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Background: Acute pancreatitis in pregnancy (APIP) with organ failure (OF) is a rare but serious disease. Here, we describe the primary characteristics associated with APIP, and explore potential predictors for early recognition of OF among the patients. Methods: A total of 3154 patients with AP from January 2018 to December 2021 were retrospectively reviewed. After screening, we enrolled 49 patients with APIP and 184 non-pregnant AP patients. Clinical characteristics and blood biochemical information were assessed using IBM SPSS 26.0 software and the rms package in R. Results: The most primary cause of APIP was hypertriglyceridemia (59.2%), while respiratory failure (46.9%) was the main type in all OF patients. Age, hemoglobin (Hb), hematocrit (HCT), aminotransferase (ALT), creatinine (Cr), blood urea nitrogen (BUN), albumin (ALB) and sodium ion (Na+) in the pregnant group were lower than in the non-pregnant group (PConclusions: APIP was highly correlated with hypertriglyceridemia and respiratory failure. Higher BMI was a distinguishing feature of OF-APIP patients. The data indicate that close monitoring of BUN, TG and TC levels is essential for early prevention of OF in APIP patients.

Intestinal dysfunction is a common complication of acute pancreatitis. MiR155 may be involved in the occurrence and development of intestinal dysfunction mediated by acute pancreatitis, but the specific mechanism is not clear. To investigate the effect of miR155 on severe acute pancreatitis (SAP)-associated intestinal dysfunction and its possible mechanism in a mice model. In this study, SAP mice model was induced by intraperitoneal injection of caerulein and LPS in combination. Adeno-associated virus (AAV) was given by tail vein injection before the SAP model. The pancreatic and intestinal histopathology changes were analyzed. Cecal tissue was collected for 16S rRNA Gene Sequencing. Intestinal barrier proteins ZO-1 and E-cad were measured by Immunohistochemistry Staining and Western Blot, respectively. Intestinal tissue miR155 and inflammatory factors TNF-α, IL-1β, and IL-6 were detected by Q-PCR. The expression levels of protein associated with TNF-α and TLR4/MYD88 pathway in the intestinal were detected. In miR155 overexpression SAP group, the levels of tissue inflammatory factor were significantly increased, intestinal barrier proteins were significantly decreased, and the injury of intestinal was aggravated. Bacterial 16S rRNA sequencing was performed, showing miR155 promotes gut microbiota dysbiosis. The levels of TNF-α, TLR4, and MYD88 in the intestinal were detected, suggesting that miR155 may regulate gut microbiota and activate the TLR4/MYD88 pathway, thereby affecting the release of inflammatory mediators and regulating SAP-related intestinal injury. After application of miR155-sponge, imbalance of intestinal flora and destruction of intestinal barrier-related proteins have been alleviated. The release of inflammatory mediators decreased, and the histopathology injury of intestinal was improved obviously. MiR155 may play an important role in SAP-associated intestinal dysfunction. MiR155 can significantly alter the intestinal microecology, aggravated intestinal inflammation through TLR4/MYD88 pathway, and disrupts the intestinal barrier in SAP mice.

Digestive system tumours are the most common malignancies worldwide, causing huge number of deaths each year. With the increases in morbidity and mortality, it is imperative to identify new therapeutic targets. Melanoma-associated antigen-A6 (MAGEA6) is a member of the cancer/testicular antigen (CTA) family. There are increasing amount of evidence supporting that MAGEA6 plays an important role in the development of solid tumours. However, there has been no comprehensive analysis of MAGEA6 in digestive system tumours. Therefore, our objective was to investigate the expression level, clinical significance and related biological functions of MAGEA6 in digestive system tumours. In this study, we integratively analysed the data from multiple databases of patients with digestive system tumours. Our results showed that MAGEA6 was highly expressed in most digestive system tumours as compared with normal tissues, whereas patients with higher expression of MAGEA6 had a worse prognosis. Based on co-expression analysis, there was a close interaction between MAGEA6 and MAGEA3. Furthermore, differential gene enrichment analysis indicated that MAGEA6 was mainly involved in the formation of extracellular structure, DNA replication, mitosis and the p53 signalling pathway. These results suggest that MAGEA6 is as a prognostic factor with functional importance in digestive system tumours.

Intestinal fibrosis is the most common complication of Crohn's disease (CD) that is one major disorder of inflammatory bowel disease (IBD), but the precise mechanism remains unclear. MiR‐155 has been involved in fibrotic diseases. Here, we determined the role of miR‐155 in regulating intestinal fibrosis. MiR‐155 levels were significantly up‐regulated in CD patients with intestinal stricture CD. The overexpression of miR‐155 significantly aggravated TNBS‐induced CD‐associated intestinal fibrosis. Mechanistically, we identified that HBP1, a negative regulator of the Wnt/β‐catenin signalling pathway, is a direct target of miR‐155. Moreover, in vitro and in vivo experiments suggested that the miR‐155/HBP1 axis activates Wnt/β‐catenin signalling pathway to induce intestinal fibrosis. Taken together, we demonstrated that miR‐155 directly targets HBP1 to induce CD‐associated intestinal fibrosis via Wnt/β‐catenin signalling pathway.

