缺血性脑卒中患者MCA血流速度及脉动指数变化的相关分析

目的探讨并分析缺血性脑卒中患者MCA血流速度及脉动指数的变化。方法选取2016年1月—2017年1月就诊于佳木斯大学附属第一医院神经三科门诊及住院部的120例缺血性脑卒中住院患者,其中男性56例,女性64例。使用经颅多普勒超声诊断仪探查患者双侧大脑中动脉,测出患者大脑中动脉的血流速度和脉动指数。比较所有患者患侧与健侧的大脑中动脉血流速度和脉动指数变化。结果所有患者患侧大脑中动脉收缩期最快血流速度(t=15.63,P﹤0.05)、舒张期最快血流速度(t=10.61,P﹤0.05)明显小于健侧;而平均血流速度患侧与健侧比较无统计学意义(t=0.58,P0.05);并且大脑中动脉供脉动指数值明显高于健侧(t=3.54,P﹤0.05)。结论缺血性脑卒中患者大脑中动脉供血区脑梗死,临床进行TCD观察患者大脑中动脉血流速度及脉动指数的变化的临床诊疗,预判病情变化有指导意义。     

Multiple liquid chromatography separations and nanoESI-ion trap detection of plasma proteins in search of stroke biomarkers: A pilot study

Stroke is the most common cause of morbidity and death in the Western world, following ischemic heart disease and cancer. Stroke can be of two types, ischemic or hemorrhagic, with ischemic stroke accounting for approximately 85% of the total number of strokes. Well-recognized environmental risk factors for stroke include hypertension, smoking, diabetes mellitus, atrial fibrillation, and atherosclerosis. Computed tomography (CT) scanning is used to diagnose hemorrhagic stroke but is relatively ineffective and may remain normal in patients with mild ischemic strokes. Magnetic Resonance Imaging (MRI) is more sensitive in detecting ischemia than CT, especially in the diagnosis of mild stroke but it is still not 100% sensitive or precise. A simple and low-cost, rapid blood test to confirm a clinical and imaging diagnosis of ischemic stroke would be extremely useful. Based on this, the central idea of this paper is to develop a method that would be applicable to a statistically viable sample set to provide candidate biomarkers for distinguishing stroke types. In search of these candidate biomarkers, different analytical separation techniques have been used to screen for major differences in the proteomes of patients plasma samples with proteomics for identification.     

Biomarkers for ischemic stroke subtypes: A protein-protein interaction analysis

According to the Trial of Org 10172 in Acute Stroke Treatment, ischemic stroke is classified into five subtypes. However, the predictive biomarkers of ischemic stroke subtypes are still largely unknown. The utmost objective of this study is to map, construct and analyze protein-protein interaction (PPI) networks for all subtypes of ischemic stroke, and to suggest the predominant biological pathways for each subtypes. Through 6285 protein data retrieved from PolySearch2 and STRING database, the first PPI networks for all subtypes of ischemic stroke were constructed. Notably, F2 and PLG were identified as the critical proteins for large artery atherosclerosis (LAA), lacunar, cardioembolic, stroke of other determined etiology (SOE) and stroke of undetermined etiology (SUE). Gene ontology and DAVID analysis revealed that GO:0030193 regulation of blood coagulation and GO:0051917 regulation of fibrinolysis were the important functional clusters for all the subtypes. In addition, inflammatory pathway was the key etiology for LAA and lacunar, while FOS and JAK2/STAT3 signaling pathways might contribute to cardioembolic stroke. Due to many risk factors associated with SOE and SUE, the precise etiology for these two subtypes remained to be concluded.     

