Treatment of glioblastoma multiforme (GBM) remains challenging. Unraveling the orchestration of glutamine metabolism may provide a novel viewpoint on GBM therapy. The study presented a full and comprehensive comprehending of the glutamine metabolism atlas and heterogeneity in GBM for facilitating the development of a more effective therapeutic choice. Transcriptome data from large GBM cohorts were integrated in this study. A glutamine metabolism-based classification was established through consensus clustering approach, and a classifier by LASSO analysis was defined for differentiating the classification. Prognosis, signaling pathway activity, tumor microenvironment, and responses to immune checkpoint blockade (ICB) and small molecular drugs were characterized in each cluster. A combinational therapy of glutaminase inhibitor CB839 with dihydroartemisinin (DHA) was proposed, and the influence on glutamine metabolism, apoptosis, reactive oxygen species (ROS), and migration was measured in U251 and U373 cells. We discovered that GBM presented heterogeneous glutamine metabolism-based clusters, with unique survival outcomes, activity of signaling pathways, tumor microenvironment, and responses to ICB and small molecular compounds. In addition, the classifier could accurately differentiate the two clusters. Strikingly, the combinational therapy of CB839 with DHA synergistically attenuated glutamine metabolism, triggered apoptosis and ROS accumulation, and impaired migrative capacity in GBM cells, demonstrating the excellent preclinical efficacy. Altogether, our findings unveil the glutamine metabolism heterogeneity in GBM and propose an innovative combination therapy of CB839 with DHA for this malignant disease.
{"title":"Glutamine Metabolism Heterogeneity in Glioblastoma Unveils an Innovative Combination Therapy Strategy.","authors":"Huangde Fu, Shengtian Wu, Hechun Shen, Kai Luo, Zhongxiang Huang, Nankun Lu, Yaolin Li, Qian Lan, Yishun Xian","doi":"10.1007/s12031-024-02201-x","DOIUrl":"10.1007/s12031-024-02201-x","url":null,"abstract":"<p><p>Treatment of glioblastoma multiforme (GBM) remains challenging. Unraveling the orchestration of glutamine metabolism may provide a novel viewpoint on GBM therapy. The study presented a full and comprehensive comprehending of the glutamine metabolism atlas and heterogeneity in GBM for facilitating the development of a more effective therapeutic choice. Transcriptome data from large GBM cohorts were integrated in this study. A glutamine metabolism-based classification was established through consensus clustering approach, and a classifier by LASSO analysis was defined for differentiating the classification. Prognosis, signaling pathway activity, tumor microenvironment, and responses to immune checkpoint blockade (ICB) and small molecular drugs were characterized in each cluster. A combinational therapy of glutaminase inhibitor CB839 with dihydroartemisinin (DHA) was proposed, and the influence on glutamine metabolism, apoptosis, reactive oxygen species (ROS), and migration was measured in U251 and U373 cells. We discovered that GBM presented heterogeneous glutamine metabolism-based clusters, with unique survival outcomes, activity of signaling pathways, tumor microenvironment, and responses to ICB and small molecular compounds. In addition, the classifier could accurately differentiate the two clusters. Strikingly, the combinational therapy of CB839 with DHA synergistically attenuated glutamine metabolism, triggered apoptosis and ROS accumulation, and impaired migrative capacity in GBM cells, demonstrating the excellent preclinical efficacy. Altogether, our findings unveil the glutamine metabolism heterogeneity in GBM and propose an innovative combination therapy of CB839 with DHA for this malignant disease.</p>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140896660","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 : 2024-05-03DOI: 10.1007/s12031-024-02228-0
Elif Kubat Oktem
Alzheimer's disease (AD) is a neurodegenerative disorder and the most common cause of dementia. Programmed cell death (PCD) is mainly characterized by unique morphological features and energy-dependent biochemical processes. The predominant pathway leading to cell death in AD has not been thoroughly analyzed, although there is evidence of neuron loss in AD and numerous pathways of PCD have been associated with this process. A better understanding of the systems biology underlying the relationship between AD and PCD could lead to the development of new therapeutic approaches. To this end, publicly available transcriptome data were examined using bioinformatic methods such as differential gene expression and weighted gene coexpression network analysis (WGCNA) to find PCD-related AD biomarkers. The diagnostic significance of these biomarkers was evaluated using a logistic regression-based predictive model. Using these biomarkers, a multifactorial regulatory network was developed. Last, a drug repositioning study was conducted to propose new drugs for the treatment of AD targeting PCD. The development of 3PM (predictive, preventive, and personalized) drugs for the treatment of AD would be enabled by additional research on the effects of these drugs on this disease.
