RESUMEN
Excision repair cross-complementing group 6 and 8 (ERCC6 and ERCC8) are two indispensable genes for the initiation of transcription-coupled nucleotide excision repair pathway. This study aimed to evaluate the interactions between single nucleotide polymorphisms of ERCC6 (rs1917799) and ERCC8 (rs158572 and rs158916) in gastric cancer and its precancerous diseases. Besides, protein level analysis were performed to compare ERCC6 and ERCC8 expression in different stages of gastric diseases, and to correlate SNPs jointly with gene expression. Sequenom MassARRAY platform method was used to detect polymorphisms of ERCC6 and ERCC8 in 1916 subjects. In situ ERCC6 and ERCC8 protein expression were detected by immunohistochemistry in 109 chronic superficial gastritis, 109 chronic atrophic gastritis and 109 gastric cancer cases. Our results demonstrated pairwise epistatic interactions between ERCC6 and ERCC8 SNPs that ERCC6 rs1917799-ERCC8 rs158572 combination was associated with decreased risk of chronic atrophic gastritis and increased risk of gastric cancer. ERCC6 rs1917799 also showed a significant interaction with ERCC8 rs158916 to reduce gastric cancer risk. The expressions of ERCC6, ERCC8 and ERCC6-ERCC8 combination have similarities that higher positivity was observed in chronic superficial gastritis compared with chronic atrophic gastritis and gastric cancer. As for the effects of ERCC6 and ERCC8 SNPs on the protein expression, single SNP had no correlation with corresponding gene expression, whereas the ERCC6 rs1917799-ERCC8 rs158572 pair had significant influence on ERCC6 and ERCC6-ERCC8 expression. In conclusion, ERCC6 rs1917799, ERCC8 rs158572 and rs158916 demonstrated pairwise epistatic interactions to associate with chronic atrophic gastritis and gastric cancer risk. The ERCC6 rs1917799-ERCC8 rs158572 pair significantly influence ERCC6 and ERCC6-ERCC8 expression.
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ADN Helicasas/genética , Enzimas Reparadoras del ADN/genética , Gastritis Atrófica/genética , Proteínas de Unión a Poli-ADP-Ribosa/genética , Neoplasias Gástricas/genética , Factores de Transcripción/genética , Estudios de Casos y Controles , ADN Helicasas/biosíntesis , Enzimas Reparadoras del ADN/biosíntesis , Femenino , Gastritis Atrófica/enzimología , Gastritis Atrófica/patología , Predisposición Genética a la Enfermedad , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Proteínas de Unión a Poli-ADP-Ribosa/biosíntesis , Polimorfismo de Nucleótido Simple , Factores de Riesgo , Neoplasias Gástricas/enzimología , Neoplasias Gástricas/patología , Factores de Transcripción/biosíntesisRESUMEN
BACKGROUND: Whether the characteristics and prognosis of gastric cancer (GC) are different in patients with and without Helicobacter pylori (HP) remains controversial. The definitions of HP status in patients with atrophic gastritis but negative tests for HP are heterogeneous. We aimed to assess the impact of HP on the prognosis of GC using different definitions. METHODS: From 1998 Nov to 2011 Jul, five hundred and sixty-seven consecutive patients with GC were included. HP status was determined by serology and histology. Patients with any positive test were defined as HP infection. Patients without HP infection whose serum pepsinogen (PG) I <70 ng/dl and PG I/II ratio < 3.0 were defined as atrophic gastritis and they were categorized into model 1: HP positive; model 2: HP negative; and model 3: exclusion of these patients. RESULTS: We found four characteristics of HP negative GC in comparison to HP positive GC: (1) higher proportion of the proximal tumor location (24.0%, P = 0.004), (2) more diffuse histologic type (56.1%, p = 0.008), (3) younger disease onset (58.02 years, p = 0.008) and (4) more stage IV disease (40.6%, p = 0.03). Patients with negative HP had worse overall survival (24.0% vs. 35.8%, p = 0.035). In Cox regression models, the negative HP status is an independent poor prognostic factor (HR: 1.34, CI:1.04-1.71, p = 0.019) in model 1, especially in stage I, II and III patients (HR: 1.62; CI:1.05-2.51,p = 0.026). CONCLUSION: We found the distinct characteristics of HP negative GC. The prognosis of HP negative GC was poor.
