bims-blobar 2025-07-13 papers

bims-blobar

Biomed News

on Blood brain barrier repair

Issue of 2025–07–13
sixteen papers selected by
Nicolas Rebergue

Impact of hyperoside on the blood-brain barrier in rats with bacterial meningitis through the microRNA-155/BDNF pathway.
A 3D In Vitro Blood-Brain Barrier Model to Study Pathogen and Drug Effects on the BBB.
Cell type-specific contributions to impaired blood-brain barrier and cerebral metabolism in presymptomatic 5XFAD mice.
Astrocytic connexin 43-hemichannels aggravate seizures by modulating blood-brain barrier permeability in temporal lobe epilepsy mice.
Macrophage-mimetic liposomes co-delivering ceria and Ac2-26 peptide for penumbra protection in ischemic stroke.
Peroxiredoxin 6 Alone or in Combination with Fingolimod Ameliorates EAE.
How endothelial cell metabolism shapes blood-brain barrier integrity in neurodegeneration.
Restoring brain barriers: an innovative approach for treating neurological disorders.
Short-chain chlorinated paraffins (C11, 64.2%Cl) induced neurotoxicity and blood-brain barrier disruption in adult male zebrafish (Danio rerio).
Link between blood-brain barrier disruption and microglial activation.
Repeated naloxone-induced morphine withdrawal alters blood brain barrier and blood spinal cord barrier integrity in mice.
Comparison of blood-brain barrier permeability changes in gyrencephalic (ferret & non-human primate) and lissencephalic (rat) models following blast overpressure exposures.
Acupuncture Alleviates Blood-Brain Barrier Damage After Delayed rtPA Thrombolysis for Acute Ischemic Stroke by Regulating Ferroptosis.
RNF213 regulates blood‒brain barrier integrity by targeting TRAF3 for type I interferon activation during A. baumannii infection.
Polystyrene microplastics impair the function of human retinal microvascular endothelial cells and pericytes and increase vascular permeability in vitro.
The MDM2-p53 axis regulates norrin/frizzled4 signaling and blood-CNS barrier function.

Neuroendocrinology. 2025 Jul 04. 1-21

Impact of hyperoside on the blood-brain barrier in rats with bacterial meningitis through the microRNA-155/BDNF pathway.

Tao Zhang, Long Zhao, Renzhao Kuang.

OBJECTIVE: This study aims to elucidate the effect and mechanism of hyperoside on blood-brain barrier (BBB) damage in bacterial meningitis (BM) by regulating the microRNA-155 (miR-155)/brain-derived neurotrophic factor (BDNF) pathway.
METHODS: A rat model of meningitis was established via intracisternal injection of Streptococcus pneumoniae (SPN), while an in vitro BBB injury model was created by treating human cerebral microvascular endothelial cells (hCMEC/D3) with lipopolysaccharide (LPS). Hyperoside was administered in both models. Evans blue staining assessed BBB permeability in rats. Brain water content was determined using the wet-dry weight method. Transendothelial electrical resistance (TEER) was measured with an endothelial resistance meter. RT-qPCR, Western blot (WB), and ELISA assessed the expression of tight junction proteins in brain tissues and cell supernatants. ELISA was also used to measure inflammatory cytokine in cerebrospinal fluid and cell culture supernatants. Bioinformatics analysis and dual-luciferase reporter assays validated the regulatory relationship between miR-155 and BDNF.
RESULTS: Hyperoside treatment reduced BBB permeability, alleviated brain edema, and suppressed inflammatory cytokine expression in SPN-infected rats. In LPS-induced hCMEC/D3 cells, hyperoside significantly increased TEER values. Hyperoside markedly downregulated miR-155 and upregulated BDNF expression. miR-155 directly targeted BDNF and negatively regulated its expression in hCMEC/D3 cells. Importantly, the administration of a miR-155 mimic or BDNF knockdown (sh-BDNF) partially reversed the protective effects of hyperoside on TEER, tight junction protein expression (ZO-1, claudin-5, AQP4), and inflammatory cytokine levels (TNF-α, IL-1β, IL-6) in LPS-induced hCMEC/D3 cells.
CONCLUSION: Hyperoside mitigates BBB damage in BM via reducing miR-155 expression and upregulating BDNF expression, leading to an increase in tight junction-related protein expression, a reduction in inflammatory factor secretion, and a decrease in BBB permeability.

