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Abstract and Figures

Anthocyanins are biologically active water-soluble plant pigments that are responsible for blue, purple, and red colors in various plant parts-especially in fruits and blooms. Anthocyanins have attracted attention as natural food colorants to be used in yogurts, juices, marmalades, and bakery products. Numerous studies have also indicated the beneficial health effects of anthocyanins and their metabolites on human or animal organisms, including free-radical scavenging and antioxidant activity. Thus, our aim was to review the current knowledge about anthocyanin occurrence in plants, their stability during processing, and also the bioavailability and protective effects related to the antioxidant activity of anthocyanins in human and animal brains, hearts, livers, and kidneys.
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Antioxidants 2020, 9, 819; doi:10.3390/antiox9090819 www.mdpi.com/journal/antioxidants
Review
Anthocyanins: From the Field to the Antioxidants
in the Body
Vidmantas Bendokas
1,
*, Vidmantas Stanys
1
, Ingrida Mažeikienė
1
, Sonata Trumbeckaite
2,3
,
Rasa Baniene
2,4
and Julius Liobikas
2,4,
*
1
Institute of Horticulture, Lithuanian Research Centre for Agriculture and Forestry, 54333 Babtai, Lithuania;
Vidmantas.stanys@lammc.lt (V.S.); ingrida.mazeikiene@lammc.lt (I.M.)
2
Laboratory of Biochemistry, Neuroscience Institute, Lithuanian University of Health Sciences,
44307 Kaunas, Lithuania; sonata.trumbeclaite@lsmuni.lt (S.T.); rasa.baniene@lsmuni.lt (R.B.)
3
Department of Pharmacognosy, Medical Academy, Lithuanian University of Health Sciences,
44307 Kaunas, Lithuania
4
Department of Biochemistry, Medical Academy, Lithuanian University of Health Sciences,
44307 Kaunas, Lithuania
* Correspondence: vidmantas.bendokas@lammc.lt (V.B.); julius.liobikas@lsmuni.lt or
julius.liobikas@outlook.com (J.L.)
Received: 22 July 2020; Accepted: 29 August 2020; Published: 2 September 2020
Abstract: Anthocyanins are biologically active water-soluble plant pigments that are responsible for
blue, purple, and red colors in various plant parts—especially in fruits and blooms. Anthocyanins
have attracted attention as natural food colorants to be used in yogurts, juices, marmalades, and
bakery products. Numerous studies have also indicated the beneficial health effects of anthocyanins
and their metabolites on human or animal organisms, including free-radical scavenging and
antioxidant activity. Thus, our aim was to review the current knowledge about anthocyanin
occurrence in plants, their stability during processing, and also the bioavailability and protective
effects related to the antioxidant activity of anthocyanins in human and animal brains, hearts, livers,
and kidneys.
Keywords: anthocyanin metabolites; antioxidants; cardioprotection; hepatoprotection;
nephroprotection; neuroprotection
1. Introduction
Anthocyanins are pigments belonging to the flavonoid group, which is widely distributed in
plants. They are responsible for blue, purple, and red colors in flowers, fruits, and vegetables and
protect plants from environmental stresses such as high sunlight irradiance [1] or low nitrogen [2].
Chemically, anthocyanins are produced when anthocyanidins are glycosylated. The most abundant
anthocyanidin in plants is cyanidin. Other anthocyanidins are less abundant, and their frequency
decreases in this order: delphinidin, peonidin, pelargonidin, petunidin, and malvidin [3].
Anthocyanidins are flavylium ion derivatives that vary in terms of their substituent groups: –H, –OH, or
–OCH
3
. Usually, anthocyanidins are glycosylated at the C3 or C3 and C5 sites, but the glycosylation
of other sites has also been reported [4]. The biological activity of anthocyanins depends on their
structure; however, all samples, including those with different compositions and amounts of
anthocyanins, extracted from various berries and vegetables, are biologically active [5]. Azevedo et al. [6]
established that the radical scavenging activity and reducing properties of anthocyanins strongly
depend on the chemical structures of particular anthocyanins; this effect increases with the presence
of catechol and pyrogallol groups in ring B of cyanidin-3-glucosides and the respective aglycones.
Antioxidants 2020, 9, 819 2 of 16
Some studies have shown that delphinidin has the highest antioxidant activity compared with the
other five anthocyanidins due to the three hydroxyl groups on the B-ring [5,7]. An increasing body
of evidence shows that anthocyanin intake can have a protective effect on human and animal brains,
hearts, livers, and kidneys, and many of the therapeutic effects may be purported to the antioxidant
activities of anthocyanins and their metabolites [8–12]. The antioxidant activity of these compounds
manifests through direct and indirect methods of action. Thus, anthocyanins can directly scavenge
reactive oxygen species (ROS) [13,14], whereas the indirect pathways involve stimulation of the
synthesis or activity of antioxidant enzymes (catalase, superoxide dismutase (SOD), glutathione
peroxidase) [15]; inhibition of ROS-forming enzymes, such as nicotinamide adenine dinucleotide
phosphate (NADPH) oxidase and others [16,17]; or even mild uncoupling of mitochondrial
respiration preventing ROS generation [9,18]. It can also be assumed that for effective therapeutic
action of anthocyanins, both the ROS scavenging activity and the modulation of cellular antioxidant
systems are required [14]. Here, we review the current knowledge about anthocyanin occurrence in
plants, their stability during processing, and the health benefits to humans and animals.
