Chinmedomics facilitated quality-marker discovery of Sijunzi decoction to treat spleen qi deficiency syndrome

Abstract

Sijunzi decoction (SJZD) is a Chinese classical formula to treat spleen qi deficiency syndrome (SQDS) and has been widely used for thousands of years. However, the quality control (QC) standards of SJZD are insufficient. Chinmedomics has been designed to discover and verify bioactive compounds of a variety of formula rapidly. In this study, we used Chinmedomics to evaluate the SJZD’s efficacy against SQDS to discover the potential quality-markers (q-markers) for QC. A total of 56 compounds in SJZD were characterized in vitro, and 23 compounds were discovered in vivo. A total of 58 biomarkers were related to SQDS, and SJZD can adjust a large proportion of marker metabolites to normal level and then regulate the metabolic profile to the health status. A total of 10 constituents were absorbed as effective ingredients that were associated with overall efficacy. We preliminarily determined malonyl-ginsenoside Rb2 and ginsenoside Ro as the q-markers of ginseng; dehydrotumulosic acid and dihydroxy lanostene-triene-21-acid as the q-markers of poria; glycyrrhizic acid, isoglabrolide, and glycyrrhetnic acid as the q-markers of licorice; and 2-atractylenolide as the q-marker of macrocephala. According to the discovery of the SJZD q-markers, we can establish the quality standard that is related to efficacy.

Keywords

traditional Chinese medicine / Sijunzi decoction / spleen qi deficiency syndrome / Chinmedomics / quality-marker

References

[1] Hu J, Liu B. The basic theory, diagnostic, and therapeutic system of traditional Chinese medicine and the challenges they bring to statistics. Stat Med 2012; 31(7): 602–605

[2] Liu X, Fu J, Fan T, Liu W, Jiang H, Zhang R, Ding H, Yang H, Hu S, Huang Y, Li G, Lan Y, She B, Mao B. The efficacy and safety of Shen Guo Lao Nian Granule for common cold of qi-deficiency syndrome: study protocol for a randomized, double-blind, placebo-controlled, multicenter, phase II clinical trial. Evid Based Complement Alternat Med 2017; 2017(6): 1806461

[3] Shu Q, Sun D, Wang H, Liang F, Gerhard L, Daniela L, Ingrid G, Chen L, He W, Wang Y. Differences of acupuncture and moxibustion on heart rate variability in qi-deficiency syndrome:a randomized controlled trial. Chin Acup Moxib (Zhongguo Zhen Jiu) 2017; 37(1): 25–30 (in Chinese)

[4] Xu D, Shen Z, Wang W. Immunoregulation of Youguiyin, Sijunzitang, Taohong Siwutang in treating patients with deficiency of kidney, spleen and blood stasis syndrome. Chin J Integr Trad West Med (Zhongguo Zhong Xi Yi Jie He Za Zhi) 1999; 19(12): 712–714 (in Chinese)

[5] Hu Q, Calduch RM. On traditional Chinese medicine regulation in China: how quality and safety of use are insured. Pharmacol Res 2017; 119: 371–372

[6] Wang G, Mao B, Xiong ZY, Fan T, Chen XD, Wang L, Liu GJ, Liu J, Guo J, Chang J, Wu TX, Li TQ; CONSORT Group for Traditional Chinese Medicine. The quality of reporting of randomized controlled trials of traditional Chinese medicine: a survey of 13 randomly selected journals from mainland China. Clin Ther 2007; 29(7): 1456–1467

[7] Ning Z, Lu C, Zhang Y, Zhao S, Liu B, Xu X, Liu Y. Application of plant metabonomics in quality assessment for large-scale production of traditional Chinese medicine. Planta Med 2013; 79(11): 897–908

[8] Cheng TF, Jia YR, Zuo Z, Dong X, Zhou P, Li P, Li F. Quality assessment of traditional Chinese medicine herb couple by high-performance liquid chromatography and mass spectrometry combined with Chemometrics. J Sep Sci 2016; 39(7): 1223–1231

[9] Wang C, Hu S, Chen X, Bai X. Screening and quantification of anticancer compounds in traditional Chinese medicine by hollow fiber cell fishing and hollow fiber liquid/solid-phase microextraction. J Sep Sci 2016; 39(10): 1814–1824

