基因芯片技术及其在补血中药研究中的应用

补血中药在我国中医药宝库中占有十分重要的地位,中药调控造血的分子机制与细胞因子网络直接相关。多维超高通量药物筛选体系的建立和从分子水平系统说明中药作用的药理学机制,使传统的中药理论与国际通用的医学理论模式接轨,是中药现代化、国际化的迫切要求。由于中药重整体、多靶点、多环节的作用方式,使得传统的研究技术难以完整地阐明其作用机制;而现今发展起来的高密度基因芯片技术,可以同时研究上千种基因的作用模式,进行平行基因分析,因此可以用来检测疾病状态下和中药作用后成千上万个基因的表达模式,并对其进行定性和定量分析,从而使从整体和分子水平上阐明中药作用机制成为可能。基因芯片这种高通量、快速、平行的基因信息处理和分析技术,是实现这一目标的绝佳实验手段。在药物领域对于药物靶标的发现、多靶位同步超高通量药物筛选、药物作用的分子机理、中医药基础理论现代化、药物活性及毒性评价等都有其他方法无可比拟的优越性。因此,建立以基因芯片技术为核心的多靶点、多层次、多水平的中药多维超高通量筛选体系具有极其重要的意义。     

代谢组学在中药研究中的应用进展

代谢组学是功能基因组学和系统生物学研究不可或缺的重要组成部分,是通过考察生物体系受刺激或扰动前后代谢产物的动态变化,研究生物体系的代谢网络的一种技术。应用代谢组学高通量、整体性的研究思路来理解中药的作用过程,与中医药的整体、辩证观点是一致的。代谢组学已成为中药研发的一个重要途径和手段,为中药现代化在技术上提供巨大支持,有助于为中药现代化研究寻找更多有效的突破口。本文在前人综述的基础上,着重概括了中药代谢组学研究方法近3年来在中药有效物质基础和作用机制、药物作用模型的鉴别和确证、毒性研究和中药安全性评价等方面的应用情况,同时展望了代谢组学方法所面临的机遇和挑战。     

降血糖中药及有效成分的研究进展

本文通过PrloQuest Medical Library和中国学术期刊教据库,对降血糖中药有效成分等设置关键词检索,综述了1994年以来国内外降血糖中药有效成分及研究现状.具有降血糖作用的中药化学成分主要包括多糖、生物碱、黄酮、皂苷、萜及含硫化合物等六大类,虽然各类中药成分的有效性及其作用机理迥异,但其研究进展,为降血糖的分子中药研究开发奠定了良好基础.降血糖中药有效成分是重要的降血糖中药分子,进一步研究和探讨这些中药分子的中药药性和组方配伍规律,对于创制高效低毒的降血糖分子中药,推进中药现代化具有重要理论和实践指导意义.     

系统生物学——生命科学的新领域

系统生物学是继基因组学、蛋白质组学之后一门新兴的生物学交叉学科,代表21世纪生物学的未来.最近,系统生物学研究机构纷纷成立.在研究上,了解一个复杂的生物系统需要整合实验和计算方法.基因组学和蛋白质组学中的高通量方法为系统生物学发展提供了大量的数据.计算生物学通过数据处理、模型构建和理论分析,成为系统生物学发展的一个必不可缺、强有力的工具.在应用上,系统生物学代表新一代医药开发和疾病防治的方向.     

中药网络药理学研究中的生物信息学方法

为了更有效地治疗癌症、心血管疾病、免疫系统疾病等复杂疾病,基于分子网络的多靶点药物发现理念逐渐成为一种新的趋势,而中药整体、辨证、协同的用药观再一次引起了药物发现领域的极大兴趣。中药在治疗复杂慢性疾病方面有确切的疗效和较小的毒副作用。中药网络药理学从分子网络调控的水平上阐明中药的作用机制,为多靶点药物发现提供有益的启示和借鉴,并有可能从临床有效的中药反向开发现代多组分、多靶点新药。针对基于生物分子网络的中药药理学研究路线中的4 个步骤,介绍近年来中药网络药理学研究中相关的生物信息学方法。     

合成生物学展望

21世纪生命科学将因系统生物学和合成生物学而进入新的发展时期,系统生物学使生命科学由实验科学转变为定量、预测的系统科学,而合成生物学是在系统生物学基础上进一步把生命科学推向工程科学．把系统生物学研究的天然元件、模块、网络、系统转变为工程化的元件、模块、网络用以构建具备各种功能的生物装置和生物体。     