Emerging evidence suggests that Helicobacter pylori infection is associated with metabolic disorders, although the underlying mechanisms are poorly defined. This study aimed to investigate the interaction among H. pylori, a high-fat diet (HFD), and the gut microbiota with glucose regulation and alterations in microbial metabolites. Mice were randomly allocated to H. pylori-infected and noninfected groups fed a chow diet or an HFD. After 4 weeks, two of the HFD groups were given antibiotic cocktails for 8 weeks to eliminate the gut microbiota. The results showed that an HFD significantly promoted increases in body weight, insulin resistance, and glucose intolerance, which were alleviated to normal after antibiotic treatment. H. pylori infection aggravated HFD-induced hyperglycemia, which could not be restored by antibiotics. The perturbation of the gut microbiota was greater in the mice cotreated with H. pylori and an HFD (HFDHp) compared to those administered either H. pylori or an HFD alone, with a loss of diversity, higher abundance of Helicobacter, and lower abundance of Lactobacillus. Furthermore, compared to that of the HFD alone group, the gut microbiota of the HFDHp group was much more susceptible to antibiotic destruction, with extremely lower diversity and dominance of Klebsiella. Fecal metabolome analyses demonstrated that the combination of H. pylori infection and an HFD altered metabolic composition and function, which were linked to glucose dysregulation. H. pylori infection may exacerbate the dysbiosis of the gut microenvironment induced by an HFD, including alterations in the microbiota and metabolites, which weakens the restorative effect of antibiotics and results in the persistence of glucose disorders. KEY POINTS: • The interplay of Hp, HFD, and antibiotics on glucose metabolism was firstly explored. • Hp infection impaired the effect of antibiotics on HFD-induced glucose dysregulation. • Hp infection altered gut microbiota and metabolites which aggravated by HFD.

Dysbiosis of gastric microbiota including Helicobacter pylori (H. pylori) infection is associated with the development of stomach cancer. Probiotics have been shown to attenuate H. pylori-induced gastritis, although their role in cancer prevention remains unclear. Thus, we aimed to explore the effects of probiotics on H. pylori-induced carcinogenesis and the alterations of gastrointestinal microbiota.Male INS-GAS mice were randomly allocated to H. pylori-infected and non-infected groups. After 4 weeks, probiotic combination (containing Lactobacillus salivarius and Lactobacillus rhamnosus) was administered in drinking water for 12 weeks. Stomachs were collected for RNA-Sequencing and the differentially expressed genes were validated using RT profiler PCR array. 16S rRNA gene sequencing was performed to assess the alterations of gastrointestinal microbiota.Probiotics significantly alleviate H. pylori-induced gastric pathology, including reduced infiltration of inflammation and lower incidence of precancerous lesions. RNA-Sequencing results showed that probiotics treatment decreased expressions of genes involved in pro-inflammatory pathways, such as NF-κB, IL-17, and TNF signaling pathway. Of note, probiotics did not suppress the growth of H. pylori, but dramatically reshaped the structure of both gastric and gut microbiota. The microbial diversity was increased in H. pylori-infected group after probiotics treatment. While gastric cancer-associated genera Lactobacillus and Staphylococcus were enriched in the stomach of H. pylori-infected group, the beneficial short-chain fatty acids-producing bacteria, including Bacteroides, Alloprevotella, and Oscellibacter, were more abundant in mice treated with probiotics. Additionally, probiotics restored the H. pylori-induced reduction of anti-inflammatory bacterium Faecalibaculum in the gut.Probiotics therapy can protect against H. pylori-associated carcinogenesis probably through remodeling gastrointestinal microbiota, which in turn prevent host cells from malignant transformation.

Helicobacter pylori (H. pylori) infection is the strongest known risk factor for the development of gastric cancer. DNA damage response (DDR) and autophagy play key roles in tumorigenic transformation. However, it remains unclear how H. pylori modulate DDR and autophagy in gastric carcinogenesis. Here we report that H. pylori infection promotes DNA damage via suppression of Rad51 expression through inhibition of autophagy and accumulation of p62 in gastric carcinogenesis. We find that H. pylori activated DNA damage pathway in concert with downregulation of repair protein Rad51 in gastric cells, C57BL/6 mice and Mongolian gerbils. In addition, autophagy was increased early and then decreased gradually during the duration of H. pylori infection in vitro in a CagA-dependent manner. Moreover, loss of autophagy led to promotion of DNA damage in H. pylori-infected cells. Furthermore, knockdown of autophagic substrate p62 upregulated Rad51 expression, and p62 promoted Rad51 ubiquitination via the direct interaction of its UBA domain. Finally, H. pylori infection was associated with elevated levels of p62 in gastric intestinal metaplasia and decreased levels of Rad51 in dysplasia compared to their H. pylori- counterparts. Our findings provide a novel mechanism into the linkage of H. pylori infection, autophagy, DNA damage and gastric tumorigenesis.

