Influence of the β-fibrinogen-455G/A polymorphism on development of ischemic stroke and coronary heart disease

Background

Ischemic stroke (IS) and coronary heart disease (CHD) are two vascular disorders that are a common cause of death worldwide. Several studies have assessed the association of the β-fibrinogen-455G/A (FGB-455G/A) polymorphism and risk of IS and CHD, but the results are still inconsistent. Our study aimed to investigate whether the FGB-455G/A polymorphism was associated with susceptibility to IS and CHD by using meta-analysis.

Methods

Relevant studies were identified from PubMed, Embase and four Chinese database up to July 2013.Data were analyzed and processed by Stata 11.2. A pooled OR with 95% CI was calculated to estimate the strength of the genetic association. Cumulative meta-analysis was performed to assess the tendency of pooled OR over time.

Results

45 studies based on a total of 7238 cases and 7395 controls were included in our meta-analysis. The results indicated that the FGB-455G/A polymorphism is associated with the risk of IS when compared with the dominant model (OR = 1.518, 95%CI = 1.279-1.802 for AA + GA vs. GG). In the subgroup analysis by ethnicity, significantly elevated risks were associated with the A allele in Asians (OR = 1.700, 95%CI = 1.417-2.040), but not in Caucasians (OR = 0.942, 95%CI = 0.813-1.091). Both the hypertension and non-hypertension subgroups reached significant results, but no significance was found when stratified according to sex or subtype of IS. Results indicate that the FGB-455G/A polymorphism is associated with CHD (OR = 1.802, 95%CI = 1.445-2.246).

Conclusion

Our meta-analysis suggests that the FGB-455G/A polymorphism contributes to susceptibility to IS and CHD.     

Angiotensin II inhibits uptake of transferrin-bound iron but not non-transferrin-bound iron by cultured astrocytes

The existence of all components of the renin–angiotensin system (RAS) and the iron metabolism system, and the recent findings on the functions of angiotensin II (ANGII) in peripheral iron metabolism imply that ANGII might play a role in iron homeostasis by regulating expression of iron transport proteins in the brain. Here, we investigated effects of ANGII on uptake and release of iron as well as expression of cell iron transport proteins in cultured astrocytes. We demonstrated that ANGII could significantly inhibit transferrin-bound iron (Tf-Fe) uptake and iron release as well as the expression of transferrin receptor 1 (TfR1) and the iron exporter ferroportin 1 (Fpn1) in cultured astrocytes. This indicated that the inhibitory role of ANGII on Tf-Fe uptake and iron release is mediated by its negative effect on the expression of TfR1 and Fpn1. We also provided evidence that ANGII had no effect on divalent metal transporter 1 (DMT1) expression as well as non-transferrin-bound iron (NTBI) uptake in the cells. Our findings showed that ANGII has a role to affect expression of iron transport proteins in astrocytes in vitro and also suggested that ANGII might have a physiological function in brain iron homeostasis.     

Type 2 corticotropin-releasing factor receptor in the ventromedial nucleus of hypothalamus is critical in regulating feeding and lipid metabolism in white adipose tissue

Ventromedial nucleus of hypothalamus (VMH) plays a critical role in regulating feeding and energy metabolism. The nucleus expresses high levels of the type 2 corticotropin-releasing factor receptor (CRFR2) and receives prominent innervation of nerve fibers containing Urocortin 3 (Ucn 3), an endogenous ligand of the receptor. In the present study, we showed that mice deficient in Ucn 3 had elevated basal feeding and increased nocturnal food intake after overnight fasting compared with the wild-type (WT) littermates. The Ucn 3 null mice also had lower circulating insulin levels compared with those of the WT mice. Interestingly, the mutant mice maintained a comparable body weight with the WT littermates. Mice with reduced CRFR2 expression in the VMH by small hairpin RNA knockdown (KD) recapitulated feeding phenotypes observed in the Ucn 3 null mice. However, VMH CRFR2 KD mice gained significantly more weight than control mice. The weight gain was due to an accumulation of white adipose tissue (WAT) accompanied by reduced plasma free fatty acids and glycerol levels, increased respiratory quotients, and improved glucose tolerance. On the other hand, plasma insulin levels were comparable with the receptor KD and control mice. Furthermore, the expression of several genes, including hormone-sensitive lipase, was significantly reduced in the WAT of VMH CRFR2 KD mice compared with controls. These results indicate that Ucn 3 signaling through CRFR2 is a critical molecular mediator in the VMH in regulating feeding and lipid metabolism in WAT.     

Kidney-targeting Smad7 gene transfer inhibits renal TGF-β/MAD homologue (SMAD) and nuclear factor κB (NF-κB) signalling pathways, and improves diabetic nephropathy in mice

Aims/hypothesis  

The TGF-β/MAD homologue (SMAD) and nuclear factor κB (NF-κB) signalling pathways have been shown to play a critical role in the development of renal fibrosis and inflammation in diabetic nephropathy. We therefore examined whether targeting these pathways by a kidney-targeting Smad7 gene transfer has therapeutic effects on renal lesions in the db/db mouse model of type 2 diabetes.     