DOI: https://doi.org/10.1159/000547276
Methods Mol Biol. 2025 ;2950 61-69

A 3D In Vitro Blood-Brain Barrier Model to Study Pathogen and Drug Effects on the BBB.

Alizé Proust, Robert J Wilkinson.

  In vitro blood-brain barrier models play a pivotal role in neuroscience research to study the intricate structure and function of the blood-brain barrier, facilitating drug development, enhancing disease understanding, and advancing treatment strategies for neurological disorders. Here, we present a triple contact coculture model with endothelial cells, astrocytes, and pericytes and offer a physiologically relevant BBB.

Keywords:  Astrocytes; Blood-brain barrier; Contact model; Endothelial cells; Pericytes

DOI:  https://doi.org/10.1007/978-1-0716-4674-8_5
bioRxiv. 2025 Apr 26. pii: 2025.04.23.650260. [Epub ahead of print]

Cell type-specific contributions to impaired blood-brain barrier and cerebral metabolism in presymptomatic 5XFAD mice.

Minmin Yao, Na Sun, Raleigh Linville, Zhiliang Wei, Aaron Kakazu, Yuxiao Ouyang, Ruoxuan Li, Lida Du, Haitong Wang, Yuan Zhou, Yanli Jiang, Ziqin Zhang, Anna Li, Hanzhang Lu, Jiadi Xu, Manolis Kellis, Myriam Heiman, Wenzhen Duan.

Altered cerebral metabolism and blood-brain barrier (BBB) dysfunction are emerging as critical contributors to the preclinical phase of Alzheimer's disease (AD), underscoring their role in early pathogenesis. To identify sensitive biomarkers before irreversible neuronal loss and cognitive decline, we examined 5XFAD mice at 3 months of age by applying multiple advanced MRI techniques. Arterial spin tagging based MRI revealed increased BBB permeability and water extraction fraction, indicating compromised BBB integrity at the early stage of pathogenesis in 5×FAD mice. Despite preserved cerebral blood flow, a decreased unit mass cerebral metabolic rate of oxygen (CMRO2) was evident in the same cohorts of 5XFAD mice. Interestingly, a region-specific decrease of tissue pH values was detected in the hippocampus of these 5XFAD mice by creatine chemical exchange saturation transfer MRI. Elevated neuronal H4K12 lactylation in the hippocampus supports the reduced pH values. To further dissect the cellular and molecular mechanisms underlying these MRI-detectable changes in 5XFAD mice, we conducted single-nucleus RNA sequencing (snRNA-Seq) with optimized blood vessel enrichment protocols. Our results revealed cell type-specific transcriptomic changes in the hippocampus of 3-month-old 5XFAD mice, including downregulation of synaptogenesis and synaptic transmission genes in the CA1 and dentate gyrus excitatory neurons, impaired endothelial gene expression linked to brain barrier function and angiogenesis, altered innate immune response genes in astrocytes, as well as upregulation of cholesterol biosynthesis and metabolism genes in the CA1 excitatory neurons. These findings underlie the intricate interplay between BBB disruption and metabolic dysregulation before the onset of cognitive decline in AD. Our study demonstrates that BBB dysfunction and cerebral metabolic alterations preceded brain hypoperfusion and cognitive decline, emphasizing potential molecular pathways for early intervention. These findings, once validated in human studies, could significantly enhance early diagnosis and inform novel therapeutic strategies targeting early AD pathogenesis.

DOI: https://doi.org/10.1101/2025.04.23.650260
Pediatr Discov. 2024 Sep;2(3): e2500

Astrocytic connexin 43-hemichannels aggravate seizures by modulating blood-brain barrier permeability in temporal lobe epilepsy mice.

Honghong Song, Yi Li, Jiayu Liu, Xianshu Bai, Li Jiang, Tingsong Li.

