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Poststroke inflammation critically influences functional outcomes following ischemic stroke. Arginase-1 (Arg1) is considered a marker for anti-inflammatory macrophages, associated with the resolution of inflammation and promotion of tissue repair in various pathological conditions. However, its specific role in poststroke recovery remains to be elucidated. This study investigates the functional impact of Arg1 expressed in macrophages on poststroke recovery and inflammatory milieu. We observed a time-dependent increase in Arg1 expression, peaking at 7 d after photothrombotic stroke in mice. Cellular mapping analysis revealed that Arg1 was predominantly expressed in LysM-positive infiltrating macrophages. Using a conditional knockout (cKO) mouse model, we examined the role of Arg1 expressed in infiltrating macrophages. Contrary to its presumed beneficial effects, Arg1 cKO in LysM-positive macrophages significantly improved skilled forelimb motor function recovery after stroke. Mechanistically, Arg1 cKO attenuated fibrotic scar formation, enhanced peri-infarct remyelination, and increased synaptic density while reducing microglial synaptic elimination in the peri-infarct cortex. Gene expression analysis of fluorescence-activated single cell sorting (FACS)-sorted CD45 low microglia revealed decreased transforming growth factor-β (TGF-β) signaling and proinflammatory cytokine activity in peri-infarct microglia from Arg1 cKO animals. In vitro coculture experiments demonstrated that Arg1 activity in macrophages modulates microglial synaptic phagocytosis, providing evidence for macrophage-microglia interaction. These findings present unique insights into the function of Arg1 in central nervous system injury and highlight an interaction between infiltrating macrophages and resident microglia in shaping the poststroke inflammatory milieu. Our study identifies Arg1 in macrophages as a potential therapeutic target for modulating poststroke inflammation and improving functional recovery., Competing Interests: Competing interests statement:The authors declare no competing interest.

This review explores the mechanisms and treatment strategies of ischemic stroke, a leading cause of morbidity and mortality worldwide. Ischemic stroke results from the obstruction of blood flow to the brain, leading to significant neurological impairment. The paper categorizes ischemic stroke into subtypes based on etiology, including cardioembolism and large artery atherosclerosis, and discusses the challenges of current therapeutic approaches. Conventional treatments like tissue plasminogen activator (tPA) and surgical interventions are limited by narrow windows and potential complications. The review highlights the promise of acupuncture, which offers neuroprotective benefits by promoting cerebral ischemic tolerance and neural regeneration. Integrating acupuncture with conventional treatments may enhance patient outcomes. Emphasis is placed on understanding the pathophysiology to develop targeted therapies that mitigate neuronal damage and enhance recovery., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 International Brain Research Organization (IBRO). Published by Elsevier Inc. All rights reserved.)

Introduction: Hyperglycemia is common in acute ischemic stroke, and associated with unfavorable outcome. However, the optimal glucose level is not known and cellular effects of hyperglycemia under hypoxia are largely unclear. We assessed how the extracellular glucose concentration affects cultured neuronal networks under experimental in vitro conditions, to provide a starting point for assessment of mechanisms at the neuronal network and cellular levels., Methods: We used in vitro cultured rat neuronal networks on micro-electrode arrays (MEAs) and glass coverslips. Twenty-four hours of controlled hypoxia was induced. We measured neuronal network activity during baseline (normoxia, 6 h), 24 h of hypoxia, and 6 h after reoxygenation, defined as the summed number of action potentials in 1 h bins. Apoptosis was determined intermittently with caspase 3/7 staining and microscopy. We compared groups of networks under glucose concentrations of 5.0 mmol/L, 7.0 mmol/L, 9.0 mmol/L, and 12.0 mmol/L., Results: Overall, during hypoxia, a gradual decrease in neuronal network activity and increase in apoptosis was found. There were faster decrease in activity (p < 0.01) and more apoptosis after 24 h of hypoxia under glucose levels of 12 mmol/L in a single-well MEA set-up (p < 0.05), and more apoptosis in glass coverslips with glucose levels of 12.0 mmol/L in comparison with 5 mmol/L (p = 0.03). These differences were not observed in multi-well MEAs, in which effects of hypoxia were much smaller than in single-well MEAs., Conclusion: Hyperglycemia was associated with a more rapid decrease of neuronal network activity during and more apoptosis after 24 h of hypoxia in cultured neuronal networks. Loss of neuronal activity and apoptosis probably play a role in poorer outcomes of stroke patients under hyperglycemia. Our model provides a starting point for further assessment of pathomechanisms., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Ischemic stroke (IS) is a severe and sudden cerebrovascular event, associated with notably high rates of mortality and morbidity. The process of apoptosis, a genetically orchestrated form of programmed cell death, is divided into two pathways: intrinsic and extrinsic. The intricate involvement of long non-coding RNA (lncRNA) in the pathobiology of IS, particularly in modulating neuronal apoptosis, is a burgeoning area of research. This review synthesizes the current understanding of the regulatory mechanisms of lncRNA on neuronal apoptosis in the context of ischemic stroke. Specifically, we highlight the roles of lncRNA such as ANRIL, C2dat1/2, H19, TUG1, MEG3, SNHG, and GAS5, which have been implicated in the facilitation of neuronal apoptosis. Conversely, the lncRNA N1LR has been shown to exert an inhibitory effect on this process. The role of MALAT1 in neuronal apoptosis remains a subject of ongoing debate, as its function oscillates between pro-apoptotic and anti-apoptotic roles, thus highlighting the need for further elucidation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Artemisinin (ART), a natural product isolated from the traditional Chinese plant Artemisia annua L., has shown neuroprotective properties in addition to its well-established antimalarial activities. This study investigates the therapeutic effect of ART in ischemic stroke (IS) and delves into its functional mechanism. Bioinformatics analyses revealed lysine demethylase 1A (KDM1A) as a promising target of ART aberrantly overexpressed in the context of IS. Increased KDM1A expression was detected in oxygen-glucose deprivation/reoxygenation (OGD/R)-treated hippocampal neurons and transient middle cerebral artery occlusion (tMCAO)-challenged mice. Treatment with ART reduced KDM1A protein level, thus protecting mouse hippocampal neurons from OGD/R-induced oxidative stress and apoptosis. In vivo, ART reduced infarct size, reduced brain content, enhanced neurological function, and enhanced neuronal survival in tMCAO. Regarding the downstream cascade, KDM1A was found to repress transcription of sphingosine kinase 2 (SPHK2) by removing H3K4me2 modification near the SPHK2 promoter. Either KDM1A overexpression or SPHK2 knockdown abrogated the neuroprotective effects of ART. The ample evidence of this study suggests that ART fulfills neuroprotective functions in the context of IS by protecting SPHK2 from KDM1A-mediated transcription repression, highlighting ART as a promising regimen for the treatment of IS., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The renin-angiotensin system (RAS), composed mainly of renin, angiotensin, and aldosterone, is a key endocrine pathway involved in cardiovascular activity regulation. Under physiological conditions, the RAS plays a vital role in water and salt metabolism, blood pressure regulation, and electrolyte balance. Angiotensin II (Ang II) is the most important active component of the RAS, and its receptors are concentrated in vascular, pulmonary, cardiac, and renal tissues in vivo. Moreover, Ang II is closely associated with the development of vascular lesions. Ang II expression is closely associated with atherosclerosis, aortic aneurysm/dissection, ischemic stroke, hypertension, pulmonary hypertension, and type 2 diabetes mellitus. Given the significant pathophysiological role of Ang II in vascular diseases and the availability of advanced detection methods, Ang II holds promise as a reliable biomarker and therapeutic target in clinical settings. This review summarizes the mechanisms through which Ang II contributes to different vascular diseases and discusses its potential application as a biomarker for disease diagnosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Background: Ischemic stroke is a leading cause of disability and mortality worldwide, with limited effective treatments. Neuroinflammation plays a crucial role in the progression of ischemic brain injury. Glycoprotein nonmetastatic melanoma protein B (GPNMB) has emerged as a potential regulator of inflammation, but its role and underlying mechanisms in ischemic stroke remain largely unknown., Methods: We investigated the expression profile, functional significance, and molecular pathways of GPNMB in ischemic stroke using a mouse model of middle cerebral artery occlusion (MCAO), transcriptome sequencing, and human serum samples. The effects of GPNMB knockdown on stroke outcomes, neuroinflammation, and neuronal damage were assessed in vivo. Bioinformatic analyses and experimental validation were performed to identify the downstream signaling pathways of GPNMB., Results: GPNMB was highly upregulated in the ischemic brain, with its expression peaking at 3-7 days post-MCAO. Serum GPNMB levels were elevated in ischemic stroke patients and correlated with stroke severity. GPNMB knockdown exacerbated stroke outcomes, neuroinflammation, and neuronal damage. Mechanistically, GPNMB positively modulated the PI3K/Akt/GSK3β pathway while negatively regulating p38 MAPK, JNK, and ERK activation. GPNMB knockdown enhanced the expression of NF-κB, a master transcriptional regulator of inflammation., Conclusion: GPNMB is highly upregulated in the ischemic brain and confers neuroprotection against ischemic injury by modulating neuroinflammation via the PI3K/Akt and p38 MAPK signaling pathways., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: In its tetrameric form, pyruvate kinase M2 isoform (PKM2) catalyzes the last step of glycolysis and plays a key role in the metabolic reprogramming via regulating the signaling of pentose phosphate pathway (PPP). But the role of PKM2 in cerebral ischemia-reperfusion (I/R) injury remains unknown., Methods: Mice model of middle cerebral artery occlusion (MCAO) and model of oxygen-glucose deprivation (OGD) injury in cultured neurons were established. PKM2 activator or inhibitor were used to test the effects of PKM2 in wild-type and PKM2 (-/-) mice after I/R injury. Biochemical and molecular approach were used to detect the level of PKM2 tetramers and PPP metabolites., Results: We showed for the first time that ischemia-induced increase of PKM2 activity promoted neuronal death via the suppression of PPP-dependent antioxidant capacity. To identify therapeutic approach that suppresses ischemia-induced increase of PKM2 activity, we tested the effect of bilateral transcranial direct-current stimulation (BtDCS), a newly established BtDCS approach by us, on PKM2 activity after mouse I/R. Our data demonstrated that BtDCS inhibited PKM2 activity in the ischemic neurons. BtDCS also reduced the cerebral infarct volume and the neurological deficits in stroke mice. We found that BtDCS-induced neuroprotection was mediated through the suppression of PKM2 activity after I/R., Conclusions: Together, this study provided novel evidence that supported PKM2 as a crucial regulator of neuronal metabolism after cerebral I/R injury, and revealed the molecular mechanism by which BtDCS protects against mouse cerebral I/R injury through regulating PKM2-mediated metabolic reprogramming., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: To compare the risk of ischemic stroke in patients with migraine treated with first-line medications, including valproate, topiramate, metoprolol, timolol, or propranolol, versus those not receiving these treatments, using data from two large electronic health records datasets., Background: The impact of first-line migraine medications on ischemic stroke risk in patients with migraine remains uncertain, highlighting the need for further investigation., Methods: We conducted a retrospective case-control study using data from Vanderbilt University Medical Center (VUMC) and the All of Us Research Program. Cases were patients with a primary ischemic stroke diagnosis after their first migraine diagnosis, while controls had no ischemic stroke following their initial migraine diagnosis., Results: In the VUMC database, 356 cases and 15,231 controls were identified; the All of Us database included 256 cases and 6590 controls. Propranolol was the only medication significantly associated with a reduced risk of ischemic stroke in female patients with migraine (VUMC: adjusted odds ratio [aOR] 0.55, 95% confidence interval [CI] 0.33-0.86, p = 0.013; All of Us: aOR 0.41, 95% CI 0.19-0.77, p = 0.010), particularly in those with migraine without aura (VUMC: aOR 0.53, 95% CI 0.29-0.90, p = 0.027; All of Us: aOR 0.28, 95% CI 0.10-0.62, p = 0.006). The Cox model showed lower ischemic stroke rates in propranolol-treated female patients with migraine at 10 years in the VUMC data (adjusted hazard ratio [aHR] 0.45, 95% CI 0.24-0.83; p = 0.011, log-rank p < 0.001) and 10 years in the All of Us data (aHR 0.29, 95% CI 0.09-0.87; p = 0.048, log-rank p = 0.003)., Conclusions: Among various migraine treatments, propranolol was notably associated with a significant reduction in ischemic stroke risk among female patients with migraine, particularly those without aura. These findings suggest a potential dual benefit of propranolol in managing migraine and reducing stroke risk, highlighting the need for further prospective studies to confirm these results and potentially inform clinical practice., (© 2025 The Author(s). Headache: The Journal of Head and Face Pain published by Wiley Periodicals LLC on behalf of American Headache Society.)

