ABSTRACT
INTRODUCTION: The epithelial tight junctions of intestine were impaired in murine model of type 2 diabetes mellitus (T2DM). The aim of this work was to investigate the alteration of intestinal barrier in T2DM patients. METHODS: 90 patients with T2DM and 28 healthy controls were recruited. Serum lipopolysaccharide (LPS), Zonulin, and intestinal fatty acid binding protein (IFABP) were measured by ELISA, based on which a derived permeability risk score (PRS) was calculated. Subgroup analyses were conducted based on the glycemic control (HbA1câ¯<â¯7%, or HbA1câ¯≥â¯7%), the amount of chronic diabetic complications, and the use of aspirin at the time. RESULTS: Serum LPS, Zonulin, and IFABP, and PRS of T2DM group were significantly higher than those of the control group (pâ¯<â¯0.05 for all). Serum LPS and PRS was higher in T2DM patients with poor glycemic control (both pâ¯<â¯0.05). Patients with more chronic complications of diabetes had higher serum LPS and IFABP, and PRS (all pâ¯<â¯0.05). No differences were found in these serum markers between T2DM patients being treated with aspirin or not. CONCLUSIONS: Intestinal barrier function was impaired in T2DM patients. Poor glycemic control and more chronic complications of diabetes were associated with worse intestinal barrier function. Treatment with aspirin did not aggravate the impairment of intestinal barrier in T2DM patients.
Subject(s)
Diabetes Mellitus, Type 2 , Fatty Acid-Binding Proteins/blood , Intestinal Mucosa/physiopathology , Lipopolysaccharides , Protein Precursors/blood , Aspirin/therapeutic use , Diabetes Mellitus, Type 2/complications , Glycated Hemoglobin , Glycemic Control , Haptoglobins , Humans , Intestinal Mucosa/metabolism , Lipopolysaccharides/bloodABSTRACT
The intestinal epithelium cells (IECs) in diabetes mellitus (DM) patients have been proven to be abnormally differentiated. During the differentiation of IECs, epigenetic modification acts as an important regulator. In this study, we aimed to examine the epigenetic alteration of Transducin-like Enhancer of Split 1 (TLE1), a multitask transcriptional co-repressor, contributing to the differentiation homeostasis in IECs of DM mice. The IECs of type 2 diabetic mice model were isolated and collected. Methylation states of whole genomic DNA promoter regions were investigated by microarray. Methylated-specific PCR was used to detect the methylation state of TLE1 promoter in DM mice IECs. The expression of TLE1, Hes1, and differentiated cell markers were measured through real-time PCR, Western blots, and immunohistochemistry; by transfection assay, TLE1 or Hes1 was independently down-regulated in intestinal epithelium cell line, IEC-6. Subsequent modulation on TLE1, Hes1, and differentiated intestinal cell markers were detected. Global gene promoter regions in DM intestinal epithelium were less methylated comparing to normal control. The expression of TLE1 was significantly increased via hypomethylated activation in DM mice IECs. Hes1 was significantly suppressed and the terminal cell markers abnormally expressed in DM mice IECs (P < 0.05). Inhibition or induction on the abundance of TLE1 in IEC-6 cell line resulted in the corresponding dysregulation of Hes1 and intestinal epithelium differentiation (P < 0.05). Demethylation of TLE1 promoter region activates the self-expression in diabetic mice IECs. Subsequently, TLE1, through the transcriptional suppression on expression of Hes1, contributes to the aberrant differentiation of IECs in DM mice.