Early dysbiosis of the gut microbiota is associated with the severity of acute pancreatitis (AP), although the underlying mechanism is unclear. Here, we investigated the role of crosstalk between NLRP3 and the gut microbiota in the development of AP utilizing gut microbiota deficient mice, as well as NLRP3 knockout (KO) mouse models. Pancreatic damage and systemic inflammation were improved in antibiotic-treated (Abx) and germ-free (GF) mice, accompanied by weakened activity of the intestinal NLRP3 inflammasome. Interestingly, fecal microbiota transplantation (FMT) reactivated the intestinal NLRP3 inflammasome and exacerbated the disease in Abx and GF mice. Although the gut barrier in GF and Abx mice was disrupted, gut microbiota deficiency ameliorated the severity of AP, probably due to the reduction in bacterial translocation from the gut to the pancreas. The composition of the gut microbiota was significantly different between NLRP3 KO mice and wild-type (WT) mice at baseline, and there were alterations in response to the induction of AP. While a dramatic shift in the gut microbiota with overgrowth of Escherichia-Shigella was observed in WT mice suffering from AP, there was no significant change in NLRP3 KO mice with or without AP, suggesting that NLRP3 deficiency counteracts AP-induced microbial disturbance. With a strengthened gut barrier and decreased systemic inflammation, NLRP3 KO mice showed less severe AP, as revealed by reduced pancreatic neutrophilic infiltration and necrosis. Taken together, these results identified the bidirectional modulation between the gut microbiota and NLRP3 in the progression of AP, which suggests the interplay of the host and microbiome during AP.

Objective Currently, insulin and/or heparin/low-molecular-weight heparin (LMWH) serve as an early lipid-lowering treatment for hypertriglyceridemic pancreatitis (HTGP). However, whether the clinical prognosis of combining LMWH with insulin is superior to using insulin alone remains unknown. This trial will compare the clinical outcomes of LMWH with insulin and an insulin regimen for emergency lipid-lowering treatment in HTGP patients. Methods In total, 476 eligible participants will be recruited from 18 hospitals throughout China. Participants in the LMWH group will receive LMWH combined with insulin, whereas insulin alone will be administered to those in the insulin group. The patients will be followed up at 3 and 6 months after discharge. Adverse reactions will be evaluated by the safety monitoring committee. Safety outcomes and adverse events will also be recorded. Results The study is registered in the Chinese Clinical Trial Registry (No: ChiCTR1900023640). Recruitment will begin in August 2019 and will be completed in December 2021 (http://www.chictr.org.cn/index.aspx). No data are available now. Conclusions The trial will investigate the efficacy of using LMWH combined with insulin as an emergency lipid-lowering treatment in reducing new organ failure, mortality, hospital stays, and expenses compared using with insulin alone for patients with HTGP.

Purpose Patients with a first attack of acute pancreatitis (AP) can develop recurrent acute pancreatitis (RAP). Hence, this study aimed to investigate the clinical features of the disease and the risk factors for RAP. Methods We performed a retrospective study of 522 patients from Jan 1 to Dec 31, 2006. All patients with AP were followed for 36 months. The primary end point was the rate of RAP. The secondary end points were the risk factors that were evaluated by Cox regression analysis. The cumulative risk of RAP was assessed using Kaplan-Meier analysis. Results 56 of the 522 patients (10.7%) developed RAP. Among those RAP patients, 37 (7.1%) experienced one relapse, 10 (1.9%) experienced two relapses, and 9 (1.7%) experienced three or more relapses. Univariate analysis indicated that age (p = 0.016), male sex, etiology of AP (p = 0.001), local complications (p = 0.001) and Length of stay (LOS) (p = 0.007) were associated with RAP. Multivariate analysis with the Cox proportional hazards model showed that male sex (HR = 2.486, 95% CI, 0.169–0.960, p = 0.04), HTG-associated etiology (HR = 5.690, 95% CI, 2.138–15.146, p = 0.001), alcohol-associated etiology (HR = 5.867, 95% CI, 1.446–23.803, p = 0.013) and current local complications at index admission (HR = 8.917, 95% CI, 3.650–21.789, p = 0.001) were significant independent risk factors for RAP. Conclusions A first attack of AP led to RAP in 10.7% of patients within 3 years. Male sex was significantly associated with RAP. The etiologies of alcohol and HTG and local complications were the strongest risk factors for recurrent disease. Patients with these characteristics should be given special attention and followed-up closely.

Background The incidence of acute pancreatitis (AP) in ageing patients has increased in recent years, and results regarding the clinical outcomes of these patients are controversial. The aim of this study was to compare the clinical outcomes of AP in ageing patients over 60 years old. Methods Eighty patients aged ≥80 years (oldest group) were compared to 393 patients aged 60 to 79 years (older group). The clinical course and biochemical and radiological data were evaluated. The primary endpoints were mortality rate, intensive care unit (ICU) admission rate and in-hospital length of stay (LOS). The secondary endpoints were the incidence of operative treatment and complications of AP. Results Abdominal pain (61.3% vs 46.3%, P=0.013) was less common in the oldest group. Jaundice (17.5% vs 8.9%, P=0.021) and dyspnoea (26.3% vs 11.5%, P=0.001) were more obvious in the oldest group than in the older group. The mean BMI was lower in the oldest group than in the older group (21.07±3.18 vs 22.36±2.89, P = 0.001). Age over 80 years (P=0.011) and organ failure (P

