Na + /H + exchanger isoform 1-induced osteopontin expression facilitates cardiac hypertrophy through p90 ribosomal S6 kinase

Cardiovascular diseases are the leading cause of death worldwide. One in three cases of heart failure is due to dilated cardiomyopathy. The Na+/H+ exchanger isoform 1 (NHE1), a multifunctional protein and the key pH regulator in the heart, has been demonstrated to be increased in this condition. We have previously demonstrated that elevated NHE1 activity induced cardiac hypertrophy in vivo. Furthermore, the overexpression of active NHE1 elicited modulation of gene expression in cardiomyocytes including an upregulation of myocardial osteopontin (OPN) expression. To determine the role of OPN in inducing NHE1-mediated cardiomyocyte hypertrophy, double transgenic mice expressing active NHE1 and OPN knockout were generated and assessed by echocardiography and the cardiac phenotype. Our studies showed that hearts expressing active NHE1 exhibited cardiac remodeling indicated by increased systolic and diastolic left ventricular internal diameter and increased ventricular volume. Moreover, these hearts demonstrated impaired function with decreased fractional shortening and ejection fraction. Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) mRNA was upregulated, and there was an increase in heart cell cross-sectional area confirming the cardiac hypertrophic effect. Moreover, NHE1 transgenic mice also showed increased collagen deposition, upregulation of CD44 and phosphorylation of p90 ribosomal s6 kinase (RSK), effects that were regressed in OPN knockout mice. In conclusion, we developed an interesting comparative model of active NHE1 transgenic mouse lines which express a dilated hypertrophic phenotype expressing CD44 and phosphorylated RSK, effects which were regressed in absence of OPN.Scopu

Enhanced direct oxidation of diclofenac (DCF) at a carbon paste electrode (CPE) modified with cellulose and its biodegradability by Scedosporium dehoogii

A novel carbon paste electrode modified with cellulose fibers and dedicated to diclofenac electroanalysis was prepared, optimized, and used for the determination of the kinetic parameters of DCF biodegradation by a filamentous fungus. The electrochemical response of the modified CPE was compared to that of the unmodified. This study conducted by cyclic voltammetry and linear sweep voltammetry allowed the optimization of the cellulose fibers modified CPE in terms of absence/presence of cellulose fibers, accumulation time (250 s), and initial potential (- 0.4 V/Ag/AgCl). Interestingly, in these conditions, the limit of detection observed through linear sweet voltammetry was found to be as low as 0.020 µmol L-1. This electrode was then used to follow the degradation of DCF. Our results demonstrated that among species belonging to the Scedosporium genus, S. dehoogii displayed the best assets in our process in terms of growth temperature and ability to metabolize DCF. More precisely, DCF biodegradation using S. dehoogii in the process revealed a kinetic of order of 1, a kinetic constant k of 0.012 day-1 and a half time of 57.8 days for an initial concentration of DCF of 1.65 ± 0.05 mg L-1 and at a temperature of 25°C. This study constitutes a solid proof of concept for future developments of fungal wastewater treatments for bioremediation of DCF which is refractory to standard bacterial-based bioprocesses

Follicular fluid high density lipoprotein-associated micronutrient levels are associated with embryo fragmentation during IVF

To investigate whether follicular fluid lipid-soluble micronutrients are associated with embryo morphology parameters during IVF. Follicle fluid and oocytes were obtained prospectively from 81 women. Embryo morphology parameters were used as surrogate markers of oocyte health. HDL lipids and lipid-soluble micronutrients were analyzed by high-pressure liquid chromatography. Non-parametric bi-variate analysis and multivariable ordinal logistic regression models were employed to examine associations between biochemical and embryo morphology parameters. Follicular fluid HDL cholesterol (r = −0.47, p < 0.01), α-tocopherol (r = −0.41, p < 0.01), δ-tocopherol (r = −0.38, p < 0.05) and β-cryptoxanthine (r = −0.42, p < 0.01) are negatively correlated with embryo fragmentation. Ordinal logistic regression models indicate that a 0.1 μmol/L increase in β-cryptoxanthine, adjusted for γ-tocopherol, is associated with a 75% decrease in the cumulative odds of higher embryo fragmentation (p = 0.010). Follicular fluid HDL micronutrients may play an important role in the development of the human oocyte as evident by embryo fragmentation during IVF

Fzd7 (Frizzled-7) Expressed by Endothelial Cells Controls Blood Vessel Formation Through Wnt/β-Catenin Canonical Signaling.

