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We assessed the amount of specific metabolites induced by Vpr and HIV-1 in macrophages at the intracellular and extracellular level in a time-dependent manner utilizing multiple reaction monitoring (MRM) targeted metabolomics. In addition, stable isotope-labeled glucose and an MRM targeted metabolomics assay were used to evaluate the de novo synthesis and release of glutamate in Vpr overexpressing macrophages and HIV-1 infected macrophages, throughout the metabolic flux of glycolytic pathway and TCA cycle activation.
The metabolic flux studies demonstrated an increase in glucose uptake, glutamate release and accumulation of α-ketoglutarate (α-KG) and glutamine in the extracellular milieu in Vpr expressing and HIV-1 infected macrophages. Interestingly, glutamate pools and other intracellular intermediates (glucose-6-phosphate (G6P), fructose-6-phosphate (F6P), citrate, malate, α-KG, and glutamine) showed a decreased trend except for fumarate, in contrast to the glutamine accumulation observed in the extracellular space in Vpr overexpressing macrophages.
Our studies demonstrate that dysregulation of mitochondrial glutamate metabolism induced by Vpr in HIV-1 infected macrophages commonly seen, may contribute to neurodegeneration via excitotoxic mechanisms in the context of NeuroAIDS. 相似文献
Corpus callosum trauma has long been implicated in mild traumatic brain injury (mTBI), yet the mechanism by which forces penetrate this structure is unknown. We investigated the hypothesis that coronal and horizontal rotations produce motion of the falx cerebri that damages the corpus callosum. We analyzed previously published head kinematics of 115 sports impacts (2 diagnosed mTBI) measured with instrumented mouthguards and used finite element (FE) simulations to correlate falx displacement with corpus callosum deformation. Peak coronal accelerations were larger in impacts with mTBI (8592 rad/s2 avg.) than those without (1412 rad/s2 avg.). From FE simulations, coronal acceleration was strongly correlated with deep lateral motion of the falx center (r = 0.85), while horizontal acceleration was correlated with deep lateral motion of the falx periphery (r > 0.78). Larger lateral displacement at the falx center and periphery was correlated with higher tract-oriented strains in the corpus callosum body (r = 0.91) and genu/splenium (r > 0.72), respectively. The relationship between the corpus callosum and falx was unique: removing the falx from the FE model halved peak strains in the corpus callosum from 35% to 17%. Consistent with model results, we found indications of corpus callosum trauma in diffusion tensor imaging of the mTBI athletes. For a measured alteration of consciousness, depressed fractional anisotropy and increased mean diffusivity indicated possible damage to the mid-posterior corpus callosum. Our results suggest that the corpus callosum may be sensitive to coronal and horizontal rotations because they drive lateral motion of a relatively stiff membrane, the falx, in the direction of commissural fibers below.
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