bims-blobar Biomed News
on Blood brain barrier repair
Issue of 2025–10–19
23 papers selected by
Nicolas Rebergue
  1. Thyroid Hormone T4 Alleviates Traumatic Brain Injury by Enhancing Blood-Brain Barrier Integrity.
  2. Vascular recanalization exacerbates BBB permeability after ischemic stroke.
  3. Integrin α8-Mediated Pericyte Morphogenesis Controls Blood-Brain Barrier Integrity.
  4. Dynamic modulation of the blood-brain barrier in the healthy brain.
  5. Pericytes repair engineered defects in the basement membrane to restore barrier integrity in an in vitro model of the blood-brain barrier.
  6. Higher Blood-Brain Barrier Permeability in Middle-Aged Adults With Hypertension.
  7. Proteoglycan 4 attenuates ischemic post-stroke hemorrhagic transformation and blood-brain barrier disruption.
  8. Computed tomography-derived Ktrans and serum S100B in quantitative evaluation of blood-brain barrier permeability in traumatic brain injury.
  9. The Effect of Long-Term Betacoronavirus Infection on the Permeability of the Blood-Brain Barrier-In Vitro Model Studies.
  10. DEAD-box helicase DDX24 is essential for endothelial mitochondrial function to maintain the blood-brain barrier.
  11. Research progress on the correlation between biological rhythms and the blood-brain barrier after ischemic stroke.
  12. Explaining blood-brain barrier permeability by synergistic effect on molecular substructures.
  13. Targeting Epac1 to protect the blood brain barrier from inflammation-induced dysfunction: Evidence from an in vitro model.
  14. Ellagic Acid as a Therapeutic Agent for Blood-Brain Barrier Restoration in Neurodegenerative Diseases.
  15. Correction to "Protein-Carbon Dot Nanohybrid-Based Early Blood-Brain Barrier Damage Theranostics".
  16. The dysbiosis of gut microbiota attributes to the impairment of blood-brain barrier in rats triggered by cadmium.
  17. The Role of the Microbiome and the Neurovascular Unit.
  18. Acetylcholine mediates nitro-PAHs induced inflammation and ameliorates the abnormalities in blood-brain barrier related proteins.
  19. Zexieyin formula attenuates Alzheimer's disease via suppressing A1 astrocyte activation: A serum pharmacochemistry and network pharmacology study.
  20. Diversity of Brain Microvascular Endothelial Cell Functions: Physiology, Ischemia/Hypoxia, and Underlying Protection.
  21. Assessment and characterization of BBB permeability parameters in autoimmune encephalitis based on 99mTc-DTPA SPECT/CT.
  22. The Role of VCAM1 in Post-Stroke Cognitive Impairment: Molecular Mechanisms and Therapeutic Potential.
  23. Expression of Concern: Netrin-1 Preserves Blood-Brain Barrier Integrity Through Deleted in Colorectal Cancer/Focal Adhesion Kinase/RhoA Signaling Pathway Following Subarachnoid Hemorrhage in Rats.
  1. Int J Mol Sci. 2025 Oct 03. pii: 9632. [Epub ahead of print]26(19):
    Thyroid Hormone T4 Alleviates Traumatic Brain Injury by Enhancing Blood-Brain Barrier Integrity.
    Mayuri Khandelwal, Zhe Ying, Fernando Gomez-Pinilla.
      Traumatic brain injury (TBI) disrupts the blood-brain barrier (BBB), resulting in increased permeability, neuronal loss, and cognitive dysfunction. This study investigates the therapeutic potential of thyroid hormone (T4) to reduce BBB dysfunction following moderate fluid percussion injury. T4 injection (intraperitoneal) after TBI restores the levels of pericytes and endothelial cells vital for BBB integrity, reduces edema by downregulating AQP-4 gene expression, and enhances levels of the tight junction protein ZO-1. T4 counteracts the TBI-related increase in MMP-9 and TLR-4, significantly reducing BBB permeability. Furthermore, T4 enhances the neuroprotective functions of astrocytes by promoting the activity of A2 astrocytes. Additionally, T4 treatment increases DHA levels (important for membrane integrity and function), stimulates mitochondrial biogenesis, and leads to a notable improvement in spatial learning and memory retention. These findings suggest that T4 has significant potential to reduce vascular leakage and inflammation after TBI, thereby improving cognitive function and maintaining BBB integrity.
    Keywords:  blood–brain barrier; cognition; thyroid hormone; traumatic brain injury
    DOI:  https://doi.org/10.3390/ijms26199632
  2. Front Neurol. 2025 ;16 1682748
    Vascular recanalization exacerbates BBB permeability after ischemic stroke.
    Rong-Fei Wang, Jing Liu, Chang-Hui Chen.
       Introduction: Ischemic stroke is a common and serious neurological disease. After cerebral ischemia occurs, the integrity of the BBB is disrupted, leading to increased permeability, causing pathophysiological changes such as brain edema and hemorrhagic transformation, which aggravates neuronal damage. Such changes become more obvious after the recovery of blood flow. However, the effect of vascular recanalization on blood-brain barrier leakage is poorly known.
    Methods: Mice were divided into the recanalization group and the non-recanalization group. Mice in the recanalization group suffered from the middle cerebral artery occlusion and were reperfused 60 min later. Mice in the non-recanalization group suffered from permanent occlusion of the middle cerebral artery. The permeability of the blood-brain barrier was tested using fluorescence staining, and the expression of tight junction proteins and transcytosis-related proteins were analyzed by western blot.
