Irisin inhibits NLRP3 inflammasome activation in HG/HF incubated cardiac microvascular endothelial cells with H/R injury.

PURPOSE: NLRP3 inflammasome mediates myocardial ischemia/reperfusion (MI/R) injury and diabetic vascular endothelia dysfunction. However, the role of NLRP3 inflammasome in MI/R injury with diabetes has not been fully described. Irisin plays an important role in anti-inflammation and improves endothelial function in type 2 diabetes. The current study aimed to investigate the effect of irisin on regulating NLRP3 inflammasome activation in diabetic vascular endothelia dysfunction. METHODS: Cardiac microvascular endothelial cells (CMECs) were cultured and subjected to high glucose/high fat (HG/HF) receiving hypoxia/reoxygenation (H/R) with irisin incubation or not. Then, apoptosis, viability, migration, NO secretion, and inflammasome activation were examined. RESULTS: The hypoxic CMECs exhibited increased apoptosis, impaired viability, and migration, even decreased NO secretion and enhanced inflammasome activation. Moreover, irisin incubation decreased NLRP3 activation and attenuated cell injury in HG/HF cultured CMECs subjected to H/R injury, which was abolished by NLRP3 inflammasome activation. Meanwhile, NLRP3 inflammasome siRNA also attenuated H/R injury in CMECs under HG/HF condition. CONCLUSION: The current study demonstrated for the first time that irisin inhibits NLRP3 inflammasome activation in CMECs as a novel mechanism in myocardial ischemia/reperfusion injury in diabetes.

Steriod for Autoimmune pancreatitis complicating by gastric varices: A case report.

BACKGROUND: Both autoimmune pancreatitis (AIP) and gastric varices are related to various diseases. However, AIP complicated by gastric varices is extremely rare, and has only been reported in a few studies. Here, we report a case of AIP complicated by gastric varices in a female Chinese patient. CASE SUMMARY: A 59-year-old Chinese woman was admitted to our hospital with mild abdominal pain. Computed tomography and magnetic resonance cholangiopancreatography revealed a diffusely enlarged pancreas, an obstructed splenic vein and slight splenomegaly. Esophagogastroduodenoscopy showed gastric varices in the partial gastric fundus and the red-color sign was positive. Blood chemistry showed that IgG4 was notablely elevated. The patient was diagnosed with AIP complicated by gastric varices. Steroid therapy was administered to this patient with the risk of gastrointestinal bleeding. After one year of therapy, the pancreas, spleen and splenic vein recovered to the normal states, and the gastric varices had disappeared. CONCLUSION: We present this case together with evidence from the literature to demonstrate the effectiveness of steroid therapy in the treatment of AIP complicated by gastric varices.

Assessment of Acute Pancreatitis Severity and Prognosis with CT-Measured Body Composition.

OBJECTIVE: The aim of this study was to investigate the possible association of muscle and adipose parameters with the severity and prognosis of patients hospitalized with acute pancreatitis (AP). METHODS: A total of 392 hospitalized patients and 309 controls were enrolled in the study analysis from April 1, 2016, to February 1, 2021. The computed tomography scans of each population were evaluated for muscle and adipose parameters. The effects of parameters on developing moderately severe acute pancreatitis (MSAP) or severe acute pancreatitis (SAP) were evaluated using univariate and multivariate logistic regression analyses. Associations with disease recurrence and death were analyzed through Cox regression analysis. RESULTS: The AP patients had higher levels of visceral adipose tissue (144.25 vs 97.81 cm2, p < 0.001) and subcutaneous adipose tissue (135 vs 120 cm2, p < 0.001) but lower levels of adipose tissue attenuation (visceral and subcutaneous) and skeletal muscle attenuation (SMA) than the controls (p < 0.05, respectively). Visceral adipose tissue (VAT) and SMA differed significantly with p-values of 0.014 and 0.003 in the different severity groups of AP. In multivariate analysis, VAT and SMA were associated with MSAP or SAP, with odds ratios of 1.003 and 0.973, respectively (95% CI 1.000-1.006, p = 0.041; 95% CI 0.953-0.993, p = 0.010). Cox regression analysis showed that low SMA was strongly associated with an increased mortality in MSAP and SAP patients (HR 10.500, 95% CI 1.344-82.025, p = 0.025). Regression analysis also showed an association of VAT loss of more than 17% with reduced 1-year recurrence of acute pancreatitis (HR 0.427, 95% CI 0.189-0.967, p = 0.041). CONCLUSION: VAT and SMA were influential factors for the severity and prognosis of patients with AP. Patients should proper diet and exercise after discharge to reduce VAT and strengthen muscle function to improve prognosis.

