Biomarker For Ischemic Stroke Research Articles

Diagnostic significance of serum hsa_circ_0000745 and hsa_circ_0001459 in ischemic stroke and its role in the prognosis of interventional therapy

ABSTRACT Objective We aimed to identify hsa_circ_0000745 and hsa_circ_0001459 expression, value as biomarkers in ischemic stroke (IS), and functions in BV2 cells. Methods RNA sequencing datasets in the GEO database were retrieved. The expression of circulating hsa_circ_0000745 and hsa_circ_0001459 was validated by RT-qPCR. The predictive values of hsa_circ_0000745 and hsa_circ_0001459 in the diagnosis and outcome of acute IS were evaluated using receiver operator characteristic curve analysis. BV2 cells were treated with lipopolysaccharide, followed by hsa_circ_0000745 or hsa_circ_0001459 downregulation and subsequent migration and apoptosis assay. The downstream miR-1287-5p was detected using the luciferase reporter gene assay. Results Hsa_circ_0000745 or hsa_circ_0001459 were upregulated in acute IS. Hsa_circ_0000745 or/and hsa_circ_0001459 differentiated between healthy control subjects and patients with IS, resulting in areas under curve (AUC) of 0.85 and 0.83, respectively. Hsa_circ_0000745 or hsa_circ_0001459 was positively correlated with serum pro-inflammatory cytokines and the NIHSS (P<0.001). Longitudinal and ROC analyses of hsa_circ_0001459 and hsa_circ_0000745 expression levels revealed the 90-day-outcome-predicting potential after stroke. Hsa_circ_0001459 and hsa_circ_0000745 promoted the apoptosis and inhibited the migration of LPS-induced BV2 cells. Hsa_circ_0001459 and hsa_circ_0000745 commonly sponged miR-1287-5p. Conclusions Hsa_circ_0001459 and hsa_circ_0000745 showed upregulations in IS and might have clinical utility as a diagnostic and outcome-predicting marker.

Astrocyte Dysfunction Reflected in Ischemia-Induced Astrocyte-Derived Extracellular Vesicles: A Pilot Study on Acute Ischemic Stroke Patients.

Extracellular vesicles (EVs) secreted by astrocytes (ADEVs) mediate numerous biological processes, providing insights into damage, repair, and protection following ischemic stroke (IS). This pilot study aimed to broaden the current knowledge on the astrocyte response to ischemia by dynamically assessing the aquaporin-4 (AQP4) and glial cell line-derived neurotrophic factor (GDNF) as cargo proteins of these vesicles in eighteen acute IS patients and nine controls. EV proteins were detected by Western blotting and followed 24 h (D1), 7 days (D7), and one month (M1) after symptoms onset. The post-ischemic ADEV AQP4 and GDNF levels were higher at D1 compared to the control group (p = 0.006 and p = 0.023). Significant differences were observed in ADEV AQP4 during the three evaluated time points (n = 12, p = 0.013) and between D1 and D7 (z = 2.858, p = 0.012), but not in EV GDNF. There was a positive relationship between the severity of stroke at D1 according to the National Institutes of Health Stroke Scale, and ADEV AQP4 at D1 (r = 0.50, p = 0.031), as well as ADEV GDNF at D1 and D7 (r = 0.49, p = 0.035 and r = 0.53, p = 0.021, respectively). The release of EVs with distinct protein profiles can be an attractive platform for the development of biomarkers in IS.

A Combined Extract Derived from Black Sticky Rice and Dill Improves Clinical Symptoms and Ischemic Stroke Biomarkers in Transient Ischemic Attack and Ischemic Stroke Patients.

