Suchergebnisse

Death receptors (DRs) and their ligands are expressed in developing nervous system. However, neurons are generally resistant to death induction through DRs and rather their activation promotes neuronal outgrowth and branching. These results suppose the existence of DRs antagonists expressed in the nervous system. Fas apoptosis inhibitory molecule (FAIMS ) was first identified as a Fas antagonist in B-cells. Soon after, a longer alternative spliced isoform with unknown function was identified and named FAIML. FAIMS is widely expressed, including the nervous system, and we have shown previously that it promotes neuronal differentiation but it is not an anti-apoptotic molecule in this system. Here, we demonstrate that FAIML is expressed specifically in neurons, and its expression is regulated during the development. Expression could be induced by NGF through the extracellular regulated kinase pathway in PC12(pheochromocytoma cell line) cells. Contrary to FAIMS , FAIML does not increase the neurite outgrowth induced by neurotrophins and does not interfere with nuclear factor ĸB pathway activation as FAIMS does. Cells overexpressing FAIML are resistant to apoptotic cell death induced by DRs such as Fas or tumor necrosis factor R1. Reduction of endogenous expression by small interfering RNA shows that endogenousFAIML protects primary neurons from DR-induced cell death. The detailed analysis of this antagonism shows thatFAIML can bind to Fas receptor and prevent the activation of the initiator caspase-8 induced by Fas. In conclusion, our results indicate that FAIML could be responsible for maintaining initiator caspases inactive after receptor engagement protecting neurons from the cytotoxic action of death ligands. ; This work was supported by Spanish Government "Ministerio de Sanidad y Consumo" (contract number PI020051, PI04/2364, Redes Temáticas de Investigación Cooperativa, and CiberNed), Fundació La Caixa (Ayudas a la Investigación en Enfermedades Neurodegenerativas 02/055-00), Ministerio de Educacio´n y Ciencia (SAF-2005- 0176), and Generalitat de Catalunya (Suport als Grups de Recerca Consolidats and Distinció a Joves Investigadors). M.F.S., C.S., and M.J.P.-G. were supported by a postgraduate fellowship from the Spanish Government, Ministerio de Educación y Ciencia and Fondo de Investigación Sanitaria, respectively. R.G. holds a postgraduate fellowship from the Department d'Universitat, Recerca i Societat de la Informació (Generalitat de Catalunya) and Fons Social Europeu. N.B. is the recipient of a postgraduate fellowship from the Gobierno Vasco. V.J.Y. was under a Beatriu de Pino´s contract from Generalitat de Catalunya.

Producción Científica ; Gram-negative bacterial infections are accompanied by inflammation and somatic or visceral pain. These symptoms are generally attributed to sensitization of nociceptors by inflammatory mediators released by immune cells. Nociceptor sensitization during inflammation occurs through activation of the Toll-like receptor 4 (TLR4) signalling pathway by lipopolysaccharide (LPS), a toxic by-product of bacterial lysis. Here we show that LPS exerts fast, membrane delimited, excitatory actions via TRPA1, a transient receptor potential cation channel that is critical for transducing environmental irritant stimuli into nociceptor activity. Moreover, we find that pain and acute vascular reactions, including neurogenic inflammation (CGRP release) caused by LPS are primarily dependent on TRPA1 channel activation in nociceptive sensory neurons, and develop independently of TLR4 activation. The identification of TRPA1 as a molecular determinant of direct LPS effects on nociceptors offers new insights into the pathogenesis of pain and neurovascular responses during bacterial infections and opens novel avenues for their treatment. ; Projects SAF2010-14990 and PROMETEO2010-046. Instituto de Salud Carlos III. CONSOLIDER-INGENIO 2010. ISCIII grants R006/009 (Red Heracles), the Spanish Fundación Marcelino Botín and Belgian Federal Government (IUAP P6/28 and P7/13), the Research Foundation-Flanders and the Research Council of the KU Leuven.

Risk prediction tools cannot identify most individuals at high coronary artery disease (CAD) risk. Oxidized low-density lipoproteins (oxLDLs) and microRNAs are actively involved in atherosclerosis. Our aim was to examine the association of CAD and oxLDLs-induced microRNAs, and to assess the microRNAs predictive capacity of future CAD events. Human endothelial and vascular smooth muscle cells were treated with oxidized/native low-density lipoproteins, and microRNA expression was analyzed. Differentially expressed and CAD-related miRNAs were examined in serum samples from (1) a case-control study with 476 myocardial infarction (MI) patients and 487 controls, and (2) a case-cohort study with 105 incident CAD cases and 455 randomly-selected cohort participants. MicroRNA expression was analyzed with custom OpenArray plates, log rank tests and Cox regression models. Twenty-one microRNAs, two previously undescribed (hsa-miR-193b-5p and hsa-miR-1229-5p), were up- or down-regulated upon cell treatment with oxLDLs. One of the 21, hsa-miR-122-5p, was also upregulated in MI cases (fold change = 4.85). Of the 28 CAD-related microRNAs tested, 11 were upregulated in MI cases -1 previously undescribed (hsa-miR-16-5p)-, and 1/11 was also associated with CAD incidence (adjusted hazard ratio = 0.55 (0.35-0.88)) and improved CAD risk reclassification, hsa-miR-143-3p. We identified 2 novel microRNAs modulated by oxLDLs in endothelial cells, 1 novel microRNA upregulated in AMI cases compared to controls, and one circulating microRNA that improved CAD risk classification. ; This work was supported by the Spain's Ministry of Science and Innovation (Madrid, Spain), co-financed with European Union European Regional Development Funds –ERDF- (FIS-CP12/03287, FIS-14/00449, FIS-PI081327, INTRASALUD PI11/01801, PI15/00064, IJCI-2016-29393 to DdG-C, CIBERCV (CB16/11/00229, 00246, 00403), CIBERESP CB06/02/0029, CIBEROBN CB06/03/0028); the Spain's ministry of Economy and Competiveness (Madrid, Spain) (BFU2016-75360-R); the BBVA Foundation (Bilbao, Spain) (PR-16-BIO-CAR-0041); the Health Departament of the Generalitat de Catalunya (Barcelona, Spain) through the Agència de Gestió d'Ajuts Universitaris de Recerca de Catalunya (AGAUR) (Barcelona, Spain) (2017SGR222), the Strategic Plan for research and health innovation (PERIS) (Barcelona, Spain) (SLT006/17/00234, SLT002/16/00145, SLT006/17/00029 to IRD); and by the Junta de Castilla y León (Valladolid, Spain) (VA114P17). CIBERs of Pathophysiology of Obesity and Nutrition (CIBEROBN), Cardiovascular Diseases (CIBERCV), and Epidemiology (CIBERESP) are initiatives of the Instituto de Salud Carlos III, Madrid, Spain.