基于色谱—质谱联用的知母总皂苷抗阿尔茨海默症的药效筛选研究
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摘要
中药是中华医药学的宝贵财富，对其进行系统的研究对于继承和发展中药，并得到全世界的认同，具有非常显著的意义。尽管在中国已经应用了几千年历史，但当前中药还难以走向世界，得到国际药学同行认可，主要原因包括：(1)物质基础不明确；(2)作用机制不清楚；(3)缺乏有效手段来评价中药疗效及传统中医理论的正确性。
知母甾体皂苷具有良好的预防中枢神经系统疾病的疗效，但是其复杂的化学成分和生物利用度，特别是能够透过血脑屏障的皂苷成分及其代谢产物相关研究的大大阻碍了其用于大脑神经功能紊乱治疗药物的进展。本论文综合了多维色谱质谱联用，微透析采样，代谢组学及模式识别处理技术等药物分析学科前沿的手段和方法，系统开展了知母总皂苷成分，药效机理与阿尔茨海默症致病机制的全面研究，并为其它中药-疾病这种典型的“系统对系统”的研究模式提供参考。
1.发展了一种新的全二维液相色谱-质谱联用技术，以反相色谱(RPLC)用作第一相分离，聚胺色谱(polyamine II)用作第二相分离。该二维色谱不仅简化了复杂的植物样品制备过程，同时也扩大了峰容量增加了灵敏度，还具有高度的正交性(γ<0.2)。这些优势使该方法成功应用于复杂的知母总皂苷体系中共洗脱和微量物质的分离。本实验运用该方法成功的鉴定了31中化合物，包括5种微量化合物和4种甾体类同分异构体。该方法可作为复杂体系不分离分析的研究示范。
2.采用微透析采样结合UHPLC/QTOFMS方法检测口服知母总皂苷后大鼠血液循环中未结合成分，这些成分被认为很可能就是知母发挥药效的潜在活性成分。通过精确分子量计算和详细的裂解途经分析，得到包括七种原型成分和六种代谢产物，其中有三种代谢物之前未见报道而在本研究中首次得到鉴别。与传统的生物采样技术相比，微透析技术具有体内直接取样，组织损伤轻，实时监测及样品制备简单等优点。我们的研究证明，微透析取样辅助飞行时间质谱能够有效地在体内同时分析多种有潜在重要生物功能的微量成分。该方法的一些重要的优势包括分析时间短，不出现带同位素标记的化合物，使用简便。本研究可作为中药在哺乳动物体内代谢及药效物质成分筛选重要的研究策略。
3.本研究建立了动态微透析采样偶联UHPLC/QTOFMS的方法和基于代谢组学数据处理技术，分析检测口服知母总皂苷(TSA)的大鼠海马微透析液，共鉴定得到10种知母皂苷/代谢产物，并采用半定量的方法实时监测得到了它们在海马中浓度的动态变化。通过比较这些皂苷的药动学参数，发现知母皂苷A-III和脱氢萨尔萨皂甙元因具有更快的吸收，较慢的代谢，更高的峰浓度和更大的血药浓度曲线下面积值，因此可作为药代标示物的候选成分。另外，动物行为学的评价结果也和药动学数据一致，进一步证明了上述两种成分是知母总皂苷(TSA)神经保护作用的生物标志物。本研究表明，基于UHPLC/QTOFMS的代谢组学数据处理方法进行药动学筛选不仅可以用于中药发挥CNS疗效的潜在活性成分研究，也可以帮助我们更好的预测天然产物中新的脑靶标成分。
4.尽管近年来对阿尔茨海默症(AD)的发病机理及抗AD药物的研发，但是对于诊断AD及监测药物的资料疗效的生物标志物仍然未知。代谢组学能够提供一种有效的手段有效地发现治疗和诊断的生物标志物，他通过全面系统地分析个体对疾病刺激或者药物干预后个体的代谢物相应。在本文中，使用了GC-MS、HILIC-MS和RPLC-MS的三种手段联合检测手段，用来分析AD相关的代谢物和讲清楚知母总皂苷干预的机理。通过多元统计学分析，一共有21个生物标志物被筛选出来，其中异-肌醇、尿酸和色氨酸能够帮助AD组和对照组进行最大的区分。能量代谢、抗氧化防御系统、神经递质代谢、脂肪酸合成和磷脂在AD组中全部失调，但在给予知母总皂苷后能够部分回调。这些研究工作为寻找AD新的靶标及更有效的治疗药物奠定基础。
Traditional Chinese medicine (TCM) is the valuable treasure of Chinesepharmacology. It is very important to explore its action mechanism systematically anddevelop it drastically, then make it win the world recognition. Although it has beenused clically for thousands of years, it can not march towards the world with activeposture. The major reason lies in three key points:(1) the real bioactive componentsare not clear;(2) exact action mechanism is unambiguous;(3) there is insufficienteffective method to assess the safty of TCM and the theory of TCM uptill now.While steroid glycosides have many health benefits, the potential development ofthem for the prevention/treatment of neurological disorders is largely hindered bytheir complexity as well as by limited knowledge regarding their bioavailability,metabolism, and bioactivity, especially in the brain. This study integrated multiplemodern methodologies and techniques in the discipline of Pharmaceutical Analysisincluding multiple-dimensional liquid chromatography tandem mass, microdialysissampling, metabolomics and pattern recognition methods. The aim of this paper wasto systematically discuss the chemical substances and mechanism of TSA, and tooffer the reference of technology for related investigation of other herbal medicine.
