Instituto Ramon Y Cajal Of Investigacion Sanitaria

Madrid, Spain

Instituto Ramon Y Cajal Of Investigacion Sanitaria

Madrid, Spain
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Escobar-Morreale H.F.,University of Alcalá | Escobar-Morreale H.F.,CIBER ISCIII | Escobar-Morreale H.F.,Instituto Ramon Y Cajal Of Investigacion Sanitaria | Samino S.,CIBER ISCIII | And 13 more authors.
Clinical Chemistry | Year: 2012

BACKGROUND: Abdominal adiposity and obesity influence the association of polycystic ovary syndrome (PCOS) with insulin resistance and diabetes.Weaimed to characterize the intermediate metabolism phenotypes associated with PCOS and obesity. METHODS: We applied a nontargeted GC-MS metabolomic approach to plasma samples from 36 patients with PCOS and 39 control women without androgen excess, matched for age, body mass index, and frequency of obesity. RESULTS: Patients with PCOS were hyperinsulinemic and insulin resistant compared with the controls. The increase in plasma long-chain fatty acids, such as linoleic and oleic acid, and glycerol in the obese patients with PCOS suggests increased lipolysis, possibly secondary to impaired insulin action at adipose tissue. Conversely, nonobese patients with PCOS showed a metabolic profile consisting of suppression of lipolysis and increased glucose utilization (increased lactic acid concentrations) in peripheral tissues, and PCOS patients as a whole showed decreased 2-ketoisocaproic and alanine concentrations, suggesting utilization of branched-chain amino acids for protein synthesis and not for gluconeogenesis. These metabolic processes required effective insulin signaling; therefore, insulin resistance was not universal in all tissues of these women, and different mechanisms possibly contributed to their hyperinsulinemia. PCOS was also associated with decreased α-tocopherol and cholesterol concentrations irrespective of obesity. CONCLUSIONS: Substantial metabolic heterogeneity, strongly influenced by obesity, underlies PCOS. The possibility that hyperinsulinemia may occur in the absence of universal insulin resistance in nonobese women with PCOS should be considered when designing diagnostic and therapeutic strategies for the management of this prevalent disorder. © 2012 American Association for Clinical Chemistry.


Escobar-Morreale H.F.,University of Alcalá | Escobar-Morreale H.F.,Instituto Ramon Y Cajal Of Investigacion Sanitaria | Escobar-Morreale H.F.,Research Center Biomedica | Luque-Ramirez M.,University of Alcalá | 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.


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.


Perez-Gomez E.,Complutense University of Madrid | Andradas C.,Complutense University of Madrid | Flores J.M.,Complutense University of Madrid | Quintanilla M.,Autonomous University of Madrid | And 4 more authors.
Oncogene | Year: 2013

G protein-coupled receptors (GPCRs) control crucial physiological processes and their dysfunction contributes to various human diseases, including cancer. The orphan GPCR GPR55 was identified and cloned more than a decade ago, but very little is known about its physio-pathological relevance. It has been recently shown that GPR55 controls the behavior of human cancer cell lines in culture and xenografts. However, the assessment of the actual role of this receptor in malignant transformation in vivo is hampered by the lack of studies on its functional impact in clinically-relevant models of cancer. Here we demonstrate that GPR55 drives mouse skin tumor development. Thus, GPR55-deficient mice were more resistant to DMBA/TPA-induced papilloma and carcinoma formation than their wild-type littermates. GPR55 exerted this pro-tumor effect primarily by conferring a proliferative advantage on cancer cells. In addition, GPR55 enhanced skin cancer cell anchorage-independent growth, invasiveness and tumorigenicity in vivo, suggesting that it promotes not only tumor development but also tumor aggressiveness. Finally, we observed that GPR55 is upregulated in human skin tumors and other human squamous cell carcinomas compared with the corresponding healthy tissues. Altogether, these findings reveal the pivotal importance of GPR55 in skin tumor development, and suggest that this receptor may be used as a new biomarker and therapeutic target in squamous cell carcinomas. © 2013 Macmillan Publishers Limited.


