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Blood-brain barrier disruption and neuroinflammation in the hippocampus of a cardiac arrest porcine model:Single-cell RNA sequencing analysis 认领 引用 被引量：1
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作者 Tangxing Jiang Yaning Li +11 位作者 Hehui Liu Yijun Sun Huidan Zhang Qirui Zhang Shuyao Tang Xu Niu Han Du Yinxia Yu Hongwei Yue Yunyun Guo Yuguo Chen Feng Xu 《Neural Regeneration Research》 SCIE CAS CSCD 2026年第2期742-755,共14页
Global brain ischemia and neurological deficit are consequences of cardiac arrest that lead to high mortality.Despite advancements in resuscitation science,our limited understanding of the cellular and molecular mecha... Global brain ischemia and neurological deficit are consequences of cardiac arrest that lead to high mortality.Despite advancements in resuscitation science,our limited understanding of the cellular and molecular mechanisms underlying post-cardiac arrest brain injury have hindered the development of effective neuroprotective strategies.Previous studies primarily focused on neuronal death,potentially overlooking the contributions of non-neuronal cells and intercellular communication to the pathophysiology of cardiac arrest-induced brain injury.To address these gaps,we hypothesized that single-cell transcriptomic analysis could uncover previously unidentified cellular subpopulations,altered cell communication networks,and novel molecular mechanisms involved in post-cardiac arrest brain injury.In this study,we performed a single-cell transcriptomic analysis of the hippocampus from pigs with ventricular fibrillation-induced cardiac arrest at 6 and 24 hours following the return of spontaneous circulation,and from sham control pigs.Sequencing results revealed changes in the proportions of different cell types,suggesting post-arrest disruption in the blood-brain barrier and infiltration of neutrophils.These results were validated through western blotting,quantitative reverse transcription-polymerase chain reaction,and immunofluorescence staining.We also identified and validated a unique subcluster of activated microglia with high expression of S100A8,which increased over time following cardiac arrest.This subcluster simultaneously exhibited significant M1/M2 polarization and expressed key functional genes related to chemokines and interleukins.Additionally,we revealed the post-cardiac arrest dysfunction of oligodendrocytes and the differentiation of oligodendrocyte precursor cells into oligodendrocytes.Cell communication analysis identified enhanced post-cardiac arrest communication between neutrophils and microglia that was mediated by neutrophil-derived resistin,driving pro-inflammatory microglial polarization.Our findings provide a comprehensive single-cell map of the post-cardiac arrest hippocampus,offering potential novel targets for neuroprotection and repair following cardiac arrest. 展开更多
关键词 Blood-brain barrier disruption cardiac arrest hippocampus microglia neuroinflammation neuroprotection neutrophil oligodendrocyte dysfunction S100A8 single-cell RNA sequencing
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Endothelial GATAD1 Exacerbates Blood-brain Barrier Dysfunction in Ischemic Stroke through Caveolae-mediated Transcytosis 认领 引用
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作者 Lizhen Fan Hui Liu +8 位作者 Shanshan Li Lingling Li Zhi Zhang Pinyi Liu Haiyan Yang Shengnan Xia Xiang Cao Chun Wang Yun Xu 《Neuroscience Bulletin》 SCIE CAS CSCD 2026年第3期559-575,共17页
Blood-brain barrier(BBB)dysfunction represents a critical pathological manifestation in exacerbating ischemic stroke,contributing to neuronal death,edema formation,and unfavorable clinical outcomes.GATA zinc finger do... Blood-brain barrier(BBB)dysfunction represents a critical pathological manifestation in exacerbating ischemic stroke,contributing to neuronal death,edema formation,and unfavorable clinical outcomes.GATA zinc finger domain-containing 1(GATAD1)is recognized as a critical transcription factor in cardiac development and cardiovascular disease.However,the role of GATAD1 in regulating BBB function and ischemic stroke remains elusive.Here,we found that GATAD1 was upregulated in cerebral endothelial cells(ECs)following ischemic stroke in mice.EC-specific Gatad1 deficiency demonstrated remarkable neuroprotection,manifested by reduced infarct volumes,ameliorated BBB dysfunction,and improved neurological outcomes following experimental stroke.Mechanistic investigations revealed that GATAD1 was involved in regulating CD36 expression,thereby modulating caveolae-mediated transcytosis in cerebral ECs.These findings established GATAD1 as a novel regulator of BBB permeability and a potential therapeutic target for ischemic stroke intervention. 展开更多
关键词 GATAD1 Blood-brain barrier Transcytosis Ischemic stroke
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A blood-brain barrier-penetrative fluorescent probe revealing brain hypoxia damage in hypoxic-ischemic encephalopathy 认领 引用
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作者 Yuxun Lu Ning Zhu +9 位作者 Gui Zhang Huan Liu Le Yu Qisi Sun Ruqiu Zhang Xiaojuan Su Yinuo Li Zhenhui Li Fan Li Ying Zhou 《Chinese Chemical Letters》 SCIE CAS CSCD 2026年第6期507-513,共7页
