Skip to main content
SpringerLink
Log in

Artesunate ameliorates DSS-induced ulcerative colitis by protecting intestinal barrier and inhibiting inflammatory response

  • Original Article
  • Published:
Inflammation Aims and scope Submit manuscript

Abstract

There are very few reports on the protective effect of artesunate (ARS) in ulcerative colitis (UC). This study focused on the efficacy of ARS on intestinal barrier, inflammatory response, and potential mechanism in dextran sulfate sodium (DSS)-induced ulcerative colitis in mice. The results suggested that ARS treatment markedly alleviated DSS-induced clinical symptoms by relieving body weight loss, the disease activity index (DAI) score, and preventing colonic shortening. HE staining and scanning electron microscope analysis revealed that ARS treatment significantly protected the integrity of intestinal barrier through alleviating DSS-induced erosion of surface epithelial cells, reduction of goblet cells, and destruction of the crypt accompanied with inflammatory cells infiltration. Immunofluorescence histochemical staining and western blot assay confirmed that ARS notably inhibited the loss of Muc2 and claudin-1 in mucosal layer with a relative higher level of Bcl-2/Bax ratio and, moreover, inhibited cleaved-caspase-3 expression in colon tissue. In addition, this study reconfirmed the anti-inflammatory function of ARS evidenced by remarkably suppressing the phosphorylation of nuclear factor-κBα (IκBα) and NF-κB p65 and the expression of IL-1β, IL-6, and TNF-α while enhancing IL-10 expression. Taken together, these data highlight that ARS has the protective effect on UC through maintaining the expression of intestinal mucosal barrier-related proteins, suppressing the apoptosis and inflammatory response. This study may facilitate to understand the action mechanism of ARS against UC.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Fell, J.M., R. Muhammed, C. Spray, K. Crook, and R.K. Russell. 2016. Management of ulcerative colitis. Archives of Disease in Childhood 101 (5): 469–474.

    Article  Google Scholar 

  2. Liu, Y., Q. Ye, Y. Liu, J. Kang, Y. Chen, and W. Dong. 2017. Schistosoma japonicum attenuates dextran sodium sulfate-induced colitis in mice via reduction of endoplasmic reticulum stress. World Journal of Gastroenterology 23 (31): 5700–5712.

    Article  Google Scholar 

  3. Fatani, A.J., F.S. Alrojayee, M.Y. Parmar, H.M. Abuohashish, M.M. Ahmed, and S.S. Al-Rejaie. 2016. Myrrh attenuates oxidative and inflammatory processes in acetic acid-induced ulcerative colitis. Experimental and Therapeutic Medicine 12 (2): 730–738.

    Article  CAS  Google Scholar 

  4. Russell, S.E., R.M. Horan, A.M. Stefanska, A. Carey, G. Leon, M. Aguilera, D. Statovci, T. Moran, P.G. Fallon, F. Shanahan, E.K. Brint, S. Melgar, S. Hussey, and P.T. Walsh. 2016. IL-36alpha expression is elevated in ulcerative colitis and promotes colonic inflammation. Mucosal Immuonlogy 9 (5): 1193–1204.

    Article  CAS  Google Scholar 

  5. Ordás, I., L. Eckmann, M. Talamini, D.C. Baumgart, and W.J. Sandborn. 2012. Ulcerative colitis. The Lancet 380 (9853): 1606–1619.

    Article  Google Scholar 

  6. Camilleri, M., K. Madsen, R. Spiller, B.G. Van Meerveld, and G.N. Verne. 2012. Intestinal barrier function in health and gastrointestinal disease. Neurogastroenterology & Motility 24 (6): 503–512.

    Article  CAS  Google Scholar 

  7. Merga, Y., B.J. Campbell, J.M. Rhodes, and Mucosal Barrier. 2014. Bacteria and inflammatory bowel disease: Possibilities for therapy. Digestive Diseases 32 (4): 475–483.

