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Cranberries and Their Bioactive Constituents in Human Health

Posted: November 14, 2013
Authors: Jeffrey B. Blumberg, Terri A. Camesano, Aedin Cassidy, Penny Kris-Etherton, Amy Howell, Claudine Manach, Luisa M. Ostertag, Helmut Sies, Ann Skulas-Ray, and Joseph A. Vita
Journal: Adv. Nutr. 4: 618–632, 2013

Abstract: Recent observational and clinical studies have raised interest in the
potential health effects of cranberry consumption, an association that
appearsto be due to the phytochemical content of this fruit. The profile of
cranberry bioactives is distinct from that of other berry fruit, being
rich in A-type proanthocyanidins (PACs) in contrast to the B-type PACs present
in most other fruit. Basic research has suggested a number of potential
mechanisms of action of cranberry bioactives, although further molecular
studies are necessary. Human studies on the health effects of cranberry
products have focused principally on urinary tract and cardiovascular
health, with some attention also directed to oral health and
gastrointestinal epithelia. Evidence suggesting that cranberries may decrease the
recurrence of urinary tract infections is important because a nutritional
approach to this condition could lower the use of antibiotic treatment
and the consequent development of resistance to these drugs. There is
encouraging, but limited, evidence of a cardioprotective effect of
cranberries mediated via actions on antioxidant capacity and lipoprotein
profiles. The mixed outcomes from clinical studies with cranberry
products could result from interventions testing a variety of products,
often uncharacterized in their composition of bioactives, using different
doses and regimens, as well as the absence of a biomarker for compliance
to the protocol. Daily consumption of a variety of fruit is necessary to
achieve a healthy dietary pattern, meet recommendations for micronutrient
intake, and promote the intake of a diversity of phytochemicals. Berry
fruit, including cranberries, represent a rich source of phenolic bioactives
that may contribute to human health.

A randomized clinical trial to evaluate the preventive effect of cranberry juice (UR65) for patients with recurrent urinary tract infection

Posted: September 15, 2013
Authors: Takahashi S. Hamasuna R. Yasuda M. Arakawa S. Tanaka K. Ishikawa K. Kiyota H. Hayami H. Yamamoto S. Kubo T. Matsumoto T.
Journal: J Infect Chemother 19(1):112-7

Abstract: We examined the rate of relapse, as a variable index, in patients with urinary tract infection (UTI) who suffered from multiple relapses when using cranberry juice (UR65). A randomized, placebo-controlled, double-blind study was conducted from October 2007 to September 2009 in Japan. The subjects were outpatients aged 20 to 79 years who were randomly divided into two groups. One group received cranberry juice (group A) and the other a placebo beverage (group P). To keep the conditions blind, the color and taste of the beverages were adjusted. The subjects drank 1 bottle (125 mL) of cranberry juice or the placebo beverage once daily, before going to sleep, for 24 weeks. The primary endpoint was relapse of UTI. In the group of females aged 50 years or more, there was a significant difference in the rate of relapse of UTI between groups A and P (log-rank test; p = 0.0425). In this subgroup analysis, relapse of UTI was observed in 16 of 55 (29.1 %) patients in group A and 31 of 63 (49.2 %) in group P. In this study, cranberry juice prevented the recurrence of UTI in a limited female population with 24-week intake of the beverage.

Berries reduce postprandial insulin responses to wheat and rye breads in healthy women

Posted: September 15, 2013
Authors: Torronen R. Kolehmainen M. Sarkkinen E. Poutanen K. Mykkanen H. Niskanen L.
Journal: J Nutr 143(4):430-6

Abstract: Starch in white wheat bread (WB) induces high postprandial glucose and insulin responses. For rye bread (RB), the glucose response is similar, whereas the insulin response is lower. In vitro studies suggest that polyphenol-rich berries may reduce digestion and absorption of starch and thereby suppress postprandial glycemia, but the evidence in humans is limited. We investigated the effects of berries consumed with WB or RB on postprandial glucose and insulin responses. Healthy females (n = 13-20) participated in 3 randomized, controlled, crossover, 2-h meal studies. They consumed WB or RB, both equal to 50 g available starch, with 150 g whole-berry puree or the same amount of bread without berries as reference. In study 1, WB was served with strawberries, bilberries, or lingonberries and in study 2 with raspberries, cloudberries, or chokeberries. In study 3, WB or RB was served with a mixture of berries consisting of equal amounts of strawberries, bilberries, cranberries, and blackcurrants. Strawberries, bilberries, lingonberries, and chokeberries consumed with WB and the berry mixture consumed with WB or RB significantly reduced the postprandial insulin response. Only strawberries (36%) and the berry mixture (with WB, 38%; with RB, 19%) significantly improved the glycemic profile of the breads. These results suggest than when WB is consumed with berries, less insulin is needed for maintenance of normal or slightly improved postprandial glucose metabolism. The lower insulin response to RB compared with WB can also be further reduced by berries.

Bioactivities of pilot-scale extracted cranberry juice and pomace.