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Adenocarcinoma/complicaciones , Adenocarcinoma/microbiología , Gastritis Atrófica/complicaciones , Gastritis Atrófica/microbiología , Infecciones por Helicobacter/complicaciones , Helicobacter pylori , Neoplasias Gástricas/complicaciones , Neoplasias Gástricas/microbiología , Adenocarcinoma/enzimología , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Femenino , Gastritis Atrófica/enzimología , Infecciones por Helicobacter/enzimología , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Pepsinógeno A/sangre , Pepsinógeno C/sangre , Pronóstico , Neoplasias Gástricas/enzimología , Adulto JovenRESUMEN
AIM: To measure biochemical parameters in stomach biopsies and test their suitability as diagnostic biomarkers for gastritis and precancerous lesions. METHODS: Biopsies were obtained from the stomachs of two groups of patients (n = 40) undergoing fiber-optic endoscopy due to upper gastrointestinal symptoms. In the first group (n = 17), only the corpus region was examined. Biopsies were processed for microscopic examination and measurement of mitochondrial O2 consumption (cellular respiration), cellular adenosine triphosphate (ATP), glutathione (GSH), and caspase activity. In the second group of patients (n = 23), both corpus and antral regions were studied. Some biopsies were processed for microscopic examination, while the others were used for measurements of cellular respiration and GSH level. RESULTS: Microscopic examinations of gastric corpus biopsies from 17 patients revealed normal mucosae in 8 patients, superficial gastritis in 7 patients, and chronic atrophic gastritis in 1 patient. In patients with normal histology, the rate (mean ± SD) of cellular respiration was 0.17 ± 0.02 µmol/L O2 min(-1) mg(-1), ATP content was 487 ± 493 pmol/mg, and GSH was 469 ± 98 pmol/mg. Caspase activity was detected in 3 out of 8 specimens. The values of ATP and caspase activity were highly variable. The presence of superficial gastritis had insignificant effects on the measured biomarkers. In the patient with atrophic gastritis, cellular respiration was high and ATP was relatively low, suggesting uncoupling oxidative phosphorylation. In the second cohort of patients, the examined biopsies showed either normal or superficial gastritis. The rate of cellular respiration (O2. µmol/L min(-1) mg(-1)) was slightly higher in the corpus than the antrum (0.18 ± 0.05 vs 0.15 ± 0.04, P = 0.019). The value of GSH was about the same in both tissues (310 ± 135 vs 322 ± 155, P = 0.692). CONCLUSION: The corpus mucosa was metabolically more active than the antrum tissue. The data in this study will help in understanding the pathophysiology of gastric mucosa.
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Caspasas/metabolismo , Metabolismo Energético , Gastritis Atrófica/enzimología , Glutatión/metabolismo , Estómago/enzimología , Adenosina Trifosfato/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Apoptosis , Biomarcadores/metabolismo , Biopsia , Respiración de la Célula , Endoscopía Gastrointestinal , Estudios de Factibilidad , Femenino , Mucosa Gástrica/enzimología , Gastritis Atrófica/diagnóstico , Humanos , Masculino , Persona de Mediana Edad , Consumo de Oxígeno , Valor Predictivo de las Pruebas , Estudios Prospectivos , Antro Pilórico/enzimología , Estómago/patología , Adulto JovenRESUMEN
OBJECTIVE: To study the effects of Zhiweifangbian (ZWFB) capsule on lactic dehydrogenase (LDH), succinic dehydrogenase (SDH) and ATPase activities in gastric mucosa of chronic atrophic gastritis (CAG) rats with Qi deficiency and blood stasis syndrome. METHODS: Totally 90 rats were randomly divided into 2 groups: normal group (n = 10) and model group (n = 80). The CAG rat model of Qi deficiency and blood stasis type was induced by synthetic methods. After modeling for 12 weeks and the successful CAG model was determined, the CAG model rats were divided by random number table into model group (MG), ZWFB high-dose group (ZWFBH), ZWFB middle-dose group (ZWFBM), ZWFB low-dose group (ZWFBL) and Weimeisu group (WM), 9 rats in each group. The rats in the normal and model groups were intragastrically administrated with distilled water, 10 mL/kg every day; the ZWFB high-dose group with ZWFB, 0.6 g/ kg(-1) x d(-1); the ZWFB middle-dose group with ZWFB, 0.3 g/kg(-1) x d(-1); the ZWFB low-dose group with ZWFB, 0.15 g/kg(-1) x d(-1), and the WM group with suspension of WM, 0.25 g/kg(-1) x d(-1). The treatment was given for 90 consecutive days. Then general survival states were observed and the activities of LDH, SDH, Na(+)-K(+)-ATPase and Ca(2+)-Mg(2+)-ATPase in gastric mucosa tissue were detected. RESULTS: Compared with the normal group, activity of LDH in the gastric mucosa (P < 0.05) and activities of SDH, Na(+)-K(+)-ATPase and Ca(2+)-Mg(2+)-ATPase significantly decreased in the normal group (P < 0.05). Compared with the model group the activity of LDH decreased and activities of SDH, Na(+)-K(+)-ATPase and Ca(2+)-Mg(2+)-ATPase significantly increased in the high dose ZWFB group (P < 0.05). CONCLUSION: ZWFB capsule can promote energy metabolism and ATPase activity in the gastric mucosa cell, so as to protect the function of the gastric mucosa cell.
