scholarly journals Multiomics Identification of Potential Targets for Alzheimer Disease and Antrocin as a Therapeutic Candidate

Pharmaceutics ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 1555
Author(s):  
Alexander T. H. Wu ◽  
Bashir Lawal ◽  
Li Wei ◽  
Ya-Ting Wen ◽  
David T. W. Tzeng ◽  
...  
Keyword(s):  
Early Stage ◽  
Brain Regions ◽  
Genetic Alterations ◽  
Molecular Signature ◽  
Support Vector ◽  
Specific Gene ◽  
Tor Signaling ◽  
Interacting Protein ◽  
Expression Levels ◽  
Neurodegenerative Dementia

Alzheimer’s disease (AD) is the most frequent cause of neurodegenerative dementia and affects nearly 50 million people worldwide. Early stage diagnosis of AD is challenging, and there is presently no effective treatment for AD. The specific genetic alterations and pathological mechanisms of the development and progression of dementia remain poorly understood. Therefore, identifying essential genes and molecular pathways that are associated with this disease’s pathogenesis will help uncover potential treatments. In an attempt to achieve a more comprehensive understanding of the molecular pathogenesis of AD, we integrated the differentially expressed genes (DEGs) from six microarray datasets of AD patients and controls. We identified ATPase H+ transporting V1 subunit A (ATP6V1A), BCL2 interacting protein 3 (BNIP3), calmodulin-dependent protein kinase IV (CAMK4), TOR signaling pathway regulator-like (TIPRL), and the translocase of outer mitochondrial membrane 70 (TOMM70) as upregulated DEGs common to the five datasets. Our analyses revealed that these genes exhibited brain-specific gene co-expression clustering with OPA1, ITFG1, OXCT1, ATP2A2, MAPK1, CDK14, MAP2K4, YWHAB, PARK2, CMAS, HSPA12A, and RGS17. Taking the mean relative expression levels of this geneset in different brain regions into account, we found that the frontal cortex (BA9) exhibited significantly (p < 0.05) higher expression levels of these DEGs, while the hippocampus exhibited the lowest levels. These DEGs are associated with mitochondrial dysfunction, inflammation processes, and various pathways involved in the pathogenesis of AD. Finally, our blood–brain barrier (BBB) predictions using the support vector machine (SVM) and LiCABEDS algorithm and molecular docking analysis suggested that antrocin is permeable to the BBB and exhibits robust ligand–receptor interactions with high binding affinities to CAMK4, TOMM70, and T1PRL. Our results also revealed good predictions for ADMET properties, drug-likeness, adherence to Lipinskís rules, and no alerts for pan-assay interference compounds (PAINS) Conclusions: These results suggest a new molecular signature for AD parthenogenesis and antrocin as a potential therapeutic agent. Further investigation is warranted.

scholarly journals Astrocytes and neurons share region-specific transcriptional signatures that confer regional identity to neuronal reprogramming

2021 ◽  
Vol 7 (15) ◽  
pp. eabe8978
Author(s):  
Álvaro Herrero-Navarro ◽  
Lorenzo Puche-Aroca ◽  
Verónica Moreno-Juan ◽  
Alejandro Sempere-Ferràndez ◽  
Ana Espinosa ◽  
...  
Keyword(s):  
Molecular Diversity ◽  
Regional Identity ◽  
Brain Regions ◽  
Molecular Signature ◽  
Specific Gene ◽  
Thalamic Nuclei ◽  
Brain Repair ◽  
Cell Diversity ◽  
Regional Specificity ◽  
Epigenetic Signatures

Neural cell diversity is essential to endow distinct brain regions with specific functions. During development, progenitors within these regions are characterized by specific gene expression programs, contributing to the generation of diversity in postmitotic neurons and astrocytes. While the region-specific molecular diversity of neurons and astrocytes is increasingly understood, whether these cells share region-specific programs remains unknown. Here, we show that in the neocortex and thalamus, neurons and astrocytes express shared region-specific transcriptional and epigenetic signatures. These signatures not only distinguish cells across these two brain regions but are also detected across substructures within regions, such as distinct thalamic nuclei, where clonal analysis reveals the existence of common nucleus-specific progenitors for neurons and astrocytes. Consistent with their shared molecular signature, regional specificity is maintained following astrocyte-to-neuron reprogramming. A detailed understanding of these regional-specific signatures may thus inform strategies for future cell-based brain repair.

