Skip to main content
Log in

Evaluation of the effect of Punica granatum juice and punicalagin on NFκB modulation in inflammatory bowel disease

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Punica granatum L. (Lythraceae) inhibits cancer cell proliferation and apoptosis through the modulation of cellular transcription factors and signaling proteins. No pharmacological work is reported on the effects of P. granatum juice on the cellular signaling pathways involved in initiation and progression of inflammation. The present investigation evaluates the effect of P. granatum juice (PJ) and purified punicalagin (PW) on nuclear factor kappa B (NFκB) and the signaling pathways leading to its expression in colon inflammation. Male Sprague–Dawley rats were divided into six groups: positive and negative control, vehicle (50 % ethanol), standard (5-ASA 100 mg/kg, p.o.), PJ (400 mg/kg, p.o.), PW (4 mg/kg, p.o.). Colitis was induced with 2,4-dinitrobenzene sulfonic acid and animals were euthanized on 18th day. Colon samples collected were subjected to various histological assessment (CMDI, DAI), and biochemical parameters (MPO, MDA, SOD, NO). Gene expression study was carried out using RT-PCR for cytokines (TNF-α, IL-1β, IL-18 and NF-κβ). Pretreatment with PJ and PW significantly (p < 0.05) lowered the disease extent and severity as indicated by reduction in CMDI (2 ± 0.31) and DAI (1.83# ± 0.22) when compared with DNBS-treated rats (3.83* ± 0.17). Gene expression studies showed decreased mRNA levels of TNF-α, IL-18, and IL-1β in PJ and PW-treated groups. NF-κβ mRNA levels were found to be reduced 84 and 64 % by PJ and PW, respectively. These results suggest that P. granatum juice is more biologically active over punicalagin alone and can be potentially used for the treatment of inflammatory bowel disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

  1. Cuzzocrea S, Mazzon E, Di Paola R, Patel NS, Genovese T, Muia C, De Sarro A, Thiemermann C (2004) Erythropoietin reduces the development of experimental inflammatory bowel disease. J Pharmacol Exp Ther 311(3):1272–1280. doi:10.1124/jpet.104.073197

    Article  CAS  PubMed  Google Scholar 

  2. Sood A, Midha V (2007) Epidemiology of inflammatory bowel disease in Asia. Indian J Gastroenterol 26(6):285–289

    PubMed  Google Scholar 

  3. Podolsky DK (2002) Inflammatory bowel disease. New Engl J Med 347(6):417–429. doi:10.1056/NEJMra020831

    Article  CAS  PubMed  Google Scholar 

  4. Reinisch W, Dejaco C, Knoflach P, Petritsch W, Vogelsang H, Tilg H (2004) Immunosuppressive therapy for inflammatory bowel disease: consensus by the Austrian working group on IBD. Zeitschrift fur Gastroenterologie 42(9):1033–1045. doi:10.1055/s-2004-813500 (discussion 1046–1037)

    Article  CAS  PubMed  Google Scholar 

  5. Neuman MG (2007) Immune dysfunction in inflammatory bowel disease. Transl Res 149(4):173–186. doi:10.1016/j.trsl.2006.11.009

    Article  CAS  PubMed  Google Scholar 

  6. Sanchez-Munoz F, Dominguez-Lopez A, Yamamoto-Furusho JK (2008) Role of cytokines in inflammatory bowel disease. World J Gastroenterol 14(27):4280–4288

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Cemeroglu B, Artik N, Erbas S (1992) Extraction and composition of pomegranate juice. Fluessiges Obst 59:335–340

    Google Scholar 

  8. El-Nemr SE, Ismail IA, Ragab M (1990) Chemical composition of juice and seeds of pomegranate fruit. Food/Nahrung 34(7):601–606. doi:10.1002/food.19900340706

    Article  CAS  Google Scholar 

  9. Ben Nasr C, Ayed N, Metche M (1996) Quantitative determination of the polyphenolic content of pomegranate peel. Zeitschrift fur Lebensmittel-Untersuchung und Forschung 203(4):374–378

    Article  CAS  PubMed  Google Scholar 

  10. Schubert SY, Lansky EP, Neeman I (1999) Antioxidant and eicosanoid enzyme inhibition properties of pomegranate seed oil and fermented juice flavonoids. J Ethnopharmacol 66(1):11–17

    Article  CAS  PubMed  Google Scholar 

  11. Seeram NP, Adams LS, Henning SM, Niu Y, Zhang Y, Nair MG, Heber D (2005) In vitro antiproliferative, apoptotic and antioxidant activities of punicalagin, ellagic acid and a total pomegranate tannin extract are enhanced in combination with other polyphenols as found in pomegranate juice. J Nutr Biochem 16(6):360–367. doi:10.1016/j.jnutbio.2005.01.006