Lipidomic Profiling of Ipsilateral Brain and Plasma after Celastrol Post-Treatment in Transient Middle Cerebral Artery Occlusion Mice Model

Celastrol, a pentacyclic triterpene isolated from the traditional Chinese medicine Tripterygium wilfordii Hook. F., exhibits effectiveness in protection against multiple central nervous system (CNS) diseases such as cerebral ischemia, but its influence on lipidomics still remains unclear. Therefore, in the present study, the efficacy and potential mechanism of celastrol against cerebral ischemia/reperfusion (I/R) injury were investigated based on lipidomics. Middle cerebral artery occlusion (MCAO) followed by reperfusion was operated in mice to set up a cerebral I/R model. TTC staining and TUNEL staining were used to evaluate the therapeutic effect of celastrol. Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC/MS) was employed for lipidomics analysis in ipsilateral hemisphere and plasma. Celastrol remarkably reduced cerebral infarct volume and apoptosis positive cells in tMCAO mice. Furthermore, lipidomics analysis showed that 14 common differentially expressed lipids (DELs) were identified in brain and five common DELs were identified in plasma between the Sham, tMCAO and Celastrol-treated tMCAO groups. Through enrichment analysis, sphingolipid metabolism and glycerophospholipid metabolism were demonstrated to be significantly enriched in all the comparison groups. Among the DELs, celastrol could reverse cerebral I/R injury-induced alteration of phosphatidylcholine, phosphatidylethanolamine and sulfatide, which may be responsible for the neuroprotective effect of celastrol. Our findings suggested the neuroprotection of celastrol on cerebral I/R injury may be partially associated with its regulation of lipid metabolism.     

Mesenchymal stem cells promote proliferation of endogenous neural stem cells and survival of newborn cells in a rat stroke model

Mesenchymal stem cells (MSCs) secrete bioactive factors that exert diverse responses in vivo. In the present study, we explored mechanism how MSCs may lead to higher functional recovery in the animal stroke model. Bone marrow-derived MSCs were transplanted into the brain parenchyma 3 days after induction of stroke by occluding middle cerebral artery for 2 h. Stoke induced proliferation of resident neural stem cells in subventricular zone. However, most of new born cells underwent cell death and had a limited impact on functional recovery after stroke. Transplantation of MSCs enhanced proliferation of endogenous neural stem cells while suppressing the cell death of newly generated cells. Thereby, newborn cells migrated toward ischemic territory and differentiated in ischemic boundaries into doublecortin+ neuroblasts at higher rates in animals with MSCs compared to control group. The present study indicates that therapeutic effects of MSCs are at least partly ascribed to dual functions of MSCs by enhancing endogenous neurogenesis and protecting newborn cells from deleterious environment. The results reinforce the prospects of clinical application using MSCs in the treatment of neurological disorders.     

DSA、CTA联合MR影像评估AIS患者脑支循环及预后性关系

探讨数字减影血管成像(DSA)、计算机断层扫描血管成像(CTA)联合磁共振(MR)影像评估急性缺血性卒中(AIS)患者脑支循环及预后性关系。选取60例大脑中动脉M1段急性闭塞所致AIS患者为研究对象,根据DSA、CTA与MR影像对其脑侧支循环评估,比较患者基线资料、结局指标等,并分析预后性。结果发现:基于DSA、CTA与MR影像对AIS患者脑侧支循环评估结果一致性良好;3种影像模式下脑侧支循环良好组与不良组结局资料差异显著(P<0.05);多因素分析显示,FVH-ASPECTS评分、rLMC评分、ASITN/SIR分级量表均为AIS患者神经功能预后的独立影响因素。总之,DSA、CTA、MR影像对AIS患者脑侧支循环评估具有一致性,且FVH-ASPECTS评分、rLMC评分、ASITN/SIR分级量表均为AIS患者神经功能预后的独立影响因素。     

Synthesis and pharmacological evaluation of 3-amino-1-(5-indanyloxy)-2-propanol derivatives as potent sodium channel blockers for the treatment of stroke

