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Activation of the wnt/β-catenin/CYP1B1 pathway alleviates oxidative stress and protects the blood-brain barrier under cerebral ischemia/reperfusion conditions 被引量:9
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作者 Xingyong Chen Nannan Yao +4 位作者 Yanguang Mao Dongyun Xiao Yiyi Huang Xu Zhang Yinzhou Wang 《Neural Regeneration Research》 SCIE CAS CSCD 2024年第7期1541-1547,共7页
Accumulating evidence suggests that oxidative stress and the Wnt/β-catenin pathway participate in stroke-induced disruption of the blood-brain barrier.However,the potential links between them following ischemic strok... Accumulating evidence suggests that oxidative stress and the Wnt/β-catenin pathway participate in stroke-induced disruption of the blood-brain barrier.However,the potential links between them following ischemic stroke remain largely unknown.The present study found that cerebral ischemia leads to oxidative stress and repression of the Wnt/β-catenin pathway.Meanwhile,Wnt/β-catenin pathway activation by the pharmacological inhibito r,TWS119,relieved oxidative stress,increased the levels of cytochrome P4501B1(CYP1B1)and tight junction-associated proteins(zonula occludens-1[ZO-1],occludin and claudin-5),as well as brain microvascular density in cerebral ischemia rats.Moreove r,rat brain microvascular endothelial cells that underwent oxygen glucose deprivation/reoxygenation displayed intense oxidative stress,suppression of the Wnt/β-catenin pathway,aggravated cell apoptosis,downregulated CYP1B1and tight junction protein levels,and inhibited cell prolife ration and migration.Overexpression ofβ-catenin or knockdown ofβ-catenin and CYP1B1 genes in rat brain mic rovascular endothelial cells at least partly ameliorated or exacerbated these effects,respectively.In addition,small interfering RNA-mediatedβ-catenin silencing decreased CYP1B1 expression,whereas CYP1B1 knoc kdown did not change the levels of glycogen synthase kinase 3β,Wnt-3a,andβ-catenin proteins in rat brain microvascular endothelial cells after oxygen glucose deprivatio n/reoxygenation.Thus,the data suggest that CYP1B1 can be regulated by Wnt/β-catenin signaling,and activation of the Wnt/β-catenin/CYP1B1 pathway contributes to alleviation of oxidative stress,increased tight junction levels,and protection of the blood-brain barrier against ischemia/hypoxia-induced injury. 展开更多
关键词 blood-brain barrier CYP1B1 oxidative stress oxygen glucose deprivation/reoxygenation tight junction vascular endothelial cells Wnt/β-catenin pathway β-catenin
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Blood-brain barrier pathology in cerebral small vessel disease 被引量:5
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作者 Ruxue Jia Gemma Solé-Guardia Amanda J.Kiliaan 《Neural Regeneration Research》 SCIE CAS CSCD 2024年第6期1233-1240,共8页
Cerebral small vessel disease is a neurological disease that affects the brain microvasculature and which is commonly observed among the elderly.Although at first it was considered innocuous,small vessel disease is no... Cerebral small vessel disease is a neurological disease that affects the brain microvasculature and which is commonly observed among the elderly.Although at first it was considered innocuous,small vessel disease is nowadays regarded as one of the major vascular causes of dementia.Radiological signs of small vessel disease include small subcortical infarcts,white matter magnetic resonance imaging hyperintensities,lacunes,enlarged perivascular spaces,cerebral microbleeds,and brain atrophy;however,great heterogeneity in clinical symptoms is observed in small vessel disease patients.The pathophysiology of these lesions has been linked to multiple processes,such as hypoperfusion,defective cerebrovascular reactivity,and blood-brain barrier dysfunction.Notably,studies on small vessel disease suggest that blood-brain barrier dysfunction is among the earliest mechanisms in small vessel disease and might contribute to the development of the hallmarks of small vessel disease.Therefore,the purpose of this review is to provide a new foundation in the study of small vessel disease pathology.First,we discuss the main structural domains and functions of the blood-brain barrier.Secondly,we review the most recent evidence on blood-brain barrier dysfunction linked to small vessel disease.Finally,we conclude with a discussion on future perspectives and propose potential treatment targets and interventions. 展开更多
关键词 blood-brain barrier dysfunction cerebral blood flow cerebral hypoperfusion endothelial dysfunction HYPERTENSION inflammation magnetic resonance imaging neurovascular unit oxidative stress small vessel disease tight junctions TRANSCYTOSIS
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Rebuilding insight into the pathophysiology of Alzheimer’s disease through new blood-brain barrier models 被引量:2
