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1.
Odontology ; 107(4): 530-535, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31030294

RESUMO

The aim of this study was to evaluate self-reported periodontitis (PD) prevalence in migraineurs as well as to investigate the association between both diseases. A cross-sectional survey was carried out including patients diagnosed with migraine attending 12 Spanish Headache Units. We determined diagnosis of PD administering a validated self-reported questionnaire. Socio-demographic, clinical and medical information, comorbidities, daily habits, migraine characteristics and medication were collected using a questionnaire. Of the 651 consecutive migraineurs included in the study, 393 suffered from chronic migraine (CM). Self-reported PD was detected in 327 patients with migraine (50.2%). Migraineurs with self-reported PD were significantly older and had a previous history of fibromyalgia, stress, anxiety, depression, and allodynia (all P < 0.001). Additionally, this group of patients consumed more topiramate (P = 0.008) and simple analgesics (P < 0.001) than patients with migraine and without self-reported PD. Also, they were less active physically and belonged to a low education level (both P < 0.001). Prevalence of self-reported PD was significantly higher in chronic migraineurs compared to those diagnosed with episodic migraine (EM) (53.9% vs. 44.6%, P = 0.019). Logistic regression analyses showed that self-reported PD was associated with CM (OR 1.456; 95% CI 1.062-1.997, P = 0.020). However, after adjusting for significant confounders, the association was attenuated (OR 1.100; 95% CI 0.784-1.543, P = 0.581). We concluded that self-reported PD was significantly more frequent in CM compared to EM. Self-reported PD was associated with the presence of CM, although some comorbidities shared by both diseases could have an effect on this association.


Assuntos
Transtornos de Enxaqueca , Periodontite , Estudos Transversais , Humanos , Autorrelato , Espanha , Inquéritos e Questionários
2.
Front Immunol ; 9: 77, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29434597

RESUMO

CCR9 is as an interesting target for the treatment of human CCR9+-T cell acute lymphoblastic leukemia, since its expression is limited to immature cells in the thymus, infiltrating leukocytes in the small intestine and a small fraction of mature circulating T lymphocytes. 92R, a new mouse mAb (IgG2a isotype), was raised using the A-isoform of hCCR9 as immunogen. Its initial characterization demonstrates that binds with high affinity to the CCR9 N-terminal domain, competing with the previously described 91R mAb for receptor binding. 92R inhibits human CCR9+ tumor growth in T and B-cell deficient Rag2-/- mice. In vitro assays suggested complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity as possible in vivo mechanisms of action. Unexpectedly, 92R strongly inhibited tumor growth also in a model with compromised NK and complement activities, suggesting that other mechanisms, including phagocytosis or apoptosis, might also be playing a role on 92R-mediated tumor elimination. Taken together, these data contribute to strengthen the hypothesis of the immune system's opportunistic nature.


Assuntos
Anticorpos Monoclonais/farmacologia , Leucemia/metabolismo , Leucemia/patologia , Receptores CCR/antagonistas & inibidores , Sequência de Aminoácidos , Animais , Citotoxicidade Celular Dependente de Anticorpos , Biomarcadores , Linhagem Celular , Linhagem Celular Tumoral , Quimiocinas CC/metabolismo , Citotoxicidade Imunológica , Modelos Animais de Doenças , Epitopos/química , Epitopos/imunologia , Humanos , Leucemia/tratamento farmacológico , Leucemia/genética , Camundongos , Receptores CCR/metabolismo , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Rev. Fac. Med. (Guatemala) ; 1(23 Segunda Época): 8-15, Jul-Dic 2017.
Artigo em Espanhol | LILACS-Express | LILACS | ID: biblio-1140390

RESUMO

Introducción: La diabetes mellitus está al alza en la actualidad debido a múltiples factores en el estilo de vida. Las complicaciones de la enfermedad dicen mucho del adecuado seguimiento al apego del tratamiento y los cambios a su estilo de vida. Objetivo: evaluar el apego al tratamiento farmacológico y estilo de vida en personas con diabetes mellitus tipo 2 (DM2) Métodos: estudio prospectivo realizado en 276 personas con DM2 que acudieron a consulta al Patronato del Diabético zona 1 durante agosto 2016. Para evaluar el apego al tratamiento farmacológico se utilizó la escala de adherencia a medicamentos Morisky-8 y el cuestionario IMEVID para el estilo de vida. La adherencia se clasificó como baja, media y alta y el estilo de vida como desfavorable, poco favorable o favorable dependiendo de la calificación total. Para el análisis de datos se utilizó SPSS y estadísticas descriptivas. Resultados: 56% de los pacientes encuestados tienen un nivel de adherencia bajo en la toma de sus medicamentos. 71% llevan un estilo de vida poco favorable para su enfermedad. Conclusión: el apego al tratamiento en la mayoría de pacientes que acuden al Patronato del Diabético no es óptimo. Palabras clave: Diabetes mellitus, estilo de vida, apego, adherencia


