Home | Register | Login | Inquiries | Alerts | Sitemap |  


Advanced Search
JKM > Volume 45(2); 2024 > Article
Shon, Han, Kim, and An: Prediction of Treatment Mechanisms of Scutellariae Radix on Viral Pneumonia Through Network Pharmacology: Focus on Hypoxic State Regulation Through HIF-1α and HSP90

Abstract

Objectives

In this study, we used network-based systems pharmacology analysis and molecular docking methods to predict the therapeutic mechanism of Scutellariae Radix on viral pneumonia.

Methods

We screened active components of Scutellariae Radix and its’ genes by TCMSP. Also, we extracted viral pneumonia related target genes through Gene Cards, CTD and DisGeNet. To construct Protein-protein Interaction, STRING database was used. For functional enrichment, using SRplot platform, genes were classified by 3 categories: cellular component (CC), molecular function (MF) and biological process (BP). Molecular docking was conducted by AutoDockTools (version 4.2.6).

Results

32 Network-based systematic pharmacology analysis identified 37 target genes associated with baicalein. Based on the network and gene ontology analysis of the active ingredient's target genes and disease target genes, we identified nine core genes (AKT1, BAX, BCL2, CASP3, HIF1A, PTGS2, RELA, TP53, VEGFA) and HSP90 as involved. Notably, HIF1A showed the highest relevance, overlapping with two or more utilized programs. Hypoxia-inducible factor 1-alpha (HIF-1α) has been implicated in the expression of inflammatory cytokines, the induction of hypoxia, and the triggering of cytokine storms. Baicalein, a major component of SR, binds to both HIF-1α and HSP90, suggesting that it may be a possible targeted treatment for viral pneumonia.

Conclusions

Baicalein may bind to HIF-1α to control inflammation caused by viral infectious diseases and may also regulate hypoxic conditions to prevent impairment of lung function caused by an overactive immune system. These findings suggest further research into the molecular mechanisms involved in hypoxia and provide a scientific basis for improving the treatment of viral infectious diseases.