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Adenosina Trifosfatasas/metabolismo , Medicamentos Herbarios Chinos/administración & dosificación , Metabolismo Energético/efectos de los fármacos , Mucosa Gástrica/enzimología , Gastritis Atrófica/tratamiento farmacológico , Qi , Animales , Femenino , Mucosa Gástrica/efectos de los fármacos , Mucosa Gástrica/metabolismo , Gastritis Atrófica/enzimología , Gastritis Atrófica/metabolismo , Humanos , L-Lactato Deshidrogenasa/metabolismo , Masculino , Ratas , Ratas Wistar , Succinato Deshidrogenasa/metabolismoRESUMEN
BACKGROUND: The majority of gastric cancer cases are believed to be caused by chronic infection with the bacterium Helicobacter pylori, and atrophic corpus gastritis is a predisposing condition to gastric cancer development. We aimed to increase understanding of the molecular details of atrophy by performing a global transcriptome analysis of stomach tissue. METHODS: Biopsies from patients with different stages of H. pylori infection were taken from both the antrum and corpus mucosa and analyzed on microarrays. The stages included patients without current H. pylori infection, H. pylori-infected without corpus atrophy and patients with current or past H. pylori-infection with corpus-predominant atrophic gastritis. RESULTS: Using clustering and integrated analysis, we found firm evidence for antralization of the corpus mucosa of atrophy patients. This antralization harbored gain of gastrin expression, as well as loss of expression of corpus-related genes, such as genes associated with acid production, energy metabolism and blood clotting. The analyses provided detailed molecular evidence for simultaneous intestinal metaplasia (IM) and spasmolytic polypeptide expressing metaplasia (SPEM) in atrophic corpus tissue. Finally, acidic mammalian chitinase, a chitin-degrading enzyme produced by chief cells, was shown to be strongly down-regulated in corpus atrophy. CONCLUSIONS: Transcriptome analysis revealed several gene groups which are related to development of corpus atrophy, some of which were increased also in H. pylori-infected non-atrophic patients. Furthermore, loss of acidic chitinase expression is a promising marker for corpus atrophy.
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Quitinasas/genética , Mucosa Gástrica/microbiología , Gastritis Atrófica/enzimología , Gastritis Atrófica/genética , Helicobacter pylori/fisiología , Transcriptoma , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/metabolismo , Vasos Sanguíneos/fisiopatología , Quitinasas/deficiencia , Metabolismo Energético/genética , Femenino , Mucosa Gástrica/irrigación sanguínea , Mucosa Gástrica/metabolismo , Gastritis Atrófica/metabolismo , Gastritis Atrófica/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , Transcripción GenéticaRESUMEN
BACKGROUND: Matrix metalloproteinase-14 (MMP-14) has been considered to play an important role in invasion and metastasis of human solid tumor. AIM: The present study aimed to investigate the association of MMP-14 with overall survival in human gastric cancer. METHODS: Gastric cancer and adjacent normal specimens were collected from 205 patients who had not received neoadjuvant chemotherapy. MMP-14 expression was investigated by immunohistochemistry assay and staining evaluation results were analyzed statistically in relation to overall survival of patients. RESULTS: MMP-14 expression proved to be increased in gastric cancer compared with that in normal tissues. It was also proved that MMP-14 expression was associated with tumor invasion, metastasis, and TNM stage while no correlations were detected between MMP-14 expression and age, sex, differentiation status, or Lauren's classification. Moreover, patients with gastric cancer of MMP-14-positive expression tend to have worse overall survival compared with those with MMP-14 negative expression. CONCLUSIONS: The present study confirmed the over-expression of MMP-14 in human gastric cancer and its association with tumor progression. It also provided the first evidence that MMP-14 expression in gastric cancer was an independent negative prognostic factor of patients.
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Gastritis Atrófica/enzimología , Metaloproteinasa 14 de la Matriz/metabolismo , Neoplasias Gástricas/enzimología , Neoplasias Gástricas/mortalidad , Anciano , Biomarcadores/metabolismo , China/epidemiología , Femenino , Gastritis Atrófica/patología , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Estómago/patología , Neoplasias Gástricas/patologíaRESUMEN
BACKGROUND AND AIM: Histamine plays important physiological roles in upper gastrointestinal tract and acts via the H2 receptor. A polymorphism -1018 G>A (rs2067474) was identified in an enhancer element of the HRH2 promoter. We attempted to clarify the associations of this polymorphism with the progression of gastric mucosal atrophy. METHODS: Gastric mucosa samples were obtained from 398 subjects with no malignancies. The rs2067474 genotype was determined by PCR-SSCP method. The degree of gastritis was assessed in 366 subjects and serum pepsinogen (PG) I/II levels were measured in 108 subjects. The subjects with atrophy score higher or equal to 2 and metaplasia score higher or equal to1 were classified into the severe atrophic gastritis group (SA group). RESULTS: The -1018G>A minor allele frequencies in SA and non-SA groups were 8.02% and 13.3%, respectively (p=0.057). The -1018 GG homozygote had a significantly high risk for gastric mucosal atrophy (OR: 2.03, 95%CI: 1.03-4.01, p=0.042). In H. pylori positive subjects, GG homozygote was a more significant risk factor for gastric mucosal atrophy (OR: 2.32, 95%CI: 1.12-4.81, p=0.023). In addition, in the subjects older than 60 years, GG homozygote had also a significant risk for gastric mucosal atrophy (OR: 2.63, 95%CI: 1.15-6.00, p=0.022). In -1018 GG homozygote, PG I/II ratio was significantly lower in H. pylori positive than negative subjects and was significantly decreased with age (p=0.0032 by ANOVA), whereas it was not in the A carrier. CONCLUSIONS: Our results suggest that HRH2 -1018 GG homozygote is a risk factor for the severity of gastric mucosal atrophy under the influence of H. pylori infection, especially in older subjects.
