Patent foramen ovale closure reduces recurrent stroke risk in cryptogenic stroke:A systematic review and metaanalysis of randomized controlled trials

AIM To investigate if patent foramen ovale(PFO) closure device reduces the risk of recurrent stroke in patients with cryptogenic stroke.METHODS We searched five databases-Pub Med,EMBASE,Cochrane,CINAHL and Web-of-Science and clinicaltrials.gov from January 2000 to September 2017 for randomized trials comparing PFO closure to medical therapy in cryptogenic stroke.Heterogeneity was determined using Cochrane's Q statistics.Random effects model was used.RESULTS Five randomized controlled trials with 3440 patients were included in the analysis.Mean follow-up was 50 ± 20 mo.PFO closure was associated with a 41% reduction in incidence of recurrent strokes when compared to medical therapy alone in patients with cryptogenic stroke [risk ratio(RR): 0.59,95%CI: 0.40-0.87,P = 0.008].Atrial fibrillation was higher with device closure when compared to medical therapy alone(RR: 4.97,95%CI: 2.22-11.11,P < 0.001).There was no difference between the two groups with respect to all-cause mortality,major bleeding or adverse events.CONCLUSION PFO device closure in appropriately selected patients with moderate to severe right-to-left shunt and/or atrial septal aneurysm shows benefit with respect to recurrent strokes,particularly in younger patients.Further studies are essential to evaluate the impact of higher incidence of atrial fibrillation seen with the PFO closure device on long-term mortality and stroke rates.

Evaluation of right-to-left shunt on contrast-enhanced transcranial Doppler in patent foramen ovale-related cryptogenic stroke: Research based on imaging

BACKGROUND Cardiogenic embolism caused by patent foramen ovale(PFO)is a common etiology of cryptogenic stroke(CS),particularly in young and middle-aged patients.Studies about right-to-left shunt(RLS)detection using contrast-enhanced transcranial Doppler(c-TCD)are numerous.According to the time phase and number of microbubbles detected on c-TCD,RLS can be classified and graded.We hypothesized that the characteristics of an infarction lesion on diffusion-weighted imaging differs when combining the type and grade of RLS on c-TCD in patients with PFO-related CS.AIM To explore the characteristics of infarction lesions on diffusion-weighted imaging when combining the RLS type and grade determined by c-TCD.METHODS We retrospectively evaluated CS patients from August 2015 to December 2019 at a tertiary hospital.In total,111 PFO-related CS patients were divided according to whether RLS was permanent(microbubbles detected both at resting state and after the Valsalva maneuver)or latent(microbubbles detected only after the Valsalva maneuver)on c-TCD.Each group was subdivided into small,mild and large RLS according to the grade of shunt on c-TCD.A normal control group was composed of 33 patients who suffered from simple dizziness.Intragroup and intergroup differences were analyzed in terms of clinical,laboratory and diffusion-weighted imaging lesion characteristics.The correlation between RLS grade evaluated by c-TCD and size of PFO determined by transesophageal echocardiography were also analyzed.RESULTS In 111 patients with PFO-related CS,68 had permanent RLS and 43 had latent RLS.Clinical characteristics and laboratory tests were not significantly different among the permanent RLS,latent RLS and normal control groups.The proportion of patients with multiple territory lesions in the permanent RLS group(50%)was larger than that in the latent RLS group(27.91%;P=0.021).Posterior circulation was more likely to be affected in the latent RLS group than in the permanent RLS group(30.23%vs 8.82%,P=0.004).Permanent-large and latent-large RLS were both more likely to be related to multiple(P_(trend)=0.017 and 0.009,respectively),small(P_(trend)=0.035 and 0.006,respectively)and cortical(P_(trend)=0.031 and 0.033,respectively)lesions.The grade of RLS evaluated by c-TCD was correlated to the size of PFO determined by transesophageal echocardiography(r=0.758,P<0.001).CONCLUSION Distribution of the infarct suggested the possible type of RLS.Multiple,small and cortical infarcts suggest large RLS induced by a large PFO.

