Journal of Molecular Neuroscience最新文献

Astrocytes, the most prevalent cells in the central nervous system (CNS), can be transformed into neurons and oligodendrocyte progenitor cells (OPCs) using specific transcription factors and some chemicals. In this study, we present a cocktail of small molecules that target different signaling pathways to promote astrocyte conversion to OPCs. Astrocytes were transferred to an OPC medium and exposed for five days to a small molecule cocktail containing CHIR99021, Forskolin, Repsox, LDN, VPA and Thiazovivin before being preserved in the OPC medium for an additional 10 days. Once reaching the OPC morphology, induced cells underwent immunocytofluorescence evaluation for OPC markers while checked for lacking the astrocyte markers. To test the in vivo differentiation capabilities, induced OPCs were transplanted into demyelinated mice brains treated with cuprizone over 12 weeks. Two distinct lines of astrocytes demonstrated the potential of conversion to OPCs using this small molecule cocktail as verified by morphological changes and the expression of PDGFR and O4 markers as well as the terminal differentiation to oligodendrocytes expressing MBP. Following transplantation into demyelinated mice brains, induced OPCs effectively differentiated into mature oligodendrocytes. The generation of OPCs from astrocytes via a small molecule cocktail may provide a new avenue for producing required progenitors necessary for myelin repair in diseases characterized by the loss of myelin such as multiple sclerosis.

Previous studies have indicated a potential relationship between zinc and epilepsy. The aim of this study is to investigate the causal relationship between zinc, zinc-dependent carbonic anhydrase, and gray matter volume in brain regions enriched with zinc and epilepsy, as well as explore the possible mechanisms by which zinc contributes to epilepsy. First, this study assessed the risk causality between zinc, carbonic anhydrase, and gray matter volume alterations in zinc-enriched brain regions and various subtypes of epilepsy based on Two-sample Mendelian randomization analysis. And then, this study conducted GO/KEGG analysis based on colocalization analysis, MAGMA analysis, lasso regression, random forest model, and XGBoost model. The results of Mendelian randomization analyses showed a causal relationship between zinc, carbonic anhydrase-4, and generalized epilepsy (p = 0.044 , p= 0.010). Additionally, carbonic anhydrase-1 and gray matter volume of the caudate nucleus were found to be associated with epilepsy and focal epilepsy (p= 0.014, p = 0.003 and p = 0.022, p = 0.009). A colocalization relationship was found between epilepsy and focal epilepsy (PP.H4.abf = 97.7e − 2). Meanwhile, the MAGMA analysis indicated that SNPs associated with epilepsy and focal epilepsy were functionally localized to zinc-finger-protein-related genes (p < 1.0e − 5). The genes associated with focal epilepsy were found to have a molecular function of zinc ion binding (FDR = 2.3e − 6). After the onset of epilepsy, the function of the gene whose expression changed in the rats with focal epilepsy was enriched in the biological process of vascular response (FDR = 4.0e − 5). These results revealed mechanism of the increased risk of epilepsy caused by elevated zinc may be related to the increase of zinc ion-dependent carbonic anhydrase or the increase of the volume of zinc-rich caudate gray matter.