Subject(s)
Co-Repressor Proteins/biosynthesis , DNA Methylation , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Type 2/metabolism , Epigenesis, Genetic , Intestinal Mucosa/metabolism , Promoter Regions, Genetic , Animals , Co-Repressor Proteins/genetics , Diabetes Mellitus, Experimental/genetics , Diabetes Mellitus, Experimental/pathology , Diabetes Mellitus, Type 2/genetics , Diabetes Mellitus, Type 2/pathology , Intestinal Mucosa/pathology , MiceABSTRACT
Proliferative change and intestinal barrier dysfunction in intestinal mucosa of diabetes have been described, but the differentiation characteristics of intestinal epithelial cells (IECs) and the mechanisms in the IECs development remain unclear. To explore the intestinal epithelial constitution patterns and barrier function, the diabetic mouse model was induced by streptozotocin. Tight junctions between IECs were significantly damaged and the serum level of D-lactate was raised in diabetic mice (P < 0.05). The expression of Zo1 and Ocln in the small intestine of diabetic mice were lower, while the markers for absorptive cell (SI) and Paneth cell (Lyz1) were significantly higher than in control mice (P < 0.05). The expression of Msi1, Notch1, and Dll1 in small intestine gradually increased throughout the course of hyperglycemia in diabetic mice (P < 0.05). However, the expression of NICD, RBP-jκ, Math1, and Hes1 had a reverse trend compared with Msi1 and Notch1. Intestinal absorptive cells and Paneth cells had a high proliferation rate in diabetic mice. However, the intestinal barrier dysfunction associated with the decreased expressions of Zo1 and Ocln was detected throughout hyperglycemia. In conclusion, downregulation of Notch/Hes1 signal pathway caused by depressed Notch/NICD transduction is associated with the abnormal differentiation of IECs and intestinal barrier dysfunction in diabetic mice.
Subject(s)
Basic Helix-Loop-Helix Transcription Factors/metabolism , Cell Differentiation , Diabetes Mellitus, Experimental , Homeodomain Proteins/metabolism , Intestinal Mucosa/cytology , Intestinal Mucosa/metabolism , Receptor, Notch1/metabolism , Signal Transduction , Animals , Basic Helix-Loop-Helix Transcription Factors/genetics , Cell Membrane Permeability , Diabetes Mellitus, Experimental/chemically induced , Diabetes Mellitus, Experimental/pathology , Down-Regulation , Homeodomain Proteins/genetics , Intestinal Mucosa/pathology , Mice , Mice, Inbred C57BL , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , RNA-Binding Proteins/genetics , RNA-Binding Proteins/metabolism , Receptor, Notch1/genetics , Transcription Factor HES-1ABSTRACT
AIMS: ß-Catenin accumulation promotes proliferation. However, the correlation between proliferation of colorectal epithelium and ß-catenin in type 2 diabetes mellitus (DM) patients remains unclear. METHODS: Colorectal epithelium samples from distal ends of colorectal adenocarcinomas without histological aberrances were divided into two groups: DM patients with type 2 DM for more than 1year (n=27) and non-DM patients without hyperglycemia (n=20). Samples from patients without colorectal epithelial disease or hyperglycemia served as a control group (n=6). Proliferative index was calculated as the percentage of proliferating cell nuclear antigen positive cells. Wnt/ß-catenin signaling was assessed immunohistochemically and phosphorylation of ß-catenin was assessed by immunofluorescence. RESULTS: Compared with the non-DM or control group, the proliferative index and expression of lactate dehydrogenase A and Wnt/ß-catenin signaling were significantly higher in the DM group (all p<0.01). The proliferative index correlated positively with ß-catenin expression (Spearman correlation coefficient=0.55; p<0.01). Reduced phosphorylation at serine 33/37 and increased phosphorylation at serine 675 of ß-catenin were detected in the DM group (all p<0.01). CONCLUSIONS: Enhanced proliferation, accompanied by increased aerobic glycolysis, was detected in colorectal epithelium of patients with diabetes. ß-Catenin accumulation with altered phosphorylation correlated with the proliferative changes.
Subject(s)
Adenoma , Cell Proliferation , Colorectal Neoplasms , Diabetes Mellitus, Type 2 , Intestinal Mucosa/metabolism , Intestinal Mucosa/pathology , beta Catenin/metabolism , Adenoma/complications , Adenoma/metabolism , Adenoma/pathology , Adult , Aged , Case-Control Studies , Colorectal Neoplasms/complications , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/pathology , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/metabolism , Diabetes Mellitus, Type 2/pathology , Female , Humans , Isoenzymes/metabolism , L-Lactate Dehydrogenase/metabolism , Lactate Dehydrogenase 5 , Male , Middle Aged , Proliferating Cell Nuclear Antigen/metabolismABSTRACT
Colon cancer is one of the most common cancers in the world. Multidrug resistance is related to poor prognosis of advanced colon cancer. The side population plays an important role in multiple drug resistance (MDR) of colon cancer. MicroRNA biomarkers of the side population of colon cancer is still unknown. In the present study, we aimed to explore miRNA markers of side population (SP) cells of colon cancer. The side population was sorted by flow cytometry. Cell viability was measured using an MTT assay. MicroRNA profiling analysis was performed to compare microRNA expression levels in the SP cells of colon cancer with levels in the non-SP cells of colon cancer. RT-PCR was applied to verify the result obtained from the microRNA profiling analysis. miR-5000-3p, miR-5009-3P and miR-552 were all found to be upregulated in SP cells of the colon cancer cell lines HCT-15, HT-29 and LoVo. RT-PCR confirmed the result from the microRNA profiling analysis. This implied that miR-5000-3p, miR-5009-3P and miR-552 may be potential microRNA biomarkers of the side population in colon cancer, which may provide new specific targets of the side population for the reversal of MDR of colon cancer.
