Silencing of Mig-7 expression inhibits in-vitro invasiveness and vasculogenic mimicry of human glioma U87 Cells Gliomas are the most common malignant primary brain tumors with poor prognosis. The migration-inducing gene-7 (Mig-7) protein is a cysteine-rich protein. Vasculogenic mimicry can replace endothelium-dependent blood vessels and supply blood to tumors, thus promoting tumor invasion and metastasis. They have also been shown to play critical roles in the development and progression of various cancers. We attempted to explore the role of Mig-7 and vasculogenic mimicry in glioma progression. We demonstrated that Mig-7 and vasculogenic mimicry were not expressed in normal tissues. In glioma, Mig-7 expression was positively associated with vasculogenic mimicry formation, the expression of both increased with increasing glioma pathological grade. In-vitro, Mig-7 silencing may inhibit the in-vitro invasiveness and formation of vasculogenic mimicry in human glioma U87 cells by inhibiting the phosphatidylinositol 3-kinase/AKT/ matrix metalloproteinases 2 and matrix metalloproteinases 9 signaling pathway. The present study thus indicates a potential role for Mig-7 as a target in the treatment of glioma.

Cocaine-induced inheritable epigenetic marks may be altered by changing early postnatal fostering Here, we explored the hypothesis that parental cocaine exposure could alter epigenetic machinery in their drug-naive offspring while early postnatal fostering may further modify the accompanied neurochemical and functional components. Variant drug-naive pups were produced from cocaine-exposed or unexposed C57BL/6 female mice that were matched with their male counterparts for mating. Within 3 days of birth, half of the pups were cross-fostered and nurtured by non-biological lactating dams. The pups were initially examined for locomotor activity and memory performance and subsequently for changes in DNA methylation in promoter regions of cAMP response element modulator (Crem) and Fosb in the prefrontal cortex at 48 days postnatum. The impact of postnatal fostering on these parameters was also investigated. Our results showed that cocaine exposure significantly decreased both Crem and Fosb methylation in the prefrontal cortex of progenitor mice, while similar patterns of methylation were replicated in the brains of drug-naive non-fostered offspring mice but reversed by postnatal fostering. Furthermore, offspring raised by cocaine-exposed dams were impaired in discriminative learning and exhibited memory decline, whereas locomotor activity remains unaltered in all groups of mice. Our data provide some evidence that indirect exposure to cocaine may cause marked epigenetic changes within the cortical networks of drug-naive descendants and that mediation by Crem/Fosb signalling in this brain region may be beneficial, while early postnatal fostering may further engineer molecular switching that may predispose the individual to future risky behaviours as well as accumulative potential to developing cognitive impairment later in life.

The small RNA microRNA-212 regulates sirtuin 2 expression in a cellular model of oxygen-glucose deprivation MicroRNA-212 has been found to play an important role in several types of diseases, but the functional and potential mechanisms of microRNA-212 in ischemic brain injury are still unclear. The aims of this study were to investigate the potential role of microRNA-212 in ischemic brain injury and to reveal potential molecular mechanisms. The rat oxygen-glucose deprivation and simulated reperfusion model was established to study the role of microRNA-212 in ischemic brain injury. The expression of microRNA-212 in oxygen-glucose deprivation and simulated reperfusion model and its effect on cell proliferation were measured by quantitative reverse transcription PCR and Cell Counting Kit-8 assay, respectively. The relationships between microRNA-212 and sirtuin 2 were confirmed by luciferase-reporter assay. We observed that microRNA-212 was downregulated after oxygen-glucose deprivation and simulated reperfusion treatment. Besides, the cells viabilities were increased/decreased in oxygen-glucose deprivation and simulated reperfusion model after transfection with microRNA-212 agomir (agonist of microRNA-212 action) and microRNA-212 antagomir (inhibitor of microRNA-212 action). In addition, luciferase and western blot experiments showed that microRNA-212 directly regulated sirtuin 2 changes. Furthermore, promotion of neuronal survival by microRNA-212 was blocked by overexpression of sirtuin 2, whereas the neuronal death induced by microRNA-212 inhibition was rescued by sirtuin 2 inhibition. Taken together, our study revealed that the role of miR-212 in the modulation of ischemic brain injury might be achieved by regulating sirtuin 2, which provides potential biomarkers and candidates for the treatment of cerebral ischemia.

