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This study aimed to investigate the mechanism of "Trichosanthis Fructus-Allii Macrostemonis Bulbus" (GX) on phlegm and blood stasis syndrome (PBSS) rats combining the methods of network pharmacology and experimental verification. Animal experiment ethical requirements were approved by the Ethical Committee Experimental Animal Center of Anhui University of Chinese Medicine (grant number: AHUCM-rats-2021070). Based on the HPLC-Q-TOF-MS analysis and database, 69 chemical constituents of GX and 163 targets of GX for the treatment of phlegm and blood stasis-related cardiovascular diseases were obtained. Then, key targets such as serine/threonine kinase 1 (Akt1), tumor necrosis factor (TNF), interleukin 6 (IL6), vascular endothelial growth factor A (VEGFA), cellular tumor antigen p53 (Tp53) were screened. Pathway analysis showed that the targets of GX in the treatment of phlegm and blood stasis-relate cardiovascular diseases were mainly involved in PI3K/Akt signaling pathway, sphingolipid metabolism, platelet activation, hypoxia inducible factor-1 (HIF-1), ras-proximate-1 (rap1) and other signaling pathways. In addition, molecular docking analysis showed that apigenin, cucurbitacin D, linolenic acid and kaempferol and other key components had potential binding ability with Akt1, TNF, IL6, VEGFA and Tp53. In the animal experiments, compared to the phlegm and blood stasis syndrome group, GX could significantly improve the traditional Chinese medicine syndrome score, blood lipid, vascular endothelial structure disorders and reduce serum endothelin-1 (ET-1) level, increase serum nitric oxide (NO) and endothelial nitric oxide synthase (eNOS) levels, which could restore aortic endothelial function. In addition, the expression of intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in aorta could be significantly reduced, which could improve the vascular endothelial injury of aorta. Western blot revealed that GX could significantly decrease the phosphorylation levels of phosphoinositide 3-kinase (PI3K) and Akt in aorta. This study revealed the mechanism of GX in treatment of phlegm and blood stasis-relate cardiovascular diseases is consistent with the characteristics of multiple ingredients, multiple targets and multiple pathways. In addition, this study also clarified that the reversal of pathological of phlegm and blood stasis syndrome rats may be related to GX inhibiting PI3K/Akt signaling pathway, which could improve vascular inflammation and vascular endothelial function injury.
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Objective:To reveal the regular pattern characteristics of different diseases with the same treatment in the most common diseases with blood stasis syndrome; To provide reference for the clinical treatment of blood stasis syndrome and the development of new drugs.Methods:RCTs of blood stasis syndrome were retrieved from CNKI, Chongqing VIP, Wanfang Data, SinoMed, and China Medical Journal Full-text Database from the establishment of the databases to December 31, 2022. Diseases, accompanied symptoms, prescriptions and medicines were extracted. The diseases with the highest frequency among the three disease systems with the highest frequency were collected, and their medication characteristics and prescription rules were analyzed using frequency statistics and association rules Apriori algorithm. The core prescriptions of blood stasis syndrome of three kinds of diseases were excavated and their network similarity was analyzed.Results:A total of 2 052 articles were included. Stable coronary heart disease, ischemic stroke and DN were more common diseases with blood stasis syndrome. The common drugs for the three diseases were Chuanxiong Rhizoma, Carthami Flos, Persicae Semen, Angelicae Sinensis Radix. The core prescription of stable coronary heart disease was Persicae Semen- Carthami Flos- Chuanxiong Rhizoma- Angelicae Sinensis Radix- Paeoniae Radix Rubra; the core prescription of ischemic stroke is Buyang Huanwu Decoction; the core prescription of DN was Persicae Semen- Carthami Flos- Chuanxiong Rhizoma- Angelicae Sinensis Radix- Cornus Officinalis- Dioscoreae Rhizoma- Astragali Radix. The similarity between stable coronary heart disease and ischemic stroke core prescription network was 0.35, the similarity between ischemic stroke and DN core prescription network was 0.29, and the similarity between stable coronary heart disease and DN core prescription network was 0.26. Conclusions:The theory of "different diseases with the same treatment" can profoundly guide clinical practice. The core medicines of blood stasis syndrome are Persicae Semen, Carthami Flos, Angelicae Sinensis Radix, and Chuanxiong Rhizoma. On this basis, combined with different diseases and syndromes to make changes of adding and subtracting.
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@#【Objective】 To investigate the correlations between intestinal flora, plasma metabolites, and blood stasis syndrome in coronary heart disease (CHD), and the mechanisms of Yangxin Tongmai Formula (养心通脉方, YXTMF) for blood stasis syndrome in CHD rats. 【Methods】 A total of 18 specific pathogen free (SPF) male Sqrague-Dawley (SD) rats were used to establish CHD rat models with blood stasis syndrome, which were then randomized into model, YXTMF, and atorvastatin calcium (AVT) groups, with six rats in each group, and were intervened through gavage for two weeks. Subsequently, additional six rats that received normal diet were included as normal group. The pathological changes in the CHD rat models were identified by hematoxylin-eosin (HE) staining. The electrocardiogram, hemodynamics, and lipid profiles of the rats were detected as well. The untargeted plasma metabolomics of rats were analyzed by liquid chromotography-tandem mass spectrometry (LC-MS/MS), their ileal mucosal flora by 16S rRNA sequencing, and the correlation between the two results were also analyzed. 【Results】 The whole blood viscosity, total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) of rats in the model group increased compared with those in the control group (P < 0.05). In the model group, the proliferation of endothelial cells in the coronary artery of rats was damaged, with quite a few vacuolated pathological changes observed. However, the endothelial lesions in the coronary artery of rats were alleviated in the intervention groups (YXTMF and AVT groups). With the use of LC-MS/MS, a total of 33 potential endogenous metabolites were identified in plasma, among which 1-methylhistidine, N-acetylhistamine, progesterone, and deoxycorticosterone were expected to be the differential metabolites in CHD rats with blood stasis syndrome. The 16S rRNA sequencing results showed that improved diversity and abundance of intestinal flora were observed in the YXTMF group. The correlation analysis suggested that Hydrogenophaga, Limnohabitans, and Polaromonas, which were highly related to the formation of blood stasis syndrome in CHD patients, were positively correlated with plasma metabolites such as 5-hydroxyindole, N-acetylhistamine, and progesterone (P < 0.01), but were negatively correlated with plasma metabolites such as L-arginine, homoarginine, and Boc-beta-cyano-L-alanine (P < 0.01). After YXTMF intervention, Lactobacillus, Corynebacterium, and Candidatus Nitrososphaera were positively correlated with plasma metabolites such as Boc-β-cyano-L-alanine, stachydrine, and naringenin (P < 0.05), while negatively correlated with 5-hydroxyindole, N-acetylhistamine, and oleoylethanolamide (P < 0.05). 【Conclusion】 YXTMF could alleviate blood stasis syndrome in CHD rats through improving their plasma metabolisms achieved by regulating the intestinal flora.
