Combinatorial Chemistry & High Throughput Screening

Author(s): Yuzhe Ren, Haijing Zhang, Zhou Yu, Xiangzheng Yang and Deyou Jiang*

DOI: 10.2174/1386207326666230503112343

Mechanisms of Er Chen Tang on Treating Asthma Explored by Network Pharmacology and Experimental Verification

Page: [227 - 237] Pages: 11

  • * (Excluding Mailing and Handling)

Abstract

Objective: The aim of this study is to explore the active ingredients of ECT and their targets for asthma and investigate the potential mechanism of ECT on asthma.

Methods: Firstly, the active ingredients and target of ECT were screened for BATMAN and TCMSP, and functional analysis was done via DAVID. Then, the animal model was induced by ovalbumin (OVA) and aluminum hydroxide. Eosinophil (EOS) counts, EOS active substance Eosinophilic cationic protein (ECP) and eotaxin levels were detected following the instruction. Pathological changes in lung tissue were examined by H&E staining and transmission electron microscopy. Interleukin (IL-4, IL-10, IL-13, TNF-α), TIgE and IgE levels in bronchoalveolar lavage fluid (BALF) were measured by ELISA. Finally, the protein expression of the TGF-β / STAT3 pathway to lung tissue was detected by Western Blot.

Results: A total of 450 compounds and 526 target genes were retrieved in Er Chen Tang. Functional analysis indicated that its treatment of asthma was associated with inflammatory factors and fibrosis. In the animal experiment, the results showed that ECT significantly regulated inflammatory cytokine (IL-4, IL-10, IL-13, TNF-α) levels in (P<0.05, P<0.01, reduced EOS number (P<0.05) and also ECP and Eotaxin levels in the blood (P<0.05) in BALF and/or plasma. Bronchial tissue injury was obviously improved on ECT treatment. Associated proteins in TGF-β / STAT3 pathway were significantly regulated by ECT (P<0.05).

Conclusion: This study originally provided evidence that the Er Chen Tang was effective in the treatment of asthma symptoms, and its underlying mechanism might be the regulation of inflammatory factor secretion and the TGF-β/STAT3 signaling pathway.

