Fluids and Barriers of the CNS最新文献

{"title":"Neisseria meningitidis regulates P-glycoprotein transporter activity in brain endothelial cells via sphingosine 1-phosphate receptor 1.","authors":"Fatemeh Nosratabadi, Leo M Endres, Fabian Schumacher, Heike Claus, Burkhard Kleuser, Brandon J Kim, Alexandra Schubert-Unkmeir","doi":"10.1186/s12987-025-00687-0","DOIUrl":"https://doi.org/10.1186/s12987-025-00687-0","url":null,"abstract":"<p><strong>Background: </strong>The brain endothelial cells (BECs) are essential for protecting the central nervous system (CNS) from xenobiotics and pathogens, including Neisseria meningitidis, while maintaining CNS homeostasis through tight junction (TJ) proteins and specialized transporters. Among these, multidrug resistance (MDR) transporters such as P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are pivotal in restricting the entry of neurotoxic substances. Although the impact of N. meningitidis infection on BBB TJ is well-documented, its effect on MDR transporters remains largely unexplored.</p><p><strong>Methods: </strong>We employed induced pluripotent stem cell-derived brain-like endothelial cells (iBECs) as an in vitro BECs model due to their human-like morphology and expression of junctional proteins and MDR transporters. iBECs were exposed to various N. meningitidis strains, isogenic mutants, heat-inactivated bacteria, conditioned media, or purified capsule polysaccharide (CPS). P-gp and BCRP activities were assessed using intracellular accumulation assays with Rhodamine 123 and Chlorin e6, respectively, in the presence of P-gp inhibitors cyclosporin A and PSC833 and BCRP inhibitor Ko143. Gene expression and protein levels were determined by qPCR and western blotting, and sphingolipid quantification was performed via liquid chromatography tandem-mass spectrometry (LC-MS/MS).</p><p><strong>Results: </strong>Infection of iBECs with N. meningitidis inhibited P-gp activity, whereas BCRP activity remained unaffected. P-gp inhibition occurred without changes in gene expression or protein abundance. Cells infected with N. meningitidis showed reduced efficacy of P-gp inhibitors, an effect not seen with the BCRP inhibitor Ko143. N. meningitidis CPS was identified as a key factor in modulating P-gp activity. Notably, the inhibitory effect of N. meningitidis on P-gp activity was blocked by a specific sphingosine 1-phosphate receptor 1 (S1PR₁) antagonist as well as by sphingosine kinase inhibitors, revealing a mechanistic link between S1PR₁ signaling and P-gp modulation during infection. Furthermore, S1PR₁ was upregulated in infected iBECs. Although LC-MS/MS measurement showed no increase in S1P levels in infected cells compared to uninfected controls, these findings suggest a crucial role for S1PR₁ signaling in mediating the observed effects.</p><p><strong>Conclusions: </strong>These findings demonstrate that N. meningitidis infection impairs P-gp function through S1PR₁-dependent pathways, suggesting that targeting this signaling cascade may offer a novel therapeutic strategy to preserve BBB integrity during bacterial infections.</p>","PeriodicalId":12321,"journal":{"name":"Fluids and Barriers of the CNS","volume":"22 1","pages":"78"},"PeriodicalIF":5.9,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144689698","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neuroprotective role of pyrroloquinoline quinone in folate deficiency-induced blood-brain barrier disruption.","authors":"Sara Aboulhassane, Vishal Sangha, Md Tozammel Hoque, Reina Bendayan","doi":"10.1186/s12987-025-00689-y","DOIUrl":"https://doi.org/10.1186/s12987-025-00689-y","url":null,"abstract":"<p><p>Healthy neurodevelopment requires adequate folates (vitamin B9), which are critical for key biosynthetic and homeostatic processes in the central nervous system (CNS). In the brain, folate transport is mediated by three major pathways: folate receptor alpha (FRα), proton-coupled folate transporter (PCFT), and reduced folate carrier (RFC). Folate uptake primarily occurs at the blood-cerebrospinal fluid barrier (BCSFB) by concerted actions of FRα and PCFT. Alterations in this transport pathway can result in cerebral folate deficiency (CFD), a rare but devastating pediatric condition associated with neuroinflammation and oxidative stress. Recent findings highlight the blood-brain barrier (BBB) as an alternative route for folate delivery, particularly