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1.
Virchows Arch ; 477(4): 489-496, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32356024

RESUMO

Pyloric metaplasia (PM) and pseudopyloric metaplasia (PPM) are metaplastic changes resulting in pyloric-type glands in the gastric oxyntic mucosa that mainly occur in chronic gastritis caused by Helicobacter pylori (H. pylori) infection. Focusing on PM and PPM, we classified the histological changes in gastric mucosa according to the Updated Sydney System, using 314 biopsy specimens of gastric greater curvature of the middle body before H. pylori eradication (HPE). Next, the numbers of PM and PPM glands were counted in 47 specimens, and subjects were followed up over 10 years after HPE. PPM was recognized jointly with inflammation, activity, atrophy, and intestinal metaplasia, but PM was recognized more frequently than PPM as atrophy and intestinal metaplasia progressed. Both PM and PPM regressed significantly within 6 years after HPE. Additionally, we demonstrated that PM and PPM are not always coincident with spasmolytic polypeptide-expressing metaplasia (SPEM). In conclusion, PM and PPM are considered different modulations of the same line of differentiation, which are both reversible, with PM potentially emerging from PPM upon progression.


Assuntos
Mucosa Gástrica/patologia , Gastrite/patologia , Infecções por Helicobacter/patologia , Helicobacter pylori/patogenicidade , Biópsia , Diferenciação Celular , Doença Crônica , Mucosa Gástrica/química , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/microbiologia , Gastrite/tratamento farmacológico , Gastrite/metabolismo , Gastrite/microbiologia , Infecções por Helicobacter/tratamento farmacológico , Infecções por Helicobacter/metabolismo , Infecções por Helicobacter/microbiologia , Helicobacter pylori/efeitos dos fármacos , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/administração & dosagem , Metaplasia , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento
2.
Curr Med Sci ; 40(1): 95-103, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32166670

RESUMO

Helicobacter pylori (H. pylori) was reported to be associated with gastric carcinogenesis. Resistin-like molecule beta (RELMß), a recently described goblet cell-specific protein, was demonstrated to aberrantly express in gastric cancer and correlated with its clinicopathological features. This study aimed to examine the association between H. pylori and RELMß expression in gastric carcinoma and precursor lesions. H. pylori infection and RELMß expression were immunohistochemically evaluated in gastric biopsies from 230 patients. The biopsies consisted of normal gastric mucosa (n=20), mucosa with chronic gastritis (n=41), intestinal metaplasia (n=42), dysplasia (n=31), intestinal-type adenocarcinoma (n=56), and diffuse-type adenocarcinoma (n=40). RELMß expression was measured in gastric biopsies after H. pylori eradication therapy in a subgroup of 32 patients. Cultured gastric cancer cell line SGC-7901 was infected with H. pylori strains, and RELMß expression was detected by reverse transcription PCR, real-time PCR and Western blotting. Higher RELMß immunoreactivity was observed in H. pylori-positive intestinal metaplasia (P=0.003), dysplasia (P=0.032), intestinal-type (P=0.037) and diffuse-type adenocarcinomas (P=0.001) than in H. pylori-negative specimens. Expression rates of RELMß in dysplasia (P=0.005), intestinal-type adenocarcinoma (P<0.001), and diffuse-type adenocarcinoma (P=0.001) were significantly correlated with the grade of H. pylori density. In addition, H. pylori eradication reduced the RELMß intensity in intestinal metaplasia (P=0.001). Infection of gastric cancer SGC-7901 cells with cag pathogenicity island (PAI)-positive H. pylori TN2, but not with its PAI totally deleted mutant (TN2-ΔPAI) for 4-8 h, resulted in enhanced protein and transcript levels of RELMß (P<0.05). In summary, our study suggested that H. pylori infection facilitated the expression of RELMß in gastric garcinoma and precursor lesions.


Assuntos
Infecções por Helicobacter/tratamento farmacológico , Helicobacter pylori/patogenicidade , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Neoplasias Gástricas/metabolismo , Regulação para Cima , Adenocarcinoma/metabolismo , Adenocarcinoma/microbiologia , Adenocarcinoma/patologia , Adulto , Idoso , Amoxicilina/farmacologia , Amoxicilina/uso terapêutico , Linhagem Celular Tumoral , Feminino , Regulação Neoplásica da Expressão Gênica , Infecções por Helicobacter/complicações , Infecções por Helicobacter/metabolismo , Helicobacter pylori/efeitos dos fármacos , Humanos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Masculino , Metaplasia , Metronidazol/farmacologia , Metronidazol/uso terapêutico , Pessoa de Meia-Idade , Neoplasias Gástricas/microbiologia
3.
Cancer Sci ; 111(5): 1596-1606, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32198795

RESUMO

Chronic infection with Helicobacter pylori cagA-positive strains is causally associated with the development of gastric diseases, most notably gastric cancer. The cagA-encoded CagA protein, which is injected into gastric epithelial cells by bacterial type IV secretion, undergoes tyrosine phosphorylation at the Glu-Pro-Ile-Tyr-Ala (EPIYA) segments (EPIYA-A, EPIYA-B, EPIYA-C, and EPIYA-D), which are present in various numbers and combinations in its C-terminal polymorphic region, thereby enabling CagA to promiscuously interact with SH2 domain-containing host cell proteins, including the prooncogenic SH2 domain-containing protein tyrosine phosphatase 2 (SHP2). Perturbation of host protein functions by aberrant complex formation with CagA has been considered to contribute to the development of gastric cancer. Here we show that SHIP2, an SH2 domain-containing phosphatidylinositol 5'-phosphatase, is a hitherto undiscovered CagA-binding host protein. Similar to SHP2, SHIP2 binds to the Western CagA-specific EPIYA-C segment or East Asian CagA-specific EPIYA-D segment through the SH2 domain in a tyrosine phosphorylation-dependent manner. In contrast to the case of SHP2, however, SHIP2 binds more strongly to EPIYA-C than to EPIYA-D. Interaction with CagA tethers SHIP2 to the plasma membrane, where it mediates production of phosphatidylinositol 3,4-diphosphate [PI(3,4)P2 ]. The CagA-SHIP2 interaction also potentiates the morphogenetic activity of CagA, which is caused by CagA-deregulated SHP2. This study indicates that initially delivered CagA interacts with SHIP2 and thereby strengthens H. pylori-host cell attachment by altering membrane phosphatidylinositol compositions, which potentiates subsequent delivery of CagA that binds to and thereby deregulates the prooncogenic phosphatase SHP2.


