Molecules 27 03294 v22522

molecules
Review
Cherries and Blueberries-Based Beverages: Functional Foods
with Antidiabetic and Immune Booster Properties
Ana C. Gonçalves 1,2,† , Ana R. Nunes 1,3,† , José D. Flores-Félix 1,† , Gilberto Alves 1 and Luís R. Silva 1,4, *,†
1 CICS-UBI—Health Sciences Research Centre, University of Beira Interior, Av. Infante D. Henrique,
6200-506 Covilhã, Portugal; anacarolinagoncalves@sapo.pt (A.C.G.); araqueln@gmail.com (A.R.N.);
jdflores@usal.es (J.D.F.-F.); gilberto@fcsaude.ubi.pt (G.A.)
2 CIBIT—Coimbra Institute for Biomedical Imaging and Translational Research, University of Coimbra,
3000-548 Coimbra, Portugal
3 CNC—Centre for Neuroscience and Cell Biology, Faculty of Medicine, University of Coimbra,
3000-548 Coimbra, Portugal
4 CPIRN-UDI-IPG—Center of Potential and Innovation of Natural Resources,
Research Unit for Inland Development, Polytechnic Institute of Guarda, 6300-559 Guarda, Portugal
* Correspondence: luisfarmacognosia@gmail.com
† These authors contributed equally to this work.
Abstract: Nowadays, it is largely accepted that the daily intake of fruits, vegetables, herbal products
and derivatives is an added value in promoting human health, given their capacity to counteract
oxidative stress markers and suppress uncontrolled pro-inflammatory responses. Given that, natural-
based products seem to be a promising strategy to attenuate, or even mitigate, the development of
chronic diseases, such as diabetes, and to boost the immune system. Among fruits, cherries and
blueberries are nutrient-dense fruits that have been a target of many studies and interest given
Citation: Gonçalves, A.C.; Nunes, their richness in phenolic compounds and notable biological potential. In fact, research has already
A.R.; Flores-Félix, J.D.; Alves, G.; demonstrated that these fruits can be considered functional foods, and hence, their use in functional
Silva, L.R. Cherries and beverages, whose popularity is increasing worldwide, is not surprising and seem to be a promising
Blueberries-Based Beverages:
and useful strategy. Therefore, the present review reinforces the idea that cherries and blueberries
Functional Foods with Antidiabetic
can be incorporated into new pharmaceutical products, smart foods, functional beverages, and
and Immune Booster Properties.
nutraceuticals and be effective in preventing and/or treating diseases mediated by inflammatory
Molecules 2022, 27, 3294. https://
doi.org/10.3390/molecules27103294
mediators, reactive species, and free radicals.
Academic Editors: Dalene De Beer, Keywords: functional foods; functional beverages; cherry; blueberry; health properties
Lizette Joubert, Elisabetta Damiani
and Tiziana Bacchetti
Received: 28 April 2022

Accepted: 19 May 2022 1. Introduction
Published: 20 May 2022 Food is any substance consumed capable of providing nutrients required for several
Publisher’s Note: MDPI stays neutral
functions, such as producing energy, supporting various metabolic activities, growing pro-
with regard to jurisdictional claims in cesses, and promoting wellness and a healthy status [1,2]. In recent decades, the demand
published maps and institutional affil- for healthy foods and beverages has increased worldwide, mainly due to their nutritional
iations. values and health-promoting properties, demonstrating their ability to reduce the risk of
oxidative stress-related disorders and others [3–5]. Given that, it is not surprising that
the knowledge about the influence of nutrition on health and well-being has greatly in-
creased, leading to the development of new and healthier foods, which are called functional
Copyright: © 2022 by the authors. foods [6].
Licensee MDPI, Basel, Switzerland. The concept of functional foods was firstly described in ancient Vedic texts from India
This article is an open access article and was also an integral part of traditional Chinese medicine since early times [7]. In
distributed under the terms and the 1980s, it was introduced in Japan, in the face of escalating processed foods that, in
conditions of the Creative Commons
addition to their nutritional function, contained ingredients with specific bodily functions
Attribution (CC BY) license (https://
and beneficial physiological effects [7]. In 1984, after the increase in healthcare costs, an ad
creativecommons.org/licenses/by/
hoc group of the Ministry of Education, Science, and Culture in Japan launched a national
4.0/).
Molecules 2022, 27, 3294. https://doi.org/10.3390/molecules27103294 https://www.mdpi.com/journal/molecules

Molecules 2022, 27, 3294 2 of 44
project to explore the link between medical sciences and foods, and to legislate these
products into Foods Of Specified Health Use (FOSHU) (Table 1) [8] given their biological
potential [9]. To receive a FOSHU designation, manufacturers must complete an application
that includes scientific evidence of the proposed medical or nutritional relationship, the
proposed dose of the functional food, the safety of the food, and a description of the
physical/chemical properties, experimental methods, and composition of the food [10].
Table 1. The Japanese FOSHU criteria for functional food.
1. They are food (not capsules, pills, or powder) based on naturally occurring food components
2. They can and should be consumed as part of the normal daily diet
3. They have a defined function on the human organism:
• To improve immune function
• To prevent specific diseases
• To support recovery from specific diseases
• To control physical and physic complaints
• To slow down the ageing process
The term “functional food” was first mentioned in 1993 in a scientific paper in Nature
News Magazine entitled “Japan explores the boundary between food and medicine” [11]. There
is no doubt about the interest of Japanese consumers in functional foods, and consequently,
the growing awareness of functional products throughout the world. However, there is no
consensus between Europe and the United States of America (USA) on a relatively concrete
definition for functional foods, resulting in a variety of different terms: nutraceutical,
designer food, pharmafood, and others, which contribute to increasing the confusion
between professionals and consumers [12]. The USA prefers the term “nutraceutical”,
while European experts decided to adopt the term “functional food” with a consensus
definition within the FUFOSE (Functional Food Science in Europe) project (Table 2).
Table 2. The FUFOSE definition of functional food in Europe [13].
Functional foods are:

• Conventional or everyday food consumed as part of the normal diet
• Composed of naturally occurring components, sometimes in increased concentration or
present in foods that would not normally supply them
• Scientifically demonstrated to promote positive effects on target functions beyond basic
nutrition
• Thought to provide enhancement of the state of well-being and health in order to improve
the quality of life and = or reduce the risk of disease
• Advertised by authorized claims
However, it is important to emphasize that functional foods must be foods and not
medicines. Furthermore, the positive health effects should be achieved by consuming
normal amounts of the functional food in question as part of a normal daily diet and should
improve the quality of life. Interest in functional foods and beverages continues to grow,
driven by ongoing research efforts to identify potential health-promoting properties and
potential applications of nutraceuticals, resulting in increasing consumers’ interest in the
role of foods and beverages in health and wellness. Within the emerging paradigm of
functional foods, functional beverages can help to promote daily consumption of fruits and
vegetables, as recommended by WHO/FAO [14], which recommends 400 g of edible fruits
and vegetables per day. However, it is important to bear in mind that the consumption of
juices intake does not equate to the ingestion of whole fruits and vegetables.
Given the mentioned, this review aims to summarize data on functional beverages
made from cherries and blueberry and their various physiological functions, which allow
them to be classified as functional foods for which health claims will be approved in
the future.
Molecules 2022, 27, 3294 3 of 44
2. Functional Foods Definition

Functional foods are used to increase certain physiological functions, and to prevent
or even cure, diseases [15]. The concept of functional foods encompasses the idea that
foods can play a role beyond gastronomic providing energy and nutrients [12]. Examples
include conventional foods, fortified, enriched, or enhanced foods, and dietary supplements.
For instance, the enrichment of traditional beverages, such as traditional beers, with
phenolic compounds in order to increase, not only their flavor and attractivity for the
consumer but also their nutritional values, have been increasing worldwide [16]. Therefore,
functional foods provide essential nutrients in amounts beyond what is necessary for
normal maintenance, growth, and development, and/or provide other biologically active
components that have health benefits or desirable physiological effects. Functional foods
are essentially a marketing term that is not recognized worldwide [7]. Several definitions
of functional foods have been given (Table 3).
In the USA, there is no formal definition of functional foods, instead, the terms
nutraceutical, dietary supplement, or medical foods, are used (Table 4), and therefore,
functional foods cannot be regulated differently from other foods. Despite government
authorities, national and international organizations have proposed their definitions of
functional foods. The lack of a uniform definition in different countries has resulted in
the unregulated publication of health claims for functional foods and a lack of clarity for
scientists, governments, and consumers as to what “functional foods” actually are. There is
an urgent need for researchers to rethink the meaning of functional food and agree on a
new formal definition of functional foods that applies to all countries.
Although the terms “nutraceuticals” and “functional foods” are commonly used
worldwide, there is no consensus on their meaning. Therefore, the Bureau of Nutritional
Sciences, of the Food Directorate of Health Canada, has proposed the following definitions:
a nutraceutical is a product isolated or purified from food, generally sold in medicinal
forms (powders, pills, and other medicinal forms) that are not normally associated with
food. A nutraceutical has been shown to have physiological benefits or provide protection
against chronic diseases. Functional food has a possible appearance of a conventional
food, and can be consumed as part of the usual diet. Beyond basic nutritional functions, it
demonstrates several physiological benefits and/or the ability to reduce the risk of chronic
disease [17]. According to regulation (functional food [17]), a functional food is a food with
specific beneficial effects on one or more target functions in the body that go beyond basic
nutritional functions and result in improved health status and well-being or a reduction in
the risk of disease. It is consumed as part of a normal diet and is not used in the form of
pills or capsules or any other form of dietary supplement [18].
Functional foods are clearly in a different category than nutraceuticals, pharmafood,
or dietary supplements. They are considered food, not a pharmaceutical drug because
they have health-promoting properties, which are usually disease-preventive, rather than
therapeutic properties (Tables 3 and 4).
Molecules 2022, 27, 3294 4 of 44
Table 3. Several definitions of functional foods.
Reference Definition
Foods for specified health use. The FOSHU can be foods that
FOSHAN [19] exhibit health effect, used as foods in a diet, and are in the form
of foods, not as supplements
A functional food to be similar in appearance to conventional
food, to be consumed as part of the usual diet, to demonstrate
Health Canada, Ontario, Canada [20]
physiologic benefits, and/or to reduce the risk of chronic
disease beyond basic nutritional functions.
Foods or dietary components may provide a health benefit
International Food Information Council, Washington, USA [21]
beyond basic nutrition.
International Life Sciences Institute of North America (ILSI Foods that by physiologically active food components provide
North America) [22] health benefits beyond basic nutrition.
Functional food is a food with certain beneficial effects on one
or more target functions in the body beyond the basic
nutritional effects with a result of the improved health state and
Regulation (EC) No 1924/2006 [18]
well-being or reduction of risk of diseases. It is consumed as a
part of a normal diet and is not used in the form of a pill or
capsule or any other form of dietary supplement.
A food product can be made functional by using any of the five
approaches listed below:
(1) Eliminating a component known to cause or identified as
causing a deleterious effect when consumed (for example, an
allergenic protein). (2) Increasing the concentration of a
component naturally present in food to a point at which it will
induce predicted effects (for example, fortification with a
micronutrient to reach a daily intake higher than the
recommended daily intake). (3) Adding a component that is not
[7] normally present in most foods and is not necessarily a
macronutrient or a micronutrient, but for which beneficial
effects have been shown (for example, non-vitamin antioxidant
or prebiotic fructans). (4) Replacing a component, usually a
macronutrient (for example, fats), intake of which is usually
excessive and replacing it with a component for which
beneficial effects have been shown (for example, modified
starch). (5) Increasing bioavailability or stability of a component
known to produce a functional effect or to reduce the
disease-risk potential of the food.
Natural or processed foods that contain known or unknown
biologically-active compounds; which, in defined, effective
non-toxic amounts, provide a clinically proven and documented
health benefit for the prevention, management, or treatment of
chronic disease. In this definition, first functional foods can be
Functional Food Center (FFC) [10] natural or processed. Second, bioactive compounds, which are
considered to be the source of the functionality of the foods, are
secondary metabolites that occur in food usually in small
amounts that act synergistically to benefit health. Specifically,
bioactive compounds may exert antioxidant, cardio-protective
and chemo-preventive effects.
Functional food is one that encompasses potentially healthful
Food and Nutrition Board (FNB) of the National Academy of products, including any modified food or food ingredient that
Sciences, Washington, USA) [23] may provide a health benefit beyond that of the traditional
nutrient it contains.
Molecules 2022, 27, 3294 5 of 44
Table 4. Terms linked with functional foods.
Bioactive Compounds:
The Office of Dietary Supplements at the NIH has defined bioactive compounds as constituents in
foods or dietary supplements, other than those needed to meet basic human nutritional needs,
which are responsible for changes in health status [24].
Dietary Supplements:
Dietary supplements mean foodstuffs, the purpose of which is to supplement the normal diet, and
which are concentrated sources of nutrients or other substances with a nutritional or physiological
effect, alone or in combination, marketed in dose form, namely forms such as capsules, pastilles,
tablets, pills and other similar forms, and sachets of powder, ampoules of liquids, drop dispensing
bottles, and other similar forms of liquids and powders designed to be taken in measured small
unit quantities [25].
Functional Ingredients:
Functional ingredients are a diverse group of compounds; health benefits have been attributed,
for example, to allyl compounds found in garlic, carotenoids, and flavonoids, found in fruits and
vegetables, glucosinolates, found in cruciferous vegetables, hypericin and pseudohypericin found
in St. John’s wort, peptides such as epidermal growth factor, opioid peptides, and lactoferrin,
found in milk, and arachidonic and docosahexaenoic acids, found in human milk and derived for
use in infant formulas from various algal, bacteria, and fish sources. Functional ingredients can be
marketed as part of dietary supplements, food additives, or generally recognized as safe (GRAS)
ingredients included in functional foods [23].
Medical Foods:
A Medical Food is a food that is “formulated to be consumed or administered under the
supervision of a physician and which is intended for the specific dietary management of a disease
or condition for which distinctive nutritional requirements are established by medical
evaluation [26].
Natural health products:
Natural health products (NHPs) include homoeopathic preparations, substances used in
traditional medicine, a mineral or trace element, a vitamin, an amino acid, an essential fatty acid,
or other botanical-, animal-, or microorganism-derived substance [27].
Nutraceutical:
The term nutraceutical is a substance that may be considered a food or part of a food that
provides medical or health benefits, encompassing prevention and treatment of disease. Products
as diverse as isolated nutrients, dietary supplements, and diets, to genetically engineered
“designer” foods, herbal products, and processed foods (cereals, soups, beverages) may be
included under the umbrella of nutraceuticals [28].
Together with fruits, vegetables, nuts, seeds, and grains, some beverages can also be
considered functional foods (Table 5) [12,29,30]. For example, oats contain beta-glucan,
a dietary fiber associated with reducing inflammation, boosting immune function, and
improving heart health [31]. In addition, fruits and vegetables are packed with antioxidants,
which are beneficial compounds that protect against disease [7,29]. This category also
includes foods enriched with vitamins, minerals, fatty acids, probiotics, and prebiotics
(fiber, fructooligosaccharides, inulin, lactulose, and sugar alcohols) [12].
Several dairy products have also been explored, such as yogurts with live cultures and
lactose-free cheeses. The addition of margarine is another commonly available functional
food product. Examples of functional beverages are energy drinks and those enriched with
vitamins and minerals or lactose-free milk (Table 5) [7].
In conclusion, there is a consensus about the term functional which is used to enhance
certain physiological functions in order or even cure medical conditions; however, some
control exists about the fact that capsules, pills, and powders might be included [15]. A
functional food can be (i) a natural food, (ii) a food to which a component has been added,
(iii) a food from which a component has been removed, (iv) a food where one or more
components has been modified, (v) a food in which the bioavailability has been modified,
or (vi) any combination of these [7]. There is no EU legislation on functional foods, so
this definition has legal force. It is only a current working definition: functional foods are
Molecules 2022, 27, 3294 6 of 44
not pills, capsules, or any form of food supplement, but in any case, they must retain the
character of a food, and their consumption must be part of a normal diet.
Table 5. Categories of functional foods.
Category Example
Carrots (containing the antioxidant β-carotene);
Basic food Turmeric (containing curcumin); Grapes
(containing resveratrol)
Processed foods Oat bran cereal
Calcium-enriched fruit juice; margarine
Processed foods with added ingredients enriched in phytosterols; Beverages enriched
with vitamins and minerals
Food enhanced to have more of a functional
Tomatoes with a higher level of lycopene
component
Isoflavones from soy
Isolated, purified preparations of active food
β-Glucan from oat bran
ingredients (dosage form)
Anthocyanins from red fruits
3. Fruits and Beverages as Functional Foods

