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1.
PLoS One ; 14(7): e0219349, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31260505

RESUMO

[This corrects the article DOI: 10.1371/journal.pone.0217803.].

2.
PLoS One ; 14(6): e0217803, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31170225

RESUMO

COPD patients are prone to acute infectious exacerbations that impair their quality of life and hamper prognosis. The purpose of the present study was to investigate the in situ IFN-ß response in the lungs of stable COPD and non-COPD patients. Lung samples from 70 subjects (9 control never smokers, 19 control smokers without COPD, 21 patients with moderate COPD and 21 patients with very severe COPD) were studied for the expression of IFN-ß, its main transcription factor, IRF-7, and two products of its autocrine function, namely RIG-I and MDA-5, by immunohistochemical techniques and quantitative real-time PCR. IFN-ß, IRF-7, RIG-I and MDA-5 were widely detected in most lung cell types. In epithelial tissues and alveolar macrophages, IFN-ß and IRF-7 labeling scores were decreased up to 65% and 74%, respectively, for COPD patients, paralleling an analogous reduction (43% and 65%, respectively) in the amount of their lung mRNA. Moreover, this decreased production of IFN-ß in COPD patients correlated with a similar decrease in the expression of RIG-I and MDA-5, two essential members of the innate immune system. Our study indicates that most lung cells from stable COPD patients show a constitutive decreased expression of IFN-ß, IRF-7, RIG-I and MDA-5, suggesting that this deficiency is the main cause of their acute viral exacerbations.


Assuntos
Interferon beta/metabolismo , Pulmão/metabolismo , Doença Pulmonar Obstrutiva Crônica/metabolismo , Proteína DEAD-box 58/metabolismo , Feminino , Humanos , Fator Regulador 7 de Interferon/metabolismo , Helicase IFIH1 Induzida por Interferon/metabolismo , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/patologia , Transdução de Sinais
3.
Diaeta (B. Aires) ; 37(167): 18-29, jun. 2019. ilus, tab
Artigo em Espanhol | LILACS-Express | LILACS | ID: biblio-1056027

RESUMO

Introducción: el tratamiento de la diabetes tipo 1 (DM1) requiere de la administración de insulina exógena; dentro de las variables a tener en cuenta para calcular la dosis se encuentra el contenido de hidratos de carbono (HC) de la comida a ingerir. Este macronutriente es considerado, desde hace varios años, el responsable del aumento de la glucemia postprandial (GPP). El conteo de hidratos de carbono (CHC) es el método más aceptado y utilizado actualmente en el tratamiento nutricional, aunque cada vez existe más evidencia de que hay otros macronutrientes, como las proteínas y las grasas, que pueden influir en la variación de la GPP. Objetivo: el objetivo de esta revisión bibliográfica es reunir los resultados de publicaciones científicas que analizaron la respuesta glucémica (RG) al consumo de comidas con alto contenido de proteínas y grasas y hacer un análisis de las diferentes intervenciones. Materiales y método: búsqueda bibliográfica en PUBMED, inicialmente 196 artículos. Luego de aplicar los criterios de inclusión y exclusión se seleccionaron 26 artículos realizados en personas con DM1 de los últimos 10 años (2007-2017) referidos al consumo de comidas altas en proteínas y grasas. Resultados: hay una significativa variación interpersonal en los requerimientos de insulina en respuesta a las grasas y proteínas dietarias, que puede fluctuar en un 65% ± 10%. En los estudios randomizados se logró determinar que en las comidas altas en grasas el pico de GPP fue demorado y la sensibilidad a la insulina fue menor. Uno de los estudios logró demostrar que el 100% de las comidas altas en grasa se asociaron con hiperglucemia tardía. En relación a las dos revisiones sistemáticas encontradas, se hace hincapié en la búsqueda de datos para mejorar el tratamiento intensificado de la DM1, siendo el control de la GPP el indicador principal, ponderando la importancia de considerar la ingesta proteica y grasa de manera adicional al CHC. Conclusión: se concluye que el efecto de una comida con un alto contenido en proteínas y grasas sobre la glucemia suele presentarse entre las 3 a 6 hs de consumidas, siempre teniendo en cuenta la respuesta individual y el modo de administrar la insulina. La tarea del equipo interdisciplinario es fundamental para conocer la respuesta individual en el paciente con DM1 ante el consumo de comidas altas en proteínas y grasas, pudiendo así orientar la toma de decisión.


