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Absorption, Metabolism and Excretion of Cranberry (Poly)Phenols in Humans: a Dose Response Study and Assessment of Inter-Individual Variability

Posted: 
August 15, 2017
Authors: 
Feliciano, R. P. Mills, C. E. Istas, G. Heiss, C. Rodriguez-Mateos, A.
Journal: 
Nutrients 9(3):268
Abstract: 

The beneficial health effects of cranberries have been attributed to their (poly)phenol content. Recent studies have investigated the absorption, metabolism and excretion of cranberry (poly)phenols; however, little is known about whether they follow a dose response in vivo at different levels of intake. An acute double-blind randomized controlled trial in 10 healthy men with cranberry juices containing 409, 787, 1238, 1534 and 1910 mg total (poly)phenols was performed. Blood and urine were analyzed by UPLC-Q-TOF-MS. Sixty metabolites were identified in plasma and urine including cinnamic acids, dihydrocinnamic, flavonols, benzoic acids, phenylacetic acids, benzaldehydes, valerolactones, hippuric acids, catechols, and pyrogallols. Total plasma, but not excreted urinary (poly)phenol metabolites, exhibited a linear dose response (r2=0.74, p<0.05), driven by caffeic acid 4-O- beta -D-glucuronide, quercetin-3-O- beta -D-glucuronide, ferulic acid 4-O- beta -D-glucuronide, 2,5-dihydroxybenzoic acid, 2,4-dihydroxybenzoic acid, ferulic acid, caffeic acid 3-O- beta -D-glucuronide, sinapic acid, ferulic acid 4-O-sulfate, 3-hydroxybenzoic acid, syringic acid, vanillic acid-4-O-sulfate, (4R)-5-(3'-hydroxyphenyl)- gamma -valerolactone-4'-O-sulfate, 4-methylgallic acid-3-O-sulfate, and isoferulic acid 3-O-sulfate (all r2 >=0.89, p<0.05). Inter-individual variability of the plasma metabolite concentration was broad and dependent on the metabolite. Herein, we show that specific plasma (poly)phenol metabolites are linearly related to the amount of (poly)phenols consumed in cranberry juice. The large inter-individual variation in metabolite profile may be due to variations in the gut microbiome.

Anti-Aging and Redox State Regulation Effects of A-type Proanthocyanidins-Rich Cranberry Concentrate and its Comparison with Grape Seed Extract in Mice.

Posted: 
August 15, 2017
Authors: 
Jiao JJ, Wei Y, Chen J, Chen X, Zhang Y.
Journal: 
Journal of Functional Foods 30:63-73
Abstract: 

We investigated the anti-aging and redox state regulation effects by A-type proanthocyanidins (PACs)-rich cranberry concentrate (CBC) and its comparison with B-type PACs-rich grape seed extract (GSE). Using the Q-Extractive mass spectrometry, PACs dimer A and B were identified as predominant phenolic compounds of CBC and GSE, respectively, while epicatechin was present in both extracts. Using the d-galactose-induced aging mice model, effects were investigated via an 8-week oral gavage considering water-soluble vitamin E as the positive control. Both CBC and GSE reduced hepatic and brain thiobarbituric acid reactive substances, and plasma 8-isoprostane levels by 30-57%, 24-30% and 11-62%, respectively, and decreased brain and plasma monoamine oxidase activities by 27-59% and 65-71%, respectively. CBC could improve hepatic glutathione peroxidase activity by 42%, while GSE increased hepatic superoxide dismutase activity by 13%. Therefore, both extracts exerted anti-aging effects probably via regulating in vivo redox state. However, neither generated any effect on catalase activities.

Characterization of Non-Dialyzable Constituents from Cranberry Juice that Inhibit Adhesion, Co-Aggregation and Biofilm Formation by Oral Bacteria

Posted: 
August 15, 2017
Authors: 
Neto CC; Penndorf KA; Feldman M; Meron-Sudai S; Zakay-Rones Z; Steinberg D; Fridman M; Kashman Y; Ginsburg I; Ofek I; Weiss EI.
Journal: 
Food & Function. 8(5):1955-1965
Abstract: 