1. In the work presented here a novel approach to comprehensive two-dimensionalliquid chromatography is evaluated. Reversed-phase liquid chromatography wasemployed for the frst-dimension separation and polyamine chromatography waschosen for the second-dimension separation mode. The comprehensive RP×polyamine II-MS system proposed here not only simplifed complex plant samples,but also enlarged peak capacity and enhanced selectivity. The two dimensions arehighly orthogonal and the separation efficacy of the developed octadecylsilica×polyamine was tested by separating an extract from Anemarrhena asphodeloides. Thisallowed for the successful separation of co-eluted and minor compounds. As a result,a total of31compounds, including5compounds of low amount and4steroid isomerswere unambiguously identifed with this approach. In contrast only22compounds, allof which were highly abundant in their samples, could be identifed usingconventional1D-LC. This method could be considered as an important demonstrationfor “nonseparation analysis” of complex system.
2. The present work aims to elucidate the multi-component metabolic characteristics of herbal medicine by the combination of plasma pharmacochemistry andmicrodialysis sampling. Anemarrhena asphodeloides, a well-known traditionalChinese medicine, was chosen as a model. After oral administration of A.asphodeloides saponin extract to rats, microdialysis samples were collectedcontinuously in the jugular vein and analyzed by ultrahigh-performance liquidchromatography/quadrupole-time-of-fight mass spectrometry. The identification ofcompounds in bio-samples was achieved by accurate mass measurement and detailedfragmentation pathway analysis. The results showed that unbound constituents inblood circulation of the rat included seven parent saponins and six metabolites, whichmight be the potential active components in vivo. Among which, three metaboliteshave not been previously reported and were identifed in this study. Compared withconventional biological sampling techniques, microdialysis offers direct in vivosampling, low invasiveness, real-time monitoring and simple sample preparation. Asdemonstrated in our study, microdialysis sampling assisted QTOFMS effectively forsimultaneous analysis of multiple minor drug metabolites with potentially importantfunctions in vivo. Some important advantages of this approach are: the short analysistime, the absence of any unlabelled compounds, and also the ease of use. In summary,this developed method is generally applicable to include more active componentsscreening of TCM in mammalian body and to better clarify its pharmacological actionmechanism.
3. We established a dynamic microdialysis sampling method coupled withultrahigh-performance liquid chromatography/quadrupole-time-of-fight massspectrometry (UHPLC/QTOFMS) based metabolomics. By using this approach, tensaponins/metabolites have been identified in rat hippocampus microdialysates after asingle oral administration of total saponins of Anemarrhena asphodeloides (TSA), andthe pharmacokinetic behaviors of them were real-time monitored. Comparing thebody dynamics of each constituent, timosaponin A-III and dehydrogenatedsarsasapogenin, with faster absorption, slower metabolism, higher peak concentrationand larger AUC values were considered to be candidate hit. Furthermore, behavioralassessment was consistent with pharmacokinetic data, which suggested these twocomponents were bioactive markers in TSA for its neuroprotective effects. This is thefirst attempt to systematically reveal the in vivo process of steroid glycoside in thebrain. Our results indicated that pharmacokinetics screening using UHPLC/QTOFMSbased metabolomics can not only be used to explore potential active components contributing to central nervous system (CNS) pharmacological effects of herbalmedicine, but also to get a promising perspective of new brain-targeted leads in drugdiscovery from natural agents.
4. Despite recent advances in understanding the pathophysiology of dementia and themechanisms of anti-dementia drug action, the development of biomarkers fordiagnosis and therapeutic monitoring in dementia remains challenging. Metabolomicsprovides a powerful approach to discover diagnostic and therapeutic biomarkers byanalyzing global changes in an individual’s metabolic profle in response topathophysiological stimuli or drug therapy. In this study, we performed combined gaschromatography-mass spectrometry (GC-MS), reversed-phase iquidchromatography mass spectrometry (RPLC-MS) and a hydrophilic interaction liquidchromatography-mass spectrometry (HILIC-MS)-based metabonomics in serum ofscopolamine-induced demented rat models before and after2-week total saponins ofAnemarrhena asphodeloides (TSA) treatment, to detect potential biomarkersassociated with dementia and intervention effects of TSA. Twenty-one markermetabolites contributing to the complete separation of demented rats from matchedhealthy controls were identifed, with myo-inositol, uric acid, and tryptophan showingthe maximum combined classifcation performance. Metabolic pathways includingenergy metabolism, antioxidant defense systems, neurotransmitter metabolism, fattyacid biosynthesis, and phospholipid metabolism were found to be disturbed indemented rats and partially normalized following TSA treatment. Further study ofthese metabolites may facilitate the development of new potential biomarkers andmore efficient therapeutic strategies for dementia.