[1]
Katoh, S. Critical involvement of CD44 in T helper type 2 cell-mediated eosinophilic airway inflammation in a mouse model of acute asthma. Front. Immunol., 2022, 12, 811600.
[http://dx.doi.org/10.3389/fimmu.2021.811600] [PMID: 35069598]
[2]
Hur, G.Y.; Broide, D.H. Genes and pathways regulating decline in lung function and airway remodeling in asthma. Allergy Asthma Immunol. Res., 2019, 11(5), 604-621.
[http://dx.doi.org/10.4168/aair.2019.11.5.604] [PMID: 31332973]
[3]
Lambrecht, B.N.; Hammad, H.; Fahy, J.V. The cytokines of asthma. Immunity, 2019, 50(4), 975-991.
[http://dx.doi.org/10.1016/j.immuni.2019.03.018] [PMID: 30995510]
[4]
Gowthaman, U.; Chen, J.S.; Zhang, B.; Flynn, W.F.; Lu, Y.; Song, W.; Joseph, J.; Gertie, J.A.; Xu, L.; Collet, M.A.; Grassmann, J.D.S.; Simoneau, T.; Chiang, D.; Berin, M.C.; Craft, J.E.; Weinstein, J.S.; Williams, A.; Eisenbarth, S.C. Identification of a T follicular helper cell subset that drives anaphylactic IgE. Science, 2019, 365(6456), eaaw6433.
[http://dx.doi.org/10.1126/science.aaw6433] [PMID: 31371561]
[5]
Wieczfinska, J.; Pawliczak, R. Relaxin affects airway remodeling genes expression through various signal pathways connected with transcription factors. Int. J. Mol. Sci., 2022, 23(15), 8413.
[http://dx.doi.org/10.3390/ijms23158413] [PMID: 35955554]
[6]
Wang, C.; Zheng, M.; Choi, Y.; Jiang, J.; Li, L.; Li, J.; Xu, C.; Xian, Z.; Li, Y.; Piao, H.; Li, L.; Yan, G. Cryptotanshinone attenuates airway remodeling by inhibiting crosstalk between tumor necrosis factor-like weak inducer of apoptosis and transforming growth factor beta 1 signaling pathways in asthma. Front. Pharmacol., 2019, 10, 1338.
[http://dx.doi.org/10.3389/fphar.2019.01338] [PMID: 31780948]
[7]
Tian, C.; Gao, F.; Li, X.; Li, Z. Icariside II attenuates eosinophils-induced airway inflammation and remodeling via inactivation of NF-κB and STAT3 in an asthma mouse model. Exp. Mol. Pathol., 2020, 113, 104373.
[http://dx.doi.org/10.1016/j.yexmp.2020.104373] [PMID: 31917285]
[8]
Yi, F.; Zhan, C.; Liu, B.; Li, H.; Zhou, J.; Tang, J.; Peng, W.; Luo, W.; Chen, Q.; Lai, K. Effects of treatment with montelukast alone, budesonide/formoterol alone and a combination of both in cough variant asthma. Respir. Res., 2022, 23(1), 279.
[http://dx.doi.org/10.1186/s12931-022-02114-6] [PMID: 36217131]
[9]
Miwa, N.; Nagano, T.; Ohnishi, H.; Nishiuma, T.; Takenaka, K.; Shirotani, T.; Nakajima, T.; Dokuni, R.; Kawa, Y.; Kobayashi, K.; Funada, Y.; Kotani, Y.; Nishimura, Y. An open-label, multi-institutional, randomized study to evaluate the additive effect of a leukotriene receptor antagonist on cough score in patients with cough-variant asthma being treated with inhaled corticosteroids. Kobe J. Med. Sci., 2018, 64(4), E134-E139.
[PMID: 30728339]
[10]
Guo, R.; Li, L.; Su, J.; Li, S.; Duncan, S.E.; Liu, Z.; Fan, G. Pharmacological activity and mechanism of tanshinone IIA in related diseases. Drug Des. Devel. Ther., 2020, 14, 4735-4748.
[http://dx.doi.org/10.2147/DDDT.S266911] [PMID: 33192051]
[11]
Liu, L.; Wang, L.; He, S.; Ma, Y. Immune Homeostasis: Effects of Chinese herbal formulae and herb-derived compounds on allergic asthma in different experimental models. Chin. J. Integr. Med., 2018, 24(5), 390-398.
[http://dx.doi.org/10.1007/s11655-018-2836-2] [PMID: 29752613]
[12]
Deng, L.; Zhang, X.; Dong, Y.; Wang, L.; Chen, K.; Zheng, M.; Yang, Z.; Tang, H.; Liao, W.; Shi, Q. Erchen decoction combined with Sanziyangqin decoction for chronic obstructive pulmonary disease. Medicine, 2020, 99(40), e22315.
[http://dx.doi.org/10.1097/MD.0000000000022315] [PMID: 33019407]
[13]
Cheng, Huang Y.C. Research progress in animal model of bronchial asthma. Med. Recapitul., 2009, 23, 647-647.
[http://dx.doi.org/10.3969/j.issn.1006-2084.2012.19.025]
[14]
Kun, Yang XG; Wu, Wenbin Effect of sanzi yangqin decoction on Th17/Treg imbalance in bronchial asthma model rats. Pharmacol. Clinic Chinese Materia Med., 2019, 35(3), 28-32.
[15]
