药学学报, 2022, 57(3): 716-723
引用本文:
杨吾燕, 闫姣姣, 高丽, 秦雪梅. 基于生物信息分析研究黄芩素通过NOX2/STAT1/NF-κB通路抑制LPS诱导的BV-2细胞神经炎症的作用机制[J]. 药学学报, 2022, 57(3): 716-723.
YANG Wu-yan, YAN Jiao-jiao, GAO Li, QIN Xue-mei. Baicalein inhibits neuroinflammation via NOX2/STAT1/NF-κB pathway in LPS-induced BV-2 cells based on bioinformatics methods[J]. Acta Pharmaceutica Sinica, 2022, 57(3): 716-723.

基于生物信息分析研究黄芩素通过NOX2/STAT1/NF-κB通路抑制LPS诱导的BV-2细胞神经炎症的作用机制
杨吾燕1,2,3, 闫姣姣1,2,3, 高丽1,2,3*, 秦雪梅1,2,3*
1. 山西大学中医药现代研究中心, 山西 太原 030006;
2. 山西大学化学生物学与分子工程教育部重点实验室, 山西 太原 030006;
3. 地产中药功效物质研究与利用山西省重点实验室, 山西 太原 030006
摘要:
本研究旨在确定黄芩素对脂多糖(lipopolysaccharide,LPS)诱导的BV-2细胞神经炎症的分子机制。采用生物信息分析、分子对接方法预测黄芩素的潜在靶点和作用机制,并使用免疫荧光染色和Western blot技术对关键靶点一氧化氮合酶(inducible nitric oxide synthase,iNOS)和环氧合酶-2 (cyclooxygenase-2,COX-2)、信号转导子和转录激活子1/核因子κB (signal transducer and activator of transcription 1/nuclear factor kappa-B,STAT1/NF-κB)信号通路相关蛋白及其上游调控因子NADPH氧化酶2 (NADPH oxidase-2,NOX2)进行验证,研究黄芩素改善神经炎症的作用机制。结果表明,生物信息分析和分子对接技术预测出iNOS和COX-2为关键靶点,NF-κB信号通路为关键通路。实验验证表明,在LPS诱导的BV-2细胞中,黄芩素能显著降低iNOS和COX-2的表达水平,有效抑制NF-κB和STAT1的磷酸化及NOX2的生成。综上,黄芩素可通过NOX2 (gp91phox/p47phox)/STAT1/NF-κB途径显著抑制LPS诱导的BV-2细胞炎症。
关键词:    黄芩素      神经炎症      网络药理学      分子对接      作用机制     
Baicalein inhibits neuroinflammation via NOX2/STAT1/NF-κB pathway in LPS-induced BV-2 cells based on bioinformatics methods
YANG Wu-yan1,2,3, YAN Jiao-jiao1,2,3, GAO Li1,2,3*, QIN Xue-mei1,2,3*
1. Modern Research Center for Traditional Chinese Medicine, Shanxi University, Taiyuan 030006, China;
2. The Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Shanxi University, Taiyuan 030006, China;
3. The Key Laboratory of Effective Substances Research and Utilization in TCM of Shanxi Province, Taiyuan 030006, China
Abstract:
This study identified the exact molecular mechanisms of baicalein on neuroinflammation in lipopolysaccharide (LPS)-induced BV-2 cells. Bioinformatics methods and molecular docking were integrated for predicting the potential targets and mechanisms of baicalein. Immunofluorescence staining and Western blot were used to analyze the predicted key targets [inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2)], the expression level of protein related to signal transducer and activator of transcription 1/nuclear factor kappa-B (STAT1/NF-‍κB) signaling pathway and its upstream regulator NADPH oxidase-2 (NOX2), and then the mechanism of baicalein in alleviating neuroinflammation was explored. The results showed that iNOS and COX-2 were predicted as the key targets and NF-κB signaling pathway was one of the important pathways by bioinformatics methods and molecular docking. Experimental verification showed that baicalein could significantly reduce the expression of iNOS and COX-2, inhibit the phosphorylation of NF-κB and STAT1 and the production of NOX2 in LPS-induced BV-2 cells. To sum up, baicalein could effectively inhibit the inflammatory reaction in LPS-induced BV-2 cells through regulating NOX2 (gp91phox/p47phox)/STAT1/NF-κB pathway.
