Dihydroartemisinin inhibits EMT of glioma via gene BASP1 in extrachromosomal DNA.

The mechanism of dihydroartemisinin (DHA) inhibiting the migration and invasion of glioma in an ROS-DSB-dependent manner has been revealed. Extrachromosomal DNAs (ecDNAs) which are generated by DNA damage have great potential in glioma treatment. However, the role of ecDNAs in DHA's pharmacological mechanisms in glioma is still unknown. In this study, DHA was found to inhibit proliferative activity, increase ROS levels and promote apoptosis in U87 and U251 cells. Migration and invasion have also been suppressed. ecDNA expression profiles were found in gliomas. EcDNA-BASP1 was found, by means of bioinformatics analysis, to be present in GBM tissues and positively correlated with patient prognosis. Proliferation, migration and invasion were upregulated after knockdown of ecDNA-BASP1. The expression of vimentin and N-cadherin also had the same tendency. Finally, we found that the ecDNA-BASP1 content in nude mouse transplant tumors was significantly increased after DHA treatment, which might exert a better suppressive effect on glioma. The upregulation of tumor suppressor ecDNA-BASP1 played an important role in the suppression of glioma progression induced by DHA. EcDNA-BASP1 may inhibit glioma migration and invasion through repressing epithelial-mesenchymal transition (EMT).

Powder Metallurgy Route to Ultrafine-Grained Refractory Metals.

Ultrafine-grained (UFG) refractory metals are promising materials for applications in aerospace, microelectronics, nuclear energy, and many others under extreme environments. Powder metallurgy (PM) allows to produce such materials with well-controlled chemistry and microstructure at multiple length scales and near-net shape manufacturing. However, sintering refractory metals to full density while maintaining a fine microstructure is still challenging due to the high sintering temperature and the difficulty to separate the kinetics of densification versus grain growth. Here an overview of the sintering issues, microstructural design rules, and PM practices towards UFG and nanocrystalline refractory metals are sought to be provided. The previous efforts shall be reviewed to address the processing challenges, including the use of fine/nanopowders, second-phase grain growth inhibitors, and field-assisted sintering techniques. Recently, pressureless two-step sintering has been successfully demonstrated in producing dense UFG refractory metals down to ≈300 nm average grain size with a uniform microstructure and this technological breakthrough shall be reviewed. PM progresses in specific materials systems shall be next reviewed, including elementary metals (W and Mo), refractory alloys (W-Re), refractory high-entropy alloys, and their composites. Last, future developments and the endeavor towards UFG and nanocrystalline refractory metals with exceptionally uniform microstructure and improved properties are outlined.

TTBK2 circular RNA promotes glioma malignancy by regulating miR-217/HNF1ß/Derlin-1 pathway.

BACKGROUND: Circular RNAs are a subgroup of non-coding RNAs and generated by a mammalian genome. Herein, the expression and function of circular RNA circ-TTBK2 were investigated in human glioma cells. METHODS: Fluorescence in situ hybridization and quantitative real-time PCR were conducted to profile the cell distribution and expression of circ-TTBK2 and microRNA-217 (miR-217) in glioma tissues and cells. Immunohistochemical and western blot were used to determine the expression of HNF1ß and Derlin-1 in glioma tissues and cells. Stable knockdown of circ-TTBK2 or overexpression of miR-217 glioma cell lines (U87 and U251) were established to explore the function of circ-TTBK2 and miR-217 in glioma cells. Further, luciferase reports and RNA immunoprecipitation were used to investigate the correlation between circ-TTBK2 and miR-217. Cell Counting Kit-8, transwell assays, and flow cytometry were used to investigate circ-TTBK2 and miR-217 function including cell proliferation, migration and invasion, and apoptosis, respectively. ChIP assays were used to ascertain the correlations between HNF1ß and Derlin-1. RESULTS: We found that circ-TTBK2 was upregulated in glioma tissues and cell lines, while linear TTBK2 was not dysregulated in glioma tissues and cells. Enhanced expression of circ-TTBK2 promoted cell proliferation, migration, and invasion, while inhibited apoptosis. MiR-217 was downregulated in glioma tissues and cell lines. We also found that circ-TTBK2, but not linear TTBK2, acted as miR-217 sponge in a sequence-specific manner. In addition, upregulated circ-TTBK2 decreased miR-217 expression and there was a reciprocal negative feedback between them in an Argonaute2-dependent manner. Moreover, reintroduction of miR-217 significantly reversed circ-TTBK2-mediated promotion of glioma progression. HNF1ß was a direct target of miR-217, and played oncogenic role in glioma cells. Remarkably, circ-TTBK2 knockdown combined with miR-217 overexpression led to tumor regression in vivo. CONCLUSIONS: These results demonstrated a novel role circ-TTBK2 in the glioma progression.

Long non-coding RNA NEAT1 regulates permeability of the blood-tumor barrier via miR-181d-5p-mediated expression changes in ZO-1, occludin, and claudin-5.

