- University Reasearch
Pomegranate Extracts Should be Further Studied for Therapeutic Potential Especially for Influenza Epidemics.
Pomegranate (Punica granatum) purified polyphenol extract inhibits influenza virus and has a synergistic effect with oseltamivir.Haidari M, Ali M, Ward Casscells S 3rd, Madjid M.University of Texas Health Science Center at Houston, USA; Texas Heart Institute, 6770 Bertner Ave., MC 2-255, Houston, TX 77030, USA.
Influenza epidemics cause numerous deaths and millions of hospitalizations each year. Because of the alarming emergence of resistance to anti-influenza drugs, there is a need to identify new naturally occurring antiviral molecules. We tested the hypothesis that pomegranate polyphenol extract (PPE) has anti-influenza properties. Using real time PCR, plaque assay, and TCID 50% hemagglutination assay, we have shown that PPE suppresses replication of influenza A virus in MDCK cells. PPE inhibits agglutination of chicken red blood cells (cRBC) by influenza virus and is virucidal. The single-cycle growth conditions indicated that independent of the virucidal effect PPE also inhibits viral RNA replication. PPE did not alter virus ribonucleoprotein (RNP) entry into nucleus or translocation of virus RNP from nucleus to cytoplasm in MDCK cells. We evaluated four major Polyphenols in PPE (ellagic acid, caffeic acid, luteolin, and punicalagin) and demonstrated that punicalagin is the effective, anti-influenza component of PPE. Punicalagin blocked replication of the virus RNA, inhibited agglutination of chicken RBC's by the virus and had virucidal effects. Furthermore, the combination of PPE and oseltamivir synergistically increased the anti-influenza effect of oseltamivir. In conclusion, PPE inhibited the replication of human influenza A/Hong Kong (H3N2) in vitro. Pomegranate extracts should be further studied for therapeutic and prophylactic potential especially for influenza epidemics and pandemics.
Ellagic Acid May Aid As a Brain CancerTreatment
The inhibition of glioma growth in vitro and in vivo by a chitosan/ellagic acid composite biomaterial. Kim S, Gaber MW, Zawaski JA, Zhang F, Richardson M, Zhang XA, Yang Y.School of Biomedical Engineering and Imaging, University of Tennessee Health Science Center, Memphis, TN 31863, USA.
This study has developed a chitosan-based delivery system to locally administer ellagic acid for brain cancer treatment. We fabricated chitosan/ellagic acid composite films with various concentrations of ellagic acid. In vitro release study was performed by using a UV spectrophotometer, and enzymatic degradation rate was determined by analyzing the increased free amino groups. Viability of brain cancer cells (human U87 glioblastomas and rat C6 glioma cells) was measured via direct and indirect cell culture on the films by MTS assay. Caspase-3 activation, Western blot for p53, and anti-angiogenesis assays were also examined. In the in vivo study, GFP-tagged rat C6 glioma cells were implanted subcutaneously at the right flank region of nude mice and treatments were initiated by implanting the films subcutaneously. Tumor growth was evaluated by measuring tumor volume using a caliper, an ultrasound machine, and an optical imaging system. The chitosan/ellagic acid composite films were enzymatically degradable and exhibited a sustained slow release of ellagic acid. These materials could inhibit the cancer cell growth in an ellagic acid concentration-dependent manner by inducing apoptosis of cancer cells as well as suppressing angiogenesis. These materials also significantly suppressed tumor tissuegrowth in vivo.
Ellagic Acid May Serve as an Effective Therapeutic Agent for Allergic DiseasesDepartment of Anatomy, Chonbuk National University Medical School, Jeonbuk, Republic of Korea.