    Results: The IgG results revealed a significantly larger area of leakage in the recanalization group compared to the non-recanalization group. A consistent trend was observed in the FITC-dextran leakage experiment. Moreover, after blood flow recanalization, there was a significant reduction in tight junctions-related proteins, occludin and ZO-1. Meanwhile, both ischemia and reperfusion caused changes in the ratio of transcytosis related protein Caveolin-1 /MFSD2a, and this is more obvious in the blood flow recanalization group.
    Conclusion: Vascular recanalization can exacerbate blood-brain barrier disruption, concurrently impairing both the paracellular and transcytosis pathways. This finding provides a rationale for exploring new approaches for protecting the integrity of the blood-brain barrier, reducing its permeability, and lowering the risk of hemorrhagic transformation.
    Keywords:  blood–brain barrier; ischemic stroke; recanalization; tight junctions; transcytosis
    DOI:  https://doi.org/10.3389/fneur.2025.1682748
  3. Adv Sci (Weinh). 2025 Oct 14. e15374
    Integrin α8-Mediated Pericyte Morphogenesis Controls Blood-Brain Barrier Integrity.
    Chang-Xiong Gong, Lin-Lin Hu, Ling Jiang, Pei-Xia Shi, Shuang Zhang, Yuan Zhao, Bing-Qiao Wang, Xiao-Feng Cheng, Cheng-Kang He, Sen Lin, Yue Dai, Zhao-You Meng, Chen-Hao Zhao, Bao-Liang Sun, Qi Xie, Fang-Fei Li, Qing-Wu Yang.
      Pericytes exhibits distinct morphological features on microvessels during various stages of brain-blood barrier (BBB) development and neurological disorders. However, the underlying mechanisms by which pericyte morphology influences BBB integrity are not yet fully understood. Integrin α8 (ITGA8) is prominently expressed in mature pericytes, which tightly associate with endothelial cells during BBB maturation and post-ischemic vascular remodeling. ITGA8-deficient mice shows the disrupted pericyte morphology, including shortened processes and reduced vascular coverage, leads to compromised BBB integrity. Mechanistically, ITGA8 regulates pericyte morphology via the Rho-ROCK signaling, subsequently impacting BBB function through TGF-β1 activation, which underscores its role in cytoskeletal organization and microvascular stability. In an ischemic stroke model, ITGA8 deficiency results in increased BBB permeability, reduced pericyte coverage, and worsened neurological recovery. Conversely, adeno-associated virus (AAV)-mediated ITGA8 overexpression restores pericyte morphology and improveS post-stroke neurological outcomes. ITGA8 is identified as a key regulator of pericyte morphology and function, which are essential for maintaining BBB integrity, thereby highlighting the therapeutic potential of targeting ITGA8 for BBB repair and neurovascular recovery.
    Keywords:  BBB; ITGA8; morphology; pericyte
    DOI:  https://doi.org/10.1002/advs.202415374
  4. Nat Rev Neurosci. 2025 Oct 15.
    Dynamic modulation of the blood-brain barrier in the healthy brain.
    Alon Friedman, Ofer Prager, Yonatan Serlin, Daniela Kaufer.
      The blood-brain barrier (BBB) performs intricate and dynamic functions that extend far beyond its traditional role as a static protective barrier, playing a pivotal role in maintaining CNS homeostasis. These multifaceted functions are rooted in its specialized architectural and cellular composition. In this Review, we examine the dynamic modulation of BBB function during physiological conditions and the hypothesis that such modulation contributes directly to neural and glial plasticity. We provide an integrated examination of the BBB's diverse cellular components - endothelial cells, pericytes, astrocytes, microglia and vascular smooth muscle cells - across different CNS vascular segments. We discuss how physiological features and states, including circadian rhythms, physical activity, stress and hormonal fluctuations, dynamically alter BBB permeability and signalling, potentially shaping synaptic function, neuronal circuit dynamics and glial responsiveness. Understanding these mechanisms offers new insights into the neurovascular basis of synaptic plasticity and suggests that the BBB may be an under-recognized regulator and modulator of brain adaptability in both health and disease.
    DOI:  https://doi.org/10.1038/s41583-025-00976-5
  5. Mater Today Bio. 2025 Dec;35 102361
    Pericytes repair engineered defects in the basement membrane to restore barrier integrity in an in vitro model of the blood-brain barrier.
    Michelle A Trempel, Yimei Du, Louis P Widom, Emily E Reitz, Alexis M Feidler, Pelin Kasap, Britta Engelhardt, Thomas R Gaborski, Harris A Gelbard, Niccolo Terrando, James L McGrath.
      Pericytes play a key role in the brain where they support brain microvascular endothelial cells (BMECs) in forming the tightly regulated blood-brain barrier (BBB). The loss of pericytes, and corresponding weakening of the BBB, has been reported in response to episodes of systemic inflammation and in neurodegenerative disease. We recently demonstrated that iPSC-derived pericyte-like and BMEC-like cells form a nascent, 3D basement membrane when cultured across an ultrathin (100 nm thick) and highly nanoporous membrane (McCloskey, Ahmed et al., AHCM 2024). We also concluded that the pericyte-like cells did not contribute soluble factors to enhance permeability. Given the structural role of pericytes in vivo, here we sought to engineer defects in the basement membrane to see if pericytes could repair them. In BMEC-like monocultures, we found that micropore (3 μm and 5 μm) patterns in nanomembranes appeared as corresponding discontinuities in basement membrane laminin and destabilized barrier function. Both the laminin defects and the baseline barrier function were restored with the addition of pericytes on the basal side of the membrane. We further found that: 1) BMECs transmigrate through large micropores in monocultures but not in co-culture with pericytes, and 2) pericytes stabilized barrier function. Our results align with the role of pericytes as structural support cells for the microvasculature and encourage the use of our tissue barrier platform (the μSiM) to model acute and chronic neurological disorders involving pericyte dysfunction and/or disruption of basement membrane integrity.