  The involvement of astrocytic connexin 43 (Cx43) in epileptogenesis has been extensively studied through various approaches, yet the underlying mechanism remains enigmatic. In this study, we explored whether astrocytic Cx43 forms hemichannels (HCs) that contribute to seizure progression in temporal lobe epilepsy (TLE) in mice. We focused on how these HCs influence the permeability of the blood-brain barrier (BBB), a crucial factor in the pathophysiology of epilepsy. Immunofluorescence staining and western blot analysis were employed to assess Cx43 expression in kainic acid-induced TLE mice, while BBB permeability was evaluated in TLE mice and those treated with TAT-Gap19 (an astrocytic Cx43 HC inhibitor) using Evans Blue permeation, serum S100β protein quantification, ZO-1 expression, and albumin extravasation into brain parenchyma via western blotting. Furthermore, seizure burden was monitored continuously using telemetric electroencephalography (EEG) and video monitoring in epileptic and TAT-Gap19-treated mice. Results demonstrated a significant increase in Cx43 content in hippocampal tissue in the TLE group, with a pronounced expression around blood vessels. TAT-GAP19 treatment alleviated EEG seizures and BBB permeability in TLE mice. These findings suggest that astrocytic Cx43 HCs in the hippocampus play a crucial role in epileptogenesis and seizure progression by regulating BBB permeability. Targeting Cx43-formed HCs distributed around the neurovascular unit may offer a novel therapeutic approach for epilepsy.

Keywords:  Cx43; astrocytes; blood‐brain barrier; epilepsy; hippocampus

DOI:  https://doi.org/10.1002/pdi3.2500
J Nanobiotechnology. 2025 Jul 05. 23(1): 488

Macrophage-mimetic liposomes co-delivering ceria and Ac2-26 peptide for penumbra protection in ischemic stroke.

Lingyun Bai, Na Li, Huiqin Li, Yuxuan Dai, Yi Bai, Feiyu Ma, Dujuan Sha, Shengnan Xia, Yun Xu, Xiang Cao.

  Ischemic stroke is one of the most severe central nervous system disease with high disability and mortality rates worldwide. Effective treatment requires strategies that address the multifaceted pathophysiology of ischemic penumbra, including oxidative stress-induced neuronal apoptosis and blood-brain barrier (BBB) disruption. Here, inspired by the inflammation-homing property of macrophages, we developed macrophage-mimetic liposomes (MM-LPs) by integrating macrophage membranes with liposomes for the co-delivery of cerium oxide nanoparticles (CeO2) and the Ac2-26 peptide (CeO2-Ac2-26@MM-LPs). CeO2 effectively scavenged reactive oxygen species (ROS), improving mitochondrial function and inhibiting neuronal apoptosis, while Ac2-26 upregulated tight junction proteins to enhance BBB integrity. In a transient middle cerebral artery occlusion (tMCAO) mouse model, CeO2-Ac2-26@MM-LPs exhibited significant accumulation in ischemic regions, where they exerted dual protective effects on the ischemic penumbra by mitigating neuronal damage and preserving BBB integrity. This resulted in improved neurological function, reduced infarct volume, and attenuated BBB disruption. Mechanistically, CeO2-Ac2-26@MM-LPs activated the NRF2 signaling pathway, upregulating antioxidant enzymes (HO-1 and NQO1), while simultaneously suppressing NF-κB activation, thereby reducing neuronal death and BBB damage in the penumbra. This multi-target combination strategy provides a promising platform for ischemic stroke treatment, with potential applicability to other neurological disorders characterized by oxidative stress and BBB disruption.

Keywords:  Blood-brain barrier; Ceria; Ischemic stroke; Macrophage membrane; Neurons; Reactive oxygen species

DOI:  https://doi.org/10.1186/s12951-025-03575-9
Curr Neuropharmacol. 2025 Jul 07.

Peroxiredoxin 6 Alone or in Combination with Fingolimod Ameliorates EAE.

Lunin S M, Novoselova E G, Glushkova O V, Parfenyuk S B, Kuzekova A A, Novoselova T V, Sharapov M G, Mubarakshina E K, Goncharov R G, Khrenov M O.

