Circular RNA CircPDS5B impairs angiogenesis following ischemic stroke through its interaction with hnRNPL to inactivate VEGF-A.

BACKGROUND: Ischemic stroke (IS) is the primary cause of mortality and disability worldwide. Circular RNAs (circRNAs) have been proposed as crucial regulators in IS. This study focused on the role of circPDS5B in IS and its underlying mechanism. METHOD: Transient middle cerebral artery occlusion (tMCAO) mice and glucose deprivation/reoxygenation (OGD/R)-exposed human brain microvascular endothelial cells (BMECs) were used as IS models. Expression levels of circPDS5B, heterogenous nuclear ribonucleoprotein L (hnRNPL), runt-related transcription factor-1 (Runx1), and Zinc finger protein 24 (ZNF24) were quantified by qRT-PCR. MTT, wound healing, transwell and tube formation assays were employed to evaluate the cell proliferation, migration, and angiogenesis, respectively. Moreover, RNA pull-down, and RIP assay were performed to investigate the interaction among circPDS5B, hnRNPL and vascular endothelial growth factor-A (VEGF-A). RESULTS: circPDS5B was significantly up-regulated in IS patients and tMCAO mice. Deficiency of circPDS5B relieved brain infarction and neuronal injury of tMCAO mice. OGD/R-induced apoptosis, inhibition in viability, migration, and angiogenesis in BMECs were dramatically abrogated by circPDS5B knockdown. Mechanistically, circPDS5B stabilized Runx1 and ZNF24 via recruiting hnRNPL, thereby suppressing the transcription and expression of VEGFA. hnRNPL silencing strengthened circPDS5B knockdown-mediated beneficial effect on IS. CONCLUSION: Altogether, our study showed that high expression of circPDS5B exacerbated IS through recruitment of hnRNPL to stabilize Runx1/ZNF24 and subsequently inactivate VEGFA. Our findings suggest circPDS5B may be a novel therapeutic target for IS.

Silencing of Long Noncoding RNA GAS5 Blocks Experimental Cerebral Ischemia-Reperfusion Injury by Restraining AQP4 Expression via the miR-1192/STAT5A Axis.

The long noncoding RNA (lncRNA) GAS5 has been shown to affect disease development in stroke. This study aimed to elucidate the regulatory mechanism of the lncRNA GAS5 on STAT5A in cerebral ischemia/reperfusion (I/R) injury. First, GAS5 and STAT5A levels in the blood of patients with stroke were determined. Then, a middle cerebral artery occlusion and reperfusion rat model was established in which short hairpin RNAs targeting GAS5 or STAT5A were intracranially injected, followed by the assessment of neurological function, cerebral injury and water content, and inflammation. Primary rat astrocytes were induced with oxygen-glucose deprivation/reoxygenation (OGD/R), and cell proliferation, apoptosis, and inflammation were evaluated. Moreover, the interplay between GAS5, miR-1192, and STAT5A and the binding of STAT5A to the AQP4 promoter were identified. GAS5 and STAT5A were strongly expressed in stroke patients, and inhibition of GAS5 or STAT5A in model rats improved neurological function, reduced infarction and neuronal apoptosis, and diminished cerebral water content and astrocyte activation. Furthermore, GAS5 or STAT5A downregulation restored proliferation and restrained apoptosis and inflammation in OGD/R-induced astrocytes. Mechanistically, GAS5 targeted miR-1192, which negatively regulated STAT5A. Astrocytes showed perturbed proliferation and strengthened apoptosis and inflammation when miR-1192 was inhibited despite the silencing of GAS5, while these unfavorable effects were abolished by STAT5A silencing. STAT5A binds to the AQP4 promoter and regulates its expression. Silencing of GAS5 and overexpresion of AQP4 led to lower cell viability and higher apoptosis and inflammation than GAS5 silencing alone. Overall, GAS5 silencing inhibited AQP4 through the miR-1192/STAT5A axis, thus alleviating cerebral I/R injury.

lncRNA DHFRL1­4 knockdown attenuates cerebral ischemia/reperfusion injury by upregulating the levels of angiogenesis­related genes.

The present study aimed to investigate the effects of long non­coding (lncRNA) dihydrofolate reductase­like 1 (DHFRL1­4) on cerebral ischemia/reperfusion (I/R)­induced injury. For this purpose, mice injected with lentivirus with small interfering RNA targeting DHFRL1­4 or negative control siRNA were used to construct models of cerebral I/R injury. Following the establishment of the model, the infarct size, neurological deficit score, apoptosis and the expression levels of basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), Wnt family member 3a (Wnt3a), glycogen synthase kinase­3ß (GSK­3ß) and phosphorylated GSK­3ß were assessed. The expression of DHFRL1­4 was significantly upregulated in the I/R model. In the control and sham groups, the boundaries between the cortex and gray matter were clear, and no edema or necrosis were observed. The nerve cells were arranged orderly and evenly, and the cell membranes were intact with visible nucleus and nucleolus. In the model group however, the nerve fibers were slightly necrotic and swollen, and the number of nerve cells was reduced. In the mice injected with si­DHFRL1­4 lentivirus, the brain tissues exhibited less liquefaction and degeneration, as well as less edema. Compared with the control and sham groups, the model group had a significantly larger infarct area, a higher apoptotic rate, higher bFGF, VEGF, Wnt3a and GSK­3ß expression levels and a greater neurological deficit score. However, the mice injected with si­DHFRL1­4 lentivirus exhibited a significantly reduced infarct area, a lower apoptotic rate, lower Wnt3a and GSK­3ß expression levels, a lower neurological deficit score, and significantly upregulated bFGF and VEGF levels.

