系统药理学原理、方法及在中医药中的应用

目的：建立科学有效的现代中药研究体系,是中医药现代化进程中亟待解决的关键问题之一,然而目前从系统和整体水平研究中药的理论和方法均不成熟。方法：本文将综述当前系统药理学的最新进展,阐明如何整合药效学、药动学以及基因、蛋白、药物网络分析等技术,形成一个完整的可供中药药理学、药效学预测和验证的技术体系。结果：重点从中药基础理论、复方解析、注射液的研究、老方优化和新药开发方面介绍系统药理学在中医药中的应用。结论：本文提出的系统药理学研究体系为中药的现代研究提供了新方法学,将有助于系统、深刻地从系统水平和分子水平揭示中药和机体的相互作用机制,从而指导中药新药研发。     

基因组尺度分析和代谢工程策略

代谢工程是近年来发展起来的新技术,随着各种组学技术的发展,高通量数据整合方法用于分析细胞的代谢网络,改造代谢途径,以提高目标产物的产量。本文就代谢工程的发展状况,基因组尺度的分析技术,以及代谢工程策略进行了综述。分析了生物信息学和系统生物学方法在代谢途径构建和代谢网络分析中的作用,并就存在的问题和可能的解决途径进行了阐述。     

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。     

代谢组学技术发展及其在农业动植物研究中的应用

代谢组学是依赖灵敏、稳定的分析流程和数据库,利用色谱–质谱联用、核磁共振技术对生物体内以及生物样品所有的小分子代谢物进行鉴定和定量分析的学科,在医学、食品科学、畜牧学、植物学等领域得到广泛应用。代谢组学方法可将代谢物种类和含量的变化与生物表型变化建立更直接的联系,因此代谢组学逐渐成为继基因组学、转录组学、蛋白组学后对复杂性状系统解析的新的研究手段。本文介绍了代谢组学常用分析策略、检测平台和常用数据库。在此基础上,综述了代谢组学在农业动物重要经济性状代谢分子鉴定、疾病诊断、肉品质及动物制品安全检测等领域取得的进展,并总结了利用代谢组学、转录组学和基因组学等多组学研究在动植物重要性状的发育、形成和解析等领域取得的最新成果。代谢组学与其他多组学方法整合分析,可以更全面地阐述各类复杂性状的遗传机制,有助于完善"突变–基因–表达–代谢–表型"的完整生物学过程,为复杂性状的机理解析提供新方法,为新型农业育种提供新思路。     

转录组-代谢组分析方法及其在药物作用机理研究中的应用

随着高通量测序技术的发展,目前高通量整合分析技术是获取最终生物学信息必不可少的重要手段,是对传统药物作用机理研究方法的一次革命性变革。转录组学、代谢组学及二者联合应用是系统生物学的重要组成部分,近年来广泛应用在药物作用机理研究相关的各个领域,如新药开发、提高药效和评价药物毒性、指导药物联合治疗等方面,已成为研究药物作用机理中不可或缺的筛选阶段。同时对转录组学、代谢组学、四种转录组-代谢组联合分析方法进行了综述,对不同联合分析方法的优缺点及存在的问题进行简要分析,阐述了近几年两组学联合分析方法在药物作用机理研究中的应用,展望其下一步的发展前景与挑战,以期探讨转录组学和代谢组学及其二者联合应用在药物作用机制研究中的策略,为今后药物作用的分子机理研究提供借鉴与参考,进而基于现有研究基础发掘新的研究方法与途径。     

系统生物学视野下的功能氨基酸组学

传统营养学将氨基酸作为蛋白质的构建单元来研究蛋白质和氨基酸。近年来的研究表明,氨基酸在物质代谢和免疫功能调控等方面亦发挥重要作用,并提出功能性氨基酸的概念。随着各种组学技术的不断发展,通过系统生物学的理念与方法整合组学数据,系统地分析功能氨基酸的分子作用机制、药效学、体内动态过程成为可能。为此,本文提出功能氨基酸组学的概念,指出功能氨基酸组学领域的科学问题,提出功能氨基酸组学的研究内容。研究结果可用于朝向特定目标的氨基酸组合设计。     

