基于代谢组学的肺卫气虚证候变化规律及中药复方干预的临床研究
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摘要
肺卫理论是中医基础体系中的重要组成部分，《内经》中有数十篇章专题论述，奠定了它的基本学术观点和理论框架。卫气主要是肺所主之气，主要功能是抵御外邪、温养肌肤腠理；肺主气，宣发卫气于体表，完成其抵御外邪的功能。卫气以肺气为基础，依赖于肺气的宣发，两者功能紧密相连，故统而称之“肺卫之气”。
不断发展的现代研究和临床实践，使医家及学者逐步认识到肺卫之气对人体的重要性：治未病重在调摄肺卫，治已病重在调和肺卫。因此肺卫之气的研究对疾病的防治具有重要指导意义，也一直是中医学研究的重要课题之一。以往的研究主要集中在其所出部位、运行、功能等方面的学术争鸣上；近年来，随着科学技术的进步，一些学者尝试借助现代医学手段对肺卫之气进行阐释，由此提出了一系列学说：如免疫学说、神经、神经-内分泌-免疫学说等，这些研究成果在一定程度上促进了肺卫理论体系的完善和发展。
然而这些研究集中在从单一的功能方面探求，对肺卫之气的物质基础缺乏系统而全面的阐述。在整体观念和天人相应理论指导下的肺卫理论认为，人体的肺卫之气受自然界日光、温度等外源性影响，呈现节律性变化。但肺卫节律的内源性物质基础和调控机制研究尚少，有待进一步的探讨；更有待于借助新的技术平台在新的技术层面上深入研究。新兴的代谢组学技术提供了很好的切入点。
代谢组学(metabolomics)是继基因组学、转录组学和蛋白质组学之后兴起的系统生物学的一个新的分支，它是通过考察生物体系受刺激或扰动前后(如将某个特定的基因变异或环境变化后)代谢产物图谱及其动态变化来研究生物体系的代谢网络的一种技术。代谢组学抛开机体内部复杂的生化分子相互作用和网络式的代谢变化过程，对代谢终端产物进行多元化综合分析，在整体上展示生物体内在的动态变化状况，避免了以往采用单一或少数几个指标研究某种生理和病理变化的弊端。这种在方法学上具有融整体、动态、综合、分析于一体的特点，符合中医学整体性的原则。
为此，本课题组突破以往从肺卫之气单一的功能来探求其物质基础的研究框架，采用代谢组学技术来研究伴随肺卫节律和药物干预而出现的内源性代谢的变化。通过对临床肺卫气虚证患者采用玉屏风颗粒干预前后代谢物的分析，确定伴随肺卫节律波动的“代谢组学特征”的小分子标志化合物，进而从临床角度验证和筛选与肺卫节律相吻合的物质分类及范围界定，为肺卫相关的呼吸系统疾病的诊断和治疗提供新的方法。
本篇论文主要包括理论和实验两大部分。
第一部分肺卫理论的概述
目的：通过对肺卫理论的概述，阐述课题组对肺卫之气的理解、认识研究成果及利用新技术平台对肺卫证候展开深入、全面的探索。方法：从肺与卫的关系、肺卫之气的物质基础、肺卫之气的功能、肺
卫气虚证的病理基础、肺卫之气的年节律、代谢组学技术研究肺卫证候的可行性等方面予详细论述。结论：目前肺卫物质基础的研究仅着眼于从单一功能上探求，而忽略
了从其节律等方面作为切入点的研究方法，故而难以进行全方位诠释。因此对肺卫物质基础的范围还应在一个整体而全面的层面进一步展开研究，代谢组学技术提供了这方面研究的可行性。
第二部分肺卫气虚证候的实验与临床研究
实验一：玉屏风颗粒治疗反复上呼吸道感染肺卫气虚证患者的临床
观察目的：观察玉屏风颗粒治疗反复上呼吸道感染肺卫气虚证患者的临床
疗效。方法：选出符合诊断条件的反复上呼吸道感染肺卫气虚证患者40例
为治疗组，给予玉屏风颗粒口服；同时设对照组22例，给予胸腺五肽肌注、穴位注射交替治疗。两组均以60天为1个疗程。分别记录治疗前后患者的症状积分。结果：玉屏风颗粒可显著改善反复上呼吸道感染肺卫气虚证患者临床
症状（P＜0.01）、明显减少上呼吸道感染反复发作次数（P＜0.01）、总有效率为92.5%；胸腺五肽亦可明显改善患者的症状（P＜0.01、P＜0.05）明显减少上呼吸道感染反复发作次数（P＜0.01）、总有效率为90.9%。两者对患者症状改善、减少上呼吸道感染发作次数、治疗有效率经统计学处理无差异（P＞0.05）。
结论：玉屏风颗粒和胸腺五肽治疗反复上呼吸道感染肺卫气虚证患者均有较好的效果，疗效相似；该观察为课题深入研究提供了坚实的临床支持。