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Gastritis Atrófica/genética , Polimorfismo Genético , Receptores Histamínicos H2/genética , Adulto , Factores de Edad , Anciano , Femenino , Mucosa Gástrica/patología , Gastritis Atrófica/enzimología , Gastritis Atrófica/microbiología , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Infecciones por Helicobacter/complicaciones , Infecciones por Helicobacter/enzimología , Helicobacter pylori , Heterocigoto , Homocigoto , Humanos , Masculino , Persona de Mediana Edad , Pepsinógeno A/sangre , Polimorfismo Conformacional Retorcido-Simple , Índice de Severidad de la EnfermedadRESUMEN
In a prospective study the risk of subsequent gastric cancer (GC) was assessed in persons aged 45-69 over 5 years after the initial testing with a set of serological tests (pepsinogen I, pepsinogen II, gastrin-17, antibodies to Helicobacter pylori). The presence of gastric atrophy markers was a significant predictor of GC in the forthcoming years. Non-invasive techniques may be used in the formation of high-risk groups, followed by GC active surveillance.
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Anticuerpos Antibacterianos/sangre , Gastrinas/sangre , Gastritis Atrófica/sangre , Helicobacter pylori/inmunología , Pepsinógenos/sangre , Neoplasias Gástricas/sangre , Anciano , Biomarcadores/sangre , Estudios de Cohortes , Femenino , Gastritis Atrófica/enzimología , Gastritis Atrófica/inmunología , Gastritis Atrófica/microbiología , Infecciones por Helicobacter/sangre , Infecciones por Helicobacter/complicaciones , Humanos , Masculino , Persona de Mediana Edad , Pepsinógeno A/sangre , Pepsinógeno C/sangre , Estudios Retrospectivos , Pruebas Serológicas , Neoplasias Gástricas/enzimología , Neoplasias Gástricas/inmunología , Neoplasias Gástricas/microbiologíaRESUMEN
OBJECTIVE: There is debate whether infection with Helicobacter (H.) pylori, the main inducer of chronic atrophic gastritis (CAG), is a risk factor for cardiovascular disease and premature mortality. METHODS: Serological measurements of H. pylori infection and pepsinogen (PG) I and II were obtained in a population-based German cohort of 9953 older adults (50-74 years). Cox regression was employed to estimate hazard ratios (HR) and 95% confidence intervals (CI) for myocardial infarction, stroke, cardiovascular and all-cause mortality during five-year follow-up. RESULTS: According to serology, 4977 participants (51.9%) were infected with H. pylori (2604 with cytotoxin-associated gene A (cagA) strains) and 541 (5.7%) had CAG (PGI<70 ng/mL and PGI/PGII<3). During follow-up, 540 participants died (163 from cardiovascular causes), 170 experienced a primary myocardial infarction and 241 had a stroke. Neither cytotoxin-associated gene A (cagA) negative nor cagA positive H. pylori infections were associated with an increased risk for myocardial infarction, stroke or all-cause mortality. Intriguingly, infection with cagA positive H. pylori strains was inversely associated with cardiovascular mortality (HR, 0.62; CI: 0.41-0.94). No statistically significant associations were observed for the small group of participants with CAG, but point estimates of adjusted HRs for myocardial infarction, stroke and cardiovascular mortality were all below 1 (0.71, 0.59 and 0.65, respectively). CONCLUSIONS: Our results do not support the hypothesis that H. pylori infection or CAG are risk factors for cardiovascular disease or mortality and instead suggest an inverse relationship of cagA positive H. pylori infection with fatal cardiovascular events.
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Enfermedades Cardiovasculares/epidemiología , Gastritis Atrófica/epidemiología , Infecciones por Helicobacter/epidemiología , Helicobacter pylori/patogenicidad , Anciano , Biomarcadores/sangre , Enfermedades Cardiovasculares/microbiología , Enfermedades Cardiovasculares/mortalidad , Enfermedad Crónica , Femenino , Gastritis Atrófica/enzimología , Gastritis Atrófica/microbiología , Gastritis Atrófica/mortalidad , Alemania/epidemiología , Infecciones por Helicobacter/microbiología , Infecciones por Helicobacter/mortalidad , Humanos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/epidemiología , Pepsinógeno A/sangre , Pepsinógeno C/sangre , Modelos de Riesgos Proporcionales , Medición de Riesgo , Factores de Riesgo , Accidente Cerebrovascular/epidemiología , Factores de TiempoRESUMEN
AIM: To investigate the association between Ser326Cys human oxoguanine glycosylase 1 (hOGG1) polymorphism and atrophic gastritis and gastric cancer after Helicobacter pylori (H. pylori) eradication. METHODS: A total of 488 subjects (73 patients with gastric cancer, 160 with atrophic gastritis after H. pylori eradication and 255 controls) were prospectively collected. Polymerase chain reaction-restriction fragment length polymorphism analysis was performed to distinguish hOGG1 Ser326Cys polymorphism. Statistical analysis was conducted by two-sample t test for continuous variables and χ(2) test for categorical variables. Logistic regression models were used to find the risk factors for gastric cancer and atrophic gastritis. RESULTS: Neither the hOGG1 Ser/Cys nor the Cys/Cys genotype was associated with gastric cancer. Compared with the Ser/Ser genotype, odds ratio (OR) for Ser/Cys was 0.96, (95% CI: 0.51-1.84) and OR for Cys/Cys was 1.1 (95% CI: 0.48-2.1). No association was detected between hOGG1 polymorphism and Lauren type of gastric cancer (P = 0.61) either. However, Ser/Cys and Cys/Cys were significantly associated with atrophic gastritis with OR: 1.76 for Ser/Cys (95% CI: 1.03-3.0) and 2.38 for Cys/Cys (95% CI: 1.34-4.23). After controlling for age, gender, smoking and alcohol, there were still significant associations with OR: 2.05 for Ser/Cys (95% CI: 1.14-3.68) and 2.76 for Cys/Cys (95% CI: 1.47-5.18). CONCLUSION: HOGG1 polymorphisms (Cys/Cys and Ser/Cys) are associated with atrophic gastritis. No significant association is detected between hOGG1 polymorphisms (Cys/Cys or Ser/Cys) and gastric cancer.
