离子通道与人类遗传病

细胞膜离子通道结构和功能正常是细胞进行生理活动的基础,对离子通道功能具有决定性意义的特定位点的突变导致其开放、关闭或激活、失活功能异常,引起组织机能紊乱,形成各种遗传性疾病。本文从水通道蛋白,钙通道,钠通道,钾通道等多种通道蛋白引起的遗传病的现象以及机理做较深入的阐述。     

TRPM7生理病理学功能及其小分子调节剂的发现

TRPM7（transient receptor potential melastatin 7）通道属于TRPM亚家族，是一种具有离子通道结构域和激酶结构域的双功能跨膜蛋白。作为非选择性阳离子通道，TRPM7可通透Ca²⁺、Mg²⁺、Zn²⁺、Na⁺、K⁺等和其他微量金属离子。TRPM7在人体各组织广泛表达，参与Mg²⁺的稳态调控、细胞增殖、分化、黏附和迁移等生理过程。临床上，TRPM7功能紊乱与神经退行性疾病、中风、癌症等多种疾病关系密切。本文主要综述TRPM7通道在生理、病理及小分子调节剂方面的研究进展，为相关疾病的药物开发提供新的思路。     

动物离子通道毒素与药物开发

就离子通道和动物离子通道毒素的来源、种类、特性及其对新药开发的意义进行了综述。各种来源的动物毒素通常分子量较小,富含二硫键,是直接作用于分子靶标（如离子通道、受体及酶）的小分子蛋白质。很多动物毒素对电压门控离子通道具有高度的专一性和有效性,具有独特、简洁的三维空间结构。其对新药的发现、设计以及寻找潜在的治疗靶标具有重要的指导意义。     

离子通道与肿瘤

钾、钙、氯等离子通道在肿瘤细胞中异常表达,与肿瘤的发生发展密切相关。其可能机制是离子通道通过调节细胞膜电位、细胞周期、细胞体积、胞内钙浓度和胞质pH值等调控肿瘤细胞增殖与凋亡。本文综述了离子通道与肿瘤关系的研究进展,随着研究不断深入,离子通道有可能成为防治肿瘤的新靶标。     

斑马鱼与人类疾病模型的研究

斑马鱼是一种很好的用于研究脊椎动物胚胎学和发育遗传学的模型生物,它有其他模型生物所不具备的优点。最近研究较多的是在斑马鱼中建立人类疾病研究模型。本文就斑马鱼在造血障碍和心血管障碍等方面的疾病模型建立及主要的技术做简要论述。     

缝隙连接及其与人类疾病的关系

缝隙连接是由多基因家族编码的连接蛋白构成的、细胞间的跨膜水相通道。目前已确定小鼠连接蛋白基因家族含有20个成员,人类连接蛋白基因家族含有21个成员,其中有19种在人类和小鼠中均有表达,具有很高的同源性;不同的连接蛋白可形成同型和异型两种连接子,不同类型连接子可形成4种不同类型的缝隙连接通道。越来越多的研究表明,连接蛋白基因突变与人类遗传性疾病密切相关。     

唾液酸生物学与人类健康和疾病

唾液酸（sialicacid）是一类酸性九碳单糖,是所有神经氨酸或酮基一脱氧壬酮糖酸（KDN）的N-或O-衍生物的总称。唾液酸作为复合糖的组成部分镶嵌于所有细胞表面以及人多数脊椎动物糖蛋白和糖脂分予的末端最外侧。唾液酸家族成员已经达到五十多个,其分子结构多样,在生物体内分布广泛。唾液酸介导或调制了发育、炎症、病原感染、肿瘤发生发展等诸多生理和病理过程,与人类健康和疾病密切关联。对唾液酸生物学的研究已成为糖生物学研究的热点之一。对唾液酸与人类健康与疾病研究的新进展做一综述。     

模式动物与人类疾病的动物模型

围绕疾病所开展的基础研究已成为当今生物医学研究领域中的主要内容,而利用模式动物建立疾病的动物模型已是其研究的重要手段,对疾病的基础研究和转化研究均具有重要意义,已成为影响该领域发展的一个关键因素。我国医学研究领域中加强人类疾病动物模型研究既是一个现实问题,更是一个迫切问题,国家自然科学基金委员会医学科学部将在这方面予以倾斜支持。     

基因组学与人类疾病

近年来,以高密度基因芯片和高通量测序为核心的基因组学技术迅速发展,已广泛应用到生物医学的各个领域并取得突出进展,使我们对于疾病的分子与遗传学基础的认识达到了一个新的水平。这     

配体门控离子通道受体别构调节研究

配体门控离子通道(LGIC)在中枢神经系统信息处理的过程中起着极其重要的作用,与多种神经性疾病有着密切联系.与受体正位调节作用相比,别构调节效应具有类内源性生理作用、高选择性及不易过度调节的优点,从而避免了一系列不良反应发生.目前,各种LGIC受体超家族均有别构调节剂发现,部分已在临床上得到应用.在未来的研究中,通过建立及完善针对别构调节剂的筛选策略,别构调节剂的发现效率及生物活性将得到极大地提高,更多的药物将会不断涌现.     

