{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T06:22:46Z","timestamp":1787638966202,"version":"build-2736575974"},"reference-count":48,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T00:00:00Z","timestamp":1787616000000},"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. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Alzheimer\u2019s disease (AD) is a complex neurodegenerative disorder characterized by the accumulation and aggregation of \u03b2-amyloid (A\u03b2) and chronic neuroinflammation mediated by the receptor for advanced glycation end products (RAGE). Current therapeutic candidates targeting RAGE signaling or A\u03b2 aggregation continue to face challenges, including off-target toxicity, poor blood-brain barrier (BBB) penetration, and limited multi-target efficacy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Naringenin (NAR), a naturally occurring flavanone polyphenol prioritized through structure-based virtual screening and preliminary biological evaluation, was selected for further mechanistic investigation as a potential dual-target modulator of RAGE-associated inflammatory signaling and A\u03b242 fibrillization.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Molecular docking analyses showed that NAR interacts with the RAGE interface (PDB: 6XQ3) via \u03c0-cation interactions with ARG_98 and LYS_110 (docking score: \u22125.072 kcal\/mol). At the A\u03b2 fibril (PDB: 2MXU), NAR showed a superior docking score than ALZ-801 (valiltramiprosate), involving hydrogen bonding and \u03c0\u2013\u03c0 stacking with HIS_A14 (docking score: \u22128.098 kcal\/mol). 100 ns molecular dynamics simulations supported the stability of these binding modes, with RMSD and RMSF values within acceptable ranges. MM-GBSA rescoring indicated competitive predicted binding free energies (\u0394GBind: \u221230.260 kcal\/mol at RAGE; \u2212220.162 kcal\/mol at the fibril, compared to ALZ- 801\u2019s \u2212214.482 kcal\/mol), influenced by electrostatic and hydrophobic interactions. Per-residue energy decomposition indicated PHE_20 (\u22129.10 kcal\/ mol) as the dominant hotspot residue, alongside ARG_98 (\u22124.71 kcal\/mol) and LYS_52 (\u22123.96 kcal\/mol) as key RAGE anchors.\n                      <jats:italic>In silico<\/jats:italic>\n                      ADMET profiling suggested favorable predicted BBB accessibility (score: 0.001), Caco-2 permeability, Lipinski compliance, and a more favorable predicted cardiac safety profile (hERG: 0.145) relative to V6Y. Experimentally, NAR reduced A\u03b242-induced NF-\u03baB activation in RAGE-positive C6 cells, protected SH-SY5Y neurons from A\u03b242 toxicity, and inhibited A\u03b242 fibrillization\n                      <jats:italic>in vitro<\/jats:italic>\n                      , producing non-seeding aggregates consistent with impaired fibril formation, and attenuated rotenone-induced \u03b1-synuclein-associated cellular stress.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>Collectively, these findings support further investigation of NAR as a mechanistically plausible multi-target candidate for protein aggregation and RAGE-associated inflammatory signaling in neurodegenerative disease models.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1901236","type":"journal-article","created":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T05:34:48Z","timestamp":1787636088000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Naringenin as a dual-target modulator of RAGE\u2013NF-\u03baB signaling and A\u03b2 fibrillization in Alzheimer\u2019s disease: integrated computational and experimental analyses"],"prefix":"10.3389","volume":"17","author":[{"given":"Inderjeet","family":"Bhogal","sequence":"first","affiliation":[{"name":"Department of Biomedical Engineering, Faculty of Electrical Engineering and Communication, Brno University of Technology","place":["Brno, Czechia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivo","family":"Frydrych","sequence":"additional","affiliation":[{"name":"Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palack\u00fd University and University Hospital Olomouc","place":["Olomouc, Czechia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ajay","family":"Modi","sequence":"additional","affiliation":[{"name":"International Clinical Research Centre, St. Anne University Hospital","place":["Brno, Czechia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vaishali","family":"Pankaj","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Faculty of Electrical Engineering and Communication, Brno University of Technology","place":["Brno, Czechia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akhil","family":"Kumar","sequence":"additional","affiliation":[{"name":"Amity School of Biological Sciences, Amity University Punjab","place":["Mohali, Punjab, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amit","family":"Khairnar","sequence":"additional","affiliation":[{"name":"International Clinical Research Centre, St. Anne University Hospital","place":["Brno, Czechia"]},{"name":"International Clinical Research Centre, Faculty of Medicine, Masaryk University","place":["Brno, Czechia"]},{"name":"Department of Physiology, Faculty of Medicine, Masaryk University","place":["Brno, Czechia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Viswanath","family":"Das","sequence":"additional","affiliation":[{"name":"Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palack\u00fd University and University Hospital Olomouc","place":["Olomouc, Czechia"]},{"name":"Institute of Molecular and Translational Medicine, Czech Advanced Technologies and Research Institute, Palack\u00fd University Olomouc","place":["Olomouc, Czechia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sudeep","family":"Roy","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Faculty of Electrical Engineering and Communication, Brno University of Technology","place":["Brno, Czechia"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,25]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1016\/j.neurobiolaging.2020.04.012","article-title":"Resveratrol-mediated cleavage of amyloid \u03b21-42 peptide: potential relevance to Alzheimer\u2019s disease","volume":"94","author":"Al-Edresi","year":"2020","journal-title":"Neurobiol. 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