Network Pharmacology-Based Exploration of Synergistic Mechanism of Guanxin II Formula (II) for Coronary Heart Disease / 中国结合医学杂志

OBJECTIVE@#To study the pharmacological mechanism of Guanxin II formula (II) for treatment of coronary heart disease (CHD).@*METHODS@#A network pharmacology-based method was utilized. First candidate compounds, targets of GX II were collected using PharmMapper, BATMAN-TCM, DrugBank and SwissTargetPrediction, and targets on CHD were mined from GeneCards, DisGenet, DrugBank and GEO. Afterwards, the big hub compounds and targets were chosen in the candidate compounds-direct therapeutic targets on the CHD (C-T) network and the direct therapeutic targets on the CHD (T-D) network. Furthermore, the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis were performed to identify the enriched terms. Finally, a molecular docking simulation strategy was adopted to verify the binding capacity between the big hub compounds and big hub targets on CHD.@*RESULTS@#First, 114 candidate compounds were selected with the following criteria: OB⩾30%, DL⩾0.18, and HL ⩾4 h. Then, 1,035 targets of GX II were gathered, while 928 targets on CHD were collected. Afterwards, 196 common targets of compound targets and therapeutic targets on CHD were defined as direct therapeutic targets acting on CHD. In addition, the contribution index (CI) in the C-T network was calculated, and 4 centrality properties, including degree, betweenness, closeness and coreness, in the T-D network, 4 big hub compounds, and 6 big hub targets were eventually chosen. Furthermore, the GO and KEGG analysis indicated that GX II acted on CHD by regulating the reactive oxygen species metabolism, steroid metabolism, lipid metabolism, inflammatory response, proliferation, differentiation and apoptosis. The docking results manifested excellent binding capacity between the 4 big hub compounds and 6 big hub targets on CHD.@*CONCLUSION@#This network pharmacology-based exploration revealed that GX II might prevent and inhibit the primary pathological processes of CHD.

Effect of Qinghuang Powder () Combined with Bupi Yishen Decoction () in Treating Patients with Refractory Cytopenia with Multilineage Dysplasia through Regulating DNA Methylation / 中国结合医学杂志

OBJECTIVE@#To explore the effect of Qinghuang Powder (QHP,()combined with Bupi Yishen Decoction (BPYS, ) on myelodysplastic syndromes (MDS) patients with refractory cytopenia with multilineage dysplasia (RCMD) and determine the change of DNA methylation in MDS-RCMD patients after the treatment of Chinese medicine formula.@*METHODS@#All 308 MDS-RCMD patients were treated with QHP combined with BPYS for 2 months at least, absolute neutrophil count (ANC), hemoglobin (Hb), platelets (PLT), primitive bone marrow cells and chromosome karyotype were chosen as the main evaluation indexes to analyze the treatment effect according to criteria from the MDS International Working Group. Then 43 bone marrow samples from 15 MDS-RCMD patients and 28 healthy donors were obtained for the examination of DNA methylation. Gene Ontology (GO) and Pathway analysis were applied to analyze the methylation data.@*RESULTS@#The overall MDS response rate to QHP was 61.68% (190/360) including hematologic improvement-neutrophil (HI-N) or hematologic improvement-erythroid (HI-E) or hematologic improvement-platelet (HI-P). Patients with anemia had a better response rate than patients with neutropenia or thrombocypenia (55.88% vs 31.54% or 55.88% vs. 36.9%). The DNA methylation microarray analysis disclosed that 4,257 hypermethylated genes were demethylated upon the treatment with QHP and BPYS. GO analysis and Pathway analysis showed that these demethylated genes were involved in a lot of tumor-related pathways and functions.@*CONCLUSIONS@#QHP combined with BPYS could effectively treat MDS-RCMD patients through hematologic improvement (HI-N, HI-P or HI-E) and PLT and RBC transfusion independence due to the demethylation, thereby providing another choice for the treatment of patients with MDS-RCMD.

