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Introduction: Chronic inflammation of the gastrointestinal tissues underlies gastrointestinal inflammatory disorders, leading to tissue damage and a constellation of painful and debilitating symptoms. These disorders include inflammatory bowel diseases (Crohn's disease and ulcerative colitis), and eosinophilic disorders (eosinophilic esophagitis and eosinophilic duodenitis). Gastrointestinal inflammatory disorders can often present with overlapping symptoms necessitating the use of invasive procedures to give an accurate diagnosis. Methods: This study used peripheral blood mononuclear cells from individuals with Crohn's disease, ulcerative colitis, eosinophilic esophagitis, and eosinophilic duodenitis to better understand the alterations to the transcriptome of individuals with these diseases and identify potential markers of active inflammation within the peripheral blood of patients that may be useful in diagnosis. Single-cell RNA-sequencing was performed on peripheral blood mononuclear cells isolated from the blood samples of pediatric patients diagnosed with gastrointestinal disorders, including Crohn's disease, ulcerative colitis, eosinophilic esophagitis, eosinophilic duodenitis, and controls with histologically healthy gastrointestinal tracts. Results: We identified 730 (FDR < 0.05) differentially expressed genes between individuals with gastrointestinal disorders and controls across eight immune cell types. Discussion: There were common patterns among GI disorders, such as the widespread upregulation of MTRNR2L8 across cell types, and many differentially expressed genes showed distinct patterns of dysregulation among the different gastrointestinal diseases compared to controls, including upregulation of XIST across cell types among individuals with ulcerative colitis and upregulation of Th2-associated genes in eosinophilic disorders. These findings indicate both overlapping and distinct alterations to the transcriptome of individuals with gastrointestinal disorders compared to controls, which provide insight as to which genes may be useful as markers for disease in the peripheral blood of patients.
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Eosinofilia , Análisis de la Célula Individual , Humanos , Niño , Masculino , Femenino , Eosinofilia/genética , Eosinofilia/inmunología , Adolescente , Gastritis/genética , Gastritis/diagnóstico , Gastritis/inmunología , Transcriptoma , Esofagitis Eosinofílica/genética , Esofagitis Eosinofílica/diagnóstico , Esofagitis Eosinofílica/inmunología , Preescolar , Colitis Ulcerosa/genética , Colitis Ulcerosa/diagnóstico , Colitis Ulcerosa/inmunología , Enteritis/genética , Enteritis/diagnóstico , Enteritis/inmunología , Perfilación de la Expresión Génica , Enfermedad de Crohn/genética , Enfermedad de Crohn/diagnóstico , Enfermedad de Crohn/inmunología , Leucocitos Mononucleares/metabolismo , Leucocitos Mononucleares/inmunología , Genómica/métodos , BiomarcadoresRESUMEN
BACKGROUND: Helicobacter pylori eradication therapy based on antimicrobial susceptibility in Vietnamese children currently get low efficiency. There are causes of treatment failure, among host genetic factors namely MDR1 C3435T and CYP2C19 affect the absorption and metabolism of proton pump inhibitors - a crucial component of eradication therapy. The study aimed to investigate the effect of MDR1 C3435T and CYP2C19 genetic polymorphisms on the cure rate. METHODS: 207 pediatric patients with gastritis and peptic ulcer infecting Helicobacter pylori completed the eradication therapy based on antimicrobial susceptibility with proton pump inhibitor esomeprazole. Eradication efficacy was assessed after at least 4 weeks by the urease breath test. MDR1 C3435T genetic polymorphism and CYP2C19 genotype were determined using a sequencing method based on Sanger's principle. RESULTS: Among 207 children recruited in this study, the ratio of CYP2C19 EM, IM, and PM phenotypes was 40.1%, 46.4%, and 16.9%, respectively. The patient with MDR1 3435 C/C polymorphism accounted for 43.0%, MDR1 3435 C/T was 40.1%, and MDR1 3435T/T was 16.9%. The cure rate of Helicobacter pylori infection in patients with CYP2C19 EM genotype was 78.3%; 83.3% of those with the IM genotype, and PM genotype was 96,4% (p = 0.07). Successful eradication rates for Helicobacter pylori were 85.4%, 86.7%, and 68.6% in patients with the MDR1 3435 C/C, C/T, and T/T, respectively (p = 0.02). Multiple logistic regression analysis found that MDR1 C3435T genetic polymorphisms of patients were significant independent risk factors for treatment failure, and CYP2C19 genotype did not affect Helicobacter pylori eradication. CONCLUSIONS: The Helicobacter pylori eradication rates by regimens based on antibiotic susceptibility and esomeprazole were not significantly different between the CYP2C19 phenotypes. The MDR1 C3435T polymorphism is one of the factors impacting Helicobacter pylori eradication results in children.