Congenital Cardiac Defects, Such as Eustachian Valve, May Increase the Risk of Cryptogenic Stroke: A Case Report

Eustachian valve is an embryonic endocardial heart structure;after birth it becomes an embryogenic residue and its persistance in adult life is unusual. The literature reports some cases of association between Eustachian valve and PFO and is known that the prominent Eustachian valve can represent a way facilitating systemic embolism.Several studies also investigated the role of Eustachian valve in the pathophysiology of both migraine and cerebral embolism. In addiction is known how Eustachian valve may increase the risk of endocarditis, which mostly affects intravenous drug abusers or those with implanted medical devices or central venous catheters. The most commonly identified organism is Staphylococcus aureus (approximately 53% of cases). We present a case of a 46-year-old woman with known migraine. She was hospitalized in Stroke Unit for a cryptogenic stroke with a right-to-left shunt detected with transcranial doppler ultrasound with “bubble test” and a patent foramen ovale with right-to-left shunt with a fenestration of atrial septum and a voluminous Eustachian valve detected with transesophageal echocardiography;she developed fever with a blood cultures positive for methicillin-resis- tant Staphylococcus aureus (MRSA), even if without evidence of endocarditis vegetations. In summary, the objective of our paper is to present an example of a correlation between the persistence of the Eustachian valve with bothcryptogenetic stroke, possible valve infection and migraine.

Percutaneous Patent Foramen Ovale Closure versus Medical Therapy in Cryptogenic Stroke: An Update Meta-Analysis of Randomized Controlled Trials

Objectives: Concerns regarding the real efficacy of transcatheter patent foramen ovale (PFO) closure versus medical therapy in patients with cryptogenic stroke remained unresolved. We performed a meta-analysis using the randomized controlled trials on the efficacy and safety of transcatheter PFO closure in patients with cryptogenic stroke. Methods: Web of Science, EMBASE, PubMed, and the Cochrane Library were searched for relevant randomized controlled trials (RCTs). The primary outcome was recurrent stroke and transient-ischemic attack (TIA). Original data, hazard ratio (HR) with 95% confidence interval (95% CI) were abstracted to calculate a pooled effect size. Results: Our meta-analysis showed benefit with device closure when compared with medical therapy with an HR of 0.54 (95% CI: 0.39 - 0.74, P = 0.108) in the intention-to-treat cohort, 0.44 (95% CI: 0.24 - 0.82, P = 0.103) in the per-protocol populations, and 0.43 (95% CI: 0.31 - 0.60, P = 0.019) in the as-treated populations. There was a significantly higher incidence of new-onset atrial fibrillation in PFO closure patients (OR = 4.53, 95% CI: 2.58 - 7.97, P = 0.094). PFO Patients with an atrial septal aneurysm benefit from device closure (OR = 0.39, 95% CI: 0.22 - 0.69, P = 0.053). Patients with a substantial PFO shunt benefit the greatest with device closure with a pooled OR of 0.27 (95% CI: 0.14 - 0.56, P = 0.525). Conclusions: The meta-analysis concluded that PFO closure was associated with significantly lower risk of recurrent stroke in PFO patients with cryptogenic stroke than with medical therapy alone. The benefit of PFO closure was greater in patients with a substantial shunt and atrial septal aneurysm. PFO closure was associated with higher rates of new-onset atrial fibrillation.

Patent foramen ovale closure in non-lacunar cryptogenic ischemic stroke:where are we now?

Patent foram ovale(PFO)is the most common anatomical cause of an interarterial shunt.It is usually asymptomatic but may cause paradoxical embolism and is a risk factor for non-lacunar cryptogenic cerebral ischemia in young adults.Although the first clinical trials did not show a significant superiority of PFO closure in the secondary prevention of cerebral ischemia as compared with standard antithrombotic treatment,six subsequent randomized clinical trials(CLOSURE I,PC Trial,RESPECT,CLOSE,REDUCE,and DEFENSE-PFO)performed in a sample of cryptogenic stroke in patients aged 60 years or younger provided evidence of a significant reduction of recurrent cerebral ischemia after percutaneous PFO closure.However,the use of percutaneous PFO closure cannot be generalized to the entire population of patients with cerebral ischemia and PFO,but it is indicated in highly selected patients with non-lacunar cryptogenic cerebral infarction with a large right-to-left shunt,an atrial septal aneurysm and no evidence of atrial fibrillation,as well as in association with antithrombotic treatment for an optimal secondary prevention of cerebral ischemia.