Background Pancreatic endocrine insufficiency after acute pancreatitis (AP) has drawn increasing attention in recent years. Aim To assess the impact of risk factors on the development of pancreatic endocrine insufficiency after AP. Methods This retrospective observational long-term follow-up study was conducted in a tertiary hospital. Endocrine function was evaluated by the oral glucose tolerance test. The data, including age, sex, body mass index, APACHE II score, history of smoking and drinking, organ failure, pancreatic necrosis, debridement of necrosis (minimally invasive and/or open surgery), and time interval, were collected from the record database. Results A total of 361 patients were included in the study from January 1, 2012 to December 30, 2018. A total of 150 (41.6%) patients were diagnosed with dysglycemia (including diabetes mellitus and impaired glucose tolerance), while 211 (58.4%) patients had normal endocrine function. The time intervals (mo) of the above two groups were 18.73 ± 19.10 mo and 31.53 ± 27.27 mo, respectively (P = 0.001). The morbidity rates of pancreatic endocrine insufficiency were 46.7%, 28.0%, and 25.3%, respectively, in the groups with different follow-up times. The risk factors for pancreatic endocrine insufficiency after AP were severity (odds ratio [OR] = 3.489; 95% confidence interval [CI]: 1.501-8.111; P = 0.004) and pancreatic necrosis (OR = 4.152; 95%CI: 2.580-6.684; P = 0.001). Conclusion Pancreatic necrosis and severity are independent risk factors for pancreatic endocrine insufficiency after AP. The area of pancreatic necrosis can affect pancreatic endocrine function.

A complex microbiota in the gastric mucosa (GM) has been unveiled recently and its dysbiosis is identified to be associated with gastric cancer (GC). However, the microbial composition in gastric fluid (GF) and its correlation with GM during gastric carcinogenesis are unclear.We obtained GM and GF samples from 180 patients, including 61 superficial gastritis (SG), 55 intestinal metaplasia (IM) and 64 GC and performed 16S rRNA gene sequencing analysis. The concentration of gastric acid and metabolite nitrite has been measured.Overall, the composition of microbiome in GM was distinct from GF with less diversity, and both were influenced by H. pylori infection. The structure of microbiota changed differentially in GM and GF across histological stages of GC, accompanied with decreased gastric acid and increased carcinogenic nitrite. The classifiers of GC based on microbial markers were identified in both GM and GF, including Lactobacillus, Veillonella, Gemella, and were further validated in an independent cohort with good performance. Interestingly, paired comparison between GM and GF showed that their compositional distinction remarkably dwindled from SG to GC, with some GF-enriched bacteria significantly increased in GM. Moreover, stronger interaction network between microbes of GM and GF was observed in GC compared to SG.Our results, for the first time, revealed a comprehensive profile of both GM and GF microbiomes during the development of GC. The convergent microbial characteristics between GM and GF in GC suggest that the colonization of carcinogenic microbes in GM might derive from GF.

Helicobacter pylori (H. pylori) infection is a well-recognized contributing factor to gastritis, but the underlying mechanisms remain to be established. It is interesting to note that AQP5 was predicted to be highly expressed in intestinal metaplasia (IM) based on H. pylori infection-related microarray data, and the transcription factor ASCL1 was bioinformatically predicted to associate with AQP5. Therefore, the purpose of this study is to evaluate the mechanistic significance of ASCL1 and AQP5 in H. pylori infection of gastritis. Gastritis mouse models were established by H. pylori infection, followed by determination of AQP5 and ASCL1 in gastric mucosa. Besides, the effects of AQP5 on H. pylori-induced gastritis were explored using AQP5−/− mice. It was observed that H. pylori infection elevated expression of AQP5 and ASCL1 in gastric mucosa and gastric epithelial cells (GECs). H. pylori induced AQP5 expression by regulating ASCL1 and activated WNT/β-catenin signaling pathway in GECs. It was also found that AQP5 knockdown suppressed inflammatory response and apoptosis in H. pylori-infected mice. Moreover, H. pylori infection-elevated ASCL1 and AQP5 expression promoted apoptosis and inflammation in GECs. Taken together, the key findings of the present study demonstrate that H. pylori infection activated WNT/β-catenin signaling pathway by upregulating ASCL1/AQP5 to induce gastritis.

BACKGROUND Activin A receptor type I (ACVR1) is involved in tumorigenesis. However, the underlying molecular mechanisms of ACVR1 in gastric cancer (GC) and its association with Helicobacter pylori remained unclear. MATERIALS AND METHODS The Cancer Genome Atlas (TCGA) and Gene Expression Profiling Interactive Analysis (GEPIA) database were utilized to explore the ACVR1 expression in GC and normal control and its association with survival. The ACVR1 was knocked out using CRISPR/Cas-9; RNA sequencing analysis was performed in AGS cells with ACVR1 knockout and normal control. Functional experiments (CCK-8, colony-forming, and transwell assays) were conducted to demonstrate the role of ACVR1 in cell proliferation, invasion, and metastasis. H. pylori-infected C57/BL6 models were established. ACVR1, p-Smad1/5, and CDX2 were detected in AGS cells cocultured with H. pylori strains. The CDX2 and key elements of BMP signaling pathway were detected in AGS cells with ACVR1 knockout and normal control. In addition, Immunohistochemistry was performed to detect the ACVR1 and CDX2 expression in gastric samples. RESULTS ACVR1 expression was higher in GC than normal control from TCGA, GEPIA, and samples collected from our hospital (p