IL-9 contributes to the host immune response against Helicobacter pylori and helps limit infection in a Mouse Model.

BACKGROUND: As an important mediator in lots of diseases, interleukin-9 (IL-9) can be a protector or pro-inflammatory cytokine depending on the complicated inflammatory milieu. Helicobacter pylori (H. pylori) induced a series of immunology cells and cytokines change, and however, the role of IL-9 in H. pylori infection remains unknown. MATERIALS AND METHODS: Wild-type and IL-9 deficient mice were infected with H. pylori by means of intragastric administration. The colonization of H. pylori bacteria was measured by detecting specific 16s rDNA, and the intensity of inflammation was observed by H&E stain. The expression level of inflammation cytokines was determined by ELISA and quantitative real-time PCR. RESULTS: IL-9 was increased due to the attack of H. pylori, besides deletion of Il9 aggravated the bacterial colonization and inflammation intensity. In addition, treatment of rmIL-9 reduced colonized H. pylori and inflammation level, indicated that IL-9 was a protector for the host against this bacterium. Followed by the H. pylori infection, interferon (IFN)-γ and interleukin (IL)-17A were up-regulated as expected, and nevertheless, the expression of IL-17A shared a positive relationship with IL-9 while IFN-γ negative associated with IL-9. Moreover, we also proved that Treg cells were not involved in the protective effect of IL-9, and meanwhile, CD4+ CD25- T cells secreted more IFN-γ and less IL-17A in vitro due to the deletion of Il9. CONCLUSIONS: IL-9 plays a protective role against H. pylori and the protection associated with cytokines change including IFN-γ and IL-17A.

Long Noncoding RNA Lnc-TLN2-4:1 Suppresses Gastric Cancer Metastasis and Is Associated with Patient Survival.

Gastric cancer (GC) is one of the most common malignancies worldwide, and the tumor metastasis leads to poor outcomes of GC patients. Long noncoding RNAs (lncRNAs) have emerged as new regulatory molecules that play a crucial role in tumor metastasis. However, the biological function and underlying mechanism of numerous lncRNAs in GC metastasis remain largely unclear. Here, we report a novel lncRNA, lnc-TLN2-4:1, whose expression is decreased in GC tissue versus matched normal tissue, and its low expression is involved in the lymph node and distant metastases of GC, as well as poor overall survival rates of GC patients. We further found that lnc-TLN2-4:1 inhibits the ability of GC cells to migrate and invade but does not influence GC cell proliferation and confirmed that lnc-TLN2-4:1 is mainly located in the cytoplasm of GC cells. We then found that lnc-TLN2-4:1 increases the mRNA and protein expression of TLN2 in GC cells and there is a positive correlation between the expression of lnc-TLN2-4:1 and TLN2 mRNA in GC tissue. Collectively, we identified a novel lncRNA, lnc-TLN2-4:1, in GC, where lnc-TLN2-4:1 represses cell migration and invasion. The low expression of lnc-TLN2-4:1 is associated with poor overall survival rates of GC patients. These suggest that lnc-TLN2-4:1 may be a tumor suppressor during GC metastasis.

The prognostic significance of hTERT overexpression in cancers: A systematic review and meta-analysis.

