Danhong Injection Up-regulates miR-125b in Endothelial Exosomes and Attenuates Apoptosis in Post-Infarction Myocardium / 中国结合医学杂志

OBJECTIVE@#To investigate the involvement of endothelial cells (ECs)-derived exosomes in the anti-apoptotic effect of Danhong Injection (DHI) and the mechanism of DHI-induced exosomal protection against postinfarction myocardial apoptosis.@*METHODS@#A mouse permanent myocardial infarction (MI) model was established, followed by a 14-day daily treatment with DHI, DHI plus GW4869 (an exosomal inhibitor), or saline. Phosphate-buffered saline (PBS)-induced ECs-derived exosomes were isolated, analyzed by miRNA microarray and validated by droplet digital polymerase chain reaction (ddPCR). The exosomes induced by DHI (DHI-exo), PBS (PBS-exo), or DHI+GW4869 (GW-exo) were isolated and injected into the peri-infarct zone following MI. The protective effects of DHI and DHI-exo on MI hearts were measured by echocardiography, Masson's trichrome staining, and TUNEL apoptosis assay. The Western blotting and quantitative reverse transcription PCR (qRT-PCR) were used to evaluate the expression levels of miR-125b/p53-mediated pathway components, including miR-125b, p53, Bak, Bax, and caspase-3 activities.@*RESULTS@#DHI significantly improved cardiac function and reduced infarct size in MI mice (P<0.01), which was abolished by the GW4869 intervention. DHI promoted the exosomal secretion in ECs (P<0.01). According to the results of exosomal miRNA microarray assay, 30 differentially expressed miRNAs in the DHI-exo were identified (28 up-regulated miRNAs and 2 down-regulated miRNAs). Among them, DHI significantly elevated miR-125b level in DHI-exo and DHI-treated ECs, a recognized apoptotic inhibitor impeding p53 signaling (P<0.05). Remarkably, treatment with DHI and DHI-exo attenuated apoptosis, elevated miR-125b expression level, inhibited capsase-3 activity, and down-regulated the expression levels of proapoptotic effectors (p53, Bak, and Bax) in post-MI hearts, whereas these effects were blocked by GW4869 (P<0.05 or P<0.01).@*CONCLUSION@#DHI and DHI-induced exosomes inhibited apoptosis, promoted the miR-125b expression level, and regulated the p53 apoptotic pathway in post-infarction myocardium.

Class-imbalance Prediction and High-dimensional Risk Factor Identification of Adverse Reactions of Traditional Chinese Medicine with Centralized Monitoring in Real-world Hospitals / 中国实验方剂学杂志

ObjectiveTo achieve high-dimensional prediction of class imbalanced of adverse drug reaction（ADR） of traditional Chinese medicine（TCM） and to classify and identify risk factors affecting the occurrence of ADR based on the post-marketing safety data of TCM monitored centrally in real world hospitals. MethodThe ensemble clustering resampling combined with regularized Group Lasso regression was used to perform high-dimensional balancing of ADR class-imbalanced data， and then to integrate the balanced datasets to achieve ADR prediction and the risk factor identification by category. ResultA practical example study of the proposed method on a monitoring data of TCM injection performed that the accuracy of the ADR prediction， the prediction sensitivity， the prediction specificity and the area under receiver operating characteristic curve（AUC） were all above 0.8 on the test set. Meanwhile， 40 risk factors affecting the occurrence of ADR were screened out from total 600 high-dimensional variables. And the effect of risk factors on the occurrence of ADR was identified by classification weighting. The important risk factors were classified as follows：past history， medication information， name of combined drugs， disease status， number of combined drugs and personal data. ConclusionIn the real world data of rare ADR with a large amount of clinical variables， this paper realized accurate ADR prediction on high-dimensional and class imbalanced condition， and classified and identified the key risk factors and their clinical significance of categories， so as to provide risk early warning for clinical rational drug use and combined drug use， as well as scientific basis for reevaluation of safety of post-marketing TCM.

Post-marketing effectiveness evaluation of traditional Chinese medicine in paradigm based on "proving efficacy, conforming standard, and exploring mechanism":a case study of Danhong Injection / 中国中药杂志

At present, new concepts, new technologies, and new methods are emerging in the field of medical research, breaking through the inherent thinking patterns and research models, and promoting the transformation of the research paradigm of traditional Chinese medicine(TCM). This paper gave a case study of clinical research in Danhong Injection in the treatment of chronic stable angina, and based on the background of the study, index evaluation model, experimental design method, blind implementation of placebo, data management system, and exploration of clinical efficacy mechanism of traditional Chinese medicine compounds under the framework of modular pharmacology, the scientific idea of "proving efficacy, conforming standard, and exploring mechanism" was used as the guideline to discuss the research model of reevaluation of the effectiveness of post-marketing TCM varieties. This paper drew a target network map of Danhong Injection in the treatment of chronic stable angina for the first time, which was composed of targeted functional modules. By combining evidence-based clinical research with modular pharmacology framework, changes in the pharmacolo-gical mechanism were finally associated with changes in clinical efficacy, and the advantages of phenotypic correlation of efficacy were explored. This study is expected to provide references for the post-marketing effectiveness evaluation and new ideas for the phenotypic pharmacological mechanism study of multi-target TCM compounds and precise treatment, thereby promoting the innovative development of TCM.

