About this Journal Submit a Manuscript Table of Contents
Evidence-Based Complementary and Alternative Medicine
Volume 2013 (2013), Article ID 789764, 18 pages
http://dx.doi.org/10.1155/2013/789764
Review Article

Preventive and Prophylactic Mechanisms of Action of Pomegranate Bioactive Constituents

1Nutritional Immunology and Molecular Medicine Laboratory, Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, VA 24060, USA
2Center for Modeling Immunity to Enteric Pathogens, Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, VA 24060, USA
3Department of Biomedical Sciences and Pathobiology, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Tech, Blacksburg, VA 24061, USA

Received 29 November 2012; Accepted 20 March 2013

Academic Editor: Edwin L. Cooper

Copyright © 2013 Monica Viladomiu et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. E. P. Lansky and R. A. Newman, “Punica granatum (pomegranate) and its potential for prevention and treatment of inflammation and cancer,” Journal of Ethnopharmacology, vol. 109, no. 2, pp. 177–206, 2007. View at Publisher · View at Google Scholar · View at Scopus
  2. M. Viuda-Martos, J. Fernández-Lóaez, and J. A. Pérez-álvarez, “Pomegranate and its many functional components as related to human health: a review,” Comprehensive Reviews in Food Science and Food Safety, vol. 9, no. 6, pp. 635–654, 2010. View at Publisher · View at Google Scholar · View at Scopus
  3. S. A. H. Naqvi, M. S. Y. Khan, and S. B. Vohora, “Anti-bacterial, anti-fungal and anthelmintic investigations on Indian medicinal plants,” Fitoterapia, vol. 62, no. 3, pp. 221–228, 1991. View at Scopus
  4. A. Caceres, L. M. Giron, S. R. Alvarado, and M. F. Torres, “Screening of antimicrobial activity of plants popularly used in Guatemala for the treatment of dermatomucosal diseases,” Journal of Ethnopharmacology, vol. 20, no. 3, pp. 223–237, 1987. View at Scopus
  5. F. de Nigris, M. L. Balestrieri, S. Williams-Ignarro et al., “The influence of pomegranate fruit extract in comparison to regular pomegranate juice and seed oil on nitric oxide and arterial function in obese Zucker rats,” Nitric Oxide, vol. 17, no. 1, pp. 50–54, 2007. View at Publisher · View at Google Scholar · View at Scopus
  6. S. D. Johanningsmeier and G. K. Harris, “Pomegranate as a functional food and nutraceutical source,” Annual Review of Food Science and Technology, vol. 2, pp. 181–201, 2011.
  7. J. Jurenka, “Therapeutic applications of pomegranate (Punica granatum L.): a review,” Alternative Medicine Review, vol. 13, no. 2, pp. 128–144, 2008. View at Scopus
  8. M. I. Gil, F. A. Tomas-Barberan, B. Hess-Pierce, D. M. Holcroft, and A. A. Kader, “Antioxidant activity of pomegranate juice and its relationship with phenolic composition and processing,” Journal of Agricultural and Food Chemistry, vol. 48, no. 10, pp. 4581–4589, 2000. View at Publisher · View at Google Scholar · View at Scopus
  9. Y. Li, C. Guo, J. Yang, J. Wei, J. Xu, and S. Cheng, “Evaluation of antioxidant properties of pomegranate peel extract in comparison with pomegranate pulp extract,” Food Chemistry, vol. 96, no. 2, pp. 254–260, 2006. View at Publisher · View at Google Scholar · View at Scopus
  10. C. Guo, J. Yang, J. Wei, Y. Li, J. Xu, and Y. Jiang, “Antioxidant activities of peel, pulp and seed fractions of common fruits as determined by FRAP assay,” Nutrition Research, vol. 23, no. 12, pp. 1719–1726, 2003. View at Publisher · View at Google Scholar · View at Scopus
  11. S. Okonogi, C. Duangrat, S. Anuchpreeda, S. Tachakittirungrod, and S. Chowwanapoonpohn, “Comparison of antioxidant capacities and cytotoxicities of certain fruit peels,” Food Chemistry, vol. 103, no. 3, pp. 839–846, 2007. View at Publisher · View at Google Scholar · View at Scopus
  12. J. Sacheck, “Pediatric obesity: an inflammatory condition?” Journal of Parenteral and Enteral Nutrition, vol. 32, no. 6, pp. 633–637, 2008. View at Publisher · View at Google Scholar · View at Scopus
  13. I. O. C. M. Vroegrijk, J. A. van Diepen, S. van den Berg et al., “Pomegranate seed oil, a rich source of punicic acid, prevents diet-induced obesity and insulin resistance in mice,” Food and Chemical Toxicology, vol. 49, no. 6, pp. 1426–1430, 2011. View at Publisher · View at Google Scholar · View at Scopus
  14. J. He and M. M. Giusti, “Anthocyanins: natural colorants with health-promoting properties,” Annual Review of Food Science and Technology, vol. 1, pp. 163–187, 2010.
