Neuritin attenuates neuroinflammation and apoptosis in early brain injury after subarachnoid hemorrhage via endoplasmic reticulum stress-related inflammatory pathways.

Neuroinflammation is a key destructive pathophysiological process in early brain injury (EBI) following subarachnoid hemorrhage (SAH). Recent studies have discovered that endoplasmic reticulum stress-related inflammatory pathways include the IRE1α-TRAF2-NF-κB pathway, PERK-eIF2α-NF-κB pathway, and ATF6-AKT -NF-κB pathway leading to neuroinflammatory response. Neuritin is a neurotrophin that is involved in neuronal plasticity and regeneration. Studies have suggested that Neuritin has a vital role in reducing neuroinflammation, and can also decrease the expression of proteins related to endoplasmic reticulum stress following SAH. This suggests that Neuritin could be a potential therapeutic target for SAH and other neurological conditions. However, the regulatory mechanisms of Neuritin in ER stress-related inflammatory pathways after SAH are not yet fully understood. In this work, we discovered that the activation of ER stress-related inflammatory pathways leads to neuroinflammation, which further aggravates neuronal apoptosis after SAH. Our findings indicate that Neuritin overexpression play a neuroprotective role by inhibiting IRE1α-TRAF2-NF-κB pathway, PERK-eIF2α-NF-κB pathway, and ATF6-AKT-NF-κB pathway associated with endoplasmic reticulum stress. These inhibitory effects on neuroinflammation ultimately reduce nerve cell apoptosis.

A Study on the Efficacy of Thrombectomy in Patients with Atherosclerotic and Cardioembolic Basilar Artery Occlusion.

Background Studies on basilar artery occlusion are relatively few compared with those of anterior circulation stroke. The aim of the present study was to compare the efficacy of endovascular therapy (EVT) in patients with basilar artery occlusion classified as large artery atherosclerosis (LAA) and cardioembolism (CE), and to analyze the independent risk factors affecting the prognosis of EVT. Methods A total of 123 people were assigned to the LAA and CE groups (97 to the LAA and 26 to the CE). The primary outcome was a modified Rankin Scale (mRS) score of 2 or lower at 90 days. The primary safety outcome was mortality at 90 days. Secondary safety endpoints included the rates of symptomatic intracranial hemorrhage and reinfarction. Multiple logistic regression was used to screen out independent risk factors for EVT prognosis of the LAA and CE groups. Results In the analysis, the patients with LAA stroke had better collateral circulation (American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology [SIR] score of 2-4; 61.9 vs. 19.2%, p = 0.000), and higher angioplasty rate (32.0 vs. 3.8%, p = 0.002). The proportions of patients with a 90-day mRS score of 0 to 2 and 90-day mortality were not found to be statistically significant between the two groups. Multivariate logistic regression analysis indicated that age, SIR, white blood cell, blood glucose, and modified thrombolysis in cerebral infarction were independent risk factors for the poor prognosis of EVT in the LAA group. Conclusion Although there were differences in clinical characteristics and imaging features between LAA and CE, there was no evidence of a significant difference in prognosis after EVT. In addition, the National Institutes of Health Stroke Scale score was not among the independent risk factors affecting the prognosis of the LAA group.

Neuritin promotes autophagic flux by inhibiting the cGAS-STING pathway to alleviate brain injury after subarachnoid haemorrhage.

