Deciphering potential pharmacological mechanisms of Danhong injection to treat chronic stable angina based on drug response-related modules and genes.

ETHNOPHARMACOLOGICAL RELEVANCE: Danhong injection (DHI), a traditional Chinese medicine (TCM) injection that has been widely used to treat coronary heart disease and angina pectoris. However, its underlying pharmacological mechanisms have not been fully elucidated. Not all patients benefit from DHI to the same extent. We attempted to explore the characteristics of potential therapeutic targets in different responsive populations. AIM OF THE STUDY: This study aimed to reveal the potential molecular mechanisms of DHI in treating chronic stable angina and identify potential therapeutic targets for DHI. MATERIALS AND METHODS: Based on a previous phase IV clinical trial of DHI in treating chronic stable angina, drug response modules were identified through structural entropy and similarity. Drug response-related genes were screened out based on the correlations between drug response module/module-related genes and clinical features and were assessed using a random forest model. Further validation was conducted using a hypoxia/reoxygenation (H/R) model. RESULTS: Seven DHI-related response modules were identified. Eight drug response-related genes were screened out, and principal component analysis showed that DHI responders were distinguished from responders in the control group based on their expression values. The combination of the two most important genes, SHC4 and PIP5K1P1, discriminated between responders and nonresponders with an area under the receiver operating characteristic curve (AUC) of 0.714; however, no significant difference was found in the AUC between the combination and a single gene. Reverse transcription-polymerase chain reaction showed that middle-dose DHI treatment significantly decreased SHC4 mRNA expression compared with that in the H/R group (P = 0.026), a finding consistent with our previous analysis of differentially expressed genes. CONCLUSIONS: DHI comprehensively exerted a therapeutic effect by acting on multiple response modules related to angina pectoris and drug response-related genes. Our findings indicate that the dimensionality reduction strategy based on the target network-drug response module-therapeutic targets can contribute to revealing the mechanism of action of TCM compounds and guiding precise clinical medication.

The Synergistic Effects of Astragalus mongholicus and Salvia miltiorrhiza on Coronary Heart Disease Identified by Network Pharmacology and Experiment.

BACKGROUND AND PURPOSE: Two Chinese herbal medicines Huang Qi (HQ, Astragalus mongholicus) and Dan Shen (DS, Salvia miltiorrhiza) are often combined to treat coronary heart disease (CHD). The purpose of this study was to identify the underlying synergistic effects and mechanisms of HQ and DS against CHD. METHODS: The active components and targets of HQ and DS, CHD-related genes, and the biological progression were analysed by network pharmacology. The myocardial infarction (MI) rat model was established by ligating the left anterior descending coronary artery. Cardiac function was detected by ultrasonic electrocardiography. The MI size, fibrosis, cardiac hypertrophy, lipid metabolism, blood viscosity, and coagulation indexes were analysed by histological staining or chemical methods, respectively. RESULTS: A total of 170 shared and specific seed genes of HQ and DS against CHD were identified. The shared and specific biological processes of HQ and DS against CHD were obtained. The LVEF and LVFS values significantly increased, the myocardium infarct size and fibrosis significantly decreased, the values of lipid metabolism indexes and blood viscosity indexes significantly reduced in the HQ + DS treatment group vs HQ or DS single treatment (P < 0.05); the LVEDd, LVEDs, and the CSA values significantly reduced in HQ single and HQ + DS treatment groups vs MI group (P < 0.05); the coagulation index (APTT, PT, TT, and FIB) values decreased significantly in the DS single and HQ + DS treatment groups vs MI group (P < 0.05). CONCLUSION: In MI rats, HQ and DS exhibited synergistic effects on improving cardiac function, reducing MI size, fibrosis, regulating hyperlipidaemia, and maintaining circulatory system homeostasis; HQ had the specific advantage of alleviating cardiac remodelling; DS had the specific advantage of regulating hypercoagulability. This study revealed that HQ and DS not only exerted synergistic effects but also exhibited complementary effects on CHD.

Uncovering the protective mechanism of Huoxue Anxin Recipe against coronary heart disease by network analysis and experimental validation.

