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

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

Relationship between interleukin-10 polymorphisms and susceptibility to ischemic stroke: a Meta-analysis.

Some previous studies already explored associations between interleukin-10 (IL-10) polymorphisms and ischemic stroke (IS), with conflicting results. In this meta-analysis, we aimed to better analyze the relationship between IL-10 polymorphisms and IS in a larger pooled population. We performed a systematic search of PubMed, Web of Science, Embase and CNKI. We calculated pooled odds ratios (ORs) and 95% confidence intervals (CIs) to estimate associations between IL-10 polymorphisms and IS. Totally 17 studies with 3610 cases and 5,171 controls were included. A significant association with IS was observed for IL-10 rs1800896 polymorphism in AA versus GG + GA (recessive model, p = .001, OR = 1.42, 95%CI 1.15-1.75, I2 = 48%) in overall population. Further subgroup analyses showed that rs1800896 polymorphism was significantly associated with cerebral infarction in GG versus GA + AA (dominant model, p = .02, OR = 2.04, 95%CI 1.14-3.64, I2 = 59%), GA versus GG + AA (overdominant model, p = .03, OR = 0.50, 95%CI 0.27-0.93, I2 = 64%) and G versus A (allele model, p = .01, OR = 1.92, 95%CI 1.16-3.17, I2 = 53%). Nevertheless, no any positive findings were detected for rs1800871 and rs1800872 polymorphisms in pooled analyses. In conclusion, our findings indicated that IL-10 rs1800896 polymorphism was significantly associated with individual susceptibility to IS, especially for cerebral infarction.

A meta-analysis on correlations of OX40L variants with atherosclerotic disorders.

BACKGROUND: This meta-analysis was conducted to analyze the correlations of OX40 ligand (OX40L) variants with atherosclerotic cardio-cerebral vascular diseases (ASCVD). METHODS: Systematic literature research was conducted in PubMed, Medline, and Embase. All statistical analyses were conducted with Review Manager. RESULTS: Totally eighteen studies were enrolled for analyses. Although no any significant correlations between OX40L variants and ASCVD were detected in overall analyses. Further subgroup analyses by ethnicity revealed that rs1234314 variant was significantly associated with ASCVD in East Asians (dominant model: P = 0.03, odds ratios [OR] = 1.15, 95% confidence interval [CI], 1.01-1.31; allele model: P = 0.04, OR = 1.10, 95%CI, 1.00-1.20). When we stratified eligible studies by type of disease, positive results were observed for rs17568 variant in subjects with acute coronary syndrome (ACS) (allele model: P = 0.04, OR = 0.81, 95%CI, 0.65-0.99), for rs1234314 variant in subjects with coronary artery disease (CAD) (dominant model: P = 0.04, OR = 1.16, 95%CI, 1.00-1.35), for rs3850641 variant in subjects with CAD (recessive model: P = 0.02, OR = 1.42, 95%CI, 1.05-1.90) and myocardial infarction (MI) (recessive model: P = 0.03, OR = 1.49, 95%CI, 1.05-2.11). CONCLUSIONS: Our findings suggested that rs17568, rs1234314, and rs3850641 variants might serve as genetic biomarkers of certain types of CAD.

Genetic variants in CYP4F2 were significantly correlated with susceptibility to ischemic stroke.

BACKGROUND: Ischemic stroke (IS) is a serious cardiovascular disease and is associated with several single nucleotide polymorphisms (SNPs). However, the role of Cytochrome P450 family 4 subfamily F member 2 (CYP4F2) gene in IS remains unknown. Our study aimed to explore whether CYP4F2 polymorphisms influenced IS risk in the Han Chinese population. METHODS: We selected 477 patients and 495 controls to do a case-control study, and five SNPs in CYP4F2 gene were successfully genotyped. And we evaluated the associations using the Chi-squared test, independent sample t test, and genetic models analyses. Logistic regression analysis was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: In this study, rs12459936 and rs3093144 were associated with IS risk in the overall. After stratified analysis by age (> 61 years), rs3093193 and rs3093144 were related to an increased risk of IS, whereas rs12459936 was related to a decreased risk of IS. In addition, we found that three SNPs (rs3093193, rs3093144 and rs12459936) were associated with the susceptibility to IS in males. We also found five SNPs in the CYP4F2 gene had strong linkage. CONCLUSIONS: Three SNPs (rs3093193, rs3093144 and rs12459936) in the CYP4F2 were associated with IS risk in a Chinese Han population. And, CYP4F2 gene may be involved in the development of IS.