Introduction. Type 2 diabetes is on the rise mainly due to several factors involved but mainly due to changes in life style. Its complications reflex none adequate adherence to recommended treatment. Objective: To evaluate medication adherence and lifestyle in persons with type 2 diabetes mellitus Methods: prospective study carried out in 276 patients of Patronato del Diabético during august 2016. To determine adherence to pharmacologic treatment, the Morisky-8 medication adherence scale was used and to determine lifestyle the IMEVID questionnaire. Depending on the total score medication adherence was classified as low, medium or high; and lifestyle as unfavorable, poor and favorable. Data were analyzed using descriptive statistics and SPSS program. Results: 56% of patients have low adherence in taking their medication for diabetes and 71% have a poor lifestyle for their disease Conclusion: adherence to treatment in the majority of patients that go for medical attention in Patronato del Diabético is not optimal. Keywords: Diabetes mellitus, adherence, life style

4.
BMC Pharmacol Toxicol ; 16: 9, 2015 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-25889594

RESUMO

BACKGROUND: In vitro and animal experiments have shown that the transport and signaling of ß2-adrenergic agonists are pH-sensitive. Inhaled albuterol, a hydrophilic ß2-adrenergic agonist, is widely used for the treatment of obstructive airway diseases. Acute exacerbations of obstructive airway diseases can be associated with changes in ventilation leading to either respiratory acidosis or alkalosis thereby affecting albuterol responsiveness in the airway. The purpose of this study was to determine if airway pH has an effect on albuterol-induced vasodilation in the airway. METHODS: Ten healthy volunteers performed the following respiratory maneuvers: quiet breathing, hypocapnic hyperventilation, hypercapnic hyperventilation, and eucapnic hyperventilation (to dissociate the effect of pH from the effect of ventilation). During these breathing maneuvers, exhaled breath condensate (EBC) pH and airway blood flow response to inhaled albuterol (ΔQ̇aw) were assessed. RESULTS: Mean ± SE EBC pH (units) and ΔQ̇aw (µl.min(-1).mL(-1)) were 6.4 ± 0.1 and 16.8 ± 1.9 during quiet breathing, 6.3 ± 0.1 and 14.5 ± 2.4 during eucapnic hyperventilation, 6.6 ± 0.2 and -0.2 ± 1.8 during hypocapnic hyperventilation (p = 0.02 and <0.01 vs. quiet breathing), and 5.9 ± 0.1 and 2.0 ± 1.5 during hypercapnic hyperventilation (p = 0.02 and <0.02 vs quiet breathing). CONCLUSIONS: Albuterol responsiveness in the airway as assessed by ΔQ̇aw is pH sensitive. The breathing maneuver associated with decreased and increased EBC pH both resulted in a decreased responsiveness independent of the level of ventilation. These findings suggest an attenuated response to hydrophilic ß2-adrenergic agonists during airway disease exacerbations associated with changes in pH. TRIAL REGISTRATION: Registered at clinicaltrials.gov: NCT01216748 .


Assuntos
Acidose Respiratória/fisiopatologia , Albuterol/farmacologia , Alcalose Respiratória/fisiopatologia , Músculo Liso Vascular/efeitos dos fármacos , Administração por Inalação , Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Adulto , Albuterol/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Liso Vascular/irrigação sanguínea , Músculo Liso Vascular/fisiologia , Adulto Jovem
5.
J Biol Chem ; 287(50): 42288-98, 2012 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-23048036

RESUMO

Cigarette smoke (CigS) exposure is associated with increased bronchial epithelial permeability and impaired barrier function. Primary cultures of normal human bronchial epithelial cells exposed to CigS exhibit decreased E-cadherin expression and reduced transepithelial electrical resistance. These effects were mediated by hyaluronan (HA) because inhibition of its synthesis with 4-methylumbelliferone prevented these effects, and exposure to HA fragments of <70 kDa mimicked these effects. We show that the HA receptor layilin is expressed apically in human airway epithelium and that cells infected with lentivirus expressing layilin siRNAs were protected against increased permeability triggered by both CigS and HA. We identified RhoA/Rho-associated protein kinase (ROCK) as the signaling effectors downstream layilin. We conclude that HA fragments generated by CigS bind to layilin and signal through Rho/ROCK to inhibit the E-cadherin gene and protein expression, leading to a loss of epithelial cell-cell contact. These studies suggest that HA functions as a master switch protecting or disrupting the epithelial barrier in its high versus low molecular weight form and that its depolymerization is a first and necessary step triggering the inflammatory response to CigS.


Assuntos
Caderinas/biossíntese , Regulação da Expressão Gênica , Ácido Hialurônico/biossíntese , Lectinas Tipo C/metabolismo , Mucosa Respiratória/metabolismo , Transdução de Sinais , Fumar/efeitos adversos , Caderinas/genética , Células Cultivadas , Impedância Elétrica , Feminino , Humanos , Ácido Hialurônico/genética , Himecromona/análogos & derivados , Himecromona/farmacologia , Inflamação/induzido quimicamente , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Lectinas Tipo C/genética , Lentivirus , Masculino , Permeabilidade/efeitos dos fármacos , Mucosa Respiratória/patologia , Fumar/genética , Fumar/metabolismo , Transdução Genética , Quinases Associadas a rho/genética , Quinases Associadas a rho/metabolismo
6.
Am J Physiol Lung Cell Mol Physiol ; 300(2): L204-15, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21097527

