The role of DPP4 activity in cardiovascular districts: in vivo and in vitro evidence.

The introduction of incretin hormone-based therapies represents a novel therapeutic strategy, since these drugs not only improve glycemia with minimal risk of hypoglycemia, but also have other extraglycemic beneficial effects. These agents, which are effective in improving glucose control, could also have positive effects on the incidence of cardiovascular events. The aim of this review is to summarize the present literature about the role of dipeptidyl peptidase 4 (DPP4) in cardiovascular districts, not only strictly correlated to its effect on glucagon-like peptide-1 (GLP-1) circulating levels, but also to what is known about possible cardiovascular actions. Actually, DPP4 is known to be present in many cells and tissues and its effects go beyond purely metabolic aspects. Almost always the inhibition of DPP4 activity is associated with improved cardiovascular profile, but it has shown to possess antithrombotic properties and these different effects could be connected with a site and/or species specificity of DPP4. Certainly, DPP4 seems to exert many functions, both directly and indirectly, on cardiovascular districts, opening new possibilities of prevention and treatment of complications at this level, not only in patients affected by diabetes mellitus

The "Click-tail approach" for the design and synthesis of novel carbonic anhydrase inhibitors

The Carbonic Anhydrases (CAs) are a family of zinc enzymes deputed to the interconversion of carbonic dioxide to hydrogen carbonate. Herein, we report on a sustainable modular strategy, also called "clicktail approach", used to obtain two series of 4-(4-substituted-lH-l,2,3-triazol-lyl) benzenesulfonamides. Design and synthesis strategies, x-ray derived CA-ligand binding mode and enzyme-based inhibition results will be presented

From Theory to Clinical Practice in the Use of GLP-1 Receptor Agonists and DPP-4 Inhibitors Therapy

Promoting long-term adherence to lifestyle modification and choice of antidiabetic agent with low hypoglycemia risk profile and positive weight profile could be the most effective strategy in achieving sustained glycemic control and in reducing comorbidities. From this perspective, vast interest has been generated by glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 inhibitors (DPP-4i). In this review our ten-year clinical and laboratory experience by in vitro and in vivo studies is reported. Herein, we reviewed available data on the efficacy and safety profile of GLP-1 receptor agonists and DPP-4i. The introduction of incretin hormone-based therapies represents a novel therapeutic strategy, because these drugs not only improve glycemia with minimal risk of hypoglycemia but also have other extraglycemic beneficial effects. In clinical studies, both GLP-1 receptor agonists and DPP-4i, improve β cell function indexes. All these agents showed trophic effects on beta-cell mass in animal studies. The use of these drugs is associated with positive or neucral effect on body weight and improvements in blood pressure, diabetic dyslipidemia, hepatic steazosis markets, and myocardial function. These effects have the potential to reduce the burden of cardiovascular disease, which is a major cause of mortality in patients with diabetes

Valutazione sismica di edifici in c.a. anni '60: il complesso comunale di Piazza Risorgimento a Rosignano Solvay

Studio dell'edificio su piazza Risorgimento (struttura itelaiata in c.a. anni '50). Analisi sismica (dinamica modale) dello stato attuale. Proposte di intervento di adeguamento sismico

Src kinase inhibition promotes the chondrocyte phenotype

Regulated differentiation of chondrocytes is essential for both normal skeletal development and maintenance of articular cartilage. The intracellular pathways that control these events are incompletely understood, and our ability to modulate the chondrocyte phenotype in vivo or in vitro is therefore limited. Here we examine the role played by one prominent group of intracellular signalling proteins, the Src family kinases, in regulating the chondrocyte phenotype. We show that the Src family kinase Lyn exhibits a dynamic expression pattern in the chondrogenic cell line ATDC5 and in a mixed population of embryonic mouse chondrocytes in high-density monolayer culture. Inhibition of Src kinase activity using the pharmacological compound PP2 (4-Amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo [3,4-d]pyrimidine) strongly reduced the number of primary mouse chondrocytes. In parallel, PP2 treatment increased the expression of both early markers (such as Sox9, collagen type II, aggrecan and xylosyltransferases) and late markers (collagen type X, Indian hedgehog and p57) markers of chondrocyte differentiation. Interestingly, PP2 repressed the expression of the Src family members Lyn, Frk and Hck. It also reversed morphological de-differentiation of chondrocytes in monolayer culture and induced rounding of chondrocytes, and reduced stress fibre formation and focal adhesion kinase phosphorylation. We conclude that the Src kinase inhibitor PP2 promotes chondrogenic gene expression and morphology in monolayer culture. Strategies to block Src activity might therefore be useful both in tissue engineering of cartilage and in the maintenance of the chondrocyte phenotype in diseases such as osteoarthritis

Mendelian breeding units <i>versus</i> standard sampling strategies: mitochondrial DNA variation in southwest Sardinia

