线粒体融合与分裂:治疗缺血性心脏疾病的潜在靶点

线粒体是一种高度动态变化的细胞器,在细胞中不断融合与分裂,形成紧密连接的线粒体网络。这种融合与分裂的变化主要通过线粒体融合、分裂蛋白控制,并且越来越多的调控机制在逐渐被阐明。在线粒体融合、分裂蛋白的精确控制下,线粒体可在不断变化的生理环境中做出迅速准确的反应,这不仅对于线粒体的遗传以及维持其功能至关重要,还影响着细胞的生存状态。该变化过程与诸多生物学过程有着密切关系,如能量代谢、胚胎发育、自噬和凋亡等。近些年的研究发现,线粒体融合与分裂参与了缺血/再灌注损伤、心肌肥厚、心衰等过程。本文对线粒体融合与分裂的生物学过程进行阐述的同时,主要综述该过程与缺血性心脏疾病的研究进展及其潜在的治疗靶点。     

线粒体动力学失衡和环境神经毒物对阿尔茨海默病病理进程影响的研究进展

线粒体动力学指细胞中的线粒体不断进行分裂融合的一种动态变化,是维持胞内物质与能量运输的重要保障,发动蛋白相关GTP酶1、Fis1、线粒体分裂因子、线粒体融合蛋白1/2和视神经萎缩蛋白1等蛋白为这一过程的直接参与者,它们受到磷酸化、S-亚硝基化、泛素化、小泛素化和蛋白酶解等信号的精密调控。神经细胞的突触形态与功能维持极度依赖线粒体正常分布与功能,而体内外神经毒性物质可能通过干扰线粒体动力学平衡引发神经元能量代谢障碍,活性氧释放增多,并可加速细胞凋亡。越来越多研究表明,线粒体动力学失衡是阿尔兹海默综合征早期病理进程中的关键事件之一。     

Bcl-2家族对线粒体质量控制的调控研究北大核心CSCD

线粒体质量控制是维持细胞生存及生存状态的重要机制,通过对线粒体形态、数量与质量的多维调控,维持细胞内稳态。研究发现Bcl-2家族与线粒体多种功能的调控密切相关,并参与调控线粒体自噬/细胞凋亡互调节及线粒体分裂、融合的动态变化,是线粒体质量控制的关键调控因子。该文主要综述Bcl-2家族对线粒体质量控制的影响及其主要调控机制。     

Bcl-2家族对线粒体质量控制的调控研究

线粒体质量控制是维持细胞生存及生存状态的重要机制,通过对线粒体形态、数量与质量的多维调控,维持细胞内稳态。研究发现Bcl-2家族与线粒体多种功能的调控密切相关,并参与调控线粒体自噬/细胞凋亡互调节及线粒体分裂、融合的动态变化,是线粒体质量控制的关键调控因子。该文主要综述Bcl-2家族对线粒体质量控制的影响及其主要调控机制。     

七氟醚后处理对糖尿病模型大鼠心肌缺血再灌注时作用的研究进展

<正>在缺血再灌注的情况下,恢复组织血流灌注的同时,组织功能未能恢复正常,并且引发相关功能障碍和结构损伤,称之为再灌注损伤。心肌组织氧需求大而冠状动脉的侧支循环少,成为易发生再灌注损伤的组织。前期研究提示,再灌注损伤的同时出现了线粒体结构和形态动力学改变[1],线粒体的正常结构依赖于不断地融合、裂解过程。线粒体融合过程与裂解过程之间的相对平衡,被称为线粒体动力学。线粒体融合蛋白1(Mfnl)位于线粒体外膜,在外膜的融合过程中必     