through RFC upregulation. We hypothesized that pyrroloquinoline quinone (PQQ), an activator of nuclear respiratory factor 1 (NRF-1) and PGC-1α, key regulators of mitochondrial biogenesis, could enhance RFC expression at the BBB and mitigate CFD-induced damage. Using in vitro and in vivo models of folate deficiency, we investigated its impact on BBB integrity, inflammation, oxidative stress, mitochondrial dysfunction, and assessed PQQ's ability to reverse these effects. Human brain microvessel endothelial cells (hCMEC/D3) cultured in control folate-sufficient (FS) or folate-deficient (FD) medium were treated with PQQ (1 or 5 µM) or vehicle control for 24 h. Wildtype (C57BL6/N) mice received FD (0 mg/kg folate), or FS (2 mg/kg folate) diet and underwent a 10-day (20 mg/kg/day, i.p) PQQ treatment. Following treatment, hCMEC/D3 cells and isolated mouse brain capillaries were analyzed using qPCR, ELISA, and immunoblotting to assess gene and protein expression of tight junction proteins, inflammatory and oxidative stress markers, mitochondrial transcription factors, and folate transporters. BBB permeability was evaluated in vivo using the sodium fluorescein (NaFl) assay. FD significantly increased the gene and/or protein expression of inflammatory cytokines/chemokines, endothelial adhesion molecules and oxidative stress markers, while tight junction proteins were significantly downregulated both in vitro and in vivo. The NaFl assay confirmed increased BBB permeability in FD mice. PQQ treatment effectively reversed these changes by upregulating RFC and PCFT expression, restoring BBB permeability, mitigating inflammatory and oxidative stress responses and improving mitochondrial biogenesis via PGC-1α/NRF-1 signaling. These results highlight the impact of brain FD on BBB integrity, potentially contributing to neurological deficits seen in CFD disorders with PQQ providing a promising therapeutic strategy.</p>","PeriodicalId":12321,"journal":{"name":"Fluids and Barriers of the CNS","volume":"22 1","pages":"77"},"PeriodicalIF":5.9,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144689699","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MRI contrast accumulation in features of cerebral small vessel disease: blood-brain barrier dysfunction or elevated vascular density?","authors":"Tomas Vikner, Anders Garpebring, Cecilia Björnfot, Jan Malm, Anders Eklund, Anders Wåhlin","doi":"10.1186/s12987-025-00675-4","DOIUrl":"10.1186/s12987-025-00675-4","url":null,"abstract":"<p><strong>Background: </strong>White matter lesions (WML) and dilated perivascular spaces (PVS) are features of small vessel disease (SVD), commonly observed in aging and dementia, with unknown pathophysiology. Human studies have documented contrast accumulation within and in proximity of SVD-lesions. However, whether such observations mainly reflect excessive blood-brain barrier (BBB) leakage, or altered microvascular density in the investigated regions, remains unclear.</p><p><strong>Methods: </strong>To evaluate the roles of BBB leakage and vascular density in aging and SVD, dynamic contrast enhanced (DCE) MRI was used to estimate the permeability-surface area product (PS) and fractional plasma volume ([Formula: see text]) in normal-appearing brain tissue and in proximity of and within WML and PVS in a population-based cohort (N = 56; 34/22 m/f; age 64 to 84 years). Analysis of variance (ANOVA) was used to assess regional differences in PS and [Formula: see text] and analysis of covariance (ANCOVA) was used to assess regional differences in PS with [Formula: see text] and vascular risk as covariates.</p><p><strong>Results: </strong>Pronounced increases in PS and [Formula: see text] were observed from normal-appearing white matter (NAWM) to WML peripheries to WMLs. Similar PS and [Formula: see text]increases were observed from basal ganglia (BG) to BG-PVS. Further, PS in NAWM and white matter (WM) PVS were found to increase with cortex-to-ventricular depth. However, ANCOVA models with [Formula: see text] as a covariate showed that variance in PS was mainly explained by v_p (η²=0.17 to η²=0.35; all p < 10^- 3), whereas the effect of region was only borderline-significant when comparing NAWM, WML peripheries and WML (p = 0.03) and non-significant for the other comparisons (p > 0.29).