Bioactive Compounds, Antioxidant Activity, and Biological Effects of European Cranberry (Vaccinium oxycoccos)

Abstract

Lesser known fruits or underutilized fruit species are recently of great research interest due to the presence of phytochemicals that manifest many biological effects. European cranberry, Vaccinium oxycoccos fruit, as an important representative of this group, is a valuable source of antioxidants and other biologically active substances, similar to American cranberry (V. macrocarpon) which is well known and studied. European cranberry fruit is rich especially in polyphenolic compounds anthocyanins (12.4–207.3 mg/100 g fw), proanthocyanins (1.5–5.3 mg/100 g fw), and flavonols, especially quercetin (0.52–15.4 mg/100 g fw), which mostly contribute to the antioxidant activity of the fruit. Small cranberry is also important due to its various biological effects such as urinary tract protection (proanthocyanidins), antibacterial and antifungal properties (quercetin, proanthocyanidins, anthocyanins), cardioprotective (proanthocyanidins) and anticancer activities (proanthocyanidins), and utilization in food (juice drinks, jams, jellies, sauces, additive to meat products) and pharmacological industries, and in folk medicine.

Full text

molecules
Review
Bioactive Compounds, Antioxidant Activity, and
Biological Effects of European Cranberry
(Vaccinium oxycoccos)
Tunde Jurikova 1, Sona Skrovankova 2, Jiri Mlcek 2,*, Stefan Balla 1and Lukas Snopek 2
1Institute for teacher training, Faculty of Central European Studies, Constantine the Philosopher University
in Nitra, SK-949 74 Nitra, Slovakia; tjurikova@ukf.sk (T.J.); sballa@ukf.sk (S.B.)
2Department of Food Analysis and Chemistry, Faculty of Technology, Tomas Bata University in Zlín,
CZ-760 01 Zlín, Czech Republic; skrovankova@utb.cz (S.S.); lsnopek@utb.cz (L.S.)
*Correspondence: mlcek@utb.cz; Tel.: +420-576-033-030
Received: 27 November 2018; Accepted: 18 December 2018; Published: 21 December 2018


Abstract:
Lesser known fruits or underutilized fruit species are recently of great research interest
due to the presence of phytochemicals that manifest many biological effects. European cranberry,
Vaccinium oxycoccos fruit, as an important representative of this group, is a valuable source of
antioxidants and other biologically active substances, similar to American cranberry (V. macrocarpon)
which is well known and studied. European cranberry fruit is rich especially in polyphenolic
compounds anthocyanins (12.4–207.3 mg/100 g fw), proanthocyanins (1.5–5.3 mg/100 g fw),
and flavonols, especially quercetin (0.52–15.4 mg/100 g fw), which mostly contribute to the
antioxidant activity of the fruit. Small cranberry is also important due to its various biological
effects such as urinary tract protection (proanthocyanidins), antibacterial and antifungal properties
(quercetin, proanthocyanidins, anthocyanins), cardioprotective (proanthocyanidins) and anticancer
activities (proanthocyanidins), and utilization in food (juice drinks, jams, jellies, sauces, additive to
meat products) and pharmacological industries, and in folk medicine.
Keywords: cranberry; Vaccinium oxycoccos; polyphenols; antioxidant effect; biological activities
1. Introduction
Berries, especially members of several families such as Ericaceae, belong to the best dietary sources
of bioactive compounds. They have a typical flavor and often possess antioxidant properties, and
therefore, are of great interest for nutritionists and food technologists [
1
]. The genus Vaccinium of family
Ericaceae comprises more than 450 species across Europe, North America, Central America, Central and
South East Africa, Madagascar, Japan, and Asia [
2
]. Blueberry (Vaccinium ashei,V. angustifolium
Aiton, V. corymbosum L.), bilberry (Vaccinuim myrtillus), cranberry (Vaccinium macrocarpon, V. oxycoccos),
huckleberry (Vaccinium ovatum, V. parvifolium), and lingonberry (Vaccinium vitis-idaea) are the most
known and popular berries of this genus.
Lots of researchers have focused their attention on “large cranberry” or “American cranberry”
(Vaccinium macrocarpon Aits) which is native in the northeastern part of the USA and widely
commercially planted in British Columbia, Canada. Also lingonberry or cowberry or “rock cranberry”
(Vaccinium vitis-idaea), native in North America and Europe, is the considerable lesser known crop.
But till now only little research has dealt with “European cranberry” (Vaccinium oxycoccos L.), commonly
known as “small cranberry” or “bog cranberry” [
3
,
4
]. Vaccinium oxyccocos plants include forms such
as the little-leaf cranberry, V. oxycoccos f. microphylla, syn. = Oxycoccus microcarpos (Turcz.), and the
larger-leaf form V. oxycoccos L. subsp. paulustris =Oxycoccus quadripetalus (Turcz.) [
5
]. However,
Molecules 2019,24, 24; doi:10.3390/molecules24010024 www.mdpi.com/journal/molecules

Molecules 2019,24, 24 2 of 21
according to Côtéet al. [
6
] the taxonomic relationship between the cytotypes is uncertain, and
nowadays Vaccinium oxycoccos is considered as a complex of diploid and polyploid plants.
In comparison with the large cranberry, the geographical distribution of European cranberry
is considerably wider. It occurs in forest areas in Europe, Asia, and North America. The species of
this shrub are widely commercially cultivated in Russia and Estonia, and also Lithuania [
7
]. It is an
evergreen shrub with creeping stems that grows on peat in low drained sites. In European conditions
it usually appears on sphagnum bogs in the north-western part of the European continent as far as
North Asia and Japan. Cranberries ripen during late August and through September and can persist
on plants until spring. The berries have pink, red or dark red color, strong acidic flavor and can be
pear- or egg-shaped, round, oval, oblate or cylindrical [4,7,8].
Generally, the bioactive compounds in different types of berries contain mainly phenolic
compounds such as flavonoids and ascorbic acid. These compounds, either individually or combined,
are responsible for various health benefits of berries [
1
]. While the biologically active substances
of large cranberry have been relatively extensively studied, there are only few studies focused on
European small cranberry (V. oxycoccos). Similarly, also health effects of V. macrocarpon in prevention
of some chronic diseases are well examined, wild cranberry fruits, including V. oxycoccos, did not
get enough attention yet, even the fruit is widely used in food and pharmaceutical industries. It is
great for use in juice drinks, jams, jellies, and sauces, and also as an additive to meat products [
9
].
European cranberry fruits represent an important natural source of antioxidants, such as polyphenolic
compounds (i.e., anthocyanins, flavonols, phenolic acids, and proanthocyanidins), and ascorbic acid
that are all attributed to antioxidant properties [10,11].
The review offers a recent view of European cranberry as an underutilized berry crop in respect to
biologically active substances, especially polyphenolic compounds, antioxidants, antioxidant activity
of berries, and different biological activities.
2. Bioactive Compounds of European Cranberry
Nowadays, the interest in bioactive compounds of European cranberry has increased due to its
long-standing usage in folk medicine, especially in Eastern Europe, Finland, Sweden, and Russia [
12
].
On the other hand, there are only a few papers presenting results of studies relating to the bioactive
compounds profile of the fruit.
According to Brown et al. [
3
] there are approximately 8000–10,000 phytochemicals detected in
V. macrocarpon,V. vitis-idaea, and V. oxycoccos. The berries of large cranberry and European cranberry
can be characterized by the accumulation of a high level of phenolic compounds, such as anthocyanins,
flavonoids, and phenolic acids [
8
]. The phenolic compounds are important for plants for their normal
growth and defense against biological and environmental stresses, infection, and injury [
13
]. Generally,
cranberries have a diverse phytochemical profile with phenolic acids such as hydroxycinnamic acid,
three classes of flavonoids (i.e., flavonols, anthocyanins, and proanthocyanidins), catechins, and
triterpenoids [14].
Similarly to American cranberry, European cranberry contains flavonoids, anthocyanins, and other
bioactive compounds with antioxidant activity and also a great amount of organic acids, and vitamin C
as well [
15
]. ˇ
Cesonien
˙
e et al. [
16
] compared the amount of biologically active compounds among
40 genotypes (13 certified cultivars and 27 wild clones) of V. oxycoccos fruit of different origins (Estonian,
Russian, and Lithuanian), grown under uniform ecological conditions in Lithuania. They found
great variation in anthocyanin content, organic acids, and sugar content in fruits of cultivated types
and wild clones, therefore the content of presented compounds differs depending on the cultivars.
Analogously to the berries of V. macrocarpon,V. oxycoccos berries also contain citric acid (10.8 to
54.3 g/kg), malic (14.1 to 43.3 g/kg), and quinic (3.81 to 13.3 g/kg) acids as the main organic acids.
The average content of fructose in fruits (42.1 g/kg) was analogous to glucose content (45.1 g/kg).
The HPLC (high-performance liquid chromatography) method with UV and MS (mass spectrometry)
detection used Jensen et al. [
17
] for the quantification of hydrophilic organic acids of cranberry,

Molecules 2019,24, 24 3 of 21
lingonberry, and blueberry juices. The highest content of hydrophilic carboxylic acids was evaluated for
cranberries (2.67–3.57%) and lingonberries (2.27–3.05%), and a much lower amount was in blueberries
(0.35–0.75%), with the presence of quinic acid, malic, shikimic, and citric acids.
Also ascorbic acid (vitamin C) is accumulated in cranberries. Due to some researchers European
varieties have lower content of ascorbic acid than American cranberries; however, the results for
vitamin C amounts in these fruits are quite dissimilar [
18
]. Tikuma et al. [
19
] mentioned that fresh
berries of wild cranberry V. oxycoccos contain more ascorbic acid (31 mg/100 g) in comparison to
cultivars of large cranberry (cultivars “Early Black”, “Stevens”, “Bergman”, “Pilgrim”). Especially the
Latvian bred big cranberry cultivar “Septembra” showed a higher amount of ascorbic acid compared
to other surveyed species. As Viskelis et al. [
20
] reported, the amount of ascorbic acid in American
berries increases during ripening, from the beginning of ripening with white berries to 50% reddish
berries, and ripe berries on average from 9.25 mg/100 g to 14.2 mg/100 g, and slightly decreases in
overripe berries (10.3 mg/100 g).
Cranberry fruit represents an exceptional source of bioactive compounds of which also fatty
acids have high biological activity even though the lipid amount in berries is low. The lipid profile
of different berries reflects their taxonomy. There is a high amount of C18 unsaturated fatty acids in
fresh berries, and also phytosterols, as it have been proved by GC-MS analyses [
21
]. The chemical
composition of wild cranberry (V. oxycoccos) extracts from fresh fruit originating from the Russian
Siberia, growing under natural conditions, and analyzed by GC-MS showed as major constituents
benzyl alcohol,
α
-terpineol and 2-methylbutyric acid, and malic, citric, benzoic, and cinnamic acids in
addition to fatty alcohols and acids [22].
2.1. Phenolic Compounds of European Cranberry
The berries of European cranberry belong to important sources of phenolic compounds, similarly
as other berries. The phenolic content among different distinguished berry genera, such as family
Ericaceae with genus Vaccinium; family Rosaceae with genera Rubus,Fragaria,Sorbus,Aronia; family
Grossulariaceae with genus Ribes; and family Empetraceae with genus Empetrum, varies considerably
as Moyer et al. [
23
] and Kähkönen et al. [
24
] found out. They evaluated anthocyanins as the main
phenolic constituents in cranberries, in bilberries too, but not in lingonberries, belonging also to the
genus Vaccinium, where flavanols and procyanidins predominate.
Generally, cranberry fruit is characterized by a diverse phytochemical profile with flavonoids
such as flavonols, anthocyanins, and proanthocyanidins; catechins, phenolic acids, and triterpenoids.
The overview of major phenolic compounds in European cranberry (V. oxycoccos) is shown in
Table 1.
Table 1. The overview of major phenolic compounds in European cranberry.
Phenolic Compounds
Content
(mg/100 g fw or as Mentioned
in the Brackets)
References
Phenolic acids
Benzoic acid 99.6–214.6 Stobnicka and Gniewosz [11]
p-coumaric acid 2.0–78.0 Stobnicka and Gniewosz [11],
Ehala et al. [15]
Chlorogenic acid 61.0–96.3
7.8% (% of all phenolic acids)
Stobnicka and Gniewosz [11]
Häkkinen et al. [25]
Caffeic acid 0.7–1.4
12.2% (% of all phenolic acids)
Stobnicka and Gniewosz [11]
Häkkinen et al. [25]
Ferrulic acid 68.1% (% of all phenolic acids) Häkkinen et al. [25]

