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Alis R.,University of Valencia | Sanchis-Gomar F.,University of Valencia | Sanchis-Gomar F.,Fundacion Investigacion Hospital Clinico Universitario | Risso-Ballester J.,University of Valencia | And 5 more authors.
Atherosclerosis | Year: 2015

Although statins remain the cornerstone of lipid-lowering therapy for reducing the burden of atherosclerotic vascular disease, their administration has been associated with muscle-related adverse effects, including myalgia and rhabdomyolysis. Such adverse events are probably due to reduced antioxidant defenses associated with fewer intermediate metabolites in the cholesterol synthesis pathway. We hypothesize that the concomitant inhibition of xanthine oxidase via coadministration of allopurinol with statins could diminish reactive oxygen species (ROS)-related muscle damage, which would have in turn have positive effects on both the incidence of muscle-related adverse events and cardiovascular outcomes. Accordingly, inhibition of xanthine oxidase has been previously shown to be effective for reducing biomarkers of muscle damage following exercise in professional athletes. Because of the widespread statin utilization and increasing trends in their therapeutic use in atherosclerotic vascular diseases, the proposed strategy could have important clinical implications for reducing statin-induced myalgia and rhabdomyolysis. © 2014 Elsevier Ireland Ltd.


Felipo V.,Centro Investigacion Principe Felipe | Ordono J.F.,Hospital Arnau Of Vilanova | Ordono J.F.,Psychopatology and Neurophysiology Unit | Urios A.,Fundacion Investigacion Hospital Clinico Universitario | And 10 more authors.
Hepatology | Year: 2012

Attention deficit is an early event in the cognitive impairment of patients with minimal hepatic encephalopathy (MHE). The underlying mechanisms remain unclear. Mismatch negativity (MMN) is an auditory event-related potential that reflects an attentional trigger. Patients with schizophrenia show impaired attention and cognitive function, which are reflected in altered MMN. We hypothesized that patients with MHE, similarly to those with schizophrenia, should show MMN alterations related with attention deficits. The aims of this work were to assess whether (1) MMN is altered in cirrhotic patients with MHE, compared to those without MHE, (2) MMN changes in parallel with performance in attention tests and/or MHE in a longitudinal study, and (3) MMN predicts performance in attention tests and/or in the Psychometric Hepatic Encephalopathy Score (PHES). We performed MMN analysis as well as attention and coordination tests in 34 control subjects and in 37 patients with liver cirrhosis without MHE and 23 with MHE. Patients with MHE show reduced performance in selective and sustained attention tests and in visuomotor and bimanual coordination tests. The MMN wave area was reduced in patients with MHE, but not in those without MHE. In the longitudinal study, MMN area improved in parallel with performance in attention tests and PHES in 4 patients and worsened in parallel in another 4. Logistic regression analyses showed that MMN area predicts performance in attention tests and in PHES, but not in other tests or critical flicker frequency. Receiver operating characteristic curve analyses showed that MMN area predicts attention deficits in the number connection tests A and B, Stroop tasks, and MHE, with sensitivities of 75%-90% and specificities of 76%-83%. Conclusion: MMN area is useful to diagnose attention deficits and MHE in patients with liver cirrhosis. © 2011 American Association for the Study of Liver Diseases.


Badia M.-C.,University of Valencia | Giraldo E.,University of Valencia | Dasi F.,University of Valencia | Alonso D.,Fundacion Investigacion Hospital Clinico Universitario | And 3 more authors.
Free Radical Biology and Medicine | Year: 2013

Oxidative stress is a hallmark of Alzheimer disease (AD) but this has not been studied in young healthy persons at risk of the disease. Carrying an Apo e4 allele is the major genetic risk factor for AD. We have observed that lymphocytes from young, healthy persons carrying at least one Apo e4 allele suffer from reductive rather than oxidative stress, i.e., lower oxidized glutathione and P-p38 levels and higher expression of enzymes involved in antioxidant defense, such as glutamylcysteinyl ligase and glutathione peroxidase. In contrast, in the full-blown disease, the situation is reversed and oxidative stress occurs, probably because of the exhaustion of the antioxidant mechanisms just mentioned. These results provide insights into the early events of the progression of the disease that may allow us to find biomarkers of AD at its very early stages. © 2013 Elsevier Inc. All rights reserved.


Sanchis-Gomar F.,University of Valencia | Sanchis-Gomar F.,Fundacion Investigacion Hospital Clinico Universitario | Lippi G.,Academic Hospital of Parma
Biochemia Medica | Year: 2014

The concentration of several biochemical and hematological biomarkers is strongly influenced by a number of preanalytical variables. Several lines of evidence attest that short, middle, and long-term exercise, as well as the relative intensity of physical effort (from mild to strenuous), may influence a broad array of laboratory variables. The amount of extracellular release and clearance from blood of most of these biomarkers is markedly influenced by the biological characteristics of the molecule(s), level of training, type, intensity and duration of exercise, and time of recovery after training. It is hence noteworthy that test results that fall outside the conventional reference ranges in athletes not only may reflect the presence of a given disease, but may frequently mirror an adaptation to regular training or changes that have occurred during and/or following strenuous exercise, and which should be clearly acknowledged to prevent misinterpretation of laboratory data. The aim of this narrative review is to provide an update about the most significant changes of some biochemical and hematological biomarkers in response to physical exercise, for appropriate interpretation of these changes in the context of physically active subjects. © by Croatian Society of Medical Biochemistry and Laboratory Medicine.


