Skip to main content

Advertisement

SpringerLink
Log in

High-throughput metabolomics reveals the perturbed metabolic pathways and biomarkers of Yang Huang syndrome as potential targets for evaluating the therapeutic effects and mechanism of geniposide

  • Research Article
  • Published:
Frontiers of Medicine Aims and scope Submit manuscript

Abstract

High-throughput metabolomics can clarify the underlying molecular mechanism of diseases via the qualitative and quantitative analysis of metabolites. This study used the established Yang Huang syndrome (YHS) mouse model to evaluate the efficacy of geniposide (GEN). Urine metabolic data were quantified by ultraperformance liquid chromatography-tandem mass spectrometry. The non-target screening of the massive biological information dataset was performed, and a total of 33 metabolites, including tyramine glucuronide, aurine, and L-cysteine, were identified relating to YHS. These differential metabolites directly participated in the disturbance of phase I reaction and hydrophilic transformation of bilirubin. Interestingly, they were completely reversed by GEN. While, as the auxiliary technical means, we also focused on the molecular prediction and docking results in network pharmacological and integrated analysis part. We used integrated analysis to communicate the multiple results of metabolomics and network pharmacology. This study is the first to report that GEN indirectly regulates the metabolite “tyramine glucuronide” through its direct effect on the target heme oxygenase 1 in vivo. Meanwhile, heme oxygenase-1, a prediction of network pharmacology, was the confirmed metabolic enzyme of phase I reaction in hepatocytes. Our study indicated that the combination of high-throughput metabolomics and network pharmacology is a robust combination for deciphering the pathogenesis of the traditional Chinese medicine (TCM) syndrome.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Zhang A, Liu Q, Zhao H, Zhou X, Sun H, Nan Y, Zou S, Ma CW, Wang X. Phenotypic characterization of nanshi oral liquid alters metabolic signatures during disease prevention. Sci Rep 2016; 6(1): 19333

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Zhang A, Yan G, Sun H, Cheng W, Meng X, Liu L, Xie N, Wang X. Deciphering the biological effects of acupuncture treatment modulating multiple metabolism pathways. Sci Rep 2016; 6(1): 19942

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Wang X, Zhang A, Sun H, 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

    CAS  Google Scholar 

  4. Zhang A, Sun H, Wang X. Mass spectrometry-driven drug discovery for development of herbal medicine. Mass Spectrom Rev 2018; 37(3): 307–320

    CAS  PubMed  Google Scholar 

  5. Zhang AH, Ma ZM, Sun H, Zhang Y, Liu JH, Wu FF, Wang XJ. High-throughput metabolomics evaluate the efficacy of total lignans from acanthophanax senticosus stem against ovariectomized osteoporosis rat. Front Pharmacol 2019; 10: 553

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Zhang A, Sun H, Yan G, Wang P, Wang X. Mass spectrometrybased metabolomics: applications to biomarker and metabolic pathway research. Biomed Chromatogr 2016; 30(1): 7–12

    PubMed  Google Scholar 

  7. Zhang A, Wang H, Sun H, Zhang Y, An N, Yan G, Meng X, Wang X. Metabolomics strategy reveals therapeutical assessment of limonin on nonbacterial prostatitis. Food Funct 2015; 6(11): 3540–3549

    CAS  PubMed  Google Scholar 

  8. Fang H, Zhang A, Yu J, Wang L, Liu C, Zhou X, Sun H, Song Q, Wang X. Insight into the metabolic mechanism of scoparone on biomarkers for inhibiting Yanghuang syndrome. Sci Rep 2016; 6(1): 37519

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Sun H, Wang M, Zhang A, Ni B, Dong H, Wang X. UPLC-Q-TOFHDMS analysis of constituents in the root of two kinds of Aconitum using a metabolomics approach. Phytochem Anal 2013; 24(3): 263–276

    CAS  PubMed  Google Scholar 

  10. Wu YB, Zeng CC, Peng QH, Deng X, Nie G. Study on differences of colorimetric between Yin Zheng and Yang Zheng jaundice in patients with hepatogenic jaundice. Chin J Integr Tradit West Med Liver Dis (Zhong Xi Yi Jie He Gan Bing Za Zhi) 2013; 23(3):139–141 (in Chinese)

    Google Scholar 

  11. Kim HJ, Lee SK, Ryu CH, Park DH, Lee SS, Seo DW, Kim MH. The clinical usefulness of simultaneous placement of double endoscopic nasobiliary biliary drainage. Clin Endosc 2015; 48(6): 542–548