知母甾体皂苷具有良好的预防中枢神经系统疾病的疗效，但是其复杂的化学成分和生物利用度，特别是能够透过血脑屏障的皂苷成分及其代谢产物相关研究的大大阻碍了其用于大脑神经功能紊乱治疗药物的进展。本论文综合了多维色谱质谱联用，微透析采样，代谢组学及模式识别处理技术等药物分析学科前沿的手段和方法，系统开展了知母总皂苷成分，药效机理与阿尔茨海默症致病机制的全面研究，并为其它中药-疾病这种典型的“系统对系统”的研究模式提供参考。
1.发展了一种新的全二维液相色谱-质谱联用技术，以反相色谱(RPLC)用作第一相分离，聚胺色谱(polyamine II)用作第二相分离。该二维色谱不仅简化了复杂的植物样品制备过程，同时也扩大了峰容量增加了灵敏度，还具有高度的正交性(γ<0.2)。这些优势使该方法成功应用于复杂的知母总皂苷体系中共洗脱和微量物质的分离。本实验运用该方法成功的鉴定了31中化合物，包括5种微量化合物和4种甾体类同分异构体。该方法可作为复杂体系不分离分析的研究示范。
2.采用微透析采样结合UHPLC/QTOFMS方法检测口服知母总皂苷后大鼠血液循环中未结合成分，这些成分被认为很可能就是知母发挥药效的潜在活性成分。通过精确分子量计算和详细的裂解途经分析，得到包括七种原型成分和六种代谢产物，其中有三种代谢物之前未见报道而在本研究中首次得到鉴别。与传统的生物采样技术相比，微透析技术具有体内直接取样，组织损伤轻，实时监测及样品制备简单等优点。我们的研究证明，微透析取样辅助飞行时间质谱能够有效地在体内同时分析多种有潜在重要生物功能的微量成分。该方法的一些重要的优势包括分析时间短，不出现带同位素标记的化合物，使用简便。本研究可作为中药在哺乳动物体内代谢及药效物质成分筛选重要的研究策略。
3.本研究建立了动态微透析采样偶联UHPLC/QTOFMS的方法和基于代谢组学数据处理技术，分析检测口服知母总皂苷(TSA)的大鼠海马微透析液，共鉴定得到10种知母皂苷/代谢产物，并采用半定量的方法实时监测得到了它们在海马中浓度的动态变化。通过比较这些皂苷的药动学参数，发现知母皂苷A-III和脱氢萨尔萨皂甙元因具有更快的吸收，较慢的代谢，更高的峰浓度和更大的血药浓度曲线下面积值，因此可作为药代标示物的候选成分。另外，动物行为学的评价结果也和药动学数据一致，进一步证明了上述两种成分是知母总皂苷(TSA)神经保护作用的生物标志物。本研究表明，基于UHPLC/QTOFMS的代谢组学数据处理方法进行药动学筛选不仅可以用于中药发挥CNS疗效的潜在活性成分研究，也可以帮助我们更好的预测天然产物中新的脑靶标成分。
4.尽管近年来对阿尔茨海默症(AD)的发病机理及抗AD药物的研发，但是对于诊断AD及监测药物的资料疗效的生物标志物仍然未知。代谢组学能够提供一种有效的手段有效地发现治疗和诊断的生物标志物，他通过全面系统地分析个体对疾病刺激或者药物干预后个体的代谢物相应。在本文中，使用了GC-MS、HILIC-MS和RPLC-MS的三种手段联合检测手段，用来分析AD相关的代谢物和讲清楚知母总皂苷干预的机理。通过多元统计学分析，一共有21个生物标志物被筛选出来，其中异-肌醇、尿酸和色氨酸能够帮助AD组和对照组进行最大的区分。能量代谢、抗氧化防御系统、神经递质代谢、脂肪酸合成和磷脂在AD组中全部失调，但在给予知母总皂苷后能够部分回调。这些研究工作为寻找AD新的靶标及更有效的治疗药物奠定基础。
Traditional Chinese medicine (TCM) is the valuable treasure of Chinesepharmacology. It is very important to explore its action mechanism systematically anddevelop it drastically, then make it win the world recognition. Although it has beenused clically for thousands of years, it can not march towards the world with activeposture. The major reason lies in three key points:(1) the real bioactive componentsare not clear;(2) exact action mechanism is unambiguous;(3) there is insufficienteffective method to assess the safty of TCM and the theory of TCM uptill now.While steroid glycosides have many health benefits, the potential development ofthem for the prevention/treatment of neurological disorders is largely hindered bytheir complexity as well as by limited knowledge regarding their bioavailability,metabolism, and bioactivity, especially in the brain. This study integrated multiplemodern methodologies and techniques in the discipline of Pharmaceutical Analysisincluding multiple-dimensional liquid chromatography tandem mass, microdialysissampling, metabolomics and pattern recognition methods. The aim of this paper wasto systematically discuss the chemical substances and mechanism of TSA, and tooffer the reference of technology for related investigation of other herbal medicine.
