Sphingosine kinase 1 promotes cerebral ischemia-reperfusion injury through inducing ER stress and activating the NF-κB signaling pathway.

Endoplasm reticulum stress and inflammation response have been found to be linked to cerebral ischemia-reperfusion (IR) injury. Sphingosine kinase 1 (SPHK1) has been reported to be a novel endoplasm reticulum regulator. The aim of our study is to figure out the role of SPHK1 in cerebral IR injury and verify whether it has an ability to regulate inflammation and endoplasm reticulum stress. Hydrogen peroxide was used to induce cerebral IR injury. Enzyme-linked immunosorbent assay, quantitative polymerase chain reaction, western blots, and immunofluorescence were used to measure the alterations of cell viability, inflammation response, and endoplasm reticulum stress. The results demonstrated that after exposure to hydrogen peroxide, cell viability was reduced whereas SPHK1 expression was significantly elevated. Knockdown of SPHK1 attenuated hydrogen peroxide-mediated cell death and reversed cell viability. Our data also demonstrated that SPHK1 deletion reduced endoplasm reticulum stress and alleviated inflammation response in hydrogen peroxide-treated cells. In addition, we also found that SHPK1 modulated endoplasm reticulum stress and inflammation response to through the NF-κB signaling pathway. Inhibition of NF-κB signaling pathway has similar results when compared with the cells with SPHK1 deletion. Altogether, our results demonstrated that SPHK1 upregulation, induced by hydrogen peroxide, is responsible for cerebral IR injury through inducing endoplasm reticulum stress and inflammation response in a manner working through the NF-κB signaling pathway. This finding provides new insight into the molecular mechanism to explain the neuron death induced by cerebral IR injury.

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.

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.

[Application of LVIS stents in very small intracranial aneurysms].

OBJECTIVE: To investigate the safety and short-term efficacy of stent on 17 patients with very small intracranial aneurysms.
 METHODS: A total of 17 patients with very small intracranial aneurysms were treated by LVIS stent from October 2014 to November 2015. The location, size of the aneurysms and the branch around aneurysms were evaluated by digital subtraction angiography (DSA). The metal coverage for aneurysms was enhanced by using deployment technology ("compression" mode). The safety and efficacy were assessed after operation.
 RESULTS: LVIS stents-assisted treatments for very small aneurysms were carried out in 17 cases, including 7 cases of paraclinoid aneurysms, 4 cases of posterior communicating artery aneurysms, 3 cases of anterior communicating artery aneurysms, 2 cases of carotid bifurcation aneurysms, 1 case of the superior cerebellar artery aneurysm. The stents for 17 patients with very small intracranial aneurysms were released completely (100%); Raymond grade I embolization was seen in 13 cases (76.5%); Raymond grade II embolization was seen in 4 cases (23.5%); during the follow up from a month to a year, 16 patients showed good curative effect (with the mRS score at 0-2), 1 showed poor effect (with the mRS score at 3-6), and the efficacy rate was 94.1%; no perioperative hemorrhagic and ischemic complications happened.
 CONCLUSION: LVIS stent-assisted therapy for very small intracranial aneurysms by using deployment technology was safe and feasible, which can significantly improve the embolization rate for very small aneurysms.

DRAM1 protects neuroblastoma cells from oxygen-glucose deprivation/reperfusion-induced injury via autophagy.

