经前期综合征（PMS）肝气逆证代谢组学研究
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摘要
目的:运用代谢组学方法,研究PMS肝气逆证大鼠模型及PMS肝气逆证患者尿样代谢物变化及白香丹胶囊、经前平颗粒对其的干预作用。探索与PMS肝气逆证发病机理密切相关的代谢组学特征和小分子标志化合物,为PMS肝气逆证证候生物学本质及白香丹胶囊、经前平颗粒作用机理的系统研究提供科学依据。也试图以PMS肝气逆证为切入点,运用代谢组学的技术与方法,探索出一种中医病证结合研究的新方法、新途径。
方法:以情志刺激多因素法复制PMS肝气逆证大鼠模型,白香丹胶囊干预。受试者按照诊断标准、纳入标准、排除标准等纳入PMS肝气逆证病例,经前平颗粒治疗。应用UPLC-Q-TOF结合PCA模式分析,对PMS肝气逆证模型大鼠及PMS肝气逆证患者不同时间点尿样进行代谢组学分析,区分代谢轮廓并寻找可能的生物标记物及代谢通路。
结果:UPLC-Q-TOF代谢图谱经PCA分析,得分图显示正常组与模型组分别落在不同区域,给药组有落回空白组区域趋势。模型组在造模0-5天内,代谢轨迹发生明显变化。PMS肝气逆证模型大鼠尿样较正常组大鼠2-氨基己二酸、5,7,4'-三羟基异黄酮、4-羟基谷氨酸、褪黑激素显著升高;前列腺素F2α显著降低。正常组、PMS肝气逆证组、PMS肝气逆证治疗组经前尿样代谢轮廓存在明显差异。PMS肝气逆证组经前尿样代谢轮廓显著偏离正常组经前、经后及PMS肝气逆证组经后尿样。PMS肝气逆证组尿样较正常组N-乙酰谷氨酸-γ-半醛显著降低;组氨酸、香草扁桃酸显著升高。
结论:本课题首次从代谢组学角度研究了PMS肝气逆与正常组及给药组的代谢模式差异,白香丹胶囊、经前平颗粒可以显著修复PMS肝气逆证内源性小分子代谢紊乱。直观揭示了PMS肝气逆证大鼠模型在代谢层次的发病轨迹,为PMS肝气逆证大鼠模型评价客观化提供佐证,为PMS肝气逆证大鼠模型的推广提供客观依据。进而从微观代谢物角度印证了PMS肝气逆证患者经前系列症状及“经前症状,经后消失”的特点。研究认为2-氨基己二酸、5,7,4'-三羟基异黄酮、4-羟基谷氨酸、褪黑激素、前列腺素F2α可作为PMS肝气逆证模型大鼠潜在生物标记物;组氨酸、N-乙酰谷氨酸-γ-半醛、香草扁桃酸可作为PMS肝气逆证患者潜在生物标记物。为“肝主疏泄”理论提供代谢组学新证据,也为证候客观诊断提供一条新思路。同时,由于尿样采集的无侵害性,容易被患者接受,值得进行大样本检测,以期为中医证型客观化研究提供参考。
Objectives: The aim of this study is to investigate the variation of urinary metabolite and the intervention of Baixiangdan capsule,jingqianping granula of Premenstrual syndrome(PMS) liver-qi invasion model rats and patients with metabonomics method.We also wish to explore the metabonomics character and micromolecule marking compound closely related to pathogenesis of PMS liver-qi invasion,and to provid scientific basis for PMS liver-qi invasion systematic research of syndrome biological essential and mechanism of action of Baixiangdan capsule,jingqianping granula. Furthermore, we try to take PMS liver-qi invasion as a breakthrough point to find a new method and a way studing traditional Chinese medicine disease-syndrome combination by metabonomics technology and method.
Methods: The PMS liver-qi invasion model was induced in rats by multiple emotional stimulations, and was interventioned by Baixiangdan capsule. The PMS liver-qi invasion patients were internalized according to diagnostic criteria, included criteria and excluded criteria, and were treated with jingqianping granula. Urine samples in different time courses of PMS liver-qi invasion model rats and patients were investigated to measure metabonomics using UPLC-Q-TOF combinating PCA pattern analysis, discriminating metabolic outline,searching possible biological tag and metabolic pathway.