    PubMed  PubMed Central  Google Scholar 

  12. Okamura S, Mikami K, Murata K, Nushijima Y, Okada K, Yanagisawa T, Fukuchi N, Ebisui C, Yokouchi H, Kinuta M. Long-term multidisciplinary therapy for multiple liver metastases from colorectal cancer with biliary drainage for occlusive jaundice—a case report. Gan To Kagaku Ryoho 2015; 42(12): 1740–1742 (in Japanese)

    CAS  PubMed  Google Scholar 

  13. Lammert C, Bjornsson E, Niklasson A, Chalasani N. Oral medications with significant hepatic metabolism at higher risk for hepatic adverse events. Hepatology 2010; 51(2): 615–620

    CAS  PubMed  Google Scholar 

  14. Mendizabal M, Silva MO. Liver transplantation in acute liver failure: a challenging scenario. World J Gastroenterol 2016; 22(4): 1523–1531

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Muttaqillah N A S, Abdul Wahab A, Ding CH, Mohammad M, Biswas S, Rahman MM. Presence of anti-mitochondrial antibodies and elevated serum immunoglobulin G levels: is this primary biliary cirrhosis-autoimmune hepatitis overlap syndrome? EXCLI J 2015; 14: 175–178

    PubMed  PubMed Central  Google Scholar 

  16. Yeluru A, Cuthbert JA, Casey L, Mitchell MC. Alcoholic hepatitis: risk factors, pathogenesis, and approach to treatment. Alcohol Clin Exp Res 2016; 40(2): 246–255

    CAS  PubMed  Google Scholar 

  17. Issa D, Eghtesad B, Zein NN, Yerian L, Cruise M, Alkhouri N, Adams R, Hanouneh IA. Sofosbuvir and simeprevir for the treatment of recurrent hepatitis C with fibrosing cholestatic hepatitis after liver transplantation. Int J Organ Transplant Med 2016; 7(1): 38–45

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Tang X, Yang C, Gu Y, Song C, Zhang X, Wang Y, Zhang J, Hew CL, Li S, Xia N, Sivaraman J. Structural basis for the neutralization and genotype specificity of hepatitis E virus. Proc Natl Acad Sci USA 2011; 108(25): 10266–10271

    CAS  PubMed  Google Scholar 

  19. Friedman LS, Gee MS, Misdraji J. Case records of the Massachusetts General Hospital. Case 39-2010. A 19-year-old woman with nausea, jaundice, and pruritus. N Engl J Med 2010; 363(26): 2548–2557

    CAS  PubMed  Google Scholar 

  20. Zhu J, Li XW, Li L, Zhong GY, Xiong HZ, Liu CH, Luo GM. Therapeutic effects of Zhizi Baipi Decoction and its separated prescriptions on relieving jaundice of jaundice rat with Yangjaundice syndrome. Tradit Chin Drug Res Clin Pharmacol (Zhong Yao Xin Yao Yu Lin Chuang Yao Li) 2015; 26(1): 25–30 (in Chinese)

    Google Scholar 

  21. Mu CS. Factors of Yin and Yang transformation of neonates with breast milk jaundice. J Liaoning Univ Tradit Chin Med (Liao Ning Zhong Yi Yao Da Xue Xue Bao) 2013; 15(11): 200–202 (in Chinese)

    Google Scholar 

  22. Suthar PP, Bumiya RG, Patel K, Patel AB. Incidental diagnosis of liver tuberculosis in a patient with jaundice. BMJ Case Rep 2015; 2015: pii: bcr2014206866

    Google Scholar 

  23. Wang X, Zhang A, Han Y, Wang P, Sun H, Song G, Dong T, Yuan Y, Yuan X, Zhang M, Xie N, Zhang H, Dong H, Dong W. Urine metabolomics analysis for biomarker discovery and detection of jaundice syndrome in patients with liver disease. Mol Cell Proteomics 2012; 11(8): 370–380

    PubMed  PubMed Central  Google Scholar 

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

    CAS  Google Scholar 

  25. Fujiwara R, Maruo Y, Chen S, Tukey RH. Role of extrahepatic UDP-glucuronosyltransferase 1A1: advances in understanding breast milk-induced neonatal hyperbilirubinemia. Toxicol Appl Pharmacol 2015; 289(1): 124–132

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Yin J, Wennberg RP, Miller M. Induction of hepatic bilirubin and drug metabolizing enzymes by individual herbs present in the traditional Chinese medicine, yin zhi huang. Dev Pharmacol Ther 1993; 20(3-4): 186–194

