Version updates of strategies for drug discovery based on effective constituents of traditional Chinese medicine

Abstract

The discovery of effective constituents of traditional Chinese medicine (TCM) is an important approach in new drug development. Several well-known drugs, such as artemisinin, berberine, and ephedrine have been developed using this approach. However, the efficacy and safety of TCM, two key issues for drug development based on TCM clinical experience, remain unclear worldwide. The discovery strategy of relevant constituents is the most important step for determining efficacy and safety, which still a key scientific problem that restricts the development of new drugs. Furthermore, TCM formulas used as clinical drugs address a specific TCM syndrome (Zheng), and the complexity of the formula and vagueness of the syndrome make the identification of the effective constituents related to clinical effectiveness challenging. Over decades, researchers have developed transdisciplinary technologies and research methodologies to identify effective constituents in vivo. In this paper, the history of strategy development for identifying the effective constituents related to the clinical efficacy of TCM is reviewed and summarized. The main approaches include the phytochemical method, which involves the classical systematic separation and screening (extraction, separation, purification, structure identification, and activity test); bioactivity-guided separation; serum pharmacochemistry of TCM in vivo; and Chinmedomics, which connects in vivo constituents with the biomarkers of the relevant TCM syndrome. Chinmedomics is a promising strategy that conforms to the theory and characteristics of TCM. By clarifying the effective constituents, targets and pathways of medicines, it can promote the discovery of lead compounds and the research of innovative drugs, and continuously promote the modernization of TCM.

Keywords

Chinmedomics / Effective constituents of TCM / New drug discovery strategy / Serum pharmacochemistry of TCM / Traditional Chinese medicine

References

[[1]] Cheung F. TCM: made in China. Nature 2011;480(7378):S82-S83.

[[2]] Tu Y. Artemisinin-a gift from Traditional Chinese Medicine to the World (Nobel Lecture). Angew Chem Int Ed Engl 2016;55(35):10210-10226.

[[3]] Hou Q, He WJ, Wu YS, et al. Berberine: a traditional natural product with novel biological activities. Altern Ther Health Med 2020;26(S2):20-27.

[[4]] Song D, Hao J, Fan D. Biological properties and clinical applications of berberine. Front Med 2020;14(5):564-582.

[[5]] Shao F, Wilson IW, Qiu D. The research progress of taxol in Taxus. Curr Pharm Biotechnol 2021;22(3):360-366.

[[6]] Lyu M, Fan G, Xiao G, et al. Traditional Chinese medicine in COVID-19. Acta Pharm Sin B 2021;11(11):3337-3363.

[[7]] National Medical Products Administration. National Medical Products Administration approved the marketing of Qingfei Didu Granules, Huashi Baidu Granules and Xuanfei Baidu Granules. Available from: https://www.nmpa.gov.cn/zhuanti/yqyjzxd/yqyjxd/20210302190503177.html. Accessed March 2, 2021.

[[8]] Xu X, Xia J, Zhao S, et al. Qing-Fei-Pai-Du decoction and wogonoside exert anti-inflammatory action through down-regulating USP14 to promote the degradation of activating transcription factor 2. FASEB J 2021;35(9):e21870.

[[9]] Hao P, Jiang F, Cheng J, et al. Traditional Chinese Medicine for cardiovascular disease: evidence and potential mechanisms. J Am Coll Cardiol 2017;69(24):2952-2966.

[[10]] Zhang HY, Tian JX, Lian FM, et al. Therapeutic mechanisms of traditional Chinese medicine to improve metabolic diseases via the gut microbiota. Biomed Pharmacother 2021;133:110857.

[[11]] Guo R, Li L, Su J, et al. Pharmacological activity and mechanism of Tanshinone IIA in related diseases. Drug Des Devel Ther 2020;14:4735-4748.

[[12]] Wang P, Chen Z. Traditional Chinese medicine ZHENG and Omics convergence: a systems approach to post-genomics medicine in a global world. Omics 2013;17(9):451-459.

[[13]] Tang JL, Liu BY, Ma KW. Traditional Chinese medicine. Lancet 2008;372(9654):1938-1940.

[[14]] Chen KK, Schmidt CF. The action and clinical use of ephedrine, an alkaloid isolated from the Chinese drug ma Huang; historical document. Ann Allergy 1959;17:605-618.

[[15]] Wani MC, Taylor HL, Wall ME, et al. Plant antitumor agents. VI. The isolation and structure of taxol, a novel antileukemic and antitumor agent from Taxus brevifolia. J Am Chem Soc 1971;93(9):2325-2327.

[[16]] Wang XJ. Study on serum pharmacochemistry of Traditional Chinese Medicine. Modernization of Traditional Chinese Medicine and Materia Medica-World Science and Technology 2002;4(2):1-4+78.

