Objective: This study explored the multicomponent, multitarget, and multipathway mechanism of Danhe granules (DG) against hyperlipidemia through network pharmacology. The relevant targets and pathways were verified by preliminary experiments. Methods: The active components of DG were selected by TCMSP and TCMIP database, and the component-target network diagram was constructed by Cytoscape 3.7.1. The protein–protein interaction network of targets was constructed and core targets were screened out by STRING11.0 database. Metascape database and Cytoscape 3.7.1 were used to enrich the target and establish a hyperlipidemia model in Sprague-Dawley (SD) rats to detect blood lipid and oxidative stress indexes and observed pathological changes of aorta by H and E staining. Results: The results showed that a total of seven active components of DG were screened out, including quercetin, sitosterol, luteolin, kaempferol, etc. There were 127 corresponding targets, including AKT1, tumor necrosis factor, TP53, interleukin-6, RELA, vascular endothelial growth factor, superoxide dismutases, and catalase. It is mainly involved in biological processes such as drug response, regulation of apoptosis, redox reaction, and lipid reaction. There were 573 signal pathways corresponding to the target, including HIF-1 signal pathway, TNF signal pathway, VEGF signal pathway, nonalcoholic fatty liver disease, etc. The experiment verified that DG can reduce the blood lipid of SD rats by regulating the process of oxidative stress. Conclusions: This study made a preliminary study on the pharmacological mechanism of DG against hyperlipidemia and laid the foundation for the research and development of new drugs and subsequent in-depth research.
Keywords: Component-target network construction, Danhe granules, hyperlipidemia, network pharmacology, oxidative stress
|How to cite this URL:|
Zhang ZQ, Chen AP, Yu T, Yang SJ, Yu DS, Yang R, Chai XL. Exploring the pharmacological mechanism of danhe granules against hyperlipidemia by means of network pharmacology and verified by preliminary experiments. World J Tradit Chin Med [Epub ahead of print] [cited 2022 Aug 8]. Available from: https://www.wjtcm.net/preprintarticle.asp?id=326585
| Introduction|| |
Abnormal lipid metabolism diseases with elevated total cholesterol (TC), triglycerides (TG) and low-density lipoprotein cholesterol (LDL-C), or high-density lipoprotein cholesterol (HDL-C) reduction, which are the onset factors of coronary heart disease. Cardiovascular disease (CVD) has become the world's leading cause of death. Compared with people with normal TC levels, the incidence of CVD in patients with hyperlipidemia has doubled. In the past 30 years, the incidence of hyperlipidemia in Chinese has increased significantly. Taking an adult blood lipid data study in Shandong province as an example, among 10,028 samples of people 40 years old, 56.02% of the samples have high TC levels, which reveals that China's future CVD incidence is not optimistic. Therefore, it is of great significance to detect and treat hyperlipidemia as soon as possible to reduce the occurrence of CVD. At present, statin-related drugs are the main drugs for the treatment of hyperlipidemia, which are well tolerated, but some patients will experience a series of adverse reactions, including liver enzyme damage, musculoskeletal pain, respiratory tract infections and headaches, and reports of cognitive impairment. Traditional Chinese medicine believes that hyperlipidemia is deficiency in origin and excess in superficiality and belongs to the category of “blood stasis” and “phlegm turbidity,” so treatment can also start from the two aspects. Danhe granules (DG) is a well-known traditional Chinese medicine doctor Guo Weiqin's clinical experience prescription, which is composed of salvia miltiorrhiza, polygonum cuspidatum, coix seed, tangerine peel, crataegus pinnatifida, and lotus leaf. Salvia miltiorrhiza is the principal drug, promoting blood circulation and nourishing blood; the assistant drug is polygonum cuspidatum, clearing away pathogenic heat and remove the toxin; the adjuvant drugs are: (a) coix seed, invigorating the spleen and replenishing qi; (b) tangerine peel, invigorating the spleen, promoting qi and resolving the phlegm; (c) crataegus pinnatifida, promoting blood circulation and removing blood stasis; improving digestion and removing retention of food; the mediating drug is lotus leaf, elevating yang, and replenishing qi. The prescription is currently in the preclinical pharmaceutical research stage of a new Chinese medicine and has been successfully made into DG. It is clinically used for the treatment of hyperlipidemia with mutual resistance of phlegm and blood stasis. This study is based on network pharmacology to explore the targets and related pathways of traditional Chinese medicine DG against hyperlipidemia and provides ideas for further experimental verification of its pharmacological mechanism.
