Focusing on scRNA-seq-Derived T Cell-Associated Genes to Identify Prognostic Signature and Immune Microenvironment Status in Low-Grade Glioma.

Background: The clinical outcomes of low-grade glioma (LGG) are associated with T cell infiltration, but the specific contribution of heterogeneous T cell types remains unclear. Method: To study the different functions of T cells in LGG, we mapped the single-cell RNA sequencing results of 10 LGG samples to obtain T cell marker genes. In addition, bulk RNA data of 975 LGG samples were collected for model construction. Algorithms such as TIMER, CIBERSORT, QUANTISEQ, MCPCOUTER, XCELL, and EPIC were used to depict the tumor microenvironment landscape. Subsequently, three immunotherapy cohorts, PRJEB23709, GSE78820, and IMvigor210, were used to explore the efficacy of immunotherapy. Results: The Human Primary Cell Atlas was used as a reference dataset to identify each cell cluster; a total of 15 cell clusters were defined and cells in cluster 12 were defined as T cells. According to the distribution of T cell subsets (CD4+ T cell, CD8+ T cell, Naïve T cell, and Treg cell), we selected the differentially expressed genes. Among the CD4+ T cell subsets, we screened 3 T cell-related genes, and the rest were 28, 4, and 13, respectively. Subsequently, according to the T cell marker genes, we screened six genes for constructing the model, namely, RTN1, HERPUD1, MX1, SEC61G, HOPX, and CHI3L1. The ROC curve showed that the predictive ability of the prognostic model for 1, 3, and 5 years was 0.881, 0.817, and 0.749 in the TCGA cohort, respectively. In addition, we found that risk scores were positively correlated with immune infiltration and immune checkpoints. To this end, we obtained three immunotherapy cohorts to verify their predictive ability of immunotherapy effects and found that high-risk patients had better clinical effects of immunotherapy. Conclusion: This single-cell RNA sequencing combined with bulk RNA sequencing may elucidate the composition of the tumor microenvironment and pave the way for the treatment of low-grade gliomas.

Comparison of Yizhiqingxin formula extraction methods and their pharmacodynamic differences.

Objectives: This study compared different extraction methods of Yizhiqingxin formula (YQF) and its neuroprotective effects based on pharmacodynamic indices such as learning and memory ability, brain tissue histopathology and morphology, and inflammatory factor expression in a mouse model of Alzheimer's disease (AD). Methods: The pharmaceutical components of YQF were extracted using three extraction processes, and the components were analyzed by high performance liquid chromatography. Donepezil hydrochloride was used as a positive control drug. Fifty 7-8-month-old 3 × Tg AD mice were randomly divided into three YQF groups (YQF-1, YQF-2, and YQF-3), a donepezil group, and a model group. Ten age-matched C57/BL6 mice were used as normal controls. YQF and Donepezil were administered by gavage at a clinically equivalent dose of 2.6 and 1.3 mg⋅kg-1⋅d-1, respectively, with a gavage volume of 0.1 ml/10 g. Control and model groups received equal volumes of distilled water by gavage. After 2 months, the efficacy was evaluated using behavioral experiments, histopathology, immunohistochemistry, and serum assays. Results: The main components in YQF are ginsenoside Re, ginsenoside Rg1, ginsenoside Rb1, epiberberine, coptisine chloride, palmatine, berberine, and ferulic acid. YQF-3 (alcohol extraction) has the highest content of active compounds, followed by YQF-2 (water extraction and alcohol precipitation method). Compared to the model group, the three YQF groups showed alleviated histopathological changes and improved spatial learning and memory, with the effect in YQF-2 being the most significant. YQF showed protection of hippocampal neurons, most significantly in the YQF-1 group. YQF significantly reduced Aß pathology and tau hyperphosphorylation, decreased expressions of serum pro-inflammatory factors interleukin-2 and interleukin-6 as well as serum chemokines MCP-1 and MIG. Conclusion: YQF prepared by three different processes showed differences in pharmacodynamics in an AD mouse model. YQF-2 was significantly better than the other extraction processes in improving memory.

Pharmaceutical and pharmacological studies of Shen Ma Yi Zhi granule for prevention of vascular dementia: A review.

Background: With dementia significantly increasing hospitalization and disability rates, worldwide aging of the population presents major challenges to public health. The majority of cases of cognitive dysfunction among the elderly, however, are characterized by an identifiable, preventable and treatable vascular component. As such, increased study of preventative methods in the context of dementia is warranted. Traditional Chinese medicine compounds have been reported to be neuroprotective and improve cognitive function via a variety of mechanisms. Shen Ma Yi Zhi granule (SMYZG) is one such collection of compounds that has been proven clinically effective. Pharmacological mechanisms of action, pharmacokinetics and clinical applications of SMYZG have been previously studied using a variety of vascular dementia animal models. SMYZG activates and regulates four main signaling pathways relevant to vascular dementia including the AMPK/PPARα/PGC-1α/UCP2, Nrf2/HO-1, HIF-1/VEGF/Notch, and VEGF/Flk-1/p8 MAPK pathways. Furthermore, SMYZG influences anti-inflammatory and anti-oxidant stress responses, reverses demyelination of brain white matter and vascular endothelium, regulates pericyte function and normalizes mitochondrial metabolism. Neuroprotective effects of SMYZG, as well as those promoting regeneration of vascular endothelium, have also been reported in studies of rat models of vascular dementia. Future research concerning SMYG is warranted for development of vascular dementia preventative management strategies.