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ADN Glicosilasas/genética , Gastritis Atrófica/genética , Infecciones por Helicobacter/tratamiento farmacológico , Polimorfismo Genético , Neoplasias Gástricas/genética , Adulto , Anciano , Estudios de Casos y Controles , Femenino , Gastritis Atrófica/enzimología , Gastritis Atrófica/patología , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Neoplasias Gástricas/enzimología , Neoplasias Gástricas/patologíaRESUMEN
BACKGROUND: Gastric atrophy caused by Helicobacter pylori (H. pylori) infection is a risk factor for gastric cancer. We aimed to evaluate the relationship between gastric cancer risk and tumor markers in the general population. MATERIALS AND METHODS: A total of 688 volunteers were examined to test their serum pepsinogen (PG) levels and anti-H. pylori antibodies, in addition to a total of 22 serum tumor markers. The participants were classified into four groups according to their anti-H. pylori antibody and serum PG serological status. Accordingly, groups A and D were negative, whereas groups B and C were positive for anti-H. pylori antibodies; and groups A and B were normal, whereas groups C and D were abnormal for serum PG levels. All the blood examination results were statistically evaluated using Student's t-test among these groups. RESULTS: There were 424, 202, 50, and 12 individuals in groups A, B, C, and D, respectively. Because of the small number of participants in groups C and D, we combined these two groups. Compared to the normal group (A), a statistically significant higher in adenosine deaminase level was found in group C+D (p=0.01). CONCLUSION: This result supports a previous study indicating that adenosine deaminase is involved in the regulatory system of chronic atrophic gastritis and gastric cancer risk.
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Adenosina Desaminasa/sangre , Neoplasias Gástricas/enzimología , Adenosina Desaminasa/fisiología , Adulto , Anciano , Enfermedad Crónica , Femenino , Gastritis Atrófica/enzimología , Gastritis Atrófica/etiología , Humanos , Masculino , Persona de Mediana Edad , Pepsinógeno A/sangre , Factores de Riesgo , Neoplasias Gástricas/etiologíaRESUMEN
The lipid peroxidation state and the system functioning of antioxidant protection in parietal cells under rat chronic atrophic gastritis development was investigated. It was detected that the compensatory increase of superoxide dismutase and catalase activity did not affect the lipoperoxidation process and this resulted in accumulation of toxic TBA reactive substances and diene conjugates during the whole stages of the experimental pathology development. It was shown that the reserved power of the glutathione antioxidant system is sufficient to provide adoptable response in the acute period of the disease owing to increasing intracellular found of the reduced glutathione, but it is insufficient to prevent its decreasing in parietal cells in case of the chronic atrophic gastritis development. Our findings suggest that glutathione system is involved in processes of gastric atrophy. The obtained results testify about considerable system dysfunctions of lipid peroxidation and the antioxidant protection in processes of the rat experimental atrophic gastritis development.
