Ischemic stroke is a major cause of neurological deficits and high disability rate.As the primary immune cells of the central nervous system,microglia play dual roles in neuroinflammation and tissue repair following a...Ischemic stroke is a major cause of neurological deficits and high disability rate.As the primary immune cells of the central nervous system,microglia play dual roles in neuroinflammation and tissue repair following a stroke.Their dynamic activation and polarization states are key factors that influence the disease process and treatment outcomes.This review article investigates the role of microglia in ischemic stroke and explores potential intervention strategies.Microglia exhibit a dynamic functional state,transitioning between pro-inflammatory(M1)and anti-inflammatory(M2)phenotypes.This duality is crucial in ischemic stroke,as it maintains a balance between neuroinflammation and tissue repair.Activated microglia contribute to neuroinflammation through cytokine release and disruption of the blood-brain barrier,while simultaneously promoting tissue repair through anti-inflammatory responses and regeneration.Key pathways influencing microglial activation include Toll-like receptor 4/nuclear factor kappa B,mitogen-activated protein kinases,Janus kinase/signal transducer and activator of transcription,and phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin pathways.These pathways are targets for various experimental therapies aimed at promoting M2 polarization and mitigating damage.Potential therapeutic agents include natural compounds found in drugs such as minocycline,as well as traditional Chinese medicines.Drugs that target these regulatory mechanisms,such as small molecule inhibitors and components of traditional Chinese medicines,along with emerging technologies such as single-cell RNA sequencing and spatial transcriptomics,offer new therapeutic strategies and clinical translational potential for ischemic stroke.展开更多
The mechanisms underlying the pathophysiology of ischemic stroke are complex and multifactorial and include excitotoxicity,oxidative stress,inflammatory responses,and blood–brain barrier disruption.While vascular rec...The mechanisms underlying the pathophysiology of ischemic stroke are complex and multifactorial and include excitotoxicity,oxidative stress,inflammatory responses,and blood–brain barrier disruption.While vascular recanalization treatments such as thrombolysis and mechanical thrombectomy have achieved some success,reperfusion injury remains a significant contributor to the exacerbation of brain injury.This emphasizes the need for developing neuroprotective strategies to mitigate this type of injury.The purpose of this review was to examine the application of nanotechnology in the treatment of ischemic stroke,covering research progress in nanoparticlebased drug delivery,targeted therapy,and antioxidant and anti-inflammatory applications.Nanobased drug delivery systems offer several advantages compared to traditional therapies,including enhanced blood–brain barrier penetration,prolonged drug circulation time,improved drug stability,and targeted delivery.For example,inorganic nanoparticles,such as those based on CeO_(2),have been widely studied for their strong antioxidant capabilities.Biomimetic nanoparticles,such as those coated with cell membranes,have garnered significant attention owing to their excellent biocompatibility and targeting abilities.Nanoparticles can be used to deliver a wide range of neuroprotective agents,such as antioxidants(e.g.,edaravone),anti-inflammatory drugs(e.g.,curcumin),and neurotrophic factors.Nanotechnology significantly enhances the efficacy of these drugs while minimizing adverse reactions.Although nanotechnology has demonstrated great potential in animal studies,its clinical application still faces several challenges,including the long-term safety of nanoparticles,the feasibility of large-scale production,quality control,and the ability to predict therapeutic effects in humans.In summary,nanotechnology holds significant promise for the treatment of ischemic stroke.Future research should focus on further exploring the mechanisms of action of nanoparticles,developing multifunctional nanoparticles,and validating their safety and efficacy through rigorous clinical trials.Moreover,interdisciplinary collaboration is essential for advancing the use of nanotechnology in stroke treatment.展开更多
Stroke remains a leading cause of death and disability worldwide,and electroacupuncture has a long history of use in stroke treatment.This meta-analysis and systematic review aimed to evaluate the efficacy of electroa...Stroke remains a leading cause of death and disability worldwide,and electroacupuncture has a long history of use in stroke treatment.This meta-analysis and systematic review aimed to evaluate the efficacy of electroacupuncture and explore its potential mechanisms in animal models of ischemic stroke.The PubMed,EMBASE,Web of Science,CENTRAL,and CINAHL databases were comprehensively searched up to May 1,2024.This review included articles on preclinical investigations of the efficacy and mechanisms of electroacupuncture in treating ischemic stroke.Data from 70 eligible studies were analyzed in Stata 18.0,using a random-effects model to calculate the standardized mean difference(Hedge’s g).The risk of bias was assessed using RevMan 5.4 software,and the quality of evidence was rated according to the Grading of Recommendations,Assessment,Development,and Evaluation(GRADE)system.Subgroup analyses were conducted to test the consistency of the results and sensitivity analyses were used to assess their robustness.The quality assessment revealed that most studies adequately handled incomplete data and selective reporting.However,several methodological limitations were identified:only 4 studies demonstrated a low risk of allocation concealment,26 achieved a low risk of outcome assessment bias,and 9 had a high risk of randomization bias.Additionally,there was an unclear risk regarding participant blinding and other methodological aspects.The GRADE assessment rated 12 outcomes as moderate quality and 6 as low quality.The mechanisms of electroacupuncture treatment for ischemic stroke can be categorized as five primary pathways:(1)Electroacupuncture significantly reduced infarct volume and apoptotic cell death(P<0.01)in ischemic stroke models;(2)electroacupuncture significantly decreased the levels of pro-inflammatory factors(P<0.01)while increasing the levels of anti-inflammatory factors(P=0.02);(3)electroacupuncture reduced the levels of oxidative stress indicators(P<0.01)and enhanced the expression of antioxidant enzymes(P<0.01);(4)electroacupuncture significantly promoted nerve regeneration(P<0.01);and(5)electroacupuncture influenced blood flow remodeling(P<0.01)and angiogenesis(P<0.01).Subgroup analyses indicated that electroacupuncture was most effective in the transient middle cerebral artery occlusion model(P<0.01)and in post-middle cerebral artery occlusion intervention(P<0.01).Dispersive waves were found to outperform continuous waves with respect to neuroprotection and anti-inflammatory effects(P<0.01),while scalp acupoints demonstrated greater efficacy than body acupoints(P<0.01).The heterogeneity among the included studies was minimal,and sensitivity analyses indicated stable results.Their methodological quality was generally satisfactory.In conclusion,electroacupuncture is effective in treating cerebral ischemia by modulating cell apoptosis,oxidative stress,inflammation,stroke-induced nerve regeneration,blood flow remodeling,and angiogenesis.The efficacy of electroacupuncture may be influenced by factors such as the middle cerebral artery occlusion model,the timing of intervention onset,waveform,and acupoint selection.Despite the moderate to low quality of evidence,these findings suggest that electroacupuncture has clinical potential for improving outcomes in ischemic stroke.展开更多
