CoFe2O4@SiO2-NH2@MOF-5 magnetic nanocatalyst for the synthesis of biologically active quinazoline derivatives.

Metal-organic frameworks (MOFs) offered excellent catalytic activity due to their superior porosity, and high densities of catalytic sites in remarkable specific surfaces. In this research, we prepared a magnetic nanocomposite based on MOF-5 which is one of the prominent and practical structures that have been reported in many applications, and investigated the advantages of it as a catalyst. The multi-functional catalyst was prepared in five steps including (1) preparation of cobalt ferrite nanoparticles (CoFe2O4), (2) surface modification of cobalt ferrite using tetraethyl orthosilicate, (3) surface functionalization using 3-aminopropyl triethoxysilane, (4) preparation of MOF-5, (5) preparation of CoFe2O4@SiO2-NH2@MOF-5 nanocomposite. The resulting catalyst was evaluated by FTIR, FESEM, EDX, XRD, and VSM analyses. The CoFe2O4@SiO2-NH2@MOF-5 nanocomposite was applied as a catalyst for the quinazoline derivatives' synthesis. Various products were prepared with significant yields (90-98%) in short reaction times (20-60 min) without difficult work-up. In addition, the magnetic behavior of the catalyst allows it to be collected and recycled by a magnet and applied for six consecutive cycles without significantly reducing its efficiency. Quinazoline derivatives showed significant biological activities so their antioxidant activity was between 23.7% and 88.9% and their antimicrobial activity was in contradiction of E. coli, S. enterica, L. monocytogenes, S. aureus, and E. faecalis.

Recombinant human annexin A5 inhibits proinflammatory response and improves cardiac function and survival in mice with endotoxemia.

OBJECTIVES: Annexin A5 is a 35-kDa protein with high affinity binding to negatively charged phospholipids. However, its effects on sepsis are not known. Our aim was to study the effects of annexin A5 on myocardial tumor necrosis factor-α expression, cardiac function, and animal survival in endotoxemia. DESIGN: Prospective experimental study. SETTING: University laboratory. SUBJECTS: Adult male C57BL/6 mice. INTERVENTIONS: Mice were challenged with lipopolysaccharide (4 or 20 mg/kg, i.p.) to induce endotoxemia with and without recombinant human annexin A5 treatment (5 or 10 µg/kg, i.v.). Cytokine expression and cardiac function were assessed, and animal survival was monitored. MEASUREMENTS AND MAIN RESULTS: Treatment with annexin A5 inhibited myocardial mitogen-activated protein kinase, and nuclear factor-κB activation in mice with endotoxemia. Furthermore, annexin A5-treated animals showed significant reductions in myocardial and plasma levels of tumor necrosis factor-α and interleukin-1ß while cardiac function was significantly improved during endotoxemia. Additionally, 5-day animal survival was significantly improved by either an immediate or a 4-hour delayed annexin A5 treatment after lipopolysaccharide challenge. Importantly, annexin A5 dose-dependently inhibited lipopolysaccharide binding to a toll-like receptor-4/myeloid differentiation factor 2 fusion protein. CONCLUSIONS: Annexin A5 treatment decreases cytokine expression and improves cardiac function and survival during endotoxemia. These effects of annexin A5 are mediated by its ability to inhibit lipopolysaccharide binding to toll-like receptor-4, leading to reductions in mitogen-activated protein kinase and Akt signaling. Our study suggests that annexin A5 may have therapeutic potential in the treatment of sepsis.

Heightened alpha1A-adrenergic receptor activity suppresses ischaemia/reperfusion-induced Ins(1,4,5)P3 generation in the mouse heart: a comparison with ischaemic preconditioning.

Reperfusion of ischaemic rat or mouse hearts causes NE [noradrenaline ('norepinephrine')] release, stimulation of alpha(1)-ARs (alpha(1)-adrenergic receptors), PLC (phospholipase C) activation, Ins(1,4,5)P(3) generation and the development of arrhythmias. In the present study, we examined the effect of increased alpha(1A)-AR drive on these responses. In hearts from non-transgenic mice (alpha(1A)-WT), Ins(1,4,5)P(3) generation was observed after 2 min of reperfusion following 30 min of zero-flow ischaemia. No Ins(1,4,5)P(3) response was observed in hearts from transgenic mice with 66-fold overexpression of alpha(1A)-AR (alpha(1A)-TG). This was despite the fact that alpha(1A)-TG hearts had 8-10-fold higher PLC responses to NE than alpha(1A)-WT under normoxic conditions. The immediate phospholipid precursor of Ins(1,4,5)P(3), PtdIns(4,5)P(2), responded to ischaemia and reperfusion similarly in alpha(1A)-WT and alpha(1A)-TG mice. Thus the lack of Ins(1,4,5)P(3) generation in alpha(1A)-TG mice is not caused by limited availability of PtdIns(4,5)P(2). Overall, alpha(1)-AR-mediated PLC activity was markedly enhanced in alpha(1A)-WT mice under reperfusion conditions, but responses in alpha(1A)-TG mice were not significantly different in normoxia and post-ischaemic reperfusion. Ischaemic preconditioning prevented Ins(1,4,5)P(3) generation after 30 min of ischaemic insult in alpha(1A)-WT mice. However, the precursor lipid PtdIns(4,5)P(2) was also reduced by preconditioning, whereas heightened alpha(1A)-AR activity did not influence PtdIns(4,5)P(2) responses in reperfusion. Thus preconditioning and alpha(1A)-AR overexpression have different effects on early signalling responses, even though both prevented Ins(1,4,5)P(3) generation. These studies demonstrate a selective inhibitory action of heightened alpha(1A)-AR activity on immediate post-receptor signalling responses in early post-ischaemic reperfusion.

Protective effects of exercise and phosphoinositide 3-kinase(p110alpha) signaling in dilated and hypertrophic cardiomyopathy.

Physical activity protects against cardiovascular disease, and physiological cardiac hypertrophy associated with regular exercise is usually beneficial, in marked contrast to pathological hypertrophy associated with disease. The p110alpha isoform of phosphoinositide 3-kinase (PI3K) plays a critical role in the induction of exercise-induced hypertrophy. Whether it or other genes activated in the athlete's heart might have an impact on cardiac function and survival in a setting of heart failure is unknown. To examine whether progressive exercise training and PI3K(p110alpha) activity affect survival and/or cardiac function in two models of heart disease, we subjected a transgenic mouse model of dilated cardiomyopathy (DCM) to swim training, genetically crossed cardiac-specific transgenic mice with increased or decreased PI3K(p110alpha) activity to the DCM model, and subjected PI3K(p110alpha) transgenics to acute pressure overload (ascending aortic constriction). Life-span, cardiac function, and molecular markers of pathological hypertrophy were examined. Exercise training and increased cardiac PI3K(p110alpha) activity prolonged survival in the DCM model by 15-20%. In contrast, reduced PI3K(p110alpha) activity drastically shortened lifespan by approximately 50%. Increased PI3K(p110alpha) activity had a favorable effect on cardiac function and fibrosis in the pressure-overload model and attenuated pathological growth. PI3K(p110alpha) signaling negatively regulated G protein-coupled receptor stimulated extracellular responsive kinase and Akt (via PI3K, p110gamma) activation in isolated cardiomyocytes. These findings suggest that exercise and enhanced PI3K(p110alpha) activity delay or prevent progression of heart disease, and that supraphysiologic activity can be beneficial. Identification of genes important for hypertrophy in the athlete's heart could offer new strategies for treating heart failure.