| Since the concept of "double heart medicine" was put forward,coronary heart disease combined with depression has received increasing attention and has become the focus of current research.With the deepening of research,it has been proved that the two have a close and complex two-way relationship before,but the specific pathogenesis is not yet clear,and there is no uniformly recognized diagnosis and treatment plan.This study conducted preliminary research on Wu Long Tong Luo Jie Yu Decoction in the treatment of stable angina pectoris complicated with depression from four aspects:literature collation,clinical evaluation,network pharmacology prediction,and animal experiment verification.It provides a new idea for the treatment of stable angina pectoris combined with depression in coronary heart disease with traditional Chinese medicine.Objectives1.Organize the treatment ideas and experience of traditional Chinese medicine in the treatment of coronary heart disease combined with depression in ancient literature,sort out the pathogenesis and treatment methods,and provide theoretical support for the"tonifying qi,activating blood,and relieving depression" method.2.The clinical effectiveness and safety of Wu Long Tong Luo Jie Yu Decoction were preliminarily evaluated through clinical trials.3.Through network pharmacology,the possible targets of Wu Long Tong Luo Jie Yu Decoction in the treatment of stable angina pectoris combined with depression of coronary heart disease were initially explored and verified by animal experiments.Method1 Literature ResearchBased on the collections of the Beijing University of Traditional Chinese Medicine Library and the National Library,combined with the Chaoxing reader and the network database "Master of Chinese Studies",search for ancient Chinese medicine documents from the pre-Qin to Ming and Qing Dynasties,with the theme of "Chest impediment" and"Depression"and formulate relevant restriction words.Relevant sentences are sorted according to the method of TCM literature,divided into categories and combined with the style of literature.2 Small exploratory clinical researchThe 65 patients with stable angina pectoris and depression meeting the diagnostic criteria were randomly divided into treatment group and control group.The control group was given the best treatment plan recommended by the guidelines,and the treatment group was added with Wu Long Tong Luo Jie Yu Decoction on this basis.Treatment for 4 weeks.The angina pectoris episodes(SAQ points),depression status(HAMD points,PHQ-9 points),TCM syndrome scores and safety indicators of the two groups of patients before and after treatment were compared and observed.3 Network Pharmacology ResearchObtain the active ingredients and targets of Wu Long Tong Luo Jie Yu Decoction,and the disease target of stable angina pectoris combined with depression,and connect the two to obtain the possible target of Wu Long Tong Luo Jie Yu Decoction for the treatment of stable angina pectoris combined with depression.Use Cytoscape software to construct a"drug-disease" network,screen potential therapeutic targets,select key targets,and conduct further verification through animal experiments.4 Experimental Study4.1 Effect of Wu Long Tong Luo Jie Yu Decoction on behavior of zebrafish intersegmental vessels damaged modelInduced by vascular endothelial cell growth factor receptor tyrosine kinase inhibitor(VEGFR tyrosine kinase inhibitor II,VRI)to establish a zebrafish intersegmental vessels damaged model,collect zebrafish’s parade trajectory,parade distance,parade speed,and active time through the zebrafish behavior analyzer.Observe the effect of different concentrations of Wu Long Tong Luo Jie Yu Decoction on the behavior of zebrafish with intersegmental vessels damaged.4.2 Effects of Wu Long Tong Luo Jie Yu Decoction on angiogenesis in zebrafishVEGFR tyrosine kinase inhibitor II(VRI)-induced zebrafish intersegmental vessels(IS Vs)damaged model was established to observe the protective effect of Wu Long Tong Luo Jie Yu Decoction on ISVs under fluorescence microscope.4.3 Effect of Wu Long Tong Luo Jie Yu Decoction on zebrafish inflammation modelThe migration and aggregation model of zebrafish macrophages was established by cutting tails,and the effects of Wu Long Tong Luo Jie Yu Decoction on the migration and aggregation of macrophages at different concentrations were observed under an inverted fluorescence microscope.Result1 Literature researchAfter sorting out the treatment ideas and methods recorded in ancient documents,it is found that the ancient physicians believed that lack of heart-qi is an important pathogenesis of stable angina pectoris combined with depression in coronary heart disease,and stagnation of qi is a key factor.After sorting out the medicine experience of ancient physicians,it is found that the proportion of benefiting qi and warming yang medicine is the largest,and the frequency of occurrence is also the highest,followed by qi regulating drugs,although the number of activating blood drugs is less,the frequency of occurrence is second only to benefiting qi drugs and qi regulating drugs.In addition to benefiting qi and warming yang,qi-regulating,and blood-activating drugs,this study also found that ancient physicians also used a certain proportion of wind drugs,such as Fangfeng,Mahuang and Manjinshi,when treating chest impediment combined with emotional diseases.2 Small exploratory clinical researchIn terms of S AQ scores,the total SAQ scores of the two groups after treatment were lower than before treatment,and the therapeutic effect of the treatment group was better than that of the control group(P<0.05).In the four dimensions of AS,AF,TS,and DP,the therapeutic effect of the treatment group was better than that of the control group(P<0.05).In the PL dimension,there was no statistical difference between the treatment group and the control group(P>0.05).In terms of HAMD,the total scores of HAMD in both groups after treatment were lower than before treatment(P<0.05),and the therapeutic effect of the treatment group was better than that of the control group(P<0.05).In terms of block state,sleep disturbance,and anxiety somatization,the treatment group was better than the control group(P<0.05).In terms of cognitive impairment,there