BackgroundCerebral ischemia/reperfusion (I/R) injury severely limits the efficacy of recanalization therapy for ischemic stroke. Activin A (Act A), a neurotrophic cytokine, shows protective potential, but its mechanisms related to mitochondrial biogenesis and ferroptosis regulation remain unclear.MethodsIn vivo, adult male Wistar rats (12/group) underwent 2 h middle cerebral artery occlusion (MCAO) and 24 h reperfusion. Act A (7.5 μg/kg) or vehicle was administered intracerebroventricularly pre-ischemia. TTC, TEM, and IHC were used to analyze cerebral I/R injury and PGC-1α expression. In vitro, HT22 cells exposed to oxygen–glucose deprivation/reoxygenation (OGD/R, 8 h/24 h) were treated with Act A (100 ng/mL). Ferroptosis markers, mitochondrial function and signaling pathways were assessed via qPCR, western blot, flow cytometry, laser confocal and ChIP.ResultsIn vivo, Act A significantly reduced cerebral infarct volume versus vehicle (***p < 0.001), decreased MDA levels (***p < 0.001), and increased PGC-1α expression (***p < 0.001) along with mtDNA copy number (*p < 0.05). In vitro, Act A rescued OGD/R-induced ferroptosis, suppressing lipid ROS (**p < 0.01) and Fe2+ accumulation (*p < 0.05). It activated the PGC-1α/NRF1/TFAM axis (*p < 0.05) and enhanced mitochondrial biogenesis. Mechanistically, Act A promoted PGC-1α transcription via Smad3 binding to its promoter (*p < 0.05) and enhanced PGC-1α activity through p38-MAPK phosphorylation (***p < 0.001). Silencing PGC-1α abolished Act A’s neuroprotection effects.ConclusionAct A mitigates cerebral I/R injury by dual activation of PGC-1α through Smad3 and p38-MAPK pathways, enhancing mitochondrial biogenesis and inhibiting neuronal ferroptosis. This highlights Act A as a therapeutic candidate for ischemic stroke.

Cerebral ischemia/reperfusion injury (CIRI) is a critical factor leading to adverse outcomes in acute ischemic stroke with reperfusion therapy. The occurrence of CIRI involves several cell death pathways, such as ferroptosis. Peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) a vital role in mitochondrial biogenesis and induces several crucial reactive oxygen species (ROS) detoxifying enzymes. Nonetheless, the role of activated PGC-1α in CIRI is still unclear. In this research, we utilized a PGC-1α agonist (ZLN005) in both in vitro and in vivo models of CIRI and found that ZLN005 ameliorates neurologic deficits, reduces infarct volume, and inhibits neuronal ferroptosis in CIRI. Furthermore, CIRI led to a decrease in neuronal mitochondrial quantity and downregulation of uncoupling protein 2 (UCP2) expression. Treatment with ZLN005 activated PGC-1α, promoted neuronal mitochondrial biogenesis, and upregulated UCP2 expression, thereby reducing mitochondrial oxidative stress. The application of the mitochondria-targeted antioxidant Mito-TEMPO inhibited ferroptosis, while UCP2 silencing induced mitochondrial oxidative stress and weakened ZLN005 inhibitory effect of ferroptosis, confirming the dependency of ferroptosis on mitochondrial oxidative stress in CIRI. According to these findings, targeting PGC-1α may offer an effective therapeutic strategy for CIRI by regulating mitochondrial homeostasis and protecting neurons from ferroptotic damage.

BackgroundThis meta-analysis aimed to investigate the effect of statins on the prognosis of patients with intracerebral hemorrhage (ICH).MethodsWe conducted a systematic search using the keywords “statin” and “intracerebral hemorrhage” across four electronic databases (PubMed, Cochrane Library, Web of Science, and Embase) from their inception to October 31, 2023, to identify studies comparing the effects of statins on the prognosis of patients with ICH. The primary outcome was total mortality after ICH. This meta-analysis was registered online (PROSPERO ID: CRD42023493063).ResultsOur initial search identified 5,543 studies. After applying inclusion criteria, 30 studies with a total of 42,298 patients were included in the final analysis. Our meta-analysis showed that statins significantly reduced overall mortality in patients with ICH (OR: 0.61; 95% CI: 0.51–0.73; I2 = 87%; p < 0.01). Subgroup analyses further demonstrated lower mortality in ICH patients treated with statins compared to those not treated, including in the propensity score matching (PSM) group (OR: 0.59; 95% CI: 0.48–0.74; I2 = 90%; p < 0.01), the prospective cohort study (PCS) group (OR: 0.56; 95% CI: 0.40–0.77; I2 = 89%, p < 0.01), and the retrospective cohort study (RCS) group (OR: 0.64; 95% CI: 0.51–0.81; I2 = 87%, p < 0.01).ConclusionOur meta-analysis of 30 studies suggests that statin use may be associated with improved mortality and functional outcomes in patients with intracerebral hemorrhage (ICH).Systematic Review Registrationhttps://www.crd.york.ac.uk/PROSPERO/, CRD42023493063.

