丙戊酸与缺血性脑卒中相关研究进展

动脉粥样硬化和缺血性脑损伤是防治缺血性脑卒中所面临的两大难题,而细胞炎症损伤是它们的共同诱因。丙戊酸作为组蛋白去乙酰化酶抑制剂,具有抑制细胞炎症因子释放及保护神经的作用,所以丙戊酸可能是防治缺血性脑卒中的潜在治疗药物。本文从组蛋白去乙酰化酶对缺血性脑卒中的影响以及丙戊酸的抗炎机制两个方面进行综述。     

中药通过调节小胶质细胞激活改善缺血性脑卒中

炎症反应是造成脑卒中继发性脑损伤的关键因素之一。小胶质细胞作为脑内免疫细胞,在脑卒中的炎症反应具有重要作用。传统观念认为小胶质细胞促进炎症反应加重脑损伤。近年来的研究发现激活的小胶质细胞还能产生抗炎作用来加速脑损伤修复。因此,目前的研究将小胶质细胞分为促炎的M1型和抗炎的M2型。结合目前缺血性脑卒中的神经保护剂相对较少,靶向调控小胶质细胞的极化可能成为脑卒中新的治疗策略。研究发现中药能够通过抑制M1型小胶质细胞,并促进M2型的小胶质细胞来改善缺血性脑损伤,从而展现出对缺血性脑卒中的治疗潜力。本文综述了中药通过调节小胶质细胞极化表型来治疗脑卒中的相关研究,以期为缺血性脑卒中药物开发提供新的思路。     

中药通过调节小胶质细胞激活改善缺血性脑卒中（英文）

炎症反应是造成脑卒中继发性脑损伤的关键因素之一.小胶质细胞作为脑内免疫细胞,在脑卒中的炎症反应具有重要作用.传统观念认为小胶质细胞促进炎症反应加重脑损伤.近年来的研究发现,激活的小胶质细胞还能产生抗炎作用来加速脑损伤修复.因此,目前的研究将小胶质细胞分为促炎的M1型和抗炎的M2型.结合目前缺血性脑卒中的神经保护剂相对较少,靶向调控小胶质细胞的极化可能成为脑卒中新的治疗策略.研究发现中药能够通过抑制M1型小胶质细胞,并促进M2型的小胶质细胞来改善缺血性脑损伤,从而展现出对缺血性脑卒中的治疗潜力.本文综述中药通过调节小胶质细胞极化表型来治疗脑卒中的相关研究,以期为缺血性脑卒中药物开发提供新的思路.     

MicroRNA对缺血性脑卒中自噬调控作用的研究进展

脑卒中可造成严重的脑部损伤,是人类第二大死亡原因。患者中,缺血性脑卒中更为常见,其发病机制复杂,近年的研究提示细胞自噬参与其中。自噬是一种通过自身降解异常蛋白和受损细胞器维持细胞内环境稳态的分解代谢途径,该过程受基因调控,可抵抗缺血性脑卒中造成的缺血缺氧环境,维持存活状态,但过度的自噬也可直接导致细胞死亡。MicroRNA是一种非编码RNA,可通过与mRNA反向结合,从基因水平上调控多种细胞活动。microRNA可通过对自噬过程的调节而参与缺血性脑卒中多种病理过程的调节。但microRNA在缺血性脑卒中自噬过程中的作用还未完全明晰。本文汇总近年来此领域的最新研究进展,旨在为缺血性脑卒中的基础研究与临床应用奠定理论基础。     

基质金属蛋白酶9与缺血性脑卒中的研究进展

基质金属蛋白酶9(MMP-9)是一种具有降解功能的锌依赖性内肽酶,在神经系统生理发育及病理损伤过程中起重要作用。在缺血性脑卒中过程中,MMP-9通过破坏血脑屏障、促进炎性细胞浸润及炎性因子释放、诱发神经细胞死亡、介导出血转化等诸多机制参与脑组织损伤。本文对MMP-9在缺血性脑卒中的损伤及修复中的作用机制进行综述,以期为缺血性脑卒中提供新的诊疗靶点。     

