血管性认知障碍的关键蛋白研究进展

血管性认知障碍是指由各种脑血管疾病引起的认知损害,范围包括从轻度认知损害到血管性痴呆。它通常会影响大脑的高级功能,特别是在执行功能和记忆方面。近年来随着血管性认知障碍发病率的逐步上升,针对血管性认知障碍发病机制的通路研究也在不断深入。本文对血管性认知障碍的关键靶蛋白进行综述,为血管性认知障碍的治疗和用药提供参考。     

丁苯酞治疗血管性认知障碍动物模型涉及信号通路研究进展

血管性认知障碍(VCI)是指由脑血管病变或其相关危险因素所致的一组认知障碍疾病，主要临床特征为认知功能障碍以及注意力、记忆力及执行力等的降低，严重者表现为血管性痴呆。DL-3-正丁基苯酞(NBP)是一种可用于改善血管性认知障碍的药物，能够增加海马神经元存活数量、促进神经突触形成、利于脑血管再生、调控细胞凋亡等，可起到改善神经功能的作用。近年，关于DL-3-正丁基苯酞治疗血管性认知障碍的作用机制的文献越来越多，以下将对目前已被研究发现的一些DL-3-正丁基苯酞发挥治疗作用时涉及的信号通路及其机制进行系统阐述，为进一步对防治血管性认知障碍的研究提供参考和支持。     

尼莫地平、多奈哌齐联合奥拉西坦治疗血管性认知障碍的机制研究

目的 探讨尼莫地平、多奈哌齐联合奥拉西坦治疗血管性认知障碍的机制,为血管性认知障碍的临床治疗提供帮助.方法 选取收治的血管性认知障碍患者84例,随机分为研究组和对照组,每组42例.对照组患者给予奥拉西坦治疗,研究组患者给予尼莫地平、多奈哌齐与奥拉西坦的联合治疗,检测2组血管性认知障碍患者治疗前后血液流变学指标、氧化应激指标以及相关细胞因子变化情况.结果 治疗前2组血管性认知障碍患者血液流变学指标、氧化应激指标以及相关细胞因子水平比较差异无统计学意义(P>0.05).治疗后2组患者MDA、血液流变学指标(BVH、BVM、BVL、FIB和PCV)和相关细胞因子(PRA、Ang Ⅱ、Ald和ET-1)显著降低,氧化应激反应指标(GSH-Px、CAT和SOD)显著升高,差异有统计学意义(P<0.05).研究组患者氧化应激反应指标(GSH-Px、CAT和SOD)显著高于治疗后对照组,MDA、血液流变学指标(BVH、BVM、BVL、FIB和PCV)和相关细胞因子(PRA、Ang Ⅱ、Ald和ET-1)显著低于治疗后对照组,差异有统计学意义(P<0.05).结论 尼莫地平、多奈哌齐与奥拉西坦的联合治疗能够减缓血管性认知障碍患者的氧化应激反应、提高血液流动能力以及改善相关细胞因子水平,对血管性认知障碍患者的临床治疗有重要的意义.     

脑小血管病认知障碍的药物治疗研究进展

脑小血管病（CSVD）是导致血管性认知障碍的主要原因,老年人群发病率高。目前针对CSVD认知障碍的药物治疗尚无明确的标准和特定的药物。本文围绕CSVD认知障碍的降压治疗、抗血小板治疗、溶栓治疗、他汀治疗以及尚处于临床研究阶段的治疗药物和相关临床前研究药物进行了综述。     

甘草中黄酮类化合物的网络药理学研究

目的:分析、预测甘草中黄酮类化合物的潜在药理作用及可能作用机制。方法:采用网络药理学方法,依据中药整合药理学计算平台(TCMSP)等数据库,以化合物的口服药物生物利用度(OB)>30%和类药性(DL)>0.18为标准,筛选甘草中的黄酮类化合物。采用药效团匹配与PharmMapper数据库预测其潜在的作用靶点,随后借助生物学信息注释数据库V 6.8(DAVID V 6.8)分析工具对获得的靶点蛋白进行京都基因与基因组数据库(KEGG)信号通路分析和基因本体(GO)生物过程富集分析(以P<0.05为标准判断相关),并运用Cytoscape 3.5.1软件构建甘草中黄酮类化合物-靶点蛋白-信号通路网络图。结果:共从甘草中筛选出了19个黄酮类化合物(如甘草苷、异甘草苷、甘草素等),涉及细胞视黄酸结合蛋白2、脑啡肽酶等78个靶点蛋白(共188次),以及胰岛素信号通路、磷脂酰肌醇3激酶-丝氨酸/苏氨酸激酶(PI3K-Akt)等40条信号通路(其中与癌症相关的通路8条、与内分泌系统相关的通路7条、与信号转导相关的通路6条、与传染病相关的通路5条、与代谢相关的通路3条等);所建黄酮类化合物-靶点蛋白-信号通路网络图显示,甘草中黄酮类化合物可通过多个靶点作用于不同的疾病代谢通路。结论:甘草中黄酮类化合物对癌症、内分泌系统、传染病、代谢系统等方面疾病可能具有治疗作用,且可能有潜在的抗帕金森症作用。     