Background Activin A receptor type I (ACVR1) is involved in tumorigenesis. However, the underlying molecular mechanisms of ACVR1 in gastric cancer (GC) and its association with Helicobacter pylori (H. pylori) remained unclear. Methods The Cancer Genome Atlas (TCGA) and Gene Expression Profiling Interactive Analysis (GEPIA) database were utilized to explore the ACVR1 expression in GC and normal control and its association with survival. The ACVR1 was knocked out using CRISPR/Cas-9, RNA sequencing analysis was performed in AGS cells with ACVR1 knockout and normal control. Functional experiments (CCK-8, colony-forming and transwell assays) were conducted to demonstrate the role of ACVR1 in cell proliferation, invasion and metastasis. ACVR1 and CDX2 were detected in AGS cells cocultured with wild type or cagA- H. pylori strains (7.13 and PMSS1) at different MOIs or times. The CDX2 and key elements of BMP signaling pathway were detected in AGS cells with ACVR1 knockout and normal control. In addition, Immunohistochemistry was performed to detect the ACVR1 and CDX2 expression in gastric samples. Results ACVR1 expression was higher in GC than normal control from TCGA, GEPIA and samples collected from our hospital (P Conclusions Our data indicate that H. pylori infection increases ACVR1 expression, promoting gastric IM via regulating CDX2, which is an essential step in H. pylori carcinogenesis.

The Hippo and Wnt signalling pathways play crucial roles in maintaining tissue homeostasis and organ size by orchestrating cell proliferation, differentiation and apoptosis. These pathways have been frequently found to be dysregulated in human cancers. While the canonical signal transduction of Hippo and Wnt has been well studied, emerging evidence shows that these two signalling pathways contribute to and exhibit overlapping functions in gastrointestinal (GI) tumorigenesis. In fact, the core effectors YAP/TAZ in Hippo signalling pathway cooperate with β-catenin in Wnt signalling pathway to promote GI neoplasia. Here, we provide a brief review to summarize the molecular mechanisms underlying the crosstalk between these two pathways and elucidate their involvement in GI tumorigenesis, particularly focusing on the intestine, stomach and liver.

Receptor of activated protein kinase C 1 (RACK1) is downregulated in gastric cancer and is involved in modulating NF-κB signaling pathway activity. However, the underlying molecular mechanisms regulating RACK1 expression are unclear. In this study, we demonstrated that downregulated expression of RACK1 was observed in gastric cancer tissue compared to adjacent normal tissue and was correlated with poor prognosis in patients. Helicobacter pylori (H. pylori) infection downregulated RACK1 expression in concert with canonical NF-κB signaling pathway activation in vivo and in vitro. RACK1 overexpression suppressed NF-κB signaling pathway activation as well as the release of downstream proinflammatory cytokines. In addition, RACK1 downregulation increased integrin β-1 expression, while integrin β-1 silencing decreased NF-κB signaling activation. Moreover, H. pylori infection downregulated RACK1 but upregulated integrin β-1 expression at the precancerous lesion stages in human subjects. Our data indicate that H. pylori infection promotes the upregulation of integrin β-1 expression via downregulation of RACK1 expression, which subsequently leads to the elevated activation of the NF-κB signaling pathway, an essential step in H. pylori-induced carcinogenesis.

Background Helicobacter pylori (H. pylori) is a major risk factor for gastric cancer. The water channel protein Aquaporin 5 (AQP5) is involved in the tumorigenesis and progression of various cancers. In this study, we aimed to explore the role of AQP5 in H. pylori-induced gastric carcinogenesis. Materials and methods We collected 160 samples which inculded CNAG, IM, Dys and gastric cancer from patients who underwent endoscopy and detected the expression of AQP5. In vivo and vitro H. pylori infection models, we explored the relationship between AQP5 and H. pylori. Plasmid, siRNA and inhibitors were used to investigated the relationship between AQP5 and EMT and the role of AQP5 in H. pylori-induced gastric carcinogenesis. Result AQP5 expression was gradually increased in human gastric tissues with the progression of chronic nonatrophic gastritis to gastric cancer and associated with the H. pylori infection status. In vivo and in vitro studies showed that H. pylori infection induced AQP5 expression in gastric epithelial cells in a CagA-dependent manner. Knockdown of AQP5 reversed H. pylori-induced cell proliferation and invasion, and -suppressed cell apoptosis. Additionally, knockdown of AQP5 suppressed H. pylori-induced Epithelial-mesenchymal transition (EMT) phenotypes by regulating transcriptional factors, mesenchymal markers, and epithelial markers. Conclusions We explored the underlying mechanism and our results indicated that knockdown of AQP5 significantly suppressed H. pylori infection-induced phosphorylation of ERK1/2, MEK and the expression levels of downstream genes. Treatment with an ERK inhibitor suppressed the EMT induced by H. pylori infection. Taken together, this study suggest that pathogenic H. pylori infection promotes AQP5 expression to induce the EMT via the MEK/ERK signaling pathway.