Effects of Danhong injection combined with bisoprolol on ventricular arrhythmia in patients with type 2 diabetes mellitus complicated by coronary heart disease / 中国基层医药

Objective:To investigate the efficacy and safety of Danhong injection combined with Bisoprolol on ventricular arrhythmia in patients with type 2 diabetes mellitus complicated by coronary heart disease. Methods:A total of 100 patents with type 2 diabetes mellitus complicated by coronary heart disease who received treatment in Dezhou Second People's Hospital, China between January and December 2019 were included in this study. They were randomly assigned to receive treatment either with bisoprolol (control group, n = 50) or bisoprolol + Danhong injection (treatment group, n = 50) based on routine treatment. Therapeutic effects, arrhythmia improvement, blood glucose index, islet function index, and adverse reactions during treatment were compared between the control and treatment groups. Results:Total effective rate in the observation group was significantly higher than that in the control group (88.0% vs. 70.0%, χ2 = 4.883, P < 0.05). After treatment, there were significant differences in the number of ventricular premature beats [(1 412.52 ± 587.85) beats/24 hours vs. (2 247.96 ± 761.52) beats/24 hours], paroxysmal supraventricular tachycardia [(46.58 ± 10.12) bursts/24 hours vs. (79.45 ± 12.01) bursts/24 hours], and ST segment depression [(1.24 ± 0.19) mm vs. (1.41 ± 0.24) mm] between the observation and control groups ( t = -6.141, -14.799, -3.927, all P < 0.001). After treatment, fasting blood glucose level, 2-hour postprandial glucose value and glycosylated hemoglobin level in the treatment group were (6.58 ± 1.61) mmol/L, (8.35 ± 1.72) mmol/L, and (6.14 ± 1.58)%, respectively, which were significantly lower than those in the control group [(8.24 ± 1.87) mmol/L, (9.69 ± 1.91) mmol/L, (7.68 ± 1.92)%, t = -4.757, -3.686, -4.379, all P < 0.001]. After treatment, islet beta cell function in the observation group was significantly higher than that in the control group [(56.52 ± 10.28) % vs. (47.96 ± 9.72)%, t = 4.278, P < 0.001). Insulin resistance index in the observation group was significantly lower than that in the control group [(2.06 ± 0.32) vs. (2.54 ± 0.35), t = -7.157, P < 0.001]. After treatment, there was no significant difference in the incidence of adverse reactions between the control and observation groups (12.00% vs. 8.00%), χ2 = 0.444, P > 0.05]. Conclusion:Danhong injection combined with bisoprolol is more effective in treating ventricular arrhythmia in patients with type 2 diabetes mellitus complicated by coronary heart disease than Danhong injection and bisoprolol alone. The combined treatment can reduce the incidence of ventricular arrhythmia, regulate blood glucose level, and improve islet function.

Effects of Danhong injection combined with intravenous thrombolysis on cardiac function, myocardial zymogram and lipoprotein-associated phospholipase A2 level in older adult patients with acute myocardial infarction / 中国基层医药

Objective:To investigate the effects of Danhong injection combined with intravenous recombinant tissue plasminogen activator (rt-PA) on cardiac function, myocardial zymogram and lipoprotein associated phospholipase A2 (Lp-PLA2) level in older adult patients with acute myocardial infarction (AMI). Methods:Eighty older adult patients with acute myocardial infarction who received treatment in Community-based General Hospital of Shaoxing Central Hospital, China between January 2017 and December 2019 were included in this study. They were randomly assigned to receive either intravenous thrombolysis with rt-PA (control group, n = 40) or Danhong injection combined with intravenous thrombolysis with rt-PA (observation group, n = 40). The changes in traditional Chinese medicine syndrome score, left ventricular ejection fraction, left ventricular end diastolic diameter, creatine kinase, creatine kinase-MB and lipoprotein associated phospholipase A2 level as well as adverse cardiovascular events were compared between the control and observation groups. Results:After treatment, the score of chest tightness, dark purple tongue, palpitation and shortness of breath in the two groups were decreased. After treatment, the score of chest tightness, dark purple tongue, palpitation and shortness of breath in the observation group was (2.13 ± 0.31) points, (1.98 ± 0.41) points, (1.77 ± 0.29) points, respectively, which was significantly lower than that in the control group [(2.98 ± 0.37) points, (2.52 ± 0.56) points, (2.13 ± 0.32) points, t = 11.137, 4.920, 5.272, all P < 0.001]. After treatment, left ventricular end diastolic diameter in each group was decreased compared with before treatment. After treatment, left ventricular end diastolic diameter in the observation group was significantly lower than that in the control group [(46.12 ± 4.11) mm vs. (49.74 ± 4.32) mm], and left ventricular ejection fraction in the observation group was significantly higher than that in the control group [(47.02 ± 3.55) % vs. (43.25 ± 4.10) %, t = 3.839, 4.396, both P < 0.001). After treatment, Lp-PLA2, creatine kinase, creatine kinase-MB levels in each group were decreased compared with before treatment. After treatment, Lp-PLA2, creatine kinase, creatine kinase-MB levels in the observation group were (171.02 ± 12.52) μg /L, (10.52 ± 2.11) U/L, (24.12 ± 3.52) U/L), respectively, which were significantly lower than those in the control group [(189.63 ± 11.98) μg/L, (14.71 ± 2.62) U/L, (32.79 ± 4.79) U/L), t = 6.792, 7.877, 9.224, all P < 0.001]. The incidence of adverse cardiovascular events in the observation group was significantly lower than that in the control group (5.00% vs. 22.50%, χ2 = 5.165, P < 0.05). Conclusion:Danhong injection combined with intravenous rt-PA for the treatment of acute myocardial infarction in older adult patients can greatly decrease traditional Chinese medicine syndrome score, improve cardiac function, regulate myocardial zymogram and Lp-PLA2 levels, and decrease the incidence of adverse cardiovascular events.