   INTRODUCTION: Multiple Sclerosis (MS) is characterized by the infiltration of leukocytes into the nervous tissue, and disruption of the Blood-Brain Barrier (BBB) is one of the main factors in the progression of MS and its model, Experimental Autoimmune Encephalomyelitis (EAE). Furthermore, some anti-lymphocytic drugs against MS may inherently produce BBB disruption as their side effect. This study hypothesized that drugs restoring the BBB may be useful for the treatment of MS and EAE, as well as for ameliorating the side effects of modern anti-lymphocytic drugs.
METHODS: EAE was induced in SJL/J mice. EAE progression was evaluated by a severity score and a plasma cytokine profile, while a BBB condition was evaluated by the Evans dye method, Tight Junction Proteins (TJPs) content, and leukocyte infiltration.
RESULTS: The mice with EAE demonstrated neurological symptoms, a cytokine response, and BBB deterioration, which was associated with upregulation of the NADPH oxidases NOX1 and NOX4 in the brain. Administration of the anti-lymphocyte drug fingolimod to EAE mice caused lymphopenia, improved animal health, enhanced the BBB function during the administration period, and decreased the pro-inflammatory response, but it was accompanied by a "withdrawal effect," defined as a sharp increase in the IL-17 and IFN-gamma to levels higher than those in untreated animals, lymphocyte hyperactivation, worsening symptoms, and increasing BBB permeability after discontinuation of fingolimod. Administration of peroxiredoxin 6 (Prdx6) to EAE mice also improved BBB, decreased lymphocyte infiltration and NADPH oxidase expression, and ameliorated symptoms. Preliminary administration of Prdx6 before the fingolimod treatment eliminated the "withdrawal effect" of fingolimod and led to full recovery of the EAE mice. This Prdx6 effect was associated with the activation of anti-proliferative and pro-apoptotic signaling cascades in lymphocytes.
DISCUSSION AND CONCLUSION: Both fingolimod and Prdx6 produced beneficial effects, while Prdx6 may be useful for ameliorating the side effects of anti-lymphocytic drugs. Accounting for literature data that discontinuation of MS treatment is very likely to lead to a severe MS rebound, a drug that prevents the rebound should be useful.

Keywords:  EAE; Multiple sclerosis; autoimmune response.; blood-brain barrier; fingolimod; peroxiredoxin 6

DOI:  https://doi.org/10.2174/011570159X372166250619064636
Front Mol Neurosci. 2025 ;18 1623321

How endothelial cell metabolism shapes blood-brain barrier integrity in neurodegeneration.

Jiaxin Wang, Yuchun Chen, Shiteng Chen, Zihan Mu, Jun Chen.

   Background/objective: Endothelial cells, a monolayer of cells adjacent to blood vessels, play a critical role in maintaining vascular function through metabolic pathways such as glycolysis, fatty acid, and amino acid metabolism. Recent studies have revealed their significant involvement in neurodegenerative diseases, although the underlying mechanisms remain unclear.
Methods: By reviewing literature from the past decade, we summarized the metabolic alterations and functional changes of endothelial cells in neurological disorders.
Results: In neurodegenerative diseases such as stroke, Alzheimer's disease, multiple sclerosis, and aging, metabolic dysregulation in cerebral vascular endothelial cells disrupts their normal function and is closely associated with blood-brain barrier impairment.
Conclusion: Aberrant endothelial cell metabolism compromises the integrity of the blood-brain barrier and exacerbates the pathological progression of neurodegenerative diseases. Our review further explores the therapeutic potential of targeting endothelial cell metabolism in various pathological contexts, aiming to provide novel insights for the prevention and treatment of related disorders.

Keywords:  Alzheimer’s disease; aging; blood–brain barrier; endothelial cell; metabolism; multiple sclerosis; stroke

DOI:  https://doi.org/10.3389/fnmol.2025.1623321
Fluids Barriers CNS. 2025 Jul 10. 22(1): 72

Restoring brain barriers: an innovative approach for treating neurological disorders.

Sighild Lemarchant, Britta Engelhardt, Francesca Cicchetti, Gregory J Bix, Annette Janus, Yann Godfrin, Hélène Blasco, Matthew Campbell, Aurélie de Rus Jacquet.

  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.

Keywords:  Alzheimer’s disease; Amyotrophic lateral sclerosis; BBB disruption; BSCB disruption; Claudin-5; Huntington’s disease; Multiple sclerosis; Parkinson’s disease; Therapeutic strategies; Tight junction

DOI:  https://doi.org/10.1186/s12987-025-00688-z
Environ Pollut. 2025 Jul 04. pii: S0269-7491(25)01155-8. [Epub ahead of print] 126782

Short-chain chlorinated paraffins (C11, 64.2%Cl) induced neurotoxicity and blood-brain barrier disruption in adult male zebrafish (Danio rerio).

Xinyu Liu, Jingui Liu, Shiqiang Dong, Chen Liu, Chao Wei, Jianan Ling, Ji Zheng, Xin Zheng.

