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Cranberry Proanthocyanidins Inhibit Esophageal Adenocarcinoma In Vitro and In Vivo Through Pleiotropic Cell Death Induction and PI3K/AKT/mTOR Inactivation.

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Authors
Kresty LA, Weh KM, Zeyzus-Johns B, Perez LN, Howell AB
Journal
Oncotarget 6(32):33438-55
Abstract

Cranberries are rich in bioactive constituents known to improve urinary tract health and more recent evidence supports cranberries possess cancer inhibitory properties. However, mechanisms of cancer inhibition by cranberries remain to be elucidated, particularly in vivo. Properties of a purified cranberry-derived proanthocyanidin extract (C-PAC) were investigated utilizing acid-sensitive and acid-resistant human esophageal adenocarcinoma (EAC) cell lines and esophageal tumor xenografts in athymic NU/NU mice. C-PAC induced caspase-independent cell death mainly via autophagy and low levels of apoptosis in acid-sensitive JHAD1 and OE33 cells, but resulted in cellular necrosis in acid-resistant OE19 cells. Similarly, C-PAC induced necrosis in JHAD1 cells pushed to acid-resistance via repeated exposures to an acidified bile cocktail. C-PAC associated cell death involved PI3K/AKT/mTOR inactivation, pro-apoptotic protein induction (BAX, BAK1, deamidated BCL-xL, Cytochrome C, PARP), modulation of MAPKs (P-P38/P-JNK) and G2-M cell cycle arrest in vitro. Importantly, oral delivery of C-PAC significantly inhibited OE19 tumor xenograft growth via modulation of AKT/mTOR/MAPK signaling and induction of the autophagic form of LC3B supporting in vivo efficacy against EAC for the first time. C-PAC is a potent inducer of EAC cell death and is efficacious in vivo at non-toxic behaviorally achievable concentrations, holding promise for preventive or therapeutic interventions in cohorts at increased risk for EAC, a rapidly rising and extremely deadly malignancy.

Cranberry Products for the Prophylaxis of Urinary Tract Infections in Pediatric Patients.

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Authors
Durham SH, Stamm PL, Eiland LS
Journal
Ann Pharmacother 49(12):1349-56
Abstract

OBJECTIVE: To evaluate the existing data regarding the use of cranberry products for the prevention of urinary tract infections (UTIs) in pediatric patients.
DATA SOURCES: A literature search of Medline databases from 1966 to June 2015 was conducted.
STUDY SELECTION AND DATA EXTRACTION: The databases were searched using the terms ""pediatrics,"" ""children,"" ""cranberry,"" ""cranberry juice,"" and ""urinary tract infections."" The identified trials were then searched for additional references applicable to this topic.
DATA SYNTHESIS: A total of 8 clinical trials were identified that examined the use of cranberry products, mostly juice, for the prevention of UTIs in children. Three trials examined the use in otherwise healthy children. Five trials examined the use in pediatric patients with underlying urogenital abnormalities of which 2 compared cranberry to antibiotics. In healthy pediatric patients, cranberry use was associated with a reduction in the overall number of UTIs and a decrease in the number of antibiotic days per year for UTI treatment. In patients with urogenital abnormalities, results were conflicting, with some studies showing no reduction in UTIs compared with placebo, but others demonstrating a significant reduction. However, cranberry products had similar efficacy when compared with both cefaclor and trimethoprim. All studies used a wide variety of doses and frequencies of cranberry, making specific product recommendations difficult.
CONCLUSIONS: Cranberry appears effective for the prevention of UTIs in otherwise healthy children and is at least as effective as antibiotics in children with underlying urogenital abnormalities. However, recommendations for cranberry dosing and frequency cannot be confidently made at this time. Larger, well-designed trials are recommended.

Effect of Dried Powder Preparation Process on Polyphenolic Content and Antioxidant Capacity of Cranberry (Vaccinium macrocarpon L.).

