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Life Extension Magazine November 2009


Ellagic acid, pomegranate and prostate cancer — a mini review.

There is currently a shifting focus towards finding natural compounds that may prevent or treat cancer, due to the problems that exist with current chemotherapeutic regimens. The fruit of the Punica granatum (pomegranate) contains hundreds of phytochemicals and pomegranate extracts have recently been shown to exhibit antioxidant properties, thought to be due to the action of ellagic acid, the main polyphenol in pomegranate. In this mini review the effects of pomegranate extracts and ellagic acid on the proliferation of prostate cancer cells and their future potential are discussed.

J Pharm Pharmacol. 2008 Feb;60(2):139-44

Therapeutic applications of pomegranate (Punica granatum L.): a review.

The pomegranate, Punica granatum L., is an ancient, mystical, unique fruit borne on a small, long-living tree cultivated throughout the Mediterranean region, as far north as the Himalayas, in Southeast Asia, and in California and Arizona in the United States. In addition to its ancient historical uses, pomegranate is used in several systems of medicine for a variety of ailments. The synergistic action of the pomegranate constituents appears to be superior to that of single constituents. In the past decade, numerous studies on the antioxidant, anticarcinogenic, and anti-inflammatory properties of pomegranate constituents have been published, focusing on treatment and prevention of cancer, cardiovascular disease, diabetes, dental conditions, erectile dysfunction, bacterial infections and antibiotic resistance, and ultraviolet radiation-induced skin damage. Other potential applications include infant brain ischemia, male infertility, Alzheimer’s disease, arthritis, and obesity.

Altern Med Rev. 2008 Jun;13(2):128-44

Pomegranate juice: a heart-healthy fruit juice.

Pomegranate juice is a polyphenol-rich fruit juice with high antioxidant capacity. In limited studies in human and murine models, pomegranate juice has been shown to exert significant antiatherogenic, antioxidant, antihypertensive, and anti-inflammatory effects. Pomegranate juice significantly reduced atherosclerotic lesion areas in immune-deficient mice and intima media thickness in cardiac patients on medications. It also decreased lipid peroxidation in patients with type 2 diabetes, and systolic blood pressure and serum angiotensin converting enzyme activity in hypertensive patients. Thus, the potential cardioprotective benefits of pomegranate juice deserve further clinical investigation, and evidence to date suggests it may be prudent to include this fruit juice in a heart-healthy diet.

Nutr Rev. 2009 Jan;67(1):49-56

Pomegranate derived products for cancer chemoprevention.

Because treatment options for advanced metastasized cancers remain inadequate, developing effective approaches for the prevention of cancer has become an important goal to reduce cancer burden. One such strategy is through chemoprevention, preferably by the use of non-toxic dietary substances and botanical products. Pomegranate, used for centuries for its medicinal properties is now being recognized as a potential chemopreventive and anticancer agent. Increasing body of evidence has underscored the cancer preventive efficacy of pomegranate both in vitro and in vivo animal models. The emerging data provide new insights into the molecular framework needed to establish novel mechanism-based chemopreventive strategies for various human cancers.

Semin Cancer Biol. 2007 Oct;17(5):377-85

Pomegranate juice supplementation to atherosclerotic mice reduces macrophage lipid peroxidation, cellular cholesterol accumulation and development of atherosclerosis.