    CAS  PubMed  Google Scholar 

  27. Huang W, Zhang J, Moore DD. A traditional herbal medicine enhances bilirubin clearance by activating the nuclear receptor CAR. J Clin Invest 2004; 113(1): 137–143

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Wang H, Yan G, Zhang A, Li Y, Wang Y, Sun H, Wu X, Wang X. Rapid discovery and global characterization of chemical constituents and rats metabolites of Phellodendri amurensis cortex by ultraperformance liquid chromatography-electrospray ionization/quadrupole- time-of-flight mass spectrometry coupled with pattern recognition approach. Analyst (Lond) 2013; 138(11): 3303–3312

    CAS  Google Scholar 

  29. Yang D, Yang J, Shi D, Deng R, Yan B. Scoparone potentiates transactivation of the bile salt export pump gene and this effect is enhanced by cytochrome P450 metabolism but abolished by a PKC inhibitor. Br J Pharmacol 2011; 164(5): 1547–1557

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Wu S, Wu G, Wu H. Hemolytic jaundice induced by pharmacological dose ascorbic acid in glucose-6-phosphate dehydrogenase deficiency: a case report. Medicine (Baltimore) 2018; 97(51): e13588

    Google Scholar 

  31. Kuipers F, Bloks VW, Groen AK. Beyond intestinal soap—bile acids in metabolic control. Nat Rev Endocrinol 2014; 10(8): 488–498

    CAS  PubMed  Google Scholar 

  32. Heidari R, Jamshidzadeh A, Keshavarz N, Azarpira N. Mitigation of methimazole-induced hepatic injury by taurine in mice. Sci Pharm 2015; 83(1): 143–158

    CAS  PubMed  Google Scholar 

  33. Fujiya K, Ganno H, Ando M, Chong JM. Clonorchis sinensis ova in bile juice cytology from a patient with severe hyperbilirubinemia and portal vein thrombosis. Diagn Cytopathol 2016; 44(3): 223–225

    PubMed  Google Scholar 

  34. Malla T, Singh S, Poudyal P, Sathian B, Bk G, Malla KK. A prospective study on exchange transfusion in neonatal unconjugated hyperbilirubinemia—in a tertiary care hospital, Nepal. Kathmandu Univ Med J (KUMJ) 2015; 13(50): 102–108

    CAS  Google Scholar 

  35. Song Q, Zhang A, Yan G, Liu L, Wang X. Technological advances in current metabolomics and its application in tradition Chinese medicine. RSC Adv 2017; 7(84): 53516–53524

    CAS  Google Scholar 

  36. Xie J, Zhang A, Sun H, Yan G, Wang X. Recent advances and effective strategies in the discovery and applications of natural products. RSC Adv 2018; 8(2): 812–824

    CAS  Google Scholar 

  37. Zhang A, Fang H, Wang Y, Yan G, Sun H, Zhou X, Wang Y, Liu L, Wang X. Discovery and verification of the potential targets from bioactive molecules by network pharmacology-based target prediction combined with high-throughput metabolomics. RSC Advances 2017; 7(81): 51069–51078

    CAS  Google Scholar 

  38. Qiu S, Zhang A, Zhang T, Sun H, Guan Y, Yan G, Wang X. Dissect new mechanistic insights for geniposide efficacy on the hepatoprotection using multiomics approach. Oncotarget 2017; 8(65): 108760–108770

    PubMed  PubMed Central  Google Scholar 

  39. Yu J, Kong L, Zhang A, Han Y, Liu Z, Sun H, Liu L, Wang X. Highthroughput metabolomics for discovering potential metabolite biomarkers and metabolic mechanism from APPswe/PS1dE9 transgenic model of Alzheimer’s disease. J Proteome Res 2017; 16(9): 3219–3228

    CAS  PubMed  Google Scholar 

  40. Zhang A, Sun H, Wang X. Emerging role and recent applications of metabolomics biomarkers in obesity diseases research. RSC Adv 2017; 7(25): 14966–14973

    CAS  Google Scholar 

  41. Li X, Zhang A, Sun H, Liu Z, Zhang T, Qiu S, Liu L, Wang X. Metabolic characterization and pathway analysis of berberine protects against prostate cancer. Oncotarget 2017; 8(39): 65022–65041

    PubMed  PubMed Central  Google Scholar 

  42. Zhang A, Sun H, Yan G, Wang X. Recent developments and emerging trends of mass spectrometry for herbal ingredients analysis. Trends Analyt Chem 2017; 94: 70–76

