《代谢组学及其应用的评估中国传统草药品的疗效和毒性.doc》由会员分享，可在线阅读，更多相关《代谢组学及其应用的评估中国传统草药品的疗效和毒性.doc（14页珍藏版）》请在taowenge.com淘文阁网|工程机械CAD图纸|机械工程制图|CAD装配图下载|SolidWorks_CaTia_CAD_UG_PROE_设计图分享下载上搜索。
1、Journal of Chromatography B, 1026 (2016) 204216 Metabolomics and its application to the evaluation of the efcacy and toxicity of traditional Chinese herb medicines Jian Shia,b, Bei Caoa,b, Xin-Wen Wanga, Ji-Ye Aaa,c, Jin-Ao Duand, Xuan-Xuan Zhud, Guang-Ji Wanga, Chang-Xiao Liue a State Key Laborator
2、y of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, Jiangsu Key laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, China b Pharmacy Department, Drum Tower Hospital Afliated to Medical School of Nanjing University, Nanjing, China c Collab
3、orative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, China d Key Lab of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China e Research Center of New Drug Evaluation, The National Laboratory of Pharma
4、codynamics and Pharmacokinetics, Tianjin Institute of Pharmaceutical Research, Tianjin, China a r t i c l e i n f o a b s t r a c t Article history: Received 11 May 2015 Received in revised form 27 September 2015 Accepted 14 October 2015 Available online 24 November 2015 Keywords: Metabolomics Drug
5、efcacy Toxicity Traditional Chinese herb medicines Traditional Chinese herb medicines (TCHMs) have been used in the treatment of a variety of diseases for thousands of years in Asian countries. The active components of TCHMs usually exert combined synergistic therapeutic effects on multiple targets,
6、 but with less potential therapeutic effect based on routine indices than Western drugs. These complex effects make the assessment of the efcacy of TCHMs and the clarication of their underlying mechanisms very challenging, and therefore hinder their wider application and acceptance. Metabolomics is
7、a crucial part of systems biology. It allows the quantitative measurement of large numbers of the low-molecular endogenous metabolites involved in metabolic pathways, and thus reects the fundamental metabolism status of the body. Recently, dozens of metabolomic studies have been devoted to prove the
8、 efcacy/safety, explore the underlying mechanisms, and identify the potential biomarkers to access the action targets of TCHMs, with fruitful results. This arti- cle presents an overview of these studies, focusing on the progress made in exploring the pharmacology and toxicology of various herbal me
9、dicines. 2015 Elsevier B.V. All rights reserved. 1. Introduction Traditional Chinese herb medicines (TCHMs) have been used for the treatment of a variety of diseases for thousands of years in Asian countries. The major theories of TCHMs include yinyang, the ve Abbreviations: COMET, Consortium for Me
10、tabonomic Toxicology; GCMS, gas chromatographymass spectrometry; HPLC/DAD/ESIMS, high performance liquid chromatography/diode-array detection/electrospray ionizationmass spectrome- try; HPLC-MS, high performance liquid chromatography mass spectrometry; NMR, nuclear magnetic resonance; PCA, principal
11、 component analysis; PLS-DA, partial least squares discriminate analysis; SD, Sprague-Dawley; TCA, tricarboxylic acid; TCHMs, Traditional Chinese herb medicines; TCM, traditional Chinese medicine; TSG, tanshinone IIA (T), salvianolic acid B (S) and ginsenoside Rb1 (G); UPLCQ- TOF-MS, ultra-performan
12、ce liquid chromatography/quadrupole time-of-ight mass spectrometry. Corresponding author at: Key Laboratory of Drug Metabolism and Phar- macokinetics, China Pharmaceutical University, Nanjing 210009, China. Tel.: +86 25 83271081; fax: +86 25 83271060. E-mail addresses: , jiye (J.-Y. Aa). phases, Za
13、ng Fu organ theory, six-channel pattern identication, four-aspect pattern identication, etc. Among them, the principle of Yin and Yang is one of the most fundamental concept in Traditional Chinese Medicine (TCM). An imbalance of yin and yang in the body, i.e., hyperactivity or hypoactivity of yin an
14、d yang, could lead to dis- ease. TCM aims to rectify these imbalances in body using various strategies, emphasizing the holistic and personalized concepts. In general, the practitioner diagnoses patients using various methods, such as observation, smell, interrogation, and palpation, to dene a uniqu
15、e characteristic of each individual patient. Based on these information, the TCM practitioner formulates a personalized ther- apeutic strategy, including the combinations of multicomponent herbal medicines, acupuncture, exercise, diet, and lifestyle factors 1. In contrast, Western science (including
16、 Western medicine) accustomed to understanding the nature of complex things by reducing them to simpler or more fundamental elements, and has therefore been called “reductionism” 2. Reductionism has been the principal paradigm of science for at least the past 200 years. http:/dx.doi.org/10.1016/j.jc