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This study aimed to investigate the relationship between coagulating cold and blood stasis syndrome and glycolysis, and observe the intervention effect of Liangfang Wenjing Decoction(LFWJD) on the expression of key glycolytic enzymes in the uterus and ovaries of rats with coagulating cold and blood stasis. The rat model of coagulating cold and blood stasis syndrome was established by ice-water bath. After modeling, the quantitative scoring of symptoms were performed, and according to the scoring results, the rats were randomly divided into a model group and LFWJD low-, medium-and high-dose groups(4.7, 9.4, 18.8 g·kg~(-1)·d~(-1)), with 10 in each group. Another 10 rats were selected as the blank group. After 4 weeks of continuous administration by gavage, the quantitative scoring of symptoms was repeated. Laser speckle flowgraphy was used to detect the changes of microcirculation in the ears and uterus of rats in each group. Hematoxylin-eosin(HE) staining was used to observe the pathological morphology of uterus and ovaries of rats in each group. The mRNA and protein expressions of pyruvate dehydrogenase kinase 1(PDK1), hexokinase 2(HK2) and lactate dehydrogenase A(LDHA) in the uterus and ovaries of rats were examined by real-time quantitative polymerase chain reaction(RT-qPCR) and Western blot, respectively. The rats in the model group showed signs of coagulating cold and blood stasis syndrome, such as curl-up, less movement, thickened veins under the tongue, and reduced blood perfusion in the microcirculation of the ears and uterus, and HE staining revealed a thinning of the endometrium with disorganized arrangement of epithelial cells and a decrease in the number of ovarian follicles. Compared with the model group, the treatment groups had alleviated coagulating cold and blood stasis, which was manifested as red tongue, reduced nail swelling, no blood stasis at the tail end as well as increased blood perfusion of the microcirculation in the ears and uterus(P<0.05 or P<0.01). Among the groups, the LFWJD medium-and high-dose groups had the most significant improvement in coagulating cold and blood stasis, with neatly arranged columnar epithelial cells in uterus, and the number of ovarian follicles was higher than that in the model group, especially mature follicles. The mRNA and protein expressions of PDK1, HK2, LDHA in uterus and ovaries were up-regulated in the model group(P<0.05 or P<0.01), while down-regulated in LFWJD medium-and high-dose groups(P<0.05 or P<0.01). The LFWJD low-dose group presented a decrease in the mRNA expressions of PDK1, HK2 and LDHA in uterus and ovaries as well as in the protein expressions of HK2 and LDHA in uterus and HK2 and PDK1 in ovaries(P<0.05 or P<0.01). The therapeutic mechanism of LFWJD against coagulating cold and blood stasis syndrome is related to the down-regulation of key glycolytic enzymes PDK1, HK2 and LDHA, and the inhibition of glycolytic activities in uterus and ovaries.
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Female , Animals , Rats , Ovary , Uterus , Ovarian Follicle , Lactate Dehydrogenase 5 , GlycolysisABSTRACT
This study aimed to analyze the biological foundation and biomarkers of stable coronary heart disease(CHD) with phlegm and blood stasis(PBS) syndrome based on RNA-seq and network pharmacology. Peripheral blood nucleated cells from five CHD patients with PBS syndrome, five CHD patients with non-PBS syndrome, and five healthy adults were collected for RNA-seq. The specific targets of CHD with PBS syndrome were determined by differential gene expression analysis and Venn diagram analysis. The active ingredients of Danlou Tablets were screened out from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform, and the "component-target" prediction was completed through PubChem and SwissTargetPrediction. The "drug-ingredient-target-signaling pathway" network of Danlou Tablets against CHD with PBS syndrome was optimized by Cytoscape software. After the target biomarkers were identified, 90 participants were enrolled for diagnostic tests, and 30 CHD patients with PBS syndrome were included in before-and-after experiment to determine the therapeutic effect of Danlou Tablets on those targets. As revealed by RNA-seq and Venn diagram analysis, 200 specific genes were identified for CHD with PBS syndrome. A total of 1 118 potential therapeutic targets of Danlou Tablets were predicted through network pharmacology. Through integrated analysis of the two gene sets, 13 key targets of Danlou Tablets in the treatment of CHD with PBS syndrome were screened out, including CSF1, AKR1C2, PDGFRB, ARG1, CNR2, ALOX15B, ALDH1A1, CTSL, PLA2G7, LAP3, AKR1C3, IGFBP3, and CA1. They were presumably the biomarkers of CHD with PBS syndrome. The ELISA test further showed that CSF1 was significantly up-regulated in the peripheral blood of CHD patients with PBS syndrome, and was significantly down-regulated after Danlou Tablets intervention. CSF1 may be a biomarker for CHD with PBS syndrome, and it is positively correlated with the severity of the disease. The diagnostic cut-off of CSF1 for CHD with PBS syndrome was 286 pg·mL~(-1).