DNA damage-regulated autophagy modulator protein 1 (DRAM1), a multi-pass membrane lysosomal protein, is reportedly a tumor protein p53 (TP53) target gene involved in autophagy. During cerebral ischemia/reperfusion (I/R) injury, DRAM1 protein expression is increased, and autophagy is activated. However, the functional significance of DRAM1 and the relationship between DRAM1 and autophagy in brain I/R remains uncertain. The aim of this study is to investigate whether DRAM1 mediates autophagy activation in cerebral I/R injury and to explore its possible effects and mechanisms. We adopt the oxygen-glucose deprivation and reperfusion (OGD/R) Neuro-2a cell model to mimic cerebral I/R conditions in vitro, and RNA interference is used to knock down DRAM1 expression in this model. Cell viability assay is performed using the LIVE/DEAD viability/cytotoxicity kit. Cell phenotypic changes are analyzed through Western blot assays. Autophagy flux is monitored through the tandem red fluorescent protein-Green fluorescent protein-microtubule associated protein 1 light chain 3 (RFP-GFP-LC3) construct. The expression levels of DRAM1 and microtubule associated protein 1 light chain 3II/I (LC3II/I) are strongly up-regulated in Neuro-2a cells after OGD/R treatment and peaked at the 12 h reperfusion time point. The autophagy-specific inhibitor 3-Methyladenine (3-MA) inhibits the expression of DRAM1 and LC3II/I and exacerbates OGD/R-induced cell injury. Furthermore, DRAM1 knockdown aggravates OGD/R-induced cell injury and significantly blocks autophagy through decreasing autophagosome-lysosome fusion. In conclusion, our data demonstrate that DRAM1 knockdown in Neuro-2a cells inhibits autophagy by blocking autophagosome-lysosome fusion and exacerbated OGD/R-induced cell injury. Thus, DRAM1 might constitute a new therapeutic target for I/R diseases.

Knowledge, attitude, practice and illness perception toward subarachnoid hemorrhage prevention and management among intracranial aneurysm patients.

OBJECTIVE: This study aims to explore the knowledge, attitude, practice and illness perception toward prevention and management of subarachnoid hemorrhages (SAH) among intracranial aneurysm (IA) patients. METHODS: A cross-sectional study was conducted between March 2023 and June 2023; demographic characteristics and KAP scores were collected by a self-administered questionnaire and analyzed by linear regression and path analysis. RESULTS: A total of 455 patients with IA were included, of them 26.37% experienced SAH before. Mean knowledge, attitude and practice scores were 16.60 ± 5.86, 16.39 ± 1.84, and 35.07 ± 3.51, respectively. The linear regression showed ethnic minority, married, education, family members in healthcare system, monthly per capita household income, experience ruptured intracranial aneurysms, smoking, hypertension, hyperlipidemia, diabetes, and aortic lesion were associated with knowledge scores. Age, ethnic minority, urban residence, education, family members in healthcare system, monthly per capita household income, duration of IA ≥6 months, experience ruptured intracranial aneurysms, smoking, diabetes, and aortic lesion were associated with attitude scores. Age, urban residence, monthly per capita household income, duration of IA ≥6 months, experience of ruptured intracranial aneurysms, smoking, diabetes, and aortic lesion were associated with practice scores. According to the path analysis, knowledge directly affected illness perception (ß=0.156, P<0.001) and attitude (ß=0.708, P<0.001), while attitude (ß=0.909, P<0.001) and illness perception (ß=0.039, P=0.027) affected practice. CONCLUSIONS: Patients had positive attitudes towards SAH prevention and management, but a substantial knowledge gap was found along with notably delayed medical help-seeking behavior.

Transcription Factor TFAP2B Exerts Neuroprotective Effects Targeting BNIP3-Mediated Mitophagy in Ischemia/Reperfusion Injury.

Cerebral ischemia-reperfusion injury (CIRI) leads to malignant brain edema, blood-brain barrier destruction, and neuronal apoptosis. N6-methyladenosine (m6A) RNA modification in CIRI was still limited explored. In this study, MeRIP- and RNA-sequencing were performed of middle cerebral artery occlusion and reperfusion (MCAO/R) rats to find novel potential molecular targets. Transcription factor TFAP2B stood out of which its m6A abundance decreased associated with a marked reduction of its mRNA based on cojoint interactive bioinformatics analysis of the MeRIP- and RNA-sequencing data. It was suggested TFAP2B could have a role in CIRI. Functionally, overexpression of TFAP2B in cultured primary neurons could effectively improve the cell survival and pro-survival autophagy in parallel with reduced cell apoptosis during OGD/R in vitro. Through the RNA-sequencing of TFAP2B overexpressed primary neurons and subsequent validation experiments, it was found that mitophagy receptor BNIP3 was one of the important targets of TFAP2B in OGD/R neurons through which TFAP2B could bind to its promoter region for transcriptional activation of BNIP3, thereby enhancing BNIP3-mediated mitophagy to protect against OGD/R injury of neurons. Lastly, TFAP2B was demonstrated to alleviate the MCAO/R damage to a certain extent in vivo. Although it failed to confirm TFAP2B dysregulation was m6A dependent in current research, this is the first research of TFAP2B in CIRI field with important guiding significance.