阿尔茨海默病(AD)是一种神经退行性疾病,也是最常见的痴呆症病因。程序性细胞死亡(PCD)的主要特征是独特的形态特征和依赖能量的生化过程。虽然有证据表明 AD 中神经元丢失,而且有许多 PCD 途径与此过程相关,但导致 AD 中细胞死亡的主要途径尚未得到彻底分析。更好地理解AD与PCD之间关系的系统生物学基础,有助于开发新的治疗方法。为此,我们使用生物信息学方法(如差异基因表达和加权基因共表达网络分析(WGCNA))对公开的转录组数据进行了研究,以寻找与PCD相关的AD生物标志物。利用基于逻辑回归的预测模型评估了这些生物标志物的诊断意义。利用这些生物标志物,建立了一个多因素调控网络。最后,进行了一项药物重新定位研究,以提出针对 PCD 的治疗 AD 的新药。如果能进一步研究3PM(预测性、预防性和个性化)药物对该疾病的影响,就能开发出治疗AD的药物。
{"title":"Biomarkers of Alzheimer's Disease Associated with Programmed Cell Death Reveal Four Repurposed Drugs.","authors":"Elif Kubat Oktem","doi":"10.1007/s12031-024-02228-0","DOIUrl":"10.1007/s12031-024-02228-0","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a neurodegenerative disorder and the most common cause of dementia. Programmed cell death (PCD) is mainly characterized by unique morphological features and energy-dependent biochemical processes. The predominant pathway leading to cell death in AD has not been thoroughly analyzed, although there is evidence of neuron loss in AD and numerous pathways of PCD have been associated with this process. A better understanding of the systems biology underlying the relationship between AD and PCD could lead to the development of new therapeutic approaches. To this end, publicly available transcriptome data were examined using bioinformatic methods such as differential gene expression and weighted gene coexpression network analysis (WGCNA) to find PCD-related AD biomarkers. The diagnostic significance of these biomarkers was evaluated using a logistic regression-based predictive model. Using these biomarkers, a multifactorial regulatory network was developed. Last, a drug repositioning study was conducted to propose new drugs for the treatment of AD targeting PCD. The development of 3PM (predictive, preventive, and personalized) drugs for the treatment of AD would be enabled by additional research on the effects of these drugs on this disease.</p>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":null,"pages":null},"PeriodicalIF":2.8,"publicationDate":"2024-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140855121","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 : 2024-05-02DOI: 10.1007/s12031-024-02227-1
Anowarul Islam, Zeeshan Shaukat, Rashid Hussain, Michael G. Ricos, Leanne M. Dibbens, Stephen L. Gregory
Aneuploidy, having an aberrant genome, is gaining increasing attention in neurodegenerative diseases. It gives rise to proteotoxic stress as well as a stereotypical oxidative shift which makes these cells sensitive to internal and environmental stresses. A growing body of research from numerous laboratories suggests that many neurodegenerative disorders, especially Alzheimer’s disease and frontotemporal dementia, are characterised by neuronal aneuploidy and the ensuing apoptosis, which may contribute to neuronal loss. Using Drosophila as a model, we investigated the effect of induced aneuploidy in GABAergic neurons. We found an increased proportion of aneuploidy due to Mad2 depletion in the third-instar larval brain and increased cell death. Depletion of Mad2 in GABAergic neurons also gave a defective climbing and seizure phenotype. Feeding animals an antioxidant rescued the climbing and seizure phenotype. These findings suggest that increased aneuploidy leads to higher oxidative stress in GABAergic neurons which causes cell death, climbing defects, and seizure phenotype. Antioxidant feeding represents a potential therapy to reduce the aneuploidy-driven neurological phenotype.