Molecules 2019,24, 24 4 of 21
Table 1. Cont.
Phenolic Compounds
Content
(mg/100 g fw or as Mentioned
in the Brackets)
References
Anthocyanins
Anthocyanins 12.4–207.3 Kivimäki et al. [26],
ˇ
Cesonien˙
e et al. [27]
Cyanidin-3-
galactoside
13.1–26.8% (mean 19.8% of all anthocyanins)
19.3% (% of all anthocyanins)
20.4% (% of all anthocyanins)
ˇ
Cesonien˙
e et al. [27]
ˇ
Cesonien˙
e et al. [16]
ˇ
Cesonien˙
e et al. [28]
Cyanidin-3-
glucoside
0.09–13.4% (mean 3.4% of all anthocyanins)
2.8% (% of all anthocyanins)
3.2% (% of all anthocyanins)
ˇ
Cesonien˙
e et al. [27]
ˇ
Cesonien˙
e et al. [16]
ˇ
Cesonien˙
e et al. [28]
Cyanidin-3-
arabinoside
16.5–40.5% (mean 21.7% of all anthocyanins)
20.2% (% of all anthocyanins)
21.3% (% of all anthocyanins)
ˇ
Cesonien˙
e et al. [27]
ˇ
Cesonien˙
e et al. [16]
ˇ
Cesonien˙
e et al. [28]
Peonidin-3-
galactoside
5.9–42.8% (mean 30% of all anthocyanins)
29.6% (% of all anthocyanins)
29.2% (% of all anthocyanins)
ˇ
Cesonien˙
e et al. [27]
ˇ
Cesonien˙
e et al. [16]
ˇ
Cesonien˙
e et al. [28]
Peonidin-3-
glucoside
1.4–23.3% (mean 7.4% of all anthocyanins)
8.1% (% of all anthocyanins)
6.2% (% of all anthocyanins)
ˇ
Cesonien˙
e et al. [27]
ˇ
Cesonien˙
e et al. [16]
ˇ
Cesonien˙
e et al. [28]
Peonidin-3-
arabinoside
3.4–28.5% (mean 17.4% of all anthocyanins)
19.8% (% of all anthocyanins)
19.6% (% of all anthocyanins)
ˇ
Cesonien˙
e et al. [27]
ˇ
Cesonien˙
e et al. [16]
ˇ
Cesonien˙
e et al. [28]
Flavonoids
Quercetin 0.52–15.4
79.9% (% of all flavonoids)
Ehala et al. [15],
Stobnicka and Gniewosz [11],
Häkkinen et al. [25]
Myricetin 8.4–11.2
18.2% (% of all flavonoids)
Stobnicka and Gniewosz [11],
Häkkinen et al. [25]
Epicatechin 3.1–6.3 Stobnicka and Gniewosz [11]
Proanthocyanins 1.5–5.3
Kivimäki et al. [
26
], Koponen et al. [
29
],
Ogawa et al. [30]
Borowska et al. [
31
] provided the comparative study on polyphenols of wild-grown common
cranberry (Vaccinium oxycoccus) and American cranberry cultivars “Ben Lear”, “Bergman”,
“Early Richard”, “Pilgrim”, and “Stevens”, all originating from Poland. Statistically significant
differences (p< 0.05) were found for total polyphenols and anthocyanins in the fruit of the analyzed
cultivars. Total phenolic contents for American cultivars were in the range of 192.1 (“Pilgrim”) to
374.2 mg/100 g (“Ben Lear”), European cranberry cultivar reached 288.5 mg/100 g. The fruit of
common cranberry contained the highest quantity of trans-resveratrol (712.3 mg/g), large cranberry
ranged from 533.4 (“Stevens”) to 598.2 mg/g (“Ben Lear”). Tikuma et al. [
19
] also found in cultivars
of V. macrocarpon Ait. much more phenolics than in European cranberry in the previous study.
In the cultivar “Early Black” there was determined the highest amount of phenolics (441 mg/100 g)
in comparison to other cultivars (“Stevens”, “Bergman”, “Pilgrim”), whereas the results showed
significant differences in biochemical composition between the studied cranberry cultivars and species.
The content of total phenolics among clones of European cranberry cultivated in Lithuania
ascertained ˇ
Cesonien
˙
e et al. [
27
]. Cranberry fruits of 21 clones, in different shape and berry size
raised under the same growth conditions, accumulated from 224.1 mg/100 g to 498.2 mg/100 g
of phenolic compounds. However, the relationship between the total amount of phenolics and
berry weight of Vaccinium oxycoccos was only weak with a regression coefficient of R
2
= 0.22.
Negative correlation between the average berry weight and total phenolics content was detected
by
ˇ
Cesonien˙
e et al.
[
8
]. Anthocyanins in cranberry clones comprised 18.3% to 42.7% of total phenolic
content [
27
]. The quantification of total polyphenols confirmed variations in their content depending
mainly on the studied cultivars. Also
ˇ
Cesonien˙
e et al.
[
28
] demonstrated in their study that the
biochemical components of V. macrocarpon and V. oxycoccos juices are affected by genotype.
Results of the study of Povilaitytéet al. [
18
] have shown that there are differences in the total
amount of phenolics among American cranberry and European cranberry cultivars too. The berries of
European cultivars accumulated from 100.4 mg/100 g (“Virussare”) to 154.8 mg/100 g (“Soontagana”),
whereas American cultivars had about twice to four times higher content (192.3–676.4 mg/100 g).

Molecules 2019,24, 24 5 of 21
Eighteen clones of European cranberry of Lithuanian origin from strictly protected areas ˇ
Cepkeliai
and Žuvintas were tested by ˇ
Cesonien
˙
e et al. [
8
] for the amount of total phenolics. Clones of
Vaccinium oxycoccos accumulated different levels of phenolic compounds. The phenolic content ranged
from 197 to 584 mg/100 g. The amount of phenolics in ˇ
Cepkeliai clones was assessed on average
389 mg/100 g, in Žuvintas clones 347 mg/100 g. Except for genotype, the content of phenolics was
also dependent on place of samples origin.
Both large cranberry (Vaccinium macrocarpon) as a commercially used crop and European
cranberry (Vaccinium oxycoccos) as a traditionally used crop accumulated a high level of polyphenols.
The comparison of the polyphenolic spectrum of Vaccinium oxycoccos and Vaccinium macrocarpon in
fruit and pomace extract (crushed cranberry macerated with the solvent and its filtrate is concentrated
by solvent evaporation) is shown in Table 2. Researchers [
11
,
32
] assessed more phenolic acids and
flavonols in European cranberry pomace extracts than in fruit extracts, and the presence of resveratrol
in pomace extract that was not found in fruit extract. The results of the studies also pointed out that
fruits of European cranberry represent more valuable sources of caffeic acid and quercetin with higher
values of total flavonols in comparison to American cranberry (Vaccinium macrocarpon).
Table 2.
Comparison of the polyphenolic spectrum of V. oxycoccos and V. macrocarpon fruit and pomace
ethanol extracts [11,32].
Phenolic Compounds
Content (mg/100 g fw)
V. oxycoccos
Fruit Extract
V. oxycoccos
Pomace Extract
V. macrocarpon
Pomace Extract
Benzoic acid 214.6 115.0 256.9
p-coumaric acid 77.0 175.0 184.3
Chlorogenic acid 96.3 408.7 656.9
Caffeic acid 1.4 36.5 31.2
Sum of acids 389.5 777.0 1173.8
Quercetin 15.4 25.2 11.5
Epicatechin 6.3 5.7 12
Isorhamnetin 3.5 1.5 0.9
Sum of flavonols 36.3 81.5 42.9
Polyphenolic profiles of cranberries were studied also by Koponen et al. [
29
], Ogawa et al. [
30
],
and Määttä-Riihinen et al. [
33
]. They determined that the concentration of hydroxycinnamic acids in
European cranberry represented 7.6 mg/100 g, anthocyanins content in the berries was in the range of
66–86 mg/100 g, flavonols 27 mg/100 g, flavan-3-ols 3.1 mg/100 g, and proanthocyanidins were in the
amount of 1.5–2.0 mg/100 g.
Researches of Häkkinen and Törrönen [
34
] and Viskelis et al. [
20
] have shown that berries of
European cranberry grown in colder climates, without fertilizers or pesticides, can be characterized
by higher content of phenolics than the cultivars grown in a milder climate. The differences in an
accumulation of phenolic compounds can be also given by various conditions of cultivation, region,
weather conditions, harvesting time, and maturity stage.
Kivimäki et al. [
26
] analyzed phenolic composition of cold-compressed berry juice from European
cranberry. The results of the experiment showed that the content of total phenolic compounds in
cranberry juice reached up to 29.4 mg/100 g which was less than in lingonberry or blackcurrant
juices, as it reached about
1
2
or one third of their values. As for particular phenolic components the
juice contained anthocyanins in the amount 12.4 mg/100 g, hydroxycinammic acids 5.2 mg/100 g,
g flavan-3-ols 0.7 mg/100 g, flavonols 5.7 mg/100 g, and proanthocyanidins in the content of
5.3 mg/100 g.
The study of Mazur and Borowska [
35
] showed that the phenolic amount in the cranberry
(V. oxycoccos) products is dependent on the used technological processes. Thus, in frozen fruits the
content of phenolics is much lower (178.5 mg gallic acid equivalent (GAE) /100 g) than in freeze-dried

