Institute Investigacion Sanitaria La Fe

Valencia, Spain

Institute Investigacion Sanitaria La Fe

Valencia, Spain
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Benito M.,Advanced Imaging Unit | Benito M.,CIBER ISCIII | De Molina A.,Comparative Medicine Unit | Sepulveda P.,Institute Investigacion Sanitaria La Fe | Cervera A.M.,Institute Investigacion Sanitaria La Fe
Diabetes | Year: 2015

A number of metabolites have signaling properties by acting through G-protein-coupled receptors. Succinate, a Krebs cycle intermediate, increases after dysregulated energy metabolism and can bind to its cognate receptor succinate receptor 1 (Sucnr1, or GPR91) to activate downstream signaling pathways. We show that Sucnr1 is highly expressed in the white adipose tissue (WAT) compartment of mice and regulates adipose mass and glucose homeostasis. Sucnr1-/- mice were generated, and weight gain was monitored under basal and nutritional stress (high-fat diet [HFD]) conditions. On chow diet, Sucnr1-/- mice had increased energy expenditure, were lean with a smaller WAT compartment, and had improved glucose buffering. Lipolysis measurements revealed that Sucnr1-/- mice were released from succinate-induced inhibition of lipolysis, demonstrating a function of Sucnr1 in adipose tissue. Sucnr1 deletion also protected mice from obesity on HFD, but only during the initial period; at later stages, body weight of HFD-fed Sucnr1-/- mice was almost comparable with wild-type (WT) mice, but WAT content was greater. Also, these mice became progressively hyperglycemic and failed to secrete insulin, although pancreas architecture was similar to WT mice. These findings suggest that Sucnr1 is a sensor for dietary energy and raise the interesting possibility that protocols to modulate Sucnr1 might have therapeutic utility in the setting of obesity. © 2015 by the American Diabetes Association.

Vriezinga S.L.,Leiden University | Auricchio R.,University of Naples Federico II | Bravi E.,Triesty | Castillejo G.,Rovira i Virgili University | And 29 more authors.
New England Journal of Medicine | Year: 2014

BACKGROUND A window of opportunity has been suggested for reducing the risk of celiac disease by introducing gluten to infants at 4 to 6 months of age.METHODS We performed a multicenter, randomized, double-blind, placebo-controlled dietaryintervention study involving 944 children who were positive for HLA-DQ2 or HLA-DQ8 and had at least one first-degree relative with celiac disease. From 16 to 24 weeks of age, 475 participants received 100 mg of immunologically active gluten daily, and 469 received placebo. Anti-transglutaminase type 2 and antigliadin antibodies were periodically measured. The primary outcome was the frequency of biopsy-confirmed celiac disease at 3 years of age.RESULTS Celiac disease was confirmed by means of biopsies in 77 children. To avoid underestimation of the frequency of celiac disease, 3 additional children who received a diagnosis of celiac disease according to the 2012 European Society for Pediatric Gastroenterology, Hepatology, and Nutrition diagnostic criteria (without having undergone biopsies) were included in the analyses (80 children; median age, 2.8 years; 59% were girls). The cumulative incidence of celiac disease among patients 3 years of age was 5.2% (95% confidence interval [CI], 3.6 to 6.8), with similar rates in the gluten group and the placebo group (5.9% [95% CI, 3.7 to 8.1] and 4.5% [95% CI, 2.5 to 6.5], respectively; hazard ratio in the gluten group, 1.23; 95% CI, 0.79 to 1.91). Rates of elevated levels of anti-transglutaminase type 2 and antigliadin antibodies were also similar in the two study groups (7.0% [95% CI, 4.7 to 9.4] in the gluten group and 5.7% [95% CI, 3.5 to 7.9] in the placebo group; hazard ratio, 1.14; 95% CI, 0.76 to 1.73). Breast-feeding, regardless of whether it was exclusive or whether it was ongoing during gluten introduction, did not significantly influence the development of celiac disease or the effect of the intervention.CONCLUSIONS As compared with placebo, the introduction of small quantities of gluten at 16 to 24 weeks of age did not reduce the risk of celiac disease by 3 years of age in this group of high-risk children. (Funded by the European Commission and others; PreventCD Current Controlled Trials number, ISRCTN74582487.). Copyright © 2014 Massachusetts Medical Society.

