Mechanism of inflammatory response and therapeutic effects of stem cells in ischemic stroke:current evidence and future perspectives

Ischemic stroke is a leading cause of death and disability worldwide,with an increasing trend and tendency for onset at a younger age.China,in particular,bears a high burden of stroke cases.In recent years,the inflammatory response after stroke has become a research hotspot:understanding the role of inflammatory response in tissue damage and repair following ischemic stroke is an important direction for its treatment.This review summarizes several major cells involved in the inflammatory response following ischemic stroke,including microglia,neutrophils,monocytes,lymphocytes,and astrocytes.Additionally,we have also highlighted the recent progress in various treatments for ischemic stroke,particularly in the field of stem cell therapy.Overall,understanding the complex interactions between inflammation and ischemic stroke can provide valuable insights for developing treatment strategies and improving patient outcomes.Stem cell therapy may potentially become an important component of ischemic stroke treatment.

Epigenetic regulation of the inflammatory response in stroke

Stroke is classified as ischemic or hemorrhagic,and there are few effective treatments for either type.Immunologic mechanisms play a critical role in secondary brain injury following a stroke,which manifests as cytokine release,blood–brain barrier disruption,neuronal cell death,and ultimately behavioral impairment.Suppressing the inflammatory response has been shown to mitigate this cascade of events in experimental stroke models.However,in clinical trials of anti-inflammatory agents,longterm immunosuppression has not demonstrated significant clinical benefits for patients.This may be attributable to the dichotomous roles of inflammation in both tissue injury and repair,as well as the complex pathophysiologic inflammatory processes in stroke.Inhibiting acute harmful inflammatory responses or inducing a phenotypic shift from a pro-inflammatory to an anti-inflammatory state at specific time points after a stroke are alternative and promising therapeutic strategies.Identifying agents that can modulate inflammation requires a detailed understanding of the inflammatory processes of stroke.Furthermore,epigenetic reprogramming plays a crucial role in modulating post-stroke inflammation and can potentially be exploited for stroke management.In this review,we summarize current findings on the epigenetic regulation of the inflammatory response in stroke,focusing on key signaling pathways including nuclear factor-kappa B,Janus kinase/signal transducer and activator of transcription,and mitogen-activated protein kinase as well as inflammasome activation.We also discuss promising molecular targets for stroke treatment.The evidence to date indicates that therapeutic targeting of the epigenetic regulation of inflammation can shift the balance from inflammation-induced tissue injury to repair following stroke,leading to improved post-stroke outcomes.

Association of DNA methylation/demethylation with the functional outcome of stroke in a hyperinflammatory state

Inflammation is closely related to stroke prognosis, and high inflammation status leads to poor functional outcome in stroke. DNA methylation is involved in the pathogenesis and prognosis of stroke. However, the effect of DNA methylation on stroke at high levels of inflammation is unclear. In this study, we constructed a hyperinflammatory cerebral ischemia mouse model and investigated the effect of hypomethylation and hypermethylation on the functional outcome. We constructed a mouse model of transient middle cerebral artery occlusion and treated the mice with lipopolysaccharide to induce a hyperinflammatory state. To investigate the effect of DNA methylation on stroke, we used small molecule inhibitors to restrain the function of key DNA methylation and demethylation enzymes. 2,3,5-Triphenyltetrazolium chloride staining, neurological function scores, neurobehavioral tests, enzyme-linked immunosorbent assay, quantitative reverse transcription PCR and western blot assay were used to evaluate the effects after stroke in mice. We assessed changes in the global methylation status by measuring DNA 5-mc and DNA 5-hmc levels in peripheral blood after the use of the inhibitor. In the group treated with the DNA methylation inhibitor, brain tissue 2,3,5-triphenyltetrazolium chloride staining showed an increase in infarct volume, which was accompanied by a decrease in neurological scores and worsening of neurobehavioral performance. The levels of inflammatory factors interleukin 6 and interleukin-1 beta in ischemic brain tissue and plasma were elevated, indicating increased inflammation. Related inflammatory pathway exploration showed significant overactivation of nuclear factor kappa B. These results suggested that inhibiting DNA methylation led to poor functional outcome in mice with high inflammation following stroke. Further, the effects were reversed by inhibition of DNA demethylation. Our findings suggest that DNA methylation regulates the inflammatory response in stroke and has an important role in the functional outcome of hyperinflammatory stroke.