Molecules 2019,24, 24 6 of 21
fruits (678.9 mg GAE/100 g). Lyophilization of the fruits of this species resulted in the phenolic content
reduction compared to fresh fruit.
Kylli et al. [
36
] compared the phenolic spectrum of European cranberry and lingonberry fruits.
The major phenolic fraction of cranberry and lingonberry presents flavan-3-ols and proanthocyanidins.
The main phenolic compounds in both fruits were proanthocyanidins, representing 63% and 71%
of the total phenolic compounds. Anthocyanins (16% and 15%), flavonols (14% and 9%), and
hydroxycinnamic acid (7% and 5%) were also detected. In cranberries there were therefore more
anthocyanins, flavanols, and hydroxycinnamic acids than in lingonberries.
Ehala et al. [
15
] summed up that the main phenolic compounds identified in cranberry were
quercetin and trans-resveratrol. These results are in agreement with the study by Taruscio et al. [
37
].
Resveratrol is an important antioxidant, phytoalexin stilbenoid, (3,5,4’-trihydroxy-trans-stilbene)
that is found in high content in fruits such as cowberry (Vaccinium vitis-idae) (3.0 mg/100 g fw),
followed by European cranberry (1.9 mg/100 g) and red currant (1.7 mg/100 g), and then bilberry and
strawberry [15].
Also, ursolic acid (3
β
-hydroxy-urs-12-en-28-oic acid), a pentacyclic triterpenoid, is present in
fruits such as Vaccinium oxycoccos. It has several biological effects such as protection against oxidative
damage [38] and lipid oxidation [39].
2.1.1. Phenolic Acids
The main representatives of phenolic acids in cranberries belong to cinnamic and
benzoic acid derivatives. There are presented hydroxybenzoic acid derivatives such as gallic
acid (3,4,5-trihydroxybenzoic acid), dihydroxybenzoic acids (vanilic), 2,3-dihydroxybenzoic,
2,4-dihydroxybenzoic acids, p-hydroxyphenylacetic, hydroxycinnamic (coumaric) acids such as
m-coumaric and p-coumaric acids, caffeic (3,4-dihydroxycinnamic), and ferrulic (4-hydroxy-3-
methoxycinnamic) acids [
37
,
40
]. However Tian et al. [
41
] identified in press cake from cranberry
(V. oxyccocos) juice processing only two phenolic acids, 3-O-caffeoylquinic acid and caffeic acid.
Benzoic acid level in European cranberry is cultivar dependent which has been confirmed by
a study by ˇ
Cesonien
˙
e et al. [
28
] in 13 berry cultivars, with values from 4.3 mg/L for “Amalva”
to 32.12 mg/L for “Maima” cultivars, with an average of 17.5 mg/L. However, berry juices of
V. macrocarpon cultivars were defined by higher benzoic acid amounts, from 19.37 (“Howes”) to
72.42 mg/L (“Searles”); cultivars “Franklin”, “Le Munyon”, “Searles”, and “Early Richard” were
selected as the best according to the benzoic acid amounts.
Due to Stobnicka and Gniewosz [
11
], the fruits of Vaccinium oxyccocos contain phenolic acids
in the total amount of 389.5 mg/100 g, individually benzoic acid in the content of 214.6 mg/100 g,
p-coumaric acid 77 mg/100 g, chlorogenic acid 96.3 mg/100 g, caffeic acid 1.4 mg/100 g, and gentistic
acid 0.3 mg/100 g.
Ehala et al. [
15
] compared the phenolic acids profile of small berries such as European cranberry,
bilberry, cowberry, strawberry, black currant, and red currant. The results showed that European
cranberries and cowberries reached the highest levels of p-coumaric acid (2.03 and 1.71 mg/100 g,
respectively) which is the predominant acid of all mentioned berries. However, it is much less than in
the previously referred study.
2.1.2. Flavonoids
Generally, in Vaccinium genus and so in cranberry fruit, there are three classes of flavonoids
such as flavonols, anthocyanins, and proanthocyanidins [
14
]. To the predominated flavonoids in
cranberry fruit belong flavonols included myricetin-3-galactoside, myricetin-3-arabinofuranoside,
quercetin-3-galactoside, quercetin-3-glucoside, quercetin-3-rhamnospyranoside, and quercetin-3-O-
(600 -p-benzoyl)-galactoside [42].
Ehala et al. [
15
] determined flavonoid profiles of European cranberry (V. oxycoccos), bilberry
(V. myrtillus), cowberry (V. vitis-idae), black currant, and strawberry. The results proved that

Molecules 2019,24, 24 7 of 21
predominant flavonol present in the assayed berry crops was quercetin, with the highest level in
bilberry (1.28 mg/100 g fw) and European cranberry (0.52 mg/100 g fw) fruits. But the detected
amounts were much lower than in the study of Häkkinen et al. [
43
], who also found quercetin as
the main flavonoid in 25 different berries. The highest content they evaluated in bog whortleberry
(15.8 mg/100 g fw), lingonberry (7.4–14.6 mg/100 g), and cranberry (8.3–12.1 mg/100 g), followed
by chokeberry, sweet rowan, rowanberry, sea buckthorn berry, and crowberry. The concentration of
quercetin evaluated by Stobnicka and Gniewosz [
11
] in ethanolic extract of Vaccinium oxyccocos fruit
reached up 15.4 mg/100 g.
Another important flavonoid, myricetin, was also detected in cranberry and other fruits such
as black currant, crowberry, bog whortleberry, blueberry, and bilberry, in amounts from 1.4 to
14.2 mg/100 g fw [
43
]. In V. oxyccocos, Stobnicka and Gniewosz [
11
] determined the content of
myricetin in the level of 8.4 mg/100 g. Further there was found isorhamnetin too, 2.1 mg/100 g.
Flavonols represented 23 to 31% of the phenolics analyzed in Vaccinium species [43].
Taruscio et al. [
37
] evaluated the content and profile of flavonoids (by HPLC/ Diode-Array
Detection (DAD-) /MS techniques) presented in nine Vaccinium species extracts, including
Vaccinium oxycoccos. The results of an experiment showed that flavonoid fraction contained
anthocyanidins, flavan-3-ols, and flavonol aglycons. The highest variation, detected among six
cranberry varieties, was characterized for flavonol content (50–70%) (quercetin, kaempferol, and
myricetin) that has been proved also by study of Bilyk and Sapers [
44
]. Differences were found
also in the flavan-3-ol profile of three Vaccinium species (European cranberry, American cranberry,
lingonberry) in an epicatechin/catechin ratio in American cranberry concentrates compared with the
other berries [45].
The content of flavonoids could be affected not only by vegetational conditions but also by
processing procedures such as drying technics that may influence their values. The effect of freeze
and thermal drying on the flavonoid content in the fruits of European cranberry (Oxycoccus palustris
Pers.) was studied by Adamczak et al. [
46
]. The results of the experiment showed a significant
influence of drying conditions on flavonoids content. The level of flavonoids in the thermally-dried
fruits was from 144 to 167 mg/100 g dw, which are higher values compared to freeze-dried samples
(123–141 mg/100 g dw
). The drying of European cranberry fruit at the temperatures 35–40
◦
C
guarantees higher flavonoid content than by lyophilization drying. In the thermally-dried fruits
of Oxycoccus palustris they found twice more flavonoids than in the commercial raw material of this
species dried under similar conditions, as evaluated Bylka and Witkowska-Banaszczak [
47
]. According
to Abascal et al. [
48
], freeze drying insufficiently stabilizes some groups of pharmacologically active
compounds, such as phenolics and others.
2.1.3. Anthocyanins
Generally, Vaccinium fruits belong to the most important food sources of anthocyanins of blue, red,
and purple colors. The best representative of this group is bilberry fruit (Vaccinium myrtillus L.),
that comprise phenolic compounds as anthocyanins in amounts up to 90%, an amount of
600 mg/100 g fw, with glycosides of cyanidin, delphinidin, malvidin, peonidin, and petunidin [49].
In cranberries, the amount of anthocyanins is much lower than in bilberries and significant
genetic variability was found especially in the levels of total and individual anthocyanins
(i.e., cyanidin-3-galactoside, cyanidin-3-glucoside, cyanidin-3-arabinoside, peonidin-3-galactoside,
peonidin-3-glucoside, and peonidin-3-arabinoside) [
16
]. Juices of cranberry fruit cultivars could
be distinguished by prevailing individual anthocyanins with thermostable galactoside and
glucoside conjugates.
The clones of European cranberry (18) of Lithuanian origin, due to a study by ˇ
Cesonien
˙
e et al. [
8
],
accumulate anthocyanins on the average 99 mg/100 g. The amount of anthocyanins in Lithuanian
Žuvintas clones was in the range from 56 to 137 mg/100 g, and in ˇ
Cepkeliai clones from 36 to
206 mg/100 g.

Molecules 2019,24, 24 8 of 21
The content in American cranberries measured for eight cultivars reached about two-fold higher
values than European cranberries, due to results of 13 the cultivar determinations. The amount of total
anthocyanins in European cranberries ranged from 40.7 mg/100 g to 207.3 mg/100 g. The accumulation
and the content of anthocyanins are also dependent on berries ripening [
16
], and therefore, their exact
color could be quite meaningful. Studies of the localization of anthocyanins in the berries of European
cranberry showed that the amounts of these compounds in the berry skin are 6 to 10 times higher than
in the pulp [31].
However, due to the examined accumulation of anthocyanins in berries of different wild clones of
European cranberry, there was confirmed a strong negative correlation between berry weight and the
amount of anthocyanins [16].
The differences among anthocyanin content of V. oxycoccos and V. macrocarpon species studied
ˇ
Cesonien
˙
e et al. [
28
], who compared total anthocyanins content in berry juice of nine American
cranberry and thirteen European cranberry cultivars. Cultivars of V. macrocarpon accumulated on
average 92.45 mg/L of total anthocyanins and therefore they are better sources of anthocyanins
than European cranberry considering the average content that was approximately half of the
amount (42.54 mg/L). Wang et al. [
50
] detected among large cranberry cultivars wide variability
for anthocyanins content, averaging 25–65 mg/100 g of ripe fruit at harvest. As Tikuma et al. [
19
]
determined the cultivar of V. macrocarpon Ait. “Early Black” contained the highest amount of
anthocyanins (105 mg/100 g) in comparison to other cultivars. Also Latvian bred big cranberry
cultivar “Septembra” showed a high level of anthocyanins (82.5 mg/100 g).
The highest anthocyanin content in juices from thirteen European cranberry cultivars
(“Vaiva”, “Reda”, “Žuvinta”, “Vita”, “Amalva”, “Krasa Severa”, “Dar Kostromy”, “Sazonovskaja”,
“Soontagana”, “Kuressoo”, “Nigula”, “Virussaare”, and “Maima”) was determined in “Sazonovskaja”
and “Nigula” (93; 84.78 mg/L) cultivars, moderate amount contained cultivars “Amalva”, “Vaiva”,
“Dar Kostromy”, “Kuressoo” (59.05–40.58 mg/L). “Vita”, “Maima”, and “Virussaare” cultivars were
characterized by very low amount of anthocyanins in cranberry juice (28.19–12.29 mg/L) [28].
Andersen [
51
] proved that the anthocyanin pattern of European cranberry fruit is different from
the mostly studied American cranberry varieties. In respect to anthocyanidins, peonidin-3-glucoside
(41.9%) and cyanidin-3-glucoside (38.3%) represented the main fractions of anthocyanins isolated
from fruits of V. oxycoccus L. Smaller amounts of 3-monoglucosides of delphinidin, petunidin, and
malvidin and 3-monoarabinosides of peonidin and cyanidin were found, all anthocyanins together in
the amount of 78 mg/100 g fw.
Generally, galactoside together with glucoside conjugates of cyanidin and petunidin comprised
the largest percentage of total anthocyanins in the juices of V. macrocarpon and V. oxycoccos
cultivars [
14
,
16
,
28
]. Quantitative HPLC-UV analysis revealed six anthocyanins in the berries of
European cranberry, among which anthocyanin peonidin-3-galactoside dominated and comprised from
20.3 to 40.4% of the total anthocyanins in the juice. There were also detected cyanidin-3-galactoside
(average 19.3%), cyanidin-3-glucoside (2.8%), cyanidin-3-arabinoside (20.2%), peonidin-3- galactoside
(29.6%), peonidin-3-glucoside (8.1%), and peonidin-3-arabinoside (19.8%), whereas proportions of
different compounds vary between the studied genotypes [
16
]. As the most abundant individual
anthocyanins in freshly prepared juice from Finish cranberries (V. oxycoccos), cyanidin-3-arabinoside
(23.1%), peonidin-3-galactoside (21.5%), cyanidin-3-galactoside (19.2%), and peonidin-3-arabinoside
(14.1%) were also specified [52].
In the experiment by Brown et al. [
53
] and ˇ
Cesonien
˙
e et al. [
28
], the same six major anthocyanins
were quantified in V. oxycoccos and V. macrocarpon berries. However, the ratio of glycosylated peonidins
to cyanidins was about 20:80, as compared to 60:40 in V. macrocarpon [
53
]. Galactoside conjugates were
the most prevalent anthocyanins and comprised 57.54% and 49.59%; arabinoside conjugates comprised
34.73% and 40.97%; and glucoside conjugates comprised 7.87% and 9.44% of TAC (total antioxidant
capacity) in V. macrocarpon and V. oxycoccos berry juices, respectively. The most prevalent anthocyanins
in both cranberry species are peonidin-3-galactoside (33.29 and 29.15%), cyanidin-3-galactoside