Involvement of hypoxia-inducible factor-1 alpha in the upregulation of P-glycoprotein in refractory epilepsy To explore the involvement of hypoxia-inducible factor-1 alpha (HIF-1α) in the upregulation of P-glycoprotein (P-gp) in refractory epilepsy. Brain tissue specimens were collected and analyzed for expression of HIF-1α and P-gp using an immunohistochemical (IHC) staining method in both refractory epilepsy group and control group. Correlation between HIF-1α and P-gp expression level in refractory epilepsy group was analyzed. Then, a hypoxia cell model was established by simulating the nerve cell hypoxic microenvironment in the human U251 cell line using cobalt chloride (CoCl2). Western blot analysis was used to detect expression levels of HIF-1α and P-gp in the hypoxic cell model. Finally, expression of HIF-1α and P-gp was detected using real-time quantitative PCR and Western blot, respectively, after U251 hypoxic model cells were infected with HIF-1α siRNA. IHC scores of HIF-1α and P-gp in refractory epilepsy group were significantly higher than that in control group. In addition, the expression of HIF-1α was positively correlated with the expression of P-gp in refractory epilepsy group. Expression levels of HIF-1α and P-gp in U251 cells cultured with 250 µmol/L CoCl2 for 48 hours were significantly higher than that in controls. After transfection with siRNA targeting HIF-1α, expressions of HIF-1α and P-gp at mRNA and protein level were decreased, respectively, in the hypoxia cell model. HIF-1α may be involved in the upregulation of P-gp in refractory epilepsy through inducement of P-gp expression. Therefore, activation of the HIF-1α/P-gp pathway is one hypothesis proposed to explain the pathogenesis of refractory epilepsy.

Effects of ketamine on voltage-gated sodium channels in the barrel cortex and the ventral posteromedial nucleus slices of rats Ketamine is commonly used as a dissociative anesthetic with unique actions in the central nervous system. Previous studies have found that the thalamocortical systems play an important role in general anesthetics induced unconsciousness. Whether the voltage-gated sodium channels in the thalamocortical systems are the target of ketamine remain unclear. The present study used a whole-cell patch-clamp technique to observe the effects of ketamine on voltage-gated Na+ channels in thalamocortical pyramidal neurons. We found that IC50 of ketamine on Na+ currents in the primary somatosensory barrel cortex pyramidal neurons and the thalamus ventral posteromedial nucleus pyramidal neurons was 686.72 ± 39.92 and 842.65 ± 87.28 μM, respectively. Ketamine accelerated the Na+ channels inactivation and slowed inactivation of Na+ channels after recovery but did not affect the activation. We demonstrated the detailed suppression process of neural voltage-gated Na+ channels by ketamine on thalamocortical slice. This may provide a new insight into the mechanical explanation for the ketamine anesthesia.

Protective effects of fusidic acid against sodium nitroprusside-induced apoptosis in C6 glial cells Fusidic acid, a steroidal antibiotic, possesses antimicrobial, antioxidant, and anti-inflammatory properties, but the effect of fusidic acid against neurodegenerative disease-related cell death has not been studied. Here, we investigated the protective effects of fusidic acid on sodium nitroprusside (SNP)-induced toxicity in C6 glial cells. Fusidic acid (5–20 μM) prevented SNP (100 μM)-induced cell death dose dependently, and effectively attenuated SNP-induced generation of nitric oxide (NO), total reactive oxygen species (ROS), and peroxynitrite (ONOO−). Fusidic acid (20 μM) pretreatment significantly suppressed SNP (100 μM)-induced apoptotic events, such as nuclear condensation and caspase-3 activation. In addition, fusidic acid effectively attenuated SNP-induced endoplasmic reticulum (ER) stress markers, such as GRP78, IRE1, ATF6, PERK, XBP1s, eIF2α, CHOP, and caspase-12. A specific adenosine monophosphate-activated protein kinase (AMPK) inhibitor, compound C (10 μM), reversed the preventive effects of fusidic acid against SNP-induced cytotoxicity, CHOP elevation, and caspase-3 activation. These results suggest that fusidic acid can protect C6 glial cells against cytotoxicity, through the regulation of AMPK pathway and apoptotic events.

