NSUN5/TET2-directed chromatin-associated RNA modification of 5-methylcytosine to 5-hydroxymethylcytosine governs glioma immune evasion.

Malignant glioma exhibits immune evasion characterized by highly expressing the immune checkpoint CD47. RNA 5-methylcytosine(m5C) modification plays a pivotal role in tumor pathogenesis. However, the mechanism underlying m5C-modified RNA metabolism remains unclear, as does the contribution of m5C-modified RNA to the glioma immune microenvironment. In this study, we demonstrate that the canonical 28SrRNA methyltransferase NSUN5 down-regulates ß-catenin by promoting the degradation of its mRNA, leading to enhanced phagocytosis of tumor-associated macrophages (TAMs). Specifically, the NSUN5-induced suppression of ß-catenin relies on its methyltransferase activity mediated by cysteine 359 (C359) and is not influenced by its localization in the nucleolus. Intriguingly, NSUN5 directly interacts with and deposits m5C on CTNNB1 caRNA (chromatin-associated RNA). NSUN5-induced recruitment of TET2 to chromatin is independent of its methyltransferase activity. The m5C modification on caRNA is subsequently oxidized into 5-hydroxymethylcytosine (5hmC) by TET2, which is dependent on its binding affinity for Fe2+ and α-KG. Furthermore, NSUN5 enhances the chromatin recruitment of RBFOX2 which acts as a 5hmC-specific reader to recognize and facilitate the degradation of 5hmC caRNA. Notably, hmeRIP-seq analysis reveals numerous mRNA substrates of NSUN5 that potentially undergo this mode of metabolism. In addition, NSUN5 is epigenetically suppressed by DNA methylation and is negatively correlated with IDH1-R132H mutation in glioma patients. Importantly, pharmacological blockage of DNA methylation or IDH1-R132H mutant and CD47/SIRPα signaling synergistically enhances TAM-based phagocytosis and glioma elimination in vivo. Our findings unveil a general mechanism by which NSUN5/TET2/RBFOX2 signaling regulates RNA metabolism and highlight NSUN5 targeting as a potential strategy for glioma immune therapy.

Silencing long noncoding RNA LINC01138 inhibits aerobic glycolysis to reduce glioma cell proliferation by regulating the microRNA­375/SP1 axis.

Glioma is a primary cerebral neoplasm that originates from glial tissue and spreads to the central nervous system. Long noncoding RNAs are known to play a role in glioma cells by regulating cell proliferation, migration and invasion. The aim of the present study was to investigate the mechanism by which long intergenic non­protein coding RNA (LINC) 01138 affects glycolysis and proliferation in glioma cells via the microRNA (miR)­375/specificity protein 1 (SP1) axis. LINC01138 expression was assessed in glioma tissues and cells using reverse transcription­quantitative PCR and the association between LINC01138 and patient clinicopathological features was analyzed. Glucose uptake, lactic acid secretion, cell proliferation, and glycolysis­related enzyme levels were detected following LINC01138 silencing using CCK­8, EDU assay and western blot analysis. miR­375 and SP1 expression levels were also assessed, and the distribution of LINC01138 in the nucleus and cytoplasm was investigated using subcellular fractionation localization. Furthermore, the binding relationships between LINC01138 and miR­375, and between miR­375 and SP1 were assessed via dual­luciferase experiment, RIP and RNA pull­down assays. Finally, xenograft transplantation models were used to verify the in vitro results. LINC01138 was highly expressed in glioma, which was independent of patient sex or age but was significantly related to tumor diameter, the World Health Organization tumor grade and lymph node metastasis. Silencing LINC01138 significantly reduced glioma glycolysis and cell proliferation. Moreover, LINC01138 acted as a competing endogenous RNA to sponge miR­375 and promote SP1 expression. miR­375 inhibition significantly reversed the effect of LINC01138 silencing. In addition, silencing LINC01138 significantly reduced tumor growth in vivo. The present study demonstrated that silencing LINC01138 inhibited aerobic glycolysis and thus reduced glioma cell proliferation, potentially by modulating the miR­375/SP1 axis.

Eucalyptol ameliorates early brain injury after subarachnoid haemorrhage via antioxidant and anti-inflammatory effects in a rat model.

