There are three commercially important fruits native to North America; one of them is cranberry (Vaccinium macrocarpon). Cranberries were used by Native New Englanders for food, fabric dye, and in poultices to treat wounds and blood poisoning. Early American sailors, including whalers and mariners, consumed cranberries as an antiscorbutic agent during ocean voyages. Scurvy, caused by vitamin C deficiency, is characterized by weakness, bleeding gums, and bleeding beneath the skin.
Recent researches have focused on cranberries and their components' use in the prevention and treatment of cardiovascular disease (CVD). Epidemiological studies have consistently shown that the consumption of fruits and vegetables is inversely associated with the risk of developing CVD and stroke; their phytochemical constituents appear to contribute substantially to this benefit.
Cranberries are particularly rich in phenolic phytochemicals, which have a wide range of biological effects; for example, they can serve as antioxidants, modulate enzyme activity, and regulate gene expression. Cranberries have the highest total phenol content among the 20 most commonly consumed fruits in the American diet. Experimental in vitro studies suggest that these phenolic compounds increase the resistance of low-density lipoproteins (LDL) to oxidation, prevent platelet aggregation and thrombosis, reduce blood pressure, and inhibit inflammation. As a result, they can affect the pathogenesis of CVD. (1)
In this paper, human studies regarding the bioactivity of cranberry and its constituents on risk factors for CVD, as well as the impact of cranberry and cranberry products on each component of the metabolic syndrome are reviewed.
Metabolic syndrome (MetS) is generally defined as a complex disorder represented by a cluster of cardiovascular risk factors such as central obesity, dyslipidemia, hypertension, and impaired glucose metabolism, leading to an increased risk of coronary heart diseases, other types of atherosclerotic cardiovascular diseases, and type 2 diabetes (DT2). (2)
1. Nutrient and Phytochemical Constituents:
In order to reduce the risk of chronic diseases, particularly CVD, type-2 diabetes, osteoporosis, and some types of cancer, "Dietary Guidelines for Americans" issued by the US Department of Health and Human Services / US Department of Agriculture in 2005, and “dietary recommendations” issued by the American Heart Association have both suggested daily consumption of fresh fruit and 100% fruit juices as part of a healthy diet. Whole fruits like cranberries are naturally low in calories, fat, and sodium. They contain no cholesterol and are a good source of dietary fiber. (1)
Cranberries contain low carbohydrate concentrations in comparison to other fruits. Furthermore, they are a good source of vitamins and minerals. (2)
Dried cranberries, cranberry juice, and juice cocktail similarly contain little sodium and fat. The predominant type of fatty acids present in cranberries and cranberry products are polyunsaturated and include α-linolenic acid, 18:3n-3, which is present in the seed oil (22 g/100 g fatty acids). A diet composed of foods that contain ω-3 fatty acids and are low in saturated fat and cholesterol has been shown to have a positive effect on plasma lipid profiles. Fiber intake, especially soluble fiber like pectin naturally abundant in cranberries, is also an established part of heart-healthy diets. Further, the high ratio of potassium to sodium in cranberries and cranberry products may contribute to the promotion of lower blood pressure. Compared to other common fruits, cranberries contain a higher amount of total phenols per serving (507–709 mg gallic acid equivalents/100 g); the same in some other fruits are as follows: Blueberries (258–531 mg/100 g), apples (185–347 mg/100 g), red grapes (175–370 mg/100 g), and strawberries (132–368 mg/100g). Researchers have also identified the stilbene resveratrol in cranberries, which has several biological effects related to cardiovascular health, including quenching reactive oxygen species, inhibiting platelet aggregation, and reducing inflammation. (1)
Cranberries contain a high amount of A-type proanthocyanidins, while other berries predominantly have B-type proanthocyanidins believed to be less bioavailable than the A-type. (2)
2. Bioavailability
Bioavailability means the extent a substance or drug becomes completely available to its intended biological destinations.
Zhang and Zuo developed a gas chromatography-mass spectrometry method for detecting various cranberry juice phenolic compounds, including benzoic acids and flavonoids, in human plasma. When this method was applied to the cranberry juice cocktail, they detected the presence of 16 phenolic compounds in a single subject. Before consumption of the cranberry juice, no benzoic, phenolic, or flavonoid compounds were observed in the fasting plasma sample. 45 min after consumption of 1800 ml juice, benzoic acid, o-hydroxybenzoic acid, p-Hydroxyphenylacetic acid, 2,3-dihydroxybenzoic acid, and 2,4-dihydroxybenzoic acid were detected in plasma. 270 min after consumption, seven benzoic and phenolic compounds were detected, including the five compounds listed above plus ferulic and sinapic acids. Benzoic acid was the most prevalent aromatic compound present both in the cranberry juice (54 g/ml) and in plasma after juice consumption. Many of the phenolic compounds identified in the cranberry juice cocktail were not detected in the plasma samples. On the other hand, p-Hydroxyphenylacetic and 2,4-dihydroxybenzoic acid were identified in plasma but not in juice. These compounds are likely metabolites of the cranberry juice phenolics.
In a placebo-controlled study of 22 healthy women (mean age 27.5 years) not taking aspirin or other salicylate drugs, Duthie et al. determined that cranberry juice consumption increased the absorption of dietary salicylic acid. A daily, low-dose (75 mg) aspirin (acetylsalicylic acid) is an established therapy for patients at risk for CVD. Both groups were matched in terms of age, height, and weight. For two weeks, they received either the cranberry juice cocktail (3 daily servings of 250 ml) or a placebo beverage containing 9% (w/v) of sucrose. The total salicylate content of the cranberry juice was 7.04 mg/L; none was found in the placebo beverage. Within 1 week, urinary salicylic acid and salicyluric acid increased in subjects consuming the cranberry juice compared to the placebo subjects. After 2 weeks, salicylic acid levels increased in the plasma of the cranberry juice group. (1)
3. Antioxidant Status and Oxidative Stress
Metabolic syndrome (MetS) is mainly characterized by central obesity and insulin resistance, but a major link between MetS and CVD is low-grade chronic inflammation. In MetS, central obesity is considered an important source of low-grade chronic inflammation. Normal products of cellular metabolism are free radicals and reactive metabolites, also known as reactive oxygen species (ROS). They are both generated primarily by the mitochondrial respiratory chain. An imbalance between "these reactive species production" and "their elimination by antioxidant mechanisms" causes ROS accumulation, resulting in oxidative stress. (2)
The effects of cranberry juice consumption on plasma antioxidant activity and biomarkers of oxidative stress were examined in 20 healthy young females (age 18–40 years) in a placebo-controlled trial by Duthie et al. The subjects consumed 750 ml/d of either cranberry juice cocktail or a placebo drink containing strawberry flavored mineral water plus 9 g/100 ml sucrose for 2 weeks. Anthocyanin glycosides were identified in the cranberry juice by tandem mass spectrometry; however, no anthocyanins or catechins were detected in the plasma of the subjects following either treatment. Urinary malondialdehyde, a biomarker of lipid oxidation, and 8-oxo-deoxyguanosine, a biomarker of oxidative DNA damage, were measured.
After 1 week, they noticed a significant increase in plasma levels of the antioxidant vitamin C (from 63.0 to 89.6 M) in the subjects who consumed the cranberry juice; but no changes in the antioxidant capacity of plasma or oxidative stress biomarkers in urine were detected in either group. (1)
4. Lipid Profile Effects
A preliminary study was done to investigate the effects of cranberry juice consumption on lipid profile changes. They reported the effect of consuming either low-calorie cranberry juice (4.3 ml/ kg) or an isocaloric placebo twice daily for 28 days. The subjects who consumed the cranberry juice had significantly reduced TC and LDL compared to the placebo control subjects. No statistically significant differences were observed for HDL or triglyceride concentrations.
In another study, they observed significantly improved HDL concentrations with either 2 or 3 servings of cranberry juice and also decreased LDL with 2 servings of cranberry juice daily. No effect on TC was observed.
