Construction Of "Fang-Disease-Syndrome" Network Of FTZ In The Treatment Of Hyperlipidemia With Liver Depression And Spleen Deficiency Syndrome And Mining The Action Characteristics Of Fang

Background:Hyperlipidemia is a common clinical disease.Because it is closely related to atherosclerotic diseases,it has attracted more and more attention and become a research hotspot.Especially in recent years,it has been found that hyperlipidemia is often accompanied by abnormal glucose metabolism and nonalcoholic fatty liver disease.A variety of metabolic disorders coexist,which increases the difficulty of treatment.Traditional Chinese medicine is mainly based on syndrome differentiation and treatment.It shows certain advantages and characteristics in dealing with the difficult clinical problems of the coexistence of multiple metabolic disorders.Liver depression and spleen deficiency syndrome is not only a common clinical syndrome,but also one of the main syndromes of hyperlipidemia.FTZ is a compound traditional Chinese medicine for the treatment of hyperlipidemia.It has the effects of regulating the liver and activating the pivot,drying dampness and resolving phlegm,removing blood stasis and removing turbidity.Previous clinical and experimental studies have shown that it has the comprehensive effects of lipid-lowering,hypoglycemic and anti-inflammatory.Because the traditional Chinese medicine compound has the characteristics of multi-component and multi-target;The pathological mechanism of hyperlipidemia is polygenic,multi-target and multi-channel;At the same time,the modern research of liver depression and spleen deficiency syndrome(LDSD)also suggests that the biological mechanism of this syndrome is multi-target,multi-channel and multi systematic.In the face of three complex systems,how to establish their "prescription disease syndrome" network and visualize the relationship between the three is one of the key scientific problems to be solved in the study of TCM syndrome,and it is also a beneficial exploration and attempt of new technologies and methods in the study of TCM.Based on this,this study attempts to establish three databases of FTZ component target,hyperlipidemia related genes and LDSD related genes respectively based on the principles and technologies of network pharmacology and using the existing research results of diseases,prescriptions and syndromes,and establish three networks of FTZhyperlipidemia(Fang-disease),FTZ-LDSD(Fang-syndrome)and hyperlipidemia-LDSD(disease-syndrome)by using network pharmacology technology.Through the comparative analysis of the three networks,the "Fang-disease-syndrome" network system is finally established,and the above network system is used to systematically and visually present the functional characteristics of FTZ in treating the disease syndrome.This study presents the research results of FTZ(Fang),hyperlipidemia(disease)and LDSD(syndrome)in a systematic and networked way,which provides a reference technology and method for the study of "modern scientific interpretation of the principles of traditional Chinese medicine".At the same time,the relevant database established has laid a solid foundation for the later establishment of the "Fang-disease-syndrome" prediction model.The revealed action characteristics of FTZ have important guiding significance for the clinical application of this prescription.Method:1.Search the relevant literature of LDSD in China National Knowledge Infrastructure,and use Cite Space V 5.6 R5 software carries out visual analysis on personnel and keywords,and analyzes the evolution of keywords,so as to understand the research status in this field,the evolution of research hotspots and research methods,and predict its research trend.2.Finding the effective components and action targets of FTZ,hyperlipidemia related targets,LDSD related targets through text data mining and database,and using uniport database to standardize the targets.The "drug-ingredient-target" network will be constructed,and the potential action targets of FTZ,hyperlipidemia targets and targets of LDSD will be analyzed.3.Building the "Fangn-disease" network,"Fang-syndrome" network,"diseased-syndrome" network and "Fang-disease-syndrome" network by Network Pharmacology.The "Fang-disease" protein protein interaction networks(PPI),"Fang-syndrome" PPI network,"disease-syndrome" PPI network and "Fang-disease-syndrome" PPI network will be constructe,and the key targets and core targets will be screened.Go analysis and KEGG pathway analysis on the key genes of FTZ in the treatment of hyperlipidemia,the key genes of FTZ in the treatment of LDSD,the genes of hyperlipidemia with LDSD,and the key genes of FTZ in the treatment of hyperlipidemia.4.Searching the literature related to FTZ in relevant databases,Meta analysis was used to evaluate the efficacy of FTZ in the treatment of dyslipidemia.And the correlation analysis between the actual clinical and experimental research results of FTZ and the constructed network is used to explain the function characteristics of FTZ.Results:1.The research hotspots in the field of LDSD focus on the basic research of syndrome biology and the treatment of traditional Chinese medicine;The research trend has shifted from clinical research to basic research,such as neuroendocrine network,brain gut axis,intestinal flora and so on.In addition,the disease spectrum studied in this field has changed,from the main nervous system and digestive system diseases to gradually pay attention to Hashimoto’s thyroiditis,metabolic syndrome,DM,dyslipidemia and other immune and endocrine system diseases.2.FTZ component-target database,hyperlipidemia-target database and LDSD-target database were established.The GO analysis and KEGG pathway analysis results of the above targets are as follows:(1)There are 174 active components and 368 potential targets of FTZ;The results of GO analysis were the response to lipopolysaccharide,alcohol,nutritional level,oxygen level,neurotransmitter activity,ligand activated transcription factor activity,DNA binding,transcription factor binding,etc;The most significantly KEGG pathway is lipid and atherosclerosis.