Special Article November 2007: 490-502

Cranberries (Vaccinium macrocarpon) and Cardiovascular Disease Risk Factors Diane L. McKay, PhD, and Jeffrey B. Blumberg, PhD

The American (Vaccinium macrocarpon) is produced in Chile. Products of the cranberry industry one of the three commercially important fruits native include fresh fruit (5%), juices (60%), and sauces, dried to North America. are a particularly rich fruit and ingredients (35%), such as frozen fruit, juice source of phenolic phytochemicals, including phenolic concentrates, and spray-dried powders."2 acids (benzoic, hydroxycinnamic, and ellagic acids) Cranberries were used by Native New Englanders and flavonoids (anthocyanins, flavonols, and flavan- for food, fabric dye, and in poultices to treat wounds and 3-ols). A growing body of evidence suggests that blood poisoning. Early American sailors, including polyphenols, including those found in cranberries, whalers and mariners, consumed cranberries as an anti- may contribute to reducing the risk of cardiovascular scorbutic agent during ocean voyages. 3 Today, health disease (CVD) by increasing the resistance of LDL to benefits attributed to cranberries include the prevention oxidation, inhibiting platelet aggregation, reducing 7,8 blood pressure, and via other anti-thrombotic and of urinary tract infections46 and stomach ulcers as anti-inflammatory mechanisms. Research regarding well as improved oral hygiene. 9" 0 These benefits appear the bioactivity of cranberries and their constituents on to be due principally to the ability of cranberries to risk factors for CVD is reviewed. interfere with the adhesion of some bacteria to select cell Key words: cranberry, Vaccinium macrocarpon, fla- types and surfaces. For example, cranberries can prevent vonoid, proanthocyanidin, cardiovascular disease pathogenic P-fimbriated Escherichia coli from adhering © 2007 International Life Sciences Institute to uroepithelial cells, thereby reducing their ability to doi: 10. 1301/nr.2007.nov.490-502 proliferate in the urinary tract. Similarly, cranberries can prevent the adhesion of Helicobacter pylon, the caus- ative agent of most gastric and duodenal ulcers, to INTRODUCTION gastrointestinal mucosa, and inhibit the adhesion of oral pathogens such as Streptococcus mutans to tooth hy- The American cranberry (Vaccinium macrocarpon) droxyapatite. Cranberries and cranberry constituents is a low-growing, vining, woody perennial plant native to have also been shown to possess antibacterial, 1,12 anti- the northeastern part of North America, from eastern viral, 13 antimutageflic,4 anticarcinogenic, 15 antitumori- Canada to the US state of North Carolina. The edible red genic, 6 antiangiogenic, 7 and antioxidant activities." fruit, or cranberry, is one of only three commercially Recently, research on the effects of cranberries and important fruits native to North America, along with the their components has also focused on their use in the blueberry and Concord . Approximately 500-700 prevention and treatment of cardiovascular disease million pounds of cranberries are commercially pro- (CVD). Epidemiological studies have consistently shown duced worldwide, primarily across the northern United that the consumption of fruits and vegetables is inversely States (85%) and Canada (15%), with smaller amounts associated with the risk of developing CVD 19 and stroke .20 The phytochemical constituents of these foods 21,22 Drs. McKay and Blumberg are with the Antioxi- appear to contribute substantially to this benefit. dants Research Laboratory, Jean Mayer USDA Hu- Cranberries are a particularly rich source of phenolic man Nutrition Research Center on Aging, Tufts Uni- phytochemicals. Among the 20 most commonly con- versity, Boston, Massachussetts, USA sumed fruits in the American diet, cranberries have the Please direct all correspondence to: Dr. Diane L. highest total phenol content. 8 These phenolic com- McKay, Antioxidants Research Laboratory, Jean Mayer USDA Human Nutrition Research Center on pounds have a wide range of biological effects including Aging, Tufts University, 711 Washington Street, Bos- the ability to serve as antioxidants, modulate enzyme ton, MA 02111, USA. Phone: +1-671-556-3333; Fax: activity, and regulate gene expression. Experimental in + 1-617-556-3344; E-mail: [email protected] vitro studies suggest phenolics may affect the pathogen-