1. In the work presented here a novel approach to comprehensive two-dimensionalliquid chromatography is evaluated. Reversed-phase liquid chromatography wasemployed for the frst-dimension separation and polyamine chromatography waschosen for the second-dimension separation mode. The comprehensive RP×polyamine II-MS system proposed here not only simplifed complex plant samples,but also enlarged peak capacity and enhanced selectivity. The two dimensions arehighly orthogonal and the separation efficacy of the developed octadecylsilica×polyamine was tested by separating an extract from Anemarrhena asphodeloides. Thisallowed for the successful separation of co-eluted and minor compounds. As a result,a total of31compounds, including5compounds of low amount and4steroid isomerswere unambiguously identifed with this approach. In contrast only22compounds, allof which were highly abundant in their samples, could be identifed usingconventional1D-LC. This method could be considered as an important demonstrationfor “nonseparation analysis” of complex system.
2. The present work aims to elucidate the multi-component metabolic characteristics of herbal medicine by the combination of plasma pharmacochemistry andmicrodialysis sampling. Anemarrhena asphodeloides, a well-known traditionalChinese medicine, was chosen as a model. After oral administration of A.asphodeloides saponin extract to rats, microdialysis samples were collectedcontinuously in the jugular vein and analyzed by ultrahigh-performance liquidchromatography/quadrupole-time-of-fight mass spectrometry. The identification ofcompounds in bio-samples was achieved by accurate mass measurement and detailedfragmentation pathway analysis. The results showed that unbound constituents inblood circulation of the rat included seven parent saponins and six metabolites, whichmight be the potential active components in vivo. Among which, three metaboliteshave not been previously reported and were identifed in this study. Compared withconventional biological sampling techniques, microdialysis offers direct in vivosampling, low invasiveness, real-time monitoring and simple sample preparation. Asdemonstrated in our study, microdialysis sampling assisted QTOFMS effectively forsimultaneous analysis of multiple minor drug metabolites with potentially importantfunctions in vivo. Some important advantages of this approach are: the short analysistime, the absence of any unlabelled compounds, and also the ease of use. In summary,this developed method is generally applicable to include more active componentsscreening of TCM in mammalian body and to better clarify its pharmacological actionmechanism.
3. We established a dynamic microdialysis sampling method coupled withultrahigh-performance liquid chromatography/quadrupole-time-of-fight massspectrometry (UHPLC/QTOFMS) based metabolomics. By using this approach, tensaponins/metabolites have been identified in rat hippocampus microdialysates after asingle oral administration of total saponins of Anemarrhena asphodeloides (TSA), andthe pharmacokinetic behaviors of them were real-time monitored. Comparing thebody dynamics of each constituent, timosaponin A-III and dehydrogenatedsarsasapogenin, with faster absorption, slower metabolism, higher peak concentrationand larger AUC values were considered to be candidate hit. Furthermore, behavioralassessment was consistent with pharmacokinetic data, which suggested these twocomponents were bioactive markers in TSA for its neuroprotective effects. This is thefirst attempt to systematically reveal the in vivo process of steroid glycoside in thebrain. Our results indicated that pharmacokinetics screening using UHPLC/QTOFMSbased metabolomics can not only be used to explore potential active components contributing to central nervous system (CNS) pharmacological effects of herbalmedicine, but also to get a promising perspective of new brain-targeted leads in drugdiscovery from natural agents.
4. Despite recent advances in understanding the pathophysiology of dementia and themechanisms of anti-dementia drug action, the development of biomarkers fordiagnosis and therapeutic monitoring in dementia remains challenging. Metabolomicsprovides a powerful approach to discover diagnostic and therapeutic biomarkers byanalyzing global changes in an individual’s metabolic profle in response topathophysiological stimuli or drug therapy. In this study, we performed combined gaschromatography-mass spectrometry (GC-MS), reversed-phase iquidchromatography mass spectrometry (RPLC-MS) and a hydrophilic interaction liquidchromatography-mass spectrometry (HILIC-MS)-based metabonomics in serum ofscopolamine-induced demented rat models before and after2-week total saponins ofAnemarrhena asphodeloides (TSA) treatment, to detect potential biomarkersassociated with dementia and intervention effects of TSA. Twenty-one markermetabolites contributing to the complete separation of demented rats from matchedhealthy controls were identifed, with myo-inositol, uric acid, and tryptophan showingthe maximum combined classifcation performance. Metabolic pathways includingenergy metabolism, antioxidant defense systems, neurotransmitter metabolism, fattyacid biosynthesis, and phospholipid metabolism were found to be disturbed indemented rats and partially normalized following TSA treatment. Further study ofthese metabolites may facilitate the development of new potential biomarkers andmore efficient therapeutic strategies for dementia.
引文
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[1] Y. Zhang, P. Shi, H. Yao, Q. Shao, X. Fan, Metabolite profiling and pharmacokinetics of herbalcompounds following oral administration of a cardiovascular multi-herb medicine (Qishen yiqipills) in rats, Curr Drug Metab,13(2012)510-523.
