Search

Aims: Diabetic cardiomyopathy, characterized by myocardial structural and functional changes, is a specific cardiomyopathy develops in patients with diabetes mellitus. The present study was to investigate the role of kinin B2 receptor-Akt-glycogen synthase kinase (GSK)-3β signalling pathway in mediating the protective effects of tanshinone IIA (TSN) on diabetic cardiomyopathy. Methods and results: Streptozocin (STZ) induced diabetic rats (n = 60) were randomized to receive TSN, TSN plus HOE140 (a kinin B2 receptor antagonist), or saline. Healthy Sprague-Dawley (SD) rats (n = 20) were used as control. Left ventricular function, myocardial apoptosis, myocardial ultrastructure, Akt, GSK-3β and NF-κB phosphorylation, the expression of TNF-α, IL-6 and myeloperoxidase (MPO) were examined. Cardiac function was well preserved as evidenced by increased left ventricular ejection fraction (LVEF) and ± dp/dt (maximum speed of contraction/ relaxation), along with decreased myocardial apoptotic death after TSN administration. TSN pretreatment alleviated mitochondria ultrastructure changes. TSN also enhanced Akt and GSK-3β phosphorylation and inhibited NF-κB phosphorylation, resulting in decreased TNF-α, IL-6 and MPO activities. Moreover, pretreatment with HOE140 abolished the beneficial effects of TSN: a decrease in LVEF and ± dp/dt, an inhibition of cardiomyocyte apoptosis, a destruction of cardiomyocyte mitochondria cristae, a reduction of Akt and GSK-3β phosphorylation, an enhancement of NF-κB phosphorylation and an increase of TNF-α, IL-6 and MPO production. Conclusion: These data indicated that TSN is cardioprotective in the context of diabetic cardiomyopathy through kinin B2 receptor-Akt-GSK-3β dependent pathway. [ABSTRACT FROM AUTHOR]

Objective: This study was designed to detect the role of Toll-like receptor 4 (TLR4) signaling in the dysfunction of cardiac microvascular endothelial cells (CMECs) after hypoxia/reoxygenation (H/R). Methods: The cell viability of CMECs was measured by MTT assay. The migration of CMECs was detected by cell scratch wound assay. The expressions of TLR4, nuclear factor-kappa B (NF-κB) and eNOS were analyzed by Western blot. Secretions of nitric oxide (NO) and tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) were determined by NO detection kit and ELISA. Results: Lipopolysaccharide (LPS) incubation increased the expressions of TLR4, NF-κB, IL-6 and TNF-α in CMECs ( P < 0.05 vs. control). The CMECs after H/R injury had impaired cell viability ( P < 0.01 vs. control) and migration ability ( P < 0.05 vs. control). Moreover, the expressions of TLR4, NF-κB, IL-6 and TNF-α were elevated after H/R in CMECs ( P < 0.01 vs. control), while NO and the eNOS expression were significantly decreased. In contrast, administration of the TLR4-neutralizing antibody MTS510 prior to H/R injury down-regulated the expressions of IL-6 and TNF-α and attenuated the dysfunction of CMECs. Conclusion: TLR4 and its signaling components can be activated by LPS and H/R in CMECs. Blocking the TLR4 signal pathway before H/R injury attenuates CMEC dysfunction. [ABSTRACT FROM AUTHOR]

Diseases caused by pathogenic bacilli pose an increasing threat to human health. A common feature of these bacteria is a complete cell wall; therefore, drugs that can penetrate this protective barrier could be used as a novel approach for treating these infections. Here we present a simple method for synthesizing a silica mesoporous material loaded with cadmium selenide (CdSe) and chlorogenic acid. Using UV–visible, fluorescence, and infrared imaging in combination with transmission electron microscopy, it was shown that CdSe and chlorogenic acid could be successfully embedded in the mesopores of silica nanoparticles (CSC NPs), and these NPs presented with a strong fluorescence, uniform size, and good dispersion. Additionally, the results of these analyses indicated that the fluorescence of the CSC NPs was localized within the cells of Escherichia coli and Bacillus subtilis, signifying that these NPs could breach the cell wall and enter the cells of these two bacilli. Additional assessments found that these CSC NPs inhibited the proliferation of the bacteria by disrupting the cell wall, and this was most likely due to the overproduction of reactive oxygen species induced by chlorogenic acid. Importantly, histopathology analysis indicated that the CSC NPs had limited side effects and high biocompatibility. [ABSTRACT FROM AUTHOR]

Pheromone communication is an essential component of reproductive isolation in animals. As such, evolution of pheromone signaling can be linked to speciation. For example, the evolution of sex pheromones is thought to have played a major role in the diversification of moths. In the crop pests Spodoptera littoralis and S. litura, the major component of the sex pheromone blend is (Z,E)-9,11-tetradecadienyl acetate, which is lacking in other Spodoptera species. It indicates that a major shift occurred in their common ancestor. It has been shown recently in S. littoralis that this compound is detected with high specificity by an atypical pheromone receptor, named SlitOR5. Here, we studied its evolutionary history through functional characterization of receptors from different Spodoptera species. SlitOR5 orthologs in S. exigua and S. frugiperda exhibited a broad tuning to several pheromone compounds. We evidenced a duplication of OR5 in a common ancestor of S. littoralis and S. litura and found that in these two species, one duplicate is also broadly tuned while the other is specific to (Z,E)-9,11-tetradecadienyl acetate. By using ancestral gene resurrection, we confirmed that this narrow tuning evolved only in one of the two copies issued from the OR5 duplication. Finally, we identified eight amino acid positions in the binding pocket of these receptors whose evolution has been responsible for narrowing the response spectrum to a single ligand. The evolution of OR5 is a clear case of subfunctionalization that could have had a determinant impact in the speciation process in Spodoptera species. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to an article by Jing Chen and colleagues published in the March 7, 2009 issue about the relation between metabolic syndrome and blood pressure response to sodium intake.

