{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T17:52:05Z","timestamp":1792173125667,"version":"4.4.0"},"reference-count":68,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2025,2,13]],"date-time":"2025-02-13T00:00:00Z","timestamp":1739404800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the National Key Research and Development Program of China","award":["2018YFE0127000"],"award-info":[{"award-number":["2018YFE0127000"]}]},{"name":"the National Key Research and Development Program of China","award":["32272967"],"award-info":[{"award-number":["32272967"]}]},{"name":"the National Key Research and Development Program of China","award":["2020QFY10-04"],"award-info":[{"award-number":["2020QFY10-04"]}]},{"name":"the National Key Research and Development Program of China","award":["242102111037"],"award-info":[{"award-number":["242102111037"]}]},{"name":"Japanese Society of Eucommia, the National Natural Science Foundation of China","award":["2018YFE0127000"],"award-info":[{"award-number":["2018YFE0127000"]}]},{"name":"Japanese Society of Eucommia, the National Natural Science Foundation of China","award":["32272967"],"award-info":[{"award-number":["32272967"]}]},{"name":"Japanese Society of Eucommia, the National Natural Science Foundation of China","award":["2020QFY10-04"],"award-info":[{"award-number":["2020QFY10-04"]}]},{"name":"Japanese Society of Eucommia, the National Natural Science Foundation of China","award":["242102111037"],"award-info":[{"award-number":["242102111037"]}]},{"name":"Shaanxi Provincial Regional Innovation Capability Guiding Plan Project","award":["2018YFE0127000"],"award-info":[{"award-number":["2018YFE0127000"]}]},{"name":"Shaanxi Provincial Regional Innovation Capability Guiding Plan Project","award":["32272967"],"award-info":[{"award-number":["32272967"]}]},{"name":"Shaanxi Provincial Regional Innovation Capability Guiding Plan Project","award":["2020QFY10-04"],"award-info":[{"award-number":["2020QFY10-04"]}]},{"name":"Shaanxi Provincial Regional Innovation Capability Guiding Plan Project","award":["242102111037"],"award-info":[{"award-number":["242102111037"]}]},{"name":"Key Science and Technology Program of Henan Province","award":["2018YFE0127000"],"award-info":[{"award-number":["2018YFE0127000"]}]},{"name":"Key Science and Technology Program of Henan Province","award":["32272967"],"award-info":[{"award-number":["32272967"]}]},{"name":"Key Science and Technology Program of Henan Province","award":["2020QFY10-04"],"award-info":[{"award-number":["2020QFY10-04"]}]},{"name":"Key Science and Technology Program of Henan Province","award":["242102111037"],"award-info":[{"award-number":["242102111037"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Ischemic stroke ranks as the second leading cause of global mortality. The limited time for effective thrombolytic treatment has prompted the exploration of alternative prevention approaches. Eucommia ulmoides (E. ulmoides) Oliv. bark has shown multiple pharmacological effects, including neuroprotection, anti-inflammation and autophagy modulation. This study aims to elucidate the neuroprotective effects of water extract of E. ulmoides (WEU) supplementation in a middle cerebral artery occlusion (MCAO) mouse model and to further explore the underlying molecular mechanisms. Seven bioactive compounds in WEU\u2014aucubin, chlorogenic acid, geniposidic acid, quercetin, protocatechuic acid, betulin and pinoresinol diglucoside\u2014were identified using HPLC-MS. Our results showed that WEU supplementation significantly decreased infarct volume and ameliorated neurological dysfunction in mice following MCAO\/reperfusion (MCAO\/R) injury. Furthermore, the administration of WEU significantly attenuated microglia activation induced by cortical ischemia in mice and inhibited the production of pro-inflammatory mediators, including interleukin-1\u03b2 (IL-1\u03b2), interleukin-6 (IL-6) and tumor necrosis factor-\u03b1 (TNF-\u03b1). Importantly, in contrast with the vehicle group, the protein expression levels of Toll-like receptor 4 (TLR4), phospho-p38 (p-p38) and nuclear factor kappa B (NF-\u03baB) were reduced in the WEU group. Therefore, this present study provides evidence that E. ulmoides improves neurological behaviors by suppressing neuroinflammation and inhibiting the activation of the TLR4\/ p38 MAPK and NF-\u03baB pathways in mice after ischemia, which indicates that E.ulmoides is a promising candidate for alleviating gray matter ischemic change.