The global consumption of fruit beverages reached 95.69 billion liters in 2018, repre-
senting 0.78% less compared to 2017, accounting for 37.23 billion juice drinks, 10.92 billion
liters for nectar, and 30.55 billion for powdered and concentrated juice [32], revealing its
great importance in the world economy. Consumers demonstrated an increased interest
in juices with innovative and functional juice ingredients that help improve health. With
the pandemic coronavirus in 2020, demand for juice in Europe rapidly increased. It is
common to see orange juice consumption increase during the flu season in Europe. How-
ever, COVID-19 completely changed consumption patterns. Until 2019, European juice
consumption decreased at an annual rate of 1% for almost a decade. But in 2020/2021,
consumption increased again in several European markets. After the COVID-19 pandemic
began, consumers regained some interest in citrus juices and red fruits. They also became
more interested in functional ingredients in drinks [33].
Functional beverages occupied over half (USD 99 billion) [13] of the total market value
(USD 168 billion) of functional foods in 2019 [14], with approximately 1/3 of the market
value (USD 36 billion) being contributed by the Asia Pacific region [13].
The growth of functional beverages and novel ingredients has led to improved leg-
islation (Regulation No. 258/97) [34] from the European Commission (EC), which now
requires the submission of a comprehensive safety document before novel ingredients can
be used in foods. The EC is willing to grant approval and support the industry provided
their development is based on scientific evidence and validated in human populations [33].
Within the emerging paradigm of functional foods, functional beverages may help increase
the consumption of fruits and vegetables to restore the balance between recommenda-
tions and actual consumption, although consumption of juices is not equivalent to the
consumption of whole fruits or vegetables.
In 2007, the regulation regarding nutrition and health claims made on foods was intro-
duced in the European Union. This regulation provides opportunities for the use of health
claims on foods in Europe, including claims to reduce the risk of disease. Nutrition and
health claims must be based on and substantiated by generally accepted scientific evidence;
EFSA requires RCT (Randomized Control to demonstrate the beneficial physiological effects
on a healthy population [35,36].
Consumers around the world are looking for healthier, more natural, and functional
products, looking for relaxation, energy, performance, and memory, as well as the addition
of exotic ingredients and vegetables [29]. The consumption of low-sugar options has already
been consolidated in the market by natural substitutes [32]. Beverages are commonly used
to deliver high concentrations of functional ingredients (e.g., sports and performance
drinks, ready-to-drink teas, vitamin-enriched water, soy, and energy beverages) [29].
Molecules 2022, 27, 3294 7 of 44
Functional beverages have been reported as the most active and popular among
consumers, taking into account meeting consumer demands for desirable nutrients and
bioactive compounds, easiness in distribution and storage, size, shape, and appearance [37].
Beverages have been used habitually to deliver high concentrations of functional ingredi-
ents, associated with their easy delivery and human body need. Beverages represent an
appropriate solution for the dissolution of functional ingredients, but also a convenient
and widely accepted method of consumption. The processing of beverages can contribute
to some sensory barriers (e.g., bitter taste, grainy texture, etc.), and they provide a proper
method of ingestion [29]. The different types of commercially available beverages could be
grouped into: (i) dairy-based beverages including probiotics and minerals/ω-3 enriched
drinks, (ii) vegetable and fruit beverages, and (iii) sports and energy drinks [37].
As far as the study of fruit juice is concerned, two major groups have been focused
on: (i) juices high in antioxidants, or (ii) juices relatively low in antioxidants, but widely
consumed by the general public. However, there are also mixed juices with high antioxidant
activity that are consumed in relatively large quantities [29]. The first group of juices
includes pomegranate, cranberry, and blueberry, as well as other dark fruits, such as cherry
and blackcurrant, which have higher levels of phenolic compounds (e.g., phenolic acids,
flavonoids, anthocyanins, and tannins) [38–40] In the other category, research focused
on orange, grape, and apple juices, which contain mainly hydroxycinnamic acids and
vitamins [29,41,42].
Berries, such as blueberries and sweet cherries, are usually consumed as fresh fruits,
however, but various technological products are also widely available. They are usually
processed into juices, concentrate, and jams/purees; additionally, their oils can be ex-
tracted from seeds [30]. Interest in beverages has increased significantly in recent years.
Studies have demonstrated more beneficial effects of berries phytochemicals, which has
led to an increase in consumption associated with increased health awareness among
consumers [30,39,40,43,44].
Red fruits such as berries are an important component of a healthy diet due to their
high content of phenolic acids and flavonoids, especially anthocyanins [30,40,43,44]. Blue-
berries (Vaccinium spp.) and cherries (Prunus spp.) are considered one of the five healthy
foods certified by the International Food and Agriculture Organization (FAO) because
they are rich in phenolic compounds, anthocyanins, and other nutrients [45]. Their con-
sumption has increased in recent years, partially due to the health benefits attributed to
their phenolic content. Blueberries are composed of high levels of anthocyanins, flavonols,
and flavan-3-ols, as well as benzoic and cinnamic acids [43,46,47]. Several health benefits
were reported for blueberries and cherries given their capacity to offer protection against
metabolic disorders thanks to their remarkable antioxidant, anti-inflammatory anti-diabetic
properties [48,49].
4. An Overview Regarding Cherry and Blueberry Phenolic Compounds