Subject(s)
Colonic Neoplasms/genetics , Drug Resistance, Neoplasm , MicroRNAs/genetics , Side-Population Cells/metabolism , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacology , Biomarkers, Tumor/genetics , Cell Line, Tumor , Gene Expression Regulation, Neoplastic , HT29 Cells , Humans , Oligonucleotide Array Sequence Analysis , Side-Population Cells/drug effectsABSTRACT
BACKGROUND: Although the chemopreventive effect of 5-aminosalicylates on patients with ulcerative colitis has been extensively studied, the results remain controversial. This updated review included more recent studies and evaluated the effectiveness of 5-aminosalicylates use on colorectal neoplasia prevention in patients with ulcerative colitis. METHODS: Up to July 2013, we searched Medline, Embase, Web of Science, Cochrane CENTRAL, and SinoMed of China for all relevant observational studies (case-control and cohort) about the effect of 5-aminosalicylates on the risk of colorectal neoplasia among patients with ulcerative colitis. The Newcastle-Ottawa Scale was used to assess the quality of studies. Adjusted odds ratios (ORs) were extracted from each study. A random-effects model was used to generate pooled ORs and 95% confidence intervals (95%CI). Publication bias and heterogeneity were assessed. RESULTS: Seventeen studies containing 1,508 cases of colorectal neoplasia and a total of 20,193 subjects published from 1994 to 2012 were analyzed. 5-aminosalicylates use was associated with a reduced risk of colorectal neoplasia in patients with ulcerative colitis (OR 0.63; 95%CI 0.48-0.84). Pooled OR of a higher average daily dose of 5-aminosalicylates (sulfasalazine ≥ 2.0 g/d, mesalamine ≥ 1.2 g/d) was 0.51 [0.35-0.75]. Pooled OR of 5-aminosalicylates use in patients with extensive ulcerative colitis was 1.00 [0.53-1.89]. CONCLUSION: Our pooled results indicated that 5-aminosalicylates use was associated with a reduced risk of colorectal neoplasia in patients with ulcerative colitis, especially in the cases with a higher average daily dose of 5-aminosalicylates use. However, the chemopreventive benefit of 5-aminosalicylates use in patients with extensive ulcerative colitis was limited.
Subject(s)
Colitis, Ulcerative/complications , Colorectal Neoplasms/complications , Colorectal Neoplasms/prevention & control , Mesalamine/pharmacology , Humans , RiskABSTRACT
BACKGROUND: Enteral nutrition is increasingly advocated in the treatment of acute pancreatitis, but its timing is still controversial. The aim of this meta-analysis was to find out the feasibility of early enteral nutrition within 48 hours of admission and its possible advantages. METHODS AND FINDINGS: We searched PubMed, EMBASE Databases, Web of Science, the Cochrane library, and scholar.google.com for all the relevant articles about the effect of enteral nutrition initiated within 48 hours of admission on the clinical outcomes of acute pancreatitis from inception to December 2012. Eleven studies containing 775 patients with acute pancreatitis were analyzed. Results from a pooled analysis of all the studies demonstrated that early enteral nutrition was associated with significant reductions in all the infections as a whole (OR 0.38; 95%CI 0.21-0.68, P<0.05), in catheter-related septic complications (OR 0.26; 95%CI 0.11-0.58, P<0.05), in pancreatic infection (OR 0.49; 95%CI 0.31-0.78, P<0.05), in hyperglycemia (OR 0.24; 95%CI 0.11-0.52, P<0.05), in the length of hospitalization (mean difference -2.18; 95%CI -3.48-(-0.87); P<0.05), and in mortality (OR 0.31; 95%CI 0.14-0.71, P<0.05), but no difference was found in pulmonary complications (P>0.05). The stratified analysis based on the severity of disease revealed that, even in predicted severe or severe acute pancreatitis patients, early enteral nutrition still showed a protective power against all the infection complications as a whole, catheter-related septic complications, pancreatic infection complications, and organ failure that was only reported in the severe attack of the disease (all P<0.05). CONCLUSION: Enteral nutrition within 48 hours of admission is feasible and improves the clinical outcomes in acute pancreatitis as well as in predicted severe or severe acute pancreatitis by reducing complications.