The placenta plays an important role in nutrient transport to maintain the growth and development of the embryo. Gestational diabetes mellitus (GDM), the most common complication during pregnancy, highly affects placental function in late gestation. Advanced glycation end-products (AGEs), a complex and heterogeneous group of compounds engaged by the receptor for AGEs (RAGE), are closely associated with diabetes-related complications. In this study, AGEs induced a decrease in the expression of tight junction (TJ) proteins in BeWo cells and increased the paracellular permeability of trophoblast cells by regulating RAGE/NF-κB. Sprague-Dawley (SD) rats injected with 100 mg/kg AGEs-rat serum albumin (RSA) via the tail vein from embryo day 2 were set as the placental barrier dysfunction model group (n = 10). The effect of AGEs on placental permeability was determined using the Evans-Blue dye extravasation method. The ultrastructure of the placenta samples was observed by transmission electron microscopy. The effects of AGEs on the placenta were confirmed by treating rats with RAGE antagonist FPS-ZM1 and soluble forms of RAGE (sRAGE). AGEs treatment increased placental permeability and disrupted the tight junctions in pregnant rat placenta, but has no effect on blood glucose. The expression of TJ-related proteins, including ZO-1, Occludin, and Claudin 5, were downregulated after AGEs treatment. Further, AGEs treatment increased the expression of RAGE and nuclear factor-κB in the placenta of rats and upregulated the levels of vascular endothelial growth factor. The effects of AGEs on the placenta were blocked by RAGE antagonist FPS-ZM1 and sRAGE. This study demonstrates the mechanism underlying AGEs-induced disturbance in placental function in pregnant rats and highlights the potential of AGEs in the treatment of GDM. [ABSTRACT FROM AUTHOR]

Objective(s): Physical exercise has emerged as an effective therapy to mitigate cardiac remodelling in diabetic cardiomyopathy (DCM). The results of our previous studies revealed mammalian sterile 20-like kinase 1 (Mst1) is a key regulator of the progression of DCM. However, the precise molecular mechanism of physical exercise-induced cardiac protection and its association with Mst1 inhibition remain unclear. Materials and Methods: Wildtype and Mst1 transgenic mice were challenged with streptozotocin (STZ) to induce experimental diabetes and were divided into sedentary and exercise groups. The DCM phenotype was evaluated by echocardiography, Masson's trichrome staining, TUNEL and immunoblotting analyses. The exercise-regulated miRNAs targeting Mst1 were predicted by bioinformatic analysis and later confirmed by RT-qPCR, immunoblotting, and dual-luciferase reporter assays. In addition, cultured neonatal mouse cardiomyocytes were subjected to simulate diabetes to elucidate the underlying mechanisms. Results: Compared to the sedentary diabetic control, physical exercise inhibited Mst1 and alleviated cardiac remodelling in mice with DCM, as evidenced by decreases in the left ventricular end-systolic internal dimension (LVESD) and left ventricular end-diastolic internal dimension (LVEDD), increases in the left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS), attenuation of collagen deposition, and the suppression of apoptosis. Bioinformatic analysis and apoptosis assessments revealed exercise exerted protective effects against DCM through miR-486a- 5p release. Moreover, luciferase reporter assays confirmed miR-486a-5p directly suppressed the expression of Mst1, thereby inhibiting the apoptosis of cardiomyocytes subjected to high glucose treatment. Conclusion: Physical exercise inhibits cardiac remodelling in DCM, and the mechanism is associated with miR-486a-5p release-induced Mst1 inhibition. [ABSTRACT FROM AUTHOR]

The African swine fever virus (ASFV) is the deadly pathogen of African swine fever (ASF) that induces high mortality, approaching 100% in domestic pigs, causes enormous losses to the global pig industry and threatens food security. Currently, there is no effective treatment or preventive countermeasure. dUTPases (deoxyuridine 5'-triphosphate pyrophosphatases) are ubiquitous enzymes that are essential for the hydrolysis of dUTP and prevent the misincorporation of dUTP into newly synthesized DNA. Here, we present the crystal structures of the ASFV dUTPase in complex with the product dUMP and cofactor Mg2+ at a resolution of 2.2 angstroms. We observed that a unique "turning point" at G125 plays an unexpected critical role in the swapping region of the C-terminal segment, which is further stabilized by the interactions of the last C-terminal ß strand with the ß1 and ß2 strands, thereby positioning the catalytic motif 5 into the active site of its own subunit instead of into a third subunit. Therefore, the ASFV dUTPase employs a novel two-subunit active site that is different than the classic trimeric dUTPase active site, which is composed of all three subunits. Meanwhile, further results confirmed that the configuration of motifs 1 to 5 has high structural homology with and a catalytic mechanism similar to that of the known trimeric dUTPases. In general, our study expands the information not only on the structural diversity of the conserved dUTPase family but also on the details needed to utilize this dUTPase as a novel target in the treatment of ASF. [ABSTRACT FROM AUTHOR]