Hypoxic-ischemic encephalopathy(HIE) is a major cause of infant mortality and permanent neurological abnormalities,highlighting the importance of early identification and accurate diagnosis.Fluorescence sensing provid... Hypoxic-ischemic encephalopathy(HIE) is a major cause of infant mortality and permanent neurological abnormalities,highlighting the importance of early identification and accurate diagnosis.Fluorescence sensing provides various benefits over traditional diagnostic methods,including real-time detection of hypoxia,which is often linked to HIE,and molecular-level insights.Herein,a novel hypoxia-responsive fluorescent probe,BOD,was created to overcome the difficulties associated with blood-brain barrier(BBB)penetration for brain damage imaging using a HIE model.BOD can be cleaved by azoreductase to produce a red fluorescent signal,with excellent sensitivity,selectivity,and biocompatibility.Crucially,BOD effectively monitors neural cells across varying oxygen concentrations,particularly in hypoxic microenvironments,providing vital insights into the impact of oxygen deprivation on neural cell function during HIE.In both cellular and ex vivo mouse brain tissue models,the effectiveness of BOD was confirmed:it outperformed conventional techniques in the reliable identification of hypoxic injury sites,differentiating between mild,moderate,and severe injury.Thanks to its excellent permeability due to its lipophilicity and positive charge,BOD can pass through the BBB,with strong fluorescence in the periventricular white matter(PWM) and cortex strongly correlated with injury severity.This study is novel in its application of a hypoxia-responsive fluorescent probe for brain damage imaging in an HIE model,highlighting the substantial potential of BOD for real-time,in vivo imaging,representing a promising tool for early diagnosis and investigation of HIE. 展开更多
关键词 Blood-brain barrier penetration Hypoxia-responsive Small-molecule fluorescent probe Neural cell imaging Hypoxic-ischemic encephalopathy
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Battle of the wall for aromatic“orifice-opening”agents:defending and breaching the blood-brain barrier 认领 引用
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作者 Xiaoman Yang Jing Zhang +4 位作者 Hao Yu Yulei Zhao Guanqun Hou Shijun Wang Bingbing Han 《Chinese Journal of Natural Medicines》 SCIE CAS CSCD 2026年第7期769-790,共22页
The brain is the most stringently safeguarded organ in the human body.The 7-mm-thick cranial vault shields the central nervous system(CNS)from external damage,while the blood-brain barrier(BBB)functions as a specific ... The brain is the most stringently safeguarded organ in the human body.The 7-mm-thick cranial vault shields the central nervous system(CNS)from external damage,while the blood-brain barrier(BBB)functions as a specific physiological barrier,successfully safeguarding it from circulating toxins and pathogens.BBB disruption is closely linked to the emergence and development of various CNS disorders,and the strong constraints of BBB on substance exchange present a considerable obstacle to medicine administration for the treatment of neurological diseases.Aromatic orifice-opening agents(AOOAs),a specific class of traditional Chinese medicine(TCM),exhibit a unique bidirectional interaction with BBB.Such agents can loosen the BBB junctions,transiently enhance its permeability,and ease the passage of medications into the brain,a phenomenon referred to as the“permeability-promoting”effect on BBB.In contrast,under pathological conditions,AOOAs can preserve BBB integrity and exert a“permeability-restricting”effect by reducing inflammatory responses and alleviating oxidative stress.This review systematically analyzes the regulatory factors affecting BBB permeability,investigates the dual mechanisms by which AOOAs protect and penetrate the BBB,and highlights the innovative opportunities and significant potential these agents present for treating CNS disorders. 展开更多
关键词 Central nervous system Blood-brain barrier Aromatic“orifice-opening”agents
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Blood-brain barrier permeability assessment:from biomimetic models to multimodal imaging 认领 引用 被引量：1
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作者 Miaomiao WANG Lu GAN +4 位作者 Yiru FAN Chenxi DUAN Ying ZHU Shihua LUO Yanhong SUN 《Journal of Zhejiang University-SCIENCE B》 SCIE CAS CSCD 2026年第7期715-735,I0004,共21页
The blood-brain barrier(BBB)is a vital physiological structure that maintains the microenvironmental homeostasis in the central nervous system(CNS).Imbalances in its permeability play a key role in various neurologica... The blood-brain barrier(BBB)is a vital physiological structure that maintains the microenvironmental homeostasis in the central nervous system(CNS).Imbalances in its permeability play a key role in various neurological disorders,including stroke,neurodegenerative diseases,and brain tumors.The development of precise techniques for assessing BBB permeability is therefore paramount for elucidating the mechanisms of neurological diseases,overcoming drug development challenges,and achieving precise diagnosis and treatment of CNS disorders.This review systematically summarizes the latest advances in the assessment of BBB permeability.Regarding in vitro models,platforms have evolved from the traditional transwell system to microfluidic chips incorporating fluid shear forces and subsequently to highly biomimetic brain organoids,with continuous improvements in the ability to simulate the neurovascular unit(NVU)microenvironment.For in vivo assessment,we detail the principles and applications of imaging techniques,including dynamic contrast-enhanced magnetic resonance imaging(DCEMRI),positron emission tomography(PET),near-infrared II(NIR-II)fluorescence imaging(FI),and two-photon microscopy(TPM),highlighting their complementary strengths in macroscopic quantification,molecular targeting,and microscopic dynamic observation.The integration of multi-modal technologies and precise quantitative assessment is a prominent trend.Future investigations will focus on artificial intelligence(AI)-driven personalized permeability assessment,the development of novel intelligent probes,and the dynamic real-time monitoring of the BBB,thereby providing powerful methodological support for neurological disease research. 展开更多
关键词 Blood-brain barrier(BBB) Permeability assessment In vitro BBB model In vivo imaging Central nervous system(CNS)
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Advances in CNS drug delivery strategies to cross the blood-brain barrier 认领 引用
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作者 Guanlong Li Zhuoyan Li +6 位作者 Yan Sun Tiange Bu Shaochuan Chen Leixin Yang Zhi Li Wenyue Mao Yanpeng Jia 《Chinese Chemical Letters》 SCIE CAS CSCD 2026年第1期159-167,共9页