Mechanically enhanced and osteobioactive synthetic periosteum via development of poly(ε-caprolactone)/microtantalum composite.

Periosteum, the thin layer covering adjacent to bone containing specific architecture, is important for functional bone regeneration and remodeling. Synthetic periosteum investigated presently lacks the resemblance of natural periosteum, suffering from poor mechanical strength and cell attachment. Here, we report a newly-developed biomimetic film to function as synthetic periosteum. Based on poly(ε-caprolactone) (PCL), where surface wettability of the synthetic periosteum is enhanced by microtantalum (mTa) particle blending and after a cold drawing process, further obtains topographical anisotropy without any involvement of solvent. This new blend shows mechanical enhancement over pure PCL, with yield stress and elastic strain approaching the natural periosteum. A distinct degradation mechanism is proposed for the blend, and by seeding with mouse calvarial preosteoblasts, cell proliferation is promoted on surface of the drawn PCL but delayed on the mTa-blended PCL. However, cell mineralization is accelerated on the mTa-blended surface. This is less on the drawn PCL. The synergistical integration of cellular proliferation, alignment and osteogenic enhancement suggest that the cold drawn PCL/Ta blend has unique potential for developing into a synthetic periosteum and other tissue-engineering products.

MiR-421 Binds to PINK1 and Enhances Neural Stem Cell Self-Renewal via HDAC3-Dependent FOXO3 Activation.

Dysfunctions of neural stem cells (NSCs) often lead to a variety of neurological diseases. Thus, therapies based on NSCs have gained increasing attention recently. It has been documented that microRNA (miR)-421 represses the autophagy and apoptosis of mouse hippocampal neurons and confers a role in the repair of ischemic brain injury (IBI). Herein, we aimed to illustrate the effects of miR-421 on NSC self-renewal. The downstream factors of miR-421 were predicted initially, followed by gain- and loss-of-function assays to examine their effects on NSC self-renewal. Immunoprecipitation and dual luciferase assays were conducted to validate the interaction among miR-421, PTEN-induced putative kinase 1 (PINK1), HDAC3, and forkhead box O3 (FOXO3). A mouse model with IBI was developed to substantiate the impact of the miR-421/PINK1/HDAC3/FOXO3 axis on NSC self-renewal. The expression of miR-421 was downregulated during differentiation of human embryonic NSCs, and miR-421 overexpression accelerated NSC self-renewal. Besides, miR-421 targeted PINK1 and restricted its expression in NSCs and further suppressed HDAC3 phosphorylation and enhanced FOXO3 acetylation. In conclusion, our data elucidated that miR-421 overexpression may facilitate NSC self-renewal through the PINK1/HDAC3/FOXO3 axis, which may provide potential therapeutic targets for the development of novel therapies for IBI.

MicroRNA-361-5p slows down gliomas development through regulating UBR5 to elevate ATMIN protein expression.

