Microbiology and Biotechnology Letters (한국미생물·생명공학회지)

The Korean Society for Microbiology and Biotechnology (한국미생물·생명공학회)
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Pomegranate (Punica granatum) as Resources of Phytoestrogen and Anticancer Substances.

석류(Punica granatum)의 Phytoestrogen 및 항암 활성 성분

  • Song, Bang-Ho (Department of Biology Education, Kyungpook National University) ;
  • Tran, Hoang Ngoc Ai (Department of Biology Education, Kyungpook National University) ;
  • Bae, Soo-Young (Department of Biology Education, Kyungpook National University)
  • Published : 2007.06.28
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Abstract

Punica granatum, L. (Pomegranate) has 613 seeds which accidentally corresponds to the 613 commandments in the Bible. Accordingly, the fruit has been worshipped by the Jewish and other religious people from the ancient. Pomegranate's seed, peel and juice contain a variety of ethnomedical components so much as the sum of three kinds of other common fruits. The number of published papers related to the pomegranate in recent 7 years flourished 7 times more than before at the bases of Medline record. Since the containments of estrogen, as $17{\alpha}-estradiol,\;17{\beta}-estradiol$, estrone, and estradiol, etc., in pomegranate have been reported, public interests and commercial values of pomegranate arose considerably. The report was disproved later, however, merits of this fruit remained yet; clinical efficacy for preventing and remediating cancers including breast and prostate cancers by oral administration of the juice, seed oil, and peel extract is still believed to be true. In this review, target components of pomegranate such as antioxidants, anticancers, antiestrogens and ethnomedical components were analyzed and discussed along with examining its pharmaceutical efficacy and prescription to postmenopausal lesion, cardiosclerosis, cosmetic beautification, viral and allergic symptoms, and diabetes mellitus, etc.

Keywords

References

  1. 강춘기. 1990. 우리나라 과실류의 역사적 고찰, Korean. J. Dietary Culture, 5:301-312
  2. 김학규, 노치웅, 정병만, 하용근, 신원교. 1994. 석류재배실태조사 및 우량품종 수집(과수재배 및 품질향상 연구), 농진청 보고서. pp. 448-450
  3. 이성우, 김광수, 김순동. 1974. 석류과실의 성숙에 따른 성분변화에 관한 연구 I, II, J. Kor. Soc. Hort. Sci., 15: 57-71
  4. Afaq, F., A. Malik, D. Syed, D. Maes, M. S. Matsui, and H. Mukhtar. 2005. Pomegranate fruit extract modulates UV-B-mediated phosphorylation of mitogen-activated protein kinases and activation of NF-${\kappa}$B in normal human epidermal keratinocytes paragraph sign. Photochem. and Photobiol. 81: 38-45 https://doi.org/10.1562/2004-08-06-RA-264.1
  5. Afaq, F., M. Saleem, C. G Krueger, J. D. Reed, and H. Mukhtar. 2005. Anthocyanin-and hydrolyzable tannin-rich pomegranate fruit extract modulates MAPK and NF-kB pathways and inhibits skin tumorigenesis in CD-1 mice. Int. J. Cancer 113: 423-433 https://doi.org/10.1002/ijc.20587
  6. Aggarwal, B. B. and S. Shishodia. 2006. Molecular targets of dietary agents for prevention and therapy of cancer. Biochem Pharmacol. 71: 1397-1421 https://doi.org/10.1016/j.bcp.2006.02.009
  7. Ajaikumar, K. B., M. Asheef, B. H. Babu, and J. Padikkala. 2005. The inhibition of gastric mucosal injury by Punica granatum L. (pomegranate) methanolic extract. J. Ethno-Pharmacol. 96: 171-176 https://doi.org/10.1016/j.jep.2004.09.007
