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Highlights:
  • The first ever double-blind placebo controlled human trial of apple polyphenol extracts and serum cholesterol shows "significant reduction" in LDL and total cholesterol. An interview with researchers on the details of this groundbreaking study will be available soon.

  • In a well-conceived and important presentation, Cornell scientists outline a new approach to treating high cholesterol, and conclude that "apple phytochemicals can potentially improve human cardiovascular health by both lowering blood LDL cholesterol and preventing LDL oxidation."

  • Studies in humans, animals, and labs show that apple polyphenol extracts, juices and diet lower LDL cholesterol and triglycerides, and protect against lipid peroxidation.

  • Apple polyphenols clearly inhibit lipid peroxidation, which may be even more important than overall cholesterol levels in prevention of  cardiovascular disease.

  • In the latest study, apple polyphenol extracts decreased triglyceride levels by 92% in laboratory tests. The same study showed no effects from wine polyphenols.

New Clinical Trial:
Serum Cholesterol-Lowering Effect of Apple Polyphenols in Healthy Subjects, Journal of Oleo Science, Vol. 54 (2005) , No. 3 143-151
Newly Posted Studies:
Cardioprotective potentials of apple phytochemicals in LDL oxidation and LDL receptor expression Cornell Institute of Food Science Symposium, May 22-24 2005
Differential inhibition of oxidized LDL-induced apoptosis in human endothelial cells treated with different flavonoids, Br J Nutr, May 1, 2005; 93(5): 581-91.

Apple juice inhibits human low density lipoprotein oxidation, Life Sci. 1999
Apple Juice Consumption Reduces Plasma Low-Density Lipoprotein Oxidation in Healthy Men and Women, Journal of Medicinal Food, 2000
Apple phytochemicals and their health benefits, Nutr J. 2004
Apple procyanidins decrease cholesterol esterification and lipoprotein secretion in Caco-2/TC7 enterocytes, J Lipid Res. 2004
Apple and pear peel and pulp and their influence on plasma lipids and antioxidant potentials in rats fed cholesterol-containing diets, J Agric Food Chem. 2003
Lyophilized Apple Counteracts the Development of Hypercholesterolemia, Oxidative Stress, and Renal Dysfunction in Obese Zucker Rats, J. Nutr. 2002
The antioxidant activity of phloretin: the disclosure of a new antioxidant pharmacophore in flavonoids, Biochem Biophys Res Commun. 2002
Comparative content of some bioactive compounds in apples, peaches and pears and their influence on lipids and antioxidant capacity in rats, J Nutr Biochem. 2002

 

Journal of Oleo Science, Vol. 54 (2005) , No. 3 143-151
Serum Cholesterol-Lowering Effect of Apple Polyphenols in Healthy Subjects

Yoko NAGASAKO-AKAZOME1), Tomomasa KANDA1), Mitsuo IKEDA1) and Hiroyuki SHIMASAKI2)

1) Fundamental Research Laboratory, Asahi Breweries, Ltd.
2) Department of Biochemistry, Teikyo University School of Medicine

Abstract: We performed a clinical study using healthy male and female subjects who had slightly elevated cholesterol levels in their serum to examine the effects of food tablets containing apple polyphenols (Applephenon®), which are effective for improving serum cholesterol concentrations in rats, on lipid metabolism in humans. The total period of this study was four weeks and we obtained blood samples at week 0 and week 4. Total cholesterol levels of the intervention groups decreased significantly and dose-dependently compared with that of the control group. We also found LDL-cholesterol decreased significantly and HDL-cholesterol increased. No abnormalities were detected in biochemical examinations of any of the subjects during the test period. We concluded that the study product is useful as a food additive that improves serum cholesterol concentrations. Such improvement is expected to decrease the risk of atherosclerosis for people with a slightly elevated total cholesterol level.
 
