miR-145-5p targets paxillin to attenuate angiotensin II-induced pathological cardiac hypertrophy via downregulation of Rac 1, pJNK,p-c-Jun,NFATc3, ANP and by Sirt-1 upregulation

Pathological cardiac hypertrophy is associated with many diseases including hypertension. Recent studies have identified important roles for microRNAs (miRNAs) in many cardiac pathophysiological processes, including the regulation of cardiomyocyte hypertrophy. However, the role of miR-145-5p in the cardiac setting is still unclear. In this study, H9C2 cells were overexpressed with microRNA-145-5p, and then treated with Ang-II for 24 h, to study the effect of miR-145-5p on Ang-II-induced myocardial hypertrophy in vitro. Results showed that Ang-II treatment down-regulated miR-145-5p expression were revered after miR-145-5p overexpression. Based on results of bioinformatics algorithms, paxillin was predicted as a candidate target gene of miR-145-5p, luciferase activity assay revealed that the luciferase activity of cells was substantial downregulated the following co-transfection with wild paxillin 3′UTR and miR-145-5p compared to that in scramble control, while the inhibitory effect of miR-145-5p was abolished after transfection of mutant paxillin 3′UTR. Additionally, overexpression of miR-145-5p markedly inhibited activation of Rac-1/ JNK /c-jun/ NFATc3 and ANP expression and induced SIRT1 expression in Ang-II treated H9c2 cells. Jointly, our study suggested that miR-145-5p inhibited cardiac hypertrophy by targeting paxillin and through modulating Rac-1/ JNK /c-jun/ NFATc3/ ANP / Sirt1 signaling, therefore proving novel downstream molecular pathway of miR-145-5p in cardiac hypertrophy

     

Chemical Modulation of Endocytic Sorting Augments Adeno-associated Viral Transduction

Intracellular trafficking of viruses can be influenced by a variety of inter-connected cellular sorting and degradation pathways involving endo-lysosomal vesicles, the ubiquitin-proteasome system, and autophagy-based or endoplasmic reticulum-associated machinery. In the case of recombinant adeno-associated viruses (AAV), proteasome inhibitors are known to prevent degradation of ubiquitinated AAV capsids, thereby leading to increased nuclear accumulation and transduction. However, the impact of other cellular degradation pathways on AAV trafficking is not well understood. In the current study, we screened a panel of small molecules focused on modulating different cellular degradation pathways and identified eeyarestatin I (EerI) as a novel reagent that enhances AAV transduction. EerI improved AAV transduction by an order of magnitude regardless of vector dose, genome architecture, cell type, or serotype. This effect was preceded by sequestration of AAV within enlarged vesicles that were dispersed throughout the cytoplasm. Specifically, EerI treatment redirected AAV particles toward large vesicles positive for late endosomal (Rab7) and lysosomal (LAMP1) markers. Notably, MG132 and EerI (proteasomal and endoplasmic reticulum-associated degradation inhibitors, respectively) appear to enhance AAV transduction by increasing the intracellular accumulation of viral particles in a mutually exclusive fashion. Taken together, our results expand on potential strategies to redirect recombinant AAV vectors toward more productive trafficking pathways by deregulating cellular degradation mechanisms.     

Distribution of natural radionuclide40K in biotic and abiotic components of the Cauvery river system,Tiruchirapalli, India

Abiotic components like water and sediment, and biotic components such as mussels, fish and grass collected from Cauvery river at Tiruchirapalli were analysed for⁴⁰K activity. The highest level of⁴⁰K activity was found in the sediment (342 mBq g^-1 dry weight) and the lowest activity was found in water (2·209 mBq ml⁻¹). In the freshwater musselParreysia favidens (Benson)⁴⁰K activity was estimated in the total soft tissues and shells of mussels belonging to three different size groups. In all the size groups⁴⁰K activity was two times higher in shells (68–39 mBq g^-1 fresh weight) than in the total soft tissues (25–17 mBq g^-1 fresh weight). The results indicate that the younger mussels accumulated more⁴⁰K than the older ones. The ability of internal organs of mussels belonging to group III to accumulate⁴⁰K was in the following order: gills > digestive gland > foot > mantle. The values ranged from 47 to 18 mBq g⁻¹ fresh weight in the various organs. Concentration of⁴⁰K in the mussel was distinctly higher than in the grassEchinochloa colonum (J Koenig) (95 mBq g⁻¹ fresh weight), and the concentration of⁴⁰K in the bone of the fishCirrhina cirrhosa (Bloch) (126 mBq g⁻¹ fresh weight) was higher than to that of muscle (113 mBq g⁻¹ fresh weight)