BACKGROUND: Human telomerase reverse transcriptase (hTERT) plays an important role in cancer progression. Recently, several clinical studies investigated how the overexpression of hTERT predicts the poor prognosis of solid tumors. However, the results were inconclusive, partly because of the small numbers of patients included. METHOD: We systematically searched PubMed, Web of Science, and Embase to identify relevant studies until August 2017. Hazard ratios (HRs) with 95% confidence intervals (CIs) were used to evaluate the association of hTERT expression and survival outcomes. RESULTS: A total of 27studies enrolling 2530 solid tumor patients were included in this meta-analysis. There were strong significant associations between hTERT overexpression and all endpoints: overall survival (OS) (HR = 1.50, 95% CI: 1.31-1.73, P = .00), disease-free survival (HR = 1.84, 95% CI: 1.38-2.46; P = .00), and recurrence-free survival (HR = 1.79, 95% CI: 1.07-2.99; P = .028). In the subgroup analysis, it was found that the overexpression of hTERT induced poor OS in lung cancer (HR = 1.51, 95% CI: 1.21-1.89; P = .00). CONCLUSION: Our comprehensive systematic review concluded that the overexpression of hTERT was associated with poor survival in human solid tumors. hTERT may be a valuable predictive biomarker for prognosis.

Correlation between Helicobacter pylori Infection and Metabolic Abnormality in General Population: A Cross-Sectional Study.

BACKGROUND: Previous studies have suggested a link between Helicobacter pylori (H. pylori) and metabolic abnormality. This study aimed at investigating the correlation between H. pylori infection and metabolic abnormality in a general population. METHODS: All enrolled participants underwent a carbon-13 urea breath test (13C-UBT). For each individual, the following data were collected: age, gender, alanine transaminase (ALT), total protein, albumin, cholesterol, triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), urea nitrogen, creatinine, uric acid, fasting plasma glucose, postprandial blood sugar, nonalcoholic fatty liver disease (NAFLD), and bone mineral density (BMD). RESULTS: The study included 1867 (393 females and 1474 males, aged 54.0 ± 9.6 years) people that took a physical examination. There was no significant difference in gender and age between the study participants with and without H. pylori infection. The statistical data are as follows: albumin: P = 0.045, uric acid: P = 0.025, fasting glucose: P = 0.043, and postprandial blood glucose: P = 0.035. In terms of the patients with NAFLD, there were significant differences in ALT and HDL-C between the study participants with and without H. pylori infection. TG (P = 0.048), HDL-C (P = 0.011), and fasting blood glucose (P = 0.018) were significantly different in both groups among individuals who got osteopenia. CONCLUSION: H. pylori infection may be an important factor affecting metabolic abnormality and osteoporosis.

The role of miRNA and lncRNA in gastric cancer.

Gastric cancer is one of the most common cancers and has the highest mortality rate worldwide. It is worthwhile to explore the mechanism of gastric cancer progression. An increasing number of studies have found that non-coding RNAs including miRNA and lncRNA play important roles in gastric cancer progression. This review summarized the role of ectopic miRNA in gastric cancer proliferation, growth, migration, invasion and apoptosis. Meantime, aberrantly expressed miRNA also received a great deal of attention as potential biomarker for gastric cancer diagnosis and therapy. Over the last decade, lncRNA was considered to regulate gastric cancer progression at the transcript and post-transcript level. At the transcript level, lncRNA induced gastric cancer progression by changing chromatin modification and mRNA stabilization to regulate mRNA and miRNA expression. Furthermore, lncRNA regulated gastric cancer progression by completely combining with miRNA to produce ceRNA or promote protein stabilization at the post-transcript level. Greater attention of miRNA and lncRNA in gastric cancer can provide new insight of mechanism of cancer development and may be acted as a new anticancer target.

microRNA inhibitors: Natural and artificial sequestration of microRNA.

MicroRNA (miRNAs) is post-transcriptional regulator of mRNA. However, the prevalence and activity of miRNA are regulated by other regulators. miRNA inhibitors are natural or artificial RNA transcripts that sequestrate miRNAs and decrease or even eliminate miRNA activity. Competing endogenous RNAs (ceRNAs) are natural and intracellular miRNA inhibitors that compete to bind to shared miRNA recognition elements (MREs) to decrease microRNA availability and relieve the repression of target RNAs. In recent years, studies have revealed that ceRNA crosstalk is involved in many pathophysiological processes and adds a new dimension to miRNA regulation. Artificial miRNA inhibitors are RNA transcripts that are synthesized via chemical and genetic methods. Artificial miRNA inhibitors can be used in miRNA loss-of-function research and gene therapies for certain diseases. In this review, we summarize the recent advances in the two different types of miRNA inhibitors.

SDF-1/CXCR4 Axis Promotes MSCs to Repair Liver Injury Partially through Trans-Differentiation and Fusion with Hepatocytes.

