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1.
Eur J Pharm Sci ; 97: 218-226, 2017 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-27916693

RESUMO

Pyridoclax is an original oligopyridine lead, very promising in treatment of chemoresistant cancers. However, from solubility measurement and permeability evaluation, it appeared that this compound can be considered as a BCS II drug, with a poor water solubility. To overcome this unfavorable property, two strategies were proposed and compared: pyridoclax di-hydrochloride salt synthesis and formulation of pyridoclax-loaded nanoemulsions (PNEs) efficiently performed by transposing the spontaneous emulsification process previously developed by our team. Whereas the salt improved the thermodynamic solubility of the drug by a factor 4, the apparent solubility of the encapsulated pyridoclax was 1000-fold higher. Their stability was assessed upon dilution in various complex biomimetic media relevant for oral administration (SGF, FaSSIF-V2, FeSSIF-V2) or for the intravenous route (PBS). The solubility of the salt was affected by the nature of the medium, indicating that it could precipitate after administration, negatively impacting its bioavailability and its efficiency in vivo. On the contrary, in all media, PNEs remained stable in terms of granulometric properties (determined by DLS), ζ-potential and encapsulation efficiency (measured by HPLC). Thus, such nanomedicines appear as a valuable option to perform preclinical studies on the promising pyridoclax.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Nanopartículas/química , Piridinas/síntese química , Cloreto de Sódio/síntese química , Composição de Medicamentos , Emulsões , Nanopartículas/administração & dosagem , Piridinas/administração & dosagem , Cloreto de Sódio/administração & dosagem , Solubilidade
2.
Platelets ; 25(4): 252-6, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-23855408

RESUMO

Abstract Platelet derivatives are commonly used in wound healing and tissue regeneration. Different procedures of platelet preparation may differentially affect growth factor release and cell growth. Preparation of platelet-rich fibrin (PRF) is accompanied by release of growth factors, including platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF) and transforming growth factor ß1 (TGFß1), and several cytokines. When compared with the standard procedure for platelet-rich plasma (PRP), PRF released 2-fold less PDGF, but >15-fold and >2-fold VEGF and TGFß1, respectively. Also, the release of several cytokines (IL-4, IL-6, IL-8, IL-10, IFNγ, MIP-1α, MIP-1ß and TNFα) was significantly increased in PRF-conditioned medium (CM), compared to PRP-CM. Incubation of both human skin fibroblasts and human umbilical vein endothelial cells (HUVECs) with PRF-derived membrane (mPRF) or with PRF-CM enhanced cell proliferation by >2-fold (p<0.05). Interestingly, PRP elicited fibroblast growth at a higher extent compared to PRF. At variance, PRF effect on HUVEC growth was significantly greater than that of PRP, consistent with a higher concentration of VEGF in the PRF-CM. Thus, the procedure of PRP preparation leads to a larger release of PDGF, as a possible result of platelet degranulation, while PRF enhances the release of proangiogenic factors.


Assuntos
Plaquetas/fisiologia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Plasma Rico em Plaquetas , Adulto , Proliferação de Células/efeitos dos fármacos , Citocinas/metabolismo , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Masculino , Adulto Jovem
3.
Phys Rev Lett ; 106(20): 201101, 2011 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-21668214

RESUMO

Precision measurements of the electron component in the cosmic radiation provide important information about the origin and propagation of cosmic rays in the Galaxy. Here we present new results regarding negatively charged electrons between 1 and 625 GeV performed by the satellite-borne experiment PAMELA. This is the first time that cosmic-ray e⁻ have been identified above 50 GeV. The electron spectrum can be described with a single power-law energy dependence with spectral index -3.18 ± 0.05 above the energy region influenced by the solar wind (> 30 GeV). No significant spectral features are observed and the data can be interpreted in terms of conventional diffusive propagation models. However, the data are also consistent with models including new cosmic-ray sources that could explain the rise in the positron fraction.