实验二：肺卫气虚证患者玉屏风颗粒干预的血浆代谢组学研究
目的：运用代谢组学方法研究反复上呼吸道感染肺卫气虚证患者经玉屏风颗粒干预的血浆代谢组学特征，对发现的潜在证候标记物进行反证，以明确其可靠性。
方法：选择符合诊断条件肺卫气虚患者85例，设为疾病组，给予玉屏风颗粒口服，60天为一个疗程。同时设健康对照组85例。分别对健康组及疾病组治疗前后采集血液；采用高效液相色谱-质谱联用仪（HPLC-MS）检测三组的血浆代谢物，利用主成分分析法(principalcomponent analysis，PCA)和偏最小二乘法(partial least squares，PLS)对检测的数据进行统计分析，比较三组血浆代谢组学原始谱图和数据。
结果：疾病组在治疗前和健康组的代谢谱存在明显不同，初步推测出半胱氨酸、L-亮氨酸、L-蛋氨酸、苏氨酸、焦谷氨酸等5种物质为肺卫气虚证的潜在标志物；经玉屏风颗粒治疗后疾病组的代谢谱有积极改变，向健康组回归；治疗后半胱氨酸、L-蛋氨酸、苏氨酸、焦谷氨酸出现回调，向健康组接近，L-亮氨酸反而进一步偏离健康组。
结论：玉屏风颗粒干预后肺卫气虚证患者出现代谢谱的回归；半胱氨酸、L-蛋氨酸、苏氨酸、焦谷氨酸在治疗后回调，反证了这四种物质作为肺卫气虚证潜在证候标记物的可靠性；纠正紊乱的氨基酸代谢可能是玉屏风颗粒在分子层面治疗肺卫气虚证的作用机制之一。
实验三：基于代谢组学的肺卫气虚证年节律的实验研究
目的：运用代谢组学方法研究肺卫气虚证患者的血浆代谢组学特征，探索伴随其年节律出现的潜在证候标记物。
方法：春、夏、秋、冬四个季节分别选择符合诊断条件的肺卫气虚证患者23例、17例、15例、30例，设为疾病组，同时每个季节设对应健康组26例、10例、18例、31例。分别对健康组及疾病组采集血液；采用高效液相色谱-质谱联用仪（HPLC-MS）检测两组的血浆代谢物，利用主成分分析法(principal component analysis，PCA)和偏最小二乘法(partial least squares，PLS)对检测的数据进行统计分析，比较四个季节每两组血浆的代谢组学原始谱图和数据。
结果：春、夏、秋、冬发现肺卫气虚证的潜在标志物不完全相同，分别为L-天冬氨酸、半胱氨酸、L-蛋氨酸、赖氨酸、高半胱氨酸等。其中半胱氨酸、L-蛋氨酸在四个季节均出现，呈现春夏较强、秋冬较弱的规律，与肺卫之气本身的春夏强、秋冬弱的年节律相符合。
结论：四季发现不完全相同的证候标志物是因为季节变化刺激机体，使体内的代谢模式或代谢通路随之发生改变，代谢产物产生变化导致，与肺卫的节律存在相关性；半胱氨酸、L-蛋氨酸在四个季节均出现，其春夏较强、秋冬较弱的规律符合肺卫之气本身的年节律，推测是伴随肺卫年节律的潜在证候标记物。
The theory of Fei-Wei(肺卫), as an important part of Traditional ChineseMedicine (TCM), has been expounded in Huang-di Nei-jing(黄帝内经)andlaid its basic academic ideas and theoretical framework at the same time.Wei-qi(卫气) refers to the qi that Fei governs, and the main function of whichis to resist exogenous pathogenic factors, warm the skin, open and close thesweat pore. The Fei (肺) governs qi and disperse Wei-qi to body surface toagainst invaded. Wei-qi bases on Fei-qi and relies on its dispersing. Theirfunctions are closely related to each other, so they are collectively called the"qi of Fei-Wei"(QFW) generally.