食欲素与缺血性脑卒中关系的研究进展

缺血性脑卒中是严重威胁我国人民生命和健康的疾病,具有高发病率、高死亡率和高致残率。食欲素是下丘脑分泌的一种神经肽,包括食欲素A和食欲素B有调节能量平衡、刺激食欲、内分泌、睡眠-苏醒、心血管系统的功能。近年来有研究发现食欲素通过对血糖、血压、炎症以及缺血性脑卒中后抑郁及认知功能的调节,进而影响缺血性脑卒中的预后。本文将对食欲素与缺血性脑卒中的关系做一综述。     

外泌体源性蛋白对缺血性脑卒中的作用

缺血性脑卒中严重危害人类健康和生活质量,探寻其发病机制和保护策略一直是脑血管研究领域的重点问题。外泌体作为细胞主动分泌的纳米级囊泡,通过携带丰富的蛋白质、DNA、miRNA等生物大分子,在胞间的物质运输和信息交换中发挥重要作用。研究表明,中枢外泌体在缺血性脑卒中的发病及后期的修复的病理生理过程中均发挥了重要的作用。外泌体源性蛋白作为外泌体的重要组成部分,参与了缺血性脑卒中的发生和发展。本文就外泌体源性蛋白质的生物学特性及其在缺血性脑卒中的作用和机制研究进行综述。     

从反面利用G-CSF的癌增殖作用

日本中外制药公司和麒麟啤洒-三共公司最近进行粒状白细胞集落刺激因子(G-CSF)的临床试验,探讨它作为增强抗癌剂效果的增强因子的作用。这是从反面利用分化增殖因子的癌增殖作用。以前,因为担心癌增殖作用,所以在日本分化生长因子等迟迟不能进入临床试验。这次试验也许能成为生物技术医药开发的典型实例。 G-CSF和粒状白细胞巨噬细胞集落刺激因子、白细胞介素1～8、上皮细胞生长因子等体内的分化生长因子不仅有诱引正常细胞分化、增殖的作用,而且还有使某种癌细胞自     

鼠粒细胞集落刺激因子受体的纯化及鉴定

粒细胞集落刺激因子受体(G-CSFR)在鼠NFS-60细胞中有较高的含量,通过对NFS-60细胞的大规模培养,用CHAPS及超速离心抽提G-CSFR, 经G-CSF亲和层析纯化获得G-CSFR, 采用ABC-ELISA进行鉴定.     

长链非编码RNA调节缺血性脑卒中损伤和修复的研究进展

长链非编码RNA(long noncoding RNA,lnc RNA)是一组在转录、转录后和表观遗传水平发挥作用的调控序列,其在中枢神经系统中特异性高表达,对中枢神经系统发育和疾病发展具有重要调控作用。缺血性脑卒中诱导脑内大量lnc RNA表达改变,提示lnc RNA与缺血性脑卒中复杂的病理过程有关,这将有利于全面认识缺血性脑卒中的病理机制及脑缺血损伤后的分子调控网络,并提供新的治疗方向。尽管有少数研究报道lnc RNA在缺血性心脏病中的作用,但目前对于其在缺血性脑卒中病理发展中的作用知之甚少。综述目前已知的lnc RNA在脑缺血再灌注损伤、细胞凋亡与抗凋亡及损伤后神经再生与修复中的作用,并提出了未来可能的lnc RNA在缺血性脑卒中损伤与修复中的研究方向。     

Effects of G-CSF on cardiac remodeling after acute myocardial infarction in swine

