Material basis and pharmacodynamic mechanism of YangshenDingzhi granules in the intervention of viral pneumonia: Based on serum pharmacochemistry and network pharmacology

Abstract

Background: YangshenDingzhi granules (YSDZ) are clinically effective in preventing and treating COVID-19. The present study elucidates the underlying mechanism of YSDZ intervention in viral pneumonia by employing serum pharmacochemistry and network pharmacology.

Methods: The chemical constituents of YSDZ in the blood were examined using ultra-performance liquid chromatography-quadrupole/orbitrap high-resolution mass spectrometry (UPLC-Q-Exactive Orbitrap MS). Potential protein targets were obtained from the SwissTargetPrediction database, and the target genes associated with viral pneumonia were identified using GeneCards, DisGeNET, and Online Mendelian Inheritance in Man (OMIM) databases. The intersection of blood component-related targets and disease-related targets was determined using Venny 2.1. Protein–protein interaction networks were constructed using the STRING database. The Metascape database was employed to perform enrichment analyses of Gene Ontology (GO) functions and Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathways for the targets, while the Cytoscape 3.9.1 software was utilized to construct drug-component-disease-target-pathway networks. Further, in vitro and in vivo experiments were performed to establish the therapeutic effectiveness of YSDZ against viral pneumonia.

Results: Fifteen compounds and 124 targets linked to viral pneumonia were detected in serum. Among these, MAPK1, MAPK3, AKT1, EGFR, and TNF play significant roles. In vitro tests revealed that the medicated serum suppressed the replication of H1N1, RSV, and SARS-CoV-2 replicon. Further, in vivo testing analysis shows that YSDZ decreases the viral load in the lungs of mice infected with RSV and H1N1.

Conclusion: The chemical constituents of YSDZ in the blood may elicit therapeutic effects against viral pneumonia by targeting multiple proteins and pathways.

Keywords

network pharmacology / pharmacodynamical material basis / serum pharmacochemistry / viral pneumonia / YangshenDingzhi granules

References

[1] Jain S. Epidemiology of viral pneumonia. Clin Chest Med. 2017;38(1):1-9.

[2] Zhang Z. Inner Canon of Yellow Emperor. Northern Literature and Art Publishing House; 2007.

[3] Luo C, Ye Y, Sheng G, Li X, Zheng L, Ke J. Research progress on pneumonia-related signaling pathways and traditional Chinese medicine treatment. World Chin Med. 2023;18(12):1778-1783+1788.

[4] Li C. Introduction to Medicine. China Traditional Chinese Medicine Publishing House; 1995.

[5] Liu P. Clinical Observation of YSDZ Granule in the Treatment of Somatic Symptom Disorder. Shandong University of Traditional Chinese Medicine. MA thesis; 2022.

[6] Lv S, Dai W, Zheng Y, et al. Anxiolytic effect of YangshenDingzhi granules: integrated network pharmacology and hippocampal metabolomics. Front Pharmacol. 2022;13:966218.

[7] Zhao R. The Effects of YangShenDingZhi Granule on cAMP-PKA-CREB-BDNF Signaling Pathway and Inflammatory Factors in Insomnia Rats. Shandong University of Traditional Chinese Medicine. MA thesis; 2022.

[8] Lv S. Study on the Anxiolytic Mechanism of YangShenDingzhi Granule Based on YangXinAnShen Therapy[D]. Shandong University of Traditional Chinese Medicine. MA thesis; 2023.

[9] Chen W, Jie X, Chen T, Zhang Y, Hao X. Status quo of research on the serum pharmaceutical chemistry of Chinese materia medica. Chin Med Pharm. 2023;13(4):26-29+86.

[10] Wang X, Liu X, Han Y, et al. Overview on main research method of effective material basis of Chinese materia medica. Chin Tradit Herb Drug. 2018;49(4):941-947.

[11] Zhuang Y, Cai B, Zhang Z. Application Progress of network pharmacology in traditional Chinese medicine research. J Nanjing Univ Tradit Chin Med. 2021;37(1):156-160.

[12] Yuan H, Ma Q, Cui H, et al. How can synergism of traditional medicines benefit from network pharmacology? Molecules. 2017;22(7):1135.

[13] Wu Y, Cheng Y, Yang Y, et al. Mechanisms of Gegen Qinlian Pill to ameliorate irinotecan-induced diarrhea investigated by the combination of serum pharmacochemistry and network pharmacology. J Ethnopharmacol. 2021;276:114200.

[14] Wang X, Wang ZY, Zheng JH, Li S. TCM network pharmacology: a new trend towards combining computational, experimental and clinical approaches. Chin J Nat Med. 2021;19(1):1-11.

[15] 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.

[16] Paolacci S, Precone V, Acquaviva F, et al. Genetics of lipedema: new perspectives on genetic research and molecular diagnoses. Eur Rev Med Pharmacol Sci. 2019;23(13):5581-5594.

[17] Piñero J, Rodriguez Fraga PS, Valls-Margarit J, et al. Genomic and proteomic biomarker landscape in clinical trials. Comput Struct Biotechnol J. 2023;21:2110-2118.

[18] Amberger JS, Bocchini CA, Schiettecatte F, Scott AF, Hamosh A. OMIM.org: online Mendelian Inheritance in Man (OMIM®), an online catalog of human genes and genetic disorders. Nucleic Acids Res. 2015;43(Database issue):D789-D798.

[19] Tang S, Jing H, Huang Z, et al. Identification of key candidate genes in neuropathic pain by integrated bioinformatic analysis. J Cell Biochem. 2019;121(2):1635-1648.