490 Nutrition Reviews®, Vol. 65, No. 11

esis of CVD by increasing the resistance of low-density tion. One serving of either product contains <0.6 g total lipoproteins (LDL) to oxidation, 23 preventing platelet fat, <0.05 g saturated fat, and no cholesterol or trans fat. aggregation and thrombosis, reducing blood pressure, In addition, dried cranberries provide >10% of the daily and/or inhibiting inflammation.2426 value of fiber and cocktail contains >100% of the daily value of vitamin C. With the NUTRIENT AND PHYTOCHEMICAL exception of cranberry juice cocktail, to which vitamin C CONSTITUENTS is added during processing, none of the cranberry prod- ucts listed in Table 1 is particularly high in the antioxi- The US Department of Health and Human Services! dant vitamins C or E or the mineral selenium, a cofactor US Department of Agriculture 2005 Dietary Guidelines for glutathione peroxidase. Thus, the reported antioxi- for Americans, 27 as well as dietary recommendations dant activity of cranberries is due to their constituent issued by the American Heart Association 28 promote the phenolics and carotenoids. daily consumption of fresh fruit and 100% fruit juices as Cranberries contain a higher amount of total phenols part of a healthy eating plan to reduce the risk of chronic per serving (507-709 mg gallic acid equivalents!100 g) diseases, particularly CVD, type-2 diabetes, osteoporo- than other common fruits including blueberries (258- sis, and some forms of cancer. Whole fruits like cran- 531 mg/100 g), apples (185-347 mg!100 g), red berries are naturally low in calories, fat, and sodium, (175-370 mg/100 g), and strawberries (132-368 mg!100 .34 contain no cholesterol, and are a good source of dietary g). 83233 Chen et al reported a total of 413 mgfL in fiber 29 (Table 1). Dried cranberries, cranberry juice, and freshly squeezed cranberry juice and 51 mg/L in a 27% juice cocktail similarly contain little sodium and fat. The cranberry juice cocktail. Vinson et al. 35 found a higher predominant type of fatty acids present in cranberries concentration (870 mg catechin equivalents/100 g total and cranberry products are polyunsaturated, and include phenols) in dried cranberries. Most of the phenolics in a-linolenic acid, 18:3n-3, which is present in the seed oil cranberries are present in a soluble free form (91.3- (22 g1100 g fatty acids) .30 A diet composed of foods low 96.2%).18.32 Cranberries are one of the few fruits con- in saturated fat and cholesterol, that also includes w-3 taining a large proportion of free phenolics, the others fatty acids, has been shown to have a positive effect on being avocados, honeydew melons, and oranges. plasma lipid profiles. Fiber intake, especially soluble The two major classes of phenolics identified in fiber like the pectin present in cranberries, 31 is also an cranberries are phenolic acids and fiavonoids (44% and 34 established part of "heart healthy" diets. Further, the high 56%, respectively, in freshly squeezed juice )(Table 2). ratio of potassium to sodium in cranberries and cranberry The most abundant phenolic acid identified by Zuo et al.2 products may contribute to the promotion of lower blood was benzoic acid (4.7 g/kg fresh weight), followed by the pressure. - hydroxycinnamic acids p-coumaric (0.25 g/kg fresh wt), Specific cranberry products, i.e., dried sweetened sinapic (0.21 glkg), caffeic (0.16 glkg), and ferulic acids cranberries and cranberry juice cocktail (27% juice), (0.088 glkg). Quantities of these and other phenolic acids have been recognized by the American Heart Associa- in cranberry juice have been reported by Zhang and tion as "heart healthy" based on their nutrient composi- Zuo.36

Table 1. Nutrient Content of Cranberries and Select Cranberry Products Whole raw Dried sweetened Juice, unsweetened Juice (27%) cocktail Nutrient (1 c or 95 g) (0.33 c or 40 g) (1 c or 253 g) (1 c or 253g)

123 116 137 44Energy (kcal) 6 220 218 Water (g) 83 0.03 0.99 0.00 Protein (g) 0.37 32.94 30.87 34.21 Carbohydrate (g) 11.59 0.55 0.32 0.25 Total lipid (g) 0.12 4.4 2.3 0.3 0 Fiber (g) 16 194 35 Potassium (mg) 81 4 5 Sodium (mg) 2 0.2 0.4 0.5 Selenium (p.g) 0.1 0 6 0 Vitamin A (g RAE) 3 12.6 0.1 23.6 107.0 Vitamin C (mg) 1.14 0.43 3.04 0.56 Vitamin E (mg c1-tocopherol) 0.0 68.3 13.0 n-Carotene (jig) 34.2 Lutein + zeaxanthin (jig) 86.45 13.40 172.67 33.00