Role of Aß in Alzheimer's-related synaptic dysfunction.

Synaptic dysfunction is closely related to Alzheimer's disease (AD) which is also recognized as synaptic disorder. ß-amyloid (Aß) is one of the main pathogenic factors in AD, which disrupts synaptic plasticity and mediates the synaptic toxicity through different mechanisms. Aß disrupts glutamate receptors, such as NMDA and AMPA receptors, which mediates calcium dyshomeostasis and damages synapse plasticity characterized by long-term potentiation (LTP) suppression and long-term depression (LTD) enhancement. As Aß stimulates and Ca2+ influx, microglial cells and astrocyte can be activated and release cytokines, which reduces glutamate uptake and further impair synapse function. Besides, extracellular glutamate accumulation induced by Aß mediates synapse toxicity resulting from reduced glutamate receptors and glutamate spillovers. Aß also mediates synaptic dysfunction by acting on various signaling pathways and molecular targets, disrupting mitochondria and energy metabolism. In addition, Aß overdeposition aggravates the toxic damage of hyperphosphorylated tau to synapses. Synaptic dysfunction plays a critical role in cognitive impairment of AD. The review addresses the possible mechanisms by which Aß mediates AD-related synaptic impairment from distant perspectives.

Integrated Network Pharmacology and Comprehensive Bioinformatics Identifying the Mechanisms and Molecular Targets of Yizhiqingxin Formula for Treatment of Comorbidity With Alzheimer's Disease and Depression.

Background: The Yizhiqinxin formula (YZQX) has been used to treat Alzheimer's disease (AD) or major depression disorder (MDD). However, its specific underlying mechanisms and therapeutic targets remain unclear. Methods: The ingredients and putative targets of YZQX were screened using the TCMSP and Drugbank databases. Next, the GEO database was used to retrieve relevant differentially expressed genes (DEGs) in AD or MDD and normal tissues. The PPI network was established, merged, and further screened to identify the main ingredients and core targets of YZQX against AD and MDD comorbidities. We performed enrichment analysis of core targets to identify biological processes and pathways. Finally, AutoDock software was used to validate the binding affinity between the crucial targets of direct action and their corresponding ingredients. Results: A total of 43 ingredients were identified from YZQX, of which 43 were screened to yield 504 targets. By establishing the PPI network, 92 targets were regarded as targets of YZQX against AD and MDD comorbidities in the core network. Promising targets (HSP90AA1, ESR1, AKT1, VCAM1, EGFR, CDK1, MAPK1, CDK2, MYC, HSPB1, and HSPA5) and signaling pathways (PI3K-Akt signaling pathway, ubiquitin-mediated proteolysis, MAPK signaling pathway, etc.) were filtered and refined to elucidate the underlying mechanism of YZQX against AD and MDD comorbidities. Molecular docking confirmed the ingredients of YZQX (quercetin and kaempferol) could bind well to multiple crucial targets. Conclusion: The ingredients of YZQX, such as quercetin and kaempferol, might treat AD and MDD comorbidities by acting on multiple targets and pathways.

A network meta-analysis on the improvement of cognition in patients with vascular dementia by different acupuncture therapies.

Introduction: The second most prevalent cause of dementia is vascular dementia (VaD). Furthermore, acupuncture is a relatively safe and effective traditional therapy for individuals with VaD. We performed a network meta-analysis to assess the effectiveness and safety of various acupuncture therapies for VaD based on existing research. Methods: We searched six electronic databases to screen for randomized controlled trials (RCTs) comparing different acupuncture treatments in VaD patients. The Cochrne tool (Review Manager 5.3) was used to evaluate the risk of bias of the included RCTs. Based on the Grading of Recommendations Assessment, Development and Evaluation framework, we assessed the confidence in the evidence using the Confidence In the results from Network Meta-Analysis approach. We used the frequency approach to perform the network meta-analysis. Data were analyzed using R 4.1.1. Results: In total, we included 46 eligible studies. The results of the network analysis showed that the combined interventions of moxibustion (MB) with body acupuncture (BA) (MB + BA) and electroacupuncture (EA) with scalp acupuncture (SA) with BA (EA + SA + BA) were more effective in improving cognitive functions and activities of daily living compared with SA or BA alone. However, in the subgroup analysis, EA + SA + BA showed better efficacy in short- and mid-term acupuncture compared with other acupuncture therapies. Conclusion: Combined acupuncture therapy may be a safe and effective intervention for individuals with VaD, and MB + BA and EA + SA + BA appear to be the most effective interventions. However, because the analysis of this study was based on low-to-moderate evidence, there remains no strong supporting evidence. Thus, high-quality, large-scale, and long-term studies should be conducted in the future to assess the effectiveness and safety of acupuncture in VaD. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier: CRD42022354573.