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Catalasa/metabolismo , Gastritis Atrófica/enzimología , Glucosafosfato Deshidrogenasa/metabolismo , Glutatión/metabolismo , Superóxido Dismutasa/metabolismo , Administración Oral , Animales , Antioxidantes/análisis , Enfermedad Crónica , Ácido Desoxicólico/administración & dosificación , Ácido Desoxicólico/efectos adversos , Modelos Animales de Enfermedad , Gastritis Atrófica/inducido químicamente , Glutatión Peroxidasa/metabolismo , Glutatión Reductasa/metabolismo , Glutatión Transferasa/metabolismo , Peroxidación de Lípido , Masculino , Células Parietales Gástricas/enzimología , Ratas , Salicilato de Sodio/administración & dosificación , Salicilato de Sodio/efectos adversos , Tiobarbitúricos/análisisRESUMEN
AIM: To study the value of serum biomarker tests to differentiate between patients with healthy or diseased stomach mucosa: i.e. those with Helicobacter pylori (H pylori) gastritis or atrophic gastritis, who have a high risk of gastric cancer or peptic ulcer diseases. METHODS: Among 162 Japanese outpatients, pepsinogen I (Pg I) and II (Pg II) were measured using a conventional Japanese technique, and the European GastroPanel examination (Pg I and Pg II, gastrin-17 and H pylori antibodies). Gastroscopy with gastric biopsies was performed to classify the patients into those with healthy stomach mucosa, H pylori non-atrophic gastritis or atrophic gastritis. RESULTS: Pg I and Pg II assays with the GastroPanel and the Japanese method showed a highly significant correlation. For methodological reasons, however, serum Pg I, but not Pg II, was twice as high with the GastroPanel test as with the Japanese test. The biomarker assays revealed that 5% of subjects had advanced atrophic corpus gastritis which was also verified by endoscopic biopsies. GastroPanel examination revealed an additional seven patients who had either advanced atrophic gastritis limited to the antrum or antrum-predominant H pylori gastritis. When compared to the endoscopic biopsy findings, the GastroPanel examination classified the patients into groups with "healthy" or "diseased" stomach mucosa with 94% accuracy, 95% sensitivity and 93% specificity. CONCLUSION: Serum biomarker tests can be used to differentiate between subjects with healthy and diseased gastric mucosa with high accuracy.
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Gastritis Atrófica/sangre , Gastritis Atrófica/diagnóstico , Gastritis/sangre , Estómago/fisiología , Adulto , Anciano , Biopsia , Diagnóstico Diferencial , Gastrinas/sangre , Gastritis/enzimología , Gastritis/microbiología , Gastritis/patología , Gastritis Atrófica/enzimología , Gastritis Atrófica/patología , Infecciones por Helicobacter/complicaciones , Infecciones por Helicobacter/enzimología , Infecciones por Helicobacter/patología , Helicobacter pylori , Humanos , Japón , Persona de Mediana Edad , Pacientes Ambulatorios , Pepsinógeno A/sangre , Pepsinógeno C/sangre , Úlcera Péptica/epidemiología , Prevalencia , Valores de Referencia , Factores de Riesgo , Neoplasias Gástricas/epidemiología , Adulto JovenRESUMEN
In India, the role of host genetic factors is poorly studied for Helicobacter pylori associated diseases. Therefore, we evaluated the association of functionally relevant COX-2 gene polymorphisms (-765 G>C and +8473 T>C) in gastritis and precancerous lesions susceptibility. After upper GI endoscopy, 130 rapid urease test positive patients with non-ulcer dyspepsia, also showed positivity for H. pylori using modified Geimsa staining and anti-CagA IgG serology were included. All patients and 260 asymptomatic controls were genotyped for COX-2 variations using PCR-RFLP. COX-2 -765 (GC+CC) genotypes, -765 C allele, +8473 CC genotype, +8473 (TC+CC) genotypes, +8473 C allele, and variant haplotypes imparted high risk for gastritis (P = 0.036, OR = 1.82; P = 0.007, 1.92; P = 0.025, OR = 2.13; P = 0.017, OR = 1.80; P = 0.017, OR = 1.45; P = 0.010, OR = 2.40; P = 0.023, OR = 1.50 and P = 0.012, OR = 2.20 folds, respectively). In contrast, COX-2 -765 C allele carriers had low risk for lymphocyte (P = 0.020, OR = 0.35), plasma cell infiltrations (P = 0.016, OR = 0.33), and gastric atrophy (GA) development (P = 0.019, OR = 0.35). In conclusion, COX-2 variant allele/genotype/haplotype carriers may be at high risk for gastritis. However, COX-2 -765 C allele carriers may be at low risk for GA development.
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Ciclooxigenasa 2/genética , Gastritis Atrófica/enzimología , Gastritis Atrófica/genética , Infecciones por Helicobacter/enzimología , Infecciones por Helicobacter/genética , Helicobacter pylori/patogenicidad , Polimorfismo Genético , Adulto , Gastritis Atrófica/epidemiología , Gastritis Atrófica/patología , Predisposición Genética a la Enfermedad , Genotipo , Haplotipos , Infecciones por Helicobacter/epidemiología , Infecciones por Helicobacter/patología , Humanos , India/epidemiología , Masculino , Persona de Mediana Edad , Lesiones Precancerosas/patologíaRESUMEN
BACKGROUND & OBJECTIVE: The expression of human telomerase reverse transcriptase (hTERT) is positively correlated to the activity of telomerase. Alternative splicing exists in the transcription of hTERT and special splicing patterns may change during tumor progression. This study was to reveal the changes of hTERT alterative splicing pattern in gastric carcinogenesis. METHODS: Three alternative splicing sites (alpha, beta, gamma) were selected to design primers. The expression of eight hTERT alternative splicing variants (ASVs) in 18 specimens of normal gastric mucosa, 20 specimens of precancerous lesions and 19 specimens of gastric cancer was detected by semi-nested reverse transcription-polymerase chain reaction (RT-PCR). The expression of beta site-remaining ASV (beta+ hTERT mRNA) in precancerous lesions and gastric cancer tissues was detected by SYBR Green real-time RT-PCR. RESULTS: The positive rate of alpha+beta+gamma+ hTERT mRNA was significantly higher in gastric cancer than in precancerous lesions and normal mucosa (94.7% vs. 40.0% and 0, P<0.05). The positive rates of other ASVs were not different among the three groups. The positive rates of beta-deletion ASV were 72.2% in normal mucosa, 95.0% in precancerous lesions and 100.0% in gastric cancer. The positive rates of beta+ hTERT mRNA (including alpha+beta+gamma+ hTERT mRNA, alpha-deletion ASV, gamma-deletion ASV, alphagamma-deletion ASV) were 11.1% in normal mucosa, 40.0% in precancerous lesions and 94.7% in gastric cancer (P<0.05). The mRNA level of beta+ hTERT was 6.99 times higher in gastric cancer than in precancerous lesions. CONCLUSIONS: hTERT alternative splicing pattern changes during gastric carcinogenesis. beta+ hTERT mRNA is expressed increasingly during gastric carcinogenesis and may provide useful information for diagnosis of gastric cancer or precancerous lesions.
