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The impact of cranberry (Vaccinium
macrocarpon) and cranberry products
on each component of the metabolic
syndrome: a review
Nataly Simões Bandiera Thimóteo
1
, Bruna Miglioranza Scavuzzi
1
, Andréa Name Colado Simão
2
and Isaias Dichi
3*
Abstract
Background: Some studies have shown that cranberry (Vaccinium macrocarpon) has beneficial effects on the
components of the metabolic syndrome (MetS), a condition characterized by a cluster of cardiovascular risk factors such
as central obesity, hypertension, impaired glucose homeostasis, elevated triglycerides, and decreased HDL cholesterol
levels. Cranberry is very rich in polyphenols, which may significantly reduce cardiovascular disease (CVD) risk.
Main body of the abstract: Nutritional intervention studies have indicated that the intake of cranberries and cranberry
products may have the following impact on metabolic health: (1) attenuate markers of obesity such as body weight,
body mass index, and waist circumference; (2) reduce systolic and diastolic pressures; (3) decrease plasma concentrations
of triglycerides and oxidized LDL-cholesterol, as well as increase HDL cholesterol; and (4) promote glucose homeostasis.
In addition, nutritional intervention with cranberries could confer antioxidant and anti-inflammatory properties and the
ability to reduce biomarkers of atherosclerosis associated with the MetS, such as homocysteine.
Short conclusion: Although there has been promising results, particularly related to lipid profile and blood pressure,
further research is needed to support the recommendation of cranberry intake as a nutritional intervention for the
treatment of MetS.
Keywords: Cranberry, Inflammation, Bioactive compounds, Polyphenols, Metabolic syndrome
Background
Metabolic syndrome (MetS) is generally defined as a
complex disorder represented by a cluster of cardiovas-
cular 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) [1]. Recent evidence suggests that the
prevalence of MetS is increasing in both developed and
developing countries, such as Brazil [2, 3].
Diets rich in fruits and vegetables, especially those
considered berries, increase the intake of polyphenols,
which are known to confer benefits to the cardiovascular
health [4, 5]. Cranberries (Vaccinium macrocarpon) are
native fruits from North America that contain low
carbohydrate concentrations in comparison to other
fruits. Furthermore, they have high content of vitamins,
minerals, and polyphenolic compounds [6], such as
flavan-3-ols, anthocyanins, benzoic acid, and ursolic acid
[7]. A-type proanthocyanidins are also present in high
concentrations in cranberry, while other berries pre-
dominantly have B-type proanthocyanidins. B-type
proanthocyanidins are believed to be less bioavailable
than the A-type [8]. The most abundant flavonoids in
cranberries consist mainly of quercetin and myricitrin [7].
Moreover, it has been demonstrated that cranberry juice
may contain resveratrol in concentrations similar to grape
juice [9]. Resveratrol has several biological effects related
to cardiovascular health, including inhibition of platelet
aggregation and reduction of inflammation [6]. The
* Correspondence: dichi@sercomtel.com.br
3
Department of Internal Medicine, University of Londrina, Rua Robert Koch
nº 60 Bairro Cervejaria, Londrina, Paraná 86038-440, Brazil
Full list of author information is available at the end of the article
Nutrir
e
© The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Thimóteo et al. Nutrire (2017) 42:25
DOI 10.1186/s41110-017-0048-8
polyphenols present in cranberry have a wide variety
of biological effects, including antibacterial, anticarcino-
genic, antiangiogenic, anti-inflammatory, antioxidant,
modulating enzyme activity, and gene expression regula-
tion [7, 10–16].
Cranberry juice may contain 100% of the daily require-
ment of vitamin C, contributing to the beneficial effects of
the fruit [10]. Cranberries can be consumed in various
products such as industrialized juice, jam, frozen fruit
pulp, sauce, cereal bars, and capsules and have become in-
creasingly popular and consumed, after several researches
have indicated health benefits including possibly prevent-
ing diseases such as urinary tract infection [17].
According to observational and interventional studies
in humans, consumption of cranberry and cranberry
products may be associated with beneficial effects on
MetS, affecting one or more of its components [6, 18], a
variety of inflammatory biomarkers and oxidative stress
[19]. Thus, the present review gathers recent and rele-
vant literature involving the consumption of cranberry
products and the components of the MetS in humans,
in addition to highlighting the most relevant mecha-
nisms involved.
Main text
Cranberry and obesity
Obesity has become a major public health issue, and it is
growing worldwide. In 2012, approximately 34.9% of
American adults were classified as obese [20]. Obesity is
usually defined when body mass index (BMI) is greater
than or equal to 30 kg/m
2
. Abdominal obesity is defined
as a waist circumference (WC) above 102 cm in men
and 88 cm in women [21]. Additionally, other waist cir-
cumference values have been applied for the diagnosis of
abdominal obesity in MetS to improve their applicability
to different ethnic groups [21, 22]. Some recom-
mended waist circumference thresholds are as follows:
for Europeans and South Americans (≥94 cm in men
and ≥80 cm in women), South Asians and Chinese
(≥90 cm in men and ≥80 cm in women), Japanese
(≥85 cm in men and ≥90 cm in women), and
Americans and Canadians (≥102 cm in men and ≥88 cm
in women) [21, 22].