Alzheimer’s disease (AD) is the main cause of dementia in older age. The prevalence of AD is growing worldwide, causing a tremendous burden to societies and families. Due to the complexity of its pathogenesis, the current treatment of AD is not satisfactory, and drugs acting on a single target may not prevent AD progression. This review summarizes the multi-target pharmacological effects of thiazolidinediones (TZDs) on AD. TZDs act as peroxisome proliferator-activated receptor gamma (PPAR γ) agonists and long-chain acyl-CoA synthetase family member 4 (ACSL4) inhibitors. TZDs ameliorated neuroinflammation and ferroptosis in preclinical models of AD. Here, we discussed recent findings from clinical trials of pioglitazone in the treatment of AD, ischemic stroke, and atherosclerosis. We also dissected the major limitations in the clinical application of pioglitazone and explained the potential benefit of pioglitazone in AD. We recommend the use of pioglitazone to prevent cognitive decline and lower AD risk in a specific group of patients.

Activin A (Act A) is a member of the transforming growth factor-β (TGF-β) superfamily and can protect against ischemic cerebral injury. Ferroptosis, a newly discovered type of programmed cell death, contributes to the pathogenesis of cerebral ischemia-reperfusion injury (CIRI). However, little is known on whether Act A can modulate neuronal ferroptosis to protect against CIRI in a mouse model of middle cerebral artery occlusion (MCAO) and an HT22 cell model of oxygen-glucose deprivation/reoxygenation (OGD/R). The results indicated that Act A treatment relieved CIRI by improving neurological deficits and reducing the infarct volume in mice. MCAO stimulated iron accumulation and malondialdehyde formation and upregulated ACSL4 expression but downregulated GPX4 expression, a hallmark of ferroptosis in the brain of mice. Treatment with Act A significantly mitigated MCAO-triggered ferroptosis in the brain of mice. Furthermore, Act A treatment enhanced the MCAO-upregulated nuclear factor erythroid-2-related factor 2 (Nrf2) expression in the brains of mice. Similar results were observed in HT22 cells following OGD/R and pretreatment with Act A. The neuronal protective effect of Act A in HT22 cells was attenuated by treatment with ML385, an Nrf2 inhibitor. To conclude, Act A attenuated CIRI by enhancing Nrf2 expression and inhibiting neuronal ferroptosis.

Objective This study aims to explore the clinical characteristics of common mutation sites in the SOD1 gene and provide assistance for the early identification,diagnosis,and course evaluation of amyotrophic lateral sclerosis(ALS).Methods The clinical data and genetic testing results of a patient with ALS caused by the c.131A>G:p.H44R muta-tion in the second exon of the SOD1 gene were retrospectively analyzed and discussed in conjunction with the literature.Results The patient presented with pain and weakness in the right lower limb accompanied by muscle atrophy.No posi-tive signs were observed in the sensory system.The electromyogram revealed subclinical neurogenic changes in the unaf-fected limbs.Whole-exome sequencing identified a rare mutation in exon c.131A>G:p.H44R of the SOD1 gene.Conclusion Early diagnosis of ALS is challenging,and the clinical manifestations vary depending on the gene site muta-tions.Genetic testing can assist in diagnosis and has significant identification value in the early stages of the disease.

Cerebral ischemic stroke (CIS) is an acute cerebrovascular disease that is caused by the sudden rupture of blood vessels inside the brain and the intervention of reperfusion to the brain, resulting in severe cerebral injury. Autophagy has been reported to be involved in the occurrence and progression of CIS. Betulinic acid (BA) is a pentacyclic triterpene acid mainly extracted from birch bark. Studies have shown the neuroprotective effects of BA. Here, the effect and mechanism of BA on ischemia-reperfusion induced cerebral injury was explored using a CIS model in vivo via 1 h middle cerebral artery occlusion (MCAO) and 24 h reperfusion in rats and in vitro via oxygen-glucose deprivation/reperfusion (OGD/R) of PC12 cells, respectively. We found that BA not only reduced cerebral injury by reducing oxidative stress but also activated the SIRT1/FoxO1 pathway to suppress autophagy and improve cerebral injury in MCAO rats. These results provide a basis for the potential clinical application of BA.