We examined whether granulocyte colony-stimulating factor (G-CSF) prevents cardiac dysfunction and remodeling after myocardial infarction (MI) in large animals. MI was produced by ligation of left anterior descending coronary artery in swine. G-CSF (10 microg/kg/day, once a day) was injected subcutaneously from 24h after ligation for 7 days. Echocardiographic examination revealed that the G-CSF treatment induced improvement of cardiac function and attenuation of cardiac remodeling at 4 weeks after MI. In the ischemic region, the number of apoptotic endothelial cells was smaller and the number of vessels was larger in the G-CSF treatment group than in control group. Moreover, vascular endothelial growth factor was more abundantly expressed and Akt was more strongly activated in the ischemic region of the G-CSF treatment group than of control group. These findings suggest that G-CSF prevents cardiac dysfunction and remodeling after MI in large animals.     

G-CSF Protects Human Brain Vascular Endothelial Cells Injury Induced by High Glucose,Free Fatty Acids and Hypoxia through MAPK and Akt Signaling

Granulocyte-colony stimulating factor (G-CSF) has been shown to play a neuroprotective role in ischemic stroke by mobilizing bone marrow (BM)-derived endothelial progenitor cells (EPCs), promoting angiogenesis, and inhibiting apoptosis. Impairments in mobilization and function of the BM-derived EPCs have previously been reported in animal and human studies of diabetes where there is both reduction in the levels of the BM-derived EPCs and its ability to promote angiogenesis. This is hypothesized to account for the pathogenesis of diabetic vascular complications such as stroke. Here, we sought to investigate the effects of G-CSF on diabetes-associated cerebral vascular defect. We observed that pretreatment of the cultured human brain vascular endothelial cells (HBVECs) with G-CSF largely prevented cell death induced by the combination stimulus with high glucose, free fatty acids (FFA) and hypoxia by increasing cell viability, decreasing apoptosis and caspase-3 activity. Cell ultrastructure measured by transmission electron microscope (TEM) revealed that G-CSF treatment nicely reduced combination stimulus-induced cell apoptosis. The results from fluorescent probe Fluo-3/AM showed that G-CSF greatly suppressed the levels of intracellular calcium ions under combination stimulus. We also found that G-CSF enhanced the expression of cell cycle proteins such as human cell division cycle protein 14A (hCdc14A), cyclinB and cyclinE, inhibited p53 activity, and facilitated cell cycle progression following combination stimulus. In addition, activation of extracellular signal-regulated kinase1/2 (ERK1/2) and Akt, and deactivation of c-Jun N terminal kinase (JNK) and p38 were proved to be required for the pro-survival effects of G-CSF on HBVECs exposed to combination stimulus. Overall, G-CSF is capable of alleviating HBVECs injury triggered by the combination administration with high glucose, FFA and hypoxia involving the mitogen-activated protein kinases (MAPK) and Akt signaling cascades. G-CSF may represent a promising therapeutic agent for diabetic stroke.     

Immediate remote ischemic postconditioning reduces cerebral damage in ischemic stroke mice by enhancing leptomeningeal collateral circulation

Remote ischemic postconditioning (RIPC) is a promising neuroprotective strategy for ischemic stroke. Here, we employed a focal ischemic stroke mouse model to test the hypothesis that poststroke collateral circulation as a potent mechanism of action underlying the therapeutic effects of immediate RIPC. During reperfusion of cerebral ischemia, the mice were randomly assigned to receive RIPC, granulocyte colony-stimulating factor (G-CSF) as a positive control, or no treatment. At 24 hr, we found RIPC and G-CSF increased monocytes/macrophages in the dorsal brain surface and in the spleen, coupled with enhanced leptomeningeal collateral flow compared with nontreatment group. Blood monocytes depletion by 5-fluorouracil (5-FU) significantly limited the neuroprotection of RIPC or G-CSF treatment. The protein expression of proangiogenic factors such as Ang-2 was increased by ischemia, but treatment with either RIPC or G-CSF showed no further upregulation. Thus, immediate RIPC confers neuroprotection, in part, by enhancing leptomeningeal collateral circulation in a mouse model of ischemic stroke.     