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作者 Kinya Matsuo Hideaki Nshihara 《Neural Regeneration Research》 SCIE CAS CSCD 2024年第9期1954-1960,共7页
The blood-brain barrier is a unique function of the microvasculature in the brain parenchyma that maintains homeostasis in the central nervous system.Blood-brain barrier breakdown is a common pathology in various neur... The blood-brain barrier is a unique function of the microvasculature in the brain parenchyma that maintains homeostasis in the central nervous system.Blood-brain barrier breakdown is a common pathology in various neurological diseases,such as Alzheimer’s disease,stroke,multiple sclerosis,and Parkinson’s disease.Traditionally,it has been considered a consequence of neuroinflammation or neurodegeneration,but recent advanced imaging techniques and detailed studies in animal models show that blood-brain barrier breakdown occurs early in the disease process and may precede neuronal loss.Thus,the blood-brain barrier is attractive as a potential therapeutic target for neurological diseases that lack effective therapeutics.To elucidate the molecular mechanism underlying blood-brain barrier breakdown and translate them into therapeutic strategies for neurological diseases,there is a growing demand for experimental models of human origin that allow for functional assessments.Recently,several human induced pluripotent stem cell-derived blood-brain barrier models have been established and various in vitro blood-brain barrier models using microdevices have been proposed.Especially in the Alzheimer’s disease field,the human evidence for blood-brain barrier dysfunction has been demonstrated and human induced pluripotent stem cell-derived blood-brain barrier models have suggested the putative molecular mechanisms of pathological blood-brain barrier.In this review,we summarize recent evidence of blood-brain barrier dysfunction in Alzheimer’s disease from pathological analyses,imaging studies,animal models,and stem cell sources.Additionally,we discuss the potential future directions for blood-brain barrier research. 展开更多
关键词 Alzheimer’s disease blood-brain barrier human induced pluripotent stem cells
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Post-acute ischemic stroke hyperglycemia aggravates destruction of the blood-brain barrier 被引量:1
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作者 Tianqi Xu Jianhong Yang +5 位作者 Yao Xu Xiaofeng Wang Xiang Gao Jie Sun Chenhui Zhou Yi Huang 《Neural Regeneration Research》 SCIE CAS CSCD 2024年第6期1344-1350,共7页
Post-acute ischemic stroke hyperglycemia increases the risk of hemorrhagic transformation,which is associated with blood-brain barrier disruption.Brain microvascular endothelial cells are a major component of the bloo... Post-acute ischemic stroke hyperglycemia increases the risk of hemorrhagic transformation,which is associated with blood-brain barrier disruption.Brain microvascular endothelial cells are a major component of the blood-brain barrier.Intercellular mitochondrial transfer has emerged as a novel paradigm for repairing cells with mitochondrial dysfunction.In this study,we first investigated whether mitochondrial transfer exists between brain microvascular endothelial cells,and then investigated the effects of post-acute ischemic stroke hyperglycemia on mitochondrial transfer between brain microvascular endothelial cells.We found that healthy brain microvascular endothelial cells can transfer intact mitochondria to oxygen glucose deprivation-injured brain microvascular endothelial cells.However,post-oxygen glucose deprivation hyperglycemia hindered mitochondrial transfer and exacerbated mitochondrial dysfunction.We established an in vitro brain microvascular endothelial cell model of the blood-brain barrier.We found that post-acute ischemic stroke hyperglycemia reduced the overall energy metabolism levels of brain microvascular endothelial cells and increased permeability of the blood-brain barrier.In a clinical study,we retrospectively analyzed the relationship between post-acute ischemic stroke hyperglycemia and the severity of hemorrhagic transformation.We found that post-acute ischemic stroke hyperglycemia serves as an independent predictor of severe hemorrhagic transformation.These findings suggest that post-acute ischemic stroke hyperglycemia can aggravate disruption of the blood-brain barrier by inhibiting mitochondrial transfer. 展开更多
关键词 acute ischemic stroke blood-brain barrier brain microvascular endothelial cells mitochondrial transfer stress hyperglycemia
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Targeting brain tumors with innovative nanocarriers:bridging the gap through the blood-brain barrier
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作者 KARAN WADHWA PAYAL CHAUHAN +7 位作者 SHOBHIT KUMAR RAKESH PAHWA RAVINDER VERMA RAJAT GOYAL GOVIND SINGH ARCHANA SHARMA NEHA RAO DEEPAK KAUSHIK 《Oncology Research》 SCIE 2024年第5期877-897,共21页