</p><p><strong>Conclusions: </strong>Our findings support the notion that contrast leakage across the BBB accumulates within and in proximity of SVD-related lesions. However, high contrast accumulation may mainly reflect high vascularization, and to a lesser degree than previously recognized BBB dysfunction.</p>","PeriodicalId":12321,"journal":{"name":"Fluids and Barriers of the CNS","volume":"22 1","pages":"74"},"PeriodicalIF":5.9,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12265124/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144648969","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Apocrine secretion by the choroid plexus.","authors":"Ya'el Courtney, Maria K Lehtinen","doi":"10.1186/s12987-025-00684-3","DOIUrl":"10.1186/s12987-025-00684-3","url":null,"abstract":"<p><p>The choroid plexus (ChP) epithelium secretes cerebrospinal fluid (CSF) and signaling factors that influence brain development. In addition to classical secretory pathways, the ChP also employs apocrine secretion, in which large cytoplasmic portions bud from the apical surface in structures called aposomes. Although historically underappreciated, recent imaging and molecular studies demonstrate that this process is calcium-dependent and regulated by neuromodulators such as serotonin. Apocrine secretion contributes distinct cytoplasmic cargo-proteins, organelles, and signaling molecules-to the CSF, with evidence for developmental roles in neurogenesis and progenitor cell differentiation. This review synthesizes structural, functional, and proteomic data supporting ChP apocrine secretion, compares it to other epithelial release mechanisms, and highlights outstanding questions about its regulation and physiological roles. By focusing on this unconventional and understudied mode of secretion, we provide a framework for understanding how ChP-mediated cargo release shapes the CSF environment and contributes to brain development.</p>","PeriodicalId":12321,"journal":{"name":"Fluids and Barriers of the CNS","volume":"22 1","pages":"75"},"PeriodicalIF":5.9,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12269182/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144648967","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Imatinib prevents blood-spinal cord barrier disruption by inhibiting PDGFR-mediated JMJD3 expression and activation after spinal cord injury.","authors":"Chan Sol Park, Jee Youn Lee, Tae Young Yune","doi":"10.1186/s12987-025-00690-5","DOIUrl":"10.1186/s12987-025-00690-5","url":null,"abstract":"<p><strong>Background: </strong>After a spinal cord injury (SCI), disruption of the blood-spinal cord barrier (BSCB) leads to secondary injuries, including inflammatory responses and apoptotic cell death, ultimately causing permanent neurological deficits. Imatinib, a tyrosine kinase inhibitor, has been reported to enhance BSCB integrity and improve functional recovery after SCI. However, the mechanism by which imatinib regulates BSCB integrity remains unclear. Recent studies have identified the histone H3K27me3 demethylase JMJD3 as a key mediator of BSCB disruption, with high expression observed in blood vessels after SCI. In this study, we investigated whether imatinib regulates JMJD3 expression and activation through PDGFR signaling, thereby mitigating BSCB disruption following SCI.</p><p><strong>Methods: </strong>Imatinib (100 mg/kg) was administered intraperitoneally to rats subjected to a contusion injury at the T9 level of the spinal cord and was continued daily for 14 days.</p><p><strong>Results: </strong>Our results indicate that imatinib inhibited the phosphorylation of PDGFRα and PDGFRβ, both tyrosine kinase receptors, without affecting their expression levels. Additionally, imatinib reduced JMJD3 and MMP-9 expression and activation in blood vessels, thereby decreasing macrophage infiltration after SCI. In an oxygen-glucose deprivation (OGD)-induced bEnd.3 cell model, phosphorylated PDGFRα and PDGFRβ, along with JMJD3 expression and activation, were significantly upregulated but were effectively inhibited by imatinib treatment. Furthermore, imatinib suppressed secondary damage, including cell death, blood cell infiltration (e.g., neutrophils and macrophages), inflammation, axonal and myelin loss, and lesion volume. These effects collectively resulted in significant improvements in functional recovery after SCI.</p><p><strong>Conclusion: </strong>Based on these findings, we propose that imatinib exerts a neuroprotective effect, in part by inhibiting PDGFR-mediated JMJD3 expression and activation following SCI.