  8. Albertazzi, P. and D. W. Purdie. 2001. The life and times of the estrogen receptors: an interim report. Climacteric 4: 194-202 https://doi.org/10.1080/713605097
  9. Albrecht, M., W. Jiang, J. Kumi-Diaka, E. P. Lansky, L. M. Gommersall, A. Patel, R. E. Mansel, I. Neeman, A. A. Geldof, and M. J. Campbell. 2004. Pomegranate extracts potently suppress proliferation, xenograft growth, and invasion of human prostate cancer cells. J. Med. Food 7: 274-283 https://doi.org/10.1089/jmf.2004.7.274
  10. Aslam, M. N., H. Fligiel, H. Lateef, G. J. Fisher, I. Ginsburg, and J. Varani. 2005. PADMA28: a multi-component herbal preparation with retinoid-like dermal activity but without epidermal effects. J. Invest. Dermatol. 124: 524-529 https://doi.org/10.1111/j.0022-202X.2004.23596.x
  11. Aviram, M., M. Rosenblat, D. Gaitini, S. Nitecki, A. Hoffman, L. Dornfeld, N. Volkova, D. Presser, J. Attias, H. Liker, and T. Hayek. 2004. Pomegranate juice consumption for 3 years by patients with carotid artery stenosis reduces common carotid intima-media thickness, blood pressure and LDL oxidation. Clin. Nutr. 23: 423-433 https://doi.org/10.1016/j.clnu.2003.10.002
  12. Azadzoi, K. M., R. N. Schulman, M. Aviram, and M. B. Siroky. 2005. Oxidative stress in arteriogenic erectile dysfunction: prophylactic role of antioxidants. J. Urol. 174: 386-393 https://doi.org/10.1097/01.ju.0000161209.39959.67
  13. Bachrach, U. 2004. Polyamines and cancer: minireview article. Amino Acids 26: 307-309
  14. Balkwill, F., K. A. Charles, and A. Mantovani. 2005. Smoldering inflammation in the initiation and promotion of malignant disease. Cancer Cell 7: 211-217 https://doi.org/10.1016/j.ccr.2005.02.013
  15. Bouker, K. B. and L. Hilakivi-Clarke. 2000. Genistein: does it prevent or promote breast cancer? Environ. Health Perspect. 108: 701-708 https://doi.org/10.2307/3434722
  16. Cerda, B., C. Soto, M. D. Albaladejo, P. Martinez, F. Sanchez-Gascon, F. Tomas-Barberan, and J. C. Espin. 2006. Pomegranate juice supplementation in chronic obstructive pulmonary disease: a 5-week randomized, double-blind, placebo-controlled trial. Eur. J. Clin. Nutr. 60: 245-253 https://doi.org/10.1038/sj.ejcn.1602309
  17. Choi, D. W., J. Y. Kim, S. H. Choi, H. S. Jung, H. J. Kim, S. Y. Cho, C. S. Kang, and S. Y. Chang. 2006. Identification of steroid hormones in pomegranate using HPLC and GC-mass spectrometry. Food Chem. 96: 562-571 https://doi.org/10.1016/j.foodchem.2005.03.010
  18. Cowley, S. M., S. Hoare, S. Mosselman, and M. G. Parker. 1997. Estrogen receptors ${\alpha}\;&{\beta}$ form heterodimers on DNA. J. Biol. Chem. 272: 19858-19862 https://doi.org/10.1074/jbc.272.32.19858
  19. Cunningham, D. C., L. Y. Harrison, and T. D. Shultz. 1997. Proliferative responses of normal human mammary and MCF-7 breast cancer cells to linoleic acid, conjugated linoleic acid and eicosanoid synthesis inhibitors in culture. Anticancer Res. 17: 197-203
  20. Deitch, H. R., J. L. Mershon, and K. E. Clark. 2001. Estrogen receptor ${\beta}$ is the predominant isoform expressed in the brain of adult and fetal sheep. Am. J. Obstet. Gynecol. 184: 1077-1079 https://doi.org/10.1067/mob.2001.115223
