Modeling alcohol-associated liver disease in humans using adipose stromal or stem cell-derived organoids.

Alcohol-associated liver disease (ALD) is a prevalent liver disease, yet research is hampered by the lack of suitable and reliable human ALD models. Herein, we generated human adipose stromal/stem cell (hASC)-derived hepatocellular organoids (hAHOs) and hASC-derived liver organoids (hALOs) in a three-dimensional system using hASC-derived hepatocyte-like cells and endodermal progenitor cells, respectively. The hAHOs were composed of major hepatocytes and cholangiocytes. The hALOs contained hepatocytes and nonparenchymal cells and possessed a more mature liver function than hAHOs. Upon ethanol treatment, both steatosis and inflammation were present in hAHOs and hALOs. The incubation of hALOs with ethanol resulted in increases in the levels of oxidative stress, the endoplasmic reticulum protein thioredoxin domain-containing protein 5 (TXNDC5), the alcohol-metabolizing enzymes ADH1B and ALDH1B1, and extracellular matrix accumulation, similar to those of liver tissues from patients with ALD. These results present a useful approach for understanding the pathogenesis of ALD in humans, thus facilitating the discovery of effective treatments.

Blockade of TGF-ß signalling alleviates human adipose stem cell senescence induced by native ECM in obesity visceral white adipose tissue.

BACKGROUND: Abdominal obesity is appreciated as a major player in insulin resistance and metabolically dysfunctional adipose tissue. Inappropriate extracellular matrix (ECM) remodelling and functional alterations in human adipose stromal/stem cells (hASCs) have been linked with visceral white adipose tissue (vWAT) dysfunction in obesity. Understanding the interactions between hASCs and the native ECM environment in obese vWAT is required for the development of future therapeutic approaches for obesity-associated metabolic complications. METHODS: The phenotypes and transcriptome properties of hASCs from the vWAT of obese patients and lean donors were assessed. The hASC-derived matrix from vWAT of obese or lean patients was generated in vitro using a decellularized method. The topography and the major components of the hASC-derived matrix were determined. The effects of the obese hASC-derived matrix on cell senescence and mitochondrial function were further determined. RESULTS: We showed that hASCs derived from the vWAT of obese patients exhibited senescence and were accompanied by the increased production of ECM. The matrix secreted by obese hASCs formed a fibrillar suprastructure with an abundance of fibronectin, type I collagen, and transforming growth factor beta 1 (TGF-ß1), which resembles the native matrix microenvironment of hASCs in vWAT derived from obese patients. Furthermore, the obese hASC-derived matrix promoted lean hASC ageing and induced mitochondrial dysfunction compared to the lean hASC-derived matrix. Blockade of TGF-ß1 signalling using an anti-TGF-ß1 neutralizing antibody alleviated the lean hASC senescence and mitochondrial dysfunction induced by the obese hASC-derived matrix. CONCLUSIONS: Native ECM in obesity vWAT initiates hASC senescence through TGF-ß1-mediated mitochondrial dysfunction. These data provide a key mechanism for understanding the importance of cell-ECM interactions in hASCs senescence in obesity.

Efficacy and safety of one anastomosis gastric bypass versus Roux-en-Y gastric bypass for type 2 diabetes remission (ORDER): protocol of a multicentre, randomised controlled, open-label, superiority trial.

