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.

A network-based approach to identify deregulated pathways and drug effects in metabolic syndrome / Misselbeck, K.; Parolo, S.; Lorenzini, F.; Savoca, V.; Leonardelli, L.; Bora, P.; Morine, M. J.; Mione, M. C.; Domenici, E.; Priami, C.. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - 10:(2019), pp. 521501-521514. [10.1038/s41467-019-13208-z]

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

Misselbeck K.;Savoca V.;Mione M. C.;Domenici E.;Priami C.
2019-01-01

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.
2019
Misselbeck, K.; Parolo, S.; Lorenzini, F.; Savoca, V.; Leonardelli, L.; Bora, P.; Morine, M. J.; Mione, M. C.; Domenici, E.; Priami, C.
A network-based approach to identify deregulated pathways and drug effects in metabolic syndrome / Misselbeck, K.; Parolo, S.; Lorenzini, F.; Savoca, V.; Leonardelli, L.; Bora, P.; Morine, M. J.; Mione, M. C.; Domenici, E.; Priami, C.. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - 10:(2019), pp. 521501-521514. [10.1038/s41467-019-13208-z]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11572/253520
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