4.
Science ; 332(6025): 69-72, 2011 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-21385721

RESUMO

Protons and helium nuclei are the most abundant components of the cosmic radiation. Precise measurements of their fluxes are needed to understand the acceleration and subsequent propagation of cosmic rays in our Galaxy. We report precision measurements of the proton and helium spectra in the rigidity range 1 gigavolt to 1.2 teravolts performed by the satellite-borne experiment PAMELA (payload for antimatter matter exploration and light-nuclei astrophysics). We find that the spectral shapes of these two species are different and cannot be described well by a single power law. These data challenge the current paradigm of cosmic-ray acceleration in supernova remnants followed by diffusive propagation in the Galaxy. More complex processes of acceleration and propagation of cosmic rays are required to explain the spectral structures observed in our data.

5.
Phys Rev Lett ; 105(12): 121101, 2010 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-20867623

RESUMO

The satellite-borne experiment PAMELA has been used to make a new measurement of the cosmic-ray antiproton flux and the antiproton-to-proton flux ratio which extends previously published measurements down to 60 MeV and up to 180 GeV in kinetic energy. During 850 days of data acquisition approximately 1500 antiprotons were observed. The measurements are consistent with purely secondary production of antiprotons in the Galaxy. More precise secondary production models are required for a complete interpretation of the results.

6.
Rev Sci Instrum ; 80(9): 095108, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19791965

RESUMO

The silicon photomultiplier (SiPM) is a recently developed photosensor used in particle physics, e.g., for detection of minimum ionizing particles and/or Cherenkov radiation. Its performance is comparable to that of photomultiplier tubes, but with advantages in terms of reduced volume and magnetic field insensitivity. In the present study, the performance of a gamma ray detector made of an yttrium aluminum perovskite scintillation crystal and a SiPM-based readout is assessed for use in time of flight neutron spectroscopy. Measurements performed at the ISIS pulsed neutron source demonstrate the feasibility of gamma-detection based on the new device.

7.
Nature ; 458(7238): 607-9, 2009 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-19340076

RESUMO

Antiparticles account for a small fraction of cosmic rays and are known to be produced in interactions between cosmic-ray nuclei and atoms in the interstellar medium, which is referred to as a 'secondary source'. Positrons might also originate in objects such as pulsars and microquasars or through dark matter annihilation, which would be 'primary sources'. Previous statistically limited measurements of the ratio of positron and electron fluxes have been interpreted as evidence for a primary source for the positrons, as has an increase in the total electron+positron flux at energies between 300 and 600 GeV (ref. 8). Here we report a measurement of the positron fraction in the energy range 1.5-100 GeV. We find that the positron fraction increases sharply over much of that range, in a way that appears to be completely inconsistent with secondary sources. We therefore conclude that a primary source, be it an astrophysical object or dark matter annihilation, is necessary.

8.
Phys Rev Lett ; 102(5): 051101, 2009 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-19257498

RESUMO

A new measurement of the cosmic-ray antiproton-to-proton flux ratio between 1 and 100 GeV is presented. The results were obtained with the PAMELA experiment, which was launched into low-Earth orbit on-board the Resurs-DK1 satellite on June 15th 2006. During 500 days of data collection a total of about 1000 antiprotons have been identified, including 100 above an energy of 20 GeV. The high-energy results are a tenfold improvement in statistics with respect to all previously published data. The data follow the trend expected from secondary production calculations and significantly constrain contributions from exotic sources, e.g., dark matter particle annihilations.

9.
Arch Biochem Biophys ; 447(2): 97-106, 2006 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-16530159

RESUMO

In skin, vitamin E acts as the predominant lipophilic antioxidant with a protective function against irradiation and oxidative stress. In addition to that, vitamin E can also modulate signal transduction and gene expression. To study whether the four natural tocopherol analogues (alpha-, beta-, gamma-, delta-tocopherol) can influence transcriptional activity by modulating the activity of nuclear receptors, a human keratinocytes cell line (NCTC 2544) was transfected with plasmids containing the luciferase reporter gene under control by direct repeat elements (DR1-DR4), representing binding sites for four different classes of nuclear receptors. In this model, the tocopherols positively modulated only the reporter construct containing a consensus element for peroxisome proliferator-activated receptors (PPARs). The induction was strongest with gamma-tocopherol and was most likely the direct consequence of stimulation of PPARgamma protein expression in keratinocytes. Vitamin E treatment also led to increased expression of a known PPARgamma target gene involved in terminal keratinocytes differentiation, the transglutaminase-1.