Trimethylamine N-oxide as a risk marker for ischemic stroke in patients with atrial fibrillation.

Trimethylamine N-oxide (TMAO) is an independent risk factor of cardiovascular disease. Our objective was to explore the relation between TMAO and ischemic stroke (IS) in patients with atrial fibrillation (AF). A total of 68 patients with AF with IS and 111 ones without IS were enrolled. The plasma levels of TMAO remarkably increased in IS-AF patients (8.25 ± 1.58 µM) compared with patients with AF (2.22 ± 0.09 µM, P < 0.01). The receiver operating characteristic analysis revealed that the best cutoff value of TMAO to predict IS in patients with AF was 3.53 µM with 75.0% sensitivity and 92.8% specificity (area under the curve: 0.917, 95% confidence intervals: 0.877-0.957). Univariate and multivariate logistic regression analysis showed that TMAO was an independent predictor in IS. The level of TMAO was correlated with the CHA2DS2-VASc score. In conclusion, TMAO was an independent predictor of IS, which could potentially refine stroke stratification in patients with AF.

Associations of ß-Fibrinogen Polymorphisms with the Risk of Ischemic Stroke: A Meta-analysis.

BACKGROUND: Recently, the roles of ß-fibrinogen (FGß) polymorphisms in ischemic stroke (IS) were intensively analyzed, but the results of these studies were inconsistent. Thus, we performed this study to better assess potential relationship between FGß polymorphisms and the risk of IS. METHODS: Eligible studies were searched in PubMed, Medline, Embase, and CNKI. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to evaluate correlations between FGß polymorphisms and IS. RESULTS: A total of 49 studies were included for analyses. Significant associations with the risk of IS were detected for FGß -148 C/T and -455 G/A polymorphisms in overall analyses. Further subgroup analyses according to ethnicities of participants revealed that the -148 C/T polymorphism was significantly correlated with the risk of IS in both Asians and Caucasians, while the -455 G/A polymorphism was only significantly correlated with the risk of IS in Asians. When we stratified available data according to types of disease, we found that both FGß -148 C/T and -455 G/A polymorphisms were significantly correlated with the risk of cerebral infarction. CONCLUSIONS: Our findings indicated that FGß -148 C/T and -455 G/A polymorphisms may serve as potential biological markers for IS in Asians. Moreover, the FGß -148 C/T polymorphism may also serve as a potential biological marker for IS in Caucasians.

Combined polygenic scores for ischemic stroke risk factors aid risk assessment of ischemic stroke.

BACKGROUND: Current risk assessment for ischemic stroke (IS) is limited to clinical variables. We hypothesize that polygenic scores (PGS) of IS (PGSIS) and IS-associated diseases such as atrial fibrillation (AF), venous thromboembolism (VTE), coronary artery disease (CAD), hypertension (HTN), and Type 2 diabetes (T2D) may improve the performance of IS risk assessment. METHODS: Incident IS was followed for 479,476 participants in the UK Biobank who did not have an IS diagnosis prior to the recruitment. Lifestyle variables (obesity, smoking and alcohol) at the time of study recruitment, clinical diagnoses of IS-associated diseases, PGSIS, and five PGSs for IS-associated diseases were tested using the Cox proportional-hazards model. Predictive performance was assessed using the C-statistic and net reclassification index (NRI). RESULTS: During a median average 12.5-year follow-up, 8374 subjects were diagnosed with IS. Known clinical variables (age, gender, clinical diagnoses of IS-associated diseases, obesity, and smoking) and PGSIS were all independently associated with IS (P < 0.001). In addition, PGSIS and each PGS for IS-associated diseases was also independently associated with IS (P < 0.001). Compared to the clinical model, a joint clinical/PGS model improved the C-statistic for predicting IS from 0.71 to 0.73 (P < 0.001) and significantly reclassified IS risk (NRI = 0.017, P < 0.001), and 6.48% of subjects were upgraded from low to high risk. CONCLUSIONS: Adding PGSs of IS and IS-associated diseases to known clinical risk factors statistically improved risk assessment for IS, demonstrating the supplementary value of inherited susceptibility measurement . However, its clinical utility is likely limited due to modest improvements in predictive values.

