Mechanism of Yinchenhao decoction in the treatment of jaundice based on network pharmacology

Nan Zhang, Shu-Ying Zhang, Wei-Yi Sun*

ARTICLE

Mechanism of Yinchenhao decoction in the treatment of jaundice based on network pharmacology

Nan Zhang1, Shu-Ying Zhang2*, Wei-Yi Sun1*

1Department of General Surgery, First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, China;2Hexing Town Health Center, Suiping County, Zhumadian City, China.

This study aimed to examine the mechanism of classic ancient prescription of Chinese medicine Yinchenhao decoction in treating jaundice based on network pharmacology.An oral bioavailability of ≥ 30%, a drug likeness of ≥ 0.18, and literature studies were used to screen for Yinchen (), Zhizi (), Dahuang ()in the Chinese Medicine System Pharmacology Database and Analysis Platform. The active ingredient was introduced into the PubChem database to collect drug component targets and import into the Uniprot database for gene standardization. The target gene of Yinchen ()was screened via Human Gene Database (GeneCards). Then, use the Cytoscape 3.7.2 software was used for network visualization analysis, and the R3.6.1 software was used for gene ontology functional and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses.We collected a total of 47 active constituents of classic ancient prescription of Chinese medicine Yinchenhao decoction, of which 17 were related to jaundice; 189,9 targets of jaundice were screened, of which 41 were interdigitated with the targets of classic ancient prescription of Chinese medicine Yinchenhao decoction. Gene ontology functional enrichment analysis revealed 111 biological processes, 14 cellular components, and 28 molecular functions, and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis showed 34 Kyoto Encyclopedia of Genes and Genomes pathways including hepatocellular carcinoma, PI3K-Akt signaling pathway, HIF-1 signaling pathway, prolactin signaling pathway, and non-alcoholic fatty liver disease.Based on the network pharmacology, the analysis of jaundice and classic ancient prescription of Chinese medicine Yinchenhao decoction provides a novel idea and direction for the study of classic ancient prescription of Chinese medicine Yinchenhao decoction in the treatment of jaundice.

Classic ancient prescription of Chinese medicine Yinchenhao decoction, Network pharmacology, Jaundice, Mechanism of action

This study aimed to examine the mechanism of classic ancient prescription of Chinese medicine Yinchenhao decoction in treating jaundice based on network pharmacology. Based on the network pharmacology, the analysis of jaundice and classic ancient prescription of Chinese medicine Yinchenhao decoction provides a novel idea and direction for the study of classic ancient prescription of Chinese medicine Yinchenhao decoction in the treatment of jaundice.

Background

Jaundice is a disease in which the concentration of serum bilirubin increases because of the disturbance of bilirubin metabolism, consequently staining the sclera, mucosa, skin, and other tissues yellow. The main clinical symptoms are the yellowness of the eyes, body, and urine, among which the yellowness of the eyes is the most important feature of the disease. Traditional Chinese medicine (TCM) specializes in the category of “jaundice” [1]. It is called recessive jaundice when the concentration of serum bilirubin is 17.1–34.2 μmol/L (1–2 mg/dL), that is, the jaundice is not visible to the naked eye; it is dominant jaundice when the concentration of serum bilirubin is higher than 34.2 μmol/L (2 mg/dL). According to the theory of TCM, jaundice is caused by exogenous damp-heat epidemic toxin, irregular diet, fatigue, and spleen injury. Major types of jaundice in the western medicine, such as hemolytic jaundice, hepatocyte jaundice, obstructive jaundice, and bilirubin metabolic deficiency diseases, may have different clinical manifestations, but they may have the same etiology (chemical inflammation, infection, and obstruction), which can coexist or evolve with each other [2].