Combined therapy of calcium dobesilate capsules, oral administration of Dahuoluo capsules, and intravenous drip of Danhong injection in treatment of patients with nonproliferative diabetic retinopathy / 中华内分泌外科杂志

Objective:To investigate the combined therapy of calcium dobesilate capsules, oral administration of Dahuoluo capsules, and intravenous drip of Danhong injection in treatment of patients with nonproliferative diabetic retinopathy.Methods:106 cases were randomly selected from the patients with nonproliferative diabetic retinopathy admitted in Traditional Chinese and Western Hospital of Dazhou City from Jan. 2019 to Dec. 2019. Based on the random numbers table, the cases were divided into control group and intervention group, with each group 53 patients. They were respectively treated with the therapy of calcium dobesilate capsules alone and the combined therapy of calcium dobesilate capsules, oral administration of Dahuoluo capsules and intravenous drip of Danhong injection, and the therapeutic effects were compared.Results:After treatment, the visual acuity of patients in both groups significantly improved ( P<0.05) , and the visual acuity of patients in the intervention group was higher than that of patients in the control group ( P<0.05) ; after treatment, the peak systolic velocity (PSV) and end diastolic velocity (EDV) of the central retinal artery (CRA) and posterior ciliary artery (PCA) of the patients in both groups significantly increased ( P<0.05) , while RI significantly reduced ( P<0.05) , and PSV and EDV of CRA and PCA in the intervention group were significantly higher than those of the control group ( P<0.05) , while RI was significantly lower than that of the control group ( P<0.05) . After treatment, the therapeutic efficiency of the intervention group was 96.23%, significantly higher than 79.25% in the control group ( χ2=7.102, P<0.05) . The incidence of adverse reactions in the intervention group was 9.43%, which had no significant difference with 3.78% in the control group ( χ2=1.377, P>0.05) . After targeted treatment was given, the adverse reactions disappeared. Conclusion:The combined therapy of calcium dobesilate capsules, oral administration of Dahuoluo capsules, and intravenous drip of Danhong injection was significantly effective in treatment of patients with nonproliferative diabetic retinopathy.

Research Progress on Pharmacological Mechanism of Danhong Injection in Treatment of Cardiovascular and Cerebrovascular Diseases / 中国实验方剂学杂志

Cardiovascular and cerebrovascular diseases are one of the major diseases endangering human health， and its morbidity and mortality are still in the rising stage in our country. Traditional Chinese medicine （TCM） injections play an important role in the prevention and treatment of cardiovascular and cerebrovascular diseases due to their advantages of rapid onset， remarkable curative effect， and convenient use. Among them， Danhong injection （DHI）， a Chinese medicine injection for promoting blood circulation and removing blood stasis， is widely used in the clinical treatment of cardio-cerebrovascular diseases. DHI is composed of Salviae Miltiorrhizae Radix et Rhizoma （Danshen in Chinese） and Carthami Flos （Honghua in Chinese）， and mainly contains phenolic acids， tanshinones and flavonoids. A large number of studies have shown that DHI has a significant effect in the treatment of ischemic cardio-cerebrovascular diseases， is a representative drug of co-therapy of brain and heart of TCM， its pharmacological effects related to many aspects such as anti-inflammatory， anti-oxidation， anti-coagulation. At the same time， Other studies have also explained the protective effects of DHI on cardiovascular and cerebrovascular diseases through the overall regulation and intervention of multiple targets and pathways. However， DHI has a wide range of clinical applications， there are still many unknown pharmacological effects to be further explored. Therefore， this article summarizes the current researches on the chemical components of DHI， the multi-target and multi-path pharmacological mechanisms of DHI in the treatment of cardiovascular and cerebrovascular diseases， and introduces the latest pharmacological research progress， so as to provide theoretical guidance for clinical rational drug use and subsequent in-depth research.

