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Long non-coding RNA urothelial carcinoma associated 1 (lncRNA UCA1) promotes cancer progression and enhances chemoresistance through miR-204-5p in a few cancers. However, no studies have investigated whether UCA1 regulates glioma metastasis through miR-204-5p and its target. In the present study, cell migration, invasion and epithelial-mesenchymal transition (EMT) were evaluated in glioma cells overexpressing UCA1. The relationships among UCA1, miR-204-5p and ZEB1 were examined by real-time PCR, western blotting and dual-luciferase reporter assays. The effect of UCA1 knockdown on xenograft tumor growth was investigated. The levels of miR-204-5p, fibronectin, COL5 A1 and ZEB1 in tumor tissues were also determined. The results showed that UCA1 overexpression promoted cell migration, invasion and EMT. UCA1 interacted with miR-204-5p and decreased its level. ZEB1 was identified as a direct target of miR-204-5p and miR-204-5p negatively regulated ZEB1 expression. Moreover, UCA1 sponged miR-204-5p and partially rescued the inhibitory effect of miR-204-5p on ZEB1. In our in vivo studies, UCA1 knockdown reduced tumor volume and tumor weight. In addition, the levels of fibronectin, COL5 A1 and ZEB1 were decreased, while miR-204-5p level was increased. The present study provides the first evidence that UCA1 promotes glioma metastasis through the miR-204-5p/ZEB1 axis, contributing to the understanding of the pathogenesis of glioma.

Bone morphogenetic protein (BMP)-7 mediated neuroprotective effect of cerebral ischemic preconditioning (IPC) has been studied in an ischemic animal model, but the underlying cellular mechanisms have not been clearly clarified. In this study, primary cortical neurons and the SH-SY5Y cell line were used to investigate the role of BMP-7 and its downstream signals in the neuroprotective effects of oxygen-glucose deprivation preconditioning (OGDPC). Immunocytochemistry was used to detect the expression of neurofilament in neurons. MTT and lactate dehydrogenase activity assays were used to measure the cytotoxicity. Western blot was used to detect the protein expression of BMP-7 and downstream signals. BMP inhibitor, mitogen-activated protein kinase inhibitors, Smad inhibitor and siRNA of Smad 1 were used to investigate the role of corresponding signalling pathways in the OGDPC. Results showed that OGDPC-induced overexpression of BMP-7 in primary cortical neurons and SH-SY5Y cells. Both of endogenous and exogenous BMP-7 could replicate the neuroprotective effects seen in OGDPC pretreatment. In addition, extracellular regulated protein kinases, p38 and Smad signalling pathway were found to be involved in the neuroprotective effects mediated by OGDPC via BMP-7. This study primarily reveals the cellular mechanisms of the neuroprotection mediated by OGDPC, and provides evidence for better understanding of this intrinsic factor against ischemia.

Stroke is a common cerebrovascular disease in aging populations, and constitutes the second highest principle cause of mortality and the principle cause of permanent disability, and ischemic stroke is the primary form. Osthole is a coumarin derivative extracted from the fruits of Cnidium monnieri (L.) Cusson. In this study, we established a rat model of middle cerebral artery occlusion/reperfusion (MCAO/R) in vivo and found that MCAO/R caused cerebral infarction, hippocampus neuronal injury and apoptosis, and also activated the Notch 1 signaling pathway. However, treatment with osthole further enhanced the activity of Notch 1 signaling and reduced the cerebral infarction as well as the hippocampus neuronal injury and apoptosis induced by MCAO/R in a dose-dependent manner. The same results were observed in a primary neuronal oxygen glucose deficiency/reperfusion (OGD/R) model in vitro, and the effect of osthole could be blocked by an inhibitor of Notch 1 signaling, N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine tert-butyl ester (DAPT). Therefore, we demonstrated that osthole injection prevented rat ischemia–reperfusion injury via activating the Notch 1 signaling pathway in vivo and in vitro in a dose-dependent manner, which may be significant for clinical treatment of ischemic stroke.

Biomarkers in blood have become increasingly appreciated in the diagnosis of glioma, but most of their diagnostic accuracy was not high enough to be used widely in a clinical context. MicroRNA-125b (miRNA-125b, miR-125b), a member of microRNA cluster, is widely considered as ideal biomarkers for clinical diagnosis in various human cancers. In the current study, we first explored the diagnostic value of serum miR-125b for glioma in a Chinese population, which has not been studied yet. Additionally, we conducted a meta-analysis to assess the diagnostic accuracy of miR-125b in human cancers. Serum miR-125b from the 33 patients with glioma (WHO grades I-IV) and 33 healthy controls were compared. Our results showed that the serum miR-125b level was significantly lower in glioma patients when compared with normal population, and an obvious decreasing trend of miR-125b level along tumor stages was found. The receiver operating characteristic (ROC) curve analysis of the accuracy in distinguishing glioma cancer patients from healthy controls yielded an area under the curve (AUC) value of 0.839 (95 % confidence interval (CI), 0.743-0.935). When glioma patients at different stages were compared with normal controls, the AUC values of WHO grade II (0.868) and WHO grade III-IV (0.959) were higher than WHO grade I (0.691). In the meta-analysis, the overall sensitivity, specificity, and AUC for miR-125b in human cancers diagnosis were 82 % (95 % CI, 76-87 %), 77 % (95 % CI, 70-84 %), and 0.84 (95 % CI, 0.81-0.87), respectively. The results of the present study suggested that miR-125b could be a potential biomarker with relatively high accuracy in the diagnosis of glioma as well as other human cancers.