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Adult , Humans , Network Pharmacology , RNA-Seq , Coronary Disease/genetics , Drugs, Chinese Herbal/therapeutic use , Medicine, Chinese Traditional , Biomarkers , Syndrome , Tablets , Molecular Docking SimulationABSTRACT
Blood stasis syndrome is one of the core clinical syndrome of rheumatoid arthritis (RA), but the biological connotation of this syndrome is not clear, and there is a lack of disease improved animal models that match the characteristics of this disease and syndrome. The aim of this study was to screen the candidate biomarker gene set of blood stasis syndrome of RA, reveal the biological connotation of this syndrome, and explore and evaluate the preparation method of the improved animal model based on the characteristics of "disease-syndrome-symptom". The study was approved by the ethics committee of Guang'anmen Hospital, Chinese Academy of Traditional Chinese Medicine (No. 2019-073-KY-01) and the First Affiliated Hospital of Tianjin University of Traditional Chinese Medicine (No. TYLL2021[K]018), and the study subjects gave their informed consent. Animal welfare and experimental procedures followed the regulations of the Experimental Animal Ethics Committee of the Chinese Academy of Traditional Chinese Medicine (No. IBTCMCACMS21-2207-01). The whole blood samples were collected clinically from RA patients with blood stasis syndrome (3 cases) or other syndromes (7 types, 3 cases/type), and healthy volunteers (4 cases), and then transcriptome sequencing, KEGG, gene set enrichment analysis (GSEA) and weighted correlation network analysis (WGCNA) analysis were performed. 126 pivotal genes were screened, and their functional annotation results were significantly enriched in "immune-inflammation" related pathways and lipid metabolism regulation (sphingolipids, ether lipid metabolism and steroid biosynthesis). Syndrome-symptom mapping of hub gene set to the TCM primary and secondary symptoms, Western phenotypic symptoms and pathological links showed that joint tingling, abnormal joint morphology, petechiae and abnormal blood circulation are representative of blood stasis syndrome of RA. The results of the improved animal model showed that the rats in the collagen-induced arthritis + adrenaline hydrochloride (CIA+Adr) 3 model group had increased blood rheology, coagulation, platelet function and endothelial function abnormalities compared with the CIA-alone model group, suggesting that the rats with blood stasis syndrome of RA may be in a state of "blood stasis". The results of the study can help to advance the objective study of the evidence of blood stasis syndrome in RA, and provide new ideas for the establishment of an animal model that reflects the clinical characteristics of the disease and syndrome.
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The abnormality of platelet function plays an important role in the pathogenesis and evolution of blood stasis syndrome (BSS). The explanation of its mechanism is a key scientific issue in the study of cardiovascular and cerebrovascular diseases and treatment. System biology technology provides a good technical platform for further development of platelet multi-omics, which is conducive to the scientific interpretation of the biological mechanism of BSS. The article summarized the pathogenesis of platelets in BSS, the mechanism of action of blood activating and stasis resolving drugs, and the application of genomics, proteomics, and metabonomics in platelet research, and put forward the concept of "plateletomics in BSS". Through the combination and cross-validation of multi-omics technology, it mainly focuses on the clinical and basic research of cardiovascular and cerebrovascular diseases; through the interactive verification of multi-omics technology and system biology, it mainly focuses on the platelet function and secretion system. The article systematically explains the molecular biological mechanism of platelet activation, aggregation, release, and other stages in the formation and development of BSS, and provides a new research idea and method for clarifying the pathogenesis of BSS and the mechanism of action of blood activating and stasis resolving drugs.
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Blood Platelets , Hemostasis , Platelet Activation , Proteomics , TechnologyABSTRACT
The cold congeal and blood stasis syndrome is a common clinical traditional Chinese medicine（TCM） syndrome. The animal model of cold ongeal and blood stasis syndrome is the basis for exploring the essence of TCM cold congeal and blood stasis syndrome，and the premise of follow-up TCM clinical research.This paper summarized the preparation method， theoretical support，and evaluation method of animal models of cold congeal and blood stasis syndrome in recent years and analysed the strengthens and weaknesses of different models. At present，the common animal models of cold congeal and blood stasis syndrome mainly include etiological model，etiological and pathological composite model and disease-syndrome combination model. The etiological model was mainly prepared by cold exposure，which could be divided into whole-body freezing， ice bath and local frostbite. The etiological and pathological composite model was mainly prepared by cold stimulation combined with epinephrine injection. The common disease-syndrome combination models included the coronary heart disease model of cold congeal and blood stasis syndrome，primary dysmenorrhea model of cold congeal and blood stasis syndrome，endometriosis model of cold congeal and blood stasis syndrome， and arteriosclerosis obliterans model of cold congeal and blood stasis syndrome. The three models have both advantages and disadvantages. Specifically， the disease-syndrome combination model had the highest consistency with clinical practice and was more reliable and practical. However， the disease types of this model were specific，and the combination method of disease and syndrome was controversial. The evaluation indicators of the animal models of cold congeal and blood stasis syndrome focused on the characterization of the syndrome and the physico-chemical indicators related to blood flow，such as blood rheology，coagulation function and microcirculation. In addition， some scholars explored the evaluation indicators from the aspects of vasomotor function，endocrine and energy metabolism. The objectivity and specificity of the current model evaluation methods needed to be further improved. The research of animal model of cold congeal and blood stasis syndrome should be based on clinical practice and oriented by clinical demand. Only by establishing animal models that are highly consistent with the characteristics of clinical disease and syndrome can we better reveal the essence of cold congeal and blood stasis syndrome and promote the modernization of TCM.