N-Cinnamoylpyrrole-derived alkaloids from the genus Piper as promising agents for ischemic stroke by targeting eEF1A1.

BACKGROUND: Ischemic stroke (IS) is a serious cerebrovascular disease characterized by significantly elevated mortality and disability rates, and the treatments available for this disease are limited. Neuroinflammation and oxidative stress are deemed the major causes of cerebral ischemic injury. N-Cinnamoylpyrrole alkaloids form a small group of natural products from the genus Piper and have not been extensively analyzed pharmacologically. Thus, identifying the effect and mechanism of N-cinnamoylpyrrole-derived alkaloids on IS is worthwhile. PURPOSE: The present research aimed to explore the antineuroinflammatory and antioxidative stress effects of N-cinnamoylpyrrole-derived alkaloids isolated from the genus Piper and to explain the effects and mechanism on IS. METHODS: N-cinnamoylpyrrole-derived alkaloids were isolated from Piper boehmeriaefolium var. tonkinense and Piper sarmentosum and identified by various chromatographic methods. Lipopolysaccharide (LPS)-induced BV-2 microglia and a mouse model intracerebroventricularly injected with LPS were used to evaluate the antineuroinflammatory and antioxidative stress effects. Oxygen‒glucose deprivation/reperfusion (OGD/R) and transient middle cerebral artery occlusion (tMCAO) models were used to evaluate the effect of PB-1 on IS. To elucidate the fundamental mechanism, the functional target of PB-1 was identified by affinity-based protein profiling (ABPP) strategy and verified by cellular thermal shift assay (CETSA), drug affinity responsive target stability (DARTS), and circular dichroism (CD) analyses. The effect of PB-1 on the NF-κB and NRF2 signaling pathways was subsequently evaluated via western blotting and immunofluorescence staining. RESULTS: The results showed that N-cinnamoylpyrrole-derived alkaloids significantly affected neuroinflammation and oxidative stress. The representative compound, PB-1 not only inhibited neuroinflammation and oxidative stress induced by LPS or OGD/R insult, but also alleviated cerebral ischemic injury induced by tMCAO. Further molecular mechanism research found that PB-1 promoted antineuroinflammatory and antioxidative stress activities via the NF-κB and NRF2 signaling pathways by targeting eEF1A1. CONCLUSION: Our research initially unveiled that the therapeutic impact of PB-1 on cerebral ischemic injury might rely on its ability to target eEF1A1, leading to antineuroinflammatory and antioxidative stress effects. The novel discovery highlights eEF1A1 as a potential target for IS treatment and shows that PB-1, as a lead compound that targets eEF1A1, may be a promising therapeutic agent for IS.

Isoquercitrin alleviates OGD/R-induced oxidative stress and impaired mitochondrial biogenesis in SH-SY5Y cells via the NRF1/TFAM pathway.

Isoquercitrin (ISO) is a traditional Chinese medicine extract, that has been found to possess potent neuroprotective properties. However, its precise role in the context of ischemic stroke (IS) remains to be fully elucidated. We constructed an in vitro model of IS induced by OGD/R in SH-SY5Y cells. Cell viability, the levels of oxidative stress-related indicators (8-OHDG, MDA, SOD, GSH, and GSH-Px), ROS, and mitochondrial membrane potential were measured by using detection kits. The protein levels of GPX1, SOD, Cytc were measured. The mRNA levels of mitochondrial biogenesis-related indicators (Cytb, CO1, ND2, ND5, and ND6), and mtDNA copy number were measured by RT-qPCR. ATP levels were measured. Molecular docking between ISO and NRF1, and Co-IP assay for NRF1 and TFAM interaction were performed. Expression of NRF1 and TFAM was evaluated. ISO treatment reversed the detrimental effects of OGD/R on cell viability, attenuated the elevation of oxidative stress markers, restored antioxidant levels, and alleviated the impairment of mitochondrial biogenesis in SH-SY5Y cells. ISO interacted with NRF1 and increased its expression along with TFAM. Silencing NRF1 reversed the protective effects of ISO, suggesting its involvement in mediating the neuroprotective effects of ISO. ISO alleviates oxidative stress and mitochondrial biogenesis damage induced by OGD/R in SH-SY5Y cells by upregulating the NRF1/TFAM pathway.

