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Rojo J.M.,CSIC - Biological Research Center | Ojeda G.,Institute Salud Carlos III | Acosta Y.Y.,CSIC - Biological Research Center | Montes-Casado M.,Institute Salud Carlos III | And 2 more authors.
Journal of Leukocyte Biology | Year: 2014

Tregs are anergic CD4+CD25+Foxp3+ T lymphocytes exerting active suppression to control immune and autoimmune responses. However, the factors in TCR recognition underlying Treg differentiation are unclear. Based on our previous data, we hypothesized that Treg TCR/CD3 antigen receptor complexes might differ from those of CD4+CD25- Tconv. Expression levels of TCR/CD3, CD3ε, ζ chains, or other molecules involved in antigen signaling and the characteristics of CD3ε chains were analyzed in thymus or spleen Treg cells from normal mice. Tregs had quantitative and qualitatively distinct TCR/CD3 complexes and CD3ε chains. They expressed significantly lower levels of the TCR/CD3 antigen receptor, CD3ε chains, TCR-ζ chain, or the CD4 coreceptor than Tconv. Levels of kinases, adaptor molecules involved in TCR signaling, and early downstream activation pathways were also lower in Tregs than in Tconv. Furthermore, TCR/CD3 complexes in Tregs were enriched in CD3ε chains conserving their N-terminal, negatively charged amino acid residues; this trait is linked to a higher activation threshold. Transfection of mutant CD3ε chains lacking these residues inhibited the differentiation of mature CD4+Foxp3- T lymphocytes into CD4+Foxp3+ Tregs, and differences in CD3ε chain recognition by antibodies could be used to enrich for Tregs in vivo. Our results show quantitative and qualitative differences in the TCR/CD3 complex, supporting the hyporesponsive phenotype of Tregs concerning TCR/CD3 signals. These differences might reconcile avidity and flexible threshold models of Treg differentiation and be used to implement therapeutic approaches involving Treg manipulation. © Society for Leukocyte Biology.

Fernandez-Ruiz J.,Complutense University of Madrid | Fernandez-Ruiz J.,CIBER ISCIII | Fernandez-Ruiz J.,Instituto Ramon Y Cajal Of Investigacion Sanitaria Irycis | Moro M.A.,Complutense University of Madrid | And 2 more authors.
Neurotherapeutics | Year: 2015

Cannabinoids form a singular family of plant-derived compounds (phytocannabinoids), endogenous signaling lipids (endocannabinoids), and synthetic derivatives with multiple biological effects and therapeutic applications in the central and peripheral nervous systems. One of these properties is the regulation of neuronal homeostasis and survival, which is the result of the combination of a myriad of effects addressed to preserve, rescue, repair, and/or replace neurons, and also glial cells against multiple insults that may potentially damage these cells. These effects are facilitated by the location of specific targets for the action of these compounds (e.g., cannabinoid type 1 and 2 receptors, endocannabinoid inactivating enzymes, and nonendocannabinoid targets) in key cellular substrates (e.g., neurons, glial cells, and neural progenitor cells). This potential is promising for acute and chronic neurodegenerative pathological conditions. In this review, we will collect all experimental evidence, mainly obtained at the preclinical level, supporting that different cannabinoid compounds may be neuroprotective in adult and neonatal ischemia, brain trauma, Alzheimer’s disease, Parkinson’s disease, Huntington’s chorea, and amyotrophic lateral sclerosis. This increasing experimental evidence demands a prompt clinical validation of cannabinoid-based medicines for the treatment of all these disorders, which, at present, lack efficacious treatments for delaying/arresting disease progression, despite the fact that the few clinical trials conducted so far with these medicines have failed to demonstrate beneficial effects. © 2015, The American Society for Experimental NeuroTherapeutics, Inc.

Llibre J.M.,Autonomous University of Barcelona | Pulido F.,Institute Investigacion Hospital 12 Of Octubre I12 | Garcia F.,Hospitales Universitarios Of Granada | Garcia Deltoro M.,Consorcio Hospital General Universitario Of Valencia | And 2 more authors.
AIDS reviews | Year: 2015

