{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T00:56:14Z","timestamp":1794012974932,"version":"4.8.0"},"reference-count":42,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2025,3,7]],"date-time":"2025-03-07T00:00:00Z","timestamp":1741305600000},"content-version":"vor","delay-in-days":65,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,1,1]],"date-time":"2025-01-01T00:00:00Z","timestamp":1735689600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81870943"],"award-info":[{"award-number":["81870943"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Mediators of Inflammation"],"published-print":{"date-parts":[[2025,1]]},"abstract":"<jats:p>\n                    <jats:bold>Background:<\/jats:bold>\n                    Diabetes can cause an increase in intracellular glucose, leading to neuronal damage and microvascular dysfunction. Neuroprotective agents 1\n                    <jats:italic>\u03b1<\/jats:italic>\n                    ,25\u2010dihydroxyvitamin D3 (1,25\u2010D3) can reduce neurological complications. The main purpose of this study is to evaluate the levels of inflammatory factors and vascular protective factors in streptozotocin (STZ)\u2010induced diabetic rats and determine whether 1,25\u2010D3 can protect the rat brains from hyperglycemia through the glucagon\u2010like peptide\u20101 (GLP\u20101)R\/PI3K\/AKT signal pathway.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Methods:<\/jats:bold>\n                    We first evaluated whether the relevant target could effectively bind to 1,25\u2010D3 through molecular docking. Next, we established STZ\u2010induced diabetic rat models for in vivo experiments to verify the targets in molecular docking that have good binding effects on 1,25\u2010D3. After 8 weeks of a high\u2010fat diet (HFD) and an intraperitoneal injection of STZ (35\u2009mg\/kg body weight), the experimental type 2 diabetic rat model was created, and the morphological changes of the cerebral cortex were measured by performing hematoxylin and eosin (H&amp;E) staining. Western blotting (WB) was used to detect the proteins\u2019 expression of relevant targets, and the RT\u2010qPCR was used to analyze the mRNA levels of relevant targets in the cerebral cortex. We also utilized the enzyme\u2010linked immunosorbent assay (ELISA) kit for detecting the protein content of relevant targets.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Results:<\/jats:bold>\n                    Molecular docking showed that 1,25\u2010D3 had good binding ability with related targets, such as GLP\u20101R, PI3K, AKT1, vascular endothelial growth factor\u2010\n                    <jats:italic>\u03b1<\/jats:italic>\n                    (VEGF\u2010\n                    <jats:italic>\u03b1<\/jats:italic>\n                    ), endothelial nitric oxide (NO) synthase (e\u2010NOS), intercellular adhesion molecule\u20101 (ICAM\u20101), and vascular intercellular adhesion molecule\u20101 (VCAM\u20101). Experimental verification results found that 1,25\u2010D3 partially prevented abnormalities in brain function and structure caused by diabetes. Meanwhile, the ICAM\u20101 and VCAM\u20101 levels were increased in the high\u2010glucose group, e\u2010NOS levels were decreased, and the relative expression of GLP\u20101R, VEGF\u2010\n                    <jats:italic>\u03b1<\/jats:italic>\n                    , p\u2010PI3K\/PI3K, and p\u2010AKT\/AKT was reduced. 1,25\u2010D3 abolished these changes, and these effects were suppressed by specific inhibitors.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>Conclusions:<\/jats:bold>\n                    1,25\u2010D3 alleviates neuroinflammation and improves vascular endothelial dysfunction through multitarget and multipathway by upregulating the GLP\u20101R\/PI3K\/AKT signaling axis to improve diabetes\u2010induced brain injury.\n                  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