Network Pharmacology Integrated with Transcriptomics Deciphered the Potential Mechanism of Codonopsis pilosula against Hepatocellular Carcinoma.
Hepatocellular carcinoma (HCC) is the fourth main reason of cancer-related death. Codonopsis pilosula is a commonly used traditional Chinese medicine (TCM) for patients with HCC. However, its potential mechanism for treatment of HCC remains unclear. Here, we used transcriptomics and network pharmacology to explore the potential molecular mechanisms of Codonopsis pilosula. In our study, twelve differentially expressed genes (DEGs) (5 upregulated and 7 downregulated) of Codonopsis pilosula treating HepG2 cells (a kind of HCC cell) were identified. Among the 12 DEGs, HMOX1 may play an essential role. Codonopsis pilosula mainly affects the mineral absorption pathway in HCC. We acquired 2957, 1877, and 255 targets from TCMID, SymMap, and TCMSP, respectively. Codonopsis pilosula could upregulate HMOX1 via luteolin, capsaicin, and sulforaphane. Our study provided new understanding of the potential pharmacological mechanisms of Codonopsis pilosula in treating HCC and pointed out a direction for further experimental research.
Liu Z
，Sun Y
，Zhen H
，Nie C
... -
《-》
Integrating Network Pharmacology and Bioinformatics to Explore the Effects of Dangshen (Codonopsis pilosula) Against Hepatocellular Carcinoma: Validation Based on the Active Compound Luteolin.
This study aimed to explore the pharmacological mechanism of Dangshen (Codonopsis pilosula) against hepatocellular carcinoma (HCC) based on network pharmacology and bioinformatics, and to verify the anticancer effect of luteolin, the active ingredient of Codonopsis pilosula, on HCC cells.
The effective compounds and potential targets of Codonopsis pilosula were established using the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) database. The genes related to HCC were obtained through the GeneCards database. The interactive genes were imported into the Visualization and Integrated Discovery database for Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) signal enrichment, and the hub genes were screened out. The Cancer Genome Atlas database was used to construct a prognosis model, and the prognosis and clinicopathological correlation were analyzed. In in vitro experiments, we verified the effects of luteolin, an active compound of Codonopsis pilosula, on the proliferation, cell cycle, apoptosis and migration of HCC cells.
A total of 21 effective compounds of Codonopsis pilosula and 98 potential downstream target genes were screened through the TCMSP database, and 1406 HCC target genes were obtained through the GeneCards database. Finally, 53 interacting genes between the two databases were obtained, among which, the 10 key node genes were CASP3, TP53, MDM2, AKT1, ESR1, BCL2L1, MCL1, HSP90AA1, CASP9, and CCND1, involving 77 typical GO terms and 72 KEGG signals. The Kaplan-Meier survival curve of the model group showed that the overall survival of the low-risk group was significantly higher than that of the high-risk group. Luteolin significantly inhibited the proliferation and migration of HCC cells, induced apoptosis, and increased the G2/M phase ratio. Mechanistically, luteolin significantly inhibited the phosphorylation of MAPK-JNK and Akt (Thr308) and subsequently led to upregulation of ESR1. Pharmacological inhibition of ESR1 with fulvestrant enhanced cell viability and migration and attenuated apoptosis.
Codonopsis pilosula has potential for clinical development due to its anti-HCC properties. Luteolin, the effective component of Codonopsis pilosula, plays anti-HCC role through AKT- or MAPK-JNK signaling mediated ESR1.
Yu Y
，Ding S
，Xu X
，Yan D
，Fan Y
，Ruan B
，Zhang X
，Zheng L
，Jie W
，Zheng S
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《Drug Design Development and Therapy》
Molecular mechanisms of Codonopsis pilosula in inhibiting hepatocellular carcinoma growth and metastasis.
Liver cancer, one of the most common types of cancer worldwide, accounts for millions of cases annually. With its multi-target and wide-ranging therapeutic effects, traditional Chinese medicine has emerged as a potential approach for treating various tumors. Codonopsis pilosula, a traditional herb, is known for its anti-inflammatory and antioxidant properties. In this study, we investigated the potential molecular mechanisms of Codonopsis pilosula in regulating the inhibition of CDK1 and the modulation of PDK1/β-catenin, which are involved in hepatocellular carcinoma growth and metastasis.
