NOX介导的MAPK、PI3K/Akt信号通路与肝纤维化的研究进展

肝星状细胞(hepatic stellate cells,HSC)是肝纤维化的主要细胞,是细胞外基质(extracellular matrix,ECM)的重要来源.烟酰胺腺嘌呤二核苷酸磷酸氧化酶(NADPH oxidase,NOX)产生活性氧(reactive oxygen species,ROS),调控HSCs内信号转导,在肝纤维化发病中起关键作用.NOX产生的ROS可介导丝裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK)和磷脂酰肌醇-3激酶/蛋白激酶(phosphatidylin-ositol-3 kinase/Akt,PI3K/Akt)信号通路激活,促进HSC增殖、抑制其凋亡,导致肝纤维化形成.抑制NOX产生ROS,阻断相应的信号通路可诱导HSC凋亡.因此,探索出以NOX为作用靶点的抗纤维化药物意义重大.     

NOX通过ROS介导的信号通路与肝纤维化

还原型烟酰胺腺嘌呤二核苷酸磷酸氧化酶(NOX)是一种多蛋白质亚基组成的复合物,它存在于吞噬型细胞及非吞噬型细胞中,现在已经证实与肝纤维化的形成密切相关.NOX通过产生活性氧簇(ROS)介导了多种细胞内的信号转导,如通过激活细胞外信号调节激酶(ERK)以及活化蛋白-1(AP-1)和核因子(NF)-κB等转录因子,参与了肝...     

NADPH氧化酶源性活性氧在糖尿病及其血管并发症发生中的作用机制

2型糖尿病的发病机制为胰岛素抵抗和胰岛素分泌受损.最新的研究结果显示,氧化应激在糖尿病及其并发症的发病机制中起重要作用.在高游离脂肪酸(FFA)条件下,由于活性氧(ROS)产生过多引起的氧化应激可造成胰岛素抵抗和胰岛B细胞功能丧失,导致糖尿病的发生,而血糖升高进一步加重氧化应激,引发大血管和微血管病变,产生糖尿病并发症.通过研究氧化应激在糖尿病及其并发症发病中的作用机制,为防治糖尿病及其并发症提供新的理论依据.机体内多种酶体参与了ROS的生成,如NADPH氧化酶(NOX)、黄嘌呤氧化酶、线粒体呼吸链酶复合体、内皮型一氧化氮合酶(eNOS)及脂氧合酶(LOX)等.本研究旨在探讨NOX源性ROS在糖尿病及其血管并发症发生中的作用机制.     

NADPH氧化酶产生的活性氧簇对肝星状细胞内信号转导的调控

活性氧簇(ROS)长期被认为是一类损伤DNA、蛋白等生物分子,引起脂质过氧化反应的细胞有害分子.现在认为NADPH氧化酶(Nox)/Dual氧化酶(Duox)家族是以精确调节的方式产生ROS,能作为第二信使影响包括肝星状细胞(HSCs)在内的各种细胞的信号转导.本文讨论NOX/Duox产生的ROS调控信号转导的机制,并对近年来关于ROS介导的促肝纤维化因子(如转化生长因子(TGF-β)、血小板衍生生长因子(PDGF)、血管紧张素Ⅱ(Ang Ⅱ)和瘦素(1eptin)等)在HSCs内信号转导的研究作一综述.     

血管性认知损害的危险因素

血管性认知损害(vascular cognitive impairment,VCI)是指由各种血管性因素引起的不同程度的认知功能损害综合征,其发病率日益增高,但其危险因素尚不明确.注重VCI的早期预防可有效减少血管性痴呆的发生.文章对VCI的危险因素进行了综述.     

血管性认知功能障碍防治

血管性认知功能障碍(vascular cognitive impairment,VCI) 是指由脑血管病危险因素( 如高血压病、糖尿病和高 脂血症等)、显性( 如脑梗死和脑出血等) 或非显性的脑血管病( 如白质疏松和慢性脑缺血) 引起的从轻度认知损害 到痴呆的一大类综合征。VCI 极大提前了血管性痴呆的诊断,有利于在最有利的时机进行防治,具有重要的临床和 社会意义。VCI 患者的治疗包括脑血管危险因素、脑血管病、认知障碍以及合并症或并发症等多方面的治疗,对患者 要进行综合干预。     

熊果酸对肝星状细胞烟酰胺腺嘌呤二核苷酸磷酸氧化酶的影响

近年来研究表明,肝星状细胞(hepatic stellate cell,HSC)表达的烟酰胺腺嘌呤二核苷酸磷酸氧化酶(NADPH oxidase,NOX)在肝纤维化发病中起关键作用[1].NOX产生的活性氧(reactive oxygen species,ROS)介导了各种促肝纤维化因子在HSC内的信号转导,有望成为抗肝纤维化的新靶点[2].熊果酸(ursolic acid)是从中药植物(如丹参、女贞子等)中提取的单体成分,具有保护肝细胞的作用[3],但其抗肝纤维化作用研究甚少.申月明等[4]在体外研究发现熊果酸能抑制HSC增殖,诱导其凋亡;体内实验证实熊果酸有显著的抗肝纤维化作用[5],但熊果酸抗肝纤维化的作用靶点及机制尚不清楚.Steinkamp-fenske等[6] 报道熊果酸能下调人内皮细胞NOX4的表达并抑制ROS的产生.本实验旨在观察熊果酸对HSC中NOX的影响,以探索熊果酸抗肝纤维化的作用靶点及机制.     