[2] J. van der Greef, S. Martin, P. Juhasz, A. Adourian, T. Plasterer, E.R. Verheij, R.N. McBurney,The art and practice of systems biology in medicine: mapping patterns of relationships, JProteome Res,6(2007)1540-1559.
[3] M. Homma, K. Oka, T. Yamada, T. Niitsuma, H. Ihto, N. Takahashi, A strategy for discoveringbiologically active compounds with high probability in traditional Chinese herb remedies: anapplication of saiboku-to in bronchial asthma, Anal Biochem,202(1992)179-187.
[4] C. Wang, S. Wang, G. Fan, H. Zou, Screening of antinociceptive components in Corydalisyanhusuo W.T. Wang by comprehensive two-dimensional liquid chromatography/tandem massspectrometry, Anal Bioanal Chem,396(2010)1731-1740.
[5] L. Novakova, H. Vlckova, A review of current trends and advances in modern bio-analyticalmethods: chromatography and sample preparation, Anal Chim Acta,656(2009)8-35.
[6] P. Nandi, S.M. Lunte, Recent trends in microdialysis sampling integrated with conventionaland microanalytical systems for monitoring biological events: A review, Analytica Chimica Acta,651(2009)1-14.
[7] C. Xue, J. Guo, D. Qian, J.-a. Duan, E. Shang, Y. Shu, Y. Lu, Identification of the potentialactive components of Abelmoschus manihot in rat blood and kidney tissue by microdialysiscombined with ultra-performance liquid chromatography/quadrupole time-of-flight massspectrometry, Journal of Chromatography B,879(2011)317-325.
[8] X.-D. Wen, J. Yang, R.-H. Ma, W. Gao, L.-W. Qi, P. Li, B.A. Bauer, G.-J. Du, Z. Zhang, J.Somogyi, C.-Z. Wang, C.-S. Yuan, Analysis of Panax notoginseng metabolites in rat bile by liquidchromatography–quadrupole time-of-flight mass spectrometry with microdialysis sampling,Journal of Chromatography B,895-896(2012)162-168.
[9] G. Cao, H. Cai, Y. Zhang, X. Cong, C. Zhang, B. Cai, Identification of metabolites of crudeand processed Fructus Corni in rats by microdialysis sampling coupled with electrosprayionization linear quadrupole ion trap mass spectrometry, Journal of Pharmaceutical andBiomedical Analysis,56(2011)118-125.
[10] D. Guillarme, J. Schappler, S. Rudaz, J.-L. Veuthey, Coupling ultra-high-pressure liquidchromatography with mass spectrometry, TrAC Trends in Analytical Chemistry,29(2010)15-27.
[11] C.P. Committee, Pharmacopoeia of the People's Republic of China, Vol.1, People's MedicalPublishing House, Beijing,(2010)197-198.
[12] S. Ouyang, L.S. Sun, S.L. Guo, X. Liu, J.P. Xu, Effects of timosaponins on learning andmemory abilities of rats with dementia induced by lateral cerebral ventricular injection of amyloidbeta-peptide, Di Yi Jun Yi Da Xue Xue Bao,25(2005)121-126.
[13] F.W. King, S. Fong, C. Griffin, M. Shoemaker, R. Staub, Y.L. Zhang, I. Cohen, E. Shtivelman,Timosaponin AIII is preferentially cytotoxic to tumor cells through inhibition of mTOR andinduction of ER stress, PLoS One,4(2009) e7283.
[14] B. Lee, K. Jung, D.-H. Kim, Timosaponin AIII, a saponin isolated from Anemarrhenaasphodeloides, ameliorates learning and memory deficits in mice, Pharmacology Biochemistryand Behavior,93(2009)121-127.
[15] T.J. Li, Y. Qiu, P.Y. Yang, Y.C. Rui, W.S. Chen, Timosaponin B-II improves memory andlearning dysfunction induced by cerebral ischemia in rats, Neurosci Lett,421(2007)147-151.
[16] Y. Hu, Z. Xia, Q. Sun, A. Orsi, D. Rees, A new approach to the pharmacological regulation ofmemory: Sarsasapogenin improves memory by elevating the low muscarinic acetylcholinereceptor density in brains of memory-deficit rat models, Brain Res,1060(2005)26-39.
[17] Z. Meng, S. Xu, L. Meng,[Timosaponins E1and E2], Yao Xue Xue Bao,33(1998)693-696.
[18] K. Wang, Z. Zhu, L. Yang, Y. Gao, W. Liu, H. Zhang, Y. Chai, Detection, characterization andidentification of major constituents in Zhimu-Baihe herb-pair extract by fast high-performanceliquid chromatography and time-of-flight mass spectrometry through dynamic adjustment offragmentor voltage, Rapid Commun Mass Spectrom,25(2011)9-19.
