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Background: Subarachnoid hemorrhage (SAH) serves as a disease characterized by high incidence rate, which is exceedingly prevalent and severe. Presently, there is no unambiguous or efficacious intervention for the neurological impairment following SAH. Administering multi-targeted neuroprotective agents to reduce oxidative stress (OS) and neuroinflammation caused by early brain injury (EBI) has been demonstrated to improve neurological function and prognosis following SAH. Edaravone dexborneol (EDB), a novel multi targeted neuroprotective medication, combines four parts edaravone (EDA) with 1 part (+)-borneol in proportion. Clinical trials conducted in China have revealed during 2 days of acute ischemic stroke (AIS), early administration of EDB leads to improved therapeutic outcomes compared to treatment in EDA monotherapy. Currently, there is no clear evidence that EDB can effectively treat SAH, therefore, our study aims to investigate its potential therapeutic effects and mechanisms on EBI after SAH. Method: We used the intravascular threading method to establish a mouse model of SAH to explore whether EDA and EDB could produce anti-OS and anti-apoptosis effects. Behavioral assessment of mice was conducted using the balance beam experiment and the modified Garcia scoring system. Neuronal damage due to OS and Keap1/Nrf2 signaling pathway were detected through techniques of immunofluorescence, Western blotting, spectrophotometry. The group of EDA and EDB were injected intraperitoneally for 72 h after SAH. Results: The experiment results indicated that EDB lead to remarkably positive results by significantly enhancing neurological function, reducing blood-brain barrier (BBB) injury, and effectively inhibiting neuronal apoptosis after SAH. Further examination indicated EDB significantly reduced the expression of Keap1 and increased the expression of Nrf2, and it inhibited MDA, and enhanced SOD activity after SAH. These outcomes surpassed the effectiveness observed in EDA monotherapy. However, the application of ML385 reversed the anti-OS effects of EDB and EDA. Conclusion: Our experimental findings indicated that EDB could activate Keap1/Nrf2 signaling pathway to reduce OS damage, thereby protecting neurological function and enhancing behavioral abilities after SAH. These outcomes could facilitate the creation of new approaches for the clinical management of SAH.

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Introduction: As a rare type of cerebral venous thrombosis, isolated cortical vein thrombosis (ICVT) is easily misdiagnosed as brain tumor, especially in the cases with prominent signs of parenchymal brain lesions. Despite controversy concerning the efficacy and safety, anticoagulant treatment dominates in current therapeutic strategies for ICVT. As yet, surgical thrombectomy in the treatment of ICVT has not been reported. We present hereafter a female with ICVT previously misdiagnosed as brain tumor who had successful surgical thrombectomy. Case description: A 54-year-old female with progressive left-sided limb weakness suddenly developed focal tonic-clonic epileptic seizure. Physical examination indicated strength of 0/5 in the left limbs. Magnetic resonance imaging (MRI) showed an irregular juxtacortical lesion surrounded with massive edema in the frontoparietal cortex, which was initially diagnosed as glioma. However, it turned out to be ICVT of the central sulcus vein during craniotomy. Then, venotomy and thrombectomy were performed, with instant recanalization of the vein noticed during surgery. In retrospect, we identified the suspected ICVT of the central sulcus vein in preoperative magnetic resonance venotography (MRV) and contrast MRI images. Laboratory tests also revealed homocysteinemia and hypercoagulable states in the patient. Follow-up MRV obtained 3 months after discharge showed cortical vein recanalization. At the one-year follow-up, she exhibited subtle sequelae of weakness in the left lower limb with a modified Rankin scale score of 1. Discussion: Physicians should be aware of ICVT in the differential diagnoses in patients with risk factors, classical symptoms, and parenchymal brain lesions in or near cortex. Surgical thrombectomy excels at realizing definite recanalization and avoiding systematic complications of anticoagulation. It might be a therapeutic alternative for ICVT, especially when craniotomy is performed for treating intracranial hypertension or a definite diagnosis is made during craniotomy.