Asunto(s)
Empalme Alternativo , Sitios de Empalme de ARN/genética , Neoplasias Gástricas/enzimología , Telomerasa/biosíntesis , Mucosa Gástrica/enzimología , Gastritis Atrófica/enzimología , Gastritis Atrófica/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Lesiones Precancerosas/enzimología , Lesiones Precancerosas/genética , ARN Mensajero/metabolismo , Neoplasias Gástricas/genética , Telomerasa/genéticaRESUMEN
BACKGROUND: The relationship between Helicobacter pylori (HP) infection and body mass index (BMI) is controversial. Several reports have indicated that eradication of HP infection induces an increase in BMI. In contrast, epidemiological case-control studies have failed to show an association between HP infection and BMI. Therefore, we investigated whether HP and atrophic gastritis (AG) were associated with BMI. METHODS: A total of 617 individuals were recruited for the measurements of BMI, serum leptin, pepsinogens (PGs) I and II, and IgG antibody to HP (HP-IgG). BMI and leptin of the subjects were compared when the subjects were stratified by HP-IgG and PGs. RESULTS: The subjects were divided into AG-positive and AG-negative groups according to PGs (AG-positive: PG I < or = 70 ng/ml and PG I/II ratio < or =3.0). BMI after adjusting for sex and age was significantly lower in the AG-positive group than in the AG-negative group (23.47 +/- 3.05 vs. 24.18 +/- 3.25, P = 0.010). When the subjects were divided into two groups according to HP-IgG, BMI tended to be lower in the HP-IgG-positive group, though the difference was not large. When the subjects were divided into four groups for different combinations of AG and HP-IgG, BMI was the lowest in the AG-positive and HP-IgG-negative group. CONCLUSIONS: BMI was associated with AG, as diagnosed by PGs, but not with HP infection status. These results mean that HP infection affects BMI via atrophic gastritis.
Asunto(s)
Anticuerpos Antibacterianos/sangre , Índice de Masa Corporal , Gastritis Atrófica/sangre , Helicobacter pylori/inmunología , Inmunoglobulina G/sangre , Anciano , Anciano de 80 o más Años , Pueblo Asiatico , Estudios de Casos y Controles , Estudios de Cohortes , Femenino , Gastritis Atrófica/enzimología , Gastritis Atrófica/etnología , Humanos , Japón , Leptina/sangre , Masculino , Persona de Mediana Edad , Pepsinógeno A/sangre , Pepsinógeno C/sangreRESUMEN
BACKGROUND AND AIM: Induction of inducible nitric oxide synthase (iNOS) may be involved in carcinogenesis of the stomach, because nitric oxide (NO) derived from iNOS can exert DNA damage and post-transcriptional modification of target proteins. In the present study, we investigated the correlation between endoscopic findings and iNOS mRNA expression/NO-modified proteins in the gastric mucosa. METHODS: Fifty patients were prospectively selected from subjects who underwent upper gastrointestinal chromoendoscopy screening for abdominal complaints. The Helicobacter pylori (H. pylori) status of patients was determined by anti-H. pylori IgG antibody levels. We classified the mucosal area of the fundus as F0, fine small granules; F1, edematous large granules without a sulcus between granules; F2, reduced-size granules with a sulcus between granules; and F3, irregular-sized granules with extended sulcus between granules. Gastritis was graded using the visual analog scale of the Updated Sydney System. The expression of interleukin (IL)-8 and iNOS mRNA was assayed in gastric biopsy specimens by reverse transcription-polymerase chain reaction. NO-modified proteins were analyzed by Western blotting using novel monoclonal antibodies against nitrotyrosine. RESULTS: A total of 91.7% (11/12) of the F0 group was H. pylori-negative, whereas 94.7% (36/38) of the F1-3 groups was H. pylori-positive. Spearman's analysis showed good correlation between the endoscopic grading and the score of chronic inflammation (r=0.764) and glandular atrophy (r=0.751). The expression of IL-8 mRNA was significantly increased in F1, F2, and F3 cases compared with the F0 group, with no significant differences among them. iNOS mRNA was significantly increased in the F3 group compared with the other groups, with increased nitration of tyrosine residues of proteins. CONCLUSION: The proposed classification by chromoendoscopy is useful for screening patients for atrophic and iNOS-expressing gastric mucosa with NO-modified proteins in H. pylori-associated atrophic gastric mucosa.