  21. Esmaillzadeh, A., F. Tahbaz, I. Gaieni, H. Alavi-Majd, and L. Azadbakht. 2004. Concentrated pomegranate juice improves lipid profiles in diabetic patients with hyperlipidemia. J. Med. Food 7: 305-308 https://doi.org/10.1089/jmf.2004.7.305
  22. Fatope, M. O., S. K. Al Burtomani, and Y. Takeda. 2002. Monoacylglycerol from Punica granatum seed oil. J. Agr. Food Chem. 50: 357-360 https://doi.org/10.1021/jf010711w
  23. Folkman, J. 1972. Anti-angiogenesis: new concept for therapy of solid tumors. Annals Surgery 175: 409-416 https://doi.org/10.1097/00000658-197203000-00014
  24. Ghadirian, P., J. M. Ekoe, and J. P. Thouez. 1992. Food habits and esophageal cancer: an overview. Cancer Detect. Prev. 16: 163-168
  25. Grosser, T., S. Fries, and G. A. FitzGerald. 2006. Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities. J. Clin. Invest. 116: 4-15 https://doi.org/10.1172/JCI27291
  26. Halicka, H. D., X. Huang, F. Traganos, M. A. King, W. Dai, and Z. Darzynkiewicz. 2005. Histone H2AX phosphorylation after cell irradiation with UV-B: relationship to cell cycle phase and induction of apoptosis. Cell Cycle 4: 339-345
  27. Halvorsen, B. L., K. Holte, M. C. W. Myhrstad, J. Barikmo, E. Hvattum, S. F. Remberg, A-B. Wold, K. Haffner, H. Baugerod, L. F. Andersen, J. O. Moskaug, D. R. Jr. Jacobs, and R. Blorr hoff. 2002. A systematic screening of total antioxidants in dietary plants. J. Nutr. 132: 461-471
  28. Harris, H. A. 2007. Estrogen receptor: Recent lessons from in vivo studies. Mol. Endocrinol. 21: 1-13 https://doi.org/10.1210/me.2005-0459
  29. Hartman, R. E., A. Shah, A. M. Fagan, K. E. Schwetye, M. Parsadanian, R. N. Schulman, M. B. Firm, and D. M. Holtzman. 2006. Pomegranate juice decreases amyloid load and improves behavior in a mouse model of Alzheimer's disease. Neurobiol Dis. 24: 506-515 https://doi.org/10.1016/j.nbd.2006.08.006
  30. Henry, R. P. and E. R. Swenson. 2000. The distribution and physiological significance of carbonic anhydrase in vertebrate gas exchange organs. Resp. Physiol. 121: 1-12 https://doi.org/10.1016/S0034-5687(00)00110-9
  31. Hora, J. J., E., R. Maydew, E. P. Lansky, and C. Dwivedi. 2003. Chemopreventive effects of pomegranate seed oil on skin tumor development in CD1 mice. J. Med. Food 6: 157-161 https://doi.org/10.1089/10966200360716553
  32. Huang, T H. W., G. Peng, B. P. Kota, G. Q. Li, J. Yamahara, B. D. Rouforalis, and Y. Li. 2005. Anti-diabetic action of Punica granatum flower extract: Activiation of PPAR-r and identification of an active component. Toxicol. Appl. Pharmacol. 207: 160-169 https://doi.org/10.1016/j.taap.2004.12.009
  33. Hwang, H. J., H. J. Park, H. J. Chung, H. Y. Min, E. J. Park, J. Y. Hong, and S. K. Lee. 2006. Inhibitory effects of caffeic acid phenethyl ester on cancer cell metastasis mediated by the down-regulation of matrix metalloproteinase expression in human HT1080 fibrosarcoma cells. J. Nutr. Biochem. 17: 352-362
  34. Ishunina, T. A., F. P. Kruijver, R. Balesar, and D. F. Swaab. 2000. Differential expression of estrogen receptor ${\alpha}$ and ${\beta}$ immunoreacivity in the human supraoptic nucleus in relation to sex and aging. J. Clin. Endocrinol. Metab. 85: 3283-3291 https://doi.org/10.1210/jc.85.9.3283
  35. Jahfar, M., K. K. Vijayan, and P. Azadi. 2003. Studies on a polysaccharide from the fruit rind of Punica granatum. Res. J. Chem. Environ. 7: 43-50