  15. A. Basu and K. Penugonda, “Pomegranate juice: a heart-healthy fruit juice,” Nutrition Reviews, vol. 67, no. 1, pp. 49–56, 2009. View at Publisher · View at Google Scholar · View at Scopus
  16. C. B. Stowe, “The effects of pomegranate juice consumption on blood pressure and cardiovascular health,” Complementary Therapies in Clinical Practice, vol. 17, no. 2, pp. 113–115, 2011. View at Publisher · View at Google Scholar · View at Scopus
  17. R. P. Singh, K. N. C. Murthy, and G. K. Jayaprakasha, “Studies on the antioxidant activity of pomegranate (Punica granatum) peel and seed extracts using in vitro models,” Journal of Agricultural and Food Chemistry, vol. 50, no. 1, pp. 81–86, 2002. View at Publisher · View at Google Scholar · View at Scopus
  18. A. P. Kulkarni, H. S. Mahal, S. Kapoor, and S. M. Aradhya, “In vitro studies on the binding, antioxidant, and cytotoxic action of punicalagin,” Journal of Agricultural and Food Chemistry, vol. 55, no. 4, pp. 1491–1500, 2007. View at Publisher · View at Google Scholar · View at Scopus
  19. M. Falsaperla, G. Morgia, A. Tartarone, R. Ardito, and G. Romano, “Support ellagic acid therapy in patients with hormone refractory prostate cancer (HRPC) on standard chemotherapy using vinorelbine and estramustine phosphate,” European Urology, vol. 47, no. 4, pp. 449–454, 2005. View at Publisher · View at Google Scholar · View at Scopus
  20. E. A. Hassoun, J. Vodhanel, and A. Abushaban, “The modulatory effects of ellagic acid and vitamin E succinate on TCDD-induced oxidative stress in different brain regions of rats after subchronic exposure,” Journal of Biochemical and Molecular Toxicology, vol. 18, no. 4, pp. 196–203, 2004. View at Publisher · View at Google Scholar · View at Scopus
  21. E. P. Lansky, W. Jiang, H. Mo et al., “Possible synergistic prostate cancer suppression by anatomically discrete pomegranate fractions,” Investigational New Drugs, vol. 23, no. 1, pp. 11–20, 2005. View at Publisher · View at Google Scholar · View at Scopus
  22. E. P. Lansky, G. Harrison, P. Froom, and W. G. Jiang, “Pomegranate (Punica granatum) pure chemicals show possible synergistic inhibition of human PC-3 prostate cancer cell invasion across Matrigel,” Investigational New Drugs, vol. 23, no. 2, pp. 121–122, 2005. View at Publisher · View at Google Scholar · View at Scopus
  23. S. H. Mirdehghan and M. Rahemi, “Seasonal changes of mineral nutrients and phenolics in pomegranate (Punica granatum L.) fruit,” Scientia Horticulturae, vol. 111, no. 2, pp. 120–127, 2007. View at Publisher · View at Google Scholar · View at Scopus
  24. N. P. Seeram, R. Lee, and D. Heber, “Bioavailability of ellagic acid in human plasma after consumption of ellagitannins from pomegranate (Punica granatum L.) juice,” Clinica Chimica Acta, vol. 348, no. 1-2, pp. 63–68, 2004. View at Publisher · View at Google Scholar · View at Scopus
  25. N. P. Seeram, S. M. Henning, Y. Zhang, M. Suchard, Z. Li, and D. Heber, “Pomegranate juice ellagitannin metabolites are present in human plasma and some persist in urine for up to 48 hours,” Journal of Nutrition, vol. 136, no. 10, pp. 2481–2485, 2006. View at Scopus
  26. A. González-Sarrías, M. Larrosa, F. A. Toms-Barberán, P. Dolara, and J. C. Espín, “NF-κB-dependent anti-inflammatory activity of urolithins, gut microbiota ellagic acid-derived metabolites, in human colonic fibroblasts,” British Journal of Nutrition, vol. 104, no. 4, pp. 503–512, 2010. View at Publisher · View at Google Scholar · View at Scopus
  27. B. Dobroslawa, S. G. Kasimsetty, S. I. Khan, and F. Daneel, “Urolithins, intestinal microbial metabolites of pomegranate ellagitannins, exhibit potent antioxidant activity in a cell-based assay,” Journal of Agricultural and Food Chemistry, vol. 57, no. 21, pp. 10181–10186, 2009. View at Publisher · View at Google Scholar · View at Scopus
  28. N. P. Seeram, Y. Zhang, R. McKeever et al., “Pomegranate juice and extracts provide similar levels of plasma and urinary ellagitannin metabolites in human subjects,” Journal of Medicinal Food, vol. 11, no. 2, pp. 390–394, 2008. View at Publisher · View at Google Scholar · View at Scopus
  29. B. Cerdá, J. C. Espín, S. Parra, P. Martínez, and F. A. Tomás-Barberán, “The potent in vitro antioxidant ellagitannins from pomegranate juice are metabolised into bioavailable but poor antioxidant hydroxy-6H-dibenzopyran-6-one derivatives by the colonic microflora of healthy humans,” European Journal of Nutrition, vol. 43, no. 4, pp. 205–220, 2004. View at Publisher · View at Google Scholar · View at Scopus
