Cerebral Ischemic Stroke Research Articles

Traditional Chinese Medicine Borneol-Based Polymeric Micelles Intracerebral Drug Delivery System for Precisely Pathogenesis-Adaptive Treatment of Ischemic Stroke.

The scarcity of effective neuroprotective agents and the presence of blood-brain barrier (BBB)-mediated extremely inefficient intracerebral drug delivery are predominant obstacles to the treatment of cerebral ischemic stroke (CIS). Herein, ROS-responsive borneol-based amphiphilic polymeric NPs are constructed by using traditional Chinese medicine borneol as functional blocks that served as surface brain-targeting ligand, inner hydrophobic core for efficient drug loading of membrane-permeable calcium chelator BAPTA-AM, and neuroprotective structural component. In MCAO mice, the nanoformulation (polymer: 3.2 mg·kg-1, BAPTA-AM: 400 µg·kg-1) reversibly opened the BBB and achieved high brain biodistribution up to 12.7%ID/g of the total administered dose after 3 h post single injection, effectively restoring intracellular Ca2+ and redox homeostasis, improving cerebral histopathology, and inhibiting mitochondrial PI3K/Akt/Bcl-2/Bax/Cyto-C/Caspase-3,9 apoptosis pathway for rescuing dying neurons (reduced apoptosis cell from 59.5% to 7.9%). It also remodeled the inflammatory microenvironment in cerebral ischemic penumbra by inhibiting astrocyte over-activation, reprogramming microglia polarization toward an anti-inflammatory phenotype, and blocking NF-κB/TNF-α/IL-6 signaling pathways. These interventions eventually reduced the cerebral infarction area by 96.3%, significantly improved neurological function, and restored blood flow reperfusion from 66.2% to ≈100%, all while facilitating BBB repair and avoiding brain edema. This provides a potentially effective multiple-stage sequential treatment strategy for clinical CIS.

Mechanism of Ligusticum wallichii-Borneol in the Treatment of Cerebral Ischemic Stroke in Rats Based On Network Pharmacology, Molecular Docking, and Experimental Verification.

The pharmacodynamics, molecular biology, network pharmacology, and molecular docking mechanisms of the Ligusticum wallichii and borneol medication pair (CXBP) were investigated for ischemic stroke treatment. Effective chemical components and targets of CXBP were identified using TCMSP, ETCM, and SymMap databases, whereas ischemic stroke targets were sourced from OMIM, GeneCards, TTD, PubMed, Web of Science, CNKI, Wanfang Data, and VIP databases. Protein-protein interaction (PPI) networks were generated using the STRING database, and GO and KEGG enrichment analyses were conducted using Metascape. A "disease-pathway-target-component-drug" network was created in Cytoscape, and molecular docking was confirmed with PyMOL and AutoDock tools. Rat models of MCAO were established to evaluate neurological scores, triphenyltetrazolium chloride (TTC) staining, and Nissl staining. Key components were validated through enzyme-linked immunosorbent assay (ELISA), real-time polymerase chain reaction (PCR), and immunohistochemistry. Thirty-three active ingredients and 419 potential targets for CXBP, with key compounds including Z-6,8',7,3'-diligustilide, cedrene, (+)-alpha-funebrene, POL, dipterocarpol, oleanolic acid, 1-acetyl-beta-carboline, and erythrodiol. Critical targets included ESR1, PRKCA, and PTPN6. KEGG pathway analysis revealed 179 signaling pathways, primarily neuroactive ligand-receptor interactions, whereas GO enrichment analysis identified 2911 biological processes, 398 molecular activities, and 203 cellular components. The neurological function scores and TTC staining of the infarcted brain regions were significantly improved following CXBP intervention compared to the MCAO group. These findings were supported by Nissl staining, which demonstrated better preserved cellular morphology and a significantly higher number of Nissl vesicles in the CXBP group. ELISA analysis revealed substantial modulation in gene expression: levels of PRKCA, PTPN6, ESR1, and TNF-α changed significantly, whereas IL-1β, IL-6, and TNF-α were notably downregulated compared to the MCAO group. PCR results corroborated these findings, showing a significant decrease in PRKCA expression and marked downregulation of IL-1β, IL-6, and TNF-α, whereas ESR1 and PTPN6 levels increased significantly. Immunohistochemical analysis further confirmed these results, with the CXBP and nimodipine groups exhibiting higher ESR1 and PTPN6 expression and lower PRKCA expression compared to the MCAO group. To improve cerebral ischemia and reperfusion injury, CXBP improves ischemic stroke outcomes through key active ingredients (e.g., Z-6,8',7,3'-diligustilide, cedrene, and oleanolic acid) and targets ESR1, PRKCA, and PTPN6, modulating multiple signaling pathways to alleviate cerebral ischemia-reperfusion injury.

