{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T03:46:34Z","timestamp":1763696794373,"version":"3.45.0"},"reference-count":37,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T00:00:00Z","timestamp":1763683200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"},{"start":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T00:00:00Z","timestamp":1763683200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"}],"funder":[{"name":"the hospital-level research project of the affiliated Hospital of Xuzhou Medical University","award":["2022ZL20"],"award-info":[{"award-number":["2022ZL20"]}]},{"name":"the medical science and technology innovation project of Xuzhou Municipal Health Commission","award":["XWKYHT20230067"],"award-info":[{"award-number":["XWKYHT20230067"]}]},{"name":"the Construction Project of High Level Hospital of Jiangsu Province","award":["LCZX202412"],"award-info":[{"award-number":["LCZX202412"]}]},{"name":"the Project Funded by Priority Academic Program Development of Jiangsu Higher Education Institutions","award":["XZSYSKF2022020"],"award-info":[{"award-number":["XZSYSKF2022020"]}]},{"name":"the Xuzhou Science and Technology Program","award":["KC22243"],"award-info":[{"award-number":["KC22243"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Mol Neurobiol"],"published-print":{"date-parts":[[2026,1]]},"DOI":"10.1007\/s12035-025-05439-7","type":"journal-article","created":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T02:33:50Z","timestamp":1763692430000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Mendelian Randomization Unlocks Stroke Therapeutics: Dioscin Inhibits CD27-Driven Neuroinflammation via Gut Microbiota Modulation"],"prefix":"10.1007","volume":"63","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-5175-9833","authenticated-orcid":false,"given":"Haozhou","family":"Tan","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shengli","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Han","family":"Yan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fangfang","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yang","family":"Yao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-2891-9863","authenticated-orcid":false,"given":"Ying","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4752-0770","authenticated-orcid":false,"given":"Qian","family":"Feng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,11,21]]},"reference":[{"key":"5439_CR1","doi-asserted-by":"publisher","first-page":"e153","DOI":"10.1161\/CIR.0000000000001052","volume":"145","author":"CW Tsao","year":"2022","unstructured":"Tsao CW, Aday AW, Almarzooq ZI et al (2022) Heart disease and stroke statistics-2022 update: a report from the American Heart Association. Circulation 145:e153\u2013e639. https:\/\/doi.org\/10.1161\/CIR.0000000000001052","journal-title":"Circulation"},{"key":"5439_CR2","doi-asserted-by":"publisher","first-page":"e279","DOI":"10.1212\/WNL.0000000000013115","volume":"98","author":"Q Ding","year":"2022","unstructured":"Ding Q, Liu S, Yao Y et al (2022) Global, regional, and national burden of ischemic stroke, 1990\u20132019. Neurology 98:e279\u2013e290. https:\/\/doi.org\/10.1212\/WNL.0000000000013115","journal-title":"Neurology"},{"key":"5439_CR3","doi-asserted-by":"publisher","first-page":"2003","DOI":"10.2147\/IJGM.S353276","volume":"15","author":"Q Huang","year":"2022","unstructured":"Huang Q, Cai G, Liu T, Liu Z (2022) Relationships among gut microbiota, ischemic stroke and its risk factors: based on research evidence. Int J Gen Med 15:2003\u20132023. https:\/\/doi.org\/10.2147\/IJGM.S353276","journal-title":"Int J Gen Med"},{"key":"5439_CR4","doi-asserted-by":"publisher","DOI":"10.1097\/MD.0000000000012805","volume":"97","author":"W Wang","year":"2018","unstructured":"Wang W, Li X, Yao X et al (2018) The characteristics analysis of intestinal microecology on cerebral