With the continuous development of modern research and clinical practice,physicians and scholars gradually realize the importance of QFW on humanbody. Therefore, study on QFW has a great guiding significance to preventand cure disease. Recently, some scholars tried to explain the essence of QFWvia the modern technology. The theories such as immune andthermometabolism are connected with the material basis of QFW and docontribute to the improvement of the theory.
But these theories explained QFW from its segmentary function and lackedcomprehensive elaboration of its material basis. The theory of Fei-Wei, underthe guidance of “the integration concept” and “correspondence between manand nature”, considers that QFW shows rhythmic changes which are due tobeing affected by natural sunlight, temperature and other exogenousinfluences. But the studies on endogenous substance basic and regulatorymechanism study of Fei-Wei rhythm are less studied up to now and remain tobe further discussed. More should to be done by using the new technology platform in the new technical level. Metabonomics technology provides agood starting point.
Metabonomics is a new branch of system biology after the rise of genomics,transcriptomics and proteomics. It is a kind of technology that studies themetabolic network of biological systems by investigating the metabolite mapand its dynamic change before or after the biological systems is stimulated ordisturbed (such as a particular genetic mutation or environmental changes).Regardless of the complicated interactions among biochemical molecules andchanges in metabolic process, metabonomics has analyzed comprehensivelythe terminal product of metabolic as a whole in a diversified way and showedthe changes of organic inner state. It avoids using a single or a few indicatorsto research a certain pathological and physiological changes. With the holistic,dynamic and comprehensive characteristics, this analysis method is in linewith the integrity principle of TCM.
For the first time, we break the framework which searches the essence ofQFW from its single function, using metabonomics technology to study thechange of endogenous metabolism by medicine interference along withFei-Wei rhythm changes. We expect to discover the small molecular metabolicmarkers of Fei-we-qi deficiency syndrome (FWQDS) through comparing thepatients with FWQDS before and after being invented by YuPingFeng Granule(玉屏风,YPFG). Furthermore, to select the material classification and scopeconsistent with the Fei-Wei rhythm, providing a new method to diagnose andtreat the respiratory system disease related to Fei-Wei.This paper mainly includes two parts: the theory and experiment.
Part1Overview Resarch on Fei-Wei Theroy
Objective: Summarize the understanding, research results andexploration of the Fei-Wei syndrome useing new technology platform throughthe overview of Fei-Wei theory.
Method: Elaborate the relationship between Fei and Wei, the materialbasis, function, year rhythm of QFW, the pathological basis of FWQDS, andfeasibility of study Fei-Wei syndrome via metabonomics and so on.
Conclusion: At present, researches of QFW focus on searching theessence from single function rather than exploring the material method fromthe circadian rhythms. Therefore, it is difficult to fully interpret the essence ofit. The range of material base of QFW should be studied further in an overalland comprehensive level. The metabonomics technology provides thepossibility.
Part2Experiment and Clinical Researchs on FWQDS
Experiment1Curative Efficacy Observation of Yupingfeng Granule inTreating the Patients of Recurrent Upper Respiratory Infection withFei-Wei-qi deficiency syndrome (FWQDS)
Objective: Evaluate the clinical efficacy of Yupingfeng Granule (YPFG)in treating the patients of recurrent upper respiratory infection (RURI) withFWQDS by means of observing its influence on the clinical syndromes, totaleffective.