Ischemic stroke,which is characterized by hypoxia and ischemia,triggers a cascade of injury responses,including neurotoxicity,inflammation,oxidative stress,disruption of the blood-brain barrier,and neuronal death.In t...Ischemic stroke,which is characterized by hypoxia and ischemia,triggers a cascade of injury responses,including neurotoxicity,inflammation,oxidative stress,disruption of the blood-brain barrier,and neuronal death.In this context,tryptophan metabolites and enzymes,which are synthesized through the kynurenine and 5-hydroxytryptamine pathways,play dual roles.The delicate balance between neurotoxic and neuroprotective substances is a crucial factor influencing the progression of ischemic stroke.Neuroprotective metabolites,such as kynurenic acid,exert their effects through various mechanisms,including competitive blockade of N-methyl-D-aspartate receptors,modulation ofα7 nicotinic acetylcholine receptors,and scavenging of reactive oxygen species.In contrast,neurotoxic substances such as quinolinic acid can hinder the development of vascular glucose transporter proteins,induce neurotoxicity mediated by reactive oxygen species,and disrupt mitochondrial function.Additionally,the enzymes involved in tryptophan metabolism play major roles in these processes.Indoleamine 2,3-dioxygenase in the kynurenine pathway and tryptophan hydroxylase in the 5-hydroxytryptamine pathway influence neuroinflammation and brain homeostasis.Consequently,the metabolites generated through tryptophan metabolism have substantial effects on the development and progression of ischemic stroke.Stroke treatment aims to restore the balance of various metabolite levels;however,precise regulation of tryptophan metabolism within the central nervous system remains a major challenge for the treatment of ischemic stroke.Therefore,this review aimed to elucidate the complex interactions between tryptophan metabolites and enzymes in ischemic stroke and develop targeted therapies that can restore the delicate balance between neurotoxicity and neuroprotection.展开更多
Ischemic stroke is a serious medical event that cannot be predicted in advance and can have longlasting effects on patients,families,and communities.A deeper understanding of the changes in gene expression and the fun...Ischemic stroke is a serious medical event that cannot be predicted in advance and can have longlasting effects on patients,families,and communities.A deeper understanding of the changes in gene expression and the fundamental molecular mechanisms involved could help address this critical issue.In recent years,research into regulatory long non-coding(lnc)RNAs,a diverse group of RNA molecules with regulatory functions,has emerged as a promising direction in the study of cerebral infarction.This review paper aims to provide a comprehensive exploration of the roles of regulatory lncRNAs in cerebral infarction,as well as potential strategies for their application in clinical settings.LncRNAs have the potential to act as“sponges”that attract specific microRNAs,thereby regulating the expression of microRNA target genes.These interactions influence various aspects of ischemic stroke,including reperfusion-induced damage,cell death,immune responses,autophagy,angiogenesis,and the generation of reactive oxygen species.We highlight several regulatory lncRNAs that have been utilized in animal model treatments,including lncRNA NKILA,lncRNA Meg8,and lncRNA H19.Additionally,we discuss lncRNAs that have been used as biomarkers for the diagnosis and prognosis of cerebral infarction,such as lncRNA FOXO3,lncRNA XIST,and lncRNA RMST.The lncRNAs hold potential for genetic-level treatments in patients.However,numerous challenges,including inefficiency,low targeting accuracy,and side effects observed in preliminary studies,indicate the need for thorough investigation.The application of lncRNAs in ischemic stroke presents challenges that require careful and extensive validation.展开更多
Ischemic stroke is a significant global health crisis,frequently resulting in disability or death,with limited therapeutic interventions available.Although various intrinsic reparative processes are initiated within t...Ischemic stroke is a significant global health crisis,frequently resulting in disability or death,with limited therapeutic interventions available.Although various intrinsic reparative processes are initiated within the ischemic brain,these mechanisms are often insufficient to restore neuronal functionality.This has led to intensive investigation into the use of exogenous stem cells as a potential therapeutic option.This comprehensive review outlines the ontogeny and mechanisms of activation of endogenous neural stem cells within the adult brain following ischemic events,with focus on the impact of stem cell-based therapies on neural stem cells.Exogenous stem cells have been shown to enhance the proliferation of endogenous neural stem cells via direct cell-tocell contact and through the secretion of growth factors and exosomes.Additionally,implanted stem cells may recruit host stem cells from their niches to the infarct area by establishing so-called“biobridges.”Furthermore,xenogeneic and allogeneic stem cells can modify the microenvironment of the infarcted brain tissue through immunomodulatory and angiogenic effects,thereby supporting endogenous neuroregeneration.Given the convergence of regulatory pathways between exogenous and endogenous stem cells and the necessity for a supportive microenvironment,we discuss three strategies to simultaneously enhance the therapeutic efficacy of both cell types.These approaches include:(1)co-administration of various growth factors and pharmacological agents alongside stem cell transplantation to reduce stem cell apoptosis;(2)synergistic administration of stem cells and their exosomes to amplify paracrine effects;and(3)integration of stem cells within hydrogels,which provide a protective scaffold for the implanted cells while facilitating the regeneration of neural tissue and the reconstitution of neural circuits.This comprehensive review highlights the interactions and shared regulatory mechanisms between endogenous neural stem cells and exogenously implanted stem cells and may offer new insights for improving the efficacy of stem cell-based therapies in the treatment of ischemic stroke.展开更多
AAV-PHP.eB is an artificial adeno-associated virus(AAV)that crosses the blood-brain barrier and targets neurons more efficiently than other AAVs when administered systematically.While AAV-PHP.eB has been used in vario...AAV-PHP.eB is an artificial adeno-associated virus(AAV)that crosses the blood-brain barrier and targets neurons more efficiently than other AAVs when administered systematically.While AAV-PHP.eB has been used in various disease models,its cellular tropism in cerebrovascular diseases remains unclear.In the present study,we aimed to elucidate the tropism of AAV-PHP.eB for different cell types in the brain in a mouse model of ischemic stroke and evaluate its effectiveness in mediating basic fibroblast growth factor(bFGF)gene therapy.Mice were injected intravenously with AAV-PHP.eB either 14 days prior to(pre-stroke)or 1 day following(post-stroke)transient middle cerebral artery occlusion.Notably,we observed a shift in tropism from neurons to endothelial cells with post-stroke administration of AAV-PHP.eB-mNeonGreen(mNG).This endothelial cell tropism correlated strongly with expression of the endothelial membrane receptor lymphocyte antigen 6 family member A(Ly6A).Furthermore,AAV-PHP.eB-mediated overexpression of bFGF markedly improved neurobehavioral outcomes and promoted long-term neurogenesis and angiogenesis post-ischemic stroke.Our findings underscore the significance of considering potential tropism shifts when utilizing AAV-PHP.eB-mediated gene therapy in neurological diseases and suggest a promising new strategy for bFGF gene therapy in stroke treatment.展开更多