Coronary heart disease (CHD) is a leading cause of death and disability worldwide. Huoxue Anxin Recipe (HAR) is a novel Chinese Herbal Medicine formula of that has been used to treat CHD for several decades. Our previous study found that HAR had anti-oxidative effects, and could promote myocardial angiogenesis and improve cardiac function following myocardial infarction (MI) in rats. However, the active compounds, potential targets, and biological processes related to HAR have not been systematically investigated. Here, network pharmacology and experimental validation were used to study the protective mechanisms of HAR against CHD. We identified 124 active components, 124 verified targets, and 111 predictive targets. A total of 1192 genes related to CHD were identified by cDNA microarray and database analysis. A total of 47 putative targets of HAR against CHD were identified, including 32 verified targets and 15 predictive targets. ClueGo enrichment analysis identified 49 biological processes involved in the anti-CHD effects of HAR. Among them, the negative regulation of blood coagulation and regulation of collagen biosynthetic process were experimentally validated. After constructing a protein-protein interaction network and clustering with MECODE and ClusterONE, 162 key proteins (from ClueGo and clustering) were used to construct an internal interaction network. Complement C3 (C3), Fibrinogen alpha (FGA), Fibrinogen gamma (FGG), interleukin-6 (IL6), and Apolipoprotein A1 (APOA1) were the top 5 hub proteins identified by cytoHubber analysis. HAR limited the concentrations of C3, FGA, FGG, and IL6 and increased APOA1 levels. The results indicated that HAR could down-regulate blood coagulation, regulate collagen biosynthesis, inhibit peroxidation and inflammation injury, and promote cholesterol efflux. HAR could be a potential source of novel and effective drugs for CHD.

[Module-based analysis: deciphering pathological and pharmacological mechanisms of complex diseases and multi-target drugs].

A complex disease is rarely a consequence of abnormality in a single gene. It is known that many drugs exhibit a therapeutic effect by acting on multiple targets, produce synergies to intervene the occurrence and development of diseases. Unlike the traditional methods which act on single molecule or pathway, this disease-drug target network constructed with high throughput data vividly showed the complex relationship between drugs, their targets and diseases. However, the networks are usually extremely complex. In order to reduce the complexity, it is necessary to deconstruct the network and identify module structures. In this study, framework of module analysis was summarized from four aspects: module concept, structure and identification methods, importance of disease-drug module identification, and its application. Module-based analysis provides a new perspective for deciphering the drug intervention mechanisms for complex diseases, and provides new ideas and pathways to reveal the mechanisms of multi-target and multi-component drugs.

[Situation analysis for drug clinical trial institutions].

Drug clinical trial is an important link in the chain of new drug research and development. The results of drug discovery and development directly depend on the extent of standardization of clinical trials. Therefore, improving the quality of drug clinical trials is of great importance, and drug clinical trial institutions play a crucial role in the quality management of drug clinical trials. After years of development, the overall level of drug clinical trials has advanced rapidly in China, and a large number of clinical trials of traditional Chinese medicine have also been carried out. However, there is still a big gap between our country and developed countries. Therefore, for the construction and management of Chinese drug clinical trial institutions, there is still a long way to go. This study aims to analyze the current development of drug clinical trial institutions in China and explore the existing problems from three aspects, including current situations of institutional organization and management, regional and professional distributions, and quality control. And some suggestions are put forward finally, including support of traditional Chinese medicine, introduction of drug-risk management system, and construction of information management.

A randomized controlled trial of single point acupuncture in primary dysmenorrhea.

BACKGROUND: Acupuncture is often used for primary dysmenorrhea. But there is no convincing evidence due to low methodological quality. We aim to assess immediate effect of acupuncture at specific acupoint compared with unrelated acupoint and nonacupoint on primary dysmenorrhea. METHODS: The Acupuncture Analgesia Effect in Primary Dysmenorrhoea-II is a multicenter controlled trial conducted in six large hospitals of China. Patients who met inclusion criteria were randomly assigned to classic acupoint (N = 167), unrelated acupoint (N = 167), or non-acupoint (N = 167) group on a 1:1:1 basis. They received three sessions with electro-acupuncture at a classic acupoint (Sanyinjiao, SP6), or an unrelated acupoint (Xuanzhong, GB39), or nonacupoint location, respectively. The primary outcome was subjective pain as measured by a 100-mm visual analog scale (VAS). Measurements were obtained at 0, 5, 10, 30, and 60 minutes following the first intervention. In addition, patients scored changes of general complaints using Cox retrospective symptom scales (RSS-Cox) and 7-point verbal rating scale (VRS) during three menstrual cycles. Secondary outcomes included VAS score for average pain, pain total time, additional in-bed time, and proportion of participants using analgesics during three menstrual cycles. FINDINGS: Five hundred and one people underwent random assignment. The primary comparison of VAS scores following the first intervention demonstrated that classic acupoint group was more effective both than unrelated acupoint (-4.0 mm, 95% CI -7.1 to -0.9, P = 0.010) and nonacupoint (-4.0 mm, 95% CI -7.0 to -0.9, P = 0.012) groups. However, no significant differences were detected among the three acupuncture groups for RSS-Cox or VRS outcomes. The per-protocol analysis showed similar pattern. No serious adverse events were noted. CONCLUSION: Specific acupoint acupuncture produced a statistically, but not clinically, significant effect compared with unrelated acupoint and nonacupoint acupuncture in primary dysmenorrhea patients. Future studies should focus on effects of multiple points acupuncture on primary dysmenorrhea.

Convergent and divergent pathways decoding hierarchical additive mechanisms in treating cerebral ischemia-reperfusion injury.