    Article  CAS  PubMed  Google Scholar 

  12. Rosenblat M, Volkova N, Coleman R, Aviram M (2006) Pomegranate byproduct administration to apolipoprotein e-deficient mice attenuates atherosclerosis development as a result of decreased macrophage oxidative stress and reduced cellular uptake of oxidized low-density lipoprotein. J Agric Food Chem 54(5):1928–1935. doi:10.1021/jf0528207

    Article  CAS  PubMed  Google Scholar 

  13. Lee SI, Kim BS, Kim KS, Lee S, Shin KS, Lim JS (2008) Immune-suppressive activity of punicalagin via inhibition of NFAT activation. Biochem Biophys Res Commun 371(4):799–803. doi:10.1016/j.bbrc.2008.04.150

    Article  CAS  PubMed  Google Scholar 

  14. Ukil A, Maity S, Karmakar S, Datta N, Vedasiromoni JR, Das PK (2003) Curcumin, the major component of food flavour turmeric, reduces mucosal injury in trinitrobenzene sulphonic acid-induced colitis. Br J Pharmacol 139(2):209–218. doi:10.1038/sj.bjp.0705241

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Ackerman Z, Karmeli F, Cohen P, Rachmilewitz D (2003) Experimental colitis in rats with portal hypertension and liver disease. Inflamm Bowel Dis 9(1):18–24

    Article  PubMed  Google Scholar 

  16. Santiago OI, Rivera E, Ferder L, Appleyard CB (2008) An angiotensin II receptor antagonist reduces inflammatory parameters in two models of colitis. Regul Pept 146(1–3):250–259. doi:10.1016/j.regpep.2007.10.004

    Article  CAS  PubMed  Google Scholar 

  17. Gil MI, Tomas-Barberan FA, Hess-Pierce B, Holcroft DM, Kader AA (2000) Antioxidant activity of pomegranate juice and its relationship with phenolic composition and processing. J Agric Food Chem 48(10):4581–4589

    Article  CAS  PubMed  Google Scholar 

  18. Aviram M, Dornfeld L, Rosenblat M, Volkova N, Kaplan M, Coleman R, Hayek T, Presser D, Fuhrman B (2000) Pomegranate juice consumption reduces oxidative stress, atherogenic modifications to LDL, and platelet aggregation: studies in humans and in atherosclerotic apolipoprotein E-deficient mice. Am J Clin Nutr 71(5):1062–1076

    CAS  PubMed  Google Scholar 

  19. Kim ND, Mehta R, Yu W, Neeman I, Livney T, Amichay A, Poirier D, Nicholls P, Kirby A, Jiang W, Mansel R, Ramachandran C, Rabi T, Kaplan B, Lansky E (2002) Chemopreventive and adjuvant therapeutic potential of pomegranate (Punica granatum) for human breast cancer. Breast Cancer Res Treat 71(3):203–217

    Article  CAS  PubMed  Google Scholar 

  20. Albrecht M, Jiang W, Kumi-Diaka J, Lansky EP, Gommersall LM, Patel A, Mansel RE, Neeman I, Geldof AA, Campbell MJ (2004) Pomegranate extracts potently suppress proliferation, xenograft growth, and invasion of human prostate cancer cells. J Med Food 7(3):274–283. doi:10.1089/1096620041938704

    Article  CAS  PubMed  Google Scholar 

  21. Toi M, Bando H, Ramachandran C, Melnick SJ, Imai A, Fife RS, Carr RE, Oikawa T, Lansky EP (2003) Preliminary studies on the anti-angiogenic potential of pomegranate fractions in vitro and in vivo. Angiogenesis 6(2):121–128. doi:10.1023/B:AGEN.0000011802.81320.e4

    Article  CAS  PubMed  Google Scholar 

  22. Kulkarni AP, Aradhya SM, Divakar S (2004) Isolation and identification of a radical scavenging antioxidant—punicalagin from pith and carpellary membrane of pomegranate fruit. Food Chem 87(4):551–557. doi:10.1016/j.foodchem.2004.01.006

    Article  CAS  Google Scholar 

  23. Baeuerle PA, Baltimore D (1996) NF-kappa B: ten years after. Cell 87(1):13–20

    Article  CAS  PubMed  Google Scholar 

  24. Newberry RD, Stenson WF, Lorenz RG (1999) Cyclooxygenase-2-dependent arachidonic acid metabolites are essential modulators of the intestinal immune response to dietary antigen. Nat Med 5(8):900–906. doi:10.1038/11341

    Article  CAS  PubMed  Google Scholar 

  25. Cheng G, Cleary AM, Ye ZS, Hong DI, Lederman S, Baltimore D (1995) Involvement of CRAF1, a relative of TRAF, in CD40 signaling. Science 267(5203):1494–1498