Dolutegravir is a novel integrase strand-transfer inhibitor that displays potent in vitro activity and a remarkably different resistance profile. Its robust pharmacokinetic/pharmacodynamic properties - long plasma t1/2, high plasma inhibition quotient, and slow dissociation rate from the integrase complex - suggest it should present a high barrier to resistance development. This has been confirmed in pivotal phase III studies of initial therapy, with none out of 1,118 treated individuals selecting resistance-associated mutations at the integrase or reverse transcriptase. In integrase-naive subjects with virological failure, a rescue intervention with dolutegravir has shown significantly higher rates of virological suppression than raltegravir, as well as significantly lower rates of selection of resistance both at the integrase and against the optimized background. Unexpectedly, a mutation rarely selected in this scenario (R263K) induces a fitness cost that prevents HIV-1 from evading drug pressure, and accumulation of further secondary mutations does not occur and has not been able to compensate the replication capacity deficit in the aftermath of the appearance of a single drug resistance mutation. Therefore, both in vitro and in vivo, it leads the virus to a previously unnoticed evolutionary pathway with low chances to develop resistance to both dolutegravir and other families of antiretrovirals present in the background. This high genetic barrier to resistance development in early stages of antiretroviral treatment can help preserve future treatment options in patients who fail antiretroviral therapy.

Sierra-Hidalgo F.,Hospital Universitario 12 Of Octubre | Sierra-Hidalgo F.,Institute Investigacion Hospital 12 Of Octubre I12 | De Pablo-Fernandez E.,Kings College
Clinical Neuropharmacology | Year: 2013

Palinopsia is an illusory visual phenomenon consisting in the persistence or recurrence of visual images after the exciting stimulus object has been removed. It has been reported in association with parietal and occipital lobe lesions, migraine auras, and related to the use of several drugs and illicit drugs. Here, we report the case of a 23-year-old woman with a 4-year history of episodic migraine with aura who developed palinopsia during sequential prophylactic therapies with topiramate and zonisamide. Although the exact physiopathology of this phenomenon remains unknown, topiramate-and zonisamide-induced palinopsia support an increase on serotonergic activity as a possible mechanism for this visual disorder. © 2013 by Lippincott Williams & Wilkins.

de Andres M.C.,Complejo Hospitalario Universitario runa CHUAC | Maneiro E.,Complejo Hospitalario Universitario runa CHUAC | Martin M.A.,Institute Investigacion Hospital 12 Of Octubre I12 | Arenas J.,Institute Investigacion Hospital 12 Of Octubre I12 | Blanco F.J.,Complejo Hospitalario Universitario runa CHUAC
Arthritis Research and Therapy | Year: 2013

Introduction: The pathogenesis of osteoarthritis (OA) is characterized by the production of high amounts of nitric oxide (NO), as a consequence of up-regulation of chondrocyte-inducible nitric oxide synthase (iNOS) induced by inflammatory cytokines. NO donors represent a powerful tool for studying the role of NO in the cartilage in vitro. There is no consensus about NO effects on articular cartilage in part because the differences between the NO donors available. The aim of this work is to compare the metabolic profile of traditional and new generation NO donors to see which one points out the osteoarthritic process in the best way. Methods: Human healthy and OA chondrocytes were isolated from patients undergoing joint replacement surgery, and primary cultured. Cells were stimulated with NO donors (NOC-12 or SNP). NO production was evaluated by the Griess method, and apoptosis was quantified by flow cytometry. Mitochondrial function was evaluated by analysing respiratory chain enzyme complexes, citrate synthase (CS) activities by enzymatic assay, mitochondrial membrane potential (Δψm) by JC-1 using flow cytometry, and ATP levels were measured by luminescence assays. Glucose transport was measured as the uptake of 2-deoxy-[3H]glucose (2-[3H]DG). Statistical analysis was performed using the Mann-Whitney U test. Results: NOC-12 liberates approximately ten times more NO2 -than SNP, but the level of cell death induced was not as profound as that produced by SNP. Normal articular chondrocytes stimulated with NOC-12 had reduced activity from complexes I, III y IV, and the mitochondrial mass was increased in these cells. Deleterious effects on ΔΨm and ATP levels were more profound with SNP, and this NO donor was able to reduce 2-[3H]DG levels. Both NO donors had opposite effects on lactate release, SNP diminished the levels and NOC-12 lead to lactate accumulation. OA chondrocytes incorporate significantly more 2-[3H]DG than healthy cells. Conclusions: These findings suggest that the new generation donors, specifically NOC-12, mimic the OA metabolic process much better than SNP. Previous results using SNP have to be considered prudently since most of the effects observed can be induced by the interactions of secondary products of NO. © 2013 de Andrés et al.; licensee BioMed Central Ltd.

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