{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T13:08:35Z","timestamp":1791896915345,"version":"4.3.4"},"reference-count":42,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2025,9,3]],"date-time":"2025-09-03T00:00:00Z","timestamp":1756857600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT","award":["RS-2023-00208567"],"award-info":[{"award-number":["RS-2023-00208567"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Neuroinflammation plays a central role in the pathogenesis of Alzheimer\u2019s disease (AD), with amyloid-\u03b2 (A\u03b2) deposition and neurofibrillary tangles driving both central and peripheral inflammatory responses. This study investigated the neuroprotective and anti-inflammatory effects of Vitex trifolia (VT), Plantago major (PM), Apocyni Veneti Folium (AVF), and Eucommiae folium (EF) using network pharmacology and a co-culture model of PC12 neuronal and Caco-2 intestinal epithelial cells. Bioactive compounds were identified via high-performance liquid chromatography (HPLC) and screened with network pharmacology analysis, yielding 27 for VT, 10 for PM, 6 for AVF, and 3 for EF. Molecular docking confirmed strong binding affinities between the key bioactive compounds and AD-related targets. A co-culture system of PC12 neuronal and Caco-2 intestinal epithelial cells was established to evaluate the effects of VT, PM, AVF, and EF extracts (at concentrations of 10 \u00b5g\/mL, 20 \u00b5g\/mL, and 50 \u00b5g\/mL) and donepezil hydrochloride (positive-control) on A\u03b225\u201335-induced neurotoxicity and lipopolysaccharide (LPS)-induced intestinal inflammation, to assess cell viability, and effects on oxidative stress, mitochondrial function, and inflammatory markers. The VT, PM, AVF, and EF extracts activated phosphoinositide 3-kinase (PI3K)-Akt-glycogen synthase kinase-3\u03b2 (GSK-3\u03b2) signaling, enhanced phosphorylation of AMP kinase, suggesting inhibition of A\u03b2 accumulation and tau hyperphosphorylation (p &lt; 0.05). However, donepezil hydrochloride only enhanced AMPK phosphorylation. The extracts reduced lipid peroxidation and acetylcholinesterase by about 5-fold. JC-1 staining confirmed preserved mitochondrial membrane potential, while hematoxylin and eosin staining indicated improved intestinal barrier integrity (p &lt; 0.05). PM and AVF reduced the number of mast cells (p &lt; 0.05). In conclusion, these findings highlight the multi-target potential of VT, PM, AVF, and EF in mitigating both neuronal and intestinal inflammation. Their dual regulatory effects on the gut\u2013brain axis suggest promising therapeutic applications in AD through the modulation of central and peripheral immune responses.<\/jats:p>","DOI":"10.3390\/ijms26178545","type":"journal-article","created":{"date-parts":[[2025,9,3]],"date-time":"2025-09-03T08:04:15Z","timestamp":1756886655000},"page":"8545","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Network Pharmacology-Guided Discovery of Traditional Chinese Medicine Extracts for Alzheimer\u2019s Disease: Targeting Neuroinflammation and Gut\u2013Brain Axis Dysfunction"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5949-3941","authenticated-orcid":false,"given":"Ting","family":"Zhang","sequence":"first","affiliation":[{"name":"Key Laboratory of Biological Resources and Ecology of Pamirs Plateau in Xinjiang Uygur Autonomous Region, College of Life and Geographic Sciences, Kashi University, Kashi 844000, China"},{"name":"Department of Bioconvergence, Hoseo University, Asan 31499, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6092-8340","authenticated-orcid":false,"given":"Sunmin","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Bioconvergence, Hoseo University, Asan 31499, Republic of Korea"},{"name":"Department of Food and Nutrition, Obesity\/Diabetes Research Center, Hoseo University, Asan 31499, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1016\/S1474-4422(20)30440-3","article-title":"New insights into atypical Alzheimer\u2019s disease in the era of biomarkers","volume":"20","author":"Yong","year":"2021","journal-title":"Lancet. 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