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Subfamilia B de Transportador de Casetes de Unión a ATP , Citocromo P-450 CYP2C19 , Gastritis , Infecciones por Helicobacter , Helicobacter pylori , Úlcera Péptica , Inhibidores de la Bomba de Protones , Humanos , Citocromo P-450 CYP2C19/genética , Infecciones por Helicobacter/tratamiento farmacológico , Infecciones por Helicobacter/genética , Helicobacter pylori/efectos de los fármacos , Niño , Masculino , Femenino , Vietnam , Gastritis/tratamiento farmacológico , Gastritis/microbiología , Gastritis/genética , Úlcera Péptica/tratamiento farmacológico , Úlcera Péptica/genética , Úlcera Péptica/microbiología , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Inhibidores de la Bomba de Protones/uso terapéutico , Adolescente , Preescolar , Genotipo , Polimorfismo Genético , Resultado del Tratamiento , Esomeprazol/uso terapéutico , Antibacterianos/uso terapéuticoRESUMEN
Patients with autoimmune gastritis (AIG) have a 13-fold risk of developing type-1 neuroendocrine tumors, whereas the risk for gastric adenocarcinoma is still uncertain. Here we describe the clinicopathologic and molecular features of a series of gastric carcinomas (GC) arising in the context of AIG. A total of 26 AIG-associated GC specimens were collected from 4 Italian Institutions. Immunohistochemistry for MUC1, MUC2, MUC5AC, MUC6, CDX2, HER2, PD-L1, CLDN18, mismatch repair (MMR) proteins, and p53 and EBV-encoded RNA (EBER) in situ hybridization were performed. Histologic and immunohistochemical features were jointly reviewed by 5 expert gastrointestinal pathologists. Next-generation sequencing analysis (TrueSight Oncology 500, Illumina) of 523 cancer-related genes was performed on 19 cases. Most tumors were diagnosed as pT1 (52%) and they were located in the corpus/fundus (58%) and associated with operative link for gastritis assessment stage II gastritis (80.8%), absence of parietal cells, complete intestinal metaplasia, and enterochromaffin-like-cell micronodular hyperplasia. Only 4 (15.4%) GCs were diagnosed during follow-up for AIG. The following histotypes were identified: 20 (77%) adenocarcinomas; 3 (11%) mixed neuroendocrine-non-neuroendocrine neoplasms, and 2 (8%) high-grade solid adenocarcinomas with focal neuroendocrine component, 1 (4%) adenocarcinoma with an amphicrine component. Overall, 7 cases (27%) showed MMR deficiency, 3 (12%) were positive (score 3+) for HER2, 6 (23%) were CLDN18 positive, and 11 (42%) had PD-L1 combined positive score ≥ 10. EBER was negative in all cases. Molecular analysis revealed 5/19 (26%) microsatellite instability (MSI) cases and 7 (37%) tumor mutational burden (TMB) high. The most frequently altered genes were TP53 (8/19, 42%), RNF43 (7/19, 37%), ERBB2 (7/19, 37% [2 amplified and 5 mutated cases]), ARID1A (6/19, 32%), and PIK3CA (4/19, 21%). In summary, AIG-associated GCs are often diagnosed at low stage in patients with longstanding misrecognized severe AIG; they often display a neuroendocrine component or differentiation, have relatively higher rates of MMR deficiency, and TMB high.
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Enfermedades Autoinmunes , Gastritis , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/patología , Neoplasias Gástricas/genética , Masculino , Femenino , Gastritis/patología , Gastritis/genética , Gastritis/inmunología , Anciano , Persona de Mediana Edad , Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/patología , Adulto , Adenocarcinoma/genética , Adenocarcinoma/patología , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/análisis , Anciano de 80 o más AñosRESUMEN
Helicobacter pylori (H. pylori) is associated with gastric inflammation and mucosal antibodies against its cytotoxin-associated gene A (CagA) are protective. Vaccine-elicited immunity against H. pylori requires MHC class II expression, indicating that CD4+ T cells are protective. We hypothesized that the HLA-DR genotypes in human populations include protective alleles that more effectively bind immunogenic CagA peptide fragments and susceptible alleles with an impaired capacity to present CagA peptides. We recruited patients (n = 170) admitted for gastroendoscopy procedures and performed high-resolution HLA-DRB1 typing. Serum anti-CagA IgA levels were analyzed by ELISA (23.2% positive) and H. pylori classified as positive or negative in gastric mucosal tissue slides (72.9% positive). Pearson Chi-square analysis revealed that H. pylori infection was significantly increased in DRB1*11:04-positive individuals (p = 0.027). Anti-CagA IgA was significantly decreased in DRB1*11:04 positive individuals (p = 0.041). In contrast, anti-CagA IgA was significantly increased in DRB1*03:01 positive individuals (p = 0.030). For these HLA-DRB1 alleles of interest, we utilized two in silico prediction methods to compare their capacity to present CagA peptides. Both methods predicted increased numbers of peptides for DRB1*03:01 than DRB1*11:04. In addition, both alleles preferred distinctively different CagA 15mer peptide sequences for high affinity binding. These observations suggest that DRB1*11:04 is a susceptible genotype with impaired CagA immunity, whereas DRB1*03:01 is a protective genotype that promotes enhanced CagA immunity.
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Gastritis , Helicobacter pylori , Humanos , Helicobacter pylori/genética , Antígenos Bacterianos/genética , Proteínas Bacterianas/genética , Cadenas HLA-DRB1/genética , Citotoxinas , Gastritis/genética , Genotipo , Péptidos/genética , Inmunoglobulina A/genéticaRESUMEN
BACKGROUND: Nodular gastritis (NG) is characterized by marked antral lymphoid follicle formation, and is a strong risk factor for diffuse-type gastric cancer in adults. However, it is unknown whether aberrant DNA methylation, which is induced by atrophic gastritis (AG) and is a risk for gastric cancer, is induced by NG. Here, we analyzed methylation induction by NG. METHODS: Gastric mucosal samples were obtained from non-cancerous antral tissues of 16 NG and 20 AG patients with gastric cancer and 5 NG and 6 AG patients without, all age- and gender-matched. Genome-wide methylation analysis and expression analysis were conducted by a BeadChip array and RNA-sequencing, respectively. RESULTS: Clustering analysis of non-cancerous antral tissues of NG and AG patients with gastric cancer was conducted using methylation levels of 585 promoter CpG islands (CGIs) of methylation-resistant genes, and a large fraction of NG samples formed a cluster with strong methylation induction. Promoter CGIs of CDH1 and DAPK1 tumor-suppressor genes were more methylated in NG than in AG. Notably, methylation levels of these genes were also higher in the antrum of NG patients without cancer. Genes related to lymphoid follicle formation, such as CXCL13/CXCR5 and CXCL12/CXCR4, had higher expression in NG, and genes involved in DNA demethylation TET2 and IDH1, had only half the expression in NG. CONCLUSIONS: Severe aberrant methylation, involving multiple tumor-suppressor genes, was induced in the gastric antrum and body of patients with NG, in accordance with their high gastric cancer risk.