Subject(s)
Enteral Nutrition , Pancreatitis, Acute Necrotizing/therapy , Postoperative Complications/prevention & control , Databases, Bibliographic , Humans , Length of Stay , Pancreatitis, Acute Necrotizing/mortality , Pancreatitis, Acute Necrotizing/pathology , Survival Analysis , Time Factors , Treatment OutcomeABSTRACT
BACKGROUND: The long-term effectiveness and safety of lamivudine in patients with decompensated hepatitis B virus-related cirrhosis are still not clear. The present study attempted to describe the clinical outcomes of lamivudine therapy in these special patients over three years. METHODS: This study was a retrospective, controlled cohort study which involved 153 patients with decompensated hepatitis B virus-related cirrhosis. Of these, 86 patients received lamivudine 100 mg daily accompanied with general internal treatment, and the other 67 were given general internal treatment only. Significant clinical responses were recorded after years of antiviral treatment. RESULTS: The patients in both groups were matched in terms of age, sex and laboratory results at baseline. After years of therapy, the Child-Pugh-Turcotte scores and laboratory values of the patients receiving lamivudine were remarkably improved compared to the patients in the control group. The mortality rate and the incidence of cirrhosis-related complications were much lower in the lamivudine group than in the control group. Genotypic resistance tyrosine, methionine, aspartate, aspartate mutations developed in 26.7 percent of the patients during 3-year lamivudine treatment, and cirrhosis-related death and the hepatocellular carcinoma were more likely to occur in patients with these mutations than in the other patients who were treated with lamivudine. CONCLUSIONS: Continuous long-term lamivudine treatment in patients with decompensated hepatitis B virus-related cirrhosis delays clinical progression, and significantly improves hepatic function and prognosis. However, the use of a retrospective control cohort precludes drawing definitive conclusions.
Subject(s)
Antiviral Agents/therapeutic use , Hepatitis B/drug therapy , Lamivudine/therapeutic use , Liver Cirrhosis/mortality , Adult , Aged , Cohort Studies , Female , Hepatitis B/complications , Hepatitis B virus/genetics , Humans , Lamivudine/adverse effects , Liver Cirrhosis/complications , Male , Middle Aged , Mutation , Prognosis , Retrospective StudiesABSTRACT
OBJECTIVE: To review the development, mechanism, necessity and limitation of antiviral therapy in decompensated hepatitis B virus-related cirrhosis. DATA SOURCES: Most information was pulled from a literature search (Pubmed 2000 to 2011) using the keywords of antiviral and decompensated hepatitis B virus-related cirrhosis. Relevant book chapters were also reviewed. STUDY SELECTION: Well-controlled, prospective landmark studies and review articles on antiviral therapy in decompesated hepatitis B virus-related cirrhosis were selected. RESULTS: Specific antiviral agents not only control viral replication, which permits liver transplantation, but also improve liver function so significantly that patients could be removed from the transplant waiting list. However, the emergence of drug-resistant mutants can result in treatment failure. Combination therapy is a save-strategy in drug-resistant. CONCLUSIONS: Although the treatment of end-stage liver disease is still a challenge worldwide, antiviral therapy has altered the natural history of hepatitis B patients with decompensated cirrhosis. The approval of the new generation of antivirals is opening new perspectives for finding the optimal antiviral treatment for patients with decompensated cirrhosis and preventing antiviral resistance. A combination of antivirals may be one of the future strategies for fulfilling these goals.