Prognostic Value and Therapeutic Perspectives of CXCR Members in the Glioma Microenvironment.

Background: CXCR (CXC Chemokine Receptor) is a complex of the immune-associated protein involved in tumor activation, invasion, migration, and angiogenesis through various chemical signals in the tumor microenvironment (TME). However, significant prognostic characteristics of CXCR members and their impact on the occurrence and progression of glioma have not yet been fully elucidated. Methods: In this research, we used Oncomine, TCGA, GTEx, and CGGA databases to analyze the transcription and survival data of glioma patients. Afterward, the influence of CXCR members on the TME was explored using comprehensive bioinformatics analysis. Results: The mRNA expression levels of CXCR1/2/3/4/7 were significantly up-regulated in glioma than in normal samples, whereas the mRNA expression level of CXCR5 was decreased. We then summarized the genetic alteration landscape of CXCR and identified two molecular subtypes based on CXCR expression patterns in glioma. The characteristics of CXCRs were also investigated, including the clinicopathological parameters, TME cell infiltration, and prognosis of patients with glioma. After Lasso and multivariable Cox regression, a CR-Score for predicting overall survival (OS) was constructed and the predictive performance of the signature was validated. The high-risk group was a significantly poorer prognostic group than the low-risk group as judged by the CR-Score (TCGA cohort, p < 0.001, CGGA cohort, p < 0.001). Moreover, the CR-Score was significantly correlated to the tumor-immune infiltration and cancer stem cell (CSC) index. A risk scale-based nomogram incorporating clinical factors for individual risk estimation was established thereby. Conclusion: These findings may pave the way for enhancing our understanding of CXCR modification patterns and developing better immune therapeutic approaches for glioma.

Histone deacetylase 9 inhibition upregulates microRNA-92a to repress the progression of intracranial aneurysm via silencing Bcl-2-like protein 11.

OBJECTIVE: Histone deacetylases (HDACs) have been revealed to be involved in cerebrovascular diseases, while the role of HDAC9 in intracranial aneurysm (IA) remains seldom studied. We aim to explore the role of the HDAC9/microRNA-92a (miR-92a)/Bcl-2-like protein 11 (BCL2L11) axis in IA progression. METHODS: Expression of HDAC9, miR-92a and BCL2L11 in IA tissues was assessed. IA rat models were established by ligation of left renal artery and common carotid artery, and the rats were respectively injected with relative plasmid vectors and/or oligonucleotides. The blood pressure was measured to estimate the IA degree, and the pathological changes were observed. The expression of matrix metalloproteinase (MMP)-2, MMP-9 and vascular endothelial growth factor (VEGF) was detected, and the levels of inflammatory factors were evaluated. Expression of apoptosis-related proteins, HDAC9, miR-92a and BCL2L11 was assessed. RESULTS: HDAC9 and BCL2L11 were upregulated while miR-92a was downregulated in IA clinical samples and rat models. HDAC9 inhibition or miR-92a elevation improved pathological changes and repressed apoptosis and expression of MMP-2, MMP-9, VEGF and inflammatory factors in vascular tissues from IA rats. Oppositely, HDAC9 overexpression or miR-92a reduction had contrary effects. miR-92a downregulation reversed the effect of silenced HDAC9 on IA rats. CONCLUSION: HDAC9 inhibition upregulates miR-92a to repress the progression of IA via silencing BCL2L11.

Etiological factors of spontaneous primary intraventricular hemorrhage.

Objectives: Spontaneous primary intraventricular hemorrhage (SPIVH) is a distinct subtype of nontraumatic intracerebral hemorrhage in the ventricular system without a recognizable parenchymal component. The purpose of this study was to analyze the etiological characteristics of SPIVH.Patients and Methods: We analyzed the records of 88 patients with SPIVH that had been evaluated and treated at our institute from January 2011 to May 2018. All the patients with IVH associated with trauma were excluded. All the patients underwent at least 1 vascular imaging examination.Results: There were 52 (59.1%) males and 36 females, aged between 5 and 76, with an average age of 38.1 years. Fourteen (15.9%) patients were in pediatric age range. Out of the 88 patients, vascular lesions were found in 46 patients (52.3%), hypertension in 21 (23.9%), coagulopathy in 1 (1.1%), tumor in 1 (1.1%), and idiopathic causes in 19 (21.6%). Among patients with vascular lesions, AVMs (43.5%) were the most dominant form (20/46), followed by MMD (28.2%), aneurysms (23.9%), AVMs with aneurysm (2.2%) and dAVF (2.2%).Conclusions: Spontaneous primary intraventricular hemorrhage is rare in clinical practice, hypertension and arteriovenous malformation are the most common factor. The main etiological factors of hemorrhage are various in different age groups.