Diminished food-related motivation in adult rats treated with methamphetamine during adolescence Drug use among adolescents continues to be an area of concern because of the possibility of long-lasting physical and mental changes. The aim of this study was to determine whether methamphetamine exposure during adolescence results in long-lasting neurobehavioral alterations in adulthood. Sprague–Dawley rats were injected with methamphetamine (4 mg/kg/day) during postnatal days 28–37. Once rats reached postnatal days 150, they were placed in standard operant chambers, where they were trained to respond to a lever for sucrose pellets, the experimental reinforcement. Methamphetamine exposure during adolescence did not result in a noteworthy impairment in the development of the correct lever touch response in the autoshaped learning test with 4 seconds delayed reinforcement. These rats were also tested for the motivation to obtain sucrose pellets under a progressive ratio schedule of the reinforcement on postnatal days 170. Decreased lever-pressing response was noted in male rats exposed to methamphetamine during adolescence, but not in female rats. These results indicate that methamphetamine exposure during adolescence results in a decrease in the motivation for a natural reinforcer later in adulthood, particularly in male rats. From our data, we suggest that male brains are less capable of facilitating recovery than female brains after methamphetamine-induced perturbation of brain function during the adolescent period.

Protective effects of polygalasaponin F on oxidative stress and apoptosis-induced ischemic myocardial injury in neonatal rats with hypoxic-ischemic brain damage The aim of the present study was to evaluate the role of polygalasaponin F on ischemic myocardial injury in neonatal rats with hypoxic-ischemic brain damage. A primary in-vitro myocardial cell oxygen-glucose deprivation/reperfusion model and an in-vivo middle cerebral artery occlusion model were established. The results demonstrated that polygalasaponin F protects myocardium in hypoxic-ischemic brain injury. The mechanisms of its protective effect involved in (1) reducing oxidant stress injury, (2) reducing the apoptosis rate of myocardial cells through increasing the Bcl-2 protein level and decreasing the Cyt-C and Bax values, and (3) alleviating liver and kidney damage caused by cerebral hypoxia and ischemia via reducing the damage markers. The results of the present study may contribute toward the development of novel strategies for clinical cardioprotection with hypoxic-ischemic brain damage.

The effect of response frequency on cognitive brain activity during an alertness task A required response forces the brain to react overtly on a stimulus. This may be a factor that influences cognitive activity during a task, as it could facilitate for instance alertness, especially in tasks that are relatively easy. In the current article, we therefore tested the hypothesis that response frequency affects cognitive brain activity in an alertness task. In this 3T functional MRI study, healthy volunteers performed a continuous performance task with three conditions with increasing response frequency. Only scans during presentation of non-targets were analyzed, to exclude activity related to the change in frequency in response selection and motor responses between conditions. To evaluate changes in cognitive brain activity, a network analysis was performed based on two main networks including regions with task-induced activation and task-induced deactivation. We tested for differences in brain activity as an effect of target frequency. Performance results indicated no effect of target frequency on accuracy or reaction time. During non-targets, we found significant signal changes in TID for all three conditions, whereas TIA showed no significant signal changes in any condition. Target frequency did not have a significant effect on the level of signal change at network level, as well as at individual region level. Our study showed predominantly deactivation during non-responses in all three task conditions. Furthermore, our results indicate that response frequency does not influence brain activity during an alertness task. Our results provide additional information relevant for the understanding of the neurophysiological implementation of cognitive control or alertness.

Patterns of electrical brain activation in response to socially-disputed perceptual judgments In recent years, neuroscience has begun to investigate brain responses to social stimuli. To date, however, the effects of social feedback on attentional and perceptual processes remain unclear. In this study, participants were asked to judge the hues of distinct, or ambiguously coloured stimuli, and to indicate their confidence ratings. Alleged social feedback was then provided, either endorsing or disputing the participants’ responses. Participants were then presented the stimulus a second time and given the option to reconsider their decision. Behavioural findings showed that confidence levels decreased both with task difficulty and with conflicting social feedback. Event-related potential data showed greater P2 and N2 amplitudes for ambiguous squares compared to distinct squares upon initial stimulus presentations, compatible with heightened attention. Moreover, a decreased P300 was found for ambiguous stimuli, consistent with an increase in metacognitive activity. After social feedback, an early-late positive potential between 270 and 370 ms continued to distinguish ambiguous from distinct stimuli. More importantly, after 400 ms, the late positive potential distinguished endorsed from disputed stimuli. These results reveal that social feedback, while decreasing effects linked to uncertainty, gives rise to later processes associated with enhanced motivational significance of the stimulus following divergence from social approval.