Deciphering the mechanistic impact of acupuncture on the neurovascular unit in acute ischemic stroke: Insights from basic research in a narrative review.

Ischemic stroke(IS), a severe acute cerebrovascular disease, not only imposes a heavy economic burden on society but also presents numerous challenges in treatment. During the acute phase, while thrombolysis and thrombectomy serve as primary treatments, these approaches are restricted by a narrow therapeutic window. During rehabilitation, commonly used neuroprotective agents struggle with their low drug delivery efficiency and inadequate preclinical testing, and the long-term pharmacological and toxicity effects of nanomedicines remain undefined. Meanwhile, acupuncture as a therapeutic approach is widely acknowledged for its effectiveness in treating IS and has been recommended by the World Health Organization (WHO) as an alternative and complementary therapy, even though its exact mechanisms remain unclear. This review aims to summarize the known mechanisms of acupuncture and electroacupuncture (EA) in the treatment of IS. Research shows that acupuncture treatment mainly protects the neurovascular unit through five mechanisms: 1) reducing neuronal apoptosis and promoting neuronal repair and proliferation; 2) maintaining the integrity of the blood-brain barrier (BBB); 3) inhibiting the overactivation and polarization imbalance of microglia; 4) regulating the movement of vascular smooth muscle (VSM) cells; 5) promoting the proliferation of oligodendrocyte precursors. Through an in-depth analysis, this review reveals the multi-level, multi-dimensional impact of acupuncture treatment on the neurovascular unit (NVU) following IS, providing stronger evidence and a theoretical basis for its clinical application.

Zhachong Shisanwei pill drug-containing serum protects H2O2-Induced PC12 cells injury by suppressing apoptosis, oxidative stress via regulating the MAPK signaling pathway.

Introduction: Zhachong Shisanwei Pill (ZSP) is a classical Mongolian formula that combines 13 types of Chinese medicinal materials and has been used for treating ischemic stroke (IS) for centuries. However, the underlying molecular mechanisms have yet to be fully elucidated. The aim of this study is to explore potential mechanism of ZSP on nerve cells in cerebral ischemic injury. Methods: To simulate the pathological process of oxidative stress following IS, an injury model using PC12 cells was induced with hydrogen peroxide (H2O2). Afterward, PC12 cells were treated with ZSP medicated serum at low, medium, and high doses. Various assays were conducted to assess cell viability and oxidative stress indicators, including lactate dehydrogenase (LDH), malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), reactive oxygen species (ROS), and mitochondrial membrane potential (MMP). Cell apoptosis was evaluated through morphological assessment and flow cytometry. Additionally, the expression levels of apoptosis-related proteins (Bcl-2, Bax, Caspase-9, Caspase-3, PARP) and signaling pathway proteins (JNK, phosphorylated JNK, ERK, phosphorylated ERK, p38, and phosphorylated p38) were measured using automated Western blotting. Results: Our findings indicate that ZSP medicated serum preconditioning improves the condition of PC12 cells injured by H2O2. Specifically, it increased cell survival rates and reduced LDH release. Additionally, ZSP treatment decreased ROS levels and MDA content, while enhancing the activity of SOD and CAT in the injured PC12 cells. ZSP also reversed the depolarization of mitochondrial membrane potential and protected cells from apoptosis by modulating the expression of apoptosis-related proteins, including Bcl-2, Bax, Caspase-9, Caspase-3, and PARP. Furthermore, the overactivation of the MAPK signaling pathway due to H2O2-induced injury was inhibited, as evidenced by the downregulation of phosphorylated JNK, ERK, and p38 levels. Discussion: Mongolian medicine ZSP demonstrates protective effects against H2O2-induced oxidative stress and apoptosis in PC12 cells. The underlying mechanism may involve the inhibition of the MAPK signaling pathway, enhancement of antioxidant enzyme activity, reduction of intracellular peroxidation levels, and suppression of intrinsic apoptosis pathways.

Research progress of prodrugs for the treatment of cerebral ischemia.

