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1.
Anticancer Res ; 39(12): 6711-6722, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31810936

RESUMO

BACKGROUND/AIM: Autophagy is a cellular mechanism that recycles cellular components to maintain homeostasis. To investigate the clinical implication of autophagy in gastric cancer, the autophagy markers with autophagosome formation, LC3B and selective autophagy substrate p62/SQSTM1 (P62) were validated. MATERIALS AND METHODS: LC3B and p62 expression was examined using immunohistochemistry, western blot assays, and reverse-transcription polymerase chain reaction (RT-PCR). The relationship of LC3B and p62 expression in gastric adenocarcinomas with clinicopathological parameters, including patient survival, were analyzed. RESULTS: Normal gastric mucosae exhibit no LC3B and p62 expression, while tubular adenoma and gastric adenocarcinomas exhibit variable nuclear or cytoplasmic p62 expression. High LC3B, high cytoplasmic p62, and low nuclear p62 protein expression in gastric adenocarcinomas is positively correlated with poor prognostic factors including survival. CONCLUSION: Dynamic LC3B and p62 changes are suggested to be involved in gastric tumorigenesis and cancer progression. LC3B and p62 could be used as prognostic biomarkers and potential therapeutic targets for gastric adenocarcinomas.


Assuntos
Adenocarcinoma/metabolismo , Adenoma/metabolismo , Biomarcadores Tumorais/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Proteína Sequestossoma-1/metabolismo , Neoplasias Gástricas/metabolismo , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adenoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Núcleo Celular/metabolismo , Citoplasma/metabolismo , Feminino , Mucosa Gástrica/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/patologia , Adulto Jovem
2.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 35(11): 1000-1007, 2019 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-31878996

RESUMO

Objective To screen a standard homogenous cDNA library of human gastric mucosal epithelium with yeast two-hybrid system and find the proteins that interact with Src-homology 2-containing inositol 5-phosphatase 2 (SHIP2). Methods Using the yeast two-hybrid system, P1 (SH2+5-Ptase) and P2 (PRD+SAM) segments of SHIP2 were used as bait proteins to screen the proteins that bind to SHIP2 from the homogenous cDNA library of human gastric mucosal epithelium. The selected interacting proteins of SHIP2 were verified by co-immunoprecipitation assay. Results A total of 39 positive clones were selected and sequenced for alignment analysis. It was verified that PHB interacted with SHIP2 by reductive hybridization and co-immunoprecipitation assays. Conclusion PHB, the interacting protein of SHIP2 was screened by yeast two-hybrid system from the homogenous cDNA library of human gastric mucosal epithelium.


Assuntos
Epitélio/metabolismo , Mucosa Gástrica/metabolismo , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatases/metabolismo , Proteínas Repressoras/metabolismo , Biblioteca Gênica , Humanos , Inositol Polifosfato 5-Fosfatases , Técnicas do Sistema de Duplo-Híbrido
3.
J Agric Food Chem ; 67(50): 13978-13985, 2019 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-31757126

RESUMO

Protein oxidation results in structural modification which affects its digestion. The objective of this work was to investigate the influence of lipoxygenases (LOX) catalyzed linoleic acid (LA) oxidation on the structure and in vitro gastric digests of soybean protein isolate (SPI). Fluorescence recovery after photobleaching (FRAP) was used to evaluate the relationship between pepsin diffusion and gastric digestion. Results indicated that oxidation induced carbonyl formation and loss of free sulfhydryl. Increased surface hydrophobicity and zeta-potential verified the protein unfolding and thus resulted in a small particle size and low fluorescence intensity. Fourier transform infrared spectroscopy (FTIR) showed that oxidation caused the increases in ß-sheets mostly at the expense of α-helix and random coils. Fluorescein isothiocyanate (FITC)-pepsin in SPI solution modified with 3 mL LA showed a faster diffusion rate with 80.51 µm2/s as well as a higher DH value of 9.11%, showing that pepsin diffusivity might play an important role in protein gastric digestion.


Assuntos
Mucosa Gástrica/metabolismo , Ácido Linoleico/metabolismo , Lipoxigenase/metabolismo , Proteínas de Soja/química , Proteínas de Soja/metabolismo , Digestão , Humanos , Interações Hidrofóbicas e Hidrofílicas , Ácido Linoleico/química , Lipoxigenase/química , Modelos Biológicos , Oxirredução , Pepsina A/química , Pepsina A/metabolismo , Dobramento de Proteína , Espectroscopia de Infravermelho com Transformada de Fourier
4.
BMC Complement Altern Med ; 19(1): 318, 2019 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-31744486

