Interference with long noncoding RNA SNHG3 alleviates cerebral ischemia-reperfusion injury by inhibiting microglial activation.

Neuroinflammation plays a strong part in cerebral ischemia-reperfusion injury, and microglial activation is regarded as a marker for neuroinflammation. Long noncoding RNA small nucleolar RNA host gene 3 (lncRNA SNHG3) is heavily expressed in cerebral ischemia-reperfusion models, but its mechanism is rarely studied. This study aims to explore whether SNHG3 is involved in cerebral ischemia-reperfusion injury by promoting microglial activation and inflammatory factor secretion. Activation of microglia was induced through oxygen-glucose deprivation/reoxygenation (OGD/R) or LPS and the cerebral ischemia-reperfusion injury in mice was induced by transient middle cerebral artery occlusion (tMCAO). Levels of SNHG3, IL-6, and TNF-α were determined by quantitative real-time PCR. Immunofluorescence was used for the detection of Iba-1 expression. Western blot was carried out for the detection of Iba-1 and histone deacetylase 3 (HDAC3) protein levels. An ELISA was performed to detect TNF-α and IL-6 levels. RNA pull-down, RNA immunoprecipitation, and co-Immunoprecipitation assays were conducted to detect the binding between SNHG3 and HDAC3. A H&E staining assay was applied to observe pathologic changes. Microglial activation was observed with immunohistochemistry. Levels of SNHG3, microglial activation marker Iba-1, proinflammatory factors (TNF-α and IL-6) were highly expressed in cell models (treated with OGD/R or LPS) and mouse models (tMCAO). Besides, SNHG3 could bind to HDAC3 and promote its expression. Through further study, we found that SNHG3 could stabilize the protein levels of HDAC3 and inhibit the ubiquitination of HDAC3. Furthermore, interference with SNHG3 down-regulated the levels of HDAC3, Iba-1, TNF-α, and IL-6, whereas the overexpression of HDAC3 reversed the results. The H&E staining assay demonstrated that the condition of vacuoles of different sizes, uneven cytoplasmic staining, and inflammatory infiltration in the brain tissue was improved by interference with SNHG3. The immunohistochemistry result showed that microglial activation marker Iba-1 was increased in the shRNA-SNHG3 group, indicating that interference with SNHG3 inhibited the activation of microglia in the brain. LncRNA SNHG3 aggravated cerebral ischemia-reperfusion injury by promoting the activation of microglia, increasing the levels of HDAC3, and the secretion of inflammatory factors.

Inhibition of glioma using a novel non-neurotoxic vesicular stomatitis virus.

OBJECTIVE: The aim of this study was to demonstrate the in vivo safety and antitumor effect of a novel recombinant vesicular stomatitis virus (VSV): G protein less (GLESS)-fusion-associated small transmembrane (FAST)-VSV. METHODS: Viral infection efficiency and cell proliferation were detected using an inverted fluorescence microscope and alarmaBlue assay, respectively. To evaluate the safety of the virus, different doses of GLESS-FAST-VSV and a positive control virus (VSV∆M51) were injected into normal F344 rats and C57BL/6 mice, and each animal's weight, survival time, and pathological changes were examined on the following day. To evaluate the efficacy of the virus, RG2 and GL261 cells were used to construct rat and mouse glioma models, respectively, via a stereotactic method. After multiple intratumoral injections of the virus, tumor growth (size) and the survival time of the animals were observed. RESULTS: In vitro experiments showed that GLESS-FAST-VSV could infect and kill brain tumor cells and had less toxic effects on normal cells. After direct injection of GLESS-FAST-VSV into the animal brains, all animals tolerated the virus well, and no animal death, encephalitis, or ventriculitis was observed. In contrast, all animals that received brain injections of VSV∆M51 in the brain died. Moreover, multiple injections of GLESS-FAST-VSV in brain tumors significantly prolonged the survival of normal-immunity animals harboring brain tumors. CONCLUSIONS: GLESS-FAST-VSV exhibited little neurotoxicity and could be injected directly into the tumor to effectively inhibit tumor growth and prolong the survival of normal-immunity animals, laying a theoretical foundation for the early application of such viruses in clinical trials.

Stent retriever thrombectomy combined with long-term local thrombolysis for severe hemorrhagic cerebral venous sinus thrombosis.

