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Table of Contents
ORIGINAL ARTICLE
Year : 2020  |  Volume : 6  |  Issue : 3  |  Page : 341-352

Network pharmacology approach to determine active compounds and potential targets associated with the anti-abortion effects of scutellariae radix


1 College of Electronic Information, Jincheng College, Sichuan University, Chengdu, Sichuan, China
2 College of Pharmacy, Chengdu Medical College, Chengdu, Sichuan, China

Date of Submission11-Mar-2020
Date of Acceptance17-May-2020
Date of Web Publication05-Aug-2020

Correspondence Address:
Prof. Qing Su
College of Pharmacy, Chengdu Medical College, Chengdu, Sichuan 610083
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/wjtcm.wjtcm_35_20

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  Abstract 


Background: It is widely accepted that the causes and mechanisms of abortion are very complicated. In China, Scutellariae Radix (SR) (Scutellaria baicalensis Georgi) is widely used as a traditional Chinese herbal medicine with anti-abortion effects. However, the chemical components and pharmacologic profiles of SR have not been elucidated. The network pharmacology approach can provide a system-level perspective to explore the components, targets, and mechanism of herbal medicines. Thus, this approach was employed to identify the absorbable compounds, potential targets, and signaling pathways associated with SR. Materials and Methods: In this study, we used the Lipinski rule and an oral bioavailability of >30% to identify the bioactive compounds in SR. Targets of the anti-abortion activity of SR were obtained from the PharmMapper website server database. The Search Tool for the Retrieval of Interacting Genes and DAVID databases were utilized to perform protein–protein interaction analysis and pathway enrichment analysis, respectively. Finally, Cytoscape software was used to visualize the active compound–target–Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway network of SR. Results: In total, 286 chemical compounds were identified in SR; of these, 27 compounds could be absorbed into the blood, and 10 compounds that had a high docking score with their corresponding targets were determined. These potentially active compounds of SR regulated 142 targets and clearly affected 29 KEGG pathways. From these targets, a total of 11 targets, which were expressed in the breast and female reproductive system, were associated with the anti-abortion effects of SR: EGFR, HRAS, HSP90AA1, ESR1, PRKACA, SRC, GSK3B, JAK2, IGF1R, CDK2, and AR. In the KEGG pathway analysis, five pathways were related to the anti-abortion effect of SR, including the estrogen signaling pathway, the prolactin signaling pathway, progesterone-mediated oocyte maturation, and oocyte meiosis. Conclusions: The network pharmacology approach used in our study attempted to explain the mechanism of the anti-abortion effects of SR and has provided an alternative approach for the investigation of the effects of this complex compound.

Keywords: Anti-abortion, computational biology, herbal medicine, network pharmacology, Scutellariae Radix


How to cite this article:
Ma L, Lei QL, Su Q. Network pharmacology approach to determine active compounds and potential targets associated with the anti-abortion effects of scutellariae radix. World J Tradit Chin Med 2020;6:341-52

How to cite this URL:
Ma L, Lei QL, Su Q. Network pharmacology approach to determine active compounds and potential targets associated with the anti-abortion effects of scutellariae radix. World J Tradit Chin Med [serial online] 2020 [cited 2020 Sep 26];6:341-52. Available from: http://www.wjtcm.net/text.asp?2020/6/3/341/291406




  Introduction Top


The causes and mechanisms of abortion are very complicated. Most scholars believe that the early abortion has a clear relationship with the maternal-fetal-immune status and hormone levels. Several anti-abortion treatments have been made available, including progestin therapy,[1] dydrogesterone therapy,[2] and other hormonal treatments.