Key words:    baicalein    neuroinflammation    network pharmacology    molecular docking    mechanism   
收稿日期: 2021-09-13
DOI: 10.16438/j.0513-4870.2021-1339
基金项目: 国家自然科学基金资助项目(81603319);山西省面上青年基金资助项目(201801D221374)。
通讯作者: 高丽,Tel:86-351-7018379,E-mail:gaoli87@sxu.edu.cn;秦雪梅,Tel:86-351-7011501,E-mail:qinxm@sxu.edu.cn
Email: gaoli87@sxu.edu.cn;qinxm@sxu.edu.cn
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参考文献:
[1] You MM, Chen YF, Pan YM, et al. Royal Jelly attenuates LPS-induced inflammation in BV-2 microglial cells through modulating NF-κB and p38/JNK signaling pathways[J]. Mediators Inflamm, 2018, 2018:7834381.
[2] Ransohoff RM. How neuroinflammation contributes to neurodegeneration[J]. Science, 2016, 353:777-783.
[3] Chen J, Yin W, Tu Y, et al. L-F001, a novel multifunctional ROCK inhibitor, suppresses neuroinflammation in vitro and in vivo:involvement of NF-κB inhibition and Nrf2 pathway activation[J]. Eur J Pharmacol, 2017, 806:1-9.
[4] Loane DJ, Kumar A. Microglia in the TBI brain:the good, the bad, and the dysregulated[J]. Exp Neurol, 2016, 275 Pt 3:316-327.
[5] Yao C, Liu X, Zhou Z, et al. Melatonin attenuates expression of cyclooxygenase-2(COX-2) in activated microglia induced by lipopolysaccharide (LPS)[J]. J Toxicol Environ Health A, 2019, 82:437-446.
[6] Dinda B, Dinda S, DasSharma S, et al. Therapeutic potentials of baicalin and its aglycone, baicalein against inflammatory disorders[J]. Eur J Med Chem, 2017, 131:68-80.
[7] Duan DD, Wang KX, Zhou YZ, et al. Baicalein exerts beneficial effects in D-galactose-induced aging rats through attenuation of inflammation and metabolic dysfunction[J]. Rejuvenation Res, 2017, 20:506-516.
[8] Gao L, Li J, Zhou Y, et al. Effects of baicalein on cortical proinflammatory cytokines and the intestinal microbiome in senescence accelerated mouse prone 8[J]. ACS Chem Neurosci, 2018, 9:1714-1724.
[9] Yan JJ, Gao L, Qin XM et al. Baicalein attenuates the neuro-inflammation in LPS-activated BV-2 microglial cells through suppression of pro-inflammatory cytokines, COX2/NF-κB expressions and regulation of metabolic abnormality[J]. Int Immunopharmacol, 2020, 79:1060902.
[10] Song H, Lu Y, Qu Z, et al. Effects of aged garlic extract and FruArg on gene expression and signaling pathways in lipopolysaccharide-activated microglial cells[J]. Sci Rep, 2016, 6:35323.
[11] Juknat A, Pietr M, Kozela E, et al. Microarray and pathway analysis reveal distinct mechanisms underlying cannabinoid-mediated modulation of LPS-induced activation of BV-2 micro-glial cells[J]. PLoS One, 2013, 8:e61462.
[12] Zhou H, Qu Z, Mossine VV, et al. Proteomic analysis of the effects of aged garlic extract and its FruArg component on lipopolysaccharide-induced neuroinflammatory response in microglial cells[J]. PLoS One, 2014, 9:e113531.
[13] Lee SB, Lee WS, Shin JS, et al. Xanthotoxin suppresses LPS-induced expression of iNOS, COX-2, TNF-α, and IL-6via AP-1, NF-κB, and JAK-STAT inactivation in RAW264.7 macrophages[J]. Int Immunopharmacol, 2017, 49:21-29.
[14] Yauger YJ, Bermudez S, Moritz KE, et al. Iron accentuated reactive oxygen species release by NADPH oxidase in activated microglia contributes to oxidative stress in vitro[J]. J Neuroinflammation, 2019, 16:41.
[15] Rendra E, Riabov V, Mossel DM, et al. Reactive oxygen species (ROS) in macrophage activation and function in diabetes[J]. Immunobiology, 2019, 224:242-253.
[16] Qi Z, Yin F, Lu L, et al. Baicalein reduces lipopolysaccharide-induced inflammation via suppressing JAK/STATs activation and ROS production[J]. Inflamm Res, 2013, 62:845-855.
[17] Zheng C, Qu YX, Wang B, et al. COX-2/PGE2 facilitates fracture healing by activating the Wnt/β-catenin signaling pathway[J]. Eur Rev Med Pharmacol Sci, 2019, 23:9721-9728.