Molecules 2019,24, 24 9 of 21
(24.11 and 20.44%), and peonidin-3-arabinoside (16 and 19.64%) [
28
]. Similar amounts of prevailing
anthocyanins were also examined by Vorsa and Polashock [54].
Depending on the type of product obtained in various processes, the amount of phenolic
compounds of fresh, frozen, and freeze-dried cranberry fruit differ. Mazur and Borowska [
35
] showed
that lyophilization of European cranberry fruit resulted in a seven-fold reduction in the content of
anthocyanins, compared to the fresh fruit. In the fresh fruit, the content of cyanidin-3-glucoside was
58.3 mg/100 g of the product, while in frozen and freeze-dried fruits it was 39.8 and 55.2 mg/100 g,
respectively. Due to study of Tian et al. [
41
], anthocyanins in the European cranberry press cake from
juice processing, were represented by glycosides of cyanidin and peonidin, mainly as 3-O-galactoside,
3-O-glucoside, and 3-O-arabinoside.
Although anthocyanidins belong to the important antioxidants, Brown et al. [
53
] detected a
strong negative correlation (r=
−
0.92) between the anthocyanin content and the relative antioxidant
potential. No linear dependence between total amount of anthocyanins and phenolics was found
by
ˇ
Cesonien˙
e et al.
[
8
]. The amount of anthocyanins was not the main factor, which determines total
amount of polyphenols in the berries of European cranberry.
2.1.4. Proanthocyanidins
Proanthocyanidins belong to the class of polyphenols with repeating catechin and
epicatechin monomeric units. Proanthocyanidins are the leading compounds of the phenolic
compounds of European cranberry [
16
]. The European cranberry accumulated 1.5–2.0 mg/100 g
proanthocyanidins [33].
Catechin, epicatechin, and A-type dimers and trimers were found to be the terminal units of
isolated proanthocyanidin fractions. Cranberry proanthocyanidins are primarily dimers, trimers, and
larger oligomers of epicatechin [
14
]. European cranberries were noted to contain A-type dimers
and trimers also by Määttä-Riihinen et al. [
55
]. Kylli et al. [
36
] tested European, small-fruited
cranberries (V. microcarpon) and lingonberries (V. vitis-idaea) for their flavonoid profile. The results of
experiments proved that the main phenolic compounds in them were proanthocyanidins comprising
63–71% of the total phenolic content. Proanthocyanidins were presented mainly by catechin,
epicatechin, gallocatechin, and epigallocatechin units. Cranberry proanthocyanidins comprise a
group of heterogeneous chemical structures, characterized by their constitutive units, types of linkage,
and degree of polymerization. Proanthocyanidins of cranberry fruit are represented by dimers and
trimers, oligomers, and polymers. Proanthocyanidins can be divided into three groups: dimers
and trimers, oligomers (mDP (mean degree of polymerization) = 4–10), and polymers (mDP > 10).
Catechin, epicatechin, and A-type dimers and trimers were found to be the terminal units of isolated
proanthocyanidin fractions.
Jungfer et al. [
56
] found that three A-type trimers and procyanidin A2, identified as major
bioactive compounds in V. macrocarpon, are present only in trace amounts in the European cranberry
(V. oxycoccus L.), and at substantially higher amounts in lingonberry (V. vitis-idaea L.). According to the
authors, the mentioned differences are responsible for different biological and clinical effect of berries,
especially on the urinary tract. Differences can be used to prove the authenticity of compared species.
But Boudesocque et al. [
57
] determined losses of proanthocyanidins A2 and B1 that may occur during
manufacturing processes and storage of cranberry extracts.
Proanthocyanidins are responsible for organoleptic, anti-inflammatory, antibacterial, and antiviral
properties of cranberry fruits [16].
3. Antioxidant Activity of Cranberry Fruit
Generally, the most important groups of bioactive compounds in European cranberry fruit are
polyphenolic and triterpene compounds, displaying strong antioxidant properties and the ability to
alleviate some chronic diseases [58].

Molecules 2019,24, 24 10 of 21
Antioxidants are abundantly present in the genus Vaccinium, and numerous studies have been
focused on their antioxidant activity [
59
–
61
]. Berries of all important Vaccinium species (V. macrocarpon,
V. oxycoccos L., V. vitis-idaea L.) have been proved to possess a strong potential to prevent the free
radical reactions from continuing [
31
,
62
]. Cranberry fruits inhibit oxidative processes including
oxidation of low-density lipoproteins [
63
], and oxidative and inflammatory damage to the vascular
endothelium [64].
Denev et al. [
65
] evaluated antioxidant properties of 26 Bulgarian fruits by ORAC (Oxygen radical
absorbance capacity) method. From investigated fruits, cranberries (70
µ
mol TE.g
−1
fw) showed
the 10th best result after elderberry (205
µ
mol TE.g
−1
fw), brier, chokeberry, hawthorn, blueberry,
black currant, rowanberry, blackthorn, and blackberry. They found a good linear correlation between
total polyphenol content and antioxidant capacity with R2= 0.899.
Borowska et al. [
31
] compared wild cranberry (V. oxycoccos) fruit and five American cranberry
cultivars (“Ben Lear”, “Bergman”, “Early Richard”, “Pilgrim”, and “Stevens”) in terms of their
antioxidant properties measured as DPPH
·
,
·
OH, and ABTS
+
radical scavenging capacity. The results
showed that widely grown European cranberry is characterized by high antioxidant activity (highest
ABTS
+
scavenging capacity of all cultivars, similar OH, and lower DPPH scavenging capacity).
Statistically significant differences (p< 0.05) were observed between the wild cranberry and other
analyzed cultivars.
Three Vaccinium fruits species (V. oxycoccos L., V. vitis-idaea L., and V. macrocarpon Aiton) due to
their antioxidant potential studied Brown et al. [
3
]. An amount of cranberry tissue for 50% reduction
in DPPH response was the lowest for V. oxycoccos berries, therefore European cranberry has better
relative antioxidant potential than American cranberry or cowberry.
In the research of Ehala et al. [
15
], the antioxidant capacity of Vaccinium oxycoccus, V. myrtillus,
and V. vitis-idaea species with the results 0.84, 1.89, 1.76
µ
M of ascorbic acid equivalent per 100 g of
frozen berries was compared. Berries of bilberry and cowberry showed better results of antioxidant
capacity than European cranberry. They studied also a possible relation to the total polyphenols
content, with the amount for the berries 18.08, 43.43, and 35.95 mg of tannic acid equivalent per 100 g,
respectively. The experiment outcomes proved that total phenolic level of Vaccinium species berries
was correlated with their antioxidant activity.
The positive correlation between phenolic compounds and antioxidant activity of Vaccinium
genus was confirmed also by experiments by Viskelis et al. [
20
], Seeram et al. [
66
], and Zheng and
Wang [
67
]. The high values of antioxidant activities of lingonberry (V. vitis-idaea L.), cranberry
(V. oxycoccus L.), and bog blueberry (V. uliginosum L.) seem to be related to their high content
of catechin or proanthocyanidins, in comparison to other berry crops [
33
,
55
,
67
], while in the
studies of
Kähkönen et al.
[
24
] and Brown et al. [
3
] an antioxidant activity of Vaccinium oxycoccos L.,
V. vitis-idaea L.
, and V. macrocarpon was not found to correlate with indolamine levels, and anthocyanin
content was in a negative correlation with antioxidant activity. Vitamin C content positively correlated
with an antioxidant activity of these berries. However, the presence of antioxidants and their amount
in fruits, due to the presented results of mentioned studies, depends on genetic and environmental
factors such as cultivar and variety, climate, place of origin, sun exposure, fertilization, harvest
time, irrigation, etc. The concentrations of individual polyphenols during cranberry fruits ripening,
as
Oszmia´nski et al.
[
68
] detected, were similar, but their overall values differed significantly. Immature
fruits had the lowest level of polyphenols that increased in semi-mature fruits and did not change in
mature cranberry fruits too much. The quantity of phytochemical compounds during cranberry fruit
ripening depended on cultivar.
Due to the good antioxidant activity of European cranberry fruit, the extract could be utilized
as an additive to meat products for inhibiting unfavorable storage changes of lipids to impede
lipid oxidation [
69
]. The effect of cranberry juice on oxidative changes occurring in meat products
determined also Tyburcy et al. [
70
]. Cranberry juice, in the amount of 5% of the meat weight, was added
to the thermally processed pork burgers, which were stored for seven days at 3 to 7
◦
C, and juice was

Molecules 2019,24, 24 11 of 21
added also to a raw beef stuffing. A 5% addition of the cranberry juice caused decreasing of TBARS
(thiobarbituric acid reactive substances) values, which are formed as a byproduct of lipid peroxidation
of burgers, to twice or by three times the value of the control sample. As authors mentioned too,
cranberry juice was a good color stabilizer of the raw beef stuffing.
4. Biological Activities of European Cranberry
Vaccinium macrocarpon is commercially utilized species and the subject of biological and clinical
research, whereas there has been a limited number of studies on Vaccinium oxycoccos, especially in
anticancer, cardioprotective or treatment of the urinary tract. The majority of published papers have
been focused on antimicrobial effect of European cranberry.
4.1. Antiinflammatory Effect
Among the important biological activities of cranberries is also anti-inflammatory activity.
Anti-inflammatory properties of cranberry fruit can be explained by a high level of quercetin [
71
]
that decreases cytokine production in macrophages, reduces COX-2 mRNA expression, and inhibits
TNF-α–dependent NF-κB activation [72,73].
Kylli et al. [
36
] studied the mechanism of anti-inflammatory effect of small cranberry and
lingonberry extracts. The results of experiment showed that cranberry (V. microcarpon) phenolic extract
inhibited LPS (lipopolysaccharide) induced NO (nitric oxide) production in a dose-dependent manner,
but it had no major effect on iNOS of COX-2 expression. At a concentration of 100
µ
g/mL cranberry
phenolic extract inhibited LPS-induced IL (interleukin)-6, IL-1
β
, and TNF-
α
production (tumor necrosis
factor). Lingonberry phenolics had no significant effect on IL-1
β
production but inhibited IL-6 and
TNF-αproduction at a concentration of 100 µg/mL similar to cranberry phenolic extract.
4.2. Antimicrobial and Antiviral Activity of Cranberry Fruit
Plant materials, in general, are often rich in various secondary metabolites that are important as
a natural defense mechanism for living organisms and are known to have antimicrobial properties
in vitro
. Natural antimicrobial compounds could be effective against selected bacteria and fungi
components such as flavonoids, e.g., quercetin [
74
,
75
]. Before bacterial infection, bacterial adhesion
to the cell surface is crucial. Berries from the Vaccinium species represent a possible source of
anti-adhesives against bacterial infections [76,77].
The antimicrobial effects of American cranberry concentrates against bacterial pathogens
(Staphylococcus aureus,E. coli O157:H7) are well known [
78
,
79
]. Rauha et al. [
10
] proved this fact
also for Vaccinium oxyccocos fruits with a methanolic extract isolated from Finnish berries. They
demonstrated an effectiveness of the berry extract against bacterial strains. Moderate activity has
been shown against Staphylococcus aureus and clear antimicrobial activity against Escherichia coli,
an important Gram-negative bacterium. The berry extract failed to inhibit Staphylococcus epidermidis,
Bacillus subtilis,Micrococcus luteus, and the mold Aspergillus niger, and also the growth of the yeast
Candida albicans. Also, ˇ
Cesonien
˙
e et al. [
27
] determined the antimicrobial properties of different wild
clones of European cranberry by the agar well diffusion method against these bacteria. European
cranberry extracts inhibited the growth of a wide range of human pathogenic bacteria, both
Gram-negative (Escherichia coli and Salmonella typhimurium) and Gram-positive (Enterococcus faecalis,
Listeria monocytogenes, Staphylococcus aureus, and Bacillus subtilis).
Moreover, berry juice of V. oxycoccus displayed binding activity of Streptococcus agalactiae and
Streptococcus pneumoniae [
77
]. It has been determined that S. pneumoniae has binding activity to low
molecular size fractions of cranberry (V. oxycoccos L.) and bilberry (V. myrtillus L.) juices in a microtiter
well assay.
Antibacterial inhibitory activity of European cranberry, as Hellström [
80
] evaluated, is given
by polyphenolic subfraction at a concentration of 5 mg/100 ml. The activity can be explained by
high level of polyphenols, especially proanthocyanidins, about 400 mg/100 g. Proanthocyanidins are

