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Martinez-Frias M.L.,Institute of Health Carlos III ISCIII | Martinez-Frias M.L.,CIBER ISCIII | Martinez-Frias M.L.,Complutense University of Madrid
Journal of Medical Genetics | Year: 2010

Having identified teratogenic factors, primary prevention of congenital defects is possible by the implementation of specific measures in pregnant women or those planning pregnancy. Our current understanding of the epigenetic processes acting during reproductive events raises new possibilities to prevent both heritable and sporadic congenital anomalies. Cell differentiation during embryonice - fetal development involves different epigenetic processes which, if altered, may affect either somatic or germ cells. Epigenetic alterations can occur in somatic cells at different stages of life, from fecundation to adulthood, and when germ cells are affected, such changes can even be passed on to future generations. This review summarises the main epigenetic processes that influence gene expression and cell specification at different stages of development. The experimental and epidemiological evidence of environmental agents that cause epigenetic alterations is evaluated, as well as their effects in males and females. As a result, new avenues for primary prevention are proposed. Source

Corral M.J.,Complutense University of Madrid | Benito-Pena E.,Complutense University of Madrid | Jimenez-Anton M.D.,Complutense University of Madrid | Cuevas L.,Institute of Health Carlos III ISCIII | And 2 more authors.
PLoS Neglected Tropical Diseases | Year: 2016

Background: Allicin has shown antileishmanial activity in vitro and in vivo. However the mechanism of action underlying its antiproliferative effect against Leishmania has been virtually unexplored. In this paper, we present the results obtained in L.infantum and a mechanistic basis is proposed. Methodology/Principal Finding: Exposure of the parasites to allicin led to high Ca2+ levels and mitochondrial reactive oxygen species (ROS), collapse of the mitochondrial membrane potential, reduced production of ATP and elevation of cytosolic ROS. The incubation of the promastigotes with SYTOX Green revealed that decrease of ATP was not associated with plasma membrane permeabilization. Annexin V and propidium iodide (PI) staining indicated that allicin did not induce phospholipids exposure on the plasma membrane. Moreover, DNA agarose gel electrophoresis and TUNEL analysis demonstrated that allicin did not provoke DNA fragmentation. Analysis of the cell cycle with PI staining showed that allicin induced cell cycle arrest in the G2/M phase. Conclusions/Significance: We conclude that allicin induces dysregulation of calcium homeostasis and oxidative stress, uncontrolled by the antioxidant defense of the cell, which leads to mitochondrial dysfunction and a bioenergetic catastrophe leading to cell necrosis and cell cycle arrest in the premitotic phase. © 2016 Corral et al. Source

Slot I.G.M.,Maastricht University | Van Den Borst B.,Maastricht University | Hellwig V.A.C.V.,Maastricht University | Barreiro E.,Research Institute of Hospital Del Mar IMIM | And 3 more authors.
PLoS ONE | Year: 2014

Already in an early disease stage, patients with chronic obstructive pulmonary disease (COPD) are confronted with impaired skeletal muscle function and physical performance due to a loss of oxidative type I muscle fibers and oxidative capacity (i.e. oxidative phenotype; Oxphen). Physical activity is a well-known stimulus of muscle Oxphen and crucial for its maintenance. We hypothesized that a blunted response of Oxphen genes to an acute bout of exercise could contribute to decreased Oxphen in COPD. For this28 patients with less advanced COPD (age 6567 yrs, FEV1 59616% predicted) and 15 age- and gender-matched healthy controls performed an incremental cycle ergometry test. The Oxphen response to exercise was determined by the measurement of gene expression levels of Oxphen markers in pre and 4h-post exercise quadriceps biopsies. Because exercise-induced hypoxia and oxidative stress may interfere with Oxphen response, oxygen saturation and oxidative stress markers were assessed as well. Regardless of oxygen desaturation and absolute exercise intensities, the Oxphen regulatory response to exercise was comparable between COPD patients and controls with no evidence of increased oxidative stress. In conclusion, the muscle Oxphen regulatory response to acute exercise is not blunted in less advanced COPD, regardless of exercise-induced hypoxia. Hence, this study provides further rationale for incorporation of exercise training as integrated part of disease management to prevent or slow down loss of muscle Oxphen and related functional impairment in COPD. © 2014 Slot et al. Source

Maronas O.,Foundation Medicine | Latorre A.,University of Santiago de Compostela | Dopazo J.,Institute of Health Carlos III ISCIII | Dopazo J.,Research Center Principe Felipe | And 8 more authors.
Drug Metabolism and Personalized Therapy | Year: 2016

Pharmacogenetics (PGx), as a field dedicated to achieving the goal of personalized medicine (PM), is devoted to the study of genes involved in inter-individual response to drugs. Due to its nature, PGx requires access to large samples; therefore, in order to progress, the formation of collaborative consortia seems to be crucial. Some examples of this collective effort are the European Society of Pharmacogenomics and personalized Therapy and the Ibero-American network of Pharmacogenetics. As an emerging field, one of the major challenges that PGx faces is translating their discoveries from research bench to bedside. The development of genomic high-throughput technologies is generating a revolution and offers the possibility of producing vast amounts of genome-wide single nucleotide polymorphisms for each patient. Moreover, there is a need of identifying and replicating associations of new biomarkers, and, in addition, a greater effort must be invested in developing regulatory organizations to accomplish a correct standardization. In this review, we outline the current progress in PGx using examples to highlight both the importance of polymorphisms and the research strategies for their detection. These concepts need to be applied together with a proper dissemination of knowledge to improve clinician and patient understanding, in a multidisciplinary team-based approach. © 2016 by De Gruyter. Source

De Iriarte Rodriguez R.,Institute Investigaciones Biomedicas Alberto Sols | De Iriarte Rodriguez R.,Institute of Health Carlos III ISCIII | Magarinos M.,Institute Investigaciones Biomedicas Alberto Sols | Magarinos M.,Institute of Health Carlos III ISCIII | And 7 more authors.
Cellular and Molecular Life Sciences | Year: 2015

The family of RAF kinases transduces extracellular information to the nucleus, and their activation is crucial for cellular regulation on many levels, ranging from embryonic development to carcinogenesis. B-RAF and C-RAF modulate neurogenesis and neuritogenesis during chicken inner ear development. C-RAF deficiency in humans is associated with deafness in the rare genetic insulin-like growth factor 1 (IGF-1), Noonan and Leopard syndromes. In this study, we show that RAF kinases are expressed in the developing inner ear and in adult mouse cochlea. A homozygous C-Raf deletion in mice caused profound deafness with no evident cellular aberrations except for a remarkable reduction of the K+ channel Kir4.1 expression, a trait that suffices as a cause of deafness. To explore the role of C-Raf in cellular protection and repair, heterozygous C-Raf +/- mice were exposed to noise. A reduced C-RAF level negatively affected hearing preservation in response to noise through mechanisms involving the activation of JNK and an exacerbated apoptotic response. Taken together, these results strongly support a role for C-RAF in hearing protection. © 2015 The Author(s). Source

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