A network pharmacology approach to investigating the mechanism of Tanshinone IIA for the treatment of liver fibrosis

2020 ◽  
Vol 253 ◽  
pp. 112689 ◽  
Author(s):  
Miao-Juan Shi ◽  
Xiu-Li Yan ◽  
Ben-Sheng Dong ◽  
Wen-Na Yang ◽  
Shi-Bing Su ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Tanshinone Iia ◽  
Network Pharmacology

scholarly journals Active Compounds Derived from Fuzheng Huayu Formula Protect Hepatic Parenchymal Cells from Apoptosis Based on Network Pharmacology and Transcriptomic Analysis

Molecules ◽  
2019 ◽  
Vol 24 (2) ◽  
pp. 338 ◽  
Author(s):  
Rong Wu ◽  
Shu Dong ◽  
Fei-Fei Cai ◽  
Xiao-Le Chen ◽  
Meng-Die Yang ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Cell Apoptosis ◽  
Caspase 3 ◽  
Stellate Cell ◽  
Parenchymal Cell ◽  
Transcriptomic Analysis ◽  
Tanshinone Iia ◽  
Network Pharmacology ◽  
Active Compounds ◽  
Parenchymal Cells

Fuzheng huayu formula (FZHY), an antifibrotic traditional Chinese medicine, is frequently used for the treatment of liver fibrosis. In this study, network analysis, transcriptomic analysis, assays of cell apoptosis, viability and protein expression were used for investigating the effects and mechanisms of compounds derived from FZHY on hepatic parenchymal cell (HPC) protection and hepatic stellate cell activation. Network pharmacology analysis found that 6 major compounds and 39 potential targets were important network nodes. Our analysis predicted that the active compounds of FZHY, including hederagenin, luteolin and tanshinone IIA inhibited cell apoptosis (p < 0.05), increased PI3K expression and reduced cleaved caspase 3 expression and the Bax/Bcl-w ratio (p < 0.05) in L02 cells that had apoptosis induced by TNF-α. Few significant changes caused by FZHY, hederagenin, luteolin and tanshinone IIA were observed in hepatic stellate Lx2 cells upon TGF-β1 induction. These data suggest that FZHY is active against liver fibrosis, protects hepatic parenchymal cells from apoptosis, and recovers liver function, possibly through the effects of its active compounds hederagenin, luteolin and tanshinone IIA and is involved in the inhibition of apoptosis in HPCs, possibly through regulating the PI3K, ERK, cleaved caspase 3 and Bax/Bcl-w levels.

scholarly journals Insights into the molecular mechanisms of Huangqi decoction on liver fibrosis via computational systems pharmacology approaches

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Biting Wang ◽  
Zengrui Wu ◽  
Weihua Li ◽  
Guixia Liu ◽  
Yun Tang
Keyword(s):  
Molecular Docking ◽  
Liver Fibrosis ◽  
Molecular Mechanisms ◽  
Docking Simulation ◽  
Chinese Herbs ◽  
Network Pharmacology ◽  
Bipartite Network ◽  
Metabolomics Data ◽  
Metabolic Products ◽  
Compound Target

Abstract Background The traditional Chinese medicine Huangqi decoction (HQD) consists of Radix Astragali and Radix Glycyrrhizae in a ratio of 6: 1, which has been used for the treatment of liver fibrosis. In this study, we tried to elucidate its action of mechanism (MoA) via a combination of metabolomics data, network pharmacology and molecular docking methods. Methods Firstly, we collected prototype components and metabolic products after administration of HQD from a publication. With known and predicted targets, compound-target interactions were obtained. Then, the global compound-liver fibrosis target bipartite network and the HQD-liver fibrosis protein–protein interaction network were constructed, separately. KEGG pathway analysis was applied to further understand the mechanisms related to the target proteins of HQD. Additionally, molecular docking simulation was performed to determine the binding efficiency of compounds with targets. Finally, considering the concentrations of prototype compounds and metabolites of HQD, the critical compound-liver fibrosis target bipartite network was constructed. Results 68 compounds including 17 prototype components and 51 metabolic products were collected. 540 compound-target interactions were obtained between the 68 compounds and 95 targets. Combining network analysis, molecular docking and concentration of compounds, our final results demonstrated that eight compounds (three prototype compounds and five metabolites) and eight targets (CDK1, MMP9, PPARD, PPARG, PTGS2, SERPINE1, TP53, and HIF1A) might contribute to the effects of HQD on liver fibrosis. These interactions would maintain the balance of ECM, reduce liver damage, inhibit hepatocyte apoptosis, and alleviate liver inflammation through five signaling pathways including p53, PPAR, HIF-1, IL-17, and TNF signaling pathway. Conclusions This study provides a new way to understand the MoA of HQD on liver fibrosis by considering the concentrations of components and metabolites, which might be a model for investigation of MoA of other Chinese herbs.

