Moncayo-Arlandi J.,Institute of Biomedical Research of Girona IDIBGI |
Moncayo-Arlandi J.,University of Valencia |
Guasch E.,University of Barcelona |
la Garza M.S.,University of Barcelona |
And 12 more authors.
Human Molecular Genetics | Year: 2015
Arrhythmogenic cardiomyopathy (ACM) is a disorder characterized by a progressive ventricular myocardial replacement by fat and fibrosis, which lead to ventricular arrhythmias and sudden cardiac death. Mutations in the desmosomal gene Plakophilin-2 (PKP2) accounts for>40% of all known mutations, generally causing a truncated protein. In a PKP2-truncated mouse model, we hypothesize that content of transgene, endurance training and aging will be determinant in disease progression. In addition, we investigated the molecular defects associated with the phenotype in this model. We developed a transgenic mouse model containing a truncated PKP2 (PKP2-Ser329) and generated three transgenic lines expressing increasing transgene content. The pathophysiological features of ACM in this model were assessed. While we did not observe fibrofatty replacement, ultrastructural defects were exhibited. Moreover, we observed transgene content-dependent development of structural (ventricle dilatation and dysfunction) and electrophysiological anomalies in mice (PR interval and QRS prolongation and arrhythmia induction). In concordance with pathological defects, we detected a content reduction and remodeling of the structural proteins Desmocollin-2, Plakoglobin, native Plakophilin-2, Desmin and b-Catenin as well as the electrical coupling proteins Connexin 43 and cardiac sodium channel (Nav1.5). Surprisingly, we observed structural but not electrophysiological abnormalities only in trained and old mice. We demonstrated that truncated PKP2 provokes ACM in the absence of fibro-fatty replacement in the mouse. Transgene dose is essential to reveal the pathology, whereas aging and endurance training trigger limited phenotype. Molecular abnormalities underlay the structural and electrophysiological defects. © The Author 2016. Published by Oxford University Press. All rights reserved.
Castilla A.M.,Ministry of Environment |
Castilla A.M.,Qatar Foundation |
Huey R.B.,University of Washington |
Calvete J.J.,Institute of Biomedicine of Valencia |
And 2 more authors.
Journal of Arid Environments | Year: 2014
We review the literature on the geographic and taxonomic diversity of species of lizards and scorpions that are involved in predator-prey interactions. Somewhat surprisingly, lizards are often the predators in these interactions. Consequently, our goals were to evaluate whether lizard predators had evolved morphological or physiological resistance to scorpion venom or whether the rely on behavioral evasions, and also to document co-evolutionary patterns. Diverse lizards prey on scorpions, but most studies are surprisingly anecdotal. Whether lizard predators tolerate scorpion venom is largely unexplored. Our review highlights opportunities for studies of the evolution of tolerance to scorpion venom by lizards and of the ecology and evolution of lizard-scorpion interactions in arid zones. Progress will be facilitated by collaborations between experts in ecology and toxicology, and by incorporating molecular approaches such as proteomics and transcriptomics. Much is to be learned about scorpion venoms and their effects on predators, with potential benefits to humans. © 2014 Elsevier Ltd. All rights reserved.
Redondo S.,Complutense University of Madrid |
Ruiz E.,Complutense University of Madrid |
Gordillo-Moscoso A.,Complutense University of Madrid |
Navarro-Dorado J.,Complutense University of Madrid |
And 6 more authors.