In current days, a crescent interest in natural antioxidant molecules has been increasing
worldwide, once, contrary to synthetic antioxidants, it is believed that their continuous
intake does not present, or presents fewer, undesirable side effects [50]. In line with the
mentioned, it is not surprising that cherries and blueberries, particularly Prunus cerasus (tart
cherries) and P. avium (sweet cherries), and Vaccinium corymbosum (highbush blueberries)
and Vaccinium ashei (rabbiteye blueberries), are a target of much research [40,51–54]. Indeed,
they are considered super red fruits, given their fullness in several phenolic compounds
(total phenolic compounds (TPC) of around 275.3–484.1 for tart cherries [55,56], 28.3–493.6
for sweet cherries [53,57,58] and 2.7–585.3 and 390–2625 mg gallic acid equivalents (GAE)
per 100 g fresh weight (fw) for highbush and rabbiteye blueberries, respectively [53,55–66])
(Table 6). Of course, these amounts depend on many factors, including genotype, local
origin, methods of cultivation, and maturation stage, processing, and storage conditions,
among others [40,52].
Molecules 2022, 27, 3294 8 of 44
Phenolic compounds are secondary plant metabolites produced via shikimic and acetic
acids, and phenylpropanoid and flavonoid pathways, to offer protection to plants against
biotic and abiotic factors [67]. Given that, it is not surprising that their intake is also an
added value [65]. Among phenolic subclasses, it is important to underline the presence of
anthocyanins, i.e., the glycosides of anthocyanidins (total anthocyanin concentrations (TAC)
of around 21.0–295 for tart cherries [54,68], 3.7–98.4 [53,54] for sweet cherries and 34.5–552.2
and 69.97–378.31 mg cyanidin 3-O-glucoside equivalents per 100 g fw for highbush blue-
berries and rabbiteye blueberries, respectively [53,54,64,68–71]) (Table 6). These molecules
are considered the key responsible for the organoleptic properties and biological potential
demonstrated by these fruits given their multiple hydroxyl groups, and also owing to their
electron deficiency, which confers to them the easy capacity to neutralize and/or reduce
free radicals and reactive species. In most fruits, including red fruits, anthocyanins are com-
monly found conjugated with arabinose, galactose, glucose, or rutinoside sugar in order to
be more stable (Figure 1). Among them, cyanidin 3-O-glucosyl-rutinoside (89.0–227.66 mg
per 100 g fw), cyanidin 3-O-rutinoside (1.76–74.7 per 100 g fw), cyanidin 3-O-sophoroside
(0.13–10.0 mg per 100 g fw), cyanidin 3-O-glucoside (0.01–1.03 mg per 100 g fw), and
cyanidin aglycone (31–6.64 mg per 100 g fw) are the main anthocyanins reported in tart
cherries [54,70,72,73]. Additionally, trace amounts of peonidin 3-O-glucoside, cyanidin 3-O-
xylosylrutinoside, cyanidin 3-O-galactoside, delphinidin 3-O-rutinoside, and delphinidin,
malvidin, peonidin, and pelargonidin aglycones are also detected [70,72,74,75]. On the
other hand, sweet cherry fruits present higher amounts of cyanidin 3-O-rutinoside, which
represents around 90.0% of total anthocyanins found, and from 42.5 to 68.6% of total phe-
nolic compounds detected, followed by cyanidin 3-O-glucoside, at levels varying between
0.20 and 389.9, and from 0.0 to 142.03 mg per 100 g fw, respectively [40,43,76,77], and by
vestigial amounts of pelargonidin and delphinidin 3-O-rutinoside, peonidin, and malvidin
derivatives, and cyanidin and malvidin aglycones [40,43,53,54,78,79]. Regarding highbush
blueberries, they are richer in malvidin 3-O-galactoside (12.11–67.45 mg per 100 g fw),
peonidin 3-O-glucoside (12–54.37 mg/100 g fw), delphinidin 3-O-glucoside (1.21–53.62 mg
per 100 g fw), delphinidin 3-O-galactoside (2.29–53.29 mg per 100 g fw), delphinidin 3-
O-arabinoside (1.66–41.07 mg per 100 g fw), malvidin 3-O-glucoside (0.68–34.75 mg per
100 g fw), petunidin 3-O-galactoside (2.57–28.54 mg per 100 g fw), and petunidin 3-O-
glucoside (0.67–25.14 mg per 100 g fw) [59,80–82]. Additionally, they also contain trace
amounts of cyanidin 3-O-glucoside, cyanidin 3-O-arabinoside, cyanidin 3-O-galactoside,
cyanidin 3-O-hexoside, petunidin 3-O-arabinoside, malvidin 3-O-arabinoside, malvidin-3-
(600 -acetyl-galactoside), malvidin-3-(600 -acetyl) glucoside, malvidin 3-O-xyloside, peonidin-
3-O-pentose, peonidin 3-O-galactoside, and cyanidin, delphinidin, cyanidin, peonidin,
malvidin, and petunidin aglycones [59,81–83]. On the other hand, peonidin 3-O-glucoside
is the most abundant in rabbiteye blueberries, followed by malvidin 3-O-glucoside, mal-
vidin 3-O-arabinoside, and delphinidin 3-O-galactoside [84,85].
Molecules 2022, 27, 3294 9 of 44
Table 6. Nutritional composition and main phenolic compounds found in tart and sweet cherries, and highbush and rabbiteye blueberries (mg per 100 g of fresh
weight (fw)) and juices (mg/L).
Fruits Juices
Tart Cherries Sweet Cherries Blueberries Tart Cherries Sweet Cherries Blueberries References
Basic chemical composition
Water (g per 100 g) 86.1 82.2 84.2 85.2 85.0 89.7
Energy (kcal per 100 g) 50.0 63.0 57.0 59.0 54.0 37.0 [86]
Energy (kJ per 100 g) 209.0 263.0 240.0 248.0 226.0 -
Macronutrients
Total protein (g per 100 g) 1.0 1.1 0.74 0.31 0.91 0.48
Betaine (mg per 100 g) - - 0.20 - - -
Tryptophan (mg per 100 g) - 0.009 0.030 - - -
Threonine (mg per 100 g) - 0.022 0.020 - - -
Isoleucine (mg per 100 g) - 0.020 0.023 - - -
Leucine (mg per 100 g) - 0.030 0.044 - - -
Lysine (mg per 100 g) - 0.032 0.013 - - -
Methionine (mg per 100 g) - 0.010 0.012 - - -
Cystine (mg per 100 g) - 0.010 0.008 - - -
Phenylalanine (mg per 100 g) - 0.024 0.026 - - -
Tyrosine (mg per 100 g) - 0.014 0.009 - - -
Valine (mg per 100 g) - 0.024 0.031 - - -
Arginine (mg per 100 g) - 0.018 0.037 - - -
Histidine (mg per 100 g) - 0.015 0.011 - - -
Alanine (mg per 100 g) - 0.026 0.031 - - -
Aspartic acid (mg per 100 g) - 0.569 0.057 - - -
Glutamic acid (mg per 100 g) - 0.083 0.091 - - -
Glycine (mg per 100 g) - 0.023 0.031 - - -
Proline (mg per 100 g) - 0.039 0.028 - - -
Serine (mg per 100 g) - 0.03 0.022 - - -
Total lipids (g per 100 g) 0.3 0.2 0.33 0.54 0.02 0.21
[86]
Fatty acids, total saturated
0.068 0.038 0.028 - 0.004 0.018
(g per 100 g)
SFA 14:0 (g per 100 g) 0.002 0.001 - - - -
SFA 16:0 (g per 100 g) 0.048 0.027 0.017 - 0.003 0.011
SFA 18:0 (g per 100 g) 0.016 0.009 0.005 - 0.001 0.003
Molecules 2022, 27, 3294 10 of 44
Table 6. Cont.
Fruits Juices
Fatty acids, total
0.082 0.047 0.047 - 0.005 0.031
monounsaturated (g per 100 g)
MUFA 16:1 (g per 100 g) 0.001 0.001 0.002 - - 0.001
MUFA 18:1 (g per 100 g) 0.081 0.047 0.047 - 0.005 0.031
Fatty acids, total polyunsaturated
0.09 0.052 0.146 - 0.006 0.095
(g per 100 g)
PUFA 18:2 (g per 100 g) 0.046 0.027 0.088 - 0.003 0.057
PUFA 18:3 (g per 100 g) 0.044 0.026 0.058 - 0.003 0.038
Carbohydrates (g per 100 g)
12.2 16 14.5 13.7 13.8 9.42
(by difference)
Total ash (g per 100 g) 0.4 0.48 0.24 0.28 0.031 -
Total dietary fiber (g per 100 g) 1.6 2.1 2.4 - 1.5 1.6
Total sugars (g per 100 g) 8.49 12.8 9.96 12.2 12.3 6.47
Fructose (g per 100 g) 3.51 5.37 4.97 4.95 - -
Glucose (g per 100 g) 4.18 6.59 4.88 7.26 - -
Sucrose (g per 100 g) 0.8 0.15 0.11 - - -
Lactose (g per 100 g) - - - - - -
Maltose (g per 100 g) - 0.12 - - - -
Galactose (g per 100 g) - 0.59 - - - -
Starch (g per 100 g) - 0 0.03 - - -
Micronutrients
Minerals
Calcium (mg per 100 g) 16.0 13.0 6.0 13.0 14.0 5.0
Iron (mg per 100 g) 0.32 0.36 0.28 0.42 0.58 0.18
Magnesium (mg per 100 g) 9.0 11.0 6.0 11.0 12.0 4.0
Phosphorus (mg per 100 g) 15.0 21.0 12.0 17.0 22.0 8.0
Potassium (mg per 100 g) 173.0 222.0 77.0 161 131.0 50.0
Sodium (mg per 100 g) 3.0 - 1.0 4.0 3.0 2.0 [86]
Zinc (mg per 100 g) 0.1 0.07 0.16 0.03 0.1 0.1
Cooper (mg per 100 g) 0.104 0.06 0.057 0.042 0.073 0.04
Manganese (mg per 100 g) 0.112 0.07 0.336 0.06 0.061
Fluoride (µg per 100 g) - 2.0 - - - -
Selenium (µg per 100 g) - - 0.1 - 0 0.1
Molecules 2022, 27, 3294 11 of 44
Table 6. Cont.
Fruits Juices
Vitamins
Vitamin C (mg per 100 g) 10.0 7.0 9.7 - 2.5 6.3
Thiamin (mg per 100 g) 0.03 0.027 0.037 0.06 0.018 0.024
Riboflavin (mg per 100 g) 0.04 0.033 0.041 - 0.024 0.027
Niacin (mg per 100 g) 0.4 0.154 0.418 - 0.406 0.272
Pantothenic acid (mg per 100 g) 0.143 0.199 0.124 - 0.127
Vitamin B6 (mg per 100 g) 0.044 0.049 0.052 0.037 0.03 0.034
Folate, total (µg per 100 g) 8.0 4.0 6.0 - 4.0 4.0
Folate, DFE (µg per 100 g) 8.0 4.0 6.0 - 4.0 4.0
Folate, food (µg per 100 g) 8.0 4.0 6.0 - 4.0 4.0
Choline (mg per 100 g) 6.1 6.1 6.0 - 4.7 3.9 [86]
Vitamin A, RAE (µg per 100 g) 64.0 3.0 3.0 - 6.0 2.0
Vitamin A, IU (IU per 100 g) 1280.0 64.0 54.0 - 125 -
Vitamin D (D2 + D3) IU
- 64.0 - - - -
(IU per 100 g)
β-Carotene (µg per 100 g) 770.0 38.0 32.0 - 75.0 21.0
Lutein + zeaxanthin (µg per
85.0 85.0 80.0 - 57.0 52.0
100 g)
Vitamin E (mg per 100 g) 0.07 0.07 0.57 - 0.23 -
β-Tocopherol (mg per 100 g) - 0.01 0.01 - - -
γ-Tocopherol (mg per 100 g) - 0.04 0.36 - - -
∆-Tocopherol (mg per 100 g) - - 0.03 - - -
γ-Tocotrienol (mg per 100 g) - 0.04 0.07 - - -
Vitamin K (µg per 100 g) 2.1 2.1 19.3 - 1.4 12.5
Phenolic Profile
Cherries Blueberries Juices
Tart Cherries Sweet Cherries Highbush Rabbiteye Tart Cherries Sweet Cherries Blueberries
TPC (mg GAE per 100 g fw) 275.3–652.27 28.3–493.6 2.7–585.3 390.0–2625.0 1510.0–2550.0 a 582.7–4757.9 a 1.65 [53,55–66,87]
TAC (mg C3G per 100 g fw) 15.5–295.0 3.7–98.4 34.5–552.2 69.97–378.31 553.0 a 85.1–1095.9 a 29.00–32.73 a [53,54,64,68–71]
Anthocyanins
Cyanidin 3-O-glucosyl-rutinoside 89.0–227.66 - - - 92.86–441.11 - - [54,72–74,87,88]
Molecules 2022, 27, 3294 12 of 44
Table 6. Cont.
Fruits Juices
[40,43,54,72,73,76,
Cyanidin 3-O-rutinoside 1.76–74.7 0.20–389.9 - - 0.38–85.5 104.0–210.0 -
77,87–90]
Cyanidin 3-O-sophoroside 0.13–10.44 t.r. - - 1.62–292.21 - - [54,72–74,76,87,88]
[40,43,54,59,66,72,
Cyanidin 3-O-glucoside 0.01–142.03 0.0–142.03 0.11–3.09 t.r.–8.20 c 2.0–9.9 22.0–37.0 0.26–89.0 73,76,77,81,84,85,
87,89–91]
Cyanidin 3-O-xylosylrutinoside t.r. - - - - - - [53]
Cyanidin
- 0.001–0.44 - - - - - [76]
3-coumaroyl-diglucoside
Cyanidin 3-5-diglucoside - 0.16–1.05 - - - - 0.0–28.5 [76,92]
Cyanidin 3-O-hexoside - - 19.23 - - - - [82]
[59,74,75,81,84,85,
Cyanidin 3-O-galactoside 0.0–2.63 t.r. 0.80–9.96 5.40–8.90 c - - 13–59
91]
cyanidin 3-(600 -acetyl-glucoside) - - - - - - 20.0 [93]
Cyanidin 3-O-sambubioside - 0.09–0.16 - - - - - [76]
Cyanidin 3-O-arabinoside - 0.25–0.40 0.42–1.09 2.62 c - - 1.40–160 [66,76,81,85,91]
Petunidin 3-O-galactoside - - 2.57–28.54 6.94 c - - 0.34–125 [59,66,81,85,91]
[59,81,82,84,85,91,
Petunidin 3-O-glucoside - - 0.67–25.14 t.r.–9.93 c - - 7.70–365.0
93]
Petunidin 3-O-arabinoside - - 1.82–12.70 3.5.–4.30 c - - 0.53–59.0 [59,66,81,84,91]
Petunidin 3-(600 -acetyl)glucoside - - - - - - 57.0 [93]
[59,66,76,78,84,90,
Peonidin 3-O-glucoside t.r. 0.0–0.38 12.00–54.37 17.6–30.3 c - - 0.63–91.0
91,93]
Peonidin 3-O-rutinoside - 0.0–6.7 - - - 29.0–36.0 - [54,78,89,90]
Peonidin 3-O-pentose - - 0.52–0.69 - - - - [81]
Peonidin 3-O-galactoside - - 0.77–125.79 2.90–3.80 c - - 0.54–19.0 [59,66,81,84,85,91]
Peonidin 3-O-arabinoside - - - 2.4–13.4 c - - <1–2 [84,85,91]
Peonidin 3-(600 -acetyl)galactoside - - - - - - 6.0 [93]
Peonidin 3-(600
- - - - - - 40.0 [93]
-acetyl)glucoside
Pelargonidin 3-O-rutinoside - 0.0–7.97 - - 0.11–131.42 7.0–9.0 - [76,78,88–90]
Pelargonidin 3-O-glucoside - 0.22–0.71 - - - - 10.1–35.6 [76,92]
[59,66,78,81,85,91,
Malvidin 3-O-glucoside - 0.08–0.45 0.68–34.75 21.53 c - - 6.25–271.0
93]
Molecules 2022, 27, 3294 13 of 44
Table 6. Cont.
Fruits Juices
[59,66,80,81,85,91,
Malvidin 3-O-galactoside - - 12.11–67.45 19.57 c - - 6.0–160
93]
Malvidin 3-O-arabinoside - - 6.77–9.41 4.64–17.80 c - - 4.60–73.0 [66,81,84,85,91,93]
Malvidin-3-(600 -acetyl-
- - 0.99–1.74 - - - 34.0 [81,93]
galactoside)
Malvidin 3-O-xyloside - - 0.56 - - - - [81]
Malvidin-3-(600 -acetyl) glucoside - - 1.63 - - - 131.0 [81,93]
Malvidin
- 0.08–0.11 - - - - - [76]
3-O-glucoside-acetaldehyde
Delphinidin 3-O-rutinoside t.r. t.r. - - - - - [53]
Delphinidin 3-O-glucoside - - 1.21–53.62 0.2–8.08 c - - 7.70–365.0 [59,81,84,85,91,92]
[59,66,81,84,85,91,
Delphinidin 3-O-galactoside - - 2.29–53.29 7.97–16.3 c - - 0.14–223.0
93]
Delphinidin 3-O-arabinoside - - 1.66–41.07 4.67–5.6 c - - 0.67–134.0 [59,66,81,84,91]
Delphinidin
- - - - - - 2.0 [93]
3-(600 -acetyl)glucoside
Delphinidin
- - - - - - 86.0 [93]