Background:Glioblastoma multiforme(GBM)is recognized as the most lethal and most highly invasive tumor.The high likelihood of treatment failure arises fromthe presence of the blood-brain barrier(BBB)and stemcells arou... Background:Glioblastoma multiforme(GBM)is recognized as the most lethal and most highly invasive tumor.The high likelihood of treatment failure arises fromthe presence of the blood-brain barrier(BBB)and stemcells around GBM,which avert the entry of chemotherapeutic drugs into the tumormass.Objective:Recently,several researchers have designed novel nanocarrier systems like liposomes,dendrimers,metallic nanoparticles,nanodiamonds,and nanorobot approaches,allowing drugs to infiltrate the BBB more efficiently,opening up innovative avenues to prevail over therapy problems and radiation therapy.Methods:Relevant literature for this manuscript has been collected from a comprehensive and systematic search of databases,for example,PubMed,Science Direct,Google Scholar,and others,using specific keyword combinations,including“glioblastoma,”“brain tumor,”“nanocarriers,”and several others.Conclusion:This review also provides deep insights into recent advancements in nanocarrier-based formulations and technologies for GBM management.Elucidation of various scientific advances in conjunction with encouraging findings concerning the future perspectives and challenges of nanocarriers for effective brain tumor management has also been discussed. 展开更多
关键词 GLIOBLASTOMA Brain tumor blood-brain barrier Liposomes Metallic nanoparticles NANOCARRIERS
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Functionalized lipid nanoparticles modulate the blood-brain barrier and eliminate α-synuclein to repair dopamine neurons
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作者 Xiaomei Wu Renxiang Yuan +4 位作者 Yichong Xu Kai Wang Hong Yuan Tingting Meng Fuqiang Hu 《Asian Journal of Pharmaceutical Sciences》 SCIE CAS 2024年第2期120-135,共16页
The challenge in the clinical treatment of Parkinson's disease lies in the lack of disease-modifying therapies that can halt or slow down the progression. Peptide drugs, such as exenatide (Exe), with potential dis... The challenge in the clinical treatment of Parkinson's disease lies in the lack of disease-modifying therapies that can halt or slow down the progression. Peptide drugs, such as exenatide (Exe), with potential disease-modifying efficacy, have difficulty in crossing the blood-brain barrier (BBB) due to their large molecular weight. Herein, we fabricate multi-functionalized lipid nanoparticles (LNP) Lpc-BoSA/CSO with BBB targeting, permeability-increasing and responsive release functions. Borneol is chemically bonded with stearic acid and, as one of the components of Lpc-BoSA/CSO, is used to increase BBB permeability. Immunofluorescence results of brain tissue of 15-month-old C57BL/6 mice show that Lpc-BoSA/CSO disperses across the BBB into brain parenchyma, and the amount is 4.21 times greater than that of conventional LNP. Motor symptoms of mice in Lpc-BoSA/CSO-Exe group are significantly improved, and the content of dopamine is 1.85 times (substantia nigra compacta) and 1.49 times (striatum) that of PD mice. α-Synuclein expression and Lewy bodies deposition are reduced to 51.85% and 44.72% of PD mice, respectively. Immunohistochemical mechanism studies show AKT expression in Lpc-BoSA/CSO-Exe is 4.23 times that of PD mice and GSK-3β expression is reduced to 18.41%. Lpc-BoSA/CSO-Exe could reduce the production of α-synuclein and Lewy bodies through AKT/GSK-3β pathway, and effectively prevent the progressive deterioration of Parkinson's disease. In summary, Lpc-BoSA/CSO-Exe increases the entry of exenatide into brain and promotes its clinical application for Parkinson's disease therapy. 展开更多
关键词 blood-brain barrier Lipid nanoparticles Brain delivery facilitation α-Symuclein Parkinson's disease
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Ultrasound combined blood-brain barrier targeting brain delivery of four-in-one molecular aggregates for the enhancement of anesthetic efficacy and toxicity reduction via propofol-etomidate synergistically inhibition GABA receptor
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作者 Shuo Zhang Yishu Wang +11 位作者 Mingting Zhu Bingyang Liu Wenpu Zhao Shuai Zhang Ji Xia Lei Shi Peng Tang Feiqian Wang Siyuan Zhang Mingxi Wan Daocheng Wu Wei Gao 《Aggregate》 EI CAS 2024年第5期245-264,共20页