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Islas de CpG , Metilación de ADN , Mucosa Gástrica , Gastritis Atrófica , Neoplasias Gástricas , Humanos , Masculino , Femenino , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Persona de Mediana Edad , Anciano , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patología , Islas de CpG/genética , Gastritis Atrófica/genética , Proteínas Proto-Oncogénicas/genética , Regiones Promotoras Genéticas , Cadherinas/genética , Quimiocina CXCL12/genética , Quimiocina CXCL12/metabolismo , Quimiocina CXCL13/genética , Quimiocina CXCL13/metabolismo , Dioxigenasas/genética , Antígenos CD/genética , Antígenos CD/metabolismo , Adulto , Proteínas de Unión al ADN/genética , Gastritis/genética , Antro Pilórico/patología , Antro Pilórico/metabolismo , Factores de RiesgoRESUMEN
Background/Aims: While DNA methylation and gastric microbiome are each associated with gastric cancer (GC), their combined role in predicting GC remains unclear. This study investigated the potential of a combined DNA methylation and gastric microbiome signature to predict Helicobacter pylori-negative GC. Methods: In this case-control study, we conducted quantitative methylation-specific polymerase chain reaction to measure the methylation levels of DKK3, SFRP1, EMX1, NKX6-1, MIR124-3, and TWIST1 in the gastric mucosa from 75 H. pylori-negative patients, including chronic gastritis (CG), intestinal metaplasia (IM), and GC. A combined analysis of DNA methylation and gastric microbiome, using 16S rRNA gene sequencing, was performed in 30 of 75 patients. Results: The methylation levels of DKK3, SFRP1, EMX1, MIR124-3, and TWIST1 were significantly higher in patients with GC than in controls (all q<0.05). MIR124-3 and TWIST1 methylation levels were higher in patients with IM than those with CG and also in those with GC than in those with IM (all q<0.05). A higher methylation level of TWIST1 was an independent predictor for H. pylori-negative GC after adjusting for age, sex, and atrophy (odds ratio [OR], 15.15; 95% confidence interval [CI], 1.58 to 145.46; p=0.018). The combination of TWIST1 methylation and GC microbiome index (a microbiome marker) was significantly associated with H. pylori-negative GC after adjusting for age, sex, and atrophy (OR, 50.00; 95% CI, 1.69 to 1,476; p=0.024). Conclusions: The combination of TWIST1 methylation and GC microbiome index may offer potential as a biomarker for predicting H. pylori-negative GC.
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Metilación de ADN , Mucosa Gástrica , Microbioma Gastrointestinal , Helicobacter pylori , Neoplasias Gástricas , Humanos , Masculino , Femenino , Neoplasias Gástricas/microbiología , Neoplasias Gástricas/genética , Persona de Mediana Edad , Estudios de Casos y Controles , Helicobacter pylori/genética , Mucosa Gástrica/microbiología , Microbioma Gastrointestinal/genética , Proteína 1 Relacionada con Twist/genética , Anciano , MicroARNs/análisis , Proteínas Nucleares/genética , Gastritis/microbiología , Gastritis/genética , Biomarcadores de Tumor/genética , ARN Ribosómico 16S/análisis , ARN Ribosómico 16S/genética , Infecciones por Helicobacter/microbiología , Metaplasia/microbiología , Metaplasia/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Adulto , Péptidos y Proteínas de Señalización Intercelular/genética , Proteínas de HomeodominioRESUMEN
CONTEXT: Helicobacter pylori ( H. pylori ), a spiral-shaped bacterium, is closely associated with chronic, progressive gastric mucosal damage, gastric atrophy, and even gastric cancer (GC). An increasing number of studies have addressed the correlation between long noncoding RNAs (lncRNAs) and H. pylori pathogenicity in GC. OBJECTIVE: In this study, we found that the expression level of LINC00659 gradually increased in the progression from atrophic gastritis, intestinal metaplasia, and dysplasia to GC in H. pylori -infected patients. Thus, we aimed to further explore the function of LINC00659 in the progression of gastritis to cancer under H. pylori infection. MATERIALS AND METHODS: StarBase predictions, ribonucleic acid (RNA)-binding protein immunoprecipitation assays, and gene ontology functional annotation (GO)/Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis were performed to identify the RNA-binding proteins of LINC00659; moreover, qRTâPCR, western blotting, RNA interference, and immunofluorescence assays were used to investigate the function of LINC00659. RESULTS: LINC00659 bound directly to the RNA-binding protein polypyrimidine tract-binding protein (PTBP1). Importantly, qRTâPCR and western blot assays demonstrated that PTBP1 expression increased in the progression from inflammation to cancer in the stomach of H. pylori -infected patients and H. pylori -infected GES-1 cells. However, LINC00659 knockdown downregulated PTBP1 expression and inhibited PTBP1 binding under H. pylori infection. Finally, LINC00659 knockdown significantly reduced H. pylori -induced human gastric epithelial cell senescence and suppressed interleukin (IL)-6 and IL-8 secretion by reducing the phosphorylation level of NF-κB p65. CONCLUSIONS: This study indicated that LINC00659 may have the potential to be a novel promising prognostic and therapeutic marker for H. pylori -associated gastric diseases.
