{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T18:27:52Z","timestamp":1793039272777,"version":"4.5.0"},"reference-count":81,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,5,30]],"date-time":"2024-05-30T00:00:00Z","timestamp":1717027200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Aging Neurosci."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p><jats:italic>Gastrodia elata Blume<\/jats:italic> is a widely used medicinal and edible herb with a rich chemical composition. Moreover, prescriptions containing <jats:italic>Gastrodia elata<\/jats:italic> are commonly used for the prevention and treatment of cardiovascular, cerebrovascular, and aging-related diseases. Recent pharmacological studies have confirmed the antioxidant and neuroprotective effects of <jats:italic>Gastrodia elata<\/jats:italic>, and, in recent years, this herb has also been used in the treatment of Alzheimer\u2019s disease (AD) and other neurodegenerative disorders. We have previously shown that 4,4\u2032-methylenediphenol, a key active ingredient of <jats:italic>Gastrodia elata<\/jats:italic>, can mitigate amyloid-\u03b2 (A\u03b2)-induced paralysis in AD model worms as well as prolong the lifespan of the animals, thus displaying potential as a treatment of AD.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We investigated the effects of 4,4\u2032-methylenediphenol on AD and aging through paralysis, lifespan, and behavioral assays. In addition, we determined the anti-AD effects of 4,4\u2032-methylenediphenol by reactive oxygen species (ROS) assay, lipofuscin analysis, thioflavin S staining, metabolomics analysis, GFP reporter gene worm assay, and RNA interference assay and conducted in-depth studies on its mechanism of action.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>4,4\u2032-Methylenediphenol not only delayed paralysis onset and senescence in the AD model worms but also enhanced their motility and stress tolerance. Meanwhile, 4,4\u2032-methylenediphenol treatment also reduced the contents of reactive oxygen species (ROS) and lipofuscin, and decreased A\u03b2 protein deposition in the worms. Broad-spectrum targeted metabolomic analysis showed that 4,4\u2032-methylenediphenol administration had a positive effect on the metabolite profile of the worms. In addition, 4,4\u2032-methylenediphenol promoted the nuclear translocation of DAF-16 and upregulated the expression of SKN-1, SOD-3, and GST-4 in the respective GFP reporter lines, accompanied by an enhancement of antioxidant activity and a reduction in A\u03b2 toxicity; importantly, our results suggested that these effects of 4,4\u2032-methylenediphenol were mediated, at least partly, via the activation of DAF-16.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>We have demonstrated that 4,4\u2032-methylenediphenol can reduce A\u03b2-induced toxicity in AD model worms, suggesting that it has potential for development as an anti-AD drug. Our findings provide ideas and references for further research into the anti-AD effects of <jats:italic>Gastrodia elata<\/jats:italic> and its active ingredients.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fnagi.2024.1393721","type":"journal-article","created":{"date-parts":[[2024,5,30]],"date-time":"2024-05-30T13:45:42Z","timestamp":1717076742000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":12,"title":["4,4\u2032-methylenediphenol reduces A\u03b2-induced toxicity in a Caenorhabditis elegans model of Alzheimer\u2019s disease"],"prefix":"10.3389","volume":"16","author":[{"given":"Xingzhi","family":"Yu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Tao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tian","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohua","family":"Duan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,5,30]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"820","DOI":"10.1021\/cn300077c","article-title":"Role of ABC transporters in the pathogenesis of Alzheimer's disease","volume":"3","author":"Abuznait","year":"2012","journal-title":"ACS Chem. 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