PubMed | Donders Institute for Brain, University of Alcalá, Instituto Ramon Y Cajal Of Investigacion Sanitaria, Radboud University Nijmegen and Baylor College of Medicine
Type: Journal Article | Journal: American journal of human genetics | Year: 2015

Linkage analysis combined with whole-exome sequencing in a large family with congenital and stable non-syndromic unilateral and asymmetric hearing loss (NS-UHL/AHL) revealed a heterozygous truncating mutation, c.286_303delinsT (p.Ser96Ter), in KITLG. This mutation co-segregated with NS-UHL/AHL as a dominant trait with reduced penetrance. By screening a panel of probands with NS-UHL/AHL, we found an additional mutation, c.200_202del (p.His67_Cys68delinsArg). Invitro studies revealed that the p.His67_Cys68delinsArg transmembrane isoform of KITLG is not detectable at the cell membrane, supporting pathogenicity. KITLG encodes a ligand for the KIT receptor. Also, KITLG-KIT signaling and MITF are suggested to mutually interact in melanocyte development. Because mutations in MITF are causative of Waardenburg syndrome type 2 (WS2), we screened KITLG in suspected WS2-affected probands. A heterozygous missense mutation, c.310C>G (p.Leu104Val), that segregated with WS2 was identified in a small family. Invitro studies revealed that the p.Leu104Val transmembrane isoform of KITLG is located at the cell membrane, as is wild-type KITLG. However, in culture media of transfected cells, the p.Leu104Val soluble isoform of KITLG was reduced, and no soluble p.His67_Cys68delinsArg and p.Ser96Ter KITLG could be detected. These data suggest that mutations in KITLG associated with NS-UHL/AHL have a loss-of-function effect. We speculate that the mechanism of the mutation underlying WS2 and leading to membrane incorporation and reduced secretion of KITLG occurs via a dominant-negative or gain-of-function effect. Our study unveils different phenotypes associated with KITLG, previously associated with pigmentation abnormalities, and will thereby improve the genetic counseling given to individuals with KITLG variants.


Gonzalo-Gobernado R.,Instituto Ramon Y Cajal Of Investigacion Sanitaria | Calatrava-Ferreras L.,Instituto Ramon Y Cajal Of Investigacion Sanitaria | Reimers D.,Instituto Ramon Y Cajal Of Investigacion Sanitaria | Herranz A.S.,Instituto Ramon Y Cajal Of Investigacion Sanitaria | And 5 more authors.
PLoS ONE | Year: 2013

Liver growth factor (LGF) is a hepatic mitogen purified some years ago that promotes proliferation of different cell types and the regeneration of damaged tissues, including brain tissue. Considering the possibility that LGF could be used as a therapeutic agent in Parkinson's disease, we analyzed its potential neuroregenerative and/or neuroprotective activity when peripherally administered to unilaterally 6-hydroxydopamine (6-OHDA)-lesioned rats. For these studies, rats subjected to nigrostriatal lesions were treated intraperitoneally twice a week with LGF (5 microg/rat) for 3 weeks. Animals were sacrificed 4 weeks after the last LGF treatment. The results show that LGF stimulates sprouting of tyrosine hydroxylase-positive terminals and increases tyrosine hydroxylase and dopamine transporter expression, as well as dopamine levels in the denervated striatum of 6-OHDA-lesioned rats. In this structure, LGF activates microglia and raises tumor necrosis factor-alpha protein levels, which have been reported to have a role in neuroregeneration and neuroprotection. Besides, LGF stimulates the phosphorylation of MAPK/ERK1/2 and CREB, and regulates the expression of proteins which are critical for cell survival such as Bcl2 and Akt. Because LGF partially protects dopamine neurons from 6-OHDA neurotoxicity in the substantia nigra, and reduces motor deficits in these animals, we propose LGF as a novel factor that may be useful in the treatment of Parkinson's disease. © 2013 Gonzalo-Gobernado et al.


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.


Alvarez R.,Hospital Universitario Ramon y Cajal | Masjuan J.,Hospital Universitario Ramon y Cajal | Masjuan J.,Instituto Ramon Y Cajal Of Investigacion Sanitaria
Revista Clinica Espanola | Year: 2016

Visual agnosia is defined as an impairment of object recognition, in the absence of visual acuity or cognitive dysfunction that would explain this impairment. This condition is caused by lesions in the visual association cortex, sparing primary visual cortex. There are 2 main pathways that process visual information: the ventral stream, tasked with object recognition, and the dorsal stream, in charge of locating objects in space. Visual agnosia can therefore be divided into 2 major groups depending on which of the two streams is damaged. The aim of this article is to conduct a narrative review of the various visual agnosia syndromes, including recent developments in a number of these syndromes. © 2015 Elsevier España, S.L.U. y Sociedad Española de Medicina Interna (SEMI).


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.


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.

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