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ObjectiveTo observe the effects of five Huoxue Huayu prescriptions on blood lipid metabolism， liver tissue and adenosine triphosphate binding cassette transporter A1 （ABCA1） and peroxisome proliferator-activated receptor γ（PPARγ） expression in New Zealand rabbits with blood stasis syndrome， and to compare their differences in order to provide laboratory evidence for clinical selection of prescriptions and drugs. MethodSeventy New Zealand rabbits were randomly divided into normal group （n=10） and model group （n=60）. The blood stasis syndrome was modeled by the method of starvation+high-fat feed+adrenaline. After the models were successfully established， they were randomly divided into Xuefu Zhuyutang（3.55 g·kg-1·d-1） group， Danshenyin（1.962 g·kg-1·d-1） group， Shixiaosan（0.56 g·kg-1·d-1） group， Huoluo Xiaolingdan（2.80 g·kg-1·d-1） group， and Taohong Siwutang（2.66 g·kg-1·d-1） group， and were given corresponding compound prescriptions by gavage. The normal group and model group were given the same dose of distilled water. After the treatment of 30 consecutive days， blood was taken from the abdominal aorta to detect the content of total cholesterol （TC）， triglycerides （TG）， high-density lipoprotein cholesterol （HDL-C）， low-density lipoprotein cholesterol（LDL-C） and apolipoprotein A1 （ApoA1）. Hematoxylin-eosin（HE） staining was used to observe the changes in liver tissue. Real-time polymerase chain reaction （Real-time PCR） and Western blot were used to detect the mRNA and protein expression of ABCA1 and PPARγ in liver tissue， respectively. ResultCompared with the conditions in the normal group， increased mRNA and protein levels of HDL-C， LDL-C， TG， TC， and PPARγ （P<0.01）， decreased ApoA1 level （P<0.05） and decreased mRNA and protein levels of ABCA1 （P<0.01） were found in the model group. Compared with the conditions in the model group， the HDL-C level in the five Huoxue Huayu prescriptions was lowered （P<0.05）， and lowered TG level in Xuefu Zhuyutang group and Shixiaosan group （P<0.05）， decreased LDL-C and TC levels in Shixiaosan group （P<0.05）， and increased ApoA1 level in the Huoluo Xiaolingdan group （P<0.01） and Taohong Siwutang group （P<0.05） were observed. Furthermore， the mRNA and protein levels of ABCA1 in Xuefu Zhuyutang group， Shixiaosan group， Huoluo Xiaolingdan group and Taohong Siwutang group were elevated （P<0.05， P<0.01）， and the elevated levels were higher than that of Danshenyin group （P<0.05）. The mRNA level of PPARγ in the five Huoxue Huayu prescriptions was reduced （P<0.01）， and its protein level was also decreased in Xuefu Zhuyutang group， Shixiaosan group， Huoluo Xiaolingdan group and Taohong Siwutang group （P<0.01）. ConclusionThe five Huoxue Huayu prescriptions had a certain therapeutic effect on dyslipidemia，which might be achieved by up-regulating the expression of ApoA1 and ABCA1 to promote the production of HDL-C and strengthen the excretion of dysfunctional HDL-C. And Xuefu Zhuyutang had the optimal effect in lowering lipid.
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ObjectiveTo evaluate the clinical efficacy and safety of Yangxin Dawayimicol honey ointment （YDHO） in the treatment of insomnia with the syndrome of Qi stagnation and blood stasis. MethodEighty insomnia patients who met the inclusion criteria in the Department of Encephalopathy of the Third Affiliated Hospital of Henan University of Chinese Medicine from November 2019 to October 2020 were randomly divided into an experimental group （48 cases） and a control group （32 cases）. The experimental group was treated with YDHO + Xuefu Zhuyu capsule simulators，and the control group was treated with Xuefu Zhuyu capsules + YDHO simulators for eight weeks. The changes in Pittsburgh sleep quality index（PSQI）score，traditional Chinese medicine （TCM） syndrome score，insomnia severity index （ISI），neurotransmitter indexes ［γ-aminobutyric acid（GABA），glutamic acid（Glu），and 5-hydroxy tryptamine（5-HT）］，serum inflammatory indexes ［interleukin-6（IL-6）and interleukin-10（IL-10）］， and safety index of the two groups were compared. ResultThe total effective rate was 97.83%（45/46） in the experimental group， higher than 68.75%（22/32） in the control group（Z=-4.292，P<0.01）. The experimental group was superior to the control group in PSQI score，ISI score，TCM syndrome score， and sleep duration（P<0.05）. The curative effects were equivalent between the two groups in shortening the time to fall asleep. The experimental group showed increased serum content of GABA，5-HT， and IL-10 and reduced content of Glu and IL-6，with few adverse reactions （P<0.05）. ConclusionYDHO is effective，safe， and reliable in the treatment of insomnia with Qi stagnation and blood stasis syndrome.
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ObjectiveTo explore the differences in the protective effects of five formulas for promoting blood circulation and removing blood stasis on the aortic endothelial cells of New Zealand rabbits with heart blood stasis syndrome. MethodEighty New Zealand rabbits were randomly divided into a normal group （n=10） and an experimental group （n=70）. The heart blood stasis syndrome model was induced by starvation combined with a high-fat diet and adrenaline in the rabbits of the experimental group. Subsequently， the model rabbits were randomly divided into a model group， a Xuefu Zhuyutang group （3.55 g·kg-1·d-1）， a Taohong Siwutang group （2.66 g·kg-1·d-1）， a Danshenyin group （1.962 g·kg-1·d-1）， a Huoluo Xiaolingdan group （2.80 g·kg-1·d-1）， a Shixiaosan group （0.56 g·kg-1·d-1）， and a c-Jun N-terminal kinase （JNK） inhibitor （SP600125， 5 μg·kg-1）group. The normal group and the model group received the same amount of distilled water. The rabbits in five Chinese medicine groups were treated correspondingly by gavage， and those in the SP600125 group were injected with 0.5 mL of SP600125-dimethyl sulfoxide diluent. After the treatment， the aorta was collected， and terminal deoxynucleotidyl transferase dUTP nick end labeling （TUNEL） assay was used to detect the apoptosis of aortic endothelial cells. The enzyme-linked immunosorbent assay （ELISA） was used to detect serum levels of tumor necrosis factor-α （TNF-α） and interleukin-6 （IL-6）. Western blot was used to detect the protein expression of JNK， phosphorylated JNK （p-JNK）， B-cell lymphoma-2 （Bcl-2）， Bcl-2-associated X protein （Bax）， cysteinyl aspartate-specific protease-9 （Caspase-9）， and cysteinyl aspartate-specific protease-3 （Caspase-3） in aortic tissues. Real-time fluorescence-based quantitative polymerase chain reaction （Real-time PCR） was used to detect the mRNA levels of JNK， Bcl-2， Bax， Caspase-9， and Caspase-3 in aortic tissues. ResultFive formulas could improve the apoptosis of aortic endothelial cells to varying degrees. To be specific， Xuefu Zhuyutang and Taohong Siwutang were optimal in efficacy， followed by Huoluo Xiaolingdan， Shixiaosan， and Danshenyin， and SP600125 was the worst （P<0.05， P<0.01）. Five formulas could reduce the content of TNF-α and IL-6 （P<0.05， P<0.01）， down-regulate the protein expression levels of JNK， p-JNK， Bax， Caspase-9， and Caspase-3 （P<0.05， P<0.01）， decrease the mRNA expression levels of JNK， Bax， Caspase-9， and Caspase-3 （P<0.05， P<0.01）， and up-regulate the protein and mRNA expression levels of Bcl-2 （P<0.05， P<0.01）. ConclusionFive formulas can all reduce the apoptosis of aortic endothelial cells in New Zealand rabbits with heart blood stasis syndrome with different efficacies. It may be related to the different effects of five formulas on the JNK signaling pathway.