CONTEXT: As the terpenoid oxide extracted from Eucalyptus L. Herit (Myrtaceae), eucalyptol (EUC) has anti-inflammatory and antioxidant effects. OBJECTIVE: To evaluate the neuroprotective role of EUC in subarachnoid haemorrhage (SAH). MATERIALS AND METHODS: Sprague-Dawley rats were divided into 4 groups: sham group, SAH group, SAH + vehicle group, and SAH + EUC group. SAH was induced by endovascular perforation. In SAH + EUC group, 100 mg/kg EUC was administrated intraperitoneally at 1 h before SAH and 30 min after SAH, respectively. Neurological deficits were examined by modified Neurological Severity Scores (mNSS). The brain edoema was evaluated by wet-dry method. Neuronal apoptosis was detected by Nissl staining. The expression of Bcl-2, cleaved caspase-3, phospho-NF-κB p65, ionised calcium-binding adapter molecule-1 (Iba-1), nuclear factor erythroid-2 (Nrf-2), and haem oxygenase 1 (HO-1) were measured by Western blot. Expression of pro-inflammatory cytokines was detected by qRT-PCR. Oxidative stress markers were also measured. RESULTS: EUC markedly relieved brain edoema (from 81.22% to 78.33%) and neurological deficits [from 16.28 to 9.28 (24 h); from 12.50 to 7.58 (48 h)]. EUC reduced neuronal apoptosis, microglial activation, and oxidative stress. EUC increased the expression of HO-1 (1.15-fold), Nrf2 (1.34-fold) and Bcl-2 (1.17-fold) in the rats' brain tissue, and down-regulated the expressions of cleaved caspase-3 (41.09%), phospho-NF-κB p65 (14.38%) and pro-inflammatory cytokines [TNF-α (34.33%), IL-1ß (50.40%) and IL-6 (59.13%)]. DISCUSSION AND CONCLUSION: For the first time, this study confirms that EUC has neuroprotective effects against early brain injury after experimental SAH in rats.

Down-regulation of STIP1 regulate apoptosis and invasion of glioma cells via TRAP1/AKT signaling pathway.

BACKGROUND: In recent years, many studies have confirmed that STIP1 (phosphorylation-induced protein 1) is involved in the development and progression of various tumors. However, its potential role in glioma progression and the underlying mechanisms of glioma development remain unclear. METHODS: We analyzed the expression of STIP1 in 35 human glioma tissue specimens of different grades, using 6 normal brain tissues for comparison. We transfected U87 and U251 cell lines with small interfering RNA (siRNA) to downregulate STIP1, and set up a negative control group and a blank group for comparison. The MTT assay was used to detect cell proliferation, and cell cycle progression and apoptosis were analyzed through flow cytometry. Transwell experiments were employed to detect the invasion and migration of STIP1-depleted and control U87 and U251 cells and western blotting was used to detect the expression of TRAP1/Akt pathway proteins. In addition, immunohistochemical analysis was used to reveal differences in expression and localization between transplanted tumor specimens of each group. RESULTS: We observed a high expression of STIP1 in glioblastoma, MTT assay revealed a decreased cell proliferation rate in the STIP1-downregulated cells. Cell cycle analysis revealed an increased proportion of cells in G1 phase, as well as an increase in apoptosis, upon STIP1 downregulation. Western blotting showed that TRAP1, pAkt, and MMP2 expression was decreased upon STIP1 downregulation. In addition, TRAP1, ki-67, and MMP2 displayed a decreased expression in vivo. CONCLUSIONS: STIP1 is highly expressed in glioblastoma compared to normal brain tissues. Downregulation of STIP1 in glioma cells reduces cell proliferation rate and invasion and increases cell apoptosis.

SALL4 suppresses PTEN expression to promote glioma cell proliferation via PI3K/AKT signaling pathway.

Spalt-like transcription factor 4 (SALL4), a oncogene, is known to participate in multiple carcinomas, and is up-regulated in glioma. However, its actual role and underlying mechanisms in the development of glioma remain unclear. The present study explored the molecular functions of SALL4 in promoting cell proliferation in glioma. The expression level of SALL4 in 69 human glioma samples and six non-tumor brain tissues was determined using real-time polymerase chain reaction (PCR). Then, we transfected U87 and U251 cell lines with siRNA, and assessed cellular proliferation and cell cycle to understand the function of SALL4, and the relationship between SALL4, PTEN and PI3K/AKT pathway. PCR confirmed that the expression of SALL4 was higher in the glioma samples than non-tumor brain tissues. Cellular growth and proliferation were dramatically reduced following inhibition of SALL4 expression. Western blot showed increase in PTEN expression when SALL4 was silenced, which in turn depressed the activation of PI3K/AKT pathway, suggesting that PTEN was a downstream target of SALL4 in glioma development. Therefore, SALL4 could act as a proto-oncogene by regulating the PTEN/PI3K/AKT signaling pathway, thereby facilitating proliferation of glioma cells.