Atrial Fibrillation and Retinal Stroke

Atrial fibrillation (AF) is the most common, chronic, cardiac arrythmia in older US adults. It is not known whether AF is independently associated with increased risk of retinal stroke (central retinal artery occlusion), a subtype of ischemic stroke that causes severely disabling visual loss in most cases and is a harbinger of further vascular events. To determine whether there is an association between AF and retinal stroke. This retrospective cohort study was performed between July 2023 and May 2024 using computerized inpatient, outpatient, emergency department, and skilled nursing facility claims files for a 5% sample of US fee-for-service Medicare beneficiaries aged 66 years and older between 2000 and 2020. Follow-up ended at death, conclusion of fee-for-service Medicare coverage, end of the study period, or loss to follow-up of 85% of the study cohort. AF, based on validated International Classification of Diseases, Ninth Revision, Clinical Modification and International Statistical Classification of Diseases, Tenth Revision, Clinical Modification diagnosis codes. The primary end point was incident retinal stroke in the primary diagnostic position of a single claim in any venue of care. Secondary end points included retinal stroke in any position of a single claim, 1 positive control end point (cerebral ischemic stroke), and 4 negative control end points (central retinal vein occlusion, urinary tract infection, humeral fracture, and cataract). Unadjusted and adjusted hazard ratios (HRs) and rate differences were computed across matched and overlap-weighted cohorts with and without AF (defined as 1 inpatient claim or 2 outpatient claims within a 365-day period). In total, 1 090 144 patients (591 400 female [54.3%]; mean [SD] age, 76.92 [7.09] years) were included in the study; 545 072 patients had AF and 545 072 were matched controls. The median (IQR) follow-up was 45 (18 to 90) months. In total, 1333 patients with AF (rate, 0.55 per 1000 person-years) and 1082 AF-free matched controls (rate, 0.50 per 1000 person-years) experienced retinal stroke. The cause-specific, adjusted HR of retinal stroke after overlap weighting was 1.14 (95% CI, 1.02 to 1.28; adjusted rate difference, 0.05 [95% CI, -0.01 to 0.11]). AF was associated with cerebral ischemic stroke (adjusted HR, 1.73 [95% CI, 1.69 to 1.76]; adjusted rate difference, 10.11 [95% CI, 9.72 to 10.49]). Of 4 prespecified negative control end points, AF was not associated with central retinal vein occlusion but was associated with urinary tract infection, cataract, and humeral fracture. In this cohort study of Medicare beneficiaries aged 66 years and older, AF was independently associated with retinal stroke. The magnitude of the association was small, and a contribution from residual, unmeasured confounding could not be excluded.

Elective Thoracic Surgical Resections for Pulmonary Arteriovenous Malformations - A 16 Year Single-Center Experience.

Pulmonary arteriovenous malformations (PAVMs) cause cerebral abscess and ischemic stroke due to paradoxical emboli, risks that are increasingly recognized. We report the evolving placement of thoracic surgery in multi-disciplinary team management of PAVMs that were sporadic or associated with hereditary hemorrhagic telangiectasia. From 1983 to 2006, all patients receiving elective treatment had embolization. Between January 2006 and July 2022, 24 of 714 (3%) patients reviewed at our institution underwent elective surgical resection of one or more PAVMs. Initially, the bar for elective surgery had been set very high, and only patients with persistent symptoms of cerebral ischemia after maximal embolization and medical therapy were referred. As PAVM natural history, follow-up radiation exposures for residual PAVMs, and good surgical outcomes were appreciated, PAVM resection became part of the discussion for highly localized, very complex PAVMs which we consider are best treated surgically. Elective surgical intervention may be considered for other selected patients.