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Mucosa Gástrica/enzimología , Gastritis Atrófica/enzimología , Infecciones por Helicobacter/microbiología , Helicobacter pylori/patogenicidad , Óxido Nítrico Sintasa de Tipo II/análisis , Tirosina/análogos & derivados , Anticuerpos Antibacterianos/sangre , Atrofia , Biomarcadores/análisis , Mucosa Gástrica/microbiología , Mucosa Gástrica/patología , Gastritis Atrófica/microbiología , Gastritis Atrófica/patología , Gastroscopía/métodos , Infecciones por Helicobacter/enzimología , Infecciones por Helicobacter/patología , Helicobacter pylori/inmunología , Humanos , Interleucina-8/análisis , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo II/genética , Estudios Prospectivos , Proteínas/metabolismo , ARN Mensajero/análisis , Índice de Severidad de la Enfermedad , Tirosina/análisisRESUMEN
Helicobacter pylori infection has been suggested to stimulate expression of the NADPH oxidase 1 (Nox1)-based oxidase system in guinea pig gastric epithelium, whereas Nox1 mRNA expression has not yet been documented in the human stomach. PCR of human stomach cDNA libraries showed that Nox1 and Nox organizer 1 (NOXO1) messages were absent from normal stomachs, while they were specifically coexpressed in intestinal- and diffuse-type adenocarcinomas including signet-ring cell carcinoma. Immunohistochemistry showed that Nox1 and NOXO1 proteins were absent from chronic atrophic gastritis (15 cases), adenomas (4 cases), or surrounding tissues of adenocarcinomas (45 cases). In contrast, Nox1 and its partner proteins were expressed in intestinal-type adenocarcinomas (19/21 cases), diffuse-type adenocarcinomas (15/15 cases), and signet-ring cell carcinomas (9/9 cases). Confocal microscopy revealed that Nox1, NOXO1, Nox activator 1, and p22(phox) were predominantly associated with Golgi apparatus in these cancer cells, while diffuse-type adenocarcinomas also contained cancer cells having Nox1 and its partner proteins in their nuclei. Nox1-expressing cancer cells exhibited both gastric and intestinal phenotypes, as assessed by expression of mucin core polypeptides. Thus, the Nox1-base oxidase may be a potential marker of neoplastic transformation and play an important role in oxygen radical- and inflammation-dependent carcinogenesis in the human stomach.
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NADPH Oxidasas/genética , NADPH Oxidasas/metabolismo , Neoplasias Gástricas/enzimología , Neoplasias Gástricas/genética , Proteínas Adaptadoras Transductoras de Señales , Proteínas Adaptadoras del Transporte Vesicular/genética , Proteínas Adaptadoras del Transporte Vesicular/metabolismo , Adenocarcinoma/enzimología , Adenocarcinoma/genética , Adenoma/enzimología , Adenoma/genética , Animales , Carcinoma de Células en Anillo de Sello/enzimología , Carcinoma de Células en Anillo de Sello/genética , Radicales Libres/metabolismo , Mucosa Gástrica/enzimología , Gastritis Atrófica/enzimología , Gastritis Atrófica/genética , Regulación Enzimológica de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Cobayas , Infecciones por Helicobacter/complicaciones , Helicobacter pylori/patogenicidad , Humanos , Inmunohistoquímica , NADPH Oxidasa 1 , ARN Mensajero/genética , ARN Mensajero/metabolismo , ARN Neoplásico/genética , ARN Neoplásico/metabolismo , Neoplasias Gástricas/etiología , Neoplasias Gástricas/patologíaRESUMEN
Chronic atrophic gastritis (CAG), a precursor of intestinal gastric cancer, is mostly ascertained noninvasively by serum pepsinogens in epidemiologic studies. However, serological definitions vary widely. We aimed to investigate the impact of this variation on estimated prevalence of CAG and its association with its main risk factors, age and Helicobacter pylori infection. Serum pepsinogen I and II and antibodies against H. pylori were measured by ELISA among 9,444 women and men aged 50-74 years in a population-based cohort study in Saarland/Germany. Application of the various definitions resulted in a wide range of prevalence estimates of CAG prevalence (2.1%-8.2%, with an outlier of 18.8% for one particular definition) and its associations with age and H. pylori infection (age adjusted odds ratios, OR, for CagA positive H. pylori infection: 0.98-4.48). Definitions of CAG based on both pepsinogen I and the pepsinogen I/II ratio or on the pepsinogen I/II ratio only revealed much clearer associations with both age and H. pylori infection than definitions of CAG based on pepsinogen I only (ORs for H. pylori infection: 1.45-4.48 and 0.86-1.30, respectively). Epidemiologic findings on CAG lack comparability due to the heterogeneity in serologic definitions of CAG. The association of age and H. pylori infection with CAG may be strongly underestimated in studies in which CAG is defined by pepsinogen I only.