Observing Extracellular Vesicles Originating from Endothelial Cells in Vivo Demonstrates Improved Astrocyte Function Following Ischemic Stroke via Aggregation-Induced Emission Luminogens.

Extracellular vesicles (EVs) obtained from endothelial cells (ECs) have significant therapeutic potential in the clinical management of individuals with ischemic stroke (IS) because they effectively treat ischemic stroke in animal models. However, because molecular probes with both high labeling efficiency and tracer stability are lacking, monitoring the actions of EC-EVs in the brain remains difficult. The specific intracellular targets in the brain that EC-EVs act on to produce their protective effects are still unknown, greatly impeding their use in clinical settings. For this research, we created a probe that possessed aggregation-induced emission (AIE) traits (namely, TTCP), enabling the effective labeling of EC-EVs while preserving their physiological properties. In vitro, TTCP simultaneously had a higher EC-EV labeling efficiency and better tracer stability than the commercial EV tags PKH-67 and DiI. In vivo, TTCP precisely tracked the actions of EC-EVs in a mouse IS model without influencing their protective effects. Furthermore, through the utilization of TTCP, it was determined that astrocytes were the specific cells affected by EC-EVs and that EC-EVs exhibited a safeguarding impact on astrocytes following cerebral ischemia-reperfusion (I/R) injury. These protective effects encompassed the reduction of the inflammatory reaction and apoptosis as well as the enhancement of cell proliferation. Further analysis showed that miRNA-155-5p carried by EC-EVs is responsible for these protective effects via regulation of the c-Fos/AP-1 pathway; this information provided a strategy for IS therapy. In conclusion, TTCP has a high EC-EV labeling efficiency and favorable in vivo tracer stability during IS therapy. Moreover, EC-EVs are absorbed by astrocytes during cerebral I/R injury and promote the restoration of neurological function through the regulation of the c-Fos/AP-1 signaling pathway.

A systematic review and meta-analysis of surgeries performed for cerebral cavernous malformation-related epilepsy in pediatric patients.

Background: The clinical benefit of surgery for the treatment of cerebral cavernous malformation (CCM)-related epilepsy in pediatric patients is still controversial. Although surgical treatment of CCM-related epilepsy in children is widely recognized, the clinical benefits of controlling the seizure rate must be balanced against the risk of leading to perioperative morbidity. Methods: We conducted a comprehensive search to identify relevant studies via Ovid Medline, Web of Science and PubMed (January 1995-June 2020). The following search terms were used: "hemangioma, cavernous, central nervous system," "brain cavernous hemangioma," "cerebral cavernous hemangioma," "CCM," "epilepsy," and "seizures." The seizure control rate and the risk of postoperative adverse outcomes along with their 95% confidence intervals (CIs) were calculated. Results: A total of 216 patients across 10 studies were included in meta-analysis. The results showed that the control rate of epilepsy was 88% (95% CI: 76-95%). Four percent (95% CI: 2-10%) of the patients experienced temporary symptomatic adverse effects following surgical resection, and 3% (95% CI: 0-26%) of the patients developed permanent symptomatic adverse effects in the long-term follow-up after surgical excision of the CCMs. None of the patients died as a result of the CCMs or surgical treatment. Conclusion: Surgery is an effective and safe treatment for CCM -related epilepsy in pediatric patients with a low risk of postoperative complications and death.

Top-down stepwise refinement identifies coding and noncoding RNA-associated epigenetic regulatory maps in malignant glioma.