RESUMO

BACKGROUND: Altered cellular metabolism is considered to be one of the hallmarks of cancer (Coller, Am J Pathol 184:4-17, 2014; Kim and Bae, Curr Opin Hematol 25:52-59, 2018). However, few studies have investigated the role of metabolism in the development of gastric precancerous lesions (GPLs). Weipiling (WPL), a traditional Chinese medicine formula for treatment of GPLs. In this study, we evaluated the amelioration of GPLs by WPL and investigated the possible role of WPL in regulating glucose metabolism. METHODS: Firstly, the major components of WPL are chemically characterized by HPLC analytical method. In this study, we chose the Atp4a-/- mouse model (Spicer etal., J Biol Chem 275:21555-21565, 2000) for GPL analysis. Different doses of WPL were administered orally to mice for 10 weeks. Next, the pathological changes of gastric mucosa were assessed by the H&E staining and AB-PAS staining. In addition, TUNEL staining was used to evaluate apoptosis, and we further used immunohistochemically labelled CDX2, MUC2, ki-67, PTEN, and p53 proteins to assess the characteristic changes of gastric mucosa in precancerous lesions. The levels of such transporters as HK-II, PKM2, ENO1, MPC1, and LDHA were determined by Western blot analysis. Finally, we assessed the expression of mTOR, HIF-1α, AMPK, Rheb, TSC1 and TSC2 protein in the gastric mucosa of Atp4a-/-mice. RESULTS: In this work, we evaluated the protective effect of WPL on gastric mucosa in mice with precancerous lesions. The aberrant apoptosis in gastric mucosa of gastric pre-cancerous lesions was controlled by WPL (P<0.05). Furthermore, WPL suppressed the expression of CDX2, MUC2, ki-67, PTEN and p53, as the levels of these proteins decreased significantly compared with the model group (P<0.05). In parallel, WPL significantly suppressed the expression of transporters, such as HK-II, PKM2, ENO1, MPC1 and LDHA (P<0.05). In addition, mTOR, HIF-1a, AMPK, Rheb, TSC1 and TSC2 protein levels in gastric mucosa of Atp4a-/- mice in the high- and low-dose WPL groups were significantly lower than those in the model group (P<0.05), while the expression of TSC1 and TSC2 protein was significantly higher (P<0.05). CONCLUSIONS: Conclusively, WPL could ameliorate GPLs in Atp4a-/- mice by inhibiting the expression of transporters and suppressing the aberrant activation of mTOR/HIF-1α.


Assuntos
Medicamentos de Ervas Chinesas/administração & dosagem , Mucosa Gástrica/efeitos dos fármacos , Lesões Pré-Cancerosas/tratamento farmacológico , Animais , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patologia , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Lesões Pré-Cancerosas/genética , Lesões Pré-Cancerosas/metabolismo , Lesões Pré-Cancerosas/patologia , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismo , Proteína 1 do Complexo Esclerose Tuberosa/genética , Proteína 1 do Complexo Esclerose Tuberosa/metabolismo
5.
Biochimie ; 167: 42-48, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31509760

RESUMO

Gastrokine1 (GKN1), important for maintaining the physiological function of the gastric mucosa, is highly expressed in the stomach of healthy individuals but is down-regulated or absent in gastric tumor tissues and derived cell lines. The mechanisms underlying GKN1 gene inactivation are still unknown. We previously showed that GKN1 downregulation in gastric tumors is likely associated with an epigenetic transcriptional complex that negatively regulates GKN1 expression. In addition, TSA-mediated inhibition of HDACs leads to GKN1 restoration at the transcriptional level, but no at the translational level. These findings led to hypothesize the activation of a second regulatory mechanism microRNAs-mediated, thus resulting in translational repression and gene silencing. Bioinformatic analyses performed with 5 different algorithms highlighted that 4 miRNAs contained a seed sequence for the 3'UTR of GKN1 mRNA. Among these, only two miRNAs, hsa-miR-544a and miR-1245b-3p directly target the GKN1-3'UTR as evaluated by luciferase reporter assays. TaqMan miRNA assay performed on gastric cancer cell lines after TSA treatment showed a stronger increase of miR-544a expression than that of miR-1245b-3p. Finally, co-transfection of AGS cells with GKN1-3'UTR and premiR-544a showed compared to controls, a strong reduction of GKN1 expression both at translational and transcriptional levels. The up-regulation of miR-544a could be crucially involved in the GKN1 translational repression, thus suggesting its potential role as a biomarker and therapeutic target in GC patients. These findings indicate that epigenetic mechanisms leading to the inactivation of GKN1 play a key role in the multi-step process of gastric carcinogenesis and would provide an essential starting point for the development of new therapeutic strategies based on epigenetic targets for alternatives gene.