The Value of c-TCD in the Diagnosis of Migraine and Cryptogenic Stroke Caused by PFO

Objective:To investigate the value of contrast-enhanced transcranial doppler(c-TCD)in the diagnosis of patent foramen ovale(PFO)of patients with migraine and cryptogenic stroke.Methods:A retrospective analysis of 160 patients undergoing c-TCD monitoring in our hospital from June 2014 to June 2019 was performed.Among them,there were 80 cases of patients with migraine(38 cases with aura and 42 cases without aura)in group A,and 80 cases of patients with cryptogenic stroke in group B.The positive detectable rate of PFO in the two groups were calculated and analyzed.Results:The detectable rate was 50.00%in group A,and 40.00%in group B.There was no statistical significance between the two groups(P>0.05).Among them,the detectable rate of PFO in migraine with aura in group A(62.50%)was higher than that in group B(37.50%).The difference was statistically significant(P<0.05);In the two groups of PFO-positive patients,the difference didn’t have statistical significance,comparing the proportion of the inherent type to that of potential type(P>0.05);There was no statistical significance of the difference between the RLS incidence of grade I and that of grade II among two groups of PFO-positive patients(P>0.05);the incidence of RLS in grade III in group B(50.00%)was higher than that in group A(25.00%),and the difference was statistically significant(P<0.05).Conclusion:c-TCD can accurately screen migraine and cryptogenic stroke caused by PFO,and grade and classify it as a clinical diagnosis of migraine and cryptogenic caused by PFO.It can also act as a objective reference of estimating the effect of treatment in different diseases and preventing cryptogenic stroke.

Logistic Regression Analysis of the Influencing Factors of Cryptogenic Stroke with Positive c-TCD

Objective:To explore the influencing factors and logistic regression characteristics of cryptogenic stroke in patients with positive transcranial doppler bubble test(c-TCD).Methods:A total of 134 cases of cryptogenic stroke that were diagnosed by Tianshui First People's Hospital from November 2018 to April 2020 were selected according to the TOAST(Trial of ORG 10172 in Acute Stroke Treatment)classification criteria.According to c-TCD results,there were 70 cases of right to left shunt that were included in the positive group and 64 cases without right to left shunt in the negative group.Gender,age,smoking,diabetes,hypertension,and factors affecting the positive rate of foam were analyzed.According to the abnormal embolism scale scores,logistic regression equation was used to analyze the independent influencing factors.Results:The influencing factors of cryptogenic stroke in patients with positive c-TCD were correlated with age,gender,and abnormal embolism scale scores(p<0.05).For each grade increase in age,the proportion of positive foam test was calculated to be 3.21 times,and the proportion of female to male was calculated to be 2.25 times.For each grade increase in the scores,the proportion of positive foam test was calculated to be 2.55 times.Conclusion:Female,older age,and higher scores in the abnormal embolism scale are the influencing factors for cryptogenic stroke in patients with positive c-TCD.

The potential mechanism and clinical application value of remote ischemic conditioning in stroke

Some studies have confirmed the neuroprotective effect of remote ischemic conditioning against stroke. Although numerous animal researches have shown that the neuroprotective effect of remote ischemic conditioning may be related to neuroinflammation, cellular immunity, apoptosis, and autophagy, the exact underlying molecular mechanisms are unclear. This review summarizes the current status of different types of remote ischemic conditioning methods in animal and clinical studies and analyzes their commonalities and differences in neuroprotective mechanisms and signaling pathways. Remote ischemic conditioning has emerged as a potential therapeutic approach for improving stroke-induced brain injury owing to its simplicity, non-invasiveness, safety, and patient tolerability. Different forms of remote ischemic conditioning exhibit distinct intervention patterns, timing, and application range. Mechanistically, remote ischemic conditioning can exert neuroprotective effects by activating the Notch1/phosphatidylinositol 3-kinase/Akt signaling pathway, improving cerebral perfusion, suppressing neuroinflammation, inhibiting cell apoptosis, activating autophagy, and promoting neural regeneration. While remote ischemic conditioning has shown potential in improving stroke outcomes, its full clinical translation has not yet been achieved.

