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  • Gene chip is a detection technique that

    2019-09-11

    Gene chip is a detection technique that can detect all the time-point differentially expressed genes (DEGs) information within the same sample. However, due to sample heterogeneity or different sequencing platform, the results for the expressed mRNAs are inconsistent with different gene profile. Therefore, the integrated bioinformatics methods will solve the disadvantages and identify the more reliable hub genes in astrocytes involved in glaucoma. In this work, we have downloaded two microarray datasets GSE2378 and GSE758 from NCBI-Gene Expression Omnibus (NCBI-GEO) database and screened out DEGs between reactive optic nerve head astrocytes (ONHAs) by hypertensions and normal controls. Gene ontology (GO) and pathways enrichment analysis of DEGs were applied and functional module analysis of the protein-protein interaction (PPI) network was also constructed. The study aimed to identify hub genes and explore the intrinsic molecular mechanisms of astrocyte involved in glaucoma.
    Materials and Methods
    Results
    Discussion Glaucoma is defined as a progressive optic neuropathy and is characterized by an irreversible loss of retinal ganglion cells. The main risk factor to develop glaucoma is an increased IOP, and current medications focus on lowering the IOP. IOP-lowering treatments just address a risk factor; there are profound alterations in tissue composition and architecture, disruptions in axonal transport, and critical axonal insult[24], [25]. Therefore, studying the potential role of nonneuronal cell in supporting the ganglion cells, including glial Amodiaquine dihydrochloride dihydrate mass such as astrocytes, is an important step to better understand the pathogenic mechanisms underlying glaucoma. In this study, we have identified 281 commonly changed DEGs from the two cohort profile data sets (GSE2378 and GSE758). A total of 119 consistently expressed genes were identified from 281 commonly changed DEGs, including 68 up-regulated genes and 51 down-regulated genes in reactive ONHAs from glaucoma samples compare to normal samples by using integrated bioinformatics analysis. PPI network complex filtered 75 DEGs (43 up-regulated and 32 down-regulated genes) of the 119 consistently altered DEGs and developed 117 edges, and 10 hub genes were identified. The DEGs in glaucoma with ocular hypertension analyzed by GO functional enrichment analysis showed that down-regulated DEGs were mainly enriched in immune response, cell migration and differentiation, and extracellular matrix, while up-regulated DEGs were shown to be concerned with immune response, cell stress response and neurotransmitter pathway regulation. The results of the current study are accordance with our knowledge that immune response, cell stress response, cell migration and extracellular matrix are the main mechanisms of glaucoma development and astrocyte activation[26], [27], [28], [29]. Reactive astrocytes are generally characterized by hypertrophy, hyperplasia, as well as increased expression of GFAP and vimentin. In glaucoma or with experimentally elevated IOP, ONH astrocytes in the prelaminar ONH round up and migrate, abandoning their columnar organization. The PPI network was constructed with DEGs, and the top 10 hub genes were as follows: ALB, FOS, FGFR3, GNAO1, BMP4, MAPK10, VWF, IFNG, PG5 and PRKCE. Module analysis of the PPI network suggested that extracellular exosome, ADCC and Hippo signaling pathway might be involved in glaucoma with ocular hypertension. Extracellular exosome are cell-derived vesicles have specialized functions and play a key role in processes such as immune system, coagulation and intercellular signaling[30], [31]. Increased tissue stress in the ONH from elevated IOP may be detected by glial cells via transmembrane integrin receptor signaling, and providing receptors for fibrillar and basement membrane collagens, fibronectin, matrix metalloproteinases, reelin and astrocytic hemidesmosomes[28], [32]. While integrins act as mechanoreceptors, transducing the stresses induced by elevated IOP, the matrix metalloproteinases (MMP) are key elements in the regulation of ECM remodeling. The ADCC is a mechanism of cell-mediated immune defense. The astrocytes of the ONH undergo a reactivation in glaucoma with ocular hypertension, which was characterized by morphologic alterations and expression changes, they expressed major histocompatibility complex class II proteins and became more potent inducers of T-cell activation. Further, ADCC mediated by activation of macrophages and neutrophils cells[34], [35]. The Hippo signaling pathway regulates cell proliferation and apoptosis. At three days following IOP elevation in a rat glaucoma model, the labeling of anterior ONH glial nuclei with antibodies to proliferating cell nuclear antigen coincided with the first alterations in connexin-43 labeling and preceded obvious morphological alterations in the glial columns. A near doubling of optic nerve astrocytes in a mouse glaucoma model was also indicated ocular hypertension induced cell proliferation. Undergo with hypoxia, metabolic or something lead to cellular stress, reactive oxygen species may accumulate to a point that critical cellular are apoptosis.