J Viña

Fundación de Investigación del Hospital Clínico Universitario de Valencia INCLIVA, Valenza, Valencia, Spain

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Publications (174)710.34 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Early pregnancy is associated with a reduction in a woman's lifetime risk for breast cancer. However, different studies have demonstrated an increase in breast cancer risk in the years immediately following pregnancy. Early and long-term risk is even higher if the mother age is above 35 years at the time of first parity. The proinflammatory microenvironment within the mammary gland after pregnancy renders an "ideal niche" for oncogenic events. Signaling pathways involved in programmed cell death and tissue remodeling during involution are also activated in breast cancer. Herein, the major signaling pathways involved in mammary gland involution, signal transducer and activator of transcription (STAT3), nuclear factor-kappa B (NF-κB), transforming growth factor beta (TGFβ), and retinoid acid receptors (RARs)/retinoid X receptors (RXRs), are reviewed as part of the complex network of signaling pathways that crosstalk in a contextual-dependent manner. These factors, also involved in breast cancer development, are important regulatory nodes for signaling amplification after weaning. Indeed, during involution, p65/p300 target genes such as MMP9, Capn1, and Capn2 are upregulated. Elevated expression and activities of these proteases in breast cancer have been extensively documented. The role of these proteases during mammary gland involution is further discussed. MMPs, calpains, and cathepsins exert their effect by modification of the extracellular matrix and intracellular proteins. Calpains, activated in the mammary gland during involution, cleave several proteins located in cell membrane, lysosomes, mitochondria, and nuclei favoring cell death. Besides, during this period, Capn1 is most probably involved in the modulation of preadipocyte differentiation through chromatin remodeling. Calpains can be implicated in cell anchoring loss, providing a proper microenvironment for tumor growth. A better understanding of the role of any of these proteases in tumorigenesis may yield novel therapeutic targets or prognostic markers for breast cancer. © 2015 IUBMB Life, 2015. © 2015 International Union of Biochemistry and Molecular Biology.
    International Union of Biochemistry and Molecular Biology Life 04/2015; DOI:10.1002/iub.1365 · 2.76 Impact Factor
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    ABSTRACT: Neurofibrillary tangles (aggregates of cytoskeletal tau protein) and senile plaques (aggregates mainly formed by amyloid beta peptide) are two landmark lesions in Alzheimer's disease. Some researchers proposed tangles while others proposed plaques as primary lesions. For a long time, these were thought of as independent mechanisms. However, experimental evidence suggests that both lesions are intimately related. We review here some molecular pathways linking amyloid beta and tau toxicities involving, among others, glycogen synthase kinase 3 beta (GSK 3β), p38, Pin1, cyclin dependent kinase 5 (CDK5), and regulator of calcineurin 1 (RCAN1). Understanding amyloid beta and tau toxicities as part of a common pathophysiological mechanism may help to find molecular targets to prevent or even treat the disease. Copyright © 2015. Published by Elsevier Inc.
    Free Radical Biology and Medicine 03/2015; 83. DOI:10.1016/j.freeradbiomed.2015.02.028 · 5.71 Impact Factor
  • XXXVII Congreso de la Sociedad Española de Ciencias Fisiológicas (SECF), Granada. España; 09/2014
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    ABSTRACT: Xanthine oxidase (XO), a free radical-generating enzyme, is involved in tissue damage produced during exhaustive exercise. Our aim was to test whether allopurinol, a powerful inhibitor of XO, may be effective in preventing exercise-induced tissue damage in soccer players. Twelve soccer players were randomized into two experimental groups. One received allopurinol, before a match of the premier Spanish Football League, and the other placebo. Allopurinol prevented the exercise-induced increase in all the markers of skeletal muscle damage analyzed: creatine kinase, lactate dehydrogenase, aspartate aminotransferase, and myoglobin. Creatine kinase-MB isoenzyme and highly sensitive troponin T, specific biomarkers of myocardial injury, increased significantly in the placebo but not in the allopurinol-treated group after the football match. We also found that the exercise-induced lipid peroxidation, as reflected by malondialdehyde measurements, was prevented after allopurinol administration. However, inhibition of XO did not prevent the increment in the activity of alanine aminotransferase found after the match. No changes in the serum gamma glutamyltransferase activity was found after the match on either the placebo and the allopurinol groups. These two enzymes were determined as biomarkers of liver injury. Allopurinol represents an effective and inexpensive pharmacological agent to prevent tissue damage in soccer players.