TCM has multitarget and multi-component characteristics that are useful to treat jaundice. Classic ancient prescription of Chinese medicine Yinchenhao decoction (CAPCMYD), which is introduced by(, written by Zhang Zhongjing in 219 C.E.), is a commonly used TCM to treat of damp-heat jaundice [3]. It comprised 18 g of Yinchen (); 12 g of Zhizi (); 6 g of Dahuang (), with 3 flavors; 2 L of water, first boiled wormwood, minus 6 liters, 2 flavors, 3 liters boiled, I removed, and three servings taken. It can detoxify and relieve jaundice, clear heat, and promote dampness. This prescription is widely used in clinic to treat damp-heat jaundice [4–6]. Network pharmacology is based on the theory of system biology. The network analysis of biological system and the selection of specific signal nodes for multitarget drug molecular design can reveal the potential complex relationship between TCM formulations and disease targets. As a key concept of TCM network pharmacology, “network target” can help us understand the effective components of TCM compound prescription and the rationality of the combination of Chinese herbal medicine compound prescription. In this study, we first collected the information of the main active components and targets of CAPCMYD from TCM Systems Pharmacology Database and Analysis Platform (TCMSP) and TCM Integrated Database (TCMID). Based on the absorption, distribution, metabolism, and excretion (ADME) parameter attributes provided by TCMSP database, an oral bioavailability (OB) of ≥ 30% and a drug likeness (DL) of ≥ 0.18 were used as the conditions for screening the effective components of CAPCMYD. This study aims to construct a drug targeting network and re-understand the compatibility law of TCM compound prescription from the perspective of active molecules, targets, networks, and systems, providing a basis for an in-depth understanding of the effectiveness and rationality of TCM in the treatment of jaundice. Figure 1 shows the specific process of network pharmacology.

Figure 1 Specific process of network pharmacology.TCMSP, TCM Systems Pharmacology Database and Analysis Platform; TCMID, TCM Integrated Database; OMIM, Online Mendelian Inheritance in Man; PPI, protein-protein interaction; TCM, traditional Chinese medicine.

Materials and methods

Collection of pharmaceutical ingredients

The active components of,, andin CAPCMYD were screened from TCMSP (http://lsp.nwu.edu.cn/tcmsp.php)[7] and TCMID( http://bidd.nus.edu.sg/group/TCMsite/)[8] under the conditions of OB ≥ 30% and DL ≥ 0.18.

Prediction of drug composition targets

The target of the active components in CAPCMYD was queried by the TCMSP target module, and the target protein name was converted into gene name by Perl5.30.2.1 software and UniProt database. In the PubChem database, the active components of the target in TCMSP were searched; the 2-D/3-D structure, small incision lenticule extraction structure, and small incision lenticule extraction number were queried; and the effective component target was predicted through the Swiss Target Prediction database. Finally, all the active ingredient targets were organized and summarized.

Collection of target information related to jaundice

The Human Genome Database GeneCards is a comprehensive database that provides information regarding all annotated and predicted human genes, including genomics, transcriptome, proteomics, genetics, clinical, and functional information. The human Mendelian genetics database Online Mendelian Inheritance in Man (OMIM) contains information regarding all known Mendelian diseases and more than 15000 genes. OMIM focuses on the relationship between phenotypes and genotypes. Target genes related to jaundice were searched in human genetic database GeneCards [9] ( https://www.genecards.org) and human Mendelian genetics OMIM database [10](https://omim.org) and then summarized.

Intersection of compound active components and disease targets

We first downloaded R-3.6.1 software, opened the input command code, and installed the toolkit “VennDiagram” [11], which was used to draw the Venn diagram in R software. Then, using the previously sorted files of active ingredients and disease targets, a specific command code in R software was entered, which generated a Venn diagram and an intersection file of active ingredients and disease targets, which would be used in subsequent work.

Network construction

To construct the CAPCMYD-active ingredient-target network, jaundice target network, jaundice-CAPCMYD-target network, the active ingredients and targets of CAPCMYD were introduced into Cytoscape3.7.2 software [12] (https://cytoscape.org).

Protein interaction network

STRING [13](https://string-db.org) is a database of known and protein-protein interaction (PPI). Interactions include direct (physical) and indirect (functional) associations; they are derived from computational predictions, knowledge transfer between organisms, and interactions from other (major) databases. To draw PPI map, the intersection genes of effective component target gene and disease target gene were introduced into STRING11.0.

Analysis of bioinformatics function and pathway

Visualization and Integration Discovery Database [14] (DAVID, https://david.ncifcrf.gov/home.jsp) provides query-based access to an integrated database that spreads biologically rich information across large datasets and displays graphics of functional information. The intersection genes of effective component target gene and disease target gene were introduced into the DAVID database for gene ontology (GO) functional enrichment analysis and plotted by R-3.6.1 software.