Inhibition of lipid peroxidation contributes to the attenuation of macrophage cholesterol accumulation, foam-cell formation and atherosclerosis. Evidence suggests that nutritional antioxidants such as pomegranate juice (PJ) can contribute to the reduction of oxidative stress and atherogenesis. The goals of the present study were to determine whether such beneficial effects of PJ exist when supplemented to apolipoprotein E-deficient (E(0)) mice with advanced atherosclerosis and to analyze the antiatherosclerotic activity of a tannin-fraction isolated from PJ. Mice (4-mo-old) were supplemented with PJ in their drinking water for 2 mo and compared with age-matched placebo-treated mice, as well as to young (4-mo-old) control mice, for their mouse peritoneal macrophage (MPM) oxidative state, cholesterol flux and mice atherosclerotic lesion size. PJ supplementation reduced each of the proatherogenic variables determined in the present study compared with age-matched placebo-treated mice. It significantly induced serum paraoxonase activity and reduced MPM lipid peroxide content compared with placebo-treated mice and control mice. PJ administration to E(0) mice significantly reduced the oxidized (Ox)-LDL MPM uptake by 31% and MPM cholesterol esterification and increased macrophage cholesterol efflux by 39% compared with age-matched, placebo-treated mice. PJ consumption reduced macrophage Ox-LDL uptake and cholesterol esterification to levels lower than those in 4-mo-old, unsupplemented controls. PJ supplementation to E(0) mice with advanced atherosclerosis reduced the lesion size by 17% compared with placebo-treated mice. In a separate study, supplementation of young (2-mo-old) E(0) mice for 2 mo with a tannin fraction isolated from PJ reduced their atherosclerotic lesion size, paralleled by reduced plasma lipid peroxidation and decreased Ox-LDL MPM uptake. PJ supplementation to mice with advanced atherosclerosis reduced their macrophage oxidative stress, their macrophage cholesterol flux and even attenuated the development of atherosclerosis. Moreover, a tannin-fraction isolated from PJ had a significant antiatherosclerotic activity.

J Nutr. 2001 Aug;131(8):2082-9

Pomegranate juice consumption reduces oxidative stress, atherogenic modifications to LDL, and platelet aggregation: studies in humans and in atherosclerotic apolipoprotein E-deficient mice.

BACKGROUND: Dietary supplementation with nutrients rich in antioxidants is associated with inhibition of atherogenic modifications to LDL, macrophage foam cell formation, and atherosclerosis. Pomegranates are a source of polyphenols and other antioxidants. OBJECTIVE: We analyzed, in healthy male volunteers and in atherosclerotic apolipoprotein E-deficient (E(0)) mice, the effect of pomegranate juice consumption on lipoprotein oxidation, aggregation, and retention; macrophage atherogenicity; platelet aggregation; and atherosclerosis. DESIGN: Potent antioxidative effects of pomegranate juice against lipid peroxidation in whole plasma and in isolated lipoproteins (HDL and LDL) were assessed in humans and in E(0) mice after pomegranate juice consumption for </=2 and 14 wk, respectively. RESULTS: In humans, pomegranate juice consumption decreased LDL susceptibility to aggregation and retention and increased the activity of serum paraoxonase (an HDL-associated esterase that can protect against lipid peroxidation) by 20%. In E(0) mice, oxidation of LDL by peritoneal macrophages was reduced by up to 90% after pomegranate juice consumption and this effect was associated with reduced cellular lipid peroxidation and superoxide release. The uptake of oxidized LDL and native LDL by mouse peritoneal macrophages obtained after pomegranate juice administration was reduced by 20%. Finally, pomegranate juice supplementation of E(0) mice reduced the size of their atherosclerotic lesions by 44% and also the number of foam cells compared with control E(0) mice supplemented with water. CONCLUSION: Pomegranate juice had potent antiatherogenic effects in healthy humans and in atherosclerotic mice that may be attributable to its antioxidative properties.

Am J Clin Nutr. 2000 May;71(5):1062-76

Pomegranate juice flavonoids inhibit low-density lipoprotein oxidation and cardiovascular diseases: studies in atherosclerotic mice and in humans.

The beneficial health effects attributed to the consumption of fruit and vegetables are related, at least in part, to their antioxidant activity. Of special interest is the inverse relationship between the intake of dietary nutrients rich in polyphenols and cardiovascular diseases. This effect is attributed to polyphenols’ ability to inhibit low-density lipoprotein (LDL) oxidation, macrophage foam cell formation and atherosclerosis. Pomegranate polyphenols can protect LDL against cell-mediated oxidation via two pathways, including either direct interaction of the polyphenols with the lipoprotein and/or an indirect effect through accumulation of polyphenols in arterial macrophages. Pomegranate polyphenols were shown to reduce the capacity of macrophages to oxidatively modify LDL, due to their interaction with LDL to inhibit its oxidation by scavenging reactive oxygen species and reactive nitrogen species and also due to accumulation of polyphenols in arterial macrophages; hence, the inhibition of macrophage lipid peroxidation and the formation of lipid peroxide-rich macrophages. Furthermore, pomegranate polyphenols increase serum paraoxonase activity, resulting in the hydrolysis of lipid peroxides in oxidized lipoproteins and in atherosclerotic lesions. These antioxidative and antiatherogenic effects of pomegranate polyphenols were demonstrated in vitro, as well as in vivo in humans and in atherosclerotic apolipoprotein E deficient mice. Dietary supplementation of polyphenol-rich pomegranate juice to atherosclerotic mice significantly inhibited the development of atherosclerotic lesions and this may be attributed to the protection of LDL against oxidation.