Diabetologia | Year: 2011
Aims/hypothesis: Inflammation is a common feature in cardiovascular diseases, including diabetes mellitus. In addition to the well-known inflammatory role of cyclooxygenase-2 (COX-2), this protein has also been implicated in apoptosis resistance in tumour cells. Vascular smooth muscle cells (VSMC) from diabetic patients are also resistant to apoptosis because of an increased abundance of B cell lymphoma 2 protein (BCL2). In this work, we investigated whether overproduction of COX-2 was involved in the resistance to apoptosis in VSMC fromdiabetic patients. Methods: VSMC were obtained from internal mammary arteries from patients who had undergone coronary artery bypass graft surgery. Apoptosis was measured by DNA fragmentation, BCL2 degradation and cytochrome c release. Results: Apoptosis induced by C-reactive protein in cells from non-diabetic patients was mediated by COX-2. VSMC from diabetic patients showed higher basal levels of COX-2 compared with those from non-diabetic patients. Transfection of VSMC from non-diabetic patients with a plasmid containing COX-2 (also known as PTGS2) increased basal production of COX-2 and BCL2 and mimicked the resistance to apoptosis that occurs in diabetic patients. We also found a significant correlation (R=0.846, p=0.016) between COX-2 and BCL2 production in arterial rings from diabetic patients measured by confocal microscopy. However, inhibition of COX-2 production by small interfering RNA proved unable to reverse BCL2 production in diabetic VSMC. Conclusions/interpretation: These results suggest a link between inflammation (COX-2) and apoptosis resistance (BCL2) in the arteries of diabetic patients. This relationship is not causative and the common production of these two proteins may be co-regulated by shared regulatory elements in diabetes. © Springer-Verlag 2010.
Haworth A.,National Hospital of Neurology and Neurosurgery |
Bertram L.,Max Planck Institute for Molecular Genetics |
Carrera P.,San Raffaele Scientific Institute |
Elson J.L.,Northumbria University |
And 21 more authors.
Neurogenetics | Year: 2011
The rate of DNA variation discovery has accelerated the need to collate, store and interpret the data in a standardised coherent way and is becoming a critical step in maximising the impact of discovery on the understanding and treatment of human disease. This particularly applies to the field of neurology as neurological function is impaired in many human disorders. Furthermore, the field of neurogenetics has been proven to show remarkably complex genotype-to-phenotype relationships. To facilitate the collection of DNA sequence variation pertaining to neurogenetic disorders, we have initiated the "Neurogenetics Consortium" under the umbrella of the Human Variome Project. The Consortium's founding group consisted of basic researchers, clinicians, informaticians and database creators. This report outlines the strategic aims established at the preliminary meetings of the Neurogenetics Consortium and calls for the involvement of the wider neurogenetic community in enabling the development of this important resource. © Springer-Verlag 2011.
Rodriguez-Martinez H.,Linköping University |
Kvist U.,Karolinska University Hospital |
Ernerudh J.,Linköping University |
Sanz L.,Institute of Biomedicine of Valencia |
Calvete J.J.,Institute of Biomedicine of Valencia
American Journal of Reproductive Immunology | Year: 2011
Problem Semen is a heterogenous and complex cell suspension in a protein-rich fluid with different functions, some of them well known, others still obscure. Method of study This paper reviews, comparatively, our current knowledge on the growing field of proteomics of the SP and its relevance in relation to the invivo situation, for the sake of reproductive biology, diagnostics and treatment. Results Ejaculated spermatozoa, primarily bathing in cauda epididymal fluid, are (in vitro) bulky, exposed to most, if not all, secretions from the accessory sexual glands. In vivo, however, not all spermatozoa are necessarily exposed to all secretions from these glands, because sperm cohorts are delivered in differential order and bathe in seminal plasma (SP) with different concentrations of constituents, including peptides and proteins. Proteins are relevant for sperm function and relate to sperm interactions with the various environments along the female genital tract towards the oocyte vestments. Specific peptides and proteins act as signals for the female immune system to modulate sperm rejection or tolerance, perhaps even influencing the relative intrinsic fertility of the male and/or couple by attaining a status of maternal tolerance towards embryo and placental development. Conclusions Proteins of the seminal plasma have an ample panorama of action, and some appear responsible for establishing fertility. © 2011 John Wiley & Sons A/S.
Diaz-Moralli S.,University of Barcelona |
Ramos-Montoya A.,University of Barcelona |
Marin S.,University of Barcelona |
Fernandez-Alvarez A.,Institute of Biomedicine of Valencia |
And 3 more authors.