    Keywords:  Basement membrane; Blood-brain barrier; Human BBB-On-a-chip; Nanomembrane
    DOI:  https://doi.org/10.1016/j.mtbio.2025.102361
  6. Hypertension. 2025 Oct 15.
    Higher Blood-Brain Barrier Permeability in Middle-Aged Adults With Hypertension.
    Esther Janssen, Joost J A de Jong, Esmee Verburgt, Annemieke Ter Telgte, Danielle T N A van den Berg, José P Marques, Marnix C Maas, Frederick J A Meijer, Anil Tuladhar, Niels P Riksen, Jaap Deinum, Walter H Backes, Frank-Erik de Leeuw.
       BACKGROUND: Hypertension is a major risk factor for cerebral small vessel disease (SVD), but the underlying mechanisms remain incompletely understood. Blood-brain barrier (BBB) leakage is hypothesized to be involved in SVD pathogenesis, but this was mainly demonstrated in older patients with established SVD on magnetic resonance imaging. We investigated BBB leakage in young patients with hypertension, at risk for SVD, compared with controls.
    METHODS: BBB leakage of gadolinium contrast agent was measured with 3T magnetic resonance imaging in 59 patients with hypertension (mean age, 35.8±9.7 years; 54% female; mean blood pressure, 146/92 mm Hg) and 21 healthy controls (mean age, 29.9±4.8 years; 52% female; mean blood pressure, 120/75 mm Hg). Dynamic contrast-enhanced magnetic resonance imaging was used to measure BBB leakage (leakage rate, Ki [min-1] and blood plasma volume fraction [Vp]). Linear regression adjusted for age and sex was used to compare BBB leakage between patients and controls. We additionally adjusted for the amended SVD score and white matter hyperintensity volume. We also compared patients with primary aldosteronism to those with hypertension due to other causes.
    RESULTS: Patients with hypertension had 17% higher BBB leakage (Ki) in the white matter (P=0.049) and 15% in the gray matter (P=0.070) compared with controls, independent of SVD burden. No differences were found in Vp or between patients with primary aldosteronism and other causes.
    CONCLUSIONS: Young patients with hypertension show BBB disruption independent of magnetic resonance imaging-detectable SVD. This suggests a possible role of BBB dysfunction in SVD pathogenesis. Restoration of BBB integrity may be a relevant target for interventions in SVD, but longitudinal and intervention studies are needed to confirm causality.
    REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT06175663.
    Keywords:  adults; blood-brain barrier; cerebral small vessel diseases; hypertension; magnetic resonance imaging
    DOI:  https://doi.org/10.1161/HYPERTENSIONAHA.125.25290
  7. IBRO Neurosci Rep. 2025 Dec;19 661-667
    Proteoglycan 4 attenuates ischemic post-stroke hemorrhagic transformation and blood-brain barrier disruption.
    Jing Yang, Ning Tang, Ruanxian Dai, Jiajie Chen, Zhaojiao Li, Fengwen Jiang, Shiyi Li, Qiang Meng.
       Background: Proteoglycan 4 (PRG4) possesses biological characteristics of anti-inflammation, lubrication, anti-apoptosis, and immunomodulation, and regulates the homeostasis of articular cartilage, myocardium, brain, and skin tissues. Nevertheless, the function of PRG4 in post-stroke hemorrhagic transformation (HT) and blood-brain barrier (BBB) disruption is unknown.
    Methods: A post-stroke HT mouse model (MACO-HT) was constructed and subsequently treated with recombinant PRG4 by tail vein injection. Neurologic impairment in mice was evaluated using mNSS and Zea longa score. The effect of recombinant PRG4 on HT was assessed using HE and TTC staining and hemoglobin assays. The effect of recombinant PRG4 on BBB repair was evaluated using Evan's blue leakage, western blotting, and IF staining assays.
    Results: Recombinant PRG4 reduced mNSS and Zea longa scores in MACO-HT mice. Infarct and hemorrhage areas and hemoglobin level in brain tissues of MACO-HT mice were significantly diminished after treatment with recombinant PRG4. MACO-HT mice exhibited significant Evan's blue leakage, which was ameliorated by reconstituted PRG4. Moreover, recombinant PRG4 notably diminished the levels of TLR2, MMP-2, and MMP-9 proteins, and augmented the levels of Claudin-5, Occludin, and ZO-1 in the brain tissues of MACO-HT mice.
    Conclusion: Recombinant PRG4 ameliorated post-stroke neurological impairment, HT, and BBB disruption. This finding identifies a biological function for PRG4 in stroke and provides support for therapeutic strategies targeting HT and BBB injury.
    Keywords:  Blood-brain barrier; Hemorrhagic transformation; Proteoglycan 4; Stroke
    DOI:  https://doi.org/10.1016/j.ibneur.2025.09.008
  8. Neuroradiology. 2025 Oct 13.
    Computed tomography-derived Ktrans and serum S100B in quantitative evaluation of blood-brain barrier permeability in traumatic brain injury.
    Jakob Meglič, Katarina Šurlan Popović, Fajko F Bajrović, Primož Gradišek, Jasna Rapnik, Jernej Avsenik.