(2)There are 5597 targets related of hyperlipidemia;Go analysis showed that disease targets were mainly involved in biological processes such as lipid localization and transport,steroid metabolism,lipopolysaccharide,peptide hormones and so on;The most significant KEGG pathway is the AGE-RAGE signaling pathway in diabetic complications.(3)There are 1355 targets related to LDSD.The go analysis results are the response to lipopolysaccharide,nutritional level,regulation of chemical synaptic transmission,aging and so on.The most significantly KEGG signaling pathway is through active ligand receptor interaction.3.The "Fang-disease" network,"Fang-syndrome" network,"disease-syndrome" network and "Fang-disease-syndrome" network were established.The following results can be obtained by analyzing the above networks:(1)The "Fang-disease" network has 484 nodes and 2298 edges,and its network density is 0.020.The target of FTZ treat hyperlipidemia involving the biological processes such as response to lipopolysaccharide,response to oxidative stress,response to peptide hormones and so on;The pathways involving lipid and atherosclerosis,AGE-RAGE signaling pathway in diabetes complications,IL-17 signaling pathway and so on..(2)The "Fang-syndrome" network has 337 nodes,1497 edges and its network density of 0.026.The target of FTZ in the treatment of LDSD may be involved in biological processes such as response to lipopolysaccharide,proliferation and regulation of smooth muscle cells,regulation of peptide hormones and apoptotic cells;The pathways involved include AGE-RAGE signaling pathway,HIF-1 signaling pathway,IL-17 signaling pathway,blood shear stress and atherosclerosis in diabetic complications..(3)The "disease-syndrome" network has 801 nodes,20921 edges,and the network density is 0.065.Go analysis showed that the pathological process mainly involved the response to lipopolysaccharide,positive regulation of cytokine production,epithelial cell proliferation,cytokine mediated signal pathway and so on;The most significantly enriched KEGG pathway is lipid and atherosclerosis.(4)the "Fang-disease-syndrome" network has 327 nodes,1455 sides and its network density is 0.027.The key targets of its treatment are involved in lipopolysaccharide reactions,regulation of proliferation of smooth muscle cells,regulation of apoptotic cells and reactions to metal ions.The main pathways involved include AGE-RAGE signaling pathway,HIF-1 signaling pathway and IL-17 signaling pathway.4.A total of 17 randomized controlled studies were included.The results showed that FTZ can reduce TC,TG,LDL-C and increase HDL-C level.Correlation analysis between the actual research and the constructed networkrevealed that FTZ can synergistically regulate multiple systems such as endocrine system,nervous system,and immune system through174 components,368 targets and 211 pathways,and can act on AMPK signal pathway,PPAR signal pathway and other pathways to exert multiple effects,such as lipid regulation,hypoglycemia reduction,bone quality improvement,anti intestinal aging,energy metabolism and amino acid metabolism.It also can achieve long-term stability of lipid-lowering efficacy by regulating the synthesis,transport,and decomposition of lipids.Conclusion:1.Using the methods of network pharmacology and knowledge mapping,the complex system of "Fang-disease" network,"Fang-syndrome" network,"disease-syndrome" network and visual presentation of "Fang-disease-syndrome" can be constructed.2.The pathogenesis of hyperlipidemia is closely related to the occurrence and development of diabetes,atherosclerosis,nonalcoholic fatty liver disease and other diseases;lipid metabolism targets and glucose metabolism targets have commonalities,and the proposal of glucose and lipid metabolism diseases is reasonable and can be integrated understanding and comprehensive prevention and treatment.3.There are 801 nodes(targets)in the "disease-syndrome" network,suggesting that there may be a common biological basis between LDSD and hyperlipidemia,explaining the complexity of the development process of LDSD in hyperlipidemia and its correlation at the molecular level,providing theoretical basis and data support for the study of the combination of disease and syndrome4.FTZ has the characteristics of multi-component,multi-target and multi-pathway synergistic effect,which can comprehensively regulate multiple systems to exert multiple effects such as lipid regulation,hypoglycemic,improvement of bone quality,anti-intestinal aging,regulation of energy metabolism and amino acid metabolism,and can regulate the whole process of lipid metabolism to achieve long-term stability of lipid-lowering efficacy.