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Microglial activation underlies cerebellar deficits produced by repeated cannabis exposure

  • Cutando Ruiz, Laura, 1985-
  • Busquets Garcia, Arnau, 1985-
  • Puighermanal Puigvert, Emma, 1983-
  • Gomis González, Maria
  • Delgado García, José María
  • Gruart, Agnès
  • Maldonado, Rafael, 1961-
  • Ozaita Mintegui, Andrés, 1969-
Chronic cannabis exposure can lead to cerebellar dysfunction in humans, but the neurobiological mechanisms involved remain incompletely understood. Here, we found that in mice, subchronic administration of the psychoactive component of cannabis, delta9-tetrahydrocannabinol (THC), activated cerebellar microglia and increased the expression of neuroinflammatory markers, including IL-1β. This neuroinflammatory phenotype correlated with deficits in cerebellar conditioned learning and fine motor coordination. The neuroinflammatory phenotype was readily detectable in the cerebellum of mice with global loss of the CB1 cannabinoid receptor (CB1R, Cb1(-/-) mice) and in mice lacking CB1R in the cerebellar parallel fibers, suggesting that CB1R downregulation in the cerebellar molecular layer plays a key role in THC-induced cerebellar deficits. Expression of CB2 cannabinoid receptor (CB2R) and Il1b mRNA was increased under neuroinflammatory conditions in activated CD11b-positive microglial cells. Furthermore, administration of the immunosuppressant minocycline or an inhibitor of IL-1β receptor signaling prevented the deficits in cerebellar function in Cb1(-/-) and THC-withdrawn mice. Our results suggest that cerebellar microglial activation plays a crucial role in the cerebellar deficits induced by repeated cannabis exposure., This study was supported by grants from the Ministerio de Ciencia e Innovación (BFU2008-03390, to A. Gruart; BFU2008-00899, to J.M. Delgado-García; SAF2007-64062 and SAF2011-29864, to R. Maldonado; and SAF2009-07309 and BFU2012-33500, to A. Ozaita); the European Commission (PHECOMP, LSHM-CT-2007-037669, to R. Maldonado); the Instituto de Salud Carlos III (RTA-RETICS, RD06/001/001, to R. Maldonado); the Generalitat de Catalunya (SGR2009-SGR00731, to R. Maldonado); the Fundació La Marató de TV3 (090910, to A. Ozaita); and the ICREA Academia (to R. Maldonado). Partial support from the EU FEDER funds is also acknowledged.
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Cannabinoid-hypocretin cross-talk in the central nervous system: what we know so far

  • Flores de los Heros, África, 1985-
  • Maldonado, Rafael, 1961-
  • Berrendero Díaz, Fernando, 1971-
Emerging findings suggest the existence of a cross-talk between hypocretinergic and endocannabinoid systems. Although few studies have examined this relationship, the apparent overlap observed in the neuroanatomical distribution of both systems as well as their putative functions strongly point to the existence of such cross-modulation. In agreement, biochemical and functional studies have revealed the existence of heterodimers between CB1 cannabinoid receptor and hypocretin receptor-1, which modulates the cellular localization and downstream signaling of both receptors. Moreover, the activation of hypocretin receptor-1 stimulates the synthesis of 2-arachidonoyl glycerol culminating in the retrograde inhibition of neighboring cells and suggesting that endocannabinoids could contribute to some hypocretin effects. Pharmacological data indicate that endocannabinoids and hypocretins might have common physiological functions in the regulation of appetite, reward and analgesia. In contrast, these neuromodulatory systems seem to play antagonistic roles in the regulation of sleep/wake cycle and anxiety-like responses. The present review attempts to piece together what is known about this interesting interaction and describes its potential therapeutic implications., This work was supported by the Instituto de Salud CarlosIII grants, #PI07/0559, #PI10/00316 and #RD06/001/001 (RTA-RETICS), by the Spanish Ministry of Science and Technology, Consolider-C #SAF2007-64062 and #SAF2011-29864, the Catalan Government (SGR2009-00731), and by the Catalan Institution for Research and Advanced Studies (ICREA Academia program). África Flores is recipient of a predoctoral fellowship from the Spanish Ministry of Education
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DREAM controls the on/off switch of specific activity-dependent transcription pathways