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in

Table 2. Major Classes of Phenolic bonds .44,46,47 The A-type linkage is a structural feature Phytochemicals Identified in Cranberries that appears to be responsible for the unique antiadhesion Class Subclass Compound action and some of the antioxidant properties of cranber- ries.46464849 Phenolic acid Benzoic acid Hydroxycinnamic p-Coumaric Hammerstone, et al.50 calculated the procyanidin acid Sinapic content of cranberry juice to be 31.9 mg/8 oz serving Caffeic (0.14 gIL) by adding together the individual concentra- Ferulic tions of dimers through decamers. These authors also Ellagic acid reported that the most prevalent proanthocyanidins were Flavonoids Flavonols Quercetin the oligomers (0.13 of 0.14 gIL total procyanidins). In Myricetin comparision, a 3.5 oz serving of red wine contains 22.0 Flavan-3-ols Proanthocyanidins mg of proanthocyanindins, with a much higher propor- Epicatechin tion present as monomers (0.05 of 0.21 gIL total procya- Anthocyanins Cyanidin nidins). However, Hammerstone et al .50 did not account Peonidin for the polymeric proanthocyanidin content reported by Stilbenes Resveratrol Gu et al. 44 who analyzed freeze-dried cranberry material and found the concentration of higher oligomers (>10 mers) to be 20.58 of 32.65 mglg total procyanidins. The predominant flavonoids present in cranberries Taking the polymeric proanthocyanidins into account, include the anthocyanins, flavonols, and flavan-3-ols the total proanthocyanidin contents of whole cranberries (particularly proanthocyanidins). In cranberries, the six and cranberry juice cocktail have been reported as 418.8 major anthocyanins are peonidin-3 -galactoside, cyani- mg/100 g fresh weight and 85.5 mgIL (54.7 mg/8 oz din-3-galactoside, cyanidin-3-arabinoside, peonidin-3- serving), respectively, which consist entirely of proan- arabinoside, peonidin-3-glucoside, and cyanidin-3-glu- thocyanidins with the A-type linkage .5 The distribution coside. Quantities of these anthocyanins were reported in of proanthocyanidin monomers, dimers, trimers, oh- cranberry juice cocktail to be 2.8, 2.0, 1.4, 1.1, 0.3, and gomers, and polymers in these cranberry products is 0.2 ppm, respectively. , 3738 listed in Table 3,51 Quercetin, myricetin, and their glycosides are the The stilbene resveratrol has also been identified in major flavonols present in cranberries. 394 Chen et al.34 cranberries. Resveratrol has several biological effects reported that quercetin accounted for 75% of the total related to cardiovascular health including quenching re- flavonoids detected in their analysis of acid-hydrolyzed active oxygen species, inhibiting platelet aggregation, cranberry juice. Acid hydrolysis prior to high perfor- and reducing inflammation. 52 Stilbenes have also been mance liquid chromatography analysis yielded 175 mg/L identified in grapes, wine, and other Vaccinium berries. 53 quercetin and 47 mgIL myricetin from freshly squeezed Wang et al .52 found the resveratrol content of raw cran- 100% cranberry juice, while 12 mgfL quercetin and 2.9 berry juice (1.07 nmollg) to be comparable to grape juice mgtL myricetin were found in canned cranberry juice (1.56 nmollg). Rimando et al. 53 reported 900 ng/g dry cocktail (27% juice). Without acid hydrolysis, quercetin weight of resveratrol in freeze-dried cranberries, similar was not detected in freshly squeezed juice, whereas to that of highbush blueberries (V. corymbosum; myricetin was present at only 8.3 mg/L. According to the 1074 ng/g). US Department of Agriculture Database for the Fla- Other phenolic components of cranberry include vonoid Content of Selected Foods 42 the quercetin content ellagic acid (120 ppm on a dry weight basis, 3" 350 igIg dry of whole cranberries is 14.0 mgIlOO g, myricetin is 4.3 mg/100 g, and kaempferol is 0.1 mg/100 g. Proanthocyanidins, also called condensed tannins, Table 3. Distribution of Proanthocyanidins in are ubiquitous in plants, with fruits being the major Cranberries and Cranberry Juice source in the diet. 43 Procyanidins, a subclass of proan- Degree of polymerization thocyanidins, are mixtures of oligomers and polymers consisting of catechin and epicatechin units linked Raw Juice cocktail Proanthocyanidin (mg/100 g) (27%) (mg/8 oz) mainly through B-type bonds. 44 In experimental studies, procyanidins possess a variety of activities, including Monomers 7.3 1.4 antioxidant, antimicrobial, antiallergy, and antihyperten- Dimers 25.9 6.9 Trimers sive actions. 45 The procyanidins in cranberries contain 18.9 4.0 4-6 mers 70.3 11.6 more epicatechin than catechin (46.5% vs. 7.4% of 7-10 mers 62.9 9.7 terminal units) which, unlike most other procyanidin- Polymers (>10 mers) 233.5 21.1 containing foods, are predominantly linked via A-type

