Exosomes:the next-generation therapeutic platform for ischemic stroke

Current therapeutic strategies for ischemic stroke fall short of the desired objective of neurological functional recovery.Therefore,there is an urgent need to develop new methods for the treatment of this condition.Exosomes are natural cell-derived vesicles that mediate signal transduction between cells under physiological and pathological conditions.They have low immunogenicity,good stability,high delivery efficiency,and the ability to cross the blood–brain barrier.These physiological properties of exosomes have the potential to lead to new breakthroughs in the treatment of ischemic stroke.The rapid development of nanotechnology has advanced the application of engineered exosomes,which can effectively improve targeting ability,enhance therapeutic efficacy,and minimize the dosages needed.Advances in technology have also driven clinical translational research on exosomes.In this review,we describe the therapeutic effects of exosomes and their positive roles in current treatment strategies for ischemic stroke,including their antiinflammation,anti-apoptosis,autophagy-regulation,angiogenesis,neurogenesis,and glial scar formation reduction effects.However,it is worth noting that,despite their significant therapeutic potential,there remains a dearth of standardized characterization methods and efficient isolation techniques capable of producing highly purified exosomes.Future optimization strategies should prioritize the exploration of suitable isolation techniques and the establishment of unified workflows to effectively harness exosomes for diagnostic or therapeutic applications in ischemic stroke.Ultimately,our review aims to summarize our understanding of exosome-based treatment prospects in ischemic stroke and foster innovative ideas for the development of exosome-based therapies.

Emerging strategies for nerve repair and regeneration in ischemic stroke:neural stem cell therapy

Ischemic stroke is a major cause of mortality and disability worldwide,with limited treatment options available in clinical practice.The emergence of stem cell therapy has provided new hope to the field of stroke treatment via the restoration of brain neuron function.Exogenous neural stem cells are beneficial not only in cell replacement but also through the bystander effect.Neural stem cells regulate multiple physiological responses,including nerve repair,endogenous regeneration,immune function,and blood-brain barrier permeability,through the secretion of bioactive substances,including extracellular vesicles/exosomes.However,due to the complex microenvironment of ischemic cerebrovascular events and the low survival rate of neural stem cells following transplantation,limitations in the treatment effect remain unresolved.In this paper,we provide a detailed summary of the potential mechanisms of neural stem cell therapy for the treatment of ischemic stroke,review current neural stem cell therapeutic strategies and clinical trial results,and summarize the latest advancements in neural stem cell engineering to improve the survival rate of neural stem cells.We hope that this review could help provide insight into the therapeutic potential of neural stem cells and guide future scientific endeavors on neural stem cells.

Identification of microRNAs and messenger RNAs involved in human umbilical cord mesenchymal stem cell treatment of ischemic cerebral infarction using integrated bioinformatics analysis

In recent years,a large number of differentially expressed genes have been identified in human umbilical cord mesenchymal stem cell(hUMSC)transplants for the treatment of ischemic cerebral infarction.These genes are involved in various biochemical processes,but the role of microRNAs(miRNAs)in this process is still unclear.From the Gene Expression Omnibus(GEO)database,we downloaded two microarray datasets for GSE78731(messenger RNA(mRNA)profile)and GSE97532(miRNA profile).The differentially expressed genes screened were compared between the hUMSC group and the middle cerebral artery occlusion group.Gene ontology enrichment and pathway enrichment analyses were subsequently conducted using the online Database for Annotation,Visualization,and Integrated Discovery.Identified genes were applied to perform weighted gene co-suppression analyses,to establish a weighted co-expression network model.Furthermore,the protein-protein interaction network for differentially expressed genes from turquoise modules was built using Cytoscape(version 3.40)and the most highly correlated subnetwork was extracted from the protein-protein interaction network using the MCODE plugin.The predicted target genes for differentially expressed miRNAs were also identified using the online database starBase v3.0.A total of 3698 differentially expressed genes were identified.Gene ontology analysis demonstrated that differentially expressed genes that are related to hUMSC treatment of ischemic cerebral infarction are involved in endocytosis and inflammatory responses.We identified 12 differentially expressed miRNAs in middle cerebral artery occlusion rats after hUMSC treatment,and these differentially expressed miRNAs were mainly involved in signaling in inflammatory pathways,such as in the regulation of neutrophil migration.In conclusion,we have identified a number of differentially expressed genes and differentially expressed mRNAs,miRNA-mRNAs,and signaling pathways involved in the hUMSC treatment of ischemic cerebral infarction.Bioinformatics and interaction analyses can provide novel clues for further research into hUMSC treatment of ischemic cerebral infarction.