Accurate segmentation of ischemic stroke lesions is crucial for refining diagnosis, prognosis, and treatment planning. Manual identification is time-consuming and challenging, especially in urgent clinical scenarios. This paper presents an innovative deep learning-based system for automated segmentation of ischemic stroke lesions from Computed Tomography Perfusion (CTP) datasets. This paper introduces a deep learning-based system designed to segment ischemic stroke lesions from Computed Tomography Perfusion (CTP) datasets. The proposed approach integrates Edge Enhancing Diffusion (EED) filtering as a preprocessing step, acting as a form of hard attention to emphasize affected regions. Besides the Attention ResUnet (AttResUnet) architecture with a modified decoder path, incorporating spatial and channel attention mechanisms to capture long-range dependencies. The system was evaluated using the ISLES challenge 2018 dataset with a fivefold cross-validation approach. The proposed framework achieved a noteworthy average Dice Similarity Coefficient (DSC) score of 59%. This performance underscores the effectiveness of combining EED filtering with attention mechanisms in the AttResUnet architecture for accurate stroke lesion segmentation. The fold-wise analysis revealed consistent performance across different data subsets, with slight variations highlighting the model's generalizability. The proposed approach offers a reliable and generalizable tool for automated ischemic stroke lesion segmentation, potentially improving efficiency and accuracy in clinical settings., Competing Interests: Declarations. Ethical Approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. For this type of study, formal consent is not required. Consent to Participate: Informed consent was obtained from all individual participants included in the study. Conflict of Interest: The authors declare no competing interests., (© 2025. The Author(s) under exclusive licence to Society for Imaging Informatics in Medicine.)

Introduction: The degree of culprit artery stenosis affects the risk of early neurological deterioration (END) after acute ischemic stroke (AIS). The TREND trial demonstrated the efficacy of tirofiban in preventing END in patients with AIS. We aimed to investigate whether the degree of intracranial artery stenosis affects the efficacy of tirofiban in preventing END in patients with AIS., Patients and Methods: We conducted a post hoc analysis of the TREND trial, which enrolled patients within 24 h of onset and randomly allocated to receive intravenous tirofiban or oral aspirin. We stratified the stenosis degrees into three subgroups: no stenosis, mild-to-moderate stenosis (stenosis <70%), and severe stenosis or occlusion (stenosis ⩾70%). The primary endpoint is END 4 defined as an increase of the NIHSS ⩾4 within 72 h after randomization. Secondary outcomes include END 2 (defined as an increase of NIHSS ⩾2) within 72 h after randomization, the proportion of mRS 0-1 and 0-2 at 90 days., Results: A total of 296 patients were analyzed. In patients with severe stenosis or occlusion, tirofiban significantly reduced the incidence of END 4 (5.7% vs 30.8%, adjusted OR 0.156, 95% CI 0.028-0.873, adjusted p  = 0.034), whereas its effects in preventing END 4 were similar to those of aspirin in patients with no stenosis (2.4% vs 4.6%, adjusted OR 0.193, 95% CI 0.018-2.083, adjusted p  = 0.175) or mild-to-moderate stenosis (2.9% vs 10.0%, adjusted OR 0.171, 95% CI 0.015-1.943, adjusted p  = 0.155). The p value for interaction between stenosis subgroups and treatment was 0.513. Furthermore, tirofiban significantly reduced the incidence of END 2 in patients with mild-to-moderate stenosis (5.9% vs 22.5%, OR 0.146, 95% CI 0.022-0.951, adjusted p  = 0.044) and severe stenosis or occlusion (11.4% vs 43.6%, adjusted OR 0.140, 95% CI 0.036-0.540, adjusted p  = 0.004). A significant improvement in favorable outcomes with a 90-day mRS of 0-1 was observed only in patients with mild-to-moderate stenosis (85.3% vs 70.0%, adjusted OR 4.617, 95% CI 1.077-19.798, adjusted p  = 0.039)., Discussion and Conclusion: Tirofiban may significantly reduce the incidence of END in patients with severe arterial stenosis or occlusion. Further studies are required to confirm the effects of intracranial artery stenosis on the benefits of intravenous tirofiban., Trial Registration: ClinicalTrials.gov; identifier: NCT04491695., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Mechanical thrombectomy is the standard of care for patients with ischemic stroke from large vessel occlusion. Blood pressure variability (BPV) in the post thrombectomy period is associated with poor functional outcomes. To determine predictive factors associated with increased BPV, a machine learning algorithm was used to identify factors that are linked with increased BPV indices at 24 hours post thrombectomy (24HR)., Methods: This retrospective study examined all patients from a Comprehensive Stroke Center's registry who underwent mechanical thrombectomy between January 2016 and December 2019. The primary outcome was BPV between patients who had adequate reperfusion post thrombectomy (Thrombolysis in Cerebral Infarction [TICI] grading 2b+) and those who did not. The secondary outcomes were good functional status at 90 days (Modified Rankin Scale [mRS] ≤2) and reperfusion (TICI 2b+). Random forest (RF) analysis was leveraged to determine predictors for BPV with reported root-mean-square error (RMSE) and normalized-RMSE (nRMSE) metrics. Multivariable regression analysis was used to determine factors significantly associated with secondary outcomes. P <0.05 was the threshold for statistical significance., Results: A total of 395 patients (49%, n=195 females and 51%, n=200 males) were included in the final analysis with mean age (± standard deviation) of 65 (±15) years. TICI 2b+ was achieved in 322 (82%) patients. Median ASPECTS and NIHSS were 9 and 18, respectively. Higher Age, NIHSS, number of passes, and mechanical ventilation were significantly associated with lower likelihood of mRS ≤2 at 90 days in multivariable regression analysis., Conclusions: This study identified the interval from last-known-well time-to-groin puncture, age, and NIHSS as factors significantly associated with increased 24HR BPV in RF analysis. These predisposing factors in our machine learning analysis allow clinicians to identify patients who are at risk of having increased BPV and opportunities to augment these patients' BP control., (Copyright © 2025 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Evidence suggests that environmental factors may influence the risk of ischemic stroke(IS). 1 Nevertheless, the majority of existing research has concentrated on correlation analysis, with only a limited number of studies employing specific methodologies to investigate the causal dynamics of this relationship with external drivers., Method: In this study, we employed an approach known as convergent cross-mapping to identify and elucidate the causal effects of significant air pollutants and meteorological factors on the pathogenesis of IS. The city of Shouguang in the Shandong Peninsula region was selected for this study, primarily because of the environmental characteristics of the region and the notable prevalence of cases during the study period., Results: Key air pollutants and several meteorological factors in the region have a causal effects on IS. A general trend can be drawn. SO 2 2 (ρ = 0.215, ∂=0.016), PM 2.5 3 (ρ = 0.077, ∂=0.002), and PM 10 4 (ρ = 0.058, ∂=0.0014) had a positive causal effects on IS,and relative humidity (ρ = 0.050, ∂=-0.009) tended to reduce the number of IS cases., Conclusion: Through this case study, a causal network was developed with the aim of integrating the study of the interactions between variables and providing a clear model to aid the management of IS., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: This study analyzes the factors influencing the 90-day prognosis of acute ischemic stroke (AIS) patients after mechanical thrombectomy (MT) and established a multidimensional risk model to predict postoperative 90-day outcomes., Methods: A retrospective analysis of clinical data was conducted for AIS patients who underwent MT at our hospital. A total of 111 patients who met the inclusion criteria were included in the study. Based on the modified Rankin Scale scores from follow-up records at 3 months postsurgery, the patients were divided into a good prognosis group (88 cases, 79.28%) and a poor prognosis group (23 cases, 20.72%). Receiver operating characteristic curves were plotted using MedCalc software, and area under the curve (AUC) values were calculated to establish a risk prediction model, presented in the form of a nomogram., Results: Logistic regression analysis showed that C-reactive protein (T3) (P < 0.001), National Institutes of Health Stroke Scale score at admission (P = 0.001), and a history of atrial fibrillation (P = 0.004) were independent predictors of poor prognosis, while albumin (T2) (P = 0.008) was a protective factor for the 90-day outcome. The AUC values for these factors were 0.812, 0.760, 0.655, and 0.757, respectively. The AUC value of Normotu was 0.945. Calibration slope = 0.856, calibration-in-the-large ≈ 0, and observed/expected ratio ≈ 1., Conclusions: Post-MT C-reactive protein levels, National Institutes of Health Stroke Scale score at admission, and a history of atrial fibrillation are significantly associated with poor prognosis in these patients. Moreover, higher levels of endogenous albumin are a protective factor for the 3-month prognosis of AIS patients after MT., (Copyright © 2025 The Author(s). Published by Elsevier Inc. All rights reserved.)