| Methods|| |
Screening-related targets of Danhe granules
Using the Chinese medicine system pharmacology database and analysis platform TCMSP (https://old.tcmsp-e.com/tcmsp.php) to find the main components of salvia miltiorrhiza, polygonum cuspidatum, coix seed, tangerine peel, crataegus pinnatifida, and lotus leaf, combined with TCMIP (http://www.tcmip.cn/) and references to supplement. Preliminary screening of active ingredients according to four attribute values: oral availability (OB) ≥30%, drug-like properties (DL) ≥0.18, permeability (Caco-2) ≥−0.4, and half-life (HL) ≥4, to obtain active compounds and their protein targets. After the screening, converted the protein target of the compound into the corresponding gene to standardize the protein target information by the UniProt protein database (https://uniprot.org/).
Visualization network of active ingredients-targets of Danhe granules
We constructed a network diagram of ingredients-targets of DG by Cytoscape 3.7.1 and analyzed the network topology parameters through its built-in Network Analyzer software to obtain the core ingredients.
Protein–protein interaction network construction of active ingredients-antihyperlipidemic targets of Danhe granules
Using “hyperlipidemia” as a keyword, searching the Online Mendelian Inheritance in Man (OMIM) database (https://omim.org/), GeneCards (https://www.genecards.org/) databases, and SymMap (https://www. symmap.org/) to retrieve target information related to hyperlipidemia. Obtain the intersection of active ingredient targets and hyperlipidemia-related targets of Danhe granule through R software and draw the Venn diagram. The intersection targets were entered into the STRING 11.0 data platform (https://string-db.org/). We constructed a protein interaction network model by using Cytoscape 3.7.1 database and obtained key targets. We analyzed the degree of network node and betweenness centrality by the Network Analyzer plug-in in the software. The greater the degree of freedom and betweenness of a node, the more important the node is in the network.
Enrichment analysis of functions and pathways of active ingredients-hyperlipidemic targets of Danhe granules
To clarify the role of Danhe granule's target protein in gene function and signal pathways, annotation, visualization, and integrated discovery database, metascape (http://metascape.org) was used to analyze the combined active ingredients-potential targets were analyzed for enrichment pathways.
DG; Atorvastatin calcium (Lipitor): Pfizer Pharmaceutical Co., Ltd., National Medicine Standard H 20051408, each tablet contains 20 mg of atorvastatin; cholesterol: Beijing Soleibao Technology Co., Ltd., NO 1215I036; refined lard: Xincheng Jinluo Meat Products Group Co., Ltd.; yolk powder: Beijing Aoboxing Biotechnology Co., Ltd., BR biological reagents; propylthiouracil: Shanghai Chaohui Pharmaceutical Co., Ltd., National Medicine Standard H31021082, each containing propylthiooxide Pyrimidine 50 mg; Tween 80: Alfa Aesar, NO10213022. The levels test box: serum superoxide dismutase (SOD), glutathion peroxidase (GSH-Px), catalase (CAT), and malondialdehyde (MDA) were purchased from Nanjing Jiancheng Institute of Biological Engineering. Automatic biochemical analyzer Chemray 800, automatic grinder KH-III, enzyme label detector Epoch, spectrophotometer, water bath box.
Fifty-four healthy male Sprague-Dawley (SD) rats, weighing (180 hing) g, were purchased from Beijing Sibeifu Company, certificate number: SYXK (Jing) 2019–0010. They were raised in a laboratory with a room temperature of 20°C–25°C and a relative humidity of 40%–70%. The cages and litter were regularly cleaned and replaced, and they were free to eat and drink. All operations comply with the ethical requirements of animal science experiments.
Emulsion preparation and model establishment
Preparation of high-fat emulsion: According to the ratio of 30% lard, 5% cholesterol, 5% yolk powder, 4% tween, 0.5% propylthiouracil, stir and mix well for use.
Animal modeling: 48 rats in the high-fat emulsion group were fed with high-fat emulsion, and 6 rats in the blank group were fed with the same amount of normal saline. After the hyperlipidemia model was modeled for 2 weeks, the rats in each group were fasted for 12 h. Blood was collected from the posterior orbital venous plexus to measure TG, TC, LDL-C, and HDL-C to test whether the model was successful.