Assuntos
Carcinogênese/metabolismo , MicroRNAs/fisiologia , Hormônios Peptídicos/metabolismo , Neoplasias Gástricas/metabolismo , Biomarcadores Tumorais/fisiologia , Carcinogênese/genética , Linhagem Celular Tumoral , Regulação para Baixo , Mucosa Gástrica/metabolismo , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Células HEK293 , Humanos , Hormônios Peptídicos/genética , Neoplasias Gástricas/genética
6.
J Agric Food Chem ; 67(39): 10930-10936, 2019 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-31496247

RESUMO

The stability of lipids in meat products depends on the initial concentration of hydroperoxides, the catalytic involvement of metal ions and myoglobin, endogenous antioxidants, and biological and technological factors. Ground meat was treated with additives, sealed in vacuum bags, heated to 75 °C, and stored opened to air at 4 °C. S-Nitroso-N-acetylcysteine (NAC-SNO) at concentration like nitrite used by the industry prevents lipid peroxidation in the product, even after storage for 1 month at 4 °C. The same simulated treatments at different concentrations of both compounds show that NAC-SNO acts as an antioxidant ∼4-fold better than nitrite at pH 6.2 or 3.0. Ascorbic acid significantly improves nitrite antioxidant effect. NAC-SNO was found to prevent, much better than nitrite, accumulation of reactive aldehydes and hydroxynonenal protein modification. In condition like those used by the industry for meat products processing, NAC-SNO acts better than nitrite to provide antioxidant protection without the side effect of N-nitrosation, oxidation, and the loss of nutrient generated by nitrite.


Assuntos
Acetilcisteína/análogos & derivados , Antioxidantes/análise , Conservantes de Alimentos/análise , Mucosa Gástrica/metabolismo , Produtos da Carne/análise , Acetilcisteína/análise , Acetilcisteína/metabolismo , Animais , Antioxidantes/metabolismo , Conservantes de Alimentos/metabolismo , Temperatura Alta , Peroxidação de Lipídeos , Nitritos/análise , Oxirredução , Perus
7.
Clin Lab ; 65(12)2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31414587

RESUMO

BACKGROUND: Screening and timely treatment of precancerous gastric cancer diseases or of gastric cancer in the early stages has important significance in reducing the incidence and mortality of gastric cancer. Gastroscopy and histopathological biopsy are still the gold standards for the diagnosis of gastric diseases. But the application of astroscopy for the screening and diagnosis of gastric diseases is limited. In recent years, serum pepsinogen (PG), gastrin, and Helicobacter pylori (H. pylori) IgG antibodies have become indicators for "serological biopsy" of the gastric mucosa. METHODS: From January 2016 to January 2018, a total of 2,394 patients with digestive tract symptoms underwent gastroscopy. According to the endoscopic examination and pathological diagnosis, there were four case groups: 1,376 cases of chronic non-atrophic gastritis, 708 cases of chronic atrophic gastritis, 265 cases of gastric ulcer, and 45 cases of gastric cancer. Serological gastric biopsies were performed and analyzed. RESULTS: The serum levels of PGI in the chronic atrophic gastritis group was significantly lower than that in the chronic non-atrophic gastritis group, gastric ulcer group, and gastric cancer group (p < 0.05). The serum levels of PGII and G-17 in the gastric cancer group were significantly higher than those in the chronic non-atrophic Gastritis group, chronic atrophic gastritis group, and gastric ulcer group (p < 0.05). The PGR in the gastric cancer group was significantly lower than that in the chronic non-atrophic gastritis group, chronic atrophic Gastritis group, and gastric ulcer group (p < 0.05). The H. pylori positive rates in the chronic atrophic gastritis group and gastric cancer group were higher than those in the chronic non-atrophic gastritis group and gastric ulcer Group (p < 0.05). CONCLUSIONS: Serological gastric biopsy is closely correlated to gastric mucosal disease and can be used as a Screening tool in gastric disease.


Assuntos
Anticorpos Antibacterianos/sangue , Biomarcadores/sangue , Mucosa Gástrica/metabolismo , Gastrinas/sangue , Pepsinogênio A/sangue , Neoplasias Gástricas/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Antibacterianos/imunologia , Biópsia , Feminino , Mucosa Gástrica/microbiologia , Mucosa Gástrica/patologia , Infecções por Helicobacter/sangue , Infecções por Helicobacter/diagnóstico , Infecções por Helicobacter/microbiologia , Helicobacter pylori/imunologia , Helicobacter pylori/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Sensibilidade e Especificidade , Neoplasias Gástricas/patologia , Adulto Jovem
8.
J Agric Food Chem ; 67(34): 9591-9600, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31414795

RESUMO

Process conditions that are applied to make structured soy-protein-based food commonly include high temperatures. Those conditions can induce protein oxidation, leading to a decrease in their susceptibility to proteolysis by digestive enzymes. We aimed to investigate the effects of thermomechanical processing on oxidation and in vitro gastric digestion of commercial soy protein ingredients. Samples were sheared at 100 to 140 °C and characterized for acid uptake, carbonyl content, electrophoresis, and surface hydrophobicity. The enzymatic hydrolysis was determined in simulated gastric conditions. Protein ingredients were already oxidized and showed higher surface hydrophobicity and hydrolysis rate compared with those of the processed matrices. However, no clear correlation between the level of carbonyls and the hydrolysis rate was found. Therefore, we conclude that gastric digestion is mostly driven by the matrix structure and composition and the available contact area between the substrate and proteolytic enzymes.