scholarly journals Network Pharmacological Analysis and Experimental Validation of the Mechanisms of Action of Si-Ni-San Against Liver Fibrosis

2021 ◽  
Vol 12 ◽  
Author(s):  
Siliang Wang ◽  
Cheng Tang ◽  
Heng Zhao ◽  
Peiliang Shen ◽  
Chao Lin ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Hepatic Stellate Cells ◽  
Stellate Cells ◽  
Mechanisms Of Action ◽  
Network Pharmacology ◽  
Related Factor ◽  
Alcoholic Fatty Liver ◽  
Ppar Γ ◽  
Liver Tissues

Background: Si-Ni-San (SNS), a commonly used traditional Chinese medicine (TCM) formula, has potency against liver diseases, such as hepatitis and non-alcoholic fatty liver disease (NAFLD). However, the therapeutic efficacy and pharmacological mechanisms of action of SNS against liver fibrosis remain largely unclear.Methods: A carbon tetrachloride (CCl4)-induced liver fibrosis mouse model was adopted for the first time to investigate the beneficial effects of SNS on liver fibrosis. The potential mechanisms of action of SNS were explored using the network pharmacology-based strategy and validated with the aid of diverse assays.Results: SNS treatment reduced collagen and ECM deposition, downregulated fibrosis-related factor (hyaluronic acid and laminin) contents in serum, maintained the morphological structure of liver tissue, and improved liver function in the liver fibrosis model. Based on network pharmacology results, apoptosis, inflammation and angiogenesis, together with the associated pathways (including VEGF, TNF, caspase, PPAR-γ and NF-κB), were identified as the mechanisms underlying the effects of SNS on liver fibrosis. Further in vivo experiments validated the significant mitigatory effects of SNS on inflammatory infiltration and pro-inflammatory cytokine contents (IFNγ, IL-1β and TGF-β1) in liver tissues of mice with liver fibrosis. SNS suppressed pathologic neovascularization as well as levels of VEGFR1, VEGF and VEGFR2 in liver tissues. SNS treatment additionally inhibited hepatic parenchyma cell apoptosis in liver tissues of mice with liver fibrosis and regulated apoptin expression while protecting L02 cells against apoptosis induced by TNF-α and Act D in vitro. Activation of hepatic stellate cells was suppressed and the balance between MMP13 and TIMP1 maintained in vitro by SNS. These activities may be associated with SNS-induced NF-κB suppression and PPAR-γ activation.Conclusion: SNS effectively impedes liver fibrosis progression through alleviating inflammation, ECM accumulation, aberrant angiogenesis and apoptosis of hepatic parenchymal cells along with inhibiting activation of hepatic stellate cells through effects on multiple targets and may thus serve as a novel therapeutic regimen for this condition.

scholarly journals Elucidating the Mechanisms of Hugan Buzure Granule in the Treatment of Liver Fibrosis via Network Pharmacology

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Yi Zhu ◽  
Ming Qiao ◽  
Jianhua Yang ◽  
Junping Hu
Keyword(s):  
Liver Fibrosis ◽  
Rna Polymerase Ii ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Docking Simulation ◽  
Interaction Network ◽  
Network Pharmacology ◽  
Transcription Activator ◽  
Active Ingredients ◽  
Oxidoreductase Activity