RESUMO

Cigarette smoke represents a major risk factor for the development of chronic obstructive pulmonary disease (COPD), a respiratory condition associated with airflow obstruction, mucus hypersecretion, chronic inflammation, and upregulation of inflammatory mediators such as the monocyte chemotactic protein-1 (MCP-1). MCP-1 through its receptor CCR2 induces chemotaxis and activates (44/42)MAPK, a kinase known to play a key role in mucin regulation in bronchial epithelium. In the present study we used differentiated primary cultures of normal human bronchial epithelial (NHBE) cells to test whether MCP-1 through its receptor CCR2 induces mucin upregulation. We have provided evidence that NHBE cells release MCP-1 to the epithelial surface and express the CCR2B isoform of the receptor mainly at the apical pole. In addition, we found that MCP-1 has a novel function in airway epithelium, increasing the two major airway mucins MUC5AC and MUC5B, an effect mediated, at least in part, by a cascade of events initiated by interaction of its receptor CCR2B with G(q) subunits in caveolae, followed by PLCß, PKC, and (44/42)MAPK activation. We also have shown that MCP-1 is able to induce its own expression using the same receptor but through a different pathway that involves RhoA GTPase. Furthermore, we found that a single exposure to MCP-1 is enough to induce MCP-1 secretion and sustained mucin upregulation up to 7 days after initial exposure, an effect mediated by CCR2B as confirmed using short hairpin RNA. These results agree with our data in smoker's airway epithelium, where CCR2B is present in MUC5AC- and MUC5B-expressing cells and augmented MCP-1 expression is associated with increased MUC5AC and MUC5B immunolabeling, suggesting that the mechanisms described in primary cell cultures in the present study are operative in vivo. Therefore, therapeutic approaches targeting MCP-1/CCR2B may be useful in preventing not only influx of inflammatory cells to the airways but also mucus hypersecretion and goblet cell hyperplasia.


Assuntos
Quimiocina CCL2/metabolismo , Mucina-5AC/metabolismo , Mucina-5B/metabolismo , Receptores CCR2/metabolismo , Mucosa Respiratória/metabolismo , Adulto , Brônquios/efeitos dos fármacos , Brônquios/metabolismo , Cavéolas/metabolismo , Caveolina 1/metabolismo , Células Cultivadas , Quimiocina CCL2/genética , Quimiocina CCL2/farmacologia , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/metabolismo , Técnicas de Silenciamento de Genes , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Pessoa de Meia-Idade , Modelos Biológicos , Doença Pulmonar Obstrutiva Crônica/etiologia , Doença Pulmonar Obstrutiva Crônica/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores CCR2/antagonistas & inibidores , Receptores CCR2/genética , Mucosa Respiratória/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Fumar/efeitos adversos , Fumar/metabolismo , Adulto Jovem , Proteína rhoA de Ligação ao GTP/metabolismo
7.
J Biol Chem ; 285(34): 26126-34, 2010 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-20554532

RESUMO

Hyaluronidase 2 (Hyal2) is a hyaluronan (HA)-degrading enzyme found intracellularly or/and anchored to the plasma membrane through glycosylphosphatidylinositol (GPI). Normal human bronchial epithelial cells (NHBE) grown at the air-liquid interphase (ALI), treated with PI-specific phospholipase C (PI-PLC), exhibited increased Hyal activity in secretions and decreased protein and activity on the apical membrane, confirming that GPI-anchored Hyal2 is expressed in NHBE cells and it remains active in its soluble form. We have reported that HA degradation was mediated by reactive oxygen species (ROS) in human airways. Here we show that ROS increase Hyal2 expression and activity in NHBE cells and that the p38MAPK signaling pathway is involved in this effect. Hyal2 induction was confirmed by using small interfering RNA (siRNA) expressing lentivirus. These in vitro findings correlated in vivo with smokers, where increased Hyal2 immunoreactivity in the epithelium was associated with augmented levels of HA and the appearance of low molecular mass HA species in bronchial secretions. In summary, this work provides evidence that ROS induce Hyal2, suggesting that Hyal2 is likely responsible for the sustained HA fragmentation in the airway lumen observed in inflammatory conditions associated with oxidative stress.


Assuntos
Antígenos de Neoplasias/metabolismo , Histona Acetiltransferases/metabolismo , Ácido Hialurônico/metabolismo , Hialuronoglucosaminidase/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Mucosa Respiratória/metabolismo , Células Cultivadas , Glicosilfosfatidilinositóis , Humanos , Inflamação , Sistema de Sinalização das MAP Quinases , Estresse Oxidativo , Mucosa Respiratória/citologia
8.
Am J Respir Cell Mol Biol ; 40(3): 277-85, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18757307