Introduction: the treatment of type 1 diabetes (DM1) requires the administration of exogenous insulin, being the carbohydrate (HC) content of the meal to be ingested one of the variables to be considered to calculate the insulin dose. For several years, this macronutrient has been considered responsible for the increase in postprandial glycemia (PPG). Carbohydrate Counting (CHC) is the most accepted and currently used method in the nutritional treatment, although there is enough evidence that other macronutrients, such as protein and fat, can influence on the variation of PPG. Objective: to gather the results of scientific publications which analysed the glycemic response (GR) to the consumption of high-protein and high-fat meals and to analyse de different interventions. After applying the inclusion and exclusion criteria, 24 articles were selected including those with individuals with DM1 from the past 10 years (with the exception of one) referring to the consumption of high-protein and high-fat meals. Results: there is a significant interpersonal variation in insulin requirements in response to dietary fat and protein, which can fluctuate by 65% +/- 10%. Randomized studies showed that in the high-fat meals, the peak of PPG was delayed and insulin sensitivity was lower. One of the studies showed that 100% of high-fat meals were associated with late hyperglycemia. Both systematic reviews emphasize the need to search for data to improve the intensive treatment of DM1, with the control of PPG being the main indicator, considering protein and fat intake, in addition to CHC. Conclusion: the effect on blood glucose of high-protein and high-fat meals usually occurs between 3 to 6 hours after being consumed, always considering the individual response and the insulin administration method. The task of the interdisciplinary team is essential to know the individual response in the DM1 patient to the consumption of high-protein and high-fat meals, thus being able to guide the decision-making process.

4.
Hum Mutat ; 40(10): 1700-1712, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31058414

RESUMO

3-Methylglutaconic aciduria (3-MGA-uria) syndromes comprise a heterogeneous group of diseases associated with mitochondrial membrane defects. Whole-exome sequencing identified compound heterozygous mutations in TIMM50 (c.[341 G>A];[805 G>A]) in a boy with West syndrome, optic atrophy, neutropenia, cardiomyopathy, Leigh syndrome, and persistent 3-MGA-uria. A comprehensive analysis of the mitochondrial function was performed in fibroblasts of the patient to elucidate the molecular basis of the disease. TIMM50 protein was severely reduced in the patient fibroblasts, regardless of the normal mRNA levels, suggesting that the mutated residues might be important for TIMM50 protein stability. Severe morphological defects and ultrastructural abnormalities with aberrant mitochondrial cristae organization in muscle and fibroblasts were found. The levels of fully assembled OXPHOS complexes and supercomplexes were strongly reduced in fibroblasts from this patient. High-resolution respirometry demonstrated a significant reduction of the maximum respiratory capacity. A TIMM50-deficient HEK293T cell line that we generated using CRISPR/Cas9 mimicked the respiratory defect observed in the patient fibroblasts; notably, this defect was rescued by transfection with a plasmid encoding the TIMM50 wild-type protein. In summary, we demonstrated that TIMM50 deficiency causes a severe mitochondrial dysfunction by targeting key aspects of mitochondrial physiology, such as the maintenance of proper mitochondrial morphology, OXPHOS assembly, and mitochondrial respiratory capacity.


Assuntos
Proteínas de Membrana Transportadoras/genética , Mitocôndrias/genética , Mitocôndrias/metabolismo , Mutação , Biomarcadores , Transporte de Elétrons , Metabolismo Energético , Fibroblastos/metabolismo , Expressão Gênica , Predisposição Genética para Doença , Humanos , Lactente , Masculino , Mitocôndrias/ultraestrutura , Doenças Mitocondriais/genética , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Músculo Esquelético/metabolismo , Músculo Esquelético/ultraestrutura , Fenótipo , Transporte Proteico , Espasmos Infantis/diagnóstico , Espasmos Infantis/genética , Sequenciamento Completo do Exoma
6.
Diaeta (B. Aires) ; 35(159): 37-44, abr.-mayo 2017. tab
Artigo em Espanhol | LILACS | ID: biblio-868864