Recent studies have shown that fibrotic scar formation following cerebral ischemic injury has varying effects depending on the microenvironment.However,little is known about how fibrosis is induced and regulated after...Recent studies have shown that fibrotic scar formation following cerebral ischemic injury has varying effects depending on the microenvironment.However,little is known about how fibrosis is induced and regulated after cerebral ischemic injury.Sonic hedgehog signaling participates in fibrosis in the heart,liver,lung,and kidney.Whether Shh signaling modulates fibrotic scar formation after cerebral ischemic stroke and the underlying mechanisms are unclear.In this study,we found that Sonic Hedgehog expression was upregulated in patients with acute ischemic stroke and in a middle cerebral artery occlusion/reperfusion injury rat model.Both Sonic hedgehog and Mitofusin 2 showed increased expression in the middle cerebral artery occlusion rat model and in vitro fibrosis cell model induced by transforming growth factor-beta 1.Activation of the Sonic hedgehog signaling pathway enhanced the expression of phosphorylated Smad 3 and Mitofusin 2 proteins,promoted the formation of fibrotic scars,protected synapses or promoted synaptogenesis,alleviated neurological deficits following middle cerebral artery occlusion/reperfusion injury,reduced cell apoptosis,facilitated the transformation of meninges fibroblasts into myofibroblasts,and enhanced the proliferation and migration of meninges fibroblasts.The Smad3 phosphorylation inhibitor SIS3 reversed the effects induced by Sonic hedgehog signaling pathway activation.Bioinformatics analysis revealed significant correlations between Sonic hedgehog and Smad3,between Sonic hedgehog and Mitofusin 2,and between Smad3 and Mitofusin 2.These findings suggest that Sonic hedgehog signaling may influence Mitofusin 2 expression by regulating Smad3 phosphorylation,thereby modulating the formation of early fibrotic scars following cerebral ischemic stroke and affecting prognosis.The Sonic Hedgehog signaling pathway may serve as a new therapeutic target for stroke treatment.展开更多
Intrathecal administration of human umbilical cord mesenchymal stem cells may be a promising approach for the treatment of stroke,but its safety,effectiveness,and mechanism remain to be elucidated.In this study,good m...Intrathecal administration of human umbilical cord mesenchymal stem cells may be a promising approach for the treatment of stroke,but its safety,effectiveness,and mechanism remain to be elucidated.In this study,good manufacturing practice-grade human umbilical cord mesenchymal stem cells(5×105 and 1×106 cells)and saline were administered by cerebellomedullary cistern injection 72 hours after stroke induced by middle cerebral artery occlusion in rats.The results showed(1)no significant difference in mortality or general conditions among the three groups.There was no abnormal differentiation or tumor formation in various organs of rats in any group.(2)Compared with saline-treated animals,those treated with human umbilical cord mesenchymal stem cells showed significant functional recovery and reduced infarct volume,with no significant differences between different human umbilical cord mesenchymal stem cell doses.(3)Human umbilical cord mesenchymal stem cells were found in the ischemic brain after 14 and 28 days of follow-up,and the number of positive cells significantly decreased over time.(4)Neuronal nuclei expression in the human umbilical cord mesenchymal stem cell group was greater than that in the saline group,while glial fibrillary acidic protein and ionized calcium binding adaptor molecule 1 expression levels decreased.(5)Human umbilical cord mesenchymal stem cell treatment increased the number of CD31+microvessels and doublecortin-positive cells after ischemic stroke.Human umbilical cord mesenchymal stem cells also upregulated the expression of CD31+/Ki67+.(6)At 14 days after intrathecal administration,brain-derived neurotrophic factor expression in the peri-infarct area and the concentrations of brain-derived neurotrophic factor in the cerebrospinal fluid in both human umbilical cord mesenchymal stem cell groups were significantly greater than those in the saline group and persisted until the 28th day.Taken together,these results indicate that the intrathecal administration of human umbilical cord mesenchymal stem cells via cerebellomedullary cistern injection is safe and effective for the treatment of ischemic stroke in rats.The mechanisms may include alleviating the local inflammatory response in the peri-infarct region,promoting neurogenesis and angiogenesis,and enhancing the production of neurotrophic factors.展开更多
Background:Neurological disorders(NDs),including ischemic stroke(IS),Parkinson’s disease(PD),and Alzheimer’s disease(AD),are major contributors to global morbidity and mortality.Boswellia extract has demonstrated ne...Background:Neurological disorders(NDs),including ischemic stroke(IS),Parkinson’s disease(PD),and Alzheimer’s disease(AD),are major contributors to global morbidity and mortality.Boswellia extract has demonstrated neuroprotective properties,yet a comprehensive systematic review assessing its efficacy remains absent.This study aims to evaluate the efficacy of Boswellia extract in treating NDs,with a particular focus on its effects in AD and its potential for long-term neurorestoration,thereby supporting further investigation into Boswellia’s therapeutic role in ND management.Methods:A systematic literature search was performed in PubMed,Web of Science,ScienceDirect,and Google Scholar for English-language studies published up to March 2024.Eighteen studies met the inclusion criteria and were included in the meta-analysis.The study protocol was registered on PROSPERO(CRD42024524386).Eligible studies involved rodent models of IS,PD,or AD with post-operative interventions using Boswellia extract.Data extraction focused on mechanisms of action,dosages,treatment durations,and therapeutic outcomes.Studies were excluded if they involved non-ND models,combined treatments,or had incomplete data.Two researchers independently conducted literature screening and data extraction.Statistical analyses were conducted using Stata(version 17)and RevMan(version 5.4),employing fixed or random-effects models based on heterogeneity assessments.Result s:Boswellia extract significantly improved the mean effect size for NDs(ES=1.28,95%CI(1.05,1.51),P<0.001).Specifically,it reduced cerebral infarct volume in IS(SMD=−2.87,95%CI(−3.42,−2.32))and enhanced behavioral outcomes in AD(SMD=3.26,95%CI(2.07,5.14))and PD(SMD=5.37,95%CI(3.93,6.80)).Subgroup analyses revealed that Boswellia extract exhibited superior efficacy in AD when administered orally and via intra-cerebroventricular injection.Long-term treatment with Boswellia extract suggested potential neurorestorative effects.Additionally,Boswellia extract was more effective than its monomeric constituents,highlighting its promising role in ND treatment.Conclusion:Boswellia extract demonstrates significant neuroprotective effects across various NDs,particularly in AD and in promoting long-term neurorestoration.These findings support the need for further research into Boswellia’s potential as a therapeutic agent in the management of neurological disorders.展开更多
BACKGROUND Ischemic stroke is one of the leading global causes of disability and death.Despite advances in modern medical technology that improve acute treatment and rehabilitation measures,post-stroke anxiety and dep...BACKGROUND Ischemic stroke is one of the leading global causes of disability and death.Despite advances in modern medical technology that improve acute treatment and rehabilitation measures,post-stroke anxiety and depression(PSD)do not receive sufficient attention.AIM To systematically evaluate risk factors and early identification markers for PSD for more precise screening and intervention strategies in clinical practice.METHODS This retrospective study analyzed clinical data from 112 patients with ischemic stroke admitted between January 2022 and December 2024.Based on assessments using the Hamilton Rating Scale for Anxiety(HAMA)and Hamilton Rating Scale for Depression(HAMD)at 2 weeks(±3 days)post-stroke,patients were classified into the PSD group(HAMA≥7 and/or HAMD≥7)and the non-PSD group(HAMA<7 and HAMD<7).Observation indicators included psychological assessment,demographic and clinical characteristics,stroke-related clinical indicators,neuroimaging assessments,and laboratory biomarkers.Multivariate logistic regression analysis was used to identify independent risk factors for PSD,and receiver operating characteristic curve analysis was used to evaluate the diagnostic value of potential biomarkers.RESULTS Of the 112 patients,46(41.1%)were diagnosed with PSD.Multivariate analysis identified five independent risk factors:Female gender[Odds ratio(OR)=2.32,95%confidence interval(CI):1.56-3.45],history of mental disorders prior to stroke(OR=3.17,95%CI:1.89-5.32),infarct location in the frontal lobe or limbic system(OR=2.86,95%CI:1.73-4.71),stroke severity with National Institutes of Health Stroke Scale≥8 at admission(OR=2.54,95%CI:1.62-3.99),and low social support(Social Support Rating Scale<35,OR=2.18,95%CI:1.42-3.36).Subgroup analysis showed that depression patients more commonly had left hemisphere lesions(68.4%vs 45.2%),while anxiety patients more frequently presented with right hemisphere lesions(59.5%vs 39.5%).The PSD group exhibited larger infarct volumes(8.7 cm^(3) vs 5.3 cm^(3)),more severe white matter hyperintensities,and more pronounced frontal lobe atrophy.Analysis of inflammatory markers showed significantly elevated levels of interleukin-6(7.8 pg/mL vs 4.5 pg/mL)and tumor necrosis factor-alpha(15.6 pg/mL vs 9.8 pg/mL)in the PSD group,while hypothalamicpituitary-adrenal axis function assessment revealed higher cortisol levels(386.5±92.3 nmol/L vs 328.7±75.6 nmol/L)and flattened diurnal rhythm in the PSD group.CONCLUSION PSD is a complex neuropsychiatric consequence of stroke involving disruption of the frontal-limbic circuitry,neuroinflammatory responses,and dysfunction of the hypothalamic-pituitary-adrenal axis.展开更多
