Fatty acid nitroalkenes ameliorate glucose intolerance and pulmonary hypertension in high-fat diet-induced obesity

Aims Obesity is a risk factor for diabetes and cardiovascular diseases, with the incidence of these disorders becoming epidemic. Pathogenic responses to obesity have been ascribed to adipose tissue (AT) dysfunction that promotes bioactive mediator secretion from visceral AT and the initiation of pro-inflammatory events that induce oxidative stress and tissue dysfunction. Current understanding supports that suppressing pro-inflammatory and oxidative events promotes improved metabolic and cardiovascular function. In this regard, electrophilic nitro-fatty acids display pleiotropic anti-inflammatory signalling actions. Methods and results It was hypothesized that high-fat diet (HFD)-induced inflammatory and metabolic responses, manifested by loss of glucose tolerance and vascular dysfunction, would be attenuated by systemic administration of nitrooctadecenoic acid (OA-NO2). Male C57BL/6j mice subjected to a HFD for 20 weeks displayed increased adiposity, fasting glucose, and insulin levels, which led to glucose intolerance and pulmonary hypertension, characterized by increased right ventricular (RV) end-systolic pressure (RVESP) and pulmonary vascular resistance (PVR). This was associated with increased lung xanthine oxidoreductase (XO) activity, macrophage infiltration, and enhanced expression of pro-inflammatory cytokines. Left ventricular (LV) end-diastolic pressure remained unaltered, indicating that the HFD produces pulmonary vascular remodelling, rather than LV dysfunction and pulmonary venous hypertension. Administration of OA-NO2 for the final 6.5 weeks of HFD improved glucose tolerance and significantly attenuated HFD-induced RVESP, PVR, RV hypertrophy, lung XO activity, oxidative stress, and pro-inflammatory pulmonary cytokine levels. Conclusions These observations support that the pleiotropic signalling actions of electrophilic fatty acids represent a therapeutic strategy for limiting the complex pathogenic responses instigated by obesity.Fil: Kelley, Eric E.. University of Pittsburgh; Estados UnidosFil: Baust, Jeff. University of Pittsburgh; Estados UnidosFil: Bonacci, Gustavo Roberto. University of Pittsburgh; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Golin Bisello, Franca. University of Pittsburgh; Estados UnidosFil: Devlin, Jason E.. University of Pittsburgh; Estados UnidosFil: Croix, Claudette M. St.. University of Pittsburgh; Estados UnidosFil: Watkins, Simon C.. University of Pittsburgh; Estados UnidosFil: Gor, Sonia. University of Pittsburgh; Estados UnidosFil: Cantu Medellin, Nadiezhda. University of Pittsburgh; Estados UnidosFil: Weidert, Eric R.. University of Pittsburgh; Estados UnidosFil: Frisbee,Jefferson C.. University of Virginia; Estados UnidosFil: Gladwin, Mark T.. University of Pittsburgh; Estados UnidosFil: Champion, Hunter C.. University of Pittsburgh; Estados UnidosFil: Freeman, Bruce A.. University of Pittsburgh; Estados UnidosFil: Khoo, Nicholas K.H.. University of Pittsburgh; Estados Unido

Experimental intravascular hemolysis induces hemodynamic and pathological pulmonary hypertension: association with accelerated purine metabolism

Pulmonary hypertension (PH) is emerging as a serious complication associated with hemolytic disorders, and plexiform lesions (PXL) have been reported in patients with sickle cell disease (SCD). We hypothesized that repetitive hemolysis per se induces PH and angioproliferative vasculopathy and evaluated a new mechanism for hemolysis-associated PH (HA-PH) that involves the release of adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP) from erythrocytes. In healthy rats, repetitive admin- istration of hemolyzed autologous blood (HAB) for 10 days produced reversible pulmonary parenchymal injury and vascular remodeling and PH. Moreover, the combination of a single dose of Sugen-5416 (SU, 200mg/kg) and 10-day HAB treatment resulted in severe and progressive obliterative PH and formation of PXL (Day 26, right ventricular peak systolic pressure (mmHg): 26.1 1.1, 41.5 0.5 and 85.1 5.9 in untreated, HAB treated and SUþHAB treated rats, respectively). In rats, repeti- tive administration of HAB increased plasma ADA activity and reduced urinary adenosine levels. Similarly, SCD patients had higher plasma ADA and PNP activity and accelerated adenosine, inosine, and guanosine metabolism than healthy controls. Our study provides evidence that hemolysis per se leads to the development of angioproliferative PH. We also report the development of a rat model of HA-PH that closely mimics pulmonary vasculopathy seen in patients with HA-PH. Finally, this study suggests that in hemolytic diseases released ADA and PNP may increase the risk of PH, likely by abolishing the vasoprotective effects of adenosine, inosine and guanosine. Further characterization of this new rat model of hemolysis-induced angioproliferative PH and additional studies of the role of purines metabolism in HA-PH are warranted