An extract prepared from cranberry juice by dialysis known as nondialyzable material (NDM) has been shown previously to possess anti-adhesion activity toward microbial species including oral bacteria, uropathogenic Escherichia coli and Helicobacter pylori. Bioassay-guided fractionation of cranberry NDM was therefore undertaken to identify the anti-adhesive constituents. An aqueous acetone-soluble fraction (NDMac) obtained from Sephadex LH-20 inhibited adhesion-linked activities by oral bacteria, including co-aggregation of oral bacteria Fusobacterium nucleatum with Streptococcus sanguinis or Porphyromonas gingivalis, and biofilm formation by Streptococcus mutans. Analysis of NDMac and subsequent subfractions by MALDI-TOF MS and 1H NMR revealed the presence of A-type proanthocyanidin oligomers (PACs) of 3-6 degrees of polymerization composed of (epi)catechin units, with some (epi)gallocatechin and anthocyanin units also present, as well as quercetin derivatives. Subfractions containing putative xyloglucans in addition to the mixed polyphenols also inhibit biofilm formation by S. mutans (MIC = 125-250 mug mL-1). These studies suggest that the anti-adhesion activities of cranberry NDM on oral bacteria may arise from a combination of mixed polyphenol and non-polyphenol constituents.

Comparative Evaluation of Anti-Microbial Efficacy of Cranberry Extract and Chlorhexidine Mouthwash on Periodontal Pathogens: An In-vitro Study

Posted: 
August 15, 2017
Authors: 
Dandekar S, Deshpande N, Dave D
Journal: 
J. Periodont. Pract. DOI: http://dx.doi.org/10.20936/jpp/170102
Abstract: 

BACKGROUND: Chlorhexidine gluconate is considered as the gold standard among various anti-plaque agents. However, many local side effects have been reported on its long term use. Cranberry (Vaccinium macrocarpon) is rich in polyphenols, including flavonoids and proanthrocyanidins. Insufficient evidences are available to support antimicrobial property of Cranberry extract mouthwash in context to red, orange and green complexes of periodontal pathogens and even comparison of same with clinically used and accepted 0.2% Chlorhexidine. MATERIALS AND METHODS: Sterilised nutrient agar plates were inoculated with suspensions of P. gingivalis, T. forsythia, P. intermedia and A. actinomycetemcomitans (overnight cultures grown at 37° on nutrient agar). The strains were allowed to grow in strict anaerobic condition. 1, 5, 10 and 15 mg/ml Cranberry extract, 0.2% Chlorhexidine and distilled water were added into wells. Plates were then again incubated at 37° for 24 hours. Diameter of zones of inhibition of all the plates was measured using digital vernier callipers. The mean score of zones of inhibition was calculated. RESULTS: Results of the study showed that all four concentrations of Cranberry extract showed comparatively less significant antimicrobial property against the microorganisms, compared to 0.2% Chlorhexidine. CONCLUSION: This study showed that 1, 5, 10 and 15 mg/ml Cranberry extract does not have significant antimicrobial efficacy against periodontopathogens, compared to that of 0.2% Chlorhexidine.

Cranberry (Vaccinium macrocarpon ) Proanthocyanadin Complexes with Proteins Modulate the Macrophage Activation

Posted: 
August 15, 2017
Authors: 
Carballo S, Haas L, Krueger C, Reed JD
Journal: 
Food Funct DOI:10.1039/C7FO00688H
Abstract: 

In this work we characterize the interaction of cranberry (Vaccinium macrocarpon) proanthocyanidins (PAC) with bovine serum albumin (BSA) and hen egg-white lysozyme (HEL) and determine the effects of these complexes on macrophage activation and antigen presentation. We isolated PAC from cranberry and complexed the isolated PAC with BSA and HEL. The properties of the PAC-protein complexes were studied by matrix assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF MS), gel electrophoresis and zeta-potential. The effects of PAC-BSA complexes on macrophage activation were studied in RAW 264.7 macrophage like cells after treatment with lipopolysaccharide (LPS). Fluorescent microscopy was used to study endocytosis of PAC-BSA complexes. The effects of PAC complexes on macrophage antigen presentation was studied in an in vitro model of HEL antigen presentation by mouse peritoneal mononuclear cells to a T-cell hybridoma. Mass spectra of PAC complexes with BSA and HEL differed from spectra of the proteins alone by the presence of broad shoulders on the singly and doubly charged protein peaks. Complexation with PAC altered the electrophoretic mobility shift assay in native agarose gel and the electrophoretic mobility (ζ-potential) values. These results indicate that the PAC-protein complexes are stable and alter protein structure without precipitating the protein. Fluorescent microscopy showed that RAW 264.7 macrophages endocytosed BSA and PAC-BSA complexes in discrete vesicles that surrounded the nucleus. Macrophages treated with increasing amounts of PAC-BSA complexes had significantly reduced COX-2 and iNOS expression in response to treatment with lipopolysaccharide (LPS) in comparison to controls. PAC-HEL complexes modulated antigen uptake, processing and presentation in murine peritoneal macrophages. After 4 h of pre-incubation, only trace amounts of IL-2 were detected in the co-cultures treated with HEL alone, whereas a PAC-HEL complex had already reached maximum IL-2 expression. Cranberry PAC may increase rate of endocytose of HEL and subsequent expression of IL-2 by the T-cell hybridomas. These results suggest that PAC-protein complexes modulate aspects of innate and acquired immune responses in macrophages.