血管性认知障碍的诊断

血管性认知障碍(vascular cognitive inpairment,VCI)是由脑血管危险因素(如高血压、糖尿病和高脂血症等)、明显(如脑梗死和脑出血等)或不明显的脑血管病(如白质疏松症和慢性脑缺血)引起的从轻度认知障碍到痴呆的一大类综合征.准确的早期诊断町提供最佳的治疗机会,并延缓病情的发展.近年来,对VCI的研究取得了很大进展.文章对VCI从病因、临床表现、神经心理学、影像学、神经电生理、生物学标志物和诊断标准等方面做了综述.     

载脂蛋白E基因多态性与血管性认知功能障碍的相关性

目的 探讨载脂蛋白E基因(ApoEε4)多态性与血管性认知功能障碍(VCI)患者认知功能及脂代谢相关性.方法 采用基因测序法测定VCI患者的载脂蛋白E基因型,检测VCI患者血清血脂指标及评价简易MMSE、画钟测验等积分.结果 VCI患者中携带ε4等位基因频率占30.7%.ApoEε4等位基因携带者总胆固醇(TC)、低密度脂蛋白胆固醇(LDL-C)高于非携带者,MMSE积分明显低于非携带者.结论 ApoEε4等位基因可能是VCI发生遗传危险因素之一,与VCI患者的脂代谢和认知功能相关.     

脑血管病与血管性认知障碍的相关性研究

目的探讨脑血管病及其危险因素与血管性认知障碍(VCI)的相关性。方法选择急性脑血管病患者231例,脑血管病急性期后,根据神经认知行为量表评分分为VCI组(82例)和对照组(149例),对2组的性别、年龄、脑血管病危险因素、脑血管病所致损伤(包括急性病变、陈旧病变及腔隙灶)的部位、大小及损伤结构的总数进行比较。结果VCI组平均年龄明显高于对照组(P<0.01);腔隙性脑血管病、大面积病变及双侧大脑半球的病变与VCI的发病有关;性别、高血压、糖尿病、心律失常、高脂血症、脑萎缩不是VCI直接的危险因素。除基底节损伤外,脑血管病其他损伤均与VCI发病无关。结论VCI是一种与隐匿性脑血管病高度相关的老年性疾病,大面积病变及双侧大脑半球的病变会加重认知功能的损害。     

Diagnosis and management of vascular cognitive impairment

Accurate diagnosis of vascular cognitive impairment (VCI) is important but may be difficult. VCI diagnoses depend on determinations of the presence of both cognitive impairment and cerebrovascular disease (CVD), temporal causal links between cognitive impairment and CVD, and the presence or absence of other potential contributors to cognitive impairment, such as Alzheimer’s disease (AD). Diagnostic criteria differ across currently utilized systems, resulting in widely differing VCI prevalence rates. Also, current systems may not be able to differentiate “pure” VCI from “mixed” AD and CVD. National Institute of Neurological Disorders and Stroke harmonization criteria for VCI have been developed for study and validation to help bridge gaps in our understanding of VCI diagnosis. VCI management begins with atherogenic risk factor control. Current VCI treatment options demonstrate statistical improvement but not consistent global clinical efficacy. Future clinical trials should concentrate on both primary risk factor control and development of new therapeutic agents to treat patients already diagnosed with VCI.     

血管性认知障碍研究进展

血管性认知障碍是由脑血管危险因素、临床或无症状脑血管病引起的从轻度认知障碍到痴呆的一大类综合征.其发病率日益增高,但发病机制尚不明确,也缺乏有效的治疗手段,因此各方面的研究日益受到重视.文章主要从概念、分型、诊断和防治等方面对血管性认知障碍的研究进展做了综述.     

血管性认知障碍的相关指标

血管性认知障碍是由脑血管危险因素(如高血压、糖尿病和高脂血症等)、明显(如脑梗死和脑出血等)或不明显的脑血管病(如脑白质疏松和慢性脑缺血)引起的从轻度认知障碍到痴呆的一大类综合征。其发病率日益增高,但发病机制尚不明确,也缺乏有效的治疗手段,因此各方面的研究日益受到重视。文章主要从神经心理学、影像学、电生理学、生物学和基因方面对VCI的研究近况进行综述。     