TRIM28 activates autophagy and promotes cell proliferation in glioblastoma.

BACKGROUND: Tripartite motif-containing protein 28 (TRIM28) is a transcriptional corepressor involved in the regulation of several cancers, including glioma. It has been reported that TRIM28 takes part in the process of autophagy. However, its effect on the autophagy and cell proliferation in gliomas has not been elucidated. Here, we report a novel tumor cell proliferation mechanism in which TRIM28-regulated autophagy promotes glioma tumor cell proliferation. MATERIALS AND METHODS: We analyzed the expressions of TRIM28 and LC3 in different WHO grades of gliomas by IHC assays. We then knocked down and overexpressed TRIM28 or knocked down ATG5 in U251 cells and confirmed its roles in autophagy and cell proliferation via cell counting, immunofluorescence, and Western blot. RESULTS: The results showed that TRIM28 and autophagy levels were significantly increased with the progression of tumor grade in glioma. TRIM28 promoted glioblastoma cell proliferation. Knockdown of TRIM28 inhibited autophagy in glioblastoma cells. Meanwhile, TRIM28 promoted glioblastoma cell proliferation by modulating TRIM28. CONCLUSION: These data demonstrated that TRIM28 activates autophagy and increases cell proliferation in glioma.

Endoscopic endonasal resection of symptomatic Rathke cleft cysts: clinical outcomes and prognosis.

The aim of this study is to investigate the clinical presentation and outcomes associated with endoscopic endonasal resection of Rathke cleft cysts (RCCs). The authors retrospectively studied a series of 13 patients who were diagnosed with RCCs after endoscopic endonasal resection at the Second Xiangya Hospital between June 2016 and December 2017. All 13 patients (8 women) underwent a purely endoscopic endonasal approach (EEA) for fenestration and aspiration of RCCs with excision of the cystic wall. The patient ages varied from 25 to 67 years (mean, 45.1 years), and the follow-up period ranged from 8 to 25 months (mean, 16.6 months). Headache was a presenting symptom in all 13 patients, with 11 (80%) out of the 13 having experienced postoperative improvement of their headaches. Six (46%) of the 13 patients were admitted with pituitary dysfunction, all of them had postoperative improvement. Four (31%) of the 13 patients had temporary postoperative pituitary dysfunction, although there was not any permanent pituitary dysfunction. Six patients had intraoperative complications with CSF leaks, and after the operation, three of them developed temporary diabetes insipidly, one of them had a postoperative infection, and another one had postoperative cerebrospinal fluid leaks, who was treated with absolute bed rest for 7 days. No patient experienced recurrent cysts. EEA is a safe and effective approach for the treatment of symptomatic RCCs. Notably, it is appreciated for protecting and restoring pituitary function; however, the postoperative recurrence rate still lacks a large sample related to the long time follow-up study. Complete aspiration of the cysts' contents with partial excision of the cyst wall is usually sufficient for treatment.

Oncogenic DIRAS3 promotes malignant phenotypes of glioma by activating EGFR-AKT signaling.

Epidermal growth factor receptor (EGFR)-Akt signaling cascade activation plays a pivotal role in gliomas malignant phenotype, especially in Classical and Mesenchymal subtype gliomas. However, the molecules and mechanisms underlying regulate and maintain the activation of EGFR-AKT signaling remains unclear. Previously reports showed that DIRAS3 inhibits cell proliferation and induces autophagy in ovarian, breast, lung and prostate cancers, which is heterozygosity loss or down-regulated in aforementioned cancers and functionally as a tumor suppressor, whereas the role of DIRAS3 in glioma is still veiled. Here, in this study, we investigated the biological function and role of DIRAS3 in gliomas, and found that DIRAS3 is up-regulated in gliomas and is positively correlated with poor prognosis of glioma patients, meanwhile, over-expressed DIRAS3 promotes glioma cells proliferation and invasion. Further mechanistic study showed that the expression level of DIRAS3 in Classical and Mesenchymal subtype GBMs is higher, and over-expression of DIRAS3 promotes EGFR-AKT signaling activation at the downstream of EGFR and increases AKT phosphorylation, meanwhile suppression of AKT by MK-2206 reverses the tumor promoting function of DIRAS3. Taken together, these findings reveal a novel oncogenic role of DIRAS3 in the development and progression of glioma, which suggest that DIRAS3 could serve as a potential diagnostic marker and a promising therapeutic target of gliomas.