Deciphering the molecular mechanism of tetrandrine in inhibiting hepatocellular carcinoma and increasing sorafenib sensitivity by combining network pharmacology and experimental evaluation

This study elucidated the potential molecular mechanism of chrysin in hepatocellular carcinoma (HCC) treatment using network pharmacology and in vitro experiments. Chrysin and candidate targets of HCC were obtained from the TCMSP and DrugBank databases, followed by mapping and screening of chrysin and HCC targets to identify the core targets of chrysin in HCC treatment. The interaction of chrysin and its targets, including CDK1, CDK5, as well as MMP9, were evaluated by molecular docking. The STRING database and Cytoscape (version 3.8.2) software were used to construct protein interactions and component-target networks of the core targets. Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathway enrichment analysis of the core target genes were performed using the DAVID database. Network pharmacology results showed that chrysin treatment of HCC was mainly related to cell proliferation and cell cycle. Accordingly, the cell counting kit-8 method and flow cytometry were used to detect the cell viability and cell cycle of hepatocarcinoma cells HCCLM3 and BEL-7402 in vitro. A total of 142 compound targets of chrysin, 12,179 HCC-related targets, and 116 intersecting targets were screened. The first 20 GO biological annotations of 17 core targets and the first 20 KEGG pathways mainly involved cell proliferation and cell cycle. In vitro experiments showed that chrysin inhibits the proliferation of human hepatocarcinoma cells (HCCLM3 and BEL-7402) in a dose-dependent manner. Moreover, chrysin induced cell cycle arrest in HCCLM3 and BEL-7402 cells in the G2 phase, and the expression was downregulated of cyclin-dependent kinases (CDKs), CDK2 and CDK4. Chrysin can offset HCC mainly by regulating the cell cycle and inhibiting cell proliferation. The network pharmacology results were verified, providing the basis for further study on the mechanism of chrysin intervention in HCC.

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Preliminary Study on the Mechanism of Carvacrol Regulating Hepatocellular Carcinoma Based on Network Pharmacology

Letters in Drug Design & Discovery ◽

10.2174/1570180816666190516105906 ◽

2019 ◽

Vol 16 (11) ◽

pp. 1286-1295

Author(s):

Sha Li ◽

Haixia Zhao ◽

Lidao Bao

Keyword(s):

Hepatocellular Carcinoma ◽

Western Blot ◽

Target Prediction ◽

Network Pharmacology ◽

Literature Mining ◽

Active Compounds ◽

Prediction Server ◽

Preliminary Study ◽

Alignment Analysis ◽

Endogenous Interactions

Objective: To predict and analyze the target of anti-Hepatocellular Carcinoma (HCC) in the active constituents of Safflower by using network pharmacology. Methods: The active compounds of safflower were collected by TCMSP, TCM-PTD database and literature mining methods. The targets of active compounds were predicted by Swiss Target Prediction server, and the target of anti-HCC drugs was collected by DisGeNET database. The target was subjected to an alignment analysis to screen out Carvacrol, a target of safflower against HCC. The mouse HCC model was established and treated with Carvacrol. The anti-HCC target DAPK1 and PPP2R2A were verified by Western blot and co-immunoprecipitation. Results: A total of 21 safflower active ingredients were predicted. Carvacrol was identified as a possible active ingredient according to the five principles of drug-like medicine. According to Carvacrol's possible targets and possible targets of HCC, three co-targets were identified, including cancer- related are DAPK1 and PPP2R2A. After 20 weeks of Carvacrol treated, Carvacrol group significantly increased on DAPK1 levels and decreased PPP2R2A levels in the model mice by Western blot. Immunoprecipitation confirmed the endogenous interaction between DAPK1 and PPP2R2A. Conclusion: Safflower can regulate the development of HCC through its active component Carvacrol, which can affect the expression of DAPK1 and PPP2R2A proteins, and the endogenous interactions of DAPK1 and PPP2R2A proteins.

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Bioactive constituents and the molecular mechanism of Curcumae Rhizoma in the treatment of primary dysmenorrhea based on network pharmacology and molecular docking

Phytomedicine ◽

10.1016/j.phymed.2021.153558 ◽

2021 ◽

pp. 153558

Author(s):

Huangjin Tong ◽

Mengting Yu ◽

Chenghao Fei ◽

De JI ◽

Jiajia Dong ◽

...

Keyword(s):

Molecular Docking ◽

Molecular Mechanism ◽

Network Pharmacology ◽

Primary Dysmenorrhea ◽

Bioactive Constituents

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Molecular mechanism underlying the hypolipidemic effect of Shanmei Capsule based on network pharmacology and molecular docking

Technology and Health Care ◽

10.3233/thc-218023 ◽

2021 ◽

Vol 29 ◽

pp. 239-256

Author(s):

Qian Wang ◽

Lijing Du ◽

Jiana Hong ◽

Zhenlin Chen ◽

Huijian Liu ◽

...

