Pathophysiology Of Ischemic Stroke Research Articles

Transcriptome Analysis Reveals Dynamic Microglial-Induced A1 Astrocyte Reactivity via C3/C3aR/NF-κB Signaling After Ischemic Stroke.

Microglia and astrocytes are key players in neuroinflammation and ischemic stroke. A1 astrocytes are a subtype of astrocytes that are extremely neurotoxic and quickly kill neurons. Although the detrimental A1 astrocytes are present in many neurodegenerative diseases and are considered to accelerate neurodegeneration, their role in the pathophysiology of ischemic stroke is poorly understood. Here, we combined RNA-seq, molecular and immunological techniques, and behavioral tests to investigate the role of A1 astrocytes in the pathophysiology of ischemic stroke. We found that astrocyte phenotypes change from a beneficial A2 type in the acute phase to a detrimental A1 type in the chronic phase following ischemic stroke. The activated microglial IL1α, TNF, and C1q prompt commitment of A1 astrocytes. Inhibition of A1 astrocytes induction attenuates reactive gliosis and ameliorates morphological and functional defects following ischemic stroke. The crosstalk between astrocytic C3 and microglial C3aR contributes to the formation of A1 astrocytes and morphological and functional defects. In addition, NF-κB is activated following ischemic stroke and governs the formation of A1 astrocytes via direct targeting of inflammatory cytokines and chemokines. Taken together, we discovered that A2 astrocytes and A1 astrocytes are enriched in the acute and chronic phases of ischemic stroke respectively, and that the C3/C3aR/NF-κB signaling leads to A1 astrocytes induction. Therefore, the C3/C3aR/NF-κB signaling is a novel therapeutic target for ischemic stroke treatment.

The case for neuregulin-1 as a clinical treatment for stroke.

Ischemic stroke is the leading cause of serious long-term disability and the 5th leading cause of death in the United States. Revascularization of the occluded cerebral artery, either by thrombolysis or endovascular thrombectomy, is the only effective, clinically-approved stroke therapy. Several potentially neuroprotective agents, including glutamate antagonists, anti-inflammatory compounds and free radical scavenging agents were shown to be effective neuroprotectants in preclinical animal models of brain ischemia. However, these compounds did not demonstrate efficacy in clinical trials with human patients following stroke. Proposed reasons for the translational failure include an insufficient understanding on the cellular and molecular pathophysiology of ischemic stroke, lack of alignment between preclinical and clinical studies and inappropriate design of clinical trials based on the preclinical findings. Therefore, novel neuroprotective treatments must be developed based on a clearer understanding of the complex spatiotemporal mechanisms of ischemic stroke and with proper clinical trial design based on the preclinical findings from specific animal models of stroke. We and others have demonstrated the clinical potential for neuregulin-1 (NRG-1) in preclinical stroke studies. NRG-1 significantly reduced ischemia-induced neuronal death, neuroinflammation and oxidative stress in rodent stroke models with a therapeutic window of >13 h. Clinically, NRG-1 was shown to be safe in human patients and improved cardiac function in multisite phase II studies for heart failure. This review summarizes previous stroke clinical candidates and provides evidence that NRG-1 represents a novel, safe, neuroprotective strategy that has potential therapeutic value in treating individuals after acute ischemic stroke.

N6022 attenuates cerebral ischemia/reperfusion injury-induced microglia ferroptosis by promoting Nrf2 nuclear translocation and inhibiting the GSNOR/GSTP1 axis