INTRODUCTION: Cerebral ischemia is considered to be a highly complex disease resulting from the complicated interplay of multiple pathways. Disappointedly, most of the previous studies were limited to a single gene or a single pathway. The extent to which all involved pathways are translated into fusing mechanisms of a combination therapy is of fundamental importance. AIMS: We report an integrative strategy to reveal the additive mechanism that a combination (BJ) of compound baicalin (BA) and jasminoidin (JA) fights against cerebral ischemia based on variation of pathways and functional communities. RESULTS: We identified six pathways of BJ group that shared diverse additive index from 0.09 to 1, which assembled broad cross talks from seven pathways of BA and 16 pathways of JA both at horizontal and vertical levels. Besides a total of 60 overlapping functions as a robust integration background among the three groups based on significantly differential subnetworks, additive mechanism with strong confidence by networks altered functions. CONCLUSIONS: These results provide strong evidence that the additive mechanism is more complex than previously appreciated, and an integrative analysis of pathways may suggest an important paradigm for revealing pharmacological mechanisms underlying drug combinations.

[Application of network analysis in diseases and drug studies].

A disease is rarely caused by a single virulence gene, but by an imbalanced regulatory network arising from dysfunction of multiple genes or their products. However, drugs intervene the occurrence and development of a disease by acting on multiple target points in the disease network and making a synergy effect on each target point, in order to achieve the therapeutic effect. Unlike traditional approaches focusing on a single molecule or pathway, network analysis with high-throughput data provides a new perspective for studying disease pathobiology and pharmacological mechanisms, and brings forth new ideas for multi-component and multi-target-point pharmacologic mechanisms of traditional Chinese medicines, in three aspects-establishment of relevant disease and drug network, network decomposition, and biological significant of sub-network.

[Advance in study on pharmacological mechanisms of Qingkailing injection in intervention of ischemic cerebral injury].

As a severe threat to human health, ischemic brain injury has a very complex pathological mechanism involving excitotoxic amino acids, oxygen free radical formation, nitric oxide (NO), Ca2+ overload and inflammation. Traditional Chinese medicine Qingkailing injection have shown good clinical efficacy in the treatment of cerebrovascular disease, and thus it is very significant to studies on its pharmacological mechanism. This essay summarizes relevant studies on pharmacological mechanism of a new compound traditional Chinese medicine Jingzhiqiangkailing (JZQKL) injection in treatment on cerebral ischemia, and explains the pharmacological mechanism of its single effective compounds and their compatibility in treatment of schemic brain injury in the aspects of regulating inflammatory response, neurotrophic factors, vascular protection, blood-brain barrier (BBB) protection and others, and thus providing information for further studies.

[Advances of studies on acupuncture and moxibustion for perimenopausal syndrome].

The literatures are retrieved in the Chinese science and technology periodical database of VIP (1989-2009). The clinical application and its mechanism of perimenopausal syndrome treated with acupuncture and moxibustion are summarized. The summarized literatures indicate that body acupuncture, auricular acupuncture, acupoint catgut embedding and combined therapy are used in acupuncture and moxibustion for treatment of perimeno-pausal syndrome. The research of mechanism includes regulation of nerve-endocrine-immunity net, regulation of free radical metabolism, regulation of blood lipid and bone metabolism. The literatures suggest that acupuncture and moxibustion has definite therapeutic effect on perimenopausal syndrome with advantages of convenience, lower cost and safety.

[A comparative study of effects of electroacupuncture with different stimulation parameters on medicine-induced abortion].

OBJECTIVE: To observe the effect of electroacupuncture (EA) with different stimulation parameters on medicine-induced abortion. METHODS: One hundred and nine cases of early pregnancy who asked medicine-induced abortion were allocated to an EA group A (n = 37), an EA group B (n = 38) and a medication group (n = 34). Within 30-60 min after oral administration of Misoprostol, in the EA group A, EA was given at bilateral Hegu (LI 4) and Sanyinjiao (SP 6) with cluster waves of 100 Hz and in the EA group B, EA was given at Hegu (LI 4) for 20 min and then at Sanyinjiao (SP 6) for 5 min with continuous waves of 50 Hz. EA was not given to the medication group. The complete abortion rate, duration of eliminating embryonic sac, colporrhagia lasting time and abdominal pain condition were recorded. RESULTS: The complete abortion rate was 91.9% in the EA group A and 86.8% in the EA group B, which were higher than 82.4% in the medication group, with no significant differences between the 3 groups (P>0.05); the duration of eliminating embryonic sac and the colporrhagia lasting time in the two EA groups were significantly shorter than those in the medication group (P<0.05, P<0.01); alleviation of abdominal pain in the EA group B was better than the medication group (P<0.01) and the EA group A (P<0.05). CONCLUSION: Different stimulation parameters of EA have different effects on abortion.