In recent years,development of strategies to treat central nervous system(CNS) diseases has attracted extensive attention.A major obstacle in this field is the blood-brain barrier(BBB),which significantly limits the e... In recent years,development of strategies to treat central nervous system(CNS) diseases has attracted extensive attention.A major obstacle in this field is the blood-brain barrier(BBB),which significantly limits the efficient delivery of therapeutic agents to the brain and hinders the treatment of CNS diseases.Overcoming the restrictive nature of the BBB has thus emerged as a key objective in CNS drug development.Nanomaterials have garnered growing interest due to their unique physicochemical properties and potential to traverse the BBB,enabling targeted drug delivery to brain tissue and improving therapeutic efficacy.In this review,we present current insights into the structure and function of the BBB and highlight a range of nanomaterial-based strategies for BBB penetration,including receptor-mediated transport(RMT),adsorptive-mediated transcytosis,reversible BBB disruption,and intranasal administration.Finally,we summarize recent advances in enhancing BBB permeability for CNS therapeutics and discuss persisting challenges,offering perspectives for future research in this field. 展开更多
关键词 Blood-brain barrier Brain target Central nervous system diseases Drug delivery Nanomaterials
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Boosting Blood-Brain Barrier Crossing with a Mannosylated Nanocarrier 认领 引用
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作者 Nan-Nan Gu Ping Wei +1 位作者 Jin-Hui Jiang Jing-Hua Chen 《Chinese Journal of Polymer Science》 SCIE EI CAS CSCD 2026年第8期2524-2533,I0010,共10页
The blood-brain barrier(BBB)is a major obstacle to the delivery of most therapeutic molecules to the brain,thereby preventing the effective treatment of numerous neurological disorders.However,this barrier can be bypa... The blood-brain barrier(BBB)is a major obstacle to the delivery of most therapeutic molecules to the brain,thereby preventing the effective treatment of numerous neurological disorders.However,this barrier can be bypassed by exploiting receptors and transport proteins that are highly expressed in the brain capillary endothelial cells(BCECs).Given the overexpression of glucose transporter 1(GLUT1)at the BBB and in glioma cells,a mannosylated nanocarrier was developed as a potential dual-targeted drug delivery system to enhance BBB penetration via GLUT1-mediated transcytosis and improve drug accumulation in glioma cells via GLUT1-mediated endocytosis.In vitro physicochemical characterization revealed that the mannosylated nanocarrier presented a satisfactory size of 123 nm with a uniform distribution and high encapsulation efficiency for a newly developed aggregation-induced emission(AIE)photosensitizer.Our findings revealed that this mannosylated nanocarrier represents a promising nanoplatform capable of crossing the BBB and enabling effective photodynamic therapy. 展开更多
关键词 Self-assembly Blood-brain barrier Photodynamic therapy Aggregation-induced emission
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Human-induced pluripotent stem cell-derived neural stem cell exosomes improve blood-brain barrier function after intracerebral hemorrhage by activating astrocytes via PI3K/AKT/MCP-1 axis 认领 引用 被引量：10
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作者 Conglin Wang Fangyuan Cheng +9 位作者 Zhaoli Han Bo Yan Pan Liao Zhenyu Yin Xintong Ge Dai Li Rongrong Zhong Qiang Liu Fanglian Chen Ping Lei 《Neural Regeneration Research》 SCIE CAS CSCD 2025年第2期518-532,共15页
Cerebral edema caused by blood-brain barrier injury after intracerebral hemorrhage is an important factor leading to poor prognosis.Human-induced pluripotent stem cell-derived neural stem cell exosomes(hiPSC-NSC-Exos)... Cerebral edema caused by blood-brain barrier injury after intracerebral hemorrhage is an important factor leading to poor prognosis.Human-induced pluripotent stem cell-derived neural stem cell exosomes(hiPSC-NSC-Exos)have shown potential for brain injury repair in central nervous system diseases.In this study,we explored the impact of hiPSC-NSC-Exos on blood-brain barrier preservation and the underlying mechanism.Our results indicated that intranasal delivery of hiPSC-NSC-Exos mitigated neurological deficits,enhanced blood-brain barrier integrity,and reduced leukocyte infiltration in a mouse model of intracerebral hemorrhage.Additionally,hiPSC-NSC-Exos decreased immune cell infiltration,activated astrocytes,and decreased the secretion of inflammatory cytokines like monocyte chemoattractant protein-1,macrophage inflammatory protein-1α,and tumor necrosis factor-αpost-intracerebral hemorrhage,thereby improving the inflammatory microenvironment.RNA sequencing indicated that hiPSC-NSC-Exo activated the PI3K/AKT signaling pathway in astrocytes and decreased monocyte chemoattractant protein-1 secretion,thereby improving blood-brain barrier integrity.Treatment with the PI3K/AKT inhibitor LY294002 or the monocyte chemoattractant protein-1 neutralizing agent C1142 abolished these effects.In summary,our findings suggest that hiPSC-NSC-Exos maintains blood-brain barrier integrity,in part by downregulating monocyte chemoattractant protein-1 secretion through activation of the PI3K/AKT signaling pathway in astrocytes. 展开更多
关键词 AKT astrocyte blood-brain barrier cerebral edema exosomes human-induced pluripotent stem cells intracerebral hemorrhage neural stem cells neuroinflammation PI3K
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The nanocarrier strategy for crossing the blood-brain barrier in glioma therapy 认领 引用 被引量：1
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作者 Han Wu Yumei Wang +3 位作者 Zekai Ren Hailin Cong Youqing Shen Bing Yu 《Chinese Chemical Letters》 SCIE CAS CSCD 2025年第4期9-19,共11页
