| Background:China has abundant ginkgo leaf resources.Ginkgo biloba accounts for about 90%of the global ginkgo tree resources and is the main producing area of ginkgo leaves.China is also the world’s largest producer of ginkgo biloba extract.In 2017,the output reached 558.4 tons,and the production scale exceeded 190 million yuan,indicating that the use of ginkgo leaf preparations in China has gradually increased,and the acceptance of ginkgo leaf preparations has gradually increased.Increase.Ginkgo biloba preparations entered the national essential medicines catalogue and were included in the medical insurance catalogue,indicating that the demand for ginkgo leaf preparations is gradually increasing.At present,ginkgo leaf preparation is widely used for the treatment of coronary heart disease,stroke,hyperlipidemia,dementia and other diseases,but it is often used as an auxiliary medicine in clinical application,and it is necessary to actively explore the specific target population of ginkgo leaf preparation Therefore,Ginkgo biloba leaves were measured in the whole background,and the clinical application and research status of Ginkgo biloba preparations were analyzed.Related studies have shown that Ginkgo biloba extract has the function of blocking the binding of platelet activating factor and receptor,thereby reducing blood viscosity,lowering blood lipids,improving vascular endothelial cell function,and preventing the occurrence and development of cardiovascular and cerebrovascular diseases.At the same time,Ginkgo biloba leaves are one of the recommended drugs for the treatment of hyperlipidemia.Therefore,the use of ginkgo leaf preparation for the treatment of hyperlipidemia as the research direction of this study.In this study,meta-analysis and network pharmacology were used to investigate the therapeutic characteristics and mechanism of Ginkgo biloba preparation in the treatment of hyperlipidemia,which provided the basis and direction for the high-quality evidence-based evaluation of Ginkgo biloba preparation in clinical application.Study 1 Bibliometric analysis of the full background study of Ginkgo biloba leaves Objective:To analyze the clinical application and research status of ginkgo leaf preparation by bibliometric method.Research methods:Computer search CNKI,CBM,Wan Fang Data and other databases,using Ginkgo biloba as the key word,collect research literature on Ginkgo biloba leaves.The search time is from database construction to June 2018.The literature was screened and classified according to publication time,literature publication type,ginkgo leaf preparation dosage form,adverse reactions,etc.,and the clinical application and research status of Ginkgo biloba leaves were analyzed and evaluated.Results:1 A total of 8932 articles on Ginkgo biloba leaves were included in the study,of which 3,945 were related to the basic research of Ginkgo biloba;3,837 were related to the clinical study of Ginkgo biloba;994 were related to the extraction and preparation of Ginkgo biloba preparation;The article deals with the distribution,planting and cultivation of ginkgo leaves.2 Published literature is divided into 4 categories according to their types:journal articles,dissertations,conference papers,newspaper articles and other types.The annual average literature on ginkgo leaf research has increased from 1 article before 1985 to 42 articles from 1985 to 1998,and then to 424 articles from 1998 to 2011,and finally to 410 articles from 2011 to 2018.3 3945 basic research literatures:1004 articles related to experimental research on cell proliferation and apoptosis;845 articles related to experimental research of ischemia-reperfusion model;542 articles related to experimental research on hypoxia model;There are 368 articles related to the experimental study of atherosclerosis model;255 articles related to the experimental study of diabetes-related models;112 articles related to the experimental study of dementia model;the remaining 855 articles are difficult to classify due to the mechanism of action For the other.4 3837 clinical studies were divided into 1742 injections,1222 tablets,288 pills,465 capsules,12 granules,15 other dosage forms,such as tinctures and ointments,and the remaining 93 articles were not specific.Describe the dosage form.3,837 clinical studies have 1468 articles on cerebrovascular diseases;1346 articles on cardiovascular diseases;394 articles on endocrine diseases;159 articles on ENT diseases;142 on kidney systems Disease literature;103 literature on lung system diseases;72 articles on other systemic diseases.5 Clinical research 3,837 articles are distributed in 545 journals,and the journals are scattered.Among them,there are 218 journals that publish only one document,accounting for 40%of the total number of journals.There