    Article  Google Scholar 

  8. Vindigni, S.M., T.L. Zisman, D.L. Suskind, and C.J. Damman. 2016. The intestinal microbiome, barrier function, and immune system in inflammatory bowel disease: A tripartite pathophysiological circuit with implications for new therapeutic directions. SAGE Publications, London, England pp.: 606–625.

  9. Turner, J.R. 2009. Intestinal mucosal barrier function in health and disease. Nature Reviews Immunology 9 (11): 799–809.

    Article  CAS  Google Scholar 

  10. Lechuga, S., and A.I. Ivanov. 2017. Disruption of the epithelial barrier during intestinal inflammation: Quest for new molecules and mechanisms. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 1864 (7): 1183–1194.

    Article  CAS  Google Scholar 

  11. Yan, Y., M. Shao, Q. Qi, Y. Xu, X. Yang, F. Zhu, S. He, P. He, C. Feng, Y. Wu, H. Li, W. Tang, and J. Zuo. 2018. Artemisinin analogue SM934 ameliorates DSS- induced mouse ulcerative colitis via suppressing neutrophils and macrophages. Acta Pharmacologica Sinica 39: 1633–1644.

    Article  CAS  Google Scholar 

  12. Shi, C., H. Li, Y. Yang, and L. Hou. 2015. Anti-inflammatory and immunoregulatory functions of artemisinin and its derivatives. Mediators of Inflammation 435713.

  13. Hou, L., and H. Huang. 2016. Immune suppressive properties of artemisinin family drugs. Pharmacology & Therapeutics 166: 123–127.

    Article  CAS  Google Scholar 

  14. Yang, Z., J. Ding, C. Yang, Y. Gao, X. Li, X. Chen, Y. Peng, J. Fang, and S. Xiao. 2012. Immunomodulatory and anti-inflammatory properties of Artesunate in experimental colitis. Current Medicinal Chemistry 19: 4541–4551.

    Article  CAS  Google Scholar 

  15. Wirtz, S., and M.F. Neurath. 2007. Mouse models of inflammatory bowel disease. Advanced Drug Delivery Reviews 59 (11): 1073–1083.

    Article  CAS  Google Scholar 

  16. Maxwell, J.R., W.A. Brown, C.L. Smith, F.R. Byrne, and J.L. Viney. 2009. Methods of inducing inflammatory bowel disease in mice. Current Protocols in Pharmacology Chapter 5: t5–t58.

    Google Scholar 

  17. Zhu, G., H. Wang, T. Wang, and F. Shi. 2017. Ginsenoside Rg1 attenuates the inflammatory response in DSS-induced mice colitis. International Immunopharmacology 50: 1–5.

    Article  CAS  Google Scholar 

  18. Liu, S., Y. Liu, Q. Ma, S. Cui, and J. Liu. 2015. Expression and localization of cysteine sulfinate decarboxylase in major salivary glands of male mice. Archives of Oral Biology 60 (4): 615–621.

    Article  CAS  Google Scholar 

  19. WIRTZ, S., and M. NEURATH. 2007. Mouse models of inflammatory bowel disease. Advanced Drug Delivery Reviews 59 (11): 1073–1083.

    Article  CAS  Google Scholar 

  20. Williams, K.L., C.R. Fuller, L.A. Dieleman, C.M. DaCosta, K.M. Haldeman, R.B. Sartor, and P.K. Lund. 2001. Enhanced survival and mucosal repair after dextran sodium sulfate–induced colitis in transgenic mice that overexpress growth hormone. Gastroenterology 120 (4): 925–937.

    Article  CAS  Google Scholar 

  21. Merga, Y., B.J. Campbell, and J.M. Rhodes. 2014. Mucosal Barrier, Bacteria and inflammatory bowel disease: Possibilities for therapy. Digestive Diseases 32 (4): 475–483.