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Cardiovascular diseases， with high incidence and high mortality， belong to the category of "chest impediment and heart pain" in traditional Chinese medicine （TCM）. Chinese medicines have unique effect on the prevention and treatment of cardiovascular diseases with little side effects. Huoxin pills， one of the National Essential Drugs， is formulated based on the basic pathogenesis of weak pulse at Yang and wiry pulse at Yin and the pathological basis of myocardial ischemia and hypoxia and used for treating angina pectoris of coronary heart disease （Qi deficiency and blood stasis syndrome）. This medicine is derived from the classic famous prescription and is composed of ten precious Chinese medicinal herbs. It can replenish Qi， activate blood， and warm collaterals to diffuse impediment by enhancing myocardial contractility and cardiac output to improve micro-circulation and increase coronary blood flow， regulating immune functions， alleviating inflammation， detoxifying， and tranquilizing mind. Clinically， it is suitable for patients with angina pectoris caused by the lack of heart Yang， chest tightness， shortness of breath， palpitation， fear of cold for limbs and so on， especially for the elderly with Yang deficiency or the patients with a history of myocardial infarction. On the basis of the available research reports， this paper explains the formula meaning of Huoxin pills from the perspective of the basic pathogenesis of coronary heart disease and predicts its action targets， location and links. Furthermore， we expound the mechanism of action of Huoxin pills based on basic research and clinical evidence-based research， aiming to provide data support and evidence for the clinical application of this medicine.
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This study aims to comprehensively summarize articles on the treatment of coronary heart disease angina pectoris with heart blood stasis syndrome(CHD-AP-HBSS) by Guanxin Shutong Capsules(GSC), and comprehensively evaluate the evidence and value of the formula in "6+1" dimensions based on multi-criteria decision analysis(MCDA) model and Guidelines for Management of Comprehensive Clinical Evaluation of Drugs(trial version 2021) with quantitative and qualitative methods, which is expected to highlight the clinical characteristics and advantages of the prescription and serve as a reference for medical and health departments. The dimensions are grade A, B, C, or D. In terms of safety, according to the reports from the spontaneous reporting system of National Center for ADR Monitoring, and literature analysis, GSC mainly results in the adverse reactions of mild or moderate nausea, diarrhea, rash, palpitation, and headache, with favorable prognosis in patients. Nevertheless, severe adverse reactions have been reported after marketing. Thus, additional evidence for its safety should be accumulated, and the current safety is grade B. Meta-analysis proves that GSC in combination with conventional treatment is superior to conventional treatment alone in alleviating AP and symptoms indicated by electrocardiogram(ECG). Therefore, the effectiveness of the medicine is grade A. As for the pharmacoeconomic value, based on the assumption that the per capita disposable income in 2020 is the willingness-to-pay threshold, it is more economical for CHD-AP patients to use GSC combined with conventional treatment than conventional treatment alone. However, as the currently available clinical parameters fail to support the difference in indirect cost between the two groups, the accuracy in the cost of intervention plan needs to be further improved. Therefore, the economy of the prescription is grade B. GSC has been awarded 13 national invention patents and 1 utility model patent, and won a lot of national and provincial patent awards, marking the enterprise service awareness and innovativeness. As a result, it is grade A in aspect of innovation. A questionnaire on the suitability of GSC suggests that publicity and promotion influence patients' choice and thus additional efforts should be made in this aspect. The suitability of this formula is grade B. Both rural and urban residents can afford the medicine for the whole course and the price is close to that of similar Chinese patent medicines. In addition, it is accessible regardless of season and place, so accessibility is grade A. As a Mongolian empirical formula destined to treat heart stabbing pain, it has the effects of activating blood and resolving stasis, dredging channels and activating collaterals, and moving Qi to relieve pain, and boasts the empirical evidence of more than 2 000 human cases. With prominent characteristics of traditional Chinese medicine, it is grade B. Based on the MCDA model and CSC v2.0, GSC is comprehensively class A in the treatment of CHD-AP-HBSS. The result can serve as a reference for basic clinical medication management.
Subject(s)
Humans , Angina Pectoris/drug therapy , Capsules , Coronary Disease/drug therapy , Drugs, Chinese Herbal/adverse effectsABSTRACT
The present study systematically sorted out the existing research on Qilong Capsules in the treatment of ischemic stroke with Qi deficiency and blood stasis syndrome and comprehensively evaluated its clinical evidence and value to highlight the advantages and characteristics of products and provide references for the decision-making of national pharmaceutical management departments. Based on the evidence-based medicine, epidemiology, clinical medicine, evidence-based pharmacy, and pharmacoeconomics, the qualitative and quantitative evaluation of "6+1" dimensions of safety, effectiveness, economy, innovation, suitability, and accessibility, as well as characteristics of traditional Chinese medicine(TCM) was performed with multi-criteria decision analysis(MCDA) mo-del using the information, such as public data, literature data, pharmaceutical research, and questionnaire survey, and CSC v2.0 was used to calculate the clinical value of Qilong Capsules. The evaluation results were grade A, B, C, or D. Spontaneous reporting system(SRS) monitoring data, literature reports, clinical trials, and other multi-source safety evidence showed that the main adverse reactions of this drug included dry mouth, nausea, and rash, and no severe adverse reactions was found. The evidence was sufficient with small and controllable known risks, and the safety was grade A. Meta-analysis showed that Qilong Capsules combined with conventional western medicine in the treatment of acute ischemic stroke was superior to the control group in improving neurological deficits, clinical total response rate, patients' activities of daily living, and hemorheological indexes. The level of evidence was high with manifest clinical significance, and the effectiveness was grade A. The results of pharmacoeconomic research showed that Qilong Capsules combined with conventional western medicine in the treatment of ischemic stroke were advantageous in cost-effectiveness as compared with conventional western medicine alone, but the incremental effect was not significant. The quality evaluation results of the economic report were comparatively clear, and the economy was grade B. Aiming at major cerebrovascular diseases in the society and giving full play to the advantages of TCM, Qilong Capsules focused on the inheritance of classics and scientific and technological innovation, and innovation was grade B. The results of the questionnaire survey showed that the technical characteristics and drug application could meet the medication needs of clinical doctors and patients, and the suitability was grade B. The price level of this drug was comparatively high and the affordability was good since the treatment cost accounted for a small proportion of disposable income. The drug accessibility was good with a wide range of drug sales, sufficient production capacity, and sustainable medicinal materials resources, and was grade B. This drug was derived from the classic prescription Buyang Huanwu Decoction with rich experience of human application, which could regulate Qi and blood circulation, and the section of TCM characteristics was grade B. Based on the evidence evaluation results of "6+1" dimensions of Qilong Capsules, the comprehensive evaluation of clinical value was class A. It is suggested that it can be transformed into relevant policy results of basic clinical medication management according to procedures.