Models of focal cerebral ischemia in the nonhuman primate

Ischemic stroke is a uniquely human disease syndrome. Models of focal cerebral ischemia developed in nonhuman primates provide clinically relevant platforms for investigating pathophysiological alterations associated with ischemic brain injury, microvascular responses, treatment responses, and clinically relevant outcomes that may be appropriate for ischemic stroke patients. A considerable number of advantages attend the use of nonhuman primate models in cerebral vascular research. Appropriate development of such models requires neurosurgical expertise to produce single or multiple vascular occlusions. A number of experimentally and clinically accessible outcomes can be measured, including neurological deficits, neuron injury, evidence of non-neuronal cell injury, infarction volume, real-time imaging of injury development, vascular responses, regional cerebral blood flow, microvascular events, the relation between neuron and vascular events, and behavioral outcomes. Nonhuman primate models of focal cerebral ischemia provide excellent opportunities for understanding the vascular and cellular pathophysiology of cerebral ischemic injury, which resembles human ischemic stroke, and the appropriate study of pharmacological interventions in a human relevant setting.     

Therapeutic Strategy for Ischemic Stroke

Possible strategies for treating ischemic stroke include: (1) Neuroprotection: preventing damaged neurons from undergoing apoptosis in the acute phase of cerebral ischemia; (2) Stem cell therapy: the repair of broken neuronal networks with newly born neurons in the chronic phase of cerebral ischemia. Firstly, we studied the neuroprotective effect of a calcium channel blocker, azelnidipine, or a by-product of heme degradation, biliverdin, in the ischemic brain. These results revealed both azelnidipine and biliverdin had a neuroprotective effect in the ischemic brain through their anti-oxidative property. Secondly, we investigated the role of granulocyte colony-stimulating factor (G-CSF) by administering G-CSF to rats after cerebral ischemia and found G-CSF plays a critical role in neuroprotection. Lastly, we developed a restorative stroke therapy with a bio-affinitive scaffold, which is able to provide an appropriate environment for newly born neurons. In the future, we will combine these strategies to develop more effective therapies for treatment of strokes. Special issue article in honor of Dr. Akitane Mori.     

An extended window of opportunity for G-CSF treatment in cerebral ischemia

Background  

Granulocyte-colony stimulating factor (G-CSF) is known as a powerful regulator of white blood cell proliferation and differentiation in mammals. We, and others, have shown that G-CSF is effective in treating cerebral ischemia in rodents, both relating to infarct size as well as functional recovery. G-CSF and its receptor are expressed by neurons, and G-CSF regulates apoptosis and neurogenesis, providing a rational basis for its beneficial short- and long-term actions in ischemia. In addition, G-CSF may contribute to re-endothelialisation and arteriogenesis in the vasculature of the ischemic penumbra. In addition to these trophic effects, G-CSF is a potent neuroprotective factor reliably reducing infarct size in different stroke models.     