[[17]] Han Y, Sun H, Zhang A, et al. Chinmedomics, a new strategy for evaluating the therapeutic efficacy of herbal medicines. Pharmacol Ther 2020;216:107680.

[[18]] Phillipson JD. Phytochemistry and medicinal plants. Phytochem 2001;56(3):237-243.

[[19]] Ji D, Wang Q, Wang H, et al. Preparative separation of gallic acid from Fallopia aubertii using middle-pressure chromatogram isolated gel coupled with reversed-phase chromatography with hydrophilic groups. RSC Adv 2021;11(44):27276-27282.

[[20]] Santiago M, Strobel S. Thin layer chromatography. Methods Enzymol 2013;533:303-324.

[[21]] McChesney JD, Rodenburg DL. Preparative chromatography and natural products discovery. Curr Opin Biotechnol 2014;25:111-113.

[[22]] Chen KK, Schmidt CF. The action of ephedrine, an alkaloid from Ma Huang. Proc Soc Exp Biol Med 1924;21(6):351-354.

[[23]] Chen KK. A study of ephedrine. Br Med J 1927;2(3482):593.

[[24]] Wall ME, Wani MC, Cook CE, et al. Plant antitumor agents. I. The isolation and structure of camptothecin, a novel alkaloidal leukemia and tumor inhibitor from Camptotheca acuminata1,2. J Am Chem Soc 1966;88(16):3888-3890.

[[25]] Ikeya Y, Taguchi H, Yosioka I, et al. The constituents of Schizandra chinensis Baill. I. Isolation and structure determination of five new lignans, gomisin A, B, C, F and G, and the absolute structure of schizandrin. Chem Pharm Bull (Tokyo) 1979;27(6):1383-1394.

[[26]] Maeda S, Sudo K, Aburada M, et al. Pharmacological studies on Schizandra fruit. I. General pharmacological effects of gomisin A and schizandrin (author’s transl). Yakugaku Zasshi 1981;101(11):1030-1041.

[[27]] Schulz ER. Berberine in the common barberry (berberis vulgaris L.). J Am Pharm Assoc (Wash) 1926;15(1):33-39.

[[28]] Oshio H, Inouye H. Iridoid glycosides of Rehmannia glutinosa. Phytochem 1982;2(1):133-138.

[[29]] Rogelj B, Popovic T, Ritonja A, et al. Chelidocystatin, a novel phytocystatin from Chelidonium majus. Phytochem 1998;49(6):1645-1649.

[[30]] Yasukawa K, Kaminaga T, Kitanaka S, et al. 3 beta-p-hydroxybenzoyldehydrotumulosic acid from Poria cocos, and its anti-inflammatory effect. Phytochem 1998;48(8):1357-1360.

[[31]] Tan RX, Kong LD, Wei HX. Secoiridoid glycosides and an antifungal anthranilate derivative from Gentiana tibetica. Phytochem 1998;47(7):1223-1226.

[[32]] el-Mekkawy S, Meselhy MR, Nakamura N, et al. Anti-HIV-1 and anti-HIV-1-protease substances from Ganoderma lucidum. Phytochem 1998;49(6):1651-1657.

[[33]] Lin LC, Yang LL, Chou CJ. Cytotoxic naphthoquinones and plumbagic acid glucosides from Plumbago zeylanica. Phytochem 2003;62(4):619-622.

[[34]] Dai SJ, Tao JY, Liu K, et al. neo-Clerodane diterpenoids from Scutellaria barbata with cytotoxic activities. Phytochem 2006;67(13):1326-1330.

[[35]] Don MJ, Shen CC, Syu WJ, et al. Cytotoxic and aromatic constituents from Salvia miltiorrhiza. Phytochem 2006;67(5):497-503.

[[36]] Xu M, Wang D, Zhang YJ, et al. Dammarane triterpenoids from the roots of Gentiana rigescens. J Nat Prod 2007;70(5):880-883.

[[37]] Pan Y, Wang X, Hu X. Cytotoxic withanolides from the flowers of Datura metel. J Nat Prod 2007;70(7):1127-1132.

[[38]] Jin HZ, Wang XL, Wang HB, et al. Morphinane alkaloid dimers from Sinomenium acutum. J Nat Prod 2008;71(1):127-129.

[[39]] Yuan D, Ma B, Wu C, et al. Alkaloids from the leaves of Uncaria rhynchophylla and their inhibitory activity on NO production in lipopolysaccharide-activated microglia. J Nat Prod 2008;71(7):1271-1274.

[[40]] Liu XT, Wang ZZ, Xiao W, et al. Cholestane and spirostane glycosides from the rhizomes of Dioscorea septemloba. Phytochem 2008;69(6):1411-1418.

[[41]] Lu ZQ, Guan SH, Li XN, et al. Cytotoxic diterpenoids from Euphorbia helioscopia. J Nat Prod 2008;71(5):873-876.

