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CC BY 4.0 · Pharmaceutical Fronts 2021; 03(02): e65-e76
DOI: 10.1055/s-0041-1735147
Original Article

Unveiling Potential Active Constituents and Pharmacological Mechanisms of Pudilanxiaoyan Oral Liquid for Anti-Coronavirus Pneumonia Using Network Pharmacology

Ying-Peng Tong
1   Institute of Natural Medicine and Health Product, School of Advanced Study, Taizhou University, Taizhou, People's Republic of China
,
Xiao-Fei Shen
2   TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, People's Republic of China
,
Chao Li
3   Jiangsu Key Laboratory of Chinese Medicine and Characteristic Preparations for Paediatrics, Jumpcan Pharmaceutical Co., Ltd., Taizhou, People's Republic of China
,
Qi Zhou
1   Institute of Natural Medicine and Health Product, School of Advanced Study, Taizhou University, Taizhou, People's Republic of China
,
Chun-Xiao Jiang
1   Institute of Natural Medicine and Health Product, School of Advanced Study, Taizhou University, Taizhou, People's Republic of China
,
Na Li
1   Institute of Natural Medicine and Health Product, School of Advanced Study, Taizhou University, Taizhou, People's Republic of China
,
Zhen-Da Xie
1   Institute of Natural Medicine and Health Product, School of Advanced Study, Taizhou University, Taizhou, People's Republic of China
,
Zi-Ping Zhu
1   Institute of Natural Medicine and Health Product, School of Advanced Study, Taizhou University, Taizhou, People's Republic of China
,
Jian-Xin Wang
1   Institute of Natural Medicine and Health Product, School of Advanced Study, Taizhou University, Taizhou, People's Republic of China
4   Department of Pharmaceutics, School of Pharmacy, Fudan University & Key Laboratory of Smart Drug Delivery, Ministry of Education, Shanghai, People's Republic of China
5   Institute of Integrative Medicine, Fudan University, Shanghai, People's Republic of China
› Institutsangaben Funding This research was funded by the Development Project of Shanghai Peak Disciplines-Integrative Medicine (Grant No. 20180101), the Special Project of International Technology Cooperation of One Belt and One Road (Grant No. 2017C04009), and the National Key Research and Development Program of China (Grant No. 2017YFC1703903).
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Abstract

The outbreak of novel coronavirus pneumonia (COVID-19), defined as a worldwide pandemic, has been a public health emergency of international concern. Pudilanxiaoyan oral liquid (PDL), an effective drug of Traditional Chinese Medicine (TCM), is considered to be an effective and alternative means for clinical prevention of COVID-19. The purpose of this study was to identify potential active constituents of PDL, and explore its underlying anti-COVID-19 mechanism using network pharmacology. Integration of target prediction (SwissTargetPrediction and STITCH database) was used to elucidate the active components of PDL. Protein–protein interaction network analyses, gene ontology, Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses, network construction, and molecular docking were applied to analyze the prospective mechanisms of the predicted target genes. Our results showed that the key active ingredients in PDL were luteolin, apigenin, esculetin, chrysin, baicalein, oroxylin A, baicalin, wogonin, cymaroside, and gallic acid. A majority of the predicted targets were mainly involved in the pathways related to viral infection, lung injury, and inflammatory responses. An in vitro study further inferred that inhibiting the activity of nuclear factor (NF)-кB signaling pathway was a key mechanism by which PDL exerted anti-COVID-19 effects. This study not only provides chemical basis and pharmacology of PDL but also the rationale for strategies to exploring future TCM for COVID-19 therapy.

