Bone tissue relies on the intricate interplay between blood vessels and nerve fibers,both are essential for many physiological and pathological processes of the skeletal system.Blood vessels provide the necessary oxyg...Bone tissue relies on the intricate interplay between blood vessels and nerve fibers,both are essential for many physiological and pathological processes of the skeletal system.Blood vessels provide the necessary oxygen and nutrients to nerve and bone tissues,and remove metabolic waste.Concomitantly,nerve fibers precede blood vessels during growth,promote vascularization,and influence bone cells by secreting neurotransmitters to stimulate osteogenesis.Despite the critical roles of both components,current biomaterials generally focus on enhancing intraosseous blood vessel repair,while often neglecting the contribution of nerves.Understanding the distribution and main functions of blood vessels and nerve fibers in bone is crucial for developing effective biomaterials for bone tissue engineering.This review first explores the anatomy of intraosseous blood vessels and nerve fibers,highlighting their vital roles in bone embryonic development,metabolism,and repair.It covers innovative bone regeneration strategies directed at accelerating the intrabony neurovascular system over the past 10 years.The issues covered included material properties(stiffness,surface topography,pore structures,conductivity,and piezoelectricity)and acellular biological factors[neurotrophins,peptides,ribonucleic acids(RNAs),inorganic ions,and exosomes].Major challenges encountered by neurovascularized materials during their clinical translation have also been highlighted.Furthermore,the review discusses future research directions and potential developments aimed at producing bone repair materials that more accurately mimic the natural healing processes of bone tissue.This review will serve as a valuable reference for researchers and clinicians in developing novel neurovascularized biomaterials and accelerating their translation into clinical practice.By bridging the gap between experimental research and practical application,these advancements have the potential to transform the treatment of bone defects and significantly improve the quality of life for patients with bone-related conditions.展开更多
Neurovascularization serves as the prerequisite and assurance for fostering neurogenesis after peripheral nerve injury(PNI),not only contributing to the reconstruction of the regenerative neurovascular niche but also ...Neurovascularization serves as the prerequisite and assurance for fostering neurogenesis after peripheral nerve injury(PNI),not only contributing to the reconstruction of the regenerative neurovascular niche but also providing a surface and directionality for Schwann cell(SC)cords migration and axons elongation.Despite the development of nerve tissue engineering techniques has drawn increasing attention to the intervention approach for repairing nerve defects,systematic generalization summary of the efficient intervention to expedite nerve angiogenesis is still scarce.This review delves into the mechanisms by which macrophages within the nerve defect trigger angiogenesis after PNI and elucidates how the newborn vessels support nerve regeneration,and then extracts three major categories of strategies for producing vascularized nerves in vitro and in vivo from them,encompassing(1)in vitro prevascularization,(2)in vivo prevascularization,and(3)stimulation of neurovascularization in situ.Furthermore,we emphasize that the lack of accuracy for structure and spatiotemporal regulation,as well as the operational inconvenience and delayed connection to the host's nerve stumps,have stuck the existing neurovascularization technology in the preclinical stage.The successful design of a future prospective clinical vascularized nerve scaffold should be guided by a comprehensive consideration of these aspects.展开更多
Stroke-induced alterations in cerebral blood flow trigger neurovascular remodeling,as manifested by the blood-brain barrier dysfunction and subs equent neurovascular repair activities such as angiogenesis.This process...Stroke-induced alterations in cerebral blood flow trigger neurovascular remodeling,as manifested by the blood-brain barrier dysfunction and subs equent neurovascular repair activities such as angiogenesis.This process involves neurovascular communication that facilitates the transport of mediators among cerebrovascular endothelial cells,pericytes,glial cells,and neurons,thereby transmitting signals from donor to recipient cells to elicit a collaborative response.展开更多
Pericytes are multi-functional mural cells of the central nervous system that cover the capillary endothelial cells. Pericytes play a vital role in nervous system development, significantly influencing the formation, ...Pericytes are multi-functional mural cells of the central nervous system that cover the capillary endothelial cells. Pericytes play a vital role in nervous system development, significantly influencing the formation, maturation, and maintenance of the central nervous system. An expanding body of studies has revealed that pericytes establish carefully regulated interactions with oligodendrocytes, microglia, and astrocytes. These communications govern numerous critical brain processes, including angiogenesis, neurovascular unit homeostasis, blood–brain barrier integrity, cerebral blood flow regulation, and immune response initiation. Glial cells and pericytes participate in dynamic and reciprocal interactions, with each influencing and adjusting the functionality of the other. Pericytes have the ability to control astrocyte polarization, trigger differentiation of oligodendrocyte precursor cells, and initiate immunological responses in microglia. Various neurological disorders that compromise the integrity of the blood–brain barrier can disrupt these communications, impair waste clearance, and hinder cerebral blood circulation, contributing to neuroinflammation. In the context of neurodegeneration, these disruptions exacerbate pathological processes, such as neuronal damage, synaptic dysfunction, and impaired tissue repair. This article explores the complex interactions between pericytes and various glial cells in both healthy and pathological states of the central nervous system. It highlights their essential roles in neurovascular function and disease progression, providing important insights that may enhance our understanding of the molecular mechanisms underlying these interactions and guide potential therapeutic strategies for neurodegenerative disorders in future research.展开更多
The nervous system processes a vast amount of information,performing computations that underlie perception,cognition,and behavior.During development,neuronal guidance genes,which encode extracellular cues,their recept...The nervous system processes a vast amount of information,performing computations that underlie perception,cognition,and behavior.During development,neuronal guidance genes,which encode extracellular cues,their receptors,and downstream signal transducers,organize neural wiring to generate the complex architecture of the nervous system.It is now evident that many of these neuroguidance cues and their receptors are active during development and are also expressed in the adult nervous system.This suggests that neuronal guidance pathways are critical not only for neural wiring but also for ongoing function and maintenance of the mature nervous system.Supporting this view,these pathways continue to regulate synaptic connectivity,plasticity,and remodeling,and overall brain homeostasis throughout adulthood.Genetic and transcriptomic analyses have further revealed many neuronal guidance genes to be associated with a wide range of neurodegenerative and neuropsychiatric disorders.Although the precise mechanisms by which aberrant neuronal guidance signaling drives the pathogenesis of these diseases remain to be clarified,emerging evidence points to several common themes,including dysfunction in neurons,microglia,astrocytes,and endothelial cells,along with dysregulation of neuron-microglia-astrocyte,neuroimmune,and neurovascular interactions.In this review,we explore recent advances in understanding the molecular and cellular mechanisms by which aberrant neuronal guidance signaling contributes to disease pathogenesis through altered cell-cell interactions.For instance,recent studies have unveiled two distinct semaphorin-plexin signaling pathways that affect microglial activation and neuroinflammation.We discuss the challenges ahead,along with the therapeutic potentials of targeting neuronal guidance pathways for treating neurodegenerative diseases.Particular focus is placed on how neuronal guidance mechanisms control neuron-glia and neuroimmune interactions and modulate microglial function under physiological and pathological conditions.Specifically,we examine the crosstalk between neuronal guidance signaling and TREM2,a master regulator of microglial function,in the context of pathogenic protein aggregates.It is well-established that age is a major risk factor for neurodegeneration.Future research should address how aging and neuronal guidance signaling interact to influence an individual’s susceptibility to various late-onset neurological diseases and how the progression of these diseases could be therapeutically blocked by targeting neuronal guidance pathways.展开更多