<\/jats:p>","DOI":"10.3390\/ijms26041572","type":"journal-article","created":{"date-parts":[[2025,2,13]],"date-time":"2025-02-13T05:10:22Z","timestamp":1739423422000},"page":"1572","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Eucommia ulmoides Oliv. Bark Extracts Alleviate MCAO\/Reperfusion-Induced Neurological Dysfunction by Suppressing Microglial Inflammation in the Gray Matter"],"prefix":"10.3390","volume":"26","author":[{"given":"Jiarong","family":"Pan","sequence":"first","affiliation":[{"name":"College of Veterinary Medicine, Northwest A&F University, Yangling 712100, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuejun","family":"Chai","sequence":"additional","affiliation":[{"name":"College of Basic Medicine, Xi\u2019an Medical University, Xi\u2019an 710021, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cixia","family":"Li","sequence":"additional","affiliation":[{"name":"College of Life Science and Technology, Xinxiang Medical University, Xinxiang 453003, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongji","family":"Wu","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine, Northwest A&F University, Yangling 712100, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Ma","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine, Northwest A&F University, Yangling 712100, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Songlin","family":"Wang","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine, Northwest A&F University, Yangling 712100, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhuan","family":"Xue","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine, Northwest A&F University, Yangling 712100, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongkang","family":"Zhao","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine, Northwest A&F University, Yangling 712100, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shulin","family":"Chen","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine, Northwest A&F University, Yangling 712100, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6967-8942","authenticated-orcid":false,"given":"Xiaoyan","family":"Zhu","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine, Northwest A&F University, Yangling 712100, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2619-4467","authenticated-orcid":false,"given":"Shanting","family":"Zhao","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine, Northwest A&F University, Yangling 712100, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,2,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1161\/CIRCULATIONAHA.116.025250","article-title":"Prevalence, Incidence, and Mortality of Stroke in China: Results from a Nationwide Population-Based Survey of 480\u2009687 Adults","volume":"135","author":"Wang","year":"2017","journal-title":"Circulation"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Jia, J., Yang, L., Chen, Y., Zheng, L., Chen, Y., Xu, Y., and Zhang, M. (2021). The Role of Microglial Phagocytosis in Ischemic Stroke. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.790201"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Lian, L., Zhang, Y., Liu, L., Yang, L., Cai, Y., Zhang, J., and Xu, S. (2020). Neuroinflammation in Ischemic Stroke: Focus on MicroRNA-mediated Polarization of Microglia. Front. Mol. Neurosci., 13.","DOI":"10.3389\/fnmol.2020.612439"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"113518","DOI":"10.1016\/j.expneurol.2020.113518","article-title":"Emerging neuroprotective strategies for the treatment of ischemic stroke: An overview of clinical and preclinical studies","volume":"335","author":"Paul","year":"2021","journal-title":"Exp. Neurol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1500","DOI":"10.1177\/0271678X17700913","article-title":"Imaging the physiological evolution of the ischemic penumbra in acute ischemic stroke","volume":"38","author":"Leigh","year":"2018","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1007\/s00415-018-8933-5","article-title":"Time window and \u201ctissue window\u201d: Two approaches to assist decision-making in strokes","volume":"266","author":"Xiang","year":"2019","journal-title":"J. Neurol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1007\/s11655-019-3064-0","article-title":"Network Pharmacology in Research of Chinese Medicine Formula: Methodology, Application and Prospective","volume":"26","author":"Luo","year":"2020","journal-title":"Chin. J. Integr. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1038\/nchembio.118","article-title":"Network pharmacology: The next paradigm in drug discovery","volume":"4","author":"Hopkins","year":"2008","journal-title":"Nat. Chem. Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"7129","DOI":"10.1073\/pnas.1820799116","article-title":"From single drug targets to synergistic network pharmacology in ischemic stroke","volume":"116","author":"Casas","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"105650","DOI":"10.1016\/j.phrs.2021.105650","article-title":"Xiao-Xu-Ming decoction prevented hemorrhagic transformation induced by acute hyperglycemia through inhibiting AGE-RAGE-mediated neuroinflammation","volume":"169","author":"Liu","year":"2021","journal-title":"Pharmacol. Res."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Yu, P., Wang, J., Liu, J., Zhou, Y., Luo, F., Yang, M., and Ai, X. (2024). Preparation techniques, structural features, and bioactivities of Eucommia ulmoides polysaccharides: A review. Int. J. Biol. Macromol., 275.","DOI":"10.1016\/j.ijbiomac.2024.133686"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.jep.2013.11.023","article-title":"Eucommia ulmoides Oliv.: Ethnopharmacology, phytochemistry and pharmacology of an important traditional Chinese medicine","volume":"151","author":"He","year":"2014","journal-title":"J. Ethnopharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"5202908","DOI":"10.1155\/2016\/5202908","article-title":"Health-Promoting Properties of Eucommia ulmoides: A Review","volume":"2016","author":"Hussain","year":"2016","journal-title":"Evid. -Based Complement. Altern. Med. eCAM"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1142\/S0192415X19500137","article-title":"Ethnobotany, Phytochemistry and Pharmacological Properties of Eucommia ulmoides: A Review","volume":"47","author":"Wang","year":"2019","journal-title":"Am. J. Chin. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.neulet.2010.10.042","article-title":"Neuroprotective effects of Eucommia ulmoides Oliv. Bark on amyloid beta(25-35)-induced learning and memory impairments in mice","volume":"487","author":"Kwon","year":"2011","journal-title":"Neurosci. Lett."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"462","DOI":"10.4062\/biomolther.2013.074","article-title":"Inhibitory Effects of Eucommia ulmoides Oliv. Bark on Scopolamine-Induced Learning and Memory Deficits in Mice","volume":"21","author":"Kwon","year":"2013","journal-title":"Biomol. Ther."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"113016","DOI":"10.1016\/j.jep.2020.113016","article-title":"Anti-neuroinflammatory effects of Eucommia ulmoides Oliv. In a Parkinson\u2019s mouse model through the regulation of p38\/JNK-Fosl2 gene expression","volume":"260","author":"Fan","year":"2020","journal-title":"J. Ethnopharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2232","DOI":"10.1136\/gutjnl-2020-322260","article-title":"Mucus barrier, mucins and gut microbiota: The expected slimy partners?","volume":"69","author":"Paone","year":"2020","journal-title":"Gut"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1016\/j.jep.2012.04.010","article-title":"Eucommia ulmoides Oliv. Bark. protects against hydrogen peroxide-induced neuronal cell death in SH-SY5Y cells","volume":"142","author":"Kwon","year":"2012","journal-title":"J. Ethnopharmacol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Lee, H.S., Kim, J.M., Lee, H.L., Go, M.J., Lee, D.Y., Kim, C.-W., Kim, H.-J., and Heo, H.J. (2024). Eucommia ulmoides Leaves Alleviate Cognitive Dysfunction in Dextran Sulfate Sodium (DSS)-Induced Colitis Mice through Regulating JNK\/TLR4 Signaling Pathway. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25074063"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2098","DOI":"10.1016\/j.euroneuro.2015.08.004","article-title":"Microglial activation in the rat brain following chronic antipsychotic treatment at clinically relevant doses","volume":"25","author":"Cotel","year":"2015","journal-title":"Eur. Neuropsychopharmacol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/0361-9230(94)90189-9","article-title":"Cellular forms and functions of brain microglia","volume":"34","author":"Davis","year":"1994","journal-title":"Brain Res. Bull."