Decreased levels of phosphorylated synuclein in plasma are correlated with poststroke cognitive impairment

Poststro ke cognitive impairment is a major secondary effect of ischemic stroke in many patients;however,few options are available for the early diagnosis and treatment of this condition.The aims of this study were to(1)determine the specific relationship between hypoxic andα-synuclein during the occur of poststroke cognitive impairment and(2)assess whether the serum phosphorylatedα-synuclein level can be used as a biomarker for poststro ke cognitive impairment.We found that the phosphorylatedα-synuclein level was significantly increased and showed pathological aggregation around the cerebral infa rct area in a mouse model of ischemic stroke.In addition,neuronalα-synuclein phosphorylation and aggregation were observed in the brain tissue of mice subjected to chronic hypoxia,suggesting that hypoxia is the underlying cause ofα-synuclein-mediated pathology in the brains of mice with ischemic stroke.Serum phosphorylatedα-synuclein levels in patients with ischemic stroke were significantly lower than those in healt hy subjects,and were positively correlated with cognition levels in patients with ischemic stroke.Furthermore,a decrease in serum high-density lipoprotein levels in stroke patie nts was significantly correlated with a decrease in phosphorylatedα-synuclein levels.Although ischemic stroke mice did not show significant cognitive impairment or disrupted lipid metabolism 14 days after injury,some of them exhibited decreased cognitive function and reduced phosphorylatedα-synuclein levels.Taken together,our results suggest that serum phosphorylatedα-synuclein is a potential biomarker for poststroke cognitive impairment.

Mechanism of inflammatory response and therapeutic effects of stem cells in ischemic stroke:current evidence and future perspectives

Ischemic stroke is a leading cause of death and disability worldwide,with an increasing trend and tendency for onset at a younger age.China,in particular,bears a high burden of stroke cases.In recent years,the inflammatory response after stroke has become a research hotspot:understanding the role of inflammatory response in tissue damage and repair following ischemic stroke is an important direction for its treatment.This review summarizes several major cells involved in the inflammatory response following ischemic stroke,including microglia,neutrophils,monocytes,lymphocytes,and astrocytes.Additionally,we have also highlighted the recent progress in various treatments for ischemic stroke,particularly in the field of stem cell therapy.Overall,understanding the complex interactions between inflammation and ischemic stroke can provide valuable insights for developing treatment strategies and improving patient outcomes.Stem cell therapy may potentially become an important component of ischemic stroke treatment.

Early identification of stroke through deep learning with multi-modal human speech and movement data

Early identification and treatment of stroke can greatly improve patient outcomes and quality of life.Although clinical tests such as the Cincinnati Pre-hospital Stroke Scale(CPSS)and the Face Arm Speech Test(FAST)are commonly used for stroke screening,accurate administration is dependent on specialized training.In this study,we proposed a novel multimodal deep learning approach,based on the FAST,for assessing suspected stroke patients exhibiting symptoms such as limb weakness,facial paresis,and speech disorders in acute settings.We collected a dataset comprising videos and audio recordings of emergency room patients performing designated limb movements,facial expressions,and speech tests based on the FAST.We compared the constructed deep learning model,which was designed to process multi-modal datasets,with six prior models that achieved good action classification performance,including the I3D,SlowFast,X3D,TPN,TimeSformer,and MViT.We found that the findings of our deep learning model had a higher clinical value compared with the other approaches.Moreover,the multi-modal model outperformed its single-module variants,highlighting the benefit of utilizing multiple types of patient data,such as action videos and speech audio.These results indicate that a multi-modal deep learning model combined with the FAST could greatly improve the accuracy and sensitivity of early stroke identification of stroke,thus providing a practical and powerful tool for assessing stroke patients in an emergency clinical setting.

