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1.
J Surg Res ; 245: 552-563, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31472311

RESUMO

BACKGROUND: It is elusive which subtypes of immune cells are pivotal in cancer progression and prognosis in gastric cancer (GC). The aim of this study is to clarify clinical impact of immature myeloid-derived immune cells in patients with GC who underwent curative gastrectomy with curative lymphadenectomy and treated with S-1 (tegafur/gimeracil/oteracil) postoperatively. METHODS: The prognostic impact of recruited CD33+ immature myeloid-derived cells were clinicopathologically analyzed in curatively resected stage II and III GC. Correlation of preoperative peripheral leukocyte fractions with recruited CD33+ immature cells was also assessed. RESULTS: Patients with high CD33+ cell counts in primary tumor showed dramatically worse prognosis (5-y recurrence-free survival 29.0%) than that of the counterparts (79.4%). High CD33+ cell counts independently predicted poor prognosis in stage II/III (hazard ratio, 4.34; P < 0.001). In analyses of each stage, high CD33+ cell count was pivotally associated with poor prognosis in both stages. There was no significant correlation of each peripheral leukocyte fraction with CD33+ cell recruitment. Of note, high CD33+ cell count was significantly correlated with hematogenous recurrence. CONCLUSIONS: Recruitment of CD33+ immature myeloid cells critically predict hematogenous recurrences in curatively resected advanced GC. These results give rational to focusing on CD33+ myeloid-derived cells as a novel approach to tackle advanced GC.


Assuntos
Células Supressoras Mieloides/imunologia , Recidiva Local de Neoplasia/diagnóstico , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/metabolismo , Neoplasias Gástricas/terapia , Estômago/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Quimioterapia Adjuvante/métodos , Intervalo Livre de Doença , Combinação de Medicamentos , Feminino , Gastrectomia , Humanos , Excisão de Linfonodo , Masculino , Pessoa de Meia-Idade , Células Supressoras Mieloides/metabolismo , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/imunologia , Estadiamento de Neoplasias , Ácido Oxônico/administração & dosagem , Prognóstico , Estômago/citologia , Estômago/cirurgia , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/patologia , Tegafur/administração & dosagem
2.
World J Gastroenterol ; 25(32): 4673-4681, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31528093

RESUMO

Zollinger-Ellison syndrome (ZES) is characterized by gastric acid hypersecretion causing severe recurrent acid-related peptic disease. Excessive secretion of gastrin can now be effectively controlled with powerful proton pump inhibitors, but surgical management to control gastrinoma itself remains controversial. Based on a thorough literature review, we design a surgical algorithm for ZES and list some significant consensus findings and recommendations: (1) For sporadic ZES, surgery should be routinely undertaken as early as possible not only for patients with a precisely localized diagnosis but also for those with negative imaging findings. The surgical approach for sporadic ZES depends on the lesion location (including the duodenum, pancreas, lymph nodes, hepatobiliary tract, stomach, and some extremely rare sites such as the ovaries, heart, omentum, and jejunum). Intraoperative liver exploration and lymphadenectomy should be routinely performed; (2) For multiple endocrine neoplasia type 1-related ZES (MEN1/ZES), surgery should not be performed routinely except for lesions > 2 cm. An attempt to perform radical resection (pancreaticoduodenectomy followed by lymphadenectomy) can be made. The ameliorating effect of parathyroid surgery should be considered, and parathyroidectomy should be performed first before any abdominal surgery for ZES; and (3) For hepatic metastatic disease, hepatic resection should be routinely performed. Currently, liver transplantation is still considered an investigational therapeutic approach for ZES. Well-designed prospective studies are desperately needed to further verify and modify the current considerations.


Assuntos
Gastroenterologia/normas , Oncologia/normas , Guias de Prática Clínica como Assunto , Síndrome de Zollinger-Ellison/cirurgia , Duodeno/citologia , Duodeno/patologia , Duodeno/cirurgia , Células Secretoras de Gastrina/patologia , Gastrinas/metabolismo , Gastroenterologia/métodos , Hepatectomia , Humanos , Fígado/citologia , Fígado/patologia , Fígado/cirurgia , Excisão de Linfonodo , Oncologia/métodos , Pâncreas/citologia , Pâncreas/patologia , Pâncreas/cirurgia , Pancreaticoduodenectomia , Paratireoidectomia , Estômago/citologia , Estômago/patologia , Estômago/cirurgia , Fatores de Tempo , Síndrome de Zollinger-Ellison/patologia
3.
Int J Oncol ; 54(6): 2200-2210, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31081048