Method: Forty cases of FWQDS were recruited as treated group, YPFGwas given as an intervention; twenty-two cases as controlled group,Thymopentin (TP-5) was given as intervention. Two months is one therapeuticcourse. The integral of symptoms were recorded respectively before and aftertreatment.
Results: After60days the clinical symptoms of treated group improvedsignificantly(P＜0.01), upper respiratory infection(URI)numbers reducedclearly(P＜0.01),the total-clinical effective rate was92.5%.The clinicalsymptoms of controlled group improved obviously(P＜0.01,P＜0.05), URInumbers reduced clearly(P＜0.01),the total-clinical effective rate was90.9%.The change of clinical symptoms,URI numbers and the total-clinical effectiverate of the two groups have no statistical significance (P＞0.05).
Conclusions: YPFG and TP-5both have good effect in treating thepatients of RRI with FWQDS. The curative effect is similar. This observationprovides a solid clinical support to in-depth study on our paper.
Experiment2Studies of Plasma Metabonomics on Fei-Wei-Qi DeficiencySyndrome Patients which are Intervened by Yupingfeng Granule
Objective: Use metabonomics methods to study the patients of recurrentupper respiratory infection with FWQDS and intervened by YupingfengGranule (YPFG) thus disproving the reliability of the possibly existentbiomarkers.
Methods: Eighty-five cases of FWQDS were recruited as sick group,YPFG was given as intervention, two mouths is one therapeutic course; Ahealthy control group (eighty-five cases) was set up at the same time．Theblood was collected respectively on patients in control group and sick groupbefore and after treatment. The plasma metabolites were detected using highperformance liquid chromatography-mass spectrometry (HPLC-MS),statisticaldata were analyzed by principal component analysis (PCA) and partial leastsquares (PLS).The original spectrum and data of plasma metabolites werecompared among the three groups．
Results: The metabolic spectrum before treatment in sick group wassignificantly different with control group.L-Cystein, L-Leucine, L-Methionine,L-Threonine and Pyroglutamic acid were inferred as possibly potentialsyndrome biomarkers of FWQDS at first. The spectrum showing regressivetrend to control group after the patients were intervened by YPFG. L-Cysteine,L-Methionine, L-Threonine and Pyroglutamic acid showed callback to controlgroup after treatment but L-Leucine deviated from control group further.
Conclusions: There are positive changes in the metabolic profiling of thepatients with FWQDS which intervened by YPFG. L-Cysteine, L-Methionine,L-Threonine and Pyroglutamic acid showed callback after the patientsreceived treatment and were disproved their reliability as possibly potentialsyndrome biomarkers of FWQDS, correcting the amino acid metabolismdisorder may be one of mechanisms of YPFG in treating FWQDS at themolecular level.
Experiment3Research on year biorhythm of Fei-Wei-qi DeficiencySyndrome Based on the Plasma Metabonomics
Objective: Study the Plasma metabonomics characteristics of Fei-Wei-qideficiency syndrome (FWQS), and explore the potential syndrome biomarkersalong with its year biorhythm.
Methods:23cases,17cases,15cases,30cases of FWQS were recruitedas sick groups respectively in spring, summer, autumn, and winter.26cases,10cases,18cases,31cases of health people were set as control groupscorrespondently. The blood was collected respectively from sick groups andcontrol groups in every season. The plasma metabolites were detected usinghigh performance liquid chromatography-mass spectrometry(HPLC-MS),Statistical data were analyzed by principal component analysis (PCA) andpartial least squares (PLS).The original spectrum and data of plasmametabolites were compared among the two groups in every season.
Results: The potential syndrome biomarkers of FWQDS were inferredrespectively in spring, summer, autumn and winter, such as L-Cysteine,L-Methionine, L-Leucine, L-Aspartic acid, L-Homocysteine and others.Among these markers, L-Cysteine and L-Methionine can be found in fourseasons and are strong in spring and summer, weak in autumn and winter. Thistrend conformed to the year biorhythm of FWQS.
