Dataset Information

Network Pharmacology and Molecular Docking on the Molecular Mechanism of Jiawei-Huang Lian-Gan Jiang Decoction in the Treatment of Colorectal Adenomas.

ABSTRACT:

Purpose

Jiawei-Huang Lian-Gan Jiang decoction (JWHLGJD) was developed to treat and prevent the patients with colorectal adenomas (CRA) in China. This study is aimed to discover JWHLGJD's active compounds and demonstrate mechanisms of JWHLGJD against CRA through network pharmacology and molecular docking techniques.

Methods

All the components of JWHLGJD were retrieved from the pharmacology database of Traditional Chinese Medicine Systems Pharmacology (TCMSP). The GeneCards database, the Online Mendelian Inheritance in Man database (OMIM), the DrugBank database, and PharmGKB were used to obtain the genes matching the targets. Cytoscape created the compound-target network. The network of target protein-protein interactions (PPI) was constructed using the STRING database. Gene Ontology (GO) functional and the Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathways involved in the targets were analyzed by using the DAVID database. Cytoscape created the component-target-pathway (C-T-P) network. AutoDock Vina software was used to verify the molecular docking of JWHLGJD components and key targets. Core genes linked with survival and tumor microenvironment were analyzed through the Kaplan-Meier plotter and TIMER 2.0 databases, respectively.

Results

Compound-target network mainly contained 38 compounds and 130 targets of the JWHLGJD associated with CRA. TP53, MAPK1, JUN, HSP90AA1, and AKT1 were identified as core targets by the PPI network. KEGG pathway shows that the pathways in cancer, lipids, and atherosclerosis, PI3K-Akt signaling pathway and MAPK signaling pathway, are the most relevant pathways to CRA. The C-T-P network suggests that the active component in JWHLGJD is capable of regulating target genes of these related pathways. The results of molecular docking showed that berberine and stigmasterol were the top two compounds of JWHLGJD, which had high affinity with TP53 and MAPK1, respectively. And, MAPK1 exerted a more significant effect on the prognosis of adenocarcinoma, for it was highly associated with various immune cells.

Conclusion

Findings in this study provided light on JWHLGJD's active components, prospective targets, and molecular mechanism. It also gave a potential way to uncovering the scientific underpinning and therapeutic mechanism of traditional Chinese medicine (TCM) formulas.

SUBMITTER: Ji S

PROVIDER: S-EPMC9313928 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:BackgroundUlcerative colitis (UC), a chronic and nonspecific inflammatory bowel disease, seriously affects the quality of patients' life. Han Re Bing Yong Fa (treating diseases with both cool- and warm-natured herbs) is a classical therapeutic principle of traditional Chinese medicine (TCM), which is often used to treat chronic diseases, including UC. The Gan Jiang-Huang Qin-Huang Lian-Ren Shen decoction (GJHQHLRSD), a representative of Han Re Bing Yong Fa, is effective in alleviating inflammatory symptoms in UC. However, the pharmacological mechanism underlying its anti-inflammatory effect remains unclear.MethodsA network pharmacology strategy, including the construction and analysis of the drug-disease network, was used to explore the complex mechanism of GJHQHLRSD treatment of UC. In addition, molecular docking technology was used to preliminarily examine the binding ability of the potential active components and core therapeutic targets of GJHQHLRSD.ResultsThe network pharmacology results revealed 140 targets of GJHQHLRSD which are involved in UC. The PPI network analysis identified seven target genes: BCL2L1, NR3C1, ALOX5, S1PR5, NR1I2, CYP2D6, and LPAR6. The molecular docking results revealed that the following displayed strongest combined effects: EGFR with kaempferol, ERK1 with worenine, STAT3 with Palmidin A, BCL2L1 with diop and VEGFA with ginsenoside Rg3. The KEGG and gene ontology enrichment analyses results indicated that GJHQHLRSD functions by regulating the EGFR signaling pathway in UC treatment. Other effective biological processes involved in UC treatment included cancer-related as well as inflammation and viral infection signaling pathways, such as the "MicroRNAs in cancer," "TNF signaling pathway," and "JAK-STAT signaling pathway."ConclusionsThis study reflects the multicomponent, multitarget, and multipathway characteristics of the action mechanism of GJHQHLRSD in treating UC. Furthermore, it helps better understand the TCM therapeutic principle of Han Re Bing Yong Fa and explore novel candidate drug targets for UC treatment.