Chinese Stroke Association guidelines for clinical management of ischaemic cerebrovascular diseases:executive summary and 2023 update

Background China is one of the countries with the highest burden of stroke.Implementing multidimensional management guidelines will help clinicians practise evidence-based care,improve patient outcomes and alleviate societal burdens.This update of the 2019 edition will provide the latest comprehensive recommendations for the diagnosis and treatment of ischaemic cerebrovascular diseases.Methods We conducted a comprehensive search on MEDLINE(via PubMed)up to 31 August 2023.The writing team established the recommendations through multiple rounds of online and offline discussions.Each recommendation was graded using the evidence grading algorithm developed by the Chinese Stroke Association(CSA).The draft was reviewed and finalised by the CSA Stroke Guidelines Writing Committee.Results This update included revisions of 15 existing recommendations and 136 new recommendations in the following areas of stroke care:emergency assessment and diagnosis of ischaemic cerebrovascular disease,acute-phase reperfusion therapy,evaluation of underlying mechanisms,antithrombotic therapy,prevention and treatment of complications,and risk factor management.Conclusions This guideline updated the recommendations for the clinical management of ischaemic cerebrovascular disease from 2019.

GRP per capita and hospital characteristics associated with intravenous tissue plasminogen activator adherence rate:evidence from the Chinese Stroke Center Alliance

Background Timely delivery of intravenous tissue plasminogen activator(IV-rt PA)is pivotal to eligible patients who had a stroke while achieving higher rates of IV-rt PA has been problematic.This paper focuses on investigating influential factors associated with the administration of IV-rt PA,primarily per capita gross regional product(GRP)and healthcare system factors.Methods The study included 980 hospitals in the Chinese Stroke Center Alliance where 158003 patients who had an acute ischaemic stroke received IV-rt PA between August 2015 and August 2019.The adherence rate to IV-rt PA within 4.5 hours time window in each hospital was the primary outcome.Influential factors were grouped into two categories:macroeconomic status and hospital characteristics.The outcome was analysed using multivariable linear regression.Results GRP per capita(β=2.37,p<0.001),hospital stroke centre certification(β=3.77,p<0.001),number of neurologists(β=0.12,p<0.001),existence of emergency services for neurological treatment(β=7.43,p=0.014),presence of emergency department(β=10.03,p=0.019)and cooperating with emergency centre(β=4.65,p=0.029)were significantly positively associated with the adherence rate to IV-rt PA.Conclusions Higher GRP per capita,affluent neurological personnel,well-equipped emergency services for neurological treatment and routine cooperation with the emergency centre were important for enhancing the adherence rate to IV-rt PA among patients who had an acute ischaemic stroke in China.

Temporal trends and rural-urban disparities in cerebrovascular risk factors,in-hospital management and outcomes in ischaemic strokes in China from 2005 to 2015:a nationwide serial cross-sectional survey

Background Stroke is the leading cause of mortality in China,with limited evidence of in-hospital burden obtained from nationwide surveys.We aimed to monitor and track the temporal trends and rural-urban disparities in cerebrovascular risk factors,management and outcomes from 2005 to 2015.Methods We used a two-stage random sampling survey to create a nationally representative sample of patients admitted for ischaemic stroke in 2005,2010 and 2015.We sampled participating hospitals with an economic-geographical region-stratified random-sampling approach first and then obtained patients with a systematic sampling approach.We weighed our survey data to estimate the national-level results and assess changes from 2005 to 2015.Results We analysed 28277 ischaemic stroke admissions from 189 participating hospitals.From 2005 to 2015,the estimated national hospital admission rate for ischaemic stroke per 100000 people increased(from 75.9 to 402.7,Ptrend<0.001),and the prevalence of risk factors,including hypertension,diabetes,dyslipidaemia and current smoking,increased.The composite score of diagnostic tests for stroke aetiology assessment(from 0.22 to 0.36,Ptrend<0.001)and secondary prevention treatments(from 0.46 to 0.70,Ptrend<0.001)were improved.A temporal decrease was found in discharge against medical advice(DAMA)(from 15.2%(95%CI 13.7%to 16.7%)to 8.6%(8.1%to 9.0%);adjusted Ptrend=0.046),and decreases in in-hospital mortality(0.7%in 2015 vs 1.8%in 2005;adjusted OR(aOR)0.52;95%CI 0.32 to 0.85)and the composite outcome of in-hospital mortality or DAMA(8.4%in 2015 vs 13.9%in 2005;aOR 0.65;95%CI 0.47 to 0.89)were observed.Disparities between rural and urban hospitals narrowed;however,disparities persisted in in-hospital management(brain MRI:rural-urban difference from−14.4%to−11.2%;cerebrovascular assessment:from−20.3%to−16.7%;clopidogrel:from−2.1%to−10.3%;anticoagulant for atrial fibrillation:from−10.9%to−8.2%)and in-hospital outcomes(DAMA:from 2.7%to 5.0%;composite outcome of in-hospital mortality or DAMA:from 2.4%to 4.6%).Conclusions From 2005 to 2015,improvements in hospital admission and in-hospital management for ischaemic stroke in China were found.A temporal improvement in DAMA and improvements in in-hospital mortality and the composite outcome of in-hospital mortality or DAMA were observed.Disparities between rural and urban hospitals generally narrowed but persisted.