Drugs Exp Clin Res. 2002;28(2-3):49-62

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.

The effects of a pomegranate byproduct (PBP, which includes the whole pomegranate fruit left after juice preparation) on atherosclerosis development in apolipoprotein E-deficient (E degrees ) mice were studied. Consumption of PBP (17 or 51.5 microg of gallic acid equiv/kg/day) by the mice resulted in a significant reduction in atherosclerotic lesion size by up to 57%. PBP consumption significantly reduced oxidative stress in the mice peritoneal macrophages (MPM): Cellular lipid peroxide content decreased by up to 42%, the reduced glutathione levels increased by up to 53%, and paraoxonase 2 lactonase activity increased by up to 50%, as compared to MPM from E degrees mice that consumed only water. Furthermore, oxidized low-density lipoprotein (Ox-LDL) uptake by the MPM was reduced by up to 19%. Similar results were observed also in vitro. Treatment of J774A.1 macrophages with PBP (10 or 50 micromol/L of total polyphenols) significantly decreased both cellular total peroxide content and Ox-LDL uptake. It was thus concluded that PBP significantly attenuates atherosclerosis development by its antioxidant properties.

J Agric Food Chem. 2006 Mar 8;54(5):1928-35

Pomegranate juice consumption inhibits serum angiotensin converting enzyme activity and reduces systolic blood pressure.

Consumption of pomegranate juice which is rich in tannins, possess anti-atherosclerotic properties which could be related to its potent anti-oxidative characteristics. As some antioxidants were recently shown to reduce blood pressure, we studied the effect of pomegranate juice consumption (50 ml, 1.5mmol of total polyphenols per day, for 2 weeks) by hypertensive patients on their blood pressure and on serum angiotensin converting enzyme (ACE) activity. A 36% decrement in serum ACE activity and a 5% reduction in systolic blood pressure were noted. Similar dose-dependent inhibitory effect (31%) of pomegranate juice on serum ACE activity was observed also in vitro. As reduction in serum ACE activity, even with no decrement in blood pressure, was previously shown to attenuate atherosclerosis, pomegranate juice can offer a wide protection against cardiovascular diseases which could be related to its inhibitory effect on oxidative stress and on serum ACE activity.

Atherosclerosis. 2001 Sep;158(1):195-8

Pomegranate juice consumption for 3 years by patients with carotid artery stenosis reduces common carotid intima-media thickness, blood pressure and LDL oxidation.

Dietary supplementation with polyphenolic antioxidants to animals was shown to be associated with inhibition of LDL oxidation and macrophage foam cell formation, and attenuation of atherosclerosis development. We investigated the effects of pomegranate juice (PJ, which contains potent tannins and anthocyanins) consumption by atherosclerotic patients with carotid artery stenosis (CAS) on the progression of carotid lesions and changes in oxidative stress and blood pressure. Ten patients were supplemented with PJ for 1 year and five of them continued for up to 3 years. Blood samples were collected before treatment and during PJ consumption. In the control group that did not consume PJ, common carotid intima-media thickness (IMT) increased by 9% during 1 year, whereas, PJ consumption resulted in a significant IMT reduction, by up to 30%, after 1 year. The patients’ serum paraoxonase 1 (PON 1) activity was increased by 83%, whereas serum LDL basal oxidative state and LDL susceptibility to copper ion-induced oxidation were both significantly reduced, by 90% and 59%, respectively, after 12 months of PJ consumption, compared to values obtained before PJ consumption. Furthermore, serum levels of antibodies against oxidized LDL were decreased by 19%, and in parallel serum total antioxidant status (TAS) was increased by 130% after 1 year of PJ consumption.