线粒体铁蛋白与铁相关的神经退行性疾病

在哺乳动物体内,线粒体铁蛋白(mitochondrial ferritin,MtFt)是一个无内含子的基因编码的蛋白,与胞质中的H-ferritin具有较高的同源性,也具有亚铁氧化酶的活性,特异性地在线粒体中表达。近年来的研究发现,过表达MtFt可以使线粒体免受由铁引起的氧化损伤。本文主要介绍MtFt在结构功能上的特点,及其在与铁相关的一些神经退行性疾病中的保护作用。     

瞬时感受器电位通道与疾病

哺乳动物瞬时感受器电位(transient receptor potential,TRP)通道超家族由TRPC、TRPM、TRPV、TRPA、TRPP和TRPML六个亚家族组成。这些亚家族的29个离子通道几乎表达于所有的组织和细胞。大多对单价和二价阳离子都有通透性。TRP通道与多种生物学功能有关,包括高血压、温度觉、血管炎症、刺激感、肿瘤增生、细胞内离子稳态及神经细胞信号转导。对这些通道的生理功能及其与人类疾病的关系的研究有助于开发具有潜在治疗价值的TRP通道调节剂。     

MicroRNAs in Common Human Diseases

MicroRNAs (miRNAs) are a class of short non-coding RNA molecules that have attracted tremendous attention from the biological and biomedical research communities over the past decade. With over 1900 miRNAs discovered in humans to date, many of them have already been implicated in common human disorders. Facilitated by high-throughput genomics and bioinformatics in conjunction with traditional molecular biology techniques and animal models, miRNA research is now positioned to make the transition from laboratories to clinics to deliver profound benefits to public health. Herein, we overview the progress of miRNA research related to human diseases, as well as the potential for miRNA to becoming the next generation of diagnostics and therapeutics.     

谷胱甘肽在肝脏疾病相关信号通路中的作用及研究进展

谷胱甘肽(GSH)是细胞内主要的抗氧剂和氧化还原、细胞信号调节器,它能还原过氧化氢、清除活性氧(ROS)和含氮自由基使细胞免受氧化应激损伤。不管细胞内是否存在ROS氧化细胞蛋白,谷胱甘肽均能诱导氧化还原反应发生转变,进一步使信号传导功能及转录因子分子功能发生改变。大量实验表明,ROS和GSH在多条细胞信号调节通路中发挥着重要作用。主要阐述了Fas、TNF-α和NF-κB信号通路及线粒体凋亡途径及GSH在这些通路中的作用。尤其是线粒体GSH耗竭能诱导线粒体内ROS显著增加,从而损害细胞生物能量和诱导线粒体通透性转换孔开启。根据线粒体损害程度,NF-κB信号通路可被抑制,肝细胞也可能经历不同的死亡模式(凋亡或坏死)并对刺激细胞死亡信号(如TNF-α)也更敏感。这些过程涉及许多肝脏疾病的发病机理。     

Human Adipose Cells Have Voltage-dependent Potassium Currents

The whole-cell patch-clamp method was used to study the membrane electrical properties of human adipocyte cells obtained by differentiating from precursors of human abdominal and mammary tissues. All differentiated cells exhibited outward currents with sigmoidal activation kinetics. The outward currents showed activation thresholds between –20 to –30 mV and slow inactivation. The ionic channels underlying the macroscopic current were highly selective for K⁺. Their selectivity was for typical K⁺ channels with relative permeabilities of K⁺>NH ₄ ⁺ >Cs⁺>Na⁺. No evidence of any other type of voltage-gated channel was found. The potassium currents (I _KV) were blocked reversibly by tetraethylammonium and barium. The IC ₅₀ value and Hill coefficient of tetraethylammonium inhibition of I _KV were 0.56 mM and 1.17 respectively. These results demonstrate that human adipose cells have voltage-dependent potassium currents.     

