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1.
BMC Med Genet ; 21(1): 205, 2020 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-33066747

RESUMO

BACKGROUND: CpG methylation of tumor suppressor genes occurs in the early stage of carcinogenesis. Detecting risk factors for aberrant CpG methylation is clinically important for predicting cancer development. DNA methyltransferase (DNMT) 3a is considered to play critical roles in the DNA methylation process during pathogenesis. In this study, we evaluated the association between DNMT3A polymorphisms (rs6733868 and rs13428812) and CpG methylation status in non-cancerous gastric mucosa. METHODS: We determined the DNMT3A genotype and CpG methylation status of 4 genes (p14ARF, p16INK4a, DAPK, and CDH1) in 510 subjects without gastric cancer. Helicobacter pylori (HP) infection status was determined by the rapid urease test, urea breath test, speculum examination, or serum antibody test. We determined the DNMT3A genotype using polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP). CpG methylation status was determined by methylation-specific polymerase chain reaction (MSP). When the methylated band was stronger than 10 ng/µL according to the DNA marker, we judged CpG island hypermethylation (CIHM) to be present. Associations between genotypes and susceptibilities were assessed by logistic regression analysis. RESULTS: The minor allele frequencies of both polymorphisms (rs6733868 and rs13428812) were lower in the CpG methylated groups of each of the 4 genes (p14ARF, p16INK4a, DAPK, and CDH1). Using a dominant genetic model, rs6733868 was significantly associated with the hypermethylation of each gene, whereas rs13428812 was associated with the methylation of 3 genes (all except p14ARF). When low-CIHM was defined as 1 or 2 CpG islands methylated and high-CIHM was defined as 3 or more CpG islands methylated, carrying the minor allele of rs6733868 was associated with both decreased low- and high-CIHM, and that of rs13428812 also was associated with a decrease. Comparing low-CIHM with high-CIHM, carrying the minor alleles of rs6733868 or rs13428812 was related to decreased susceptibility to high-CIHM. In HP-infected subjects, carrying the minor alleles of rs6733868 or rs13428812 had a significantly greater association with decreased susceptibility to high-CIHM. CONCLUSIONS: Our study indicates that polymorphisms of DNMT3A are associated with the accumulation of gene methylation in gastric mucosa. Carrying the minor alleles of rs6733868 or rs13428812 inhibits aberrant gene methylations, which are typically enhanced by HP infection.


Assuntos
Ilhas de CpG/genética , DNA (Citosina-5-)-Metiltransferases/genética , Metilação de DNA , Mucosa Gástrica/metabolismo , Polimorfismo de Nucleotídeo Único , Idoso , Alelos , Antígenos CD/genética , Caderinas/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Proteínas Quinases Associadas com Morte Celular/genética , Feminino , Mucosa Gástrica/microbiologia , Frequência do Gene , Genótipo , Infecções por Helicobacter/diagnóstico , Infecções por Helicobacter/microbiologia , Helicobacter pylori/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade
2.
Chemosphere ; 254: 126904, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32957297

RESUMO

Estimating bioaccessible content of mercury in soils is essential in evaluating risks that contaminated soils pose. In this study, soil samples spiked with HgCl2 through adsorption were used to test the effects of liming, soil organic matter, soil depth, and Hg concentration on the following bioaccessibility tests: dilute nitric acid at room temperature, dilute nitric acid at body temperature, Simplified Bioaccessibility Extraction Test (SBET) method, and gastric phase of the In vitro Gastrointestinal (IVG) protocol. Soil and sediment samples from Descoberto, Minas Gerais (Brazil), a city with a well-known record of Hg contamination from artisanal mining, were subjected to these bioaccessibility tests for the first time, and the different methods of estimating bioaccessible content were compared. Bioaccessible fractions in spiked samples ranged from 10% to 60%, and this high bioaccessibility was due to the highly soluble species of Hg and the short time under adsorption. In general, clay and organic matter decreased bioaccessible content. Although the soil in Descoberto is undoubtedly polluted, mercury bioaccessibility in that area is low. In general, dilute nitric acid estimated higher bioaccessible content in soil samples, whereas the SBET method estimated higher bioaccessible content in sediment samples. In multivariate analysis, two groups of bioaccessibility tests arise: one with the two nitric acid tests, and the other with SBET and the gastric phase of the IVG protocol. The addition of pepsin and glycine in the last two tests suggests a more reliable test for assessing mercury bioaccessibility.