Currently, the adjuvant therapy to optimize the restorative process after stroke is required due to the unsatisfied therapeutic efficacy. A combined extract of black sticky rice and dill showed potential in the preclinical state, so we hypothesized that it could provide clinical benefits. A three-arm, randomized, placebo-controlled study was set up to elucidate this issue. Both males and females (18-80 years old) who had experienced transient ischemic attacks or ischemic strokes within the last 5-10 days with an NIHSS score ≤ 7 and received standard treatment were randomly assigned to receive either a placebo or capsule containing a combined extract of black sticky rice and dill at a dose of 600 or 1200 mg per day. The safety parameters, movement control, and degree of disability were assessed 1, 2, and 6 weeks after the intervention, and serum stroke biomarkers were assessed at the mentioned time points, except at 2 weeks. After week 1, the high-dose (1200 mg/day) treatment group had improved NIHSSS, VCAM1, and MMP-9. Both S100β and VCAM1 also improved at week 6, while the low-dose treatment group (600 mg/day) only exhibited improved VCAM1. Therefore, a high dose of the developed adjuvant supplement improves stroke recovery by improving motor impairment by reducing endothelial dysfunction and inflammation.

Plasma Phenylacetylglutamine Levels and Prognosis of Ischemic Stroke: A Multicenter Prospective Study Based on the CATIS Trial.

Phenylacetylglutamine is implicated in platelet clotting and thrombosis, but its prognostic value in ischemic stroke remains unclear. We aimed to explore the associations of plasma phenylacetylglutamine levels with adverse outcomes after ischemic stroke in a multicenter prognostic cohort study. Our multicenter prognostic cohort study included 3564 Chinese patients with ischemic stroke from the CATIS (China Antihypertensive Trial in Acute Ischemic Stroke). All patients were followed up at 3 months after ischemic stroke onset. The primary outcome was the composite outcome of death or major disability (modified Rankin Scale score, 3-6) at 3 months after ischemic stroke. During 3 months of follow-up, 877 participants experienced the primary outcome. After multivariate adjustment, each 500 ng/mL increase of phenylacetylglutamine was associated with a 7% (P=0.012), 6% (P=0.016), and 6% (P=0.028) increased risk of the primary outcome, major disability, and death, respectively. The odds ratios or hazard ratios in the highest versus the lowest quartile of plasma phenylacetylglutamine were 1.62 ([95% CI, 1.18-2.23]; Ptrend=0.001) for the primary outcome, 1.62 ([95% CI, 1.16-2.24]; Ptrend=0.001) for major disability, and 2.59 ([95% CI, 1.19-5.60]; Ptrend=0.025) for death, respectively. There was a significantly worse shift in the distribution of modified Rankin Scale score at 3 months with higher phenylacetylglutamine quartiles (Ptrend=0.003). Multiple-adjusted spline regression model showed a linear relationship between phenylacetylglutamine and primary outcome (P value for linearity<0.001). The addition of plasma phenylacetylglutamine to conventional risk factors significantly improved the risk reclassification for the primary outcome (net reclassification improvement, 19.34%; P<0.001; integrated discrimination improvement, 0.23%; P=0.019). Elevated plasma phenylacetylglutamine levels at baseline were associated with increased risks of adverse clinical outcomes at 3 months after ischemic stroke, suggesting that phenylacetylglutamine may be a promising prognostic biomarker for ischemic stroke. Further studies are needed to investigate whether phenylacetylglutamine is a stroke-specific biomarker.

Exploring common biomarkers of ischemic stroke and obstructive sleep apnea through bioinformatics analysis.

Clinical observations have shown that many patients with ischemic stroke (IS) have a history of obstructive sleep apnea (OSA) both before and after the stroke's onset, suggesting potential underlying connections and shared comorbid mechanisms between the two conditions. The aim of this study is to identify the genetic characteristics of OSA patients who develop IS and to establish a reliable disease diagnostic model to assess the risk of IS in OSA patients. We selected IS and OSA datasets from the Gene Expression Omnibus (GEO) database as training sets. Core genes were identified using the Limma package, Weighted Gene Co-expression Network Analysis (WGCNA), and machine learning algorithms. Gene Set Variation Analysis (GSVA) was conducted for pathway enrichment analysis, while single-sample gene set enrichment analysis (ssGSEA) was employed for immune infiltration analysis. Finally, a diagnostic model was developed using Least Absolute Shrinkage and Selection Operator (LASSO) regression, with its diagnostic efficacy validated using receiver operating characteristic (ROC) curves across two independent validation sets. The results revealed that differential analysis and machine learning identified two common genes, TM9SF2 and CCL8, shared between IS and OSA. Additionally, seven signaling pathways were found to be commonly upregulated in both conditions. Immune infiltration analysis demonstrated a significant decrease in monocyte levels, with TM9SF2 showing a negative correlation and CCL8 showing a positive correlation with monocytes. The diagnostic model we developed exhibited excellent predictive value in the validation set. In summary, two immune-related core genes, TM9SF2 and CCL8, were identified as common to both IS and OSA. The diagnostic model developed based on these genes may be used to predict the risk of IS in OSA patients.