Cornell Institute of Food Science Symposium, May 22-24 2005
Cardioprotective potentials of apple phytochemicals in LDL oxidation and LDL receptor expression

Yi-Fang Chu and Rui Hai Liu, Cornell University

Cardiovascular disease is the leading cause of death in most industrialized countries. Both elevated blood LDL cholesterol level and LDL oxidation lead to an enhanced atherogenicity. Therapeutic strategies have been developed based on targeting the pathogenesis; one is to prevent LDL oxidation by increasing antioxidant levels, and another, as employed by statin drugs, is to lower levels of plasma LDL cholesterol by increasing LDL uptake by hepatocytes through LDL receptors and subsequent sterol excretion through bile acids. Our objectives were to determine: 1) the effect of apple extracts on human LDL oxidation; 2) if apple extracts affected hepatic LDL receptor expression and the level of intracellular cholesterol in HepG2 hepatocytes; 3) if apple extracts affected the expression of sterol regulatory-element binding proteins (SREBPs). Apple phytochemicals were extracted using 80% acetone. LDL was isolated from human plasma by sequential ultracentrifugation. Prevention of human LDL oxidation was studied using a LDL Oxidation Model for Antioxidant Capacity (LOMAC) assay. The expression of LDL receptors and SREBPs in HepG2 hepatocytes was quantified by western blotting. Intracellular cholesterol was measured by gas chromatography. Apple extracts had potent antioxidant capacity against human LDL oxidation and increased delay and suppression of LDL oxidation in a dose-dependent manner. Apple extracts also significantly induced expression of hepatic LDL receptors in a dose-dependent manner (p<0.05) and increased intracellular uptake of cholesterol by HepG2 hepatocytes (p<0.05). These results suggest that apple phytochemicals could lower plasma LDL cholesterol by enhancing uptake of LDL in liver and increase subsequent sterol excretion as bile acids. The attenuated level of active SREBP expression by apple phytochemicals indicates a decrease in intracellular lipogenesis and cholesterol synthesis, similar to the results caused by statin drugs such as Lipitor. Apple phytochemicals can potentially improve human cardiovascular health by both lowering blood LDL cholesterol and preventing LDL oxidation.

 

Br J Nutr, May 1, 2005; 93(5): 581-91
Differential inhibition of oxidized LDL-induced apoptosis in human endothelial cells treated with different flavonoids

YJ Jeong, YJ Choi, HM Kwon, SW Kang, HS Park, M Lee, and YH Kang

Division of Life Sciences, Hallym University, Chuncheon, South Korea.

High plasma level of cholesterol is a well-known risk factor for atherosclerotic diseases. Oxidized LDL induces cellular and nuclear damage that leads to apoptotic cell death. We tested the hypothesis that flavonoids may function as antioxidants with regard to LDL incubated with 5 mum-Cu(2+) alone or in combination with human umbilical vein endothelial cells (HUVEC). Cytotoxicity and formation of thiobarbituric acid-reactive substances induced by Cu(2+)-oxidized LDL were examined in the presence of various subtypes of flavonoid. Flavanols, flavonols and flavanones at a non-toxic dose of 50 mum markedly inhibited LDL oxidation by inhibiting the formation of peroxidative products. In contrast, the flavones luteolin and apigenin had no such effect, with >30 % of cells killed after exposure to 0.1 mg LDL/ml. Protective flavonoids, especially (-)-epigallocatechin gallate, quercetin, rutin and hesperetin, inhibited HUVEC nuclear condensation and fragmentation induced by Cu(2+)-oxidized LDL. In addition, immunochemical staining and Western blot analysis revealed that anti-apoptotic Bcl-2 expression was enhanced following treatment with these protective flavonoids. However, Bax expression and caspase-3 cleavage stimulated by 18 h incubation with oxidized LDL were reduced following treatment with these protective flavonoids. The down-regulation of Bcl-2 and up-regulation of caspase-3 activation were reversed by the cytoprotective flavonoids, (-)-epigallocatechin gallate, quercetin and hesperetin, at >/=10 mum. These results suggest that flavonoids may differentially prevent Cu(2+)-oxidized LDL-induced apoptosis and promote cell survival as potent antioxidants. Survival potentials of certain flavonoids against cytotoxic oxidized LDL appeared to stem from their disparate chemical structure. Furthermore, dietary flavonoids may have therapeutic potential for protecting the endothelium from oxidative stress and oxidized LDL-triggered atherogenesis.