网络药理学与药物发现研究进展

将生物学网络与药物作用网络整合,分析药物在网络中与节点或网络模块的关系,由寻找单一靶点转向综合网络分析,就形成了网络药理学.通过系统生物学的研究方法进行网络药理学分析,能够在分子水平上更好的理解细胞以及器官的行为,加速药物靶点的确认以及发现新的生物标志物.这使得我们有可能系统地预测和解释药物的作用,优化药物设计,发现影响药物作用有效性和安全性的因素,从而设计多靶点药物或药物组合.本文综述了网络药理学的新近研究进展,介绍在生物学网络的各个层面上网络药理学的研究和应用,展望网络药理未来的发展方向,对药物发现具有重要意义.     

计算系统生物学:理论、方法及在药物研发中的应用

计算系统生物学是一个多学科交叉的新兴领域,旨在通过整合海量数据建立其生物系统相互作用的复杂网络。数据的整合和模型的建立需要发展合适的数学方法和软件工具,这也是计算系统生物学的主要任务。生物系统模型有助于从整体上理解生物体的内在功能和特性。同时,生物网络模型在药物研发中的应用也越来越受到制药企业以及新药研发机构的重视,如用于特异性药物作用靶点的预测和药物毒性评估等。该文简要介绍计算系统生物学的常见网络和计算模型,以及建立模型所用的研究方法,并阐述其在建模和分析中的作用及面临的问题和挑战。     

“2009植物生物学研讨会”将在山东烟台举行

为展示植物发育、环境应答和分子进化等研究领域的最新成果,探讨分子遗传学、基因组学和系统生物学研究技术的发展,2009年8月在山东烟台举行“2009植物生物学研讨会”。     

《组合中药学》及其理论系统的建立

我们以传统中医药理论与现代科技的结合为出发点,提出了《组合中药学》新理论体系,试图解答中药现代化中基础理论方面的关键问题。中药的本质就是“组合”。无论是主或复方都是一个庞大的分子库,具有相同或相似功能的分子组合成一个群体。这些群体表现出特定的药效。“组合”有三层意思：生药的组合、分子群的组合与特定药效功能的组合。分子群是特定药效功能的物质基础。分子群的观念表明了东方医药不同于西方的本质之所在,西方医药学研究的对象是单一的化合物。复方是特定药效的组合,分别具有不同或相同或相似药效的几类分子群的组合。即为中药的复方制剂。这些分子群体的组合或相辅相成,或减毒增效,以达到治疗的目的。本论文阐述了《组合中药学》的目的、意义和研究方法。《组合中药学》作为一大研究领域,可以建立一整套现代中药学的新理论体系,为中药的现代化提供科学依据,并可以此作为中药现代化切入点,以解决中医药科学化的关键问题。遵循这一理论体系,可以使中医药研究系统化,起到提纲挈领的作用,具有重要的理论价值和指导意义。《组合中药学》就是从《组合分子》水平上研究中药及其药效的物质基础,阐明中药活性部位的相互作用与药效的相互关系及其作用机制。《组合中药学》的三个新概念：中药功效分子族：具有相似药效作用的一类分子的组合,其骨架及功能团相同或相似。中药表征性组合分子：单味中药药效的代表性功效分子族,即主要药效分子组合。中药非表征性组合分子：单味中药表征性分子以外的其他功效分子族,即辅助药效分子的组合。     

A survey of web resources and tools for the study of TCM network pharmacology

Background: Traditional Chinese medicine (TCM) treats diseases in a holistic manner, while TCM formulae are multi-component, multi-target agents at the molecular level. Thus there are many parallels between the key ideas of TCM pharmacology and network pharmacology. These years, TCM network pharmacology has developed as an interdisciplinary of TCM science and network pharmacology, which studies the mechanism of TCM at the molecular level and in the context of biological networks. It provides a new research paradigm that can use modern biomedical science to interpret the mechanism of TCM, which is promising to accelerate the modernization and internationalization of TCM. Results: In this paper we introduce state-of-the-art free data sources, web servers and softwares that can be used in the TCM network pharmacology, including databases of TCM, drug targets and diseases, web servers for the prediction of drug targets, and tools for network and functional analysis. Conclusions: This review could help experimental pharmacologists make better use of the existing data and methods in their study of TCM.     