    Scandinavian Journal of Medicine and Science in Sports 04/2014; 25(1). DOI:10.1111/sms.12213 · 3.17 Impact Factor
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    ABSTRACT: Oxidative stress is a hallmark of Alzheimer’s disease (AD). We propose that rather than causing damage because of the action of free radicals, oxidative stress deranges signaling pathways leading to tau hyperphosphorylation, a hallmark of the disease. Indeed, incubation of neurons in culture with 5 µM beta-amyloid peptide (Aβ) causes an activation of p38 MAPK (p38) that leads to tau hyperphosphorylation. Inhibition of p38 prevents Aβ-induced tau phosphorylation. Aβ-induced effects are prevented when neurons are co-incubated with trolox (the water-soluble analog of vitamin E). We have confirmed these results in vivo, in APP/PS1 double transgenic mice of AD. We have found that APP/PS1 transgenic mice exhibit a high level of P-p38 in the hippocampus but not in cortex and this is prevented by feeding animals with a diet supplemented with vitamin E. Our results underpin the role of oxidative stress in the altered cell signaling in AD pathology and suggest that antioxidant prevention may be useful in AD therapeutics.
    03/2014; 2. DOI:10.1016/j.redox.2014.03.002
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    ABSTRACT: The inhibitor of differentiation Id2, a protein lacking the basic DNA-binding domain, is involved in the modulation of a number of biological processes. The molecular mechanisms explaining Id2 pleiotropic functions are poorly understood. Id2 and E2F4 are known to bind simultaneously to c-myc promoter. To study whether Id2 plays a global role on transcriptional regulation, we performed in vivo genome-wide ChIP/chip experiments for Id2 and E2F4 in adult mouse liver. An Id2-containing complex was bound to a common sequence downstream from the TSS on a subset of 442 E2F4 target genes mainly related to cell development and chromatin structure. We found a positive correlation between Id2 protein levels and the expression of E2F4/Id2 targets in fetal and adult liver. Id2 protein stability increased in fetal liver by interaction with USP1 de-ubiquitinating enzyme, which was induced during development. In adult liver, USP1 and Id2 levels dramatically decreased. In differentiated liver tissue, when Id2 concentration was low, E2F4/Id2 was bound to the same region as paused Pol II and target genes remained transcriptionally inactive. Conversely, in fetal liver when Id2 levels were increased, Id2 and Pol II were released from gene promoters and target genes up-regulated. During liver regeneration after partial hepatectomy, we obtained the same results as in fetal liver. Our results suggest that Id2 might be part of a reversible development-related program involved in the paused-ON/OFF state of Pol II on selected genes that would remain responsive to specific stimuli.
    Cellular and Molecular Life Sciences CMLS 02/2014; DOI:10.1007/s00018-014-1588-1 · 5.86 Impact Factor
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    ABSTRACT: Calpains become activated in mammary gland early during weaning, cleaving several proteins located mainly in the cell membrane, but also in other organelles such as lysosomes, mitochondria and nuclei. By immunofluorescence and western blot analysis, we demonstrated the nuclear translocation of calpain-1 and calpain-2, together with the cleavage of several cytoplasmic nucleoporins in epithelial cells of the lobulo-alveolar compartment. In vivo and in vitro calpain inhibition prevented this nucleoporin degradation. Besides, calpain-1 was also present in the nucleus of non-epithelial mammary tissue cells, concomitant with adipocyte re-differentiation. Calpain-1 was internalized within nuclei and found to be present in the nuclear chromatin-enriched fraction, associated to histone H3. Furthermore, we have demonstrated both, in vivo and in vitro the cleavage of the amino-terminal residue of histone H3 by calpain-1. Calpain-1 co-localized with both H3K4me3 and H3K27me3 at the nuclear periphery, a bivalent epigenetic signal essential for cell differentiation. By ChIP assay we could confirm the presence of calpain-1 in the promoters of key genes expressed in adipose tissue such as C/EBPa and leptin. These results highlight a dual role for calpain-1 in the weaned gland after the pregnancy/lactation cycle, controlling programmed cell death and participating in the epigenetic program during adipocyte differentiation.