INTRODUCTION: Previous studies have demonstrated that one anastomosis gastric bypass (OAGB) is not inferior to Roux-en-Y gastric bypass (RYGB) in treating obesity. However, high level evidence comparing the efficacy and safety of both procedures in type 2 diabetes (T2D) treatment is still lacking, which is another main aim of bariatric surgery. The presented trial has been designed to aim at investigating the superiority of OAGB over the reference procedure RYGB in treating T2D as primary endpoint. And diabetes-related microvascular and macrovascular complications, cardiovascular comorbidities, weight loss, postoperative nutritional status, quality of life and overall complications will be followed up for 5 years as secondary endpoints. METHODS AND ANALYSIS: This prospective, multicentre, randomised superiority open-label trial will be conducted in patients of Asian descent. A total of 248 patients (BMI≥27.5 kg/m2) who are diagnosed with T2D will be randomly assigned (1:1) to OAGB or RYGB with blocks of four. The primary endpoint is the complete diabetes remission rate defined as HbA1c≤6.0% and fasting plasma glucose≤5.6 mmol/L without any antidiabetic medications at 1 year after surgery. All secondary endpoints will be measured at different follow-up visit points, which will start at least 3 months after enrolment, with a continuous annual follow-up for five postoperative years in order to provide solid evidence on the efficacy and safety of OAGB in patients with T2D. ETHICS AND DISSEMINATION: The study has been approved by the ethics committee of leading centre (Beijing Friendship Hospital, Capital Medical University, no. 2021-P2-037-03). The results generated from this work will be disseminated to academic audiences and the public via publications in international peer-reviewed journals and conferences. The data presented will be imported into a national data registry. Findings are expected to be available in 2025, which will facilitate clinical decision-making in the field. TRIAL REGISTRATION NUMBER: NCT05015283.

Bariatric surgery for non-alcoholic fatty liver disease in individuals with obesity (Base-NAFLD): protocol of a prospective multicenter observational follow-up study.

BACKGROUND: Bariatric surgery may be indicated in patients with nonalcoholic fatty liver disease (NAFLD) to achieve and maintain the degree of weight loss required to ensure therapeutic effects. However, bariatric surgery is still underrecognized in the treatment of NAFLD, including its inflammatory subtype, nonalcoholic steatohepatitis (NASH). Moreover, there is a lack of follow-up outcome data on different types of bariatric surgery in patients with NAFLD. This study aims to adequately assess the effect of bariatric surgery on NAFLD remission in obese patients. METHODS: This prospective multicentre observational follow-up study will include 142 obese patients with NAFLD scheduled to undergo one of the following surgical procedures: sleeve gastrostomy, Roux-en-Y gastric bypass, and one anastomosis gastric bypass. The primary outcome is the complete remission rate of NAFLD one year postoperatively, which is defined by liver fat fraction < 5% on magnetic resonance imaging; the secondary outcomes includes (i) changes in NASH and liver fibrosis biopsy findings, (ii) changes in body weight and abdominal adipose weight, (iii) resolution of obesity-related comorbidities, and (iv) incidence of adverse events. A long-term follow-up related to this study will also be conducted. DISCUSSION: This study will provide a necessary and preliminary foundation for the early identification and targeted treatment of patients with NAFLD who can be referred for bariatric surgery, as indicated for management of obesity and metabolic disease. TRIAL REGISTRATION: Clinicaltrials.gov: NCT04366999. Registered 21 April 2020. ( https://clinicaltrials.gov/ct2/show/NCT04366999 ).

The Choice of Gastric Bypass or Sleeve Gastrectomy for Patients Stratified by Diabetes Duration and Body Mass Index (BMI) level: Results from a National Registry and Meta-analysis.

