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Combinatorial Chemistry & High Throughput Screening

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ISSN (Print): 1386-2073
ISSN (Online): 1875-5402

Research Article

Antipyretic Mechanism Exploration of HuanglianShangqing Pill Based on Metabolomics and Network Pharmacology

Author(s): Pingting Mao, Bo Mai, Xi Mai*, Lei Zheng, Na Li, Yijing Liao, Ling He, Weibao He and Qimin Zhang

Volume 25, Issue 12, 2022

Published on: 15 March, 2022

Page: [2112 - 2125] Pages: 14

DOI: 10.2174/1386207325666220215144847

Price: $65

Abstract

Background and Objective: HuanglianShangqing pill (HLSQ), a well-known traditional Chinese medicine (TCM), has been used to treat fever in China for a long time. Our previous study had demonstrated that a total of 45 prototype components of HLSQ could be absorbed into the plasma of rats after intragastric administration. However, the detailed mechanisms related to the antipyretic effects of HLSQ were still unclear.

Methods: In the present work, urinary metabolomics coupled with network pharmacology were employed to evaluate the mechanisms of HLSQ in the treatment of fever compared with ibuprofen (IBU) and paracetamol (APAP).

Results: In pyrexia rats, a total of 11 potential metabolites and a disturbed TCA cycle were found. The metabolic regulation effects of HLSQ on fever rats were similar to APAP and could make the TCA cycle disorder return to normal by reducing citrate, β-hydroxybutyrate, succinate. In addition, HLSQ could adjust the intestinal microbial disorder and inhibit inflammatory factors, including IL6, TNF, VEGFA, TP53, STAT3, etc. There were 40 components acting on fever targets in HLSQ; among them, luteolin, apigenin, ursolic acid, kaempferol, wogonin, daidzein, baicalein, emodin, berberine, and oroxylin A were the main active compounds of HLSQ in the treatment of fever.

Conclusion: The antipyretic mechanisms of HLSQ are inhibition of inflammatory factors, action on the TCA cycle, and regulation of gut microbiota.

Keywords: HuanglianShangqing pill, metabolomics, network, pharmacology, fever, NMR spectroscopy, antipyretic.