Keywords

pudilanxiaoyan oral liquid - COVID-19 - active ingredients - network pharmacology - NF-кB signaling pathway

Supplementary Material



Publikationsverlauf

Eingereicht: 09. Mai 2021

Angenommen: 22. Juni 2021

Artikel online veröffentlicht:
27. August 2021

© 2021. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Lazarus JV, Ratzan SC, Palayew A. et al. A global survey of potential acceptance of a COVID-19 vaccine. Nat Med 2021; 27 (02) 225-228
    CrossrefPubMedGoogle Scholar
  • 2 Coronavirus WHO. (COVID-19) Dashboard. China. Accessed July, 2021 at: https://covid19.who.int/region/wpro/country/cn
    Google Scholar
  • 3 Wang D, Hu B, Hu C. et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus–infected pneumonia in Wuhan, China. JAMA 2020; 323 (11) 1061-1069
    CrossrefPubMedGoogle Scholar
  • 4 Luo H, Tang QL, Shang YX. et al. Can Chinese medicine be used for prevention of corona virus disease 2019 (COVID-19)? A review of historical classics, research evidence and current prevention programs. Chin J Integr Med 2020; 26 (04) 243-250
    CrossrefPubMedGoogle Scholar
  • 5 Committee NP. Chinese Pharmacopoeia. Beijing: Chemical Industry Press; 2015
    Google Scholar
  • 6 Yi Y. The effect of Pudilan Xiaoyan oral liquid (PDL) on the treatment of herpes simplex ulcerative esophagitis influenza A (H1N1). Mod J Integr Tradit Chin West Med 2010; 19: 2925-2926
    Google Scholar
  • 7 Wang LX, Miao Q, Xie YM. et al. Expert consensus statement on Pudilan Xiaoyan Oral Liquid in clinical practice [in Chinese]. Zhongguo Zhongyao Zazhi 2019; 44 (24) 5277-5281
    PubMedGoogle Scholar
  • 8 Xuan W, Li Y, Tao H. et al. Antiviral effects of pudilan xiaoyan oral liquid on respiratory syncytial virus and adenovirus in vitro . J Pract Med 2015; 31: 1838-1840
    Google Scholar
  • 9 Feng L, Yang N, Li C. et al. Pudilan xiaoyan oral liquid alleviates LPS-induced respiratory injury through decreasing nitroxidative stress and blocking TLR4 activation along with NF-ΚB phosphorylation in mice. J Ethnopharmacol 2018; 214: 292-300
    CrossrefPubMedGoogle Scholar
  • 10 Tian G, Li C, Zhai Y. et al. GC-MS based metabolomic profiling of lung tissue couple with network pharmacology revealed the possible protection mechanism of Pudilan Xiaoyan oral liquid in LPS-induced lung injury of mice. Biomed Pharmacother 2020; 124: 109833
    CrossrefPubMedGoogle Scholar
  • 11 Jin Y, Lin X, Song L. et al. The effect of pudilan anti-inflammatory oral liquid on the treatment of mild recurrent aphthous ulcers. Evid Based Complement Alternat Med 2017; 2017: 6250892
    PubMedGoogle Scholar
  • 12 Rujun S, Yuyu H, Xikun S. et al. Discussion on rational use of chinese patent medicine recommended from diagnosis and treatment protocols for COVID-19. Chin J Mod Appl Pharm 2020; 37: 782-787
    Google Scholar
  • 13 Deng W, Xu Y, Kong Q. et al. Therapeutic efficacy of Pudilan Xiaoyan Oral Liquid (PDL) for COVID-19 in vitro and in vivo. Signal Transduct Target Ther 2020; 5 (01) 66
    CrossrefPubMedGoogle Scholar
  • 14 Hopkins AL. Network pharmacology: the next paradigm in drug discovery. Nat Chem Biol 2008; 4 (11) 682-690
    CrossrefPubMedGoogle Scholar
  • 15 Cui S, Chen S, Wu Q, Chen T, Li S. A network pharmacology approach to investigate the anti-inflammatory mechanism of effective ingredients from Salvia miltiorrhiza. Int Immunopharmacol 2020; 81: 106040
    CrossrefPubMedGoogle Scholar