在病因和发病机制的 TOAST分型中,以大动脉粥样硬化型脑梗死最为常见.随着分子生物学技术的发展,越来越多的 microRNA被发现参与机体代谢的各个途径,对动脉粥样硬化斑块形成起到重要调节作用.本文针对大动脉粥样硬化型脑梗死发生、发展的关键环节,综述了 microRNA 在其中的作用和预测价值.

Stroke is one of the most common causes of death worldwide. The subsequent development of neuroinflammation and brain edema dramatically increases the risks associated with stroke, leading to a substantial increase in mortality. Although considerable progress has been made in improving cerebral perfusion in the acute phase of stroke, effective treatment options for the subacute and chronic phases associated with cerebral infarction are limited. Microglia, the innate immune cells of the central nervous system (CNS), can be activated and polarized to take on different phenotypes in response to stimulations associated with stroke, including pro-inflammatory and anti-inflammatory phenotypes, which affect the prognosis of stroke. Therefore, investigation of the activation and polarizing mechanisms of microglia plays a critical role in treating stroke. The aim of this article was to investigate the significance of microglial phenotype regulation in stroke treatment by summarizing the activation, polarizing mechanisms, and general microglia characteristics.

Chronic cerebral ischemia (CCI) is one of the critical factors in the occurrence and development of vascular cognitive impairment (VCI). Apoptosis of nerve cells and changes in synaptic activity after CCI are the key factors to induce VCI. Synaptic stimulation up-regulates intraneuronal Ca2+ level through N-methyl-D-aspartic acid receptor (NMDAR) via induction of the activity-regulated inhibitor of death (AID) expression to produce active-dependent neuroprotection. Moreover, the regulation of synaptic plasticity could improve cognition and learning ability. Activin A (ActA), an exocrine protein of AID, can promote NMDAR phosphorylation and participate in the regulation of synaptic plasticity. We previously found that exogenous ActA can improve the cognitive function of rats with chronic cerebral ischemia and enhance the oxygenated glucose deprivation of intracellular Ca2+ level. In addition to NMDAR, the Wnt pathway is critical in the positive regulation of LTP through activation or inhibition. It plays an essential role in synaptic transmission and activity-dependent synaptic plasticity. The enriched environment can increase ActA expression during CCI injury. We speculated that the NMDAR-Ca2+-ActA signal pathway has a loop-acting mode, and the environmental enrichment could improve chronic cerebral ischemia cognitive impairment via NMDAR-Ca2+-ActA, Wnt/β-catenin pathway is involved in this process. For the hypothesis verification, this study intends to establish chronic cerebral hypoperfusion (CCH) rat model, explore the improvement effect of enriched environment on VCI, detect the changes in plasticity of synaptic morphology and investigate the regulatory mechanism NMDAR-Ca2+-ActA-Wnt/β-catenin signaling loop, providing a therapeutic method for the treatment of CCH.

目的探讨microRNA-17（miR-17）在体外脑缺血损伤中对Smad锚着蛋白（Smad anchor for receptor activation,SARA）的调控机制。方法使用大鼠高分化嗜铬细胞瘤PC12细胞,经连二亚硫酸钠（NaS2O4）构建氧糖剥夺模型（Oxygen Glucose Deprivation,OGD）,计时0h、1.5h、3h、6h和12h,实时定量PCR检测miR-17的表达变化。利用miR-17mimic瞬时转染PC12细胞,western blot检测转染24h、48h和72h后SARA蛋白表达情况。利用MiRDB和TargetScan网站预测miR-17对SARA的调控位点,并构建双荧光素酶报告基因载体。将报告载体与miR-17mimic共转染,荧光素分析miR-17对SARA的调控靶点。结果 miR-17在OGD损伤早期表达上调,OGD 3h时达高峰,超过OGD 0h组10倍。miR-17mimic转染可显著下调SARA蛋白表达,转染24h组SARA蛋白水平下调了57.01%。MiRDB和TargetScan网站预测miR-17对SARA的调控位点,荧光素酶报告基因检测示位点（57-64）和位点（403-409）是miR-17调控SARA表达的靶点。结论 miR-17可负性调控SARA蛋白表达。