RESUMO

Introducción: En Argentina un 37,1% de la población padece sobrepeso, un 20,8% obesidad y un 9,8% diabetes. La prevalencia de síndrome metabólico oscila entre el 20 y 25%. Según el estudio HIDRATAR, el consumo promedio de agua, bebidas e infusiones era de 2.050 ml/día, de los cuales un 29% correspondió a bebidas endulzadas artificialmente (BEA). No existe consenso de los organismos internacionales para su consumo. Metodología: Se llevó a cabo una búsqueda bibliográfica en PubMed, Scielo y Cochrane, de artículos publicados a partir del año 2005, con el objetivo de conocer la relación entre el consumo de BEA y el riesgo de desarrollo de síndrome metabólico y diabetes mellitus tipo 2. Resultados: Se encontraron 12 trabajos que señalan los efectos adversos de las BEA. Los mismos representan una mayor población en estudio, seguida durante más tiempo. Es un tema controvertido con mucha disparidad en la obtención de la información, teniendo en cuenta además que, en el caso de estudios con humanos, son muchos los componentes del plan alimentario que hay que considerar. Conclusiones: Ha quedado demostrado que los edulcorantes no nutritivos no son sustancias metabólicamente inertes y hay evidencia que sugiere que las BEA no son completamente inocuas, siendo primordial y necesaria la educación para limitar su consumo y promover la ingesta de agua.


Assuntos
Humanos , Bebidas Gaseificadas/efeitos adversos , Diabetes Mellitus , Adoçantes não Calóricos/efeitos adversos , Sucos , Síndrome Metabólica
7.
Mediators Inflamm ; 2014: 120673, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25276049

RESUMO

Endometriosis, defined as the growth of endometrial tissue outside the uterus, is a common gynecologic condition affecting millions of women worldwide. It is an inflammatory, estrogen-dependent complex disorder, with broad symptomatic variability, pelvic pain, and infertility being the main characteristics. Ovarian endometriomas are frequently developed in women with endometriosis. Late diagnosis is one of the main problems of endometriosis; thus, it is important to identify biomarkers for early diagnosis. The aim of the present work is to evaluate the ecto-nucleotidases activities in the contents of endometriomas. These enzymes, through the regulation of extracellular ATP and adenosine levels, are key enzymes in inflammatory processes, and their expression has been previously characterized in human endometrium. To achieve our objective, the echo-guided aspirated fluids of endometriomas were analyzed by evaluating the ecto-nucleotidases activities and compared with simple cysts. Our results show that enzyme activities are quantifiable in the ovarian cysts aspirates and that endometriomas show significantly higher ecto-nucleotidases activities than simple cysts (5.5-fold increase for ATPase and 20-fold for ADPase), thus being possible candidates for new endometriosis biomarkers. Moreover, we demonstrate the presence of ecto-nucleotidases bearing exosomes in these fluids. These results add up to the knowledge of the physiopathologic mechanisms underlying endometriosis and, open up a promising new field of study.


Assuntos
Adenosina Trifosfatases/metabolismo , Biomarcadores/metabolismo , Endometriose/metabolismo , Trifosfato de Adenosina/metabolismo , Adulto , Feminino , Humanos , Microscopia Eletrônica , Pessoa de Meia-Idade , Cistos Ovarianos/metabolismo , Adulto Jovem
8.
Diaeta (B. Aires) ; 32(148): 7-23, jul.-sept. 2014. tab
Artigo em Espanhol | LILACS | ID: lil-733355

RESUMO

El control del fósforo dietario es una de las intervenciones más importantes en el cuidado nutricional de los pacientes con Enfermedad Renal Crónica, lo que implica dificultad en la adherencia al tratamiento. La proteína y el fósforo están estrechamente relacionados en los alimentos. La guía K/DOQI recomienda la estimación de la relación fósforo/proteína de los alimentos. Existe evidencia de tablas publicadas con la relación fósforo/proteína. Hasta el momento no se dispone de una tabla de alimentos habituales en la población argentina con la estimación de la relación. Objetivo: estimar la relación fósforo/proteína de alimentos de uso habitual en la población y establecer su aplicación en el tratamiento nutricional de la Enfermedad Renal Crónica. Material y método: las tablas se elaboraron a partir de la Base de Datos de Composición de Alimentos ARGENFOODS, Vademecum Nutrinfo, SARA-Ministerio de Salud de la Nación Argentina e información de etiquetas nutricionales. Resultados: se encuentran comprendidos en las tablas. Conclusiones: La selección de alimentos del plan alimentario del paciente con Enfermedad Renal Crónica, debería considerar la relación fósforo/proteína de los mismos. Las tablas proporcionan un análisis de los alimentos permitiendo adecuar la variedad de la alimentación de los pacientes. La relación fósforo/proteína es una herramienta valiosa para el tratamiento dietético y la educación alimentaria.