  • 16 Zhang J, Liang R, Wang L, Yang B. Effects and mechanisms of Danshen-Shanzha herb-pair for atherosclerosis treatment using network pharmacology and experimental pharmacology. J Ethnopharmacol 2019; 229: 104-114
    CrossrefPubMedGoogle Scholar
  • 17 Zhao LJ, Gao WY, Gu XR, Wang HJ, Zhao HY, Bian BL. Identification and attribution of chemical compounds of Pudilan Antiphlogistic Oral Liquid [in Chinese]. Zhongguo Zhongyao Zazhi 2019; 44 (08) 1573-1587
    PubMedGoogle Scholar
  • 18 Daina A, Michielin O, Zoete V. SwissTargetPrediction: updated data and new features for efficient prediction of protein targets of small molecules. Nucleic Acids Res 2019; 47 (W1): W357-W364
    CrossrefPubMedGoogle Scholar
  • 19 Gfeller D, Grosdidier A, Wirth M, Daina A, Michielin O, Zoete V. SwissTargetPrediction: a web server for target prediction of bioactive small molecules. Nucleic Acids Res 2014; 42 (Web Server issue): W32-W38
    CrossrefPubMedGoogle Scholar
  • 20 Kuhn M, von Mering C, Campillos M, Jensen LJ, Bork P. STITCH: interaction networks of chemicals and proteins. Nucleic Acids Res 2008; 36 (Database issue): D684-D688
    CrossrefPubMedGoogle Scholar
  • 21 Zeng Q, Li L, Siu W. et al. A combined molecular biology and network pharmacology approach to investigate the multi-target mechanisms of Chaihu Shugan San on Alzheimer's disease. Biomed Pharmacother 2019; 120: 109370
    CrossrefPubMedGoogle Scholar
  • 22 Kuhn M, Szklarczyk D, Franceschini A, von Mering C, Jensen LJ, Bork P. STITCH 3: zooming in on protein-chemical interactions. Nucleic Acids Res 2012; 40 (Database issue): D876-D880
    CrossrefPubMedGoogle Scholar
  • 23 Szklarczyk D, Gable AL, Lyon D. et al. STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res 2019; 47 (D1): D607-D613
    CrossrefPubMedGoogle Scholar
  • 24 Wu C, Liu Y, Yang Y. et al. Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods. Acta Pharm Sin B 2020; 10 (05) 766-788
    CrossrefPubMedGoogle Scholar
  • 25 Xu H, Zhong L, Deng J. et al. High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa. Int J Oral Sci 2020; 12 (01) 8
    CrossrefPubMedGoogle Scholar
  • 26 O'Boyle NM, Banck M, James CA, Morley C, Vandermeersch T, Hutchison GR. Open Babel: an open chemical toolbox. J Cheminform 2011; 3: 33
    CrossrefPubMedGoogle Scholar
  • 27 Trott O, Olson AJ. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 2010; 31 (02) 455-461
    PubMedGoogle Scholar
  • 28 Jin Z, Du X, Xu Y. et al. Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors. Nature 2020; 582 (7811): 289-293
    CrossrefPubMedGoogle Scholar
  • 29 Hoffmann M, Kleine-Weber H, Schroeder S. et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 2020; 181 (02) 271.e8-280.e8
    Google Scholar
  • 30 Wang M, Cao R, Zhang L. et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res 2020; 30 (03) 269-271
    CrossrefPubMedGoogle Scholar
  • 31 Huang Y, Yang R, Xu Y, Gong P. Clinical characteristics of 36 non-survivors with COVID-19 in Wuhan, China. medRxiv 2020; Accessed July 1, 2021 at: https://www.medrxiv.org/content/10.1101/2020.02.27.20029009v2
    Google Scholar
  • 32 Li G, De Clercq E. Therapeutic options for the 2019 novel coronavirus (2019-nCoV). Nat Rev Drug Discov 2020; 19 (03) 149-150
    CrossrefPubMedGoogle Scholar
  • 33 Ruan RY, Deng XM, Wang Z. et al. Simultaneous determination of 9 constituents in Pudilan Xiaoyan Oral Liquid by UPLC [in Chinese]. Xibei Yaoxue Zazhi 2021; 36: 194-197
    Google Scholar