Beyond wrecking a wall:revisiting the concept of blood–brain barrier breakdown in ischemic stroke

The blood–brain barrier constitutes a dynamic and interactive boundary separating the central nervous system and the peripheral circulation.It tightly modulates the ion transport and nutrient influx,while restricting the entry of harmful factors,and selectively limiting the migration of immune cells,thereby maintaining brain homeostasis.Despite the well-established association between blood–brain barrier disruption and most neurodegenerative/neuroinflammatory diseases,much remains unknown about the factors influencing its physiology and the mechanisms underlying its breakdown.Moreover,the role of blood–brain barrier breakdown in the translational failure underlying therapies for brain disorders is just starting to be understood.This review aims to revisit this concept of“blood–brain barrier breakdown,”delving into the most controversial aspects,prevalent challenges,and knowledge gaps concerning the lack of blood–brain barrier integrity.By moving beyond the oversimplistic dichotomy of an“open”/“bad”or a“closed”/“good”barrier,our objective is to provide a more comprehensive insight into blood–brain barrier dynamics,to identify novel targets and/or therapeutic approaches aimed at mitigating blood–brain barrier dysfunction.Furthermore,in this review,we advocate for considering the diverse time-and location-dependent alterations in the blood–brain barrier,which go beyond tight-junction disruption or brain endothelial cell breakdown,illustrated through the dynamics of ischemic stroke as a case study.Through this exploration,we seek to underscore the complexity of blood–brain barrier dysfunction and its implications for the pathogenesis and therapy of brain diseases.

Utilizing engineered extracellular vesicles as delivery vectors in the management of ischemic stroke:a special outlook on mitochondrial delivery

Ischemic stroke is a secondary cause of mortality worldwide,imposing considerable medical and economic burdens on society.Extracellular vesicles,serving as natural nanocarriers for drug delivery,exhibit excellent biocompatibility in vivo and have significant advantages in the management of ischemic stroke.However,the uncertain distribution and rapid clearance of extracellular vesicles impede their delivery efficiency.By utilizing membrane decoration or by encapsulating therapeutic cargo within extracellular vesicles,their delivery efficacy may be greatly improved.Furthermore,previous studies have indicated that microvesicles,a subset of large-sized extracellular vesicles,can transport mitochondria to neighboring cells,thereby aiding in the restoration of mitochondrial function post-ischemic stroke.Small extracellular vesicles have also demonstrated the capability to transfer mitochondrial components,such as proteins or deoxyribonucleic acid,or their sub-components,for extracellular vesicle-based ischemic stroke therapy.In this review,we undertake a comparative analysis of the isolation techniques employed for extracellular vesicles and present an overview of the current dominant extracellular vesicle modification methodologies.Given the complex facets of treating ischemic stroke,we also delineate various extracellular vesicle modification approaches which are suited to different facets of the treatment process.Moreover,given the burgeoning interest in mitochondrial delivery,we delved into the feasibility and existing research findings on the transportation of mitochondrial fractions or intact mitochondria through small extracellular vesicles and microvesicles to offer a fresh perspective on ischemic stroke therapy.

Relationship between longitudinal changes in lipid composition and ischemic stroke among hypertensive patients

BACKGROUND Dyslipidemia was strongly linked to stroke,however the relationship between dyslipidemia and its components and ischemic stroke remained unexplained.AIM To investigate the link between longitudinal changes in lipid profiles and dyslipidemia and ischemic stroke in a hypertensive population.METHODS Between 2013 and 2014,6094 hypertension individuals were included in this,and ischemic stroke cases were documented to the end of 2018.Longitudinal changes of lipid were stratified into four groups:(1)Normal was transformed into normal group;(2)Abnormal was transformed into normal group;(3)Normal was transformed into abnormal group;and(4)Abnormal was transformed into abnormal group.To examine the link between longitudinal changes in dyslipidemia along with its components and the risk of ischemic stroke,we utilized multivariate Cox proportional hazards models with hazard ratio(HR)and 95%CI.RESULTS The average age of the participants was 62.32 years±13.00 years,with 329 women making up 54.0%of the sample.Over the course of a mean follow-up of 4.8 years,143 ischemic strokes happened.When normal was transformed into normal group was used as a reference,after full adjustments,the HR for dyslipidemia and ischemic stroke among abnormal was transformed into normal group,normal was transformed into abnormal group and abnormal was transformed into abnormal Wei CC et al.Dyslipidemia changed and ischemic stroke WJCC https://www.wjgnet.com 2 February 6,2025 Volume 13 Issue 4 group were 1.089(95%CI:0.598-1.982;P=0.779),2.369(95%CI:1.424-3.941;P<0.001)and 1.448(95%CI:1.002-2.298;P=0.047)(P for trend was 0.233),respectively.CONCLUSION In individuals with hypertension,longitudinal shifts from normal to abnormal in dyslipidemia-particularly in total and low-density lipoprotein cholesterol-were significantly associated with the risk of ischemic stroke.