An epidemiological study with data from the National
Health and Nutrition Examination Survey (NHANES)
including 10,891 American adults showed that cranberry
juice consumers were more likely to have normal weight
and lower waist circumference. The authors attributed
the favorable effects on body composition to flavonoids,
which are present in high levels in cranberries [23].
Other studies have demonstrated that bioactive com-
pounds such as flavonoids have the potential to inhibit
lipogenesis and adipogenesis, stimulate lipolysis, and in-
duce apoptosis in adipocytes [24]. It has been previously
demonstrated that cranberry reduces the proliferation
and viability of 3T3-L1 pre-adipocytes in a dose-
dependent manner. The nutritional intervention with
this berry also reduced the number of adipocytes and
reduced the accumulation of lipids in the 3T3-L1 pre-
adipocytes, indicating an inhibitory effect on lipogenesis.
Furthermore, it was demonstrated that cranberry in-
duced lipolysis in adipocytes and reduced the expression
of PPARγ, C/EBPb, and SREBP1, which are important
transcription factors of the adipogenesis pathway [25].
Diet is closely related to the development of obesity;
therefore, a diet enriched with these compounds may
serve as an additional strategy for the prevention and
treatment of obesity. The main human-interventional
studies with cranberry or cranberry products considering
markers of obesity are listed in Table 1. In sum, although
an epidemiological study [23] verified that consumers of
cranberry drinks were more likely to have more
favorable anthropometric measures, clinical trials on this
subject are still scarce and the results are inconsistent.
Therefore, more work is needed to obtain stronger
evidence.
Cranberry and glucose metabolism
Glucose homeostasis is disturbed when insulin and fast-
ing glucose are greater than 20 mU/mL and 110 mg/dL,
respectively, or when the patient has to use medication
to control blood glucose [26]. Matthews et al. [27] de-
scribed a mathematical relationship (HOMA-IR model)
between fasting glycemia and insulin to predict insulin
resistance [28]. Lower HOMA-IR values represent
higher insulin sensitivity, and higher values correspond
to decreased insulin sensitivity, also known as insulin
resistance (IR). IR and hyperinsulinemia contribute to
the pathogenesis of type 2 diabetes.
Wilson et al. [29] studied postprandial insulin and
glucose response in patients with type 2 diabetes. The
subjects were allocated into four groups that received: a
single serving of white bread (57 g, 160 calories, 1 g of
fiber); raw cranberries (55 g, 21 calories, 1 g of fiber);
sweetened cranberries (40 g, 138 calories, 2.1 g of fiber);
or cranberries with low sugar and high fiber content
(40 g, 113 calories, 1.8 g of fiber, and 10 g polydextrose).
The investigators found that the consumption of low-
sugar, high-fiber cranberries resulted in more favorable
glucose and insulin peaks. Thus, the selection of dry
cranberries, a natural source of polyphenols and fibers,
would enable a more favorable glycemic response in
patients with T2D. The decrease in glucose peak may be
due to the presence of the soluble fibers polydextrose
and β-Glucan, which were present in the low-calorie
serving, since these compounds have been related to
the reduction in the rate of gastric glucose absorption
[30, 31]. The presence of flavonoids in cranberry juice
Thimóteo et al. Nutrire (2017) 42:25 Page 2 of 12
can also delay the intestinal absorption of glucose
[32], contributing to the improvement in the glycemic
response observed in previous studies carried out by
the same research group [33].
In vitro studies have demonstrated that the extent of
inhibition of α-glucosidase by berry extracts is related to
its anthocyanin content [34]. Cyanidin-3-rutinoside [35]
and cyanidin-3-galactoside [36] are considered α-
glucosidase inhibitors. Proanthocyanidins are also con-
sidered potent α-glucosidase inhibitors [37]. Barrett
et al. [38] conducted an in vitro study to investigate if
the tannins (proanthocyanidins and elagitannins) present
in pomegranate, cranberry, grape, and cocoa extracts
could bind to the digestive enzymes α-amylase and glu-
coamylase, thus inhibiting starch hydrolysis. The authors
concluded that not only were tannins capable of inhi-
biting these enzymes but also larger and more complex
tannins such as cranberries would have the ability to
inhibit enzymes more effectively than less polymerized
tannins, such as those present in cocoa [38]. Another
in vitro study has shown that cranberry procyanidins
have the ability to inhibit the glycation of human
hemoglobin and serum albumin by elimination of reactive
carbonyl radicals [39].
Some phenolic acids, such as chlorogenic, ferulic, and
caffeic acids, competitively inhibit glucose uptake medi-
ated by sodium‐dependent glucose transporter 1
(SGLT1) [19]. This inhibition has also been observed by
other glucosides and quercetin [32]. SGLT1 assists in the
intestinal absorption of glucose through the aid of
sodium-dependent transport and thereby facilitates the
independent transport of sodium via GLUT [9]. The fla-
vonoids mycetin and quercetin were responsible for the
inhibition of GLUT2 glucose transport [37, 40]. These
compounds that inhibit glucose uptake, such as phenolic
acids and flavonoids, are components present in berries
[41–43]. Furthermore, it has been demonstrated in
porcine models that quercetin inhibits gastric uptake of
glucose. Quercetin and myricetin have also been shown
to inhibit GLUT4-mediated glucose uptake in rodent
adipocytes, to inhibit aldose reductase, α-amylase and α-
glucosidase in vitro [44].