Kang et al.published a research article on the treatment of ischemic stroke using engineered Treg cells(Kang et al.,Prog Biochem Biophys,2025,52(4):946-956.DOI:10.16476/j.pibb.2025.0019).Their study mainly explores th...Kang et al.published a research article on the treatment of ischemic stroke using engineered Treg cells(Kang et al.,Prog Biochem Biophys,2025,52(4):946-956.DOI:10.16476/j.pibb.2025.0019).Their study mainly explores the immunoregulatory role of regulatory T(Treg)cells in ischemic stroke,providing an innovative therapeutic strategy.Neuroinflammation is a major driver of secondary injury after stroke.Existing treatments focus on vascular recanalization while neglecting immune regulation.Their study proposes to modulate neuroinflammation through in vitro-induced Treg cells,offering a novel approach distinct from traditional thrombolysis and endovascular interventions.展开更多
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 a...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.展开更多
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 i...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.展开更多
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.E...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.展开更多
Differentiation of oligodendrocyte progenitor cells into mature myelin-forming oligodendrocytes contributes to remyelination.Failure of remyelination due to oligodendrocyte progenitor cell death can result in severe n...Differentiation of oligodendrocyte progenitor cells into mature myelin-forming oligodendrocytes contributes to remyelination.Failure of remyelination due to oligodendrocyte progenitor cell death can result in severe nerve damage.Ferroptosis is an iron-dependent form of regulated cell death caused by membrane rupture induced by lipid peroxidation,and plays an important role in the pathological process of ischemic stroke.However,there are few studies on oligodendrocyte progenitor cell ferroptosis.We analyzed transcriptome sequencing data from GEO databases and identified a role of ferroptosis in oligodendrocyte progenitor cell death and myelin injury after cerebral ischemia.Bioinformatics analysis suggested that perilipin-2(PLIN2)was involved in oligodendrocyte progenitor cell ferroptosis.PLIN2 is a lipid storage protein and a marker of hypoxia-sensitive lipid droplet accumulation.For further investigation,we established a mouse model of cerebral ischemia/reperfusion.We found significant myelin damage after cerebral ischemia,as well as oligodendrocyte progenitor cell death and increased lipid peroxidation levels around the infarct area.The ferroptosis inhibitor,ferrostatin-1,rescued oligodendrocyte progenitor cell death and subsequent myelin injury.We also found increased PLIN2 levels in the peri-infarct area that co-localized with oligodendrocyte progenitor cells.Plin2 knockdown rescued demyelination and improved neurological deficits.Our findings suggest that targeting PLIN2 to regulate oligodendrocyte progenitor cell ferroptosis may be a potential therapeutic strategy for rescuing myelin damage after cerebral ischemia.展开更多
Neurotoxic astrocytes are a promising therapeutic target for the attenuation of cerebral ischemia/reperfusion injury.Low-density lipoprotein receptor,a classic cholesterol regulatory receptor,has been found to inhibit...Neurotoxic astrocytes are a promising therapeutic target for the attenuation of cerebral ischemia/reperfusion injury.Low-density lipoprotein receptor,a classic cholesterol regulatory receptor,has been found to inhibit NLR family pyrin domain containing protein 3(NLRP3)inflammasome activation in neurons following ischemic stroke and to suppress the activation of microglia and astrocytes in individuals with Alzheimer’s disease.However,little is known about the effects of low-density lipoprotein receptor on astrocytic activation in ischemic stroke.To address this issue in the present study,we examined the mechanisms by which low-density lipoprotein receptor regulates astrocytic polarization in ischemic stroke models.First,we examined low-density lipoprotein receptor expression in astrocytes via immunofluorescence staining and western blotting analysis.We observed significant downregulation of low-density lipoprotein receptor following middle cerebral artery occlusion reperfusion and oxygen-glucose deprivation/reoxygenation.Second,we induced the astrocyte-specific overexpression of low-density lipoprotein receptor using astrocyte-specific adeno-associated virus.Low-density lipoprotein receptor overexpression in astrocytes improved neurological outcomes in middle cerebral artery occlusion mice and reversed neurotoxic astrocytes to create a neuroprotective phenotype.Finally,we found that the overexpression of low-density lipoprotein receptor inhibited NLRP3 inflammasome activation in oxygen-glucose deprivation/reoxygenation injured astrocytes and that the addition of nigericin,an NLRP3 agonist,restored the neurotoxic astrocyte phenotype.These findings suggest that low-density lipoprotein receptor could inhibit the NLRP3-meidiated neurotoxic polarization of astrocytes and that increasing low-density lipoprotein receptor in astrocytes might represent a novel strategy for treating cerebral ischemic stroke.展开更多
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 inflamm...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.展开更多
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 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.展开更多
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 bioc...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.展开更多
基金supported by the National Natural Science Foundation of China,82471345(to LC)the Key Research and Development Program for Social Development by the Jiangsu Provincial Department of Science and Technology.No.BE2022668(to LC).
文摘Ischemic stroke is a major cause of neurological deficits and high disability rate.As the primary immune cells of the central nervous system,microglia play dual roles in neuroinflammation and tissue repair following a stroke.Their dynamic activation and polarization states are key factors that influence the disease process and treatment outcomes.This review article investigates the role of microglia in ischemic stroke and explores potential intervention strategies.Microglia exhibit a dynamic functional state,transitioning between pro-inflammatory(M1)and anti-inflammatory(M2)phenotypes.This duality is crucial in ischemic stroke,as it maintains a balance between neuroinflammation and tissue repair.Activated microglia contribute to neuroinflammation through cytokine release and disruption of the blood-brain barrier,while simultaneously promoting tissue repair through anti-inflammatory responses and regeneration.Key pathways influencing microglial activation include Toll-like receptor 4/nuclear factor kappa B,mitogen-activated protein kinases,Janus kinase/signal transducer and activator of transcription,and phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin pathways.These pathways are targets for various experimental therapies aimed at promoting M2 polarization and mitigating damage.Potential therapeutic agents include natural compounds found in drugs such as minocycline,as well as traditional Chinese medicines.Drugs that target these regulatory mechanisms,such as small molecule inhibitors and components of traditional Chinese medicines,along with emerging technologies such as single-cell RNA sequencing and spatial transcriptomics,offer new therapeutic strategies and clinical translational potential for ischemic stroke.