Assuntos
Humanos , Dieta , Nefropatias , Fósforo , Proteínas , Insuficiência Renal Crônica
9.
Diaeta (B. Aires) ; 32(148): 7-23, jul.-sept. 2014. tab
Artigo em Espanhol | BINACIS | ID: bin-131614

RESUMO

El control del fósforo dietario es una de las intervenciones más importantes en el cuidado nutricional de los pacientes con Enfermedad Renal Crónica, lo que implica dificultad en la adherencia al tratamiento. La proteína y el fósforo están estrechamente relacionados en los alimentos. La guía K/DOQI recomienda la estimación de la relación fósforo/proteína de los alimentos. Existe evidencia de tablas publicadas con la relación fósforo/proteína. Hasta el momento no se dispone de una tabla de alimentos habituales en la población argentina con la estimación de la relación. Objetivo: estimar la relación fósforo/proteína de alimentos de uso habitual en la población y establecer su aplicación en el tratamiento nutricional de la Enfermedad Renal Crónica. Material y método: las tablas se elaboraron a partir de la Base de Datos de Composición de Alimentos ARGENFOODS, Vademecum Nutrinfo, SARA-Ministerio de Salud de la Nación Argentina e información de etiquetas nutricionales. Resultados: se encuentran comprendidos en las tablas. Conclusiones: La selección de alimentos del plan alimentario del paciente con Enfermedad Renal Crónica, debería considerar la relación fósforo/proteína de los mismos. Las tablas proporcionan un análisis de los alimentos permitiendo adecuar la variedad de la alimentación de los pacientes. La relación fósforo/proteína es una herramienta valiosa para el tratamiento dietético y la educación alimentaria.(AU)


Assuntos
Humanos , Nefropatias , Insuficiência Renal Crônica , Proteínas , Fósforo , 24439
10.
Mediators Inflamm ; 2014: 509027, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24707115

RESUMO

One of the strategies used by tumors to evade immunosurveillance is the accumulation of extracellular adenosine, which has immunosupressive and tumor promoting effects. The study of the mechanisms leading to adenosine formation at the tumor interstitium are therefore of great interest in oncology. The dominant pathway generating extracellular adenosine in tumors is the dephosphorylation of ATP by ecto-nucleotidases. Two of these enzymes acting sequentially, CD39 and CD73, efficiently hydrolyze extracellular ATP to adenosine. They have been found to play a crucial role in a variety of tumors, but there were no data concerning endometrial cancer, the most frequent of the invasive tumors of the female genital tract. The aim of the present work is to study the expression of CD39 and CD73 in human endometrial cancer. We have analyzed protein and gene expression, as well as enzyme activity, in type I endometrioid adenocarcinomas and type II serous adenocarcinomas and their nonpathological endometrial counterparts. High levels of both enzymes were found in tumor samples, with significantly increased expression of CD39 in type II serous tumors, which also coincided with the higher tumor grade. Our results reinforce the involvement of the adenosinergic system in cancer, emphasizing the relevance of ecto-nucleotidases as emerging therapeutic targets in oncology.


Assuntos
5'-Nucleotidase/metabolismo , Adenocarcinoma/metabolismo , Antígenos CD/metabolismo , Apirase/metabolismo , Neoplasias do Endométrio/metabolismo , Adenocarcinoma/genética , Adenosina/metabolismo , Idoso , Idoso de 80 Anos ou mais , Neoplasias do Endométrio/genética , Feminino , Proteínas Ligadas por GPI/metabolismo , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Pessoa de Meia-Idade
11.
Diaeta (B. Aires) ; 31(145): 22-30, jul.-sept. 2013.
Artigo em Espanhol | LILACS | ID: lil-700240