Pareja-Galeano H.,University of Valencia | Pareja-Galeano H.,Fundacion Investigacion Hospital Clinico Universitario | Sanchis-Gomar F.,University of Valencia | Sanchis-Gomar F.,Fundacion Investigacion Hospital Clinico Universitario | Lucia A.,European University at Madrid
Journal of Cellular Physiology | Year: 2014

Aging-related chronic illness is a price we have to pay to live longer. Prevalent among the oldest old, the condition limits their functional independence and also aggravates the course of several age-related chronic diseases. Thus, the search is on for efficient therapies that will mitigate age-related pathologies. In this article, we point out the potential clinical implications of recent provocative basic research in the field. New possible targets have been recently discovered, are clearly involved in age-related pathologies and might benefit the treatment of other age-related conditions, particularly metabolic diseases. J. Cell. Physiol. 229: 1575-1576, 2014. © 2014 Wiley Periodicals, Inc.


Vina J.,Fundacion Investigacion Hospital Clinico Universitario | Borras C.,Fundacion Investigacion Hospital Clinico Universitario | Sanchis-Gomar F.,Fundacion Investigacion Hospital Clinico Universitario | Martinez-Bello V.E.,Fundacion Investigacion Hospital Clinico Universitario | And 4 more authors.
Current Pharmaceutical Design | Year: 2014

Scientific evidence links physical activity to several benefits. Recently, we proposed the idea that exercise can be regarded as a drug. As with many drugs, dosage is of great importance. However, to issue a public recommendation of physical activity in aging is not an easy task. Exercise in the elderly needs to be carefully tailored and individualized with the specific objectives of the person or group in mind. The beneficial effects of exercise in two of the main age-related diseases, sarcopenia and Alzheimer's Disease, are dealt with at the beginning of this report. Subsequently, dosage of exercise and the molecular signaling pathways involved in its adaptations are discussed. Exercise and aging are associated with oxidative stress so the paradox arises, and is discussed, as to whether exercise would be advisable for the aged population from an oxidative stress point of view. Two of the main redox-sensitive signaling pathways altered in old skeletal muscle during exercise, NF-κB and PGC-1α, are also reviewed. The last section of the manuscript is devoted to the age-associated diseases in which exercise is contraindicated. Finally, we address the option of applying exercise mimetics as an alternative for disabled old people. The overall denouement is that exercise is so beneficial that it should be deemed a drug both for young and old populations. If old adults adopted a more active lifestyle, there would be a significant delay in frailty and dependency with clear benefits to individual well-being and to the public's health. © 2014 Bentham Science Publishers.


Sanchis-Gomar F.,University of Valencia | Sanchis-Gomar F.,Fundacion Investigacion Hospital Clinico Universitario | Garcia-Gimenez J.L.,University of Valencia | Garcia-Gimenez J.L.,Fundacion Investigacion Hospital Clinico Universitario | And 7 more authors.
International Journal of Cardiology | Year: 2014

Erythropoietin (Epo) has been thought to act exclusively on erythroid progenitor cells. The identification of Epo receptor (EpoR) in non-haematopoietic cells and tissues including neurons, astrocytes, microglia, immune cells, cancer cell lines, endothelial cells, bone marrow stromal cells, as well as cells of myocardium, reproductive system, gastrointestinal tract, kidney, pancreas and skeletal muscle indicates that Epo has pleiotropic actions. Epo shows signals through protein kinases, anti-apoptotic proteins and transcription factors. In light of interest of administering recombinant human erythropoietin (rhEpo) and its analogues for limiting infarct size and left ventricular (LV) remodelling after acute myocardial infarction (AMI) in humans, the foremost studies utilising rhEpo are reviewed. The putative mechanisms involved in Epo-induced cardioprotection are related to the antiapoptotic, anti-inflammatory and angiogenic effects of Epo. Thus, cardioprotective potentials of rhEpo are reviewed in this article by focusing on clinical applicability. An overview of non-haematopoietic Epo analogues, which are a reliable alternative to the classic EpoR agonists and may prevent undesired side effects, is also provided. © 2013 Published by Elsevier Ireland Ltd.