The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors

CD47, a "don't eat me" signal for phagocytic cells, is expressed on the surface of all human solid tumor cells. Analysis of patient tumor and matched adjacent normal (nontumor) tissue revealed that CD47 is overexpressed on cancer cells. CD47 mRNA expression levels correlated with a decreased probability of survival for multiple types of cancer. CD47 is a ligand for SIRPα, a protein expressed on macrophages and dendritic cells. In vitro, blockade of CD47 signaling using targeted monoclonal antibodies enabled macrophage phagocytosis of tumor cells that were otherwise protected. Administration of anti-CD47 antibodies inhibited tumor growth in orthotopic immunodeficient mouse xenotransplantation models established with patient tumor cells and increased the survival of the mice over time. Anti-CD47 antibody therapy initiated on larger tumors inhibited tumor growth and prevented or treated metastasis, but initiation of the therapy on smaller tumors was potentially curative. The safety and efficacy of targeting CD47 was further tested and validated in immune competent hosts using an orthotopic mouse breast cancer model. These results suggest all human solid tumor cells require CD47 expression to suppress phagocytic innate immune surveillance and elimination. These data, taken together with similar findings with other human neoplasms, show that CD47 is a commonly expressed molecule on all cancers, its function to block phagocytosis is known, and blockade of its function leads to tumor cell phagocytosis and elimination. CD47 is therefore a validated target for cancer therapies.     

Hierarchical nanostructured conducting polymer hydrogel with high electrochemical activity

Conducting polymer hydrogels represent a unique class of materials that synergizes the advantageous features of hydrogels and organic conductors and have been used in many applications such as bioelectronics and energy storage devices. They are often synthesized by polymerizing conductive polymer monomer within a nonconducting hydrogel matrix, resulting in deterioration of their electrical properties. Here, we report a scalable and versatile synthesis of multifunctional polyaniline (PAni) hydrogel with excellent electronic conductivity and electrochemical properties. With high surface area and three-dimensional porous nanostructures, the PAni hydrogels demonstrated potential as high-performance supercapacitor electrodes with high specific capacitance (~480 F·g(-1)), unprecedented rate capability, and cycling stability (~83% capacitance retention after 10,000 cycles). The PAni hydrogels can also function as the active component of glucose oxidase sensors with fast response time (~0.3 s) and superior sensitivity (~16.7 μA · mM(-1)). The scalable synthesis and excellent electrode performance of the PAni hydrogel make it an attractive candidate for bioelectronics and future-generation energy storage electrodes.     

Structural and energetic basis of ALS-causing mutations in the atypical proline-tyrosine nuclear localization signal of the Fused in Sarcoma protein (FUS)

Mutations in the proline/tyrosine-nuclear localization signal (PY-NLS) of the Fused in Sarcoma protein (FUS) cause amyotrophic lateral sclerosis (ALS). Here we report the crystal structure of the FUS PY-NLS bound to its nuclear import receptor Karyopherinβ2 (Kapβ2; also known as Transportin). The FUS PY-NLS occupies the structurally invariant C-terminal arch of Kapβ2, tracing a path similar to that of other characterized PY-NLSs. Unlike other PY-NLSs, which generally bind Kapβ2 in fully extended conformations, the FUS peptide is atypical as its central portion forms a 2.5-turn α-helix. The Kapβ2-binding epitopes of the FUS PY-NLS consist of an N-terminal PGKM hydrophobic motif, a central arginine-rich α-helix, and a C-terminal PY motif. ALS mutations are found almost exclusively within these epitopes. Each ALS mutation site makes multiple contacts with Kapβ2 and mutations of these residues decrease binding affinities for Kapβ2 (K(D) for wild-type FUS PY-NLS is 9.5 nM) up to ninefold. Thermodynamic analyses of ALS mutations in the FUS PY-NLS show that the weakening of FUS-Kapβ2 binding affinity, the degree of cytoplasmic mislocalization, and ALS disease severity are correlated.     

Association of body image and health beliefs with health behaviors in patients with diabetes: a cross-sectional study

Purpose The purpose of this study was to investigate relationships between body image, health beliefs, and health behavior in patients with diabetes classified according to body mass index (BMI). Methods A cross-sectional study was conducted in a community hospital between January and April 2010. One-hundred-sixty-eight patients with diabetes were enrolled. Main measure was the previously published and validated Health Belief Questionnaire. Data were analyzed and compared between two groups, one with BMI ≥ 24 Kg/m(2) and another with BMI < 24 Kg/m(2). Results Perceived body image affected health behavior of patients with BMI ≥ 24 Kg/m(2) but did not affect health behavior in patients with BMI < 24 Kg/m(2). Multivariate analysis found a positive association between health behavior and appearance evaluation and between health behavior and health evaluation in high BMI group. No significant association was found between body image and health behavior in the low BMI group. Patients with high BMI had lower body image than patients with low BMI as demonstrated by results of appearance evaluation, health evaluation, prevention behavior, and benefits. Conclusions Perceived body image and health beliefs are associated with self-reported health behavior among patients with diabetes with BMI measurement greater than 24 Kg/m(2). Diabetes educators may apply the findings of this study and the Health Belief Questionnaire to instruct and monitor patients with diabetes about self management behaviors.