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Introduction: The management of retroinfundibular craniopharyngioma (CP) remains the ultimate challenge for both transsphenoidal and open transcranial surgery because of their anatomical location and proximity to vital neurovascular structures. In this report, we aim to describe the technique and feasibility of a novel approach, the purely endoscopic far-lateral supracerebellar infratentorial approach (EF-SCITA), for resection of retroinfundibular CP. Case description: A 63-year-old women presented with progressive visual disturbance, polyuria, and spiritlessness of a 3-month duration. Imaging studies revealed a typical retroinfundibular CP containing solid and cystic components with calcification, which extended inferiorly in front of the brainstem and upward into the third ventricle. The EF-SCITA approach was attempted for resection of the tumor. During surgery, lateral prone positioning with upper flexion of the head and early CSF release allowed for download retraction of the cerebellum. This, in combination with tentorium incision, created a working corridor toward retrosellar and suprasellar spaces. This approach required working between neurovascular structures in the crural cistern, with tumor removal permitted in supra-oculomotor and infra-oculomotor spaces. After aspiration of the fluid contents through the supra-oculomotor triangle, the solid lesion was found tightly adhering to the distal part of the pituitary stalk, and subtotal resection was achieved for maintaining the integrity of pituitary function. In the immediate postoperative period, the patients exhibited oculomotor paralysis and was discharged with hormonal replacement therapy three weeks after operation. At her three-month follow-up appointment, she reported obvious vision improvement. Physical examinations showed partial alleviation of oculomotor paralysis. Pathological analyses confirmed the diagnosis of papillary CP. Discussion: The purely EF-SCITA approach combines the advantages of both the posterolateral approach and endoscopic technique, which offers access to retrosellar and suprasellar spaces with seemingly low risks of postoperative morbidity. It would be a safe and effective alternative for the treatment of retroinfundibular CP, especially those with lateral extension to the temporal lobe or posterolateral extension to the petroclival region. Further observational studies in a larger cohort are urgently needed to assess the long-term efficacy of this minimal access approach.

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BACKGROUND: The main pathological change causing carotid artery stenosis is atherosclerosis, and studies suggest that tumor necrosis factor-stimulated gene-6 (TSG-6) has an anti-atherogenic effect and may be a new target for the diagnosis of carotid artery stenosis disease. We hypothesized that serum TSG-6 levels might also be associated with carotid artery stenosis. The aim of this study was to evaluate the diagnostic significance and potential predictive value of serum TSG-6 levels in patients with severe carotid artery stenosis and symptomatic stenosis. METHODS: Serum TSG-6 levels were measured in 96 patients with carotid stenosis and 40 sex and age matched control healthy subjects. The expression of TSG-6 in carotid plaques (4 severe stenoses, 4 moderate stenoses, and 4 mild stenoses) and 4 superficial temporal artery vascular tissues of 12 patients with carotid stenosis who underwent endarterectomy at our hospital were detected by Western blot. Histological analysis of carotid plaque and superficial temporal artery tissues was also performed. RESULTS: Compared with controls, serum TSG-6 levels were higher in patients with carotid stenosis, TSG-6 expression was increased in tissues with moderate and severe stenosis, and TSG-6 expression was significantly higher in the fibrous cap component of the plaque than in the non-fibrous cap component. Serum TSG-6 levels were higher in patients with symptomatic stenosis than in patients with asymptomatic stenosis. Tissue TSG-6 staining levels and serum TSG-6 levels were positively correlated (r = 0.694, p < 0.05) and tissue TSG-6 staining levels were positively correlated with macrophage staining levels (r = 0.932, p < 0.05). Logistic regression analysis showed that serum TSG-6 was an independent factor for the presence of severe carotid stenosis and symptomatic stenosis in patients (p < 0.001). Serum TSG-6 levels were more diagnostically efficient than other indices in identifying severe and symptomatic carotid stenosis (p < 0.05), especially in identifying symptomatic stenosis (p < 0.01). We further significantly increased the diagnostic power of symptomatic stenosis using a combined model of serum TSG-6 and homocysteine (p < 0.05). CONCLUSIONS: Serum TSG-6 may serve as a new non-invasive and easily measured biomarker to better screen people with severe and symptomatic carotid stenosis in clinical practice.

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Primary glioblastoma (GBM) is the most prevalent brain cancer, with fast progression and a poor prognosis. Current treatment options are unable to fully manage GBM since it is highly resistant to radiation and chemotherapy, and it cannot be completely removed by surgery. Thus, immunotherapeutic strategies utilizing tumor-infiltrating T cells have been investigated. In the present study, the T-cell response in GBM patients was examined in resected tumor samples and peripheral blood samples by flow cytometry. It was found that tumor-infiltrating T cells represented a rare population in all tumor cells, and were more refractory to anti-cluster of differentiation 3 (CD3) stimulation than their peripheral blood counterparts. A number of strategies were then assessed to boost tumor-infiltrating T-cell proliferation, and it was found that pre-incubation with 20 U/ml interleukin (IL)-2, as well as sequestration of IL-10 in culture, improved tumor T-cell proliferation following anti-CD3 stimulation. The stimulation of blood antigen-presenting cells by lipopolysaccharide, however, did not improve tumor T-cell proliferation. Overall, the present results provided a viable strategy for improving tumor-infiltrating CD3+ T-cell responses in GBM patients.