In investigating potent sodium (Na(+)) channel blockers for the treatment of ischemic stroke, we synthesized a novel series of 3-amino-1-(5-indanyloxy)-2-propanol derivatives and evaluated their inhibitory effects on neuronal Na(+) channels. The 3-amino-1-(5-indanyloxy)-2-propanol derivatives exhibited potent blocking activity for Na(+) channels and a significantly low affinity for dopamine D(2) receptors, which demonstrates a minimal clinical risk for extrapyramidal side effects. In particular, compound 4b, a 3-amino-1-(5-indanyloxy)-2-propanol derivative bearing a benzimidazole moiety, showed desirable neuroprotective activity in a rat transient middle cerebral artery occlusion model. Furthermore, compound 4b displayed a high binding affinity for neurotoxin receptor site 2 of the Na(+) channels, which suggests that 4b would act as a use-dependent Na(+) channel blocker in sustained depolarization during ischemic stroke.     

微量元素与脑卒中(4)

脑卒中是目前中国最重要的公共卫生问题,正以其高发病率、高死亡率对我国造成巨大的社会、经济困难。从脑卒中的流行病学特征、脑卒中发病的危险因素、脑卒中患者的微量元素失衡及微量元素检测的临床意义四个方面阐述了微量元素与脑卒中的关系。     

微量元素与脑卒中(2)

脑卒中是目前中国最重要的公共卫生问题,正以其高发病率、高死亡率对我国造成巨大的社会、经济困难。从脑卒中的流行病学特征、脑卒中发病的危险因素、脑卒中患者的微量元素失衡及微量元素检测的临床意义四个方面阐述了微量元素与脑卒中的关系。     

微量元素与脑卒中(3)

脑卒中是目前中国最重要的公共卫生问题,正以其高发病率、高死亡率对我国造成巨大的社会、经济困难。从脑卒中的流行病学特征、脑卒中发病的危险因素、脑卒中患者的微量元素失衡及微量元素检测的临床意义四个方面阐述了微量元素与脑卒中的关系。     

The potential of tetrandrine as a protective agent for ischemic stroke

Stroke is one of the leading causes of mortality, with a high incidence of severe morbidity in survivors. The treatment to minimize tissue injury after stroke is still unsatisfactory and it is mandatory to develop effective treatment strategies for stroke. The pathophysiology of ischemic stroke is complex and involves many processes including energy failure, loss of ion homeostasis, increased intracellular calcium level, platelet aggregation, production of reactive oxygen species, disruption of blood brain barrier, and inflammation and leukocyte infiltration, etc. Tetrandrine, a bisbenzylisoquinoline alkaloid, has many pharmacologic effects including anti-inflammatory and cytoprotective effects. In addition, tetrandrine has been found to protect the liver, heart, small bowel and brain from ischemia/reperfusion injury. It is a calcium channel blocker, and can inhibit lipid peroxidation, reduce generation of reactive oxygen species, suppress the production of cytokines and inflammatory mediators, inhibit neutrophil recruitment and platelet aggregation, which are all devastating factors during ischemia/reperfusion injury of the brain. Because tetrandrine can counteract these important pathophysiological processes of ischemic stroke, it has the potential to be a protective agent for ischemic stroke.     

LC-MS-based multi-omics analysis of brain tissue for the evaluation of the anti-ischemic stroke potential of Tribulus terrestris L. fruit extract in MCAO rats

This study aimed to investigate the chemical composition of Tribulus terrestris L. fruit (TT) extract named TT15 and its protective effect against ischemic stroke (IS) as well as corresponding mechanisms. The chemical composition of TT15 was analyzed by liquid chromatography-mass spectrometry (LC-MS), and the compound identification was conducted via searching the in-house database. The LC-MS-based multi-omics approach was applied to search the differential metabolites and differential proteins in rat brain tissue and to explore the biomarker and molecular mechanism of TT15 against middle cerebral artery occlusion (MCAO). A total of 20 compounds were identified from TT15, mainly including alkaloids, flavonoids, phenols, quinones, and esters. These 20 compounds significantly affected the metabolism of 44 metabolites and the expression of 51 proteins. Joint pathway analysis showed that these metabolites and proteins were mainly involved in the response to elevated platelet cytosolic Ca²⁺ and platelet activation, which inferred that TT15 may exert a protective effect against cerebral ischemic injury via regulating platelet function. This study provides useful information for further exploration of the mechanisms of TT extract against IS.     