Animal grouping and administration methods
The high-fat emulsion group was randomly divided into the model group, the positive drug group, and the Danhe granule low, medium, and high dose groups according to body weight, 6 in each group. The low, medium, and high doses of Danhe granule groups were 0.367, 1.10, and 3.30 g/kg/day, respectively, and the positive drug group was given atorvastatin 2.1 mg/kg/day, and the administration was continued at the same time. The gastric high-fat emulsion was administered to the end of the experiment. After 6 weeks of administration, blood was taken from the abdominal aorta of the rats, and the aorta was quickly dissected and cryopreserved.
The fat and surrounding tissues attached to the abdominal aorta of the rat were cleaned up, washed with saline, and then the artery was cut into a 2–3-mm wide ring and fixed with 4% paraformaldehyde. The tissues were embedded in paraffin and sectioned, stained with H and E, and the stained specimens were observed and photographed using an optical microscope.
Effect of Danhe Granules on lipid levels in rats
After 6 weeks of administration, the rats were fasted overnight. The blood was taken from the abdominal aorta after anesthesia. Let stand for 1 h, centrifuged at 3000 r/min, 4°C for 15 min to separate serum, and determine TC, TG, HDL-C, and LDL-C with an automatic biochemical analyzer.
The effect of Danhe granules on the level of oxidative stress in rats
Cut the rat artery into small pieces, add 10 times volume of cold saline. Perform ice bath homogenization at the ratio of aortic tissue mass (g): Reagent volume in the kit (ml) =1: (5–10), centrifuged at 8000 r/min, 4°C for 10 min, take the supernatant. The values of SOD, MDA, GSH-PX, GSH, and CAT were measured according to the kit operating instructions.
| Results|| |
Active ingredients and target screening of Danhe granules
Preliminary screening of active ingredients according to four attribute values: OB ≥30%, DL properties ≥0.18, permeability (Caco-2) ≥−0.4, and HL ≥4, to obtain 78 active ingredients, including 48 of salvia miltiorrhiza, 7 of polygonum cuspidatum, 7 of coix seed, 5 of tangerine peel, 5 of crataegus pinnatifida, 6 of lotus leaf, including 4 common ingredients quercetin, luteolin, kaempferol, and sitosterol [Table 1].
Visualization network of active ingredients-targets of Danhe granules
We constructed a network diagram of ingredients-targets of DG by Cytoscape 3.7.1, including 6 of traditional Chinese medicine, 74 of active ingredients, and 250 targets [Figure 1]. We analyzed the network topology parameters through its built-in Network Analyzer software to obtain the core ingredients. Among them, quercetin has the largest connectivity (degree = 146), betweenness (betweenness centrality, BC) and closeness (Closeness Centrality, CC) are 0.48 and 0.52, respectively. The remaining ingredients are ranked kaempferol (degree = 57), luteolin (degree = 56), tanshinone IIA (degree = 40), sitosterol (degree = 36), cysticercine (degree = 36), and Naringenin (degree = 36) according to the connectivity.
|Figure 1: Visualization network of active ingredients-targets of Danhe granules (the square represented traditional Chinese medicine, the octagon represented ingredients, the prism represented targets, and different colors represented ingredients from different traditional Chinese medicine)|
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Protein–protein interaction network construction of active ingredients-anti-hyperlipidemic targets of Danhe granules
One hundred and thirteen hyperlipidemia protein targets were obtained from the OMIM database; 1373 protein targets were obtained from GeneCards database (the correlation score was greater than the median), and 61 protein targets were obtained from SymMap database, for a total of 1547 targets. We obtained 127 antihyperlipidemic targets of DG through R software and draw a Venn diagram [Figure 2]. The intersection targets were entered into the STRING 11.0 data platform. We set the protein interaction score confidence to 0.900 and hide discrete targets and exported to the Cytoscape 3.7.1 database to construct a protein–protein interaction (PPI) protein interaction network model, which is mapped according to the degree and the combined score to obtain the key nodes: AKT1, tumor necrosis factor (TNF), TP53, interleukin-6 (IL-6), RELA, vascular endothelial growth factor (VEGF), SOD, and CAT [Figure 3].
|Figure 3: Protein–protein interaction network construction of active ingredients-antihyperlipidemic targets of Danhe granules (the greater the degree, the greater the target, the greater the intensity, the thicker the connection)|
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Analysis of related pathways of potential targets
Using metascape to enrich and analyze the intersection targets, the results showed that DG was mainly involved in a total of 573 biological processes. According to the P value, the analysis results of the first 20 signal pathways enriched by Gene Ontology database (GO, http://geneontology.org/) were shown in [Figure 4], and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis (https://www. kegg.jp/) showed that the main targets were involved in HIF-1 signaling pathway, TNF signaling pathway, VEGF signaling pathway, nonalcoholic fatty liver disease, etc. The signal pathway analysis of KEGG enrichment was shown in [Figure 5], and the target-pathway network diagram is constructed to intuitively reflect the complex network relationship of DG in the treatment of hyperlipidemia, as shown in [Figure 6].