Posted: September 15, 2013
Authors: Harrison JE, Oomah BD, Diarra MS, Ibarra-Alvarado C
Journal: J Food Process Pres 37(4):356-365

Abstract: Fresh cranberries were processed by two pilot-scale methods to recover juice and extracts from cranberry pomace. Press cake was extracted with three successive ethanol soaks followed by decanting in trial 1 versus one ethanol soak and solvent removal by decanting and compressing with the bladder press in trial 2. Yields and recoveries of juice, dry juice solids, press cake, press cake extractives (PCEs), polyphenolics and antioxidant capacity were determined relative to the input material of fresh cranberries or press cake. PCEs from both processes exhibited strong dose-dependant vasorelaxant effects on rat aorta rings with EC50 of 2.3-3.9 micro g/mL and Emax of 96-98%. PCEs contained three to four times the phenolic acids, tartaric esters and antioxidant activities plus five to 10 times the flavonols and anthocyanins of their respective juice powders. The polyphenolic levels were 121-142, 7-10, 9-11 and 10-19 mg equivalents of catechin, caffeic acid, quercetin and cyanidin-3-glucoside/g of extract, respectively. Antioxidant activities of the PCEs and juices were 201-296 and 64-75 mg trolox equivalents/g powder. Juice yields of 47-58% accounted for only 18-50% of the bioactives recovered from whole fruit. Sequential extraction of the press cake with 95% ethanol and removal of the extract with the bladder press favored high recoveries of polyphenolics with increased antioxidant and vasorelaxant benefits.

Chronic cranberry juice consumption restores cholesterol profiles and improves endothelial function in ovariectomized rats.

Posted: September 15, 2013
Authors: Yung LM, Tian XY, Wong WT, Leung FP, Yung LH, Chen ZY, Lau CW, Vanhoutte PM, Yao X, Huang Y
Journal: Eur J Nutr 52(3):1145-55

Abstract: PURPOSE: Postmenopausal women experience higher risks for cardiovascular diseases than age-matched men and pre-menopausal women. There is a need for better treatment strategy for estrogen-deficient-related cardiovascular complications. We and others have recently reported that activated renin-angiotensin system and the associated oxidative stress impaired endothelium-dependent relaxation in ovariectomized rat, while angiotensin receptor blocker rescues endothelial dysfunction. Dietary supplements and lifestyle modifications provide an alternative way to improve cardiovascular health. The present study tests the hypothesis that chronic cranberry juice consumption improves cholesterol profiles and vascular functions in estrogen-deficient animal model. The effect of cranberry consumption on expression and activity of renin-angiotensin system in the vasculature will be determined.
METHODS: Ovariectomized rats were treated daily with commercial cranberry juice at 7 mg/kg for 8 weeks, a dosage comparable to recent clinical studies. Serum was collected for measuring cholesterol levels while aorta was isolated for isometric force assay and expression studies.
RESULTS: Cranberry juice consumption reduced circulating levels of total cholesterol, triacylglycerols, HDL, nHDL, and nHDL/HDL ratio. Meanwhile, cranberry juice consumption improved endothelium-dependent relaxation in aorta of ovariectomized rats by restoring p-eNOS level (endothelial nitric oxide synthase phosphorylated at ser-1177), reversing the up-regulated levels of renin-angiotensin system markers (angiotensin-converting enzyme, angiotensin II, and angiotensin II type 1 receptor), and normalizing the elevated NAD(P)H oxidase expression and oxidative stress.
CONCLUSIONS: Our data demonstrate the novel cardiovascular benefits of cranberry juice consumption in improving both vascular functions and cholesterol profiles, providing insight into developing cranberry products into useful dietary supplements for postmenopausal women.

Cranberries and wild blueberries treated with gastrointestinal enzymes positively modify glutathione mechanisms in Caco-2 cells in vitro

Posted: September 15, 2013
Authors: Slemmer JE, Livingston-Thomas JM, Gottschall-Pass KT, Sweeney MI
Journal: J Food Sci 78(6):H943-7

Abstract: Beneficial health effects of cranberries (CBs) and wild blueberries (BBs), such as reduced levels of oxidative stress, have been demonstrated in feeding studies. These Vaccinium berries contain high levels of flavonoids; however, the bioavailability of flavonoids is generally low. We investigated the in vitro effects of these berries on intestinal cells, focusing on mitigating oxidative stress and associated reactive oxygen species (ROS). First, we simulated the passage of CB and BB through the gastrointestinal (GI) tract by treating berry homogenates to a battery of digestive enzymes. Then, Caco-2 cells, a model of small intestine epithelial uptake, were exposed to these homogenates for 60 min. Using a cell-free assay, we found that the antioxidant activity in CB homogenates was not affected by these enzymes, but that BB homogenates treated with gut enzymes had 43% lower free-radical quenching activity (P < 0.05). However, both of the enzyme-treated homogenates were still able to counteract the ROS-generating ability of H2O2 added exogenously to Caco-2 cells. Berry homogenates also increased mitochondrial metabolic rates at 60 min posttreatment, as measured by MTT assays. Enzyme-treated CB (but not BB) homogenates increased the levels of reduced glutathione (GSH) relative to oxidized glutathione (GSSG), a critical indicator of the cellular redox state (P < 0.05). Our data suggest that CBs do not lose their antioxidant ability when passing through the GI tract, and specifically, digested CB may serve to enhance cytoprotective effects in intestinal cells by reducing potential damage caused by free radicals and ROS derived from other food sources

