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El Assar M.,Hospital Universitario Of Getafe | Ruiz de Adana J.C.,Hospital Universitario Of Getafe | Angulo J.,Instituto Ramon Y Cajal Of Investigacion Sanitaria | Pindado Martinez M.L.,Hospital Universitario Of Getafe | And 2 more authors.
Journal of Translational Medicine | Year: 2013

Background: Insulin resistance (IR) is frequently associated with endothelial dysfunction and has been proposed to play a major role in cardiovascular disease (CVD). On the other hand, obesity has long been related to IR and increased CVD. However it is not known if IR is a necessary condition for endothelial dysfunction in human obesity, allowing for preserved endothelial function in obese people when absent. Therefore, the purpose of the study was to assess the relationship between IR and endothelial dysfunction in human obesity and the mechanisms involved.Methods: Twenty non-insulin resistant morbid obese (NIR-MO), 32 insulin resistant morbid obese (IR-MO), and 12 healthy subjects were included. Serum concentrations of glucose, insulin, interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), resistin and adiponectin were determined. IR was evaluated by HOMA-index. Endothelium-dependent relaxation to bradykinin (BK) in mesenteric microvessels was assessed in wire myograph.Results: Serum IL-6, and TNF-α levels were elevated only in IR-MO patients while resistin was elevated and adiponectin reduced in all MO individuals. Mesenteric arteries from IR-MO, but not from NIR-MO subjects displayed blunted relaxation to BK. Vasodilatation was improved in IR-MO arteries by the superoxide scavenger, superoxide dismutase (SOD) or the mitochondrial-targeted SOD mimetic, mito-TEMPO. NADPH oxidase inhibitors (apocynin and VAS2870) and the nitric oxide synthase (NOS) cofactor, tetrahydrobiopterin failed to modify BK-induced vasodilatations. Superoxide generation was higher in vessels from IR-MO subjects and reduced by mito-TEMPO. Blockade of TNF-α with infliximab, but not inhibition of inducible NOS or cyclooxygenase, improved endothelial relaxation and decreased superoxide formation.Conclusions: Endothelial dysfunction is observed in human morbid obesity only when insulin resistance is present. Mechanisms involved include augmented mitochondrial superoxide generation, and increased systemic inflammation mediated by TNF-α. These findings may explain the different vascular risk of healthy vs unhealthy obesity. © 2013 El Assar et al.; licensee BioMed Central Ltd. Source

Escobar-Morreale H.F.,University of Alcala | Escobar-Morreale H.F.,Instituto Ramon Y Cajal Of Investigacion Sanitaria | Escobar-Morreale H.F.,Research Center Biomedica | Luque-Ramirez M.,University of Alcala | Luque-Ramirez M.,Research Center Biomedica
Fertility and Sterility | Year: 2011

Objective: To determine whether androgen excess contributes to the increased body iron stores of polycystic ovary syndrome (PCOS) by stimulating erythropoietic activity, by measuring serum soluble transferrin receptor (sTfR) concentrations and its ratio to ferritin levels in patients with PCOS, as surrogate markers of erythropoietic activity and of the appropriateness of cellular iron demands for the total body iron contents, respectively. Design: Case-control study. Setting: Academic hospital. Patient(s): One hundred-four patients with PCOS and 100 controls without androgen excess. Intervention(s): Blood sampling and oral glucose tolerance test. Main Outcome Measure(s): Serum sTfR and ferritin concentrations, as well as indexes of androgen excess, inflammation, obesity, and insulin and glucose metabolism. Result(s): Serum ferritin levels increased in women presenting with PCOS, obesity, and/or abnormal glucose tolerance, but these disorders did not influence sTfR concentrations. The sTfR/ferritin ratio decreased with obesity and abnormal glucose tolerance, and its logarithm correlated inversely with body mass index, free T, and C-reactive protein levels and directly with the insulin sensitivity and disposition indexes. A stepwise multiple regression analysis indicated that the changes in the insulin sensitivity index explained 7% of the variability of the logarithm of sTfR/ferritin ratio. Conclusion(s): Increased serum ferritin levels in patients with PCOS are associated with a reduction in insulin sensitivity but do not result from a putative enhancement of erythropoiesis by androgen excess. Copyright © 2011 American Society for Reproductive Medicine, Published by Elsevier Inc. Source

Angulo J.,Instituto Ramon Y Cajal Of Investigacion Sanitaria | Vallejo S.,Autonomous University of Madrid | El Assar M.,Hospital Universitario Of Getafe | Garcia-Septiem J.,Hospital Universitario Of Getafe | And 2 more authors.
Experimental Gerontology | Year: 2012

