DOI QR코드

DOI QR Code

네트워크 약리학 분석을 통한 황금의 바이러스성 폐렴 치료 기전 예측: HIF-1α와 HSP90 조절을 통한 저산소 상태 조절을 중심으로

Prediction of Treatment Mechanisms of Scutellariae Radix on Viral Pneumonia Through Network Pharmacology: Focus on Hypoxic State Regulation Through HIF-1α and HSP90

  • 손지원 (부산대학교 한의학전문대학원 한의학과) ;
  • 한도경 (부산대학교 한의학전문대학원 한의학과) ;
  • 김윤숙 (부산대학교 장수웰빙연구소) ;
  • 안원근 (부산대학교 한의학전문대학원 한의학과)
  • Jee-won Shon (Department of Korean Medicine, School of Korean Medicine, Pusan National University) ;
  • Do Kyung Han (Department of Korean Medicine, School of Korean Medicine, Pusan National University) ;
  • Youn Sook Kim (Research Institute for Longevity and Well-Being, Pusan National University) ;
  • Won Gun An (Department of Korean Medicine, School of Korean Medicine, Pusan National University)
  • 투고 : 2024.04.15
  • 심사 : 2024.05.14
  • 발행 : 2024.06.01

초록

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.

키워드

과제정보

본 연구는 한국연구재단 [NRF-2021R1I1A3A04037158], [NRF-2021R1I1A1A01058697] 지원을 받아 수행되었음.

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.
  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.
  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), 449. 10.1136/bmj.b3172.
  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.
  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.
  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.
  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), 169. 10.4168/aard.2017.5.3.169.
  9. National University of Dept. of Internal Medicine. Pulmonary system. Internal Medicine Pulmonary system. Seoul: Han culture; 2002. 249-313 p.
  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. 137 p.
  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.
  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.
  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.
  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.
  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), E30853. 10.1097/MD.0000000000030853.
  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.
  19. Hwang WD, Im YG, Son BY, Park C, Park D Il, 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
  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.
  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. 259 p.
  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.
  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.
  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.
  26. Wang J, Basagoudanavar SH, Wang X, Hopewell E, Albrecht R, Garcia-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.
  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.
  28. Korbecki J, Kojder K, Kapczuk P, Kupnicka P, Gawronska-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 Linne 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.
  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.
  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.
  32. Frohlich 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.
  33. Serebrovska ZO, Chong EY, Serebrovska T V., Tumanovska L V., 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, Pouyssegur 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.
  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.
  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.
  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.
  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.
  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.
  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.
  41. Lubkowska A, Pluta W, Stronska 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.
  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.