ACE2 Rescues Impaired Autophagic Flux Through the PI3K/AKT Pathway After Subarachnoid Hemorrhage.

Subarachnoid hemorrhage (SAH) is one of the life-threatening neurosurgical diseases in central nervous system. Autophagy has been previously demonstrated to exert vital roles in SAH development. Angiotensin I converting enzyme 2 (ACE2) has been revealed as a regulator of autophagy in neurosurgical diseases. However, effect of ACE2 on autophagy in SAH progression has not been clarified. First, we explored the relationship between autophagy and SAH progression by establishing a mouse model of SAH under the administration of 3-MA (the autophagy inhibitor). Next, we examined ACE2 expression in the cerebral cortex of SAH mice ex vivo with RT-qPCR. Subsequently, we assessed the biological function of ACE2 on brain injury, the autophagic flux pathway and the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling ex vivo via neurological scoring, TUNEL assay, western blot analysis and immunofluorescence staining assay. Finally, we carried out rescue assays under chloroquine (CQ, the autophagic flux inhibitor) and LY294002 (the PI3K/AKT signaling inhibitor) administration. 3-MA mitigated brain injury after SAH, and ACE2 was downregulated in cerebral cortex of SAH mice. Moreover, ACE2 elevation alleviated cell apoptosis, cerebral edema, and neurological deficits, ameliorated the autophagic flux pathway and activated the PI3K/AKT signaling in SAH mice. Furthermore, CQ and LY294002 neutralized the effects of overexpressed ACE2 on neuronal apoptosis, cerebral edema, and neurological deficits in SAH mice. Overall, ACE2 lessened neuronal injury via the autophagic flux and PI3K/AKT pathways. This research might provide a potential novel direction for clinical treatment of SAH.

Suppression of MALAT1 alleviates neurocyte apoptosis and reactive oxygen species production through the miR-499-5p/SOX6 axis in subarachnoid hemorrhage.

Subarachnoid hemorrhage (SAH), a common devastating cerebrovascular accident, is a great threat to human health and life. Exploration of the potential therapeutic target of SAH is urgently needed. Previous studies showed that long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) promotes cell apoptosis in various diseases, while its role in SAH remains unclear. In our study, we established a mouse model of SAH and used the oxyhemoglobin (OxyHb) to induce neuronal injury in vitro. Interestingly, MALAT1 was found upregulated in brain tissues of SAH mice and OxyHb-stimulated neurons. In addition, knockdown of MALAT1 attenuated apoptosis and decreased reactive oxygen species (ROS) production in OxyHb-stimulated neurons. Mechanistically, we demonstrated that MALAT1 bound with miR-499-5p. Furthermore, our findings indicated that miR-499-5p bound to SOX6 3' untranslated region (UTR) and negatively regulated SOX6 mRNA and protein levels. Rescue assays suggested that SOX6 overexpression counteracted the effects of MALAT1 knockdown on neurocyte apoptosis, and ROS production in OxyHb-stimulated neurons. The in vivo assays indicated that knockdown of MALAT1 improved brain injury of SAH mice. Our study demonstrates that silencing of MALAT1 alleviates neurocyte apoptosis and reduces ROS production through the miR-499-5p/SOX6 axis after SAH injury.

Endoscopic Anatomic Study Via Grinding Partial Petrous Ridge to the Middle Fossa in Retromastoid Keyhole Approach.

OBJECTIVE: This study aimed to observe the range of exposure, indications, and feasibility of the retromastoid keyhole approach via grinding partial petrous ridge to the middle fossa. METHODS: Simulated endoscopic surgeries via grinding suprameatal tubercle and petrous ridge to expose the middle fossa in retromastoid keyhole approach were performed on 8 adult cadaver heads (16 sides) fixed by formalin. The maximum exposure range in endoscope was observed. The boundaries of Parkinson triangle and the anatomic structures contained by Meckel cave and cavernous sinus (CS) lateral wall were revealed. The distances from midpoint of sigmoid sinus posterior border to every important anatomic structures in the middle fossa and the length of all sides of Parkinson triangle were measured. RESULTS: By using endoscope, the exposure of the cerebellopontine angle, ventrolateral brainstem, incisure of tentorium, petroclival region, and CS lateral wall were satisfactory. Many important anatomic structures in middle fossa were exposed well. The distances from midpoint of posterior border of sigmoid sinus to suprameatal tubercle, trigeminal semilunar ganglion, posterior curve segment of internal carotid artery were 34.42 ± 2.14, 54.52 ±â€Š2.87, and 65.15 ±â€Š3.13 mm. The lengths of all sides of Parkinson triangle were 18.97 ±â€Š2.93, 16.23 ±â€Š2.02, and 8.04 ±â€Š2.34 mm. CONCLUSION: The retromastoid keyhole approach via grinding partial petrous ridge to the middle fossa by using endoscope can increase the exposure of middle fossa effectively, which is proper for most lesions in posterior cranial fossa while some parts extend to middle fossa.