are 34 journals that publish more than 12 documents,accounting for journals,6%of the total.Among them,authors in East China have the most literature;authors in Northwest China and Southwest have the least amount of literature.6 A total of 43 articles describing the adverse reactions of Ginkgo biloba preparations,including 10 reviews,were included in the study.The adverse reactions in 30 of the 33 literatures were due to the use of Ginkgo biloba injections,and the remaining three documents did not specify which dosage form to use.Ginkgo biloba injection adverse reactions are mainly reflected in skin and vascular damage,systemic damage,central and peripheral nerve damage,cardiovascular and cerebrovascular damage,digestive system damage,respiratory damage.Among them,serious adverse reactions are anaphylactic shock,angina pectoris,liver damage and the like.Ginkgo biloba preparations are incompatible with some drugs,mainly Shuxuening injection and pantoprazole sodium injection,alprostadil injection,breviscapine injection,prostaglandin E1 injection,Brucea javanica oil emulsion injection There are incompatible contraindications for anti-infectives such as cefradine;there is also a contraindication between Ginaton and furosemide injection.Summary of research:1 The number of research literatures on Ginkgo biloba leaves is increasing year by year,indicating that the research on Ginkgo biloba leaves has received more and more attention,and the number of clinical studies and basic research literatures of Ginkgo biloba leaves are basically the same,indicating that researchers pay attention to the clinical aspects of Ginkgo biloba leaves.Applying curative effect,and paying attention to its mechanism of action,basis of drug efficacy and research of pharmaceutical ingredients;2 Ginkgo biloba preparations include a variety of dosage forms,and the commonly used dosage form in the clinic is an injection;3 The most commonly used disease in Ginkgo biloba preparation is cardiovascular and cerebrovascular diseases;4 Ginkgo biloba injection has many adverse reactions in the clinic,the main adverse reactions are skin and vascular damage and systemic damage;5 Shuxuening injection in Ginkgo biloba preparation is incompatible with various drugs,so it is clinically necessary to reduce or avoid compatibility with other injections.Study 2 Meta-analysis of Ginkgo biloba preparation for treatment of hyperlipidemiaObjective:To evaluate the efficacy and safety of ginkgo leaf preparation in the treatment of hyperlipidemia based on meta-analysis.Research methods:Search PubMed,Embase,Cochranelibrary,Wangfang Data,CBM,VIP,CNKI and other databases,and incorporate Ginkgo biloba preparations to treat hyperlipidemia in randomized controlled trials.The literature was checked,screened and extracted according to the standard of the row.Meta-analysis of various indicators of blood lipids was performed using RevMan5.3 software,and safety analysis and bias analysis were performed.Results:1 Inclusion of the literature:9 articles using Ginkgo biloba preparation alone to treat hyperlipidemia;16 articles using Ginkgo biloba preparation for hyperlipidemia.The final literature included is Chinese literature.Most of the included literature did not mention its method of allocation concealment;the funnel plot suggests that the included literature may have a publication bias.2 In the 9 studies using Ginkgo biloba preparation alone,the control drugs of 5 studies were proprietary Chinese medicines,namely Xuezhikang Capsule,Gynostemma Pentaphyllum capsule,lipid tablets;the control drugs with 4 studies were Western medicine,respectively simvastatin,smoke Acid inositol ester.The comparators for the 16 studies using the Ginkgo biloba formulation were all statins.The 12 of each of the above studies was greater than 50%,so a random effects model was used.3 Clinical efficacy of Ginkgo biloba preparation alone:3.1 Improve the efficacy of TC:After treatment,in the reduction of TC levels,Ginkgo biloba leaf preparation efficacy is higher than the Chinese patent medicine group,the difference between the two groups was statistically significant[95%CI(-0.77,-0.12),P=0.007<0.05];The efficacy of ginkgo leaf preparation was not lower than that of western medicine group,and the difference between the two groups was not statistically significant.[95%CI(-1.48,0.86),P=0.60>0.05].3.2 Improve the efficacy of TG:After treatment,the efficacy of Ginkgo biloba leaf preparation was not lower than that of Chinese patent medicine group in reducing TG level.There was no significant difference between the two groups[95%CI(-1.00,0.35),P=0.34>0.05];Ginkgo biloba leaf preparation effect was not lower than Western medicine group,the difference between the two groups was not statistically significant[995%CI(-0.34,0.13),P=0.38>0.05].3.3 Improve the efficacy of HDL-C:After treatment,the efficacy of Ginkgo biloba leaf preparation was higher than that of the Chinese patent medicine group in improving HDL-C level.The difference between the two groups was statistically significant.