492 - Nutrition Reviews®, Vol. 65, No. 11 weight in cranberry pomace 54); the lignan secoisolarici- a variation of the oxygen radical absorbance capacity resinol (10.54 ppm on a dry weight basis); and the assay measuring antioxidant capacity to quench peroxyl triterpene ursolic acid. 55 Importantly, variability in the radicals in both lipophilic and hydrophilic compartments. nutrient and phytochemical composition of cranberries The total antioxidant capacity of cranberries, expressed occurs during fruit growth and ripening, 56 between cul- as trolox equivalents (TE), ranked highest (94.56 j.tmol 57 tivars,39 under different storage conditions, with envi- TE/g) among 24 commonly consumed fruits, followed ronmental stresses, and during post-harvest processing. closely by lowbush blueberries (92.60 j.tmol TE/g). Variations in the quantitative analyses of cranberry Cranberry was also ranked highest in total antioxidant components may also occur with different solvent ex- activity to quench peroxyl radicals in a study by Sun et traction and detection methodologies. Table 4 lists the al .32 using the total oxyradical scavenging capacity as- average quantities of selected phytochemicals ascer- say. The values for 11 common fruits were expressed as tained during a retail audit of cranberry juice cocktail micromoles of vitamin C equivalents/gram fresh weight samples (data provided by Ocean Spray Cranberries, and the antioxidant activity of a soluble, free phenolic Inc., Lakeville-Middleboro, MA, USA). extract of cranberry (177.0 jmol/g) was higher (P<0.01) than any other fruit tested including apple IN VITRO STUDIES (97.6 /Lmol/g), red grape (64.7 ,itmol/g), and strawberry (64.4 /Lmol/g). In one study, neither 100% cranberry Antioxidant Capacity juice nor cranberry juice cocktail was as effective as pomegranate juice in quenching the 1,1 -diphenyl-2-pic- Dietary antioxidants are associated with a reduced rylhydrazyl (DPPH) radical.62 511-60 risk of CVD and hypertension. The high concentra- The antioxidant activities of cranberry juice (from tion of phenolic compounds found in cranberries corre- pulverized de-seeded fruit pulp) against superoxide rad- lates with their high antioxidant capacity in vitro, 33,61 icals, hydrogen peroxide (H 202), hydroxyl radicals, and though this association varies depending on the assay singlet oxygen were among the highest in a study by used to assess this parameter. The total antioxidant ca- Wang et al .63 comparing different genotypes of cran- pacity of whole fruit was measured by Wu et al. 33 using berry, blackberry, blueberry, raspberry, and strawberry. Cold-pressed oil from cranberry seeds was shown to Table 4. Phenolic Phytochemical Content of have scavenging activity against the radicals 2,2-azino- Cranberry Juice Cocktail bis(3-ethylbenzthiazoline-6-sulfonic acid) and DPPH.64 Content Among four extracted seed oils tested (cranberry, black Phenolic compound (mg/8 oz serving) caraway, carrot, hemp), cranberry seed oil had the great- Proanthocyanidins 90 est DPPH scavenging activity (95% of DPPH quenched Total phenolics 211 with 11.3 mg oil equiv/mL), comparable to vitamin C Total anthocyanins 1.23 (8.8 mg/mL) and higher than vitamin E (21.5 mg/mL).64 Anthocyanins Roy et al. 17 found the oxygen radical absorbance capac- Cyanidin-3-galactoside 0.28 ity value of methanol-solubilized cranberry powder was Cyanidin-3-glucoside 0.003 comparable to elderberry and raspberry seed powders, Cyanidin-3-arabinoside 0.13 but lower (P<0.05) than strawberry, wild bilberry, and Peonidin-3-galactoside 0.58 wild blueberry powders. Antioxidant activity has also Peonidin-3-glucoside 0.034 been demonstrated in the extracted flavonol 41 procyani- Peonidin-3-arabinoside 0.20 din, anthocyanin, and phenolic of cran- Flavonols 49 Hyperoside 5.57 berries. Quercetin 3.12 Cranberries consistently rank high among common Myricetin 1.27 fruits in antioxidant activity. According to Halvorsen et Quercitrin 1.25 al.65 cranberries and cranberry juice also ranked high Avicularin 0.43 among other foods commonly found in the US diet. Phenolic acids Using the ferric reducing ability of plasma assay (FRAP) Benzoic acid 12.0 to analyze and rank 1113 food samples according to total Chlorogenic acid 2.64 concentration of redox-active compounds, whole cran- 4-Hydroxycinnamic acid 1.06 berries had the fifth highest concentration with 3.125 3,4-Dihydroxybenzoic acid 0.55 mmollserving (95 g or 1 cup), while cranberry juice was 0.29 Vanillic acid ranked thirteenth with 2.474 mmollserving (240 mL or 8 Caffeic acid 0.26 oz). When these same foods were ranked by antioxidant

Nutrition Reviews®, Vol. 65, No. 11 493 content per 100 g sample, cranberries were ranked twen- effective (P<0.05) at increasing the lag time: after , mix- ty-first with 3.289 mmol/100g. . ing with serum than fractions containing proanthocyani- Several in vitro studies have demonstrated the anti- dins -with a lower degree of polymerization (trimer - oxidant, activity of. cranberries using. assays measuring heptamer), flavonols, anthocyanins; or cinnamic acids. linoleic acid peroxidation, dieneconjugation1formation, or other end products of lipid peroxidation in LDL. I Wilson et al. 66 were the first to report the LDL protective Cholesterol Processing properties of cranberry juice (pressed berries) using this model. The formation of thiobarbituric acid reactive In addition to the anti -atherogenic potential of cran- substances from Cu2 4 -induced oxidation of LDL was berries increasing the resistance of LDL to oxidation, an suppressed at a dilution of 0.10% juice (P<0.001) com- acetone extract of this fruit has also been shown to pared to a control sample with no cranberry juice. Wilson increase cholesterol uptake by HepG2 hepatocytes and to elevate the synthesis of LDL receptors. Chu et al.68 et al .67 also observed the inhibition of 2,2-azobis-amidi- nopropane-initiated LDL oxidation by cranberry juice at demonstrated that adding a cranberry extract (15 and 30 mg/mL) to HepG2 cells increased LDL receptor expres- a dilution of 1:5000 (P<0.05), indicating the antioxidant sion (230% and 540%, respectively; P<0.05) and cho- action was not mediated via chelation of Cu 2 4. Chu et lesterol uptake (270% and 280%, respectively; P<0.05) al.68 determined the median effective dose (EC 50) of compared to controls. The enhanced synthesis of hepatic cranberry in a LDL oxidation model for antioxidant LDL receptors and influx of LDL cholesterol into hepa- capacity assay to be 1.46 mg cranberry/mL indicating the tocytes are actions suggesting accelerated cholesterol antioxidant activity of 100 g cranberries is equipotent to excretion may occur in vivo. 1012 mg vitamin C or 3700 mg vitamin E in this assay. Inhibition of LDL oxidation in vitro has also been dem- onstrated with cold-pressed cranberry seed oil (at Enzyme Modulation 2.8 mg/g oil)M as well as cranberry fractions composed of proanthocyanidins, 46469 procyanidins,49 and se- The antioxidant potential of phenolic compounds is lected flavonols and anthocyanins.41 not limited to their direct action in scavenging free Vinson et al. 8 used the phenl antioxidant index, a radicals. Phenolic compounds may also decrease oxida- combined measure of quantity and quality of phenol tive stress indirectly by inhibiting endogenous enzymes antioxidants, to rate 20 fruits consjmed in the American that generate reactive oxygen species, binding pro-oxi- diet. Antioxidant quality was measured by determining dant transition minerals like Cu 2 and Fe 3+ or activating th IC50 (concentration required to inhibit oxidation by antioxidant enzymes like superoxide: dismutase .70 Xan- 50%) in an assay using Cu 2 4-induced oxidation of thine oxidase (XO) converts xanthine to uric acid and LDL plus very low density lidprotein with thiobarbitu- generates superoxide and H202 as byproducts. Dew et tic acid.Although the IC 50 of botH free (0.86 1.tM) and al.7 examined the XO inhibitory activity of several plant total phols (0.75 j.M)extracted from cranberry was foods. In their analysis of fruit juices, only cranberry and quite potent in this assay it, as less effective than purple grape juices were able to inhibit XO with IC50 etrats from cherries, red , grapes, bluebeiries, strawber- values of 2.4 and 3.5%, respectively, while apple, or- ri, aridwhite graes.1n ompâiisoriof s,35 ange, pineapple, and pink grapefruit juices promoted XO the ic;0 of crnhèrristi 0.42 LiM, indicating it was activity. less potnt than figs (0.23iM), diièd plurii (0.23 ,i.ti4), Treatment with cranberry juice powder.stimulated and raisiiis (0:29 AM). Adcàrdingtb Vinson etil., 35 the the cellular antioxidant systems involving superoxide 1C 0 values f6rfresh ctanberries(0.86 j.tM) gripés (0.75 dismutase, catalase, and peroxidase in oxidatively stressed .tM), and plums (0.70 M) are much lower than values porcine muscle tissue according to Vattern etal.72.. of their respective dried fruits (P0.05), suggdstiñ that Cranberry components have also been shown to the antioxidants in dried fruits are of higher "ualit modulate the activity of enzymes produced byperiodon- according to Phenol AntiOXidant Index criteria. tal pathogens and cariogenic bacteria. Proteinaises pro- Cranberry phenolics, when mixed with plasma or duced by , Porphyromonas gingivalis, Tannerella for- tc modified serum prior to LDL isolation, remain associated sythia, and Treponema denticola participate in 1 the with lipoproteins after their isolation, and subsequently development of periodontis by degrading connective increase the lag time of Cu2tinduced LDL oxida: tissue proteins, disrupting host defense mechanisnis, and tion. 869 Porter et al .69 determined that a cranberry- enabling these pathogens to derive nergy from prdtein derived fraction containing proanthocyanidin oligorners sources. Bodet et al. 73 demonstrated that high molecular with a higher degree of polymerization (pentamer - weight nob-dialyzable material extracted from cranberry nonamer) and more than one A-type bond was more juice doncentrate (65.1% proanthocyanidins, 0.35% an-