infarction patients and its correlation with apolipoprotein E. Medicine (Baltimore) 97:e12805. https:\/\/doi.org\/10.1097\/MD.0000000000012805","journal-title":"Medicine (Baltimore)"},{"key":"5439_CR5","doi-asserted-by":"publisher","first-page":"7428","DOI":"10.1523\/JNEUROSCI.1114-16.2016","volume":"36","author":"V Singh","year":"2016","unstructured":"Singh V, Roth S, Llovera G et al (2016) Microbiota dysbiosis controls the neuroinflammatory response after stroke. J Neurosci 36:7428\u20137440. https:\/\/doi.org\/10.1523\/JNEUROSCI.1114-16.2016","journal-title":"J Neurosci"},{"key":"5439_CR6","doi-asserted-by":"publisher","DOI":"10.1111\/ene.16226","volume":"31","author":"X Deng","year":"2024","unstructured":"Deng X, Hou S, Wang Y et al (2024) Genetic insights into the relationship between immune cell characteristics and ischemic stroke: a bidirectional mendelian randomization study. Eur J Neurol 31:e16226. https:\/\/doi.org\/10.1111\/ene.16226","journal-title":"Eur J Neurol"},{"key":"5439_CR7","doi-asserted-by":"publisher","DOI":"10.3390\/cells9051072","volume":"9","author":"S Pasquini","year":"2020","unstructured":"Pasquini S, Vincenzi F, Casetta I et al (2020) Adenosinergic system involvement in ischemic stroke patients\u2019 lymphocytes. Cells 9:1072. https:\/\/doi.org\/10.3390\/cells9051072","journal-title":"Cells"},{"key":"5439_CR8","doi-asserted-by":"publisher","first-page":"320","DOI":"10.1111\/cns.12361","volume":"21","author":"Z-J Liu","year":"2015","unstructured":"Liu Z-J, Chen C, Li F-W et al (2015) Splenic responses in ischemic stroke: new insights into stroke pathology. CNS Neurosci Ther 21:320\u2013326. https:\/\/doi.org\/10.1111\/cns.12361","journal-title":"CNS Neurosci Ther"},{"key":"5439_CR9","doi-asserted-by":"publisher","first-page":"e2250233","DOI":"10.1002\/eji.202250233","volume":"53","author":"N Blank-Stein","year":"2023","unstructured":"Blank-Stein N, Mass E (2023) Macrophage and monocyte subsets in response to ischemic stroke. Eur J Immunol 53:e2250233. https:\/\/doi.org\/10.1002\/eji.202250233","journal-title":"Eur J Immunol"},{"key":"5439_CR10","doi-asserted-by":"publisher","first-page":"2825","DOI":"10.1161\/STROKEAHA.124.047820","volume":"55","author":"JJ McCabe","year":"2024","unstructured":"McCabe JJ, Walsh C, Gorey S et al (2024) Interleukin-6, C-reactive protein, and recurrence after stroke: a time-course analysis of individual-participant data. Stroke 55:2825\u20132834. https:\/\/doi.org\/10.1161\/STROKEAHA.124.047820","journal-title":"Stroke"},{"key":"5439_CR11","doi-asserted-by":"publisher","first-page":"867","DOI":"10.1007\/s11481-013-9469-1","volume":"8","author":"CJ Smith","year":"2013","unstructured":"Smith CJ, Lawrence CB, Rodriguez-Grande B et al (2013) The immune system in stroke: clinical challenges and their translation to experimental research. J Neuroimmune Pharmacol 8:867\u2013887. https:\/\/doi.org\/10.1007\/s11481-013-9469-1","journal-title":"J Neuroimmune Pharmacol"},{"key":"5439_CR12","doi-asserted-by":"publisher","first-page":"64","DOI":"10.3390\/ijms17010064","volume":"17","author":"R Shim","year":"2016","unstructured":"Shim R, Wong CHY (2016) Ischemia, immunosuppression and infection\u2013tackling the predicaments of post-stroke complications. Int J Mol Sci 17:64. https:\/\/doi.org\/10.3390\/ijms17010064","journal-title":"Int J Mol Sci"},{"key":"5439_CR13","doi-asserted-by":"publisher","first-page":"1036","DOI":"10.1038\/s41588-020-0684-4","volume":"52","author":"V Orr\u00f9","year":"2020","unstructured":"Orr\u00f9 V, Steri M, Sidore C et al (2020) Complex genetic signatures in immune cells underlie autoimmunity and inform therapy. Nat Genet 52:1036\u20131045. https:\/\/doi.org\/10.1038\/s41588-020-0684-4","journal-title":"Nat Genet"},{"key":"5439_CR14","doi-asserted-by":"publisher","first-page":"1540","DOI":"10.1038\/s41590-023-01588-w","volume":"24","author":"JH