2021, Volume 7, Issue 9
Engineering >> 2021, Volume 7, Issue 9 doi: 10.1016/j.eng.2020.12.016
A Clinical and Animal Experiment Integrated Platform for Small-Molecule Screening Reveals Potential Targets of Bioactive Compounds from a Herbal Prescription Based on the Therapeutic Efficacy of Yinchenhao Tang for Jaundice Syndrome
a National Chinmedomics Research Center & National TCM Key Laboratory of Serum Pharmacochemistry, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, Harbin 150040, China
b State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau 999078, China
c National Engineering Laboratory for the Development of Southwestern Endangered Medicinal Materials, Guangxi Botanical Garden of Medicinal Plant, Nanning 530023, China
# These authors contributed equally to this work.
Next Previous
Abstract
A herbal prescription in traditional Chinese medicine (TCM) has great complexity, with multiple components and multiple targets, making it extremely challenging to determine its bioactive compounds. Yinchenhao Tang (YCHT) has been extensively used for the treatment of jaundice disease. Although many studies have examined the efficacy and active ingredients of YCHT, there is still a lack of an in-depth systematic analysis of its effective components, mechanisms, and potential targets—especially one based on clinical patients. This study established an innovative strategy for discovering the potential targets and active compounds of YCHT based on an integrated clinical and animal experiment platform. The serum metabolic profiles and constituents of YCHT in vivo were determined by ultra-performance liquid chromatography–quadrupole time-of-flight mass spectrometry (UPLC-Q-ToF-MS)-based metabolomics combined with a serum pharmacochemistry method. Moreover, a compound–target–pathway network was constructed and analyzed by network pharmacology and ingenuity pathway analysis (IPA). We found that eight active components could modulate five key targets. These key targets were further verified by enzyme-linked immunosorbent assay (ELISA), which indicated that YCHT exerts therapeutic effects by targeting cholesterol 7a-hydroxylase (CYP7A1), multidrug-resistance-associated protein 2 (ABCC2), multidrug-resistance-associated protein 3 (ABCC3), uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1), and farnesoid X receptor (FXR), and by regulating metabolic pathways including primary bile acid biosynthesis, porphyrin and chlorophyll metabolism, and biliary secretion. Eight main effective compounds were discovered and correlated with the key targets and pathways. In this way, we demonstrate that this integrated strategy can be successfully applied for the effective discovery of the active compounds and therapeutic targets of an herbal prescription.
Keywords
Efficacy ; Bioactive compound ; Small molecule ; Targets ; Herbal medicine ; Metabolomics
SupplementaryMaterials
Figures
Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
References
[ 1 ] Zhang A, Sun H, Yan G, Wang X. Recent developments and emerging trends of mass spectrometry for herbal ingredients analysis. TrAC Trends Anal Chem 2017;94:70–6. link1
[ 2 ] Tang J, Gautam P, Gupta A, He L, Timonen S, Akimov Y, et al. Network pharmacology modeling identifies synergistic Aurora B and ZAK interaction in triple-negative breast cancer. NPJ Syst Biol Appl 2019;5(1):20. link1
[ 3 ] Zhang A, Sun H, Wang X. Urinary metabolic profiling of rat models revealed protective function of scoparone against alcohol induced hepatotoxicity. Sci Rep 2014;4(1):6768. link1
[ 4 ] Zhang AH, Ma ZM, Sun H, Zhang Y, Liu JH, Wu FF, et al. High-throughput metabolomics evaluate the efficacy of total lignans from acanthophanax senticosus stem against ovariectomized osteoporosis rat. Front Pharmacol 2019;10:553. link1