Edaravone reduces the markers of oxidative stress and neuroinflammation in neocortex of rats with acute intracerebral hemorrhage and type 2 diabetes mellitus

Type 2 diabetes mellitus (T2DM) is associated with a higher incidence of hemorrhagic stroke in a severe form. The aim of this study was to estimate the markers of oxidative stress and neuroinflammation in the brain of rats with acute intracerebral hemorrhage (ICH) and T2DM after treatment with edaravone. T2DM was induced by a single intraperitoneal injection of nicotinamide/streptozotocin, ICH – by stereotactic microinjection of bacterial collagenase. Rats were randomized into four groups: 1 – intact control; 2 – T2DM; 3 – T2DM+ICH; 4 – T2DM+ICH+edaravone 6 mg/kg/day. Edaravone (a drug to treat neural injury after acute cerebral ischemic stroke) was administered intraperitoneally for 10 days starting from the 60th day after diabetes mellitus induction and 30 min after ICH induction. Brain homogenates were assessed for the content of advanced glycation end products (AGEs) and advanced oxidation protein products (AOPPs). The levels of TNF-α and 8-hydroxy-2′-deoxyguanosine (8-OHdG) were measured with ELISA. The increased content of 8-OHdG and TNF-α in brain homogenates of animals of T2DM group compared to the control was shown. It was revealed that in brain homogenates of animals of T2DM+ICH group the content of these markers­ significantly exceeds that for T2DM group, and in addition, an elevated AOPPs level was observed. Our results demonstrated that edaravone prevented the elevation of TNF-α level, reduced oxidative DNA damage by decreasing 8-OHdG content, and attenuated the formation of AGEs and AOPPs in the brains of experimental animals. These findings suggest that edaravone may have therapeutic potential in diabetic patients with acute ICH. Keywords: edaravone, intracerebral hemorrhage, neuroinflammation, oxidative stress, TNF-α, type 2 diabetes mellitus

Gut-Brain Axis Microbiota in Stroke Pathogenesis

Stroke is the second cause of death globally and the third cause of global disability, causing substantial health and socioeconomic problems. Clinically, Stroke is defined as brain tissue injury caused by a lack of blood supply to a particular area, resulting in permanent nerve damage or death. Stroke is also frequently associated with metabolic causes, including insulin resistance, obesity, hypertension, and type 2 diabetes mellitus (T2DM), significantly influencing the composition and abundance of the gut microbiota. Therefore, identifying potential risk factors influencing stroke prognosis and underlying pathogenic mechanisms is essential for better management and treatment of Stroke. Several studies show the existence of two-way communication between the gut and the brain through the gut microbiota. Intimate two-way interactions between the gut and the brain occur via neural (central, autonomic, and enteric nervous systems), hormonal (endocrine system), and immunological (innate and acquired immune systems) pathways, commonly referred to as the gut-microbiota axis. Brain or gut-brain axis (Gut-Brain Axis/GBA). Gut microbiota and derived metabolites play an important role in brain function by regulating GBA signaling. Recent evidence also suggests that GBA is critical in regulating immune function post-stroke. Intestinal dysbiosis provides a chronic peripheral and central inflammatory response that accelerates stroke pathology. Gut microbial dysbiosis is a significant risk factor positively correlated with poor post-stroke outcomes. This literature review summarizes the pathogenesis of ischemic Stroke, the description of the gut microbiota, and preclinical and clinical evidence indicating the pathogenic influence of gut dysbiosis in cerebral ischemic Stroke. Keywords: Stroke, Gut-brain axis, dysbiosis

Modified human mesenchymal stromal/stem cells restore cortical excitability after focal ischemic stroke in rats.

Allogeneic modified bone marrow-derived mesenchymal stromal/stem cells (hMSC-SB623 cells) are in clinical development for the treatment of chronic motor deficits after traumatic brain injury and cerebral ischemic stroke. However, their exact mechanisms of action remain unclear. Here, we investigated the effects of this cell therapy on cortical network excitability, brain tissue and peripheral blood at a chronic stage after ischemic stroke in a rat model. One month after focal cortical ischemic stroke, hMSC-SB623 cells or the vehicle solution were injected into the peri-stroke cortex. Starting one-week post-treatment, cortical excitability was assessed ex vivo. hMSC-SB623 cell transplants reduced stroke-induced cortical hyperexcitability, restoring cortical excitability to control levels. Histology of brain tissue revealed an increase of factors relevant to neuroregeneration and synaptic and cellular plasticity. Whole-blood RNA sequencing and serum protein analyses showed that intracortical hMSC-SB623 cell transplantation reversed effects of stroke on peripheral blood factors known to be involved in stroke pathophysiology. Our findings demonstrate that intra-cortical transplants of hMSC-SB623 cells correct stroke-induced circuit disruptions even at the chronic stage, suggesting broad utility as a therapeutic for neurological conditions with network hyperexcitability. Additionally, the transplanted cells exert far-reaching immunomodulatory effects whose therapeutic impact remains to be explored.

