The active thyroid hormone, triiodothyronine (T3), regulates mitochondrial uncoupling protein activity and related thermogenesis in peripheral tissues. Type 2 deiodinase (DII), an enzyme that catalyzes active thyroid hormone production, and mitochondrial uncoupling protein 2 (UCP2) are also present in the hypothalamic arcuate nucleus, where their interaction and physiological significance have not been explored. Here, we report that DII-producing glial cells are in direct apposition to neurons coexpressing neuropeptide Y (NPY), agouti-related protein (AgRP), and UCP2. Fasting increased DII activity and local thyroid hormone production in the arcuate nucleus in parallel with increased GDP-regulated UCP2-dependent mitochondrial uncoupling. Fasting-induced T3-mediated UCP2 activation resulted in mitochondrial proliferation in NPY/AgRP neurons, an event that was critical for increased excitability of these orexigenic neurons and consequent rebound feeding following food deprivation. These results reveal a physiological role for a thyroid-hormone-regulated mitochondrial uncoupling in hypothalamic neuronal networks.
Neuronal apoptosis is a suspected cause of neurodegeneration in Alzheimer's disease (AD). Increased levels of amyloid beta peptide (Abeta) induce neuronal apoptosis in vitro and in vivo. The underlying molecular mechanism of Abeta neurotoxicity is not clear. The normal concentration of Abeta in cerebrospinal fluid is 4 nM. We treated human neuron primary cultures with 100 nM amyloid beta peptides Abeta(1-40) and Abeta(1-42) and the control reverse peptide Abeta(40-1). We find that although little neuronal apoptosis is induced by either peptide after 3 d of treatment, Abeta(1-42) provokes a rapid and sustained downregulation of a key anti-apoptotic protein, bcl-2, whereas it increases levels of bax, a protein known to promote cell death. In contrast, the Abeta(1-40) downregulation of bcl-2 is gradual, although the levels are equivalent to those of Abeta(1-42)-treated neurons by 72 hr of treatment. Abeta(1-40) does not upregulate bax levels. The control, reverse peptide Abeta(40-1), does not affect either bcl-2 or bax protein levels. In addition, we found that the Abeta(1-40)- and Abeta(1-42)- but not Abeta(40-1)-treated neurons had increased vulnerability to low levels of oxidative stress. Therefore, we propose that although high physiological amounts of Abeta are not sufficient to induce apoptosis, Abeta depletes the neurons of one of its anti-apoptotic mechanisms. We hypothesize that increased Abeta in individuals renders the neurons vulnerable to age-dependent stress and neurodegeneration.
The 2009 pandemic H1N1 (H1N1pdm09) influenza virus is naturally susceptible to neuraminidase (NA) inhibitors, but mutations in the NA protein can cause oseltamivir resistance. The H275Y and I223V amino acid substitutions in the NA of the H1N1pdm09 influenza strain have been separately observed in patients exhibiting oseltamivir-resistance. Here, we apply mathematical modelling techniques to compare the fitness of the wild-type H1N1pdm09 strain relative to each of these two mutants. We find that both the H275Y and I223V mutations in the H1N1pdm09 background significantly lengthen the duration of the eclipse phase (by 2.5 h and 3.6 h, respectively), consistent with these NA mutations delaying the release of viral progeny from newly infected cells. Cells infected by H1N1pdm09 virus carrying the I223V mutation display a disadvantageous, shorter infectious lifespan (17 h shorter) than those infected with the wild-type or MUT-H275Y strains. In terms of compensating traits, the H275Y mutation in the H1N1pdm09 background results in increased virus infectiousness, as we reported previously, whereas the I223V exhibits none, leaving it overall less fit than both its wild-type counterpart and the MUT-H275Y strain. Using computer simulated competition experiments, we determine that in the presence of oseltamivir at doses even below standard therapy, both the MUT-H275Y and MUT-I223V dominate their wild-type counterpart in all aspects, and the MUT-H275Y outcompetes the MUT-I223V. The H275Y mutation should therefore be more commonly observed than the I223V mutation in circulating H1N1pdm09 strains, assuming both mutations have a similar impact or no significant impact on between-host transmission. We also show that mathematical modelling offers a relatively inexpensive and reliable means to quantify inter-experimental variability and assess the reproducibility of results.
Peroxisome proliferator-activated receptors (PPARs) are involved in energy expenditure, regulation of inflammatory processes, and cellular protection in peripheral tissues. Among the different types of PPARs, PPARb is the only one to be widely expressed in cortical neurons. Using PPARb knockout (KO) mice, we report here a detailed investigation of the role of PPARb in cerebral ischemic damage, associated inflammatory and antioxidant processes as well as food intake regulation after middle cerebral artery occlusion (MCAO). The PPARb KO mice had a two-fold increase in infarct size compared with wild-type (WT) mice. Brain oxidative stress was dramatically enhanced in these KO mice, as documented by an increased content of malondialdehyde, decreased levels of glutathione and manganese superoxide dismutase, and no induction of uncoupling protein 2 (UCP2) mRNA. Unlike WT mice, PPARb KO mice showed a marked increase of prooxidant interferon-gamma but no induction of nerve growth factor and tumor necrosis factor alpha after MCAO. In WT mice, MCAO resulted in inflammation-specific transient hyperphagia from day 3 to day 5 after ischemia, which was associated with an increase in neuropeptide Y (NPY) mRNA. This hyperphagic phase and NPY mRNA induction were not observed in PPARb KO mice. Furthermore, our study also suggests for the first time that UCP2 is involved in MCAO food intake response. These data indicate that PPARb plays an important role in integrating and regulating central inflammation, antioxidant mechanisms, and food intake after MCAO, and suggest that the use of PPARb agonists may be of interest for the prevention of central ischemic damage.
Purpose To assess the dosimetric accuracy of synthetic CT volumes generated from MRI data for focal brain radiotherapy. Methods A study was conducted on 12 patients with gliomas who underwent both MR and CT imaging as part of their simulation for external beam treatment planning. Synthetic CT (MRCT) volumes were generated from the MR images. The patients’ clinical treatment planning directives were used to create 12 individual Volumetric Modulated Arc Therapy (VMAT) plans, which were then optimized 10 times on each of their respective CT and MRCT-derived electron density maps. Dose metrics derived from optimization criteria, as well as monitor units and gamma analyses, were evaluated to quantify differences between the imaging modalities. Results Mean differences between Planning Target Volume (PTV) doses on MRCT and CT plans across all patients were 0.0% (range −0.1 to 0.2%) for D95%, 0.0% (−0.7 to 0.6%) for D5%, and −0.2% (−1.0 to 0.2%) for Dmax. MRCT plans showed no significant change in monitor units (−0.4%) compared to CT plans. Organs at risk (OARs) had an average Dmax difference of 0.0 Gy (−2.2 to 1.9 Gy) over 85 structures across all 12 patients, with no significant differences when calculated doses approached planning constraints. Conclusions Focal brain VMAT plans optimized on MRCT images show excellent dosimetric agreement with standard CT-optimized plans. PTVs show equivalent coverage, and OARs do not show any overdose. These results indicate that MRI-derived synthetic CT volumes can be used to support treatment planning of most patients treated for intracranial lesions.
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