Emerging evidence is elucidating how non-nutrient phytochemicals underlie the health promotion afforded by fruits and vegetables. This review focuses on Vaccinium macrocarpon, the American cranberry, compiling a comprehensive list of its known phytochemical components, and detailing their prevalence in cranberry fruit and its products. Flavonoids, especially colored anthocyanins, abundant flavonols, and unique proanthocyanidins, have attracted major research attention. Other notable active components include phenolic acids, benzoates, hydroxycinnamic acids, terpenes and organic acids. Health effects of cranberries, cranberry products, and isolated cranberry components in humans and animals, as well as in vitro, are debated. Evidence for protection from several bacterial pathogens, cancer, cardiovascular disease, and inflammation is compelling, while neuroprotection and anti-viral activity also have begun to draw new consideration. Emerging bioavailability data is considered and potential molecular mechanisms are evaluated, linking phytochemicals to health effects through their biochemical properties and reactions. Finally, the effects of processing and storage on cranberry phytochemicals is discussed, with a focus on identifying research gaps and novel means to preserve their natural, health-promoting components.

Phytochemicals of cranberries and cranberry products: characterization, potential health effects, and processing stability.

Cranberry (Vaccinium macrocarpon Ait.) ingestion has long been associated with prevention of urinary tract infections. The beneficial mechanism was historically thought to be due to the fruit acids causing a bacteriostatic effect in the urine. However, recently, a group of proanthocyanidins (PACs) with A-type linkages were isolated from cranberry which exhibit bacterial antiadhesion activity against both antibiotic susceptible and resistant strains of uropathogenic P-fimbriated Escherichia coli bacteria. The link between cranberry ingestion and maintenance of urinary tract health as well as the structural diversity, pharmacokinetics, quantification, and bacterial antiadhesion bioactivity of the A-linked cranberry PACs are reviewed.

Bioactive compounds in cranberries and their role in prevention of urinary tract infections

Background: Ingestion of cranberry (Vaccinium macrocarpon Ait.) has traditionally been utilized for prevention of urinary tract infections. The proanthocyanidins (PACs) in cranberry, in particular the A-type linkages have been implicated as important inhibitors of primarily P-fimbriated E. coli adhesion to uroepithelial cells. Additional experiments were required to investigate the persistence in urine samples over a broader time period, to determine the most effective dose per day and to determine if the urinary anti-adhesion effect following cranberry is detected within volunteers of different origins. Methods: Two separate bioassays (a mannose-resistant hemagglutination assay and an original new human T24 epithelial cell-line assay) have assessed the ex-vivo urinary bacterial anti-adhesion activity on urines samples collected from 32 volunteers from Japan, Hungary, Spain and France in a randomized, double-blind versus placebo study. An in vivo Caenorhabditis elegans model was used to evaluate the influence of cranberry regimen on the virulence of E. coli strain. Results: The results indicated a significant bacterial anti-adhesion activity in urine samples collected from volunteers that consumed cranberry powder compared to placebo (p < 0.001). This inhibition was clearly dose-dependent, prolonged (until 24 h with 72 mg of PAC) and increasing with the amount of PAC equivalents consumed in each cranberry powder regimen. An in vivo Caenorhabditis elegans model showed that cranberry acted against bacterial virulence: E. coli strain presented a reduced ability to kill worms after a growth in urines samples of patients who took cranberry capsules. This effect is particularly important with the regimen of 72 mg of PAC. Conclusions: Administration of PAC-standardized cranberry powder at dosages containing 72 mg of PAC per day may offer some protection against bacterial adhesion and virulence in the urinary tract. This effect may offer a nyctohemeral protection.