MSCs have become a popular target for developing end-stage liver therapies. In this study, two models of bone marrow chimeric mice were used to construct the liver failure models. Then it was found that MSCs can transdifferentiate into hepatocyte-like cells and these hepatocyte-like cells can significantly express albumin. Furthermore it was also found that MSCs can fuse with the hepatocytes and these cells had the proliferation activity. However, the percentage of transdifferentiation was significantly higher than fusion. So it was considered that MSCs which transdifferentiated into hepatocyte-likes cells played important roles for repairing the injuring liver function.

Quantitative assessment of the association between AXIN2 rs2240308 polymorphism and cancer risk.

Axin2 is involved in the regulation of Wnt/ß-catenin pathway and implicated in cancer development and progression. The association between AXIN2 rs2240308 polymorphism and cancer risk has been examined in several case-control studies, but the conclusions were conflicting. Here we performed a meta-analysis to evaluate the role of rs2240308 in cancer risk. A total of 8 studies were included in this meta-analysis (1559 cancer cases and 1503 controls). The pooled odds ratios (OR) and the 95% confidence intervals (CIs) were assessed to evaluate the association of the AXIN2 rs2240308 polymorphism with a susceptibility to cancer. A significantly decreased overall cancer risk was observed in the homozygous (TT vs. CC), heterozygous (CT vs. CC), dominant (CT+TT vs. CC) and allelic (T vs. C) models (P < 0.005), rather than that in the recessive (TT vs. CT+CC) model (P = 0.092). AXIN2 polymorphism rs2240308 was also associated with decreased cancer risk under all five models in lung cancer. However, AXIN2 rs2240308 polymorphism was not associated with cancer risk under any above model in Turkish population and under homozygous, heterozygous, recessive models in Japanese population. These findings indicate that AXIN2 rs2240308 polymorphism significantly and race-specifically correlates with decreased cancer risk.

Hepatocyte growth factor (HGF) upregulates heparanase expression via the PI3K/Akt/NF-κB signaling pathway for gastric cancer metastasis.

Heparanase (HPA) is an endoglucuronidase that can promote the shedding of associated cytokines in several types of tumors. However, little is known about what controls the expression of HPA or its role in gastric cancer. In this study, we report for the first time that HGF regulates HPA expression to promote gastric cancer metastasis. In this study, HGF and HPA were found to be significantly expressed in 58 gastric cancer patients. High expression of both HGF and HPA was positively associated with TNM stage, invasion depth and poor prognosis. In MKN74 cells, exogenous HGF significantly increased HPA expression at both the mRNA and protein levels. Further study revealed that HGF first activated PI3K/Akt signaling. NF-κB signaling was activated downstream of PI3K/Akt and promoted HPA expression. However, when c-met, PI3K/Akt or NF-κB signal inhibitors were used, HPA expression was significantly decreased. All of these results indicate that HGF regulates HPA expression by PI3K/Akt and downstream NF-κB signaling. Using bioinformatics and the ChIP assay, p65 was observed to bind to the HPA promoter. Furthermore, HGF significantly induced tumor cell migration, whereas treatment with an NF-κB inhibitor decreased migration. Moreover, when HPA was overexpressed in MKN74 cells, migration was significantly enhanced, and the HGF concentration was increased. However, when HPA was down-regulated in MKN45 cells, migration and HGF levels decreased. Together, these results demonstrate that HGF/c-met can activate PI3K/Akt and downstream NF-κB signaling to promote HPA expression and subsequent tumor metastasis.

miR-1182 attenuates gastric cancer proliferation and metastasis by targeting the open reading frame of hTERT.

