Exendin-4 Protects Oxidative Stress-Induced β-Cell Apoptosis through Reduced JNK and GSK3β Activity

Oxidative stress induced by chronic hyperglycemia in type 2 diabetes plays a crucial role in progressive loss of β-cell mass through β-cell apoptosis. Glucagon like peptide-1 (GLP-1) has effects on preservation of β-cell mass and its insulin secretory function. GLP-1 possibly increases islet cell mass through stimulated proliferation from β-cell and differentiation to β-cell from progenitor cells. Also, it probably has an antiapoptotic effect on β-cell, but detailed mechanisms are not proven. Therefore, we examined the protective mechanism of GLP-1 in β-cell after induction of oxidative stress. The cell apoptosis decreased to ~50% when cells were treated with 100 µM H2O2 for up to 2 hr. After pretreatment of Ex-4, GLP-1 receptor agonist, flow cytometric analysis shows 41.7% reduction of β-cell apoptosis. This data suggested that pretreatment of Ex-4 protect from oxidative stress-induced apoptosis. Also, Ex-4 treatment decreased GSK3β activation, JNK phosphorylation and caspase-9, -3 activation and recovered the expression of insulin2 mRNA in β-cell lines and secretion of insulin in human islet. These results suggest that Ex-4 may protect β-cell apoptosis by blocking the JNK and GSK3β mediated apoptotic pathway

ENPP1 Affects Insulin Action and Secretion: Evidences from In Vitro Studies

The aim of this study was to deeper investigate the mechanisms through which ENPP1, a negative modulator of insulin receptor (IR) activation, plays a role on insulin signaling, insulin secretion and eventually glucose metabolism. ENPP1 cDNA (carrying either K121 or Q121 variant) was transfected in HepG2 liver-, L6 skeletal muscle- and INS1E beta-cells. Insulin-induced IR-autophosphorylation (HepG2, L6, INS1E), Akt-Ser473, ERK1/2-Thr202/Tyr204 and GSK3-beta Ser9 phosphorylation (HepG2, L6), PEPCK mRNA levels (HepG2) and 2-deoxy-D-glucose uptake (L6) was studied. GLUT 4 mRNA (L6), insulin secretion and caspase-3 activation (INS1E) were also investigated. Insulin-induced IR-autophosphorylation was decreased in HepG2-K, L6-K, INS1E-K (20%, 52% and 11% reduction vs. untransfected cells) and twice as much in HepG2-Q, L6-Q, INS1E-Q (44%, 92% and 30%). Similar data were obtained with Akt-Ser473, ERK1/2-Thr202/Tyr204 and GSK3-beta Ser9 in HepG2 and L6. Insulin-induced reduction of PEPCK mRNA was progressively lower in untransfected, HepG2-K and HepG2-Q cells (65%, 54%, 23%). Insulin-induced glucose uptake in untransfected L6 (60% increase over basal), was totally abolished in L6-K and L6-Q cells. GLUT 4 mRNA was slightly reduced in L6-K and twice as much in L6-Q (13% and 25% reduction vs. untransfected cells). Glucose-induced insulin secretion was 60% reduced in INS1E-K and almost abolished in INS1E-Q. Serum deficiency activated caspase-3 by two, three and four folds in untransfected INS1E, INS1E-K and INS1E-Q. Glyburide-induced insulin secretion was reduced by 50% in isolated human islets from homozygous QQ donors as compared to those from KK and KQ individuals. Our data clearly indicate that ENPP1, especially when the Q121 variant is operating, affects insulin signaling and glucose metabolism in skeletal muscle- and liver-cells and both function and survival of insulin secreting beta-cells, thus representing a strong pathogenic factor predisposing to insulin resistance, defective insulin secretion and glucose metabolism abnormalities

The Glycosyltransferase Repertoire of the Spikemoss Selaginella moellendorffii and a Comparative Study of Its Cell Wall

Spike mosses are among the most basal vascular plants, and one species, Selaginella moellendorffii, was recently selected for full genome sequencing by the Joint Genome Institute (JGI). Glycosyltransferases (GTs) are involved in many aspects of a plant life, including cell wall biosynthesis, protein glycosylation, primary and secondary metabolism. Here, we present a comparative study of the S. moellendorffii genome across 92 GT families and an additional family (DUF266) likely to include GTs. The study encompasses the moss Physcomitrella patens, a non-vascular land plant, while rice and Arabidopsis represent commelinid and non-commelinid seed plants. Analysis of the subset of GT-families particularly relevant to cell wall polysaccharide biosynthesis was complemented by a detailed analysis of S. moellendorffii cell walls. The S. moellendorffii cell wall contains many of the same components as seed plant cell walls, but appears to differ somewhat in its detailed architecture. The S. moellendorffii genome encodes fewer GTs (287 GTs including DUF266s) than the reference genomes. In a few families, notably GT51 and GT78, S. moellendorffii GTs have no higher plant orthologs, but in most families S. moellendorffii GTs have clear orthologies with Arabidopsis and rice. A gene naming convention of GTs is proposed which takes orthologies and GT-family membership into account. The evolutionary significance of apparently modern and ancient traits in S. moellendorffii is discussed, as is its use as a reference organism for functional annotation of GTs