  Short-chain chlorinated paraffins (SCCPs) are a series of persistent, bioaccumulative and toxic (PBT) substances that are widely distributed in the environment. However, little information is available on SCCPs neurotoxicity. In present research, adult male zebrafish (Danio rerio) were used as a model and exposed to 0, 50, or 250 μg/L SCCPs for 21 days to investigate the neurotoxicity effect of SCCPs. We evaluated the swimming behavior traits, acetylcholinesterase (AChE) levels, neuroinflammatory response, tight junction-related mRNA and protein levels and blood-brain barrier (BBB) ultrastructural changes of fish following 21 days of SCCPs exposure. Our research showed that SCCPs significantly weakened swimming ability and locomotor activity of zebrafish, activated the neuroinflammatory response, decreased AChE content and activity, and the tight junction-related mRNA and protein levels in the fish brain. In addition, the results of transmission electron microscopy (TEM) revealed the ultrastructural changes of BBB and brain cell apoptosis in zebrafish, further proving that chronic exposure to SCCPs can cause BBB damage. In summary, this study focused on the chronic exposure of zebrafish to SCCPs, revealing that such exposure can damage the BBB and lead to nerve injury, and will provide important insights into the potential health risks associated with SCCPs and emphasize the necessity for further research.

Keywords:  Blood-brain barrier (BBB); Impairment; Neurotoxicity; Short-chain chlorinated paraffins (SCCPs); Zebrafish (Danio rerio)

DOI:  https://doi.org/10.1016/j.envpol.2025.126782
Neural Regen Res. 2025 Jul 05.

Link between blood-brain barrier disruption and microglial activation.

Arjun Sapkota, Sebok K Halder, Richard Milner.

DOI: https://doi.org/10.4103/NRR.NRR-D-25-00103
Mol Brain. 2025 Jul 07. 18(1): 59

Repeated naloxone-induced morphine withdrawal alters blood brain barrier and blood spinal cord barrier integrity in mice.

Yuta Kohro, Craig E Brown, Tuan Trang.

  Passage of molecules across the central nervous system is tightly regulated by the blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB), which restrict entry of many substances, including opioid medications. Here, we examined the effects of opioid withdrawal on BBB and BSCB integrity by measuring extravascular levels of peripherally injected dyes - Evans Blue (high molecular weight) and sodium fluorescein (NaFl, low molecular weight) - in the brain and spinal cord. In morphine-dependent male and female mice, repeated naloxone challenge induced robust withdrawal behaviors concomitant with region specific dye extravasation. In a fixed dose morphine paradigm, Evans Blue extravasation was highest within the cortex, hippocampus, cerebellum, and brainstem (pons and medulla) in male mice, and in the hypothalamus in female mice. By contrast, NaFl extravasation remained unchanged in both sexes. In an escalating dose morphine paradigm, Evans Blue extravasation was most prominent in the brainstem (pons and medulla) of both sexes, as well as in the lumbar of male mice and cervical spinal cord of female mice. NaFl extravasation in these regions was unchanged in male but reduced in female mice. These findings suggest that repeated opioid withdrawal alters permeability of the BBB and BSCB in discrete regions of the brain and spinal cord.

Keywords:  Blood brain barrier; Blood spinal cord barrier; Brainstem; Opioid; Opioid withdrawal

DOI:  https://doi.org/10.1186/s13041-025-01231-9
Exp Neurol. 2025 Jul 07. pii: S0014-4886(25)00239-0. [Epub ahead of print]392 115375

Comparison of blood-brain barrier permeability changes in gyrencephalic (ferret & non-human primate) and lissencephalic (rat) models following blast overpressure exposures.

Kakulavarapu V Rama Rao, Victor L McLean, Donna M Wilder, Shataakshi Dahal, Malavika Kattuparambil, Joseph B Long, Venkatasivasai Sujith Sajja.

