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1.
Biochem Pharmacol ; 106: 56-69, 2016 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-26883061

RESUMEN

Class IA phosphoinositide 3-kinases (PI3Ks) are essential to function of normal and tumor cells, and to modulate immune responses. T lymphocytes express high levels of p110α and p110δ class IA PI3K. Whereas the functioning of PI3K p110δ in immune and autoimmune reactions is well established, the role of p110α is less well understood. Here, a novel dual p110α/δ inhibitor (ETP-46321) and highly specific p110α (A66) or p110δ (IC87114) inhibitors have been compared concerning T cell activation in vitro, as well as the effect on responses to protein antigen and collagen-induced arthritis in vivo. In vitro activation of naive CD4(+) T lymphocytes by anti-CD3 and anti-CD28 was inhibited more effectively by the p110δ inhibitor than by the p110α inhibitor as measured by cytokine secretion (IL-2, IL-10, and IFN-γ), T-bet expression and NFAT activation. In activated CD4(+) T cells re-stimulated through CD3 and ICOS, IC87114 inhibited Akt and Erk activation, and the secretion of IL-2, IL-4, IL-17A, and IFN-γ better than A66. The p110α/δ inhibitor ETP-46321, or p110α plus p110δ inhibitors also inhibited IL-21 secretion by differentiated CD4(+) T follicular (Tfh) or IL-17-producing (Th17) helper cells. In vivo, therapeutic administration of ETP-46321 significantly inhibited responses to protein antigen as well as collagen-induced arthritis, as measured by antigen-specific antibody responses, secretion of IL-10, IL-17A or IFN-γ, or clinical symptoms. Hence, p110α as well as p110δ Class IA PI3Ks are important to immune regulation; inhibition of both subunits may be an effective therapeutic approach in inflammatory autoimmune diseases like rheumatoid arthritis.


Asunto(s)
Artritis Experimental/tratamiento farmacológico , Linfocitos T CD4-Positivos/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Imidazoles/farmacología , Inhibidores de las Quinasa Fosfoinosítidos-3 , Subunidades de Proteína/antagonistas & inhibidores , Pirazinas/farmacología , Animales , Anticuerpos/farmacología , Artritis Experimental/enzimología , Artritis Experimental/inmunología , Artritis Experimental/patología , Antígenos CD28/genética , Antígenos CD28/inmunología , Complejo CD3/genética , Complejo CD3/inmunología , Linfocitos T CD4-Positivos/enzimología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/patología , Fosfatidilinositol 3-Quinasa Clase Ia/genética , Fosfatidilinositol 3-Quinasa Clase Ia/inmunología , Quinasas MAP Reguladas por Señal Extracelular/genética , Quinasas MAP Reguladas por Señal Extracelular/inmunología , Expresión Génica , Interferón gamma/genética , Interferón gamma/inmunología , Interleucina-10/genética , Interleucina-10/inmunología , Interleucina-2/genética , Interleucina-2/inmunología , Ganglios Linfáticos/efectos de los fármacos , Ganglios Linfáticos/enzimología , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/patología , Activación de Linfocitos/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Factores de Transcripción NFATC/genética , Factores de Transcripción NFATC/inmunología , Subunidades de Proteína/genética , Subunidades de Proteína/inmunología , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/inmunología , Proteínas de Dominio T Box/genética , Proteínas de Dominio T Box/inmunología
2.
J Struct Biol ; 177(2): 248-58, 2012 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-22182732

RESUMEN

Very little is known about the sub-cellular distribution of metal ions in cells. Some metals such as zinc, copper and iron are essential and play an important role in the cell metabolism. Dysfunctions in this delicate housekeeping may be at the origin of major diseases. There is also a prevalent use of metals in a wide range of diagnostic agents and drugs for the diagnosis or treatment of a variety of disorders. This is becoming more and more of a concern in the field of nanomedicine with the increasing development and use of nanoparticles, which are suspected of causing adverse effects on cells and organ tissues. Synchrotron-based X-ray and Fourier-transformed infrared microspectroscopies are developing into well-suited sub-micrometer analytical tools for addressing new problems when studying the role of metals in biology. As a complementary tool to optical and electron microscopes, developments and studies have demonstrated the unique capabilities of multi-keV microscopy: namely, an ultra-low detection limit, large penetration depth, chemical sensitivity and three-dimensional imaging capabilities. More recently, the capabilities have been extended towards sub-100nm lateral resolutions, thus enabling sub-cellular chemical imaging. Possibilities offered by these techniques in the biomedical field are described through examples of applications performed at the ESRF synchrotron-based microspectroscopy platform (ID21 and ID22 beamlines).


Asunto(s)
Tecnología Biomédica , Sincrotrones , Animales , Células 3T3 BALB , Neuronas Dopaminérgicas/metabolismo , Francia , Hepatocitos/metabolismo , Humanos , Masculino , Manganeso/metabolismo , Melaninas/metabolismo , Metales/metabolismo , Ratones , Microespectrofotometría/métodos , Células PC12 , Fósforo/metabolismo , Potasio/metabolismo , Ratas , Espectroscopía Infrarroja por Transformada de Fourier , Espermatozoides/metabolismo , Rayos X
3.
Rheumatology (Oxford) ; 46(9): 1428-32, 2007 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-17644821

RESUMEN

OBJECTIVES: The degradation of tryptophan by indoleamine 2,3-dioxygenase yields a number of immunomodulatory metabolites, including 3-hydroxyanthranilic acid, 3-hydroxykynurenic acid and quinolinic acid. N-(3',4'-dimethoxycinnamonyl) anthranilic acid (3,4-DAA) is a synthetic anthranilic acid derivative that has been used therapeutically in Japan for many years as an anti-allergic drug and has recently been shown to be effective in a murine model of multiple sclerosis. METHODS: In the present study, we tested the efficacy of 3,4-DAA in collagen-induced arthritis, a mouse model of rheumatoid arthritis, and analysed its mechanism of action. RESULTS: Administration of 3,4-DAA after arthritis onset reduced clinical and histological severity of arthritis and reduced pain. It completely abrogated thermal and mechanical hyperalgesia. 3,4-DAA also suppressed Th1 cell activity in lymph node cell cultures and raised serum levels of IL-10. In vitro, 3,4-DAA suppressed IFNgamma production and proliferation of both T and B lymphocytes in a manner comparable with the endogenous tryptophan metabolite, 3-hydroxyanthranilic acid, suggesting similar mechanisms of action. CONCLUSION: It is concluded that 3,4-DAA has both anti-inflammatory and analgesic properties, and may therefore be useful in filling an unmet need, in the treatment of rheumatoid and other forms of arthritis, especially in the light of its analgesic properties.


Asunto(s)
Analgésicos no Narcóticos/uso terapéutico , Antiinflamatorios no Esteroideos/uso terapéutico , Artritis Experimental/tratamiento farmacológico , ortoaminobenzoatos/uso terapéutico , Ácido 3-Hidroxiantranílico/farmacología , Animales , Artritis Experimental/inmunología , Artritis Experimental/prevención & control , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/inmunología , Artritis Reumatoide/prevención & control , Linfocitos B/efectos de los fármacos , Linfocitos B/inmunología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Hiperalgesia/prevención & control , Activación de Linfocitos/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos DBA , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología
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