Glioma is the most common malignant tumor of the brain. The postoperative recurrence rate was high,and the 2-year survival rate only increased by 20%–25%. The reason is the blood-brain barrier(BBB). BBB is a physical... Glioma is the most common malignant tumor of the brain. The postoperative recurrence rate was high,and the 2-year survival rate only increased by 20%–25%. The reason is the blood-brain barrier(BBB). BBB is a physical barrier that stabilizes the physiological environment of brain tissue and protects the central nervous system from the invasion of harmful substances. Drug delivery based on nanotechnology and nanocarriers has attracted much attention due to its biological safety, continuous drug release time,increasing solubility, biological drug activity, and enhanced BBB permeability. By modifying different substances on the surface of nanocarriers, the BBB is bypassed by receptor-mediated and cell endocytosis and exocytosis. In addition, the purpose of bypassing BBB-targeted drug delivery can also be achieved by intranasal administration and local administration. This paper reviews different target transport mechanisms, mainly in invasive and non-invasive strategies, the nanocarriers that have made progress and the nanocarrier strategy of bypassing BBB are listed. 展开更多
关键词 Glioma Blood-brain barrier Nanocarriers Drug delivery Adsorption-mediated transport Receptor-mediated transport
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Effect of electroacupuncture on the MMP-2/9 pathway mediated blood-brain barrier permeability in mice with Parkinson’s disease 认领 引用
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作者 Xiao-lei ZHANG Meng-ni HU +3 位作者 Ya-nan LI Yao WANG Zhen RONG Jun MA 《World Journal of Acupuncture-Moxibustion》 CAS CSCD 2025年第1期58-65,共8页
Objective:To investigate the effects of electroacupuncture(EA)on the blood-brain barrier permeability and the regulation of matrix metalloproteinases(MMPs)in the mice with Parkinson’s disease(PD).Methods:Forty-eight ... Objective:To investigate the effects of electroacupuncture(EA)on the blood-brain barrier permeability and the regulation of matrix metalloproteinases(MMPs)in the mice with Parkinson’s disease(PD).Methods:Forty-eight C57BL/6 mice were randomly assigned into the normal control(NC)group,the PD model(PD)group,the EA group and the EA+SB-3CT inhibitor group(EA+SB-3CT),with 12 mice in each group.In this experiment,the PD model was established by intragastric administration(IG)with rotenone for 4 wk in the PD group,EA group and EA+SB-3CT group.In the EA+SB-3CT group,1 h after IG with rotenone,the mice were intraperitoneally injected with MMP-2/9 inhibitor,SB-3CT(25 mg/kg/d).After successfully modeled,in the EA group and EA+SB-3CT group,EA was conducted at“Fengfu(GV16)”and bilateral“Taichong(LR3)”and“Zusanli(ST36)”,at 1 mA and 2 Hz for 30 min each time,once a day,for consecutive 2 wk.The behavioral changes of the mice were observed in each group using the open field test,the level of tyrosine hydroxylase(TH)in the substantia nigra was determined by immunohistochemistry,the permeability of the blood-brain barrier was detected by Evans blue staining,and the protein expression of ZO-1,ocludin,claudin-1,MMP-2 and MMP-9 in the substantia nigra was detected by Western blotting.Results:Compared with the NC group,the behavioral scores increased(P<0.05),while total time of locomotion,total distance and average speed were reduced(P<0.05)in the PD group.The expression of TH in the substantia nigra decreased(P<0.05),Evans blue level in the brain tissue increased(P<0.05),and the protein expression of ZO-1,occludin and claudin-1 was lower(P<0.05),whereas MMP-2 and MMP-9 expression was higher(P<0.05)in the PD group.Compared with the PD group,behavioral scores decreased(P<0.05),while the total time of locomotion,total distance and average speed increased(P<0.05)in the EA group.Additionally,TH expression in the substantia nigra was elevated(P<0.05),Evans blue level in the brain tissue was lower(P<0.05),the protein expression of ZO-1,occludin and claudin-1 was up-regulated(P<0.05),and MMP-2 and MMP-9 expression was down-regulated(P<0.05)in the EA group.Compared with the EA group,Evans blue level was reduced(P<0.05),the protein expression of ZO-1 and occludin was up-regulated(P<0.05),and MMP-2 and MMP-9 expression was further down-regulated(P<0.05)in the EA+SB-3CT group.Conclusion:EA can effectively ameliorate the motor dysfunction of PD mice,reduce the damage of dopaminergic neurons,and play a neuroprotective role.EA can effectively improve the blood–brain barrier permeability in PD mice by up-regulating the expression of tight junction proteins,ZO-1 and occludin,and down-regulating the expression of matrix metalloporteinases,MMP-2 and MMP-9.The neuroprotective role of EA may be obtained by improving the blood-brain barrier permeability mediated by MMP-2/9 pathway. 展开更多
关键词 Parkinson’s disease Electroacupuncture Blood-brain barrier Tight junction protein MMP-2 MMP-9
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Velogenic Newcastle disease virus invades chicken brain by infecting brain microvascular endothelial cells to increase blood-brain barrier permeability 认领 引用
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作者 Jie Zhao Sa Xiao +4 位作者 Wei Yao Xudong Chang Xinglong Wang Zengqi Yang Wenbin Wang 《Journal of Integrative Agriculture》 SCIE CAS CSCD 2025年第2期712-723,共12页
