Metabolomics

, Volume 11, Issue 2, pp 380–390

Anti-malarial drug artesunate restores metabolic changes in experimental allergic asthma

  • Wanxing Eugene Ho
  • Yong-Jiang Xu
  • Fengguo Xu
  • Chang Cheng
  • Hong Yong Peh
  • Shao-Min Huang
  • Steven R. Tannenbaum
  • Choon Nam Ong
  • W. S. Fred Wong
Original Article

Abstract

The anti-malarial drug artesunate possesses anti-inflammatory and anti-oxidative actions in experimental asthma, comparable to corticosteroid. We hypothesized that artesunate may modulate disease-relevant metabolic alterations in allergic asthma. To explore metabolic profile changes induced by artesunate in allergic airway inflammation, we analysed bronchoalveolar lavage fluid (BALF) and serum from naïve and ovalbumin-induced asthma mice treated with artesunate, using both gas and liquid chromatography-mass spectrometry metabolomics. Pharmacokinetics analyses of serum and lung tissues revealed that artesunate is rapidly converted into the active metabolite dihydroartemisinin. Artesunate effectively suppressed BALF total and differential counts, and repressed BALF Th2 cytokines, IL-17, IL-12(p40), MCP-1 and G-CSF levels. Artesunate had no effects on both BALF and serum metabolome in naïve mice. Artesunate promoted restoration of BALF sterols (cholesterol, cholic acid and cortol), phosphatidylcholines and carbohydrates (arabinose, mannose and galactose) and of serum 18-oxocortisol, galactose, glucose and glucouronic acid in asthma. Artesunate prevented OVA-induced increases in pro-inflammatory metabolites from arginine–proline metabolic pathway, particularly BALF levels of urea and alanine and serum levels of urea, proline, valine and homoserine. Multiple statistical correlation analyses revealed association between altered BALF and serum metabolites and inflammatory cytokines. Dexamethasone failed to reduce urea level and caused widespread changes in metabolites irrelevant to asthma development. Here we report the first metabolome profile of artesunate treatment in experimental asthma. Artesunate restored specific metabolic perturbations in airway inflammation, which correlated well with its anti-inflammatory actions. Our metabolomics findings further strengthen the therapeutic value of using artesunate to treat allergic asthma.

Keywords

Metabolome Artemisinins Mass spectrometry Allergic asthma Corticosteroid 

Supplementary material

11306_2014_699_MOESM1_ESM.docx (425 kb)
Supplementary material 1 (DOCX 425 kb)

