Mechanistic exploration of Yiqi Liangxue Shengji prescription on restenosis after balloon injury by integrating metabolomics with network pharmacology.

CONTEXT: Yiqi Liangxue Shengji prescription (YQLXSJ) is a traditional Chinese medicine (TCM) formula that has long been used for treatment after percutaneous coronary intervention (PCI). OBJECTIVE: To investigate the putative pharmacological mechanism of YQLXSJ on restenosis through an integrated approach utilizing metabolomics and network pharmacology. MATERIALS AND METHODS: Forty male Sprague-Dawley rats were divided into sham, model, YQLXSJ, and positive groups. YQLXSJ group received the treatment of YQLXSJ (6 g/kg/d, i.g.) and the positive group was treated with atorvastatin (2 mg/kg/d, i.g.). After 4 weeks, the improvement in intimal hyperplasia was evaluated by ultrasound, H&E staining, and immunofluorescence. UPLC-MS/MS technology was utilized to screen the differential metabolites. Network pharmacology was conducted using TCMSP, GeneCards, and Metascape, etc., in combination with metabolomics. Eventually, the core targets were acquired and validated. RESULTS: Compared to models, YQLXSJ exhibited decreased intima-media thickness on ultrasound (0.23 ± 0.02 mm vs. 0.20 ± 0.01 mm, p < 0.01) and reduced intima thickness by H&E (30.12 ± 6.05 µm vs. 14.32 ± 1.37 µm, p < 0.01). We identified 18 differential metabolites and 5 core targets such as inducible nitric oxide synthase (NOS2), endothelial nitric oxide synthase (NOS3), vascular endothelial growth factor-A (VEGFA), ornithine decarboxylase-1 (ODC1) and group IIA secretory phospholipase A2 (PLA2G2A). These targets were further confirmed by molecular docking and ELISA. DISCUSSION AND CONCLUSIONS: This study confirms the effects of YQLXSJ on restenosis and reveals some biomarkers. TCM has great potential in the prevention and treatment of restenosis by improving metabolic disorders.

Anti-inflammatory Therapy Progress in Major Adverse Cardiac Events after PCI: Chinese and Western Medicine.

Acute coronary syndrome (ACS) is one of the leading causes of death in cardiovascular disease. Percutaneous coronary intervention (PCI) is an important method for the treatment of coronary heart disease (CHD), and it has greatly reduced the mortality of ACS patients since its application. However, a series of new problems may occur after PCI, such as in-stent restenosis, no-reflow phenomenon, in-stent neoatherosclerosis, late stent thrombosis, myocardial ischemia-reperfusion injury, and malignant ventricular arrhythmias, which result in the occurrence of major adverse cardiac events (MACE) that seriously reduce the postoperative benefit for patients. The inflammatory response is a key mechanism of MACE after PCI. Therefore, examining effective anti-inflammatory therapies after PCI in patients with ACS is a current research focus to reduce the incidence of MACE. The pharmacological mechanism and clinical efficacy of routine Western medicine treatment for the anti-inflammatory treatment of CHD have been verified. Many Chinese medicine (CM) preparations have been widely used in the treatment of CHD. Basic and clinical studies showed that effectiveness of the combination of CM and Western medicine treatments in reducing incidence of MACE after PCI was better than Western medicine treatment alone. The current paper reviewed the potential mechanism of the inflammatory response and occurrence of MACE after PCI in patients with ACS and the research progress of combined Chinese and Western medicine treatments in reducing incidence of MACE. The results provide a theoretical basis for further research and clinical treatment.

Astragaloside IV for Heart Failure: Preclinical Evidence and Possible Mechanisms, A Systematic Review and Meta-Analysis.