Donato M.T.,Institute Investigacion Sanitaria la Fe | Donato M.T.,University of Valencia | Donato M.T.,CIBER ISCIII | Jover R.,Institute Investigacion Sanitaria la Fe | And 4 more authors.
Current Drug Metabolism | Year: 2013

One key issue in the pharmaceutical development of new compounds is knowledge on metabolism, the enzymes involved and the potential hepatotoxicity of a drug. Primary cultured hepatocytes are a valuable in vitro model for drug metabolism studies. However, human hepatocytes show phenotypic instability and have restricted accessibility and high batch-to-batch functional variability, which seriously complicates their use in routine testing. Therefore, several liver-derived cell models have been developed for drug metabolism and hepatotoxicity screening to circumvent these drawbacks. Hepatoma cell lines offer important advantages, availability, an unlimited life span and a stable phenotype, thus rendering them suitable models for such studies. However, currently available human hepatoma cell lines are not a good alternative to cultured hepatocytes as they show very limited expression for most drug-metabolising enzymes. Other approaches have been developed to generate immortalised hepatic cells with metabolic competence (use of plasmids encoding immortalising genes to transform human hepatocytes, cell lines obtained from transgenic animals, hepatocytomes or hydrid cells). Recombinant models heterologously expressing cytochrome P450 enzymes in hepatoma cells have also been generated, and are widely used in drug metabolism and toxicity evaluations. In recent years, new approaches to up-regulate the expression of drug-biotransformation enzymes in human cell lines (i.e., transfection with the expression vectors encoding key hepatic transcription factors) have also been investigated. This paper reviews the features of liver-derived cell lines, their suitability for drug metabolism and hepatotoxicity studies, and the state-of-the-art strategies pursued to generate metabolically competent hepatic cell lines. © 2013 Bentham Science Publishers.

Sabater L.,Institute dInvestigacions Biomediques August Pi i Sunyer IDIBAPS | Gaig C.,Institute dInvestigacions Biomediques August Pi i Sunyer IDIBAPS | Gelpi E.,Institute dInvestigacions Biomediques August Pi i Sunyer IDIBAPS | Gelpi E.,Neurological Tissue Bank of the Biobanc Hospital Clinic IDIBAPS | And 12 more authors.
The Lancet Neurology | Year: 2014

Background: Autoimmunity might be associated with or implicated in sleep and neurodegenerative disorders. We aimed to describe the features of a novel neurological syndrome associated with prominent sleep dysfunction and antibodies to a neuronal antigen. Methods: In this observational study, we used clinical and video polysomnography to identify a novel sleep disorder in three patients referred to the Sleep Unit of Hospital Clinic, University of Barcelona, Spain, for abnormal sleep behaviours and obstructive sleep apnoea. These patients had antibodies against a neuronal surface antigen, which were also present in five additional patients referred to our laboratory for antibody studies. These five patients had been assessed with polysomnography, which was done in our sleep unit in one patient and the recording reviewed in a second patient. Two patients underwent post-mortem brain examination. Immunoprecipitation and mass spectrometry were used to characterise the antigen and develop an assay for antibody testing. Serum or CSF from 298 patients with neurodegenerative, sleep, or autoimmune disorders served as control samples. Findings: All eight patients (five women; median age at disease onset 59 years [range 52-76]) had abnormal sleep movements and behaviours and obstructive sleep apnoea, as confirmed by polysomnography. Six patients had chronic progression with a median duration from symptom onset to death or last visit of 5 years (range 2-12); in four the sleep disorder was the initial and most prominent feature, and in two it was preceded by gait instability followed by dysarthria, dysphagia, ataxia, or chorea. Two patients had a rapid progression with disequilibrium, dysarthria, dysphagia, and central hypoventilation, and died 2 months and 6 months, respectively, after symptom onset. In five of five patients, video polysomnography showed features of obstructive sleep apnoea, stridor, and abnormal sleep architecture (undifferentiated non-rapid-eye-movement [non-REM] sleep or poorly structured stage N2, simple movements and finalistic behaviours, normalisation of non-REM sleep by the end of the night, and, in the four patients with REM sleep recorded, REM sleep behaviour disorder). Four of four patients had HLA-DRB1*1001 and HLA-DQB1*0501 alleles. All patients had antibodies (mainly IgG4) against IgLON5, a neuronal cell adhesion molecule. Only one of the 298 controls, who had progressive supranuclear palsy, had IgLON5 antibodies. Neuropathology showed neuronal loss and extensive deposits of hyperphosphorylated tau mainly involving the tegmentum of the brainstem and hypothalamus in the two patients studied. Interpretation: IgLON5 antibodies identify a unique non-REM and REM parasomnia with sleep breathing dysfunction and pathological features suggesting a tauopathy. Funding: Fondo de Investigaciones Sanitarias, Centros de Investigación Biomédica en Red de enfermedades neurodegenerativas (CIBERNED) and Respiratorias (CIBERES), Ministerio de Economía y Competitividad, Fundació la Marató TV3, and the National Institutes of Health. © 2014 Elsevier Ltd.