  30. B. Cerdá, R. Llorach, J. J. Cerón, J. C. Espín, and F. A. Tomás-Barberán, “Evaluation of the bioavailability and metabolism in the rat of punicalagin, an antioxidant polyphenol from pomegranate juice,” European Journal of Nutrition, vol. 42, no. 1, pp. 18–28, 2003. View at Publisher · View at Google Scholar · View at Scopus
  31. B. Cerdá, J. J. Cerón, F. A. Tomás-Barberán, and J. C. Espín, “Repeated oral administration of high doses of the pomegranate ellagitannin punicalagin to rats for 37 days is not toxic,” Journal of Agricultural and Food Chemistry, vol. 51, no. 11, pp. 3493–3501, 2003. View at Publisher · View at Google Scholar · View at Scopus
  32. S. U. Mertens-Talcott, P. Jilma-Stohlawetz, J. Rios, L. Hingorani, and H. Derendorf, “Absorption, metabolism, and antioxidant effects of pomegranate (Punica granatum L.) polyphenols after ingestion of a standardized extract in healthy human volunteers,” Journal of Agricultural and Food Chemistry, vol. 54, no. 23, pp. 8956–8961, 2006. View at Publisher · View at Google Scholar · View at Scopus
  33. J. C. Espín, R. González-Barrio, B. Cerdá, C. López-Bote, A. I. Rey, and F. A. Tomás-Barberán, “Iberian pig as a model to clarify obscure points in the bioavailability and metabolism of ellagitannins in humans,” Journal of Agricultural and Food Chemistry, vol. 55, no. 25, pp. 10476–10485, 2007. View at Publisher · View at Google Scholar · View at Scopus
  34. N. P. Seeram, W. J. Aronson, Y. Zhang et al., “Pomegranate ellagitannin-derived metabolites inhibit prostate cancer growth and localize to the mouse prostate gland,” Journal of Agricultural and Food Chemistry, vol. 55, no. 19, pp. 7732–7737, 2007. View at Publisher · View at Google Scholar · View at Scopus
  35. A. González-Sarrías, J. A. Giménez-Bastida, M. T. García-Conesa et al., “Occurrence of urolithins, gut microbiota ellagic acid metabolites and proliferation markers expression response in the human prostate gland upon consumption of walnuts and pomegranate juice,” Molecular Nutrition and Food Research, vol. 54, no. 3, pp. 311–322, 2010. View at Publisher · View at Google Scholar · View at Scopus
  36. P. A. Crawford and J. I. Gordon, “Microbial regulation of intestinal radiosensitivity,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 37, pp. 13254–13259, 2005. View at Publisher · View at Google Scholar · View at Scopus
  37. D. Bialonska, P. Ramnani, S. G. Kasimsetty, K. R. Muntha, G. R. Gibson, and D. Ferreira, “The influence of pomegranate by-product and punicalagins on selected groups of human intestinal microbiota,” International Journal of Food Microbiology, vol. 140, no. 2-3, pp. 175–182, 2010. View at Publisher · View at Google Scholar · View at Scopus
  38. G. R. Gibson, “Prebiotics as gut microflora management tools,” Journal of Clinical Gastroenterology, vol. 42, supplement 2, pp. S75–S79, 2008. View at Scopus
  39. R. A. Rastall, G. R. Gibson, H. S. Gill et al., “Modulation of the microbial ecology of the human colon by probiotics, prebiotics and synbiotics to enhance human health: an overview of enabling science and potential applications,” FEMS Microbiology Ecology, vol. 52, no. 2, pp. 145–152, 2005. View at Publisher · View at Google Scholar · View at Scopus
  40. D. Bialonska, S. G. Kasimsetty, K. K. Schrader, and D. Ferreira, “The effect of pomegranate (Punica granatum L.) byproducts and ellagitannins on the growth of human gut bacteria,” Journal of Agricultural and Food Chemistry, vol. 57, no. 18, pp. 8344–8349, 2009. View at Publisher · View at Google Scholar · View at Scopus
  41. A. H. Mokdad, B. A. Bowman, E. S. Ford, F. Vinicor, J. S. Marks, and J. P. Koplan, “The continuing epidemics of obesity and diabetes in the United States,” Journal of the American Medical Association, vol. 286, no. 10, pp. 1195–1200, 2001. View at Scopus
  42. B. Desvergne and W. Wahli, “Peroxisome proliferator-activated receptors: nuclear control of metabolism,” Endocrine Reviews, vol. 20, no. 5, pp. 649–688, 1999. View at Scopus
  43. R. W. Nesto, D. Bell, R. O. Bonow, et al., “Thiazolidinedione use, fluid retention, and congestive heart failure: a consensus statement from the American Heart Association and American Diabetes Association,” Diabetes Care, vol. 27, no. 1, pp. 256–263, 2004. View at Publisher · View at Google Scholar
