Pub Date : 2024-04-06DOI: 10.1007/s12031-024-02213-7
Abstract
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.
{"title":"Systematic Analysis of the Relationship Between Elevated Zinc and Epilepsy","authors":"","doi":"10.1007/s12031-024-02213-7","DOIUrl":"https://doi.org/10.1007/s12031-024-02213-7","url":null,"abstract":"<h3>Abstract</h3> <p>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 (<em>p</em> = 0.044 , <em>p</em> = 0.010). Additionally, carbonic anhydrase-1 and gray matter volume of the caudate nucleus were found to be associated with epilepsy and focal epilepsy (<em>p</em> = 0.014, <em>p</em> = 0.003 and <em>p</em> = 0.022, <em>p</em> = 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 (<em>p</em> < 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. </p>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140563238","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-04DOI: 10.1007/s12031-024-02216-4
Abstract
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.
{"title":"Signature Construction and Disulfidptosis-Related Molecular Cluster Identification for Better Prediction of Prognosis in Glioma","authors":"","doi":"10.1007/s12031-024-02216-4","DOIUrl":"https://doi.org/10.1007/s12031-024-02216-4","url":null,"abstract":"<h3>Abstract</h3> <p>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.</p>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140563214","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-03DOI: 10.1007/s12031-024-02190-x
Renbo Yang, Wei Kong, Kun Liu, Gen Wen, Yaling Yu
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.
阿尔茨海默病(AD)是一种不可逆的神经系统疾病,其特点是起病隐匿。识别阿尔茨海默病发生和发展的潜在标志物对于早期诊断和治疗至关重要。成像遗传学通常将遗传变异与多种成像参数相结合,采用各种关联分析算法来研究病理表型与遗传变异之间的联系,并从大脑图像中发现分子层面的见解。然而,现有的成像遗传学算法大多基于稀疏学习,假定遗传因素与大脑功能之间存在线性关系,从而限制了其辨别复杂的非线性相关模式的能力,导致准确性降低。为了解决这些问题,我们提出了一种新型非线性成像遗传关联分析方法--基于深度自重构的自适应稀疏多视角深度广义卡农关联分析(DSR-AdaSMDGCCA)。这种方法通过整合三种不同类型的数据:结构磁共振成像(sMRI)、单核苷酸多态性(SNP)和基因表达数据,促进了病理表型与遗传变异之间非线性关系的联合学习。通过在 DGCCA 中加入非线性变换,我们的模型可以有效地发现多种数据类型之间的非线性关联。此外,DSR 算法对具有相同标签的样本进行聚类,将标签信息纳入非线性特征提取过程,从而提高了关联分析的性能。DSR-AdaSMDGCCA 算法在真实数据集上的应用确定了几个 AD 风险区域(如海马、海马旁和纺锤形回)和风险基因(包括 VSIG4、NEDD4L 和 PINK1),与基线算法相比,以最少的特征选择达到了最高的分类准确率。分子生物学富集分析表明,这些顶级基因所富集的通路与AD进展密切相关,这证明我们的算法不仅提高了相关性分析性能,而且还能识别具有生物学意义的标记。
{"title":"Exploring Imaging Genetic Markers of Alzheimer’s Disease Based on a Novel Nonlinear Correlation Analysis Algorithm","authors":"Renbo Yang, Wei Kong, Kun Liu, Gen Wen, Yaling Yu","doi":"10.1007/s12031-024-02190-x","DOIUrl":"https://doi.org/10.1007/s12031-024-02190-x","url":null,"abstract":"<p>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.</p>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140563237","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-03DOI: 10.1007/s12031-024-02215-5
Ping Qian, Shan Wang, Ting Zhang, Jianxin Wu
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.
