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Network Pharmacology-Based Study on the Mechanism of Scutellariae Radix for Hepatocellular Carcinoma Treatment.

ABSTRACT: Hepatocellular carcinoma (HCC) is a malignant tumor without effective therapeutic drugs for most patients in advanced stages. Scutellariae Radix (SR) is a well-known anti-inflammatory and anticarcinogenic herbal medicine. However, the mechanism of SR against HCC remains to be clarified. In the present study, network pharmacology was utilized to characterize the mechanism of SR on HCC. The active components of SR and their targets were collected from the traditional Chinese medicine systems pharmacology database and the traditional Chinese medicine integrated database. HCC-related targets were acquired from the liver cancer databases OncoDB.HCC and Liverome. The gene ontology and the Kyoto Encyclopedia of Genes and Genomes pathway were analyzed using the Database for Annotation, Visualization, and Integrated Discovery. Component-component target and protein-protein interaction networks were set up. A total of 143 components of SR were identified, and 37 of them were considered as candidate active components. Fifty targets corresponding to 29 components of SR were mapped with targets of HCC. Functional enrichment analysis indicated that SR exerted an antihepatocarcinoma effect by regulating pathways in cancer, hepatitis B, viral carcinogenesis, and PI3K-Akt signaling. The holistic approach of network pharmacology can provide novel insights into the mechanistic study and therapeutic drug development of SR for HCC treatment.

SUBMITTER: Wang Q

PROVIDER: S-EPMC7607277 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Network Pharmacology-Based Study on the Mechanism of <i>Scutellariae Radix</i> for Hepatocellular Carcinoma Treatment.

Wang Qian Q Liang Yan Y Peng Can C Jiang Peng P

Evidence-based complementary and alternative medicine : eCAM 20201026

Hepatocellular carcinoma (HCC) is a malignant tumor without effective therapeutic drugs for most patients in advanced stages. <i>Scutellariae Radix</i> (SR) is a well-known anti-inflammatory and anticarcinogenic herbal medicine. However, the mechanism of SR against HCC remains to be clarified. In the present study, network pharmacology was utilized to characterize the mechanism of SR on HCC. The active components of SR and their targets were collected from the traditional Chinese medicine system ...[more]

PMID: 33163086

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Project description:Viral hepatitis B is caused by the hepatitis B virus, which is characterized by liver lesions. Bupleuri Radix and Scutellariae Radix are the main traditional medicine pairs with remarkable efficacy in hepatitis B. However, their molecular mechanisms are incompletely understood. The main active components of Bupleuri Radix and Scutellariae Radix, as well as therapeutic targets for the treatment of hepatitis B, were identified through network pharmacology techniques. We identified viral hepatitis B targets using the GeneCards, online mendelian inheritance in man, and therapeutic target databases. We discovered the active components of Bupleuri Radix and Scutellariae Radix as well as therapeutic targets using the encyclopedia of traditional Chinese medicine, HERB, traditional Chinese medicine systems pharmacology database, and a bioinformatics analysis tool for molecular mechanism of traditional Chinese medicine databases. VENNY obtained the intersections. Cytoscape and STRING were used to create the “active ingredient-potential target” network and protein interaction network. The DAVID database was used to enrich GO and KEGG pathways. The results were confirmed using the molecular docking method. There were 1827 viral hepatitis B targets, and 37 active ingredients for Bupleuri and Scutellariae Radix, with the main components being quercetin, wogonin, baicalein, and kaempferol. Tumor necrosis factor (TNF), mitogen-activated protein kinase 3 (MAPK3), interleukin-6 (IL-6), vascular endothelial growth factor A, cysteinyl aspartate specific proteinase 3, transcription factor AP-1 (JUN), RAC-alpha serine/threonine-protein kinase, and cellular tumor antigen p53 are among the 78 common targets of Bupleuri Radix and Scutellariae Radix intervention in viral hepatitis B. KEGG enrichment resulted in 107 pathways, including cancer, hepatitis B, and TNF signaling pathways. According to the molecular docking technique, quercetin, wogonin, baicalein, and kaempferol had strong binding activities with TNF, MAPK3, and IL-6. In this study, we initially identified various molecular targets and multiple pathways involved in hepatitis B treatment with Bupleuri Radix and Scutellariae Radix.