Transcriptome Sequencing-Based Screening of Key Melatonin-Related Genes in Ischemic Stroke.

Ischemic stroke (IS) is a complex syndrome of neurological deficits due to stenosis or occlusion of the carotid and vertebral arteries for which there is still no effective treatment. Melatonin, a hormone secreted by the pineal gland, has multiple biological effects, such as antioxidant and anti-inflammatory properties, circadian rhythm regulation, and tissue regeneration, demonstrating potential applications in the treatment of IS. The aim of this study was to investigate key melatonin-regulated genes associated with IS using transcriptome sequencing and bioinformatics analyses and to explore their potential mechanisms of action in the disease process. We obtained gene expression data related to ischemic stroke (IS) from the Gene Expression Omnibus (GEO) database and identified candidate genes using machine learning algorithms. We then assessed the predictive power of these genes using PPI network analysis and diagnostic models. Finally, a series of enrichment analyses identified four key genes: ADM, PTGS2, MMP9, and VCAN. In addition, we determined the mRNA levels of these four key genes in an IS rat model using qPCR and found that all of these genes were significantly upregulated in the IS model compared to the control group, which is consistent with the results of previous analyses. Meanwhile, these genes have biological functions such as regulating vascular tone, participating in the inflammatory response, influencing tissue remodeling, and regulating cell adhesion and proliferation, playing key roles in the pathogenesis of IS. Therefore, we suggest that these four key genes may serve as prospective biomarkers for IS and help predict the risk of developing IS. In conclusion, this study elucidates for the first time the potential role of melatonin in the pathogenesis of IS and lays the foundation for in-depth studies on the functions of these key genes in the pathophysiology of IS and their potential applications in clinical diagnosis and treatment.

Exploring Lysophosphatidylcholine as a Biomarker in Ischemic Stroke: The Plasma-Brain Disjunction.

Lipids and their bioactive metabolites, notably lysophosphatidylcholine (LPC), are increasingly important in ischemic stroke research. Reduced plasma LPC levels have been linked to stroke occurrence and poor outcomes, positioning LPC as a potential prognostic or diagnostic marker. Nonetheless, the connection between plasma LPC levels and stroke severity remains unclear. This study aimed to elucidate this relationship by examining plasma LPC levels in conjunction with brain LPC levels to provide a deeper understanding of the underlying mechanisms. Adult male Sprague-Dawley rats underwent transient middle cerebral artery occlusion and were randomly assigned to different groups (sham-operated, vehicle, LPC supplementation, or LPC inhibition). We measured multiple LPC species in the plasma and brain, alongside assessing sensorimotor dysfunction, cerebral perfusion, lesion volume, and markers of BBB damage, inflammation, apoptosis, and oxidative stress. Among five LPC species, plasma LPC(16:0) and LPC(18:1) showed strong correlations with sensorimotor dysfunction, lesion severity, and mechanistic biomarkers in the rat stroke model. Despite notable discrepancies between plasma and brain LPC levels, both were strongly linked to functional outcomes and mechanistic biomarkers, suggesting that LPC's prognostic value is retained extracranially. This study advances the understanding of LPC as a blood marker in ischemic stroke and highlights directions for future research to further elucidate its association with stroke severity, particularly through investigations in more clinically representative models.

Transfer RNAs are Linked to Ischemic Stroke and Major Bleeding in Patients with End-Stage Kidney Disease.

Patients with end-stage kidney disease (ESKD) are at very high risk for thromboembolism and bleeding. This study aimed to identify small noncoding RNAs (sncRNAs), specifically microRNAs and transfer-RNA (tRNA)-derived fragments (tRFs), as potential novel biomarkers for predicting thromboembolism and bleeding in this high-risk population. In this sncRNA discovery research, we leveraged the VIVALDI cohort, consisting of 625 ESKD patients on hemodialysis, to conduct two nested case-control studies, each comprising 18 participants. The primary outcomes were ischemic stroke in the first study and major bleeding in the second. Plasma samples were processed using the miND pipeline for RNA-seq analysis to investigate differential expression of microRNAs and tRNA/tRFs between cases and their respective matched controls, with results stringently adjusted for the false discovery rate (FDR). No significant differential expression of microRNAs for either ischemic stroke or major bleeding outcomes was observed in the two nested case-control studies. However, we identified four tRNAs significantly differentially expressed in ischemic stroke cases and seven in major bleeding cases, compared with controls (FDR < 0.1). Coverage plots indicated that specific tRNA fragments (tRFs), rather than full-length tRNAs, were detected, however. Alternative mapping approaches revealed challenges and technical limitations that precluded in-depth differential expression analyses on these specific tRFs. Yet, they also underscored the potential of tRNAs and tRFs as markers for thromboembolism and bleeding. While microRNAs did not show significant differential expression, our study identifies specific tRNAs/tRFs as potential novel biomarkers for ischemic stroke and major bleeding in ESKD patients.

Association between the serum glucose-to-potassium ratio and clinical outcomes in ischemic stroke patients after endovascular thrombectomy.

The baseline glucose-to-potassium ratio (GPR) is associated with poor outcomes in patients with acute brain injury and intracranial hemorrhage. However, the impact of serum GPR on clinical outcomes after endovascular thrombectomy (EVT) is unclear. This study aimed to evaluate the association between the GPR at admission and functional outcomes at 90 days after EVT. We retrospectively reviewed our database for patients with acute ischemic stroke involving an anterior circulation large-vessel occlusion who received EVT between October 2019 and December 2021. The baseline serum GPR was measured after admission. The primary outcome was a 90-day poor outcome, which was defined as a modified Rankin scale score of 3-6. A total of 273 patients (mean age, 70.9 ± 11.9 years; 161 men) were finally included for analyses. During the 90-day follow-up, 151 patients (55.3%) experienced an unfavorable outcome. After adjusting for demographic characteristics and other potential confounders, the increased GPR was significantly associated with a higher risk of a 90-day poor outcome (odds ratio, 1.852; 95% confidence interval, 1.276-2.688, p = 0.001). Similar results were observed when the GPR was analyzed as a categorical variable. In addition, the restricted cubic spline observed a positive and linear association between the GPR and poor outcomes at 90 days (p = 0.329 for linearity; p = 0.001 for linearity). Our study found that ischemic stroke patients with the higher GPR at admission were more likely to have an unfavorable prognosis at 3 months, suggesting that GPR may be a potential prognostic biomarker for ischemic stroke after EVT.

Combined Analysis of Human and Experimental Rat Samples Identified Biomarkers for Ischemic Stroke.

The genetic transcription profile and underlying molecular mechanisms of ischemic stroke (IS) remain elusive. To address this issue, four mRNA and one miRNA expression profile of rats with middle cerebral artery occlusion (MCAO) were acquired from the Gene Expression Omnibus (GEO) database. A total of 780 differentially expressed genes (DEGs) and 56 miRNAs (DEMs) were screened. Gene set and functional enrichment analysis revealed that a substantial number of immune-inflammation-related pathways were abnormally activated in IS. Through weighted gene co-expression network analysis, the turquoise module was identified as meaningful. By taking the intersection of the turquoise module genes, DEM-target genes, and all DEGs, 354 genes were subsequently obtained as key IS-related genes. Among them, six characteristic genes were identified using the least absolute shrinkage and selection operator. After validation with three external datasets, transforming growth factor beta 1 (Tgfb1) was selected as the hub gene. This finding was further confirmed by gene expression pattern analysis in both the MCAO model rats and clinical IS patients. Moreover, the expression of the hub genes exhibited a negative correlation with the modified Rankin scale score (P < 0.05). Collectively, these results expand our knowledge of the genetic profile and molecular mechanisms involved in IS and suggest that the Tgfb1 gene is a potential biomarker of this disease.

