Discovery of pharmacological effects and _targets of <em>Citri Grandis Exocarpium based</em> on SYSTCM and virtual screening

Qinqi Feng; Xinyang Shu; Hanyu Fang; Xiaoxi Shi; Yanling Zhang; Hongchun Zhang

doi:10.29219/fnr.v68.10618

Qinqi Feng Beijing University of Chinese Medicine, Beijing, China;; and Department of Traditional Chinese Medicine for Pulmonar y Diseases, National Center for Respirator y Medicine, National Clinical Research Center for Respirator y Diseases, Institute of Respirator y Medicine, Center of Respirator y Medicine, China-Japan Friendship Hospital Chinese Academy of Medical Sciences, Beijing, China
Xinyang Shu Department of Traditional Chinese Medicine for Pulmonar y Diseases, National Center for Respirator y Medicine, National Clinical Research Center for Respirator y Diseases, Institute of Respirator y Medicine, Center of Respirator y Medicine, China-Japan Friendship Hospital Chinese Academy of Medical Sciences, Beijing, China
Hanyu Fang Beijing University of Chinese Medicine, Beijing, China; and Department of Traditional Chinese Medicine for Pulmonar y Diseases, National Center for Respirator y Medicine, National Clinical Research Center for Respirator y Diseases, Institute of Respirator y Medicine, Center of Respirator y Medicine, China-Japan Friendship Hospital Chinese Academy of Medical Sciences, Beijing, China
Xiaoxi Shi Beijing University of Chinese Medicine, Beijing, China; and Department of Traditional Chinese Medicine for Pulmonar y Diseases, National Center for Respirator y Medicine, National Clinical Research Center for Respirator y Diseases, Institute of Respirator y Medicine, Center of Respirator y Medicine, China-Japan Friendship Hospital Chinese Academy of Medical Sciences, Beijing, China
Yanling Zhang Key Laboratory of TCM-information Engineer of State Administration of TCM, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China
Hongchun Zhang Department of Traditional Chinese Medicine for Pulmonar y Diseases, National Center for Respirator y Medicine, National Clinical Research Center for Respirator y Diseases, Institute of Respirator y Medicine, Center of Respirator y Medicine, China-Japan Friendship Hospital Chinese Academy of Medical Sciences, Beijing, China

DOI: https://doi.org/10.29219/fnr.v68.10618

Keywords: Citri Grandis Exocarpium, Antiallergic effect, TCM, SYSTCM

Abstract

Citri Grandis Exocarpium (Huajuhong, CGE) is the peel of the unripe fruits of Citrus grandis ‘Tomentosa’ and Citrus grandis (L.) Osbeck, which is commonly used in the clinic for the treatment of cough and indigestion. The pharmacological mechanism of CGE is unclear. In this study, the pharmacological effect of CGE was predicted by System Traditional Chinese Medicine (SYSTCM), which integrated the pharmacological effect prediction approach by artificial intelligence into the systemic traditional Chinese medicine (TCM) platform. The main pharmacological effect of CGE was antiallergy, promoting bile, blood lipid regulation, cardiotonics, diuresis, and antiarrhythmia by prediction of SYSTCM. In vitro cell experiments were carried out to identify the antiallergic effect of CGE. Extracts of Citri Grandis Exocarpium (ECGE) inhibited lipopolysaccharide-induced cell injury and nitric oxide release in RAW264.7 cells. ECGE and naringin-inhibited immunoglobulin E-induced cell degranulation in RBL-2H3 cells. _target profiling, protein interaction network, and molecular docking of compounds from CGE indicated that mitogen-activated protein kinase 14 (MAPK14) and matrix metalloprotease 9 (MMP9) were key potential _targets of CGE with antiallergic activity. This study identified and validated the antiallergic effect of CGE by combining SYSTCM, cell experiments, and virtual screening, which provided a new paradigm and approach for studying the pharmacological effect and mechanism of TCM.

