| Metabolic syndrome is a pathological state of a variety of diseases such as abnormal blood glucose,dyslipidemia,obesity and hypertension,which directly leads to serious cardiovascular disease and its complications,even death.Traditional Chinese medicine has a long history in treatment of diabetes and hypertension,which has a remarkable effect.At the same time,compared with chemical drugs,it has the characteristics of“multi-component,multi-target,small side effects”.Plantaginis Semen powder was first recorded in Shengji General Record with a long history of application,which consisted of one two Plantaginis Semen and one two Coptidis Rhizoma.In ancient times,Plantaginis Semen powder treated eys with wind-heat,dark,dry,astringent and dull pain,while modern medicine applies it in the treatment of hyperglycemia,hyperlipidemia,hypertension,ophthalmopathy and nephropathy.However,its pharmacodynamics and mechanism are not clear.In the early stage,our research team has determined the effects of Plantaginis Semen powder on lipid-lowering,blood sugar-lowering and blood pressure-lowering in hyperlipidemia mice induced by high-fat diet and primary hypertension rats.The purpose of this study was to utilize the research thought of translational medicine,carrying out non-targeted serum metabonomics analysis by metabonomics technology for animal models which are close to clinical metabolic syndrome,such as hyperlipidemia mice induced by high-fat diet,primary hypertension rats.Then finding pharmacodynamic biomarkers of Plantaginis Semen powder in lipid-lowering,blood sugar-lowering and blood pressure-lowering,and for quantitative evaluation of drug efficacy in combination with mathematical modeling,further evaluating the Plantaginis Semen powder' drug actions in treatment of metabolic syndrome,in order to provide a scientific basis for further exploring the clinical pharmacodynamic mechanism.1.Study on pharmacodynamic biomarkers of Plantaginis Semen powder in lipid-lowering and blood sugar-loweringSerum metabolomics analysis was carried out on a high-fat mice model induced by a high-fat diet.Firstly,the results indicated the effect in lipid-lowering and blood sugar-lowering of the Plantago asiatica L.' seed was better through comparing the protective effects of Plantago asiatica L.' seed and Plantago depressa Willd.' seed on high-fat model mice,nine endogenous compounds related to lipid-lowering efficacy were screened out(TG(16:1/16:0/o-18:0)? Lyso PC(P-16:0)? Lyso PC(18:2)?Lyso PC(20:5)?Lyso PC(22:4)?Lyso PC(16:0)?cholesterol sulfate?PC(14:0/14:0)?Glucosylceramide(d18:1/18:0)),providing a scientific basis for the selection of Plantaginis Semen in Plantaginis Semen powder;secondly,non-targeted metabolomics and multivariate statistical analysis were used to evaluate the hypolipidemic and hypoglycemic effects of Plantaginis Semen powder and its prescription Plantaginis Semen(Plantago asiatica L.' seed was determined based on the above study),Coptidis Rhizome,the results showed that the callback ranges and improvement effects of the Plantaginis Semen powder in the high-fat model were preferable,14 biomarkers related to the efficacy were screened out(Glycerophosphocholine ? Lyso PC(P-18:0)?Clupanodonyl carnitine ? Lyso PC(18:2)? Lyso PE(0:0/22:0)? Glycocholic acid ?Lyso PC(22:5)? Lyso PC(22:4)? 18-Hydroxyretinoic acid ? Alpha-Linolenic acid ?Cholesterol sulfate ? Lyso PE(18:2/0:0)? Palmitic acid ?1-Arachidonoylglycerophosphoinositol).The synergistic action of the traditional Chinese medicine compound was demonstrated from the aspect of endogenous small molecule compounds;then,a targeted lipidomics analysis was used to analyze the mice serum,and six lipid biomarkers related to lipid-lowering efficacy of Plantaginis Semen powder were screened out(12,13-Di HOME?9,10-Di HOME?13-HOTr E?13-HODE?15-HETE ? 9-KODE),showing that the superior efficacy of the Plantaginis Semen powder on lipid-lowering and blood sugar-lowering.To sum up the above research results,high-fat model mice have significant changes in the metabolism of glycerol phosphate,biosynthesis of unsaturated fatty acids and ?-linolenic acid metabolism.Mitochondrial fatty acid elongation,fatty acid metabolism,fatty acid biosynthesis,primary bile acid biosynthesis,steroid hormone biosynthesis and other pathways have also been affected.However,the blood lipid and blood sugar of hyperlipidemia mice could be improved through repairing the above metabolic pathways by Plantaginis Semen powder.2.Study on pharmacodynamic biomarkers of Plantaginis Semen powder in blood pressure-loweringSerum metabolomics analysis was carried out on a primary hypertension rat model.Firstly,through comparing the protective effects of Plantago asiatica L.' seed and Plantago depressa Willd.' seed on primary hypertension rat model,the results indicated the effect in blood pressure-lowering of the Plantago asiatica L.' seed was better,and then provided a scientific basis for the determination of the base of Plantaginis Semen in Plantaginis Semen powder;secondly,non-targeted metabolomics combined with multivariate statistical analysis screened out 20 biomarkers(Retinal ?Linoleic acid ?Dodecanoylcarnitine?Amoxicillin?PE(P-16:0e/0:0)?(R)-3-Hydroxyisobutyric acid?TG(16:0/15:0/14:1)? 17a-Ethynylestradiol ? Sphinganine ? 9-HODE ?N-Hexadecanoylpyrrolidine?Verapamil?Deferoxamine?Lyso PC(18:2)?Lyso PC(20:3)?Lyso PE(0:0/20:1)? 13-cis-Retinoic acid ? Nevskin ? CL(8:0/8:0/12:0/i-12:0)?TG(22:6/20:5/22:6)),showed that the callback ranges and improvement effects of the Plantaginis Semen powder in the primary hypertension model were preferable.The synergistic action of the traditional Chinese medicine compound was demonstrated from the aspect of endogenous small molecule compounds once more,further verifying its good efficacy of blood pressure-lowering.In the process of hypertensive disease,the substances in the organism mainly changed significantly in the pathways of linoleic acid metabolism,retinol metabolism,sphingolipid metabolism,glycerol phosphate metabolism and biosynthesis of unsaturated fatty acids,but the therapy of Plantaginis Semen powder could alleviate the above metabolic disorders and improved hypertension.3.Mathematical modeling to evaluate the efficacy of Plantaginis Semen powderBased on metabolomics methods,14 biomarkers of high-fat model and 20 biomarkers of primary hypertension model were listed as independent variables in mathematical model respectively,and partial least squares-discriminate analysis(PLS-DA),truth-label clustering(TLC)reverse evaluation algorithm based on unsupervised k-means clustering information proposed by us,and supervised logical regression classification algorithm were applied to quantify pharmacodynamics of Plantaginis Semen powder and its single prescription,showing that the score of Plantaginis Semen powder group was closer to that of normal animals,which proved that the effect of Plantaginis Semen powder on lowering blood lipid,blood sugar and blood pressure was better than that of its single prescription.In summary,a series of biomarkers related to the pathology of metabolic syndrome and pharmacodynamics of Plantaginis Semen powder in the treatment of metabolic syndrome were screened by using omics technology,and various mathematical models were applied to quantitatively evaluate the efficacy of traditional Chinese medicine Plantaginis Semen powder in the treatment of metabolic syndrome,providing a supplement for the research on the efficacy of Plantaginis Semen powder.In addition,the mathematical modeling methods proposed in this study could also provide a reference for the pharmacodynamic study of other traditional Chinese medicine compound.Systematic biology was integrated to clarify the multi-target and multi-pathway characteristics of traditional Chinese medicine compound. |
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