Although polyphenolic compounds present in berries
have been associated with the enhancement of glycemic
regulation, other components may contribute to these
effects. Törrönen et al. [45] investigated the effects of
whole-berry purées on the postprandial glucose and in-
sulin responses after consumption of white wheat bread
or rye bread. The berry mixture (strawberries, bil-
berries, cranberries, and blackcurrants) significantly re-
duced the postprandial insulin response after the intake
of white wheat bread or rye bread. The researchers ob-
served that although the consumption of berries did
not suppress postprandial peak glucose, less insulin was
required for the maintenance of postprandial glucose
metabolism [45]. According to the investigators, the
more desirable postprandial insulin response did not
appear to be related to the polyphenol composition of
Table 1 Intervention studies with cranberry products evaluating markers of obesity
Authors Studies Population/intervention Conclusion
Ruel et al., 2006 [12] Intervention study to evaluate the
effect of increasing daily consumption
of a low-calorie cranberry juice cocktail
on plasma lipid profile in abdominally
obese men.
30 men consumed increasing
doses of cranberry juice for three
consecutive 4-week periods
(125 mL, 250 mL e 500 mL/d).
There was a decrease in adiposity
measures after the intervention
period, with reduction of body
weight (p = 0.0263), BMI
(p = 0.0386) and WC (p <0.0001).
Basu et al., 2011 [16] Randomized, double-blind,
placebo-controlled clinical trial
to assess the effect of intake of
low calorie cranberry juice on CVD
risk factors such as lipid oxidation,
inflammation and dyslipidemia in
subjects with MetS.
31 patients with MetS consumed
480 mL of juice/day (n = 15) or
placebo (n = 16) for 8 weeks.
Consumption of 480 mL of cranberry
juice/day for 8 weeks showed no
significant effect on WC reduction.
Duffey and Sutherland, 2013 [23] A study to verify the association
between consumption of cranberry
beverage, macronutrient intake and
body mass of patients who participated
in the National Health and Nutrition
Examination Survey (NHANES) between
2005-2008.
10891 American adults aged
19 years or older selected by the
National Health and Nutrition
Examination Survey (NHANES)
between 2005-2008.
Consumers of cranberry drinks
were more likely to have normal
body weight (p <0.001) and less
likely to be overweight or obese
(BMI ≥25 kg/m
2
, p <0.001)
compared to non-consumers.
Simão et al., 2013 [6] Clinical trial to evaluate the effect of
intake of low calorie cranberry juice
on metabolic and inflammatory
biomarkers in MetS patients.
56 patients with MetS participated
in a 60-day study; 20 patients
consumed 700 mL of cranberry
juice/day and 36 did not consume
the juice.
The consumption of 700 mL of
cranberry juice/day for 60 days
showed no significant effects on
the reduction of BMI or WC.
BMI body mass index, CVD cardiovascular disease, WC waist circumference, MetS metabolic syndrome
Thimóteo et al. Nutrire (2017) 42:25 Page 3 of 12
the berries, but rather the fiber content, especially
soluble fiber [45].
The main human-interventional studies with cranberry
or cranberry products considering glycemic metabolism
are listed in Table 2. In sum, although nutritional inter-
vention studies with cranberries on glucose metabolism
are still scarce, some of them have shown that cranberry
products may promote glucose homeostasis by reducing
fasting glycemia, improving HOMA-IR, increasing insu-
lin sensitivity, and preventing compensatory insulin se-
cretion [44, 46, 47], whereas others did not demonstrate
any significant change on this feature [16, 48]. From
these studies, it is still not possible to define if duration
and consumed amount of cranberry are responsible for
these controversial results. Certainly, more work is
warranted on this issue.
Cranberry and blood pressure
Polyphenols may significantly reduce cardiovascular dis-
ease (CVD) risk [49, 50]. In a study conducted during
18 years, it was demonstrated that the combined intake
three times a week of berries was associated with a lower
risk of myocardial infarction in middle-aged women [5].
Cranberries are rich sources of several polyphenols, such
as quercetin which has been associated with significant
blood pressure reduction in animal models [51–54] and
human trials [51–54]. Mechanistic studies in mouse
models have reported that cranberry juice induces
vasodilation via endothelial nitric oxide synthase (eNOS)
and significant reduction of blood pressure. These vasor-
elaxing properties would be comparable to those of red
wine [55].
Thirty men participated in a 12-week intervention
study and were asked to consume increasing daily doses
of a cranberry juice cocktail (125, 250, and 500 mL/day)
over three successive periods of 4 weeks. The investiga-
tors noted a slight but significant decrease in SBP
(−3 mm Hg) over the course of the intervention [13].
This reduction was likely associated with the poly-
phenolic content of the beverage. Furthermore, nutri-
tional studies have associated the intake of berries with
cardioprotective effects [49, 56–58]. Intervention studies
with flavonoids and anthocyanins have indicated that
possible mechanisms for the reduction of blood pressure
are inhibition of the activity of the angiotensin-
converting enzyme [13], a significant increase in nitric
Table 2 Intervention studies with cranberry products evaluating markers of glucose metabolism
Authors Studies Population/intervention Conclusion
Lee et al. [48] A randomized double blind,
controlled study evaluating the
effect of cranberry intake on the lipid
profile of patients with T2D.
30 type 2 diabetic subjects received
cranberry supplements (500 mg/
capsule) or placebo, 3×/day, for
12 weeks.
Neither fasting glucose nor glycated
hemoglobin improved in either
group.