In humans, telomerase reverse transcriptase (hTERT) determines the activity of telomerase. hTERT is an ideal anticancer target because it is universally expressed in cancer cells and plays a crucial role in carcinogenesis. In this study, we report the miR-1182-mediated post-transcriptional regulation of hTERT. Over-expression of miR-1182 in different gastric cancer cells decreased hTERT protein levels. Bioinformation and dual-luciferase assays revealed that miR-1182 modulated hTERT by binding to its open reading frame (ORF), and this miRNA recognizes elements in the nucleotide region between 2695 and 2719 of hTERT mRNA. Over-expression of hTERT by transfecting pIRES2-hTERT into U2OS cells was abolished by miR-1182, while pIRES2-hTERT-MT, in which miR-1182 target site was synonymously mutated, failed to respond to miR-1182. Further investigation revealed that miR-1182 inhibited gastric cancer proliferation and migration by targeting the ORF1 of hTERT. We also found that miR-1182 could attenuate the proliferative and metastatic potential of SGC-7901 cell in vivo. Moreover, we found a statistically significant inverse correlation between miR-1182 and hTERT protein levels in tissues from 42 gastric cancer patients. These data indicate that miR-1182 suppresses TERT, and thus it could be an effective target for the treatment of gastric cancer.

Small Bowel Endoscopy Diagnostic Yield and Reasons of Obscure GI Bleeding in Chinese Patients.

Aim. To investigate the diagnostic yield and etiologies of patients with obscure gastrointestinal bleeding (OGIB) using capsule endoscopy (CE) or double-balloon enteroscopy (DBE). Method. We studied the data of 532 consecutive patients with OGIB that were referred to Xinqiao Hospital in Chongqing from December 2005 to January 2012. A lesion that was believed to be the source of the bleeding (ulceration, mass lesion, vascular lesion, visible blood, inflammation, or others) was considered to be a positive finding. We analyzed the diagnostic yield of CE and SBE and the etiologies of OGIB. Result. CE and SBE have similar diagnostic yields, at 71.9% (196/231) and 71.8% (251/304), respectively. The most common etiology was erosions/ulceration (27.1%) followed by mass lesion (19.4%) and angiodysplastic/vascular lesions (13.9%). By stratified analysis, we found that erosions/ulceration (27.1%) was the most common etiology for the 21-40-year age group. Mass lesion was the most common etiology in the 41-60-year age group. However, in the >60 years age group, angiodysplastic/vascular lesions were significantly increased compared with the other groups, even though erosions/ulceration was most common. Conclusion. In this study, we found that CE and SBE have similar diagnostic yields and erosions/ulceration was the most common reason for OGIB, followed by mass lesion and angiodysplasias.

Macrophage migration inhibitory factor polymorphism and the risk of ulcerative colitis and Crohn's disease in Asian and European populations: a meta-analysis.

OBJECTIVE: To determine whether macrophage migration inhibitory factor (MIF) gene polymorphism is associated with the risk of inflammatory bowel disease (IBD). DESIGN: System review and meta-analysis. METHODS: MEDLINE, EMBASE, Web of Science databases, Cochrane Library and the Chinese Biomedical Literature database (CBM) were searched for the case-control trails for MIF and IBD. All the studies included in this manuscript met the inclusion and exclusion criteria. An OR analysis using a 95% CI was employed to assess the association of the MIF-173 G/C polymorphism with IBD susceptibility. RESULTS: There was a significant association between the MIF-173 G/C gene polymorphism and IBD in the total population under the recessive model (CC vs GC+GG; OR=1.75, CI 1.04 to 2.95, p=0.04 for heterogeneity) and the codominant model (CC vs GG; OR=1.74, CI 1.02 to 2.97, p=0.04 for heterogeneity). In the stratified analysis by ethnicity, significantly increased risks were observed for Asians using the recessive (OR=1.75, CI 1.04 to 2.95, p=0.04 for heterogeneity) and codominant models (OR=1.74, CI 1.02 to 2.97, p=0.04 for heterogeneity). Within the subgroups of UC and CD, significant differences were observed regarding UC using the recessive (OR=1.60, CI 1.09 to 2.35, p=0.02 for heterogeneity) and codominant models (OR=1.64, CI 1.12 to 2.41, p=0.01 for heterogeneity). In the stratified analysis by ethnicity for UC, significant differences were observed regarding CC in Asians vs GC+GG (OR=1.73, CI 1.02 to 2.94, p=0.04 for heterogeneity). CONCLUSIONS: The meta-analysis suggested that the MIF-173 G/C polymorphism contributed to the susceptibility of IBD. When considering the subgroups of ethnicity and UC and CD, the results suggested that the polymorphism is more significant for UC in Asians.

PLCE1 polymorphism and upper gastrointestinal cancer risk: a meta-analysis.