Fig. 1
Investigating overlaps between genes derived by applying four keywords related to viral pneumonia to three databases: GeneCards (G), DisGeNET (D), and CTD (C), and Baicalein's target genes.
(A) The keyword is 'Viral Pneumonia’. (B) The keyword is 'Pneumonia Influenza’. (C) The keyword is 'SARS’. (D) The keyword is 'Coronavirus Infection’. The number of genes overlapping between disease-related genes and Baicalein's target genes is represented by black circles.
jkm-45-2-55f1.gif
Fig. 2
Nine Key Genes Common in Four Keywords.
jkm-45-2-55f2.gif
Fig. 3
Protein-Protein Interaction of 26 Key Duplicated Genes Overlapping in Two or More Disease keywords. PPI enrichment p-value: < 1.0e-16.
jkm-45-2-55f3.gif
Fig. 4
Protein-Protein Interaction (PPI) Involving 9 Key Duplicated Genes and HSP90, as Represented in STRING.
(A) 10 nodes connected by 36 edges, averaging 7.2 nodes interacting. PPI enrichment p-value: 0.00267. (B) Genes associated with lung tissue (green nodes). (C) Genes involved in host-virus interaction (blue nodes) and apoptosis (red nodes).
jkm-45-2-55f4.gif
Fig. 5
Ten Compounds and Targets with a High Degree of Association Among the Compounds of Scutellariae Radix and Target genes.
jkm-45-2-55f5.gif
Fig. 6
Gene Ontology Analysis of Scutellariae Radix and Baicalein.
The results for three ontologies, namely Biological Process (BP), Cellular Component (CC), and Molecular Function (MF), for both (A) Scutellariae Radix and (B) Baicalein.
jkm-45-2-55f6.gif
Fig. 7
Predictive model of the binding of baicalein to HSP90 and HIF1A
(A) Gray: protein, HSP90 (PDB ID: 1YET), pink: ligand, baicalein, affinity: −6.7 kcal/mol. (B) Light green: van der waals, Green: conventional hydrogen bond, Pink: Pi-alkyl, Yellow: Pi-sulfur, Purple: Pi-sigma. (C) 3D structure of the intermolecular docking of baicalein and HSP90. (D) Gray: protein, HIF1A (PDB ID: 8HE3), Pink: ligand, baicalein, affinity: −6.6 kcal/mol. (E) Light green: van der waals, Green: conventional hydrogen bond, Pink: Pi-alkyl, Yellow: Pi-anion. (F) 3D detailed structure of the intermolecular docking of baicalein and HIF1A.
jkm-45-2-55f7.gif
Table 1
Active Compounds of Scutellariae Radix
Molecule ID Molecule Name Structure and Formula OB (%) Caco-2 DL
MOL000073 ent-Epicatechin jkm-45-2-55f8.gif 48.96 0.02 0.24
MOL000173 wogonin jkm-45-2-55f9.gif 30.68 0.79 0.23
MOL000228 (2R)-7-hydroxy-5-methoxy-2-p henylchroman-4-one jkm-45-2-55f10.gif 55.23 0.87 0.2
MOL000358 beta-sitosterol jkm-45-2-55f11.gif 36.91 1.32 0.75
MOL000449 Stigmasterol jkm-45-2-55f12.gif 43.83 1.44 0.76
MOL000525 Norwogonin jkm-45-2-55f13.gif 39.4 0.6 0.21
MOL000552 5,2'-Dihydroxy-6,7,8-trimethox yflavone jkm-45-2-55f14.gif 31.71 0.93 0.35
MOL001458 coptisine jkm-45-2-55f15.gif 30.67 1.21 0.86
MOL001490 bis[(2S)-2-ethylhexyl] benzene-1,2-dicarboxylate jkm-45-2-55f16.gif 43.59 0.98 0.35
MOL001506 Supraene jkm-45-2-55f17.gif 33.55 2.08 0.42
MOL001689 acacetin jkm-45-2-55f18.gif 34.97 0.67 0.24
MOL002714 Baicalein jkm-45-2-55f19.gif 33.52 0.63 0.21
MOL002879 Diop jkm-45-2-55f20.gif 43.59 0.79 0.39
MOL002897 epiberberine jkm-45-2-55f21.gif 43.09 1.17 0.78
MOL002908 5,8,2'-Trihydroxy-7-methoxyfl avone jkm-45-2-55f22.gif 37.01 0.76 0.27
MOL002909 5,7,2,5-tetrahydroxy-8,6-dimet hoxyflavone jkm-45-2-55f23.gif 33.82 0.35 0.45
MOL002910 Carthamidin jkm-45-2-55f24.gif 41.15 0.16 0.24
MOL002914 Eriodyctiol (flavanone) jkm-45-2-55f25.gif 41.35 0.05 0.24