With the emergence of the molecular era and retreat of the histology epoch in malignant glioma, it is becoming increasingly necessary to research diagnostic/prognostic/therapeutic biomarkers and their related regulatory mechanisms. While accumulating studies have investigated coding gene-associated biomarkers in malignant glioma, research on comprehensive coding and noncoding RNA-associated biomarkers is lacking. Furthermore, few studies have illustrated the cross-talk signalling pathways among these biomarkers and mechanisms in detail. Here, we identified DEGs and ceRNA networks in malignant glioma and then constructed Cox/Lasso regression models to further identify the most valuable genes through stepwise refinement. Top-down comprehensive integrated analysis, including functional enrichment, SNV, immune infiltration, transcription factor binding site, and molecular docking analyses, further revealed the regulatory maps among these genes. The results revealed a novel and accurate model (AUC of 0.91 and C-index of 0.84 in the whole malignant gliomas, AUC of 0.90 and C-index of 0.86 in LGG, and AUC of 0.75 and C-index of 0.69 in GBM) that includes twelve ncRNAs, 1 miRNA and 6 coding genes. Stepwise logical reasoning based on top-down comprehensive integrated analysis and references revealed cross-talk signalling pathways among these genes that were correlated with the circadian rhythm, tumour immune microenvironment and cellular senescence pathways. In conclusion, our work reveals a novel model where the newly identified biomarkers may contribute to a precise diagnosis/prognosis and subclassification of malignant glioma, and the identified cross-talk signalling pathways would help to illustrate the noncoding RNA-associated epigenetic regulatory mechanisms of glioma tumorigenesis and aid in targeted therapy.

Temozolomide Treatment Induces HMGB1 to Promote the Formation of Glioma Stem Cells via the TLR2/NEAT1/Wnt Pathway in Glioblastoma.

Formation of glioma stem cells (GSCs) is considered as one of the main reasons of temozolomide (TMZ) resistance in glioma patients. Recent studies have shown that tumor microenvironment-derived signals could promote GSCs formation. But the critical molecule and underlying mechanism for GSCs formation after TMZ treatment is not entirely identified. Our study showed that TMZ treatment promoted GSCs formation by glioma cells; TMZ treatment of biopsy-derived glioblastoma multiforme cells upregulated HMGB1; HMGB1 altered gene expression profile of glioma cells with respect to mRNA, lncRNA and miRNA. Furthermore, our results showed that TMZ-induced HMGB1 increased the formation of GSCs and when HMGB1 was downregulated, TMZ-mediated GSCs formation was attenuated. Finally, we showed that the effect of HMGB1 on glioma cells was mediated by TLR2, which activated Wnt/ß-catenin signaling to promote GSCs. Mechanistically, we found that HMGB1 upregulated NEAT1, which was responsible for Wnt/ß-catenin activation. In conclusion, TMZ treatment upregulates HMGB1, which promotes the formation of GSCs via the TLR2/NEAT1/Wnt pathway. Blocking HMGB1-mediated GSCs formation could serve as a potential therapeutic target for preventing TMZ resistance in GBM patients.

Microsurgery vs. Gamma Knife Radiosurgery for the Treatment of Brainstem Cavernous Malformations: A Systematic Review and Meta-Analysis.

Background: Brainstem cavernous malformations (BSCMs) are a subset of cerebral cavernous malformations with precarious locations and potentially devastating clinical courses. The effects and outcomes of treating BSCMs by microsurgery or gamma knife radiosurgery (GKRS) vary across studies. Methods: We searched the Medline, Web of Science, The Cochrane Library, PubMed, and China Biology Medicine disc databases for original articles published in peer-reviewed journals of cohort studies reporting on 20 or more patients of any age with BSCMs with at least 80% completeness of follow-up. Results: We included 43 cohorts involving 2,492 patients. Both microsurgery (RR = 0.04, 95% CI 0.01-0.16, P < 0.01) and GKRS (RR = 0.11, 95% CI 0.08-0.16, P < 0.01) demonstrated great efficacy in reducing the rehemorrhage rate after treatment for BSCMs. The incidence rates of composite outcomes were 19.8 (95% CI 16.8-22.8) and 15.7 (95% CI 11.7-19.6) after neurosurgery and radiosurgery, respectively. In addition, we found statistically significant differences in the median numbers of patients between neurosurgical and radiosurgical cohorts in terms of symptomatic intracranial hemorrhage (ICH; neurosurgical cohorts: median 0, range 0-33; radiosurgical cohorts: median 4, range 1-14; P < 0.05) and persistent focal neurological deficit (FND; neurosurgical cohorts: median 5, range 0-140; radiosurgical cohorts: median 1, range 0-3; P < 0.05). Conclusions: The reported effects of treating BSCMs by microsurgery or GKRS are favorable for reducing recurrent hemorrhage from BSCMs. Patients in the neurosurgery cohort had a lower incidence of symptomatic ICH, while patients in the radiosurgical cohort had a lower incidence of persistent FND.