was no statistical difference between the treatment group and the control group(P>0.05).In terms of PHQ-9,the total scores of PHQ-9 in both groups after treatment were lower than before treatment(P<0.05),and the therapeutic effect of the treatment group was better than that of the control group(P<0.05).In terms of TCM syndrome scores,including total scores,primary symptoms and secondary symptoms,there were statistical differences between the two groups after treatment compared with before treatment(P<0.05).There were statistical differences between the two groups after treatment(P<0.05),and the treatment group was better than the control group.After treatment,the two groups of patients did not experience arrhythmia(such as increased heart rate,prolonged PR interval,atrioventricular block,prolonged QTc interval,etc.),abnormal coagulation function,abnormal liver and kidney function and other adverse reactions.3 Network Pharmacology ResearchBased on the clinical efficacy of Wu Long Tong Luo Jie Yu Decoction,predicted by network pharmacology,it may act on 97 targets such as VEGFA,IL6,STAT3,AKT1,MAPK1,APP,EGFR,MMP9,CTNNB1,and IL-1β.Finally,we selected the top two important VEGFA and IL6 as targets,predicting that Wu Long Tong Luo Jie Yu Decoction may treat stable angina pectoris complicated with depression by improving vascular endothelial function and inhibiting inflammation,and verify it through animal experiments.4 Experimental Study4.1 Effect of Wu Long Tong Luo Jie Yu Decoction on behavior of zebrafish intersegmental vessels damaged modelIn terms of parade distance,the parade distance of the model group was significantly reduced,which was statistically significant compared with the blank control group(P<0.05);different concentrations of Wu Long Tong Luo Jie Yu Decoction could increase the parade distance of the intersegmental vessels damaged model zebrafish;Among them,the VRI+100μg/mL group was statistically significant compared with the model group(P<0.05);while the VRI+30 μg/mL,VRI+300 μg/mL,and VRI+1000 μg/mL groups were not statistically significant compared with the model group(P>0.05).In terms of parade speed,the parade speed of the model group slowed down significantly,which was statistically significant compared with the blank control group(P<0.05);the different concentrations of Wu Long Tong Luo Jie Yu Decoction increased the parade speed of the intersegmental vessels damaged model zebrafish;Among them,the VRI+100 μg/mL group was statistically significant compared with the model group(P<0.05);while the VRI+30 μg/mL,VRI+300 μg/mL,and VRI+1000 μg/mL groups were not statistically significant compared with the model group(P>0.05).In terms of active time,the active time of zebrafish in the model group was significantly shortened,which was statistically significant compared with the blank control group(P<0.05);the different concentration groups of Wu Long Tong Luo Jie Yu Decoction all prolonged the active time of zebrafish in intersegmental vessels damaged model;Among them,the VRI+100 μg/mL group was statistically significant compared with the model group(P<0.05);while the VRI+30 μg/mL,VRI+300 μg/mL,and VRI+1000 μg/mL groups were not statistically significant compared with the model group(P>0.05).In terms of parade trajectory,compared with the blank control group,the parade trajectory of the model group is obviously sparse;compared with the model group,the different concentration groups of Wu Long Tong Luo Jie Yu Decoction can increase the zebrafish marching route,with VRI+100 μg/mL group is the most obvious4.2 Effects of Wu Long Tong Luo Jie Yu Decoction on Angiogenesis in ZebrafishThe results showed that compared with the blank control group,the zebrafish intersegmental vessels in the model group were significantly reduced,which was statistically significant compared with the blank control group(P<0.001);compared with the model group,different concentrations of Wu Long Tong Luo Jie Yu Decoction can promote zebrafish angiogenesis,and the difference is statistically significant[VRI+30μg/mL(P<0.001),VRI+100μg/mL(P<0.001),VRI+300μg/mL(P<0.001),VRI+1000 μg/mL(P<0.001)].4.3 Effect of Wu Long Tong Luo Jie Yu Decoction on Zebrafish Inflammation ModelThe results showed that compared with the blank control group,the zebrafish tail of the model group showed significant macrophage migration and aggregation,and the difference was statistically significant(P<0.001);compared with the model group,different concentrations of Wu Long Tong Luo Jie Yu Decoction can reduce the migration and aggregation of macrophages in the tail of the zebrafish.Among them,the 300 μg/mL group and 1000 μg/mL inhibited the migration and aggregation of macrophages by 26%and 31%,respectively,and the difference was statistically significant(P<0.001);the 30 μg/mL group and 100 μg/mL inhibited the migration and aggregation of macrophages by 7.8%and 8.7%,respectively,and the difference was not statistically significant(P>0.05).Conclusion1.Insufficiency of heart yang(qi)is the root cause of chest impediment combined with emotional diseases,while stagnation of qi is a key factor,and the disease mainly relates to the heart,liver,and spleen.The treatment is mainly to tonify qi,activate blood,and relieve depression,and on this basis,the wind medicine is used for treatment.2.Wu Long Tong Luo Jie Yu Decoction can improve angina pectoris and depression in patients with stable angina pectoris combined with depression(qi deficiency and blood stasis,liver depression and qi stagnation syndrome)and its clinical application is safe and effective.3.Combined with the results of network pharmacology and animal experiments,Wu Long Tong Luo Jie Yu Decoction may play a therapeutic role in the treatment of stable angina pectoris combined with depression by improving vascular endothelial function and inhibiting inflammation.In summary,the method of "tonifying qi,activating blood,relieving depression,dispelling wind,dredging collaterals and relieving pain" based on the theory of "endogenous collateral wind-collaterals damage and expression injury" provides a new idea for TCM treatment of coronary heart disease with stable angina pectoris combined with depression,and is worthy of clinical promotion and application. |
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