MOL002915 Salvigenin jkm-45-2-55f26.gif 49.07 0.86 0.33
MOL002917 5,2',6'-Trihydroxy-7,8-dimetho xyflavone jkm-45-2-55f27.gif 45.05 0.48 0.33
MOL002925 5,7,2',6'-Tetrahydroxyflavone jkm-45-2-55f28.gif 37.01 0.18 0.24
MOL002926 dihydrooroxylin A jkm-45-2-55f29.gif 38.72 0.71 0.23
MOL002927 Skullcapflavone II jkm-45-2-55f30.gif 69.51 0.68 0.44
MOL002928 oroxylin a jkm-45-2-55f31.gif 41.37 0.76 0.23
MOL002932 Panicolin jkm-45-2-55f32.gif 76.26 0.84 0.29
MOL002933 5,7,4'-Trihydroxy-8-methoxyfl avone jkm-45-2-55f33.gif 36.56 0.46 0.27
MOL002934 NEOBAICALEIN jkm-45-2-55f34.gif 104.34 0.74 0.44
MOL008206 Moslosooflavone jkm-45-2-55f35.gif 44.09 1.01 0.25
MOL010415 11,13-Eicosadienoic acid, methyl ester jkm-45-2-55f36.gif 39.28 1.46 0.23
MOL012245 5,7,4'-trihydroxy-6-methoxyfla vanone jkm-45-2-55f37.gif 36.63 0.43 0.27
MOL012246 5,7,4'-trihydroxy-8-methoxyfla vanone jkm-45-2-55f38.gif 74.24 0.37 0.26
MOL012266 rivularin jkm-45-2-55f39.gif 37.94 0.65 0.37
Table 2
Targets of Baicalein
Target Proteins of Baicalein Gene name UniProt ID
Aryl hydrocarbon receptor AHR P35869
RAC-alpha serine/threonine-protein kinase AKT1 P31749
Arachidonate 12-lipoxygenase, 12S-type ALOX12 P18054
Apolipoprotein D APOD P05090
Androgen receptor AR P10275
Apoptosis regulator BAX BAX Q07812
Apoptosis regulator Bcl-2 BCL2 P10415
Calmodulin CALM1 P0DP23
Caspase-3 CASP3 P42574
G2/mitotic-specific cyclin-B1 CCNB1 P14635
Cell division control protein 2 homolog CDK1 P06493
Cytochrome c CYCS P99999
Dipeptidyl peptidase IV DPP4 P27487
Egl nine homolog 1 EGLN1 Q9GZT9
Fatty acid-binding protein, epidermal FABP5 Q01469
Proto-oncogene c-Fos FOS P01100
Fos-related antigen 1 FOSL1 P15407
Fos-related antigen 2 FOSL2 P15408
Hypoxia-inducible factor 1-alpha HIF1A Q16665
Heat shock protein HSP 90 HSP90AB1 P08238
Insulin-like growth factor II IGF2 P01344
Matrix metalloproteinase-9 MMP9 P14780
Myeloperoxidase MPO P05164
Nuclear receptor coactivator 1 NCOA1 Q15788
Nuclear receptor coactivator 2 NCOA2 Q15596
Nuclear factor of activated T-cells, cytoplasmic 1 NFATC1 O95644
NADPH oxidase 5 NOX5 Q96PH1
CGMP-inhibited 3',5'-cyclic phosphodiesterase A PDE3A Q14432
Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit, gamma isoform PIK3CG P48736
mRNA of PKA Catalytic Subunit C-alpha PRKACA P17612
Trypsin-1 PRSS1 P07477
Prostaglandin G/H synthase 1 PTGS1 P23219
Prostaglandin G/H synthase 2 PTGS2 P35354
Transcription factor p65 RELA Q04206
Tudor domain-containing protein 7 TDRD7 Q8NHU6
Cellular tumor antigen p53 TP53 P04637
Vascular endothelial growth factor A VEGFA P15692
Table 3
Common Genes between Baicalein Target Genes between Each Diseases Keyword.
Viral Pneumonia Pneumonia Influenza SARS Coronavirus Infection
AHR AHR CASP3 DPP4
AKT1 AKT1 AKT1 AHR
APOD BAX APOD AKT1
AR BCL2 AR APOD
BAX CASP3 BAX AR
BCL2 DPP4 BCL2 BAX
CASP3 FABP5 CCNB1 BCL2
CDK1 FOSL1 CYCS CALM1
CYCS HIF1A FOS CASP3
EGLN1 MMP9 FOSL1 CCNB1
FABP5 MPO HIF1A CDK1
FOS PIK3CG MMP9 FABP5
FOSL1 PRSS1 MPO FOS
FOSL2 PTGS1 NFATC1 HIF1A
HIF1A PTGS2 PTGS2 HSP90AB1
IGF2 RELA RELA PIK3CG
MMP9 TP53 TP53 PRKACA
MPO VEGFA VEGFA PRSS1
NFATC1 PTGS2
NOX5 RELA
PDE3A TP53
PIK3CG VEGFA
PRKACA
PRSS1
PTGS1
PTGS2
RELA
TP53
VEGFA
Table 4
26 Genes Duplicated Two or More Times in Four Disease Names
Duplicated 4 times Duplicated 3 times Duplicated 2 times
AKT1 AHR CDK1
BAX FABP5 PRKACA
BCL2 PIK3CG PTGS1
CASP3 PRSS1 DPP4
HIF1A FOSL1 CYCS
PTGS2 MMP9 NFATC1
RELA MPO CCNB1
TP53 APOD
VEGFA AR
FOS

