Paraoxonase 2 Induces a Phenotypic Switch in Macrophage Polarization Favoring an M2 Anti-Inflammatory State

Inflammatory processes are involved in atherosclerosis development. Macrophages play a major role in the early atherogenesis, and they are present in the atherosclerotic lesion in two phenotypes: proinflammatory (M1) or anti-inflammatory (M2). Paraoxonase 2 (PON2) is expressed in macrophages, and it was shown to protect against atherosclerosis. Thus, the aim of our study was to analyze the direct effect of PON2 on macrophage inflammatory phenotypes. Ex vivo studies were performed with murine peritoneal macrophages (MPM) harvested from control C57BL/6 and PON2-deficient (PON2KO) mice. PON2KO MPM showed an enhanced proinflammatory phenotype compared to the control, both in the basal state and following M1 activation by IFNγ and lipopolysaccharide (LPS). In parallel, PON2KO MPM also showed reduced anti-inflammatory responses in the basal state and also following M2 activation by IL-4. Moreover, the PON2-null MPM demonstrated enhanced phagocytosis and reactive oxygen species (ROS) production in the basal state and following M1 activation. The direct effect of PON2 was shown by transfecting human PON2 (hPON2) into PON2KO MPM. PON2 transfection attenuated the macrophages’ response to M1 activation and enhanced M2 response. These PON2 effects were associated with attenuation of macrophages’ abilities to phagocyte and to generate ROS. We conclude that PON2 promotes an M1 to M2 switch in macrophage phenotypes

HDL Apolipoprotein A-I Attenuates Oxidative Modification of Low Density Lipoprotein: Studies in Transgenic Mice

Peer Reviewe

Leucine supplementation attenuates macrophage foamâ cell formation: Studies in humans, mice, and cultured macrophages

Whereas atherogenicity of dietary lipids has been largely studied, relatively little is known about the possible contribution of dietary amino acids to macrophage foamâ cell formation, a hallmark of early atherogenesis. Recently, we showed that leucine has antiatherogenic properties in the macrophage model system. In this study, an inâ depth investigation of the role of leucine in macrophage lipid metabolism was conducted by supplementing humans, mice, or cultured macrophages with leucine. Macrophage incubation with serum obtained from healthy adults supplemented with leucine (5 g/d, 3 weeks) significantly decreased cellular cholesterol mass by inhibiting the rate of cholesterol biosynthesis and increasing cholesterol efflux from macrophages. Similarly, leucine supplementation to C57BL/6 mice (8 weeks) resulted in decreased cholesterol content in their harvested peritoneal macrophages (MPM) in relation with reduced cholesterol biosynthesis rate. Studies in J774A.1 murine macrophages revealed that leucine doseâ dependently decreased cellular cholesterol and triglyceride mass. Macrophages treated with leucine (0.2 mM) showed attenuated uptake of very lowâ density lipoproteins and triglyceride biosynthesis rate, with a concurrent downâ regulation of diacylglycerol acyltransferaseâ 1, a key enzyme catalyzing triglyceride biosynthesis in macrophages. Similar effects were observed when macrophages were treated with αâ ketoisocaproate, a key leucine metabolite. Finally, both in vivo and in vitro leucine supplementation significantly improved macrophage mitochondrial respiration and ATP production. The above studies, conducted in human, mice, and cultured macrophages, highlight a protective role for leucine attenuating macrophage foamâ cell formation by mechanisms related to the metabolism of cholesterol, triglycerides, and energy production. © 2018 BioFactors, 44(3):245â 262, 2018Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/144642/1/biof1415.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/144642/2/biof1415_am.pd

Industrial strategy and the UK regions: Sectorally narrow and spatially blind

The UK government's new Industrial Strategy could have a significant impact on the country's regions and localities. However, this has received little attention to date. The analysis presented here examines the existing location of the sectors targeted by the first phase of the Industrial Strategy Challenge Fund and the location of the R&D laboratories likely to be first in line for funding. In focusing on an extremely narrow range of sectors, the Fund is likely to have limited impact on the UK's persistent regional inequalities. The activities eligible for support account for relatively little of manufacturing or the rest of the economy and the basis of this targeting and its potential distributional consequences are spatially blind. As such, it runs the risk of widening regional divides in prosperity

p38 MAPK in Glucose Metabolism of Skeletal Muscle: Beneficial or Harmful?

Skeletal muscles respond to environmental and physiological changes by varying their size, fiber type, and metabolic properties. P38 mitogen-activated protein kinase (MAPK) is one of several signaling pathways that drive the metabolic adaptation of skeletal muscle to exercise. p38 MAPK also participates in the development of pathological traits resulting from excessive caloric intake and obesity that cause metabolic syndrome and type 2 diabetes (T2D). Whereas p38 MAPK increases insulin-independent glucose uptake and oxidative metabolism in muscles during exercise, it contrastingly mediates insulin resistance and glucose intolerance during metabolic syndrome development. This article provides an overview of the apparent contradicting roles of p38 MAPK in the adaptation of skeletal muscles to exercise and to pathological conditions leading to glucose intolerance and T2D. Here, we focus on the involvement of p38 MAPK in glucose metabolism of skeletal muscle, and discuss the possibility of targeting this pathway to prevent the development of T2D