Stroke

摘要： Stroke is the second leading cause of death and a major cause of disability worldwide,and biological sex is an important determining factor in stroke incidence and pathology.From childhood through adulthood,men have a higher incidence of stroke compared with women.Abundant research has confirmed the beneficial effects of estrogen in experimental ischemic stroke but genetic factors such as the X-chromosome complement can also play an important role in determining sex differences in stroke.Autophagy is a self-degrading cellular process orchestrated by multiple core proteins,which leads to the engulfment of cytoplasmic material and degradation of cargo after autophagy vesicles fuse with lysosomes or endosomes.The levels and the activity of components of these signaling pathways and of autophagy-related proteins can be altered during ischemic insults.Ischemic stroke activates autophagy,however,whether inhibiting autophagy after stroke is beneficial in the brain is still under a debate.Autophagy is a potential mechanism that may contribute to differences in stroke progression between the sexes.Furthermore,the effects of manipulating autophagy may also differ between the sexes.Mechanisms that regulate autophagy in a sex-dependent manner in ischemic stroke remain unexplored.In this review,we summarize clinical and pre-clinical evidence for sex differences in stroke.We briefly introduce the autophagy process and summarize the effects of gonadal hormones in autophagy in the brain and discuss X-linked genes that could potentially regulate brain autophagy.Finally,we review pre-clinical studies that address the mechanisms that could mediate sex differences in brain autophagy after stroke.

摘要： β2-Microglobulin(β2M),a component of the major histocompatibility complex class I molecule,is associated with aging-related cognitive impairment and Alzheimer’s disease.Although upregulation ofβ2M is considered to be highly related to ischemic stroke,the specific role and underlying mechanistic action ofβ2M are poorly understood.In this study,we established a rat model of focal cerebral ischemia by occlusion of the middle cerebral artery.We found thatβ2M levels in the cerebral spinal fluid,serum,and brain tissue were significantly increased in the acute period but gradually decreased during the recovery period.RNA interference was used to inhibitβ2M expression in the acute period of cerebral stroke.Tissue staining with 2,3,5-triphenyltetrazolium chloride and evaluation of cognitive function using the Morris water maze test demonstrated that decreasedβ2M expression in the ischemic penumbra reduced infarct volume and alleviated cognitive deficits,respectively.Notably,glial cell,caspase-1(p20),and Nod-like receptor pyrin domain containing 3(NLRP3)inflammasome activation as well as production of the inflammatory cytokines interleukin-1β,interleukin-6,and tumor necrosis factor-αwere also effectively inhibited byβ2M silencing.These findings suggest thatβ2M participates in brain injury and cognitive impairment in a rat model of ischemic stroke through activation of neuroinflammation associated with the NLRP3 inflammasome.

摘要： Although bone marrow mesenchymal stem cells(BMSCs)might have therapeutic potency in ischemic stroke,the benefits are limited.The current study investigated the effects of BMSCs engineered to overexpress vascular endothelial growth factor(VEGF)on behavioral defects in a rat model of transient cerebral ischemia,which was induced by middle cerebral artery occlusion.VEGF-BMSCs or control grafts were injected into the left striatum of the infarcted hemisphere 24 hours after stroke.We found that compared with the stroke-only group and the vehicle-and BMSCs-control groups,the VEGF-BMSCs treated animals displayed the largest benefits,as evidenced by attenuated behavioral defects and smaller infarct volume 7 days after stroke.Additionally,VEGF-BMSCs greatly inhibited destruction of the blood-brain barrier,increased the regeneration of blood vessels in the region of ischemic penumbra,and reducedneuronal degeneration surrounding the infarct core.Further mechanistic studies showed that among all transplant groups,VEGF-BMSCs transplantation induced the highest level of brain-derived neurotrophic factor.These results suggest that BMSCs transplantation with vascular endothelial growth factor has the potential to treat ischemic stroke with better results than are currently available.