    CAS  Google Scholar 

  43. Xie J, Zhang A, Wang X. Metabolomic applications in hepatocellular carcinoma: toward the exploration of therapeutics and diagnosis through small molecules. RSC Adv 2017; 7(28): 17217–17226

    CAS  Google Scholar 

  44. 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

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Dong W, Wang P, Meng X, Sun H, Zhang A, Wang W, Dong H, Wang X. 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

    CAS  PubMed  Google Scholar 

  46. Wang X, Wang Q, Zhang A, Zhang F, Zhang H, Sun H, Cao H, Zhang H. 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

    CAS  PubMed  Google Scholar 

  47. Sun H, Wu F, Zhang A, Wei W, Han Y, Wang X. Profiling and identification of the absorbed constituents and metabolites of schisandra lignans by ultra-performance liquid chromatography coupled to mass spectrometry. Biomed Chromatogr 2013; 27(11): 1511–1519

    CAS  PubMed  Google Scholar 

  48. 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

    PubMed  PubMed Central  Google Scholar 

  49. Sun H, Zhang A, Yan G, Han Y, Sun W, Ye Y, Wang X. Proteomics study on the hepatoprotective effects of traditional Chinese medicine formulae Yin-Chen-Hao-Tang by a combination of two-dimensional polyacrylamide gel electrophoresis and matrix-assisted laser desorption/ionization-time of flight mass spectrometry. J Pharm Biomed Anal 2013; 75: 173–179

    CAS  PubMed  Google Scholar 

  50. Sun H, Zhang HL, Zhang AH, Zhou XH, Wang XQ, Han Y, Wang XJ. Network pharmacology combined with functional metabolomics discover bile acid metabolism as a promising target for mirabilite against colorectal cancer. RSC Adv 2018; 8(53): 30061–30070

    CAS  Google Scholar 

  51. Sun H, Wang H, Zhang A, Yan G, Zhang Y, An N, Wang X. Berberine ameliorates nonbacterial prostatitis via multi-target metabolic network regulation. OMICS 2015; 19(3): 186–195

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Du H, Zhao X, Zhang A. Identifying potential therapeutic targets of a natural product Jujuboside B for insomnia through network pharmacology. Plant Sci Today 2014; 1(2): 69–79

    Google Scholar 

Download references

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 2015ZX- 09101043-011), TCM State Administration Subject of Public Welfare (No. 2015468004), Major Projects of Application Technology Research and Development Plan in Heilongjiang Province (No. GX16C003), Young Talent Lift Engineering Project of China Association of Traditional Chinese Medicine (No. QNRC2-B06), Natural Science Foundation of Heilongjiang Province (Nos. YQ2019H030 and H2016056), and Foundation of Heilongjiang University of Chinese Medicine (Nos. 2018jc01, 2018bs02, and 201809).

Author information

Authors and Affiliations

  1. Sino-America Chinmedomics Technology Collaboration Center, National TCM Key Laboratory of Serum Pharmacochemistry, Laboratory of Metabolomics, Department of Pharmaceutical Analysis, Heilongjiang University of Chinese Medicine, National Chinmedomics Research Center, Harbin, 150040, China

    Heng Fang, Aihua Zhang, Xiaohang Zhou, Jingbo Yu, Qi Song & Xijun Wang

  2. State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau, 519020, China

    Xijun Wang

Authors
  1. Heng Fang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Aihua Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xiaohang Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jingbo Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Qi Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xijun Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Xijun Wang.

Additional information

Compliance with ethics guidelines

Heng Fang, Aihua Zhang, Xiaohang Zhou, Jingbo Yu, Qi Song, and Xijun Wang declare that they have no potential financial conflict of interests related to this manuscript. The research program was approved by the Ethics Committee of Heilongjiang University of Chinese Medicine, and the study was conducted in accordance with the Declaration of Helsinki.

Electronic Supplementary Material

11684_2019_709_MOESM1_ESM.pdf

Supplementary material is available in the online version of this article at https://doi.org/10.1007/s11684-019-0709-5 and is accessible for authorized users.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fang, H., Zhang, A., Zhou, X. et al. High-throughput metabolomics reveals the perturbed metabolic pathways and biomarkers of Yang Huang syndrome as potential targets for evaluating the therapeutic effects and mechanism of geniposide. Front. Med. 14, 651–663 (2020). https://doi.org/10.1007/s11684-019-0709-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11684-019-0709-5

Keywords

Search

Navigation