Systolic blood pressure was reduced after 1 year of PJ consumption by 12% [corrected] and was not further reduced along 3 years of PJ consumption. For all studied parameters, the maximal effects were observed after 1 year of PJ consumption. Further consumption of PJ, for up to 3 years, had no additional beneficial effects on IMT and serum PON1 activity, whereas serum lipid peroxidation was further reduced by up to 16% after 3 years of PJ consumption. The results of the present study thus suggest that PJ consumption by patients with CAS decreases carotid IMT and systolic blood pressure and these effects could be related to the potent antioxidant characteristics of PJ polyphenols.

Clin Nutr. 2004 Jun;23(3):423-33

Consumption of wonderful variety pomegranate juice and extract by diabetic patients increases paraoxonase 1 association with high-density lipoprotein and stimulates its catalytic activities.

Association of paraoxonase 1 (PON1) with high-density lipoprotein (HDL) stabilizes the enzyme. In diabetic patients, PON1 dissociates from HDL and, as a consequence, is less biologically active. Our aim was to investigate the effects of Wonderful variety pomegranate juice (WPJ) and pomegranate polyphenol extract (WPOMxl) consumption on PON1 association with HDL in diabetic patients. Thirty patients with type 2 diabetes mellitus participated in the study. Ten male patients and 10 female patients received concentrated WPJ (50 mL/day for 4 weeks), while another group of 10 male patients received WPOMxl (5 mL/day for 6 weeks). There were no significant effects of WPJ or WPOMxl consumption on fasting blood glucose or hemoglobin A1c levels. After 4 weeks of WPJ consumption by male patients, basal serum oxidative stress was significantly decreased by 35%, whereas serum concentrations of thiol groups significantly increased by 25%. Moreover, HDL-associated PON1 arylesterase, paraoxonase, and lactonase activities increased significantly after WPJ consumption by 34-45%, as compared to the baseline levels. PON1 protein binding to HDL was significantly increased by 30% following WPJ consumption, and the enzyme became more stable. In male patients that consumed WPOMxl and in female patients that consumed PJ, a similar pattern was observed, although to a lesser extent. We conclude that WPJ as well as WPOMxl consumption by diabetic patients does not worsen their diabetic parameters. Furthermore, WPJ as well as WPOMxl consumption contribute to PON1 stabilization, increased association with HDL, and enhanced catalytic activities. These beneficial effects of pomegranate consumption on serum PON1 stability and activity could lead to retardation of atherosclerosis development in diabetic patients.

J Agric Food Chem. 2008 Sep 24;56(18):8704-13

Macrophage paraoxonase 2 (PON2) expression is up-regulated by pomegranate juice phenolic anti-oxidants via PPAR gamma and AP-1 pathway activation.

Paraoxonase 2 (PON2), a member of the paraoxonase gene family, was shown to protect macrophages against oxidative stress. Pomegranate juice (PJ), which contains potent polyphenol anti-oxidants, exhibits similar effects. We questioned possible association between PJ polyphenolics, macrophage oxidative stress, and cellular PON2 expression, in relation to the activation of specific PON2 transcription factors. Incubation of J774A.1 macrophages with PJ (0-50 microM of total polyphenols) dose-dependently increased expression (mRNA, protein) and activity and reduced macrophage oxidative status. These effects could be attributed to the PJ unique polyphenols, punicalagin and gallic acid. PJ polyphenol-induced up-regulation of PON2 was inhibited by 40% upon using the PPAR gamma inhibitor GW9662 (50 microM). Accordingly, the PPAR gamma ligand, rosiglitazone, dose-dependently stimulated macrophage PON2 expression, by up to 80%. Inhibition of AP-1 activation with SP600125, attenuated PJ-induced up-regulation of PON2 by 40%. Similarly, incubation of macrophages with PJ polyphenols in the presence of GW9662 or SP600125, significantly reduced their capacity to protect the cells against oxidative stress. We conclude that the anti-oxidative characteristics of PJ unique phenolics punicalagin and gallic acid could be related, at least in part, to their stimulatory effect on macrophage PON2 expression, a phenomenon which was shown to be associated with activation of the transcription factors PAPR gamma and AP-1.

Atherosclerosis. 2007 Dec;195(2):313-21

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