KOBAS, a Kyoto Encyclopedia of Genes and Genomes (KEGG) orthology-based annotation system [15], is a Web server for gene/protein functional annotation (annotation module) and functional set enrichment of (Enrichmentmodule). The intersection genes of effective component target gene and disease target gene were introduced into the KOBAS database for KEGG pathway enrichment analysis and plotted by R3.6.1 software.

Result

Collection and screening of effective components of CAPCMYD

The effective components of each TCM in CAPCMYD were screened and intersected by TCMSP and TCMID database. Thirteen active components were obtained from CAPCMYD; 5, from; and 16, from. Table 1 shows the specific effective components. According to the analysis of its parameters, the hydrophobicity ofwas the strongest, with an average AlogP of 4.67, followed by(3.35) and(2.87). The highest OB (%) of,, andwas 49.68%, 46.67%, and 45.92%, respectively. As shown in Table 2, the average DL of,, andwas 0.53, 0.42, and 0.35, respectively. Although the single medicine in CAPCMYD is different, it has many similar chemical components.

Table 1 Effective components and main targets of classic ancient prescription of Chinese medicine Yinchenhao decoction

Note: effective components are screened based on the condition of the ADME parameter OB ≥ 30% DL ≥ 0.18.

OB, oral bioavailability; DL, drug likeness; ADME, absorption, distribution, metabolism, and excretion.

Table 2 ADME parameters of effective components (`c ± s)

OB, oral bioavailability; DL, drug likeness; ADME, absorption, distribution, metabolism, and excretion.

Prediction of targets for active components of drugs

The effective molecules of a single drug were queried for their targets through the TCMSP target module, and the active components with no corresponding targets in TCMSP were predicted via reverse molecular docking in the PubChem database and Swiss Target Prediction database. There were 89 targets in, 48 in, and 69 in. Among them, 25 are common targets of 3 TCM. The Venn diagram is drawn via venny2.1 online software (Figure 2).

Collection, screening, and mapping of disease target network of jaundice target genes

We searched the GeneCard database for target genes related to jaundice and obtained 1,940 potential targets for jaundice. Furthermore, 90 genes were screened with a relevance score of > 10, and jaundice target gene network was constructed using Cytoscape3.7.2 software (Figure 3).

Intersection of drug component target genes and disease target genes

The above-mentioned drug target genes and disease target genes were introduced into R3.6.1 software, and the intersection file and Venn Diagram were output through the R software toolkit. As shown in Figure 4, there are 41 overlapping genes between drug target genes and disease target genes.

Construction and analysis of component target network of CAPCMYD

The predictive target genes of the effective components and active components of CAPCMYD in the treatment of jaundice were sorted out, and the component target network of CAPCMYD was constructed (Figure 5). The target network of CAPCMYD for the treatment of jaundice has 60 nodes and 148 edges, including 41 predictive targets, 15 active components (including repetition value), and three TCM component nodes. The cytoscape plug-in cytoHubba is utilized to analyze the topology of the network. The first five active components are quercetin, β-sitosterol, isorhamnetin, aloe-emodin, and eupatin.

Construction of PPI network

The common target was imported into the STRING database, and the species selection Homosapiens was used to construct the protein interaction diagram between the common targets (Figure 5). The results showed that the number of nodes is 41, the number of edges is 173, the average degree of nodes is 8.44, and the local clustering coefficient is 0.616, with a-value of < 0.001. Finally, the PPI network diagram and string-interactions.tsv file are exported. The results are imported into Cytoscape for topology analysis through the three topology parameters in the degree, closeness centrality, betweenness centrality (Figure 6). The values of these three topology parameters are proportional to the importance of nodes in the network. Therefore, these three topology parameters are selected to further screen the potential targets of primary screening. We screened out the nodes whose three parameters are greater than or equal to the mean and obtained that the key targets of CAPCMYD for the treatment of jaundice are INS, IL-6, VEGFA, EGFR, MAPK8, ESR1, CYP3A4, GSTP1, and NQO1 (Figure 7).

Analysis of bioinformatics function and pathway

Functional enrichment analysis of GO. Forty-one common targets of CAPCMYD and jaundice were imported into the DOSE, clusterProfiler, and pathview programs of R3.6.1 software in bioconductor (org.Hs.eg.db) database. The enrichment files were obtained by screening GO function with a-value of ≤ 0.05. The column chart (Figure 8) and the bubble chart (Figure 9) were the outputs. The results showed that CAPCMYD could treat jaundice by affecting nuclear receptor activity, transcription factor activity, direct ligand regulation sequence-specific DNA binding, cofactor binding, proximal promoter sequence-specific DNA binding, serine hydrolase activity, peptide binding, sulfur compound binding, RNA polymeraseⅡproximal promoter sequence-specific DNA binding, protein heterodimerization activity and so on.