    Article  CAS  PubMed  Google Scholar 

  26. Hsu H, Shu HB, Pan MG, Goeddel DV (1996) TRADD-TRAF2 and TRADD-FADD interactions define two distinct TNF receptor 1 signal transduction pathways. Cell 84(2):299–308

    Article  CAS  PubMed  Google Scholar 

  27. Palombella VJ, Rando OJ, Goldberg AL, Maniatis T (1994) The ubiquitin proteasome pathway is required for processing the NF-κB1 precursor protein and the activation of NF-κB. Cell 78(5):773–785. doi:10.1016/S0092-8674(94)90482-0

    Article  CAS  PubMed  Google Scholar 

  28. Stallmach A, Schuppan D, Riese HH, Matthes H, Riecken EO (1992) Increased collagen type III synthesis by fibroblasts isolated from strictures of patients with Crohn’s disease. Gastroenterology 102(6):1920–1929

    Article  CAS  PubMed  Google Scholar 

  29. Ludwiczek O, Vannier E, Borggraefe I, Kaser A, Siegmund B, Dinarello CA, Tilg H (2004) Imbalance between interleukin-1 agonists and antagonists: relationship to severity of inflammatory bowel disease. Clin Exp Immunol 138(2):323–329. doi:10.1111/j.1365-2249.2004.02599.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Eigler A, Sinha B, Hartmann G, Endres S (1997) Taming TNF: strategies to restrain this proinflammatory cytokine. Immunol Today 18(10):487–492

    Article  CAS  PubMed  Google Scholar 

  31. Kim HK, Son KH, Chang HW, Kang SS, Kim HP (1999) Inhibition of rat adjuvant-induced arthritis by ginkgetin, a biflavone from ginkgo biloba leaves. Planta Med 65(5):465–467. doi:10.1055/s-2006-960815

    Article  CAS  PubMed  Google Scholar 

  32. Bobin-Dubigeon C, Collin X, Grimaud N, Robert JM, Le Baut G, Petit JY (2001) Effects of tumour necrosis factor-alpha synthesis inhibitors on rat trinitrobenzene sulphonic acid-induced chronic colitis. Eur J Pharmacol 431(1):103–110

    Article  CAS  PubMed  Google Scholar 

  33. Krawisz JE, Sharon P, Stenson WF (1984) Quantitative assay for acute intestinal inflammation based on myeloperoxidase activity. Assessment of inflammation in rat and hamster models. Gastroenterology 87(6):1344–1350

    CAS  PubMed  Google Scholar 

  34. Boughton-Smith NK, Wallace JL, Morris GP, Whittle BJ (1988) The effect of anti-inflammatory drugs on eicosanoid formation in a chronic model of inflammatory bowel disease in the rat. Br J Pharmacol 94(1):65–72

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Otamiri T, Lindahl M, Tagesson C (1988) Phospholipase A2 inhibition prevents mucosal damage associated with small intestinal ischaemia in rats. Gut 29(4):489–494

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Han SN, Meydani SN (2000) Antioxidants, cytokines, and influenza infection in aged mice and elderly humans. J Infect Dis 182(Suppl 1):S74–80. doi:10.1086/315915

    Article  CAS  PubMed  Google Scholar 

  37. McCafferty DM (2000) Peroxynitrite and inflammatory bowel disease. Gut 46(3):436–439

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Seril DN, Liao J, Yang GY, Yang CS (2003) Oxidative stress and ulcerative colitis-associated carcinogenesis: studies in humans and animal models. Carcinogenesis 24(3):353–362

    Article  CAS  PubMed  Google Scholar 

  39. Barazzone C, White CW (2000) Mechanisms of cell injury and death in hyperoxia: role of cytokines and Bcl-2 family proteins. Am J Respir Cell Mol Biol 22(5):517–519. doi:10.1165/ajrcmb.22.5.f180

    Article  CAS  PubMed  Google Scholar 

  40. Yue G, Lai PS, Yin K, Sun FF, Nagele RG, Liu X, Linask KK, Wang C, Lin KT, Wong PY (2001) Colon epithelial cell death in 2,4,6-trinitrobenzenesulfonic acid-induced colitis is associated with increased inducible nitric-oxide synthase expression and peroxynitrite production. J Pharmacol Exp Ther 297(3):915–925

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

Authors are grateful to Dr. Mehta for providing help and facilities for molecular work at Om Research Facility, Anand Agricultural University, Anand, Gujarat, India.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Mihir Parikh.

Ethics declarations

Conflicts of interest

None to declare.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 899 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shah, T.A., Parikh, M., Patel, K.V. et al. Evaluation of the effect of Punica granatum juice and punicalagin on NFκB modulation in inflammatory bowel disease. Mol Cell Biochem 419, 65–74 (2016). https://doi.org/10.1007/s11010-016-2750-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-016-2750-x

Keywords

Navigation