Network Pharmacology-Based Approach to Investigate the Mechanisms of Hedyotis diffusa Willd. in the Treatment of Gastric Cancer.
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ABSTRACT:
SUBMITTER: Liu X
PROVIDER: S-EPMC5954954 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background:As one of the most frequently diagnosed cancer diseases globally, colorectal cancer (CRC) remains an important cause of cancer-related death. Although the traditional Chinese herb Hedyotis diffusa Willd. (HDW) has been proven to be effective for treating CRC in clinical practice, its definite mechanisms have not been completely deciphered. Objective:The aim of our research is to systematically explore the multiple mechanisms of HDW on CRC. Methods:This study adopted the network pharmacology approach, which was mainly composed of active component gathering, target prediction, CRC gene collection, network analysis, and gene enrichment analysis. Results:The network analysis showed that 10 targets might be the therapeutic targets of HDW on CRC, namely, HRAS, PIK3CA, KRAS, TP53, APC, BRAF, GSK3B, CDK2, AKT1, and RAF1. The gene enrichment analysis implied that HDW probably benefits patients with CRC by modulating pathways related to cancers, infectious diseases, endocrine system, immune system, nervous system, signal transduction, cellular community, and cell motility. Conclusions:This study partially verified and predicted the pharmacological and molecular mechanism of HDW against CRC from a holistic perspective, which will also lay a foundation for the further experimental research and clinical rational application of HDW.
| S-EPMC5829364 | biostudies-literature
Project description:Hedyotis diffusa Willd (HDW) is one of the most well-known herbs used in the treatment of prostate cancer. However, the potential mechanisms of its anti-tumor effects have not been fully explored. Here, we applied a network pharmacology approach to explore the potential mechanisms of HDW against prostate cancer (PCa). We obtained 14 active compounds from HDW and 295 potential PCa related targets in total to construct a network, which indicated that quercetin and ursolic acid served as the main ingredients in HDW. Mitogen-activated Protein Kinase 8 (MAPK8), Interleukin 6 (IL6), Vascular Endothelial Growth Factor A (VEGFA), Signal Transducer and Activator of Transcription 3 (STAT3), Jun Proto-Oncogene (JUN), C-X-C Motif Chemokine Ligand 8 (CXCL8), Interleukin-1 Beta (IL1B), Matrix Metalloproteinase-9 (MMP9), C-C Motif Chemokine Ligand 2 (CCL2), RELA Proto-Oncogene (RELA), and CAMP Responsive Element Binding Protein 1 (CREB1) were identified as key targets of HDW in the treatment of PCa. The protein-protein interaction (PPI) cluster demonstrated that CREB1 was the seed in this cluster, indicating that CREB1 plays an important role in connecting other nodes in the PPI network. This enrichment demonstrated that HDW was highly related to translesion synthesis, unfolded protein binding, regulation of mitotic recombination, phosphatidylinositol and its kinase-mediated signaling, nucleotide excision repair, regulation of DNA recombination, and DNA topological change. The enrichment results also showed that the underlying mechanism of HDW against PCa may be due to its coordinated regulation of several cancer-related pathways, such as angiogenesis, cell differentiation, migration, apoptosis, invasion, and proliferation.
| S-EPMC6843553 | biostudies-literature
Project description:Hedyotis diffusa Willd (HDW) possesses heat-clearing, detoxification, anti-cancer, and anti-inflammatory properties. However, its effects on rheumatoid arthritis (RA) remain under-researched. In this study, we identified potential targets of HDW and collected differentially expressed genes of RA from the GEO dataset GSE77298, leading to the construction of a drug-component-target-disease regulatory network. The intersecting genes underwent GO and KEGG analysis. A PPI protein interaction network was established in the STRING database. Through LASSO, RF, and SVM-RFE algorithms, we identified the core gene MMP9. Subsequent analyses, including ROC, GSEA enrichment, and immune cell infiltration, correlated core genes with RA. mRNA-miRNA-lncRNA regulatory networks were predicted using databases like TargetScan, miRTarBase, miRWalk, starBase, lncBase, and the GEO dataset GSE122616. Experimental verification in RA-FLS cells confirmed HDW's regulatory impact on core genes and their ceRNA expression. We obtained 11 main active ingredients of HDW and 180 corresponding targets, 2150 RA-related genes, and 36 drug-disease intersection targets. The PPI network diagram and three machine learning methods screened to obtain MMP9, and further analysis showed that MMP9 had high diagnostic significance and was significantly correlated with the main infiltrated immune cells, and the molecular docking verification also showed that MMP9 and the main active components of HDW were well combined. Next, we predicted 6 miRNAs and 314 lncRNAs acting on MMP9, and two ceRNA regulatory axes were obtained according to the screening. Cellular assays indicated HDW inhibits RA-FLS cell proliferation and MMP9 protein expression dose-dependently, suggesting HDW might influence RA's progression by regulating the MMP9/miR-204-5p/MIAT axis. This innovative analytical thinking provides guidance and reference for the future research on the ceRNA mechanism of traditional Chinese medicine in the treatment of RA.
