Shexiang Tongxin Dropping Pill Allieviates Heart Failure via Extracellula Matrix-Receptor Interaction Pathways Based on RNA-Seq Transcriptomics and Experimental Studies / 中国结合医学杂志

OBJECTIVE@#To investigate the protective mechanisms of Chinese medicine Shexiang Tongxin Dropping Pills (STDP) on heart failure (HF).@*METHODS@#Isoproterenol (ISO)-induced HF rat model and angiotensin II (Ang II)-induced neonatal rat cardiac fibroblast (CFs) model were used in the present study. HF rats were treated with and without STDP (3 g/kg). RNA-seq was performed to identify differentially expressed genes (DEGs). Cardiac function was evaluated by echocardiography. Hematoxylin and eosin and Masson's stainings were taken to assess cardiac fibrosis. The levels of collagen I (Col I) and collagen III (Col III) were detected by immunohistochemical staining. CCK8 kit and transwell assay were implemented to test the CFs' proliferative and migratory activity, respectively. The protein expressions of α-smooth muscle actin (α-SMA), matrix metalloproteinase-2 (MMP-2), MMP-9, Col I, and Col III were detected by Western blotting.@*RESULTS@#The results of RNA-seq analysis showed that STDP exerted its pharmacological effects on HF via multiple signaling pathways, such as the extracellular matrix (ECM)-receptor interaction, cell cycle, and B cell receptor interaction. Results from in vivo experiments demonstrated that STDP treatment reversed declines in cardiac function, inhibiting myocardial fibrosis, and reversing increases in Col I and Col III expression levels in the hearts of HF rats. Moreover, STDP (6, 9 mg/mL) inhibited the proliferation and migration of CFs exposed to Ang II in vitro (P<0.05). The activation of collagen synthesis and myofibroblast generation were markedly suppressed by STDP, also the synthesis of MMP-2 and MMP-9, as well as ECM components Col I, Col III, and α-SMA were decreased in Ang II-induced neonatal rats' CFs.@*CONCLUSIONS@#STDP had anti-fibrotic effects in HF, which might be caused by the modulation of ECM-receptor interaction pathways. Through the management of cardiac fibrosis, STDP may be a compelling candidate for improving prognosis of HF.

Antiplatelet and myocardial protective effect of Shexiang Tongxin Dropping Pill in patients undergoing percutaneous coronary intervention: A randomized controlled trial / 中西医结合学报

BACKGROUND@#High on-clopidogrel platelet reactivity could be partially explained by loss-of-function alleles of CYP2C19, the enzyme that converts clopidogrel into its active form. Shexiang Tongxin Dropping Pill (STDP) is a traditional Chinese medicine to treat angina pectoris. STDP has been shown to improve blood flow in patients with slow coronary flow and attenuate atherosclerosis in apolipoprotein E-deficient mice. However, whether STDP can affect platelet function remains unknown.@*OBJECTIVE@#The purpose of this study is to examine the potential effects of STDP on platelet function in patients undergoing percutaneous coronary intervention (PCI) for unstable angina. The interaction between the effects of STDP with polymorphisms of CYP2C19 was also investigated.@*DESIGN, PARTICIPANTS AND INTERVENTION@#This was a single-center, randomized controlled trial in patients undergoing elective PCI for unstable angina. Eligible subjects were randomized to receive STDP (210 mg per day) plus dual antiplatelet therapy (DAPT) with clopidogrel and aspirin or DAPT alone.@*MAIN OUTCOME MEASURES@#The primary outcome was platelet function, reflected by adenosine diphosphate (ADP)-induced platelet aggregation and platelet microparticles (PMPs). The secondary outcomes were major adverse cardiovascular events (MACEs) including recurrent ischemia or myocardial infarction, repeat PCI and cardiac death; blood biomarkers for myocardial injury including creatine kinase-MB isoenzyme (CK-MB) and high-sensitive troponin I (hsTnI); and biomarkers for inflammation including intercellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), monocyte chemoattractant protein-1 (MCP-1) and galectin-3.@*RESULTS@#A total of 118 subjects (mean age: [66.8 ± 8.9] years; male: 59.8%) were included into analysis: 58 in the control group and 60 in the STDP group. CYP2C19 genotype distribution was comparable between the 2 groups. In comparison to the control group, the STDP group had significantly lower CK-MB (P < 0.05) but similar hsTnI (P > 0.05) at 24 h after PCI, lower ICAM-1, VCAM-1, MCP-1 and galectin-3 at 3 months (all P < 0.05) but not at 7 days after PCI (P > 0.05). At 3 months, the STDP group had lower PMP number ([42.9 ± 37.3] vs. [67.8 ± 53.1] counts/μL in the control group, P = 0.05). Subgroup analysis showed that STDP increased percentage inhibition of ADP-induced platelet aggregation only in slow metabolizers (66.0% ± 20.8% in STDP group vs. 36.0% ± 28.1% in the control group, P < 0.05), but not in intermediate or fast metabolizers. The rate of MACEs during the 3-month follow-up did not differ between the two groups.@*CONCLUSION@#STDP produced antiplatelet, anti-inflammatory and cardioprotective effects. Subgroup analysis indicated that STDP inhibited residual platelet reactivity in slow metabolizers only.@*TRIAL REGISTRATION@#This study was registered on www.chictr.org.cn: ChiCTR-IPR-16009785.