/pdf/dosage-effect-on-uropathogenic-escherichia-coli-anti-x7oenogipd.pdf

Dosage effect on uropathogenic Escherichia coli anti-adhesion activity in urine following consumption of cranberry powder standardized for proanthocyanidin content: a multicentric randomized double blind study

Urinary tract infection (UTI) refers to the presence of clinical signs and symptoms arising from the genitourinary tract plus the presence of one or more micro-organisms in the urine exceeding a threshold value for significance (ranges from 102 to 103 colony-forming units/mL). Infections are localized to the bladder (cystitis), renal parenchyma (pyelonephritis) or prostate (acute or chronic bacterial prostatitis). Single UTI episodes are very common, especially in adult women where there is a 50-fold predominance compared with adult men. In addition, recurrent UTIs are also common, occurring in up to one-third of women after first-episode UTIs. Recurrences requiring intervention are usually defined as two or more episodes over 6 months or three or more episodes over 1 year (this definition applies only to young women with acute uncomplicated UTIs). A cornerstone of prevention of UTI recurrence has been the use of low-dose once-daily or post-coital antimicrobials; however, much interest has surrounded non-antimicrobial-based approaches undergoing investigation such as use of probiotics, vaccines, oligosaccharide inhibitors of bacterial adherence and colonization, and bacterial interference with immunoreactive extracts of Escherichia coli. Local (intravaginal) estrogen therapy has had mixed results to date. Cranberry products in a variety of formulations have also undergone extensive evaluation over several decades in the management of UTIs. At present, there is no evidence that cranberry can be used to treat UTIs. Hence, the focus has been on its use as a preventative strategy. Cranberry has been effective in vitro and in vivo in animals for the prevention of UTI. Cranberry appears to work by inhibiting the adhesion of type I and P-fimbriated uropathogens (e.g. uropathogenic E. coli) to the uroepithelium, thus impairing colonization and subsequent infection. The isolation of the component(s) of cranberry with this activity has been a daunting task, considering the hundreds of compounds found in the fruit and its juice derivatives. Reasonable evidence suggests that the anthocyanidin/proanthocyanidin moieties are potent antiadhesion compounds. However, problems still exist with standardization of cranberry products, which makes it extremely difficult to compare products or extrapolate results. Unfortunately, most clinical trials have had design deficiencies and none have evaluated specific key cranberry-derived compounds considered likely to be active moieties (e.g. proanthocyanidins). In general, the preventive efficacy of cranberry has been variable and modest at best. Meta-analyses have established that recurrence rates over 1 year are reduced approximately 35% in young to middle-aged women. The efficacy of cranberry in other groups (i.e. elderly, paediatric patients, those with neurogenic bladder, those with chronic indwelling urinary catheters) is questionable. Withdrawal rates have been quite high (up to 55%), suggesting that these products may not be acceptable over long periods. Adverse events include gastrointestinal intolerance, weight gain (due to the excessive calorie load) and drug-cranberry interactions (due to the inhibitory effect of flavonoids on cytochrome P450-mediated drug metabolism). The findings of the Cochrane Collaboration support the potential use of cranberry products in the prophylaxis of recurrent UTIs in young and middle-aged women. However, in light of the heterogeneity of clinical study designs and the lack of consensus regarding the dosage regimen and formulation to use, cranberry products cannot be recommended for the prophylaxis of recurrent UTIs at this time.

Cranberry and urinary tract infections.