To enhance the anesthetic efficacy and reduce toxic side effects,a strategy is proposed involving the utilization of general anesthetics of Propofol(Pro)and Eto-midate(Eto)to synergistic inhibition GABA receptors simul... To enhance the anesthetic efficacy and reduce toxic side effects,a strategy is proposed involving the utilization of general anesthetics of Propofol(Pro)and Eto-midate(Eto)to synergistic inhibition GABA receptors simultaneously.Four-in-one molecular aggregates were prepared to implement this strategy,which comprised of Pro and Eto with the bridging molecule monoglyceride monooleate(GMO)and sur-factant F127 through intermolecular forces.The blood-brain barrier(BBB)targeted lactoferrin(LF)is affixed to their surface,obtaining thefinal molecular aggregates.By employing lactoferrin enrich aggregates to the BBB,followed by ultrasound combine microbubbles to open the BBB,a remarkable 4.5-fold enhancement in brain drug delivery was achieved.The molecular aggregates group maintained sta-ble parameters of heart rate,diastolic blood pressure,and systolic blood pressure.A notable increase of more than twice therapeutic index(TI)value was observed,implying their higher anesthesia efficiency and reduced toxicity.Electroencephalo-gram(EEG)experiments demonstrate a significant elevation in the proportion of θ waves from 28%to 80%for aggregates,accompanied by a nearlyfivefold reduc-tion in the proportion ofθwaves,meaning a significant improvement in synergistic anesthesia effectiveness(interaction index 0.289)with lower drug dosage.Further-more,mouse immunofluorescence brain slice experiments suggest Pro and Eto enter the GABA receptor simultaneously,resulting in synergistic inhibition of GABA receptors. 展开更多
关键词 blood-brain barrier brain delivery GABA receptor molecular aggregates synergistic anesthetic efficacy
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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
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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 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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Interaction of major facilitator superfamily domain containing 2A with the blood-brain barrier
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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 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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Association between intercellular adhesion molecule-1 to depression and blood-brain barrier penetration in cerebellar vascular disease
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作者 Ju-Luo Chen Rui Wang +2 位作者 Pei-Qi Ma You-Meng Wang Qi-Qiang Tang 《World Journal of Psychiatry》 SCIE 2024年第11期1661-1670,共10页
BACKGROUND Cerebral small vessel disease(CSVD)is a prevalent cerebrovascular disease in clinical practice that is often associated with macrovascular disease.A clear understanding of the underlying causes of CSVD rema... BACKGROUND Cerebral small vessel disease(CSVD)is a prevalent cerebrovascular disease in clinical practice that is often associated with macrovascular disease.A clear understanding of the underlying causes of CSVD remains elusive.AIM To explore the association between intercellular adhesion molecule-1(ICAM-1)and blood-brain barrier(BBB)penetration in CSVD.METHODS This study included patients admitted to Fuyang People’s Hospital and Fuyang Community(Anhui,China)between December 2021 and March 2022.The study population comprised 142 patients,including 80 in the CSVD group and 62 in the control group.Depression was present in 53 out of 80 patients with CSVD.Multisequence magnetic resonance imaging(MRI)and dynamic contrast-enhanced MRI were applied in patients to determine the brain volume,cortical thickness,and cortical area of each brain region.Moreover,neuropsychological tests including the Hamilton depression scale,mini-mental state examination,and Montreal cognitive assessment basic scores were performed.RESULTS The multivariable analysis showed that age[P=0.011;odds ratio(OR)=0.930,95%confidence interval(CI):0.880-0.983]and ICAM-1 levels(P=0.023;OR=1.007,95%CI:1.001-1.013)were associated with CSVD.Two regions of interest(ROIs;ROI3 and ROI4)in the white matter showed significant(both P<0.001;95%CI:0.419-0.837 and 0.366-0.878)differences between the two groups,whereas only ROI1 in the gray matter showed signi-ficant difference(P=0.046;95%CI:0.007-0.680)between the two groups.ICAM-1 was significantly correlated(all P<0.05)with cortical thickness in multiple brain regions in the CSVD group.CONCLUSION This study revealed that ICAM-1 levels were independently associated with CSVD.ICAM-1 may be associated with cortical thickness in the brain,predominantly in the white matter,and a significant increase in BBB permeability,proposing the involvement of ICAM-1 in BBB destruction. 展开更多
关键词 Cerebral small vessel disease Intercellular adhesion molecule-1 blood-brain barrier penetration Cortical thickness White matter
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Dysfunction of blood-brain barrier in cerebral amyloid angiopathy