</p>","PeriodicalId":12321,"journal":{"name":"Fluids and Barriers of the CNS","volume":"22 1","pages":"76"},"PeriodicalIF":5.9,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12269138/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144648968","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Substrate stiffness and shear stress collectively regulate the inflammatory phenotype in cultured human brain microvascular endothelial cells.","authors":"Alexis K Yates, Heather Murray, Andrew Kjar, Daniel Chavarria, Haley Masters, Hyosung Kim, Alexander P Ligocki, Angela L Jefferson, Ethan S Lippmann","doi":"10.1186/s12987-025-00683-4","DOIUrl":"10.1186/s12987-025-00683-4","url":null,"abstract":"<p><p>Brain endothelial cells experience mechanical forces in the form of blood flow-mediated shear stress and underlying matrix stiffness, but intersectional contributions of these factors towards blood-brain barrier (BBB) impairment and neurovascular dysfunction have not been extensively studied. Here, we developed in vitro models to examine the sensitivity of primary human brain microvascular endothelial cells (BMECs) to substrate stiffness, with or without exposure to fluid shear stress. Using a combination of molecular profiling techniques, we show that BMECs exhibit an inflammatory signature at both the mRNA and protein level when cultured on gelatin substrates of intermediate stiffness (~ 30 kPa) versus soft substrates (~ 6 kPa). Exposure to modest fluid shear stress (1.7 dyne/cm²) partially attenuated this signature, including reductions in levels of soluble chemoattractants and surface ICAM-1. Overall, our results indicate that increased substrate stiffness promotes an inflammatory phenotype in BMECs that is dampened in the presence of fluid shear stress.</p>","PeriodicalId":12321,"journal":{"name":"Fluids and Barriers of the CNS","volume":"22 1","pages":"73"},"PeriodicalIF":5.9,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12261575/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144642193","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Restoring brain barriers: an innovative approach for treating neurological disorders.","authors":"Sighild Lemarchant, Britta Engelhardt, Francesca Cicchetti, Gregory J Bix, Annette Janus, Yann Godfrin, Hélène Blasco, Matthew Campbell, Aurélie de Rus Jacquet","doi":"10.1186/s12987-025-00688-z","DOIUrl":"10.1186/s12987-025-00688-z","url":null,"abstract":"<p><p>The complex etiology of neurological disorders is a major challenge to the identification of therapeutic candidates. Tackling brain vascular dysfunction is gaining attention from the scientific community, neurologists and pharmaceutical companies, as a novel disease-modifying strategy. Here, we provide evidence that at least 41% of neurological diseases and related conditions/injuries display a co-pathology of blood-brain and blood-spinal cord barrier alterations and dysfunctions, and we discuss why this figure may represent only a fraction of a larger phenomenon. We further provide clinical evidence that barrier status may contribute to pathological and functional outcomes in patients. Finally, we discuss drug candidates under development to repair brain barriers.</p>","PeriodicalId":12321,"journal":{"name":"Fluids and Barriers of the CNS","volume":"22 1","pages":"72"},"PeriodicalIF":5.9,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12243347/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144607895","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Peripheral inflammatory state in idiopathic normal pressure hydrocephalus patients: a cross-sectional study.","authors":"Yang Yang, Dandan Guo, Qingchao Yang, Chenlu Yang, Jinde Liu, Heyin Liu, Wen Liu, Yuqian Liu, Yi Li, Yiming Liu","doi":"10.1186/s12987-025-00682-5","DOIUrl":"10.1186/s12987-025-00682-5","url":null,"abstract":"<p><strong>Background: </strong>Neuroinflammation may be involved in the pathogenesis of idiopathic normal pressure hydrocephalus (iNPH). However, the specific changes in the peripheral inflammatory state of patients with iNPH remain unclear.</p><p><strong>Objective: </strong>To explore the changes in the peripheral inflammatory state of patients with iNPH and their potential value as biomarkers of clinical diagnosis and disease severity.