Assuntos
Argila/química , Substâncias Húmicas/análise , Mercúrio/análise , Mineração , Poluentes do Solo/análise , Solo/química , Adsorção , Disponibilidade Biológica , Brasil , Cidades , Mucosa Gástrica/metabolismo , Humanos , Mucosa Intestinal/metabolismo , Mercúrio/metabolismo , Modelos Biológicos , Ácido Nítrico/química , Poluentes do Solo/metabolismo
3.
Life Sci ; 260: 118412, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32926924

RESUMO

AIMS: Rat models of duodenogastric reflux have been used to study gastric stump cancer (GSC), but the underlying molecular mechanisms are poorly understood. Unlike rats, mice can be genetically modified, providing a superior model for studying the molecular mechanisms underlying GSC development, which is associated with duodenogastric reflux. This study aimed at developing a mouse model of duodenogastric reflux. MAIN METHOD: C57BL/6 mice were randomly assigned to the control (n = 6), sham operation (n = 9), or gastrojejunostomy group (n = 12). Mice were sacrificed at 1, 3, and 6 months after surgery. Stomach tissue was stained with hematoxylin and eosin. Lesions were classified as chronic inflammation, intestinal metaplasia, or atypical hyperplasia. KEY FINDINGS: Nine mice underwent gastrojejunostomy without mortality. The animals in the gastrojejunostomy group exhibited chronic inflammation at 1, 3, and 6 months after surgery, showing intestinal metaplasia (n = 2) and atypical hyperplasia (n = 1) at 3 months and intestinal metaplasia (n = 2) and atypical hyperplasia (n = 2) at 6 months. The mice in the control group did not exhibit chronic inflammation or intestinal metaplasia, whereas those in the sham operation group exhibited chronic inflammation at 1, 3, and 6 months after surgery, without intestinal metaplasia or atypical hyperplasia. Intestinal metaplasia or atypical hyperplasia were more common in the gastrojejunostomy group than in the sham operation group (p = 0.012). SIGNIFICANCE: A duodenogastric reflux mouse model can be created using gastrojejunostomy without gastrectomy.


Assuntos
Modelos Animais de Doenças , Refluxo Duodenogástrico/patologia , Mucosa Gástrica/patologia , Hiperplasia/patologia , Inflamação/patologia , Animais , Refluxo Duodenogástrico/cirurgia , Gastrectomia , Mucosa Gástrica/imunologia , Mucosa Gástrica/metabolismo , Hiperplasia/imunologia , Hiperplasia/metabolismo , Inflamação/imunologia , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL
4.
PLoS One ; 15(9): e0239436, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32966332

RESUMO

An accurate description of trophic interactions is crucial to understand ecosystem functioning and sustainably manage marine ecosystems exploitation. Carbon and nitrogen stable isotopes were coupled with stomach content analyses to investigate whiting (Merlangius merlangus, Linnaeus, 1758) feeding behavior in the Eastern English Channel and Southern North Sea. Whiting juveniles and adults were sampled in autumn and winter to investigate both ontogenetic and seasonal changes. In addition, queen scallops (Aequipecten opercularis) samples were collected along with fish to be used as isotopic benthic baseline. Results indicated an ontogenetic diet change from crustaceans to fish and cephalopods. In autumn, δ15N values generally increased with fish size while in winter, a decrease of δ15N values with fish size was observed, as a potential result of spatial variation in baseline δ15N values. In winter, a nutrient-poor period, an increase in feeding intensity was observed, especially on the copepod Temora longicornis. This study provides further insights into whiting trophic ecology in relation to ontogenetic and seasonal variations, and it confirms the importance of combining several trophic analysis methods to understand ecosystem functioning.


Assuntos
Dieta , Gadiformes/crescimento & desenvolvimento , Estações do Ano , Animais , Cadeia Alimentar , Gadiformes/metabolismo , Mucosa Gástrica/metabolismo , Mar do Norte
5.
PLoS One ; 15(8): e0237215, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32797106

RESUMO

In 1978, Thomas J. Sorensen defended a thesis in chemical engineering at the University of California, Berkeley, where he proposed an extensive model of glucose-insulin control, model which was thereafter widely employed for virtual patient simulation. The original model, and even more so its subsequent implementations by other Authors, presented however a few imprecisions in reporting the correct model equations and parameter values. The goal of the present work is to revise the original Sorensen's model, to clearly summarize its defining equations, to supplement it with a missing gastrio-intestinal glucose absorption and to make an implementation of the revised model available on-line to the scientific community.