Ellagic acid is known to have anti-oxidant, anti-carcinogenic and anti-mutagenic effects. However, roles of ellagic acid in the immediate-type allergic reactions have not yet been investigated. In the present study, we have demonstrated that ellagic acid attenuates immunoglobulin (Ig)E-mediated allergic response in mast cells and in vivo. Oral administration of ellagic acid inhibited anti-dinitrophenyl (DNP) IgE-mediated passive cutaneous anaphylaxis. Ellagic acid dose-dependently reduced histamine release and the expression and secretion of pro-inflammatory cytokines, such as tumor necrosis factor-alpha and interleukin-6 in rat peritoneal mast cells (RPMC) activated by anti-DNP IgE. Moreover, ellagic acid suppressed an increase in intracellular calcium ion concentration ([Ca(2+)](i)) in RPMC. Furthermore, ellagic acid decreased the activation of nuclear factor-kappa B (NF-kappaB). Decreased NF-kappaB activity as well as reduced [Ca(2+)](i) might be involved in the inhibitory effect of ellagic acid on the secretory response. Our findings provide possibility that ellagic acid may serve as an effective therapeutic agent for allergic diseases.
Anti-oxidant Efficacy of Ellagic Acid May Be ImprovedEnhanced oral bioavailability and antioxidant profile of ellagic acid by phospholipids.Murugan V, Mukherjee K, Maiti K, Mukherjee PK.
Department of Pharmaceutical Technology, Faculty of Engineering and Technology, School of Natural Product Studies, Jadavpur University, Kolkata, India.
Ellagic acid (EA) has been reported as a potent antioxidant from natural resources with several nutritional benefits. The major disadvantage of this phytoconstituent is its rapid elimination from the body after administration. To overcome this limitation, a novel dietary formulation of EA with phospholipid was developed to investigate the effect of this complex on carbon tetrachloride induced liver damage in rats. The antioxidant activity of the complex (equivalent of EA = 25 and 50 mg/kg of body weight) and free EA (25 and 50 mg/kg of body weight) was evaluated by measuring various enzymes in oxidative stress condition. The complex significantly protected the liver by restoring the activity of superoxide dismutase, catalase and liver glutathione, and thiobarbituric acid reactive substances with respect to the carbon tetrachloride treated group (P < 0.05 and < 0.01). The complex provided better protection to rat liver than free EA at the same dose. The serum concentration of EA obtained from the complex (equivalent to 80 mg/kg of EA) was higher (C(max) = 0.54 microg/mL) than that of pure EA (80 mg/kg) (C(max) = 0.21 microg/mL), and the complex maintained effective concentration for a longer period of time in serum. The experimental outcome highlighted better hepatoprotective activity of the EA complex due to its potential antioxidant property compared with the free EA tested at the same dose level.
Ellagic Acid benefits and side effects
updated on March 7, 2009
Recent Article 2008 Dec Girish C and Pradhan SC. from Jawaharlal Institute of Postgraduate Medical Education and Research proposed four phytochemicals for liver diseases - ellagic acid for antifibrotic treatment, phyllanthin for treating chronic hepatitis B, glycyrrhizin to treat chronic viral hepatitis and picroliv for liver regeneration. [B1]
Ellagic acid is usually stored as ellagitannin (a tannin) in raspberries, strawberries, cranberries, walnuts, pecans, pomegranates, and other plant foods. Hydrolysis of ellagitannin yields ellagic acid and the dilactone of hexahydroxydiphenic acid.
RESEARCH FINDINGS CANCER
The highest levels of ellagic acid are found in raspberries, strawberries, and pomegranates, especially when they are freeze-dried. Studies have shown that ellagic acid is able to cause apoptosis (cell death) in cancer cells. Some also claim that it can prevent the binding of carcinogens to DNA, and strengthens connective tissue, which may keep cancer cells from spreading [1-9]. Some studies demonstrate that ellagic acid is able to reduce heart disease, birth defects, liver fibrosis, and to promote wound healing.
The vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptors play essential roles in angiogenesis and inhibition of these receptors has been shown to result in potent anti-tumor activity in vivo. Labrecque L et al reported that ellagic acid inhibits VEGF-induced phosphorylation of VEGFR-2 in endothelial cell as well as PDGF-induced phosphorylation of PDGFR in smooth muscle cells. 