Chinese herbal medicines have been evaluated for their anti-abortion effects in preclinical and clinical studies.[3] Scutellariae Radix (SR) has been used widely as a traditional Chinese herbal medicine with anti-abortion effects[4] and is considered the “anti-abortion holy medicine.” SR has various functions, including effects on heat and dampness, hemostasis, use as an antidote, and anti-inflammatory, anticancer, antibacterial, antiviral, and anti-abortion effects. However, the mechanism of the anti-abortion effects of SR is unclear. Recently, the anti-abortion mechanism of SR has been investigated from an immunomodulatory perspective.[5] These studies have not involved in the regulation of endocrine hormones and related targets. Similarly, systematic in silico approaches based on network pharmacology have made a significant contribution to the elucidation of the possible mechanisms of modern medicine through pharmacokinetic evaluation, target prediction, and network/pathway analysis.[6] Network pharmacology has become a promising drug development method. In this study, a network pharmacology method was employed to find the active compounds, targets, and signaling pathways related to the anti-abortion effect of SR. The network pharmacological analysis of SR will provide a novel understanding of its anti-abortion effects.


  Materials and Methods Top


The research methodology applied in this study is illustrated in [Figure 1].
Figure 1: The research method of this study

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Construction of chemical compound set

The Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) (http://lsp.nwu.edu.cn/tcmsp.php)[7] was searched for the keyword “Huang Qin” (the pinyin of SR). In total, 286 chemical compounds were identified in SR.

Calculation and prediction of absorbable chemical compounds

The TCMSP database, PubChem substance,[8] and ChemDraw software were used to obtain the chemical structure of the compounds in SR. Subsequently, information that was treated as an indicators of oral bioavailability (OB) and drug absorption was obtained from the TCMSP database and Molinspiration SMILES website (http://molinspiration. com). When Lipinski's rule was combined with an OB cutoff of >30%, a compound was identified as an absorbable drug, if Hdon, the number of hydrogen atoms attached to the O and N, was ≤5; Hacc, the number of O and N atoms, was ≤10; the oil-water partition coefficient (AlogP) was ≤5; and the relative molecular mass (MW) was ≤500; and OB was >30%.

Prediction and screening of targets

The ChemBIO3D Ultra 12.0 informatics system was employed to transform structures of absorbable compounds of SR into MOL2 file format. To obtain the possible targets of SR, compounds that were able to be absorbed into the blood were imported into the PharmMapper server website (http://www.lilab-ecust.cn/pharmmapper/).[9] PharmMapper server is a freely accessible web server designed to identify potential target candidates for a given small-molecule probe, such as a small-molecule drug or natural products, using a pharmacophore mapping approach. Benefiting from a highly efficient and robust mapping method, PharmMapper has high-throughput ability and can identify potential target candidates from the database within a few hours. The results were downloaded from the PharmMapper server and targets were arranged in descending order of Z values; the top 20 targets of each compound were selected for the subsequent study. The Search Tool for the Retrieval of Interacting Genes (STRING) database (version 10.5) (https://string-db.org/)[10] was used to predict the potential interactions among the targets. In addition, the Human Protein Atlas database (https://www. proteinatlas.org/) was used to search for tissue-specific targets in the breast and female reproductive system of women. This problem has not been addressed in a tissue-specific manner in previous studies.

Prediction and screening of pathways

To explore the functions and processes that may be altered by the identified targets, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was performed using the DAVID database (version 6.8) (https://david. ncifcrf.gov/).[11] The cutoff for the screening of significant functions and pathways was P < 0.01.

Construction of the component–target–KEGG pathway network

Based on the identified compounds and their predicted targets, a compound–target network was established using Cytoscape 3.4.0 software (version 3.4.2; http://www.cytoscape.org/).[12] After the protein–protein interaction analysis and the KEGG pathway enrichment analysis between these predicted targets were performed using the STRING and DAVID databases, respectively, the compound–target–KEGG pathway network was established using the merge function in Cytoscape.