  Blast wave (BW)-associated brain injury criteria to assess risk of Warfighters are currently inadequate due to lack a suitable animal model that does not represent human blast injury pathology. We hypothesize that animal models with brain structures more closely resemble the human brain (e.g. gyrencephalic models) could better translate to recreate and identify human blast pathology. As a one-of-a kind evaluation, this study compared the blood brain barrier (BBB) integrity, gliovascular changes and neuroinflammation in lissencephalic (rats) and gyrencephalic (ferrets) models exposed to blast waves at varying overpressures (10, 15 and 20 psig) with a validation study in non-human primates exposed to a single BW at 20 psig. BBB disruption was measured by Evans blue extravasation. The extent of gliosis in brain sections was measured by immunofluorescence analysis of glial fibrillary acidic protein (GFAP), ionized calcium binding adaptor molecule 1 (Iba-1), and neurodegeneration was determined by silver staining. Ferrets exposed to BW had a statistically significant increase in extravasation of Evans blue in different brain regions while a no such changes were observed in the rat model. Blast also induced a significant reactive astrogliosis and microglial activation in ferrets. NHPs exposed to a single BW at 20 psig showed a significant increase in EB extravasation in only thalamus. These results suggest that gyrencephalic brain structures may be more vulnerable to vascular disruption compared to lissencephalic models and these models may have better translatability to human blast injuries and potentially better suited to identify injury thresholds.

Keywords:  Blast induced neurotrauma; Blood-brain barrier; Ferret; Gyrencephalic brain; Lissencephalic brain; Non-human primates; Traumatic brain injury

DOI:  https://doi.org/10.1016/j.expneurol.2025.115375
Brain Behav. 2025 Jul;15(7): e70644

Acupuncture Alleviates Blood-Brain Barrier Damage After Delayed rtPA Thrombolysis for Acute Ischemic Stroke by Regulating Ferroptosis.

Zheng Huang, Tianliang Lu, Xinyu Liu, Zhihui Zhang, Yangyang Song, Yiyang Li, Wentao Xu, Xinchang Zhang, Guangxia Ni.

   BACKGROUND: Acute ischemic stroke (AIS) is the second leading cause of death and disability worldwide. Recombinant tissue plasminogen activator (rtPA) was the first FDA-approved thrombolytic drug for AIS. However, delayed administration of rtPA exacerbates brain injury and increases the risk of hemorrhagic transformation (HT) and mortality. Ferroptosis, an iron-dependent form of cell death, is closely associated with the pathological process of AIS. Acupuncture, a vital component of traditional Chinese medicine, has been widely used in clinical practice for AIS treatment. This study aims to investigate the protective effects of acupuncture on rats subjected to delayed rtPA thrombolysis in cerebral infarction and its relationship with ferroptosis.
METHODS: Adult male Sprague-Dawley rats were used to establish a thromboembolic stroke model and were randomly assigned to different treatment groups. Xingnao Kaiqiao (XNKQ) acupuncture (at Neiguan and Shuigou acupoints) or sham acupuncture was administered in combination with rtPA thrombolysis. Outcome measures included neurological scores, infarct volume, brain water content, blood-brain barrier (BBB) permeability, expression of iron metabolism-related proteins, lipid peroxidation levels, and mitochondrial ultrastructural changes.
RESULTS: XNKQ acupuncture significantly improved neurological deficits following delayed rtPA thrombolysis, reduced infarct volume and brain water content, and decreased the incidence of HT and brain edema. By modulating iron metabolism, inhibiting lipid peroxidation, and preserving mitochondrial integrity, acupuncture attenuated neuronal damage and BBB disruption mediated by ferroptosis.
CONCLUSION: XNKQ acupuncture inhibits neuronal ferroptosis by improving iron metabolism disorders, lipid peroxidation accumulation, and mitochondrial structure, thereby alleviating neuronal damage and BBB disruption, and exerting a protective effect on brain tissue after delayed rtPA thrombolysis.

Keywords:  acupuncture; acute ischemic stroke; blood–brain barrier; cerebral infarction; ferroptosis; neuron; rtPA thrombolysis

DOI:  https://doi.org/10.1002/brb3.70644
PLoS Pathog. 2025 Jul;21(7): e1013333

RNF213 regulates blood‒brain barrier integrity by targeting TRAF3 for type I interferon activation during A. baumannii infection.

Yanfeng Li, Qingqing Xie, Luyu Yang, Qian Jiang, Zhiping Liu, Chengjiang Gao, Xiaopeng Qi, Tao Xu.

