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Martin-Calvo N.,University of Navarra | Ochoa M.C.,Research Center Medica Aplicada | Marti A.,University of Navarra | Marti A.,CIBER ISCIII | And 2 more authors.
Nutricion Hospitalaria | Year: 2013

Introduction: The high prevalence of obesity among Spanish children and adolescents has become an important public health problem. Objective: To assess the association between dietary macronutrient intake and obesity in a case-control study of children and adolescents (aged 5.5 to 18.8) from Navarra. Methods: Cases were 178 obese children (body mass index > 97th percentile), from Navarra. Controls were individually matched by sex and age. Anthropometric data were collected by trained personal using standardized procedures. Personal interviews were performed to collect previously validated semiquantitative food frequency questionnaires (FFQs). From these FFQs we calculated the intake of macronutrients (carbohydrates, proteins and fats) and types of fatty acids. Energy-adjusted macronutrient intake was divided into quintiles. Conditional logistic regression was used and confounder factors were taken into account. Results: The macronutrient composition of the diet was similar between cases and controls, except for polyunsaturated fatty acids (PUFA) intake, which was significantly inversely associated with obesity (p for trend < 0.01), with adjusted odds ratio = 0.34 (95% CI: 0.15 to 0.77) for the fifth versus the first quintile. Conclusions: An inverse and significant association between PUFA intake and obesity was found in this casecontrol study.

Sangro B.,Liver Unit | Sangro B.,Research Center Biomedica En Red Of Enfermedades Hepaticas gestivas | Prieto J.,Liver Unit | Prieto J.,Research Center Biomedica En Red Of Enfermedades Hepaticas gestivas | Prieto J.,Research Center Medica Aplicada
Current Opinion in Molecular Therapeutics | Year: 2010

In contrast to the large quantity of preclinical evidence for efficacy, few gene therapy agents have reached clinical development for the treatment of primary and secondary liver cancer. This review discusses the published clinical trials that have explored the feasibility, safety and efficacy of gene therapy strategies for the treatment of liver cancer. Strategies include restoration of tumor suppressor genes, genetic prodrug-activating therapy, genetic immunotherapy and oncolytic virotherapy. In these trials, transgene expression of varying degrees has been detected. Globally, gene therapy has proven to be safe, with none of the agents tested reaching the MTD. Although none of the phase II trials provided significant response rates, objective remissions have occasionally been observed and proof-of-concept for the ability of gene therapy to produce significant tumor cell killing has been determined. Insufficient delivery following intravascular administration and short-lived transgene expression are likely to be the cause of this limited antitumor efficacy. The development of new gene therapy vectors with improved characteristics will increase the probability of success of gene therapy for the treatment of liver cancer. © 2010 Thomson Reuters (Scientific) Ltd.

Martin-Calvo N.,Public University of Navarra | Martinez-Gonzalez M.-A.,Public University of Navarra | Martinez-Gonzalez M.-A.,Institute Salud Carlos III | Bes-Rastrollo M.,Public University of Navarra | And 4 more authors.
Public Health Nutrition | Year: 2013

Objective: To assess the association between the consumption of sugar-sweetened carbonated beverages (SSCB) and obesity in children and adolescents from Navarra (Spain). Design: We used a matched case-control study design. The exposure, SSCB consumption (1 serving: 200 ml), was measured with a previously validated FFQ. Anthropometrical measures were taken using standardized protocols. The outcome, obesity, was defined as BMI above the age- and sex-specific 97th percentile according to the Spanish reference charts. In the analysis we used conditional logistic regression. Potential confounders were controlled using a multivariable model. Setting: Subjects were recruited in the paediatric departments of the Universidad de Navarra Clinic and the Navarra Hospital Complex, and in three primary health centres of Navarra. Controls were recruited when attending for a routine medical examination or vaccination. Subjects: One hundred and seventy-four obese children and 174 individually sex- and age-matched controls, 52.87% boys, with a mean age of 11.6 years. Exclusion criteria were dietary interventions, exposure to hormone treatment, development of secondary obesity due to endocrinopathy and serious intercurrent illness. Results: Independently of other factors, high consumption of SSCB (>4 servings/week) was significantly associated with obesity (OR = 3.46; 95% CI 1.24, 9.62; P = 0.01). Besides, each additional daily serving of SSCB was associated with a 69% relative increase in the risk of obesity (OR = 1.69; 95% CI 1.04, 2.73; P = 0.03). Conclusions: We found a strong and significant association between SSCB consumption and obesity risk. Our results suggest a monotonic dose-response linear shape for this association in children and adolescents (P for trend = 0.02). © The Authors 2014.