Ischemic stroke (IS) is a cerebrovascular disease that predominantly affects middle-aged and elderly populations, exhibiting high mortality and disability rates. At present, the incidence of IS is increasing annually, with a notable trend towards younger affected individuals. Recent discoveries concerning the "gut-brain axis" have established a connection between the gut and the brain. Numerous studies have revealed that intestinal microbes play a crucial role in the onset, progression, and outcomes of IS. They are involved in the entire pathophysiological process of IS through mechanisms such as chronic inflammation, neural regulation, and metabolic processes. Although numerous studies have explored the relationship between IS and intestinal microbiota, comprehensive analyses of specific microbiota is relatively scarce. Therefore, this paper provides an overview of the typical changes in gut microbiota following IS and investigates the role of specific microorganisms in this context. Additionally, it presents a comprehensive analysis of post-stroke microbiological therapy and the relationship between IS and diet. The aim is to identify potential microbial targets for therapeutic intervention, as well as to highlight the benefits of microbiological therapies and the significance of dietary management. Overall, this paper seeks to provide key strategies for the treatment and management of IS, advocating for healthy diets and health programs for individuals. Meanwhile, it may offer a new perspective on the future interdisciplinary development of neurology, microbiology and nutrition., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025. Published by Elsevier Inc.)

Introduction: The functions of S1P receptors have been revealed using genetic and pharmacological tools, including the potent non-selective modulator FTY720. However, studies on subtype-specific agonists and antagonists are limited; hence, the role of S1P 4 remains unclear., Objectives: To identify a novel function of S1P 4 as a pathogenic factor in stroke using a newly developed S1P 4 -selective modulator and S1P 4 knockdown., Methods: Heteroaromatic analogs of FTY720 were synthesized, a β-arrestin assay was conducted against S1P receptors, and the developed compound (NXC736) was characterized as a functional S1P 4 antagonist. To clarify the function of S1P 4 , the therapeutic potential of NXC736 in ischemic stroke was determined using a transient middle cerebral artery occlusion (tMCAO) mouse model, which was validated using S1P 4 knockdown. The S1P 4 -dependent pathogenic mechanisms were determined using immunohistochemical and biochemical analyses., Results: Molecular modeling studies provide valuable clues for understanding S1P 4 selectivity of NXC736. NXC736 contains a triazole ring instead of a phenyl ring and exhibits S1P 4 -selective activity as a functional antagonist. Its action on S1P 4 does not require phosphorylation by sphingosine kinase 2. Notably, NXC736 exhibited substantial therapeutic activity against ischemic stroke by attenuating tMCAO-induced acute brain injuries, including brain infarction, neurological deficits, and neuronal apoptosis. This suggested that S1P 4 is a pathogenic factor in ischemic stroke. This function was confirmed using AAV-based S1P 4 knockdown. NXC736 or S1P 4 knockdown attenuated blood-brain barrier disruption, neutrophil infiltration, microglial activation and proliferation, and the upregulation of pro-inflammatory cytokines, thereby demonstrating that S1P 4 influences neuroinflammatory responses in ischemic stroke. The underlying mechanisms were activation of NLRP3 inflammasome, NF-κB, and MAPKs. S1P 4 also contributed to chronic brain injuries caused by ischemic stroke because NXC736 exerted long-term neuroprotective effects against tMCAO challenge., Conclusion: Using a functional S1P 4 antagonist (NXC736) and a genetic tool for S1P 4 knockdown, we identified S1P 4 as a novel pathogenic factor in ischemic stroke., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025. Published by Elsevier B.V.)

Background: Head and neck cancer (HNC) due to its nature and proximity to essential vasculature, along with different treatments, can lead to stroke, significantly contributing to morbidity and mortality. Our aim is to systematically evaluate the association of stroke incidence, mortality, and predictors with HNC treatment., Methods: Pubmed, Web of Science, Embase, and ScienceDirect were searched from inception to July 2024 for articles reporting stroke incidences, mortality, or associated risk factors following treatment in HNC patients. A random-effects meta-analysis assessed cumulative incidence and mortality rates with proportional analysis and risk factors using hazard ratios (HRs) associated with HNC treatment. Subgroup analyses of incidence and mortality were conducted for pre- and post-2010 periods, reflecting changes in stroke protocols., Results: Out of 1561 studies, 69 studies with 258 850 HNC patients were included. The global cumulative incidence of stroke in HNC was 4.1% (95% CI: 3.3%-5.0%), with similar rates before and after 2010 (4.4% vs. 4.0%). In patients undergoing chemoradiotherapy (CRT), stroke incidence was 4.9% (95% CI: 3.5%-6.7%) with a median time to first stroke of 45 months (range: 14-51.7 months). Following radiation therapy (RT), stroke incidence was 3.8% (95% CI: 2.7%-5.3%) with a median time to stroke of 36 months (range: 6.8-130 months). The incidence rates of stroke in HNC patients were higher compared to the general population (HR: 1.69, 95% CI: 1.24-2.31, p = 0.001). Stroke mortality decreased from 28.5% (95% CI: 11.6%-54.9%) pre-2010 to 14.5% (95% CI: 11.6%-17.9%) 2010-2024. Stroke mortality was 39.3% (95% CI: 17.8%-66.0%) post-CRT and 21% (95% CI: 7.2%-47.7%) post-RT. Hypertension (HR = 1.75), diabetes (HR = 1.71), and age > 65 (HR = 2.17) increased stroke risk (p < 0.0001 for all). Geographically, South Korea (6.6%) had the highest incidence of stroke., Conclusion: This is the first systematic review to analyze the association between stroke and HNC treatment. Stroke mortality decreased from 28.5% to 14.5% (pre-2010 vs. 2010-2024), with the highest mortality in the CRT group (39.3%). Given that stroke occurs 36-45 months after CRT, a screening protocol within 3-4 years is crucial., (© 2025 Wiley Periodicals LLC.)

Background: The relative risk of ischemic stroke (IS) in head and neck cancer (HNC) patients developing carotid artery stenosis (CAS) or vertebral artery stenosis (VAS) after radiation therapy (RT) remains uncertain due to limited studies, complicating vascular follow-ups and preventive strategies., Methods: We included HNC patients who received RT between 2010 and 2023. The patients were divided into nasopharyngeal carcinoma (NPC) and non-NPC groups. The primary outcome was the occurrence of IS after RT, and the secondary outcomes included the development of > 50% CAS or > 50% VAS after RT., Results: Of the 1,423 HNC patients, there were 19% of patients developed > 50% CAS, 6.8% of patients developed > 50% VAS, and 2.3% of patients developed IS. In patients with HNC, > 50% CAS (adjusted hazard ratio [HR] = 3.21, 95% confidence interval [CI] = 1.53-6.71), and > 50% VAS (adjusted HR = 2.89, 95% CI = 1.28-6.53) were both the independent predictors of IS. In the patients with NPC, > 50% CAS was an independent predictor of anterior circulation IS (adjusted HR = 4.39, 95% CI = 1.17-16.47). By contrast, > 50% VAS emerged as a predictor of posterior circulation IS in both the NPC (adjusted HR = 15.02, 95% CI = 3.76-60.06) and non-NPC groups (adjusted HR = 13.59, 95% CI = 2.21-83.46)., Conclusion: HNC patients with > 50% CAS or > 50% VAS after RT had an increased risk of IS within their corresponding vascular territory. CAS could be an important predictor of IS in NPC patients, whereas VAS might also be a significant predictor of IS in both NPC and non-NPC patients. Evaluation both the carotid and vertebral arteries after RT might be necessary., Trial Registration: ClinicalTrials.gov identifier No.: NCT06111430., Competing Interests: Declarations. Ethics approval and consent to participate: The study was approved by the Ethics Institutional Review Board of Chang Gung Memorial Hospital (202101981B0, 202200464B0, and 202400107B0). Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Ischemic stroke (IS) represents a harmful neurological disorder with limited treatment options. Ferroptosis accounts for the iron-dependent, nonapoptotic cell death pattern, which shows the feature of fatal lipid ROS accumulation. Nonetheless, ferroptosis-related biomarkers for identifying IS early are currently lacking. The present study focused on investigating the possible ferroptosis-related biomarkers for IS and analyzing their effects on immune infiltration. Altogether five hub differentially expressed ferroptosis-related genes (DEFRGs) were identified from the relevant databases. Additionally, single-cell RNA-sequencing (seq) analysis was conducted for the comprehensive mapping of cell populations based on the IS database. These five hub DEFRGs were analyzed using gene set enrichment analysis, miRNA prediction, and single-cell RNA-seq analysis. A transient middle cerebral artery occlusion mouse model was constructed. We also adopted bioinformatics methods combined with western blot, changes to mitochondria, hematoxylin & eosin staining, Nissl staining, ROS fluorescence staining, immunohistochemistry, and quantitative real-time polymerase chain reaction (qRT-PCR) to show the involvement of ferroptosis in IS progression. The results revealed that nuclear factor erythroid-derived 2-like 2 (Nfe2l2) was the potential candidate biomarker for IS diagnosis, and ferroptosis may be suppressed via the Nfe2l2/HO-1 pathway. Thus, drug targeting Nfe2l2 can shed novel lights on IS treatment., Competing Interests: Declarations. Ethics approval and consent to participate: The animal study gained approval from the Committee of the Fourth Affiliated Hospital of Harbin Medical University (IACUC2022136). Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Background: The nuclear Overhauser enhancement (NOE)-mediated saturation transfer effect at -1.6 ppm, termed NOE(-1.6 ppm), has demonstrated potential for detecting ischemic stroke. However, the quantification of the NOE(-1.6 ppm) effect usually relies on a multiple-pool Lorentzian fit method, which necessitates a time-consuming acquisition of the entire chemical exchange saturation transfer (CEST) Z-spectrum with high-frequency resolution, thus hindering its clinical applications., Purpose: This study aims to assess the feasibility of employing asymmetry analysis, a rapid CEST data acquisition and analysis method, for quantifying the NOE(-1.6 ppm) effect in an animal model of ischemic stroke., Methods: We examined potential contaminations from guanidinium/amine CEST, NOE(-3.5 ppm), and asymmetric magnetization transfer (MT) effects, which could reduce the specificity of the asymmetry analysis of NOE(-1.6 ppm). First, a Lorentzian difference (LD) analysis was used to mitigate direct water saturation and MT effects, providing separate estimations of the contributions from the guanidinium/amine CEST and NOE effects. Then, the asymmetry analysis of the LD fitted spectrum was compared with the asymmetry analysis of the raw CEST Z-spectrum to evaluate the contribution of the asymmetric MT effect at -1.6 ppm., Results: Results show that the variations of the LD quantified NOE(-1.6 ppm) in stroke lesions are much greater than that of the CEST signals at +1.6 ppm and NOE(-3.5 ppm), suggesting that NOE(-1.6 ppm) has a dominating contribution to the asymmetry analysis at -1.6 ppm compared with the guanidinium/amine CEST and NOE(-3.5 ppm) in ischemic stroke. The NOE(-1.6 ppm) variations in the asymmetry analysis of the raw CEST Z-spectrum are close to those in the asymmetry analysis of the LD fitted spectrum, revealing that the NOE(-1.6 ppm) dominates over the asymmetric MT effects., Conclusion: Our study demonstrates that the asymmetry analysis can quantify the NOE(-1.6 ppm) contrast in ischemic stroke with high specificity, thus presenting a viable alternative for rapid mapping of ischemic stroke., (© 2025 The Author(s). Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