Drug development for Alzheimer’s disease is extremely challenging,as demonstrated by the repeated failures of amyloid-β-targeted therapeutics and the controversies surrounding the amyloid-βcascade hypothesis.More r...Drug development for Alzheimer’s disease is extremely challenging,as demonstrated by the repeated failures of amyloid-β-targeted therapeutics and the controversies surrounding the amyloid-βcascade hypothesis.More recently,advances in the development of Lecanemab,an anti-amyloid-βmonoclonal antibody,have shown positive results in reducing brain A burden and slowing cognitive decline in patients with early-stage Alzheimer’s disease in the Phase Ⅲ clinical trial(Clarity Alzheimer’s disease).Despite these promising results,side effects such as amyloid-related imaging abnormalities(ARIA)may limit its usage.ARIA can manifest as ARIA-E(cerebral edema or effusions)and ARIA-H(microhemorrhages or superficial siderosis)and is thought to be caused by increased vascular permeability due to inflammatory responses,leading to leakages of blood products and protein-rich fluid into brain parenchyma.Endothelial dysfunction is an early pathological feature of Alzheimer’s disease,and the blood-brain barrier becomes increasingly leaky as the disease progresses.In addition,APOE4,the strongest genetic risk factor for Alzheimer’s disease,is associated with higher vascular amyloid burden,increased ARIA incidence,and accelerated blood-brain barrier disruptions.These interconnected vascular abnormalities highlight the importance of vascular contributions to the pathophysiology of Alzheimer’s disease.Here,we will closely examine recent research evaluating the heterogeneity of brain endothelial cells in the microvasculature of different brain regions and their relationships with Alzheimer’s disease progression.展开更多
In patients with Alzheimer’s disease,gamma-glutamyl transferase 5(GGT5)expression has been observed to be downregulated in cerebrovascular endothelial cells.However,the functional role of GGT5 in the development of A...In patients with Alzheimer’s disease,gamma-glutamyl transferase 5(GGT5)expression has been observed to be downregulated in cerebrovascular endothelial cells.However,the functional role of GGT5 in the development of Alzheimer’s disease remains unclear.This study aimed to explore the effect of GGT5 on cognitive function and brain pathology in an APP/PS1 mouse model of Alzheimer’s disease,as well as the underlying mechanism.We observed a significant reduction in GGT5 expression in two in vitro models of Alzheimer’s disease(Aβ_(1-42)-treated hCMEC/D3 and bEnd.3 cells),as well as in the APP/PS1 mouse model.Additionally,injection of APP/PS1 mice with an adeno-associated virus encoding GGT5 enhanced hippocampal synaptic plasticity and mitigated cognitive deficits.Interestingly,increasing GGT5 expression in cerebrovascular endothelial cells reduced levels of both soluble and insoluble amyloid-βin the brains of APP/PS1 mice.This effect may be attributable to inhibition of the expression ofβ-site APP cleaving enzyme 1,which is mediated by nuclear factor-kappa B.Our findings demonstrate that GGT5 expression in cerebrovascular endothelial cells is inversely associated with Alzheimer’s disease pathogenesis,and that GGT5 upregulation mitigates cognitive deficits in APP/PS1 mice.These findings suggest that GGT5 expression in cerebrovascular endothelial cells is a potential therapeutic target and biomarker for Alzheimer’s disease.展开更多
Photon-counting computed tomography(PCCT)represents a transformative advancement in neuroimaging,offering superior spatial resolution,spectral imaging capabilities,reduced radiation dose,and enhanced contrast-to-noise...Photon-counting computed tomography(PCCT)represents a transformative advancement in neuroimaging,offering superior spatial resolution,spectral imaging capabilities,reduced radiation dose,and enhanced contrast-to-noise ratios.This review explores the technical foundations of PCCT,its advantages over conventional CT,and its growing applications in neuroimaging.PCCT has shown promise in improving neurovascular imaging,detecting small vessels,and reducing artifacts near metallic implants.It also enhances the visualization of spontaneous intracranial hypotension and cerebrospinal fluid leaks and provides superior diagnostic accuracy in acute ischemic stroke imaging.However,current limitations,including protocol complexity,high data volume,and the absence of integrated artificial intelligence noise reduction algorithms,pose challenges to widespread adoption.Future research should address these limitations and refine PCCT’s applications to unlock its full clinical potential.展开更多
Post-stroke depression(PSD)is a prevalent but often underdiagnosed complication affecting stroke survivors,with significant implications for recovery and quality of life.Emerging evidence suggests that central obesity...Post-stroke depression(PSD)is a prevalent but often underdiagnosed complication affecting stroke survivors,with significant implications for recovery and quality of life.Emerging evidence suggests that central obesity,as measured by the weight-to-waist index(WWI),may play a crucial role in PSD risk and severity.Traditional obesity metrics,such as body mass index,may not accurately capture the impact of visceral fat distribution on neuropsychiatric outcomes.This letter highlights the growing recognition of WWI as a precise indicator of metabolic and inflammatory disturbances linked to post-stroke mental health.Integrating WWI into routine stroke rehabilitation assessments could facilitate early identification of high-risk patients and improve intervention strategies.Further research is needed to establish standardized WWI cutoff values and explore potential therapeutic targets for PSD prevention.展开更多
Objective As the core unit of the limbic system,the hippocampus is involved in the regulation of higher neural activity by integrating emotional encoding and memory storage functions.In the pathological process of epi...Objective As the core unit of the limbic system,the hippocampus is involved in the regulation of higher neural activity by integrating emotional encoding and memory storage functions.In the pathological process of epilepsy,structural remodeling and functional disorders in this region have become the focus of research,and the existing evidence mostly focuses on hippocampal sclerosis,a typical neurodegenerative change.However,there is still a lack of systematic analysis of the pathological subtypes under the International League Against Epilepsy(ILAE)classification system in cross-scale molecular events such as epigenetic regulation and microbiome-brain axis.By integrating clinical cohort data and experimental model evidence,this article focuses on the association characteristics between hippocampal sclerosis subtypes and seizure patterns,and reveals the formation of abnormal hippocampal network and the cascading effect of abnormal hippocampus-related neurotransmitters in the formation of epileptogenic network.The study found that specific pathological subtypes showed a significant correspondence with seizure frequency and drug sensitivity,suggesting that hippocampal sclerosis drives epilepsy progression through multidimensional molecular events.In the future,it is necessary to combine spatial transcriptome and targeted metabolomics technology to analyze the cell interaction network in the hippocampal microenvironment,so as to provide a theoretical basis for the development of subtype-specific antiepileptic strategies.展开更多
Objective:Microvascular decompression(MVD)is the gold standard for treating drug-resistant classic trigeminal neuralgia(dcTN),with endoscopy enhancing surgical precision through improved visualization.This study evalu...Objective:Microvascular decompression(MVD)is the gold standard for treating drug-resistant classic trigeminal neuralgia(dcTN),with endoscopy enhancing surgical precision through improved visualization.This study evaluates the efficacy of fully endoscopic MVD for dcTN and presents our early experience.Methods:This retrospective study included patients with dcTN who underwent fully endoscopic MVD in the Department of Neurosurgery,the First Affiliated Hospital,Zhejiang University School of Medicine from November 2020 to February 2023.We recorded basic patient clinical information,clinical outcomes,offending vessels,complications,and recurrences,and assessed outcomes via the Barrow Neurological Institute(BNI)pain intensity score and the numeric rating scale(NRS)score.Results:All 42 patients had dcTN with preoperative BNI scores of V and NRS scores of 8e10.Endoscopic visualization enabled the precise identification of neurovascular conflicts,including small and deeply located vessels.Immediately after surgery,90.5%of patients achieved complete pain relief(BNI score of I,NRS score of 0).At the final follow-up,85.7%of patients had complete pain relief.All patients’pain was significantly relieved at immediate after surgery(0 vs.9,p<0.001)and at the final follow-up(0 vs.9,p<0.001),with lower NRS scores.Complications,including vertigo,headache,and transient facial numbness,occurred in 14.4%of patients and were manageable.展开更多
