期刊首页 优先出版 当期阅读 过刊浏览 作者中心 关于期刊 English

《工程(英文)》 >> 2023年 第20卷 第1期 doi: 10.1016/j.eng.2021.09.007

基于转录组学及多尺度生物测定多模态鉴定宣肺败毒方抑制巨噬细胞免疫反应的活性成分

a Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
b State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China

# These authors contributed equally to this paper.

收稿日期: 2021-05-24 修回日期: 2021-07-23 录用日期: 2021-09-21 发布日期: 2021-11-15

下一篇 上一篇

摘要

宣肺败毒方(XFBD)是一种临床用于治疗新型冠状病毒肺炎(COVID-19)病患的中药方剂,在临床实践中表现出了显著的疗效,但对其潜在的药理学机制尚不清楚。本研究结合网络药理学、转录组学和多模型系统生物测定等综合研究方法,研究了XFBD生物活性物质及其药理作用机制。通过高分辨质谱与分子网络相结合,对XFBD中的主要活性物质进行了分析,共鉴定或初步鉴定了104种化合物,包括黄酮类、萜类、羧酸类和其他类型的成分。基于所鉴定的XFBD化学组分,开展了网络药理学分析并将炎症相关通路确定为主要靶点。在脂多糖诱导的急性炎症小鼠模型中,XFBD明显减轻了肺部炎症,降低了血清促炎细胞因子水平。转录组学分析表明,经XFBD治疗后,与巨噬细胞功能相关的基因表达水平发生改变。在巨噬细胞细胞系和斑马鱼创伤模型中,XFBD对巨噬细胞的激活和迁移均有很强的抑制作用。最终,通过多模型系统筛选,发现XFBD中虎杖、芦根、化橘红显著下调巨噬细胞活化,虎杖苷、异甘草苷、毛蕊花糖苷为活性化合物;青蒿和麻黄显著抑制内源性巨噬细胞迁移,麻黄碱、白术内酯和山奈酚为活性化合物。综上所述,本研究通过多模态方法研究了XFBD调节炎症的活性成分以及相关药理学机制,从而为XFBD的临床疗效提供了生物学例证。

补充材料

图片

图1

图2

图3

图4

图5

图6

参考文献

[ 1 ] Asselah T, Durantel D, Pasmant E, Lau G, Schinazi RF. COVID-19: discovery, diagnostics and drug development. J Hepatol 2021;74(1):168‒84. 链接1

[ 2 ] Hu B, Guo H, Zhou P, Shi ZL. Characteristics of SARS-CoV-2 and COVID-19. Nat Rev Microbiol 2021;19(3):141‒54. 链接1

[ 3 ] Sette A, Crotty S. Adaptive immunity to SARS-CoV-2 and COVID-19. Cell 2021;184(4):861‒80. 链接1

[ 4 ] www.who.int [Internet]. Geneva: World Health Organization; 2021 [cited 2021 Sep 22]. Available from: https://covid19.who.int. 链接1

[ 5 ] Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ; Across Speciality CollaborationHLH, UK. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet 2020;395(10229):1033‒4. 链接1

[ 6 ] Wang Y, Li X, Zhang JH, Xue R, Qian JY, Zhang XH, et al. Mechanism of Xuanfei Baidu Tang in treatment of COVID-19 based on network pharmacology. China J Chin Mater Med 2020;45(10):2249‒56. Chinese.

[ 7 ] Xiong WZ, Wang G, Du J, Ai W. Efficacy of herbal medicine (Xuanfei Baidu decoction) combined with conventional drug in treating COVID-19: a pilot randomized clinical trial. Integr Med Res 2020;9(3):100489. 链接1

[ 8 ] Pluskal T, Castillo S, Villar-Briones A, Oresic M. MZmine 2: modular framework for processing, visualizing, and analyzing mass spectrometry-based molecular profile data. BMC Bioinf 2010;11:395. 链接1

[ 9 ] Myers OD, Sumner SJ, Li S, Barnes S, Du X. One step forward for reducing false positive and false negative compound identifications from mass spectrometry metabolomics data: new algorithms for constructing extracted ion chromatograms and detecting chromatographic peaks. Anal Chem 2017;89(17):8696‒703. 链接1

[10] Wang M, Carver JJ, Phelan VV, Sanchez LM, Garg N, Peng Y, et al. Sharing and community curation of mass spectrometry data with Global Natural Products Social Molecular Networking. Nat Biotechnol 2016;34(8):828‒37.