[10] Zhuo L, Peng J, Zhao Y, Li D, Xie X, Tong L, Yu Z. Screening bioactive quality control markers of QiShenYiQi dripping pills based on the relationship between the ultra-high performance liquid chromatography fingerprint and vascular protective activity. J Sep Sci 2017; 40(20): 4076–4084

[11] Wang X, Zhang A, Sun H, Yan G. Precision diagnosis of Chinese medicine syndrome and evaluation of prescription efficacy based on Chinmedomics. Modernization Tradit Chin Med Materia Medica—World Sci Technol (Shi Jie Ke Xue Ji Shu— Zhong Yi Yao Xian Dai Hua) 2017; 19(1): 30–34 (in Chinese)

[12] Zhang A, Sun H, Yan G, Wang P, Han Y, Wang X J. Chinmedomics: a new strategy for research of traditional Chinese medicine. China J Chin Materia Medica (Zhongguo Zhong Yao Za Zhi) 2015; 40(4): 569–576 (in Chinese)

[13] Wang H, Shi S, Wang S. Can highly cited herbs in ancient traditional Chinese medicine formulas and modern publications predict therapeutic targets for diabetes mellitus? J Ethnopharmacol 2018; 213: 101–110

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

[15] Wang X, Zhang A, Hui S, Han Y, Yan G. Discovery and development of innovative drug from traditional medicine by integrated Chinmedomics strategies in the post-genomic era. Trends Analyt Chem 2016; 76: 86–94

[16] Li XN, Zhang A, Wang M, Sun H, Liu Z, Qiu S, Zhang T, Wang X. Screening the active compounds of Phellodendri amurensis cortex for treating prostate cancer by high-throughput Chinmedomics. Sci Rep 2017; 7(1): 46234

[17] Zhou XH, Zhang AH, Wang L, Tan YL, Guan Y, Han Y, Sun H, Wang XJ. Novel Chinmedomics strategy for discovering effective constituents from ShenQiWan acting on ShenYangXu syndrome. Chin J Nat Med 2016; 14(8): 561–581

[18] Wang X, Zhang A, Zhou X, Liu Q, Nan Y, Guan Y, Kong L, Han Y, Sun H, Yan G. An integrated Chinmedomics strategy for discovery of effective constituents from traditional herbal medicine. Sci Rep 2016; 6(1): 18997

[19] Liu F, Liu Y, Tian C. Effect of Rhizoma Atractylodis extract in protecting gastric mucosa and modulating gastrointestinal immune function in a rat model of spleen deficiency. J Southern Med Univ (Nan Fang Yi Ke Da Xue Xue Bao) 2015; 35(3): 343–347, 354 (in Chinese)

[20] Lu S, Han Y, Chu H, Kong L, Zhang A, Yan G, Sun H, Wang P, Wang X. Characterizing serum metabolic alterations of Alzheimer’s disease and intervention of Shengmai-San by ultra-performance liquid chromatography/electrospray ionization quadruple time-of-flight mass spectrometry. Food Funct 2017; 8(4): 1660–1671

[21] Zhao Q, Zhang A, Zong W, An N, Zhang H, Luan Y, Sun H, Wang X, Cao H. Exploring potential biomarkers and determining the metabolic mechanism of type 2 diabetes mellitus using liquid chromatography coupled to high-resolution mass spectrometry. RSC Adv 2017; 7(70): 44186–44198

[22] de Passillé AM, Pelletier G, Ménard J, Morisset J. Relationships of weight gain and behavior to digestive organ weight and enzyme activities in piglets. J Anim Sci 1989; 67(11): 2921–2929

[23] Tharakan A, Norton IT, Fryer PJ, Bakalis S. Mass transfer and nutrient absorption in a simulated model of small intestine. J Food Sci 2010; 75(6): E339–E346

[24] Clara R, Schumacher M, Ramachandran D, Fedele S, Krieger JP, Langhans W, Mansouri A. Metabolic adaptation of the small intestine to short- and medium-term high-fat diet exposure. J Cell Physiol 2017; 232(1): 167–175

[25] Mansi C, Borro P, Giacomini M, Biagini R, Mele MR, Pandolfo N, Savarino V. Comparative effects of levosulpiride and cisapride on gastric emptying and symptoms in patients with functional dyspepsia and gastroparesis. Aliment Pharmacol Ther 2000; 14(5): 561–569