3-(malonyl)glucoside
Delphinidin 0.01–0.52 - 8.51–141.1 - - - 5.40–25.7 [70,72,82,83,92]
Malvidin 0.27–8.31 0.04–0.06 131.3–154.6 - - - 0.37 [66,70,72,79,83]
Peonidin 0.01–0.19 0.11–3.93 14.28–36.9 - - - - [70,72,79,82,83]
Cyanidin 3.41–6.64 0.04–0.18 21.17–66.3 - - - 0.09 [66,70,72,79,82,83]
Pelargonidin 1.35–64.36 - - - - - - [70,72]
Petunidin - - 1.78–87.6 - - - - [82,83]
Hydroxybenzoic acids
ρ-Hydroxybenzoic acid - 10.3–19.1 0.054–59.89 0.0–103.67 - - t.r. [63,64,77,90,94,95]
Protocatechuic acid - 0.054–3.28 5.22–41.45 - - - - [63,76,77,96]
Hydroxybenzoic acid-glycoside - 0.15–0.32 - - - - - [76]
Hydroxybenzoyl hexose - 0.14–0.70 - - - - - [76]
Vanillic acid-glycoside - 0.76–3.05 - - - - - [76]
Vanillic acid - - 0.011–0.027 - - - t.r. [94,95]
Syringic acid - 0.0–0.071 0.034–9.95 - - 6.64–14.46 t.r. [63,77,94–97]
[60,63,64,77,78,96–
Gallic acid - 0.0018–10.64 0.02–5.68 1.53–258.9 - 0.0–6.55 -
98]
Ethyl gallate - 0.0003–0.0014 - - - - - [96]
Molecules 2022, 27, 3294 14 of 44
Table 6. Cont.
Fruits Juices
Propyl gallate - 0.0005–0.0099 - - - - - [96]
Ellagic acid - - 0.75–6.65 0.0–19.25 - - - [60,64]
2,5-Dihydroxybenzoic acid - 0.0–1.50 - - - - - [78,96]
Hydroxycinnamic acids
Salicylic acid - 0.0037–1.31 - - - - - [90,96]
Cinnamic acid - 7.8–11.1 0.003–0.07 - - - - [90,94]
[60,64,77,90,94–
Ferulic acid - 0–5.7 0.018–4.16 0.0–16.97 1.14–1.27 1.01–6.35 t.r.
97,99]
[54,60,74,76,77,81,
3-Caffeoylquinic acid 5.24–27.79 38.0–187.0 0.46–7.12 0.039–2.46 82.0–183.0 24.77–37.78 -
90,97,100]
4-Caffeoylquinic acid - 2.6–29.2 - - - - - [90]
[54,63,74,76,90,95,
5-Caffeoylquinic acid 0.58–60.33 0.21–120.8 13.52–65.24 - 28.30–995 - t.r.
99–101]
3-Coumaroylquinic acid - 37.0–452.52 - - 91.0–555.0 - - [76,90,100]
4-Coumaroylquinic acid cis - 0.74–18.58 - - - - - [76]
4-Coumaroylquinic acid trans - 4.92–19.46 - - - - - [76]
5-Coumaroylquinic acid cis - 0.38–0.96 - - 12.0–81.0 - - [76,100]
5-Coumaroylquinic acid trans - 0.53–1.53 - - - - - [76]
3-Feruloylquinic acid cis - 0.64–2.30 - - - - - [76]
3-Feruloylquinic acid trans - 0.72–5.86 - - - - - [76]
5-Feruloylquinic acid trans - 0.04–0.25 - - - - - [76]
Caffeoylquinic acid glycoside - 0.11–1.71 - - - - - [76]
3,5-diCaffeoylquinic acid - 0.26–2.87 - - - - - [76]
4,5-diCaffeoylquinic acid - 0.09–0.78 - - - - - [76]
Caffeoylshikimic acid - 0.26–0.56 - - - - - [76]
3- and 4-Caffeoylquinic lactone - 0.39–2.26 - - - - - [76]
Caftaric acid - - 4.71 - - - - [77]
3-Coumaroylquinic lactone - 0.39–0.99 - - - - - [76]
4-Coumaroylquinic lactone - 0.11–2.02 - - - - - [76]
3-Coumaroyl-5-
- 0.03–0.76 - - - - - [76]
caffeoylquinicacid
3-Caffeoyl-4-
- 0.02–0.46 - - - - - [76]
coumaroylquinic acid
Molecules 2022, 27, 3294 15 of 44
Table 6. Cont.
Fruits Juices
Coumaroyl hexose - 2.95 - - - - - [76]
Caffeoyl hexose - 0.32–2.02 0.19–0.22 - - - - [76,81]
Caffeic acid - 0.0–0.83 0.042–32.3 - 5.39–15.50 3.74–4.00 t.r. [64,77,94–97,99]
Caffeic acid glycoside - 0.52–8.79 - - - - - [76]
Caffeoyl alcohol 3/4-O-hexoside - 0.7–0.78 - - - - - [76]
[54,60,63,64,74,77,
ρ-Coumaric acid 0.89–50.69 0.11–70.45 2.40–25.49 0.0–15.78 11.30–12.10 0.0–0.15 -
78,96,97,99]
Feruloyl hexose - 0.33–0.39 0.91–1.63 - - - - [76,81]
Sinapoyl hexose - 0.20–0.50 - - - - - [76]
Sinapic acid - - 0.005–0.11 - - - - [63,94]
3-O-Coumaroyl quinic acid - 0.35–1.7 - - - - - [102]
3-O-Coumaroyl quinic acid II - 3.1–15 - - - - - [102]
5-O-Feruloyl quinic acid - 0.34 - - - - - [102]
3-O-Feruloyl quinic acid - 0.038–0.44 - - - - - [102]
Chlorogenic acid isomer II - 0.24–0.63 - - - - - [102]
4-O-Coumaroyl quinic acid I - 0.12–0.61 - - - - - [102]
4-O-Coumaroyl quinic acid II - 0.50–3.0 - - - - - [102]
Malonyl-dicaffeoylquinic acid - - 0.76 - - - - [81]
Malonyl-caffeoylquinic acid - - 9.32 - - - - [81]
Flavonols
Myricetin - 0.0005–0.014 6.72–6.98 0.0–8.62 - - - [64,96]
Myricetin 3-O-glucuronide - - - 91.0–482.0 b - - - [51]
Myricetin 3-O-galactoside - - - 44.0–564.0 b - - - [51]
Myricetin-3-(600 -
- - - 0.0–1.1 b - - - [51]
rhamnosyl)galactoside
Myricetin 3-O-glucoside - - - 66.0–121.0 b - - - [51]
Myricetin-3-(600 -
- - - 0.0–210.0 b - - - [51]
rhamnosyl)glucoside
Isomers of myricetin
- - - 0.0–110.0 b - - - [51]
3-O-pentoside
Myricetin 3-O-rhamnoside - - - 0.0–971.0 b - - - [51]
[51,60,64,77,90,94,
Quercetin - 0.0–2.51 0.29–21.48 0.046–9.97 184.0–739.0 b - 51.2
96,103]
Quercetin 3-O-galactoside - - 0.19–31 269.0–1174.0 b 0.0–4.0 - - [51,77,94,100]
Molecules 2022, 27, 3294 16 of 44
Table 6. Cont.
Fruits Juices
Quercetin 3-O-glucuronide - - 0.06–1.76 475.0–3353.0 b - - - [51,63,77]
Quercetin 3-O-hexoside - 0.99–1.39 - - - - - [76]
Quercetin 3-O-arabinoside - - 0.58 - 0.0–16.0 - - [81,100]
[51,54,63,76,77,81,
Quercetin 3-O-glucoside 0.21–0.44 0.0–26.55 0.9–34.64 81.0–203.0 b - - t.r.
95]
Quercetin-3-O-[400 -(3-hydroxy-3-
methylglutaroyl)]-α-rhamnoside - - - 0.0–1719.0 b - - - [51]
syringetin-3-rhamnoside
Isomers of quercetin
- - - 0.0–1005.0 b - - - [51]
3-O-pentoside
Quercetin 3-O-rhamnoside - - 26.0 88.10–4292.0 b 18.0–45.0 - - [63,100]
[54,60,74,76,94,97,
Quercetin 3-O-rutinoside 0.84–7.63 0.78–51.97 0.008–0.056 0.044–6.74 4.10–53.80 0.0–4.74 65.0
99,102,103]
Quercetin
- 0.08–5.56 - - - - - [76,102]
7-O-glucoside-3-O-rutinoside
Quercetin
- 3.67–132.7 - - - - - [98]
O-glucoside-O-rutinoside II
[63,64,77,94,96,
Kaempferol - 0.0028–10 0.061–19.65 0.0–3.72 5.60 - 12.1
103]
[51,63,76,77,94,
Kaempferol 3-O-glucoside - 0.024–1.36 0.008–6.01 - 3.40 - 0.30
102,103]
Kaempferol 3-O-rutinoside 0.30–1.29 0.9–8.13 - - - - - [54,76,90,102]
Kaempferol rutinoside-hexoside - 0.13–1.08 - - - - - [76]
Laricitrin - - - 0.0–65.0 b - - - [51]
Laricitrin 3-O-galactoside - - - 41.0–710.0 b - - - [51]
Laricitrin-3-O-glucuronide - - - 151.0–640.0 b - - - [51]
Laricitrin 3-O-glucoside - - 0.61–0.65 - - - - [81]
Isorhamnetin - 0.0004–0.0024 - - - - - [96]
Isorhamnetin 3-O-rutinoside 0.0–5.37 0.08–0.13 - - - - - [54,74]
Isorhamnetin 3-O-glucoside - - - 0.0–76.0 b - - - [51]
Syringetin - - - 0.0–119.0 b - - - [51]
Syringetin 3-O-galactoside - - - 70.0–742.0 b - - - [51]
Syringetin 3-O-glucoside - - 0.77–0.97 85.0–594.0 b - - - [51,81]
Syringetin 3-O-glucuronide - - - 53.0–594.0 b - - - [51]
Syringetin 3-O-rhamnoside - - - 0.0–447.0 b - - - [51]
Molecules 2022, 27, 3294 17 of 44
Table 6. Cont.
Fruits Juices
Syringetin 3-O-pentoside - - - 0.0–109.0 b - - - [51]
Flavan-3-ols
[57,60,64,76,77,81,
(+)-Catechin - 0.13–84.34 0.067–81.8 0.13–387.48 4.0–77.0 0.38–1.44 -
94,96,97,99,100]
[60,63,64,76,77,94,
(−)-Epicatechin 0.0–28.22 0.23–397.19 0.0014–20.70 0.0–129.51 13.60–369.0 1.17–1.54 -
97,99,100,104]
Epigallocatechin - - 0.21–0.40 - 0.0–17.20 - - [94,99]
Epicatechin 3-gallate - 0.29–3.12 0.48–19.27 - - - - [63,76]
Catechin glucoside - 2.03–1.16 - - - - - [76]
Procyanidin tetramer B type 1 - 0.33–1.01 - - - - - [76]
Procyanidin tetramer B type 2 - 0.62–2.95 - - - - - [76]
Procyanidin dimer B type 1 - 2.24–6.99 - - - - - [76]
Propelargonidin dimer - 0.29–0.77 - - - - - [76]
Procyanidin pentamer B type - 0.18–1.68 - - - - - [76]
Dimer B2 - - 0.40–1.51 - - - - [81]
Procyanidin B1 0.0–27.69 0.55–7.29 - - 12.0–92.0 - - [57,74,100]
Procyanidin C1 0.0–8.6 - - - - - - [74]
Flavanones
Naringenin - - 0.024–0.028 - - - - [94]
Naringenin hexoside - 0.38–3.41 - - - - - [76]
Flavanonols
Taxifolin 3-O-rutinoside - 0.43–100.52 - - - - - [76]
Taxifolin
- 0.0–21.1 - - - - - [90]
O-deoxyhexosylhexoside
Flavones
Luteolin - 0.0027–0.020 - - - - - [96]
Luteolin 7-O-glucoside - - - - 56.0 - 102.0 [103]
Molecules 2022, 27, 3294 18 of 44
Table 6. Cont.
Fruits Juices
Apigenin 8-C-glucoside - - 0.057–0.14 - - - - [94]
Coumarins
Aesculin - - 0.003–0.0011 - - - - [94]
Chalcones
Phlorizin - - 0.041–0.57 - - - - [96]
TPC: total phenolic content; TAC: total anthocyanin content; GAE: gallic acid equivalents; C3G: cyanidin 3-O-glucoside equivalents; fw: fresh weight; t.r.: trace residues; *: g GAE/L;
a : mg/L; b : mg per 100 g dry weight as equivalents of quercetin 3-O-glucoside; c : relative content regarding total anthocyanins detected (%).
Molecules 2022, 27, 3294 19 of 44
Figure 1. Main anthocyanins reported in tart cherries (brown color), sweet cherries (pink color), and
both cherries (green color), highbush blueberries (purple color), rabbiteye blueberries (blue color), and
both blueberries (orange color). (Figure created with ChemDraw Professional 16.0 (CambridgeSoft,
Perkin Elmer Inc., Waltham, MA, USA)).
As well as other food matrices, these super red fruits also contain other phenolics
in their composition capable of reinforcing their putative biological properties, namely
phenolic acids, flavonols, flavan-3-ols, and flavones [40,67,81,101,105]. Regarding hydroxy-
benzoic acids (Figure 2A), none are reported yet in tart cherries, however, ρ-hydroxybenzoic,
gallic, and protocatechuic acids are found in the sweet ones, at levels of 10.3–19.1, 0.0018–
1064 and 0.054–3.28 mg per 100 g fw, respectively [40,76,78,96,106]. In addition, residual
amounts of protocatechuic acid glycoside and protocatechuoyl hexose are also reported in
sweet cherries [76]. Comparatively to cherries, ellagic acid was, until now, only detected
in both blueberries, at amounts varying from 0.75–6.65 to 0.0–19.25 mg per 100 g fw for
highbush and rabbiteye, respectively [60,64]. Vanillic acid was only found in the highbush
fruits (0.011–0.027 mg per 100 g fw) [94], which in turn, also present higher levels of ρ-
hydroxybenzoic, protocatechuic, and syringic acids than cherries (0.054–59.78, 5.22–41.45,
and 0.034–9.95 mg per 100 g fw, respectively) [63,64,94].
Molecules 2022, 27, 3294 20 of 44
Figure 2. Main hydroxybenzoic (A) and hydroxycinnamic (B) acids reported in sweet cherries (pink
color), and both tart and sweet cherries (green color), highbush blueberries (purple color), rabbiteye
blueberries (blue color), and both blueberries (orange color). Vanillic, caftaric and sinapic acids were
only detected in highbush blueberries [60,74,91]. (Figure created with ChemDraw Professional 16.0
(CambridgeSoft, Perkin Elmer Inc., Waltham, MA, USA)).
Concerning the presence of hydroxycinnamic acids (Figure 2B), some differences are
also noticed. For instance, ρ-coumaric acid is the most abundant in tart cherries (0.89–
5.69 mg per 100g fw), followed by 3-caffeoylquinic and 5-caffeoylquinic acids (values
ranging from 0.58 and 60.33, and 5.24.27.79 mg per 100 g fw, respectively) [54,56,74]. These
phenolic acids, together with 3-coumaroylquinic acid, are also the predominant ones in
sweet cherries [40,43,54,57,76,96]. As well as cherries, both highbush and rabbiteye blue-
berries present considerable amounts of 5-caffeoylquinic and ρ-coumaric acids [60,64,94].
Nevertheless, sinapic and caftaric acids were only detected in highbush blueberries, at
amounts fluctuating between 0.005 and 0.11, and around 4.71 mg per 100 g fw, respec-
tively [63,77,94].
Regarding flavonols (Figure 3), quercetin 3-O-rutinoside and kaempferol 3-O-rutinoside
are the most prevalent in tart cherries, at levels ranging from 0.84 to 7.63, and between
0.30 and 1.29 mg per 100 g fw, respectively [54,65,74,99]. Additionally, Sokół-Ł˛etowska and
coworkers [74] revealed the presence of isorhamnetin 3-O-rutinoside in Polish sour cherries
(0.0 to 5.37 mg per 100 g fw). As well as tart cherries, the sweet ones also present consid-
erable levels of quercetin 3-O-rutinoside and kaempferol 3-O-rutinoside (0.78–51.97 and
0.90–8.13 mg per 100 g fw, respectively), and also higher amounts of quercetin O-glucoside-
O-rutinoside II (3.67–132.7 mg per 100 g fw) [43,65,76,98]. On the other hand, quercetin
(0.29–21.48 mg per 100 g fw), kaempferol (0.061–19.65 mg per 100 g fw) and myricetin (6.72–
6.98 mg per 100 g fw) aglycones, and quercetin 3-O-glucoside (0.90–34.64 mg per 100 g fw)
are commonly the most reported in highbush blueberry cultivars [51,59,64,80]. Relatively to
rabbiteye blueberries, they are also rich in myricetin and quercetin aglycones (6.72–6.98 and
0.046–9.97 mg per 100 g fw, respectively) [51,60,64]. Additionally, they also present various
derivatives of myricetin, quercetin, laricitrin and syringetin, demonstrating the presence
of myricetin 3-O-rhamnoside, myricetin 3-O-glucuronide and myricetin 3-O-glucoside,
Molecules 2022, 27, 3294 21 of 44
quercetin 3-O-glucuronide, quercetin 3-O-hexoside, quercetin 3-O-rutinoside, quercetin

