Exploration Of The Effect And Mechanism Of Xuefu Zhuyu Decoction In Preventing And Treating Hyperlipidemia Based On The Theory Of "Treatment From Blood Stasis"

Objective:Based on the theory of visceral manifestation in traditional Chinese medicine(TCM),this paper explores the treatment of hyperlipidemia in TCM,investigates the relationship between blood stasis caused by the five zangorgans and the incidence of hyperlipidemia,and demonstrates the feasibility of treating hyperlipidemia using the method of activating blood and resolving stasis in clinical practice.Additionally,commonly used activating blood and resolving stasis compound prescriptions for the clinical treatment of hyperlipidemia were statistically ranked using the bibliometric method,and the most commonly used blood-activating and stasis-resolving compound prescriptions in clinical practice were identified.The efficacy of the most commonly used activating blood and resolving stasis compound prescriptions for preventing and treating hyperlipidemia was evaluated using evidence-based medicine and animal experiments.Finally,network pharmacology was used to analyze and predict the potential mechanisms of the most commonly used activating blood and resolving stasis compound prescriptions for the prevention and treatment of hyperlipidemia,in order to explore and reveal their clinical efficacy and modern scientific mechanisms,and to serve the construction of a healthy China by effectively preventing and treating hyperlipidemia.Methods:1.Literature and theoretical research: The ancient literature related to hyperlipidemia was collected using the Super Star Huiya e-book platform to explore the ancients’ understanding of the causes of hyperlipidemia.Additionally,modern literature related to hyperlipidemia was searched through China National Knowledge Infrastructure(CNKI)to collect the therapeutic methods and principles of modern physicians in the treatment of hyperlipidemia.2.Bibliometric research: A comprehensive search was conducted across China National Knowledge Infrastructure,Wanfang Database,VIP Journal Resource Database,and China Biomedical Literature Service System for all clinical research literature on compound prescriptions used in activating blood and resolving stasis for the prevention and treatment of hyperlipidemia.The search period was from the inception of each database to December 31,2021.Following this,literature screening was conducted based on predetermined inclusion and exclusion criteria.Finally,the names of compound prescriptions for activating blood and resolving stasis used in the selected clinical studies were recorded and sorted to obtain the most commonly used prescription names.3.Evidence-based research: Evidence-based research was conducted by comprehensively searching various databases including China National Knowledge Infrastructure,Wanfang Database,VIP Periodical Resource Database,China Biomedical Literature Service System,Pub Med,and Embase.All clinical randomized controlled trials of Xuefu Zhuyu Decoction in treating hyperlipidemia were searched within the date ranges of each database up to February 1,2022.The quality of the included studies was evaluated using the Ro B2 tool,and meta-analysis,sensitivity analysis,and Egger’s test were performed using Stata17.0.4.The Efficacy of Xuefu Zhuyu Decoction in preventing and delaying hyperlipidemia: Thirty-four male Apo E-/-mice were randomly divided into three groups: control(n=11),model(n=11),and Xuefu Zhuyu Decoction(n=12).The control group was given a normal diet and normal saline by gavage.The model group was fed a high-fat diet and normal saline by gavage,while the Xuefu Zhuyu Decoction group was fed a high-fat diet and given Xuefu Zhuyu Decoction by gavage.The duration of the intervention was four weeks.After the last administration,food and water were withdrawn for 12 hours before collecting the samples on the next morning after anesthesia.The serum of the mice was collected and the levels of total cholesterol(TC),triglyceride(TG),low-density lipoprotein cholesterol(LDL-C),and high-density lipoprotein cholesterol(HDL-C)were detected using a micro-plate method to observe the effect of Xuefu Zhuyu Decoction in preventing and delaying hyperlipidemia.5.The Efficacy of Xuefu Zhuyu Decoction in treating hyperlipidemia:Thirty-seven male Apo E-/-mice were randomly divided into a control group(n=12),a model group(n=12),and a Xuefu Zhuyu decoction group(n=13).The control group was fed a regular diet for 4 weeks,while the model group and Xuefu Zhuyu decoction group were fed a high-fat diet for 4 weeks.Subsequently,the control group and the model group were administered normal saline by gavage,while the Xuefu Zhuyu decoction group was given Xuefu Zhuyu decoction by gavage.Blood samples were collected at the 4th and 8th weeks after gavage.The sample collection and index detection procedures after the last administration were the same as those used in the study on the preventive and therapeutic effects.6.Network pharmacology research: The chemical components of Xuefu Zhuyu Decoction were screened in TCMSP database and HERB database,and the active components of Xuefu Zhuyu Decoction were screened using OB and DL parameters in TCMSP platform.The active components of Xuefu Zhuyu Decoction were supplemented through reading the literature review.Disease targets were collected