[18] Tse JKY. Gut microbiota, nitric oxide, and microglia as prerequisites for neurodegenerative disorders[J]. ACS Chem Neurosci, 2017, 8:1438-1447.
[19] Zoete V, Schuepbach T, Bovigny C, et al. Attracting cavities for docking. Replacing the rough energy landscape of the protein by a smooth attracting landscape[J]. J Comput Chem, 2016, 37:437-447.
[20] Sayers EW, Beck J, Bolton EE, et al. Database resources of the national center for biotechnology information[J]. Nucleic Acids Res, 2021, 49:D10-D17.
[21] David G, Grosdidier A, Wirth M, et al. SwissTargetPrediction:a web server for target prediction of bioactive small molecules[J]. Nucleic Acids Res, 2014, 42:32-38.
[22] Keiser MJ, Roth BL, Armbruster BN, et al. Relating protein pharmacology by ligand chemistry[J]. Nat Biotechnol, 2007, 25:197-206.
[23] Szklarczyk D, Franceschini A, Wyder S, et al. STRING v10:protein-protein interaction networks, integrated over the tree of life[J]. Nucleic Acids Res, 2015, 43:D447-D452.
[24] Lopes CT, Franz M, Kazi F, et al. Cytoscape web:an interactive web-based network browser[J]. Bioinformatics, 2010, 26:2347-2348.
[25] Assenov Y, Ramírez F, Schelhorn SE, et al. Computing topological parameters of biological networks[J]. Bioinformatics, 2008, 24:282-284.
[26] Bader GD, Hogue CW. An automated method for finding mole-cular complexes in large protein interaction networks[J]. BMC Bioinformatics, 2003, 4:2.
[27] Sterling T, Irwin JJ. ZINC 15——ligand discovery for everyone[J]. J Chem Inf Model, 2015, 55:2324-2337.
[28] Berman HM, Westbrook J, Feng Z, et al. The protein data bank[J]. Nucleic Acids Res, 2000, 28:235-242.
[29] Trott O, Olson AJ. AutoDock Vina:improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading[J]. J Comput Chem, 2010, 31:455-461.
[30] Nathan A, Nils W, Jens M. bcl::Cluster:a method for clustering biological molecules coupled with visualization in the Pymol molecular graphics system[J]. IEEE Int Conf Comput Adv Bio Med Sci, 2011, 2011:13-18.
[31] Sherman BT, Hosack DA, Yang J, et al. DAVID:database for annotation, visualization, and integrated discovery[J]. Genome Biol, 2003, 4:P3.
[32] Irwin JJ, Shoichet BK, Mysinger MM, et al. Automated docking screens:a feasibility study[J]. J Med Chem, 2009, 52:5712-5720.
[33] Morris GM, Huey R, Olson AJ. Using AutoDock for ligand-receptor docking[J]. Curr Protoc Bioinformatics, 2008, Chapter 8:Unit 8.14.
[34] Li S, Fan TP, Zhang WD, et al. Network pharmacology in traditional Chinese medicine[J]. Evid Based Complement Alternat Med, 2014, 2014:138460.
[35] Farkhondeh T, Pourbagher-Shahri AM, Ashrafizadeh M, et al. Green tea catechins inhibit microglial activation which prevents the development of neurological disorders[J]. Neural Regen Res, 2020, 15:1792-1798.
[36] Orihuela R, McPherson CA, Harry GJ. Microglial M1/M2 polari-zation and metabolic states[J]. Br J Pharmacol, 2016, 173:649-665.
[37] Zhang J, Zheng Y, Luo Y, et al. Curcumin inhibits LPS-induced neuroinflammation by promoting microglial M2 polarization via TREM2/TLR4/NF-κB pathways in BV2 cells[J]. Mol Immunol, 2019, 116:29-37.
[38] Chhor V, Le Charpentier T, Lebon S, et al. Characterization of phenotype markers and neuronotoxic potential of polarised primary microglia in vitro[J]. Brain Behav Immun, 2013, 32:70-85.
[39] Nogawa S, Forster C, Zhang F, et al. Interaction between indu-cible nitric oxide synthase and cyclooxygenase-2 after cerebral ischemia[J]. Proc Natl Acad Sci U S A, 1998, 95:10966-10971.
[40] Brown GC, Bal-Price A. Inflammatory neurodegeneration mediated by nitric oxide, glutamate, and mitochondria[J]. Mol Neurobiol, 2003, 27:325-355.
[41] Kawano T, Anrather J, Zhou P, et al. Prostaglandin E2 EP1 receptors:downstream effectors of COX-2 neurotoxicity[J]. Nat Med, 2006, 12:225-229.