  Results Top


Absorption parameters of chemical compounds

The oral route is a convenient and common method to deliver drugs to the systemic circulation for patients.[13] In this study, a total of 286 compounds of SR were identified. Natural compounds with poor aqueous solubility are expected to exhibit low efficiency after oral intake and thereby provide few beneficial therapeutic effects in patients. Consequently, Lipinski's rule and an OB of >30% were used to screen the absorbability of the identified compounds. By evaluating the absorbability parameters associated with the properties of this compound, 27 potentially active compounds were selected, which accounted for 9.75% of all compounds. The absorbability parameters of the 27 identified compounds selected by combining Lipinski's rule with an OB of >30% are shown in [Table 1].
Table 1: Absorption parameters of the compounds of Scutellariae Radix

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Construction and analysis of compound–target–pathway interaction network

We obtained 183 candidate targets for 27 potentially active compounds using the PharmMapper website server. After mapping the tissue-specific targets, 149 targets were obtained that corresponded with the anti-abortion effect. This included 10 targets that were only expressed in the breast and reproductive system of women. This tissue-specific problem has been ignored previously. The 27 potentially active compounds with 149 targets were subsequently used to construct the compound–target interaction network [Figure 2]a. The results showed that 23 flavonoids were the main active compounds and played a major role in the anti-abortion effect of SR. The comparison of alkaloid and phenolic compounds showed that more targets were alkaloids and that they may have more extensive pharmacological effects [Figure 2]b and [Figure 2]c.
Figure 2: Compound–target interaction network. By valuating the drug-like and absorption-associated properties of compounds, the 28 potentially active compounds with 149 targets were used to construct the CTI network. (a) The potential compound–target network. (b) Alkaloid's targets using PharmMapper web server. (c) Phenolic targets using PharmMapper web server

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After sorting the docking scores between the compounds and their associated targets, the top 10 compounds with high docking scores were selected as lead compounds that may play a role in the anti-abortion effects. These compounds and their targets with “medium” or “high” expression in the breast and female reproductive system were selected for further research.

The top 10 compounds with higher docking scores and their corresponding targets with high expression scores in the breast and female reproductive system were used to establish the lead compound–target network [LCT network, [Figure 3]a. The data analysis revealed that the network average degree of the LCT network of lead compounds and their targets was 9.735, and there were 25 targets with a higher than the average degree, including BL1, AR, CASP3, CDK2, CDK6, DHFR, EGFR, EIF4E, ESR1, GART, GSK3B, GSR, HRAS, HSD17B1, HSP90AA1, IGF1R, JAK2, NR3C1, NT5M, PRKACA, SHMT1, SRC, TPI1, and TYMS. The highest degree was HSP90AA1, which interacted with 34 targets, followed by SRC, which interacted with 31 targets; the third highest was EGFR, which interacted with 25 targets. The targets that had more than 15° were considered as key targets and used in subsequent studies [Table 2]. There were 18 of these targets, and these were subjected to KEGG pathway enrichment analysis of these targets, which was performed by the DAVID database. Twenty-nine pathways with significant differences (P < 0.01) were identified that were regulated by SR [Table 3]. Among these, the pathways associated with female reproduction include the estrogen signaling pathway, prolactin (PRL) signaling pathway, progesterone-mediated oocyte maturation, oocyte meiosis, and the oxytocin signaling pathway. However, the oxytocin signaling pathway was removed because the best time for the applicable of anti-abortion prevention is before the 12th week of pregnancy.
Figure 3: Network of major targets of Scutellariae Radix with corresponding compounds and pathways. (a) Network of major targets of Scutellariae Radix with corresponding lead compounds. (b) The network of lead compound–major target–Kyoto Encyclopedia of Genes and Genomes pathways which related to the effect of anti-abortion of Scutellariae Radix

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Table 2: Key targets of expression of breast and female reproductive system and their extension coefficients

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Table 3: The Kyoto Encyclopedia of Genes and Genomes pathway of the key targets of the effect of Scutellariae Radix (P<0.01)

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A lead compound–target–KEGG pathway network (LCTK network) was obtained by merging the pregnancy-related signaling pathway with the LCT network. There were 11 targets in LCTK network [Figure 3]b: EGFR, HRAS, HSP90AA1, ESR1, PRKACA, SRC, GSK3B, JAK2, IGF1R, CDK2, and AR.