Oral Chinese Herbal Medicine for Heart Failure with Preserved Ejection Fraction: A Meta-Analysis / 中国结合医学杂志

OBJECTIVE@#To evaluate the effectiveness and safety of oral Chinese herbal medicine (OCHM) for heart failure with preserved ejection fraction (HFpEF).@*METHODS@#PubMed, Excerpta Medica Database (EMBASE), Cochrane Library, Chinese Biological Medicine Database (CBM), Wanfang Database, Chongqing VIP Information (VIP) and China National Knowledge Infrastructure (CNKI) were searched for appropriate articles from respective inceptions until June 3, 2018. Randomized controlled trials (RCTs) investigating the effectiveness of OCHM for the patients with HFpEF were eligible. Quality assessment was performed by employing the Cochrane Risk of Bias assessment tool. Papers were independently reviewed by two reviewers and analyzed using Cochrane software Revman 5.3. Dichotomous data were analyzed by relative risk (RR) with a 95% confidence interval (CI), while continuous variables were analyzed by using mean difference (MD) with 95% CI for effect size.@*RESULTS@#A total of 16 RCTs involving 1,320 participants were identified. Fourteen of the trials used conventional Western medicine (CWM) as the control, the control of 1 trial was no treatment, and another was placebo. Three of the trials served Chinese patent medicine (CPM) as interventions, and other OCHM were Chinese medicine decoctions (CMDs). Only limited evidence showed experimental group with OCHM may get better effect on brain natriuretic peptide (BNP: MD -37.29, 95% CI -53.08 to -21.50, P<0.00001) or N terminal pro B type natriuretic peptide (NT-proBNP: MD -236.04, 95% CI -356.83 to -115.25, P=0.0001), Minnesota Living with Heart Failure questionnaire (MLHFQ, MD -9.94, 95% CI -16.77 to -3.11, P=0.004), but the results had high heterogeneities. With concerns on 12 of 16 trials, the meta-analysis found that the adjuvant therapy of OCHM might be more effective in increasing overall response rate (RR 1.17, 95% CI 1.11 to 1.24, P<0.00001), when compared with CWM alone. Subgroup meta-analysis between CPMs and CMDs showed that the two CPMs may have more therapeutic effect on MLHFQ, but not on NT-proBNP, and CMD came to the opposite conclusion. No significant differences were found between experimental groups and control groups on 6-min walk test (6MWT). Adverse events, such as more defecation, weakness, cardiopalmus, edema, cough and hypotension, were mild in all groups and disappeared after the easement of pharmacological intervention.@*CONCLUSIONS@#Due to the insufficient quality of trials that were analyzed, it is not appropriate to confirm or deny the potency of OCHMs in treating HFpEF at the present time. More rigorously designed RCTs focusing on primary endpoints with long-term follow-up are warranted to validate the effect of OCHMs for patients with HFpEF.

Chinese Medicine for Alzheimer's Disease: A Meta-Analysis of Randomized Controlled Trials / 中国结合医学杂志

