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The protective effects of resveratrol on ulcerative colitis via changing the profile of Nrf2 and IL-1β protein

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Abstract

Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) with increasing incidence and prevalence in developed countries. The presence of inflammatory cytokines is considered the main detrimental factor in severe types of IBD. The Nrf2 transcription factor plays an important role in reducing the expression of inflammatory agents such as interleukin (IL)-1β and increasing reparative factors such as IL-11. Resveratrol, a plant-derived phenolic compound, reduces the damage in chronic experimentally induced colitis. Twenty patients with UC and also 20 healthy controls were recruited in this study. The proteins expression of Nrf2 and IL-1β was assessed in colonic biopsies by Western blotting. Caco-2 cells were challenged with TNF-α (in vitro simulation of UC), in the presence or not of 190 nM (24 h) and 75 nM (48 h) Resveratrol. Then, Nrf2 and IL-1β in gene and protein expression were measured by real time-PCR and Western blotting in different treatments. Finally, IL-11 proteins expression was measured in culture supernatant by ELISA. A significant increase of IL-1β protein was detected in inflamed colonic tissues from UC patients compared with the control individuals. In Caco-2 cells challenged with TNF-α, protein expression of IL-1β and p-Nrf2 showed an increase, while gene expression of Nrf2 did not show a significant difference. After treatment with Resveratrol, both IL-1β mRNA and protein levels were reduced, while IL-11 protein levels showed any increase. The p-Nrf2 is a dominant form which is prevalent in inflamed tissues from UC patients. Resveratrol can reverse the inflammatory effects of TNF-α by reducing IL-1β and increasing IL-11 production.

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References

  1. Sartor RB (2006) Mechanisms of disease: pathogenesis of Crohn’s disease and ulcerative colitis. Nat Clin Pract Gastroenterol Hepatol 3:390–407

    Article  CAS  Google Scholar 

  2. Wu Y, Antony S, Meitzler JL, Doroshow JH (2014) Molecular mechanisms underlying chronic inflammation-associated cancers. Cancer Lett 345:164–173

    Article  CAS  Google Scholar 

  3. Moran GW, Dubeau MF, Kaplan GG, Panaccione R, Ghosh S (2014) Novel concepts in inflammatory bowel disease. Br Med Bull 109:55–72

    Article  CAS  Google Scholar 

  4. Shohan M, Sabzevary-Ghahfarokhi M, Bagheri N et al (2018) Intensified Th9 response is associated with the immunopathogenesis of active ulcerative colitis. Immunol Invest 47:700–711

    Article  CAS  Google Scholar 

  5. Turner JR (2006) Molecular basis of epithelial barrier regulation: from basic mechanisms to clinical application. Am J Pathol 169:1901–1909

    Article  CAS  Google Scholar 

  6. Hamer HM, Jonkers DM, Vanhoutvin SA et al (2010) Effect of butyrate enemas on inflammation and antioxidant status in the colonic mucosa of patients with ulcerative colitis in remission. Clin Nutr 29:738–744

    Article  CAS  Google Scholar 

  7. Jena G, Trivedi PP, Sandala B (2012) Oxidative stress in ulcerative colitis: an old concept but a new concern. Free Radic Res 46:1339–1345

    Article  CAS  Google Scholar 

  8. Zhu H, Li YR (2012) Oxidative stress and redox signaling mechanisms of inflammatory bowel disease: updated experimental and clinical evidence. Exp Biol Med (Maywood) 237:474–480

    Article  CAS  Google Scholar 

  9. Matsuura A, Ishima T, Fujita Y et al (2018) Dietary glucoraphanin prevents the onset of psychosis in the adult offspring after maternal immune activation. Sci Rep 8:2158

    Article  Google Scholar 

  10. Wen Z, Liu W, Li X et al (2019) A protective role of the NRF2-Keap1 pathway in maintaining intestinal barrier function. Oxid Med Cell Longev 2019:1759149

    PubMed  PubMed Central  Google Scholar 

  11. Saber S, Khalil RM, Abdo WS, Nassif D, El-Ahwany E (2019) Olmesartan ameliorates chemically-induced ulcerative colitis in rats via modulating NFkappaB and Nrf-2/HO-1 signaling crosstalk. Toxicol Appl Pharmacol 364:120–132