494 Nutrition Reviews®, Vol. 65, No. 11 thocyanins) is able to inhibit proteinases from these cyanin fraction was also able to suppress the up-regula periodoñtopathogens, thereby reducing their pathogenic- tion of the inflammatory mediators interleukin (IL)-8, ity. In a study by Duarte et al .74 flavonol and proantho- intercellular adhesion molecule-1 (ICAM-1),and mono- cyanidin-rich cranberry fractions inhibited the activites cyte chemoattractant protein-] (MCP-1) in humaii mi- of surface-absorbed glucosyltransferases and F-ATPases crovascular endothelial cells following exposure to the produced by the oral bacteria Streptococcus mutans. pro-inflammatory cytokine tumor necrosis factor-a Topical application of these cranberry phenolics signif- (TNF-a) compared to non-treated control cells icantly affected S. mutans bioflim development and aci- (P<0.001). In contrast, the hydroxycinnamic acid frac- dogenicity (P<0.05), which could prevent the develop- tion was not able to suppress MCP-l. Bodet et al.8 ment of dental caries. Given the emerging connection found that treating macrophages with non-dialyzable between oral health and CVD, 7576 it is possible that cranberry material prior to lipopolysaccharide stimula- cranberries may play a role in preventing heart disease tion also reduced (P<0.05) the production of pro-inflam- via this mechanism. However, further research is re- matory cytokines and chemokines. quired before any conclusions about this mechanism can be drawn. ANIMAL MODELS Neuroprotection Vasodilation/Hypotensive Effect In vitro studies simulating stroke in rat brain neurons The in vivo vasodilatory effects of cranberry juice were reported by Neto et al .77 They observed that rat were demonstrated in a rat model by Maher et al. 82 A brain neurons treated with whole cranberry extracts suf- bolus of either cranberry juice (first press) or saline was fered 43% less necrosis induced by oxidative stress administered intravenously to anesthetized rats (N= 12) compared to controls, and that necrosis induced by con- ditions of ischemia declined by 49%•77 Among the dif- at a dose approximately 1/100 of their blood volume and ferent fractions derived from the cranberry extract, a heart rate and blood pressure measured for 20 mm. combination of anthocyanins and flavonols was most Although the baseline mean arterial blood pressure effective at reducing cell death (40% at 100 g/mL). (MAP) was 15% higher in the rats treated with cranberry Joseph et al .78 tested extracts of cranberry, blue- juice (100 vs. 85 mmHg in saline1reated rats), the berry, grape, boysenberry, black currant, dried plum, and cranberry treatment decreased MAP to 80 mmHg (16% strawberry, for their ability to protect muscarinic recep- below baseline). In contrast, the saline treatment in- tors in transfected COS-7 cells from oxidative stress. creased MAP to 105 mmHg (24% higher than baseline). Muscarinic receptors are involved in neuronal and vas- Interestingly, the heart rate of the cranberry-treated rats cular functioning and show differential sensitivity to increased progressively over the course of the experi- oxidative stress. Each of the fruit extracts showed some ment (from 216 to 253 bpm), whereas the heart rate degree of protection with pretreatment. Blueberry, boy- increased only slightly (from 240 to 247 bpm) in saline- senberry, and grape provided the most protection, i.e:, treated rats. The cardioaccelerator effect of cranberry they were not significantly different from their respective juice may be a result of arterial dilation, where reduced non-stressed controls, .while dried plum and strawberry vascular resistance requires a compensatory increase in were the least effective (P<0.001 from respective con- cardiac output. trols). Black currant and cranberry were considered In an accompanying experiment, .cranberry juice somewhat protective (P<0.05 from respective control). was able to vasodilate isolated rat aorta in the presence of a functional endothelium. Intact rings were dilated Anti-inflammation 56.7% by cranberry juice compared to 8.9% in denuded ... ..- I. rings (P<0.002). N-nitro-L-arginine methyl ester, a Oxidative stress and , inflammationare risk factors competitive inhibitor of nitric oxide synthase, was-added for the intiation and pathogenesis, of CVD. 79 Cranberry to assess whether the effects of cranberry were depen- flavonoidshave beenshown to protect endothelial, cells dent on nitric oxide formation by the endothelium. N- against oxidative stress.arid inhibit s pro-inflammatory nitro-L-arginine methyl ester reversed cranberry-induced responses in vitro .80,81 .-For example: .Youdim -et al.8? vasorelaxation in intact rings (0.54 g contraction) and found treatment of -human - microvascular endothelial slightly increased tension in denuded rings (0.04 g; cells with either cranberry anthocyanins (0.1 mg/mL) or P<0.007). These results indicate that the vasodilatory hydroxycinnamic acids (0.1 mg/mL) reduced (P<0.05) effects of cranberry juice are dependent on endothelial intracellular H202-induced damage and inhibited oxida- cell, nitric oxide formation. Similar effects have been tionof cell membrane fatty acids. The cranberry antho- previously, observed with grape juice and wine. 83,84