PMID: 15975156
 
Life Sci. 1999;64(21):1913-20.

Apple juice inhibits human low density lipoprotein oxidation.

Pearson DA, Tan CH, German JB,
Davis PA, Gershwin ME.

Department of Food Science and Technology, University of California at Davis, 95616, USA.

Dietary phenolic compounds, ubiquitous in vegetables and fruits and their juices possess antioxidant activity that may have beneficial effects on human health. The phenolic composition of six commercial apple juices, and of the peel (RP), flesh (RF) and whole fresh Red Delicious apples (RW), was determined by high performance liquid chromatography (HPLC), and total phenols were determined by the Folin-Ciocalteau method. HPLC analysis identified and quantified several classes of phenolic compounds: cinnamates, anthocyanins, flavan-3-ols and flavonols. Phloridzin and hydroxy methyl furfural were also identified. The profile of phenolic compounds varied among the juices. The range of concentrations as a percentage of total phenolic concentration was: hydroxy methyl furfural, 4-30%; phloridzin, 22-36%; cinnamates, 25-36%; anthocyanins, n.d.; flavan-3-ols, 8-27%; flavonols, 2-10%. The phenolic profile of the Red Delicious apple extracts differed from those of the juices. The range of concentrations of phenolic classes in fresh apple extracts was: hydroxy methyl furfural, n.d.; phloridzin, 11-17%; cinnamates, 3-27%; anthocyanins, n.d.-42%; flavan-3-ols, 31-54%; flavonols, 1-10%. The ability of compounds in apple juices and extracts from fresh apple to protect LDL was assessed using an in vitro copper catalyzed human LDL oxidation system. The extent of LDL oxidation was determined as hexanal production using static headspace gas chromatography. The apple juices and extracts, tested at 5 microM gallic acid equivalents (GAE), all inhibited LDL oxidation. The inhibition by the juices ranged from 9 to 34%, and inhibition by RF, RW and RP was 21, 34 and 38%, respectively. Regression analyses revealed no significant correlation between antioxidant activity and either total phenolic concentration or any specific class of phenolics. Although the specific components in the apple juices and extracts that contributed to antioxidant activity have yet to be identified, this study found that both fresh apple and commercial apple juices inhibited copper-catalyzed LDL oxidation. The in vitro antioxidant activity of apples support the inclusion of this fruit and its juice in a healthy human diet.

PMID: 10353589 [PubMed - indexed for MEDLINE]

 

Journal of Medicinal Food, Volume 3, Number 4, 2000

Apple Juice Consumption Reduces Plasma Low-Density Lipoprotein Oxidation in Healthy Men and Women

DIANNE HYSON, M.S., R.D.,1DEBORAH STUDEBAKER-HALLMAN, B.S.,1PAUL A. DAVIS, Ph.D.,1,2and M. ERIC GERSHWIN.