基金supported by the National Natural Science Foundation of China,Nos.82301093(to QC)and 22334004(to HY)the Fuzhou University Fund for Testing Precious Equipment,No.2025T038(to QC)。
文摘The mechanisms underlying the pathophysiology of ischemic stroke are complex and multifactorial and include excitotoxicity,oxidative stress,inflammatory responses,and blood–brain barrier disruption.While vascular recanalization treatments such as thrombolysis and mechanical thrombectomy have achieved some success,reperfusion injury remains a significant contributor to the exacerbation of brain injury.This emphasizes the need for developing neuroprotective strategies to mitigate this type of injury.The purpose of this review was to examine the application of nanotechnology in the treatment of ischemic stroke,covering research progress in nanoparticlebased drug delivery,targeted therapy,and antioxidant and anti-inflammatory applications.Nanobased drug delivery systems offer several advantages compared to traditional therapies,including enhanced blood–brain barrier penetration,prolonged drug circulation time,improved drug stability,and targeted delivery.For example,inorganic nanoparticles,such as those based on CeO_(2),have been widely studied for their strong antioxidant capabilities.Biomimetic nanoparticles,such as those coated with cell membranes,have garnered significant attention owing to their excellent biocompatibility and targeting abilities.Nanoparticles can be used to deliver a wide range of neuroprotective agents,such as antioxidants(e.g.,edaravone),anti-inflammatory drugs(e.g.,curcumin),and neurotrophic factors.Nanotechnology significantly enhances the efficacy of these drugs while minimizing adverse reactions.Although nanotechnology has demonstrated great potential in animal studies,its clinical application still faces several challenges,including the long-term safety of nanoparticles,the feasibility of large-scale production,quality control,and the ability to predict therapeutic effects in humans.In summary,nanotechnology holds significant promise for the treatment of ischemic stroke.Future research should focus on further exploring the mechanisms of action of nanoparticles,developing multifunctional nanoparticles,and validating their safety and efficacy through rigorous clinical trials.Moreover,interdisciplinary collaboration is essential for advancing the use of nanotechnology in stroke treatment.
基金supported by the National Natural Science Foundation of China,Nos.82174496(to NW),82374574(to NW),82302865(to LL)Shanghai Science and Technology Committee Sailing Program,Nos.23YF1403800(to LL),23YF1405200(to YX)Shanghai Hospital Development Center Foundation-Shanghai Municipal Hospital Rehabilitation Medicine Specialty Alliance,No.SHDC22023304(to YW).
文摘Stroke remains a leading cause of death and disability worldwide,and electroacupuncture has a long history of use in stroke treatment.This meta-analysis and systematic review aimed to evaluate the efficacy of electroacupuncture and explore its potential mechanisms in animal models of ischemic stroke.The PubMed,EMBASE,Web of Science,CENTRAL,and CINAHL databases were comprehensively searched up to May 1,2024.This review included articles on preclinical investigations of the efficacy and mechanisms of electroacupuncture in treating ischemic stroke.Data from 70 eligible studies were analyzed in Stata 18.0,using a random-effects model to calculate the standardized mean difference(Hedge’s g).The risk of bias was assessed using RevMan 5.4 software,and the quality of evidence was rated according to the Grading of Recommendations,Assessment,Development,and Evaluation(GRADE)system.Subgroup analyses were conducted to test the consistency of the results and sensitivity analyses were used to assess their robustness.The quality assessment revealed that most studies adequately handled incomplete data and selective reporting.However,several methodological limitations were identified:only 4 studies demonstrated a low risk of allocation concealment,26 achieved a low risk of outcome assessment bias,and 9 had a high risk of randomization bias.Additionally,there was an unclear risk regarding participant blinding and other methodological aspects.The GRADE assessment rated 12 outcomes as moderate quality and 6 as low quality.The mechanisms of electroacupuncture treatment for ischemic stroke can be categorized as five primary pathways:(1)Electroacupuncture significantly reduced infarct volume and apoptotic cell death(P<0.01)in ischemic stroke models;(2)electroacupuncture significantly decreased the levels of pro-inflammatory factors(P<0.01)while increasing the levels of anti-inflammatory factors(P=0.02);(3)electroacupuncture reduced the levels of oxidative stress indicators(P<0.01)and enhanced the expression of antioxidant enzymes(P<0.01);(4)electroacupuncture significantly promoted nerve regeneration(P<0.01);and(5)electroacupuncture influenced blood flow remodeling(P<0.01)and angiogenesis(P<0.01).Subgroup analyses indicated that electroacupuncture was most effective in the transient middle cerebral artery occlusion model(P<0.01)and in post-middle cerebral artery occlusion intervention(P<0.01).Dispersive waves were found to outperform continuous waves with respect to neuroprotection and anti-inflammatory effects(P<0.01),while scalp acupoints demonstrated greater efficacy than body acupoints(P<0.01).The heterogeneity among the included studies was minimal,and sensitivity analyses indicated stable results.Their methodological quality was generally satisfactory.In conclusion,electroacupuncture is effective in treating cerebral ischemia by modulating cell apoptosis,oxidative stress,inflammation,stroke-induced nerve regeneration,blood flow remodeling,and angiogenesis.The efficacy of electroacupuncture may be influenced by factors such as the middle cerebral artery occlusion model,the timing of intervention onset,waveform,and acupoint selection.Despite the moderate to low quality of evidence,these findings suggest that electroacupuncture has clinical potential for improving outcomes in ischemic stroke.
基金supported by Shanghai Shenkang Center Demonstration Research Ward Construction,No.SHDC2022CRW010(to MF)Shanghai Shenkang Center Medical Enterprise Integration and Innovation Collaborative Special Project,No.SHDC2022CRT018(to MF)+4 种基金Shanghai Health System Key Supported Discipline-Rehabilitation Medicine,No.2023ZDFC0301(to JT)Science and Technology Development Project of Shanghai University of Traditional Chinese Medicine,No.23KFL009(to JT)Shanghai Postdoctoral Excellence Program,No.2022515(to CY)Yangfan Special Project of Shanghai Science and Technology Innovation Action Plan,No.23YF1447600(to CY)China Postdoctoral Science Foundation,No.2023M732338(to CY).
文摘Ischemic stroke,which is characterized by hypoxia and ischemia,triggers a cascade of injury responses,including neurotoxicity,inflammation,oxidative stress,disruption of the blood-brain barrier,and neuronal death.In this context,tryptophan metabolites and enzymes,which are synthesized through the kynurenine and 5-hydroxytryptamine pathways,play dual roles.The delicate balance between neurotoxic and neuroprotective substances is a crucial factor influencing the progression of ischemic stroke.Neuroprotective metabolites,such as kynurenic acid,exert their effects through various mechanisms,including competitive blockade of N-methyl-D-aspartate receptors,modulation ofα7 nicotinic acetylcholine receptors,and scavenging of reactive oxygen species.In contrast,neurotoxic substances such as quinolinic acid can hinder the development of vascular glucose transporter proteins,induce neurotoxicity mediated by reactive oxygen species,and disrupt mitochondrial function.Additionally,the enzymes involved in tryptophan metabolism play major roles in these processes.Indoleamine 2,3-dioxygenase in the kynurenine pathway and tryptophan hydroxylase in the 5-hydroxytryptamine pathway influence neuroinflammation and brain homeostasis.Consequently,the metabolites generated through tryptophan metabolism have substantial effects on the development and progression of ischemic stroke.Stroke treatment aims to restore the balance of various metabolite levels;however,precise regulation of tryptophan metabolism within the central nervous system remains a major challenge for the treatment of ischemic stroke.Therefore,this review aimed to elucidate the complex interactions between tryptophan metabolites and enzymes in ischemic stroke and develop targeted therapies that can restore the delicate balance between neurotoxicity and neuroprotection.
