Sirt1 activator SRT2104 protects against oxygen-glucose deprivation/reoxygenation-induced injury via regulating microglia polarization by modulating Sirt1/NF-κB pathway.

Cerebral ischemic/reperfusion injury is the most common neurological disorder and the second leading cause of death worldwide. Modulating microglia polarization from pro-inflammatory M1 phenotype to anti-inflammatory M2 state has been suggested as a potential therapeutic approach in the treatment of this injury. SRT2104, a novel activator of histone deacetylase Sirtuin-1 (Sirt1), has recently been shown to have anti-inflammation properties. However, the effect of SRT2104 on cerebral ischemic/reperfusion injury has not been elucidated. Here, we found that SRT2104 inhibited neuron and microglia death directly and indirectly through microglia condition medium from an oxygen glucose deprivation/reoxygenation (OGD/R) -induced cell injury models. Moreover, SRT2104 treatment modulated the microglia polarization shift from the M1 phenotype and skewed toward the M2 phenotype. Additionally, we found that SRT2104 could significant inhibit the activation of NF-κB and enhanced Sirt1 expression in microglia. Mechanism studies using the BV2 microglial cell line confirmed that knockdown Sirt1 significantly reduced the effect of SRT2104 on the activation of NF-κB pathway and microglial phenotype shift. Altogether, our result shows SRT2104 protect OGD/R-induced injury through shifting microglia phenotype, which may have potential in further studies as a novel neuroprotective agent for cerebral ischemic/reperfusion injury therapy.

Increased risk of post-stroke epilepsy in Chinese patients with a TRPM6 polymorphism.

OBJECTIVES: We attempted to determine whether a functional polymorphism of TRPM6 (rs2274924) is associated with susceptibility to epilepsy following ischemic stroke, and to further explore the effect of this polymorphism on serum levels of Mg2+ in post-stroke patients. METHODS: We carried out a case-control study on 378 post-stroke epilepsy patients and 420 controls (stroke patients without secondary epilepsy). We used DNA sequencing to determine the genotypes of the TRPM6 rs2274924 polymorphism, and used the ion selective electrode method to measure serum levels of Mg2+. RESULTS: The distribution of the CC genotype and the frequency of the C allele were significantly higher in the post-stroke epilepsy patients than in the controls (P < 0.01). With regard to the post-stroke epilepsy patients, the serum levels of Mg2+ decreased significantly in the TRPM6 rs2274924 C allele carriers compared to the rs2274924 T allele carriers. CONCLUSION: The TRPM6 rs2274924 polymorphism may be associated with susceptibility to epilepsy following stroke, and the C allele may be associated with increased risk of post-stroke epilepsy. The TRPM6 rs2274924 polymorphism may also influence serum levels of Mg2+ in post-stroke epilepsy patients.

Kissing aneurysms of the distal anterior cerebral artery: A case report and literature review.

Intracranial 'kissing' aneurysms are rare types of multiple aneurysms referring to two adjacent aneurysms arising from identical or different arteries with separate origins and partially adherent walls. The present study reported a 54-year-old female patient, who was identified with a 'kissing' aneurysm in the A3 segment of the bilateral anterior cerebral arteries, as demonstrated by head computed tomography and emergency cerebral digital subtraction angiography analysis. In total, 12 days following the clipping of the aneurysms, the patient was discharged with a Modified Rankin Scale=0 and recovered well with no neurological deficits. Based on previous literature, it was indicated that the majority of patients with 'kissing' aneurysm have a good prognosis and the cure rate is as high as 96.8%. However, the recovery rate may not be that high as the sample size is not large enough to thoroughly demonstrate the complete prognosis of 'kissing' aneurysms.

Complete Mitochondrial Genome Sequence of the Human Neuroblastoma Cell Line 751-NA.

We report here for the first time the 16,566-bp mitochondrial genome sequence of the human neuroblastoma cell line 751-NA. The 13 protein-coding genes, 2 rRNAs, and 22 tRNAs are organized in a virtually identical fashion to a previously reported human mitochondrial genome, except that the 1,136-bp d-loop region is slightly variable between them.

Upregulation of miR-181a suppresses the formation of glioblastoma stem cells by targeting the Notch2 oncogene and correlates with good prognosis in patients with glioblastoma multiforme.