Full text of this study is available here in PDF format

ABSTRACT

Epidemiological studies show that consumption of fruits and vegetables is associated with beneficial effects on human health including reduced risk of coronary artery disease (CAD). Fruits and their juices contain phytochemicals that inhibit in vitro low-density lipoprotein (LDL) oxidation and may account, in part, for their protective effect. However, reports of in vivo antioxidant effects from fruit intake are limited. We conducted a human trial to examine the in vivo effect of consumption of apples (both whole and juice) in an unblinded, randomized, crossover design. Healthy men and women added 375 ml of unsupplemented apple juice or 340 g of cored whole apple to their daily diet for 6 weeks, then crossed over to the alternate product for 6 weeks. Blood samples were obtained at baseline and after each dietary period. Compliance was monitored via biweekly 5-day food records, bodyweight checks, and meetings with study personnel. There were no significant differences between groups in intake of dietary fat, cholesterol, total carbohydrate, sugar, or calories throughout the study. Dietary fiber intake increased by 22% with whole apple consumption. Body weight, fasting serum lipid concentration, and other lipoprotein parameters were unchanged. Apple juice consumption increased ex vivo copper (Cu )-mediated LDL oxidation lag time by 20% compared with baseline. Apples and apple juice both reduced conjugated diene formation. Moderate apple juice consumption provides in vivo antioxidant activity. In view of the current understanding of CAD, the observed effect on LDL might be associated with reduced CAD risk and supports the inclusion of apple juice in a healthy human diet.

 

Nutr J. 2004 May 12;3(1):5.
Apple phytochemicals and their health benefits.

Boyer J, Liu RH.

Department of Food Science and Institute of Comparative and Environmental Toxicology, Cornell University, Ithaca, New York 14853-7201 USA. RL23@cornell.edu

Evidence suggests that a diet high in fruits and vegetables may decrease the risk of chronic diseases, such as cardiovascular disease and cancer, and phytochemicals including phenolics, flavonoids and carotenoids from fruits and vegetables may play a key role in reducing chronic disease risk. Apples are a widely consumed, rich source of phytochemicals, and epidemiological studies have linked the consumption of apples with reduced risk of some cancers, cardiovascular disease, asthma, and diabetes. In the laboratory, apples have been found to have very strong antioxidant activity, inhibit cancer cell proliferation, decrease lipid oxidation, and lower cholesterol. Apples contain a variety of phytochemicals, including quercetin, catechin, phloridzin and chlorogenic acid, all of which are strong antioxidants. The phytochemical composition of apples varies greatly between different varieties of apples, and there are also small changes in phytochemicals during the maturation and ripening of the fruit. Storage has little to no effect on apple phytochemicals, but processing can greatly affect apple phytochemicals. While extensive research exists, a literature review of the health benefits of apples and their phytochemicals has not been compiled to summarize this work. The purpose of this paper is to review the most recent literature regarding the health benefits of apples and their phytochemicals, phytochemical bioavailability and antioxidant behavior, and the effects of variety, ripening, storage and processing on apple phytochemicals.

PMID: 15140261 [PubMed - as supplied by publisher]

 

J Lipid Res. 2004 Dec 1
Apple procyanidins decrease cholesterol esterification and lipoprotein secretion in Caco-2/TC7 enterocytes.


Vidal R, Hernandez-Vallejo S, Pauquai T, Texier O, Rousset M, Chambaz J, Demignot S, Lacorte JM.

Decrease of plasma lipid levels by polyphenols was linked to impairment of hepatic lipoproteins secretion. However, intestine is the first epithelium that faces dietary compounds and contributes to lipid homeostasis by secreting triglyceride-rich lipoproteins during the postprandial state. The purpose of this study was thus to examine the effect of apple and wine polyphenols extracts on lipoprotein synthesis and secretion in human, Caco-2/TC7 enterocytes apically supplied with complex lipid micelles. Our results clearly demonstrate that apple, but not wine polyphenols extract, dose-dependently decreases the esterification of cholesterol and the enterocyte secretion of lipoproteins. Apple polyphenols decrease apoB secretion by inhibition of apoB synthesis without increasing the degradation of the newly synthesized protein. In our conditions, cholesterol uptake, apoB mRNA and MTP activity were not modified by apple polyphenols. The main monomers present in our mixture did not interfere with the intestinal lipid metabolism. By contrast, apple-procyanidins reproduced the inhibition of both cholesterol ester synthesis and lipoprotein secretion. Overall, our results are compatible with a mechanism of action of polyphenols resulting into an impaired lipid availability that could induce inhibition of intestinal lipoprotein secretion and contribute to the hypolipidemic effect of these compounds in vivo.
 