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[1]
Livingston, E.; Bucher, K.; Rekito, A. Coronavirus disease 2019 and influenza 2019-2020. JAMA, 2020, 323(12), 1122.
[http://dx.doi.org/10.1001/jama.2020.2633] [PMID: 32207769]
[2]
Vogel, G. Fever dilemma; , 2018. Available from:
[http://dx.doi.org/10.1126/science.359.6380.1090]
[3]
Kiriakidou, M.; Ching, C.L. Systemic lupus erythematosus. Ann. Intern. Med., 2020, 172(11), ITC81-ITC96.
[http://dx.doi.org/10.7326/AITC202006020] [PMID: 32479157]
[4]
Killeen, S.D.; Wang, J.H.; Andrews, E.J.; Redmond, H.P. Bacterial endotoxin enhances colorectal cancer cell adhesion and invasion through TLR-4 and NF-kappaB-dependent activation of the urokinase plasminogen activator system. Br. J. Cancer, 2009, 100(10), 1589-1602.
[http://dx.doi.org/10.1038/sj.bjc.6604942] [PMID: 19436306]
[5]
Liu, X.; Li, Z.; Liu, H.; Zhu, Y.; Xia, D.; Wang, S.; Gu, R.; Wu, W.; Zhang, P.; Liu, Y.; Zhou, Y. Low concentration flufenamic acid en-hances osteogenic differentiation of mesenchymal stem cells and suppresses bone loss by inhibition of the NF-κB signaling pathway. Stem Cell Res. Ther., 2019, 10(1), 213.
[http://dx.doi.org/10.1186/s13287-019-1321-y] [PMID: 31324207]
[6]
Ma, H.; Liu, Y.; Mai, X.; Liao, Y.; Zhang, K.; Liu, B.; Xie, X.; Du, Q. Identification of the constituents and metabolites in rat plasma after oral administration of HuanglianShangqing pills by ultra high-performance liquid chromatography/quadrupole time-of-flight mass spec-trometry. J. Pharm. Biomed. Anal., 2016, 125, 194-204.
[http://dx.doi.org/10.1016/j.jpba.2016.03.038] [PMID: 27031575]
[7]
Chang, J. Heat clearing medicine: "Huanglian Shangqing pill" (In Chinese). 2002, (07), 49.
[8]
Liu, J. New use of Huanglian Shangqing pill (In Chinese). Family Doc, 2006, 004.
[9]
Pharmacopeia of People’s Republic of China; 2020a China Medical Science Press: Beijing, 2020, pp. 1593-1594.
[10]
Kong, X.; Wan, H.; Su, X.; Zhang, C.; Yang, Y.; Li, X.; Yao, L.; Lin, N. Rheum palmatum L. and Coptis chinensis Franch., exert antipyretic effect on yeast-induced pyrexia rats involving regulation of TRPV1 and TRPM8 expression. J. Ethnopharmacol., 2014, 153(1), 160-168.
[http://dx.doi.org/10.1016/j.jep.2014.02.007] [PMID: 24530855]
[11]
Tseng, S.H.; Lee, H.H.; Chen, L.G.; Wu, C.H.; Wang, C.C. Effects of three purgative decoctions on inflammatory mediators. J. Ethnopharmacol., 2006, 105(1-2), 118-124.
[http://dx.doi.org/10.1016/j.jep.2005.10.003] [PMID: 16310993]
[12]
Linte, R.M.; Ciobanu, C.; Reid, G.; Babes, A. Desensitization of cold- and menthol-sensitive rat dorsal root ganglion neurones by inflam-matory mediators. Exp. Brain Res., 2007, 178(1), 89-98.
[http://dx.doi.org/10.1007/s00221-006-0712-3] [PMID: 17006682]
[13]
Yan, D.; Jin, C.; Xiao, X.H.; Dong, X.P. Antimicrobial properties of berberines alkaloids in Coptis chinensis Franch by microcalorimetry. J. Biochem. Biophys. Methods, 2008, 70(6), 845-849.
[http://dx.doi.org/10.1016/j.jbbm.2007.07.009] [PMID: 17804078]
[14]
Jia, F.; Zou, G.; Fan, J.; Yuan, Z. Identification of palmatine as an inhibitor of West Nile virus. Arch. Virol., 2010, 155(8), 1325-1329.