    Article  Google Scholar 

  22. Johansson, M.E., D. Ambort, T. Pelaseyed, A. Schutte, J.K. Gustafsson, A. Ermund, D.B. Subramani, J.M. Holmen-Larsson, K.A. Thomsson, J.H. Bergstrom, S. van der Post, A.M. Rodriguez-Pineiro, H. Sjovall, M. Backstrom, and G.C. Hansson. 2011. Composition and functional role of the mucus layers in the intestine. Cellular and Molecular Life Sciences 68 (22): 3635–3641.

    Article  CAS  Google Scholar 

  23. Tytgat, K.M., H.A. Buller, F.J. Opdam, Y.S. Kim, A.W. Einerhand, and J. Dekker. 1994. Biosynthesis of human colonic mucin: Muc2 is the prominent secretory mucin. Gastroenterology 107 (5): 1352–1363.

    Article  CAS  Google Scholar 

  24. J-W Van Klinken, B., J.-W.G. Van der Wal, A.W.C. Einerhand, H.A. Büller, and J. Dekker. 1999. Sulphation and secretion of the predominant secretory human colonic mucin MUC2 in ulcerative colitis. Gut 44: 387–393.

    Article  Google Scholar 

  25. Van der Sluis, M., B.A. De Koning, A.C. De Bruijn, A. Velcich, J.P. Meijerink, J.B. Van Goudoever, H.A. Buller, J. Dekker, I. Van Seuningen, I.B. Renes, and A.W. Einerhand. 2006. Muc2-deficient mice spontaneously develop colitis, indicating that MUC2 is critical for colonic protection. Gastroenterology 131 (1): 117–129.

    Article  Google Scholar 

  26. Yu, Q.H., and Q. Yang. 2009. Diversity of tight junctions (TJs) between gastrointestinal epithelial cells and their function in maintaining the mucosal barrier. Cell Biology International 33 (1): 78–82.

    Article  Google Scholar 

  27. Singh, R., S. Chandrashekharappa, S.R. Bodduluri, B.V. Baby, B. Hegde, N.G. Kotla, A.A. Hiwale, T. Saiyed, P. Patel, M. Vijay-Kumar, M.G.I. Langille, G.M. Douglas, X. Cheng, E.C. Rouchka, S.J. Waigel, G.W. Dryden, H. Alatassi, H. Zhang, B. Haribabu, P.K. Vemula, and V.R. Jala. 2019. Enhancement of the gut barrier integrity by a microbial metabolite through the Nrf2 pathway. Nature Communications 10 (1).

  28. Al-Sadi, R., M. Boivin, and T. Ma. 2009. Mechanism of cytokine modulation of epithelial tight junction barrier. Frontiers in Bioscience-Landmark 14: 2765–2778.

    Article  CAS  Google Scholar 

  29. Suzuki, T. 2013. Regulation of intestinal epithelial permeability by tight junctions. Cellular and Molecular Life Sciences 70 (4): 631–659.

    Article  CAS  Google Scholar 

  30. Chen, Y., M. Zhang, and F. Ren. 2019. A role of exopolysaccharide produced by Streptococcus thermophilus in the intestinal inflammation and mucosal Barrier in Caco-2 monolayer and dextran sulphate sodium-induced experimental murine colitis. Molecules 24 (3): 513.

    Article  Google Scholar 

  31. Gitter, A.H., K. Bendfeldt, J.D. Schulzke, and M. Fromm. 2000. Leaks in the epithelial barrier caused by spontaneous and TNF-alpha-induced single-cell apoptosis. The FASEB Journal 14 (12): 1749–1753.

    Article  CAS  Google Scholar 

  32. Heller, F., P. Florian, C. Bojarski, J. Richter, M. Christ, B. Hillenbrand, J. Mankertz, A.H. Gitter, N. Bürgel, M. Fromm, M. Zeitz, I. Fuss, W. Strober, and J.D. Schulzke. 2005. Interleukin-13 is the key effector Th2 cytokine in ulcerative colitis that affects epithelial tight junctions, apoptosis, and cell restitution. Gastroenterology 129 (2): 550–564.