OBJECTIVE: To explore the cardioprotective effects of astragaloside IV (AS-IV) in heart failure (HF). METHODS: PubMed, Excerpta Medica Database (EMBASE), Cochrane Library, Web of Science, Wanfang Database, Chinese Bio-medical Literature and Retrieval System (SinoMed), China Science and Technology Journal Database (VIP), and China National Knowledge Infrastructure (CNKI) were searched from inception to November 1, 2021 for animal experiments to explore AS-IV in treating HF in rats or mice. The left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS), left ventricular end-diastolic dimension (LVEDD), left ventricular end-systolic dimension (LVESD), left ventricular weight-to-body weight (LVW/BW) and B-type brain natriuretic peptide (BNP) were recorded. The qualities of included studies were assessed by the risk of bias according to the Cochrane handbook. Meta-analysis was performed using Stata 13.0. RESULTS: Twenty-one articles involving 558 animals were considered. Compared with the control group, AS-IV improved cardiac function, specifically by increasing LVEF (mean difference (MD)=6.97, 95% confidence interval (CI)=5.92 to 8.03, P<0.05; fixed effects model) and LVFS (MD=7.01, 95% CI=5.84 to 8.81, P<0.05; fixed effects model), and decreasing LVEDD (MD=-4.24, 95% CI=-4.74 to -3.76, P<0.05; random effects model) and LVESD (MD=-4.18, 95% CI=-5.26 to -3.10, P<0.05; fixed effects model). In addition, the BNP and LVW/BW levels were decreased in the AS-IV treatment group (MD=-9.18, 95% CI=-14.13 to -4.22, P<0.05; random effects model; MD=-1.91, 95% CI=-2.42 to -1.39, P<0.05; random effects model). CONCLUSIONS: AS-IV is a promising therapeutic agent for HF. However, this conclusion needs to be clinically validated in the future.

Specialised metabolites as chemotaxonomic markers of Coptosapelta diffusa, supporting its delimitation as sisterhood phylogenetic relationships with Rubioideae.

From the aerial extracts of Coptosapelta diffusa (Champ. ex Benth.) Steenis, twenty-one compounds were isolated and identified by means of column chromatography and NMR and MS techniques, respectively. Amongst, ten ones were determined to be undescribed compounds including six seco-iridoid glucosides (1-6), 2-(hydroxymethyl)-1,2,3,4-tetrahydroanthracene-9,10-dione (7) and three guaiane-type sesquiterpenes (15-17). Compounds 7, 8 and 9 exhibited inhibitory activities against Staphylococcus aureus ATCC25923 with MIC of 8, 4 and 8 µg/mL. The use of 1-6 (iridoids), 7-14 (anthraquinones) and 15-17 (sesquiterpenes) as chemotaxonomic markers for this species was evidenced. Structurally, 7-14 are similar to those anthraquinones isolated from other species of the family Rubiaceae, confirming their close phylogenetic relationship. Whereas, these iridoids and sesquiterpenes with unique structures provided chemotaxonomic evidence to support the genus Coptosapelta (the tribe Coptosapelteae) as a sister of the subfamily Rubioideae. These results contrast with the general producing tendency of indole alkaloids by the species of the subfamily Cinchonoideae, and merit chemotaxonomic significance for the delimitation of Coptosapelta.

Promising Therapeutic Candidate for Myocardial Ischemia/Reperfusion Injury: What Are the Possible Mechanisms and Roles of Phytochemicals?

Percutaneous coronary intervention (PCI) is one of the most effective reperfusion strategies for acute myocardial infarction (AMI) despite myocardial ischemia/reperfusion (I/R) injury, causing one of the causes of most cardiomyocyte injuries and deaths. The pathological processes of myocardial I/R injury include apoptosis, autophagy, and irreversible cell death caused by calcium overload, oxidative stress, and inflammation. Eventually, myocardial I/R injury causes a spike of further cardiomyocyte injury that contributes to final infarct size (IS) and bound with hospitalization of heart failure as well as all-cause mortality within the following 12 months. Therefore, the addition of adjuvant intervention to improve myocardial salvage and cardiac function calls for further investigation. Phytochemicals are non-nutritive bioactive secondary compounds abundantly found in Chinese herbal medicine. Great effort has been put into phytochemicals because they are often in line with the expectations to improve myocardial I/R injury without compromising the clinical efficacy or to even produce synergy. We summarized the previous efforts, briefly outlined the mechanism of myocardial I/R injury, and focused on exploring the cardioprotective effects and potential mechanisms of all phytochemical types that have been investigated under myocardial I/R injury. Phytochemicals deserve to be utilized as promising therapeutic candidates for further development and research on combating myocardial I/R injury. Nevertheless, more studies are needed to provide a better understanding of the mechanism of myocardial I/R injury treatment using phytochemicals and possible side effects associated with this approach.

Efficacy and Safety of Bushenjiangya-Optimized Granule for Left Ventricular Diastolic Dysfunction in Hypertensive Patients: A Double-Blind, Randomized, Placebo-Controlled Trial.