Peng, Zhang D.Y.; Nie, B. Effects of modified yinchenhao decoction combined with budesonide on airway responsiveness and expression of inflammatory cytokines in lung. World Chinese Med., 2019, 14, 1393-1396.
[16]
Yongying, G. The experimental Study of Sang Su Er Chen Tang Modified allergic bronchial asthma; Hebei Medical University, 2009.
[http://dx.doi.org/10.7666/d.y1637337]
[17]
Vieira, C.P.; de Oliveira, L.P.; Da Silva, M.B.; Majolli Andre, D.; Tavares, E.B.G.; Pimentel, E.R.; Antunes, E. Role of metalloproteinases and TNF-α in obesity-associated asthma in mice. Life Sci., 2020, 259, 118191.
[http://dx.doi.org/10.1016/j.lfs.2020.118191] [PMID: 32777302]
[18]
Gao, Miaoran S.L.; Xie, W. Effect of erchen decoction on lung function and pathological changes of chronic branchitis model rats. Zhongguo Zhongyiyao Xiandai Yuancheng Jiaoyu, 2016, 14, 143-145.
[http://dx.doi.org/10.3969/j.issn.1672-2779.2016.14.065]
[19]
Guo, B.; Zhao, C.; Zhang, C.; Xiao, Y.; Yan, G.; Liu, L.; Pan, H. Elucidation of the anti-inflammatory mechanism of Er Miao San by integrative approach of network pharmacology and experimental verification. Pharmacol. Res., 2022, 175, 106000.
[http://dx.doi.org/10.1016/j.phrs.2021.106000] [PMID: 34838694]
[20]
Li, X.; Wei, S.; Niu, S.; Ma, X.; Li, H.; Jing, M.; Zhao, Y. Network pharmacology prediction and molecular docking-based strategy to explore the potential mechanism of Huanglian Jiedu Decoction against sepsis. Comput. Biol. Med., 2022, 144, 105389.
[http://dx.doi.org/10.1016/j.compbiomed.2022.105389] [PMID: 35303581]
[21]
Lee, D.; Lee, W.Y.; Jung, K.; Kwon, Y.; Kim, D.; Hwang, G.; Kim, C.E.; Lee, S.; Kang, K. The inhibitory effect of cordycepin on the proliferation of MCF-7 breast cancer cells, and its mechanism: An investigation using network pharmacology-based analysis. Biomolecules, 2019, 9(9), 414.
[http://dx.doi.org/10.3390/biom9090414] [PMID: 31454995]
[22]
Bi, Y.H.; Zhang, L.; Chen, S.; Ling, Q. Antitumor mechanisms of curcumae rhizoma based on network pharmacology. Evid. Based Complement. Alternat. Med., 2018, 2018, 1-9.
[http://dx.doi.org/10.1155/2018/4509892] [PMID: 29636777]
[23]
Jung, S.; Park, J.; Park, J.; Jo, H.; Seo, C.S.; Jeon, W.Y.; Lee, M.Y.; Kwon, B.I. Sojadodamgangki-tang attenuates allergic lung inflammation by inhibiting T helper 2 cells and Augmenting alveolar macrophages. J. Ethnopharmacol., 2020, 263, 113152.
[http://dx.doi.org/10.1016/j.jep.2020.113152] [PMID: 32755652]
[24]
Wang, M.; Yang, X.; Zhao, J.; Lu, C.; Zhu, W. Structural characterization and macrophage immunomodulatory activity of a novel polysaccharide from Smilax glabra Roxb. Carbohydr. Polym., 2017, 156, 390-402.
[http://dx.doi.org/10.1016/j.carbpol.2016.09.033] [PMID: 27842838]
[25]
Bui, T.T.; Piao, C.H.; Kim, S.M.; Song, C.H.; Shin, H.S.; Lee, C.H.; Chai, O.H. Citrus tachibana leaves ethanol extract alleviates airway inflammation by the modulation of Th1/Th2 imbalance via inhibiting NF-κ B signaling and histamine secretion in a mouse model of allergic asthma. J. Med. Food, 2017, 20(7), 676-684.
[http://dx.doi.org/10.1089/jmf.2016.3853] [PMID: 28598706]
[26]
Liu, L.; Xing, Q.; Zhao, X.; Tan, M.; Lu, Y.; Dong, Y.; Dai, C.; Zhang, Y. Proteomic analysis provides insights into the therapeutic effect of GU-BEN-FANG-XIAO decoction on a persistent asthmatic mouse model. Front. Pharmacol., 2019, 10, 441.
[http://dx.doi.org/10.3389/fphar.2019.00441] [PMID: 31133848]
[27]
McCracken, J.L.; Veeranki, S.P.; Ameredes, B.T.; Calhoun, W.J. Diagnosis and management of asthma in adults. JAMA, 2017, 318(3), 279-290.
[http://dx.doi.org/10.1001/jama.2017.8372] [PMID: 28719697]
[28]
Mishra, V.; Banga, J.; Silveyra, P. Oxidative stress and cellular pathways of asthma and inflammation: Therapeutic strategies and pharmacological targets. Pharmacol. Ther., 2018, 181, 169-182.
[http://dx.doi.org/10.1016/j.pharmthera.2017.08.011] [PMID: 28842273]
[29]
Fehrenbach, H.; Wagner, C.; Wegmann, M. Airway remodeling in asthma: What really matters. Cell Tissue Res., 2017, 367(3), 551-569.
[http://dx.doi.org/10.1007/s00441-016-2566-8] [PMID: 28190087]