{"title":"Aneuploidy is Linked to Neurological Phenotypes Through Oxidative Stress","authors":"Anowarul Islam, Zeeshan Shaukat, Rashid Hussain, Michael G. Ricos, Leanne M. Dibbens, Stephen L. Gregory","doi":"10.1007/s12031-024-02227-1","DOIUrl":"https://doi.org/10.1007/s12031-024-02227-1","url":null,"abstract":"<p>Aneuploidy, having an aberrant genome, is gaining increasing attention in neurodegenerative diseases. It gives rise to proteotoxic stress as well as a stereotypical oxidative shift which makes these cells sensitive to internal and environmental stresses. A growing body of research from numerous laboratories suggests that many neurodegenerative disorders, especially Alzheimer’s disease and frontotemporal dementia, are characterised by neuronal aneuploidy and the ensuing apoptosis, which may contribute to neuronal loss. Using <i>Drosophila</i> as a model, we investigated the effect of induced aneuploidy in GABAergic neurons. We found an increased proportion of aneuploidy due to <i>Mad2</i> depletion in the third-instar larval brain and increased cell death. Depletion of <i>Mad2</i> in GABAergic neurons also gave a defective climbing and seizure phenotype. Feeding animals an antioxidant rescued the climbing and seizure phenotype. These findings suggest that increased aneuploidy leads to higher oxidative stress in GABAergic neurons which causes cell death, climbing defects, and seizure phenotype. Antioxidant feeding represents a potential therapy to reduce the aneuploidy-driven neurological phenotype.</p>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140829411","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 : 2024-04-23DOI: 10.1007/s12031-024-02220-8
Hala M. Zeidan, N. Nashaat, Maha Hemimi, A. Hashish, Amal Elsaeid, Nagwa Abd El-Ghaffar, Suzette I Helal, N. Meguid
{"title":"Expression Patterns of miRNAs in Egyptian Children with ADHD: Clinical Study with Correlation Analysis","authors":"Hala M. Zeidan, N. Nashaat, Maha Hemimi, A. Hashish, Amal Elsaeid, Nagwa Abd El-Ghaffar, Suzette I Helal, N. Meguid","doi":"10.1007/s12031-024-02220-8","DOIUrl":"https://doi.org/10.1007/s12031-024-02220-8","url":null,"abstract":"","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140669019","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 : 2024-04-18DOI: 10.1007/s12031-024-02219-1
Felicia Jennysdotter Olofsgård, Caroline Ran, Yuyan Qin, Carmen Fourier, Elisabet Waldenlind, Anna Steinberg, Christina Sjöstrand, Andrea Carmine Belin
Up to 25% of individuals who live with cluster headache (CH), an extremely painful primary headache disorder, do not adequately respond to the first-line treatment, triptans. Studies have indicated that genetic variants can play a role in treatment response. Likewise, differences in clinical characteristics can give clues to mechanisms underlying triptan non-response. Our aim was to investigate five genetic variants previously implicated in triptan response and their relation to triptan usage in our Swedish CH cohort and to investigate potential distinctions in clinical characteristics. 545 CH patients were screened for the genetic variants rs1024905, rs6724624, rs4795541, rs5443, and rs2651899 with a case control design based on triptan usage. Analysis of clinical characteristics was based on self-reported questionnaire data from 893 patients. One genetic variant, rs1024905, was significantly associated with triptan non-usage in CH (Pc = 0.010). In addition, multi-allele effector analysis showed that individuals with a higher number of effector variants were less likely to use triptans (P = 0.007). Analysis of clinical characteristics showed that triptan users were more likely to have alcohol as a trigger (57.4% vs 43.4%, P = 0.002), have autonomic symptoms (95.1% vs 88.1%, P = 0.002), and be current smokers (27.0% vs 21.9%, P = 0.033) compared to non-users. These results support the hypothesis that genetic variants can play a role in triptan usage in CH and that patients with a typical CH phenotype are more likely to use triptans.