  44. K. Katayama, K. Wada, A. Nakajima et al., “A novel PPARγ gene therapy to control inflammation associated with inflammatory bowel disease in a murine model,” Gastroenterology, vol. 124, no. 5, pp. 1315–1324, 2003. View at Publisher · View at Google Scholar · View at Scopus
  45. L. Dubuquoy, E. Å Jansson, S. Deeb et al., “Impaired expression of peroxisome proliferator-activated receptor γin ulcerative colitis,” Gastroenterology, vol. 124, no. 5, pp. 1265–1276, 2003. View at Publisher · View at Google Scholar · View at Scopus
  46. T. Ogata, T. Miyauchi, S. Sakai, Y. Irukayama-Tomobe, K. Goto, and I. Yamaguchi, “Stimulation of peroxisome-proliferator-activated receptor α (PPARα) attenuates cardiac fibrosis and endothelin-1 production in pressure-overloaded rat hearts,” Clinical Science, vol. 103, supplement 48, pp. 284S–288S, 2002. View at Scopus
  47. S. C. Hsu and C. J. Huang, “Changes in liver PPARα mRNA expression in response to two levels of high-safflower-oil diets correlate with changes in adiposity and serum leptin in rats and mice,” Journal of Nutritional Biochemistry, vol. 18, no. 2, pp. 86–96, 2007. View at Publisher · View at Google Scholar · View at Scopus
  48. R. A. Daynes and D. C. Jones, “Emerging roles of PPARs in inflammation and immunity,” Nature Reviews Immunology, vol. 2, no. 10, pp. 748–759, 2002. View at Publisher · View at Google Scholar · View at Scopus
  49. D. J. Mangelsdorf, C. Thummel, M. Beato et al., “The nuclear receptor super-family: the second decade,” Cell, vol. 83, no. 6, pp. 835–839, 1995. View at Scopus
  50. G. Chinetti, S. Lestavel, V. Bocher et al., “PPAR-α and PPAR-γ activators induce cholesterol removal from human macrophage foam cells through stimulation of the ABCA1 pathway,” Nature Medicine, vol. 7, no. 1, pp. 53–58, 2001. View at Publisher · View at Google Scholar · View at Scopus
  51. B. H. Park, B. Vogelstein, and K. W. Kinzler, “Genetic disruption of PPARδ decreases the tumorigenicity of human colon cancer cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 5, pp. 2598–2603, 2001. View at Publisher · View at Google Scholar · View at Scopus
  52. M. Ricote, A. C. Li, T. M. Willson, C. J. Kelly, and C. K. Glass, “The peroxisome proliferator-activated receptor-γ is a negative regulator of macrophage activation,” Nature, vol. 391, no. 6662, pp. 79–82, 1998. View at Publisher · View at Google Scholar · View at Scopus
  53. W. Wahli, “A gut feeling of the PXR, PPAR and NF-κB connection,” Journal of Internal Medicine, vol. 263, no. 6, pp. 613–619, 2008. View at Publisher · View at Google Scholar · View at Scopus
  54. J. Bassaganya-Riera, K. Reynolds, S. Martino-Catt et al., “Activation of PPAR γ and δ by conjugated linoleic acid mediates protection from experimental inflammatory bowel disease,” Gastroenterology, vol. 127, no. 3, pp. 777–791, 2004. View at Publisher · View at Google Scholar · View at Scopus
  55. J. Bassaganya-Riera, A. J. Guri, and R. Hontecillas, “Treatment of obesity-related complications with novel classes of naturally occurring PPAR agonists,” Journal of Obesity, vol. 2011, Article ID 897894, 7 pages, 2011. View at Publisher · View at Google Scholar
  56. J. D. Lewis, G. R. Lichtenstein, J. J. Deren et al., “Rosiglitazone for active ulcerative colitis: a randomized placebo-controlled trial,” Gastroenterology, vol. 134, no. 3, pp. 688–695, 2008. View at Publisher · View at Google Scholar · View at Scopus
  57. T. A. Elasy and M. Griffin, “Thiazolidinedione use, fluid retention, and congestive heart failure: a consensus statement from the American Heart Association and American Diabetes Association: response to Nesto,” Diabetes Care, vol. 27, no. 8, article 2096, 2004. View at Scopus
  58. J. Bassaganya-Riera, M. Viladomiu, M. Pedragosa, et al., “Probiotic bacteria produce conjugated linoleic acid locally in the gut that targets macrophage PPAR gamma to suppress colitis,” PLoS One, vol. 7, no. 2, Article ID e31238, 2012.
  59. S. N. Lewis, L. Brannan, A. J. Guri, et al., “Dietary alpha-eleostearic acid ameliorates experimental inflammatory bowel disease in mice by activating peroxisome proliferator-activated receptor-gamma,” PLoS One, vol. 6, no. 8, Article ID e24031, 2011.
  60. J. Bassaganya-Riera, M. DiGuardo, M. Climent, et al., “Activation of PPARgamma and delta by dietary punicic acid ameliorates intestinal inflammation in mice,” British Journal of Nutrition, vol. 106, no. 6, pp. 878–886, 2011.