Assuntos
Glucose/metabolismo , Insulina/metabolismo , Algoritmos , Glicemia/metabolismo , Absorção Gástrica , Mucosa Gástrica/metabolismo , Humanos , Absorção Intestinal , Modelos Biológicos
6.
Am J Gastroenterol ; 115(10): 1707-1715, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32852340

RESUMO

INTRODUCTION: Proton pump inhibitors (PPIs) increase the risk for enteric infections that is likely related to PPI-induced hypochlorhydria. Although the impact of acid suppression on severe acute respiratory syndrome coronavirus 2 is unknown thus far, previous data revealed that pH ≤3 impairs the infectivity of the similar severe acute respiratory syndrome coronavirus 1. Thus, we aimed to determine whether use of PPIs increases the odds for acquiring coronavirus disease 2019 (COVID-19) among community-dwelling Americans. METHODS: From May 3 to June 24, 2020, we performed an online survey described to participating adults as a "national health survey." A multivariable logistic regression was performed on reporting a positive COVID-19 test to adjust for a wide range of confounding factors and to calculate adjusted odds ratios (aORs) and 95% confidence intervals (CIs). RESULTS: Of 53,130 participants, 3,386 (6.4%) reported a positive COVID-19 test. In regression analysis, individuals using PPIs up to once daily (aOR 2.15; 95% CI, 1.90-2.44) or twice daily (aOR 3.67; 95% CI, 2.93-4.60) had significantly increased odds for reporting a positive COVID-19 test when compared with those not taking PPIs. Individuals taking histamine-2 receptor antagonists were not at elevated risk. DISCUSSION: We found evidence of an independent, dose-response relationship between the use of antisecretory medications and COVID-19 positivity; individuals taking PPIs twice daily have higher odds for reporting a positive test when compared with those using lower-dose PPIs up to once daily, and those taking the less potent histamine-2 receptor antagonists are not at increased risk. These findings emphasize good clinical practice that PPIs should only be used when indicated at the lowest effective dose, such as the approved once-daily label dosage of over-the-counter and prescription PPIs. Further studies examining the association between PPIs and COVID-19 are needed.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/epidemiologia , Ácido Gástrico/metabolismo , Inquéritos Epidemiológicos/estatística & dados numéricos , Pneumonia Viral/epidemiologia , Inibidores da Bomba de Prótons/efeitos adversos , Adolescente , Adulto , Betacoronavirus/isolamento & purificação , Técnicas de Laboratório Clínico/estatística & dados numéricos , Fatores de Confusão Epidemiológicos , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/fisiopatologia , Infecções por Coronavirus/virologia , Prescrições de Medicamentos/estatística & dados numéricos , Feminino , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/metabolismo , Refluxo Gastroesofágico/tratamento farmacológico , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/fisiologia , Azia/tratamento farmacológico , Humanos , Concentração de Íons de Hidrogênio/efeitos dos fármacos , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/fisiopatologia , Pneumonia Viral/virologia , Adulto Jovem
7.
Mol Immunol ; 126: 14-24, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32739720

RESUMO

Leucine-rich repeat-containing G-protein-coupled receptors (LGRs) form a subfamily of the large superfamily of G-protein-coupled receptors. LGRs can be divided into three groups. LGR2 from Drosophila melanogaster is involved in cuticle tanning (melanization and sclerotization). In this study, one LGR2 (MnLGR2) was identified from Macrobrachium nipponense. MnLGR2 has an open reading frame of 4515 bp encoding a protein with 1504 amino acids. MnLGR2 is comprised of a 7-transmembrane domain, 12 leucine-rich repeats, and 5 low-complexity regions. The highest expression level of MnLGR2 was observed in gills. The expression levels of MnLGR2 in gills and stomach could be regulated by bacterial challenge. Knockdown of MnLGR2 upregulated the expression of anti-microbial peptide (AMP) genes. Further study indicated that inhibition of AMP expression by MnLGR2 was through inhibition of relish-mediated AMP expression. In addition to the negative regulation of AMP expression, MnLGR2 participated in positive regulation of phenol oxidase (PO) activity and expression of proPO activating pathway-related genes (proPO-activating factor and proPO-activating enzymes). Therefore, MnLGR2 plays an important role in prawn innate immunity.