Calvarial nerves,along with vasculature,influence skull formation during development and following injury,but it remains unclear how calvarial nerves are spatially distributed during postnatal growth and aging.Studyin...Calvarial nerves,along with vasculature,influence skull formation during development and following injury,but it remains unclear how calvarial nerves are spatially distributed during postnatal growth and aging.Studying the spatial distribution of nerves in the skull remains a challenge due to a lack of methods to quantify 3D structures in intact bone.To visualize calvarial 3D neurovascular architecture,we imaged nerves and endothelial cells with lightsheet microscopy.展开更多
BACKGROUND The trigeminal nerve(TN)is frequently implicated in neurovascular conflicts,most commonly with the superior cerebellar artery(SCA),its predominant arterial counterpart in the cerebellopontine angle.AIM To e...BACKGROUND The trigeminal nerve(TN)is frequently implicated in neurovascular conflicts,most commonly with the superior cerebellar artery(SCA),its predominant arterial counterpart in the cerebellopontine angle.AIM To examine the relationship between the SCA and TN utilizing high-resolution magnetic resonance imaging and evaluated whether particular anatomical configurations predispose to clinically significant contact.METHODS Magnetic resonance imaging scans from 80 patients(160 sides)were retrospectively analyzed,excluding cases with pathological processes affecting the TN.Using multiplanar reconstruction,the TN root was identified and its spatial relationship with the SCA was evaluated.RESULTS Eight distinct topographic patterns were identified.The SCA most commonly coursed superior(30.6%),lateral(18.8%),or superolateral(17.5%)to the TN.Medial configurations,although less frequent,were associated with the shortest artery-nerve distance(mean 1.85±1.28 mm)and significantly higher contact rates(P<0.001).Overall,SCA-TN contact was observed in 14.4%of sides,but only 20%of these patients reported ipsilateral facial numbness.Variations in SCA origin(basilar artery,posterior cerebral artery,or common origin)and duplication did not significantly influence the artery-nerve distance.CONCLUSION Although SCA-TN contact is relatively frequent,only particular medial and superior configurations seem to predispose individuals to symptomatic compression.These observations are consistent with cadaveric and surgical evidence highlighting the significance of root entry zone contact in trigeminal neuralgia.Vascular contact alone should not serve as a diagnostic criterion;instead,geometric configuration and related nerve alterations must also be incorporated into preoperative assessment.展开更多
Previous studies have shown that models of depression exhibit structural and functional changes to the neurovascular unit. Thus, we hypothesized that diabetes-related depression might be associated with damage to the ...Previous studies have shown that models of depression exhibit structural and functional changes to the neurovascular unit. Thus, we hypothesized that diabetes-related depression might be associated with damage to the hippocampal neurovascular unit. To test this hypothesis, neurons, astrocytes and endothelial cells were isolated from the brain tissues of rat embryos and newborn rats. Hippocampal neurovascular unit co-cultures were produced using the Transwell chamber co-culture system. A model of diabetes-related depression was generated by adding 150 mM glucose and 200 μM corticosterone to the culture system and compared with the neuron + astrocyte and astrocyte + endothelial cell co-culture systems. Western blot assay was used to measure levels of structural proteins in the hippocampal neurovascular unit co-culture system. Levels of basic fibroblast growth factor, angiogenic factor 1, glial cell line–derived neurotrophic factor, transforming growth factor β1, leukemia inhibitory factor and 5-hydroxytryptamine in the hippocampal neurovascular unit co-culture system were measured by enzyme-linked immunosorbent assay. Flow cytometry and terminal deoxynucleotidyl transferase(TdT)-mediated dUTP nick end labeling staining was used to assess neuronal apoptosis in the hippocampal neurovascular unit. The neurovascular unit triple cell co-culture system had better barrier function and higher levels of structural and secretory proteins than the double cell co-culture systems. In comparison, in the model of diabetes-related depression, the neurovascular unit was damaged with decreased barrier function, poor structural integrity and impaired secretory function. Moreover, neuronal apoptosis was markedly increased, and 5-hydroxytryptamine levels were reduced. These results suggest that diabetes-related depression is associated with structural and functional damage to the neurovascular unit. Our findings provide a foundation for further studies on the pathogenesis of diabetes-related depression.展开更多
Calculus bovis is commonly used for the treatment of stroke in traditional Chinese medicine. Hyodeoxycholic acid(HDCA) is a bioactive compound extracted from calculus bovis. When combined with cholic acid, baicalin an...Calculus bovis is commonly used for the treatment of stroke in traditional Chinese medicine. Hyodeoxycholic acid(HDCA) is a bioactive compound extracted from calculus bovis. When combined with cholic acid, baicalin and jas-minoidin, HDCA prevents hypoxia-reoxygenation-induced brain injury by suppressing endoplasmic reticulum stress-mediated apoptotic signaling. However, the effects of HDCA in ischemic stroke injury have not yet been studied. Neurovascular unit(NVU) dysfunction occurs in ischemic stroke. Therefore, in this study, we investigated the effects of HDCA on the NVU under ischemic conditions in vitro. We co-cultured primary brain microvascular endothelial cells, neurons and astrocytes using a transwell chamber co-culture system. The NVU was pre-treated with 10.16 or 2.54 μg/mL HDCA for 24 hours before exposure to oxygen-glucose deprivation for 1 hour. The cell counting kit-8 assay was used to detect cell activity. Flow cytometry and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling were used to assess apoptosis. Enzyme-linked immunosorbent assay was used to measure the expression levels of inflammatory cytokines, including interleukin-1β, interleukin-6 and tumor necrosis factor-α, and neurotrophic factors, including brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor. Oxidative stress-related factors, such as superoxide dismutase, nitric oxide, malondialdehyde and γ-glutamyltransferase, were measured using kits. Pretreatment with HDCA significantly decreased blood-brain barrier permeability and neuronal apoptosis, significantly increased transendothelial electrical resistance and γ-glutamyltransferase activity, attenuated oxidative stress damage and the release of inflammatory cytokines, and increased brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor expression. Our findings suggest that HDCA maintains NVU morphological integrity and function by modulating inflammation, oxidation stress, apoptosis, and the expression of neurotrophic factors. Therefore, HDCA may have therapeutic potential in the clinical management of ischemic stroke. This study was approved by the Ethics Committee of Experimental Animals of Beijing University of Chinese Medicine(approval No. BUCM-3-2016040201-2003) in April 2016.展开更多
Constraint-induced movement therapy after cerebral ischemia stimulates axonal growth by decreasing expression levels of Nogo-A,RhoA,and Rho-associated kinase(ROCK)in the ischemic boundary zone.However,it remains uncle...Constraint-induced movement therapy after cerebral ischemia stimulates axonal growth by decreasing expression levels of Nogo-A,RhoA,and Rho-associated kinase(ROCK)in the ischemic boundary zone.However,it remains unclear if there are any associations between the Nogo-A/RhoA/ROCK pathway and angiogenesis in adult rat brains in pathological processes such as ischemic stroke.In addition,it has not yet been reported whether constraint-induced movement therapy can promote angiogenesis in stroke in adult rats by overcoming Nogo-A/RhoA/ROCK signaling.Here,a stroke model was established by middle cerebral artery occlusion and reperfusion.Seven days after stroke,the following treatments were initiated and continued for 3 weeks:forced limb use in constraint-induced movement therapy rats(constraint-induced movement therapy group),intraperitoneal infusion of fasudil(a ROCK inhibitor)in fasudil rats(fasudil group),or lateral ventricular injection of NEP1-40(a specific antagonist of the Nogo-66 receptor)in NEP1-40 rats(NEP1-40 group).Immunohistochemistry and western blot assay results showed that,at 2 weeks after middle cerebral artery occlusion,expression levels of RhoA and ROCK were lower in the ischemic boundary zone in rats treated with NEP1-40 compared with rats treated with ischemia/reperfusion or constraint-induced movement therapy alone.However,at 4 weeks after middle cerebral artery occlusion,expression levels of RhoA and ROCK in the ischemic boundary zone were markedly decreased in the NEP1-40 and constraint-induced movement therapy groups,but there was no difference between these two groups.Compared with the ischemia/reperfusion