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Peinado J.R.,University of Sfax | Pardo M.,Complejo Hospitalario Universitario Of Santiago Chus | Pardo M.,CIBER ISCIII | De la Rosa O.,Cellerix TM | And 2 more authors.
Proteomics | Year: 2012

The original concept of adipose tissue as an inert storage depot for the excess of energy has evolved over the last years and it is now considered as one of the most important organs regulating body homeostasis. This conceptual change has been supported by the demonstration that adipose tissue serves as a major endocrine organ, producing a wide variety of bioactive molecules, collectively termed adipokines, with endocrine, paracrine and autocrine activities. Adipose tissue is indeed a complex organ wherein mature adipocytes coexist with the various cell types comprising the stromal-vascular fraction (SVF), including preadipocytes, adipose-derived stem cells, perivascular cells, and blood cells. It is known that not only mature adipocytes but also the components of SVF produce adipokines. Furthermore, adipokine production, proliferative and metabolic activities and response to regulatory signals (i.e. insulin, catecholamines) differ between the different fat depots, which have been proposed to underlie their distinct association to specific diseases. Herein, we discuss the recent proteomic studies on adipose tissue focused on the analysis of the separate cellular components and their secretory products, with the aim of identifying the basic features and the contribution of each component to different adipose tissue-associated pathologies. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Crujeiras A.B.,Complejo Hospitalario Universitario Of Santiago Chus | Crujeiras A.B.,CIBER ISCIII | Carreira M.C.,Complejo Hospitalario Universitario Of Santiago Chus | Carreira M.C.,CIBER ISCIII | And 5 more authors.
Free Radical Research | Year: 2013

Diabetes mellitus and breast cancer are two important health problems. Type 2 diabetes (T2DM) and obesity are closely linked with both being associated with breast cancer. Despite abundant epidemiological data, there is no definitive evidence regarding the mechanisms responsible for this association. The proposed mechanisms by which diabetes affects breast cancer risk and prognosis are the same as the mechanisms hypothesised for the contribution of obesity to breast cancer risk. The obesity-induced inflammation promoted by adipose tissue dysfunction is a key feature, which is thought to be an important link between obesity and cancer. Inflammation induces an increase in free radicals and subsequently promotes oxidative stress, which may create a microenvironment favourable to the tumor development in obese persons. Oxidative stress is also proposed as the link between obesity and diabetes mellitus. Therefore, obesity-related oxidative stress could be a direct cause of neoplastic transformation associated with obesity and T2DM in breast cancer cells. This review is focused on the role of obesity-related oxidative stress in the context of chronic inflammation, on the time of breast cancer onset and progression, which provide targets for preventive and therapeutic strategies in the fields of diabetes and obesity-related breast cancer. © 2013 Informa UK, Ltd.


Al-Massadi O.,Complejo Hospitalario Universitario Of Santiago Chus | Al-Massadi O.,CIBER ISCIII | Trujillo M.L.,University of Santiago de Compostela | Senaris R.,University of Santiago de Compostela | And 10 more authors.
Regulatory Peptides | Year: 2011

The growth hormone (GH) axis is mainly regulated by the growth hormone releasing hormone (GHRH) and somatostatin (SS) hypothalamic peptides. Nevertheless, since ghrelin peptide was discovered as the natural ligand for growth hormone secretagogue receptor (GHS-R), the mechanism of GH regulation has acquired a new dimension. It was described that ghrelin possesses a relevant effect inducing GH secretion when it is administered peripherally. A role of the vagus nerve mediating ghrelin action has been described although this effect is not understood. Under this context the main objective of this work was to determine the possible involvement of the vagus in the somatotroph axis regulation. The results in this manuscript show that animals with a disruption of the vagus connection presented lower basal IGF-1 and GH levels, a decreased GH response to peripheral GHRH administration and a marked diminution in the GH response to peripheral and central ghrelin treatments. In addition, vagotomized animals showed a down-regulation of GHRH mRNA in the arcuate nucleus of the hypothalamus and a down-regulation in both GHRH and GHS receptors' mRNA at the pituitary level. In conclusion, the present work reveals that the vagus nerve is crucial in growth hormone regulation and essential for the full GH-releasing effect of ghrelin. © 2010 Elsevier B.V.