    Biochemical Journal 01/2014; DOI:10.1042/BJ20130847 · 4.78 Impact Factor
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    ABSTRACT: The aim of our study was to elucidate the role of growth hormone (GH) replacement therapy in three of the main mechanisms involved in sarcopenia: alterations in mitochondrial biogenesis, increase in oxidative stress, and alterations in protein balance. We used young and old Wistar rats that received either placebo or low doses of GH to reach normal insulin-like growth factor-1 values observed in the young group. We found an increase in lean body mass and plasma and hepatic insulin-like growth factor-1 levels in the old animals treated with GH. We also found a lowering of age-associated oxidative damage and an induction of antioxidant enzymes in the skeletal muscle of the treated animals. GH replacement therapy resulted in an increase in the skeletal muscle protein synthesis and mitochondrial biogenesis pathways. This was paralleled by a lowering of inhibitory factors in skeletal muscle regeneration and in protein degradation. GH replacement therapy prevents sarcopenia by acting as a double-edged sword, antioxidant and hypertrophic.
    The Journals of Gerontology Series A Biological Sciences and Medical Sciences 12/2013; 69(10). DOI:10.1093/gerona/glt187 · 4.98 Impact Factor
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    Jurnal Pengurusan 09/2013;
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    ABSTRACT: Objectives: We aimed to determine the effect of exercise training on plasma levels of brain-derived neurotrophic factor (BDNF), and serum insulin-like growth factor-1 (IGF-1) as well as cAMP response element-binding (CREB) activation in peripheral blood mononuclear cells (PBMCs) in adolescents. Methods: Nine trained and seven sedentary male adolescents, matched in age (14.0±2.2 years), were recruited for the study. Trained boys performed higher physical activity levels (expressed both as total energy expenditure and as physical activity energy expenditure) and showed significant bradycardia when compared with sedentary ones. Results: We found that BDNF and IGF-1 levels were significantly higher in trained adolescents than in sedentary ones. However, no effect of training was found in the activation of CREB in PBMCs. Conclusions: We demonstrated the increase of neuroplasticity-related proteins due to exercise training in adolescents. Our results emphasize the significance and impact of exercise in this developmental period.
    Journal of musculoskeletal & neuronal interactions 09/2013; 13(3):330-3. · 2.40 Impact Factor
  • Free Radical Biology and Medicine 09/2013; 65:S30-S31. DOI:10.1016/j.freeradbiomed.2013.08.030 · 5.71 Impact Factor
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    ABSTRACT: Despite recent advances in the diagnosis of myocardial ischemia, its biochemical identification in patients with acute chest pain is still a challenge, and alternative approaches for further improvement are needed. Metabolic alterations are the first consequences of acute myocardial ischemia. Metabolomics coupled with potent multivariate analyses allows for a simultaneous and relative quantification of thousands of different metabolites within a given sample. Thus, this discipline might exert a great impact on medical practice in cardiovascular medicine by providing a wealth of relevant biochemical data. Metabolomics is a promising tool to improve current, single biomarker-based approaches by identifying metabolic biosignatures that embody global biochemical changes in disease. This is especially relevant for conditions requiring early treatment like myocardial ischemia. This review discusses the potential application of metabolomics in the diagnosis of myocardial ischemia.