Assuntos
Antígenos de Bactérias/metabolismo , Proteínas de Bactérias/metabolismo , Células Epiteliais/metabolismo , Mucosa Gástrica/metabolismo , Infecções por Helicobacter/metabolismo , Helicobacter pylori/metabolismo , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatases/metabolismo , Motivos de Aminoácidos , Animais , Antígenos de Bactérias/química , Antígenos de Bactérias/genética , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Linhagem Celular , Membrana Celular/metabolismo , Células Epiteliais/microbiologia , Células Epiteliais/patologia , Transição Epitelial-Mesenquimal , Mucosa Gástrica/microbiologia , Mucosa Gástrica/patologia , Infecções por Helicobacter/microbiologia , Helicobacter pylori/genética , Humanos , Fosfatos de Fosfatidilinositol/metabolismo , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatases/química , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatases/genética , Fosforilação , Ligação Proteica , Transporte Proteico , Proteína Tirosina Fosfatase não Receptora Tipo 11/química , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Domínios de Homologia de src
4.
Am J Pathol ; 190(6): 1256-1270, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32201262

RESUMO

Gastric cancer is associated with chronic inflammation (gastritis) triggered by persistent Helicobacter pylori (H. pylori) infection. Elevated tyrosine phosphorylation of the latent transcription factor STAT3 is a feature of gastric cancer, including H. pylori-infected tissues, and aligns with nuclear transcriptional activity. However, the transcriptional role of STAT3 serine phosphorylation, which promotes STAT3-driven mitochondrial activities, is unclear. Here, by coupling serine-phosphorylated (pS)-STAT3-deficient Stat3SA/SA mice with chronic H. felis infection, which mimics human H. pylori infection in mice, we reveal a key role for pS-STAT3 in promoting Helicobacter-induced gastric pathology. Immunohistochemical staining for infiltrating immune cells and expression analyses of inflammatory genes revealed that gastritis was markedly suppressed in infected Stat3SA/SA mice compared with wild-type mice. Stomach weight and gastric mucosal thickness were also reduced in infected Stat3SA/SA mice, which was associated with reduced proliferative potential of infected Stat3SA/SA gastric mucosa. The suppressed H. felis-induced gastric phenotype of Stat3SA/SA mice was phenocopied upon genetic ablation of signaling by the cytokine IL-11, which promotes gastric tumorigenesis via STAT3. pS-STAT3 dependency by Helicobacter coincided with transcriptional activity on STAT3-regulated genes, rather than mitochondrial and metabolic genes. In the gastric mucosa of mice and patients with gastritis, pS-STAT3 was constitutively expressed irrespective of Helicobacter infection. Collectively, these findings suggest an obligate requirement for IL-11 signaling via constitutive pS-STAT3 in Helicobacter-induced gastric carcinogenesis.


Assuntos
Mucosa Gástrica/metabolismo , Gastrite/metabolismo , Infecções por Helicobacter/metabolismo , Fator de Transcrição STAT3/metabolismo , Animais , Mucosa Gástrica/patologia , Gastrite/patologia , Helicobacter , Infecções por Helicobacter/patologia , Humanos , Camundongos , Mitocôndrias/metabolismo , Fosforilação , Transdução de Sinais
5.
FASEB J ; 34(1): 1169-1181, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31914631

RESUMO

BHLHE40, a member of the basic helix-loop-helix transcription factor family, has been reported to play an important role in inflammatory diseases. However, the regulation and function of BHLHE40 in Helicobacter pylori (H pylori)-associated gastritis is unknown. We observed that gastric BHLHE40 was significantly elevated in patients and mice with H pylori infection. Then, we demonstrate that H pylori-infected GECs express BHLHE40 via cagA-ERK pathway. BHLHE40 translocates to cell nucleus, and then binds to cagA protein-activated p-STAT3 (Tyr705). The complex increases chemotactic factor CXCL12 expression (production). Release of CXCL12 from GECs fosters CD4+ T cell infiltration in the gastric mucosa. Our results identify the cagA-BHLHE40-CXCL12 axis that contributes to inflammatory response in gastric mucosa during H pylori infection.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Quimiocina CXCL12/metabolismo , Células Epiteliais/metabolismo , Gastrite/microbiologia , Infecções por Helicobacter/metabolismo , Proteínas de Homeodomínio/metabolismo , Fator de Transcrição STAT3/metabolismo , Animais , Linfócitos T CD4-Positivos/citologia , Núcleo Celular/metabolismo , Feminino , Mucosa Gástrica/metabolismo , Mucosa Gástrica/microbiologia , Gastrite/metabolismo , Regulação da Expressão Gênica , Helicobacter pylori , Humanos , Inflamação , Camundongos , Camundongos Endogâmicos C57BL , Estômago/microbiologia , Regulação para Cima
6.
Proc Natl Acad Sci U S A ; 117(5): 2645-2655, 2020 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-31964836