Gurriaran-Rodriguez U.,Complejo Hospitalario Universitario Of Santiago Chus | Gurriaran-Rodriguez U.,CIBER ISCIII | Al-Massadi O.,Complejo Hospitalario Universitario Of Santiago Chus | Al-Massadi O.,CIBER ISCIII | And 16 more authors.
Journal of Cellular and Molecular Medicine | Year: 2011

The role of obestatin, a 23-amino-acid peptide encoded by the ghrelin gene, on the control of the metabolism of pre-adipocyte and adipocytes as well as on adipogenesis was determined. Forin vitroassays, pre-adipocyte and adipocyte 3T3-L1 cells were used to assess the obestatin effect on cell metabolism and adipogenesis based on the regulation of the key enzymatic nodes, Akt and AMPK and their downstream targets. Forin vivoassays, white adipose tissue (WAT) was obtained from male rats under continuous subcutaneous infusion of obestatin. Obestatin activated Akt and its downstream targets, GSK3α/β, mTOR and S6K1, in 3T3-L1 adipocyte cells. Simultaneously, obestatin inactivated AMPK in this cell model. In keeping with this, ACC phosphorylation was also decreased. This fact was confirmedin vivoin white adipose tissue (omental, subcutaneous and gonadal) obtained from male rats under continuousscinfusion of obestatin (24 and 72 hrs). The relevance of obestatin as regulator of adipocyte metabolism was supported by AS160 phosphorylation, GLUT4 translocation and augment of glucose uptake in 3T3-L1 adipocyte cells. In contrast, obestatin failed to modify translocation of fatty acid transporters, FATP1, FATP4 and FAT/CD36, to plasma membrane. Obestatin treatment in combination with IBMX and DEX showed to regulate the expression of C/EBPα, C/EBPβ, C/EBPδ and PPARγ promoting adipogenesis. Remarkable, preproghrelin expression, and thus obestatin expression, increased during adipogenesis being sustained throughout terminal differentiation. Neutralization of endogenous obestatin secreted by 3T3-L1 cells by anti-obestatin antibody decreased adipocyte differentiation. Furthermore, knockdown experiments by preproghrelin siRNA supported that obestatin contributes to adipogenesis. In summary, obestatin promotes adipogenesis in an autocrine/paracrine manner, being a regulator of adipocyte metabolism. These data point to a putative role in the pathogenesis of metabolic syndrome. © 2011 The Authors Journal compilation © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.


PubMed | University of Leicester, Center for Research in Molecular Medicine and Chronic Diseases, Complejo Hospitalario Universitario Of Santiago Chus and CIBER ISCIII
Type: | Journal: Scientific reports | Year: 2016

The growth hormone secretagogue receptor, GHSR1a, mediates the biological activities of ghrelin, which includes the secretion of growth hormone, as well as the stimulation of appetite, food intake and maintenance of energy homeostasis. Mapping phosphorylation sites on GHSR1a and knowledge of how these sites control specific functional consequences unlocks new strategies for the development of therapeutic agents targeting individual functions. Herein, we have identified the phosphorylation of different sets of sites within GHSR1a which engender distinct functionality of -arrestins. More specifically, the Ser(362), Ser(363) and Thr(366) residues at the carboxyl-terminal tail were primarily responsible for -arrestin 1 and 2 binding, internalization and -arrestin-mediated proliferation and adipogenesis. The Thr(350) and Ser(349) are not necessary for -arrestin recruitment, but are involved in the stabilization of the GHSR1a--arrestin complex in a manner that determines the ultimate cellular consequences of -arrestin signaling. We further demonstrated that the mitogenic and adipogenic effect of ghrelin were mainly dependent on the -arrestin bound to the phosphorylated GHSR1a. In contrast, the ghrelin function on GH secretion was entirely mediated by G protein signaling. Our data is consistent with the hypothesis that the phosphorylation pattern on the C terminus of GHSR1a determines the signaling and physiological output.


