Increased Expression of System x_c^- in Glioblastoma Confers an Altered Metabolic State and Temozolomide Resistance

Glioblastoma multiforme is the most aggressive malignant primary brain tumor in adults. Several studies have shown that glioma cells upregulate the expression of xCT (SLC7A11), the catalytic subunit of system x_c^-, a transporter involved in cysteine import, that modulates glutathione production and glioma growth. However, the role of system x_c^- in regulating the sensitivity of glioma cells to chemotherapy is currently debated. Inhibiting system x_c^- with sulfasalazine decreased glioma growth and survival via redox modulation, and use of the chemotherapeutic agent temozolomide together with sulfasalazine had a synergistic effect on cell killing. To better understand the functional consequences of system x_c^- in glioma, stable SLC7A11-knockdown and -overexpressing U251 glioma cells were generated. Modulation of SLC7A11 did not alter cellar proliferation but overexpression did increase anchorage-independent cell growth. Knockdown of SLC7A11 increased basal reactive oxygen species (ROS) and decreased glutathione generation resulting in increased cell death under oxidative and genotoxic stress. Overexpression of SLC7A11 resulted in increased resistance to oxidative stress and decreased chemosensitivity to temozolomide. In addition, SLC7A11 overexpression was associated with altered cellular metabolism including increased mitochondrial biogenesis, oxidative phosphorylation, and ATP generation. These results suggest that expression of SLC7A11 in the context of glioma contributes to tumorigenesis, tumor progression, and resistance to standard chemotherapy

The Influences of Reproductive Status and Acute Stress on the Levels of Phosphorylated Mu Opioid Receptor Immunoreactivity in Rat Hippocampus

Opioids play a critical role in hippocampally dependent behavior and plasticity. In the hippocampal formation, mu opioid receptors (MOR) are prominent in parvalbumin (PARV) containing interneurons. Previously we found that gonadal hormones modulate the trafficking of MORs in PARV interneurons. Although sex differences in response to stress are well documented, the point at which opioids, sex, and stress interact to influence hippocampal function remains elusive. Thus, we used quantitative immunocytochemistry in combination with light and electron microscopy for the phosphorylated MOR (pMOR) at the SER375 carboxy-terminal residue in male and female rats to assess these interactions. In both sexes, pMOR-immunoreactivity (ir) was prominent in axons and terminals and in a few neuronal somata and dendrites, some of which contained PARV in the mossy fiber pathway region of the dentate gyrus (DG) hilus and CA3 stratum lucidum. In unstressed rats, the levels of pMOR-ir in the DG or CA3 were not affected by sex or estrous cycle stage. However, immediately following 30 min of acute immobilization stress (AIS), males had higher levels of pMOR-ir whereas females at proestrus and estrus (high estrogen stages) had lower levels of pMOR-ir within the DG. In contrast, the number and types of neuronal profiles with pMOR-ir were not altered by AIS in either males or proestrus females. These data demonstrate that although gonadal steroids do not affect pMOR levels at resting conditions, they are differentially activated both pre and postsynaptic MORs following stress. These interactions may contribute to the reported sex differences in hippocampally dependent behaviors in stressed animals

miR-132 Enhances Dendritic Morphogenesis, Spine Density, Synaptic Integration, and Survival of Newborn Olfactory Bulb Neurons

An array of signals regulating the early stages of postnatal subventricular zone (SVZ) neurogenesis has been identified, but much less is known regarding the molecules controlling late stages. Here, we investigated the function of the activity-dependent and morphogenic microRNA miR-132 on the synaptic integration and survival of olfactory bulb (OB) neurons born in the neonatal SVZ. In situ hybridization revealed that miR-132 expression occurs at the onset of synaptic integration in the OB. Using in vivo electroporation we found that sequestration of miR-132 using a sponge-based strategy led to a reduced dendritic complexity and spine density while overexpression had the opposite effects. These effects were mirrored with respective changes in the frequency of GABAergic and glutamatergic synaptic inputs reflecting altered synaptic integration. In addition, timely directed overexpression of miR-132 at the onset of synaptic integration using an inducible approach led to a significant increase in the survival of newborn neurons. These data suggest that miR-132 forms the basis of a structural plasticity program seen in SVZ-OB postnatal neurogenesis. miR-132 overexpression in transplanted neurons may thus hold promise for enhancing neuronal survival and improving the outcome of transplant therapies

EP₂ receptor antagonism reduces peripheral and central hyperalgesia in a preclinical mouse model of endometriosis

Endometriosis is an incurable gynecological disorder characterized by debilitating pain and the establishment of innervated endometriosis lesions outside the uterus. In a preclinical mouse model of endometriosis we demonstrated overexpression of the PGE2-signaling pathway (including COX-2, EP2, EP4) in endometriosis lesions, dorsal root ganglia (DRG), spinal cord, thalamus and forebrain. TRPV1, a PGE2-regulated channel in nociceptive neurons was also increased in the DRG. These findings support the concept that an amplification process occurs along the pain neuroaxis in endometriosis. We then tested TRPV1, EP2, and EP4 receptor antagonists: The EP2 antagonist was the most efficient analgesic, reducing primary hyperalgesia by 80% and secondary hyperalgesia by 40%. In this study we demonstrate reversible peripheral and central hyperalgesia in mice with induced endometriosis

Mechanical properties of ceria-calcia stabilized zirconia ceramics with alumina additions

International audienceCeria-stabilized zirconia-based composites have been developed aiming to obtain ceramic materials with enhanced hardness, strength, fracture toughness, and resistance to low temperature degradation. These composites are based on ceria-calcia stabilized zirconia (10 mol% CeO2-1 mol% CaO TZP) and α-alumina (0-15 wt%) as a second phase. Raw materials in the form of powders were dispersed through ball milling, dried by slip casting and subsequently grounded before being pressed and conventionally sintered at 1450ºC. Compared to the strength and hardness of 10Ce-TZP ceramics (typically 500 MPa and 6 GPa), an increase was observed for all compositions, especially for 10Ce-1CaO-5Al2O3 (739 MPa and 10.2 GPa). Single Edge V-Notched Beam fracture toughness values ranged from 5.1 to 6.6 MPa⸱√m, indicating a loss of transformability for all compositions. As in 10Ce-1CaO-TZP co-doped ceramics, the aging resistance of all alumina containing composites was also excellent

Corrosion and Low Temperature Degradation of 3Y-TZP dental ceramics under acidic conditions

International audienceDue to its excellent properties, yttria-stabilized tetragonal zirconia ceramics (Y-TZP) are considered to be an appropriate choice for advanced dental applications. However, the long-term surface stability of these materials in a humid environment is still a matter of discussion. In the present work, two commercial and one in-house prepared 3Y-TZP ceramics were studied. The materials stability and durability were evaluated in the light of their behavior against long-term corrosion under low acidic pH (up to 265 days) and Low Temperature Degradation (LTD). The extent of corrosion and LTD was monitored by determining the content of monoclinic zirconia at the surfaces by X-Ray Diffraction. The obtained results show that leaching of yttrium from the 3Y-TZP tested materials takes place. Nonetheless, there is no significant impact of yttrium loss on the vulnerability to LTD of corroded samples in the conditions of this work

Study of transformation bands in ceria-stabilized zirconia-based composites: Does the transformation-induced plasticity induce damage?

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