4 research outputs found
TNFR1 contributes to activation-induced cell death of pathological CD4+ T lymphocytes during ischemic heart failure
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Small Molecule Mediated Restoration of Mitochondrial Function Augments Anti-Mycobacterial Activity of Human Macrophages Subjected to Cholesterol Induced Asymptomatic Dyslipidemia
Mycobacterium tuberculosis (M.tb) infection manifests into tuberculosis (TB) in a small fraction of the infected population that comprises the TB susceptible group. Identifying the factors potentiating susceptibility to TB persistence is one of the prime agenda of TB control programs. Recently, WHO recognized diabetes as a risk factor for TB disease progression. The closely related pathological state of metabolic imbalance, dyslipidemia, is yet another emerging risk factor involving deregulation in host immune responses. While high cholesterol levels are clinically proven condition for perturbations in cardiac health, a significant fraction of population these days suffer from borderline risk cholesterol profiles. This apparently healthy population is susceptible to various health risks placing them in the “pre-disease” range. Our study focuses on determining the role of such asymptomatic dyslipidemia as a potential risk factor for susceptibility to TB persistence. Macrophages exposed to sub-pathological levels of cholesterol for chronic period, besides impaired release of TNF-α, could not clear intracellular pathogenic mycobacteria effectively as compared to the unexposed cells. These cells also allowed persistence of opportunistic mycobacterial infection by M. avium and M. bovis BCG, indicating highly compromised immune response. The cholesterol-treated macrophages developed a foamy phenotype with a significant increase in intracellular lipid-bodies prior to M.tb infection, potentially contributing to pre-disease state for tuberculosis infection. The foamy phenotype, known to support M.tb infection, increased several fold upon infection in these cells. Additionally, mitochondrial morphology and function were perturbed, more so during infection in cholesterol treated cells. Pharmacological supplementation with small molecule M1 that restored mitochondrial structural and functional integrity limited M.tb survival more effectively in cholesterol exposed macrophages. Mechanistically, M1 molecule promoted clearance of mycobacteria by reducing total cellular lipid content and restoring mitochondrial morphology and function to its steady state. We further supported our observations by infection assays in PBMC-derived macrophages from clinically healthy volunteers with borderline risk cholesterol profiles. With these observations, we propose that prolonged exposure to sub-pathological cholesterol can lead to asymptomatic susceptibility to M.tb persistence. Use of small molecules like M1 sets yet another strategy for host-directed therapy where re-functioning of mitochondria in cholesterol abused macrophages can improve M.tb clearance
Glucagon-like peptide-1 receptor-mediated endosomal cAMP generation promotes glucose-stimulated insulin secretion in pancreatic β-cells
Nicotinamide Mononucleotide Prevents Free Fatty Acid-Induced Reduction in Glucose Tolerance by Decreasing Insulin Clearance
The NAD-dependent deacetylase SIRT1 improves β cell function. Accordingly, nicotinamide mononucleotide (NMN), the product of the rate-limiting step in NAD synthesis, prevents β cell dysfunction and glucose intolerance in mice fed a high-fat diet. The current study was performed to assess the effects of NMN on β cell dysfunction and glucose intolerance that are caused specifically by increased circulating free fatty acids (FFAs). NMN was intravenously infused, with or without oleate, in C57BL/6J mice over a 48-h-period to elevate intracellular NAD levels and consequently increase SIRT1 activity. Administration of NMN in the context of elevated plasma FFA levels considerably improved glucose tolerance. This was due not only to partial protection from FFA-induced β cell dysfunction but also, unexpectedly, to a significant decrease in insulin clearance. However, in conditions of normal FFA levels, NMN impaired glucose tolerance due to decreased β cell function. The presence of this dual action of NMN suggests caution in its proposed therapeutic use in humans