淫羊藿总黄酮通过抑制MAPK/NF-κB信号通路减轻自然衰老大鼠脑组织炎症反应

目的探讨淫羊藿总黄酮(total flavonoids of Epimedium,TFE)对自然衰老大鼠脑组织中MAPK/NF-κB信号通路影响及其抗炎作用。方法 HE染色观察各组大鼠海马CA1、CA3和DG区神经元形态的变化。Western blot法检测各组大鼠海马组织中衰老相关蛋白p21、凋亡相关蛋白Bax和Bcl-2的表达,核转录因子NF-κB p65及其下游炎症因子TNF-α、IL-1β和COX-2的表达,以及MAPK信号通路相关蛋白的表达。结果 TFE可明显改善自然衰老组大鼠海马神经细胞形态结构,神经细胞排列整齐紧密。同时,TFE可明显下调自然衰老组大鼠海马组织中p21、Bax蛋白表达水平,上调Bcl-2蛋白表达水平及Bcl-2/Bax的比值,且可明显降低NF-κB p65核蛋白及其下游炎症因子TNF-α、IL-1β和COX-2的表达,以及MAPK信号通路相关蛋白(p-ERK1/2、p-JNK、p-p38 MAPK)的表达。结论 TFE对自然衰老大鼠炎症反应具有保护作用,其作用机制可能是通过抑制MAPK信号通路的激活,从而抑制NF-κB的核易位及其下游炎症细胞因子表达,进而延缓脑衰老。     

黄芪-川芎药对治疗脑卒中的网络药理学研究

目的 探讨黄芪-川芎药对治疗脑卒中的药理机制。方法 通过多个数据库并结合文献调研检索黄芪、川芎的有效化学成分和相关靶点;采用Cytoscape软件绘制成分靶点可视化网络,并进行拓扑分析;以CTD在线分析平台挖掘脑卒中的相关靶点,借助STRING数据库构建化合物靶点蛋白互作网络、脑卒中靶点蛋白互作网络,应用Cytoscape软件进行网络合并获取核心网络,并对核心靶点基因进行KEGG通路富集分析。结果 共筛选出黄芪、川芎中49个有效化合物,靶点蛋白272个,核心靶点蛋白39个,KEGG富集通路10条。作用通路涉及肿瘤坏死因子（TNF）信号通路、白介素17（IL-17）信号通路、松弛素信号通路、核因子（NF）-κB信号通路、低氧诱导因子-1（HIF-1）信号通路、C型凝集素受体信号通路、Toll样信号通路、核苷酸结合寡聚化结构域（NOD）样信号通路、血管内皮生长因子（VEGF）信号通路、p53信号通路。结论 黄芪-川芎药对中槲皮素、山柰酚等化合物可能通过肿瘤坏死因子（TNF）信号通路、白介素17（IL-17）信号通路等多条通路发挥治疗脑卒中的作用。     

Wnt/β-catenin信号通路在多发性骨髓瘤中的机制研究进展

多发性骨髓瘤（MM）是一种以骨髓浆细胞恶性增殖为特征的血液肿瘤,其发生机制与相关的信号通路异常有着密切关系。Wnt/β-catenin信号通路可参与调节细胞的增殖、分化和凋亡等生物学过程,且与细胞癌变相关。在MM中,异常表达的非编码RNAs、转录因子、蛋白酶和分泌蛋白等可激活Wnt/β-catenin信号通路,进而加速MM的发生和发展。因此,Wnt/β-catenin信号通路在MM的发病机制中具有重要地位。整理总结MM中相关非编码RNAs、转录因子、蛋白酶和分泌蛋白等影响Wnt/β-catenin信号通路的研究进展,以期为相关研究提供参考。     

Epac/Rap1信号通路在急性肺损伤中作用的研究进展

急性肺损伤(ALI)中炎症信号通路的失调控以及炎症因子平衡紊乱是其发生和发展的重要原因。能直接被cAMP活化的交换蛋白(Epac)在调节肺部气道炎症和细胞增殖方面是一个新的效应器,新的关于cAMP依赖性蛋白激酶A(PKA)非依赖性通路研究表明,cAMP/Epac/Rap1信号通路参与并行使许多类型细胞的功能,包括细胞分泌、细胞间黏附和连接、细胞凋亡、细胞增殖和分化等。cAMP能通过Epac/Rap1信号通路参与ALI的发病过程,Epac/Rap1信号通路是ALI防治的潜在靶点。本文综述Epac/Rap1信号通路在肺部相关炎症及急性肺损伤中作用机制的国内外研究进展。     