[11] Andonegui G, Kerfoot SM, McNagny K, Ebbert KV, Patel KD, Kubes P. Platelets express functional Toll-like receptor-4. Blood 2005;106(7):2417‒23. 链接1

[12] Wessels I, Pupke JT, von Trotha KT, Gombert A, Himmelsbach A, Fischer HJ, et al. Zinc supplementation ameliorates lung injury by reducing neutrophil recruitment and activity. Thorax 2020;75(3):253‒61. 链接1

[13] Andonegui G, Bonder CS, Green F, Mullaly SC, Zbytnuik L, Raharjo E, et al. Endothelium-derived Toll-like receptor-4 is the key molecule in LPS-induced neutrophil sequestration into lungs. J Clin Invest 2003;111(7):1011‒20. 链接1

[14] Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J Roy Stat Soc Ser B 1995;57(1):289‒300. 链接1

[15] Wang S, Wang H, Liu Y, Wang Y, Fan X, Cheng Y. Rapid discovery and identification of anti-inflammatory constituents from traditional Chinese medicine formula by activity index, LC-MS, and NMR. Sci Rep 2016;6(1):31000. 链接1

[16] Ellett F, Pase L, Hayman JW, Andrianopoulos A, Lieschke GJ. mpeg1 promoter transgenes direct macrophage-lineage expression in zebrafish. Blood 2011;117(4):e49‒56. 链接1

[17] Hall C, Flores MV, Storm T, Crosier K, Crosier P. The zebrafish lysozyme C promoter drives myeloid-specific expression in transgenic fish. BMC Dev Biol 2007;7(1):42. 链接1

[18] Westerfield M. A guide for the laboratory use of zebrafish (Danio rerio). In: Westerfield M, editor. The zebrafish book. Eugene: University of Oregon Press; 2000.

[19] Yu Y, Chen J, Zhang X, Wang Y, Wang S, Zhao L, et al. Identification of antiinflammatory compounds from Zhongjing formulae by knowledge mining and high-content screening in a zebrafish model of inflammatory bowel diseases. Chin Med 2021;16(1):42. 链接1

[20] Xie Y, Tolmeijer S, Oskam JM, Tonkens T, Meijer AH, Schaaf MJM. Glucocorticoids inhibit macrophage differentiation towards a proinflammatory phenotype upon wounding without affecting their migration. Dis Model Mech 2019;12(5):dmm037887. 链接1

[21] Hu W, van Steijn L, Li C, Verbeek FJ, Cao Lu, Merks RMH, et al. A novel function of TLR2 and MyD88 in the regulation of leukocyte cell migration behavior during wounding in zebrafish larvae. Front Cell Dev Biol 2021;9:624571. 链接1

[22] Takeuchi O, Akira S. Pattern recognition receptors and inflammation. Cell 2010;140(6):805‒20. 链接1

[23] Rovas A, Osiaevi I, Buscher K, Sackarnd J, Tepasse PR, Fobker M, et al. Microvascular dysfunction in COVID-19: the MYSTIC study. Angiogenesis 2021;24(1):145‒57. 链接1

[24] Jeon JW, Jung JG, Shin EC, Choi HI, Kim HY, Cho ML, et al. Soluble CD93 induces differentiation of monocytes and enhances TLR responses. J Immunol 2010;185(8):4921‒7. 链接1

[25] Greenlee MC, Sullivan SA, Bohlson SS. Detection and characterization of soluble CD93 released during inflammation. Inflamm Res 2009;58 (12):909‒19. 链接1

[26] Wang H, Zhu J, Liu Z, Lv H, Lv P, Chen F, et al. Silencing of long isoforms of nuclear factor erythroid 2 like 1 primes macrophages towards M1 polarization. Free Radic Biol Med 2018;117:37‒44. 链接1

[27] Alexopoulou L, Holt AC, Medzhitov R, Flavell RA. Recognition of doublestranded RNA and activation of NF-κB by Toll-like receptor 3. Nature 2001;413(6857):732‒8. 链接1

[28] Ting Tan RS, Lin B, Liu Q, Tucker-Kellogg L, Ho B, Leung BPL, et al. The synergy in cytokine production through MyD88-TRIF pathways is co-ordinated with ERK phosphorylation in macrophages. Immunol Cell Biol 2013;91(5):377‒87. 链接1