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Authors
Oszmianski J, Kolniak-Ostek J, Lachowicz S, Gorzelany J, Matlok N
Journal
Ind Crop Prod 77:658-665.
Abstract

The aim of the study was to evaluate the effect of the degree of fragmentation of cranberry fruit (Vaccinium macrocarpon L.) on the chemical composition and antioxidant activity of fruit powders and lyophilized pomace and juices. In analyzed samples, the basic chemical composition, total polyphenolics and antioxidant capacity were determined. Thirty-nine polyphenolic compounds, including 9 phenolic acids, 7 anthocyanins, 9 flavan-3-ols and 14 flavonols, were identified. Polyphenolic concentrations in pomaces ranged from 16 038.74 mg/100 g DW in samples from whole fruits to 17 802.52 mg/100 g DW in samples from crushed fruits. In juices, phenolic concentrations ranged from 873.12 mg/100 g DW in products from whole fruits to 3177.87 mg/100 g DW in products from crushed fruits. Antioxidant capacities were higher in dry products than in juices. The highest DPPH, ABTS and FRAP values were determined in dry pomaces obtained from crushed fruits (156.94, 275.22 and 71.47 micro mol/g DW, respectively).

Efficacy and safety profile of cranberry in infants and children with recurrent urinary tract infection

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Authors
Fernandez-Puentes V, Uberos J, Rodriguez-Belmonte R, Nogueras-Ocana M, Blanca-Jover E, Narbona-Lopez E
Journal
An Pediatr (Barc) 82(6):397-403
Abstract

OBJECTIVE: Cranberry prophylaxis of recurrent urinary tract infection in infants has proven effective in the experimental model of the adult. There are few data on its efficacy, safety and recommended dose in the pediatric population.
METHODS: A controlled, double-blind Phase III clinical trial was conducted on children older than 1 month of age to evaluate the efficacy and safety of cranberry in recurrent urinary tract infection. The assumption was of the non-inferiority of cranberry versus trimethoprim. Statistical analysis was performed using Kaplan Meier analysis.
RESULTS: A total of 85 patients under 1 year of age and 107 over 1 year were recruited. Trimethoprim was prescribed to 75 patients and 117 received cranberry. The cumulative rate of urinary infection associated with cranberry prophylaxis in children under 1 year was 46% (95% CI; 23-70) in children and 17% (95% CI; 0-38) in girls, effectively at doses inferior to trimethoprim. In children over 1 year-old cranberry was not inferior to trimethoprim, with a cumulative rate of urine infection of 26% (95% CI; 12-41). The cranberry was well tolerated and with no new adverse effects.
CONCLUSIONS: Our study confirms that cranberry is safe and effective in the prophylaxis of recurrent urinary tract infection in infants and children. With the doses used, their efficiency is not less than that observed for trimethoprim among those over 1 year-old. (Clinical Trials Registry ISRCTN16968287).

Fluorescent Labeling of Cranberry Proanthocyanidins with 5-([4,6-dichlorotriazin-2-yl]amino)Fluorescein (DTAF)

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Authors
Feliciano RP, Heintz JA, Krueger CG, Vestling MM, Reed JD
Journal
Food Chem 166:337-45
Abstract

A novel methodology was developed to elucidate proanthocyanidins (PAC) interaction with extra-intestinal pathogenic Escherichia coli (ExPEC). PAC inhibit ExPEC invasion of epithelial cells and, therefore, may prevent transient gut colonization, conferring protection against subsequent extra-intestinal infections, such as urinary tract infections. Until now PAC have not been chemically labeled with fluorophores. In this work, cranberry PAC were labeled with 5-([4,6-dichlorotriazin-2-yl]amino) fluorescein (DTAF), detected by high-performance liquid chromatography with diode-array detection and characterized by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). We report single and double fluorescent-labeled PAC with one or two chlorine atoms displaced from DTAF in alkaline pH via nucleophilic substitution. Fluorescent labeling was confirmed by fragmentation experiments using MALDI-TOF/TOF MS. Fluorescent labeled PAC were able to promote ExPEC agglutination when observed with fluorescence microscopy. DTAF tagged PAC may be used to trace the fate of PAC after they agglutinate ExPEC and follow PAC-ExPEC complexes in cell culture assays.