</p><p><strong>Methods: </strong>In this cross-sectional study, 119 iNPH patients with AD-negative pathology and 200 healthy controls (HCs) were enrolled. Clinical characteristics, including the Idiopathic Normal Pressure Hydrocephalus Grading Scale (iNPHGS), Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA), were collected along with inflammatory parameters in the peripheral blood. Logistic regression was applied to evaluate differences in peripheral inflammatory indicators, adjusting for age, sex, and comorbidities. Receiver operating characteristic (ROC) analysis was used to evaluate the diagnostic performance of the inflammatory markers. Correlations between inflammatory parameters and clinical characteristics were assessed.</p><p><strong>Results: </strong>Significant differences in inflammatory parameters, such as neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), and prognostic nutritional index (PNI), were observed between iNPH patients and HCs after adjusting for age, sex and comorbidities. The combination of PNI and platelet-to-high-density lipoprotein ratio (PHR) distinguished iNPH patients from HCs most significantly (area under the curve [AUC] = 0.820). Neutrophil ratio and lymphocyte ratio were associated with clinical severity and cognitive impairment of patients with iNPH.</p><p><strong>Conclusions: </strong>iNPH patients exhibit an elevated peripheral inflammatory state. Peripheral inflammatory parameters, especially neutrophil ratio and lymphocyte ratio, are associated with disease severity and cognitive impairment, suggesting their potential as therapeutic targets and offering new insights into the pathophysiology of iNPH. Additionally, the inflammatory peripheral parameters may serve as valuable and convenient method in assisting clinical diagnosis.</p>","PeriodicalId":12321,"journal":{"name":"Fluids and Barriers of the CNS","volume":"22 1","pages":"71"},"PeriodicalIF":5.9,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12239330/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144590799","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Uptake of DU145 and LNCaP prostate cancer cell line derived extracellular vesicles is inversely correlated with blood-brain barrier integrity in vitro.","authors":"Ana Špilak, Adrián Klepe, Sophia Theresa Kriwanek, Heinz-Peter Friedl, Andreas Brachner, Christa Nöhammer, Winfried Neuhaus","doi":"10.1186/s12987-025-00680-7","DOIUrl":"10.1186/s12987-025-00680-7","url":null,"abstract":"<p><strong>Background: </strong>Tumor-derived small extracellular vesicles (sEVs) have been implicated in changes of the blood-brain barrier (BBB) during pre-metastatic niche formation. Although it was postulated that sEVs can traverse the highly restrictive BBB via transcytosis-data mostly based on the indirect detection of transported cargo-direct evidence for sEV transport across the BBB remains elusive due to challenges in sEV labelling, detection limits, and inherent limitations of existing in vitro BBB models. This study investigated the interaction and effects of sEVs derived from low (LNCaP) and moderately metastatic (DU145) prostate cancer (PCa) cell lines with the human brain endothelial cell line hCMEC/D3.</p><p><strong>Methods: </strong>Systematic optimization of the cell culture membrane insert set-up for sEV transport studies was accomplished with inserts with different pore sizes, varied coating procedures and medium compositions. Particle size distribution, quantification and zeta-potential was measured with nanoparticle tracking analysis. Uptake of fluorescent labelled sEVs by hCMEC/D3 cell layers was determined by flow cytometry, barrier integrity was measured by transendothelial electrical resistance (TEER). Effects of inflammatory cytokines and PCa lines-derived sEVs on hCMEC/D3 at the transcriptomic level were investigated by means of high-throughput qPCR based on Fluidigm Biomark® platform.</p><p><strong>Results: </strong>Improved conditions for sEV transport studies included the application of membrane inserts with 1 µm pore size and of 1% BSA in the receiver compartment. Efficiency of LNCaP- and DU145-derived sEV uptake by hCMEC/D3 cells revealed an inverse correlation between uptake of sEVs and paracellular barrier integrity (TEER). Whereas addition of sEVs of the more aggressive DU145 cells resulted in a distinct increase of TEER under regular and inflammatory conditions, LNCaP-derived sEVs affected TEER only upon inflammatory cytokine treatment. MRNA expression analyses of hCMEC/D3 cells revealed a distinct regulation of transcripts depending on TEER (i.a. FN, CDLN1) or upon inflammatory cytokines (i.a.: ABCB1, MFSD2a, VCAM1, VEGFa).