Researchers, China Medical University, Taiwan, induced cell cycle arrest and apoptosis in T24 human bladder cancer cells in vitro using ellagic acid. 
Researchers at Louisiana State University demonstrated that ellagic acid expressed a selective cytotoxicity and anti-proliferative activity, and induced apoptosis in Caco-2 colon, MCF-7 breast, Hs 578T breast, and DU 145 human prostate cancer cells. It was also observed that the mechanism of apoptosis induction in ellagic acid-treated cancer cells was associated with decreased ATP production, which is crucial for the viability of cancer cells. 
de Boer JG et al, University of Victoria, Canada, showed the mutation preventive properties of ellagic acid against the mutagenicity of the nitrosamine N-nitrosomethylbenzylamine (NMBA) in the esophagus of the rat. 
Ellagic Acid benefits and side effects updated on March 7, 2009
It has been demonstrated that quercetin and ellagic acid interacted synergistically in the induction of apoptosis in the human leukemia cell line, MOLT-4.[14-15]
Lansky EP et al, Rimonest Ltd, Israel showed the anti-tumor activities of ellagic acid against human PC-3 prostate cancer cells in vitro.
Researchers at Louisiana State University demonstrated that ellagic acidexpressed a selective cytotoxicity and anti-proliferative activity, and inducedapoptosis in Caco-2 colon, MCF-7 breast, Hs 578T breast, and DU 145human prostate cancer cells. It was also observed that the mechanism ofapoptosis induction in ellagic acid-treated cancer cells was associated withdecreased ATP production, which is crucial for the viability of cancer cells. Anti-microbial Activity
Lu HF, Cheng Hsin Rehabilitation Medical Center, Taiwan, demonstrated that ellagic acid was able to elicit dose-dependent bacteriostatic activity and inhibition of N-acetylation of 2-aminofluorene (AF). 
Ellagic acid was detected in human plasma at a maximum concentration (31.9 ng/ml) after 1 h post-ingestion of pomegranate juice but was rapidly eliminated by 4 h. 
Industrial processing reduces ohenolic content and antioxidant activity of strawberry. However, the levels are still high. .
Up to the day that this article was prepared, no serious side effect is known.
Ellagic Acid Products or Supplements
Most manufacturers derive ellagic acid from pomegranate to a standardized extract containing 40% of ellagic acid. It is believed that pomegranate is also able to relieve bacterial and viral infections, intestinal parasites, chronic mucous discharges and hemorrhages. 
Some manufacturers combine pomegranate extract (whole-fruit) and pomegranate (seed) together in the product. Citrus bioflavonoids are commonly combined with ellagic acid in a product. Manufacturers believe that citrus bioflavonoids may maximize the absorption and effects.
SELECTED, RECENT STUDIES ON ELLAGIC ACID
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. Seeram NP et, UCLA, J. Nutr Biochem. 2005 Jun; 16(6):360-7.
Pomegranate fruits are widely consumed as juice, and its antioxidant andanti-atherosclerotic activities are attributed to ellagitannin and ellagic acid.Ellagic acid, totol pomegranate tannin and punicalagin but not pomegranate juice could induce apoptosis in colon cancer cells HCT116. However,pomegranate juice had a better antioxidant activity than ellagic acid.Enhancement of radiation-induced oxidative stress and cytotoxicity in tumor cells by ellagic acid. Bhosle SM et al. Clin Chim Acta. 2005 May 26. Combined treatment of tumor with ellagic acid and radiation enhances oxidative stress and cytotoxicity in tumor cells in a study of mice. Ellagic acid generated ROS in tumor cells, which increased, by an order of magnitude when cells were treated with ellagic acid in combination with gamma radiation. Ellagic acid protects normal cells against radiation damage.