|Figure 4: Bubble chart of GO analysis (the size of the dot represented the number of targets enriched in the pathway, the redder the color represented the smaller the P value, and the abscissa is the ratio of the number of targets enriched in the pathway to the total number of targets in the pathway)|
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|Figure 5: Bubble chart of Kyoto Encyclopedia of Genes and Genomes analysis (the size of the dot represented the number of targets enriched in the pathway, the redder the color represented the smaller the P value, and the abscissa is the ratio of the number of targets enriched in the pathway to the total number of targets in the pathway)|
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|Figure 6: Enrichment analysis of functions and pathways of active ingredients-hyperlipidemic targets of Danhe granules (the yellow prisms represented the targets, and the green rectangles represented the pathways)|
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The influence of Danhe granules on lipid levels in rats
The blood lipid levels of rats in each group were shown in [Table 2]. Compared with the control group, the levels of TC, HDL-C, and LDL-C in the model group increased significantly (P < 0.001). Compared with the model group, the levels of TC and LDL-C of the rats in the western medicine group and the low, middle, and high doses of DG decreased significantly (P < 0.05). In addition, the low, medium, and high doses of Danhe granule groups have a better effect on reducing the level of TC than the western medicine group.
The effect of Danhe Granules on the level of oxidative stress in rats
The level of oxidative stress in rats was evaluated by measuring the activities of SOD, MDA, GSH-PX, GSH, and CAT. Studies have found that atorvastatin and DG have a regulatory effect on the level of oxidative stress in rats. Compared with the control group, the SOD, GSH-PX, GSH, and CAT levels of the model group decreased, and the MDA level increased. The difference was significant (P < 0.001). Compared with the model group, the levels of SOD, GSH-PX, GSH, and CAT in the western medicine group and the low-dose and high-dose Danhe granule groups were significantly increased (P < 0.05). In addition, the effect of low- and high-dose groups of DG in increasing SOD, GSH, and CAT was more obvious than that in the western medicine group (P < 0.001), which were dose-dependent. DG also showed a significant effect in reducing the level of MDA (P < 0.05) [Table 3].
|Table 3: Comparison of serum oxidative stress levels in rats in each group (X ± S)|
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H and E staining of aorta
The intima surface of the aorta of normal rats was smooth, the cells were arranged neatly. There is no obvious abnormality in the structure of each layer of tissue. In the model group, the aortic intima and sub-intima cells were arranged disorderly, and a large amount of cytoplasm were vacuolated. The intima of the aorta in the Danhe granule groups was smooth, and the structure and condition of endothelial cells were significantly improved compared with the model group. The overall structure and the endothelial cells of the positive drug group were arranged orderly [Figure 7].
|Figure 7: H and E staining of rat aorta in each group (×400). (a) Blank group (b) Model group (c) Danhe granules group (d) Positive drug group|
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| Discussion|| |
The prevalence of hyperlipidemia in China and even in the world has been greatly increased, and it has the characteristics of long course of disease and multiple secondary diseases, which poses a great threat to people's health. Clinical studies have shown that the characteristics of multiple components and multiple targets of traditional Chinese medicine show great advantages in the treatment of hyperlipidemia.
According to the TCMSP and TCMIP database, it was predicted that the main active ingredients of DG were quercetin (degree = 146), kaempferol (degree = 57), luteolin (degree = 56), tanshinone IIA (degree = 40), sitosterol (degree = 36), cysticercine (degree = 36), naringenin (degree = 36), etc., which were consistent with the previous studies confirmed that the blood components of DG were naringenin and quercetin. Studies have reported that quercetin can reduce the expression of inflammatory factors IL-1, IL-6, and IL-10 and regulate PI3K/AKT/NF-B signaling pathways to improve liver steatosis in rats with nonalcoholic steatohepatitis to reduce liver inflammation; kaempferol can prevent obesity and insulin resistance in rats on a high-fat diet and can regulate cell lipid and glucose metabolism; tanshinone can induce cell autophagy and apoptosis through reactive oxygen species (ROS)-induced endoplasmic reticulum stress and inhibition of p53 pathway to reduce oxidative stress and inhibit cell apoptosis in hepatic steatosis; salvia miltiorrhiza polyphenolic acid can reduce the content of TNF-α and inhibit IL-6 release, can also upregulate the expression of SOD, GSH-Px, which inhibit inflammation and anti-oxidant damage, and reduce atherosclerosis. Relevant pharmacological studies have confirmed that the main active ingredients of DG can achieve the effect of antihyperlipemia by participating in the process of inflammation, oxidative stress, and inducing cell apoptosis.