[19] Z. Liu, D. Zhu, Y. Qi, X. Chen, Z. Zhu, Y. Chai, Elucidation of steroid glycosides inAnemarrhena asphodeloides extract by means of comprehensive two-dimensionalreversed-phase/polyamine chromatography with mass spectrometric detection, Journal ofseparation science,35(2012)2210-2218.
[20] Y. Sun, Y. Du, Y. Liu, L. Chang, Y. Ren, L. Cao, Q. Sun, X. Shi, Q. Wang, L. Zhang,Simultaneous determination of nine components in Anemarrhena asphodeloides by liquidchromatography-tandem mass spectrometry combined with chemometric techniques, Journal ofseparation science,35(2012)1796-1807.
[21] Z. Liu, D. Zhu, L. Lv, Y. Li, X. Dong, Z. Zhu, Y. Chai, Metabolism profile of timosaponinB-II in urine after oral administration to rats by ultrahigh-performance liquidchromatography/quadrupole-time-of-flight mass spectrometry, Rapid Commun Mass Spectrom,26(2012)1955-1964.
[22] F. Cai, L. Sun, S. Gao, Y. Yang, Q. Yang, W. Chen, A rapid and sensitive liquidchromatography-tandem mass spectrometric method for the determination of timosaponin B-II inblood plasma and a study of the pharmacokinetics of saponin in the rat, J Pharm Biomed Anal,48(2008)1411-1416.
[23] D. Yeniceli, E. ener, O.T. Korkmaz, D. Do rukol-Ak, N. Tuncel, A simple and sensitiveLC–ESI-MS (ion trap) method for the determination of bupropion and its major metabolite,hydroxybupropion in rat plasma and brain microdialysates, Talanta,84(2011)19-26.
[24] G.C. Kite, E.A. Porter, M.S. Simmonds, Chromatographic behaviour of steroidal saponinsstudied by high-performance liquid chromatography-mass spectrometry, J Chromatogr A,1148(2007)177-183.
[25] Y. Liu, F. Liang, L. Cui, M. Xia, L. Zhao, Y. Yang, J. Shi, Z. Abliz, Multi-stage massspectrometry of furostanol saponins combined with electrospray ionization in positive andnegative ion modes, Rapid Commun Mass Spectrom,18(2004)235-238.
[26] F. Liang, L. Li, Z. Abliz, Y. Yang, J. Shi, Structural characterization of steroidal saponins byelectrospray ionization and fast-atom bombardment tandem mass spectrometry, Rapid CommunMass Spectrom,16(2002)1168-1173.
[27] C. Ma, M. Fan, Y. Tang, Z. Li, Z. Sun, G. Ye, C. Huang, Identification of major alkaloids andsteroidal saponins in rat serum by HPLC-diode array detection-MS/MS following oraladministration of Huangbai-Zhimu herb-pair Extract, Biomed Chromatogr,22(2008)835-850.
[28] X.-Y. Guan, H.-F. Li, W.-Z. Yang, C.-H. Lin, C. Sun, B.-R. Wang, D.-A. Guo, M. Ye,HPLC-DAD–MSn analysis and HPLC quantitation of chemical constituents in Xian-ling-gu-baocapsules, Journal of Pharmaceutical and Biomedical Analysis,55(2011)923-933.
[29] Y.M. Hu, Y.T. Wang, S.C.W. Sze, K.W. Tsang, H.K. Wong, Q. Liu, L.D. Zhong, Y. Tong,Identification of the major chemical constituents and their metabolites in rat plasma and variousorgans after oral administration of effective Erxian Decoction (EXD) fraction by liquidchromatography-mass spectrometry, Biomedical Chromatography,(2009) n/a-n/a.
[30] C. Ma, L. Wang, Y. Tang, M. Fan, H. Xiao, C. Huang, Identification of major xanthones andsteroidal saponins in rat urine by liquid chromatography-atmospheric pressure chemical ionizationmass spectrometry technology following oral administration of Rhizoma Anemarrhenae decoction,Biomed Chromatogr,22(2008)1066-1083.
[31] L. Wang, X. Wang, X. Yuan, B. Zhao, Simultaneous analysis of diosgenin and sarsasapogeninin Asparagus officinalis byproduct by thin-layer chromatography, Phytochem Anal,22(2011)14-17.
[32] X. He, A. Qiao, X. Wang, B. Liu, M. Jiang, L. Su, X. Yao, Structural identification of methylprotodioscin metabolites in rats' urine and their antiproliferative activities against human tumorcell lines, Steroids,71(2006)828-833.
[33] S.E. Jantti, A. Tammimaki, H. Raattamaa, P. Piepponen, R. Kostiainen, R.A. Ketola,Determination of steroids and their intact glucuronide conjugates in mouse brain by capillaryliquid chromatography-tandem mass spectrometry, Anal Chem,82(2010)3168-3175.
[1] J. Zhang, F. Zhou, M. Lu, W. Ji, F. Niu, W. Zha, X. Wu, H. Hao, G. Wang,Pharmacokinetics-pharmacology disconnection of herbal medicines and its potential solutions with cellularpharmacokinetic-pharmacodynamic strategy, Curr Drug Metab,13(2012)558-576.