Conclusions: There were not exactly the same potential syndromebiomarkers in every season. This result is associated with biorhythm ofFei-Wei. L-Cysteine and L-Methionine were inferred as the potentialbiomarker along with the year biorhythm of FWQDS.
不断发展的现代研究和临床实践，使医家及学者逐步认识到肺卫之气对人体的重要性：治未病重在调摄肺卫，治已病重在调和肺卫。因此肺卫之气的研究对疾病的防治具有重要指导意义，也一直是中医学研究的重要课题之一。以往的研究主要集中在其所出部位、运行、功能等方面的学术争鸣上；近年来，随着科学技术的进步，一些学者尝试借助现代医学手段对肺卫之气进行阐释，由此提出了一系列学说：如免疫学说、神经、神经-内分泌-免疫学说等，这些研究成果在一定程度上促进了肺卫理论体系的完善和发展。
然而这些研究集中在从单一的功能方面探求，对肺卫之气的物质基础缺乏系统而全面的阐述。在整体观念和天人相应理论指导下的肺卫理论认为，人体的肺卫之气受自然界日光、温度等外源性影响，呈现节律性变化。但肺卫节律的内源性物质基础和调控机制研究尚少，有待进一步的探讨；更有待于借助新的技术平台在新的技术层面上深入研究。新兴的代谢组学技术提供了很好的切入点。
代谢组学(metabolomics)是继基因组学、转录组学和蛋白质组学之后兴起的系统生物学的一个新的分支，它是通过考察生物体系受刺激或扰动前后(如将某个特定的基因变异或环境变化后)代谢产物图谱及其动态变化来研究生物体系的代谢网络的一种技术。代谢组学抛开机体内部复杂的生化分子相互作用和网络式的代谢变化过程，对代谢终端产物进行多元化综合分析，在整体上展示生物体内在的动态变化状况，避免了以往采用单一或少数几个指标研究某种生理和病理变化的弊端。这种在方法学上具有融整体、动态、综合、分析于一体的特点，符合中医学整体性的原则。
为此，本课题组突破以往从肺卫之气单一的功能来探求其物质基础的研究框架，采用代谢组学技术来研究伴随肺卫节律和药物干预而出现的内源性代谢的变化。通过对临床肺卫气虚证患者采用玉屏风颗粒干预前后代谢物的分析，确定伴随肺卫节律波动的“代谢组学特征”的小分子标志化合物，进而从临床角度验证和筛选与肺卫节律相吻合的物质分类及范围界定，为肺卫相关的呼吸系统疾病的诊断和治疗提供新的方法。
本篇论文主要包括理论和实验两大部分。
第一部分肺卫理论的概述
目的：通过对肺卫理论的概述，阐述课题组对肺卫之气的理解、认识研究成果及利用新技术平台对肺卫证候展开深入、全面的探索。方法：从肺与卫的关系、肺卫之气的物质基础、肺卫之气的功能、肺
卫气虚证的病理基础、肺卫之气的年节律、代谢组学技术研究肺卫证候的可行性等方面予详细论述。结论：目前肺卫物质基础的研究仅着眼于从单一功能上探求，而忽略
了从其节律等方面作为切入点的研究方法，故而难以进行全方位诠释。因此对肺卫物质基础的范围还应在一个整体而全面的层面进一步展开研究，代谢组学技术提供了这方面研究的可行性。
第二部分肺卫气虚证候的实验与临床研究
实验一：玉屏风颗粒治疗反复上呼吸道感染肺卫气虚证患者的临床
观察目的：观察玉屏风颗粒治疗反复上呼吸道感染肺卫气虚证患者的临床
疗效。方法：选出符合诊断条件的反复上呼吸道感染肺卫气虚证患者40例
为治疗组，给予玉屏风颗粒口服；同时设对照组22例，给予胸腺五肽肌注、穴位注射交替治疗。两组均以60天为1个疗程。分别记录治疗前后患者的症状积分。结果：玉屏风颗粒可显著改善反复上呼吸道感染肺卫气虚证患者临床
症状（P＜0.01）、明显减少上呼吸道感染反复发作次数（P＜0.01）、总有效率为92.5%；胸腺五肽亦可明显改善患者的症状（P＜0.01、P＜0.05）明显减少上呼吸道感染反复发作次数（P＜0.01）、总有效率为90.9%。两者对患者症状改善、减少上呼吸道感染发作次数、治疗有效率经统计学处理无差异（P＞0.05）。
结论：玉屏风颗粒和胸腺五肽治疗反复上呼吸道感染肺卫气虚证患者均有较好的效果，疗效相似；该观察为课题深入研究提供了坚实的临床支持。