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References

1.
Su C, Wong K-L, But PP-H, Su W-W, Shaw P-C. Molecular authentication of the Chinese herb Huajuhong and related medicinal material by DNA sequencing and ISSR markers. J Food Drug Anal 2010; 18: 161–70. doi: 10.38212/2224-6614.2267

2.
Xu Z, Li J, Zhou K, Wang K, Hu H, Hu Y, et al. Exocarpium Citri Grandis ameliorates LPS-induced acute lung injury by suppressing inflammation, NLRP3 inflammasome, and ferroptosis. J Ethnopharmacol 2024; 329: 118162. doi: 10.1016/j.jep.2024.118162

3.
Deng G, Liu C, Zhao J, Wang M, Li Y, Yang M, et al. Exocarpium Citri Grandis alleviates the aggravation of NAFLD by mitigating lipid accumulation and iron metabolism disorders. J Ethnopharmacol 2023; 313: 116559. doi: 10.1016/j.jep.2023.116559

4.
Liu G, Li S, Zhang N, Wei N, Wang M, Liu J, et al. Sequential grade evaluation method exploration of Exocarpium Citri Grandis (Huajuhong) decoction pieces based on ‘network prediction → grading quantization → efficacy validation’. J Ethnopharmacol 2022; 291: 115149. doi: 10.1016/j.jep.2022.115149

5.
Tocmo R, Pena-Fronteras J, Calumba KF, Mendoza M, Johnson JJ. Valorization of pomelo (Citrus grandis Osbeck) peel: a review of current utilization, phytochemistry, bioactivities, and mechanisms of action. Compr Rev Food Sci Food Saf 2020; 19: 1969–2012. doi: 10.1111/1541-4337.12561

6.
Ru J, Li P, Wang J, Zhou W, Li B, Huang C, et al. TCMSP: a database of systems pharmacology for drug discovery from herbal medicines. J Cheminform 2014; 6: 13. doi: 10.1186/1758-2946-6-13

7.
Xu H, Zhang Y, Liu Z, Chen T, Lv C, Tang S, et al. ETCM: an encyclopaedia of traditional Chinese medicine. Nucleic Acids Res 2019; 47: D976–82. doi: 10.1093/nar/gky987

8.
Fang S, Dong L, Liu L, Guo J, Zhao L, Zhang J, et al. HERB: a high-throughput experiment-and reference-guided database of traditional Chinese medicine. Nucleic Acids Res 2021; 49: D1197–206. doi: 10.1093/nar/gkaa1063

9.
Huo M, Peng S, Li J, Zhang Y, Qiao Y. A discovery strategy for active compounds of Chinese medicine based on the prediction model of compound-disease relationship. J Oncol 2022; 2022: 8704784. doi: 10.1155/2022/8704784

10.
Xia T, Ma J, Sun Y, Sun Y. Androgen receptor suppresses inflammatory response of airway epithelial cells in allergic asthma through MAPK1 and MAPK14. Hum Exp Toxicol 2022; 41: 9603271221121320. doi: 10.1177/09603271221121320

11.
Corry DB, Kiss A, Song LZ, Song L, Xu J, Lee SH, et al. Overlapping and independent contributions of MMP2 and MMP9 to lung allergic inflammatory cell egression through decreased CC chemokines. Faseb J 2004; 18: 995–7. doi: 10.1096/fj.03-1412fje

12.
Qiao L, He Y, Huo X, Jiang L, Chen Y, Chen X, et al. Construction and evaluation of merged pharmacophore based on peroxisome proliferator receptor-alpha agonists. Chin J Chem Phys 2016; 29: 508–16. doi: 10.1063/1674-0068/29/cjcp1602025

13.
Xiong G, Liu S, Gao J, Shumin W. Naringin protects ovalbumin-induced airway inflammation in a mouse model of asthma. Inflammation 2016; 39: 891–9. doi: 10.1007/s10753-016-0321-7