OBJECTIVES:Our study aimed to evaluate the diagnostic performances of 3 routine examination methods for cerebrovascular disease in a rabbit carotid artery atherosclerosis model.METHODS:A total of 12 New Zealand rabbits were included: 4 in a control group and 8 in an experimental group. A clinically relevant atherosclerosis rabbit model was induced by left common carotid artery ligation and a 12-week high-fat diet. Atherosclerosis was further confirmed by a histopathologic analysis. Then carotid ultrasound (US) imaging, high-resolution magnetic resonance imaging (HRMRI), and positron emission tomography (PET)/computed tomography (CT) were performed on this model to evaluate the diagnostic performances.RESULTS:Carotid US showed plaque formation in the left common carotid artery and little plaque in the right common carotid artery in the experimental group. In addition, HRMRI showed stenosis formation in the left common carotid artery in the experimental group. At the horizontal level, plaques were found in the left common carotid artery, and no plaques were found in the right common carotid artery in the experimental group. Also, PET/CT showed local hypermetabolism and vulnerable plaques in the left common carotid artery of the experimental group, whereas no hypermetabolism was found in the right common carotid artery of the experimental group. Moreover, the soft plaques detected by carotid US were different from the vulnerable plaques detected by PET/CT. The unstable plaques on HRMRI were the same as the hypermetabolic vulnerable plaques on PET/CT.CONCLUSIONS:High-resolution MRI is recommended for the evaluation of neck and intracranial vascular stenosis and plaque properties in patients with stroke.

AIM:There is no randomized controlled trial to compare the effectiveness and safety of mechanical thrombectomy (MT) to intravenous thrombolysis in patients with posterior circulation occlusion (PCO). Hence, we firstly performed a meta-analysis to investigate the outcomes of MT in PCO and then compared these outcomes to anterior circulation occlusion (ACO) to provide fundamental data to further studies.METHODS:We searched the PubMed, EMBASE, and Cochrane Library from dates of inception to June 2019 for relevant studies. Outcomes including functional independence at 90 days, successful recanalization, mortality, symptomatic intracranial hemorrhage (sICH), and futile recanalization were extracted.RESULTS:Seven studies involving 474 patients with PCO thrombectomy were analyzed. There was a lower rate of functional independence at 90 days and a higher rate of mortality after thrombectomy in PCO versus ACO (odds ratios (OR) 0.72; 95% confidence interval (CI) 0.57-0.90; OR 2.03; 95% CI 1.30-3.18). Recanalization rates were comparable (OR 1.01; 95% CI 0.62-1.65), but a higher futile recanalization rate was found in basilar artery occlusion (BAO) (OR 1.75; 95% CI 1.30-2.37). There was a lower rate of sICH in MT for patients with PCO versus ACO (OR 0.54; 95% CI 0.29-0.99).CONCLUSIONS:We found that the outcomes of MT for patients with PCO were poorer than with ACO. On the other hand, MT appears to have lower rates of sICH and to increase successful recanalization. Given the high recanalization rate, MT may serve as an adjunct to standard treatment. The key point to improve outcomes is recognizing reliable factors associated with futile recanalization and optimizing the results of MT. But in view of the different characteristics of posterior circulation stroke and anterior circulation stroke, the results are far from robust.

脑出血（ICH）占脑血管疾病的10%至15%,是脑血管病致死率与致残率均高的一类亚型,院内死亡率高达40%。自发性脑出血,是一种原发性非外伤性脑实质出血[1]。他汀类药物,可限制胆固醇合成,增加血中LDL-胆固醇颗粒的清除率[2],是治疗动脉硬化疾病常用药物,脑出血患者应用他汀类药物以及应用他汀类药物对自发性脑出血有何影响尚不清楚,本文就他汀类药物应用对自发性脑出血发生与转归作一简要综述。

Background and objectivesThe role of serotonin–norepinephrine reuptake inhibitors (SNRIs) in migraine prophylaxis has not been completely established. Current treatments for vestibular migraine (VM) are based on scarce evidence. We aimed to perform an updated review focusing on the efficacy and tolerability of SNRIs for migraine and VM prevention.MethodsWe searched the PubMed, Web of Science, and Cochrane Library databases for relevant studies. The primary outcome was migraine frequency. In the case of VM, the Dizziness Handicap Inventory (DHI) scores and Vertigo Severity Scores (VSSs) were extracted.ResultsSix randomized controlled trials involving 418 patients were analyzed. Patients receiving SNRIs had fewer migraine days than those receiving a placebo (standardized mean difference −0.38, 95% CI −0.76 to −0.01, p=0.04). The effects of SNRIs and other active drugs were comparable. In patients with VM, venlafaxine had a significant advantage over other active drugs in decreasing the VSS (weighted mean difference (MD) −1.45, 95% CI −2.11 to −0.78, p<0.0001) and the emotional domain score of the DHI (MD −2.64, 95% CI −4.97 to −0.31, p=0.03). We found no significant difference in the rate of withdrawals due to any reason or withdrawals due to side effects between SNRIs and active drugs and between SNRIs and a placebo.ConclusionsSNRIs were clinically safe and effective for migraine and VM prophylaxis, were better than a placebo, and not inferior to other active drugs. SNRIs may be a preferable choice for patients with VM with psychiatric disorders.