| S-EPMC10943027 | biostudies-literature
Project description:BackgroundGlobally, gastric cancer (GC) is recognized as the third leading cause of cancer-related deaths and the fifth most prevalent malignant disease. Multiple studies have indicated that Hedyotis diffusa Willd, in pinyin, called Bai Hua She Cao (BHSSC), a traditional Chinese medicine (TCM) is an herbal remedy for cancer treatment. However, the specific mechanisms underlying its anti-tumor properties and mode of action are still unclear.MethodsTo determine the role of BHSSC in GC, candidate target genes were selected from The Encyclopedia of Traditional Chinese Medicine (ETCM) and analyzed using network pharmacology, bioinformatics, and experimental validation. Differentially expressed genes (DEGs) associated with gastric cancer were obtained from RNA sequencing (RNA-seq) data sourced from The Cancer Genome Atlas-Stomach adenocarcinoma (TCGA-STAD). The Reactome Pathway was examined using Analysis Tools, while KEGG pathways were analyzed using KOBAS. Gene Ontology (GO) evaluations were performed using WebGestalt and DAVID. The relationships between proteins were investigated using the STRING database. Furthermore, cell viability, colony formation, and cell migration ability were conducted in gastric cancer cells, BGC-823 and MGC-803.ResultsNetwork pharmacology and bioinformatics analyses revealed a significant association between BHSSC and metabolic pathways. In vitro experiments demonstrated that BHSSC effectively suppressed gastric cancer cell proliferation and colony formation, inhibited cell migration, and activated the endoplasmic reticulum (ER) stress. Furthermore, it was found that enhancement of the expression of IRE1α and BIP is the mechanism by which BHSSC activates ER stress.ConclusionsThe findings suggest that BHSSC exerts its effects through modulation of metabolic pathways, leading to the suppression of cell proliferation, inhibition of cell migration, and activation of the endoplasmic reticulum. These results provide valuable insights into the mechanisms underlying the therapeutic effects of BHSSC in GC and support its potential as a novel treatment option.
| S-EPMC10990957 | biostudies-literature
Project description:Background Hepatocellular carcinoma (HCC) is characterized by poor diagnosis and high mortality. Novel and efficient therapeutic agents are urgently needed for the treatment. Hedyotis diffusa Willd (HDW) is used to treat cancers, especially HCC in China. Purpose The study aimed to identify the main anti-HCC extract in HDW and to explore the mechanism of the active extract. Materials and Methods The high-performance liquid chromatography-quadrupole-time of flight mass spectrometry (HPLC-QTOF-MS) method was used for the simultaneous determination of main compounds in the ethyl acetate fraction of HDW (EHDW). The toxicity test of different HDW fractions was carried out on larvae at 2 day-post-fertilization (dpf) for 72 h. The in vivo anti-HCC effect of different HDW fractions was evaluated on a zebrafish tumor model by immersion administration. The antiproliferative effect of HDW fractions was determined with MTT assay, as well as hematoxylin and eosin (HE) staining assay. Hoechst 33258 staining was used to observe changes in nucleus morphology. Flow cytometry analysis was used to investigate apoptosis induction. Western blot analysis was used to examine apoptosis-related proteins, and key proteins in JNK/Nur77 signaling pathway. SP600125 was served to validate the apoptotic mechanism. Results EHDW showed the strongest tumor cell growth inhibitory effect on zebrafish tumor model. Further study revealed that EHDW induced apoptosis in zebrafish tumor model and in cultured Hep3B cells. Meanwhile, it has been shown that the levels of BCL2-associated X (Bax), cytochrome c (cyto c), cleaved-caspase 3, and poly-ADP-ribose polymerase (PARP) cells were upregulated. In contrast, the level of antiapoptotic B cell lymphoma-2 (Bcl-2) was downregulated in Hep3B cells. Additionally, EHDW activated JNK/Nur77 pathway by increasing the levels of p-JNK(Thr183/Tyr185) and p-Nur77(Ser351). Further study showed that blockage of JNK by SP600125 reversed EHDW-induced JNK/Nur77 pathway and the downstream apoptotic proteins. Conclusion In conclusion, EHDW exerted the anti-HCC effect, which may be attributed to the activation of JNK/Nur77 pathway. This study supported the rationale of HDW as an HCC therapeutic agent.