Assuntos
Queratinócitos/metabolismo , PPAR gama/metabolismo , Tocoferóis/administração & dosagem , Transglutaminases/metabolismo , Idoso de 80 Anos ou mais , Linhagem Celular , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/fisiologia , Humanos , Queratinócitos/efeitos dos fármacos , Masculino , Vitamina E/administração & dosagem
10.
Adv Space Res ; 33(8): 1347-51, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-15803626

RESUMO

ALTEA-MICE will supplement the ALTEA project on astronauts and provide information on the functional visual impairment possibly induced by heavy ions during prolonged operations in microgravity. Goals of ALTEA-MICE are: (1) to investigate the effects of heavy ions on the visual system of normal and mutant mice with retinal defects; (2) to define reliable experimental conditions for space research; and (3) to develop animal models to study the physiological consequences of space travels on humans. Remotely controlled mouse setup, applied electrophysiological recording methods, remote particle monitoring, and experimental procedures were developed and tested. The project has proved feasible under laboratory-controlled conditions comparable in important aspects to those of astronauts' exposure to particle in space. Experiments are performed at the Brookhaven National Laboratories [BNL] (Upton, NY, USA) and the Gesellschaft für Schwerionenforschung mbH [GSI]/Biophysik (Darmstadt, FRG) to identify possible electrophysiological changes and/or activation of protective mechanisms in response to pulsed radiation. Offline data analyses are in progress and observations are still anecdotal. Electrophysiological changes after pulsed radiation are within the limits of spontaneous variability under anesthesia, with only indirect evidence of possible retinal/cortical responses. Immunostaining showed changes (e.g. increased expression of FGF2 protein in the outer nuclear layer) suggesting a retinal stress reaction to high-energy particles of potential relevance in space.


Assuntos
Íons Pesados , Retina/efeitos da radiação , Visão Ocular/efeitos da radiação , Animais , Adaptação à Escuridão , Eletrofisiologia , Camundongos , Camundongos Mutantes , Modelos Animais , Aceleradores de Partículas , Estimulação Luminosa , Doses de Radiação , Projetos de Pesquisa , Voo Espacial
11.
Adv Space Res ; 33(8): 1352-7, 2004.
Artigo em Inglês | MEDLINE | ID: mdl-15803627

RESUMO

The ALTEA project investigates the risks of functional brain damage induced by particle radiation in space. A modular facility (the ALTEA facility) is being implemented and will be operated in the International Space Station (ISS) to record electrophysiological and behavioral descriptors of brain function and to monitor their time dynamics and correlation with particles and space environment. The focus of the program will be on abnormal visual perceptions (often reported as "light flashes" by astronauts) and the impact on retinal and brain visual structures of particle in microgravity conditions. The facility will be made available to the international scientific community for human neurophysiological, electrophysiological and psychophysics experiments, studies on particle fluxes, and dosimetry. A precursor of ALTEA (the 'Alteino' project) helps set the experimental baseline for the ALTEA experiments, while providing novel information on the radiation environment onboard the ISS and on the brain electrophysiology of the astronauts during orbital flights. Alteino was flown to the ISS on the Soyuz TM34 as part of mission Marco Polo. Controlled ground experiments using mice and accelerator beams complete the experimental strategy of ALTEA. We present here the status of progress of the ALTEA project and preliminary results of the Alteino study on brain dynamics, particle fluxes and abnormal visual perceptions.


Assuntos
Encéfalo/efeitos da radiação , Radiação Cósmica , Luz , Retina/efeitos da radiação , Voo Espacial/instrumentação , Percepção Visual/efeitos da radiação , Ausência de Peso , Adaptação à Escuridão , Eletrofisiologia , Desenho de Equipamento , Meio Ambiente Extraterreno , Humanos , Monitorização Fisiológica , Fosfenos , Estimulação Luminosa , Monitoramento de Radiação , Pesquisa
13.
Adv Space Res ; 31(1): 135-40, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-12577986

RESUMO

In this work we present preliminary results of nuclear composition measurements on board space station MIR obtained with SILEYE-2 particle telescope. SILEYE-2 was placed on MIR in 1997 and has been working since then. It consists of an array of 6 active silicon strip detectors which allow nuclear and energetic identification of cosmic rays in the energy range between approximately 30 and 200 MeV/n. The device is attached to an helmet and connected to an eye mask which shields the cosmonaut eyes from light and allow studies of the Light Flashes (LF) phenomenon. In addition to the study of the causes of LF, the device is used to perform real time long term radiation environment monitoring inside the MIR, performing measurements in solar quiet and active days.