Stroke is the second leading cause of mortality worldwide, with retinal ischemia as its prominent complication. However, the pathology of retinal ischemia has not been fully elucidated, resulting in a lack of effective treatment. Stem cell therapy has been suggested to be therapeutic in retinal ischemia, with mitochondrial transfer potentially one of the underlying mechanisms. To investigate the mitochondrial function in retinal ischemia and the potential of mitochondrial transfer from mesenchymal stem cells (MSCs), in vivo middle cerebral artery occlusion (MCAO) model and in vitro oxygen-glucose deprivation (OGD) model were utilized in combination. In vivo, rats subjected to MCAO were randomly administered intravenous MSCs or vehicles. Laser doppler was used to measure the blood flow in the brain and the eye, along with immunohistochemical staining for assessing cellular degeneration. In vitro, retinal pigment epithelium (RPE) cells exposed to OGD were cocultured with or without MSCs. Mitochondrial function was measured by mitochondrial respiration, mitochondrial network analysis, mitochondria live cell imaging, and immunocytochemistry. The results demonstrated improved cell survival and restored mitochondrial function following MSC therapy. This chapter details the protocols necessary to produce the in vivo and in vitro models of ischemic stroke along with an assessment of mitochondrial function. Elucidating the mechanisms of mitochondrial transfer will further the knowledge in regenerative medicine and may enable new targets of therapeutics for stroke, especially for retinal ischemia., (© 2025. Springer Science+Business Media, LLC.)

Ethnopharmacological Relevance: Ischemic stroke (IS) is a major cause of mortality. Inflammation exerts an essential part of brain-heart communication after IS. Naoxintong capsule (NXT), derived from the classical Traditional Chinese Medicine (TCM) formulation Bu-Yang-Huan-Wu-Tang, are extensively employed in China to manage IS, myocardial infarction (MI), and atherosclerosis. Previous clinical studies have demonstrated the protective effects of NXT in anti-atherosclerosis, cerebral infarction, angina, and acute coronary syndrome. However, the potential therapeutic mechanism of NXT for IS remains unknown., Aim of the Study: This study aims to investigate a potential mechanism for enhancing brain-heart interaction following an ischemic stroke., Materials and Methods: C57BL/6J mice underwent permanent middle cerebral artery occlusion (MCAO) for durations of 6, 12, and 24 h. The effects of NXT on the brain were observed via TTC, Nissl and TUNEL staining, immunofluorescence staining, and Zea-Longa scores. Simultaneously, the effects of NXT on the heart were evaluated via H&E staining and echocardiography. Inflammatory factors in heart and serum were determined via ELISA or luminex liquid suspension chip detection. Network pharmacology predicted the targets and signaling pathways of NXT. The binding affinity between potential targets and active compounds of NXT was assessed through molecular docking. The expression levels of IκBα, IKKβ, NF-κB, NLRP3, and caspase-1 were evaluated via Western blotting., Results: The Zea-Longa scores, infarct rate, and the rate of apoptosis in the brain at 6, 12, and 24 h of MCAO mice were markedly decreased by NXT. Additionally, they clearly enhanced the NeuN positive rate and prevented microglia from activating at 24 h. NXT significantly reduced the level of myocardial injury biomarkers (Lactate dehydrogenase (LDH) and Creatine kinase isoenzyme MB (CK-MB) at 24 h, N-terminal pro-brain natriuretic peptide (NT-pro BNP) at 6, 12, and 24 h), improved ejection fraction, fractional shortening, stroke volume, and cardiac output at 24 h. The levels of MIP-1α in cardiac tissue and IL-1β in serum were both markedly lowered by NXT. Furthermore, the NF-κB/NLRP3/caspase-1 signaling pathways may be potential mechanisms of NXT. Molecular docking indicated that IKKβ, IκBα, NF-κB, NLRP3, and caspase-1 may serve as potential targets for the action of representative active ingredients in NXT. NXT could reduce the expression levels of IKKβ, NF-κB, NLRP3, and caspase-1 in brain and heart tissues while increasing the expression of IκBα., Conclusions: Our study illustrates that NXT efficiently attenuated inflammation in the brain and heart by blocking the NF-κB/NLRP3/caspase-1 signaling pathway. These findings provide appealing insights into the multi-organ perspective on human health via identifying shared inflammatory impacts and heart-brain linkages., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: Cerebrovascular hemodynamics are believed to play an important role in the development of ischemic stroke (IS). However, the relationships between hemodynamics and prognosis are not fully understood. Four-dimensional (4D) flow cardiovascular magnetic resonance (CMR) enables comprehensive characteristics of cerebrovascular hemodynamics. This study aims to investigate the associations of the different hemodynamics derived from 4D flow CMR with IS functional outcomes., Methods: 91 patients (median age 64 years, 62 males) with unilateral IS in middle cerebral artery (MCA) territory were included. All subjects underwent a CMR scan, including 4D flow, three-dimensional (3D) time-of-flight (TOF) magnetic resonance angiography (MRA), 3D whole brain black-blood high-resolution vessel wall imaging (HR-VWI) of the MCA. Six hemodynamics, including flow rate, velocity, pulsatility index, time-averaged WSS (TAWSS), oscillatory shear index and relative residence time (RRT) were calculated for the lesion site, pre-bifurcation M1 (pM1) segment and the distal M1 and/or first branches of M2 (dM1/M2) segments. Vessel characteristics such as lumen area, vessel area, wall area, maximum wall thickness and the degree of stenosis were calculated at the most stenotic lesion site. The modified Rankin Scale (mRS) scores were assessed at 90 days and one year, and a mRS >2 was considered as a poor functional outcome., Results: Lower segment-level TAWSS (OR:0.24, P=0.006 and OR: 0.29, P=0.014), higher RRT (OR: 2.74, P=0.007 and OR: 2.40, P=0.011) of dM1/M2 segments and lower segment- and lesion-level velocity (OR: 0.40, P=0.019 and OR: 0.41, P=0.025; OR: 0.41, P=0.030 and OR: 0.42, P=0.040) of pM1 segment were observed to be associated with poor functional outcome at both 90 days and one year. Using the cut-off value of 3.58Pa and 0.29, respectively, TAWSS and RRT of dM1/M2 segments showed moderate estimate performance in distinguishing poor functional outcome from favorable outcome (AUCs range from 0.642-0.687) both at 90 days and one year., Conclusion: Distal segmental TAWSS and RRT of dM1/M2 segments were associated with poor functional outcomes. Such alterations of hemodynamics might help for the identification of patients with potential unfavorable prognosis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 The Author(s). Published by Elsevier Inc. All rights reserved.)

The macrophage-derived membrane is widely applied in the targeting nanocarrier for its inflammatory tendency and long circulation ability due to the preservation of membrane protein. Few studies reported the application of macrophage membranes as biotherapeutic agents. To verify the ability of macrophage membrane as a biotherapeutic agent, ischemic stroke was selected as the model disease. Inspired by the features of macrophages infiltrating the ischemic core and the talent of M2 macrophages in modulating the inflammatory microenvironment, an M2 macrophage membrane (M2M)-disguised poly lactic-co-glycolic acid nanoparticles loaded with baicalin (BA) (M2M@BANPs) is developed. The results in vivo and in vitro indicate that M2M@BANPs could efficiently and actively target ischemic brain tissue and accumulate in microglia and neurons due to the coating of M2M. Furthermore, M2M and M2M@BANPs exhibit significant therapeutic effects in salvaging brain tissue damage and neurological functional recovery by reprogramming microglia from M1 to M2, reducing neutrophil infiltration and inhibiting neuronal apoptosis. Together, our fabrication provides a new insight and an applicative perspective for M2M in the therapy of ischemic stroke., Competing Interests: Declaration of competing interest The authors declare no competing financial interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Ischemic brain injury not only results in significant neurological, motor, and cognitive impairment but also contributes to the accumulation of toxic solutes and proinflammatory cytokines in the infarction region, exacerbating ischemic brain damage. The glymphatic system, which is crucial for brain waste clearance and homeostasis, is impaired by ischemic injury, highlighting the importance of developing therapeutic strategies for poststroke complications. Herein, a novel hybrid electro-optical stimulation device is proposed that integrates near-infrared micro-light-emitting diode with transparent microneedles, enabling efficient noninvasive stimulation of the cortical area for ischemic stroke treatment. This study investigates whether this hybrid electro-optical stimulation enhances the glymphatic system function and ameliorates ischemic brain injury in the middle cerebral artery occlusion and reperfusion (MCAO/R) mice model. The results demonstrate that hybrid stimulation improves the neurological, motor, and cognitive functions and reduces brain atrophy following MCAO/R. Moreover, hybrid stimulation restores impaired glymphatic system function by modulation of aquaporin-4 (AQP4) polarization and alleviates the accumulation of proinflammatory cytokines such as IL-1β. Notably, AQP4 inhibition partly reverses the improved functional outcomes of hybrid stimulation. The findings suggest that targeting glymphatic drainage using hybrid electro-optical stimulation is a promising therapeutic approach for treating ischemic brain injury., (© 2025 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

