PUBLICATION

A network-based approach to identify deregulated pathways and drug effects in metabolic syndrome

Authors
Misselbeck, K., Parolo, S., Lorenzini, F., Savoca, V., Leonardelli, L., Bora, P., Morine, M.J., Mione, M.C., Domenici, E., Priami, C.
ID
ZDB-PUB-191120-5
Date
2019
Source
Nature communications   10: 5215 (Journal)
Registered Authors
Mione, Marina
Keywords
none
MeSH Terms
  • Animals
  • Diet, High-Fat
  • Drug Repositioning
  • Gene Regulatory Networks*/drug effects
  • Humans
  • Lipid Metabolism/drug effects
  • Macrophages/drug effects
  • Macrophages/metabolism
  • Metabolic Syndrome/drug therapy
  • Metabolic Syndrome/genetics*
  • Organ Specificity/genetics
  • Pharmaceutical Preparations/metabolism*
  • Pyrazoles/pharmacology
  • Pyrazoles/therapeutic use
  • Pyrimidines/pharmacology
  • Pyrimidines/therapeutic use
  • Reproducibility of Results
  • Signal Transduction/genetics*
  • Zebrafish/metabolism
PubMed
31740673 Full text @ Nat. Commun.
Abstract
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.
Genes / Markers
Figures
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping