Vaccinium macrocarpon (Ericaceae) – American cranberry

Vaccinium macrocarpon, commonly known as the American cranberry, is a perennial shrub of the family Ericaceae, native to the wetlands and bogs of North America. It is a prostrate, creeping dwarf shrub, with thin, woody stems that may extend beyond one metre and readily root at the nodes, forming dense mats. The leaves are small, leathery and evergreen, alternately arranged along the stems; the upper surface is dark green, while the underside is paler and often equipped with tiny glands. The flowers, delicate and pale pink, have strongly reflexed petals and are typically pollinated by insects.

The fruit is a red berry, globose to ellipsoid, with firm flesh, high acidity and pronounced astringency. This particular sensory profile has favoured the use of cranberries mainly in processed forms (juices, sauces, extracts), as fresh consumption is generally considered too sour and astringent. The species has a physiological cycle strongly adapted to cold climates: it requires a winter dormancy period and thrives on acidic, water-saturated yet well-oxygenated substrates. The well-known cranberry bogs of North America rely on carefully managed water regimes that reproduce, in an agricultural setting, the ecological dynamics of natural peatlands.

From an ecological point of view, Vaccinium macrocarpon is adapted to oligotrophic habitats. It can persist where few other plants compete successfully, thanks to its tolerance of very low pH, low nutrient availability and low temperatures. Its berries provide a food source for numerous bird species and small mammals, which contribute to seed dispersal. The creeping growth habit and ability to root from stem nodes make cranberry an important stabilising element in the plant cover of bog ecosystems.

The main scientific interest in Vaccinium macrocarpon stems from its phytochemical profile, rich in polyphenols, including anthocyanins, flavonols, phenolic acids and, in particular, A-type proanthocyanidins (PAC-A). These latter compounds are considered a key distinguishing feature of cranberry compared with other Vaccinium species. PAC-A have been associated with a potential ability to interfere with bacterial adhesion to uroepithelial cells, especially in the case of Escherichia coli, a mechanism that underpins the use of cranberry in supporting urinary tract health.

Modern scientific literature has examined this application in depth, with overall promising but variable results depending on dose, PAC-A content, formulation and the clinical profile of the population studied. The most consistent evidence points to a reduced risk of recurrence of uncomplicated urinary tract infections, particularly in women with frequent episodes, provided that standardised extracts are used and taken regularly. It is essential to emphasise that cranberry does not replace antibiotics when these are clinically indicated, but may act as a preventive adjunct in selected cases.

Beyond the urological field, various studies have explored the potential antioxidant, anti-inflammatory, hypoglycaemic and cardiovascular effects of cranberry. The high polyphenol content appears to contribute to modulation of oxidative markers, support of endothelial function and regulation of certain metabolic parameters, although in these areas, too, the most robust findings often come from relatively short-term interventions or specific subgroups of the population. The impact of cranberry on the gut microbiota is an emerging topic: some research suggests that microbial metabolites derived from proanthocyanidins may influence the composition of certain bacterial communities in a favourable way.

From a nutritional standpoint, fresh cranberries have very low energy density and provide vitamin C, dietary fibre and a variety of phenolic compounds. However, many commercial products (such as juices and dried cranberries) contain added sugars, which substantially alter the overall nutritional profile. For this reason, health assessments must clearly distinguish between whole fruit, standardised extracts and processed products.

Agronomically, cranberry cultivation is a highly specialised system that requires strongly acidic soils, precise water management, carefully selected cultivars with staggered ripening and post-harvest practices designed to preserve physical integrity, colour and polyphenol content. The cranberry industry represents an economically important sector in the United States and Canada, supplying both the food market and the nutraceutical sector.

Botanical classification (APG IV system)

Indicative nutritional values per 100 g (fresh fruits of Vaccinium macrocarpon)
Values refer to raw, unsweetened cranberries; they may vary with cultivar, growing conditions and ripeness.

At typical serving sizes (for example 40–80 g fresh in sauces, salads or mixed fruit), American cranberry provides a moderate energy intake, almost entirely from carbohydrates, plus a meaningful amount of dietary fiber, vitamin C and manganese.
(For sweetened dried cranberries, energy and sugar content are much higher and vitamin C much lower compared with fresh fruit.)

Lipid profile note

Fresh Vaccinium macrocarpon fruits have a very low fat content. Saturated fatty acids (SFA) are present only in trace amounts; when SFA predominate over unsaturated fats in the overall diet, they are generally considered less favourable for cardiovascular health.