RESUMO

Helicobacter pylori (HP) is a pathogenic bacterium associated with chronic gastritis, gastric ulcer and gastric cancer. In the present study, the primary carcinogenesis process of normal gastric epithelial cells (GES­1) infected with HP was investigated. It was determined that infected gastric mucosal epithelial GES­1 cells secreted increased interleukin­8 (IL­8) and IL­23, and exhibited enhanced expression of inducible nitric oxide synthase and cyclooxygenase­2, inducing inflammatory reactions and resulting in apoptosis. The bacterial infection significantly increased the expression of carcinogenesis­associated genes, including p16, c­Myc, p53 and p21, as well as the expression of cell surface signaling molecules cluster of differentiation 44 (CD44) and CD54 in GES­1 cells or tissues of patients with gastritis and gastric cancer in vitro or in vivo. Simultaneously, the migration and invasion abilities of normal gastric epithelial GES­1 cells were increased following HP infection. These observations demonstrated that the inflammatory response of HP infection could cause normal gastric epithelial cells to undergo significant cancerous reactions, indicating that HP is a risk factor for gastric cancer.


Assuntos
Infecções por Helicobacter/complicações , Helicobacter pylori/imunologia , Neoplasias Gástricas/microbiologia , Estômago/citologia , Linhagem Celular , Movimento Celular , Células Epiteliais/citologia , Células Epiteliais/microbiologia , Infecções por Helicobacter/imunologia , Humanos , Interleucina-23/metabolismo , Interleucina-8/metabolismo , Invasividade Neoplásica , Óxido Nítrico Sintase Tipo II/metabolismo , Estômago/microbiologia , Estômago/patologia , Neoplasias Gástricas/imunologia
4.
PLoS One ; 14(2): e0205939, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30789939

RESUMO

Motilin is a gastrointestinal peptide hormone that stimulates gastrointestinal motility. Motilin is produced primarily in the duodenum and jejunum. Motilin receptors (MTLRs) are G protein-coupled receptors that may represent a clinically useful pharmacological target as they can be activated by erythromycin. The functions of motilin are highly species-dependent and remain poorly understood. As a functional motilin system is absent in rodents such as rats and mice, these species are not commonly used for basic studies. In this study, we examine the usefulness of human MTLR-overexpressing transgenic (hMTLR-Tg) mice by identifying the mechanisms of the gastric motor response to human motilin and erythromycin. The distribution of hMTLR was examined immunohistochemically in male wild-type (WT) and hMTLR-Tg mice. The contractile response of gastric strips was measured isometrically in an organ bath, while gastric emptying was determined using phenol red. hMTLR expression was abundant in the gastric smooth muscle layer. Interestingly, higher levels of hMTLR expression were observed in the myenteric plexus of hMTLR-Tg mice but not WT mice. hMTLR was not co-localized with vesicular acetylcholine transporter, a marker of cholinergic neurons in the myenteric plexus. Treatment with human motilin and erythromycin caused concentration-dependent contraction of gastric strips obtained from hMTLR-Tg mice but not from WT mice. The contractile response to human motilin and erythromycin in hMTLR-Tg mice was affected by neither atropine nor tetrodotoxin and was totally absent in Ca2+-free conditions. Furthermore, intraperitoneal injection of erythromycin significantly promoted gastric emptying in hMTLR-Tg mice but not in WT mice. Human motilin and erythromycin stimulate gastric smooth muscle contraction in hMTLR-Tg mice. This action is mediated by direct contraction of smooth muscle via the influx of extracellular Ca2+. Thus, hMTLR-Tg mice may be useful for the evaluation of MTLR agonists as gastric prokinetic agents.


Assuntos
Eritromicina/metabolismo , Motilidade Gastrointestinal/fisiologia , Motilina/metabolismo , Receptores dos Hormônios Gastrointestinais/metabolismo , Receptores de Neuropeptídeos/metabolismo , Animais , Cálcio/metabolismo , Cátions Bivalentes/metabolismo , Neurônios Colinérgicos/citologia , Neurônios Colinérgicos/metabolismo , Expressão Gênica , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Contração Muscular/fisiologia , Músculo Liso/citologia , Músculo Liso/metabolismo , Plexo Mientérico/citologia , Plexo Mientérico/metabolismo , Receptores dos Hormônios Gastrointestinais/genética , Receptores de Neuropeptídeos/genética , Estômago/citologia , Estômago/fisiologia , Técnicas de Cultura de Tecidos
5.
Oncol Rep ; 41(2): 981-988, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30431128