  61. A. Tenenbaum, M. Motro, and E. Z. Fisman, “Dual and pan-peroxisome proliferator-activated receptors (PPAR) co-agonism: the bezafibrate lessons,” Cardiovascular Diabetology, vol. 4, article 14, 2005. View at Publisher · View at Google Scholar · View at Scopus
  62. R. Hontecillas, M. O'Shea, A. Einerhand, M. Diguardo, and J. Bassaganya-Riera, “Activation of PPAR γ and α by punicic acid ameliorates glucose tolerance and suppresses obesity-related inflammation,” Journal of the American College of Nutrition, vol. 28, no. 2, pp. 184–195, 2009. View at Scopus
  63. T. Boussetta, H. Raad, P. Lettéron et al., “Punicic acid a conjugated linolenic acid inhibits TNFα-induced neutrophil hyperactivation and protects from experimental colon inflammation in rats,” PLoS ONE, vol. 4, no. 7, Article ID e6458, 2009. View at Publisher · View at Google Scholar · View at Scopus
  64. B. K. McFarlin, K. A. Strohacker, and M. L. Kueht, “Pomegranate seed oil consumption during a period of high-fat feeding reduces weight gain and reduces type 2 diabetes risk in CD-1 mice,” British Journal of Nutrition, vol. 102, no. 1, pp. 54–59, 2009. View at Publisher · View at Google Scholar · View at Scopus
  65. R. Hontecillas, M. Diguardo, E. Duran, M. Orpi, and J. Bassaganya-Riera, “Catalpic acid decreases abdominal fat deposition, improves glucose homeostasis and upregulates PPAR α expression in adipose tissue,” Clinical Nutrition, vol. 27, no. 5, pp. 764–772, 2008. View at Publisher · View at Google Scholar · View at Scopus
  66. E. Aasum, D. D. Belke, D. L. Severson et al., “Cardiac function and metabolism in type 2 diabetic mice after treatment with BM 17.0744, a novel PPAR-α activator,” American Journal of Physiology, vol. 283, no. 3, pp. H949–H957, 2002. View at Scopus
  67. A. Jang, P. Srinivasan, N. Y. Lee et al., “Comparison of hypolipidemic activity of synthetic gallic acid-linoleic acid ester with mixture of gallic acid and linoleic acid, gallic acid, and linoleic acid on high-fat diet induced obesity in C57BL/6 Cr Slc mice,” Chemico-Biological Interactions, vol. 174, no. 2, pp. 109–117, 2008. View at Publisher · View at Google Scholar · View at Scopus
  68. A. Esmaillzadeh, F. Tahbaz, I. Gaieni, H. Alavi-Majd, and L. Azadbakht, “Cholesterol-lowering effect of concentrated pomegranate juice consumption in type II diabetic patients with hyperlipidemia,” International Journal for Vitamin and Nutrition Research, vol. 76, no. 3, pp. 147–151, 2006. View at Publisher · View at Google Scholar · View at Scopus
  69. A. Esmaillzadeh, F. Tahbaz, I. Gaieni, H. Alavi-Majd, and L. Azadbakht, “Concentrated pomegranate juice improves lipid profiles in diabetic patients with hyperlipidemia,” Journal of Medicinal Food, vol. 7, no. 3, pp. 305–308, 2004. View at Publisher · View at Google Scholar · View at Scopus
  70. J. Bassaganya-Riera, S. Misyak, A. J. Guri, and R. Hontecillas, “PPARγ is highly expressed in F4/80hi adipose tissue macrophages and dampens adipose-tissue inflammation,” Cellular Immunology, vol. 258, no. 2, pp. 138–146, 2009. View at Publisher · View at Google Scholar · View at Scopus
  71. A. J. Guri, R. Hontecillas, G. Ferrer et al., “Loss of PPARγ in immune cells impairs the ability of abscisic acid to improve insulin sensitivity by suppressing monocyte chemoattractant protein-1 expression and macrophage infiltration into white adipose tissue,” Journal of Nutritional Biochemistry, vol. 19, no. 4, pp. 216–228, 2008. View at Publisher · View at Google Scholar · View at Scopus
  72. B. Fuhrman, N. Volkova, and M. Aviram, “Pomegranate juice inhibits oxidized LDL uptake and cholesterol biosynthesis in macrophages,” Journal of Nutritional Biochemistry, vol. 16, no. 9, pp. 570–576, 2005. View at Publisher · View at Google Scholar · View at Scopus
  73. M. Rosenblat, T. Hayek, and M. Aviram, “Anti-oxidative effects of pomegranate juice (PJ) consumption by diabetic patients on serum and on macrophages,” Atherosclerosis, vol. 187, no. 2, pp. 363–371, 2006. View at Publisher · View at Google Scholar · View at Scopus
  74. M. Aviram, L. Dornfeld, M. Rosenblat et al., “Pomegranate juice consumption reduces oxidative stress, atherogenic modifications to LDL, and platelet aggregation: studies in humans and in atherosclerotic apolipoprotein E-deficient mice,” American Journal of Clinical Nutrition, vol. 71, no. 5, pp. 1062–1076, 2000. View at Scopus