Subject(s)
Humans , Activities of Daily Living , Capsules , Ischemic Stroke , Medicine, Chinese Traditional , QiABSTRACT
Protective effect of Qilong Capsules(QL) on the myocardial fibrosis and blood circulation of rats with coronary heart disease of Qi deficiency and blood stasis type was investigated. Sleep deprivation and coronary artery ligation were used to construct a disease-symptom combination model, and 60 SD rats were divided into sham operation(sham) group, syndrome(S) group, disease and syndrome(M) group and QL group randomly. The treatment group received administration of QL 0.4 g·kg~(-1)·d~(-1). Other groups were given the same amount of normal saline. The disease indexes of each group [left ventricular end diastolic diameter(LVESD), left ventricular end systolic diameter(LVEDD), left ventricular ejection fraction(LVEF), left ventricular axis shortening rate(LVFS), myocardial histopathology, platelet morphology, peripheral blood flow] and syndrome indexes(tongue color, pulse, grip power) were detected. In sham group, cardiomyocytes and myocardial fibers were arranged neatly and densely with clear structures. The tongues' color in sham were light red, and the pulse shape were regular. RGB is a parameter reflected the brightness of the image of the tongue. In the S group, the amplitude and frequency of the animal's pulse increased accompanied by decreasing R,G,B, however, the decreased R,G,B was accompanied by reduced pulse amplitude in M group. And in M group, we observed fuzzy cell morphology, hypertrophied myocytes, disordered arrangement of cardiomyocytes and myocardial fibers, reduced peripheral blood flow and increased collagen volume fraction(CVF). Increased LVESD and LVEDD, and decreased LVEF and LVFS represented cardiac function in S group was significantly lower than that in sham. In QL group, the tongue's color was red and the pulse was smooth. The myocardial fibers of the QL group were arranged neatly and secreted less collagen. It improved the blood circulation in the sole and tail, and reversed the increasing of LVEDD, LVESD and the decreasing of LVEF and LVFS of M group. Platelets in M and S group showed high reactivity, and QL could decrease aggregation risk. In conclusion, Qilong Capsules has an obvious myocardial protective effect on ischemic cardiomyopathy, which may inhibit the degree of myocardial fibrosis and reduce platelet reactivity.
Subject(s)
Animals , Rats , Capsules , Cardiomyopathies/drug therapy , Fibrosis , Myocytes, Cardiac , Qi , Rats, Sprague-Dawley , Stroke Volume , Ventricular Function, LeftABSTRACT
Objective:To discuss the efficacy of Bushen Huoxue decoction for recovery in patients with intra uterine adhesions （IUA） after trans cervical resection adhesions （TCRA） operation， and to investigate its effect on fibrosis factor. Method:The 110 patients were randomly divided into two groups by random number table （55 cases for control group and 55 cases for observation group）. The patients in both groups got TCRA， and after the operation， they got estradiol valerate tablets+progesterone capsules. The patients in control group additionally got Jinfengwan before meals， 10 g/time， 2 times/day. Patients in observation additionally got syndrome differentiation and treatment by Bushen Huoxuetang， 1 dose/day. The treatment course was 3 months in both groups， and 6 months' follow-up was recorded. Before and after treatment， menstrual volume， period and cycle were recorded. During the follow-up， pregnancy， ectopic pregnancy and abortion were also recorded. Endoscopy and vagina color Doppler ultrasound were conducted to detect endometrial thickness， uterine volume， resistance index （RI）， pulsation index （PI） and blood flow index （FI）. Scores of IUA and syndrome of kidney deficiency and blood stasis were graded. At the 6<sup>th</sup> months after treatment， rate of intrauterine re-adhesion was recorded. Levels of transforming growth factor-<italic>β</italic><sub>1 </sub>（TGF-<italic>β</italic><sub>1</sub>）， connective tissue growth factor （CTGF）， matrix metalloproteinase inhibitor-1 （TIMP-1）， platelet-derived growth factor （PDGF）， insulin-like growth factor-1 （IGF-1） and matrix metalloproteinase-9 （MMP-9） were detected， and safety was evaluated. Result:Total effective rate of clinical efficacy was 96.36% （53/55） in observation group， higher than 83.64% （46/55） in control group （<italic>χ</italic><sup>2</sup>=4.959， <italic>P</italic><0.05）. Recovery rate of menstrual volume， period and cycle were 92.73% （51/55）， 90.91% （50/55）， and 94.55% （52/55） in observation group， higher than 72.73% （40/55）， 76.36% （42/55）， and 76.36% （42/55） in control group（<italic>χ</italic><sup>2</sup>=7.698，<italic>χ</italic><sup>2</sup>=4.245，<italic>χ</italic><sup>2</sup>=7.313，<italic>P</italic><0.05， <italic>P</italic><0.01）. During the follow-up， rate of intrauterine re-adhesions was 23.64% （13/55） in observation group， lower than 43.64% （24/55） in control group （<italic>χ</italic><sup>2</sup>=4.927，<italic>P</italic><0.05）. Pregnancy rate was 45.45% （25/55）， higher than 25.45% （14/55） in control group（<italic>χ</italic><sup>2</sup>=4.807，<italic>P</italic><0.05）. Score of syndrome of kidney deficiency and blood stasis and IUA scores in observation group were lower than those in control group （<italic>P</italic><0.01）. Endometrial thickness， uterine volume， and FI were higher than those in control group （<italic>P</italic><0.01）. Levels of RI， PI， TGF-<italic>β</italic><sub>1</sub>， CTGF， PDGF， IGF-1 and TIMP-1 were lower than those in control group （<italic>P</italic><0.01）， while level of MMP-9 was higher than that in control group （<italic>P</italic><0.01）. No adverse reactions related to traditional Chinese medicine were found. Conclusion:Bushen Huoxue decoction can promote the recovery of menstruation， increase the thickness of endometrium， improve the blood circulation of uterus， regulate the expression of fibrogenic factors<italic> in vivo</italic>， prevent and treat intrauterine adhesions， reduce the rate of intrauterine re-adhesions， and improve the rate of pregnancy， with a good comprehensive effect and high safety for clinical use.