RESUMO

The role of perfluorodecanoic acid (PFDA) in gastric carcinogenesis and its mechanism remains unknown. Our previous research revealed that PFDA regulated the growth of human gastric cells. However, its core molecules and basic mechanisms are still not clear. In the present study, cDNA microarrays were used to determine mRNA changes in AGS cells after treatment with PFDA. DAVID analysis of the genes with >2­fold increased expression in microarray data revealed five genes which were involved in cancer pathways. The most upregulated gene was cIAP2, whose upregulation in AGS was confirmed by western blot analysis and quantitative PCR (qPCR) analyses. In order to investigate the role of cIAP2 in cell proliferation, cIAP2 siRNA was employed to regulate cIAP2 expression following PFDA treatment. The results revealed that the growth rate of cIAP2­knockdown cells was reduced by about 50% compared to the control. Given that our previous flow cytometric assays revealed no significant change (3.7 vs. 6.4%) in the percentage of apoptotic cells when PFDA was added to the medium and cIAP2 expression was upregulated, we next applied flow cytometry to assess whether cIAP2 would lead to cell cycle variations. The research data revealed that the proportion of cells in the G1, S and G2 phases was not significantly altered with the decrease of cIAP2 expression. Finally, the role of cIAP2 in AGS cell senescence was investigated, and the results indicated that cell senescence was significantly increased in the cIAP2 siRNA group in comparison to the control siRNA group. Since p53 has been identified as a tumor suppressor and its molecular alterations are common in different human tumors, we investigated the relationship of p53 with cIAP2. The experimental results demonstrated that cIAP2 regulated the expression of p53 and thus was likely to be a potential mechanism for PFDA­induced growth promotion. Overall, the results revealed that PFDA may suppress cellular senescence induced by p53 through the regulation of cIAP2 protein expression.


Assuntos
Proteína 3 com Repetições IAP de Baculovírus/metabolismo , Carcinógenos Ambientais/toxicidade , Senescência Celular/efeitos dos fármacos , Ácidos Decanoicos/toxicidade , Poluentes Ambientais/toxicidade , Fluorcarbonetos/toxicidade , Neoplasias Gástricas/patologia , Proteína 3 com Repetições IAP de Baculovírus/genética , Carcinogênese/induzido quimicamente , Carcinogênese/patologia , Linhagem Celular Tumoral , Células Epiteliais , Perfilação da Expressão Gênica/métodos , Humanos , Análise de Sequência com Séries de Oligonucleotídeos/métodos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/metabolismo , Estômago/citologia , Neoplasias Gástricas/induzido quimicamente , Proteína Supressora de Tumor p53/metabolismo , Regulação para Cima/efeitos dos fármacos
6.
Int J Biol Macromol ; 122: 127-136, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30340003

RESUMO

In order to optimize drug action, new drug formulations have been developed based upon the prodrug approach. This study was inspired by the increasing interest in the field of macromolecular prodrugs and Piroxicam maleate was used as a model drug. A total of five prodrugs were synthesized using beta cyclodextrin, chitosan, pectin, egg albumin, bovine serum albumin. The synthesized conjugates were characterized on the basis of UV, IR and NMR techniques. In-vitro hydrolysis studies were carried out at pH 1.2, pH 7.4, pH 9.0 and in 80% human plasma followed by in-vivo evaluation of analgesic, anti-inflammatory and anti-ulcerogenic potential. The extent of hydrolysis was found to be proportional to increase in pH. Beta cyclodextrin conjugate was found to possess significant analgesic activity whereas chitosan conjugate was found to be the best anti-inflammatory. Pectin conjugate provided maximum protection against ulcers.


Assuntos
Albuminas/química , Quitosana/química , Pectinas/química , Piroxicam/química , Piroxicam/farmacologia , Estômago/efeitos dos fármacos , beta-Ciclodextrinas/química , Animais , Bovinos , Técnicas de Química Sintética , Citoproteção/efeitos dos fármacos , Composição de Medicamentos , Feminino , Humanos , Concentração de Íons de Hidrogênio , Hidrólise , Masculino , Camundongos , Piroxicam/síntese química , Piroxicam/metabolismo , Pró-Fármacos/metabolismo , Ratos , Estômago/citologia , Úlcera Gástrica/prevenção & controle
7.
Clin Exp Pharmacol Physiol ; 46(1): 29-39, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30225902