  36. Jensen, E. V., G. Cheng, C, Palmieri, S, Saji, S. Makela, S. Van Noorden, T. Wahlstrom, M. Warner, R. C. Coombes, and J. A. Gustafsson. 2001. Estrogen receptors and proliferation markers in primary and recurrent breast cancer. Proc. Natl. Acad. Sci. USA 98: 15197-15202
  37. Jeune, M.A., J. Kumi-Diaka, and J. Brown. 2005. Anticancer activities of pomegranate extracts and genistein in human breast cancer cells. J. Med. Food 8: 469-475 https://doi.org/10.1089/jmf.2005.8.469
  38. Johar, D., J. C. Roth, G. H. Bay, J. N. Walker, T J. Kroczak, and M. Los. 2004. Inflammatory response, reactive oxygen species, programmed (necrotic-like and apoptotic) cell death and cancer. Rocz. Akad. Med. Bialymst. 49: 31-39
  39. Jung, K.H., M. J. Kim, E. Ha, Y. K. Uhm, H. K. Kim, J. H. Chung, and S. V. Yim. 2006. Suppressive effect of Punica granatum on the production of tumor necrosis factor (Tnf) in BV2 microglial cells. Biol. Pharm. Bull. 29: 1258-1261 https://doi.org/10.1248/bpb.29.1258
  40. Karaer, O., S. Oruc, and F. M. Koyuncu. 2004. Aromatase inhibitors: possible future applications. Acta Obstet. Gynecol. Scand. 83: 699-706 https://doi.org/10.1111/j.0001-6349.2004.00562.x
  41. Kaur, G., Z. Jabbar, M. Athar, and S. Alam. 2006. Punica granatum flower extract possesses potent antioxidant activity and abrogates Fe-NTA induced hepatotoxicity in mice. Food Chem. Toxicol. 44: 984-93 https://doi.org/10.1016/j.fct.2005.12.001
  42. Kawaii, S. and E. P. Lansky. 2004. Differentiation-promoting activity of pomegranate (Punica granatum) fruit extracts in HL-60 human promyelocytic leukemia cells. J. Med. Food 7: 13-18 https://doi.org/10.1089/109662004322984644
  43. Khalifah, R. G. 2003. Reflections on Edsall' s carbonic anhydrase: paradoxes of an ultra fast enzyme. Biophy. Chem. 100: 159-170 https://doi.org/10.1016/S0301-4622(02)00277-6
  44. Kim, M.M. and S. Kim. 2002. Composition for improving oral hygiene containing Punica granatum L. extract. Korean Patent: KR 2002066042
  45. Kim, N.D., R. Mehta, W. Yu, I. Neeman, T Livney, A. Amichay, D. Poirier, P. Nicholls, A. Kirby, W. Jiang, R. Mansel, C. Ramachandran, T. Rabi, B. Kaplan, and E. Lansky. 2002. Chemopreventive and adjuvant therapeutic potential of pomegranate (Punica granatum) for human breast cancer. Breast Cancer Res. Treat. 71: 203-217 https://doi.org/10.1023/A:1014405730585
  46. Kohno, H., R. Suzuki, Y. Yasui, M. Hosokawa, K. Miyashita, and T. Tanaka. 2004. Pomegranate seed oil rich in conjugated linolenic acid suppresses chemically induced colon carcinogenesis in rats. Cancer Science 95: 481-486 https://doi.org/10.1111/j.1349-7006.2004.tb03236.x
  47. Langley, P. 2000. Why a pomegranate? B. M. J. 321: 1153-1154 https://doi.org/10.1136/bmj.321.7269.1153
  48. Lansky, E. P., G. Harrison, P. Froom, and W. G. Jiang. 2005. Pomegranate (Punica granatum) pure chemicals show possible synergistic inhibition of human PC-3 prostate cancer cell invasion across Matrigel. Inves New Drugs 23: 121-122 https://doi.org/10.1007/s10637-005-5856-7
  49. Lansky E. P. and R. A. Newman. 2007. Punica granatum (pomegranate) and its potential for prevention and treatment of inflammation and cancer. J. Ethnopharmacol. 109: 177-206 https://doi.org/10.1016/j.jep.2006.09.006