KEGG pathway enrichment analysis. Forty-one common targets of CAPCMYD and jaundice were imported into the DOSE, clusterProfiler, and pathview programs of R3.6.1 software in bioconductor (org.Hs.eg.db) database. The enrichment files were obtained by screening KEGG function with≤ 0.05, and the path map was output via pathview (Figure 10). The results showed that CAPCMYD could treat jaundice through hepatocellular carcinoma, PI3K-Akt signal pathway, HIF-1 signal pathway, prolactin signal pathway, and non-alcoholic fatty liver disease. The first 20 pathways were selected, and the network diagram of compound-component-component-gene-pathway was drawn by using Cytoscape3.7.2 software (Figure 11).

Figure 2 The Venn diagram of each component target ofclassic ancient prescription of Chinese medicine Yinchenhao decoction

Figure 3 Jaundice target gene network

Figuer 4 Drug target genes and disease target genes

Figure 5 The component target network of classic ancient prescription of Chinese medicine Yinchenhao decoction

Figure 6 Topological properties of PPI network. (a) Degree, (b) closeness centrality, and (c) betweenness centrality. PPI, protein-protein interaction.

Figure 7 Key targets of PPI network classic ancient prescription of Chinese medicine Yinchenhao decoction in the treatment of jaundice. PPI, protein-protein interaction.

Figure 8 Bar chart of GO functional enrichment analysis. GO, gene ontology.

Figure 9 GO functional enrichment analysis bubble chart. GO, gene ontology.

Figure 10 Signal pathway of classic ancient prescription of Chinese medicine Yinchenhao decoction in the prevention and treatment of jaundice

Figure 11 CAPCMYD-component-component-target-pathway network diagram. CAPCMYD, classic ancient prescription of Chinese medicine Yinchenhao decoction.

Discussion

CAPCMYD is the main prescription of TCM in the treatment of damp-heat jaundice. Clinical studies have shown that the effective rate of CAPCMYD in the treatment of hepatobiliary damp-heat jaundice is 77.14% [4]. It can significantly relieve jaundice, fever, nausea and vomiting, dry stool, dry mouth, numbness, and other six symptoms. Studies have shown that CAPCMYD can treat not only jaundice but also hepatitis, hyperlipidemia, acne, type 2 diabetes, liver fibrosis, and bronchial asthma in children [16, 17].

In this study, we used the method of network pharmacology to screen the bioactive components in CAPCMYD by OB and DL. Consequently, 243 compounds were extracted from the TCMSP database, and 34 active molecules (OB ≥ 30%, DL ≥ 0.18) were selected for further study. The network was constructed to obtain 13 active components of CAPCMYD in the treatment of jaundice, including quercetin, β-sitosterol, and isorhamnetin. Through the analysis of PPI protein network interaction, the core protein of CAPCMYD in the treatment of jaundice involves INS, IL6, GSTP1, EGFR, MAPK8, VEGFA, ESR1, CYP3A4, NQO1, and so on. It is proved via the enrichment of GO function that CAPCMYD can treat jaundice by affecting the activity of nuclear receptor and transcription factor and directly regulating sequence-specific DNA binding by ligand. Through KEGG pathway enrichment analysis, it is found that the main pathways of CAPCMYD in the treatment of jaundice include hepatocellular carcinoma, PI3K-Akt signal pathway, HIF-1 signal pathway, and prolactin signal pathway.