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Gastritis , Infecciones por Helicobacter , Helicobacter pylori , Ribonucleoproteínas Nucleares Heterogéneas , Proteína de Unión al Tracto de Polipirimidina , ARN Largo no Codificante , Neoplasias Gástricas , Humanos , ARN Largo no Codificante/genética , Infecciones por Helicobacter/genética , Infecciones por Helicobacter/microbiología , Proteína de Unión al Tracto de Polipirimidina/genética , Helicobacter pylori/genética , Helicobacter pylori/patogenicidad , Neoplasias Gástricas/genética , Neoplasias Gástricas/patología , Neoplasias Gástricas/microbiología , Gastritis/microbiología , Gastritis/genética , Gastritis/patología , Ribonucleoproteínas Nucleares Heterogéneas/genética , Mucosa Gástrica/patología , Mucosa Gástrica/microbiología , Progresión de la Enfermedad , Regulación hacia ArribaRESUMEN
Gastric carcinoma (GC) is a malignant tumor that is detrimental to human health. Transfer RNA-derived small RNAs are a newly identified class of noncoding small RNAs with specific biological functions that are aberrantly expressed in cancer. The aim of this study was to investigate the potential of hsa_tsr013526 as a biomarker for GC. Quantitative real-time fluorescence polymerase chain reaction was used to detect the expression level of hsa_tsr013526. The molecular characteristics of hsa_tsr013526 were verified by agarose gel electrophoresis, Sanger sequencing, and separation of nuclear and cytoplasmic RNA fractions. By testing the receiver operating characteristic (ROC) curves, the diagnostic efficiency of GC using hsa_tsr013526 was determined. Finally, we predicted the downstream of hsa_tsr013526 using functional assays and bioinformatics analysis. Serum expression of hsa_tsr013526 was higher in GC patients than in healthy donors. Serum expression showed differential changes in GC patients, gastritis patients, and healthy donors. Chi-squared tests showed that high expression of hsa_tsr013526 was significantly correlated with T stage, lymphatic metastasis, and tumor node metastasis stage. ROC curve analysis indicated that GC patients could be discriminated from healthy donors or gastritis patients based on their serum levels of hsa_tsr013526. Furthermore, hsa_tsr013526 expression was significantly reduced in postoperative GC patients (p = .0016). High expression of hsa_tsr013526 promotes gastric cancer cell proliferation, invasion, and migration. Serum hsa_tsr013526 was stable and specific, and could be used for dynamic monitoring of GC patients. Therefore, hsa_tsr013526 may be a new biomarker for the diagnosis and postoperative monitoring of GC patients.
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Carcinoma , Gastritis , Neoplasias Gástricas , Humanos , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Neoplasias Gástricas/genética , ARN/metabolismo , Gastritis/genética , Regulación Neoplásica de la Expresión GénicaRESUMEN
BACKGROUND: Autoimmune gastritis (AIG) is a prevalent chronic inflammatory disease with oncogenic potential that causes destruction of parietal cells and severe mucosal atrophy. We aimed to explore the distinctive gene expression profiles, activated signaling pathways, and their underlying mechanisms. METHODS: A comprehensive gene expression analysis was conducted using biopsy specimens from AIG, Helicobacter pylori-associated gastritis (HPG), and non-inflammatory normal stomachs. Gastric cancer cell lines were cultured under acidic (pH 6.5) conditions to evaluate changes in gene expression. RESULTS: Gastric mucosa with AIG had a unique gene expression profile compared with that with HPG and normal mucosa, such as extensively low expression of ATP4A and high expression of GAST and PAPPA2, which are involved in neuroendocrine tumorigenesis. Additionally, the mucosa with AIG and HPG showed the downregulation of stomach-specific genes and upregulation of small intestine-specific genes; however, intestinal trans-differentiation was much more prominent in AIG samples, likely in a CDX-dependent manner. Furthermore, AIG induced ectopic expression of pancreatic digestion-related genes, PNLIP, CEL, CTRB1, and CTRC; and a master regulator gene of the lung, NKX2-1/TTF1 with alveolar fluid secretion-related genes, SFTPB and SFTPC. Mechanistically, acidic conditions led to the downregulation of master regulator and stemness control genes of small intestine, suggesting that increased environmental pH may cause abnormal intestinal differentiation in the stomach. CONCLUSIONS: AIG induces diverse trans-differentiation in the gastric mucosa, characterized by the transactivation of genes specific to the small intestine, pancreas, and lung. Increased environmental pH owing to AIG may cause abnormal differentiation of the gastric mucosa.