实验二：肺卫气虚证患者玉屏风颗粒干预的血浆代谢组学研究
目的：运用代谢组学方法研究反复上呼吸道感染肺卫气虚证患者经玉屏风颗粒干预的血浆代谢组学特征，对发现的潜在证候标记物进行反证，以明确其可靠性。
方法：选择符合诊断条件肺卫气虚患者85例，设为疾病组，给予玉屏风颗粒口服，60天为一个疗程。同时设健康对照组85例。分别对健康组及疾病组治疗前后采集血液；采用高效液相色谱-质谱联用仪（HPLC-MS）检测三组的血浆代谢物，利用主成分分析法(principalcomponent analysis，PCA)和偏最小二乘法(partial least squares，PLS)对检测的数据进行统计分析，比较三组血浆代谢组学原始谱图和数据。
结果：疾病组在治疗前和健康组的代谢谱存在明显不同，初步推测出半胱氨酸、L-亮氨酸、L-蛋氨酸、苏氨酸、焦谷氨酸等5种物质为肺卫气虚证的潜在标志物；经玉屏风颗粒治疗后疾病组的代谢谱有积极改变，向健康组回归；治疗后半胱氨酸、L-蛋氨酸、苏氨酸、焦谷氨酸出现回调，向健康组接近，L-亮氨酸反而进一步偏离健康组。
结论：玉屏风颗粒干预后肺卫气虚证患者出现代谢谱的回归；半胱氨酸、L-蛋氨酸、苏氨酸、焦谷氨酸在治疗后回调，反证了这四种物质作为肺卫气虚证潜在证候标记物的可靠性；纠正紊乱的氨基酸代谢可能是玉屏风颗粒在分子层面治疗肺卫气虚证的作用机制之一。
实验三：基于代谢组学的肺卫气虚证年节律的实验研究
目的：运用代谢组学方法研究肺卫气虚证患者的血浆代谢组学特征，探索伴随其年节律出现的潜在证候标记物。
方法：春、夏、秋、冬四个季节分别选择符合诊断条件的肺卫气虚证患者23例、17例、15例、30例，设为疾病组，同时每个季节设对应健康组26例、10例、18例、31例。分别对健康组及疾病组采集血液；采用高效液相色谱-质谱联用仪（HPLC-MS）检测两组的血浆代谢物，利用主成分分析法(principal component analysis，PCA)和偏最小二乘法(partial least squares，PLS)对检测的数据进行统计分析，比较四个季节每两组血浆的代谢组学原始谱图和数据。
结果：春、夏、秋、冬发现肺卫气虚证的潜在标志物不完全相同，分别为L-天冬氨酸、半胱氨酸、L-蛋氨酸、赖氨酸、高半胱氨酸等。其中半胱氨酸、L-蛋氨酸在四个季节均出现，呈现春夏较强、秋冬较弱的规律，与肺卫之气本身的春夏强、秋冬弱的年节律相符合。
结论：四季发现不完全相同的证候标志物是因为季节变化刺激机体，使体内的代谢模式或代谢通路随之发生改变，代谢产物产生变化导致，与肺卫的节律存在相关性；半胱氨酸、L-蛋氨酸在四个季节均出现，其春夏较强、秋冬较弱的规律符合肺卫之气本身的年节律，推测是伴随肺卫年节律的潜在证候标记物。
The theory of Fei-Wei(肺卫), as an important part of Traditional ChineseMedicine (TCM), has been expounded in Huang-di Nei-jing(黄帝内经)andlaid its basic academic ideas and theoretical framework at the same time.Wei-qi(卫气) refers to the qi that Fei governs, and the main function of whichis to resist exogenous pathogenic factors, warm the skin, open and close thesweat pore. The Fei (肺) governs qi and disperse Wei-qi to body surface toagainst invaded. Wei-qi bases on Fei-qi and relies on its dispersing. Theirfunctions are closely related to each other, so they are collectively called the"qi of Fei-Wei"(QFW) generally.