RESUMO

The main risk factor for stomach cancer, the third most common cause of cancer death worldwide, is infection with Helicobacter pylori bacterial strains that inject cytotoxin-associated gene A (CagA). As the first described bacterial oncoprotein, CagA causes gastric epithelial cell transformation by promoting an epithelial-to-mesenchymal transition (EMT)-like phenotype that disrupts junctions and enhances motility and invasiveness of the infected cells. However, the mechanism by which CagA disrupts gastric epithelial cell polarity to achieve its oncogenicity is not fully understood. Here we found that the apoptosis-stimulating protein of p53 2 (ASPP2), a host tumor suppressor and an important CagA target, contributes to the survival of cagA-positive H. pylori in the lumen of infected gastric organoids. Mechanistically, the CagA-ASPP2 interaction is a key event that promotes remodeling of the partitioning-defective (PAR) polarity complex and leads to loss of cell polarity of infected cells. Blockade of cagA-positive H. pylori ASPP2 signaling by inhibitors of the EGFR (epidermal growth factor receptor) signaling pathway-identified by a high-content imaging screen-or by a CagA-binding ASPP2 peptide, prevents the loss of cell polarity and decreases the survival of H. pylori in infected organoids. These findings suggest that maintaining the host cell-polarity barrier would reduce the detrimental consequences of infection by pathogenic bacteria, such as H. pylori, that exploit the epithelial mucosal surface to colonize the host environment.


Assuntos
Antígenos de Bactérias/metabolismo , Proteínas Reguladoras de Apoptose/metabolismo , Proteínas de Bactérias/metabolismo , Células Epiteliais/citologia , Infecções por Helicobacter/metabolismo , Helicobacter pylori/metabolismo , Organoides/microbiologia , Antígenos de Bactérias/genética , Proteínas Reguladoras de Apoptose/genética , Proteínas de Bactérias/genética , Células Epiteliais/metabolismo , Células Epiteliais/microbiologia , Infecções por Helicobacter/genética , Infecções por Helicobacter/microbiologia , Helicobacter pylori/genética , Helicobacter pylori/crescimento & desenvolvimento , Interações Hospedeiro-Patógeno , Humanos , Organoides/metabolismo , Ligação Proteica , Estômago/microbiologia
7.
Biochem Biophys Res Commun ; 524(1): 36-42, 2020 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-31980170

RESUMO

Gastric epithelial cells (GES-1) stimulated by Helicobacter pylori (H. pylori) would affect the expression of related genes and induce the immune response of the cells. Abnormal methylation of DNA was one of the main causes. The aim of this study was to investigate phosphoinositol-3-kinase adaptor protein 1(PIK3AP1), which was screened from the chip data as an immune gene candidate to against the inflammatory response of cells caused by H. pylori infection. PIK3AP1 plays a key role in PI3K/AKT signaling pathway. The gene chip analysis and experimental results confirmed that PIK3AP1 expression was downregulated and PIK3AP1 promoter was hypermethylated after H. pylori stimulation in GES-1 cells. Meanwhile, the expression level of PIK3AP1 was significantly upregulated after 5-aza-dc treatment, and its expression was higher after 5-aza-dc and H. pylori co-treatment than that of H. pylori treatment but lower than that of 5-aza-dc treatment. Therefore, hypermethylation was the main reason for the down-regulation of PIK3AP1 after H. pylori stimulation. In addition, the intervention of PIK3AP1 inhibited the expression of downstream gene AKT, and suppressing the expression of the immunoinflammatory gene IL-6 in GES-1 cells. Furthermore, the intervention of PIK3AP1 would promote cell proliferation. In summary, hypermethylation of the PIK3AP1 promoter was accompanied by reduction of the expression level of PIK3AP1 in GES-1 cells by H. pylori stimulation. The expression of PIK3AP1, AKT, and IL-6 genes was positively correlated, Meanwhile, the PIK3AP1 can affect the proliferation of GES-1 cells. These results would be helpful to understand the innate immune response function of PIK3AP1 to pathogenic bacterial infection in the stomach.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Decitabina/química , Células Epiteliais/metabolismo , Mucosa Gástrica/citologia , Infecções por Helicobacter/metabolismo , Helicobacter pylori/efeitos dos fármacos , Proteínas Adaptadoras de Transdução de Sinal/genética , Proliferação de Células , Metilação de DNA , Decitabina/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Interleucina-6/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais
8.
Redox Biol ; 28: 101319, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31536951

RESUMO

BACKGROUND: Helicobacter pylori (H. pylori) infection is the main risk factor for gastric cancer. The role of antioxidant enzyme peroxiredoxin 2 (PRDX2) in gastric tumorigenesis remains unknown. In vitro (AGS and SNU-1 cell lines) and in vivo mouse models were utilized to investigate the role of PRDX2 in response to H. pylori infection (7.13, J166 or PMSS1 strain). We detected high levels of PRDX2 expression in gastric cancer tissues. Gastric cancer patients with high expression levels of PRDX2 had significantly worse overall and progression-free survival than those with low levels. H. pylori infection induced activation of NF-κB with increased expression of PRDX2, in in vitro and in vivo models. The knockdown of PRDX2 led to an increase in the levels of reactive oxygen species (ROS), oxidative DNA damage, and double-strand DNA breaks, in response to H. pylori infection, as measured by H2DCFDA, 8-oxoguanine, and p-H2AXγ assays. Luciferase reporter and ChIP assays confirmed the presence of a putative binding site of NF-κB-p65 on PRDX2 promoter region. The inhibition of PRDX2 significantly sensitized AGS and SNU-1 cells to cisplatin treatment. Our data suggest that the future development of therapeutic approaches targeting PRDX2 may be useful in the treatment of gastric cancer.