Systemic intravenous thrombolysis and spinal stroke: a case report and review of the literature

BackgroundSpinal cord infarction (SCI) is associated with poor clinical outcome. Intravenous thrombolysis (IVT) is a well-established treatment for cerebral ischaemic stroke. However, its efficacy in SCI is unknown.ObjectiveWe present a...

Differential analysis of microRNAs in plasma exosomes in patients with cerebral ischemic stroke.

The high incidence, disability, mortality, and recurrence rates of cerebral infarction impose a heavy burden on both the Chinese and global populations. It is essential for the early diagnosis, prevention, and protection against brain cell injury. To identify differentially expressed microRNAs (miRNAs) in plasma exosomes of patients with cerebral ischemic stroke, determine relevant biomarkers, and explore their potential signaling pathways. High-throughput sequencing was used to detect the expression of plasma exosomal miRNAs in patients with cerebral ischemic stroke and in a control group. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes enrichment, and target gene network analyses were performed to investigate the target genes and signaling pathways of the differentially expressed miRNAs. The sequencing results identified 95 differentially expressed miRNAs, with 40 upregulated and 55 downregulated miRNAs. Among these, hsa-miR-1303, hsa-miR-125b-1-3p, and hsa-miR-548ab were significantly upregulated in the stroke group and downregulated in the normal control group, whereas hsa-miR-1289 was downregulated in the stroke group and upregulated in the normal group. Gene Ontology, Kyoto Encyclopedia of Genes, and genomes enrichment analyses indicated that the differentially expressed miRNAs and their target genes were mainly concentrated in the PI3K-AKt, mitogen-activated protein kinase, calcium, Ras, Rap1, and cAMP signaling pathways. The expression of plasma exosomal hsa-miR-1303, hsa-miR-125b-1-3p, and hsa-miR-1289 was significantly different in stroke patients than in the control group. These miRNAs may be involved in various signaling pathways related to cerebral infarction, providing a reference for further experimental research.

The Therapeutic Effects of SP-8356, a Verbenone Derivative, with Multimodal Cytoprotective Mechanisms in an Ischemic Stroke Rat Model.

An ischemic cerebral stroke results from the interruption of blood flow to the brain, triggering rapid and complex cascades of excitotoxicity, oxidative stress, and inflammation. Current reperfusion therapies, including intravenous thrombolysis and mechanical thrombectomy, cause further brain injury due to reperfusion-induced cytotoxicity. To date, novel cytoprotective therapies that could address these challenges have yet to be developed, likely due to the limitations of targeting a single pathologic mechanism. To address these unmet clinical needs, we investigated a synthetic verbenone derivative, SP-8356, as a potential multi-target cytoprotective agent for acute ischemic strokes. In transient middle cerebral artery occlusion (MCAO) rats, SP-8356 significantly reduced brain infarct and edema volumes while improving acute neurological deficits in a dose-dependent manner. Furthermore, SP-8356 improved long-term outcomes, particularly by reducing mortality. These potent cytoprotective effects of SP-8356 were achieved by suppressing the excessive production of free radicals and pro-inflammatory cytokines, reducing the infiltration of inflammatory cells, and mitigating increases in blood-brain barrier permeability. Additional research is needed to determine whether co-administration of SP-8356 can extend the therapeutic time window of reperfusion therapies by mitigating ischemia/reperfusion injury.

Transcriptomic Profiling Reveals Sex-Specific Epigenetic Dynamics Involving kdm6b and H3K27 Methylation in Cerebral Ischemia-Induced Neurogenesis and Recovery.