It is well-known that pharmacotherapy plays a pivotal role in the treatment and prevention of cerebral ischemia. Nevertheless, existing drugs, including numerous natural products, encounter various challenges when applied in cerebral ischemia treatment. These challenges comprise poor brain absorption due to low blood-brain barrier (BBB) permeability, limited water solubility, inadequate bioavailability, poor stability, and rapid metabolism. To address these issues, researchers have turned to prodrug strategies, aiming to mitigate or eliminate the adverse properties of parent drug molecules. In vivo metabolism or enzymatic reactions convert prodrugs into active parent drugs, thereby augmenting BBB permeability, improving bioavailability and stability, and reducing toxicity to normal tissues, ultimately aiming to enhance treatment efficacy and safety. This comprehensive review delves into multiple effective prodrug strategies, providing a detailed description of representative prodrugs developed over the past two decades. It underscores the potential of prodrug approaches to improve the therapeutic outcomes of currently available drugs for cerebral ischemia. The publication of this review serves to enrich current research progress on prodrug strategies for the treatment and prevention of cerebral ischemia. Furthermore, it seeks to offer valuable insights for pharmaceutical chemists in this field, offer guidance for the development of drugs for cerebral ischemia, and provide patients with safer and more effective drug treatment options.

Mendelian randomization of chronic hepatitis B and cardiovascular disease.

Background: Evidence from observational studies suggests that chronic hepatitis B (CHB) is associated with cardiovascular disease (CVD). However, results have been inconsistent and causality remains to be established. We utilized two-sample Mendelian randomization (MR) to investigate potential causal associations between CHB and CVD, including atherosclerosis, coronary heart disease, hypertension, and ischemic stroke. Methods: The analysis was conducted through genome-wide association studies (GWAS), considering chronic hepatitis B as the exposure and cardiovascular disease as the endpoint. The primary method for evaluating causality in this analysis was the inverse-variance weighted (IVW) technique. Additionally, we employed the weighted median, MR-Egger regression, weighted mode, and simple mode methods for supplementary analyses. Finally, heterogeneity tests, sensitivity analyses, and multiple effects analyses were conducted. Results: In a random-effects IVW analysis, we found that genetic susceptibility to chronic hepatitis B was associated with an increased risk of atherosclerosis [OR = 1.048, 95% CI (1.022-1.075), P = 3.08E-04], as well as an increased risk of coronary heart disease [OR = 1.039, 95% CI (1.006-1.072), P = 0.020]. However, it was found to be inversely correlated with ischemic stroke risk [OR = 0.972, 95% CI (0.957-0.988), P = 4.13E-04]. There was no evidence that chronic hepatitis B was associated with hypertension [OR = 1.021, 95% CI (0.994-1.049), P = 0.121]. Conclusion: Our research indicates that chronic hepatitis B has a correlation with an elevated risk of developing atherosclerosis and coronary heart disease, while it is associated with a decreased risk of experiencing an ischemic stroke.

AC-ASPECTS, ACh-ASPECTS, and H-ASPECTS: new imaging scales to assess territorial and total cerebral hemispheric ischemic injury.

Background: The extent of ischemic injury in acute stroke is assessed in clinical practice using the Acute Stroke Prognosis Early CT Score (ASPECTS) rating system. However, current ASPECTS semi-quantitative topographic scales assess only the middle cerebral artery (MCA) (original ASPECTS) and posterior cerebral (PC-ASPECTS) territories. For treatment decision-making in patients with anterior cerebral artery (ACA) occlusions and internal carotid artery (ICA) occlusions with large ischemic cores, measures of all hemispheric regions are desirable. Methods: In this cohort study, anatomic rating systems were developed for the anterior cerebral (AC-ASPECTS, 3 points) and anterior choroidal artery (ACh-ASPECTS, 1 point) territories. In addition, a total supratentorial hemisphere (H-ASPECTS, 16 points) score was calculated as the sum of the MCA ASPECTS (10 regions), supratentorial PC-ASPECTS (2 regions), AC-ASPECTS (3 regions), and ACh-ASPECTS (1 region). Three raters applied these scales to initial and 24 h CT and MR images in consecutive patients with ischemic stroke (IS) due to ICA, M1-MCA, and ACA occlusions. Results: Imaging ratings were obtained for 96 scans in 50 consecutive patients with age 74.8 (±14.0), 60% female, NIHSS 15.5 (9.25-20), and occlusion locations ICA 34%; M1-MCA 58%; and ACA 8%. Treatments included endovascular thrombectomy +/- thrombolysis in 72%, thrombolysis alone in 8%, and hemicraniectomy in 4%. Among experienced clinicians, inter-rater reliability for AC-, ACh-, and H-ASPECTS scores was substantial (kappa values 0.61-0.80). AC-ASPECTS abnormality was present in 14% of patients, and ACh-ASPECTS abnormality in 2%. Among patients with ACA and ICA occlusions, H-ASPECTS scores compared with original ASPECTS scores were more strongly associated with disability level at discharge, ambulatory status at discharge, discharge destination, and combined inpatient mortality and hospice discharge. Conclusion: AC-ASPECTS, ACh-ASPECTS, and H-ASPECTS expand the scope of acute IS imaging scores and increase correlation with functional outcomes. This additional information may enhance prognostication and decision-making, including endovascular thrombectomy and hemicraniectomy.