3-O-rhamnoside, laricitrin 3-O-glucuronide, and syringetin 3-O-glucoside [51,63,100].
Figure 3. Main flavonols reported in sweet cherries (pink color) and both tart and sweet cherries
(green color), and both highbush and rabbiteye blueberries (orange color). (Figure created with
ChemDraw Professional 16.0 (CambridgeSoft, Perkin Elmer Inc., Waltham, MA, USA)).
Focusing on flavan-3-ols (Figure 4A), tart cherry contains (−)-epicatechin (0.0–28.22 mg

per 100 g fw), procyanidin B1 (0.0–27.69 mg per 100 g fw), and procyanidin C1 (0.0–8.60 mg
per 100 g fw) in their constitution [74]. (−)-Epicatechin is also one of the most predominant
flavan-3-ols reported in sweet cherries (0.23–397.19 mg per 100 g fw), followed by (+)-
catechin (0.13–84.34 mg per 100 g fw) and procyanidin dimer type 2 (1.59–26.47 mg per
100 g fw) [40,57,76,77,96]. Relative to blueberries, considerable amounts of (+)-catechin and
(−)-epicatechin were detected in both highbush and rabbiteye blueberries [60,64,94].
Figure 4. Main flavan-3-ols (A), flavones (B), flavanones (C), chalcones (D), and coumarins (E) re-
ported in both cherries and blueberries (grey color), sweet cherries (pink color), and highbush
blueberries (purple color). (Figure created with ChemDraw Professional 16.0 (CambridgeSoft, Perkin
Elmer Inc., Waltham, MA, USA)).
Molecules 2022, 27, 3294 22 of 44
Relatively to other non-colored phenolics, vestigial amounts of flavone luteolin, fla-

vanone naringenin hexoside, and flavanonols taxifolin 3-O-rutinoside and taxifolin O-
deoxyhexosylhexoside were already reported in sweet cherries [76,90,96]. On the other
hand, naringenin aglycone, flavone apigenin 8-C-glucoside, coumarin aesculin, and chal-
cone phlorizin were found in highbush blueberries [94,96] (Figure 4B–E).
Without surprises, and although there is still a lack regarding the red-fruit juices analy-
sis, cherry and blueberry juices also contain substantial amounts of phenolics, anthocyanins
being the most found (Table 6). Therefore, and in line with the fruit, tart cherry juice is also
rich in cyanidin 3-O-glucosyl-rutinoside (92.86–441.11 mg/L), cyanidin 3-O-sophoroside
(1.62–292.21 mg/L), and cyanidin 3-O-rutinoside (0.38–85.5 mg/L) [87,88]. On the other
hand, cyanidin 3-O-rutinoside and cyanidin 3-O-glucoside are the main ones in sweet cherry
juice, with values ranging from 104.0 to 210.0 mg/L, and between 22.0 and 37.0 mg/L,
respectively [89,97]. Regarding blueberry juices, they contain higher levels of delphinidin
3-O-galactoside (0.14–223.0 mg/L), petunidin 3-O-glucoside (7.70–365.0 mg/L), delphini-
din 3-O-arabinoside (0.67–134.0 mg/L), malvidin 3-O-arabinoside (4.60–73.0 mg/L), and
malvidin 3-O-glucoside (6.25–271.0 mg/L) [66,92,93,107,108]. Concerning non-colored phe-
nolic compounds, the most found in tart cherry juices include 5-caffeoylquinic acid (28.30–
995.0 mg/L), 3-coumarolyquinic acid (91.0–555.0 mg/L), 3-caffeoylquinic acid (82.0–183.0
mg/L), ferulic acid (1.14–1.27 mg/L), quercetin aglycone (184.0–739.0 mg/L), quercetin 3-
O-rutinoside (4.0–53.80 mg/L), and (−)-epicatechin (13.60–369.0 mg/L) [56,87,88,100,109].
On the other hand, sweet cherry juices are mainly composed of 3-caffeoylquinic acid (24.77–
37.78 mg/L), syringic acid (6.64–14.46 mg/L), gallic acid (0.0–6.55 mg/L), and quercetin
3-O-rutinoside (0.0–4.74 mg/L) [97,103]. Finally, blueberry juices are richer in luteolin
7-O-glucoside (ca., 102 mg/L) and quercetin 3-O-rutinoside (ca., 65 mg/L) [45,103,107].
Additionally, they present residual amounts of ρ-hydroxybenzoic acid, vanillic acid, 5-
caffeoylquinic acid, caffeic acid, syringic acid, ferulic acid, and quercetin 3-O-glucoside [95].
To increase the nutritional values of berry fruits and derivatives, including juices,
several efforts have been conducted. For instance, it was already reported that advanced
technologies, including ultrasonic-assisted extraction, pulsed electric fields, microwave,
and high hydrostatic pressure are more effective in extracting phenolic amounts from
cherries than conventional solvent extraction (only involving homogenization) [56,89,96].
The coating of cherries with chitosan also seems to be a promising strategy, being able
to preserve their firmness and enhance phenolic levels [110]. Additionally, Özen and
colleagues reported that sour cherry produced using the concentrate juice present higher
amounts of phenolic and volatile compounds [109], whereas Filannino et al. [111] verified
that the fermentation of cherry juice with Lactobacillus spp. enriches its juice with phenolic
derivatives with high bioavailability and biological activity. Similar data were obtained by
Ricci and coworkers [112] who proved that the fermentation of cherry juice with lactic acid
bacteria can enhance aromatic compounds and phenolic acids levels. Focusing on bilberries,
it was reported that the exposure of blueberry plants to 100 µM of cadmium and aluminium
for 14 days is effective in increasing phenolic compounds, duplicating their amounts
comparatively with samples without any treatment [113]. Furthermore, a recent study also
reported that dried blueberries at 50 ◦ C can increase TPC and TAC values of their juice by
199.11 and 166.79%, respectively [66]. Furthermore, Zhu and colleagues [107] a reported
that microchip-pulsed electric field (350 V, 0.15 ms, 7 mL/min) seems to be a promising
innovative way of processing fresh blueberry juice, being capable of extending its shelf life,
protecting its organoleptic properties (color and flavor) and enhancing its TPC values after
30 days of storage (+126.72%). It had been also reported that the acidification of blueberry
juice (pH 2.1), combined with refrigerated storage (4 ◦ C) and followed by pasteurization, is
capable of preserving more anthocyanins (+56% anthocyanins than juices storage at 25 ◦ C,
and +12% more anthocyanins than juices at pH 2.5) [114]. More recently, Martín-Gómez and
coworkers [115] mixed blueberry and grape musts with four yeast strains of Saccharomyces
cerevisiae (X5 (CECT131015), M05 Mead, QA23 commercial yeast and MP061 Viniferm EP
837) in a 1:1 ratio, and verified that the fermentation with M05 Mead yeast strain was the
Molecules 2022, 27, 3294 23 of 44
most appropriate, being effective in preventing color losses and increasing anthocyanins
amounts (+2.10% more than the initial sample without fermentation).
In addition, it is always important to take into account that cherries and blueberries are
perishable fruits and hence, it is very important to control temperature and reduce vibration
during transportation, and use adequate storage conditions and processing methods, to
preserve their nutritional value and life [116].
5. Absorption, Digestion, Metabolism, and Bioavailability of Phenolic Compounds

Although understanding the absorption, digestion, metabolism, and bioavailability
of phenolics is also not so easy, this is an essential tool to help in explaining the biological
potential of these metabolites [117,118]. Until a very short time ago, it is believed that
phenolics had lower absorption rates and were rapidly excreted; however, recent studies al-
ready reported that phenolics suffer an extensive metabolization along the gastrointestinal
tract, and therefore, the absorption rates are higher than expectable, and some of them can
be almost totally assimilated [119]. In a general way, most phenolics reach the maximum
plasma concentration 1.5–2 h after intake [120]. Among phenolic subclasses, isoflavones
seems to possess the highest absorption rates (33.0–100.0%), followed by hydroxycinnamic
acids (8.0–72.0%), anthocyanins (2.40–55.0%), flavonols and flavones (12.0–41.0%), fla-
vanones (11.0–16.0%), lignans (2.70–12.20%), and flavan-3-ols (2.0–8.0%) [121,122]. On
the other hand, their excretion content is estimated to be around 30%, varying between
12 h (flavanols) and 24 h (anthocyanins and hydroxycinnamic acids derivatives) [123,124].
Of course, these percentages are relative and highly variable, being largely influenced by
several features that can affect the transport, solubility, and permeability of each phenolic,
such as degree of polymerization, molecular size, chemical structure, glycosylation pattern,
pre-systemic metabolism, resistance to pH variations along the gastrointestinal tract and
facility to release from food matrix [125,126]. Additionally, they also depend on factors
responsible to influence phenolic content, such as agronomic practices, maturity stage,
food matrix maturity and processing, and whether phenolics are ingested after fasting
periods or not, and/or are alone or accompanied by other compounds, and also on gender,
age, dietary habits, lifestyle, and genetic, and physiological and pathological states, as the
possible existence of food intolerances and intestinal flora of each individual [127,128].
To circumvent these vicissitudes and increase the absorption and consequent bioavail-
ability of phenolics, several studies have been conducted, and their encapsulation with
proteins (e.g., gelatine, soy proteins, dairy derivatives), lipids (e.g., waxes and emulsi-
fiers), natural gums (gum Arabic and alginates), and/or carbohydrates (maltodextrins and
cellulose derivatives) seems to be a useful and promising tool [117].
Everything starts in the mouth with mastication, where, after phenolics’ intake, saliva
enzymes initiate the degradation of glycosides [129] (Figure 5). Subsequently, they are con-
ducted to the stomach [125]. Here, phenolics, namely simple aglycones (e.g., isoflavones)
and phenolic acids (e.g., gallic acid) can be directly absorbed by bilitranslocase or reach
intestinal epithelial cells by passive diffusion given their high lipophilicity, or through
the active sodium-dependent glucose cotransporter (polymers, glycosides, and esters),
becoming available for absorption [130,131]. However, most of the compounds remain
intact and are conducted to the small intestine to be hydrolyzed by lactase-phlorizin hy-
drolase (LPH) and cytosolic β-glucosidase (CBG) enzymes and/or undergo reactions of
methylation, glucuronidation, and sulfation [101,126]. After that, aglycones are conducted
to the liver via the portal vein and the non-absorbed ones go to the colon to be once more
degraded and modified into simpler monomeric units, thanks to reactions of decarboxy-
lation, demethylation, dihydroxylation, and hydrolysis carried out by bacterial esterases
(e.g., α-rhamnosidases) to suffer a new attempt of absorption by the liver [132,133]. In fact,
recent data reveal that most phenolics are only absorbed after undergoing colon metabo-
lization (90.0–95.0%) [134]. Usually, anthocyanins and proanthocyanidins are metabolized
from low molecular weight phenolic acids, flavones, and flavanones into hydroxyphenyl-
propionic acids, and polymeric phenolic compounds, flavonols to hydroxyphenylacetic
Molecules 2022, 27, 3294 24 of 44
acids, and flavanols into phenylvalerolactones and hydroxyphenylpropionic acids, and