The tiny lipid fraction is composed mainly of unsaturated fatty acids (MUFA and PUFA), which are usually regarded as more favourable when they replace part of dietary SFA. In cranberries, however, the absolute fat contribution is so low that their impact on total dietary fat balance is negligible; nutritional interest focuses primarily on fiber, vitamin C, manganese and phenolic compounds (proanthocyanidins, anthocyanins and other polyphenols).

Plant Characteristics:
Vaccinium macrocarpon is a low-growing, creeping shrub that can reach heights of 15-30 cm. It produces small, white or pale pink flowers that bloom in summer and develop into red, tart berries. It thrives in cool, wet environments, often found in bogs and marshes, and prefers acidic, well-drained soils.

Chemical Composition and Structure:
Cranberries contain several beneficial compounds:

• Vitamins: Rich in Vitamin C and Vitamin A, with some B vitamins.
• Minerals: Contains essential minerals such as potassium, calcium, and magnesium.
• Antioxidants: High concentrations of antioxidants, including flavonoids (such as quercetin and anthocyanins), ellagic acid, and proanthocyanidins, which help combat oxidative stress.
• Organic Acids: Includes citric and malic acids, contributing to the tart flavor and potential health benefits.
• Dietary Fiber: Good source of dietary fiber that supports digestive health.

How to Cultivate It:

• Climate: Prefers cool, temperate climates with cold winters and cool summers.
• Soil: Grows best in acidic, moist, and well-drained soils, such as those found in peat bogs.
• Sunlight: Requires full sun or partial shade for optimal growth.
• Watering: Needs regular watering to keep the soil moist, avoiding excess water that can cause root rot.
• Pruning: Pruning is not essential but can help maintain plant health and promote better fruit production.

Uses and Benefits:

• Culinary Uses: Cranberries are used fresh, dried, in juices, sauces, and jams. They are a common ingredient in traditional dishes like cranberry sauce for turkey.
• Medicinal Uses: Traditionally used for their antimicrobial and anti-inflammatory properties. Cranberries are known to support urinary tract health and may help prevent urinary infections.
• Economic Uses: Cultivated commercially for the food market and cranberry-based products, including supplements and juices.

Cosmetic Uses:

• Antioxidants: The antioxidants in cranberries help protect the skin from free radical damage, reducing signs of aging and promoting a youthful appearance.
• Hydration: Cranberry extracts are used in skincare products to enhance skin hydration and maintain softness.
• Brightening: Antioxidants and vitamins in cranberry extracts can help brighten the complexion and reduce the appearance of dark spots and uneven skin tone.
• Exfoliation: Natural acids in cranberries can help gently exfoliate dead skin cells, improving texture and radiance.
• Anti-inflammatory: Cranberry extracts have anti-inflammatory properties that can soothe irritated skin and reduce redness.

INCI Functions:

Skin conditioning agent. It is the mainstay of topical skin treatment as it has the function of restoring, increasing or improving skin tolerance to external factors, including melanocyte tolerance. The most important function of the conditioning agent is to prevent skin dehydration, but the subject is rather complex and involves emollients and humectants that can be added in the formulation.

CAS  91770-88-6

EC number 294-875-8

Applications:

• Skincare Products: Used in creams, masks, and serums for their hydrating, anti-aging, and brightening effects.
• Exfoliating Treatments: Incorporated into exfoliating products to remove dead skin cells and improve texture.
• Brightening Products: Formulated to address pigmentation issues and improve skin tone.

Environmental and Safety Considerations:

• Pests and Diseases: Cranberries can be susceptible to pests such as aphids and fungal diseases like gray mold. Regular monitoring and management are necessary.
• Invasive Potential: Generally not considered invasive but can spread under favorable conditions.
• Safety: Generally regarded as safe for topical application. However, like all extracts, it should be used in accordance with established guidelines to avoid potential allergic reactions or skin irritations. People with allergies or very sensitive skin should be careful.

Studies

Cranberries are generally safe for consumption and are known for their potential health benefits, including preventing urinary tract infections and protecting against some chronic diseases due to their high antioxidant content. In some individuals, excessive consumption of cranberries can cause gastrointestinal disturbances due to their acid content.

It is used in the food sector mainly for the preparation of fruit juices and sweets and in medicine to treat cystitis, kidneys and related infections (1), as well as to counteract the progression of prostate cancer (2).

It has a very high content of polyphenols, compared to fruits such as orange, grape, contains anthocyanins, polyphenols (quercetin, myricetin), malic acid, citric acid (3), vitamins (A, C, E), resveratrol. It can therefore be considered a nutraceutical.