Genetically predicted small dense low-density lipoprotein cholesterol and ischemic stroke subtype: multivariable Mendelian randomization study.

Purpose: Small dense low-density lipoprotein cholesterol (S-LDL-C) has been suggested as a particularly atherogenic factor for ischemic stroke (IS) in observational studies, but the causality regarding the etiological subtype remains unclear. This study aims to explore the causal effects of small dense low-density lipoprotein cholesterol (S-LDL-C), medium (M-LDL-C) and large (L-LDL-C) subfractions on the lifetime risk of ischemic stroke (IS) and main subtypes using two-sample Mendelian randomization (TSMR) design. Methods: We identified genetic instruments for S-LDL-C, M-LDL-C and L-LDL-C from a genome-wide association study of 115 082 UK Biobank participants. Summary-level data for genetic association of any ischemic stroke (AIS), large artery stroke (LAS), small vessel stroke (SVS) and cardioembolic stroke (CES) were obtained from MEGASTROKE consortium. Accounting for the pleiotropic effects of triglycerides (TG) and high-density lipoprotein cholesterol (HDL-C), we conducted multivariable TSMR analysis. Results: In univariable TSMR, we found a causal association between genetically predicted S-LDL-C and LAS (IVW-FE: odds ratio (OR) = 1.481, 95% confidence interval (CI): 1.117-1.963, P = 0.006, q = 0.076) but not AIS, SVS or CES. No causal effects were observed for M-LDL-C or L-LDL-C in terms of AIS and IS subtype. In multivariable analysis, the causal association between S-LDL-C and LAS remained significant (IVE-MRE: OR = 1.329, 95% CI: 1.106-1.597, P = 0.002). Conclusions: Findings supported a causal association between S-LDL-C and LAS. Further studies are warranted to elucidate the underlying mechanism and clinical benefit of targeting S-LDL-C.

Ankle-brachial index long-term outcome after first-ever ischaemic stroke.

BACKGROUND AND PURPOSE: Ankle-brachial blood pressure index (ABI) is a clinical tool to identify the presence of peripheral artery disease. There is a scarcity of data associating ABI with long-term outcome in patients with IS. The association between ABI and long-term outcome in patients with first-ever acute IS was assessed. METHODS: Ankle-brachial blood pressure index was assessed in all consecutive patients with a first-ever acute IS admitted at Alexandra University hospital (Athens, Greece) between January 2005 and December 2010. ABI was considered normal when > 0.90 and ≤ 1.30. The Kaplan-Meier product limit method was used to estimate the probability of 5-year composite cardiovascular event-free (defined as recurrent stroke, myocardial infarction or cardiovascular death) and overall survival. A multivariate analysis was performed to assess whether ABI is an independent predictor of 5-year mortality and dependence. RESULTS: Amongst 653 patients, 129 (19.8%) with ABI ≤ 0.9 were identified. Five-year cumulative composite cardiovascular event-free and overall survival rates were better in normal ABI stroke patients (log-rank test: 7.22, P = 0.007 and 23.40, P < 0.001, respectively). There was no difference in 5-year risk of stroke recurrence between low and normal ABI groups (hazard ratio, HR = 1.23, 95% CI 0.68-2.23). In multivariate Cox regression analysis, independent predictors of 5-year mortality included age (HR = 2.55 per 10 years, 95% CI 1.86-3.48, P < 0.001), the National Institutes of Health Stroke Scale (per point increase HR = 1.12, 95% CI 1.08-1.16, P < 0.001), and low ABI (HR = 2.22, 95% CI 1.22-4.03, P = 0.009). Age (HR = 1.21 per 10 years, 95% CI 1.01-1.45, P = 0.04) and low ABI (HR = 1.72, 95% CI 1.11-2.67, P = 0.01) were independent predictors of the composite cardiovascular end-point. CONCLUSIONS: Low ABI in patients with acute IS is associated with increased 5-year cardiovascular event risk and mortality. However, ABI does not appear to predict long-term stroke recurrence.