Disulfidptosis is a newly discovered form of regulatory cell death. However, the identification of disulfidptosis-related molecular subtypes and potential biomarkers in gliomas and their prognostic predictive potential need to be further elucidated. RNA sequencing profiles and the relevant clinical data were obtained from the Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA). Disulfidptosis-related clusters were identified by unsupervised clustering analysis. Immune cell infiltration analysis and drug sensitivity analysis were used to explore the differences between clusters. Gene set enrichment analysis (GSEA) of differential genes between clusters was performed to explore the potential biological functions and signaling. A disulfidptosis-related scoring system (DRSS) was constructed based on a combined COX and LASSO analysis. Mendelian randomization (MR) analyses were used to further explore the causal relationship between levels of genes in DRSS and an increased risk of glioma. A prognosis nomogram was constructed based on the DRSS and 3 clinical features (age, WHO stage, and IDH status). The accuracy and stability of the prognosis nomogram were also validated in different cohorts. We identified two clusters that exhibited different prognoses, drug sensitivity profiles, and tumor microenvironment infiltration profiles. The overall survival (OS) of Cluster2 was significantly better than Cluster1. Cluster1 had an overall greater infiltration of immune cells compared to Cluster2. However, the Monocytes, activated B cells had higher infiltration abundance in Cluster2. GSEA results showed significant enrichment of immune-related biological processes in Cluster1, while Cluster2 was more enriched for functions related to neurotransmission and regulation. PER3, RAB34, NKX3-2, GPX7, FRA10AC1, and TGIF1 were finally included to construct DRSS. DRSS was independently related to prognosis. There was a significant difference in overall survival between the low-risk score group and the high-risk score group. Among six genes in DRSS, GPX7 levels were demonstrated to have a causal relationship with an increased risk of glioma. GPX7 may become a more promising biomarker for gliomas. The prognosis nomogram constructed based on the DRSS and three clinical features has considerable potential for predicting the prognosis of patients with glioma. Free online software for implementing this nomogram was established: https://yekun-zhuang.shinyapps.io/DynNomapp/. Our study established a novel glioma classification based on the disulfidptosis-related molecular subtypes. We constructed the DRSS and the prognosis nomogram to accurately stratify the prognosis of glioma patients. GPX7 was identified as a more promising biomarker for glioma. We provide important insights into the treatment and prognosis of gliomas.

Alzheimer’s disease (AD) is an irreversible neurological disorder characterized by insidious onset. Identifying potential markers in its emergence and progression is crucial for early diagnosis and treatment. Imaging genetics typically merges genetic variables with multiple imaging parameters, employing various association analysis algorithms to investigate the links between pathological phenotypes and genetic variations, and to unearth molecular-level insights from brain images. However, most existing imaging genetics algorithms based on sparse learning assume a linear relationship between genetic factors and brain functions, limiting their ability to discern complex nonlinear correlation patterns and resulting in reduced accuracy. To address these issues, we propose a novel nonlinear imaging genetic association analysis method, Deep Self-Reconstruction-based Adaptive Sparse Multi-view Deep Generalized Canonical Correlation Analysis (DSR-AdaSMDGCCA). This approach facilitates joint learning of the nonlinear relationships between pathological phenotypes and genetic variations by integrating three different types of data: structural magnetic resonance imaging (sMRI), single-nucleotide polymorphism (SNP), and gene expression data. By incorporating nonlinear transformations in DGCCA, our model effectively uncovers nonlinear associations across multiple data types. Additionally, the DSR algorithm clusters samples with identical labels, incorporating label information into the nonlinear feature extraction process and thus enhancing the performance of association analysis. The application of the DSR-AdaSMDGCCA algorithm on real data sets identified several AD risk regions (such as the hippocampus, parahippocampus, and fusiform gyrus) and risk genes (including VSIG4, NEDD4L, and PINK1), achieving maximum classification accuracy with the fewest selected features compared to baseline algorithms. Molecular biology enrichment analysis revealed that the pathways enriched by these top genes are intimately linked to AD progression, affirming that our algorithm not only improves correlation analysis performance but also identifies biologically significant markers.