참고문헌

1. Ruuskanen O, Lahti E, Jennings LC, Murdoch DR. 2011; Viral pneumonia. Lancet. 377:1. 1264–75. 10.1016/S0140-6736(10)61459-6
crossref pmid pmc

2. Lee JY, Kim YJ, Lee ES, Lee YS. 2019; Seasonal trend and mortality in adults with viral pneumonia. Journal of the Korean Society of Emergency Medicine. 30:3. 265–72.


3. Pagliano P, Sellitto C, Conti V, Ascione T, Esposito S. 2021; Characteristics of viral pneumonia in the COVID-19 era: an update. Infection. 49:1. 607–16. 10.1007/s15010-021-01603-y
pmid pmc

4. Shun-Shin M, Thompson M, Heneghan C, Perera R, Hamden A, Mant D. 2009; Neuraminidase inhibitors for treatment and prophylaxis of influenza in children: Systematic review and meta-analysis of randomised controlled trials. BMJ. 339:1. 44910.1136/bmj.b3172
crossref

5. Jartti T, Vanto T, Heikkinen T, Ruuskanen O. 2002; Systemic glucocorticoids in childhood expiratory wheezing: relation between age and viral etiology with efficacy. Pediatr Infect Dis J. 21:9. 873–8. 10.1097/00006454-200209000-00019
crossref pmid

6. Stockman LJ, Bellamy R, Garner P. 2006; SARS: Systematic Review of Treatment Effects. PLoS Med. 3:9. 1525–31. 10.1371/journal.pmed.0030343
crossref

7. Falagas ME, Vouloumanou EK, Baskouta E, Rafailidis PI, Polyzos K, Rello J. 2010; Treatment options for 2009 H1N1 influenza: Evaluation of the published evidence. International Journal of Antimicrobial Agents. 35:1. 421–30. 10.1016/j.ijantimicag.2010.01.006
crossref pmid

8. Kwon JE, Ahn JY, Choi BS. 2017; Two patients with Mycoplasma pneumoniae pneumonia progressing to acute respiratory distress syndrome. Allergy, Asthma & Respiratory Disease. 5:3. 16910.4168/aard.2017.5.3.169


9. National University of Dept. of Internal Medicine. Pulmonary system. Internal Medicine Pulmonary system. Seoul: Han culture;2002. p. 249–313.


10. Shin WY, Hyun MK, Jeong BM, Choi EY, Yoon CH, Jeong JC. 2005; A clinical report of one old aged patient with pneumonia. Korean J Orient Int Med. 26:1. 229–35.


11. Hwang DY. Bangyakhappyeon. 14th ed. Seoul: Namsandang;2017. p. 137


12. The Committee of Herbalogy textbook. Herbalogy. 2013.


13. Liu H, Ye F, Sun Q, Liang H, Li C, Li S, et al. 2021; Scutellaria baicalensis extract and baicalein inhibit replication of SARS-CoV-2 and its 3C-like protease in vitro. J Enzyme Inhib Med Chem. 36:1. 497–503. 10.1080/14756366.2021.1873977
crossref pmid pmc

14. Xu X, Zhang W, Huang C, Li Y, Yu H, Wang Y, et al. 2012; A novel chemometric method for the prediction of human oral bioavailability. Int J Mol Sci. 13:6. 6964–82. 10.3390/ijms13066964
crossref pmid pmc

15. Zhuang Z, Wen J, Zhang L, Zhang M, Zhong X, Chen H, et al. 2020; Can network pharmacology identify the anti-virus and anti-inflammatory activities of Shuanghuanglian oral liquid used in Chinese medicine for respiratory tract infection? Eur J Integr Med. 37:1. 1–10. 10.1016/j.eujim.2020.101139
crossref

16. Szklarczyk D, Gable AL, Lyon D, Junge A, Wyder S, Huerta-Cepas J, et al. 2019; STRING v11: Protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res. 47:D1. D607–13. 10.1093/nar/gky1131
crossref pmid

17. Wu G, Hao Q, Liu B, Zhou J, Fan C, Liu R. 2022; Network pharmacology-based screening of the active ingredients and mechanisms of evodiae fructus anti-glioblastoma multiforme. Medicine. 101:1. E3085310.1097/MD.0000000000030853
crossref pmid pmc