[95%CI(0.00,0.18),P=0.04<0.05];the efficacy of ginkgo leaf preparation was not lower than that of western medicine group,and the efficacy of the two groups was statistically significant.[95%CI(0.03,0.26),P=0.02<0.05]3.4 Improve the efficacy of LDL-C:After treatment,the efficacy of Ginkgo biloba leaf preparation was not lower than that of Chinese patent medicine group in reducing LDL-C level.There was no significant difference between the two groups[95%CI(-0.64,0.26),P=0.41>0.05];the efficacy of ginkgo leaf preparation was not lower than that of western medicine group,and there was no significant difference between the two groups[95%CI(-0.52,2.02),P=0.25>0.05].4 The efficacy of combined use of Ginkgo biloba preparation:4.1 Improve the efficacy of TC:After treatment,in the reduction of TC levels,the combined use of Ginkgo biloba preparation group was significantly better than the control group,the difference between the two groups was statistically significant[95%CI(-1.21,-0.53),P<0.00001].4.2 Improve the efficacy of TG:After treatment in the reduction of TG levels,the combined use of Ginkgo biloba preparation group was significantly better than the control group,the difference between the two groups was statistically significant[95%CI(-0.61,-0.39),P<0.00001].4.3 Improve the efficacy of HDL-C:After treatment,in the increase of HDL-C level,the combined use of Ginkgo biloba preparation group was significantly better than the control group,the difference between the two groups was statistically significant[95%Cl(0.23,0.43)),P<0.00001].4.4 Improve the efficacy of LDL-C:After treatment,in the reduction of LDL-C level,the combined use of Ginkgo biloba preparation group was significantly better than the control group,the difference between the two groups was statistically significant[95%CI(-1.02,-0.55),P<0.00001].5 Subgroup analysis results of Ginkgo biloba preparations used in different age groups:According to age stratification,9 studies were divided into three groups:Ⅰ.Age≤50 years old;Ⅱ.50 years old<Age≤60 years old;Ⅲ.60<Age≤70 years old,using a random effects model.In the age group of 50 to 60 years old,the TC level in the Ginkgo biloba preparation group was better than that in the control group(Xuezhikang Capsule,Simvastatin Tablets,Inositol Nicotinate,Gynostemma Pentaphyllum).The difference between the two groups was statistically significant.[95%CI(-0.93,-0.24),P=0.0099<0.05].In the other two age groups,there was no significant difference between the Ginkgo biloba leaf preparation group and the control group,indicating that the TC level in the Ginkgo biloba leaf preparation group was not lower than that of the control group.In the<50-year-old age group,Ginkgo biloba extract reduced TG level better than the control group(Xuezhikang Capsule,Simvastatin Tablet),and the difference was statistically significant[95%CI(0.03,0.21),P=0.01<0.05].In the other two age groups,the TG level in the experimental group was not lower than that in the control group,and the difference between the two groups was not statistically significant.6 Safety results:3 of the 9 studies using Ginkgo biloba preparation alone did not mention adverse reactions;3 did not find significant adverse reactions;3 found significant adverse reactions.There were 3 cases of gastrointestinal reactions in the treatment group;10 cases of gastrointestinal reactions occurred in the control group,and 2 cases of rash appeared.Nine of the 16 studies using Ginkgo biloba preparation did not mention adverse reactions;2 had no adverse reactions;5 found adverse reactions,the main adverse reaction was elevated alanine aminotransferase(ALT),but discontinued After gradually returning to normal.Summary of the study:11 The quality of the included literature is low and biased.Most of them do not describe their random methods,how to assign concealment and how to design blind methods.It indicates that most clinical trials on ginkgo leaf preparation for treatment of hyperlipidemia exist in trial design and reporting specifications,defect;2 In the clinical treatment of hyperlipidemia,Ginkgo biloba preparations are used alone and in combination,and the most commonly combined drugs are statins;3 Through stratified analysis of age,it was found that Ginkgo biloba preparation has obvious therapeutic effect on TG level in patients aged<50 years old;Ginkgo biloba preparation has significant reduction in TC level in patients aged 50 to 60 years old effect.Ginkgo biloba preparation combined with statins for the treatment of hyperlipidemia can improve