RESUMO

Mucus hypersecretion with elevated MUC5B mucin production is a pathologic feature in many airway diseases associated with oxidative stress. In the present work, we evaluated MUC5B expression in airways and in primary cultures of normal human bronchial epithelial (NHBE) cells, as well as the mechanisms involved in its regulation. We found that oxidative stress generated by cigarette smoke or reactive oxygen species (ROS) induces MUC5B up-regulation in airway epithelium from smokers and in NHBE cells, respectively. We have previously shown that ROS-induced MUC5AC expression in NHBE cells is dependent on hyaluronan depolymerization and epidermal growth factor receptor (EGFR)/mitogen-activated protein kinase (MAPK) activation. Since hyaluronan fragments can activate MAPK through the hyaluronan receptor CD44, and CD44 heterodimerizes with EGFR, we tested whether ROS and/or hyaluronan fragments induce MUC5B mRNA and protein expression through CD44/EGFR. We found that ROS promotes CD44/EGFR interaction, EGFR/MAPK activation, and MUC5B up-regulation that are prevented by blocking CD44 and/or EGFR. These results were mimicked by hyaluronan fragments. In summary, our results show that oxidative stress in vivo (cigarette smoke) or in vitro (ROS) induces MUC5B up-regulation. This ROS-induced MUC5B expression requires CD44 as well as EGFR and MAPK activation. In addition, we also provide evidence that hyaluronan fragments are sufficient to induce CD44/EGFR interaction and downstream signaling that results in MUC5B up-regulation, suggesting that hyaluronan depolymerization during inflammatory responses could be directly involved in the induction of mucus hypersecretion.


Assuntos
Regulação da Expressão Gênica , Receptores de Hialuronatos/metabolismo , Ácido Hialurônico/metabolismo , Mucina-5B/metabolismo , Estresse Oxidativo , Fragmentos de Peptídeos/metabolismo , Mucosa Respiratória/fisiologia , Adulto , Animais , Células Cultivadas , Ativação Enzimática , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/fisiologia , Receptores ErbB/genética , Receptores ErbB/metabolismo , Humanos , Receptores de Hialuronatos/genética , Ácido Hialurônico/genética , Pessoa de Meia-Idade , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Mucina-5B/genética , Fragmentos de Peptídeos/genética , Espécies Reativas de Oxigênio/metabolismo , Mucosa Respiratória/citologia , Mucosa Respiratória/efeitos dos fármacos , Transdução de Sinais/fisiologia , Fumaça/efeitos adversos , Fumar , Tabaco/efeitos adversos , Xantina/metabolismo , Xantina Oxidase/metabolismo , Adulto Jovem
9.
J Appl Physiol (1985) ; 105(1): 54-7, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18467553

RESUMO

Cigarette smoking is associated with attenuated endothelium-dependent vasodilation (endothelial dysfunction) in the systemic circulation, including the airway circulation. We wished to determine whether an inhaled corticosteroid could restore endothelial function in the airway of lung-healthy current smokers, ex-smokers, and nonsmokers. We measured baseline airway blood flow (Qaw) and Qaw reactivity to inhaled albuterol as an index of endothelium-dependent vasodilation and to sublingual nitroglycerin as an index of endothelium-independent vasodilation in lung-healthy current smokers, ex-smokers, and nonsmokers. Current smokers were then treated with inhaled fluticasone for 3 wk, and all measurements were repeated after fluticasone treatment and after a subsequent 3-wk fluticasone washout period. Baseline mean Qaw and endothelium-independent Qaw reactivity were similar in the three groups. Mean endothelium-dependent Qaw reactivity was 49.5% in nonsmokers, 42.7% in ex-smokers, and 10.8% in current smokers (P < 0.05 vs. nonsmokers). In current smokers, mean baseline Qaw was unchanged after fluticasone treatment, but endothelium-dependent Qaw reactivity significantly increased to 34.9%. Qaw reactivity was again blunted after fluticasone washout. Endothelial dysfunction, as assessed by vascular reactivity, can be corrected with an inhaled corticosteroid in the airway of lung-healthy current smokers. This proof of concept can serve as the basis for future clinical investigations on the effect of glucocorticoids on endothelial function in smokers.


Assuntos
Androstadienos/farmacologia , Broncodilatadores/farmacologia , Endotélio/efeitos dos fármacos , Glucocorticoides/farmacologia , Fumar/fisiopatologia , Administração por Inalação , Adolescente , Adulto , Albuterol/administração & dosagem , Albuterol/farmacologia , Androstadienos/administração & dosagem , Broncodilatadores/administração & dosagem , Feminino , Fluticasona , Volume Expiratório Forçado/efeitos dos fármacos , Volume Expiratório Forçado/fisiologia , Glucocorticoides/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Relaxamento Muscular/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Nitroglicerina/farmacologia , Fluxo Sanguíneo Regional/efeitos dos fármacos , Testes de Função Respiratória , Sistema Respiratório/irrigação sanguínea , Espirometria , Vasodilatadores/farmacologia
10.
Am J Respir Cell Mol Biol ; 39(3): 289-95, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18390475

RESUMO

Hyaluronan (HA) is present at the apical surface of airway epithelium as a high-molecular-weight polymer. Since HA depolymerization initiates a cascade of events that results in kinin generation and growth factor processing, in the present work we used primary cultures of human bronchial epithelial (HBE) cells grown at the air-liquid interface (ALI) to assess hyaluronidase (Hyal) activity by HA zymography, gene expression by quantitative real-time PCR, and localization by confocal microscopy. Because TNF-alpha and IL-1beta induce Hyals in other cells, we tested their effects on Hyals expression and activity. We found that Hyal-like activity is present in the apical and basolateral secretions from HBE cells where Hyals 1, 2, and 3 are expressed, and that IL-1beta acts synergistically with TNF-alpha to increase gene expression and activity. Confocal microscopy showed that Hyals 1, 2, and 3 were localized intracellularly, while Hyal2 was also expressed at the apical pole associated with the plasma membrane, and in a soluble form on the apical secretions. Tissue sections from normal individuals and from individuals with asthma showed a Hyal distribution pattern similar to that observed on nontreated HBE cells or exposed to cytokines, respectively. In addition, increased expression and activity were observed in tracheal sections and in bronchoalveolar lavage (BAL) obtained from subjects with asthma when compared with normal lung donors and healthy volunteers. Our observations indicate that Hyal 1, 2, and 3 are expressed in airway epithelium and may operate in a coordinated fashion to depolymerize HA during inflammation associated with up-regulation of TNF-alpha and IL-1beta, such as allergen-induced asthmatic responses.