Glioblastoma stem-like cells (GSCs) are responsible for the initiation and progression of glioblastoma multiforme (GBM), and microRNAs (miRNAs) play an important role in this disease. However, the mechanisms underlying the role of miRNAs in the stemness of GSCs have not been completely elucidated. We previously showed that miR-181a is downregulated in GBM and may predict prognosis in patients with this disease. Here, we demonstrate that the upregulation of miR-181a suppressed GSC formation and inhibited GBM tumorigenesis by targeting the Notch2 oncogene. We found that miR-181a was downregulated in GSCs derived from human glioblastoma U87MG and U373MG cells. The high expression of miR-181a inhibited the levels of stemness-related markers CD133 and BMI1, attenuated sphere proliferation, promoted cell apoptosis, and reduced the tumorigenicity of GSCs. MiR-181a decreased the expression of Notch2 by targeting the 3'-untranslated region of its mRNA. Notch2 overexpression inhibited the effects of miR-181a downregulation on GSCs, and was negatively correlated with miR-181a expression. Moreover, high Notch2 expression together with low miR-181a expression was correlated with a shorter median overall survival for GBM patients. Together, these data show that miR-181a may play an essential role in GSC formation and GBM progression by targeting Notch2, suggesting that Notch2 and miR-181a have potential prognostic value as tumor biomarkers in GBM patients.

The correlation of microRNA-181a and target genes with poor prognosis of glioblastoma patients.

To investigate the expression and clinical significance of miR-181a and its target genes in glioblastoma multiforme (GBM), the expression levels of miR-181a and three target genes in human normal brain tissues and GBM were analyzed in silico using gene microarray, gene ontology, KEGG pathway and hierarchical clustering analysis followed by validation with quantitative RT-PCR. Our results show that miR-181a is down-regulated in GBM patients. The three target genes, ANGPT2, ARHGAP18 and LAMC1, are negatively correlated with the expression of miR-181a. Moreover, high expression of ANGPT2 or LAMC1 together with large size of GBM is correlated with a shorter median overall survival. In conclusion, our results showed that miR-181a and it targets ANGPT2 and LAMC1 might be predictors of prognosis in GBM patients.

Nefiracetam Attenuates Pro-Inflammatory Cytokines and GABA Transporter in Specific Brain Regions of Rats with Post-Ischemic Seizures.

BACKGROUND/AIMS: Prior studies demonstrated that pro-inflammatory cytokines (PICs) including IL-1ß, IL-6 and TNF-α contribute to regulation of epilepsy-associated pathophysiological processes in the specific brain regions, namely the parietal cortex, hippocampus and amygdala. Moreover, GABA transporter type 1 and 3 (GAT-1 and GAT-3) modulating extracellular GABA levels are engaged in the role played by PICs in epileptogenesis. Note that brain ischemic injury also elevates cerebral PICs. Thus, in this report we examined the effects of nefiracetam (NEF), a pyrrolidone derivative, on the levels of IL-1ß, IL-6 and TNF-α, and expression of GAT-1 and GAT-3 in the parietal cortex, hippocampus and amygdala using a rat model of post-ischemic nonconvulsive seizure (NCS). METHODS: NCS was evoked by the middle cerebral artery occlusion (MCAO). ELISA and Western Blot analysis were employed to determine the levels of PICs and GAT-1/GAT-3, respectively. RESULTS: MCAO significantly increased IL-1ß, IL-6 and TNF-α in the parietal cortex, hippocampus and amygdala as compared with sham control animals (P<0.05 vs. control rats). Also, in these specific brain regions expression of GAT-1 and GAT-3 was amplified; and the levels of GABA were decreased in rats following MCAO (P<0.05 vs. control rats). Systemic administration of NEF significantly attenuated the elevated PICs, amplified GAT-1 and GAT-3 as well as impaired GABA. NEF also attenuated the number of NCS events following MCAO. CONCLUSION: our data demonstrate that NEF improves post-ischemia evoked-NCS by altering PICs, GABA transporters thereby alleviating GABA in the parietal cortex, hippocampus and amygdala. This support a role for PICs and GABA in engagement of the adaptive responses associated with epileptic activity, but also suggests that NEF has anti-epileptic effects via PICs-GABA mechanisms, having pharmacological implications to target the specific PICs for neuronal dysfunction and vulnerability related to post-ischemic seizures and cognitive impairment.