钠离子通道研究进展

细胞电活动是生命现象的基本特征之一,而离子通道是其结构和功能的基础。因此,研究离子通道作用机制具有重大的理论和现实意义。许多神经系统和心血管疾病,如多发性硬化症、癫痫、脑溢血、神经痛、Brugada综合征(BrS)、进行性心脏传导缺陷(PCCD)和原发性心室纤颤(IVF)等,都与钠离子通道氨基酸序列和结构发生的改变有关。该文对钠离子通道的研究进展进行综述。     

Large Conductance Ca2+-Activated K+ Channels in Human Meningioma Cells

Cells from ten human meningiomas were electrophysiologically characterized in both living tissue slices and primary cultures. In whole cells, depolarization to voltages higher than +80 mV evoked a large K⁺ outward current, which could be blocked by iberiotoxin (100 nm) and TEA (half blocking concentration IC₅₀= 5.3 mm). Raising the internal Ca²⁺ from 10 nm to 2 mm shifted the voltage of half-maximum activation (V _1/2) of the K⁺ current from +106 to +4 mV. Respective inside-out patch recordings showed a voltage- and Ca²⁺-activated (BK _Ca ) K⁺ channel with a conductance of 296 pS (130 mm K⁺ at both sides of the patch). V _1/2 of single-channel currents was +6, −12, −46, and −68 mV in the presence of 1, 10, 100, and 1000 μm Ca²⁺, respectively, at the internal face of the patch. In cell-attached patches the open probability (P _o ) of BK _Ca channels was nearly zero at potentials below +80 mV, matching the activation threshold for whole-cell K⁺ currents with 10 nm Ca²⁺ in the pipette. Application of 20 μm cytochalasin D increased P _o of BK _Ca channels in cell-attached patches within minutes. These data suggest that the activation of BK _Ca channels in meningioma cells does not only depend on voltage and internal Ca²⁺ but is also controlled by the cytoskeleton. Received 18 June 1999/Revised: 18 January 2000     

与人类疾病相关的淀粉样短肽

有些天然蛋白质可通过错误折叠形成淀粉样纤维,并进一步沉积导致淀粉样病变,被认为是许多重大人类疾病的病理基础。因此,阐明天然蛋白质错误折叠、聚集形成淀粉样纤维的分子机制,是预防、诊断和治疗相关疾病的关键。研究者们从天然蛋白质中鉴定出许多能够形成淀粉样纤维的关键短肽片段,即淀粉样短肽,对它们形成淀粉样纤维的能力及其在完整蛋白质聚集过程中的决定性作用进行深入研究。本文对近年来人类疾病相关淀粉样短肽的研究展开综述。首先,介绍鉴定淀粉样短肽的标准及其相应的研究方法和技术手段;并回顾近年来与一些重大人类疾病相关的淀粉样短肽,尤其是与神经退行性疾病相关淀粉样短肽的进展情况,对淀粉样短肽中出现频率较高的氨基酸残基及其可能的自组装原理进行总结分析;最后,展望这些淀粉样短肽作为靶点在相关疾病诊断和治疗方面的意义,并初步探讨它们作为新型生物材料在生物医学工程领域的应用前景。本文一方面为阐明天然蛋白质形成淀粉样沉淀的分子机制提供参考,另一方面也为相关疾病的治疗提供思路,同时也为新型生物材料的开发提出潜在的可能性。     

Plasma Antioxidants and Human Aging: A Study on Healthy Elderly Tunisian Population

The aging has been described by several theories. It was proposed that free radicals are the major factor involved in this process. This gave birth to the free radical theory of aging. This current theory provides the most popular explanation for how aging occurs at the biochemical/molecular level. Ever since 1956, this theory has received widespread attention and a large body of evidence has been accumulated in support of its hypotheses which were subsequently refined. The free radical theory of aging postulates that age-associated reductions in physiological functions are caused by an irreversible accumulation of oxidative alterations to macromolecules. This accumulation increases with age and is associated with the life expectancy of organisms. Moreover, this theory suggests the existence of an imbalance between reactive oxygen species (ROS)-producing pathways and (ROS)-scavenging pathways, which is responsible for the generation of oxidative stress syndrome. In this article, we evaluate the antioxidant status in a population of healthy elderly Tunisians in comparison with a group of healthy young Tunisian subjects. This study sets out to investigate the age-related changes in glutathione peroxidase (GPx), superoxide dismutase (SOD) activities, and in total antioxidant status (TAS) of human plasma. We have concluded that healthy aging is accompanied with a disturbed antioxidant status.