| Treatment based on syndrome differentiation is the core requirement of clinical work of traditional Chinese medicine,which is the systematic integration of pathogenesis,method,prescription,syndrome and medicine.Prescription,as an important part of “pathogenesis-method-formula-syndrome-medicine”,is not only the concrete expression of abstract thinking in the link of “syndrome differentiation”,but also the executor of consolidating the constitution and curing diseases in the link of“treatment”,and compatibility is the fundamental way to realize the above functions of prescription.Therefore,it is of great significance to clarify the compatibility relationship and mechanism of prescriptions for revealing the scientific nature of prescriptions.Sini Decoction is a famous prescription of Zhang Zhongjing,and also a representative prescription of compatibility and application of traditional Chinese medicine.The prescription of Sini Decoction is exquisite and the law is rigorous.Although there are three kinds of drugs,the compatibility of Fuzi and Gancao and the compatibility of Fuzi and Ganjiang are the classical representatives of the seven emotions compatibility of traditional Chinese medicine.The three kinds of drugs help each other and play the role of restoring Yang together,which is the focus of attention in the modernization of traditional Chinese medicine.This paper has also done a lot of exploration work in the early stage.At present,related studies have made a lot of elaboration on the compatibility connotation of Sini Decoction from the perspective of“mutual fear/mutual killing” of Fuzi and Gancao and “mutual reinforcement/mutual promotion” of Fuzi and Ganjiang which reveals the prescription principle of Sini Decoction to a certain extent.However,the analysis found that the existing studies on the compatibility connotation of Sini Decoction mostly focused on the discussion of reducing the toxicity of Fuzi under normal physiological conditions and increasing the effect of Fuzi under pathological conditions,ignoring the high unity of drug-bodyefficacy/safety,as well as the influence of physiological factors on the compatibility relationship of prescriptions,which is not conducive to the objective interpretation of the compatibility connotation of Sini Decoction.Therefore,based on the interaction link of “Drug-Organism-Efficacy” in biopharmaceutics,this study adopts the integrated research methods of overall pharmacodynamics,metabolomics,network pharmacology and association analysis,and uses normal animals and model animals to comprehensively explore the compatibility relationship and mechanism of Sini Decoction.In order to interpret the scientific nature of the compatibility of Sini Decoction more comprehensively and objectively,and provide a reference for its safe and effective clinical medication.The main research contents are as follows:(1)Analysis of the differences between ancient and modern prescriptions of Sini Decoction: By sorting out the collection of Sini Decoction in ancient medical books and the current edition of Chinese Pharmacopoeia,it is found that Sini Decoction has maintained a good continuity in prescription composition and drug proportion structure.In terms of medicine varieties and preparation methods,there are some differences between the records in ancient medical books and the standards in the Chinese Pharmacopoeia,that is,in ancient medical books,raw Fuzi and fried Gancao are used as medicine and prepared by compound decoction,while in the Chinese Pharmacopoeia,Danfupian and honey-fried Gancao are used as medicine and prepared by separate decoction.The Sini decoction recorded in the Chinese Pharmacopoeia has more advantages in terms of efficacy and safety,can better meet the living habits and rhythm of modern people,and is more suitable for the medication requirements of modern society.Through the analysis of the existing research on the process optimization of Sini Decoction,it was found that it was difficult to prove the superiority of the optimization results compared with the pharmacopoeia method of Sini Decoction due to the problems of prescription composition,evaluation index and comparison benchmark.Therefore,it is still appropriate to carry out the related research of Sini Decoction according to the pharmacopoeia method.(2)The pharmacodynamic study on the key link of the compatibility of Sini Decoction: By establishing the rat model of chronic heart failure,the model rats and normal rats were used to simulate different physiological conditions of the body,and the same index was used to evaluate the drug effect difference of the compatibility of Sini Decoction under different physiological conditions.The results showed that the Fuzi decoction,Fuzi-Gancao decoction,Fuzi-Ganjiang decoction and Sini Decoction could effectively improve the abnormal levels of BNP,CK,LDH,c Tn T,CRP,TNF-αand other indicators in the model rats,improve the pathomorphological characteristics of myocardial tissue in the model rats,and show the effect of drug treatment.The pharmacodynamic effects of the Fuzi-Gancao decoction,Fuzi-Ganjiang decoction and Sini Decoction were better than that of the Fuzi decoction.At the same time,the results showed that Fuzi decoction,Fuzi-Gancao decoction,Fuzi-Ganjiang decoction and Sini decoction could cause abnormal increase of CK,LDH and c Tn T levels in normal rats,induce pathological damage of myocardial tissue in normal rats,and show different degrees of toxicity.However,the toxicity of the Fuzi-Gancao decoction,Fuzi-Ganjiang decoction and Sini Decoction were lower than that of the Fuzi decoction.Therefore,it is basically clear that the compatibility synergy is the core compatibility relationship between the compatibility of Fuzi and Gancao and the compatibility of Fuzi and Ganjiang under pathological conditions,and the compatibility attenuation is the core connotation of the compatibility relationship between them under normal physiological conditions.