group,modified neurological severity scores and foot fault scores were lower and time taken to locate the platform was shorter in the constraint-induced movement therapy and fasudil groups at 4 weeks after middle cerebral artery occlusion,especially in the constraint-induced movement therapy group.Immunofluorescent staining demonstrated that fasudil promoted an immune response of nerve-regeneration-related markers(BrdU in combination with CD31(platelet endothelial cell adhesion molecule),Nestin,doublecortin,NeuN,and glial fibrillary acidic protein)in the subventricular zone and ischemic boundary zone ipsilateral to the infarct.After 3 weeks of constraint-induced movement therapy,the number of regenerated nerve cells was noticeably increased,and was accompanied by an increased immune response of tight junctions(claudin-5),a pericyte marker(a-smooth muscle actin),and vascular endothelial growth factor receptor 2.Taken together,the results demonstrate that,compared with fasudil,constraint-induced movement therapy led to stronger angiogenesis and nerve regeneration ability and better nerve functional recovery at 4 weeks after cerebral ischemia/reperfusion.In addition,constraint-induced movement therapy has the same degree of inhibition of RhoA and ROCK as NEP1-40.Therefore,constraint-induced movement therapy promotes angiogenesis and neurogenesis after cerebral ischemia/reperfusion injury,at least in part by overcoming the Nogo-A/RhoA/ROCK signaling pathway.All protocols were approved by the Institutional Animal Care and Use Committee of China Medical University,China on December 9,2015(approval No.2015 PS326 K).展开更多
Our previous studies have shown that glutamate and hippocampal neuron apoptosis are key signals and direct factors associated with diabetes-related depression,and structural and functional damage to the hippocampal ne...Our previous studies have shown that glutamate and hippocampal neuron apoptosis are key signals and direct factors associated with diabetes-related depression,and structural and functional damage to the hippocampal neurovascular unit has been associated with diabetesrelated depression.However,the underlying mechanism remains unclear.We hypothesized that diabetes-related depression might be associated with the glutamate(Glu)/metabotropic glutamate receptor2/3(mGluR2/3)/phosphoinositide 3-kinase(PI3K)pathway,activated by glucocorticoid receptors in the hippocampal neurovascular unit.To test this hypothesis,rat hippocampal neurovascular unit models,containing hippocampal neurons,astrocytes,and brain microvascular endothelial cells,were treated with 150 mM glucose and 200μM corticosterone,to induce diabetes-related depression.Our results showed that under conditions of diabetes complicated by depression,hippocampal neurovascular units were damaged,leading to decreased barrier function;elevated Glu levels;upregulated glucocorticoid receptor,vesicular glutamate transporter 3(VGLUT-3),and metabotropic glutamate receptor 2/3(mGluR2/3)expression;downregulated excitatory amino acid transporter 1(EAAT-1)expression;and alteration of the balance of key proteins associated with the extracellular signal-regulated kinase(ERK)/glial cell-derived neurotrophic factor(GDNF)/PI3K signaling pathway.Moreover,the viability of neurons was dramatically reduced in the model of diabetes-related depression,and neuronal apoptosis,and caspase-3 and caspase-9 expression levels,were increased.Our results suggest that the Glu/mGluR2/3/PI3K pathway,induced by glucocorticoid receptor activation in the hippocampal neurovascular unit,may be associated with diabetes-related depression.This study was approved by the Laboratory Animal Ethics Committee of The First Hospital of Hunan University of Chinese Medicine,China(approval No.HN-ZYFY-2019-11-12)on November 12,2019.展开更多
Objective:To describe the anatomical characteristics and patterns of neurovascular compression (NVC) in patients suffering trigeminal neuralgia(TN) by 3D high-resolution magnetic resonance imaging(MRI) method and imag...Objective:To describe the anatomical characteristics and patterns of neurovascular compression (NVC) in patients suffering trigeminal neuralgia(TN) by 3D high-resolution magnetic resonance imaging(MRI) method and image fusion technique.Methods:The anatomic structure of trigeminal nerve,brain stem and blood vessel was observed in 100 consecutive TN patients by 3D high resolution MRI(3D SPGR,contrast-enhanced T1 3D MP-RAGE and T2/T1 3D FIESTA). The 3D image sources were fused and visualized using 3D DOCTOR software.Results:One or several NVC sites,which usually appeared 0-9.8 mm away from brain stem,were found on the symptomatic side in 93%of the TN cases.Superior cerebellar artery was involved in 76%(71/93) of these cases.The other vessels including antero-inferior cerebellar artery,vertebral artery, basilar artery and veins also contributed to the occurrence of NVC.The NVC sites were found to be located in the proximal segment in 42%of these cases(39/93) and in the distal segment in 45% (42/93).Nerve dislocation or distortion was observed in 32%(30/93).Conclusions:Various 3D high resolution MRI methods combined with the image fusion technique could provide pathologic anatomic information for the diagnosis and treatment of TN.展开更多
Houshiheisan is composed of wind-dispelling （chrysanthemun fower, divaricate saposhnikovia root, Manchurian wild ginger, cassia twig, Szechwan lovage rhizome, and platycodon root） and deficiency-nourishing （ginseng...Houshiheisan is composed of wind-dispelling （chrysanthemun fower, divaricate saposhnikovia root, Manchurian wild ginger, cassia twig, Szechwan lovage rhizome, and platycodon root） and deficiency-nourishing （ginseng, Chinese angelica, large-head atractylodes rhizome, Indian bread, and zingiber） drugs. In this study, we assumed these drugs have protective effects against cerebral ischemia, on neurovascular units. Houshiheisan was intragastrically administered in a rat model of focal cerebral ischemia. Hematoxylin-eosin staining, transmission electron microscopy, immu- nofluorescence staining, and western blot assays showed that Houshiheisan reduced pathological injury to the ischemic penumbra, protected neurovascular units, visibly up-regtflated neuronal nuclear antigen expression, and down-regulated amyloid precursor protein and amyloid-[3 42 expression. Wind-dispelling and deficiency-nourishing drugs maintained NeuN expression to varying degrees, but did not affect amyloid precursor protein or amyloid-~ 42 expression in the ischemic penumbra. Our results suggest that the compound prescription Houshiheisan effectively suppresses abnormal amyloid precursor protein accumulation, reduces amyloid substance depo- sition, maintains stabilization of the internal environment of neurovascular units, and minimizes injury to neurovascular units in the ischemic penumbra.展开更多
Whether long non-coding RNA myocardial infarction-associated transcript is involved in oxygen-induced retinopathy remains poorly understood. To validate this hypothesis, we established a newborn mouse model of oxygen-...Whether long non-coding RNA myocardial infarction-associated transcript is involved in oxygen-induced retinopathy remains poorly understood. To validate this hypothesis, we established a newborn mouse model of oxygen-induced retinopathy by feeding in an oxygen concentration of 75 ± 2% from postnatal day 8 to postnatal day 12, followed by in normal air. On postnatal day 11, the mice were injected with the myocardial infarction-associated transcript siRNA plasmid via the vitreous cavity to knockdown long non-coding RNA myocardial infarction-associated transcript. Myocardial infarction-associated transcript siRNA transcription significantly inhibited myocardial infarctionassociated transcript mRNA expression, reduced the phosphatidylinosital-3-kinase, phosphorylated Akt and vascular endothelial growth factor immunopositivities, protein and mRNA expression, and alleviated the pathological damage to the retina of oxygen-induced retinopathy mouse models. These findings suggest that myocardial infarction-associated transcript is likely involved in the retinal neovascularization in retinopathy of prematurity and that inhibition of myocardial infarction-associated transcript can downregulate phosphatidylinosital-3-kinase, phosphorylated Akt and vascular endothelial growth factor expression levels and inhibit neovascularization. This study was approved by the Animal Ethics Committee of Shengjing Hospital of China Medical University, China(approval No. 2016 PS074 K) on February 25, 2016.展开更多
基金supported by the Foundation of National Clinical Research Center for Oral Diseases(LCA202204)the Key Research and Development Program of Shaanxi(2024GH-YBXM-19)+7 种基金the Clinical New Technology Program of Air Force Medical University(LX2023-306)the China Postdoctoral Science Foundation(2019M653969)the Thousand Talents Plan of Shaanxi Province(to Jing Wang)the National Natural Science Foundation of China(82101069,22205257)the Logistics Independent Research Project of PLA(to Yang Jiao)the Beijing Natural Science Foundation(7242279),the Beijing Nova Program(20230484283)the Beijing Municipal Science&Technology Commission(Z221100007422130)the Open Project of State Key Laboratory of Trauma and Chemical poisoning(SKLO202401).