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Enfermedades Autoinmunes , Gastritis , Infecciones por Helicobacter , Helicobacter pylori , Humanos , Enfermedades Autoinmunes/genética , Gastritis/genética , Gastritis/patología , Mucosa Gástrica/patología , Páncreas/patología , Transdiferenciación CelularRESUMEN
Helicobacter pylori was reported as an important cause of gastritis, and gastric ulcers and CagA oncoprotein-producing H. pylori subgroups were blamed to increase the severity of gastritis. Disparities were reported in that the presence of serum anti-CagA IgA was not parallel with CagA-positive H. pylori cohabitation. We hypothesized that the HLA-DQA1 ~ DQB1 haplotypes in human populations include protective haplotypes that more effectively present immunogenic CagA peptides and susceptible haplotypes with an impaired capacity to present CagA peptides. We recruited patients (n = 201) admitted for gastroendoscopy procedures and performed high-resolution HLA-DQA1 and DQB1 typing. Serum anti-CagA IgA levels were analyzed by ELISA (23.0% positive), and H. pylori was classified as positive or negative in gastric mucosal tissue slides (72.6% positive). The HLA DQA1*05:05 allele (29.1%) and HLA DQB1*03:01 allele (32.8%) were found at the highest frequency among gastritis patients of Turkish descent. In HLA DQA1*05:05 ~ DQB1*03:01 double homozygous (7.3%) and heterozygous (40.7%) haplotype carriers, the presence of anti-CagA IgA decreased dramatically, the presence of H. pylori increased, and the presence of metaplasia followed a decreasing trend. The DQ protein encoded by HLA DQA1*05:05-DQ*03:01 showed a low binding affinity to the CagA peptide when binding capacity was analyzed by the NetMHCIIPan 4.0 prediction method. In conclusion, HLA DQA1 ~ DQB1 polymorphisms are crucial as host defense mechanisms against CagA H. pylori since antigen binding capacity plays a crucial role in anti-CagA IgA production.
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Gastritis , Infecciones por Helicobacter , Helicobacter pylori , Humanos , Haplotipos , Antígenos HLA-DQ/genética , Cadenas alfa de HLA-DQ/genética , Cadenas beta de HLA-DQ/genética , Gastritis/genética , Infecciones por Helicobacter/complicaciones , Infecciones por Helicobacter/genética , Alelos , Péptidos , Metaplasia , Inmunoglobulina A/genética , Frecuencia de los Genes , Cadenas HLA-DRB1RESUMEN
A whole exome sequencing (WES)-driven approach to uncover the etiology of unexplained inflammatory gastritides has been underutilized by surgical pathologists. Here, we discovered the pathobiology of an unusual chronic atrophic gastritis in two unrelated patients using this approach. The gastric biopsies were notable for an unusual pattern of gastritis with persistent dense inflammation, loss of both parietal and neuroendocrine cells in the oxyntic mucosa, and sparing of the antral mucosa. The patients were found to harbor pathogenic variants in telomeropathic genes (POT1 and DCLRE1B). Clonality testing for one of the patients showed evidence of evolving clonality of TCR-gene rearrangement. Both patients showed significantly decreased numbers of stem/progenitor cells by immunohistochemistry, which appears to be responsible for the development of mucosal atrophy. No such cases of unusual chronic atrophic gastritis in the setting of telomeropathy have been previously reported. The loss of stem/progenitor cells suggests that stem/progenitor cell exhaustion in the setting of telomere dysfunction is the likely mechanism for development of this unusual chronic atrophic gastritis. The results underscore the need for close monitoring of these gastric lesions, with special regard to their neoplastic potential. This combined WES-driven approach has promise to identify the cause and mechanism of other uncharacterized gastrointestinal inflammatory disorders.
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Gastritis Atrófica , Gastritis , Humanos , Gastritis Atrófica/genética , Gastritis Atrófica/patología , Secuenciación del Exoma , Gastritis/genética , Gastritis/patología , Biopsia , Biología , ExodesoxirribonucleasasRESUMEN
INTRODUCTION: Helicobacter pylori could colonize the gastric mucosa and cause gastritis, ulcers and cancer. Numerous virulence factors have been identified in this bacterium that play important roles in promoting gastric disorders. Although the interaction of long noncoding RNAs (lncRNAs) with transcription, processing, and translation of genes associated with different diseases are described, their interaction with the inflammatory genes and H. pylori infection in the gastric tissue is not well known. This study compared changes in common NF-κB-regulatory lncRNAs in the gastric tissue of H. pylori-infected and non-infected patients with gastritis. Moreover, a link between the virulence entity of the strains and the transcriptional changes was analyzed. METHODOLOGY: Two groups of infected and non-infected patients with chronic gastritis were included in the study. Genotyping of the H. pylori strains was done by PCR and relative changes in the expression of NF-κB and regulatory lncRNAs, lincRNA-p21, MALAT1, NKILA, were measured by relative quantitative real time-PCR. RESULTS: Transcriptional levels of MALAT1, lincRNA-p21, and NKILA genes decreased in the infected patients compared with the non-infected patients, which was significantly linked with increased NF-κB gene expression. Our results showed that a hypervirulent strain of H. pylori with oipA"on"/HP-NAP+/iceA1+/iceA2+/vacA s1m1/s1m2+/cagA+ genotype can promote a higher level of NF-κB transcription in the inflamed tissue. CONCLUSIONS: H. pylori infection could promote down-regulation of lincRNA-p21, MALAT1 and NKILA in the infected gastric tissue in correlation with NF-κB upregulation. More detailed studies are needed to show a link between the virulence genes and their impact on the regulation of lncRNAs in the stomach.