Molecules 2019,24, 24 12 of 21
known to prevent the adhesion of several bacteria. A-type dimers and trimers have been found
in European cranberries and in a good amount in lingonberries and American cranberries [
14
].
Similarly Kylli et al.
[
36
] also proved that proanthocyanidins are responsible for antimicrobial activity
of V. microcarpon. Polymeric proanthocyanidin fraction of cranberries displayed a strong antimicrobial
effect against Staphylococcus aureus; no effect was determined on other bacterial strains (S. enterica sv.
Typhimurium, Lactobacillus rhamnosus, and Escherichia coli).
In an experiment by Ermis et al. [
45
], there was shown a possibility to inhibit the growth
of visible colonies of several fungi with concentrate of cranberry in fruit spreads (raspberry–aloe
vera; strawberry–lime) with reduced sugar, which is a main reason for a growth of microorganisms
in low-calorie jams. The antifungal activities of cranberry concentrate were studied
in vitro
against selected fungi Absidia glauca, Penicillium brevicompactum, Saccharomyces cerevisiae, and
Zygosaccharomyces bailii. The concentrate was able to inhibit growth of visible colonies of most
xerophilic and non-xerophilic fungi. For both fruit spreads with cranberry concentrate A. glauca
was not able to grow, the growth of P. brevicompactum on the spread was inhibited at 3% cranberry
concentrate, and S. cerevisiae could not grow at a concentration of 18%. Z. bailii was the most resistant
fungus, the highest concentration (24%) was able to inhibit its growth by 29.8% only for raspberry–Aloe
vera spread.
Extract from European cranberry also represents an interesting candidate as a natural preservative
of minced pork meat. Water, ethanol fruit, and pomace extracts were tested due to their antimicrobial
activity as the growth inhibitors of S. aureus,Listeria monocytogenes,Salmonella enteritidis, and E. coli in
inoculated fresh minced pork meat containing 2.5% extract. Extracts inhibited Gram-positive bacteria
strains stronger than Gram-negative, but did not display antifungal activity. Water–ethanol fruit and
pomace extracts displayed more effective antibacterial properties than ethanolic and aqueous fruit and
pomace extracts [
11
]. Cranberry pomace extracts contained stilbenes (resveratrol) and more organics
acids and flavonols than fruit extracts, both contained also terpenes in ethanol extract (ursolic acid).
Wild cranberry (V. oxycoccos L.) juice fraction, and also bilberry (V. myrtillus L.), lingonberry
(V. vitis-idaea L.), and crowberry (Empetrum nigrum and E. hermaphroditum L.) were studied as
antimicrobial agents against bacterium Neisseria meningitides using a microtiter broth microdilution
assay. This bacterium infects human mucosal cell surfaces and colonizes the nasopharyngeal
epithelium, is transmitted from person to person, and causes meningitis. The berry juice molecular
size fractions of 10–100 kDa inhibited the binding of isolated N. meningitidis pili to membrane-bound
epithelial cells in a dot assay. Toivanen et al. [
76
] proved that polyphenolic fractions containing
anthocyanins and proanthocyanidins displayed antiadhesion activity against this human pathogen,
and thus Vaccinium berries could be promising sources against meningococcal adherence. The most
effective adhesion inhibition of 75% was achieved with cranberry juice polyphenolic fraction followed
by crowberry (63%), bilberry (63%), and lingonberry (57%) juice phenolic fractions.
Huttunen et al. [
81
] tested fractions of V. oxyccocos juice against pneumococcal binding in human
bronchial cells (Calu-3). The antiadhesion activity was achieved at a concentration of 8.7 mg/g of
soluble solids, which contain small amounts of polyphenols. The antimicrobial activity of the studied
berry juice fractions was found to be remarkable; pneumococcal growth was inhibited totally at a
concentration of about 86 mg/g.
As was pointed out before, cranberry fruit extracts possess, besides antibacterial [
82
] and
antifungal effect, also antiviral activity. Berries belonging to the genus Vaccinium—blueberry,
Natsuhaze (V. oldhamii), bilberry, and European cranberry were compared due to the anti-influenza
viral effects [
83
]. As the authors proved, cranberries belong to the species with the high antiviral effect,
comparable to that of bilberry, Natsuhaze, and blackcurrant, while blueberries (Rabbiteye varieties)
had the strongest effect. A positive relationship was observed between anti-influenza viral activity
and total polyphenol content, which indicates the possibility of a high content of polyphenols as one
of the most important factors in the antiviral effects of berries.

Molecules 2019,24, 24 13 of 21
Summarization of the main bioactive compounds (Table 3) of European cranberry with biological
activities, which have been proved by several studies in
in vitro
and other models, and is presented in
Table 4.
Table 3. The major bioactive compounds of European cranberry fruit and their effect.
Bioactive Compounds Biological Effect References
Quercetin anti-inflammatory Mlcek et al. [71], Liu et al. [72], Kim et al. [73]
antibacterial and antifungal Cushnie et al. [74,75]
Proanthocyanidins
anticancer Masoudi et al. [84]
antimicrobial Neto et al. [14], Kylli et al. [36]
urinary tract protection
Jungfer et al. [
56
], Ranfaing et al. [
85
], Gupta et al. [
86
],
Vasileiou et al. [87]
cardioprotective Kalt et al. [88]
Resveratrol antibacterial, antifungal Stobnicka et al. [11]
Anthocyanins antibacterial Toivanen et al. [76]
cardioprotective Kalt et al. [88]
Table 4. Summarization of the evidence of European cranberry biological activities.
Effect Studied Models Mechanism of Action References
Antibacterial and
antifungal activities
agar well diffusion
method; human
epithelial cells
antiadhesion activity (blocking bacterial
adhesion) against Neisseria meningitidis,
Streptococcus agalactiae,
Streptococcus pneumoniae
Toivanen et al. [76],
Toivanen et al. [77]
in vitro studies
(minced pork meat)
inhibition of the growth of Escherichia
coli,Salmonella Enteritidis,Listeria
monocytogenes,Staphylococcus aureus
Stobnicka and Gniewosz [
11
]
agar well diffusion
method
inhibitory effect on hemagglutination of
E. coli; the growth inhibition of
Salmonella typhimurium,Enterococcus
faecalis,Listeria monocytogenes,
Bacillus subtilis
ˇ
Cesonien˙
e et al. [27],
Kylli et al. [36]
in vitro studies
(sugar reduced fruit
spreads)
inhibition of growth of Absidia glauca,
Penicillium brevicompactum,
Saccharomyces cerevisiae and
Zygosaccharomyces bailii
Ermis et al. [45]
diffusion methods;
human bronchial
cells (Calu-3)
Antibacterial inhibitory activity against
Staphylococcus aureus,Escherichia coli,;
blocking bacterial adhesion against
pneumococcal binding of
Streptococcus pneumoniae
Rauha et al. [10],
Huttunen et al. [81]
Prevention of urinary
tract infections (UTI)
in vitro studies
effect of type-A proanthocyanidins;
inhibition of the adherence of E. coli to
uroepithelial cells
Davidson et al. [89],
Shamseer and Vohra [90]
women participants;
meta-analyses;
in vitro studies,
prevention of UTI, blocking of fimbrial
adhesion of causative bacterium E. coli
to colonise the uroepithelial cells
Kontiokari et al. [91],
Kontiokari et al. [92],
Jepson et al. [93]
, Jepson and
Craig [94], Jepson et al. [95],
Liska et al. [96],
Ranfaing et al. [85]
Cardioprotective
effect
in vitro model, rats
fed with juice
vascular anti–inflammatory properties,
inhibition of LPS (Lipopolysaccharide-)
induced NO (nitric oxide) production,
inhibition LPS-induced IL-6, IL-1βand
TNF-αproduction
Kylli et al. [36],
Kivimäki et al. [26]
Spontaneously
hypertensive rats
(SHR) model
normalization of the impaired
endothelium-dependent relaxation of
mesenteric arteries, activity of
endothelium-derived
hyperpolarizing factor
Kivimäki et al. [97]
Anticancer activity
in vitro model
(human oral, breast,
colon tumor cells)
inhibition of stages of carcinogenesis,
stimulation of the apoptosis of
cancer cells
Seeram et al. [98],
Masoudi and Saiedi [84]
human prostate
cancer cells
inhibition of specific temporal NMP
(1-Methyl-2-pyrrolidone) regulators Seeram et al. [98]

Molecules 2019,24, 24 14 of 21
4.3. Urinary Tract Protection
The numerous studies proved that species of the genus Vaccinium can be utilized in the treatment
of several health problems such as urinary tract infections, e.g., American cranberries [
99
–
102
],
as cranberry juice is the most studied means considered as greatly important for preventing urinary
infections in high-risk populations [
89
,
90
]. Otherwise, also European cranberry (V. oxycoccos),
lingonberry, and blueberry contain bioactive compounds effective against E. coli but their evidence in
urinary infection prevention is still in doubt and not exactly clear [
93
,
94
,
103
]. The positive effects of
cranberry extract have been correlated to A-type linkage proanthocyanidins.
In vivo
studies proved
that cranberry proanthocyanidins (190
µ
g/ml) have a relationship to adhesion, motility, biofilm
formation, and iron and stress response of uropathogenic Escherichia coli. Furthermore, cranberry
proanthocyanidins influence the transcriptional profiles of Escherichia coli, anti-adhesion effect is
mainly the effect of proanthocyanidins on “strategic” genes involved in E. coli adherence [85].
Commercial cranberry products for urinary infections treatment are produced as
monopreparations or the mixtures of American cranberry, European cranberry, and/or lingonberry.
They are defined by different proanthocyanidins pattern. A-type dimers and trimers reached up the
highest content in lingonberry followed by American cranberry, the lowest level was detected in the
European cranberry (V. oxycoccos). All three species contain A-type dimers of proanthocyanidins
that are the most important in the anti-adherent activity. These compounds are considered as well
effective in the treatment of urinary infections. However, there are remarkable differences in the
procyanidin profiles and concentrations, especially the lack of A-type trimers in V. oxycoccos. Therefore,
the effectiveness against urinary infections may be variable among the Vaccinium species [56].
Studies of Kontiokari et al. [
91
,
92
] pointed to the effectiveness of berry juices from a mixture
of cranberries (V. oxycoccos) and lingonberries as well as cloudberry juice against urinary tract
infection. According to research by Abascal and Yarnell [
104
], V. oxycoccos berries are more effective
against cystitis.
Generally, cranberries exhibit a dose-dependent inhibition of the adherence of E. coli to
uroepithelial cells. A-type proanthocyanidins play an important role in the mechanism of this
inhibition [
90
,
104
–
106
]. Cranberry-derived compounds such as A-type proanthocyanidins in
synergism with another polyphenols interfere with adhesion of bacteria (including multi-drug-resistant
E. coli) to epithelial cells of the urinary tract and suppress inflammatory cascades [
86
,
87
]. The research
of Kylii et al. [
36
] pointed out that although polymeric proanthocyanidin extracts of cranberries had no
effect on Escherichia coli, oligomeric and polymeric fraction of cranberries showed an inhibitory effect
on hemagglutination of E. coli, which expresses the M hemagglutinin.
According to Hidalgo et al. [
107
], more research is needed for the determination of co-active
compounds that are helpful in anti-adherence activity, especially anthocyanins with anti-inflammatory
activity. There is also no clear-cut evidence that the consumption of cranberry juice products
prevent urinary tract infections caused by E. coli [
108
]. The results of meta–analyses (24 studies
with 4473 participants) showed that effectiveness of cranberry products (juices, tablets) extracted from
V. oxyccocos,V. macrocarpon, and V. vitis-idaea were not significantly different to results with antibiotic
treatment for women and children [95,96].
4.4. Cardioprotective Effect
The regular consumption of cranberry fruit have a positive effect on hypertension, inflammation,
oxidative stress, endothelial dysfunction, arterial stiffness, and platelet function. Polyphenols in
cranberry reduce ROS (reactive oxygene species), decrease concentration of inflammatory cytokines,
and enhance endothelium—dependent vasodilation and inhibited platelet activation [109].
The anti-inflammatory effect of European cranberry could have a positive effect on blood pressure
and vascular function. Kivimäki et al. [
26
,
97
] determined the effect of eight weeks of treatment by
Finnish berry juices, European cranberry, and lingonberry on blood pressure and vascular function of
spontaneously hypertensive rats. But only the treatment with lingonberry juice mostly normalized the