去氢骆驼蓬碱诱发PC12细胞凋亡时对线粒体融合分裂的影响

目的 探讨去氢骆驼蓬碱(HM)对PC12细胞线粒体功能损伤和线粒体融合分裂相关蛋白表达水平的影响。方法 PC12细胞分为细胞对照组、HM组、线粒体分裂抑制剂Mdivi-1组、HM+Mdivi-1组、线粒体裂变激动剂WY14643组、HM+WY14643组,药物浓度均为1、10、25、50、100μmol·L^-1,处理24 h,噻唑蓝(MTT)法检测细胞存活率,显微镜观察细胞形态;MitoTracker Red探针染色观察线粒体形态和纵横轴长度比值,JC-1染色检测线粒体膜电位,试剂盒检测ROS、ATP水平和乳酸脱氢酶(LDH)活性,免疫荧光染色法和Western blotting检测胱天蛋白酶3(caspase-3)、促凋亡蛋白(Bax)、细胞色素C(cyt-c)和线粒体融合蛋白(Mfn2)、线粒体分裂蛋白(Drp-1)的表达水平;电穿孔法转染Drp1的干扰序列,筛选转染效果好的siRNA序列,协同药物干预,通过荧光法、MTT法、免疫印迹法检测相关指标。结果 MTT结果显示,与细胞对照组比较,HM组、Mdivi-1组、HM+Mdivi-1组、WY14643组和HM...     

线粒体在脓毒症肝损伤发病机制及治疗中的作用

线粒体功能障碍所致的细胞能量衰竭与脓毒症期间器官功能损害密切相关。肝脏细胞中存在丰富的线粒体,肝脏是脓毒症相关器官损伤的重要靶点。本文概述了线粒体在脓毒症肝损伤发病机制中的作用,以及线粒体修复过程的动态平衡对于维持线粒体稳态和减轻肝脏损伤的重要意义,以期为脓毒症治疗提供参考。     

线粒体糖尿病分子机制与临床研究进展

线粒体是细胞内的重要细胞器，是储存和供能场所，通过氧化磷酸化(OXPHOS)合成ATP供给细胞各种生命活动的需要。由于氧化磷酸化在胰岛β细胞胰岛素分泌过程中的重要作用，使线粒体糖尿病(MIDD)成为糖尿病(DM)的又一个重要的突变类型基因。     

线粒体基因缺陷与糖尿病关系研究的进展

线粒体是细胞内的重要细胞器,普遍存在于真核细胞中。它具有独特的超微结构,通过氧化磷酸化合成ATP供给细胞各种生命活动的需要。1981年Anderson[1]等发表了人类线粒体DNA(mtDNA)的全序列。1988年,Holt和Wal-lace分别在线粒体脑病和Leber’s遗传性视神经病(LHON)患者的细胞中发现了mtDNA突变,从而开辟了研究mTDNA突变与人类疾病的新领域。目前已发现mtDNA的50多种点突变和100多种基因重排与人类疾病相关[2]。将mtDNA分子遗传学研究与临床研究相结合,使人类对线粒体疾病的认识日益深入。近年来,线粒体基因突变与糖尿病(DM)发生发展的关系已受到广泛重视。由于氧化磷酸化在胰岛β细胞分泌胰岛素过程中的重要作用,使其成为DM的又一重要的候选基因。     

FoxO3a对线粒体功能的调控作用及机制

叉头框蛋白O3a(fork head box O3a, FoxO3a)是叉头框蛋白FOX转录因子O亚型家族中成员,作为一种转录调节因子在多种疾病的发生与发展中发挥重要调节作用。线粒体是细胞能量代谢的主要场所,也是维持细胞生长和功能的一类关键细胞器。线粒体功能受到多种转录因子调控。FoxO3a可定位于线粒体,通过调节细胞核与线粒体之间的相互作用,对线粒体功能产生重要影响,其机制与调节线粒体能量代谢、生物合成、自噬、分裂/融合,以及线粒体钙稳态密切相关。该文重点综述了FoxO3a的生物学功能、及其对线粒体的调控作用与机制。     

