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。     

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。     

肿瘤免疫疗法中免疫检查点的研究进展

免疫检查点(immune chenkpoint)是存在于免疫系统中的抑制性信号通路,对外周组织中免疫反应强度、持续性予以调节,防止组织损伤,并在维持自身抗原耐受性的过程中发挥作用。T细胞识别、清除肿瘤的过程受到诸多信号通路、配体/受体的严密调控。免疫检查点疗法就是一类通过调节T细胞活性来提高抗肿瘤免疫反应的治疗方法。目前,通过抑制免疫检查点阻断信号以调节T细胞活性增强其抗肿瘤效应是肿瘤治疗热点,例如利用CTLA-4(cytotoxic T lymphocyte antigen4)、PD-1(programmed cell death1)、PD-L1(programmed cell death 1 ligand)的拮抗剂以及其它药物干扰免疫检查点,可直接刺激细胞毒性T细胞的活化进而启动抗肿瘤免疫,介导持续的肿瘤抑制过程。而联合使用免疫检查点阻断剂加强肿瘤抑制效果也在进行深入研究。免疫检查点信号通路的生物学机制目前获得诸多进展,本文就一些已应用于临床的免疫检查点及其它新型免疫检查点的研究进展加以综述。     

大麻二酚对肿瘤中离子通道的作用

大麻是一种古老的药用植物,常被用于缓解疼痛和癫痫发作,但大麻素的成瘾性限制了它的临床使用。大麻的提取物大麻二酚没有精神活性,且不良反应明显小于Δ9-四氢大麻酚,因此受到广泛青睐。离子通道是贯穿细胞膜的亲水性蛋白质孔道,可维持机体生命活动,也与肿瘤的发生发展密切相关。该文主要关注大麻二酚作用的部分瞬时受体电位离子通道、电压依赖性阴离子选择性通道1和T型钙离子通道。大麻二酚是一个多靶点药物,对离子通道的作用受到广泛关注,但其作用机制和结合位点尚不清晰。目前已有关于大麻二酚作用于离子通道的综述及离子通道和肿瘤关系的综述,但鲜有大麻二酚对肿瘤中的离子通道作用的总结。该文主要总结了大麻二酚可能结合的离子通道及其在肿瘤细胞中的可能作用。     

异源物代谢核受体PXR与肿瘤多药耐药相关性的研究进展

肿瘤的多药耐药性是临床化疗中迫切需要解决的问题.孕烷X受体(pregnane X receptor,PXR)为配体活化的转录因子,其下游靶基因均为主司异源性药物/毒物生物转化功能的I相、II相代谢酶及III相转运蛋白,可对药物代谢动力学过程产生重要的影响,故有可能成为逆转肿瘤多药耐药的新的药物作用靶点.本文总结了PXR在肿瘤多药耐药中的作用及机制、新型PXR配体类药物研发等方面的研究进展.     

波形蛋白与肿瘤关系的研究进展

波形蛋白是中间纤维蛋白的一种,参与细胞骨架与胞膜的形成。研究发现,波形蛋白在多种上皮癌中大量表达,如前列腺癌、乳腺癌及胃肠道肿瘤等,且参与这些肿瘤的发生发展过程,但是目前其具体作用机制尚不清楚。临床研究发现,波形蛋白能够作为肿瘤诊断与治疗的标志物,探讨波形蛋白分子机制研究及在肿瘤发生发展过程中的作用十分重要。本文主要就波形蛋白在几种肿瘤中的表达及其对肿瘤细胞增殖、迁移的作用进行综述。     