Comprehensive analysis of molecular, physiological, and functional biomarkers of aging with neurological diseases using Mendelian randomization.

An increasing burden of neurological diseases (NDs) has been a public health challenge in an aging society. Age, especially biological age, is the most important risk factor for NDs. Identification of biomarkers of aging to capture NDs might lead to a better understanding of the underlying mechanisms of pathological brain aging and the implementation of effective intervention. We conducted a comprehensive two-sample Mendelian Randomization (MR) study to investigate the association between various biomarkers of aging and three leading causes of NDs: Alzheimer's disease (AD), vascular dementia (VaD), and ischemic stroke. Publicly available GWAS summary statistics on people from European ancestry were obtained for six molecular biomarkers, two physiological biomarkers, and eight functional biomarkers, and three NDs. Genetic variants serving as instrumental variables (IVs) were identified for each biomarker. The MR analysis included inverse variance weighted (IVW), weighted median, MR-Egger, and MR-PRESSO. We found that short telomere length and decrease in appendicular lean mass were associated with an increased risk for AD (OR IVW = 1.12 per 1SD decrease, 95% confidence interval 1.02-1.22, and OR IVW = 1.11, 1.06-1.16, respectively), whereas high frailty index showed a protective effect for AD. Accelerated BioAge appeared to be associated with increased risk for ischemic stroke (OR IVW = 1.3 per year in BioAge acceleration, 95% CI 1.19-1.41). Our findings implied a causal association of short telomere length and a decrease in appendicular lean mass with an increased risk for AD, while BioAge appeared to be a good biomarker for ischemic stroke. Further studies are needed to validate these associations and explore underlying mechanisms.

Identification of Blood Biomarkers in Ischemic Stroke by Integrated Analysis of Metabolomics and Proteomics.

We aimed to uncover the pathological mechanism of ischemic stroke (IS) using a combined analysis of untargeted metabolomics and proteomics. The serum samples from a discovery set of 44 IS patients and 44 matched controls were analyzed using a specific detection method. The same method was then used to validate metabolites and proteins in the two validation sets: one with 30 IS patients and 30 matched controls, and the other with 50 IS patients and 50 matched controls. A total of 105 and 221 differentially expressed metabolites or proteins were identified, and the association between the two omics was determined in the discovery set. Enrichment analysis of the top 25 metabolites and 25 proteins in the two-way orthogonal partial least-squares with discriminant analysis, which was employed to identify highly correlated biomarkers, highlighted 15 pathways relevant to the pathological process. One metabolite and seven proteins exhibited differences between groups in the validation set. The binary logistic regression model, which included metabolite 2-hydroxyhippuric acid and proteins APOM_O95445, MASP2_O00187, and PRTN3_D6CHE9, achieved an area under the curve of 0.985 (95% CI: 0.966-1) in the discovery set. This study elucidated alterations and potential coregulatory influences of metabolites and proteins in the blood of IS patients.

Unveiling circRNA-mediated ceRNA networks in ischemic stroke by integrative analysis of multi-source gene expression profiling