Garcia-Osta A.,Cell Medica | Cuadrado-Tejedor M.,Cell Medica | Garcia-Barroso C.,Cell Medica | Oyarzabal J.,Cell Medica | And 2 more authors.
ACS Chemical Neuroscience | Year: 2012

Alzheimers disease (AD) is the most common form of dementia among the elderly. In AD patients, memory loss is accompanied by the formation of beta-amyloid plaques and the appearance of tau in a pathological form. Given the lack of effective treatments for AD, the development of new management strategies for these patients is critical. The continued failure to find effective therapies using molecules aimed at addressing the anti-beta amyloid pathology has led researchers to focus on other non-amyloid-based approaches to restore memory function. Promising non-amyloid related candidate targets include phosphosdiesterases (PDEs), and indeed, Rolipram, a specific PDE4 inhibitor, was the first compound found to effectively restore cognitive deficits in animal models of AD. More recently, PDE5 inhibitors have also been shown to effectively restore memory function. Accordingly, inhibitors of other members of the PDE family may also improve memory performance in AD and non-AD animal models. Hence, in this review, we will summarize the data supporting the use of PDE inhibitors as cognitive enhancers and we will discuss the possible mechanisms of action underlying these effects. We shall also adopt a medicinal chemistry perspective that leads us to propose the most promising PDE candidates on the basis of inhibitor selectivity, brain distribution, and mechanism of action. © 2012 American Chemical Society.

Rodriguez-Ortigosa C.M.,University of Navarra | Rodriguez-Ortigosa C.M.,Research Center Medica Aplicada | Celay J.,University of Navarra | Olivas I.,University of Navarra | And 12 more authors.
Gastroenterology | Year: 2014

Background & Aims Bile salts inhibit their own production by inducing the nuclear receptor small heterodimer partner (SHP) (encoded by NR0B2), which contributes to repression of the gene encoding cholesterol 7α-hydroxylase (CYP7A1), a key enzyme for the control of bile salt synthesis. On the other hand, bile salts stimulate hepatic synthesis of nitric oxide. We investigated the role of nitric oxide signaling in the control of CYP7A1 expression and the involvement in this process of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), which participates in intracellular propagation of nitric oxide signals.Methods We studied the effects of inhibitors of nitric oxide synthesis (L-NG-nitroarginine methyl ester [L-NAME]) or protein nitrosylation (via dithiothreitol) on bile salt homeostasis in male Wistar rats placed on a cholate-rich diet for 5 days and in cultured primary hepatocytes. S-nitrosylation of GAPDH was assessed using a biotin-switch assay. Interacions of SHP with other proteins and with the Cyp7a1 promoter sequence were studied using immunoprecipitation and chromatin immunoprecipitation (ChIP) assays. We reduced the GAPDH levels in H35 cells with small interfering RNAs. GAPDH nitrosylation was assessed in normal and cholestatic rat and human livers.Results Rats placed on cholate-rich diets and given L-NAME had increased intrahepatic and biliary levels of bile salts, and deficiency in repression of CYP7A1 (at the messenger RNA and protein levels) in liver tissue, despite preserved induction of SHP. In cultured hepatocytes, L-NAME or dithiothreitol blocked cholate-induced down-regulation of CYP7A1 without impairing SHP up-regulation. In hepatocytes, cholate promoted S-nitrosylation of GAPDH and its translocation to the nucleus, accompanied by S-nitrosylation of histone deacetylase 2 (HDAC2) and Sirtuin 1 (SIRT1), deacetylases that participate, respectively, in the formation of Cyp7a1 and Shp repressor complexes. Knockdown of GAPDH prevented repression of CYP7A1 by cholate, and blocking nuclear transport of nitrosylated GAPDH reduced cholate-induced nitrosylation of HDAC2 and SIRT1; this effect was accompanied by abrogation of Cyp7a1 repression. Cholate induced binding of SHP to HDAC2 and its recruitment to the Cyp7a1 promoter; these processes were inhibited by blocking nitric oxide synthesis. Levels of nitrosylated GAPDH and nitrosylated HDAC2 were increased in cholestatic human and rat livers reflecting increased concentrations of bile salts in these conditions.Conclusions In rat liver, excess levels of bile salts activate a GAPDH-mediated transnitrosylation cascade that provides feedback inhibition of bile salt synthesis. © 2014 by the AGA Institute.

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