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转录因子 NRF2 作为慢性疾病的治疗靶点:系统医学方法。

Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach.

机构信息

Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Investigación Sanitaria La Paz (IdiPaz), Department of Biochemistry and Instituto de Investigaciones Biomédicas Alberto Sols UAM (Autonomous University of Madrid)-CSIC (Centro Superior de Investigaciones Biomédicas), Faculty of Medicine, Autonomous University of Madrid, Madrid, Spain (A.C., M.P., A.I.R., N.R.-A.); Victor Babes National Institute of Pathology, Bucharest, Romania (A.C., G.M.); Department Pharmacology and Personalized Medicine, School for Cardiovascular Medicine, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastrich, The Netherlands (A.H., H.H.H.W.S.); Instituto Interuniversitario de Investigación de Reconocimiento Molecular y Desarrollo Tecnológico, Universitat Politècnica de València, Universitat de València, Valencia, Spain (M.J.A.); Centre for Metabolomics and Bioanalysis, Facultad de Farmacia, Universidad CEU (Centro de Estudios Universitarios)-San Pablo, Madrid, Spain (C.B.); Center for Cardiology, Cardiology I-Laboratory of Molecular Cardiology, Medical Center of the Johannes Gutenberg University, Mainz, Germany (A.D.); Brighton and Sussex Medical School, Brighton, United Kingdom (P.G.); Instituto Teófilo Hernando y Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain (R.L., M.G.L.); Instituto de Investigación Sanitaria, Servicio de Farmacología Clínica, Hospital Universitario de la Princesa, Madrid, Spain (R.L., M.G.L.); GRIB (Unidad de Investigación en Informática Biomédica), Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain (B.O., E.G.); Instituto de Investigaciones Biomédicas Alberto Sols UAM-CSIC and Centro de Investigación Biomédica en Red en Diabetes y Enfermedades Metabólicas Asociadas, Madrid, Spain (A.M.V.); and Structural Bioinformatics Laboratory, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain (E.G.)

Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Investigación Sanitaria La Paz (IdiPaz), Department of Biochemistry and Instituto de Investigaciones Biomédicas Alberto Sols UAM (Autonomous University of Madrid)-CSIC (Centro Superior de Investigaciones Biomédicas), Faculty of Medicine, Autonomous University of Madrid, Madrid, Spain (A.C., M.P., A.I.R., N.R.-A.); Victor Babes National Institute of Pathology, Bucharest, Romania (A.C., G.M.); Department Pharmacology and Personalized Medicine, School for Cardiovascular Medicine, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastrich, The Netherlands (A.H., H.H.H.W.S.); Instituto Interuniversitario de Investigación de Reconocimiento Molecular y Desarrollo Tecnológico, Universitat Politècnica de València, Universitat de València, Valencia, Spain (M.J.A.); Centre for Metabolomics and Bioanalysis, Facultad de Farmacia, Universidad CEU (Centro de Estudios Universitarios)-San Pablo, Madrid, Spain (C.B.); Center for Cardiology, Cardiology I-Laboratory of Molecular Cardiology, Medical Center of the Johannes Gutenberg University, Mainz, Germany (A.D.); Brighton and Sussex Medical School, Brighton, United Kingdom (P.G.); Instituto Teófilo Hernando y Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain (R.L., M.G.L.); Instituto de Investigación Sanitaria, Servicio de Farmacología Clínica, Hospital Universitario de la Princesa, Madrid, Spain (R.L., M.G.L.); GRIB (Unidad de Investigación en Informática Biomédica), Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain (B.O., E.G.); Instituto de Investigaciones Biomédicas Alberto Sols UAM-CSIC and Centro de Investigación Biomédica en Red en Diabetes y Enfermedades Metabólicas Asociadas, Madrid, Spain (A.M.V.); and Structural Bioinformatics Laboratory, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain (E.G.).

出版信息

Pharmacol Rev. 2018 Apr;70(2):348-383. doi: 10.1124/pr.117.014753.

Abstract

Systems medicine has a mechanism-based rather than a symptom- or organ-based approach to disease and identifies therapeutic targets in a nonhypothesis-driven manner. 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 molecular profiles suggests alterations of NRF2 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.

摘要

系统医学采用基于机制而非基于症状或器官的方法来治疗疾病,并以非假设驱动的方式确定治疗靶点。在这项工作中,我们通过交叉验证其在与低水平应激、慢性炎症、代谢改变和活性氧形成相关的细胞保护功能上的蛋白-蛋白相互作用网络(NRF2 相互作用组)中的位置,将其应用于转录因子核因子(红系衍生 2)样 2(NRF2)。对这些分子谱的多尺度网络分析表明,NRF2 表达和活性的改变是疾病亚网络(NRF2 疾病组)中一种常见机制。该网络将自身免疫、呼吸、消化、心血管、代谢和神经退行性疾病以及癌症等看似不同的表型联系在一起。重要的是,这种方法与体内验证的几种 NRF2 调节药物的计算模拟相匹配并确认,这些药物在临床开发的不同阶段都得到了验证。药理学上,它们的特性与亲电二甲基富马酸、合成三萜类化合物如 bardoxolone 甲基和 sulforaphane、蛋白-蛋白或 DNA-蛋白相互作用抑制剂以及甚至已注册的药物如二甲双胍和他汀类药物一样多样化,这些药物激活 NRF2 并可能被重新用于 NRF2 疾病表型簇中的适应症。因此,NRF2 是经典和系统医学方法完全接受的首批靶点之一,通过专注于一组似乎在机制上相关的疾病表型,促进药物开发和药物再利用。由此产生的 NRF2 药物组可能会迅速为这组慢性疾病提供一些令人惊讶的临床选择。

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