Ischemic postconditioning protects cardiomyocytes against ischemia/reperfusion injury by inducing MIP2

Cardiomyocytes can resist ischemia/reperfusion (I/R) injury through ischemic postconditioning (IPoC) which is repetitive ischemia induced during the onset of reperfusion. Myocardial ischemic preconditioning up-regulated protein 2 (MIP2) is a member of the WD-40 family proteins, we previously showed that MIP2 was up-regulated during ischemic preconditioning (IPC). As IPC and IPoC engaged similar molecular mechanisms in cardioprotection, this study aimed to elucidate whether MIP2 was up-regulated during IPoC and contributed to IPoC-mediated protection against I/R injury. The experiment was conducted on two models, an in vivo open chest rat coronary artery occlusion model and an in vitro model with H9c2 myogenic cells. In both models, 3 groups were constituted and randomly designated as the sham, I/R and IPoC/hypoxia postconditioning (HPoC) groups. In the IPoC group, after 45 min of ischemia, hearts were allowed three cycles of reperfusion/ischemia phases (each of 30 s duration) followed by reperfusion. In the HPoC group, after 6 h of hypoxia, H9c2 cells were subjected to three cycles of 10 minute reoxygenation and 10 minute hypoxia followed by reoxygenation. IPoC significantly reduced the infarct size, plasma level of Lactate dehydrogenase and creatine kinase MB in rats. 12 h after the reperfusion, MIP2 mRNA levels in the IPoC group were 10 folds that of the sham group and 1.4 folds that of the I/R group. Increased expression of MIP2 mRNA and attenuation of apoptosis were similarly observed in the HPoC group in the in vitro model. These effects were blunted by transfection with MIP2 siRNA in the H9c2 cells. This study demonstrated that IPoC induced protection was associated with increased expression of MIP2. Both MIP2 overexpression and MIP2 suppression can influence the IPoC induced protection.     

Quantitative Mitochondrial Proteomics Study on Protective Mechanism of Grape Seed Proanthocyanidin Extracts Against Ischemia/Reperfusion Heart Injury in Rat

Cardiac ischemia/reperfusion(I/R) injury is a critical condition, often associated with high morbidity and mortality. The cardioprotective effect of grape seed proanthocyanidin extracts(GSPE) against oxidant injury during I/R has been described in previous studies. However, the underlying molecular mechanisms have not been fully elucidated. This study investigated the effect of GSPE on reperfusion arrhythmias especially ventricular tachycardia(VT) and ventricular fibrillation(VF), the lactic acid accumulation and the ultrastructure of ischemic cardiomyocytes as well as the global changes of mitochondria proteins in in vivo rat heart model against I/R injury. GSPE significantly reduced the incidence of VF and VT, lessened the lactic acid accumulation and attenuated the ultrastructure damage. Twenty differential proteins related to cardiac protection were revealed by isobaric tag for relative and absolute quantitation(iTRAQ) profiling. These proteins were mainly involved in energy metabolism. Besides, monoamine oxidase A(MAOA) was also identified. The differential expression of several proteins was validated by Western blot. Our study offered important information on the mechanism of GSPE treatment in ischemic heart disease.     

Monitoring serum chondroitin sulfate levels in patients submitted to coronary artery bypass surgery

Glycosaminoglycans (GAGs) are functionally important molecules of the arterial wall and play a crucial role in atherogenesis. Chondroitin sulfate/dermatan sulfate proteoglycans (CS/DSPGs) participate in several biological events through their GAG chains, and are also involved in the development of atherosclerosis. The aim of this study was to compare the pre- and post-operative levels of CS in serum of patients after coronary artery bypass graft surgery using a highly sensitive reversed-polarity capillary electrophoresis method and to investigate the correlation of CS with common biochemical lipid markers. It was found that CS values were significantly higher for all patients post-operatively and, furthermore, CS levels were statistically correlated to apolipoprotein A and B levels. Notably, the pre-operational lipid profile of the patient may be indicative of the values of 4-sulfated CS post-operationally. Furthermore, the obtained results highlight the clinical significance of CS levels in serum, since they may provide complementary information for the latent inflammatory state of the patient.     