    Journal of Cardiovascular Translational Research 08/2013; DOI:10.1007/s12265-013-9505-9 · 2.69 Impact Factor
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    ABSTRACT: The aim of our study was to elucidate the role of growth hormone (GH) replacement therapy in three of the main mechanisms involved in sarcopenia: alterations in mitochondrial biogenesis, increase in oxidative stress, and alterations in protein balance. We used young and old Wistar rats that received either placebo or low doses of GH to reach normal insulin-like growth factor-1 values observed in the young group. We found an increase in lean body mass and plasma and hepatic insulin-like growth factor-1 levels in the old animals treated with GH. We also found a lowering of age-associated oxidative damage and an induction of antioxidant enzymes in the skeletal muscle of the treated animals. GH replacement therapy resulted in an increase in the skeletal muscle protein synthesis and mitochondrial biogenesis pathways. This was paralleled by a lowering of inhibitory factors in skeletal muscle regeneration and in protein degradation. GH replacement therapy prevents sarcopenia by acting as a double-edged sword, antioxidant and hypertrophic.
    The Journals of Gerontology Series A Biological Sciences and Medical Sciences 01/2013; · 4.98 Impact Factor
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    Journal of Alzheimer's disease: JAD 01/2013; · 3.61 Impact Factor
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    ABSTRACT: Epigenetics comprises the study of chemical modifications in the DNA and histones that regulates the gene expression or cellular phenotype. However, during the last decade this term has evolved after the elucidation of different mechanisms (microRNAs and nuclear organization of the chromosomes) involved in regulating gene expression. Epigenetics and the new designed technologies capable to analyze epigenetic changes (e.g., methylated DNA, miRNAs expression, post-translational modifications on histones among others) have disclosed an appealing scenario that will offer for the biomedical sciences new biomarkers for the study of neurodegenerative diseases, multifactorial complex diseases, rare diseases and cancer. Moreover, new technologies adapted for epigenetic studies will offer promising applications that in the next years will be common technologies in clinical laboratories. In this review we discuss epigenetic modifications used as possible biomarkers in several diseases. We also present the potential of methodologies to purify histones, and high throughput technologies as candidates to be set in clinical laboratories for their high potential analyzing epigenetic processes.
    Clinica chimica acta; international journal of clinical chemistry 06/2012; 413(19-20):1576-82. DOI:10.1016/j.cca.2012.05.021 · 2.76 Impact Factor
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    ABSTRACT: Our aim was to elucidate the physiological role of calpains (CAPN) in mammary gland involution. Both CAPN-1 and -2 were induced after weaning and its activity increased in isolated mitochondria and lysosomes. CAPN activation within the mitochondria could trigger the release of cytochrome c and other pro-apoptotic factors, whereas in lysosomes it might be essential for tissue remodeling by releasing cathepsins into the cytosol. Immunohistochemical analysis localized CAPNs mainly at the luminal side of alveoli. During weaning, CAPNs translocate to the lysosomes processing membrane proteins. To identify these substrates, lysosomal fractions were treated with recombinant CAPN and cleaved products were identified by 2D-DIGE. The subunit b(2) of the v-type H(+) ATPase is proteolyzed and so is the lysosomal-associated membrane protein 2a (LAMP2a). Both proteins are also cleaved in vivo. Furthermore, LAMP2a cleavage was confirmed in vitro by addition of CAPNs to isolated lysosomes and several CAPN inhibitors prevented it. Finally, in vivo inhibition of CAPN1 in 72-h-weaned mice decreased LAMP2a cleavage. Indeed, calpeptin-treated mice showed a substantial delay in tissue remodeling and involution of the mammary gland. These results suggest that CAPNs are responsible for mitochondrial and lysosomal membrane permeabilization, supporting the idea that lysosomal-mediated cell death is a new hallmark of mammary gland involution.