Basu et al. [16] Randomized, double-blind, placebo-
controlled clinical trial to assess the
effect of intake of low calorie
cranberry juice on CVD risk factors
such as lipid oxidation, inflammation
and dyslipidemia in subjects with
MetS.
31 patients with MetS consumed
480 mL of juice/day (n= 15) or
placebo (n= 16) for 8 weeks.
Consumption of 480 mL of cranberry
juice per day for 8 weeks showed no
significant effect on the reduction of
fasting glycemia.
Shidfar et al. [44] A randomized, double-blind,
placebo-controlled clinical trial to
verify the effect of cranberry juice on
PON-1, apoA-1, apoB, glucose, and
Lp (a) in T2D patients.
Patients with T2D consumed 240 mL
of juice/day (n= 29) or placebo
(n= 29) for 12 weeks.
Patients who consumed cranberry
juice had a significant decrease in
serum glycemia when compared to
the initial value (P< 0.01) and the
control group (P< 0.05).
Novotny et al. [46] A double blind, placebo-controlled
study evaluating the consumption of
low-calorie cranberry juice and
placebo drink to decrease
cardiometabolic risk in overweight
middle-aged population.
Overweight patients consumed
240 mL of juice (n= 29) or placebo
(n= 27) two times/day for 8 weeks.
Patients who consumed low-calorie
cranberry juice had a reduction in
fasting plasma glucose (P= 0.03). The
juice also had a beneficial effect on
HOMA-IR for participants with high
baseline values (P= 0.035).
Paquette et al. [47] A parallel, double-blind, controlled,
and randomized clinical trial to
determine the effects of strawberry
and cranberry polyphenols (SCP) on
insulin sensitivity, glucose tolerance,
insulin secretion, lipid profile,
inflammation, and oxidative stress
markers in free-living insulin-resistant
overweight or obese human
subjects.
Overweight or obese patients
consumed a SCP beverage (333 mg)
(n= 20) or control beverage (n= 21)
daily for 6 weeks.
Patients who consumed the
polyphenols beverage had an
increase in insulin sensitivity and
prevention of further compensatory
insulin secretion.
MetS metabolic syndrome, PON-1 paraoxonase-1, Lp (a) lipoprotein (a), T2D type two diabetes mellitus
Thimóteo et al. Nutrire (2017) 42:25 Page 4 of 12
oxide synthesis by endothelial cells [59, 60], reduction of
vasoconstriction via nitric oxide-mediated pathway, or
reduction of renal oxidative stress [61, 62]. Dietary inter-
vention with polyphenol-rich foods and berry beverages
has led to significant changes in MetS characteristics, in-
cluding reduction of blood pressure, abdominal
adiposity, dyslipidemia, inflammation, and oxidative
stress [63].
The main human-interventional studies with cranberry
or cranberry products considering blood pressure are
listed in Table 3, and although this is a valuable area of
interest, the scarce studies have found controversial
results to date and for sure more studies are needed on
this subject.
Cranberry and dyslipidemia
Cardiovascular diseases are among the leading causes of
death in North America [64, 65]. Although LDL choles-
terol is not included in the definition of metabolic syn-
drome, elevated concentration of low-density lipoprotein
(LDL) is one of the most important cardiovascular risk
factor [66]. LDL particles, such as oxidized LDL,
could at least partially explain the atherogenicity of
LDL [67, 68]. Oxidized LDL is not recognized by
LDL receptors, but rather by cell-surface receptors on
macrophages; oxidation of LDL promotes cholesterol
absorption, leading to the formation of foam cells,
which is the first step in the formation of the first
atherosclerotic lesions [64]. A decrease in HDL con-
centration is also an independent risk factor for CVD
[69]. Although the role of HDL in the cholesterol
transport is known, HDL has several other
cardioprotective effects such as antithrombogenic,
antioxidant, fibrinolytic, antiadherence, and anti-
inflammatory properties [70].
The lipid-lowering effects of cranberry can be attrib-
uted mainly to the phytochemical compounds contained
in the fruit and to the fiber content, depending on the
form of consumption. Cranberry is a relevant source of
flavonoids, such as anthocyanidins, proanthocyanidins
[71, 72], resveratrol [73], and phenolic acid [71]. Flavo-
noids, abundantly present in cranberry, would have the
ability to inhibit the oxidation of LDL-cholesterol.
Oxidized LDL plays a critical role in the initiation and
progression of atherosclerosis; thus, supplementation
with cranberry would have the potential to delay the
process of atherosclerotic CVD [74]. In addition, flavo-
noids would have the ability to inhibit platelet adhesion
and aggregation, inhibit enzymes involved in lipid and
lipoprotein metabolism, and could increase reverse chol-
esterol transport, lowering total and LDL cholesterol [4].
Anthocyanin-rich products reduced triglycerides in ani-
mal models [75–77]. The total dietary fiber content of
cranberry may reach 5 g/100 g in dried fruit and thus
may contribute to its cholesterol lowering effects [4].
The flavonoid quercetin has been shown to inhibit de
novo TAG synthesis [78]. Casaschi et al. [78] analyzed
the activity of diacylglycerol acyltransferase (DGAT), an
enzyme in the final reaction of the glycerol phosphate
pathway for TAG synthesis, and found reduced DGAT
activity after treatment with quercetin. The investigators
also found that quercetin inhibits microsomal TAG
transfer protein (MTP) activity, an enzyme that catalyzes
the transfer of lipids, such as TAG and cholesterol
esters, which would inhibit intestinal apolipoprotein B
secretion and total cholesterol, TG and LDL levels [78].