<p><b>OBJECTIVE</b>To evaluate the effificacy of oral Chinese medicine (CM) in comparison with donepezil, a cholinesterase inhibitor (ChEI), for the treatment of Alzheimer's disease (AD).</p><p><b>METHODS</b>Randomized controlled trials (RCTs) have been searched, and the effect of CM compared with donepezil in AD has been investigated. An electronic search of MEDLINE, Excerpta Medica Database (EMBASE), Cochrane Library, Chinese Biological Medicine Database (CBMdisc), and China National Knowledge Infrastructure (CNKI) to identify articles in English and Chinese from the inception of the database until October 18, 2015. A modifified Jadad score (7-points) to judge the methodological quality of studies, comprehensive meta-analysis was performed with Cochrane Collaboration Revman 5.3. Dichotomous data were analyzed by relative risk (RR) with a 95% confifidence interval (CI), while continuous variables were analyzed by using mean differences (MD) with 95% CI for effect size.</p><p><b>RESULTS</b>Six studies involving 596 AD patients through Jadad assessment with low bias were included in the meta-analysis. No signifificant difference was observed in cognitive improvement and daily abilities of patients using the Mini Mental State Examination (MMSE) (MD: 0.69, 95% CI:-0.17 to 1.56) and Activities of Daily Living (ADL) scale (MD: 0.94, 95% CI:-1.54 to 3.43). There were no signifificant differences in status of illness or MD for mild-moderate AD patients at 24 weeks (MD: 0.62, 95% CI:-2.99 to 4.23) and 48 weeks (MD:-0.73, 95% CI:-5.02 to 3.56). Severe AD patients were also assessed at 24 weeks (MD: 3.13, 95% CI:-6.92 to 13.18) and 48 weeks (MD: 4.23, 95% CI:-6.38 to 14.84). Furthermore, compared with donepezil, Xin (Heart)-regulating CM and Shen (Kidney)-tonifying groups were observed (MD:-1.50, 95% CI:-3.08 to 0.08; MD:-1.92, 95% CI:-3.50 to-0.33; respectively). CM had fewer side effects in AD patients.</p><p><b>CONCLUSION</b>Compared with donepezil, oral CM showed no signifificant difference in effectiveness in AD patients, and more evidence is needed to verify the fifindings.</p>

Effects of Zhizi Chuanxiong Capsule () on the Abnormal Methylation in Rabbits with Atherosclerosis / 中国结合医学杂志

OBJECTIVE@#To investigate the effects of Zhizi Chuanxiong Capsule (ZCC, ) on abnormal DNA methylation in a rabbit model of atherosclerosis (AS).@*METHODS@#After 1 week of adaptive feeding, 48 New Zealand white rabbits were randomly divided into 4 groups: a control group (n=12) fed with normal diet for 22 weeks; a model group (n=12) fed with high fat diet for 14 weeks followed by 8 weeks of normal diet feeding; a low-dose ZCC group (n=12) fed with high fat diet and low-dose ZCC for 14 weeks, followed by 8 weeks of normal diet and low-dose drug; a high-dose ZCC group (n=12) fed with high fat diet and high-dose drug for 14 weeks, followed by 8 weeks of normal diet and high-dose drug. After 22 weeks of feeding, blood samples were taken from the rabbit ear vein, and the genomic DNA was extracted for methylation immunoprecipitation sequencing (Medip-seq). The aorta tissues were collected for hematoxylin-eosin (HE) staining.@*RESULTS@#Eight rabbits died during the feeding process. HE staining showed that the size of the lipid deposition on vessel wall and atherosclerotic plaque formation were reduced in both low- and high-dose group. The Medip-seq results showed that there were 146 abnormally methylated genes (including both hypermethylated gene and hypomethylated genes) in the model group, compared with the control group. Gene Ontology (GO) and Pathway analysis showed that these abnormally methylated genes were found to be involved in multiple AS-related functions and pathways, such as protein kinase C activity, cholesterol transport, mitogen-activated protein kinase (MAPK) signaling pathway, peroxisome proliferater-activated receptor signaling pathway, vascular smooth muscle contraction, inflammation and so on. The abnormal methylated genes in AS model group were altered in both low- and high-dose groups: low-dose ZCC could change 72 of the 146 abnormally methylated genes, high-dose ZCC could change 71. Through GO and Pathway analysis, these altered methylated genes were involved in protein kinase C activity, inflammatory pathway, MAPK signaling pathway, vascular endothelial growth factor signaling pathway, etc. CONCLUSION: ZCC could treat AS through regulating the abnormal hypermethylated and hypomethylated genes in AS rabbit model.