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Gastritis , Infecciones por Helicobacter , Helicobacter pylori , FN-kappa B , ARN Largo no Codificante , Humanos , Antígenos Bacterianos/genética , Proteínas Bacterianas/genética , Gastritis/genética , Genotipo , Infecciones por Helicobacter/complicaciones , Infecciones por Helicobacter/genética , Helicobacter pylori/genética , FN-kappa B/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , ARN Largo no Codificante/genéticaRESUMEN
BACKGROUND: Helicobacter pylori (H. pylori) have been accepted as having an etiologic role in gastro-duodenal diseases as chronic gastritis, peptic ulcer, and gastric carcinoma. Methylation of CGI has been correlated with the tumorigenic process since it can inactivate tumor suppressor genes. CDH1 is a tumor suppressor gene that encodes the E-cadherin protein, which is preserving cell-cell connections. Early stages of gastric carcinogenesis may be affected by the promoter methylation-mediated inactivation of this gene. OBJECTIVE: This study aimed to investigate the methylation status of CDH1 using Methylation-Specific PCR (MSP) technique in clinical suspected patients with H. pylori infection who undergoing upper gastrointestinal endoscopy and correlated it with H. pylori detection by glmM PCR test. METHODS: Fifty gastric mucosal biopsies were selected from one hundred and five samples included in this study. The detection of H. pylori was performed with the PCR primers specific to glmM gene. Bisulfite modification was done and the methylation status of the CDH1 gene was detected using MSP reaction. RESULTS: H. pylori was detected in 36% (18/50) of study population using glmM gene PCR test, 89% (16/18) of H. pylori positive cases were CDH1 methylated positive (chi-square, p-value=0.002). CDH1 methylation can be present in cancerous and noncancerous gastric mucosa, where 60% (18/30) of CDH1 methylation positive gastric mucosa showed gastritis as an endoscopy finding and gastric cancer in 6% (2/30). There was a significant correlation between and CDH1 methylation positive results and age group (P-value = 0.02). There was no significant correlation between CDH1 methylation positive results and participants gender (p-value=0.431) and clinical symptoms (all P-value > 0.05). CONCLUSION: This work suggested strong significance association between H. pylori infection and CDH1 methylation.
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Gastritis Atrófica , Gastritis , Infecciones por Helicobacter , Helicobacter pylori , Neoplasias Gástricas , Humanos , Helicobacter pylori/genética , Metilación de ADN , Gastritis/genética , Gastritis/patología , Gastritis Atrófica/patología , Mucosa Gástrica/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Biopsia , Factores de Transcripción/genética , Infecciones por Helicobacter/complicaciones , Infecciones por Helicobacter/genética , Infecciones por Helicobacter/patología , Antígenos CD/genética , Antígenos CD/metabolismo , Cadherinas/genética , Cadherinas/metabolismoRESUMEN
Osteoarthritis (OA) is a non-inflammatory degenerative joint disease that mainly involves articular cartilage damage and involves the whole joint tissue. Gastritis is a common stomach disorder, typically referring to inflammation or lesions of the gastric mucosa. However, the relationship between CD14 and colony stimulating factor-1 receptor (CSF1R) and these 2 diseases is not yet clear. OA datasets GSE46750, GSE82107 and gastritis datasets GSE54043 profiles were downloaded from gene expression omnibus databases generated by GPL10558 and GPL570.The R package limma was used to screen differentially expressed genes (DEGs). Weighted gene co-expression network analysis was performed. The construction and analysis of protein-protein interaction network, functional enrichment analysis, gene set enrichment analysis and comparative toxicogenomics database analysis were performed. TargetScan was used to screen miRNAs regulating central DEGs. A total of 568 DEGs were identified. According to the gene ontology (GO) and biological processes analysis, they were mainly enriched in ATP metabolism negative regulation, toll-like receptor TLR1:TLR2 signaling pathway, and intracellular transport. The enrichment terms for OA and gastritis were similar to the GO and Kyoto encyclopedia of gene and genome enrichment terms of DEGs, mainly enriched in ATP metabolism negative regulation, secretion granules, transmembrane receptor protein kinase activity, cytokine-cytokine receptor interaction, Toll-like receptor signaling pathway, MAPK signaling pathway, and TGF-ß signaling pathway. In the Metascape enrichment projects, GO enrichment projects showed functions related to cell-cell receptor interaction, cell secretion, and growth. Two core genes were identified through the construction and analysis of the protein-protein interaction network. The core genes (CD14 and CSF1R) exhibited high expression in OA and gastritis samples and low expression in normal samples. Comparative toxicogenomics database analysis revealed associations between core genes (CD14 and CSF1R) and diseases such as OA, osteoporosis, gastritis, juvenile arthritis, diarrhea, and inflammation. CD14 and CSF1R are highly expressed in OA and gastritis, making them potential therapeutic targets for both diseases.
Asunto(s)
Gastritis , Osteoartritis , Humanos , Adenosina Trifosfato , Biología Computacional , Bases de Datos Genéticas , Gastritis/genética , Perfilación de la Expresión Génica , Redes Reguladoras de Genes , Inflamación , Osteoartritis/metabolismo , Proteínas Tirosina Quinasas Receptoras/genética , Receptores Toll-Like/genética , Receptores de LipopolisacáridosRESUMEN
OBJECTIVE: Observational studies have posited a strong correlation between chronic gastritis (CG) and major depressive disorder (MDD), but the nature of this association remains uncertain, owing to the challenges of establishing the temporal sequence. The present study sought to elucidate the elusive relationship between CG and MDD by employing a bidirectional two-sample Mendelian randomization (MR) approach. METHODS: We extracted instrumental variants for MDD and CG from published genome-wide association study data, focusing on individuals of primarily European descent. A comprehensive suite of MR estimations and sensitivity analyses was performed to ensure the robustness of the findings. Each outcome database was analyzed separately in both directions. RESULTS: For MDD and CG, 221 and 5 genetic variants, respectively, were selectively extracted as instrumental variants. The results suggest that MDD is causally associated with an elevated risk of CG (IVW: 23andMe, OR = 1.33; 95% CI = 1.15-1.54; p = 1.06 × 10-4); conversely, no strong evidence was found to corroborate that CG exerts a causal effect on the incidence of MDD (IVW: OR = 1.01; 95% CI = 0.95-1.07; p = 0.68). CONCLUSIONS: These findings provide novel insights into the causal relationship between CG and MDD, which may have implications for clinical decision-making in patients with MDD and CG.