The ischemic strokes seriously threaten human health with high incidence and disability rates. Cerebral embolism and impaired brain function are the two major clinical features of this disease. Therefore, rapid restoration of cerebral blood supply and synchronous improvement of impaired neurological function is the key to treating strokes. Herein, based on the microenvironment of cerebral thrombosis and pathological characteristics of damaged neurons, we constructed a shear force and reactive oxygen species (ROS) dual-responsive system (UK@Fuc/CDPC-PTPCS) for sequential targeted delivery of thrombolytic agent urokinase (UK) and neuroprotective drug cytosolic choline (CDPC). Results proved that after intravenous administration, UK@Fuc/CDPC-PTPCS can quickly locate to cerebral thrombosis site via the active recognition capability of fucoidan (Fuc) to P-selectin overexpressed on activated platelets. Subsequently, the sharply increased blood shear force separated the core-shell structure by breaking the host-guest interaction of β-cyclodextrin (β-CD), so the UK loaded in the shell was first released to rapid thrombolysis and then restored cerebral blood supply. Afterward, the stroke homing peptide (SHp) modified CDPC-PTPCS core actively recognized ischemic damaged neuronal cells. Then high intracellular ROS triggered CDPC release at specific sites to exert neuroprotective effects. This study offered a new therapeutic strategy for ischemic stroke., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Infarct growth rate is remarkably heterogeneous in acute ischemic stroke, reflecting diverse clinical-physiological phenotypes. We compared different methods of estimating infarct growth rate in patients with acute ischemic stroke undergoing thrombectomy using multimodal computed tomography (CT) stroke imaging., Methods: Secondary analysis of the international ESCAPE-NA1 trial (Efficacy and Safety of Nerinetide for the Treatment of Acute Ischemic Stroke) which evaluated the effect of nerinetide in patients with large vessel occlusion undergoing thrombectomy. Infarct growth rate was estimated leveraging each component of multimodal stroke CT imaging: (1) 10 minus baseline Alberta Stroke Program Early CT Score (ASPECTS) divided by hours elapsed from symptom onset on noncontrast CT (ASPECTS decay per hour); (2) collateral status on multiphase CT angiography (mCTA), and (3) hypoperfusion intensity ratio on CT perfusion. Patients were dichotomized into intermediate and slow progressors (since fast progressors were likely to be excluded from ESCAPE-NA1 based on trial enrollment criteria) according to median ASPECTS decay, presence of good versus moderate/poor mCTA collaterals, and median hypoperfusion intensity ratio, respectively. Associations between progressor phenotypes and 90-day modified Rankin Scale score were assessed across neuroimaging modalities using adjusted logistic regression analyses., Results: Among 1105 patients enrolled in ESCAPE-NA1 between 2017 and 2019, 619 (56.0%) were assessed for progressor phenotypes using noncontrast CT, 1084 (98.1%) with mCTA, and 415 (37.6%) with CT perfusion. Median ASPECTS decay per hour was 1.05 (interquartile range, 0.05-1.85), 188/1084 (17%) patients had good collateral status on mCTA, and the median hypoperfusion intensity ratio was 0.44 (interquartile range, 0.28-0.59). Intermediate progressors showed worse functional outcomes compared with slow progressors only in CT perfusion strata: adjusted common odds ratio for modified Rankin Scale ordinal shift analysis of 1.69 (95% CI, 1.14-2.49). No significant association between progressor phenotypes and 90-day modified Rankin Scale was seen when the noncontrast CT and the mCTA approaches were used., Conclusions: Stroke progressor phenotypes based on CT perfusion criteria (using the hypoperfusion intensity ratio approach) were associated with clinical outcomes, while stroke progressor phenotypes based on noncontrast CT (ASPECTS decay) and mCTA (collateral status) criteria were not.

Ethnopharmacological Relevance: Cornus officinalis is a conventional Chinese medicine for tonifying liver and kidney in ancient China. The active ingredients from Cornus officinalis can delay the progression of cerebral aneurysms, alleviate experimental autoimmune encephalomyelitis, and show a good intervention effect on brain diseases. Loganin, the active ingredient of Cornus officinalis, has a neuroprotective effect on cerebral ischemia-reperfusion injury in mice. It is yet unknown, nevertheless, how Cornus officinalis works to treat ischemic stroke., Aim of the Study: Based on ultra-high performance liquid chromatography-quadrupole/time-of-flight mass spectrometry (UHPLC-Q-TOF-MS), network pharmacology and molecular docking, Cornus officinalis's mechanism of intervention in ischemic stroke is explored and verified by experiments., Materials and Methods: To examine the chemical components of Cornus officinalis, UHPLC-Q-TOF-MS was used. The network pharmacology was used to construct the "active ingredient-core target-main pathway" network of Cornus officinalis. Then, the link between the main active components and the key protein targets, as determined by network pharmacology, was verified through the application of molecular docking. The middle cerebral artery occlusion/reperfusion (MCAO/R) rat model used in this study was created using the suture technique. The pharmacological effects of Cornus officinalis were explored by neurological function score, behavior, TTC staining, ultrasound and flow cytometry. Western blot and qPCR were used to confirm the core target., Results: The outcomes of the investigation demonstrated that Cornus officinalis had a potent anti-ischemic stroke effect. UHPLC-Q-TOF-MS method was used to determine 24 chemical constituents in Cornus officinalis, of which 22 components had a close relationship with protein targets relevant to ischemic stroke. The 27 protein targets screened by "active ingredient-core target-main pathway" may be the possible targets of Cornus officinalis in the therapy of ischemic stroke. Most of the 27 protein targets had to do with the inflammatory response, apoptosis and energy metabolism. KEGG enrichment analysis showed that AGE/RAGE ranked high and was closely related to inflammatory response. Molecular docking predicted that the top 10 components in the network diagram had good binding with inflammatory factors IL6, IL-1β and TNF-α protein targets. Western blot research outcomes stated that Cornus officinalis could firmly impede the production of AGE, RAGE, and P-NFκB P65. Cornus officinalis had the potential to prevent ischemic stroke by drastically inhibiting the production of TNF-α, IL-1β, and IL-6, according to the results of qPCR study., Conclusion: This study found that Cornus officinalis can improve the brain injury, motor ability and blood flow velocity of MCAO/R rats and suppress the inflammatory reaction through the AGE/RAGE/NFκB pathway to exert the therapeutic effect on ischemic stroke., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Acute ischemic stroke (AIS) is associated with a high incidence and significant rates of disability, making it a critical focus of clinical research. The current review investigates the role of serum inflammatory markers in the pathogenesis and prognosis of AIS. By quantitatively analyzing specific inflammatory markers, this study aims to enhance the understanding of the pathophysiological mechanisms underlying AIS, support early diagnosis, improve disease assessment, and establish a scientific foundation for targeted treatment strategies to optimize clinical outcomes. From a pathophysiological perspective, multiple inflammatory markers are involved in the inflammatory response that occurs within brain tissue following cerebral ischemia. The serum levels of various inflammatory markers were measured in individuals with AIS, revealing strong correlations between these markers and disease severity. The findings indicate that these markers can serve as reliable indicators of disease progression. Further analysis demonstrated their prognostic value in predicting functional recovery and the risk of recurrence. Notably, during a 3-month follow-up, each 0.32 ng/mL increase in matrix metalloproteinases-9 levels was associated with a 16 % increase in the risk of disability and mortality after AIS. The findings of this review contribute to a more comprehensive understanding of the pathological and physiological mechanisms of AIS and offer a foundation for advancing early diagnostic methods, disease assessment tools, and personalized treatment strategies. Monitoring inflammatory marker levels may enable clinicians to more accurately evaluate disease severity and develop tailored therapeutic interventions, potentially reducing disability and recurrence rates while improving quality of life for individuals with AIS. The findings highlight the potential of precision medicine approaches based on inflammatory markers to shape future AIS treatment paradigms., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025. Published by Elsevier B.V.)

Background: The bidirectional causal relationship between ischemic stroke(IS) and inflammatory bowel disease(IBD) remains unclear, prompting us to propose a bidirectional Mendelian randomization study to investigate this relationship further., Methods: We obtained IS data from the MEGASTROKE consortium and IBD data, including its subtypes ulcerative colitis(UC) and Crohn's disease(CD), from the IIBDGC consortium. In this study, we utilized IBD and its subtypes as exposure variables and IS as the outcome variable, and vice versa, to explore the bidirectional relationship between them. We used the IBD genetic data from the FinnGen database as replication data to further explore the causality. In this study, we employed the inverse variance weighting method as our primary approach. For sensitivity analyses, we utilized additional methods including MR-Egger regression, weighted median estimation, MR-polymorphism residuals and outliers(MR-PRESSO), and MR-Robust adjusted profile score(MR.RPAS). Furthermore, we conducted a random-effects meta-analysis to combine the causal relationships derived from both the IIBDGC and FinnGen datasets, aiming to ascertain more robust causal associations., Results: The initial phase of the bidirectional Mendelian randomization study revealed a causal relationship between IS and the risk of CD(OR = 1.56, 95% CI: 1.20-2.02, P = 0.0008) and UC(OR = 1.33, 95% CI: 1.05-1.69, P = 0.0179), but did not find a causal relationship between IBD as a whole and the risk of IS, nor between IBD subtypes and the risk of IS. During the replication phase, the FinnGen database did not reveal any significant correlation between IS and the risk of IBD, including its subtypes CD and UC. However, additional meta-analysis of the combined data from both databases indicated that IS is significantly associated with an increased risk of CD (OR IVW = 1.38, 95%CI: 1.07-1.69, P < 0.05) and UC (OR IVW = 1.27, 95%CI: 1.04-1.50, P < 0.05), but not with the overall risk of IBD (OR IVW = 1.05, 95%CI: 0.87-1.16, P > 0.05). No significant effects were observed between IBD and IS risk, nor were there significant effects between IS and the risks of IBD, CD, or UC. To ensure the robustness of these findings, heterogeneity and pleiotropy tests were conducted., Conclusion: IBD and its subtypes were not found to be causally associated with the risk of IS, whereas IS was found to be causally associated with the risk of CD and UC. This suggests that the risks of CD and UC should be closely monitored in patients with IS., (Copyright © 2025. Published by Elsevier Inc.)