BACKGROUND: Early brain injury (EBI) is closely associated with poor prognosis in patients with subarachnoid haemorrhage (SAH), with autophagy playing a pivotal role in EBI. However, research has shown that the stimulator of interferon genes (STING) pathway impacts autophagic flux. While the regulatory impact of neuritin on EBI and autophagic flux has been established previously, the underlying mechanism remains unclear. This study aimed to determine the role of the cGAS-STING pathway in neuritin-mediated regulation of autophagic flux following SAH. METHODS: A SAH model was established in male Sprague-Dawley rats via intravascular perforation. Neuritin overexpressions using adeno-associated virus, the STING antagonist "C-176," and the activator, "CMA," were determined to investigate the cGAS-STING pathway's influence on autophagic flux and brain injury post-SAH, along with the neuritin's regulatory effect on STING. In this study, SAH grade, neurological score, haematoxylin and eosin (H&E) staining, brain water content (BWC), sandwich enzyme-linked immunosorbent assay, Evans blue staining, immunofluorescence staining, western blot analysis, and transmission electron microscopy (TEM) were examined. RESULTS: Neuritin overexpression significantly ameliorated neurobehavioural scores, blood-brain barrier injury, brain oedema, and impaired autophagic flux in SAH-induced rats. STING expression remarkably increased post-SAH. C-176 and CMA mitigated and aggravated autophagic flux injury and brain injury, respectively, while inhibiting and enhancing STING, respectively. Particularly, CMA treatment nullified the protective effects of neuritin against autophagic flux and mitigated brain injury. CONCLUSION: Neuritin alleviated EBI by restoring impaired autophagic flux after SAH through the regulation of the cGAS-STING pathway.

Cucurbitacin B exhibits antitumor effects on CD133+ HepG2 liver cancer stem cells by inhibiting JAK2/STAT3 signaling pathway.

Cancer stem cells (CSCs), a crucial cancer cell subpopulation, possess stemness phenotypic characteristics. Cucurbitacin B (CuB), a tetracyclic triterpenoid isolated from Cucurbitaceae, exerts widely pharmacological activities in many diseases. The aim of this study was to enrich, identify liver CSCs and investigate antitumor effects of CuB as well as explore the underlying molecular mechanisms in these liver CSCs. HepG2 cell lines were used for the enrichment of liver CSCs by serum-free medium culture and magnetic-activated cell sorting. The CSC characteristics were analyzed by immunofluorescent staining, sphere-forming, western blot and xenograft tumorigenicity assay. CuB' antitumor effects and underlying molecular mechanism were measured by cell counting kit-8, colony formation, sphere-forming, cell cycle, xenograft and western blot assay. Our results showed that we could enrich 97.29% CD133+ HepG2 cells, which possessed CSC characteristics including re-renewal capacity, proliferative ability, sorafenib resistance, overexpressed stemness-related molecules and enhanced tumorigenic potential. Furthermore, we also found that CuB inhibited cell viability, sphere formation, colony formation and arrested cell cycle at G2/M phase as well as sensitized CD133+ HepG2 cells to sorafenib in vitro and in vivo. Western blot assay indicated that CuB inhibited expression levels of cyclin B1, CDK1, CD133, p-JAK2 and p-STAT3. In conclusion, our findings indicated that CuB could exhibit antitumor effects on CD133+ HepG2 CSCs by inhibiting the Janus kinase 2/signal transducers and activators of transcription-3 signaling pathway, expanding basic and preclinical investigations on liver CSCs.

Neuritin Attenuates Neuronal Apoptosis Mediated by Endoplasmic Reticulum Stress In Vitro.

Neuritin is an extracellular glycophosphatidylinositol-linked protein that promotes neuronal survival, differentiation, function, and repair, but the exact mechanism of this neuroprotective effect remains unclear. Meanwhile, endoplasmic reticulum stress (ERS) induced apoptosis is attracting increased attention. In this work, we hypothesized that neuritin inhibited ERS to protect cortical neurons. To check this hypothesis, we exposed primary cultured cortical neurons to oxygen and glucose deprivation (OGD) for 45 min followed by reperfusion (R) to activate ERS. We then performed resuscitation for 6, 12, 24, and 48 h. ERS-related factors such as glucose-regulated protein 78 (GRP78), caspase-12 and CHOP were detected by Western blotting and quantitative real-time polymerase chain reaction assay. Apoptosis was assessed by Annexin V binding and propidium iodide staining. Ultrastructural changes of endoplasmic reticulum were observed under a transmission electron microscope. Results showed that GRP78 expression significantly increased at 12, 24, and 48 h and peaked at 24 h. Caspase-12 and CHOP expression significantly increased in a time-dependent manner at 12, 24, and 48 h. GRP78, caspase-12 and CHOP expression as well as apoptosis rate of primary cultured neurons and the ultrastructural changes of endoplasmic reticulum in the OGD/R + neuritin group significantly improved compared with the OGD/R group. In conclusion, the neuroprotection function of neuritin may be involved in ERS pathways.