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A Mechanism of Action Study on Danggui Sini Decoction to Discover Its Therapeutic Effect on Gastric Cancer.

ABSTRACT: Danggui Sini Decoction (DSD), a classic Chinese herb medicine (CHM) formula, has been used to treat various diseases in China for centuries. However, it remains challenging to reveal its mechanism of action through conventional pharmacological methods. Here, we first explored the mechanism of action of DSD with the assistance of network pharmacology and bioinformatic analysis tools, and found a potential therapeutic effect of DSD on cancer. Indeed, our in vivo experiment demonstrated that oral administration of DSD could significantly inhibit the growth of xenografted gastric cancer (GC) on mice. The subsequent enrichment analyses for 123 candidate core targets evacuated from the drug/disease-target protein-protein interaction network showed that DSD could affect the key biological processes involving the survival and growth of GC cells, such as apoptosis and cell cycle, and the disturbance of these biological processes is likely attributed to the simultaneous inhibition of multiple signaling pathways, including PI3K/Akt, MAPK, and p53 pathways. Notably, these in silico results were further validated by a series of cellular functional and molecular biological assays in vitro. Moreover, molecular docking analysis suggested an important role of MCM2 in delivering the pharmacological activity of DSD against GC. Together, these results indicate that our network pharmacology and bioinformatics-guided approach is feasible and useful in exploring not only the mechanism of action, but also the "new use" of the old CHM formula.

SUBMITTER: Pan B

PROVIDER: S-EPMC7830678 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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A Mechanism of Action Study on Danggui Sini Decoction to Discover Its Therapeutic Effect on Gastric Cancer.

Pan Boyu B Wang Yun Y Wu Chunnuan C Jia Junrong J Huang Chen C Fang Senbiao S Liu Liren L

Frontiers in pharmacology 20210111

Danggui Sini Decoction (DSD), a classic Chinese herb medicine (CHM) formula, has been used to treat various diseases in China for centuries. However, it remains challenging to reveal its mechanism of action through conventional pharmacological methods. Here, we first explored the mechanism of action of DSD with the assistance of network pharmacology and bioinformatic analysis tools, and found a potential therapeutic effect of DSD on cancer. Indeed, our <i>in vivo</i> experiment demonstrated that ...[more]

PMID: 33505310

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Project description:ObjectiveThis study aimed to explore the mechanism of Modified Danggui Sini Decoction in the treatment of knee osteoarthritis via a combination of network pharmacology and molecular docking.MethodsThe main chemical components and corresponding targets of Modified Danggui Sini Decoction were searched and screened in TCMSP database. The disease targets of knee osteoarthritis were summarized in GeneCards, OMIM, PharmGkb, TTD, and DrugBank databases. The visual interactive network of "drugs-active components-disease targets" was drawn by Cytoscape 3.8.1 software. The protein-protein interaction network was constructed by STRING database. Then, GO function and KEGG pathway enrichment were analyzed by Bioconductor/R, and the pathway of the highest degree of correlation with knee osteoarthritis was selected for specific analysis. Finally, molecular docking was used to screen and verify core genes by AutoDockTools software.ResultsSeventy-one main components of Modified Danggui Sini Decoction and 116 potential therapeutic targets of knee osteoarthritis were selected. The KEGG pathway and the GO function enrichment analysis showed that the targets of Modified Danggui Sini Decoction in the treatment of knee osteoarthritis were mainly concentrated on PI3K-Akt signaling pathway, TNF signaling pathway, IL-17 signaling pathway, apoptosis signaling pathway, Toll-like receptor signaling pathway, Th17 cell differentiation signaling pathway, HIF-1 signaling pathway, and NF-κB signaling pathway. It mainly involved inflammatory reaction, regulation of apoptotic signaling pathway, cellular response to regulation of inflammatory response, cellular response to oxidative stress, and other biological processes. The molecular docking results showed that ESR1-wogonin, MAPK1-quercetin, RELA-wogonin, RELA-baicalein, TP53-baicalein, TP53-quercetin, and RELA-quercetin have strong docking activities.ConclusionModified Danggui Sini Decoction has the hierarchical network characteristics of "multicomponent, multitarget, multifunction, and multipathway" in the treatment of knee osteoarthritis. It mainly regulates the proliferation and apoptosis of chondrocytes by regulating the PI3K-Akt signaling pathway and establishes cross-talk with many downstream inflammatory-related pathways to reduce the overall inflammatory response. Meanwhile, HIF-1 expression was used to ensure the normal function and metabolism of knee joint under hypoxia condition, and the above processes play a key role in the treatment of knee osteoarthritis.

