Endoscopic full-thickness resection of a large gastric schwannoma and iatrogenic cervical esophageal perforations: A case report.

INTRODUCTION: Gastrointestinal schwannomas are most commonly found in the stomach. Owing to their nonspecific clinical and endoscopic presentations, distinguishing gastric schwannomas (GS) from other gastric submucosal tumors based on typical symptoms and endoscopic features is challenging. Endoscopic full-thickness resection (EFTR) is safe and effective for GS management; however, no standard method exists for the extraction of large gastric specimens after endoscopic treatment. CASE PRESENTATION: We report the case of a 72-year-old Chinese woman who presented with abdominal distension. DIAGNOSIS, INTERVENTIONS, AND OUTCOMES: Gastroscopy revealed a submucosal bulge on the anterior wall of the lower stomach near the greater curvature. Endoscopic ultrasonography and computed tomography suggested a stromal tumor. The patient underwent EFTR of the stomach, and the tumor was successfully removed. The surgical specimen, with a long-axis diameter of approximately 5.5 cm in vitro, was extracted using a snare. Subsequent endoscopic examination revealed longitudinal, full-thickness perforations > 2 cm at the esophageal entrance. Over 10 metal clips were used to seal the mucosa, and a gastrointestinal decompression tube was placed. Follow-up radiography performed at 1 week postoperatively revealed an esophageal mediastinal fistula, which required subsequent endoscopic intervention to close the fistula using metal clips. The patient showed improvement and was discharged at 3 weeks postoperatively. Follow-up esophageal radiography revealed no abnormalities. Postoperative immunohistochemical analysis indicated CD34 (-), CD117 (-), DOG-1 (-), Ki67 (1%), S-100 (+), SDHB (+), SOX-10 (+), and Desmin (-), confirming the diagnosis of GS. Three months postoperatively, gastroscopy showed that the esophageal perforation healed well, a white ulcer scar had formed locally, metal clips were found in the stomach body, and no recurrence was found. CONCLUSION: EFTR is effective for removing giant schwannomas, although the extraction of large specimens may result in iatrogenic cervical esophageal perforations. Perforations > 2 cm can be managed using endoscopic metal clip closure.

ß-elemene alleviates esophageal fibrosis after endoscopic submucosal dissection via the FAP-mediated PTEN-PI3K/AKT signaling pathway.

Esophageal stricture caused by fibrosis is a serious complication after esophageal Endoscopic submucosal dissection (ESD). Myofibroblasts play a crucial role in esophageal fibrosis, so inhibiting activated myofibroblasts is a promising approach for treating esophageal fibrosis. ß-Elemene, a natural product with anti-tumor and anti-fibrotic properties, has not been thoroughly examined in esophageal fibrosis. Additionally, fibroblast activation protein (FAP) and PTEN-PI3K/AKT signaling pathway are both notably linked to fibrotic diseases. Therefore, we investigated the potential mechanisms of ß-elemene in esophageal fibrosis by treating primary human esophageal granulation fibroblasts (PHEGFs) with gradient concentrations of ß-elemene. Our findings demonstrated that ß-elemene inhibited the activity of PHEGFs in a dose-dependent manner, accompanied by downregulation of FAP, p-PI3K, and p-AKT protein expression, along with upregulation of p-PTEN protein expression. In addition, we substantiated the potential correlation between FAP and the PTEN-PI3K/AKT signaling pathway by establishing models of FAP overexpression and silencing. These results provide a new perspective on the potential mechanism of ß-elemene in relieving esophageal fibrosis and offer novel therapeutic strategies for managing post-esophageal ESD stricture in clinical practice.

Changes in the intestinal microbiota of individuals with non-alcoholic fatty liver disease based on sequencing: An updated systematic review and meta-analysis.