Effects of atorvastatin on chronic subdural hematoma: A systematic review.

BACKGROUND: The high recurrent rate of chronic subdural hematoma (CSDH) has consistently confused the neurosurgeons, and the role of atorvastatin in the management of CSDH has remained unclear over past decade, and atorvastatin seems to be a safe and cost-effective treatment to CSDH. Therefore, it is necessary to conduct a systematic review to discuss the effect of atorvastatin in CSDH. METHOD: We searched the PubMed, EMBASE, Cochrane Library, and the China Biology Medicine disc, up to March 2017, for published studies on the effects of atorvastatin in the management of CSDH, and reviewers performed a brief qualitative descriptive analysis of atorvastatin's efficacy in the management of CSDH. RESULTS: Three eligible studies were included in this systematic review. Results indicated that atorvastatin accelerated hematoma absorption, decreased recurrence risk, and surgical requirement. CONCLUSION: Limited evidence suggests that oral atorvastatin may be beneficial in the management of CSDH. Further high-quality studies focused on dosage, duration, hematoma size are needed to further elucidate the role of atorvastatin in the management of CSDH.

Effects of hemoglobin level on the early postsurgical cerebral metabolism in patients with severe traumatic brain injury.

OBJECTIVE: The study aims to explore the effects of different levels of haemoglobin (Hb) on early cerebral metabolism in patients with postoperative severe traumatic brain injury (TBI) . METHOD: Fifty-nine patients were randomly divided into catheter oxygen group and ventilator-assisted respiratory group. Each group was subsequently divided into three subgroups basing on different Hb level: Hb ≤ 70 g/L subgroup, 71 g/L ≤ Hb≤90 g/L subgroup and Hb ≥ 91 g/L subgroup. The blood samples from the femoral artery and the affected side internal jugular vein were, respectively, taken at the same time from the patient after postoperative 3 days. RESULTS: The incidence of anaemia after severe TBI operation was 88.14%. The VADL and cerebral glucose uptake (CMRglu) in both Hb ≤ 70 g/L and 71 g/L ≤ Hb≤90 g/L patients of oxygen catheter group were less than that in Hb ≥ 91 g/L patients. In the ventilator-assisted breathing group, the VADL and CMRglu of 71 g/L ≤ Hb≤90 g/L patients and Hb ≥ 91 g/L patients were lower than those in Hb ≤ 70 g/L patients. The result from comparing the two 71 g/L ≤ Hb ≤ 90 g/L subgroups showed that the brain metabolic indexs in the ventilator-assisted breathing group were better than those in the catheter oxygen group. CONCLUSIONS: In severe TBI postoperative patients, Hb≤90 g/L induced decrease in aerobic oxidation in brain tissue. Moreover, for the same Hb level of 71 g/L ≤ Hb≤90 g/L, ventilator-assisted breathing significantly improved cerebral metabolism.

Risk of pneumonia in central nervous system injury with alcohol intake: a meta-analysis.

OBJECTIVE: Central nervous system (CNS) injury can increased the risk of secondary mortality because of its late inflammatory complications. Alcohol intake increases the risk of damage and complications subsequent to a (CNS) injury. How about the risk of pneumonia after CNS injury under the effect of alcoholic drink? Though animal trails of material prosperity and studies for human have been investigated in recent decades, the outcome maintains poor understanding. Pneumonia is one of the serious complication at the time of hospitalization and it should be known as more as possible for steadying patient conditions in intensive care unit and shortening length of stay. Thus, we conducted a meta-analysis of published materials to assess the association between alcohol intake and pneumonia in CNS injury. METHODS: Two authors searched the PUBMED, EMBASE, Cochrane Library, and web of science up to September, 2014 for published literatures without any limitations. Reference lists from identified studies were also screened carefully by us for additional data. The summary relative risks (RRs) and 95% confidence intervals (CI) were calculated by statistical analysis software (Stata 12.0) with fixed-effects models to estimate the risk. RESULT: The results indicated that a higher incidence of pneumonia was found in CNS injury under the influence of alcohol (RR = 1.32, 95% CI = 1.21-1.43), and the risk has no relation to blood alcohol concentration (BAC) (BAC ≥ 80 mg/dl vs < 80 mg/dl, BAC ≥ 100 mg/dl vs < 100 mg/dl). CONCLUSION: Traumatic brain injury (TBI) and spinal cord injury patients who are under the influence of alcoholic drink have a higher risk of pneumonia.

Feasibility of tissue similarity map-based relative cerebral blood volume assessment in the evaluation of gliomas.