Gastric cancer (GC) is a leading cause of mortality and morbidity worldwide. We assessed the expression patterns of DNA damage response (DDR)-related markers, including ATM, CHK2, p-p53 (S15), Rad51, and BRCA2 and autophagy-related proteins including p62 and Beclin-1 in 153 GC specimens using immunohistochemistry staining. GC tissues showed lower levels of ATM, CHK2, p-p53, BRCA2, and higher levels of Rad51 compared to adjacent normal tissues. The autophagy-related protein p62 was upregulated, whereas Beclin-1 was downregulated in human GC groups. Additionally, different statuses of DDR pathways and autophagy characterized by protein expression were associated with overall survival. Our results indicated that the impairment of DNA damage and autophagy may be implicated in gastric cancer progression and its clinical prognosis.

Helicobacter pylori (H. pylori) is a main risk factor for gastric cancer (GC). Epithelial-mesenchymal transition (EMT) is involved in the development and progression of H. pylori-associated GC. However, the exact molecular mechanism of this process remains unclear. The AKT/GSK3β signaling pathway has been demonstrated to promote EMT in several types of cancer. The present study investigated whether H. pylori infection induced EMT, and promoted the development and metastasis of cancer in the normal gastric mucosa, and whether this process was dependent on AKT activation. The expression levels of the EMT-associated proteins, including E-cadherin and N-cadherin, were determined in 165 gastric mucosal samples of different disease stages by immunohistochemical analysis. The expression levels of E-cadherin, N-cadherin, AKT, phosphorylated (p-)AKT (Ser473), GSK3β and p-GSK3β (Ser9) were further determined in H. pylori-infected Mongolian gerbil gastric tissues and cells co-cultured with H. pylori by immunohistochemical analysis and western blotting. The results indicated that the expression levels of the epithelial marker E-cadherin were decreased, whereas the expression levels of the mesenchymal marker N-cadherin were increased during gastric carcinogenesis. Their expression levels were associated with H. pylori infection. Furthermore, H. pylori infection resulted in downregulation of E-cadherin expression and upregulation of N-cadherin expression in Mongolian gerbils and GES-1 cells. In addition, an investigation of the associated mechanism of action revealed that p-AKT (Ser473) and p-GSK3β (Ser9) were activated in GES-1 cells following co-culture with H. pylori. Furthermore, following pretreatment of the cells with the AKT inhibitor VIII, the expression levels of E-cadherin, N-cadherin, p-AKT and p-GSK3β did not show significant differences between GES-1 cells that were co-cultured with or without H. pylori. The levels of p-AKT and p-GSK3β were increased in H. pylori-infected Mongolian gerbils. In conclusion, the present study demonstrated that H. pylori infection activated AKT and resulted in the phosphorylation and inactivation of GSK3β, which in turn promoted early stage EMT. These effects were AKT-dependent. This mechanism may serve as a prerequisite for GC development.

Intestinal dysfunction is a common complication of acute pancreatitis. MiR155 may be involved in the occurrence and development of intestinal dysfunction mediated by acute pancreatitis, but the specific mechanism is not clear.To investigate the effect of miR155 on severe acute pancreatitis (SAP)-associated intestinal dysfunction and its possible mechanism in a mice model.In this study, SAP mice model was induced by intraperitoneal injection of caerulein and LPS in combination. Adeno-associated virus (AAV) was given by tail vein injection before the SAP model. The pancreatic and intestinal histopathology changes were analyzed. Cecal tissue was collected for 16S rRNA Gene Sequencing. Intestinal barrier proteins ZO-1 and E-cad were measured by Immunohistochemistry Staining and Western Blot, respectively. Intestinal tissue miR155 and inflammatory factors TNF-α, IL-1β, and IL-6 were detected by Q-PCR. The expression levels of protein associated with TNF-α and TLR4/MYD88 pathway in the intestinal were detected.In miR155 overexpression SAP group, the levels of tissue inflammatory factor were significantly increased, intestinal barrier proteins were significantly decreased, and the injury of intestinal was aggravated. Bacterial 16S rRNA sequencing was performed, showing miR155 promotes gut microbiota dysbiosis. The levels of TNF-α, TLR4, and MYD88 in the intestinal were detected, suggesting that miR155 may regulate gut microbiota and activate the TLR4/MYD88 pathway, thereby affecting the release of inflammatory mediators and regulating SAP-related intestinal injury. After application of miR155-sponge, imbalance of intestinal flora and destruction of intestinal barrier-related proteins have been alleviated. The release of inflammatory mediators decreased, and the histopathology injury of intestinal was improved obviously.MiR155 may play an important role in SAP-associated intestinal dysfunction. MiR155 can significantly alter the intestinal microecology, aggravated intestinal inflammation through TLR4/MYD88 pathway, and disrupts the intestinal barrier in SAP mice.