Zhao","year":"2023","unstructured":"Zhao JH, Stacey D, Eriksson N et al (2023) Genetics of circulating inflammatory proteins identifies drivers of immune-mediated disease risk and therapeutic targets. Nat Immunol 24:1540\u20131551. https:\/\/doi.org\/10.1038\/s41590-023-01588-w","journal-title":"Nat Immunol"},{"key":"5439_CR15","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1038\/s41588-021-00992-y","volume":"54","author":"EA Lopera-Maya","year":"2022","unstructured":"Lopera-Maya EA, Kurilshikov A, van der Graaf A et al (2022) Effect of host genetics on the gut microbiome in 7,738 participants of the Dutch Microbiome Project. Nat Genet 54:143\u2013151. https:\/\/doi.org\/10.1038\/s41588-021-00992-y","journal-title":"Nat Genet"},{"key":"5439_CR16","doi-asserted-by":"publisher","first-page":"524","DOI":"10.1038\/s41588-018-0058-3","volume":"50","author":"R Malik","year":"2018","unstructured":"Malik R, Chauhan G, Traylor M et al (2018) Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes. Nat Genet 50:524\u2013537. https:\/\/doi.org\/10.1038\/s41588-018-0058-3","journal-title":"Nat Genet"},{"key":"5439_CR17","doi-asserted-by":"publisher","first-page":"2333","DOI":"10.1177\/0962280215597579","volume":"26","author":"S Burgess","year":"2017","unstructured":"Burgess S, Small DS, Thompson SG (2017) A review of instrumental variable estimators for Mendelian randomization. Stat Methods Med Res 26:2333\u20132355. https:\/\/doi.org\/10.1177\/0962280215597579","journal-title":"Stat Methods Med Res"},{"key":"5439_CR18","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1177\/0962280210394459","volume":"21","author":"TM Palmer","year":"2012","unstructured":"Palmer TM, Lawlor DA, Harbord RM et al (2012) Using multiple genetic variants as instrumental variables for modifiable risk factors. Stat Methods Med Res 21:223\u2013242. https:\/\/doi.org\/10.1177\/0962280210394459","journal-title":"Stat Methods Med Res"},{"key":"5439_CR19","doi-asserted-by":"publisher","unstructured":"Jinghui, Zhong Huan, Cai Zhizhong, Zhang Jinjing, Wang Lulu, Xiao Pan, Zhang Yingjie, Xu Wenqing, Tu Wusheng, Zhu Xinfeng, Liu Wen, Sun (2024) Serum uric acid and prognosis of ischemic stroke: Cohort study meta-analysis and Mendelian randomization study. European Stroke Journal 9(1) 235\u2013243.\u00a0https:\/\/doi.org\/10.1177\/23969873231209620","DOI":"10.1177\/23969873231209620"},{"key":"5439_CR20","doi-asserted-by":"publisher","first-page":"658","DOI":"10.1002\/gepi.21758","volume":"37","author":"S Burgess","year":"2013","unstructured":"Burgess S, Butterworth A, Thompson SG (2013) Mendelian randomization analysis with multiple genetic variants using summarized data. Genet Epidemiol 37:658\u2013665. https:\/\/doi.org\/10.1002\/gepi.21758","journal-title":"Genet Epidemiol"},{"key":"5439_CR21","doi-asserted-by":"publisher","first-page":"543","DOI":"10.1007\/s10654-015-0011-z","volume":"30","author":"S Burgess","year":"2015","unstructured":"Burgess S, Scott RA, Timpson NJ et al (2015) Using published data in Mendelian randomization: a blueprint for efficient identification of causal risk factors. Eur J Epidemiol 30:543\u2013552. https:\/\/doi.org\/10.1007\/s10654-015-0011-z","journal-title":"Eur J Epidemiol"},{"key":"5439_CR22","doi-asserted-by":"publisher","first-page":"1501","DOI":"10.1093\/bioinformatics\/btz749","volume":"36","author":"J Zhao","year":"2020","unstructured":"Zhao J, Ming J, Hu X et al (2020) Bayesian weighted Mendelian randomization for causal inference based on summary statistics. Bioinformatics 36:1501\u20131508. https:\/\/doi.org\/10.1093\/bioinformatics\/btz749","journal-title":"Bioinformatics"},{"key":"5439_CR23","doi-asserted-by":"publisher","first-page":"484","DOI":"10.1093\/ije\/dyu176","volume":"44","author":"S Burgess","year":"2015","unstructured":"Burgess S, Daniel RM, Butterworth AS et al (2015) Network Mendelian randomization: using