after, degraded into hydroxybenzoic acid derivatives [131,135,136]. Additionally, it had
been recently reported that the cleavage of phenolic glycosidic bonds on the colon leads
to the formation of short-chain fatty acids, and hence, promotes the diminution of pH
values and creates favorable conditions for the proliferation of probiotic bacteria, such
as Actinobacteria, Bifidobacteria, and Lactobacilli, which in turn, exert positive effects in the
control of gastrointestinal and digestive disorders, allergies, eczema, and improvements in
delicate cases of cardiovascular and neurological ailments [117,135].
Figure 5. Schematic representation concerning phenolics’ absorption, metabolism, distribution, and

excretion (COMT, catechol O-metiltransferase; UDP, uridine 50 -diphospho-glucuronosyltransferase;
UDP-GT, glucuronil-transferase; SULT, sulfotransferase; LPH, lactase-phlorizin hydrolase; SGLT,
sodium-dependent glucose cotransporters, GLUT, glucose transporters; CBG, cytosolic β-glucosidase).
Figure created with Smart Servier Medical Art tools (https://smart.servier.com, 1 January 2022).
In the liver, most phenolics are converted into the simpler and lower molecular weight
that becomes accessible to reach the systemic circulation and be uptook by organs and
tissues after being subjected to phase I and phase II biotransformation reactions, which
include specific reactions of oxidation, hydrolysis, methylation, glucuronidation, and sulfa-
tion (phase I) and the action of sulfotransferases (SULTs), catechol-O-methyltransferases
(COMTs), and UDP-glucuronosyltransferases (UGTs) (phase II), or to enhance phenolics’
bioavailability; in the small intestine and kidneys the phase II of metabolism also oc-
curs [137,138]. Furthermore, the non-absorbed phenolics in the liver can return to the small
intestine via bile, to be again metabolized [126]. The non-absorbed phenolics are eliminated
feces and urine [118].
Nowadays, and considering the large health-promoting properties of these berries,
some research focused on studying their bioavailability-related processes has been con-
ducted. Regarding cherries, Mihaylova and coworkers [139] investigated the effect of
in vitro digestion on the phytochemical content of sweet cherry juice and only detected
chlorogenic acid after the digestion procedure, probably resulting from the anthocyanins’
metabolization. Additionally, these authors reported that cherry flavonoids were more
resistant to the digestion process, revealing bioaccessibility percentages of around 67%.
Furthermore, it was also documented that sour cherry phenolics were stable during gastric
Molecules 2022, 27, 3294 25 of 44
conditions, and around 59% of their content can be released into the bloodstream and reach
tissues and organs [127]. Additionally, Kirakosyan et al. [134] detected higher values of
cyanidin 3-glucosyl-rutinoside (2339 picograms/gram of tissue) and cyanidin 3-rutinoside
5-β-D-glucoside (916 picograms/gram) in the bladder and liver of rats, respectively. Fo-
cusing on blueberries, it was reported that their phenolics are absorbed and extensively
metabolized by phase II enzymes and gut microbiota of humans, originating various
metabolites that may be responsible for the beneficial effects observed after blueberry
consumption. In total, 61 phenolic metabolites were quantified in the plasma at baseline,
of which 43 increased after consumption of blueberries over 30 days. Among metabolites,
benzoic and catechol derivatives represented more than 80% of the changes in the phenolic
profile after 2 h of consumption, while benzoic and hippuric derivatives were the major
compounds after 30 days of daily intake. The phenolic urinary excretion remained un-
changed and no systemic toxicity was found [139]. Particularly, Zhong et al. [120] reported
that anthocyanins and 3-chlorogenic acid peaked at their maximum 2 h after blueberry
ingestion, whereas phase II metabolites, including glucuronide conjugates of peonidin,
delphinidin, cyanidin, and petunidin, peaked at 2.6, 6.3, 7, and 8.8 h, respectively. Phe-
nolic acid metabolites’ peak occurs between 0.5 and 24 h. More recently, Serra et al. [119]
subjected their anthocyanin-rich extracts to an in vitro experiment capable of mimicking
gastrointestinal digestion, and in the final experiment, they verified the maintenance of
higher monoglycosides of cyanidin, malvidin, delphinidin, peonidin, and petunidin lev-
els. Their TPC levels were 9000 mg/L and 850 mg/L GAE, before and after digestion,
respectively. Within them, derivatives of malvidin were the most predominant, which is
expected since they present fewer hydroxyl groups than other anthocyanins, and, hence,
are more resistant to digestion degradation. These data are in accordance with a previous
study, which revealed the presence of malvidin 3-O-glucoside in the plasma and urine of
human volunteers after the intake of red grape juice, indicating that it is not significantly
degraded, being absorbed in its glycosylated form [140]. Additionally, it has also been
detected that protocatechuic and vanillic acids resulted mainly from the metabolization
of cyanidin 3-O-glucoside [119]. Moreover, and as already mentioned, phenolics’ encap-
sulation seems to be an effective technique, given its capacity to enhance their stability.
Given that, Wu and collaborators [117] decided to encapsulate blueberry phenolics with
Arabic gum, maltodextrin, gelatin, and soy protein isolate and verified that the use of
the last two wall materials can increase bioaccessibility anthocyanin levels and promote
intestinal health, by increasing Bacteroidaceae levels, which in turn, leads to the production
of acetic, propionic, and butyric acids. Syringic acid was detected and its presence is from
the degradation of anthocyanins during colonic fermentation. Similar results were obtained
by conjugating blueberry anthocyanins with bovine serum albumin [141].
6. Functional Properties of Cherries and Blueberries—Focus on Antidiabetic and

Anti-Inflammatory Potential of Phenolic Compounds
Diabetes is a chronic metabolic disease affecting about 463 million people worldwide,
with major economic and well-being impacts [142]. Hyperglycemia is responsible for
structural and functional alterations in the body resulting from the increase in oxidative
stress, the formation of advanced glycation end products (AGEs), inflammation, and
protein glycation [143]. In the long term, diabetes can lead to severe complications such as
myocardial infarction and stroke [144].
New therapeutic approaches, in addition to antidiabetic drugs and insulin therapy,
are required. Beyond the side effects, conventional therapy is expensive and sometimes
not accessible to all [143,145]. Thus, the research and development of novel formulations
using natural products, rich in phenolic compounds and with antidiabetic properties, is a
promising strategy for diabetes management [43,146,147]. In this context, functional foods
are rich in bioactive ingredients with beneficial properties for preventing and managing
diabetes [148].
Molecules 2022, 27, 3294 26 of 44
Phenolic compounds are the predominant bioactive components in cherries and

blueberries [40,149]. The difference in the total content of phenolics found between the
various fruits relates to the cultivation, growth, maturity of the fruits, harvest, storage, and
also the analytical method used for its quantification [150,151]. In the Prunus genus, namely
in sweet cherry fruits, phenolic acids, flavonols, and anthocyanins are the main phenolics
identified [40,152]. On the other hand, the most abundant phenolic compounds present in
the fruits of the Vaccinium genus are procyanidins and phenolic acids; stilbene derivates (e.g.,
resveratrol), flavonols, and anthocyanins (e.g., malvidin, cyanidin, delphinidin, petunidin,
and peonidin) [149,153]. In recent years, the phenolic compounds have demonstrated to be
very promising agents in the control of hyperglycemia [146,154]. According to the literature
data, flavonoids seem to be involved in the maintenance and function of pancreatic β-
cells [145]. The reduction of oxidative stress, namely through increased endogenous
antioxidant capacity, and the decreased reactive oxygen species (ROS) accumulation and
translocation of pro-inflammatory cytokines, are among the main factors. Furthermore, the
increase in anti-apoptotic gene expression, the reduction of caspase-3 and caspase-8, and
protection against DNA damage have also been taken into account [145]. Different classes
of phenolic compounds such as flavanol derivatives, flavan-3-ols, quercetins, anthocyanins,
and phenolic acids have demonstrated the capacity to reduce ROS levels, inflammation,
and protein glycation [155]. The inhibition of the major enzymes involved in carbohydrates’
metabolism, the increase in glucose transporters expression (GLUT) (e.g., GLUT-4), and the
activation pathways responsible for signaling and secretion may be due to the action of
these compounds [155]. Below are described the principal mechanisms, through which the
phenolic compounds of cherries and blueberries can reduce hyperglycemia (Table 7).
Table 7. Antidiabetic properties of cherries and blueberries.
Part Used/
Plant Model Description Effects References
Compound
Enzymes inhibition studies
Evaluation of the inhibitory ↑ α-glycosidase and
activity of anthocyanin-rich α-amylase inhibition in a
Vaccinium myrtillus Fruits In vitro [156]
bilberry extract (BE) on mixed competitive
α-glucosidase and α-amylase manner.
Evaluation of the effect of BE
on the digestive properties of
Vaccinium myrtillus Fruits In vivo carbohydrates in ↓ Postprandial glucose [156]
eight-week-old SPF-grade
C57BL/6 J male mice
Evaluation of the highbush
Vaccinium blueberries in the inhibition of ↑ α-glycosidase and
Fruits In vitro [157]
corymbosum α-glycosidase and α-amylase α-amylase inhibition
enzymes
Evaluation of the antidiabetic ↑ α-glycosidase
Prunus avium Fruits In vitro potential of hydroethanolic inhibition in a [43,158]
extract of sweet cherry dose-dependent manner
Evaluation of the antidiabetic
↑ α-glycosidase
Stem, leaf, potential of hydroethanolic
Prunus avium In vitro inhibition in a [159]
flower extract and aqueous infusion
dose-dependent manner
of sweet cherry by-products
Resveratrol and flavone
Analysis of the inhibitory
are competitive
effect of phenolic compounds
Vaccinium inhibitors to (DPP-IV)
Fruits In vitro commonly present in berry on [160]
corymbosum Luteolin and apigenin
dipeptidyl-peptidase IV
bond to DPP-IV in a
(DPP-IV)
noncompetitive manner
Molecules 2022, 27, 3294 27 of 44
Table 7. Cont.
Part Used/
Compound
Pancreatic β-cells protection studies
↑ intracellular cAMP
Evaluation of the effects of
levels
resveratrol on pancreatic
n.a. Resveratrol In vitro ↑ insulin secretion [161]
β-cell function in mouse
↑ pancreatic β-cell
β-Min6 cells and human islets
function
↓ blood glucose
Evaluation of the effects of
↓ urinary microalbumin
Prunus avium Fruits In vivo ethanolic extract on [162]
↑ ctreatinine secretion
aloxan-induced diabetic rats
level in urea
↓ plasma glucose
↓ glycated hemoglobin
↓ insulin resistance
Analysis of the glucose ↑ mRNA levels of
homeostasis, pancreatic β-cell pancreatic β-cell
function, and insulin ↑ pancreatic insulin
Vaccinium myrtillus Leaf In vivo [163]
sensitivity in high-fat signaling
diet–induced in diabetic male ↓ transcriptional
C57BL/6J mice expression of the
β-cellimproved insulin
sensitivity
↑ insulin signaling
improved dyslipidemia
Evaluation of the effects of ↑ antioxidant status
purified anthocyanins on ↓ plasma glucose
Vaccinium myrtillus Fruits Clinical trial dyslipidemia, oxidative status, ↓ insulin resistance [164]
and insulin sensitivity in ↓ LDL cholesterol and
patients with type 2 diabetes triglycerides
↑ HDL
Insulin release and regulation
Evaluation of three different
phenolic fractions
(anthocyanins-rich fraction ↑ glucose consumption
(ARF), hydroxycinnamic ↑ insulin sensitivity
Prunus avium Fruits In vitro [165]
acids-rich fraction (HRF) and inhibited excessive
flavonols-rich fraction (FRF)) gluconeogenesis
in glucose consumption by
HepG2 cells
Analysis of blueberry effects
glucose metabolism and
↑ insulin sensitivity
Vaccinium myrtillus Fruits In vivo pancreatic β-cell proliferation [166]
↑ glucose tolerance
in high fat diet
(HFD)-induced obese mice.
Evaluation of the effect of
daily dietary supplementation
Vaccinium ashei
with bioactives from
Vaccinium Fruits Clinical trial ↑ insulin sensitivity [167]
blueberries on whole-body
corymbosum
insulin sensitivity in men and
women
↑ glucose-stimulated
Evaluation of the protective insulin secretion
n.a. Resveratrol In vitro effects of resveratrol in β-cell ↑ SIRT1 expression [168]
dysfunction in INS-1 cells restored the function of
INS-1 cell
Molecules 2022, 27, 3294 28 of 44
Table 7. Cont.
Part Used/
Compound
Analysis of the otective effects
of blueberry anthocyanin
↑ SIRT1 expression
Vaccinium myrtillus Fruits In vivo extract (BAE) against [169]
↑ SOD and GSH activity
oxidative stress and the roles
of SIRT1 and NF-κB
Evaluation of the role of berry
phenolic compounds to ↑ insulin secretion
modulate incretin-cleaving Upregulated expression
Vaccinium myrtillus Fruits In vitro [170]
DPP-IV and its substrate of mRNA of
glucagon-like peptide-1 insulin-receptor
(GLP-1), insulin secretion
↑—increase; ↓ decrease.
6.1. Enzymes’ Inhibition