Assuntos
Cisplatino/farmacologia , Infecções por Helicobacter/metabolismo , Peroxirredoxinas/genética , Peroxirredoxinas/metabolismo , Neoplasias Gástricas/metabolismo , Regulação para Cima , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Infecções por Helicobacter/complicações , Infecções por Helicobacter/genética , Helicobacter pylori/patogenicidade , Humanos , Camundongos , Estadiamento de Neoplasias , Estresse Oxidativo , Prognóstico , Neoplasias Gástricas/etiologia , Neoplasias Gástricas/genética , Análise de Sobrevida
9.
Georgian Med News ; (295): 101-105, 2019 Oct.
Artigo em Russo | MEDLINE | ID: mdl-31804208

RESUMO

The aim of the study was to investigate the influence of Hp on clinical and biochemical course of chronic hepatitis C (CHC). The study included 150 patients with a confirmed diagnosis of chronic hepatitis C, who for various reasons did not receive specific antiviral therapy. Helicobacter pylori (Нр) was determined using a quick urease test (CLO-test) and a coprological test (CITO TEST, manufactured by Pharmasco LLC), interleukin (IL) levels: IL-1ß, IL-6, tumor necrosis factor α (TNF-α) and neopterin by ELISA. Two groups were formed: the 1st (n=52) - patients with chronic hepatitis C infected with Hp and the 2nd (n=98) - patients with chronic hepatitis C without Hp. It was found that in patients with chronic hepatitis C infected with HP, dyspeptic syndrome (94.2% versus 52.0%, p<0.05), pain and severity in the right hypochondrium (65.4% versus 20.4%, p<0.05); and periodic itching of the skin (57.7% versus 12.4%, p<0.05) were significantly more often recorded, compared with patients with chronic hepatitis C without HP. Levels of total bilirubin, alkaline phosphatase and gammaglutamyltranspeptidase are significantly higher in patients with chronic hepatitis C combined with Hp, compared with patients without Hp (p<0.05), which indicates the predominance of cholestasis syndrome in them. Also, in patients with chronic hepatitis C combined with Hp, higher levels of hepatic enzyme activity (AlAT, AsAT) were detected compared with patients with chronic hepatitis C without Hp (82.3% versus 22.9%, respectively; p<0.001). More pronounced disregulatory changes in the cytokine link of the immune system, characterized by an increase in the levels of proinflammatory cytokines: IL-1ß, IL-6, TNF-α and neopterin were registered in patients with chronic hepatitis C infected with Hp, than in patients without Hp. High levels of hepatic enzyme activity (AlAT, AsAT, GGTP), as well as the predominance of cholestasis syndrome in patients with chronic hepatitis C combined with Hp, require the development of a comprehensive eradication therapy of Hp considering the results of clinical and laboratory features of the course of CHC.


Assuntos
Infecções por Helicobacter , Helicobacter pylori , Hepatite C Crônica , Citocinas/metabolismo , Infecções por Helicobacter/complicações , Infecções por Helicobacter/diagnóstico , Infecções por Helicobacter/metabolismo , Hepatite C Crônica/complicações , Hepatite C Crônica/diagnóstico , Hepatite C Crônica/metabolismo , Humanos
10.
PLoS One ; 14(12): e0225961, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31800638

RESUMO

BACKGROUND: Although the high-throughput sequencing technique is useful for evaluating gastric microbiome, it is difficult to use clinically. We aimed to develop a predictive model for gastric microbiome based on serologic testing. METHODS: This study was designed to analyze sequencing data obtained from the Hanyang University Gastric Microbiome Cohort, which was established initially to investigate gastric microbial composition according to the intragastric environment. We evaluated the relationship between the relative abundance of potential gastric cancer-associated bacteria (nitrosating/nitrate-reducing bacteria or type IV secretion system [T4SS] protein gene-contributing bacteria) and serologic markers (IgG anti-Helicobacter pylori [HP] antibody or pepsinogen [PG] levels). RESULTS: We included 57 and 26 participants without and with HP infection, respectively. The relative abundance of nitrosating/nitrate-reducing bacteria was 4.9% and 3.6% in the HP-negative and HP-positive groups, respectively, while that of T4SS protein gene-contributing bacteria was 20.5% and 6.5% in the HP-negative and HP-positive groups, respectively. The relative abundance of both nitrosating/nitrate-reducing bacteria and T4SS protein gene-contributing bacteria increased exponentially as PG levels decreased. Advanced age (only for nitrosating/nitrate-reducing bacteria), a negative result of IgG anti-HP antibody, low PG levels, and high Charlson comorbidity index were associated with a high relative abundance of nitrosating/nitrate-reducing bacteria and T4SS protein gene-contributing bacteria. The adjusted coefficient of determination (R2) was 53.7% and 70.0% in the model for nitrosating/nitrate-reducing bacteria and T4SS protein gene-contributing bacteria, respectively. CONCLUSION: Not only the negative results of IgG anti-HP antibody but also low PG levels were associated with a high abundance of nitrosating/nitrate-reducing bacteria and T4SS protein gene-contributing bacteria.