    Article  CAS  Google Scholar 

  12. Nishina T, Deguchi Y, Miura R et al (2017) Critical contribution of nuclear factor erythroid 2-related factor 2 (NRF2) to electrophile-induced interleukin-11 production. J Biol Chem 292:205–216

    Article  CAS  Google Scholar 

  13. Khor TO, Huang MT, Kwon KH, Chan JY, Reddy BS, Kong AN (2006) Nrf2-deficient mice have an increased susceptibility to dextran sulfate sodium-induced colitis. Cancer Res 66:11580–11584

    Article  CAS  Google Scholar 

  14. Lu MC, Ji JA, Jiang YL et al (2016) An inhibitor of the Keap1-Nrf2 protein-protein interaction protects NCM460 colonic cells and alleviates experimental colitis. Sci Rep 6:26585

    Article  CAS  Google Scholar 

  15. Poulsen MM, Fjeldborg K, Ornstrup MJ, Kjaer TN, Nohr MK, Pedersen SB (2015) Resveratrol and inflammation: challenges in translating pre-clinical findings to improved patient outcomes. Biochim Biophys Acta 1852:1124–1136

    Article  CAS  Google Scholar 

  16. Martin AR, Villegas I, Sanchez-Hidalgo M, de la Lastra CA (2006) The effects of resveratrol, a phytoalexin derived from red wines, on chronic inflammation induced in an experimentally induced colitis model. Br J Pharmacol 147:873–885

    Article  CAS  Google Scholar 

  17. Kruse ML, Friedrich M, Arlt A et al (2016) Colonic lamina propria inflammatory cells from patients with IBD induce the nuclear factor-E2 related factor-2 thereby leading to greater proteasome activity and apoptosis protection in human colonocytes. Inflamm Bowel Dis 22:2593–2606

    Article  Google Scholar 

  18. Lisk C, McCord J, Bose S et al (2013) Nrf2 activation: a potential strategy for the prevention of acute mountain sickness. Free Radic Biol Med 63:264–273

    Article  CAS  Google Scholar 

  19. Zhou J, Ge L, Jia C et al (2016) ROS-mediated different homeostasis of murine corneal epithelial progenitor cell line under oxidative stress. Sci Rep 6:36481

    Article  CAS  Google Scholar 

  20. Foresti R, Bucolo C, Platania CM, Drago F, Dubois-Rande JL, Motterlini R (2015) Nrf2 activators modulate oxidative stress responses and bioenergetic profiles of human retinal epithelial cells cultured in normal or high glucose conditions. Pharmacol Res 99:296–307

    Article  CAS  Google Scholar 

  21. Keshavarzian A, Banan A, Farhadi A et al (2003) Increases in free radicals and cytoskeletal protein oxidation and nitration in the colon of patients with inflammatory bowel disease. Gut 52:720–728

    Article  CAS  Google Scholar 

  22. Sabzevary-Ghahfarokhi M, Shohan M, Shirzad H et al (2018) The regulatory role of Nrf2 in antioxidants phase2 enzymes and IL-17A expression in patients with ulcerative colitis. Pathol Res Pract 214:1149–1155

    Article  CAS  Google Scholar 

  23. Cuadrado A (2015) Structural and functional characterization of Nrf2 degradation by glycogen synthase kinase 3/beta-TrCP. Free Radic Biol Med 88:147–157

    Article  CAS  Google Scholar 

  24. Kobayashi EH, Suzuki T, Funayama R et al (2016) Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription. Nat Commun 7:11624

    Article  CAS  Google Scholar 

  25. Bhattacharyya A, Chattopadhyay R, Mitra S, Crowe SE (2014) Oxidative stress: an essential factor in the pathogenesis of gastrointestinal mucosal diseases. Physiol Rev 94:329–354

    Article  CAS  Google Scholar 

  26. Sanchez-Fidalgo S, Cardeno A, Villegas I, Talero E, de la Lastra CA (2010) Dietary supplementation of resveratrol attenuates chronic colonic inflammation in mice. Eur J Pharmacol 633:78–84

    Article  CAS  Google Scholar 

  27. Bereswill S, Munoz M, Fischer A et al (2010) Anti-inflammatory effects of resveratrol, curcumin and simvastatin in acute small intestinal inflammation. PLoS ONE 5:e15099