Cerebral venous sinus thrombosis (CVST) is a rare disease associated with high disability and mortality rates. A subset of patients do not respond to standard anticoagulation therapy, leading to the progression of CVST with hemorrhagic stroke, which represents a major challenge for its treatment. Severe hemorrhagic (SH)-CVST is life-threatening due to large hematoma, edema and/or cerebral hernia. Anticoagulation or thrombolytic therapy alone may lead to further aggravation of the hematoma. Stent retriever thrombectomy combined with long-term local thrombolysis (SRT-LLT) has been used in certain centers for those refractory cases or patients with new intracranial hemorrhage. However, to date, no studies on SRT-LLT treatment specifically for SH-CVST have been performed. The aim of the present retrospective study was to specifically evaluate the effectiveness of SRT-LLT in SH-CVST. Between December 2013 and November 2018, SRT-LLT was performed at our center in 8 patients with hemorrhagic CVST who did not respond to intravenous anticoagulation. The clinical characteristics, results of the radiological evaluation, details on the surgical procedure and clinical outcomes were assessed. The patients were administered systemic intravenous anticoagulation as the initial treatment following admission. SRT-LLT was performed when their condition deteriorated with a high risk of a fatal outcome within a short time period. SRT-LLT was performed in 8 patients, with successful recanalization confirmed by angiography. In 4 of the patients, complete recanalization was achieved, whereas in the remaining 4, recanalization was partial. There were no intraoperative complications. Two patients developed rebleeding after surgery, but they all gradually recovered. There were no treatment-associated fatalities. Therefore, SRT-LLT appears to be a feasible, safe and effective option for SH-CVST and it may be used as rescue therapy for carefully selected patients with SH-CVST.

LncRNA SNHG3 promotes autophagy-induced neuronal cell apoptosis by acting as a ceRNA for miR-485 to up-regulate ATG7 expression.

Long non-coding RNAs (lncRNAs) are bound up with various human diseases. However, their roles in brain ischemia-reperfusion (I/R) injury remain largely unknown. This study aimed to reveal the potential mechanism of LncRNA SNHG3 on autophagy-induced neuronal cell apoptosis in the brain I/R injury. LncRNA SNHG3 and miR-485 or autophagy markers LC3II/I and Beclin-1 expressions were detected by qRT-PCR or Western blot and the apoptosis of N2a cells was analyzed by flow cytometry. Besides, the interactions between LncRNA SNHG3 and miR-485, miR-485 and ATG7 were validated by RNA pull-down and dual-luciferase reporter system assays. After the Oxygen and Glucose Deprivation (OGD) treatment of N2a cells transfected with pcDNA-SNHG3, pcDNA-SNHG3 + miR-485 mimic for 6 h, 1 mM autophagy inhibitor 3-MA was added and reoxygenated for 24 h, the effect of LncRNA SNHG3 on the autophagy-induced neuronal cell apoptosis was measured by Western blot and flow cytometry. LncRNA SNHG3 was highly expressed in the mouse model of transient middle cerebral artery occlusion and cell model of Oxygen and Glucose Deprivation/Reperfusion, while miR-485 was lowly expressed. Furthermore, miR-485 negatively regulated the luciferase activities of LncRNA SNHG3 and ATG7. After the OGD treatment of N2a cells transfected with pcDNA-SNHG3, pcDNA-SNHG3 + miR-485 mimic for 6 h, 1 mM 3-MA was added and reoxygenated for 24 h, the overexpression of LncRNA SNHG3 raised the ratio of LC3-II/LC3-I and Beclin-1 expression and boosted the apoptosis of N2a cells, while these effects were reversed after the transfection of miR-485 mimic. In general, our data expounded that the interference with LncRNA SNHG3 improved brain I/R injury by up-regulating miR-485 and down-regulating ATG7 to restrain autophagy and neuronal cell apoptosis.

miR-24 Reduces Serum Lipid Levels and Inhibits Brain Tissue Cells Apoptosis of Rats with Cerebral Infarction.

AIM: To study miR-24 effects on cerebral infarction in rats. MATERIAL AND METHODS: A rat middle cerebral artery occlusion model (MCAO) was constructed. Intracerebroventricular stereotactic injection of miR-24 agomir/antagomir was performed in the rat MCAO model. According to different experiences, rats were divided into normal, sham, MCAO, miR-24 agomir and miR-24 antagomir groups. Serum TCH, HDL and TG levels were detected. RESULTS: Comparingthe normal and sham groups, we observed decreased relative miR-24 expression (p < 0.05) and increased cerebral infarction area percentage, apoptotic cells and relative caspase-3 protein expression (p < 0.05) in theMCAO, miR-24 agomirand miR-24 antagomir groups. TC, TG and HDL-C levels of the MCAO and miR-24 antagomir groups were higher than those of normal and sham groups (p < 0.05).Compared with the MCAO group, increased relative miR-24 expression (p < 0.05) and decreased TC, TG and HDL-C levels,cerebral infarction area percentage, number of apoptotic cells and caspase-3 expression (p < 0.05) were found in themiR-24 agomir group, contrasting with theobservations from the miR-24 antagomir group. CONCLUSION: miR-24 reduced serum TCH, HDL and TG levels and inhibited brain tissue cell apoptosis in rats with cerebral infarction.