According to the analysis of PPI network construction, 127 key targets were obtained, among which AKT1, TNF, TP53, IL-6, RELA, VEGF, SOD, and CAT were the key nodes in the network. GO and KEGG analysis suggested that DG were involved in multiple biological processes, including lipid response, regulation of apoptosis process, redox process, regulation of cell proliferation, etc. Its pathways were mainly enriched in inflammatory pathways, tumor-related pathways, and metabolic pathways, cell apoptosis, hypoxia induction and other related pathways. Among them, HIF-1 signal pathway, TNF signal pathway, and VEGF signal pathway were significantly enriched in KEGG.
To verify the results of network pharmacology, we established an SD rat hyperlipidemia model to explore the antihyperlipidemia effect of DG on oxidative stress. The results of animal experiments have proved that DG can not only effectively reduce the levels of TC and LDL-C, maintain the stability of blood lipid levels in the body, but also regulate the body's oxidative stress process. It has a better curative effect on SOD, GSH, and GSH-Px than atovatine. Atorvastatin can reduce MDA levels,, but the same experimental results were not obtained in this experiment, possibly because of the lower dose of atorvastatin. From the H and E staining, the Danhe granule group was smoother than the model group's aortic intima surface, the cells were arranged neatly, the structure and state of endothelial cells were significantly improved, and there was no obvious abnormality in the structure of each layer of tissue. In the state of hyperlipidemia, the body's production of ROS increases, the peroxidation reaction increases, and the activities of various enzymes that scavenge oxygen free radicals decrease. ROS plays a vital role in a series of CVDs caused by hyperlipidemia, including endothelial dysfunction. Oxidized LDL (OX-LDL) induced by ROS penetrates the damaged endothelium and enters the inner membrane. Nuclear cells differentiate into macrophages, and macrophages will absorb OX-LDL, then become foam cells, which evolve into atherosclerotic plaque or rupture of atherosclerotic plaque that may cause stroke or death. Therefore, improving the body's antioxidant capacity is one of the effective means to treat hyperlipidemia. Quercetin, the core component of DG, can affect the production of GSH, signal transduction pathways and the production of ROS to inhibit oxidative stress. Tanshinone IIA can reduce the level of MDA in atherosclerotic rabbits caused by a high-fat diet and increase the level of SOD, and exerting the antioxidant effect by inhibiting the production of ROS. Naringenin can reduce the production of intracellular ROS by activating the mTOR signaling pathway. The polyphenols in salvia miltiorrhiza are common antioxidants, which have the effect of scavenging superoxide anions and peroxynitrite. They can also effectively regulate the oxidative stress-mediated enzyme activity and the chelation of transition metals during the formation of free radicals to play a certain antioxidant activity. Therefore, we preliminarily believe that the early treatment of hyperlipidemia by DG is mainly achieved through oxidative stress.
| Conclusion|| |
In summary, the quercetin, kaempferol, luteolin, tanshinone IIA, sitosterol, and other components of DG may act on key targets such as AKT1, TNF, TP53, IL-6, RELA, VEGF, SOD, and CA T through the HIF-1 signaling pathway, TNF signaling pathway, and VEGF signaling pathway to play a biological role in inflammation, oxidative stress, and to induce cell apoptosis, thereby reducing blood lipids. DG against hyperlipidemia is the result of multi-component, multi-target, and multi-pathway interaction. This provides new ideas for further cell experiment verification with traditional Chinese medicine monomers to clarify their targets. This study made a preliminary study on the pharmacological mechanism of Danhe Granules against hyperlipidemia and laid the foundation for the research and development of new drugs and subsequent in-depth research.
Financial support and sponsorship
This work was supported by National Science and Technology Major Projects of China based on big data research and development of new Chinese medicines, DG preclinical efficacy, safety and related key technology research (No. 2019ZX09201-004).
Conflicts of interest
There are no conflicts of interest.
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School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China, No. 11, Bei San Huan Dong Lu, Chaoyang District, Beijing 100029
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]
[Table 1], [Table 2], [Table 3]