Martinez-Jimenez C.P.,University of Valencia |
Sandoval J.,Institute Dinvestigacio Biomedica Of Bellvitge Idibell
Frontiers in Bioscience - Scholar | Year: 2015
Technological breakthroughs are emphasizing the impact of epigenetic mechanisms in human health highlighting the importance of a fine-tune orchestration of DNA methylation, micro RNAs, histone modifications, and chromatin structure. Transcriptional regulators sense the concentration of intermediary metabolites associated to a wide variety of biological processes including the long-term imprinting and heritable DNA methylation. Recent epigenetic mechanisms associated with cholesterol and lipid homeostasis have a critical impact in the susceptibility, development and progression of complex diseases such as type 2 diabetes mellitus, non-alcoholic fatty liver, obesity and metabolic syndrome. The heritability of epigenetic states emerge as an additional level of complexity where the extension of somatic as well as inherited epigenetic modifications may require a thoughtful reconsideration in many human diseases related with metabolic disorders. © 1996-2015.
Nualart-Marti A.,University of Barcelona |
Nualart-Marti A.,Institute Dinvestigacio Biomedica Of Bellvitge Idibell |
Nualart-Marti A.,National Health Research Institute |
Solsona C.,University of Barcelona |
And 2 more authors.
Biochimica et Biophysica Acta - Biomembranes | Year: 2013
Gap junction communication is crucial for myelination and axonal survival in both the peripheral nervous system (PNS) and central nervous system (CNS). This review examines the different types of gap junctions in myelinating glia of the PNS and CNS (Schwann cells and oligodendrocytes respectively), including their functions and involvement in neurological disorders. Gap junctions mediate intercellular communication among Schwann cells in the PNS, and among oligodendrocytes and between oligodendrocytes and astrocytes in the CNS. Reflexive gap junctions mediating transfer between different regions of the same cell promote communication between cellular compartments of myelinating glia that are separated by layers of compact myelin. Gap junctions in myelinating glia regulate physiological processes such as cell growth, proliferation, calcium signaling, and participate in extracellular signaling via release of neurotransmitters from hemijunctions. In the CNS, gap junctions form a glial network between oligodendrocytes and astrocytes. This transcellular communication is hypothesized to maintain homeostasis by facilitating restoration of membrane potential after axonal activity via electrical coupling and the re-distribution of potassium ions released from axons. The generation of transgenic mice for different subsets of connexins has revealed the contribution of different connexins in gap junction formation and illuminated new subcellular mechanisms underlying demyelination and cognitive defects. Alterations in metabolic coupling have been reported in animal models of X-linked Charcot-Marie-Tooth disease (CMTX) and Pelizaeus-Merzbarcher-like disease (PMLD), which are caused by mutations in the genes encoding for connexin 32 and connexin 47 respectively. Future research identifying the expression and regulation of gap junctions in myelinating glia is likely to provide a better understanding of myelinating glia in nervous system function, plasticity, and disease. This article is part of a Special Issue entitled: The Communicating junctions, roles and dysfunctions.
Lapunzina P.,Hospital Universitario La Paz |
Monk D.,Institute Dinvestigacio Biomedica Of Bellvitge Idibell
Biology of the Cell | Year: 2011
UPD (uniparental disomy) describes the inheritance of a pair of chromosomes from only one parent. Mechanisms that lead to UPD include trisomy rescue, gamete complementation, monosomy rescue and somatic recombination. Most of these mechanisms can involve aberrant chromosomes, particularly isochromosomes and Robertsonian translocations. In the last decade, the number of UPD cases reported in the literature has increased exponentially. This is partly due to the advances in genomic technologies that have allowed for high-resolution SNP (single nucleotide polymorphism) studies, which have complemented traditional methods relying on polymorphic microsatellite markers. In this review, we discuss aberrant cellular mechanisms leading to UPD and their impact on gene expression. Special emphasis is placed on the unmasking of mutant recessive alleles and the disruption of imprinted gene dosage, which give rise to specific and recurrent imprinting phenotypes. Finally, we discuss how copy numbermaps determined from SNP array datasets have helped identify not only deletions and duplications but also recurrent copy number neutral regions of loss-of-heterozygosity, which have been reported in many cancer types and that may constitute an important driving force in cancer. These tiny regions of UPD also alter imprinted gene dosage, which may have cumulative tumourgenic effects in addition to that of unmasking homozygous cancer-associated mutations. © The Authors Journal compilation © 2011 Portland Press Limited.