  50. Lansky, E. P., W. Jiang, H. Mo, L. Bravo, P. Froom, W. Yu, N. M. Harris, I. Neeman, and M. J. Campbell. 2005. Possible synergistic prostate cancer suppression by anatomically discrete pomegranate fractions. Invest. New Drugs 23: 11-20 https://doi.org/10.1023/B:DRUG.0000047101.02178.07
  51. Larrosa, M., F. A. Tomas-Barberan, and J. C. Espin. 2006. The dietary hydrolysable tannin punicalagin releases ellagic acid that induces apoptosis in human colon adenocarcinoma Caco-2 cells by using the mitochondrial pathway. J. Nutr. Biochem. 17: 611-725 https://doi.org/10.1016/j.jnutbio.2005.09.004
  52. Liu, J. and N. Sidell. 2005. Anti-estrogenic Effects of Conjugated Linoleic Acid through Modulation of Estrogen Receptor Phosphorylation.. Breast. Cancer. Res. Treat. 2005 94: 161-169 https://doi.org/10.1007/s10549-005-6942-4
  53. Liu, J., J. E. Burdette, Y. Sun, S. Deng, S. M. Schlecht, W. Zheng, D. Nikolic, G Mahady, R. B. van Breemen, H. H. Fong, J. M. Pezzuto, J. L. Bolton, and N. R. Farnsworth. 2004. Isolation of linoleic acid as an estrogenic compound from the fruits of V. agnus-castus L. Phytomedicine 11: 18-23 https://doi.org/10.1078/0944-7113-00331
  54. Liu, J., B. Chen, Y. Yang, and X. Wang. 2004. Effect of apoptosis in human mammary cancer (MCF-7) cells induced by cis9, tll-conjugated linoleic acid. Wei Sheng Yan Jiu. 33: 58-62
  55. Lloyd, J. U. 1897. Punica granatum. The Western Druggist, Chicago, May, 8 pp1-9. Reprinted at http://www.swsbm.com/ManualsOther/Punica granatum-Lloyd. PDF
  56. Longtin, R. 2003. The pomegranate: nature's power fruit? J. Natl. Cancer Inst. 95: 346-348 https://doi.org/10.1093/jnci/95.5.346
  57. Loren, D. J., N. P. Seeram, R. N. Schulman, and D. M. Holtzman. 2005. Maternal dietary supplementation with pomegranate juice is neuroprotective in an animal model of neonatal hypoxic-ischemic brain injury. Pediatr Res. 57: 858-864 https://doi.org/10.1203/01.PDR.0000157722.07810.15
  58. Malik, A., F. Afaq, S. Sarfaraz, V. M. Adhami, D. N. Syed, and H. Mukhtar. 2005. Pomegranate fruit juice for chemoprevention and chemotherapy of prostate cancer. Proc. Natl. Acad Sci. USA 102: 14813-14818
  59. Manas, E. S., R. J. Unwalla, Z. B. Xu, M. S. Malamas, C. P. Miller, H. A. Harris, C. Hsiao, T. Akopian, W. T. Hum, K. Malakian, S. Wolfrom, A. Bapat, R. A. Bhat, M. L. Stahl, W. S. Somers, and J. C. Alvarez. 2004. Structure-based design of estrogen receptor-${\beta}$ selective ligands. J. Am. Chem. Soc. 126: 15106-15119 https://doi.org/10.1021/ja047633o
  60. Maru, I., J. Ohnishi, S. Yamaguchi, Y. Oda, K. Kakehi, and Y. Ohta. 2001. An estrogen-like activity in pomegranate juice. Nippon Shokuhin Kagaku Kogaku Kaishi 48: 146-149 https://doi.org/10.3136/nskkk.48.146
  61. Mehta, R. and E. P. Lansky. 2004. Breast cancer chemopreventive properties of pomegranate (Punica granatum) fruit extracts in a mouse mammary organ culture. Eur. J. Cancer Prev. 13: 345-348 https://doi.org/10.1097/01.cej.0000136571.70998.5a
  62. Miguel, G., C. Fontes, D. Antunes, A. Neves, and D. Martins. 2004. Anthocyanin concentration of 'Assaria' pomegranate fruits during different cold storage conditions. J. Biomed Biotechnol. 2004: 338-342 https://doi.org/10.1155/S1110724304403076