[2] I. Kola, J. Landis, Can the pharmaceutical industry reduce attrition rates?, Nat Rev Drug Discov,3(2004)711-715.
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[6] Q.Y. Zhang, J.H. Mao, P. Liu, Q.H. Huang, J. Lu, Y.Y. Xie, L. Weng, Y. Zhang, Q. Chen, S.J. Chen, Z.Chen, A systems biology understanding of the synergistic effects of arsenic sulfide and Imatinib inBCR/ABL-associated leukemia, Proc Natl Acad Sci U S A,106(2009)3378-3383.
[7] Z. Liu, Z. Zhu, H. Zhang, G. Tan, X. Chen, Y. Chai, Qualitative and quantitative analysis of FructusCorni using ultrasound assisted microwave extraction and high performance liquid chromatographycoupled with diode array UV detection and time-of-flight mass spectrometry, Journal of Pharmaceuticaland Biomedical Analysis,55(2011)557-562.
[8] A.R. Fontana, I. Rodriguez, M. Ramil, J.C. Altamirano, R. Cela, Solid-phase extraction followed byliquid chromatography quadrupole time-of-flight tandem mass spectrometry for the selective determinationof fungicides in wine samples, J Chromatogr A,1218(2011)2165-2175.
[9] X. Wang, H. Sun, A. Zhang, G. Jiao, W. Sun, Y. Yuan, Pharmacokinetics screening formulti-components absorbed in the rat plasma after oral administration traditional Chinese medicine formulaYin-Chen-Hao-Tang by ultra performance liquid chromatography-electrosprayionization/quadrupole-time-of-flight mass spectrometry combined with pattern recognition methods,Analyst,136(2011)5068-5076.
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[12] B. Lee, K. Jung, D.H. Kim, Timosaponin AIII, a saponin isolated from Anemarrhena asphodeloides,ameliorates learning and memory deficits in mice, Pharmacol Biochem Behav,93(2009)121-127.
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[22] G.C. Kite, E.A. Porter, M.S. Simmonds, Chromatographic behaviour of steroidal saponins studied byhigh-performance liquid chromatography-mass spectrometry, J Chromatogr A,1148(2007)177-183.
[23] Z. Liu, D. Zhu, L. Lv, Y. Li, X. Dong, Z. Zhu, Y. Chai, Metabolism profile of timosaponin B-II in urineafter oral administration to rats by ultrahigh-performance liquid chromatography/quadrupole-time-of-flightmass spectrometry, Rapid Commun Mass Spectrom,26(2012)1955-1964.
[24] X. He, A. Qiao, X. Wang, B. Liu, M. Jiang, L. Su, X. Yao, Structural identification of methylprotodioscin metabolites in rats' urine and their antiproliferative activities against human tumor cell lines,Steroids,71(2006)828-833.
[1] Y. Zhang, P. Shi, H. Yao, Q. Shao, X. Fan, Metabolite profiling and pharmacokinetics of herbalcompounds following oral administration of a cardiovascular multi-herb medicine (Qishen yiqi pills) in rats,Curr Drug Metab,13(2012)510-523.
[2] J. van der Greef, S. Martin, P. Juhasz, A. Adourian, T. Plasterer, E.R. Verheij, R.N. McBurney, The artand practice of systems biology in medicine: mapping patterns of relationships, J Proteome Res,6(2007)1540-1559.
[3] M. Homma, K. Oka, T. Yamada, T. Niitsuma, H. Ihto, N. Takahashi, A strategy for discoveringbiologically active compounds with high probability in traditional Chinese herb remedies: an application ofsaiboku-to in bronchial asthma, Anal Biochem,202(1992)179-187.
[4] C. Wang, S. Wang, G. Fan, H. Zou, Screening of antinociceptive components in Corydalis yanhusuoW.T. Wang by comprehensive two-dimensional liquid chromatography/tandem mass spectrometry, AnalBioanal Chem,396(2010)1731-1740.
[5] L. Novakova, H. Vlckova, A review of current trends and advances in modern bio-analytical methods:chromatography and sample preparation, Anal Chim Acta,656(2009)8-35.
[6] P. Nandi, S.M. Lunte, Recent trends in microdialysis sampling integrated with conventional andmicroanalytical systems for monitoring biological events: A review, Analytica Chimica Acta,651(2009)1-14.
[7] C. Xue, J. Guo, D. Qian, J.-a. Duan, E. Shang, Y. Shu, Y. Lu, Identification of the potential activecomponents of Abelmoschus manihot in rat blood and kidney tissue by microdialysis combined withultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry, Journal ofChromatography B,879(2011)317-325.
[8] X.-D. Wen, J. Yang, R.-H. Ma, W. Gao, L.-W. Qi, P. Li, B.A. Bauer, G.-J. Du, Z. Zhang, J. Somogyi,C.-Z. Wang, C.-S. Yuan, Analysis of Panax notoginseng metabolites in rat bile by liquidchromatography–quadrupole time-of-flight mass spectrometry with microdialysis sampling, Journal ofChromatography B,895-896(2012)162-168.