scholarly journals Lemur Tyrosine Kinase 2 (LMTK2) Level Inversely Correlates with Phospho-Tau in Neuropathological Stages of Alzheimer’s Disease

2020 ◽  
Vol 10 (2) ◽  
pp. 68
Author(s):  
János Bencze ◽  
Máté Szarka ◽  
Viktor Bencs ◽  
Renáta Nóra Szabó ◽  
László V. Módis ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Control Region ◽  
Early Stage ◽  
Brain Regions ◽  
Double Labelling ◽  
Endogenous Control ◽  
Strong Negative Correlation ◽  
Tyrosine Kinase 2 ◽  
Neurodegenerative Dementia

Alzheimer’s disease (AD) is the most common neurodegenerative dementia. Mapping the pathomechanism and providing novel therapeutic options have paramount significance. Recent studies have proposed the role of LMTK2 in AD. However, its expression pattern and association with the pathognomonic neurofibrillary tangles (NFTs) in different brain regions and neuropathological stages of AD is not clear. We performed chromogenic (CHR) LMTK2 and fluorescent phospho-tau/LMTK2 double-labelling (FDL) immunohistochemistry (IHC) on 10–10 postmortem middle frontal gyrus (MFG) and anterior hippocampus (aHPC) samples with early and late neuropathological Braak tau stages of AD. MFG in early stage was our ‘endogenous control’ region as it is not affected by NFTs. Semiquantitative CHR-IHC intensity scoring revealed significantly higher (p < 0.001) LMTK2 values in this group compared to NFT-affected regions. FDL-IHC demonstrated LMTK2 predominance in the endogenous control region, while phospho-tau overburden and decreased LMTK2 immunolabelling were detected in NFT-affected groups (aHPC in early and both regions in late stage). Spearman’s correlation coefficient showed strong negative correlation between phospho-tau/LMTK2 signals within each group. According to our results, LMTK2 expression is inversely proportionate to the extent of NFT pathology, and decreased LMTK2 level is not a general feature in AD brain, rather it is characteristic of the NFT-affected regions.

scholarly journals Modularity-Guided Functional Brain Network Analysis for Early-Stage Dementia Identification

2021 ◽  
Vol 15 ◽  
Author(s):  
Yangyang Zhang ◽  
Xiao Jiang ◽  
Lishan Qiao ◽  
Mingxia Liu
Keyword(s):  
Clustering Algorithm ◽  
Early Stage ◽  
Brain Regions ◽  
Brain Network ◽  
Classification Performance ◽  
Brain Diseases ◽  
Support Vector ◽  
Functional Brain Network ◽  
Mri Scans ◽  
Lasso Method

Function brain network (FBN) analysis has shown great potential in identifying brain diseases, such as Alzheimer's disease (AD) and its prodromal stage, namely mild cognitive impairment (MCI). It is essential to identify discriminative and interpretable features from function brain networks, so as to improve classification performance and help us understand the pathological mechanism of AD-related brain disorders. Previous studies usually extract node statistics or edge weights from FBNs to represent each subject. However, these methods generally ignore the topological structure (such as modularity) of FBNs. To address this issue, we propose a modular-LASSO feature selection (MLFS) framework that can explicitly model the modularity information to identify discriminative and interpretable features from FBNs for automated AD/MCI classification. Specifically, the proposed MLFS method first searches the modular structure of FBNs through a signed spectral clustering algorithm, and then selects discriminative features via a modularity-induced group LASSO method, followed by a support vector machine (SVM) for classification. To evaluate the effectiveness of the proposed method, extensive experiments are performed on 563 resting-state functional MRI scans from the public ADNI database to identify subjects with AD/MCI from normal controls and predict the future progress of MCI subjects. Experimental results demonstrate that our method is superior to previous methods in both tasks of AD/MCI identification and MCI conversion prediction, and also helps discover discriminative brain regions and functional connectivities associated with AD.

scholarly journals Astrocytes and neurons share brain region-specific transcriptional signatures

2020 ◽  
Author(s):  
Álvaro Herrero-Navarro ◽  
Lorenzo Puche-Aroca ◽  
Verónica Moreno-Juan ◽  
Alejandro Sempere-Ferràndez ◽  
Ana Espinosa ◽  
...  
Keyword(s):  
Molecular Diversity ◽  
Neuronal Cell ◽  
Brain Regions ◽  
Molecular Signature ◽  
Specific Gene ◽  
Thalamic Nuclei ◽  
Brain Repair ◽  
Cell Diversity ◽  
Regional Specificity ◽  
Epigenetic Signatures

