基于网络药理学和分子对接探讨益气活血方抗脑缺血机制研究

脑缺血(cerebral ischemia,CI)具有高发病率、高致畸率,是全球第二大致死疾病.中药(traditional Chinese medicine,TCM)益气活血方(YQHX)在临床治疗CI发挥一定疗效,但其机制尚不清楚.本文基于网络药理学和分子对接探讨其作用机制.通过TCMSP和CNKI数据库获取益气活...     

脑缺血中细胞凋亡发生的多元调节机制

脑缺血中细胞凋亡发生的多元调节机制＊印克杰孙凤艳（上海医科大学神经生物学教研室、医学神经生物学国家重点实验室，上海２０００３２中国图书分类号Ｒ３２９．２１；Ｒ３２９．２６；Ｒ７４３．３细胞凋亡最早于１９７２年由ｋｅｒｒ等人首先提出。作为一种有别于坏死...     

低分子肝素对实验性脑缺血的保护作用

目的观察低分子肝素注射液对实验性脑缺血的保护作用。方法分别采用小鼠局灶性脑缺血再灌注模型、小鼠脑缺血再灌注模型,观察低分子肝素注射液对局灶性脑缺血再灌注后的小鼠神经行为和脑梗死体积,小鼠脑缺血再灌注后脑组织MDA含量,SOD、GSH-PX酶活性的影响。结果低分子肝素注射液可改善脑缺血再灌注后小鼠的神经行为,降低脑梗死体积;降低脑组织内MDA含量、升高GSH-PX、SOD酶活性。结论低分子肝素注射液对实验性脑缺血具有保护作用。     

一氧化氮在脑缺血预处理中的作用及其机制

作为一个重要的信号分子,一氧化氮可调节大脑血流量和局部大脑灌注时的新陈代谢活性。在脑缺血预处理中,一氧化氮水平发生变化,其通过调控下游信号通路,产生神经保护效应。综述一氧化氮在脑缺血预处理中的作用及其机制。     

脑缺血耐受机制及雌激素通过此机制介导的神经保护作用

目的对脑缺血耐受的分子机制新近研究及雌激素通过此机制发挥的神经保护作用进行文献综述。方法根据近年来发表的英文文献,归纳并论述脑缺血耐受发生的可能的分子机制,分析药物介导神经保护作用的潜在靶点。结果脑缺血耐受的形成涉及多种不同的信号通路,主要从HSP70、PI3K/Akt信号通路、CREB、炎症因子等方面进行了论述。在缺血预处理模型中,雌激素能够上调HSP70、CREB表达,激活PI3K/Akt信号保护通路,抑制相关炎症因子,加强脑缺血耐受,发挥神经保护作用。结论对脑缺血耐受机制及药物发挥的神经保护作用的研究,为抗脑缺血药物的开发提供新的视角和理论依据。     

丹参抗脑缺血在神经细胞、分子及递质水平的作用机制研究进展

目的为丹参抗脑缺血的药理及临床研究提供理论依据。方法查阅1989-2006年清华同方数据库,回顾分析丹参在神经细胞、分子及递质水平的脑缺血保护作用机制的研究报道。结果丹参抗脑缺血在神经细胞、分子及递质水平的作用机制主要有:通过抑制缺血区小胶质细胞的活化、抑制ICAM-1的表达等降低神经细胞的损伤;通过下调ICE表达、上调bcl-2蛋白的表达等抑制神经细胞的凋亡;通过减少NO合成、抑制EAA释放等影响神经递质水平;通过抑制ET-1表达、调节TXA2-PGI2平衡等影响血管相关活性物质的表达。结论丹参可从降低神经细胞的损伤、抑制神经细胞的凋亡、影响神经递质及血管活性物质的表达等多个方面起到脑缺血保护作用。     

