Turner Syndrome (TS) is a condition where several genes are affected but the molecular mechanism remains unknown. Identifying the genes that regulate the TS network is one of the main challenges in understanding its aetiology. Here, we studied the regulatory network from manually curated genes reported in the literature and identified essential proteins involved in TS. The power-law distribution analysis showed that TS network carries scale-free hierarchical fractal attributes. This organization of the network maintained the self-ruled constitution of nodes at various levels without having centrality–lethality control systems. Out of twenty-seven genes culminating into leading hubs in the network, we identified two key regulators (KRs) i.e. KDM6A and BDNF. These KRs serve as the backbone for all the network activities. Removal of KRs does not cause its breakdown, rather a change in the topological properties was observed. Since essential proteins are evolutionarily conserved, the orthologs of selected interacting proteins in C. elegans, cat and macaque monkey (lower to higher level organisms) were identified. We deciphered three important interologs i.e. KDM6A-WDR5, KDM6A-ASH2L and WDR5-ASH2L that form a triangular motif. In conclusion, these KRs and identified interologs are expected to regulate the TS network signifying their biological importance.
Tuberculosis (TB) is one of deadly transmissible disease that causes death worldwide; however, only 10% of people infected with Mycobacterium tuberculosis develop disease, indicating that host genetic factors may play key role in determining susceptibility to TB disease. In this way, the analysis of gene expression profiling of TB infected individuals can give us a snapshot of actively expressed genes and transcripts under various conditions. In the present study, we have analyzed microarray data set and compared the gene expression profiles of patients with different datasets of healthy control, latent infection, and active TB. We observed the transition of genes from normal condition to different stages of the TB and identified and annotated those genes/pathways/processes that have important roles in TB disease during its cyclic interventions in the human body. We identified 488 genes that were differentially expressed at various stages of TB and allocated to pathways and gene set enrichment analysis. These pathways as well as GSEA’s importance were evaluated according to the number of DEGs presents in both. In addition, we studied the gene regulatory networks that may help to further understand the molecular mechanism of immune response against the TB infection and provide us a new angle for future biomarker and therapeutic targets. In this study, we identified 26 leading hubs which are deeply rooted from top to bottom in the gene regulatory network and work as the backbone of the network. These leading hubs contains 31 key regulator genes, of which 14 genes were up-regulated and 17 genes were down-regulated. The proposed approach is based on gene-expression profiling, and network analysis approaches predict some unknown TB-associated genes, which can be considered (or can be tested) as reliable candidates for further (in vivo/in vitro) studies.
Alzheimer's disease (AD) is the leading cause of dementia, accounts for 60 to 80 percent cases. Two main factors called β-amyloid (Aβ) plaques and tangles are prime suspects in damaging and killing nerve cells. However, oxidative stress, the process which produces free radicals in cells, is believed to promote its progression to the extent that it may responsible for the cognitive and functional decline observed in AD. As of today there are few FDA approved drugs in the market for treatment, but their cholinergic adverse effect, potentially distressing toxicity and limited targets in AD pathology limits their use. Therefore, it is crucial to find an effective compounds to combat AD. We choose 45 plant-derived natural compounds that have antioxidant properties to slow down disease progression by quenching free redicals or promoting endogenous antioxidant capacity. However, we performed molecular docking studies to investigate the binding interactions between natural compounds and 13 various anti-Alzheimer drug targets. Three known Cholinesterase inhibitors (Donepezil, Galantamine and Rivastigmine) were taken as reference drugs over natural compounds for comparison and drug-likeness studies. Few of these compounds showed good inhibitory activity besides anti-oxidant activity. Most of these compounds followed pharmacokinetics properties that make them potentially promising drug candidates for the treatment of Alzheimer's disease. Graphical Abstract : Pharmacokinatics and Molecular docking studies of 45 natural antioxidant compounds with most known Alzheimer asscociated targets. Administration (FDA) have approved two medications-cholinesterase inhibitors and Memantine. Over the past decade, much of the research on Alzheimer disease (AD) has focused on oxidative stress mechanisms and its importance in disease pathogenesis. The net effect of oxygen radicals is damaging, such damage present in AD includes advanced glycation end products [2], nitration [3], lipid peroxidation adduction products [4-5] as well as carbonyl-modified neurofilament protein and free carbonyls [6-7]. Significantly, this damage involves all neurons at risk to death in AD, not just those containing neurofibrillary tangles.Nature has gifted us lots of natural remedies in the form of fruits, leaves, bark, vegetables and nuts, etc. The various ranges of bioactive nutrients present in these natural products play a vital role in prevention and cure of various neurodegenerative diseases, such as AD,Parkinson's disease and other neuronal dysfunctions. Previous studies suggested that the naturally occurring phytochemicals, such as polyphenolic antioxidants found in fruits, vegetables, herbs and nuts, may potentially hinder neurodegeneration, and improve memory and cognitive functions.