genetic variants as instrumental variables to investigate mediation in causal pathways. Int J Epidemiol 44:484\u2013495. https:\/\/doi.org\/10.1093\/ije\/dyu176","journal-title":"Int J Epidemiol"},{"key":"5439_CR24","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1016\/j.jclinepi.2014.09.005","volume":"68","author":"JF Cohen","year":"2015","unstructured":"Cohen JF, Chalumeau M, Cohen R et al (2015) Cochran\u2019s Q test was useful to assess heterogeneity in likelihood ratios in studies of diagnostic accuracy. J Clin Epidemiol 68:299\u2013306. https:\/\/doi.org\/10.1016\/j.jclinepi.2014.09.005","journal-title":"J Clin Epidemiol"},{"key":"5439_CR25","doi-asserted-by":"publisher","first-page":"376","DOI":"10.1038\/s41467-019-14156-4","volume":"11","author":"S Burgess","year":"2020","unstructured":"Burgess S, Foley CN, Allara E et al (2020) A robust and efficient method for Mendelian randomization with hundreds of genetic variants. Nat Commun 11:376. https:\/\/doi.org\/10.1038\/s41467-019-14156-4","journal-title":"Nat Commun"},{"key":"5439_CR26","doi-asserted-by":"publisher","DOI":"10.1002\/cphg.82","volume":"101","author":"D Rasooly","year":"2019","unstructured":"Rasooly D, Patel CJ (2019) Conducting a reproducible Mendelian randomization analysis using the R analytic statistical environment. Curr Protoc Hum Genet 101:e82. https:\/\/doi.org\/10.1002\/cphg.82","journal-title":"Curr Protoc Hum Genet"},{"key":"5439_CR27","doi-asserted-by":"publisher","first-page":"3364","DOI":"10.1093\/brain\/awad070","volume":"146","author":"J Lin","year":"2023","unstructured":"Lin J, Zhou J, Xu Y (2023) Potential drug targets for multiple sclerosis identified through mendelian randomization analysis. Brain J Neurol 146:3364\u20133372. https:\/\/doi.org\/10.1093\/brain\/awad070","journal-title":"Brain J Neurol"},{"key":"5439_CR28","doi-asserted-by":"publisher","first-page":"2849","DOI":"10.1038\/s41380-022-01507-9","volume":"27","author":"Y-T Deng","year":"2022","unstructured":"Deng Y-T, Ou Y-N, Wu B-S et al (2022) Identifying causal genes for depression via integration of the proteome and transcriptome from brain and blood. Mol Psychiatry 27:2849\u20132857. https:\/\/doi.org\/10.1038\/s41380-022-01507-9","journal-title":"Mol Psychiatry"},{"key":"5439_CR29","doi-asserted-by":"publisher","first-page":"164","DOI":"10.1160\/TH16-04-0318","volume":"117","author":"H Winkels","year":"2017","unstructured":"Winkels H, Meiler S, Smeets E et al (2017) CD70 limits atherosclerosis and promotes macrophage function. Thromb Haemost 117:164\u2013175. https:\/\/doi.org\/10.1160\/TH16-04-0318","journal-title":"Thromb Haemost"},{"key":"5439_CR30","doi-asserted-by":"publisher","first-page":"1362","DOI":"10.4049\/jimmunol.180.3.1362","volume":"180","author":"S Deola","year":"2008","unstructured":"Deola S, Panelli MC, Maric D et al (2008) Helper B cells promote cytotoxic T cell survival and proliferation independently of antigen presentation through CD27\/CD70 interactions. J Immunol 180:1362\u20131372. https:\/\/doi.org\/10.4049\/jimmunol.180.3.1362","journal-title":"J Immunol"},{"key":"5439_CR31","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1007\/s12026-025-09630-9","volume":"73","author":"L Hosseini","year":"2025","unstructured":"Hosseini L, Soltani-Zangbar MS, Abolhasanpour N et al (2025) The effect of anti-CD20 on inflammation and histopathological alternations in rat photothrombotic ischemic stroke model. Immunol Res 73:75. https:\/\/doi.org\/10.1007\/s12026-025-09630-9","journal-title":"Immunol Res"},{"key":"5439_CR32","doi-asserted-by":"publisher","first-page":"660","DOI":"10.3892\/mmr.2017.7900","volume":"17","author":"S Zhu","year":"2018","unstructured":"Zhu S, Tang S, Su F (2018) Dioscin inhibits ischemic stroke-induced inflammation through inhibition of the TLR4\/MyD88\/NF-\u03baB signaling pathway in a rat model. Mol Med Rep 