Development and Validation of a Prognostic Model for One-year Survival of Cirrhosis Patients with First-ever Spontaneous Bacterial Peritonitis

Background and Aims: Spontaneous bacterial peritonitis(SBP) is one of the leading causes of death in patients withliver cirrhosis. We aimed to establish a prognostic model toevaluate the 1-year survival of cirrhosis patients after thefirst episode of SBP. Methods: A prognostic model was developedbased on a retrospective derivation cohort of 309cirrhosis patients with first-ever SBP and was validated in aseparate validation cohort of 141 patients. We used Uno’sconcordance, calibration curve, and decision curve (DCA)analysis to evaluate the discrimination, calibration, and clinicalnet benefit of the model. Results: A total of 59 (19.1%)patients in the derivation cohort and 42 (29.8%) patientsin the validation cohort died over the course of 1 year. Aprognostic model in nomogram form was developed withpredictors including age [hazard ratio (HR): 1.25;95% confidenceinterval (CI): 0.92–1.71], total serum bilirubin (HR:1.66;95% CI: 1.28–2.14), serum sodium (HR: 0.94;95%CI: 0.90–0.98), history of hypertension (HR: 2.52;95% CI:1.44–4.41) and hepatic encephalopathy (HR: 2.06;95%CI: 1.13–3.73). The nomogram had a higher concordance(0.79) compared with the model end-stage liver disease(0.67) or Child-Turcotte-Pugh (0.71) score. The nomogramalso showed acceptable calibration (calibration slope, 1.12;Bier score, 0.15±0.21) and optimal clinical net benefit in thevalidation cohort. Conclusions: This prediction model developedbased on characteristics of first-ever SBP patientsmay benefit the prediction of patients’ 1-year survival.

Beyond low-density lipoprotein cholesterol levels:Impact of prior statin treatment on ischemic stroke outcomes

Although essential for cardiovascular therapy,the pleiotropic effects of statins on ischemic stroke lack clinical evidence.This study examined the effects of statins beyond low-density lipoprotein cholesterol(LDL-C)levels on mortality and stroke severity.A total of 825,874 patients with ischemic stroke were included in this study,of whom 125,650 statin users were 1:1 matched with non-users based on their LDL-C levels(±0.05 mmol/L),forming the LDL-C-matched cohort.Associations between preceding statin treatment,in-hospital mortality,and stroke severity(National Institutes of Health Stroke Scale scoreR16)were estimated by multivariate and conditional logistic regression models in overall cohort and LDL-C-matched cohort,respectively.