Cerebral ischemic stroke ranks among the leading causes of death and disability worldwide. A significant challenge, beyond the lack of effective therapies, is the frequent oversight of sex as a vital factor in stroke research. This study focuses on elucidating the sex-specific epigenetic mechanisms that contribute to neural damage and recovery in cerebral ischemia. In our previously reported study, we demonstrated that following ischemia-induced cerebral artery occlusion (ICAO), female striatal tissue exhibited an early reinstatement of H3K9me2 marks on the promoters of inflammatory genes compared to male striatal tissue. This restoration led to a reduction in the expression of inflammatory cytokines, ultimately contributing to accelerated recovery in females. Building upon these findings, the current study aimed to investigate the unidentified molecular pathways responsible for the accelerated recovery observed in females. To explore this, we performed illumina-RNA sequencing on striatal tissues 24-h post-ICAO. Interestingly, our analysis revealed differential regulation of H3K27me2 marks on the promoters of various neurogenic genes at an early stage, which facilitated early neurogenesis in the female striatum. This investigation identifies an epigenetic modulator, kdm6b/jmjd3, targeting H3K27, and delineates its sex-specific role in neural stem cell proliferation. The findings contribute to a comprehensive model linking gender-specific epigenetic regulation, neurogenesis, and post-ICAO recovery. In conclusion, the identified epigenetic modulators and their roles in neurogenesis offer potential targets for refined therapeutic interventions, emphasizing the importance of personalized and sex-specific considerations in stroke studies.

Chaperone-Mediated Autophagy Alleviates Cerebral Ischemia-Reperfusion Injury by Inhibiting P53-Mediated Mitochondria-Associated Apoptosis.

Ischemia-reperfusion is a complex brain disease involving multiple biological processes, including autophagy, oxidative stress, and mitochondria-associated apoptosis. Chaperone-mediated autophagy (CMA), a selective autophagy, is involved in the development of various neurodegenerative diseases and acute nerve injury, but its role in ischemia-reperfusion is unclear. Here, we used middle cerebral artery occlusion/reperfusion (MCAO/R) and oxygen-glucose deprivation/reoxygenation (OGD/R) models to simulate cerebral ischemic stroke in vivo and in vitro, respectively. LAMP2A (lysosome-associated membrane protein 2A), a key molecule of CMA, was dramatically downregulated in ischemia-reperfusion. Enhancement of CMA activity by LAMP2A overexpression reduced the neurological deficit, brain infarct volume, pathological features, and neuronal apoptosis of the cortex in vivo. Concomitantly, enhanced CMA activity alleviated OGD/R-induced apoptosis and mitochondrial membrane potential decline in vitro. In addition, we found that CMA inhibited the P53(Tumor protein p53) signaling pathway and reduced P53 translocation to mitochondria. The P53 activator, Nutlin-3, not only reversed the inhibitory effect of CMA on apoptosis, but also significantly weakened the protective effect of CMA on OGD/R and MCAO/R. Taken together, these results indicate that inhibition of P53-mediated mitochondria-associated apoptosis is essential for the neuroprotective effect of CMA against ischemia-reperfusion.

The Potential Effects of 2,3,4-Trihydroxybenzophenone on the Transient Cerebral Ischemic Stroke in Male Mice.

Acute ischemic stroke is a cerebrovascular disease associated with high mortality and severe aftereffects which is caused by the blockage of cerebral blood vessels by a thrombus or embolus. Treatments for this condition are extremely limited. Herein, we aimed to explore the potential of 2,3,4-trihydroxybenzophenone (THB), a drug that suppresses oxidative stress and neuroinflammation, to promote functional recovery through neurite outgrowth, and to identify its protective effects in a mouse model of ischemic stroke. To determine the effects of THB on neurite outgrowth, neurite-bearing cells and neurite lengths were measured in Neuro2a cells. 1,1-Diphenyl-2-picrylhydrazyl and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) scavenging assays were further performed to determine the antioxidant activity of THB, while lipopolysaccharide-activated BV2 cells were used to determine the anti-inflammatory effects of THB. Transient middle cerebral artery occlusion (tMCAO) was further performed in a mouse model to determine the effects of THB on ischemic stroke. THB increased neurite outgrowth in mouse neuroblastoma cell lines and exhibits antioxidant and anti-neuroinflammatory properties. In addition, THB reduced infarct volume in a concentration-dependent manner in the tMCAO model, leading to an increase in survival rate. Moreover, THB significantly suppressed microglial activation in the cortex and striatum. These results suggest that THB has potential for treating transient cerebral ischemic stroke.