T cell interactions with microglia in immune-inflammatory processes of ischemic stroke

The primary mechanism of secondary injury after cerebral ischemia may be the brain inflammation that emerges after an ischemic stroke,which promotes neuronal death and inhibits nerve tissue regeneration.As the first immune cells to be activated after an ischemic stroke,microglia play an important immunomodulatory role in the progression of the condition.After an ischemic stroke,peripheral blood immune cells(mainly T cells)are recruited to the central nervous system by chemokines secreted by immune cells in the brain,where they interact with central nervous system cells(mainly microglia)to trigger a secondary neuroimmune response.This review summarizes the interactions between T cells and microglia in the immune-inflammatory processes of ischemic stroke.We found that,during ischemic stroke,T cells and microglia demonstrate a more pronounced synergistic effect.Th1,Th17,and M1 microglia can co-secrete proinflammatory factors,such as interferon-γ,tumor necrosis factor-α,and interleukin-1β,to promote neuroinflammation and exacerbate brain injury.Th2,Treg,and M2 microglia jointly secrete anti-inflammatory factors,such as interleukin-4,interleukin-10,and transforming growth factor-β,to inhibit the progression of neuroinflammation,as well as growth factors such as brain-derived neurotrophic factor to promote nerve regeneration and repair brain injury.Immune interactions between microglia and T cells influence the direction of the subsequent neuroinflammation,which in turn determines the prognosis of ischemic stroke patients.Clinical trials have been conducted on the ways to modulate the interactions between T cells and microglia toward anti-inflammatory communication using the immunosuppressant fingolimod or overdosing with Treg cells to promote neural tissue repair and reduce the damage caused by ischemic stroke.However,such studies have been relatively infrequent,and clinical experience is still insufficient.In summary,in ischemic stroke,T cell subsets and activated microglia act synergistically to regulate inflammatory progression,mainly by secreting inflammatory factors.In the future,a key research direction for ischemic stroke treatment could be rooted in the enhancement of anti-inflammatory factor secretion by promoting the generation of Th2 and Treg cells,along with the activation of M2-type microglia.These approaches may alleviate neuroinflammation and facilitate the repair of neural tissues.

Cell polarization in ischemic stroke: molecular mechanisms and advances

Ischemic stroke is a cerebrovascular disease associated with high mortality and disability rates. Since the inflammation and immune response play a central role in driving ischemic damage, it becomes essential to modulate excessive inflammatory reactions to promote cell survival and facilitate tissue repair around the injury site. Various cell types are involved in the inflammatory response, including microglia, astrocytes, and neutrophils, each exhibiting distinct phenotypic profiles upon stimulation. They display either proinflammatory or anti-inflammatory states, a phenomenon known as ‘cell polarization.’ There are two cell polarization therapy strategies. The first involves inducing cells into a neuroprotective phenotype in vitro, then reintroducing them autologously. The second approach utilizes small molecular substances to directly affect cells in vivo. In this review, we elucidate the polarization dynamics of the three reactive cell populations(microglia, astrocytes, and neutrophils) in the context of ischemic stroke, and provide a comprehensive summary of the molecular mechanisms involved in their phenotypic switching. By unraveling the complexity of cell polarization, we hope to offer insights for future research on neuroinflammation and novel therapeutic strategies for ischemic stroke.

Small extracellular vesicles derived from cerebral endothelial cells with elevated microRNA 27a promote ischemic stroke recovery

