Cranberry extracts may provide beneficial health effects in the treatment of various diseases, including cancer. However, the underlying molecular mechanisms of antineoplastic properties are not understood. We report the effect of a proanthocyanidin (PAC)-rich isolate from cranberry (PAC-1) as a therapeutic agent with dual activity to target both ovarian cancer viability and angiogenesis in vitro. PAC-1 treatment of chemotherapy-resistant SKOV-3 cells blocked cell cycle progression through the G2/M phase, increased the generation of reactive oxygen species (ROS), and induced apoptosis through activation of intrinsic and extrinsic pathway components. Cytotoxicity of PAC-1 was partially based on ROS generation and could be blocked by co-treatment with antioxidant glutathione. PAC-1 reduced the cell viability of both SKOV-3 ovarian cancer cells and HUVEC endothelial cells in a dose-dependent manner and blocked the activation of the pro-survival factor AKT. Furthermore, PAC-1 blocked vascular endothelial growth factor (VEGF)-stimulated receptor phosphorylation in endothelial cells, which correlated with the inhibition of endothelial tube formation in vitro. Our findings suggest that PAC-1 exerts potent anticancer and anti-angiogenic properties and that highly purified PAC from cranberry can be further developed to treat ovarian cancer in combinational or single-agent therapy.

Plant material screening was performed to study anti-Helicobacter pylori activity in vitro using an agar diffusion method on Columbia blood agar. 33 substances, juices and plant extracts and 35 of their combinations were tested. Quince (Cydonia oblonga) juice demonstrated the strongest anti-H. pylori activity followed by cranberry juice. Concentrated apple juice, plum, red currant, black chokeberry, raspberry and bilberry juice also showed significant activity. Green tea and apple pomace extract as well as sweet flag rhizome, ginger and wild bergamot extract, cherry syrup, red beet juice and whey did not exhibit anti-Helicobacter activity. Quince juice in combination with bilberry, black chokeberry, red currant juice, green tea, sweet flag rhizome or apple pomace extract as well as cranberry juice in combination with sweet flag rhizome extract demonstrated a synergistic effect on inhibition of H. pylori. The obtained results offer new perspectives for development of functional anti-Helicobacter food product(s) for dietary management of H. pylori infection. The essential components of these products could be the most active juices and extracts like quince and cranberry juice supplemented with a corresponding synergist. Further studies are required to investigate the mechanism of antibacterial action of plant products and their efficacy in vivo.

The antimicrobial effect of cranberry juice and of three cranberry extracts (water-soluble (E1) and apolar phenolic compounds (E2), and anthocyanins (E3)) was investigated against seven bacterial strains (Enterococcus faecium resistant to vancomycin (ERV), Escherichia coli O157:H7 EDL 933, Escherichia coli ATCC 25922, Listeria monocytogenes HPB 2812, Pseudomonas aeruginosa ATCC 15442, Salmonella Typhimurium SL1344, and Staphylococcus aureus ATCC 29213). Each cranberry sample was analyzed to determine the minimum inhibitory concentration (MIC) and the maximal tolerated concentration (MTC) at neutral pH. The results, reported in micro g phenol/mL, indicated that all the bacterial strains, both Gram-positive and Gram-negative, were selectively inhibited by the cranberry phenolic compounds. The extract rich in water-soluble phenolic compounds caused the most important growth inhibitions. The bacteria ERV, and to a lesser degree, P. aeruginosa, S. aureus and E. coli ATCC 25922, were the most sensitive to the antimicrobial activity of extract E1. The growth of P. aeruginosa and E. coli ATCC was also affected by the presence of the anthocyanin-rich cranberry extract E3, although the observed antibacterial effect was not as important as with extract E1. In general, L. monocytogenes, E. coli O157:H7 and S. Typhimurium were the most resistant to the antibacterial activity of the cranberry extracts. Within 30 min of exposure with pure neutralized cranberry juice, L. monocytogenes and ERV were completely inactivated.

