Monoamine oxidase-dependent endoplasmic reticulum-mitochondria dysfunction and mast cell degranulation lead to adverse cardiac remodeling in diabetes.

Monoamine oxidase (MAO) inhibitors ameliorate contractile function in diabetic animals, but the mechanisms remain unknown. Equally elusive is the interplay between the cardiomyocyte alterations induced by hyperglycemia and the accompanying inflammation. Here we show that exposure of primary cardiomyocytes to high glucose and pro-inflammatory stimuli leads to MAO-dependent increase in reactive oxygen species that causes permeability transition pore opening and mitochondrial dysfunction. These events occur upstream of endoplasmic reticulum (ER) stress and are abolished by the MAO inhibitor pargyline, highlighting the role of these flavoenzymes in the ER/mitochondria cross-talk. In vivo, streptozotocin administration to mice induced oxidative changes and ER stress in the heart, events that were abolished by pargyline. Moreover, MAO inhibition prevented both mast cell degranulation and altered collagen deposition, thereby normalizing diastolic function. Taken together, these results elucidate the mechanisms underlying MAO-induced damage in diabetic cardiomyopathy and provide novel evidence for the role of MAOs in inflammation and inter-organelle communication. MAO inhibitors may be considered as a therapeutic option for diabetic complications as well as for other disorders in which mast cell degranulation is a dominant phenomenon

Synthetic methodologies and structures of metal-[c-60]fullerene complexes

A review of the chemistry of transition metal-[C-60] fullerene complexes is presented. The main focus is directed toward the different methodologies for obtaining both metal bound and ligand bound complexes of C-60, and the different types of structures which have been so far identified for metal-C-60 complexes

GPGPU based Dual Population Genetic Algorithm for solving Constrained Optimization Problem

Dual Population Genetic Algorithm is a variant of Genetic Algorithm that provides additional diversity to the main population. It covers the premature convergence problem as well as the diversity problem associated with Genetic Algorithm. But also its additional population introduces large search space that increases time required to find an optimal solution. This large scale search space problem can be easily solved using consumer-level graphics cards. The solution obtained using accelerated DPGA for solving a constrained optimization problem from CEC 2006 is compared with the obtained solution using sequential algorithm. The results show speed up maintaining solution quality.</jats:p

EXPLORATION OF STABILITY-INDICATING ASSAY UHPLC METHOD FOR SIMULTANEOUS ANALYSIS OF SITAGLIPTIN AND METFORMIN IN PURE MATERIAL AND PHARMACEUTICAL DOSAGE FORMS

The scientific novelty of designed work was to develop a specific and precise stability-indicating ultra high performance liquid chromatography (UHPLC) assay method for simultaneous quantification of Sitagliptin and Metforminin extendedrelease fixed dose combinations (FDCs). The reversed-phase UHPLC resolution was analyzed with the assistance of UPLC BEH C18 (150 mm 2.1 mm) with 1.7 µm particle size column at ambient temperature using a solvent system in a proportion of (90:10 % v/v) acetonitrile: potassium dihydrogen orthophosphate buffer; pH 3.0±0.2 was adjusted with 0.1 % ortho phosphoric acid (OPA), with flow rate of 0.4 mL/min of the solvent system. The analytes were supervised at 267 nm by employing photodiode array recognition. The retention times of Sitagliptin and Metformin were found to be1.903±0.01 and 1.301±0.022, respectively. The Sitagliptin and Metformin have confirmed the linearity ranges of 5- 30μg/mL, and 100-600 μg/mL respectively, with 0.9996 and 0.9996 determination coefficients. The UHPLC method was effectually validated concerning the accuracy, precision, sensitivity, robustness, ruggedness, selectivity, and specificity. Moreover, the anticipated UHPLC method's capability to analyze the Sitagliptin and Metformin with no obstruction from degradation products.</jats:p

Dual Population Genetic Algorithm for Solving Constrained Optimization Problems

Dual Population Genetic Algorithm is an effective optimization algorithm that provides additional diversity to the main population. It addresses the premature convergence problem as well as the diversity problem associated with Genetic Algorithm. Thus it restricts their individuals to be trapped in the local optima. This paper proposes Dual Population Genetic Algorithm for solving Constrained Optimization Problems. A novel method based on maximum constrains satisfaction is applied as constrains handling technique and Dual Population Genetic Algorithm is used as meta-heuristic. This method is verified against 9 problems from Problem Definitions and Evaluation Criteria for the Congress on Evolutionary Computation 2006 Special Session on Constrained Real-Parameter Optimization problem set. The results are compared with existing algorithms such as Ant Bee Colony Algorithm, Differential Evolution Algorithm and Genetic Algorithm that have been used for solving same problem set. Analysis shows that this technique gives results close to optimum value but fails to obtain exact optimum solution. In future Dual Population Genetic Algorithm can produce more efficient solutions using alternative constrains handling technique

Abstract 530: Cardiac Fibroblast GSK-3α Contributes to Ventricular Remodeling and Dysfunction of the Failing Heart

Background: Heart failure is the leading cause of mortality, morbidity, and healthcare expenditures worldwide. Numerous studies from our lab and others have implicated Glycogen Synthase Kinase-3 (GSK-3) as a promising therapeutic target for cardiovascular diseases. GSK-3 isoforms appear to play overlapping, unique and even opposing functions in the heart. Recently our group has identified cardiac fibroblast (CF) GSK-3β as a negative regulator of fibrotic remodeling in the ischemic heart. However, the role of CF-GSK-3α in cardiac pathophysiology is poorly understood. Methods and Results: To determine the role of CF-GSK-3α in the pathogenesis of heart failure, GSK -3α was deleted specifically from mouse resident cardiac fibroblast or myofibroblast with tamoxifen-inducible TCF21- or periostin (Postn)- promoter-driven Cre recombinase. At 2 months of age, WT and KO mice were subjected to cardiac injury and heart functions were monitored by serial echocardiography. Histological analysis and morphometric studies were performed at 8 weeks post-injury. In TCF21-KO mice, deletion of GSK-3α from resident cardiac fibroblasts significantly restricted pressure overload-induced adverse cardiac remodeling and improved cardiac function. Consistently, in Postn-KO mice, deletion of GSK-3α from myofibroblasts remarkably reduced LV scar circumference and prevented cardiac dysfunction post-MI. To gain the mechanistic insights of observed GSK-3α mediated fibrotic remodeling, we examined the effect of GSK-3α deletion on myofibroblast transformation and profibrotic TGF-β1-SMAD3 signaling in vitro . WT and GSK-3α KO mouse embryonic fibroblasts (MEFs) were treated with TGF-β1 (10 ng/mL). Indeed, a significant reduction in cell migration, collagen gel contraction, and α-SMA expression in TGF-β1 treated GSK-3α KO MEF confirmed that GSK-3α is required for myofibroblast transformation. Surprisingly, GSK-3α deletion had no effect on TGF-β1 induced SMAD3 activation indicating the potential involvement of GSK-3α in eliciting SMAD3 independent profibrotic response. Conclusion: These findings suggest the causal role of CF-GSK3α in the cardiac remodeling of the injured heart that could be a therapeutically targeted for the future clinical applications. </jats:p