using the Dis Gen NET database,and the collected targets were named using the Uni Prot database.Afterwards,the intersection of the active component action target and disease target of Xuefu Zhuyu Decoction was extracted using the Venny platform,and the active component-action target network diagram was drawn using Cytoscape3.7.2.Protein interaction network analysis of the obtained intersecting targets was performed using STRING database and Cytoscape3.7.2,and GO functional enrichment analysis and KEGG pathway enrichment analysis were performed using DAVID database.Results:1.Hyperlipidemia is classified as "blood stasis" in traditional Chinese medicine.Its pathogenesis is closely related to endogenous "blood stasis" caused by dysfunction of the physiological functions of the five Zang-viscera.Modern physicians not only focus on regulating the function of the five Zangviscera in treating hyperlipidemia,but also pay more attention to using drugs that promote blood circulation and remove blood stasis.2.For the bibliometric research,463 articles were included,and various activating blood and resolving stasis compounds were found to be used for treating hyperlipidemia.Among these compounds,Xuefu Zhuyu decoction was the most commonly used for treating hyperlipidemia.3.A total of 14 studies were included in the systematic review and metaanalysis,among which 3 studies were Xuefu Zhuyu recipe compared with lipidlowering western medicine,and 11 studies were Xuefu Zhuyu recipe combined with lipid-lowering western medicine compared with lipid-lowering western medicine alone.The results of the meta-analysis showed that Xuefu Zhuyu Decoction alone did not show significant differences in the improvement of TC(WMD =-0.64,95% CI [-1.50,0.23]),TG(WMD =-0.26,95% CI [-2.28,1.77])and total clinical effective rate(RR=1.05,95%CI[0.92,1.19])in the treatment of hyperlipidemia compared with lipid-lowering western medicine.Xuefu Zhuyu recipe combined with lipid-lowering western medicine could improve TC(WMD =-1.19,95% CI [-1.43,-1.09]),TG(WMD =-0.35,95%CI [-0.51,-0.19]),LDL-C(WMD =-0.55,95% CI [-0.84,-0.26]),HDLC(WMD=0.15,95% CI[0.02,0.29]),and the total clinical effective rate(RR=1.16,95% CI[1.11,1.21])of the combination of Xuefu Zhuyu Decoction and lipid-lowering western medicine in the regulation of blood lipids was also significantly better than that of the sole use of lipid-lowering western medicine.4.Four weeks after simultaneous administration of a high-fat diet and Xuefu Zhuyu Decoction in Apo E-/-mice,the TC level in the Xuefu Zhuyu Decoction group was significantly lower than that in the model group,with a statistically significant difference between the two groups(P < 0.05).The TG level in the Xuefu Zhuyu Decoction group was lower than that in the model group,but no statistically significant difference was observed between the two groups.Additionally,the HDL-C level in the Xuefu Zhuyu Decoction group was significantly higher than that in the model group(P < 0.05).5.After 4 weeks of gavage with Xuefu Zhuyu decoction in Apo E-/-mice with hyperlipidemia,the Xuefu Zhuyu decoction group did not exhibit an effective blood lipid regulation effect.After 8 weeks of gavage,there was no significant difference in TC level,TG level,and LDL-C level between the Xuefu Zhuyu decoction group and the model group.However,the HDL-C level in the Xuefu Zhuyu decoction group was significantly higher than that in the model group(P < 0.01).6.Xuefu Zhuyu Decoction contains a total of 198 active components,with quercetin,kaempferol,and luteolin being the main active constituents.A total of 91 potential targets for the prevention and treatment of hyperlipidemia have been identified for Xuefu Zhuyu Decoction,and 15 of these targets,including STAT3,AKT1,TNF,MAPK3,MAPK1,and MAPK14,may be key targets for disease treatment.GO enrichment and KEGG enrichment analysis suggest that Xuefu Zhuyu Decoction may exert its effects on hyperlipidemia through the regulation of glucose and lipid metabolism pathways,as well as the fluid shear stress and atherosclerosis pathways.Conclusion:1.Physiological dysfunction of the five Zang-viscera can lead to endogenous stasis,which is a significant factor contributing to the onset of hyperlipidemia.Clinical treatment of hyperlipidemia involves not only regulating the physiological function of the Zang-viscera but also utilizing the method of activating blood and resolving stasis.2.Xuefu Zhuyu decoction is the most commonly used compound for promoting blood circulation and removing blood stasis in clinical treatment of hyperlipidemia.3.Xuefu Zhuyu Decoction has been shown to exhibit superior efficacy in regulating blood lipid levels compared to the use of lipid-lowering western medicine alone.4.Xuefu Zhuyu Decoction can play a role in preventing and delaying the development of hyperlipidemia.5.The curative effect of Xuefu Zhuyu Decoction on hyperlipidemia is not as good as its effect of preventing and delaying hyperlipidemia.The consciousness of "preventive treatment" should be established and strengthened for hyperlipidemia.6.The active components in Xuefu Zhuyu Decoction can promote the cooperation of multiple targets and multiple pathways to play a role in the prevention and treatment of hyperlipidemia.The characteristics of mutual cooperation of each treatment target is consistent with the concept of holism in TCM.