With the continuous development of modern research and clinical practice,physicians and scholars gradually realize the importance of QFW on humanbody. Therefore, study on QFW has a great guiding significance to preventand cure disease. Recently, some scholars tried to explain the essence of QFWvia the modern technology. The theories such as immune andthermometabolism are connected with the material basis of QFW and docontribute to the improvement of the theory.
But these theories explained QFW from its segmentary function and lackedcomprehensive elaboration of its material basis. The theory of Fei-Wei, underthe guidance of “the integration concept” and “correspondence between manand nature”, considers that QFW shows rhythmic changes which are due tobeing affected by natural sunlight, temperature and other exogenousinfluences. But the studies on endogenous substance basic and regulatorymechanism study of Fei-Wei rhythm are less studied up to now and remain tobe further discussed. More should to be done by using the new technology platform in the new technical level. Metabonomics technology provides agood starting point.
Metabonomics is a new branch of system biology after the rise of genomics,transcriptomics and proteomics. It is a kind of technology that studies themetabolic network of biological systems by investigating the metabolite mapand its dynamic change before or after the biological systems is stimulated ordisturbed (such as a particular genetic mutation or environmental changes).Regardless of the complicated interactions among biochemical molecules andchanges in metabolic process, metabonomics has analyzed comprehensivelythe terminal product of metabolic as a whole in a diversified way and showedthe changes of organic inner state. It avoids using a single or a few indicatorsto research a certain pathological and physiological changes. With the holistic,dynamic and comprehensive characteristics, this analysis method is in linewith the integrity principle of TCM.
For the first time, we break the framework which searches the essence ofQFW from its single function, using metabonomics technology to study thechange of endogenous metabolism by medicine interference along withFei-Wei rhythm changes. We expect to discover the small molecular metabolicmarkers of Fei-we-qi deficiency syndrome (FWQDS) through comparing thepatients with FWQDS before and after being invented by YuPingFeng Granule(玉屏风,YPFG). Furthermore, to select the material classification and scopeconsistent with the Fei-Wei rhythm, providing a new method to diagnose andtreat the respiratory system disease related to Fei-Wei.This paper mainly includes two parts: the theory and experiment.
Part1Overview Resarch on Fei-Wei Theroy
Objective: Summarize the understanding, research results andexploration of the Fei-Wei syndrome useing new technology platform throughthe overview of Fei-Wei theory.
Method: Elaborate the relationship between Fei and Wei, the materialbasis, function, year rhythm of QFW, the pathological basis of FWQDS, andfeasibility of study Fei-Wei syndrome via metabonomics and so on.
Conclusion: At present, researches of QFW focus on searching theessence from single function rather than exploring the material method fromthe circadian rhythms. Therefore, it is difficult to fully interpret the essence ofit. The range of material base of QFW should be studied further in an overalland comprehensive level. The metabonomics technology provides thepossibility.
Part2Experiment and Clinical Researchs on FWQDS
Experiment1Curative Efficacy Observation of Yupingfeng Granule inTreating the Patients of Recurrent Upper Respiratory Infection withFei-Wei-qi deficiency syndrome (FWQDS)
Objective: Evaluate the clinical efficacy of Yupingfeng Granule (YPFG)in treating the patients of recurrent upper respiratory infection (RURI) withFWQDS by means of observing its influence on the clinical syndromes, totaleffective.
Method: Forty cases of FWQDS were recruited as treated group, YPFGwas given as an intervention; twenty-two cases as controlled group,Thymopentin (TP-5) was given as intervention. Two months is one therapeuticcourse. The integral of symptoms were recorded respectively before and aftertreatment.