Table 3 Intervention studies with cranberry products evaluating blood pressure
Authors Studies Population/intervention Conclusion
Ruel et al. [13] Intervention study to determine the
effect of the daily consumption of
low-calorie cranberry juice cocktail
on plasma oxidized LDL, intercellular
adhesion molecule-1, vascular cell
adhesion molecule-1, and E-selectin
concentrations in men.
30 men consumed increasing doses
of cranberry juice for 3 consecutive
4-week periods (125, 250, and
500 mL/day).
There was a slight but significant
decrease in systolic blood pressure
over the course of the intervention
(−3 mm Hg, P= 0.03).
Basu et al. [16] Randomized, double-blind, placebo-
controlled clinical trial to assess the
effect of intake of low calorie
cranberry juice on CVD risk factors
such as lipid oxidation, inflammation,
and dyslipidemia in subjects with
MetS.
31 patients with MetS consumed
480 mL of juice/day (n= 15) or
placebo (n= 16) for 8 weeks.
Consumption of 480 mL of cranberry
juice per day for 8 weeks showed a
non-significant reduction in systolic
blood pressure compared to baseline
values (−5.3%, P= 0.07).
Novotny et al. [46] A double blind, placebo-controlled
study evaluating the consumption of
low-calorie cranberry juice and
placebo drink to decrease
cardiometabolic risk in overweight
middle-aged population.
Overweight patients consumed
240 mL of cranberry juice (n= 29) or
placebo (n= 27) two times/day for
8 weeks.
After 8 weeks, diastolic pressure was
significantly lower in the cranberry
juice group than in the placebo
group (P= 0.048), with no difference
in systolic pressure.
CVD cardiovascular disease, MetS metabolic syndrome
Thimóteo et al. Nutrire (2017) 42:25 Page 5 of 12
Ruel et al. [12] proposed that the HDL increase could
be related to an increased production of apolipoprotein
A-I or a decreased clearance of HDL particles following
intervention with cranberry juice. The authors also
hypothesized that a reduction in apolipoprotein A-I oxi-
dation (related to a decrease in oxidative stress) and an
increased expression of paraoxonase-1 (related to the
high content of quercetin in the beverage) could be at least
partially responsible for the increase in HDL. Another
proposed mechanism to explain HDL increase after inter-
vention with cranberry products and reduction in serum
triglyceride (TG) levels is the inverse relationship between
TG and HDL [12, 79]. In hypertriacylglycerolemic states,
HDL particles exchange cholesterol for TG with LDL and
very low-density lipoproteins (VLDL) and become TG-
rich. The TG-rich HDL particles are more rapidly catabo-
lized in the liver than normal HDL particles. Thus, after a
decrease in serum levels of TG, an increase in serum HDL
levels may occur [12, 79, 80].
The main human-interventional studies with cranberry
or cranberry products considering lipid profile are listed
in Table 4. Collectively, these nutritional findings suggest
that although cranberry products have shown promising
beneficial effects on lipid profile, this is observed only in
Table 4 Intervention studies with cranberry products evaluating lipid profile
Authors Studies Population/intervention Conclusion
Ruel et al. [118] Intervention study to evaluate the
impact of cranberry juice
consumption on LDL oxidation and
on the antioxidant capacity of
plasma.
21 healthy men, consuming
cranberry juice (7 mL/kg body
weight/day) for 14 days.
After 14 days, no change was
observed in the levels of
LDL-cholesterol and oxidized LDL.
Ruel et al. [12] Intervention study to evaluate the
effect of increasing daily
consumption of a low-calorie
cranberry juice cocktail on plasma
lipid profile in abdominally obese
men.
30 men consumed increasing doses
of cranberry juice for 3 consecutive
4-week periods (125, 250, and
500 mL/day).
After 12 weeks, there was a
significant increase in HDL
(P= 0.001), reduction in TGs
(P= 0.0553), and significant
decrease in total cholesterol/HDL
ratio (P= 0.0005).
Ruel, et al. [13] Controlled intervention study
evaluating the effect of low-calorie
cranberry juice on plasma oxidized
LDL, ICAM-1, and VCAM-1 in healthy
subjects.
30 men consumed increasing doses
of cranberry juice for 3 consecutive
4-week periods (125, 250, and
500 mL/day).
The intervention produced a
decrease in the plasma
concentration of oxidized LDL
(P< 0.0001), but did not significantly
affect total cholesterol levels and
LDL cholesterol.
Lee et al. [48] A randomized double blind,
controlled study evaluating the
effect of cranberry intake on lipid
profile in patients with T2D.
30 type 2 diabetic subjects received
cranberry supplements (500 mg/
capsule) or placebo, 3×/day, for
12 weeks.
Supplementation with cranberry is
effective in reducing the
arteriosclerotic cholesterol profile,
including LDL, total cholesterol, and
total cholesterol/HDL ratio.
Basu et al. [16] Randomized, double-blind, placebo-
controlled clinical trial to assess the
effect of intake of low calorie
cranberry juice on CVD risk factors
such as lipid oxidation, inflammation,
and dyslipidemia in subjects with
MetS.
31 patients with MetS consumed
480 mL of juice/day (n= 15) or
placebo (n= 16) for 8 weeks.
