Transcription factor NRF2 as a therapeutic target for chronic diseases: A systems medicine approach

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dc.contributor.author Cuadrado, Antonio
dc.contributor.author Manda, Gina
dc.contributor.author Hassan, Ahmed
dc.contributor.author Alcaraz, María José
dc.contributor.author Barbas, Coral
dc.contributor.author Daiber, Andreas
dc.contributor.author Ghezzi, Pietro
dc.contributor.author León, Rafael
dc.contributor.author López, Manuela G.
dc.contributor.author Oliva, Baldo
dc.contributor.author Pajares, Marta
dc.contributor.author Rojo, Ana I.
dc.contributor.author Robledinos-Antón, Natalia
dc.contributor.author Valverde, Ángela M.
dc.contributor.author Guney, Emre
dc.contributor.author Schmidt, Harald H.H.W.
dc.contributor.other UAM. Departamento de Bioquímica es_ES
dc.contributor.other Instituto de Investigaciones Biomédicas "Alberto Sols" (IIBM) es_ES
dc.contributor.other Instituto de Investigación Sanitaria Hospital Universitario de La Paz (IdiPAZ) es_ES
dc.date.accessioned 2018-05-25T14:10:19Z
dc.date.available 2018-05-25T14:10:19Z
dc.date.issued 2018-04-01
dc.identifier.citation Pharmacological Reviews 70.2 (2018): 348–383 en_US
dc.identifier.issn 0031-6997 (print) es_ES
dc.identifier.issn 1521-0081 (online) es_ES
dc.identifier.uri http://hdl.handle.net/10486/682527
dc.description.abstract Systems medicine has a mechanism-based rather than a symptom- or organ-basedapproach to disease and identifies therapeutic targets in a nonhypothesisdrivenmanner. In this work, we apply this to transcription factor nuclear factor (erythroid-derived 2)-like 2 (NRF2) by cross-validating its position in a protein-protein interaction network (the NRF2 interactome) functionally linked to cytoprotection in low-grade stress, chronic inflammation, metabolic alterations, and reactive oxygen species formation. Multiscale network analysis of these molecularprofiles suggests alterations ofNRF2 expression and activity as a common mechanism in a subnetwork of diseases (the NRF2 diseasome). This network joins apparently heterogeneous phenotypes such as autoimmune, respiratory, digestive, cardiovascular, metabolic, and neurodegenerative diseases, along with cancer. Importantly, this approach matches and confirms in silico several applications for NRF2-modulating drugs validated in vivo at different phases of clinical development. Pharmacologically, their profile is as diverse as electrophilic dimethyl fumarate, synthetic triterpenoids like bardoxolone methyl and sulforaphane, protein-protein or DNA-protein interaction inhibitors, and even registered drugs such as metformin and statins, which activate NRF2 and may be repurposed for indications within the NRF2 cluster of disease phenotypes. Thus, NRF2 represents one of the first targets fully embraced by classic and systems medicine approaches to facilitate both drug development and drug repurposing by focusing on a set of disease phenotypes that appear to be mechanistically linked. The resulting NRF2 drugome may therefore rapidly advance several surprising clinical options for this subset of chronic diseases en_US
dc.description.sponsorship This work was supported by Grants SAF2015-71304-REDT, SAF2016-76520-R, SAF2013-4874R, SAF2015-65267-R, and BIO2014-57518 of the Spanish Ministry of Economy and Competiveness; PII4/00372 from the Health Institute Carlos III; PROMETEOII/2014/071 of Generalitat Valenciana; P_37_732/2016 REDBRAIN of the European Regional Development Fund; Competitiveness Operational Program 2014-2020; and the ERC Advanced Grant RadMed 294683 and COST action 15120 OpenMultiMed (H.H.H.W.S.). M.P. is the recipient of a FPU fellowship of Autonomous University of Madrid. E.G. is supported by a European-cofunded Beatriu de Pinos fellowship. R.L. is supproted by the Miguel Servet II fellow (CPII16/00014) en_US
dc.format.extent 36 pag. es_ES
dc.format.mimetype application/pdf en
dc.language.iso eng en
dc.publisher American Society for Pharmacology and Experimental Therapeutics (ASPET) en_US
dc.relation.ispartof Pharmacological Reviews en_US
dc.rights © 2018 by The Author(s) en_US
dc.subject.other Systems medicine en_US
dc.subject.other Therapeutic targets en_US
dc.subject.other NRF2 en_US
dc.subject.other Chronic inflammation en_US
dc.title Transcription factor NRF2 as a therapeutic target for chronic diseases: A systems medicine approach en_US
dc.type article en
dc.subject.eciencia Medicina es_ES
dc.relation.publisherversion https://doi.org/10.1124/pr.117.014753 es_ES
dc.identifier.doi 10.1124/pr.117.014753 es_ES
dc.identifier.publicationfirstpage 348 es_ES
dc.identifier.publicationissue 2 es_ES
dc.identifier.publicationlastpage 383 es_ES
dc.identifier.publicationvolume 70 es_ES
dc.relation.projectID Gobierno de España. SAF2015-71304-REDT es_ES
dc.relation.projectID Gobierno de España. SAF2016-76520-R es_ES
dc.relation.projectID Gobierno de España. SAF2013-4874R es_ES
dc.relation.projectID Gobierno de España. SAF2015-65267-R es_ES
dc.relation.projectID Gobierno de España. BIO2014-57518 es_ES
dc.relation.projectID Gobierno de España. PII4/00372 es_ES
dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/294683 en_US
dc.type.version info:eu-repo/semantics/publishedVersion en
dc.rights.cc Reconocimiento – NoComercial es_ES
dc.rights.accessRights openAccess en
dc.authorUAM León Martínez, Rafael (264118)
dc.authorUAM Robledinos Antón, Natalia (271160)


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