Activation of AMPK alpha- and gamma-isoform complexes in the intact ischemic rat heart

AMP-activated protein kinase (AMPK) plays a key role in modulating cellular metabolic processes. AMPK, a serine-threonine kinase, is a heterotrimeric complex of catalytic alpha-subunits and regulatory beta- and gamma-subunits with multiple isoforms. Mutations in the cardiac gamma(2)-isoform have been associated with hypertrophic cardiomyopathy and pre-excitation syndromes. However, physiological regulation of AMPK complexes containing different subunit isoforms is not well defined and is important for an understanding of the function of this signaling pathway in the intact heart. We evaluated the kinase activity associated with heart AMPK complexes containing specific alpha- and gamma-subunit isoforms of AMPK in an in vivo rat model of regional ischemia. Left coronary artery occlusion activated the immunoprecipitated alpha(1)-isoform (6-fold, P < 0.01) and alpha(2)-isoform (9-fold, P < 0.01) in the ischemic left ventricle compared with sham controls. The degree of alpha-subunit activation depended on the extent of ischemia and paralleled echocardiographic contractile dysfunction. The regulatory gamma(1)- and gamma(2)-isoforms were expressed in the heart. The gamma(1)- and gamma(2)-isoforms coimmunoprecipitated with alpha(1)- and alpha(2)-isoforms in proportion to alpha-subunit content. gamma(1)-Isoform immunocomplexes accounted for 70% of AMPK activity and AMPK phosphorylation (Thr(172)) in hearts. Ischemia similarly increased AMPK activity associated with the gamma(1)- and gamma(2)-isoform complexes threefold (P < 0.01 for each). Thus AMPK catalytic alpha(1)- and alpha(2)-isoforms are activated by regional ischemia in vivo in the heart, irrespective of the regulatory gamma(1)- or gamma(2)-isoforms to which they are complexed. Despite the pathophysiological importance of gamma(2)-isoform mutations, gamma(1)-isoform complexes account for most of the AMPK activity in the ischemic heart.     

Analysis of spiking synchrony in visual cortex reveals distinct types of top-down modulation signals for spatial and object-based attention

The activity of a border ownership selective (BOS) neuron indicates where a foreground object is located relative to its (classical) receptive field (RF). A population of BOS neurons thus provides an important component of perceptual grouping, the organization of the visual scene into objects. In previous theoretical work, it has been suggested that this grouping mechanism is implemented by a population of dedicated grouping (“G”) cells that integrate the activity of the distributed feature cells representing an object and, by feedback, modulate the same cells, thus making them border ownership selective. The feedback modulation by G cells is thought to also provide the mechanism for object-based attention. A recent modeling study showed that modulatory common feedback, implemented by synapses with N-methyl-D-aspartate (NMDA)-type glutamate receptors, accounts for the experimentally observed synchrony in spike trains of BOS neurons and the shape of cross-correlations between them, including its dependence on the attentional state. However, that study was limited to pairs of BOS neurons with consistent border ownership preferences, defined as two neurons tuned to respond to the same visual object, in which attention decreases synchrony. But attention has also been shown to increase synchrony in neurons with inconsistent border ownership selectivity. Here we extend the computational model from the previous study to fully understand these effects of attention. We postulate the existence of a second type of G-cell that represents spatial attention by modulating the activity of all BOS cells in a spatially defined area. Simulations of this model show that a combination of spatial and object-based mechanisms fully accounts for the observed pattern of synchrony between BOS neurons. Our results suggest that modulatory feedback from G-cells may underlie both spatial and object-based attention.     

Syntheses and properties of trimethylaminophenoxy-substituted Zn((II))-phthalocyanines

The syntheses, photophysical properties and in vitro biological behavior of a series of nine Zn((II))-phthalocyanines (ZnPcs) bearing one to eight positively-charged trimethylaminophenoxy groups are reported. All ZnPcs are highly soluble in polar organic solvents, and show fluorescence and singlet oxygen quantum yields in the ranges 0.11-0.21 and 0.16-0.47, respectively. The cytotoxicity of the ZnPcs depends on both the number of charges and their site of substitution (α vs. β) on the Pc isoindole units; the most promising for PDT application are the α-substituted di-cationic ZnPcs 6a and 17a.     

High‐Temperature Shock Enabled Nanomanufacturing for Energy‐Related Applications

Functional nanomaterials are playing a crucial role in the emerging field of energy‐related devices. Recently, as a novel synthesis method, high‐temperature shock (HTS), which is rapid, low cost, eco‐friendly, universal, scalable, and controllable, has provided a promising option for the rational design and synthesis of various high‐quality nanomaterials. In this report, the HTS technique, including the equipment setup and operating principle, is systematically introduced, and recent progress in the synthesis of nanomaterials for energy storage and conversion applications using this HTS method is summarized. The growth mechanisms of nanoparticles and carbonaceous nanomaterials are thoroughly discussed, followed by the summary of the characteristic advantages of the HTS strategy. A series of nanomaterials prepared by the HTS method, including carbon‐based films, metal nanoparticles and compound nanoparticles, show high performance in the diverse applications of storage energy batteries, highly active catalysts, and smart energy devices. Finally, the future perspectives and directions of HTS in nanomanufacturing for broader applications are presented.     

Endothelial S1pr1 regulates pressure overload‐induced cardiac remodelling through AKT‐eNOS pathway

Cardiac vascular microenvironment is crucial for cardiac remodelling during the process of heart failure. Sphingosine 1‐phosphate (S1P) tightly regulates vascular homeostasis via its receptor, S1pr1. We therefore hypothesize that endothelial S1pr1 might be involved in pathological cardiac remodelling. In this study, heart failure was induced by transverse aortic constriction (TAC) operation. S1pr1 expression is significantly increased in microvascular endothelial cells (ECs) of post‐TAC hearts. Endothelial‐specific deletion of S1pr1 significantly aggravated cardiac dysfunction and deteriorated cardiac hypertrophy and fibrosis in myocardium. In vitro experiments demonstrated that S1P/S1pr1 praxis activated AKT/eNOS signalling pathway, leading to more production of nitric oxide (NO), which is an essential cardiac protective factor. Inhibition of AKT/eNOS pathway reversed the inhibitory effect of EC‐S1pr1‐overexpression on angiotensin II (AngII)‐induced cardiomyocyte (CM) hypertrophy, as well as on TGF‐β‐mediated cardiac fibroblast proliferation and transformation towards myofibroblasts. Finally, pharmacological activation of S1pr1 ameliorated TAC‐induced cardiac hypertrophy and fibrosis, leading to an improvement in cardiac function. Together, our results suggest that EC‐S1pr1 might prevent the development of pressure overload‐induced heart failure via AKT/eNOS pathway, and thus pharmacological activation of S1pr1 or EC‐targeting S1pr1‐AKT‐eNOS pathway could provide a future novel therapy to improve cardiac function during heart failure development.     

The microRNA miR-17 regulates lung FoxA1 expression during lipopolysaccharide-induced acute lung injury

Acute lung injury (ALI) is a severe pulmonary disease that causes a high number of fatalities worldwide. Studies have shown that FoxA1 expression is upregulated during ALI and may play an important role in ALI by promoting the apoptosis of alveolar type II epithelial cells. However, the mechanism of FoxA1 overexpression in ALI is unclear. In this study, an in vivo murine model of ALI and alveolar type II epithelial cells injury was induced using lipopolysaccharide (LPS). LPS upregulated FoxA1 in the lung tissue of the in vivo ALI model and in LPS-challenged type II epithelial cells. In contrast, miR-17 was significantly downregulated in these models. After miR-17 antagomir injection, the expression of FoxA1 was significantly increased in ALI mice. MiR-17 mimics could significantly inhibit FoxA1 mRNA and protein expression, whereas the miR-17 inhibitor could significantly increase FoxA1 mRNA and protein expression in LPS-induced type II epithelial cells. Thus, our results suggest that the downregulation of miR-17 expression could lead to FoxA1 overexpression in ALI.     

Solid-state NMR investigation of the buried X-proline peptide bonds of bacteriorhodopsin

The role of proline residues in the photocycle of bacteriorhodopsin (bR) is addressed using solid-state NMR. (13)C and (15)N chemical shifts from X-Pro peptide bonds in bR are assigned from REDOR difference spectra of pairwise labeled samples, and correlations of chemical shifts with structure are explored in a series of X-Pro model compounds. Results for the three membrane-embedded X-Pro bonds of bR indicate only slight changes in the transition from the resting state of the protein to either the early or late M state of the protonmotive photocycle. These results suggest that the buried prolines serve a principally structural role in bR.     