Assuntos
Digestão , Mucosa Gástrica/metabolismo , Proteínas de Soja/metabolismo , Mucosa Gástrica/enzimologia , Humanos , Concentração de Íons de Hidrogênio , Hidrólise , Interações Hidrofóbicas e Hidrofílicas , Modelos Biológicos , Oxirredução , Proteínas de Soja/química
9.
Int J Mol Sci ; 20(16)2019 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-31405107

RESUMO

Probiotics are used in the management of some gastrointestinal diseases. However, little is known about their effects on normal gastric epithelial biology. The aim of this study was to explore how the probiotic mixture VSL#3 affects gastric cell lineages in mice with a special focus on protective and aggressive factors. Weight-matching littermate male mice (n = 14) were divided into treated and control pairs. The treated mice received VSL#3 (5 mg/day/mouse) by gastric gavage for 10 days. Control mice received only the vehicle. Food consumption and bodyweight were monitored. All mice were injected intraperitoneally with bromodeoxyuridine (120 mg/Kg bodyweight) two hours before sacrificed to label S-phase cells. Stomach tissues were processed for lectin- and immunohistochemical examination. ImageJ software was used to quantify immunolabeled gastric epithelial cells. Real-time quantitative polymerase chain reaction was used to provide relative changes in expression of gastric cell lineages specific genes. Results revealed that treated mice acquired (i) increased production of mucus, trefoil factor (TFF) 1 and TFF2, (ii) decreased production of pepsinogen, and (iii) increased ghrelin-secreting cells. No significant changes were observed in bodyweight, food consumption, cell proliferation, or parietal cells. Therefore, VSL#3 administration amplifies specific cell types specialized in the protection of the gastric epithelium.


Assuntos
Mucosa Gástrica/metabolismo , Pepsinogênio A/genética , Probióticos/farmacologia , Fatores Trefoil/genética , Animais , Regulação para Baixo , Mucosa Gástrica/citologia , Mucosa Gástrica/microbiologia , Mucosa Gástrica/ultraestrutura , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Probióticos/administração & dosagem , Regulação para Cima
10.
BMC Biol ; 17(1): 68, 2019 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-31419979

RESUMO

BACKGROUND: The functional annotation of genomes, including chromatin accessibility and modifications, is important for understanding and effectively utilizing the increased amount of genome sequences reported. However, while such annotation has been well explored in a diverse set of tissues and cell types in human and model organisms, relatively little data are available for livestock genomes, hindering our understanding of complex trait variation, domestication, and adaptive evolution. Here, we present the first complete global landscape of regulatory elements in cattle and explore the dynamics of chromatin states in rumen epithelial cells induced by the rumen developmental regulator-butyrate. RESULTS: We established the first global map of regulatory elements (15 chromatin states) and defined their coordinated activities in cattle, through genome-wide profiling for six histone modifications, RNA polymerase II, CTCF-binding sites, DNA accessibility, DNA methylation, and transcriptome in rumen epithelial primary cells (REPC), rumen tissues, and Madin-Darby bovine kidney epithelial cells (MDBK). We demonstrated that each chromatin state exhibited specific enrichment for sequence ontology, transcription, methylation, trait-associated variants, gene expression-associated variants, selection signatures, and evolutionarily conserved elements, implying distinct biological functions. After butyrate treatments, we observed that the weak enhancers and flanking active transcriptional start sites (TSS) were the most dynamic chromatin states, occurred concomitantly with significant alterations in gene expression and DNA methylation, which was significantly associated with heifer conception rate and stature economic traits. CONCLUSION: Our results demonstrate the crucial role of functional genome annotation for understanding genome regulation, complex trait variation, and adaptive evolution in livestock. Using butyrate to induce the dynamics of the epigenomic landscape, we were able to establish the correlation among nutritional elements, chromatin states, gene activities, and phenotypic outcomes.


Assuntos
Butiratos/administração & dosagem , Bovinos/genética , Cromatina/metabolismo , Genoma , Anotação de Sequência Molecular , Sequências Reguladoras de Ácido Nucleico , Animais , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/metabolismo , Rúmen/efeitos dos fármacos , Rúmen/metabolismo
11.
Pathologica ; 111(2): 76-78, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31388200

RESUMO

Russell body gastritis is caused by an accumulation of plasma cells within the gastric mucosa. These plasma cells are characterized by eosinophilic cytoplasmic inclusions of immunoglobulin which are called "Russell bodies". We report a case of Russell body gastritis in a 28-year-old male who presented with abdominal pain and rectal bleeding. Endoscopy showed erosions with edema and vascular congestion in the gastric body and antrum. The biopsy showed chronic gastritis with plasma cell infiltration of the lamina propria. Many plasma cells contained cytoplasmic Russell bodies which stained positive for CD138, CD79a, Kappa and lambda light chains. The Russell bodies were negative for pancytokeratin, excluding signet ring cell carcinoma. Russell body gastritis is an uncommon, benign reactive condition.