膜超极化激活离子通道及其靶向抗癫痫药物研究进展

癫痫是一种较为常见的神经系统疾病,主要以大量神经元同步异常放电为特征。目前普遍认为,神经元或神经网络兴奋性和抑制性 电信号传输的失衡,是癫痫发病的最根本原因。现有的抗癫痫药物主要以钠离子通道、钙离子通道、钾离子通道、谷氨酸受体和γ-氨基丁 酸离子通道为靶点,但接受这些药物治疗后,仍有近1/3的病人无法控制癫痫发作。因此,抗癫痫药物的研发亟需新靶点和新思路。许多 研究证据表明,膜超极化激活离子通道的基因突变可以导致遗传型癫痫的发作,且在脑部损伤后,膜超极化激活离子通道会发生表达水平、 通道生物物理学性质及通道亚基构成的改变,从而增加神经元和神经网络兴奋性,促使癫痫发病。故近年来,膜超极化激活离子通道及其 靶向抗癫痫药物研究引起人们广泛关注。综述膜超极化激活离子通道与癫痫发病之间的关系,并探讨以膜超极化激活离子通道为靶点进行 抗癫痫药物开发和治疗的可行性。     

MicroRNA与肿瘤及其耐药性的研究进展

MicroRNAs(miRNAs)是一类非编码的内源性小RNA分子,能影响mRNA的稳定性和/或翻译,在细胞增殖、分化、凋亡、基因调控及疾病的发生,尤其是肿瘤中扮演着重要的角色.miRNAs可广泛参与肿瘤的发生和发展,具有与原癌基因或肿瘤抑制基因相似的作用.新近的研究表明,miRNAs可能与肿瘤的多药耐药关系密切.本文从miRNAs的生物学特性、生理功能、作用机制、与肿瘤及多药耐药的关系等研究进展予以综述.     

哺乳动物及人精子膜离子通道的研究进展

离子的跨膜转动对精子的生理活动起重要的作用。近年,应用膜片钳及人工膜重组等研究通道有关的电生理技术,人们直接观察到哺乳动物及人精子膜上Ｋ、Ｎａ＾＋、Ｃａ＾２＋、Ｃｌ通道的存在。这些结果为揭示精子成熟、获能精卵结合反应等生理过程的某些细节提供了有有的资料,特别是对人精子膜的研究,还为临床应用提供了可能。     

蛋白质棕榈酰化及其与离子通道关系的研究进展

蛋白质棕榈酰化(palmitoylation)是调节蛋白定位、稳定和功能的重要机制,这一过程通常受棕榈酰基转移酶的调控,编码这些酶的基因称为含锌指DHHC(zDHHC)。随着研究方法的深入,棕榈酰化修饰在多种离子通道生理功能方面发挥重要的调节作用,为深入了解离子通道结构和功能带来新的见解。本文主要就棕榈酰化修饰过程及其在常见离子通道中的研究进展做一综述。     

Acid-sensing ion channels under hypoxia

Hypoxia represents the lack of oxygen below the basic level, and the range of known channels related to hypoxia is continually increasing. Since abnormal hypoxia initiates pathological processes in numerous diseases via, to a great degree, producing acidic microenvironment, the significance of these channels in this environment has, until now, remained completely unknown. However, recent discovery of acid-sensing ion channels (ASICs) have enhanced our understanding of the hypoxic channelome. They belong to the degenerin/epithelial Na⁺ channel family and function once extracellular pH decreases to a certain level. So does the ratiocination emerge that ASICs participate in many hypoxia-induced pathological processes, including pain, apoptosis, malignancy, which all appear to involve them. Since evidence suggests that activity of ASICs is altered under pathological hypoxia, future studies are needed to deeply explore the relationship between ASICs and hypoxia, which may provide a progressive understanding of hypoxic effects in cancer, arthritis, intervertebral disc degeneration, ischemic brain injury and so on.     

电压门控性钠离子通道与伤害性感受

伤害性感受器激活引起疼痛的概念,现已广泛被人们接受,大量实验表明,伤害性感受器兴奋性的变化与一些离子通道有关,对河豚毒素不敏感的电压依赖性钠离子通道（TTXr)选择性地分布于与伤害性感受有关的初级感受神经元,炎症反应和神经损伤诱发的慢性疼痛可诱发这种TTXr功能及基因表达的变化,TTXr通道蛋白的反义寡核苷酸（antisense ODN)处理可对抗炎症或神经损伤引起的痛觉过敏或超敏,提示TTXr在伤害性感受中起重要作用,有望成为特异性镇痛药物的药理作用靶点。     

Simulations of ion current in realistic models of ion channels: the KcsA potassium channel