Protective effects of Xiongshao Capsule () on anti-inflammatory function of high-density lipoprotein in an atherosclerosis rabbit model / 中国结合医学杂志

<p><b>OBJECTIVE</b>To observe the effects of Xiongshao Capsule (, XSC) on anti-inflflammatory properties of high-density lipoprotein (HDL), myeloperoxidase (MPO) and paraoxonase 1 (PON1) in serum of atherosclerosis (AS) rabbit model and explore the anti-inflflammatory protective effects of XSC on HDL.</p><p><b>METHODS</b>Sixty rabbits were randomized into the control, the model, XSC low-, medium- and high-dose (Rhizoma Chuanxiong + Radix Paeoniae rubra: 0.6+0.3, 1.2+0.6, 2.4+1.2g·kg·day, respectively), and simvastatin (1g·kg·day) groups. The model rabbits were fed with high-fat diet and drugs for 15 weeks. The blood and thoracic aortas samples were collected at the end of 15 weeks. The levels of serum MPO and PON1 as well as total cholesterol (TC) and free cholesterol (FC) in aorta wall cells were tested by enzyme linked immunosorbent assay.</p><p><b>RESULTS</b>TC and FC in the model group were significantly higher than those in the control group (P<0.01). Compared with the model group, TC and FC in the XSC groups were signifificantly lower (P<0.05 or P<0.01), so was simvastatin group (P<0.01). There was no signifificant difference in PON1 level between groups (P>0.05), even between model and control groups (P>0.05). The serum MPO level in the model group was signifificantly higher than that in the control group (P<0.05), which was signifificantly lower in XSC groups as well as simvastatin group (P<0.05 or P<0.01), and no difference was found between XSC groups and simvastatin group (P>0.05).</p><p><b>CONCLUSIONS</b>XSC can reduce the serum MPO level in AS rabbits to protect the anti-inflammatory function of HDL, maintaining the normal lipid transport function. TC and FC levels in aorta cells decline, and this process initiated by XSC plays an anti-AS role.</p>

A multicenter, randomized, double-blind clinical study on Wufuxinnaoqing Soft Capsule () in treatment of chronic stable angina patients with blood stasis syndrome / 中国结合医学杂志

<p><b>OBJECTIVE</b>To confirm the efficacy and safety of Wufuxinnaoqing Soft Capsule (, WSC) in the treatment of chronic stable angina (blood stasis syndrome).</p><p><b>METHODS</b>A multicenter, randomized, double-blind, placebo-controlled trial with superiority test was designed. A total of 240 patients with chronic stable angina (blood stasis syndrome) from multiple centers were randomly and equally assigned to the treatment group and the control group. Based on standard treatment of Western medicine, the treatment group was given WSC, while the control group was given WSC mimetic, both for 12 weeks. Observed indicators included the efficacy in angina, the efficacy in Chinese medicine syndrome, the withdrawal or reduce rate of nitroglycerin and routine safety indices.</p><p><b>RESULTS</b>After 12-week treatment, the significant effective rate and total effective rate of the treatment group were significantly better than those of the control group (23.5% vs. 9.2%, 64.7% vs. 30.8%), respectively, with statistically significant difference (P<0.01). After 12-week treatment, the decreased points and the decreased rate of angina symptom score in the treatment group were better than in the control group (5.1±4.2 points vs. 2.8±3.5 points, 44.9%±37.2% vs. 25.4%±30.7%) respectively, with significant difference (P<0.01). After 12-week treatment, the significant effective rate and total effective rate of the treatment group were better than the control group (respectively, 30.3% vs. 15.0%, 67.2% vs. 45.0%,P<0.01). After 8- or 12-week treatment, the decreased points and the decreased rate of Chinese medicine syndrome score in the treatment group were better than the control group (P<0.05 orP<0.01). After 12-week treatment, nitroglycerin withdrawal rate and the withdrawal or reduce rate in treatment group were better than the control group (P<0.01). On safety evaluation, the incidence of adverse events (7.563% vs. 7.500%) and the incidence of cardiovascular events (0.840% vs. 0.000%) in the treatment group were similar with the control group, and the difference was not statistically significant (P>0.05).</p><p><b>CONCLUSION</b>In treatment of chronic stable angina (blood stasis syndrome), WSC can reduce angina attacks and consumption of nitroglycerin, decrease angina severity degree, effectively relieve the blood stasis syndromes, such as chest pain, chest tightness, palpitations, dark purple tongue and other symptoms. Besides, adverse events and cardiovascular adverse events in the treatment group and the control group showed no difference. All shows that the drug is safe and effective. [This study was registered in Chinese Clinical Trial Registry (ChiCTR), with registration number: ChiCTR-TRC-14005158.].</p>