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Objective:To observe the clinical efficacy of Yishen Tongluofang in treating oligosperm type male infertility with kidney deficiency and blood stasis syndrome and explore its effect on serum sex hormones and seminal plasma microenviro. Method:One hundred and four patients were randomly divided into observation group and control group with 52 cases each. Patients in control group took compound Xuanju capsules orally， 3 capsules/time， 3 times/day. Patients in observation group took Yishen Tongluofang， 1 dose/day. Treatment courses continued three months and followed up for three months in both groups. The pregnancy situations of spouses within six months were recorded. Examination of semen parameters before and after treatment and score of kidney deficiency and blood stasis syndrome were conducted. The levels of seminal plasma zinc， fructose， elastase， acid phosphatase and <italic>α</italic>-glucosidase， serum follicle stimulating hormone （FSH）， luteinizing hormone （LH）， prolactin （PRT） and testosterone （T） were detected before and after treatment. Result:During the observation period of six months， the pregnancy rate of spouses in the observation group was 22.00%， higher than 10.00% in the control group， but the difference was not statistically significant （<italic>χ</italic><sup>2</sup>=2.678，<italic>P</italic>>0.05）. The clinical efficacy in the observation group was better than that of the control group （<italic>Z</italic>=2.326，<italic>P</italic><0.01）. Sperm concentration， sperm motility， sperm motility， normal morphological sperm and linear movement speed of the observation group were all superior to those of the control group<italic> </italic>（<italic>P</italic><0.01）. The levels of zinc and fructose in seminal plasma of the observation group were higher than those of the control group （<italic>P</italic><0.01）， and the score of kidney deficiency and blood stasis syndrome was lower than that of the control group （<italic>P</italic><0.01）. Serum FSH， LH and PRT levels in the observation group were lower than those in the control group （<italic>P</italic><0.01）， and the T level was higher than that in the control group （<italic>P</italic><0.01）. The seminal plasma elastase of the observation group was lower than that of the control group， while the levels of acid phosphatase and <italic>α</italic>-glucosidase were higher than those of the control group （<italic>P</italic><0.01）. Conclusion:Yishen Tongluofang can significantly improve sperm parameters， regulate the level of sex hormones and seminal plasma environment in patients with oligosperm type male infertility， and improve the tendency of spouse pregnancy. Its clinical efficacy is better，so it is worthy of further research and application.
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Objective:To observe the clinical efficacy as well as anti-inflammatory and anti-fibrosis mechanism of Yishen Tongluo decoction in the treatment of chronic glomerulonephritis （CGN） with spleen and kidney Qi deficiency and blood stasis syndrome. Method:According to the random number table method， one hundred and twenty patients were divided into control group （60 cases） and observation group （60 cases）. The two groups were given oral valsartan capsules， 160 mg/time， 1 time/day， and dipyridamole tablets orally， 50 mg/time， 3 times/day. Patients in control group additionally took Wubi Shanyao pills orally， 9 g/time， 2 times/day， while patients in observation group additionally took Yishen Tongluo decoction orally， 1 dose/day. Both groups were treated continuously for four months. Before and after treatment， 24 h urine total protein （24 h UTP）， creatinine （SCr）， urea nitrogen （BUN）， serum cystatin C （CysC）， tumor necrosis factor-<italic>α</italic> （TNF-<italic>α</italic>）， interleukin-6 （IL-6）， IL-17， interferon-<italic>γ</italic> （IFN-<italic>γ</italic>）， transforming growth factor-<italic>β</italic><sub>1</sub> （TGF-<italic>β</italic><sub>1</sub>）， connective tissue growth factor （CTGF）， matrix metalloproteinase-9 （MMP-9）， tissue inhibitor of metalloproteinases （TMP-1） and hypoxia inducible factor-1<italic>α </italic>（HIF-1<italic>α</italic>） levels were detected in both groups. The scores of spleen and kidney Qi deficiency and blood stasis syndrome were graded. Urine protein， and urine red blood cells （urinary RBC） were monitored. Result:The 24 h UTP， SCr， BUN and CysC levels of the observation group were lower than those of the control group （<italic>P</italic><0.01）. The score of spleen and kidney Qi deficiency and blood stasis syndrome in the observation group was lower than that in the control group （<italic>P</italic><0.01）. The levels of TNF-<italic>α</italic>， IL-6， IL-17 and IFN-<italic>γ </italic>in the observation group were lower than those in the control group （<italic>P</italic><0.01）. The levels of TGF-<italic>β</italic><sub>1</sub>， CTGF， TMP-1 and HIF-1<italic>α</italic> in the observation group were lower than those in the control group （<italic>P</italic><0.01）. While MMP-9 level was higher than that in control group （<italic>P</italic><0.01）. The clinical effective rate was 88.33% （53/60） in the observation group， higher than 73.33% （44/60） in the control group （<inline-formula><alternatives><mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M2"><mml:msup><mml:mrow><mml:mi>χ</mml:mi></mml:mrow><mml:mrow><mml:mn mathvariant="normal">2</mml:mn></mml:mrow></mml:msup></mml:math><graphic specific-use="big" xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="alternativeImage/155A9E27-C0C9-44b4-96FF-AF947372054E-M002.jpg"><?fx-imagestate width="3.30200005" height="3.64066648"?></graphic><graphic specific-use="small" xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="alternativeImage/155A9E27-C0C9-44b4-96FF-AF947372054E-M002c.jpg"><?fx-imagestate width="3.30200005" height="3.64066648"?></graphic></alternatives></inline-formula>=4.356， <italic>P</italic><0.05）. Conclusion:On the basis of conventional Western medicine treatment， Yishen Tongluo decoction in the treatment of CGN patients with spleen and kidney Qi deficiency and blood stasis syndrome can reduce proteinuria， and improve traditional Chinese medicine （TCM） syndromes， with anti-inflammatory and anti-kidney fibrosis effects. Thereby， it plays a role in protecting renal function and delaying the malignant progression of renal function， with high clinical efficacy and value of clinical use.