Cranberry juice (CJ) and grape juice (GJ) from Vaccinium macrocarpon and Vitis labrusca, respectively, and purified proanthocyanidins (PACs) from these species are recognized to possess antiviral activity. The effects of CJ and GJ on tight junction (TJ) structure and function among rotavirus-infected monkey kidney epithelial cells (MA-104) in monolayer cultures were evaluated. Antiviral activity by cranberry PACs of rotavirus in cell-free suspension was investigated by a rotavirus antigen [i.e., viral capsid protein 6 (VP6)] capture enzyme-linked immunosorbent assay (ELISA) and by transmission electron microscopy (TEM). MA-104 monolayers were treated with CJ, GJ, or cranberry juice cocktail (CJC) drink before inoculation with rotavirus. TJ function and structural integrity were measured by changes in transepithelial electrical resistance (TEER) and by reduction of signal intensity of the TJ α-claudin 1 by immunofluorescence. The inhibitory activity of CJ and GJ on viral RNA synthesis, as a function of viral concentration, was determined by reverse transcription polymerase chain reaction (rtPCR). After 4 days, virus-infected monolayers pretreated with GJ (Concord and Niagara GJs) had TEER readings similar to uninfected controls. CJ and CJC also had a significant protective effect (P 0.05) on TJ function, but to a lesser extent than GJ. Disorganization of TJ integrity commenced at 24- to 36-h post-viral inoculation, but this effect was reduced by pretreatment with CJ or GP of monolayer cultures. TEM showed aggregation of rotavirus by cranberry PACs. The destruction of rotavirus capsid proteins VP6, in cell-free suspension was inversely related to the concentration of cranberry PACs (C-PAC). Loss of rotavirus RNA by CJ or GJ was inversely related to viral infectivity titers. CJ, GJ, or PAC-associated antiviral activity has been linked to modifications in cellular physiologic events and to physical factors (e.g., PAC-mediated viral aggregation) that probably compromise viral infectivity. Multiple cell physiological and physical events must be considered when determining the mechanisms associated with the antiviral (i.e., rotavirus) activity of CJ, GJ, and PACs.

The effects of cranberry juice cocktail (CJC) and proanthocyanidins (PACs) on biofilm formation were investigated. Escherichia coli strain HB101pDC1 and nonfimbriated strain HB101 were grown in 10 wt% CJC or 120 μg/mL PACs for 12 consecutive cultures. Biofilm formation was investigated by incubating bacteria in 96-well polyvinyl chloride (PVC) plates and studying the optical density of the solution using the crystal violet method. We suspect that biofilm formation occurred due to non-specific interactions between the bacteria and the polymer. Both P-fimbriated E. coli HB101pDC1 and the non-fimbriated strain HB101 formed biofilms. E. coli strain HB101pDC1 formed a thicker and more mature biofilm. Cranberry juice inhibited biofilm formation after the first culture; however, for bacteria grown in PACs, a decrease in biofilm formation was observed with increasing number of cultures. The inhibitory effect was reversible. These results demonstrate that CJC is more effective than isolated PACs at preventing biofilm formation, possibly suggesting that other cranberry compounds also play a role in anti-biofilm activity.

Optimized purification of oligomeric proanthocyanidines (PAC) from cranberry generated PAC-1A which selectively affected the viability of various neuroblastoma (NB) cell lines representing a spectrum of high-risk NB features. PAC-1A caused a loss of mitochondrial transmembrane depolarization potential (∆Ψm) and increased generation of reactive oxygen species (ROS) which was directly correlated to the modulation of apoptotic marker proteins in SMS-KCNR cells. PAC-1A reduced the expression of pro-survival (Bcl-2, MCL-1, Bcl-xL) and increased levels of pro-apoptotic (Bax, Bad, Bid) Bcl family proteins, upregulated the activity of SAPK/JNK MAPK and downregulated expression or activity of PI3K/AKT/mTOR pathway components. PAC-1A increased the cellular uptake/retention of cyclophosphamide (CP). PAC-1A and CP synergistically increased cytotoxicity and expression of pro-apoptotic markers, reduced cellular glutathione (GSH) and superoxide dismutase (SOD) levels. Additional features of PAC-1A as an anticancer drug as shown in SMS-KCNR NB cells include delay of cell cycle progression and induction of cell death via TNF-family death receptor activity, thus, targeting both the extrinsic and intrinsic pathway of apoptosis. PAC-1A partially blocked the cell cycle in G2/M phase which correlated with a decrease of the G0/G1 subpopulation, upregulation of cyclin D1 and downregulation of CDK6 and p27 expression. In summary, PAC-1A has demonstrated chemotherapeutic potential to treat a broad spectrum of NBs including highly malignant tumors that show resistance to standard chemotherapeutics and apoptotic stimuli.