[http://dx.doi.org/10.1007/s00705-010-0702-4] [PMID: 20496087]
[15]
Tong, L.; Wan, M.; Zhang, L.; Zhu, Y.; Sun, H.; Bi, K. Simultaneous determination of baicalin, wogonoside, baicalein, wogonin, oroxylin A and chrysin of Radix scutellariae extract in rat plasma by liquid chromatography tandem mass spectrometry. J. Pharm. Biomed. Anal., 2012, 70, 6-12.
[http://dx.doi.org/10.1016/j.jpba.2012.03.051] [PMID: 22703838]
[16]
Zhi, H.J.; Zhu, H.Y.; Zhang, Y.Y.; Lu, Y.; Li, H.; Chen, D.F. in vivo effect of quantified flavonoids-enriched extract of Scutellaria bai-calensis root on acute lung injury induced by influenza A virus. Phytomedicine, 2019, 57, 105-116.
[http://dx.doi.org/10.1016/j.phymed.2018.12.009] [PMID: 30668313]
[17]
Zhang, R.; Zhu, X.; Bai, H.; Ning, K. Network pharmacology databases for traditional chinese medicine: Review and assessment. Front. Pharmacol., 2019, 10, 123.
[http://dx.doi.org/10.3389/fphar.2019.00123] [PMID: 30846939]
[18]
Xu, C.; Zhang, C.; Yang, J.; Wang, N.; Wang, J.; Ma, T. Textual research on gardeniae fructus. Zhongguo Shiyan Fangjixue Zazhi, 2020, 26, 183-191.
[19]
Tian, J.; Jiang, Z.F.; Yang, S.Y. Pharmacological action of Huanglianshangqing capsule. Pharmacol. Clin. Chinese Materia Medica., 1998, 14(2), 10-12.
[20]
Zhang, X.Q.; Zhang, H.F.; Li, R.Q. Clinical study of Huanglian Shangqing Capsules combined with tinidazole in treatment of chronic peri-odontitis. Drugs Clin., 2020, 35(06), 1216-1221.
[21]
Li, L. Effect of Huanglian Shangqing Capsule combined with Minocycline on periodontal indexes and inflammatory factors in chronic periodontitis (In Chinese). China Modern Med., 2021, 28(07), 172-175.
[22]
Johnson, C.H.; Ivanisevic, J.; Siuzdak, G. Metabolomics: beyond biomarkers and towards mechanisms. Nat. Rev. Mol. Cell Biol., 2016, 17(7), 451-459.
[http://dx.doi.org/10.1038/nrm.2016.25] [PMID: 26979502]
[23]
Robertson, D.G.; Reily, M.D.; Baker, J.D. Metabonomics in pharmaceutical discovery and development. J. Proteome Res., 2007, 6(2), 526-539.
[http://dx.doi.org/10.1021/pr060535c] [PMID: 17269709]
[24]
Nicholson, J.K.; Connelly, J.; Lindon, J.C.; Holmes, E. Metabonomics: a platform for studying drug toxicity and gene function. Nat. Rev. Drug Discov., 2002, 1(2), 153-161.
[http://dx.doi.org/10.1038/nrd728] [PMID: 12120097]
[25]
Beckonert, O.; Keun, H.C.; Ebbels, T.M.; Bundy, J.; Holmes, E.; Lindon, J.C.; Nicholson, J.K. Metabolic profiling, metabolomic and metabonomic procedures for NMR spectroscopy of urine, plasma, serum and tissue extracts. Nat. Protoc., 2007, 2(11), 2692-2703.
[http://dx.doi.org/10.1038/nprot.2007.376] [PMID: 18007604]
[26]
Brandolini-Bunlon, M.; Pétéra, M.; Gaudreau, P.; Comte, B.; Bougeard, S.; Pujos-Guillot, E. Multi-block PLS discriminant analysis for the joint analysis of metabolomic and epidemiological data. Metabolomics, 2019, 15(10), 134.
[http://dx.doi.org/10.1007/s11306-019-1598-y] [PMID: 31583480]
[27]