Effects of xinluotong tablet on stable coronary heart disease angina: a randomized controlled trial / 中国中西医结合杂志

<p><b>OBJECTIVE</b>To observe the clinical efficacy and safety of Xinluotong Tablet (XLTT, with actions of benefiting qi, activating blood, and supplementing Shen) in treatment of stable coronary heart disease angina patients of qi deficiency and blood stasis syndrome.</p><p><b>METHODS</b>240 stable coronary heart disease angina patients of qi deficiency and blood stasis syndrome were randomly assigned to the trial group and the control group, 120 in each group. The trial group was treated with XLTT, four tablets each time, three times a day, while the control group was treated with Yangxinshi Tablet (YXST), three tablets each time, three times a day. The double blinded treatment lasted for four weeks. The therapeutic effects on angina, electrocardiogram (ECG), the exercise test, the improvement of Chinese medicine syndromes, and the safety index were observed.</p><p><b>RESULTS</b>The trial group was superior to the control group after treatment in aspects of the therapeutic effects on angina (91.45% vs 84.87%) and the ECG (65.81% vs 55.46%), but with no statistical difference (P>0.05). There was no statistical difference in the the exercise test or the improvement of Chinese medicine syndromes (P>0.05). No adverse reaction occurred during the therapeutic course.</p><p><b>CONCLUSION</b>XLTT was safe and effective in treatment of stable coronary heart disease angina patients of qi deficiency blood stasis syndrome.</p>

Using Delphi method to establish diagnostic standard for Xin-blood stasis syndrome / 中国中西医结合杂志

<p><b>OBJECTIVE</b>To provide a reference for quantitative diagnosis of Xin-blood stasis syndrome (XBSS) by way of collecting experiences from experts, screening out the diagnostic indices and evaluating their significance.</p><p><b>METHODS</b>With Delphi method adopted, two rounds of questionnaire survey were carried out in 20 experts, the feedback data were statistically analyzed in terms of concentricity, coordination and authority using SPSS software.</p><p><b>RESULTS</b>The recovery rates of the two round survey were all 100%; the coordinate coefficient was 0.658 in the first round and 0.622 in the second. And results passed the Chi-square test with P < 0.05, Chi2 = 189.544 in first round and 235.232 in second round. The average degree of expert's authority was 85%.</p><p><b>CONCLUSIONS</b>The enthusiasm and speciality of the 20 experts were high, and their opinions are of high reliability with great coordination. The information entries, including chest pain, stabbing pain, pain on a relatively fixed position, chest stuffiness, ecchymosis or petechia on tongue, dark-purplish lip and unsmooth pulse, can be taken as the diagnostic indices for XBSS sydrome.</p>

Effects of Xiongshao capsule on the proliferation of vascular smooth muscle cells in rabbits with atherosclerosis / 中国中西医结合杂志