Quercetin is a powerful antioxidant flavonoid found in many common herbs and has anti-allergic, anti-viral, anti-inflammatory, and other biological activities [18]. Some studies have shown that quercetin can effectively prevent liver disease by inducing heme oxygenase-1 [19]. Quercetin also has the heart-protecting, anticancer, anti-ulcer, anti-allergy, anti-virus, anti-inflammation, anti-diabetes, protecting stomach, anti-hypertension, anti-infection, and immunomodulatory activities [21–24]. β-sitosterol is among the phytosterols and has a chemical structure similar to that of cholesterol [25]. β-sitosterol can down-regulate PGN-induced inflammatory cytokines IL-6 and IL-8, in HaCaT cells, significantly reduce the production of ROS, and induce HaCaT cells to produce anti-inflammatory protein heme oxygenase-1 after stimulation [26]. β-sitosterol also has antioxidant, antimicrobial, angiogenic, immunomodulatory, anti-diabetic, anti-inflammatory, anticancer, and anti-injury activities and is non-toxic [27]. Isorhamnetin is a natural flavonoid found in a variety of plants and plant foods and is a direct metabolite of quercetin [28].

The signal pathway of hepatocellular carcinoma occurs genetic and epigenetic changes after HBV/HCV infection, alcohol, or aflatoxin B1 exposure. Mutant genes are highly enriched in the signal transduction process of several key drivers, including the target of the PI3K-Akt signal transduction pathway. Recent studies using full exome sequencing have shown that mutations often occur in new driving genes involved in chromatin remodeling and oxidative stress pathways [29]. PI3K-Akt signal transduction pathways are activated by various types of cellular stimuli or toxic stimuli and regulate basic cellular functions such as transcription, translation, proliferation, growth, and survival [30]. Growth factor binds to its receptor tyrosine kinase to stimulate Ia and Ib PI3K subtypes, respectively. PI3K catalyzes the production of phosphatidylinositol-3-inositol-4-triphosphate on the cell membrane. phosphatidylinositol-3-inositol-4-triphosphate acts as a second messenger to help activate Akt. Once activated, Akt can affect cellular components and biological processes by phosphorylating GSK3 and B-cell lymphoma-2. Studies have shown that p-Akt promotes apoptosis-related B-cell lymphoma-2 family members, nuclear factor-κ B family, rapamycin mammalian target phosphorylated, and glycogen synthase kinase-3. Therefore, Akt can play the role of anti-apoptosis and thus play a role in the treatment of jaundice [31]. HIF-1 is a kind of DNA binding protein, which is a heterodimer that comprised β subunit and α subunit, which can be used as the main regulator of oxygen homeostasis [32]. HIF-1 is caused not only by reduced oxygen supply but also by other stimulants such as nitric oxide or various growth factors. IL-6 and IL-6R combine to express HIF-1 α, which makes HIF-1 α stable and interacts with coactivators to regulate its transcriptional activity, and ultimately affect the synthesis of TF and VEGF proteins, then affect cell composition and biological processes, and thus play a role in the treatment of jaundice. Serum IL-6 and VEGF were highly expressed in patients with jaundice [33].

In summary, we discussed the pharmacodynamic basis and mechanism of compound CAPCMYD in the treatment of jaundice based on the analysis method of network pharmacology. The effective components and related target genes in CAPCMYD were predicted. However, the effectiveness of drugs through database and statistical software analysis, which is predicted in this study, has its limitations. Thus, our future research will focus on experimental studies to verify these hypotheses.

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CAPCMYD, classic ancient prescription of Chinese medicine Yinchenhao decoction; TCM, traditional Chinese medicine; TCMSP, TCM Systems Pharmacology Database and Analysis Platform; TCMID, TCM Integrated Database; OB, oral bioavailability; DL, drug likeness; OMIM, Online Mendelian Inheritance in Man; PPI, protein-protein interaction; GO, gene ontology; KEGG, Kyoto Encyclopedia of Genes and Genomes; ADME, absorption, distribution, metabolism, and excretion.

:

The authors declare that they have no conflict of interest.

:

Nan Zhang, Shu-Ying Zhang, Wei-Yi Sun, et al. Mechanism of Yinchenhao decoction in the treatment of jaundice based on network pharmacology. Drug Combination Therapy 2020, 2 (4): 171–184.

:Xiao-Hong Sheng.

:13 January 2020,

17 June 2020,

:05 November2020

*Shu-Ying Zhang. Hexing Town Health Center, No. 1, Hexing Avenue, Suiping County, Zhumadian City, Henan Province, Zhumadian, Henan, China. Email: 2450528136@qq.com; Wei-Yi Sun. Department of General Surgery, First Affiliated Hospital of Henan University of Chinese Medicine, No. 19 Renmin Road, Jinshui District, Zhengzhou City, Henan Province, Email: sunwy110@163.com.

10.12032/DCT2020A027