Asunto(s)
Trastorno Depresivo Mayor , Gastritis , Humanos , Trastorno Depresivo Mayor/genética , Estudio de Asociación del Genoma Completo , Análisis de la Aleatorización Mendeliana , Bases de Datos Factuales , Gastritis/genética , Polimorfismo de Nucleótido SimpleRESUMEN
Helicobacter Pylori (H. Pylori) cause peptic ulcer disease (PUD), but the inflammasome's role in PUD is not well understood. Therefore this study has investigated inflammasome compartment expression and IL-1ß production in gastritis (G) and peptic ulcer disease. This study was based on gene expression of inflammasome compartments on stomach biopsies of 50 patients with PUD as cases and 50 individuals with gastritis as controls. The expression of NLRC4, ASC, IL-18, and serum IL-1ß decreased in the PUD group compared to the control group. AIM2 gene expression increased, and NLRP12 gene expression decreased in H. pylori-seropositive positive (HP+ ) individuals compared to H. pylori-seronegative (HP- ) individuals. The G-HP+ subjects had higher serum IL-1ß and AIM2 gene expression than G-HP- subjects but lower NLRP3 and NLRP12 gene expression. The PUD-HP+ had lower serum IL-1ß, but higher AIM2 and IL-18 expression than PUD-HP- . The PUD-HP- patients had decreased IL-18 expression than G-HP- group. The PUD-HP+ had lower serum IL-1ß and NLRC4 expression than G-HP+, while NLRP1 and NLRP3 were higher in expression in PUD-HP+ . The expression of caspase-1, NLRP3 and NAIP were correlated with IL-1ß and IL-18. In conclusion, a decrease in NLRC4, IL-18, ASC genes, and IL-1ß levels in PUD patients compared to gastritis may act in the development of PUD. H. pylori caused AIM2 induction and reduced NLRP12, indicating their contribution to bacterial responses. Decreased NLRC4 expression and IL-1ß protein, together with enhanced NLRP1, and NLRP3 expression, promotes H. pylori to develop peptic ulcers.
Asunto(s)
Gastritis , Infecciones por Helicobacter , Helicobacter pylori , Úlcera Péptica , Humanos , Inflamasomas/genética , Inflamasomas/metabolismo , Interleucina-18/genética , Interleucina-18/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Infecciones por Helicobacter/complicaciones , Úlcera Péptica/genética , Gastritis/genética , Gastritis/complicaciones , Gastritis/patología , Proteínas de Unión al Calcio/genética , Proteínas Adaptadoras de Señalización CARD/genética , Proteínas Adaptadoras de Señalización CARD/metabolismo , Proteínas de Unión al ADN/genéticaRESUMEN
BACKGROUND/AIMS: Based on the gene expression profiles of gastric epithelial tissue at different stages of Helicobacter pylori-infected gastritis, key long noncoding RNAs and genes in the development of Helicobacter pylori infection-induced gastritis were screened to provide a basis for early diagnosis and treatment. MATERIALS AND METHODS: We downloaded 2 sets of sample data from the database, including gastric epithelial tissue samples from gastritis patients from Bhutan and Dominican, and screened mRNAs in the differentially expressed RNAs of the 2 regions. Mfuzz clustering algorithm was used to screen RNAs related to the 3 stages of chronic gastritis. The competing endogenous RNA (ceRNA) regulation network was constructed, and the selected key RNAs were verified. Samples from Bhutan and Dominican were subdivided into the chronic gastritis/ normal comparison groups, and the differentially expressed RNAs were screened to obtain 1067 overlapping RNAs, containing 21 long noncoding RNAs and 1046 mRNAs. RESULTS: Thirty-eight significant gene ontology functional nodes and 6 expression pattern clusters were obtained. Two ceRNA regulatory networks were constructed, and 4 shared miRNAs (hsa-miR-320b, hsa-miR-320c, hsa-miR-320d, and hsa-miR-155-5p) were obtained. Eleven important long noncoding RNAs (AFAP1-AS1, MIR155HG, LINC00472, and FAM201A) and mRNAs (CASP10, SLC26A2, TRIB1, BMP2K, SCAMP1, TNKS1BP1, and MBOAT2) regulated by these 4 miRNAs were obtained. These results indicated that Helicobacter pylori infection had a certain influence on the development of gastritis. CONCLUSIONS: The 11 key RNAs can provide a target for the early diagnosis and treatment of chronic gastritis following Helicobacter pylori infection.
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Gastritis Atrófica , Gastritis , Infecciones por Helicobacter , Helicobacter pylori , MicroARNs , Humanos , Helicobacter pylori/genética , Infecciones por Helicobacter/complicaciones , Infecciones por Helicobacter/genética , MicroARNs/genética , MicroARNs/metabolismo , Gastritis/genética , ARN Mensajero/genética , Proteína 1 de Unión a Repeticiones Teloméricas , Proteínas Serina-Treonina Quinasas , Péptidos y Proteínas de Señalización Intracelular , Proteínas de Transporte VesicularRESUMEN
Chronic gastritis (CG) and osteoporosis (OP) are common and occult diseases in the elderly and the relationship of these two diseases have been increasingly exposed. We aimed to explore the clinical characteristics and shared mechanisms of CG patients combined with OP. In the cross-sectional study, all participants were selected from BEYOND study. The CG patients were included and classified into two groups, namely OP group and non-OP group. Univariable and multivariable logistic regression methods were used to evaluate the influencing factors. Furthermore, CG and OP-related genes were obtained from Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified using the GEO2R tool and the Venny platform. Protein-protein interaction information was obtained by inputting the intersection targets into the STRING database. The PPI network was constructed by Cytoscape v3.6.0 software again, and the key genes were screened out according to the degree value. Gene function enrichment of DEGs was performed by Webgestalt online tool. One hundred and thirty CG patients were finally included in this study. Univariate correlation analysis showed that age, gender, BMI and coffee were the potential influencing factors for the comorbidity (P < 0.05). Multivariate Logistic regression model found that smoking history, serum PTH and serum ß-CTX were positively correlated with OP in CG patients, while serum P1NP and eating fruit had an negative relationship with OP in CG patients. In studies of the shared mechanisms, a total of 76 intersection genes were identified between CG and OP, including CD163, CD14, CCR1, CYBB, CXCL10, SIGLEC1, LILRB2, IGSF6, MS4A6A and CCL8 as the core genes. The biological processes closely related to the occurrence and development of CG and OP mainly involved Ferroptosis, Toll-like receptor signaling pathway, Legionellosis and Chemokine signaling pathway. Our study firstly identified the possible associated factors with OP in the patients with CG, and mined the core genes and related pathways that could be used as biomarkers or potential therapeutic targets to reveal the shared mechanisms.