[20] Zhou Y, Zhou B, Pache L, et al. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat Commun. 2019;10(1):1523.

[21] Drenichev MS, Borokh VN. Purine nucleosides and analogues bearing chiral substituents: medicinal chemistry and therapeutic perspective. Curr Med Chem. 2024;31(6):671-682.

[22] Grimes SL, Choi YJ, Banerjee A, et al. A mutation in the coronavirus nsp13-helicase impairs enzymatic activity and confers partial remdesivir resistance. MBio. 2023;14(1):e0106023.

[23] Zou H, Wu T, Wang Y, et al. 5-Hydroxymethylfurfural enhances the antiviral immune response in macrophages through the modulation of RIG-I-mediated interferon production and the JAK/STAT signaling pathway. ACS Omega. 2021;6(42):28019-28030.

[24] Song J, He Y, Luo C, et al. New progress in the pharmacology of protocatechuic acid: a compound ingested in daily foods and herbs frequently and heavily. Pharmacol Res. 2020;161(161):105109.

[25] Wang Q, Ren X, Wu J, et al. Protocatechuic acid protects mice from influenza A virus infection. Eur J Clin Microbiol Infect Dis. 2022;41(4):589-596.

[26] Liu CL, Cheng L, Ko CH, et al. Bioassay-guided isolation of anti-inflammatory components from the root of Rehmannia glutinosa and its underlying mechanism via inhibition of iNOS pathway. J Ethnopharmacol. 2012;143(3):867-875.

[27] Duan F, Li Y, Zhao M, et al. Screening of anti-inflammatory components of Qin Jin Hua Tan Tang by a multivariate statistical analysis approach for Spectrum-effect relationships. J Anal Methods Chem. 2021;2021:6348979.

[28] Liu J, Xin Y, Qiu Z, et al. Bioconversion of ginsenoside Rf into its hydrated derivative with elevated anti-inflammatory effect by a highly specific biocatalytic system of Cordyceps sinensis. Chem Biodivers. 2023;20(4):e202200421.

[29] Lim HJ, Lee JH, Choi JS, Lee SK, Kim YS, Kim HP. Inhibition of airway inflammation by the roots of Angelica decursiva and its constituent, columbianadin. J Ethnopharmacol. 2014;155(2):1353-1361.

[30] Dai W, Chen J. Synthesis and anti-inflammatory structure-activity relationship of Cimifugin derivatives. Guangdong Chem Indus. 2023;50(4):13-16.

[31] Liu A, Zhao W, Zhang B, Tu Y, Wang Q, Li J. Cimifugin ameliorates imiquimod-induced psoriasis by inhibiting oxidative stress and inflammation via NF-κB/MAPK pathway. Biosci Rep. 2020;40(6):BSR20200471.

[32] Han B, Dai Y, Wu H, et al. Cimifugin inhibits inflammatory responses of RAW264.7 cells induced by lipopolysaccharide. Med Sci Monit. 2019;25:409-417.

[33] Li WJ, Luo FL, Wang FZ, et al. Exploring the mechanism of Lonicerae japonicae flos water extract in the treatment of sepsis. Chin J Comp Med. 2022;32(8):79-89.

[34] Guo MF, Dai YJ, Gao JR, Chen P-J. Uncovering the mechanism of astragalus membranaceus in the treatment of diabetic nephropathy based on network pharmacology. J Diabetes Res. 2020;2020:5947304.

[35] Di Paola R, Crisafulli C, Mazzon E, et al. Effect of PD98059, a selective MAPK3/MAPK1 inhibitor, on acute lung injury in mice. Int J Immunopathol Pharmacol. 2009;22(4):937-950.

[36] Appelberg S, Gupta S, Svensson Akusjärvi S, et al. Dysregulation in Akt/mTOR/HIF-1 signaling identified by proteo-transcriptomics of SARS-CoV-2 infected cells. Emerg Microbes Infect. 2020;9(1):1748-1760.

[37] Wu WY, Jiao X, Song WX, et al. Network pharmacology and bioinformatics analysis identifies potential therapeutic targets of Naringenin against COVID-19/LUSC. Front Endocrinol (Lausanne). 2023;14:1187882.

[38] He D, Wang Z, Cao B. Potential value of epidermal growth factor receptor inhibitors in the treatment of COVID-19. Int J Respir. 2023;43(5):497-503.

[39] Cheng W, Wang X, Wu Y, et al. Huanglian-Houpo extract attenuates DSS-induced UC mice by protecting intestinal mucosal barrier and regulating macrophage polarization. J Ethnopharmacol. 2023;307:116181.

[40] Lekshmi VS, Asha K, Sanicas M, Asi A, Arya UM, Kumar B. PI3K/Akt/Nrf2 mediated cellular signaling and virus-host interactions: latest updates on the potential therapeutic management of SARS-CoV-2 infection. Front Mol Biosci. 2023;10:1158133.

[41] Li L, Wang C, Zhang Y, Deng X. Research progress on the role of C-type lectins in immunity against infection. Int J Anesth Resus. 2021;42(1):98-102.

[42] Papin L, Lehmann M, Lagisquet J, et al. The autophagy nucleation factor ATG9 forms nanoclusters with the HIV-1 receptor DC-SIGN and regulates early antiviral autophagy in human dendritic cells. Int J Mol Sci. 2023;24(10):9008.

[43] Dandachi D, Rodriguez-Barradas MC. Viral pneumonia: etiologies and treatment. J Investig Med. 2023;66(6):957-965.

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2024 The Author(s). Animal Models and Experimental Medicine published by John Wiley & Sons Australia, Ltd on behalf of The Chinese Association for Laboratory Animal Sciences.