RNF213 is the first identified susceptibility gene for moyamoya disease, and the encoded protein was recently recognized as a key antimicrobial protein. However, the function of RNF213 in host defense against brain infection remains unclear. Here, we show that increased expression of Rnf213 is significantly regulated by interferon alpha/beta receptor (IFNAR) signaling during bacterial infection and ligand stimulation. RNF213 deficiency impairs type I interferon (IFN-I) production and decreases the expression of interferon-stimulated genes (ISGs) in response to IFN-β stimulation and Acinetobacter baumannii infection. Mechanistically, RNF213 interacts with TRAF3 and mediates the K27-linked polyubiquitination of TRAF3 at K160. RNF213 regulates the expression of the endothelial tight junction-related genes Claudin-5, Occludin, and Pecam1 via IFN-I signaling. Furthermore, RNF213 deficiency in nonimmune cells increases blood‒brain barrier (BBB) disruption and the bacterial load in the brain parenchyma in response to A. baumannii infection due to impaired IFN-I signaling. Thus, RNF213 mediates BBB integrity by targeting TRAF3 for the regulation of IFN-I signaling against bacterial brain infection. Our study principally provides a deeper understanding of the function of RNF213 and reveals potential therapeutic targets against bacterial brain infection and moyamoya disease.

DOI: https://doi.org/10.1371/journal.ppat.1013333
Front Med (Lausanne). 2025 ;12 1587759

Polystyrene microplastics impair the function of human retinal microvascular endothelial cells and pericytes and increase vascular permeability in vitro.

Jang-Hyuk Yun.

   Introduction: Polystyrene (PS) microplastics are among the most prevalent types of microplastics responsible for global pollution. Although numerous studies have investigated the effects of PS on various organs, such as the heart, lungs, liver, kidneys, nervous system, and intestines, its impact on the eyes, particularly the retina, remains largely unexplored.
Methods: To assess the effects of PS on retinal pathology, cultured retinal microvascular endothelial cells, pericytes, astrocytes, and microglial cells were exposed to 2 μm PS particles. Cell viability (MTT assay), apoptosis (Annexin V/PI flow cytometry), protein expression (Western blotting), and angiogenesis-related behaviors (tube formation, migration, and permeability assays) were evaluated.
Results: PS induced endothelial cell apoptosis by reducing the activity of AKT and ERK1/2, and induced pericyte apoptosis by reducing the activity of AKT. PS also impaired tube formation, migration, and proliferation by reducing AKT and ERK1/2 activity in retinal endothelial cells. In addition, PS induced pericyte apoptosis and increased endothelial permeability.
Conclusion: PS may worsen retinopathy by inducing endothelial cell and pericyte apoptosis and by increasing vascular leakage, although it does not promote angiogenesis.

Keywords:  endothelial cell; endothelial permeability; pericyte; polystyrene; retinopathy

DOI:  https://doi.org/10.3389/fmed.2025.1587759
Sci Signal. 2025 Jul 08. 18(894): eadt0983

The MDM2-p53 axis regulates norrin/frizzled4 signaling and blood-CNS barrier function.

Jacklyn Levey, Md Abedin, Chi Zhang, Emmanuel Odame, Lingling Zhang, Ha-Neul Jo, Kaia Douglas, Heidi Roehrich, Zhe Chen, Harald J Junge.

Norrin-induced activation of β-catenin-dependent signaling through the receptor frizzled4 in endothelial cells (ECs) is essential for establishing and maintaining blood-CNS barrier function. We sought to determine how this pathway is modulated under stress or disease conditions. Specifically, we investigated the role of p53 in endothelial blood-CNS barriers because increased abundance of the transcription factor p53 in ECs correlates with leaky CNS blood vessels in type 2 diabetes. Using transcriptomic, cell-based, and mouse genetic approaches, we identified interplay between p53 and its negative regulator MDM2 and norrin/frizzled4 signaling. Mice with an EC-specific ablation of Mdm2 showed decreased norrin/frizzled4 signaling, reduced EC proliferation and retinal angiogenesis, and disrupted blood-retina barrier function, all of which were largely restored by concurrent Trp53 deletion. Decreased norrin/frizzled4 signaling and inhibition of EC proliferation in response to p53 were associated with reduced expression of the condensin I complex component non-SMC condensin I complex subunit H (NCAPH). This study identifies a regulator of norrin/frizzled4 signaling and suggests that the clinical use of MDM2 inhibitors might impair the blood-CNS barrier. In addition, NCAPH may be a downstream effector of p53 in ECs and a candidate gene for familial exudative vitreoretinopathy (FEVR), which is caused by defects in norrin signaling.

DOI: https://doi.org/10.1126/scisignal.adt0983