[[42]] Li XN, Pu JX, Du X, et al. Lignans with anti-HIV activity from Schisandra propinqua var. sinensis. J Nat Prod 2009;72(6):1133-1141.

[[43]] Wu M, Wu P, Liu M, et al. Iridoids from Gentiana loureirii. Phytochem 2009;70(6):746-750.

[[44]] Tao Y, Wang CH, Chou GX, et al. New alkaloids from Capparis spinosa: Structure and X-ray crystallographic analysis. Food Chem 2010;123(3):705-710.

[[45]] Lin S, Chen T, Liu XH, et al. Iridoids and lignans from Valeriana jatamansi. J Nat Prod 2010;73(4):632-638.

[[46]] Wu JJ, Cheng KW, Zuo XF, et al. Steroidal saponins and ecdysterone from Asparagus filicinus and their cytotoxic activities. Steroids 2010;75(10):734-739.

[[47]] Dettweiler M, Marquez L, Bao M, et al. Quantifying synergy in the bioassay-guided fractionation of natural product extracts. PLoS One 2020;15(8):e0235723.

[[48]] Ma N, Zhang Z, Liao F, et al. The birth of artemisinin. Pharmacol Ther 2020;216:107658.

[[49]] Sezik E, Aslan M, Yesilada E, et al. Hypoglycaemic activity of Gentiana olivieri and isolation of the active constituent through bioassay-directed fractionation techniques. Life Sci 2005;76(11):1223-1238.

[[50]] Othman R, Ibrahim H, Mohd MA, et al. Bioassay-guided isolation of a vasorelaxant active compound from Kaempferia galanga L. Phytomedicine 2006;13(1-2):61-66.

[[51]] Lee MH, Lin YP, Hsu FL, et al. Bioactive constituents of Spatholobus suberectus in regulating tyrosinase-related proteins and mRNA in HEMn cells. Phytochem 2006;67(12):1262-1270.

[[52]] Tian XY, Wang YH, Yang QY, et al. Jacaranone glycosides from Senecio scandens. J Asian Nat Prod Res 2006;8(1-2):125-132.

[[53]] Tian XY, Wang YH, Liu HY, et al. On the chemical constituents of Dipsacus asper. Chem Pharm Bull (Tokyo) 2007;55(12):1677-1681.

[[54]] Ma J, Dey M, Yang H, et al. Anti-inflammatory and immunosuppressive compounds from Tripterygium wilfordii. Phytochem 2007;68(8):1172-1178.

[[55]] Xu YM, McLaughlin SP, Gunatilaka AA. Sorbifolivaltrates A-D, diene valepotriates from Valeriana sorbifolia(1). J Nat Prod 2007;70(12):2045-2048.

[[56]] Li QL, Li BG, Zhang Y, et al. Three angiotensin-converting enzyme inhibitors from Rabdosia coetsa. Phytomedicine 2008;15(5):386-388.

[[57]] Chen B, Liu Y, Liu HW, et al. Iridoid and aromatic glycosides from Scrophularia ningpoensis Hemsl. and their inhibition of [Ca2+](i) increase induced by KCl. Chem Biodivers 2008;5(9):1723-1735.

[[58]] Zhao F, Xu H, He EQ, et al. Inhibitory effects of sesquiterpenes from Saussurea lappa on the overproduction of nitric oxide and TNF-alpha release in LPS-activated macrophages. J Asian Nat Prod Res 2008;10(11-12):1045-1053.

[[59]] Ho CC, Kumaran A, Hwang LS. Bio-assay guided isolation and identification of anti-Alzheimer active compounds from the root of Angelica sinensis. Food Chem 2009;114(1):246-252.

[[60]] Dat NT, Jin X, Lee K, et al. Hypoxia-inducible factor-1 inhibitory benzofurans and chalcone-derived diels-alder adducts from Morus species. J Nat Prod 2009;72(1):39-43.

[[61]] Zhang C, Wang X, Zhang X, et al. Bioassay-guided separation of citreorosein and other oestrogenic compounds from Polygonum cuspidatum. Phytother Res 2009;23(5):740-741.

[[62]] Huang SX, Feng C, Zhou Y, et al. Bioassay-guided isolation of xanthones and polycyclic prenylated acylphloroglucinols from Garcinia oblongifolia. J Nat Prod 2009;72(1):130-135.

[[63]] Baumgartner RR, Steinmann D, Heiss EH, et al. Bioactivity-guided isolation of 1,2,3,4,6-Penta-O-galloyl-D-glucopyranose from Paeonia lactiflora roots as a PTP1B inhibitor. J Nat Prod 2010;73(9):1578-1581.

[[64]] Cicek SS, Khom S, Taferner B, et al. Bioactivity-guided isolation of GABA(A) receptor modulating constituents from the rhizomes of Actaea racemosa. J Nat Prod 2010;73(12):2024-2028.

