pci-32765 and Metabolic-Syndrome

Metabolic syndrome is a pathological condition characterized by obesity, hyperglycemia, hypertension, elevated levels of triglycerides and low levels of high-density lipoprotein cholesterol that increase cardiovascular disease risk and type 2 diabetes. Although numerous predisposing genetic risk factors have been identified, the biological mechanisms underlying this complex phenotype are not fully elucidated. Here we introduce a systems biology approach based on network analysis to investigate deregulated biological processes and subsequently identify drug repurposing candidates. A proximity score describing the interaction between drugs and pathways is defined by combining topological and functional similarities. The results of this computational framework highlight a prominent role of the immune system in metabolic syndrome and suggest a potential use of the BTK inhibitor ibrutinib as a novel pharmacological treatment. An experimental validation using a high fat diet-induced obesity model in zebrafish larvae shows the effectiveness of ibrutinib in lowering the inflammatory load due to macrophage accumulation.

Topics: Adenine; Animals; Diet, High-Fat; Drug Repositioning; Gene Regulatory Networks; Humans; Lipid Metabolism; Macrophages; Metabolic Syndrome; Organ Specificity; Pharmaceutical Preparations; Piperidines; Pyrazoles; Pyrimidines; Reproducibility of Results; Signal Transduction; Zebrafish