Realistic studies of ion current in biologic channels present a major challenge for computer simulation approaches. All-atom molecular dynamics simulations involve serious time limitations that prevent their use in direct evaluation of ion current in channels with significant barriers. The alternative use of Brownian dynamics (BD) simulations can provide the current for simplified macroscopic models. However, the time needed for accurate calculations of electrostatic energies can make BD simulations of ion current expensive. The present work develops an approach that overcomes some of the above challenges and allows one to simulate ion currents in models of biologic channels. Our method provides a fast and reliable estimate of the energetics of the system by combining semimacroscopic calculations of the self-energy of each ion and an implicit treatment of the interactions between the ions, as well as the interactions between the ions and the protein-ionizable groups. This treatment involves the use of the semimacroscopic version of the protein dipole Langevin dipole (PDLD/S) model in its linear response approximation (LRA) implementation, which reduces the uncertainties about the value of the protein "dielectric constant." The resulting free energy surface is used to generate the forces for on-the-fly BD simulations of the corresponding ion currents. Our model is examined in a preliminary simulation of the ion current in the KcsA potassium channel. The complete free energy profile for a single ion transport reflects reasonable energetics and captures the effect of the protein-ionized groups. This calculated profile indicates that we are dealing with the channel in its closed state. Reducing the barrier at the gate region allows us to simulate the ion current in a reasonable computational time. Several limiting cases are examined, including those that reproduce the observed current, and the nature of the productive trajectories is considered. The ability to simulate the current in realistic models of ion channels should provide a powerful tool for studies of the biologic function of such systems, including the analysis of the effect of mutations, pH, and electric potentials.     

miRNA在疼痛相关离子通道及受体中的作用研究

miRNA广泛表达于神经系统,与疼痛的发生、发展密切相关。近年来研究表明,抑制miRNA的合成调制伤害性神经元对炎症刺激的反应。疼痛时,背根神经节(DRG)上miRNA明显下调,该变化参与炎性疼痛和神经性疼痛的产生和维持。同时,miRNA也可以下调Navα亚基、ASIC3、TRPV1和P2X7mRNA的表达水平,还可以降低Kv电流。因此,miRNA可能成为疼痛治疗的新靶点。综述了miRNA的生物起源、分布,及其对痛觉相关离子通道Nav、Kv、ASICs、TRPV1以及嘌呤受体的调节作用。     

Progress of Breast Cancer basic research in China

Breast cancer is the most commonly diagnosed and the most lethal cancer in females both in China and worldwide. Currently, the origin of cancer stem cells, the heterogeneity of cancer cells, the mechanism of cancer metastasis and drug resistance are the most important issues that need to be addressed. Chinese investigators have recently made new discoveries in basic breast cancer researches, especially regarding cancer stem cells, cancer metabolism, and microenvironments. These efforts have led to a deeper understanding of drug resistance and metastasis and have also indicated new biomarkers and therapeutic targets. These findings emphasized the importance of the cancer stem cells for targeted therapy. In this review, we summarized the latest important findings in this field in China.     

Recent advances in ion channel research

The field of ion channels has entered into a rapid phase of development in the last few years, partly due to the breakthroughs in determination of the crystal structures of membrane proteins and advances in computer simulations of biomolecules. These advances have finally enabled the long-dreamed goal of relating function of a channel to its underlying molecular structure. Here we present simplified accounts of the competing permeation theories and then discuss their application to the potassium, gramicidin A and calcium channels.     

离子通道在肺动脉的分布及在低氧肺血管收缩反应中的作用

低氧性肺血管收缩反应（HPV）是指在急性低氧时,肺泡氧分压降到某一临界值,肺血管发生的快速、可逆的收缩反应,以纠正肺泡通气／灌流的不匹配。HPV的发生与肺动脉平滑肌细胞上K^＋、Ca^2＋、Cl^-通道的状态密切相关,而这些通道在不同部位的肺动脉上分布存在差异,因此不同部位的肺动脉在低氧中所表现的收缩反应程度也不同,本综述将对上述通道在肺动脉上的分布特点及其在HPV中的作用做一总结。