Sanchis-Gomar F.,University of Valencia | Sanchis-Gomar F.,Fundacion Investigacion Hospital Clinico Universitario | Pareja-Galeano H.,University of Valencia | Pareja-Galeano H.,Fundacion Investigacion Hospital Clinico Universitario | And 5 more authors.
Drug Testing and Analysis | Year: 2014

The Athlete Biological Passport (ABP) is principally founded on monitoring an athlete's biological variables over time, to identify abnormal biases on a longitudinal basis. Several factors are known to influence the results of these markers. However, the manner in which the altitude factor is taken into account still needs to be standardized. Causal relationships between haematological variables should be correctly integrated into ABP software. In particular, modifications of haematological parameters during and after exposure to different altitudes/hypoxic protocols need to be properly included within detection models. © 2013 John Wiley & Sons, Ltd.


Ibarrola-Villava M.,Fundacion Investigacion Hospital Clinico Universitario | Martin-Gonzalez M.,Ramon y Cajal Hospital | Lazaro P.,Gregorio Maranon Hospital | Pizarro A.,La Paz Hospital | And 2 more authors.
British Journal of Dermatology | Year: 2012

Background: Glutathione S-transferases (GSTs) GSTM1, GSTT1 and GSTP1 are multifunctional enzymes involved in the detoxification of a wide range of reactive oxygen species produced during melanin synthesis and oxidative stress processes. Objectives: Single nucleotide polymorphisms (SNPs) in GSTP1 and copy number variants in GSTM1 and GSTT1 may be candidate low-penetrance variants with a role in susceptibility to malignant melanoma (MM). Methods In this case-control study, 562 Spanish patients with sporadic MM and 338 cancer-free control subjects were included, and the role of polymorphisms in these GST genes was investigated. Genotypes were established by quantitative real-time polymerase chain reaction for GSTM1 and GSTT1 while TaqMan probes were used to genotype GSTP1 SNPs. Results: The GSTP1 polymorphism rs1695, which encodes the amino acid change p.Ile105Val, was individually associated with MM [odds ratio (OR): 1·32, 95% confidence interval (CI): 1·06-1·63]. Furthermore, individuals carrying one or two MC1R nonsynonymous changes and GSTP1 rs1695 rare allele had an increased risk of developing MM (OR: 3·34, 95% CI: 1·42-8·09 and OR: 20·42, 95% CI: 2·80-417·42, respectively). Conclusions: This is the first time that the GSTP1 rs1695 polymorphism is reported to be associated with MM. In addition, this study is one of the largest GST polymorphism studies undertaken in the Spanish population and the first time that copy number variants have been scrutinized in relation to MM. © 2012 British Association of Dermatologists.


Rodrigues P.,Fundacion Investigacion Hospital Clinico Universitario | Furriol J.,Fundacion Investigacion Hospital Clinico Universitario | Tormo E.,Fundacion Investigacion Hospital Clinico Universitario | Ballester S.,Fundacion Investigacion Hospital Clinico Universitario | And 3 more authors.
Breast Cancer Research and Treatment | Year: 2012

Vascular endothelial growth factor (VEGF) is a potent regulator of angiogenesis and thereby involved in the development and progression of solid tumours. The association between polymorphisms of angiogenesis pathway genes and risk of breast cancer (BC) has been widely studied, but the results are not conclusive. This information is especially limited in Spanish women, so we decided to conduct a case-control study. Here, we selected four commonly studied polymorphisms in VEGF, rs3025039 (known as +936 C/T), rs1109324, rs154765 and rs833052, one polymorphism at the promoter of the VEGFR1 (-710 C/T) and another in the FGF2, rs1449683, gene to explore their association with BC susceptibility. Genotyping was performed by TaqMan SNP assays and polymerase chain reaction-restriction fragment length polymorphis (PCR-RFLP) on 453 patients and 461 controls in a population from Valencia (Spain). We observed that women carriers of +936 CT + TT VEGF genotypes have a protective effect concerning this disease (p = 0.014; OR 0.67, 95% CI 0.48-0.92) in the global group of patients. The haplotype TGAC of VEGF (rs3025039, rs1109324, rs154764 and rs833052) shows a reduction of the risk to develop BC (p = 3e-04; OR 0.48, 95% CI 0.32-0.72). Furthermore, we found that carriers of -710 CT + TT VEGFR1 genotypes have also a protective effect (p = 0.039; OR 0.55, 95% CI 0.31-0.98). When we stratified by groups of ages these associations were maintained. Our data report for the first time the association of the polymorphism -710 C/T VEGFR1 with BC. Additional experiments focused on VEGF-A, VEGFR1 and sVEGFR1 gene expression demonstrated that carriers of T allele at -710 C/T VEGFR1 genotype have higher levels of sVEGFR1/VEGF-A than the C/C genotype carriers. This was consistent with the hypothesis that this polymorphism may act as low penetrance risk factor. The data provided suggest that +936 C/T VEGF and =710 C/T VEGFR1 genotypes are likely important genetic markers of susceptibility to BC. © 2012 Springer Science+Business Media, LLC.

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