[42] Mattson MP, Camandola S. NF-kappaB in neuronal plasticity and neurodegenerative disorders[J]. J Clin Invest, 2001, 107:247-254.
[43] Kim YJ, Hwang SY, Oh ES, et al. IL-1β, an immediate early protein secreted by activated microglia, induces iNOS/NO in C6 astrocytoma cells through p38 MAPK and NF-κB pathways[J]. J Neurosci Res, 2006, 84:1037-1046.
[44] Baeuerle PA, Baltimore D. NF-kappa B:ten years after[J]. Cell, 1996, 87:13-20.
[45] Ohmori Y, Schreiber RD, Hamilton TA. Synergy between interferon-gamma and tumor necrosis factor-alpha in transcriptional activation is mediated by cooperation between signal transducer and activator of transcription 1 and nuclear factor kappa B[J]. J Biol Chem, 1997, 272:14899-14907.
[46] Yang XJ, Seto E. HATs and HDACs:from structure, function and regulation to novel strategies for therapy and prevention[J]. Oncogene, 2007, 26:5310-5318.
[47] Lo JY, Kamarudin MN, Hamdi OA, et al. Curcumenol isolated from Curcuma zedoaria suppresses Akt-mediated NF-κB activation and p38 MAPK signaling pathway in LPS-stimulated BV-2 microglial cells[J]. Food Funct, 2015, 6:3550-3559.
[48] Zhong LM, Zong Y, Sun L, et al. Resveratrol inhibits inflammatory responses via the mammalian target of rapamycin signaling pathway in cultured LPS-stimulated microglial cells[J]. PLoS One, 2012, 7:e32195.
[49] Luu K, Greenhill CJ, Majoros A, et al. STAT1 plays a role in TLR signal transduction and inflammatory responses[J]. Immunol Cell Biol, 2014, 92:761-769.
[50] Lee HH, Shin JS, Lee WS, et al. Biflorin, isolated from the flower buds of Syzygium aromaticum L., suppresses LPS-induced inflam-matory mediators via STAT1 inactivation in macrophages and protects mice from endotoxin shock[J]. J Nat Prod, 2016, 79:711-720.
[51] Li JQ, Zhou YZ, Gao L, et al. Integration of transcriptomics and network analysis deciphers the mechanisms of baicalein in improving learning and memory impairment in senescence-accelerated mouse prone 8(SAMP8)[J]. Eur J Pharmacol, 2019, 865:172789.
[52] Yang CS, Kim JJ, Lee SJ, et al. TLR3-triggered reactive oxygen species contribute to inflammatory responses by activating signal transducer and activator of transcription-1[J]. J Immunol, 2013, 190:6368-6377.
[53] Sareila O, Kelkka T, Pizzolla A, et al. NOX2 complex-derived ROS as immune regulators[J]. Antioxid Redox Signal, 2011, 15:2197-2208.
[54] El-Benna J, Dang PM, Gougerot-Pocidalo MA. Priming of the neutrophil NADPH oxidase activation:role of p47phox phosphorylation and NOX2 mobilization to the plasma membrane[J]. Semin Immunopathol, 2008, 30:279-289.
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29.赵蕾, 武嫣斐, 高耀, 向欢, 秦雪梅, 田俊生.基于网络药理学的百合地黄汤干预心理亚健康作用机制研究[J]. 药学学报, 2017,52(1): 99-105
30.孙莉敏, 刘丽芳, 朱华旭, 朱宝杰, 张启春.基于网络药理学的黄连解毒汤治疗阿尔兹海默症的作用机制研究[J]. 药学学报, 2017,52(8): 1268-1275
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32.牟海栋, 屠鹏飞, 姜勇.基于网络药理学的肉桂温经通脉的作用机制研究[J]. 药学学报, 2016,51(11): 1724-1733
33.韩彦琪, 许浚, 张喜民, 张铁军, 任一杰, 刘昌孝.基于网络药理学的元胡止痛滴丸治疗原发性痛经的作用机制研究[J]. 药学学报, 2016,51(3): 380-387
34.白雨, 范雪梅, 孙瀚, 王义明, 梁琼麟, 罗国安.基于网络药理学的罗格列酮复方作用机制探讨[J]. 药学学报, 2015,50(3): 284-290
35.程彬峰, 侯媛媛, 姜 民, 赵振营, 董林毅, 白 钢.基于网络药理学的清肺消炎丸抗炎机制的初步研究[J]. 药学学报, 2013,48(5): 686-693