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Objective:To observe the effect of modified Dihuangyin on vascular dementia due to kidney empty phlegm and blood stasis syndrome，and its effect on phosphoinositol 3-kinase/protein kinase B （PI3K/Akt） signaling pathway ［PI3K，microtuble-associated protein 1 light chain 3（LC3）Ⅱ/LC3Ⅰ，Akt，phosphorylatedprotein kinase B（p-Akt）］ in peripheral blood. Method:Totally 100 cases were randomly divided into control group （50 cases） and observation group （50 cases），and were given donepezil，modified Dihuangyin combined with donepezil for 30 d，respectively. The main efficacy indicators ［mini-mental state examination （MMSE），clinical dementia rating （CDR），activity of daily living scale （ADL），traditional Chinese medcine（TCM） syndrome］ were compared in two groups. The cerebral blood flow dynamics ［middle cerebral artery （MCA），basilar artery （BA），anterior cerebral artery （ACA），posterior cerebral artery （PCA）］ speed，serum inflammatory factors ［tumor necrosis factor-<italic>α</italic> （TNF-<italic>α</italic>），interleukin-6 （IL-6），transforming growth factor-<italic>β</italic> （TGF-<italic>β</italic>），C-reactive protein （CRP）］，oxidative stress indicators ［malondialdehyde （MDA），superoxide dismutase （SOD），glutathione peroxidase （GSH-Px） ，homocysteine （Hcy）］，peripheral blood PI3K/Akt signaling pathway （PI3K，LC3Ⅱ/LC3Ⅰ，Akt，p-Akt） were tested. The efficacy and adverse reactions of the two groups were compared. Result:The total effective rate was 95.9% in observation group was higher than that 72.3% in control group （<italic>χ</italic><sup>2</sup>=5.673，<italic>P</italic><0.05）. Compared with the control group after treatment，the MMSE，ADL，SOD，GSH-Px，TGF-<italic>β</italic>，PI3K，Akt and p-Akt in the observation group were increased （<italic>P</italic><0.05），CDR，MCA，BA，ACA and PCA were increased （<italic>P</italic><0.05），and the TCM syndromes，MDA，Hcy，TNF-<italic>α</italic>，IL-6，CRP，LC3Ⅱ/LC3Ⅰ were decreased （<italic>P</italic><0.05）. There was no significant difference incidence of adverse reactions between two groups. Conclusion:Modified Dihuangyin can significantly improve the clinical symptoms of patients with vascular dementia due to kidney empty phlegm and blood stasis syndrome，and the mechanism of action may be related to PI3K/Akt signaling pathway in peripheral blood.
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Objective:To discuss clinical effect of Zhuyu Zhixuetang to chronic endometritis （CE） with syndrome of Qi deficiency and blood stasis and to study improvement effect to pregnancy outcome. Method:One hundred and forty-four patients were randomly divided into two groups， patients in control group were 72 cases and in observation group were 72 cases. In control group， 66 patients completed the therapy because of 4 falling off or missing visit and 2 eliminated， and in observation group， 65 patients completed the therapy because of 3 falling off or missing visit and 5 eliminated. In two groups. anti-infection treatment was gicen to patients. Patients in control group got Fuke Qianjin Pian， 6 tablets/time， 3 times/day. Patients in observation group got Zhuyu Zhixuetang， 1 dose/day. The treatment was continued for 3 months and the follow up was recorded for 6 months. Before and after treatment， changes of menstrual volume， period and cycle were recorded. And hysteroscopy and color Doppler ultrasound of vagina were made， and endometrial morphology and endometrial receptivity were evaluated ［endometrial thickness， resistance index （RI）， pulsation index （PI） and blood flow index （FI）］ were evaluated， and pathology of endometrial were tested. And scores of syndrome of Qi deficiency and blood stasis were graded， levels of interleukin-1 <italic>β</italic> （IL-1<italic> β</italic>）， IL-6 and tumor necrosis factor-<italic>α</italic> （TNF-<italic>α</italic>） and T-lymphoid subsets （CD3<sup>+</sup>， CD4<sup>+</sup>， CD8<sup>+</sup>） in peripheral blood were measured. Pregnancy and miscarriage were recorded and the safety was evaluated. Result:After treatment， menstrual volume， menstrual period， cycle and complete normal rate of menstruation in observation group were all higher than those in control group （<italic>P</italic><0.05）. Endometrial thickness and FI were more than those in control group （<italic>P</italic><0.01）， RI and PI were lower than RI and PI in control group （<italic>P</italic><0.01）. And compared with control group， levels of IL-1<italic>β</italic>， IL-6， TNF-<italic>α</italic> and CD8<sup>+ </sup>were less （<italic>P</italic><0.01）. And levels of CD3<sup>+</sup>， CD4<sup>+</sup> and CD4<sup>+</sup>/ CD8<sup>+</sup> were higher than the data in control group （<italic>P</italic><0.01）. During 6 months follow-up， pregnancy rate in observation group was 46.97% （31/66） was higher than 27.69% （18/65） in control group （<italic>χ</italic><sup>2</sup>=5.197， <italic>P</italic><0.05）. Total effective rate of endometrial morphology was 96.97% （64/66） higher than 86.15% （56/65） in control group （<italic>χ</italic><sup>2</sup>=4.981， <italic>P</italic><0.05）. Total effective rate endometrial pathology was 95.45% （63/66） higher than 84.62% （55/65） in control group （<italic>χ</italic><sup>2</sup>=4.304， <italic>P</italic><0.05）. Total effective rate of comprehensive clinical effect was 93.94% （62/66） higher than 81.54% （55/65） in control group （<italic>χ</italic><sup>2</sup>=4.696， <italic>P</italic><0.05）. There was no adverse reactions related to traditional Chinese medicine. Conclusion:Zhuyu Zhixuetang can regulate menstruation， relieve clinical symptoms， improve endometrial morphology under hysteroscopy， regulate systemic and local immune inflammatory response， improve CP， thus improve pregnancy outcome， with better comprehensive effect and safety.