14.
Lee C-M, Chang J-H, Jung I-D, Jeong Y-I, Tae N-K, Park H-j, et al. Naringin protects ovalbumin-induced asthma through the down-regulation of MMP-9 activity and GATA-3 gene. J Life Sci 2009; 19: 735–43. doi: 10.5352/JLS.2009.19.6.735

15.
Ni K, Guo J, Bu B, Pan Y, Li J, Liu L, et al. Naringin as a plant-derived bitter tastant promotes proliferation of cultured human airway epithelial cells via activation of TAS2R signaling. Phytomedicine 2021; 84: 153491. doi: 10.1016/j.phymed.2021.153491

16.
Wang J, Zhou Y, Zhang H, Hu L, Liu J, Wang L, et al. Pathogenesis of allergic diseases and implications for therapeutic interventions. Signal Transduct _targeted Ther 2023; 8: 138. doi: 10.1038/s41392-023-01344-4

17.
Jiménez-Andrade Y, Hillette KR, Yoshida T, Kashiwagi M, Choo M-K, Liang Y, et al. The developmental transcription factor p63 is redeployed to drive allergic skin inflammation through phosphorylation by p38α. J Immunol 2022; 208: 2613–21. doi: 10.4049/jimmunol.2101160

18.
Yong H-Y, Koh M-S, Moon A. The p38 MAPK inhibitors for the treatment of inflammatory diseases and cancer. Expert Opin Investig Drugs 2009; 18: 1893–905. doi: 10.1517/13543780903321490

19.
Bouazza B, Debba-Pavard M, Amrani Y, Isaacs L, O’Connell D, Ahamed S, et al. Basal p38 mitogen-activated protein kinase regulates unliganded glucocorticoid receptor function in airway smooth muscle cells. Am J Respir Cell Mol Biol 2014; 50: 301–15. doi: 10.1165/rcmb.2012-0522OC

20.
Suzukawa M, Komiya A, Iikura M, Nagase H, Yoshimura-Uchiyama C, Yamada H, et al. Trans-basement membrane migration of human basophils: role of matrix metalloproteinase-9. Int Immunol 2006; 18: 1575–83. doi: 10.1093/intimm/dxl090

21.
Bugdayci G, Kaymakci M, Bukan N. Matrix metalloproteinase-9 (MMP-9) in allergic nasal polyps. Acta Histochem 2010; 112: 92–5. doi: 10.1016/j.acthis.2008.07.002

22.
Wenzel SE, Balzar S, Cundall M, Chu HW. Subepithelial basement membrane immunoreactivity for matrix metalloproteinase 9: association with asthma severity, neutrophilic inflammation, and wound repair. J Allergy Clin Immunol 2003; 111: 1345–52. doi: 10.1067/mai.2003.1464

23.
Gibson PG, Wark PAB, Simpson JL, Meldrum C, Meldrum S, Saltos N, et al. Induced sputum IL-8 gene expression, neutrophil influx and MMP-9 in allergic bronchopulmonary aspergillosis. Eur Respir J 2003; 21: 582–8. doi: 10.1183/09031936.03.00001803

24.
Devillers ACA, van Toorenenbergen AW, Klein Heerenbrink GJ, Muldert PGH, Oranje AP. Elevated levels of plasma matrix metalloproteinase-9 in patients with atopic dermatitis: a pilot study. Clin Exp Dermatol 2007; 32: 311–3. doi: 10.1111/j.1365-2230.2007.02378.x

25.
Inoue H, Mashimo Y, Funamizu M, Yonekura S, Horiguchi S, Shimojo N, et al. Association of the MMP9 gene with childhood cedar pollen sensitization and pollinosis. J Hum Genet 2012; 57: 176–83. doi: 10.1038/jhg.2011.148

26.
Kanbe N, Tanaka A, Kanbe M, Itakura A, Kurosawa M, Matsuda H. Human mast cells produce matrix metalloproteinase 9. Eur J Immunol 1999; 29: 2645–9. doi: 10.1002/(SICI)1521-4141(199908)29:08<2645::AID-IMMU2645>3.0.CO;2-1