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.jneumeth.2014.01.017","article-title":"Sholl analysis: A quantitative comparison of semi-automated methods","volume":"225","author":"Binley","year":"2014","journal-title":"J. Neurosci. Methods"},{"key":"ref_24","first-page":"387","article-title":"Dendritic organization in the neurons of the visual and motor cortices of the cat","volume":"87","author":"Sholl","year":"1953","journal-title":"J. Anat."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Barthels, D., and Das, H. (2020). Current advances in ischemic stroke research and therapies. Biochim. Biophys. Acta Mol. Basis Dis., 1866.","DOI":"10.1016\/j.bbadis.2018.09.012"},{"key":"ref_26","first-page":"415","article-title":"Recovery After Stroke","volume":"26","author":"Cramer","year":"2020","journal-title":"Continuum"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1179\/1476830514Y.0000000146","article-title":"Cognitive and neuroprotective effects of chlorogenic acid","volume":"20","author":"Heitman","year":"2017","journal-title":"Nutr. Neurosci."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3175214","DOI":"10.1155\/2018\/3175214","article-title":"Aqueous Extract of Dendropanax morbiferus Leaves Effectively Alleviated Neuroinflammation and Behavioral Impediments in MPTP-Induced Parkinson\u2019s Mouse Model","volume":"2018","author":"Park","year":"2018","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/j.jep.2013.12.048","article-title":"Eucommia ulmoides Oliv. bark. attenuates 6-hydroxydopamine-induced neuronal cell death through inhibition of oxidative stress in SH-SY5Y cells","volume":"152","author":"Kwon","year":"2014","journal-title":"J. Ethnopharmacol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"172857","DOI":"10.1016\/j.ejphar.2019.172857","article-title":"Geniposidic acid ameliorates spatial learning and memory deficits and alleviates neuroinflammation via inhibiting HMGB-1 and downregulating TLR4\/2 signaling pathway in APP\/PS1 mice","volume":"869","author":"Zhou","year":"2020","journal-title":"Eur. J. Pharmacol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1161\/CIRCULATIONAHA.120.045765","article-title":"Extracellular Vesicle-Mediated Delivery of Circular RNA SCMH1 Promotes Functional Recovery in Rodent and Nonhuman Primate Ischemic Stroke Models","volume":"142","author":"Yang","year":"2020","journal-title":"Circulation"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1038\/nrn.2017.26","article-title":"Motor compensation and its effects on neural reorganization after stroke","volume":"18","author":"Jones","year":"2017","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1016\/S1474-4422(18)30290-4","article-title":"Traditional Chinese medicine for ischaemic stroke","volume":"17","author":"Liu","year":"2018","journal-title":"Lancet Neurol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"110","DOI":"10.3724\/SP.J.1009.2013.00110","article-title":"Traditional Chinese medicine network pharmacology: Theory, methodology and application","volume":"11","author":"Li","year":"2013","journal-title":"Chin. J. Nat. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1161\/CIRCRESAHA.116.308022","article-title":"Inflammatory Disequilibrium in Stroke","volume":"119","author":"Goonewardena","year":"2016","journal-title":"Circ. Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"834","DOI":"10.1007\/s12265-013-9508-6","article-title":"Role of inflammation and its mediators in acute ischemic stroke","volume":"6","author":"Jin","year":"2013","journal-title":"J. Cardiovasc. Transl. Res."