Background Helicobacter pylori (H. pylori) delivers oncoprotein CagA into gastric epithelial cells via the T4SS and drives activation of multiple oncogenic signalling pathways. YAP, a core effector of the Hippo tumour suppressor pathway, is frequently overexpressed in human cancers, suggesting its potential tumor-promoting role. Although CagA is a casual factor in H. pylori induced gastric carcinogenesis, the link between CagA and YAP pathway has not been identified. In this work, we investigated the regulation of oncogenic YAP pathway by H. pylori CagA. Methods Expression of YAP and E-cadherin protein in human gastric biopsies were assessed by immunohistochemistry. H. pylori PMSS1 cagA− isogenic mutant strains were generated. Gastric epithelial cells were co-cultured with H. pylori wild-type cagA+ strains or isogenic mutants and were also treated by recombinant CagA expression. Immunofluorescence was performed for YAP localization. Immunoblot and quantitative PCR were performed for examining levels of YAP, downstream effectors and markers of epithelial-mesenchymal transition. Verteporfin and siRNA silencing were used to inhibit YAP activity. Results YAP is significantly upregulated in human gastric carcinogenesis. We generated PMSS1 CagA isogenic mutant strains with chloramphenicol resistance successfully. Our analysis indicated that H. pylori infection induced YAP and downstream effectors in gastric epithelial cells. Importantly, knockout of CagA in 7.13 and PMSS1 strains reduced the expression of YAP by H. pylori infection. Moreover, Inhibition of YAP suppressed H. pylori infection-induced Epithelial-mesenchymal transition (EMT). Conclusion Our results indicated that H. pylori CagA as a pathogenic protein promotes oncogenic YAP pathway, which contributes to EMT and gastric tumorigenesis. This study provided a novel mechanistic insight into why cagA+ H. pylori infection is associated with a higher risk for the development of gastric cancer. Keywords: H. pyloriCagA; YAP; Epithelial-mesenchymal transition; Gastric carcinogenesis

Helicobacter pylori(H. pylori) infection is the strongest known risk factor for gastric carcinogenesis. DNA damage response (DDR) and autophagy play key roles in tumorigenic transformation. However, it remains unclear howH. pyloriinfection modulate DNA damage and autophagy. Here we report thatH. pyloriinfection promotes DNA damage via suppression of Rad51 expression through inhibition of autophagy and accumulation of p62 in gastric carcinogenesis. We find thatH. pyloriinfection caused alteration of DDR pathway and autophagy in gastric cells and Mongolian gerbils in a CagA-dependent manner. Moreover, loss of autophagy led to promotion of DNA damage inH. pylori-infected cells. Furthermore, knockdown of autophagic substrate p62 upregulated Rad51 expression, and p62 promoted ubiquitination of Rad51 via the direct interaction of the UBA domain with Rad51. Finally,H. pyloriinfection was associated with elevated levels of p62 in gastric intestinal metaplasia and decreased levels of Rad51 in dysplasia compared to theirH. pylori-counterparts. Our findings provide a novel mechanism into the linkage ofH. pyloriinfection, autophagy, DNA damage and gastric tumorigenesis.

Background. The receptor of activated protein kinase C 1 (RACK1) promotes the progression and invasion of several cancers. However, the role of RACK1 in the pathogenesis of colorectal cancer (CRC) has not been clearly defined. Herein, we aimed to investigate the biological role of RACK1 in CRC. Materials and Methods. The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) dataset were searched, and the expression of RACK1 in CRC tissues and adjacent normal tissues was evaluated. Immunohistochemical staining was performed to detect the expression of RACK1 in human CRC, adenoma, and normal tissues. Western blotting was used to detect the expression of RACK1 in human CRC cell lines. Functional assays, such as BrdU, colony formation, and wound healing and transwell invasion assays, were used to explore the biological role of RACK1 in CRC. Results. RACK1 was upregulated in CRC tissues compared with its expression in adjacent normal tissues in TCGA and the GEO dataset (P<0.05). Moreover, RACK1 was significantly overexpressed in CRC and adenoma tissues compared with its expression in normal tissues (P<0.05). Loss-of-function experiments showed that RACK1 promoted cell proliferation, migration, and invasion in vitro. Conclusions. Our data indicated that RACK1, as an oncogene, markedly promoted the progression of CRC, which suggested that RACK1 is a potential therapeutic target for CRC management.

// Nianshuang Li 1,* , Chuan Xie 1,* and Nong-Hua Lu 1 1 Department of Gastroenterology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China * These authors have contributed equally to the review and writing of this manuscript Correspondence to: Nong-Hua Lu, email: // Keywords : Helicobacter pylori; p53; tumourigenesis Received : May 08, 2016 Accepted : August 13, 2016 Published : August 19, 2016 Abstract Helicobacter pylori ( H. pylori ) is an ancient and persistent inhabitant of the human stomach that is closely linked to the development of gastric cancer (GC). . Emerging evidence suggests that H. pylori strain interactions with gastric epithelial cells subvert the best- characterized p53 tumour suppressor pathway. A high prevalence of p53 mutations is related to H. pylori infection. H. pylori also accelerates p53 protein degradation by disturbing the MDM2-P53 feedback loop. Additionally, H. pylori triggers the alteration of other p53 isoforms. Dysregulation of p53 by H. pylori infection contributes to gastric carcinogenesis by mediating cell proliferation and apoptosis. This review focuses on the regulation of p53 in H. pylori infection-associated GC.