Cranberry extract suppresses interleukin-8 secretion from stomach cells stimulated by Helicobacter pylori in every clinically separated strain but inhibits growth in part of the strains

Posted: September 15, 2013
Authors: Matsushima M, Suzuki T, Masui A, Mine T, Takagi A
Journal: J Funct Food 5(2):729–35

Abstract: It is known that cranberry inhibits the growth of Helicobacter pylori (HP). In human stomach, HP basically induces chronic inflammation by stimulating stomach cells to secrete interleukin (IL)-8 and other inflammatory cytokines, and causes stomach cancer, etc. The aim of this study was to investigate the inhibiting effects of cranberry on HP growth and IL-8 secretion from stomach cells induced by HP, using clinically separated HP strains. HP growth in liquid culture and on-plate culture was evaluated by titration after 2-day incubation and by agar dilution technique, respectively. For IL-8 experiments, MKN-45, a stomach cancer cell line, was incubated with HP for 24 h and IL-8 in the medium was assayed by ELISA. Cranberry suppressed growth of the bacteria only in six of the 27 strains. Meanwhile, it suppressed IL-8 secretion in all the strains. The results may suggest a possible role of cranberry in prevention of stomach cancer by reducing gastric inflammation.

Cranberry impairs selected behaviors essential for virulence in Proteus mirabilis HI4320

Posted: September 15, 2013
Authors: McCall J, Hidalgo G, Asadishad B, Tufenkji N
Journal: Can J Microbiol 59(6):430-436

Abstract: Proteus mirabilis is an etiological agent of complicated urinary tract infections. North American cranberries (Vaccinium macrocarpon) have long been considered to have protective properties against urinary tract infections. This work reports the effects of cranberry powder (CP) on the motility of P. mirabilis HI4320 and its expression of flaA, flhD, and ureD. Our results show that swimming and swarming motilities and swarmer-cell differentiation were inhibited by CP. Additionally, transcription of the flagellin gene flaA and of flhD, the first gene of the flagellar master operon flhDC, decreased during exposure of P. mirabilis to various concentrations of CP. Moreover, using ureD-gfp, a fusion of the urease accessory gene ureD with gfp, we show that CP inhibits urease expression. Because we demonstrate that CP does not inhibit the growth of P. mirabilis, the observed effects are not attributable to toxicity. Taken together, our results demonstrate that CP hinders motility of P. mirabilis and reduces the expression of important virulence factors.

Cranberry Proanthocyanidins Improve Intestinal sIgA During Elemental Enteral Nutrition

Posted: September 15, 2013
Authors: Pierre JF, Heneghan AF, Feliciano RP, Shanmuganayagam D, Krueger CG, Reed JD, Kudsk KA
Journal: JPEN J Parenter Enteral Nutr DOI: 10.1177/0148607112473654

Abstract: Background: Elemental enteral nutrition (EEN) decreases gut-associated lymphoid tissue (GALT) function, including fewer Peyer's patch lymphocytes and lower levels of the tissue T helper 2 (Th2) cytokines and mucosal transport protein polymeric immunoglobulin receptor (pIgR), leading to lower luminal secretory immunoglobulin A (sIgA) levels. Since we recently demonstrated that cranberry proanthocyanidins (PACs) maintain the Th2 cytokine interleukin (IL)-4 when added to EEN, we hypothesized the addition of PACs to EEN would normalize other GALT parameters and maintain luminal levels of sIgA. Methods: Institute of Cancer Research mice were randomized (12/group) to receive chow, EEN, or EEN + PACs (100 mg/kg body weight) for 5 days, starting 2 days after intragastric cannulation. Ileum tissue was collected to measure IL-4 by enzyme-linked immunosorbent assay, pIgR by Western blot, and phosphorylated STAT-6 by microarray. Intestinal wash fluid was collected to measure sIgA by Western blot. Results: Compared with chow, EEN significantly decreased tissue IL-4, phosphorylated STAT-6, and pIgR. The addition of PACs to EEN prevented these alterations. Compared with chow, EEN resulted in significantly lower levels of luminal sIgA. The addition of PACs to EEN increased luminal sIgA levels compared with EEN alone. Conclusions: This study suggests the addition of PACs to EEN may support GALT function and maintain intestinal sIgA levels compared with EEN administration alone.