27.
Xu L, Cai Z, Yang F, Chen M. Activation-induced upregulation of MMP9 in mast cells is a positive feedback mediator for mast cell activation. Mol Med Rep 2017; 15: 1759–64. doi: 10.3892/mmr.2017.6215

28.
Zhang Y, Shui J, Wang L, Wang F. Serum proteomics identifies S100A11 and MMP9 as novel biomarkers for predicting the early efficacy of sublingual immunotherapy in allergic rhinitis. Int Immunopharmacol 2023; 124: 110857. doi: 10.1016/j.intimp.2023.110857

29.
Hendrix AY, Kheradmand F. The Role of Matrix Metalloproteinases in Development, Repair, and Destruction of the Lungs. Prog Mol Biol Transl Sci 2017; 148: 1–29.

30.
Zeng W, Song Y, Wang R, He R, Wang T. Neutrophil elastase: from mechanisms to therapeutic potential. J Pharm Anal 2023; 13: 355–66. doi: 10.1016/j.jpha.2022.12.003

31.
Li L, Jia Q, Zhang H, Yi L, Tang Y, Hu P, et al. Tissue lipidomics, network pharmacology, and molecular docking to explore the therapeutic mechanism of anthocyanins from Lycium ruthenicum Murr. against gouty arthritis. Food Funct 2023; 14: 7011–23. doi: 10.1039/D1FO04377C

32.
Huang X-J, Wang J, Muhammad A, Tong H-Y, Wang D-G, Li J, et al. Systems pharmacology-based dissection of mechanisms of Tibetan medicinal compound Ruteng as an effective treatment for collagen-induced arthritis rats. Journal of Ethnopharmacology 2021; 272: 113953. doi: 10.1016/j.jep.2021.113953

33.
Qiao L, Huang W, Zhang X, Guo H, Wang D, Feng Q, et al. Evaluation of the immunomodulatory effects of anti-COVID-19 TCM formulae by multiple virus-related pathways. Signal Transduct _target Ther 2021; 6: 577–9. doi: 10.1038/s41392-021-00475-w

34.
Wang C, Cao B, Liu Q, Zou Z, Liang Z, Gu L, et al. Oseltamivir compared with the Chinese traditional therapy maxingshigan-yinqiaosan in the treatment of H1N1 influenza: a randomized trial. Ann Intern Med 2011; 155: 217–25. doi: 10.7326/0003-4819-155-4-201108160-00005

35.
Hao P, Jiang F, Cheng J, Ma L, Zhang Y, Zhao Y. Traditional Chinese medicine for cardiovascular disease: evidence and potential mechanisms. J Am Coll Cardiol 2017; 69: 2952–66. doi: 10.1016/j.jacc.2017.04.041

36.
Li X, Zhang J, Huang J, Ma A, Yang J, Li W, et al. A multicenter, randomized, double-blind, parallel-group, placebo-controlled study of the effects of qili qiangxin capsules in patients with chronic heart failure. J Am Coll Cardiol 2013; 62: 1065–72. doi: 10.1016/j.jacc.2013.05.035

37.
Jiang K, Song Q, Wang L, Xie T, Wu X, Wang P, et al. Antitussive, expectorant and anti-inflammatory activities of different extracts from Exocarpium Citri grandis. J Ethnopharmacol 2014; 156: 97–101. doi: 10.1016/j.jep.2014.08.030

38.
Peng Y, Hu M, Lu Q, Tian Y, He W, Chen L, et al. Flavonoids derived from Exocarpium Citri Grandis inhibit LPS-induced inflammatory response via suppressing MAPK and NF-κB signalling pathways. Food Agr Immunol 2019; 30: 564–80. doi: 10.1080/09540105.2018.1550056

Discovery of pharmacological effects and _targets of Citri Grandis Exocarpium based on SYSTCM and virtual screening

Abstract

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