1. Agricultural Research Services. Boosting ellagic acid in strawberries. United States Department of Agriculture Web site. October 8, 1999. 2. Ahn D, Putt D, Kresty L, Stoner GD, Fromm D, Hollenberg
PF. The effects of dietary ellagic acid on rat hepatic and esophageal mucosal cytochromes P450 and phase II enzymes. Carcinogenesis. 1996;17:821-828. 3. Fetrow CW, Avila JR. Professional's Handbook of
Complimentary and Alternative Medicines. Springhouse, PA: Springhouse Corp; 1999. 4. Harttig U, Hendricks JD, Stoner GD, Bailey GS. Organ specific, protocol dependent modulation of
7,12-dimethylbenz-[a]anthracene carcinogenesis in rainbow trout (Oncorhyncus mykiss) by dietary ellagic acid. Carcinogenesis. 1996;17:2403-2409. 5. Medical Economics. PDR for Herbal Medicines.
Montvale, NJ: Medical Economics Company; 1998. . Narayanan BA, Geoffroy O, Willingham MC, Re GG, Nixon DW. P53/p21 (WAF1/CIP1) expression and its possible role in G1 arrest and apoptosis in
ellagic acid treated cancer cells. Cancer Lett. 1999;136:215-221. 7. Stoner GD, Morse MA. Isothiocyanates and plant polyphenols as inhibitors of lung and esophageal cancer. Cancer Lett. 1997;114:113-119.
8. Thresiamma KC, George J, Kuttan R. Protective effect of curcumin, ellagic acid and bixin on radiation induced genotoxicity. J Exp Clin Cancer Res. 1998;17:431-434.  Combined inhibition of PDGF
and VEGF receptors by ellagic acid, a dietary-derived phenolic compound. Carcinogenesis. 2005 Apr;26(4):821-6. Epub 2005 Jan 20. Li TM et al, Ellagic acid induced p53/p21 expression, G1 arrest and
apoptosis in human bladder cancer T24 cells, Anticancer Res. 2005 Mar-Apr;25(2A):971-9. In vitro anti-proliferative activities of ellagic acid. J Nutr Biochem. 2004 Nov;15(11):672-8. 
Chemoprotection against N-nitrosomethylbenzylamine-induced mutation in the rat esophagus., Nutr Cancer. 2004;50(2):168-73. Mertens Talcott SU et al. Ellagic acid potentiates the effect of quercetin on
p21waf1/cip1, p53, and MAP-kinases without affecting intracellular generation of reactive oxygen species in vitro. J Nutr. 2005 Mar;135(3):609-14.]  Mertens Talcott SU et al. Ellagic acid and quercetin
interact synergistically with resveratrol in the induction of apoptosis and cause transient cell cycle arrest in human leukemia cells., Cancer Lett. 2005 Feb 10;218(2):141-51.] Pomegranate (Punica
granatum) pure chemicals show possible synergistic inhibition of human PC-3 prostate cancer cell invasion across Matrigel., Invest New Drugs. 2005 Mar;23(2):121-2.  In vitro anti-proliferative activities
of ellagic acid. J Nutr Biochem. 2004 Nov;15(11):672-8.] Ellagic acid inhibits growth and arylamine N-acetyltransferase activity and gene expression in Staphylococcus aureus. In Vivo. 2005
Jan-Feb;19(1):195-9.]  Bioavailability of ellagic acid in human plasma after consumption of ellagitannins from pomegranate (Punica granatum L.) juice. Clin Chim Acta. 2004 Oct;348(1-2):63-8.] 
Phenolic composition and antioxidant activities in flesh and achenes of strawberries (Fragaria ananassa). J Agric Food Chem. 2005 May 18;53(10):4032-40.] Nature's Benefit Ellagic Acid Plus 90 capsules,
online publication, smartbomb.com June 6, 2005] [B1] Girish C, Pradhan SC. Drug development for liver diseases: focus on picroliv, ellagic acid and curcumin. Fundam Clin Pharmacol. 2008
Dec;22(6):623-32.Click here to readBoosting ellagic acid in strawberriesAgricultural Research, August, 1997 by Doris Stanley
Of course, until recently no one knew that eight medium-size berries contained only 30 calories and had absolutely no saturated fat, cholesterol, or sodium - or that they were high in folate, overflowing with vitamin C, a good amount of dietary fiber and potassium, and traces of calcium and iron.