Assuntos
Mucosa Gástrica/patologia , Gastrite/patologia , Corpos de Inclusão/patologia , Plasmócitos/patologia , Adulto , Mucosa Gástrica/metabolismo , Gastrite/diagnóstico , Gastrite/metabolismo , Humanos , Corpos de Inclusão/metabolismo , Masculino , Plasmócitos/metabolismo
12.
Oncogene ; 38(37): 6461-6477, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31332288

RESUMO

Helicobacter pylori (Hp) infection and overexpression of hepatoma-derived growth factor (HDGF) are involved in gastric carcinogenesis. However, the relationship between Hp-induced gastric diseases and HDGF upregulation is not yet completely clear. This study aimed to elucidate the role of HDGF in Hp-induced gastric inflammation and carcinogenesis. HDGF expression in gastric biopsy and serum from patients was analyzed by immunohistochemical and ELISA analysis, respectively. Hp and gastric cells coculture system was employed to delineate the mechanism underlying HDGF overexpression during Hp infection. The gastric pathologies of wild type and HDGF knockout mice after Hp infection were investigated by immunohistochemical, immunoblot, and immunofluorescence analyses. HDGF level was significantly elevated in patients with Hp infection or intestinal metaplasia (IM, a precancerous lesion), and HDGF overexpression was positively correlated with Hp load, IM, and neutrophil infiltration in gastric biopsy. Consistently, patients with Hp infection or IM had significantly higher serum HDGF level. By using coculture assay, Hp infection led to HDGF upregulation and secretion in gastric cells. In mice model, HDGF ablation significantly suppressed the Hp-induced neutrophil infiltration and inflammatory TNF-α/COX-2 signaling, thereby relieving the tissue damage in stomach. This was further supported by that recombinant HDGF (rHDGF) stimulated the differentiation/chemotaxis of cultured neutrophils and oncogenic behaviors of gastric cells. Time series studies showed that Hp infection elicited an inflammatory TNF-α/HDGF/COX-2 cascade in stomach. HDGF secretion by Hp infection promotes the neutrophils infiltration and relays Hp-induced inflammatory signaling. Thus, HDGF may constitute a novel diagnostic marker and therapeutic target for Hp-induced gastritis and carcinogenesis.


Assuntos
Gastrite , Infecções por Helicobacter/complicações , Helicobacter pylori/fisiologia , Peptídeos e Proteínas de Sinalização Intercelular/fisiologia , Infiltração de Neutrófilos , Neoplasias Gástricas/genética , Neoplasias Gástricas/microbiologia , Animais , Carcinogênese/genética , Carcinogênese/imunologia , Carcinogênese/patologia , Células Cultivadas , Mucosa Gástrica/imunologia , Mucosa Gástrica/metabolismo , Mucosa Gástrica/microbiologia , Gastrite/genética , Gastrite/imunologia , Gastrite/microbiologia , Gastrite/patologia , Células HL-60 , Infecções por Helicobacter/genética , Infecções por Helicobacter/imunologia , Helicobacter pylori/imunologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infiltração de Neutrófilos/genética , Neutrófilos/imunologia , Neutrófilos/metabolismo , Estômago/imunologia , Estômago/microbiologia , Estômago/patologia , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/patologia
13.
Life Sci ; 231: 116688, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31348950

RESUMO

The extended infection with Helicobacter pylori (H. pylori), one of the most frequent infectious agents in humans, may cause gastritis, peptic ulcers, gastric mucosa-associated lymphoid tissue (MALT) lymphoma, and gastric cancer. During H. pylori infection, different kinds of inflammatory cells such as dendritic cells, macrophages, neutrophils, mast cells, eosinophils, T cells and B cells are accumulated into the stomach. The interactions between chemokines and their respective receptors recruit particular types of the leukocytes that ultimately determine the nature of immune response and therefore, have a main influence on the consequence of infection. The suitable production of chemokines especially in the early stages of H. pylori infection shapes appropriate immune responses that contribute to the H. pylori elimination. The unbalanced expression of the chemokines can contribute in the induction of inappropriate responses that result in the tissue damage or malignancy. Thus, chemokines and their receptors may be promising potential targets for designing the therapeutic strategies against various types H. pylori-related gastrointestinal disorders. In this review, a comprehensive explanation regarding the roles played by chemokines in H. pylori-mediated peptic ulcer, gastritis and gastric malignancies was provided while presenting the potential utilization of these chemoattractants as therapeutic elements.