Based on Lipinski's rule, an OB of >30%, and the PharmMapper website sever, 10 compounds in SR were selected and considered as lead compounds in the treatment of anti-abortion. Further, 11 targets that were expressed in the breast and female reproductive system with a “medium” or “high” expression score were identified.


  Discussion Top


From a modern medical perspective, maternal factors are a key cause of abortion. Maternal factors include a number of systemic diseases, such as bacterial infections, insufficient endocrine function of the placenta and decidua, abnormal luteal function, abnormal immune function, or abnormal uterine development.[14] SR has been used to prevent abortion since ancient times; however, some questions on the mechanism of its anti-abortion effects remain to be clarified. In this study, to understand the mechanism of anti-abortion of SR in a holistic manner, a network pharmacology approach was employed, and a multilayer networks that identified the active compounds and targets and signaling pathways were constructed. As this study has shown, the availability of large phenotypic and molecular networks may provide an opportunity to explore the correlation between diseases and proteomics datasets.

In this study, data analysis showed that EGFR, HRAS, HSP90AA1, ESR1, PRKACA, SRC, GSK3B, JAK2, IGF1R, CDK2, and AR were the main targets of SR.

Estrogen can increase the hypertrophy and proliferation of endometrial epithelial cells, thicken the muscles, increase blood supply, promote and maintain the development of the uterus, promote the development of oviductal muscle and epithelial secretion, and increase the amplitude of rhythmic contractions of the fallopian tubes. In addition, estradiol can also increase the LDL uptake and progesterone synthesis, upregulate progesterone receptors, and increase endometrial L-selective protein expression [Figure 4]a.[15]


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Progesterone is an essential steroid hormone for the establishment and maintenance of pregnancy. In this study, oocytes become mature and fertile egg cells by regulation by SR, which acts on the progesterone-mediated oocyte maturation signaling pathway and oocyte meiosis [Figure 4]b and [Figure 4]e.[16]

Recent studies have shown that PRL plays an important role in the regulation of reproductive physiology and maintenance of pregnancy. PRL is necessary to maintain pregnancy. Thus, it provides an alternative method for the treatment of miscarriage in patients with early threatened abortion.[17] PRL acts on the corpus luteum and maintains pregnancy by increasing progesterone secretion, which increases the expression of the luteinizing hormone (LH)/chorionic gonadotropin receptor or stabilizes the transcription of receptor mRNA. In this study, SR was shown to promote cell proliferation by acting on the PRL signaling pathway [Figure 4]c.

GnRH is secreted by the hypothalamus and able to regulate ovarian function by regulating the synthesis and secretion of follicle-stimulating hormone (FSH) and LH in the pituitary gland. In this study, the active ingredients in SR were able to regulate hormones, such as LH-β and FSH-β, by acting on the GnRH signaling pathway [Figure 4]d.

EGFR is an epidermal growth factor (EGF) receptor and a transforming growth factor (TGF)-α receptor. It is a member of the tyrosine kinase receptor family. EGFR impacts several signaling cascades to convert extracellular cues into appropriate cellular responses;[18] therefore, it is involved in many important biological processes, such as cell proliferation, differentiation, and apoptosis.[19] In the estrogen signaling pathway, the effects of cell proliferation and the production of cell adhesion factors, among others, are caused by the binding of HB-EGF to EGFR, which is related to the proliferation of estrogen. In the GnRH signaling pathway, HB-EGF binds to EGFR and initiates the GnRH signaling pathway, which regulates ovarian function by regulating the synthesis and secretion of FSH and LH in the pituitary gland [Figure 4]d.