Excerpts: "In the same time, apple polyphenols dose-dependently lowered the secretion of all classes of newly synthesized lipids, resulting at 500 µg/ml in a 77% decrease in cholesterol esters (0.032 ± 0.008 vs 0.14 ± 0.02 pmol / dish; p< 0.001), a 61% decrease in phospholipids (0.24 ± 0.07 vs 0.61 ± 0.12 nmol / dish; p<0.001) and a 92% decrease in triglycerides (0.16 ± 0.1 vs 1.9 ± 0.4 nmol /dish; p <0.001) in the 15 basal media. Again, no effect on the secretion of lipids was observed with wine polyphenols, whatever their concentration.

PMID: 15576849 [PubMed - as supplied by publisher]

 

J Agric Food Chem. 2003 Sep 10;51(19):5780-5.

Apple and pear peel and pulp and their influence on plasma lipids and antioxidant potentials in rats fed cholesterol-containing diets.

Leontowicz M, Gorinstein S, Leontowicz H, Krzeminski R, Lojek A, Katrich E, Ciz M, Martin-Belloso O, Soliva-Fortuny R, Haruenkit R, Trakhtenberg S.

Department of Animal Physiology, Faculty of Veterinary Medicine, Warsaw Agricultural University, Nowoursynowska 166, 02-787 Warsaw, Poland.

The aim of this study was to assess the bioactive compounds of apple and pear peel and pulp in vitro and their influence on plasma lipids and antioxidant potentials in vivo. The antioxidant potentials measured by 1,1-diphenyl-2-picrylhydrazyl (DPPH), beta-carotene bleaching (beta-carotene), and nitric oxide inhibition radical scavenging (NO) tests in apple peel and pulp were significantly higher than in pear peel and pulp, respectively. The ethanol extract of apple peels showed the strongest inhibition of lipid peroxidation as a function of its concentration and was comparable to the antioxidant activity of butylated hydroxyanisole. The pear pulp extract had the weakest antioxidant ability, whereas other extracts such as apple pulp and pear peel were nearly equal. The antioxidant activities comprised contributions from polyphenols, phenolic acids, and flavonoids and correlated well with polyphenols and flavonoids. The correlation coefficients between polyphenols and antioxidant activities by DPPH, beta-carotene, and NO were as follows: 0.9207, 0.9350, and 0.9453. Contrarily, the correlation coefficient between the content of dietary fiber and the antioxidant activities test was low. The content of all studied indices in apple and pear peel was significantly higher than in peeled fruits (p < 0.05). Diets supplemented with fruit peels exercised a significantly higher positive influence on plasma lipid levels and on plasma antioxidant capacity of rats than diets with fruit pulps.

PMID: 12952433 [PubMed - indexed for MEDLINE]

 
J. Nutr. 132:1969-1976, 2002

© 2002 The American Society for Nutritional Sciences

Nutrient Metabolism

Lyophilized Apple Counteracts the Development of Hypercholesterolemia, Oxidative Stress, and Renal Dysfunction in Obese Zucker Rats

Olivier Aprikian2, Jérôme Busserolles, Claudine Manach, André Mazur, Christine Morand, Marie-Jeanne Davicco, Catherine Besson, Yves Rayssiguier, Christian Rémésy and Christian Demigné3

Unité des Maladies Métaboliques et Micronutriments, INRA de Clermont-Ferrand/Theix and CRNH d’Auvergne, 63122 St-Genes-Champanelle, France

3To whom correspondence should be addressed. E-mail: demigne@clermont.inra.fr.