  75. M. Aviram, L. Dornfeld, M. Kaplan et al., “Pomegranate juice flavonoids inhibit low-density lipoprotein oxidation and cardiovascular diseases: studies in atherosclerotic mice and in humans,” Drugs under Experimental and Clinical Research, vol. 28, no. 2-3, pp. 49–62, 2002. View at Scopus
  76. M. Shiner, B. Fuhrman, and M. Aviram, “Macrophage paraoxonase 2 (PON2) expression is up-regulated by pomegranate juice phenolic anti-oxidants via PPARγ and AP-1 pathway activation,” Atherosclerosis, vol. 195, no. 2, pp. 313–321, 2007. View at Publisher · View at Google Scholar · View at Scopus
  77. H. S. Parmar and A. Kar, “Medicinal values of fruit peels from Citrus sinensis, Punica granatum, and Musa paradisiaca with respect to alterations in tissue lipid peroxidation and serum concentration of glucose, insulin, and thyroid hormones,” Journal of Medicinal Food, vol. 11, no. 2, pp. 376–381, 2008. View at Publisher · View at Google Scholar · View at Scopus
  78. H. S. Parmar and A. Kar, “Antidiabetic potential of Citrus sinensis and Punica granatum peel extracts in alloxan treated male mice,” BioFactors, vol. 31, no. 1, pp. 17–24, 2007. View at Publisher · View at Google Scholar · View at Scopus
  79. V. M. Abazov, B. Abbott, M. Abolins et al., “Search for neutral higgs bosons in Multi-b-Jet events in pp¯ collisions at s=1.96TeV,” Physical Review Letters, vol. 101, no. 22, Article ID 221802, 2008. View at Publisher · View at Google Scholar · View at Scopus
  80. W. Rock, M. Rosenblat, R. Miller-Lotan, A. P. Levy, M. Elias, and M. Aviram, “Consumption of Wonderful variety pomegranate juice and extract by diabetic patients increases paraoxonase 1 association with high-density lipoprotein and stimulates its catalytic activities,” Journal of Agricultural and Food Chemistry, vol. 56, no. 18, pp. 8704–8713, 2008. View at Publisher · View at Google Scholar · View at Scopus
  81. S. Medjakovic and A. Jungbauer, “Pomegranate: a fruit that ameliorates metabolic syndrome,” Food & Function, vol. 194, no. 1, pp. 19–39, 2013. View at Publisher · View at Google Scholar
  82. A. Nakajima, K. Wada, K. Katayama et al., “Gene expression profile after peroxisome proliferator activator receptor-γ ligand administration in dextran sodium sulfate mice,” Journal of Gastroenterology, vol. 37, supplement 14, pp. 62–66, 2002. View at Scopus
  83. E. M. Carlisle, V. Poroyko, M. S. Caplan, J. A. Alverdy, and D. Liu, “Gram negative bacteria are associated with the early stages of necrotizing enterocolitis,” PLoS ONE, vol. 6, no. 3, Article ID e18084, 2011. View at Publisher · View at Google Scholar · View at Scopus
  84. M. J. Morowitz, V. Poroyko, M. Caplan, J. Alverdy, and D. C. Liu, “Redefining the role of intestinal microbes in the pathogenesis of necrotizing enterocolitis,” Pediatrics, vol. 125, no. 4, pp. 777–785, 2010. View at Publisher · View at Google Scholar · View at Scopus
  85. C. M. M. W. Meijer, J. E. Degener, and G. Dzoljic Danilovic, “Quantitative study of the aerobic and anaerobic faecal flora in neonatal necrotising enterocolitis,” Archives of Disease in Childhood, vol. 58, no. 7, pp. 523–528, 1983. View at Scopus
  86. C. Hoy, M. R. Millar, P. MacKay, P. G. R. Godwin, V. Langdale, and M. I. Levene, “Quantitative changes in faecal microflora preceding necrotising enterocolitis in premature neonates,” Archives of Disease in Childhood, vol. 65, no. 10, pp. 1057–1059, 1990. View at Scopus
  87. V. Mai, C. M. Young, M. Ukhanova et al., “Fecal microbiota in premature infants prior to necrotizing enterocolitis,” PLoS ONE, vol. 6, no. 6, Article ID e20647, 2011. View at Publisher · View at Google Scholar · View at Scopus
  88. C. F. Coursodon-Boyiddle, C. L. Snarrenberg, C. K. Adkins-Rieck, et al., “Pomegranate seed oil reduces intestinal damage in a rat model of necrotizing enterocolitis,” American Journal of Physiology, vol. 303, no. 6, pp. G744–G751, 2012. View at Publisher · View at Google Scholar
  89. A. Jemal, R. Siegel, E. Ward et al., “Cancer statistics, 2008,” CA Cancer Journal for Clinicians, vol. 58, no. 2, pp. 71–96, 2008. View at Publisher · View at Google Scholar · View at Scopus