NADPH oxidases and cardiac remodelling

A heart under chronic stress undergoes cardiac remodelling, a process that comprises structural and functional changes including cardiomyocyte hypertrophy, interstitial fibrosis, contractile dysfunction, cell death and ventricular dilatation. Reactive oxygen species (ROS)-dependent modulation of intracellular signalling is implicated in the development of cardiac remodelling. Among the different ROS sources that are present in the heart, NADPH oxidases (NOXs) are particularly important in redox signalling. NOX isoforms are expressed in multiple cell types including cardiomyocytes, fibroblasts, endothelial cells and inflammatory cells—with the two main isoforms expressed in the heart being NOX2 and NOX4. Recent studies indicate that NOX-dependent signalling is involved in the development of cardiomyocyte hypertrophy, interstitial fibrosis and post-MI remodelling. NOXs may also be involved in the genesis of contractile dysfunction and myocyte apoptosis. Here, we review the main effects of NOXs in the pathogenesis of cardiac remodelling and the redox-sensitive signalling pathways that underlie these effects. The elucidation of mechanisms involved in NOX-dependent regulation of cardiac remodelling may lead to new therapeutic targets for heart failure.     

胆碱能通路损伤在血管性认知功能障碍中的现状分析

血管性认知障碍(VCI)的早期发现与防治对减少痴呆的发生具有重要意义。VCI患者常伴有胆碱能通路的白质病变,可通过胆碱能通路高信号量表评分和弥散张量成像直接评估其严重程度,具有耗时短、简便易行和相对客观等特点。本文梳理总结了胆碱能通路的白质病变与VCI患者认知功能之间的关系,发现VCI的大脑风险期、轻度认知障碍期和痴呆期三个不同阶段均存在胆碱能通路的白质病变,且其病变严重程度与认知功能呈负相关,可为VCI早期筛查和诊断提供影像学依据。     

同型半胱氨酸在脑梗死后血管性认知功能障碍老年患者血清中的变化及其意义

目的探讨同型半胱氨酸（homocysteine,Hcy）在脑梗死后血管性认知功能障碍老年患者中的变化及其临床意义。方法依据认知功能评定结果及相应的诊断标准将113例脑梗死老年患者分为两组：57例血管性认知障碍（VCI）患者（实验组）和56例认知功能正常患者（对照组）。取患者外周血,分离血清,检测血清Hcy水平,对所得数据进行组间比较。结果实验组血浆Hcy水平明显高于对照组,差异具有统计学意义（P〈0．05）。非条件Logistic回归分析表明,Hcy是脑梗死后血管性认知障碍的独立危险因素。结论血清Hcy可能是脑梗死后血管性认知功能障碍的病理机制之一。     

The current situation on vascular cognitive impairment after ischemic stroke in Changsha

The objectives of the study were to explore the prevalence and effects of vascular cognitive impairment (VCI) among ischemic stroke patients and to provide a basis for prevention and treatment strategies. A stratified cluster random sampling method was performed, and 689 ischemic stroke patients (over 40 years of age) were enrolled. All of the patients had received a neuropsychological assessment battery to assess cognitive function and self-designed questionnaires to collect relevant information. According to the cognitive status, the patients were divided into two groups, a case group and a control group. The caregivers of the patients were given a questionnaire concerning the awareness of and attitudes toward VCI. In this study, we determined that the prevalence of VCI was 41.8%. Aging, paraventricular white matter lesion (WML), macroangiopathy, high levels of alcohol, a lack of hobbies, and excessive sleep were risk factors for vascular cognitive impairment no dementia (VCIND). A high level of education, manual-work, low level of alcohol use, regular health checks, a vegetable-based diet, and more fruit and milk were protective factors for VCIND. Living alone, hyperlipidemia, transient ischemic attack, a family history of stroke, and brain atrophy were risk factors of vascular dementia (VD). A high educational level, a vegetable-based diet, and tea were protective factors for VD. The general public awareness of VCI was found to be insufficient, and there was a prejudice toward and lack of funding for the care of VCI patients. The prevalence of VCI is high in ischemic stroke patients, and there are different impact factors at different stages. Despite the high prevalence of VCI, the general public awareness is limited. Appropriate prevention measures should be developed to reduce the prevalence of VCI.     

脑小血管病与血管性认知损害:关注神经影像学

脑小血管病(cerebral small vessel disease,CSVD)是老年人群功能丧失、残疾和认知损害的重要原因,皮质下CSVD可导致腔隙性梗死和进展性脑白质损害.CSVD性认知功能障碍是血管性认知损害(vascular cognitive impairment,VCI)的重要亚型,其所致的痴呆约占血管性痴呆的36%~67%.随着技术的发展,神经影像学及其相关标志物已成为诊断CSVD及认知损害的有力手段,在脑认知学相关领域内也可探寻到CSVD发病机制的线索.神经影像学血管性改变报道标准(STandards for ReportIng Vascular changes on nEuroimaging,STRIVE)确立了代表CSVD的6种关键性损伤的神经影像学标志物,包括近期皮质下小梗死、假定血管源性的腔隙灶、假定血管源性的白质高信号、血管周围间隙、脑微出血和脑萎缩.文章对CSVD所致VCI与影像学特征的相关性进行综述.