Exploring efficacy of Chinese medicine injection for promoting blood circulation and removing blood stasis in treatment of acute cerebral infarction based on two complex network analysis methods / 中国中药杂志

This study aims to explore the efficacy of Chinese medicine injections( CMIs) for promoting blood circulation and removing blood stasis for acute cerebral infarction from the perspectives of clinical medication and mechanism of action based on two complex network analysis methods. Firstly,the current 13 kinds of CMIs for acute cerebral infarction were obtained from 2019 List of medicines for national basic medical insurance,industrial injury insurance and maternity insurance with the method of network Meta-analysis. Secondly,with the use of network pharmacology,the mechanisms of top 2 CMIs with the highest therapeutic effect for acute cerebral infarction were explored from two levels including core target and network function enrichment. The result of network Meta-analysis showed Mailuoning Injection was superior to Danhong Injection in terms of total effectiveness rate for neurological deficit score and NIHSS score. The network pharmacology results showed that Mailuoning Injection had more core targets,interaction networks,enriched biological functions and more signaling pathways than Danhong Injection for cerebral infarction. Both two CMIs can play a role in treating cerebral infarction through core targets such as TP53 and NOS3,biological processes such as fibrinolysis,nitric oxide biosynthesis,nitric oxide-mediated signal transduction,negative regulation of apoptosis in endothelial cells and apoptosis process,as well as the signaling pathways such as PI3 K-Akt signaling pathway,HIF-1 signaling pathway and cell apoptosis signaling pathways. The results of pharmacological studies explained their differences in clinical efficacy to a certain extent. A research strategy based on curative effect should be advocated in efficacy evaluation of traditional Chinese medicine,where comparative research on clinical efficacy can be conducted firstly,and then mechanism research based on outstanding effective drugs to better provide references and basis for selection of similar competitive drugs for one disease in the clinical practice.

Effect of Danhong Injection on platelet metabolites based on metabonomics technology / 中国中药杂志

The effect of Danhong Injection on the endogenous metabolites of rabbit platelets was analyzed by the liquid chromatography-mass spectrometry( LC-MS) based metabonomic approach. Anti-platelet aggregation was detected after Danhong Injection treatment and the changes of platelet metabolites were analyzed by metabonomics. Principal component analysis( PCA) and partial least squares discriminant analysis( PLS-DA) were performed to investigate the effect of Danhong Injection on endogenous metabolites of platelets,characterize the biomarkers,and explore the relevant pathways and the underlying mechanism. As demonstrated by the pharmacodynamic results,Danhong Injection of different doses and concentrations antagonized platelet aggregation in a dose-and concentration-dependent manner. In contrast to the control group,25 differential metabolites such as nicotinic acid,nicotinic acid riboside,and hypoxanthine were screened out after platelets were treated by Danhong Injection. These metabolites,serving as important biomarkers,were mainly enriched in the nicotinic acid-niacinamide metabolic pathway and purine metabolic pathway. This study explored the therapeutic mechanism of Danhong Injection from a microscopic perspective by metabonomics,which is expected to provide a new idea for the investigation of platelet-related mechanisms.

Clinical comprehensive evaluation of Danhong Injection in treatment of stroke with blood stasis syndrome / 中国中药杂志

This study systematically reviewed the existing research on Danhong Injection in the treatment of stroke with blood stasis syndrome. The methods of evidence-based medicine, epidemiology, clinical medicine, evidence-based pharmacy, drug economics, mathematical statistics, and health technology assessment(HTA) were employed to qualitatively and quantitatively evaluate the "6+1" dimensions(safety, effectiveness, economy, innovation, suitability, accessibility, and characteristics of traditional Chinese medicine) of Danhong Injection through questionnaire survey, public information, real world data, and secondary evaluation of literature. With the weights given by experts, the multi-criteria decision analysis(MCDA) model was employed to measure each dimension and highlight the clinical value of Danhong Injection. Multi-source safety evidence showed that Danhong Injection had been fully monitored and studied. The severity of adverse reactions was mostly moderate or mild, and the prognosis was good. So it was rated as grade A for safety. Compared with Ligustrazine Injection, Fufang Danshen Injection and conventional treatment of western medicine, Danhong Injection had obvious advantages in clinical response rate and NIHSS score improvement in the treatment of stroke with blood stasis syndrome. So it was rated as grade A for effectiveness. Compared with Ligustrazine Injection and Yinxing Damo Injection, Danhong Injection had a cost-effectiveness advantage in the treatment of stroke with blood stasis syndrome, and the economic results were good. According to the existing evidence, the Danhong Injection was rated as grade B for economy. Danhong Injection had won a number of national patents, which was rated as grade A for its good innovation in guaranteeing supply measures, scalability of production capacity, and production process. It had good suitability for clinicians, nurses, pharmacists, and patients using the drug, and met the needs of clinical medication, so it was rated as grade B for suitability. Danhong Injection is rich in medicinal materials, stable in price, and sustainable. However, its availability needed to be further improved due to the limitation of prescription use, so it was rated as grade B for accessibility. Danhong Injection can promote blood circulation, resolve blood stasis, warm vessels, and smooth collaterals. It had accumulated more than 30 000 pieces of empirical evidence for human use in the real world. It had prominent characteristics of traditional Chinese medicine and was rated as grade B. CSC v2.0 was used for calculation, and the clinical value of Danhong Injection was comprehensively evaluated as class A, which could be directly translated into relevant policy results of basic clinical medication management according to the Guidelines for the Management Clinical Comprehensive Evaluation of Drugs(trial version 2021).