慢性脑缺血病理机制与实验研究进展

慢性脑缺血不但可引起脑组织病理学改变，而且使学习和记忆能力明显下降，促进认知功能障碍发展发生。因此，本文主要对慢性脑缺血的发病机制及有关实验研究做一综述。     

降纤酶低分子肝素治疗短暂性脑缺血发作的研究

目的 观察降纤酶与低分子肝素治疗短暂性脑缺血发作的效果及副作用。方法 选择本院神经内科住院患者36例应用降纤酶10U加入加入250ml生理盐水中静脉滴注，隔日1次，共3次；低分子肝素0．5ml脐旁皮下注射，12h 1次，连用7—10d,同时常规给予复方丹参滴注，口服尼莫地平，维生素E，维生素C，停用低分了肝素后给予肠溶阿斯匹林75mg，每日1次口服。结果 治疗开始后TLA发作相继减少，停止发作时间分别为1d内9例，3d内15例，5d内12例。随访6个月—1年，1例2个月后复发，重新应用上药治愈。结论 降纤酶与低分子肝素治疗TLA安全有效、无明显副作用、不易复发。     

银杏叶提取物抗脑缺血作用机制研究进展

银杏叶,为银杏科乔木植物银杏的叶,性味苦、涩、平,功能主治活血化瘀、通经活络.近年来,其提取物 GBE或 EGb761)已广泛应用于治疗脑部、周边血液循环障碍,急、慢性脑机能不全及后遗症等.为深入探讨 GBE抗脑缺血的体内作用机理,国内、外诸多学者针对神经元缺血性损伤的病理生理机制,如能量代谢障碍、酸中毒、细胞内钙浓度( [Ca2 ]i)增加、兴奋性毒性作用、自由基 [活性氧自由基和一氧化氮( NO) ]损伤、炎症反应和细胞凋亡等,对 GBE的药理作用进行了大量卓有成效的研究工作.目前有关研究报道很多,现简要综述如下.     

低分子肝素治疗短暂性脑缺血发作的临床研究

目的观察低分子肝素(LMWH)治疗短暂性脑缺血发作(TIA)的疗效.方法应用LMWH治疗30例TIA患者,进行临床及实验室指标观察并与对照组比较.结果LMWH组的基本治愈率、总有效率均明显高于对照组(P＜0.01),两组的血小板计数、血流变学及血小板聚集率无明显差异,未发现明显副作用.结论LMWH是治疗TIA的一种安全、有效药物.     

Protecting mechanism of puerarin on the brain neurocyte of rat in acute local ischemia brain injury and local cerebral ischemia-reperfusion injury

The present study was designed to investigate the possible properties of the injured brain neurocytes, the expression of heat shock protein70 (HSP70) and Fas protein after acute local ischemia brain injury and local cerebral ischemia-reperfusion injury in rats and to investigate the protecting mechanism of puerarin on the brain neurocytes of rats in acute local ischemia brain injury and local cerebral ischemia-reperfusion injury. A rat model of acute local cerebral ischemia was made by ligatting the middle cerebral artery. The rat model of local cerebral ischemia and reperfusion injury was made by ligatting the middle cerebral artery for 30 min then opened for 30 min. Rats of puerarin treating group were injected with puerarin in dose of 30 mg/kg(-1) by intraperitoneal injection 30 min before ischemia. HSP70 and Fas protein expressions in brain tissue were detected by SP method of histochemistry. In addition, dead brain neurocytes were counted and their morphology was observed. The results indicated that puerarin can limit the tissue injury caused by local cerebral ischemia injury through improving expression of HSP70, and limit the tissue injury caused by local cerebral ischemia-reperfusion through decreasing the Fas expression and improving expression of HSP70. On the basis of these results, it may be concluded that puerarin can protect the brain neurocytes of rats in acute local ischemia brain injury and local cerebral ischemia-reperfusion injury, which may be different according to the different injury mechanism.     