Results: Scores map showed that there was a significant difference between normal group and model group, and administration group had a tendency similar to normal group in PCA analysising UPLC-Q-TOF metabolic map.In 0-5 days, metabolic trajectory of rats in model group took place marked change.Compared to normal group, 2-Aminoadip- ate,Genistei, 4-Hydroxy-glutamate, melatonin heighten and 11-epi-Prostag-iandin F2a cut down significantly in model group. The metabolic outline of premenstrual urine samples appeared obviouse difference in normal group, PMS liver-qi invasion group and PMS liver-qi invasion cured group. The premenstrual urine sample metabolic outline of PMS liver-qi invasion group diverged from premenstrual, postmenstrual urine samples of normal group and postmenstrual urine sample of PMS liver-qi invasion group. Compared to normal group, N-acetyl-2-glutamate-5-semial-dehyde decreased obviously, while histidine and 3-methoxy-4-hydroxymande-laldehyde increased significantly in PMS liver-qi invasion group.
Conclusions: In this study, we first time find out metabolic pattern differences between normal group and PMS administration, as well as Baixiangdan capsule and jingqianping granula can repair metabolic disturbance of endogenous micromolecule in PMS liver-qi invasion significantly from the metabonomics point. Our results reveal directly the disease trail of PMS liver-qi invasion model rats in metabolic level, providing evidence for evaluating model of PMS liver-qi invasion objectively and objective basis for the generalization of this model.Our study prove again the series of symptoms of Premenstrual and the characteristic of“symptoms appearing in Premenstrual and disappearing in postmenstrua”of PMS livromer-qi invasion patients from the point of microcosmic metabolite. We find out that 2-Aminoadipate,Genistei,4-Hydroxyglutamate, melatonin, and 11-epi-Prostag-iandin F2a can be conducted as latented biological tags of PMS liver-qi invasion rat model, and as well as N-acetyl-2-glutamate-5-semialdehyde, histidine,3-methoxy-4-hydroxymandelaldehyde as PMS liver-qi invasion patients.We hope to provide new evidence of metabonomics for“liver normalling dispersion”theory,and new idea for diagnosis objectively of syndrome. Simultaneously, for the no disoperation of collecting urine sample and patients accepting easily, it deserve to detect in large sample with a view to permit providing reference to study pattern of syndrome of traditional Chinese medicine objectively.
方法:以情志刺激多因素法复制PMS肝气逆证大鼠模型,白香丹胶囊干预。受试者按照诊断标准、纳入标准、排除标准等纳入PMS肝气逆证病例,经前平颗粒治疗。应用UPLC-Q-TOF结合PCA模式分析,对PMS肝气逆证模型大鼠及PMS肝气逆证患者不同时间点尿样进行代谢组学分析,区分代谢轮廓并寻找可能的生物标记物及代谢通路。
结果:UPLC-Q-TOF代谢图谱经PCA分析,得分图显示正常组与模型组分别落在不同区域,给药组有落回空白组区域趋势。模型组在造模0-5天内,代谢轨迹发生明显变化。PMS肝气逆证模型大鼠尿样较正常组大鼠2-氨基己二酸、5,7,4'-三羟基异黄酮、4-羟基谷氨酸、褪黑激素显著升高;前列腺素F2α显著降低。正常组、PMS肝气逆证组、PMS肝气逆证治疗组经前尿样代谢轮廓存在明显差异。PMS肝气逆证组经前尿样代谢轮廓显著偏离正常组经前、经后及PMS肝气逆证组经后尿样。PMS肝气逆证组尿样较正常组N-乙酰谷氨酸-γ-半醛显著降低;组氨酸、香草扁桃酸显著升高。
结论:本课题首次从代谢组学角度研究了PMS肝气逆与正常组及给药组的代谢模式差异,白香丹胶囊、经前平颗粒可以显著修复PMS肝气逆证内源性小分子代谢紊乱。直观揭示了PMS肝气逆证大鼠模型在代谢层次的发病轨迹,为PMS肝气逆证大鼠模型评价客观化提供佐证,为PMS肝气逆证大鼠模型的推广提供客观依据。进而从微观代谢物角度印证了PMS肝气逆证患者经前系列症状及“经前症状,经后消失”的特点。研究认为2-氨基己二酸、5,7,4'-三羟基异黄酮、4-羟基谷氨酸、褪黑激素、前列腺素F2α可作为PMS肝气逆证模型大鼠潜在生物标记物;组氨酸、N-乙酰谷氨酸-γ-半醛、香草扁桃酸可作为PMS肝气逆证患者潜在生物标记物。为“肝主疏泄”理论提供代谢组学新证据,也为证候客观诊断提供一条新思路。同时,由于尿样采集的无侵害性,容易被患者接受,值得进行大样本检测,以期为中医证型客观化研究提供参考。