The inhibition of enzymes involved in the carbohydrates’ metabolism is one of the
therapeutic strategies to control postprandial hyperglycemia, namely the α-glucosidase
and α-amylase [143,171]. The reduction of hydrolysis and absorption of carbohydrates
results in better blood glucose and the reduction of metabolic complications in diabetic
patients [146].
Recent data reported that phenolic compounds can inhibit the activity of diges-
tive enzymes [143,146]. Sweet cherry extracts from different cultivars were able to in-
hibit α-glucosidase in a dose-dependent manner (IC50 ranging from 10.25 ± 0.49 to
16.31 ± 0.71 µg/mL) [43]. Similarly, in a study with cherry by-products, it was demon-
strated that the aqueous infusion of the stems was the most active against this enzyme
(IC50 = 3.18 ± 0.23 µg/mL) [159]. In the in vitro study conducted by Ji et al. [156], it was
observed that the anthocyanin-rich bilberry extract (BE) was able to inhibit the activity of α-
glucosidase and α-amylase enzymes (IC50 = 0.31 ± 0.02 e 4.06 ± 0.12 mg/mL, respectively).
Moreover, in the same study the hypoglycemic effect of BE extract on postprandial glucose
was evaluated. The obtained results demonstrated that this extract was able to decrease
hyperglycemia in the treated group with BE when compared to the control group [156].
In another work, fifteen different cultivars of Vaccinium corymbosum exhibited greater in-
hibitory activity against α-glucosidase with values ranging between 103.22 ± 0.15% and
184.70 ± 0.01% inhibition, and α-amylase ranging from 91.79 ± 0.82% and 103.32 ± 0.34%
inhibition [157]. Moreover, a positive correlation between total phenolic content and inhibi-
tion of these enzymes was demonstrated [157]. Among anthocyanins present in cherries
and blueberries, cyanidins were able to inhibit α-amylase, which controlled postprandial
hyperglycemia [172].
The dipeptidyl-peptidase IV (DPP-IV) is the other enzyme involved in glucose home-
ostasis, which acts in the cleavage of peptide bonds and the release of compounds necessary
for the formation of several molecules [143]. According to Jufeng et al. [160], resveratrol,
luteolin, apigenin, and flavone are flavonoids present in blueberries with inhibitory effects
on DPP-IV.
6.2. Pancreatic β-Cells Protection

Pancreatic β-cells are responsible for the production and release of insulin, the only
hormone capable of lowering blood glucose concentration. The increase in oxidative
stress can lead to damage in these cells, leading to impairment of their functions [143].
Hyperglycemia, dyslipidemia, inflammation, and autoimmunity are factors responsible
for β-cells’ dysfunction and, consequently, lower insulin response [173]. When blood
glucose levels are very high, there is an increase in ROS, glycation reactions, and apoptosis
of pancreatic β-cells. In this sense, the search for bioactive compounds that can protect
Molecules 2022, 27, 3294 29 of 44
the cells, particularly phenolic compounds, has been a target of study by the scientific
community [143,146,154].
Several studies have suggested that phenolic compounds can protect pancreatic β-
cells mainly through their antioxidant potential [153,163,164]. Alloxan-induced diabetic
rats were treated with ethanolic extracts of cherries (200 mg/kg) for 30 days, and it was
observed that these extracts were able to reduce hyperglycemia and protect pancreatic
β-cells from oxidative damage [162]. Similarly, in a study developed by Li et al. [163],
C57BL/6J mice were supplemented with blueberry-leaf extract (1% w/w for 8 weeks)
and the glucose homeostasis and insulin sensitivity were evaluated. The obtained results
demonstrated that this extract was able to decrease glucose tolerance, body weight, plasma
glucose, and glycated hemoglobin [163]. Moreover, it was found that the treated group
increased the mRNA content of genes related to pancreatic β-cell proliferation, such as
neurogenin 3 (Ngn3), V-maf musculoaponeurotic fibrosarcoma homolog A (MafA), paired
box 4 (Pax4), and insulin 1 and 2 (Ins1-2). Pancreatic insulin signaling-related genes, namely
the insulin receptor substrate (IRS), glucose transporter 2 (GLUT-2), phosphatidylinositol
4,5-bisphosphate 3-kinase catalytic subunit alpha isoform (PIK3ca), and phosphoinositide-
dependent kinase (PKD1), were also increased. The transcriptional expression of genes
related to the apoptosis of β-cells was diminished [163]. Resveratrol is one of the phenolics
that can be found in blueberries, and it was described as able to protect against β-cell
dysfunction [161]. According to Rouse et al. [161], this compound (0–10 µmol/L) limited
the phosphodiesterase activity, increasing intracellular cAMP levels. Phosphodiesterase is
responsible for cAMP degradation, and its inhibition prevents this degradation, allowing
the insulin secretion and maintenance of pancreatic β-cells [161].
6.3. Insulin Release and Regulation

Insulin is synthesized by pancreatic β-cells and is involved in the regulation of glucose
metabolism, through the glucose uptake in adipose tissue and skeletal muscles and the
inhibition of gluconeogenesis in the liver [143]. Insulin secretion depends on the proper
functioning of pancreatic β-cells. In this context, the use of natural products capable of
promoting insulin secretion and reducing the adverse effects of synthetic drugs has been
evaluated by the scientific community [174].
Anthocyanin, hydroxycinnamic, and flavonol-rich extracts (25 µg/mL) of sweet cherry
promoted glucose consumption, insulin sensitivity, delayed glucose absorption, and inhib-
ited excessive gluconeogenesis in HepG2 cells [165]. More recently, it was demonstrated
that a blueberry-supplemented diet improved insulin sensitivity and glucose tolerance in
high fat diet-induced obese mice [166]. In addition, the presence of small scattered islets
in the blueberry-treated group was observed. This finding could mean that blueberries
have the potential for the regeneration of pancreatic β-cells [166]. Similarly, previous pre-
clinical studies demonstrated that dietary supplementation with blueberries in 32 obese,
non-diabetic, and insulin-resistant subjects improved insulin sensitivity [167].
The expression of Sirtuin 1 (SIRT1) stimulates insulin secretion. According to Luo
et al. [168], resveratrol (2.5, 12.5 µmol/L) improved insulin release from INS-1 cells by
disrupting the SIRT1-uncoupling protein-2 (UCP2) axis. In another study, the effects of
blueberry anthocyanin extract (5 or 10% by oral gavage: 10 mL/kg/day) were evaluated in
streptozotocin (STZ)-induced diabetic rats, for 9 weeks [169]. SIRT1 expression, superoxide
dismutase (SOD), and glutathione (GSH) activities were enhanced. In fermented berries
beverages, anthocyanins (50 µmol cyanidin-3-glucoside equivalents), namely delphinidin-
3-arabinoside, were responsible for the increased insulin secretion and the modulation of
genes and proteins related to this action [170].
On the other hand, insulin resistance is one of the main consequences of diabetes,
since high blood glucose levels reduce the ability of the cells to absorb and use the glucose
for energy production. In addition to insulin, it is known that tyrosine kinase receptor is
also involved in glucose homeostasis [143]. Tyrosine residues phosphorylation activates the
insulin receptor substrate proteins (IRS1 and IRS2) and, consequently, regulates the insulin
Molecules 2022, 27, 3294 30 of 44
action [175]. Imbalance in this phosphorylation can lead to defects in the protein signaling
of the IRS1 and IRS2 receptor substrates, leading to insulin resistance [175]. In this context,
phenolic compounds demonstrated that they were able to improve insulin resistance.
6.4. Anti-Inflammatory Properties

Inflammation is a biological process of the immune system in response to infection
or tissue injury. The expression of inflammatory cells, together with the production of
ROS, provides a microenvironment advantageous to cell damage and apoptosis and, conse-
quently, to the development of chronic diseases [176]. Thus, slowing down this process is
essential; therefore, the phenolic compounds have been an alternative to consider [177].
In ancient times, cherry juice was used in the treatment of goats through the inhibition
of inflammatory pathways [39]. In a study conducted by Kelley et al. [178], the effects of
sweet cherries ingestion on plasma lipids and markers of inflammation in healthy humans
was determined. After 28 days, a decrease in C-reactive protein (CRP), nitric oxide (NO),
plasma uric acid, LDL, and TNF-α was verified. Similar results were obtained using Jerte
Valley cherry-based beverage on the inflammatory load of rats and ringdoves, suggesting
that this type of beverage up-regulated the levels of anti-inflammatory cytokines and
down-regulated the levels of pro-inflammatory cytokines [179].
Recently, it was demonstrated that phenolic-targeted fractions of sweet cherry possess
anti-inflammatory activity against RAW macrophages and AGS cells, capturing nitric oxide
(NO), and decreasing NO synthase and cyclooxygenase-2-expression (COX-2) [180]. Similar
results have already been obtained by Seeram et al. [181] when evaluating the effects of
cyanidin alone and with other anthocyanins reported in cherries. The sweet cherries were
able to inhibit COX-1 and COX-2 by an average of 28 and 47%, respectively [181]. Moreover,
it was described that the inhibition of COX of anthocyanins of cherries and raspberries
was analogous to those of some non-steroidal anti-inflammatory drugs (NSAIDs) at 10 µm
concentration [176].
Regarding blueberries, several in vitro studies described the ability to modulate in-
flammatory markers in different types of cells [182–184]. Moreover, 48 patients with a
metabolic syndrome who received a daily dose of 50 g of blueberry powder (equivalent
to 350 g of fresh fruit) for 8 weeks demonstrated improvements in systolic and diastolic
blood pressures [185]. However, the ingestion of 375 g of blueberries by athletic individ-
uals 1 h prior to 2.5 h of treadmill running, for 6 weeks, demonstrated an increase in the
anti-inflammatory regulatory cytokine IL-10 and a decrease in oxidative stress markers,
following exercise [186].
Although cherries and blueberries present a good anti-inflammatory activity, the exact
mechanisms that explain this potential still need to be explored.
7. Impact on Gut Microbiome

In recent decades, the relationship between food, health, and microbiota (mainly
intestinal) has begun to be established, in which the consumption of a “Western diet” based
on foods with a high content of rapidly assimilated sugars, a high quantity of animal pro-
teins and a large proportion of fats produces an imbalance in intestinal populations, with
an alteration of the microbial ecosystem at the population and functional level, resulting in
health problems associated with early inflammatory and degenerative processes [187]. In
the same way, that adherence to a Mediterranean diet, varied in vegetables, legumes, fruits,
meat and fish, allows for maintaining a healthy microbiota with complete functionality asso-
ciated with disease prevention, stimulation of the host’s immune system, neuromodulation,
and improvement in the acquisition of nutrients [188]. These changes in the populations
that make up the different microbiota are mainly associated with the nutritional profile
or nutritional composition of the ingested foods that determine the dominance of one or
another microbial group; therefore, those food constituent compounds that are used by the
beneficial microbiota have been called prebiotics and their consumption is essential in the
establishment and maintenance of a functional microbiota [189,190]. In this way, phenolic
Molecules 2022, 27, 3294 31 of 44
compounds are considered prebiotics. A total of 95% of them overcome the digestive
processes intact and reach the intestine, even the colon, where they are biotransformed by
beneficial species of the microbiome such as Bifidobacterium or Akkermansia. [191].
In this way, the consumption of foods rich in phenolic compounds seems to be a
relevant factor in the dynamics of intestinal populations [192,193]. However, as indicated,
polyphenol-rich beverages based on cherry (sweet cherry or tart cherry) and blueberry
can have different presentations, with concentrations of bioactive compounds and sim-
ple preparations up to fermented preparations that can also affect the composition of
phenolic compounds. In this way, studies related to the influence of the consumption of
functional beverages made from these berries focus mainly on the use of juices or con-
centrates [194–196]. Most of the evidence about beverages rich in phenolic compounds
focuses mainly on wine, grape juice, and beers rich in phenolic compounds, such as toasted
beer [192,197], Although they have a different phenolic profile than what we can find in
beverages made from cherry or blueberry, the greater knowledge about the influence of
these beverages and their catabolism can help us understand the dynamics of the phenolic
compounds that we find in beverages. For example, quercetin metabolized by Eubacterium
oxidoreducens produces a decrease in the Firmicutes/Bacteroides ratio and the abundance
of Erysipelotrichaceae, Bacillus, and Eubacterium cylindroide [198]. In a two-week study
evaluating the consumption of a glass of beer (33 cl), it was observed that the consump-
tion of non-alcoholic beer seems to have less influence on the intestinal microbiota, and
that the consumption of black beer improves the proportion of Akkermansia related with
polyphenols’ catabolism of this bacterial genus [192]. Although other studies analyzing
the consumption of red wine demonstrate that its intake can affect the intestinal micro-
biome but that the metabolic capacities of individuals have a prominent importance in the
modulation of populations, despite finding a homogenizing effect in the consumption of
moderate amounts of this drink rich in phenolic compounds associated with these [193,197].
However, we must consider that the frequent consumption of alcoholic beverages, despite
presenting phenolic compounds that may have positive implications for health, is related to
the increase in the Bacterioides versus Firmicutes ratio, which is not always the appropriate
trend for intestinal populations [198].
Thus, studies regarding the effect of the consumption of functional beverages made
from cherry or blueberry on the intestinal microbiome are quite scarce because these bever-
ages may not be as common as those mentioned, such as red wine and beer. For example,
in a study conducted with adult men, evaluating the consumption of a drink rich in an-
thocyanins with characteristics that could be compared to a blueberry drink, consuming
750 mL/day for 55 days, a change in the microbiota was observed, as well as the function-
ality of it and a modification in the transcriptome of individuals towards the modulation
of oxidative stress [195]. This study observed that the participants who consumed the
beverage rich in anthocyanins increased the proportion of Bacterioides, and when perform-
ing an analysis of the functionality using PICRUSt, an enrichment was observed in the
routes involved in the biosynthesis of phospholipids, metabolism of carbohydrates (starch,
sucrose, frutose, and mannose) and amino acids (proline, arginine, lysine, and alanine). An
increase in the number of pathways associated with DNA repair was also observed [195].
The consumption of powdered drinks based on blueberry, with a consumption of 25 g of
the powdered drink in 250 mL for 6 weeks, generated an increase in the abundance of
Bifidobacterium and Lactobacillus compared to the control group. This fact may be due to
the fact that Bifidobacterium is a bacterial genus that is specialized in the catabolism of a
variety of nondigestible plant polymers, glycoproteins, and glycoconjugates [199].
A study carried out on mice by applying Montmorency tart cherry juice, Balaton
tart cherry juice, and sweet cherry juice for 21 days demonstrated substantial changes in
the concentration of microorganisms, diversity indices, and specific variations associated
with the concentration of the juice used. This study was carried out using five different
concentrations of juice of each of the cultivars used (1/4, 1/7, 1/10, 1/15, 1/20 v/v).
In the case of treatments with tart cherry, there is a decrease in the number of taxa as
Molecules 2022, 27, 3294 32 of 44
the concentration of the juice increases, unlike in the case of sweet cherry where there
is a decrease to intermediate concentrations and then it increases again. Regarding the
alpha diversity indices, this seems to behave in a similar way to the variation in the
number of taxa. Analyzing the taxa detected individually in the three types of juices, a
decrease in the concentration of Firmicutes and an increase in Verrucomicota was observed
as the concentration of juice increased, associated with an increase in Akkermansia and
Barnesiella, as well as a decrease in Bacteroides. It is also noteworthy that no correspondence
was found between the variations in the concentration of Lactobacillus and the different
treatments [196].
For example, some case studies analyze the use of functional beverages fermented
with different microorganisms to improve their qualities; in this way, a synbiotic is achieved,
which is a product that combines the properties of the probiotic and the prebiotic, and
the beneficial properties for the health of the beverage with a high content of phenolic
compounds [191,200]. These beverages are common in some regions such as China and
stand out for a composition of probiotic bacteria and fungi such as Lactobacillus, Issatchenkia,
and Saccharomyces, and the abundance of Lactobacillus and Dekkera was potentially related to
the antioxidant activity of the traditional fermented blueberry beverages [201]. Although
the content of anthocyanins and phenolic compounds are generally affected due to bac-
terial metabolism, a reduction in the former is observed, so a reduction in antioxidant
capacity is expected [202]. In turn, this modification of the properties is associated with
a reduction in the concentration of sugars, reducing the glycemic index [203]. For exam-
ple, Cheng et al. [204] demonstrated that the use of a blueberry drink fermented with
Lactobacillus casei was capable of improving intestinal functions and modifying the intesti-
nal microbiota. In this case, an increase in the proportion of Lactobacillus, Bifidobacterium,
Ruminococcus, Akkermansia, and the butyrate-producing bacteria in a dosage-dependent
manner was observed, accompanied by an increase in the alpha diversity indices. The in-
crease in bacterial species related to the synthesis of butyrate is especially relevant because
there is a relationship between its presence and the reduction of inflammatory processes
at the intestinal and systemic levels [205]. In addition, the increase in the proportion of
Akkermansia and Ruminococcus is related to the improvement in the secretion of the mucus
layer that is reduced by Western diets and is related to the maintenance of better intestinal
function [204]. A positive interaction between the consumption of fermented blueberry bev-
erages for 17 weeks and the modification of intestinal populations, with a reduction in the
abundance of Firmicutes, Oscillibacter, and Alistipes (which are obesity-related bacteria) and
an increase in Akkermansia, Barnesiella, Olsenella, Bifidobacterium, and Lactobacillus relative to
the control based on a high-fat diet. In addition, the consumption of these fermented and
unfermented beverages generated an increase in the alpha diversity of intestinal bacterial
populations [206].
In this way, we can indicate that the consumption of functional beverages based on
cherry and blueberry, with a high concentration of phenolic compounds, has a modulating
effect on intestinal populations, increasing the abundance or proportion of beneficial
genera such as Akkermansia, Lactobacillus, Bifidobacterium, or Ruminococcus, balancing the
Firmicutes/Bacteroides ratio, and generating positive effects at the individual level derived
from the intake of phenolic compounds but also associating with the improvement of
the structure of the microbiome, acting as an efficient and easy-to-administer prebiotic
(Figure 6).
Molecules 2022, 27, 3294 33 of 44
Figure 6. Main effects of functional beverages based on cherry and blueberry in dynamics and
functionality of gut microbiome.
8. Recent Advances and Future Perspectives and Opportunities for

