BackgroundCopper ions are essential for cellular physiology. Cuproptosis is a novel method of copper-dependent cell death, and the cuproptosis-based signature for glioma remains less studied.MethodsSeveral glioma datasets with clinicopathological information were collected from TCGA, GEO and CGGA. Robust Multichip Average (RMA) algorithm was used for background correction and normalization, cuproptosis-related genes (CRGs) were then collected. The TCGA-glioma cohort was clustered using ConsensusClusterPlus. Univariate Cox regression analysis and the Random Survival Forest model were performed on the differentially expressed genes to identify prognostic genes. The cuproptosis-signature was constructed by calculating CuproptosisScore using Multivariate Cox regression analysis. Differences in terms of genomic mutation, tumor microenvironment, and enrichment pathways were evaluated between high- or low-CuproptosisScore. Furthermore, drug response prediction was carried out utilizing pRRophetic.ResultsTwo subclusters based on CRGs were identified. Patients in cluster2 had better clinical outcomes. The cuproptosis-signature was constructed based on CuproptosisScore. Patients with higher CuproptosisScore had higher WHO grades and worse prognosis, while patients with lower grades were more likely to develop IDH mutations or MGMT methylation. Univariate and Multivariate Cox regression analysis demonstrated CuproptosisScore was an independent prognostic factor. The accuracy of the signature in prognostic prediction was further confirmed in 11 external validation datasets. In groups with high-CuproptosisScore, PIK3CA, MUC16, NF1, TTN, TP53, PTEN, and EGFR showed high mutation frequency. IDH1, TP53, ATRX, CIC, and FUBP1 demonstrated high mutation frequency in low-CuproptosisScore group. The level of immune infiltration increased as CuproptosisScore increased. SubMap analysis revealed patients with high-CuproptosisScore may respond to anti-PD-1 therapy. The IC50 values of Bexarotene, Bicalutamide, Bortezomib, and Cytarabine were lower in the high-CuproptosisScore group than those in the low-CuproptosisScore group. Finally, the importance of IGFBP2 in TCGA-glioma cohort was confirmed.ConclusionThe current study revealed the novel cuproptosis-based signature might help predict the prognosis, biological features, and appropriate treatment for patients with glioma.
Chronic pain has attracted wide interest because it is a major obstacle affecting the quality of life. Consequently, safe, efficient, and low‐addictive drugs are highly desirable. Nanoparticles (NPs) with robust anti‐oxidative stress and anti‐inflammatory properties possess therapeutic possibilities for inflammatory pain. Herein, a bioactive zeolitic imidazolate framework (ZIF)‐8‐capped superoxide dismutase (SOD) and Fe3O4 NPs (SOD&Fe3O4@ZIF‐8, SFZ) is developed to achieve enhanced catalytic, antioxidative activities, and inflammatory environment selectivity, ultimately improving analgesic efficacy. SFZ NPs reduce tert‐butyl hydroperoxide (t‐BOOH)‐induced reactive oxygen species (ROS) overproduction, thereby depressing the oxidative stress and inhibiting the lipopolysaccharide (LPS)‐induced inflammatory response in microglia. After intrathecal injection, SFZ NPs efficiently accumulate at the lumbar enlargement of the spinal cord and significantly relieve complete Freund's adjuvant (CFA)‐induced inflammatory pain in mice. Moreover, the detailed mechanism of inflammatory pain therapy via SFZ NPs is further studied, where SFZ NPs inhibit the activation of the mitogen‐activated protein kinase (MAPK)/p‐65 signaling pathway, leading to reductions in phosphorylated protein levels (p‐65, p‐ERK, p‐JNK, and p‐p38) and inflammatory factors (tumor necrosis factor [TNF]‐α, interleukin [IL]‐6, and IL‐1β), thereby preventing microglia and astrocyte activation for acesodyne. This study provides a new cascade nanoenzyme for antioxidant treatments and explores its potential applications as non‐opioid analgesics.
Background: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the current COVID-19 pandemic, resulting in a public health crisis that required immediate action. The SARS-CoV-2 virus enters human cells via three receptors, namely cathepsin, angiotensin-converting enzyme 2 (ACE2) and SARS-CoV receptors. Cathepsin destroys the spike protein (S protein), thereby allowing the entry of viral nucleic acid into human host cells.Methods: Utilizing single-cell transcriptome analysis of brain tissues, the vulnerability of the central nervous system to infection with SARS-CoV-2 in humans was investigated.Results: ACE2 is mainly expressed in endothelial cells, with the highest levels found in ageing endothelial cells. Drug prediction suggests that (-)-catechin reduces the effects of COVID-19 on the nervous system. Immunohistochemistry analysis showed that ACE2 was mainly expressed in cerebral vessels. Immunofluroscenceresults showed the co-expression of CD31 and ACE2 in human tissues. Western blot further showed that ACE2 expression was higher in old rats than in young rats.Conclusion: This study provides insight into the mechanism of SARS-CoV-2 brain invasion. Accordingly, patients with neurological symptoms who are infected with SARS-CoV-2 should be given individualised care.
Adaptin ear-binding coat-associated protein 2 (NECAP2) belongs to the family of proteins encoding adaptin-ear-binding coat-associated proteins. However, its immune effect on tumors and its microenvironment are still unclear. Here, we systematically evaluated the differences (variations) in NECAP2 expression for low-grade glioma (LGG) and pan-cancer in the LGG dataset of The Cancer Genome Atlas (TCGA) utilizing bioinformatics methods. We found for the first time that NECAP2 level was elevated in gliomas and that this upregulation increased as the tumor grade increased. In addition, Pearson correlations of NECAP2 with five immune pathways and significant gene mutations associated with NECAP2 were also analyzed. Univariate survival and multivariate Cox analyses were used to compare the clinical characteristics and survival of the patients. Glioma patients with NECAP2 overexpression have a remarkably higher risk of developing malignant behavior and a worse prognosis. The correlation between the expression levels of NECAP2 and the prognosis of glioma patients was identified. Kaplan-Meier curves showed that patients with upregulated NECAP2 expression exhibited an unfavorable prognosis. Western blotting showed that NECAP2 was overexpressed in glioma patients. IHC staining results illustrated an elevation in the NECAP2 protein expression level with the development of tumor malignancy. Additionally, qRT-PCR verified that oxidative stress in glioma tissues reduced the expression of stress-related genes and oxidative stress capacity compared to normal tissues, which may be associated with tumor evasion of immune surveillance and tumor progression. In vitro wound-healing and Transwell assay confirmed that NECAP2 promotes glioma cell migration and invasion. Our study also thoroughly examined the immune significance of NECAP2 in the TCGA-LGG samples, using CIBERSORT and ESTIMATE to explore the correlation between NECAP2 and cancer immune infiltration. The NECAP2 expression levels were correlated with the infiltration degree of immune cells such as neutrophils, CD4+ T cells, macrophages, CD8+ T cells, and B cells. Therefore, our results indicate that NECAP2 strongly correlates with the overall immune infiltration level of glioma and could independently serve as a prognostic biological marker for glioma patients.
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