{"title":"Genetic and Phenotypic Profiling of Triptan Users in a Swedish Cluster Headache Cohort","authors":"Felicia Jennysdotter Olofsgård, Caroline Ran, Yuyan Qin, Carmen Fourier, Elisabet Waldenlind, Anna Steinberg, Christina Sjöstrand, Andrea Carmine Belin","doi":"10.1007/s12031-024-02219-1","DOIUrl":"https://doi.org/10.1007/s12031-024-02219-1","url":null,"abstract":"<p>Up to 25% of individuals who live with cluster headache (CH), an extremely painful primary headache disorder, do not adequately respond to the first-line treatment, triptans. Studies have indicated that genetic variants can play a role in treatment response. Likewise, differences in clinical characteristics can give clues to mechanisms underlying triptan non-response. Our aim was to investigate five genetic variants previously implicated in triptan response and their relation to triptan usage in our Swedish CH cohort and to investigate potential distinctions in clinical characteristics. 545 CH patients were screened for the genetic variants rs1024905, rs6724624, rs4795541, rs5443, and rs2651899 with a case control design based on triptan usage. Analysis of clinical characteristics was based on self-reported questionnaire data from 893 patients. One genetic variant, rs1024905, was significantly associated with triptan non-usage in CH (<i>Pc</i> = 0.010). In addition, multi-allele effector analysis showed that individuals with a higher number of effector variants were less likely to use triptans (<i>P</i> = 0.007). Analysis of clinical characteristics showed that triptan users were more likely to have alcohol as a trigger (57.4% vs 43.4%, <i>P</i> = 0.002), have autonomic symptoms (95.1% vs 88.1%, <i>P</i> = 0.002), and be current smokers (27.0% vs 21.9%, <i>P</i> = 0.033) compared to non-users. These results support the hypothesis that genetic variants can play a role in triptan usage in CH and that patients with a typical CH phenotype are more likely to use triptans.</p>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140615410","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 : 2024-04-17DOI: 10.1007/s12031-024-02222-6
Yendubé T. Kantati, Magloire K. Kodjo, Benjamin Lefranc, Magali Basille-Dugay, Sébastien Hupin, Isabelle Schmitz, Jérôme Leprince, Messanvi Gbeassor, David Vaudry
Plants are a valuable source of information for pharmacological research and new drug discovery. The present study aimed to evaluate the neuroprotective potential of the leaves of the medicinal plant Sterculia setigera. In vitro, the effect of Sterculia setigera leaves dry hydroethanolic extract (SSE) was tested on cultured cerebellar granule neurons (CGN) survival when exposed to hydrogen peroxide (H2O2) or 6-hydroxydopamine (6-OHDA), using the viability probe fluorescein diacetate (FDA), a lactate dehydrogenase (LDH) activity assay, an immunocytochemical staining against Gap 43, and the quantification of the expression of genes involved in apoptosis, necrosis, or oxidative stress. In vivo, the effect of intraperitoneal (ip) injection of SSE was assessed on the developing brain of 8-day-old Wistar rats exposed to ethanol neurotoxicity by measuring caspase-3 activity on cerebellum homogenates, the expression of some genes in tissue extracts, the thickness of cerebellar cortical layers and motor coordination. In vitro, SSE protected CGN against H2O2 and 6-OHDA-induced cell death at a dose of 10 µg/mL, inhibited the expression of genes Casp3 and Bad, and upregulated the expression of Cat and Gpx7. In vivo, SSE significantly blocked the deleterious effect of ethanol by reducing the activity of caspase-3, inhibiting the expression of Bax and Tp53, preventing the reduction of the thickness of the internal granule cell layer of the cerebellar cortex, and restoring motor functions. Sterculia setigera exerts neuroactive functions as claimed by traditional medicine and should be a good candidate for the development of a neuroprotective treatment against neurodegenerative diseases.