  90. J. A. Eaden, K. R. Abrams, and J. F. Mayberry, “The risk of colorectal cancer in ulcerative colitis: a meta-analysis,” Gut, vol. 48, no. 4, pp. 526–535, 2001. View at Publisher · View at Google Scholar · View at Scopus
  91. P. Munkholm, “Review article: the incidence and prevalence of colorectal cancer in inflammatory bowel disease,” Alimentary Pharmacology and Therapeutics, vol. 18, supplement 2, pp. 1–5, 2003. View at Scopus
  92. M. Albrecht, W. Jiang, J. Kumi-Diaka et al., “Pomegranate extracts potently suppress proliferation, xenograft growth, and invasion of human prostate cancer cells,” Journal of Medicinal Food, vol. 7, no. 3, pp. 274–283, 2004. View at Publisher · View at Google Scholar · View at Scopus
  93. A. Malik and H. Mukhtar, “Prostate cancer prevention through pomegranate fruit,” Cell Cycle, vol. 5, no. 4, pp. 371–373, 2006. View at Scopus
  94. A. Malik, F. Afaq, S. Sarfaraz, V. M. Adhami, D. N. Syed, and H. Mukhtar, “Pomegranate fruit juice for chemoprevention and chemotherapy of prostate cancer,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 41, pp. 14813–14818, 2005. View at Publisher · View at Google Scholar · View at Scopus
  95. L. S. Meei, F. C. Kuo, J. S. Yen, W. L. Wan, Y. L. S. Shoei, and H. L. Shing, “Activation of phosphoinositide 3-kinase in response to inflammation and nitric oxide leads to the up-regulation of cyclooxygenase-2 expression and subsequent cell proliferation in mesangial cells,” Cellular Signalling, vol. 17, no. 8, pp. 975–984, 2005. View at Publisher · View at Google Scholar · View at Scopus
  96. L. S. Adams, N. P. Seeram, B. B. Aggarwal, Y. Takada, D. Sand, and D. Heber, “Pomegranate juice, total pomegranate ellagitannins, and punicalagin suppress inflammatory cell signaling in colon cancer cells,” Journal of Agricultural and Food Chemistry, vol. 54, no. 3, pp. 980–985, 2006. View at Publisher · View at Google Scholar · View at Scopus
  97. S. Shukla and S. Gupta, “Molecular mechanisms for apigenin-induced cell-cycle arrest and apoptosis of hormone refractory human prostate carcinoma DU145 cells,” Molecular Carcinogenesis, vol. 39, no. 2, pp. 114–126, 2004. View at Publisher · View at Google Scholar · View at Scopus
  98. H. Matsuura, M. Sakaue, K. Subbaramaiah et al., “Regulation of cyclooxygenase-2 by interferon γ and transforming growth factor α in normal human epidermal keratinocytes and squamous carcinoma cells. Role of mitogen-activated protein kinases,” Journal of Biological Chemistry, vol. 274, no. 41, pp. 29138–29148, 1999. View at Publisher · View at Google Scholar · View at Scopus
  99. K. Subbaramaiah and A. J. Dannenberg, “Cyclooxygenase 2: a molecular target for cancer prevention and treatment,” Trends in Pharmacological Sciences, vol. 24, no. 2, pp. 96–102, 2003. View at Publisher · View at Google Scholar · View at Scopus
  100. F. Afaq, M. Saleem, C. G. Krueger, J. D. Reed, and H. Mukhtar, “Anthocyanin- and hydrolyzable tannin-rich pomegranate fruit extract modulates MAPK and NF-κB pathways and inhibits skin tumorigenesis in CD-1 mice,” International Journal of Cancer, vol. 113, no. 3, pp. 423–433, 2005. View at Publisher · View at Google Scholar · View at Scopus
  101. S. Y. Schubert, E. P. Lansky, and I. Neeman, “Antioxidant and eicosanoid enzyme inhibition properties of pomegranate seed oil and fermented juice flavonoids,” Journal of Ethnopharmacology, vol. 66, no. 1, pp. 11–17, 1999. View at Publisher · View at Google Scholar · View at Scopus
  102. T. Okamoto, T. Akuta, F. Tamura, A. van der Vliet, and T. Akaike, “Molecular mechanism for activation and regulation of matrix metalloproteinases during bacterial infections and respiratory inflammation,” Biological Chemistry, vol. 385, no. 11, pp. 997–1006, 2004. View at Publisher · View at Google Scholar · View at Scopus
  103. S. Ahmed, N. Wang, B. B. Hafeez, V. K. Cheruvu, and T. M. Haqqi, “Punica granatum L. extracts inhibits IL-1β-induced expression of matrix metalloproteinases by inhibiting the activation of MAP kinases and NF-κB in human chondrocytes in vitro,” Journal of Nutrition, vol. 135, no. 9, pp. 2096–2102, 2005. View at Scopus
  104. D. Heber, “Multitargeted therapy of cancer by ellagitannins,” Cancer Letters, vol. 269, no. 2, pp. 262–268, 2008. View at Publisher · View at Google Scholar · View at Scopus