| S-EPMC9433286 | biostudies-literature
Project description:BackgroundMahai capsules (MHC) have been deemed to be an effective herb combination for treatment of cardiovascular diseases (CVD) development and improvement of the life quality of CVD patients. To systematically explore the mechanisms of MHC in CVD, a network pharmacology approach mainly comprising target prediction, network construction, biological process and pathway analysis, and related diseases was adopted in this study.MethodsWe collected the bioactive compounds and potential targets of MHC through the TCMSP servers. Candidate targets related to CVD were collected from Therapeutic Targets Database and PharmGkb database and analyzed using ClueGO plugin in Cytoscape. KEGG pathway was enriched and analyzed through the EnrichR platform, and protein-protein interaction networks were calculated by STRING platform. The compound-target, target-disease, and compound-target-disease networks were constructed using Cytoscape.ResultsA total of 303 targets of the 57 active ingredients in MHC were obtained. The network analysis showed that PTGS2, PTGS1, HSP90, Scn1a, estrogen receptor, calmodulin, and thrombin were identified as key targets of MHC in the treatment of CVD. The functional enrichment analysis indicated that MHC probably produced the therapeutic effects against CVD by synergistically regulating many biological pathways, such as PI3K-Akt, TNF, HIF-1, FoxO, apoptosis, calcium, T-cell receptor, VEGF, and NF-kappa B signaling pathway.ConclusionsIn summary, the analysis of the complete profile of the pharmacological properties, as well as the elucidation of targets, networks, and pathways, can further illuminate that the underlying mechanisms of MHC in CVD might be strongly associated with its synergic regulation of inflammation, apoptosis, and immune function, and provide new clues for its future development of therapeutic strategies and basic research.
| S-EPMC7243029 | biostudies-literature
Project description:ObjectiveThis study aims to investigate the hepatoprotective effect and molecular mechanism of Hedyotis diffusa Willd. ethanol extract (HDWE) against isoniazid (INH)-induced liver injury in the zebrafish model.MethodsINH-induced liver injury model was established by adding an immersion bath of INH in 3 days post-fertilisation (dpf) healthy transgenic zebrafish with liver-specific fluorescence (L-FABP: EGFP). HDWE and INH were given to the zebrafish to observe liver morphology and pathology, fluorescence intensity, and the activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and superoxide dismutase (SOD), as well as the content of glutathione (GSH). The chemical composition of HDWE was analysed using high-performance liquid chromatography coupled with a quadrupole-time-of flight hybrid mass spectrometer (HPLC-Q-TOF-MS). The bioactive compounds, molecular targets and signalling pathways of HDWE were predicted using network pharmacology. Subsequently, molecular docking was adopted to analyze the affinities between the bioactive components and targets by Autodock. Finally, in vitro experiments were conducted to further verify the findings.ResultsOur findings showed that HDWE had a remarkable protective effect on INH-induced liver injury in zebrafish. Twenty compounds in HDWE were identified. Nineteen hub targets were identified as possible targets of HDWE, and a compound-target-pathway network was constructed. Nine bioactive compounds, ten molecular targets, and seven key signalling pathways were found to play a pivotal role in the hepatoprotective effect of HDWE against INH-induced liver injury. In vitro studies revealed that the important bioactive compound quercetin-3-O-sambubioside (QSA) could significantly reverse INH-induced cell viability decreases and had a significant effect on the associated targets predicted by network pharmacology and molecular docking.ConclusionIn this study, through the research of hepatoprotective effect of HDWE and bioinformatics analysis, the bioactive compounds, important pathways and key molecular targets were discovered. These findings could provide scientific evidence for the use of HDW in liver injury and prove to help explore its efficacy and the mechanism of action.