RESUMO

La hiperfosfatemia en la Enfermedad Renal Crónica está asociada a enfermedad ósea y a incremento del riesgo de morbilidad y mortalidad cardiovascular. Su tratamiento consiste en la disminución de la absorción intestinal del fósforo a través de una dieta controlada, el uso de quelantes y la eliminación del fósforo a través de la diálisis. Existen tres fuentes básicas de fósforo dietético: el fósforo orgánico se encuentra naturalmente en los alimentos fuentes de proteínas. El fósforo proveniente de los alimentos de origen vegetal se encuentra en forma de ácido fítico cuya biodisponibilidad es de menos del 50%. El fósforo inorgánico es el componente principal de aditivos alimentarios y altamente biodisponible. Las sales de fosfato presentan numerosas aplicaciones en la industria alimentaria. Se ha elaborado un glosario de aditivos admitidos por el Código Alimentario Argentino para su adición en los alimentos industrializados. Según la legislación, no es obligatoria la inclusión del fósforo en las etiquetas nutricionales, por lo que es decisión de la industria su información. Resulta útil el conocimiento del número INS. El fósforo añadido durante el procesamiento alimentario es una importante fuente del mineral por su magnitud y su elevada biodisponibilidad. Es precisa la incorporación del fósforo en la Información nutricional de los rótulos alimentarios con el objetivo de un mejor control de la fosfatemia, sin afectar la ingesta proteica de los pacientes. Se recomienda implementar estrategias educativas para ayudar a los pacientes a identificar los aditivos con fósforo en los alimentos. El consejo nutricional debería hacer énfasis en el consumo de alimentos naturales como base de la alimentación diaria. La inclusión del fosforo total en la información nutricional ayudaría a mejorar la estimación del aporte de fósforo de la dieta


Assuntos
Doença Crônica , Aditivos Alimentares , Rim , Fósforo na Dieta
12.
Diaeta (B. Aires) ; 31(145): 22-30, jul.-sept. 2013.
Artigo em Espanhol | BINACIS | ID: bin-130514

RESUMO

La hiperfosfatemia en la Enfermedad Renal Crónica está asociada a enfermedad ósea y a incremento del riesgo de morbilidad y mortalidad cardiovascular. Su tratamiento consiste en la disminución de la absorción intestinal del fósforo a través de una dieta controlada, el uso de quelantes y la eliminación del fósforo a través de la diálisis. Existen tres fuentes básicas de fósforo dietético: el fósforo orgánico se encuentra naturalmente en los alimentos fuentes de proteínas. El fósforo proveniente de los alimentos de origen vegetal se encuentra en forma de ácido fítico cuya biodisponibilidad es de menos del 50%. El fósforo inorgánico es el componente principal de aditivos alimentarios y altamente biodisponible. Las sales de fosfato presentan numerosas aplicaciones en la industria alimentaria. Se ha elaborado un glosario de aditivos admitidos por el Código Alimentario Argentino para su adición en los alimentos industrializados. Según la legislación, no es obligatoria la inclusión del fósforo en las etiquetas nutricionales, por lo que es decisión de la industria su información. Resulta útil el conocimiento del número INS. El fósforo añadido durante el procesamiento alimentario es una importante fuente del mineral por su magnitud y su elevada biodisponibilidad. Es precisa la incorporación del fósforo en la Información nutricional de los rótulos alimentarios con el objetivo de un mejor control de la fosfatemia, sin afectar la ingesta proteica de los pacientes. Se recomienda implementar estrategias educativas para ayudar a los pacientes a identificar los aditivos con fósforo en los alimentos. El consejo nutricional debería hacer énfasis en el consumo de alimentos naturales como base de la alimentación diaria. La inclusión del fosforo total en la información nutricional ayudaría a mejorar la estimación del aporte de fósforo de la dieta (AU)


Assuntos
Doença Crônica , Rim , Aditivos Alimentares , Fósforo na Dieta
13.
Neurochem Int ; 59(6): 954-64, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21782871

