RESUMEN
BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that involves the death of neurons. ALS is associated with many gene mutations as previously studied. In order to explore the molecular mechanisms underlying ALS with C9orf72 mutation, gene expression profiles of ALS fibroblasts and control fibroblasts were subjected to bioinformatics analysis. Genes with critical functional roles can be detected by a measure of node centrality in biological networks. In gene co-expression networks, highly connected genes called as candidate hubs have been associated with key disease-related pathways. Herein, this method was applied to find the hub genes related to ALS disease. METHODS: Illumina HiSeq microarray gene expression dataset GSE51684 was retrieved from Gene Expression Omnibus (GEO) database which included four Sporadic ALS, twelve Familial ALS and eight control samples. Differentially Expressed Genes (DEGs) were identified using the Student's t test statistical method and gene co-expression networking. Gene ontology (GO) function and KEGG pathway enrichment analysis of DEGs were performed using the DAVID online tool. Protein-protein interaction (PPI) networks were constructed by mapping the DEGs onto protein-protein interaction data from publicly available databases to identify the pathways where DEGs are involved in. PPI interaction network was divided into subnetworks using MCODE algorithm and was analyzed using Cytoscape. RESULTS: The results revealed that the expression of DEGs was mainly involved in cell adhesion, cell-cell signaling, Extra cellular matrix region GO processes and focal adhesion, neuroactive ligand receptor interaction, Extracellular matrix receptor interaction. Tumor necrosis factor (TNF), Endothelin 1 (EDN1), Angiotensin (AGT) and many cell adhesion molecules (CAM) were detected as hub genes that can be targeted as novel therapeutic targets for ALS disease. CONCLUSION: These analyses and findings enhance the understanding of ALS pathogenesis and provide references for ALS therapy.
Asunto(s)
Esclerosis Amiotrófica Lateral/genética , Esclerosis Amiotrófica Lateral/metabolismo , Mapas de Interacción de Proteínas/genética , Proteínas/genética , Proteínas/metabolismo , Angiotensinas/genética , Angiotensinas/metabolismo , Proteína C9orf72 , Moléculas de Adhesión Celular/genética , Moléculas de Adhesión Celular/metabolismo , Biología Computacional , Proteína 2 Similar a ELAV/genética , Proteína 2 Similar a ELAV/metabolismo , Endotelina-1/genética , Endotelina-1/metabolismo , Ontología de Genes , Humanos , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
A convenient approach for the synthesis of novel tetracyclic scaffolds incorporating a flavonoid framework with medium sized heterocyclic rings (eight-, nine-, ten- and eleven-membered rings) containing two oxygen atoms from flavonols through alkylation using different dibromoalkanes was described. The synthesized compounds were established based on the spectral data and X-ray crystal structure for 6c. The synthesized compounds were evaluated for their in vitro antimicrobial activity. Docking studies were carried out for most active two compounds 6f and 6i.