The blood-brain barrier(BBB)keeps poisons and infections out of the brain.Some viruses can pass through this barrier and replicate in the central nervous system(CNS).Velogenic Newcastle disease virus(VNDV)is a neurotr... The blood-brain barrier(BBB)keeps poisons and infections out of the brain.Some viruses can pass through this barrier and replicate in the central nervous system(CNS).Velogenic Newcastle disease virus(VNDV)is a neurotropic virus that causes avian nonsuppurative encephalitis.VNDV often develops into a chronic infection that seriously affects poultry health in partially immune birds.The routes by which the virus enters the chicken brain are poorly understood.In this study,we discovered that VNDV increased BBB permeability in vivo and in vitro by breaking the tight junction protein zona occludens-1(ZO-1)continuity of chicken brain microvascular endothelial cells(chBMECs).By investigating the susceptibility of chBMECs to NDV infection,we found that VNDV but not lentogenic NDV was detected in the basolateral compartment in transwell assays after apical infection,suggesting that efficient replication and transcellular transport of the virus across the BBB in vitro.Furthermore,viral replication and BBB permeability were reduced during the early stage of infection by using the dynamin inhibitor dynasore.Our data demonstrate that VNDV invades the chicken brain by infecting and damaging the tight junction of chBMECs directly to increase BBB permeability.VNDV could infect chBMECs via endocytosis.As a result,our findings provide compelling evidence for VNDV entrance into the brain via the BBB,paving the way for the development of medications for NDV prevention and therapy. 展开更多
关键词 velogenic Newcastle disease virus blood-brain barrier permeability chicken brain microvascular endothelial cells
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Interaction of major facilitator superfamily domain containing 2A with the blood-brain barrier 认领 引用
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作者 Yilun Ma Taiwei Dong +3 位作者 Fei Luan Juanjuan Yang Feng Miao Peifeng Wei 《Neural Regeneration Research》 SCIE CAS CSCD 2025年第8期2133-2152,共20页
The functional and structural integrity of the blood-brain barrier is crucial in maintaining homeostasis in the brain microenvironment;however,the molecular mechanisms underlying the formation and function of the bloo... The functional and structural integrity of the blood-brain barrier is crucial in maintaining homeostasis in the brain microenvironment;however,the molecular mechanisms underlying the formation and function of the blood-brain barrier remain poorly understood.The major facilitator superfamily domain containing 2A has been identified as a key regulator of blood-brain barrier function.It plays a critical role in promoting and maintaining the formation and functional stability of the blood-brain barrier,in addition to the transport of lipids,such as docosahexaenoic acid,across the blood-brain barrier.Furthermore,an increasing number of studies have suggested that major facilitator superfamily domain containing 2A is involved in the molecular mechanisms of blood-brain barrier dysfunction in a variety of neurological diseases;however,little is known regarding the mechanisms by which major facilitator superfamily domain containing 2A affects the blood-brain barrier.This paper provides a comprehensive and systematic review of the close relationship between major facilitator superfamily domain containing 2A proteins and the blood-brain barrier,including their basic structures and functions,cross-linking between major facilitator superfamily domain containing 2A and the blood-brain barrier,and the in-depth studies on lipid transport and the regulation of blood-brain barrier permeability.This comprehensive systematic review contributes to an in-depth understanding of the important role of major facilitator superfamily domain containing 2A proteins in maintaining the structure and function of the blood-brain barrier and the research progress to date.This will not only help to elucidate the pathogenesis of neurological diseases,improve the accuracy of laboratory diagnosis,and optimize clinical treatment strategies,but it may also play an important role in prognostic monitoring.In addition,the effects of major facilitator superfamily domain containing 2A on blood-brain barrier leakage in various diseases and the research progress on cross-blood-brain barrier drug delivery are summarized.This review may contribute to the development of new approaches for the treatment of neurological diseases. 展开更多
关键词 blood-brain barrier(BBB) caveolin-1 central nervous system docosahexaenoic acid endothelial cells lysophosphatidylcholine major facilitator superfamily domain containing 2A(MFSD2A) transcytosis
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Optimizing blood-brain barrier permeability in KRAS inhibitors:A structure-constrained molecular generation approach 认领 引用 被引量：1
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作者 Xia Sheng Yike Gui +9 位作者 Jie Yu Yitian Wang Zhenghao Li Xiaoya Zhang Yuxin Xing Yuqing Wang Zhaojun Li Mingyue Zheng Liquan Yang Xutong Li 《Journal of Pharmaceutical Analysis》 SCIE CAS CSCD 2025年第8期1848-1859,共12页
Kirsten rat sarcoma viral oncogene homolog(KRAS)protein inhibitors are a promising class of therapeutics,but research on molecules that effectively penetrate the blood-brain barrier(BBB)remains limited,which is crucia... Kirsten rat sarcoma viral oncogene homolog(KRAS)protein inhibitors are a promising class of therapeutics,but research on molecules that effectively penetrate the blood-brain barrier(BBB)remains limited,which is crucial for treating central nervous system(CNS)malignancies.Although molecular generation models have recently advanced drug discovery,they often overlook the complexity of biological and chemical factors,leaving room for improvement.In this study,we present a structureconstrained molecular generation workflow designed to optimize lead compounds for both drug efficacy and drug absorption properties.Our approach utilizes a variational autoencoder(VAE)generative model integrated with reinforcement learning for multi-objective optimization.This method specifically aims to enhance BBB permeability(BBBp)while maintaining high-affinity substructures of KRAS inhibitors.To support this,we incorporate a specialized KRAS BBB predictor based on active learning and an affinity predictor employing comparative learning models.Additionally,we introduce two novel metrics,the knowledge-integrated reproduction score(KIRS)and the composite diversity score(CDS),to assess structural performance and biological relevance.Retrospective validation with KRAS inhibitors,AMG510 and MRTX849,demonstrates the framework’s effectiveness in optimizing BBBp and highlights its potential for real-world drug development applications.This study provides a robust framework for accelerating the structural enhancement of lead compounds,advancing the drug development process across diverse targets. 展开更多