SUMMARYNeuronal cell diversity is essential to endow distinct brain regions with specific functions. During development, progenitors within these regions are characterised by specific gene expression programs, contributing to the generation of diversity in postmitotic neurons and glia. While the region-specific molecular diversity of neurons and astrocytes is increasingly understood, whether these cells share region-specific programs remains unknown. Here, we show that in the neocortex and thalamus, neurons and astrocytes express shared region-specific transcriptional and epigenetic signatures. These signatures not only distinguish cells across brain regions but are also detected across substructures within regions, such as distinct thalamic nuclei, where clonal analysis revealed the existence of common nucleus-specific progenitors for neurons and glia. Consistent with their shared molecular signature, regional specificity was maintained following astrocyte-to-neuron reprogramming. A detailed understanding of these regional-specific signatures may thus inform strategies for future cell-based brain repair.

scholarly journals Analysis of the transcriptome of bovine endometrial cells isolated by laser micro-dissection (1): specific signatures of stromal, glandular and luminal epithelial cells

BMC Genomics ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Wiruntita Chankeaw ◽  
Sandra Lignier ◽  
Christophe Richard ◽  
Theodoros Ntallaris ◽  
Mariam Raliou ◽  
...  
Keyword(s):  
Gene Expression ◽  
Protein Localization ◽  
Expression Profiles ◽  
Cell Types ◽  
Molecular Signature ◽  
Receptor Protein ◽  
Specific Gene ◽  
Specific Cell ◽  
Biological Processes ◽  
Endometrial Cells

Abstract Background A number of studies have examined mRNA expression profiles of bovine endometrium at estrus and around the peri-implantation period of pregnancy. However, to date, these studies have been performed on the whole endometrium which is a complex tissue. Consequently, the knowledge of cell-specific gene expression, when analysis performed with whole endometrium, is still weak and obviously limits the relevance of the results of gene expression studies. Thus, the aim of this study was to characterize specific transcriptome of the three main cell-types of the bovine endometrium at day-15 of the estrus cycle. Results In the RNA-Seq analysis, the number of expressed genes detected over 10 transcripts per million was 6622, 7814 and 8242 for LE, GE and ST respectively. ST expressed exclusively 1236 genes while only 551 transcripts were specific to the GE and 330 specific to LE. For ST, over-represented biological processes included many regulation processes and response to stimulus, cell communication and cell adhesion, extracellular matrix organization as well as developmental process. For GE, cilium organization, cilium movement, protein localization to cilium and microtubule-based process were the only four main biological processes enriched. For LE, over-represented biological processes were enzyme linked receptor protein signaling pathway, cell-substrate adhesion and circulatory system process. Conclusion The data show that each endometrial cell-type has a distinct molecular signature and provide a significantly improved overview on the biological process supported by specific cell-types. The most interesting result is that stromal cells express more genes than the two epithelial types and are associated with a greater number of pathways and ontology terms.

scholarly journals Convergence of heteromodal lexical retrieval in the lateral prefrontal cortex

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Alexander A. Aabedi ◽  
Sofia Kakaizada ◽  
Jacob S. Young ◽  
Jasleen Kaur ◽  
Olivia Wiese ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Picture Naming ◽  
Cognitive Rehabilitation ◽  
Tumor Model ◽  
Brain Regions ◽  
Support Vector ◽  
Lexical Retrieval ◽  
Lateral Prefrontal Cortex ◽  
Lesion Symptom Mapping ◽  
Single Construct

AbstractLexical retrieval requires selecting and retrieving the most appropriate word from the lexicon to express a desired concept. Few studies have probed lexical retrieval with tasks other than picture naming, and when non-picture naming lexical retrieval tasks have been applied, both convergent and divergent results emerged. The presence of a single construct for auditory and visual processes of lexical retrieval would influence cognitive rehabilitation strategies for patients with aphasia. In this study, we perform support vector regression lesion-symptom mapping using a brain tumor model to test the hypothesis that brain regions specifically involved in lexical retrieval from visual and auditory stimuli represent overlapping neural systems. We find that principal components analysis of language tasks revealed multicollinearity between picture naming, auditory naming, and a validated measure of word finding, implying the existence of redundant cognitive constructs. Nonparametric, multivariate lesion-symptom mapping across participants was used to model accuracies on each of the four language tasks. Lesions within overlapping clusters of 8,333 voxels and 21,512 voxels in the left lateral prefrontal cortex (PFC) were predictive of impaired picture naming and auditory naming, respectively. These data indicate a convergence of heteromodal lexical retrieval within the PFC.