  • Mellström, Britt
  • Sahún, Ignasi
  • Ruiz Nuño, Ana
  • Murtra, Patricia
  • Gómez Villafuertes, Rosa
  • Savignac, Magalí
  • Oliveros, Juan C.
  • González, Paz
  • Kastanauskaite, Asta
  • Knafo, Shira
  • Zhuo, Min
  • Higuera Matas, Alejandro
  • Errington, Michael L.
  • Maldonado, Rafael, 1961-
  • De Felipe, Javier
  • Jefferys, John G.R.
  • Bliss, Tim V. P.
  • Dierssen, Mara
  • Naranjo, José R.
Changes in nuclear Ca(2+) homeostasis activate specific gene expression programs and are central to the acquisition and storage of information in the brain. DREAM (downstream regulatory element antagonist modulator), also known as calsenilin/KChIP-3 (K(+) channel interacting protein 3), is a Ca(2+)-binding protein that binds DNA and represses transcription in a Ca(2+)-dependent manner. To study the function of DREAM in the brain, we used transgenic mice expressing a Ca(2+)-insensitive/CREB-independent dominant active mutant DREAM (daDREAM). Using genome-wide analysis, we show that DREAM regulates the expression of specific activity-dependent transcription factors in the hippocampus, including Npas4, Nr4a1, Mef2c, JunB, and c-Fos. Furthermore, DREAM regulates its own expression, establishing an autoinhibitory feedback loop to terminate activity-dependent transcription. Ablation of DREAM does not modify activity-dependent transcription because of gene compensation by the other KChIP family members. The expression of daDREAM in the forebrain resulted in a complex phenotype characterized by loss of recurrent inhibition and enhanced long-term potentiation (LTP) in the dentate gyrus and impaired learning and memory. Our results indicate that DREAM is a major master switch transcription factor that regulates the on/off status of specific activity-dependent gene expression programs that control synaptic plasticity, learning, and memory., This work was supported by grants from Spanish Ministry of Health and Science, Madrid Community, La Marató, La Caixa, Reina Sofía and Areces Foundations, the EU 6th Framework Program (NeuroNE, CureFXS), the ERA-NET Program (Neuron and E-Rare), and the Medical Research Council. S.K. has a postdoctoral contract from the Ramón y Cajal Program of the Ministry of Science and Innovation.
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Long-lasting oral analgesic effects of N-protected aminophosphinic dual ENKephalinase inhibitors (DENKIs) in peripherally controlled pain

  • Bonnard, Elisabeth
  • Poras, Hervé
  • Nadal i Roura, Xavier, 1980-
  • Maldonado, Rafael, 1961-
  • Fournié-Zaluski, Marie-Claude
  • Roques, Bernard P.
The peripheral endogenous opioid system is critically involved in neuropathic and inflammatory pain generation as suggested by the modulation of opioid receptors expression and enkephalins (ENKs) release observed in these painful conditions. Accordingly, an innovative approach in the treatment of these nocifensive events is to increase and maintain high local concentrations of extracellular pain-evoked ENKs, by preventing their physiological enzymatic inactivation by two Zn metallopeptidases, the neutral endopeptidase (NEP, neprilysin, EC 3.4.24.11) and the neutral aminopeptidase (APN, EC 3.4.11.2). With this aim, new orally active dual ENKephalinase inhibitors (DENKIs) were designed as soluble prodrugs by introducing a N-terminal cleavable carbamate in the previously described aminophosphinic inhibitors. This induces long-lasting antinociceptive responses after oral administration, in various rodent models of inflammatory and neuropathic pain. These responses are mediated through stimulation of peripheral opioid receptors by DENKIs-protected ENKs as demonstrated by naloxone methiodide reversion. In all tested models, the most efficient prodrug 2a (PL265) was active, at least during 150-180 min, after single oral administration of 25-50 mg/kg in mice and of 100-200 mg/kg in rats. In models of neuropathic pain, both hyperalgesia and allodynia were markedly reduced. Interestingly, combination of inactive doses of 2a (PL265) and of the anti-epileptic drug gabapentin had synergistic effect on neuropathic pain. Pharmacokinetic studies of 2a (PL265) in rats show that the active drug is the only generated metabolite produced. These encouraging results have made 2a (PL265) a suitable candidate for clinical development.
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Uncovering adaptive evolution in the human lineage