文摘Bone tissue relies on the intricate interplay between blood vessels and nerve fibers,both are essential for many physiological and pathological processes of the skeletal system.Blood vessels provide the necessary oxygen and nutrients to nerve and bone tissues,and remove metabolic waste.Concomitantly,nerve fibers precede blood vessels during growth,promote vascularization,and influence bone cells by secreting neurotransmitters to stimulate osteogenesis.Despite the critical roles of both components,current biomaterials generally focus on enhancing intraosseous blood vessel repair,while often neglecting the contribution of nerves.Understanding the distribution and main functions of blood vessels and nerve fibers in bone is crucial for developing effective biomaterials for bone tissue engineering.This review first explores the anatomy of intraosseous blood vessels and nerve fibers,highlighting their vital roles in bone embryonic development,metabolism,and repair.It covers innovative bone regeneration strategies directed at accelerating the intrabony neurovascular system over the past 10 years.The issues covered included material properties(stiffness,surface topography,pore structures,conductivity,and piezoelectricity)and acellular biological factors[neurotrophins,peptides,ribonucleic acids(RNAs),inorganic ions,and exosomes].Major challenges encountered by neurovascularized materials during their clinical translation have also been highlighted.Furthermore,the review discusses future research directions and potential developments aimed at producing bone repair materials that more accurately mimic the natural healing processes of bone tissue.This review will serve as a valuable reference for researchers and clinicians in developing novel neurovascularized biomaterials and accelerating their translation into clinical practice.By bridging the gap between experimental research and practical application,these advancements have the potential to transform the treatment of bone defects and significantly improve the quality of life for patients with bone-related conditions.
基金financially supported by the following programs:National Key Research and Development Program of China(No.2023YFB3813003)National Natural Science Foundation of China(Nos.82430031,82122014,82071085)+1 种基金Zhejiang Provincial Natural Science Foundation of China(No.LR21H140001)the Central Universities(No.2022FZZX01-33)。
文摘Neurovascularization serves as the prerequisite and assurance for fostering neurogenesis after peripheral nerve injury(PNI),not only contributing to the reconstruction of the regenerative neurovascular niche but also providing a surface and directionality for Schwann cell(SC)cords migration and axons elongation.Despite the development of nerve tissue engineering techniques has drawn increasing attention to the intervention approach for repairing nerve defects,systematic generalization summary of the efficient intervention to expedite nerve angiogenesis is still scarce.This review delves into the mechanisms by which macrophages within the nerve defect trigger angiogenesis after PNI and elucidates how the newborn vessels support nerve regeneration,and then extracts three major categories of strategies for producing vascularized nerves in vitro and in vivo from them,encompassing(1)in vitro prevascularization,(2)in vivo prevascularization,and(3)stimulation of neurovascularization in situ.Furthermore,we emphasize that the lack of accuracy for structure and spatiotemporal regulation,as well as the operational inconvenience and delayed connection to the host's nerve stumps,have stuck the existing neurovascularization technology in the preclinical stage.The successful design of a future prospective clinical vascularized nerve scaffold should be guided by a comprehensive consideration of these aspects.
基金supported by the National Natural Science Foundation of China,Nos.82171344(to ZY),82471313(to CKT)the Guangdong Basic and Applied Basic Research Foundation,China,Nos.2023B1515120035,2024A1515012035(to CKT)The Science and Technology Projects in Guangzhou Nos.2025A03J4169(to ZY)。
文摘Stroke-induced alterations in cerebral blood flow trigger neurovascular remodeling,as manifested by the blood-brain barrier dysfunction and subs equent neurovascular repair activities such as angiogenesis.This process involves neurovascular communication that facilitates the transport of mediators among cerebrovascular endothelial cells,pericytes,glial cells,and neurons,thereby transmitting signals from donor to recipient cells to elicit a collaborative response.
文摘Pericytes are multi-functional mural cells of the central nervous system that cover the capillary endothelial cells. Pericytes play a vital role in nervous system development, significantly influencing the formation, maturation, and maintenance of the central nervous system. An expanding body of studies has revealed that pericytes establish carefully regulated interactions with oligodendrocytes, microglia, and astrocytes. These communications govern numerous critical brain processes, including angiogenesis, neurovascular unit homeostasis, blood–brain barrier integrity, cerebral blood flow regulation, and immune response initiation. Glial cells and pericytes participate in dynamic and reciprocal interactions, with each influencing and adjusting the functionality of the other. Pericytes have the ability to control astrocyte polarization, trigger differentiation of oligodendrocyte precursor cells, and initiate immunological responses in microglia. Various neurological disorders that compromise the integrity of the blood–brain barrier can disrupt these communications, impair waste clearance, and hinder cerebral blood circulation, contributing to neuroinflammation. In the context of neurodegeneration, these disruptions exacerbate pathological processes, such as neuronal damage, synaptic dysfunction, and impaired tissue repair. This article explores the complex interactions between pericytes and various glial cells in both healthy and pathological states of the central nervous system. It highlights their essential roles in neurovascular function and disease progression, providing important insights that may enhance our understanding of the molecular mechanisms underlying these interactions and guide potential therapeutic strategies for neurodegenerative disorders in future research.
基金supported by JSPS(KAKENHI:21K06205,23K06937,24K23419)AMED(to JYK,SaY,TM,SiY,YT,and NH)JYW had long been supported by the NIH.
文摘The nervous system processes a vast amount of information,performing computations that underlie perception,cognition,and behavior.During development,neuronal guidance genes,which encode extracellular cues,their receptors,and downstream signal transducers,organize neural wiring to generate the complex architecture of the nervous system.It is now evident that many of these neuroguidance cues and their receptors are active during development and are also expressed in the adult nervous system.This suggests that neuronal guidance pathways are critical not only for neural wiring but also for ongoing function and maintenance of the mature nervous system.Supporting this view,these pathways continue to regulate synaptic connectivity,plasticity,and remodeling,and overall brain homeostasis throughout adulthood.Genetic and transcriptomic analyses have further revealed many neuronal guidance genes to be associated with a wide range of neurodegenerative and neuropsychiatric disorders.Although the precise mechanisms by which aberrant neuronal guidance signaling drives the pathogenesis of these diseases remain to be clarified,emerging evidence points to several common themes,including dysfunction in neurons,microglia,astrocytes,and endothelial cells,along with dysregulation of neuron-microglia-astrocyte,neuroimmune,and neurovascular interactions.In this review,we explore recent advances in understanding the molecular and cellular mechanisms by which aberrant neuronal guidance signaling contributes to disease pathogenesis through altered cell-cell interactions.For instance,recent studies have unveiled two distinct semaphorin-plexin signaling pathways that affect microglial activation and neuroinflammation.We discuss the challenges ahead,along with the therapeutic potentials of targeting neuronal guidance pathways for treating neurodegenerative diseases.Particular focus is placed on how neuronal guidance mechanisms control neuron-glia and neuroimmune interactions and modulate microglial function under physiological and pathological conditions.Specifically,we examine the crosstalk between neuronal guidance signaling and TREM2,a master regulator of microglial function,in the context of pathogenic protein aggregates.It is well-established that age is a major risk factor for neurodegeneration.Future research should address how aging and neuronal guidance signaling interact to influence an individual’s susceptibility to various late-onset neurological diseases and how the progression of these diseases could be therapeutically blocked by targeting neuronal guidance pathways.