[ 5 ] Zhang A, Sun H, Qiu S, Wang X. Advancing drug discovery and development from active constituents of Yinchenhao Tang, a famous traditional Chinese medicine formula. Evid Based Complement Alternat Med 2013;2013:257909. link1
[ 6 ] Yan J, Xie G, Liang C, Hu Y, Zhao A, Huang F, et al. Herbal medicine Yinchenhaotang protects against a-naphthylisothiocyanate-induced cholestasis in rats. Sci Rep 2017;7(1):4211. link1
[ 7 ] Tian X, Liu H, Qiao S, Yin H, Chen M, Hu P, et al. Exploration of the hepatoprotective chemical base of an orally administered herbal formulation (YCHT) in normal and CCl4-intoxicated liver injury rats. Part 2: hepatic disposition in vivo and hepatoprotective activity in vitro. J Ethnopharmacol 2019;236:161–72. link1
[ 8 ] Liu XY, Zhang AH, Fang H, Li MX, Song Q, Su J, et al. Serum metabolomics strategy for understanding the therapeutic effects of Yin-Chen-Hao-Tang against Yanghuang syndrome. RSC Adv 2018;8(14):7403–13. link1
[ 9 ] Sun H, Zhang AH, Yang L, Li MX, Fang H, Xie J, et al. High-throughput chinmedomics strategy for discovering the quality-markers and potential targets for Yinchenhao decoction. Phytomedicine 2019;54:328–38. link1
[10] Yu G, Wang W, Wang X, Xu M, Zhang L, Ding L, et al. Network pharmacologybased strategy to investigate pharmacological mechanisms of Zuojinwan for treatment of gastritis. BMC Complement Altern Med 2018;18(1):292. link1
[11] Ligeti B, Pénzváltó Z, Vera R, Gyorffy B, Pongor S. A network-based target } overlap score for characterizing drug combinations: high correlation with cancer clinical trial results. PLoS ONE 2015;10(6):e0129267. link1
[12] Wang WF, Li SM, Ren GP, Zheng W, Lu YJ, Yu YH, et al. Recombinant murine fibroblast growth factor 21 ameliorates obesity-related inflammation in monosodium glutamate-induced obesity rats. Endocrine 2015;49(1):119–29. link1
[13] Cheng HY, Lin LT, Huang HH, Yang CM, Lin CC. Yin Chen Hao Tang, a Chinese prescription, inhibits both herpes simplex virus type-1 and type-2 infections in vitro. Antiviral Res 2008;77(1):14–9. link1
[14] Wang B, Sun MY, Long AH, Cao HY, Ren S, Bian YQ, et al. Yin-Chen-Hao-Tang alleviates biliary obstructive cirrhosis in rats by inhibiting biliary epithelial cell proliferation and activation. Pharmacogn Mag 2015;11(42):417–25. link1
[15] Sun Q, Fang F, Lu GC, Mao HH, Xu JH, Zhou SK, et al. Effects of different drainage methods on serum bile acid and hepatocyte apoptosis and regeneration after partial hepatectomy in rats with obstructive jaundice. J Biol Regul Homeost Agents 2019;33(2):571–9. link1
[16] Sun H, Yang L, Li MX, Fang H, Zhang AH, Song Q, et al. UPLC-G2Si-HDMS untargeted metabolomics for identification of metabolic targets of Yin-ChenHao-Tang used as a therapeutic agent of dampness-heat jaundice syndrome. J Chromatogr B Analyt Technol Biomed Life Sci 2018;1081–1082:41–50. link1
[17] Zhu G, Feng F. UPLC-MS-based metabonomic analysis of intervention effects of Da-Huang-Xiao-Shi decoction on ANIT-induced cholestasis. J Ethnopharmacol 2019;238:111860. link1
[18] Nandi S, Biswas S. A recyclable post-synthetically modified Al(III) based metal–organic framework for fast and selective fluorogenic recognition of bilirubin in human biofluids. Dalton Trans 2019;48(25):9266–75. link1
[19] Gonzalez-Sanchez E, Perez MJ, Nytofte NS, Briz O, Monte MJ, Lozano E, et al. Protective role of biliverdin against bile acid-induced oxidative stress in liver cells. Free Radic Biol Med 2016;97:466–77. link1
[20] Sun H, Zhang AH, Song Q, Fang H, Liu XY, Su J, et al. Functional metabolomics discover pentose and glucuronate interconversion pathways as promising targets for Yang Huang syndrome treatment with Yinchenhao Tang. RSC Adv 2018;8(64):36831–9. link1
[21] Zhao SS, Li NR, Zhao WL, Liu H, Ge MX, Zhang YX, et al. D-chiro-inositol effectively attenuates cholestasis in bile duct ligated rats by improving bile acid secretion and attenuating oxidative stress. Acta Pharmacol Sin 2018;39 (2):213–21. link1