Assuntos
Anticorpos Antibacterianos/imunologia , Infecções por Helicobacter/imunologia , Infecções por Helicobacter/metabolismo , Infecções por Helicobacter/microbiologia , Helicobacter pylori/imunologia , Microbiota , Pepsinogênio A/metabolismo , Adulto , Carga Bacteriana , Comorbidade , Feminino , Infecções por Helicobacter/diagnóstico , Humanos , Masculino , Metagenoma , Metagenômica/métodos , Pessoa de Meia-Idade , Prognóstico , Testes Sorológicos , Neoplasias Gástricas/etiologia
11.
Asian Pac J Cancer Prev ; 20(11): 3497-3503, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31759377

RESUMO

OBJECTIVE: To assess the value of Current Infection Marker (CIM) test, Campylobacter-Like Organism (CLO) test, and the multiplex polymerase chain reaction test (PCR) for the diagnosis of Helicobacter pylori (H. pylori) infection in a Vietnamese population. METHODS: Targeted suitable patients were recruited. CIM test, CLO test and multiplex PCR were used to diagnose for H. pylori infection. Patients were considered positive for H. pylori when at least two of the three tests were positive. The performance of each of the three tests was compared to the H. pylori positive populations as defined. RESULT: Amongst 201 patients with a mean age of 40.5 (range, 18-74) years, there were 115 females and 86 males. Of the 201 patients, 107 (53.2%) were diagnosed as H. pylori positive according to the defined criteria. The positive patients obtained with CLO test, CIM test and multiplex PCR were 38.3%, 59.2% and 72.1%, correspondingly. The full performance of the three tests as highlighted in order as above were 85.07%, 83.08% and 81.09%, respectively. The positive rate of CLO test was the lowest, with 38.3% positive, but this method was the most accurate, with the accuracy of 85.07%. This suggested that CLO test has the highest specificity among the three. The sensitivity, specificity, positive, negative predictive values and accuracy of the CLO / CIM / multiplex PCR tests were 71.96% / 89.72% / 100%, 100% / 75.53% / 59.57%, 100% / 80.67% / 73.79%, 75.81% / 86.59% / 100%, and 85.07% / 83.08% / 81.09%, respectively. CONCLUSION: All the three methods have high accuracy for the diagnosis of H. pylori infection in the Vietnamese population with gastritis and gastric ulcers. These tests can be employed in the clinical settings for the Vietnamese population. CLO test should be used in combination with the other tests to reduce false-negative results.


Assuntos
Campylobacter/metabolismo , Gastrite/diagnóstico , Infecções por Helicobacter/diagnóstico , Helicobacter pylori/genética , Reação em Cadeia da Polimerase Multiplex/métodos , Úlcera Gástrica/diagnóstico , Adolescente , Adulto , Idoso , Biomarcadores/metabolismo , Biópsia/métodos , Feminino , Gastrite/metabolismo , Gastrite/microbiologia , Infecções por Helicobacter/metabolismo , Infecções por Helicobacter/microbiologia , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Sensibilidade e Especificidade , Úlcera Gástrica/metabolismo , Úlcera Gástrica/microbiologia , Adulto Jovem
12.
World J Gastroenterol ; 25(41): 6222-6237, 2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31749593

RESUMO

BACKGROUND: Pediatric enteritis is one of the infectious diseases in the digestive system that causes a variety of digestive problems, including diarrhea, vomiting, and bellyache in children. Clinically, Helicobacter pylori (H. pylori) infection is one of the common factors to cause pediatric enteritis. It has been demonstrated that aberrant expression of microRNAs (miRNAs) is found in gastrointestinal diseases caused by H. pylori, and we discovered a significant increase of miR-32-5p in H. pylori-related pediatric enteritis. However, the exact role of miR-32-5p in it is still unknown. AIM: To investigate the role of aberrant miR-32-5p in pediatric enteritis induced by H. pylori. METHODS: MiR-32-5p expression was detected by quantitative real time-polymerase chain reaction. The biological role of miR-32-5p in H. pylori-treated intestinal epithelial cells was evaluated by Cell Counting Kit-8 assay and flow cytometry. The potential target of miR-32-5p was predicted with TargetScanHuman and verified by luciferase assay. The downstream mechanism of miR-32-5p was explored by using molecular biology methods. RESULTS: We found that miR-32-5p was overexpressed in serum of H. pylori-induced pediatric enteritis. Further investigation revealed that H. pylori infection promoted the death of intestinal epithelial cells, and increased miR-32-5p expression. Moreover, miR-32-5p mimic further facilitated apoptosis and inflammatory cytokine secretion of intestinal epithelial cells. Further exploration revealed that SMAD family member 6 (SMAD6) was the direct target of miR-32-5p, and SMAD6 overexpression partially rescued cell damage induced by H. pylori. The following experiments showed that miR-32-5p/SMAD6 participated in the apoptosis of intestinal epithelial cells induced by transforming growth factor-ß-activated kinase 1 (TAK1)-p38 activation under H. pylori infection. CONCLUSION: Our work uncovered the crucial role of aberrant expression of miR-32-5p in H. pylori-related pediatric enteritis, and suggested that the TAK1-p38 pathway is involved in it.


Assuntos
Enterite/patologia , Células Epiteliais/patologia , Infecções por Helicobacter/metabolismo , Helicobacter pylori/patogenicidade , MicroRNAs/metabolismo , Dor Abdominal/microbiologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Apoptose , Estudos de Casos e Controles , Sobrevivência Celular , Criança , Citocinas/metabolismo , Diarreia/microbiologia , Enterite/microbiologia , Células Epiteliais/microbiologia , Citometria de Fluxo , Regulação da Expressão Gênica , Células HEK293 , Infecções por Helicobacter/microbiologia , Humanos , Inflamação , Intestinos , RNA Interferente Pequeno/metabolismo , Proteína Smad6/metabolismo , Vômito/microbiologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
13.
Microb Pathog ; 137: 103769, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31580959

