83 research outputs found
Human Macrophages Infected with a High Burden of ESAT-6-Expressing M. tuberculosis Undergo Caspase-1- and Cathepsin B-Independent Necrosis
Mycobacterium tuberculosis (Mtb) infects lung macrophages, which instead of killing the pathogen can be manipulated by the bacilli, creating an environment suitable for intracellular replication and spread to adjacent cells. The role of host cell death during Mtb infection is debated because the bacilli have been shown to be both anti-apoptotic, keeping the host cell alive to avoid the antimicrobial effects of apoptosis, and pro-necrotic, killing the host macrophage to allow infection of neighboring cells. Since mycobacteria activate the NLRP3 inflammasome in macrophages, we investigated whether Mtb could induce one of the recently described inflammasome-linked cell death modes pyroptosis and pyronecrosis. These are mediated through caspase-1 and cathepsin-B, respectively. Human monocyte-derived macrophages were infected with virulent (H37Rv) Mtb at a multiplicity of infection (MOI) of 1 or 10. The higher MOI resulted in strongly enhanced release of IL-1ÎČ, while a low MOI gave no IL-1ÎČ response. The infected macrophages were collected and cell viability in terms of the integrity of DNA, mitochondria and the plasma membrane was determined. We found that infection with H37Rv at MOI 10, but not MOI 1, over two days led to extensive DNA fragmentation, loss of mitochondrial membrane potential, loss of plasma membrane integrity, and HMGB1 release. Although we observed plasma membrane permeabilization and IL-1ÎČ release from infected cells, the cell death induced by Mtb was not dependent on caspase-1 or cathepsin B. It was, however, dependent on mycobacterial expression of ESAT-6. We conclude that as virulent Mtb reaches a threshold number of bacilli inside the human macrophage, ESAT-6-dependent necrosis occurs, activating caspase-1 in the process
Heat shock partially dissociates the overlapping modules of the yeast protein-protein interaction network: a systems level model of adaptation
Network analysis became a powerful tool in recent years. Heat shock is a
well-characterized model of cellular dynamics. S. cerevisiae is an appropriate
model organism, since both its protein-protein interaction network
(interactome) and stress response at the gene expression level have been well
characterized. However, the analysis of the reorganization of the yeast
interactome during stress has not been investigated yet. We calculated the
changes of the interaction-weights of the yeast interactome from the changes of
mRNA expression levels upon heat shock. The major finding of our study is that
heat shock induced a significant decrease in both the overlaps and connections
of yeast interactome modules. In agreement with this the weighted diameter of
the yeast interactome had a 4.9-fold increase in heat shock. Several key
proteins of the heat shock response became centers of heat shock-induced local
communities, as well as bridges providing a residual connection of modules
after heat shock. The observed changes resemble to a "stratus-cumulus" type
transition of the interactome structure, since the unstressed yeast interactome
had a globally connected organization, similar to that of stratus clouds,
whereas the heat shocked interactome had a multifocal organization, similar to
that of cumulus clouds. Our results showed that heat shock induces a partial
disintegration of the global organization of the yeast interactome. This change
may be rather general occurring in many types of stresses. Moreover, other
complex systems, such as single proteins, social networks and ecosystems may
also decrease their inter-modular links, thus develop more compact modules, and
display a partial disintegration of their global structure in the initial phase
of crisis. Thus, our work may provide a model of a general, system-level
adaptation mechanism to environmental changes.Comment: 24 pages, 6 figures, 2 tables, 70 references + 22 pages 8 figures, 4
tables and 8 references in the enclosed Supplemen
Metabolic changes in concussed American football players during the acute and chronic post-injury phases
<p>Abstract</p> <p>Background</p> <p>Despite negative neuroimaging findings many athletes display neurophysiological alterations and post-concussion symptoms that may be attributable to neurometabolic alterations.</p> <p>Methods</p> <p>The present study investigated the effects of sports concussion on brain metabolism using <sup>1</sup>H-MR Spectroscopy by comparing a group of 10 non-concussed athletes with a group of 10 concussed athletes of the same age (mean: 22.5 years) and education (mean: 16 years) within both the acute and chronic post-injury phases. All athletes were scanned 1-6 days post-concussion and again 6-months later in a 3T Siemens MRI.</p> <p>Results</p> <p>Concussed athletes demonstrated neurometabolic impairment in prefrontal and motor (M1) cortices in the acute phase where NAA:Cr levels remained depressed relative to controls. There was some recovery observed in the chronic phase where Glu:Cr levels returned to those of control athletes; however, there was a pathological increase of m-I:Cr levels in M1 that was only present in the chronic phase.</p> <p>Conclusions</p> <p>These results confirm cortical neurometabolic changes in the acute post-concussion phase as well as recovery and continued metabolic abnormalities in the chronic phase. The results indicate that complex pathophysiological processes differ depending on the post-injury phase and the neurometabolite in question.</p
PGC-1α and exercise in the control of body weight
The increasing prevalence of obesity and its comorbidities represents a major threat to human health globally. Pharmacological treatments exist to achieve weight loss, but the subsequent weight maintenance is prone to fail in the long run. Accordingly, efficient new strategies to persistently control body weight need to be elaborated. Exercise and dietary interventions constitute classical approaches to reduce and maintain body weight, yet people suffering from metabolic diseases are often unwilling or unable to move adequately. The administration of drugs that partially mimic exercise adaptation might circumvent this problem by easing and supporting physical activity. The thermogenic peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) largely mediates the adaptive response of skeletal muscle to endurance exercise and is a potential target for such interventions. Here, we review the role of PGC-1α in mediating exercise adaptation, coordinating metabolic circuits and enhancing thermogenic capacity in skeletal muscle. We suggest a combination of elevated muscle PGC-1α and exercise as a modified approach for the efficient long-term control of body weight and the treatment of the metabolic syndrome
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