Assuntos
Citocinas/fisiologia , Hialuronoglucosaminidase/biossíntese , Mediadores da Inflamação/fisiologia , Mucosa Respiratória/enzimologia , Alérgenos/administração & dosagem , Alérgenos/imunologia , Asma/enzimologia , Líquido da Lavagem Broncoalveolar , Células Cultivadas , Imunofluorescência , Expressão Gênica , Humanos , Ácido Hialurônico/biossíntese , Reação em Cadeia da Polimerase , Traqueia/citologia , Traqueia/enzimologia
11.
Am J Respir Cell Mol Biol ; 37(2): 160-8, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17395888

RESUMO

Hyaluronan (HA) is synthesized in high-molecular-weight form at the apical pole of airway epithelial cells, covering the luminal surface. When human airway epithelial cells grown and redifferentiated at the air-liquid interface (ALI) were exposed to xanthine/xanthine oxidase (X/XO), ciliary beat frequency (CBF) increased. This effect was blocked by superoxide dismutase (SOD) and catalase. Inhibition of hyaluronan synthesis inhibited the CBF response to X/XO, while addition of exogenous HA amplified it. A functionally blocking antibody to the receptor for hyaluronic acid-mediated motility (RHAMM) reduced the CBF response to X/XO. Since RHAMM has no transmembrane domain and thus cannot signal on its own, the association of RHAMM with recepteur d'origine nantais (RON), a member of the hepatocyte growth factor receptor family, was explored. Immunohistochemistry of human airway epithelium showed co-localization of RHAMM and RON at the apex of ciliated cells. Physical association of RHAMM and RON was confirmed with co-immunoprecipitations. Macrophage-stimulating protein (MSP), an agonist of RON, stimulated CBF. Genistein, a nonspecific tyrosine kinase inhibitor, and MSP beta chain (beta-MSP), a specific RON inhibitor, blocked the X/XO-induced CBF increase. HA present in the apical secretions of human airway epithelial cells was shown to degrade upon exposure to X/XO, a process inhibited by SOD. Low-molecular-weight HA fragments stimulated CBF, an effect blocked by anti-RHAMM antibody and genistein. These data suggest that high molecular form HA is broken down by reactive oxygen species to form low-molecular-weight fragments that signal via RHAMM and RON to stimulate CBF.


Assuntos
Cílios/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Receptores de Hialuronatos/metabolismo , Ácido Hialurônico/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Mucosa Respiratória/citologia , Animais , Anticorpos/metabolismo , Polaridade Celular , Células Cultivadas , Fator de Crescimento de Hepatócito/genética , Fator de Crescimento de Hepatócito/metabolismo , Humanos , Oxirredução , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Mucosa Respiratória/metabolismo , Traqueia/anatomia & histologia , Xantina/metabolismo , Xantina Oxidase/metabolismo
12.
Am J Respir Cell Mol Biol ; 36(1): 20-31, 2007 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16873769

RESUMO

TSG-6 (the protein product of TNF-stimulated gene-6), an inflammation-associated protein, forms covalent complexes with heavy chains (HCs) from inter-alpha-inhibitor and pre-alpha-inhibitor and associates noncovalently with their common bikunin chain, potentiating the antiplasmin activity of this serine protease inhibitor. We show that TSG-6 and TSG-6.HC complexes are present in bronchoalveolar lavage fluid from patients with asthma and increase after allergen challenge. Immunodetection demonstrated elevated TSG-6 in the airway tissue and secretions of smokers. Experiments conducted in vitro with purified components revealed that bikunin.HC complexes (byproducts of TSG-6.HC formation) release bikunin. Immunoprecipitation revealed that bikunin accounts for a significant proportion of tissue kallikrein inhibition in bronchoalveolar lavage after allergen challenge but not in baseline conditions, confirming that bikunin in its free state, but not when associated with HCs, is a relevant protease inhibitor in airway secretions. In primary cultures of differentiated human airway epithelial and submucosal gland cells, TSG-6 is induced by TNF-alpha and IL-1beta, which suggests that these cells are responsible for TSG-6 release in vivo. Bikunin and HC3 (i.e., pre-alpha-inhibitor) were also induced by TNF-alpha in primary cultures. Our results suggest that TSG-6 may play an important protective role in bronchial epithelium by increasing the antiprotease screen on the airway lumen.


