Phosphodiesterase 2 inhibition preferentially promotes NO/guanylyl cyclase/cGMP signaling to reverse the development of heart failure.

Heart failure (HF) is a shared manifestation of several cardiovascular pathologies, including hypertension and myocardial infarction, and a limited repertoire of treatment modalities entails that the associated morbidity and mortality remain high. Impaired nitric oxide (NO)/guanylyl cyclase (GC)/cyclic guanosine-3',5'-monophosphate (cGMP) signaling, underpinned, in part, by up-regulation of cyclic nucleotide-hydrolyzing phosphodiesterase (PDE) isozymes, contributes to the pathogenesis of HF, and interventions targeted to enhancing cGMP have proven effective in preclinical models and patients. Numerous PDE isozymes coordinate the regulation of cardiac cGMP in the context of HF; PDE2 expression and activity are up-regulated in experimental and human HF, but a well-defined role for this isoform in pathogenesis has yet to be established, certainly in terms of cGMP signaling. Herein, using a selective pharmacological inhibitor of PDE2, BAY 60-7550, and transgenic mice lacking either NO-sensitive GC-1α (GC-1α-/-) or natriuretic peptide-responsive GC-A (GC-A-/-), we demonstrate that the blockade of PDE2 promotes cGMP signaling to offset the pathogenesis of experimental HF (induced by pressure overload or sympathetic hyperactivation), reversing the development of left ventricular hypertrophy, compromised contractility, and cardiac fibrosis. Moreover, we show that this beneficial pharmacodynamic profile is maintained in GC-A-/- mice but is absent in animals null for GC-1α or treated with a NO synthase inhibitor, revealing that PDE2 inhibition preferentially enhances NO/GC/cGMP signaling in the setting of HF to exert wide-ranging protection to preserve cardiac structure and function. These data substantiate the targeting of PDE2 in HF as a tangible approach to maximize myocardial cGMP signaling and enhancing therapy.British Heart Foundation Grant PG/10/077/28554

Generic health literacy measurement instruments for children and adolescents:a systematic review of the literature

Background Health literacy is an important health promotion concern and recently children and adolescents have been the focus of increased academic attention. To assess the health literacy of this population, researchers have been focussing on developing instruments to measure their health literacy. Compared to the wider availability of instruments for adults, only a few tools are known for younger age groups. The objective of this study is to systematically review the field of generic child and adolescent health literacy measurement instruments that are currently available. Method A systematic literature search was undertaken in five databases (PubMed, CINAHL, PsycNET, ERIC, and FIS) on articles published between January 1990 and July 2015, addressing children and adolescents ?18 years old. Eligible articles were analysed, data was extracted, and synthesised according to review objectives. Results Fifteen generic health literacy measurement instruments for children and adolescents were identified. All, except two, are self-administered instruments. Seven are objective measures (performance-based tests), seven are subjective measures (self-reporting), and one uses a mixed-method measurement. Most instruments applied a broad and multidimensional understanding of health literacy. The instruments were developed in eight different countries, with most tools originating in the United States (n =?6). Among the instruments, 31 different components related to health literacy were identified. Accordingly, the studies exhibit a variety of implicit or explicit conceptual and operational definitions, and most instruments have been used in schools and other educational contexts. While the youngest age group studied was 7-year-old children within a parent-child study, there is only one instrument specifically designed for primary school children and none for early years. Conclusions Despite the reported paucity of health literacy research involving children and adolescents, an unexpected number of health literacy measurement studies in children?s populations was found. Most instruments tend to measure their own specific understanding of health literacy and not all provide sufficient conceptual information. To advance health literacy instruments, a much more standardised approach is necessary including improved reporting on the development and validation processes. Further research is required to improve health literacy instruments for children and adolescents and to provide knowledge to inform effective interventionspublishersversionPeer reviewe

Two sulphonated dye compounds which compete for inositol 1,4, 5-trisphosphate binding to rat liver microsomes: effects on 5'-phosphatase activity

The ability of heparin to interact with the Ins 1,4,5-P3 receptor is dependent on its chain length and degree of sulphation. Here we report results obtained with two sulphonated dye compounds of known structures and molecular weights below 1000, cibacron blue and Patent blue. Both compounds compete for Ins 1,4,5-P3 binding to rat liver microsomes and also inhibit Ins 1,4,5-P3 5'-phosphatase activity in the same preparation. Comparison with the effects of heparin show these to be two separate actions of the compounds

The effect of heparin on the inositol 1,4,5-trisphosphate receptor in rat liver microsomes: dependence on sulphate content and chain length

Heparin is known to inhibit the binding of inositol 1,4,5-trisphosphate (Ins 1,4,5-P3) to high-affinity binding sites and to inhibit Ins 1,4,5-P3-induced Ca2+ release from intracellular membrane-bound stores [(1987) J. Biol. Chem. 262, 12132-12136; (1987) FEBS Lett. 228, 57-59]. We have performed studies to clarify the structural requirements for this action of heparin in rat liver microsomes. Both N- and O-linked sulphate groups contribute to binding activity, since de-N-sulphated heparin was without effect on the Ins 1,4,5-P3 receptor whereas a polyxylan bearing only O-linked sulphates (pentosan polysulphate) was as active as heparin. Therefore, the density of negative charge contributed by sulphate groups is important for the binding of heparin. Heparins with high and low affinity for antithrombin III both inhibited Ins 1,4,5-P3 binding. There was a strong dependence on chain length, since binding activity decreased dramatically as the size of the heparin chain was reduced below that of 18-24 monosaccharide units

Ca2+-Independent Alterations in Diastolic Sarcomere Length and Relaxation Kinetics in a Mouse Model of Lipotoxic Diabetic Cardiomyopathy

International audienc

Selectivity Determination of a Small Molecule Chemical Probe Using Protein Microarray and Affinity Capture Techniques

Small molecule selectivity is an essential component of candidate drug selection and target validation. New technologies are required to better understand off-target effects, with particular emphasis needed on broad protein profiling. Here, we describe the use of a tritiated chemical probe and a 9000 human protein microarray to discern the binding selectivity of an inhibitor of the mRNA decapping scavenger enzyme DcpS. An immobilized m⁷GTP resin was also used to assess the selectivity of a DcpS inhibitor against mRNA cap-associated proteins in whole cell extracts. These studies confirm the exquisite selectivity of diaminoquinazoline DcpS inhibitors, and highlight the utility of relatively simple protein microarray and affinity enrichment technologies in drug discovery and chemical biology