Until this century, it was not known that strawberries contain ellagic acid - a natural organic compound that some studies have shown to have a beneficial health effect. [See "Building a Better Strawberry," Agricultural Research, September, 1991, pp. 24-25.]
ARS scientists at Beltsville, Maryland, and Poplarville, Mississippi, are studying the genetics of different strawberry varieties, hoping to breed more ellagic acid as well as other beneficial nutrients into the fruit.
"We don't know how ellagic acid is inherited, but for several years we've been studying strawberry fruit and all parts of the plant to determine where the highest amounts of the acid accumulate," says John L. Maas. A plant pathologist with the ARS Fruit Laboratory in Beltsville, Maas and colleagues Gene J. Galletta and Shiow Y. Wang have evaluated 36 strawberry varieties for ellagic acid content.
"Interestingly, we found the highest amounts of ellagic acid in strawberry plant leaves," Maas reports. "Leaves of Tribute and Delite, two varieties introduced by ARS, showed more of the compound than any others tested. Seeds, in general, showed more ellagic acid than fruit pulp, and pulp from green strawberries contained more than pulp from red, ripe fruit."
Although the manner of inheritance of ellagic acid is not known, this study showed that the amount of the compound varies significantly by strawberry variety.
Pelican, one of the two strawberry varieties used in the Poplarville ellagic acid studies, was developed and released by Gene J. Galletta and colleagues. Galletta is a plant geneticist at the ARS Fruit Laboratory in Beltsville.
Now winding down his career, Galletta plans to retire from ARS in January 1998. He has developed and released 21 strawberry varieties for growers and 4 disease-resistant strawberries for breeders. In addition, he has released 21 new blueberries, 3 thornless blackberries, and a raspberry.
Galletta introduced five new strawberry varieties in 1994 and 1995: Delmarvel, Latestar, Mohawk, Northeaster, and Primetime. Pelican and Winona are his newest introductions, released in 1996.
Pelican, resistant to anthracnose, a major strawberry disease, was developed in conjunction with researchers from the Louisiana Agricultural Experiment Station, North Carolina Agricultural Research Service, and ARS' Small Fruits Research Station at Poplarville, Mississippi.
"Pelican is best adapted to the southern Coastal Plain and lower Piedmont, especially for fall planting and late winter and early spring production," Galletta says.
Researchers at the University of Minnesota worked with Galletta for 15 years to produce a strawberry specifically adapted to the environment of the north-central region of the United States.
"We needed a variety that would fit into an integrated pest management program that included minimal use of chemicals to control pests and diseases," Galletta says. "And we needed winter-hardy plants that could resist most pathogens."
Winona, released in 1996, is the fruit of their labor. The result of cross-breeding that included Earliglow and Lateglow, two of USDA's earlier releases, Winona has consistently produced large, bountiful fruit in Minnesota field tests.
Researchers have applied for a patent for Winona, which is now available in nurseries.
"My collaborators think Winona may replace Blomidon, a strawberry variety that was popular in Minnesota before it showed symptoms of the physiological disorder June Yellows," says Galletta. - By Doris Stanley, ARS.
Gene J. Galletta and John L. Maas are at the USDA-ARS Fruit Laboratory, Bldg. 004, 10300 Baltimore Ave., Beltsville, MD 20705-2350; phone 301-504-5652, fax 301-504-5062, e-mail firstname.lastname@example.org and email@example.com
Barbara J. Smith and James B. Magee are at the USDA-ARS Small Fruits Research Station, P.O. Box 287, Poplarville, MS 39470; phone 601-795-8751, fax 601-795-4965, e-mail firstname.lastname@example.org and email@example.com
Doris Stanley "Boosting ellagic acid in strawberries". Agricultural Research. FindArticles.com. 17 Oct, 2010. http://findarticles.com/p/articles/mi_m3741/is_n8_v45/ai_19815162/