Cranberry proanthocyanidins improve the gut mucous layer morphology and function in mice receiving elemental enteral nutrition

Posted: September 15, 2013
Authors: Pierre JF, Heneghan AF, Feliciano RP, Shanmuganayagam D, Roenneburg DA, Krueger CG, Reed JD, Kudsk KA
Journal: JPEN-Parenter Enter 37(3):401-9

Abstract: BACKGROUND: Lamina propria Th2 cytokines, interleukin (IL)-4 and IL-13, stimulate goblet cell (GC) proliferation and MUC2 production, which protect the intestinal mucosa. Elemental enteral nutrition (EEN) reduces tissue IL-4 and impairs barrier function. Proanthocyanidins (PACs) stimulate oral mucin levels. We hypothesized that adding PAC to EEN would maintain Th2-without stimulating Th1-cytokines and preserve luminal MUC2 vs EEN alone. Materials and
METHODS: Seventy mice were randomized to 5 diet groups-standard chow, intragastric EEN, or EEN with lowPAC, midPAC (50 mg), or highPAC (100 mg PAC/kg BW)-for 5 days, starting 2 days after gastric cannulation. Ileal tissue was analyzed for histomorphology and the cytokines IL-4, IL-13, IL-1, IL-6, and TNF- by enzyme-linked immunosorbent assay. MUC2 was measured in intestinal washes.
RESULTS: EEN lowered IL-13 (P < .05) compared with standard chow, whereas IL-4 was not significant (P < .07). LowPAC and midPAC increased IL-13 (P < .05), whereas highPAC increased both IL-4 and IL-13 (P < .05) compared with EEN. All EEN diets reduced (P < .05) crypt depth compared with the chow group. Compared with standard chow, GC numbers and luminal MUC2 were reduced with EEN (P < .05). These effects were attenuated (P < .05) with midPAC and highPAC. No changes were observed in tissue Th1 cytokines.
CONCLUSIONS: Adding PACs to EEN reverses impaired intestinal barrier function following EEN by improving the gut mucous layer and function through increased GC size and number as well as levels of MUC2 and ileal IL-4 and IL-13.

Effects of anthocyanins on the AhR-CYP1A1 signaling pathway in human hepatocytes and human cancer cell lines.

Posted: September 15, 2013
Authors: Kamenickova A, Anzenbacherova E, Pavek P, Soshilov AA, Denison MS, Zapletalova M, Anzenbacher P, Dvorak Z
Journal: Toxicol Lett 221(1):1-8

Abstract: Anthocyanins are plant pigments occurring in flowers and berry fruits. Since a phenomenon of food-drug interactions is increasingly emerging, we examined the effects of 21 major anthocyanins and the extracts from 3 food supplements containing anthocyanins on the aryl hydrocarbon receptor (AhR)-cytochrome P450 CYP1A1 signaling pathway in human hepatocytes and human hepatic HepG2 and intestinal LS174T cancer cells. Pelargonidin-3-O-rutinoside (PEL-2) and cyanidin-3,5-O-diglucoside (CYA-3) dose-dependently activated AhR, as revealed by gene reporter assay. PEL-2 and CYA-3 induced CYP1A1 mRNA but not protein in HepG2 and LS174T cells. Neither compounds induced CYP1A1 mRNA and protein in four different primary human hepatocytes cultures. The effects of PEL-2 and CYA-3 on AhR occurred by ligand-dependent and ligand-independent mechanisms, respectively, as demonstrated by ligand binding assay. In a direct enzyme inhibition assay, none of the antocyanins tested inhibited the CYP1A1 marker activity to less than 50% even at 100 &#956;M concentration. PEL-2 and CYA-3 at 100 &#956;M inhibited CYP1A1 to 79% and 65%, respectively. In conclusion, with exception of PEL-2 and CYA-3, there were no effects of 19 major anthocyanins and 3 food supplements containing anthocyanins on AhR-CYP1A1 signaling, implying zero potential of these compounds for food-drug interactions with respect to AhR-CYP1A1 pathway.

Effects of cranberry components on human aggressive periodontitis gingival fibroblasts.

Posted: September 15, 2013
Authors: Tipton DA, Babu JP, Dabbous MKh
Journal: J Periodontal Res 48(4):433-42

Abstract: BACKGROUND AND OBJECTIVE: Aggressive periodontitis (AgP) causes rapid periodontal breakdown involving AgP gingival fibroblast production of cytokines [i.e. interleukin (IL)-6, a bone metabolism regulator], and matrix metalloproteinase (MMP)-3. Lipopolysaccharide upregulates fibroblast IL-6 and MMP-3, via transcription factors (i.e. NF-kB). Cranberry (Vaccinium macrocarpon) inhibits lipopolysaccharide-stimulated macrophage and normal gingival fibroblast activities, but little is known of its effects on AgP fibroblasts. Objectives of this study are to use AgP fibroblasts, to determine cytotoxicity of cranberry components or periodontopathogen (Fusobacterium nucleatum, Porphyromonas gingivalis) lipopolysaccharide +/- cranberry components, and effects of cranberry components on lipopolysaccharide-stimulated NF-kB activation and IL-6 and MMP-3 production.
MATERIAL AND METHODS: AgP fibroblasts were incubated <= 6 d with high molecular weight non-dialyzable material (NDM) (derived from cranberry juice (1-500 mug/mL) or lipopolysaccharide (1 mug/mL) +/- NDM. Membrane damage and viability were assessed by enzyme activity released into cell supernatants and activity of a mitochondrial enzyme, respectively. Secreted IL-6 and MMP-3 were measured by ELISA. NF-kB p65 was measured via binding to an oligonucleotide containing the NF-kB consensus site. Data were analyzed using analysis of variance and Scheffe's F procedure for post hoc comparisons.
RESULTS: Short-term exposure to NDM, or lipopolysaccharide +/- NDM caused no membrane damage. NDM (<= 100 mug/mL) or lipopolysaccharide +/- NDM had no effect on viability <= 7 d exposure. NDM (50 mug/mL) inhibited lipopolysaccharide-stimulated p65 (P <= 0.003) and constitutive or lipopolysaccharide-stimulated MMP-3 (P <= 0.02). NDM increased AgP fibroblast constitutive or lipopolysaccharide-stimulated IL-6 (P <= 0.0001), but inhibited normal human gingival fibroblast IL-6 (P <= 0.01).
CONCLUSION: Lack of toxicity of low NDM concentrations, and its inhibition of NF-kB and MMP-3, suggest that cranberry components may regulate AgP fibroblast inflammatory responses. Distinct effects of NDM on AgP and gingival fibroblast production of IL-6 (which can have both positive and negative effects on bone metabolism) may reflect phenotypic differences in IL-6 regulation in the two cell types.

