{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T13:29:42Z","timestamp":1787923782659,"version":"build-2784847793"},"reference-count":37,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T00:00:00Z","timestamp":1787875200000},"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>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Alzheimer's disease (AD) progression involves cerebral microvascular endothelial cell senescence induced by brain hypoperfusion, which contributes to blood-brain barrier (BBB) dysfunction. While Notch1 signaling is known to exacerbate endothelial senescence and neuroinflammation via vascular cell adhesion molecule-1 (VCAM-1), the mechanism by which it mediates hypoxia-induced endothelial aging in AD remains unclear. Furthermore, although Astragaloside IV (AS-IV) has been shown to alleviate cerebral hypoperfusion in AD, whether it acts by directly modulating the Notch1\/VCAM-1 axis is unknown. This study aimed to determine whether AS-IV mitigates endothelial senescence and AD pathology by modulating the Notch1\/VCAM-1 pathway.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Transcriptomic analysis of AD patient data and network pharmacology identified\n                      <jats:italic>NOTCH1<\/jats:italic>\n                      as a key target. Molecular docking and 100-ns molecular dynamics simulations (using Desmond) characterized AS-IV\u2013Notch1 interactions. Human brain microvascular endothelial cells (HBMECs) were subjected to hypoxia-reoxygenation (HR) to model AD-associated hypoperfusion. Cells were treated with AS-IV (25, 50, or 100 \u03bcM) or N-acetylcysteine (NAC) as a positive antioxidant control. Notch1 signaling was experimentally modulated using a recombinant decoy receptor to simulate signaling blockade, creating a contrast with HR-induced overactivation. Assessments included CCK-8 assays, MDA and ROS detection, qPCR, and Western blotting.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      <jats:italic>NOTCH1<\/jats:italic>\n                      expression was upregulated in AD patients. Molecular docking and dynamics simulations predicted a stable binding mode between AS-IV and Notch1. HR exposure significantly increased oxidative stress and upregulated senescence markers (p16, p21, and p53), proinflammatory senescence-associated secretory phenotype (SASP) factors (IL-6, IL-1\u03b2, and TNF-\u03b1), and Notch1\/VCAM-1 expression. Conversely, AS-IV treatment improved cell viability, reduced oxidative stress (with efficacy comparable to NAC), and downregulated Notch1\/VCAM-1, senescence, and SASP markers. Notably, perturbing Notch signaling, either through HR-induced overactivation or decoy receptor-mediated blockade, exacerbated the senescent phenotype. Importantly, AS-IV co-treatment effectively rescued cellular damage induced by both forms of Notch pathway dysregulation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>AS-IV alleviates HR-induced endothelial senescence by modulating the Notch1\/VCAM-1 axis. Our data suggest that AS-IV does not merely inhibit Notch1 but acts by modulating its signaling toward a protective equilibrium, thereby attenuating endothelial senescence and inflammation associated with the restoration of Notch1\/VCAM-1 signaling balance. These findings highlight the potential of AS-IV as a therapeutic candidate for AD vascular pathology.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fnagi.2026.1855522","type":"journal-article","created":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T12:50:34Z","timestamp":1787921434000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Astragaloside IV attenuates hypoxia-reoxygenation-induced endothelial senescence and vascular inflammation by modulating the NOTCH1\/VCAM-1 axis"],"prefix":"10.3389","volume":"18","author":[{"given":"Dehui","family":"Huang","sequence":"first","affiliation":[{"name":"Ningbo Municipal Hospital of Traditional Chinese Medicine (TCM), Affiliated Hospital of Zhejiang Chinese Medical University","place":["Ningbo, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rongjing","family":"Zhou","sequence":"additional","affiliation":[{"name":"Ningbo Municipal Hospital of Traditional Chinese Medicine (TCM), Affiliated Hospital of Zhejiang Chinese Medical University","place":["Ningbo, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Ling","sequence":"additional","affiliation":[{"name":"Ningbo Municipal Hospital of Traditional Chinese Medicine (TCM), Affiliated Hospital of Zhejiang Chinese Medical University","place":["Ningbo, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1038\/nrd4252","volume":"13","author":"Andersson","year":"2014","journal-title":"Nat. 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