摘要： Recent studies have indicated that suppressing oxidative stress and ferroptosis can considerably improve the prognosis of intracerebral hemorrhage(ICH).Withaferin A(WFA),a natural compound,exhibits a positive effect on a number of neurological diseases.However,the effects of WFA on oxidative stress and ferroptosis-mediated signaling pathways to ICH remain unknown.In this study,we investigated the neuroprotective effects and underlying mechanism for WFA in the regulation of ICH-induced oxidative stress and ferroptosis.We established a mouse model of ICH by injection of autologous tail artery blood into the caudate nucleus and an in vitro cell model of hemin-induced ICH.WFA was injected intracerebroventricularly at 0.1,1 or 5μg/kg once daily for 7 days,starting immediately after ICH operation.WFA markedly reduced brain tissue injury and iron deposition and improved neurological function in a dose-dependent manner 7 days after cerebral hemorrhage.Through in vitro experiments,cell viability test showed that WFA protected SH-SY5Y neuronal cells against hemin-induced cell injury.Enzyme-linked immunosorbent assays in vitro and in vivo showed that WFA markedly decreased the level of malondialdehyde,an oxidative stress marker,and increased the activities of anti-oxidative stress markers superoxide dismutase and glutathione peroxidase after ICH.Western blot assay,quantitative polymerase chain reaction and immunofluorescence results demonstrated that WFA activated the nuclear factor E2-related factor 2(Nrf2)/heme oxygenase-1(HO-1)signaling axis,promoted translocation of Nrf2 from the cytoplasm to nucleus,and increased HO-1 expression.Silencing Nrf2 with siRNA completely reversed HO-1 expression,oxidative stress and protective effects of WFA.Furthermore,WFA reduced hemin-induced ferroptosis.However,after treatment with an HO-1 inhibitor,the neuroprotective effects of WFA against hemin-induced ferroptosis were weakened.MTT test results showed that WFA combined with ferrostatin-1 reduced hemin-induced SH-SY5Y neuronal cell injury.Our findings reveal that WFA treatment alleviated ICH injury-induced ferroptosis and oxidative stress through activating the Nrf2/HO-1 pathway,which may highlight a potential role of WFA for the treatment of ICH.

摘要： Vimentin is a major type Ⅲ intermediate filament protein that plays important roles in several basic cellular functions including cell migration, proliferation, and division. Although vimentin is a cytoplasmic protein, it also exists in the extracellular matrix and at the cell surface. Previous studies have shown that vimentin may exert multiple physiological effects in different nervous system injuries and diseases. For example, the studies of vimentin in spinal cord injury and stroke mainly focus on the formation of reactive astrocytes. Reduced glial scar, increased axonal regeneration, and improved motor function have been noted after spinal cord injury in vimentin and glial fibrillary acidic protein knockout(GFAPVIM) mice. However, attenuated glial scar formation in post-stroke in GFAP–/– VIM–/– mice resulted in abnormal neuronal network restoration and worse neurological recovery. These opposite results have been attributed to the multiple roles of glial scar in different temporal and spatial conditions. In addition, extracellular vimentin may be a neurotrophic factor that promotes axonal extension by interaction with the insulin-like growth factor 1 receptor. In the pathogenesis of bacterial meningitis, cell surface vimentin is a meningitis facilitator, acting as a receptor of multiple pathogenic bacteria, including E. coli K1, Listeria monocytogenes, and group B streptococcus. Compared with wild type mice, VIMmice are less susceptible to bacterial infection and exhibit a reduced inflammatory response, suggesting that vimentin is necessary to induce the pathogenesis of meningitis. Recently published literature showed that vimentin serves as a double-edged sword in the nervous system, regulating axonal regrowth, myelination, apoptosis, and neuroinflammation. This review aims to provide an overview of vimentin in spinal cord injury, stroke, bacterial meningitis, gliomas, and peripheral nerve injury and to discuss the potential therapeutic methods involving vimentin manipulation in improving axonal regeneration, alleviating infection, inhibiting brain tumor progression, and enhancing nerve myelination.

摘要： Aging is a physiological event dependent on multiple pathways that are linked to lifespan and processes leading to cognitive decline.This process represents the major risk factor for aging-related diseases such as Alzheimer’s disease,Parkinson’s disease,and ischemic stroke.The incidence of all these pathologies increases exponentially with age.Research on aging biology has currently focused on elucidating molecular mechanisms leading to the development of those pathologies.Cognitive deficit and neurodegeneration,common features of aging-related pathologies,are related to the alteration of the activity and levels of neurotrophic factors,such as brain-derived neurotrophic factor,nerve growth factor,and glial cell-derived neurotrophic factor.For this reason,treatments that modulate neurotrophin levels have acquired a great deal of interest in preventing neurodegeneration and promoting neural regeneration in several neurological diseases.Those treatments include both the direct administration of neurotrophic factors and the induced expression with viral vectors,neurotrophins’binding with biomaterials or other molecules to increase their bioavailability but also cell-based therapies.Considering neurotrophins’crucial role in aging pathologies,here we discuss the involvement of several neurotrophic factors in the most common brain aging-related diseases and the most recent therapeutic approaches that provide direct and sustained neurotrophic support.

