[Molecular Pathway and AOP Development Using Gene Network Analysis].

The Organisation for Economic Co-operation and Development (OECD) has initiated the adverse outcome pathway (AOP) Development Program in which the concept of AOP is applied to evaluate the safety of molecules such as chemicals. This program aims to assist regulatory needs and construct a knowledge base by accumulating AOP case studies. AOP consists of a molecular initiating event (MIE) as the initiating event of the pathway; key events (KEs) as the events themselves, such as cellular-molecular interactions; and adverse outcome (AO), such as signaling transduction-induced toxicity, as adverse events. KEs are extracted as important events at various levels, such as the molecular, cellular, tissue, organ, individual, and species levels; measurement of KEs and key event relationships (KERs), including mechanisms, plausibility, species differences, and empirical support information, are gathered. The development status of the AOP relating to histone deacetylase inhibition-induced testicular toxicity, currently being reviewed by the OECD, has been introduced. The AOP describing malignancies by Wnt ligand stimulation and Wnt signaling activation using gene expression network analysis-based mechanisms in molecular pathway elucidation has been suggested.

Proteomic Analysis of Morphologically Changed Tissues after Prolonged Dexamethasone Treatment.

Prolonged dexamethasone (Dex) administration leads to serious adverse and decrease brain and heart size, muscular atrophy, hemorrhagic liver, and presence of kidney cysts. Herein, we used an untargeted proteomic approach using liquid chromatography-tandem mass spectrometry (LC-MS/MS) for simultaneous identification of changes in proteomes of the major organs in Sprague-Dawley (SD rats post Dex treatment. The comparative and quantitative proteomic analysis of the brain, heart, muscle, liver, and kidney tissues revealed differential expression of proteins (n = 190, 193, 39, 230, and 53, respectively) between Dex-treated and control rats. Functional network analysis using ingenuity pathway analysis (IPA revealed significant differences in regulation of metabolic pathways within the morphologically changed organs that related to: (i) brain-cell morphology, nervous system development, and function and neurological disease; (ii) heart-cellular development, cellular function and maintenance, connective tissue development and function; (iii) skeletal muscle-nucleic acid metabolism, and small molecule biochemical pathways; (iv) liver-lipid metabolism, small molecular biochemistry, and nucleic acid metabolism; and (v) kidney-drug metabolism, organism injury and abnormalities, and renal damage. Our study provides a comprehensive description of the organ-specific proteomic profilesand differentially altered biochemical pathways, after prolonged Dex treatement to understand the molecular basis for development of side effects.

Analysis on regulatory network linked to Hpa gene in invasion and metastasis of colon cancer.

Our purpose was to discuss the biological function of Hpa gene and its regulatory network in invasion and metastasis of colon cancer. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes database were used to perform functional annotation and pathway analysis on Hpa gene. Gene Ontology analysis results showed that Hpa plays a significant role in cellular component, molecular function and biological process; and combined with Kyoto Encyclopedia of Genes and Genomes database, regulatory network of angiogenesis of colon cancer was drawn out. Through analysis of regulatory network linked to angiogenesis in invasion and metastasis of colon cancer, the study lays foundation for further prevention, diagnosis and treatment of colon cancer.

Pathway crosstalk analysis in prostate cancer based on protein-protein network data.

Prostate cancer (PCa) is one of the major leading cause in men and no effective biomarkers or therapy have been approved for it to date. This study aimed to explore the molecular mechanisms and identify the potential molecular biomarkers of PCa. The microarray profile GSE38241 including 18 prostate cancer metastasis and 21 normal prostate samples was retrieved from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified by Limma. DEGs functions were investigated by Gene Ontology (GO) and pathway enrichment analysis. Moreover, protein-protein interaction (PPI) network of DEGs was constructed, followed by functional analysis of modules. Additionally, pathway crosstalk network was constructed by integrating PPI network and Kyoto encyclopedia of genes and genomes (KEGG) pathways. Totally, 334 up - and 703 down-regulated DEGs were identified. The functions of up-regulated DEGs were significantly enriched in GO terms of cell cycle phase and cell cycle process. While down-regulated DEGs mainly participated in actin filament-based process. Among these pathways in the pathway crosstalk network, T cell receptor signaling pathway, chemokine signaling pathways, endometrial cancer and glioma were found to play critical roles during PC progression. Cell division cycle 45 (CDC45), baculoviral IAP repeat containing 5 (BIRC5) and cell division cycle associated 5 (CDCA5) may be useful markers for predicting tumor metastasis and therapeutic targets for the treatment of PCa patients. Moreover, the pathway crosstalk network provides the groundwork that targeting multiple pathways might be more effective than targeting one pathway alone.