Project description:ObjectiveThe main active components and mechanism of Danggui Sini decoction (DSD) in treating diabetic foot (DF) were studied and verified by network pharmacology and molecular docking. Evidence-based medicine was used to prove its efficacy.MethodsThe TCMSP systematic pharmacology platform screened out DSD's practical components and targets-screening disease targets in GeneCards database, using Cytoscape 3.7.2 to draw DSD-active ingredient-target network diagram, and drawing the protein interaction network diagram through STRING database. The Metascape platform was used to analyze the GO function enrichment and KEGG signal pathway. The molecular docking experiment was carried out by using Auto Dock vina 4.2. The related literature on DSD in treating DF in China Zhiwang, Wanfang, Weipu, and China Biomedical Literature Database was searched. The literature was screened, data was extracted, and quality was evaluated according to the inclusion and exclusion criteria. Then, a meta-analysis was performed using RevMan 5.3 software.ResultsA total of 256 targets of all effective components of DSD were obtained. Among 1,272 disease targets, there are 113 common targets. The GO analysis received 6,179 entries, and the KEGG pathway enrichment analysis found 251 related pathways. The molecular docking results of the main targets of diabetic foot and the active substances of DSD all showed a high docking activity. The meta-analysis included six literature, all of which were randomized controlled experiments. The quality grade of the literature was C, and the results showed that the total effective rate of clinical efficacy in the experimental group was significantly higher than that in the control group.ConclusionsDSD may treat DF by participating in biological processes such as cell proliferation regulation, inflammatory reaction, oxidative stress reaction, and promotion of angiogenesis. DSD treats DF through AKT1, TP53, IL6, TNF, VEGFA, and other targets. DSD plays a role in treating DF mainly through the AGE-RAGE signaling pathway and PI3K-AKT signaling pathway. The molecular docking results of AKT1, TP53, IL-6, TNF, and VEGFA with the active substances of DSD show that they all have a high docking activity; among them, VEGFA has a higher docking activity. Compared with conventional treatment, DSD has a high effective rate, short wound healing time, large wound healing area, and high ABI index.

Project description:BackgroundDanggui Sini decoction (DSD), a traditional Chinese medicine formula, has the function of nourishing blood, warming meridians, and unblocking collaterals. Our clinical and animal studies had shown that DSD can effectively protect against oxaliplatin (OXA)-induced peripheral neuropathy (OIPN), but the detailed mechanisms remain uncertain. Multiple studies have confirmed that gut microbiota plays a crucial role in the development of OIPN. In this study, the potential mechanism of protective effect of DSD against OIPN by regulating gut microbiota was investigated.MethodsThe neuroprotective effects of DSD against OIPN were examined on a rat model of OIPN by determining mechanical allodynia, biological features of dorsal root ganglia (DRG) as well as proinflammatory indicators. Gut microbiota dysbiosis was characterized using 16S rDNA gene sequencing and metabolism disorders were evaluated using untargeted and targeted metabolomics. Moreover the gut microbiota mediated mechanisms were validated by antibiotic intervention and fecal microbiota transplantation.ResultsDSD treatment significantly alleviated OIPN symptoms by relieving mechanical allodynia, preserving DRG integrity and reducing proinflammatory indicators lipopolysaccharide (LPS), IL-6 and TNF-α. Besides, DSD restored OXA induced intestinal barrier disruption, gut microbiota dysbiosis as well as systemic metabolic disorders. Correlation analysis revealed that DSD increased bacterial genera such as Faecalibaculum, Allobaculum, Dubosiella and Rhodospirillales_unclassified were closely associated with neuroinflammation related metabolites, including positively with short-chain fatty acids (SCFAs) and sphingomyelin (d18:1/16:0), and negatively with pi-methylimidazoleacetic acid, L-glutamine and homovanillic acid. Meanwhile, antibiotic intervention apparently relieved OIPN symptoms. Furthermore, fecal microbiota transplantation further confirmed the mediated effects of gut microbiota.ConclusionDSD alleviates OIPN by regulating gut microbiota and potentially relieving neuroinflammation related metabolic disorder.

Project description:BackgroundDue to unhealthy diet and living habits, the incidence of gout is on the rise and has become a common disease with a high incidence. Danggui Niantong decoction (DGNTD), as a classic formula composed of 15 common herbs, has been widely used in clinical practice since ancient times to prevent and treat gout. However, the pharmacological mechanism and target of DGNTD are not clear.MethodsThe potential active compounds and targets of DGNTD were obtained by traditional Chinese medicine systems pharmacology (TCMSP) database, and the differential genes of gout patients and controls were analyzed in gene expression omnibus (GEO) database. GSEA analysis of differential genes with GSEA 4.1.0 software and then the differential genes were intersected with the gout-related disease targets searched by GeneCard, CTD and OMIM disease database to obtain the final disease target. The "Traditional Chinese medicine-Active compounds-Targets" network was constructed by Cytoscape3.7.2 software. The R packet is used for enrichment analysis. The molecular docking between the active compound of DGNTD and the core target was verified by AutoDockTools software.ResultsTwo hundred eighty six and 244 targets of DGNTD-related active components and 652 targets of gout were obtained, of which 13 targets were potential targets of DGNTD in the treatment of gout. GSEA analysis showed that the differential genes were mainly involved in apoptosis, inflammatory reaction, and receptor metabolism and so on. Gene ontology (GO) functional enrichment analysis shows that DGNTD regulates many biological processes, such as the response to purine-containing compound and response to lipopolysaccharide, positive regulation of acute inflammatory response and other cellular components. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis shows that DGNTD treatment of gout is mainly related to interleukin-17 (IL-17), Toll-like receptor, rheumatoid arthritis, tumor necrosis factor (TNF) and so on. The results of molecular docking showed that the five active compounds in DGNTD had strong binding activity to core protein receptors.ConclusionsThe active compounds of DGNTD may achieve the purpose of treating gout by acting on the core target (CASP8, CXCL8, FOS, IL1B, IL6, JUN, PTGS2, STAT1, MMP1, TNF) to regulate cell metabolism, proliferation and apoptosis, and improve inflammatory response, which is the result of multi-component, multi-target and multi-pathway interaction. It provides an idea for the development of new combined drugs for gout.

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A Mechanism of Action Study on Danggui Sini Decoction to Discover Its Therapeutic Effect on Gastric Cancer.

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A Mechanism of Action Study on Danggui Sini Decoction to Discover Its Therapeutic Effect on Gastric Cancer.

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