       PURPOSE: Traumatic brain injury (TBI) often leads to blood-brain barrier (BBB) disruption, contributing to secondary brain damage. Perfusion computed tomography (PCT) may assess BBB permeability through the transfer constant (Ktrans), while serum S100 calcium-binding protein B (S100B) serves as a biomarker of BBB integrity. However, the relationship between PCT derived Ktrans and serum S100B concentrations in TBI has not been fully explored.
    METHODS: This observational study included 26 adult patients with moderate or severe TBI. PCT was performed 12-24 h after admission to measure Ktrans values in the pericontusional edema region. Serum S100B levels were measured at regular intervals during the first 36 h. Correlations between Ktrans and S100B were analyzed using Spearman's rank correlation, and the predictive capacity of mean Ktrans for serum S100B rise was evaluated using receiver operating characteristic (ROC) analysis.
    RESULTS: A significant positive correlation was found between both initial and peak serum S100B concentrations and mean Ktrans (rs = 0.52, p = 0.018 and rs = 0.47, p = 0.029, respectively) and maximum Ktrans values (rs = 0.47, p = 0.029 and rs = 0.56, p = 0.011, respectively). ROC analysis showed that mean Ktrans values predicted serum S100B rise with AUC of 0,74 (CI 95%: 0.55, 0.91).
    CONCLUSIONS: Our findings demonstrated a significant correlation between pericontusional Ktrans values and serum S100B concentrations, with mean Ktrans values showing potential as an early predictor for serum S100B rise. These findings suggest that combining PCT and serum biomarkers could improve assessment of BBB integrity and aid in the management of TBI.
    Keywords:  Blood-brain barrier; Perfusion computed tomography; Permeability imaging; Serum S100B
    DOI:  https://doi.org/10.1007/s00234-025-03809-5
  9. Cells. 2025 Sep 24. pii: 1493. [Epub ahead of print]14(19):
    The Effect of Long-Term Betacoronavirus Infection on the Permeability of the Blood-Brain Barrier-In Vitro Model Studies.
    Weronika Daria Krahel, Marcin Chodkowski, Michalina Bartak, Agnieszka Ostrowska, Michał M Godlewski, Maksymilian Adamczyk, Małgorzata Krzyżowska, Joanna Cymerys.
      The blood-brain barrier (BBB) is critical for central nervous system homeostasis, yet it is highly vulnerable to viral insults. While acute coronavirus infections are known to impair BBB integrity, the long-term impact of persistent infection on brain endothelial cells remains poorly understood. Using an in vitro BBB model, we examined the effects of a 12-week infection with the neurotropic murine coronavirus MHV-JHM. Structural and functional changes were assessed via fluorescein isothiocyanate (FITC)-dextran permeability assay, confocal imaging of mitochondria, actin cytoskeleton, reactive oxygen species (ROS), scanning electron microscopy (SEM) and RT-qPCR for viral RNA level. Long-term infection induced progressive mitochondrial fragmentation and sustained ROS overproduction. Permeability to 70 kDa dextran increased significantly at 48 h post-infection and exceeded control levels threefold by 168 h. SEM revealed gradual endothelial surface roughening, blebbing, and eventual monolayer collapse with extensive intercellular gaps by week 12. Our study demonstrates that long-term MHV-JHM infection profoundly alters brain endothelial cell structure and function, triggering a cascade of changes that culminate in the disintegration of the BBB model.
    Keywords:  F-actin; MHV-JHM; blood–brain barrier; coronavirus; mitochondria; reactive oxygen species
    DOI:  https://doi.org/10.3390/cells14191493
  10. Cell Rep. 2025 Oct 15. pii: S2211-1247(25)01199-4. [Epub ahead of print]44(10): 116428
    DEAD-box helicase DDX24 is essential for endothelial mitochondrial function to maintain the blood-brain barrier.
    Shuai Li, Yuxuan Liu, Yingying Dong, Yujiao Gong, Simeng He, Jianyu Yuan, Shengfeng Deng, Qianqian Zhang, Lijie Wang, Fei Liu, Qiuyun Tu, Hong Shan, Huanhuan He.
      The blood-brain barrier (BBB) is essential for brain function, yet its underlying regulatory mechanisms remain elusive. Here, we identify DEAD-box RNA helicase 24 (DDX24) as a regulator of the BBB. Endothelial-specific Ddx24 knockout (Ddx24ECKO) mice exhibit deficits in learning and memory and increased BBB permeability. Furthermore, DDX24 knockdown in human cerebral microvascular endothelial cells (hCMEC/D3) disrupts the barrier function through occludin phosphorylation and mitochondrial dysfunction. Targeting NADPH oxidase suppresses BBB hyperpermeability and improves learning and memory deficits in Ddx24ECKO mice. Mechanistically, the DDX24 protein binds to PPFIA4 mRNA and enhances its stability. Consistent with the function of DDX24, PPFIA4 knockdown impairs mitochondrial homeostasis and barrier function in hCMEC/D3 cells. Importantly, DDX24 overexpression attenuates Aβ1-42-induced barrier damage. Taken together, our study uncovers a pivotal role for DDX24 in regulating the BBB via mediating mitochondrial function in endothelial cells, providing a potential therapeutic target for treating BBB-related diseases.
    Keywords:  CP: Neuroscience; DDX24; PPFIA4; blood-brain barrier; brain microvascular endothelial cells; mitochondrial function
    DOI:  https://doi.org/10.1016/j.celrep.2025.116428
  11. Front Neurol. 2025 ;16 1627172
    Research progress on the correlation between biological rhythms and the blood-brain barrier after ischemic stroke.