{"title":"Neuroprotective Effect of Sterculia setigera Leaves Hydroethanolic Extract","authors":"Yendubé T. Kantati, Magloire K. Kodjo, Benjamin Lefranc, Magali Basille-Dugay, Sébastien Hupin, Isabelle Schmitz, Jérôme Leprince, Messanvi Gbeassor, David Vaudry","doi":"10.1007/s12031-024-02222-6","DOIUrl":"https://doi.org/10.1007/s12031-024-02222-6","url":null,"abstract":"<p>Plants are a valuable source of information for pharmacological research and new drug discovery. The present study aimed to evaluate the neuroprotective potential of the leaves of the medicinal plant <i>Sterculia setigera</i>. In vitro, the effect of <i>Sterculia setigera</i> leaves dry hydroethanolic extract (SSE) was tested on cultured cerebellar granule neurons (CGN) survival when exposed to hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>) or 6-hydroxydopamine (6-OHDA), using the viability probe fluorescein diacetate (FDA), a lactate dehydrogenase (LDH) activity assay, an immunocytochemical staining against Gap 43, and the quantification of the expression of genes involved in apoptosis, necrosis, or oxidative stress. In vivo, the effect of intraperitoneal (ip) injection of SSE was assessed on the developing brain of 8-day-old Wistar rats exposed to ethanol neurotoxicity by measuring caspase-3 activity on cerebellum homogenates, the expression of some genes in tissue extracts, the thickness of cerebellar cortical layers and motor coordination. In vitro, SSE protected CGN against H<sub>2</sub>O<sub>2</sub> and 6-OHDA-induced cell death at a dose of 10 µg/mL, inhibited the expression of genes <i>Casp3</i> and <i>Bad</i>, and upregulated the expression of <i>Cat</i> and <i>Gpx7</i>. In vivo, SSE significantly blocked the deleterious effect of ethanol by reducing the activity of caspase-3, inhibiting the expression of <i>Bax</i> and <i>Tp53</i>, preventing the reduction of the thickness of the internal granule cell layer of the cerebellar cortex, and restoring motor functions. <i>Sterculia setigera</i> exerts neuroactive functions as claimed by traditional medicine and should be a good candidate for the development of a neuroprotective treatment against neurodegenerative diseases.</p>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140615695","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 : 2024-04-15DOI: 10.1007/s12031-024-02211-9
Kun Tu, Wenhui Zhou, Shubing Kong
Alzheimer’s disease (AD) is a progressive and irreversible neurodegenerative disorder. Its etiology may be associated with genetic, environmental, and lifestyle factors. With the advancement of technology, the integration of genomics, transcriptomics, and imaging data related to AD allows simultaneous exploration of molecular information at different levels and their interaction within the organism. This paper proposes a hypergraph-regularized joint deep semi-non-negative matrix factorization (HR-JDSNMF) algorithm to integrate positron emission tomography (PET), single-nucleotide polymorphism (SNP), and gene expression data for AD. The method employs matrix factorization techniques to nonlinearly decompose the original data at multiple layers, extracting deep features from different omics data, and utilizes hypergraph mining to uncover high-order correlations among the three types of data. Experimental results demonstrate that this approach outperforms several matrix factorization-based algorithms and effectively identifies multi-omics biomarkers for AD. Additionally, single-cell RNA sequencing (scRNA-seq) data for AD were collected, and genes within significant modules were used to categorize different types of cell clusters into high and low-risk cell groups. Finally, the study extensively explores the differences in differentiation and communication between these two cell types. The multi-omics biomarkers unearthed in this study can serve as valuable references for the clinical diagnosis and drug target discovery for AD. The realization of the algorithm in this paper code is available at https://github.com/ShubingKong/HR-JDSNMF.
阿尔茨海默病(AD)是一种进行性、不可逆的神经退行性疾病。其病因可能与遗传、环境和生活方式等因素有关。随着技术的进步,与阿尔茨海默病相关的基因组学、转录组学和成像数据的整合可以同时探索不同层次的分子信息及其在机体内的相互作用。本文提出了一种超图正则化联合深半非负矩阵因式分解(HR-JDSNMF)算法,用于整合正电子发射断层扫描(PET)、单核苷酸多态性(SNP)和基因表达数据来研究 AD。该方法采用矩阵因式分解技术对原始数据进行多层非线性分解,从不同的 omics 数据中提取深层特征,并利用超图挖掘技术发现三类数据之间的高阶相关性。实验结果表明,这种方法优于几种基于矩阵因式分解的算法,并能有效地识别多组学的AD生物标记物。此外,该研究还收集了 AD 的单细胞 RNA 测序(scRNA-seq)数据,并利用重要模块中的基因将不同类型的细胞集群分为高风险细胞组和低风险细胞组。最后,研究广泛探讨了这两种细胞类型在分化和交流方面的差异。本研究发现的多组学生物标志物可作为AD临床诊断和药物靶点发现的重要参考。本文中算法的实现代码可在 https://github.com/ShubingKong/HR-JDSNMF 上获取。
{"title":"Integrating Multi-omics Data for Alzheimer’s Disease to Explore Its Biomarkers Via the Hypergraph-Regularized Joint Deep Semi-Non-Negative Matrix Factorization Algorithm","authors":"Kun Tu, Wenhui Zhou, Shubing Kong","doi":"10.1007/s12031-024-02211-9","DOIUrl":"https://doi.org/10.1007/s12031-024-02211-9","url":null,"abstract":"<p>Alzheimer’s disease (AD) is a progressive and irreversible neurodegenerative disorder. Its etiology may be associated with genetic, environmental, and lifestyle factors. With the advancement of technology, the integration of genomics, transcriptomics, and imaging data related to AD allows simultaneous exploration of molecular information at different levels and their interaction within the organism. This paper proposes a hypergraph-regularized joint deep semi-non-negative matrix factorization (HR-JDSNMF) algorithm to integrate positron emission tomography (PET), single-nucleotide polymorphism (SNP), and gene expression data for AD. The method employs matrix factorization techniques to nonlinearly decompose the original data at multiple layers, extracting deep features from different omics data, and utilizes hypergraph mining to uncover high-order correlations among the three types of data. Experimental results demonstrate that this approach outperforms several matrix factorization-based algorithms and effectively identifies multi-omics biomarkers for AD. Additionally, single-cell RNA sequencing (scRNA-seq) data for AD were collected, and genes within significant modules were used to categorize different types of cell clusters into high and low-risk cell groups. Finally, the study extensively explores the differences in differentiation and communication between these two cell types. The multi-omics biomarkers unearthed in this study can serve as valuable references for the clinical diagnosis and drug target discovery for AD. The realization of the algorithm in this paper code is available at https://github.com/ShubingKong/HR-JDSNMF.</p>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140563159","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}
Alzheimer’s disease (AD) is a severe neurological illness that causes memory loss and is a global problem. The calcium hypothesis recently steadily evolved in AD. The prospective targets for calcium homeostasis therapy, however, are limited, and gene expression-level research connected to calcium homeostasis in AD remains hazy. In this study, we analyzed the microarray dataset (GSE132903) taken from the Gene Expression Omnibus (GEO) database to investigate calcium homeostasis-related genes for AD. Using immunoblot analysis, we examined the association of ITPKB with inflammation in AD. Additionally, the immunofluorescence technique was employed to assess the impact of pharmacological inhibition of ITPKB on the amyloid-β (Aβ) plaque deposition in APP/PS1 mice. This article’s further exploration of calcium homeostasis-related genes has propelled the validation of the calcium homeostasis theory in AD.
{"title":"Transcriptome and Animal Model Integration Reveals Inhibition of Calcium Homeostasis-Associated Gene ITPKB Alleviates Amyloid Plaque Deposition","authors":"Yufei Hu, Zijun Zhao, Fang Xu, Xiaoqin Ren, Menglin Liu, Zilei Zheng, Qiujun Wang","doi":"10.1007/s12031-024-02221-7","DOIUrl":"https://doi.org/10.1007/s12031-024-02221-7","url":null,"abstract":"<p>Alzheimer’s disease (AD) is a severe neurological illness that causes memory loss and is a global problem. The calcium hypothesis recently steadily evolved in AD. The prospective targets for calcium homeostasis therapy, however, are limited, and gene expression-level research connected to calcium homeostasis in AD remains hazy. In this study, we analyzed the microarray dataset (GSE132903) taken from the Gene Expression Omnibus (GEO) database to investigate calcium homeostasis-related genes for AD. Using immunoblot analysis, we examined the association of ITPKB with inflammation in AD. Additionally, the immunofluorescence technique was employed to assess the impact of pharmacological inhibition of ITPKB on the amyloid-β (Aβ) plaque deposition in APP/PS1 mice. This article’s further exploration of calcium homeostasis-related genes has propelled the validation of the calcium homeostasis theory in AD.</p>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140563060","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 : 2024-04-11DOI: 10.1007/s12031-024-02217-3
Douglas E. Brenneman, William A. Kinney, Mark E. McDonnell, Michael J. Ippolito, Sara Jane Ward
KLS-13019 was reported previously to reverse paclitaxel-induced mechanical allodynia in a mouse model of chemotherapy-induced peripheral neuropathy (CIPN). Recent studies demonstrated that paclitaxel-induced increases in inflammatory markers (GPR55, NLRP3, and IL-1β) of dorsal root ganglion (DRG) cultures were shown to be reversed by KLS-13019 treatment. The mechanism of action for KLS-13019-mediated reversal of paclitaxel-induced neuroinflammation now has been explored using GPR55 siRNA. Pre-treatment of DRG cultures with GPR55 siRNA produced a 21% decrease of immunoreactive (IR) area for GPR55 in cell bodies and a 59% decrease in neuritic IR area, as determined by high-content imaging. Using a 24-h reversal treatment paradigm, paclitaxel-induced increases in the inflammatory markers were reversed back to control levels after KLS-3019 treatment. Decreases in these inflammatory markers produced by KLS-13019 were significantly attenuated by GPR55 siRNA co-treatment, with mean IR area responses being attenuated by 56% in neurites and 53% in cell bodies. These data indicate that the percentage decreases in siRNA-mediated attenuation of KLS-13019-related efficacy on the inflammatory markers were similar to the percentage knockdown observed for neuritic GPR55 IR area. Similar studies conducted with cannabidiol (CBD), the parent compound of KLS-13019, produced low efficacy (25%) reversal of all inflammatory markers that were poorly attenuated (29%) by GPR55 siRNA. CBD was shown previously to be ineffective in reversing paclitaxel-induced mechanical allodynia. The present studies indicated significant differences between the anti-inflammatory properties of KLS-13019 and CBD which may play a role in their observed differences in the reversibility of mechanical allodynia in a mouse model of CIPN.