(3)Study on metabolic regulation differences in key links of Sini Decoction prescription compatibility: In view of the important links in biopharmaceutics,it was found by using metabonomics technology that Fuzi decoction,Fuzi-Gancao decoction,Fuzi-Ganjiang decoction and Sini Decoction could improve the metabolic disorder of model rats,adjust the abnormal level of related metabolites,and the metabolic pathways involved were coincident.Compared with the Fuzi decoction,Fuzi-Gancao decoction,Fuzi-Ganjiang decoction and Sini Decoction there are more kinds of regulatable metabolites,and the regulation of the same metabolites are better,showing the compatibility relationship of compatibility and synergy.At the same time,the results showed that Fuzi decoction,Fuzi-Gancao decoction,Fuzi-Ganjiang decoction and Sini Decoction could all lead to abnormal changes in the level of metabolites in normal rats,and the effect trend of different decoctions on the same metabolites was basically the same,but the interference effect of Fuzi-Gancao decoction,Fuzi-Ganjiang decoction and Sini Decoction on metabolites was lower than that of Fuzi decoction.It shows the effect of compatibility and attenuation.Through further analysis,it was found that the regulation trend of the same metabolite in model rats or normal rats by the same decoction was the same,and whether the basic level of metabolites under different physiological conditions deviated from the normal state was an important reason for the change of drug regulation significance,which was manifested as drug efficacy or toxicity.(4)Network pharmacology study on the mechanism of synergism and attenuation of Sini Decoction: The study found that the anti-heart failure pharmacodynamic network of Fuzi consisted of 66 components,43 targets and 10 pathways.After the compatibility of Fuzi and Gancao,the number of pharmacodynamic network targets increased to 49,the number of participating components increased to 292,and 3 new action pathways(vascular smooth muscle contraction,serotonergic synapse,Rap 1signaling pathway)were added.After the compatibility of Fuzi and Ganjiang,the number of pharmacodynamic network targets increased to 47,the number of participating components increased to 188,and two new action pathways(vascular smooth muscle contraction and Rap 1 signaling pathway)were added.There are 49 regulatable targets,414 participating components and 13 action pathways in the compatibility of Sini Decoction.Therefore,the synergistic mechanism of Sini Decoction compatibility may be related to the increase of regulatable targets,participating components and action pathways.And through Calcium signal pathway,c GMP-PKG signaling pathway,Neuron-active ligand-receptor interaction,c AMP signaling pathway,Adrenergic signaling in cardiomyocytes,Renin secretion,Vascular smooth muscle contraction,Myocardial contraction,Hypertrophic cardiomyopathy,Dilated cardiomyopathy,Renin-angiotensin system,Serotonergic synapse,Rap 1 signal path and other specific paths are realized.At the same time,the study found that the cardiotoxicity network of Fuzi was composed of 46 components,16 targets and Adrenergic signaling in cardiomyocytes.After the compatibility of Fuzi and Ganjiang,the related targets were not enriched to the pathways with significant significance,suggesting that Ganjiang had a weak attenuation effect on Fuzi.The compatibility of Fuzi and Gancao can regulate the cardiotoxicity of Fuzi through 18 pathways,such as Adrenergic signaling in cardiomyocytes,Synthesis and secretion of aldosterone,etc.,while the toxicity regulation pathways of the compatibility of Sini Decoction are consistent with the compatibility links of Fuzi and Gancao,which reveals the dominant position of Gancao in the toxicity attenuation of the compatibility of Sini Decoction.(5)Association analysis and validation study of metabolomics combined with network pharmacology: It was found that Adrenergic signaling in cardiomyocytes,Calcium signal pathway,c AMP signal pathway,c GMP-PKG signal pathway,Hypertrophic cardiomyopathy,Renin secretion,Myocardial contraction,Neural active ligand-receptor interaction,Vascular smooth muscle contraction,Renin-angiotensin system and other pathways were the key links of the synergistic mechanism of Sini Decoction.Reducing the effect of Fuzi on Adrenergic signaling in cardiomyocytes,Oxytocin signal pathway,Insulin signal pathway and other key pathways is the core of the attenuation mechanism of Sini Decoction compatibility.Further Western blot validation experiments showed that Sini decoction with different combinations could significantly reduce the expression of ACE,ACE2,Ang II,ATR2 and other proteins in the Renin-angiotensin system of model rats,and compared with Fuzi decoction,FuziGancao decoction,Fuzi-Ganjiang decoction and Sini decoction had better pharmacodynamic effects.Meanwhile,different decoctions of Sini Decoction could increase the protein expression levels of AKT,ERK,TNNI3 in the Adrenergic signaling in cardiomyocytes of normal rat cardiomyocytes,but the increasing effects of FuziGancao decoction,Fuzi-Ganjiang decoction and Sini Decoction were lower than those of Fuzi decoction.To sum up,based on the linkage link of “Drug-Organism-Efficacy” in biopharmaceutics,this paper explores the core connotation of the compatibility relationship of Sini Decoction under different physiological conditions through the integrated research mode of overall pharmacodynamic evaluation,metabolomics,network pharmacology and association analysis.Under pathological conditions,the compatibility relationship is based on synergistic relationship.Under normal physiological conditions,the attenuation effect is the key point of compatibility.And on this basis,the compatibility mechanism and key links are explored,which further objectively explains the scientific essence of compatibility of Sini Decoction,and also provides a reference for clinical medication,medication risk warning,quality standard improvement and other related research. |
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