Assuntos
Proteínas de Artrópodes/metabolismo , Palaemonidae/fisiologia , Proteínas/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Transdução de Sinais/imunologia , Animais , Peptídeos Catiônicos Antimicrobianos/imunologia , Peptídeos Catiônicos Antimicrobianos/metabolismo , Proteínas de Artrópodes/genética , Proteínas de Artrópodes/imunologia , Mucosa Gástrica/metabolismo , Técnicas de Silenciamento de Genes , Brânquias/metabolismo , Interações entre Hospedeiro e Microrganismos/imunologia , Imunidade Inata , Muda/fisiologia , Monofenol Mono-Oxigenase/metabolismo , Palaemonidae/microbiologia , Proteínas/genética , Receptores Acoplados a Proteínas-G/genética , Staphylococcus aureus/imunologia , Fatores de Transcrição , Regulação para Cima/imunologia , Vibrio parahaemolyticus/imunologia , Vírus da Síndrome da Mancha Branca 1/imunologia
8.
Int J Nanomedicine ; 15: 4847-4858, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32764922

RESUMO

Background: Bisphosphonates have very low bioavailability and cause irritation of the esophagus and stomach. This study was planned to improve the oral bioavailability of ibandronate through the formation of a raft in the stomach. Bisphosphonate-induced irritation of the esophagus and stomach is prevented by the formation of a raft. Materials and Methods: The nanostructured raft was developed through the use of nanosized citrus pectin (NCP). The particle size of NCP was measured by zeta sizer and SEM. The percentage of NCP and the neutralization profile of raft was studied. The ibandronate, polymers, and the developed formulation were characterized by FTIR, XRD, TGA, and DSC. The release of ibandronate was studied in 0.1 N HCl, 0.5 N HCl, 1 N HCl, and simulated gastric fluid (SGF) and a cell viability study was performed using Caco-2 cells. The PPR5 formulation and Bonish 150 mg tablets were selected as test and reference formulations, respectively, for pharmacokinetic study. Twelve healthy albino rats were taken and divided into two groups using a Latin square crossover design, and the blood samples were collected for 24 hours. Results: The SEM image showed that the particle size of NCP was 159 nm. The raft of PPR5 showed 94% NCP and 45 minutes duration of neutralization. The FTIR and XRD showed chemical stability and a uniform distribution of ibandronate in the raft. The TGA and DSC indicated the thermal stability of formulation. The release of 99.87% ibandronate at 20 minutes was observed in the SGF. The values of C max for the reference and test formulations were 493±0.237 ng/mL and 653±0.097 ng/mL, respectively. The AUC(0-t) of the reference and test formulations was 3708.25±3.418 ng/mL.h and 6899.25±3.467 ng/mL.h, respectively. Conclusion: The NCP has been successfully prepared from citrus pectin and has shown effective porous raft formation. The bioavailability of the ibandronate from newly developed PPR5 was higher than the already marketed formulation.


Assuntos
Portadores de Fármacos/química , Mucosa Gástrica/metabolismo , Ácido Ibandrônico/farmacologia , Ácido Ibandrônico/farmacocinética , Administração Oral , Animais , Área Sob a Curva , Disponibilidade Biológica , Células CACO-2 , Humanos , Ácido Ibandrônico/administração & dosagem , Masculino , Pectinas/química , Ratos
9.
Life Sci ; 259: 118272, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32800836

RESUMO

AIM: Vanadium, a trace element found in food and water sources has been previous reported to attenuate ulcer formation without much insight into its mechanism of action. This study highlights the mechanism by which vanadium exhibits its gastro-protective activity. MAIN METHODS: Eighty male Wistar rats (80-100 g) were randomized into 8 equal groups. Groups 1 (control) and 2 (Ulcerated control) received water only, groups 3-8 received vanadium at 5, 10, 25, 50, 100 and 200 ppm respectively in their drinking water for ten weeks. Gastric ulcer was thereafter induced in groups (2-8) via ischaemia-reperfusion (IR) technique. The stomachs were excised for macroscopic examination, evaluation of mucous content, oxidative stress markers, hydrogen/potassium (H+/K+) and calcium (Ca++) ATPases activities plus expression of induced nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Vanadium at low doses inhibited IR induced gastric ulcer by 62.62% (10 ppm), 54.80% (25 ppm) and 43.50% (50 ppm). KEY FINDINGS: Low dose vanadium increased mucous content, superoxide dismutase, catalase, glutathione activities and nitrite concentrations compared to ulcerated control group. The observed increase in malondialdehyde, Ca++ and H+/K+ ATPase activities, iNOS and COX-2 expression following IR were significantly reduced by pretreatment with vanadium. SIGNIFICANCE: This study demonstrated that vanadium at low doses exhibit gastro-protective activities on IR induced gastric ulcer in rat model by inhibiting proton pump activities and decreasing expressions of iNOS and COX-2, thereby giving more insight into the protective action of vanadium.


