Identificational Research On Ancient Prescriptions For Xiaoke Disease Based On Ancient-TCM-Books-Evidence-based Medcine And Cyberpharmacology

1 Research backgroundAccording to Diabetes Atlas(10th edition)issued by International Diabetes Federation(IDF)in 2021,it is estimated that the global adult group of diabetes patients and its "reserves"(impaired fasting glucose and impaired glucose tolerance,IFG and IGT)will totally be about 1.397 billion.The epidemiological survey of diabetes in China in 2021 shows that adult diabetes is about 140.9 million,increased 21.05%compared with 2019,and has been ranking No.1 in the world since 2010.Data shows that Chinese population is huge,incidence of diabetes is relatively high,diabetes and its "reserve army" grow rapidly,more and more,which is really a very grim situation.Among the patients with diabetes,type 2 diabetes occupies the main position,which corresponds to the TCM disease Xiaoke disease.Traditional Chinese Medicine(TCM)has a long history of prevention and treatment of Xiaoke disease,and has achieved remarkable results.Those ancient prescriptions recorded in the ancient TCM books is crystallization of prevention and treatment practices of physicians in past dynasties,and is one of the important sources for screening and supplementing prescriptions for treatment of diabetes.From perspective of Evidence-based Medcine,exploring high-level evidence of ancient prescriptions for Xiaoke disease in ancient TCM books,and applying modern means to interpret microscopic mechanism of those prescriptions are possible means to quickly screen and excavate Chinese medicine for diabetes.2 Research PurposeFrom perspective of Ancient-TCM-Books-Evidence-based Medcine,we explored and analyzed the effectiveness of ancient prescriptions for Xiaoke disease in ancient TCM books,and applied Cyberpharmacology methods to explore and analyze the effectiveness and pertinence of ancient prescriptions from molecular network mechanism,in order to find out more effective prescriptions for treating type 2 diabetes from ancient TCM books,and provide support for its modern clinical application.3 Research Methods(1)Literature research method.Widely collect TCM books of Xiaoke disease related resource information scattered in ancient literature before 1911,determine the scope of literature collection,formulate the reference list and the standard of information received,and determine the research object.The resource information related to Xiaoke disease in those collected literature,such as the concept,etiology,pathogenesis and medication based on differentiation of treatment,was comprehensively and systematically sorted,classified,edited,and standardized indexed.Differentiate and analyze the relationship between Xiaoke syndrome and Xiaoke disease,relationship between generalized Xiaoke disease and narrow Xiaoke disease,etc.The historical evolution of Xiaoke disease was combed vertically and horizontally,and the pathogenesis differentiation and treatment were summarized to explore the related theory of Xiaoke disease.(2)Ancient-TCM-Books-Evidence-based Medcine.Evidence-based Medicine aims to improve medical quality and academic level by raising problems to be solved,collecting evidence of relevant problems,applying relevant evaluation criteria to evaluate authenticity and practicability of these materials,and applying the results in clinical and medical research.In this study,by determining the source of evidence retrieval and the search term of ancient TCM books,the inclusion and exclusion criteria for screening the content of ancient TCM books were formulated,and by judging the similarity criteria for diagnosis of ancient and modern diseases,the evidence collection and sorting of ancient TCM books were completed.The extracted evidence was evaluated using Evaluating and Grading Scale for Prevention and Treatment Evidence of Ancient Chinese Medical Books(abbr.Scale),and high-level evidence of ancient prescriptions for treating Xiaoke disease in ancient TCM books was excavated.(3)Cyberpharmacology.Cyberpharmacology is to explain the occurrence and development of diseases from the perspective of system biology and biological network balance,understand the interaction between drugs and body from the perspective of holistic view of improving or restoring biological network balance,and guide discovery research of new drugs.In this study,OMIM,GeneCards database and other databases were used to search for type 2 diabetes related target genes,and TCMSP,BATMAN-TCM,Swiss TargetPredict,UniProt database were used to search for effective ingredients and corresponding targets of these 8 Relevant weak recommended prescriptions.Take the intersection of the related targets of type 2 diabetes and the effective ingredient targets of each prescription to obtain the potential targets of each prescription for treatment of type 2 diabetes.String database was used to build PPI network of these 8 prescriptions for treatment of type 2 diabetes.The degree value was taken to be greater than or equal to twice the median to screen in core network,analyze the core active ingredients and core targets,carry out KEGG pathway and GO biological function enrichment analysis,and explore the effectiveness of mining ancient prescriptions at molecular network mechanism level.4 Research contents(1)Historical evolution and theoretical discussion of Xiaoke disease.Collect and sort out the ancient and modern literature of Xiaoke disease,vertically sort out the general situation of its academic development of Xiaoke disease in different historical periods,horizontally compare and analyze the similarities and differences of different doctors’ academic views in each historical periods,and explain the evolution of TCM understanding of theory of Xiaoke disease through vertical and horizontal sorting and differentiation of literature and doctors’ academic views of each dynasty.Discussed the difference between Xiaoke syndrome and Xiaoke disease,the difference between general sence Xiaoke disease and narrow sence Xiaoke disease,and the intersection relationship between narrow sence Xiaoke disease and type 2 diabetes.In the part of pathogenesis,syndrome and treatment,thesis author emphatically discusses"originated from Yang" etiology of Xiaoke disease,"Yin Fire" pathogenesis,the differentiation of treatment from Yin and Yang,and the differentiation of treatment from Five Zang.