Gene expression profiling analysis of the role of miR-22 in clear cell ovarian cancer.

This study aimed to investigate the role and potential mechanism of miR-22 in clear cell ovarian cancer (CCOC) progression. The gene expression profile of GSE16568, including 3 CCOC samples with miR-22 overexpression and 3 negative controls, was downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were screened using the limma package in R. Gene Ontology (GO) and pathway enrichment analysis of DEGs were performed by using The Database for Annotation, Visualization and Integrated Discovery (DAVID). Furthermore, protein-protein interaction (PPI) network of the DEGs was constructed using the Search Tool for the Retrieval of Interacting Genes (STRING) database. Besides, the miR-22-mRNA interaction pairs were predicted to explore the critical genes involved in the cancer. Totally, 95 up-regulated DEGs and 51 down-regulated DEGs were identified. The DEGs were enriched in different GO terms and pathways. The up-regulated genes cyclin-dependent kinases (CDK6), MDM2 oncogene, E3 ubiquitin protein ligase (MDM2), and thrombospondin 1 (THBS1) were involved in the p53 signaling pathway. The up-regulated gene FBJ murine osteosarcoma viral oncogene homolog (FOS) was a hub protein in the PPI network of the DEGs. The down-regulated DEGs including lymphoid enhancer-binding factor 1 (LEF1) and v-myb avian myeloblastosis viral oncogene homolog (MYB) were mainly associated with immunity. Nine DEGs as target genes were identified to be recognized by miR-22. Our study suggested that several key genes such as CDK6, MDM2, LEF1, MYB, and FOS that involved in different pathways including p53 signaling pathway were associated with CCOC progression. miR-22 may play an essential role in cell migration and invasion in CCOC through targeting responsive genes.

Conserved residues of the Pro103-Arg115 loop are involved in triggering the allosteric response of the Escherichia coli ADP-glucose pyrophosphorylase.

The synthesis of glycogen in bacteria and starch in plants is allosterically controlled by the production of ADP-glucose by ADP-glucose pyrophosphorylase. Using computational studies, site-directed mutagenesis, and kinetic characterization, we found a critical region for transmitting the allosteric signal in the Escherichia coli ADP-glucose pyrophosphorylase. Molecular dynamics simulations and structural comparisons with other ADP-glucose pyrophosphorylases provided information to hypothesize that a Pro103-Arg115 loop is part of an activation path. It had strongly correlated movements with regions of the enzyme associated with regulation and ATP binding, and a network analysis showed that the optimal network pathways linking ATP and the activator binding Lys39 mainly involved residues of this loop. This hypothesis was biochemically tested by mutagenesis. We found that several alanine mutants of the Pro103-Arg115 loop had altered activation profiles for fructose-1,6-bisphosphate. Mutants P103A, Q106A, R107A, W113A, Y114A, and R115A had the most altered kinetic profiles, primarily characterized by a lack of response to fructose-1,6-bisphosphate. This loop is a distinct insertional element present only in allosterically regulated sugar nucleotide pyrophosphorylases that could have been acquired to build a triggering mechanism to link proto-allosteric and catalytic sites.

Comprehensive assessment and network analysis of the emerging genetic susceptibility landscape of prostate cancer.

BACKGROUND: Recent advances in high-throughput genotyping have made possible identification of genetic variants associated with increased risk of developing prostate cancer using genome-wide associations studies (GWAS). However, the broader context in which the identified genetic variants operate is poorly understood. Here we present a comprehensive assessment, network, and pathway analysis of the emerging genetic susceptibility landscape of prostate cancer. METHODS: We created a comprehensive catalog of genetic variants and associated genes by mining published reports and accompanying websites hosting supplementary data on GWAS. We then performed network and pathway analysis using single nucleotide polymorphism (SNP)-containing genes to identify gene regulatory networks and pathways enriched for genetic variants. RESULTS: We identified multiple gene networks and pathways enriched for genetic variants including IGF-1, androgen biosynthesis and androgen signaling pathways, and the molecular mechanisms of cancer. The results provide putative functional bridges between GWAS findings and gene regulatory networks and biological pathways.