[26] Tortora GJ, Anagnostakos NP. Principles of anatomy and physiology. J Anat 2009; 86(10): 555

[27] Zhang SY, Peng GY, Gu LG, Li ZM, Yin SJ. Effect and mechanisms of Gong-tone music on the immunological function in rats with Liver (Gan)-qi depression and Spleen (Pi)-qi deficiency syndrome in rats. Chin J Integr Med 2013; 19(3): 212–216

[28] Itoh Z, Takeuchi S, Aizawa I, Mori K, Taminato T, Seino Y, Imura H, Yanaihara N. Changes in plasma motilin concentration and gastrointestinal contractile activity in conscious dogs. Am J Dig Dis 1978; 23(10): 929–935

[29] Liu Q, Cai G. Content of somatostatin and cholecystokinin-8 in hypothalamus and colons in a rat model of spleen-deficiency syndrome. J Chin Integr Med (Zhong Xi Yi Jie He Xue Bao) 2007; 5(5): 555–558 (in Chinese)

[30] Yong RL, Qu Y, Li XX, Wang JB, Xue YN, Zhang LD. Effect of electroacupuncture at “Zusanli”(ST 36) on the expression of Ghrelin/cAMP/PKA in the Jejunum in rats with spleen Qi deficiency syndrome. Acupunct Res (Zhen Ci Yan Jiu) 2016; 41(6): 497–501 (in Chinese)

[31] Chan K, Leung K, Lu G. Quality and safety should go hand in hand to monitor herbal products: examples from Chinese medicinal materials (CMM). Planta Med 2007; 73(9): 803

[32] Duan YQ, Cheng YX, Liang YJ, Cheng WD, Du J, Yang XY, Wang Y. Intervention of qi-activating and spleen-strengthening herbs on Ca²⁺/CaMK II signaling pathways key factors in skeletal muscle tissue of rats with spleen-qi deficiency. J Chin Med Mater (Zhong Yao Cai) 2015; 38(3): 562–566 (in Chinese)

[33] Zheng XF, Tian JS, Liu P, Xing J, Qin XM. Analysis of the restorative effect of Bu-zhong-yi-qi-tang in the spleen-qi deficiency rat model using ¹H-NMR-based metabonomics. J Ethnopharmacol 2014; 151(2): 912–920

[34] Sun H, Zhang AH, Yang L, Li MX, Fang H, Xie J, Wang XJ. High-throughput chinmedomics strategy for discovering the quality-markers and potential targets for Yinchenhao decoction. Phytomedicine 2019; 54: 328–338

[35] Zhao S, Liu Z, Wang M, He D, Liu L, Shu Y, Song Z, Li H, Liu Y, Lu A. Anti-inflammatory effects of Zhishi and Zhiqiao revealed by network pharmacology integrated with molecular mechanism and metabolomics studies. Phytomedicine 2018; 50: 61–72

[36] Yuan Z, Zhong L, Hua Y, Ji P, Yao W, Ma Q, Zhang X, Wen Y, Yang L, Wei Y. Metabolomics study on promoting blood circulation and ameliorating blood stasis: investigating the mechanism of Angelica sinensis and its processed products. Biomed Chromatogr 2019; 33(4): e4457

[37] Wu P, Li J, Zhang X, Zeng F, Liu Y, Sun W. Study of the treatment effects of compound Tufuling Granules in hyperuricemic rats using serum metabolomics. Evid Based Complement Alternat Med 2018; 2018: 3458185

[38] Dong Y, Qiu P, Zhao L, Zhang P, Huang X, Li C, Chai K, Shou D. Metabolomics study of the hepatoprotective effect of Phellinus igniarius in chronic ethanol-induced liver injury mice using UPLC-Q/TOF-MS combined with ingenuity pathway analysis. Phytomedicine2018 Oct 2. 152697.

