| SubjectiveTo systematically study the medical records of traditional Chinese medicine for fetal protection by using data mining technology and also to summarize the differentiation of symptoms and treatment rules of ancient and modern physicians for fetal leakage and fetal irritability;to study the chemical component,functional targets,related diseases and metabolic pathways of common used herb pairs in classical fetal protection Shoutai formula:Cuscutae semen-Herba taxilli using system pharmacology methodology.In this study,the action mechanism of Cuscutae semen-Herba taxilli herb pair were investigated and analyzed.This study provided a new reference for the studies of traditional Chinese medicine theory such as compound compatibility,flavor and meridian tropism,syndrome association and screening of active components of classical Chinese medicine prescription,systemic targets discovery,etc.The purpose of this study was to inherit and carry forward the clinical experiences of ancient and modern physicians in the diagnosis and treatment of fetal leakage and fetal disturbance,and also provide references for improving the clinical diagnostic and treat levels of fetal protection.MethodsExisting medical records of ancient and modern physicians treating fetal leakage and fetal disturbance were collected and sorted out through databases such as CNKI and Chinese Traditional Medicine Database.The formulas collected were inducted,summarized and standardized by using EXCEL data management software.The IBM SPSS Statistics 25.0 and the TCM Miner software which was developed by the Institute of Traditional Chinese Medicine Information of Chinese Academy of Sciences were used to perform frequency analysis,factor analysis,system clustering analysis and association mining analysis.The laws of syndrome and treatment of fetal leakage and fetal disturbance were systematically discussed and the clinical thinking and laws of meditation for fetal protection of past dynasties were analyzed by combining professional knowledge.System pharmacology was used to explore the action mechanism of herb pairs in classical prescriptions.Firstly,the computer model developed by team of Professor Yonghua Wang of Northwest A&F University was used to screen the active ingredients and targets of Cuscutae semen-Herba taxilli herb pair.The Uniport database(https://www.uniprot.org/)was used to search the drug pairs and also the UNIPROTKB of corresponding human gene that related with targets predicted by the active compounds of the screened herb pairs.And then the candidate compounds of herb pair Cuscutae Semen-Herba taxilli were mapped to the predicted targets for constructing the compound-target and target-disease(T-D)network.Secondly,The predicted targets were mapped into KEGG pathways to establish target-pathway network of Cuscutae semen-Herba Taxilli herb pair.All networks were drawn by using Cytoscape 3.5.1 software.Results1?Results of research on the laws of meditation for fetal protection in past dynasties(1)The top five most frequently used herbs in Han,Tang and Song dynasties were Angelica sinensis radix(8.0986%),Chuanxiong rhizoma(7.7465%),Aisni corii colla(5.9859%),Glycyrrhizae(5.8099%)and Ginseng radix(4.3134%).In Yuan,Ming and Qing dynasties,the top five most frequently used antifoetus herbs were Angelica sinensis radix(7.7609%),Atractylodes rhizome(6.7351%),Glycyrrhizae(6.4228%),Paeoniae radix alba(5.9768%)and Chuanxiong rhizoma(5.6200%).The top five most frequently used antifeticide herbs in Modern times were Dipsaci radix(7.4064%),Cuscutae semen(6.7537%),Herba taxilli(6.7253%),Atractylodes rhizome(6.5551%)and Paeoniae radix alba(6.1578%).(2)According to the analysis of the frequency of classified herbs,the top three prescriptions for the treatment of threatened abortion in Han,Tang and Song dynasties were deficiency tonifying herbs(16.36%),heat-clearing herbs(11.52%)and blood-activating and stasis-eliminating herbs(6.06%).In the Yuan,Ming and Qing dynasties,deficiency tonifying herbs(22.46%),heat-clearing herbs(14.97%)and Qi-regulating herbs(6.42%)ranked the top three in fetal-relieving prescriptions.In Modern times,deficiency tonifying herbs(28.65%),heat-clearing herbs(13.45%)and wind-dampness dispelling herbs(4.68%)were the top three ranked ones.