Wang, N.; Zheng, Y.; Gu, J.; Cai, Y.; Wang, S.; Zhang, F.; Chen, J.; Situ, H.; Lin, Y.; Wang, Z. Network-pharmacology-based validation of TAMS/CXCL-1 as key mediator of XIAOPI formula preventing breast cancer development and metastasis. Sci. Rep., 2017, 7(1), 14513.
[http://dx.doi.org/10.1038/s41598-017-15030-3] [PMID: 29109519]
[28]
Hopkins, A.L. Network pharmacology: The next paradigm in drug discovery. Nat. Chem. Biol., 2008, 4(11), 682-690.
[http://dx.doi.org/10.1038/nchembio.118] [PMID: 18936753]
[29]
Nicholls, A.W.; Mortishire-Smith, R.J.; Nicholson, J.K. NMR spectroscopic-based metabonomic studies of urinary metabolite variation in acclimatizing germ-free rats. Chem. Res. Toxicol., 2003, 16(11), 1395-1404.
[http://dx.doi.org/10.1021/tx0340293] [PMID: 14615964]
[30]
Keun, H.C.; Ebbels, T.M.; Bollard, M.E.; Beckonert, O.; Antti, H.; Holmes, E.; Lindon, J.C.; Nicholson, J.K. Geometric trajectory analysis of metabolic responses to toxicity can define treatment specific profiles. Chem. Res. Toxicol., 2004, 17(5), 579-587.
[http://dx.doi.org/10.1021/tx034212w] [PMID: 15144214]
[31]
Zheng, P.; Gao, H.C.; Li, Q.; Shao, W.H.; Zhang, M.L.; Cheng, K.; Yang, D.Y.; Fan, S.H.; Chen, L.; Fang, L.; Xie, P. Plasma metabonomics as a novel diagnostic approach for major depressive disorder. J. Proteome Res., 2012, 11(3), 1741-1748.
[http://dx.doi.org/10.1021/pr2010082] [PMID: 22239730]
[32]
Xie, B.; Liu, A.; Zhan, X.; Ye, X.; Wei, J. Alteration of gut bacteria and metabolomes after glucaro-1,4-lactone treatment contributes to the prevention of hypercholesterolemia. J. Agric. Food Chem., 2014, 62(30), 7444-7451.
[http://dx.doi.org/10.1021/jf501744d] [PMID: 24972288]
[33]
Chong, J.; Wishart, D.S.; Xia, J. Using MetaboAnalyst 4.0 for comprehensive and integrative metabolomics data analysis. Curr. Protoc. Bioinformatics, 2019, 68(1), e86.
[http://dx.doi.org/10.1002/cpbi.86] [PMID: 31756036]
[34]
Zhang, L.; Ye, Y.; An, Y.; Tian, Y.; Wang, Y.; Tang, H. Systems responses of rats to aflatoxin B1 exposure revealed with metabonomic changes in multiple biological matrices. J. Proteome Res., 2011, 10(2), 614-623.
[http://dx.doi.org/10.1021/pr100792q] [PMID: 21080729]
[35]
Akira, K.; Masu, S.; Imachi, M.; Mitome, H.; Hashimoto, M.; Hashimoto, T. 1H NMR-based metabonomic analysis of urine from young spontaneously hypertensive rats. J. Pharm. Biomed. Anal., 2008, 46(3), 550-556.
[http://dx.doi.org/10.1016/j.jpba.2007.11.017] [PMID: 18164575]
[36]
Sun, J.; Schnackenberg, L.K.; Holland, R.D.; Schmitt, T.C.; Cantor, G.H.; Dragan, Y.P.; Beger, R.D. Metabonomics evaluation of urine from rats given acute and chronic doses of acetaminophen using NMR and UPLC/MS. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci., 2008, 871(2), 328-340.
[http://dx.doi.org/10.1016/j.jchromb.2008.04.008] [PMID: 18472313]
[37]
Gallego-Sandín, S.; Novalbos, J.; Rosado, A.; Gisbert, J.P.; Gálvez-Múgica, M.A.; García, A.G.; Pajares, J.M.; Abad-Santos, F. Effect of ibuprofen on cyclooxygenase and nitric oxide synthase of gastric mucosa: correlation with endoscopic lesions and adverse reactions. Dig. Dis. Sci., 2004, 49(9), 1538-1544.
[http://dx.doi.org/10.1023/B:DDAS.0000042261.22387.06] [PMID: 15481334]