| S-EPMC9249440 | biostudies-literature
Project description:BackgroundZuojinwan (ZJW), a classic herbal formula, has been extensively used to treat gastric symptoms in clinical practice in China for centuries. However, the pharmacological mechanisms of ZJW still remain vague to date.MethodsIn the present work, a network pharmacology-based strategy was proposed to elucidate its underlying multi-component, multi-target, and multi-pathway mode of action against gastritis. First we collected putative targets of ZJW based on TCMSP and STITCH databases, and a network containing the interactions between the putative targets of ZJW and known therapeutic targets of gastritis was built. Then four topological parameters, "degree", "betweenness", "closeness", and "coreness" were calculated to identify the major targets in the network. Furthermore, the major hubs were imported to the Metacore database to perform a pathway enrichment analysis.ResultsA total of 118 nodes including 59 putative targets of ZJW were picked out as major hubs in terms of their topological importance. The results of pathway enrichment analysis indicated that putative targets of ZJW mostly participated in various pathways associated with anti-inflammation response, growth and development promotion and G-protein-coupled receptor signaling. More importantly, five putative targets of ZJW (EGFR, IL-6, IL-1?, TNF-? and MCP-1) and two known therapeutic targets of gastritis (CCKBR and IL-12?) and a link target NF-?B were recognized as active factors involved in the main biological functions of treatment, implying the underlying mechanisms of ZJW acting on gastritis.ConclusionZJW could alleviate gastritis through the molecular mechanisms predicted by network pharmacology, and this research demonstrates that the network pharmacology approach can be an effective tool to reveal the mechanisms of traditional Chinese medicine (TCM) from a holistic perspective.
| S-EPMC6211468 | biostudies-literature
Project description:BackgroundRheumatoid arthritis (RA) is a chronic inflammatory disease of the joints associated with systemic comorbidities. Sinomenium acutum is regarded as an effective traditional Chinese medicine (TCM) for the treatment of RA.Materials and methodsBased on network pharmacology and Gene Expression Omnibus (GEO) database, 33 RA-related differentially-expressed genes (DEGs) targeting active compounds of Sinomenium acutum were initially screened in our investigation.ResultsGene Ontology (GO) and Kyoto encyclopaedia of genes and genome (KEGG) analyses found the important involvement of these DEGs in osteoclast differentiation, and finally 5 core DEGs, including NCF4, NFKB1, CYBA, IL-1β and NCF1 were determined through protein-protein interaction (PPI) network. We also identified the related active component of Sinomenium acutum include Stigmasterol. Finally, in order to experimentally verify these results, a rat model of collagen-induced arthritis (CIA) was established, and subsequently treated with Stigmasterol solution.ConclusionSimilar to the healing effect of Indomethacin, Stigmasterol was observed to reduce the levels of inflammatory factors (IL-6 and IL-1β) and osteoclast differentiation-related factors (RANKL, ACP5 and Cathepsin K), which can also reduce the arthritis index score and alleviate the degree of pathological injury of rat ankle joints. The predictions and experimental data uncover the involvement of Stigmasterol, an active component of Sinomenium acutum, in regulation of osteoclast differentiation, exerting great medicinal potential in the treatment of RA.
| S-EPMC10007868 | biostudies-literature
Project description:ObjectivesThis study aims to study the material basis and effective mechanism of musk for ischemic stroke (IS) based on the network pharmacology approach.MethodsWe collected the chemical components and target gene of musk from the BATMAN-TCM analytical platform and identified ischemic stroke-related targets from the following databases: DisGeNET, NCBI-Gene, HPO, OMIM, DrugBank, and TTD. The targets of musk and IS were uploaded to the String database to construct the protein-protein interaction (PPI) network, and then, the key targets were analyzed by topological methods. At last, the function biological process and signaling pathways of key targets were carried out by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis and cluster analysis by using the Database for Annotation, Visualization, and Integrated Discovery (DAVID) server and Metascape platform.ResultsA total of 29 active compounds involving 1081 predicted targets were identified in musk and there were 1104 IS-related targets. And 88 key targets of musk for IS were obtained including AKT1, MAPK1/3, TP53, TNF, SRC, FOS, CASP3, JUN, NOS3, and IL1B. The GO and KEGG enrichment analysis suggested that these key targets are mainly involved in multiple pathways which participated in TNF signaling pathway, estrogen signaling pathway, prolactin signaling pathway, neurotrophin signaling pathway, T-cell receptor signaling pathway, cAMP signaling pathway, FoxO signaling pathway, and HIF1 signaling pathway.ConclusionThis study revealed that the effective mechanisms of musk against IS would be associated with the regulation of apoptosis, inflammatory response, and gene transcription.
| S-EPMC7354650 | biostudies-literature