PURPOSE: To determine whether sleeve gastrectomy (SG) or Roux-en-Y gastric bypass (RYGB) should be the optimal choice in patients stratified by diabetes duration and body mass index (BMI) level. METHODS: Classification tree analysis was performed to identify the influential factors for surgical procedure selection in real setting. Meta-analyses stratified by influential factors were conducted to compare the complete diabetes remission rates between SG and RYGB. The cost-effectiveness analysis was performed when results from meta-analysis remain uncertain. RESULTS: Among 3198 bariatric procedures in China, 824 (73%) SGs and 191 (17%) RYGBs were performed in patients with T2DM. Diabetes duration with a cutoff value of 5 years and BMI level with 35.5 kg/m2 were identified as the influential factors. For patients with diabetes duration > 5 years, RYGB showed a significant higher complete diabetes remission rate than SG at 1 year: 0.52 (95% confidence interval (CI): 0.46-0.58) versus 0.36 (95% CI: 0.30-0.42). For patients with diabetes duration ≤ 5 years and BMI ≥ 35.5 kg/m2, there was no significant difference between 2 procedures: 0.57 (95% CI: 0.43-0.71) for SG versus 0.66 (95% CI: 0.62-0.70) for RYGB. The cost-effectiveness ratios of SG and RYGB were 244.58 and 276.97 dollars per QALY, respectively. CONCLUSIONS: For patients with diabetes duration > 5 years, RYGB was the optimal choice with regard to achieving complete diabetes remission at 1 year after surgery. However, for patients with diabetes duration ≤ 5 years and BMI ≥ 35.5 kg/m2, SG appeared to provide a cost-effective choice.

GSK3 inhibitor ameliorates steatosis through the modulation of mitochondrial dysfunction in hepatocytes of obese patients.

Obesity is an important risk factor and a potential treatment target for hepatic steatosis. The maladaptation of hepatic mitochondrial flexibility plays a key role in the hepatic steatosis. Herein, we found that hepatocyte-like cells derived from human adipose stem cell of obese patients exhibited the characteristics of hepatic steatosis and accompanied with lower expression of the subunits of mitochondrial complex I and lower oxidative phosphorylation levels. The GSK3 inhibitor CHIR-99021 promoted the expression of NDUFB8, NDUFB9, the subunits of mitochondrial complex I, the basal oxygen consumption rate, and the fatty acid oxidation of the hepatocytes of obese patients by upregulating the expression of the transcription factor PGC-1α, TFAM, and NRF1 involved in mitochondrial biogenesis. Moreover, CHIR-99021 decreased the lipid droplets size and the triglyceride levels in hepatocytes of obese patients. The results demonstrate that GSK3 inhibition ameliorates hepatic steatosis by elevating the mitochondrial function in hepatocytes of obese patients.

Prediction of Long-Term Diabetes Remission After Metabolic Surgery in Obese East Asian Patients: a Comparison Between ABCD and IMS Scores.

PURPOSE: Recently, more than 10 models have been developed to predict remission of type 2 diabetes mellitus (T2DM) after metabolic surgery. The ABCD score was compared to the individualized metabolic surgery (IMS) score in terms of prediction of T2DM remission, but which of the two scoring systems is better remains controversial. METHODS: Patient data from 463 obese East Asian patients who underwent laparoscopic Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy (SG), or SG with duodenojejunal bypass (SG-DJB) as a primary operation and were followed for at least 3 years were retrospectively collected from 24 institutions. The correlation between the ABCD and IMS scoring systems and the discrimination power of the models was evaluated. The cut-off point for the IMS stage of T2DM severity was also revised to adjust the scoring system to obese East Asian patients. RESULTS: The two scoring systems were significantly well correlated. The IMS scoring system showed significant differences in T2DM remission rates between the procedures in the moderate stage, but the ABCD score showed no significant differences in each category. The discrimination power of the IMS score was comparable to that of the ABCD score at both 3 and 5 years. The revised IMS scoring system showed that SG-DJB had significantly higher T2DM remission rates in the moderate stage at 5 years than RYGB or SG. CONCLUSION: IMS score may be comparable to ABCD score to predict T2DM remission in obese East Asian patients. The revised IMS scoring system may also select candidates for SG or SG-DJB.

Short-Term Outcomes of Self-Expandable Metallic Stent versus Decompression Tube for Malignant Colorectal Obstruction: A Meta-Analysis of Clinical Data.