Protein acetylation, which is dynamically maintained by histone acetyltransferases (HATs) and deacetylases (HDACs), might play essential roles in hippocampal exercise physiology. However, whether HATs/HDACs are imbalanced during the recovery phase following acute exercise has not been determined. Groups of exercised mice with different recovery periods after acute exercise (0 h, 0.5 h, 1 h, 4 h, 7 h, and 24 h) were constructed, and a group of sham-exercised mice was used as the control. The mRNA levels of HATs and HDACs were detected via real-time quantitative polymerase chain reaction. Lysine acetylation on the total proteins and some specific locations on histones were detected via western blotting, as were various acylation modifications on the total proteins. Except for four unaffected genes (Hdac4, Ncoa1, Ncoa2, and Sirt1), the mRNA expression trajectories of 21 other HATs or HDACs affected by exercise could be categorized into three clusters. The genes in Cluster 1 increased quickly following exercise, with a peak at 0.5 h and/or 1 h, and remained at high levels until 24 h. Cluster 2 genes presented a gradual increase with a delayed peak at 4 h or 7 h postexercise before returning to baseline. The expression of Cluster 3 genes decreased at 0.5 h and/or 1 h, with some returning to overexpression (Hdac1 and Sirt3). Although most HATs were upregulated and half of the affected HDACs were downregulated at 0.5 h postexercise, the global or residue-specific histone acetylation levels were unchanged. In contrast, the levels of several metabolism-related acylation products of total proteins, including acetylation, succinylation, 2-hydroxyisobutyryllysine, β-hydroxybutyryllysine, and lactylation, decreased and mainly occurred on nonhistones immediately after exercise. During the 24-h recovery phase after acute exercise, the transcriptional trajectory of HATs or the same class of HDACs in the hippocampus exhibited heterogeneity. Although acute exercise did not affect the selected sites on histone lysine residues, it possibly incurred changes in acetylation and other acylation on nonhistone proteins.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by memory and cognitive impairment, often accompanied by alterations in mood, confusion, and, ultimately, a state of acute mental disturbance. The cerebral cortex is considered a promising area for investigating the underlying causes of AD by analyzing transcriptional patterns, which could be complemented by investigating blood samples obtained from patients. We analyzed the RNA expression profiles of three distinct areas of the brain cortex, including the frontal cortex (FC), temporal cortex (TC), and entorhinal cortex (EC) in patients with AD. Functional enrichment analysis was performed on the differentially expressed genes (DEGs) across the three regions. The two genes with the most significant expression changes in the EC region were selected for assessing mRNA expression levels in the peripheral blood of late-onset AD patients using quantitative PCR (qPCR). We identified eight shared DEGs in these regions, including AEBP1 and COLEC12, which exhibited prominent changes in expression. Functional enrichment analysis uncovered a significant association of these DEGs with the transforming growth factor-β (TGF-β) signaling pathway and processes related to angiogenesis. Importantly, we established a robust connection between the up-regulation of AEBP1 and COLEC12 in both the brain and peripheral blood. Furthermore, we have demonstrated the potential of AEBP1 and COLEC12 genes as effective diagnostic tools for distinguishing between late-onset AD patients and healthy controls. This study unveils the intricate interplay between AEBP1 and COLEC12 in AD and underscores their potential as markers for disease detection and monitoring.

After ischemic stroke, microRNAs (miRNAs) participate in various processes, including immune responses, inflammation, and angiogenesis. Diabetes is a key factor increasing the risk of ischemic stroke; however, the regulatory pattern of miRNAs at different stages of diabetic stroke remains unclear. This study comprehensively analyzed the miRNA expression profiles in diabetic mice at 1, 3, and 7 days post-reperfusion following the middle cerebral artery occlusion (MCAO). We identified differentially expressed (DE) miRNAs in diabetic stroke and found significant dysregulation of some novel miRNAs (novel_mir310, novel_mir89, and novel_mir396) post-stroke. These DEmiRNAs were involved in apoptosis and the formation of tight junctions. Finally, we identified three groups of time-dependent DE miRNAs (miR-6240, miR-135b-3p, and miR-672-5p). These have the potential to serve as biomarkers of diabetic stroke. These findings provide a new perspective for future research, emphasizing the dynamic changes in miRNA expression after diabetic stroke and offering potential candidates as biomarkers for future clinical applications.

Down syndrome (DS) is the most example of aneuploidy, resulting from an additional copy of all or part of chromosome 21. Competing endogenous RNAs (ceRNAs) play important roles in neuronal development and neurological defects. This study aimed to identify hub genes and synergistic crosstalk among ceRNAs in the DS fetal hippocampus as potential targets for the treatment of DS-related neurodegenerative diseases. We profiled differentially expressed long non-coding RNAs (DElncRNAs), differentially expressed circular RNAs (DEcircRNAs), differentially expressed microRNAs (DEmiRNAs), and differentially expressed messenger RNAs (DEmRNAs) in hippocampal samples from patients with or without DS. Functional enrichment analysis and gene set enrichment analysis were performed, and chromosome 21-related ceRNA and protein–protein interaction networks were constructed. Additionally, the correlations between lncRNA-mRNA and miRNA-mRNA expression in the samples and HEK293T cells were validated. Our finding of changes in the expression of some key genes and ncRNAs on chromosome 21 in DS might not fully conform to the gene dosage hypothesis. Moreover, we found that four lncRNAs (MIR99AHG, PLCB4, SNHG14, GIGYF2) and one circRNA (hsa_circ_0061697) may competitively bind with three miRNAs (hsa-miR-548b-5p, miR-730-5p, and hsa-miR-548i) and subsequently regulate five mRNAs (beta-1,3-galactosyltransferase 5 [B3GALT5], helicase lymphoid-specific [HELLS], thrombospondin-2 [THBS2], glycinamide ribonucleotide transformylase [GART], clathrin heavy chain like 1 [CLTCL1]). These RNAs, whether located on chromosome 21 or not, interact with each other and might activate the PI3K/Akt/mTOR and Wnt signaling pathways, which are involved in autophagosome formation and tau hyperphosphorylation, possibly leading to adverse consequences of trisomy 21. These findings provide researchers with a better understanding of the fundamental molecular mechanisms underlying DS-related progressive defects in neuronal development.