OBJECTIVE: The study aimed to evaluate the efficacy and safety of Bushenjiangya-optimized (BSJYO) granule on left ventricular diastolic dysfunction (LVDD) in hypertensive (HTN) patients. METHODS: 120 patients diagnosed with HTN plus LVDD were randomly assigned to the BSJYO granule group and placebo group, and all patients received basal western medicine (WM) treatment. After eight weeks of treatment, we evaluated echocardiography, traditional Chinese medicine (TCM) syndromes, 24-hour ambulatory blood pressure, liver and kidney functions, and adverse events. Major adverse cardiovascular events (MACEs) were collected at 6-month follow-up. RESULTS: Compared with pretreatment, E/Ea (Doppler-derived index of filling pressure and worsening LVDD) significantly decreased significantly after 8 weeks of treatment in the BSJYO granule plus basal WM group (10.52 ± 1.87 vs. 9.49 ± 1.49, P < 0.01), alongside reductions in significantly effective response (SER), effective response (ER), and total effective response (TER = SER + ER) in TCM symptom scores (21.59% vs. 71.70%, P < 0.01). There were no differences between treatment groups in kidney and liver function, early adverse events, or MACE. CONCLUSION: BSJYO granule plus basal WM is an effective and safe therapy for HTN patients with LVDD.

Effects of Xuezhitong in Patients with Hypertriglyceridemia: a Multicentre, Randomized, Double-Blind, Double Simulation, Positive Drug and Placebo Parallel Control Study.

BACKGROUD: Xuezhitong (XZT) is an extract of Allium macrostemon Bunge that has lipid-lowering properties. OBJECTIVE: To evaluate the effects of XZT on lipids in subjects with hypertriglyceridemia (HTG) without severe dyslipidaemia. METHODS: A total of 358 subjects with HTG were enrolled and randomly assigned to receive XZT (2700 mg daily), xuezhikang (XZK) (1200 mg daily) or placebo. The primary endpoint was the reduction or percent reduction in the TG level over 12 weeks of treatment. RESULTS: At the 12-week follow-up, a reduction in the TG level from baseline was observed in both groups, but the XZT and XZK groups demonstrated a significantly greater reduction than the placebo group (30.77%, 24.02% vs 11.59%, P < 0.0167); 70.54% of subjects in the XZT group and 62.30% of subjects in the XZK group demonstrated reductions in TG levels of at least 20%, compared with 41.67% of the subjects in the placebo group (P < 0.0167). Treatment with XZT capsules also demonstrated superior performance compared with the placebo with respect to the control of lipids (17.97% vs 5.00%), total cholesterol (TC) (14.18% vs 3.89%), low-density lipoprotein cholesterol (LDL-C) (17.98% vs 2.95%), and high-density lipoprotein cholesterol (HDL-C) (21.47% vs 2.16%). Daily use of XZT for 12 weeks resulted in statistically significant (65.22% vs 38.30%, 25.00%; P < 0.0167) and clinically meaningful increases in HDL-C levels by ≥4 mg/dl compared with XZK and placebo. XZT was safe and well tolerated; the safety and tolerability profiles were similar across treatment groups. No subject experienced myopathy or markedly elevated liver transaminases or creatine kinase. CONCLUSIONS: XZT significantly reduced TG levels and was well tolerated. Longer-term studies in more diverse patient populations are needed to corroborate these findings. CLINICAL TRIAL REGISTRATION: www.chictr.org.cn Identifier: ChiCTR1900025854.

Zika Virus Infection in Hypothalamus Causes Hormone Deficiencies and Leads to Irreversible Growth Delay and Memory Impairment in Mice.

Zika virus (ZIKV) can cause microcephaly in the fetus. However, its effects on body growth and the development of children with postnatal ZIKV infection are largely unknown. To examine this, we intraperitoneally challenged mouse pups with ZIKV. Infection causes an irreversible growth delay and deficits in spatial learning and memory, with growth-relevant hormones significantly reduced during infection. These effects are associated with ZIKV RNA expression in the hypothalamus, blood, and brain but not in the pituitary and thyroid. Infection is also associated with hypothalamic inflammation, and ZIKV antigen is detectable in neuroendocrine cells producing thyrotropin-releasing hormone. Moreover, early administration of growth hormone could significantly improve growth delay. Our results demonstrate that ZIKV can infect the hypothalamus, causing multi-hormone deficiencies and delayed growth and development in a mouse model. Therefore, prospective multidisciplinary follow-up of ZIKV-infected children may be necessary to understand potential effects of this virus on childhood development.

Effectiveness and Safety of Compound Chinese Medicine plus Routine Western Medicine in In-Stent Restenosis: A Meta-Analysis and Systematic Review.

