Chitinase‐3‐like protein 1 (CHI3L1) is a secreted glycoprotein characterized by its ability to regulate multiple biological processes, such as the inflammatory response and gene transcriptional signaling activation. Abnormal CHI3L1 expression has been associated with multiple neurological disorders and serves as a biomarker for the early detection of several neurodegenerative diseases. Aberrant CHI3L1 expression is also reportedly associated with brain tumor migration and metastasis, as well as contributions to immune escape, playing important roles in brain tumor progression. CHI3L1 is synthesized and secreted mainly by reactive astrocytes in the central nervous system. Thus, targeting astrocytic CHI3L1 could be a promising approach for the treatment of neurological diseases, such as traumatic brain injury, ischemic stroke, Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotrophic lateral sclerosis, and glioma. Based on current knowledge of CHI3L1, we assume that it acts as a molecule mediating several signaling pathways driving the initiation and progression of neurological disorders. This narrative review is the first to introduce the potential roles of astrocytic CHI3L1 in neurological disorders. We also equally explore astrocytic CHI3L1 mRNA expression under physiological and pathological conditions. Inhibiting CHI3L1 and disrupting its interaction with its receptors through multiple mechanisms of action are briefly discussed. These endeavors highlight the pivotal roles of astrocytic CHI3L1 in neurological disorders and could contribute to the development of effective inhibitors based on the strategy of structure‐based drug discovery, which could be an attractive therapeutic approach for neurological disease treatment. image

Effective immunotherapies for patients with glioblastoma (GBM) are urgently needed. Chitinase-3 like-protein-1 (CHI3L1) play important roles in the development of gliomas. However, its role in glioma-related immune responses remains unclear. We aimed to comprehensively investigate its biological features and clinical value in glioma, especially in GBM. Transcriptome, proteome and single-cell RNA-sequencing databases were enrolled in the study. Immunostaining and immunoblotting were performed for validation. CHI3L1 was highly correlated with clinical and molecular features, suggesting that high CHI3L1 expression is more likely to be predicted as malignant entities. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed CHI3L1 closely associated with immune responses and inflammatory activities in GBM. In addition, CHI3L1 also correlated with immune cell infiltration and immune checkpoints. Our study suggests that inhibition of CHI3L1 may help to reduce immunosuppression and overcome immunotherapy resistance, which would be an therapeutic area for the treatment of GBM.

Background: Calcium signaling is implicated in multiple processes including immune response that important in tumor progression. Kidney renal clear cell carcinoma (KIRC) is the most frequent histological type of renal cell carcinoma with up to a third of cases develop metastases. As a result of a lack of in-depth understanding of the mechanisms underlying KIRC, treatment options have been limited. Here, we aim to comprehensively investigate the landscape of Ca²⁺ channels, pumps and exchangers in KIRC patients.Methods: The mRNA expression profiles and gene variations of 58 calcium-related genes (CRGs) in KIRC patients and normal control cases were downloaded from TCGA database. CRGs-related risk score was constructed to quantify calcium patterns by using least absolute shrinkage and selection operator (LASSO) regression. The prognostic value, biological functions, immune landscape and therapeutic sensitivities based on CRGs-related risk score were then evaluated using multiple methods. Finally, key gene of CRGs was identified by weighted gene co-expression network analysis (WGCNA). TCGA-CPTAC, GSE53757 datasets, as well as human tissues were used for validation.Results: KIRC patients had significant differences in CRG expression, prognosis, and biological functions between two CRG clusters. CRGs-related risk score was then determined. The prognosis, tumor mutation burden, immune cell infiltration, immune checkpoints, and the response of targeted inhibitors were remarkably different between high and low CRGs-related risk subtypes. CRGs-related high-risk subtype was characterized by immunosuppressive microenvironment with poor prognosis. Meanwhile, several targeted drugs showed distinct sensitivity between CRGs-related risk subtypes. Finally, TRPM3 was identified as a key CRG based on risk score in KIRC patients. TRPM3 mRNA and protein expression were significantly lower in KIRC tumors than in normal controls. Low TRPM3 expression was associated with poor prognosis in KIRC patients.Conclusion: Our study highlighted the promising prognostic value of CRGs in KIRC tumors. The evaluation of CRGs-related risk score will contribute to predicting prognosis and clinical therapy in KIRC patients.

Introduction: Tumor transformation and progression are accompanied by multiple carcinogenic pathways that dysregulate polyamine demand and metabolism. The importance of polyamines has demonstrated that their metabolism is a potential therapeutic strategy. Yet, few prognostic models based on polyamine metabolism-related gene risk have been developed for gliomas.Methods: The mRNA expression profiles and variations in 37 polyamine metabolism-related genes (PMRGs) were obtained from the Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) databases. PMRGs-related risk model was constructed by least absolute shrinkage and selection operator (LASSO) Cox regression and tested for predictive ability across two independent datasets from the Gene Expression Omnibus (GEO). The landscape of the tumor immune microenvironment and drug sensitivity were investigated systematically using multiple methods based on PMRG-related risk subtypes. Weighted gene co-expression network analysis (WGCNA) was applied to identify the key prognostic genes of the PMRGs. In addition, key genes were validated with regard to their expression and prognostic significance in human glioma tissues. To verify the cell types, single-cell RNA sequencing was performed on the cohorts available at GEO.Results: Based on PMRG clusters, patients with glioma showed significant differences in PMRG expression, prognosis, and biological functions. A 11-gene risk model was constructed, and patients were categorized into high- and low-risk subtype according to the risk score. The high-risk subtype exhibited a poorer prognosis due to its immunosuppressive microenvironment. Furthermore, there were striking differences between the distinct subtypes in terms of immune cell infiltration, anticancer immunity cycle, tumor mutation burden, immune checkpoints, and response to targeted inhibitors. Spermine synthase (SMS) was identified as a key PMRG in patients with gliomas. A significant increase in SMS mRNA and protein expression was observed in tumors compared to normal controls. Single-cell sequencing analyses showed that SMS mRNA was highly expressed in all cell types, except oligodendrocytes.Conclusion: A PMRG-related risk model can be used as a reliable prognostic biomarker in glioma treatment. In addition, polyamine metabolism and function can be successfully targeted therapeutically.

Neuroinflammation is vital in depression’s onset and development, making its relief a key treatment goal. Orientin (ORI), a natural flavonoid, is known to modulate inflammation, but whether it can ease depression by regulating neuro-inflammation remains uncertain. This study aimed to uncover ORI’s antineuroinflammation mechanisms for treating depression. It utilized LPS-induced cell and mouse models and Chronic Unpredictable Mild Stress (CUMS) model. Enzyme-linked immunoassay, Western blotting, and immunofluorescence staining gauged ORI’s anti-inflammatory effects. Behavioral tests assessed the impact on depressive symptoms. Network pharmacology and molecular biology methods probed its action mechanism and anti-inflammation targets. ORI effectively curbed inflammation, blocked M1 polarization, and reduced the inflammatory mediator release in LPS-induced BV2 cells and mice. In LPS-induced and CUMS depression mouse models, ORI notably alleviated depression-like behavior and neuroinflammation in the prefrontal cortex (PFC). Also, ORI treatment reduced the LPS-induced spike in the frequency of spontaneous excitatory postsynaptic currents (sEPSC) in PFC neurons. The PI3K/AKT signaling pathway was found to underpin ORI’s effects. Overall, ORI shows potential as a natural remedy for depression, influencing neuroinflammation and regulating microglial polarization and neuronal excitability to improve symptoms.