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Front Pharmacol. 2019; 10: 232. 

Published online 2019 Mar 20. doi: 10.3389/fphar.2019.00232

PMCID: PMC6435518

PMID: 30949047

Analysis of Effect of Schisandra in the Treatment of Myocardial Infarction Based on Three-Mode Gene Ontology Network

Siyao Hu,1 Huali Zuo,2 Jin Qi,1 Yuanjia Hu,2,* and  Boyang Yu1,*

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Associated Data

Supplementary Materials

Data Availability Statement

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Schisandra chinensis is a commonly used traditional Chinese medicine, which has been widely used in the treatment of acute myocardial infarction in China. However, it has been difficult to systematically clarify the major pharmacological effect of Schisandra, due to its multi-component complex mechanism. In order to solve this problem, a comprehensive network analysis method was established based-on “component–gene ontology–effect” interactions. Through the network analysis, reduction of cardiac preload and myocardial contractility was shown to be the major effect of Schisandra components, which was further experimentally validated. In addition, the expression of NCOR2 and NFATin myocyte were experimentally confirmed to be associated with Schisandra in the treatment of AMI, which may be responsible for the preservation effect of myocardial contractility. In conclusion, the three-mode gene ontology network can be an effective network analysis workflow to evaluate the pharmacological effects of a multi-drug complex system.

Keywords: Schisandra, myocardial infarction, effect, three-mode network, gene ontology

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Cardiovascular disease, including atherosclerosis, myocardial infarction, heart failure and stroke, is the leading cause of morbidity and mortality in developed nations. Acute myocardial infarction (AMI) is induced through the narrowing of arteries caused by atherosclerotic plaques or the acute occlusion of the coronary artery by thrombosis, and has received extensive attention due to its high risk and poor outcome among all the symptoms of coronary heart disease (Holmes et al., 2011Husted and Ohman, 2015).

Traditional Chinese medicine (TCM) is a commonly used therapeutic strategy for the treatment of AMI in China. And Schisandra chinensis is a commonly used TCM that has been clinically proven to alleviate the damage of myocytes after the onset of AMI. Many pharmacological research results have clarified the mechanisms of Schisandra (Li et al., 1996Panossian and Wikman, 2008Chang et al., 2013Chen et al., 2013Zhan et al., 2014). However, few studies have evaluated the major effects and possible mechanisms responsible for the treatment of AMI, due to the complexity of the multi-mechanisms associated with TCM (Gao et al., 2016Tang et al., 2016). Thus, in order to research the multi-mechanism complex system in TCM, network pharmacology has been commonly used in recent years to predict the major target proteins or signal pathways of TCM.

In this study, network pharmacology was applied to analyze the major effect of Schisandra. In contrast to protein interaction networks, enriched gene ontology (GO) terms of AMI related genes were used to construct a gene ontology interaction (GOI) network, which can be used to simulate the functional interactions between differential expressed genes of disease. In general, this study aims to identify and validate major mechanism and related pharmacological effects of Schisandra in the treatment of AMI through a GOI network, which may offer a new method of network analysis to evaluate complex bio-systems.

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Materials and Methods

Component Identification

For the construction of a “component–gene ontology” network of Schisandra in the treatment of AMI, the HPLC-Q-TOF-MS was used to analyze the Schisandra extract. Targets of Schisandra ingredients were further screened to enrich and construct the “component–gene ontology” network, which was a component for the integration of a three-mode network.


Sample Solution Preparation 

To ensure the consistency of network analysis and experimental validation results, Schisandra chinensis Fructus of the same batch was utilized for the extraction, analysis and pharmacological experiment. Schisandra chinensis Fructus from Schisandra chinensis (Turcz.) Baill was obtained from Tianjin Tasly Pride Pharmaceutical Co. (Tianjin, China). The crude drug was extracted through a reflux condenser with 10 times the amount of distilled water at 100°C for 1 h. This procedure was repeated three times. The combined Schisandra extract was then concentrated under reduced pressure and dissolved through distilled water into an appropriate concentration for administration to mice. Deionized water was prepared using a Milli-Q Ultrapure water system (Millipore, Bedford, MA, United States). For analysis of the Schisandra component, dry extract was dissolved in 50% methanol and then centrifuged at 12000 rpm for 15 min. The supernatant was transferred to a 1.5 mL brown HPLC vial (Grace, Chicago, IL, United States) and stored at 4°C for analysis.