[38]
Bertolotto, M.; Contini, P.; Ottonello, L.; Pende, A.; Dallegri, F.; Montecucco, F. Neutrophil migration towards C5a and CXCL8 is prevent-ed by non-steroidal anti-inflammatory drugs via inhibition of different pathways. Br. J. Pharmacol, 2014, 171, 3376-3393.
[http://dx.doi.org/10.1111/bph.12670] [PMID: 24597536]
[39]
Grzegorz, W.P.; Konrad, A.S.; Jan, G. Paracetamol-An old drug with new mechanisms of action. Clin. Exp. Pharmacol. Physiol., 2021, 48(1), 3-19.
[40]
Krebs, H.A. Rate control of the tricarboxylic acid cycle. Adv. Enzyme Regul., 1970, 8, 335-353.
[http://dx.doi.org/10.1016/0065-2571(70)90028-2] [PMID: 4920378]
[41]
Hua, Y.L.; Ma, Q.; Zhang, X.S.; Yao, W.L.; Ji, P.; Hu, J.J.; Wei, Y.M. Urinary metabolomics analysis reveals the effect of volatile oil from Angelica sinensis on LPS-induced inflammation rats. Biomed. Chromatogr., 2019, 33(2), e4402.
[http://dx.doi.org/10.1002/bmc.4402] [PMID: 30255631]
[42]
McGarry, J.D.; Foster, D.W. Regulation of hepatic fatty acid oxidation and ketone body production. Annu. Rev. Biochem., 1980, 49, 395-420.
[http://dx.doi.org/10.1146/annurev.bi.49.070180.002143] [PMID: 6157353]
[43]
Newman, J.C.; Verdin, E. β-Hydroxybutyrate: A signaling metabolite. Annu. Rev. Nutr., 2017, 37, 51-76.
[http://dx.doi.org/10.1146/annurev-nutr-071816-064916] [PMID: 28826372]
[44]
Williams, R.E.; Eyton-Jones, H.W.; Farnworth, M.J.; Gallagher, R.; Provan, W.M. Effect of intestinal microflora on the urinary metabolic profile of rats: A (1)H-nuclear magnetic resonance spectroscopy study. Xenobiotica, 2002, 32(9), 783-794.
[http://dx.doi.org/10.1080/00498250210143047] [PMID: 12396275]
[45]
Holmes, E.; Li, J.V.; Athanasiou, T.; Ashrafian, H.; Nicholson, J.K. Understanding the role of gut microbiome-host metabolic signal dis-ruption in health and disease. Trends Microbiol., 2011, 19(7), 349-359.
[http://dx.doi.org/10.1016/j.tim.2011.05.006] [PMID: 21684749]
[46]
Clarke, E.D.; Rollo, M.E.; Collins, C.E.; Wood, L.; Callister, R.; Philo, M.; Kroon, P.A.; Haslam, R.L. The relationship between dietary polyphenol intakes and urinary polyphenol concentrations in adults prescribed a high vegetable and fruit diet. Nutrients, 2020, 12(11), 3431.
[http://dx.doi.org/10.3390/nu12113431] [PMID: 33182344]
[47]
de Mello, V.D.; Lankinen, M.A.; Lindström, J.; Puupponen-Pimiä, R.; Laaksonen, D.E.; Pihlajamäki, J.; Lehtonen, M.; Uusitupa, M.; Tuomilehto, J.; Kolehmainen, M.; Törrönen, R.; Hanhineva, K. Fasting serum hippuric acid is elevated after bilberry (Vaccinium myrtillus) consumption and associates with improvement of fasting glucose levels and insulin secretion in persons at high risk of developing type 2 diabetes. Mol. Nutr. Food Res., 2017, 61(9), 1700019.
[http://dx.doi.org/10.1002/mnfr.201700019] [PMID: 28556578]
[48]
Ge, Q.; Chen, L.; Chen, K. Treatment of diabetes mellitus using iPS cells and spice polyphenols. J. Diabetes Res., 2017, 2017, 5837804.
[http://dx.doi.org/10.1155/2017/5837804] [PMID: 28758131]
[49]
Patel, R.P.; Barnes, S. Isoflavones and PPAR Signaling: A critical target in cardiovascular, metastatic, and metabolic disease. PPAR Res., 2010, 2010, 153252.