    Yuanchen Liao, Lei Luo, Qiang Ma, Xiaofeng Gao, Yao Chen, Siyang Yan, Menghao He, Lijuan Liu, Desheng Zhou.
      Biological rhythms play a critical role in regulating human physiology and have been implicated in the onset, progression, and recovery of ischemic stroke (IS). This review summarizes recent experimental and clinical studies that associate circadian regulation with post-stroke blood-brain barrier (BBB) repair, focusing on the role of molecular clock components. Core clock components, including BMAL1 and CLOCK, influence BBB integrity by regulating tight junction protein expression, angiogenesis, neuroimmune responses, and neuroendocrine signaling. Finally, we discuss emerging chronotherapeutic strategies that integrate circadian biology into stroke rehabilitation.
    Keywords:  angiogenesis; biological rhythms; blood-brain barrier; immune system; ischemic stroke; neuroendocrine system
    DOI:  https://doi.org/10.3389/fneur.2025.1627172
  12. Comput Biol Med. 2025 Oct 13. pii: S0010-4825(25)01536-7. [Epub ahead of print]198(Pt A): 111183
    Explaining blood-brain barrier permeability by synergistic effect on molecular substructures.
    Hyeok Jae Lee, Ikhyeong Jun, Hyun Woo Kim.
      The blood-brain barrier (BBB) permeability is a critical factor in designing drug candidates intended either to act within the central nervous system (CNS) or to restrict distribution to the CNS. However, explaining BBB permeability requires accounting for multiple underlying mechanisms and diverse molecular substructures that influence this property. This complicates developing a fully interpretable understanding of BBB permeability. In this study, an explainable machine learning algorithm is proposed to BBB permeability based on synergistic effects on molecular substructures. Furthermore, our approach can be applied to mechanisms related to BBB permeability. Synergistic groups that positively or negatively influence the target property can be identified through a relative importance analysis of each substructure. This allowed us to screen for molecules with multiple positive or negative effects on the target property. Our approach can provide both explainable and predictive models for the design of drug candidates.
    Keywords:  Blood–brain barrier permeability; Chemical substructure; Classification; Explainable AI; Machine learning
    DOI:  https://doi.org/10.1016/j.compbiomed.2025.111183
  13. Life Sci. 2025 Oct 14. pii: S0024-3205(25)00658-7. [Epub ahead of print] 124022
    Targeting Epac1 to protect the blood brain barrier from inflammation-induced dysfunction: Evidence from an in vitro model.
    Nuria Seoane, Aitor Picos, Dolores Viña, Manuel Campos-Toimil.
       AIMS: Exchange protein directly activated by cyclic AMP 1 (Epac1), a direct effector of cyclic AMP (cAMP), has been implicated in the regulation of endothelial permeability in peripheral tissues. However, its potential role in protecting the blood-brain barrier (BBB) under inflammatory conditions has not been previously explored. In this study, we evaluated for the first time the impact of selective Epac1 activation on BBB integrity using an in vitro model of brain microvascular endothelial cells (bEnd.3) exposed to lipopolysaccharide (LPS).
    MATERIALS AND METHODS: Cells were cultured in Transwell systems and treated with selective activators or inhibitors of Epac1 and protein kinase A (PKA). Barrier function was assessed through transendothelial electrical resistance (TEER), tight junction protein expression and localization, reactive oxygen species (ROS) production, pro-inflammatory gene expression, and macrophage adhesion assays.
    KEY FINDINGS: Our results show that Epac1 activation significantly prevented the LPS-induced decrease in TEER values, preserved claudin-5 expression, reduced oxidative stress, and stabilized cytoskeletal organization. PKA activation alone did not restore TEER or protect barrier integrity. However, both Epac1 and PKA were required to reduce macrophage adhesion and vascular cell adhesion molecule 1 (VCAM-1) expression, suggesting complementary roles in modulating inflammatory activation.
    SIGNIFICANCE: These findings identify Epac1 as a novel modulator of BBB integrity during inflammation and support the therapeutic potential of selectively targeting cAMP signaling pathways to preserve BBB function in neurodegenerative diseases associated with neuroinflammation.
    Keywords:  Blood brain barrier; Camp pathway; Epac1; Inflammation; Neurodegenerative diseases; Transendothelial electrical resistence
    DOI:  https://doi.org/10.1016/j.lfs.2025.124022
  14. Curr Top Med Chem. 2025 Oct 10.
    Ellagic Acid as a Therapeutic Agent for Blood-Brain Barrier Restoration in Neurodegenerative Diseases.
    Mazen M Jamil Al-Obaidi, Tanweer Al Zuhaibi, Hoor Al Wahshi.
      The Blood-Brain Barrier (BBB) plays a crucial role in maintaining the stability of the Central Nervous System (CNS) by regulating what enters and protecting the brain from inflammation and damage caused by harmful molecules. The disruption of the BBB is a characteristic feature of several neurodegenerative disorders and is intimately linked to oxidative stress, inflammation, and apoptosis. Ellagic Acid (EA), a polyphenolic molecule present in several fruits and nuts, has attracted interest due to its significant antioxidant, anti-inflammatory, and neuroprotective characteristics. This review examine recent findings on how EA might help keep the BBB healthy and reduce brain damage. EA works by increasing the levels of tight junction proteins, boosting antioxidant processes, and managing cell death pathways. The review also discusses EA's limited bioavailability and emphasises the therapeutic potential of its gut-derived metabolites, urolithins, which demonstrate enhanced stability and cellular transport. Although EA has considerable potential as a neuroprotective drug, its translational use necessitates more research into its pharmacokinetics, delivery mechanisms, and therapeutic effectiveness. A comprehensive understanding of EA's molecular processes, especially in brain microvascular endothelial cells, may provide innovative therapeutic approaches for safeguarding the BBB and addressing neurodegenerative disorders.