  105. E. M. Conner and M. B. Grisham, “Inflammation, free radicals and antioxidants,” Nutrition, vol. 12, no. 4, pp. 274–277, 1996. View at Publisher · View at Google Scholar · View at Scopus
  106. Z. Rasheed, N. Akhtar, A. N. Anbazhagan, S. Ramamurthy, M. Shukla, and T. M. Haqqi, “Polyphenol-rich pomegranate fruit extract (POMx) suppresses PMACI-induced expression of pro-inflammatory cytokines by inhibiting the activation of MAP kinases and NF-κB in human KU812 cells,” Journal of Inflammation, vol. 6, article 1, 2009. View at Publisher · View at Google Scholar · View at Scopus
  107. M. Larrosa, A. González-Sarrías, M. J. Yáñez-Gascón et al., “Anti-inflammatory properties of a pomegranate extract and its metabolite urolithin-A in a colitis rat model and the effect of colon inflammation on phenolic metabolism,” Journal of Nutritional Biochemistry, vol. 21, no. 8, pp. 717–725, 2010. View at Publisher · View at Google Scholar · View at Scopus
  108. M. Toi, H. Bando, C. Ramachandran et al., “Preliminary studies on the anti-angiogenic potential of pomegranate fractions in vitro and in vivo,” Angiogenesis, vol. 6, no. 2, pp. 121–128, 2003. View at Publisher · View at Google Scholar · View at Scopus
  109. H. Kohno, R. Suzuki, Y. Yasui, M. Hosokawa, K. Miyashita, and T. Tanaka, “Pomegranate seed oil rich in conjugated linolenic acid suppresses chemically induced colon carcinogenesis in rats,” Cancer Science, vol. 95, no. 6, pp. 481–486, 2004. View at Publisher · View at Google Scholar · View at Scopus
  110. C. Patel, P. Dadhaniya, L. Hingorani, and M. G. Soni, “Safety assessment of pomegranate fruit extract: acute and subchronic toxicity studies,” Food and Chemical Toxicology, vol. 46, no. 8, pp. 2728–2735, 2008. View at Publisher · View at Google Scholar · View at Scopus
  111. I. A. Meerts, C. M. Verspeek-Rip, C. A. Buskens, et al., “Toxicological evaluation of pomegranate seed oil,” Food and Chemical Toxicology, vol. 47, no. 6, pp. 1085–1092, 2009.
  112. D. Heber, N. P. Seeram, H. Wyatt et al., “Safety and antioxidant activity of a pomegranate ellagitannin-enriched polyphenol dietary supplement in overweight individuals with increased waist size,” Journal of Agricultural and Food Chemistry, vol. 55, no. 24, pp. 10050–10054, 2007. View at Publisher · View at Google Scholar · View at Scopus
  113. M. Nagata, M. Hidaka, H. Sekiya et al., “Effects of pomegranate juice on human cytochrome P450 2C9 and tolbutamide pharmacokinetics in rats,” Drug Metabolism and Disposition, vol. 35, no. 2, pp. 302–305, 2007. View at Publisher · View at Google Scholar · View at Scopus
  114. M. Hidaka, M. Okumura, K. I. Fujita et al., “Effects of pomegranate juice on human cytochrome P450 3A (CYP3A) and carbamazepine pharmacokinetics in rats,” Drug Metabolism and Disposition, vol. 33, no. 5, pp. 644–648, 2005. View at Publisher · View at Google Scholar · View at Scopus
  115. A. Faria, R. Monteiro, I. Azevedo, and C. Calhau, “Pomegranate juice effects on cytochrome p450s expression: in vivo studies,” Journal of Medicinal Food, vol. 10, no. 4, pp. 643–649, 2007. View at Publisher · View at Google Scholar · View at Scopus
  116. H. Kim, Y. J. Yoon, J. H. Shon, I. J. Cha, J. G. Shin, and K. H. Liu, “Inhibitory effects of fruit juices on CYP3A activity,” Drug Metabolism and Disposition, vol. 34, no. 4, pp. 521–523, 2006. View at Publisher · View at Google Scholar · View at Scopus
  117. G. Klebe, “Virtual ligand screening: strategies, perspectives and limitations,” Drug Discovery Today, vol. 11, no. 13-14, pp. 580–594, 2006. View at Publisher · View at Google Scholar · View at Scopus
  118. P. Lu, R. Hontecillas, W. T. Horne, et al., “Computational modeling-based discovery of novel classes of anti-inflammatory drugs that target lanthionine synthetase C-like protein 2,” PLoS One, vol. 7, no. 4, Article ID e34643, 2012.
  119. B. K. Shoichet, “Virtual screening of chemical libraries,” Nature, vol. 432, no. 7019, pp. 862–865, 2004. View at Publisher · View at Google Scholar · View at Scopus
  120. S. N. Lewis, J. Bassaganya-Riera, and D. R. Bevan, “Virtual screening as a technique for PPAR modulator discovery,” PPAR Research, vol. 2010, Article ID 861238, 10 pages, 2010.