American Journal of Physiology - Endocrinology and Metabolism | Year: 2012
Carbohydrate response element-binding protein (ChREBP) is a transcription factor that mediates glucose signaling in mammalian liver, leading to the expression of different glycolytic and lipogenic genes, such as pyruvate kinase (L-PK) and fatty acid synthase (FAS). The current model for ChREBP activation in response to sugar phosphates holds that glucose metabolization to xylulose 5-phosphate (X-5-P) triggers the activation of protein phosphatase 2A, which dephosphorylates ChREBP and leads to its nuclear translocation and activation. However, evidence indicates that glucose 6-phosphate (G-6-P) is the most likely signal metabolite for the glucose-induced transcription of these genes. The glucose derivative that is responsible for carbohydrate-dependent gene expression remains to be identified. The difficulties in measuring G-6-P and X-5-P concentrations simultaneously and in changing them independently have hindered such identification. To discriminate between these possibilities, we adapted a liquid chromatography mass spectrometry method to identify and quantify sugar phosphates in human hepatocarcinoma cells (Hep G2) and rat hepatocytes in response to different carbon sources and in the presence/absence of a glucose-6-phosphate dehydrogenase inhibitor. We also used this method to demonstrate that these cells could not metabolize 2-deoxyglucose beyond 2-deoxyglucose-6-phosphate. The simultaneous quantification of sugar phosphates and FAS and L-PK expression levels demonstrated that both X-5-P and G-6-P play a role in the modulation of gene expression. In conclusion, this report presents for the first time a single mechanism that incorporates the effects of X-5-P and G-6-P on the enhancement of the expression of carbohydrate-responsive genes. © 2012 the American Physiological Society.
Franco M.L.,Institute of Biomedicine of Valencia |
Melero C.,Institute of Biomedicine of Valencia |
Melero C.,University of Manchester |
Sarasola E.,Basurto University Hospital Osakidetza Servicio Vasco Of Salud |
And 5 more authors.
Journal of Biological Chemistry | Year: 2016
Congenital insensitivity to pain with anhidrosis (CIPA) is a rare autosomal recessive disorder characterized by insensitivity to noxious stimuli and variable intellectual disability (ID) due to mutations in the NTRK1 gene encoding the NGF receptor TrkA. To get an insight in the effect of NTRK1 mutations in the cognitive phenotype we biochemically characterized three TrkA mutations identified in children diagnosed of CIPA with variable ID. These mutations are located in different domains of the protein; L213P in the extracellular domain, Δ736 in the kinase domain, and C300stop in the extracellular domain, a new mutation causing CIPA diagnosed in a Spanish teenager. We found that TrkA mutations induce misfolding, retention in the endoplasmic reticulum (ER), and aggregation in a mutation-dependent manner. The distinct mutations are degraded with a different kinetics by different ER quality control mechanisms; although C300stop is rapidly disposed by autophagy, Δ736 degradation is sensitive to the proteasome and to autophagy inhibitors, and L213P is a long-lived protein refractory to degradation. In addition L213P enhances the formation of autophagic vesicles triggering an increase in the autophagic flux with deleterious consequences. Mouse cortical neurons expressing L213P showed the accumulation of LC3-GFP positive puncta and dystrophic neurites. Our data suggest that TrkA misfolding and aggregation induced by some CIPA mutations disrupt the autophagy homeostasis causing neurodegeneration. We propose that distinct disease-causing mutations of TrkA generate different levels of cell toxicity, which may provide an explanation of the variable intellectual disability observed in CIPA patients. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.