[[65]] Shu X, Yu L, Tang Y, et al. Bioassay-guided separation of the proinflammatory constituents from the roots of Euphorbia kansui. J Nat Med 2010;64(1):98-103.

[[66]] Li W, Li S, Lin L, et al. Bioassay-guided isolation and quantification of the alpha-glucosidase inhibitory compound, glycyrrhisoflavone, from Glycyrrhiza uralensis. Nat Prod Commun 2010;5(7):1049-1053.

[[67]] Liu X, Hu Z, Shi Q, et al. Anti-inflammatory and anti-nociceptive activities of compounds from Tinospora sagittata (Oliv.) Gagnep. Arch Pharm Res 2010;33(7):981-987.

[[68]] Janicsak G, Zupko I, Nikolovac MT, et al. Bioactivity-guided study of antiproliferative activities of Salvia extracts. Nat Prod Commun 2011;6(5):575-579.

[[69]] Huang LZ, Huang BK, Ye Q, et al. Bioactivity-guided fractionation for anti-fatigue property of Acanthopanax senticosus. J Ethnopharmacol 2011;133(1):213-219.

[[70]] Yang Q, Wu B, Shi Y, et al. Bioactivity-guided fractionation and analysis of compounds with anti-influenza virus activity from Gardenia jasminoides Ellis. Arch Pharm Res 2012;35(1):9-17.

[[71]] Jang TS, Zhang H, Kim G, et al. Bioassay-guided isolation of fatty acid synthase inhibitory diterpenoids from the roots of Salvia miltiorrhiza Bunge. Arch Pharm Res 2012;35(3):481-486.

[[72]] Lim LS, Shen P, Gong YH, et al. Dimeric progestins from rhizomes of Ligusticum chuanxiong. Phytochem 2006;67(7):728-734.

[[73]] Xian YF, Lin ZX, Mao QQ, et al. Bioassay-guided isolation of neuroprotective compounds from uncaria rhynchophylla against beta-amyloid-induced neurotoxicity. Evid Based Complement Alternat Med 2012;2012:802625.

[[74]] Xia ZX, Zhang DD, Liang S, et al. Bioassay-guided isolation of prenylated xanthones and polycyclic acylphloroglucinols from the leaves of Garcinia nujiangensis. J Nat Prod 2012;75(8):1459-1464.

[[75]] Liu J, Zhang Q, Chen K, et al. Small-molecule STAT3 signaling pathway modulators from Polygonum cuspidatum. Planta Med 2012;78(14):1568-1570.

[[76]] Lai PK, Chan JY, Cheng L, et al. Isolation of anti-inflammatory fractions and compounds from the root of Astragalus membranaceus. Phytother Res 2013;27(4):581-587.

[[77]] Wen L, Wei Q, Chen G, et al. Bioassay- and liquid chromatography/mass spectrometry-guided acetylcholinesterase inhibitors from Picriafel-terrae. Pharmacogn Mag 2013;9(Suppl 1):S25-S31.

[[78]] Li YY, Tang XL, Jiang T, et al. Bioassay-guided isolation of neo-clerodane diterpenoids from Scutellaria barbata. J Asian Nat Prod Res 2013;15(9):941-949.

[[79]] Chen Q, Yang L, Zhang G, et al. Bioactivity-guided Isolation of antiosteoporotic compounds from Ligustrum lucidum. Phytother Res 2013;27(7):973-979.

[[80]] Yan YM, Fang P, Yang MT, et al. Anti-diabetic nephropathy compounds from Cinnamomum cassia. J Ethnopharmacol 2015;165:141-147.

[[81]] Chen J, Teng J, Ma L, et al. Flavonoids isolated from the flowers of Limonium bicolor and their in vitro antitumor evaluation. Pharmacogn Mag 2017;13(50):222-225.

[[82]] Li X, Wang W, Fan Y, et al. Anticancer efficiency of cycloartane triterpenoid derivatives isolated from Cimicifuga yunnanensis Hsiao on triple-negative breast cancer cells. Cancer Manag Res 2018;10:6715-6729.

[[83]] Zhang H, Jiang JM, Han L, et al. Uncariitannin, a polyphenolic polymer from Uncaria gambier, attenuates Staphylococcus aureus virulence through an MgrA-mediated regulation of alpha-hemolysin. Pharmacol Res 2019;147:104328.

[[84]] Zhang D, Zhang S, Jiang K, et al. Bioassay-guided isolation and evaluation of anti-osteoporotic polysaccharides from Morinda officinalis. J Ethnopharmacol 2020;261:113113.

[[85]] Shinichi T. “serumpharmacology” and “serum pharmacochemistry” - the new world of the determination of blood concentration in Kampo. TDM Res 1988;5:54.

[[86]] Kano Y, Wang XJ, Shirakawa J, et al. Pharmacological properties of galenical preparations(IX,X) pharmacokinetics study of 6,7-dimethylesculetin in rats. J Tradit Med 1994;11(3):176-180.