Assuntos
Traumatismo por Reperfusão/tratamento farmacológico , Úlcera Gástrica/prevenção & controle , Vanádio/farmacologia , Animais , Catalase/metabolismo , Ciclo-Oxigenase 2/metabolismo , Mucosa Gástrica/metabolismo , Masculino , Malondialdeído/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Estresse Oxidativo , Bombas de Próton/efeitos dos fármacos , Ratos , Ratos Wistar , Reperfusão , Estômago/fisiologia , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/tratamento farmacológico , Superóxido Dismutase/metabolismo
10.
Toxicol Lett ; 333: 232-241, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32835834

RESUMO

Ochratoxin A (OTA) is a ubiquitous mycotoxin with potential nephrotoxic, hepatotoxic and immunotoxic effects. We previously demonstrated that OTA could cause mitochondrial function disturbance in GES-1 cells in vitro, which lead to the presumption that the glucose metabolism of GES-1 cells will be altered by OTA. Therefore in the present study, we explored the toxicity of OTA on glucose metabolism of GES-1 cells and the molecular mechanism. We found that OTA could induce aerobic glycolysis, evidenced shown by increase of glucose consumption, lactate production and cellular ATP concentration. We further detected expressions of GLUT1 and glycolytic enzymes including HK2, PFK1, PKM2 and LDHA as well as tricarboxylic acid (TCA) cycle-associated enzymes including IDH1, OGDH and CS. The results showed that expression of GLUT1 as well as the activities and expressions of HK2, PFK1 and LDHA were significantly increased while IDH1 and OGDH were reduced by OTA. As to PKM2, western blot showed that OTA could elevated the phospho-PKM2 Ser37 protein level and induce the nuclear accumulation of PKM2, which was further supported by immunofluorescence analyses, in addition, pyruvate kinase activity was reduced by OTA. In conclusion, these findings suggest that OTA exposure induces the metabolic shift from oxidative phosphorylation to aerobic glycolysis via regulating the activities and expressions of glycolysis and TCA-cycle associated molecules in GES-1 cells.


Assuntos
Metabolismo Energético/efeitos dos fármacos , Poluentes Ambientais/toxicidade , Células Epiteliais/efeitos dos fármacos , Mucosa Gástrica/efeitos dos fármacos , Glucose/metabolismo , Ocratoxinas/toxicidade , Linhagem Celular , Ciclo do Ácido Cítrico/efeitos dos fármacos , Células Epiteliais/metabolismo , Mucosa Gástrica/metabolismo , Glicólise/efeitos dos fármacos , Humanos , Fosforilação Oxidativa/efeitos dos fármacos
11.
Clin Nucl Med ; 45(10): 813-816, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32604111

RESUMO

Incidental tracer uptake on DOTATATE PET is increasingly encountered in clinical practice. We describe 3 patients with suspected or known neuroendocrine tumor who were found to have diffuse and intense stomach uptake on DOTATATE PET. All patients underwent esophagogastroduodenoscopy and/or endoscopic ultrasound; the cause of the stomach uptake was attributed to proton-pump inhibitor use, chronic gastritis, and gastrinoma, respectively. These 3 cases highlight that diffuse and intense stomach DOTATATE uptake can be a benign finding probably attributed to proton-pump inhibitor use, chronic gastritis, or gastrinoma.


Assuntos
Mucosa Gástrica/metabolismo , Tumores Neuroendócrinos/diagnóstico por imagem , Tumores Neuroendócrinos/metabolismo , Compostos Organometálicos/metabolismo , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Adulto , Idoso , Transporte Biológico , Difusão , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/patologia , Estômago/diagnóstico por imagem , Estômago/patologia
12.
Am J Physiol Endocrinol Metab ; 319(2): E330-E337, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32543942