[9] G. Cao, H. Cai, Y. Zhang, X. Cong, C. Zhang, B. Cai, Identification of metabolites of crude andprocessed Fructus Corni in rats by microdialysis sampling coupled with electrospray ionization linearquadrupole ion trap mass spectrometry, Journal of Pharmaceutical and Biomedical Analysis,56(2011)118-125.
[10] D. Guillarme, J. Schappler, S. Rudaz, J.-L. Veuthey, Coupling ultra-high-pressure liquidchromatography with mass spectrometry, TrAC Trends in Analytical Chemistry,29(2010)15-27.
[11] C.P. Committee, Pharmacopoeia of the People's Republic of China, Vol.1, People's MedicalPublishing House, Beijing,(2010)197-198.
[12] S. Ouyang, L.S. Sun, S.L. Guo, X. Liu, J.P. Xu, Effects of timosaponins on learning and memoryabilities of rats with dementia induced by lateral cerebral ventricular injection of amyloid beta-peptide, DiYi Jun Yi Da Xue Xue Bao,25(2005)121-126.
[13] F.W. King, S. Fong, C. Griffin, M. Shoemaker, R. Staub, Y.L. Zhang, I. Cohen, E. Shtivelman,Timosaponin AIII is preferentially cytotoxic to tumor cells through inhibition of mTOR and induction ofER stress, PLoS One,4(2009) e7283.
[14] B. Lee, K. Jung, D.-H. Kim, Timosaponin AIII, a saponin isolated from Anemarrhena asphodeloides,ameliorates learning and memory deficits in mice, Pharmacology Biochemistry and Behavior,93(2009)121-127.
[15] T.J. Li, Y. Qiu, P.Y. Yang, Y.C. Rui, W.S. Chen, Timosaponin B-II improves memory and learningdysfunction induced by cerebral ischemia in rats, Neurosci Lett,421(2007)147-151.
[16] Y. Hu, Z. Xia, Q. Sun, A. Orsi, D. Rees, A new approach to the pharmacological regulation of memory:Sarsasapogenin improves memory by elevating the low muscarinic acetylcholine receptor density in brainsof memory-deficit rat models, Brain Res,1060(2005)26-39.
[17] Z. Meng, S. Xu, L. Meng,[Timosaponins E1and E2], Yao Xue Xue Bao,33(1998)693-696.
[18] K. Wang, Z. Zhu, L. Yang, Y. Gao, W. Liu, H. Zhang, Y. Chai, Detection, characterization andidentification of major constituents in Zhimu-Baihe herb-pair extract by fast high-performance liquidchromatography and time-of-flight mass spectrometry through dynamic adjustment of fragmentor voltage,Rapid Commun Mass Spectrom,25(2011)9-19.
[19] Z. Liu, D. Zhu, Y. Qi, X. Chen, Z. Zhu, Y. Chai, Elucidation of steroid glycosides in Anemarrhenaasphodeloides extract by means of comprehensive two-dimensional reversed-phase/polyaminechromatography with mass spectrometric detection, Journal of separation science,35(2012)2210-2218.
[20] Y. Sun, Y. Du, Y. Liu, L. Chang, Y. Ren, L. Cao, Q. Sun, X. Shi, Q. Wang, L. Zhang, Simultaneousdetermination of nine components in Anemarrhena asphodeloides by liquid chromatography-tandem massspectrometry combined with chemometric techniques, Journal of separation science,35(2012)1796-1807.
[21] Z. Liu, D. Zhu, L. Lv, Y. Li, X. Dong, Z. Zhu, Y. Chai, Metabolism profile of timosaponin B-II in urineafter oral administration to rats by ultrahigh-performance liquid chromatography/quadrupole-time-of-flightmass spectrometry, Rapid Commun Mass Spectrom,26(2012)1955-1964.
[22] F. Cai, L. Sun, S. Gao, Y. Yang, Q. Yang, W. Chen, A rapid and sensitive liquidchromatography-tandem mass spectrometric method for the determination of timosaponin B-II in bloodplasma and a study of the pharmacokinetics of saponin in the rat, J Pharm Biomed Anal,48(2008)1411-1416.
[23] D. Yeniceli, E. ener, O.T. Korkmaz, D. Do rukol-Ak, N. Tuncel, A simple and sensitive LC–ESI-MS(ion trap) method for the determination of bupropion and its major metabolite, hydroxybupropion in ratplasma and brain microdialysates, Talanta,84(2011)19-26.
[24] G.C. Kite, E.A. Porter, M.S. Simmonds, Chromatographic behaviour of steroidal saponins studied byhigh-performance liquid chromatography-mass spectrometry, J Chromatogr A,1148(2007)177-183.
[25] Y. Liu, F. Liang, L. Cui, M. Xia, L. Zhao, Y. Yang, J. Shi, Z. Abliz, Multi-stage mass spectrometry offurostanol saponins combined with electrospray ionization in positive and negative ion modes, RapidCommun Mass Spectrom,18(2004)235-238.
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