Changes in seasonal streamflow extremes experienced in rivers of Northwestern South America (Colombia)

A measure of the variability in seasonal extreme streamflow was estimated for the Colombian Caribbean coast, using monthly time series of freshwater discharge from ten watersheds. The aim was to detect modifications in the streamflow monthly distribution, seasonal trends, variance and extreme monthly values. A 20-year length time moving window, with 1-year successive shiftments, was applied to the monthly series to analyze the seasonal variability of streamflow. The seasonal-windowed data were statistically fitted through the Gamma distribution function. Scale and shape parameters were computed using the Maximum Likelihood Estimation (MLE) and the bootstrap method for 1000 resample. A trend analysis was performed for each windowed-serie, allowing to detect the window of maximum absolute values for trends. Significant temporal shifts in seasonal streamflow distribution and quantiles (QT), were obtained for different frequencies. Wet and dry extremes periods increased significantly in the last decades. Such increase did not occur simultaneously through the region. Some locations exhibited continuous increases only at minimum QT

The many meanings of evidence: a comparative analysis of the forms and roles of evidence within three health policy processes in Cambodia

Background Discussions within the health community routinely emphasise the importance of evidence in informing policy formulation and implementation. Much of the support for the evidence-based policy movement draws from concern that policy decisions are often based on inadequate engagement with high-quality evidence. In many such discussions, evidence is treated as differing only in quality, and assumed to improve decisions if it can only be used more. In contrast, political science scholars have described this as an overly simplistic view of the policy-making process, noting that research ‘use’ can mean a variety of things and rely on nuanced aspects of political systems. An approach more in recognition of how policy-making systems operate in practice can be to consider how institutions and ideas influence which pieces of evidence appear to be relevant for, and are used within, different policy processes. Methods Drawing on in-depth interviews undertaken in 2015/16 with key health sector stakeholders in Cambodia, we investigate the evidence perceived to be relevant to policy decisions for three contrasting health policy examples – tobacco control, HIV/AIDS and performance-based salary incentives. These cases allow us to examine the ways that policy relevant evidence may differ given the framing of the issue and the broader institutional context in which evidence is considered. Results The three health issues show few similarities in how pieces of evidence were used in various aspects of policy-making, despite all being discussed within a broad policy environment in which evidence-based policymaking is rhetorically championed. Instead, we find that evidence use can be better understood by mapping how these health policy issues differ in terms of the issue characteristics, and also in terms of the stakeholders structurally established as having dominant influence for each issue. Both of these have important implications for evidence use. Contrasting concerns of key stakeholders meant that evidence related to differing issues could be understood in terms of how it was policy relevant. The stakeholders involved, however, could further be seen to possess differing logics about how to go about achieving their various outcomes – logics that could further help explain the differences seen in evidence utilisation. Conclusion A comparative approach reiterates that evidence is not a uniform concept for which more is obviously better, but rather illustrates how different constructions and pieces of evidence become relevant in relation to the features of specific health policy decisions. An institutional approach that considers the structural position of stakeholders with differing core goals or objectives, as well as their logics related to evidence utilisation, can further help to understand some of the complexities of evidence use in health policymaking

Human matrix metalloproteinases: An ubiquitarian class of enzymes involved in several pathological processes

Human matrix metalloproteinases (MMPs) belong to the M10 family of the MA clan of endopeptidases. They are ubiquitarian enzymes, structurally characterized by an active site where a Zn(2+) atom, coordinated by three histidines, plays the catalytic role, assisted by a glutamic acid as a general base. Various MMPs display different domain composition, which is very important for macromolecular substrates recognition. Substrate specificity is very different among MMPs, being often associated to their cellular compartmentalization and/or cellular type where they are expressed. An extensive review of the different MMPs structural and functional features is integrated with their pathological role in several types of diseases, spanning from cancer to cardiovascular diseases and to neurodegeneration. It emerges a very complex and crucial role played by these enzymes in many physiological and pathological processes