Mitochondrial dysfunction in diabetes mellitus

This review discusses the hypothesis that mitochondrial dysfunction plays a role in the pathogenesis of the most common form of diabetes, type II diabetes mellitus. Mitochondrial mutations have been linked to the development of diabetes mellitus as part of several rare syndromes, accounting for approximately 1.5% of all cases of the disease (“classic” mitochondrial diabetes). The characteristics of classic mitochondrial diabetes are intermediate between those of type I and type II diabetes, more closely resembling the latter. By studying the biochemical, cellular, and physiologic consequences of mitochondrial DNA mutations that cause classic mitochondrial diabetes, we may also gain important insights into the pathogenesis of type II diabetes mellitus. Individuals with classic mitochondrial diabetes exhibit a variety of defects in mitochondrial electron transfer enzyme activities. Complex I and Complex IV activities in skeletal muscle are almost universally decreased in mitochondrial diabetics compared with control individuals. The major physiologic abnormality in classic mitochondrial diabetes is delayed and insufficient insulin secretion in response to a glucose load. Insulin resistance is less commonly observed in these patients. The link between mitochondrial function and insulin secretion is supported by cellular studies in which introduction of inhibitors of oxidative phosphorylation or depletion of mitochondrial DNA markedly impairs glucose mediated insulin secretion from pancreatic β‐cells. Evidence for mitochondrial dysfunction in the common form of type II diabetes includes excessive free radical levels in the plasma of diabetics, increased reactive oxygen species, and decreased ATP synthase activity in cybrids constructed from mitochondria of diabetic patients, and maternal inheritance of the disease. By using the occurrence of diabetes in rare mitochondrial syndromes as an example, evidence supporting a relationship between mitochondrial dysfunction and the common form of type II diabetes is discussed. Mitochondrial function may represent a novel area for the development of therapeutic and diagnostic strategies for type II diabetes mellitus. Drug Dev. Res. 46:67–79, 1999. © 1999 Wiley‐Liss, Inc.     

Delivery aspects of antioxidants in diabetes management

Introduction: Ample research has been done to study the role of oxidative stress due to the generation of excess reactive species in initiation and progression of diabetic complications. A positive result has been indicated hypothesizing that abating this oxidative stress can prove to be an alternate strategy in therapy apart from oral antidiabetic drugs. But these dietary antioxidants are less efficient because of poor solubility, permeability, instability on storage, gastrointestinal degradation and first-pass metabolism.

Areas covered: This review gives a brief insight into the molecular mechanism of oxidative stress in development of diabetic complications. Major hurdles limiting the translation of antioxidants to clinical area are also discussed. Various delivery approaches including both conventional and novel drug delivery systems explored so far for combating these challenges in antioxidant delivery are also explored. Mitochondrial targeting of such molecules is also briefly discussed.

Expert opinion: A thorough study of clinical efficacy and safety of antioxidants on long-term use judging its clinical applicability is required. The clinical success of antioxidants as a therapeutic strategy involves a combination of effective design of drug delivery carrier that are in turn related to their degradation profile, possibility of cellular uptake at defined site of action and so on and clinical and preclinical trials that will provide a base for the design of dose and administration regimen.     

细胞自噬：糖尿病发生发展中的积极参与者

糖尿病病因复杂,涉及自身免疫、环境及遗传等多种因素。细胞自噬是一种细胞内分解代谢过程,在维持胰岛细胞内环境稳态中发挥重要作用。自噬通过参与内质网应激、线粒体功能障碍以及炎症反应等过程,影响糖尿病的发生发展。本文就糖尿病中自噬和内质网应激、线粒体功能障碍以及炎症的相互作用作一综述,旨在探讨糖尿病的发病机制,寻找防治糖尿病的新策略。     

200例糖尿病患者血液流变学检测

通过对200例糖尿病患者进行血液流变学指标的测定,结果显示糖尿病患者全血粘度、血浆粘度、红细胞聚集性、红细胞压积、血沉均增高,提示糖尿病患者血流变学指标显著改变,进行血流流变学指标检测,可以预防心脑血管疾病的发生。     

Discontinued drug therapies to treat diabetes in 2014

Introduction: Available drugs partially attenuate the hyperglycemia characteristic of diabetes. However, successful approaches to treat the root cause or to cure or prevent diabetes remain elusive. Drug discovery and development programs continue to focus on mechanisms that impact specific symptoms of diabetes. In 2014, programs were discontinued for a variety of reasons and these discontinued programs are discussed herein.

Areas covered: A search of discontinued products in the metabolic area for 2014 identified mostly compounds that were being developed to treat diabetes (mostly type 2 diabetes). Candidates were identified through the use of PharmaProjects. The author also sought information using Google, PubMed, HighWire and ClinicalTrials.gov. The discontinued development programs that were identified were not numerous as in previous years and so they are presented here without segregation into categories.