Functional Beverages
In the last decade, functional foods have demonstrated a marked growth. Foods
and functional beverages formulated from natural products have excellent biological
properties, as they are an interesting focus of research and development in the food and
pharmaceutical industries [207]. This demand is due to many factors, such as the increased
concern with health conditions, the awareness of the association between diet and health,
and also busy and unhealthy lifestyles [208]. It is known that the consumption of fruits and
vegetables helps in health promotion and prevention of several diseases, including diabetes,
cardiovascular problems, and cancer [209]. A high standard of lifestyle in cosmopolitan
cities and the concern to mitigate chronic diseases, request greater availability of functional
foods to satisfy these needs [210].
The reduction of 20% in health-care expenses in the ingestion of functional food as one
of the strategies for the public health improvement shows the economic potential of this
type of food [211]. Phenolic compounds, minerals, fibers, vitamins, and probiotic bacterial
strains are some of the components that make a beverage “functional”. New methods
for beverage enrichment with novel constituents through “omics” technologies have been
explored [212]. In addition, the continuous development of the functional beverages market
depends on these products’ present health claims [210]. A health claim can be defined as a
description of what the product does in terms of health, well-being, and performance [213].
The beneficial health effects and detailed information about beverages’ formulation will
influence consumer knowledge and attitude. Moreover, the health claims influence the
purchasing decisions of consumers and help in making more informed choices [214].
Among the different categories of functional foods, beverages are one of the most
active. Easy delivery and storage, a greater possibility of incorporating desirable bioactive
compounds and nutrients, and the ability to respond to the needs of consumers through ap-
pearance, size, shape, and content are key factors for this growing development [210]. The
functional beverages’ industry depends on consumers’ recognition of the linkage between
health and diet. Nowadays, the baby-boom generation that is ageing is willing to buy and
consume products that improve their health. In this context, immunity enhancement has be-
come the main focus of functional beverages producers and consumers [210]. The addition
of bioactive compounds and other functional components, and/or reduction of the other
Molecules 2022, 27, 3294 34 of 44
constituents, such as fat or sugar, are part of the functional foods’ formulations [210]. Thus,
the production and sale of beverages supplemented with probiotics, natural antioxidants,
and red fruits such as cherries and blueberries have been increased [215].
The increase in consumer interest in organic constituents instead of artificial compo-
nents is another advantageous factor for the functional beverage development market [216].
This behavior allows the industry to enhance its products through supplementation with
natural products, namely those based on red fruits, with proven health benefits. Regarding
the positive factors that drive the development of functional drinks, the following should
be highlighted: consumer age, education, decrease in health-care costs, access to informa-
tion, media, nutrition labeling, aroma and texture, mood, beliefs, and appetite [210]. The
adoption and maintenance of a healthy lifestyle have led to an increase in the demand for
functional drinks and, consequently, to the development of new products that meet the
needs of today’s society, satisfying several criteria that make marketing more efficient [211].
In addition, the increase in life expectancy increases the need for a better quality of life
with healthy food choices [211]. Functional beverages such as energetic juices, supple-
mented waters, diet drinks, and antioxidant juices are opportunities for the growth of this
market type.
One of the great future challenges in the functional food market is the lack of an inter-
nationally accepted definition of the functional food and beverage [210]. However, despite
this difficulty, the global value of the functional foods market has been progressively increas-
ing with an average growth rate of 8.5%. U.S. and Japan are the main markets, followed by
Europe [217]. Functional beverages are the fastest-growing sector within functional foods.
According to Bagchi and Nair, 2016 [218], it is estimated that by 2025, functional beverages
will account for 40% of the overall consumer demand. The socio-cultural and economic
differences of consumers also influence the growth of these beverages’ market [210].
The development of new functional beverages and the improvement of existing ones
are other interesting focuses of research and innovation. In recent years, the potential of
probiotics, prebiotics, natural compounds, and by-products of fruits in the production of
new beverages without affecting their functionality has been studied [37]. Fruits-based
beverages, vegetables, cereals, and grapes are examples of functional beverages with several
bioactive compounds [210]. However, it is important to evaluate the interactions between
the various ingredients in the same product. These interactions can result in insolubility,
oxidation, precipitation, degradation, and loss of functionality of the beverage [211]. The
metabolism and bioavailability must be carefully evaluated [219].
Another challenge in the research and development of functional beverages is the
knowledge of the ideal dosage of bioactive or functional constituent to be added. The
main goal is for it to be a sufficient dosage to produce a beneficial effect without negatively
affecting other components of the formulation [210]. On the other hand, it is also essential
to ensure that the compounds will remain intact, active, and bioavailable after process-
ing and storage [220]. In an attempt to improve functional beverages, it is necessary to
improve technology in the production process, such as microencapsulation [208,221] and
metabolomics [222].
Functional beverages with antimicrobial and antioxidant compounds incorporated
are an area to be explored. Bacteriocins, oligosaccharides, and polysaccharides are natural
antimicrobials able to substitute chemical preservatives [223]. These compounds, in addi-
tion to preservative capacity, also possess health-promoting properties [224]. Furthermore,
the phenolic compounds also have excellent health-promoting properties [225].
Finally, the use and valorization of fruit and vegetable by-products have been studied
by several authors [146,226,227]. These bioresidues are very rich in phenolic compounds,
minerals, vitamins, and organic compounds, among others with proven beneficial proper-
ties [228]. These compounds can be explored, as they demonstrate promising potential in
the area of food and functional beverages.
In sum, the development of new functional beverages with new constituents/ingredients
and functionalities can have very promising results for the health of consumers. Further-
Molecules 2022, 27, 3294 35 of 44
more, the demand for products with health-promoting properties will continue to increase.
Despite the challenges and difficulties inherent to beverages and functional food, the help of
new technology and the progress of science in the exploration of new bioactive compounds
are essential for the advancement of this market niche.
9. Conclusions
Functional foods rich in phenolics, including their derivative beverages, seem to be
a promising strategy and an added value in current days. Among fruits, cherries and
blueberries have been a target of many studies, not only owing to their organoleptic
properties, such as color, aroma, and taste, but also due to their effectiveness in reducing
the risk of occurrence of many disorders, attenuating their symptoms and/or retarding
their development. These effects are closely attributed to the ability of their phenolics,
standing out anthocyanins, to counteract oxidative stress and interact with inflammatory
pathways, and in this way, promote a healthy status. Functional beverages possess several
advantages, such as lower price and facility of ingestion. However, more detailed studies,
including clinical trials and stability experiments, need to be conducted to increase their
bioacessibility and reveal the safe and ideal dosage.
Author Contributions: Conceptualization, L.R.S.; methodology, L.R.S., A.C.G., A.R.N. and J.D.F.-F.;
formal analysis, L.R.S. and G.A.; investigation, L.R.S., A.C.G., A.R.N. and J.D.F.-F.; data curation,
L.R.S., A.C.G., A.R.N. and J.D.F.-F.; writing—original draft preparation, L.R.S., A.C.G., A.R.N. and
J.D.F.-F.; writing—review and editing, L.R.S., A.C.G., A.R.N. and J.D.F.-F.; supervision, L.R.S. and
G.A.; project administration, L.R.S. and G.A.; funding acquisition, L.R.S. and G.A. All authors have
read and agreed to the published version of the manuscript.
Funding: This work was partially supported by CICS-UBI (UIDP/00709/2020) and financed by the
National Funds from Fundação para a Ciência e a Tecnologia (FCT), Community Funds (UIDB/00709/
2020) and CENTRO-04-3559-FSE-000162. The authors are grateful to FCT, Ministry of Science, Tech-
nology and Higher Education (MCTES), European Social Fund (EFS) and Europe Union (EU) for the
PhD fellowships of Ana C. Gonçalves (2020.04947.BD) and Ana R. Nunes (SFRH/BD/139137/2018).
José D. Flores-Félix was supported by European Union’s Horizon 2020 research and innovation
programme under the Marie Skłodowska-Curie grant agreement No. 101003373.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.
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Molecules 2022, 27, 3294. https://doi.org/10.3390/molecules27103294 https://www.mdpi.com/journal/molecules

Table 1. The Japanese FOSHU criteria for functional food.

Table 2. The FUFOSE definition of functional food in Europe [13].

Functional foods are:

2. Functional Foods Definition

Table 3. Several definitions of functional foods.

Table 4. Terms linked with functional foods.

Table 5. Categories of functional foods.

3. Fruits and Beverages as Functional Foods

4. An Overview Regarding Cherry and Blueberry Phenolic Compounds

quercetin 3-O-glucuronide, quercetin 3-O-hexoside, quercetin 3-O-rutinoside, quercetin

Focusing on flavan-3-ols (Figure 4A), tart cherry contains (−)-epicatechin (0.0–28.22 mg

Relatively to other non-colored phenolics, vestigial amounts of flavone luteolin, fla-

5. Absorption, Digestion, Metabolism, and Bioavailability of Phenolic Compounds

acids, and flavanols into phenylvalerolactones and hydroxyphenylpropionic acids, and

Figure 5. Schematic representation concerning phenolics’ absorption, metabolism, distribution, and

6. Functional Properties of Cherries and Blueberries—Focus on Antidiabetic and

Phenolic compounds are the predominant bioactive components in cherries and

Table 7. Antidiabetic properties of cherries and blueberries.

6.1. Enzymes’ Inhibition

6.2. Pancreatic β-Cells Protection

6.3. Insulin Release and Regulation

6.4. Anti-Inflammatory Properties

7. Impact on Gut Microbiome

8. Recent Advances and Future Perspectives and Opportunities for

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