Assuntos
Quimiocinas/metabolismo , Quimiocinas/farmacologia , Infecções por Helicobacter/terapia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Quimiocinas CXC/imunologia , Quimiocinas CXC/metabolismo , Mucosa Gástrica/metabolismo , Gastrite , Infecções por Helicobacter/complicações , Infecções por Helicobacter/imunologia , Helicobacter pylori/imunologia , Helicobacter pylori/metabolismo , Helicobacter pylori/patogenicidade , Humanos , Receptores CXCR/imunologia , Receptores CXCR/metabolismo , Receptores de Quimiocinas/imunologia , Receptores de Quimiocinas/metabolismo , Estômago/patologia , Neoplasias Gástricas/patologia , Linfócitos T/imunologia , Linfócitos T/metabolismo
14.
Mater Sci Eng C Mater Biol Appl ; 103: 109800, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31349458

RESUMO

Azelnidipine, dihydropyridine based calcium channel blocker has been used for treating ischemic heart disease and cardiac remodeling after myocardial infarction but it is having a low bioavailability due to its poor solubility. The present study is to investigate the formulation and evaluation of floating tablets of Azelnidipine for controlled release and to increase bioavailability by increasing the gastrointestinal transit time and mucoadhesion of drug. The gastro retentive tablets were prepared by direct compression method using different concentrations of combination of Polyoxyethylene oxide WSR 303 as hydrophilic polymer and Potassium bicarbonate as gas generating agent. Main effects of the formulation variables were evaluated quantitatively using design approach showing that both independent variables have significant effects on floating lag time, % drug release at 1 h (D1 h) and time required to release 90% of the drug (t90). The statistically optimized formulation (F3) released 95.11 ±â€¯1.43% drug for 12 h followed K-Peppas drug release kinetics indicating release of drug by diffusion and erosion mechanism. Evaluation of the optimized formulation in vivo in human volunteers showed that the GFT was buoyant in gastric fluid and that its gastric residence time was enhanced. Pharmacokinetics studies carried out revealed significant (P < 0.05) equivalent Cmax, longer Tmax and higher AUC values for the optimized formula compared to the marketed oral product. From the results obtained it can be concluded that Azelnidipine Gastro retentive tablets with enhanced bioavailability and better release pattern is suitable for more effective treatment compared to marketed conventional tablets.


Assuntos
Anti-Hipertensivos/farmacocinética , Ácido Azetidinocarboxílico/análogos & derivados , Di-Hidropiridinas/química , Portadores de Fármacos/química , Mucosa Gástrica/metabolismo , Comprimidos/química , Animais , Anti-Hipertensivos/química , Anti-Hipertensivos/farmacologia , Ácido Azetidinocarboxílico/química , Ácido Azetidinocarboxílico/farmacocinética , Ácido Azetidinocarboxílico/farmacologia , Bicarbonatos/química , Disponibilidade Biológica , Pressão Sanguínea/efeitos dos fármacos , Di-Hidropiridinas/farmacocinética , Di-Hidropiridinas/farmacologia , Composição de Medicamentos , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Ácido Gástrico/química , Meia-Vida , Humanos , Polietilenoglicóis/química , Compostos de Potássio/química , Coelhos
15.
Curr Gastroenterol Rep ; 21(8): 34, 2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-31289921

RESUMO

PURPOSE OF REVIEW: The gastroduodenal mucosal layer is a complex and dynamic system that functions in an interdependent manner to resist injury. We review and summarize the most updated knowledge about gastroduodenal defense mechanisms and specifically address (a) the mucous barrier, (b) membrane and cellular properties, and vascular, hormonal, and (c) gaseous mediators. RECENT FINDINGS: Trefoil factor family peptides play a crucial role in cellular restitution by increasing cellular permeability and expression of aquaporin channels, aiding cellular migration and tissue repair. Additionally, evidence suggests that the symptoms of functional dyspepsia may be attributed to alterations in the duodenum, including low-grade inflammation and increased mucosal permeability. The interaction of the various mucosal protective components helps maintain structural and functional homeostasis. There is increasing evidence suggesting that the upper GI microbiota plays a crucial role in the defense mechanisms. However, this warrants further investigation.


Assuntos
Duodeno/fisiologia , Mucosa Gástrica/fisiologia , Mucosa Intestinal/fisiologia , Duodeno/lesões , Duodeno/metabolismo , Mucosa Gástrica/lesões , Mucosa Gástrica/metabolismo , Microbioma Gastrointestinal/fisiologia , Humanos , Mucosa Intestinal/lesões , Mucosa Intestinal/metabolismo , Mucinas/fisiologia , Permeabilidade , Fatores de Proteção
16.
Toxicol Lett ; 313: 150-158, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31276768

RESUMO

Ochratoxin A (OTA), one of the most abundant food-contaminating mycotoxins, is a possible carcinogen to humans. We previously demonstrated that long-term (40 weeks) OTA exposure induces the malignant transformation of human gastric epithelium cells (GES-1) in vitro. However, the specific mechanism underlying OTA-induced gastric carcinogenesis is complex. In the present study, we used 2-DE and matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI/TOF MS) combined with bioinformatics and immunoblotting to investigate the differentially expressed proteins between GES-1 and OTA-malignant transformed GES-1 cells (OTA-GES-1T cells) in vitro. We found that four differentially expressed proteins were identified after malignant transformation, including actin, cytoplasmic 1 (ACTB), F-actin-capping protein subunit alpha-1 (CAPZA1), Annexin A3 (ANXA3), thioredoxin peroxidase B from red blood cells (TPx-B) and Fibrinogen beta B (Fibrinogen ß). Among the differentially expressed proteins, the effect of Annexin A3 was analyzed by MTT assay, western blot, cell cycle analysis, wound healing assay, Transwell assay, and colony formation assay in OTA-GES-1T cells. The results showed that inhibition of Annexin A3 by siRNA effectively prevented the proliferation, migration, and invasion abilities of OTA-GES-1T cells. Collectively, the results of this study will guide future research on OTA carcinogenicity.