RESUMO

BACKGROUND: To clarify the impact of IL-1B gene polymorphisms (IL-1B-511C/T, IL-1B-31C/T, IL-1B+3954C/T) in Helicobacter pylori (H. pylori) infection by mean of a meta-analysis. METHODS: The relevant studies were retrieved from PubMed, Web of Science, EMBASE, Cochrane Library, Chinese National Knowledge Infrastructure (CNKI) and Wanfang databases until September 9, 2018. Odds ratio (OR) and its 95% confidence intervals (CIs) were used to assess the associations. Statistical analyses of this meta-analysis were conducted by using STATA 12 software. RESULTS: Totally, 45 articles including 9606 cases and 5654 controls were enrolled in this meta-analysis. Our results indicated that IL-1B-511C/T polymorphism was significantly related to an increased the risk of H. pylori infection under recessive model (OR = 1.13, 95% CI: 1.00-1.27, P = 0.048). However, no significant associations were obtained between H. pylori infection and IL-1B-31C/T as well as IL-1B+3954C/T polymorphisms under all models. In addition, subgroup analyses were also performed by country, study design, and detection methods of H. pylori. CONCLUSIONS: This meta-analysis suggested that IL-1B-511C/T polymorphism was related to the risk of H. pylori infection. Further larger studies with high quality are needed to conform these findings.


Assuntos
Infecções por Helicobacter/genética , Helicobacter pylori/fisiologia , Interleucina-1beta/genética , Polimorfismo de Nucleotídeo Único , Predisposição Genética para Doença , Infecções por Helicobacter/metabolismo , Infecções por Helicobacter/microbiologia , Helicobacter pylori/genética , Humanos , Interleucina-1beta/metabolismo
14.
PLoS Pathog ; 15(9): e1007921, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31568537

RESUMO

Humans are frequently exposed to bacterial genotoxins involved in digestive cancers, colibactin and Cytolethal Distending Toxin (CDT), the latter being secreted by many pathogenic bacteria. Our aim was to evaluate the effects induced by these genotoxins on nuclear remodeling in the context of cell survival. Helicobacter infected mice, coculture experiments with CDT- and colibactin-secreting bacteria and hepatic, intestinal and gastric cells, and xenograft mouse-derived models were used to assess the nuclear remodeling in vitro and in vivo. Our results showed that CDT and colibactin induced-nuclear remodeling can be associated with the formation of deep cytoplasmic invaginations in the nucleus of giant cells. These structures, observed both in vivo and in vitro, correspond to nucleoplasmic reticulum (NR). The core of the NR was found to concentrate ribosomes, proteins involved in mRNA translation, polyadenylated RNA and the main components of the complex mCRD involved in mRNA turnover. These structures are active sites of mRNA translation, correlated with a high degree of ploidy, and involve MAPK and calcium signaling. Additional data showed that insulation and concentration of these adaptive ribonucleoprotein particles within the nucleus are dynamic, transient and protect the cell until the genotoxic stress is relieved. Bacterial genotoxins-induced NR would be a privileged gateway for selected mRNA to be preferably transported therein for local translation. These findings offer new insights into the context of NR formation, a common feature of many cancers, which not only appears in response to therapies-induced DNA damage but also earlier in response to genotoxic bacteria.


Assuntos
Toxinas Bacterianas/toxicidade , Helicobacter/patogenicidade , Ribonucleoproteínas/metabolismo , Animais , Linhagem Celular , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Núcleo Celular/patologia , Sobrevivência Celular , Dano ao DNA , Infecções por Helicobacter/metabolismo , Infecções por Helicobacter/patologia , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Eletrônica de Transmissão , Mutagênicos/toxicidade , Peptídeos/toxicidade , Policetídeos/toxicidade , RNA Mensageiro/metabolismo
15.
PLoS One ; 14(9): e0222295, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31537016

RESUMO

Antimicrobial peptides can protect the gastric mucosa from bacteria, but Helicobacter pylori (H. pylori) can equally colonize the gastric apparatus. To understand beta-defensin function in H. pylori-associated chronic gastritis, we investigated susceptibility, human beta-defensin mRNA expression, and DNA methylation changes to promoters in the gastric mucosa with or without H. pylori infection. We studied the expression of HBD2 (gene name DEFB4A), HBD3 (DEFB103A), and HBD4 (DEFB104) using real-time PCR in 15 control and 10 H. pylori infection patient gastric specimens. This study demonstrates that H. pylori infection is related to gastric enhancement of inducible HBD2, but inducible HBD3 and HBD4 expression levels remained unchanged. HBD2 gene methylation levels were overall higher in H. pylori-negative samples than in H. pylori-positive samples. We also assessed antimicrobial susceptibility using growth on blood agar. The H. pylori strain Tox+ was susceptible to all defensins tested and their analogs (3N, 3NI). These results show that HBD2 is involved in gastritis development driven by H. pylori, which facilitates the creation of an epigenetic field during H. pylori-associated gastric tumorigenesis.