基金supported by the National Natural Science Foundation of China,Nos.82404892(to QY),82061160374(to ZZ)the Science and Technology Development Fund,Macao Special Administrative Region,China,Nos.0023/2020/AFJ,0035/2020/AGJ+2 种基金the University of Macao Research Grant,Nos.MYRG2022-00248-ICMS,MYRG-CRG2022-00010-ICMS(to MPMH)the Natural Science Foundation of Guangdong Province,No.2024A1515012818(to ZZ)the Fundamental Research Funds for the Central Universities,No.21623114(to ZZ).
文摘Drug development for Alzheimer’s disease is extremely challenging,as demonstrated by the repeated failures of amyloid-β-targeted therapeutics and the controversies surrounding the amyloid-βcascade hypothesis.More recently,advances in the development of Lecanemab,an anti-amyloid-βmonoclonal antibody,have shown positive results in reducing brain A burden and slowing cognitive decline in patients with early-stage Alzheimer’s disease in the Phase Ⅲ clinical trial(Clarity Alzheimer’s disease).Despite these promising results,side effects such as amyloid-related imaging abnormalities(ARIA)may limit its usage.ARIA can manifest as ARIA-E(cerebral edema or effusions)and ARIA-H(microhemorrhages or superficial siderosis)and is thought to be caused by increased vascular permeability due to inflammatory responses,leading to leakages of blood products and protein-rich fluid into brain parenchyma.Endothelial dysfunction is an early pathological feature of Alzheimer’s disease,and the blood-brain barrier becomes increasingly leaky as the disease progresses.In addition,APOE4,the strongest genetic risk factor for Alzheimer’s disease,is associated with higher vascular amyloid burden,increased ARIA incidence,and accelerated blood-brain barrier disruptions.These interconnected vascular abnormalities highlight the importance of vascular contributions to the pathophysiology of Alzheimer’s disease.Here,we will closely examine recent research evaluating the heterogeneity of brain endothelial cells in the microvasculature of different brain regions and their relationships with Alzheimer’s disease progression.
基金supported by STI2030-Major Projects,No.2021ZD 0201801(to JG)Shanxi Province Basic Research Program,No.20210302123429(to QS).
文摘In patients with Alzheimer’s disease,gamma-glutamyl transferase 5(GGT5)expression has been observed to be downregulated in cerebrovascular endothelial cells.However,the functional role of GGT5 in the development of Alzheimer’s disease remains unclear.This study aimed to explore the effect of GGT5 on cognitive function and brain pathology in an APP/PS1 mouse model of Alzheimer’s disease,as well as the underlying mechanism.We observed a significant reduction in GGT5 expression in two in vitro models of Alzheimer’s disease(Aβ_(1-42)-treated hCMEC/D3 and bEnd.3 cells),as well as in the APP/PS1 mouse model.Additionally,injection of APP/PS1 mice with an adeno-associated virus encoding GGT5 enhanced hippocampal synaptic plasticity and mitigated cognitive deficits.Interestingly,increasing GGT5 expression in cerebrovascular endothelial cells reduced levels of both soluble and insoluble amyloid-βin the brains of APP/PS1 mice.This effect may be attributable to inhibition of the expression ofβ-site APP cleaving enzyme 1,which is mediated by nuclear factor-kappa B.Our findings demonstrate that GGT5 expression in cerebrovascular endothelial cells is inversely associated with Alzheimer’s disease pathogenesis,and that GGT5 upregulation mitigates cognitive deficits in APP/PS1 mice.These findings suggest that GGT5 expression in cerebrovascular endothelial cells is a potential therapeutic target and biomarker for Alzheimer’s disease.
文摘Photon-counting computed tomography(PCCT)represents a transformative advancement in neuroimaging,offering superior spatial resolution,spectral imaging capabilities,reduced radiation dose,and enhanced contrast-to-noise ratios.This review explores the technical foundations of PCCT,its advantages over conventional CT,and its growing applications in neuroimaging.PCCT has shown promise in improving neurovascular imaging,detecting small vessels,and reducing artifacts near metallic implants.It also enhances the visualization of spontaneous intracranial hypotension and cerebrospinal fluid leaks and provides superior diagnostic accuracy in acute ischemic stroke imaging.However,current limitations,including protocol complexity,high data volume,and the absence of integrated artificial intelligence noise reduction algorithms,pose challenges to widespread adoption.Future research should address these limitations and refine PCCT’s applications to unlock its full clinical potential.
基金The New Professor Research Program of Korean Technology in 2025.
文摘Post-stroke depression(PSD)is a prevalent but often underdiagnosed complication affecting stroke survivors,with significant implications for recovery and quality of life.Emerging evidence suggests that central obesity,as measured by the weight-to-waist index(WWI),may play a crucial role in PSD risk and severity.Traditional obesity metrics,such as body mass index,may not accurately capture the impact of visceral fat distribution on neuropsychiatric outcomes.This letter highlights the growing recognition of WWI as a precise indicator of metabolic and inflammatory disturbances linked to post-stroke mental health.Integrating WWI into routine stroke rehabilitation assessments could facilitate early identification of high-risk patients and improve intervention strategies.Further research is needed to establish standardized WWI cutoff values and explore potential therapeutic targets for PSD prevention.
文摘Objective As the core unit of the limbic system,the hippocampus is involved in the regulation of higher neural activity by integrating emotional encoding and memory storage functions.In the pathological process of epilepsy,structural remodeling and functional disorders in this region have become the focus of research,and the existing evidence mostly focuses on hippocampal sclerosis,a typical neurodegenerative change.However,there is still a lack of systematic analysis of the pathological subtypes under the International League Against Epilepsy(ILAE)classification system in cross-scale molecular events such as epigenetic regulation and microbiome-brain axis.By integrating clinical cohort data and experimental model evidence,this article focuses on the association characteristics between hippocampal sclerosis subtypes and seizure patterns,and reveals the formation of abnormal hippocampal network and the cascading effect of abnormal hippocampus-related neurotransmitters in the formation of epileptogenic network.The study found that specific pathological subtypes showed a significant correspondence with seizure frequency and drug sensitivity,suggesting that hippocampal sclerosis drives epilepsy progression through multidimensional molecular events.In the future,it is necessary to combine spatial transcriptome and targeted metabolomics technology to analyze the cell interaction network in the hippocampal microenvironment,so as to provide a theoretical basis for the development of subtype-specific antiepileptic strategies.
基金supported by financial assistance from the Zhejiang Provincial Natural Science Foundation of China under Grant No.LY18H160020.
文摘Objective:Microvascular decompression(MVD)is the gold standard for treating drug-resistant classic trigeminal neuralgia(dcTN),with endoscopy enhancing surgical precision through improved visualization.This study evaluates the efficacy of fully endoscopic MVD for dcTN and presents our early experience.Methods:This retrospective study included patients with dcTN who underwent fully endoscopic MVD in the Department of Neurosurgery,the First Affiliated Hospital,Zhejiang University School of Medicine from November 2020 to February 2023.We recorded basic patient clinical information,clinical outcomes,offending vessels,complications,and recurrences,and assessed outcomes via the Barrow Neurological Institute(BNI)pain intensity score and the numeric rating scale(NRS)score.Results:All 42 patients had dcTN with preoperative BNI scores of V and NRS scores of 8e10.Endoscopic visualization enabled the precise identification of neurovascular conflicts,including small and deeply located vessels.Immediately after surgery,90.5%of patients achieved complete pain relief(BNI score of I,NRS score of 0).At the final follow-up,85.7%of patients had complete pain relief.All patients’pain was significantly relieved at immediate after surgery(0 vs.9,p<0.001)and at the final follow-up(0 vs.9,p<0.001),with lower NRS scores.Complications,including vertigo,headache,and transient facial numbness,occurred in 14.4%of patients and were manageable.