Assuntos
Radiação Cósmica , Fosfenos , Monitoramento de Radiação/instrumentação , Atividade Solar , Voo Espacial/instrumentação , Relação Dose-Resposta à Radiação , Desenho de Equipamento , Meio Ambiente Extraterreno , Olho/efeitos da radiação , Dispositivos de Proteção da Cabeça , Humanos , Luz , Estimulação Luminosa , Silício , Astronave/instrumentação
14.
Adv Space Res ; 31(1): 141-6, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-12577991

RESUMO

The ALTEA project participates to the quest for increasing the safety of manned space flights. It addresses the problems related to possible functional damage to neural cells and circuits due to particle radiation in space environment. Specifically it aims at studying the functionality of the astronauts' Central Nervous Systems (CNS) during long space flights and relating it to the peculiar environments in space, with a particular focus on the particle flux impinging in the head. The project is a large international and multidisciplinary collaboration. Competences in particle physics, neurophysiology, psychophysiology, electronics, space environment, data analyses will work together to construct the fully integrated vision electrophysiology and particle analyser system which is the core device of the project: an helmet-shaped multi-sensor device that will measure concurrently the dynamics of the functional status of the visual system and passage of each particle through the brain within a pre-determined energy window. ALTEA is scheduled to fly in the International Space Station in late 2002. One part of the multi-sensor device, one of the advanced silicon telescopes, will be launched in the ISS in early 2002 and serve as test for the final device and as discriminating dosimeter for the particle fluences within the ISS.


Assuntos
Sistema Nervoso Central/efeitos da radiação , Radiação Cósmica , Fosfenos , Monitoramento de Radiação/instrumentação , Voo Espacial/instrumentação , Ausência de Peso , Adaptação Fisiológica , Medicina Aeroespacial/instrumentação , Sistema Nervoso Central/fisiologia , Eletroencefalografia , Desenho de Equipamento , Dispositivos de Proteção da Cabeça , Humanos , Monitorização Fisiológica/instrumentação , Estimulação Luminosa , Doses de Radiação , Retina/fisiologia , Retina/efeitos da radiação
15.
Toxicol In Vitro ; 16(4): 339-47, 2002 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-12110271

RESUMO

The interaction of reducing sugars, such as aldose, with proteins and the subsequent molecular rearrangements, produces irreversible advanced glycation end-products (AGEs), a heterogeneous class of non-enzymatic glycated proteins or lipids. AGEs form cross-links, trap macromolecules and release reactive oxygen intermediates. AGEs are linked to aging, and increase in several related diseases. The aim of this study was to assess, in a murine macrophage cell line, J774A.1, the effects of 48 h of exposure to glycated serum containing a known amount of pentosidine, a well-known AGE found in the plasma and tissues of diabetic and uremic subjects. Fetal bovine serum was incubated with ribose (50 mM) for 7 days at 37 degrees C to obtain about 10 nmol/ml of pentosidine. The cytotoxic parameters studied were cell morphology and viability by neutral red uptake, lactate dehydrogenase release and tetrazolium salt test. In the medium and in the intracellular compartment, bound and free pentosidine were evaluated by HPLC, as sensitive and specific glycative markers, and thiobarbituric acid reactive substances (TBARs), as index of the extent of lipid peroxidation. Our results confirm that macrophages are able to take up pentosidine. It is conceivable that bound pentosidine is degraded and free pentosidine is released inside the cell and then into the medium. The AGE increase in the medium was combined with an increase in TBARs, meaning that an oxidative stress occurred; marked cytotoxic effects were observed, and were followed by the release of free pentosidine and TBARs into the culture medium.