Abstract OBJECTIVE: Vessel formation requires precise orchestration of a series of morphometric and molecular events controlled by a multitude of angiogenic factors and morphogens. Wnt/frizzled signaling is required for proper vascular formation. In this study, we investigated the role of the Fzd7 (frizzled-7) receptor in retinal vascular development and its relationship with the Wnt/β-catenin canonical pathway and Notch signaling. APPROACH AND RESULTS: Using transgenic mice, we demonstrated that Fzd7 is required for postnatal vascular formation. Endothelial cell (EC) deletion of fzd7 (fzd7ECKO) delayed retinal plexus formation because of an impairment in tip cell phenotype and a decrease in stalk cell proliferation. Dvl (dishevelled) proteins are a main component of Wnt signaling and play a functionally redundant role. We found that Dvl3 depletion in dvl1-/- mice mimicked the fzd7ECKO vascular phenotype and demonstrated that Fzd7 acted via β-catenin activation by showing that LiCl treatment rescued impairment in tip and stalk cell phenotypes induced in fzd7 mutants. Deletion of fzd7 or Dvl1/3 induced a strong decrease in Wnt canonical genes and Notch partners' expression. Genetic and pharmacological rescue strategies demonstrated that Fzd7 acted via β-catenin activation, upstream of Notch signaling to control Dll4 and Jagged1 EC expression. CONCLUSIONS: Fzd7 expressed by EC drives postnatal angiogenesis via activation of Dvl/β-catenin signaling and can control the integrative interaction of Wnt and Notch signaling during postnatal angiogenesis

Angiotensin-Converting Enzyme (ACE) Gene Insertion/Deletion Polymorphism and ACE Inhibitor-Related Cough: A Meta-Analysis

Objective: An insertion/deletion (I/D) variant in the angiotensin-converting enzyme (ACE) gene was associated with ACE inhibitor (ACEI)-related cough in previous studies. However, the results were inconsistent. Our objective was to assess the relationship between the ACE I/D polymorphism and ACEI-related cough by meta-analysis and to summarize all studies that are related to ACE I/D polymorphism and ACEI-cough and make a summary conclusion to provide reference for the researchers who attempt to conduct such a study. Methods: Databases including PubMed, EMbase, Cochrane Library, and China National Knowledge Infrastructure, were searched for genetic association studies. Data were extracted by two independent authors and pooled odds ratio (OR) with 95% confidence interval (CI) was calculated. Metaregression and subgroup analyses were performed to identify the source of heterogeneity. Results: Eleven trials, including 906 cases (ACEI-related cough) and 1,175 controls, were reviewed in the present meta-analysis. The random effects pooled OR was 1.16 (95% CI: 0.78-1.74, p = 0.46) in the dominant model and 1.61 (95% CI: 1.18-2.20, p = 0.003) in the recessive model. Heterogeneity was found among and within studies. Metaregression indicated that the effect size was positively associated with age and negatively associated with follow-up duration of ACEI treatment. Subgroup analysis revealed a significant association between ACE I/D polymorphism and ACEI-related cough in studies with mean age >60 y, but not in studies with mean age 2 mo or in studies in Caucasians. No heterogeneity was detected in these two subgroups. Conclusions: Synthesis of the available evidence supports ACE I/D polymorphism as an age-dependent predictor for risk of ACEI-related cough

Human physiologically based pharmacokinetic model for ACE inhibitors: ramipril and ramiprilat

BACKGROUND: The angiotensin-converting enzyme (ACE) inhibitors have complicated and poorly characterized pharmacokinetics. There are two binding sites per ACE (high affinity "C", lower affinity "N") that have sub-nanomolar affinities and dissociation rates of hours. Most inhibitors are given orally in a prodrug form that is systemically converted to the active form. This paper describes the first human physiologically based pharmacokinetic (PBPK) model of this drug class. METHODS: The model was applied to the experimental data of van Griensven et. al for the pharmacokinetics of ramiprilat and its prodrug ramipril. It describes the time course of the inhibition of the N and C ACE sites in plasma and the different tissues. The model includes: 1) two independent ACE binding sites; 2) non-equilibrium time dependent binding; 3) liver and kidney ramipril intracellular uptake, conversion to ramiprilat and extrusion from the cell; 4) intestinal ramipril absorption. The experimental in vitro ramiprilat/ACE binding kinetics at 4°C and 300 mM NaCl were assumed for most of the PBPK calculations. The model was incorporated into the freely distributed PBPK program PKQuest. RESULTS: The PBPK model provides an accurate description of the individual variation of the plasma ramipril and ramiprilat and the ramiprilat renal clearance following IV ramiprilat and IV and oral ramipril. Summary of model features: Less than 2% of total body ACE is in plasma; 35% of the oral dose is absorbed; 75% of the ramipril metabolism is hepatic and 25% of this is converted to systemic ramiprilat; 100% of renal ramipril metabolism is converted to systemic ramiprilat. The inhibition was long lasting, with 80% of the C site and 33% of the N site inhibited 24 hours following a 2.5 mg oral ramipril dose. The plasma ACE inhibition determined by the standard assay is significantly less than the true in vivo inhibition because of assay dilution. CONCLUSION: If the in vitro plasma binding kinetics of the ACE inhibitor for the two binding sites are known, a unique PBPK model description of the Griensven et. al. experimental data can be obtained