(2)Evaluation and recommendation of evidence of ancient TCM prescriptions for Xiaoke disease.This research aims at problem of discovering ancient prescriptions for treatment of Xiaoke disease in TCM,systematically collects and collates the evidence of prescriptions for Xiaoke disease in ancient TCM books,and applies the Scale to carry out evidential evaluation,grading and recommendation of prescriptions recorded in ancient TCM books from two aspects of the source of evidence and the content of the evidence itself,in order to provide scientific support for identification of ancient prescriptions for the Xiaoke disease.(3)Research on molecular network mechanism of 8 relevant weak recommended prescriptions in treatment of type 2 diabetes.The Cyberpharmacology method was used to construct target PPI network of 8 relevant weak recommended prescriptions for treatment of type 2 diabetes,including Rhubarb Pill,Ginseng Granule,Astragalus Decoction,Pilose Antler Pill,shengjin Ganlu Decoction,Angelica liuhuang Decoction,Shenxiao Granule and Yuquan Pill,etc.The core components and target network were analyzed,and mechanism of these 8 prescriptions for treatment of type 2 diabetes was analyzed from the molecular network level.5 Research results(1)The cognitive development of TCM on Xiaoke disease can be divided into five stages.Pre-Qin and Han Dynasties was embryonic period of Xiaoke disease theoretical system,Wei-Jin-Sui-Tang Dynasties was mature period,Song-Jin-Yuan Dynasties was enrichment period,Ming-Qing Dynasties was improvement period,and Modern times was collection,refinement and promotion period.From the perspective of "weak endowment constitution and pathogenic factors outside" in Huang Di Nei Jing",pathogenic factors includes "originated from Yin" and "originated from Yang".Taking Baihu Decoction plus Ginseng as an example,this paper discusses the theory of "Hidden evil" that links exogenous diseases with internal injuries,and taking Shenqi Pill and Shengjin Ganlu Decoction(Shengjin Ganlu Decoction belongs to"Dongyuan Xiaoke Seven Prescriptions")as examples to discuss "Yin Fire"pathogenesis.(2)335 pieces of ancient TCM prescriptions for treating Xiaoke disease were evaluated,scored and graded item by item according to the Scale(for Xiaoke disease).Finally,48 pieces of evidence were evaluated as high-level evidence,115 pieces were evaluated as moderate-level evidence,and 172 pieces were evaluated as low-level evidence.These high-level evidences are comprehensively analyzed in combination with some possible influencing factors,then,6 strong recommended prescriptions including Baihu Decoction plus Ginseng,Shenqi Pill,Shengmai Granule,Xiaoke Formula,Liuwei Dihuang Decoction and Yuye Decoction,and 10 weak recommended prescriptions including Rhubarb Pill,Ginseng Granule,Zhudu Pill,Astragalus Decoction,Pilose Antler Pill,shengjin Ganlu Decoction,Angelica liuhuang Decoction,Poria Decoction,Shenxiao Granule and Yuquan Pill are gotten.(3)Further research was carried out on these weak recommended prescriptions.Two prescriptions,Zhudu Pill and Poria Decoction,with poor medicinal properties,were removed.Results of Cyberpharmacology research on these 8 prescriptions in this study suggested that although they could therapy type 2 diabetes,their treatment directions were slightly different from each other.Rhubarb Pill may play a role mainly through Estrogen pathway.Ginseng Granuler,Pilose Antler Pill,Shengjin Ganlu Decoction,Shenxiao Granule,Yuquan Pills may benefit cardiovascular system,Shengjin Ganlu Decoction,Shenxiao Granule may be more effective in vascular endothelial function,platelet activation.Ginseng Granule,Huangqi Decoction may benefit nervous system.Angelica liuhuang Decoction may play its role mainly through inflammatory pathway,Yuquan Pill may act on reproductive endocrine pathway to improve ovarian function.6 Conclusion(1)The combination of Ancient-TCM-Books-Evidence-based Medcine and Cyberpharmacology in identificational research of ancient prescriptions for Xiaoke disease is effective and feasible,which can provide a method choice for identificational research of ancient prescriptions for other diseases.(2)The molecular network mechanism of 8 weak recommended prescriptions,including Rhubarb Pill,Ginseng Granule,Astragalus Decoction,Pilose Antler Pill,shengjin Ganlu Decoction,Angelica liuhuang Decoction,Shenxiao Granule and Yuquan Pill,was studied.Some comparative analysis was done with literature reports of 6 strong recommended prescriptions.Strong recommend and weak recommend prescriptions are relatively consistent in terms of Core Components,Targets,pathways,etc.Moreover,these 8 weak recommended prescriptions prescriptions have their own unique directions.They are potential ancient prescriptions for treating type 2 diabetes.It is speculated that application in corresponding complications may have a better effect.(3)The six evils "originated from yang" and also some miasma,etc.which have been incubated for a relatively long perioid,can lead to Xiaoke disease.These factors may act as common causes of exogenous diseases and internal injuries,Hidden Evils Theory connects exogenous diseases with internal injuries.This paper also discussed"Yin Fire" pathogenesis from the perspective of Pivot.These discussions enrich the theoretical system of etiology and pathogenesis of Xiaoke disease and can provide some ideas for further study of theoretical system of etiology and pathogenesis of other diseases.7 Innovation(1)This paper evaluated and recommended evidence of prescription on treating Xiaoke disease in ancient TCM books from perspective of Evidence-based Medicine,explored the molecular network mechanism by means of Cyberpharmacology.An identification research study was carried on ancient Prescription treating Xiaoke disease.(2)Hidden Evils Theory connects exogenous diseases with internal injury diseases.The Six Evils,and Miasma,etc.have been incubated for a relatively long perioid,may become Hidden Evils,which may lead to Xiaoke disease.It is the common cause of exogenous diseases and internal injury miscellaneous diseases."Yin Fire" pathogenesis was discussed from the perspective of Pivot.