The integration of cranberry quercetin into the chemotherapy of ovarian cancer has produced in vitro cellular apoptotic events, including cell cycle arrest, for which it can be considered a potential dietary available therapeutic agent (4).

The scientific literature agrees in attributing to cranberry anti-tumor properties.  This in vitro study has shown that cranberry and/or its components can act as chemopreventive agents, reducing the risk of cancer by inhibiting cellular oxidation and inflammatory processes, while they can also exert chemotherapeutic effects by inhibiting cellular proliferation and angiogenesis, inducing cellular apoptosis and attenuating the ability of tumor cells to invade and metastasize (5).

The polyphenols present in the cranberry are known to have attenuating effects against different properties of cariogenic virulence responsible for the pathogenesis of dental caries (6).

Avoid drinking too much cranberry juice as it can alter the effect of warfarin (7).

Cranberry studies

References_____________________________________________________________________

(1)  Pagonas N, Hörstrup J, Schmidt D, Benz P, Schindler R, Reinke P, van der Giet M, Zidek W, Westhoff TH.   Prophylaxis of recurrent urinary tract infection after renal transplantation by cranberry juice and L-methionine. Transplant Proc. 2012 Dec;44(10):3017-21. doi: 10.1016/j.transproceed.2012.06.071.

Bruyère F, Azzouzi AR, Lavigne JP, Droupy S, Coloby P, Game X, Karsenty G, Issartel B, Ruffion A, Misrai V, Sotto A, Allaert FA. A Multicenter, Randomized, Placebo-Controlled Study Evaluating the Efficacy of a Combination of Propolis and Cranberry (Vaccinium macrocarpon) (DUAB®) in Preventing Low Urinary Tract Infection Recurrence in Women Complaining of Recurrent Cystitis.    Urol Int. 2019;103(1):41-48. doi: 10.1159/000496695.

Jepson RG, Williams G, Craig JC.  Cochrane Database Syst  Cranberries for preventing urinary tract infections.  Rev. 2012 Oct 17;10:CD001321. doi: 10.1002/14651858.CD001321.pub5. Review.

(2) Déziel B, MacPhee J, Patel K, Catalli A, Kulka M, Neto C, Gottschall-Pass K, Hurta R.  American cranberry (Vaccinium macrocarpon) extract affects human prostate cancer cell growth via cell cycle arrest by modulating expression of cell cycle regulators.   Food Funct. 2012 May;3(5):556-64. doi: 10.1039/c2fo10145a. Epub 2012 Mar 5.

Abstract. Prostate cancer is one of the most common cancers in the world, and its prevalence is expected to increase appreciably in the coming decades. As such, more research is necessary to understand the etiology, progression and possible preventative measures to delay or to stop the development of this disease. Recently, there has been interest in examining the effects of whole extracts from commonly harvested crops on the behaviour and progression of cancer. Here, we describe the effects of whole cranberry extract (WCE) on the behaviour of DU145 human prostate cancer cells in vitro. Following treatment of DU145 human prostate cancer cells with 10, 25 and 50 μg ml⁻¹ of WCE, respectively for 6 h, WCE significantly decreased the cellular viability of DU145 cells. WCE also decreased the proportion of cells in the G2-M phase of the cell cycle and increased the proportion of cells in the G1 phase of the cell cycle following treatment of cells with 25 and 50 μg ml⁻¹ treatment of WCE for 6 h. These alterations in cell cycle were associated with changes in cell cycle regulatory proteins and other cell cycle associated proteins. WCE decreased the expression of CDK4, cyclin A, cyclin B1, cyclin D1 and cyclin E, and increased the expression of p27. Changes in p16(INK4a) and pRBp107 protein expression levels also were evident, however, the changes noted in p16(INK4a) and pRBp107 protein expression levels were not statistically significant. These findings demonstrate that phytochemical extracts from the American cranberry (Vaccinium macrocarpon) can affect the behaviour of human prostate cancer cells in vitro and further support the potential health benefits associated with cranberries.

(3) Wang Y, Johnson-Cicalese J, Singh AP, Vorsa N.  Characterization and quantification of flavonoids and organic acids over fruit development in American cranberry (Vaccinium macrocarpon) cultivars using HPLC and APCI-MS/MS.  Plant Sci. 2017 Sep;262:91-102. doi: 10.1016/j.plantsci.2017.06.004.

