{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T22:41:16Z","timestamp":1792190476152,"version":"4.4.0"},"reference-count":33,"publisher":"Association of Basic Medical Sciences of FBIH","license":[{"start":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T00:00:00Z","timestamp":1792108800000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomol Biomed"],"abstract":"<jats:p>The factors influencing the severity of periventricular white matter hyperintensity (WMH) in cerebral small vessel disease (CSVD) are not fully understood. This study investigated the multiplicative interaction between circulating plasminogen activator inhibitor-1 (PAI-1) and interleukin-17 (IL-17) concerning periventricular WMH severity. In this single-center, cross-sectional study, we enrolled 151 patients with sporadic CSVD, selected from 526 consecutively screened inpatients. Serum levels of PAI-1, IL-17, and matrix metalloproteinase-9 (MMP-9) were quantified using enzyme-linked immunosorbent assays. Regional WMH was graded on magnetic resonance imaging using the Fazekas scale. Multivariable logistic regression was employed to assess the PAI-1\u2013IL-17 interaction for moderate-to-severe periventricular WMH (Fazekas scores 2\u20133 vs. 0\u20131), with additional adjustments for MMP-9 and sensitivity analyses. The primary interaction odds ratio (OR) was 1.72 per one-standard-deviation increase in the standardized product term (95% confidence interval [CI]: 1.07\u20132.77; p\u00a0= 0.026). Adjusting for MMP-9 did not substantially change this estimate. The interaction was not statistically significant in the ordinal periventricular analysis (OR: 1.40; 95% CI: 0.99\u20131.99; p\u00a0= 0.061) or the deep-WMH model (OR: 0.83; 95% CI: 0.51\u20131.37; p\u00a0= 0.468). While alternative binary models showed positive interaction estimates, resampling analyses indicated limited stability, and additive interaction lacked consistent support. These exploratory findings suggest a multiplicative statistical interaction between PAI-1 and IL-17 for dichotomized periventricular WMH severity. However, they do not establish causality, biological synergy, or clinical biomarker utility. Prospective multicenter validation is essential.<\/jats:p>","DOI":"10.17305\/bb.2026.14993","type":"journal-article","created":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T07:21:03Z","timestamp":1792135263000},"source":"Crossref","is-referenced-by-count":0,"title":["PAI-1\u2013IL-17 statistical interaction and periventricular white matter hyperintensity severity in sporadic cerebral small vessel disease"],"prefix":"10.17305","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-2876-3362","authenticated-orcid":false,"given":"Yang","family":"Zilong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hou","family":"Chunlan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wang","family":"Baoai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"6922","published-online":{"date-parts":[[2026,10,16]]},"reference":[{"key":"91978","doi-asserted-by":"crossref","unstructured":"Markus HS, de Leeuw FE. Cerebral small vessel disease: recent advances and future directions. Int J Stroke. 2023;18(1):4\u201314. https:\/\/doi.org\/10.1177\/17474930221144911","DOI":"10.1177\/17474930221144911"},{"key":"91979","doi-asserted-by":"crossref","unstructured":"Bernal M, Escarcena P, Arboix A, Garcia-Eroles L, Verg\u00e9s E, D\u00edez L, et al. Differential characteristics of ischemic and hemorrhagic stroke in patients with cerebral small vessel disease. Neurol India. 2021;69(1):85\u201390. https:\/\/doi.org\/10.4103\/0028-3886.310106","DOI":"10.4103\/0028-3886.310106"},{"key":"91980","doi-asserted-by":"crossref","unstructured":"Cao J, Yuan C, Zhang Z, Zhao X, Zhang Y, Chang P, et al. Hemodynamic changes and their relationship with white matter hyperintensities in CSVD patients with cognitive impairment: a 4D flow study. Front Aging Neurosci. 