RESUMO

Ghrelin is a predominantly stomach-derived peptide hormone with many actions including regulation of food intake, body weight, and blood glucose. Plasma ghrelin levels are robustly regulated by feeding status, with its levels increasing upon caloric restriction and decreasing after food intake. At least some of this regulation might be due to direct responsiveness of ghrelin cells to changes in circulating nutrients, including glucose. Indeed, oral and parental glucose administration to humans and mice lower plasma ghrelin. Also, dissociated mouse gastric mucosal cell preparations, which contain ghrelin cells, decrease ghrelin secretion when cultured in high ambient glucose. Here, we used primary cultures of mouse gastric mucosal cells in combination with an array of pharmacological tools to examine the potential role of changed intracellular oxidative stress in glucose-restricted ghrelin secretion. The antioxidants resveratrol, SRT1720, and curcumin all markedly increased ghrelin secretion. Furthermore, three different selective activators of Nuclear factor erythroid-derived-2-like 2 (Nrf2), a master regulator of the antioxidative cellular response to oxidative stress, increased ghrelin secretion. These antioxidant compounds blocked the inhibitory effects of glucose on ghrelin secretion. Therefore, we conclude that lowering oxidative stress within ghrelin cells stimulates ghrelin secretion and blocks the direct effects of glucose on ghrelin cells to inhibit ghrelin secretion.


Assuntos
Mucosa Gástrica/metabolismo , Grelina/metabolismo , Estresse Oxidativo/fisiologia , Animais , Antioxidantes/farmacologia , Células Cultivadas , Curcumina/farmacologia , Mucosa Gástrica/efeitos dos fármacos , Glucose/farmacologia , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/fisiologia , Resveratrol/farmacologia
13.
Am J Med Sci ; 359(6): 347-353, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32354596

RESUMO

BACKGROUND: CD19+IL-10+B cells are considered as a particular subset of immunosuppressive cells by producing interleukin 10 (IL-10), which plays an important role in infectious and autoimmune diseases. The aim of this study was to determine the number of CD19+IL-10+B cells in Helicobacter pylori (H. pylori) positive patients in comparison with H. pylori negative patients, and to determine the association with different clinical outcomes, such as gastritis and peptic ulcer disease (PUD), in infected patients. METHODS AND MATERIALS: We studied 25 infected patients with gastritis, 25 infected patients with PUD, and 25 patients negative for H. pylori. The number of CD19+IL-10+B cells was determined by immunofluorescence. RESULTS: The number of CD19+IL-10+B cells in patients infected with H. pylori was significantly 2.5-fold higher than uninfected patients (P < 0.0001). Also, the number of CD19+IL-10+B cells in infected patients with gastritis was significantly 1.45-fold elevated compared to infected patients with PUD (P = 0.001). CONCLUSIONS: These results demonstrate that the increased number of CD19+IL-10+B cells in infected patients and its association with other cells may play an important role in the pathogenesis of H. pylori infection.


Assuntos
Antígenos CD19/metabolismo , Linfócitos B/microbiologia , Mucosa Gástrica/metabolismo , Infecções por Helicobacter/imunologia , Interleucina-10/metabolismo , Adulto , Idoso , Feminino , Mucosa Gástrica/microbiologia , Gastrite/sangue , Gastrite/microbiologia , Helicobacter pylori , Humanos , Masculino , Microscopia de Fluorescência , Pessoa de Meia-Idade , Úlcera Péptica/sangue , Úlcera Péptica/microbiologia , Resultado do Tratamento
14.
Indian J Gastroenterol ; 39(2): 186-195, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32436176

RESUMO

BACKGROUND: Though a few studies in animal models suggest that intestinal helminths (IH) favorably affect evolution of gastritis associated with Helicobacter pylori (H. pylori) the studies supporting this concept in humans are only a few and are based on serological data. METHODS: To evaluate the possible influence of IH on the human gastric mucosa, three groups of Venezuelan adults with gastropathy (endoscopically diagnosed) were studied: H. pylori-/IH- (n = 17), H. pylori+/IH- (n = 18), and H. pylori+/IH+ (n = 11). Histological analysis (hematoxylin-eosin) and immunohistochemical staining (peroxidase) for cytokines interleukin-1beta (IL-1ß), tumor necrosis factor alpha (TNF-α), gamma interferon (IFN-γ), and interleukin 4 (IL-4) were undertaken in gastric antral biopsies. RESULTS: Expression of the four cytokines was detected in all individuals in varying degrees, but proinflammatory cytokines were expressed in a higher degree in the H. pylori+/IH- group, mainly IL-1ß (Th1-dominant immune response), associated with a higher degree of both histological inflammation and gastric cancer risk index (GCRI), as compared to the H. pylori-/IH- group. In contrast, an increased expression of IL-4 and a reduced expression of proinflammatory cytokines (Th2-dominant response), plus the tendency to a lower degree of mononuclear infiltration, mucosal atrophy in gastric corpus, and GCRI, were evidenced in the coinfected group. CONCLUSIONS: The findings of the present study is perhaps the first histological evidence of a possible modulatory effect of IH on the gastric mucosal inflammatory response due to H. pylori infection in humans.