摘要： CDGSH iron sulfur domain 2 can inhibit ferroptosis,which has been associated with cerebral ischemia/reperfusion,in individuals with head and neck cancer.Therefore,CDGSH iron sulfur domain 2 may be implicated in cerebral ischemia/reperfusion injury.To validate this hypothesis in the present study,we established mouse models of occlusion of the middle cerebral artery and HT22 cell models of oxygen-glucose deprivation and reoxygenation to mimic cerebral ischemia/reperfusion injury in vivo and in vitro,respectively.We found remarkably decreased CDGSH iron sulfur domain 2 expression in the mouse brain tissue and HT22 cells.When we used adeno-associated virus and plasmid to up-regulate CDGSH iron sulfur domain 2 expression in the brain tissue and HT22 cell models separately,mouse neurological dysfunction was greatly improved;the cerebral infarct volume was reduced;the survival rate of HT22 cells was increased;HT22 cell injury was alleviated;the expression of ferroptosis-related glutathione peroxidase 4,cystine-glutamate antiporter,and glutathione was increased;the levels of malondialdehyde,iron ions,and the expression of transferrin receptor 1 were decreased;and the expression of nuclear-factor E2-related factor 2/heme oxygenase 1 was increased.Inhibition of CDGSH iron sulfur domain 2 upregulation via the nuclear-factor E2-related factor 2 inhibitor ML385 in oxygen-glucose deprived and reoxygenated HT22 cells blocked the neuroprotective effects of CDGSH iron sulfur domain 2 up-regulation and the activation of the nuclear-factor E2-related factor 2/heme oxygenase 1 pathway.Our data indicate that the up-regulation of CDGSH iron sulfur domain 2 can attenuate cerebral ischemia/reperfusion injury,thus providing theoretical support from the perspectives of cytology and experimental zoology for the use of this protein as a therapeutic target in patients with cerebral ischemia/reperfusion injury.

摘要： As the average age of the world population increases,more people will face debilitating aging-associated conditions,including dementia and stroke.Not only does the incidence of these conditions increase with age,but the recovery afterward is often worse in older patients.Researchers and health professionals must unveil and understand the factors behind age-associated diseases to develop a therapy for older patients.Aging causes profound changes in the immune system including the activation of microglia in the brain.Activated microglia promote T lymphocyte transmigration leading to an increase in neuroinflammation,white matter damage,and cognitive impairment in both older humans and rodents.The presence of T and B lymphocytes is observed in the aged brain and correlates with worse stroke outcomes.Preclinical strategies in stroke target either microglia or the lymphocytes or the communications between them to promote functional recovery in aged subjects.In this review,we examine the role of the microglia and T and B lymphocytes in aging and how they contribute to cognitive impairment.Additionally,we provide an important update on the contribution of these cells and their interactions in preclinical aged stroke.

摘要： An enriched environment is used as a behavio ral intervention therapy that applies sensory,motor,and social stimulation,and has been used in basic and clinical research of va rious neurological diseases.In this study,we established mouse models of photothrombotic stroke and,24 hours later,raised them in a standard,enriched,or isolated environment for 4 weeks.Compared with the mice raised in a standard environment,the cognitive function of mice raised in an enriched environment was better and the pathological damage in the hippocampal CA1 region was remarkably alleviated.Furthermore,protein expression levels of tumor necrosis factor receptor-associated factor 6,nuclear factorκB p65,interleukin-6,and tumor necrosis factorα,and the mRNA expression level of tumor necrosis factor receptor-associated factor 6 were greatly lower,while the expression level of miR-146a-5p was higher.Compared with the mice raised in a standard environment,changes in these indices in mice raised in an isolated environment were opposite to mice raised in an enriched environment.These findings suggest that different living environments affect the hippocampal inflammatory response and cognitive function in a mouse model of stro ke.An enriched environment can improve cognitive function following stroke through up-regulation of miR-146a-5p expression and a reduction in the inflammatory response.

摘要： Recent findings have implicated inflammatory responses in the central nervous system in a variety of neuropsychiatric and neurodegenerative diseases,and the understanding and control of immunological responses could be a major factor of future therapeutic strategies for neurological disorders.Microglia,derived from myelogenous cells,respond to a number of stimuli and make immune responses,resulting in a prominent role as cells that act on inflammation in the central nervous system.Fractalkine(FKN or CX3CL1)signaling is an important factor that influences the inflammatory response of microglia.The receptor for FKN,CX3CR1,is usually expressed in microglia in the brain,and therefore the inflammatory response of microglia is modified by FKN.Reportedly,FKN often suppresses inflammatory responses in microglia and activation of its receptor may be effective in the treatment of inflammatory neurological disorders.However,it has also been suggested that inflammatory responses facilitated by FKN signaling aggravate neurological disorders.Thus,further studies are still required to resolve the conflicting interpretation of the protective or deleterious contribution of microglial FKN signaling.Yet notably,regulation of FKN signaling has recently been shown to be beneficial in the treatment of human diseases,although not neurological diseases.In addition,a CX3CR1 inhibitor has been developed and successfully tested in animal models,and it is expected to be in human clinical trials in the future.In this review,I describe the potential therapeutic consideration of microglial CX3CR1 dynamics through altered FKN signaling.