Changes of the Expression and Activity of Phosphodiesterase V in the Basilar Artery Before and After Cerebral Vasospasm in a Rabbit Model.

OBJECTIVE: To examine changes of expression and activity of phosphodiesterase V (PDE V) in the basilar artery following cerebral vasospasm (CVS) after subarachnoid hemorrhage (SAH) in a rabbit model. METHODS: A rabbit model of CVS after SAH was constructed by double blood injection into the cisterna magna. Subjects were divided into 3 groups: blank control group, normal saline group, and SAH group. Transcranial Doppler and selective vertebrobasilar digital subtraction angiography were performed to identify changes of CVS. Changes of PDE V expression and activity were examined. RESULTS: Mean basilar arterial blood flow rate measured by transcranial Doppler was significantly increased in the SAH group compared with the blank control group and normal saline group. Mean basilar artery diameter measured by digital subtraction angiography in the SAH group was narrower than in the other 2 groups. Compared with the other 2 groups, the expression of PDE V in the SAH group was significantly upregulated, and the activity was significantly enhanced. CONCLUSIONS: The rabbit model of SAH-induced CVS was successfully constructed through double blood injection method. Increased basilar artery blood flow, narrowing of the basilar artery, increased PDE V expression, and enhanced PDE V activity in the basilar artery were detected in the CVS rabbits, suggesting that PDE V has the potential to be used as a target for CVS therapy.

Molecular pathological expression in malignant gliomas resected by fluorescein sodium-guiding under the YELLOW 560 nm surgical microscope filter.

BACKGROUND: This study aimed to analyze the relationship between molecular pathologic expression of GFAP and Ki-67 and fluorescence levels, and to provide molecular pathological basis for the removal of malignant gliomas (MG) by Fluorescein Sodium (FLS) navigation under the YELLOW 560 nm surgical microscope filter. METHODS: A retrospective analysis of clinical data of 18 MG cases confirmed by the postoperative pathology was performed. All cases were resected by FLS guiding under the YELLOW 560 nm filter. Hematoxylin-eosin (HE) staining, molecular pathology markers GFAP, and Ki-67 immunohistochemical staining of the specimens were performed. The relationship between fluorescence staining levels and GFAP positive rate, Ki-67 proliferation index, and WHO grades was studied. RESULTS: There were 69 pathological specimens with fluorescence levels of "bright" fluorescence (n = 32), "low" fluorescence (n = 18), and "no" fluorescence (n = 19). Immunohistochemical staining showed GFAP-positive expression in both tumor cells and normal glial cells. The staining levels of the specimens in the fluorescence regions were higher than that in the non-fluorescence regions. GFAP expression was positive in 61 specimens and negative in 8 specimens. Comparison of Ki-67 proliferation index using chi-square test showed different fluorescence levels had different Ki-67 proliferation indexes (χ2 = 14.678, p = 0.005). With high proliferation index of specimens, fluorescence level was brighter. WHO grade had no correlation with fluorescence levels (χ2 = 3.531, p = 0.171). CONCLUSION: FLS-guided resection of MG is safe and effective. In the boundary area of MG, fluorescence levels and Ki-67 proliferation index showed correlation. FLS-guided resection achieved the function of "reducing tumor cell," thus reducing the proliferation index in the lesion area.

Endovascular treatment for hemorrhagic cerebral venous sinus thrombosis: experience with 9 cases for 3 years.

AIM: We experienced a series of patients with hemorrhagic CVST, who were successfully treated with endovascular treatment (EVT). The aim was to explore the best scheme for the future through our treatment data of hemorrhagic CVST. MATERIAL AND METHODS: A retrospective analysis was conducted, selecting nine hemorrhagic CVST patients, who were mainly treated with EVT. Characteristics of hemorrhagic CVST were recorded, including risk factors, thrombus location, presenting symptoms, and treatment details included type of EVT. We also recorded clinical outcomes, degree of sinus recanalization, thrombus recurrences, periprocedural complications, degree of neurological deficit at last follow-up. RESULTS: Catheter thrombolysis and mechanical thrombectomy were applied in all of the nine hemorrhagic CVST patients, stent retriever was used in 7 patients, one of them combined with balloon-assisted thrombectomy. Besides EVT, two patients accepted emergency surgical decompression, one in the local hospital, and the other in our hospital. The follow-up duration ranged from 4 to 28 months. All of them have a neurological and symptomatic improvement, 6 patients have a good outcome, the rest 3 patients have a poor outcome, no thrombus recurrences and death in them. Seven patients had complete recanalization and two patients had partial recanalization at last follow-up. CONCLUSION: EVT is an effective and safe procedure for potentially catastrophic hemorrhagic cerebral venous sinus thrombosis.