The consumption of 480 mL of
cranberry juice/day for 8 weeks did
not show significant effects on
reduction of lipid profile.
Novotny et al. [46] A double blind, placebo-controlled
study evaluating the consumption of
low-calorie cranberry juice and
placebo drink to decrease
cardiometabolic risk in overweight
middle-aged population.
Overweight patients consumed
240 mL of cranberry juice (n= 29) or
placebo (n= 27) two times/day for
8 weeks.
TGs were lower for those who
consumed cranberry juice compared
to the placebo group (P= 0.027).
No differences in serum total
cholesterol, LDL, and HDL.
Paquette et al. [47] A parallel, double-blind, controlled,
and randomized clinical trial to
determine the effects of strawberry
and cranberry polyphenols (SCP) on
insulin sensitivity, glucose tolerance,
insulin secretion, lipid profile,
inflammation, and oxidative stress
markers in free-living insulin-resistant
overweight or obese human
subjects.
Overweight or obese patients
consumed a SCP beverage (333 mg)
(n= 20) or control beverage (n= 21)
daily for 6 weeks.
After 6 weeks, no differences were
detected between the two groups
for lipids.
ICAM-1 intercellular adhesion molecule-1, VCAM-1 vascular cell adhesion molecule-1, TGs triglycerides
Thimóteo et al. Nutrire (2017) 42:25 Page 6 of 12
interventions lasting at least 12 weeks. Thus, further
clinical trials are needed to confirm these findings and
establish the duration and dose of the intervention.
Cranberry and markers of inflammation and oxidative
stress
Central obesity and insulin resistance are the main
features involved in MetS, but low-grade chronic inflam-
mation is considered a major link between the MetS and
CVD [81]. In MetS, central obesity is considered an im-
portant source of low-grade chronic inflammation [82].
Free radicals and reactive metabolites, also known as
reactive oxygen species (ROS), are normal products of
cellular metabolism and are generated primarily by the
mitochondrial respiratory chain. When there is an im-
balance between the production of these reactive species
and their elimination by antioxidant mechanisms, an
accumulation of ROS occurs, leading to oxidative stress.
Several diseases such as cancer, chronic inflammatory dis-
eases, and aging are all conditions associated with in-
creased oxidative stress [83–86]. Furthermore, continuous
oxidative stress may lead to chronic inflammation [87].
A methanol extract prepared from dehydrated cran-
berries inhibited the activity of cyclooxygenase-2 and
also inhibited the NF-κβ transcriptional activation in
human T lymphocytes. Furthermore, the extract inhib-
ited the release of interleukins (IL)-1β, IL-6, IL-8, and
tumor necrosis factor-αfrom lipopolysaccharide (LPS)-
stimulated human peripheral blood mononuclear cells
in vitro. The authors attributed the anti-inflammatory
effects to ursolic acid and ursolic acid derivatives present
in the cranberry extract [88].
Vinson et al. [89] investigated the quantity of both free
and total phenolic antioxidants in cranberry products
Table 5 Intervention studies with cranberry products evaluating markers of inflammation and oxidative stress
Authors Studies Population/intervention Conclusion
Ruel et al. [12] Intervention study to evaluate the
effect of increasing daily
consumption of a low-calorie
cranberry juice cocktail on plasma
lipid profile in abdominally obese
men.
30 men consumed increasing doses
of cranberry juice for 3 consecutive
4-week periods (125, 250, and
500 mL/day).
Reduction of nitrite/nitrate
concentration (P< 0.05) with a
significant association between
plasma nitrite/nitrate decrease and
apo A-1 increase (P< 0.05). After the
12-week period, the antioxidant
capacity of total plasma increased
significantly (P= 0.006).
Basu et al. [16] Randomized, double-blind, placebo-
controlled clinical trial to assess the
effect of intake of low calorie
cranberry juice on CVD risk factors
such as lipid oxidation, inflammation,
and dyslipidemia in subjects with
MetS.
31 patients with MetS consumed
480 mL of juice/day (n= 15) or
placebo (n= 16) for 8 weeks.
Cranberry juice significantly
increased plasma antioxidant
capacity (P< 0.05) and decreased
oxidized LDL and malondialdehyde
(P< 0.05) at 8 weeks versus placebo.
Simão et al. [6] Clinical trial to evaluate the effect of
low calorie cranberry juice intake on
metabolic and inflammatory
biomarkers in MetS patients.
56 patients with MetS participated in
a 60-day study; 20 patients con-
sumed 700 mL of cranberry juice/
day, and 36 did not consume the
juice.
The consumption of 700 mL of
cranberry juice/day for 60 days
decreased lipoperoxidation
(P= 0.036) and protein oxidation
(P= 0.008) and increased adiponectin
levels (P= 0.01). The metabolic and
inflammatory biomarkers C-reactive
protein, TNF-α, IL-1, and IL-6 did not
differ between the groups.
Novotny et al. [46] A double blind, placebo-controlled
study evaluating the consumption of
low-calorie cranberry juice and
placebo drink to decrease
cardiometabolic risk in overweight
middle-aged population.
Overweight patients consumed
240 mL of cranberry juice (n= 29) or
placebo (n= 27) two times/day for
8 weeks.
After 8 weeks of evaluation, there
was significant improvement in
C-reactive protein levels (P= 0.0054)
for individuals consuming the
low-calorie cranberry juice than for
individuals consuming the placebo
beverage.