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Endovascular retrograde suction decompression (RSD) with balloon occlusion of the internal carotid artery is helpful to facilitate clipping large and giant paraclinoid carotid aneurysms. The authors reported a revised endovascular technique without internal carotid access using Mo.Ma device and analyzed its feasibility. In the series, 15 consecutive patients harboring 15 large and giant paraclinoid carotid aneurysms were clipped with assistance of this revised RSD technique. The technical feasibility of the procedure, procedure-related complications, angiographic results, and clinical outcome were evaluated. Technical success was achieved in 14 patients with aneurysm neck clipping and internal carotid artery (ICA) patent. No complication related to this endovascular technique occurred. At follow-up (mean time 15.3months), the modified Rankin Scale score was excellent in 11 patients, good in two patients and poor in one patient. Their preliminary experience indicates that revised retrograde suction decompression technique with Mo.Ma device seems effective and safe in the surgical treatment of large and giant paraclinoid ICA aneurysms.

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Intracranial aneurysms (IAs) and potential IA rupture are one of the direct causes of permanent brain damage and mortality. Interestingly, the major risk factors of IA development, including hemodynamic stress, hypertension, smoking, and genetic predispositions, are closely associated with a proinflammatory immune status. Therefore, we examined the roles of CD4(+) T cells in IA pathogenesis. IA patients exhibited peripheral CD4(+) T-cell imbalance, with overrepresented T helper 1 (Th1) and Th17 activities and underrepresented Th2 and regulatory T (Treg) activities, including increased IFN-γ, TNF-α, and IL-17 production and decreased IL-10 production from total CD4(+) T cells. Chemokine receptors CXCR3 and CCR6 were used to identify Th1, Th2, and Th17 cell subsets, and CD4(+)CD25(hi) was used to identify Treg cells. Based on these markers, the data then showed altered cytokine production by each cell type and shifted subpopulation frequency. Moreover, this shift in frequency was directly correlated with IA severity. To examine the underlying mechanism of CD4(+) T cell skewing, we cocultured CD4(+) T cells with autologous monocytes and found that coculture with monocytes could significantly increase IFN-γ and IL-17 production through contact-independent mechanisms, demonstrating that monocytes could potentially contribute to the altered CD4(+) T cell composition in IA. Analyzing mRNA transcripts revealed significantly upregulated IL-1ß and TNF-α expression by monocytes from IA patients. We found a loss of CD4(+) T cell subset balance that was likely to promote a higher state of inflammation in IA, which may exacerbate the disease through a positive feedback loop.

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BACKGROUND: It is well known that estrogen receptor α (ERα) participates in the pathogenic progress of breast cancer, hepatocellular carcinoma and head and neck squamous cell carcinoma. In neuroblastoma cells and related cancer clinical specimens, moreover, the ectopic expression of ERα has been identified. However, the detailed function of ERα in the proliferation of neuroblastoma cell is yet unclear. METHODS: The transcriptional activity of ETS-1 (E26 transformation specific sequence 1) was measured by luciferase analysis. Western blot assays and Real-time RT-PCR were used to examine the expression of ERα, ETS-1 and its targeted genes. The protein-protein interaction between ERα and ETS-1 was determined by co-IP and GST-Pull down assays. The accumulation of ETS-1 in nuclear was detected by western blot assays, and the recruitment of ETS-1 to its targeted gene's promoter was tested by ChIP assays. Moreover, SH-SY5Y cells' proliferation, anchor-independent growth, migration and invasion were quantified using the MTT, soft agar or Trans-well assay, respectively. RESULTS: The transcriptional activity of ETS-1 was significantly increased following estrogen treatment, and this effect was related to ligand-mediated activation of ERα. The interaction between the ERα and ETS-1 was identified, and enhancement of ERα activation would up-regulate the ETS-1 transcription factor activity via modulating its cytoplasm/nucleus translocation and the recruitment of ETS-1 to its target gene's promoter. Furthermore, treatment of estrogen increased proliferation, migration and invasion of neuroblastoma cells, whereas the antagonist of ERα reduced those effects. CONCLUSIONS: In this study, we provided evidences that activation of ERα promoted neuroblastoma cells proliferation and up-regulated the transcriptional activity of ETS-1. By investigating the role of ERα in the ETS-1 activity regulation, we demonstrated that ERα may be a novel ETS-1 co-activator and thus a potential therapeutic target in human neuroblastoma treatment.

