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Cited by 11Computational Drug Discovery MethodsFungal Biology and ApplicationsPhytochemistry and Biological Activities

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Effect of Poria cocos Terpenes: Verifying Modes of Action Using Molecular Docking, Drug-Induced Transcriptomes, and Diffusion Network Analyses

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Park, Musun, Yi, Jin-Mu, Kim, No Soo, Lee, Seo-Young, Lee, Haeseung·2024·International Journal of Molecular Sciences
DOI 10.3390/ijms25094636PMC PMC11083729

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Abstract

We characterized the therapeutic biological modes of action of several terpenes in Poria cocos F.A Wolf (PC) and proposed a broad therapeutic mode of action for PC. Molecular docking and drug-induced transcriptome analysis were performed to confirm the pharmacological mechanism of PC terpene, and a new analysis method, namely diffusion network analysis, was proposed to verify the mechanism of action against Alzheimer’s disease. We confirmed that the compound that exists only in PC has a unique mechanism through statistical-based docking analysis. Also, docking and transcriptomic analysis results could reflect results in clinical practice when used complementarily. The detailed pharmacological mechanism of PC was confirmed by constructing and analyzing the Alzheimer’s disease diffusion network, and the antioxidant activity based on microglial cells was verified. In this study, we used two bioinformatics approaches to reveal PC’s broad mode of action while also using diffusion networks to identify its detailed pharmacological mechanisms of action. The results of this study provide evidence that future pharmacological mechanism analysis should simultaneously consider complementary docking and transcriptomics and suggest diffusion network analysis, a new method to derive pharmacological mechanisms based on natural complex compounds.

