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

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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.

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Authors and Affiliations

  1. Saw Swee Hock School of Public Health, National University Health System, National University of Singapore, 16 Medical Drive MD3, Singapore, 117597, Singapore

    Wanxing Eugene Ho, Yong-Jiang Xu, Fengguo Xu, Shao-Min Huang & Choon Nam Ong

  2. Singapore-MIT Alliance for Research and Technology (SMART), 1 CREATE Way, #03-12/13/14 Enterprise Wing, Singapore, 138602, Singapore

    Wanxing Eugene Ho & Steven R. Tannenbaum

  3. Key Laboratory of Insect Development and Evolutionary Biology, Chinese Academy of Sciences, Shanghai, 200023, China

    Yong-Jiang Xu

  4. Key Laboratory of Drug Quality Control and Pharmacovigilance, China Pharmaceutical University, Nanjing, 210009, China

    Fengguo Xu

  5. Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, 28 Medical Drive, #03-05, Center for Life Sciences, Singapore, 117456, Singapore

    Chang Cheng, Hong Yong Peh & W. S. Fred Wong

  6. Department of Biological Engineering and Chemistry, Massachusetts Institute of Technology, ROOM 56-731A, Cambridge, MA, 02139-4307, USA

    Steven R. Tannenbaum

  7. NUS Environmental Research Institute, National University of Singapore, #02-01, T-Lab Building, 5A Engineering Drive 1, Singapore, 117411, Singapore

    Choon Nam Ong

  8. Immunology Program, Life Science Institute, National University of Singapore, 28 Medical Drive, #03-05, Center for Life Sciences, Singapore, 117456, Singapore

    W. S. Fred Wong

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  1. Wanxing Eugene Ho
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  2. Yong-Jiang Xu
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Correspondence to Choon Nam Ong or W. S. Fred Wong.

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Wanxing Eugene Ho and Yong-Jiang Xu have contributed equally to this work.

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Ho, W.E., Xu, YJ., Xu, F. et al. Anti-malarial drug artesunate restores metabolic changes in experimental allergic asthma. Metabolomics 11, 380–390 (2015). https://doi.org/10.1007/s11306-014-0699-x

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