Stroke poses a significant risk of mortality, particularly among the elderly population. The pathophysiological process of ischemic stroke is complex, and it is crucial to elucidate its molecular mechanisms and explore potential protective drugs. Ferroptosis, a newly recognized form of programmed cell death distinct from necrosis, apoptosis, and autophagy, is closely associated with the pathophysiology of ischemic stroke. N6022, a selective inhibitor of S-nitrosoglutathione reductase (GSNOR), is a “first-in-class” drug for asthma with potential therapeutic applications. However, it remains unclear whether N6022 exerts protective effects in ischemic stroke, and the precise mechanisms of its action are unknown. This study aimed to investigate whether N6022 mitigates cerebral ischemia/reperfusion (I/R) injury by reducing ferroptosis and to elucidate the underlying mechanisms. Accordingly, we established an oxygen-glucose deprivation/reperfusion (OGD/R) cell model and a middle cerebral artery occlusion/reperfusion (MCAO/R) mouse model to mimic cerebral I/R injury. Our data, both in vitro and in vivo, demonstrated that N6022 effectively protected against I/R-induced brain damage and neurological deficits in mice, as well as OGD/R-induced BV2 cell damage. Mechanistically, N6022 promoted Nrf2 nuclear translocation, enhancing intracellular antioxidant capacity of SLC7A11-GPX4 system. Furthermore, N6022 interfered with the interaction of GSNOR with GSTP1, thereby boosting the antioxidant capacity of GSTP1 and attenuating ferroptosis. These findings provide novel insights, showing that N6022 attenuates microglial ferroptosis induced by cerebral I/R injury through the promotion of Nrf2 nuclear translocation and inhibition of the GSNOR/GSTP1 axis.

Ischemic stroke pathophysiology: A bibliometric and visualization analysis from 1990 to 2022

BackgroundPathophysiology plays a significant role in the scientific study of ischemic stroke, and has attracted increasing interest from researchers in the field. However, a comprehensive bibliometric analysis is lacking in this field. The purpose of this study is to identify the current research status and hotspots of ischemic stroke pathophysiology from a bibliometric perspective. MethodsThe Web of Science Core Collection database was searched for articles published from 1990 to 2022. CiteSpace, VOSviewer, and R package “bibliometrix” software were used to analyze countries/regions, institutions, journals, authors, papers, and keywords to predict the latest trends in ischemic stroke pathophysiology research. ResultsThis analysis collected 7578 records of ischemic stroke pathophysiology. China and America emerged as the leading countries in this field, with Harvard University being the most active institution. Among journals and authors in this field, journal Stroke and author Gregory YH Lip published the most papers, while Nature Medicine was the journal with the highest citation per article. Keywords and co-citation clusters were closely related to “central nervous system”, “mechanisms”, “biochemistry & molecular biology” and “radiology, nuclear medicine & medical imaging”, while other related fields, such as peripheral organs damage induced by the central nervous system and rehabilitation after ischemic stroke, require further research efforts. ConclusionThis is the first bibliometric study that comprehensively mapped out the knowledge structure and development trends of ischemic stroke pathophysiology in recent 32 years, which may provide a reference for scholars to explore ischemic stroke pathophysiology.

Arresting the bad seed: HDAC3 regulates proliferation of different microglia after ischemic stroke.

The accumulation of self-renewed polarized microglia in the penumbra is a critical neuroinflammatory process after ischemic stroke, leading to secondary demyelination and neuronal loss. Although known to regulate tumor cell proliferation and neuroinflammation, HDAC3's role in microgliosis and microglial polarization remains unclear. We demonstrated that microglial HDAC3 knockout (HDAC3-miKO) ameliorated poststroke long-term functional and histological outcomes. RNA-seq analysis revealed mitosis as the primary process affected in HDAC3-deficent microglia following stroke. Notably, HDAC3-miKO specifically inhibited proliferation of proinflammatory microglia without affecting anti-inflammatory microglia, preventing microglial transition to a proinflammatory state. Moreover, ATAC-seq showed that HDAC3-miKO induced closing of accessible regions enriched with PU.1 motifs. Overexpressing microglial PU.1 via an AAV approach reversed HDAC3-miKO-induced proliferation inhibition and protective effects on ischemic stroke, indicating PU.1 as a downstream molecule that mediates HDAC3's effects on stroke. These findings uncovered that HDAC3/PU.1 axis, which mediated differential proliferation-related reprogramming in different microglia populations, drove poststroke inflammatory state transition, and contributed to pathophysiology of ischemic stroke.

Understanding the Pathophysiology of Ischemic Stroke: The Basis of Current Therapies and Opportunity for New Ones.

The majority of approved therapies for many diseases are developed to target their underlying pathophysiology. Understanding disease pathophysiology has thus proven vital to the successful development of clinically useful medications. Stroke is generally accepted as the leading cause of adult disability globally and ischemic stroke accounts for the most common form of the two main stroke types. Despite its health and socioeconomic burden, there is still minimal availability of effective pharmacological therapies for its treatment. In this review, we take an in-depth look at the etiology and pathophysiology of ischemic stroke, including molecular and cellular changes. This is followed by a highlight of drugs, cellular therapies, and complementary medicines that are approved or undergoing clinical trials for the treatment and management of ischemic stroke. We also identify unexplored potential targets in stroke pathogenesis that can be exploited to increase the pool of effective anti-stroke and neuroprotective agents through de novo drug development and drug repurposing.