[30]
Diver, S.; Khalfaoui, L.; Emson, C.; Wenzel, S.E.; Menzies-Gow, A.; Wechsler, M.E.; Johnston, J.; Molfino, N.; Parnes, J.R.; Megally, A.; Colice, G.; Brightling, C.E. CASCADE study investigators. Effect of tezepelumab on airway inflammatory cells, remodelling, and hyperresponsiveness in patients with moderate-to-severe uncontrolled asthma (CASCADE): A double-blind, randomised, placebo-controlled, phase 2 trial. Lancet Respir. Med., 2021, 9(11), 1299-1312.
[http://dx.doi.org/10.1016/S2213-2600(21)00226-5] [PMID: 34256031]
[31]
Zhang, R.; Luo, W.; Liang, Z.; Tan, Y.; Chen, R.; Lu, W.; Zhong, N. Eotaxin and IL-4 levels are increased in induced sputum and correlate with sputum eosinophils in patients with nonasthmatic eosinophilic bronchitis. Medicine, 2017, 96(13), e6492.
[http://dx.doi.org/10.1097/MD.0000000000006492] [PMID: 28353595]
[32]
Silkoff, P.E.; Laviolette, M.; Singh, D.; FitzGerald, J.M.; Kelsen, S.; Backer, V.; Porsbjerg, C.M.; Girodet, P.O.; Berger, P.; Kline, J.N.; Chupp, G.; Susulic, V.S.; Barnathan, E.S.; Baribaud, F.; Loza, M.J.; Strambu, I.; Lam, S.; Eich, A.; Ludwig-Sengpiel, A.; Leigh, R.; Dransfield, M.; Calhoun, W.; Hussaini, A.; Chanez, P. Airways Disease Endotyping for Personalized Therapeutics (ADEPT) study investigators. Identification of airway mucosal type 2 inflammation by using clinical biomarkers in asthmatic patients. J. Allergy Clin. Immunol., 2017, 140(3), 710-719.
[http://dx.doi.org/10.1016/j.jaci.2016.11.038] [PMID: 28089872]
[33]
Rossi, A.; Caiazzo, E.; Bilancia, R.; Riemma, M.A.; Pagano, E.; Cicala, C.; Ialenti, A.; Zjawiony, J.K.; Izzo, A.A.; Capasso, R.; Roviezzo, F.; Salvinorin, A. Salvinorin A inhibits airway hyperreactivity induced by ovalbumin sensitization. Front. Pharmacol., 2017, 7, 525.
[http://dx.doi.org/10.3389/fphar.2016.00525] [PMID: 28133450]
[34]
Zeng, Z.; Xu, X.; Zhu, Y.; Wang, Q.; Zhang, Y.; Huo, X. Pb and Cd exposure linked with Il-10 and Il-13 gene polymorphisms in asthma risk relevant immunomodulation in children. Chemosphere, 2022, 294, 133656.
[http://dx.doi.org/10.1016/j.chemosphere.2022.133656] [PMID: 35051511]
[35]
Medjo, B.; Atanaskovic-Markovic, M.; Nikolic, D.; Radic, S.; Lazarevic, I.; Cirkovic, I.; Djukic, S. Increased serum interleukin-10 but not interleukin-4 level in children with Mycoplasma pneumoniae pneumonia. J. Trop. Pediatr., 2017, 63(4), fmw091.
[http://dx.doi.org/10.1093/tropej/fmw091] [PMID: 28057814]
[36]
Lai, Y.; Zhang, P.; Wang, H.; Hu, L.; Song, X.; Zhang, J.; Jiang, W.; Han, M.; Liu, Q.; Hu, G.; Sun, X.; Li, H.; Wang, D. Serum and glucocorticoid-regulated kinase 1 regulates transforming growth factor β1-connective tissue growth factor pathway in chronic rhinosinusitis. Clin. Immunol., 2022, 234, 108895.
[http://dx.doi.org/10.1016/j.clim.2021.108895] [PMID: 34826606]
[37]
Riemma, M.A.; Cerqua, I.; Romano, B.; Irollo, E.; Bertolino, A.; Camerlingo, R.; Granato, E.; Rea, G.; Scala, S.; Terlizzi, M.; Spaziano, G.; Sorrentino, R.; D’Agostino, B.; Roviezzo, F.; Cirino, G. Sphingosine-1-phosphate/TGF-β axis drives epithelial mesenchymal transition in asthma-like disease. Br. J. Pharmacol., 2022, 179(8), 1753-1768.
[http://dx.doi.org/10.1111/bph.15754] [PMID: 34825370]
[38]
Tang, L.Y.; Heller, M.; Meng, Z.; Yu, L.R.; Tang, Y.; Zhou, M.; Zhang, Y.E. Transforming Growth Factor-β (TGF-β) directly activates the JAK1-STAT3 axis to induce hepatic fibrosis in coordination with the SMAD pathway. J. Biol. Chem., 2017, 292(10), 4302-4312.
[http://dx.doi.org/10.1074/jbc.M116.773085] [PMID: 28154170]
[39]
Park, J.H.; Jang, K.; An, H.; Kim, J.Y.; Gwon, M.G.; Gu, H.; Park, B.; Park, K.K. Pomolic acid ameliorates fibroblast activation and renal interstitial fibrosis through inhibition of SMAD-STAT signaling pathways. Molecules, 2018, 23(9), 2236.
[http://dx.doi.org/10.3390/molecules23092236] [PMID: 30177595]
[40]
Saito, A.; Horie, M.; Nagase, T. TGF-β signaling in lung health and disease. Int. J. Mol. Sci., 2018, 19(8), 2460.
[http://dx.doi.org/10.3390/ijms19082460] [PMID: 30127261]