Apples may have selective effects on abnormalities associated with the plurimetabolic syndrome. Therefore, the effects of 20% lyophilized apple supplementation on plasma and tissue lipids and on protection against susceptibility to oxidative stress and renal dysfunction were investigated in Zucker lean (Fa/-) or obese (fa/fa) rats. The experimental diets were equilibrated for sugar supply, contained 0.25 g/100 g cholesterol and provided only one third of the vitamin E requirement. Obese Zucker rats were hypercholesterolemic with cholesterol accumulation in LDL and HDL fractions. The apple diet lowered plasma and LDL cholesterol (-22 and -70%, respectively, P < 0.01) in obese Zucker rats and, in parallel, reduced triglyceride accumulation in heart and liver. Zucker rats fed the apple diet also had a larger intestinal pool and greater fecal excretion of bile acids. The heart concentration and urinary excretion of malondialdehyde were reduced by apple consumption in obese Zucker rats, suggesting better protection against peroxidation. Glucosuria and proteinuria in obese Zucker rats were also suppressed by the apple diet. In conclusion, despite their moderate fiber content, apples improve substantially the lipid status and peroxidative parameters in obese Zucker rats, suggesting that other plant constituents such as polyphenols are involved in these effects.

 

Biochem Biophys Res Commun. 2002 Jul 5;295(1):9-13.

The antioxidant activity of phloretin: the disclosure of a new antioxidant pharmacophore in flavonoids.

Rezk BM, Haenen GR, van der Vijgh WJ, Bast A.

Department of Pharmacology and Toxicology, Faculty of Medicine, Universiteit Maastricht P.O. Box 616, 6200 MD Maastricht, The Netherlands.

Phloretin is a dihydrochalcone flavonoid that displays a potent antioxidant activity in peroxynitrite scavenging and the inhibition of lipid peroxidation. Comparison with structurally related compounds revealed that the antioxidant pharmacophore of phloretin is 2,6-dihydroxyacetophenone. The potent activity of 2,6-dihydroxyacetophenone is due to stabilisation of its radical via tautomerisation. The antioxidant pharmacophore in the dihydrochalcone phloretin, i.e., the 2,6-dihydroxyacetophenone group, is different from the antioxidant pharmacophores previously reported in flavonoids. (c) 2002 Elsevier Science (
USA).

PMID: 12083758 [PubMed - indexed for MEDLINE]

 

J Nutr Biochem. 2002 Oct;13(10):603-610.

Comparative content of some bioactive compounds in apples, peaches and pears and their influence on lipids and antioxidant capacity in rats.

Leontowicz H, Gorinstein S, Lojek A, Leontowicz M, Ci;z M, Soliva-Fortuny R, Park YS, Jung ST, Trakhtenberg S, Martin-Belloso O.

Department of Physiology, Biochemistry, Pharmacology and Toxicology, Faculty of Veterinary Medicine,
Warsaw Agricultural University, Nowoursynowska 166, 02-787, Warsaw, Poland

The aim of this study was to compare some bioactive compounds in apples, peaches and pears and their influence on lipids and antioxidant capacity in rats. The content of total polyphenols (g/100g) was 0.23 +/- 0.03; 0.22 +/- 0.03 and 0.68 +/- 0.1 in peeled fruits and 0.48 +/- 0.04, 0.47 +/- 0.04 and 1.2 +/- 0.12 in peels of peaches, pears and apples, respectively. Caffeic, p-coumaric and ferulic acids and the total radical-trapping antioxidative potential (TRAP) values in peeled apples and their peels were significantly higher than in peaches and pears, respectively. Contrarary, no significant differences in the content of dietary fiber among the studied fruits were found. The content of all studied indices in peels was significantly higher than peeled fruits (p < 0.05 ). A good correlation between the total polyphenols and the TRAP values was found in all fruits. Diets supplemented with apples and to a less extent with peaches and pears have improved lipid metabolism and increased the plasma antioxidant potential especially in rats fed with added cholesterol. The highest content of biologically active compounds and the best results in the experiment on rats makes apple preferable for dietary prevention of atherosclerosis and other diseases.

PMID: 12550072 [PubMed - as supplied by publisher]

(more research)
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