Purpose: To compare the short-term outcomes between self-expandable metallic stent (SEMS) and decompression tubes (DT) for malignant colorectal obstruction. Methods: A comprehensive literature search was performed from inception to 2018/12/6 covering Pubmed, Embase, and Cochrane library. Methodological assessments of eligible studies were performed by using Newcastle-Ottawa Scale (NOS). The Revman software (version 5.3) was used in our statistical analysis. Results: Totally 7 cohort studies were enrolled in our meta-analysis. All the 7 eligible studies proved to be high quality according to the NOS scale. Patients receiving SEMS had higher clinical success rates, higher laparoscopic surgery rates, and higher primary anastomosis rates compared with patients receiving DT. Conclusions: Based on evidence from eastern countries, SEMS placement is an effective procedure that treats malignant colorectal obstruction. Compared with DT placement, patients receiving SEMS may benefit from higher clinical success rates, higher laparoscopic surgery rates, and higher primary anastomosis rates.

Clinical Outcomes of One Anastomosis Gastric Bypass Versus Sleeve Gastrectomy for Morbid Obesity.

BACKGROUND: One anastomosis gastric bypass (OAGB) and sleeve gastrectomy (SG) are popular bariatric surgeries for morbid obesity. Reports on the safety and effectiveness of SG and OAGB are inconsistent. This meta-analysis investigated the clinical outcomes of SG versus those of OAGB for morbid obesity. METHODS: Based on PRISMA guidelines, we searched the published articles in English from Scopus, PubMed (Medline), Central (Cochrane), and Embase databases. Articles were retrieved from the start date of each database to February 13, 2019. Statistical analysis of this meta-analysis was conducted in Stata 14.0, and the most appropriate effect model was chosen based on heterogeneity. RESULTS: A total of 20 articles examining 4064 OAGB patients and 3733 SG patients were included in this meta-analysis. Compared with SG, OAGB showed a higher percentage excess weight loss (%EWL) at 6 months (weighted mean difference (WMD) = 11.32; 95% CI 6.00-16.64), 12 months (WMD = 8.22; 95% CI 3.78-12.66), 24 months (WMD = 10.19; 95% CI 0.88-21.25), 36 months (WMD = 7.93; 95% CI 3.37-12.48), 48 months (WMD = 17.22; 95% CI 7.37-27.06), and 60 months (WMD = 16.43; 95% CI 8.96-23.90). In addition, OAGB was associated with a lower rate of postoperative leak, gastroesophageal reflux disease, revisions, mortality, and dyslipidemia remission rates. However, OAGB increased the incidence of ulcers, malnutrition, and bile reflux. CONCLUSION: OAGB is more effective for %EWL and dyslipidemia remission than SG. In addition, OAGB may lower the risk of postoperative leak, gastroesophageal reflux disease, revision, and mortality. Further comparisons of the clinical outcomes of OAGB versus SG for morbid obesity would benefit from more high-quality controlled studies.

MicroRNA-940 restricts the expression of metastasis-associated gene MACC1 and enhances the antitumor effect of Anlotinib on colorectal cancer.

Background: Metastasis-associated with colon cancer-1 (MACC1) is an important regulator that promotes colorectal cancer (CRC) cells' proliferation and distant metastasis. Therefore, MACC1 is considered as a promising therapeutic target of CRC. This work aimed to identify the microRNA (miR) targeted to MACC1, and to study the potential of using the particular miR in enhancing the antitumor effect of chemotherapy. Materials and methods: miR prediction was performed in the miR database. The effect of miR-940 on MACC1's expression was examined by Western blot, and the effect of miR-940 on the expression of genes related to the epithelial-mesenchymal transition (EMT) was identified by quantitative real-time polymerase chain reaction experiments. In vivo growth of CRC cells were analyzed in the nude mice subcutaneous tumor model and CRC liver metastasis model. Results: By using the database, miR-940 was identified to target to the 3'UTR of MACC1's mRNA. Experimentally, transfection of miR-940 decreased the expression of MACC1 in CRC cells and inhibited the EMT process of the transfected cells. MiR-940 also enhanced the inhibitory effect of Anlotinib on CRC cells' in vivo growth and invasion. Correspondingly, ectopic expression of MACC1 mutant, which does not contain miR-940 binding site, blocked the antitumor effect of miR-940 on CRC cells. Conclusion: MiR-940 restricts the proliferation and invasion of CRC cells by targeting to MACC1's mRNA, and enhances the antitumor effect of Anlotinib on CRC tumors.