HRAS gene encodes the GTPase HRas protein, which is involved in the activation of Ras protein signal transduction.[20] Ras proteins bind GDP/GTP and possess intrinsic GTPase activity. In the estrogen signaling pathway, the PRO signaling pathway, and the GnRH signaling pathway [Figure 4]a, [Figure 4]c, and [Figure 4]d], HRAS plays a role in signal transduction and regulates upstream signal transduction to the downstream, which causes the corresponding promotion of cell proliferation and regulation of hormones, such as LH and FSH.

HSP90AA1 is a protective protein belonging to the heat shock protein (HSP) family. HSP90AA1 plays an important role in maintaining the normal physiological functions of cells and preventing the interaction of proteins that affect cell health. It assists the folding of the amino acid chain into the correct three-dimensional structure, removes damaged amino acid chains that cannot be folded correctly, and protects protein molecules to find target molecules from other molecules.[21],[22] In addition, HSP90AA1 also plays an important role in malignant transformation and metastasis of cells. In this study, in the progesterone-mediated oocyte maturation signaling pathway [Figure 4]b, translation of maternal mRNAs was protected by the interaction of HSP90AA1 with the Mos protein, which helps progesterone to promote oocyte maturation. In the estrogen signaling pathway [Figure 4]a, HSP90AA1 protects the estrogen receptor (ER), which helps estrogen to bind the ER and exert its effects.

ESR1 is an ER that belongs to the nuclear receptor superfamily of ligand-regulated transcription factors and shares similar basic structures with other nuclear receptors. Overall, ESR1 functions as a signal transduction through interaction with estrogen and promotes cell proliferation in most tissues.[23]

SRC is a proto-oncogene tyrosine receptor kinase. They can be activated by a variety of cellular receptors, including immune response receptors, integrins, and other adhesion receptors, tyrosine kinase receptor proteins, G protein-coupled receptors, and cytokine receptors. SRC is involved in the control of a variety of biological activity signaling pathways, including gene transcription, immune responses, cell adhesion, cell proliferation, apoptosis, migration, and transformation.[24] At the beginning of pregnancy, trophoblast cells are characterized by their high proliferation, low rate of apoptosis, and high migration and invasiveness, which are similar characteristics to tumor cells. In addition, the biological behavior of trophoblast cells is strictly regulated by the decidua microenvironment, which plays a key role in blastocyst implantation, embryonic development, and the maintenance of normal pregnancy. SR may exert its protective effect on oxidatively damaged trophoblasts and promote the migration and invasion of trophoblasts through the regulation of SRC expression and the MAPK signaling pathway, the estrogen signaling pathway, PRL signaling pathway, and GnRH signaling pathway [Figure 4]a, [Figure 4]c, and [Figure 4]d.[25]

GSK3B is a glycogen synthase kinase that plays a negative role in the hormonal regulation of glycogen homeostasis. It is associated with multiple signaling pathways that control metabolism, differentiation, immunity, apoptosis, and metastasis. In the PRL signaling pathway [Figure 4]c, SR may act on GSK3B to regulate cell proliferation.

JAK2 is a tyrosine-protein kinase, which affects various functions, such as cell proliferation, growth, differentiation, and histone modification. In addition, JAK2 regulates the basic signal transduction of both innate and adaptive immunities. In the cytoplasm, JAK2 plays a key role in signal transduction by interacting with type I receptors, such as PRL, and type II receptors, such as interferon (IFN)-α, IFN-β, and IFN-γ.[26] In the PRL signaling pathway [Figure 4]c, JAK2 transmits the signal for PRL binding with the short receptor (short R) and long receptor (long R) separately, which produces an effect that suppresses ovarian defects and promotes cell proliferation.