DISRUPTION OF HEMOSTASIS IN THE PATHOGENESIS OF ISCHEMIC STROKE

This review article presents current information on the pathogenetic features of hemostasis in cerebral ischemic stroke based on the analysis of scientific articles indexed in PubMed and Web of Science databases. Ischemic stroke is a sudden neurological failure due to acute focal cerebral ischemia leading to cerebral infarction. The role of hemostasis disorders in the pathogenesis of ischemic stroke has been much less publicized in scientific circles, and the dynamics of disorders and early signs of activation of the blood coagulation system, including the development of hemorrhagic transformation and secondary vasospasm, have not been sufficiently studied.

Efficacy and Safety of Sovateltide in Patients with Acute Cerebral Ischaemic Stroke: A Randomised, Double-Blind, Placebo-Controlled, Multicentre, Phase III Clinical Trial.

Sovateltide (Tycamzzi™), an endothelin-B (ET-B) receptor agonist, increases cerebral blood flow, has anti-apoptotic activity, and promotes neural repair following cerebral ischaemic stroke. The objectives of this study were to evaluate the efficacy and safety of sovateltide in adult participants with acute cerebral ischaemic stroke. This was a randomised, double-blind, placebo-controlled, multicentre, Phase III clinical trial of sovateltide in participants with cerebral ischaemic stroke receiving standard of care (SOC) in India. Patients aged 18-78 years presenting up to 24 h after the onset of symptoms with radiologic confirmation of ischaemic stroke and a National Institutes of Health Stroke Scale score (NIHSS) of ≥ 6were enrolled. Patients with recurrent stroke, receiving endovascular therapy, or with intracranial haemorrhage were excluded. The study drug (saline or sovateltide [0.3 µg/kg] was administered intravenously in three doses at 3 ± 1 h intervals on Days 1, 3, and 6, and follow-up was 90 days). The Multivariate Imputation by Chained Equations (MICE) was used to impute the missing assessments on the endpoints. An unpaired t-test, two-way analysis of variance with Tukey's multiple comparison test, and the Chi-square test were used for the statistical analysis. The objective was to determine at Day 90 (1) the number of patients with a modified Rankin Scale score (mRS) 0-2, and (2) the number of patients with an NIHSS 0-5 at 90 days. Patients were randomised with 80 patients in the sovateltide and 78 in the control group. Patients received the investigational drug at about 18 h of stroke onset in both control and sovateltide groups. The median NIHSS at randomisation was 10.00 (95% CI 9.99-11.65) in the control group and 9.00 (95% CI 9.11-10.46) in the sovateltide group. Seventy patients completed the 90-day follow-up in the control group and 67 in the sovateltide group. The proportion of intention-to-treat (ITT) patients with mRS 0-2 score at Day 90 post-randomisation was 22.67% higher (odds ratio [OR] 2.75, 95% CI 1.37-5.57); similarly, the proportion of patients with NIHSS score of 0-5 at Day 90 was 17.05% more (OR 2.67, 95% CI 1.27-5.90) in the sovateltide group than in the control group. An improvement of ≥ 2 points on the mRS was observed in 51.28% and 72.50% of patients in the control and sovateltide groups, respectively (OR 2.50, 95% CI 1.29-4.81). Seven of 78 patients (8.97%) in the control group and 7 of 80 (8.75%) in the sovateltide group developed intracranial haemorrhage (ICH). The adverse events were not related to sovateltide. The sovateltide group had a greater number of cerebral ischaemic stroke patients with lower mRS and NIHSS scores at 90 days post-treatment than the control group. This trial supported the regulatory approval of sovateltide in India, but a multinational RESPECT-ETB trial will be conducted for US approval. Clinical Trials Registry, India (CTRI/2019/09/021373) and the United States National Library of Medicine, ClinicalTrials.gov (NCT04047563).

HELMET: A Hybrid Machine Learning Framework for Real-Time Prediction of Edema Trajectory in Large Middle Cerebral Artery Stroke.