RESUMO

Exposure to stress induces gastrointestinal (GI) dysmotility. In rodents, acute restraint stress (ARS) inhibits gastric emptying (GE) and intestinal transit (IT) via central and peripheral corticotropin-releasing factor (CRF)-mediated pathways. Peripherally administered apelin-13 was shown to inhibit GI motor functions; moreover, stress-induced upregulation of gastric apelin content was demonstrated in rats suggesting that peripheral apelin may mediate stress-induced alterations in GI motility. We investigated the role of endogenous peripheral apelin in stress-induced GI dysfunction. GE, IT and gastro-duodenal fasting motility were measured in non-stressed (NS), CRF-injected and ARS-loaded rats. CRF and apelin receptor antagonists astressin or F13A was administered before ARS or peripheral CRF injection. Apelin and APJ receptor expressions were determined using immunohistochemistry and quantified by qRT-PCR. Double immunofluorescence was performed for enteric neuronal apelin. GE and IT were delayed by CRF and ARS. ARS-induced changes were attenuated by F13A, whereas astressin was ineffective. CRF-induced alterations in GE and IT were restored completely by astressin, while they were diminished by F13A. Antral phase III-like contractions were disturbed following ARS which were preserved by preadministration of astressin, but not F13A. CRF impaired gastric and duodenal fasting contractions, while these changes were not altered by F13A. ARS increased apelin expression in stomach and duodenum. Apelin immunoreactivity was detected in mucosa, smooth muscles and myenteric plexi, whereas dense APJ receptor expression was observed within tunica muscularis. APJ receptor was downregulated in rats fasted overnight. These results suggest that enteric apelin acts as an inhibitor stress mediator in the postprandial state.


Assuntos
Apelina/administração & dosagem , Apelina/farmacologia , Esvaziamento Gástrico/efeitos dos fármacos , Trânsito Gastrointestinal/efeitos dos fármacos , Estado Nutricional , Restrição Física/psicologia , Estresse Fisiológico/fisiologia , Animais , Apelina/genética , Apelina/metabolismo , Receptores de Apelina/genética , Receptores de Apelina/metabolismo , Hormônio Liberador da Corticotropina/farmacologia , Duodeno/citologia , Duodeno/efeitos dos fármacos , Duodeno/fisiologia , Jejum/fisiologia , Esvaziamento Gástrico/fisiologia , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Fragmentos de Peptídeos/farmacologia , Transporte Proteico/efeitos dos fármacos , RNA Mensageiro/genética , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Estômago/citologia , Estômago/efeitos dos fármacos , Estômago/fisiologia , Estresse Fisiológico/efeitos dos fármacos
8.
Cell Tissue Res ; 376(1): 71-81, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30560457

RESUMO

Brush cells at the gastric groove have been proposed to operate as sensory cells capable of sensing constituents of ingested food. Recent studies have indicated that these cells express GPR120 (also known as FFAR4), the G protein-coupled receptor for long-chain fatty acids (LCFAs). However, functional implications of this receptor in brush cells have remained elusive. Here, we show that a great proportion of brush cells express GPR120. We used phosphorylation of the extracellular signal-regulated kinases 1/2 (ERK1/2) as a readout to monitor brush cell responses to the LCFAs oleic acid and α-linolenic acid. Our results demonstrate that ERK1/2 phosphorylation is increased upon exposure to both fatty acids. Increased ERK1/2 phosphorylation is accompanied by upregulated mRNA and protein levels of cyclooxygenase 2 (COX-2), a key enzyme for prostaglandin biosynthesis. Immunohistochemical experiments confirmed that oleic acid caused ERK1/2 phosphorylation and induced COX-2 expression in brush cells. Our results indicate that LCFA sensing elicits a signaling process in brush cells that may be relevant for a local regulation of gastric functions.


Assuntos
Mucosa Gástrica/metabolismo , Ácido Oleico/metabolismo , Receptores Acoplados a Proteínas-G , Estômago/citologia , Ácido alfa-Linoleico/metabolismo , Animais , Ciclo-Oxigenase 2/metabolismo , Sistema de Sinalização das MAP Quinases , Camundongos Endogâmicos C57BL , Fosforilação , Receptores Acoplados a Proteínas-G/metabolismo , Receptores Acoplados a Proteínas-G/fisiologia , Transdução de Sinais
9.
Ecotoxicol Environ Saf ; 166: 474-481, 2018 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-30312946

RESUMO

Nanomaterials, such as ZrO2 nanoparticles (ZrO2 NPs), are very effective in water remediation. However, the safety issues related to nanoparticle release and toxicity to humans remain to be resolved. Here we evaluated the cytotoxicity of ZrO2 NPs and their adducts with pollutants using a human cell panel containing stomach, intestine, liver and kidney cells. We found that different pollutants or ZrO2NP/pollutant adducts targeted cells from different organs, suggesting the necessity of a cell panel to model oral exposures. The cooperation of ZrO2 NPs and pollutants was quite complex, consisting of synergistic, antagonistic, or additive effects. For example, ZrO2 NPs enhanced the cytotoxicity of Pb2+ in GES-1 cells and of Pb2+, Cd2+ in FHC cells, while alleviating the toxicity of Pb2+ and As (III) in HepG2 and Hek293 cells. Our results also indicated that even concentrations of pollutants that meet the national standard, the ZrO2 NPs concentration should be kept below 17 µg/mL to avoid ZrO2 NP/pollutant adduct synergistic toxicity.