Cranberry (Vaccinium macrocarpon) Extract Treatment Improves Triglyceridemia, Liver Cholesterol, Liver Steatosis, Oxidative Damage and Corticosteronemia in Rats Rendered Obese by High Fat Diet.

Posted: 
August 15, 2017
Authors: 
Peixoto TC; Moura EG; de Oliveira E; Soares PN; Guarda DS; Bernardino DN; Ai XX; Rodrigues VDST; de Souza GR; da Silva AJR; Figueiredo MS; Manhaes AC; Lisboa PC.
Journal: 
European Journal of Nutrition DOI 10.1007/s00394-017-1467-2
Abstract: 

PURPOSE: Obese individuals have higher production of reactive oxygen species, which leads to oxidative damage. We hypothesize that cranberry extract (CE) can improve this dysfunction in HFD-induced obesity in rats since it has an important antioxidant activity. Here, we evaluated the effects of CE in food intake, adiposity, biochemical and hormonal parameters, lipogenic and adipogenic factors, hepatic morphology and oxidative balance in a HFD model. METHODS: At postnatal day 120 (PN120), male Wistar rats were assigned into two groups: (1) SD (n = 36) fed with a standard diet and (2) HFD (n = 36), fed with a diet containing 44.5% (35.2% from lard) energy from fat. At PN150, 12 animals from SD and HFD groups were killed while the others were subdivided into four groups (n = 12/group): animals that received 200 mg/kg cranberry extract (SD CE, HFD CE) gavage/daily/30 days or water (SD, HFD). At PN180, animals were killed.RESULTS: HFD group showed higher body mass and visceral fat, hypercorticosteronemia, higher liver glucocorticoid sensitivity, cholesterol and triglyceride contents and microsteatosis. Also, HFD group had higher lipid peroxidation (plasma and tissues) and higher protein carbonylation (liver and adipose tissue) compared to SD group. HFD CE group showed lower body mass gain, hypotrygliceridemia, hypocorticosteronemia, and lower hepatic cholesterol and fatty acid synthase contents. HFD CE group displayed lower lipid peroxidation, protein carbonylation (liver and adipose tissue) and accumulation of liver fat compared to HFD group. CONCLUSION: Although adiposity was not completely reversed, cranberry extract improved the metabolic profile and reduced oxidative damage and steatosis in HFD-fed rats, which suggests that it can help manage obesity-related disorders.

Effect of Sweetened Dried Cranberry Consumption on Urinary Proteome and Fecal Microbiome in Healthy Human Subjects.

Posted: 
August 15, 2017
Authors: 
Bekiares N; Krueger CG; Meudt JJ; Shanmuganayagam D; Reed JD.
Journal: 
OMICS: A Journal of Integrative Biology DOI: 10.1089/omi.2016.016
Abstract: 

The relationship among diet, human health, and disease is an area of growing interest in biomarker research. Previous studies suggest that the consumption of cranberries (Vaccinium macrocarpon) could beneficially influence urinary and digestive health. The present study sought to determine if daily consumption of sweetened dried cranberries (SDC) changes the urinary proteome and fecal microbiome, as determined in a prospective sample of 10 healthy individuals. Baseline urine and fecal samples were collected from the subjects in the fasted (8-12h) state. The subjects then consumed one serving (42g) of SDC daily with lunch for 2 weeks. Urine and fecal samples were collected again the day after 2 weeks of SDC consumption. Orbitrap Q-Exactive mass spectrometry of urinary proteins showed that consumption of SDC resulted in changes to 22 urinary proteins. Multiplex sequencing of 16S ribosomal RNA genes in fecal samples indicated changes in relative abundance of several bacterial taxonomic units after consumption of SDC. There was a shift in the Firmicutes:Bacteroidetes ratio, increases in commensal bacteria, and decreases or the absence of bacteria associated with negative health effects. A decrease in uromodulin in all subjects and an increase in Akkermansia bacteria in most subjects were observed and warrant further investigation. Future larger clinical studies with multiomics and multitissue sampling designs are required to determine the effects of SDC consumption on nutrition and health.

Effects of Cranberry Extracts on Gene Expression in THP-1 Cells.