BACKGROUND: Alterations in the composition and abundance of the intestinal microbiota occur in non-alcoholic fatty liver disease (NAFLD). However, the results are inconsistent because of differences in the study design, subject area, and sequencing methodology. In this study, we compared the diversity and abundance of the intestinal microbiota of patients with NAFLD and healthy individuals through a systematic review and meta-analysis. METHODS: Three databases (PubMed, EMBASE, and Cochrane Library) were searched from their inception to March 20, 2023. A meta-analysis was performed using Stata software to analyze variations in the richness and abundance of the intestinal microbiota in patients with NAFLD. The Newcastle-Ottawa Quality Assessment Scale (NOS) was used for quality assessment. RESULTS: A total of 28 articles were included. Shannon diversity was reduced in patients with NAFLD (SMD = -0.24 (95% CI -0.43-0.05, I2 = 71.7%). The relative abundance of Ruminococcus, Faecalibacterium, and Coprococcus all decreased, with total SMDs of -0.96 (95% CI -1.29 to -0.63, I2 = 4.8%), -1.13 (95% CI -2.07 to -0.19, I2 = 80.5%), and -1.66 (95% CI -3.04 to -0.28, I2 = 91.5%). Escherichia was increased in individuals with NAFLD (SMD = 1.78, 95% CI 0.12 to 3.45, I2 = 94.4%). CONCLUSION: Increasing the species diversity and altering the abundance of specific gut microbiota, including Coprococcus, Faecalibacterium, Ruminococcus, and Escherichia, may be beneficial for improving NAFLD.

Association between dietary carbohydrate to fiber ratio and metabolic dysfunction associated fatty liver disease in adults: evidence from the NHANES 2017-2020.

This study aimed to explore the association of carbohydrate to fiber ratio (CFR) with metabolic dysfunction-associated fatty liver disease (MAFLD) in adults. In this study, data from the 2 cycles (2017-2018 and 2019-2020) of the NHANES were used. Univariate and multivariate weighted logistic regression analyses were applied to evaluate the association between CFR and MAFLD. Odds ratios (ORs) and 95% confidence levels (CIs) were estimated. Subgroup analysis was further performed in terms of gender, age and comorbidity (diabetes, hypertension). A total of 3180 individuals were included, with 1408 (44.28%) in the non-MAFLD group and 1772 (55.72%) in the MAFLD group. After adjusting different variables, a dietary fiber intake of 11.15-18.40 g was associated with significantly lower odds of MAFLD compared with a fiber intake < 11.15 g (OR = 0.71, 95% CI 0.54-0.93). In contrast to a dietary CFR < 12.58, a CFR > 19.91 was associated with significantly higher odds of MAFLD (OR = 1.57, 95% CI 1.09-2.27). Compared with females with a dietary CFR < 12.58, those with a CFR > 19.91 had significantly increased odds of MAFLD (OR = 1.87, 95% CI 1.29-2.73). Among individuals aged < 65 years, a dietary CFR > 19.91 was associated with higher odds of MAFLD than a dietary CFR < 12.58 (OR = 1.52, 95% CI 1.02-2.25). For participants without diabetes (OR = 1.79, 95% CI 1.26-2.54) or hypertension (OR = 1.93, 95% CI 1.02-3.65), a dietary CFR > 19.91 was associated with elevated odds of MAFLD than a CFR < 12.58. In summary, a higher CFR was associated with significantly greater odds of MAFLD, indicating the negative association between carbohydrate quality and MAFLD. The research would be conducive to metabolic dysfunction-associated fatty liver disease treatment.

Interaction between dietary flavonoid intake and trouble sleeping on non-alcoholic fatty liver disease risk: a cross-sectional study.

OBJECTIVE: The possible interaction of dietary flavonoid intake and sleep on non-alcoholic fatty liver disease (NAFLD) has not been well studied. This study investigated the interaction between dietary flavonoid intake and trouble sleeping on the risk of NAFLD. METHODS: Three discrete National Health and Nutrition Examination Survey data cycles from 2007 to 2010 and 2017 to 2018 were used. NAFLD was diagnosed by a US Fatty Liver Index ≥30. A sleep questionnaire diagnosed trouble sleeping. Univariate and multivariate logistic regression, restricted cubic spline (RCS) and subgroup analyses were used to evaluate the association between dietary flavonoids, trouble sleeping and NAFLD. We employed the relative excess risk due to interaction, attributable proportion of interaction and synergy index to evaluate additive interactions. RESULTS: Ultimately, 5056 participants were enrolled, and higher anthocyanidins and flavanones intake was negatively correlated with NAFLD. Conversely, trouble sleeping was positively associated with NAFLD. These correlations remained stable after adjusting for confounders, and there was a sex difference in this relationship. In the RCS model, anthocyanins were negatively non-linearly related to NAFLD, while flavanones showed a negative linear relationship. Moreover, there was a synergistic interplay between low dietary anthocyanin intake and trouble sleeping on the risk of NAFLD. A similar relationship existed for flavanone intake. CONCLUSION: Anthocyanin and flavanone intake were negatively associated, whereas trouble sleeping was positively associated with NAFLD risk. There was a synergistic effect of low anthocyanin intake and trouble sleeping. The same relationship existed for low flavanone intake.