Assuntos
Biodegradação Ambiental , Células Epiteliais/efeitos dos fármacos , Nanopartículas/toxicidade , Águas Residuárias , Zircônio/toxicidade , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Humanos , Rim/citologia , Fígado/citologia , Polímeros/química , Espécies Reativas de Oxigênio/metabolismo , Estômago/citologia
10.
Sci Rep ; 8(1): 15255, 2018 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-30323305

RESUMO

The processes involved in renewal of the epithelium that lines the mouse stomach remain unclear. Apart from the cells in the isthmus, several other populations located deeper in the gastric glands have been suggested to contribute to the maintenance of the gastric epithelium. Here, we reveal that Lrig1 is expressed in the basal layer of the forestomach and the lower part of glands in the corpus and pylorus. In the glandular epithelium of the stomach, Lrig1 marks a heterogeneous population comprising mainly non-proliferative cells. Yet, fate-mapping experiments using a knock-in mouse line expressing Cre specifically in Lrig1+ cells demonstrate that these cells are able to contribute to the long-term maintenance of the gastric epithelium. Moreover, when cultured in vitro, cells expressing high level of Lrig1 have much higher organoid forming potential than the corresponding cellular populations expressing lower levels of Lrig1. Taken together, these observations show that Lrig1 is expressed primarily by differentiated cells, but that these cells can be recruited to contribute to the maintenance of the gastric epithelium. This confirms previous observations that cells located in the lower segments of gastric glands can participate in tissue replenishment.


Assuntos
Biomarcadores , Proliferação de Células , Células Epiteliais/metabolismo , Mucosa Gástrica/metabolismo , Glicoproteínas de Membrana/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Animais , Biomarcadores/metabolismo , Desdiferenciação Celular/genética , Diferenciação Celular/genética , Proliferação de Células/genética , Células Cultivadas , Células Epiteliais/citologia , Células Epiteliais/fisiologia , Mucosa Gástrica/citologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Estômago/citologia
11.
Lab Chip ; 18(20): 3079-3085, 2018 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-30238091

RESUMO

Current in vitro approaches and animal models have critical limitations for modeling human gastrointestinal diseases because they may not properly represent multicellular human primary tissues. Therefore, there is a need for model platforms that recapitulate human in vivo development, physiology, and disease processes to validate new therapeutics. One of the major steps toward this goal was the generation of three-dimensional (3D) human gastric organoids (hGOs) via the directed differentiation of human pluripotent stem cells (hPSCs). The normal functions and diseases of the stomach occur in the luminal epithelium, however accessing the epithelium on the inside of organoids is challenging. We sought to develop a bioengineered platform to introduce luminal flow through hGOs to better model in vivo gastric functions. Here, we report an innovative microfluidic imaging platform housing hGOs with peristaltic luminal flow in vitro. This human stomach-on-a-chip allows robust, long-term, 3D growth of hGOs with the capacity for luminal delivery via a peristaltic pump. Organoids were cannulated and medium containing fluorescent dextran was delivered through the lumen using a peristaltic pump. This system also allowed us to rhythmically introduce stretch and contraction to the organoid, reminiscent of gastric motility. Our platform has the potential for long-term delivery of nutrients or pharmacological agents into the gastric lumen in vitro for the study of human gastric physiology, disease modeling, and drug screening, among other possibilities.


Assuntos
Motilidade Gastrointestinal , Estômago/citologia , Estômago/fisiologia , Análise Serial de Tecidos/métodos , Humanos , Organoides/citologia , Análise Serial de Tecidos/instrumentação
12.
APMIS ; 126(10): 814-821, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30264431

RESUMO

Tumor microenvironment is important in the progression and survival of cancer cells. We evaluated the prognostic significance of tumor stroma percentage (TSP), Klintrup-Mäkinen (KM) grade, which reflects the density of inflammatory cells of the tumor, and Glasgow microenvironment score (GMS), a combination of TSP and KM grade, in advanced gastric cancers. A total of 196 pT3 and pT4 gastric cancers were histologically evaluated using TSP, KM grade, and GMS. These were correlated with other clinicopathologic factors including patients' survival. High TSP (78 cases), low KM grade (124 cases), and higher GMS (score 0, 72 cases; 1, 53 cases; and 2, 71 cases) were correlated with poor differentiation, diffuse type, presence of lymphovascular invasion, perineural invasion, and lymph node metastasis. High TSP was significantly correlated with low KM grade (p < 0.001). High TSP (HR, 3.079, 95% CI, 1.612-5.883, p = 0.001), low KM grade (3.201, 1.774-5.776, p < 0.001), and higher GMS (12.274, 3.684-40.895, p < 0.001) were independent poor prognostic factors. TSP, KM grade, and GMS are significantly associated with clinicopathologic behavior and patients' survival. Assessing these factors is a feasible and cost-effective way to identify tumor microenvironment with different biological features and prognosis of gastric cancer patients.