Project description:BackgroundRadix Scutellariae (RS) has been used to treat influenza for thousands of years in China. However, its mechanisms of action remain unclear. The aim of the present study was to use a network pharmacology and molecular docking-based approach to explore active components and potential molecular mechanisms of RS for influenza A.MethodsTarget genes of RS and influenza A were attained by accessing network databases. We then determined the intersection of both genes through bioinformatics using R and Perl language. The protein-protein interaction (PPI) network was constructed by the STRING website (https://cn.string-db.org). The network analysis was done using Cytoscape software. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were applied for the above genes. Effective components as core targets were screened out based on the condition that the interaction must come first. These core targets were combined with 3D structures of main RNA coding proteins of influenza A virus. Molecular docking was used to visualize drug-target interaction via AutoDock Vina and PyMOL.ResultsTwenty-eight active components and 40 target genes were acquired through the regulatory network of active components of RS and the PPI network. Seventy-one bioinformatics expressions were obtained through GO enrichment analysis (P<0.05). A total of 124 signaling pathways were screened by KEGG enrichment analysis (P<0.05). Acacetin, wogonin, baicalein, oroxylin A, and beta-sitosterol, which are rich in RS, are closely related to hemagglutinin (HA), NeurAminidase (NA), nucleoprotein (NP), polymerase basic protein 1 (PB1), polymerase basic protein 2 (PB2), polymerase acidic (PA), matrix protein 1 (M1), matrix protein 2 (M2), and non-structural protein (NS), which are the main RNA coding proteins of influenza A virus. The binding energies of these 8 proteins were less than -5 kJ/mol, indicating that the ligands had strong affinity with receptor proteins.ConclusionsRS is rich in core target compounds, and its mechanism of action is further expressed. It could have a good therapeutic effect for influenza A through multi-compound and multi-target regulation of these specific protein targets, and targets and pathways related to immunity and inflammation.

Project description:Background: Hepatocellular carcinoma (HCC) is a malignant tumor harmful to human health. Ganji Fang (GJF) has good clinical efficacy in the treatment of HCC, but its mechanism is still unclear. Objective: The aim of this study was to investigate the mechanism of action of GJF in the treatment of HCC through network pharmacology, molecular docking and in vitro experiments. Methods: A series of network pharmacology methods were used to identify the potential targets and key pathways of GJF in the treatment of HCC. Then, molecular docking technology was used to explore the binding ability of key active ingredients and targets in GJF. Multiple external databases were used to validate the key targets. In in vitro experiments, we performed MTT assays, wound-healing assays, cell cycle assays, apoptosis assays and RT‒qPCR to verify the inhibitory effect of GJF on the Human hepatoma G2 (HepG2) cells. Result: A total of 162 bioactive components and 826 protein targets of GJF were screened, and 611 potential targets of HCC were identified. Finally, 63 possible targets of GJF acting on HCC were obtained. KEGG enrichment analyses showed that the top five pathways were the cell cycle, cellular senescence, p53 signaling pathway, PI3K/Akt signaling pathway, and progesterone-mediated oocyte maturation. Among them, we verified the PI3K/Akt signaling pathway. CCNE1, PKN1, CCND2, CDK4, EPHA2, FGFR3, CDK6, CDK2 and HSP90AAI were enriched in the PI3K/Akt pathway. The molecular docking results showed that the docking scores of eight active components of GJF with the two targets were all less than -5.0, indicating that they had certain binding activity. In vitro cell experiments showed that GJF could inhibit the proliferation and migration of HepG2 cells, block the cell cycle and induce apoptosis of HepG2 cells, which may be related to the PI3K/Akt signaling pathway. In summary, EPHA2 may be an important target of GJF in HCC, and pachymic acid may be an important critical active compound of GJF that exerts anticancer activity. Conclusion: In general, we demonstrated, for the first time, that the molecular mechanism of GJF in HCC may involve induction of G0/G1 phase cycle arrest through inhibition of the PI3K/Akt signaling pathway and promote apoptosis of hepatoma cell lines. This study provides a scientific basis for the subsequent clinical application of GJF and the in-depth study of its mechanism.

Project description:Background: Hepatocellular carcinoma is one of the most common cancers with the characteristics of invasion and high mortality. Current forms of prevention remain severe. Scutellaria barbata is widely used in traditional Chinese medicine treatment of various tumors. This study explored the mechanism of Scutellaria barbata in the treatment of hepatocellular carcinoma by network pharmacology and bioinformatics. Methods: The active ingredients of Scutellaria barbata and potential targets for the treatment of hepatocellular carcinoma were collected by network pharmacology. The protein interaction network was constructed to screen the core targets, and the association between the core targets and diseases was further verified by bioinformatics methods. Finally, the active ingredients corresponding to the targets closely related to the disease were screened for AMDE characteristics analysis. Molecular docking of drug-like ingredients with corresponding targets was performed. We used CCK-8 kit to determine the effect of active ingredients on cell proliferation. Results: 29 candidate active ingredients and 461 related targets of Scutellaria barbata were screened. A total of 8238 potential therapeutic targets for hepatocellular carcinoma were indentified. Finally, 373 potential targets for the treatment of HCC were obtained. The active ingredients: wogonin, Rhamnazin, eriodictyol, quercetin, baicalein, and luteolin, etc. The core targets were CDK1, CDK4, SRC, and E2F1. A total of 3056 GO enrichment entries were obtained, and 180 enrichment results were obtained by KEGG pathway analysis. Genes were mainly enriched in PI3K-Akt signaling pathway, IL-17 signaling pathway, TNF signaling pathway, apoptosis pathway, and hepatocellular carcinoma pathway. Molecular docking results showed that the screened compounds had strong binding ability with the corresponding target proteins. CCK8 assays showed that Rhamnazin and Luteolin suppressed the proliferation of HCC cells significantly compared with controls. Conclusion: This study revealed that the mechanism of Scutellaria barbata in the treatment of hepatocellular carcinoma may be that the active ingredients inhibit the expression of core genes and block the PI3K-AKT signaling pathway to inhibit the proliferation, and migration and induce apoptosis of cancer cells.