BackgroundCircular RNAs (circRNAs) are emerging as potential therapeutic targets for ischemic stroke (IS) due to their regulatory roles in inflammation and apoptosis. This study aimed to develop a comprehensive and robust IS-specific competing endogenous RNA (ceRNA) network to facilitate the identification of novel diagnostic and therapeutic targets. MethodsWe integrated expression data from 15 IS studies using the Rank-In algorithm to minimize batch effects. Differentially expressed circRNAs, miRNAs, and mRNAs were identified by comparing IS and control samples. Functional enrichment analysis of differentially expressed circRNA host genes revealed significantly enriched pathways and Gene Ontology (GO) terms relevant to IS pathogenesis. We further predicted miRNA-circRNA and mRNA-miRNA interactions, enabling the construction of a comprehensive ceRNA network to identify circRNA-related genes with diagnostic potential for IS. ResultsIntegrated analysis revealed 199 differentially expressed circRNAs, 103 miRNAs, and 1736 mRNAs in IS patients. Functional enrichment analysis implicated these molecules in relevant pathways like the neurotrophin signaling pathway and p53 signaling pathway. The constructed circRNA-miRNA-mRNA regulatory network provided insights into potential mechanisms underlying IS. Three circRNA-related genes (RGS2, CDK5R1, and NSF) displayed promising diagnostic potential for IS when combined. ConclusionsWe successfully constructed a robust and informative IS-specific ceRNA network by integrating data from diverse sources. This network identified differentially expressed RNAs and revealed enriched pathways potentially involved in IS pathogenesis. Notably, our analysis identified CDK5R1, RGS2, and NSF as potential diagnostic biomarkers for IS. This study sheds light on a circRNA-mediated regulatory network with potential diagnostic and therapeutic implications for ischemic stroke.

Matrix Metalloproteinases as Biomarkers for Ischemic Stroke: A Systematic Review

Background: Ischemic stroke, a leading cause of mortality and disability worldwide, occurs due to the disruption of blood flow to the brain, resulting in neuronal damage and death. Matrix metalloproteinases (MMPs), a family of zinc-dependent endopeptidases, play a crucial role in the pathophysiology of ischemic stroke by degrading the extracellular matrix and contributing to blood-brain barrier disruption, inflammation, and neuronal cell death. This systematic review aims to comprehensively evaluate the current evidence regarding the potential of MMPs as biomarkers for ischemic stroke diagnosis, prognosis, and therapeutic monitoring. Methods: A systematic search of electronic databases (PubMed, Embase, and Cochrane Library) was conducted to identify relevant studies published between 2018 and 2024. Studies investigating the association between MMPs and ischemic stroke in human subjects were included. Data extraction and quality assessment were performed independently by two reviewers. Results: The search yielded 2,182 articles, of which 8 studies met the inclusion criteria. The included studies evaluated various MMPs, including MMP-2, MMP-3, MMP-9, and MMP-12, in different biological samples (serum, plasma, cerebrospinal fluid, and brain tissue) from ischemic stroke patients. The majority of studies reported elevated levels of MMPs in ischemic stroke patients compared to healthy controls, with MMP-9 being the most extensively studied. Furthermore, several studies demonstrated a correlation between MMP levels and stroke severity, functional outcome, and the risk of hemorrhagic transformation. Conclusion: The findings of this systematic review suggest that MMPs, particularly MMP-9, hold promise as potential biomarkers for ischemic stroke. However, further research is needed to validate their clinical utility and to explore their potential as therapeutic targets.

Cardiac biomarkers are associated with increased risks of adverse clinical outcomes after ischemic stroke.

Impaired cardiac function was suggested to be implicated in the functional recovery after ischemic stroke, but the prognostic value of cardiac biomarkers among ischemic stroke patients remains unclear. We aimed to prospectively explore the associations of serum lactate dehydrogenase (LDH), plasma N-terminal pro-brain natriuretic peptide (NT-proBNP), and plasma high-sensitivity cardiac troponin T (hs-cTnT) with adverse clinical outcomes after ischemic stroke in a large-scale cohort study. We measured serum LDH, plasma NT-proBNP, and plasma hs-cTnT levels at baseline among 5056 ischemic stroke patients from the Minhang Stroke Cohort study. All patients were followed up at 3months after ischemic stroke onset. The primary outcome was composite outcome of death and major disability (modified Rankin Scale [mRS] score ≥ 3) at 3months after stroke onset, and secondary outcomes included death and ordered 7-level categorical score of the mRS. During 3months of follow-up, 1584 patients developed the primary outcome. Baseline serum LDH, plasma NT-proBNP, and plasma hs-cTnT were positively associated with the risk of adverse outcomes after ischemic stroke. The multivariable-adjusted odds ratios of primary outcome for the highest versus lowest quartile of LDH, NT-proBNP, and hs-cTnT were 1.37 (95% CI 1.13-1.66; Ptrend = 0.001), 2.51 (95% CI, 2.00-3.16; Ptrend < 0.001), and 2.24 (95% CI 1.77-2.83; Ptrend < 0.001), respectively. Each SD increase of log-transformed cardiac biomarker score was associated with a 49% (95% CI 37-62%; P < 0.001) increased risk of primary outcome. Multivariable-adjusted spline regression analyses showed linear relationships between cardiac biomarkers and the risk of primary outcome (all P for linearity < 0.001). Moreover, adding LDH, NT-proBNP, hs-cTnT, or cardiac biomarker score to conventional risk factors significantly improved the risk reclassification of primary outcome after ischemic stroke (all P < 0.05). High LDH, NT-proBNP, hs-cTnT, and cardiac biomarker score were independently associated with increased risks of adverse clinical outcomes among ischemic stroke patients, suggesting that cardiac biomarkers might be potential prognostic biomarkers for ischemic stroke.