Molecules 2019,24, 24 15 of 21
impaired endothelium-dependent relaxation in comparison with rats fed by cranberry juice and control
rats. In the arteries of lingonberry-treated rats, the relaxation was partly due to NO, but also dependent
on EDHF (endothelium-derived hyperpolarization factor). European cranberry and lingonberry
cold-compressed juices in long-term treatment of hypertensive rats showed changes in expression of
anti-inflammatory and anti-thrombotic mediators in vasculature that can explain the mechanism
of improved endothelial function. The mRNA expressions of angiotensin-converting enzyme 1
(ACE1), cyclooxygenase-2 (COX2), monocyte chemoattractant protein 1 (MCP1), and P-selectin were
significantly reduced in the cranberry and lingonberry groups.
Cranberries could be effective also in the prevention of heart diseases and ulcer illnesses of
the digestive system [
110
]. However, as Kalt et al. [
88
] pointed out, anti-adhesion and anti-platelet
bioactivities do not correlate directly with total phenolics, anthocyanins, or proanthocyanidin content,
and the beneficial effect of fruit phenolics can be realized only after their digestion and absorption in
the body.
4.5. Anticancer Effect
Because of the high antioxidant activity of Vaccinium species, especially due to anthocyanins
content, cranberry is able to inhibit the oxidative process related to tumorigenis. Furthemore,
the
in vitro
model experiment showed direct antiproliferative or growth inhibitory properties of
the in vitro model [14].
In V. oxycoccos fruits there is presented ursolic acid that inhibits UVA-radiation-induced oxidative
damage in human keratinocytes [
38
] and offers a remarkable protection against UVB-induced lipid
peroxidation, oxidative stress, and DNA damage [39].
Berry fruits such as blueberries, strawberries, raspberries, and cranberries inhibit multiple stages
of carcinogenesis, inhibits the growth of human oral (KB, CAL-27), breast (MCF-7), colon (HT-29,
HCT116), and prostate (LNCaP) tumor cell lines. With increasing concentration of berry extract
(from 25 up to 200
µ
g/mL) they detected increasing inhibition of cell proliferation in all of the cell
lines, with different degrees of potency between cell lines [93].
Some phytochemicals, contained in fruits of the Vaccinium genus, are expected to affect
cancer-related processes. Proanthocyanidins and flavonoids, presented in cranberries and other
Vaccinium berries, show some promising effects toward limiting processes involved in tumor invasion
and metastasis. The fruits of V. oxycoccos are able to suppress the proliferation of human breast cancer
MCF-7 cells which can be attributed to the initiation of apoptosis and the G1 phase arrest too [84].
Unfortunately, cranberry-based preparations (i.e., tablets, capsules) and juice available in
European market are most often originated from V. macrocarpon, and the fruit of V. oxycoccos was
used very rarely [111].
5. Conclusions
Although it has a wide range of biologicaly active substances, the European cranberry
(Vaccinium oxycoccos), a lesser known type of fruit, is still underutilized. In the same way as the
large cranberry, the European cranberry also represents an excellent source of bioactive compounds,
especially polyphenolic compounds (i.e., flavonoids, anthocyanins, and phenolic acids). On the other
hand, the geographical distribution of European cranberry is wider (in natural bogs of Europe, Asia,
and North America) and it is less demanding in comparison with large cranberry. The consumption
of European cranberry fruits and their products such as juice drinks, jams, jellies, and sauces is
beneficial especially due to its antioxidant properties. European cranberry represents important
natural preservatives against bacterial and fungal growth. Also, their anti–inflammatory properties
can be helpful in the prevention and treatment of cardiovascular problems and several types of cancer
diseases. Taking into account various beneficial effects of small cranberries on human health, also in
folk medicine, the consumption of these fruits and their products is widely recommended.

Molecules 2019,24, 24 16 of 21
Author Contributions:
All authors designed the review; T.J., S.S., J.M., S.B., and L.S. contributed to the writing of
the manuscript.
Acknowledgments:
This study was funded by internal grant agency of Tomas Bata University in Zlín, project no.
IGA/FT/2018/006 and VEGA 1/0083/16.
Conflicts of Interest: The authors declare no conflict of interest.
References
1.
Skrovankova, S.; Sumczynski, D.; Mlcek, J.; Jurikova, T.; Sochor, J. Bioactive compounds and antioxidant
activity in different types of berries. Int. J. Mol. Sci. 2015,16, 24673–24706. [CrossRef] [PubMed]
2.
Mabberley, D.J. The Plant-Book: A Portable Dictionary of the Vascular Plants, 2nd ed.; Cambridge University
Press: Cambridge, UK, 1997; p. 740.
3.
Brown, P.N.; Turi, C.E.; Shipley, P.R.; Murch, S.J. Comparisons of large (Vaccinium macrocarpon Ait.) and
small (Vaccinium oxycoccos L., Vaccinium vitis-idaea L.) cranberry in British Columbia by phytochemical
determination, antioxidant potential, and metabolomic profiling with chemometric analysis. Planta Med.
2012,78, 630–640. [CrossRef] [PubMed]
4.
Jacquemart, A.L. Vaccinium oxycoccos L. (Oxycoccos palustris Pers.) and Vaccinium microcarpum (Turcz. ex
Rupr.) schmalh. (Oxycoccos microcarpus Turcz. ex Rupr.). J. Ecol. 1997,85, 381–396. [CrossRef]
5.
Hummer, K.E.; Sabitov, A.; Cherbukin, P.; Vorsa, N. Vaccinium from primorsky, khabarovsk, amursky and
the sakhalin territories, russia. Acta Hort. 2006,715, 91–96. [CrossRef]
6.
Côté, J.; Caillet, S.; Doyon, G.; Sylvain, J.-F.; Lacroix, M. Analyzing cranberry bioactive compounds. Crit. Rev.
Food Sci. Nutr. 2010,50, 872–888. [CrossRef] [PubMed]
7.
ˇ
Cesonien
˙
e, L.; Daubaras, R.; Paulauskas, A.; Žukauskien
˙
e, J.; Zych, M. Morphological and genetic diversity
of European cranberry (Vaccinium oxycoccos L., Ericaceae) clones in Lithuanian reserves. Acta Soc. Bot. Pol.
2013,82, 211–217.
8.
ˇ
Cesonien
˙
e, L.; Daubaras, R.; Areškeviˇci
¯
ut
˙
e, J.; Viškelis, P. Evaluation of Morphological Peculiarities, Amount
of Total Phenolics and Anthocyanins in Berries of European Cranberry (Oxycoccus palustris). Balt. For.
2006
,
12, 59–63.
9.
Adamczak, A.; G ˛abka, M.; Buchwald, W. Fruit yield of European cranberry (Oxycoccus palustris Pers.) in
different plant communities of peatlands (northern Wielkopolska, Poland). Acta Agrobot.
2012
,62, 97–105.
[CrossRef]
10.
Rauha, J.P.; Remes, S.; Heinonen, M.; Hopia, A.; Kähkönen, M.; Kujala, T.; Pihlaja, K.; Vuorela, H.; Vuorela, P.
Antimicrobial effects of Finnish plant extracts containing flavonoids and other phenolic compounds. Int. J.
Food Microbiol. 2000,56, 3–12. [CrossRef]
11.
Stobnicka, A.; Gniewosz, M. Antimicrobial protection of minced pork meat with the use of Swamp Cranberry
(Vaccinium oxycoccos L.) fruit and pomace extracts. J. Food Sci. Tech. 2018,55, 62–71. [CrossRef]
12.
Kennedy, D.A.; Lupattelli, A.; Koren, G.; Nordeng, H. Herbal medicine use in pregnancy: Results of a
multinational study. BMC Complement. Altern. Med. 2013,13, 355. [CrossRef] [PubMed]
13. Kulbat, K. The role of phenolic compounds in plant resistance. Biotechnol. Food Sci. 2016,80, 97–108.
14.
Netto, C.C. Cranberry and its phytochemicals: A review of
in vitro
anticancer studies. J. Nutr.
2007
,137,
186–193. [CrossRef]
15.
Ehala, S.; Vaher, M.; Kaljurand, M. Characterization of phenolic profiles of Northern European berries by
capillary electrophoresis and determination of their antioxidant activity. J. Agric. Food Chem.
2005
,53,
6484–6490. [CrossRef] [PubMed]
16.
ˇ
Cesonien
˙
e, L.; Daubaras, R.; Jasutiene, I.; Miliauskiene, I.; Zych, M. Investigations of anthocyanins,
organic acids, and sugars show great variability in nutritional and medicinal value of European cranberry
(Vaccinium oxycoccos) fruit. J. Appl. Bot. Food Qual. 2015,88, 295–299.
17.
Jensen, H.D.; Krogfelt, K.A.; Cornett, C.; Hansen, S.H.; Christensen, S.B. Hydrophilic carboxylic acids
and iridoid glycosides in the juice of American and European cranberries (Vaccinium macrocarpon and V.
oxycoccos), lingonberries (V. vitis-idaea), and blueberries (V. myrtillus). J. Agric. Food Chem.
2002
,50, 6871–6874.
[CrossRef] [PubMed]
18.
Povilaityté, V.; Budriuniené, D.; Rimkiené, S.; Viškelis, P. Investigation of Vaccinium Macrocarpon Ait. fruits
chemical composition. Dendrol. Lith. 1998,4, 55–62.