Twenty-seven patients with indwelling urinary catheters and chronic bacteriuria were studied for methenamine efficacy. In a crossover fashion, each patient received methenamine mandelate granules 4 g/day alone, with ascorbic acid 4 g/day, and with ascorbic acid 4 g/day plus cranberry cocktail one 1/day. Proteus vulgaris, Pseudomonas aeruginosa, and E. coli were the common pathogens. Urinary acidifiers had no significant effect on mean urine pH, however, high urinary formaldehyde concentrations were associated with the use of ascorbic acid. Bacteriocidal formaldehyde levels were more frequently present in patients with acidic urine pH than those with alkaline pH. Although ascorbic acid increased formaldehyde levels, additional cranberry cocktail had no further effect. Despite higher formaldehyde levels, urine culture results were positive in most cases with or without urine acidification. Methenamine therapy may be of limited value in asymptomatic chronic bacteriuric patients with indwelling catheters.

This study involved 27 geriatric patients with asymptomatic chronic bacteriuria; all had indwelling Foley catheters. The treatment regimens (daily oral dosage) were: methenamine mandelate (MM) granules, 4 gm; MM, 4 gm, plus ascorbic acid, 4 gm; and MM, 4 gm, plus ascorbic acid, 4 gm, plus cranberry cocktail, 1 liter--administered according to a cross-over design. Proteus vulgaris, Pseudomonas aeruginosa and E. coli were the most common urinary organisms. Proteus organisms were more often found in alkaline than in acidic urines, but the type of pathogen had no influence on urinary pH. Urinary formaldehyde concentration [HCHO] was lower in patients with Proteus infection (17.7 micrograms/ml) than in those with Pseudomonas (21.9 micrograms/ml) or E. coli infection (21.8 micrograms/ml). However, for Proteus infection, [HCHO] was higher in patients receiving MM plus ascorbic acid than in those receiving MM alone. Addition of cranberry cocktail to ascorbic acid did not enhance urinary pH, [HCHO] or methenamine efficacy. Our data suggest that in Foley catheter patients with chronic asymptomatic bacteriuria secondary to Proteus, Pseudomonas or E. coli infection, the type of urinary pathogen or the urinary pH cannot be used to predict the efficacy of methenamine therapy either with or without urinary acidifying agents.

Bacterial adhesion to the cell surface is a crucial step before infection can take place. Inhibition of bacterial binding offers a novel preventive approach against infections. Cranberry (Vaccinium macrocarpon Ait.) juice has been found to have antiadhesive activity against different bacteria. Streptococcus pneumoniae is an important pathogen and the most common cause for pneumonia, meningitis, and otitis media. In this study the inhibitory activity of cranberry (Vaccinium oxycoccos L.), bilberry (Vaccinium myrtillus L.) and crowberry (Empetrum nigrum and Empetrum hermaphroditum L.) juice fractions against pneumococcal binding was tested using human bronchial cells (Calu-3) as an adhesion model. In addition, the antimicrobial activity of the berry juice fractions was tested. It was found that the studied berry juice fractions had antiadhesion activity and cranberry juice was the most active. The adhesion inhibition activity of cranberry juice was nearly 90% at a concentration of 8.7mg/g of soluble solids. The antimicrobial activity of the studied berry juice fractions was found to be remarkable; pneumococcal growth was inhibited totally at a concentration of ~86mg/g. Both antiadhesion and antimicrobial activities were reduced after solid-phase extraction of the berry juices, which may suggest molecular synergistic effects of the berry juice molecules against S. pneumoniae. The findings indicate that cranberry, bilberry and crowberry juices have potential against pneumococcal infections.

Sucrose increases postprandial blood glucose concentrations, and diets with a high glycaemic response may be associated with increased risk of obesity, type 2 diabetes and CVD. Previous studies have suggested that polyphenols may influence carbohydrate digestion and absorption and thereby postprandial glycaemia. Berries are rich sources of various polyphenols and berry products are typically consumed with sucrose. We investigated the glycaemic effect of a berry puree made of bilberries, blackcurrants, cranberries and strawberries, and sweetened with sucrose, in comparison to sucrose with adjustment of available carbohydrates. A total of twelve healthy subjects (eleven women and one man, aged 25–69 years) with normal fasting plasma glucose ingested 150 g of the berry pure´e with 35 g sucrose or a control sucrose load in a randomised, controlled cross-over design. After consumption of the berry meal, the plasma glucose concentrations were significantly lower at 15 and 30 min (P<0·05, P<0·01, respectively) and significantly higher at 150 min (P<0·05) compared with the control meal. The peak glucose concentration was reached at 45 min after the berry meal and at 30 min after the control meal. The peak increase from the baseline was 1·0 mmol/l smaller (P=0·002) after ingestion of the berry meal. There was no statistically significant difference in the 3 h area under the glucose response curve. These results show that berries rich in polyphenols decrease the postprandial glucose response of sucrose in healthy subjects. The delayed and attenuated glycaemic response indicates reduced digestion and/or absorption of sucrose from the berry meal.