关键词 KRAS inhibitors Drug design Blood-brain barrier permeability Molecular optimization Deep learning Generation models
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Diagnostic dynamic contrast-enhanced magnetic resonance imaging blood-brain barrier assessment combined with plasma biomarkers for mild cog itive impairment 认领 引用 被引量：2
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作者 Ling Sun Meng-Rong Xu +5 位作者 Cheng-Yu Zhou Shao-Dong Cao Xiao-Liang Zhang Si-Qi Guan Wen-Xu Sang Xu-Ling Li 《World Journal of Psychiatry》 SCIE 2025年第6期166-176,共11页
BACKGROUND The role of cerebral microvascular dysfunction in early cognitive impairment and dementia has become increasingly recognized.Furthermore,pathological changes in both Alzheimer’s disease and vascular dement... BACKGROUND The role of cerebral microvascular dysfunction in early cognitive impairment and dementia has become increasingly recognized.Furthermore,pathological changes in both Alzheimer’s disease and vascular dementia are almost always associated with cerebral hemodynamic deficits.AIM To investigate the diagnostic performance of dynamic contrast-enhanced magnetic resonance imaging(DCE-MRI)assessment of the blood-brain barrier(BBB)in combination with relevant plasma biomarkers for mild cognitive impairment(MCI).METHODS This study selected 50 patients with non-amnestic MCI(na-MCI group),52 patients with amnestic MCI(a-MCI group),and 55 healthy elderly controls(control group).The Chinese version of the Montreal cognitive assessment(MoCA),auditory verbal learning test(AVLT),Hamilton anxiety/depression scale(HAMA/HAMD),and activity of daily living(ADL)scales were used to analyze the characteristics of mental and behavioral symptoms of patients with MCI.The DCE-MRI technique was used to assess the contrast enhancement kinetics.The Patlak model was utilized to analyze the BBB permeability(volume transfer constants).Further,fasting blood was was used to quantify plasma homocysteine(Hcy),β-amyloid protein(Aβ)40,Aβ42,human phosphorylated tau-181 protein(p-tau181),intercellular adhesion molecule-1(ICAM-1),vascular cell adhesion molecule-1(VCAM-1),and plasminogen activator inhibitor-1(PAI-1)levels,as well as serum neurofilament light chain(NFL)and glial fibrillary acidic protein(GFAP)concentrations.RESULTS The na-MCI and a-MCI groups demonstrated significantly lower MoCA and AVLT-Huashan version scores,and statistically higher HAMA,HAMD,and ADL scores compared to the control group.Moreover,the a-MCI group showed notably higher HAMA,HAMD,and ADL scores compared to the na-MCI group.Cranial MRI results revealed significant disparities in cerebral blood flow in the left and right frontal lobes,temporal lobes,hippocampi,cuneus,precuneus,parietal lobes,basal ganglia,and occipital lobes between the a-MCI and na-MCI groups.Compared to healthy controls,patients with MCI demonstrated a smaller amplitude of hippocampal contrast enhancement kinetics and a slower decay rate,indicating smaller vascular volume and increased BBB permeability.Further,Hcy,p-tau181,ICAM-1,VCAM-1,PAI-1,and NFL levels were substantially higher in the a-MCI group than in the na-MCI group,whereas the Aβ42 level was significantly lower.We did not observe any significant differences in Aβ40 and GFAP levels.CONCLUSION Patients with MCI may have experienced cerebrovascular system changes in the hippocampal region.Disorders associated with changes in cerebral blood supply may begin before pathophysiological changes are visible by imaging,which provides references for the assessment and treatment of patients with cognitive disorders.Further,DCE-MRI provides a noninvasive approach to diagnose subtle BBB leakage associated with cerebrovascular pathology. 展开更多
关键词 Dynamic contrast-enhanced magnetic resonance imaging Blood-brain barrier Mild cognitive impairment Auditory verbal learning test Montreal cognitive assessment
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Streptococcus suis serotype 2 collagenase-like protease promotes meningitis by increasing blood-brain barrier permeability 认领 引用 被引量：1
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作者 Jikun Mei Xuan Jiang +7 位作者 Fengyang Li Zengshuai Wu Tong Wu Junhui Zhu Hexiang Jiang Ziheng Li Na Li Liancheng Lei 《Journal of Integrative Agriculture》 SCIE CAS CSCD 2025年第11期4379-4394,共16页
Streptococcus suis serotype 2(SS2)is an emerging zoonotic pathogen that causes meningitis in humans and pigs.This pathogen generates substantial economic losses in the swine industry while posing a significant threat ... Streptococcus suis serotype 2(SS2)is an emerging zoonotic pathogen that causes meningitis in humans and pigs.This pathogen generates substantial economic losses in the swine industry while posing a significant threat to public health security.The mechanisms through which SS2 penetrates the brain and induces meningitis remain incompletely understood.This study examines the role and mechanism of SS2 collagenase-like protease(Clp)in facilitating bacterial passage across the blood-brain barrier(BBB).The research demonstrates that SS2 Clp enhanced virulence and tissue colonization while promoting BBB degradation in mice.The Δclp mutant exhibited reduced ability to traverse human brain microvascular endothelial(hCMEC/D3)cell monolayers compared to wild-type SS2,while the addition of recombinant protein rClp increased permeability.Furthermore,rClp significantly enhanced SS2 adhesion to hCMEC/D3,suppressed the expression of intercellular tight junction proteins ZO-1,Occludin,and Claudin-5 independent of its enzyme activity,and triggered hCMEC/D3 apoptosis through cell receptor ligand apoptosis and mitochondrial apoptosis pathways,partially dependent on its enzyme activity,leading to BBB disruption and enhanced permeability.Additionally,Clp enhanced the infiltration of macrophages(F4/80+),monocytes(F4/80-Ly6C+),and neutrophils(Ly6G+)into the brain following SS2 infection.These findings establish that SS2 Clp is essential for bacterial passage across the BBB,offering a theoretical foundation for improved prevention and treatment strategies for SS2-induced meningitis. 展开更多