Plants are rich in a variety of compounds. Many are secondary metabolites and include aromatic substances, most of which are phenols or their oxygen-substituted derivatives such as tannins (Hartmann 2007; Jenke-Kodama, Muller, and Dittmann 2008). Many of these compounds have antioxidant properties (see Chapter 2 on antioxidants in herbs and spices). Ethnobotanicals are important for pharmacological research and drug development, not only when plant constituents are used directly as therapeutic agents, but also as starting materials for the synthesis of drugs or as models for pharmacologically active compounds (Li and Vederas 2009). About 200 years ago, the first pharmacologically active pure compound, morphine, was produced from opium extracted from seeds pods of the poppy Papaver somniferum. This discovery showed that drugs from plants can be purified and administered in precise dosages regardless of the source or age of the material (Rousseaux and Schachter 2003; Hartmann 2007). This approach was enhanced by the discovery of penicillin (Li and Vederas 2009). With this continued trend, products from plants and natural sources (such as fungi and marine microorganisms) or analogs inspired by them have contributed greatly to the commercial drug preparations today. Examples include antibiotics (e.g., penicillin, erythromycin); the cardiac stimulant digoxin from foxglove (Digitalis purpurea); salicylic acid, a precursor of aspirin, derived from willow bark (Salix spp.); reserpine, an antipsychotic and antihypertensive drug from Rauwolfia spp.; and antimalarials such as quinine from Cinchona bark and lipid-lowering agents (e.g., lovastatin) from a fungus (Rishton 2008; Schmidt et al. 2008; Li and Vederas 2009). Also, more than 60% of cancer therapeutics on the market or in testing are based on natural products. Of 177 drugs approved worldwide for treatment of cancer, more than 70% are based on natural products or mimetics, many of which are improved with combinatorial chemistry. Cancer therapeutics from plants include paclitaxel, isolated from the Pacific yew tree; camptothecin, derived from the Chinese “happy tree” Camptotheca acuminata and used to prepare irinotecan and topotecan; and combretastatin, derived from the South African bush willow (Brower 2008). It is also estimated that about 25% of the drugs prescribed worldwide are derived from plants, and 121 such active compounds are in use (Sahoo et al. 2010). Between 2005 and 2007, 13 drugs derived from natural products were approved in the United States. More than 100 natural product-based drugs are in clinical studies (Li and Vederas 2009), and of the total 252 drugs in the World Health Organization’s (WHO) essential medicine list, 11% are exclusively of plant origin (Sahoo et al. 2010).

Herbal medicine : an introduction to its history, usage, regulation, current trends and research needs

To determine the efficacy of the consumption of cranberry juice versus placebo with regard to the presence of in vitro bacterial anti-adherence activity in the urine of healthy volunteers. Twenty healthy volunteers, 10 men and 10 women, were included. The study was a double-blind, randomized, placebo-controlled, and cross-over study. In addition to normal diet, each volunteer received at dinner a single dose of 750 ml of a total drink composed of: (1) 250 ml of the placebo and 500 ml of mineral water, or (2) 750 ml of the placebo, or (3) 250 ml of the cranberry juice and 500 ml of mineral water, or (4) 750 ml of the cranberry juice. Each volunteer took the four regimens successively in a randomly order, with a washout period of at least 6 days between every change in regimen. The first urine of the morning following cranberry or placebo consumption was collected and used to support bacterial growth. Six uropathogenic Escherichia coli strains (all expressing type 1 pili; three positive for the gene marker for P-fimbriae papC and three negative for papC), previously isolated from patients with symptomatic urinary tract infections, were grown in urine samples and tested for their ability to adhere to the T24 bladder cell line in vitro. There were no significant differences in the pH or specific gravity between the urine samples collected after cranberry or placebo consumption. We observed a dose dependent significant decrease in bacterial adherence associated with cranberry consumption. Adherence inhibition was observed independently from the presence of genes encoding type P pili and antibiotic resistance phenotypes. Cranberry juice consumption provides significant anti-adherence activity against different E. coli uropathogenic strains in the urine compared with placebo.

Reduction of Escherichia coli adherence to uroepithelial bladder cells after consumption of cranberry juice: a double-blind randomized placebo-controlled cross-over trial.

(2005). Effects of Cranberry Juice on Uropathogenic Escherichia coli In Vitro Biofilm Formation. Journal of Chemotherapy: Vol. 17, No. 5, pp. 563-565.

Effects of cranberry juice on uropathogenic Escherichia coli in vitro biofilm formation.

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Reduction of Escherichia coli adherence to uroepithelial bladder cells after consumption of cranberry juice: a double-blind randomized placebo-controlled cross-over trial.

Effects of cranberry juice on uropathogenic Escherichia coli in vitro biofilm formation.