{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T19:17:52Z","timestamp":1791919072564,"version":"4.3.4"},"reference-count":223,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2020,10,24]],"date-time":"2020-10-24T00:00:00Z","timestamp":1603497600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Alzheimer\u2019s disease (AD) is a progressive neuronal\/cognitional dysfunction, leading to disability and death. Despite advances in revealing the pathophysiological mechanisms behind AD, no effective treatment has yet been provided. It urges the need for finding novel multi-target agents in combating the complex dysregulated mechanisms in AD. Amongst the dysregulated pathophysiological pathways in AD, oxidative stress seems to play a critical role in the pathogenesis progression of AD, with a dominant role of nuclear factor erythroid 2-related factor 2 (Nrf2)\/Kelch-like ECH-associated protein-1 (Keap1)\/antioxidant responsive elements (ARE) pathway. In the present study, a comprehensive review was conducted using the existing electronic databases, including PubMed, Medline, Web of Science, and Scopus, as well as related articles in the field. Nrf2\/Keap1\/ARE has shown to be the upstream orchestrate of oxidative pathways, which also ameliorates various inflammatory and apoptotic pathways. So, developing multi-target agents with higher efficacy and lower side effects could pave the road in the prevention\/management of AD. The plant kingdom is now a great source of natural secondary metabolites in targeting Nrf2\/Keap1\/ARE. Among natural entities, phenolic compounds, alkaloids, terpene\/terpenoids, carotenoids, sulfur-compounds, as well as some other miscellaneous plant-derived compounds have shown promising future accordingly. Prevailing evidence has shown that activating Nrf2\/ARE and downstream antioxidant enzymes, as well as inhibiting Keap1 could play hopeful roles in overcoming AD. The current review highlights the neuroprotective effects of plant secondary metabolites through targeting Nrf2\/Keap1\/ARE and downstream interconnected mediators in combating AD.<\/jats:p>","DOI":"10.3390\/molecules25214926","type":"journal-article","created":{"date-parts":[[2020,10,26]],"date-time":"2020-10-26T03:51:47Z","timestamp":1603684307000},"page":"4926","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":92,"title":["Attenuation of Nrf2\/Keap1\/ARE in Alzheimer\u2019s Disease by Plant Secondary Metabolites: A Mechanistic Review"],"prefix":"10.3390","volume":"25","author":[{"given":"Sajad","family":"Fakhri","sequence":"first","affiliation":[{"name":"Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah 6734667149, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mirko","family":"Pesce","sequence":"additional","affiliation":[{"name":"Department of Medicine and Aging Sciences, University G. d\u2019Annunzio CH-PE, 66100 Chieti, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonia","family":"Patruno","sequence":"additional","affiliation":[{"name":"Department of Medicine and Aging Sciences, University G. d\u2019Annunzio CH-PE, 66100 Chieti, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0579-3495","authenticated-orcid":false,"given":"Seyed Zachariah","family":"Moradi","sequence":"additional","affiliation":[{"name":"Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah 6734667149, Iran"},{"name":"Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah 6734667149, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amin","family":"Iranpanah","sequence":"additional","affiliation":[{"name":"Student Research Committee, Kermanshah University of Medical Sciences, Kermanshah 6714415153, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7081-6521","authenticated-orcid":false,"given":"Mohammad Hosein","family":"Farzaei","sequence":"additional","affiliation":[{"name":"Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah 6734667149, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2790-2544","authenticated-orcid":false,"given":"Eduardo","family":"Sobarzo-S\u00e1nchez","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmaceutical Chemistry, Department of Organic Chemistry, Faculty of Pharmacy, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain"},{"name":"Instituto de Investigaci\u00f3n e Innovaci\u00f3n en Salud, Facultad de Ciencias de la Salud, Universidad Central de Chile, Santiago 8330507, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,10,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e40","DOI":"10.1016\/j.jalz.2014.01.004","article-title":"Deaths in the United States among persons with Alzheimer\u2019s disease (2010\u20132050)","volume":"10","author":"Weuve","year":"2014","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1208","DOI":"10.1016\/j.bbadis.2013.12.011","article-title":"Oxidative damage and the Nrf2-ARE pathway in neurodegenerative diseases","volume":"1842","author":"Gan","year":"2014","journal-title":"Biochim. 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