Serrano F.,Institute Investigacion Sanitaria La Fe | Calatayud C.F.,Institute Investigacion Sanitaria La Fe | Blazquez M.,Institute Investigacion Sanitaria La Fe | Torres J.,University of Valencia | And 2 more authors.
Stem Cells | Year: 2013

Somatic cells can be reprogrammed to induced pluripotent stem (iPS) cells by ectopic expression of the four factors Oct4, Klf4, Sox2, and Myc. Here, we investigated the role of Gata4 in the reprogramming process and present evidence for a negative role of this family of transcription factors in the induction of pluripotency. Coexpression of Gata4 with Oct4, Klf4, and Sox2 with or without Myc in mouse embryonic fibroblasts greatly impaired reprogramming and endogenous Nanog expression. The lack of Nanog upregulation was associated with a blockade in the transition from the initiation phase of reprogramming to the full pluripotent state characteristic of iPS cells. Addition of Nanog to the reprogramming cocktail blocked the deleterious effects observed with Gata4 expression. Downregulation of endogenous Gata4 by short hairpin RNAs during reprogramming both accelerated and increased the efficiency of the process and augmented the mRNA levels of endogenous Nanog. Using comparative genomics, we identified a consensus binding site for Gata factors in an evolutionary conserved region located 9 kb upstream of the Nanog gene. Using chromatin immunoprecipitation, gel retardation, and luciferase assays, we found that Gata4 bound to this region and inhibited Nanog transcription in mouse embryonic stem cells. Overall, our results describe for first time the negative effect of Gata4 in the reprogramming of somatic cells and highlight the role of Gata factors in the transcriptional networks that control cell lineage choices in the early embryo. © AlphaMed Press.

Morales Rosello J.,Polytechnic University of Valencia | Morales Rosello J.,Hospital Of La Plana | Hervas Marin D.,Institute Investigacion Sanitaria La Fe | Fillol Crespo M.,Hospital Of La Plana | Perales Marin A.,Polytechnic University of Valencia
Prenatal Diagnosis | Year: 2012

Objective: To determine the association between Doppler changes in the fetal vertebral (VA), middle cerebral (MCA), and umbilical arteries (UA) and severity of growth restriction (FGR) in fetuses delivered after 34weeks. Method: Five hundred seventy-one Doppler examinations of the VA, MCA, and UA were performed between 26 and 41weeks of gestation. Values were converted into multiples of the median and divided into birth weight (BW) categories: BW>P10th, BW

Garcia N.A.,Institute Investigacion Sanitaria La Fe | Ontoria-Oviedo I.,Institute Investigacion Sanitaria La Fe | Gonzalez-King H.,Institute Investigacion Sanitaria La Fe | Diez-Juan A.,Fundacion IVI | Sepulveda P.,Institute Investigacion Sanitaria La Fe
PLoS ONE | Year: 2015

Cardiomyocytes (CMs) and endothelial cells (ECs) have an intimate anatomical relationship that is essential for maintaining normal development and function in the heart. Little is known about the mechanisms that regulate cardiac and endothelial crosstalk, particularly in situations of acute stress when local active processes are required to regulate endothelial function. We examined whether CM-derived exosomes could modulate endothelial function. Under conditions of glucose deprivation, immortalized H9C2 cardiomyocytes increase their secretion of exosomes. CM-derived exosomes are loaded with a broad repertoire of miRNA and proteins in a glucose availability-dependent manner. Gene Ontology (GO) analysis of exosome cargo molecules identified an enrichment of biological process that could alter EC activity. We observed that addition of CM-derived exosomes to ECs induced changes in transcriptional activity of pro-angiogenic genes. Finally, we demonstrated that incubation of H9C2-derived exosomes with ECs induced proliferation and angiogenesis in the latter. Thus, exosome-mediated communication between CM and EC establishes a functional relationship that could have potential implications for the induction of local neovascularization during acute situations such as cardiac injury. © 2015 Garcia et al.