Cerebral ischemic preconditioning (IPC), which refers to a transient and noninjurious ischemia is able to induce tolerance against the subsequent lethal ischemia, including ischemic stroke. We have previously reported that bone morphogenic protein-7 (BMP-7) contributes to the neuroprotective effects of IPC-induced ischemic tolerance, and thus ameliorates the following ischemia/reperfusion (I/R) injury in rats. Consequently, in the present study, we continued to explore the underlying regulatory mechanisms involved in BMP-7-mediated cerebral IPC in the rat model of ischemic tolerance. Male Wistar rats were preconditioned by 15-min middle cerebral artery occlusion (MCAO). After 2-day reperfusion, these animals were subjected to prolonged MCAO for 2 h. Our results showed that the phosphorylated p38 mitogen-activated protein kinase (MAPK) paralleling to BMP-7 was up-regulated by IPC in rat brain. Inactivation of p38 MAPK by pretreatment of SB203580, a p38 MAPK-specific suppressor, weakened the protective effect of IPC on CA1 neurons. Moreover, the enhanced phosphorylation of p38 MAPK induced by IPC was attenuated when the endogenous BMP-7 was inhibited by BMP-7 antagonist noggin. Besides, blockade of p38 MAPK signal transduction pathway via SB203580 abrogated the protective effects of exogenous BMP-7 against cerebral infraction. These present findings suggest that BMP-7 contributes to cerebral IPC-induced ischemic tolerance via activating p38 MAPK signaling pathway.

A mild cerebral ischemic insult, also known as ischemic preconditioning (IPC), confers transient tolerance to a subsequent ischemic challenge in the brain. This study was conducted to investigate whether bone morphogenetic protein-7 (BMP-7) is involved in neuroprotection elicited by IPC in a rat model of ischemia. Ischemic tolerance was induced in rats by IPC (15 min middle cerebral artery occlusion, MCAO) at 48 h before lethal ischemia (2h MCAO). The present data showed that IPC increased BMP-7 mRNA and protein expression after 24h reperfusion following ischemia in the brain. In rats of ischemia, IPC-induced reduction of cerebral infarct volume and improvement of neuronal morphology were attenuated when BMP-7 was inhibited either by antagonist noggin or short interfering RNA (siRNA) pre-treatment. Besides, cerebral IPC-induced up-regulation of B-cell lymphoma 2 (Bcl-2) and down-regulation of cleaved caspase-3 at 24h after ischemia/reperfusion (I/R) injury were reversed via inhibition of BMP-7. These findings indicate that BMP-7 mediates IPC-induced tolerance to cerebral I/R, probably through inhibition of apoptosis.

Background Glioma is the most common and lethal primary brain tumors, and is regarded as one of the deadliest of human cancers. To date, a growing number of studies have tested the diagnostic accuracy of microRNAs (miRNAs) in glioma detection and altered levels of characteristic miRNAs have also been identified in glioma. However, there are some conflicting conclusions. Thus, we conducted this meta-analysis to evaluate the overall accuracy of miRNAs in the diagnosis of glioma. Methods A comprehensive literature search was conducted using a combination of keywords. The random effect model was used to calculate the pooled diagnostic parameters. The summary receiver operator characteristic (SROC) curves were plotted to assess the overall diagnostic performance of miRNAs. Subgroup and sensitivity analyses were conducted to analyze the potential sources of heterogeneity. Results In total, 28 studies from 11 articles covering 1729 patients and 1491 controls were available in this meta–analysis. The pooled sensitivity, specificity, PLR, NLR, DOR, and AUC were 0.87 (95% CI: 0.83–0.91), 0.87 (95% CI: 0.81–0.91), 6.6 (95% CI: 4.5–9.6), 0.15 (95% CI: 0.10–0.21), 45 (95% CI: 23–90), and 0.93 (95% CI: 0.91–0.95), respectively. Subgroup analysis demonstrated that panels of multiple miRNAs could largely improve the diagnostic accuracy. An independent meta-analysis of five included studies was conducted to evaluate the diagnostic efficacy of miR-21 in patients with glioma, with a pooled sensitivity of 0.82, specificity of 0.94, PLR of 13.2, NLR of 0.19, DOR of 69 and AUC of 0.95. Conclusion This meta-analysis indicated the great potential of miRNAs, especially panels of multiple miRNAs, as promising biomarkers in glioma detection and monitoring. As one of the most representative miRNAs, we also found that a single miR-21 could be a powerful clinical biomarker in glioma diagnosis.

MicroRNAs are currently considered as an active and rapidly evolving area for the treatment of tumors. In this study, we elucidated the biological significance of miR-330 in glioblastoma stem cells (GSCs) as well as the possible molecular mechanisms. SH3GL2 is mainly distributed in the central nervous system and considered to be a tumor suppressor in many tumors. In the present study, we identified miR-330 as a potential regulator of SH3GL2 and we found that it was to be inversely correlated with SH3GL2 expression in GSCs which were isolated from U87 cell lines. The expression of miR-330 enhanced cellular proliferation, promoted cell migration and invasion, and dampened cell apoptosis. When the GSCs were co-transfected with the plasmid containing short hairpin RNA directed against human SH3GL2 gene and miR-330 mimic, we found that miR-330 promoted the malignant behavior of GSCs by down-regulating the expression of SH3GL2. Meanwhile, the ERK and PI3K/AKT signaling pathways were significantly activated, leading to the decreased expression of apoptotic protein and increased expression of anti-apoptotic protein. Furthermore, in orthotopic mouse xenografts, the mice given stable over-expressed SH3GL2 cells co-transfected with miR-330 knockdown plasmid had the smallest tumor sizes and longest survival. In conclusion, these results suggested that miR-330 negatively regulated the expression of SH3GL2 in GSCs, which promoted the oncogenic progression of GSCs through activating ERK and PI3K/AKT signaling pathways. The elucidation of these mechanisms will provide potential therapeutic approaches for human glioblastoma.