Assuntos
alfa-Globulinas/fisiologia , Asma/metabolismo , Moléculas de Adesão Celular/fisiologia , Glicoproteínas de Membrana/fisiologia , Subunidades Proteicas/metabolismo , Calicreínas Teciduais/fisiologia , Adolescente , Adulto , Lavagem Broncoalveolar , Células Cultivadas , Ativação Enzimática , Células Epiteliais/metabolismo , Glândulas Exócrinas/citologia , Feminino , Humanos , Interleucina-1beta/fisiologia , Masculino , Pessoa de Meia-Idade , Ligação Proteica , Fumar/metabolismo , Fator de Necrose Tumoral alfa/fisiologia
13.
Am J Respir Cell Mol Biol ; 34(5): 581-91, 2006 May.
Artigo em Inglês | MEDLINE | ID: mdl-16424381

RESUMO

Mucus overproduction in inflammatory and obstructive airway diseases is associated with goblet cell (GC) metaplasia in airways. Although the mechanisms involved in GC metaplasia and mucus hypersecretion are not completely understood, association with oxidative stress and epidermal growth factor receptor (EGFR) signaling has been reported. To explore the mechanisms involved in oxidative stress-induced GC metaplasia, cultures of differentiated normal human bronchial epithelial cells grown at the air-liquid interface were exposed to reactive oxygen species (ROS) generated by xanthine/xanthine oxidase. EGFR activation and signaling was assessed by measuring EGF and transforming growth factor-alpha release and EGFR and (44/42)MAPK phosphorylation. The GC population was evaluated by confocal microscopy. ROS-induced EGFR activation resulted in GC proliferation and increased MUC5AC gene and protein expression. Signaling was due to pro-EGF processing by tissue kallikrein (TK), which was activated by ROS-induced hyaluronan breakdown. It was inhibited by catalase, a TK inhibitor, and EGF-blocking antibodies. Exposure to recombinant TK mimicked the ROS effects, increasing the expression of MUC5AC and lactoperoxidase. In addition, ROS induced the antiapoptotic factor Bcl-2 in a TK-dependent fashion. In conclusion, ROS-induced GC metaplasia in normal human bronchial epithelial cells is associated with HA depolymerization and EGF processing by TK followed by EGFR signaling, suggesting that increases in TK activity could contribute to GC metaplasia and mucus hypersecretion in diseases such as asthma and chronic bronchitis. The data also suggest that increases in GC population could be sustained by the associated upregulation of Bcl-2 in airway epithelial cells.


Assuntos
Fator de Crescimento Epidérmico/metabolismo , Receptores ErbB/metabolismo , Células Caliciformes/efeitos dos fármacos , Células Caliciformes/patologia , Oxidantes/farmacologia , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/patologia , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Células Caliciformes/citologia , Humanos , Ácido Hialurônico/metabolismo , Lactoperoxidase/metabolismo , Metaplasia , Mucina-5AC , Mucinas/metabolismo , Estresse Oxidativo , Polímeros , Precursores de Proteínas/metabolismo , Transporte Proteico , Proteínas Proto-Oncogênicas c-bcl-2/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Mucosa Respiratória/metabolismo , Transdução de Sinais/efeitos dos fármacos , Calicreínas Teciduais/metabolismo , Xantina Oxidase/metabolismo
14.
Am J Respir Cell Mol Biol ; 34(2): 135-41, 2006 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-16195536

RESUMO

Glycosaminoglycans (GAGs), known to be present in airway mucus, are macromolecules with a variety of structural and biological functions. In the present work, we used fluorophore-assisted carbohydrate electrophoresis (FACE) to identify and relatively quantify GAGs in human tracheal aspirates (HTA) obtained from healthy volunteers. Primary cultures of normal human bronchial epithelial (NHBE) and submucosal gland (SMG) cells were used to assess their differential contribution to GAGs in mucus. Distribution was further assessed by immunofluorescence in human trachea tissue sections and in cell cultures. HTA samples contained keratan sulfate (KS), chondroitin/dermatan sulfate (CS/DS), and hyaluronan (HA), whereas heparan sulfate (HS) was not detected. SMG cultures secreted CS/DS and HA, CS/DS being the most abundant GAGs in these cultures. NHBE cells synthesized KS, HA, and CS/DS. Confocal microscopy showed that KS was exclusively found at the apical border of NHBE cells and on the apical surface of ciliated epithelial cells in tracheal tissues. CS/DS and HA were present in both NHBE and SMG cells. HS was only found in the extracellular matrix in trachea tissue sections. In summary, HTA samples contain KS, CS/DS, and HA, mirroring a mixture of secretions originated in surface epithelial cells and SMGs. We conclude that surface epithelium is responsible for most HA and all KS present in secretions, whereas glands secrete most of CS/DS. These data suggest that, in diseases where the contribution to secretions of glands versus epithelial cells is altered, the relative concentration of individual GAGs, and therefore their biological activities, will also be affected.