[http://dx.doi.org/10.1155/2010/153252] [PMID: 21461045]
[50]
Zeisel, S.H.; daCosta, K.A.; Youssef, M.; Hensey, S. Conversion of dietary choline to trimethylamine and dimethylamine in rats: dose-response relationship. J. Nutr., 1989, 119(5), 800-804.
[http://dx.doi.org/10.1093/jn/119.5.800] [PMID: 2723829]
[51]
Aziz, N.; Kim, M.Y.; Cho, J.Y. Anti-inflammatory effects of luteolin: A review of in vitro, in vivo, and in silico studies. J. Ethnopharmacol., 2018, 225, 342-358.
[http://dx.doi.org/10.1016/j.jep.2018.05.019] [PMID: 29801717]
[52]
Park, C.H.; Min, S.Y.; Yu, H.W.; Kim, K.; Kim, S.; Lee, H.J.; Kim, J.H.; Park, Y.J. Effects of apigenin on RBL-2H3, RAW264.7, and Ha-CaT cells: Anti-allergic, anti-inflammatory, and skin-protective activities. Int. J. Mol. Sci., 2020, 21(13), 4620.
[http://dx.doi.org/10.3390/ijms21134620] [PMID: 32610574]
[53]
Dong, X.; Fu, J.; Yin, X.; Cao, S.; Li, X.; Lin, L.; Ni, J. Huyiligeqi, Ni J Emodin: A review of its pharmacology, toxicity and pharmacoki-netics. Phytother. Res., 2016, 30(8), 1207-1218.
[http://dx.doi.org/10.1002/ptr.5631] [PMID: 27188216]
[54]
Jeong, H.W.; Hsu, K.C.; Lee, J.W.; Ham, M.; Huh, J.Y.; Shin, H.J.; Kim, W.S.; Kim, J.B. Berberine suppresses proinflammatory responses through AMPK activation in macrophages. Am. J. Physiol. Endocrinol. Metab., 2009, 296(4), E955-E964.
[http://dx.doi.org/10.1152/ajpendo.90599.2008] [PMID: 19208854]
[55]
Kang, S.; Tanaka, T.; Narazaki, M.; Kishimoto, T. Targeting interleukin-6 signaling in clinic. Immunity, 2019, 50(4), 1007-1023.
[http://dx.doi.org/10.1016/j.immuni.2019.03.026] [PMID: 30995492]
[56]
Albè, E.; Chang, J.H.; Azar, N.F.; Ivanov, A.R.; Azar, D.T. Proteomic analysis of the hyaloid vascular system regression during ocular development. J. Proteome Res., 2008, 7(11), 4904-4913.
[http://dx.doi.org/10.1021/pr800551m] [PMID: 18841878]
[57]
Shang, J.; He, Q.; Chen, Y.; Yu, D.; Sun, L.; Cheng, G.; Liu, D.; Xiao, J.; Zhao, Z. miR-15a-5p suppresses inflammation and fibrosis of peritoneal mesothelial cells induced by peritoneal dialysis via targeting VEGFA. J. Cell. Physiol., 2019, 234(6), 9746-9755.
[http://dx.doi.org/10.1002/jcp.27660] [PMID: 30362573]
[58]
Barabutis, N.; Schally, A.V.; Siejka, A. P53, GHRH, inflammation and cancer. EBioMedicine, 2018, 37, 557-562.
[http://dx.doi.org/10.1016/j.ebiom.2018.10.034] [PMID: 30344124]
[59]
Sun, D.; Wang, J.; Han, Y.; Dong, X.; Ge, J.; Zheng, R.; Shi, X.; Wang, B.; Li, Z.; Ren, P.; Sun, L.; Yan, Y.; Zhang, P.; Zhang, F.; Li, T.; Wang, C. TISCH: a comprehensive web resource enabling interactive single-cell transcriptome visualization of tumor microenvironment. Nucleic Acids Res., 2021, 49(D1), D1420-D1430.
[http://dx.doi.org/10.1093/nar/gkaa1020] [PMID: 33179754]
[60]
Chow, E.M.; Batty, S.; Mogridge, J. Anthrax lethal toxin promotes dephosphorylation of TTP and formation of processing bodies. Cell. Microbiol., 2010, 12(4), 557-568.
[http://dx.doi.org/10.1111/j.1462-5822.2009.01418.x] [PMID: 19995385]

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