Association of the Neutrophil-to-Lymphocyte Ratio with 90-Day Functional Outcomes in Patients with Acute Ischemic Stroke.

The neutrophil-to-lymphocyte ratio (NLR), an inflammatory marker, plays an important role in the inflammatory mechanisms of the pathophysiology and progression of acute ischemic stroke (AIS). The aim of this study was to identify the potential factors associated with functional prognosis in AIS. A total of 303 AIS patients were enrolled in this study; baseline information of each participant, including demographic characteristics, medical history, laboratory data, and 90-day functional outcome, was collected. Multivariate logistic regression analysis revealed that NLR, systolic blood pressure (SBP) and National Institutes of Health Stroke Scale (NIHSS) score were found to be independent factors for poor functional outcomes. Receiver operating characteristic (ROC) curve analysis was performed to estimate the predictive value of the NLR for 90-day functional outcome, with the best predictive cutoff value being 3.06. In the multivariate logistic regression analysis, three models were constructed: Model 1, adjusted for age, sex, SBP, and TOAST classification (AUC = 0.694); Model 2, further adjusted for the NIHSS score at admission (AUC = 0.826); and Model 3, additionally adjusted for the NLR (AUC = 0.829). The NLR at admission was an independent predictor of 90-day prognosis in patients with AIS. The risk factors related to poor 90-day functional outcomes were higher SBP, higher NLR, and a greater NIHSS score.

Cerebroprotective effects of khellin: validation through computational studies in a bilateral common carotid artery occlusion/reperfusion (BCCAO/R) model

ABSTRACT This study investigates the molecular interactions between khellin and nitric oxide synthase, which plays a significant role in the pathophysiology of acute ischemic stroke. Molecular docking, dynamic simulation, and in vivo approaches were used to explore these interactions, revealing that khellin has a superior binding affinity for nitric oxide synthase compared to its co-crystallized ligand. The cerebroprotective effect of khellin was evaluated in a rat model of cerebral stroke induced by bilateral common carotid artery occlusion and reperfusion (BCCAO/R), and the results showed that khellin treatment significantly decreased infarct size, increased antioxidant levels, decreased oxidative stress, and improved EEG function. Histological analysis also revealed increased pyramidal cell layer thickness and reduced apoptosis in the hippocampus. These findings suggest that khellin may be a promising therapeutic agent for cerebral ischemia by targeting the nitric oxide synthase-nitric oxide pathway.

MRPS9-Mediated Regulation of the PI3K/Akt/mTOR Pathway Inhibits Neuron Apoptosis and Protects Ischemic Stroke.