scholarly journals FGF23, a novel muscle biomarker detected in the early stages of ALS

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ying Si ◽  
Mohamed Kazamel ◽  
Michael Benatar ◽  
Joanne Wuu ◽  
Yuri Kwon ◽  
...  
Keyword(s):  
Biomarker Discovery ◽  
Clinical Symptoms ◽  
Early Stage ◽  
Fold Increase ◽  
Progressive Increase ◽  
Molecular Signature ◽  
Muscle Membrane ◽  
Sequencing Project ◽  
Progressive Muscle Weakness ◽  
End Stage

AbstractAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive muscle weakness. Skeletal muscle is a prime source for biomarker discovery since it is one of the earliest sites to manifest disease pathology. From a prior RNA sequencing project, we identified FGF23 as a potential muscle biomarker in ALS. Here, we validate this finding with a large collection of ALS muscle samples and found a 13-fold increase over normal controls. FGF23 was also increased in the SOD1G93A mouse, beginning at a very early stage and well before the onset of clinical symptoms. FGF23 levels progressively increased through end-stage in the mouse. Immunohistochemistry of ALS muscle showed prominent FGF23 immunoreactivity in the endomysial connective tissue and along the muscle membrane and was significantly higher around grouped atrophic fibers compared to non-atrophic fibers. ELISA of plasma samples from the SOD1G93A mouse showed an increase in FGF23 at end-stage whereas no increase was detected in a large cohort of ALS patients. In conclusion, FGF23 is a novel muscle biomarker in ALS and joins a molecular signature that emerges in very early preclinical stages. The early appearance of FGF23 and its progressive increase with disease progression offers a new direction for exploring the molecular basis and response to the underlying pathology of ALS.

scholarly journals Genes associated with inflammation and bone remodeling are highly expressed in the bone of patients with the early-stage cam-type femoroacetabular impingement

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Guanying Gao ◽  
Ruiqi Wu ◽  
Rongge Liu ◽  
Jianquan Wang ◽  
Yingfang Ao ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bone Tissue ◽  
Bone Remodeling ◽  
Femoroacetabular Impingement ◽  
Early Stage ◽  
Control Group ◽  
Tissue Samples ◽  
Expression Levels ◽  
Normal Bone ◽  
Impingement Zone

Abstract Background Recent studies have shown high expression levels of certain inflammatory, anabolic, and catabolic genes in the articular cartilage from the impingement zone of the hips with femoroacetabular impingement (FAI), representing an increased metabolic state. Nevertheless, little is known about the molecular properties of bone tissue from the impingement zone of hips with FAI. Methods Bone tissue samples from patients with early-stage cam-type FAI were collected during hip arthroscopy for treatment of cam-type FAI. Control bone tissue samples were collected from six patients who underwent total hip replacement because of a femoral neck fracture. Quantitative real-time polymerase chain reaction (PCR) was performed to determine the gene expression associated with inflammation and bone remodeling. The differences in the gene expression in bone tissues from the patients with early-stage cam-type FAI were also evaluated based on clinical parameters. Results In all, 12 patients with early-stage cam-type FAI and six patients in the control group were included in this study. Compared to the control samples, the bone tissue samples from patients with FAI showed higher expression levels of interleukin-6 (IL-6), alkaline phosphatase (ALP), receptor activator of nuclear factor-kB ligand (RANKL), and osteoprotegerin (OPG) (P < 0.05). IL-1 expression was detected only in the control group. On the other hand, there was no significant difference in IL-8 expression between the patients with FAI and the control group. The patients with FAI having a body mass index (BMI) of >24 kg/m2 showed higher ALP expression (P < 0.05). Further, the expression of IL-6 and ALP was higher in the patients with FAI in whom the lateral center-edge angle was >30° (P < 0.05). Conclusions Our results indicated the metabolic condition of bone tissues in patients with early-stage cam-type FAI differed from that of normal bone in the femoral head-neck junction. The expression levels of the genes associated with inflammation and bone remodeling were higher in the bone tissue of patients with early-stage cam-type FAI than in the patients with normal bone tissue.