Evidence that cranberry juice may improve augmentation index in overweight men.

Posted: September 15, 2013
Authors: Ruel G. Lapointe A. Pomerleau S. Couture P. Lemieux S. Lamarche B. Couillard C.
Journal: Nutr Res 33(1):41-9

Abstract: The stiffening of arteries is a key step in atherogenesis leading to cardiovascular disease. It has been suggested that dietary polyphenols may be cardioprotective through possible favorable effects on oxidative stress and vascular function. The present study was undertaken in order to examine the effect of consuming low-calorie cranberry juice cocktail (CJC), a source of polyphenols, on arterial stiffness in abdominally obese men. We hypothesize that regular CJC consumption will reduce circulating oxidized low-density lipoproteins concentrations and have a beneficial impact on endothelial function. Thirty-five men (mean age +/- SD: 45 +/- 10 years) were randomly assigned to drink 500 mL CJC/day (27% juice) or 500 mL placebo juice (PJ)/day for 4 weeks in a double-blind crossover design. Augmentation index (AIx), an index of arterial stiffness, was measured by applanation tonometry of the radial artery and the cardiometabolic profile was assessed in each participant before and after each phase of the study. We found no significant difference in AIx changes between men who consumed CJC or PJ for 4 weeks (P = .5820). Furthermore, there was no between-treatment difference in changes in AIx responses to salbutamol (P = .6303) and glyceryl trinitrate (P = .4224). No significant difference was noted in other cardiometabolic variables between men consuming PJ or CJC. However, a significant within group decrease in AIx (mean decrease +/- SE; -14.0 +/- 5.8%, P = .019) was noted following the consumption of 500 mL CJC/day for 4 weeks. Our results indicate that the effect of chronic consumption of CJC on AIx was not significantly different from changes associated with the consumption of PJ. However, the significant within-group decrease in AIx following CJC consumption in abdominally obese men may deserve further investigation.

Identification of polyphenols and their metabolites in human urine after cranberry-syrup consumption

Posted: September 15, 2013
Authors: Iswaldi I, Arraez-Roman D, Gomez-Caravaca AM, Contreras Mdel M, Uberos J, Segura-Carretero A, Fernandez-Gutierrez A
Journal: Food Chem Toxicol 55:484-92

Abstract: As the beneficial effects of American cranberry (Vaccinium macrocarpon) can be partly attributed to its phenolic composition, the evaluation of the physiological behaviour of this fraction is crucial. A rapid and sensitive method by ultra-performance liquid chromatography coupled to quadrupole-time-of-flight mass spectrometry (UPLC-Q-TOF-MS) has been used to identify phenolic metabolites in human urine after a single dose of cranberry syrup. Prior to the analysis, metabolites were extracted using an optimised solid-phase extraction procedure. All possible metabolites were investigated based on retention time, accurate mass data and isotope and fragmentation patterns. Free coumaroyl hexose (isomer 1 and 2), dihydroxybenzoic acid, caffeoyl glucose, dihydroferulic acid 4-O--d-glucuronide, methoxyquercetin 3-O-galactoside, scopoletin, myricetin and quercetin, together with other 23 phase-I and phase-II metabolites, including various isomers, could be tentatively identified in the urine. Afterwards, the metabolites were simultaneously screened in the urine of different subjects at 0, 2, 4, and 6h after the ingestion of cranberry syrup by Target Analysis(TM) software.