基金supported by funding from NIDCR(1R01DE027957)Maryland Stem Cell Research Fund(2022-MSCRFV-5782)the NSF GRFP and NCI(5R01CA237597-05,2R01CA196701-06A1).
文摘Calvarial nerves,along with vasculature,influence skull formation during development and following injury,but it remains unclear how calvarial nerves are spatially distributed during postnatal growth and aging.Studying the spatial distribution of nerves in the skull remains a challenge due to a lack of methods to quantify 3D structures in intact bone.To visualize calvarial 3D neurovascular architecture,we imaged nerves and endothelial cells with lightsheet microscopy.
文摘BACKGROUND The trigeminal nerve(TN)is frequently implicated in neurovascular conflicts,most commonly with the superior cerebellar artery(SCA),its predominant arterial counterpart in the cerebellopontine angle.AIM To examine the relationship between the SCA and TN utilizing high-resolution magnetic resonance imaging and evaluated whether particular anatomical configurations predispose to clinically significant contact.METHODS Magnetic resonance imaging scans from 80 patients(160 sides)were retrospectively analyzed,excluding cases with pathological processes affecting the TN.Using multiplanar reconstruction,the TN root was identified and its spatial relationship with the SCA was evaluated.RESULTS Eight distinct topographic patterns were identified.The SCA most commonly coursed superior(30.6%),lateral(18.8%),or superolateral(17.5%)to the TN.Medial configurations,although less frequent,were associated with the shortest artery-nerve distance(mean 1.85±1.28 mm)and significantly higher contact rates(P<0.001).Overall,SCA-TN contact was observed in 14.4%of sides,but only 20%of these patients reported ipsilateral facial numbness.Variations in SCA origin(basilar artery,posterior cerebral artery,or common origin)and duplication did not significantly influence the artery-nerve distance.CONCLUSION Although SCA-TN contact is relatively frequent,only particular medial and superior configurations seem to predispose individuals to symptomatic compression.These observations are consistent with cadaveric and surgical evidence highlighting the significance of root entry zone contact in trigeminal neuralgia.Vascular contact alone should not serve as a diagnostic criterion;instead,geometric configuration and related nerve alterations must also be incorporated into preoperative assessment.
基金supported by the National Natural Science Foundation of China,No.81373578(to YHW),81573965(to YHW)the Natural Science Foundation of Hunan Province of China,No.2017JJ3241(to JL)the Education Department Scientific Research Foundation of Hunan Province of China,No.17C1229(to JL)
文摘Previous studies have shown that models of depression exhibit structural and functional changes to the neurovascular unit. Thus, we hypothesized that diabetes-related depression might be associated with damage to the hippocampal neurovascular unit. To test this hypothesis, neurons, astrocytes and endothelial cells were isolated from the brain tissues of rat embryos and newborn rats. Hippocampal neurovascular unit co-cultures were produced using the Transwell chamber co-culture system. A model of diabetes-related depression was generated by adding 150 mM glucose and 200 μM corticosterone to the culture system and compared with the neuron + astrocyte and astrocyte + endothelial cell co-culture systems. Western blot assay was used to measure levels of structural proteins in the hippocampal neurovascular unit co-culture system. Levels of basic fibroblast growth factor, angiogenic factor 1, glial cell line–derived neurotrophic factor, transforming growth factor β1, leukemia inhibitory factor and 5-hydroxytryptamine in the hippocampal neurovascular unit co-culture system were measured by enzyme-linked immunosorbent assay. Flow cytometry and terminal deoxynucleotidyl transferase(TdT)-mediated dUTP nick end labeling staining was used to assess neuronal apoptosis in the hippocampal neurovascular unit. The neurovascular unit triple cell co-culture system had better barrier function and higher levels of structural and secretory proteins than the double cell co-culture systems. In comparison, in the model of diabetes-related depression, the neurovascular unit was damaged with decreased barrier function, poor structural integrity and impaired secretory function. Moreover, neuronal apoptosis was markedly increased, and 5-hydroxytryptamine levels were reduced. These results suggest that diabetes-related depression is associated with structural and functional damage to the neurovascular unit. Our findings provide a foundation for further studies on the pathogenesis of diabetes-related depression.
基金supported by the National Natural Science Foundation of China,No.81430102(to QGW)
文摘Calculus bovis is commonly used for the treatment of stroke in traditional Chinese medicine. Hyodeoxycholic acid(HDCA) is a bioactive compound extracted from calculus bovis. When combined with cholic acid, baicalin and jas-minoidin, HDCA prevents hypoxia-reoxygenation-induced brain injury by suppressing endoplasmic reticulum stress-mediated apoptotic signaling. However, the effects of HDCA in ischemic stroke injury have not yet been studied. Neurovascular unit(NVU) dysfunction occurs in ischemic stroke. Therefore, in this study, we investigated the effects of HDCA on the NVU under ischemic conditions in vitro. We co-cultured primary brain microvascular endothelial cells, neurons and astrocytes using a transwell chamber co-culture system. The NVU was pre-treated with 10.16 or 2.54 μg/mL HDCA for 24 hours before exposure to oxygen-glucose deprivation for 1 hour. The cell counting kit-8 assay was used to detect cell activity. Flow cytometry and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling were used to assess apoptosis. Enzyme-linked immunosorbent assay was used to measure the expression levels of inflammatory cytokines, including interleukin-1β, interleukin-6 and tumor necrosis factor-α, and neurotrophic factors, including brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor. Oxidative stress-related factors, such as superoxide dismutase, nitric oxide, malondialdehyde and γ-glutamyltransferase, were measured using kits. Pretreatment with HDCA significantly decreased blood-brain barrier permeability and neuronal apoptosis, significantly increased transendothelial electrical resistance and γ-glutamyltransferase activity, attenuated oxidative stress damage and the release of inflammatory cytokines, and increased brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor expression. Our findings suggest that HDCA maintains NVU morphological integrity and function by modulating inflammation, oxidation stress, apoptosis, and the expression of neurotrophic factors. Therefore, HDCA may have therapeutic potential in the clinical management of ischemic stroke. This study was approved by the Ethics Committee of Experimental Animals of Beijing University of Chinese Medicine(approval No. BUCM-3-2016040201-2003) in April 2016.
基金supported by the National Natural Science Foundation of China(General Program),No.81771271(to JF)
文摘Constraint-induced movement therapy after cerebral ischemia stimulates axonal growth by decreasing expression levels of Nogo-A,RhoA,and Rho-associated kinase(ROCK)in the ischemic boundary zone.However,it remains unclear if there are any associations between the Nogo-A/RhoA/ROCK pathway and angiogenesis in adult rat brains in pathological processes such as ischemic stroke.In addition,it has not yet been reported whether constraint-induced movement therapy can promote angiogenesis in stroke in adult rats by overcoming Nogo-A/RhoA/ROCK signaling.Here,a stroke model was established by middle cerebral artery occlusion and reperfusion.Seven days after stroke,the following treatments were initiated and continued for 3 weeks:forced limb use in constraint-induced movement therapy rats(constraint-induced movement therapy group),intraperitoneal infusion of fasudil(a ROCK inhibitor)in fasudil rats(fasudil group),or lateral ventricular injection of NEP1-40(a specific antagonist of the Nogo-66 receptor)in NEP1-40 rats(NEP1-40 group).Immunohistochemistry and western blot assay results showed that,at 2 weeks after middle cerebral artery occlusion,expression levels of RhoA and ROCK were lower in the ischemic boundary zone in rats treated with NEP1-40 compared with rats treated with ischemia/reperfusion or constraint-induced movement therapy alone.However,at 4 weeks after middle cerebral artery occlusion,expression levels of RhoA and ROCK in the ischemic boundary zone were markedly decreased in the NEP1-40 and constraint-induced movement therapy groups,but there was no difference between these two groups.Compared with the ischemia/reperfusion group,modified neurological severity scores and foot fault scores were lower and time taken to locate the platform was shorter in the constraint-induced movement therapy and fasudil groups at 4 weeks after middle cerebral artery occlusion,especially in the constraint-induced movement therapy group.Immunofluorescent staining demonstrated that fasudil promoted an immune response of nerve-regeneration-related markers(BrdU in combination with CD31(platelet endothelial cell adhesion molecule),Nestin,doublecortin,NeuN,and glial fibrillary acidic protein)in the subventricular zone and ischemic boundary zone ipsilateral to the infarct.After 3 weeks of constraint-induced movement therapy,the number of regenerated nerve cells was noticeably increased,and was accompanied by an increased immune response of tight junctions(claudin-5),a pericyte marker(a-smooth muscle actin),and vascular endothelial growth factor receptor 2.Taken together,the results demonstrate that,compared with fasudil,constraint-induced movement therapy led to stronger angiogenesis and nerve regeneration ability and better nerve functional recovery at 4 weeks after cerebral ischemia/reperfusion.In addition,constraint-induced movement therapy has the same degree of inhibition of RhoA and ROCK as NEP1-40.Therefore,constraint-induced movement therapy promotes angiogenesis and neurogenesis after cerebral ischemia/reperfusion injury,at least in part by overcoming the Nogo-A/RhoA/ROCK signaling pathway.All protocols were approved by the Institutional Animal Care and Use Committee of China Medical University,China on December 9,2015(approval No.2015 PS326 K).