OBJECTIVE: To investigate the feasibility of tissue similarity map (TSM)-based relative cerebral blood volume (rCBV) assessment in evaluating the hemodynamic characteristics of gliomas and in differentiating high-grade gliomas from low-grade ones without concentration time curve (CTC). MATERIALS AND METHODS: TSM-based rCBV (rCBV TSM ) and conventional rCBV (rCBV PWI ) maps were generated (n = 35). The differences in percentage and concordance correlation coefficient (CCC) of the rCBV TSM and rCBV PWI ratios were calculated. The Mann-Whitney test and the receiver operating characteristic (ROC) curve analysis were also performed to examine the relationships of rCBV ratios between high- and low-grade gliomas. The improvement factors of signal to noise ratio (SNR) of rCBV TSM maps were also calculated. RESULTS: The mean difference in percentage between rCBV TSM and rCBV PWI ratios was 4.29 ± 2.62%. The CCC of rCBV TSM and rCBV PWI ratios was 0.9974, with 95% confidence interval of 0.9948, 0.9987, which implied a high agreement between them. The Mann-Whitney test suggested that the rCBV TSM and rCBV PWI ratios of high-grade gliomas were significantly different from those of low-grade gliomas (P < 0.001). The improvement factors of SNR of the rCBV TSM map were 1.31 ± 0.24 for glioma and 1.28 ± 0.24 for normal white matter. CONCLUSION: It is feasible to use rCBV TSM in the evaluation of hemodynamic characteristics of gliomas and differentiation of high- and low-grade gliomas without CTC. Moreover, rCBV TSM maps possess a higher SNR, which allows potentially more accurate diagnosis compared with the conventional ones.

MicroRNA-199a-3p suppresses glioma cell proliferation by regulating the AKT/mTOR signaling pathway.

Glioma has been investigated for decades, but the prognosis remains poor because of rapid proliferation, its aggressive potential, and its resistance to chemotherapy or radiotherapy. The mammalian target of rapamycin (mTOR) is highly expressed and regulates cellular proliferation and cell growth. MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene transcription and translation via up-regulating or down-regulating the levels of miRNAs. This study was conducted to explore the molecular functions of miR-199a-3p in glioma. We detected the expression of miR-199a-3p in glioma samples by quantitative PCR (qPCR). Then, we transfected the U87 and U251 cell lines with miR-199a-3p. Cellular proliferation, invasion, and apoptosis were assessed to explain the function of miR-199a-3p. PCR confirmed that the expression of miR-199a-3p was lower in glioma samples combined with normal brain tissues. The over-expression of miR-199a-3p might target mTOR and restrained cellular growth and proliferation but not invasive and apoptosis capability. Results indicated that cellular proliferation was inhibited to regulate the AKT/mTOR signaling pathway by elevating levels of miR-199a-3p. MiR-199a-3p in glioma cell lines has effects similar to the tumor suppressor gene on cellular proliferation via the AKT/mTOR signaling pathway.

Parkinson's disease-associated PINK1 G309D mutation increases abnormal phosphorylation of Tau.

Mutations in PINK1 gene have been considered the second most common cause of Autosomal Recessive Parkinsonism (ARP). So far, different homozygous PINK1 mutations have been identified in different ARP patients. Abnormal hyperphosphorylation of tau leads to the loss of its biological activity. Multiple lines of evidence have demonstrated that hyperphosphorylated tau is associated with Alzheimer's disease and Parkinson's disease (PD). However, the effects of PD associated PINK1 mutations in tau phosphorylation are unknown. In this study, we investigated the effect of G309D PINK1 mutation in tau phosphorylation. Cells transfected with mutant G309D PINK1 exhibited a significant increase in the phosphorylation of tau protein at the PHF-1 (ser396/404) site. The levels of CDK5, an important activator of tau phosphorylation, did not change in mutant G309D PINK1 transfected cells, suggesting that CDK5 is not involved in tau phosphorylation induced by mutant G309D PINK1. Notably, we found that mutant G309D PINK1 significantly reduced phosphorylation of GSK3ß at serine 9, suggesting that alterations in GSK3ß activity play an essential role in mutant G309D PINK1-induced tau phosphorylation at the PHF-1 site. PP2A activity maintained consistent in mutant G309D PINK1 transfected cells, suggesting that the increased tau hyperphosphorylation is not ascribed to reduction in PP2A activity.

High-performance inverted solar cells based on blend films of ZnO Naoparticles and TiO(2) nanorods as a cathode buffer layer.