Multiple sclerosis and sexual dysfunction

Multiple sclerosis （MS） is a chronic inflammatory demyelinating disorder of the central nervous system characterized by episodic and progressive neurologic dysfunction resulting from inflammatory and autoimmune reactions. The underlying pathogenesis of MS remains largely unclear. However, it is currently accepted as a T cell-mediated autoimmune disease. Among other clinical manifestations, sexual dysfunction （SD） is a painful but still underreported and underdiagnosed symptom of the disorder. SD in MS patients may result from a complex set of conditions and may be associated with multiple anatomic, physiologic, biologic, medical and psychological factors. SD arises primarily from lesions affecting the neural pathways involved in physiologic function. In addition, psychological factors, the side effects of medications and physical symptoms such as fatigue, muscular weakness, menstrual changes, pain and concerns about bladder and bowel incontinence may also be involved. Since MS primarily affects young people, SD secondary to MS may have a great impact on quality of life. Thus, maintaining a healthy sexual life with MS is an important priority. The treatment of SD requires multidisciDlinarv teamwork and coooeration amone specialists,individual patients, partners and the society.

Fabry disease with acute cerebral infarction onset in a young patient

To the Editor:Fabry disease (FD)is a recessive X-linked hereditary disease.The onset age of the disease is in children and adolescents mostly.The average time from the onset of symptoms to the definite diagnosis needs 13.7 years in male patients and 16.3 years in female patients.FD happens rarely and it is easy to cause diagnosis and treatment delay.Here,we report a case of FD in a 27-year-old man who developed clinical symptoms with acute cerebral infarction onset to improve doctors' understanding of FD.

Increased globulin and its association with hemorrhagic transformation in patients receiving intra-arterial thrombolysis therapy

Previous studies have identified a diverse set of predisposing factors for the occurrence of hemorrhagic transformation （HT）, but the independent clinical predictors of HT after intra- arterial thrombolysis have not been determined. In this retrospective study, we investigated the characteristics of patients with or without HT who had received intra-arterial thrombolysis therapy, using biochemical analysis, renal function test, routine blood test, blood lipid test, coagulation blood test, liver function test, random blood glucose test, time- window for intra-arterial thrombolysis, recanalization, National Institutes of Health Stroke Scale （NIHSS） score and systolic blood pressure before intra-artedal thrombolysis. The mortality rates were similar in the HT and non-HT groups （P = 0.944）. In the single- factor analysis, patients with a higher globulin level （P 〈0.002）, prothrombin time activity percentage （PTA; P = 0.026）, and NIHSS score （P = 0.002）, had a significantly increased risk of developing HT. In the multifactor logistic regression model involving globulin level, PTA, white blood cell count, and NIHSS score, the globulin level （P 〈0.001; OR, 1.185; 95% confidence interval [CI], 1.090-1.288）, PTA （P = 0.018; OR, 1.016; 95% CI, 1.003-1.029）, white blood cell count （P = 0.025; OR, 1.097; 95% CI, 1.012-1.190） and NIHSS score （P = 0.003; OR, 1.097; 95% CI, 1.031-1.166） were significantly increased in the HT group. The increase in globulin level is an independent risk factor for HT in patients receiving intra-arterial thrombolysis. The possible mechanisms may involve inflammatory cytokines, matrix metalloproteinase 9, and positive acute-phase reactants synthesized by the liver.

Compromised cerebrovascular modulation in chronic anxiety:evidence from cerebral blood flow velocity measured by transcranial Doppler sonography

Objective Cerebral autoregulation （CA） is the mechanism by which constant cerebral blood flow is maintained despite changes in cerebral perfusion pressure. CA can be evaluated by dynamic monitoring of cerebral blood flow velocity （CBFV） with transcranial Doppler sonography （TCD）. The present study aimed to explore CA in chronic anxiety. Methods Subjects with Hamilton anxiety scale scores 〉14 were enrolled and the dynamic changes of CBFV in response to an orthostatic challenge were investigated using TCD. Results In both the anxious and the healthy subjects, the mean CBFV was significantly lower in the upright position than when supine. However, the CBFV changes from supine to upright differed between the anxious and the healthy groups. Anxious subjects showed more pronounced decreases in CBFV with abrupt standing. Conclusion Our results indicate that cerebrovascular modulation is compromised in chronic anxiety; anxious subjects have some insufficiency in maintaining cerebral perfusion after postural change. Given the fact that anxiety and impaired CA are associated with cardiovascular disease, early ascertainment of compromised cerebrovascular modulation using TCD might suggest interventional therapies in the anxious population, and improve the primary prevention of cardiovascular disease.