Results: After60days the clinical symptoms of treated group improvedsignificantly(P＜0.01), upper respiratory infection(URI)numbers reducedclearly(P＜0.01),the total-clinical effective rate was92.5%.The clinicalsymptoms of controlled group improved obviously(P＜0.01,P＜0.05), URInumbers reduced clearly(P＜0.01),the total-clinical effective rate was90.9%.The change of clinical symptoms,URI numbers and the total-clinical effectiverate of the two groups have no statistical significance (P＞0.05).
Conclusions: YPFG and TP-5both have good effect in treating thepatients of RRI with FWQDS. The curative effect is similar. This observationprovides a solid clinical support to in-depth study on our paper.
Experiment2Studies of Plasma Metabonomics on Fei-Wei-Qi DeficiencySyndrome Patients which are Intervened by Yupingfeng Granule
Objective: Use metabonomics methods to study the patients of recurrentupper respiratory infection with FWQDS and intervened by YupingfengGranule (YPFG) thus disproving the reliability of the possibly existentbiomarkers.
Methods: Eighty-five cases of FWQDS were recruited as sick group,YPFG was given as intervention, two mouths is one therapeutic course; Ahealthy control group (eighty-five cases) was set up at the same time．Theblood was collected respectively on patients in control group and sick groupbefore and after treatment. The plasma metabolites were detected using highperformance liquid chromatography-mass spectrometry (HPLC-MS),statisticaldata were analyzed by principal component analysis (PCA) and partial leastsquares (PLS).The original spectrum and data of plasma metabolites werecompared among the three groups．
Results: The metabolic spectrum before treatment in sick group wassignificantly different with control group.L-Cystein, L-Leucine, L-Methionine,L-Threonine and Pyroglutamic acid were inferred as possibly potentialsyndrome biomarkers of FWQDS at first. The spectrum showing regressivetrend to control group after the patients were intervened by YPFG. L-Cysteine,L-Methionine, L-Threonine and Pyroglutamic acid showed callback to controlgroup after treatment but L-Leucine deviated from control group further.
Conclusions: There are positive changes in the metabolic profiling of thepatients with FWQDS which intervened by YPFG. L-Cysteine, L-Methionine,L-Threonine and Pyroglutamic acid showed callback after the patientsreceived treatment and were disproved their reliability as possibly potentialsyndrome biomarkers of FWQDS, correcting the amino acid metabolismdisorder may be one of mechanisms of YPFG in treating FWQDS at themolecular level.
Experiment3Research on year biorhythm of Fei-Wei-qi DeficiencySyndrome Based on the Plasma Metabonomics
Objective: Study the Plasma metabonomics characteristics of Fei-Wei-qideficiency syndrome (FWQS), and explore the potential syndrome biomarkersalong with its year biorhythm.
Methods:23cases,17cases,15cases,30cases of FWQS were recruitedas sick groups respectively in spring, summer, autumn, and winter.26cases,10cases,18cases,31cases of health people were set as control groupscorrespondently. The blood was collected respectively from sick groups andcontrol groups in every season. The plasma metabolites were detected usinghigh performance liquid chromatography-mass spectrometry(HPLC-MS),Statistical data were analyzed by principal component analysis (PCA) andpartial least squares (PLS).The original spectrum and data of plasmametabolites were compared among the two groups in every season.
Results: The potential syndrome biomarkers of FWQDS were inferredrespectively in spring, summer, autumn and winter, such as L-Cysteine,L-Methionine, L-Leucine, L-Aspartic acid, L-Homocysteine and others.Among these markers, L-Cysteine and L-Methionine can be found in fourseasons and are strong in spring and summer, weak in autumn and winter. Thistrend conformed to the year biorhythm of FWQS.
Conclusions: There were not exactly the same potential syndromebiomarkers in every season. This result is associated with biorhythm ofFei-Wei. L-Cysteine and L-Methionine were inferred as the potentialbiomarker along with the year biorhythm of FWQDS.
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