Assuntos
Arginina/análogos & derivados , Arginina/efeitos adversos , Produtos Finais de Glicação Avançada/efeitos adversos , Lisina/análogos & derivados , Lisina/efeitos adversos , Macrófagos/patologia , Estresse Oxidativo , Ribose/metabolismo , Animais , Arginina/farmacocinética , Linhagem Celular , Cromatografia Líquida de Alta Pressão , Diabetes Mellitus/fisiopatologia , Peroxidação de Lipídeos , Lisina/farmacocinética , Camundongos
16.
Acta Astronaut ; 50(8): 511-25, 2002 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-11962526

RESUMO

The phenomenon of light flashes (LF) in eyes for people in space has been investigated onboard Mir. Data on particles hitting the eye have been collected with the SilEye detectors, and correlated with human observations. It is found that a nucleus in the radiation environment of Mir has roughly a 1% probability to cause an LF, whereas the proton probability is almost three orders of magnitude less. As a function of LET, the LF probability increases above 10 keV/micrometer, reaching about 5% at around 50 keV/micrometer.


Assuntos
Radiação Cósmica , Olho/efeitos da radiação , Luz , Monitoramento de Radiação/instrumentação , Voo Espacial , Percepção Visual/efeitos da radiação , Medicina Aeroespacial , Astronautas , Íons Pesados , Humanos , Transferência Linear de Energia , Masculino , Fosfenos , Prótons , Radiometria , Silício , Atividade Solar , Fatores de Tempo , Visão Ocular/efeitos da radiação , Ausência de Peso
17.
J Immunol ; 166(5): 3522-32, 2001 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-11207312

RESUMO

Trinitrobenzene sulfonic acid (TNBS)-induced colitis is an IL-12-driven, Th1 T cell-mediated colitis that resembles human Crohn's disease. In the present study, we showed initially that the oral administration of recombinant subunit B of cholera toxin (rCT-B) at the time of TNBS-induced colitis by intrarectal TNBS instillation inhibits the development of colitis or, at later time when TNBS-induced colitis is well established, brings about resolution of the colitis. Dose-response studies showed that a majority of mice (68%) treated with rCT-B at a dose of 100 microg (times four daily doses) exhibited complete inhibition of the development of colitis, whereas a minority (30%) treated with rCT-B at a dose of 10 microg (times four daily doses) exhibited complete inhibition; in both cases, however, the remaining mice exhibited some reduction in the severity of inflammation. In further studies, we showed that rCT-B administration is accompanied by prevention/reversal of increased IFN-gamma secretion (the hallmark of a Th1 response) without at the same time causing an increase in IL-4 secretion. This decreased IFN-gamma secretion was not associated with the up-regulation of the secretion of counterregulatory cytokines (IL-10 or TGF-beta), but was associated with a marked inhibition of IL-12 secretion, i.e., the secretion of the cytokine driving the Th1 response. Finally, we showed that rCT-B administration results in increased apoptosis of lamina propria cells, an effect previously shown to be indicative of IL-12 deprivation. From these studies, rCT-B emerges as a powerful inhibitor of Th1 T cell-driven inflammation that can conceivably be applied to the treatment of Crohn's disease.


Assuntos
Toxina da Cólera/administração & dosagem , Toxina da Cólera/imunologia , Colite/imunologia , Colite/prevenção & controle , Interleucina-12/antagonistas & inibidores , Interleucina-12/fisiologia , Ácido Trinitrobenzenossulfônico , Administração Oral , Administração Retal , Animais , Apoptose/imunologia , Células Cultivadas , Colite/induzido quimicamente , Colite/patologia , Colo/imunologia , Colo/metabolismo , Colo/patologia , Progressão da Doença , Interferon gama/biossíntese , Interleucina-10/biossíntese , Interleucina-12/biossíntese , Interleucina-4/biossíntese , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos , Oxazolona/administração & dosagem , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/imunologia , Fator de Crescimento Transformador beta/biossíntese , Ácido Trinitrobenzenossulfônico/administração & dosagem , Ácido Trinitrobenzenossulfônico/antagonistas & inibidores
18.
Phys Med ; 17 Suppl 1: 255-7, 2001.
Artigo em Inglês | MEDLINE | ID: mdl-11776990

RESUMO

The ALTEA project studies the problems related to possible functional damage to the Central Nervous System (CNS) due to particle radiation in space environment. The project is a large international and multi-disciplinary collaboration. The ALTEA instrumentation is an helmet-shaped multi-sensor device that will measure concurrently the dynamics of the functional status of the visual system and the passage of each particle through the brain within a pre-determined energy window. ALTEA is scheduled to fly in the International Space Station in February 2003. One part of the multi-sensor device, one of the advanced silicon telescopes, will be launched in the ISS in early 2002 and serve as test for the final device and as discriminating dosimeter for the particle fluences within the ISS.