四妙勇安汤对糖尿病大鼠肢体缺血治疗作用及其分子机制

目的研究四妙勇安汤对糖尿病后肢缺血大鼠的治疗作用及对丝苏氨酸蛋白激酶（Akt）、p38丝裂原活化蛋白激酶（P38）蛋白水平的影响。方法40只Wistar大鼠完全随机分为4组：对照组、对照治疗组建立单纯缺血模型;模型组、模型治疗组建立糖尿病肢体缺血模型,对照治疗组、模型治疗组给予四妙勇安汤治疗。分别于术前、术后即刻、术后第3、7、14天测下肢血流变化,术后15d取腓肠肌组织免疫组织化学CD31染色血管内皮细胞观察新生血管密度,及蛋白印迹法检测内皮细胞Akt、P38蛋白变化情况。结果模型组血管损伤严重,血管重建能力明显降低,第7天对照组、对照治疗组、模型组、模型治疗组血流比值为（45±4）、（49±3）、（364-3）、（48±6）％,第14天血流比值为（63±6）、（66±4）、（45±4）、（61±4）％,与模型组比较,其余3组差异均有统计学意义（P〈0．05）。模型组术后15d新生血管密度明显减低,Akt蛋白表达明显降低,P38表达明显升高,其他3组与其差异均有统计学意义（P〈0．05）;四妙勇安汤能够明显增加新生血管数量[模型组、模型治疗组分别为（9．1±2．0）、（16．4±2．9）个,P〈0．05,模型组、模型治疗组比值分别为（0．62±0．15）、（0．86±0．18）％,P〈0．05],增加Akt蛋白表达,降低P38表达,差异均有统计学意义[模型组与模型治疗组蛋白相对光密度比值：Akt：（0．20±0．07）、（0．28±0．56）％;P38：（1．18±0．23）、（0．99±0．04）％,P〈0．05],对照治疗组未发现中药治疗后副作用。结论四妙勇安汤能够改善糖尿病下肢缺血血运重建过程,加快血管新生速度,其作用机制可能是通过促进Akt表达,抑制P38表达实现的。     

藁本内酯对小鼠海马区损伤的保护作用及其作用机制

目的 研究藁本内酯(Lig)对小鼠海马区损伤的保护作用及其作用机制.方法 将24只小鼠随机均分为假手术组、模型组和Lig组,采用双侧颈总动脉结扎法(2VO)建立全脑缺血再灌注模型;Nissl染色观察小鼠海马CA1、CA2区的神经元计数;免疫组化检测海马区胶质纤维酸性蛋白(GFAP)、肿瘤坏死因子(TNFα)的表达.结果 与模型组比较,Lig能减轻缺血再灌带来的损伤,减少海马CA1、CA2区神经元的丢失,降低GFAP、TNFα的表达.结论 Lig能明显减轻全脑缺血再灌注所致的小鼠海马区损伤,其机制与抑制星形胶质细胞激活、减轻炎症反应有关.     

The mechanism study of the effect of neutrophil elastase on brain microvascular endothelial cells in ischemia/reperiusion injury

Objective： （ 1 ） To isolate and to observe the morphology of brain microvascular endothelial cells （BMEC） from Wistar rat. （2） To study the effect of neutrophil elastase （NE） on BMEC in ischemia/reperfusion （I/R） injury. Methods： Through a mesh . centrifugation and collagenase digestion, primary cuhure BMEC. Cells were divided into 6 groups： normal group, model group, Sir （NE inhibitor , sivelestat） group, NE group, NE ＋ Sir group, Adr group （ positive control group）. Observe the activity of cells by MTT, LDH; measure the content of ET - 1 by radioimmunoassay; investigate the expression of ICAM - 1 by immunohistochemistry and flow cytometry ; detective the expression of Tie - 2 mRNA by RTPCR. Results： （1） The characterization of BMEC was confirmed based on the morphology and immunohistochemistry. （2） Compared with the normal group , model group, and Sly group, LDH, ET- 1, ICAM - 1, Tie -2 content in NE group was obviously higher （ P 〈 0. 05 ）, MTT was obviously lower （ P 〈0. 05 ）. Compared with the NE group, LDH, ET - 1, ICAM - 1, Tie - 2 content in NE ＋ Sly group was obviously lower （ P 〈0.05）,     

JNK抑制剂保护肾缺血/再灌注损伤及其分子机制

肾脏对缺血/再灌注损伤(ischemic reperfusion injury,IRI)较敏感,在相关手术中易发生不同程度的再灌注损伤,可能与细胞凋亡及JNK信号通路的激活有关"[1,2].     

基于网络药理学和分子对接预测金雀异黄素治疗创伤性脑损伤的机制

目的 研究金雀异黄素治疗创伤性脑损伤的潜在分子机制.方法 通过中药系统药理学数据库(TCMSP)、SymMap、CTD、GeneCards数据库获得金雀异黄素在治疗创伤性脑损伤的潜在作用靶点,通过Metascape数据库进行GO和KEGG富集分析,使用薛定谔Maestro 10.2软件进行金雀异黄素与核心靶点的分子对接...     

