Glycaemic control improves perfusion recovery and VEGFR2 protein expression in diabetic mice following experimental PAD

Aims Diabetes mellitus (DM) is associated with poor clinical outcomes in humans with peripheral arterial disease (PAD) and in pre-clinical models of PAD, but the effects of glycaemic control are poorly understood. We investigated the effect of glycaemic control on experimental PAD in mice with Type 1 DM and explored the effects of hyperglycaemia on vascular endothelial growth factor receptor 2 (VEGFR2) expression in ischaemia. Methods and results Hind limb ischaemia was induced in non-diabetic, untreated Type 1 DM, and treated Type 1 DM mice. We assessed perfusion recovery, capillary density, VEGFR2 levels, and VEGFR2 ubiquitination in ischaemic hind limbs. We found that untreated Type 1 DM mice showed impaired perfusion recovery, lower hind limb capillary density 5 weeks post-ischaemia, and lower VEGFR2 protein in Day 3 post-ischaemic hind limbs when compared with non-DM controls. Treated Type 1 DM mice had perfusion recovery, capillary density, and VEGFR2 protein levels comparable with that of non-diabetic mice at the same time points. Treatment with anti-VEGFR2 antibody negated that the improved perfusion recovery displayed by treated Type 1 DM mice. In ischaemic Type 1 DM hind limbs and endothelial cells exposed to simulated ischaemia, high glucose impaired VEGFR2 expression and was associated with increased VEGFR2 ubiquitination. Inhibition of the ubiquitin-proteasome complex restored normal endothelial VEGFR2 expression in simulated ischaemia. Conclusion Hyperglycaemia in Type 1 DM impairs VEGFR2 protein expression in ischaemic hind limbs, likely due to increased ubiquitination and degradation by the proteasome complex. Glycaemic control allows normal levels of VEGFR2 in ischaemia and improved perfusion recover

Update on lessons learned from glycemia control studies

Diabetes is a major health disorder affecting millions of people worldwide. Numerous studies have confirmed that micro and macrovascular complications ensue as a result of hyperglycemia. Initial studies show that while intensive glycemic control has been shown to reduce microvascular complications in both type 1 and 2 diabetics, macrovascular benefits have only been clearly seen in type 1 diabetics. Conflicting results have emerged regarding the benefits and potential adverse effects of tight glycemic control. Recent studies have emerged demonstrating some macrovascular benefits in type 2 diabetics, though this was associated with increased risk of hypoglycemia in some individuals. Thus, glycemic control in individuals with diabetes may need to be individualized in order to maximize benefits while minimizing adverse effects.Keywords: Glycemic control, Hyperglycemia, Type 2 diabetes, Glucos

Liver-resident NK cells confer adaptive immunity in skin-contact inflammation

Liver natural killer (NK) cells were recently reported to possess memory-like properties in contact hypersensitivity (CHS) models. However, the phenotype and origin of these “memory” NK cells cannot be distinguished from other NK cell subpopulations. Here, we define the transcriptional, phenotypic, and functional features of liver NK cell subsets and their roles in mediating CHS. Liver NK cells can be divided into two distinct subsets: CD49a(+)DX5(–) and CD49a(–)DX5(+). Substantial transcriptional and phenotypic differences existed between liver CD49a(+)DX5(–) NK cells and other NK cell subsets. CD49a(+)DX5(–) NK cells possessed memory potential and conferred hapten-specific CHS responses upon hapten challenge. Importantly, CD49a(+)DX5(–) NK cells were liver resident and were present in the liver sinusoidal blood, but not the afferent and efferent blood of the liver. Moreover, they appeared to originate from hepatic hematopoietic progenitor/stem cells (HPCs/HSCs) but not from the bone marrow, and maintained their phenotypes in the steady state. Our findings of liver-resident NK cells shed new light on the acquisition of memory-like properties of NK cells

Does the use of a web-based collaborative platform reduce cognitive load and influence project-based student engagement?

The web-based supported collaborative learning is increasingly used to support student social activities in higher institutions. However, little is known about the factors of collaborative learning in a web-based supported learning environment. Therefore, this study examines the use of a web-based supported collaborative platform to enhance project-based student engagement. This research aims to determine the factors that determine collaborative learning and subsequent student satisfaction. Moreover, this research determines students’ cognitive load understanding, social influence, and learner’s motivation towards collaborative learning and the resultant impact of the web-based supported collaborative platform on student satisfaction. The data was collected from university post-graduate students who used the TRELLO platform. A total of 115 post-graduate students participated in this study, and the resulting data were analyzed based on partial least squares structural equation modelling statistical approach. The study results suggest that students’ social influence and motivation positively influence collaborative learning; directly and indirectly, students are satisfied using a web-based supported collaborative learning platform to support project-based student engagement

Diabetes mellitus in peripheral artery disease: Beyond a risk factor

Peripheral artery disease (PAD) is one of the major cardiovascular diseases that afflicts a large population worldwide. PAD results from occlusion of the peripheral arteries of the lower extremities. Although diabetes is a major risk factor for developing PAD, coexistence of PAD and diabetes poses significantly greater risk of developing critical limb threatening ischemia (CLTI) with poor prognosis for limb amputation and high mortality. Despite the prevalence of PAD, there are no effective therapeutic interventions as the molecular mechanism of how diabetes worsens PAD is not understood. With increasing cases of diabetes worldwide, the risk of complications in PAD have greatly increased. PAD and diabetes affect a complex web of multiple cellular, biochemical and molecular pathways. Therefore, it is important to understand the molecular components that can be targeted for therapeutic purposes. In this review, we describe some major developments in enhancing the understanding of the interactions of PAD and diabetes. We also provide results from our laboratory in this context