clinical efficacy.Study 3 Analysis of the target and mechanism of Ginkgo biloba treatment for hyperlipidemia based on network pharmacologyObjective:Using network pharmacology analysis method to construct a bio-network of Ginkgo biloba treatment for hyperlipidemia,analyze the effective target of Ginkgo biloba treatment for hyperlipidemia,explore its mechanism of treatment of hyperlipidemia,and provide theoretical basis for clinical treatment..Research methods:(1)Screening the active constituents of Ginkgo biloba leaves and predicting the target components.Based on OB>30%and DL>0.18,the effective active components of Ginkgo biloba leaves were screened in the TCMSP database,and the target of active ingredients was predicted in the Swiss Target Prediction database.(2)Search for disease targets of hyperlipidemia through UniProt,Therapeutic Target Database,and Online Mendelian Inheritance in Man database.(3)Using Cytoscape software to construct a target network map of effective active ingredients of Ginkgo biloba leaves in the treatment of hyperlipidemia,and perform GO Ontology(GO annotation)and KEGG pathway analysis on the target by DAVID database.Results:1 Active components and targets of Ginkgo biloba:26 effective active components of Ginkgo biloba leaves were screened in the TCMSP database,and 390 potential targets of 26 active components were predicted based on the Swiss Target Prediction platform.2 To construct a network map of hyperlipidemia disease targets:construct a network map of hyperlipidemia disease targets through String online software and Cytoscape software.3 Ginkgo biloba treatment of hyperlipidemia target analysis:mapping the target of Ginkgo biloba active ingredient and hyperlipidemia target,and obtaining 18 targets of Ginkgo biloba active ingredient in the treatment of hyperlipidemia.GO annotation and KEGG pathway analysis of 18 targets by DAVID database.The top 10 in biological process analysis are positive regulation of RNA polymerase Ⅱ promoter transcription,signal transduction,and negative transcription of RNA polymerase Ⅱ promoter.Regulation,regulation of lipid metabolism,regulation of cholesterol homeostasis,receptor-mediated endocytosis,response to drugs,peptidyl-threonine phosphorylation,circadian rhythm,response to low density lipoprotein particles;cell group The top 10 nucleus,membrane,nucleoplasm,cytoplasm,plasma membrane,receptor complex,Golgi,microtubule-associated complex,spindle microtubule,ER to Golgi transport vesicle membrane in the analysis;molecular function analysis Top 10 in protein binding,enzyme binding,chromatin binding,very low density lipoprotein particle receptor activity,low density lipoprotein receptor activity,apolipoprotein binding,RNA polymerase Ⅱ transcription factor activity,ligand activation Sequence-specific DNA binding,core promoter sequence-specific DNA binding,steroid hormone receptor activity,glycoprotein binding;KEGG pathway analysis tops the estrogen signaling pathway,reminder Signaling pathway,of GnRH signaling pathway,insulin resistance,toxoplasmosis,hepatitis C,of MAPK signaling pathways,type Ⅱ diabetes,ovarian steroidogenesis.Summary of the study:This study describes the effects of Ginkgo biloba on the regulation of lipid metabolism,regulation of cholesterol balance in the body,and reduction of low-density lipoproteins in the treatment of hyperlipidemia from the perspective of network pharmacology.Ginkgo biloba mainly acts through MAPT.Targets such as ESR1,ABCC3,ESR2,LDLR,LRP8,and VLDLR play a role in regulating blood lipids.The target is mainly enriched in estrogen signaling pathway,insulin resistance,type Ⅱ diabetes,etc.,and is highly therapeutic for the clinical use of ginkgo leaf preparations.The validity of lipidemia provides a theoretical basis.Conclusions:1 The results of bibliometric studies suggest that the commonly used dosage forms of ginkgo biloba preparations are injections,common diseases are cardiovascular and cerebrovascular diseases,and the adverse reactions are mainly ginkgo biloba injections,and common adverse reactions are skin and vascular damage;2 Based on the meta-analysis results of this study,the combination of Ginkgo biloba preparation and statin can improve the efficacy of treatment of hyperlipidemia,and the use of Ginkgo biloba preparation alone has a significant therapeutic effect on TG levels in patients aged<50 years.It has obvious therapeutic effects on TC levels in patients aged 50 to 60 years.The results of network pharmacology suggest that Ginkgo biloba mainly regulates cholesterol balance and regulates female body through targets such as MAPT,ESR1,ABCC3,ESR2,LDLR,LRP8 and VLDLR.Hormone levels,lowering LDL,triglycerides,regulating lipid metabolism,and correcting dyslipidemia. |
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