Objective. To holistically explore the latent active ingredients, targets, and related mechanisms of Hugan buzure granule (HBG) in the treatment of liver fibrosis (LF) via network pharmacology. Methods. First, we collected the ingredients of HBG by referring the TCMSP server and literature and filtered the active ingredients though the criteria of oral bioavailability ≥30% and drug-likeness index ≥0.18. Second, herb-associated targets were predicted and screened based on the BATMAN-TCM and SwissTargetPrediction platforms. Candidate targets related to LF were collected from the GeneCards and OMIM databases. Furthermore, the overlapping target genes were used to construct the protein-protein interaction network and “drug-compound-target-disease” network. Third, GO and KEGG pathway analyses were carried out to illustrate the latent mechanisms of HBG in the treatment of LF. Finally, the combining activities of hub targets with active ingredients were further verified based on software AutoDock Vina. Results. A total of 25 active ingredients and 115 overlapping target genes of HBG and LF were collected. Besides, GO enrichment analysis exhibited that the overlapping target genes were involved in DNA-binding transcription activator activity, RNA polymerase II-specific, and oxidoreductase activity. Simultaneously, the key molecular mechanisms of HBG against LF were mainly involved in PI3K-AKT, MAPK, HIF-1, and NF-κB signaling pathways. Also, molecular docking simulation demonstrated that the key targets of HBG for antiliver fibrosis were IL6, CASP3, EGFR, VEGF, and MAPK. Conclusion. This work validated and predicted the underlying mechanisms of multicomponent and multitarget about HBG in treating LF and provided a scientific foundation for further research.

scholarly journals Development of A Novel Anti-Liver Fibrosis Formula with luteolin, licochalcone A, aloe-emodin and acacetin by network pharmacology and transcriptomics analysis

2020 ◽  
Author(s):  
Yuan Zhou ◽  
Rong Wu ◽  
Fei-Fei Cai ◽  
Wen-Jun Zhou ◽  
Yi-Yu Lu ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Topological Analysis ◽  
Deficiency Syndrome ◽  
Network Pharmacology ◽  
Individual Compound ◽  
Licochalcone A ◽  
Spleen Deficiency ◽  
Ppar Signaling ◽  
Aloe Emodin ◽  
Spleen Deficiency Syndrome

Abstract Background: Liver fibrosis leads to loss of liver function. Xiaoyaosan decoction (XYS) as a classical Traditional Chinese Medicine (TCM) formula is used to treatment liver fibrosis in clinical and alleviated CCl4-induced liver fibrosis in our previous study.Xiaoyaosan decoction was composed of many ingredients, and the active ingredients is not clear. The Aim of this study is to explore the clarified compounds or compound combinations to treat liver fibrosis.Methods: Network pharmacology combined with transcriptomics analysis were used to analyze the Xiaoyaosan decoction (XYS) and liver depression and spleen deficiency syndrome liver fibrosis. This consisted constructed XYS-Syndrome-liver fibrosis network, the predict formula named LLAAF was develop from the network by topological analysis according to network stability. The anti-fibrosis effect was evaluated by in vitro and in vivo study.Results: According to the network XYS-Syndrome-liver fibrosis network, luteolin, licochalcone A, aloe-emodin, and acacetin formula (LLAAF) was predicted from 8 key compounds and 255 combinations in XYS, and LLAAF had a synergistic effect on the proliferation inhibition of hepatic stellate cells (HSCs) compared to each individual compound alone. The treatment of XYS and LLAAF showed a similar anti-liver fibrotic effect that reduced histopathological changes of liver fibrosis, Hyp content and levels of α-SMA and collagen I in CCl4-induced liver fibrosis in rat. Transcriptomics analysis revealed LLAAF regulated PI3K-Akt, AMPK, FoxO, Jak-STAT3, P53, cell cycle, focal adhesion, and PPAR signaling. Furthermore, LLAAF was confirmed to regulate Jak-STAT and PI3K-Akt-FoxO signaling in vitro and in vivo.Conclusions: This study developed a novel anti-liver formula, LLAAF from XYS demonstrated the anti-liver fibrotic activity may be involved in the regulation of Jak-STAT and PI3K-Akt-FoxO signaling.