Project description:To analyse the mechanism of Nardostachyos Radix et Rhizoma-Salidroside in the treatment of Premature Ventricular Brats by using network pharmacology and molecular docking and to provide the basis for developing the use of experimental and clinical traditional Chinese medicine. The chemical compositions of Nardostachyos Radix et Rhizoma and Salidroside were determined, and their related targets were predicted. The disease-related targets were obtained by searching the common disease databases Genecards, OMIM, Drugbank and DisGeNET, and the intersection between the predicted targets and the disease targets was determined. Then using the STRING database to set up the protein‒protein interactions (PPIs) network between Nardostachyos Radix et Rhizoma-Salidroside and the common targets of PVB. An "herb-ingredient-target" network was constructed and analyzed by Cytoscape3.7.2 software. Using the metascape database to analysis the predicted therapeutic targets based on the GO and KEGG. Finally, molecular docking technology was used toconfirm the capacity of the primary active ingredients of the 2 herbs to bind to central targets using the online CB-Dock2 database. 41 active components of Nardostachyos Radix et Rhizoma-Salidroside were detected, with 420 potential targets of action, with a total of 1688 PVB targets, and the top 10 core targets of herb-disease degree values were AKT1, TNF, GAPDH, SRC, PPARG, EGFR, PTGS2, ESR1, MMP9, and STAT3. KEGG analysis indicated that its mechanism may be related to the calcium signalling pathway, cancer signalling pathway, AGE-RAGE signalling pathway and other pathways. Molecular docking suggested that main of the active ingredients of the Nardostachyos Radix et Rhizoma-Salidroside pairs were well bound to the core targets. Based on novel network pharmacology and molecular docking validation research methods, we revealed for the first time the potential mechanism of Nardostachyos Radix et Rhizoma-Salidroside in PVB therapy.

Project description:BACKGROUND:Flavonoids from plant medicines are supposed to be viable alternatives for the treatment of type 2 diabetes (T2D) as less toxicity and side effects. Radix scutellariae (RS) is a widely used traditional medicine in Asia. It has shown great potential in the research of T2D. However, the pharmacological actions remain obscured due to the complex chemical nature of plant medicines. METHODS:In the present study, a systematic method combining ultrafiltration UPLC-TripleTOF-MS/MS and network pharmacology was developed to screen α-glucosidase inhibitors from flavonoids of RS, and explore the underlying mechanism for the treatment of T2D. RESULTS:The n-butanol part of ethanol extract from RS showed a strong α-glucosidase inhibition activity (90.55%, IC50 0.551 mg/mL) against positive control acarbose (90.59%, IC50 1.079 mg/mL). A total of 32 kinds of flavonoids were identified from the extract, and their ESI-MS/MS behaviors were elucidated. Thirteen compounds were screened as α-glucosidase inhibitors, including viscidulin III, 2',3,5,6',7-pentahydroxyflavanone, and so on. A compound-target-pathway (CTP) network was constructed by integrating these α-glucosidase inhibitors, target proteins, and related pathways. This network exhibited an uneven distribution and approximate scale-free property. Chrysin (k = 87), 5,8,2'-trihydroxy-7-methoxyflavone (k = 21) and wogonin (k = 20) were selected as the main active constituents with much higher degree values. A protein-protein interaction (PPI) weighted network was built for target proteins of these α-glucosidase inhibitors and drug targets of T2D. PPARG (Cd = 0.165, Cb = 0.232, Cc = 0.401), ACACB (Cd = 0.155, Cb = 0.184, Cc = 0.318), NFKB1 (Cd = 0.233, Cb = 0.161, Cc = 0.431), and PGH2 (Cd = 0.194, Cb = 0.157, Cc = 0.427) exhibited as key targets with the highest scores of centrality indices. Furthermore, a core subnetwork was extracted from the CTP and PPI weighted network. Type II diabetes mellitus (hsa04930) and PPAR signaling pathway (hsa03320) were confirmed as the critical pathways. CONCLUSIONS:These results improved current understanding of natural flavonoids on the treatment of T2D. The combination of ultrafiltration UPLC-TripleTOF-MS/MS and network pharmacology provides a novel strategy for the research of plant medicines and complex diseases.

Dataset Information

Network Pharmacology-Based Study on the Mechanism of Scutellariae Radix for Hepatocellular Carcinoma Treatment.

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Network Pharmacology-Based Study on the Mechanism of <i>Scutellariae Radix</i> for Hepatocellular Carcinoma Treatment.

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