[39] Tripathi N, Shrivastava D, Ahmad Mir B, Kumar S, Govil S, Vahedi M, Bisen PS. Metabolomic and biotechnological approaches to determine therapeutic potential of Withania somnifera (L.) Dunal: a review. Phytomedicine 2018; 50: 127–136

[40] Xu Y, Chen S, Yu T, Qiao J, Sun G. High-throughput metabolomics investigates anti-osteoporosis activity of oleanolic acid via regulating metabolic networks using ultra-performance liquid chromatography coupled with mass spectrometry. Phytomedicine 2018; 51: 68–76

[41] Duan L, Guo L, Wang L, Yin Q, Zhang CM, Zheng YG, Liu EH. Application of metabolomics in toxicity evaluation of traditional Chinese medicines. Chin Med 2018; 13(1): 60

[42] Wang X, Zhang S, Zhang A, Yan G, Wu X, Han Y, Sun H. Metabolomics study of type 2 diabetes and therapeutic effects of Tianqijiangtang-capsule using ultra-performance liquid chromatography/electrospray ionization quadruple time-of-flight mass spectrometry. Anal Methods 2013; 5(9): 2218–2226

[43] Zhang Y, Klaassen CD. Effects of feeding bile acids and a bile acid sequestrant on hepatic bile acid composition in mice. J Lipid Res 2010; 51(11): 3230–3242

[44] Roberts AB, Frolik CA, Nichols MD, Sporn MB. Retinoid-dependent induction of the in vivo and in vitro metabolism of retinoic acid in tissues of the vitamin A-deficient hamster. J Biol Chem 1979; 254(14): 6303–6309

[45] Hall JA, Grainger JR, Spencer SP, Belkaid Y. The role of retinoic acid in tolerance and immunity. Immunity 2011; 35(1): 13–22

[46] Wang XJ. Progress and future developing of the serum pharmacochemistry of traditional Chinese medicine. China J Chin Mater Med (Zhongguo Zhong Yao Za Zhi) 2006; 31(10): 789–792, 835 (in Chinese)

[47] Zhang AH, Yu JB, Sun H, Kong L, Wang XQ, Zhang QY, Wang XJ. Identifying quality-markers from Shengmai San protects against transgenic mouse model of Alzheimer’s disease using Chinmedomics approach. Phytomedicine 2018; 45: 84–92

[48] Sun H, Zhang AH, Song Q, Fang H, Liu XY, Su J, Yang L, Yu MD, Wang XJ. 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

[49] Zhang AH, Sun H, Yan GL, Zhao QQ, Wang XJ. Chinmedomics: a powerful approach integrating metabolomics with serum pharmacochemistry to evaluate the efficacy of traditional Chinese medicine. Engineering (Beijing) 2019; 5(1): 60–68

[50] Wang XJ, Lv HT, Zhang AH, Sun WJ, Liu L, Wang P, Wu ZM, Zou DX, Sun H. Metabolite profiling and pathway analysis of acute hepatitis rats by UPLC-ESI MS combined with pattern recognition methods. Liver Int 2014; 34(5): 759–770

[51] Zhang AH, Sun H, Xu HY, Qiu S, Wang XJ. Cell metabolomics. OMICS 2013; 17(10): 495–501

[52] Sun H, Zhang AH, Liu SB, Qiu S, Li XN, Zhang TL, Liu L, Wang XJ. Cell metabolomics identify regulatory pathways and targets of magnoline against prostate cancer. J Chromatogr B Analyt Technol Biomed Life Sci 2018; 1102–1103: 143–151

[53] Zhang AH, Sun H, Wang XJ. Urinary metabolic profiling of rat models revealed protective function of scoparone against alcohol induced hepatotoxicity. Sci Rep 2015; 4(1): 6768

[54] Liu XY, Zhang AH, Fang H, Li MX, Song Q, Su J, Yu MD, Yang L, Wang XJ. Serum metabolomics strategy for understanding the therapeutic effects of Yin-Chen-Hao-Tang against Yanghuang syndrome. RSC Adv 2018; 8(14): 7403–7413

[55] 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): 117–128

[56] Song Q, Zhang AH, Yan GL, Liu L, Wang XJ. Technological advances in current metabolomics and its application in tradition Chinese medicine. RSC Adv 2017; 7(84): 53516–53524

[57] Zhang AH, Sun H, Sun WJ, Wang XJ. Metabolomics and Proteomics Annotate Therapeutic Mechanisms of Geniposide[M]//Chinmedomics. Amsterdam: Academic Press, 2015: 157–173