References

  1. Barbul, A. (2008). Proline precursors to sustain mammalian collagen synthesis. Journal of Nutrition, 138(10), 2021S–2024S.PubMedGoogle Scholar
  2. Cheng, C., Ho, W. E., Goh, F. Y., Guan, S. P., Kong, L. R., Lai, W. Q., et al. (2011). Anti-malarial drug artesunate attenuates experimental allergic asthma via inhibition of the phosphoinositide 3-kinase/Akt pathway. PLoS ONE, 6(6), e20932.CrossRefPubMedCentralPubMedGoogle Scholar
  3. Cheng, C., Ng, D. S., Chan, T. K., Guan, S. P., Ho, W. E., Koh, A. H., et al. (2013). Anti-allergic action of anti-malarial drug artesunate in experimental mast cell-mediated anaphylactic models. Allergy, 68(2), 195–203.CrossRefPubMedGoogle Scholar
  4. Dai, C. L., Yao, X. L., Keeran, K. J., Zywicke, G. J., Qu, X., Yu, Z. X., et al. (2012). Apolipoprotein A-I attenuates ovalbumin-induced neutrophilic airway inflammation via a granulocyte colony-stimulating factor-dependent mechanism. American Journal of Respiratory Cell and Molecular Biology, 47(2), 186–195.CrossRefPubMedCentralPubMedGoogle Scholar
  5. Fessler, M. B., Massing, M. W., Spruell, B., Jaramillo, R., Draper, D. W., Madenspacher, J. H., et al. (2009). Novel relationship of serum cholesterol with asthma and wheeze in the United States. Journal of Allergy and Clinical Immunology, 124(5), 967–974.CrossRefPubMedCentralPubMedGoogle Scholar
  6. Ho, W. E., Cheng, C., Peh, H. Y., Xu, F., Tannenbaum, S. R., Ong, C. N., et al. (2012). Anti-malarial drug artesunate ameliorates oxidative lung damage in experimental allergic asthma. Free Radical Biology & Medicine, 53(3), 498–507.CrossRefGoogle Scholar
  7. Ho, W. E., Peh, H. Y., Chan, T. K., & Wong, W. S. F. (2014a). Artemisinins: Pharmacological actions beyond anti-malarial. Pharmacology & Therapeutics, 142(1), 126–139.CrossRefGoogle Scholar
  8. Ho, W. E., Xu, Y.-J., Cheng, C., Peh, H. Y., Tannenbaum, S. R., Wong, W. S. F., et al. (2014b). Metabolomics reveals inflammatory-linked pulmonary metabolic alterations in a murine model of house dust mite-induced allergic asthma. Journal of Proteome Research. doi:10.1021/pr5003615.
  9. Ho, W. E., Xu, Y. J., Xu, F., Cheng, C., Peh, H. Y., Tannenbaum, S. R., et al. (2013). Metabolomics reveals altered metabolic pathways in experimental asthma. American Journal of Respiratory Cell and Molecular Biology, 48(2), 204–211.CrossRefPubMedGoogle Scholar
  10. Huang, Y.-S., Huang, W.-C., Li, C.-W., & Chuang, L.-T. (2011). Eicosadienoic acid differentially modulates production of pro-inflammatory modulators in murine macrophages. Molecular and Cellular Biochemistry, 358(1–2), 85–94.CrossRefPubMedGoogle Scholar
  11. Jiang, W., Li, B., Zheng, X., Liu, X., Cen, Y., Li, J., et al. (2011). Artesunate in combination with oxacillin protect sepsis model mice challenged with lethal live methicillin-resistant Staphylococcus aureus (MRSA) via its inhibition on proinflammatory cytokines release and enhancement on antibacterial activity of oxacillin. International Immunopharmacology, 11(8), 1065–1073.CrossRefPubMedGoogle Scholar
  12. Jin, O., Zhang, H., Gu, Z., Zhao, S., Xu, T., Zhou, K., et al. (2009). A pilot study of the therapeutic efficacy and mechanism of artesunate in the MRL/lpr murine model of systemic lupus erythematosus. Cellular & Molecular Immunology, 6(6), 461–467.CrossRefGoogle Scholar
  13. Jung, J., Kim, S.-H., Lee, H.-S., Choi, G. S., Jung, Y.-S., Ryu, D. H., et al. (2013). Serum metabolomics reveals pathways and biomarkers associated with asthma pathogenesis. Clinical and Experimental Allergy, 43(4), 425–433.CrossRefPubMedGoogle Scholar
  14. Lara, A., Khatri, S. B., Wang, Z., Comhair, S. A., Xu, W., Dweik, R. A., et al. (2008). Alterations of the arginine metabolome in asthma. American Journal of Respiratory and Critical Care Medicine, 178(7), 673–681.CrossRefPubMedCentralPubMedGoogle Scholar
  15. Li, B., Li, J., Pan, X., Ding, G., Cao, H., Jiang, W., et al. (2010). Artesunate protects sepsis model mice challenged with Staphylococcus aureus by decreasing TNF-alpha release via inhibition TLR2 and Nod2 mRNA expressions and transcription factor NF-kappaB activation. International Immunopharmacology, 10(3), 344–350.CrossRefPubMedGoogle Scholar