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Evidence has shown that inflammation acts as a critical contributor to the pathogenesis of intracranial aneurysm (IA), a potentially devastating clinical problem. T cell immunoglobulin and mucin protein 3 (Tim-3) is a negative regulatory molecule and plays important roles in the inflammation process. In the current study, we investigated the expression of Tim-3 and its correlation with tumor necrosis factor alpha (TNF-α) in IA patients. Data showed that both messenger RNA (mRNA) level and protein level of Tim-3 were significantly decreased in CD4+ T cells and CD8+ T cells from IA patients than from healthy controls (P < 0.001). However, expression of Tim-3 was not altered in monocytes between patients and healthy donors. Further analyses revealed that patients with ruptured aneurysm had significantly lower level of Tim-3 in CD8+ T cells than those with un-ruptured aneurysm. In addition, a negative correlation between serum level of TNF-α and the expression of Tim-3 in CD4+ T cells was observed in IA patients. Similar correlation was also identified in CD8+ T cells from IA patients. Our study suggests that Tim-3 may participate in the development and progression of IA by probably its negative regulation on TNF-α.

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Tim-3 acts as a negative regulatory molecule and plays a critical role in immune tolerance. The purpose of this study was to investigate the expression of Tim-3 on peripheral CD4⁺ and CD8⁺ T cells in glioma. A total of 30 newly diagnosed glioma patients and 30 healthy controls were recruited and leukocytes from peripheral blood mononuclear cells were analyzed for Tim-3 surface expression by flow cytometry. Plasma tumor necrosis factor-alpha (TNF-α) was also measured. Data showed that expression of Tim-3 was significantly increased in both CD4⁺ and CD8⁺ T cells in glioma patients than in controls (p<0.001 and p<0.001, respectively). Patients with a higher tumor grade revealed further elevated Tim-3 expression in CD8⁺ T cells compared with those with a lower tumor grade. Also, the Karnofsky score of patients was negatively correlated with the percentage of Tim-3⁺CD8⁺ T cells in glioma patients (p=0.007). In addition, an inverse correlation was observed between the plasma level of TNF-α and Tim-3⁺CD4⁺ T cells (p=0.005) or Tim-3⁺CD8⁺ T cells (p<0.001) in glioma patients. Our results suggested that Tim-3 may be involved in the development of glioma.

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Onyx has been widely adopted for the treatment of arteriovenous malformations (AVMs). However, its control demands operators accumulate a considerable learning curve. We describe our initial experience using a novel injection method for the embolization of AVMs. We retrospectively reviewed the data of all 22 patients with brain AVMs (12 men, 10 women; age range, 12-68 years; mean age, 43.2 years) treated by the transarterial coil-augmented Onyx injection technique. The size of the AVMs ranged from 25 mm to 70 mm (average 35.6 mm). The technical feasibility of the procedure, procedure-related complications, angiographic results, and clinical outcome were evaluated. In every case, endovascular treatment (EVT) was completed. A total of 31 sessions were performed, with a mean injection volume of 6.1 mL (range, 1.5-16.0 mL). An average of 96.7% (range 85%-100%) estimated size reduction was achieved, and 18 AVMs could be completely excluded by EVT alone. The results remained stable on follow-up angiograms. A procedural complication occurred in one patient, with permanent mild neurologic deficit. Our preliminary series demonstrated that the coil-augmented Onyx injection technique is a valuable adjunct achieving excellent nidal penetration and improving the safety of the procedure.

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The key signaling networks regulating glioma cell proliferation remain poorly defined. The leucine-rich repeat containing G-protein coupled receptor 4 (Lgr4) has been implicated in intestinal, gastric, and epidermal cell functions. We investigated whether Lgr4 functions in glioma cells and found that Lgr4 expression was significantly increased in glioma tissues. In addition, Lgr4 overexpression promoted while its knockdown using small interfering RNA oligos inhibited glioma cell proliferation. In addition, Wnt/ß-catenin signaling was activated in cells overexpressing Lgr4. Therefore, our results revealed that Lgr4 activates Wnt/ß-catenin signaling to regulate glioma cell proliferation.

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Phytochemical investigation of the ethanol extract of the bulbs of Lycoris caldwellii afforded four new alkaloids, (+)-N-methoxylcarbonyl-nandigerine (1), (+)-N-methoxycarbonyl-lindcarpine (2), (+)-10-O-methylhernovine N-oxide (3), and (+)-3-hydroxy-anhydrolycorine N-oxide (4). Structural elucidation of all the compounds were performed by spectral methods such as 1D and 2D (¹H-¹H COSY, HMQC, and HMBC) NMR spectroscopy, in addition to high resolution mass spectrometry. All the alkaloids were in vitro evaluated for their cytotoxic activities against eight tumor cell lines (BEN-MEN-1, CCF-STTG1, CHG-5, SHG-44, U251, BGC-823, HepG2, and SK-OV-3). Alkaloids 1 and 2 exhibited particular cytotoxic activities against astrocytoma and glioma cell lines with IC50 of 9.2-11.3 µM and 10.4-12.2 µM respectively.

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