Paquette et al. [47] A parallel, double-blind, controlled,
and randomized clinical trial to
determine the effects of strawberry
and cranberry polyphenols (SCP) on
insulin sensitivity, glucose tolerance,
insulin secretion, lipid profile,
inflammation, and oxidative stress
markers in free-living insulin-resistant
overweight or obese human
subjects.
Overweight or obese patients
consumed a SCP beverage (333 mg)
(n= 20) or control beverage (n= 21)
daily for 6 weeks.
After 6 weeks, no differences were
detected between the two groups
for markers of inflammation and
oxidative stress.
CVD cardiovascular disease, MetS metabolic syndrome, TNF tumor necrosis factor, IL interleukin
Thimóteo et al. Nutrire (2017) 42:25 Page 7 of 12
and plasma antioxidant capacity after the consumption
of a single 24-mL serving of cranberry juice. The authors
found cranberries and cranberry products to be a signifi-
cant source of antioxidants both in vitro and in vivo.
Anthocyanin-rich products reduced inflammatory fac-
tors in humans [90, 91]. Furthermore, several studies
have shown that antioxidant compounds, especially
polyphenols, can inhibit the oxidation of LDL, which in
turn, would reduce the expression of adhesion molecules
in the endothelium [92, 93]. In addition, cranberry has
salicylic acid [94], which has anti-inflammatory activity
and has been shown to decrease the expression of vascu-
lar cell-1 adhesion molecule in vitro [95].
In a comparative study, cranberry juice had the same
amount of resveratrol as grape juice [73]. The health
benefits associated to resveratrol are many, especially in
promoting cardiovascular health, elimination of reactive
oxygen species, inhibition of platelet aggregation, and
decrease of inflammation [9].
Although cranberries are rich in known antioxidant
substances, the number of human-interventional
studies with this berry considering oxidative stress is
unexpectedly small. The main intervention studies
considering oxidative stress and markers of inflammation
are shown in Table 5. Altogether, these nutritional inter-
vention studies seem to confirm the expected antioxi-
dant action effect of cranberry products. However, the
effects on inflammatory markers are still inconsistent.
Certainly, more studies are required to confirm these
results and define the optimal dose and duration of
treatment.
Cranberry and other markers of cardiovascular risk
The intake of fruits and vegetables is beneficial for
reducing the risks of some human diseases, such as
CVD and cancer. In addition to being rich in soluble
and insoluble fibers, the positive health effects are attrib-
uted to elements with antioxidant properties such as
vitamins E, C, and carotenoids, which have the capacity
to inactivate ROS involved in the process or progression
of chronic diseases [96]. The presence of anthocyanins
in berries is responsible for its coloration and comprises
the largest group of natural species with water soluble
vegetable pigments [97–100]. Normally, the intensity
Table 6 Studies considering other cardiovascular risk markers and consumption of cranberry
Authors Studies Population/intervention Conclusion
Ruel et al. [13] Intervention study to determine the
effect of the daily consumption of
low-calorie cranberry juice cocktail
on plasma oxidized LDL, intercellular
adhesion molecule-1, vascular cell
adhesion molecule-1, and E-selectin
concentrations in men.
30 men consumed increasing doses
of cranberry juice for 3 consecutive
4-week periods (125, 250, and
500 mL/day).
There was a significant decrease in
plasma intercellular adhesion
molecule-1 (P< 0.0001) and vascular
cell adhesion molecule-1 (P< 0.05)
concentrations over the course of
the intervention.
Ruel et al. [18] Intervention study to determine the
effect of consuming increasing daily
doses of low-calorie cranberry juice
cocktail (CJC) on plasma matrix
metalloproteinase (MMP)-9
concentrations in abdominally
obese men.
30 men consumed increasing doses
of cranberry juice for 3 consecutive
4-week periods (125, 250, and
500 mL/day).
There was a significant decrease in
plasma MMP-9 concentrations
(P< 0.0005) over the course of the
intervention.
Dohadwala et al. [15] This study was carried out in two
stages: (1) an uncontrolled pilot
study to determine the acute effects
of cranberry juice consumption and
(2) a randomized, double blind,
cross-over study to examine
vascular functions before and after
consumption of cranberry juice and
placebo in patients with stable
coronary disease.
An acute non-placebo pilot study in
participants (n= 15) who consumed
480 mL cranberry juice and a
placebo crossover study (n= 44)
480 mL/day for 4 weeks with 2-week
washout period between placebo/
cranberry drinks.
After the pilot study, there was a
significant improvement in the
brachial artery dilation. No effects on
blood pressure, basal, or hyperemic
flow were observed. In the crossover
study, there was a significant
decrease of arterial stiffness with
consumption of the cranberry
beverage.
Simão et al. [6] Clinical trial to evaluate the effect of
intake of low calorie cranberry juice
on metabolic and inflammatory
biomarkers in MetS patients.
56 patients with MetS participated in
a 60-day study; 20 patients
consumed 700 mL of cranberry
juice/day, and 36 did not consume
the juice.
The consumption of 700 mL of
cranberry juice/day for 60 days
significantly decreased homocysteine
levels (P< 0.001).
Ruel et al. [119] Double-blind crossover design
intervention study to determine the
effect of consuming daily doses of
low-calorie cranberry juice cocktail
(CJC) on arterial stiffness in
abdominally obese men.