经穴注射BMSCs联合中药对大鼠血清VEGF、G-CSF、SDF-1浓度的影响

目的：前期基础实验发现经穴注射骨髓间充质干细胞联合益气活血中药对大鼠缺血后肢骨骼肌血管密度以及后肢血流恢复具有明显促进作用,为进一步明确其机制,本研究着重经穴注射骨髓间充质干细胞（BMSCs）联合益气活血方对大鼠血清中血管内皮细胞生长因子（VGEF）,粒细胞集落刺激因子（G-CSF）,基质细胞衍生因子-1（SDF-1）浓度的影响,从而为临床中医血管外科防治后肢动脉缺血性疾病提供新的思路和方法。方法：25只大鼠随机分为空白对照组（CG）、下肢缺血模型组（IG）、益气活血方缺血组（HG）、经穴注射BMSCs缺血组（BG）,经穴注射BMSCs＋益气活血方缺血组（BHG）,每组5只,在给予相应干预措施后,于7天后取血清,用酶联免疫吸附法（ELISA）测定大鼠血清中VEGF、G-CSF、SDF-1质量浓度。结果：1与CG比较,IG、HG、BG、BHG大鼠血清中VEGF、SDF-1、G-CSF浓度显著升高（P〈0.01）;2与IG比较,HG、BG、BHG组大鼠血清中VEGF,G-CSF浓度显著升高（P〈0.01）,BG、BHG大鼠血清中SDF-1浓度显著升高（P〈0.01）;3与HG比较,BG、BHG大鼠血清中VEGF,SDF-1,G-CSF浓度显著升高（P〈0.01）;4与BG比较,BHG大鼠血清中VEGF,SDF-1,G-CSF浓度显著升高（P〈0.01）,以上差异均有统计学意义。结论：经穴注射BMSCs联合益气活血中药可大幅提升下肢缺血模型大鼠血清中VEGF、G-CSF、SDF-1质量浓度,为临床中医血管外科防治后肢动脉缺血性疾病提供了新的思路和方法。     

颅内血管介入治疗缺血性脑血管病的疗效及预后分析

目的:探讨颅内血管介入治疗对缺血性脑血管病的临床疗效并分析预后效果。方法:选取2012年6月至2016年6月在我院接受治疗的缺血性脑血管病患者85例,根据患者治疗方式的不同分为观察组43例和对照组42例,其中观察组患者给予血管内支架植入治疗,对照组患者则给予常规药物治疗。观察两组治疗前、后血管收缩期峰流速(Vs)、舒张末期流速(Vd)情况,并比较治疗前、治疗6个月、1年后美国国立卫生院卒中量表(NIHSS)评分以及患者预后情况。结果:治疗后观察组病变血管Vs、Vd均显著低于对照组、治疗前(P0.05)。治疗6个月、1年后观察组NIHSS评分均显著低于对照组、治疗前(P0.05)。治疗1年后观察组脑梗塞与短暂性脑缺血发作率以及病死率均显著低于对照组(均P0.05)。结论:颅内血管介入治疗缺血性脑血管病的疗效显著,可有效促进患者神经功能恢复,同时降低脑血管病事件的发生率及病死率。     

ROBO4 与缺血性脑血管病相关的研究进展

Roundabout(Robo)蛋白是神经轴突导向分子家族Slit蛋白的单次跨膜受体,属于一种神经细胞粘附分子。Robo蛋白在神经系统已被确认具有重要轴突导向功能。近年来研究发现,血管新生的内皮细胞表面只特异性地表达Robo4,且Robo4对内皮细胞迁移、病理性血管生成和血管完整性都具有调节作用。缺血性脑血管病是人类致残甚至死亡的主要疾病之一,由于短暂或持续的脑血流减少而造成脑细胞损伤,因此,恢复脑血流、促进血管再生对脑功能恢复至关重要。Robo4对血管方面的作用为我们进一步研究及了解其在血管生成中的机制提供重要依据,也为缺血性脑血管病的治疗提供新的发展方向。     

The Therapeutic Use of High-Pressure Oxygen

The therapeutic use of a high-pressure oxygen atmosphere is of current research interest. Accounts of this means of treatment have come mainly from Amsterdam and Glasgow, but also from the United States. Reports indicate its value in treatment of coronary artery disease, severe shock, cerebral vascular accidents, gangrene, infections, carbon monoxide poisoning and bowel infarction. Hyaline membrane disease responds dramatically. The treatment has demonstrated value in conjunction with the operation of heart-lung machines, for patients with severe injuries of the extremities where blood supply is impaired, and in the treatment of rest pain in ischemic limbs. Converted hospital autoclaves have been used as an inexpensive means of initiating research projects in this field. One American supplier already has orders for construction of eight high-pressure oxygen treatment tanks in U.S. centres.