Endoscopic papillectomy combined with endoscopic retrograde cholangio-pancreatography for duodenal gangliocytic paraganglioma: A case report.

RATIONALE: Gangliocytic paraganglioma is a rare tumor that can occur in several organs throughout the body. Gangliocytic paraganglioma of the main duodenal papilla is even rarer. This study analyzes and discusses the endoscopic management of a case of gangliocytic paraganglioma of the main duodenal papilla and reviews the relevant literature. It is hoped that this study will increase clinicians' awareness of this disease. PATIENT CONCERNS: Electron endoscopy reveals a duodenal main papillary tumor, and the patient desires further clarification of the nature of the tumor and the next step in the treatment plan. DIAGNOSES: Duodenal gangliocytic paraganglioma. INTERVENTIONS: As the patient lesion was located in the main duodenal papilla, we successfully performed endoscopic minimally invasive treatment of the tumor by endoscopic papillectomy combined with endoscopic retrograde cholangiopancreatography. OUTCOMES: The patient was discharged after the postoperative removal of the nasobiliary drain and returned to the hospital 2 months later to have the biliary stent removed; the patient was in good general condition at follow-up. LESSONS: For duodenal main papillary tumor, we need to be alert to the possibility of gangliocytic paraganglioma. Since the tumor is located in the submucosa of the juxta-abdominal region, the preoperative biopsy positivity rate is low, and the tumor is often adjacent to or involves the biliopancreatic duct, endoscopic resection combined with endoscopic retrograde cholangiopancreatography can be considered for diagnosis and treatment.

Exploration of key ferroptosis-related genes and immune infiltration in Crohn's disease using bioinformatics.

Crohn's disease (CD) is a type of inflammatory bowel disease (IBD) that manifests mainly as chronic inflammation in different parts of the gastrointestinal tract, and its incidence has come to be increasing in recent years. Ferroptosis, a novel type of programmed cell death, it seems the role of ferroptosis-related biomarkers in CD has not been mentioned. Thus, the role of ferroptosis in CD and its relationship with immune infiltration were explored in this study. The CD dataset was downloaded from the Gene Expression Omnibus database. The validated ferroptosis genes (FRGs) were retrieved from the public FerrDb database. The gene expression matrix of the CD dataset was analyzed with the "limma" package in R language to obtain differentially expressed genes (DEGs) between diseased and healthy samples. Then, intersecting genes between DEGs and FRGs were identified as differentially expressed ferroptosis-associated genes (DE-FRGs). Protein-protein interaction (PPI) network analysis and visualization were carried out with STRING and Cytoscape, and key CD ferroptosis-related genes (CD-FRGs) were identified along with their Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways using the clusterProfiler package. Immune cell infiltration was analyzed with CIBERSORT. The correlation between key CD-FRGs and immune-infiltrated cells in CD was studied by Spearman's correlation method. A total of 37 DE-FRGs and 6 key CD-FRGs (CAV1, CD44, HIF1A, IFNG, TIMP1 and TLR4) were identified. GO and KEGG functional analysis indicated these genes enrichment in programmed cell death and apoptotic process, HIF-1 signaling pathway and IBD. Infiltration matrix analysis of immune cells showed abundant T cells CD4 memory activated, M1 macrophages, M2 macrophages, Mast cells activated and Neutrophils in CD intestinal tissues. The 6 key CD-FRGs were correlated with immune-infiltrated cells in CD based on correlation analysis. Taken together, immune cells with abnormal infiltration can be implicated in CD due to ferroptosis. This study identified 6 key CD-FRGs that may be key biomarkers of ferroptosis in CD; they include CAV1, CD44, HIF1A, IFNG, TIMP1 and TLR4. These findings suggest that the immune response is critical in CD caused by ferroptosis through the interaction between key CD-FRGs and immune infiltrating cells.