Mesenchymal stem cell (MSC)-derived exosomes are considered as alternative to cell therapy in various diseases. This study aimed to understand the effect of bone marrow MSC-derived exosomes (BMMSC-exos) on spinal cord injury (SCI) and to unveil its regulatory mechanism on ferroptosis. Exosomes were isolated from BMMSCs and the uptake of BMMSCs-exos by PC12 cells was determined using PKH67 staining. The effect of BMMSC-exos on SCI in rats was studied by evaluating pathological changes of spinal cord tissues, inflammatory cytokines, and ferroptosis-related proteins. Transcriptome sequencing was used to discover the differential expressed genes (DEGs) between SCI rats and BMMSC-exos-treated rats followed by functional enrichment analyses. The effect of BMMSC-exos on ferroptosis and interleukin 17 (IL-17) pathway was evaluated in SCI rats and oxygen–glucose deprivation (OGD)-treated PC12 cells. The results showed that particles extracted from BMMSCs were exosomes that could be taken up by PC12 cells. BMMSC-exos treatment ameliorated injuries of spinal cord, suppressed the accumulation of Fe²⁺, malondialdehyde (MDA), and reactive oxygen species (ROS), with the elevated glutathione (GSH). Also, BMMSC-exos downregulated the expression of acyl-CoA synthetase long chain family member 4 (ACSL4) and upregulated glutathione peroxidase 4 (GPX4) and cysteine/glutamate antiporter xCT. A total of 110 DEGs were discovered and they were mainly enriched in IL-17 signaling pathway. Further in vitro and in vivo experiments showed that BMMSC-exos inactivated IL-17 pathway. BMMSC-exos promote the recovery of SCI and inhibit ferroptosis by inhibiting the IL-17 pathway, which provides BMMSC-exos as an alternative to the management of SCI.

Dysphagia is often a long-term problem after ischemic stroke, which are often accompanied by complications and results in poor outcome. This study aimed to investigate the influencing factors associated with the prognosis of dysphagia after senile ischemic stroke and evaluate the diagnostic performance of crucial factors. A total of 192 elderly ischemic stroke patients (96 patients without dysphagia with average age of 69.81 ± 4.61 years and 96 patients with dysphagia with average of 70.00 ± 6.66 years) were enrolled in the retrospective study. The clinical factors of the patients were collected and recorded for chi-square analysis and logistic analysis. The receiver operating characteristic (ROC) curve was performed to evaluate the diagnostic performance of international normalized ratio (INR) and homocysteine (Hcy) in senile ischemic stroke patients. The age, cough reflex, history of stroke, mechanical ventilation, eating posture, insufficient elevation of the larynx, standard swallowing assessment (SSA) score, Hcy value, and INR were closely related to endpoint events of patients with dysphagia. The joint model (combined INR and Hcy value) can increase the area under the curve (AUC) value (0.948) with higher sensitivity and specificity for predicting patients with dysphagia occurred endpoint events. The influencing factors for older ischemic stroke patients with dysphagia include age, cough reflex, history of stroke, mechanical ventilation, eating posture, insufficient elevation of the larynx, SSA score, Hcy value, and INR. INR and Hcy were independent risk factors for prognosis and diagnostic markers for patients with dysphagia after senile ischemic stroke.