Application of Shouwu Yizhi prescription in decubation of patients with ischemic stroke.

We investigate the application of Shouwu Yizhi prescription (SYP) in decubation of patients with ischemic stroke (IS). The clinical data of 106 patients recovering from IS who came to our hospital from December 2019 to December 2020 were selected for retrospective analysis, and they were separated into experimental group (n = 53, basic treatment + SYP) and control group (n = 53, basic treatment) based on the principle of random grouping. The clinical indexes such as lipid indexes and neurological disability score (NDS) after treatment were compared between both groups to comprehensively evaluate the clinical effects of different treatment regimens. Except for high-density lipoprotein cholesterol value, the lipid indexes in the experimental group after treatment were remarkably lower than those in the control group (P < 0.001). After treatment, the levels of hypersensitive C-reactive protein, homocysteine and lipoprotein-associated phospholipase A2 were remarkably lower in the experimental group than control group (P < 0.05). After treatment, the experimental group had remarkably higher mean scores of Montreal Cognitive Assessment, Fugl-Meyer Assessment in upper and lower limbs and lower NDS than control group (P < 0.001). SYP is an efficient treatment plan in decubation of IS, which can effectively improve the blood lipid indexes and neurological function of patients, and further studies will help establish a better solution for such patients.

Identification of cell death-related biomarkers and immune infiltration in ischemic stroke between male and female patients.

Background: Stroke is the second leading cause of death and the third leading cause of disability worldwide, with ischemic stroke (IS) being the most prevalent. A substantial number of irreversible brain cell death occur in the short term, leading to impairment or death in IS. Limiting the loss of brain cells is the primary therapy target and a significant clinical issue for IS therapy. Our study aims to establish the gender specificity pattern from immune cell infiltration and four kinds of cell-death perspectives to improve IS diagnosis and therapy. Methods: Combining and standardizing two IS datasets (GSE16561 and GSE22255) from the GEO database, we used the CIBERSORT algorithm to investigate and compare the immune cell infiltration in different groups and genders. Then, ferroptosis-related differently expressed genes (FRDEGs), pyroptosis-related DEGs (PRDEGs), anoikis-related DEGs (ARDEGs), and cuproptosis-related DEGs (CRDEGs) between the IS patient group and the healthy control group were identified in men and women, respectively. Machine learning (ML) was finally used to generate the disease prediction model for cell death-related DEGs (CDRDEGs) and to screen biomarkers related to cell death involved in IS. Results: Significant changes were observed in 4 types of immune cells in male IS patients and 10 types in female IS patients compared with healthy controls. In total, 10 FRDEGs, 11 PRDEGs, 3 ARDEGs, and 1 CRDEG were present in male IS patients, while 6 FRDEGs, 16 PRDEGs, 4 ARDEGs, and 1 CRDEG existed in female IS patients. ML techniques indicated that the best diagnostic model for both male and female patients was the support vector machine (SVM) for CDRDEG genes. SVM's feature importance analysis demonstrated that SLC2A3, MMP9, C5AR1, ACSL1, and NLRP3 were the top five feature-important CDRDEGs in male IS patients. Meanwhile, the PDK4, SCL40A1, FAR1, CD163, and CD96 displayed their overwhelming influence on female IS patients. Conclusion: These findings contribute to a better knowledge of immune cell infiltration and their corresponding molecular mechanisms of cell death and offer distinct clinically relevant biological targets for IS patients of different genders.