Keyword(s):

Molecular Docking ◽

Signaling Pathway ◽

Molecular Mechanism ◽

Kegg Pathway ◽

Network Pharmacology ◽

Pathway Enrichment Analysis ◽

Signal Pathways ◽

Hypolipidemic Effect ◽

Active Ingredients ◽

Pathway Enrichment

BACKGROUND: Shanmei Capsule is a famous preparation in China. However, the related mechanism of Shanmei Capsule against hyperlipidemia has yet to be revealed. OBJECTIVE: To elucidate underlying mechanism of Shanmei Capsule against hyperlipidemia through network pharmacology approach and molecular docking. METHODS: Active ingredients, targets of Shanmei Capsule as well as targets for hyperlipidemia were screened based on database. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment were performed via Database for Annotation, Visualization, and Integrated Discovery (DAVID) 6.8 database. Ingredient-target-disease-pathway network was visualized utilizing Cytoscape software and molecular docking was performed by Autodock Vina. RESULTS: Seventeen active ingredients in Shanmei Capsule were screened out with a closely connection with 34 hyperlipidemia-related targets. GO analysis revealed 40 biological processes, 5 cellular components and 29 molecular functions. A total of 15 signal pathways were enriched by KEGG pathway enrichment analysis. The docking results indicated that the binding activities of key ingredients for PPAR-α are equivalent to that of the positive drug lifibrate. CONCLUSIONS: The possible molecular mechanism mainly involved PPAR signaling pathway, Bile secretion and TNF signaling pathway via acting on MAPK8, PPARγ, MMP9, PPARα, FABP4 and NOS2 targets.

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SPARC regulates ferroptosis induced by sorafenib in human hepatocellular carcinoma

Cancer Biomarkers ◽

10.3233/cbm-200101 ◽

2021 ◽

pp. 1-9

Author(s):

Hong-Wei Hua ◽

Hao-Sheng Jiang ◽

Ling Jia ◽

Yi-Ping Jia ◽

Yu-Lan Yao ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Molecular Mechanism ◽

Cancer Progression ◽

Hepg2 Cells ◽

Cytotoxic Effect ◽

Cell Viability Assay ◽

Viability Assay ◽

Ldh Release ◽

Related Proteins ◽

Hcc Cells

BACKGROUND: Secreted protein acidic and rich in cysteine (SPARC) is implicated in cancer progression, but its role and associated molecular mechanism in the sorafenib sensitivity of hepatocellular carcinoma cells (HCC) remains elusive. METHODS: Human HCC cell lines Hep3B and HepG2 were treated with sorafenib alone or combined with activator or inhibitor of ferroptosis. Cell viability assay, reactive oxygen species (ROS) assay, lactate dehydrogenase (LDH) assay and western blot were used to study the regulatory mechanism of SPARC on HCC cells. RESULTS: Overexpression of SPARC enhanced the cytotoxic effect of sorafenib in Hep3B and HepG2 cells compared with parental cells. Depletion of SPARC decreased the cytotoxic effect of sorafenib in Hep3B and HepG2 cells compared with parental cells. Moreover, overexpression of SPARC significantly induced LDH release, whereas depletion of SPARC suppressed the release of LDH in Hep3B and HepG2 cells. Inhibition of ferroptosis exerted a clear inhibitory role against LDH release, whereas activation of ferroptosis promoted the release of LDH in HCC cells, as accompanied with deregulated expression of ferroptosis-related proteins. Furthermore, overexpression of SPARC induced oxidative stress, whereas depletion of SPARC suppressed the production of ROS. Deferoxamine (DFX)-induced inhibition of ferroptosis suppressed the production of ROS, while activation of ferroptosis promoted the contents of ROS in HCC cells exposed to sorafenib. CONCLUSION: Our findings give a better understanding of ferroptosis and its molecular mechanism in HCC cells that is regulated by SPARC in response to sorafenib.