基金supported by the China Postdoctoral Science Foundation,No.2022M712689the Natural Science Foundation of the Jiangsu Higher Education Institutions of China,No.22KJB1800029+1 种基金The University Student Innovation Project of Yangzhou University,No.XCX20240856The Jiangsu Provincial Science and Technology Talent Project,No.FZ20240964(all to TX).
文摘Ischemic stroke is a serious medical event that cannot be predicted in advance and can have longlasting effects on patients,families,and communities.A deeper understanding of the changes in gene expression and the fundamental molecular mechanisms involved could help address this critical issue.In recent years,research into regulatory long non-coding(lnc)RNAs,a diverse group of RNA molecules with regulatory functions,has emerged as a promising direction in the study of cerebral infarction.This review paper aims to provide a comprehensive exploration of the roles of regulatory lncRNAs in cerebral infarction,as well as potential strategies for their application in clinical settings.LncRNAs have the potential to act as“sponges”that attract specific microRNAs,thereby regulating the expression of microRNA target genes.These interactions influence various aspects of ischemic stroke,including reperfusion-induced damage,cell death,immune responses,autophagy,angiogenesis,and the generation of reactive oxygen species.We highlight several regulatory lncRNAs that have been utilized in animal model treatments,including lncRNA NKILA,lncRNA Meg8,and lncRNA H19.Additionally,we discuss lncRNAs that have been used as biomarkers for the diagnosis and prognosis of cerebral infarction,such as lncRNA FOXO3,lncRNA XIST,and lncRNA RMST.The lncRNAs hold potential for genetic-level treatments in patients.However,numerous challenges,including inefficiency,low targeting accuracy,and side effects observed in preliminary studies,indicate the need for thorough investigation.The application of lncRNAs in ischemic stroke presents challenges that require careful and extensive validation.
基金supported by the National Key Research and Development Program of China,No.2018YFA0108602the CAMS Initiative for Innovative Medicine,No.2021-1-I2M-019National High-Level Hospital Clinical Research Funding,No.2022-PUMCH-C-042(all to XB)。
文摘Ischemic stroke is a significant global health crisis,frequently resulting in disability or death,with limited therapeutic interventions available.Although various intrinsic reparative processes are initiated within the ischemic brain,these mechanisms are often insufficient to restore neuronal functionality.This has led to intensive investigation into the use of exogenous stem cells as a potential therapeutic option.This comprehensive review outlines the ontogeny and mechanisms of activation of endogenous neural stem cells within the adult brain following ischemic events,with focus on the impact of stem cell-based therapies on neural stem cells.Exogenous stem cells have been shown to enhance the proliferation of endogenous neural stem cells via direct cell-tocell contact and through the secretion of growth factors and exosomes.Additionally,implanted stem cells may recruit host stem cells from their niches to the infarct area by establishing so-called“biobridges.”Furthermore,xenogeneic and allogeneic stem cells can modify the microenvironment of the infarcted brain tissue through immunomodulatory and angiogenic effects,thereby supporting endogenous neuroregeneration.Given the convergence of regulatory pathways between exogenous and endogenous stem cells and the necessity for a supportive microenvironment,we discuss three strategies to simultaneously enhance the therapeutic efficacy of both cell types.These approaches include:(1)co-administration of various growth factors and pharmacological agents alongside stem cell transplantation to reduce stem cell apoptosis;(2)synergistic administration of stem cells and their exosomes to amplify paracrine effects;and(3)integration of stem cells within hydrogels,which provide a protective scaffold for the implanted cells while facilitating the regeneration of neural tissue and the reconstitution of neural circuits.This comprehensive review highlights the interactions and shared regulatory mechanisms between endogenous neural stem cells and exogenously implanted stem cells and may offer new insights for improving the efficacy of stem cell-based therapies in the treatment of ischemic stroke.
基金supported by the National Natural Science Foundation of China,Nos.81870921(to YW),81974179(to ZZ),82271320(to ZZ),82071284(to YT)National Key R&D Program of China,No.2022YFA1603600(to ZZ),2019YFA0112000(to YT)+1 种基金Scientific Research and Innovation Program of Shanghai Education Commission,No.2019-01-07-00-02-E00064(to GYY)Scientific and Technological Innovation Act Program of Shanghai Science and Technology Commission,No.20JC1411900(to GYY).
文摘AAV-PHP.eB is an artificial adeno-associated virus(AAV)that crosses the blood-brain barrier and targets neurons more efficiently than other AAVs when administered systematically.While AAV-PHP.eB has been used in various disease models,its cellular tropism in cerebrovascular diseases remains unclear.In the present study,we aimed to elucidate the tropism of AAV-PHP.eB for different cell types in the brain in a mouse model of ischemic stroke and evaluate its effectiveness in mediating basic fibroblast growth factor(bFGF)gene therapy.Mice were injected intravenously with AAV-PHP.eB either 14 days prior to(pre-stroke)or 1 day following(post-stroke)transient middle cerebral artery occlusion.Notably,we observed a shift in tropism from neurons to endothelial cells with post-stroke administration of AAV-PHP.eB-mNeonGreen(mNG).This endothelial cell tropism correlated strongly with expression of the endothelial membrane receptor lymphocyte antigen 6 family member A(Ly6A).Furthermore,AAV-PHP.eB-mediated overexpression of bFGF markedly improved neurobehavioral outcomes and promoted long-term neurogenesis and angiogenesis post-ischemic stroke.Our findings underscore the significance of considering potential tropism shifts when utilizing AAV-PHP.eB-mediated gene therapy in neurological diseases and suggest a promising new strategy for bFGF gene therapy in stroke treatment.
基金supported by the National Natural Science Foundation of China,Nos.82171456(to QY)and 81971229(to QY)the Natural Science Foundation of Chongqing,Nos.CSTC2021JCYJ-MSXMX0263(to QY)and CSTB2023NSCQ-MSX1015(to XL)Doctoral Innovation Project of The First Affiliated Hospital of Chongqing Medical University,Nos.CYYY-BSYJSCXXM-202318(to JW)and CYYY-BSYJSCXXM-202327(to HT).
文摘Recent studies have shown that fibrotic scar formation following cerebral ischemic injury has varying effects depending on the microenvironment.However,little is known about how fibrosis is induced and regulated after cerebral ischemic injury.Sonic hedgehog signaling participates in fibrosis in the heart,liver,lung,and kidney.Whether Shh signaling modulates fibrotic scar formation after cerebral ischemic stroke and the underlying mechanisms are unclear.In this study,we found that Sonic Hedgehog expression was upregulated in patients with acute ischemic stroke and in a middle cerebral artery occlusion/reperfusion injury rat model.Both Sonic hedgehog and Mitofusin 2 showed increased expression in the middle cerebral artery occlusion rat model and in vitro fibrosis cell model induced by transforming growth factor-beta 1.Activation of the Sonic hedgehog signaling pathway enhanced the expression of phosphorylated Smad 3 and Mitofusin 2 proteins,promoted the formation of fibrotic scars,protected synapses or promoted synaptogenesis,alleviated neurological deficits following middle cerebral artery occlusion/reperfusion injury,reduced cell apoptosis,facilitated the transformation of meninges fibroblasts into myofibroblasts,and enhanced the proliferation and migration of meninges fibroblasts.The Smad3 phosphorylation inhibitor SIS3 reversed the effects induced by Sonic hedgehog signaling pathway activation.Bioinformatics analysis revealed significant correlations between Sonic hedgehog and Smad3,between Sonic hedgehog and Mitofusin 2,and between Smad3 and Mitofusin 2.These findings suggest that Sonic hedgehog signaling may influence Mitofusin 2 expression by regulating Smad3 phosphorylation,thereby modulating the formation of early fibrotic scars following cerebral ischemic stroke and affecting prognosis.The Sonic Hedgehog signaling pathway may serve as a new therapeutic target for stroke treatment.
