Inhibition of neutrophil extracellular trap formation ameliorates neuroinflammation and neuronal apoptosis via STING-dependent IRE1α/ASK1/JNK signaling pathway in mice with traumatic brain injury.

BACKGROUND: Neuroinflammation is one of the most important pathogeneses in secondary brain injury after traumatic brain injury (TBI). Neutrophil extracellular traps (NETs) forming neutrophils were found throughout the brain tissue of TBI patients and elevated plasma NET biomarkers correlated with worse outcomes. However, the biological function and underlying mechanisms of NETs in TBI-induced neural damage are not yet fully understood. Here, we used Cl-amidine, a selective inhibitor of NETs to investigate the role of NETs in neural damage after TBI. METHODS: Controlled cortical impact model was performed to establish TBI. Cl-amidine, 2'3'-cGAMP (an activator of stimulating Interferon genes (STING)), C-176 (a selective STING inhibitor), and Kira6 [a selectively phosphorylated inositol-requiring enzyme-1 alpha [IRE1α] inhibitor] were administrated to explore the mechanism by which NETs promote neuroinflammation and neuronal apoptosis after TBI. Peptidyl arginine deiminase 4 (PAD4), an essential enzyme for neutrophil extracellular trap formation, is overexpressed with adenoviruses in the cortex of mice 1 day before TBI. The short-term neurobehavior tests, magnetic resonance imaging (MRI), laser speckle contrast imaging (LSCI), Evans blue extravasation assay, Fluoro-Jade C (FJC), TUNEL, immunofluorescence, enzyme-linked immunosorbent assay (ELISA), western blotting, and quantitative-PCR were performed in this study. RESULTS: Neutrophils form NETs presenting in the circulation and brain at 3 days after TBI. NETs inhibitor Cl-amidine treatment improved short-term neurological functions, reduced cerebral lesion volume, reduced brain edema, and restored cerebral blood flow (CBF) after TBI. In addition, Cl-amidine exerted neuroprotective effects by attenuating BBB disruption, inhibiting immune cell infiltration, and alleviating neuronal death after TBI. Moreover, Cl-amidine treatment inhibited microglia/macrophage pro-inflammatory polarization and promoted anti-inflammatory polarization at 3 days after TBI. Mechanistically, STING ligand 2'3'-cGAMP abolished the neuroprotection of Cl-amidine via IRE1α/ASK1/JNK signaling pathway after TBI. Importantly, overexpression of PAD4 promotes neuroinflammation and neuronal death via the IRE1α/ASK1/JNK signaling pathway after TBI. However, STING inhibitor C-176 or IRE1α inhibitor Kira6 effectively abolished the neurodestructive effects of PAD4 overexpression after TBI. CONCLUSION: Altogether, we are the first to demonstrate that NETs inhibition with Cl-amidine ameliorated neuroinflammation, neuronal apoptosis, and neurological deficits via STING-dependent IRE1α/ASK1/JNK signaling pathway after TBI. Thus, Cl-amidine treatment may provide a promising therapeutic approach for the early management of TBI.

ADAMTS8 inhibits glioma development in vitro and in vivo.

INTRODUCTION: In recent years, novel RNAs have been revealed to be regulators in glioma. ADAMTS8 has been reported to be reduced in brain tumours. In this study, we aimed to explore the role of ADAMTS8 in glioma. MATERIAL AND METHODS: Online bioinformatic tools, Gepia and Chinese Glioma Genome Atlas database (CGGA) were used to analyse the differential expression of ADAMTS8, overall survival and disease-free survival rates and the correlations between ADAMTS8 and matrix metallopeptidases (MMP2 and MMP9) in glioma. RT-qPCR and western blot experiments were performed to measure the mRNA and protein expression. ADAMTS8 expression was regulated in cells through transfection. Thereafter, the effect of ADAMTS8 on cells was investigated through the cell viability, apoptosis and transwell experiments. The epithelial-mesenchymal transition (EMT)-related proteins and also MMP2 and MMP9 were examined. The subcutaneous tumour model was established to validate the suppressive role of ADAMTS8 in tumour growth. RESULTS: ADAMTS8 expression was reduced in glioma tissues and cells. Higher expression of ADAMTS8 was correlated with higher survival rates. ADAMTS8 was correlated with MMP2 and MMP9 in glioma tissues. In glioma cells, overexpression of ADAMTS8 could inhibit the viability, invasion, migration and EMT, and MMP2 and MMP9, but promote the apoptosis of cells. The upregulation of ADAMTS8 could inhibit the tumour growth in vivo. CONCLUSIONS: ADAMTS8 was inhibited in glioma and the higher expression of ADAMTS8 might be related to better prognosis among glioma patients. Overexpression of ADAMTS8 inhibited the development of glioma in vitro and in vivo.

Application of intraoperative indocyanine green videoangiography for resection of spinal cord hemangioblastoma: advantages and limitations.

Hemangioblastomas constitute 2-15% of intramedullary spinal cord tumors. Identification of the feeding arteries and draining veins is crucial for an en bloc tumor resection and cure. We report our experience using intraoperative indocyanine green (ICG) videoangiography during the surgical resection of spinal cord hemangioblastomas (SH) and evaluate the advantages and limitations of this technique. Seven patients with an SH underwent resection with the assistance of intraoperative ICG videoangiography. The ICG videoangiography images were analyzed, and the preoperative, intraoperative, and postoperative images were compared. ICG videoangiography clearly revealed the feeding arteries and enlarged draining veins and assisted in defining the tumor borders in five of the seven patients (patients one, two, four, five, and seven). By contrast, patient three had a devascularized residual tumor located deep in the spinal cord parenchyma, which did not take up the fluorescent dye and therefore was not visualized by ICG videoangiography. In addition, in patient six, only the draining veins could be visualized in the ventrolateral tumor, because it was covered by the spinal cord parenchyma. Six tumors were completely removed, and one was partially removed. None of our patients had significant neurological deterioration after surgery. ICG videoangiography provided real-time information about the tumor vasculature during surgery for SH and aided in intraoperative decision-making. However, for deep tumors and ventral tumors, the benefits of this technique might be limited.

Surgical treatment of spinal vascular malformations performed using intraoperative indocyanine green videoangiography.

This study aims to evaluate the benefits of intraoperative indocyanine green (ICG) videoangiography and associated surgical outcomes of patients with spinal vascular malformations. ICG videoangiography was used during 24 surgical interventions to treat spinal vascular malformations at the Beijing Tiantan Hospital from August 2009 to May 2011. The vascular malformations were removed or the fistulae were occluded with the assistance of ICG videoangiography. The completeness of fistula clipping or nidus extirpation and each patient's neurological status were evaluated. Among these 24 patients, there were seven with spinal dural arteriovenous fistulae, five glomus arteriovenous malformations, one juvenile arteriovenous malformation, nine perimedullary arteriovenous fistulae, and two perimedullary arteriovenous fistulae in combination with perimedullary arteriovenous malformations. Intraoperative ICG videoangiography confirmed the definite clipping of the fistulous points and complete removal of intramedullary arteriovenous malformations in all but one patient. All patients had satisfactory preservation of spinal cord blood supply and venous return. No adverse effects or complications related to ICG videoangiography occurred. Three patients were lost to follow up; 21 patients were followed clinically with a mean follow up of 7.5 months. The neurological deficits completely resolved in six patients, improved significantly in 10, remained stable in two, and were aggravated in three patients. Our experience shows that intraoperative ICG videoangiography offers useful information on the pathological and physiological vascular anatomy encountered during surgery for spinal vascular malformations.