Corrigendum to "Sodium Fluorescein-Guided Resection under the YELLOW 560 nm Surgical Microscope Filter in Malignant Gliomas: Our First 38 Cases Experience".

[This corrects the article DOI: 10.1155/2017/7865747.].

WITHDRAWN: To evaluate the Changes of the expression and activity of Phosphodiesterase V in the Basilar Artery Before and After Cerebral Vasospasm in Rabbits model.

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miR-24 reduces serum lipid levels and inhibits brain tissue cells apoptosis of rats with cerebral infarction.

AIM: To study miR-24 effects on cerebral infarction in rats. MATERIAL AND METHODS: A rat middle cerebral artery occlusion model (MCAO) was constructed. Intracerebroventricular stereotactic injection of miR-24 agomir/antagomir was performed in the rat MCAO model. According to different experiences, rats were divided into normal, sham, MCAO, miR-24 agomir and miR-24 antagomir groups. Serum TCH, HDL and TG levels were detected. RESULTS: Comparing the normal and sham groups, we observed decreased relative miR-24 expression (P 0.05) and increased cerebral infarction area percentage, apoptotic cells and relative caspase-3 protein expression (P 0.05) in the MCAO, miR-24 agomir and miR-24 antagomir groups. TC, TG and HDL-C levels of the MCAO and miR-24 antagomir groups were higher than those of normal and sham groups (P 0.05). Compared with the MCAO group, increased relative miR-24 expression (P 0.05) and decreased TC, TG and HDL-C levels, cerebral infarction area percentage, number of apoptotic cells and caspase-3 expression (P 0.05) were found in the miR-24 agomir group, contrasting with the observations from the miR-24 antagomir group. CONCLUSION: miR-24 reduced serum TCH, HDL and TG levels and inhibited brain tissue cell apoptosis in rats with cerebral infarction.

Sodium Fluorescein-Guided Resection under the YELLOW 560 nm Surgical Microscope Filter in Malignant Gliomas: Our First 38 Cases Experience.

OBJECTIVE: Sodium fluorescein (FL) had been safely used in fluorescence-guided microsurgery for imaging various brain tumors. Under the YELLOW 560 nm surgical microscope filter, low-dose FL as a fluorescent dye helps in visualization. Our study investigated the safety and efficacy of this innovative technique in malignant glioma (MG) patients. PATIENTS AND METHOD: 38 patients suffering from MGs confirmed by pathology underwent FL-guided resection under YELLOW 560 nm surgical microscope filter. We retrospectively analyzed the clinical characters, microsurgery procedure, extent of resection, pathology of MGs, progression-free survival (PFS), and overall survival (OS). RESULTS: Thirty-eight patients had MGs (10 WHO grade III, 28 WHO grade IV). With YELLOW 560 nm surgical microscope filter combined with neuronavigation, sodium fluorescein-guided gross total resection (GTR) was achieved in 35 (92.1%) patients and subtotal resection in 3 (7.69%). The sensitivity and specificity of FL were 94.4% and 88.6% regardless of radiographic localization. Intraoperatively, 10 biopsies (10/28 FL[+]) showed "low" or "high" fluorescence in non-contrast-enhancement region and are also confirmed by pathology. Our data showed 6-month PFS of 92.3% and median survival of 11 months. CONCLUSION: FL-guided resection of MGs under the YELLOW 560 nm surgical microscope filter combined with neuronavigation was safe and effective, especially in non-contrast-MRI regions. It is feasible for improving the extent of resection in MGs especially during emergency cases.

Temozolomide resistant human brain tumor stem cells are susceptible to recombinant vesicular stomatitis virus and double-deleted Vaccinia virus in vitro.