Firstly, we screened the active chemical constituents of Codonopsis pilosula and identified their respective target proteins using the Herb database. Then, we applied the GeneCards database and transcriptome sequencing analysis to screen for critical genes associated with the occurrence and development of liver cancer. The intersection of the target proteins and disease-related genes was used to determine the potential targets of Codonopsis pilosula in hepatocellular carcinoma. Protein-protein interaction analysis and GO/KEGG analysis were subsequently performed to uncover the pathways through which Codonopsis pilosula acts on liver cancer. The Huh-7 cell line, exhibiting the highest sensitivity to Codonopsis pilosula polysaccharide solution (CPP) intervention, was chosen for subsequent studies. Cell viability was evaluated using the CCK-8 assay, colony formation assay was conducted to determine cell proliferation capacity, flow cytometry was used to analyze cell cycle, TUNEL staining was performed to assess cell apoptosis, scratch assay was carried out to evaluate cell migration ability, the expression of EMT-related proteins was detected and analyzed, and cell sphere formation assay was conducted to investigate cell stemness. Finally, a liver cancer animal model was established, and different doses of CPP were administered via gavage the next day. The expression levels of CDK1, PDK1, and β-catenin in mouse liver tissues were detected and analyzed, immunohistochemistry staining was performed to assess the expression of tumor cell proliferation-related proteins Ki67 and PCNA in mouse xenografts, and TUNEL staining was carried out to evaluate cell apoptosis in mouse liver tissues. After intervention with CDK1 expression, the expression levels of CDK1, PDK1, and β-catenin proteins and mRNA in each group of cells were detected using Western blot and RT-qPCR.
Through network pharmacology analysis, transcriptome sequencing, and bioinformatics analysis, 35 target genes through which Codonopsis pilosula acts on liver cancer were identified. Among them, CDK1, with the highest degree in the PPI network, was considered an essential target protein for Codonopsis pilosula in treating liver cancer. In vitro cell experiments revealed that CPP could inhibit the expression of CDK1/PDK1/β-catenin signaling axis factors, suppress cell proliferation, decrease cell migration ability, influence the EMT process, and reduce cell stemness by inhibiting CDK1 and affecting the PDK1/β-catenin signaling axis. Similarly, in vivo experiments demonstrated that CPP could regulate the CDK1/PDK1/β-catenin signaling axis, inhibit tumor growth, and induce cell apoptosis.
Codonopsis pilosula may inhibit hepatocellular carcinoma growth by suppressing CDK1 and affecting the PDK1/β-catenin signaling axis, limiting cell EMT and reducing cell stemness. These findings provide insights into the potential therapeutic role of Codonopsis pilosula in liver cancer.
Li N
，Yang C
，Xia J
，Wang W
，Xiong W
... -
《-》
Revealing the potential mechanism of Astragalus membranaceus improving prognosis of hepatocellular carcinoma by combining transcriptomics and network pharmacology.
Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related death. Traditional Chinese medicine (TCM) has special advantages in relieving HCC, while Astragalus membranaceus is commonly used in TCM treatment. However, its underlying mechanisms for treatment of HCC are unclear.
Differentially expressed genes (DEGs) of Astragalus membranaceus treatment in HepG2 cells were identified, and Astragalus membranaceus-gene network was constructed. The hub genes were then obtained via protein-protein interaction (PPI) analysis. Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO), and Gene Set Enrichment Analysis (GSEA) were subsequently performed. Furthermore, prognosis genes related to HCC from The Cancer Genome Atlas Program (TCGA) was identified to explore the correlation between Astragalus membranaceus treatment and prognosis of HCC. Finally, Astragalus membranaceus-component-target network was established through SymMap.
Twenty five DEGs (15 up-regulated and 10 down-regulated) of Astragalus membranaceus treatment in HepG2 cells were identified. Among the 25 genes, MT1F, MT1G, MT1X and HMOX1 may play essential roles. Astragalus membranaceus mainly affects the Mineral absorption pathway in HCC. A total of 256 genes (p < 0.01) related to prognosis of HCC were identified, and MT1G is a common gene between prognosis genes and DEGs. Furthermore, Astragalus membranaceus may directly down-regulate MT1G through daidzein to promote ferroptosis of HCC cells and improve prognosis for HCC.
Our study provided new understandings of the pharmacological mechanisms by which Astragalus membranaceus improves the prognosis of HCC, and showed that the combination of transcriptomics and network pharmacology is helpful to explore mechanisms of TCM and traditional medicines from other nations.
Liu Z
，Ma H
，Lai Z
《BMC Complementary Medicine and Therapies》
ResearchGate
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