Intestinal Mucosa Integrity and GLP-2 Gene Functions upon Porcine Epidemic Diarrhea Virus Infection in Pigs

Animals ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 644
Author(s):  
Yajing Zhou ◽  
Zhanshi Ren ◽  
Shuai Zhang ◽  
Haifei Wang ◽  
Shenglong Wu ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Intestinal Mucosa ◽  
Porcine Epidemic Diarrhea Virus ◽  
Intestinal Epithelial Cells ◽  
Mrna Level ◽  
Mucosal Barrier ◽  
Intestinal Epithelial ◽  
Intestinal Mucosal Barrier ◽  
Diarrhea Virus ◽  
Porcine Epidemic Diarrhea

Porcine epidemic diarrhea virus (PEDV) infects intestinal epithelial cells, destroys the intestinal mucosal barrier and then causes diarrhea in piglets. Glucagon-like peptide-2 (GLP-2) is a specific intestinal growth hormone that promotes the repair of damaged intestinal mucosa and improves the intestinal barrier. In this study, we investigated the functions of porcine GLP-2 gene in regulating PEDV infection. The intestinal tissues with damaged intestinal structures caused by PEDV infection were first confirmed and collected. Expression analysis indicated that the GLP-2 gene was expressed in the duodenum, jejunum and ileum tissues, and the mRNA level was significantly down-regulated in jejunum and ileum of piglets with damaged intestinal mucosa. Infection of PEDV to porcine small intestinal epithelial cells in vitro showed that GLP-2 gene was significantly decreased, which was consistent with the expression pattern in intestinal tissues. In addition, we silenced the GLP-2 gene by shRNA interfering and found that the copy numbers of PEDV were remarkably increased in the GLP-2 gene silencing cells. Our findings suggest that the GLP-2 gene was potentially involved in regulating PEDV infection and in maintaining the integrity of the intestinal mucosal barrier structure, which could contribute to our understanding of the mechanisms of PEDV pathogenesis and provide a theoretical basis for the identification and application of resistant genes in pig selective breeding for porcine epidemic diarrhea.

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

2021 ◽  
Vol 65 (s1) ◽  
Author(s):  
Carolina Pellegrini ◽  
Vanessa D'Antongiovanni ◽  
Chiara Ippolito ◽  
Cristina Segnani ◽  
Luca Antonioli ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Morphological Changes ◽  
Intestinal Barrier ◽  
Enteric Bacteria ◽  
Mucosal Barrier ◽  
Intestinal Epithelial ◽  
Intestinal Mucosal Barrier ◽  
Morphological Alterations ◽  
Neuromuscular Compartment

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.

scholarly journals Fusobacterium Nucleatum Promotes the Development of Acute Liver Failure by Inhibiting the NAD+ Salvage Metabolic Pathway

2021 ◽  
Author(s):  
Pan Cao ◽  
Qian Chen ◽  
Chunxia Shi ◽  
Luwen Wang ◽  
Zuojiong Gong
Keyword(s):  
Energy Metabolism ◽  
Liver Failure ◽  
Acute Liver Failure ◽  
Fusobacterium Nucleatum ◽  
Mucosal Barrier ◽  
Liver Inflammation ◽  
Ampk Signaling ◽  
Inflammatory Damage

Abstract Background: Acute liver failure (ALF) patients are often accompanied by severe energy metabolism abnormalities and intestinal microecological imbalance. The intestinal mucosal barrier is severely damaged. Intestinal endotoxin can induce intestinal endotoxemia through the "Gut-Liver axis". More and more evidence shows that members of the gut microbiota, especially Fusobacterium nucleatum (F. nucleatum), are related to inflammatory bowel disease, but whether F. nucleatum is involved in the development of ALF and whether it affects the liver energy metabolism is unclear. Methods: This study first detected the abundance of F. nucleatum and its effect on ALF disease, and explored whether F. nucleatum aggravated liver inflammation in vitro and in vivo. Results: Our data showed that liver tissues of ALF patients contained different abundances of F. nucleatum, which were related to the degree of liver inflammation. In addition, we found that F. nucleatum infection affected the energy metabolism of the liver during the development of ALF, inhibited the synthesis pathway of nicotinamide adenine dinucleotide (NAD+)'s salvage metabolism, and promoted inflammatory damage in the liver. In terms of mechanism, F. nucleatum inhibited NAD+ and the NAD+-dependent SIRT1/AMPK signaling pathway, and promoted liver damage of ALF. Conclusions: F. nucleatum coordinates a molecular network including NAD+ and SIRT1 to control the progress of ALF. Detection and targeting of F. nucleatum and its related pathways may provide valuable insights for the treatment of ALF.

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.

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