Assuntos
Metilação de DNA , Infecções por Helicobacter/metabolismo , Helicobacter pylori , beta-Defensinas/metabolismo , Adulto , Relação Dose-Resposta a Droga , Feminino , Mucosa Gástrica/metabolismo , Mucosa Gástrica/microbiologia , Gastrite/etiologia , Gastrite/metabolismo , Infecções por Helicobacter/complicações , Infecções por Helicobacter/patologia , Helicobacter pylori/efeitos dos fármacos , Humanos , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase em Tempo Real , Transcriptoma , beta-Defensinas/farmacologia
16.
Proc Natl Acad Sci U S A ; 116(39): 19652-19658, 2019 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-31488717

RESUMO

Helicobacter pylori-induced gastritis is the strongest risk factor for gastric adenocarcinoma, a malignancy preceded by a series of well-defined histological stages, including metaplasia. One microbial constituent that augments cancer risk is the cag type 4 secretion system (T4SS), which translocates the oncoprotein CagA into host cells. Aberrant stem cell activation is linked to carcinogenesis, and Lrig1 (leucine-rich repeats and Ig-like domains 1) marks a distinct population of progenitor cells. We investigated whether microbial effectors with carcinogenic potential influence Lrig1 progenitor cells ex vivo and via lineage expansion within H. pylori-infected gastric mucosa. Lineage tracing was induced in Lrig1-CreERT2/+;R26R-YFP/+ (Lrig1/YFP) mice that were uninfected or subsequently infected with cag + H. pylori or an isogenic cagE - mutant (nonfunctional T4SS). In contrast to infection with wild-type (WT) H. pylori for 2 wk, infection for 8 wk resulted in significantly increased inflammation and proliferation in the corpus and antrum compared with uninfected or mice infected with the cagE - mutant. WT H. pylori-infected mice harbored significantly higher numbers of Lrig1/YFP epithelial cells that coexpressed UEA1 (surface cell marker). The number of cells coexpressing intrinsic factor (chief cell marker), YFP (lineage marker), and GSII lectin (spasmolytic polypeptide-expressing metaplasia marker) were increased only by WT H. pylori In human samples, Lrig1 expression was significantly increased in lesions with premalignant potential compared with normal mucosa or nonatrophic gastritis. In conclusion, chronic H. pylori infection stimulates Lrig1-expressing progenitor cells in a cag-dependent manner, and these reprogrammed cells give rise to a full spectrum of differentiated cells.


Assuntos
Helicobacter pylori/metabolismo , Glicoproteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Sistemas de Secreção Tipo IV/metabolismo , Adenocarcinoma/metabolismo , Adenocarcinoma/microbiologia , Animais , Carcinogênese/patologia , Modelos Animais de Doenças , Células Epiteliais/metabolismo , Feminino , Mucosa Gástrica/metabolismo , Gastrite/metabolismo , Gastrite/patologia , Infecções por Helicobacter/metabolismo , Infecções por Helicobacter/microbiologia , Infecções por Helicobacter/patologia , Humanos , Masculino , Camundongos , Camundongos Knockout , Lesões Pré-Cancerosas/metabolismo , Lesões Pré-Cancerosas/microbiologia , Lesões Pré-Cancerosas/patologia , Cultura Primária de Células , Fatores de Risco , Células-Tronco/metabolismo , Estômago/microbiologia , Estômago/patologia , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/microbiologia , Neoplasias Gástricas/patologia
17.
Arch Med Res ; 50(3): 113-121, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31495388

RESUMO

BACKGROUND: Peptic ulcer disease (PUD) is a common disease worldwide moreover known as stomach ulcer or peptic ulcer. Increased the number of T CD4+ helper cells in response to gastric infection by Helicobacter pylori (H. pylori) play an important role in the development of PUD. The aim of this study was to determine the frequency of T-bet+ cells in H. pylori-infection, its interaction with Th17/Treg cells and its association with the clinical consequences of the infection. METHODS: A total of 63 patients with PUD, 89 patients with gastritis and 48 H. pylori-negative subjects were enrolled in this study. The number of T-bet+ cells were determined by immunohistochemistry. RESULTS: The numbers of T-bet+ cells and INF-γ expression in infected patients were significantly higher than uninfected. Moreover, the number of T-bet+ cells and INF-γ expression in infected patients with PUD were significantly higher than infected patients with gastritis. Additionally, the number of T-bet+ cells and INF-γ expression were found to be inversely correlated with degree of H. pylori density and chronic inflammation score (CIS) in infected patients with gastritis disease, but this correlation was positive in the infected patients with PUD. The number of T-bet+ cells was found to be positively correlated with the number of Th17 cells and inversely correlated with the number of Treg cells in infected patients with gastritis and PUD. CONCLUSION: Abnormal hyper-activation of T-bet+ cells during H. pylori-infection may lead to tissue damage caused by immunopathologic reactions.


Assuntos
Gastrite/patologia , Úlcera Péptica/epidemiologia , Úlcera Péptica/microbiologia , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Adulto , Feminino , Mucosa Gástrica/imunologia , Mucosa Gástrica/microbiologia , Mucosa Gástrica/fisiologia , Gastrite/imunologia , Infecções por Helicobacter/metabolismo , Helicobacter pylori/imunologia , Humanos , Imuno-Histoquímica , Interferon gama/biossíntese , Masculino , Pessoa de Meia-Idade
18.
Int J Mol Sci ; 20(15)2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31370155

RESUMO

Despite the significant recent advances in clinical practice, gastric cancer (GC) represents a leading cause of cancer-related deaths in the world. In fact, occurrence of chemo-resistance still remains a daunting hindrance to effectiveness of the current approach to GC therapy. There is accumulating evidence that a plethora of cellular and molecular factors is implicated in drug-induced phenotypical switching of GC cells. Among them, epithelial-mesenchymal transition (EMT), autophagy, drug detoxification, DNA damage response and drug target alterations, have been reported as major determinants. Intriguingly, resistant GC phenotype may be the result of GC cell-induced tumor microenvironment (TME) remodeling, which is currently emerging as a key player in promoting drug resistance and overcoming cytotoxic effects of drugs. In this review, we discuss the possible mechanisms of drug resistance and their involvement in determining current GC therapies failure.