摘要： 本发明公开了基于stroke末梢特征的路网孤立网眼消除方法，应用于地理制图学技术领域，包括获取地形图原始路网数据；为原始路网数据构造节点‑弧段‑多边形拓扑；计算原始路网中每个网眼的密度，并利用样图统计法确定网眼密度阈值，将网眼密度超过该阈值的网眼定义为小网眼；构建道路stroke，并识别道路stroke末梢弧段；提取包含道路stroke末梢弧段的小网眼，并将其定义为stroke末梢网眼，不包含道路stroke末梢弧段的小网眼，定义为stroke非末梢网眼；将步骤5得到的stroke末梢网眼放入待处理网眼候选集；等步骤。本发明将路网中的网眼分类进行定义，将与道路边缘相关的小网眼定义为末梢网眼并对其进行消除，避免道路网眼消除不合理对道路连通性和完整性形成的破坏。

摘要： 本发明公开了一种stroke特征约束的树状河系层次关系构建及简化方法，根据实际空间数据库中树状河系的组织方式，建立包含语义特征、几何特征和拓扑特征的树状河系的有向拓扑树；再综合stroke对象语义、几何特征及拓扑特征，从河口出发，采取下游向上游追踪构建stroke特征约束的树状河系，依据stroke特征约束的树状河系自动识别包括河流间距与河网密度的结构特征，根据河系层次关系的简化方法，实现树状河系的自动简化。本发明简化了人工操作，自动化程度高，且能够有效地智能识别河系空间分布特征，准确率提高，精确度提高。本发明保持河系的整体空间分布结构方面效果良好，保证了简化后图形保持河系的基本轮廓。

摘要： 本发明涉及一种生成道路网stroke的迭代方法。本方法首先设定路段连接规则，然后对确定连接的路段预先连接，达到压缩搜索空间的目的，最后以网络全局效率为目标函数进行迭代生成stroke。该方法能够在产生确定结果的同时，兼顾局部的路段连接满足“好的连续律”和全局的网络功能，从而使得结果更加科学合理，为道路网综合与拓扑分析、示意性道路网图生成、道路网模式识别提供支持。

摘要： 本发明公开了基于stroke末梢特征的路网孤立网眼消除方法，应用于地理制图学技术领域，包括获取地形图原始路网数据；为原始路网数据构造节点‑弧段‑多边形拓扑；计算原始路网中每个网眼的密度，并利用样图统计法确定网眼密度阈值，将网眼密度超过该阈值的网眼定义为小网眼；构建道路stroke，并识别道路stroke末梢弧段；提取包含道路stroke末梢弧段的小网眼，并将其定义为stroke末梢网眼，不包含道路stroke末梢弧段的小网眼，定义为stroke非末梢网眼；将步骤5得到的stroke末梢网眼放入待处理网眼候选集；等步骤。本发明将路网中的网眼分类进行定义，将与道路边缘相关的小网眼定义为末梢网眼并对其进行消除，避免道路网眼消除不合理对道路连通性和完整性形成的破坏。

摘要： 本发明公开了一种stroke特征约束的树状河系层次关系构建及简化方法，根据实际空间数据库中树状河系的组织方式，建立包含语义特征、几何特征和拓扑特征的树状河系的有向拓扑树；再综合stroke对象语义、几何特征及拓扑特征，从河口出发，采取下游向上游追踪构建stroke特征约束的树状河系，依据stroke特征约束的树状河系自动识别包括河流间距与河网密度的结构特征，根据河系层次关系的简化方法，实现树状河系的自动简化。本发明简化了人工操作，自动化程度高，且能够有效地智能识别河系空间分布特征，准确率提高，精确度提高。本发明保持河系的整体空间分布结构方面效果良好，保证了简化后图形保持河系的基本轮廓。

摘要： 本发明涉及一种生成道路网stroke的迭代方法。本方法首先设定路段连接规则，然后对确定连接的路段预先连接，达到压缩搜索空间的目的，最后以网络全局效率为目标函数进行迭代生成stroke。该方法能够在产生确定结果的同时，兼顾局部的路段连接满足“好的连续律”和全局的网络功能，从而使得结果更加科学合理，为道路网综合与拓扑分析、示意性道路网图生成、道路网模式识别提供支持。