A novel genetic programming approach to the design of engine control systems for the voltage stabilisation of hybrid electric vehicle generator outputs

This paper describes a Genetic Programming based automatic design methodology applied to the maintenance of a stable generated electrical output from a series-hybrid vehi- cle generator set. The generator set comprises a 3-phase AC generator whose output is subsequently rectified to DC.The engine/generator combination receives its control input via an electronically actuated throttle, whose control integration is made more complex due to the significant system time delay. This time delay problem is usually addressed by model predictive design methods, which add computational complexity and rely as a necessity on accurate system and delay models. In order to eliminate this reliance, and achieve stable operation with disturbance rejection, a controller is designed via a Genetic Programming framework implemented directly in Matlab, and particularly, Simulink. the principal objective is to obtain a relatively simple controller for the time-delay system which doesn’t rely on computationally expensive structures, yet retains inherent disturabance rejection properties. A methodology is presented to automatically design control systems directly upon the block libraries available in Simulink to automatically evolve robust control structures

Reporting on sustainability and HRM: a comparative study of sustainability reporting practices by the world’s largest companies

As a response to the growing public awareness on the importance of organisational contributions to sustainable development, there is an increased incentive for corporations to report on their sustainability activities. In parallel with this has been the development of ‘Sustainable HRM’ which embraces a growing body of practitioner and academic literature connecting the notions of corporate sustainability to HRM. The aim of this article is to analyse corporate sustainability reporting amongst the world’s largest companies and to assess the HRM aspects of sustainability within these reports in comparison to environmental aspects of sustainable management and whether organisational attributes – principally country-of-origin – influences the reporting of such practices. A focus in this article is the extent to which the reporting of various aspects of sustainability may reflect dominant models of corporate governance in the country in which a company is headquartered. The findings suggest, first and against expectations, that the overall disclosure on HRM-related performance is not lower than that on environmental performance. Second, companies report more on their internal workforce compared to their external workforce. Finally, international differences, in particular those between companies headquartered in liberal market economies and coordinated market economies, are not as apparent as expected

Use of Complex Lie Symmetries for Linearization of Systems of Differential Equations - II: Partial Differential Equations

The linearization of complex ordinary differential equations is studied by extending Lie's criteria for linearizability to complex functions of complex variables. It is shown that the linearization of complex ordinary differential equations implies the linearizability of systems of partial differential equations corresponding to those complex ordinary differential equations. The invertible complex transformations can be used to obtain invertible real transformations that map a system of nonlinear partial differential equations into a system of linear partial differential equation. Explicit invariant criteria are given that provide procedures for writing down the solutions of the linearized equations. A few non-trivial examples are mentioned.Comment: This paper along with its first part ODE-I were combined in a single research paper "Linearizability criteria for systems of two second-order differential equations by complex methods" which has been published in Nonlinear Dynamics. Due to citations of both parts I and II these are not replaced with the above published articl