基金This study was supported by the National Natural Science Foundation of China,Nos.81573965(to YHW),81874464(to YHW)the Natural Science Foundation of Hunan Province of China,No.2017JJ3241(to JL)the Education Department Scientific Research Foundation of Hunan Province of China,No.17C1229(to JL).
文摘Our previous studies have shown that glutamate and hippocampal neuron apoptosis are key signals and direct factors associated with diabetes-related depression,and structural and functional damage to the hippocampal neurovascular unit has been associated with diabetesrelated depression.However,the underlying mechanism remains unclear.We hypothesized that diabetes-related depression might be associated with the glutamate(Glu)/metabotropic glutamate receptor2/3(mGluR2/3)/phosphoinositide 3-kinase(PI3K)pathway,activated by glucocorticoid receptors in the hippocampal neurovascular unit.To test this hypothesis,rat hippocampal neurovascular unit models,containing hippocampal neurons,astrocytes,and brain microvascular endothelial cells,were treated with 150 mM glucose and 200μM corticosterone,to induce diabetes-related depression.Our results showed that under conditions of diabetes complicated by depression,hippocampal neurovascular units were damaged,leading to decreased barrier function;elevated Glu levels;upregulated glucocorticoid receptor,vesicular glutamate transporter 3(VGLUT-3),and metabotropic glutamate receptor 2/3(mGluR2/3)expression;downregulated excitatory amino acid transporter 1(EAAT-1)expression;and alteration of the balance of key proteins associated with the extracellular signal-regulated kinase(ERK)/glial cell-derived neurotrophic factor(GDNF)/PI3K signaling pathway.Moreover,the viability of neurons was dramatically reduced in the model of diabetes-related depression,and neuronal apoptosis,and caspase-3 and caspase-9 expression levels,were increased.Our results suggest that the Glu/mGluR2/3/PI3K pathway,induced by glucocorticoid receptor activation in the hippocampal neurovascular unit,may be associated with diabetes-related depression.This study was approved by the Laboratory Animal Ethics Committee of The First Hospital of Hunan University of Chinese Medicine,China(approval No.HN-ZYFY-2019-11-12)on November 12,2019.
基金Supported by the Science Foundation of Haikou Health Bureau (grant No.2010-SWY-13-058)Haikou Science Technology Information Bureau (grant No.2009-049-1)
文摘Objective:To describe the anatomical characteristics and patterns of neurovascular compression (NVC) in patients suffering trigeminal neuralgia(TN) by 3D high-resolution magnetic resonance imaging(MRI) method and image fusion technique.Methods:The anatomic structure of trigeminal nerve,brain stem and blood vessel was observed in 100 consecutive TN patients by 3D high resolution MRI(3D SPGR,contrast-enhanced T1 3D MP-RAGE and T2/T1 3D FIESTA). The 3D image sources were fused and visualized using 3D DOCTOR software.Results:One or several NVC sites,which usually appeared 0-9.8 mm away from brain stem,were found on the symptomatic side in 93%of the TN cases.Superior cerebellar artery was involved in 76%(71/93) of these cases.The other vessels including antero-inferior cerebellar artery,vertebral artery, basilar artery and veins also contributed to the occurrence of NVC.The NVC sites were found to be located in the proximal segment in 42%of these cases(39/93) and in the distal segment in 45% (42/93).Nerve dislocation or distortion was observed in 32%(30/93).Conclusions:Various 3D high resolution MRI methods combined with the image fusion technique could provide pathologic anatomic information for the diagnosis and treatment of TN.
基金supported by the National Natural Science Foundation of China,No.30973782,81373526the Natural Science Foundation of Beijing,No.7102014,7122018the Beijing Municipal Higher Learning Institution Talent Teaching Plan"Young and Middle-aged Talented People Training"Project,No.PXM2011014226
文摘Houshiheisan is composed of wind-dispelling （chrysanthemun fower, divaricate saposhnikovia root, Manchurian wild ginger, cassia twig, Szechwan lovage rhizome, and platycodon root） and deficiency-nourishing （ginseng, Chinese angelica, large-head atractylodes rhizome, Indian bread, and zingiber） drugs. In this study, we assumed these drugs have protective effects against cerebral ischemia, on neurovascular units. Houshiheisan was intragastrically administered in a rat model of focal cerebral ischemia. Hematoxylin-eosin staining, transmission electron microscopy, immu- nofluorescence staining, and western blot assays showed that Houshiheisan reduced pathological injury to the ischemic penumbra, protected neurovascular units, visibly up-regtflated neuronal nuclear antigen expression, and down-regulated amyloid precursor protein and amyloid-[3 42 expression. Wind-dispelling and deficiency-nourishing drugs maintained NeuN expression to varying degrees, but did not affect amyloid precursor protein or amyloid-~ 42 expression in the ischemic penumbra. Our results suggest that the compound prescription Houshiheisan effectively suppresses abnormal amyloid precursor protein accumulation, reduces amyloid substance depo- sition, maintains stabilization of the internal environment of neurovascular units, and minimizes injury to neurovascular units in the ischemic penumbra.
基金supported by the National Natural Science Foundation of China,No.81600747(to YD)the Start-Up Foundation for Doctors of Liaoning Province,China,No.201501020(to YD)。
文摘Whether long non-coding RNA myocardial infarction-associated transcript is involved in oxygen-induced retinopathy remains poorly understood. To validate this hypothesis, we established a newborn mouse model of oxygen-induced retinopathy by feeding in an oxygen concentration of 75 ± 2% from postnatal day 8 to postnatal day 12, followed by in normal air. On postnatal day 11, the mice were injected with the myocardial infarction-associated transcript siRNA plasmid via the vitreous cavity to knockdown long non-coding RNA myocardial infarction-associated transcript. Myocardial infarction-associated transcript siRNA transcription significantly inhibited myocardial infarctionassociated transcript mRNA expression, reduced the phosphatidylinosital-3-kinase, phosphorylated Akt and vascular endothelial growth factor immunopositivities, protein and mRNA expression, and alleviated the pathological damage to the retina of oxygen-induced retinopathy mouse models. These findings suggest that myocardial infarction-associated transcript is likely involved in the retinal neovascularization in retinopathy of prematurity and that inhibition of myocardial infarction-associated transcript can downregulate phosphatidylinosital-3-kinase, phosphorylated Akt and vascular endothelial growth factor expression levels and inhibit neovascularization. This study was approved by the Animal Ethics Committee of Shengjing Hospital of China Medical University, China(approval No. 2016 PS074 K) on February 25, 2016.