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Yang, S., Wang, H., Yang, Y., Wang, R., Wang, Y., Wu, C., and Du, G. (2019). Baicalein administered in the subacute phase ameliorates ischemia-reperfusion-induced brain injury by reducing neuroinflammation and neuronal damage. Biomed. Pharmacother., 117.","DOI":"10.1016\/j.biopha.2019.109102"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1093\/brain\/awn109","article-title":"Debris clearance by microglia: An essential link between degeneration and regeneration","volume":"132","author":"Neumann","year":"2009","journal-title":"Brain J. Neurol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1007\/s13311-016-0483-x","article-title":"Inflammation and Stroke: An Overview","volume":"13","author":"Anrather","year":"2016","journal-title":"Neurotherapeutics"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1161\/01.STR.0000259709.16654.8f","article-title":"Absence of the chemokine receptor CCR2 protects against cerebral ischemia\/reperfusion injury in mice","volume":"38","author":"Dimitrijevic","year":"2007","journal-title":"Stroke"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1677","DOI":"10.1038\/jcbfm.2012.88","article-title":"Inflammatory cytokines in experimental and human stroke","volume":"32","author":"Lambertsen","year":"2012","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1186\/s12974-015-0329-1","article-title":"Functional differences between microglia and monocytes after ischemic stroke","volume":"12","author":"Ritzel","year":"2015","journal-title":"J. Neuroinflammation"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"113308","DOI":"10.1016\/j.expneurol.2020.113308","article-title":"Neuroprotective and neuro-rehabilitative effects of acute purinergic receptor P2X4 (P2X4R) blockade after ischemic stroke","volume":"329","author":"Srivastava","year":"2020","journal-title":"Exp. Neurol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1038\/nn.2341","article-title":"Adenosine A(2A) receptor mediates microglial process retraction","volume":"12","author":"Orr","year":"2009","journal-title":"Nat. Neurosci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1016\/j.immuni.2011.05.006","article-title":"Toll-like receptors and their crosstalk with other innate receptors in infection and immunity","volume":"34","author":"Kawai","year":"2011","journal-title":"Immunity"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1128\/CMR.16.4.637-646.2003","article-title":"Role of Toll-like receptors in pathogen recognition","volume":"16","author":"Janssens","year":"2003","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1016\/j.neuroscience.2010.08.054","article-title":"Toll-like receptor 4 (TLR4), but not TLR3 or TLR9, knock-out mice have neuroprotective effects against focal cerebral ischemia","volume":"171","author":"Hyakkoku","year":"2010","journal-title":"Neuroscience"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.jneuroim.2016.03.003","article-title":"Splenectomy following MCAO inhibits the TLR4-NF-\u03baB signaling pathway and protects the brain from neurodegeneration in rats","volume":"293","author":"Belinga","year":"2016","journal-title":"J. Neuroimmunol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.brainres.2013.06.032","article-title":"Neuroprotective effect of bicyclol in rat ischemic stroke: Down-regulates TLR4, TLR9, TRAF6, NF-\u03baB, MMP-9 and up-regulates claudin-5 expression","volume":"1528","author":"Zhang","year":"2013","journal-title":"Brain Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1111\/j.1749-6632.2010.05735.x","article-title":"NF-\u03baB and innate immunity in ischemic stroke","volume":"1207","author":"Harari","year":"2010","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1038\/s41419-020-03278-z","article-title":"TRAF3 mediates neuronal apoptosis in early brain injury following subarachnoid hemorrhage via targeting TAK1-dependent MAPKs and NF-\u03baB pathways","volume":"12","author":"Zhou","year":"2021","journal-title":"Cell Death Dis."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.jep.2014.12.061","article-title":"Eucommia ulmoides Oliv. bark aqueous extract inhibits osteoarthritis in a rat model of osteoarthritis","volume":"162","author":"Xie","year":"2015","journal-title":"J. Ethnopharmacol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1097\/01.WCB.0000125365.83980.00","article-title":"Progesterone enhances functional recovery after middle cerebral artery occlusion in male mice","volume":"24","author":"Gibson","year":"2004","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1016\/j.jad.2023.04.117","article-title":"Eucommiae cortex polysaccharides attenuate gut microbiota dysbiosis and neuroinflammation in mice exposed to chronic unpredictable mild stress: Beneficial in ameliorating depressive-like behaviors","volume":"334","author":"Wang","year":"2023","journal-title":"J. Affect. Disord."