Molecules 2019,24, 24 17 of 21
19.
Tikuma, B.; Liepniece, M.; Sterne, D.; Abolins, M.; Seglina, D.; Krasnova, I. Preliminary Results of Biochemical
Composition of Two Cranberry Species Grown in Latvia. Acta Hortic. 2014,1017, 209–214. [CrossRef]
20.
Viskelis, P.; Rubinskien
˙
e, M.; Jasutien
˙
e, I.; Sarkinas, A.; Daubaras, R.; Cesoniene, L. Anthocyanins,
antioxidative, and antimicrobial properties of American cranberry (Vaccinium macrocarpon Ait.) and their
press cakes. J. Food Sci. 2009,74, C157–C161. [CrossRef]
21.
Klavins, L.; Kviesis, J.; Steinberga, I.; Klavina, L. Gas chromatography-mass spectrometry study of lipids in
northern berries. Agron. Res. 2016,14, 1328–1346.
22.
Lyutikova, M.N.; Turov, Y.P. Chemical constituents from wild Oxycoccus palustris fruit from north Tyumen
oblast. Chem. Nat. Comp. 2011,46, 848–851. [CrossRef]
23.
Moyer, R.A.; Hummer, K.A.; Finn, C.E.; Frei, B.; Wrolstad, R.E. Anthocyanins, phenolics, and antioxidant
capacity in diverse small fruits: Vaccinium,Rubus, and Ribes.J. Agric. Food Chem.
2002
,50, 519–525. [CrossRef]
[PubMed]
24.
Kähkönen, M.P.; Hopia, A.I.; Heinonen, M. Berry phenolics and their antioxidant activity. J. Agric. Food Chem.
2001,49, 4076–4082. [CrossRef] [PubMed]
25.
Häkkinen, S.H.; Kärenlampi, S.O.; Heinonen, I.M.; Mykkänen, H.M.; Törrönen, A.R. Content of the flavonols
quercetin, myricetin, and kaempferol in 25 edible berries. J. Agric. Food Chem.
1999
,47, 2274–2279. [CrossRef]
[PubMed]
26.
Kivimäki, A.S.; Ehlers, P.I.; Siltari, A.; Turpeinen, A.M.; Vapaatalo, H.; Korpela, R. Lingonberry, cranberry
and blackcurrant juices affect mRNA expressions of inflammatory and atherothrombotic markers of SHR in
a long-term treatment. J. Funct. Foods 2012,4, 496–503. [CrossRef]
27.
ˇ
Cesonien
˙
e, L.; Jasutiene, I.; Šarkinas, A. Phenolics and anthocyanins in berries of European cranberry and
their antimicrobial activity. Medicina (Kaunas) 2009,45, 992–999. [CrossRef]
28.
ˇ
Cesonien
˙
e, L.; Daubaras, R.; Jasutiene, I.; Vencloviene, J.; Miliauskiene, I. Evaluation of the Biochemical
Components and Chromatic Properties of the Juice of Vaccinium macrocarpon Aiton and Vaccinium oxycoccos
L. Plant Foods Hum. Nutr. 2011,66, 238–244. [CrossRef]
29.
Koponen, J.M.; Happonen, A.M.; Mattila, P.H.; Törrönen, A.R. Contents of anthocyanins and ellagitannins in
selected foods consumed in Finland. J. Agric. Food Chem. 2007,55, 1612–1619. [CrossRef]
30.
Ogawa, K.; Sakakibara, H.; Iwata, R.; Ishii, T.; Sato, T.; Goda, T.; Shimoi, K.; Kumazawa, S. Anthocyanin
composition and antioxidant activity of the crowberry (Empetrum nigrum) and other berries. J. Agric. Food
Chem. 2008,56, 4457–4462. [CrossRef]
31.
Borowska, E.J.; Mazur, B.; Kopciuch, R.G.; Buszewski, B. Polyphenol, anthocyanin and resveratrol mass
fractions and antioxidant properties of cranberry cultivars. Food Tech. Biotech. 2009,47, 56–61.
32.
Gniewosz, M.; Stobnicka, A. Bioactive components content, antimicrobial activity, and foodborne pathogen
control in minced pork by cranberry pomace extracts. J. Food Safety 2018,38, 1–11. [CrossRef]
33.
Määttä-Riihinen, K.; Kamal-Eldin, A.; Mattila, P.H.; Gonzalez-Paramas, A.; Törrönen, A.R. Distribution
and contents of phenolic compounds in eighteen Scandinavian berry species. J. Agric. Food Chem.
2004
,52,
4477–4486. [CrossRef] [PubMed]
34.
Häkkinen, S.H.; Törrönen, A.R. Content of flavonols and selected phenolic acids in strawberries and
Vaccinium species: Influence of cultivar, cultivation site and technique. Food Res. Int.
2000
,33, 517–524.
[CrossRef]
35.
Mazur, B.; Borowska, E.J. Produkty z owoców˙
zurawiny błotnej-zawarto´s´c zwi ˛azków fenolowych i
wła´sciwo´sci przeciwutleniaj ˛ace. Bromat. Chem. Toksykol. 2007,40, 239–243.
36.
Kylli, P.; Nohynek, L.; Puupponen-Pimiä, R.; Westerlund-Wikström, B.; Leppänen, T.; Welling, J.;
Moilanen, E.; Heinonen, M. Lingonberry (Vaccinium vitis-idaea) and European cranberry (Vaccinium
microcarpon) proanthocyanidins: Isolation, identification, and bioactivities. J. Agric. Food Chem.
2011
,
59, 3373–3384. [CrossRef] [PubMed]
37.
Taruscio, T.G.; Barney, D.L.; Exon, J. Content and profile of flavonoid and phenolic acid compounds in
conjuction with the antioxidant capacity for a variety of Northwest Vaccinium berries. J. Agric. Food Chem.
2004,52, 3169–3176. [CrossRef]
38.
Lee, Y.S.; Jin, D.Q.; Beak, S.M.; Lee, E.S.; Kim, J.A. Inhibition of UVA modulated signaling pathways by
asiatic acid and ursolic acid in HaCaT human kerotinocytes. Eur. J. Pharmacol. 2003,476, 173–178.

Molecules 2019,24, 24 18 of 21
39.
Ramachandran, S.; Prasad, N.R. Effect of ursolic acid, a triterpenoid antioxidant, on ultraviolet-B
radiation-induced cytotoxicity, lipid peroxidation and DNA damage in human lymphocytes.
Chem. Biol. Interact. 2008,176, 99–107. [CrossRef]
40.
Abeywickrama, G.; Debnath, S.C.; Ambigaipalan, P.; Shahidi, F. Phenolics of Selected Cranberry Genotypes
(Vaccinium macrocarpon Ait.) and Their Antioxidant Efficacy. J. Agric. Food Chem.
2016
,64, 9342–9351.
[CrossRef]
41.
Tian, Y.; Liimatainen, J.; Alanne, A.L.; Lindstedt, A.; Liu, P.; Sinkkonen, J.; Kallio, H.; Yang, B. Phenolic
compounds extracted by acidic aqueous ethanol from berries and leaves of different berry plants. Food Chem.
2017,220, 266–281. [CrossRef]
42.
Singh, A.P.; Wilson, T.; Kalk, A.J.; Cheong, J.; Vorsa, N. Isolation of Specific Cranberry Flavonoids for
Biological Activity Assessment. Food Chem. 2009,116, 963–968. [CrossRef] [PubMed]
43.
Häkkinen, S.H.; Kärenlampi, S.O.; Heinonen, I.M.; Mykkänen, H.M.; Törrönen, A.R.R. HPLC method for
screening of flavonoids and phenolic acids in berries. J. Sci. Food. Agric. 1998,77, 543–551. [CrossRef]
44.
Bilyk, A.; Sapers, G.M. Varietal differences in the quercetin, kaempferol, and myricetin contents of highbush
blueberry, cranberry, and thornless blackberry fruits. J. Agric. Food Chem. 1986,34, 585–588. [CrossRef]
45.
Ermis, E.; Hertel, C.; Schneider, C.; Carle, R.; Stintzing, F.; Schmidt, H. Characterization of
in vitro
antifungal
activities of small and American cranberry (Vaccinium oxycoccos L. and V. macrocarpon Aiton) and lingonberry
(Vaccinium vitis-idaea L.) concentrates in sugar reduced fruit spreads. Int. J. Food Microbiol.
2015
,204, 111–117.
[CrossRef] [PubMed]
46.
Adamczak, A.; Buchwald, W.; Kozłowski, J.; Mielcarek, S. The effect of thermal and freeze drying on the
content of organic acids and flavonoids in fruit of European cranberry (Oxycoccus palustris Pers.). Herba Pol.
2009,55, 94–102.
47.
Bylka, W.; Witkowska-Banaszczak, E. Zawarto´s´c flawonoidów w owocach ˙
zurawiny błotnej i
wielkoowocowej. Herba Pol.
2007
,53, 122. Available online: https://www.infona.pl/resource/bwmeta1.
element.agro-article-67ad5d42-126d-4b3a-8cff-ca31b08d4425 (accessed on 14 December 2018).
48.
Abascal, K.; Ganora, L.; Yarnell, E. The effect of freeze-drying and its implications for botanical medicine:
A review. Phytother. Res. 2005,19, 655–660. [CrossRef] [PubMed]
49.
Kähkönen, M.; Heinämäki, J.; Ollilainen, V.; Heinonen, M. Berry anthocyanins: Isolation, analysis and
antioxidant activities. J. Sci. Food Agric. 2003,83, 1403–1411. [CrossRef]
50.
Wang, S.Y.; Stretch, A.W. Antioxidant capacity in cranberry is influenced by cultivar and storage temperature.
J. Agric. Food Chem. 2001,49, 969–974. [CrossRef]
51.
Andersen, Y.M. Anthocyanins in Fruits of Vaccinium oxycoccus L. (Small Cranberry). Food Sci.
1989
,54,
383–384. [CrossRef]
52.
Huopalahti, R.; Jarvenpaa, E.; Katina, K. A novel solid-phase extraction-HPLC method for the analysis of
anthocyanin and organic acid composition of finnish cranberry. J. Liq. Chrom. Relat. Tech.
2000
,23, 2695–2701.
[CrossRef]
53.
Brown, P.N.; Murch, S.J.; Shipley, P. Phytochemical diversity of cranberry (Vaccinium macrocarpon Aiton)
cultivars by anthocyanin determination and metabolomic profiling with chemometric analysis. J. Agric.
Food Chem. 2012,60, 261–271. [CrossRef] [PubMed]
54.
Vorsa, N.; Polashock, J.J. Alteration of anthocyanin glycosyla-tion in cranberry through interspecific
hybridization. J. Am. Soc. Hortic. Sci. 2005,130, 711–715.
55.
Määttä-Riihinen, K.R.; Kahkonen, M.P.; Torronen, A.R.; Heinonen, I.M. Catechins and proanthocyanidins in
berries of Vaccinium species and their antioxidant activity. J. Agric. Food Chem.
2005
,53, 8485–8491. [CrossRef]
[PubMed]
56.
Jungfer, E.; Zimmermann, B.F.; Ruttkat, A.; Galensa, R. Comparing procyanidins in selected Vaccinium
species by UHPLC-MS(2) with regard to authenticity and health effects. J. Agric. Food Chem.
2012
,60,
9688–9696. [CrossRef] [PubMed]
57.
Boudesocque, L.; Dorat, J.; Pothier, J.; Gueiffier, A.; Enguehard-Gueiffier, C. High performance thin layer
chromatography-densitometry: A step further for quality control of cranberry extracts. Food Chem.
2013
,139,
866–871. [CrossRef] [PubMed]
58.
Canja, C.M.; Lupu, M.I.; Boeriu, A.E.; Mărgean, A.; Măzărel, A. The Impact of Cranberry (Vaccinium Oxycoccos)
Bioactive Compounds on Contemporary Diet, Proceedings of COMAT 2016, Bra¸sov, Romania, 24–25 November 2016;
Transilvania University Press of Bra¸sov: Bra¸sov, Romania, 2016; pp. 358–362. ISSN 1844-9336.