Assuntos
Autofagia/genética , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Neovascularização Patológica/genética , Neoplasias Gástricas/genética , Microambiente Tumoral/genética , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Antineoplásicos/uso terapêutico , Autofagia/efeitos dos fármacos , Proteínas Relacionadas à Autofagia/genética , Proteínas Relacionadas à Autofagia/metabolismo , Sobrevivência Celular/genética , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Transição Epitelial-Mesenquimal/genética , Infecções por Helicobacter/tratamento farmacológico , Infecções por Helicobacter/genética , Infecções por Helicobacter/metabolismo , Infecções por Helicobacter/patologia , Helicobacter pylori/crescimento & desenvolvimento , Helicobacter pylori/patogenicidade , Humanos , Hipóxia/tratamento farmacológico , Hipóxia/genética , Hipóxia/metabolismo , Hipóxia/patologia , Inativação Metabólica/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Microambiente Tumoral/efeitos dos fármacos
19.
Med Sci Monit ; 25: 4837-4848, 2019 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-31256192

RESUMO

BACKGROUND Helicobacter pylori infection is associated with various vascular diseases. However, its mechanism is yet to be defined. The present study aimed to investigate the effect of H. pylori on vascular endothelial cells as well as the GATA3-related mechanism of H. pylori infection-induced endothelial injuries. MATERIAL AND METHODS A co-culture of H. pylori with human umbilical endothelial cells (HUVECs) was produced. The proliferation of HUVECs that had been incubated with H. pylori were examined via CCK-8 (Cell Counting Kit-8) and EdU (5-ethynyl-2'-deoxyuridine) staining. Cell migration and microtubules formation were studied using Transwell and tube formation respectively. Construction of a mouse model of H. pylori infection as well as the expression of GATA3 and CHI3L1 in vessels were tested using western blot and immunohistochemistry. Small interfering RNA (siRNA) of GATA3 were transfected into HUVECs in order to establish cell lines with knocked-down GATA3. The production of the aforementioned molecules and p38 mitogen-activated protein kinase (MAPK) related molecules in HUVECs was measured using quantitative real-time polymerase chain reaction and western blot. RESULTS H. pylori significantly inhibited the proliferation, migration, and tube formation of HUVECs, as well as increased the production of the inflammatory factor CHI3L1 and phosphorylated p38 from endothelial cells along with an increased expression of GATA3. Elevated levels of the GATA3 and CHI3L1 were also found in the arteries of H. pylori-infected mice. Following GATA3 knockdown, the H. pylori-induced dysfunction of HUVECs was restored. CONCLUSIONS H. pylori impaired vascular endothelial function. This might be due to the H. pylori-induced increased expression of GATA3, as well as the GATA3 mediated upregulated CHI3L1 and activation of the p38 MAPK pathway.


Assuntos
Proteína 1 Semelhante à Quitinase-3/biossíntese , Células Endoteliais/microbiologia , Fator de Transcrição GATA3/metabolismo , Infecções por Helicobacter/patologia , Helicobacter pylori/metabolismo , Animais , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Células Cultivadas , Proteína 1 Semelhante à Quitinase-3/metabolismo , Quitinases/metabolismo , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Fator de Transcrição GATA3/biossíntese , Infecções por Helicobacter/metabolismo , Infecções por Helicobacter/microbiologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Sistema de Sinalização das MAP Quinases , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação , RNA Interferente Pequeno/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
20.
Microb Pathog ; 135: 103634, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31325568

RESUMO

BACKGROUND: Research indicates that Helicobacter pylori can inflict severe histological damage through the modulation of host-related genes. The current study investigated the effect of H. pylori genotypes in the outcome of disease, and the expression of anti-apoptotic related genes, COX-1, COX-2, and iNOS genes in benign, pre-malignant, and malignant lesions of gastric carcinogenesis. MATERIALS AND METHODS: Tissue samples from H. pylori positive patients were graded based on the genotype of the infected H. pylori strain. Expression of COX-1, COX-2 and iNOS was assessed using a combination of real-time PCR and immunohistochemistry. RESULTS: Gene expression studies confirmed that COX-2 and iNOS expression was highly and selectively induced in epithelium with premalignant changes such as atrophic conditions, metaplasia and dysplasia, suggesting an important role of these genes in the sequence to gastric carcinoma of the intestinal type. Furthermore, the expression of COX-2 and iNOS was also dependent on the genotype of H. pylori and subjects with genotype-1 exhibited significantly higher expressions of COX-2 and iNOS compared to other genotypes. Comparison of the expression levels among infected and uninfected individuals demonstrated significant difference in the expression pattern of COX-2 gene whereas iNOS expression was found only in subjects infected H. pylori (p < 0.001). Immunohistochemical staining showed 1.5619 folds higher propensity of COX-2 and 3.2941 folds higher intensity of iNOS expression in subjects infected with H. pylori genotype 1. CONCLUSION: The up-regulation of COX-2 and iNOS was associated with the genotype of the H. pylori strain and the presence of certain genotype may greatly affect early events during carcinogenesis.


Assuntos
Ciclo-Oxigenase 1/metabolismo , Ciclo-Oxigenase 2/metabolismo , Expressão Gênica , Infecções por Helicobacter/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Adenocarcinoma , Adulto , Ciclo-Oxigenase 1/genética , Ciclo-Oxigenase 2/genética , Mucosa Gástrica/patologia , Gastrite , Gastrite Atrófica , Genótipo , Infecções por Helicobacter/genética , Infecções por Helicobacter/patologia , Helicobacter pylori/patogenicidade , Humanos , Imuno-Histoquímica , Metaplasia , Pessoa de Meia-Idade , Óxido Nítrico Sintase Tipo II/genética , RNA Mensageiro/metabolismo , Neoplasias Gástricas/patologia , Regulação para Cima
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