Leucine-Rich Repeat Kinase 2 Binds to Neuronal Vesicles through Protein Interactions Mediated by Its C-Terminal WD40 Domain

Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) are associated with familial and sporadic Parkinson''s disease (PD). LRRK2 is a complex protein that consists of multiple domains, including predicted C-terminal WD40 repeats. In this study, we analyzed functional and molecular features conferred by the WD40 domain. Electron microscopic analysis of the purified LRRK2 C-terminal domain revealed doughnut-shaped particles, providing experimental evidence for its WD40 fold. We demonstrate that LRRK2 WD40 binds and sequesters synaptic vesicles via interaction with vesicle-associated proteins. In fact, a domain-based pulldown approach combined with mass spectrometric analysis identified LRRK2 as being part of a highly specific protein network involved in synaptic vesicle trafficking. In addition, we found that a C-terminal sequence variant associated with an increased risk of developing PD, G2385R, correlates with a reduced binding affinity of LRRK2 WD40 to synaptic vesicles. Our data demonstrate a critical role of the WD40 domain within LRRK2 function.     

A Modularity-Based Method Reveals Mixed Modules from Chemical-Gene Heterogeneous Network

For a multicomponent therapy, molecular network is essential to uncover its specific mode of action from a holistic perspective. The molecular system of a Traditional Chinese Medicine (TCM) formula can be represented by a 2-class heterogeneous network (2-HN), which typically includes chemical similarities, chemical-target interactions and gene interactions. An important premise of uncovering the molecular mechanism is to identify mixed modules from complex chemical-gene heterogeneous network of a TCM formula. We thus proposed a novel method (MixMod) based on mixed modularity to detect accurate mixed modules from 2-HNs. At first, we compared MixMod with Clauset-Newman-Moore algorithm (CNM), Markov Cluster algorithm (MCL), Infomap and Louvain on benchmark 2-HNs with known module structure. Results showed that MixMod was superior to other methods when 2-HNs had promiscuous module structure. Then these methods were tested on a real drug-target network, in which 88 disease clusters were regarded as real modules. MixMod could identify the most accurate mixed modules from the drug-target 2-HN (normalized mutual information 0.62 and classification accuracy 0.4524). In the end, MixMod was applied to the 2-HN of Buchang naoxintong capsule (BNC) and detected 49 mixed modules. By using enrichment analysis, we investigated five mixed modules that contained primary constituents of BNC intestinal absorption liquid. As a matter of fact, the findings of in vitro experiments using BNC intestinal absorption liquid were found to highly accord with previous analysis. Therefore, MixMod is an effective method to detect accurate mixed modules from chemical-gene heterogeneous networks and further uncover the molecular mechanism of multicomponent therapies, especially TCM formulae.     

中西医结合治疗溃疡性结直肠炎的临床疗效分析

目的:探讨中西医结合治疗溃疡性结直肠炎的临床疗效。方法:将2009年6月~2011年6月我院收治的126例溃疡性结直肠炎患者,随机分为治疗组(65例)和对照组(61例)。对照组采用柳氮磺吡啶口服治疗,治疗组采用口服柳氮磺吡啶加中药保留灌肠治疗。7d为1个疗程,连续治疗3个疗程。结果:治疗组总有效率92.31%,显著优于对照组80.33%,差异有统计学意义(P<0.05);治疗后治疗组症状、体征改善程度优于对照组,差异有统计学意义(P<0.05);随访1年,治疗组和对照组痊愈者中复发率分别为22.22%、61.11%,差异有统计学意义(P<0.05)。结论:中西医结合治疗溃疡性结直肠炎疗效确切,药物毒副反应少,复发率低,值得临床推广。     

Evaluating the Pharmacological Mechanism of Chinese Medicine Si-Wu-Tang through Multi-Level Data Integration