Molecules 2019,24, 24 19 of 21
59.
Kalt, W.; Forney, C.F.; Martin, A.; Prior, R.L. Antioxidant capacity, vitamin C, phenolics, and anthocyanins
after fresh storage of small fruits. J. Agric. Food Chem. 1999,47, 4638–4644. [CrossRef] [PubMed]
60.
Wang, S.Y.; Chen, H.; Camp, M.J.; Ehlenfeldt, M.K. Flavonoid constituents and their contribution to
antioxidant activity in cultivars and hybrids of rabbiteye blueberry (Vaccinium ashei Reade). Food Chem.
2012
,
132, 855–864. [CrossRef]
61.
Tsuda, H.; Kunitake, H.; Kawasaki-Takaki, R.; Nishiyama, K.; Yamasaki, M.; Komatsu, H.; Yukizaki, C.
Antioxidant activities and anti-cancer cell proliferation properties of Natsuhaze (Vaccinium oldhamii Miq.),
Shashanbo (V. bracteatum Thunb.) and Blueberry cultivars. Plants 2013,2, 57–71. [CrossRef]
62.
Yao, Y.; Vieira, A. Protective activities of Vaccinium antioxidants with potential relevance to mitochondrial
dysfunction and neurotoxicity. Neurotoxicology 2007,28, 93–100. [CrossRef]
63.
Porter, M.L.; Krueger, C.G.; Wiebe, D.A.; Cunningham, D.G.; Reed, J.D. Cranberry proanthocyanidins
associate with low-density lipoprotein and inhibit
in vitro
Cu
2+
-induced oxidation. J. Sci. Food Agric.
2001
,
81, 1306–1313. [CrossRef]
64.
Youdim, K.A.; McDonald, J.; Kalt, W.; Joseph, J.A. Potential role of dietary flavonoids in reducing
microvascular endothelium vulnerability to oxidative and inflammatory insults. J. Nutr. Biochem.
2002
,13,
282–288. [CrossRef]
65.
Denev, P.; Lojek, A.; Ciz, M.; Kratchanova, M. Antioxidant activity and polyphenol content of Bulgarian
fruits. Bulg. J. Agric. Sci. 2013,19, 22–27.
66.
Seeram, N.P. Berry fruits: Compositional elements, biochemical activities, and the impact of their intake on
human health, performance, and disease. J. Agric. Food Chem. 2008,56, 627–629. [CrossRef] [PubMed]
67.
Zheng, W.; Wang, S.Y. Oxygen radical absorbing capacity of phenolics in blueberries, cranberries,
chokeberries, and lingonberries. J. Agric. Food Chem. 2003,51, 502–509. [CrossRef] [PubMed]
68.
Oszmia´nski, J.; Lachowicz, S.; Gorzelany, J.; Matłok, N. The effect of different maturity stages on
phytochemical composition and antioxidant capacity of cranberry cultivars. Eur. Food Res. Technol.
2018
,244,
705–719. [CrossRef]
69.
Raghavan, S.; Richards, M.P. Comparison of solvent and microwave extracts of cranberry press cake on the
inhibition of lipid oxidation in mechanically separated Turkey. Food Chem. 2007,102, 818–826. [CrossRef]
70.
Tyburcy, A.; ´
Scibisz, I.; Rostek, E.; Pasierbiewicz, A.; Florowski, T. Antioxidative properties of cranberry and
rose juices in meat products made of defrosted meat ([Przeciwutleniaj ˛ace wła´sciwo´sci soków z ˙
zurawiny i z
ró˙
zy w produktach z mi˛esa rozmro˙
zonego]). ˙
Zywno´s´c Nauka Technologia Jako´s´c 2014,5, 72–84. [CrossRef]
71.
Mlcek, J.; Jurikova, T.; Skrovankova, S.; Sochor, J. Quercetin and Its Anti-Allergic Immune Response.
Molecules 2016,21, 623. [CrossRef] [PubMed]
72.
Liu, H.; Ma, Y.; Pagliari, L.J.; Perlman, H.; Yu, C.; Lin, A.; Pope, R.M. TNF-alpha-induced apoptosis of
macrophages following inhibition of NF-kappa B: A central role for disruption of mitochondria. J. Immunol.
2004,172, 1907–1915. [CrossRef] [PubMed]
73.
Kim, H.; Kong, H.; Choi, B.; Yang, Y.; Kim, Y.; Lim, M.J.; Neckers, L.; Jung, Y. Metabolic and pharmacological
properties of rutin, a dietary quercetin glycoside, for treatment of inflammatory bowel disease. Pharm. Res.
2005,22, 1499–1509. [CrossRef] [PubMed]
74.
Cushnie, T.P.; Lamb, A.J. Antimicrobial activity of flavonoids. Int. J. Antimicrob. Agents
2005
,26, 343–356.
[CrossRef]
75.
Cushnie, T.P.; Lamb, A.J. Recent advances in understanding the antibacterial properties of flavonoids. Int. J.
Antimicrob. Agents 2011,38, 99–107. [CrossRef]
76.
Toivanen, M.; Ryynänen, A.; Huttunen, S.; Duricová, J.; Riihinen, K.; Törrönen, R.; Lapinjoki, S.;
Tikkanen-Kaukanen, C. Binding of Neisseria meningitidis pili to berry polyphenolic fractions. J. Agric.
Food Chem. 2009,57, 3120–3127. [CrossRef] [PubMed]
77.
Toivanen, M.; Huttunen, S.; Duricová, J.; Soininen, P.; Laatikainen, R.; Loimaranta, V.; Haataja, S.; Finne, J.;
Lapinjoki, S.; Tikkanen-Kaukanen, C. Screening of binding activity of Streptococcus pneumoniae,Streptococcus
agalactiae and Streptococcus suis to berries and juices. Phytother. Res.
2010
,24, S95–S101. [CrossRef] [PubMed]
78.
Lian, P.Y.; Maseko, T.; Rhee, M.; Ng, K. The antimicrobial effects of cranberry against Staphylococcus aureus.
Food Sci. Technol. Int. 2012,18, 179–186. [CrossRef] [PubMed]

Molecules 2019,24, 24 20 of 21
79.
Lacombe, A.; McGivney, C.; Tadepalli, S.; Sun, X.; Wu, V.C.H. The effect of American cranberry
(Vaccinium macrocarpon) constituents on the growth inhibition, membrane integrity, and injury of Escherichia
coli O157:H7 and Listeria monocytogenes in comparison to Lactobacillus rhamnosus.Food Microbiol.
2013
,34,
352–359. [CrossRef] [PubMed]
80.
Hellström, J.; Törrönen, R.; Mattila, P. Proanthocyanidins in common food products of plant origin. J. Agric.
Food Chem. 2009,57, 7899–7906. [CrossRef] [PubMed]
81.
Huttunen, S.; Toivanen, M.; Arkko, S.; Ruponen, M.; Tikkanen-Kaukanen, C. Inhibition activity of wild berry
juice fractions against Streptococcus pneumoniae binding to human bronchial cells. Phytother. Res.
2011
,25,
122–127. [CrossRef]
82.
Lai, Y.F.; Yinrong, L.; Howell, A.B.; Vorsa, N. The structure of cranberry proanthocyanidins which inhibit
adherence of uropathogenic pfimbriated Escherichia coli in vitro. Phytochemistry 2000,54, 173–181.
83.
Sekizawa, H.; Ikuta, K.; Mizuta, K.; Takechi, S.; Suzutani, T. Relationship between polyphenol content and
anti-influenza viral effects of berries. J. Sci. Food Agric. 2013,93, 2239–2241. [CrossRef] [PubMed]
84. Masoudi, M.; Saiedi, M. Anti-carcinoma activity of Vaccinium oxycoccos.Pharm. Lett. 2017,9, 74–79.
85.
Ranfaing, J.; Dunyach, R.C.; Louis, L.; Lavigne, J.P.; Sotto, A. Propolis potentiates the effect of cranberry
(Vaccinium macrocarpon) against the virulence of uropathogenic Eschericia coli.Sci. Rep.
2018
,8, 10706.
[CrossRef] [PubMed]
86.
Gupta, A.; Dwivedi, M.; Mahdi, A.A.; Nagana Gowda, G.A.; Khetrapal, C.L.; Bhandari, M. Inhibition of
adherence of multi-drug resistant E. coli by proanthocyanidin. Urol. Res.
2012
,40, 143–150. [CrossRef]
[PubMed]
87.
Vasileiou, I.; Katsargyris, A.; Theocharis, S.; Giaginis, C. Current clinical status on the preventive effects of
cranberry consumption against urinary tract infections. Nutr. Res. 2013,33, 595–607. [CrossRef] [PubMed]
88.
Kalt, W.; Howell, A.B.; MacKinnon, S.L.; Goldman, I.L. Selected bioactivities of Vaccinium berries and other
fruit crops in relation to their phenolic contents. J. Sci. Food Agric. 2007,87, 2279–2285. [CrossRef]
89.
Davidson, E.; Zimmermann, B.F.; Jungfer, E.; Chrubasik-Hausmann, S. Prevention of urinary tract infections
with vaccinium products. Phytother. Res. 2014,28, 465–470. [CrossRef]
90.
Shamseer, L.; Vohra, S. Complementary, holistic, and integrative medicine: Cranberry. Pediat. Rev.
2007
,28,
e43–e45. [CrossRef]
91.
Kontiokari, T.; Sundqvist, K.; Nuutinen, M.; Pokka, T.; Koskela, M.; Uhari, M. Randomized trial of
cranberry-lingonberry juice and Lactobacillus GG drink for the prevention of urinary tract infections in
women. Br. Med. J. 2001,322, 1571–1573. [CrossRef]
92.
Kontiokari, T.; Laitinen, J.; Järvi, L.; Pokka, T.; Sundqvist, K.; Uhari, M. Dietary factors protecting women
from urinary tract infection. Am. J. Clin. Nutr. 2003,77, 600–604. [CrossRef]
93.
Jepson, R.G.; Mihaljevic, L.; Craig, J. Cranberries for preventing urinary tract infections. Cochrane Database
Syst. Rev. 2004,2, CD001321.
94.
Jepson, R.G.; Craig, J.C. A systematic review of the evidence for cranberries and blueberries in UTI prevention.
Mol. Nutr. Food Res. 2007,51, 738–745. [CrossRef] [PubMed]
95.
Jepson, R.G.; Williams, G.; Craig, J.C. Cranberries for preventing urinary tract infections. Cochrane Database
Syst. Rev. 2012,10, CD001321. [CrossRef] [PubMed]
96.
Liska, D.J.; Kern, H.J.; Maki, K.C. Cranberries and Urinary tract infections: How can the same evidence lead
to conflicting advice? Adv. Nutr. 2016,7, 498–506. [CrossRef]
97.
Kivimäki, A.S.; Ehlers, P.I.; Turpeinen, A.M.; Vapaatalo, H.; Korpela, R. Lingonberry juice improves
endothelium-dependent vasodilatation of mesenteric arteries in spontaneously hypertensive rats in a
long-term intervention. J. Funct. Foods 2011,3, 267–274. [CrossRef]
98.
Seeram, N.P.; Adams, L.S.; Zhang, Y.; Lee, R.; Sand, D.; Scheuller, H.S.; Heber, D. Blackberry, black raspberry,
blueberry, cranberry, red raspberry, and strawberry extracts inhibit growth and stimulate apoptosis of human
cancer cells in vitro. J. Agric. Food Chem. 2006,54, 9329–9339. [CrossRef]
99.
Nowack, R. Cranberry juice—A well-characterized folk-remedy against bacterial urinary tract infection.
Wien Med. Wochenschr. 2007,157, 325–330. [CrossRef]
100.
Nowack, R.; Schmitt, W. Cranberry juice for prophylaxis of urinary tract infections—Conclusions from
clinical experience and research. Phytomedicine 2008,15, 653–667. [CrossRef]
101. Guay, D.R. Cranberry and urinary tract infections. Drugs 2009,69, 775–807. [CrossRef]

Molecules 2019,24, 24 21 of 21
102.
Asma, B.; Vicky, L.; Stephanie, D.; Yves, D.; Amy, H.; Sylvie, D. Standardised high dose versus low dose
cranberry Proanthocyanidin extracts for the prevention of recurrent urinary tract infection in healthy women
[PACCANN]: A double blind randomised controlled trial protocol. BMC Urol. 2018,18, 29. [CrossRef]
103.
Hisano, M.; Bruschini, H.; Nicodemo, A.C.; Srougi, M. Cranberries and lower urinary tract infection
prevention. Clinics (Sao Paulo) 2012,67, 661–668. [CrossRef]
104.
Abascal, K.; Yarnell, E. Botanical medicine for cystitis. Altern. Complement. Ther.
2008
,14, 69–77. [CrossRef]
[PubMed]
105.
Howell, A.B.; Reed, J.D.; Krueger, C.G.; Winterbottom, R.; Cunningham, D.G.; Leahy, M. A-type cranberry
proanthocyanidins and uropathogenic bacterial anti-adhesion activity. Phytochemistry
2005
,66, 2281–2291.
[CrossRef]
106.
Ermel, G.; Georgeault, S.; Inisan, C.; Besnard, M. Inhibition of adhesion of uropathogenic Escherichia coli
bacteria to uroepithelial cells by extracts from cranberry. J. Med. Food 2012,15, 126–134. [CrossRef]
107.
Hidalgo, M.; Martin-Santamaria, S.; Recio, I.; Sanchez-Moreno, C.; de Pascual-Teresa, B.; Rimbach, G.;
de Pascual-Teresa, S. Potential anti-inflammatory, anti-adhesive, anti/estrogenic, and angiotensin-converting
enzyme inhibitory activities of anthocyanins and their gut metabolites. Genes Nutr.
2012
,7, 295–306.
[CrossRef] [PubMed]
108.
Howell, A.B. Update on health benefits of cranberry and blueberry. Acta Hort.
2009
,810, 779–784. [CrossRef]
109.
Blumberg, J.B.; Camesano, T.A.; Cassidy, A.; Etherton, P.K.; Howel, A.; Manach, C.; Ostertag, L.M.; Sies, H.;
Ray, A.S.; Vita, J.A. Cranberries and their bioactive constituents in human health. Adv. Nutr.
2013
,4, 618–632.
[CrossRef]
110.
Vattem, D.A.; Lin, Y.-T.; Ghaedian, R.; Shetty, K. Cranberry synergies for dietary management of
Helicobacter pylori infections. Process. Biochem. 2005,40, 1583–1592. [CrossRef]
111.
Banaszczak, E.W.; Sroka, E.S.; Bylka, W. Comparison of the contents of selected phenolic componds in the
fruit of Vaccinium macrocarpon Ait. and Vaccinium oxycoccos L. Herba Polonica 2010,56, 38–46.
©
2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).