[58] Zhao QQ, Zhang AH, Zong WJ, An N, Zhang HM, Luan YH, Cao HX, Sun H, Wang XJ. Chemometrics strategy coupled with high resolution mass spectrometry for analyzing and interpreting comprehensive metabolomic characterization of hyperlipemia. RSC Adv 2016; 6(113): 112534–112543

[59] Wang XJ, Han Y, Zhang AH, Sun H. Metabolic profiling provides a system for the understanding of Alzheimer’s disease in rats post-treatment with Kaixin San[M]//Chinmedomics. Amsterdam: Academic Press, 2015: 347–362

[60] Zhang AH, Wang HY, Sun H, Zhang Y, An N, Yan GL, Meng XC, Wang XJ. Metabolomics strategy reveals therapeutical assessment of limonin on nonbacterial prostatitis. Food Funct 2015; 6(11): 3540–3549

[61] Ren JL, Zhang AH, Kong L, Wang XJ. Advances in mass spectrometry-based metabolomics for investigation of metabolites. RSC Adv 2018; 8(40): 22335–22350

[62] Zhang AH, Sun H, Wang XJ. Mass spectrometry-driven drug discovery for development of herbal medicine. Mass Spectrom Rev 2018; 37(3): 307–320

[63] Sun H, Wang M, Zhang AH, Ni B, Dong H, Wang XJ. UPLC-Q-TOF-HDMS analysis of constituents in the root of two kinds of Aconitum using a metabolomics approach. Phytochem Anal 2013; 24(3): 263–276

[64] Wu FF, Sun H, Wei WF, Han Y, Wang P, Dong TW, Yan GL, Wang XJ. Rapid and global detection and characterization of the constituents in ShengMai San by ultra-performance liquid chromatography-high-definition mass spectrometry. J Sep Sci 2011; 34(22): 3194–3199

[65] Wang XJ, Zhang AH, Sun H, Han Y, Yan GL. Discovery and development of innovative drug from traditional medicine by integrated Chinmedomics strategies in the post-genomic era. TrAC Trends in Analytical Chemistry 2016; 76: 86–94

[66] Zhang AH, Sun H, Qiu S, Wang XJ. 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

[67] Wang XJ, Wang QQ, Zhang AH, Zhang FM, Zhang H, Sun H, Cao HX, Zhang HM. Metabolomics study of intervention effects of Wen-Xin-Formula using ultra high-performance liquid chromatography/mass spectrometry coupled with pattern recognition approach. J Pharm Biomed Anal 2013; 74: 22–30

[68] Dong W, Wang P, Meng XC, Sun H, Zhang AH, Wang WM, Dong H, Wang XJ. Ultra-performance liquid chromatography-high-definition mass spectrometry analysis of constituents in the root of Radix Stemonae and those absorbed in blood after oral administration of the extract of the crude drug. Phytochem Anal 2012; 23(6): 657–667

Acknowledgements

This work was supported by grants from the National Key Research and Development Program of China (No. 2018YFC1706103), Key Program of National Natural Science Foundation of China (Nos. 81830110, 8181101160, 81430093, 81673586, 81703685, 81302905, 81503386, and 81373930), National Key Subject of Drug Innovation (Nos. 2015ZX09101043-005 and 2015ZX09101043-011), TCM State Administration Subject of Public Welfare of (No. 2015468004), Major Projects of Application Technology Research and Development Plan in Heilongjiang Province (No. GX16C003), TCM State Administration Subject of Public Welfare (No. 2015468004), Young Talent Lift Engineering Project of China Association of Traditional Chinese Medicine (No. QNRC2-B06), and Outstanding Talents Foundation of Heilongjiang University of Chinese Medicine (No. 2018jc01).

Compliance with ethics guidelines

Qiqi Zhao, Xin Gao, Guangli Yan, Aihua Zhang, Hui Sun, Ying Han, Wenxiu Li, Liang Liu, and Xijun Wang declared no conflicts of interest. All institutional and national guidelines for the care and use of laboratory animals were followed. Approval for the animal experimental studies was received from the Institutional Animal Care and Use Committees of Heilongjiang University of Chinese Medicine.

Electronic Supplementary Material

Supplementary material is available in the online version of this article at https://doi.org/10.1007/s11684-019-0705-9 and is accessible for authorized users.

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