OBJECTIVE: To examine the effects and safety of oral compound Chinese medicine (CCM) plus routine western medicine (RWM) in in-stent restenosis (ISR). METHODS: Various electronic databases (CBM, CNKI, VIP, Wanfang, PubMed, EMBASE, and Cochrane Library) were searched until April 2017. The quality of the included studies was evaluated, and meta-analyses were performed using RevMan5.3 and STATA 12.0 software. Moreover, funnel plot and Egger's publication bias plots were analysed to identify publication bias and adverse reactions were reported. A sensitive analysis was carried out according to the quality score. RESULTS: In all, 40 RCTs involving 4536 patients were selected for this review. The pooled estimates of three studies showed that the benefit to the number of ISRs (NoR) was more substantial for CCM plus RWM than for RWM alone (RR 0.24, 95% CI 0.10 to 0.57, P = 0.001; I2 = 0%, P = 0.81). The rate of ISR was significantly lower for CCM plus RWM than for the same RWM alone (RR 0.44, 95% CI 0.37 to 0.53, P < 0.00001; I2 = 0%, P = 0.95). CCM plus RWM benefitted the rate of ISR when a CM placebo plus RWM was used as the control intervention (RR 0.34, 95% CI 0.20 to 0.57, P < 0.0001; I2 = 0%, P = 0.95). The difference of adverse reactions was not significant. For secondary outcomes, the CCM plus RWM group did not reduce the rates of revascularization and cardiac death, but it did reduce the rate of recurrent angina over the results observed in the RWM alone group. In addition, funnel plot and Egger's publication bias plot indicated that there was publication bias. The association between the use of CCM plus RWM and RWM alone remained significant after the sensitivity analysis excluding studies with low quality score (quality score ⩽ 4) with a pooled RR of 0.41 (95% CI, 0.34-0.50). CONCLUSION: Oral CCM plus RWM clearly benefitted patients with percutaneous coronary intervention (PCI) because it prevented and treated ISR better than was observed for either RWM alone or a CM placebo plus RWM.

Comparison of the efficacy and acceptability of Chinese herbal medicine in adult patients with heart failure and reduced ejection fraction: study protocol for a systematic review and network meta-analysis.

INTRODUCTION: Heart failure with reduced ejection fraction (HFrEF) is defined as the clinical diagnosis of heart failure (HF) and ejection fraction (EF) ≤40%, which is a severe public healthcare issue and brings a heavy social and economic burden for patients with HFrEF. Chinese herbal medicine (CHM) has a long history in treating HF. Questions concerning the efficacy and acceptability of CHM-related interventions in adult patients with HFrEF led us to use the method of systematic review and network meta-analysis to integrate direct and indirect evidence to create hierarchies for all CHM. METHODS AND ANALYSIS: Nine medical databases, including PubMed, EMBASE (OVID), the Cochrane Library, Google Scholar, Web of Science, CNKI, VIP, Wanfang Database and CBM will be searched from the date of database inception to June 2015 (updated to March 2017) without language and publication status restriction. Completely randomised controlled trials (RCTs) comparing CHM or CHM plus routine treatment with CHM, CHM plus routine treatment, routine treatment, no treatment or placebo for adults with HFrEF will be examined. Our primary outcomes will include all-cause mortality, HF-related death, all-cause rehospitalisation, HF-related rehospitalisation and acceptability (discontinuation due to any adverse events during treatment). Secondary outcomes will include response rate, mean value or mean difference from baseline of surrogate indexes. We will perform the Bayesian network meta-analyses (NMA) for the most frequently reported primary or secondary outcome and the acceptability outcome, if available. Meta-regression, subgroup analyses and sensitivity analyses will be conducted based on prespecified effect modifiers to assess the robustness of the findings. DISSEMINATION: The results of this NMA will provide useful information about the effectiveness and acceptability of CHM in adults with HFrEF, which will also have implications for clinical practice and further research. Findings will be disseminated through peer-reviewed journal publication and conference presentations. PROSPERO REGISTRATION NUMBER: CRD42016053854.

Conventional Acupuncture for Cardiac Arrhythmia: A Systematic Review of Randomized Controlled Trials.