We report a sampling strategy based on Mendelian Breeding Units (MBUs), representing an interbreeding group of individuals sharing a common gene pool. The identification of MBUs is crucial for case-control experimental design in association studies. The aim of this work was to evaluate the possible existence of bias in terms of genetic variability and haplogroup frequencies in the MBU sample, due to severe sample selection. In order to reach this goal, the MBU sampling strategy was compared to a standard selection of individuals according to their surname and place of birth. We analysed mitochondrial DNA variation (first hypervariable segment and coding region) in unrelated healthy subjects from two different areas of Sardinia: the area around the town of Cabras and the western Campidano area. No statistically significant differences were observed when the two sampling methods were compared, indicating that the stringent sample selection needed to establish a MBU does not alter original genetic variability and haplogroup distribution. Therefore, the MBU sampling strategy can be considered a useful tool in association studies of complex traits

The impact of a microsavings intervention on reducing violence against women engaged in sex work: a randomized controlled study

Background Women who engage in sex work are at risk for experiencing violence from numerous perpetrators, including paying partners. Empirical evidence has shown mixed results regarding the impact of participation in microfinance interventions on women’s experiences of violence, with some studies demonstrating reductions in intimate partner violence (IPV) and others showing heightened risk for IPV. The current study reports on the impact of participation in a microsavings intervention on experiences of paying partner violence among women engaged in sex work in Mongolia. Methods Between 2011 and 2013, we conducted a two-arm, non-blinded randomized controlled trial (RCT) comparing an HIV/STI risk reduction intervention (HIVSRR) (control condition) to a combined microsavings and HIVSRR intervention (treatment condition). Eligible women (aged 18 or older, reported having engaged in unprotected sex with paying partner in past 90 days, expressed interest in microsavings intervention) were invited to participate. One hundred seven were randomized, including 50 in the control and 57 in the treatment condition. Participants completed assessments at baseline, immediate post-test following HIVSRR, and at 3-months and 6-months after completion of the treatment group intervention. Outcomes for the current study include any violence (physical and/or sexual), sexual violence, and physical violence from paying partners in the past 90 days. Results An intention-to-treat approach was utilized. Linear growth models revealed significant reductions over time in both conditions for any violence (β = −0.867, p < 0.001), physical violence (β = −0.0923, p < 0.001), and sexual violence (β = −1.639, p = 0.001) from paying partners. No significant differences between groups were found for any violence (β = 0.118, p = 0.389), physical violence (β = 0.091, p = 0.792), or sexual violence (β = 0.379, p = 0.114) from paying partners. Conclusions Microsavings participation did not significantly impact women’s risk for paying partner violence. Qualitative research is recommended to understand the cause for reductions in paying partner violence in both study conditions

Serum S-100B adds incremental value for the prediction of symptomatic intracranial hemorrhage and brain edema after acute ischemic stroke

Brain edema; Intracranial hemorrhage; Serum biomarkerEdema cerebral; Hemorragia intracraneal; Biomarcador séricoEdema cerebral; Hemorràgia intracranial; Biomarcador sèricBackground: Early identification of patients developing symptomatic intracranial hemorrhage and symptomatic brain edema after acute ischemic stroke is essential for clinical decision-making. Astroglial protein S-100B is a marker of blood-brain barrier disruption, which plays an important role in the formation of intracranial hemorrhage and brain edema. In this study, we assessed the prognostic value of serum S-100B for the development of these complications. Methods: Serum S-100B levels were measured within 24 h from symptom onset in 1749 consecutive acute ischemic stroke patients from the prospective, observational, multicenter BIOSIGNAL cohort study (mean age 72.0 years, 58.3% male). To determine symptomatic intracranial hemorrhage or symptomatic brain edema, follow-up neuroimaging was performed in all patients receiving reperfusion therapy or experiencing clinical worsening with an NIHSS increase of ⩾4. Results: Forty six patients (2.6%) developed symptomatic intracranial hemorrhage and 90 patients (5.2%) developed symptomatic brain edema. After adjustment for established risk factors, log10S-100B levels remained independently associated with both symptomatic intracranial hemorrhage (OR 3.41, 95% CI 1.7–6.9, p = 0.001) and symptomatic brain edema (OR 4.08, 95% CI 2.3–7.1, p < 0.001) in multivariable logistic regression models. Adding S-100B to the clinical prediction model increased the AUC from 0.72 to 0.75 (p = 0.001) for symptomatic intracranial hemorrhage and from 0.78 to 0.81 (p < 0.0001) for symptomatic brain edema. Conclusions: Serum S-100B levels measured within 24 h after symptom onset are independently associated with the development of symptomatic intracranial hemorrhage and symptomatic brain edema in acute ischemic stroke patients. Thus, S-100B may be useful for early risk-stratification regarding stroke complications.This study was supported with research grants from the Swiss National Science Foundation (142422), the Swiss Heart Foundation, the Göhner Foundation and the Swiss Seaside Foundation