In vitro and in vivo antibacterial activities of cranberry press cake extracts alone or in combination with -lactams against Staphylococcus aureus

Posted: September 15, 2013
Authors: Diarra MS, Block G, Rempel H, Oomah BD, Harrison J, McCallum J, Boulanger S, Brouillette E, Gattuso M, Malouin F
Journal: BMC Complem Altern M 13:90

Abstract: BACKGROUND: Cranberry fruits possess many biological activities partly due to their various phenolic compounds; however the underlying modes of action are poorly understood. We studied the effect of cranberry fruit extracts on the gene expression of Staphylococcus aureus to identify specific cellular processes involved in the antibacterial action.
METHODS: Transcriptional profiles of four S. aureus strains grown in broth supplemented or not with 2 mg/ml of a commercial cranberry preparation (Nutricran90) were compared using DNA arrays to reveal gene modulations serving as markers for biological activity. Ethanol extracted pressed cakes from fresh fruits also produced various fractions and their effects on marker genes were demonstrated by qPCR. Minimal inhibitory concentrations (MICs) of the most effective cranberry fraction (FC111) were determined against multiple S. aureus strains and drug interactions with -lactam antibiotics were also evaluated. Incorporation assays with [(3)H]-radiolabeled precursors were performed to evaluate the effect of FC111 on DNA, RNA, peptidoglycan (PG) and protein biosynthesis.
RESULTS: Treatment of S. aureus with Nutricran90 or FC111 revealed a transcriptional signature typical of PG-acting antibiotics (up-regulation of genes vraR/S, murZ, lytM, pbp2, sgtB, fmt). The effect of FC111 on PG was confirmed by the marked inhibition of incorporation of D-[(3)H]alanine. The combination of -lactams and FC111 in checkerboard assays revealed a synergistic activity against S. aureus including strain MRSA COL, which showed a 512-fold drop of amoxicillin MIC in the presence of FC111 at MIC/8. Finally, a therapeutic proof of concept was established in a mouse mastitis model of infection. S. aureus-infected mammary glands were treated with amoxicillin, FC111 or a combination of both; only the combination significantly reduced bacterial counts from infected glands (P<0.05) compared to the untreated mice.
CONCLUSIONS: The cranberry fraction FC111 affects PG synthesis of S. aureus and acts in synergy with -lactam antibiotics. Such a fraction easily obtained from poorly exploited press-cake residues, may find interesting applications in the agri-food sector and help reduce antibiotic usage in animal food production.

Inhibition of -amylase and glucoamylase by tannins extracted from cocoa, pomegranates, cranberries, and grapes

Posted: September 15, 2013
Authors: Barrett A, Ndou T, Hughey CA, Straut C, Howell A, Dai Z, Kaletunc G
Journal: J Agric Food Chem 61(7):1477-86

Abstract: Proanthocyanidins and ellagitannins, referred to as "tannins", exist in many plant sources. These compounds interact with proteins due to their numerous hydroxyl groups, which are suitable for hydrophobic associations. It was hypothesized that tannins could bind to the digestive enzymes -amylase and glucoamylase, thereby inhibiting starch hydrolysis. Slowed starch digestion can theoretically increase satiety by modulating glucose "spiking" and depletion that occurs after carbohydrate-rich meals. Tannins were isolated from extracts of pomegranate, cranberry, grape, and cocoa and these isolates tested for effectiveness to inhibit the activity of -amylase and glucoamylase in vitro. The compositions of the isolates were confirmed by NMR and LC/MS analysis, and tannin-protein interactions were investigated using relevant enzyme assays and differential scanning calorimetry (DSC). The results demonstrated inhibition of each enzyme by each tannin, but with variation in magnitude. In general, larger and more complex tannins, such as those in pomegranate and cranberry, more effectively inhibited the enzymes than did less polymerized cocoa tannins. Interaction of the tannins with the enzymes was confirmed through calorimetric measurements of changes in enzyme thermal stability.

Inhibition of bacterial motility and spreading via release of cranberry derived materials from silicone substrates

Posted: September 15, 2013
Authors: Chan M, Hidalgo G, Asadishad B, Almeida S, Muja N, Mohammadi MS, Nazhat SN, Tufenkji N
Journal: Colloid Surface B 110:275-80

Abstract: The motility of bacteria plays a key role in their colonization of surfaces during infection. Derivatives of cranberry fruit have been shown to interfere with bacterial motility. Herein, we report on the incorporation of cranberry derived materials (CDMs) into silicone substrates with the aim of impairing bacterial pathogen motility and spreading on the substrate surface. The release of CDMs from the silicone substrates when soaking in an aqueous medium was quantified for a period of 24h. Next, we showed that CDMs released from two silicone substrates remain bioactive as they downregulate the expression of the flagellin gene of two key uropathogens - Escherichia coli CFT073 and Proteus mirabilis HI4320. Furthermore, we demonstrate that CDM-modified silicone inhibits the swarming motility of P. mirabilis, an aggressive swarmer. The bioactive, CDM-modified substrates can find broad applications in the medical device and food industries where the impairment of bacterial colonization of surfaces is of paramount importance.

Protective potential of non-dialyzable material fraction of cranberry juice on the virulence of P. gingivalis and F. nucleatum mixed infection.