Assuntos
Anexina A3/metabolismo , Carcinógenos/toxicidade , Transformação Celular Neoplásica/induzido quimicamente , Células Epiteliais/efeitos dos fármacos , Mucosa Gástrica/efeitos dos fármacos , Ocratoxinas/toxicidade , Neoplasias Gástricas/induzido quimicamente , Anexina A3/genética , Western Blotting , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Biologia Computacional , Eletroforese em Gel Bidimensional , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patologia , Humanos , Invasividade Neoplásica , Proteômica/métodos , Transdução de Sinais/efeitos dos fármacos , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia
17.
Eur J Pharm Biopharm ; 142: 307-314, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31288077

RESUMO

The influence of physiological factors on the solubility of drug compounds has been thoroughly investigated in humans. However, as these factors vary between species and since many in vivo studies are carried out in rats or mice, it has been difficult to establish sufficient in vitro in vivo relations. The aim of this study was to develop a physiologically relevant in vitro dissolution model simulating the gastrointestinal (GI) fluids of fasted rats and compare it to previously published in vitro and in vivo data. To develop the in vitro model, the pH was measured in situ in six segments of the GI tract of anesthetised rats, then the fluids from the stomach, the proximal and the distal small intestine were collected and characterized with regard to osmolality, and bile acid and phospholipid concentration. The pH and osmolality were found to increase throughout the GI tract. The bile acids and phospholipids were present in high concentrations in the proximal small intestine, and the bile acid concentration doubled in the distal part, where the phospholipid concentration decreased. Matrix-assisted laser desorption ionisation mass spectrometry imaging was applied on a cross section of the small intestine, to study which bile acids and phospholipid classes were present in the small intestine of rats. Both cholic acid, taurocholic acid and glycocholic acid were detected, and phosphatidylcholine (34:2) was found to be mainly present in the intestinal wall or mucus, whereas lysophosphatidylcholine (16:0) was also detected in the lumen. Based on these observations, biorelevant media were developed to simulate fluids in the stomach and the proximal part of the small intestine in fasted rats. The media were implemented in a two-step in vitro dissolution model, which was found to better predict the in vivo performance of furosemide, when compared to previously published in vitro and in vivo data.


Assuntos
Líquidos Corporais/metabolismo , Líquidos Corporais/fisiologia , Mucosa Gástrica/metabolismo , Intestino Delgado/metabolismo , Intestino Delgado/fisiologia , Preparações Farmacêuticas/metabolismo , Estômago/fisiologia , Animais , Humanos , Concentração de Íons de Hidrogênio , Masculino , Camundongos , Concentração Osmolar , Ratos , Ratos Sprague-Dawley , Solubilidade
18.
Biol Pharm Bull ; 42(7): 1120-1127, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31257288

RESUMO

Hydroxytyrosol (HT) is a simple phenol compound present in olive oil. In a previous in vitro study, we showed that HT downregulated lipopolysaccharide-mediated expression of inducible nitric oxide synthase, cyclooxygenase-2 (COX-2), tumor necrosis factor alpha, and interleukin-1ß, resulting in reduced nitric oxide and prostaglandin E2 production. In the present study, we aimed to determine whether HT suppresses COX-2-induced inflammation in a carrageenan-induced rat paw edema model. Additionally, we compared its activity with those of the selective COX-2 inhibitor, celecoxib for a comparative control, and a representative nonsteroidal anti-inflammatory drug (NSAID), indomethacin for a positive control. HT, celecoxib, and indomethacin significantly suppressed swelling in carrageenan-injected rat paws. Although HT was less effective than celecoxib and indomethacin, it had a delayed onset of action. Moreover, we evaluated whether HT aggravates gastric damage, which is a typical adverse effect associated with NSAIDs and COX-2 inhibitors under low dose aspirin (LDA) treatment, in an aspirin-induced gastric damage rat model. Unlike celecoxib and indomethacin, HT did not cause gastric damage when co-administered with aspirin. Our results indicate that HT exerts a delayed but sustained anti-inflammatory effect against COX-2-mediated inflammation. Finally, the combination of short-acting conventional anti-inflammatory drugs and long-acting HT can be considered a new, safe, and effective anti-inflammatory treatment modality even when continuously administered for a long period under LDA treatment.