  16. Li, Y., Wang, S., Wang, Y., Zhou, C., Chen, G., Shen, W., et al. (2013). Inhibitory effect of the antimalarial agent artesunate on collagen-induced arthritis in rats through nuclear factor kappa B and mitogen-activated protein kinase signaling pathway. Translational Research, 161(2), 89–98.CrossRefPubMedGoogle Scholar
  17. Marescau, B., De Deyn, P. P., Lowenthal, A., Qureshi, I. A., Antonozzi, I., Bachmann, C., et al. (1990). Guanidino compound analysis as a complementary diagnostic parameter for hyperargininemia: Follow-up of guanidino compound levels during therapy. Pediatric Research, 27(3), 297–303.CrossRefPubMedGoogle Scholar
  18. Mattarucchi, E., Baraldi, E., & Guillou, C. (2012). Metabolomics applied to urine samples in childhood asthma; differentiation between asthma phenotypes and identification of relevant metabolites. Biomedical Chromatography, 26(1), 89–94.CrossRefPubMedGoogle Scholar
  19. Mehta, A. K., Arora, N., Gaur, S. N., & Singh, B. P. (2009). Choline supplementation reduces oxidative stress in mouse model of allergic airway disease. European Journal of Clinical Investigation, 39(10), 934–941.CrossRefPubMedGoogle Scholar
  20. Mehta, A. K., Singh, B. P., Arora, N., & Gaur, S. N. (2010). Choline attenuates immune inflammation and suppresses oxidative stress in patients with asthma. Immunobiology, 215(7), 527–534.CrossRefPubMedGoogle Scholar
  21. Meurs, H., McKay, S., Maarsingh, H., Hamer, M. A. M., Macic, L., Molendijk, N., et al. (2002). Increased arginase activity underlies allergen-induced deficiency of cNOS-derived nitric oxide and airway hyperresponsiveness. British Journal of Pharmacology, 136(3), 391–398.CrossRefPubMedCentralPubMedGoogle Scholar
  22. Meyts, I., Hellings, P. W., Hens, G., Vanaudenaerde, B. M., Verbinnen, B., Heremans, H., et al. (2006). IL-12 contributes to allergen-induced airway inflammation in experimental asthma. Journal of Immunology, 177(9), 6460–6470.CrossRefGoogle Scholar
  23. Mirshafiey, A., Saadat, F., Attar, M., Di Paola, R., Sedaghat, R., & Cuzzocrea, S. (2006). Design of a new line in treatment of experimental rheumatoid arthritis by artesunate. Immunopharmacology and Immunotoxicology, 28(3), 397–410.CrossRefPubMedGoogle Scholar
  24. Morris, C. A., Duparc, S., Borghini-Fuhrer, I., Jung, D., Shin, C. S., & Fleckenstein, L. (2011). Review of the clinical pharmacokinetics of artesunate and its active metabolite dihydroartemisinin following intravenous, intramuscular, oral or rectal administration. Malaria Journal, 10, 263.CrossRefPubMedCentralPubMedGoogle Scholar
  25. Newton, P., Suputtamongkol, Y., Teja-Isavadharm, P., Pukrittayakamee, S., Navaratnam, V., Bates, I., et al. (2000). Antimalarial bioavailability and disposition of artesunate in acute falciparum malaria. Antimicrobial Agents and Chemotherapy, 44(4), 972–977.CrossRefPubMedCentralPubMedGoogle Scholar
  26. Ng, D. P. K., Salim, A., Liu, Y., Zou, L., Xu, F. G., Huang, S., et al. (2012). A metabolomic study of low estimated GFR in non-proteinuric type 2 diabetes mellitus. Diabetologia, 55(2), 499–508.CrossRefPubMedGoogle Scholar
  27. Peebles, R. S., Togias, A., Bickel, C. A., Diemer, F. B., Hubbard, W. C., & Schleimer, R. P. (2000). Endogenous glucocorticoids and antigen-induced acute and late phase pulmonary responses. Clinical and Experimental Allergy, 30(9), 1257–1265.CrossRefPubMedGoogle Scholar
  28. Peters, M., Kauth, M., Scherner, O., Gehlhar, K., Steffen, I., Wentker, P., et al. (2010). Arabinogalactan isolated from cowshed dust extract protects mice from allergic airway inflammation and sensitization. Journal of Allergy and Clinical Immunology, 126(3), 648–656.CrossRefPubMedGoogle Scholar
  29. Pluskal, T., Castillo, S., Villar-Briones, A., & Oresic, M. (2010). MZmine 2: Modular framework for processing, visualizing, and analyzing mass spectrometry-based molecular profile data. BMC Bioinformatics. doi:10.1186/1471-2105-11-395.PubMedCentralPubMedGoogle Scholar
  30. Ried, J. S., Baurecht, H., Stuckler, F., Krumsiek, J., Gieger, C., Heinrich, J., et al. (2013). Integrative genetic and metabolite profiling analysis suggests altered phosphatidylcholine metabolism in asthma. Allergy, 68(5), 629–636.CrossRefPubMedGoogle Scholar
  31. Saude, E. J., Obiefuna, I. P., Somorjai, R. L., Ajamian, F., Skappak, C., Ahmad, T., et al. (2009). Metabolomic biomarkers in a model of asthma exacerbation: urine nuclear magnetic resonance. American Journal of Respiratory and Critical Care Medicine, 179(1), 25–34.CrossRefPubMedGoogle Scholar