Endothelial vasodilation in human vessels is impaired by aging and other cardiovascular risk factors (CVRF) but the differential impact of aging and CVRF in human endothelial function is not completely elucidated. The aim of this work was to evaluate the influence of aging on the effects of peroxisome proliferator-activated receptor (PPAR)-α and -γ subtype agonists on endothelium-dependent vasodilation of isolated human vessels from subjects with or without CVRF. Human mesenteric microarteries were dissected from omentum specimens obtained from subjects younger or older than 60. years having or not CVRF and mounted in wire myographs to evaluate endothelium-dependent relaxation to bradykinin (BK). Aging and CVRF independently reduced endothelium-dependent relaxations. An additional impairment was produced when aging and CVRF co-existed (p< 0.001). In vessels from adult subjects PPARγ agonist, GW1929 (1 μM) improved BK-induced responses only in those obtained from subjects with CVRF. By contrast, GW1929 improved the responses in vessels from elderly subjects having or not CVRF. PPARα agonist, GW7647 (1 μM), enhanced endothelial vasodilation in adults with CVRF (p< 0.001) but lack any effect in vessels from older subjects having or not CVRF. In vessels from subjects with CVRF, superoxide dismutase (SOD; 100. U/ml) improved BK-induced responses only in elderly subjects (p< 0.001). Vascular aging negatively impacts endothelial function independently of the presence of additional CVRF through specific molecular mechanisms involving superoxide generation. While PPARγ activation remains effective, the improving effects of PPARα agonists on endothelial responses disappear in aged human vessels. © 2012 Elsevier Inc. Source

El Assar M.,Hospital Universitario Of Getafe | Angulo J.,Hospital Universitario Of Getafe | Angulo J.,Instituto Ramon Y Cajal Of Investigacion Sanitaria | Vallejo S.,Universidadautonoma Of Madrid | And 3 more authors.
Frontiers in Physiology | Year: 2012

Vascular aging is a key process determining health status of aged population. Aging is an independent cardiovascular risk factor associated to an impairment of endothelial function, which is a very early and important event leading to cardiovascular disease. Vascular aging, formerly being considered an immutable and inexorable risk factor, is now viewed as a target process for intervention in order to achieve a healthier old age. A further knowledge of the mechanisms underlying the age-related vascular dysfunction is required to design an adequate therapeutic strategy to prevent or restore this impairment of vascular functionality. Among the proposed mechanisms that contribute to age-dependent endothelial dysfunction, this review is focused on the following aspects occurring into the vascular wall: (1) the reduction of nitric oxide (NO) bioavailability, caused by diminished NO synthesis and/or by augmented NO scavenging due to oxidative stress, leading to peroxynitrite formation (ONOO -); (2) the possible sources involved in the enhancement of oxidative stress; (3) the increased activity of vasoconstrictor factors; and (4) the development of a low-grade pro-inflammatory environment. Synergisms and interactions between all these pathways are also analyzed. Finally, a brief summary of some cellular mechanisms related to endothelial cell senescence (including telomere and telomerase, stress-induced senescence, as well as sirtuins) are implemented, as they are likely involved in the age-dependent endothelial dysfunction, as well as in the lower vascular repairing capacity observed in the elderly. Prevention or reversion of those mechanisms leading to endothelial dysfunction through life style modifications or pharmacological interventions could markedly improve cardiovascular health in older people. © 2012 El Assar, Angulo, Vallejo, Peiró, Sánchez-Ferrer and Rodríguez-Mañas. Source

Galan J.-C.,Hospital Universitario Ramon y Cajal | Galan J.-C.,Instituto Ramon Y Cajal Of Investigacion Sanitaria | Gonzalez-Candelas F.,University of Valencia | Rolain J.-M.,Aix - Marseille University | Canton R.,Hospital Universitario Ramon y Cajal
Frontiers in Microbiology | Year: 2013

Antibiotics and antibiotic resistance determinants, natural molecules closely related to bacterial physiology and consistent with an ancient origin, are not only present in antibiotic-producing bacteria. Throughput sequencing technologies have revealed an unexpected reservoir of antibiotic resistance in the environment. These data suggest that co-evolution between antibiotic and antibiotic resistance genes has occurred since the beginning of time. This evolutionary race has probably been slow because of highly regulated processes and low antibiotic concentrations. Therefore to understand this global problem, a new variable must be introduced, that the antibiotic resistance is a natural event, inherent to life. However, the industrial production of natural and synthetic antibiotics has dramatically accelerated this race, selecting some of the many resistance genes present in nature and contributing to their diversification. One of the best models available to understand the biological impact of selection and diversification are β-lactamases. They constitute the most widespread mechanism of resistance, at least among pathogenic bacteria, with more than 1000 enzymes identified in the literature. In the lastyears, there has been growing concern about the description, spread, and diversification of β-lactamases with carbapenemase activity and AmpC-type in plasmids. Phylogenies of these enzymes help the understanding of the evolutionary forces driving their selection. Moreover, understanding the adaptive potential of β-lactamases contribute to exploration the evolutionary antagonists trajectories through the design of more efficient synthetic molecules. In this review, we attempt to analyze the antibiotic resistance problem from intrinsic and environmental resistomes to the adaptive potential of resistance genes and the driving forces involved in their diversification, in order to provide a global perspective of the resistance problem. © 2013 Galán, González-Candelas, Rolain and Cantón. Source

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