Muscle cell derived angiopoietin-1 contributes to both myogenesis and angiogenesis in the ischemic environment

Recent strategies to treat peripheral arterial disease (PAD) have focused on stem cell based therapies, which are believed to result in local secretion of vascular growth factors. Little is known, however, about the role of ischemic endogenous cells in this context. We hypothesized that ischemic muscle cells (MC) are capable of secreting growth factors that act as potent effectors of the local cellular regenerative environment. Both muscle and endothelial cells (ECs) were subjected to experimental ischemia, and conditioned medium (CM) from each was collected and analyzed to assess myogenic and/or angiogenic potential. In muscle progenitors, mRNA expression of VEGF and its cognate receptors (Nrp1, Flt, Flk) was present and decreased during myotube formation in vitro, and EC CM or VEGF increased myoblast proliferation. Angiopoietin-1 (Ang-1), Tie1, and Tie2 mRNA increased during MC differentiation in vitro. Exogenous Ang-1 enhanced myogenic (MyoD and Myogenin) mRNA in differentiating myoblasts and increased myosin heavy chain protein. Myotube formation was enhanced by MC CM and inhibited by EC CM. Ang-1 protein was present in CM from MCs isolated from both the genetically ischemia-susceptible BALB/c and ischemia-resistant C57BL/6 mouse strains, and chimeric Tie2 receptor trapping in situ ablated Ang-1's myogenic effects in vitro. Ang-1 or MC CM enhanced myotube formation in a mixed isolate of muscle progenitors as well as a myoblast co-culture with pluripotent mesenchymal cells (10T1/2) and this effect was abrogated by viral expression of the extracellular domain of Tie2 (AdsTie2). Furthermore, mesh/tube formation by HUVECs was enhanced by Ang-1 or MC CM and abrogated by Tie2 chimeric receptor trapping. Our results demonstrate the ability of muscle and endothelial cell-derived vascular growth factors, particularly Ang-1, to serve as multi-functional stimuli regulating crosstalk between blood vessels and muscle cells during regeneration from ischemic myopathy

Using Multi-Theory Model to Predict Low Salt Intake - Nigerian Adults with Hypertension

Hypertension is a chronic non-communicable disease and a major risk factor for cardiovascular diseases, renal malfunction, disability, and premature death. One of the public health recommendations for the management of hypertension is the reduction of sodium/salt intake. There is need to develop and implement new evidence-based theoretical interventions to initiate and sustain behavior change in health education and promotion. Therefore, the quantitative cross-sectional method and design was used to investigate the adequacy of multi-theory model (MTM) constructs for the initiation and the sustenance of low sodium/salt intake behavior in hypertensive Nigerian adults. In addition, the impact of the MTM (initiation) constructs on actual salt/sodium intake was evaluated to validate self-reported behavior. A convenience sample of 149 consenting Nigerian adults with hypertension and of ages 20 to 60 years, self -administered the valid and reliable 39-item MTM instrument. The findings of confirmatory factor analysis showed construct validity of subscales for the initiation and sustenance model. All items loading for the two models were significant, p \u3c 0.001. Multivariate regression analysis revealed 40.6% of the variance in initiating the consumption of low salt diets explained by advantages outweighing disadvantages, behavioral confidence, and changes in physical environment. About 41.8 % of the variance to sustain the intake of low salt diet was explained by emotional transformation, practice for change, and changes in social environment. The results justified the predictive role of MTM and adequacy of its utility to build evidence-based health education programs and interventions to address the health need of people with hypertension and contribute to social change in the country

Mechanistic model of natural killer cell proliferative response to IL-15 receptor stimulation

Natural killer (NK) cells are innate lymphocytes that provide early host defense against intracellular pathogens, such as viruses. Although NK cell development, homeostasis, and proliferation are regulated by IL-15, the influence of IL-15 receptor (IL-15R)-mediated signaling at the cellular level has not been quantitatively characterized. We developed a mathematical model to analyze the kinetic interactions that control the formation and localization of IL-15/IL-15R complexes. Our computational results demonstrated that IL-15/IL-15R complexes on the cell surface were a key determinant of the magnitude of the IL-15 proliferative signal and that IL-15R occupancy functioned as an effective surrogate measure of receptor signaling. Ligand binding and receptor internalization modulated IL-15R occupancy. Our work supports the hypothesis that the total number and duration of IL-15/IL-15R complexes on the cell surface crosses a quantitative threshold prior to the initiation of NK cell division. Furthermore, our model predicted that the upregulation of IL-15Rα on NK cells substantially increased IL-15R complex formation and accelerated the expansion of dividing NK cells with the greatest impact at low IL-15 concentrations. Model predictions of the threshold requirement for NK cell recruitment to the cell cycle and the subsequent exponential proliferation correlated well with experimental data. In summary, our modeling analysis provides quantitative insight into the regulation of NK cell proliferation at the receptor level and provides a framework for the development of IL-15 based immunotherapies to modulate NK cell proliferation