A case report of heterotopic gastric mucosa in the rectum treated by endoscopic submucosal dissection and a systematic review.

RATIONALE: Heterotopic gastric mucosa (HGM) can occur in all segments of the gastrointestinal tract, but rectal is very rare. In recent years, rectal HGM is more often treated by endoscopic resection (ER). PATIENT CONCERNS: A 28-year-old female was admitted to the hospital with the chief complaint of "a rectal lesion found on physical examination". DIAGNOSES: Heterotopic gastric mucosa (HGM). INTERVENTIONS: An endoscopic submucosal dissection (ESD) was performed to completely dissect the lesion. OUTCOMES: The patient recovered well at 1 month of follow-up and did not suffer from further blood in the stool. LESSONS: Rectal HGM has acid secretion function and HP can be colonized, causing a variety of symptoms such as abdominal pain, bloody stool, and anal pain and has the potential risk of malignant transformation; resection is the best treatment method, and ESD has its unique advantages and can be promoted in the clinic.

Identification of hub genes and immune infiltration in ulcerative colitis using bioinformatics.

Ulcerative colitis (UC) is a chronic inflammatory disease of the intestine, whose pathogenesis is not fully understood. Given that immune infiltration plays a key role in UC progression, our study aimed to assess the level of immune cells in UC intestinal mucosal tissues and identify potential immune-related genes. The GSE65114 UC dataset was downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) between healthy and UC tissues were identified using the "limma" package in R, while their Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were determined with the clusterProfiler package. Protein-protein interaction network analysis and visualization were performed with STRING and Cytoscape. Immune cell infiltration was calculated with CIBERSORT. The relationship between hub genes and immune-infiltrated cells in UC was determined by Pearson correlation. A total of 206 DEGs were identified, of which 174 were upregulated and 32 downregulated. GO and KEGG functional classification indicated DEG enrichment in immune response pathways, including Toll-like receptor signaling, IL-17 signaling, and immune system process and chemokine signaling. 13 hub genes were identified. Infiltration matrix analysis of immune cells showed abundant plasma cells, memory B cells, resting CD4 memory T cells, γδ T cells, M0 and M1 macrophages, and neutrophils in UC intestinal tissues. Correlation analysis revealed 13 hub genes associated with immune-infiltrated cells in UC. 13 hub genes associated with immune-infiltrated cells in UC were identified; they included CXCL13, CXCL10, CXCL9, CXCL8, CCL19, CTLA4, CCR1, CD69, CD163, IL7R, PECAM1, TLR8 and TLR2. These genes could potentially serve as markers for the diagnosis and treatment of UC.

Butyrate prevents the migration and invasion, and aerobic glycolysis in gastric cancer via inhibiting Wnt/ß-catenin/c-Myc signaling.

Gastric cancer (GC) remains a common cause of cancer death worldwide. Evidence has found that butyrate exhibited antitumor effects on GC cells. However, the mechanism by which butyrate regulate GC cell proliferation, migration, invasion, and aerobic glycolysis remains largely unknown. The proliferation, migration, and invasion of GC cells were tested by EdU staining, transwell assays. Additionally, protein expressions were determined by western blot assay. Next, glucose uptake, lactate production, and cellular ATP levels in GC cells were detected. Furthermore, the antitumor effects of butyrate in tumor-bearing nude mice were evaluated. We found, butyrate significantly prevented GC cell proliferation, migration, and invasion (p < .01). Additionally, butyrate markedly inhibited GC cell aerobic glycolysis, as shown by the reduced expressions of GLUT1, HK2, and LDHA (p < .01). Moreover, butyrate notably decreased nuclear ß-catenin and c-Myc levels in GC cells (p < .01). Remarkably, through activating Wnt/ß-catenin signaling with LiCl, the inhibitory effects of butyrate on the growth and aerobic glycolysis of GC cells were diminished (p < .01). Moreover, butyrate notably suppressed tumor volume and weight in GC cell xenograft nude mice in vivo (p < .01). Meanwhile, butyrate obviously reduced nuclear ß-catenin, c-Myc, GLUT1, HK2 and LDHA levels in tumor tissues in GC cell xenograft mice (p < .01). Collectively, butyrate could suppress the growth and aerobic glycolysis of GC cells in vitro and in vivo via downregulating wnt/ß-catenin/c-Myc signaling. These findings are likely to prove useful in better understanding the role of butyrate in GC.