<p><b>OBJECTIVE</b>To study the effects of Xiongshao Capsule (XSC) on the proliferation of vascular smooth muscle cells (VSMC) in rabbits with experimental atherosclerosis (AS), and to explore its possible mechanisms.</p><p><b>METHODS</b>Rabbit's fractional AS model was established by denuding and injuring the endodermis of abdominal aorta with 4F * Fogarty catheter, followed with feeding of high cholesterol forage. The animals were randomly divided into 8 groups, the model groups of 3 days, 2 weeks and 6 weeks after modeling (Group A, B and C); the single endothelium injury group (Group D), the probucol treated group (Group E), the low-dose and high-dose XSC treated groups (Group F and G) and the sham operative group (Group N). All were fed with high fat forage except those in Group N and D. The proliferative activity of neogenetic SMC at abdominal aorta with the most obvious pathological changes was analyzed by proliferating cell nuclear antigen immunohistochemical method; the VSMC phenotypic modulation was detected by transmission electron microscope (TEM), and the level of plasma angiotensin (Ang II) was measured by radioimmunoassay. And the effects of treatment on them were observed as well.</p><p><b>RESULTS</b>The plasma Ang II level elevated gradually in Group A, and showed significant difference as compared that between Group C and Group N (P < 0.01); as compared with Group C, that in Group G was reduced significantly (P < 0.05); a reducing tendency was shown in Group E and F, but the difference of them with Group C was insignificant. Immunohistochemical dyeing showed that PCNA positive expressing cell was not found in the blood vessels of Group N, few was seen in Group A, while the upmost positive expression was shown in Group B, as for in Group C, significantly thickened endomembrane appeared, but the PCNA positive expression dropped. Number of PCNA positive cells reduced significantly (P < 0.05) in the drug treated groups, especially in Group G, showing significant difference as compared with that in Group C (P < 0.05, P < 0.01). TEM demonstrated normal shaped VSMC of aortic medial tunica in Group N, basically normal in Group A, but in Group B, migration of VSMCs into intima was found, as for in Group C, abundant lipid granules and bigger vacuoles appeared in VSMCs with markedly proliferated intercellular collagenous fibers. Synthetic transformation could also be found in Group D. The transform VSMCs in neogenetic endothelium was fewer in the drug treated groups than that in Group C. Morphology of VSMC was basically normal in Group G, with few intercellular collagenous fiber proliferation, while in Group E and F, many lipid droplets in VSMC and lot of collagenous fibers proliferation in intercellular space still retained.</p><p><b>CONCLUSIONS</b>XSC can prevent the genesis and development of AS through significantly lowering the plasma Ang II level and inhibiting the migration and proliferation of VSMC.</p>

Effect of xiongshao capsule on vascular remodeling in rabbit with experimental atherosclerosis / 中国中西医结合杂志

<p><b>OBJECTIVE</b>To study the effect of Xiongshao Capsule (XSC) on vascular remodeling in experimental atherosclerotic (AS) rabbits, and to explore the possible mechanisms.</p><p><b>METHODS</b>Rabbit's fractional AS model was established by denuding and injuring the abdominal artery with 4F.Fogarty catheter, and followed with high cholesterol feeding. The animals were randomly divided into 8 groups, namely, the modeled group of 3 days, 2 weeks and 6 weeks after balloon injury (A, B and C); the single endothelium injury group (D), the probucol treating group (E), the low-dose and high-dose XSC treating group (F and G) and the normal control group (N). Except the rabbits in Group N and D, the other groups were all fed with high fat forage. Histopathological examination of abdominal aorta with the most obvious lesion was performed, and the changes of related vascular remodeling indexes after arterial injury were observed using computerized image analyzing system; the correlation analysis between progress of intimal proliferation and vascular remodeling were performed as well.</p><p><b>RESULTS</b>Artery intimal proliferation progressed gradually as time went on, which was more significant in Group C as compared with that in Group B and D (P < 0.01). All the drugs could reduce the maximum intima thickness (MIT). Moreover, both high-dose XSC and Probucol profoundly decreased the intima area (IA), showing significant difference as compared with that in Group C (P < 0.01). The internal elastic laminal area (IELa), external elastic laminal area (EELa), minimum lumen diameter (MLD) and lumen area (LA) in Group A increased significantly, as compared with that in Group N (P < 0.01). At 6 weeks after balloon injury, with the further intimal thickening, IELa, EELa reduced contrarily, resulting in insufficient vascular compensation, lumen stricture and MLD reduction (P < 0.01). Improvement of MLD and LA was shown in all the drug treated groups, with significant difference in comparing with those in Group C (P < 0.01).</p><p><b>CONCLUSION</b>Single endothelium injury may be one of the initiating elements of pathological vascular remodeling, which could be intensified by hyperlipemia. Intimal proliferation and vascular remodeling jointly participated in the pathological course of AS lumen stricture after endothelium injury. XSC plays its action in preventing and treating AS through inhibiting intimal proliferation after balloon injury and intervening pathological vascular remodeling.</p>