We reported the favorable cathode buffer layer based on a blend of ZnO nanoparticles (NPs) and TiO2 nanorods (NRs) applied to inverted solar cells. In addition to the high optical transmittance, the resultant blend film gave a relatively dense film with lower roughness than that of the respective single-component film. This improved the interface contact between the buffer layer and photoactive layer and therefore reduced the contact resistance and leakage current. Moreover, the combination of NRs and NPs increased the efficiency of electron transport and collection by providing both a direct path for electron transport from TiO2 NRs and a large contact area between ZnO NPs and the active layer. Consequently, both the short-circuit current density (Jsc) and fill factor (FF) in the device were improved, leading to an improvement of the device performance. The best power conversion efficiency (PCE) based on the blend film as the buffer layer reached 8.82%, which was preferable to those of a single ZnO NP film (7.76%) and a TiO2 NR-based device (7.66%).

Manipulating surface ligands of copper sulfide nanocrystals: synthesis, characterization, and application to organic solar cells.

CuS NCs were synthesized via a facile sol-gel method without post-thermal treatment. The as-prepared CuS NCs were analyzed and confirmed by XRD, HR-TEM, EDS and XPS as hexagonal covellite CuS. The average diameter of the samples was about 3nm with narrow size distribution. CuS NCs can form a thin and smooth film without ligand-exchange that can be used as hole transport layer in organic solar cell. These hydrophilic CuS NCs with pyridine ligands can be exchanged with OAm and OA rapidly at room temperature and present hydrophobic characteristic, resulting in forming oil-soluble CuS NCs. This makes it possible tuning the surface property of CuS NCs and has the potential application for different fields.

Improving efficiency by hybrid TiO(2) nanorods with 1,10-phenanthroline as a cathode buffer layer for inverted organic solar cells.

We reported a significant improvement in the efficiency of organic solar cells by introducing hybrid TiO2:1,10-phenanthroline as a cathode buffer layer. The devices based on polymer thieno[3,4-b]thiophene/benzodithiophene:[6,6]-phenyl C71-butyric acid methyl ester (PTB7:PC71BM) with hybrid buffer layer exhibited an average power conversion efficiency (PCE) as high as 8.02%, accounting for 20.8% enhancement compared with the TiO2 based devices. The cathode modification function of this hybrid material could also be extended to the poly(3-hexylthiophene):[6,6]-phenyl-C61-butyric acid methyl ester (P3HT:PC61BM) system. We anticipate that this study will stimulate further research on hybrid materials to achieve more efficient charge collection and device performance.

Highly efficient organic photovoltaics via incorporation of solution-processed cesium stearate as the cathode interfacial layer.

Highly efficient organic solar cells were successfully demonstrated by incorporating a solution-processed cesium stearate between the photoactive layer and metal cathode as a novel cathode interfacial layer. The analysis of surface potential change indicated the existence of an interfacial dipole between the photoactive layer and metal electrode, which was responsible for the power conversion efficiency (PCE) enhancement of devices. The significant improvement in the device performance and the simple preparation method by solution processing suggested a promising and practical pathway to improve the efficiency of the organic solar cells.

Analysis of isocitrate dehydrogenase 1 mutation in 97 patients with glioma.

The objective of this study is to investigate the expression and significance of isocitrate dehydrogenase 1 (IDH1) mutation in different subtypes of human gliomas. Direct DNA sequencing, western blot, and immunohistochemistry were used to detect IDH1 mutation and IDH1 gene expression levels in 97 cases of glioma and 9 cases of other CNS tumors. IDH1 mutation was heterozygous, with wild-type arginine 132 replaced by histidine (R132H). Expression in different glioma subtypes was (1) 0 out if 5 in pilocytic astrocytoma; (2) 15 out of 22 in diffuse astrocytoma, 6 out of 9 in oligodendroglioma, 4 out of 6 in oligoastrocytoma, and 0 out of 4 in ependymoma; (3) 11 out of 19 in anaplastic astrocytoma, 4 out of 7 in anaplastic oligodendroglioma, 3 out of 4 in anaplastic oligoastrocytoma, and 0 out of 3 in anaplastic ependymoma; and (4) 1 out of 6 in primary glioblastoma, 8 out of 10 in secondary glioblastoma, and 0 out of 2 in medulloblastoma. IDH1 mutation is a somatic mutation that is found only in some glioma subtypes. It can be used as a molecular marker for glioma subtypes. For example, it can be used to distinguish primary glioblastoma from secondary glioblastoma, combining TP53 mutation and loss of heterozygosity involving 1p/19q. It can also be used as a marker for some gliomas. For example, it can be used to distinguish pilocytic astrocytoma from diffuse astrocytoma, combining detected BRAF proto-oncogene mutations.