The molecular basis of the associations between non-alcoholic fatty liver disease and colorectal cancer.

Background: Given the ongoing research on non-alcoholic fatty liver disease (NAFLD) and colorectal cancer (CRC), the number of studies suggesting a strong link between NAFLD and CRC is on the rise, while its underlying pathological mechanisms remain uncertain. This study aims to explore the shared genes and mechanisms and to reveal the molecular basis of the association between CRC and NAFLD through bioinformatics approaches. Methods: The Gene Expression Omnibus (GEO) dataset GSE89632 is downloaded for NAFLD cases and healthy controls. Additionally, the GSE4107 and GSE9348 datasets are obtained for CRC cases and healthy controls. Differentially expressed genes (DEGs) are obtained for NAFLD and CRC datasets, as well as shared genes between the two disorders. GO and KEGG enrichment analyses are further conducted. Subsequently, the STRING database and Cytoscape software are utilized to establish the PPI network and identify the hub genes. Then, co-expression analysis is performed using GeneMANIA. Subsequently, ROC curves and external datasets validation were applied to further screen the candidate markers. Finally, NetworkAnalyst is available as a means to construct a miRNA-gene regulatory network. Results: Under the threshold of FDR ≤ 0.01, 147 common genes are obtained in NAFLD and CRC. Categorization of GO functions shows that DEGs are predominantly enriched in "response to organic substance", "cellular response to chemical stimulus", and "response to external stimulus". The predominant KEGG pathways in DEGs are the "IL-17 signaling pathway", the "TNF signaling pathway", "Viral protein interaction with cytokine and cytokine receptor", "Cytokine-cytokine receptor interaction", and the "Toll-like receptor signaling pathway". Additionally, MYC, IL1B, FOS, CXCL8, PTGS2, MMP9, JUN, and IL6 are identified as hub genes by the evaluation of 7 algorithms. With the construction of miRNA-gene networks, 2 miRNAs, including miR-106a-5p, and miR-204-5p are predicted to be potential key miRNAs. Conclusion: This study identifies possible hub genes acting in the co-morbidity of NAFLD and CRC and discovers the interaction of miRNAs and hub genes, providing a novel understanding of the molecular basis for the relevance of CRC and NAFLD, thus contributing to the development of new therapeutic strategies to combat NAFLD and CRC.

Identifying hub genes and miRNAs in Crohn's disease by bioinformatics analysis.

Introduction: Crohn's disease (CD) is a disease that manifests mainly as chronic inflammation of the gastrointestinal tract, which is still not well understood in terms of its pathogenesis. The aim of this study was to use bioinformatics analysis to identify differentially expressed genes (DEGs) and miRNAs with diagnostic and therapeutic potential in CD. Materials and methods: Three CD datasets (GSE179285, GSE102133, GSE75214) were downloaded from the Gene Expression Omnibus (GEO) database. DEGs between normal and CD tissues were identified using the GEO2R online tool. The Gene Ontology (GO) term and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of the DEGs were conducted using the clusterProfiler function in the R package. Protein-protein interaction network (PPI) analysis and visualization were performed with STRING and Cytoscape. Ten hub genes were identified using cytoHubba's MCC algorithm and validated with datasets GSE6731 and GSE52746. Finally, the miRNA gene regulatory network was constructed by Cytoscape and NetworkAnalyst to predict potential microRNAs (miRNAs) associated with DEGs. Results: A total of 97 DEGs were identified, consisting of 88 downregulated genes and 9 upregulated genes. The enriched functions and pathways of the DEGs include immune system process, response to stress, response to cytokine and extracellular region. KEGG pathway analysis indicates that the genes were significantly enriched in Cytokine-cytokine receptor interaction, IL-17 signaling pathway, Rheumatoid arthritis and TNF signaling pathway. In combination with the results of the protein-protein interaction (PPI) network and CytoHubba, 10 hub genes including IL1B, CXCL8, CXCL10, CXCL1, CXCL2, CXCL5, ICAM1, IL1RN, TIMP1 and MMP3 were selected. Based on the DEG-miRNAs network construction, 5 miRNAs including hsa-mir-21-5p, hsa-mir-93-5p, hsa-mir-98-5p, hsa-mir-1-3p and hsa-mir-335-5p were identified as potential critical miRNAs. Conclusion: In conclusion, a total of 97 DEGs, 10 hub genes and 5 miRNAs that may be involved in the progression or occurrence of CD were identified in this study, which could be regarded as biomarkers of CD.