Differential composition of gut microbiota among healthy volunteers, morbidly obese patients and post-bariatric surgery patients.

The modulation of the gut microbiota was recently deemed one of the mechanisms responsible for the excellent outcomes of bariatric surgery. However, to date, only few studies have assessed this, and they have high heterogeneity. In the present study, next-generation 16S ribosomal DNA amplicon sequencing was used to characterize the gut microbiota of healthy volunteers, as well as patients prior to and after sleeve gastrectomy (SG) or Roux-en-Y gastric bypass (RYGB). Significant differences in α diversity, ß diversity and species were identified between the different groups/time-points. The results demonstrated excellent outcomes of SG and RYGB. The ß diversity was lower in healthy volunteers compared with that in morbidly obese patients with or without type 2 diabetes mellitus. At 3 months after SG, the α diversity was increased and the ß diversity was decreased. The abundance of certain species changed significantly after SG and RYGB. It was also revealed that the abundance of certain microbes was significantly correlated with the body mass index, fasting blood glucose and glycosylated haemoglobin. It may be concluded that bariatric surgery may cause obvious alterations in the gut microbiota and compared with healthy volunteers and obese patients without bariatric surgery, the microbiota composition of post-bariatric surgery has unique characteristics. However, studies with a larger cohort and longer follow-up may be required to confirm these results.

Analysis of Predictors of Type 2 Diabetes Mellitus Remission After Roux-en-Y Gastric Bypass in 101 Chinese Patients.

BACKGROUND: To investigate prognostic factors for complete remission in type 2 diabetes mellitus (T2DM) patients who underwent gastric bypass (GBP) and to establish a prognostic model for risk stratification. METHODS: We evaluated the baseline clinical features of patients with T2DM who received at Beijing Tian Tan Hospital from April 2012 to December 2015. Complete remission of T2DM was defined as meeting the following criteria: HbA1c < 6.5%, fasting plasma glucose (FPG) < 100 mg/dL, and absence of hypoglycemic drugs for 1 year following GBP. RESULTS: A total of 101 patients were enrolled in our study, and the complete remission rate of T2DM was 70.3% (71/101). Compared with patients with incomplete remission, patients with complete remission of T2DM had higher C-peptide levels, lower HbA1c, shorter disease duration, better ß cell function, and an absence of insulin therapy. HbA1c level, fasting C-peptide, duration of T2DM, and history of medical therapy were important prognostic factors for complete remission of T2DM (P = 0.001, 0.002, 0.01, 0.028, respectively). Patients with HbA1c lower than 7.5%, a history of T2DM shorter than 9.5 years, fasting C-peptide higher than 1.2 ng/mL, and absence of insulin therapy before GBP achieved a higher complete remission rate of T2DM after GBP (AUC of the model was 0.825, 95% CI, 0.741-0.910; P = 0.001). CONCLUSIONS: The duration of T2DM, history of medical therapy, and levels of HbA1c and fasting C-peptide are independent predictors for the prognosis of T2DM patients undergoing GBP. Patients with HbA1c lower than 7.5%, a history of T2DM shorter than 9.5 years, a fasting C-peptide higher than 1.2 ng/mL, and an absence of insulin therapy may have a higher complete remission rate of T2DM after GBP.

Preoperative Fasting Plasma C-Peptide Levels as Predictors of Remission of Type 2 Diabetes Mellitus after Bariatric Surgery: A Systematic Review and Meta-Analysis.