Posted: September 15, 2013
Authors: Polak D, Naddaf R, Shapira L, Weiss EI, Houri-Haddad Y
Journal: J Periodontol 84(7):1019-25

Abstract: BACKGROUND: Periodontitis is a polymicrobial infectious disease. A novel potential chemical treatment modality may lie in bacterial anti-adhesive materials, such as cranberry juice fractions. The aim of this study is to explore the effect of high molecular weight cranberry constituent (non-dialyzable material [NDM]) on the virulence of a mixed infection with Porphyromonas gingivalis and Fusobacterium nucleatum in mice.
METHODS: In vitro, the anti-adhesive property of NDM was validated on epithelial cell culture, and inhibition of coaggregation was tested using a coaggregation assay. The in vivo effect was tested on the outcome of experimental periodontitis induced by a P. gingivalis and F. nucleatum mixed infection, and also on the local host response using the subcutaneous chamber model of infection. Phagocytosis was also tested on RAW macrophages by the use of fluorescent-labeled bacteria.
RESULTS: NDM was found to inhibit the adhesion of both species of bacteria onto epithelial cells and to inhibit coaggregation in a dose-dependent manner. NDM consumption by mice attenuated the severity of experimental periodontitis compared with a mixed infection without NDM treatment. In infected subcutaneous chambers, NDM alone reduced tumor necrosis factor-alpha (TNF-alpha) levels induced by the mixed infection. In vitro, NDM eliminated TNF-alpha expression by macrophages that were exposed to P. gingivalis and F. nucleatum, without impairing their viability. Furthermore, NDM increased the phagocytosis of P. gingivalis.
CONCLUSIONS: The results indicate that the use of NDM may hold potential protective and/or preventive modalities in periodontal disease. Underlying mechanisms for this trait may perhaps be the anti-adhesive properties of NDM or its potential effect on inflammation.

Reduced-energy cranberry juice increases folic acid and adiponectin and reduces homocysteine and oxidative stress in patients with the metabolic syndrome.

Posted: September 15, 2013
Authors: Simão TN, Lozovoy MA, Simão AN, Oliveira SR, Venturini D, Morimoto HK, Miglioranza LH, Dichi I
Journal: Br J Nutr DOI: 10.1017/S0007114513001207

Abstract: The metabolic syndrome (MetS) comprises pathological conditions that include insulin resistance, arterial hypertension, visceral adiposity and dyslipidaemia, which favour the development of CVD. Some reports have shown that cranberry ingestion reduces cardiovascular risk factors. However, few studies have evaluated the effect of this fruit in subjects with the MetS. The objective of the present study was to assess the effect of reduced-energy cranberry juice consumption on metabolic and inflammatory biomarkers in patients with the MetS, and to verify the effects of cranberry juice concomitantly on homocysteine and adiponectin levels in patients with the MetS. For this purpose, fifty-six individuals with the MetS were selected and divided into two groups: control group (n 36) and cranberry-treated group (n 20). After consuming reduced-energy cranberry juice (0·7 litres/d) containing 0·4 mg folic acid for 60 d, the cranberry-treated group showed an increase in adiponectin (P= 0·010) and folic acid (P= 0·033) and a decrease in homocysteine (P< 0·001) in relation to baseline values and also in comparison with the controls (P< 0·05). There was no significant change in the pro-inflammatory cytokines TNF-&#945;, IL-1 and IL-6. In relation to oxidative stress measurements, decreased (P< 0·05) lipoperoxidation and protein oxidation levels assessed by advanced oxidation protein products were found in the cranberry-treated group when compared with the control group. In conclusion, the consumption of cranberry juice for 60 d was able to improve some cardiovascular risk factors. The present data reinforce the importance of the inverse association between homocysteine and adiponectin and the need for more specifically designed studies on MetS patients.

The effect of American cranberry (Vaccinium macrocarpon) constituents on the growth inhibition, membrane integrity, and injury of Escherichia coli O157:H7 and Listeria monocytogenes in comparison to Lactobacillus rhamnosus.

Posted: September 15, 2013
Authors: Lacombe A, McGivney C, Tadepalli S, Sun XiaoHong Wu VCH
Journal: Food Microbiol 34(2):352-359

Abstract: The antimicrobial properties of the American cranberry were studied against Escherichia coli O157:H7, Listeria monocytogenes, and Lactobacillus rhamnosus to determine the effects on growth inhibition, membrane permeability, and injury. Cranberry powder was separated using a C-18 Sep-Pak cartridge into sugars plus organic acids (F1), monomeric phenolics (F2), and anthocyanins plus proanthocyanidins (F3). Fraction 3 was further separated into anthocyanins (F4) and proanthocyanidins (F5) using an LH-20 Sephadex column. Each fraction was diluted in the brain heart infusion (BHI) broth to determine the minimum inhibitory/bactericidal concentrations (MIC/MBC). L. monocytogenes was the most susceptible to cranberry fraction treatment with the lowest MIC/MBC for each treatment, followed by E. coli O157:H7 and L. rhamnosus. Membrane permeability and potential was studied using LIVE/DEAD viability assay and using Bis (1, 3-dibutylbarbituric acid) trimethine oxonol (DiBAC4), respectively. L. rhamnosus demonstrated the highest permeability followed by E. coli O157:H7, and L. monocytogenes. L. rhamnosus demonstrated the highest recovery followed by E. coli O157:H7, and L. monocytogenes. Each cranberry fraction demonstrated membrane hyperpolarization at their native pH, while F2, F3, and F5 demonstrated membrane depolarization at neutral pH. With this knowledge cranberry compounds may be used to prevent maladies and potentially substitute for synthetic preservatives and antibiotics.