Identification of Differentially Expressed Genes and miRNAs for Ulcerative Colitis Using Bioinformatics Analysis.

Introduction: Ulcerative colitis (UC) is a chronic inflammatory disease of the intestine whose cause and underlying mechanisms are not fully understood. The aim of this study was to use bioinformatics analysis to identify differentially expressed genes (DEGs) with diagnostic and therapeutic potential in UC. Materials and methods: Three UC datasets (GSE179285, GSE75214, GSE48958) were downloaded from the Gene Expression Omnibus (GEO) database. DEGs between normal and UC tissues were identified using the GEO2R online tool. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of the DEGs were performed using Metascape. Protein-protein interaction network (PPI) analysis and visualization using STRING and Cytoscape. Finally, the miRNA gene regulatory network was constructed by Cytoscape to predict potential microRNAs (miRNAs) associated with DEGs. Results: A total of 446 DEGs were identified, consisting of 309 upregulated genes and 137 downregulated genes. The enriched functions and pathways of the DEGs include extracellular matrix, regulation of cell adhesion, inflammatory response, response to cytokine, monocarboxylic acid metabolic process, response to toxic substance. The analysis of KEGG pathway indicates that the DEGs were significantly enriched in Complement and coagulation cascades, Amoebiasis, TNF signaling pathway, bile secretion, and Mineral absorption. Combining the results of the PPI network and CytoHubba, 9 hub genes including CXCL8, ICAM1, CXCR4, CD44, IL1B, MMP9, SPP1, TIMP1, and HIF1A were selected. Based on the DEG-miRNAs network construction, 7 miRNAs including miR-335-5p, mir-204-5p, miR-93-5p, miR106a-5p, miR-21-5p, miR-146a-5p, and miR-155-5p were identified as potential critical miRNAs. Conclusion: In summary, we identified DEGs that may be involved in the progression or occurrence of UC. A total of 446 DEGs,9 hub genes and 7 miRNAs were identified, which may be considered as biomarkers of UC. Further studies, however, are needed to elucidate the biological functions of these genes in UC.

CircRNA ACVR2A Sponges miR-1290 to Modulate Cell Progression in Gastric Cancer.

BACKGROUND: In recent years, the abnormal expression of circRNAs has been identified to be strongly associated with tumor tissues. In this study, we focused on circACVR2A with a remarkably upregulated expression in gastric tissues and further explored its role in the pathogenic progression of gastric cancer (GC). METHODS: The differentially expressed circACVR2A in GC tissues and four cell lines (MKN-45, SNU-1, HGC-27, and SGC-7901) was identified by qRT-PCR method. Then, the effect of circACVR2A and miR-1290 on HGC-27 cell proliferation was measured by CCK8 and the colony formation methods. The effect of circACVR2A and miR-1290 on HGC-27 cell metastasis was estimated by transwell assay. The interaction of circACVR2A and miR-1290 was further detected. RESULTS: The relative level of circACVR2A in GC tissues and cell lines is remarkably upregulated. The downregulation of circACVR2A promotes GC cell proliferation and metastasis and suppressed the expression level of E-cadherin and Vimentin. The miR-1290 inhibitor reversed the effect of circACVR2A on cell progression in GC cell. CONCLUSION: circACVR2A competitively sponged miR-1290 and was exerted as a tumor suppressor gene oncogene via a circACVR2A/miR-1290 axis, suggesting it as a possible biomarker for GC therapy.