HPLC-Q-TOF-MS-MS Analysis Conditions 

Chromatographic experiments were conducted on a Shimadzu Shimadzu (Kyoto, Japan) LC-2010 series. Chromatographic separation was performed on a Kromasil 100-5C18 (250 × 4.6 mm, 5 μm particle size) column, with the column temperature maintained at 30°C. The mobile phase was composed of solvent A (acetonitrile containing 0.01% v/v formic acid) and solvent B (ultrapure water containing 0.02% v/v acetic acid). The gradient elution conditions were: 0-15 min, 20% A; 15-25 min, 20-22% A; 25-45 min, 22-32% A; 45-65 min, 32-34% 75 min, 34-42% A; 75-95 min, 42-60% A; 95-110 min, 60-70% A; 110-125 min, 70-100% A; 125-130 min, 100% A. The injection volume was 15 μL. The elution rate was 0.8 mL/min and the detector was set at 203 nm.

The 6520 Q-TOF mass spectrometer (Agilent Technologies, Santa Clara, CA, United States) was equipped with an electrospray ionization (ESI) source. Ultrahigh purity argon was used as the collision gas and high purity nitrogen as the nebulizing gas. The following MS conditions were used: detector voltage was 1.65 kV, capillary voltage was 3.5 kV, heat block temperature was 325°C, nebulizer was 35 psig, nebulizing gas (N2) flow was 8.0 L/min, drying gas pressure (N2) was 72 kPa, ion trap pressure was 1.9 × 102 Pa, TOF pressure was 2.2 × 104 Pa, ion accumulation time was 100 ms. Scan ranges were set at m/z 100–1000 in both the positive and negative modes. The accurate mass determination was corrected by calibration using the sodium trifluoroacetate clusters as a reference. The peak area of molecular ion was then measured and normalized for the rough quantification of identified Schisandra components.

Construction and Analysis of “Component-Gene Ontology-Effect” Three-Mode Network

In order to simulate and analyze the correlation between components and pharmacological effects, a three-mode network model, which included the pathological relationship between component and pharmacological effect, was constructed (Figure 1A).

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J Ethnopharmacol. 2011 Apr 12;134(3):668-75. doi: 10.1016/j.jep.2011.01.019. Epub 2011 Jan 20.

Cardioprotective effects of aqueous Schizandra chinensis fruit extract on ovariectomized and balloon-induced carotid artery injury rat models: effects on serum lipid profiles and blood pressure.

Kim EY1, Baek IHRhyu MR.

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The fruit from Schizandra chinensis, a member of the Magnoliaceae family, has been used to treat menopause-related symptoms. We have previously reported that an aqueous extract of Schizandra chinensis fruit (ScEx) caused vascular relaxation via the production of endothelial nitric oxide. Estrogen-like molecules are known to play a protective role in cardiovascular diseases through several mechanisms, but the cardioprotective effects of ScEx have not been clearly demonstrated. Therefore, we investigated the vasculoprotective effects of ScEx on ovariectomized (OVX) and balloon-induced carotid artery injury rat models.


An aqueous extract of Schizandra chinensis (ScEx) was examined for its cardioprotective effects. To test the arterial response to injury, we applied the balloon-induced carotid artery model to OVX Sprague-Dawley (SD) rats. Rats were subcutaneously administered vehicle, 17β-estradiol (E2; 0.02 or 0.2mg/kg/day), or ScEx (0.2 or 2.0mg/kg/day) over the course of the study. Vessel morphology was assessed two weeks after injury. To identify the cardioprotective effects after ScEx treatment, we measured serum lipid profiles and blood pressure levels in the OVX- and sham-operated normotensive and spontaneously hypertensive rats (SHR). Serum lipid profiles were measured in OVX rats after five weeks of treatment with vehicle, E2 (0.5mg/kg/day), or ScEx (0.5 or 5.0mg/kg/day). Tail systolic blood pressure in OVX SHR was measured weekly.


In the balloon-induced carotid artery injury model, treatment with E2 (0.2mg/kg/day) or ScEx (2.0mg/kg/day) reduced the intimal area and the intima-to-media ratio compared to control animals. Injection of ScEx or E2 reduced body weight gain but did not inhibit the decrease in uterine weight. Treatment with ScEx (5.0mg/kg/day) or E2 (0.5mg/kg/day) in OVX SD rats reduced total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), TC/high-density lipoprotein cholesterol (HDL-C), and TC-(HDL-C)/HDL-C compared to control animals. In OVX rats, treatment with ScEx or E2 also significantly reduced LDL-C compared with the OVX control rats, and systolic blood pressure was significantly attenuated compared to OVX control and the sham control rats.


ScEx treatment restored endothelial function in rats that underwent balloon-induced carotid artery injury, and it reduced serum cholesterol levels in OVX rats. Similar to E2, ScEx exhibited hypotensive effects in OVX SHR. Therefore, ScEx and E2 exhibited similar cardioprotective effects, thereby suggesting that ScEx is a potential candidate to replace estradiol in the prevention and treatment of cardiovascular diseases.

Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.





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