18. Burnett BP, Jia Q, Zhao Y, Levy RM, Chen S. 2007; A medicinal extract of Scutellaria baicalensis and Acacia catechu acts as a dual inhibitor of cyclooxygenase and 5-lipoxygenase to reduce inflammation. J Med Food, 2007. 10:3. 442–51. 10.1089/jmf.2006.255
crossref

19. Hwang WD, Im YG, Son BY, Park C, Park D, Choi YH. 2013; Induction of Apoptosis by Ethanol Extract of Scutellaria baicalensis in Renal ell Carcinoma Caki-1 Cells. J Life Sci. 23:4. 518–28. 10.5352/JLS.2013.23.4.518
crossref

20. Shen YC, Chiou WF, Chou YC, Chen CF. 2003; Mechanisms in mediating the anti-inflammatory effects of baicalin and baicalein in human leukocytes. Eur J Pharmacol. 465:1–2. 171–81. 10.1089/jmf.2006.255
crossref pmid

21. Yong HS, Ko SG. 2004; Inhibition of Cellular Proliferation and Apoptosis by Scutellaria Bicalensis in MDA-MB-231 Breast Cancer Cells. Korean J Orient Int Med. 25:3. 451–60.


22. Heo J. Dongeuibogam. 5th ed. Hadong: Dongeuibogam Publishser;2016. p. 259


23. Moya AS, Elena SF, Bracho A, Miralles R, Barrio E. 2000; The evolution of RNA viruses: A population genetics view RNA Viruses: Biological and Population Properties. PNAS. 97:13. 6967–73. 10.1073/pnas.97.13.6967
pmid pmc

24. Zhao J, Tian S, Lu D, Yang J, Zeng H, Zhang F, et al. 2021; Systems pharmacological study illustrates the immune regulation, anti-infection, anti-inflammation, and multi-organ protection mechanism of Qing-Fei-Pai-Du decoction in the treatment of COVID-19. Phytomedicine. 85:1. 1–15. 10.1016/j.phymed.2020.153315
crossref

25. Brocard M, Lu J, Hall B, Borah K, Moller-Levet C, Georgana I, et al. 2021; Murine Norovirus Infection Results in Anti-inflammatory Response Downstream of Amino Acid Depletion in Macrophages. J Virol. 95:20. e01134–21. 10.1128/JVI.01134-21
pmid pmc

26. Wang J, Basagoudanavar SH, Wang X, Hopewell E, Albrecht R, García-Sastre A, et al. 2010; NF-κB RelA Subunit Is Crucial for Early IFN-β Expression and Resistance to RNA Virus Replication. The Journal of Immunology. 185:3. 1720–9. 10.4049/jimmunol.1000114
pmid

27. Wang Y, Guo X, Fan X, Zhang H, Xue D, Pan Z. 2022; The Protective Effect of Mangiferin on Osteoarthritis: An In Vitro and In Vivo Study. Physiol Res. 71:1. 135–45. 10.33549/physiolres.934747
crossref pmid pmc

28. Korbecki J, Kojder K, Kapczuk P, Kupnicka P, Gawrońska-Szklarz B, Gutowska I, et al. 2021; The effect of hypoxia on the expression of CXC chemokines and CXC chemokine receptors. International Journal of Molecular Sciences. 22:1. 1–30. 10.3390/ijms22020843


29. Kim EJ, Kim GT, Kim BM, Lim EG, Kim SY, Kim YM. 2017; Apoptosis-induced effects of extract from Artemisia annua Linné by modulating PTEN/p53/PDK1/Akt/signal pathways through PTEN/p53-independent manner in HCT116 colon cancer cells. BMC Complement Altern Med. 17:1. 1–12. 10.1186/s12906-017-1702-7
pmid pmc

30. Semenza GL. 2001; HIF-1 and mechanisms of hypoxia sensing. Curr Opin Cell Biol. 13:2. 167–71. 10.1016/s0955-0674(00)00194-0
crossref pmid

31. Hwang KY, Oh YT, Yoon H, Lee J, Kim H, Choe W, et al. 2008; Baicalein suppresses hypoxia-induced HIF-1α protein accumulation and activation through inhibition of reactive oxygen species and PI 3-kinase/Akt pathway in BV2 murine microglial cells. Neurosci Lett. 444:3. 264–9. 10.1016/j.neulet.2008.08.057
crossref pmid