[29] Nguyen-Chi M, Laplace-Builhe B, Travnickova J, Luz-Crawford P, Tejedor G, Phan QT, et al. Identification of polarized macrophage subsets in zebrafish. eLife 2015;4:e07288. 链接1

[30] Kim HS, Asmis R. Mitogen-activated protein kinase phosphatase 1 (MKP-1) in macrophage biology and cardiovascular disease. A redox-regulated master controller of monocyte function and macrophage phenotype. Free Radic Biol Med 2017;109:75‒83. 链接1

[31] Nakata S, Tsutsui M, Shimokawa H, Tamura M, Tasaki H, Morishita T, et al. Vascular neuronal NO synthase is selectively upregulated by platelet-derived growth factor: involvement of the MEK/ERK pathway. Arterioscler Thromb Vasc Biol 2005;25(12):2502‒8. 链接1

[32] Muniyappa H, Das KC. Activation of c-Jun N-terminal kinase (JNK) by widely used specific p38 MAPK inhibitors SB202190 and SB203580: a MLK-3-MKK7- dependent mechanism. Cell Signal 2008;20(4):675‒83. 链接1

[33] Guo M, Härtlova A, Gierlin´ ski M, Prescott A, Castellvi J, Losa JH, et al. Triggering MSR1 promotes JNK-mediated inflammation in IL-4-activated macrophages. EMBO J 2019;38(11):e100299. 链接1

[34] Beigel JH, Tomashek KM, Dodd LE, Mehta AK, Zingman BS, Kalil AC, et al. Remdesivir for the treatment of COVID-19—preliminary report. N Engl J Med 2020;383(19):1813‒36. 链接1

[35] Liu J, Cao R, Xu M, Wang Xi, Zhang H, Hu H, et al. Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro. Cell Discov 2020;6(1):16. 链接1

[36] Cao B, Wang Y,Wen D, Liu W, Wang J, Fan G, et al. A trial of lopinavir‒ritonavir in adults hospitalized with severe COVID-19.NEngl JMed 2020;382(19):1787‒99.

[37] Ledford H. Coronavirus breakthrough: dexamethasone is first drug shown to save lives. Nature 2020;582(7813):469. 链接1

[38] Vinetz JM. Lack of efficacy of hydroxychloroquine in COVID-19. BMJ 2020;369: m2018. 链接1

[39] Horby P, Lim WS, Emberson JR, Mafham M, Bell JL, Linsell L, et al.; RECOVERY Collaborative Group. Dexamethasone in hospitalized patients with COVID-19. N Engl J Med 2021;384(8):693‒704. 链接1

[40] Tay MZ, Poh CM, Rénia L, MacAry PA, Ng LFP. The trinity of COVID-19: immunity, inflammation and intervention. Nat Rev Immunol 2020;20(6):363‒74. 链接1

[41] Montón C, Ewig S, Torres A, El-Ebiary M, Filella X, Rañó A, et al. Role of glucocorticoids on inflammatory response in nonimmunosuppressed patients with pneumonia: a pilot study. Eur Respir J 1999;14(1):218‒20. 链接1

[42] Russell CD, Millar JE, Baillie JK. Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury. Lancet 2020;395(10223):473‒5. 链接1

[43] Rizk JG, Kalantar-Zadeh K, Mehra MR, Lavie CJ, Rizk Y, Forthal DN. Pharmacoimmunomodulatory therapy in COVID-19. Drugs 2020;80(13):1267‒92. 链接1

[44] Yao XH, Li TY, He ZC, Ping YF, Liu HW, Yu SC, et al. A pathological report of three COVID-19 cases by minimally invasive autopsies. Chin J Pathol 2020;49(5):411‒7.