Assuntos
Coinfecção/metabolismo , Coinfecção/patologia , Citocinas/metabolismo , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patologia , Gastrite/microbiologia , Gastrite/patologia , Infecções por Helicobacter , Helicobacter pylori , Mediadores da Inflamação/metabolismo , Enteropatias Parasitárias/metabolismo , Enteropatias Parasitárias/patologia , Adolescente , Adulto , Atrofia , Coinfecção/imunologia , Feminino , Mucosa Gástrica/imunologia , Gastrite/imunologia , Gastrite/metabolismo , Humanos , Imuno-Histoquímica , Enteropatias Parasitárias/imunologia , Leucócitos Mononucleares/patologia , Masculino , Pessoa de Meia-Idade , Adulto Jovem
15.
J Pathol ; 251(3): 336-347, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32432338

RESUMO

Intestinal-type gastric adenocarcinoma arises in a field of pre-existing metaplasia. While biomarkers of cancer and metaplasia have been identified, the definition of dysplastic transition as a critical point in the evolution of cancer has remained obscure. We have evaluated Trop2 as a putative marker of the transition from metaplasia to dysplasia in the stomach in multiple mouse models of metaplasia induction and progression. In addition, TROP2 expression was evaluated in human samples by immunostaining tissue microarrays for metaplasia, dysplasia, and gastric cancer. Dysplastic mouse organoids were evaluated in vitro following shRNA knockdown of Trop2 expression. In mouse models, no Trop2 was observed in the normal corpus and Trop2 was not induced in acute models of metaplasia induction with either L635 or DMP-777. In Mist1-Kras mice, Trop2 expression was not observed in metaplasia at 1 month after Kras induction, but was observed in dysplastic glands at 3-4 months after Kras induction. In human tissues, no Trop2 was observed in normal corpus mucosa or SPEM, but Trop2 expression was observed in incomplete intestinal metaplasia, with significantly less expression in complete intestinal metaplasia. Trop2 expression was observed in all dysplastic and 84% of gastric cancer lesions, although expression levels were variable. Dysplastic mouse organoids from Mist1-Kras mice expressed Trop2 strongly. Knockdown of Trop2 with shRNA markedly reduced organoid growth and budding behavior, and induced the upregulation of apical villin expression. We conclude that Trop2 is upregulated in the transition to dysplasia in the stomach and promotes dysplastic cell behaviors. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Assuntos
Antígenos de Neoplasias/metabolismo , Moléculas de Adesão Celular/metabolismo , Transformação Celular Neoplásica/metabolismo , Mucosa Gástrica/metabolismo , Lesões Pré-Cancerosas/metabolismo , Neoplasias Gástricas/metabolismo , Animais , Antígenos de Neoplasias/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Moléculas de Adesão Celular/genética , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Células Cultivadas , Modelos Animais de Doenças , Mucosa Gástrica/patologia , Genes ras , Humanos , Metaplasia , Camundongos Transgênicos , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , Organoides , Lesões Pré-Cancerosas/genética , Lesões Pré-Cancerosas/patologia , Transdução de Sinais , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Regulação para Cima
16.
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
17.
Immunity ; 52(3): 557-570.e6, 2020 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-32160523

RESUMO

The intestine contains some of the most diverse and complex immune compartments in the body. Here we describe a method for isolating human gut-associated lymphoid tissues (GALTs) that allows unprecedented profiling of the adaptive immune system in submucosal and mucosal isolated lymphoid follicles (SM-ILFs and M-ILFs, respectively) as well as in GALT-free intestinal lamina propria (LP). SM-ILF and M-ILF showed distinct patterns of distribution along the length of the intestine, were linked to the systemic circulation through MAdCAM-1+ high endothelial venules and efferent lymphatics, and had immune profiles consistent with immune-inductive sites. IgA sequencing analysis indicated that human ILFs are sites where intestinal adaptive immune responses are initiated in an anatomically restricted manner. Our findings position ILFs as key inductive hubs for regional immunity in the human intestine, and the methods presented will allow future assessment of these compartments in health and disease.