Tapia N.,Institute of Biomedicine of Valencia |
Scholer H.R.,Max Planck Institute for Molecular Biomedicine |
Scholer H.R.,University of Munster
Cell Stem Cell | Year: 2016
The ability to reprogram somatic cells into induced pluripotent stem cells (iPSCs) using defined factors provides new tools for biomedical research. However, some iPSC clones display tumorigenic and immunogenic potential, thus raising concerns about their utility and safety in the clinical setting. Furthermore, variability in iPSC differentiation potential has also been described. Here we discuss whether these therapeutic obstacles are specific to transcription-factor-mediated reprogramming or inherent to every cellular reprogramming method. Finally, we address whether a better understanding of the mechanism underlying the reprogramming process might improve the fidelity of reprogramming and, therefore, the iPSC quality. © 2016 Elsevier Inc.
Rodriguez-Martinez H.,Swedish University of Agricultural Sciences |
Saravia F.,Swedish University of Agricultural Sciences |
Wallgren M.,Swedish University of Agricultural Sciences |
Martinez E.A.,University of Murcia |
And 4 more authors.
Journal of Reproductive Immunology | Year: 2010
Seminal plasma (SP) is a complex fluid which exerts biological actions in the female reproductive tract. In pigs, SP elicits endometrial inflammation and consequent immune changes after mating. This study tested whether heparin-binding spermadhesins (HBPs) and the heterodimer of porcine sperm adhesions I and II (PSP-I/PSP-II) in SP recruit different lymphocyte subsets (CD2+, CD4+ and CD8+ T cells) or polymorphonuclear leukocytes (PMNs) to the superficial endometrium or luminal epithelium and lumen, respectively, of oestrous sows. In Experiment 1, endometrial biopsies were taken between 2 and 120 min after infusion of uterine horns with HBPs, PSP-I/PSP-II or saline and evaluated by immunohistochemistry or histology. In Experiment 2, the uterus of oestrous sows was infused with PSP-I/PSP-II or saline to assess PMN numbers in the uterine lumen 3 h later. PSP-I/PSP-II elicited CD2+ T cell recruitment from 10 min, and CD8+ T cells from 60 min after infusion, while HBPs increased CD4+ T cell recruitment by 120 min. PSP-I/PSP-II but not HBPs induced PMN migration to the surface epithelium by 10 min. PMN numbers were elevated 5-fold by 30 min and 7-fold from 60 min, with PMNs detectable in the lumen from 30 min after infusion. Six-fold more PMNs were collected from the uterine lumen of PSP-I/PSP-II-infused sows compared to controls at 3 h after infusion. These data show that PSP-I/PSP-II heterodimer in seminal plasma has a predominant role in triggering the recruitment of uterine PMNs and T cells after mating, initiating a cascade of transient and long-lasting immunological events. © 2009 Elsevier Ireland Ltd. All rights reserved.
PubMed | Karolinska Institutet, Fundacion IVI INCLIVA and IGENOMIX, University of Barcelona, Institute of Biomedicine of Valencia and 2 more.
Type: Journal Article | Journal: Human molecular genetics | Year: 2016
Arrhythmogenic cardiomyopathy (ACM) is a disorder characterized by a progressive ventricular myocardial replacement by fat and fibrosis, which lead to ventricular arrhythmias and sudden cardiac death. Mutations in the desmosomal gene Plakophilin-2 (PKP2) accounts for>40% of all known mutations, generally causing a truncated protein. In a PKP2-truncated mouse model, we hypothesize that content of transgene, endurance training and aging will be determinant in disease progression. In addition, we investigated the molecular defects associated with the phenotype in this model. We developed a transgenic mouse model containing a truncated PKP2 (PKP2-Ser329) and generated three transgenic lines expressing increasing transgene content. The pathophysiological features of ACM in this model were assessed. While we did not observe fibro-fatty replacement, ultrastructural defects were exhibited. Moreover, we observed transgene content-dependent development of structural (ventricle dilatation and dysfunction) and electrophysiological anomalies in mice (PR interval and QRS prolongation and arrhythmia induction). In concordance with pathological defects, we detected a content reduction and remodeling of the structural proteins Desmocollin-2, Plakoglobin, native Plakophilin-2, Desmin and -Catenin as well as the electrical coupling proteins Connexin 43 and cardiac sodium channel (Na