BACKGROUND: In recent years, the PLCE1 rs2274223 polymorphism has been extensively investigated as a potential risk factor for upper gastrointestinal cancers, including squamous cell carcinoma (ESCC) and gastric cancer. However, the results of these studies have been inconsistent. METHODS: A meta-analysis of 13 case-control studies was performed including more than 11,000 subjects with genotyped PLCE1 rs2274223 polymorphisms. Odds ratios (OR) with 95% confidence intervals (CI) were employed to assess the association of the PLCE1 rs2274223 polymorphism with a susceptibility to ESCC or gastric cancer. RESULTS: A statistically significant increase in the risk of ESCC was associated with the PLCE1 rs2274223 polymorphism. This included the homozygous genetic model (OR = 1.46), heterozygous genetic model (OR = 1.25) and allelic genetic model (OR = 1.23). Similar results were consistently found for gastric cancer. In a subgroup analysis, the PLCE1 rs2274223 polymorphism was found to be a very sensitive marker for gastric cardia cancer as shown by the homozygous genetic model (OR = 2.23), heterozygous genetic model(OR = 1.59) and allelic genetic model (OR = 1.47). The risk associations of all of the gastric cardia cancer models were statistically significant. In contrast, none of the genetic models for non-cardia gastric cancer were significant. CONCLUSIONS: In this meta-analysis, the PLCE1 rs2274223 polymorphism was confirmed to have a statistically significant association with an increasing risk of ESCC and gastric cancer. The increase risk was especially observed for gastric cardia cancer.

HBV infection increases the risk of pancreatic cancer: a meta-analysis.

BACKGROUND: Hepatitis B virus (HBV) infection is reported to be associated with an increased risk of pancreatic cancer (PaC), but it remains controversial whether this is a causal relationship. In addition, it is unclear whether the status of HBV infection also affects PaC risk. Therefore, we conducted a meta-analysis to more closely examine the association between HBV infection and PaC. METHOD: The studies included in the meta-analysis were identified and retrieved from PubMed and several other databases. The literature search was conducted up until August 2012. We adopted the Cochrane Collaboration's RevMan 5.1 in a combined analysis of pooled relative risk (RR) with their corresponding 95 % confidence intervals (CIs) using a random-effects and a fixed-effects model. RESULTS: Nine studies including 6 case-control and 3 cohort studies met eligibility criteria. The meta-analysis showed that the PaC risk was positively correlated with HBV infection when comparing with 'never exposed to HBV' subgroup, the pooled RR was 1.39 (95 % CI 1.22-1.59, p < 0.00001) in chronic HBV carriers, 1.41 (95 % CI 1.06-1.87, p = 0.02) in past exposure to HBV, and 3.83 (95 % CI 1.76-8.36, p = 0.0007) in active HBV infection. Using a stratified analysis, we also found that the risk of PaC was independent of smoking, alcohol drinking, and diabetes. CONCLUSION: Findings from this meta-analysis strongly support that HBV infection is associated with an increased risk of PaC.

Macrophages in tumor microenvironments and the progression of tumors.

Macrophages are widely distributed innate immune cells that play indispensable roles in the innate and adaptive immune response to pathogens and in-tissue homeostasis. Macrophages can be activated by a variety of stimuli and polarized to functionally different phenotypes. Two distinct subsets of macrophages have been proposed, including classically activated (M1) and alternatively activated (M2) macrophages. M1 macrophages express a series of proinflammatory cytokines, chemokines, and effector molecules, such as IL-12, IL-23, TNF-α, iNOS and MHCI/II. In contrast, M2 macrophages express a wide array of anti-inflammatory molecules, such as IL-10, TGF-ß, and arginase1. In most tumors, the infiltrated macrophages are considered to be of the M2 phenotype, which provides an immunosuppressive microenvironment for tumor growth. Furthermore, tumor-associated macrophages secrete many cytokines, chemokines, and proteases, which promote tumor angiogenesis, growth, metastasis, and immunosuppression. Recently, it was also found that tumor-associated macrophages interact with cancer stem cells. This interaction leads to tumorigenesis, metastasis, and drug resistance. So mediating macrophage to resist tumors is considered to be potential therapy.