{"title":"Transcriptional Expression of Histone Acetyltransferases and Deacetylases During the Recovery of Acute Exercise in Mouse Hippocampus","authors":"Ping Qian, Shan Wang, Ting Zhang, Jianxin Wu","doi":"10.1007/s12031-024-02215-5","DOIUrl":"https://doi.org/10.1007/s12031-024-02215-5","url":null,"abstract":"<p>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 (<i>Hdac4</i>, <i>Ncoa1</i>, <i>Ncoa2</i>, and <i>Sirt1</i>), 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 (<i>Hdac1</i> and <i>Sirt3</i>). 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.</p>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140563160","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-03DOI: 10.1007/s12031-024-02212-8
Abstract
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.
{"title":"Dysregulated AEBP1 and COLEC12 Genes in Late-Onset Alzheimer’s Disease: Insights from Brain Cortex and Peripheral Blood Analysis","authors":"","doi":"10.1007/s12031-024-02212-8","DOIUrl":"https://doi.org/10.1007/s12031-024-02212-8","url":null,"abstract":"<h3>Abstract</h3> <p>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 <em>AEBP1</em> and <em>COLEC12</em>, which exhibited prominent changes in expression. Functional enrichment analysis uncovered a significant association of these DEGs with the transforming growth factor-β (<em>TGF-β</em>) signaling pathway and processes related to angiogenesis. Importantly, we established a robust connection between the up-regulation of <em>AEBP1</em> and <em>COLEC12</em> in both the brain and peripheral blood. Furthermore, we have demonstrated the potential of <em>AEBP1</em> and <em>COLEC12</em> genes as effective diagnostic tools for distinguishing between late-onset AD patients and healthy controls. This study unveils the intricate interplay between <em>AEBP1</em> and <em>COLEC12</em> in AD and underscores their potential as markers for disease detection and monitoring.</p>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140563255","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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.
{"title":"MicroRNA Regulatory Pattern in Diabetic Mouse Cortex at Different Stages Following Ischemic Stroke","authors":"Yifei Lv, Guanghui Xie, Yujie Xi, Liu Zhang, Jiajun Wang, Jianhua Wu","doi":"10.1007/s12031-024-02207-5","DOIUrl":"https://doi.org/10.1007/s12031-024-02207-5","url":null,"abstract":"<p>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.</p>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140563059","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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.
{"title":"Competing Endogenous RNAs Crosstalk in Hippocampus: A Potential Mechanism for Neuronal Developing Defects in Down Syndrome.","authors":"Huiru Zhao, Guiyu Lou, Yupu Shao, Tao Wang, Hongdan Wang, Qiannan Guo, Wenke Yang, Hongyan Liu, Shixiu Liao","doi":"10.1007/s12031-024-02205-7","DOIUrl":"10.1007/s12031-024-02205-7","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140304319","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-27DOI: 10.1007/s12031-024-02209-3
Wen Tang, Kai Zhao, Xiaobo Li, Xiaozhong Zhou, Peigen Liao
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.
{"title":"Bone Marrow Mesenchymal Stem Cell-Derived Exosomes Promote the Recovery of Spinal Cord Injury and Inhibit Ferroptosis by Inactivating IL-17 Pathway.","authors":"Wen Tang, Kai Zhao, Xiaobo Li, Xiaozhong Zhou, Peigen Liao","doi":"10.1007/s12031-024-02209-3","DOIUrl":"10.1007/s12031-024-02209-3","url":null,"abstract":"<p><p>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 Fe<sup>2+</sup>, 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.</p>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140304318","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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.