  • 34 Shao ZB, Zhu YX, Liu SH, Jiang KJ, Liu WW. A review on the clinical application of high frequency traditional Chinese medicine in the treatment of new coronavirus pneumonia. Chin Tradit Herbal Drugs 2020; 51: 1153-1158
    Google Scholar
  • 35 Yang A, Liu H, Liu F. et al. Study of the mechanism of the Reyanning mixture involved in treating novel coronavirus pneumonia based on network pharmacology. Nat Prod Commun 2020; 15: 1-12
    Google Scholar
  • 36 Li Y, Zhang J, Li S. et al. Efficacy and safety of Reyanning mixture combined with conventional Western medicine for treating COVID-19: a protocol for systematic review and meta-analysis. Medicine (Baltimore) 2021; 100 (03) e24169
    CrossrefPubMedGoogle Scholar
  • 37 Zhai XT, Chen JQ, Jiang CH. et al. Corydalis bungeana Turcz. attenuates LPS-induced inflammatory responses via the suppression of NF-κB signaling pathway in vitro and in vivo. J Ethnopharmacol 2016; 194: 153-161
    CrossrefPubMedGoogle Scholar
  • 38 Lin CW, Tsai FJ, Tsai CH. et al. Anti-SARS coronavirus 3C-like protease effects of Isatis indigotica root and plant-derived phenolic compounds. Antiviral Res 2005; 68 (01) 36-42
    CrossrefPubMedGoogle Scholar
  • 39 Fung TS, Liu DX. Activation of the c-Jun NH2-terminal kinase pathway by coronavirus infectious bronchitis virus promotes apoptosis independently of c-Jun. Cell Death Dis 2017; 8 (12) 3215
    CrossrefPubMedGoogle Scholar
  • 40 Pleschka S. RNA viruses and the mitogenic Raf/MEK/ERK signal transduction cascade. Biol Chem 2008; 389 (10) 1273-1282
    CrossrefPubMedGoogle Scholar
  • 41 Yin Q, Han T, Fang B. et al. K27-linked ubiquitination of BRAF by ITCH engages cytokine response to maintain MEK-ERK signaling. Nat Commun 2019; 10 (01) 1870
    CrossrefPubMedGoogle Scholar
  • 42 Mizutani T, Fukushi S, Saijo M, Kurane I, Morikawa S. JNK and PI3k/Akt signaling pathways are required for establishing persistent SARS-CoV infection in Vero E6 cells. Biochim Biophys Acta 2005; 1741 (1–2): 4-10
    CrossrefPubMedGoogle Scholar
  • 43 Chen N, Zhou M, Dong X. et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet 2020; 395 (10223): 507-513
    CrossrefPubMedGoogle Scholar
  • 44 Schett G, Sticherling M, Neurath MF. COVID-19: risk for cytokine targeting in chronic inflammatory diseases?. Nat Rev Immunol 2020; 20 (05) 271-272
    CrossrefPubMedGoogle Scholar
  • 45 Bradbury RS, Piedrafita D, Greenhill A, Mahanty S. Will helminth co-infection modulate COVID-19 severity in endemic regions?. Nat Rev Immunol 2020; 20 (06) 342
    CrossrefPubMedGoogle Scholar
  • 46 Cao X. COVID-19: immunopathology and its implications for therapy. Nat Rev Immunol 2020; 20 (05) 269-270
    CrossrefPubMedGoogle Scholar
  • 47 Jackson DJ, Busse WW, Bacharier LB. et al. Association of respiratory allergy, asthma, and expression of the SARS-CoV-2 receptor ACE2. J Allergy Clin Immunol 2020; 146 (01) 203.e3-206.e3
    CrossrefPubMedGoogle Scholar
  • 48 Kai H, Kai M. Interactions of coronaviruses with ACE2, angiotensin II, and RAS inhibitors-lessons from available evidence and insights into COVID-19. Hypertens Res 2020; 43 (07) 648-654
    CrossrefPubMedGoogle Scholar
  • 49 Li Y, Zeng Z, Cao Y. et al. Angiotensin-converting enzyme 2 prevents lipopolysaccharide-induced rat acute lung injury via suppressing the ERK1/2 and NF-κB signaling pathways. Sci Rep 2016; 6: 27911
    CrossrefPubMedGoogle Scholar
  • 50 Fung TS, Liu DX. Human coronavirus: host-pathogen interaction. Annu Rev Microbiol 2019; 73: 529-557