17:660\u2013666. https:\/\/doi.org\/10.3892\/mmr.2017.7900","journal-title":"Mol Med Rep"},{"key":"5439_CR33","doi-asserted-by":"publisher","first-page":"1199","DOI":"10.1007\/s11357-020-00242-9","volume":"42","author":"EB Engler-Chiurazzi","year":"2020","unstructured":"Engler-Chiurazzi EB, Monaghan KL, Wan ECK, Ren X (2020) Role of B cells and the aging brain in stroke recovery and treatment. Geroscience 42:1199\u20131216. https:\/\/doi.org\/10.1007\/s11357-020-00242-9","journal-title":"Geroscience"},{"key":"5439_CR34","doi-asserted-by":"publisher","first-page":"619","DOI":"10.2174\/1389450116666150825120536","volume":"17","author":"MH Brown","year":"2016","unstructured":"Brown MH (2016) CD6 as a cell surface receptor and as a target for regulating immune responses. Curr Drug Targets 17:619\u2013629. https:\/\/doi.org\/10.2174\/1389450116666150825120536","journal-title":"Curr Drug Targets"},{"key":"5439_CR35","doi-asserted-by":"publisher","DOI":"10.1002\/brb3.70350","volume":"15","author":"B Jevti\u0107","year":"2025","unstructured":"Jevti\u0107 B, Stegnjai\u0107 G, Stanisavljevi\u0107 S et al (2025) Amelioration of central nervous system autoimmunity through FFAR2 agonism is associated with changes in gut microbiota. Brain Behav 15:e70350. https:\/\/doi.org\/10.1002\/brb3.70350","journal-title":"Brain Behav"},{"key":"5439_CR36","doi-asserted-by":"publisher","first-page":"1989","DOI":"10.2147\/NDT.S290237","volume":"17","author":"Y Zhou","year":"2021","unstructured":"Zhou Y, Yang L, Bo C et al (2021) Microrna-9-3p aggravates cerebral ischemia\/reperfusion injury by targeting fibroblast growth factor 19 (FGF19) to inactivate GSK-3\u03b2\/Nrf2\/ARE signaling. Neuropsychiatr Dis Treat 17:1989\u20132002. https:\/\/doi.org\/10.2147\/NDT.S290237","journal-title":"Neuropsychiatr Dis Treat"},{"key":"5439_CR37","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1016\/j.clnu.2025.03.013","volume":"48","author":"X Ren","year":"2025","unstructured":"Ren X, Yang P, Sun L et al (2025) High plasma fibroblast growth factor 19 is associated with improved prognosis in patients with acute ischemic stroke. Clin Nutr 48:16\u201324. https:\/\/doi.org\/10.1016\/j.clnu.2025.03.013","journal-title":"Clin Nutr"}],"container-title":["Molecular Neurobiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12035-025-05439-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s12035-025-05439-7\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12035-025-05439-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T02:33:53Z","timestamp":1763692433000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s12035-025-05439-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,21]]},"references-count":37,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2026,1]]}},"alternative-id":["5439"],"URL":"https:\/\/doi.org\/10.1007\/s12035-025-05439-7","relation":{},"ISSN":["0893-7648","1559-1182"],"issn-type":[{"value":"0893-7648","type":"print"},{"value":"1559-1182","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,21]]},"assertion":[{"value":"30 April 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 August 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 November 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"This secondary analysis used public GWAS summary statistics. Since the original studies had\u00a0ethics approval and this study used only de-identified, aggregated data, no additional ethicsapproval was required.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics Approval and Consent to Participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to Participate"}},{"value":"All authors critically reviewed the manuscript and approved the final submitted version.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for Publication"}},{"value":"The authors declare no competing interests.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"110"}}