Neuronal apoptosis is crucial in the pathophysiology of ischemic stroke (IS), albeit its underly24ing mechanism remaining elusive. Investigating the mechanism of neuronal apoptosis in the context of IS holds substantial clinical value for enhancing the prognosis of IS patients. Notably, the MRPS9 gene plays a pivotal role in regulating mitochondrial function and maintaining structural integrity. Utilizing bioinformatic tactics and the extant gene expression data related to IS, we conducted differential analysis and weighted correlation network analysis (WGCNA) to select important modules. Subsequent gene interaction analysis via the STRING website facilitated the identification of the key gene-mitochondrial ribosomal protein S9 (MRPS9)-that affects the progression of IS. Moreover, possible downstream signaling pathways, namely PI3K/Akt/mTOR, were elucidated via Kyoto Encyclopedia of Gene and Genomes (KEGG) and Gene Ontology (GO) pathway analysis. Experimental models were established utilizing oxygen-glucose deprivation/reoxygenation (OGD/R) in vitro and middle cerebral artery occlusion/reperfusion (MCAO/R) in mice. Changes in gene and protein expression, as well as cell proliferation and apoptosis, were monitored through qPCR, WB, CCK8, and flow cytometry. An OGD/R cell model was further employed to investigate the role of MRPS9 in IS post transfusion of MRPS9 overexpression plasmids into cells. Further studies were conducted by transfecting overexpressed cells with PI3K/Akt/mTOR signaling pathway inhibitor LY294002 to unveil the mechanism of MRPS9 in IS. Bioinformatic analysis revealed a significant underexpression of MRPS9 in ischemic stroke patients. Correspondingly, in vitro experiments with HN cells subjected to OGD/R treatment demonstrated a marked reduction in MRPS9 expression, accompanied by a decline in cell viability, and an increase cell apoptosis. Notably, the overexpression of MRPS9 mitigated the OGD/R-induced decrease in cell viability and augmentation of apoptosis. In animal models, MRPS9 expression was significantly lower in the MCAO/R group compared to the sham surgery group. Further, the KEGG pathway analysis associated MRPS9 expression with the PI3K/Akt/mTOR signaling pathway. In cells treated with the specific PI3K/Akt/mTOR inhibitor LY294002, phosphorylation levels of Akt and mTOR were decreased, cell viability decreased, and apoptosis increased compared to the MRPS9 overexpression group. These findings collectively indicate that MRPS9 overexpression inhibits PI3K/Akt/mTOR pathway activation, thereby protecting neurons from apoptosis and impeding IS progression. However, the PI3K/Akt/mTOR inhibitor LY294002 is capable of counteracting the protective effect of MRPS9 overexpression on neuronal apoptosis and IS. Our observations underscore the potential protective role of MRPS9 in modulating neuronal apoptosis and in attenuating the pathophysiological developments associated with IS. This is achieved through the regulation of the PI3K/Akt/mTOR pathway. These insights forge new perspectives and propose novel targets for the strategic diagnosis and treatment of IS.

Polymorphism in Genes Encoding Adaptor Proteins ST13 and STIP1 and the Risk of Ischemic Stroke: a Pilot Study.

Adaptor proteins stress induced phosphoprotein 1 (STIP1) and ST13 Hsp70 interacting protein (ST13) may play a crucial role in the pathophysiology of ischemic stroke through controlling protein folding, neuronal survival, and regulation of HSP70/HSP90. The present pilot study investigated whether tagSNPs in genes encoding ST13 (rs138335, rs138344, rs7290793, and rs138344) and STIP1 (rs4980524) are associated with ischemic stroke. DNA samples from 721 ischemic stroke patients and 471 healthy controls were genotyped using the MassArray-4. Our research revealed a relationship between rs138344 ST13 and the risk of ischemic stroke, which was seen only in females (risk allele G; OR=1.34, 95%CI=1.07-1.69; p=0.01). The haplotype rs138335G-rs138344C-rs7290793C ST13 was linked with lower risk of ischemic stroke in females: OR=0.42; 95%CI=0.26-0.68; p=0.0005. Thus, ST13 represents a novel genetic marker for ischemic stroke.

Immune-Neurovascular Interactions in Experimental Perinatal and Childhood Arterial Ischemic Stroke.

Emerging clinical and preclinical data have demonstrated that the pathophysiology of arterial ischemic stroke in the adult, neonates, and children share similar mechanisms that regulate brain damage but also have distinct molecular signatures and involved cellular pathways due to the maturational stage of the central nervous system and the immune system at the time of the insult. In this review, we discuss similarities and differences identified thus far in rodent models of 2 different diseases-neonatal (perinatal) and childhood arterial ischemic stroke. In particular, we review acquired knowledge of the role of resident and peripheral immune populations in modulating outcomes in models of perinatal and childhood arterial ischemic stroke and the most recent and relevant findings in relation to the immune-neurovascular crosstalk, and how the influence of inflammatory mediators is dependent on specific brain maturation stages. Finally, we discuss the current state of treatments geared toward age-appropriate therapies that signal via the immune-neurovascular interaction and consider sex differences to achieve successful translation.