  63. Mori-Okamoto, J., Y. Otawara-Hamamoto, H. Yamato, and H. Yoshimura. 2004. Pomegranate extract improves a depressive state and bone properties in menopausal syndrome model ovariectomized mice. J. Ethnopharmacol. 92: 93-101 https://doi.org/10.1016/j.jep.2004.02.006
  64. Mosselman S., J. Polman, R. Dijkema, ER${\beta}$: identification and characterization of a novel human estrogen receptor, FEBS Lett. 392, 49-53, 1996 https://doi.org/10.1016/0014-5793(96)00782-X
  65. Munde, S. S., V. K. Patil, and S. D. Chavan. 1981. Chemical composition of pomegranate (Punica granatum L.) leaves sampled during different stages of crop. Food Farm. Agr. 13: 177-181
  66. Newton, K. M., S. D. Reed, L. Grothaus, K. Ehrlich, J. Guiltinan, E. Ludman, and A. Z. Larcroix. 2005, The Herbal Alternatives for Menopause (HALT) Study: background and study design, Endocrinol. 52: 134-46
  67. Noguchi, K., K. Iwasaki, H. Endo, H. Kondo, M. Shitashige, and I. Ishikawa. 2000. Prostaglandins E2 and I2 downregulate tumor necrosis factor alphainduced intercellular adhesion molecule-1 expression in human oral gingival epithelial cells. Oral Microbiol. Immunol. 15: 299-304 https://doi.org/10.1034/j.1399-302x.2000.150505.x
  68. Ozcal, N. and S. Dine, 1993. Evaluation of the pomegranate (Punica granatum L.) peels from the standpoint of pharmacy. Eczacilik Fakultesi Dergisi 22: 21-29
  69. Palmieri, C., G J. Cheng, S. Saji, M. Zelada-Hedman, A. Warri, Z. Weihua, S. Van Noorden, T. Wahlstrom, R. C. Coombes, M. Warner, and J. A. Gustafsson. 2002. Estrogen receptor ${\beta}$ in breast cancer. Endocr. Relat. Cancer. 9: 1-13 https://doi.org/10.1677/erc.0.0090001
  70. Pantuck, A. J., J. T. Leppert, N. Zomorodian, W. Aronson, J. Hong, R. J. Barndard, M. Seera, H. Liker, H. Wang, R. Elashoff, D. Heber, M. Aviram, L. Ignarro, and A. Belldegrun. 2006. Phase II study of pomegranate juice for men with rising prostate-specific antigen following surgery or radiation for prostate cancer. Clin. Cancer Res. 12: 4018-4026 https://doi.org/10.1158/1078-0432.CCR-05-2290
  71. Pantuck, A. J., N. Zomorodian, and A. S. Belldegrun. 2006. Phase-II study of pomegranate juice for men with prostate cancer and increasing PSA. Cur. Urol. Rep. 7: 7
  72. Pastorekova, S., S. Parkkila, J. Pastorek, and C. T. Supuran. 2004. Carbonic anhydrases: current state of the art, therapeutic applications and future prospects. J. Enzyme Inhib. Med Chem. 19: 199-229 https://doi.org/10.1080/14756360410001689540
  73. Polagruto, J. A., D. D. Schramm, J. F. Wang-Polagruto, L. Lee, and C. L. Keen. 2003. Effects of flavonoid-rich beverages on prostacyclin synthesis in humans and human aortic endothelial cells: association with ex vivo platelet function. J. Med Food 6: 301-308 https://doi.org/10.1089/109662003772519840
  74. Ricci, D., L. Giamperi, A. Bucchini, and D. Fraternale. 2006. Antioxidant activity of Punica granatum fruits. Fitoterapia 77: 310-312 https://doi.org/10.1016/j.fitote.2006.01.008
  75. Salvi, G. E. and N. P. Lang. 2005. Host response modulation in the management of periodontal diseases. J. Clin. Periodontol. 32: 108-129. Comment: J. Clin. Periodontol. 32: Suppl 6: 130-131 https://doi.org/10.1111/j.1600-051X.2005.00785.x
  76. Sastravaha, G., G. Gassmann, P. Sangtherapitikul, and W. D. Grimm. 2005. Adjunctive periodontal treatment with Centella asiatica and Punica granatum extracts in supportive periodontal therapy. J. Int. Acad. Periodontol. 7: 70-79