OBJECTIVE: To exam the effect and safety of conventional acupuncture (CA) on cardiac arrhythmia. METHODS: Nine medical databases were searched until February 2016 for randomized controlled trials. Heterogeneity was measured by Cochran Q test. Meta-analysis was conducted if I2 was less than 85% and the characteristics of included trials were similar. RESULTS: Nine qualified studies involving 638 patients were included. Only 1 study had definitely low risk of bias, while 7 trials were rated as unclear and 1 as high. Meta-analysis of CA alone did not have a significant benefit on response rate compared to amiodarone in patients with atrial fibrillation (Af) and atrial flutter (AF) [relative risk (RR): 1.09; 95% confidence interval (CI): 0.79-1.49; P=0.61; I2=61%, P=0.11]. However, 1 study with higher methodological quality detected a lower recurrence rate of Af in CA alone as compared with sham acupuncture plus no treatment, and benefits on ventricular rate and time of conversion to normal sinus rhythm were found in CA alone group by 1 study, as well as the response rate in CA plus deslanoside group by another study. Meta-analysis of CA plus anti-arrhythmia drug (AAD) was associated with a significant benefit on the response rate when compared with AAD alone in ventricular premature beat (VPB) patients (RR, 1.19, 95% CI: 1.05-1.34; P=0.005; I2=13%, P=0.32), and an improvement in quality-of-life score (QOLS) of VPB also showed in 1 individual study. Besides, a lower heart rate was detected in the CA alone group by 1 individual study when compared with no treatment in sinus tachycardia patients (MD-21.84 [-27.21,-16.47]) and lower adverse events of CA alone were reported than amiodarone. CONCLUSIONS: CA may be a useful and safe alternative or additive approach to AADs for cardiac arrhythmia, especially in VPB and Af patients, which mainly based on a pooled estimate and result from 1 study with higher methodological quality. However, we could not reach a robust conclusion due to low quality of overall evidence.

Astragalus Granule Prevents Ca2+ Current Remodeling in Heart Failure by the Downregulation of CaMKII.

BACKGROUND: Astragalus was broadly used for treating heart failure (HF) and arrhythmias in East Asia for thousands of years. Astragalus granule (AG), extracted from Astragalus, shows beneficial effect on the treatment of HF in clinical research. We hypothesized that administration of AG prevents the remodeling of L-type Ca2+ current (ICa-L) in HF mice by the downregulation of Ca2+/calmodulin-dependent protein kinase II (CaMKII). METHODS: HF mice were induced by thoracic aortic constriction (TAC). After 4 weeks of AG treatment, cardiac function and QT interval were evaluated. Single cardiac ventricular myocyte was then isolated and whole-cell patch clamp was used to record action potential (AP) and ICa-L. The expressions of L-type calcium channel alpha 1C subunit (Cav1.2), CaMKII, and phosphorylated protein kinase A (p-PKA) were examined by western blot. RESULTS: The failing heart manifested distinct electrical remodeling including prolonged repolarization time and altered ICa-L kinetics. AG treatment attenuated this electrical remodeling, supported by AG-related shortened repolarization time, decreased peak ICa-L, accelerated ICa-L inactivation, and positive frequency-dependent ICa-L facilitation. In addition, AG treatment suppressed the overexpression of CaMKII, but not p-PKA, in the failing heart. CONCLUSION: AG treatment protected the failing heart against electrical remodeling and ICa-L remodeling by downregulating CaMKII.

[Effect of liangxue shengji recipe on incidence of post-percutaneous coronary intervention restenosis and adverse cardiovascular events].

OBJECTIVE: To observe the intervention effect of Liangxue Shengji Recipe (LSR) on incidence of post-percutaneous coronary intervention (post-PCI) restenosis and adverse cardiovascular events. METHODS: With a randomized, single-blinded methods adopted, 100 patients with coronary artery disease (CHD) and underwent stent implantation were randomized into two groups, the control group and the treated group, conventional Western treatment was administered to them all, but with LSR to patients in the treated group additionally. They were followed up for at least six months. The incidences of post-PCI restenosis and adverse events, including cardiogenic death, acute myocardial infarction, recurrent angina pectoris, severe heart failure, further intervention and coronary artery bypass grafting, were observed to estimate the effect of LSR. RESULTS: No statistically significant difference between the two groups was shown in terms of incidences of intra-stent restenosis, recurrent angina pectoris, estimator of restenosis and its cumulative risk, as well as in reducing the incidence of single adverse event, but did show statistically significant difference between groups in reducing the incidence of united cardiovascular event (P=0.032) and its cumulative risk (P=0.036). CONCLUSION: Administration of LSR in post-PCI stage could significantly reduce the probability and cumulative risk of united cardiovascular events, and the beneficial effect presents at about six months post-PCI.