Abstract WP128: Using Clinical Data to Reclassify ESUS Patients to Either Large Artery Atherosclerotic or Cardioembolic Stroke Mechanisms

Introduction: Defining the specific underlying pathophysiology of ischemic stroke is critical for minimizing the risk of recurrent events with personalized secondary prevention treatments. A notable portion of ischemic strokes are classified as embolic stroke of undetermined source (ESUS), leaving these patients without optimal treatment tailored to their pathophysiology. Hypothesis: Standard clinically collected data can reliably reclassify a substantial portion of ESUS patients into either a large artery atherosclerotic (LAA) or cardioembolic (CE) cause. Methods: A statistical model was developed to discriminate LAA from CE using a retrospective cohort of ischemic stroke patients treated at the University of Washington. A total of 189 patients were included (79 CE and 61 LAA to train the model, 49 ESUS patients to assess reclassification). Sixteen candidate predictors were collected across several sources: clinical risk factors, blood tests, echocardiography, ECG, and neurovascular imaging (Table 1). The LASSO (least absolute shrinkage and selection operator) was used to select important predictors in a penalized logistic regression model with stroke etiology (LAA vs. CE) as the outcome. ESUS patients were considered reclassified if the model-based probability of CE or LAA was at least 75%. Results: Of 189 patients, the mean (SD) age was 68 (14) years and 40% were women. The LASSO selected 12 predictors to discriminate CE vs. LAA (Table 1), with a corresponding cross-validated C-statistic = 0.87 (95% CI: 0.82-0.94). When the model was applied to the 49 ESUS patients, 23 (47%) were reclassified to LAA and 6 (12%) to CE. Conclusions: A multivariate model based on standard clinical data can separate LAA from CE with a high degree of discrimination. Applying this model led to reclassification to either LAA or CE in 59% of ESUS patients. Such approaches may enable more personalized secondary prevention strategies, but need to be tested in future trials.

Pathophysiology of parenchymal injury in ischemic stroke

Pathophysiology of parenchymal injury in ischemic stroke

Exploring the Neuroprotective Effects of Lithium in Ischemic Stroke: A literature review.

Ischemic stroke ranks among the foremost clinical causes of mortality and disability, instigating neuronal degeneration, fatalities, and various sequelae. While standard treatments, such as intravenous thrombolysis and endovascular thrombectomy, prove effective, they come with limitations. Hence, there is a compelling need to develop neuroprotective agents capable of improving the functional outcomes of the nervous system. Numerous preclinical studies have demonstrated that lithium can act in multiple molecular pathways, including glycogen synthase kinase 3(GSK-3), the Wnt signaling pathway, the mitogen-activated protein kinase (MAPK)/ extracellular signal-regulated kinase (ERK) signaling pathway, brain-derived neurotrophic factor (BDNF), mammalian target of rapamycin (mTOR), and glutamate receptors. Through these pathways, lithium has been shown to affect inflammation, autophagy, apoptosis, ferroptosis, excitotoxicity, and other pathological processes, thereby improving central nervous system (CNS) damage caused by ischemic stroke. Despite these promising preclinical findings, the number of clinical trials exploring lithium's efficacy remains limited. Additional trials are imperative to thoroughly ascertain the effectiveness and safety of lithium in clinical settings. This review delineates the mechanisms underpinning lithium's neuroprotective capabilities in the context of ischemic stroke. It elucidates the intricate interplay between these mechanisms and sheds light on the involvement of mitochondrial dysfunction and inflammatory markers in the pathophysiology of ischemic stroke. Furthermore, the review offers directions for future research, thereby advancing the understanding of the potential therapeutic utility of lithium and establishing a theoretical foundation for its clinical application.

Exploring the diagnostic potential of mean platelet volume and C-reactive protein levels in ischemic stroke patients

Background: Ischemic stroke remains one of the leading causes of morbidity and mortality worldwide. Thus, developing more efficient tools to diagnose the condition promptly is critical. Mean platelet volume (MPV) and C-reactive protein (CRP), markers that reflect thrombotic and inflammatory pathways, respectively, are closely associated with the pathophysiology of ischemic stroke and may serve as biomarkers. Aims and Objectives: This study aimed to assess the diagnostic potential of MPV and CRP when measured in patients with ischemic stroke against these markers’ levels in healthy persons. The association between these two biomarkers, as measured in ischemic stroke cases, was also explored. Materials and Methods: A cross-sectional comparison study recruited 54 patients with acute ischemic stroke and 54 age- and sex-matched healthy persons at Government Medical College, Kozhikode. MPV and CRP were measured 24 h post-stroke. The variable comparisons across the groups were made using SPSS; similarly, correlation tests were run considering all subjects experiencing stroke. Results: Patients with ischemic stroke had higher MPV levels of 9.17 ± 0.48 fL than controls: 8.25 ± 0.45 fL P < 0.001. The CRP levels were similarly higher in the stroke group: 3.087 ± 1.11 mg/L versus 0.437 ± 0.24 mg/L, P < 0.001. MPV and CRP had a significant positive correlation after analyzing patients with ischemic stroke (r = 0.332, P = 0.014). Conclusion: The results show that MPV and CRP are robust biomarkers for diagnosing ischemic stroke early, as they represent the underlying inflammatory and thrombotic processes. Implementing them in routine checks can promote early detection and management, improving patient outcomes. Further, longitudinal research is critical to confirm and refine their predictive value.

