{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T15:56:45Z","timestamp":1791561405108,"version":"4.3.4"},"reference-count":62,"publisher":"Wiley","issue":"14","license":[{"start":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T00:00:00Z","timestamp":1783987200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T00:00:00Z","timestamp":1783987200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100020950","name":"National Science and Technology Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100020950","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["scijournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J Sci Food Agric"],"published-print":{"date-parts":[[2026,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>BACKGROUND<\/jats:title>\n                    <jats:p>\n                      Nobiletin, a citrus polymethoxyflavone recognized as a functional food component with diverse health benefits, has been reported to exhibit antioxidant, anti\u2010inflammatory and neuroprotective properties. Methylglyoxal (MG), a highly reactive dicarbonyl compound and precursor of advanced glycation end products, contributes to oxidative stress, tau hyperphosphorylation and amyloid\u2010\n                      <jats:italic>\u03b2<\/jats:italic>\n                      (A\n                      <jats:italic>\u03b2<\/jats:italic>\n                      ) accumulation, which are key events linking diabetes to Alzheimer's disease. In this study, an acetylated derivative of nobiletin, 5\u2010acetoxy\u20106,7,8,3\u2032,4\u2032\u2010pentamethoxyflavone (5\u2010AN), was evaluated for its neuroprotective and gut microbiota\u2010modulating effects against MG\u2010induced Alzheimer\u2010like cognitive deficits in mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>\n                      Oral administration of 5\u2010AN (10 and 20\u2009mg\u2009kg\n                      <jats:sup>\u20131<\/jats:sup>\n                      \u2009day\n                      <jats:sup>\u20131<\/jats:sup>\n                      for 13\u2009weeks) improved behavioral performance in MG\u2010treated mice, with the 20\u2009mg\u2009kg\n                      <jats:sup>\u20131<\/jats:sup>\n                      group showing significant improvement in spatial learning, recognition memory and anxiety\u2010like behavior. Immunohistochemical and Western blot analyses showed that 5\u2010AN reduced hippocampal tau phosphorylation and A\n                      <jats:italic>\u03b2<\/jats:italic>\n                      accumulation at the same time as restoring phosphoinositide 3\u2010kinase (PI3K)\/Akt\/glycogen synthase kinase\u20103\n                      <jats:italic>\u03b2<\/jats:italic>\n                      signaling, enhancing brain\u2010derived neurotrophic factor expression and reducing cleaved caspase\u20103 expression. Gut microbiota analysis showed that MG exposure induced dysbiosis, characterized by reduced\n                      <jats:italic>Bacteroides_H acidifaciens<\/jats:italic>\n                      and increased MG\u2010associated taxa such as\n                      <jats:italic>Alistipes<\/jats:italic>\n                      and\n                      <jats:italic>Dysosmobacter<\/jats:italic>\n                      , whereas 5\u2010AN supplementation significantly reversed these alterations. Functional prediction analysis further indicated that MG\u2010induced dysbiosis was associated with disruptions in neuroimmune\u2010related pathways, including circadian entrainment, Th17 cell differentiation, interleukin\u201017 signaling and PI3K\/Akt signaling, whereas 5\u2010AN supplementation significantly restored these pathways.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSION<\/jats:title>\n                    <jats:p>These findings indicate that acetylated nobiletin may serve as a promising food\u2010derived bioactive compound for mitigating cognitive impairment through coordinated modulation of neuronal function and gut microbiota. \u00a9 2026 Society of Chemical Industry.<\/jats:p>\n                  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