دورية أكاديمية
Drug repurposing on Alzheimer's disease through modulation of NRF2 neighborhood.
| العنوان: | Drug repurposing on Alzheimer's disease through modulation of NRF2 neighborhood. |
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| المؤلفون: | Bourdakou MM; Bioinformatics Department, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus., Fernández-Ginés R; Instituto de Investigaciones Biomédicas 'Alberto Sols' UAM-CSIC, Instituto de Investigación Sanitaria La Paz (IdiPaz), Department of Biochemistry, Faculty of Medicine, Autonomous University of Madrid, Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), ISCIII, Madrid, Spain., Cuadrado A; Instituto de Investigaciones Biomédicas 'Alberto Sols' UAM-CSIC, Instituto de Investigación Sanitaria La Paz (IdiPaz), Department of Biochemistry, Faculty of Medicine, Autonomous University of Madrid, Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), ISCIII, Madrid, Spain., Spyrou GM; Bioinformatics Department, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus. Electronic address: georges@cing.ac.cy. |
| المصدر: | Redox biology [Redox Biol] 2023 Nov; Vol. 67, pp. 102881. Date of Electronic Publication: 2023 Sep 07. |
| نوع المنشور: | Meta-Analysis; Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Elsevier, B.V Country of Publication: Netherlands NLM ID: 101605639 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2213-2317 (Electronic) Linking ISSN: 22132317 NLM ISO Abbreviation: Redox Biol Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: [Amsterdam]: Elsevier, B.V., [2013]- |
| مواضيع طبية MeSH: | Alzheimer Disease*/drug therapy , Alzheimer Disease*/genetics , Alzheimer Disease*/metabolism, Humans ; NF-E2-Related Factor 2/genetics ; NF-E2-Related Factor 2/metabolism ; Drug Repositioning ; Hippocampus/metabolism |
| مستخلص: | Alzheimer's disease (AD) is an age-dependent neurodegenerative disorder and the most common cause of cognitive decline. The alarming epidemiological features of Alzheimer's disease, combined with the high failure rate of candidate drugs tested in the preclinical phase, impose more intense investigations for new curative treatments. NRF2 (Nuclear factor-erythroid factor 2-related factor 2) plays a critical role in the inflammatory response and in the cellular redox homeostasis and provides cytoprotection in several diseases including those in the neurodegeneration spectrum. These roles suggest that NRF2 and its directly associated proteins may be novel attractive therapeutic targets in the fight against AD. In this study, through a systemics perspective, we propose an in silico drug repurposing approach for AD, based on the NRF2 interactome and regulome, with the aim of highlighting possible repurposed drugs for AD. Using publicly available information based on differential expressions of the NRF2-neighborhood in AD and through a computational drug repurposing pipeline, we derived to a short list of candidate repurposed drugs and small molecules that affect the expression levels of the majority of NRF2-partners. The relevance of these findings was assessed in a four-step computational meta-analysis including i) structural similarity comparisons with currently ongoing NRF2-related drugs in clinical trials ii) evaluation based on the NRF2-diseasome iii) comparison of relevance between targeted pathways of shortlisted drugs and NRF2-related drugs in clinical trials and iv) further comparison with existing knowledge on AD and NRF2-related drugs in clinical trials based on their known modes of action. Overall, our analysis yielded in 5 candidate repurposed drugs for AD. In cell culture, these 5 candidates activated a luciferase reporter for NRF2 activity and in hippocampus derived TH22 cells they increased NRF2 protein levels and the NRF2 transcriptional signatures as determined by increased expression of its downstream target heme oxygenase 1. We expect that our proposed candidate repurposed drugs will be useful for further research and clinical translation for AD. Competing Interests: Declaration of competing interest None declared. (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.) |
| فهرسة مساهمة: | Keywords: Alzheimer's disease; Association network; Differentially expressed genes; In silico drug repurposing; NFE2L2; NRF2 |
| المشرفين على المادة: | 0 (NF-E2-Related Factor 2) |
| تواريخ الأحداث: | Date Created: 20230911 Date Completed: 20231030 Latest Revision: 20231031 |
| رمز التحديث: | 20231215 |
| مُعرف محوري في PubMed: | PMC10500459 |
| DOI: | 10.1016/j.redox.2023.102881 |
| PMID: | 37696195 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 2213-2317 |
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| DOI: | 10.1016/j.redox.2023.102881 |