The specific degree-of-polymerization of A-type proanthocyanidin oligomers impacts Streptococcus mutans glucan-mediated adhesion and transcriptome responses within biofilms

Posted: September 15, 2013
Authors: Feng G, Klein MI, Gregoire S, Singh AP, Vorsa N, Koo H
Journal: Biofouling 29(6):629-40

Abstract: Cranberry A-type proanthocyanidins (PACs) have been recognized for their inhibitory activity against bacterial adhesion and biofilm-derived infections. However, the precise identification of the specific classes of degree-of-polymerization (DP) conferring PACs bioactivity remains a major challenge owing to the complex chemistry of these flavonoids. In this study, chemically characterized cranberries were used in a multistep separation and structure-determination technique to isolate A-type PAC oligomers of defined DP. The influences of PACs on the 3D architecture of biofilms and Streptococcus mutans-transcriptome responses within biofilms were investigated. Treatment regimens that simulated topical exposures experienced clinically (twice-daily, 60s each) were used over a saliva-coated hydroxyapatite biofilm model. Biofilm accumulation was impaired, while specific genes involved in the adhesion of bacteria, acid stress tolerance, and glycolysis were affected by the topical treatments (vs the vehicle-control). Genes (rmpC, mepA, sdcBB, and gbpC) associated with sucrose-dependent binding of bacteria were repressed by PACs. PACs of DP 4 and particularly DP 8 to 13 were the most effective in disrupting bacterial adhesion to glucan-coated apatitic surface (>85% inhibition vs vehicle control), and gene expression (eg rmpC). This study identified putative molecular targets of A-type cranberry PACs in S. mutans while demonstrating that PAC oligomers with a specific DP may be effective in disrupting the assembly of cariogenic biofilms.

Deconvolution of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry isotope patterns to determine ratios of A-type to B-type interflavan bonds in cranberry proanthocyanidins

Posted: February 15, 2013
Authors: Feliciano RP, Krueger CG, Shanmuganayagam D, Vestling MM, Reed JD
Journal: Food Chem 135(3):1485-93

Abstract: A method to deconvolute overlapping isotope patterns in positive mode matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) was developed to determine ratios of A- to B-type interflavan bonds in proanthocyanidins that were isolated from cranberry (Vaccinium macrocarpon, Ait.) press cake (c-PAC). Precision and accuracy was validated for binary mixtures of procyanidins A2 and B2. Deconvolution of c-PAC spectra indicated that oligomers with one or more A-type interflavan bonds occur in a higher proportion than oligomers with all B-type interflavan bonds. c-PAC with at least one A-type bond accounted for more than 91% of the oligomers between trimers and undecamers. The c-PAC isotope patterns are highly repeatable, suggesting that the method can be applied to authentication, standardization and efficacy of cranberry products in relationship to urinary tract health. This is the first time MALDI-TOF MS has been used for estimating ratios of A- to B-type bonds in PAC.

Prophylaxis of recurrent urinary tract infection after renal transplantation by cranberry juice and L-methionine

Posted: February 15, 2013
Authors: Pagonas N, Horstrup J, Schmidt D, Benz P, Schindler R, Reinke P, van der Giet M, Zidek W, Westhoff TH
Journal: Transplant Proc 44(10):3017-21

Abstract: BACKGROUND: Recurrent urinary tract infections (UTIs) increase mortality and reduce graft survival after renal transplantation. Strategies to prevent recurrent UTIs include L-methionine, cranberry juice, and antibiotics. Data on the efficacy of cranberry and L-methionine, however, are controversial in the general population; there are few data in renal transplant recipients.
METHODS: We performed a retrospective analysis of 82 transplant recipients with recurrent UTIs, who underwent prophylaxis with cranberry juice (2 x 50 mL/d, n = 39, 47.6%), or L-methionine (3 x 500 mg/d, n = 25, 30.5%), or both modalities (n = 18, 21.9%). Thirty patients without prophylaxis served as controls. We analyzed symptoms, pyuria/nitrituria, and incidence of UTI events during 1 year before versus after initiation of prophylaxis.
RESULTS: Prophylaxis highly significantly decreased the annual UTI incidence by 58.3% (P < .001) in the study population with no change in the control group (P = .85); in addition, 53.7% of symptomatic patients reported relief of symptoms and pyuria/nitrituria disappeared in 42.4% of the dipstick-positive patients (P < .001 each). Cranberry reduced the annual number of UTI episodes by 63.9% from 3.6 +/- 1.4 to 1.3 +/- 1.3/year (P < .001) and L-methionine by 48.7% from 3.9 +/- 1.8 to 2.0 +/- 1.3/year (P < .001).
CONCLUSION: Cranberry juice and L-methionine successfully reduced the incidence of UTI after renal transplantation.