IGF1R, insulin-like growth factor 1 receptor, compared with insulin, has a higher affinity with IGF1 and IGF2. Activated IGF1R is involved in cell growth and survival control, which is critical for tumor metastasis and the survival of malignant tumor cells. In the progesterone-mediated oocyte maturation signaling pathway [Figure 4]b, IGF1R interacts with IGF-1 and insulin to indirectly active the downstream cascade of Ras, which is able to prevent follicular rupture and meiosis, thereby promoting oocyte maturation. However, in oocyte meiosis [Figure 4]e, IGF1R interacts with IGF-1 and INS to indirectly influence the subsequent effects that are activated by cAMP, which inhibit the effect of DNA replication, bipolar spindle formation, and Stage I meiosis.[27]

CDK2 is a cyclin-dependent kinase that belongs to the serine/threonine-protein kinase family. It is not necessary for mitosis but is still necessary for cell cycle and meiotic processes. CDK2 can phosphorylate CTNNB1, USP37, p53/TP53, NPM1, CDK7, RB1, BRCA2, MYC, NPAT, EZH2, and other proteins and trigger centrosome and DNA replication. In addition, CDK2 controls the time of the initiation of silk/meiosis. CDK2 also plays a key role in coordinating the balance of cell proliferation, cell death, and DNA repair in human embryonic stem cells (hESCs). Therefore, SR may regulate oocyte division and maturation by acting on CDK2 [Figure 4]b and [Figure 4]e.

AR is an androgen receptor. Recent studies have shown that, besides estrogen and progesterone, androgens also play a crucial role in the development of follicles. Androgens are able to increase ovarian sensitivity to exogenous gonadotropins.[28] However, excessive androgen levels have an antagonistic effect on estrogen and retard the growth and proliferation of the uterus and endometrium. In the oocyte meiotic signaling pathway, androgen receptors can receive signals from progesterone and indirectly inhibit the production of cAMP, which is able to promote DNA replication, bipolar spindle formation, and Stage I meiosis. Therefore, we inferred that SR inhibits the interaction between the androgen receptor and progesterone and participates in the promotion of oocyte meiosis [Figure 4]e.

The anti-abortion effect of SR has been confirmed. A molecular docking simulation was performed, and the results [Figure 5] showed that the compounds in SR had strong binding efficiencies with their targets. These compounds were considered as the main compounds that exerted the anti-abortion effect and were predominantly flavonoids.
Figure 5: Molecular docking simulation shows that the compounds had strong binding efficiencies with their main targets of Scutellariae Radix

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This is the first report to show the mechanism of the anti-abortion effect of SR using a network pharmacology approach. We successfully predicted the main targets and pathway for SR as an anti-abortion medication and have provided a basis for further research. This approach may also benefit studies of other Chinese herbal medicines and complex drugs. The findings of this study indicate that SR, an herbal medicine commonly used for anti-abortion, exerts its therapeutic effects through multiple targets and multiple pathways. However, it must be stressed that computational models can only provide network data-driven indications for complex therapeutic compounds; thus, the findings of this study should be verified by controlled clinical studies and real-world evidence.


  Conclusions Top


In this study, we demonstrated a novel approach to the investigation of the mechanism of action of the Chinese herbal medicine, SR, by combining absorption property screening, target prediction, protein–protein interaction analysis, and network pharmacology. The network pharmacology approach used in our study has attempted to explain the mechanisms of the anti-abortion effects of SR and provides an alternative approach to the investigation of other complex compounds and Chinese herbal medicines.

Acknowledgments

It is a pleasure to thank Dr. Y. J. Liu, Dr. L. T. Ma, Dr. M. Wu, and Dr. X. Y. Yan for their helpful discussions.

Financial support and sponsorship

  1. 2018 Sichuan Retirement and Old-age Health Collaborative Innovation Project, project number (No: YLZBZ1810)
  2. 2017 Sichuan Provincial Health and Family Planning Commission Research Project (No: 17PJ568)
  3. Innovation and Entrepreneurship Project of Chengdu Medical College in 2019, project number (No: s201913705109).


Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
 
 
    Tables

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