17、hromb.2015.10.014 1570-0232/ 2015 Elsevier B.V. All rights reserved. Contents lists available at ScienceDirect Journal of Chromatography B journal homepage: J. Shi et al. / J. Chromatogr. B 1026 (2016) 204216 205 It pervades the medical and pharmaceutical sciences and deeply affects the way we diag
18、nose, treat, and prevent diseases. In fact, reductionism has achieved dramatic successes in modern medicine. However, it also has major drawbacks, such as its oversimplica- tion of complex diseases, universal side effects, and astonishing R&D expenditure 2. Currently, there is a new focus on traditi
19、onal medicine, par- ticularly TCHMs, which interact with multiple targets with fewer adverse effects and lower toxicity, such as Dan-shen extracts in the management of myocardial ischemia 3 and the Chinese medici- nal formulation Realgar-Indigo naturalis as an effective treatment for promyelocytic l
20、eukemia 4. Because two or more chemicals in these herbal medicines interact with multiple targets simulta- neously, they are considered to be rational and efcient forms of therapy designed to control complex diseases 5,6. One of the fun- damental advantages of multicomponent therapeutic agents is th
21、e production of “synergy”, whereby the combined effects of the com- ponents are greater than the sum of their individual effects. This makes multicomponent therapeutics a systematic approach, rather than a reductionist approach, which produces an additive effect. It has been observed that the combin
22、ations of agents can effectively reduce the adverse effects and ameliorate the adaptive resistance to a drug in a synergistic manner, thereby increasing the likelihood of conquering chronic complex diseases such as cancer 7. However, on the other hand, the multiple components and their effects on mu
23、ltiple targets make the assessment of TCHMs ef- cacy and the investigation of the underlying mechanisms very challenging. The key issue that the value of TCM has not been fully recognized worldwide is mainly due to the lack of scientic approaches. In recent decades, rapid progress in genomics, prote
24、omics, and metabolomics (or metabonomics) has greatly facilitated the study of systems biology, which is an exciting development 8. Gen- erally, systems biology accommodates the holistic and composite characteristics of a problem and evaluates the problem using com- putational and mathematical tools
25、, rather than reducing a complex thing to its component parts 2. The holistic properties of systems biology correspond well to those of TCM, which is also char- acterized by holistic concepts, such as the use of the multiple components of herbal medicines, and making diagnoses and evalu- ating drug
26、efcacy based on the output of the whole body, including the information from the patients pulse, smell, face, and tongue. 2. Metabolomics in TCHMs research: opportunities and challenges Metabolomics is dened as “the quantitative measurement of the dynamic multiparametric metabolic response of living
27、 systems to pathophysiological stimuli or genetic modication” by Nicholson et al. 9. It allows the quantitative measurement of large num- bers of low-molecular-weight endogenous metabolites, including lipids, amino acids, peptides, nucleic acids, organic acids, vitamins, thiols and carbohydrates, wh
28、ich have an important role in bio- logical systems and represent attractive candidates to understand phenotypes. Therefore, it is a crucial component of systems biol- ogy. Instead of assessing a few compounds in a targeted analysis, metabolomics is a non-targeted method that analyzes as many low- mo
29、lecular-weight compounds as possible, with sufciently high sensitivity 10. Metabolomics focuses on the analysis of global metabolites and their functions in the biological system, thus any factor affect- ing this system, can be reected by the metabolome. The integral and systematic study of metabolo
30、mics is in agreement with TCM theory in nature; consequently, the metabolomics may be the best approach to t the holistic concept of TCM. Therefore, the Fig. 1. Numbers of publications involved in metabolomics and Traditional Chinese medicine in recent years. introduction of the concept of metabolom
31、ics offers great and novel opportunities to reinvestigate TCM 11. In recent years, metabolomics research in various elds of TCHMs has increased dramatically as shown in Fig. 1, including efcacy/safety stud- ies, mechanistic studies, TCHM products ngerprinting studies, active/toxic components discove
32、ry studies, and so on. Despite its potential and advantages, there are still great chal- lenges for the metabolomics, especially for studies on TCHMs 12,13. One of these challenges is the high sensitivity of the metabolome to various genetic and environmental stimuli, which might make data analysis
33、and interpretation very difcult. Gen- erally, the variation in clinical studies is greater than animal and cell studies because it is harder to control the genetics, nutritional status, disease, environmental factors. So it is extremely important to have an adequate sample size to get condent conclu