Assuntos
Neoplasias Gástricas/patologia , Estômago/patologia , Microambiente Tumoral , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Prognóstico , Estômago/citologia , Neoplasias Gástricas/diagnóstico
13.
Helicobacter ; 23(6): e12538, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30246423

RESUMO

BACKGROUND: Major human gastrointestinal pathogen Helicobacter pylori (H. pylori) colonizes the gastric mucosa causing inflammation and severe complications including cancer, but the involvement of fibroblasts in the pathogenesis of these disorders in H. pylori-infected stomach has been little studied. Normal stroma contains few fibroblasts, especially myofibroblasts. Their number rapidly increases in the reactive stroma surrounding inflammatory region and neoplastic tissue; however, the interaction between H. pylori and fibroblasts remains unknown. We determined the effect of coincubation of normal rat gastric fibroblasts with alive H. pylori (cagA+vacA+) and H. pylori (cagA-vacA-) strains on the differentiation of these fibroblasts into cells possessing characteristics of cancer-associated fibroblasts (CAFs) able to induce epithelial-mesenchymal transition (EMT) of normal rat gastric epithelial cells (RGM-1). MATERIALS AND METHODS: The panel of CAFs markers mRNA was analyzed in H. pylori (cagA+vacA+)-infected fibroblasts by RT-PCR. After insert coculture of differentiated fibroblasts with RGM-1 cells from 24 up to 48, 72, and 96 hours, the mRNA expression for EMT-associated genes was analyzed by RT-PCR. RESULTS: The mRNA expression for CAFs markers was significantly increased after 72 hours of infection with H. pylori (cagA+vacA+) but not H. pylori (cagA-vacA-) strain. Following coculture with CAFs, RGM-1 cells showed significant decrease in E-cadherin mRNA, and the parallel increase in the expression of Twist and Snail transcription factors mRNA was observed along with the overexpression of mRNAs for TGFßR, HGFR, FGFR, N-cadherin, vimentin, α-SMA, VEGF, and integrin-ß1. CONCLUSION: Helicobacter pylori (cagA+vacA+) strain induces differentiation of normal fibroblasts into CAFs, likely to initiate the EMT process in RGM-1 epithelial cell line.


Assuntos
Fibroblastos Associados a Câncer/citologia , Infecções por Helicobacter/metabolismo , Infecções por Helicobacter/patologia , Helicobacter pylori/patogenicidade , Animais , Fibroblastos Associados a Câncer/metabolismo , Diferenciação Celular/genética , Diferenciação Celular/fisiologia , Células Cultivadas , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Transição Epitelial-Mesenquimal/genética , Transição Epitelial-Mesenquimal/fisiologia , Infecções por Helicobacter/microbiologia , Humanos , RNA Mensageiro/genética , Ratos , Estômago/citologia
14.
Chem Pharm Bull (Tokyo) ; 66(9): 896-900, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30175749

RESUMO

To investigate the inhibitory effect of a commercial proton pump inhibitor (lansoprazole) on the gastric proton pump H+,K+-ATPase in vitro, we used orally disintegrating (OD) tablets including original brand-name and generic tablets. In the course of the development of generic products, dissolution and clinical tests are necessary to ensure their bioequivalence to the original brand-name products; by contrast, there is almost no opportunity to demonstrate their activity in vitro. This study initially compared the similarity of the dissolution of test generic tablets with that of the original brand-name tablets. The dissolution tests for 15 and 30-mg lansoprazole tablets found their dissolution properties were similar. Subsequently, the dissolution media were sampled and then their effects on the H+,K+-ATPase activity were measured using tubulovesicles prepared from the gastric mucosa of hogs. We confirmed that the inhibitory effects of the generic tablets on H+,K+-ATPase activity were consistent with those of the original brand-name tablets. Furthermore, lansoprazole contents in each tablet estimated from their inhibitory effects were in good agreement with their active pharmaceutical ingredient content. To our knowledge, this is the first technical report to compare the in vitro biochemical activity of lansoprazole OD tablets between the original brand-name and generic commercial products.