[[87]] Wang XJ, Sun H, Zhu DM, et al. Chemical analysis of Yinchen Wuling powder. National Sympos Chin Patent Med 1994;1(1):221.

[[88]] Wang XJ, Sun WJ, Zhang N, et al. Isolation and identification of constituents absorbed into blood after oral administration of Liuwei Dihuang Pill. Chin J Nat Med 2007;5(4):277-280.

[[89]] Xijun W, Ning Z, Hui S, et al. Study on serum medicinal chemistry of liuwei dihuang pills. Chin Nat Med 2004;2(4):219-222.

[[90]] Yan GL, Sun H, Zhang AH, et al. Progress of serum pharmacochemistry of traditional Chinese medicine and further development of its theory and method. China J Chin Mat Med 2015;40(17):3406-3412.

[[91]] Wang X, Sun W, Sun H, et al. Analysis of the constituents in the rat plasma after oral administration of Yin Chen Hao Tang by UPLC/Q-TOF-MS/MS. J Pharm Biomed Anal 2008;46(3):477-490.

[[92]] Wang XJ. Serum Pharmacochemistry of Yin Chen Hao Decoction. Serum Pharmacochemistry of Traditional Chinese Medicine. Beijing: Science Press; 2010:72-160.

[[93]] Zhang A, Sun H, Wang X, et al. Simultaneous in vivo RP-HPLC-DAD quantification of multiple-component and drug-drug interaction by pharmacokinetics, using 6,7-dimethylesculetin, geniposide and rhein as examples. Biomed Chromatogr 2012;26(7):844-850.

[[94]] Bioanalysis Zone. Sutton CE. Three’s a crowd: but could three be better than one. Available from: https://www.bioanalysis-zone.com/interview-with-maureenhighkin-on-mass-spectrometry-analysis-to-assist-discovery-of-sphingosine-kinase-inhibitors/. Accessed March 2, 2021.

[[95]] Huang L, Zhao H, Huang B, et al. Acanthopanax senticosus: review of botany, chemistry and pharmacology. Pharmazie 2011;66(2):83-97.

[[96]] Wang XJ. Serum pharmacochemistry of Ci Wu Jia. Serum Pharmacochemistry of Traditional Chinese Medicine. Beijing: Science Press; 2010:395-416.

[[97]] Jiang P, Liu R, Dou S, et al. Analysis of the constituents in rat plasma after oral administration of Shexiang Baoxin pill by HPLC-ESI-MS/MS. Biomed Chromatogr 2009;23(12):1333-1343.

[[98]] Su S, Guo J, Duan JA, et al. Ultra-performance liquid chromatography-tandem mass spectrometry analysis of the bioactive components and their metabolites of Shaofu Zhuyu decoction active extract in rat plasma. J Chromatogr B Analyt Technol Biomed Life Sci 2010;878(3-4):355-362.

[[99]] Wang XJ, Zhang AH, Sun H, et al. Serum pharmacochemistry of Yin Chen Si Ni Decoction. Serum Pharmacochemistry of Traditional Chinese medicines. Beijing: Science Press; 2017:231-301.

[[100]] Lv YH, Zhang X, Liang X, et al. Characterization of the constituents in rat biological fluids after oral administration of Fufang Danshen tablets by ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry. J Pharm Biomed Anal 2010;52(1):155-159.

[[101]] Hu Y, Jiang P, Wang S, et al. Plasma pharmacochemistry based approach to screening potential bioactive components in Huang-Lian-Jie-Du-Tang using high performance liquid chromatography coupled with mass spectrometric detection. J Ethnopharmacol 2012;141(2):728-735.

[[102]] Miao WJ, Wang Q, Bo T, et al. Rapid characterization of chemical constituents and rats metabolites of the traditional Chinese patent medicine Gegen-Qinlian-Wan by UHPLC/DAD/qTOF-MS. J Pharm Biomed Anal 2013;72:99-108.

[[103]] Yan GL, Zhang AH, Sun H, et al. An effective method for determining the ingredients of Shuanghuanglian formula in blood samples using high-resolution LC-MS coupled with background subtraction and a multiple data processing approach. J Sep Sci 2013;36(19):3191-3199.

[[104]] Wang H, Sun H, Zhang A, et al. Rapid identification and comparative analysis of the chemical constituents and metabolites of Phellodendri amurensis cortex and Zhibai dihuang pill by ultra-performance liquid chromatography with quadrupole TOF-MS. J Sep Sci 2013;36(24):3874-3882.

[[105]] Wang H, Yan G, Zhang A, et al. Rapid discovery and global characterization of chemical constituents and rats metabolites of Phellodendri amurensis cortex by ultra-performance liquid chromatography-electrospray ionization/quadrupole-time-of-flight mass spectrometry coupled with pattern recognition approach. Analyst 2013;138(11):3303-3312.