AIMS: The study evaluated the predictive role of preoperative fasting C-peptide, hemoglobin (Hb)A1c, fasting plasma glucose (FPG), and body mass index (BMI) levels on diabetes remission in patients with type 2 diabetes following bariatric surgery. METHODS: Medline, PubMed, Central, and Google Scholar databases of up to September 7, 2016 were searched using the following terms: type 2 diabetes mellitus, gastric bypass, Roux-en-Y, anastomosis, C-peptide, weight loss, HbA/HbA1c, predictive/predictor. RESULTS: Meta-analysis of the pooled data indicated that fasting C-peptide was predictive of increased chance of remission of type 2 diabetes (pooled difference in means = 0.93, 95% confidence interval [CI] = 0.61 to 1.25, p < .001). The analysis also found that FPG (pooled standardized mean difference = -0.42, 95% CI: -0.64 to -0.20, p < .004) and HbA1c levels (pooled difference in means = -1.05, 95% CI: -1.48 to -0.62, p < .001) were associated with reduced odds of type 2 diabetes remission. BMI was not found to be associated with remission (pooled difference in means = 0.29, 95% CI: 0.30 to 0.88, p = .343). In general, subgroup analysis, which evaluated the pooled data from the retrospective and prospective studies separately, gave similar results. CONCLUSIONS: Preoperative fasting plasma C-peptide was associated with increased type 2 diabetes remission after bariatric surgery, whereas baseline HbA1c and FPG levels were associated with reduced chance of remission. These parameters may be used as a guideline in weighing the risks and benefits for surgical intervention in patients with type 2 diabetes.

Application of side-to-side anastomosis of the lesser curvature of stomach and jejunum in gastric bypass.

AIM: To evaluate the feasibility of side-to-side anastomosis of the lesser curvature of stomach and jejunum in laparoscopic Roux-en-Y gastric bypass (LRYGB). METHODS: Seventy-seven patients received side-to-side anastomosis of the lesser curvature of stomach and jejunum by utilization of linear stapler in LRYGB from April 2012 to July 2015 were retrospectively analyzed. RESULTS: All patients were successfully completed laparoscopic gastric bypass with the side-to-side anastomosis of the lesser curvature of stomach and jejunum. No patient was switched to laparotomy during operation. No early complications including gastrointestinal anastomotic bleeding, fistula, obstruction, deep vein thrombosis, incision infections, intra-abdominal hernia complications were found. One patient complicated with stricture of gastrojejunal anastomosis (1.3%) and six patients complicated with incomplete intestinal obstruction (7.8%). BMI and HbA1c determined at 3, 6, 12, 24 mo during follow up period were significantly reduced compared with preoperative baselines respectively. The percentage of patients who maintain HbA1c (%) < 6.5% without taking antidiabetic drugs reached to 61.0%, 63.6%, 75.0%, and 63.6% respectively. The outcome parameters of concomitant diseases were significantly improved too. CONCLUSION: Present surgery is a safety and feasibility procedure. It is effective to lighten the body weight of patients and improve type 2 diabetes and related complications.

Effect of Roux-en-Y gastric bypass surgery on intestinal Akkermansia muciniphila.