(4)  Wang Y, Han A, Chen E, Singh RK, Chichester CO, Moore RG, Singh AP, Vorsa N. The cranberry flavonoids PAC DP-9 and quercetin aglycone induce cytotoxicity and cell cycle arrest and increase cisplatin sensitivity in ovarian cancer cells.  Int J Oncol. 2015 May;46(5):1924-34. doi: 10.3892/ijo.2015.2931.

Abstract. Cranberry flavonoids (flavonols and flavan-3-ols), in addition to their antioxidant properties, have been shown to possess potential in vitro activity against several cancers. However, the difficulty of isolating cranberry compounds has largely limited anticancer research to crude fractions without well-defined compound composition. In this study, individual cranberry flavonoids were isolated to the highest purity achieved so far using gravity and high performance column chromatography and LC-MS characterization. MTS assay indicated differential cell viability reduction of SKOV-3 and OVCAR-8 ovarian cancer cells treated with individual cranberry flavonoids. Treatment with quercetin aglycone and PAC DP-9, which exhibited the strongest activity, induced apoptosis, led to caspase-3 activation and PARP deactivation, and increased sensitivity to cisplatin. Furthermore, immunofluorescence microscopy and western blot study revealed reduced expression and activation of epidermal growth factor receptor (EGFR) in PAC DP-9 treated SKOV-3 cells. In addition, quercetin aglycone and PAC DP-9 deactivated MAPK-ERK pathway, induced downregulation of cyclin D1, DNA-PK, phospho-histone H3 and upregulation of p21, and arrested cell cycle progression. Overall, this study demonstrates promising in vitro cytotoxic and anti-proliferative properties of two newly characterized cranberry flavonoids, quercetin aglycone and PAC DP-9, against ovarian cancer cells.

(5) Mantzorou M, Zarros A, Theocharis S, Pavlidou E, Giaginis C.  Cranberry as a Promising Natural Source of Potential Nutraceuticals with Anticancer Activity.    Anticancer Agents Med Chem. 2019 Jul 4. doi: 10.2174/1871520619666190704163301.

(6)  Philip N, Bandara HMHN, Leishman SJ, Walsh LJ. Effect of polyphenol-rich cranberry extracts on cariogenic biofilm properties and microbial composition of polymicrobial biofilms.  Arch Oral Biol. 2019 Jun;102:1-6. doi: 10.1016/j.archoralbio.2019.03.026.

(7)  Srinivas NR  Cranberry juice ingestion and clinical drug-drug interaction potentials; review of case studies and perspectives.  Pharm Pharm Sci. 2013 J Pharm Pharm Sci. 2013;16(2):289-303. doi: 10.18433/j3ng6z. 

Abstract. Cranberry juice is a popular beverage with many health benefits. It has anthocyanins to supplement dietary needs. Based on in vitro evidence cranberry juice is an inhibitor of CYP enzymes and at higher amounts as potent as ketoconazole (CYP3A) and fluconazole (CYP2C9). There is, however, a discrepancy between in vitro and in vivo observations with respect to a number of substrates (cyclosporine, warfarin, flurbiprofen, tizanidine, diclofenac, amoxicillin, ceflacor); with the exception of a single report on midazolam, where there was a moderate increase in the AUC of midazolam in subjects pre-treated with cranberry juice. However, another study questions the clinical relevancy of in vivo pharmacokinetic interaction between cranberry juice and midazolam. The controversy may be due to a) under in vitro conditions all anthocyanin principles may be available to have a concerted effort in CYP inhibition; however, limited anthocyanin principles may be bioavailable with varying low levels in the in vivo studies; b) a faster clearance of the active anthocyanin principles under in vivo conditions may occur, leading to low threshold levels for CYP inhibition; c) efficient protein binding and/or rapid tissue uptake of the substrate may have precluded the drug availability to the enzymes in the in vivo studies. With respect to pharmacodynamic aspects, while the debate continues on the issue of an interaction between warfarin and cranberry juice, the summation of the pharmacodynamics data obtained in patients and healthy subjects from different prospectively designed and controlled clinical trials does not provide overwhelming support for the existence of a pharmacodynamic drug interaction for normal cranberry juice ingestion. However, it is apparent that consumption of large quantities of cranberry juice (about 1-2 L per day) or cranberry juice concentrates in supplements for an extended time period (>3-4 weeks) may temporally alter the effect of warfarin. Therefore, the total avoidance of cranberry juice by warfarin users may not be warranted by the published studies. However, in certain situations of higher intake of cranberry juice or concentrate there may be a need to monitor both warfarin doses and its effect.