Mechanism of Danhong injection in improving therapeutic effect of neural stem cell transplantation for cerebral ischemia injury / 器官移植

Objective To investigate whether Danhong injection can enhance the therapeutic effect of neural stem cell (NSC) transplantation in repairing cerebral ischemia injury by regulating the nuclear factor E2-related factor 2 (Nrf2) signaling pathway. Methods Forty male SD rats were randomly divided into the NSC transplantation group (NSC group), Danhong injection group (DH group), NSC+ Danhong injection group (N+D group), NSC+ Danhong injection group +ML385 group(N+D+M group) and PBS control group (PBS group), 8 rats in each group. All rat models of cerebral ischemia were established by embolization of the middle cerebral artery. Reperfusion was performed at 1.5 h after embolization. All rats in each group received corresponding interventions at 3 d after reperfusion. The neurological function score was evaluated before and 1, 2, 4 weeks after NSC transplantation. All rats were sacrificed at 4 weeks after NSC transplantation. The parameters related to oxidative stress were detected. The expression levels of neuron-specific nuclear protein (NeuN) and von Willebrand factor (vWF) were determined by immunofluorescence staining. Results Before NSC transplantation, the neurological function scores did not significantly differ among different groups (all P > 0.05). At postoperative 1, 2 and 4 weeks, the neurological function scores in the NSC, DH and N+D groups were significantly lower than those in the PBS and N+D+M groups (all P < 0.05). Compared with the PBS and N+D+M groups, the malondialdehyde (MDA) levels were significantly decreased, whereas the superoxide dismutase (SOD) and glutathione peroxidase (GPX) levels were considerably increased in the NSC, DH and N+D groups (all P < 0.05). The GPX level in the N+D+M group was significantly lower than that in the PBS group (P < 0.05). Immunofluorescence staining showed that the transplant NSC in the rat brain migrated to the surrounding area of cerebral infarction and survived, and expressed neuronal marker NeuN and neovascularization marker vWF. However, the number of living NSC in the N+D+M group was significantly lower compared with those in the remaining groups. Conclusions Danhong injection may improve the microenvironment of stem cell transplantation, enhance the survival rate of transplant NSC and improve the therapeutic effect of NSC transplantation for cerebral ischemia injury probably by regulating the Nrf2 signaling pathway.

Effect of Danhong Injection () on Improving Coronary Microcirculation Injury after Percutaneous Coronary Intervention / 中国结合医学杂志

OBJECTIVE@#To explore the effectiveness of Danhong Injection () on improving microcirculatory injury after percutaneous coronary intervention (PCI) in patients with coronary heart disease (CHD).@*METHODS@#A randomized controlled trial was conducted and 90 patients were enrolled. A random sequence was generated using statistical analysis software. Patients with microcirculatory injuries after PCI were randomly divided into 3 groups for treatment (30 subjects in each group): Danhong Injection group: after PCI, Danghong Injections were given with intravenous administration with 40 mL twice a day for a week; statins intensive group: after PCI, atorvastatin calcium tablets were given oral medication with 80 mg once, and then atorvastatin 40 mg daily for 1 week; the control group: after PCI, atorvastatin calcium tablets were given oral medication with 10-20 mg daily for 1 week. The index of microcirculation resistance (IMR) was used to assess microcirculatory injury during PCI. The IMR of the target vessel was reexamined after 1 week of drug treatment.@*RESULTS@#After one week's drug treatment, IMR was significantly decreased in both statins intensive group and Danhong Injection group compared with the control group (P<0.01), but no difference was found between statins intensive group and Danhong injection group (14.03 ± 2.54 vs. 16.03 ± 5.72 U, P=0.080).@*CONCLUSIONS@#The efficacy of Danhong Injection is non-inferior to statin. Early use of Danhong Injection after PCI can effectively improve coronary microcirculation injury after PCI.

Meta-analysis of Danhong Injection in treatment of diabetes mellitus complicated with coronary heart disease / 中国中药杂志