Expert opinion: In general, the specific reasons for the discontinuation of these programs have not been clearly disclosed. In some cases, business considerations are given, whereas in others, there are specific safety issues that emerged which were not expected from nonclinical experience. In the final analysis, it is clear that all of these programs have been discontinued because the evidence does not favor the type of efficacy and risk:benefit ratio that justifies additional expenditures. There remains a clear need for precise addressable mechanisms to affect the root causes of diabetes.     

益生菌对糖尿病作用的相关研究进展

本文通过综述相关文献,探讨肠道菌群与1型糖尿病、2型糖尿病和益生菌之间的关联。结果表明,益生菌可以减少炎症反应、氧化应激反应,增加肠道上皮细胞中粘附蛋白的表达,减少肠道通透性,从而增加胰岛素的敏感性和降低自身免疫反应。     

妊娠期糖尿病孕期干预方法的研究

目的 探讨了妊娠期糖尿病的一些预防和干预方法.方法 回顾分析广州新海医院2014年10月至2015年10月共收治孕期未经干预的产妇,选取85例孕期糖尿病筛查阳性的孕妇作为观察组,采取早期系统干预;将住院分娩时才被诊断为GDM并且整个孕期都没有接受系统干预的85例产妇作为对照组.结果 观察组GDM患者经过系统干预后,发生先兆子痫的3例、羊水过多5例、胎膜旱破3例、巨大儿7例、胎儿宫内窘迫3例、新生儿窒息3例,未发生新生儿低血糖,GDM并发症的发生率均低于同期未干预的GDM患者,差异有统计学意义(均P＜0.05).结论 妊娠期糖尿病在各国的发病呈上升趋势,可严重威胁母子的身心健康,经过心理、饮食、运动等及时干预措施可以很好地降低该病的发病几率.     

糖尿病治疗历史

糖尿病是一种以长期血糖升高为特点的代谢性疾病。人类对糖尿病的认识最早可追溯至公元前1 500年的古埃及。目前对于糖尿病有饮食、运动、药物、代谢手术等多种治疗方式。作者简要回顾了人类对于糖尿病的认识和治疗历史。     

The use of animal models in diabetes research

Diabetes is a disease characterized by a relative or absolute lack of insulin, leading to hyperglycaemia. There are two main types of diabetes: type 1 diabetes and type 2 diabetes. Type 1 diabetes is due to an autoimmune destruction of the insulin-producing pancreatic beta cells, and type 2 diabetes is caused by insulin resistance coupled by a failure of the beta cell to compensate. Animal models for type 1 diabetes range from animals with spontaneously developing autoimmune diabetes to chemical ablation of the pancreatic beta cells. Type 2 diabetes is modelled in both obese and non-obese animal models with varying degrees of insulin resistance and beta cell failure. This review outlines some of the models currently used in diabetes research. In addition, the use of transgenic and knock-out mouse models is discussed. Ideally, more than one animal model should be used to represent the diversity seen in human diabetic patients.     

肠道菌群与糖尿病

摘要： 近年来, 肠道菌群与糖尿病的关系成为研究热点。随着对肠道菌群认识的深入, 肠道菌群作为环境因素在调节免疫及代谢性疾病发生中的作用逐渐被大家认识。目前国内外已有大量研究关注肠道菌群影响肥胖和糖尿病的发病机制, 也有研究发现肠道菌群能够从食物难以消化的成分中获取能量, 从而影响人体的能量平衡和代谢。人们通过基因组测序的方法揭示不同类型糖尿病患者肠道菌群的组成、 丰度等, 并在动物体内进行验证, 明确和糖尿病相关的细菌功能。肠道菌群携带的遗传信息可能是未来治疗糖尿病的新突破口。关于2型糖尿病 （T2DM） 及1 型糖尿病 （T1DM） 肠道菌群的研究较多, 但妊娠期糖尿病 （GDM） 肠道菌群的相关研究报道较少。因此, 本文对不同类型糖尿病的肠道菌群特点及肠道菌群参与糖尿病发生的机制作一综述。