植物应答非生物胁迫的代谢组学研究进展

代谢组学技术是研究植物代谢的理想平台, 通过现代检测分析技术对胁迫环境下植物中代谢产物进行定性和定量分析, 可以监测其随时间变化的规律。而各种组学平台包括基因组学、转录组学及代谢组学的整合, 更是一个强有力的工具箱, 将所获得的不同组学的信息联系起来, 有利于从整体研究生物系统对基因或环境变化的响应, 如可判断代谢物的变化是从哪一个层面开始发生的, 帮助人们揭开复杂的植物胁迫应答机制。该文对近期代谢组学技术及其与蛋白质组学、基因组学技术相结合探索植物应答非生物胁迫的研究进行了综述。代谢组学的应用, 拓展了对植物耐受非生物胁迫分子机制的认识, 开展更多这方面的研究, 再通过植物代谢组学、转录组学、蛋白质组学和基因组学整合, 有助于从整体水平上把握植物胁迫应答机制。     

代谢组学在临床研究中的应用及进展

代谢组学是"后基因组学"时期新兴的一门学科,也是系统生物学的重要组成部分。代谢组学通过全面、定量检测生物样本中多种类型小分子化合物,来了解在内在和外界因素作用下生物体内源性物质的变化及规律,特别适合于临床上研究机体因受到遗传、生长、生理、环境因素和异物、病源等刺激的影响而产生的变化。借助于代谢组学技术不仅能够描述疾病发生、发展以及治疗过程中机体代谢机能的状态和变化,为临床疾病的诊断、病理机制的探索、新治疗靶点的发现等提供新的途径和思路,还可以揭示外界干扰因素(药物/毒物、环境、饮食、生活方式等)对机体的影响,为药效评价和疾病病因的筛查提供基础数据。近年来,代谢组学在临床研究方面得到了广泛的应用,取得了巨大的进展并展现了鼓舞人心的应用前景。该文分别就代谢组学在描述疾病发展状态、研究疾病诊断方法、探索疾病发病原因和发病机理、药效学评价等几个方面的应用及进展进行回顾和综述。     

巨大芽胞杆菌与普通生酮基古龙酸菌共培养过程中相互作用分子机制研究进展

混菌发酵法广泛应用于维生素C前体2-酮基-L-古龙酸的生产.为进一步改善工艺,多年来,科研人员一直致力于研究发酵过程中两菌相互作用的科学本质.目前,随着组学技术、高通量技术、生物信息学和生理学等多种技术与学科的迅速发展,为深入研究相互作用分子机制提供了新的方法和工具.通过蛋白质组学、代谢组学、比较基因组学、转录组学等多种组学数据的挖掘和分析,提供了系统中各层次之间的相互作用关系网络.在此基础上结合高通量的生理学验证分析,为诠释两菌相互作用分子机制和开发代谢工程改造策略奠定了基础.本文就近些年来在该研究方向的进展及其应用进行了简要归纳,并提出进一步研究的方向.     

通过尿蛋白质组探索两种中成药对机体的整体影响

中药学作为一种独特的医学体系,是世界传统医学的重要组成部分.然而,中药组分的复杂性和多味中药的配伍应用使其发挥功效的作用机制尚不完全明确,在一定程度上阻滞了中药的现代化发展.尿液不受体内稳态的调节,这使得其能够敏感反映机体发生的变化.本研究分别建立两种中药(复方丹参滴丸和藿香正气口服液)的大鼠灌胃模型,收集健康大鼠灌胃前后的尿液,并使用液相色谱串联质谱技术(liquid chromatography-mass spectrometry, LC-MS/MS)对提取的尿蛋白进行分析,并对差异蛋白进行生物学通路的分析.与灌胃前比,在复方丹参滴丸灌胃模型组中鉴定到84个差异蛋白,在藿香正气口服液灌胃模型组中鉴定到64个差异蛋白.其中,复方丹参滴丸组差异蛋白富集到的生物学通路与其治疗心血管疾病的作用机制有关,如糖酵解、脂类代谢等.结果表明,尿液蛋白质组学可以直接系统反映中药对机体的整体影响,这提供了一种研究中药作用功效的新方法.     

代谢组学在肿瘤药物靶点筛选中的应用进展

肿瘤是一种多因素参与造成机体各系统功能平衡紊乱的代谢性疾病,代谢重编程是恶性肿瘤的重要特征之一.研究"代谢指纹图谱"的代谢组学,通过揭示肿瘤或药物引起的宿主内源性代谢物的变化,为肿瘤药物靶点的筛选提供了可能.但目前对代谢组在肿瘤药物靶点筛选中的整体性综述并不多见,因此,本文在介绍了代谢组学筛选肿瘤药物靶点的流程的基础上...     