(3)Factor analysis divided the anti-abortion prescriptions in Han,Tang,Song dynasties into 9 factors,Yuan,Ming and Qing dynasties into 8 factors,Modern times into 12 factors,respectively.Basically,it is suggested that the treatment should be based on the differentiation of several syndromes including kidney deficiency,Qi deficiency,spleen deficiency,blood heat,blood stasis,etc.Different treatment methods should be developed according to different pathogenesis,for example,kidney deficiency syndrome should be treated with kidney-Qi tonifying and Chongren firming methods.The treatment of Qi deficiency should be Qi tonifying and Chongren firming methods;Spleen deficiency should be treated with spleen-invigorating and Qi-supplementing methods;Blood deficiency syndrome should be treated by blood-tonifying methods;Blood heat syndrome should be treated by heat-clearing and blood-cooling methods;The treatment of blood stasis should be blood stasis-removing and bleed-stopping methods.(4)Cluster analysis results:A total of 18 groups of meaningful clusters were summarized,including 6 groups in the Han,Tang and Song Dynasties,5 groups in the Yuan,Ming and Qing Dynasties,and 7 groups in the modern period.The 6 groups in the Han,Tang and Song Dynasties were the Baotai Pills for liver/kidney replenishing,blood-filling and fetus-relieving;the Xiangshayangwei pills for regulating Qi-flowing,harmonizing stomach and preventing nausea;the Magnolia and Ginger for Qi regulation and activation,stagnation dispersing and stasis removing;Rehmanniae and Herba taxilli for nourishing yin,liver and kidney;Jiaoai formula for blood tonification and bleed-stopping;Glutinous rice and Allii fistulosi bulbus for tonifying spleen and stomach.The five groups during Yuan,Ming and Qing dynasties were Duzhong pills with functions of Qi invigorating and liver-kidney nourishing;Jiaoai tang whose effects are blood-nourishing,bleed-stopping and miscarriage preventing;Baoqi powder and Antaiheqi decoction which can sooth liver,regulate Qi,alleviate pain and prevent miscarriage;Antai pills which can regulate Qi and nourish blood,clear heat and prevent miscarriage;Zengye tang,whose effectiveness are nourishing Yin,removing heat,moistening dryness and inducing laxation,respectively.The seven groups in the modern era were followed by Shoutai pills(functional at spleen and kidney tonifying,Qi regulating and miscarriage preventing),Sugengsharen tang(functional at Qi promoting and kidney-liver fortifying and miscarriage preventing),Baoyin decoction(functional at yin tonifying,heat clearing,blood cooling and bleed-stopping)and Taiyuan decoction(functional at kidney tonifying and miscarriage preventing).(5)Association analysis results:Association analysis showed that Angelica sinensis radix+Chuanxiong rhizoma,Angelica sinensis radix+Glycyrrhizae,Angelica sinensis radix+Glycyrrhizae were the top three herb pairs in the Han,Tang and Song dynasties,while Aisni corii colla,Chuanxiong rhizoma,Angelica sinensis radix and Glycyrrhizae were the strongly correlated herb combinations.The second-order and third-order analyses were arranged and combined in these herbs.In the Yuan,Ming and Qing dynasties,the top three herb pairs were Atractylodes rhizome+Angelica sinensis radix,Paeoniae radix alba+Angelica sinensis radix,Chuanxiong rhizoma+Angelica sinensis radix,and Angelica sinensis radix,Chuanxiong rhizoma,Glycyrrhizae,Aisni corii colla,Paeoniae radix alba,Atractylodes rhizome,Scutellariae radix were strongly associated.The top three herb pairs in Modern era were Herba taxilli+Dipsaci radix,Cuscutae semen+Dipsaci radix,Herba taxilli+Cuscutae semen.The third-order association analysis was combined among the medicinal herbs of Herba taxilli,Cuscutae semen,Dipsaci radix,Aisni corii colla,Atractylodes rhizome and lanceolata.2?Analysis results of the target and mechanism of the Cuscutae semen-Herba taxilli herb pair in the classic prescription(1)By calculating the ADME properties of all active molecules of the Cuscutae semen-Herba taxilli herb pair,12 active molecules(OB?30%,DL?0.18)were obtained,and 153 direct targets of these 12 molecules were predicted by WES(two of them had no direct targets)and these active compounds exert their pharmacological activities through these targets.A total of 75 ingredients of Cuscutae semen-Herba taxilli herb pair had been established and a database of chemical compositions has been established.(2)A total of 455 targets related to threatened abortion were collected through OMIM database,and a T-D network map was constructed for analysis.31 common targets were obtained by compared with 153 targets corresponding to the active ingredients of the Cuscutae semen-Herba taxilli herb pair which are predicted targets against threatened abortion.The main targets are is NOS3,TNF,L-6,Caspase,PTGS1,etc.