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Figures

Figure 1 ORA results using lanostane terpenes and seco-lanostane terpenes. ORA was performed on the EnrichR platform using proteins that specifically bind to lanostane and seco-lanostane terpenes, which are unique terpenes of PC. The lightest color has a higher combined score, and as the color becomes darker, the combined score decreases. Gray are terms that did not pass the significance test. (A) ORA results using the KEGG gene set. (B) ORA results using the GO biological process gene set. (C) ORA results using the OMIM disease gene set. ORA, Over-representation analysis. PC, Poria cocos F.A. Wolf; KEGG, Kyoto Encyclopedia of Genes and Genomes; GO, Gene Ontology; OMIM, Online Mendelian Inheritance in Man.
Figure 1 ORA results using lanostane terpenes and seco-lanostane terpenes. ORA was performed on the EnrichR platform using proteins that specifically bind to lanostane and seco-lanostane terpenes, which are unique terpenes of PC. The lightest color has a higher combined score, and as the color becomes darker, the combined score decreases. Gray are terms that did not pass the significance test. (A) ORA results using the KEGG gene set. (B) ORA results using the GO biological process gene set. (C) ORA results using the OMIM disease gene set. ORA, Over-representation analysis. PC, Poria cocos F.A. Wolf; KEGG, Kyoto Encyclopedia of Genes and Genomes; GO, Gene Ontology; OMIM, Online Mendelian Inheritance in Man.CC BY · PubMed Central
Figure 2 GSEA results using the SW1783 cell line–based PC-induced transcriptomes. GSEA was performed using the KEGG pathway gene set. Poria Cocos_High, Poria Cocos_Middle, and Poria Cocos_Low are the results of analyzing the gene expression values obtained by treating the PC water extract with high (500 µg/mL), medium (100 µg/mL), and low (20 µg/mL) concentrations, respectively. Wortmannin, LY294002, and thioridazine are positive controls. Wortmannin and LY294002 are known to inhibit inflammation by acting on the cell cycle, and thioridazine is a known dopaminergic receptor antagonist. GSEA, gene set enrichment analysis. PC, Poria cocos F.A. Wolf; KEGG, Kyoto Encyclopedia of Genes and Genomes. * p < 0.05, ** p < 0.01.
Figure 2 GSEA results using the SW1783 cell line–based PC-induced transcriptomes. GSEA was performed using the KEGG pathway gene set. Poria Cocos_High, Poria Cocos_Middle, and Poria Cocos_Low are the results of analyzing the gene expression values obtained by treating the PC water extract with high (500 µg/mL), medium (100 µg/mL), and low (20 µg/mL) concentrations, respectively. Wortmannin, LY294002, and thioridazine are positive controls. Wortmannin and LY294002 are known to inhibit inflammation by acting on the cell cycle, and thioridazine is a known dopaminergic receptor antagonist. GSEA, gene set enrichment analysis. PC, Poria cocos F.A. Wolf; KEGG, Kyoto Encyclopedia of Genes and Genomes. * p < 0.05, ** p < 0.01.CC BY · PubMed Central
Figure 3 MOA analysis of PC using AD–related DN. (A) DN associated with AD. In layer 1, terms related to AD were selected from the results of MDA, and in layer 5, DEGs were selected and a DN was built using them. Orange circles indicate proteins included in the KEGG AD gene set. (B) MOA analysis result of PC using AD–related DN. Each layer was rebuilt using only the orange circles in the network above. Layers 2 and 3 were grouped so that it was possible to identify which protein signal transduction was initiated in layer 1. The AD submodule that each group specifically acts on was confirmed using KEGG Mapper. MOA, mode of action; PC, Poria cocos F.A. Wolf; AD, Alzheimer’s disease; DN, diffusion network; MDA, molecular docking analysis, DEGs, differentially expressed genes; KEGG, Kyoto Encyclopedia of Genes and Genomes.
Figure 3 MOA analysis of PC using AD–related DN. (A) DN associated with AD. In layer 1, terms related to AD were selected from the results of MDA, and in layer 5, DEGs were selected and a DN was built using them. Orange circles indicate proteins included in the KEGG AD gene set. (B) MOA analysis result of PC using AD–related DN. Each layer was rebuilt using only the orange circles in the network above. Layers 2 and 3 were grouped so that it was possible to identify which protein signal transduction was initiated in layer 1. The AD submodule that each group specifically acts on was confirmed using KEGG Mapper. MOA, mode of action; PC, Poria cocos F.A. Wolf; AD, Alzheimer’s disease; DN, diffusion network; MDA, molecular docking analysis, DEGs, differentially expressed genes; KEGG, Kyoto Encyclopedia of Genes and Genomes.CC BY · PubMed Central
Figure 4 Antioxidant activity of PC. (A) Pretreatment of water (WEPC) and 70% ethanol (EEPC) extracts of PC inhibits LPS–mediated ROS production in the BV2 microglial cells. Intracellular ROS was monitored by DCF–DA staining (left, scale bar 400 μm) and their fluorescence intensities were quantified (right). Black bars, without LPS treatment; gray bars, with LPS treatment. (B) Changes in Nos2 (left) and Hmox1 (right) mRNA levels in BV2 microglial cells by PC in the absence (black bars) and the presence (gray bars) of LPS stimulation were determined by qPCR. (C) Activation of Nrf2/Hmox1 antioxidant signaling pathway by PC in the absence and the presence of LPS stimulation was observed by Western blotting (top). Expression of Nrf2 (left) and Hmox1 (right) proteins were quantified by image analysis. NAC was used as a positive control with antioxidant activity. β–actin was included as a loading control. Data are presented as means ± SD (n = 3 except for figure (A), n = 6). # p < 0.05, ## p < 0.01, ### p < 0.001 vs. vehicle-treated control without LPS treatment. * p < 0.05, ** p < 0.01, *** p < 0.001 vs. vehicle-treated control with LPS treatment.
Figure 4 Antioxidant activity of PC. (A) Pretreatment of water (WEPC) and 70% ethanol (EEPC) extracts of PC inhibits LPS–mediated ROS production in the BV2 microglial cells. Intracellular ROS was monitored by DCF–DA staining (left, scale bar 400 μm) and their fluorescence intensities were quantified (right). Black bars, without LPS treatment; gray bars, with LPS treatment. (B) Changes in Nos2 (left) and Hmox1 (right) mRNA levels in BV2 microglial cells by PC in the absence (black bars) and the presence (gray bars) of LPS stimulation were determined by qPCR. (C) Activation of Nrf2/Hmox1 antioxidant signaling pathway by PC in the absence and the presence of LPS stimulation was observed by Western blotting (top). Expression of Nrf2 (left) and Hmox1 (right) proteins were quantified by image analysis. NAC was used as a positive control with antioxidant activity. β–actin was included as a loading control. Data are presented as means ± SD (n = 3 except for figure (A), n = 6). # p < 0.05, ## p < 0.01, ### p < 0.001 vs. vehicle-treated control without LPS treatment. * p < 0.05, ** p < 0.01, *** p < 0.001 vs. vehicle-treated control with LPS treatment.CC BY · PubMed Central
Figure 5 Method for constructing the DN. The DN was constructed to integrate results from MDA and DTA. (A) DN construction method. A new layer was assigned to the protein derived from the MDA results and the interacting proteins, and the process of connecting the previous layer and the new layer was repeated three times to add a total of three layers. In the fourth layer, the network was completed by adding connections that interact with genes derived from DTA. Numbers (1) through (4) indicate the order in which DNs are constructed. (B) DN modification method. In the fourth layer, nodes that did not have a connection with the last layer were deleted. In this manner, the network was completed by sequentially deleting nodes using the backpropagation method up to the second layer. Numbers (1) through (4) indicate the order in which DNs are constructed. Nodes marked in yellow indicate nodes that will be removed in the next sequence. DN, diffusion network; MDA, molecular docking analysis; DTA, drug-induced transcriptome analysis.
Figure 5 Method for constructing the DN. The DN was constructed to integrate results from MDA and DTA. (A) DN construction method. A new layer was assigned to the protein derived from the MDA results and the interacting proteins, and the process of connecting the previous layer and the new layer was repeated three times to add a total of three layers. In the fourth layer, the network was completed by adding connections that interact with genes derived from DTA. Numbers (1) through (4) indicate the order in which DNs are constructed. (B) DN modification method. In the fourth layer, nodes that did not have a connection with the last layer were deleted. In this manner, the network was completed by sequentially deleting nodes using the backpropagation method up to the second layer. Numbers (1) through (4) indicate the order in which DNs are constructed. Nodes marked in yellow indicate nodes that will be removed in the next sequence. DN, diffusion network; MDA, molecular docking analysis; DTA, drug-induced transcriptome analysis.CC BY · PubMed Central