Corral L.,Hospital Universitari Of Bellvitge |
Corral L.,University of Barcelona |
Javierre C.F.,University of Barcelona |
Ventura J.L.,Hospital Universitari Of Bellvitge |
And 4 more authors.
Critical Care | Year: 2012
Introduction: Non-neurological complications in patients with severe traumatic brain injury (TBI) are frequent, worsening the prognosis, but the pathophysiology of systemic complications after TBI is unclear. The purpose of this study was to analyze non-neurological complications in patients with severe TBI admitted to the ICU, the impact of these complications on mortality, and their possible correlation with TBI severity.Methods: An observational retrospective cohort study was conducted in one multidisciplinary ICU of a university hospital (35 beds); 224 consecutive adult patients with severe TBI (initial Glasgow Coma Scale (GCS) < 9) admitted to the ICU were included. Neurological and non-neurological variables were recorded.Results: Sepsis occurred in 75% of patients, respiratory infections in 68%, hypotension in 44%, severe respiratory failure (arterial oxygen pressure/oxygen inspired fraction ratio (PaO 2/FiO 2) < 200) in 41% and acute kidney injury (AKI) in 8%. The multivariate analysis showed that Glasgow Outcome Score (GOS) at one year was independently associated with age, initial GCS 3 to 5, worst Traumatic Coma Data Bank (TCDB) first computed tomography (CT) scan and the presence of intracranial hypertension but not AKI. Hospital mortality was independently associated with initial GSC 3 to 5, worst TCDB first CT scan, the presence of intracranial hypertension and AKI. The presence of AKI regardless of GCS multiplied risk of death 6.17 times (95% confidence interval (CI): 1.37 to 27.78) (P < 0.02), while ICU hypotension increased the risk of death in patients with initial scores of 3 to5 on the GCS 4.28 times (95% CI: 1.22 to15.07) (P < 0.05).Conclusions: Low initial GCS, worst first CT scan, intracranial hypertension and AKI determined hospital mortality in severe TBI patients. Besides the direct effect of low GCS on mortality, this neurological condition also is associated with ICU hypotension which increases hospital mortality among patients with severe TBI. These findings add to previous studies that showed that non-neurological complications increase the length of stay and morbidity in the ICU but do not increase mortality, with the exception of AKI and hypotension in low GCS (3 to 5). © 2012 Corral et al.; licensee BioMed Central Ltd.
Tirado O.M.,Institute Dinvestigacio Biomedica Of Bellvitge Idibell |
MacCarthy C.M.,Georgetown University |
Fatima N.,Georgetown University |
Villar J.,Georgetown University |
And 3 more authors.
International Journal of Cancer | Year: 2010
Caveolin-1 (CAV1) has been implicated in the regulation of several signaling pathways and in oncogenesis. Previously, we identified CAV1 as a key determinant of the oncogenic phenotype and tumorigenic activity of cells from tumors of the Ewing's Sarcoma Family (ESFT). However, the possible CAV1 involvement in the chemotherapy resistance commonly presented by an ESFT subset has not been established to date. This report shows that CAV1 expression determines the sensitivity of ESFT cells to clinically relevant chemotherapeutic agents. Analyses of endogenous CAV1 levels in several ESFT cells and ectopic CAV1 expression into ESFT cells expressing low endogenous CAV1 showed that the higher the CAV1 levels, the greater their resistance to drug treatment. Moreover, results from antisense- and shRNA-mediated gene expression knockdown and protein re-expression experiments demonstrated that CAV1 increases the resistance of ESFT cells to doxorubicin (Dox)- and cisplatin (Cp)-induced apoptosis by a mechanism involving the activating phosphorylation of PKCα. CAV1 knockdown in ESFT cells led to decreased phospho(Thr638)- PKCα levels and a concomitant sensitization to apoptosis, which were reversed by CAV1 re-expression. These results were recapitulated by PKCα knockdown and re-expression in ESFT cells in which CAV1 was previously knocked down, thus demonstrating that phospho(Thr638)-PKCα acts downstream of CAV1 to determine the sensitivity of ESFT cells to chemotherapeutic drugs. These data, along with the finding that CAV1 and phospho(Thr638)-PKCα are co-expressed in ∼45% of ESFT specimens tested, imply that targeting CAV1 and/or PKCα may allow the development of new molecular therapeutic strategies to improve the treatment outcome for patients with ESFT. © 2009 UICC.