基金supported by the Medicine-Engineering Interdisciplinary Project of Sun Yat-sen Memorial Hospital,China,No.YXYGRH202203(to YW)Key-Area Research and Development Program of Guangdong Province,China,No.2023B1111050003(to HC)Guangzhou Science and Technology Talent Project of China,No.201909020006(to HC).
文摘Intrathecal administration of human umbilical cord mesenchymal stem cells may be a promising approach for the treatment of stroke,but its safety,effectiveness,and mechanism remain to be elucidated.In this study,good manufacturing practice-grade human umbilical cord mesenchymal stem cells(5×105 and 1×106 cells)and saline were administered by cerebellomedullary cistern injection 72 hours after stroke induced by middle cerebral artery occlusion in rats.The results showed(1)no significant difference in mortality or general conditions among the three groups.There was no abnormal differentiation or tumor formation in various organs of rats in any group.(2)Compared with saline-treated animals,those treated with human umbilical cord mesenchymal stem cells showed significant functional recovery and reduced infarct volume,with no significant differences between different human umbilical cord mesenchymal stem cell doses.(3)Human umbilical cord mesenchymal stem cells were found in the ischemic brain after 14 and 28 days of follow-up,and the number of positive cells significantly decreased over time.(4)Neuronal nuclei expression in the human umbilical cord mesenchymal stem cell group was greater than that in the saline group,while glial fibrillary acidic protein and ionized calcium binding adaptor molecule 1 expression levels decreased.(5)Human umbilical cord mesenchymal stem cell treatment increased the number of CD31+microvessels and doublecortin-positive cells after ischemic stroke.Human umbilical cord mesenchymal stem cells also upregulated the expression of CD31+/Ki67+.(6)At 14 days after intrathecal administration,brain-derived neurotrophic factor expression in the peri-infarct area and the concentrations of brain-derived neurotrophic factor in the cerebrospinal fluid in both human umbilical cord mesenchymal stem cell groups were significantly greater than those in the saline group and persisted until the 28th day.Taken together,these results indicate that the intrathecal administration of human umbilical cord mesenchymal stem cells via cerebellomedullary cistern injection is safe and effective for the treatment of ischemic stroke in rats.The mechanisms may include alleviating the local inflammatory response in the peri-infarct region,promoting neurogenesis and angiogenesis,and enhancing the production of neurotrophic factors.
基金supported by the National Natural Science Foundation of China,specifically through grants(No.8227431382304947)Key Research and Development Project of Shaanxi Province(2023GHZD43).Peer re v iew information。
文摘Background:Neurological disorders(NDs),including ischemic stroke(IS),Parkinson’s disease(PD),and Alzheimer’s disease(AD),are major contributors to global morbidity and mortality.Boswellia extract has demonstrated neuroprotective properties,yet a comprehensive systematic review assessing its efficacy remains absent.This study aims to evaluate the efficacy of Boswellia extract in treating NDs,with a particular focus on its effects in AD and its potential for long-term neurorestoration,thereby supporting further investigation into Boswellia’s therapeutic role in ND management.Methods:A systematic literature search was performed in PubMed,Web of Science,ScienceDirect,and Google Scholar for English-language studies published up to March 2024.Eighteen studies met the inclusion criteria and were included in the meta-analysis.The study protocol was registered on PROSPERO(CRD42024524386).Eligible studies involved rodent models of IS,PD,or AD with post-operative interventions using Boswellia extract.Data extraction focused on mechanisms of action,dosages,treatment durations,and therapeutic outcomes.Studies were excluded if they involved non-ND models,combined treatments,or had incomplete data.Two researchers independently conducted literature screening and data extraction.Statistical analyses were conducted using Stata(version 17)and RevMan(version 5.4),employing fixed or random-effects models based on heterogeneity assessments.Result s:Boswellia extract significantly improved the mean effect size for NDs(ES=1.28,95%CI(1.05,1.51),P<0.001).Specifically,it reduced cerebral infarct volume in IS(SMD=−2.87,95%CI(−3.42,−2.32))and enhanced behavioral outcomes in AD(SMD=3.26,95%CI(2.07,5.14))and PD(SMD=5.37,95%CI(3.93,6.80)).Subgroup analyses revealed that Boswellia extract exhibited superior efficacy in AD when administered orally and via intra-cerebroventricular injection.Long-term treatment with Boswellia extract suggested potential neurorestorative effects.Additionally,Boswellia extract was more effective than its monomeric constituents,highlighting its promising role in ND treatment.Conclusion:Boswellia extract demonstrates significant neuroprotective effects across various NDs,particularly in AD and in promoting long-term neurorestoration.These findings support the need for further research into Boswellia’s potential as a therapeutic agent in the management of neurological disorders.
文摘BACKGROUND Ischemic stroke is one of the leading global causes of disability and death.Despite advances in modern medical technology that improve acute treatment and rehabilitation measures,post-stroke anxiety and depression(PSD)do not receive sufficient attention.AIM To systematically evaluate risk factors and early identification markers for PSD for more precise screening and intervention strategies in clinical practice.METHODS This retrospective study analyzed clinical data from 112 patients with ischemic stroke admitted between January 2022 and December 2024.Based on assessments using the Hamilton Rating Scale for Anxiety(HAMA)and Hamilton Rating Scale for Depression(HAMD)at 2 weeks(±3 days)post-stroke,patients were classified into the PSD group(HAMA≥7 and/or HAMD≥7)and the non-PSD group(HAMA<7 and HAMD<7).Observation indicators included psychological assessment,demographic and clinical characteristics,stroke-related clinical indicators,neuroimaging assessments,and laboratory biomarkers.Multivariate logistic regression analysis was used to identify independent risk factors for PSD,and receiver operating characteristic curve analysis was used to evaluate the diagnostic value of potential biomarkers.RESULTS Of the 112 patients,46(41.1%)were diagnosed with PSD.Multivariate analysis identified five independent risk factors:Female gender[Odds ratio(OR)=2.32,95%confidence interval(CI):1.56-3.45],history of mental disorders prior to stroke(OR=3.17,95%CI:1.89-5.32),infarct location in the frontal lobe or limbic system(OR=2.86,95%CI:1.73-4.71),stroke severity with National Institutes of Health Stroke Scale≥8 at admission(OR=2.54,95%CI:1.62-3.99),and low social support(Social Support Rating Scale<35,OR=2.18,95%CI:1.42-3.36).Subgroup analysis showed that depression patients more commonly had left hemisphere lesions(68.4%vs 45.2%),while anxiety patients more frequently presented with right hemisphere lesions(59.5%vs 39.5%).The PSD group exhibited larger infarct volumes(8.7 cm^(3) vs 5.3 cm^(3)),more severe white matter hyperintensities,and more pronounced frontal lobe atrophy.Analysis of inflammatory markers showed significantly elevated levels of interleukin-6(7.8 pg/mL vs 4.5 pg/mL)and tumor necrosis factor-alpha(15.6 pg/mL vs 9.8 pg/mL)in the PSD group,while hypothalamicpituitary-adrenal axis function assessment revealed higher cortisol levels(386.5±92.3 nmol/L vs 328.7±75.6 nmol/L)and flattened diurnal rhythm in the PSD group.CONCLUSION PSD is a complex neuropsychiatric consequence of stroke involving disruption of the frontal-limbic circuitry,neuroinflammatory responses,and dysfunction of the hypothalamic-pituitary-adrenal axis.