Glycemic Responses to Sweetened Dried and Raw Cranberries in Humans with Type 2 Diabetes

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Authors
Wilson T, Luebke JL, Morcomb EF, Carrell EJ, Leveranz MC, Kobs L, Schmidt TP, Limburg PJ, Vorsa N, Singh AP
Journal
J Food Sci 75(8):H218-23
Abstract

This study assessed the metabolic response to sweetened dried cranberries (SDC), raw cranberries (RC), and white bread (WB) in humans with type 2 diabetes. Development of palatable cranberry preparations associated with lower glycemic responses may be useful for improving fruit consumption and glycemic control among those with diabetes. In this trial, type 2 diabetics (n= 13) received WB (57 g, 160 cal, 1 g fiber), RC (55 g, 21 cal, 1 g fiber), SDC (40 g, 138 cal, 2.1 g fiber), and SDC containing less sugar (SDC-LS, 40 g, 113 cal, 1.8 g fiber + 10 g polydextrose). Plasma glucose (mmol/L) peaked significantly at 60 min for WB, and at 30 min for RC, SDC, and SDC-LS at 9.6 ± 0.4, 7.0 ± 0.4, 9.6 ± 0.5, and 8.7 ± 0.5, respectively, WB remained significantly elevated from the other treatments at 120 min. Plasma insulin (pmol/mL) peaked at 60 min for WB and SDC and at 30 min for RC and SDC-LS at 157 ± 15, 142 ± 27, 61 ± 8, and 97 ± 11, respectively. Plasma insulin for SDC-LS was significantly lower at 60 min than either WB or SDC. Insulin area under the curve (AUC) values for RC and SDC-LS were both significantly lower than WB or SDC. Phenolic content of SDC and SDC-LS was determined following extraction with 80% acetone prior to high-performance liquid chromatography (HPLC) and electronspray ionization-mass spectrometry (ESI-MS) and found to be rich in 5-caffeoylquinic cid, quercetin-3-galactoside, and quercetin-3-galactoside, and the proanthocyanidin dimer epicatechin. In conclusion, SDC-LS was associated with a favorable glycemic and insulinemic response in type 2 diabetics. Practical Application: This study compares phenolic content and glycemic responses among different cranberry products. The study seeks to expand the palatable and portable healthy food choices for persons with type 2 diabetes. The novel use of polydextrose as a bulking agent making possible a reduction in caloric content and potential glycemic response is also characterized in this study.

In Vitro Activity of Vaccinium Macrocarpon (cranberry) on Urinary Tract Pathogens in Uncomplicated Urinary Tract Infection.

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Authors
Bukhari S, Chiragh S, Tariq S, Alam MA, Wazir MS, Suleman M.
Journal
J Ayub Med Coll Abbottabad 27(3):660-3.
Abstract

Background: Urinary tract infection is the most common bacterial infection in the community, mainly caused by Escherichia coli (E. coli). Due to its high incidence and recurrence, problems are faced in the treatment with antibiotics. Cranberry being herbal remedy have long been the focus of interest for their beneficial effects in preventing urinary tract infections. This study was conducted to analyse in vitro activity of cranberry (Vaccinium macrocarpon) on uropathogenic E. coli in uncomplicated urinary tract infections. Methods: In this laboratory based single group experimental study, anti-bacterial activity of Vaccinium macrocarpon concentrate on urinary tract E. coli was investigated, in vitro. Ninety-six culture positive cases of different uropathogens were identified. Vaccinium macrocarpon concentrate at different concentrations was prepared in distilled water and put in wells punched in nutrient agar. E. coli isolates were inoculated on the plates and incubated at 37 oC for 24 hours. A citric acid solution of the same pH as that of Vaccinium macrocarpon was used and put in a well on the same plate to exclude the effect of pH. Results: A total of 35 isolates of E. coli were identified out of 96 culture positive specimens of urine and found sensitive to Vaccinium macrocarpon (p<0.000). Results revealed that Vaccinium macrocarpon has antibacterial effect against E. coli. Furthermore the antibacterial activity of Vaccinium macrocarpon has dose response relationship. Acidic nature of Vaccinium macrocarpon due to its pH is not contributory towards its antibacterial effect. Conclusion: Vaccinium macrocarpon concentrate may be used in urinary tract infection caused by E. coli.

In Vivo Consumption of Cranberry Exerts ex Vivo Antiadhesive Activity against FimH-Dominated Uropathogenic Escherichia coli: A Combined in Vivo, ex Vivo, and in Vitro Study of an Extract from Vaccinium macrocarpon.