scholarly journals Mechanism of Salviae Miltiorrhizae Radix et Rhizoma in the treatment of knee osteoarthritis based on network pharmacology

2020 ◽  
Author(s):  
Xiaoqing Shi ◽  
Haosheng Zhang ◽  
Yue Hu ◽  
Xiaochen Li ◽  
Songjiang Yin ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Knee Osteoarthritis ◽  
Molecular Mechanism ◽  
Tanshinone Iia ◽  
Inflammatory Factors ◽  
Venn Diagram ◽  
Network Pharmacology ◽  
Bioinformatics Analyses ◽  
Salviae Miltiorrhizae ◽  
Salviae Miltiorrhizae Radix

Abstract Objective: The molecular mechanism of Salviae Miltiorrhizae Radix et Rhizoma (SMRR) in the treatment of knee osteoarthritis (KOA) was analyzed based on network pharmacology.Methods: Active components and potential targets of SMRR were obtained from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). KOA targets were obtained from the OMIM, DisGeNET, DrugBank, PharmGKB and GeneCards Databases. The potential targets of SMRR in the treatment of KOA were identified by Venn diagram. A protein-protein interaction network was generated with the STRING database. Visualization of the interactions in a potential pharmacodynamic component-target network was accomplished with Cytoscape software. The DAVID database and R software were used for Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway annotation analyses of common targets. Molecular docking of the potential leading components, as determined by efficacy with the core target molecules, was performed with Discovery Studio.Results: Fifty-seven potential pharmacodynamic components and 58 potential targets of SMRR in the treatment of KOA were found. Bioinformatics analyses showed that the IL-17, HIF-1 and TNF signaling pathways, as well as the AGE-RAGE signaling pathway in cases of diabetic complications, are related to the molecular mechanism of SMRR in the treatment of KOA. Molecular docking results showed that luteolin, Tanshinone IIA, Cryptotanshinone and other components of SMRR had strong affinity for MYC, STAT3, CASP3, JUN, CCND1, PTGS2, EGFR, MAPK1, AKT1, VEGFA and other targets.Conclusion: SMRR indirectly regulates IL-17, HIF-1, TNF and other signal transduction pathways by regulating the expression of proteins including PTGS2, MAPK1, EGFR and CASP3, thus playing a role in promoting chondrocyte proliferation, improving microcirculation, eliminating free radicals, and inhibiting inflammatory factors.

scholarly journals Exploring the Mechanism of Action Compound-Xueshuantong Capsule in Diabetic Retinopathy Treatment Based on Network Pharmacology

2020 ◽  
Vol 2020 ◽  
pp. 1-12
Author(s):  
Haoran Li ◽  
Biao Li ◽  
Yanlin Zheng
Keyword(s):  
Diabetic Retinopathy ◽  
Active Ingredient ◽  
Diabetic Complications ◽  
Interaction Network ◽  
Signal Pathway ◽  
Tanshinone Iia ◽  
Network Pharmacology ◽  
Active Components ◽  
Disease Treatment