BACKGROUND: Malignant glioma still has a poor prognosis and remains incurable. Although temozolomide (TMZ) has demonstrated antitumor activity, its use recently has been halted because of some patients' resistance to this drug. New treatments are desperately needed. An oncolytic virus (virotherapy) is being developed as a novel cancer therapy. We have previously reported that recombinant Vesicular Stomatitis Virus (VSV-ΔM51) and double deleted Vaccinia Virus (vvDD) infected and killed glioma cell lines in vitro and prolonged survival in animal glioma models. As a proposed ex vivo test, the oncolytic potential of VSV-ΔM51 and vvDD in the established human brain tumor stem cells (BTSCs) and the differentiated cells from fresh brain tumor tissues in vitro were further investigated. METHODS: BTSCs from fresh surgical glioblastoma multiforme (GBM) specimens were isolated and cultured, and the characterization of BTSCs were tested. The sensitivity of BTSCs to TMZ and the susceptibility of TMZ resistant BTSCs and their differentiated cells to both oncolytic viruses were examined. RESULTS: The BTSC spheres cultured had all the characteristics of stem cells. The GFP-labeled VSV-ΔM51 and vvDD could infect TMZ resistant BTSCs and cause cytopathic effects. The VSV-ΔM51and vvDD inhibited the self-renewal activity of TMZ resistant BTSCs. And the VSV-ΔM51and vvDD also infected and caused cytopathic effects in differentiated BTSCs. CONCLUSION: VSV-ΔM51and vvDD could infect and kill both the TMZ resistant BTSCs and the differentiated compartments of GBMs in vitro, suggesting that they may be an effective treatment supplement for GBM therapy, particularly for TMZ resistant GBM patients.

Risk factors for the recurrence of an intracranial saccular aneurysm following endovascular treatment.

BACKGROUND: This study was aimed to determine risk factors for the recurrence of an intracranial saccular aneurysm (ISA) following endovascular treatment. The findings will help medical professionals to identify patients having a high risk of ISA recurrence and assist them in developing appropriate follow-up plans. RESULTS: During the follow-up period, 12.6% of the patients (83/658) experienced recurrent ISAs. An analysis of related factors, including gender, age, hypertension, diabetes mellitus, smoking, tumor size, width of the aneurysm neck, the presence or absence of a rupture, the volume embolization ratio (VER), the application or nonapplication of a stent, and follow-up time, revealed that a tumor size > 10 mm in diameter, wide-necked aneurysms, an anterior communicating or middle cerebral artery aneurysm, an aneurysm rupture, a VER < 20%, the absence of stent assistance, and follow-up time were high-risk factors for the recurrence of ISAs. MATERIALS AND METHODS: We retrospectively reviewed the records of 658 patients who underwent endovascular treatment for ISAs from January 2010 through December 2014. Multivariable logistic regression was performed on the candidates' risk factors, which were identified via univariable screening analysis. CONCLUSIONS: Smoking, a large tumor size, a wide-necked aneurysm, an anterior communicating or middle cerebral artery aneurysm, an aneurysm rupture, a VER < 20%, and an absence of stent assistance are significant risk factors for the postoperative recurrence of an aneurysm. Strict follow-up plans should be created for ISA patients having these high-risk factors.

HydroCoil occlusion for treatment of traumatic carotid-cavernous fistula: preliminary experience.

OBJECTIVE: To summarize our preliminary experiences regarding HydroCoil occlusion for the treatment of carotid-cavernous fistula (CCF), and to evaluate the effectiveness of this treatment. METHODS: From January 2006 to June 2007, 15 patients with traumatic CCF who were treated using HydroCoil occlusion were included in this study. All the patients presented with symptoms such as intracranial pulsatile noise, bulbar conjunctival hyperemia, and pulsatile exophthalmia. Cerebral angiography revealed that the fistula was located in the right internal carotid-cavernous segment in 6 cases, in the left internal carotid-cavernous segment in 8 cases, and on both sides in 1 case. RESULTS: After CCF procedure, in 15 patients, the fistula was no longer visualized, the internal carotid artery on the affected side remained patent, and intracranial noise disappeared immediately. The preoperative symptoms exophthalmia, bulbar conjunctival hyperemia, etc., returned to normal 1 week after the operation. Vision recovered to varying extents. In the 9 patients who underwent 1-3 months of follow-up cerebral angiography, CCF recurrences and neurological complications were not observed. CONCLUSION: Intravascular occlusion has been widely used for CCF treatment, and detachable balloon embolization remains the preferred treatment. In the case of failure of detachable balloon embolization because the patient cannot tolerate the procedure or internal carotid artery occlusion on the affected side is contraindicated, HydroCoil occlusion is a safe and effective though expensive alternative and a stable method of maintaining high carotid artery patency.