Background: Atrial fibrillation (AF) significantly increases the ischemic stroke risk. However, the relationship between age at diagnosis of AF and subsequent stroke risk remains poorly understood., Methods and Results: We analyzed data from 5 prospective cohorts: ARIC (Atherosclerosis Risk in Communities) study, CHS (Cardiovascular Health Study), CARDIA (Coronary Artery Risk Development in Young Adults), MESA (Multi-Ethnic Study of Atherosclerosis), and Framingham Heart Study (including Offspring cohort and the Third-Generation cohorts). Cox regression models and competing risk survival analyses were used to assess incidence rates and hazard ratios (HRs) for ischemic stroke stratified by age groups. Among 47 239 participants (median follow-up: 21.1 years), 6689 (14.2%) developed AF, and 536 (8.0%) subsequently experienced ischemic stroke. Younger age at AF diagnosis was significantly associated with a higher ischemic stroke risk. Fully adjusted HRs for ischemic stroke were 5.35 (95% CI, 3.56-8.03), 2.99 (95% CI, 2.32-3.86), 2.13 (95% CI, 1.75-2.58), and 1.93 (95% CI, 1.59-2.34) for AF diagnosed at ages 55, 65, 75, and 85, respectively. Compared with participants without AF at age 55, HRs for ischemic stroke were 7.30 (95% CI, 3.27-16.31) for AF diagnosed >10 years earlier, 4.98 (95% CI, 2.99-8.29) for 6 to 10 years earlier, and 4.60 (95% CI, 1.48-14.34) for ≤5 years earlier ( P -trend <0.001). The presence of AF yielded a 13.9 years earlier occurrence of ischemic stroke among those with AF diagnosis at 55 years compared with 1.5 years earlier at age 85., Conclusions: Younger age at AF diagnosis was associated with a higher risk of subsequent ischemic stroke.

Background: Early stroke complications (ESCs) impair recovery and provide an important therapeutic target. Our multicenter prospective cohort study examined the prevalence and amount of poor outcomes attributable to ESCs., Methods and Results: In patients with stroke, 16 ESCs were monitored by clinical assessment ("basic definition") and by inclusion of laboratory values and clinical scales ("extended definition"). The association of complications with poor outcome (death or functional impairment: modified Rankin Scale score >3 or Barthel Index <60) at 3 months was analyzed using multiple logistic regression adjusted for stroke severity, age, and sex. Complications were stratified by their early treatment options, and average sequential population-attributable fractions were estimated for treatable early complications. Of 1202 patients, outcome data were available for 1105 (91.9%; 43.0% women; mean age 68.3 years; baseline median National Institutes of Health Stroke Scale score on admission 3 points). Poor outcome was recorded for 100 patients (9.0%). By basic definition, recurrent stroke, fever, pneumonia, depression, urinary tract infection, and delirium were significantly associated with poor outcomes. The occurrence of 1 or more of these ESCs was associated with up to 19.6% of poor outcomes. By extended definition, urinary tract infection, depression, and delirium were significantly associated with poor outcomes. The occurrence of 1 or more of these ESCs was associated with up to 15.9% of poor outcomes., Conclusions: In our cohort of patients with mild to moderate stroke, we identified a set of treatable ESCs with clinically relevant impact on outcome that may be targeted in future interventional trials., Registration: URL: https://www.bfarm.de; Unique identifier: DRKS00004712.

This investigation aims to screen ischemic stroke (IS)-related hub genes of central post-stroke pain (CPSP) from public databases and predict their potential roles through bioinformatics analysis to better interpret CPSP in IS. First, based on differential analysis, Venn analysis, and enrichment analyses, we identified 13 differently expressed genes in CPSP (CPSP-DEGs) related to the TNF signaling pathway, Vascular smooth muscle contraction, and IL-17 signaling pathway. Subsequently, through screening and analysis of the PPI network constructed by the Search Tool for the Retrieval of Interacting Genes (STRING) database, we obtained 3 CPSP-related hub genes (CD163, MMP9, and ARG1). They were all highly expressed in the IS group, exhibiting good diagnostic performance, with area under curve (AUC) value > 0.85. The immune-related analysis demonstrated that the infiltration levels of various immune cells in the IS group and the normal group were substantially different. In addition, by utilizing some online websites, we not only predicted some microRNAs (miRNAs) and transcription factors (TFs) that may target hub genes but also mined small molecular drugs that may target differentially expressed genes (DEGs) in IS. In conclusion, this project first investigated the role of CPSP-related genes in IS and identified 3 hub genes. At the same time, we predicted some miRNAs, TFs, and candidate drugs that may target hub genes. Our research uncovered the potential mechanism of CPSP-related genes in IS from multiple perspectives. Furthermore, it also laid a research foundation for the future study of the mechanisms of IS disease., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Unrecognized or silent myocardial infarction (MI) detected on an ECG is associated with first-ever stroke, but the impact on stroke recurrence is unknown. We aimed to determine the association of silent MI with stroke recurrence in patients with a recent ischemic stroke., Methods and Results: Subjects from the IRIS (Insulin Resistance Intervention After Stroke) trial with an available ECG were included. Clinical MI was defined as a history of hospitalization for MI. Silent MI was defined as ECG evidence of MI in the absence of clinical MI. The primary outcome was recurrent stroke. Ischemic stroke and subtype were assessed as secondary outcomes. Multivariable Cox regression analysis adjusted for demographics, pioglitazone, and vascular risk factors was used to examine the association between MI and stroke recurrence. A total of 2282 participants met the inclusion criteria. Clinical and silent MI were identified in 161 (7.1%) and 94 (4.1%) subjects, respectively. Over the study period, 209 recurrent strokes occurred, with 191 classified as ischemic. In the fully adjusted model, silent MI was significantly associated with any stroke (hazard ratio [HR], 2.29 [95% CI, 1.34-3.90]) and ischemic stroke (HR, 2.09 [95% CI, 1.18-3.70]) recurrence. Clinical MI was associated with stroke recurrence in the unadjusted analysis but not in the fully adjusted model (HR, 1.31 [95% CI, 0.81-2.11]). Silent MI was not associated with potential cardioembolic subtypes (HR, 1.50 [95% CI, 0.70-3.22])., Conclusions: Among patients with a recent ischemic stroke, silent MI was associated with stroke recurrence. Tailored prevention strategies in this population warrant future investigation., Registration: URL: https://clinicaltrials.gov. Unique Identifier: NCT00091949.

Background: Early screening is critical for the prevention of ischemic stroke. miR-574-5p was considered a promising biomarker for ischemic stroke but lacks direct confirmation. This study evaluated miR-574-5p in discriminating ischemic stroke and predicting the severity and prognosis of patients, aiming to provide novel insights into the clinical prevention of ischemic stroke., Methods: The clinical significance of miR-574-5p was evaluated in 103 ischemic stroke patients with 87 healthy individuals as control. The potential of serum miR-574-5p in the diagnosis and prognosis of ischemic stroke was assessed by ROC and logistic regression analyses. In vitro, oxygen-glucose deprivation (OGD)-induced microglia was established. The regulation of inflammation, oxidative stress, and proliferation of microglia by miR-574-5p were assessed by cell transfection. The downstream targets of miR-574-5p were predicted from public databases, and the targeting relationship was evaluated by luciferase reporter assay., Results: Reducing serum miR-574-5p was observed in ischemic stroke patients relative to healthy individuals, which discriminated ischemic stroke patients. Serum miR-574-5p was negatively correlated with the NIHSS score of ischemic stroke patients and was identified as a risk factor for patients' adverse prognosis. In OGD-induced microglia, overexpressing miR-574-5p could alleviate OGD-induced inflammation and oxidative stress and promote cell growth. Among predicted targets, ATP2B2 was upregulated in ischemic stroke and showed a negative correlation with miR-574-5p. miR-574-5p negatively regulated ATP2B2 in OGD-induced microglia, and the overexpression of ATP2B2 reversed the protective effect of miR-574-5p., Conclusion: miR-574-5p acted as a biomarker for ischemic stroke and mediated neuroinflammation via targeting ATP2B2., (Copyright © 2025 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Stroke is the second leading cause of death worldwide, and currently, there is no effective neuroprotective agent available for its treatment. Though apolipoprotein E (ApoE) showed potential as a neuroprotective agent for CNS disorders, however, its large size limits its clinical application. To overcome this issue, smaller ApoE-mimetic peptides that mimic the biological functions of ApoE have been developed. In this study, we designed and characterized a novel ApoE-mimetic peptide, ApoEFrag, and explored its neuroprotective potential in experimental stroke models. ApoEFrag was evaluated for its ability to interact with oxidized lipids and lack of self-aggregation potential. In the in vitro cerebral ischemia model, ApoEFrag demonstrated neuroprotection against glutamate-induced neuronal damage in SH-SY5Y cells by maintaining mitochondrial health and reducing reactive oxygen species (ROS) levels. To confirm ApoEFrag's neuroprotective potential, ApoEFrag was investigated in middle cerebral artery occlusion (MCAO) induced ischemic stroke in rats. ApoEFrag administration significantly reduced infarct size, improved neurological function, and lowered mortality. ApoEFrag exhibited anti-inflammatory effects, reduced astrocyte activation and apoptosis, and promoted neurogenesis. Overall, ApoEFrag shows promising neuroprotective effects and could be a potential therapeutic approach for stroke., Competing Interests: Declaration of competing interest Authors declare there's no financial/personal interest or belief that could affect their objectivity., (Copyright © 2025. Published by Elsevier B.V.)