2025;17:1578288. https:\/\/doi.org\/10.3389\/fnagi.2025.1578288","DOI":"10.3389\/fnagi.2025.1578288"},{"key":"91981","doi-asserted-by":"crossref","unstructured":"Chung J, Oh H, Gwak DS, Kim DE. Multimodal magnetic resonance imaging signatures of white matter hyperintensities: mechanistic insights into pathobiological heterogeneity. J Stroke. 2026;28(1):1\u201328. https:\/\/doi.org\/10.5853\/jos.2025.04168","DOI":"10.5853\/jos.2025.04168"},{"key":"91982","doi-asserted-by":"crossref","unstructured":"Roseborough AD, Saad L, Goodman M, Cipriano LE, Hachinski VC, Whitehead SN. White matter hyperintensities and longitudinal cognitive decline in cognitively normal populations and across diagnostic categories: a meta-analysis, systematic review, and recommendations for future study harmonization. Alzheimers Dement. 2023;19(1):194\u2013207. https:\/\/doi.org\/10.1002\/alz.12642","DOI":"10.1002\/alz.12642"},{"key":"91983","doi-asserted-by":"crossref","unstructured":"Bai T, Yu S, Feng J. Advances in the role of endothelial cells in cerebral small vessel disease. Front Neurol. 2022;13:861714. https:\/\/doi.org\/10.3389\/fneur.2022.861714","DOI":"10.3389\/fneur.2022.861714"},{"key":"91984","doi-asserted-by":"crossref","unstructured":"Cif\u00f9 A, Janes F, Mio C, Domenis R, Pessa ME, Garbo R, et al. Brain endothelial cells activate neuroinflammatory pathways in response to early cerebral small vessel disease (CSVD) patients' plasma. Biomedicines. 2023;11(11):3055. https:\/\/doi.org\/10.3390\/biomedicines11113055 MDPI","DOI":"10.3390\/biomedicines11113055"},{"key":"91985","doi-asserted-by":"crossref","unstructured":"Tj\u00e4rnlund-Wolf A, Brogren H, Lo EH, Wang X. Plasminogen activator inhibitor-1 and thrombotic cerebrovascular diseases. Stroke. 2012;43(10):2833\u20139. https:\/\/doi.org\/10.1161\/STROKEAHA.111.622217","DOI":"10.1161\/STROKEAHA.111.622217"},{"key":"91986","doi-asserted-by":"crossref","unstructured":"Xu Q, Lian Z, Ye Y, Wang J, Shafiq Z, Xiong X, et al. IL17A mediates glycolysis-dependent primary angiogenesis and exacerbates ischemic stroke injury. Mol Neurobiol. 2026;63(1):169. https:\/\/doi.org\/10.1007\/s12035-025-05387-2 Springer","DOI":"10.1007\/s12035-025-05387-2"},{"key":"91987","doi-asserted-by":"crossref","unstructured":"Singh S, Houng A, Reed GL. Thromboembolic ischemic stroke induces neutrophil recruitment and matrix metalloproteinase-9 release to enhance ischemic brain injury. Res Pract Thromb Haemost. 2026;10(4):106645. https:\/\/doi.org\/10.1016\/j.rpth.2026.106645","DOI":"10.1016\/j.rpth.2026.106645"},{"key":"91988","doi-asserted-by":"crossref","unstructured":"Whyte CS. All tangled up: interactions of the fibrinolytic and innate immune systems. Front Med (Lausanne). 2023;10:1212201. https:\/\/doi.org\/10.3389\/fmed.2023.1212201","DOI":"10.3389\/fmed.2023.1212201"},{"key":"91989","doi-asserted-by":"crossref","unstructured":"Gautam AS, Pandey SK, Balki S, Panda ES, Singh RK. IL-17A exacerbated neuroinflammatory and neurodegenerative biomarkers in intranasal amyloid-beta model of Alzheimer's disease. J Neuroimmune Pharmacol. 2025;20(1):29. https:\/\/doi.org\/10.1007\/s11481-025-10192-8","DOI":"10.1007\/s11481-025-10192-8"},{"key":"91990","doi-asserted-by":"crossref","unstructured":"Lu Y, Zhang P, Xu F, Zheng Y, Zhao H. Advances in the study of IL-17 in neurological diseases and mental disorders. Front Neurol. 2023;14:1284304. https:\/\/doi.org\/10.3389\/fneur.2023.1284304","DOI":"10.3389\/fneur.2023.1284304"},{"key":"91991","doi-asserted-by":"crossref","unstructured":"Wang B, Sun W, Bi K, Li Y, Li F. Apremilast prevents IL-17-induced cellular senescence in ATDC5 chondrocytes mediated by SIRT1. Int J Mol Med. 2021;47(3):12. https:\/\/doi.org\/10.3892\/ijmm.2021.4845 Spandidos Publications","DOI":"10.3892\/ijmm.2021.4845"},{"key":"91992","doi-asserted-by":"crossref","unstructured":"Wang G, Wu K, Li W, Zhao E, Shi L, Wang J, et al. Role of IL-17 and TGF-\u03b2 in peritoneal adhesion formation after surgical trauma. Wound Repair Regen. 