    Article  CAS  Google Scholar 

  28. Ido Y, Duranton A, Lan F, Weikel KA, Breton L, Ruderman NB (2015) Resveratrol prevents oxidative stress-induced senescence and proliferative dysfunction by activating the AMPK-FOXO3 cascade in cultured primary human keratinocytes. PLoS ONE 10:e0115341

    Article  Google Scholar 

  29. Cheng L, Jin Z, Zhao R, Ren K, Deng C, Yu S (2015) Resveratrol attenuates inflammation and oxidative stress induced by myocardial ischemia-reperfusion injury: role of Nrf2/ARE pathway. Int J Clin Exp Med 8:10420–10428

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Liu L, Gu H, Liu H et al (2014) Protective effect of resveratrol against IL-1beta-induced inflammatory response on human osteoarthritic chondrocytes partly via the TLR4/MyD88/NF-kappaB signaling pathway: an “in vitro study”. Int J Mol Sci 15:6925–6940

    Article  Google Scholar 

  31. Zhu X, Liu Q, Wang M et al (2011) Activation of Sirt1 by resveratrol inhibits TNF-alpha induced inflammation in fibroblasts. PLoS ONE 6:e27081

    Article  CAS  Google Scholar 

  32. Sabzevary-Ghahfarokhi M, Shohan M, Shirzad H et al (2018) The expression analysis of Fra-1 gene and IL-11 protein in Iranian patients with ulcerative colitis. BMC Immunol 19:17

    Article  Google Scholar 

  33. Ropeleski MJ, Tang J, Walsh-Reitz MM, Musch MW, Chang EB (2003) Interleukin-11-induced heat shock protein 25 confers intestinal epithelial-specific cytoprotection from oxidant stress. Gastroenterology 124:1358–1368

    Article  CAS  Google Scholar 

  34. Putoczki TL, Thiem S, Loving A et al (2013) Interleukin-11 is the dominant IL-6 family cytokine during gastrointestinal tumorigenesis and can be targeted therapeutically. Cancer Cell 24:257–271

    Article  CAS  Google Scholar 

  35. Reuter BK, Pizarro TT (2004) Commentary: the role of the IL-18 system and other members of the IL-1R/TLR superfamily in innate mucosal immunity and the pathogenesis of inflammatory bowel disease: friend or foe? Eur J Immunol 34:2347–2355

    Article  CAS  Google Scholar 

  36. Nishina T, Komazawa-Sakon S, Yanaka S et al (2012) Interleukin-11 links oxidative stress and compensatory proliferation. Sci Signal 5:ra5

    Article  Google Scholar 

  37. Gibson DL, Montero M, Ropeleski MJ et al (2010) Interleukin-11 reduces TLR4-induced colitis in TLR2-deficient mice and restores intestinal STAT3 signaling. Gastroenterology 139:1277–1288

    Article  CAS  Google Scholar 

  38. Negahdaripour M, Nezafat N, Ghasemi Y (2016) A panoramic review and in silico analysis of IL-11 structure and function. Cytokine Growth Factor Rev 32:41–61

    Article  CAS  Google Scholar 

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Acknowledgements

The authors are grateful to the staff of Cellular & Molecular Research Center, Shahrekord University of Medical Sciences, Shahrekord, Iran, and the authorities of the endoscopy unit of Shahrekord Hajar Hospital, Shahrekord, Iran, for their cooperation.

Funding

This work was supported by the National Institute for Medical Research Development (Nimad), Tehran, Iran, with Grant Number of 971537.

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Correspondence to Nader Bagheri.

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Authors declare no conflict of interest.

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The Ethical Board of Shahrekord University of Medical Sciences supported this work (Number IR.SKUMS.REC.1395.313). The aim of the study was explained to each study individuals. They were informed that personal data were not published. All patients signed written informed consent to donate their tissue samples for research.

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Sabzevary-Ghahfarokhi, M., Soltani, A., Luzza, F. et al. The protective effects of resveratrol on ulcerative colitis via changing the profile of Nrf2 and IL-1β protein. Mol Biol Rep 47, 6941–6947 (2020). https://doi.org/10.1007/s11033-020-05753-4

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  • DOI: https://doi.org/10.1007/s11033-020-05753-4

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