Haptoglobin improves shock, lung injury, and survival in canine pneumonia

During the last half-century, numerous antiinflammatory agents were tested in dozens of clinical trials and have proven ineffective for treating septic shock. The observation in multiple studies that cell-free hemoglobin (CFH) levels are elevated during clinical sepsis and that the degree of increase correlates with higher mortality suggests an alternative approach. Human haptoglobin binds CFH with high affinity and, therefore, can potentially reduce iron availability and oxidative activity. CFH levels are elevated over approximately 24-48 hours in our antibiotic-treated canine model of S. aureus pneumonia that simulates the cardiovascular abnormalities of human septic shock. In this 96-hour model, resuscitative treatments, mechanical ventilation, sedation, and continuous care are translatable to management in human intensive care units. We found, in this S. aureus pneumonia model inducing septic shock, that commercial human haptoglobin concentrate infusions over 48-hours bind canine CFH, increase CFH clearance, and lower circulating iron. Over the 96-hour study, this treatment was associated with an improved metabolic profile (pH, lactate), less lung injury, reversal of shock, and increased survival. Haptoglobin binding compartmentalized CFH to the intravascular space. This observation, in combination with increasing CFHs clearance, reduced available iron as a potential source of bacterial nutrition while decreasing the ability for CFH and iron to cause extravascular oxidative tissue injury. In contrast, haptoglobin therapy had no measurable antiinflammatory effect on elevations in proinflammatory C-reactive protein and cytokine levels. Haptoglobin therapy enhances normal host defense mechanisms in contrast to previously studied antiinflammatory sepsis therapies, making it a biologically plausible novel approach to treat septic shock

Exploring an absent presence: Wayfinding as an embodied sociocultural experience

Wayfinding has often been seen as being about the quickest or shortest possible route between two points (Hölscher et al 2011; Tam 2011; Haque et al 2006). Moreover, this process has very often been seen as a cognitive one, with the experiential nature of wayfinding and with the embodied, emotional and sociocultural aspects of this experience conspicuously absent. We argue that wayfinding is rarely a purely cognitive process that involves an individual person, who is entirely instrumental in navigating a direct and precise route, but instead that this is a process almost always directed according to embodied and sociocultural needs. We propose a reassessment of present wayfinding definitions and suggest an alternative understanding that includes sociocultural elements, embodied individuals and experience through their embodied senses, as crucial elements of the concept. Seeing wayfinding from this different sociocultural ontological viewpoint, opens up new ways of understanding and planning wayfinding systems

Control of star formation by supersonic turbulence

Understanding the formation of stars in galaxies is central to much of modern astrophysics. For several decades it has been thought that stellar birth is primarily controlled by the interplay between gravity and magnetostatic support, modulated by ambipolar diffusion. Recently, however, both observational and numerical work has begun to suggest that support by supersonic turbulence rather than magnetic fields controls star formation. In this review we outline a new theory of star formation relying on the control by turbulence. We demonstrate that although supersonic turbulence can provide global support, it nevertheless produces density enhancements that allow local collapse. Inefficient, isolated star formation is a hallmark of turbulent support, while efficient, clustered star formation occurs in its absence. The consequences of this theory are then explored for both local star formation and galactic scale star formation. (ABSTRACT ABBREVIATED)Comment: Invited review for "Reviews of Modern Physics", 87 pages including 28 figures, in pres

Vascular Endothelial Dysfunction in β-Thalassemia Occurs Despite Increased eNOS Expression and Preserved Vascular Smooth Muscle Cell Reactivity to NO

The hereditary β-thalassemia major condition requires regular lifelong blood transfusions. Transfusion-related iron overloading has been associated with the onset of cardiovascular complications, including cardiac dysfunction and vascular anomalies. By using an untransfused murine model of β-thalassemia major, we tested the hypothesis that vascular endothelial dysfunction, alterations of arterial structure and of its mechanical properties would occur despite the absence of treatments.Vascular function and structure were evaluated ex vivo. Compared to the controls, endothelium-dependent vasodilation with acetylcholine was blunted in mesenteric resistance arteries of β-thalassemic mice while the endothelium-independent vasodilator (sodium nitroprusside) produced comparable vessel dilation, indicating endothelial cell impairment with preserved smooth muscle cell reactivity to nitric oxide (NO). While these findings suggest a decrease in NO bioavailability, Western blotting showed heightened expression of aortic endothelial NO synthase (eNOS) in β-thalassemia. Vascular remodeling of the common carotid arteries revealed increased medial elastin content. Under isobaric conditions, the carotid arteries of β-thalassemic mice exhibited decreased wall stress and softening due to structural changes of the vessel wall.A complex vasculopathy was identified in untransfused β-thalassemic mice characterized by altered carotid artery structure and endothelial dysfunction of resistance arterioles, likely attributable to reduced NO bioavailability despite enhanced vascular eNOS expression