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"3637","DOI":"10.7150\/thno.72756","article-title":"Eucommiae cortex polysaccharides mitigate obesogenic diet-induced cognitive and social dysfunction via modulation of gut microbiota and tryptophan metabolism","volume":"12","author":"Sun","year":"2022","journal-title":"Theranostics"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.plaphy.2012.02.016","article-title":"ROS signaling as common element in low oxygen and heat stresses","volume":"59","author":"Pucciariello","year":"2012","journal-title":"Plant Physiol. Biochem."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1016\/j.expneurol.2006.09.006","article-title":"Sensorimotor and cognitive deficits after transient middle cerebral artery occlusion in the mouse","volume":"203","author":"Freret","year":"2007","journal-title":"Exp. Neurol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.bbr.2018.11.040","article-title":"Behavioral tests that reveal long-term deficits after permanent focal cerebral ischemia in mouse","volume":"360","author":"Margaill","year":"2019","journal-title":"Behav. Brain Res."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"882","DOI":"10.3171\/jns.1985.62.6.0882","article-title":"High-dose glucocorticoid treatment improves neurological recovery in head-injured mice","volume":"62","author":"Hall","year":"1985","journal-title":"J. Neurosurg."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1304","DOI":"10.1161\/01.STR.17.6.1304","article-title":"Evaluation of 2,3,5-triphenyltetrazolium chloride as a stain for detection and quantification of experimental cerebral infarction in rats","volume":"17","author":"Bederson","year":"1986","journal-title":"Stroke"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"108038","DOI":"10.1016\/j.neuropharm.2020.108038","article-title":"Dose-dependent and long-term cerebroprotective effects of intranasal delivery of progesterone after ischemic stroke in male mice","volume":"170","author":"Zhu","year":"2020","journal-title":"Neuropharmacology"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1.2.1","DOI":"10.1002\/cpbi.27","article-title":"Searching Online Mendelian Inheritance in Man (OMIM): A Knowledgebase of Human Genes and Genetic Phenotypes","volume":"58","author":"Amberger","year":"2017","journal-title":"Curr. Protoc. Bioinform."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1.30.1","DOI":"10.1002\/cpbi.5","article-title":"The GeneCards Suite: From Gene Data Mining to Disease Genome Sequence Analyses","volume":"54","author":"Stelzer","year":"2016","journal-title":"Curr. Protoc. Bioinform."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"D1074","DOI":"10.1093\/nar\/gkx1037","article-title":"DrugBank 5.0: A major update to the DrugBank database for 2018","volume":"46","author":"Wishart","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Fern\u00e1ndez-Arjona, M.D.M., Grondona, J.M., Granados-Dur\u00e1n, P., Fern\u00e1ndez-Llebrez, P., and L\u00f3pez-\u00c1valos, M.D. (2017). Microglia Morphological Categorization in a Rat Model of Neuroinflammation by Hierarchical Cluster and Principal Components Analysis. Front. Cell. Neurosci., 11.","DOI":"10.3389\/fncel.2017.00235"},{"key":"ref_67","first-page":"57648","article-title":"Quantifying Microglia Morphology from Photomicrographs of Immunohistochemistry Prepared Tissue Using ImageJ","volume":"136","author":"Young","year":"2018","journal-title":"J. Vis. Exp."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"e2200711","DOI":"10.1002\/mnfr.202200711","article-title":"Ketogenic Diet Alleviates Hypoglycemia-Induced Neuroinflammation via Modulation the Gut Microbiota in Mice","volume":"67","author":"Li","year":"2023","journal-title":"Mol. Nutr. Food Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/4\/1572\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T16:32:52Z","timestamp":1760027572000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/4\/1572"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,13]]},"references-count":68,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2025,2]]}},"alternative-id":["ijms26041572"],"URL":"https:\/\/doi.org\/10.3390\/ijms26041572","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,2,13]]}}}