Reprogramming A375 cells to induced­resembled neuronal cells by structured overexpression of specific transcription genes.

Induced-resembled neuronal cells (irNCs) are generated by reprogramming human melanoma cells through the introduction of key transcription factors, providing novel concepts in the treatment of malignant tumor cells and making it possible to supply neural cells for laboratory use. In the present study, irNCs were derived from A375 cells by inducing the 'forced' overexpression of specific genes, including achaete­scute homolog 1 (Ascl1), neuronal differentiation factor 1 (Neurod1), myelin transcription factor 1 (Myt1), brain protein 2 (Brn2, also termed POU3F2) and human brain­derived neurotrophic factor (h­BDNF). irNCs induced from A375 cells express multiple neuronal markers and fire action potentials, exhibiting properties similar to those of motor neurons. The reprogramming procedure comprised reverse transcription­polymerase chain reaction and immunofluorescence staining; furthermore, electrophysiological profiling demonstrated the characteristics of the induced­resembled neurons. The present study obtained a novel type of human irNC from human melanoma, which secreted BDNF continuously, providing a model for neuron­like cells. Thus, irNCs offer promise in investigating various neural diseases by using neural­like cells derived directly from the patient of interest.

Neuroendoscopic surgery versus external ventricular drainage alone or with intraventricular fibrinolysis for intraventricular hemorrhage secondary to spontaneous supratentorial hemorrhage: a systematic review and meta-analysis.

BACKGROUND AND PURPOSE: Although neuroendoscopy (NE) has been applied to many cerebral diseases, the effect of NE for intraventricular hemorrhage (IVH) secondary to spontaneous supratentorial hemorrhage remains controversial. The purpose of this study was to analyze the effect of NE compared with external ventricular drainage (EVD) alone or with intraventricular fibrinolysis (IVF) on the management of IVH secondary to spontaneous supratentorial hemorrhage. METHODOLOGY/ PRINCIPAL FINDINGS: A systematic search of electronic databases (PubMed, EMBASE, OVID, Web of Science, The Cochrane Library, CBM, VIP, CNKI, and Wan Fang database) was performed to identify related studies published from 1970 to 2013. Randomized controlled trials (RCTs) or observational studies (OS) comparing NE with EVD alone or with IVF for the treatment of IVH were included. The quality of the included trials was assessed by Jaded scale and the Newcastle-Ottawa Scale (NOS). RevMan 5.1 software was used to conduct the meta-analysis. RESULTS: Eleven trials (5 RCTs and 6 ORs) involving 680 patients were included. The odds ratio (OR) showed a statistically significant difference between the NE + EVD and EVD + IVF groups in terms of mortality (OR, 0.31; 95% CI, 0.16-0.59; P=0.0004), effective hematoma evacuation rate (OR, 25.50, 95%CI; 14.30, 45.45; P<0.00001), good functional outcome (GFO) (OR, 4.51; (95%CI, 2.81-7.72; P<0.00001), and the ventriculo-peritoneal (VP) shunt dependence rate (OR, 0.16; 95%CI; 0.06, 0.40; P<0.0001). CONCLUSION: Applying neuroendoscopic approach with EVD may be a better management for IVH secondary to spontaneous supratentorial hemorrhage than NE + IVF. However, there is still no conclusive evidence regarding the preference of NE vs. EVD alone in the case of IVH, because insufficient data has been published thus far. This study suggests that the NE approach with EVD could become an alternative to EVD + IVF for IVH in the future.