Advertisement

Journal of Endocrinological Investigation

, Volume 39, Issue 1, pp 83–91 | Cite as

Artesunate protects pancreatic beta cells against cytokine-induced damage via SIRT1 inhibiting NF-κB activation

  • L. Yu
  • J. F. Chen
  • X. Shuai
  • Y. Xu
  • Y. Ding
  • J. Zhang
  • W. Yang
  • X. Liang
  • D. SuEmail author
  • C. YanEmail author
Original Article

Abstract

Aim

Artesunate (ART) has been known as the most effective and safe reagents to treat malaria for many years. In this study, we explored whether ART could protect pancreatic beta-cell against cytokine-induced damage.

Materials and methods

The production of nitrite (NO) was detected with the Griess Assay Kit. SIRT1 and inducible nitric oxide synthase (iNOS) expression were determined with Western blot. The transcriptional activity of NF-κB was evaluated by luciferase reporter assay. The expression of Sirt1 was silenced by RNA interference. Glucose-stimulated insulin secretion (GSIS) and potassium-stimulated insulin secretion (KSIS) assays were performed to measure the effect of ART on pancreatic beta-cells’ function. The effect of ART on beta-cells apoptosis was evaluated by using Hochest/PI staining and TUNEL assay.

Results

ART enhanced GSIS (KSIS) and reduced apoptosis of pancreatic beta-cells induced by IL-1β. Further study showed that ART inhibited IL-1β-induced increase of NF-κB activity, iNOS expression, and NO production. Moreover, ART up-regulated SIRT1 expression in INS-1 cells and islets exposed to IL-1β. Inhibition of SIRT1 expression could partially abolished the inhibitory effect of ART on NF-κB activity in IL-1β-treated beta-cells. More importantly, the protective effect of ART on cytokine-induced damage was reversed by silencing SIRT1 expression.

Conclusions

ART can elicit a protective effect on beta-cells exposed to IL-1β by stimulating SIRT1 expression, which resulted in the decrease of NF-κB activity, iNOS expression, and NO production. Hence, ART might be an effective drug for diabetes.

Keywords

Artesunate Pancreatic beta-cell IL-1β SIRT1 NF-κB 

Abbreviations

ART

Artesunate

GSIS

Glucose-stimulates insulin secretion

KSIS

Potassium-stimulated insulin secretion

KRB

Krebs-Ringer bicarbonate

MTT

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

iNOS

Inducible nitric oxide synthase

NO

Nitrite

Notes

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This study was carried out in accordance with the guidelines of the Institutional Animal Care and Use Committee at Nanjing Medical University and was approved by the Committee on the Ethics of Animal Experiments of Nanjing Medical University.

Informed consent

This study does not involve human subjects.