2014;22(5):631\u20139. https:\/\/doi.org\/10.1111\/wrr.12203","DOI":"10.1111\/wrr.12203"},{"key":"91993","doi-asserted-by":"crossref","unstructured":"Moideen FM, Rahamathulla MP, Charavu R, Alghofaili F, Sha M, Bhandary YP. PAI-1 influences and curcumin destabilizes MMP-2, MMP-9 and basement membrane proteins during lung injury and fibrosis. Int Immunopharmacol. 2024;143(Pt 3):113587. https:\/\/doi.org\/10.1016\/j.intimp.2024.113587","DOI":"10.1016\/j.intimp.2024.113587"},{"key":"91994","doi-asserted-by":"crossref","unstructured":"Ge W, Gong Y, Li Y, Wu N, Ruan Y, Xu T, et al. IL-17 induces non-small cell lung cancer metastasis via GCN5-dependent SOX4 acetylation enhancing MMP9 gene transcription and expression. Mol Carcinog. 2023;62(9):1399\u2013416. https:\/\/doi.org\/10.1002\/mc.23585","DOI":"10.1002\/mc.23585"},{"key":"91995","doi-asserted-by":"crossref","unstructured":"Luo BL, He SP, Zhang YF, Yang QW, Zhuang JC, Zhu RJ, et al. Correlation between matrix metalloproteinase-2, matrix metalloproteinase-9, and tissue inhibitor of metalloproteinases-1 and white matter hyperintensities in patients with cerebral small vessel disease based on cranial magnetic resonance 3D imaging. Magn Reson Imaging. 2024;113:110213. https:\/\/doi.org\/10.1016\/j.mri.2024.110213","DOI":"10.1016\/j.mri.2024.110213"},{"key":"91996","doi-asserted-by":"crossref","unstructured":"Duering M, Biessels GJ, Brodtmann A, Chen C, Cordonnier C, de Leeuw FE, et al. Neuroimaging standards for research into small vessel disease\u2013advances since 2013. Lancet Neurol. 2023;22(7):602\u201318. https:\/\/doi.org\/10.1016\/S1474-4422(23)00131-X","DOI":"10.1016\/S1474-4422(23)00131-X"},{"key":"91997","doi-asserted-by":"crossref","unstructured":"von Elm E, Altman DG, Egger M, Pocock SJ, G\u00f8tzsche PC, Vandenbroucke JP. Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. BMJ. 2007;335(7624):806\u20138. https:\/\/doi.org\/10.1136\/bmj.39335.541782.AD","DOI":"10.1136\/bmj.39335.541782.AD"},{"key":"91998","doi-asserted-by":"crossref","unstructured":"Zhang H, Guo T, Zhang R, Yan H, Yang S, Gao Y, et al. Clinical and neuroimaging correlates of motoric cognitive risk syndrome in cerebral small vessel disease: a cross-sectional study. Front Aging Neurosci. 2026;18:1853965. https:\/\/doi.org\/10.3389\/fnagi.2026.1853965","DOI":"10.3389\/fnagi.2026.1853965"},{"key":"91999","doi-asserted-by":"crossref","unstructured":"Chai C, Cui Y, Li M, Xia J, Wang Y, Ren F, et al. Association between serum uric acid levels and white matter hyperintensities in patients with mild ischemic stroke. Front Neurol. 2025;16:1590408. https:\/\/doi.org\/10.3389\/fneur.2025.1590408","DOI":"10.3389\/fneur.2025.1590408"},{"key":"92000","doi-asserted-by":"crossref","unstructured":"Knol MJ, VanderWeele TJ. Recommendations for presenting analyses of effect modification and interaction. Int J Epidemiol. 2012;41(2):514\u201320. https:\/\/doi.org\/10.1093\/ije\/dyr218","DOI":"10.1093\/ije\/dyr218"},{"key":"92001","doi-asserted-by":"crossref","unstructured":"Noz MP, Ter Telgte A, Wiegertjes K, Joosten LAB, Netea MG, de Leeuw FE, et al. Trained immunity characteristics are associated with progressive cerebral small vessel disease. Stroke. 2018;49(12):2910\u20137. https:\/\/doi.org\/10.1161\/STROKEAHA.118.023192","DOI":"10.1161\/STROKEAHA.118.023192"},{"key":"92002","doi-asserted-by":"crossref","unstructured":"Nagai M, Hoshide S, Kario K. Association of prothrombotic status with markers of cerebral small vessel disease in elderly hypertensive patients. Am J Hypertens. 