Glioma stem cells but not bulk glioma cells upregulate IL-6 secretion in microglia/brain macrophages via toll-like receptor 4 signaling

Peripheral macrophages and resident microglia constitute the dominant glioma-infiltrating cells. The tumor induces an immunosuppressive and tumor-supportive phenotype in these glioma-associated microglia/brain macrophages (GAMs). A subpopulation of glioma cells acts as glioma stem cells (GSCs). We explored the interaction between GSCs and GAMs. Using CD133 as a marker of stemness, we enriched for or deprived the mouse glioma cell line GL261 of GSCs by fluorescence-activated cell sorting (FACS). Over the same period of time, 100 CD133(+ )GSCs had the capacity to form a tumor of comparable size to the ones formed by 10,000 CD133(-)GL261 cells. In IL-6(-/-)mice, only tumors formed by CD133(+ )cells were smaller compared with wild type. After stimulation of primary cultured microglia with medium from CD133-enriched GL261 glioma cells, we observed an selective upregulation in microglial IL-6 secretion dependent on Toll-like receptor (TLR) 4. Our results show that GSCs, but not the bulk glioma cells, initiate microglial IL-6 secretion via TLR4 signaling and that IL-6 regulates glioma growth by supporting GSCs. Using human glioma tissue, we could confirm the finding that GAMs are the major source of IL-6 in the tumor context

Анализ эффективности электростанции с водородным перегревом

Объектом исследования является анализ эффективности применения водородного перегрева на приме энергоблока К-500-240. Цель работы – проведение анализа использования водорода, как источника тепловой и электрической энергии в водородно-угольных ТЭС.The object of the study is to analyze the effectiveness of the use of hydrogen overheating at the power unit K-500-240. The purpose of the work is to analyze the use of hydrogen as a source of thermal and electric energy in hydrogen-coal thermal power plants

Разработка основных узлов установки для изучения сорбции и десорбции водорода пористыми материалами

Целью данной работой является разработка основных узлов установки для изучения сорбции и десорбции пористыми материалами.The purpose of this work is to develop the basic units of the plant for the study of sorption and desorption by porous materials

Glial cell line‐derived neurotrophic factor increases matrix metallopeptidase 9 and 14 expression in microglia and promotes microglia‐mediated glioma progression

Glial cell line‐derived neurotrophic factor (GDNF) is released by glioma cells and promotes tumor growth. We have previously found that GDNF released from the tumor cells is a chemoattractant for microglial cells, the immune cells of the central nervous system. Here we show that GDNF increases matrix metalloproteinase (MMP) 9 and MMP14 expression in cultured microglial cells from mixed sexes of neonatal mice. The GDNF‐induced microglial MMP9 and MMP14 upregulation is mediated by GDNF family receptor alpha 1 receptors and dependent on p38 mitogen‐activated protein kinase signaling. In organotypic brain slices, GDNF promotes the growth of glioma and this effect depends on the presence of microglia. We also previously found that MMP9 and MMP14 upregulation can be mediated by Toll‐like receptor (TLR) 2 signaling and here we demonstrate that GDNF increases the expression of TLR1 and TLR2. In conclusion, GDNF promotes the pro‐tumorigenic phenotype of microglia

Neurofibromatosis 1 - mutant microglia exhibit sexually-dimorphic cyclic AMP-dependent purinergic defects

As critical regulators of brain homeostasis, microglia are influenced by numerous factors, including sex and genetic mutations. To study the impact of these factors on microglia biology, we employed genetically engineered mice that model Neurofibromatosis type 1 (NF1), a disorder characterized by clinically relevant sexually dimorphic differences. While microglia phagocytic activity was reduced in both male and female heterozygous Nf1 mutant (Nf1+/-) mice, purinergic control of phagocytosis was only affected in male Nf1+/- mice. ATP-induced P2Y-mediated membrane currents and P2RY12-dependent laser lesion-induced accumulation of microglial processes were also only impaired in male, but not female Nf1+/-, microglia. These defects resulted from Nf1+/- male-specific defects in cyclic AMP regulation, rather than from changes in purinergic receptor expression. Cyclic AMP elevation by phosphodiesterase blockade restored the male Nf1+/- microglia defects in P2Y-dependent membrane currents and process motility. Taken together, these data establish a sex-by-genotype interaction important to microglia function in the adult mouse brain

Enantioselective pharmacokinetics of tramadol and its three main metabolites; impact of CYP2D6, CYP2B6, and CYP3A4 genotype

Tramadol is a complex drug, being metabolized by polymorphic enzymes and administered as a racemate with the (+)- and (−)-enantiomers of the parent compound and metabolites showing different pharmacological effects. The study aimed to simultaneously determine the enantiomer concentrations of tramadol, O-desmethyltramadol, N-desmethyltramadol, and N,O-didesmethyltramadol following a single dose, and elucidate if enantioselective pharmacokinetics is associated with the time following drug intake and if interindividual differences may be genetically explained. Nineteen healthy volunteers were orally administered either 50 or 100 mg tramadol, whereupon blood samples were drawn at 17 occasions. Enantiomer concentrations in whole blood were measured by LC-MS/MS and the CYP2D6, CYP2B6 and CYP3A4 genotype were determined, using the xTAG CYP2D6 Kit, pyrosequencing and real-time PCR, respectively. A positive correlation between the (+)/(−)-enantiomer ratio and time following drug administration was shown for all four enantiomer pairs. The largest increase in enantiomer ratio was observed for N-desmethyltramadol in CYP2D6 extensive and intermediate metabolizers, rising from about two to almost seven during 24 hours following drug intake. CYP2D6 poor metabolizers showed metabolic profiles markedly different from the ones of intermediate and extensive metabolizers, with large area under the concentration curves (AUCs) of the N-desmethyltramadol enantiomers and low corresponding values of the O-desmethyltramadol and N,O-didesmethyltramadol enantiomers, especially of the (+)-enantiomers. Homozygosity of CYP2B6 *5 and *6 indicated a reduced enzyme function, although further studies are required to confirm it. In conclusion, the increase in enantiomer ratios over time might possibly be used to distinguish a recent tramadol intake from a past one. It also implies that, even though (+)-O-desmethyltramadol is regarded the enantiomer most potent in causing adverse effects, one should not investigate the (+)/(−)-enantiomer ratio of O-desmethyltramadol in relation to side effects without consideration for the time that has passed since drug intake