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Hypercholesterolemic Effects juice consumption increased the absorption of dietary salicylic acid. A daily, low-dose (-75 mg) aspirin (ace- An atherogenic animal model was also used by tylsalicylic acid) is an established therapy for patients at 85 Reed to examine the effects of cranberry juice powder risk for CVD. 87 The two groups, matched for age, on blood cholesterol levels. Normal and familial hyper- weight, and height, were randomized to receive either cholesterolemic (FH) swine (N = 4/group) were fed a diet cranberry juice cocktail (consumed in 3 daily servings of supplemented for 2 weeks with 57 g/d fructose and 47 250 mL) or a placebo beverage containing 9% (w/v) of g/d citric acid to simulate the amounts of these ingredi- sucrose for 2 weeks. The total salicylate content of the ents in cranberry juice cocktail. On day 15 the swine cranberry juice was 7.04 mg/L; none was found in the were fed cranberry juice powder at 150 g/d for 4 weeks. placebo beverage. Within 1 week, increases in urinary Total blood cholesterol (TC), LDL and high density salicylic acid and salicyluric acid were detected in sub- lipoprotein (HDL) levels were determined weekly. At jects consuming the cranberry juice compared to the baseline, the TC level in FH pigs was 7-times higher than placebo subjects (P<0.001). After 2 weeks, salicylic in normal pigs (458 vs. 67 mg/dL, respectively; acid levels had increased in the plasma of the cranberry P<0.0001), while LDL levels were 11-times higher (428 juice group (P<0.05). vs. 37 mg/dL). By the end of the intervention, TC in FH pigs decreased by 92 mg/dL and LDL decreased by 94 mg/dL. No effects on TC or LDL were observed in Antioxidant Status and Oxidative Stress normal pigs. The results of this experiment suggest that The effects of cranberry juice consumption on cranberry juice or powder may have the potential to plasma antioxidant activity and biomarkers of oxidative lower cholesterol in hypercholesterolemic patients. stress were examined in 20 healthy young females (age 18-40 years) in a placebo-controlled trial by Duthie et HUMAN STUDIES al.88 Free-living subjects consumed 750 mL/d of either cranberry juice cocktail or a placebo drink containing Bioavailability strawberry-flavored mineral water plus 9 g1100 mL su- crose for 2 weeks. Anthocyanin glycosides were identi- Zhang and Zuo36 developed a gas chromatography- fied in the cranberry juice by tandem mass spectrometry; mass spectrometry method for detecting various cran- however, no anthocyanins or catechins were detected in berry juice phenolic compounds, including benzoic acids the plasma of subjects following either treatment. The and flavonoids, in human plasma. The presence of 16 antioxidant capacity of plasnii was measured with elec- phenolic compounds was detected in a single subject tron spin resonance spectrometry, the FRAP assay, and when this method was applied to cranberry juice cock- changes in the activity of superoxide dismutase, glu- tail. Prior to the consumption of the cranberry juice, no tathione peroxidase, and catalase. In urine, malondi- benzoic, phenolic, or flavonoid compounds were ob- aldehyde, a biomarker of lipid oxidation, and 8-oxo- served in the fasting plasma sample. At 45 min after deoxyguanosine, a biomarker of oxidative DNA consumption of 1800 mL juice, benzoic acid, o-hydroxy- damage, were measured. Although plasma levels of benzoic acid, p-hydroxyphenylacetic acid, 2,3-dihy- the antioxidant vitamin C increased significantly in droxybenzoic acid, and 2,4-dihydroxybenzoic acid were subjects who consumed the cranberry juice (from 63.0 detected in plasma. At 270 min after consumption, seven to 89.6 1LM after 1 week; P<0.01), no changes in the benzoic and phenolic compounds were detected, includ- antioxidant capacity of plasma or oxidative stress ing the five compounds listed above plus ferulic and biomarkers in urine were detected in either group. sinapic acids. Benzoic acid was the most prevalent aro- Similarly, TC, HDL, LDL, triglyceride, and total ho- matic compound present both in the cranberry juice (54 mocysteine levels were unchanged. The absence of an J.Lg/mL) and in plasma after juice consumption (4.40 increase in the FRAP contrasts with other reports that tg/mL after 40 mm; 3.11 g/mL after 270 mm). Many found an increase in this parameter after comparable of the phenolic compounds identified in the cranberry changes in plasma vitamin C.899 juice cocktail were not detected in the plasma samples, Using a Latin square design, Pedersen et al. 92 were although p-hydroxyphenylacetic and 2,4-dihydroxyben- able to detect changes in plasma phenols and antioxidant zoic acid were identified in plasma but not in juice. These potential in nine healthy women (age 23-41 y) within compounds are likely metabolites of the cranberry juice hours of consuming cranberry juice cocktail. After fast- phenolics. ing overnight, each subject consumed 500 mL of either In a placebo-controlled study of 22 healthy women cranberry juice, blueberry juice, or a control beverage (mean age 27.5 years) not taking aspirin or other salic- containing 9% (w/v) sucrose in water. Each volunteer ylate drugs, Duthie et al. 86 determined that cranberry participated on three occasions separated by I week, con-

