Babunageswararao Kanuri

Scientific Reports 7: Article number: 41009; published online: 20 January 2017; updated: 06 April 2017 In the original version of this Article, the link to the Supplementary Information file was omitted. This has now been corrected in the PDF and HTML versions of the paper.

Abstract On the basis of diet induced obesity and KO mice models, nitric oxide is implied to play an important role in the initiation of dyslipidemia induced insulin resistance. However, outcomes using iNOS KO mice have so far remained inconclusive. The present study aimed to assess IR in iNOS KO mice after 5 weeks of LFD feeding by monitoring body composition, energy homeostasis, insulin sensitivity/signaling, nitrite content and gene expressions changes in the tissues. We found that body weight and fat content in KO mice were significantly higher while the respiratory exchange ratio (RER), volume of carbon dioxide (VCO 2 ), and heat production were lower as compared to WT mice. Furthermore, altered systemic glucose tolerance, tissue insulin signaling, hepatic gluconeogenesis, augmented hepatic lipids, adiposity, as well as gene expression regulating lipid synthesis, catabolism and efflux were evident in iNOS KO mice. Significant reduction in eNOS and nNOS gene expression, hepatic and adipose tissue nitrite content, circulatory nitrite was also observed. Oxygen consumption rate of mitochondrial respiration has remained unaltered in KO mice as measured using extracellular flux analyzer. Our findings establish a link between the NO status with systemic and tissue specific IR in iNOS KO mice at 5 weeks.

Smoking is one of the most prominent addictions of the modern world, and one of the leading preventable causes of death worldwide. Although the number of tobacco smokers is believed to be at a historic low, electronic cigarette use has been on a dramatic rise over the past decades. Used as a replacement for cigarette smoking, electronic cigarettes were thought to reduce the negative effects of burning tobacco. Nonetheless, the delivery of nicotine by electronic cigarettes, the most prominent component of cigarette smoke (CS) is still delivering the same negative outcomes, albeit to a lesser extent than CS. Smoking has been shown to affect both the structural and functional aspects of major organs, including the lungs and vasculature. Although the deleterious effects of smoking on these organs individually is well-known, it is likely that the adverse effects of smoking on these organs will have long-lasting effects on the cardiovascular system. In addition, smoking has been shown to play an independent role in the homeostasis of the immune system, leading to major sequela. Both the adaptive and the innate immune system have been explored regarding CS and have been demonstrated to be altered in a way that promotes inflammatory signals, leading to an increase in autoimmune diseases, inflammatory diseases, and cancer. Although the mechanism of action of CS has not been fully understood, disease pathways have been explored in both branches of the immune system. The pathophysiologically altered immune system during smoking and its correlation with cardiovascular diseases is not fully understood. Here we highlight some of the important pathological mechanisms that involve cigarette smoking and its many components on cardiovascular disease and the immune systems in order to have a better understanding of the mechanisms at play.

Background Pyroptosis executor GsdmD (gasdermin D) promotes atherosclerosis in mice and humans. Disulfiram was recently shown to potently inhibit GsdmD, but the in vivo efficacy and mechanism of disulfiram's antiatherosclerotic activity is yet to be explored. Methods and Results We used human/mouse macrophages, endothelial cells, and smooth muscle cells and a hyperlipidemic mouse model of atherosclerosis to determine disulfiram antiatherosclerotic efficacy and mechanism. The effects of disulfiram on several atheroprotective pathways such as autophagy, efferocytosis, phagocytosis, and gut microbiota were determined. Atomic force microscopy was used to determine the effects of disulfiram on the biophysical properties of the plasma membrane of macrophages. Disulfiram‐fed hyperlipidemic apolipoprotein E −/− mice showed significantly reduced interleukin‐1β release upon in vivo Nlrp3 (NLR family pyrin domain containing 3) inflammasome activation. Disulfiram‐fed mice showed smaller atherosclerotic lesions (~27% and 29% reduction in males and females, respectively) and necrotic core areas (~50% and 46% reduction in males and females, respectively). Disulfiram induced autophagy in macrophages, smooth muscle cells, endothelial cells, hepatocytes/liver, and atherosclerotic plaques. Disulfiram modulated other atheroprotective pathways (eg, efferocytosis, phagocytosis) and gut microbiota. Disulfiram‐treated macrophages showed enhanced phagocytosis/efferocytosis, with the mechanism being a marked increase in cell‐surface expression of efferocytic receptor MerTK. Atomic force microscopy analysis revealed altered biophysical properties of disulfiram‐treated macrophages, showing increased order‐state of plasma membrane and increased adhesion strength. Furthermore, 16sRNA sequencing of disulfiram‐fed hyperlipidemic mice showed highly significant enrichment in atheroprotective gut microbiota Akkermansia and a reduction in atherogenic Romboutsia species. Conclusions Taken together, our data show that disulfiram can simultaneously modulate several atheroprotective pathways in a GsdmD‐dependent as well as GsdmD‐independent manner.