To systematically evaluate the clinical efficacy and safety of Danhong Injection combined with conventional therapy in improving diabetes mellitus complicated with coronary heart disease. Based on the online literature database(CNKI, Wanfang, VIP, PubMed, Web of Science, Cochran Library), the Chinese and English papers about the randomized controlled trial(RCT) of Danhong Injection in the treatment of diabetes mellitus complicated with coronary heart disease were searched comprehensively from the establishment of the databases to January 1, 2020. The papers were screened strictly according to the inclusion and exclusion criteria. Based on Jadad scale, the risk assessment of literature was carried out, and Meta-analysis was performed by STATA 12.0 software. Seventeen RCTs were included, involving 1 453 patients. The results of Meta-analysis showed that the combination of Danhong Injection and conventio-nal treatment could improve the clinical comprehensive effective rate(RR=1.47, 95%CI[1.38, 1.58], P<0.000 1), electrocardiogram(ECG) efficiency(RR=1.30, 95%CI[1.16, 1.46], P<0.000 1), efficiency of the angina pectoris(RR=1.41, 95%CI[1.25, 1.58], P<0.000 1), cholesterol level(SMD=-1.05, 95%CI[-1.95,-0.16], P=0.02), low-density lipoprotein(LDL) level(SMD=-0.50, 95%CI[-0.79,-0.21], P<0.000 1), coronary angina attack frequency(SMD=-3.71, 95%CI[-4.05,-3.36], P<0.000 1) and duration of angina pectoris(SMD=-2.96, 95%CI[-3.25,-2.66], P<0.000 1), with statistically significant differences. But the differences in fasting plasma glucose(FPG)(SMD=-0.19, 95%CI[-0.45, 0.08], P=0.16), plasma glucose of two hours after meal(2 hPG)(SMD=0.19, 95%CI[-0.11, 0.49], P=0.22), and high-density lipoprotein(HDL) level(SMD=0.10, 95%CI[-0.30, 0.49], P=0.62) after treatment were not statistically significant. Compared with the control group, there was no significant difference in adverse reactions(SMD=-2.96, 95%CI[-3.25,-2.66], P=0.75). The existing evidence shows that the combination of Western medicine and Danhong Injection can improve the clinical effect for diabetes mellitus complicated with coronary heart disease and has no obvious adverse reactions. However, due to the low level of overall literature evidence, high risk and some kind of publication bias, it still needs more high-quality randomized controlled trials and low-bias studies for further verification.

Lipid-lowering effect and mechanism of Danhong Injection on hyperlipidemia rats based on lipid metabolism disorder / 中国中药杂志

The animal model of hyperlipidemia in rats was established to investigate the lipid-lowering effect and mechanism of Danhong Injection on hyperlipidemic rats. SD rats were selected as the research object. The rats in normal group were fed with basic diet, and the rats in other groups were fed with high-fat diet to establish hyperlipidemia model. The successfully modeled rats were randomly divided into model group, Danhong Injection low, medium, high dose(1.0, 2.0, 4.0 mL·kg~(-1)) groups, and simvastatin(2.0 mg·kg~(-1)) group. Danhong Injection groups received intraperitoneal administration, and simvastatin group received intragastrical administration, once a day for 4 weeks. At the first, second, third, and fourth weekends after administration, blood was collected from the orbital vein to detect the levels of total cholesterol(TC), triglyceride(TG), low-density lipoprotein cholesterol(LDL-C), and high-density lipoprotein cholesterol(HDL-C), and then the atherosclerosis index(AI) was calculated. After 4 weeks of administration, the animals were sacrificed, and their heart, liver, spleen, lung, kidney and adipose tissue were extracted and weighed respectively to calculate the organ index of each group. The expressions of acyl-coaoxidase 1(Acox1), adenosine 5'-monophosphate(AMP)-activated protein kinase alpha(AMPK-α), bile salt export pump(BSEP), peroxisome proliferator-activated receptor gamma(PPAR-γ), catalase(CAT) and superoxide dismutase(SOD) mRNA in liver tissues were detected by fluorescence quantitative PCR; the content of cholesteryl ester transfer protein(CETP) and lecithin cholesterol acyltransferase(LCAT) in serum was detected by ELISA. The results showed that as compared with the normal group, the levels of serum TC, TG and LDL-C in the model group were significantly increased, and the level of HDL-C was significantly decreased, indicating that the hyperlipidemia rat model was successfully constructed. As compared with the model group, Danhong Injection could decrease the contents of TC, TG, LDL-C and increase the content of HDL-C in hyperlipidemia rats; reduce the body weight of hyperlipidemia rats, and reduce the liver weight, liver index, fat weight and fat index; it had no significant effect on the main organ indexes such as heart, spleen, lung and kidney; but it could increase the expressions of Acox1, AMPK-α, BSEP, PPAR-γ, CAT and SOD mRNA in liver tissues of rats; it could also reduce the level of CETP and increase the level of LCAT in serum; and the regulatory effect of Danhong Injection groups all showed a dose-dependent effect. It can be concluded that Danhong Injection can regulate the blood lipid contents, reduce the blood lipid levels and alleviate the accumulation of body fat in rats with hyperlipidemia. The mechanism may be related to inhibiting lipid metabolism disorder and oxidative stress induced by high-fat diet feeding, and improving the imbalance of lipid transport system.