Assuntos
Glicosaminoglicanos/análise , Traqueia/metabolismo , Brônquios/citologia , Células Cultivadas , Eletroforese/métodos , Células Epiteliais/química , Glândulas Exócrinas/citologia , Glicosaminoglicanos/imunologia , Humanos
15.
J Biol Chem ; 279(20): 21606-16, 2004 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-14988406

RESUMO

In human airways, oxidative stress-induced submucosal gland cell hypertrophy and hyperplasia, histological features of chronic bronchitis, have been linked to epidermal growth factor receptor (EGFR) activation. To explore mechanisms of oxidative stress-induced EGFR activation and signaling, primary cultures of human tracheal submucosal gland (SMG) cells were used to assess EGFR ligand release, EGFR phosphorylation, p44/42 MAPK phosphorylation, and mucin 5AC synthesis in response to reactive oxygen species generated by xanthine/xanthine oxidase (X/XO). Exposure to X/XO increased release of epidermal growth factor (EGF) from these cells, thereby activating EGFR, phosphorylating MAPK, and increasing mucin 5AC production. The importance of EGF was confirmed by transfection of small interfering RNA inhibiting pro-EGF production, which resulted in inhibition of EGFR and MAPK phosphorylation despite X/XO exposure. Blocking signaling by using specific protease inhibitors showed that tissue kallikrein (TK) processed pro-EGF in response to X/XO. Airway TK is bound and inactivated by luminal hyaluronan (HA), and treatment of submucosal gland cells with X/XO induced HA depolymerization and TK activation. These events were blocked by reactive oxygen species scavengers and addition of exogenous excess HA and TK inhibitors. Thus, HA plays a crucial role in regulating airway TK activity and thereby TK-mediated release of active EGF from human SMG cells. Sustained HA depolymerization is expected to cause TK activation, EGF release, and EGFR signaling and to lead to SMG cell hypertrophy and hyperplasia as well as mucus hypersecretion with subsequent airflow obstruction.


Assuntos
Brônquios/fisiologia , Receptores ErbB/fisiologia , Ácido Hialurônico/fisiologia , Espécies Reativas de Oxigênio/metabolismo , Calicreínas Teciduais/fisiologia , Traqueia/fisiologia , Receptores ErbB/genética , Humanos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fosforilação , Biossíntese de Proteínas
16.
Biochem Biophys Res Commun ; 299(5): 739-43, 2002 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-12470640

RESUMO

Ghrelin is a peptide found in the hypothalamus and stomach that stimulates food intake and whose circulating concentrations are affected by nutritional state. Very little is known about other central behavioral effects of ghrelin, and thus, we investigated the effects of ghrelin on anxiety and memory retention. The peptide was injected intracerebroventricularly in rats and we performed open-field, plus-maze, and step-down tests (inhibitory avoidance). The administration of ghrelin increased freezing in the open field and decreased the number of entries into the open spaces and the time spent on the open arms in the plus-maze, indicating an anxiogenic effect. Moreover, the peptide increased in a dose-dependent manner the latency time in the step-down test. A rapid and prolonged increase in food intake was also observed. Our results indicate that ghrelin induces anxiogenesis in rats. Moreover, we show for the first time that ghrelin increases memory retention, suggesting that the peptide may influence processes in the hippocampus.


Assuntos
Ansiedade , Memória , Hormônios Peptídicos/farmacologia , Animais , Regulação do Apetite/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ingestão de Alimentos/efeitos dos fármacos , Grelina , Habituação Psicofisiológica/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Masculino , Memória/efeitos dos fármacos , Hormônios Peptídicos/fisiologia , Ratos , Ratos Wistar
17.
Peptides ; 23(12): 2213-21, 2002 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-12535701

RESUMO

The present study attempts to determine, if the effect of melanin-concentrating hormone (MCH) upon memory retention is correlated with changes in nitric oxide synthase (NOS) activity and tissue levels of nitric oxide (NO) and cGMP. We used a behavioral experiment using a step-down inhibitory avoidance test, the biochemical determinations of NO and cGMP, and electrophysiological model. Results of behavioral studies (step-down test) showed that MCH administration reverts the amnesic effects induced by N(G)-nitro-L-arginine (L-NOArg). Moreover, electrophysiological studies demonstrated that L-NOArg did not block the potentiation induced by the peptide. Hippocampal NO and cGMP levels increased after MCH injection.


Assuntos
Hipocampo/metabolismo , Hormônios Hipotalâmicos/metabolismo , Melaninas/metabolismo , Memória/fisiologia , Óxido Nítrico/metabolismo , Hormônios Hipofisários/metabolismo , Animais , Comportamento Animal/fisiologia , GMP Cíclico/metabolismo , Eletrofisiologia , Masculino , Óxido Nítrico Sintase/antagonistas & inibidores , Ratos , Ratos Wistar
18.
Asunción; EFACIM-EDUNA; ene.2000. 7-12 p.
Monografia em Espanhol | LILACS, BDNPAR | ID: biblio-1018306