  • Gayà Vidal, Magdalena
  • Albà Soler, Mar
Background: The recent increase in human polymorphism data, together with the availability of genome sequences from several primate species, provides an unprecedented opportunity to investigate how natural selection has shaped human evolution. Results: We compared human branch-specific substitutions with variation data in the current human population to measure the impact of adaptive evolution on human protein coding genes. The use of single nucleotide polymorphisms (SNPs) with high derived allele frequencies (DAFs) minimized the influence of segregating slightly deleterious mutations and improved the estimation of the number of adaptive sites. Using DAF ≥ 60% we showed that the proportion of adaptive substitutions is 0.2% in the complete gene set. However, the percentage rose to 40% when we focused on genes that are specifically accelerated in the human branch with respect to the chimpanzee branch, or on genes that show signatures of adaptive selection at the codon level by the maximum likelihood based branch-site test. In general, neural genes are enriched in positive selection signatures. Genes with multiple lines of evidence of positive selection include taxilin beta, which is involved in motor nerve regeneration and syntabulin, and is required for the formation of new presynaptic boutons. Conclusions: We combined several methods to detect adaptive evolution in human coding sequences at a genome-wide level. The use of variation data, in addition to sequence divergence information, uncovered previously undetected positive selection signatures in neural genes., This work was financially supported by the Ministerio de Economía y Competitividad from the Spanish Government (Plan Nacional project BFU2012-36820), and Institució Catalana de Recerca i Estudis Avançats (ICREA) from Generalitat de Catalunya
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Thermal niche evolution and geographical range expansion in a species complex of western Mediterranean diving beetles

  • Hidalgo Galiana, Amparo
  • Sánchez Fernández, David
  • Bilton, David T
  • Cieslak, Alexandra
  • Ribera, Ignacio
Background: Species thermal requirements are one of the principal determinants of their ecology and biogeography, although our understanding of the interplay between these factors is limited by the paucity of integrative empirical studies. Here we use empirically collected thermal tolerance data in combination with molecular phylogenetics/phylogeography and ecological niche modelling to study the evolution of a clade of three western Mediterranean diving beetles, the Agabus brunneus complex. Results: The preferred mitochondrial DNA topology recovered A. ramblae (North Africa, east Iberia and Balearic islands) as paraphyletic, with A. brunneus (widespread in the southwestern Mediterranean) and A. rufulus (Corsica and Sardinia) nested within it, with an estimated origin between 0.60-0.25 Ma. All three species were, however, recovered as monophyletic using nuclear DNA markers. A Bayesian skyline plot suggested demographic expansion in the clade at the onset of the last glacial cycle. The species thermal tolerances differ significantly, with A. brunneus able to tolerate lower temperatures than the other taxa. The climatic niche of the three species also differs, with A. ramblae occupying more arid and seasonal areas, with a higher minimum temperature in the coldest month. The estimated potential distribution for both A. brunneus and A. ramblae was most restricted in the last interglacial, becoming increasingly wider through the last glacial and the Holocene. Conclusions: The A. brunneus complex diversified in the late Pleistocene, most likely in south Iberia after colonization from Morocco. Insular forms did not differentiate substantially in morphology or ecology, but A. brunneus evolved a wider tolerance to cold, which appeared to have facilitated its geographic expansion. Both A. brunneus and A. ramblae expanded their ranges during the last glacial, although they have not occupied areas beyond their LGM potential distribution except for isolated populations of A. brunneus in France and England. On the islands and possibly Tunisia secondary contact between A. brunneus and A. ramblae or A. rufulus has resulted in introgression. Our work highlights the complex dynamics of speciation and range expansions within southern areas during the last glacial cycle, and points to the often neglected role of North Africa as a source of European biodiversity., This work was supported by an FPI grant to AH-G and projects CGL2007-61665 and CGL2010-15755 from the Spanish government to IR
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Structural and intermediary determinants of social inequalities in the mental well-being of European workers: a relational approach