    Keywords:  Antioxidants; Apoptosis; Blood-Brain Barrier; Central Nervous System; Ellagic Acid; and Neuroinflammation.; tight junction
    DOI:  https://doi.org/10.2174/0115680266411446250926102553
  15. ACS Appl Mater Interfaces. 2025 Oct 17.
    Correction to "Protein-Carbon Dot Nanohybrid-Based Early Blood-Brain Barrier Damage Theranostics".
    Yuefang Niu, Hui Tan, Xiaofeng Li, Lingling Zhao, Zheng Xie, Yuan Zhang, Shuyun Zhou, Xiaozhong Qu.
      
    DOI:  https://doi.org/10.1021/acsami.5c19068
  16. Toxicology. 2025 Oct 13. pii: S0300-483X(25)00262-8. [Epub ahead of print]519 154303
    The dysbiosis of gut microbiota attributes to the impairment of blood-brain barrier in rats triggered by cadmium.
    Tao Wang, Xinyu Huang, Le Lu, Xianzu Luo, Yi Wang, Yonggang Ma, Xishuai Tong, Hui Zou, Jianhong Gu, Xuezhong Liu, Jianchun Bian, Zongping Liu, Yan Yuan.
      Cadmium (Cd) is a non-biodegradable heavy metal with a long biological half-life that is detrimental to human health. As Cd can increase blood-brain barrier (BBB) permeability and disturb the gut microbiota, the relationship between the BBB and gut microbiota disturbance induced by Cd consumption remains unclear. This study aims to identify whether Cd-induced gut microbiota dysbiosis is associated with rat BBB injury and investigate the possible mechanism. Here, we conducted analyses of variations in the composition of the gut microbiota and its metabolites, as well as BBB permeability and the results of the Morris water maze test, in rats treated with Cd by gavage. Fecal microbiota transplantation was performed to verify the role of the microbiota in altering BBB permeability induced by Cd. The results showed that Cd disturbed the gut microbiota, decreasing the levels of short-chain fatty acids (SCFAs). Furthermore, Cd-induced BBB permeability was substantiated by FITC-dextran leakage, ultrastructural observations, and diminished Claudin-5, Occludin, and ZO-1 protein expression, all of which were mitigated by FMT. In vitro, sodium butyrate (SOB) alleviated Cd-induced oxidative stress and increased the expression levels of GPX4 and FTH. Taken together, these findings suggest that Cd disrupts the microbiota and SCFAs components in rats, thereby contributing to BBB damage. SOB prevents Cd-induced BBB damage by suppressing ferroptosis in microvascular endothelial cells. This exhaustive study considerably enhances our comprehension of the health hazards posed by Cd to the central nervous system via the gut-brain axis.
    Keywords:  BBB; Cadmium; Ferroptosis; Gut microbiota; Tight junction
    DOI:  https://doi.org/10.1016/j.tox.2025.154303
  17. Surg Clin North Am. 2025 Oct;pii: S0039-6109(25)00059-3. [Epub ahead of print]105(5): 857-869
    The Role of the Microbiome and the Neurovascular Unit.
    Sean P Polster.
      The gut-brain axis plays a crucial role in neurovascular diseases, linking gut microbiota to blood-brain barrier integrity, neuroinflammation, and disease progression. Conditions such as cerebral cavernous malformations, traumatic brain injury, radiation-induced damage, and stroke exhibit microbiome-driven modulation that may be relevant to explain disease variance. Microbial metabolites have been shown to influence endothelial function and secondary brain injury mechanisms. Emerging interventions of dietary modifications, probiotics, fecal microbiota transplantation, and metabolite-based therapies show promise in mitigating neurovascular damage. Future research should focus on microbiome-targeted treatments, biomarker discovery, and personalized strategies to optimize neurovascular health through gut microbiome modulation.
    Keywords:  Cerebral cavernous malformations; Gut-brain axis; Microbiome; Neurosurgery; Neurovascular unit; Radiation damage; Stroke; Traumatic brain injury
    DOI:  https://doi.org/10.1016/j.suc.2025.06.008
  18. Ecotoxicol Environ Saf. 2025 Oct 11. pii: S0147-6513(25)01518-0. [Epub ahead of print]305 119173
    Acetylcholine mediates nitro-PAHs induced inflammation and ameliorates the abnormalities in blood-brain barrier related proteins.
    Yu Shang, Huijuan Wang, Jin Huang, Jing An, Guofa Ren, Yangjun Wang, Qisheng Tang, Xinghua Qiu, Bingye Xu.