Assuntos
Radiação Cósmica , Olho/efeitos da radiação , Luz , Fosfenos , Voo Espacial/instrumentação , Percepção Visual/efeitos da radiação , Medicina Aeroespacial/instrumentação , Adaptação à Escuridão/efeitos da radiação , Eletroencefalografia , Desenho de Equipamento , Meio Ambiente Extraterreno , Humanos , Estimulação Luminosa/instrumentação , Astronave
19.
Adv Space Res ; 25(10): 2075-9, 2000.
Artigo em Inglês | MEDLINE | ID: mdl-11542859

RESUMO

The SilEye experiment aims to study the cause and processes related to the anomalous Light Flashes (LF) perceived by astronauts in orbit and their relation with Cosmic Rays. These observations will be also useful in the study of the long duration manned space flight environment. Two PC-driven silicon detector telescopes have been built and placed aboard Space Station MIR. SilEye-1 was launched in 1995 and provided particles track and LF information; the data gathered indicate a linear dependence of FLF(Hz) ( 4 2) 10(3) 5.3 1.7 10(4) Fpart(Hz) if South Atlantic Anomaly fluxes are not included. Even though higher statistic is required, this is an indication that heavy ion interactions with the eye are the main LF cause. To improve quality and quantity of measurements, a second apparatus, SilEye-2, was placed on MIR in 1997, and started work from August 1998. This instrument provides energetic information, which allows nuclear identification in selected energy ranges; we present preliminary measurements of the radiation field inside MIR performed with SilEye-2 detector in June 1998.


Assuntos
Radiação Cósmica , Luz , Prótons , Voo Espacial/instrumentação , Percepção Visual/efeitos da radiação , Adaptação à Escuridão , Interpretação Estatística de Dados , Humanos , Estimulação Luminosa , Doses de Radiação , Silício , Astronave/instrumentação
20.
Proc Natl Acad Sci U S A ; 93(19): 10360-5, 1996 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-8816805

RESUMO

Small changes in the complex between a peptide and a molecule of the major histocompatibility complex generate ligands able to partially activate (partial agonist) or even inhibit (antagonist) T-cell functions. T-cell receptor engagement of antagonist complex results in a partial zeta chain phosphorylation without activation of the associated ZAP-70 kinase. Herein we show that, despite a strong inhibition of both inositol phospholipid hydrolysis and extracellular increasing antagonist concentrations increased the activity of the CD4-Lck kinase. Addition of anti-CD4 antibody to culture medium prevented inhibitory effects induced by antagonist ligand. We propose that CD4-Lck activation triggered by antagonist complexes may act in a dominant negative mode, thus overriding stimulatory signals coming from agonist ligand. These findings identify a new T-cell signaling profile that may explain the ability of some T-cell receptor variant ligands to inhibit specific biological activities or trigger alternative activation programs.


Assuntos
Células Apresentadoras de Antígenos/imunologia , Antígenos CD4/fisiologia , Receptores de Antígenos de Linfócitos T/fisiologia , Linfócitos T/imunologia , Quinases da Família src/fisiologia , Sequência de Aminoácidos , Animais , Anticorpos Monoclonais , Células Clonais , Columbidae , Grupo dos Citocromos c/biossíntese , Grupo dos Citocromos c/imunologia , Citotoxicidade Imunológica , Variação Genética , Fosfatos de Inositol/metabolismo , Interleucina-2/biossíntese , Ativação Linfocitária , Proteína Tirosina Quinase p56(lck) Linfócito-Específica , Complexo Principal de Histocompatibilidade , Camundongos , Camundongos Endogâmicos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Dados de Sequência Molecular , Proteínas do Tecido Nervoso/metabolismo , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/imunologia , Fragmentos de Peptídeos/farmacologia , Receptores de Antígenos de Linfócitos T/biossíntese , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/imunologia , Transdução de Sinais/imunologia , Transfecção
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