Assuntos
Imunidade Adaptativa/imunologia , Imunidade nas Mucosas/imunologia , Mucosa Intestinal/imunologia , Intestinos/imunologia , Tecido Linfoide/imunologia , Imunidade Adaptativa/genética , Animais , Citometria de Fluxo , Mucosa Gástrica/imunologia , Mucosa Gástrica/metabolismo , Mucosa Gástrica/ultraestrutura , Humanos , Imunidade nas Mucosas/genética , Imunoglobulina A/genética , Imunoglobulina A/imunologia , Imunoglobulina M/genética , Imunoglobulina M/imunologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/ultraestrutura , Intestinos/ultraestrutura , Linfócitos/imunologia , Linfócitos/metabolismo , Tecido Linfoide/metabolismo , Tecido Linfoide/ultraestrutura , Microscopia Confocal , Microscopia Eletrônica de Varredura , Nódulos Linfáticos Agregados/imunologia , Nódulos Linfáticos Agregados/metabolismo , Nódulos Linfáticos Agregados/ultraestrutura , Análise de Sequência de DNA
18.
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
19.
J Endocrinol ; 245(2): 327-342, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32176867

RESUMO

Circulating growth hormone (GH) concentrations increase during pregnancy in mice and remain pituitary-derived. Whether abundance or activation of the GH secretagogue ghrelin increase during pregnancy, or in response to dietary octanoic acid supplementation, is unclear. We therefore measured circulating GH profiles in late pregnant C57BL/6J mice and in aged-matched non-pregnant females fed with standard laboratory chow supplemented with 5% octanoic or palmitic (control) acid (n = 4-13/group). Serum total and acyl-ghrelin concentrations, stomach and placenta ghrelin mRNA and protein expression, Pcsk1 (encoding prohormone convertase 1/3) and Mboat4 (membrane bound O-acyl transferase 4) mRNA were determined at zeitgeber (ZT) 13 and ZT23. Total and basal GH secretion were higher in late pregnant than non-pregnant mice (P < 0.001), regardless of diet. At ZT13, serum concentrations of total ghrelin (P = 0.004), but not acyl-ghrelin, and the density of ghrelin-positive cells in the gastric antrum (P = 0.019) were higher, and gastric Mboat4 and Pcsk1 mRNA expression were lower in pregnant than non-pregnant mice at ZT23. In the placenta, ghrelin protein was localised mostly to labyrinthine trophoblast cells. Serum acyl-, but not total, ghrelin was lower at mid-pregnancy than in non-pregnant mice, but not different at early or late pregnancy. In conclusion, dietary supplementation with 5% octanoic acid did not increase activation of ghrelin in female mice. Our results further suggest that increases in maternal GH secretion throughout murine pregnancy are not due to circulating acyl-ghrelin acting at the pituitary. Nevertheless, time-dependent increased circulating total ghrelin could potentially increase ghrelin action in tissues that express the acylating enzyme and receptor.


Assuntos
Caprilatos/farmacologia , Suplementos Nutricionais , Grelina/efeitos dos fármacos , Hormônio do Crescimento/efeitos dos fármacos , Acilação , Animais , Feminino , Mucosa Gástrica/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Placenta/metabolismo , Gravidez , RNA Mensageiro/metabolismo
20.
Vet Res ; 51(1): 44, 2020 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-32178732

RESUMO

Gastrointestinal nematode (GIN) infections are one of the major constraints for grazing sheep and goat production worldwide. Genetic selection for resistant animals is a promising control strategy. Whole-transcriptome analysis via RNA-sequencing (RNA-seq) provides knowledge of the mechanisms responsible for complex traits such as resistance to GIN infections. In this study, we used RNA-seq to monitor the dynamics of the response of the abomasal mucosa of Creole goat kids infected with Haemonchus contortus by comparing resistant and susceptible genotypes. A total of 8 cannulated kids, 4 susceptible and 4 resistant to GIN, were infected twice with 10 000 L3 H. contortus. During the second infection, abomasal mucosal biopsies were collected at 0, 8, 15 and 35 days post-infection (dpi) from all kids for RNA-seq analysis. The resistant animals showed early activation of biological processes related to the immune response. The top 20 canonical pathways of differentially expressed genes for different comparison showed activation of the immune response through many relevant pathways including the Th1 response. Interestingly, our results showed a simultaneous time series activation of Th2 related genes in resistant compared to susceptible kids.


Assuntos
Abomaso/parasitologia , Mucosa Gástrica/metabolismo , Doenças das Cabras/fisiopatologia , Hemoncose/veterinária , Haemonchus/fisiologia , Transcriptoma , Animais , Mucosa Gástrica/parasitologia , Cabras , Hemoncose/fisiopatologia
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