[22] El Kasmi KC, Vue PM, Anderson AL, Devereaux MW, Ghosh S, Balasubramaniyan N, et al. Macrophage-derived IL-1b/NF-jB signaling mediates parenteral nutrition-associated cholestasis. Nat Commun 2018;9 (1):1393. link1
[23] Zhang AH, Sun H, Yan GL, Yuan Y, Han Y, Wang XJ. Metabolomics study of type 2 diabetes using ultra-performance LC-ESI/quadrupole-TOF high-definition MS coupled with pattern recognition methods. J Physiol Biochem 2014;70 (1):117–28. link1
[24] Blazquez AMG, Macias RIR, Cives-Losada C, de la Iglesia A, Marin JJG, Monte MJ. Lactation during cholestasis: role of ABC proteins in bile acid traffic across the mammary gland. Sci Rep 2017;7(1):7475. link1
[25] Chai J, Cai SY, Liu X, Lian W, Chen S, Zhang L, et al. Canalicular membrane MRP2/ABCC2 internalization is determined by Ezrin Thr567 phosphorylation in human obstructive cholestasis. J Hepatol 2015;63(6):1440–8. link1
[26] Keppler D. The roles of MRP2, MRP3, OATP1B1, and OATP1B3 in conjugated hyperbilirubinemia. Drug Metab Dispos 2014;42(4):561–5. link1
[27] Henkel SA, Squires JH, Ayers M, Ganoza A, Mckiernan P, Squires JE. Expanding etiology of progressive familial intrahepatic cholestasis. World J Hepatol 2019;11(5):450–63. link1
[28] Zhang A, Liu Q, Zhao H, Zhou X, Sun H, Nan Y, et al. Phenotypic characterization of nanshi oral liquid alters metabolic signatures during disease prevention. Sci Rep 2016;6(1):19333. link1
[29] Feldman AG, Sokol RJ. Neonatal cholestasis: emerging molecular diagnostics and potential novel therapeutics. Nat Rev Gastroenterol Hepatol 2019;16 (6):346–60. link1
[30] Zhang AH, Sun H, Qiu S, Wang XJ. Recent highlights of metabolomics in Chinese medicine syndrome research. Evid-Based Compl Alt 2013;2013: 402159. link1
[31] Wei J, Chen J, Fu L, Han L, Gao X, Sarhene M, et al. Polygonum multiflorum Thunb suppress bile acid synthesis by activating Fxr–Fgf15 signaling in the intestine. J Ethnopharmacol 2019;235:472–80. link1
[32] Qiu S, Zhang AH, Guan Y, Sun H, Zhang T, Han Y, et al. Functional metabolomics using UPLC-Q/TOF-MS combined with ingenuity pathway analysis as a promising strategy for evaluating the efficacy and discovering amino acid metabolism as a potential therapeutic mechanism-related target for geniposide against alcoholic liver disease. RSC Adv 2020;10(5):2677–90. link1
[33] Kringen MK, Piehler AP, Grimholt RM, Opdal MS, Haug KB, Urdal P. Serum bilirubin concentration in healthy adult North-Europeans is strictly controlled by the UGT1A1 TA-repeat variants. PLoS ONE 2014;9(2):e90248. link1
[34] Memon N, Weinberger BI, Hegyi T, Aleksunes LM. Inherited disorders of bilirubin clearance. Pediatr Res 2016;79(3):378–86. link1
[35] Fujimori N, Komatsu M, Tanaka N, Iwaya M, Nakano H, Sugiura A, et al. Cimetidine/lactulose therapy ameliorates erythropoietic protoporphyriarelated liver injury. Clin J Gastroenterol 2017;10(5):452–8. link1
[36] Zhang AH, Fang H, Wang YY, Yan GL, Sun H, Zhou XH, et al. Discovery and verification of the potential targets from bioactive molecules by network pharmacology-based target prediction combined with high-throughput metabolomics. RSC Adv 2017;7(81):51069–78. link1
[37] Fang H, Zhang A, Yu J, Wang L, Liu C, Zhou X, et al. Insight into the metabolic mechanism of scoparone on biomarkers for inhibiting Yanghuang syndrome. Sci Rep 2016;6(1):37519. link1
[38] Li JY, Cao HY, Sun L, Sun RF, Wu C, Bian YQ, et al. Therapeutic mechanism of Yın-Chén-Ha¯o decoction in hepatic diseases. World J Gastroenterol 2017;23 (7):1125–38. link1
[39] Qiu S, Zhang A, Zhang T, Sun H, Guan Y, Yan G, et al. Dissect new mechanistic insights for geniposide efficacy on the hepatoprotection using multiomics approach. Oncotarget 2017;8(65):108760–70. link1
京公网安备 11010502051620号