RESUMO

El diagnóstico de la enfermedad de Chagas por métodos parasitológicos se realiza mediante la visualización directa o indirecta del parásito. La detección del mismo es relativamente fácil en la fase aguda, cuando la parasistemia es alta; sin embargo, durante las fases intermedias y la cronica se debe recurrir a métodos que requieren una observación más prologada como el xenodiagnóstico y el hemocultivo, siendo la sensibilidad de estos últimos menor. En este trabajo se determino la sensibilidad del hemocultivo en paciente chagasicos y se provee informaciones complementaria sobre las carácteristicas epidemiólogicas de los mismos. Se realizó un levantamiento retrospectivos de datos obtenidos de fichas de 100 pacientes chagasicos que consultaron en el Departamento de Medicina Tropical del IICS durante el periodo de enero 1984 a enero 1992. A todos estos pacientes se le realizo la prueba de hemocultivo en forma de rutina. El 21 por ciento de estos pacientes presentaron resultados positivos para T.cruzi por la tecnica de hemocultivo. Teniendo en cuenta el cuadro clinico de los pacientes, se observo que el 100 por ciento (4/4) de los casos agudos, el 73,2 por ciento (6/25) de los pacientes con lesiones cardiacas o digestivas y el 16,4 por ciento (11/67) de los individuos en la etapa indeterminada fueron positivos a la T.cruzi y el resto de los pacientes sin diagnostico clinico fue negativo por esta técnica. Teniendo en cuenta la edad de estos pacientes se encontro que los menores de 30 años dieron hemocultivo positivo más frecuentemente que aquellos que pertenecieron a grupos de mayor edad. En este estudio, la psibilidad del hemocultivo mostro cierta asociación con la edad y la procedencia del paciente chagasico


Assuntos
Doença de Chagas/diagnóstico , Trypanosoma cruzi/parasitologia
19.
Asunción; EFACIM-EDUNA; ene.2000. 1-6 p. tab.
Monografia em Espanhol | LILACS, BDNPAR | ID: biblio-1018307

RESUMO

Se reconocen varias formas etiológicamente distintas de virus causantes de hepatitis entre las que se encuentran el Virus de la Hepatitis B (VHB) y el Virus de la Hepatitis C (VHC entre otros. Estos virus se transmiten por vía intravenosa, sexual y perinatal y con menor frecuencia por medio de acupuntura, circuncsión, tatuaje y otras perforaciones de la piel. La hepatitis vírica es uno de los principales problemas de salud pública en toda América. Teniendo encuenta la elevada frecuencia mundial de la hepatitis D y C, las altas prevalencia en grupos indigenas sudamericanos considerados las escases de datos nacionales sobre estas enfermedades en tribus indigenas del Paraguay, se ha realizado este estudio efectivo de la corte transverso. La población en estudio incluyo a 178 aborigenes de la parcialidad Ayoreo, provenientes de Kucaani e Islas Alta comunidades ubicadas en el Chaco Paraguayo, en las proximidades Carmelo Peralta e Islas Margarita, a 594 km al noreste de Asunción, frente a la ciudad brasilera de Puerto Murtinho. Se incluyeron individuos de ambos sexos con un rango de edad comprendida entre 15 y 65 años. El presente estudio nos proporciona evidencia de la presencia de VHB y VHC en las poblaciones estudiadas, con una prevalencia de HBsAg de 17.4 por ciento y con el mayor porcentaje (32.3 por ciento) de la posibilidad en mujeres de más de 40 años. La prevalencia del VHC fue del 14,9 por ciento y la distribución fue similar a ambos sexos. Se detecto la presencia coinfecciones en 7 individuos. Son necesarios estudios posteriores que influyan un mayornumero de individuos jóvenes y niños para identificar individuos no infectados. Las personas no infectados obligatoriamente deberian ser vacunados de manera a evitar el contagio, considerando que esta población tiene por costumbre mantener relaciones sexuales libres poco después de la pubertad. De esta manera se estaría previniendo la apariciones de las enfermedades hepatocelulares y la sobre infección por otras hepatitis. Es importante el seguimiento o vigilancia de la infección, así como la educación para la prevención, considerando que estas comunidades viven en condiciones de hacinamiento


Assuntos
Adulto , Hepatite B/prevenção & controle , Hepatite B/transmissão , Hepatite B/virologia , Hepatite C/prevenção & controle , Hepatite C/transmissão , Hepatite C/virologia , Paraguai
20.
Arch. venez. farmacol. ter ; 18(1): 32-36, 1999. graf
Artigo em Espanhol | LILACS | ID: lil-325667

RESUMO

Estudios como el de Ascardio y Proyecto Venezuela demostraron la homogeneidad de los resultados del perfil lipídico dentro del país. A través de estos se concluye que los niveles de TAG en la poblacion urbana son superiores a los considerados como normales y las HDL se encuentran a una concentracion sub-optima, lo que en conjunto se considera como un perfil de alto riesgo para aterosclerosis. El proposito de esta investigacion fue estudiar el perfil lipídico de una poblacion cerrada de la Sierra de Perijá de la etnia Barí, la cual presenta una incidencia extremadamente baja de coronariopatías. Para este fin se tomo una muestra de sangre después de ayuno de 12 horas a 67 individuos adultos de un total de 130 de la localidad, para la determinacion del perfil lipídico a traves de metodos enzimáticos y espectrofotométricos. La concentracion promedio de CT fue de 157 mg/dl, TAG de 128 mg/dl, HDL-col de 41,89 mg/dl LDL-col de 141 mg/dl y Colesterol de lipoproteína de muy baja densidad (VLDL-col): 25,64 mg/dl. Nuestros resultados indican que esta poblacion presenta bajas concentraciones séricas de CT, LDL-col y TAG y concentraciones mayores de HDL-col comparadas con la poblacion urbana, lo que puede explicar la baja incidencia de cardiopatía isquémica en esta poblacion


Assuntos
Humanos , Masculino , Feminino , Doenças Cardiovasculares , Grupos Étnicos , Lipídeos/análise , Medicina , Farmacologia , Venezuela
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