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Authors
Rafsanjany N, Senker J, Brandt S, Dobrindt U, Hensel A
Journal
J Agric Food Chem 63(40):8804-18
Abstract

For investigation of the molecular interaction of cranberry extract with adhesins of uropathogenic Escherichia coli (UPEC), urine from four volunteers consuming standardized cranberry extract (proanthocyanidin content = 1.24%) was analyzed within ex vivo experiments, indicating time-dependent significant inhibition of 40-50% of bacterial adhesion of UPEC strain NU14 to human T24 bladder cells. Under in vitro conditions a dose-dependent increase in bacterial adhesion was observed with proanthocyanidin-enriched cranberry Vaccinium macrocarpon extract (proanthocyanidin content = 21%). Confocal laser scanning microscopy and scanning electron microscopy proved that V.m. extract led to the formation of bacterial clusters on the outer plasma membrane of the host cells without subsequent internalization. This agglomerating activity was not observed when a PAC-depleted extract (V.m. extract(PAC)) was used, which showed significant inhibition of bacterial adhesion in cases where type 1 fimbriae dominated and mannose-sensitive UPEC strain NU14 was used. V.m. extract(PAC) had no inhibitory activity against P- and F1C-fimbriae dominated strain 2980. Quantitative gene expression analysis indicated that PAC-containing as well as PAC-depleted cranberry extracts increased the fimH expression in NU14 as part of a feedback mechanism after blocking FimH. For strain 2980 the PAC-containing extract led to up-regulation of P- and F1C-fimbriae, whereas the PAC-depleted extract had no influence on gene expression. V.m. and V.m. extract(PAC) did not influence biofilm and curli formation in UPEC strains NU14 and 2980. These data lead to the conclusion that also proanthocyanidin-free cranberry extracts exert antiadhesive activity by interaction with mannose-sensitive type 1 fimbriae of UPEC.

Influence of Polyphenols from Lingonberry, Cranberry, and Red Grape on In Vitro Digestibility of Rice.

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Authors
Quek R, Henry CJ
Journal
Int J Food Sci Nutr 66(4):378-82
Abstract

Dietary polyphenols are abundant antioxidants in the human diet and are associated with lower rates of diabetes and cardiovascular disease. This study aims to determine the effects of cooking white rice (WR) added with lingonberry (WRLB), cranberry (WRCB), and red grape (WRRG) on in vitro digestibility. There was significantly lower level of glucose release for WRRG compared with WR (p0.05). WRLB and WRCB showed no effect on glucose release compared with WR (p>0.05). Increasing concentrations of red grape polyphenol decreased digestibility of white rice (p0.05). A positive correlation between the red grape phenolic content and the resistant starch was observed (R=0.9854). Red grape polyphenol had the greatest impact on reducing in vitro digestibility of white rice. The addition of polyphenols in carbohydrate-rich foods may be a practical means to reduce the high glycemic response of rice eaten around the world.

Inhibitory Effect of Six Herbal Extracts on CYP2C8 Enzyme Activity in Human Liver Microsomes.

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Authors
Albassam AA, Mohamed ME, Frye RF
Journal
Xenobiotica 45(5):406-12
Abstract

1. Herbal supplements widely used in the US were screened for the potential to inhibit CYP2C8 activity in human liver microsomes. The herbal extracts screened were garlic, echinacea, saw palmetto, valerian, black cohosh and cranberry. N-desethylamodiaquine (DEAQ) and hydroxypioglitazone metabolite formation were used as indices of CYP2C8 activity. 2. All herbal extracts showed inhibition of CYP2C8 activity for at least one of three concentrations tested. A volume per dose index (VDI) was calculated to determine the volume in which a dose should be diluted to obtain IC50 equivalent concentration. Cranberry and saw palmetto had a VDI value > 5.0 l per dose unit, suggesting a potential for interaction. 3. Inhibition curves were constructed and the IC50 (mean +/- SE) values were 24.7 +/- 2.7 mug/ml for cranberry and 15.4 +/- 1.7 mug/ml for saw palmetto. 4. The results suggest a potential for cranberry or saw palmetto extracts to inhibit CYP2C8 activity. Clinical studies are needed to evaluate the significance of this interaction.