Castel V.,Polytechnic University of Valencia | Castel V.,Institute Investigacion Sanitaria la Fe | Segura V.,Institute Investigacion Sanitaria la Fe | Berlanga P.,Polytechnic University of Valencia | Berlanga P.,Institute Investigacion Sanitaria la Fe
Expert Opinion on Emerging Drugs | Year: 2013

Introduction: Neuroblastoma accounts for 8-10% of pediatric cancers and is responsible for 15% of childhood cancer deaths. Despite multimodality treatment, the overall survival (OS) and event-free survival (EFS) in high-risk patients remain suboptimal. More than half of children diagnosed with high-risk neuroblastoma either do not respond to conventional therapies or relapse after treatment. Areas covered: This review discusses about the unmet medical needs for new therapeutic options against high-risk neuroblastoma. New drugs and therapeutic strategies that are under development in clinical trials, which are currently recruiting patients. Expert opinion: There is a need to improve the response rate of induction chemotherapy, which is not effective in a third of patients and also the other components of the current treatment, little efficacious in avoiding the relapses. Few drugs have been introduced as upfront therapy in the last years. Topotecan, irinotecan and temozolomide are expected to improve the response in high-risk neuroblastoma, but their impact on OS and EFS is unknown. Anti-GD2 antibodies combined with other immunomodulators (IL-2, GM-CSF) are an important advance in the treatment of these children. Nevertheless, the hope is put in the new drugs directed to molecular targets of neuroblastoma. Anti-angiogenic drugs, ALK antagonist and PI3K/Akt/mTOR inhibitors are among the most promising. © Informa UK, Ltd.

Morales-Rosello J.,Polytechnic University of Valencia | Hervas-Marin D.,Institute Investigacion Sanitaria la Fe | Perales-Marin A.,Polytechnic University of Valencia
Journal of Maternal-Fetal and Neonatal Medicine | Year: 2014

Objective: To determine the existence of Doppler changes in the fetal vertebral, middle cerebral and umbilical arteries prior to term labor. Methods: Five hundred and twenty eight Doppler examinations of the vertebral (VA), middle cerebral (MCA) and umbilical (UA) arteries resistance indices (RI) were performed between 37 and 41 weeks gestation. For each artery, values were converted into multiples of the median (MoM) and were divided into four groups according to the interval to labor and compared using Kruskal-Wallis tests. Subsequently, values were plotted in scattergrams and linear regressions and 95% confidence intervals were calculated. Finally, using multivariate analysis and model averaging, the importance and interrelationship of Doppler measurements in the explanation of the interval to labor was evaluated. Results: Univariate and multivariate analysis confirmed that, independently of gestational age, fetuses examined close to labor presented more intense Doppler changes in the cerebral arteries with a significant reduction of the VA RI and MCA RI. This reduction was larger in the MCA. No significant changes were detected in the UA. Conclusion: Before the onset of term labor, the fetal cerebral flow presents an additional reduction of impedance, which is more intense in the MCA system. © 2014 Informa UK Ltd. All rights reserved.

Morales Rosello J.,Polytechnic University of Valencia | Hervas Marin D.,Institute Investigacion Sanitaria La Fe | Perales Marin A.,Polytechnic University of Valencia
Prenatal Diagnosis | Year: 2014

Objective: The objective of this article is to show the clinical utility of the vertebral artery Doppler as an alternative to the middle cerebral artery Doppler in the follow-up of fetuses affected with early-onset growth restriction [fetal growth restriction (FGR)]. Methods: We present a group of fetuses with early-onset FGR in which the vertebral artery resistance index (VA RI) and pulsatility index (VA PI) were measured and plotted along with their references earlier calculated using 1980 Doppler examinations. In addition, the VA and middle cerebral artery (MCA) performance was compared using values converted into multiples of the median. Results: Similar to that of the MCA, VA RI and VA PI percentiles showed curve shapes with higher values at the beginning of the third trimester. The majority of growth-restricted fetuses showed a notorious decrease in the VA impedance, which was not statistically different to that of the MCA. Conclusion: Vertebral artery Doppler values can be obtained throughout the second half of pregnancy. Preliminary data suggest a clinical application in the management of early-onset FGR. © 2013 John Wiley & Sons, Ltd.

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