    Article  CAS  Google Scholar 

  33. Dong, J., H. Wang, J. Zhao, J. Sun, T. Zhang, L. Zuo, W. Zhu, J. Gong, Y. Li, L. Gu, and J. Li. 2015. SEW2871 protects from experimental colitis through reduced epithelial cell apoptosis and improved barrier function in interleukin-10 gene-deficient mice. Journal of Immunology Research 61 (3): 303–311.

    Article  CAS  Google Scholar 

  34. Zhao, X., Z. Li, J. Wang, X. Xing, Z. Wang, L. Wang, and Z. Wang. 2015. Effects of chelated Zn/cu/Mn on redox status, immune responses and hoof health in lactating Holstein cows. Journal of Veterinary Science 16 (4): 439–446.

    Article  Google Scholar 

  35. J. Chen, J. Lin, H, Luo, and M. Li. 2019. Effects of human Interleukin-10 on ventilator-associated lung injury in rats. Inflammation 42 (2) 538–547.

  36. Hasnain, S.Z., S. Tauro, I. Das, H. Tong, A.C.H. Chen, P.L. Jeffery, V. McDonald, T.H. Florin, and M.A. McGuckin. 2013. IL-10 promotes production of intestinal mucus by suppressing protein misfolding and endoplasmic reticulum stress in goblet cells. Gastroenterology 144 (2): 357–368.

    Article  CAS  Google Scholar 

  37. Xavier, R.J., and D.K. Podolsky. 2007. Unravelling the pathogenesis of inflammatory bowel disease. Nature 448 (7152): 427–434.

    Article  CAS  Google Scholar 

  38. Choi, J.H., K.S. Chung, B.R. Jin, S.Y. Cheon, A. Nugroho, S.S. Roh, and H.J. An. 2017. Anti-inflammatory effects of an ethanol extract of Aster glehni via inhibition of NF-κB activation in mice with DSS-induced colitis. Food & Function 8: 2611–2620.

    Article  CAS  Google Scholar 

  39. Kang, J., S. Choi, J.E. Jang, P. Ramalingam, Y.T. Ko, S.Y. Kim, and S.H. Oh. 2017. Wasabia japonica is a potential functional food to prevent colitis via inhibiting the NF- κB signaling pathway. Food & Function 8: 2865–2874.

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by the grants from National Natural Science Foundation (Nos. 31672595) and the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).

Author information

Author notes

  1. ShaoJie Yin and HaiFeng Yang contributed equally to this work.

Authors and Affiliations

  1. School of Veterinary Medicine, Yangzhou University, Yangzhou, 225009, People’s Republic of China

    ShaoJie Yin, Ya Tao, SiMin Wei, LiuHui Li, MingJiang Liu & JinGui Li

  2. Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou, 225009, People’s Republic of China

    ShaoJie Yin, Ya Tao, SiMin Wei, LiuHui Li, MingJiang Liu & JinGui Li

  3. Jiangsu Agri-animal Husbandry Vocational College, Taizhou, 225300, People’s Republic of China

    HaiFeng Yang

Authors
  1. ShaoJie Yin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. HaiFeng Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ya Tao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. SiMin Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. LiuHui Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. MingJiang Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. JinGui Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to JinGui Li.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Additional information

Author contributions

S. J. Yin, H. F. Yang, and J. G. Li designed the study. S. J. Yin and H. F. Yang performed the immunofluorescence staining and western blot experiments. S. M. Wei and L. H. Li help to perform the scanning electron microscope and HE staining. Y. Tao helps to perform the inflammatory cytokines assay. S. J. Yin and J.G. Li wrote the manuscript. Y. Tao and M. J. Liu reviewed the manuscript.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yin, S., Yang, H., Tao, Y. et al. Artesunate ameliorates DSS-induced ulcerative colitis by protecting intestinal barrier and inhibiting inflammatory response. Inflammation 43, 765–776 (2020). https://doi.org/10.1007/s10753-019-01164-1

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10753-019-01164-1

KEY WORDS

Search

Navigation