Analysis of Modular Network Mechanism of Danhong Injection in Treatment of Coronary Angina Pectoris / 中国实验方剂学杂志

Objective:To explore the pharmacological mechanism of Danhong injection (DHI) in the treatment of coronary heart disease with angina pectoris from the level of functional modules by modular pharmacological analysis framework. Method:The targets of drug components in the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and the angina-related genes in DisGeNET, OMIM and CTD databases were combined to construct the target network of DHI for the treatment of coronary angina pectoris by STRING version 11.0. Functional modules were identified by the molecular complex detection (MCODE), Markov cluster (MCL) and GLay algorithms, and the results were optimized by the minimum network structure entropy algorithm. The Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis was performed on the modules by DAVID version 6.8 bioinformatics analysis platform. Result:By integrating 262 genes related to DHI and 192 genes related to angina pectoris, the target network of DHI for angina pectoris was constructed, including 414 nodes and 6 621 edges. After optimization of the minimum network structure entropy, 12 functional modules (number of nodes>3) were identified by MCODE algorithm, of which the largest module (module 1) has 47 nodes and 962 edges, MCODE score=41.826. KEGG pathway enrichment analysis was conducted on the gene network of DHI for angina pectoris and the modules divided by MCODE, and 37 and 58 KEGG signaling pathways were obtained respectively, with the coverage rate of 86.5%. The pathways enriched by the modules could be roughly divided into 11 categories, among which human diseases (45%), signal transduction (17%), and amino acid metabolism (14%) were involved in a large proportion. Module 1 was enriched into 39 pathways, which was signal transduction-related module. Module 3 was amino acid metabolism-related module. Conclusion:The therapeutic effect of DHI on coronary heart disease with angina pectoris is achieved through multiple modules, multiple pathways and multiple functions, mainly by regulating modules related to signal transduction, amino acid metabolism, neuroactive ligand-receptor interaction, Ca2+ and p53 signaling.

Effects and Mechanisms of Danhong Injection on Cerebral Ischemia-Reperfusion Injury in Rats with Hyperlipemia / 中国药学杂志

OBJECTIVE: To study the effects and mechanisms of danhong injection on cerebral ischemia reperfusion injury in rats with hyperlipidemia. METHODS: Hyperlipidemia model was established by feeding SD rats with high-fat diet for 6 weeks. Then hyperlipidemia rats were randomly divided into sham operation group, model group and danhong injection low (0.5 mL•kg-1), medium (1.0 mL•kg-1) and high (2.0 mL•kg-1) dose groups with six rats for each group. Danhong injection groups were injected for 7 consecutive days before the establishment of the model of middle cerebral artery occlusion (MCAO), and the corresponding dose was given once at 1 h before modeling and 6 h after reperfusion. After 24 h of reperfusion, rats were evaluated in terms of neurological function. The changes of histopathology were observed in the cerebral cortex of ischemic rats by HE staining; RT-PCR was used to detect the mRNA expressions of Nox2, Rac1, ASC, NLRP3, caspase-1, IL-1β and IL-18 in cerebral ischemia area. In addition, the content of triglyceride (TG) and total cholesterol (TC) in serum were detected by the kits. The expression of NLRP3 protein was evaluated by immunohistochemical. RESULTS: Compared with MCAO group, Danhong injection groups improved the reperfusion injury of cerebral ischemia in varying degrees, significantly reduced the mRNA expression of Nox2, Rac1, ASC, NLRP3, caspase-1, IL-1β and IL-18, increased the neurological score of MCAO rats, and reduced the contents of TC and TG besides the expression of NLRP3 protein. CONCLUSION: Danhong injection could effectively regulate blood lipid level and play a obvious protective effect on the reperfusion injury in MCAO rats with hyperlipidemia. The mechanism might be related to the inhibition of the formation of NLRP3 inflammatory body and the decrease of the inflammation-related factors expression of caspase-1, IL-1β and IL-18.

Clinical efficacy of Danhong injection in preventing contrast-induced acute kidney injury based on propensity score matching method / 中南大学学报(医学版)

OBJECTIVES@#Contrast-induced acute kidney injury (CI-AKI) is the third cause of hospital-acquired AKI, and existing clinical prevention and treatment measures such as hydration therapy and/or administration of antioxidants N-acetylcysteine treatment and other treatments still show little effect on the prevention and treatment of CI-AKI. This study aims to explore the effect of Danhong injection on prevention of CI-AKI.@*METHODS@#A total of 12 867 patients, who received coronary angiography, percutaneous coronary intervention, enhanced CT or vascular intervention in a tertiary hospital, were enrolled for this study. Among them, 423 in the treatment group received intravenous drip of Danhong injection, and 12 444 in the control group received routine medicine. Propensity score matching was conducted to balance confounding factors between the 2 groups and then the prevention effect of Danhong injection on CI-AKI was compared between them.@*RESULTS@#A total of 423 pairs of patients were matched successfully. The incidence of CI-AKI in the non-Danhong control group was higher than that in the Danhong treatment group (5.7% vs 2.4%). The difference between the 2 groups was statistically significant (@*CONCLUSIONS@#The results of this study support the use of Danhong injection in the prevention of the Stage 1 of CI-AKI.