Malignant cerebral edema occurs when brain swelling displaces and compresses vital midline structures within the first week of a large middle cerebral artery stroke. Early interventions such as hyperosmolar therapy or surgical decompression may reverse secondary injury but must be administered judiciously. To optimize treatment and reduce secondary damage, clinicians need strategies to frequently and quantitatively assess the trajectory of edema using updated, relevant information. However, existing risk assessment tools are limited by the absence of structured records capturing the evolution of edema and typically estimate risk at a single time point early in the admission, therefore failing to account for changes in variables over the following hours or days. To address this, we developed and validated dynamic machine learning models capable of accurately predicting the severity of midline structure displacement, an established indicator of malignant edema, in real-time. Our models can provide updated estimations as frequently as every hour, using data from structured time-varying patient records, radiographic text, and human-curated neurological characteristics. Our work resulted in two novel multi-class classification models, collectively named Hybrid Ensemble Learning Models for Edema Trajectory (HELMET), predicting the progression of midline shift over 8-hour (HELMET-8) and 24-hour windows (HELMET-24), respectively. HELMET combines transformer-based large language models with supervised ensemble learning, demonstrating the value of merging human expertise and multimodal health records in developing clinical risk scores. Both models were trained on a retrospective cohort of 15,696 observations from 623 patients hospitalized with large middle cerebral artery ischemic stroke and were externally validated using 3,713 observations from 60 patients at a separate hospital system. Our HELMET models are accurate and generalize effectively to diverse populations, achieving a cross-validated mean area under the receiver operating characteristic score of 96.6% in the derivation cohort and 92.5% in the external validation cohort. Moreover, our approach provides a framework for developing hybrid risk prediction models that integrate both human-extracted and algorithm-derived multi-modal inputs. Our work enables accurate estimation of complex, dynamic, and highly specific clinical targets, such as midline shift, in real-time, even when relevant structured information is limited in electronic health record databases.

E3 Ubiquitin Ligase Ring Finger Protein 2 Alleviates Cerebral Ischemia-Reperfusion Injury by Stabilizing Mesencephalic Astrocyte-Derived Neurotrophic Factor Through Monoubiquitination.

Cerebral ischemic stroke (IS) is one of the leading causes of morbidity and mortality globally. However, the mechanisms underlying IS injury remain poorly understood. Ring finger protein 2 (RNF2), the member of the polycomb family (PcG), has been implicated in diverse biological and pathological conditions. However, whether RNF2 plays a role in IS progression is not clarified. This study aims to investigate the potential effects of RNF2 on IS. The effects of RNF2 were studied in human postmortem IS brains, a rat model of IS, tunicamycin (TM)-induced mouse neuroblastoma neuro2a (N2a) cells, and oxygen-glucose deprivation/reperfusion (OGD/R)-induced SH-SY5Y cells. Here, we demonstrated that RNF2 was markedly upregulated both in human postmortem IS brains and ischemic rat brains and RNF2 overexpression alleviated brain injury induced by middle cerebral artery occlusion by reducing neuron apoptosis. Mechanistically, we found that RNF2 is an E3 ubiquitin ligase for the mesencephalic astrocyte-derived neurotrophic factor (MANF), which confers protection against brain ischemia. RNF2 interacted with MANF and promoted the monoubiquitination of MANF, consequently facilitating its stability and nuclear localization. Collectively, RNF2 is identified as a critical inhibitor of IS injury by stabilizing MANF through monoubiquitination, suggesting that RNF2 is a potential therapeutic target for IS.

Long-term cognitive outcomes after decompressive hemicraniectomy for right-hemisphere large middle cerebral artery ischemic stroke.

Decompressive hemicraniectomy (DH) improves survival and functional outcome in large middle cerebral artery (MCA) infarcts. However, long-term cognitive outcomes after DH remain underexplored. In a cohort of patients with large right-hemisphere MCA infarction undergoing DH, we assessed the rates of long-term cognitive impairment over 3-year follow-up. We prospectively evaluated consecutive patients included in the Lille Decompressive Surgery Database (May 2005-April 2022) undergoing DH according to existing guidelines for large hemisphere MCA infarction. We included patients with right-sided stroke andscreened with the Mini-Mental State Examination (MMSE) in at least one of the prespecified follow-ups (3-month, 1-year, 3-year). Cognitive impairment was defined as an MMSE score < 24. We included only right-hemisphere strokes to avoid testing biases related to severe aphasia. We compared clinical and neuroimaging data in patients with and without cognitive impairment. Three hundred four patients underwent DH during the study period. Among 3-month survivors, 95 had a right-hemisphere stroke and underwent at least one cognitive screening (median age = 51 years, 56.8% men). Forty-four patients (46.3%) exhibited cognitive impairment at least once during the 3-year follow-up. Baseline characteristics did not significantly differ between patients with and without cognitive impairment. Regarding long-term temporal trends, cognitive impairment was observed in 23 of 76 (30.3%), 25 of 80 (31.3%), and 19 of 66 (28.8%) patients at 3-month, 1-year, and 3-year follow-up, respectively, and it was associated with higher rates of functional disability (all p < 0.05). The persistently high rates of cognitive impairment after DH highlight the importance of cognitive monitoring to improve the long-term management of survivors.