Sepsis is a dysregulated immune response disease affecting millions worldwide. Delayed diagnosis, poor prognosis, and disease heterogeneity make its treatment ineffective. miRNAs are imposingly involved in personalized medicine such as therapeutics, due to their high sensitivity and accuracy. Our study aimed to reveal the biomarkers that may be involved in the dysregulated immune response in sepsis and lung injury using a computational approach and in vivo validation studies. A sepsis miRNA Gene Expression Omnibus (GEO) dataset based on the former analysis of blood samples was used to identify differentially expressed miRNAs (DEMs) and associated hub genes. Sepsis-associated genes from the Comparative Toxicogenomics Database (CTD) that overlapped with identified DEM targets were utilized for network construction. In total, 317 genes were found to be regulated by 10 DEMs (three upregulated, namely miR-4634, miR-4638-5p, and miR-4769-5p, and seven downregulated, namely miR-4299, miR-451a, miR181a-2-3p, miR-16-5p, miR-5704, miR-144-3p, and miR-1290). Overall hub genes (HIP1, GJC1, MDM4, IL6R, and ERC1) and for miR-16-5p (SYNRG, TNRC6B, and LAMTOR3) were identified based on centrality measures (degree, betweenness, and closeness). In vivo validation of miRNAs in lung tissue showed significantly downregulated expression of miR-16-5p corroborating with our computational findings, whereas expression of miR-181a-2-3p and miR-451a were found to be upregulated in contrast to the computational approach. In conclusion, the differential expression pattern of miRNAs and hub genes reported in this study may help to unravel many unexplored regulatory pathways, leading to the identification of critical molecular targets for increased prognosis, diagnosis, and drug efficacy in sepsis and associated organ injuries.
Cardiorenal syndromes constellate primary dysfunction of either heart or kidney whereby one organ dysfunction leads to the dysfunction of another. The role of several microRNAs (miRNAs) has been implicated in number of diseases, including hypertension, heart failure, and kidney diseases. Wide range of miRNAs has been identified as ideal candidate biomarkers due to their stable expression. Current study was aimed to identify crucial miRNAs and their target genes associated with cardiorenal syndrome and to explore their interaction analysis. Three differentially expressed microRNAs (DEMs), namely, hsa-miR-4476, hsa-miR-345-3p, and hsa-miR-371a-5p, were obtained from GSE89699 and GSE87885 microRNA data sets, using R/GEO2R tools. Furthermore, literature mining resulted in the retrieval of 15 miRNAs from scientific research and review articles. The miRNAs-gene networks were constructed using miRNet (a Web platform of miRNA-centric network visual analytics). CytoHubba (Cytoscape plugin) was adopted to identify the modules and the top-ranked nodes in the network based on Degree centrality, Closeness centrality, Betweenness centrality, and Stress centrality. The overlapped miRNAs were further used in pathway enrichment analysis. We found that hsa-miR-21-5p was common in 8 pathways out of the top 10. Based on the degree, 5 miRNAs, namely, hsa-mir-122-5p, hsa-mir-222-3p, hsa-mir-21-5p, hsa-mir-146a-5p, and hsa-mir-29b-3p, are considered as key influencing nodes in a network. We suggest that the identified miRNAs and their target genes may have pathological relevance in cardiorenal syndrome (CRS) and may emerge as potential diagnostic biomarkers.
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