PubMed | Servicio de Anatomia Patologica, IDIS, Complejo Hospitalario Universitario Of Santiago Chus and CIBER ISCIII
Type: Journal Article | Journal: Oncotarget | Year: 2016

Obestatin, a 23-amino acid peptide encoded by the ghrelin gene, and the GPR39 receptor were reported to be involved in the control of mitogenesis of gastric cancer cell lines; however, the relationship between the obestatin/GPR39 system and gastric cancer progression remains unknown. In the present study, we determined the expression levels of the obestatin/GPR39 system in human gastric adenocarcinomas and explored their potential functional roles. Twenty-eight patients with gastric adenocarcinomas were retrospectively studied, and clinical data were obtained. The role of obestatin/GPR39 in gastric cancer progression was studied in vitro using the human gastric adenocarcinoma AGS cell line. Obestatin exogenous administration in these GPR39-bearing cells deregulated the expression of several hallmarks of the epithelial-mesenchymal transition (EMT) and angiogenesis. Moreover, obestatin signaling promoted phenotypic changes via GPR39, increasingly impacting on the cell morphology, proliferation, migration and invasion of these cells. In healthy human stomachs, obestatin expression was observed in the neuroendocrine cells and GPR39 expression was localized mainly in the chief cells of the oxyntic glands. In human gastric adenocarcinomas, no obestatin expression was found; however, an aberrant pattern of GPR39 expression was discovered, correlating to the dedifferentiation of the tumor. Altogether, our data strongly suggest the involvement of the obestatin/GPR39 system in the pathogenesis and/or clinical outcome of human gastric adenocarcinomas and highlight the potential usefulness of GPR39 as a prognostic marker in gastric cancer.


Martinez-Navarro E.M.,USP Hospital San Jaime | Rebollo J.,USP Hospital San Jaime | Gonzalez-Manzano R.,USP Hospital San Jaime | Sureda M.,USP Hospital San Jaime | And 5 more authors.
Clinical and Translational Oncology | Year: 2011

Introduction Epidermal growth factor receptor (EGFR) mutation related to tyrosine kinase inhibitors' (TKIs) responsiveness in non-small cell lung cancer (NSCLC) has become an important issue for therapeutic decision-making in NSCLC patients. Material and methods Sixty-nine Caucasian NSCLC patients were screened for mutations in the tyrosine kinase (TK) domain of EGFR by direct sequencing from December 2005 to September 2010. Results Activating mutations in the EGFR TK domain were found in 8 of 69 (11.6%) (7 deletions in exon 19 and one L858R mutation in exon 21). Seven of those mutations were found in adenocarcinoma and one mutation in bronchiolo-alveolar carcinoma; five of them in females (one smoker) and three of them in males (one smoker). All patients carrying activating mutations in the TK domain of EGFR were treated with TKIs. Ten patients not carrying an activating mutation in EGFR, who progressed after chemotherapy, were also treated with compassionate use of EGFR-specifi c TKIs (gefi tinib or erlotinib). An objective response (partial response) was observed in all patients carrying an activating mutation in EGFR that received TKIs. Median overall survival for these patients has not been reached, however mean survival has been estimated at 39.5 months (95% CI, 22-57). Conclusions As previously reported, EGFR TK mutational analysis was a predictive test for response to targeted therapy with EGFR TKIs. The early identifi cation of these patients consistently attains disease response and clearly improves outcomes.


Cuatrecasas G.,Centro Medico Teknon | Alegre C.,Institute Universitari Dexeus | Fernandez-Sola J.,University of Barcelona | Gonzalez M.J.,Institute Universitari Dexeus | And 14 more authors.
Pain | Year: 2012

