**1. Introduction**

Coronary Artery Disease (CAD) is a cardiovascular disease with significant morbidity and mortality, especially among the elderly [1], and imposes a heavy burden on health care systems worldwide [2–4]. CAD is caused by excessive lipid accumulation in the vessel wall because of long-term exposure to lifestyle risk factors such as high sugar and fat. This accumulation results in reduced endothelial function, which in turn leads to stenosis and blockage [5]. A study has shown that vascular regeneration in the infarcted areas of the heart and the construction of new vascular transport channels at the onset of CAD are essential for alleviating CAD symptoms [6]. In this regard, phytotherapy has been used in China for thousands of years to regulate human health, especially in the case of cardiovascular and cerebrovascular diseases [7].

**Citation:** Zhang, Y.-G.; Liu, X.-X.; Zong, J.-C.; Zhang, Y.-T.-J.; Dong, R.; Wang, N.; Ma, Z.-H.; Li, L.; Wang, S.-L.; Mu, Y.-L.; et al. Investigation Driven by Network Pharmacology on Potential Components and Mechanism of DGS, a Natural Vasoprotective Combination, for the Phytotherapy of Coronary Artery Disease. *Molecules* **2022**, *27*, 4075. https://doi.org/10.3390/ molecules27134075

Academic Editors: Tanveer A. Wani, Seema Zargar and Afzal Hussain

Received: 11 May 2022 Accepted: 21 June 2022 Published: 24 June 2022

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**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

As an important part of phytotherapy, Traditional Chinese Medicine (TCM) provides us with a vast resource to develop supplements for health care and disease treatment [8]. In previous research in our laboratory, DGS was screened as a novel natural vasoprotective combination. DGS was composed of three Chinese medicinal materials, namely, Salviae Miltiorrhizae Radix et Rhizoma (Danshen), Puerariae Lobatae Radix (Gegen), and Crataegi Folium (Shanzhaye). Modern pharmacological studies have shown that Danshen can increase blood flow [9], improve circulation [10], and preserve endothelial function [11]. Danshen is the most representative herbal medicine in the Chinese medicine formula repertoire for the treatment of ischemic diseases [12]. Gegen is usually used as a "medicinal pair" with Danshen. Shanzhaye is also commonly utilized for promoting blood circulation and resolving blood stasis. All three herbs are used as dietary supplements for the prevention and treatment of diseases [13–15]. Further studies have reported salvianolic acid B in Danshen exerts significant anti-myocardial ischemic effects and can alleviate oxidative stress damage caused by myocardial ischemia [16]. Hyperoside, one of the important flavonoids in Gegen, is known for its vasoprotective effects [17]. However, the potential components and mechanisms of this combination have not been thoroughly reported.

TCM exerts a multi-component, multi-target, and multi-pathway synergistic effect [18]. However, this complexity is a bottleneck for revealing its modern scientific significance. Network pharmacology is a new approach that analyzes the complexities of drugs and diseases and visualizes the drug treatment mechanisms through the construction of biological association networks, which are in line with TCM philosophy [19]. Therefore, this study aimed to devise a new network pharmacology-driven strategy to investigate the active components and network molecular mechanism of DGS. Moreover, transgenic zebrafish were used as the in vivo experimental animal model to evaluate the bioactive effects of DGS samples. Finally, this research aspired to reveal the potential components and pharmacodynamic mechanisms of DGS in the intervention of CAD.