Comparative Targeted Metabolomics of Ischemic Stroke: Thrombi and Serum Profiling for the Identification of Stroke-Related Metabolites.

Ischemic stroke is one of the leading causes of death and permanent disability in the world. Rapid diagnosis and intervention are crucial for reducing its consequences on individuals and societies. Therefore, identifying reliable biomarkers for early detection, prognostics, and therapy can facilitate the early prediction and prevention of stroke. Metabolomics has been shown as a promising tool for biomarker discovery since many post-ischemic metabolites can be found in the plasma or serum of the patient. In this research, we performed a comparative targeted metabolomic analysis of stroke thrombi, stroke patient serums, and healthy control serums in order to determine the alteration in the patients' metabolomes, which might serve as biomarkers for early prediction or stroke prevention. The most statistically altered metabolites characterized in the patient serums compared with the control serums were glutamate and serotonin, followed by phospholipids and triacylglycerols. In stroke thrombi compared with the patients' serums, the most significantly altered metabolites were classified as lipids, with choline-containing phospholipids and sphingomyelins having the highest discriminatory score. The results of this preliminary study could help in understanding the roles of different metabolic changes that occur during thrombosis and cerebral ischemia and possibly suggest new metabolic biomarkers for ischemic stroke.

Discovering novel plasma biomarkers for ischemic stroke: Lipidomic and metabolomic analyses in an aged mouse model

Ischemic stroke remains a leading cause of mortality and long-term disability worldwide, necessitating efforts to identify biomarkers for diagnosis, prognosis, and treatment monitoring. The present study aimed to identify novel plasma biomarkers of neurodegeneration and inflammation in a mouse model of stroke induced by distal middle cerebral artery occlusion. Using targeted lipidomic and global untargeted metabolomic profiling of plasma collected from aged male mice 24 h after stroke and weekly thereafter for 7 weeks, we discovered distinct acute and chronic signatures. In the acute phase, we observed elevations in myelin-associated lipids, including sphingomyelin (SM) and hexosylceramide (HCER) lipid species, indicating brain lipid catabolism. In the chronic phase, we identified 12-hydroxyeicosatetraenoic acid (12-HETE) as a putative biomarker of prolonged inflammation, consistent with our previous observation of a biphasic pro-inflammatory response to ischemia in the mouse brain. These results provide insight into the metabolic alterations detectable in the plasma after stroke and highlight the potential of myelin degradation products and arachidonic acid derivatives as biomarkers of neurodegeneration and inflammation, respectively. These discoveries lay the groundwork for further validation in human studies and may improve stroke management strategies.

The Non-Targeted Lipidomic-Based Classifier Reveals Two Candidate Biomarkers for Ischemic Stroke in Hypertensive Individuals.