      Nitro-polycyclic aromatic hydrocarbons (nitro-PAHs) are important organic components in fine particulate matter (PM2.5). Recent studies found nitro-PAHs have adverse effects on central nervous system, leading to an increased risk of neurodegenerative diseases (NDDs). Oxidative stress and neuroinflammation can synergistically interfere with multiple signaling pathways regulating blood-brain barrier (BBB) damage, thereby contributing to NDDs. To investigate the roles of nitro-PAHs in mediating PM2.5-induced nervous system effects and their underlying mechanisms, human glioma cells (U251) were treated with 1-nitropyrene and 9-nitroanthracene, two typical nitro-PAHs in the air. The study demonstrated nitro-PAHs caused extensive neuronal damage, including cellular membrane disruption, mitochondrial membrane potential collapse, and apoptosis. Nitro-PAHs induced neuroinflammation and BBB disruption, as indicated by cytokine release and abnormalities in BBB-related proteins. Inhibitor experiments suggested that cytokines were involved in dysregulation of BBB-related proteins. Furthermore, nitro-PAHs elevated acetylcholinesterase activity and disrupted acetylcholine balance in U251 cells, which modulated neuroinflammation and downstream BBB damage. Finally, inhibitor studies confirmed that oxidative stress played an important regulatory role in acetylcholine balance, as well as in neuroinflammatory responses and the subsequent BBB injuries. This study highlighted the urgent need to identify neurotoxic substances and to establish priority control measures to protect human health.
    Keywords:  Acetylcholine; Blood-brain barrier; Neuroinflammation; Nitro-polycyclic aromatic hydrocarbons; Oxidative stress
    DOI:  https://doi.org/10.1016/j.ecoenv.2025.119173
  19. Phytomedicine. 2025 Oct 07. pii: S0944-7113(25)01013-X. [Epub ahead of print]148 157375
    Zexieyin formula attenuates Alzheimer's disease via suppressing A1 astrocyte activation: A serum pharmacochemistry and network pharmacology study.
    Shihan Zhou, Minjie Sun, Zhouchenghao Song, Zizhen Qin, Haoxin Wu, Mingqiang Wang, Boran Zhu.
       BACKGROUND: Disruption of the blood-brain barrier (BBB) is a critical pathological event in Alzheimer's disease (AD) progression. The ZeXieYin Formula (ZXYF), as described in the ancient Chinese medical text Huangdi Neijing, has shown multitarget neuroprotective effects and promising pharmacokinetics in preclinical studies with transgenic AD rodent models. Despite these findings, the exact molecular mechanisms by which its bioactive components interact with BBB regulatory pathways are not fully understood, necessitating comprehensive analysis through integrated systems pharmacology approaches.
    PURPOSE: The primary objective of this study is to explore the protective properties of ZXYF against BBB disruption in the context of AD. Additionally, the investigation seeks to elucidate the molecular pathways underlying the therapeutic effects of ZXYF in this scenario.
    METHODS: In vivo, APP/PS1 mice modeled AD. Y-maze and MWM tests assessed ZXYF's effects on cognition. Transmission electron microscopy (TEM) evaluated ZXYF's impact on BBB ultrastructure, while immunohistochemistry (IHC) and western blotting (WB) quantified tight junction (TJ) protein expression. Immunofluorescence detected GFAP (astrocytic marker), and ELISA measured hippocampal neuroinflammatory cytokines. Bioactive ZXYF components in systemic circulation were identified via UPLC-Q-TOF-MS/MS, followed by compound-target network construction and computational prioritization of AD pathways via multiplex network analysis. In vitro, ZXYF (2/6 mg/ml, 24 h) was applied to two BBB models: (1) LPS+TNF-α+IL-1α-stimulated bEnd.3 monolayers and (2) bEnd.3/C8-D1A astrocyte co-cultures. qPCR and WB assessed A1-specific astrocyte gene and protein expression. Molecular docking, Molecular dynamics (MD), Cellular thermal shift assay (CETSA) and Surface plasmon resonance (SPR) binding analysis simulations characterized ZXYF constituent binding to JAK2. Furthermore, siRNA was applied to knockdown JAK2 in the C8-D1A cell to further verify the role of JAK2/STAT3 pathway in ZXYF inhibition of A1 astrocyte activation.
    RESULTS: Our findings demonstrated that ZXYF preserved BBB integrity and improved cognitive function in AD mice. Mechanistically, ZXYF restored TJ protein expression (ZO-1, occludin, claudin-5), attenuated astrocyte activation (GFAP↓), and reduced neuroinflammation. Systemic component analysis identified 13 major bioactive constituents of ZXYF. Network pharmacology and GO/KEGG enrichment revealed the JAK2/STAT3 pathway as the core mechanism underlying ZXYF's anti-AD effects. In vitro, ZXYF protected endothelial cells in co-cultured BBB models against LPS/cytokine-induced injury by suppressing A1 astrocyte polarization. Crucially, molecular docking/dynamics confirmed strong binding affinity of key ZXYF components to JAK2, while WB validated ZXYF-mediated inhibition of JAK2/STAT3 phosphorylation (p-JAK2↓, p-STAT3↓) in AD mice.
    CONCLUSIONS: Our study shows that ZXYF significantly improved cognitive impairments and maintained BBB integrity in an AD mouse model. Compositional analysis revealed 13 major bioactive components of ZXYF. Mechanistically, ZXYF inhibited A1 astrocyte activation by suppressing the JAK2/STAT3 signaling pathway, enhancing endothelial barrier function. These results provide a mechanistic foundation for further investigation of ZXYF's therapeutic potential for AD and other cognitive disorders involving BBB dysfunction.
    Keywords:  Alzheimer’s disease; Astrocyte polarization; Hippocampus; JAK2; Molecular docking; Network pharmacology; ZXYF
    DOI:  https://doi.org/10.1016/j.phymed.2025.157375
  20. Aging Dis. 2025 Sep 20.
    Diversity of Brain Microvascular Endothelial Cell Functions: Physiology, Ischemia/Hypoxia, and Underlying Protection.
    Mingxuan Cao, Jia Liu, Xunming Ji.