AIM: To investigated changes in intestinal Akkermansia muciniphila (A. muciniphila) and explored the mechanism underlying the therapeutic effects of Roux-en-Y gastric bypass (RYGB) surgery on type 2 diabetes in diabetic Goto-Kakizaki (GK) rats. METHODS: Male diabetic GK rats (n = 12) aged 8 wk were randomly assigned to the surgery group (GK-RYGB) or sham surgery group (GK-Sham) (n = 6 per group), and another 6 male Wistar rats aged 8 wk served as controls (WS-Sham). In the surgery group, RYGB surgery was conducted, and a sham operation was performed in both sham groups. Fasting blood glucose (FBG) levels before and after surgery, fasting levels of serum insulin and serum glucagon-like peptide-1 (GLP-1) and levels 30 min after intragastric injection of glucose, and the amount of A. muciniphila in the stool were determined. Insulin and GLP-1 were measured by enzyme-linked immunosorbent assay, and A. muciniphila were detected by fluorescence-based quantitative polymerase chain reaction. RESULTS: The FBG was improved, and serum GLP-1 and insulin increased significantly (P < 0.05) in the GK-RYGB group after surgery compared to levels before surgery and to levels in the GK-Sham group. Before surgery, the amounts of A. muciniphila in the GK-RYGB and GK-Sham groups were significantly lower than in the WS-Sham group (P < 0.05). After surgery, the amount of A. muciniphila in the GK-RYGB group increased markedly compared to that before surgery and to that in the GK-Sham and WS-Sham groups (P < 0.05). In addition, the A. muciniphila amount was positively related to GLP-1 (r = 0.86, P < 0.05). CONCLUSION: Our results demonstrated RYGB surgery may increase GLP-1 secretion, elevate serum insulin after intragastric injection of glucose, and improve insulin resistance in diabetic GK rats, thereby contributing to a significant reduction in blood glucose. The increased amount of A. muciniphila after RYGB surgery may be related to elevated GLP-1 secretion.

Identification of potential therapeutic targets for colorectal cancer by bioinformatics analysis.

The aim of the present study was to identify potential therapeutic targets for colorectal cancer (CRC). The gene expression profile GSE32323, containing 34 samples, including 17 specimens of CRC tissues and 17 of paired normal tissues from CRC patients, was downloaded from the Gene Expression Omnibus database. Following data preprocessing using the Affy and preprocessCore packages, the differentially-expressed genes (DEGs) between the two types of samples were identified with the Linear Models for Microarray Analysis package. Next, functional and pathway enrichment analysis of the DEGs was performed using the Database for Annotation Visualization and Integrated Discovery. The protein-protein interaction (PPI) network was established using the Search Tool for the Retrieval of Interacting Genes database. Utilizing WebGestalt, the potential microRNAs (miRNAs/miRs) of the DEGs were screened and the integrated miRNA-target network was built. A cohort of 1,347 DEGs was identified, the majority of which were mainly enriched in cell cycle-related biological processes and pathways. Cyclin-dependent kinase 1 (CDK1), cyclin B1 (CCNB1), MAD2 mitotic arrest deficient-like 1 (MAD2L1) and BUB1 mitotic checkpoint serine/threonine kinase B (BUB1B) were prominent in the PPI network, while the over-represented genes in the integrated miRNA-target network were SRY (sex determining region Y)-box 4 (SOX4; targeted by hsa-mir-129), v-myc avian myelocytomatosis viral oncogene homolog (MYC; targeted by hsa-let-7c and hsa-mir-145) and cyclin D1 (CCND1; targeted by hsa-let-7b). CDK1, CCNB1 and CCND1 were also associated with the p53 signaling pathway. Overall, several genes associated with the cell cycle and p53 pathway were identified as biomarkers for CRC. CDK1, CCNB1, MAD2L1, BUB1B, SOX4, collagen type I α2 chain and MYC may play significant roles in CRC progression by affecting the cell cycle-related pathways, while CDK1, CCNB1 and CCND1 may serve as crucial regulators in the p53 signaling pathway. Furthermore, SOX4, MYC and CCND1 may be targets of miR-129, hsa-mir-145 and hsa-let-7c, respectively. However, further validation of these data is required.

Ileal interposition reduces blood glucose levels and decreases insulin resistance in a type 2 diabetes mellitus animal model by up-regulating glucagon-like peptide-1 and its receptor.