Effect of histaminergic system on brain ischemia

Ischemic stroke is a disease with high mortality and a main leading cause of disability.However,few effective therapeutic approaches are available at present.This may attribute to the complex pathological process of cerebral ischemia.Therefore,the multiple therapeutic requirements with multiple targets in individual stage are needed.Brain histaminergic system is important in regulating physiological functions.We found that activating histaminergic system in brain is effective in rescuing acute ischemic neuronal injury,either by direct inhibition of excitotocixity or regulating astrocytes glutamate metabolism.Further works revealed that both carnosine,the precursor of histamine,and H3R antagonist,potentiation histamine release,act in a histamine-independent manner.Instead,antioxidation and H3R-mediated autophagy reinforcement may underly their neuroprotection(unpublished data).Histamine also provides therapy opportunities in recovery phase after cerebral ischemia.Our recent data suggested that histamine may prevent the glial scar formation and consequently improve neurons regeneration.Interestingly,we found a variety of dosage combination of histidine in different phase of recovery will further improve the effects of inhibiting glial scar.Histamine may direct regulating matrix proteins expression and promoting astrocytes migration to ischemic region via H2R signaling in early and late phase,respectively.Besides the external activation of histaminergic system,histamine is involved in endogenous protective strategy as well.We reported that hypoxic preconditioning protects against cerebral ischemia in histamine-VEGF signaling pathway.Further works indicated that low glucose and acidosis postconditioning also provide robust neuronal protection,although histamine may not be involved in these context(unpublished data).These important histamine-independent pathologcal characteristics of brain ischemia may be valuable in developing novel therapeutic strategies.In conclusion,our investigations provide evidences indicating that activation of brain histaminergic system protects against ischemic neuronal injury in distinct pathological stages.These data shed light on the role of histaminergic system as potential multiple therapeutic targets in cerebral ischemia.     

表观遗传调控在心肌缺血作用机制中的研究进展

随着现代生活方式的转变,缺血性心脏病已成为全球心血管疾病患者的主流死亡因素。迅速恢复血流灌注是治疗心肌缺血的重要途径,然而血流再灌注会诱发心肌梗死,甚至会引起无法逆转的心肌细胞死亡,因此寻找新的途径治疗心肌缺血迫在眉睫。DNA甲基化、组蛋白乙酰化与非编码RNA等表观遗传调控是后基因时代的重点研究对象,越来越多的证据表明表观遗传学调控直接影响心脏的发育,参与多种缺血性心脏病的发生与发展过程,对心肌缺血的诊断和治疗具有重要意义。对近年来DNA甲基化、组蛋白乙酰化与非编码RNA在心肌缺血中的作用机制做一综述。     

Pentylenetetrazole-induced convulsions affect cellular and molecular parameters of the mechanism of action of triiodothyronine in adult rat brain

The aim of the current study was to elucidate whether the response of the adult rat brain to thyroid hormones is affected by the intensity of neuronal activity. For this purpose, the kinetic characteristics of nuclear T3 binding, the relative expression of thyroid hormone receptor (TR) isoforms and the synaptosomal content of thyroid hormones in adult rat brain were examined after administration of a single convulsion dose of pentylenetetrazole (PTZ). Experiments in adult Wistar rats revealed an increase (33%) of the density of specific T3 nuclear receptors in cerebral hemispheres 4h after PTZ-induced seizures while no changes were observed in the dissociation constant. The relative expression of the T3-binding isoforms of TRs was not affected, while there was a gradual decrease of the relative expression of the TR alpha2 variant (non-T3 binding isoform). The above changes were coupled with an increase of the synaptosomal T3 levels during the epileptic seizures. Our study revealed inversely proportional changes between the nuclear T3 binding sites and the TR alpha2 mRNA levels 4 h after PTZ-induced seizures, suggesting that the regulation of the expression of the non-T3 binding variant of TRs determines the nuclear T3 binding sites in adult rat brain, while the synaptosomal T3 levels could play a novel functional role in the signaling from the synapse to the nucleus.