Intermittent fasting (IF) is known to induce significant ischemic tolerance. Diet is a major proponent of gut microbiota, and gut microbial dysbiosis plays a role in post-stroke brain damage. Hence, we currently evaluated whether IF-mediated ischemic tolerance is mediated by gut microbiota. Additionally, circadian cycle is known to modulate post-ischemic outcomes, and thus we further evaluated if gut microbiota would be influenced by prophylactic IF during the inactive phase (fasting during daytime; IIF) or active phase (fasting during nighttime; AIF). The AIF, but not IIF, cohort showed a significantly decreased fecal Firmicutes/Bacteroidetes ratio compared with the ad libitum (AL) cohort. Moreover, the levels of gut microbiota-derived metabolites butyrate and propionate decreased in AL cohort following focal ischemia, whereas they increased in AIF cohort. However, fecal microbiota transplantation (FMT) from IIF or AIF cohort had no significant effects on post-ischemic motor and cognitive function recovery, anxiety-, and depression-like behaviors compared with FMT from AL cohort. Furthermore, FMT from IIF or AIF cohort did not influence the post-ischemic infarct volume, atrophy volume or white matter damage. Overall, the current findings indicate that the beneficial effects of IF after focal ischemia are not mediated by the gut microbiota., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The etiology and mechanisms of ischemic stroke are complex, encompassing a variety of pathological processes including atherosclerosis, energy failure, neuroinflammation, blood-brain barrier damage, abnormal glial cell activation, and neuronal edema and necrosis. Endothelial cell-derived extracellular vesicles have garnered significant attention in various diseases, including ischemic stroke, owing to their widespread distribution, rich content, diverse functional sites, low immunogenicity, and ability to cross the blood-brain barrier. This study reviewed the current status of research on endothelial cell-derived extracellular vesicles and their roles and potential mechanisms in ischemic stroke. It aimed to elucidate the potential of these extracellular vesicles for clinical translation related to ischemic stroke, thereby providing new strategies and directions for treating patients with stroke. The findings indicated that endothelial cell-derived extracellular vesicles reduce the occurrence of stroke and improve post-stroke ischemic injury and prognosis through various mechanisms. Although studies have demonstrated the significant potential of endothelial cell-derived extracellular vesicles in treating ischemic stroke, their clinical translation remains challenging. Further research is needed to elucidate the specific roles of endothelial cell-derived extracellular vesicles in ischemic stroke, using additional in vitro or animal models. This will enable a more comprehensive assessment of the benefits and risks of endothelial cell-derived extracellular vesicles, thereby facilitating their clinical translation., Competing Interests: Declarations. Ethics Approval: Not applicable. Consent to Participate: Not applicable. Conflict of Interest: The authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Dyslipidemia was strongly linked to stroke, however the relationship between dyslipidemia and its components and ischemic stroke remained unexplained., Aim: To investigate the link between longitudinal changes in lipid profiles and dyslipidemia and ischemic stroke in a hypertensive population., Methods: Between 2013 and 2014, 6094 hypertension individuals were included in this, and ischemic stroke cases were documented to the end of 2018. Longitudinal changes of lipid were stratified into four groups: (1) Normal was transformed into normal group; (2) Abnormal was transformed into normal group; (3) Normal was transformed into abnormal group; and (4) Abnormal was transformed into abnormal group. To examine the link between longitudinal changes in dyslipidemia along with its components and the risk of ischemic stroke, we utilized multivariate Cox proportional hazards models with hazard ratio (HR) and 95%CI., Results: The average age of the participants was 62.32 years ± 13.00 years, with 329 women making up 54.0% of the sample. Over the course of a mean follow-up of 4.8 years, 143 ischemic strokes happened. When normal was transformed into normal group was used as a reference, after full adjustments, the HR for dyslipidemia and ischemic stroke among abnormal was transformed into normal group, normal was transformed into abnormal group and abnormal was transformed into abnormal group were 1.089 (95%CI: 0.598-1.982; P = 0.779), 2.369 (95%CI: 1.424-3.941; P < 0.001) and 1.448 (95%CI: 1.002-2.298; P = 0.047) ( P for trend was 0.233), respectively., Conclusion: In individuals with hypertension, longitudinal shifts from normal to abnormal in dyslipidemia-particularly in total and low-density lipoprotein cholesterol-were significantly associated with the risk of ischemic stroke., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.)

Ethnopharmacological Relevance: Angong Niuhuang pill (ANP) is effective in preventing and treating ischemic stroke, however, the pharmacodynamic substances and mechanism of ANP have not been scientifically clarified., Aim of the Study: This study aims to identify the bioactive equivalence of combinatorial components (BECCs) of ANP for treating ischemic stroke and discuss the underlying mechanisms., Materials and Methods: Network pharmacology was performed to screen key compounds and predict potential pathways. The effect of BECCs on ischemic stroke was screened and verified in ponatinib-induced zebrafish model and mice middle cerebral artery occlusion (MCAO) model. Finally, the mechanism of BECCs was preliminarily investigated., Results: Through network pharmacology, the degree values of each component in ANP were determined, and five candidate BECCs were obtained by combining the content of the components in the original prescription. The BECCs V has the same efficacy as the original formula in reducing the movement disorder and neuronal injury of zebrafish cerebral ischemia models and lowering the neurologic deficits and cerebral infarction volume of mouse MCAO models. Mechanistically, BECCs V and ANP blocked neuronal autophagy through the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) axis, inhibited microglial inflammatory activation through the PI3K/AKT/hypoxia inducible factor-1α (HIF-1α) axis, protected microvascular endothelial function through the PI3K/AKT/forkhead box O3 (FoxO3a) axis, thereby improving ischemic cerebral injury., Conclusions: The newly discovered BECCs V is equivalent to ANP in regulating the motor function recovery rate and neuroprotective rate of zebrafish and the neurological deficit scores and the average infarct volume of MCAO mice. This study suggests that the PI3K/AKT signaling axis plays a key role in neuronal autophagy, microglial inflammatory activation and microvascular endothelial dysfunction induced by cerebral ischemic injury, suggesting that the regulation of PI3K/AKT may be a potential therapeutic strategy for neuroprotection and ischemic stroke injury., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Background: Stroke is globally one of the leading causes of mortality and disability. Adhering to evidence-based guidelines and protocols can improve quality of care for ischemic stroke patients. We aimed to compare the availability and content of specific protocols versus adherence to these key intervention in clinical daily practice among Flemish hospitals. We selected five key interventions for managing ischemic stroke patients. These key interventions encompassed the measurement of body temperature, glycaemia monitoring, screening of Swallowing function according to the Fever, Sugar and Swallowing protocol (FeSS protocol) and depression and Activities of Daily Living (ADL), (FeSS+ key-interventions)., Methods: A systematic quantitative and qualitative approach was designed to analyse specific protocols from 24 hospitals. A predefined data extraction matrix for the five FeSS+ key interventions was utilized for data collection. Using this matrix, protocols were scored according to completeness of content, regarding the FeSS+ interventions. These scores were used to calculate a total protocol content score, i.e. a total score for the five FeSS+ interventions and an individual score for each key intervention separately, ranging between 0 and 1, per hospital. A score of zero indicates absence of the FeSS+ interventions in the protocols, while a score of one signifies complete coverage of these interventions. In addition, we assessed the correlation between the availability and content of these protocols in relation to the adherence to interventions documented for 30 patients per hospital., Results: The mean total protocol content score was 0.40±0.20, ranging from 0.64±0.25 for glycaemia management to 0.1±0.28 for ADL screening. With regard to the individual FeSS+ key interventions, we identified a correlation between protocol characteristics and adherence for glycaemia (rs = 0.42, p = 0.04), depression screening (rs = 0.43, p = 0.04) and ADL screening (rs = 0.44, p = 0.03). Total FeSS+-protocol content also correlated with adherence (r = 0.6140, p = 0.0014)., Conclusion: Protocol characteristics for the FeSS+ key interventions were variable and rather limited, especially for ADL- and depression screening. The identified relationship between the content of protocols and adherence to interventions underscores the value of defining these activities in hospital documentation to improve stroke care., (© The Author(s) 2025. Published by Oxford University Press on behalf of International Society for Quality in Health Care. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site–for further information please contact journals.permissions@oup.com.)

Objectives: The association of neuroticism and cerebral small vessel disease (CSVD) development remains unclear. In this study, we used Mendelian randomization (MR) to explore the potential role of neuroticism in CSVD development., Methods: We collected data on ischemic stroke (IS); small vessel stroke (SVS); three neuroimaging markers altered in CSVD, including white matter hyperintensity (WMH), fractional anisotropy (FA), and mean diffusivity (MD); and three neuroticism clusters, including depressed affect, worry, sensitivity to environmental stress and adversity (SESA), from large-scale genome-wide association studies (GWAS). Bidirectional MR analyses were used to evaluate the association between neuroticism and CSVD, primarily estimated using the inverse variance weighted (IVW) method. The linkage disequilibrium score (LDSC) regression was employed to assess the association between various phenotypes., Results: LDSC analysis unveiled a noteworthy genetic correlation between depressed affect and IS (rg = 0.111, p = 0.001) as well as between worry and SVS (rg = -0.111, p = 0.032). Our study revealed a causal correlation between SESA and FA using both forward and reverse MR analyses (SESA on FA, odds ratio (OR) = 0.186 (0.071 to 0.483), p = 5.50 × 10 -4 ; FA on SESA, OR = 0.996 (0.9916 to 0.9997), p = 0.035). Meanwhile, FA also exerted a statistical causal influence on depressed affect cluster (OR = 0.992 (0.987 to 0.997), p = 0.001)., Interpretation: This research suggests a potential correlation between certain aspects of neuroticism and CSVD, with further studies needed to better understand the causal relationship and its implications for patient intervention., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 International Brain Research Organization (IBRO). Published by Elsevier Inc. All rights reserved.)