Si-Wu-Tang (SWT) is a Traditional Chinese Medicine (TCM) formula widely used for the treatments of gynecological diseases. To explore the pharmacological mechanism of SWT, we incorporated microarray data of SWT with our herbal target database TCMID to analyze the potential activity mechanism of SWT''s herbal ingredients and targets. We detected 2,405 differentially expressed genes in the microarray data, 20 of 102 proteins targeted by SWT were encoded by these DEGs and can be targeted by 2 FDA-approved drugs and 39 experimental drugs. The results of pathway enrichment analysis of the 20 predicted targets were consistent with that of 2,405 differentially expressed genes, elaborating the potential pharmacological mechanisms of SWT. Further study from a perspective of protein-protein interaction (PPI) network showed that the predicted targets of SWT function cooperatively to perform their multi-target effects. We also constructed a network to combine herbs, ingredients, targets and drugs together which bridges the gap between SWT and conventional medicine, and used it to infer the potential mechanisms of herbal ingredients. Moreover, based on the hypothesis that the same or similar effects between different TCM formulae may result from targeting the same proteins, we analyzed 27 other TCM formulae which can also treat the gynecological diseases, the subsequent result provides additional insight to understand the potential mechanisms of SWT in treating amenorrhea. Our bioinformatics approach to detect the pharmacology of SWT may shed light on drug discovery for gynecological diseases and could be utilized to investigate other TCM formulae as well.     

花青素转录因子调控机制及代谢工程研究进展

花青素是广泛存在于植物中的一类重要的类黄酮化合物, 在植物生长发育和人类营养保健方面具有重要价值。花青素的生物合成途径已经解析得比较清楚, 但花青素的代谢调控网络还在不断完善。调控花青素生物合成的转录因子主要包括MYB、bHLH和WD40三大类, 这些转录因子通过激活或抑制CHS、ANS和DFR等花青素途径关键结构基因的表达水平, 进而决定花青素积累的部位与水平。该文结合国内外花青素生物合成与转录调控方面的研究进展, 简要介绍了花青素的生物合成途径, 归纳总结了模式植物中花青素代谢调控的分子机理, 尤其是MYB、bHLH和WD40三类主要转录因子的调控机理, 以及这些转录因子在观赏植物和水果等经济作物花青素代谢工程中的应用。该文将为系统阐明花青素的转录调控机制和利用代谢工程改良花青素的相关研究提供有益参考。     

Traditional Chinese medicines with caspase-inhibitory activity

Clinical evidence indicates that traditional Chinese medicine (TCM) drugs can reduce stroke-inflicted brain damage. To date, the molecular basis of the apparent neuroprotective effects of these TCM drugs remains largely obscure. Several lines of evidence indicate that the activation of cell death programs leads to the loss of neurons during the reperfusion phase of ischemic stroke. In particular, activation of caspases (cysteinyl aspartate-specific proteinases) is a critical step in neuronal apoptosis. Using nuclear magnetic resonance (NMR) and fluorescence assays, we screened a collection of 58 TCM drugs that are commonly used in stroke therapy for caspase inhibitory activity. We found that aqueous extracts of Lianqiao (Fructus Forsythiae) and Shouwuteng (Caulis Polygoni multiflori) blocked the activity of the initiator caspase-8 as well as the effector caspase-3 and caspase-7 in a dose-dependent manner with an IC(50)10 microg/ml. Identification of caspase inhibitory activity of these TCM drugs, allows the formulation of testable hypotheses and design of further investigations aimed at the elucidation of the molecular basis of TCM stroke therapy.     

Comparative chemical profiling of three TCM drugs in the Paeoniaceae family by UPLC-MS/MS combined with chemometric methods

Paeoniae Radix Rubra (Chi-Shao in Chinese) and Paeoniae Radix Alba (Bai-Shao in Chinese) are two valuable traditional Chinese medicine (TCM) drugs, usually indicated for menstrual disorders and viral infections. Paeonia anomala subsp. anomala (Xinjiang-Shaoyao in Chinese) is taken as Chi-Shao substitute in Xinjiang, China. Due to the diverse growing conditions, there are some differences in chemical compositions of three TCM drugs. An UPLC fingerprint analysis with chemometric methods, including similarity analysis and hierarchical clustering analysis, was applied in the study. By virtue of UPLC-QTOF-MS, 29 components including 18 monoterpene glycosides, 5 galloyl glucoses and 6 phenolic compounds were simultaneously identified. It could be concluded that the UPLC-QTOF-MS combined with chemometric methods could efficiently identify the three TCM drugs, and was a powerful approach for the chemical profiling of three TCM drugs. The developed method provide an available approach for quality control of three TCM drugs.