ß-Elemene Attenuates Fibrosis after Esophageal Endoscopic Submucosal Dissection via Modulating the HIF-1α/HK2/p38-MAPK Signaling Axis.

Esophageal fibrosis and stricture after endoscopic submucosal dissection (ESD) are serious postoperative complications. Previous evidence has highlighted an anticancer role of ß-elemene in esophageal squamous cell carcinoma. This study put forward a hypothesis on the inhibitory effect of ß-elemene on esophageal fibrosis after ESD and aimed to elaborate the underlying mechanisms. Our initial network pharmacology analyses determined hypoxia-inducible factor-1alpha (HIF-1α), hexokinase 2 (HK2), and p38MAPK in association with the effect of ß-elemene. We validated that the levels of HIF-1α, HK2, and p-p38MAPK were elevated in esophageal granulation tissue after ESD and corresponding fibroblasts. Esophageal fibroblasts were treated with ß-elemene of gradient concentrations. The results indicated that ß-elemene repressed the proliferation of esophageal fibroblasts and the levels of fibrosis-related factors. Further, ß-elemene inhibited HIF-1α expression leading to restricted proliferation and augmented apoptosis of fibroblasts. HIF-1α induced p38MAPK phosphorylation by activating the HK2 transcription and consequently accelerated fibroblast proliferation. Together, ß-elemene diminished HIF-1α expression and impaired the HK2-mediated p38MAPK phosphorylation, thereby repressing the esophageal fibrosis.

Oral glutamine inhibits tumor growth of gastric cancer bearing mice by improving immune function and activating apoptosis pathway.

Gastric cancer is one of the most common cancers in the world. It has been shown that exogenous glutamine (GLN) can inhibit the growth of tumor in vivo, but the relationship between GLN and gastric cancer has not been studied. The gastric cancer bearing mouse model was constructed and taken GLN orally at the same time, and the results found that oral GLN (1 or 2 g/kg/d) significantly inhibited the growth rate of tumor and reduce the weight of tumor tissues. Immunohistochemistry showed that oral GLN significantly reduced the PCNA index, which further proved that GLN could inhibit the growth of tumor cells. At the same time, TUNEL assay showed that oral GLN significantly enhanced the apoptosis levels of tumor cells. In addition, GLN reduced GSH levels in tumor tissues, but increased the levels of GSH in plasma, improved the T-lymphocyte transformation rate and NK cell activity, significantly inhibited the secretion of TNF-α and promoted the secretion of IL-2, thus regulating the immune function in vivo. Further detection of apoptosis pathway showed that oral GLN significantly enhanced the expression of pro-apoptotic factor Bad and inhibited the expression of Bcl-2. Meanwhile, GLN significantly increased the activities of Caspase-3, Caspase-8, caspase-9 and PARP. GSH activator NAC had a similar effect to GLN, which could improve the immune function and activate apoptosis pathway, while GSH inhibitor BSO significantly blocked the regulation of GLN, destroyed the immune balance and inhibited apoptosis, but IL-2 significantly blocked the anti-apoptotic effect of BSO. Therefore, oral GLN can improve immune function and activate apoptosis pathway through GSH, and then inhibit the growth of tumor in vivo.

Glucagon Like Peptide-1 Receptor Agonists Alter Pancreatic and Hepatic Histology and Regulation of Endoplasmic Reticulum Stress in High-fat Diet Mouse Model.