Research Progress on the Pharmacological Mechanism of Traditional Chinese Medicine Danshen in the Treatment of Cerebral Ischemic Stroke

Cerebral ischemic stroke (CIS) is an acute cerebrovascular disease characterized by focal neurological deficits. Many modern scholars believe that the pathogenesis of CIS is related to factors such as endothelial injury, oxidative stress imbalance, neuroinflammation, cell apoptosis and autophagy, calcium overload, and excessive accumulation of oxygen free radicals. Traditional Chinese medicine believes that the pathogenesis of CIS is obstructed meridians, phlegm and blood stasis, and obstruction of the brain and orifices. Danshen, as a commonly used traditional Chinese medicine in clinical practice, has the effects of promoting blood circulation and removing blood stasis, unblocking meridians and relieving pain, clearing the heart and eliminating restlessness, cooling blood and eliminating carbuncle. In addition, modern pharmacological research has found that the specific pharmacological components of Salvia miltiorrhiza include tanshinone, salvianolic acid, shikimic acid, danshensu, protocatechualdehyde, etc. It has antioxidant stress, regulation of cell autophagy, anti-inflammatory factors, antiplatelet aggregation, and protection of vascular endothelium. This article aims to analyze and summarize the pharmacological mechanism of salvia miltiorrhiza in treating CIS, providing scientific basis for clinical application of salvia miltiorrhiza in treating CIS.

Outcome and life expectancy associated with novel subgroups of atrial fibrillation: a data-driven cluster analysis

Abstract Background/Introduction Atrial fibrillation (AF) presents a significant global health burden, affecting millions and associated with elevated risks of mortality, heart failure, and stroke despite current treatment strategies. The current diagnosis of AF relies on episode characteristics, yet its heterogeneity calls for personalized assessment incorporating clinical features, biomarkers, and substrate determination for improved classification and management. Purpose This study aimed to develop a refined classification of AF according to comprehensive risk factors to identify patients at high-risk for poor prognosis and their life expectancy, aiming to facilitate personalized interventions. Methods A total of 7,391 participants aged 40-69 with AF at baseline, from UK Biobank, were recruited in the main analyses. Firstly, LASSO regression with Cox model and factor analysis were adopted for identification and integration of principal risk factors. Second, Consensus clustering analysis was employed to estimate the optimal cluster number and group all 7,391 participants. Difference in the risk of death and major complications, as well as reductions in life expectancy, among clusters were estimated. Replication was done in 2,399 participants with newly diagnosed AF within two years after baseline. Results Risk factors for AF were categorized into seven aspects (metabolic factors, respiratory factors, cardiovascular factors, renal and immunity diseases, mental health, acute illness, age), based on the correlation between them. Five distinct AF clusters were identified according to these seven characteristics: acute illness-related (Cluster 1), mental health-related (Cluster 2), cardiovascular disease-related (Cluster 3), immune-and-renal disease-related (Cluster 4), and respiratory-and-metabolism disease-related AF (Cluster 5). Patients with respiratory-and-metabolism disease-related AF had the highest risk of death, acute myocardial infarction, heart failure, and cerebral ischemic stroke, while those with acute illness-related AF had the lowest corresponding risk. In addition, compared with individuals with acute illness-related AF, those with respiratory-and-metabolism disease-related and mental health-related AF had the top 2 greatest loss of life expectancy. Furthermore, genetic variants for AF had different effect among the five clusters. Replication analysis confirmed the result stability. Conclusion A novel AF classification was developed, which provided insights into varying life expectancy and risks of death and complications among AF subgroups with distinct characteristics. It offers a practical approach for identifying high-risk patients, which may help to tailor precise interventions for AF management.Graphic abstractCluster features