Chemokine receptor CCR5 functionally couples to inhibitory G proteins and undergoes desensitization

Chemokine receptor CCR5 is not only essential for chemotaxis of leukocytes but also has been shown to be a key coreceptor for HIV-1 infection. In the present study, hemagglutinin epitope-tagged human CCR5 receptor was stably expressed in Chinese hamster ovary cells or transiently expressed in NG108–15 cells to investigate CCR5-mediated signaling events. The surface expression of CCR5 was confirmed by flow cytometry analysis. The CCR5 agonist RANTES stimulated [³⁵S]GTPγS binding to the cell membranes and induced inhibition on adenylyl cyclase activity in cells expressing CCR5. The effects of RANTES were CCR5 dependent and could be blocked by pertussis toxin. Furthermore, overexpression of Giα2 strongly increased both RANTES-dependent G-protein activation and inhibition on adenylyl cyclase in cells cotransfected with CCR5. These data demonstrated directly that activation of CCR5 stimulated membrane-associated inhibitory G proteins and indicated that CCR5 could functionally couple to G-protein subtype Giα2. The abilities of CCR5 to activate G protein and to inhibit cellular cAMP accumulation were significantly diminished after a brief prechallenge with RANTES, showing rapid desensitization of the receptor-mediated responsiveness. Prolonged exposure of the cells to RANTES caused significant reduction of surface CCR5 as measured by flow cytometry, indicative of agonist-dependent receptor internalization. Our data thus demonstrated that CCR5 functionally couples to membrane-associated inhibitory G proteins and undergoes agonist-dependent desensitization and internalization. J. Cell. Biochem. 71:36–45, 1998. © 1998 Wiley-Liss, Inc.     

Serum Concentrations of 15 Elements Among <Emphasis Type="Italic">Helicobacter Pylori</Emphasis>-Infected Residents from Lujiang County with High Gastric Cancer Risk in Eastern China

Data on the effects of magnesium-zinc-calcium-vitamin D co-supplementation on hormonal profiles, biomarkers of inflammation, and oxidative stress among women with polycystic ovary syndrome (PCOS) are scarce. The objective of this study was to assess the effects of magnesium-zinc-calcium-vitamin D co-supplementation on hormonal profiles, biomarkers of inflammation, and oxidative stress in women with PCOS. Sixty PCOS women were randomized into two groups and treated with 100 mg magnesium, 4 mg zinc, 400 mg calcium plus 200 IU vitamin D supplements (n = 30), or placebo (n = 30) twice a day for 12 weeks. Hormonal profiles, biomarkers of inflammation, and oxidative stress were assessed at baseline and at end-of-treatment. After the 12-week intervention, compared with the placebo, magnesium-zinc-calcium-vitamin D co-supplementation resulted in significant reductions in hirsutism (?2.4 ± 1.2 vs. ?0.1 ± 0.4, P < 0.001), serum high sensitivity C-reactive protein (?0.7 ± 0.8 vs. +0.2 ± 1.8 mg/L, P < 0.001), and plasma malondialdehyde (?0.4 ± 0.3 vs. +0.2 ± 1.0 μmol/L, P = 0.01), and a significant increase in plasma total antioxidant capacity concentrations (+46.6 ± 66.5 vs. ?7.7 ± 130.1 mmol/L, P = 0.04). We failed to find any significant effect of magnesium-zinc-calcium-vitamin D co-supplementation on free androgen index, and other biomarkers of inflammation and oxidative stress. Overall, magnesium-zinc-calcium-vitamin D co-supplementation for 12 weeks among PCOS women had beneficial effects on hormonal profiles, biomarkers of inflammation, and oxidative stress.     

Clinical Significance of MiR-137 Expression in Patients with Gastric Cancer After Radical Gastrectomy

The dysregulation of miR-137 plays vital roles in the oncogenesis and progression of various types of cancer, but its role in prognosis of gastric cancer patients remains unknown. This study was designed to investigate the expression and prognostic significance of miR-137 in gastric cancer patients after radical gastrectomy. Quantitative real-time PCR (qRT-PCR) was performed to evaluate the expression of miR-137 in human gastric cancer cell lines and tissues in patients with gastric adenocarcinoma. Results were assessed for association with clinical factors and overall survival by using Kaplan-Meier analysis. Prognostic values of miR-137 expression and clinical outcomes were evaluated by Cox regression analysis. The results exhibited that the expression level of miR-137 was decreased in human gastric cancer cell lines and tissues, and down-regulated expression of miR-137 was associated with tumor cell differentiation, N stage, and TNM stage. Decreased miR-137 expression in gastric cancer tissues was positively correlated with poor overall survival of gastric cancer patients. Further multivariate Cox regression analysis suggested that miR-137 expression was an independent prognostic indicator for gastric cancer except for TNM stage. Applying the prognostic value of miR-137 expression to TNM stage III group showed a better risk stratification for overall survival. In conclusion, the results reinforced the critical role for the down-regulated miR-137 expression in gastric cancer and suggested that miR-137 expression could be a prognostic indicator for this disease. In addition, these patients with TNM stage III gastric cancer and low miR-137 expression might need more aggressive postoperative treatment and closer follow-up.