The role of NLRP3 inflammasome-mediated pyroptosis in ischemic stroke and the intervention of traditional Chinese medicine.

Ischemic stroke (IS) is the second leading cause of death and disability in the world. Pyroptosis, a form of programmed cell death initiated by caspases, participates in the occurrence and development of IS. Because it can increase cell membrane permeability, mediate the release of inflammatory factors, and aggravate inflammation, inhibiting this process can significantly reduce the pathological injury of IS. The nucleotide binding oligomerization domain-like receptor family pyrin domain protein 3 (NLRP3) is a multiprotein complex whose activation is the core link of pyroptosis. In recent years, studies have reported that traditional Chinese medicine (TCM) could regulate pyroptosis mediated by NLRP3 inflammasome through multi-channel and multi-target networks and thus exert the effect against IS. This article reviews 107 papers published in recent years in PubMed, Chinese National Knowledge Infrastructure (CNKI), and WanFang Data in recent years. It has found that the activation factors of NLRP3 inflammasome include ROS, mitochondrial dysfunction, K+, Ca2+, lysosome rupture, and trans-Golgi breakdown. TLR4/NF-κB/NLRP3, ROS/TXNIP/NLRP3, AMPK/Nrf2/NLRP3, DRP1/NLRP3, TAK1/JNK/NLRP3 signaling pathways regulate the initiation and assembly of the NLRP3 inflammasome, subsequently induce pyroptosis, affecting the occurrence and development of IS. TCM can affect the above signaling pathways and regulate the pyroptosis mediated by NLRP3 inflammasome, so as to play a protective role against IS, which provides a new entry point for discussing the pathological mechanism of IS and a theoretical basis for developing TCM treasure house.

Association of oral bisphosphonates with cardioembolic ischemic stroke: a nested case-control study.

Background: Bisphosphonates have been reported to increase the risk of atrial fibrillation. Therefore, it is conceivable that they may increase the risk of cardioembolic ischemic stroke (IS). However, most epidemiological studies carried out thus far have not shown an increased risk of IS, though none separated by the main pathophysiologic IS subtype (cardioembolic and non-cardioembolic) which may be crucial. In this study, we tested the hypothesis that the use of oral bisphosphonates increases specifically the risk of cardioembolic IS, and explored the effect of treatment duration, as well as the potential interaction between oral bisphosphonates and calcium supplements and anticoagulants. Methods: We performed a case-control study nested in a cohort of patients aged 40-99 years, using the Spanish primary healthcare database BIFAP, over the period 2002-2015. Incident cases of IS were identified and classified as cardioembolic or non-cardioembolic. Five controls per case were randomly selected, matched for age, sex, and index date (first recording of IS) using an incidence-density sampling. The association of IS (overall and by subtype) with the use of oral bisphosphonates within the last year before index date was assessed by computing the adjusted odds ratios (AOR) and their 95% CI using a conditional logistic regression. Only initiators of oral bisphosphonates were considered. Results: A total of 13,781 incident cases of IS and 65,909 controls were included. The mean age was 74.5 (SD ± 12.4) years and 51.6% were male. Among cases, 3.15% were current users of oral bisphosphonates, while among controls they were 2.62%, yielding an AOR of 1.15 (95% CI:1.01-1.30). Of all cases, 4,568 (33.1%) were classified as cardioembolic IS (matched with 21,697 controls) and 9,213 (66.9%) as non-cardioembolic IS (matched with 44,212 controls) yielding an AOR of 1.35 (95% CI:1.10-1.66) and 1.03 (95% CI: 0.88-1.21), respectively. The association with cardioembolic IS was clearly duration-dependent (AOR≤1 year = 1.10; 95% CI:0.82-1.49; AOR>1-3 years = 1.41; 95% CI:1.01-1.97; AOR>3 years = 1.81; 95% CI:1.25-2.62; p for trend = 0.001) and completely blunted by anticoagulants, even in long-term users (AOR>1 year = 0.59; 0.30-1.16). An interaction between oral bisphosphonates and calcium supplements was suggested. Conclusion: The use of oral bisphosphonates increases specifically the odds of cardioembolic IS, in a duration-dependent manner, while leaves materially unaffected the odds of non-cardioembolic IS.