This study is to explore the possible mechanism of ileal interposition (IT) treatment of glycemic control of the type 2 diabetes mellitus (T2DM) by establishing an IT animal model. Twelve T2DM rats (GK rats) of 8-week old were divided into GK IT surgery group (GK-IT) and GK sham group (GK-Sham). Six Wistar rats were used as the non-T2DM sham group (WS-Sham). Enzyme-linked immunosorbent assay was used to detect plasma insulin concentration and fasting pancreas glucagon-like peptide-1 (GLP-1) concentration changes. Homeostasis model assessment of insulin resistance was used to quantitatively measure insulin resistance. Glucagon-like peptide-1 receptor (GLP-1R) expression was detected by Western blotting. IT significantly decreased fasting blood glucose level and the oral glucose tolerance, and reduced insulin resistance of GK rats by increasing GLP-1 concentration and GLP-1R levels. The postoperative pancreatic ß-cell apoptosis rate of GK-Sham group was significantly higher than those in the GK-IT group and the WS-Sham group. IT significantly reduces blood glucose and decreases insulin resistance by up-regulating GLP-1 concentrations and GLP-1R levels, which may contribute to insulin secretion of pancreatic ß-cells and decreases apoptosis of pancreatic ß-cell.

DNA methylation of trefoil factor 1 (TFF1) is associated with the tumorigenesis of gastric carcinoma.

Trefoil factor 1 (TFF1) is a tumor suppressor gene that encodes a peptide belonging to the trefoil factor family of protease­resistant peptides. Although TFF1 expression is frequently lost in gastric carcinomas (GCs), the tumorigenic pathways that are affected have yet to be determined. The aim of the current study was to identify the mechanism(s) by which the TFF1 gene is regulated in gastric carcinogenesis. In this study, TFF1 was shown to be silenced or downregulated in gastric tumor tissue compared with matched non­cancerous tissue. In addition, human gastric cells weakly expressed TFF1. The hypermethylation status in the promoter CpG islands appeared to be correlated with TFF1 expression levels in gastric cell lines or specimen tissue. Further molecular analysis indicated that the CpG islands play a role in the promoter activity of the TFF1 gene. The expression of TFF1 and DNA methylation of its promoter affected cell proliferation and apoptosis. The expression of TFF1 in gastric cell lines was restored with a demethylating agent, 5­azacytidine. Low expression of TFF1 in gastric cell lines and cancer tissue is associated with TP 53. In conclusion, the current study demonstrates that DNA methylation is a key mechanism of silencing TFF1 expression in human gastric cells and TFF1 gene hypermethylation of the CpG islands is a potential biomarker for GC.

[The effects of gastric bypass procedures on blood glucose, gastric inhibitory polypeptide and glucagon-like peptide-1 of normal glucose tolerance dogs].

OBJECTIVE: To observe postoperative glucose tolerance, gastric inhibitory polypeptide (GIP) , and glucogan-like peptide-1 (GLP-1) in normal glucose level dogs after undergoing gastric bypass procedures, and to explore the mechanism of gastric bypass procedures to treat type 2 diabetes. METHODS: The 6 dogs with normal glucose tolerance had undergone gastric bypass procedures, and measure preoperative and postoperative oral and intravenous glucose tolerance (at time points 1, 2, and 4 weeks) through changes in blood glucose, insulin, gastric inhibitory polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and measure preoperative and postoperative week 4 pancreatic tissue morphology. RESULTS: Second weeks after operation, the fasting blood sugar was (3.58 ± 0.33) mmol/L, and significantly lower than preoperative (t = 3.571, P < 0.05). The GLP-1 level before oral glucose tolerance test (OGTT) and 30 minutes after OGTT were (0.90 ± 0.21) and (0.91 ± 0.19) pmol/L respectively, and significantly higher than preoperative (t value were -3.660 and -2.971, P < 0.05). GLP-1 levels began to decrease in the second week after surgery. After 4 weeks, the index recovered to the preoperative level. Four weeks after surgery when compared with preoperative, islet morphology, islet number (6.8 ± 0.8 and 7.1 ± 0.8 respectively) and islet cells (16.7 ± 2.5 and 16.3 ± 3.1 respectively) did not change significantly (P > 0.05). CONCLUSION: Gastric bypass procedures could be briefly affect normal glucose tolerance in dogs' blood glucose, insulin and diabetes-related gastrointestinal hormones.