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作者 Mengke Zhang Chuanjie Wu +2 位作者 Wenbo Zhao Changhong Ren Xunming Ji 《Journal of Translational Neuroscience》 2024年第3期15-20,共6页
Increasing evidence demonstrated that the blood-brain barrier(BBB)was involved in developing cerebral amyloid angiopathy(CAA).The BBB participates in the neurovascular coupling and regulates the transport of substance... Increasing evidence demonstrated that the blood-brain barrier(BBB)was involved in developing cerebral amyloid angiopathy(CAA).The BBB participates in the neurovascular coupling and regulates the transport of substances,which is closely related to neurodegenerative diseases.In CAA,the deposition of amyloid beta(Aβ)in arteries,capillaries,and arterioles of meninges and cerebral cortex results in the destruction of the BBB,chronic inflammatory response,chronic cerebral hypoperfusion,and dysfunction of the neurovascular unit,which eventually leads to neurodegeneration.At the same time,CAA is an age-related disease.Patients with CAA often have some risk factors for cerebrovascular diseases,such as hypertension and diabetes,which can further aggravate the damage to the BBB.Thus,it is of great significance to pay attention to the BBB in the pathogenesis and future intervention targets of CAA.Therefore,this manuscript reviewed the dysfunction of the BBB in CAA. 展开更多
关键词 cerebral amyloid angiopathy cerebrovascular endothelial cells blood-brain barrier
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Multimodal comparison of plasma proteins associated with blood-brain barrier impairment in Alzheimer’s disease
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作者 Elisa Giunti Roberto Collu +3 位作者 Joel Reisman Jong Soo Lee Noureddine Melikechi Weiming Xia 《Aging Communications》 2024年第1期1-9,共9页
Background:Vascular impairment is one of the major contributors to dementia.We aimed to identify blood biomarkers suggestive of potential impairment of the blood-brain barrier(BBB)in subjects with Alzheimer’s disease... Background:Vascular impairment is one of the major contributors to dementia.We aimed to identify blood biomarkers suggestive of potential impairment of the blood-brain barrier(BBB)in subjects with Alzheimer’s disease(AD).Methods:We used administrative data from the VA Informatics and Computing Infrastructure Resource Center to study both inpatients and outpatients with AD.Plasma samples from healthy control and AD individuals were analyzed using enzyme-linked immunosorbent assay and proteomics approaches to identify differentially expressed proteins.Bioinformatic analysis was applied to explore significantly enriched pathways.Results:In the same cohort of patients with AD,we found twice number of subjects with cerebral amyloid angiopathy in the two-year period after the onset of AD,compared to the number of subjects with cerebral amyloid angiopathy in the two-year period prior to AD onset.Different pathways related to BBB,like cell adhesion,extracellular matrix organization and Wnt signaling,were activated and differentially expressed proteins such as ADAM22,PDGFR-α,DKK-4,Neucrin and RSOP-1 were identified.Moreover,matrix metalloproteinase-9,which is implicated in causing degradation of basal lamina and BBB disruption,was significantly increased in the plasma of AD patients.Conclusions:Alteration of proteins found in AD subjects could provide new insights into biomarkers regulating permeability and BBB integrity. 展开更多
关键词 Alzheimer’s disease blood-brain barrier peripheral biomarkers matrix metalloproteinases cerebral amyloid angiopathy
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Mechanisms of imperatorin on regulating Pglycoprotein in blood-brain barrier based on network pharmacology and in vitro experiment
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作者 SONG Yizhen YIN Wanxin +5 位作者 MA Yicong AN Yufan HUANG Jiaqi YAN Zhongjie WU Xiuwen WANG Yuanyu 《中国药理学与毒理学杂志》 CAS 北大核心 2023年第S01期17-18,共2页
OBJECTIVE To explore mecha⁃nisms of imperatorin on regulating P-glycoprotein(P-gp)in blood-brain barrier(BBB)based on net⁃work pharmacology combined with in vitro experi⁃ment.METHODS Drug targets were predicted using ... OBJECTIVE To explore mecha⁃nisms of imperatorin on regulating P-glycoprotein(P-gp)in blood-brain barrier(BBB)based on net⁃work pharmacology combined with in vitro experi⁃ment.METHODS Drug targets were predicted using the Pharmapper and Swiss targets data⁃bases;disease targets were obtained through the Genecards database;intersections between drugs and disease targets were screened by Cytoscape software;the obtained core targets were used to construct protein-protein interaction(PPI)network,gene ontology(GO)functions,and Kyoto encyclopedia of genes and genomes(KEGG)pathway enrichment analysis.The effects of imperatorin(20,50,100μmol·L^(-1))on P-gp activity were monitored in hCMEC/D3 in vitro BBB