  • Moortel, Deborah De
  • Vandenheede, Hadewijch
  • Muntaner, Carles, 1957-
  • Vanroelen, Christophe
Background: The objective of this study is to examine social inequalities in employee mental well-being, using relational social class indicators. Relational social class indicators are based on theoretical insights about the mechanisms generating social (health) inequalities. Additionally, it is examined whether the psychosocial work environment and employment quality act as intermediary determinants of social class inequalities in mental well-being, simultaneously testing the mediation (differential exposure) and moderation (differential vulnerability) hypotheses. Methods: Data from the European Social Survey Round 2 (2004/5) and Round 5 (2010) were analysed. Mental well-being was assessed by the WHO Well-being Index. The measure for social class was inspired by E.O. Wright’s class scheme. Three-level linear multilevel modelling was used to account for clustering of employees within research years and countries. Results: We found social class inequalities in mental well-being in the European working population for both men and women. Compared to unskilled workers, managers reported the best mental well-being, while supervisors held an intermediary position. As regards the mediation hypothesis, an unfavourable psychosocial work environment and low-quality employment conditions mediated the relation between social class and poor mental well-being in both men and women. However, low quality of employment relations only mediated the “social class-mental well-being” association in the male sample. As regards the moderation hypothesis, modification effects were seen for the psychosocial work environment and employment conditions in both men and women. Conclusion: Relational indicators of social class are related to mental well-being in European employees. Relational accounts of social class are complementary to stratification indicators in social epidemiology. From a policy perspective, better employee mental well-being and less social class inequality could be achieved through initiatives addressing the unequal social relations generated by structural positions in the labour process., The research for this article has been supported by the Research council of the Vrije Universiteit Brussel, Belgium (research grant ‘OZR2094’), by the Research Foundation Flanders (G.0440.09 N) and the SOPHIE-project which has received funding from the European Community’s Seventh Framework Program Health (FP7/2007-2013) under grant agreement no. 278173.
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Novel and optimized strategies for inducing fibrosis in vivo: focus on Duchenne Muscular Dystrophy

  • Pessina, Patrizia
  • Cabrera, Daniel
  • Morales, María Gabriela
  • Riquelme, Cecilia A
  • Gutiérrez, Jaime
  • Serrano, Antonio L.
  • Brandan, Enrique
  • Muñoz Cánoves, Pura, 1962-
Background: Fibrosis, an excessive collagen accumulation, results in scar formation, impairing function of vital organs and tissues. Fibrosis is a hallmark of muscular dystrophies, including the lethal Duchenne muscular dystrophy (DMD), which remains incurable. Substitution of muscle by fibrotic tissue also complicates gene/cell therapies for DMD. Yet, no optimal models to study muscle fibrosis are available. In the widely used mdx mouse model for DMD, extensive fibrosis develops in the diaphragm only at advanced adulthood, and at about two years of age in the ‘easy-to-access’ limb muscles, thus precluding fibrosis research and the testing of novel therapies.Methods: We developed distinct experimental strategies, ranging from chronic exercise to increasing muscle damage on limb muscles of young mdx mice, by myotoxin injection, surgically induced trauma (laceration or denervation) or intramuscular delivery of profibrotic growth factors (such as TGFβ). We also extended these approaches to muscle of normal non-dystrophic mice. Results: These strategies resulted in advanced and enhanced muscle fibrosis in young mdx mice, which persisted over time, and correlated with reduced muscle force, thus mimicking the severe DMD phenotype. Furthermore, increased fibrosis was also obtained by combining these procedures in muscles of normal mice, mirroring aberrant repair after severe trauma. Conclusions: We have developed new and improved experimental strategies to accelerate and enhance muscle fibrosis in vivo. These strategies will allow rapidly assessing fibrosis in the easily accessible limb muscles of young mdx mice, without necessarily having to use old animals. The extension of these fibrogenic regimes to the muscle of non-dystrophic wild-type mice will allow fibrosis assessment in a wide array of pre-existing transgenic mouse lines, which in turn will facilitate understanding the mechanisms of fibrogenesis. These strategies should improve our ability to combat fibrosis-driven dystrophy progression and aberrant regeneration., The authors acknowledge funding from MINECO-Spain (SAF2012-38547, FIS-PS09/01267, FIS-PI13/02512, PLE2009-0124), AFM, E-Rare, Fundació-MaratóTV3, Duchenne PP-NL, EU-FP7 (Myoage, Optistem and Endostem), MDA, CARE PFB12/2007 and FONDECYT 1110426
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MAPK-activated protein kinase 2-deficiency causes hyperacute tumor necrosis factor-induced inflammatory shock