35 men consumed 500 mL of
cranberry juice or placebo for
4 weeks.
A significant (P= 0.019) within group
decrease in augmentation index, an
index of arterial stiffness, was noted
following the consumption of
500 mL CJC/day for 4 weeks.
MetS metabolic syndrome
Thimóteo et al. Nutrire (2017) 42:25 Page 8 of 12
of the color is directly proportional to its anthocyanin
content and can range from 2–4g/kg,increasingas
berries ripen. The average anthocyanin consumption
in the USA is 12.5–215 mg per day [101]. Studies
have shown that anthocyanins have low bioavailability,
are widely conjugated in the liver and the intestine,
and are excreted by the kidney within 2–8hofinges-
tion [102, 103]. The content of polyphenols (including
anthocyanins) and some vitamins in berries may be
affected by post-harvest processing techniques, such
as pressing and pasteurization, and thus reduce their
effects on CVD risk [104–106].
In an in vitro study, anthocyanins were shown to be
effective biomarkers of heart diseases and cancer, inhibiting
the release of ROS from active human granulocytes [107]
and suppressing free radical-mediated lipid peroxidation
and apoptosis in cultured aortic endothelial cells [108, 109].
In addition, anthocyanins, aglycones, and glycosides are
effective inhibitors of oxidative-induced DNA damage in
human colon cells [110] and are potent inhibitors of tumor
cell growth in vitro [111, 112].
The main intervention studies considering other
markers of cardiovascular risks are shown in Table 6. The
findings suggest that cranberry products may significantly
improve several markers of cardiovascular risk, such as
adhesion molecules, homocysteine, and arterial stiffness.
Nevertheless, it still remains to be determined if this
changes translate into prevention of cardiovascular events.
Gut microbiota and metabolism
A large body of evidence has elegantly demonstrated
that the gut microbiome regulates fat storage, lipid me-
tabolism, insulin resistance, and overall metabolism
[113–115]. A disturbance in gut microbiota, marked by
an imbalance between intestinal bacteria (e.g., increase
in Firmicutes and reduction in the abundance of
Bacteroidetes), known as dysbiosis, has been associated
with several components of MetS, such as obesity and
IR, via modulation of inflammatory pathways. Thus,
microbiota modulation through various nutritional inter-
ventions has been researched [80]. Recently, it has been
demonstrated that polyphenolic compounds from vari-
ous berries may possess prebiotic activity [116]. Add-
itionally, Anhê et al. [117] recently demonstrated that
oral administration of a cranberry extract prevented sev-
eral detrimental features of the MetS in a mouse model.
The authors associated these metabolic improvements
with a remarkable increase in the abundance of the mu-
cin-degrading bacterium Akkermansia in the gut micro-
biota of mice [117]. Thus, although we are not aware to
date of any human intervention study with cranberries
investigating gut microbiota, this prebiotic effect may
also be at least partially responsible for the beneficial
health effects demonstrated.
Conclusions
Although several studies have shown beneficial effects,
there are still few clinical and epidemiological studies
evaluating the relationship between cranberry intake and
the various components directly or indirectly associated
with the MetS. In addition, most clinical studies are of
relatively short duration (8 to 12 weeks), which often
prevents the verification of additional beneficial effects.
Another factor to consider is the amount of product to be
ingested. The antioxidant action of cranberry is already
well known and some authors have suggested the conduc-
tion of clinical trials to verify anti-inflammatory activity.
The mechanisms of action associated to cranberry also
require further studies. Although results especially related
to lipid profile and blood pressure are promising, further
research is needed to support the recommendation of
cranberry intake as a nutritional intervention for the
treatment of metabolic syndrome.
Abbreviations
BMI: Body mass index; BP: Blood pressure; CRP: C-reactive protein;
CVD: Cardiovascular disease; FFAs: Free fatty acids; HDL: High-density
lipoprotein; HOMA: Homeostatic model assessment; ICAM-1: Intercellular
adhesion molecule-1; IL: Interleukin; IR: Insulin resistance; LDL: Low-density
lipoprotein; MetS: Metabolic syndrome; Ox-LDL: Oxidized LDL; PAI-
1: Plasminogen activator inhibitor-1; ROS: Reactive oxygen species;
SBP: Systolic blood pressure; T2D: Type 2 diabetes; TG: Triglycerides;
VCAM-1: Vascular cell adhesion molecule-1; WC: Waist circumference
Acknowledgements
Not applicable.
Funding
Not applicable.
Availability of data and materials
Not applicable.
Authors’contributions
NSBT, BMS, and ID performed the bibliographic research and writing. ANCS
and ID conceived, designed, and revised the manuscript. All authors read
and approved the final manuscript.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Publisher’sNote
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
Author details
1
Post Graduate Program in Health Science, University of Londrina, Rua Robert
Koch nº 60 Bairro Cervejaria, Londrina, Paraná, Brazil.
2
Department of
Pathology, Clinical Analysis and Toxicology, University of Londrina, Rodovia
Celso Garcia Cid - PR 445, Km 380, Londrina, Paraná, Brazil.
3
Department of
Internal Medicine, University of Londrina, Rua Robert Koch nº 60 Bairro
Cervejaria, Londrina, Paraná 86038-440, Brazil.
Thimóteo et al. Nutrire (2017) 42:25 Page 9 of 12
Received: 16 April 2017 Accepted: 5 July 2017
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