  77. Satomi, H., K. Umemura, A. Ueno, T. Hatano, T. Okuda, and T. Nora. 1993. Carbonic anhydrase inhibitors from the pericarps of Punica granatum L. Biol. Pharm. Bull. 16: 787-790 https://doi.org/10.1248/bpb.16.787
  78. Schubert, S. Y., E. P. Lansky, and I. Neeman. 1999. Antioxidant and eicosanoid enzyme inhibition properties of pomegranate seed oil and fermented juice flavonoids. J. Ethnopharmacol. 66: 11-17 https://doi.org/10.1016/S0378-8741(98)00222-0
  79. Schubert, S. Y., I. Neeman, and N. Resnick. 2002. A novel mechanism for the inhibition of NF-kappaB activation in vascular endothelial cells by natural antioxidants. FASEB (Fed. Amer. Soc. Exp. Biol.) J. 16: 1931-1933
  80. Seeram, N. P., L. S. Adams, S. M. Henning, Y. Niu, Y. Zhang, M. Ci Nair, and D. Heber. 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: 360-367 https://doi.org/10.1016/j.jnutbio.2005.01.006
  81. Seeram, N. P., L. S. Adams, Y. Zhang, R. Lee, D. Sand, H. S. Scheuller, and D. Heber. 2006. Blackberry, black raspberry, blueberry, cranberry, red raspberry, and strawberry extracts inhibit growth and stimulate apoptosis of human cancer cells in vitro. J. Agric. Food. Chem. 54: 9329-9339 https://doi.org/10.1021/jf061750g
  82. Settheetham, W. and T. Ishida, 1995. Study of genotoxic effects of antidiarrheal medicinal herbs on human cells in vitro. The Southeast Asian J. Trop. Med. Public Health 26: 306-310
  83. Sharaf, A. and S. A. R. Nigm. 1964. The estrogenic activity of pomegranate seed oil, J. Endocrinol. 29: 91-92 https://doi.org/10.1677/joe.0.0290091
  84. Shukla, S. and S. Gupta. 2004. Molecular mechanisms for apigenin-induced cellcycle arrest and apoptosis of hormone refractory human prostate carcinoma DU145 cells. Mol. Carcinog. 39: 114-126 https://doi.org/10.1002/mc.10168
  85. Simmons, D. L. and C. D. Buckley. 2005. Some new, and not so new, antiinflammatory targets. Curr. Opinion Pharmacol. 5: 394-397 https://doi.org/10.1016/j.coph.2005.05.001
  86. Smith, R. G. 2000. The aging process: where are the drug opportunities? Curr. Opin. Chem. Biol. 4: 371-376 https://doi.org/10.1016/S1367-5931(00)00104-6
  87. Song, R. X. and R. J. Santen. 2003. Apoptotic action of estrogen. Apoptosis 8: 55-60 https://doi.org/10.1023/A:1021649019025
  88. Song, B. H., K. S. Song, J. G. Kim, Y. H. Kim, Y. B. Seu, S. Y. Ghim, J. M. Lee, and S. H. Kim. 2005. Development of functional food using Reinforced antioxidants and phytoestrogens from Punica granatum. Final Report for ARPC Project. pp19-100, Ministry of Agriculture, Seoul, Korea
  89. Sushanta, K., A. Banerjee, A. Islam, and S. Banerjee, 2005. The regulatory role of estrogen in carcinogenesis: an overview. Phytopharmaceuticals in Cancer Chemoprevention. pp105-121. CRC Press. U.S.A
  90. Suzuki, R., R. Noguchi, T. Ota, M. Abe, K. Miyashita, and T. Kawada. 2001. Cytotoxic effect of conjugated trienoic fatty acids on mouse tumor and human monocytic leukemia cells. Lipids 36: 477-482 https://doi.org/10.1007/s11745-001-0746-0
  91. Toi, M., H. Bando, C. Ramachandran, S. J. Melnick, A. Imai, R. S. File, R. E. Carr, T. Oikawa, and E. P. Lansky. 2003. Preliminary studies on the anti-angiogenic potential of pomegranate fractions in vitro and in vivo. Angiogenesis 6: 121-128 https://doi.org/10.1023/B:AGEN.0000011802.81320.e4