Background: MLC1501, consisting of four herbs, that is, Radix Astragali , Radix Angelicae sinensis , Rhizoma Chuanxiong , Radix Polygalae , has the same pharmacological properties as its precursors MLC601 and MLC901 which contain extracts of nine herbs and showed neuroprotective, anti-inflammatory and neurorestorative properties in non-clinical models, as well as clinical benefits in improving functional and neurological recovery after brain injuries., Aims: To determine the efficacy of MLC1501 on motor recovery as measured by Fugl-Meyer motor Assessment (FMA) total score at 24 weeks in patients with ischaemic stroke (IS)., Design: A total of 300 patients aged >18 years, diagnosed with IS in the prior 2-10 days, with National Institute of Health Stroke Scale (NIHSS) total score of 8-18 and a combined score of ≥3 on NIHSS motor items 5A, 5B, 6A and/or 6B, will be randomised in a 1:1:1 ratio to receive oral placebo, MLC1501 low dose or MLC1501 high dose for 6 months. The study is governed by a Steering Committee. An independent Data Monitoring Committee oversees patient safety., Outcomes: The primary outcome is mean change from baseline in FMA total score at 24 weeks. Efficacy outcomes evaluated in person at baseline, 12 weeks and 24 weeks include the FMA (total, upper extremity and lower extremity motor scores), modified Rankin Scale (mRS), Patient-Reported Outcomes Measurement Information System-Global Health (PROMIS-10) and NIHSS. Additionally, telephone assessment at week 4 includes the simplified mRS and PROMIS-10.Safety will be evaluated by standard assessments and occurrence of adverse events over the duration of the study., Discussion: Interventions that enhance recovery beyond the acute period of stroke are needed. MLC1501 has a good safety profile as well as potential to be a treatment for recovery after brain injury. The results of this study will provide objective level B evidence on the efficacy of MLC1501 on long-term recovery and safety of 24 weeks of treatment among patients with IS., Trial Registration Number: NCT05289947., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Background: The effects of blood pressure (BP) lowering in patients treated with intravenous tissue plasminogen activator (IV tPA) before endovascular thrombectomy (EVT) are unclear., Aims: This study aims to investigate whether intensive and conventional BP management affects outcomes differently, depending on IV tPA administration before EVT., Methods: In this subgroup analysis of the Outcome in Patients Treated with Intra-Arterial Thrombectomy-Optimal Blood Pressure Control (OPTIMAL-BP; ClinicalTrials.gov Identifier: NCT04205305) trial, patients were divided into groups based on IV tPA use before EVT. Clinical outcomes of intensive (systolic BP target < 140 mm Hg) or conventional BP management (systolic BP target 140-180 mm Hg) were compared among groups. The primary efficacy outcome was a favorable outcome at 3 months (modified Rankin Scale score of 0-2). Primary safety outcomes included symptomatic intracerebral hemorrhage (sICH) within 36 h and stroke-related death within 3 months., Results: Among the 302 patients, the IV tPA group included 98 (32.5%) and the non-IV tPA group comprised 204 subjects (67.5%). In the IV tPA group, intensive BP management significantly lowered the favorable outcome rate (intensive, 27.3% vs. conventional, 51.9%; adjusted odds ratio [aOR], 0.36; 95% confidence interval [CI], 0.13-0.93; p  = 0.04). In the non-IV tPA group, the risk difference rate of favorable outcome was not significantly different between intensive and conventional BP management (44.1% vs. 55.9%; aOR, 0.62; 95% CI, 0.31-1.22; p  = 0.17). Notably, the proportion of malignant cerebral edema within 36 h in the IV tPA group was significantly higher in the intensive management group (18.2%) than in the conventional management group (1.9%; aOR, 10.72; 95% CI, 1.24-92.29; p  = 0.03). sICH and mortality rates were not significantly different between intensive and conventional BP management in either study groups., Conclusions: Intensive BP management worsens 3-month functional outcomes after successful EVT without reducing sICH among patients who received IV tPA before EVT, indicating that BP lowering in this population should be cautious., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: The authors have no financial conflicts of interest except for J.K. and J.Y., who report research grants from Chong Kun Dang Pharm.

Vascular obstruction often causes inadequate oxygen and nutrient supply to the brain. This deficiency results in cerebral ischemic injury, which significantly impairs neurological function. This review aimed to explore the neuroprotective and regenerative effects of nerve growth factor (NGF) in cerebral ischemic injury. NGF, a crucial neurotrophic factor, could inhibit neuronal apoptosis, reduce inflammatory responses, and promote axon regeneration and angiogenesis through its interaction with TrkA, a high-affinity receptor. These functions were closely related to the activation of Phosphatidylinositol 3-kinase/Protein kinase B (PI3K/AKT) and Mitogen-Activated Protein Kinase (MAPK) pathways. Moreover, the mechanisms of NGF in the acute and recovery phases, along with the strategies to enhance its therapeutic effects using delivery systems (such as intranasal administration, nanovesicles, and gene therapy) were also summarized. Although NGF shows great potential for clinical application, its delivery efficiency and long-term safety still need more research and improvements. Future research should focus on exploring the specific action mechanism of NGF, optimizing the delivery strategy, and evaluating its long-term efficacy and safety to facilitate its clinical transformation in cerebral ischemic stroke., (Copyright © 2024 International Brain Research Organization (IBRO). Published by Elsevier Inc. All rights reserved.)

Objectives: Recurrent stroke results in higher disability and mortality but might be mitigated through interventions that improve medication adherence. The medication possession ratio (MPR) is an objective proxy for adherence that may provide an individualized risk assessment for recurrent stroke., Methods: This is a retrospective, longitudinal cohort study of patients with recent ischemic stroke or TIA referred to a Veterans Affairs vascular neurology outpatient clinic between 2010 and 2016. We calculated average MPR quartile for four medication classes used for secondary stroke prevention by reviewing pharmacy and medical records following an incident cerebral ischemic event. Traditional stroke risk factors were quantified using the Framingham Stroke Risk Profile (FSRP) score. We hypothesized that lower average MPR would relate to higher recurrent stroke risk more than FSRP or stroke etiological classification., Results: For 255 patients with stroke or TIA, 57 (22.4 %) patients had recurrent stroke during a median follow-up period of 5.0 years (IQR 2.0). Compared to optimal average MPR, each quartile lower average MPR was associated with higher cumulative incidence of recurrent stroke (subhazard ratio 1.63, 95 %CI: 1.24 to 2.14, p<0.001) while accounting for the competing risk of death and covarying for FSRP. Neither FSRP nor stroke etiology were associated with recurrent stroke. However, higher baseline systolic blood pressure starting at 132 mm Hg was independently associated with stroke recurrence., Conclusions: MPR is an effective proxy measurement to assess risk of recurrent stroke. Systems-based and individualized interventions to improve medication adherence are needed to reduce recurrent stroke rates in VA populations., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025. Published by Elsevier Inc.)

For ruptured cerebral aneurysms over 90 years of age, the outcome and the safety after endovascular treatment are not well-known. This multicenter retrospective registry enrolled patients with ruptured cerebral aneurysms after endovascular treatment from January 2015 to December 2019 in Japan. We investigated differences between the patients over 90 years (age ≥ 90) and those under 90 years of age (age <90). The primary outcome was defined as a modified Rankin scale 0-2 at 30 days. Secondary outcomes were all-cause death and returned to premorbid modified Rankin scale at 30 days. Safety outcomes were the incidence of ischemic stroke and technical complications. Among 8,024 patients with aneurysm, 204 were aged ≥ 90 years and 7,820 were <90 years, those of median age were 92 and 65 years. The proportion of females and premorbid modified Rankin scale was higher in the age ≥ 90 group (n [%]; 191 [93.6] vs. 5,395 [69.0], median [interquartile range]; 1 [0-2] vs. 0 [0-0]). The modified Rankin scale 0-2 at 30 days was lower in age ≥ 90 patients than in age <90 patients (13.2% vs. 56.2%, adjusted odds ratio [95% confidence intervals]; 0.13 [0.08-0.21]). In age ≥ 90 patients, all-cause death was significantly higher (adjusted odds ratio [95% confidence intervals]; 1.85 [1.19-2.86]) and returned to premorbid modified Rankin scale was significantly lower (adjusted odds ratio [95% confidence intervals]; 0.26 [0.17-0.39]). However, safety outcomes were not significantly different between both groups. In this population undergoing endovascular treatment for ruptured cerebral aneurysms, patients older than 90 years had a poor prognosis but no difference in having perioperative complications.

Background: Although the prognostic value of the CHA 2 DS 2 -VASc (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, prior stroke or transient ischemic attack, vascular disease, age 65-74 years, and female sex) scoring system in patients with stroke has been explored in several studies, a research gap exists in its application, especially in patients without atrial fibrillation (AF)., Methods: This study investigated the association between CHA 2 DS 2 -VASc score and prognosis at 1 year in patients with acute ischemic stroke (AIS) who do not have AF. A total of 993 patients with AIS but without AF were recruited between January 2019 and December 2022. Patients were categorized into high-risk (CHA 2 DS 2 -VASc score, >2; n = 424), moderate-risk (CHA 2 DS 2 -VASc score, 2; n = 218), and low-risk (CHA 2 DS 2 -VASc score, 0-1; n = 351) groups. The primary outcome was major adverse cardiac events (MACE) at 1 year after index AIS. Multivariate Cox regression analyses evaluated the prognostic value of CHA 2 DS 2 -VASc scores after controlling for potential confounding factors. A sensitivity analysis was performed based on 3 CHA 2 DS 2 -VASc groups generated using propensity score matching., Results: The rate of MACE during 12-month follow-up was statistically significantly higher ( P < .01) in patients with a CHA 2 DS 2 -VASc score greater than 2 (34.7%) than in patients with a score of 2 (23.9%) or of 0 or 1 (14.8%). Multivariate Cox regression models indicated that, compared with a CHA 2 DS 2 -VASc score of 0 or 1, the hazard ratio (HR) of MACE occurrence was 3.22 (95% CI, 1.93-5.37; P < .01) for a CHA 2 DS 2 -VASc score greater than 2 and 1.92 (95% CI, 1.24-2.98; P < .01) for a CHA 2 DS 2 -VASc score of 2. When included in the Cox regression model as a continuous variable, the CHA 2 DS 2 -VASc score remained strongly associated with higher risks of MACE (HR, 1.19 [95% CI, 1.11-1.26]; P < .01), all-cause mortality (HR, 1.14 [95% CI, 1.05-1.23]; P < .01), and recurrent stroke (HR, 1.15 [95% CI, 1.06-1.256]; P < .01). Sensitivity analyses based on populations generated by propensity score matching yielded similar results., Conclusion: The CHA 2 DS 2 -VASc score effectively predicts MACE in patients with AIS but without AF, providing more accurate risk stratification., Competing Interests: Conflict of Interest Disclosure: None., (© 2025 The Authors. Published by The Texas Heart Institute®.)