RESUMO

Amyotrophic lateral sclerosis (ALS) is a neuromuscular disease characterized by the selective loss of both upper and lower motoneurons (MNs). The familial form of the illness is associated with mutations in the gene encoding Cu/Zn superoxide dismutase 1 (SOD-1) enzyme, but it accounts for fewer than 10% of cases; the rest, more than 90%, correspond to the sporadic form of ALS. Although many proposals have been suggested over the years, the mechanisms underlying the characteristic selective killing of MN in ALS remain unknown. In this study we tested the effect of sera from sporadic ALS patients on NMDA receptors (NMDAR). We hypothesize that an endogenous seric factor is implicated in neuronal death in ALS, mediated by the modulation of NMDAR. Sera from ALS patients and from healthy subjects were pretreated to inactivate complement pathways and dialyzed to remove glutamate and glycine. IgGs from ALS patients and healthy subjects were obtained by affinity chromatography and dialyzed against phosphate-buffered saline. Human NMDAR were expressed in Xenopus laevis oocytes, and ionic currents were recorded using the two-electrode voltage clamp technique. Sera from sporadic ALS patients induced transient oscillatory currents in oocytes expressing NMDAR with a significantly higher total electrical charge than that induced by sera from healthy subjects. Sera from patients with other neuromuscular diseases did not exert this effect. The currents were inhibited by MK-801, a noncompetitive blocker of NMDAR. The PLC inhibitor, U-73122, and the IP(3) receptor antagonist, 2-APB, also inhibited the sera-induced currents. The oscillatory signal recorded was due to internal calcium mobilization. Isolated IgGs from ALS patients significantly affected the activity of oocytes injected with NMDAR, causing a 2-fold increase over the response recorded for IgGs from healthy subjects. Our data support the notion that ALS sera contain soluble factors that mobilize intracellular calcium, not opening directly the ionic conductance, but through the non-canonical activation of NMDAR.


Assuntos
Esclerose Amiotrófica Lateral/sangue , Esclerose Amiotrófica Lateral/fisiopatologia , Proteínas Sanguíneas/toxicidade , Sinalização do Cálcio/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/agonistas , Adulto , Idoso , Animais , Sinalização do Cálcio/fisiologia , Agonistas de Aminoácidos Excitatórios/toxicidade , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Feminino , Ácido Glutâmico/fisiologia , Ácido Glutâmico/toxicidade , Humanos , Técnicas In Vitro , Masculino , Pessoa de Meia-Idade , Degeneração Neural/induzido quimicamente , Degeneração Neural/fisiopatologia , Neurotoxinas/toxicidade , Oócitos , Receptores de N-Metil-D-Aspartato/fisiologia , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia , Xenopus laevis
14.
Cell Calcium ; 49(3): 184-90, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21349580

RESUMO

Amyloid beta (Aß) oligomers accumulate in the brain tissue of Alzheimer disease patients and are related to disease pathogenesis. The precise mechanisms by which Aß oligomers cause neurotoxicity remain unknown. We recently reported that Aß oligomers cause intracellular Ca(2+) overload and neuronal death that can be prevented by NMDA receptor antagonists. This study investigated whether Aß oligomers directly activated NMDA receptors (NMDARs) using NR1/NR2A and NR1/NR2B receptors that were heterologously expressed in Xenopus laevis oocytes. Indeed, Aß oligomers induced inward non-desensitizing currents that were blocked in the presence of the NMDA receptor antagonists memantine, APV, and MK-801. Intriguingly, the amplitude of the responses to Aß oligomers was greater for NR1/NR2A heteromers than for NR1/NR2B heteromers expressed in oocytes. Consistent with these findings, we observed that the increase in the cytosolic concentration of Ca(2+) induced by Aß oligomers in cortical neurons is prevented by AP5, a broad spectrum NMDA receptor antagonist, but slightly attenuated by ifenprodil which blocks receptors with the NR2B subunit. Together, these results indicate that Aß oligomers directly activate NMDA receptors, particularly those with the NR2A subunit, and further suggest that drugs that attenuate the activity of such receptors may prevent Aß damage to neurons in Alzheimers disease.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Fragmentos de Peptídeos/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Cálcio/metabolismo , Células Cultivadas , Maleato de Dizocilpina/farmacologia , Fenômenos Eletrofisiológicos , Feminino , Humanos , Memantina/farmacologia , Neurônios/metabolismo , Oócitos/metabolismo , Piperidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/genética , Valina/análogos & derivados , Valina/farmacologia , Xenopus laevis/embriologia
15.
J Neuroimmunol ; 229(1-2): 157-68, 2010 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-20800908

RESUMO

Massive programmed cell death (PCD) of developing chick embryo motoneurons (MNs) occurs in a well defined temporal and spatial sequence between embryonic day (E) 6 and E10. We have found that, when administered in ovo, either circulating immunoglobulins G (IgGs) or cerebrospinal fluid from patients with MN disease can rescue a significant number of chick embryo MNs from normally occurring PCD. An increase of branching of intramuscular nerves was also observed that may account for the rescuing effects of pathologic IgGs. Proteomic analysis and further analysis by ELISA indicated that these effects may be mediated by the interaction of circulating human immunoglobulins with proteins of the semaphorin family.