      Ischemic stroke is a global health crisis associated with high mortality, long-term disability, and high healthcare costs. Microvascular dysfunction is pivotal in its pathophysiology. The brain microvasculature, far from a passive set of structures, is a complex system participating in multiple biological processes, including controlling angiogenesis, maintaining blood‒brain barrier (BBB) integrity, regulating cerebral blood flow (CBF) via neurovascular coupling, managing substance transport, and modulating central nervous system immune responses. Brain microvascular endothelial cells (BMECs) are central to the pleiotropic functions of the brain microvasculature; however, ischemia and hypoxia severely affect BMECs and disrupt microvascular functions. Angiogenesis is dysregulated, the BBB becomes permeable, the regulation of CBF becomes unbalanced, nutrient transport is disrupted, and immune modulation is disrupted. Targeted strategies to safeguard BMECs against ischemic-hypoxic injury have great potential for the treatment of ischemic stroke patients. This review comprehensively outlines the diversity of BMECs under normal conditions, delves into the effects of ischemia and hypoxia on these cells, and explores emerging protective strategies. By integrating these elements, this study offers a holistic perspective on the role of BMECs in ischemic stroke pathophysiology and aims to inspire future research in this crucial field.
    DOI:  https://doi.org/10.14336/AD.2025.0664
  21. BMC Neurol. 2025 Oct 14. 25(1): 417
    Assessment and characterization of BBB permeability parameters in autoimmune encephalitis based on 99mTc-DTPA SPECT/CT.
    Jianfang Li, Liangjun Xie, Li Xiao, Yaxin Lu, Luping Qin, Hongmei Lin, Yueming Zha, Bingjun Zhang, Jigang Yang, Wei Qiu, Jinchi Liao, Muhua Cheng, Yaqing Shu.
      
    Keywords:   99mTc-DTPA; Autoimmune encephalitis; Blood-brain barrier; Multiple correspondence analysis; Single-photon emission computed tomography/Computed tomography; Statistical parametric mapping
    DOI:  https://doi.org/10.1186/s12883-025-04454-4
  22. Brain Res Bull. 2025 Oct 14. pii: S0361-9230(25)00396-X. [Epub ahead of print] 111584
    The Role of VCAM1 in Post-Stroke Cognitive Impairment: Molecular Mechanisms and Therapeutic Potential.
    Qinli Zhang, Hua Xu, XiuYan Han, Xu Liu, Xiaoshu Guo, Hong Liu, Changyun Liu.
      Ischemic stroke constitutes a critical medical condition that can lead to post-stroke cognitive impairment (PSCI), yet the underlying molecular mechanisms remain incompletely understood. This study investigated the role of vascular cell adhesion molecule 1 (VCAM1) in cognitive dysfunction following ischemic stroke and evaluated its therapeutic potential. In a rat model of middle cerebral artery occlusion (MCAO), VCAM1 knockdown resulted in improved motor function, enhanced spatial memory, and reduced infarct size. Mechanistically, silencing VCAM1 was found to have mitigated blood-brain barrier (BBB) disruption by upregulating tight junction proteins such as Claudin-5, ZO-1, and Occludin. Additionally, it had suppressed cerebral microvascular hyperproliferation and decreased neuronal death via modulation of the Bax/Bcl-2 pathway. VCAM1 knockdown had also alleviated neuroinflammation by promoting microglial polarization toward the anti-inflammatory state (Arg1, CD206), while reducing the pro-inflammatory state (Iba-1, CD86). Concurrently, it had downregulated pro-inflammatory cytokines TNF-α and IL-1β and upregulated the anti-inflammatory cytokine IL-4. Transcriptome analysis identified VCAM1 as a key regulator within immune pathways, particularly enhancing PD-1/PD-L1 signaling, which was associated with cognitive recovery. Enrichment analyses demonstrated that VCAM1 knockdown alleviated cerebral ischemia-reperfusion injury in MCAO rats by modulating ion channel activity, calcium signaling pathways, and extracellular matrix interactions, while restoring dysregulated immune responses and cellular localization processes. Therefore, VCAM1 may be a promising therapeutic target for the treatment of PSCI.
    Keywords:  PD-1/PD-L1; VCAM1; cerebrovascular microcirculation dysfunction; neuroinflammation; post-stroke cognitive impairment
    DOI:  https://doi.org/10.1016/j.brainresbull.2025.111584
  23. J Am Heart Assoc. 2025 10 14. e044453
    Expression of Concern: Netrin-1 Preserves Blood-Brain Barrier Integrity Through Deleted in Colorectal Cancer/Focal Adhesion Kinase/RhoA Signaling Pathway Following Subarachnoid Hemorrhage in Rats.
      The Editors of the Journal of the American Heart Association (JAHA) are issuing an Expression of Concern regarding the article, "Netrin-1 Preserves Blood-Brain Barrier Integrity Through Deleted in Colorectal Cancer/Focal Adhesion Kinase/RhoA Signaling Pathway Following Subarachnoid Hemorrhage in Rats" (JAHA. 2017. DOI: https://doi.org/10.1161/JAHA.116.005198). Concerns have been raised regarding the quality of data and images in the aforementioned article. The editors and Scientific Publishing Committee are in communication with the authors regarding the integrity of the image data, and Loma Linda University has confirmed the concerns are being reviewed. While we await the outcome of this review, we are publishing this Expression of Concern to indicate that the data and statements in the article may not be reliable.
    DOI:  https://doi.org/10.1161/JAHA.125.044453
This page is being maintained by Thomas Krichel. It was last updated on 2025‒10‒20 at 14:00.