[[106]] Wang P, Yin QW, Zhang AH, et al. Preliminary identification of the absorbed bioactive components and metabolites in rat plasma after oral administration of Shaoyao-Gancao decoction by ultra-performance liquid chromatography with electrospray ionization tandem mass spectrometry. Pharmacogn Mag 2014;10(40):497-502.

[[107]] Geng JL, Dai Y, Yao ZH, et al. Metabolites profile of Xian-Ling-Gu-Bao capsule, a traditional Chinese medicine prescription, in rats by ultra performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry analysis. J Pharm Biomed Anal 2014;96:90-103.

[[108]] Han Y, Wu FF, Zhang AH, et al. Characterization of multiple constituents in rat plasma after oral administration of Shengmai San using ultra-performance liquid chromatography coupled with electrospray ionization/quadrupole-time-of-flight high-definition mass spectrometry. Anal Methods 2015;7(3):830-837.

[[109]] Liu C, Zhang AH, Han Y, et al. Ultra-high performance liquid chromatography coupled with time-of-flight mass spectrometry screening and analysis of potential bioactive compounds from traditional chinese medicine Kai-Xin-San, using a multivariate data processing approach and the MetaboLynx tool. RSC Adv 2015;5(1):85-92.

[[110]] Li XN, Zhang A, Sun H, et al. Rapid discovery of absorbed constituents and metabolites in rat plasma after the oral administration of Zi Shen Wan using high-throughput UHPLC-MS with a multivariate analysis approach. J Sep Sci 2016;39(24):4700-4711.

[[111]] Zhang Y, Zhang A, Zhang Y, et al. Application of ultra-performance liquid chromatography with time-of-flight mass spectrometry for the rapid analysis of constituents and metabolites from the extracts of Acanthopanax senticosus Harms Leaf. Pharmacogn Mag 2016;12(46):145-152.

[[112]] Li X, Sun H, Zhang A, et al. High-throughput LC-MS method for the rapid characterization of multiple chemical constituents and metabolites of Da-Bu-Yin-Wan. J Sep Sci 2017;40(21):4102-4112.

[[113]] Yao ZH, Qin ZF, He LL, et al. Identification, bioactivity evaluation and pharmacokinetics of multiple components in rat serum after oral administration of Xian-Ling-Gu-Bao capsule by ultra performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 2017;1041-1042:104-112.

[[114]] Wang XJ, Liu JH, Zhang AH, et al. Serum pharmacochemistry of TCM screening the bioactive components from Moutan Cortex. Serum Pharmacochemistry of Traditional Chinese Medicine. London: Elsevier; 2017:287-302.

[[115]] Wang XJ, Wu FF, Sun H, et al. Serum pharmacochemistry of TCM for screening the active ingredients from Wen-Xin Formulae. Serum Pharmacochemistry of Traditional Chinese Medicine. London: Elsevier; 2017:73-101.

[[116]] Wang XJ, Liu JH, Zhang AH, et al. Systematic characterization of the absorbed components of Acanthopanax senticosus Stem. Serum Pharmacochemistry of Traditional Chinese Medicine. London: Elsevier; 2017:313-336.

[[117]] Wei M, Liu Y, Pi Z, et al. Systematically characterize the anti-Alzheimer’s disease mechanism of Lignans from S. chinensis based on in vivo ingredient analysis and target-network pharmacology strategy by UHPLC-Q-TOF-MS. Molecules 2019;24(7):1203.

[[118]] Dou XX, Lin S, Tian XH, et al. Systematic characterization of the chemical constituents in vitro and prototypes in vivo of Dingkun Dan using ultra-high-performance liquid chromatography quadrupole time-of-flight mass spectrometry combined with the UNIFI software. Biomed Chromatogr 2020;34(10):e4914.

[[119]] Zhang J, Yin Y, Xu Q, et al. Integrated serum pharmacochemistry and investigation of the anti-gastric ulcer effect of Zuojin pill in rats induced by ethanol. Pharm Biol 2022;60(1):1417-1435.

[[120]] Yin FT, Zhou XH, Kang SY, et al. Prediction of the mechanism of Dachengqi Decoction treating colorectal cancer based on the analysis method of “ into serum components -action target-key pathway”. J Ethnopharmacol 2022;293:115286.

[[121]] Zhang AH, Sun H, Yan GL, et al. Chinmedomics: a powerful approach integrating metabolomics with serum pharmacochemistry to evaluate the efficacy of Traditional Chinese Medicine. Engineering (Beijing) 2019;5(1):132-149.

[[122]] Liu SB, Lu SW, Sun H, et al. Deciphering the Q-markers of nourishing kidney-yin of Cortex Phellodendri amurense from ZhibaiDihuang pill based on Chinmedomics strategy. Phytomedicine 2021;91:153690.