References

  1. 1.
    Bernardo AS, Hay CW, Docherty K (2008) Pancreatic transcription factors and their role in the birth, life and survival of the pancreatic beta cell. Mol Cell Endocrinol 294:1–9CrossRefPubMedGoogle Scholar
  2. 2.
    Potter KJ, Westwell-Roper CY, Klimek-Abercrombie AM, Warnock GL, Verchere CB (2014) Death and dysfunction of transplanted β-cells: lessons learned from type 2 diabetes? Diabetes 63:12–19CrossRefPubMedGoogle Scholar
  3. 3.
    Morgan D, Oliveira-Emilio HR, Keane D et al (2007) Glucose, palmitate and pro-inflammatory cytokines modulate production and activity of aphagocyte-like NADPH oxidase in rat pancreatic islets and a clonal beta cell line. Diabetologia 50:359–369CrossRefPubMedGoogle Scholar
  4. 4.
    Cnop M, Welsh N, Jonas JC, Jörns A, Lenzen S, Eizirik DL (2005) Mechanisms of pancreatic beta-cell death in type 1 and type 2 diabetes: many differences, few similarities. Diabetes 54(Suppl 2):S97–S107CrossRefPubMedGoogle Scholar
  5. 5.
    Donath MY, Størling J, Berchtold LA, Billestrup N, Mandrup-Poulsen T (2008) Cytokines and beta-cell biology: from concept to clinical translation. Endocr Rev 29:334–350CrossRefPubMedGoogle Scholar
  6. 6.
    Ortis F, Cardozo AK, Crispim D, Störling J, Mandrup-Poulsen T, Eizirik DL (2006) Cytokine-induced proapoptotic gene expression in insulin-producing cells is related to rapid, sustained, and nonoscillatory nuclear factor-kappaB activation. Mol Endocrinol 20:1867–1879CrossRefPubMedGoogle Scholar
  7. 7.
    Heimberg H, Heremans Y, Jobin C et al (2001) Inhibition of cytokine-induced NF-kappaB activation by adenovirus-mediated expression of a NF-kappaB super-repressor prevents beta-cell apoptosis. Diabetes 50:2219–2224CrossRefPubMedGoogle Scholar
  8. 8.
    Monteiro JP, Cano MI (2011) SIRT1 deacetylase activity and the maintenance of protein homeostasis in response tostress: an overview. Protein Pept Lett 18:167–173CrossRefPubMedGoogle Scholar
  9. 9.
    Yang H, Zhang W, Pan H et al (2012) SIRT1 activators suppress inflammatory responses through promotion of p65 deacetylation and inhibition of NF-κB activity. PLoS One 7:e46364CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Lai CS, Tsai ML, Badmaev V, Jimenez M, Ho CT, Pan MH (2012) Xanthigen suppresses preadipocyte differentiation and adipogenesis through down-regulation of PPARγ and C/EBPs and modulation of SIRT-1, AMPK, and FoxO pathways. J Agric Food Chem 60:1094–1101CrossRefPubMedGoogle Scholar
  11. 11.
    Kitada M, Koya D (2013) SIRT1 in type 2 diabetes: mechanisms and therapeutic potential. Diabetes Metab J 37:315–325CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Bordone L, Motta MC, Picard F (2006) Sirt1 regulates insulin secretion by repressing UCP2 in pancreatic beta cells. PLoS Biol 4:e31CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Lee JH, Song MY, Song EK et al (2009) Overexpression of SIRT1 protects pancreatic beta-cells against cytokine toxicity by suppressing the nuclear factor-kappaB signaling pathway. Diabetes 58:344–351CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Teja-Isavadharm P, Watt G, Eamsila C et al (2001) Comparative pharmacokinetics and effect kinetics of orally administered artesunate in healthy volunteers and patients with uncomplicated falciparum malaria. Am J Trop Med Hyg 65:717–721PubMedGoogle Scholar
  15. 15.
    Price RN (2000) Artemisinin drugs: novel antimalarial agents. Expert Opin Investig Drugs 9:1815–1827CrossRefPubMedGoogle Scholar
  16. 16.
    He RR, Zhou HJ (2008) Progress in research on the anti-tumor effect of artesunate. Chin J Integr Med 14:312–316CrossRefPubMedGoogle Scholar
  17. 17.
    Efferth T, Romero MR, Wolf DG, Stamminger T, Marin JJ, Marschall M (2008) The antiviral activities of artemisinin and artesunate. Clin Infect Dis 47:804–811CrossRefPubMedGoogle Scholar
  18. 18.