496 Nutrition Reviews®, Vol. 65, No. 11 suming one of the beverages during each visit; blood studies by Caron et al.,95 Ruel et al. (unpublished), and samples were collected 5 min before and 0.5, 1.0, 2.0, Vinson et al.96 Caron et al.95 reported the effect of and 4.0 h after consumption. Total phenols in plasma and consuming either low-calorie cranberry juice (4.3 mL/ urine were measured using Folin-Ciocalteu reagent with kg) or an isocaloric placebo twice daily for 28 days. a modification to remove protein interference in the Subjects who consumed the cranberry juice had signifi- samples. Consumption of the cranberry juice resulted in cantly reduced TC (P<0.026) and LDL (P<0.014) com- a significant increase in total phenols after 1 h compared pared to the placebo control subjects. No statistically with the control (P<0.05), whereas the blueberry juice significant differences were observed for HDL or triglyc- did not. Plasma antioxidant potential, measured with eride concentrations. electron spin resonance and the FRAP assay, also in- Ruel et al. (unpublished) and Vinson et al.96 each creased after consumption of the cranberry juice but not reported the results of uncontrolled studies examining the blueberry juice (P<0.001). The investigators attrib- the effects of cranberry juice consumption over 3 months uted these changes primarily to the 30% increase in subjects with hypercholesterolemia. Ruel et al. had 14 (P<0.001) in plasma vitamin C concentrations that ap- men (mean age 48 years) consume 125 mL/d of juice for peared between 0.5 and 4.0 h following cranberry juice 4 weeks, then 250 mL/d for the next 4 weeks, followed consumption. by 500 mL/d for the last 4-week period. At the end of In an uncontrolled study of 21 healthy men (mean their experiment, HDL concentrations were increased age 38 years), Ruel et al. 93 assessed the antioxidant compared to baseline (6.4% or 0.12 mmolIL; P<0.05). capacity of plasma following the daily consumption of With 19 subjects (11 females) and a similarly designed light cranberry juice cocktail at 7 mL/kg for 14 days. An intervention, Vinson et al .96 observed significantly im- increase in the plasma total antioxidant capacity, mea- proved HDL concentrations with either 2 or 3 servings of sured with the 2,2-azino-bis(3-ethylbenzthiazoline-6- cranberry juice daily. In this experiment, 2 daily servings sulfonic acid) radical cation (+0.11 tmol/L; P<0.05), of cranberry juice also decreased LDL, though no effect and a reduction in plasma oxidized LDL concentration, on TC was observed. As anticipated, triglycerides were measured with an enzyme-linked immunoabsorbent as- elevated in the subjects who consumed 3 servings/d of say kit (-6.0 UIL; P<0.05), from baseline to the end of cranberry juice cocktail due to the 9% (w/v) sugar, but the intervention were observed. No changes were ob- not in those who consumed the cranberry juice cocktail served in the lipoprotein-lipid profile of subjects, includ- containing artificial sweetener. ing LDL peak particle sizing, after the intervention. Ruel et al.94 later reported additional findings from Ruel et al.94 also examined total antioxidant capacity their completed experimental cohort of 31 men (mean and oxidative stress levels following the consumption of age 51 years). At baseline, subjects had mildly elevated increasing doses of light cranberry juice cocktail (125, fasting LDL (3.4-5.0 mmolJL) and an initial waist cir- 250, and 500 mL) over a 3-month period. In this uncon- cumference of ^90 cm. Prior to the 3-month intervention trolled study of 31 men with mildly elevated LDL (3.4- with progressively increased doses of low-calorie, sugar- 5.0 mmolIL) and increased waist circumference (^-90 free cranberry juice cocktail (described above), subjects cm), the antioxidant capacity of plasma, measured with a consumed 500 mL/d of a placebo juice for a 4-week commercial kit (ImAnOx; ALPCO Diagnostics, run-in period. HDL levels in the complete cohort in- Windham, NH, USA) significantly changed over the creased significantly over the course of the intervention course of the intervention (P<0.006). After an intial (P<0.001). Compared to values after the run-in period, increase (from 244.8 to 256.9 .tmoWL) following the 125 HDL concentration increased by 8.6% (P<0.05) after mL dose of cranberry juice, plasma antioxidant capacity the consumption of 250 mL/d, and plateaued after 500 declined after the 250 mL (250.3 .tmolfL) and 500 mL mL/d was consumed (8.1% increase, P<0.001). In- doses (241.5 j.molIL) to a level below baseline. How- creases in HDL were correlated with changes in body ever, oxidative stress, measured as nitrite/nitrate (NO) weight (r=-0.37, P<0.04), BMI (r=-0.42, P<0.02), concentrations, significantly decreased following the 500 apo A-I concentration (r=0.62, P<0.00), and triglycer- mL dose compared to baseline (-7.4%, P<0.05). Inter- ides (r=-0.39, P<0.03). In a multivariate regression estingly the change in NO was correlated with increased analysis, only the changes in plasma apo A-I (R2=48%, apo A-I concentrations over the course of the interven- P<0.00) and triglycerides (R2 = 16%, P<0.001) were tion (R-4.5, P<0.013). related to the increase in HDL. Increased production of apo A-I has been observed following the consumption of Lipid Profile Effects wine, 97 although this mechanism has not been examined with cranberry consumption. It is also possible that the The effects of cranberry juice consumption on lipid cranberry juice protected apo A-I from oxidation, though profile changes have been investigated in preliminary this parameter was not measured. While it appears that