原子荧光光谱法测定褪黑素治疗组兔肝脏硒含量

为探讨褪黑素对实验性动脉粥样硬化兔肝脏组织中硒含量的影响,用高脂饮食复制兔动脉粥样硬化,然后给予褪黑素建立治疗组模型,获取肝脏,用硝酸、过氧化氢混合液微波消解样品,采用原子荧光光谱法测定肝脏组织中硒的含量。结果表明,正常组、高脂组和褪黑素治疗组硒在肝脏组织中质量分数分别为3.31、2.14和1.34 mg/kg。提示给予褪黑素治疗后,褪黑素治疗组的硒平均含量比高脂组的平均含量降低37.4%,所以褪黑素对肝脏硒的吸收具有明显的抑制作用。     

SP600125, a selective JNK inhibitor, aggravates hepatic ischemia-reperfusion injury

c-Jun N-terminal kinase (JNK) is activated during hepatic reperfusion, and JNK inhibitors are known to protect other major organs from ischemia-reperfusion (I/R) injury. We attempted to determine the effect of SP600125, a JNK inhibitor, on hepatic I/R injury using a partial ischemia model in mice. Compared to a vehicle-treated group, the SP600125- treated group showed a greater increase in serum ALT levels 24 h after reperfusion with more severe parenchymal destruction and leukocyte infiltration. Similarly, tissue myeloperoxidase and malondialdehyde levels were higher in the SP600125-treated group, and chemokine expression was also higher in the SP600125-treated group. These data, which are contradictory to previous results, indicate that JNK inhibition by SP600125 may be harmful in hepatic I/R injury. Therefore, care must be taken when investigating the therapeutic use of JNK inhibitors in hepatic I/R injury, especially in the context of the effects of JNK inhibition on inflammatory infiltration.     

Evaluation of the antioxidant potential of Salvia miltiorrhiza ethanol extract in a rat model of ischemia-reperfusion injury

The present study was undertaken to evaluate the protection potential of ethanol extract of Salvia miltiorrhiza (SMEE) against oxidative injury in the ischemia-reperfusion (I/R) model of rats in vivo. Rats were divided into six groups of 10 rats each. Group I/R model and sham were fed with a standard rat chow, groups SMEE I and SMEE II were fed with a standard rat chow and 400 or 800 mg/kg b.w. ethanol extract for 12 days before the beginning of I/R studies. Positive control group was fed with a standard rat chow and salvianolic acid B (55 mg/kg b.w.) or tanshinone II-A (55 mg/kg b.w.) for 12 days before the beginning of I/R studies. To produce I/R, the left anterior descending artery (LAD) was occluded in anesthetized rats for 15 min, followed by 120 min reperfusion. Infarct sizes were found significantly decreased in SMEE-treated and positive control groups compared to I/R model group. Serum AST, LDH and CK-MB activities were significantly reduced and myocardium Na+-K+ ATPase, Ca2+-Mg2+ ATPase activities and antioxidant enzyme activities (SOD, CAT, GSH-Px) were markedly increased in SMEE-treated and salvianolic acid B or tanshinone II-A positive control groups compared to the I/R model group. Pretreatment of S. miltiorrhiza ethanol extract and salvianolic acid B or tanshinone II-A dose-dependently reduced significantly myocardium MDA level, ROS and NOS activities and enhanced myocardium GSH level in I/R rats compared to I/R rats model. In conclusion, we clearly demonstrated that S. miltiorrhiza ethanol extract pretreatment can decrease oxidative injury in rats subjected to myocardial I/R.