Axonal remodeling is a critical aspect of ischemic brain repair processes and contributes to spontaneous functional recovery.Our previous in vitro study demonstrated that exosomes/small extracellular vesicles(sEVs)isolated from cerebral endothelial cells(CEC-sEVs)of ischemic brain promote axonal growth of embryonic cortical neurons and that microRNA 27a(miR-27a)is an elevated miRNA in ischemic CEC-sEVs.In the present study,we investigated whether normal CEC-sEVs engineered to enrich their levels of miR-27a(27a-sEVs)further enhance axonal growth and improve neurological outcomes after ischemic stroke when compared with treatment with non-engineered CEC-sEVs.27a-sEVs were isolated from the conditioned medium of healthy mouse CECs transfected with a lentiviral miR-27a expression vector.Small EVs isolated from CECs transfected with a scramble vector(Scra-sEVs)were used as a control.Adult male mice were subjected to permanent middle cerebral artery occlusion and then were randomly treated with 27a-sEVs or Scra-sEVs.An array of behavior assays was used to measure neurological function.Compared with treatment of ischemic stroke with Scra-sEVs,treatment with 27a-sEVs significantly augmented axons and spines in the peri-infarct zone and in the corticospinal tract of the spinal grey matter of the denervated side,and significantly improved neurological outcomes.In vitro studies demonstrated that CEC-sEVs carrying reduced miR-27a abolished 27a-sEV-augmented axonal growth.Ultrastructural analysis revealed that 27a-sEVs systemically administered preferentially localized to the pre-synaptic active zone,while quantitative reverse transcription-polymerase chain reaction and Western Blot analysis showed elevated miR-27a,and reduced axonal inhibitory proteins Semaphorin 6A and Ras Homolog Family Member A in the peri-infarct zone.Blockage of the Clathrin-dependent endocytosis pathway substantially reduced neuronal internalization of 27a-sEVs.Our data provide evidence that 27a-sEVs have a therapeutic effect on stroke recovery by promoting axonal remodeling and improving neurological outcomes.Our findings also suggest that suppression of axonal inhibitory proteins such as Semaphorin 6A may contribute to the beneficial effect of 27a-sEVs on axonal remodeling.

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.

PI3K/AKT signaling and neuroprotection in ischemic stroke:molecular mechanisms and therapeutic perspectives

It has been reported that the PI3K/AKT signaling pathway plays a key role in the pathogenesis of ischemic stroke.As a result,the development of drugs targeting the PI3K/AKT signaling pathway has attracted increasing attention from researchers.This article reviews the pathological mechanisms and advancements in research related to the signaling pathways in ischemic stroke,with a focus on the PI3K/AKT signaling pathway.The key findings include the following:(1)The complex pathological mechanisms of ischemic stroke can be categorized into five major types:excitatory amino acid toxicity,Ca^(2+)overload,inflammatory response,oxidative stress,and apoptosis.(2)The PI3K/AKT-mediated signaling pathway is closely associated with the occurrence and progression of ischemic stroke,which primarily involves the NF-κB,NRF2,BCL-2,mTOR,and endothelial NOS signaling pathways.(3)Natural products,including flavonoids,quinones,alkaloids,phenylpropanoids,phenols,terpenoids,and iridoids,show great potential as candidate substances for the development of innovative anti-stroke medications.(4)Recently,novel therapeutic techniques,such as electroacupuncture and mesenchymal stem cell therapy,have demonstrated the potential to improve stroke outcomes by activating the PI3K/AKT signaling pathway,providing new possibilities for the treatment and rehabilitation of patients with ischemic stroke.Future investigations should focus on the direct regulatory mechanisms of drugs targeting the PI3K/AKT signaling pathway and their clinical translation to develop innovative treatment strategies for ischemic stroke.

A promising approach for quantifying focal stroke modeling and assessing stroke progression:optical resolution photoacoustic microscopy photothrombosis

To investigate the mechanisms underlying the onset and progression of ischemic stroke,some methods have been proposed that can simultaneously monitor and create embolisms in the animal cerebral cortex.However,these methods often require complex systems and the effect of age on cerebral embolism has not been adequately studied,although ischemic stroke is strongly age-related.In this study,we propose an optical-resolution photoacoustic microscopy-based visualized photothrombosis methodology to create and monitor ischemic stroke in mice simultaneously using a 532 nm pulsed laser.We observed the molding process in mice of different ages and presented age-dependent vascular embolism differentiation.Moreover,we integrated optical coherence tomography angiography to investigate age-associated trends in cerebrovascular variability following a stroke.Our imaging data and quantitative analyses underscore the differential cerebrovascular responses to stroke in mice of different ages,thereby highlighting the technique's potential for evaluating cerebrovascular health and unraveling age-related mechanisms involved in ischemic strokes.