Aim of the Study. To study the mechanism of Compound-Xueshuantong Capsule in diabetic retinopathy treatment based on network pharmacology. Materials and Methods. The components with oral bioavailability ≥30% and drug similarity ≥0.18 were screened by the Traditional Chinese Medicine System Pharmacology Database and Analysis Platform (TCMSP), and the effective grouping of Compound-Xueshuantong Capsule was obtained. At the same time, the targets of each drug active component in the Compound-Xueshuantong Capsule were obtained by searching the TCMSP. The effective components and targets of the Compound-Xueshuantong Capsule were annotated by the UniProt database, and the disease treatment targets were searched by the GeneCards database. The disease treatment target is intersected with the drug target and the Wayne diagram is drawn by VennDiagram. The active ingredient targets of the intersection and Compound-Xueshuantong Capsule were inputted into Cytoscape 3.7.2 software to construct the active ingredient-target-disease interaction network. The above targets were inputted into the String database for protein-protein interaction network prediction. Finally, by using the DAVID database, GO and KEGG enrichment analysis was carried out to reveal the potential signal pathway of the Compound-Xueshuantong Capsule in diabetic retinopathy treatment. Results. 93 active components of the Compound-Xueshuantong Capsule and 92 targets for treating diabetic retinopathy were screened. The main active components of the Compound-Xueshuantong Capsule in treating diabetic retinopathy were quercetin, luteolin, kaempferol, beta-sitosterol, isorhamnetin, and tanshinone IIa. The effect of the Compound-Xueshuantong Capsule on diabetic retinopathy may be related to IL6, EFGR, CASP3, and VEGFA. In addition, the treatment of diabetic retinopathy mainly involves in the regulation of nuclear receptors and transcription factors in vivo. The target of the Compound-Xueshuantong Capsule in diabetic retinopathy treatment is significantly enriched in the AGE-RAGE signal pathway, TNF signal pathway, HIF-1 signal pathway, and VEGF signal pathway in diabetic complications. Conclusion. Compound-Xueshuantong Capsule can treat diabetic retinopathy through multitarget, multipathway, and multipathway regulation of the biomolecular network. The potential biological mechanism of the Compound-Xueshuantong Capsule in diabetic retinopathy treatment may be related to the AGE-RAGE signal pathway, TNF signal pathway, HIF-1 signal pathway, and VEGF signal pathway in diabetic complications, but these findings still need to be confirmed by further clinical research.

Molecular Mechanisms of TanshinoneIIA in Hepatocellular carcinomatherapy via WGCNA-based Network Pharmacology Analysis

2021 ◽  
Author(s):  
Han Zhao ◽  
Jing Guo ◽  
Qingjia Chi ◽  
Meng Fang
Keyword(s):  
Hepatocellular Carcinoma ◽  
Clinical Features ◽  
Molecular Mechanisms ◽  
Tanshinone Iia ◽  
Network Pharmacology ◽  
Specific Gene ◽  
Advanced Tumor Stage ◽  
Overlapping Genes ◽  
Hub Genes ◽  
Advanced Tumor

Abstract Background: Hepatocellular carcinoma (HCC) is a worldwide malignant tumor that caused irreversible consequences. The studies of Tanshinone IIA showed that Tanshinone IIA has played a notable role in HCC treatment. However, it is still to be investigated to discover the potential targets and associating mechanism of Tanshinone IIA against HCC. Methods: To analyze the correlation between genes and specific clinical features, we applied weighted gene co-expression network analysis (WGCNA), which can help us identify the targets of Tanshinone IIA related to the clinical features of Hepatocellular carcinoma. Results: We screened out 105 overlapping genes by integrating the predicted targets of Tanshinone IIA and the gene expression profile of HCC from the Cancer Genome Atlas (TCGA) database. For WGCNA, we used the RNA-seq profile of the overlapping genes and the related clinical information of HCC from TCGA. And 23 genes related to clinical tumor grade in the important module (R2 = 0.37) were imported for Gene Ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis and protein-protein interaction (PPI) analysis. Compared to the key genes in the significant module from WGCNA with the high connectivity nodes from the PPI network, we can analyze three hub genes, AURKB, KIF11, and PLK1, for further verification. We tested the binding of Tanshinone IIA to the targets of Hepatocellular carcinoma using Autodock Vina. The survival curve validated that the three hub genes represented a poor prognosis. Receiver operating characteristic (ROC) curves demonstrated that the three hub genes were effective in diagnosis. The mRNA expression of the three hub genes was upregulated in the HCC than the normal. AURKB, KIF11 and PLK1 were further upregulated in advanced tumor stage and grade. Moreover, AURKB, KIF11 and PLK1 also had higher protein expression in HCC tissues. Conclusions: In the study, WGCNA revealed grade-specific gene modules, indicating that Tanshinone IIA probably plays its therapeutical effect in the differentiation process of HCC. And the study partly interpreted the pharmacological mechanism of Tanshinone IIA against HCC.

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