Nutrition Reviews®, Vol. 65, No. 11 497 changes in HDL may occur only with increased dosage tabolized almost exclusively by CYP2C9 in humans. and duration of cranberry juice consumption, it is not According to Greenblatt et al., 102 the administration of clear why changes in LDL or TC do not. 8 oz cranberry juice, grape juice, or tea did not alter the CYP2C9-mediated clearance of flurbiprofen in 14 Platelet Aggregation healthy volunteers, although grape juice and tea did impair this activity in vitro. Grenier et al. 103 found that A preliminary investigation by Wilson et a] .98 eval- 240 mL cranberry juice had no significant effect on the uated the ability of cranberry juice to inhibit platelet overall disposition of cyclosporine (200 mg), a sub- aggregation in vivo. After 4 days of consuming cranberry strate for CYP3A, when administered together, al- juice four times daily, platelet-rich plasma aggregation though 240 mL of pomelo juice did when compared to values, in response to adenosine diphosphate and colla- water as the control (P<0.00, N= 12). gen, declined significantly compared to baseline values. These aggregation reponses returned to near baseline CONCLUSION levels 4 days after cessation of cranberry juice consump- tion. Attempts to recreate the inhibition of adenosine A growing body of literature indicates polypheno- diphosphate- and collagen-induced aggregation in vitro lics, including those found in cranberries, may contribute by adding cranberry juice to platelet-rich plasma from to reducing the risk of CVD by increasing the resistance subjects who did not consume cranberry juice were not of LDL to oxidation, inhibiting platelet aggregation, successful. reducing blood pressure, and via other anti-thrombotic and anti-inflammatory mechanisms. 26,104 While most of this evidence is derived from in vitro studies and animal Control of Blood Glucose models, a limited number of human studies indicate these phytochemicals are bioavailable and bioactive. More Diabetic patients are at increased risk of developing information is required on the bioavailability and metab- CVD. In a placebo-controlled study of 27 adults diagnosed olism of cranberry polyphenolics as well as on the with type 2 diabetes within the previous 4-6 years, Cham- relationship between cranberry dose and duration of use bers et al.99 examined the effect of cranberry juice concen- to better understand their impact on risk factors for CVD, trate powder on measures of glucose control. Subjects in the particularly clinically meaningful parameters such as treatment group (N=14, mean age 57.9 years) consumed inflammation, insulin resistance, vascular reactivity, and six capsules of cranberry powder (equivalent to a 240 mL vascular remodeling. serving of cranberry juice cocktail) daily for 12 weeks. Control subjects (N= 13, mean age 52.6 years) received ACKNOWLEDGEMENTS capsules containing a placebo powder. At baseline, >50% of subjects were reported to have good control of their Support for this review was provided by the US blood glucose levels (<7.0 mmolfL). After 6 and 12 weeks, Department of Agriculture (USDA) Agricultural Re- no differences were observed between groups in fasting search Service under Cooperative Agreement No. 58- glucose, glycosylated hemoglobin (HbA 1 ), fructosaniine, 1950-7-707. We thank Dr. David Cunningham and triglyceride, HDL, or LDL concentration. However, at Robin Roderick at Ocean Spray Cranberries, Inc. for week 12, cranberry-supplemented subjects had lower providing the data presented in Table 4. The contents of insulin levels (86 pmolIL) than placebo subjects (P<0.05) this publication do not necessarily reflect the views or (160 pmollL). policies of the USDA, nor does mention of trade names, commercial products or organizations imply endorse- SAFETY ment by the US government.

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