[[123]] Wei WF, Sun H, Liu SB, et al. Targets and effective constituents of ZhiziBaipi Decoction for treating damp-heat jaundice syndrome based on Chinmedomics coupled with UPLC-MS/MS. Front Pharmacol 2022;13:857361.

[[124]] Bian L, Tang J, Zi M, et al. Discussions on Symptomatic Assessment in Clinical Evaluation of FGIDs. Modernization of Traditional Chinese Medicine and Materia Medica-World Science and Technology 2020;22(10):3636-3639.

[[125]] Wang XJ. Methodology for systematic analysis of in vivo efficacy material base of traditional Chinese medicine--Chinmedomics. China J Chin Mat Med 2015;40(1):13-17.

[[126]] Wishart DS. Emerging applications of metabolomics in drug discovery and precision medicine. Nat Rev Drug Discov 2016;15(7):473-484.

[[127]] Wang X, Zhang A, Sun H. Future perspectives of Chinese medical formulae: chinmedomics as an effector. OMICS 2012;16(7-8):414-421.

[[128]] Ren JL, Yang L, Qiu S, et al. Efficacy evaluation, active ingredients, and multitarget exploration of herbal medicine. Trends Endocrinol Metab 2023;34(3):146-157.

[[129]] Wang XJ. Inside view. Nature 2015;5128(7582).

[[130]] Rahman J, Rahman S. Mitochondrial medicine in the omics era. Lancet 2018;391(10139):2560-2574.

[[131]] Wang X. Chinmedomics-preface. Chinmedomics. Boston: Academic Press; 2015:xxi-xxii.

[[132]] Wang XJ. Research Progress of Chinmedomics (Volume 2016). Beijing: Science Press; 2016.

[[133]] Wang XJ. Research Progress of Chinmedomics (Volume 2017). Beijing: Science Press; 2017.

[[134]] Wang XJ. Research Progress of Chinmedomics (Volume 2018). Beijing: Science Press; 2018.

[[135]] Wang XJ. Research Progress of Chinmedomics (Volume 2019). Beijing: Science Press; 2019.

[[136]] Wang XJ. Research Progress of Chinmedomics (Volume 2020). Beijing: Science Press; 2020.

[[137]] Wang XJ. Research Progress of Chinmedomics (Volume 2021). Beijing: Science Press; 2021.

[[138]] Cao H, Zhang A, Zhang FM, et al. Ultra-performance liquid chromatography tandem mass spectrometry combined with automated MetaboLynx analysis approach to screen the bioactive components and their metabolites in Wen-Xin-Formula. Biomed Chromatogr 2014;28(12):1774-1781.

[[139]] Wang X, Zhang A, Zhou X, et al. An integrated chinmedomics strategy for discovery of effective constituents from traditional herbal medicine. Sci Rep 2016;6:18997.

[[140]] Zhang AH, Liu Q, Zhao HW, et al. A research of chinmedomics on the pharmacodynamic basis of nanshi oral liquid and its mechanism behind the efficacy on kidney-yang deficiency syndrome. Modernization of Traditional Chinese Medicine and Materia Medica-World Science and Technology 2016;18(10):1670-1683.

[[141]] Liu Q, Zhang A, Wang L, et al. High-throughput chinmedomics-based prediction of effective components and targets from herbal medicine AS1350. Sci Rep 2016;6:38437.

[[142]] Liu Q, Zhao HW, Zhang AH, et al. Chinmedomics strategy to discover effective constituents and elucidate action mechanism of Nanshi capsule against kidney-yang deficiency syndrome. China J Chin Mat Med 2016;41(15):2901-2914.

[[143]] Li XN, Zhang A, Wang M, et al. Screening the active compounds of Phellodendri Amurensis cortex for treating prostate cancer by high-throughput chinmedomics. Sci Rep 2017;7:46234.

[[144]] Zhang AH, Yu JB, Sun H, et al. Identifying quality-markers from Shengmai San protects against transgenic mouse model of Alzheimer’s disease using chinmedomics approach. Phytomedicine 2018;45:84-92.

[[145]] Wang XJ, Zhang AH, Kong L, et al. Rapid discovery of quality-markers from Kaixin San using chinmedomics analysis approach. Phytomedicine 2019;54:371-381.

[[146]] Sun H, Zhang AH, Yang L, et al. High-throughput chinmedomics strategy for discovering the quality-markers and potential targets for Yinchenhao decoction. Phytomedicine 2019;54:328-338.

[[147]] Yang B, Han Y, Zhang QY, et al. Study on absorbed components of Aconitum kusnezoffiunder Yunnan Baiyao compatibility in effect of activating blood circulation and removing blood stasis. China J Chin Mat Med 2019;44(15):3349-3357.