关键词 Streptococcus suis serotype 2 collagenase-like protease Meningitis blood-brain barrier permeability
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Cancer cell-derived migrasomes harboring ATF6 promote breast cancer brain metastasis via endoplasmic reticulum stress-mediated disruption of the blood-brain barrier 认领 引用
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作者 Song Wang Guohao Gu +10 位作者 Xinmiao Xian Jun Li Di Zhang Jianran Guo Anqi Zhang Shen Chen Dong Yan Bingwu Yang Meng An Wei Zhang Bo Fu 《Cancer Biology & Medicine》 SCIE CAS CSCD 2025年第6期690-713,共24页
Objective:Migrasomes,an emerging class of migration-facilitating membranous extracellular vesicles,remain largely uncharted in the intricate landscape of tumor metastasis.This study aimed to illuminate the roles and m... Objective:Migrasomes,an emerging class of migration-facilitating membranous extracellular vesicles,remain largely uncharted in the intricate landscape of tumor metastasis.This study aimed to illuminate the roles and mechanisms underlying cancer cell-derived migrasomes in breast cancer brain metastasis(BCBM).Methods:Migrasomes were isolated and purified from BCBM cells(231-BR)and non-specific organotropic parental counterparts(MDA-MB-231),specifically designated as Mig-BCBM and Mig-BC,respectively.The role of Mig-BCBM in BCBM was investigated using an in vitro endothelial cell layer permeability model and a BCBM mouse model.The regulatory mechanism underlying Mig-BCBM was assessed using RT-qPCR,western blotting,immunofluorescence,ex vivo fluorescence imaging,and a series of rescue experiments.Results:Mig-BCBM potently augmented the permeability of vascular endothelial layers,which facilitated the efficient migration of 231-BR cells across endothelial barriers in vitro.The administration of Mig-BCBM significantly disrupted the blood-brain barrier(BBB)and accelerated BCBM progression in vivo,as evidenced in mouse models,compared to the Mig-BC and control groups.Mechanistically,Mig-BCBM harbored ATF6,a critical transducer of endoplasmic reticulum(ER)stress.Upon internalization into hCMEC/D3 cells,ATF6 elicited robust ER stress responses,culminating in downregulation of ZO-1 and VE-cadherin.Digital PCR analysis disclosed significant upregulation of ATF6 in serum migrasomes derived from BCBM patients compared to migrasomes from breast cancer patients and healthy individuals.Conclusions:This study uncovered a pivotal role of cancer cell-derived in BCBM by harnessing ATF6-mediated ER stress to disrupt the BBB and promote metastasis,suggesting novel diagnostic and therapeutic strategies targeting migrasomes and migrasome cargo. 展开更多
关键词 Breast cancer brain metastasis migrasome blood-brain barrier ATF6 endoplasmic reticulum stress
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Krüppel-like factor 4 transcription factor in blood-brain barrier endothelial cells:A potential role in Alzheimer's disease 认领 引用
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作者 Ziying Wei Chunhua Liu +2 位作者 Jianyu Chen Yuxiao Yao Dajiang Qin 《Animal Models and Experimental Medicine》 CAS CSCD 2025年第5期819-828,共10页
Alzheimer's disease is the most prevalent chronic neurodegenerative disorder worldwide,with no sufficient cure.Ongoing research is focused on developing new therapies aimed at preventing or delaying the onset of s... Alzheimer's disease is the most prevalent chronic neurodegenerative disorder worldwide,with no sufficient cure.Ongoing research is focused on developing new therapies aimed at preventing or delaying the onset of symptoms,slowing disease progression,and improving cognitive and behavioral outcomes in individuals affected by Alzheimer's disease.Among the various pathological changes associated with this condition,blood-brain barrier(BBB)leakage plays a crucial role as it serves as a vital boundary for maintaining central nervous system(CNS)health.Preserving the integrity and functionality of the BBB is essential to protect the brain from amyloid-β accumulation,neuroinflammation,and neuronal degeneration.This review summarizes models of Alzheimer's disease characterized by BBB leakage over time.More importantly,we introduce Krüppel-l ike factor 4(KLF4),a transcription factor involved in vascular systems,and discuss its relevance to Alzheimer's disease.By elucidating the functions of KLF4 within both vascular and CNSs,this review highlights its potential role in modulating BBB integrity in Alzheimer's pathology,which may contribute to therapeutic strategies for managing this debilitating condition. 展开更多
关键词 Alzheimer's disease blood-brain barrier endothelial cells Krüppel-like factor 4
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Insights into the mechanism of reversible blood-brain barrier opening via second near-infrared region excited gold nanorods photothermal effect:Regulation of the tight junction protein occludin 认领 引用
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作者 Kaili Liang Li Yang +6 位作者 Bo Liu Xinying Wang Liyan Wang Jiawei Kang Zhang Ding Wei Wang Qing Wang 《Smart Molecules》 CSCD 2025年第3期88-98,共11页