{"title":"Knockdown siRNA Targeting GPR55 Reveals Significant Differences Between the Anti-inflammatory Actions of KLS-13019 and Cannabidiol","authors":"Douglas E. Brenneman, William A. Kinney, Mark E. McDonnell, Michael J. Ippolito, Sara Jane Ward","doi":"10.1007/s12031-024-02217-3","DOIUrl":"https://doi.org/10.1007/s12031-024-02217-3","url":null,"abstract":"<p>KLS-13019 was reported previously to reverse paclitaxel-induced mechanical allodynia in a mouse model of chemotherapy-induced peripheral neuropathy (CIPN). Recent studies demonstrated that paclitaxel-induced increases in inflammatory markers (GPR55, NLRP3, and IL-1β) of dorsal root ganglion (DRG) cultures were shown to be reversed by KLS-13019 treatment. The mechanism of action for KLS-13019-mediated reversal of paclitaxel-induced neuroinflammation now has been explored using GPR55 siRNA. Pre-treatment of DRG cultures with GPR55 siRNA produced a 21% decrease of immunoreactive (IR) area for GPR55 in cell bodies and a 59% decrease in neuritic IR area, as determined by high-content imaging. Using a 24-h reversal treatment paradigm, paclitaxel-induced increases in the inflammatory markers were reversed back to control levels after KLS-3019 treatment. Decreases in these inflammatory markers produced by KLS-13019 were significantly attenuated by GPR55 siRNA co-treatment, with mean IR area responses being attenuated by 56% in neurites and 53% in cell bodies. These data indicate that the percentage decreases in siRNA-mediated attenuation of KLS-13019-related efficacy on the inflammatory markers were similar to the percentage knockdown observed for neuritic GPR55 IR area. Similar studies conducted with cannabidiol (CBD), the parent compound of KLS-13019, produced low efficacy (25%) reversal of all inflammatory markers that were poorly attenuated (29%) by GPR55 siRNA. CBD was shown previously to be ineffective in reversing paclitaxel-induced mechanical allodynia. The present studies indicated significant differences between the anti-inflammatory properties of KLS-13019 and CBD which may play a role in their observed differences in the reversibility of mechanical allodynia in a mouse model of CIPN.</p>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140563210","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 : 2024-04-09DOI: 10.1007/s12031-024-02206-6
Mohsen Sharifi-Kelishadi, Leila Zare, Yaghoub Fathollahi, Mohammad Javan
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.
{"title":"Conversion of Astrocyte Cell Lines to Oligodendrocyte Progenitor Cells Using Small Molecules and Transplantation to Animal Model of Multiple Sclerosis","authors":"Mohsen Sharifi-Kelishadi, Leila Zare, Yaghoub Fathollahi, Mohammad Javan","doi":"10.1007/s12031-024-02206-6","DOIUrl":"https://doi.org/10.1007/s12031-024-02206-6","url":null,"abstract":"<p>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.</p>","PeriodicalId":652,"journal":{"name":"Journal of Molecular Neuroscience","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140563259","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}