  32. Saude, E. J., Skappak, C. D., Regush, S., Cook, K., Ben-Zvi, A., Becker, A., et al. (2011). Metabolomic profiling of asthma: diagnostic utility of urine nuclear magnetic resonance spectroscopy. Journal of Allergy and Clinical Immunology, 127(3), 757–764 e, 751–756.Google Scholar
  33. Sell, D. R., Strauch, C. M., Shen, W., & Monnier, V. M. (2007). 2-Aminoadipic acid is a marker of protein carbonyl oxidation in the aging human skin: Effects of diabetes, renal failure and sepsis. Biochemical Journal, 404, 269–277.CrossRefPubMedCentralPubMedGoogle Scholar
  34. Serrano-Mollar, A., & Closa, D. (2005). Arachidonic acid signaling in pathogenesis of allergy: Therapeutic implications. Current Drug Targets—Inflammation & Allergy, 4(2), 151–155.CrossRefGoogle Scholar
  35. Smith, C. B., & Sun, Y. (1995). Influence of valine flooding on channeling of valine into tissue pools and on protein synthesis. American Journal of Physiology, 268(4 Pt 1), E735–E744.PubMedGoogle Scholar
  36. Tan, S. S. L., Ong, B., Cheng, C., Ho, W. E., Tam, J. K. C., Stewart, A. G., et al. (2013). The antimalarial drug artesunate inhibits primary human cultured airway smooth muscle cell proliferation. American Journal of Respiratory Cell and Molecular Biology, 50(2), 451–458.Google Scholar
  37. Teja-Isavadharm, P., Watt, G., Eamsila, C., Jongsakul, K., Li, Q., Keeratithakul, G., et al. (2001). Comparative pharmacokinetics and effect kinetics of orally administered artesunate in healthy volunteers and patients with uncomplicated falciparum malaria. American Journal of Tropical Medicine and Hygiene, 65(6), 717–721.PubMedGoogle Scholar
  38. Weber, N., Richter, K.-D., Schulte, E., & Mukherjee, K. D. (1995). Petroselinic acid from dietary triacylglycerols reduces the concentration of arachidonic acid in tissue lipids of rats. Journal of Nutrition, 125(6), 1563–1568.PubMedGoogle Scholar
  39. Weeda, E., de Kort, C. A. D., & Beenakkers, A. M. T. (1980). Oxidation of proline and pyruvate by flight muscle mitochondria of the Colorado beetle, Leptinotarsa decemlineata say. Insect Biochemistry, 10(3), 305–311.Google Scholar
  40. Wright, S. M., Hockey, P. M., Enhorning, G., Strong, P., Reid, K. B. M., Holgate, S. T., et al. (2000). Altered airway surfactant phospholipid composition and reduced lung function in asthma. Journal of Applied Physiology, 89(4), 1283–1292.PubMedGoogle Scholar
  41. Xu, Y.-J., Wang, C., Ho, W. E., & Ong, C. N. (2014). Recent developments and applications of metabolomics in microbiological investigations. TrAC Trends in Analytical Chemistry, 56, 37–48.CrossRefGoogle Scholar
  42. Xu, X. L., Xie, Q. M., Shen, Y. H., Jiang, J. J., Chen, Y. Y., Yao, H. Y., et al. (2008). Mannose prevents lipopolysaccharide-induced acute lung injury in rats. Inflammation Research, 57(3), 104–110.CrossRefPubMedGoogle Scholar
  43. Xu, F. G., Zou, L., & Ong, C. N. (2009). Multiorigination of chromatographic peaks in derivatized GC/MS metabolomics: A confounder that influences metabolic pathway interpretation. Journal of Proteome Research, 8(12), 5657–5665.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Wanxing Eugene Ho
    • 1
    • 2
  • Yong-Jiang Xu
    • 1
    • 3
  • Fengguo Xu
    • 1
    • 4
  • Chang Cheng
    • 5
  • Hong Yong Peh
    • 5
  • Shao-Min Huang
    • 1
  • Steven R. Tannenbaum
    • 2
    • 6
  • Choon Nam Ong
    • 1
    • 7
  • W. S. Fred Wong
    • 5
    • 8
  1. 1.Saw Swee Hock School of Public Health, National University Health SystemNational University of SingaporeSingaporeSingapore
  2. 2.Singapore-MIT Alliance for Research and Technology (SMART)SingaporeSingapore
  3. 3.Key Laboratory of Insect Development and Evolutionary BiologyChinese Academy of SciencesShanghaiChina
  4. 4.Key Laboratory of Drug Quality Control and PharmacovigilanceChina Pharmaceutical UniversityNanjingChina
  5. 5.Department of Pharmacology, Yong Loo Lin School of MedicineNational University Health SystemSingaporeSingapore
  6. 6.Department of Biological Engineering and ChemistryMassachusetts Institute of TechnologyCambridgeUSA
  7. 7.NUS Environmental Research InstituteNational University of SingaporeSingaporeSingapore
  8. 8.Immunology Program, Life Science InstituteNational University of SingaporeSingaporeSingapore

Personalised recommendations