Objectives: The aim of this study is to investigate the variation of urinary metabolite and the intervention of Baixiangdan capsule,jingqianping granula of Premenstrual syndrome(PMS) liver-qi invasion model rats and patients with metabonomics method.We also wish to explore the metabonomics character and micromolecule marking compound closely related to pathogenesis of PMS liver-qi invasion,and to provid scientific basis for PMS liver-qi invasion systematic research of syndrome biological essential and mechanism of action of Baixiangdan capsule,jingqianping granula. Furthermore, we try to take PMS liver-qi invasion as a breakthrough point to find a new method and a way studing traditional Chinese medicine disease-syndrome combination by metabonomics technology and method.
Methods: The PMS liver-qi invasion model was induced in rats by multiple emotional stimulations, and was interventioned by Baixiangdan capsule. The PMS liver-qi invasion patients were internalized according to diagnostic criteria, included criteria and excluded criteria, and were treated with jingqianping granula. Urine samples in different time courses of PMS liver-qi invasion model rats and patients were investigated to measure metabonomics using UPLC-Q-TOF combinating PCA pattern analysis, discriminating metabolic outline,searching possible biological tag and metabolic pathway.
Results: Scores map showed that there was a significant difference between normal group and model group, and administration group had a tendency similar to normal group in PCA analysising UPLC-Q-TOF metabolic map.In 0-5 days, metabolic trajectory of rats in model group took place marked change.Compared to normal group, 2-Aminoadip- ate,Genistei, 4-Hydroxy-glutamate, melatonin heighten and 11-epi-Prostag-iandin F2a cut down significantly in model group. The metabolic outline of premenstrual urine samples appeared obviouse difference in normal group, PMS liver-qi invasion group and PMS liver-qi invasion cured group. The premenstrual urine sample metabolic outline of PMS liver-qi invasion group diverged from premenstrual, postmenstrual urine samples of normal group and postmenstrual urine sample of PMS liver-qi invasion group. Compared to normal group, N-acetyl-2-glutamate-5-semial-dehyde decreased obviously, while histidine and 3-methoxy-4-hydroxymande-laldehyde increased significantly in PMS liver-qi invasion group.
Conclusions: In this study, we first time find out metabolic pattern differences between normal group and PMS administration, as well as Baixiangdan capsule and jingqianping granula can repair metabolic disturbance of endogenous micromolecule in PMS liver-qi invasion significantly from the metabonomics point. Our results reveal directly the disease trail of PMS liver-qi invasion model rats in metabolic level, providing evidence for evaluating model of PMS liver-qi invasion objectively and objective basis for the generalization of this model.Our study prove again the series of symptoms of Premenstrual and the characteristic of“symptoms appearing in Premenstrual and disappearing in postmenstrua”of PMS livromer-qi invasion patients from the point of microcosmic metabolite. We find out that 2-Aminoadipate,Genistei,4-Hydroxyglutamate, melatonin, and 11-epi-Prostag-iandin F2a can be conducted as latented biological tags of PMS liver-qi invasion rat model, and as well as N-acetyl-2-glutamate-5-semialdehyde, histidine,3-methoxy-4-hydroxymandelaldehyde as PMS liver-qi invasion patients.We hope to provide new evidence of metabonomics for“liver normalling dispersion”theory,and new idea for diagnosis objectively of syndrome. Simultaneously, for the no disoperation of collecting urine sample and patients accepting easily, it deserve to detect in large sample with a view to permit providing reference to study pattern of syndrome of traditional Chinese medicine objectively.
引文
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