model,and the effects of imperatorin on the expression of target proteins were verified using Western blot method.RESULTS 55 drug targets and 3102 disease targets were obtained from the network pharmacology screening,and 37 core targets were obtained after the combination.Enrichment analysis showed that core targets were closely related to chemical synaptic trans⁃mission regulation,neurotransmitter receptor activity,protein kinase regulation activity,G proteincoupled receptor signaling pathway,neural active ligand receptor interaction pathway,PI3K-Akt sig⁃naling pathway,VEGF signaling pathway,etc..In vitro experimental validation suggested that all tested concentration groups of imperatorin signifi⁃cantly reduced the activity and expression of P-gp,which were achieved by significantly downregu⁃lating the phosphorylation levels of PI3K and Akt,and repressing the expression of VEGFR2 pro⁃tein.CONCLUSION Network pharmacology was used to predict the core targets and signaling pathways of imperatorin on regulating P-gp in BBB and relevant validation was conducted through in vitro experiments,providing a refer⁃ence basis for further exploration of the mecha⁃nisms of imperatorin on regulating P-gp in BBB. 展开更多
关键词 IMPERATORIN blood-brain barrier P-GLYCOPROTEIN network pharmacology in vitro experiment
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Emerging roles of astrocytes in blood-brain barrier disruption upon amyloid-beta insults in Alzheimer's disease 被引量:8
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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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The importance of laminin at the blood-brain barrier 被引量:5
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作者 Sebok K.Halder Arjun Sapkota Richard Milner 《Neural Regeneration Research》 SCIE CAS CSCD 2023年第12期2557-2563,共7页
The blood-brain barrier is a unique property of central nervous system blood vessels that protects sensitive central nervous system cells from potentially harmful blood components.The mechanistic basis of this barrier... The blood-brain barrier is a unique property of central nervous system blood vessels that protects sensitive central nervous system cells from potentially harmful blood components.The mechanistic basis of this barrier is found at multiple levels,including the adherens and tight junction proteins that tightly bind adjacent endothelial cells and the influence of neighboring pericytes,microglia,and astrocyte endfeet.In addition,extracellular matrix components of the vascular basement membrane play a critical role in establishing and maintaining blood-brain barrier integrity,not only by providing an adhesive substrate for blood-brain barrier cells to adhere to,but also by providing guidance cues that strongly influence vascular cell behavior.The extracellular matrix protein laminin is one of the most abundant components of the basement membrane,and several lines of evidence suggest that it plays a key role in directing blood-brain barrier behavior.In this review,we describe the basic structure of laminin and its receptors,the expression patterns of these molecules in central nervous system blood vessels and how they are altered in disease states,and most importantly,how genetic deletion of different laminin isoforms or their receptors reveals the contribution of these molecules to blood-brain barrier function and integrity.Finally,we discuss some of the important unanswered questions in the field and provide a“to-do”list of some of the critical outstanding experiments. 展开更多
关键词 ASTROCYTES basement membrane blood vessels blood-brain barrier integrity DYSTROGLYCAN endothelial cells inflammation INTEGRINS LAMININ PERICYTES
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The role of fibronectin in multiple sclerosis and the effect of drug delivery across the blood-brain barrier 被引量:3
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作者 Shuang-Shuang Wei Le Chen +2 位作者 Feng-Yuan Yang Si-Qi Wang Peng Wang 《Neural Regeneration Research》 SCIE CAS CSCD 2023年第10期2147-2155,共9页
Remyelination failure is one of the main characteristics of multiple sclerosis and is potentially correlated with disease progression.Previous research has shown that the extracellular matrix is associated with remyel... Remyelination failure is one of the main characteristics of multiple sclerosis and is potentially correlated with disease progression.Previous research has shown that the extracellular matrix is associated with remyelination failure because remodeling of the matrix often fails in both chronic and progressive multiple sclerosis.Fibronectin aggregates are assembled and persistently exist in chronic multiple sclerosis,thus inhibiting remyelination.Although many advances have been made in the mechanisms and treatment of multiple sclerosis,it remains very difficult for drugs to reach pathological brain tissues;this is due to the complexity of brain structure and function,especially the existence of the blood-brain barrier.Therefore,herein,we review the effects of fibronectin aggregates on multiple sclerosis and the efficacy of different forms of drug delivery across the blood-brain barrier in the treatment of this disease. 展开更多