Adenosine monophosphate-activated protein kinase (AMPK) acts as a fuel gauge that maintains energy homeostasis in both normal and cancerous cells, and has emerged as a tumor suppressor. The present study aims to delineate the functional relationship between AMPK and transforming growth factor beta (TGF-β). Our results showed that expression of liver kinase B1 (LKB1), an upstream kinase of AMPK, impeded TGF-β-induced Smad phosphorylation and their transcriptional activity in breast cancer cells, whereas knockdown of LKB1 or AMPKα1 subunit by short hairpin RNA (shRNA) enhanced the effect of TGF-β. Furthermore, AMPK activation reduced the promoter activity of TGF-β1. In accordance, type 2 diabetic patients taking metformin displayed a trend of reduction of serum TGF-β1, as compared with those without metformin. A significant reduction of serum TGF-β1 was found in mice after treatment with metformin. These results suggest that AMPK inhibits the transcription of TGF-β1, leading to reduction of its concentration in serum. Finally, metformin suppressed epithelial-to-mesenchymal transition of mammary epithelial cells. Taken together, our study demonstrates that AMPK exerts multiple actions on TGF-β signaling and supports that AMPK can serve as a therapeutic drug target for breast cancer.

Background Phosphatase and tensin homolog (PTEN) is an important tumor suppressor gene, and its encoded protein has activities of both a protein phosphatase and a lipid phosphatase. However, the substitution effect of protein phosphatase activity remains unclear. PI3K/Akt is the most common pathway negatively regulated by PTEN. The Hippo and PI3K/Akt pathways have a joint effect in regulating cell proliferation and apoptosis. Therefore, how PTEN lipid phosphatase inactivation contributes to the occurrence and development of gastric cancer and the potential role of the Hippo and PI3K/Akt pathways in PTEN lipid phosphatase inactivation mediated gastric tumorigenesis remain to be explored. Methods Immunohistochemical staining was performed to detect the expression of p-PTEN and YAP in a gastric cancer tissue microarray. Stable cell lines expressing a wild-type or dominant-negative mutant PTEN were established. The proliferation and migration of stable cells were detected by MTT, BrdU, and colony-formation, transwell assay and high content analysis in vitro, and tumor growth differences were observed in xenograft nude mice. Changes in the expression of key molecules in the Hippo and Akt signaling pathways were detected by western blot. Nuclear-cytoplasm separation, immunofluorescence and coimmunoprecipitation analyses were conducted to explore the dysregulation of Hippo in the stable cell lines. Results PTEN lipid phosphatase inactivation strongly promoted the proliferation and migration of gastric cancer cells in vitro and tumor growth in vivo. A immunohistochemical analysis of gastric cancer tissues revealed a significant correlation between phosphorylated PTEN and nuclear YAP expression, and both were determined to be independent prognostic factors for gastric cancer. Mechanistically, PTEN lipid phosphatase inactivation abolished the MOB1-LATS1/2 interaction, decreased YAP phosphorylation and finally promoted YAP nuclear translocation, which enhanced the synergistic effect of YAP-TEAD, thus inducing cell proliferation and migration. Moreover, PTEN lipid phosphatase inactivation promoted the PI3K/Akt pathway, and disruption of YAP-TEAD-driven transcription decreased the activation of Akt in a dose-dependent manner. Conclusions Taken together, our findings indicate that PTEN lipid phosphatase inactivation links the Hippo and PI3K/Akt pathways to promote gastric tumorigenesis and cancer development. Electronic supplementary material The online version of this article (10.1186/s13046-018-0795-2) contains supplementary material, which is available to authorized users.

BACKGROUND Helicobacter pylori (H. pylori) infection is associated with the development of gastric cancer, although the mechanism is unclear. Herein, this study aimed to clarify the key genes and signaling pathways involved in H. pylori pathogenesis based on The Cancer Genome Atlas (TCGA) database and RNA sequencing analysis. MATERIALS AND METHODS Forty-nine gastric cancer samples (16 with H. pylori and 33 without H. pylori) and 35 cancer-adjacent normal samples from TCGA database were analyzed by bioinformatics. The differentially expressed genes between H. pylori-positive and H. pylori-negative patients were verified in 18 gastric cancer (GC) samples (9 with H. pylori and 9 without H. pylori), which were analyzed using RNA sequencing. Survival analysis was carried out to explore associations between the differentially expressed genes and prognosis. Bioinformatics analysis was performed to determine the signaling pathways associated with H. pylori. RESULTS The baseline level of clinical features from TCGA database and RNA sequencing showed no differences between the H. pylori-positive and H. pylori-negative GC groups (P > 0.05). TP53 was shown to be upregulated in the H. pylori-positive group in both TCGA database and RNA sequencing data, which also showed higher expression in the GC tissues than in adjacent normal tissues (P

Table S1. Correlation of YAP expression and clinic pathological status of the patient with GC. (DOCX 14 kb)

Table S2. YAP expression in GC tissues and ANTTs. (DOCX 13 kb)

Table S2. Correlation of TAZ expression and clinic pathological status of the patient with GC. (DOCX 14 kb)

Table S3. The primers used in this study. (DOCX 13 kb)