As anticipated, triglycerides increased in the subjects who consumed 3 servings/d of cranberry juice cocktail due to the 9% (w/v) sugar, but not in those who consumed the cranberry juice cocktail containing artificial sweetener. (1)
5. Platelet Aggregation
A preliminary investigation evaluated the ability of cranberry juice to inhibit platelet aggregation in vivo. After 4 days of consuming cranberry juice four times a day, platelet-rich plasma aggregation values, in response to adenosine diphosphate and collagen, declined significantly compared to baseline values. These aggregation responses returned to near baseline levels 4 days after cessation of cranberry juice consumption. Attempts to recreate the inhibition of adenosine diphosphate- and collagen-induced aggregation in vitro by adding cranberry juice to platelet-rich plasma from the subjects who did not consume cranberry juice were not successful.
6. Control of Blood Glucose
Diabetic patients are at increased risk of developing CVD. In a placebo-controlled study of 27 adults diagnosed with type 2 diabetes within the previous 4–6 years, they examined the effect of cranberry juice concentrate powder on measures of glucose control. 14 subjects in the treatment group (average age 57.9 years) consumed six capsules of cranberry powder a day (equivalent to a 240 ml serving of cranberry juice cocktail) for 12 weeks. 13 control subjects (average age 52.6 years) received capsules containing a placebo powder. At the beginning of the study, 50% of the subjects were reported to have good control of their blood glucose levels (7.0 mmol/L). After 6 and 12 weeks, they observed no differences between groups in fasting glucose, glycosylated hemoglobin (HbA1c), fructosamine, triglyceride, HDL, or LDL concentration. However, at week 12, cranberry-supplemented subjects had lower insulin levels (86 pmol/L) than placebo subjects (160 pmol/L). (1)
7. Blood Pressure
Polyphenols are associated with decreased risk for cardiovascular disease (CVD). In an 18-year study, they revealed that consuming the combination of berries three times a week was associated with a lower risk of myocardial infarction in middle-aged women. Cranberries are rich in several polyphenols such as quercetin, which has significantly decreased blood pressure in animal models and human trials. Mechanistic studies in mouse models have reported that cranberry juice causes vasodilation via endothelial nitric oxide synthase (eNOS) and significantly reduces blood pressure.
8. Gut Microbiota and Metabolism
Numerous evidence has illustrated that the gut microbiome regulates fat storage, lipid metabolism, insulin resistance, and overall metabolism. A disturbance in gut microbiota is marked by an imbalance between intestinal bacteria, also known as dysbiosis. To exemplify, we can refer to an increase in Firmicutes or a reduction in the abundance of Bacteroidetes. This disturbance via modulation of inflammatory pathways has been associated with several components of MetS, such as obesity and insulin resistance. Thus, Modulation of the gut microbiome through various dietary interventions has been researched. The researchers have recently demonstrated that polyphenolic compounds found in various types of berries may possess prebiotic activity. Moreover, another research has shown that oral administration of a cranberry extract prevented several detrimental features of the MetS in a mouse model. The authors suggested that these metabolic improvements were associated with a remarkable increase in the abundance of the mucin-degrading bacterium Akkermansia in the gut microbiota of mice. (2)
Conclusion
Many evidence indicates that polyphenols, including those in cranberries, increase the resistance of LDL to oxidation, inhibit platelet aggregation, reduce blood pressure, and have some other anti-thrombotic and anti-inflammatory mechanisms. As a result, they may reduce the risk of cardiovascular disease (CVD). While most of this evidence is derived from in vitro studies and animal models, a limited number of human studies indicate these phytochemicals are bioavailable and bioactive. (1)
According to observational and interventional studies in humans, consumption of cranberry and cranberry products may be associated with beneficial effects on MetS and may affect not only one or more of its components, but also a variety of inflammatory biomarkers and oxidative stress. (2)
References
1- McKay, D.L., and Blumberg, J.B. (2007). Cranberries (Vaccinium macrocarpon) and Cardiovascular Disease Risk Factors. Nutrition Reviews, 65(11), 490-502. Retrieved from https://academic.oup.com/nutritionreviews/article/65/11/490/1907389
2- Thimóteo, N.S.B., Scavuzzi, B.M., Simão, A.N.C., and Dichi, I. (2017). The impact of cranberry (Vaccinium macrocarpon) and cranberry products on each component of the metabolic syndrome: a review. Nutrire, 42(25). Retrieved from https://www.researchgate.net/publication/319491277