  • Vandendriessche, Benjamin
  • Goethals, An
  • Simats, Alba
  • Hamme, Evelien Van
  • Brouckaert, Peter
  • Cauwels, Anje
Background: MAPK-activated protein kinase 2 (MK2) plays a pivotal role in the cell response to (inflammatory) stress. Among others, MK2 is known to be involved in the regulation of cytokine mRNA metabolism and regulation of actin cytoskeleton dynamics. Previously, MK2-deficient mice were shown to be highly resistant to LPS/D-Galactosamine-induced hepatitis. Additionally, research in various disease models has indicated the kinase as an interesting inhibitory drug target for various acute or chronic inflammatory diseases. Results: We show that in striking contrast to the known resistance of MK2-deficient mice to a challenge with LPS/D-Gal, a low dose of tumor necrosis factor (TNF) causes hyperacute mortality via an oxidative stress driven mechanism. We identified in vivo defects in the stress fiber response in endothelial cells, which could have resulted in reduced resistance of the endothelial barrier to deal with exposure to oxidative stress. In addition, MK2-deficient mice were found to be more sensitive to cecal ligation and puncture-induced sepsis. Conclusions: The capacity of the endothelial barrier to deal with inflammatory and oxidative stress is imperative to allow a regulated immune response and maintain endothelial barrier integrity. Our results indicate that, considering the central role of TNF in pro-inflammatory signaling, therapeutic strategies examining pharmacological inhibition of MK2 should take potentially dangerous side effects at the level of endothelial barrier integrity into account., Research was supported by the agency for Innovation by Science and Technology (IWT); Research Foundation Flanders (FWO); and Ghent University: Concerted Research Actions (GOA)
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Chronic Obstructive Pulmonary Disease heterogeneity: challenges for health risk assessment, stratification and management

  • Roca, Josep
  • Vargas, Claudia
  • Cano, Isaac
  • Selivanov, Vitaly
  • Barreiro Portela, Esther
  • Maier, Dieter
  • Falciani, Francesco
  • Wagner, Peter
  • Cascante, Marta
  • García Aymerich, Judith
  • Kalko, Susana G.
  • Marin de Mas, Igor
  • Tegnér, Jesper
  • Escarabill, Joan
  • Agustí, Alvar
  • Gomez Cabrero, David
  • Synergy-COPD consortium
Background and hypothesis: Heterogeneity in clinical manifestations and disease progression in Chronic Obstructive Pulmonary Disease (COPD) lead to consequences for patient health risk assessment, stratification and management. Implicit with the classical "spill over" hypothesis is that COPD heterogeneity is driven by the pulmonary events of the disease. Alternatively, we hypothesized that COPD heterogeneities result from the interplay of mechanisms governing three conceptually different phenomena: 1) pulmonary disease, 2) systemic effects of COPD and 3) co-morbidity clustering, each of them with their own dynamics. Objective and method: To explore the potential of a systems analysis of COPD heterogeneity focused on skeletal muscle dysfunction and on co-morbidity clustering aiming at generating predictive modeling with impact on patient management. To this end, strategies combining deterministic modeling and network medicine analyses of the Biobridge dataset were used to investigate the mechanisms of skeletal muscle dysfunction. An independent data driven analysis of co-morbidity clustering examining associated genes and pathways was performed using a large dataset (ICD9-CM data from Medicare, 13 million people). Finally, a targeted network analysis using the outcomes of the two approaches (skeletal muscle dysfunction and co-morbidity clustering) explored shared pathways between these phenomena. Results: (1) Evidence of abnormal regulation of skeletal muscle bioenergetics and skeletal muscle remodeling showing a significant association with nitroso-redox disequilibrium was observed in COPD; (2) COPD patients presented higher risk for co-morbidity clustering than non-COPD patients increasing with ageing; and, (3) the on-going targeted network analyses suggests shared pathways between skeletal muscle dysfunction and co-morbidity clustering. Conclusions: The results indicate the high potential of a systems approach to address COPD heterogeneity. Significant knowledge gaps were identified that are relevant to shape strategies aiming at fostering 4P Medicine for patients with COPD., The research described in this paper is partly supported by the Synergy-COPD European project (FP7-ICT-270086). Publication of this article has been funded by the Synergy-COPD European project (FP7-ICT-270086)
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