2012;25(10):1088\u201394. https:\/\/doi.org\/10.1038\/ajh.2012.85","DOI":"10.1038\/ajh.2012.85"},{"key":"92003","doi-asserted-by":"crossref","unstructured":"Dobrynina LA, Makarova AG, Shabalina AA, Burmak AG, Shlapakova PS, Shamtieva KV, et al. The role of changes in the expression of inflammation-associated genes in the variants of cerebral small vessel disease. Int J Mol Sci. 2024;25(15):8113. https:\/\/doi.org\/10.3390\/ijms25158113 MDPI","DOI":"10.3390\/ijms25158113"},{"key":"92004","doi-asserted-by":"crossref","unstructured":"Roseborough AD, Zhu Y, Zhao L, Laviolette SR, Pasternak SH, Whitehead SN. Fibrinogen primes the microglial NLRP3 inflammasome and propagates pro-inflammatory signaling via extracellular vesicles: implications for blood\u2013brain barrier dysfunction. Neurobiol Dis. 2023;177:106001. https:\/\/doi.org\/10.1016\/j.nbd.2023.106001","DOI":"10.1016\/j.nbd.2023.106001"},{"key":"92005","doi-asserted-by":"crossref","unstructured":"Beach TG, Sue LI, Scott S, Intorcia AJ, Walker JE, Arce RA, et al. Cerebral white matter rarefaction has both neurodegenerative and vascular causes and may primarily be a distal axonopathy. J Neuropathol Exp Neurol. 2023;82(6):457\u201366. https:\/\/doi.org\/10.1093\/jnen\/nlad026","DOI":"10.1093\/jnen\/nlad026"},{"key":"92006","doi-asserted-by":"crossref","unstructured":"Illes Z, J\u00f8rgensen MM, B\u00e6k R, Bente LM, Lauridsen JT, Hyrlov KH, et al. New enhancing MRI lesions associate with IL-17, neutrophil degranulation and integrin microparticles: multi-omics combined with frequent MRI in multiple sclerosis. Biomedicines. 2023;11(12):3170. https:\/\/doi.org\/10.3390\/biomedicines11123170 MDPI","DOI":"10.3390\/biomedicines11123170"},{"key":"92007","doi-asserted-by":"crossref","unstructured":"Debette S, Markus HS. The clinical importance of white matter hyperintensities on brain magnetic resonance imaging: systematic review and meta-analysis. BMJ. 2010;341:c3666. https:\/\/doi.org\/10.1136\/bmj.c3666","DOI":"10.1136\/bmj.c3666"},{"key":"92008","doi-asserted-by":"crossref","unstructured":"Vermeer SE, Longstreth WT Jr, Koudstaal PJ. Silent brain infarcts: a systematic review. Lancet Neurol. 2007;6(7):611\u20139. https:\/\/doi.org\/10.1016\/S1474-4422(07)70170-9","DOI":"10.1016\/S1474-4422(07)70170-9"},{"key":"92009","doi-asserted-by":"crossref","unstructured":"Sillen M, Declerck PJ. A narrative review on plasminogen activator inhibitor-1 and its (patho)physiological role: to target or not to target? Int J Mol Sci. 2021;22(5):2721. https:\/\/doi.org\/10.3390\/ijms22052721 MDPI","DOI":"10.3390\/ijms22052721"},{"key":"92010","doi-asserted-by":"crossref","unstructured":"Uscamaita K, Parra Ordaz O, Yazbeck Morell I, Pla MG, S\u00e1nchez-L\u00f3pez MJ, Arboix A. From molecular to clinical implications of sleep-related breathing disorders on the treatment and recovery of acute stroke: a scoping review. Curr Issues Mol Biol. 2025;47(3):138. https:\/\/doi.org\/10.3390\/cimb47030138","DOI":"10.3390\/cimb47030138"}],"container-title":["Biomolecules and Biomedicine"],"original-title":[],"link":[{"URL":"https:\/\/bjbms.org\/ojs\/index.php\/bjbms\/article\/download\/14993\/4364","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/bjbms.org\/ojs\/index.php\/bjbms\/article\/download\/14993\/4364","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T22:00:43Z","timestamp":1792188043000},"score":1,"resource":{"primary":{"URL":"https:\/\/bjbms.org\/ojs\/index.php\/bjbms\/article\/view\/14993"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,16]]},"references-count":33,"URL":"https:\/\/doi.org\/10.17305\/bb.2026.14993","relation":{},"ISSN":["2831-090X","2831-0896"],"issn-type":[{"value":"2831-090X","type":"electronic"},{"value":"2831-0896","type":"print"}],"subject":[],"published":{"date-parts":[[2026,10,16]]}}}