关键词 blood-brain barrier brain delivery EXOSOMES extracellular matrix fibronectin aggregates FIBRONECTIN intestinal flora multiple sclerosis remyelination failure REMYELINATION
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Overexpression of mitogen-activated protein kinase phosphatase-1 in endothelial cells reduces blood-brain barrier injury in a mouse model of ischemic stroke 被引量:2
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作者 Xiu-De Qin Tai-Qin Yang +6 位作者 Jing-Hui Zeng Hao-Bin Cai Shao-Hua Qi Jian-Jun Jiang Ying Cheng Long-Sheng Xu Fan Bu 《Neural Regeneration Research》 SCIE CAS CSCD 2023年第8期1743-1749,共7页
Ischemic stroke can cause blood-brain barrier(BBB)injury,which worsens brain damage induced by stroke.Abnormal expression of tight junction proteins in endothelial cells(ECs)can increase intracellular space and BBB le... Ischemic stroke can cause blood-brain barrier(BBB)injury,which worsens brain damage induced by stroke.Abnormal expression of tight junction proteins in endothelial cells(ECs)can increase intracellular space and BBB leakage.Selective inhibition of mitogen-activated protein kinase,the negative regulatory substrate of mitogen-activated protein kinase phosphatase(MKP)-1,improves tight junction protein function in ECs,and genetic deletion of MKP-1 aggravates ischemic brain injury.However,whether the latter affects BBB integrity,and the cell type-specific mechanism underlying this process,remain unclear.In this study,we established an adult male mouse model of ischemic stroke by occluding the middle cerebral artery for 60 minutes and overexpressed MKP-1 in ECs on the injured side via lentiviral transfection before stroke.We found that overexpression of MKP-1 in ECs reduced infarct volume,reduced the level of inflammatory factors interleukin-1β,interleukin-6,and chemokine C-C motif ligand-2,inhibited vascular injury,and promoted the recovery of sensorimotor and memory/cognitive function.Overexpression of MKP-1 in ECs also inhibited the activation of cerebral ischemia-induced extracellular signal-regulated kinase(ERK)1/2 and the downregulation of occludin expression.Finally,to investigate the mechanism by which MKP-1 exerted these functions in ECs,we established an ischemic stroke model in vitro by depriving the primary endothelial cell of oxygen and glucose,and pharmacologically inhibited the activity of MKP-1 and ERK1/2.Our findings suggest that MKP-1 inhibition aggravates oxygen and glucose deprivation-induced cell death,cell monolayer leakage,and downregulation of occludin expression,and that inhibiting ERK1/2 can reverse these effects.In addition,co-inhibition of MKP-1 and ERK1/2 exhibited similar effects to inhibition of ERK1/2.These findings suggest that overexpression of MKP-1 in ECs can prevent ischemia-induced occludin downregulation and cell death via deactivating ERK1/2,thereby protecting the integrity of BBB,alleviating brain injury,and improving post-stroke prognosis. 展开更多
关键词 blood-brain barrier brain injury cerebral ischemia endothelial cells extracellular signal-regulated kinase 1/2 functional recovery mitogenactivated protein kinase phosphatase 1 OCCLUDIN oxygen and glucose deprivation transient middle cerebral artery occlusion
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In vitro model of the blood-brain barrier established by co-culture of primary cerebral microvascular endothelial and astrocyte cells 被引量:7
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作者 Yan Wang Ning Wang +3 位作者 Biao Cai Guang-yun Wang Jing Li Xing-xing Piao 《Neural Regeneration Research》 SCIE CAS CSCD 2015年第12期2011-2017,共7页
Drugs for the treatment and prevention of nervous system diseases must permeate the bloodbrain barrier to take effect.In vitro models of the blood-brain barrier are therefore important in the investigation of drug per... Drugs for the treatment and prevention of nervous system diseases must permeate the bloodbrain barrier to take effect.In vitro models of the blood-brain barrier are therefore important in the investigation of drug permeation mechanisms.However,to date,no unified method has been described for establishing a blood-brain barrier model.Here,we modified an in vitro model of the blood-brain barrier by seeding brain microvascular endothelial cells and astrocytes from newborn rats on a polyester Transwell cell culture membrane with 0.4-μm pores,and conducted transepithelial electrical resistance measurements,leakage tests and assays for specific bloodbrain barrier enzymes.We show that the permeability of our model is as low as that of the bloodbrain barrier in vivo.Our model will be a valuable tool in the study of the mechanisms of action of neuroprotective drugs. 展开更多