Drugs/agents for the treatment of ischemic stroke: Advances and perspectives.

Ischemic stroke (IS) poses a significant threat to global human health and life. In recent decades, we have witnessed unprecedented progresses against IS, including thrombolysis, thrombectomy, and a few medicines that can assist in reopening the blocked brain vessels or serve as standalone treatments for patients who are not eligible for thrombolysis/thrombectomy therapies. However, the narrow time windows of thrombolysis/thrombectomy, coupled with the risk of hemorrhagic transformation, as well as the lack of highly effective and safe medications, continue to present big challenges in the acute treatment and long-term recovery of IS. In the past 3 years, several excellent articles have reviewed pathophysiology of IS and therapeutic medicines for the treatment of IS based on the pathophysiology. Regretfully, there is no comprehensive overview to summarize all categories of anti-IS drugs/agents designed and synthesized based on molecular mechanisms of IS pathophysiology. From medicinal chemistry view of point, this article reviews a multitude of anti-IS drugs/agents, including small molecule compounds, natural products, peptides, and others, which have been developed based on the molecular mechanism of IS pathophysiology, such as excitotoxicity, oxidative/nitrosative stresses, cell death pathways, and neuroinflammation, and so forth. In addition, several emerging medicines and strategies, including nanomedicines, stem cell therapy and noncoding RNAs, which recently appeared for the treatment of IS, are shortly introduced. Finally, the perspectives on the associated challenges and future directions of anti-IS drugs/agents are briefly provided to move the field forward.

Drivers of Chronic Pathology Following Ischemic Stroke: A Descriptive Review.

Stroke is the third leading cause of death and long-term disability in the world. Considered largely a disease of aging, its global economic and healthcare burden is expected to rise as more people survive into advanced age. With recent advances in acute stroke management, including the expansion of time windows for treatment with intravenous thrombolysis and mechanical thrombectomy, we are likely to see an increase in survival rates. It is therefore critically important to understand the complete pathophysiology of ischemic stroke, both in the acute and subacute stages and during the chronic phase in the months and years following an ischemic event. One of the most clinically relevant aspects of the chronic sequelae of stroke is its extended negative effect on cognition. Cognitive impairment may be related to the deterioration and dysfunctional reorganization of white matter seen at later timepoints after stroke, as well as ongoing progressive neurodegeneration.The vasculature of the brain also undergoes significant insult and remodeling following stroke, undergoing changes which may further contribute to chronic stroke pathology. While inflammation and the immune response are well established drivers of acute stroke pathology, the chronicity and functional role of innate and adaptive immune responses in the post-ischemic brain and in the peripheral environment remain largely uncharacterized. In this review, we summarize the current literature on post-stroke injury progression, its chronic pathological features, and the putative secondary injury mechanisms underlying the development of cognitive impairment and dementia. We present findings from clinical and experimental studies and discuss the long-term effects of ischemic stroke on both brain anatomy and functional outcome. Identifying mechanisms that occur months to years after injury could lead to treatment strategies in the chronic phase of stroke to help mitigate stroke-associated cognitive decline in patients.

The advantages of multi-level omics research on stem cell-based therapies for ischemic stroke.