(3)Through the target-pathway network analysis,we found that Cuscutae semen-Herba taxilli herb pair prevents miscarriage through MAPKs,PI3K-AKT and TGF-? signaling pathways.Conclusion1?Research conclusions on the data mining of fetal-preserving Chinese traditional medicine(1)In the Han,Tang,Song,Yuan,Ming and Qing dynasties,the most frequently used herbs were assigned to blood regulating herbs such as Angelica sinensis radix and Chuanxiong rhizoma;The most frequently used herbs in Modern times were Dipsaci radix and Cuscutae semen,which were mainly used to strengthen the kidney;The most important functions of Angelica sinensis radix,Chuanxiong rhizoma,Atractylodes rhizome,Paeoniae radix alba,Dipsaci radix,Herba taxilli are to regulate uteri ne smooth muscle contraction.(2)The use of fetal-preserving prescriptions in different periods had different emphatic points:the deficiency tonifying herbs were most frequently used in all three periods,among them,Qi tonifying herbs(Atractylodes rhizome,Ginseng radix)and blood tonic herbs(Angelica sinensis radix and Aisni corii colla)were more frequently used,and Yang tonifying herbs(Dipsaci radix and,Cuscutae semen)were more frequently used in Modern times.Herbs for activating blood circulation and removing blood stasis were widely used in the Han,Tang and Song dynasties.Herbs for regulating Qi were frequently used in the Yuan,Ming and Qing dynasties.(3)Factor analysis suggested that the causes of threatened abortion can be summarized as follows:spleen and kidney deficiency,Qi and blood deficiency,blood heat,blood stasis,etc;The pathogenesis was Chongren injury,spleen and kidney deficiency,while the kidney deficiency was the main pathogenesis.(4)Cluster analysis showed that the methods of tonifying liver-kidney,Qi and blood were the main principles for the treatment of threatened abortion,and the methods of heat-clearing and blood-cooling were more commonly used in all three stages,while the methods of blood-activating and blood-stasis removing were gradually decreased in the three stages.(5)The correlation analysis showed that the formulas with strong association in Han,Tang and Song dynasties were similar to jiaoai formula and siwu formula;the formulas with strong association in Yuan,Ming and Qing dynasties were similar to jiajian gutaiyinzi formula and the formulas with strong association in Modern times were similar to shoutai formula.It indicates that the practitioners in Han,Tang and Song dynasties mostly used jiaoai formula and siwu formula as the basic prescription for treatment of threatened abortion;practitioners in Yuan,Ming,and Qing dynasties usually adopted jiajian gutaiyinzi formula as the basic prescription;while shoutai formula was used as basic formula in Modern times.2?Research conclusions on the action mechanism of herb pair in the classical prescriptions of fetal protection(1)Through the study on the effects of the Cuscutae semen-Herba taxilli herb pair on all active molecules and high connection targets,it showed that the involved mechanism of preventing miscarriage was mainly about hematopoiesis and improving the immune function.(2)By analyzing the constructed T-D network map,we found that 31 targets in the corresponding target of the Cuscutae semen-Herba taxilli herb pair are directly related to threatened abortion.Through GO analysis,we also found threatened abortion is a complex disease caused by many factors,and the multi-angle treatment is of great significance.(3)Through the target-pathway network enrichment analysis,it was found that the active molecules of Cuscutae semen-Herba taxilli herb pair acts on multiple pathways.The mechanism of this herb pair is mainly about regulating the expression of multiple signaling pathways,correcting the state of under/over-expression so that maintain normal pregnancy.System pharmacology analyses in this study found that the effect of Cuscutae semen-Herba taxilli herb pair on threatened abortion is mainly achieved by hematopoiesis and improving the immune function,which showed the interaction characteristics of the "multi-components,multi-targets,multi-channels" in.traditional Chinese medicine.This study provided a scientific basis for further exploring its action mechanism,and also provided a research thinking for the pharmacodynamic substance basis and action mechanism of Chinese herbal compounds preventing and treating threatened abortion. |
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