This study constructed an in vitro blood-brain barrier(BBB)transwell model to investigate the regulatory effects and mechanisms of the photothermal effects of gold nanorods(AuNRs)excited by the second near-infrared re... This study constructed an in vitro blood-brain barrier(BBB)transwell model to investigate the regulatory effects and mechanisms of the photothermal effects of gold nanorods(AuNRs)excited by the second near-infrared region(NIR-II)on BBB permeability.The experimental results showed that the photothermal effects of NIR-II t AuNRs significantly decreased trans-epithelial electrical resistance(TEER)and increased the permeability of fluorescein isothiocyanate(FITC)-dextran,indicating that it can effectively open the BBB.This effect was reversible,and the TEER and FITC permeability returned to baseline levels within 24 h after treatment.Mechanistic studies revealed that BBB opening did not rely on apoptosis,cytoskeletal disruption,mitochondrial dysfunction,or inflammation.The opening of the BBB was closely associated with a temporary decrease in the expression and conformational change of the tight junction protein occludin due to the photothermal effect.Molecular simulations and docking analysis revealed that the heat shock protein HSP70 could bind to the conformationally altered occludin,supporting the regulatory role of photothermal effects on tight junction proteins.In summary,NIR-II t AuNRs achieved safe and reversible opening of the BBB by regulating the conformation and expression of tight junction proteins,providing a deeper insight for further research on BBB and the treatment of neurological diseases. 展开更多
关键词 blood-brain barrier occludin protein conformation tight junction protein
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Emerging roles of astrocytes in blood-brain barrier disruption upon amyloid-beta insults in Alzheimer's disease 认领 引用 被引量：15
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作者 Qian Yue Maggie Pui Man Hoi 《Neural Regeneration Research》 SCIE CAS CSCD 2023年第9期1890-1902,共13页
Blood-brain barrier disruption occurs in the early stages of Alzheimer’s disease.Recent studies indicate a link between blood-brain barrier dysfunction and cognitive decline and might accelerate Alzheimer’s disease ... Blood-brain barrier disruption occurs in the early stages of Alzheimer’s disease.Recent studies indicate a link between blood-brain barrier dysfunction and cognitive decline and might accelerate Alzheimer’s disease progression.Astrocytes are the most abundant glial cells in the central nervous system with important roles in the structural and functional maintenance of the blood-brain barrier.For example,astrocytic cove rage around endothelial cells with perivascular endfeet and secretion of homeostatic soluble factors are two major underlying mechanisms of astrocytic physiological functions.Astrocyte activation is often observed in Alzheimer’s disease patients,with astrocytes expressing a high level of glial fibrillary acid protein detected around amyloid-beta plaque with the elevated phagocytic ability for amyloid-beta.Structural alte rations in Alzheimer’s disease astrocytes including swollen endfeet,somata shrinkage and possess loss contribute to disruption in vascular integrity at capillary and arte rioles levels.In addition,Alzheimer’s disease astrocytes are skewed into proinflammatory and oxidative profiles with increased secretions of vasoactive mediators inducing endothelial junction disruption and immune cell infiltration.In this review,we summarize the findings of existing literature on the relevance of astrocyte alte ration in response to amyloid pathology in the context of blood-brain barrier dysfunction.First,we briefly describe the physiological roles of astrocytes in blood-brain barrier maintenance.Then,we review the clinical evidence of astrocyte pathology in Alzheimer’s disease patients and the preclinical evidence in animal and cellular models.We further discuss the structural changes of blood-brain barrier that correlates with Alzheimer’s disease astrocyte.Finally,we evaluate the roles of soluble factors secreted by Alzheimer’s disease astrocytes,providing potential molecular mechanisms underlying blood-brain barrier modulation.We conclude with a perspective on investigating the therapeutic potential of targeting astrocytes for blood-brain barrier protection in Alzheimer’s disease. 展开更多
关键词 Alzheimer’s disease amyloid-beta astrocyte(astroglial)-endothelial interaction astrocyte pathology blood-brain barrier blood-brain barrier disruption brain endothelial cell neuroinflammation reactive astrocyte
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Intranasal nerve growth factor bypasses the blood-brain barrier and affects spinal cord neurons in spinal cord injury 认领 引用 被引量：19
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作者 Luigi Aloe Patrizia Bianchi +2 位作者 Alberto De Bellis Marzia Soligo Maria Luisa Rocco 《Neural Regeneration Research》 SCIE CAS CSCD 2014年第10期1025-1030,共6页
The purpose of this work was to investigate whether, by intranasal administration, the nerve growth factor bypasses the blood-brain barrier and turns over the spinal cord neurons and if such therapeutic approach could... The purpose of this work was to investigate whether, by intranasal administration, the nerve growth factor bypasses the blood-brain barrier and turns over the spinal cord neurons and if such therapeutic approach could be of value in the treatment of spinal cord injury. Adult Sprague-Dawley rats with intact and injured spinal cord received daily intranasal nerve growth factor administration in both nostrils for 1 day or for 3 consecutive weeks. We found an in-creased content of nerve growth factor and enhanced expression of nerve growth factor receptor in the spinal cord 24 hours after a single intranasal administration of nerve growth factor in healthy rats, while daily treatment for 3 weeks in a model of spinal cord injury improved the deifcits in locomotor behaviour and increased spinal content of both nerve growth factor and nerve growth factor receptors. These outcomes suggest that the intranasal nerve growth factor bypasses blood-brain barrier and affects spinal cord neurons in spinal cord injury. They also suggest exploiting the possible therapeutic role of intranasally delivered nerve growth factor for the neuroprotection of damaged spinal nerve cells. 展开更多
关键词 nerve regeneration spinal cord injury nerve growth factor intranasal delivery blood-brain barrier motor function leptin neuroprotection rats neural regeneration
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