    Miranda AS, Brant F, Rocha NP (2013) Further evidence for an anti-inflammatory role of artesunate in experimental cerebral malaria. Malar J 12:388CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Su D, Zhang N, He J et al (2007) Angiopoietin-1 production in islets improves islet engraftment and protects islets from cytokine-induced apoptosis. Diabetes 56:2274–2283CrossRefPubMedGoogle Scholar
  20. 20.
    Chen F, Zhu Y, Tang X (2011) Dynamic regulation of PDX-1 and FoxO1 expression by FoxA2 in dexamethasone-induced pancreatic β-cells dysfunction. Endocrinology 152:1779–1788CrossRefPubMedGoogle Scholar
  21. 21.
    Jia L, Xing J, Ding Y et al (2013) Hyperuricemia causes pancreatic β-cell death and dysfunction through NF-κB signaling pathway. PLoS One 8:e78284CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Han X, Sun Y, Scott S, Bleich D (2001) Tissue inhibitor of metalloproteinase-1 prevents cytokine-mediated dysfunction and cytotoxicity in pancreatic islets and beta-cells. Diabetes 50:1047–1055CrossRefPubMedGoogle Scholar
  23. 23.
    Dejardin E (2006) The alternative NF-kappaB pathway from biochemistry to biology: pitfalls and promises for future drug development. Biochem Pharmacol 72:1161–1179CrossRefPubMedGoogle Scholar
  24. 24.
    May MJ, Ghosh S (1998) Signal transduction through NF-kappa B. Immunol Today 19:80–88CrossRefPubMedGoogle Scholar
  25. 25.
    Bordone L, Motta MC, Picard F et al (2006) Sirt1 regulates insulin secretion by repressing UCP2 in pancreatic beta cells. PLoS Biol 4:e31CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Kim SJ, Ao Z, Warnock G, McIntosh CH (2013) Incretin-stimulated interaction between β-cell Kv1.5 and Kvβ2 channel proteins involves acetylation/deacetylation by CBP/SirT1. Biochem J 451:227–234CrossRefPubMedGoogle Scholar
  27. 27.
    Li T, Chen H, Wei N (2012) Anti-inflammatory and immunomodulatory mechanisms of artemisinin on contact hypersensitivity. Int Immunopharmacol 12:144–150CrossRefPubMedGoogle Scholar
  28. 28.
    Jin O, Zhang H, Gu Z et al (2009) A pilot study of the therapeutic efficacy and mechanism of artesunate in the MRL/lpr murine model of systemic lupus erythematosus. Cell Mol Immunol 6:461–467CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Thanaketpaisarn O, Waiwut P, Sakurai H, Saiki I (2011) Artesunate enhances TRAIL-induced apoptosis in human cervical carcinoma cells through inhibition of the NF-κB and PI3K/Akt signaling pathways. Int J Oncol 39:279–285PubMedGoogle Scholar
  30. 30.
    Corbett JA, Sweetland MA, Wang JL, Lancaster JR Jr, McDaniel ML (1993) Nitric oxide mediates cytokine-induced inhibition of insulin secretion by human islets of langerhans. Proc Natl Acad Sci 90:1731–1735CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Andersson AK, Börjesson A, Sandgren J, Sandler S (2005) Cytokines affect PDX-1 expression, insulin and proinsulin secretion from iNOS deficient murine islets. Mol Cell Endocrinol 240:50–57CrossRefPubMedGoogle Scholar
  32. 32.
    Huxford T, Huang DB, Malek S, Ghosh G (1998) The crystal structure of the IkappaBalpha/NF-kappaB complex reveals mechanisms of NF-kappaB inactivation. Cell 95:759–770CrossRefPubMedGoogle Scholar
  33. 33.
    Xu H, He Y, Yang X et al (2007) Anti-malarial agent artesunate inhibits TNF-alpha-induced production of proinflammatory cytokines via inhibition of NF-kappaB and PI3 kinase/Akt signal pathway in human rheumatoid arthritis fibroblast-like synoviocytes. Rheumatology (Oxford) 46:920–926CrossRefGoogle Scholar

Copyright information

© Italian Society of Endocrinology (SIE) 2015

Authors and Affiliations

  1. 1.Department of PathologyNanjing Medical UniversityNanjingChina
  2. 2.Department of EndocrinologyZhangzhou Affiliated Hospital of Fujian Medical UniversityZhangzhouChina
  3. 3.Department of Laboratory MedicineJiangsu Province Hospital on Integration of Chinese and Western MedicineNanjingChina
  4. 4.The Center of Metabolic Disease ResearchNanjing Medical UniversityNanjingChina
  5. 5.Department of EndocrinologyClinical Medical College of Yangzhou UniversityYangzhouChina

Personalised recommendations