The effects of resveratrol on various conditions have been widely studied previously. This paper aimed to investigate the influence of resveratrol on atherosclerosis (AS). Twenty-four New Zealand male rabbits were randomly and equally assigned to the normal diet group (NDG), fat diet group (FDG), and fat diet with resveratrol group (80 mg/kg/d, RFG). Biochemical indicators from blood samples were analyzed at baseline and 3 months to investigate the effects of resveratrol on blood lipid, lipoprotein-associated phospholipase A2 (Lp-PLA2), liver, and renal function. The indicators including alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine (CREA), triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and Lp-PLA2. At 3 months, arteries were stained with hematoxylin and eosin to study the influence of resveratrol on the aortic intima, smooth muscle layer, and the intima/media ratio. Comparisons of weight, ALT, AST, CREA, TG, TC, HDL-C, LDL-C, and Lp-PLA2 among the three groups showed no significant difference at baseline. However, at the end of 3 months, significant differences were observed in AST, CREA, TC, HDL-C, LDL-C, and Lp-PLA2 between the three groups (P<0.05). In pairwise comparison, CREA, TC, LDL-C, and Lp-PLA2 had significant differences between any two groups (P<0.05). In addition, there were significant differences in the AST and HDL-C levels between RFG and NDG groups (P<0.05). Meanwhile, the HDL-C levels were also significantly different between the FDG and NDG groups (P<0.01). The histologic analysis also showed that the thickness of the aortic intima and the ratio of the intima and aortic tunica media (P<0.05) significantly decreased in RFG compared to FDG. Resveratrol may have an antiatherosclerosis effect on a rabbit model of AS.

目的 探究白藜芦醇对慢性脑低灌注大鼠认知功能障碍的改善作用,以及AKT/mTOR信号通路在其中的调控机制.方法 采用永久结扎双侧颈总动脉法制作慢性脑低灌注大鼠模型.随机将大鼠分为假手术组、慢性脑低灌注模型组、白藜芦醇+慢性脑低灌注组,每组30只.采用Morris水迷宫定向航行试验和空间探索试验评价大鼠认知功能;采用神经功能缺损评分测试大鼠行为学;采用HE染色观察大鼠额颞叶皮层、海马区病理学改变以及神经元丢失情况;采用TUNEL染色检测神经元凋亡;采用Western blotting检测AKT/mTOR信号通路相关蛋白的表达情况.结果 白藜芦醇能改善由于长期低灌注造成的大鼠行为学损伤以及认知功能障碍.白藜芦醇治疗后,海马萎缩现象得到改善,神经元丢失和形态学异常现象得到缓解;大鼠神经元细胞凋亡率下降,抑制慢性低灌注大鼠脑组织AKT/mTOR信号通路相关蛋白表达.结论 白藜芦醇对慢性脑低灌注大鼠认知功能障碍具有改善作用,这种作用可能是通过AKT/mTOR信号通路调控的.

Conflicting findings have been reported on the prognostic significance of serum 25-hydroxyvitamin D level in patients with stroke. The objective of this meta-analysis was to evaluate the prognostic utility of serum 25-hydroxyvitamin D in stroke patients. PubMed and Embase databases were systematically searched for potentially eligible studies until October 16, 2019. Observational studies investigating the association between serum 25-hydroxyvitamin D level and prognosis of patients with stroke were eligible. Multivariable adjusted risk ratios (RR) with 95% confidence intervals (CI) of poor functional outcome, all-cause mortality, and recurrence of stroke were pooled with the lowest versus the highest category of 25-hydroxyvitamin D level. Eleven articles (ten studies) involving 6845 stroke patients satisfied our predefined inclusion criteria. Lower serum 25-hydroxyvitamin D level was associated with an increased risk of poor functional outcome (RR 1.86; 95% CI 1.16–2.98), all-cause mortality (RR 3.56; 95% CI 1.54–8.25), and recurrence of stroke (RR 5.49; 95% CI 2.69–11.23). Sensitivity analysis further confirmed the above findings. Lower serum 25-hydroxyvitamin D level is significantly associated with poorer prognosis in stroke patients. Future prospective studies are warranted to verify the prognostic role and to examine the association in different subtypes of stroke.