关键词 nerve regeneration blood-brain barrier ASTROCYTES brain microvascular endothelial cells permeability CO-CULTURE Transwell chamber neural regeneration
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Biochanin A,as the Lrg1/TGF-β/Smad2 pathway blockade,attenuates blood-brain barrier damage after cerebral ischemiareperfusion by modulating leukocyte migration patterns
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作者 LONGSHENG FU JINFANG HU +6 位作者 FENG SHAO YAOQI WU WEI BAI MINGJIN JIANG HAO CHEN LIHUA CHEN YANNI LV 《BIOCELL》 SCIE 2023年第8期1869-1883,共15页
Background:Biochanin A is an excellent dietary isoflavone that has the concomitant function of both medicine and foodstuff.The attenuation function of biochanin A on blood-brain barrier(BBB)damage induced by cerebral ... Background:Biochanin A is an excellent dietary isoflavone that has the concomitant function of both medicine and foodstuff.The attenuation function of biochanin A on blood-brain barrier(BBB)damage induced by cerebral ischemia-reperfusion remains unclear.Methods:C57BL/6 mice were subjected to 1 h middle cerebral artery occlusion(MCAO)followed by 24 h reperfusion.The infarct volume of the brain was stained by TTC,while leakage of the brain was quantitatively stained by Evans blue,and the neurologic deficit score was measured.Microglial-induced morphologic changes were observed via immunofluorescence staining,and rolling and adhering leukocytes in venules were observed via two-photon imaging,while the inner fluorescein isothiocyanate-albumin of venules were compared with those of surrounding interstitial area through venular albumin leakage.Results:The attenuation effect of biochanin A on tight junction injury was compared in ischemia-reperfusion mice or conventional knockdown of leucine-richα2-glycoprotein 1(Lrg1)mice.Biochanin A could ameliorate BBB injury in mice with cerebral ischemiareperfusion in a dose-dependent manner by strengthening the immunostaining volume of occludin,claudin-5,and zonula occludens-1.The amoeba morphologic changes of microglial combined with the elevated expression of Lrg1 could be relieved under the treatment of biochanin A.Biochanin A played a countervailing role on the rolling leukocytes in the vessel,while the leakage of blood vessels was reduced.Biochanin A diminished its functions to further improved attenuation for tight junction injury on conventional Lrg1-knockout mice,as well as the inhibition effects on TGF-β1,and the phosphorylation of suppressor of mothers against decapentaplegic 2(Smad2)/Smad2 via western blot assay.Conclusion:Biochanin A could alleviate tight junction injury induced by cerebral ischemiareperfusion and blocked the Lrg1/TGF-β/Smad2 pathway to modulate leukocyte migration patterns. 展开更多
关键词 Biochanin A BLOCKADE Leukocyte migration blood-brain barrier damage ISCHEMIA-REPERFUSION Lrg1
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The barriers of joining in vitro fertilization programs among infertile couples in developing countries:A scoping review
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作者 Andriana K Dewi Anggi L Wicaksana +1 位作者 Muhammad Lutfi Agung Dewanto 《Asian pacific Journal of Reproduction》 2023年第4期147-154,I0001-I0003,共11页
Objective:To determine the barriers of joining in-vitro fertilization(IVF)programs among infertile couples in developing countries.Methods:This study assessed infertile couples and the barriers or associated factors r... Objective:To determine the barriers of joining in-vitro fertilization(IVF)programs among infertile couples in developing countries.Methods:This study assessed infertile couples and the barriers or associated factors resulting in delayed decision-making of joining IVF program by searching databases PubMed,ScienceDirect,EBSCO,ClinicalKey,and Cochrane Library from inception until December 31,2021.Additional search strategies were snowballing literature search and citation tracking.Results:Eleven articles were included in the scoping review.The cost was the greatest barrier of joining IVF program.Limited access and lack of assisted reproductive technology centers,few qualified infertility trained staff,insufficient government support,low priority in government policy,along with sociocultural factors,such as religion and false beliefs or myths were also majorly considered to be associated obstacles.Conclusions:The main barrier associated with IVF program among infertile couples in developing countries is the high cost of the IVF services. 展开更多
关键词 In vitro fertilization Assisted reproductive technology barrier Developing countries
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