    Cell death and differentiation 05/2012; 19(9):1536-48. DOI:10.1038/cdd.2012.46 · 8.39 Impact Factor
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    ABSTRACT: The aim of this study was to investigate the metabolomic profile of acute myocardial ischemia (MIS) using nuclear magnetic resonance spectroscopy of peripheral blood serum of swine and patients undergoing angioplasty balloon-induced transient coronary occlusion. Biochemical detection of MIS is a major challenge. The validation of novel biosignatures is of utmost importance. High-resolution nuclear magnetic resonance spectroscopy was used to profile 32 blood serum metabolites obtained (before and after controlled ischemia) from swine (n = 9) and patients (n = 20) undergoing transitory MIS in the setting of planned coronary angioplasty. Additionally, blood serum of control patients (n = 10) was sequentially profiled. Preliminary clinical validation of the developed metabolomic biosignature was undertaken in patients with spontaneous acute chest pain (n = 30). Striking differences were detected in the blood profiles of swine and patients immediately after MIS. MIS induced early increases (10 min) of circulating glucose, lactate, glutamine, glycine, glycerol, phenylalanine, tyrosine, and phosphoethanolamine; decreases in choline-containing compounds and triacylglycerols; and a change in the pattern of total, esterified, and nonesterified fatty acids. Creatine increased 2 h after ischemia. Using multivariate analyses, a biosignature was developed that accurately detected patients with MIS both in the setting of angioplasty-related MIS (area under the curve 0.94) and in patients with acute chest pain (negative predictive value 95%). This study reports, to the authors' knowledge, the first metabolic biosignature of acute MIS developed under highly controlled coronary flow restriction. Metabolic profiling of blood plasma appears to be a promising approach for the early detection of MIS in patients.
    Journal of the American College of Cardiology 05/2012; 59(18):1629-41. DOI:10.1016/j.jacc.2011.09.083 · 15.34 Impact Factor
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    ABSTRACT: The beneficial effects of regular exercise for the promotion of health and cure of diseases have been clearly shown. In this review, we would like to postulate the idea that exercise can be considered as a drug. Exercise causes a myriad of beneficial effects for health, including the promotion of health and lifespan, and these are reviewed in the first section of this paper. Then we deal with the dosing of exercise. As with many drugs, dosing is extremely important to get the beneficial effects of exercise. To this end, the organism adapts to exercise. We review the molecular signalling pathways involved in these adaptations because understanding them is of great importance to be able to prescribe exercise in an appropriate manner. Special attention must be paid to the psychological effects of exercise. These are so powerful that we would like to propose that exercise may be considered as a psychoactive drug. In moderate doses, it causes very pronounced relaxing effects on the majority of the population, but some persons may even become addicted to exercise. Finally, there may be some contraindications to exercise that arise when people are severely ill, and these are described in the final section of the review. Our general conclusion is that exercise is so effective that it should be considered as a drug, but that more attention should be paid to the dosing and to individual variations between patients.
    British Journal of Pharmacology 04/2012; 167(1):1-12. DOI:10.1111/j.1476-5381.2012.01970.x · 4.99 Impact Factor
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    ABSTRACT: This study aimed at further investigating the antioxidant effect of smoked paprika (Pimentón La Vera, Spain) in healthy subjects. Crossover study included male students (age 20.6 ± 1.7 years) who consumed smoked or non-smoked paprika (2 g/day, 20 times, over 30 days). After ingestion of smoked paprika, plasma malondialdehyde (MDA) levels were significantly (p
    CyTA - Journal of Food 01/2012; 11(2):1-5. DOI:10.1080/19476337.2012.700952 · 0.50 Impact Factor

Publication Stats

5k Citations
710.34 Total Impact Points

Institutions

  • 2010–2014
    • Fundación de Investigación del Hospital Clínico Universitario de Valencia INCLIVA
      Valenza, Valencia, Spain
  • 1989–2013
    • University of Valencia
      • • Biochemistry and Molecular Biology
      • • Departamento de Fisiología
      Valenza, Valencia, Spain
  • 1983–2010
    • Facultad de Medicina
      Madrid, Madrid, Spain
  • 2006
    • City University of New York - LaGuardia Community College
      New York City, New York, United States
  • 2004–2006
    • Rosalind Franklin University of Medicine and Science
      • Physiology and Biophysics
      North Chicago, Illinois, United States
    • University of Wisconsin, Madison
      • Department of Kinesiology
      Madison, MS, United States
  • 2003–2004
    • Università degli studi di Foggia
      Foggia, Apulia, Italy
  • 2002
    • Hospital Clínico Universitario de Valencia
      Valenza, Valencia, Spain
  • 1999
    • The American Society for Biochemistry and Molecular Biology
      California, United States
  • 1994–1996
    • Adventist University of Health Sciences
      Orlando, Florida, United States
  • 1984
    • Pennsylvania State University
      • Department of Medicine
      University Park, Maryland, United States