  92. Tran H. N. A. and B. H. Song. 2005. Existence of ${\alpha}$-eleostearic acid in pomegranate seed oil and its binding activity against $ER{\alpha}\;&\;ER{\beta}$. Proc. KSMCS Int. Symposium. 13: 205-206
  93. Tran H. N. A., S. H. Yoon, Y. S. Bae, and B. H. Song. 2005. Effect of punicic acid in pomegranate seed oil to the human breast cancer cell proliferation. Proc. KSMCS Int. Symposium. 13: 203-204
  94. Tsutsui, T. and I. C. Barrett. 1997. Neoplastic transformation of cultured mammalian cells by estrogens and estrogen like chemicals. Environ. Health. Perspect. 3: 619-624
  95. Tsuzuki, T., M. Igarashi, and T. Miyazawa. 2004. Conjugated eicosapentaenoic acid (EPA) inhibits transplanted tumor growth via membrane lipid peroxidation in nude mice. J. Nutr. 134: 1162-1166
  96. Tsuzuki, T., Y. Tokuyama, M. Igarashi, and T. Miyazawa. 2004. Tumor growth suppression by ${\alpha}$-eleostearic acid, a linolenic acid isomer with a conjugated triene system, via lipid peroxidation. Carcinogenesis. 25: 1417-1425 https://doi.org/10.1093/carcin/bgh109
  97. Vidal, A., A. Fallarero, B. R. Pena, M. E. Medina, B. Gra, F. Rivera, Y. Gutierrez, and P. M. Vuorela. 2003. Studies on the toxicity of Punica granatum L. (punicaceae) whole fruit extracts. J. Ethnopharmacol. 89: 295-300 https://doi.org/10.1016/j.jep.2003.09.001
  98. Wang, R., W. Wang, L. Wang, R. Liu, D. Y Li, and L. Du. 2006. Constituents of the flowers of Punica granatum. Fitoterapia 77: 534-537 https://doi.org/10.1016/j.fitote.2006.06.011
  99. Xu, J., C. J. Guo, J. J. Yang, J. Y. Wei, Y. F. Li, W. Pang, Y. G. Jiang, and S. Cheng. 2005. Intervention of antioxidant system function of aged rats by giving fruit juices with different antioxidant capacities. Zhonghua Yu Fang Yi Xue Za Zhi 39: 80-83
  100. Yasui, Y., M. Hosokawa, H. Kohno, T. Tanaka, and K. Miyashita. 2006. Growth inhibition and apoptosis induction by all-trans-conjugated linolenic acids on human colon cancer cells. Anticancer Res. 26: 1855-1860
  101. Zand, R. S., D. J. Jenkins, and E. P. Diamandis. 2000. Steroid hormone activity of flavonoids and related compounds. Breast Cancer Res. and Treat. 62: 35-49 https://doi.org/10.1023/A:1006422302173
  102. Zhu, B. T., G. Z. Han, J. Y. Shim, Y. Wen, and X. R. Jiang. 2006. Quentitative structure-activity relationship of various endogeneous estrogen metabolites for human $ER{\alpha}\;&\;{\beta}$ subtypes: Insights into the structural determinants favoring a differential subtype binding. Endocrinol. 147: 4132-4150 https://doi.org/10.1210/en.2006-0113
  103. Zhu, Y., Z. Bian, P. Lu, R. H. Karas, L. Bao, D. Cox, J. Hodgin, P. W. Shaul, P. Thoren, O. Smithies, J. A. Gustafsson, and M. E. Mendelsohn. 2002. Abnormal vascular function and hypertension in mice deficient in estrogen receptor ${\beta}$. Science 295: 505-508 https://doi.org/10.1126/science.1065250
  104. Zhu, Y. S., L. Q. Cai, Y. Huang, J. Fish, L. Wang, Z. K. Zhang, and J. L. Imperato-McGinley. 2005. Receptor isoform and ligand-specific modulation of dihydrotestosterone-induced prostate specific antigen gene expression and prostate tumor cell growth by estrogens. J. Androl. 26: 500-510 https://doi.org/10.2164/jandrol.05002