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Metadata

Authors
Park, M., Yi, J.-M., Kim, N. S., Lee, S.-Y., & Lee, H.
Affiliations
  • Korea Institute of Oriental Medicine (KR)
  • KM Science Research Division, Korea Institute of Oriental Medicine, Daejeon 34054, Republic of Korea
  • Pusan National University (KR)
Corresponding author
Park, Musun
ORCID
Venue
International Journal of Molecular Sciences
Publisher
MDPI AG
Published
2024-04-24
Volume
25
Issue
9
Pages
4636
ISSN
1422-0067 (ISSN-L)
DOI
10.3390/ijms25094636
PMC
PMC11083729
OpenAlex
W4395082416
Cited by
11
References
55
Citations by year
2026: 4 · 2025: 5 · 2024: 2
FWCI
2.33
Type
journal article
Language
en
Open access
Licence
Locations
  • International Journal of Molecular Sciences (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • Korea Institute of Oriental Medicine (KSN1722122, NSN2312040)
  • National Research Foundation of Korea (NRF) (KSN1722122, NSN2312040)
Topics
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Drug Discovery › Computational Drug Discovery Methods
  • Health Sciences › Medicine › Pharmacology (medical) › Fungal Biology and Applications
  • Life Sciences › Agricultural and Biological Sciences › Plant Science › Phytochemistry and Biological Activities
Keywords
Poria cocos, terpenes, Alzheimer's disease, microglial cells, antioxidant activity, molecular docking
MeSH terms
Wolfiporia, Alzheimer Disease, Animals, Antioxidants, Humans, Terpenes, Microglia, Computational Biology, Gene Expression Profiling, Transcriptome, Molecular Docking Simulation

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Park, M., Yi, J.-M., Kim, N. S., Lee, S.-Y., & Lee, H. (2024). Effect of Poria cocos Terpenes: Verifying Modes of Action Using Molecular Docking, Drug-Induced Transcriptomes, and Diffusion Network Analyses. International Journal of Molecular Sciences. https://doi.org/10.3390/ijms25094636

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