通过靶向自噬治疗动脉粥样硬化的天然产物研究进展

动脉粥样硬化（AS）是心血管疾病中常见的慢性炎症性疾病,是心肌梗死、心力衰竭和卒中等多种致命疾病的病理基础。自噬是一种保护性的细胞内过程,通过控制蛋白质质量起到保持细胞稳态作用。越来越多研究表明,自噬参与了AS及相关疾病的发生发展。天然产物,如槲皮素、山奈酚、姜黄素、丹参酚酸B和小檗碱等,具有靶向自噬治疗AS的潜力。本综述总结了天然产物靶向自噬治疗AS的分子机制,包括诱导内皮细胞自噬抑制炎症和氧化应激反应、促进巨噬细胞自噬抑制脂质积累以及诱导血管平滑肌细胞自噬,减少凋亡等,涉及信号通路主要包括磷脂酰肌醇-3激酶/蛋白激酶B/哺乳动物雷帕霉素靶蛋白信号通路、NF-κB信号通路、P38丝裂原活化蛋白激酶信号通路、c-Jun氨基端激酶信号通路和腺苷酸蛋白活化激酶/哺乳动物雷帕霉素靶蛋白/unc-51样自噬激活激酶1信号通路等,以期为AS治疗提供新的研究思路。     

Mechanisms Underlying the Effect of Acupuncture on Cognitive Improvement: A Systematic Review of Animal Studies

Acupuncture has been reported to be beneficial in treating cognitive impairment in various pathological conditions. This review describes the effort to understand the signaling pathways that underlie the acupunctural therapeutic effect on cognitive function. We searched the literature in 12 electronic databases from their inception to November 2013, with full text available and language limited to English. Twenty-three studies were identified under the selection criteria. All recruited animal studies demonstrate a significant positive effect of acupuncture on cognitive impairment. Findings suggest acupuncture may improve cognitive function through modulation of signaling pathways involved in neuronal survival and function, specifically, through promoting cholinergic neural transmission, facilitating dopaminergic synaptic transmission, enhancing neurotrophin signaling, suppressing oxidative stress, attenuating apoptosis, regulating glycometabolic enzymes and reducing microglial activation. However, the quality of reviewed studies has room for improvement. Further high-quality animal studies with randomization, blinding and estimation of sample size are needed to strengthen the recognition of group differences.     

Oxidative stress impairs learning and memory in apoE knockout mice

Cardiovascular risk factors, such as oxidative stress and elevated lipids, are linked to the development of cognitive impairment. A mediator common to both stressors is the apolipoprotein E (apoE). The objectives of this study are to determine the effects of apoE deficiency and diet-induced systemic oxidative stress in mice on vascular expression of inflammatory proteins and on cognitive function. Mice are placed on a diet enriched in homocysteine for fifteen weeks and then assessed for spatial learning using an eight-arm radial maze and for inflammatory protein expression by immunohistochemistry. Our results show that diet-induced oxidative stress does not affect cognitive function in normal mice. In contrast, apoE−/− mice on the homocysteine diet show significantly impaired (p < 0. 001) maze performance. ApoE−/− mice also have high cholesterol levels. There is no expression of inflammatory proteins IL-6 and IL-8 in the vasculature of control mice on normal or homocysteine diet and little in apoE−/− mice on normal diet. In contrast, apoE−/− mice on homocysteine diet show pronounced vascular reactivity to IL-6 and IL-8 antibodies. These data show that systemic oxidative stress correlates with expression of inflammatory proteins in the cerebral vasculature and impaired cognitive function. These results are consistent with the hypothesis that an oxidative-inflammatory cycle in the cerebral vasculature could have deleterious consequences for cognition.     

Vascular cognitive impairment and Alzheimer’s disease: role of cerebral hypoperfusion and oxidative stress

Cerebrovascular disease may lead to a wide range of cognitive changes, referred to collectively as vascular cognitive impairment. Stroke increases the risk of cognitive impairment and dementia, and may contribute to the progression of Alzheimer's disease (AD). Apart from clinical stroke itself, vascular risk factors are associated with the development of cognitive impairment and dementia. Animal models involving a temporary or permanent interruption of blood flow in the common carotid arteries develop nonprogressive cognitive impairment. Oxidative stress during cerebral hypoperfusion in animal models plays a key role in neuronal death and may thus contribute to the development of cognitive impairment in cerebrovascular disease. Genetic and pharmacological interventions to inhibit the major source of reactive oxygen species, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, are neuroprotective in experimental cerebral ischemia. Recent studies have demonstrated that inhibition of NADPH oxidase activity can mitigate cognitive impairment in rodent models of cerebral hypoperfusion. In this article, we review the evidence linking cognitive impairment and/or AD with NADPH oxidase-dependent oxidative stress, including the renin-angiotensin system.     