Addressing high excitation conditions in time-resolved X-ray diffraction experiments and issues of biological relevance

One of the most important fundamental questions connecting chemistry to biology is how chemistry scales in complexity up to biological systems where there are innumerable possible pathways and competing processes. With the development of ultrabright electron and x-ray sources, it has been possible to literally light up atomic motions to directly observe the reduction in dimensionality in the barrier crossing region to a few key reaction modes. How do these chemical processes further couple to the surrounding protein or macromolecular assembly to drive biological functions? Optical methods to trigger photoactive biological processes are needed to probe this issue on the relevant timescales. However, the excitation conditions have been in the highly nonlinear regime, which questions the biological relevance of the observed structural dynamics.     

Nitric oxide bioactivity of traditional Chinese medicines used for cardiovascular indications

Traditional Chinese medicine (TCM) has been used for centuries to treat and prevent certain ailments and diseases. Although TCM has served as mainstream medical care throughout Asia for many generations, it is considered an alternative medical system in much of the Western world. Because many TCMs are used primarily for cardiovascular indications characterized by a nitric oxide (NO) insufficiency, we hypothesized that some, if not all, of these TCMs have a robust NO bioactivity that may act to restore NO homeostasis. We tested a group of convenience samples of TCMs obtained in the United States for endogenous nitrite, nitrate, nitroso, and nitrite reductase activity as well as their ability to relax isolated aortic rings. The results from this study reveal that all of the TCMs tested reveal NO bioactivity through their inherent nitrite and nitrate content and their ability to reduce nitrite to NO. Many of the TCM extracts contain a nitrite reductase activity greater by 1000 times that of biological tissues. Repletion of biological nitrite and nitrate by these extracts and providing a natural system for NO generation in both endothelium-dependent and -independent mechanisms may account for some of the therapeutic effects of TCMs.     

Current progress in computational metabolomics

Being a relatively new addition to the 'omics' field, metabolomics is still evolving its own computational infrastructure and assessing its own computational needs. Due to its strong emphasis on chemical information and because of the importance of linking that chemical data to biological consequences, metabolomics must combine elements of traditional bioinformatics with traditional cheminformatics. This is a significant challenge as these two fields have evolved quite separately and require very different computational tools and skill sets. This review is intended to familiarize readers with the field of metabolomics and to outline the needs, the challenges and the recent progress being made in four areas of computational metabolomics: (i) metabolomics databases; (ii) metabolomics LIMS; (iii) spectral analysis tools for metabolomics and (iv) metabolic modeling.     

Stroke therapy in traditional Chinese medicine (TCM): prospects for drug discovery and development.

Brain injuries resulting from stroke are a major and increasing public health problem in both developed and developing countries worldwide. China's extensive experience in the use of traditional Chinese medicines (TCMs) in stroke therapy indicates that TCM preparations are effective, with few or no side-effects. There are more than 100 traditional medicines in use for stroke therapy in China. Some of their therapeutic effects in stroke have been confirmed by recent clinical studies. A large number of compounds have been isolated from TCMs and most of these resources have not yet been characterized for pharmacological purposes. Here, this article explains how TCM provides an extensive and knowledge-rich foundation for implementing a strategically focused pharmacological research program aimed at the development of new drugs.     

Metabolomics technology and bioinformatics

Metabolomics is the global analysis of all or a large number of cellular metabolites. Like other functional genomics research, metabolomics generates large amounts of data. Handling, processing and analysis of this data is a clear challenge and requires specialized mathematical, statistical and bioinformatics tools. Metabolomics needs for bioinformatics span through data and information management, raw analytical data processing, metabolomics standards and ontology, statistical analysis and data mining, data integration and mathematical modelling of metabolic networks within a framework of systems biology. The major approaches in metabolomics, along with the modern analytical tools used for data generation, are reviewed in the context of these specific bioinformatics needs.     

LC-MS-based metabonomics analysis

Metabonomics aims at the comprehensive and quantitative analysis of wide arrays of metabolites in biological samples. It has shown particular promise in the areas of toxicology and drug development, functional genomics, systems biology, and clinical diagnosis. Comprehensive metabonomics investigations are primarily a challenge for analytical chemistry. High-performance liquid chromatography-mass spectrometry (HPLC-MS) is an established technology in drug metabolite analysis and is now expanding into endogenous metabolite research. Its main advantages include wide dynamic range, reproducible quantitative analysis, and the ability to analyze biofluids with extreme molecular complexity. The aims of developing HPLC-MS for metabonomics range from understanding basic biochemistry to biomarker discovery and the structural characterization of physiologically important metabolites. In this review, the strategy and application of HPLC-MS-based metabonomics are reviewed.