32. Fröhlich S, Boylan J, Mcloughlin P. 2013; Hypoxia-induced inflammation in the lung: A potential therapeutic target in acute lung injury? American Journal of Respiratory Cell and Molecular Biology. 48:1. 271–9. 10.1165/rcmb.2012-0137TR
pmid

33. Serebrovska ZO, Chong EY, Serebrovska TV, Tumanovska LV, Xi L. 2020; Hypoxia, HIF-1α, and COVID-19: from pathogenic factors to potential therapeutic targets. Acta Pharmacologica Sinica. Springer Nature. 41:1. 1539–46. 10.1038/s41401-020-00554-8


34. Brahimi-Horn C, Mazure N, Pouysségur J. 2005; Signalling via the hypoxia-inducible factor-1α requires multiple posttranslational modifications. Cellular Signalling. 17:1. 1–9. 10.1016/j.cellsig.2004.04.010
crossref pmid

35. Liu J, Liu J, Tong X, Peng W, Wei S, Sun T, et al. 2021; Network pharmacology prediction and molecular docking-based strategy to discover the potential pharmacological mechanism of huai hua san against ulcerative colitis. Drug Des Devel Ther. 15:1. 3255–76. 10.2147/DDDT.S319786
pmid pmc

36. Zeng Z, Hu J, Jiang J, Xiao G, Yang R, Li S, et al. 2021; Network Pharmacology and Molecular Docking-Based Prediction of the Mechanism of Qianghuo Shengshi Decoction against Rheumatoid Arthritis. Biomed Res Int. 2021:1. 1–15. 10.1155/2021/6623912
pmid

37. Li X, Tang H, Tang Q, Chen W. 2021; Decoding the Mechanism of Huanglian Jiedu Decoction in Treating Pneumonia Based on Network Pharmacology and Molecular Docking. Front Cell Dev Biol. 18:9. 1–15. 10.3389/fcell.2021.638366
crossref

38. Li C, Pan J, Xu C, Jin Z, Chen X. 2022; A Preliminary Inquiry Into the Potential Mechanism of Huang-Lian-Jie-Du Decoction in Treating Rheumatoid Arthritis via Network Pharmacology and Molecular Docking. Front Cell Dev Biol. 9:1. 1–15. 10.3389/fcell.2021.740266
crossref

39. Fan L, Warnecke A, Weder J, Preller M, Zeilinger C. 2022; Triiodothyronine Acts as a Smart Influencer on Hsp90 via a Triiodothyronine Binding Site. Int J Mol Sci. 23:13. 1–12. 10.3390/ijms23137150
crossref

40. Ramos-Duarte VA, Orlowski A, Jaquenod de Giusti C, Corigliano MG, Legarralde A, Mendoza-Morales LF, et al. 2024; Safe plant Hsp90 adjuvants elicit an effective immune response against SARS-CoV2-derived RBD antigen. Vaccine. 42:14. 3355–3364. 10.1016/j.vaccine.2024.04.036
crossref pmid

41. Lubkowska A, Pluta W, Strońska A, Lalko A. 2021; Role of heat shock proteins (Hsp70 and hsp90) in viral infection. International Journal of Molecular Sciences. 22:1. 1–15. 10.3390/ijms22179366
crossref

42. Qin S, Hu X, Lin S, Xiao J, Wang Z, Jia J, et al. 2022; Hsp90 Inhibitors Prevent HSV-1 Replication by Directly Targeting UL42-Hsp90 Complex. Front Microbiol. 12:1. 1–10. 10.3389/fmicb.2021.797279
crossref

TOOLS
PDF Links  PDF Links
Full text via DOI  Full text via DOI
PubReader  PubReader
Download Citation  Download Citation
  Print
Share:      
METRICS
0
Crossref
300
View
13
Download
Editorial office contact information
3F, #26-27 Gayang-dong, Gangseo-gu Seoul, 157-200 Seoul, Korea
The Society of Korean Medicine
Tel : +82-2-2658-3627   Fax : +82-2-2658-3631   E-mail : skom1953.journal@gmail.com
About |  Browse Articles |  Current Issue |  For Authors and Reviewers
Developed in M2PI