文摘Kang et al.published a research article on the treatment of ischemic stroke using engineered Treg cells(Kang et al.,Prog Biochem Biophys,2025,52(4):946-956.DOI:10.16476/j.pibb.2025.0019).Their study mainly explores the immunoregulatory role of regulatory T(Treg)cells in ischemic stroke,providing an innovative therapeutic strategy.Neuroinflammation is a major driver of secondary injury after stroke.Existing treatments focus on vascular recanalization while neglecting immune regulation.Their study proposes to modulate neuroinflammation through in vitro-induced Treg cells,offering a novel approach distinct from traditional thrombolysis and endovascular interventions.
基金supported by the National Natural Science Foundation of China,Nos.82274313(to YD),82204746(to ML),82003982(to TL).
文摘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.
基金supported by the National Natural Science Foundation of China,Nos.82104560(to CL),U21A20400(to QW)the Natural Science Foundation of Beijing,No.7232279(to XW)the Project of Beijing University of Chinese Medicine,No.2022-JYB-JBZR-004(to XW)。
文摘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.
基金supported by the National Natural Science Foundation of China,Nos.82071291(to YY),82301464(to HM)the Norman Bethune Health Science Center of Jilin University,No.2022JBGS03(to YY)+2 种基金a grant from Department of Science and Technology of Jilin Province,Nos.YDZJ202302CXJD061(to YY),20220303002SF(to YY)a grant from Jilin Provincial Key Laboratory,No.YDZJ202302CXJD017(to YY)Talent Reserve Program of First Hospital of Jilin University,No.JDYYCB-2023002(to ZNG)。
文摘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.
基金supported by the National Natural Science Foundation of China,Nos.82071307(to HL),82271362(to HL),82171294(to JW),82371303(to JW),and 82301460(to PX)the Natural Science Foundation of Jiangsu Province,No.BK20211552(to HL)+1 种基金Suzhou Medical Technology Innovation Project-Clinical Frontier,No.SKY2022002(to ZY)the Science and Education Foundation for Health of Suzhou for Youth,No.KJXW2023001(to XL)。
文摘Differentiation of oligodendrocyte progenitor cells into mature myelin-forming oligodendrocytes contributes to remyelination.Failure of remyelination due to oligodendrocyte progenitor cell death can result in severe nerve damage.Ferroptosis is an iron-dependent form of regulated cell death caused by membrane rupture induced by lipid peroxidation,and plays an important role in the pathological process of ischemic stroke.However,there are few studies on oligodendrocyte progenitor cell ferroptosis.We analyzed transcriptome sequencing data from GEO databases and identified a role of ferroptosis in oligodendrocyte progenitor cell death and myelin injury after cerebral ischemia.Bioinformatics analysis suggested that perilipin-2(PLIN2)was involved in oligodendrocyte progenitor cell ferroptosis.PLIN2 is a lipid storage protein and a marker of hypoxia-sensitive lipid droplet accumulation.For further investigation,we established a mouse model of cerebral ischemia/reperfusion.We found significant myelin damage after cerebral ischemia,as well as oligodendrocyte progenitor cell death and increased lipid peroxidation levels around the infarct area.The ferroptosis inhibitor,ferrostatin-1,rescued oligodendrocyte progenitor cell death and subsequent myelin injury.We also found increased PLIN2 levels in the peri-infarct area that co-localized with oligodendrocyte progenitor cells.Plin2 knockdown rescued demyelination and improved neurological deficits.Our findings suggest that targeting PLIN2 to regulate oligodendrocyte progenitor cell ferroptosis may be a potential therapeutic strategy for rescuing myelin damage after cerebral ischemia.
基金supported by the National Natural Science Foundation of China,No.82201460(to YH)Nanjing Medical University Science and Technology Development Fund,No.NMUB20210202(to YH).
文摘Neurotoxic astrocytes are a promising therapeutic target for the attenuation of cerebral ischemia/reperfusion injury.Low-density lipoprotein receptor,a classic cholesterol regulatory receptor,has been found to inhibit NLR family pyrin domain containing protein 3(NLRP3)inflammasome activation in neurons following ischemic stroke and to suppress the activation of microglia and astrocytes in individuals with Alzheimer’s disease.However,little is known about the effects of low-density lipoprotein receptor on astrocytic activation in ischemic stroke.To address this issue in the present study,we examined the mechanisms by which low-density lipoprotein receptor regulates astrocytic polarization in ischemic stroke models.First,we examined low-density lipoprotein receptor expression in astrocytes via immunofluorescence staining and western blotting analysis.We observed significant downregulation of low-density lipoprotein receptor following middle cerebral artery occlusion reperfusion and oxygen-glucose deprivation/reoxygenation.Second,we induced the astrocyte-specific overexpression of low-density lipoprotein receptor using astrocyte-specific adeno-associated virus.Low-density lipoprotein receptor overexpression in astrocytes improved neurological outcomes in middle cerebral artery occlusion mice and reversed neurotoxic astrocytes to create a neuroprotective phenotype.Finally,we found that the overexpression of low-density lipoprotein receptor inhibited NLRP3 inflammasome activation in oxygen-glucose deprivation/reoxygenation injured astrocytes and that the addition of nigericin,an NLRP3 agonist,restored the neurotoxic astrocyte phenotype.These findings suggest that low-density lipoprotein receptor could inhibit the NLRP3-meidiated neurotoxic polarization of astrocytes and that increasing low-density lipoprotein receptor in astrocytes might represent a novel strategy for treating cerebral ischemic stroke.
基金supported by grants from the Major Program of National Key Research and Development Project,Nos.2020YFA0112600(to ZH)the National Natural Science Foundation of China,No.82171270(to ZL)+5 种基金Public Service Platform for Artificial Intelligence Screening and Auxiliary Diagnosis for the Medical and Health Industry,Ministry of Industry and Information Technology of the People’s Republic of China,No.2020-0103-3-1(to ZL)the Natural Science Foundation of Beijing,No.Z200016(to ZL)Beijing Talents Project,No.2018000021223ZK03(to ZL)Beijing Municipal Committee of Science and Technology,No.Z201100005620010(to ZL)CAMS Innovation Fund for Medical Sciences,No.2019-I2M-5-029(to YW)Shanghai Engineering Research Center of Stem Cells Translational Medicine,No.20DZ2255100(to ZH).
文摘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.
基金supported by the grants from the Spanish Ministry of Economy and Competitiveness(SAF2017-85602-R)the Spanish Ministry of Science and Innovation(PID2020-119638RB-I00 to EGR)FPU-program(FPU17/02616 to JCG)。
文摘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.
基金supported by the grants from University of Macao,China,Nos.MYRG2022-00221-ICMS(to YZ)and MYRG-CRG2022-00011-ICMS(to RW)the Natural Science Foundation of Guangdong Province,No.2023A1515010034(to YZ)。
文摘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.