Traditional clinical risk factors are insufficient to estimate the residual risk of large-vessel ischemic stroke. Non-targeted lipidomic techniques provide an opportunity to evaluate these risks. Plasma samples were collected from 113 hypertensive individuals, including 55 individuals at high risk of ischemic stroke and 58 matched individuals, in a prospective nested case-control cohort. To identify dysregulated lipid metabolites, we conducted multivariate and univariate analyses. A classifier based on a cross-validated procedure was employed to select the optimal combination of lipid species and their ratios. We identified 23 dysregulated lipid species in patients with and without ischemic stroke, including 16 (69.6%) up-regulated and 7 (30.4%) down-regulated lipid species. Through internal cross-validation, the optimal combination of two lipid features (phosphatidylcholine 34:2 and triglyceride 18:1/18:1/22:1 / phosphatidylcholine 34:2, referred to as ischemic stroke-related 2 lipid features - IS2LP) was selected, leading to a more precise prediction probability for ischemic stroke within 3.9 years. In the comparison of different risk factors, the traditional risk score, the IS2LP risk score, and the combination of the traditional risk score with IS2LP yield AUC values of 0.613(95% CI:0.509-0.717), 0.833(95% CI:0.755-0.911), and 0.843(95% CI:0.777-0.916), respectively. The combination of the traditional risk score and IS2LP exhibited significantly improved discriminative performance, with an integrated discrimination improvement (IDI) of 0.31 (p<0.001) and a continuous net reclassification improvement (NRI) of 1.06 (p < 0.001) compared to the traditional risk score. We identified new lipidomic biomarkers associated with the futural event of large-vessel ischemic stroke. These lipid species could serve as potential blood biomarkers for assessing the residual risk of ischemic stroke in hypertensive individuals.

Single-cell RNA sequencing and multiple bioinformatics methods to identify the biomarkers of ischemic stroke to alzheimer’s disease

Ranked as the world’s second leading cause of mortality, ischemic stroke (IS) imposes a significant global burden, marked by its substantial incidence and economic impact across nations and regions, chiefly attributed to its elevated disability rates. Alzheimer’s disease (AD) is linked to a heightened susceptibility to IS. However, few studies have been reported to explain the potential correlation between IS and AD. We investigated the relationship and relevant mechanisms between IS and AD using single-cell RNA sequencing and multiple bioinformatics approaches. By intersecting differentially expressed genes and WGCNA critical module genes, we obtained 15 IS related AD genes. According to the KEGG pathway analysis, the IS related AD disease genes were significantly enriched in the parkinson disease pathway, oxidative phosphorylation pathway, thermogenesis pathway, alzheimer disease pathway and neurodegeneration pathway. Finally, five genes associated with immunity (TXN, HINT1, TOMM7, COX7C, RPL17) were identified in IS related AD. Significantly, it was found that all hub genes were mainly highly expressed in epithelial cells, endothelial cells, monocytes and oligodendrocytes by single cell RNA sequencing. We believe these hub genes may regulate the immune pathway which may contribute to the development of IS related AD. In addition, these genes may be potential targets for the treatment of IS related AD.

Exploring the anti-ischemic stroke potential of wogonoside: Insights from Nrf2/Sirt3 signaling pathway and UPLC-TripleTOF-MS/MS-based metabolomics

Ischemic stroke, accounting for 80 % of all strokes, is a major cause of morbidity and mortality worldwide. However, effective and safe pharmacotherapy options for ischemic injury are limited. This study investigated the therapeutic effects of wogonoside, a compound derived from Radix Scutellariae, on ischemia/reperfusion (I/R) injury. The results showed that wogonoside treatment had significant therapeutic effects in rats with middle cerebral artery occlusion. It effectively reduced mortality rates, neurological deficits, cerebral infarct size, and brain water content. In an in vitro model using PC12 cells, wogonoside activated the Nrf2/Sirt3 signaling pathway. This activation contributed to the attenuation of oxidative damage and inflammation. Metabolomics analysis revealed increased levels of γ-aminobutyric acid (GABA) and glutathione in response to wogonoside treatment, suggesting their potential as therapeutic biomarkers for ischemic stroke. Additionally, wogonoside restored perturbed energy metabolism, including the tricarboxylic acid cycle. Wogonoside has the potential to ameliorate cerebral ischemic injury by targeting GABA-related amino acid metabolism, energy metabolism, and glutathione metabolism, maintaining redox homeostasis, and attenuating oxidative stress. These findings provide valuable insights into the protective mechanisms of wogonoside in cerebral I/R injury and highlight the promising therapeutic approach of wogonoside in the treatment of ischemic stroke.