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CircSOD2 induced epigenetic alteration drives hepatocellular carcinoma progression through activating JAK2/STAT3 signaling pathway

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-020-01769-7 ◽

2020 ◽

Vol 39 (1) ◽

Author(s):

Zhongwei Zhao ◽

Jingjing Song ◽

Bufu Tang ◽

Shiji Fang ◽

Dengke Zhang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Cycle ◽

Cell Migration ◽

Real Time ◽

Signaling Pathway ◽

Molecular Mechanism ◽

Stat3 Signaling ◽

Stat3 Signaling Pathway ◽

Signaling Axis

Abstract Background Emerging evidence suggests that circular RNAs play critical roles in disease development especially in cancers. Previous genome-wide RNA-seq studies found that a circular RNA derived from SOD2 gene was highly upregulated in hepatocellular carcinoma (HCC), however, the role of circSOD2 in HCC remains largely unknown. Methods The expression profiling of circSOD2 and microRNA in HCC patients were assessed by Real-Time Quantitative Reverse Transcription PCR (qRT-PCR). SiRNA or CRISPR-CAS9 were used to silence gene expression. The biological function of circSOD2 in HCC was investigated using in vitro and in vivo studies including, trans-well cell migration, cell apoptosis, cell cycle, CCK8, siRNA interference, western blots, and xenograft mouse model. The underlying molecular mechanism was determined by Chromatin Immunoprecipitation quantitative real time PCR (ChIP-qPCR), bioinformatic analysis, biotin-pull down, RNA immunoprecipitation, 5-mc DNA pulldown and luciferase assays. Results In accordance with previous sequencing results, here, we demonstrated that circSOD2 was highly expressed in HCC tumor tissues compared with normal liver tissues. Mechanically, we showed that histone writer EP300 and WDR5 bind to circSOD2 promoter and trigger its promoter H3K27ac and H3K4me3 modification, respectively, which further activates circSOD2 expression. SiRNA mediated circSOD2 suppression impaired liver cancer cell growth, cell migration, prohibited cell cycle progression and in vivo tumor growth. By acting as a sponge, circSOD2 inhibits miR-502-5p expression and rescues miR-502-5p target gene DNMT3a expression. As a DNA methyltransferase, upregulated DNMA3a suppresses SOCS3 expression by increasing SOCS3 promoter DNA methylation. This event further accelerates SOCS3 downstream JAK2/STAT3 signaling pathway activation. In addition, we also found that activated STAT3 regulates circSOD2 expression in a feedback way. Conclusion The novel signaling axis circSOD2/miR-502-5p/DNMT3a/JAK2/STAT3/circSOD2 provides a better understanding of HCC tumorigenesis. The molecular mechanism underlying this signaling axis offers new prevention and treatment of HCC.

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Insight into the molecular mechanism of a herbal injection by integrating network pharmacology and in vitro

Journal of Ethnopharmacology ◽

10.1016/j.jep.2015.07.016 ◽

2015 ◽

Vol 173 ◽

pp. 91-99 ◽

Cited By ~ 10

Author(s):

Yi-min Ma ◽

Xin-zhuang Zhang ◽

Zhen-zhen Su ◽

Na Li ◽

Liang Cao ◽

...

Keyword(s):

Molecular Mechanism ◽

Network Pharmacology ◽

Insight Into

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Molecular Mechanism of The Effect of Huanglian Jiedu Decoction On Ulcerative Colitis Based On Network Pharmacology And Molecular Docking

10.21203/rs.3.rs-807332/v1 ◽

2021 ◽

Author(s):

Jing Yang ◽

Chao-Tao Tang ◽

Ruiri Jin ◽

Bixia Liu ◽

Peng Wang ◽

...

Keyword(s):

Ulcerative Colitis ◽

Molecular Docking ◽

Molecular Mechanism ◽

Target Genes ◽

Signal Pathway ◽

Intestinal Barrier Function ◽

Network Pharmacology ◽

Bioactive Components ◽

Ppi Network ◽

Active Components

Abstract Huanglian jiedu decoction (HLJDD) is a heat-clearing and detoxifying agent composed of four kinds of Chinese herbal medicine. Previous studies have shown that HLJDD can improve the inflammatory response of ulcerative colitis (UC) and maintain intestinal barrier function. However, its molecular mechanism is not completely clear. In this study, we verified the bioactive components (BCI) and potential targets of HLJDD in the treatment of UC by means of network pharmacology and molecular docking, and constructed the pharmacological network and PPI network. Then the core genes were enriched by GO and KEGG. Finally, the bioactive components were docked with the key targets to verify the binding ability between them. A total of 54 active components related to UC were identified. Ten genes are considered to be very important to PPI network. Functional analysis showed that these target genes were mainly involved in the regulation of cell response to different stimuli, IL-17 signal pathway and TNF signal pathway. The results of molecular docking showed that the active components of HLJDD had good affinity with Hub gene. This study systematically elucidates the "multi-component, multi-target, multi-pathway" mechanism of anti-UC with HLJDD for the first time, suggesting that HLJDD or its active components may be candidate drugs for the treatment of ulcerative colitis.

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