非痴呆性血管性认知功能障碍的中、西医研究现况

非痴呆性血管性认知功能障碍是血管性认知功能障碍的早期阶段,具有可逆性,故对该病的防治倍受关注。本文就目前中、西医对非痴呆性血管性认知功能障碍的认识及其治疗方法作一概述,以期为该病的临床治疗和科研活动提供一些新思路。     

卒中后认知功能损害的演变及治疗进展

脑卒中是我国中老人群最主要的死亡原因之一.卒中可导致神经功能缺损、行为、情感障碍外,认知功能损害很常见.认知功能损害是卒中复发的重要危险因子,使血管性痴呆发生的风险增高并影响病人的康复.研究卒中后认知功能损害的特征,以及病程中的演变轨迹及其相关影响因素,给予针对性干预及治疗,以减少及延缓认知损害的发生.该文对卒中后认知功能损害的演变及治疗进展进行综述.     

Oxidative stress,redox signalling and endothelial dysfunction in ageing-related neurodegenerative diseases: a role of NADPH oxidase 2

Chronic oxidative stress and oxidative damage of the cerebral microvasculature and brain cells has become one of the most convincing theories in neurodegenerative pathology. Controlled oxidative metabolism and redox signalling in the central nervous system are crucial for maintaining brain function; however, excessive production of reactive oxygen species and enhanced redox signalling damage neurons. While several enzymes and metabolic processes can generate intracellular reactive oxygen species in the brain, recently an O₂⁻-generating enzyme, NADPH oxidase 2 (Nox2), has emerged as a major source of oxidative stress in ageing-related vascular endothelial dysfunction and neurodegenerative diseases. The currently available inhibitors of Nox2 are not specific, and general antioxidant therapy is not effective in the clinic; therefore, insights into the mechanism of Nox2 activation and its signalling pathways are needed for the discovery of novel drug targets to prevent or treat these neurodegenerative diseases. This review summarizes the recent developments in understanding the mechanisms of Nox2 activation and redox-sensitive signalling pathways and biomarkers involved in the pathophysiology of the most common neurodegenerative diseases, such as ageing-related mild cognitive impairment, Alzheimer’s disease and Parkinson’s disease.     

2型糖尿病患者血管性认知功能障碍发生机制的研究进展

血管性认知功能障碍（vascular cognitive impairment, VCI）是由脑血管病及血管性危险因素引起的一组以认知功能受损为特点的临床综合征。2型糖尿病是认知功能障碍的危险因素,而认知功能受损又会影响到2型糖尿病患者对血糖水平的自我管理能力,导致其脑血管并发症及低血糖事件发生率增加,从而进一步加重认知功能障碍。本文概要介绍2型糖尿病相关VCI的发生机制,以期为2型糖尿病患者VCI的预防与治疗提供新思路。     

Effect of alpha lipoic acid on intracerebroventricular streptozotocin model of cognitive impairment in rats.

In the present study, the effect of alpha lipoic acid, a potent free radical scavenger, was investigated against the intracerebroventricular streptozotocin model of cognitive impairment in rats, which is characterized by a progressive deterioration of memory, cerebral glucose and energy metabolism, and oxidative stress. Wistar rats were injected with intracerebroventricular streptozotocin bilaterally. The rats were treated chronically with alpha lipoic acid (50, 100 and 200 mg/kg) orally for 21 days starting from day 1 of streptozotocin injection in separate groups. The learning and memory behavior was evaluated and the rats were sacrificed for estimation of oxidative stress. The intracerebroventricular streptozotocin rats treated with alpha lipoic acid (200 mg/kg, p.o.) showed significantly less cognitive impairment as compared to the vehicle treated rats. There was also an insignificant increase in oxidative stress in the alpha lipoic acid treated groups. The study demonstrated the effectiveness of alpha lipoic acid in preventing cognitive impairment and oxidative stress induced by intracerebroventricular streptozotocin and its potential in dementia associated with age and age related neurodegenerative disorders where oxidative stress is involved such as Alzheimer's disease.     

左侧丘脑结节动脉梗死患者的认知功能障碍：1例病例报告及文献复习

血管性认知功能障碍目前正逐步成为脑卒中后临床关注的重点。多种机制介导的血管性认知功能障碍是一类异质性疾病,而作为与血管性事件直接相关的重要部位的梗死在其中起着重要作用。左侧丘脑结节动脉梗死所造成的急性认知功能障碍因病变部位较局限,易为临床医生忽略。本文报告1例左侧丘脑结节动脉梗死患者的诊治情况,并就此种重要部位梗死患者的认知功能障碍作一简要介绍。