Shexiang Tongxin Dropping Pill () Reduces Coronary Microembolization in Rats via Regulation of Mitochondrial Permeability Transition Pore Opening and AKT-GSK3β Phosphorylation / 中国结合医学杂志

OBJECTIVE@#To investigate the protective effects of Shexiang Tongxin Dropping Pill (, STDP) following sodium laurate-induced coronary microembolization (CME) in rats.@*METHODS@#Forty rats were divided into 4 groups: the control (sham) group, CME group, low-dose STDP pretreatment group (20 mg·kg@*RESULTS@#The rats in the CME group showed a significant increase in the fibrinogen-like protein 2 expression level and mitochondrial dysfunction and a decrease in the expression level of antioxidant biomarkers (superoxide dismutase and catalase, P<0.01 for all). In contrast, the rats in the low- and high-dose STDP pretreatment groups showed a significant decrease in coronary microthrombi (P<0.05); moreover, STDP restored the antioxidant-related protein activities and mitochondrial function, inhibited mPTP opening, decreased AKT-Ser473 phosphorylation, and increased GSK3β-Ser9 phosphorylation (P<0.05 or P<0.01).@*CONCLUSION@#STDP may be useful for treatment of CME, possibly via regulation of mPTP opening and AKT/GSK3β phosphorylation.

Shexiang Tongxin Dropping Pill () Protects against NaSO-Induced Hypoxia-Reoxygenation Injury in H9c2 Cells / 中国结合医学杂志

OBJECTIVES@#To investigate the protective effects of Shexiang Tongxin Dropping Pill (, STP) on NaSO-induced hypoxia-reoxygenation injury in cardiomyoblast H9c2 cells.@*METHODS@#The cell viability and levels of mRNA and protein expression in H9c2 cells were determined following NaSO-induced hypoxia using Hoechst staining, annexin V/propidium iodide (PI) flow cytometry, real-time polymerase chain reaction and Western blot analysis.@*RESULTS@#STP pretreatment significantly increased the viability and inhibited aberrant morphological changes in H9c2 cardiomyoblast cells induced by NaSO treatment (P<0.05). In addition, STP pretreatment attenuated NaSO-induced hypoxic damage, down-regulated the expression of pro-apoptotic Bax, and up-regulated the expression of anti-apoptotic Bcl-2 in H9c2 cells (P<0.05).@*CONCLUSIONS@#STP was strongly cardioprotective in hypoxia-reoxygenation injury by preventing hypoxic damage and inhibiting cellular apoptosis. These results further support the use of STP as an effective drug for the treatment of ischemic heart disease.

Clinical Evidence Evaluation of Shexiang Tongxin Dropping Pill for Slow Blood Flow after PCI / 世界科学技术-中医药现代化

Objective: To evaluate the efficacy and safety of Shexiang Tongxin dropping pill (ShXT) in the treatment ofslow blood flow after PCI (Percutaneous Transluminal Coronary Intervention), and to provide evidence for clinicaltreatment of patients with slow blood flow after PCI or to provide evidence for further research and design. Methods: "Shexiang Tongxin", "PCI", "percutaneous coronary intervention", "shexiangtongxin", "shexiang tongxin", "percutaneouscoronary intervention" were used as key words. Randomized controlled clinical trial (RCT), system evaluation, retrospective case analysis and case-control trials of randomized controlled clinical trials were searched in the databasesof Pubmed, Cochrane, web of science, CNKI, WIP, CBM, and other databases. Cochrane risk assessment tool and NOSrating scale were used to evaluate the quality of literature, and the classification of literature evidence was evaluatedaccording to Oxford criteria of evidence classification and recommended opinion strength in 2001. Results: A total of 3 articles of RCT related to the subject were selected, including 1 case control trial, including 335 patients. The resultsshowed that: (1) The frequency of thrombolysis, heart ejection fraction and TIMI blood flow in patients with slow coronaryartery flow after treatment with Shexiang Tongxin dropping pills were significantly higher than those before treatment. (P ＜ 0.05) . (2) After treatment with Shexiang Tongxin dropping pills, the effective rate of clinical symptoms was 97.8％, which was higher than that of the treatment group 11.1％. (3) There were no adverse reactions in the ShXT group duringthe treatment period. Conclusion: The efficacy and safety of Shexiang Tongxin dropping pills for patients with slow bloodflow after PCI were good. However, the dosage, method, period and outcome of the clinical study of slow blood flow afterPCI were not uniform because of the dosage, method, period of taking Shexiang Tongxin dropping pills in patients afterPCI. It is suggested that the clinical study should be aimed at the choice of different dosages before and after theadministration of drugs. The multicenter prospective randomized controlled trial can provide more evidence for itsclinical application.