Asunto(s)
Gastritis , Osteoporosis , Humanos , Anciano , Estudios Transversales , Biomarcadores , Programas Informáticos , Osteoporosis/genética , Osteoporosis/metabolismo , Gastritis/genética , Biología Computacional/métodos , Perfilación de la Expresión Génica/métodosRESUMEN
Spasmolytic polypeptide-expressing metaplasia (SPEM), as a pre-neoplastic precursor of intestinal metaplasia (IM), plays critical roles in the development of chronic atrophic gastritis (CAG) and gastric cancer (GC). However, the pathogenetic targets responsible for the SPEM pathogenesis remain poorly understood. Gene associated with retinoid-IFN-induced mortality 19 (GRIM-19), an essential subunit of the mitochondrial respiratory chain complex I, was progressively lost along with malignant transformation of human CAG, little is known about the potential link between GRIM-19 loss and CAG pathogenesis. Here, we show that lower GRIM-19 is associated with higher NF-кB RelA/p65 and NLR family pyrin domain-containing 3 (NLRP3) levels in CAG lesions. Functionally, GRIM-19 deficiency fails to drive direct differentiation of human GES-1 cells into IM or SPEM-like cell lineages in vitro, whereas parietal cells (PCs)-specific GRIM-19 knockout disturbs gastric glandular differentiation and promotes spontaneous gastritis and SPEM pathogenesis without intestinal characteristics in mice. Mechanistically, GRIM-19 loss causes chronic mucosal injury and aberrant NRF2 (Nuclear factor erythroid 2-related factor 2)- HO-1 (Heme oxygenase-1) activation via reactive oxygen species (ROS)-mediated oxidative stress, resulting in aberrant NF-кB activation by inducing p65 nuclear translocation via an IKK/IкB partner, while NRF2-HO-1 activation contributes to GRIM-19 loss-driven NF-кB activation via a positive feedback NRF2-HO-1 loop. Furthermore, GRIM-19 loss did not cause obvious PCs loss but triggers NLRP3 inflammasome activation in PCs via a ROS-NRF2-HO-1-NF-кB axis, leading to NLRP3-dependent IL-33 expression, a key mediator for SPEM formation. Moreover, intraperitoneal administration of NLRP3 inhibitor MCC950 drastically attenuates GRIM-19 loss-driven gastritis and SPEM in vivo. Our study suggests that mitochondrial GRIM-19 maybe a potential pathogenetic target for the SPEM pathogenesis, and its deficiency promotes SPEM through NLRP3/IL-33 pathway via a ROS-NRF2-HO-1-NF-кB axis. This finding not only provides a causal link between GRIM-19 loss and SPEM pathogenesis, but offers potential therapeutic strategies for the early prevention of intestinal GC.
Asunto(s)
Gastritis , NADH NADPH Oxidorreductasas , FN-kappa B , Animales , Humanos , Ratones , Gastritis/genética , Hemo-Oxigenasa 1/genética , Hemo-Oxigenasa 1/metabolismo , Inflamasomas/genética , Inflamasomas/metabolismo , Interleucina-33 , Metaplasia , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , FN-kappa B/genética , FN-kappa B/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Dominio Pirina , Especies Reactivas de Oxígeno/metabolismo , NADH NADPH Oxidorreductasas/genéticaRESUMEN
OBJECTIVE: This study aimed to identify Helicobacter pylori virulence factors and examine their associations with clinical outcomes in Thai patients. Moreover, the association between these genotypes and gastric mucosa morphological patterns was investigated. METHODS: This retrospective study enrolled patients who underwent esophagogastroduodenoscopy at Suranaree University of Technology Hospital. The presence of the cagA and vacA genes was investigated by real-time polymerase chain reaction. RESULTS: The H. pylori-specific genes ureA and 16S rRNA were detected in all 698 gastric biopsy specimens. In total, 567 (81.23%) patients with H. pylori infection were positive for the cagA gene, 443 (63.46%) were positive for the vacA gene, and 370 (53.0%) were positive for both. The cagA genotype was significantly more common in patients with chronic gastritis and peptic ulcers (78.99% and 79.41%, respectively) than the vacA gene (51.48% and 55.88%, respectively) and combined genotypes (32.34% and 47.05%, respectively). Moreover, the cagA genotype was significantly more common in patients with type 4 or 5 gastric mucosa patterns (69.49% and 76.31%, respectively). CONCLUSIONS: The cagA genotype is the main cause of serious inflammation of the gastric mucosa. The cagA gene is possibly an important factor explaining gastroduodenal disease outcomes in Thai patients with H. pylori infection.