</p><p><strong>Conclusions: </strong>Differences upon treatment of hCMEC/D3 layers with LNCaP-and DU145 derived sEVs indicated that vesicles retain and transport molecular features of their originating cells. Careful optimization of the test set-up for studies with sEVs in vitro is recommended, including medium controls for sEV purification and labelling as well as addition of proteins for sEV recovery.</p>","PeriodicalId":12321,"journal":{"name":"Fluids and Barriers of the CNS","volume":"22 1","pages":"70"},"PeriodicalIF":5.9,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12232752/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144583506","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characteristics of patients with idiopathic normal pressure hydrocephalus for whom neurosurgeons hesitate to perform shunt surgery: a nationwide hospital-based survey in Japan.","authors":"Ryo Kawai, Hiroaki Kazui, Tetsuya Ueba, Natsuko Nakamura, Marina Minami, Madoka Nakajima, Shigeki Yamada, Haruhiko Kishima, Hideki Kanemoto, Chifumi Iseki, Etsuro Mori","doi":"10.1186/s12987-025-00681-6","DOIUrl":"10.1186/s12987-025-00681-6","url":null,"abstract":"<p><strong>Background: </strong>There is no consensus regarding the indications for shunt surgery in patients with idiopathic normal pressure hydrocephalus (iNPH) aged ≥ 85 years or in those with severe physical or mental comorbidities. This nationwide study investigates the current approaches of neurosurgeons regarding iNPH treatment and surgical indications.</p><p><strong>Methods: </strong>A questionnaire, developed in collaboration with neurosurgeons and dementia specialists, was distributed to 1,220 facilities from October 10, 2023. Responses were collected through December 11, 2023 and analyzed to assess current practices and factors influencing surgical decisions.</p><p><strong>Results: </strong>In total, 656 facilities (53.8%) responded. Of them, 30 (4.6%) had a policy of not performing shunt surgery at their own facility and referred patients to other appropriate facilities, and 139 (21.2%) did not perform any shunt surgeries in 2022. The most common number of shunt surgeries performed in 2022 was 1-5 surgeries per facility, accounting for 257 facilities (57.1%). Regarding age-related indications for shunt surgery, 159 facilities (35.3%) reported no age restrictions, whereas 155 facilities (57.8%) among the 268 facilities considering age (59.6%) responded that patients aged ≥ 90 years were not indicated for shunt surgery. Among 450 facilities that performed shunt surgeries in 2022, hesitations resulting from comorbidities were reported as follows: cerebrovascular disease (10.0%), orthopedic disease (11.5%), dialysis (29.8%), Parkinson's syndrome (19.5%), Alzheimer's disease (AD) (42.7%), schizophrenia (44.2%), absence of disproportionately enlarged subarachnoid space hydrocephalus (DESH) (41.5%), and insufficient care or institutionalization (56.0%). Logistic regression analyses showed that the number of shunt surgeries performed in 2022 was significant predictor of age ≥ 90 years, cerebrovascular disease, Parkinson's syndrome, AD, no DESH, and insufficient care or institutionalization. Significant predictors for dialysis, AD, and schizophrenia included the presence of collaborating internal medicine facilities. For dialysis and AD, the classification of facilities and having a qualified dementia specialist were significant predictors, respectively.</p><p><strong>Conclusions: </strong>A number of Japanese neurosurgeons hesitate to perform shunt surgery in patients with iNPH aged ≥ 90 years, with comorbid AD or schizophrenia, lacking DESH findings, or having insufficient care support or are institutionalized. Multidisciplinary collaboration with internal medicine, including neurology and psychiatry, may help expand appropriate surgical indications for these patients.</p>","PeriodicalId":12321,"journal":{"name":"Fluids and Barriers of the CNS","volume":"22 1","pages":"69"},"PeriodicalIF":5.9,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12228187/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144564728","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}