{"title":"Factors Influencing Early Diagnosis and Poor Prognosis of Dysphagia After Senile Ischemic Stroke.","authors":"Qingxian Fan, Yan Zhao, Jianrong Zhang, Yu'e Wu, Qingping Huang, Ying Gao, Jingqin Wang, Changqiong Guo, Shuqing Zhang","doi":"10.1007/s12031-024-02210-w","DOIUrl":"10.1007/s12031-024-02210-w","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140189310","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Microglia are resident macrophages within the central nervous system, serving as the first responders to neuroinflammation. Glucocorticoids (GCs) may cause damage to brain tissue, but the specific mechanism remains unclear. This study was divided into two parts: a glucocorticoid receptor (GR) mitochondrial translocation intervention experiment and a mitochondrial oxidative stress inhibition experiment. BV-2 microglia were stimulated with dexamethasone (DEX) and treated with either tubastatin-A or mitoquinone (MitoQ) for 24 h. Our results showed that DEX increased the translocation of GRs to mitochondria, and this effect was accompanied by decreases in the expression of mitochondrially encoded cytochrome c oxidase 1 (MT-CO1) and mitochondrially encoded cytochrome c oxidase 3 (MT-CO3) and increases in the expression of NOD-like receptor thermal protein domain-associated protein 3 (NLRP3), caspase-1, and Gasdermin D (GSDMD). The level of mitochondrial respiratory chain complex IV (MRCC IV) and adenosine triphosphate (ATP) was decreased. An elevation in the level of mitochondrial oxidative stress and the opening of the mitochondrial permeability transition pore (mPTP) was also observed. Mechanistically, tubastatin-A significantly suppressed the mitochondrial translocation of GRs, improved the expression of mitochondrial genes, promoted the restoration of mitochondrial function, and inhibited pyroptosis. MitoQ significantly prevented mitochondrial oxidative stress, improved mitochondrial function, and reduced apoptosis and pyroptosis. Both tubastatin-A and MitoQ suppressed DEX-induced pyroptosis. This study substantiates that the increase in the mitochondrial translocation of GRs mediated by GCs exacerbates oxidative stress and pyroptosis in microglia, which indicates that the regulation of mitochondrial pathways by GCs is pathogenic to microglia.
{"title":"Effects of the Glucocorticoid-Mediated Mitochondrial Translocation of Glucocorticoid Receptors on Oxidative Stress and Pyroptosis in BV-2 Microglia.","authors":"Ruonan Dang, Xuyang Hou, Xinglan Huang, Caifeng Huang, Xiaoqing Zhao, Xingrong Wang, Ning Zhang, Yuqi Yang, Nan Li, Sheng Liu, Peng Yan, Ping Fan, Xinghua Song, Suiying Zhang, Yuqiong Deng, Xiping Cheng, Xinhua Xia","doi":"10.1007/s12031-024-02192-9","DOIUrl":"10.1007/s12031-024-02192-9","url":null,"abstract":"<p><p>Microglia are resident macrophages within the central nervous system, serving as the first responders to neuroinflammation. Glucocorticoids (GCs) may cause damage to brain tissue, but the specific mechanism remains unclear. This study was divided into two parts: a glucocorticoid receptor (GR) mitochondrial translocation intervention experiment and a mitochondrial oxidative stress inhibition experiment. BV-2 microglia were stimulated with dexamethasone (DEX) and treated with either tubastatin-A or mitoquinone (MitoQ) for 24 h. Our results showed that DEX increased the translocation of GRs to mitochondria, and this effect was accompanied by decreases in the expression of mitochondrially encoded cytochrome c oxidase 1 (MT-CO1) and mitochondrially encoded cytochrome c oxidase 3 (MT-CO3) and increases in the expression of NOD-like receptor thermal protein domain-associated protein 3 (NLRP3), caspase-1, and Gasdermin D (GSDMD). The level of mitochondrial respiratory chain complex IV (MRCC IV) and adenosine triphosphate (ATP) was decreased. An elevation in the level of mitochondrial oxidative stress and the opening of the mitochondrial permeability transition pore (mPTP) was also observed. Mechanistically, tubastatin-A significantly suppressed the mitochondrial translocation of GRs, improved the expression of mitochondrial genes, promoted the restoration of mitochondrial function, and inhibited pyroptosis. MitoQ significantly prevented mitochondrial oxidative stress, improved mitochondrial function, and reduced apoptosis and pyroptosis. Both tubastatin-A and MitoQ suppressed DEX-induced pyroptosis. This study substantiates that the increase in the mitochondrial translocation of GRs mediated by GCs exacerbates oxidative stress and pyroptosis in microglia, which indicates that the regulation of mitochondrial pathways by GCs is pathogenic to microglia.</p>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140118396","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}