Chinese Stroke Association guidelines for clinical management of cerebrovascular disorders:executive summary and 2019 update of clinical management of spontaneous subarachnoid haemorrhage

caused by ruptured cerebral aneurysm is a severe subtype of haemorrhagic stroke.Although the incidence of SAH is relatively low among all cerebrovascular diseases,the mortality is the highest.The critical management of SAH is challenging.We provide this evidence-based guideline to present current and comprehensive recommendations for the diagnosis and treatment of non-trauma SAH.Methods A formal literature search of MEDLINE(1 January 1990-30 June 2019)was performed.Data were synthesised with the use of evidence tables.Writing group members met by teleconference to discuss data-derived recommendations.The Chinese Stroke Association’s levels of evidence grading algorithm was used to grade each recommendation.The guideline draft was reviewed by Chinese Stroke Association’s Stroke Fellow Committees.It is intended that this guideline be fully updated every 3 years.results Evidence-based guidelines are presented for the care of patients presenting with non-trauma SAH.The focus of the guideline was subdivided into transfer and systems of care,diagnosis flowchart,aetiology and differentiation,prevention of rebleeding,surgical and endovascular repair of ruptured aneurysms,management of vasospasm and delayed cerebral ischaemia,management of hydrocephalus,management of seizures and management of medical complications.Conclusions The guideline offers a framework for SAH management.Early professional and aggressive care of SAH might help dramatically.

3D T1-weighted black blood sequence at 3.0 Tesla for the diagnosis of cervical artery dissection

Objective:We aimed to investigate the value of threedimensional(3D)T1 volumetric isotropic turbo spin echo acquisition(VISTA)in the diagnosis of cervical artery dissection(CAD).Methods:We prospectively included patients who were suspected as having a CAD within 1 month of onset.For T1 VISTA,the diagnosis of the dissection was based on the presence of intramural high-signal,intimal flap,double lumen and aneurysmal dilation.The final diagnosis of dissection was based on the clinical history,physical examination,and all of the imaging tests.Results:A total of 46 patients were included in this study.The final diagnosis of CAD was made for 21 patients.Diagnosis of dissection was made for 20 of the 21 patients after assessing T1 VISTA.A definitive diagnosis of dissection was not made for 5 patients(including 3 patients with digital subtraction angiography)before the T1 VISTA examination.The sensitivity and specificity for T1 VISTA were 95.2%(95%CI,76.2%to 99.9%)and 100%(95%CI,86.3%to 100%),respectively.The agreement between the two researchers for T1 VISTA for diagnosis of CAD was very good(k=0.91).For patients without acute artery occlusion,all of them had a definite conclusion with or without dissection by T1 VISTA(n=29).However,for 17 patients with acute artery occlusion,the possibility of dissection could not be excluded for 6 of them by T1 VISTA(p=0.001).Conclusions:3D T1 VISTA at 3.0 Tesla was useful in the diagnosis of acute CAD.However,for some patients with total occlusion of the artery without typical imaging features of dissection,the unequivocal distinction between intramural haematoma and intraluminal thrombus may be not adequate by T1 VISTA alone.Future studies should investigate whether a follow-up scan,a contrast-enhanced imaging or an optimal VISTA technique could be useful.

Xenon-enhanced CT assessment of cerebral blood flow in stroke-in-progress patients with unilateral internal carotid artery or middle cerebral artery stenosis

Carotid or cerebral artery stenosis resulting in low perfusion is a major cause of ischemic stroke.Understanding the unique hemodynamic features in each patient undergoing a stroke-in-progress（SIP） and the correlation between progression and cerebral blood flow（CBF） status would help in the diagnosis and treatment of individual patients.We used xenonenhanced CT（Xe-CT） to examine cerebral perfusion in patients with or without SIP（30 patients/group）,recruited from October 2009 to October 2010.Only SIP patients with unilateral stenosis in the internal or middle cerebral artery were recruited.The occurrence of watershed infarction was higher in the SIP group than in the non-SIP group（P ＆lt;0.05）.In the SIP group,larger hypoperfused areas were found around the lesions than in the non-SIP group.In the SIP group,the CBF values in the ipsilateral areas were significantly lower than those in corresponding regions on the contralateral side.CBF values in the contralateral hemisphere were significantly lower in the SIP group than in the non-SIP group.In SIP patients,infarctions were surrounded by larger hypoperfused areas than in non-SIP patients.These larger hypoperfused areas may result in pathological damage to the brain that is responsible for the progression of stroke.