BACKGROUND: Obesity is a major health problem worldwide, and non-alcoholic fatty pancreas disease (NAFPD) and non-alcoholic fatty liver disease (NAFLD) are obesity-associated complications. Liraglutide, a glucagon-like peptide-1 (GLP-1) agonist, has been approved for treatment of obesity. We aimed to evaluate the therapeutic effects of liraglutide on the complications through its regulation of endoplasmic reticulum (ER) stress. METHODS: A high-fat diet mouse model was established in C57BL/6J mice. Two groups of mice were fed a high-fat diet with 60% fat for 16 weeks and control mice were fed standard chow. A four-week 0.6 mg/kg/day liraglutide treatment was started in one high-fat diet group after 12 weeks of the high-fat diet. After sacrificing the mice, pancreatic and hepatic tissues were prepared for western blot and immunohistochemistry for ER stress proteins, including activating transcription factor 4 (ATF4), caspase 12, C/EBP homologous protein (CHOP) eukaryotic initiation factor 2 α (eIF2α), glucose regulated protein (GRP) 78 and protein kinase RNA-like endoplasmic reticulum kinase (PERK). RESULTS: Liraglutide significantly decreased body weight gained by mice consuming a high-fat diet (27.6 g vs. 34.5 g, P<0.001), and levels of all ER proteins increased significantly in both the pancreas and liver (all P<0.05). Expression of most ER stress proteins in pancreatic tissue correlated with disease scores of NAFLD (all P<0.05). However, no significant differences were found in pancreatic ATF 4 expression between mice without NAFLD, and those with early non-alcoholic steatohepatitis (NASH) and fibrotic NASH (P=0.122). CONCLUSION: Liraglutide may reduce the severity of NAFPD and NAFLD through regulating the ER stress pathway and downstream apoptosis signaling.

LOC441178 Overexpression Inhibits the Proliferation and Migration of Esophageal Carcinoma Cells via Methylation of miR-182.

BACKGROUND: Long noncoding RNAs (lncRNAs) have been shown to play an important role in the development and progression of esophageal carcinoma (EC). Recently, lncRNA LOC441178 was shown to be dysregulated in many cancer types; however, the role of LOC441178 in EC remains unclear. MATERIALS AND METHODS: Flow cytometry, transwell and wound healing assays were used to measure the apoptosis and migration in esophageal squamous cell carcinoma (ESCC) cells. RT-qPCR was used to detect the level of miR-182 in LOC441178-overexpressed EC cells. In addition, DNA methylation status of miR-182 promoter in LOC441178-overexpressed ESCC cells was detected by methylation-specific PCR (MSP) and bisulfite sequencing PCR. RESULTS: In this study, we found that LOC441178 negatively regulated miR-182 expression in ESCC cells. In addition, overexpression of LOC441178 inhibited the proliferation and migration and induced apoptosis in ESCC cells via downregulation of miR-182. Moreover, overexpression of LOC441178 markedly inhibited the phosphorylation of Akt and phosphorylation FOXO3a and increased the expression of FOXO3a in ESCC cells via downregulation of miR-182. Mechanistically, LOC441178 overexpression epigenetically suppressed miR-182 expression via DNA methylation. In vivo experiments revealed that overexpression of LOC441178 inhibited ESCC tumor growth in mouse xenograft model. CONCLUSION: Collectively, our data suggested that LOC441178 overexpression epigenetically inhibited tumorigenesis of ESCC via DNA methylation of miR-182. These data indicated that the LOC441178/miR-182 axis might represent a novel therapeutic option for the treatment of ESCC.

Tumor mutation burden associated with miRNA-gene interaction outcome mediates the survival of patients with liver hepatocellular carcinoma.

Tumor mutation burden (TMB) is associated with immunogenic responses and the survival of cancer patients. This study demonstrates how TMB levels impact the immune-related cells, genes, and miRNAs, and how miRNA/gene interactions respond to variations in the survival rate of patients with liver hepatocellular carcinoma (LIHC). LIHC patients were divided into two groups, either a low TMB (< median) or a high TMB (≥ median) group. We found that high TMB plays a positive role in immune-mediated infiltration, generating more CD4 T-cells and memory B cells. Among the 21 immune genes that altered significantly, only C9orf24 and CYP1A1 were expected to up-regulate in LIHC patients with high TMB. A total of 19 miRNAs, which regulate various functional pathways, were significantly altered in patients with LIHC. One of the miRNA/gene pair, hsa-miR-33a/ALDH1A3 was significantly associated with the survival rate of LIHC patients. Our results suggest that LIHC patients with high TMB can be treated more effectively with immunotherapy.