Treatment of Cerebral Cavernous Malformations Presenting With Seizures: A Systematic Review and Meta-Analysis.

Background: Cerebral cavernous malformations (CCMs) presenting with seizures can be treated with neurosurgery or radiosurgery, but the ideal treatment remains unclear. Currently, there is no adequate randomized controlled trial comparing surgical treatment and radiotherapy for epileptogenic CCMs. Therefore, we conducted a systematic review and meta-analysis of available data from published literature to compare the efficacy and safety of neurosurgery and radiosurgery for epileptogenic CCMs. Methods: We performed a comprehensive search of the Ovid MEDLINE, Web of Science, PubMed, China Biological Medicine and China National Knowledge Infrastructure databases for studies published between January 1994 and October 2019. The search terms were as follows: "epilepsy," "seizures," "brain cavernous hemangioma," "cerebral cavernous malformation," "cerebral cavernous hemangioma," "hemangioma, cavernous, central nervous system." Two researchers independently extracted the data and reviewed all the articles. We compared the advantages and disadvantages of the two treatments. Results: A total of 45 studies were included in our analysis. Overall, the seizure control rate was 79% (95% CI: 75-83%) for neurosurgery and 49% (95% CI: 38-59%) for radiosurgery. In the neurosurgery studies, 4.4% of patients experienced permanent morbidity, while no patients in the radiotherapy studies had permanent morbidity. In addition, the results of subgroup analysis showed that ethnicity, CCMs location and average lesion number are likely significant factors influencing the seizure outcome following treatment. Conclusions: The epilepsy control rate after neurosurgery was higher than that after radiosurgery, but neurosurgery also had a relatively higher rate of permanent morbidity.

Endothelial Notch activation promotes neutrophil transmigration via downregulating endomucin to aggravate hepatic ischemia/reperfusion injury.

Inflammatory leukocytes infiltration is orchestrated by mechanisms involving chemokines, selectins, addressins and other adhesion molecules derived from endothelial cells (ECs), but how they respond to inflammatory cues and coordinate leukocyte transmigration remain elusive. In this study, using hepatic ischemia/reperfusion injury (HIRI) as a model, we identified that endothelial Notch activation was rapidly and dynamically induced in liver sinusoidal endothelial cells (LSECs) in acute inflammation. In mice with EC-specific Notch activation (NICeCA), HIRI induced exacerbated liver damage. Consistently, endothelial Notch activation enhanced neutrophil infiltration and tumor necrosis factor (TNF)-α expression in HIRI. Transcriptome analysis and further qRT-PCR as well as immunofluorescence indicated that endomucin (EMCN), a negative regulator of leukocyte adhesion, was downregulated in LSECs from NICeCA mice. EMCN was downregulated during HIRI in wild-type mice and in vitro cultured ECs insulted by hypoxia/re-oxygenation injury. Notch activation in ECs led to increased neutrophil adhesion and transendothelial migration, which was abrogated by EMCN overexpression in vitro. In mice deficient of RBPj, the integrative transcription factor of canonical Notch signaling, although overwhelming sinusoidal malformation aggravated HIRI, the expression of EMCN was upregulated; and pharmaceutical Notch blockade in vitro also upregulated EMCN and inhibited transendothelial migration of neutrophils. The Notch activation-exaggerated HIRI was compromised by blocking LFA-1, which mediated leukocyte adherence by associating with EMCN. Therefore, endothelial Notch signaling controls neutrophil transmigration via EMCN to modulate acute inflammation in HIRI.