Assuntos
Adenosina Trifosfatases/antagonistas & inibidores , Lansoprazol/farmacologia , Inibidores da Bomba de Prótons/farmacologia , Adenosina Trifosfatases/metabolismo , Administração Oral , Animais , Medicamentos Genéricos , Humanos , Lansoprazol/química , Inibidores da Bomba de Prótons/química , Solubilidade , Estômago/citologia , Estômago/enzimologia , Suínos , Comprimidos , Equivalência Terapêutica
15.
J Cell Sci ; 131(16)2018 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-30072444

RESUMO

The role of the actin cytoskeleton in the sequence of physiological epithelial repair in the intact epithelium has yet to be elucidated. Here, we explore the role of actin in gastric repair in vivo and in vitro gastric organoids (gastroids). In response to two-photon-induced cellular damage of either an in vivo gastric or in vitro gastroid epithelium, actin redistribution specifically occurred in the lateral membranes of cells neighboring the damaged cell. This was followed by their migration inward to close the gap at the basal pole of the dead cell, in parallel with exfoliation of the dead cell into the lumen. The repair and focal increase of actin was significantly blocked by treatment with EDTA or the inhibition of actin polymerization. Treatment with inhibitors of myosin light chain kinase, myosin II, trefoil factor 2 signaling or phospholipase C slowed both the initial actin redistribution and the repair. While Rac1 inhibition facilitated repair, inhibition of RhoA/Rho-associated protein kinase inhibited it. Inhibitors of focal adhesion kinase and Cdc42 had negligible effects. Hence, initial actin polymerization occurs in the lateral membrane, and is primarily important to initiate dead cell exfoliation and cell migration to close the gap.


Assuntos
Actinas/metabolismo , Mucosa Gástrica/lesões , Organoides/lesões , Multimerização Proteica/fisiologia , Reepitelização/fisiologia , Estômago/citologia , Animais , Movimento Celular , Células Cultivadas , Células Epiteliais/fisiologia , Feminino , Mucosa Gástrica/metabolismo , Mucosa Gástrica/fisiologia , Masculino , Camundongos , Camundongos Transgênicos , Organoides/citologia , Organoides/fisiologia , Polimerização , Regeneração/fisiologia , Estômago/lesões
17.
World J Gastroenterol ; 24(24): 2567-2581, 2018 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-29962814

RESUMO

Gastric cancer (GC) remains one of the most common and malignant types of cancer due to its rapid progression, distant metastasis, and resistance to conventional chemotherapy, although efforts have been made to understand the underlying mechanism of this resistance and to improve clinical outcome. It is well recognized that tumor heterogeneity, a fundamental feature of malignancy, plays an essential role in the cancer development and chemoresistance. The model of tumor-initiating cell (TIC) has been proposed to explain the genetic, histological, and phenotypical heterogeneity of GC. TIC accounts for a minor subpopulation of tumor cells with key characteristics including high tumorigenicity, maintenance of self-renewal potential, giving rise to both tumorigenic and non-tumorigenic cancer cells, and resistance to chemotherapy. Regarding tumor-initiating cell of GC (GATIC), substantial studies have been performed to (1) identify the putative specific cell markers for purification and functional validation of GATICs; (2) trace the origin of GATICs; and (3) decode the regulatory mechanism of GATICs. Furthermore, recent studies demonstrate the plasticity of GATIC and the interaction between GATIC and its surrounding factors (TIC niche or tumor microenvironment). All these investigations pave the way for the development of GATIC-targeted therapy, which is in the phase of preclinical studies and clinical trials. Here, we interpret the heterogeneity of GC from the perspectives of TIC by reviewing the above-mentioned fundamental and clinical studies of GATICs. Problems encountered during the GATIC investigations and the potential solutions are also discussed.


Assuntos
Carcinogênese/patologia , Células-Tronco Neoplásicas/patologia , Neoplasias Gástricas/patologia , Microambiente Tumoral/genética , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/metabolismo , Carcinogênese/efeitos dos fármacos , Carcinogênese/genética , Linhagem Celular Tumoral , Ensaios Clínicos como Assunto , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Estômago/citologia , Estômago/patologia , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Microambiente Tumoral/efeitos dos fármacos
18.
World J Gastroenterol ; 24(26): 2806-2817, 2018 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-30018476

RESUMO

Gastrointestinal stromal tumors (GISTs) are the most common malignant subepithelial lesions (SELs) of the gastrointestinal tract. They originate from the interstitial cells of Cajal located within the muscle layer and are characterized by over-expression of the tyrosine kinase receptor KIT. Pathologically, diagnosis of a GIST relies on morphology and immunohistochemistry [KIT and/or discovered on gastrointestinal stromal tumor 1 (DOG1) is generally positive]. The prognosis of this disease is associated with the tumor size and mitotic index. The standard treatment of a GIST without metastasis is surgical resection. A GIST with metastasis is usually only treated by tyrosine kinase inhibitors without radical cure; thus, early diagnosis is the only way to improve its prognosis. However, a GIST is usually detected as a SEL during endoscopy, and many benign and malignant conditions may manifest as SELs. Conventional endoscopic biopsy is difficult for tumors without ulceration. Most SELs have therefore been managed without a histological diagnosis. However, a favorable prognosis of a GIST is associated with early histological diagnosis and R0 resection. Endoscopic ultrasonography (EUS) and EUS-guided fine needle aspiration (EUS-FNA) are critical for an accurate diagnosis of SELs. EUS-FNA is safe and effective in enabling an early histological diagnosis and adequate treatment. This review outlines the current evidence for the diagnosis and management of GISTs, with an emphasis on early management of small SELs.