Promoción de la salud y entornos saludables

A forestar forestalAplicación de un programa educativo participativo en salud  bucal a una comunidad de adultos mayoresBiblioteca móvil y su implementación en el hospital Padre HurtadoConsumo de riesgo de alcohol en Chile: una propuesta innovadora de intervenciónDiseño de un programa interactivo de promoción de la salud vocal para NB1Encuentro formativo en promoción de salud y gestión de entornos saludables para TenoExperiencia docente: programa intersectorial de promoción/prevención en preescolares de comunas vulnerables, Región MetropolitanaFiltrado glomerular, método preventivo aparición de fibrosis sistémica nefrogénica por gadolinio en examen de RMImplementación de consejerías en vida sana en APS, Región de los RíosMedicina preventiva en feria libre de la población San Gregorio: Cecof San Gregorio, Contagiando SaludMetodología innovadora en la enseñanza de una ectoparasitosisPrevención de accidentes por monóxido de carbono en edificios, Providencia 2002-2009Programa de promoción y prevención en salud bucal para preescolaresPromoviendo hábitos saludables en los vecinos de Reñaca Alto, Viña del Mar, 2009Rol de la capacitación en la implementación de acciones para la prevención de la obesidadSatisfacción usuaria en el Cesfam Natales a un año de su funcionamientoTres estrategias publicitarias y de comunicación aplicadas al consumo de alcohol de bajo riesgoTropa de la salud: uso de los medios como forma de promover la salu

Computational and Statistical Analyses of Amino Acid Usage and Physico-Chemical Properties of the Twelve Late Embryogenesis Abundant Protein Classes

Late Embryogenesis Abundant Proteins (LEAPs) are ubiquitous proteins expected to play major roles in desiccation tolerance. Little is known about their structure - function relationships because of the scarcity of 3-D structures for LEAPs. The previous building of LEAPdb, a database dedicated to LEAPs from plants and other organisms, led to the classification of 710 LEAPs into 12 non-overlapping classes with distinct properties. Using this resource, numerous physico-chemical properties of LEAPs and amino acid usage by LEAPs have been computed and statistically analyzed, revealing distinctive features for each class. This unprecedented analysis allowed a rigorous characterization of the 12 LEAP classes, which differed also in multiple structural and physico-chemical features. Although most LEAPs can be predicted as intrinsically disordered proteins, the analysis indicates that LEAP class 7 (PF03168) and probably LEAP class 11 (PF04927) are natively folded proteins. This study thus provides a detailed description of the structural properties of this protein family opening the path toward further LEAP structure - function analysis. Finally, since each LEAP class can be clearly characterized by a unique set of physico-chemical properties, this will allow development of software to predict proteins as LEAPs

The kallikrein–kinin system in diabetic nephropathy

Diabetic nephropathy is the major cause of end-stage renal disease worldwide. Although the renin-angiotensin system has been implicated in the pathogenesis of diabetic nephropathy, angiotensin I-converting enzyme (ACE) inhibitors have a beneficial effect on diabetic nephropathy independently of their effects on blood pressure and plasma angiotensin II levels. This suggests that the kallikrein-kinin system (KKS) is also involved in the disease. To study the role of the KKS in diabetic nephropathy, mice lacking either the bradykinin B1 receptor (B1R) or the bradykinin B2 receptor (B2R) have been commonly used. However, because absence of either receptor causes enhanced expression of the other, it is difficult to determine the precise functions of each receptor. This difficulty has recently been overcome by comparing mice lacking both receptors with mice lacking each receptor. Deletion of both B1R and B2R reduces nitric oxide (NO) production and aggravates renal diabetic phenotypes, relevant to either lack of B1R or B2R, demonstrating that both B1R and B2R exert protective effects on diabetic nephropathy presumably via NO. Here, we review previous epidemiological and experimental studies, and discuss novel insights regarding the therapeutic implications of the importance of the KKS in averting diabetic nephropathy