34、sions. It is also helpful to minimize confounding variables by utilizing certain strategies in the design of a study such as restriction, matching and randomization. Another challenge maybe the choice of analytical platform. The main analytical methods have been discussed in several excel- lent revi
35、ews of metabolomics 12,14,15. In brief, nuclear magnetic resonance (NMR) and mass spectrometry (MS)-based techniques are the most widely used platforms in metabolomics research 9. The key advantages of NMR are its high reproduciblility and min- imal sample preparation requirement 12,16. And the anal
36、ysis process of NMR is non-destructive to samples, making it possi- ble to facilitate other related studies especially when the samples are scarce and precious. Furthermore, NMR could provide struc- tural information which is quite useful in the identication of unknown metabolites. However, the majo
37、r limitations of NMR include lower sensitivity (usually 110 mol/L) and resolution compared to MS-based techniques 17. MS, usually coupled with separation techniques, particularly liquid chromatography (LC) and gas chromatography (GC), have much higher resolution and sensi- tivity than NMR, although
38、it has lower reproducibility. Therefore, MS-based techniques have the ability to detect a huge number of metabolites with a broad range of concentrations in a biological sample. Generally, GC/MS is often simpler, faster and give higher resolution than LC/MS, but it could not deal with the metabolite
39、s which cannot be readily derivatized and volatilized. For the LC/MS, the many different separation modes, such as normal phase liq- uid chromatography, reversed phase liquid chromatography and hydrophilic interaction chromatography, make it a more exible method than GC/MS. Normally, the choice depe
40、nds on the purpose of the study and the nature of the samples, as each method has its own advantages and disadvantages. In fact, due to the large 206 J. Shi et al. / J. Chromatogr. B 1026 (2016) 204216 number of metabolites, physicochemical diversity, wide concen- tration range of the metabolome and
41、 the complications of herbal medicines, the integrated approaches have been frequently used to provide sensitive, accurate and reliable results. This article reviews the current progress of metabolomics in the study of herbal medicines, focusing on the application of metabolomics to the assessment o
42、f drug efcacy and toxicity in TCHMs. 3. Metabolomic approach to evaluating drug efcacy in TCHMs Any disturbance on living systems, regardless of physiological, pathological, or other factors, will cause changes in the metabo- lites. Therefore the metabolome represents the physiological or pathologic
43、al status of organisms. So theoretically, we can simply determine the effect of TCHMs by the global metabolome state, regardless of the complex components of TCHMs. A successful treatment or therapy can normalize the perturbed metabolism of the disease state so that the overall systemic environment
44、and the levels of metabolites are restored to the normal state. In addition to the classic criteria for assessing drug efcacy, metabolomic stud- ies offer two novel criteria: the dynamic restoration of the treated samples to normal, shown in a scores plot, and the relative levels of the metabolic ma
45、rkers that characterize the effectiveness of the TCHM treatment. Recent metabolomics studies on the efcacy of TCHMs were summarized in Supplemental Table 1. 3.1. Verify the efcacy of TCHMs 3.1.1. Single- or multiple-component of TCHMs Metabolomic studies have demonstrated the efcacy of the active co
46、mponents of herbal medicines. For examples, Wang et al. have demonstrated that the ginsenoside Rg3 extracted from ginseng had a considerable impact on the metabolic prole in a liver-tumor-bearing rats model after three days treat- ment using an automatic hydrophilic interaction/reversed-phase column
47、-switching HPLC-ESIMS 18. Berberine was found to play a role in the treatment of type 2 diabetes by down-regulating the high levels of free fatty acids in a 60 patients clinical metabolomic study using ultra-performance liquid chromatography quadrupole time of ight mass spectrom- etry (UPLCQ-TOF-MS)
48、 19. Hydroxysafor yellow A, the main active component of the Chinese herb Carthamus tinctorius L., can improve the neurological functions of rats with ischemia by mod- ulating the metabolic perturbation involved in energy metabolism, excitatory amino acids, oxidative stress 20. MDG-1, A polysac- cha
49、ride from Ophiopogon japonicus, actions against diabetes was accomplished by the absorbable monosugars and butanedioic acid on inhibiting intestinal glucose absorption and glycogenolysis, and enhancing liver glycogenesis 21. Geniposide, an important constituent of Gardenia jasminoides Ellis, has potential pharmacological effect on preven