缺血性卒中后感染介导了低密度脂蛋白胆固醇与全因死亡风险之间的U形曲线关系

在缺血性卒中急性期,尚不清楚低水平的低密度脂蛋白胆固醇(LDL-C)的病理生理意义,本研究旨在评估LDL-C水平、卒中后感染和全因死亡间的关系.研究共纳入804,855名缺血性卒中患者.通过多元logistic回归模型分析LDL-C水平、感染和死亡之间的关系,采用基于反事实框架的中介分析,以阐明卒中后感染的中介效应,研究发现LDL-C与死亡风险之间呈U形曲线关系,死亡风险最低的LDL-C水平为2.67mmol/L.经多因素校正后,与LDL-C=2.50~2.99mmol/L相比,LDL-C<1.0mmol/L患者的死亡风险比值比(OR)为2.22(95%置信区间(CI):1.77~2.79),LDL-C5.0mmol/L患者的OR为1.22(95%CI:0.98~1.50).LDL-C与死亡之间关联的38.20%(95%CI:5.96~70.45,P=0.020)由感染介导:在逐步剔除存在心血管危险因素的患者后,LDL-C与全因死亡间的U形曲线关系及感染的中介效应与主要分析一致,而死亡风险最低时的LDL-C水平逐渐升高.在缺血性卒中急性期,LDL-C水平与全因死亡之间存在U形曲线关系,其被卒中后感染介导。

China Stroke Statistics 2019:A Report From the National Center for Healthcare Quality Management in Neurological Diseases,China National Clinical Research Center for Neurological Diseases,the Chinese Stroke Association,National Center for Chronic and Non-communicable Disease Control and Prevention,Chinese Center for Disease Control and Prevention and Institute for Global Neuroscience and Stroke Collaborations

China faces the greatest challenge from stroke in the world.The death rate for cerebrovascular diseases in China was 149.49 per 100000,accounting for 1.57 million deaths in 2018.It ranked third among the leading causes of death behind malignant tumours and heart disease.The age-standardised prevalence and incidence of stroke in 2013 were 1114.8 per 100000 population and 246.8 per 100000 person-years,respectively.According to the Global Burden of Disease Study 2017,the years of life lost(YLLs)per 100000 population for stroke increased by 14.6%;YLLs due to stroke rose from third highest among all causes in 1990 to the highest in 2017.The absolute numbers and rates per 100000 population for all-age disability-adjusted life years(DALYs)for stroke increased substantially between 1990 and 2017,and stroke was the leading cause of all-age DALYs in 2017.The main contributors to cerebrovascular diseases include behavioural risk factors(smoking and alcohol use)and pre-existing conditions(hypertension,diabetes mellitus,dyslipidaemia and atrial fibrillation(AF)).The most prevalent risk factors among stroke survivors were hypertension(63.0%-84.2%)and smoking(31.7%-47.6%).The least prevalent was AF(2.7%-7.4%).The prevalences for major risk factors for stroke are high and most have increased over time.Based on the latest national epidemiological data,26.6%of adults aged≥15 years(307.6 million adults)smoked tobacco products.For those aged≥18 years,age-adjusted prevalence of hypertension was 25.2%;adjusted prevalence of hypercholesterolaemia was 5.8%;and the standardised prevalence of diabetes was 10.9%.For those aged≥40 years,the standardised prevalence of AF was 2.31%.Data from the Hospital Quality Monitoring System showed that 3010204 inpatients with stroke were admitted to 1853 tertiary care hospitals during 2018.Of those,2466785(81.9%)were ischaemic strokes(ISs);447609(14.9%)were intracerebral haemorrhages(ICHs);and 95810(3.2%)were subarachnoid haemorrhages(SAHs).The average age of patients admitted was 66 years old,and nearly 60%were male.A total of 1555(0.1%),2774(0.6%)and 1347(1.4%)paediatric strokes(age<18 years)were identified among IS,ICH and SAH,respectively.Over one-third(1063892(35.3%))of the patients were covered by urban resident basic medical insurance,followed by urban employee basic medical insurance(699513(23.2%))and new rural cooperative medical schema(489361(16.3%)).The leading risk factor was hypertension(67.4%for IS,77.2%for ICH and 49.1%for SAH),and the leading comorbidity was pneumonia or pulmonary infection(10.1%for IS,31.4%for ICH and 25.2%for SAH).In-hospital death/discharge against medical advice rate was 8.3%for stroke inpatients,ranging from 5.8%for IS to 19.5%for ICH.The median and IQR of length of stay was 10.0(7.0-14.0)days,ranging from 10.0(7.0-13.0)in IS to 14.0(8.0-22.0)in SAH.Data from the Chinese Stroke Center Alliance demonstrated that the composite scores of guideline-recommended key performance indicators for patients with IS,ICH and SAH were 0.77±0.21,0.72±0.28 and 0.59±0.32,respectively.