[45] Wynn TA, Chawla A, Pollard JW. Macrophage biology in development, homeostasis and disease. Nature 2013;496(7446):445‒55. 链接1

[46] Shapouri-Moghaddam A, Mohammadian S, Vazini H, Taghadosi M, Esmaeili SA, Mardani F, et al. Macrophage plasticity, polarization, and function in health and disease. J Cell Physiol 2018;233(9):6425‒40. 链接1

[47] Wan S, Yi Q, Fan S, Lv J, Zhang X, Guo L, et al. Characteristics of lymphocyte subsets and cytokines in peripheral blood of 123 hospitalized patients with 2019 novel coronavirus pneumonia (NCP). MedRxiv 2020. 链接1

[48] Norelli M, Camisa B, Barbiera G, Falcone L, Purevdorj A, Genua M, et al. Monocyte-derived IL-1 and IL-6 are differentially required for cytokine-release syndrome and neurotoxicity due to CAR T cells. Nat Med 2018;24(6):739‒48. 链接1

[49] Crayne CB, Albeituni S, Nichols KE, Cron RQ. The immunology of macrophage activation syndrome. Front Immunol 2019;10:119. 链接1

[50] Tisoncik JR, Korth MJ, Simmons CP, Farrar J, Martin TR, Katze MG. Into the eye of the cytokine storm. Microbiol Mol Biol Rev 2012;76(1):16‒32. 链接1

[51] www.gov.cn [Internet]. Beijing: The State Council of the People’s Republic of China; 2020 [cited 2021 Sep 22]. Available from: http://english.www.gov.cn/ news/topnews/202003/23/content_WS5e787a9dc6d0c201c2cbf3b4.html. 链接1

[52] Yang Q, Sun Q, Jiang B, Xu H, Luo M, Xie P, et al. Retrospective clinical study on treatment of COVID-19 patients with integrated traditional Chinese and western medicine. Chin Tradit Herb Drugs 2020;51(8):2050‒4. Chinese.

[53] Peng W, Qin R, Li X, Zhou H. Botany, phytochemistry, pharmacology, and potential application of Polygonum cuspidatum Sieb.et Zucc.: a review. J Ethnopharmacol 2013;148(3):729‒45. 链接1

[54] Park SJ, Kim YW, Park MK, Byun SH, Kim SC, Lee JR. Anti-inflammatory steroid from Phragmitis Rhizoma modulates LPS-mediated signaling through inhibition of NF-κB pathway. Inflammation 2016;39(2):727‒34. 链接1

[55] 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. 链接1

[56] Yuan YP, Zhai HQ, Guo ZJ, Kong LT, Jia XY, Wang NN, et al. Analysis of historical origin and standardization system construction of Citri Grandis Exocarpium. China J Chin Mater Med 2017;42(11):2214‒8. Chinese.

[57] Lou T, Jiang W, Xu D, Chen T, Fu Y. Inhibitory effects of polydatin on lipopolysaccharide-stimulated RAW 264.7 cells. Inflammation 2015;38(3):1213‒20. 链接1

[58] Liu YY, Wu JQ, Fan RY, He ZH, Li CY, He MF. Isoliquiritin promote angiogenesis by recruiting macrophages to improve the healing of zebrafish wounds. Fish Shellfish Immunol 2020;100:238‒45. 链接1

[59] Wang R, Zhang CY, Bai LP, Pan HD, Shu LM, Kong AN, et al. Flavonoids derived from liquorice suppress murine macrophage activation by up-regulating heme oxygenase-1 independent of Nrf2 activation. Int Immunopharmacol 2015;28(2):917‒24. 链接1

[60] Kim JY, Park SJ, Yun KJ, Cho YW, Park HJ, Lee KT. Isoliquiritigenin isolated from the roots of Glycyrrhiza uralensis inhibits LPS-induced iNOS and COX-2 expression via the attenuation of NF-κB in RAW 264.7 macrophages. Eur J Pharmacol 2008;584(1):175‒84. 链接1

[61] Zheng Y, Guo Z, He W, Yang Y, Li Y, Zheng A, et al. Ephedrine hydrochloride protects mice from LPS challenge by promoting IL-10 secretion and inhibiting proinflammatory cytokines. Int Immunopharmacol 2012;13(1):46‒53. 链接1

[62] Wang A, Xiao Z, Zhou L, Zhang J, Li X, He Q. The protective effect of atractylenolide I on systemic inflammation in the mouse model of sepsis created by cecal ligation and puncture. Pharm Biol 2016;54(1):146‒50. 链接1

[63] Ren J, Lu Y, Qian Y, Chen B, Wu T, Ji G. Recent progress regarding kaempferol for the treatment of various diseases. Exp Ther Med 2019;18(4):2759‒76. †† http://gnps.ucsd.edu. 链接1

相关研究