Assuntos
Detecção Precoce de Câncer/métodos , Tumores do Estroma Gastrointestinal/terapia , Gastroscopia/métodos , Inibidores de Proteínas Quinases/uso terapêutico , Neoplasias Gástricas/terapia , Endossonografia , Gastrectomia/métodos , Tumores do Estroma Gastrointestinal/diagnóstico , Tumores do Estroma Gastrointestinal/mortalidade , Tumores do Estroma Gastrointestinal/patologia , Humanos , Células Intersticiais de Cajal/patologia , Laparoscopia/métodos , Prognóstico , Estômago/citologia , Estômago/patologia , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Fatores de Tempo , Resultado do Tratamento
19.
Microsc Microanal ; 24(3): 277-283, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29952282

RESUMO

BACKGROUND: Helicobacter pylori is a major cause of gastric diseases including gastric cancer. This study was aimed to explore whether hydrotalcite can inhibit H. pylori infection of gastric epithelial cells. METHODS: the gastric epithelial cell line GES-1 and the gastric cancer cell line BGC823 were infected with H. pylori at multiplicities of infections (MOIs) of 50:1 and 100:1. Hydrotalcite was added to cell cultures. Cell apoptosis and cell cycle analysis were performed to measure the situation of cell growth. The main changes of cell ultrastructure were observed by transmission electron microscopy. H. pylori cell adhesion was observed by scanning electron microscopy. RESULTS: hydrotalcite could significantly inhibit cell apoptosis of GES-1 and cell proliferation of BGC823 induced by H. pylori infection at an MOI of 50:1. Hydrotalcite treatment protected gastric cells from H. pylori infection, and H. pylori adhesion to gastric cells was reduced. However, hydrotalcite could not reverse damage induced by H. pylori infection at an MOI of 100:1. CONCLUSION: hydrotalcite can protect gastric cells from H. pylori infection when cell damage is not serious. It can weaken the damage of cells induced by H. pylori and decrease H. pylori adhesion to gastric cells.


Assuntos
Hidróxido de Alumínio/farmacologia , Células Epiteliais/microbiologia , Infecções por Helicobacter/prevenção & controle , Helicobacter pylori/efeitos dos fármacos , Hidróxido de Magnésio/farmacologia , Estômago/microbiologia , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Células Epiteliais/citologia , Infecções por Helicobacter/microbiologia , Infecções por Helicobacter/fisiopatologia , Helicobacter pylori/fisiologia , Humanos , Estômago/citologia
20.
Zoology (Jena) ; 128: 38-45, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29755007

RESUMO

The alimentary tract of oxudercine gobies is characterized by a lack of an anatomically distinct stomach, owing to which they are classified as stomachless. Since the environment, food requirements, and feeding habits have a significant impact on the anatomy of the alimentary tract of fish, it was assumed that predominantly carnivorous, semi-terrestrial mudskippers would have a stomach. In order to verify this hypothesis, anatomical, histological, histochemical and ultrastructural analysis of the alimentary tract of the Atlantic mudskipper Periophthalmus barbarus was performed. The results revealed that despite a lack of clear anatomical distinction within the alimentary tract, there were four well-distinguished sections visible at the histological level: oesophagus, stomach, intestine, and rectum. The division was enhanced by the presence of a pyloric sphincter and an ileorectal valve. The stomach contained tubular glands composed of oxynticopeptic cells. Gland cells had pepsinogen granules and a well-developed tubulovesicular network of smooth membranes, which indicates the secretion of gastric juice. The presence of neutral mucus in the apical region of surface epithelial cells as protection against hydrochloric acid as well as the presence of active pepsin also confirm gastric function. However, low pepsin activity seems to implies low protein digestion. The results of this study indicate that the Atlantic mudskipper P. barbarus has a functional stomach.


Assuntos
Trato Gastrointestinal/ultraestrutura , Perciformes/anatomia & histologia , Animais , Trato Gastrointestinal/citologia , Estômago/citologia , Estômago/ultraestrutura
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