Functional defects in growth hormone (GH) secretion and its efficacy as a complementary treatment have been suggested for fibromyalgia. This study investigated the efficacy and safety of low-dose GH as an add-on therapy in patients with both severe FM and low insulin-like growth factor 1 levels. A total of 120 patients were enrolled in a multicenter, placebo-controlled study for 18 months. They were randomly assigned to receive either 0.006 mg/kg/day of GH subcutaneously (group A, n = 60) or placebo (group B, n = 60) for 6 months (blind phase). The placebo arm was switched to GH treatment from month 6 to month 12 (open phase), and a follow-up period after GH discontinuation was performed until month 18. Standard treatment for fibromyalgia (selective serotonin re-uptake inhibitors, opioids, and amitriptyline) was maintained throughout the study. Number and intensity of tender points, Fibromyalgia Impact Questionnaire (FIQ) with its subscales, and EuroQol 5 dimensions test (EQ5D) with visual analogue scale (VAS) were assessed at different time points. At the end of the study, 53% of group A patients obtained fewer than 11 positive tender points, vs 33% of group B patients (P < .05). 39.1% vs 22.4% reached more than 50% improvement in VAS (P < .05). Group A patients showed significantly improved FIQ scores (P = .01) compared with group B. Although GH discontinuation worsened all scores in both groups during follow-up, impairment in pain perception was less pronounced in the GH-treated group (P = .05). In this largest and longest placebo-controlled trial performed in FM (NCT00933686), addition of GH to the standard treatment is effective in reducing pain, showing sustained action over time. © 2012 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.


Martinez-Mera J.A.,University of Santiago de Compostela | Tahoces P.G.,University of Santiago de Compostela | Varela-Ponte R.,Complejo Hospitalario Universitario Of Santiago Chus | Suarez-Cuenca J.J.,Complejo Hospitalario Universitario Of Santiago Chus | And 2 more authors.
Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics) | Year: 2015

The aim of this study was to clinically evaluate a fully automatic method for segmentation and characterizing the thoracic aorta. From 2010 to 2013, a total of 27 patients were randomly selected for the study. The automatic method was compared with two segmentations manually performed by two independent radiologists amd a commercial software for gauging calibres. The results of the segmentation measurements showed a Dice Similarity Coefficient of 93.98 ± 0.27, a correlation coefficient of 0.875 ± 0.012, and an intraclass correlation coefficient of 0.909 ± 0.011 for both experts. For the diameter measurements, the values were a Pearson’s Correlation Coefficient of 0.933, and an intraclass correlation of 0.913. The Bland- Altman plots showed no statistically significant differences between the commercial method and the proposed method. In conclusion, the method developed is capable of automatically calculating the diameters, and the segmentation of the thoracic aorta. © Springer International Publishing Switzerland 2015.


Souto Bayarri M.,University of Santiago de Compostela | Garcia Tahoces P.,University of Santiago de Compostela | Masip Capdevila L.R.,University of Santiago de Compostela | Suarez Cuenca J.J.,University of Santiago de Compostela | And 2 more authors.
Radiologia | Year: 2011

Objectives: The aim of this study was to compare a semiautomatic segmentation method to quantify the function of both ventricles in magnetic resonance imaging (MRI) with the manual tracing method. Material and methods: We examined 17 patients with diverse cardiovascular diseases on a 1.5 Tesla MRI unit (Magnetom Symphony Quantum; Siemens Medical Systems, Erlangen, Germany) using the following parameters: maximum gradient, 30 mT/m; and slew rate, 125 T/m/s. In all studies, we acquired images in cine mode in the short axis (SSFP, 6 mm slice thickness, from the base to the ventricular apex) with breath holding. To reduce the user interaction, we used only one image per patient to initiate the semiautomatic method. The semiautomatic method was based on a specifically designed algorithm of regional growth and border detection. We quantified the end-diastolic volume (EDV), end-systolic volume (ESV), and the ejection fraction (EF) for both ventricles in all patients. Results: No significant differences between the two segmentation techniques were found in the quantification of either ventricle (p > 0.05). The difference in the volumes, although nearly significant, are clinically irrelevant. The correlation for the estimation of left ventricular function was excellent (r > 0.9), and the correlation for the estimation of right ventricular function was good (r > 0.7). Conclusions: Our semiautomatic segmentation method enables the function of both ventricles to be quantified as accurately as the conventional method. © 2010 SERAM. Published by Elsevier España, S.L. All rights reserved.

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