Assuntos
Apoptose/efeitos dos fármacos , Imunoglobulinas/farmacologia , Doença dos Neurônios Motores/imunologia , Neurônios Motores/efeitos dos fármacos , Músculo Esquelético/inervação , Junção Neuromuscular/efeitos dos fármacos , Análise de Variância , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Embrião de Galinha , Chlorocebus aethiops , Relação Dose-Resposta a Droga , Eletroforese em Gel Bidimensional/métodos , Ensaio de Imunoadsorção Enzimática/métodos , Feminino , Gânglios Espinais/citologia , Cones de Crescimento/efeitos dos fármacos , Humanos , Imunoglobulinas/imunologia , Técnicas In Vitro , Masculino , Doença dos Neurônios Motores/sangue , Neurônios Motores/citologia , Músculo Esquelético/embriologia , Junção Neuromuscular/fisiologia , Proteômica/métodos , Semaforinas/metabolismo , Soro/química , Soro/imunologia , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Estatística como Assunto , Estatísticas não Paramétricas , Transfecção/métodos , Tubulina (Proteína)/metabolismo
16.
J Biol Chem ; 281(49): 37675-85, 2006 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-17038323

RESUMO

Voltage-dependent K(+) (Kv) currents in macrophages are mainly mediated by Kv1.3, but biophysical properties indicate that the channel composition could be different from that of T-lymphocytes. K(+) currents in mouse bone marrow-derived and Raw-264.7 macrophages are sensitive to Kv1.3 blockers, but unlike T-cells, macrophages express Kv1.5. Because Shaker subunits (Kv1) may form heterotetrameric complexes, we investigated whether Kv1.5 has a function in Kv currents in macrophages. Kv1.3 and Kv1.5 co-localize at the membrane, and half-activation voltages and pharmacology indicate that K(+) currents may be accounted for by various Kv complexes in macrophages. Co-expression of Kv1.3 and Kv1.5 in human embryonic kidney 293 cells showed that the presence of Kv1.5 leads to a positive shift in K(+) current half-activation voltages and that, like Kv1.3, Kv1.3/Kv1.5 heteromers are sensitive to r-margatoxin. In addition, both proteins co-immunoprecipitate and co-localize. Fluorescence resonance energy transfer studies further demonstrated that Kv1.5 and Kv1.3 form heterotetramers. Electrophysiological and pharmacological studies of different ratios of Kv1.3 and Kv1.5 co-expressed in Xenopus oocytes suggest that various hybrids might be responsible for K(+) currents in macrophages. Tumor necrosis factor-alpha-induced activation of macrophages increased Kv1.3 with no changes in Kv.1.5, which is consistent with a hyperpolarized shift in half-activation voltage and a lower IC(50) for margatoxin. Taken together, our results demonstrate that Kv1.5 co-associates with Kv1.3, generating functional heterotetramers in macrophages. Changes in the oligomeric composition of functional Kv channels would give rise to different biophysical and pharmacological properties, which could determine specific cellular responses.


Assuntos
Canal de Potássio Kv1.3/metabolismo , Canal de Potássio Kv1.5/metabolismo , Macrófagos/metabolismo , Animais , Sequência de Bases , Linhagem Celular , Primers do DNA/genética , Feminino , Humanos , Técnicas In Vitro , Canal de Potássio Kv1.3/química , Canal de Potássio Kv1.3/genética , Canal de Potássio Kv1.5/química , Canal de Potássio Kv1.5/genética , Macrófagos/ultraestrutura , Potenciais da Membrana , Camundongos , Camundongos Endogâmicos BALB C , Microscopia Imunoeletrônica , Oócitos/metabolismo , Estrutura Quaternária de Proteína , Subunidades Proteicas , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Transfecção , Xenopus laevis
17.
An. R. Acad. Farm ; 71(4): 821-833, oct. 2005. ilus, tab
Artigo em Inglês | IBECS | ID: ibc-044379