[[148]] Gao X, Hu X, Zhang Q, et al. Characterization of chemical constituents and absorbed components, screening the active components of gelanxinning capsule and an evaluation of therapeutic effects by ultra-high performance liquid chromatography with quadrupole time of flight mass spectrometry. J Sep Sci 2019;42(22):3439-3450.

[[149]] Liu X, Zhou QG, Zhu XC, et al. Screening for potential active components of Fangji Huangqi Tang on the treatment of nephrotic syndrome by using integrated metabolomics based on “Correlations Between Chemical and Metabolic Profiles”. Front Pharmacol 2019;10:1261.

[[150]] Cai H, Xu Y, Xie L, et al. Investigation on spectrum-effect correlation between constituents absorbed into blood and bioactivities of Baizhu Shaoyao San before and after processing on ulcerative colitis rats by UHPLC/Q-TOF-MS/MS coupled with gray correlation analysis. Molecules 2019;24(5):940.

[[151]] Xiong H, Zhang AH, Zhao QQ, et al. Discovery of quality-marker ingredients of Panax quinquefolius driven by high-throughput chinmedomics approach. Phytomedicine 2020;74:152928.

[[152]] Zhao Q, Gao X, Yan G, et al. Chinmedomics facilitated quality-marker discovery of Sijunzi decoction to treat spleen qi deficiency syndrome. Front Med 2020;14(3):335-356.

[[153]] Kong L, Sun Y, Sun H, et al. Chinmedomics strategy for elucidating the pharmacological effects and discovering bioactive compounds from Keluoxin against diabetic retinopathy. Front Pharmacol 2022;13:728256.

[[154]] Wang Y, Yang L, Zhang X, et al. Quality marker discovery of Danggui Jianzhong decoction for treating primary dysmenorrhoea based on chinmedomics strategy. Phytomedicine 2023;115:154724.

[[155]] Cao HX, Sun H, Jiang XG, et al. Comparative study on the protective effects of Yinchenhao Decoction against liver injury induced by alpha-naphthylisothiocyanate and carbon tetrachloride. Chin J Integr Med 2009;15(3):204-209.

[[156]] Zhang A, Sun H, Qiu S, et al. 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.

[[157]] Wang X, Zhang A, Han Y, et al. Urine metabolomics analysis for biomarker discovery and detection of jaundice syndrome in patients with liver disease. Mol Cell Proteomics 2012;11(8):370-380.

[[158]] Xiong H, Zhang A-H, Guo Y-J, et al. 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. Engineering 2021;7(9):1293-1305.

[[159]] Fang H, Zhang A, Yu J, et al. Insight into the metabolic mechanism of scoparone on biomarkers for inhibiting Yanghuang syndrome. Sci Rep 2016;6:37519.

[[160]] Liu XY, Zhang AH, Fang H, et al. Serum metabolomics strategy for understanding the therapeutic effects of Yin-Chen-Hao-Tang against Yanghuang syndrome. RSC Adv 2018;8(14):7403-7413.

[[161]] Sun H, Zhang AH, Song Q, 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):36831-36839.

[[162]] Sun H, Yang L, Li MX, et al. UPLC-G2Si-HDMS untargeted metabolomics for identification of metabolic targets of Yin-Chen-Hao-Tang used as a therapeutic agent of dampness-heat jaundice syndrome. J Chromatogr B Analyt Technol Biomed Life Sci 2018;1081-1082:41-50.

[[163]] Fang H, Zhang A, Zhou X, et al. Study on the target of intervention of Genipine side in Yanghuang Syndrome based on metabolic regulation pathway. Modernization of Traditional Chinese Medicine and Materia Medica-World Science and Technology 2016;18(10):1697-1708.

[[164]] Nie Q, Chen H, Hu J, et al. Dietary compounds and traditional Chinese medicine ameliorate type 2 diabetes by modulating gut microbiota. Crit Rev Food Sci Nutr 2019;59(6):848-863.

[[165]] Jia Q, Wang L, Zhang X, et al. Prevention and treatment of chronic heart failure through traditional Chinese medicine: Role of the gut microbiota. Pharmacol Res 2020;151:104552.

[[166]] Zhao H, He M, Zhang M, et al. Colorectal cancer, gut microbiota and Traditional Chinese Medicine: a systematic review. Am J Chin Med 2021;49(4):805-828.

[[167]] Harvey AL, Edrada-Ebel R, Quinn RJ. The re-emergence of natural products for drug discovery in the genomics era. Nat Rev Drug Discov 2015;14(2):111-129.

[[168]] Yu Z, Liao J, Chen Y, et al. Single-cell transcriptomic map of the human and mouse bladders. J Am Soc Nephrol 2019;30(11):2159-2176.

[[169]] Giudice G, Petsalaki E. Proteomics and phosphoproteomics in precision medicine: applications and challenges. Brief Bioinform 2019;20(3):767-777.

RIGHTS & PERMISSIONS

2023 Acupuncture and Herbal Medicine