Project description:Huang-Lian-Jie-Du Decoction (HLJDD) is a "Fangji" made up of well-designed Chinese herb array and widely used to treat ischemic stroke. Here we aimed to investigate pharmacological mechanism by introducing an inter-module analysis to identify an overarching view of target profile and action mode of HLJDD. Stroke-related genes were obtained from OMIM (Online Mendelian Inheritance in Man). And the potential target proteins of HLJDD were identified according to TCMsp (Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform). The two sets of molecules related to stroke and HLJDD were respectively imported into STRING database to construct the stroke network and HLJDD network, which were dissected into modules through MCODE, respectively. We analyzed the inter-module connectivity by quantify "coupling score" (CS) between HLJDD-modules (H-modules) and stroke-modules (S-module) to explore the pharmacological acting pattern of HLJDD on stroke. A total of 267 stroke-related proteins and 15 S-modules, 335 HLJDD putative targeting proteins, and 13 H-modules were identified, respectively. HLJDD directly targeted 28 proteins in stroke network, majority (16, 57.14%) of which were in S-modules 1 and 4. According to the modular map based on inter-module CS analysis, H-modules 1, 2, and 8 densely connected with S-modules 1, 3, and 4 to constitute a module-to-module bridgeness, and the enriched pathways of this bridgeness with top significance were TNF signaling pathway, HIF signaling pathway, and PI3K-Akt signaling pathway. Furthermore, through this bridgeness, H-modules 2 and 4 cooperatively work together to regulate mitochondrial apoptosis against the ischemia injury. Finally, the core protein in H-module 4 account for mitochondrial apoptosis was validated by an in vivo experiment. This study has developed an integrative approach by inter-modular analysis for elucidating the "shotgun-like" pharmacological mechanism of HLJDD for stroke.

Project description:Huang-Lian-Jie-Du Decoction (HLJDD) is a classical Traditional Chinese Medicine (TCM) formula with heat-dissipating and detoxifying effects. It is used to treat inflammation-associated diseases. However, no systematic pharmacokinetic (PK) and pharmacodynamic (PD) data concerning the activity of HLJDD under inflammatory conditions is available to date. In the present study, the concentration-time profiles and the hepatic clearance rates (HCR) of 41 major components in rat plasma in response to the oral administration of a clinical dose of HLJDD were investigated by LC-QqQ-MS using a dynamic multiple reaction monitoring (DMRM) method. Additionally, the levels of 7 cytokines (CKs) in the plasma and the body temperature of rats were analyzed. Furthermore, a PK-PD model was established to describe the time course of the hemodynamic and anti-inflammatory effects of HLJDD. As one of the three major active constituents in HLJDD, iridoids were absorbed and eliminated more easily and quickly than alkaloids and flavonoids. Compared with the normal controls, the flavonoids, alkaloids and iridoids in inflamed rats exhibited consistently changing trends of PK behaviors, such as higher bioavailability, slower elimination, delays in reaching the maximum concentration (Tmax) and longer substantivity. The HCR of iridoids was different from that of alkaloids and flavonoids in inflamed rats. Furthermore, excellent pharmacodynamic effects of HLJDD were observed in inflamed rats. The levels of tumor necrosis factor-? (TNF-?), interleukin-6 (IL-6), IL-1?, IL-10, and macrophage inflammatory protein-2 (MIP-2) and body temperature significantly decreased after the administration of HLJDD. Based on PK-PD modeling with the three-phase synchronous characterization of time-concentration-effect, flavonoids exhibited one mechanism of action in the anti-inflammatory process, while iridoids and alkaloids showed another mechanism of action. Taken together, the results demonstrated that HLJDD may restrain inflammation synergistically via its major constituents (alkaloids, flavonoids and iridoids). A correlation between the exposure concentration of different types of compounds and their anti-inflammatory effects in the body was shown. This study provides a comprehensive understanding of the anti-inflammatory activity of HLJDD.

Project description:ObjectiveUlcerative colitis is an intestinal condition that severely affects the life quality of a patient. Jiawei Zhengqi powder (JWZQS) has some therapeutic benefits for ulcerative colitis. The current study investigated the therapeutic mechanism of JWZQS for ulcerative colitis using a network pharmacology analytical approach.MethodsIn this study, network pharmacology was used to investigate the potential mechanism of JWZQS in treating ulcerative colitis. The common targets between the two were identified, and a network map was created with the Cytoscape software. The Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analyses of JWZQS was performed using the Metascape database. Protein-protein interaction networks (PPI) was created to screen core targets and main components, and molecular docking was conducted between the main components and core targets. The expression levels of IL-1β, IL-6, and TNF-α were detected in animal experiments. Their effect on the NF-κB signaling pathway and the protective mechanism of JWZQS on the colon by tight junction protein were investigated.ResultsThere were 2127 potential ulcerative colitis targets and 35 components identified, including 201 non-reproducible targets and 123 targets shared by drugs and diseases. Following the analysis, we discovered 13 significant active components and 10 core targets. The first 5 active ingredients and their corresponding targets were molecularly docked, and the results showed a high level of affinity. GO analysis showed that JWZQS participate in multiple biological processes to treat UC. KEGG analysis showed that JWZQS may be involved in regulating multiple pathways, and the NF-κB signaling pathway was selected for analysis and verification. JWZQS has been shown in animal studies to effectively inhibit the NF-κB pathway; reduce the expression of IL-1β, TNF-α, and IL-6 in colon tissue; and increase the expression of ZO-1, Occludin, and Claudin-1.ConclusionThe network pharmacological study provides preliminary evidence that JWZQS can treat UC through multiple components and targets. JWZQS has been shown in animal studies to effectively reduce the expression levels of IL-1β, TNF-α, and IL-6, inhibit the phosphorylation of the NF-κB pathway, and alleviate colon injury. JWZQS can be used in clinical, but the precise mechanism of UC treatment requires further investigation.