RESUMO

Corrientes colinérgicas de cerebro humano fueron registradas en oocitos de Xenopus laevis trasplantados con membranas de cerebro humano procedentes de dos zonas diferentes, la corteza frontal y el hipocampo. Las corrientes registradas fueron activadas por el receptor nicotínico o por el receptor nicotínico o muscarínico de la acetilcolina. Se probaron los efectos de diferentes agonistas nicotínicos como acetilcolina, nicotina y yoduro de 1,1-dimetil-4-fenil-piperazinio (DMPP), y antagonistas del receptor nicotínico como a-bungarotoxina y d-tubocurarina en los oocitos transplantados. Detectamos cuatro clases de cinéticas de corrientes nicotínicas. Las diferencias en la amplitud y en la carga eléctrica total de las corrientes provocadas por varios agonistas en el rango de potencial mantenido no fueron significativas, excepto en el caso del DMPP a un potencial mantenido de -90 mV. Nuestros resultados indican que las formas alfa4beta2, alfa3beta4 y alfa7 son los principales receptores nicotínicos en el cerebro humano


Cholinergic human brain currents were recorded in Xenopus laevis oocytes transplanted with human cerebral membranes from two different zones, the frontal cortex and the hippocampus. The recorded currents were supported by the nicotinic or the muscarinic acetylcholine receptor. We tested the effects of a number of several nicotinic agonists acetylcholine, nicotine and 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP), and the nicotinic receptor antagonists a-bungarotoxin and d-tubocurarine on the transplanted oocytes. We detected four kinds of nicotinic current kinetics. The differences in the amplitude and in the total electric charge of the currents elicited by various agonists at a range of holding potentials were not significant, except in the case of DMPP at a holding potential of -90 mV. Our results indicate that alpha4beta2, alpha3beta4 and alpha7 are the main nicotinic receptors in human brain


Assuntos
Oócitos , Membranas , Xenopus laevis/cirurgia , Acetilcolina/farmacologia , Colinérgicos/química , Colinérgicos/farmacologia , Nicotina/química , Nicotina/farmacologia , Telencéfalo , Química Encefálica , Protocolos , Oócitos/química , Acetilcolina/química , Telencéfalo/ultraestrutura
18.
Br J Pharmacol ; 145(5): 672-8, 2005 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15834443

RESUMO

1. Various types of anticholinesterasic agents have been used to improve the daily activities of Alzheimer's disease patients. It was recently demonstrated that Galantamine, described as a molecule with anticholinesterasic properties, is also an allosteric enhancer of human alpha4beta2 neuronal nicotinic receptor activity. We explored its effect on the human alpha7 neuronal nicotinic acetylcholine receptor (nAChR) expressed in Xenopus oocytes. 2. Galantamine, at a concentration of 0.1 microM, increased the amplitude of acetylcholine (ACh)-induced ion currents in the human alpha7 nAChR expressed in Xenopus oocytes, but caused inhibition at higher concentrations. The maximum effect of galantamine, an increase of 22% in the amplitude of ACh-induced currents, was observed at a concentration of 250 microM Ach. 3. The same enhancing effect was obtained in oocytes transplanted with Torpedo nicotinic acetylcholine receptor (AChR) isolated from the electric organ, but in this case the optimal concentration of galantamine was 1 microM. In this case, the maximum effect of galantamine, an increase of 35% in the amplitude of ACh-induced currents, occurred at a concentration of 50 microM ACh. 4. Galantamine affects not only the activity of post-synaptic receptors but also the activity of nerve terminals. At a concentration of 1 microM, quantal spontaneous events, recorded in a cholinergic synapse, increased their amplitude, an effect which was independent of the anticholinesterasic activity associated with this compound. The anticholinesterasic effect was recorded in preparations treated with a galantamine concentration of 10 microM. 5. In conclusion, our results show that galantamine enhances human alpha7 neuronal nicotinic ACh receptor activity. It also enhances muscular AChRs and the size of spontaneous cholinergic synaptic events. However, only a very narrow range of galantamine concentrations can be used for enhancing effects.


Assuntos
Inibidores da Colinesterase/farmacologia , Galantamina/farmacologia , Nootrópicos/farmacologia , Sistema Nervoso Parassimpático/efeitos dos fármacos , Receptores Nicotínicos/efeitos dos fármacos , Sinapses/efeitos dos fármacos , Animais , Feminino , Humanos , Técnicas In Vitro , Potenciais da Membrana/efeitos dos fármacos , Oócitos/efeitos dos fármacos , Técnicas de Patch-Clamp , Transmissão Sináptica/efeitos dos fármacos , Torpedo , Xenopus laevis , Receptor Nicotínico de Acetilcolina alfa7
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