Stem cell transplantation is a potential therapeutic strategy for ischemic stroke. However, despite many years of preclinical research, the application of stem cells is still limited to the clinical trial stage. Although stem cell therapy can be highly beneficial in promoting functional recovery, the precise mechanisms of action that are responsible for this effect have yet to be fully elucidated. Omics analysis provides us with a new perspective to investigate the physiological mechanisms and multiple functions of stem cells in ischemic stroke. Transcriptomic, proteomic, and metabolomic analyses have become important tools for discovering biomarkers and analyzing molecular changes under pathological conditions. Omics analysis could help us to identify new pathways mediated by stem cells for the treatment of ischemic stroke via stem cell therapy, thereby facilitating the translation of stem cell therapies into clinical use. In this review, we summarize the pathophysiology of ischemic stroke and discuss recent progress in the development of stem cell therapies for the treatment of ischemic stroke by applying multi-level omics. We also discuss changes in RNAs, proteins, and metabolites in the cerebral tissues and body fluids under stroke conditions and following stem cell treatment, and summarize the regulatory factors that play a key role in stem cell therapy. The exploration of stem cell therapy at the molecular level will facilitate the clinical application of stem cells and provide new treatment possibilities for the complete recovery of neurological function in patients with ischemic stroke.

Effects of electroacupuncture on imaging and behavior in rats with ischemic stroke through miR-212-5p

BackgroundIschemic stroke is a serious disease leading to significant disability in humans worldwide. Increasing evidence suggests that some microRNAs (miRNAs) participate in the pathophysiology of ischemic stroke. A key role for MiR-212 has been found in neuronal function and synaptic plasticity. Ischemic stroke can be effectively treated with electroacupuncture (EA); however, there is a lack of understanding of the relevant mechanisms. In this study, we employed behavioral test and resting-state functional magnetic resonance imaging (rs-fMRI) to detect behavioral and brain function alterations in rats suffering from ischemic stroke. The efficacy of EA therapy and miR-212-5p’s role in this process were also evaluated.Methods and resultsForty rats were randomly divided into the following groups: Sham, middle cerebral artery occlusion/reperfusion (MCAO/R), MCAO/R + EA, MCAO/R + EA + antagomir-negative control and MCAO/R + EA + antagomir-212-5p groups. Behavioral changes were assessed by Catwalk gait analysis prior to and after modeling. Rs-fMRI was performed at one week after EA treatment, amplitude of low-frequency fluctuations (ALFF) and regional homogeneity (ReHo) were calculated to reveal neural activity. Furthermore, neuronal apoptosis in the ischemic penumbra was analyzed using a TUNEL assay. Treatment with EA significantly improved the performance of rats in the behavioral test. The motor and cognition-related brain regions showed decreased ALFF and ReHo following focal cerebral ischemia-reperfusion, and EA treatment could reactivate these brain regions. Moreover, EA treatment significantly decreased MCAO/R-induced cell death. However, the transfection of antagomir-212-5p attenuated the therapeutic effect of EA.ConclusionsIn conclusion, the results suggested that EA improved the behavioral and imaging outcomes of ischemic stroke through miR-212-5p.

Thrombus Aspirates From Patients With Acute Ischemic Stroke Are Infiltrated by Viridans Streptococci.

Acute ischemic stroke may be due to embolism from ruptured atherosclerotic carotid arteries. DNA of oral bacteria, mainly the viridans streptococci group, has been detected in thrombus aspirates of patients with ischemic stroke as well as in carotid endarterectomy samples. Because viridans streptococci are known to possess thrombogenic properties, we studied whether their presence in thrombus aspirates and in carotid artery specimens can be confirmed using bacterial immunohistochemistry. Thrombus aspirates from 61 patients with ischemic stroke (70.5% men; mean age, 66.8 years) treated with mechanical thrombectomy, as well as carotid endarterectomy samples from 20 symptomatic patients (65.0% men; mean age, 66.2 years) and 48 carotid artery samples from nonstroke autopsy cases (62.5% men; mean age, 66.4 years), were immunostained with an antibody cocktail against 3 species (Streptococcus sanguinis, Streptococcus mitis, and Streptococcus gordonii) of viridans streptococci. Of the thrombus aspirates, 84.8% were immunopositive for viridans streptococci group bacteria, as were 80.0% of the carotid endarterectomy samples, whereas immunopositivity was observed in 31.3% of the carotid artery samples from nonstroke autopsies. Most streptococci were detected inside neutrophil granulocytes, but there were also remnants of bacterial biofilm as well as free bacterial infiltrates in some samples. Oral streptococci were found in aspirated thrombi of patients with acute ischemic stroke as well as in carotid artery samples. Our results suggest that viridans streptococci group bacteria may play a role in the pathophysiology of ischemic stroke.