Assuntos
Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Edema/tratamento farmacológico , Álcool Feniletílico/análogos & derivados , Úlcera Gástrica/tratamento farmacológico , Estômago/efeitos dos fármacos , Animais , Aspirina , Carragenina , Celecoxib , Inibidores de Ciclo-Oxigenase 2/farmacologia , Dinoprostona/metabolismo , Edema/induzido quimicamente , Edema/metabolismo , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/metabolismo , Indometacina , Masculino , Olea , Álcool Feniletílico/farmacologia , Álcool Feniletílico/uso terapêutico , Ratos Sprague-Dawley , Estômago/patologia , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/metabolismo
19.
Mar Drugs ; 17(7)2019 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-31336895

RESUMO

The Atlantic mackerel, Scomber scombrus, is one of the most fished species in the world, but it is still largely used for low-value products, such as bait; mainly for crustacean fishery. This resource could be transformed into products of high value and may offer new opportunities for the discovery of bioactive molecules. Mackerel hydrolysate was investigated to discover antibacterial peptides with biotechnological potential. The proteolytic process generated a hydrolysate composed of 96% proteinaceous compounds with molecular weight lower than 7 kDa. From the whole hydrolysate, antibacterial activity was detected against both Gram-negative and Gram-positive bacteria. After solid phase extraction, purification of the active fraction led to the identification of 4 peptide sequences by mass spectrometry. The peptide sequence N-KVEIVAINDPFIDL-C, called Atlantic Mackerel GAPDH-related peptide (AMGAP), was selected for chemical synthesis to confirm the antibacterial activity and to evaluate its stability through in vitro digestibility. Minimal inhibitory concentrations of AMGAP revealed that Listeria strains were the most sensitive, suggesting potential as food-preservative to prevent bacterial growth. In addition, in vitro digestibility experiments found rapid (after 20 min) and early digestibility (stomach). This study highlights the biotechnological potential of mackerel hydrolysate due to the presence of the antibacterial AMGAP peptide.


Assuntos
Antibacterianos/farmacologia , Peptídeos Catiônicos Antimicrobianos/farmacologia , Conservantes de Alimentos/farmacologia , Perciformes , Hidrolisados de Proteína/farmacologia , Animais , Antibacterianos/química , Antibacterianos/isolamento & purificação , Peptídeos Catiônicos Antimicrobianos/química , Peptídeos Catiônicos Antimicrobianos/isolamento & purificação , Biotecnologia/métodos , Conservantes de Alimentos/química , Conservantes de Alimentos/isolamento & purificação , Mucosa Gástrica/metabolismo , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Hidrolisados de Proteína/química , Hidrolisados de Proteína/isolamento & purificação , Estabilidade Proteica , Proteólise , Suínos
20.
J Exp Clin Cancer Res ; 38(1): 283, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31262330

RESUMO

BACKGROUND: Mucins are key components of the mucosal barrier in the stomach that protects epithelia from carcinogenic effects of chronic inflammation. Analysis of The Cancer Genome Atlas database indicated that mucin-17 (MUC17) was more highly expressed in gastric cancer (GC) specimens, with favourable prognosis for patients. To explore the underlying mechanisms, we investigated the potential role of MUC17 in controlling chronic gastric inflammation. METHODS: We initially quantified the expression of MUC17 and inflammatory factor, as well as the association of MUC17 with survive in GC using immunohistochemistry. To establish how the inflammatory factors affect MUC17 expression, we explored luciferase reporter, chromatin immunoprecipitation (ChIP), and electrophoretic mobility shift (EMSA) assays. The role and mechanism that MUC17 plays in inflammation-induced cell proliferation was examined in AGS cells with reduced MUC17 expression and MKN45 cells overexpressing a truncated MUC17. RESULTS: We found MUC17 was induced by inflammatory cytokines in GC cells via CDX1upregulation. MUC17 thus inactivated NFκB to inhibit GC cell proliferation in response to pro-inflammatory cytokines. We also revealed that the function of MUC17 was dependent on its conserved epidermal growth factor domain and on downstream sequences to enable its interaction with myosin-9, resulting in a sustained regulatory feedback loop between myosin-9, p53, and RhoA, and then activation of p38 to negatively regulate the NFκB pathway in GC cells. This mechanism was also confirmed in vivo. CONCLUSIONS: Our study demonstrates MUC17 as a GC suppressor protein which has the therapeutic potential for human GC.


Assuntos
Proteínas Motores Moleculares/metabolismo , Mucinas/metabolismo , Cadeias Pesadas de Miosina/metabolismo , Neoplasias Gástricas/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Proteína rhoA de Ligação ao GTP/metabolismo , Animais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Ciclo Celular/genética , Linhagem Celular Tumoral , Progressão da Doença , Retroalimentação Fisiológica , Mucosa Gástrica/imunologia , Mucosa Gástrica/metabolismo , Proteínas de Homeodomínio/metabolismo , Humanos , Inflamação/metabolismo , Interleucina-8/metabolismo , Camundongos , Mucinas/genética , NF-kappa B/metabolismo , Transdução de Sinais , Neoplasias Gástricas/genética , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/mortalidade , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
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