MicroRNA (miR)-361-5p has been studied to suppress gliomas development. Based on that, an insight into the regulatory mechanism of miR-361-5p in gliomas was supplemented from ubiquitin protein ligase E3 component N-recognin 5 (UBR5)-mediated ubiquitination of ataxia-telangiectasia mutated interactor (ATMIN). miR-361-5p, ATMIN, and UBR5 levels were clinically analyzed in gliomas tissues, which were further validated in gliomas cell lines. Loss/gain-of-function method was applied to determine the roles of miR-361-5p and UBR5 in gliomas, as to cell viability, migration, invasion, colony formation ability, and apoptosis in vitro and tumorigenesis in vivo. The relationship between miR-361-5p and UBR5 was verified and the interaction between UBR5 and ATMIN was explored. It was detected that reduced miR-361-5p and ATMIN and enhanced UBR5 levels showed in gliomas. Elevating miR-361-5p was repressive in gliomas progression. UBR5 was directly targeted by miR-361-5p. UBR5 can ubiquitinate ATMIN. miR-361-5p suppressed gliomas by regulating UBR5-mediated ubiquitination of ATMIN. Downregulating UBR5 impeded gliomas tumor growth in vivo. Upregulating miR-361-5p targets UBR5 to promote ATMIN protein expression, thus to recline the malignant phenotype of gliomas cells.

Efficacy and safety of stenting for elderly patients with severe and symptomatic carotid artery stenosis: a critical meta-analysis of randomized controlled trials.

OBJECTIVE: To investigate both short-term and long-term therapeutic efficacy and safety of carotid artery stenting (CAS) and carotid artery endarterectomy (CEA) for elderly patients with severe and symptomatic carotid artery stenosis. METHODS: PubMed, EMBASE, Cochrane Library, Clinical Trials Register Centers, and Google Scholar were comprehensively searched. After identifying relevant randomized controlled trials, methodological quality was assessed by using Cochrane tools of bias assessment. Meta-analysis was performed by RevMan software, and subgroup analyses according to different follow-up periods were also conducted. RESULTS: Sixteen articles of nine randomized controlled trials containing 6,984 patients were included. Compared with CEA, CAS was associated with high risks of stroke during periprocedural 30 days (risk ratio [RR]=1.47, 95% confidence interval [CI]: 1.15-1.88), 48 months (RR=1.37, 95% CI: 1.11-1.70), and >48 months (RR=1.76, 95% CI: 1.34-2.31). There was no significant difference in the aspects of death, disabling stroke, or death at any time between the groups. For other periprocedural complications, CAS decreased the risk of myocardial infarction (RR=0.44, 95% CI: 0.26-0.75), cranial nerve palsy (RR=0.09, 95% CI: 0.04-0.22) and hematoma (RR=0.31, 95% CI: 0.14-0.68) compared with CEA, while it increased the risk of bradycardia or hypotension (RR=8.45, 95% CI 2.91-24.58). CONCLUSION: Compared with CEA, CAS reduced hematoma, periprocedural myocardial infarction, and cranial nerve palsy, while it was associated with higher risks of both short-term and long-term nondisabling stroke. And they seemed to be equivalent in other outcome measures. As regards to its minimal invasion, it should be applied only in specific patients.

Regulation of smooth muscle contractility by competing endogenous mRNAs in intracranial aneurysms.

Alterations in vascular smooth muscle cells (SMCs) contribute to the pathogenesis of intracranial aneurysms (IAs), but the genetic mechanisms underlying these alterations are unclear. We used microarray analysis to compare tissue small noncoding RNA and messenger RNA expression profiles in vessel wall samples from patients with late-stage IAs. We identified myocardin (MYOCD), a key contractility regulator of vascular SMCs, as a critical factor in IA progression. Using a multifaceted computational and experimental approach, we determined that depletion of competitive endogenous RNAs (ARHGEF12, FGF12, and ADCY5) enhanced factors that downregulate MYOCD, which induces the conversion of SMCs from differentiated contractile states into dedifferentiated phenotypes that exhibit enhanced proliferation, synthesis of new extracellular matrix, and organization of mural thrombi. These effects may lead to the repair and maintenance of IAs. This study presents guidelines for the prediction and validation of the IA regulator MYOCD in competitive endogenous RNA networks and facilitates the development of novel therapeutic and diagnostic tools for IAs.