Production and quality control of original herbal materials of Danhong Injection / 中国中药杂志

Cardiovascular and cerebrovascular diseases are the leading cause of death for residents in China. Danhong Injection(DHI) decoction piece is prepared from Salviae Miltiorrhizae Radix et Rhizoma and Carthami Flos, with the function of promoting the blood circulation, removing the blood stasis, relaxing the sinews and dredging the collaterals. In recent years, about 100 million bottles of DHI have been sold. Consequently, its safety and effectiveness are very important to a large number of patients. Raw materials are the source and foundation for production of traditional Chinese medicine injections. In this article, we reviewed the identification of Salviae Miltiorrhizae Radix et Rhizoma and Carthami Flos, resource distribution, cultivation, quality control, and detection of xenobiotic pollutants, in order to guide the production of high-quality, stable, and pollution-free raw materials. This will be a benefit in ensuring the safety and effectiveness of DHI and reducing the incidence of adverse reactions from the raw materials. By comparing the similarities and differences between the quality standards of Salviae Miltiorrhizae Radix et Rhizoma, Carthami Flos and DHI, we provided some comments for improving the quality standards and post-marketing reevaluation of DHI, and provided some theoretical supports for the production of high-quality herbal raw materials.

Mechanism and Clinical Efficacy of Danhong Injection in Treatment of Coronary Heart Disease / 中国实验方剂学杂志

Coronary heart disease (CHD) is one of the leading causes of death in the world and has become a major public health problem worldwide. CHD belongs to the category of "chest stuffiness" in traditional Chinese medicine, and the blood stasis syndrome is the most common syndrome.Danhong injection is prepared from the extract of Salviae Miltiorrhizae Radix et Rhizoma and Carthami Flos. It has the functions of promoting blood circulation and removing blood stasis. It has anti-inflammatory damage, anti-apoptosis, protection of vascular endothelium, inhibition of platelet aggregation, anti-hyperlipidemia, anticoagulation, improvement of blood rheology and other effects.It also could improve myocardial ischemia and relieve angina symptoms.Danhong injection is widely used in various stages of CHD, including stable angina pectoris, unstable angina pectoris, acute myocardial infarction, postoperative percutaneous coronary intervention(PCI), ischemic cardiomyopathy, CHD with arrhythmia, CHD with hyperlipidemia, CHD with heart failure and CHD with diabetes.

Effect of Danhong injection on serumα-klotho protein, lipid metabolism and atherosclerotic plaque in patients with chronic renal failure undergoing hemodialysis / 国际检验医学杂志

Objective To investigate the effect of Danhong injection on serumα-klotho protein, lipid metabolism and atherosclerotic plaque in patients with chronic renal failure undergoing hemodialysis.Methods A total of 100 patients with chronic renal failure treated in the hospital from February 2013 to April 2016 were selected and randomly divided into the control group and the observation group with 50 cases in each group.The two groups were treated with hemodialysis, and the observation group was additionally treated with Danhong injection.Changes in serumα-klotho protein, fibroblast growth factor 23 (FGF-23), lipid metabolism indexes, such as total cholesterol (TC), triglyceride (TG), high density lipoprotein cholesterol (HDL-C) and low density lipoprotein cholesterol (LDL-C), renal function indexes, such as serum creatinine (Scr), blood urea nitrogen (BUN) and endogenous creatinine clearance rate (Ccr) in the two groups were determined before and after treatment.Carotid artery ultrasonography was performed to observe changes in the size, number and thickness of atherosclerotic plaques and carotid intima-media thickness (IMT) before and after treatment.Results FGF-23, TC, TG, Scr and BUN in the observation group were decreased after 8 weeks of treatment[ (1 526.25±46.87) pg/mL, (5.21±1.23) mmol/L, (1.26±0.23) mmol/L, (390.11±52.26) μmol/L, (14.11±3.26) mmol/L vs. (1 768.74±54.26) pg/mL, (5.93±0.26) mmol/L, (1.63±0.14) mmol/L, (443.26±47.85) μmol/L, (18.52±2.79) mmol/L], whileα-Klotho protein, HDL-C and Ccr were increased[ (790.44±40.61) pg/mL, (1.21±0.21) mmol/L, (37.41±3.26) mL/min vs. (662.25±76.54) pg/mL, (1.00±0.29) mmol/L, (33.51±3.41) mL/min].Compared with those in the control group, there were statistically significant differences (t=23.914, 4.049, 9.716, 5.304, 7.267, 10.461, 4.147, 5.845, P＜0.05).In 6 months of follow-up, plaques shrank, the thickness of plaque and IMT decreased, and the number of plaques decreased in the observation group[ (0.06±0.01) cm2, (1.11±0.23) mm, (1.01±0.23) mm, (2.86±0.51) vs. (0.10±0.06) cm2, (1.87±0.49) mm, (1.43±0.20) mm, (3.41±1.03) ].Compared with those in the control group, the differences were statistically significant (t=4.649, 9.928, 9.743, 3.383, all P＜0.05).Conclusion Danhong injection can increase the expression level ofα-klotho protein in serum of patients with chronic renal failure undergoing hemodialysis, down regulate the expression of FGF-23, improve lipid metabolism and renal function in patients, reduce the degree of atherosclerosis, the number of patches and the thickness of plaque.