scholarly journals Long Non-coding RNA GAS5 Worsens Coronary Atherosclerosis Through MicroRNA-194-3p/TXNIP Axis

2021 ◽  
Author(s):  
Yanbing Li ◽  
Yu Geng ◽  
Boda Zhou ◽  
Xuejiao Wu ◽  
Ou Zhang ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Coronary Atherosclerosis ◽  
Growth Arrest ◽  
Interacting Protein ◽  
Expression Levels ◽  
Thioredoxin Interacting Protein ◽  
Non Coding Rna ◽  
Proliferation And Apoptosis ◽  
Regulatory Effects ◽  
Long Non Coding Rna

AbstractIt is formerly conducted that long non-coding RNA growth arrest-specific 5 (GAS5) is involved in the process of coronary atherosclerosis (AS). The regulatory effects of GAS5 on the microRNA (miR)-194-3p/thioredoxin-interacting protein (TXNIP) axis in AS have been insufficiently explored yet. Thereafter, this work is started from GAS5/miR-194-3p/TXNIP axis in AS. AS rats were modeled to obtain their coronary vascular tissues and endothelial cells (ECs), in which GAS5, miR-194-3p, and TXNIP expression were tested. ECs were identified by immunohistochemistry. The mechanism among GAS5, miR-194-3p, and TXNIP was determined. ECs were transfected with inhibited GAS5 or overexpressed miR-194-3p to decipher their functions in proliferation and apoptosis of ECs in AS. Raised GAS5 and TXNIP and degraded miR-194-3p expression levels exhibited in AS. GAS5 bound to miR-194-3p while miR-194-3p targeted TXNIP. Depleting GAS5 or restoring miR-194-3p enhanced proliferation and depressed apoptosis of ECs in AS. This work clearly manifests that inhibited GAS5 facilitates the growth of ECs through miR-194-3p-targeted TXNIP in AS, consolidating the basal reference to the curing for AS.

scholarly journals Tick Importin-α Is Implicated in the Interactome and Regulome of the Cofactor Subolesin

Pathogens ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 457
Author(s):  
Sara Artigas-Jerónimo ◽  
Margarita Villar ◽  
Alejandro Cabezas-Cruz ◽  
Grégory Caignard ◽  
Damien Vitour ◽  
...  
Keyword(s):  
Rational Design ◽  
Fat Body ◽  
Animal Health ◽  
Direct Interaction ◽  
Vaccine Antigen ◽  
Tick Feeding ◽  
Interacting Protein ◽  
Expression Levels ◽  
Importin Α

Ticks and tick-borne diseases (TBDs) represent a burden for human and animal health worldwide. Currently, vaccines constitute the safest and most effective approach to control ticks and TBDs. Subolesin (SUB) has been identified as a vaccine antigen for the control of tick infestations and pathogen infection and transmission. The characterization of the molecular function of SUB and the identification of tick proteins interacting with SUB may provide the basis for the discovery of novel antigens and for the rational design of novel anti-tick vaccines. In the present study, we used the yeast two-hybrid system (Y2H) as an unbiased approach to identify tick SUB-interacting proteins in an Ixodes ricinus cDNA library, and studied the possible role of SUB as a chromatin remodeler through direct interaction with histones. The Y2H screening identified Importin-α as a potential SUB-interacting protein, which was confirmed in vitro in a protein pull-down assay. The sub gene expression levels in tick midgut and fat body were significantly higher in unfed than fed female ticks, however, the importin-α expression levels did not vary between unfed and fed ticks but tended to be higher in the ovary when compared to those in other organs. The effect of importin-α RNAi was characterized in I. ricinus under artificial feeding conditions. Both sub and importin-α gene knockdown was observed in all tick tissues and, while tick weight was significantly lower in sub RNAi-treated ticks than in controls, importin-α RNAi did not affect tick feeding or oviposition, suggesting that SUB is able to exert its function in the absence of Importin-α. Furthermore, SUB was shown to physically interact with histone 4, which was corroborated by protein pull-down and western blot analysis. These results confirm that by interacting with numerous tick proteins, SUB is a key cofactor of the tick interactome and regulome. Further studies are needed to elucidate the nature of the SUB-Importin-α interaction and the biological processes and functional implications that this interaction may have.

Sign in / Sign up

Export Citation Format

Share Document