The blood-tumor barrier (BTB) constitutes an efficient organization of tight junctions that limits the delivery of chemotherapeutic drugs to brain tumor tissues and impacts the treatment of glioma. Long non-coding RNAs (lncRNAs) are non-protein coding RNAs regulating gene expression, some lncRNAs play a crucial role in BTB permeability. However, the function of lncRNAs in BTB permeability is still largely unclear. Here, we have identified lncRNA nuclear paraspeckle assembly transcript 1 (NEAT1), was remarkably up-regulated in glioma endothelial cells (GECs) obtained from an in vitro BTB model. Knockdown of NEAT1 impaired the integrity and increased the permeability of the BTB, accompanied by downregulation of expression of the tight junction proteins ZO-1, occludin and claudin-5 in GECs. Both bioinformatics data and results of luciferase reporter assays demonstrated that NEAT1 influenced BTB permeability by binding to miR-181d-5p. Knockdown of NEAT1 also down-regulated the expression of sex determining region Y-box protein 5 (SOX5), which was defined as a direct and functional downstream target of miR-181d-5p. SOX5 interacts with the promoter region of ZO-1, occludin and claudin-5 in GECs. In conclusion, knockdown of NEAT1 increased BTB permeability by binding to miR-181d-5p and then reducing tight junction protein expression by targeting SOX5. These results suggest an important role for NEAT1 in regulating BTB permeability and provide an additional strategy for treating glioma.

Dihydroartemisin inhibits glioma invasiveness via a ROS to P53 to ß-catenin signaling.

Dihydroartemisinin(DHA) is the active metabolic derivative of artemisinin. DHA has potential therapeutic effects on glioma but the detailed mechanism is unclear. In this study, we investigated the role and the underlying mechanisms of DHA in its inhibition of glioma cells. U87 cells are wild-type p53 glioblastoma cells and U251 cells contain mutant p53. DHA inhibited the proliferation, migration and invasion of glioma cells in a dose-dependent manner. DHA promoted reactive oxygen species production and activated p53 in two glioma cell lines, U87 and U251. In U87 cells, DHA significantly up-regulated the expression of p-ß-catenin (S45) and inhibited EGFR, ß-catenin, p-ß-catenin (Y333) and matrix metalloprotease7/9 activity. In U251 cells, DHA significantly up-regulated p-ß-catenin (S45), p-ß-catenin (Y333) and EGFR, but the expression of ß-cateninwas unchanged. We also found that DHA and sh-ß-catenin prevented the proliferation of U87 and U251 cells in vivo. In conclusion, DHA inhibited the migration and invasion of human glioma cells with different types of p53 via different pathways.

Stent-Assisted Coil Embolization of Ruptured Supraclinoid Blood Blister-Like Aneurysm of Internal Carotid Artery.

AIM: To report angiographic and clinical results obtained in patients with supraclinoid segment blood blister-like aneurysms (BBLAs) of the internal carotid artery treated with stent-assisted coil embolization. MATERIAL AND METHODS: A retrospective review of patients, who were treated for a ruptured supraclinoid BBLAs of the internal carotid artery (ICA) from 2004 to 2010, was performed. Clinical data, including hospital records, operative reports, and angiograms, were analyzed. Outcome was assessed using the modified Rankin scale (mRS). RESULTS: Thirteen ruptured supraclinoid BBLAs in 13 patients were treated with stent-assisted coil embolization without any complication. Six patients recovered without any neurological deficits and three patients had mild neurological deficits (mRS 1 in one and 2 in two patients) due to late ischemic deficit. Three patients died of rebleeding and one died of intracranial infection after ventricular puncture for hydrocephalus. CONCLUSION: In our experience, the natural history of supraclinoid BBLAs is dismal. Some of the lesions rebled after stent-assisted coil embolization.

Shikonin Inhibits the Migration and Invasion of Human Glioblastoma Cells by Targeting Phosphorylated ß-Catenin and Phosphorylated PI3K/Akt: A Potential Mechanism for the Anti-Glioma Efficacy of a Traditional Chinese Herbal Medicine.

Shikonin is an anthraquinone derivative extracted from the root of lithospermum. Shikonin is traditionally used in the treatment of inflammatory and infectious diseases such as hepatitis. Shikonin also inhibits proliferation and induces apoptosis in various tumors. However, the effect of shikonin on gliomas has not been fully elucidated. In the present study, we aimed to investigate the effects of shikonin on the migration and invasion of human glioblastoma cells as well as the underlying mechanisms. U87 and U251 human glioblastoma cells were treated with shikonin at 2.5, 5, and 7.5 µmol/L and cell viability, migration and invasiveness were assessed with CCK8, scratch wound healing, in vitro Transwell migration, and invasion assays. The expression and activity of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) and the expression of phosphorylated ß-catenin (p-ß-catenin) and phosphorylated PI3K/Akt were also checked. Results showed that shikonin significantly inhibited the cell proliferation, migration, invasion, and expression of MMP-2 and MMP-9 in U87 and U251 cells. The expression of p-ß-catenin showed contrary trends in two cell lines. It was significantly inhibited in U87 cells and promoted in U251 cells. Results in this work indicated that shikonin displayed an inhibitory effect on the migration and invasion of glioma cells by inhibiting the expression and activity of MMP-2 and -9. In addition, shikonin also inhibited the expression of p-PI3K and p-Akt to attenuate cell migration and invasion and MMP-2 and MMP-9 expression in both cell lines, which could be reversed by the PI3K/Akt pathway agonist, insulin-like growth factor-1 (IGF-1).