Posted: 
August 15, 2017
Authors: 
Hannon DB; Thompson JT; Khoo C; Juturu V; Vanden Heuvel JP.
Journal: 
Food Sciences and Nutrition. 5(1):148-159
Abstract: 

Cranberry contains high levels of nutrients and bioactive molecules that have health-promoting properties. The purpose of the present studies was to determine if cranberry extracts (CEs) contain phytochemicals that exert anti-inflammatory effects. The human monocytic cell line THP-1 was treated with two CEs (CE and 90MX) and subsequently challenged with Lipopolysaccharides (LPS). Tumor necrosis factor alpha (TNF alpha) expression was decreased in the CE-treated cells, indicative of an anti-inflammatory effect. Gene expression microarrays identified several immune-related genes that were responsive to CEs including interferon-induced protein with tetratricopeptide repeats 1 and 3 (IFIT 1 and 3), macrophage scavenger receptor 1 (MSR1) and colony-stimulating factor 2 (CSF2). In addition, in the CE-treated cells, metallothionein 1F and other metal-responsive genes were induced. Taken together, this data indicates that CEs contain bioactive components that have anti-inflammatory effects and may protect cells from oxidative damage.

Formulation of Thermoreversible Gel of Cranberry Juice Concentrate: Evaluation, Biocompatibility Studies and its Antimicrobial Activity Against Periodontal Pathogens.

Posted: 
August 15, 2017
Authors: 
Rajeshwari HR; Dhamecha D; Jagwani S; Patil D; Hegde S; Potdar R; Metgud R; Jalalpure S; Roy S; Jadhav K; Tiwari NK; Koduru S; Hugar S; Dodamani S.
Journal: 
Materials Science & Engineering. C, Materials for Biological Applications. 75:1506-1514
Abstract: 

The present work aims to investigate the efficacy of thermoreversible gel of cranberry juice concentrate (CJC) as local drug delivery for the treatment of periodontitis. CJC was initially tested for its antimicrobial activities like MIC, MBC, antiadhesion, antibiofilm and time kill assay against the panel of organisms (S. mutans (SM), E. faecalis (EF), A. actinomycetemcomitans (AA), P. gingivalis (PG), T. forsythia (TF)) responsible for periapical and periodontal infections. Antimicrobial activity of CJC showed MIC value of 50mg/ml and MBC value of 100mg/ml with desirable antiadhesion (83-90%) and antibiofilm activity (70-85%). CJC was evaluated for its biocompatibility using periodontal fibroblasts by cell based MTT assay and found to be nontoxic. Influence of CJC on periodontopathogen PG derived virulence factors (fimA and kgp) was studied using real time polymerase chain reaction (RT-PCR) technique wherein down regulation of selected genes demonstrated inhibitory effect against PG virulence factors. Thermoreversible gel of CJC was formulated by cold method using poloxamer 407 as thermosensitive polymer and carbopol 934 as mucoadhesive polymer and evaluated for its gelation temperature, viscosity, gel strength and mucoadhesive strength. Comparison of optimized thermoreversible gel of CJC (500mg/ml) with commercially available chlorhexidine gluconate gel (0.2%) using agar well diffusion demonstrated equal zone of inhibition against SM, EF, AA, PG & TF. Hence the formulated thermoreversible gel of CJC could serve as a novel herbal alternative to currently available periodontal treatment modalities.

Mechanism of Anti-rotavirus Synergistic Activity by Epigallocatechin Gallate and a Proanthocyanidin-Containing Nutraceutical.

Posted: 
August 15, 2017
Authors: 
Lipson SM; Karalis G; Karthikeyan L; Ozen FS; Gordon RE; Ponnala S; Bao J; Samarrai W; Wolfe E.
Journal: 
Food & Environmental Virology DOI 10.1007/s12560-017-9299-z
Abstract: 

Epigallocatechin gallate (EGCG) of green tea and the nutraceutical CystiCran-40 (containing 40% proanthocyanidins) of the cranberry plant have been associated with antiviral activity. The purpose of this work was to determine the mechanism of antiviral synergy between each compound. Coliphage T4II (phage T4) and the rotavirus strain SA-11(RTV) were used as model virus systems. Individual and combined flavonoids structural and molecular weight analyses were performed by NMR and HPCL/MS, respectively. A suboptimal concentration of EGCG or C-40 alone or in combination reduced phage infectivity by <=10%. Similarly, EGCG (30 micro g/ml) and C-40 (25 micro g/ml), respectively, reduced RTV titers by 3 and 13%. However, RTV titers were reduced by 32% (p < .05) with both flavonoids used in combination. RTV was not recognized in host cells by electron microscopy 24-h post-inoculation. NMR and HPLC/MS findings revealed significant structural and potential changes in molecular weight of the flavonoids in complex.

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