    CrossrefPubMedGoogle Scholar
  • 51 Gao Y, Kang L, Li C. et al. Resveratrol ameliorates diabetes-induced cardiac dysfunction through AT1R-ERK/p38 MAPK signaling pathway. Cardiovasc Toxicol 2016; 16 (02) 130-137
    CrossrefPubMedGoogle Scholar
  • 52 Yan YS, Cao X, Zhang Y. et al. Discovery of anti-2019-nCoV agents from 38 Chinese patent drugs toward respiratory diseases via docking screening. Preprints 2020; 2020020254 . Accessed July 1, 2021 at: https://www.preprints.org/manuscript/202002.0254/v2
    Google Scholar
  • 53 Chen H, Du Q. Potential natural compounds for preventing 2019-nCoV infection. Preprints 2020; 2020010358 . Accessed July 1, 2021 at: https://www.preprints.org/manuscript/202001.0358/v2
    Google Scholar
  • 54 Chen F, Chan KH, Jiang Y. et al. In vitro susceptibility of 10 clinical isolates of SARS coronavirus to selected antiviral compounds. J Clin Virol 2004; 31 (01) 69-75
    CrossrefPubMedGoogle Scholar
  • 55 Zhou Y, Hou Y, Shen J. et al. Network-based drug repurposing for human coronavirus. medRxiv 2020; Accessed July 1, 2021 at: https://www.medrxiv.org/content/10.1101/2020.02.03.20020263v1
    Google Scholar
  • 56 Zheng N, Li Q, Sun S. et al. The synergistic effects of the bupleurum-scutellaria herbal pair in alcoholic liver injury revealed by metabolomics and metallomics. Front Pharmacol 2019; 10: 254
    CrossrefPubMedGoogle Scholar
  • 57 Luan X, Zhang LJ, Li XQ. et al. Compound-based Chinese medicine formula: from discovery to compatibility mechanism. J Ethnopharmacol 2020; 254: 112687
    CrossrefPubMedGoogle Scholar
  • 58 Zhang B, Saatman KE, Chen L. Therapeutic potential of natural compounds from Chinese medicine in acute and subacute phases of ischemic stroke. Neural Regen Res 2020; 15 (03) 416-424
    CrossrefPubMedGoogle Scholar
  • 59 Caesar LK, Cech NB. Synergy and antagonism in natural product extracts: when 1 + 1 does not equal 2. Nat Prod Rep 2019; 36 (06) 869-888
    CrossrefPubMedGoogle Scholar
  • 60 Shi XQ, Yue SJ, Tang YP. et al. A network pharmacology approach to investigate the blood enriching mechanism of Danggui buxue decoction. J Ethnopharmacol 2019; 235: 227-242
    CrossrefPubMedGoogle Scholar
  • 61 Cai FF, Bian YQ, Wu R. et al. Yinchenhao decoction suppresses rat liver fibrosis involved in an apoptosis regulation mechanism based on network pharmacology and transcriptomic analysis. Biomed Pharmacother 2019; 114: 108863
    CrossrefPubMedGoogle Scholar
  • 62 Tao Y, Tian K, Chen J. et al. Network pharmacology-based prediction of the active compounds, potential targets, and signaling pathways involved in Danshiliuhao Granule for treatment of liver fibrosis. Evid Based Complement Alternat Med 2019; 2019: 2630357
    PubMedGoogle Scholar
  • 63 Blaženović I, Kind T, Ji J, Fiehn O. Software tools and approaches for compound identification of LC-MS/MS data in metabolomics. Metabolites 2018; 8 (02) 1-23
    CrossrefPubMedGoogle Scholar
  • 64 Schulte-Michels J, Keksel C, Häberlein H, Franken S. Anti-inflammatory effects of ivy leaves dry extract: influence on transcriptional activity of NFκB. Inflammopharmacology 2019; 27 (02) 339-347
    CrossrefPubMedGoogle Scholar
  • 65 Ma Q, Pan W, Li R. et al. Liu Shen capsule shows antiviral and anti-inflammatory abilities against novel coronavirus SARS-CoV-2 via suppression of NF-κB signaling pathway. Pharmacol Res 2020; 158: 104850
    CrossrefPubMedGoogle Scholar