2. Natural Sources of Anthocyanins
Anthocyanins are natural, water-soluble plant pigments that are responsible for blue, red, or
purple colors in plants. Plant genotypes, agro-climatic conditions, and fruit or vegetable maturity are
significant factors in the composition and quantity of anthocyanins [19]. Therefore, the main sources
of anthocyanins in human diet are fruits and vegetables, which accumulate anthocyanins in both the
peel and flesh; however, their content varies greatly (Table 1).
Table 1. Maximum amount of anthocyanins (mg 100 g1 of fresh weight (FW)) in fruits and vegetables.
Source Anthocyanin amount mg 100 g1
FW Dominant Anthocyanins References
Bilberry 772.4
Dp3gal, Dp3glc, Dp3ara, Mv3glc, Cy3gal, Cy3glc,
Cy3ara [20]
Blackcurrant 478.6 Dp3rut, Cy3rut, Dp3glc, Cy3glc
[21,22] Golden currant 615.5 Cy3rut, Cy3glc, Pn3rut
Redcurrant 66.7 Cy3glc, Cy3rut, Cy3sam
Elderberry 580.0 Cy3sam, Cy3glc [19]
Grapes 116.4 Mv3glc, Cy3glc, Dp3glc, Pt3glc, Pn3glc [23]
Sour cherry 147.0 Cy3rut [24]
Sweet cherry 244.0 Cy3rut, Pn3rut [25]
Wild
strawberry 10.0 Pg3glc, Cy3glc [26]
Black carrot 126.4 Cy3xylglcgal, Cy3xylgal [27]
Eggplant 8.7 Dp3glc, Dp3rut, [28,29]
Red cabbage 23.4 Cy3glc, Cy3rut, Dp3glc, Dp3rut, Cy3diglc5glc [30,31]
Red chicory 39.2 Cy3glc [29]
Purple wheat 23.5 Cy3glc [32]
Cy—cyanidin; Dp—delphinidin; Mv—malvidin; Pg—pelargonidin; Pn—peonidin; Pt—petunidin;
ara—arabinoside; gal—galactoside; glc—glucoside; rut—rutinoside; sam—sambubioside; xyl—
xyloside.
Fruits, especially dark blue berries, accumulate a large total amount of anthocyanins, while
vegetables tend to have lower anthocyanin concentrations. One of the highest anthocyanin
concentrations was identified in bilberries, with delphinidins being the dominant anthocyanins
making up over 57.6% of the total, with cyanidins representing 23.7% and malvidins representing
14.1% of the total [20]. Berries of the golden currant cultivar ‘Corona’ are the richest in anthocyanins
among Ribes spp., with cyanidins being the dominant type [21]. Blackcurrants have a higher
proportion of delphinidins, ranging from 66.7% to 70.2%, as shown in various studies [20,21]. In
contrast, cyanidins dominate in redcurrant, elderberry, sweet cherry, and sour cherry, and
sometimes, they are the only anthocyanins [11,20,22,23] (Mikulic-Petkovsek et al., 2014; Veberic et al.,
Antioxidants 2020, 9, 819 3 of 16
2015; Bendokas et al., 2017, Blackhall et al., 2018). Malvidins are the main anthocyanin in grapes with
a relative content ranging from 35.8% to 67.1% [25].
In terms of vegetables, red chicory has been shown to have the highest concentration of
anthocyanins; however, it is 2–20 times lower than that in berries. Cyanidins are major anthocyanins
in most vegetables; however, eggplant only accumulates delphinidins.
The consumption of anthocyanins varies from 9 mg/day on average in the United States to 19 mg/day
in Europe, but daily consumption may reach 28 mg in some European countries [33]. The main
sources of anthocyanins are berries (39% in the US and 43% in Europe), wine (18% in the US and 22%
in Europe), and fruits (9% in the US and 19% in Europe), with other sources being vegetables and
other foods [34].
3. Stability of Anthocyanins in Foods and Beverages
Anthocyanins are natural plant compounds that are increasingly being used in the food and
pharmaceutical industry due to their effects on human health. However, the low stability of
anthocyanins is still an obstacle to their use [35]. The stability of anthocyanins depends on the pH,
temperature, light, presence of solvents and oxygen, and other factors [36]. Anthocyanins are more
stable under acidic conditions. At a pH of 1.0, flavylium cations are the predominant species and
contribute to the development of purple and red pigments, while at pH 2.0–4.0, the blue quinoidal
species predominates. When the pH value reaches 7.0, anthocyanins are usually degraded [36]. The
storage temperature affects the concentration of anthocyanins in extracts; for instance, 11% of rosella
anthocyanins were lost after storage for 60 days at 4 °C, while 99% of anthocyanins were degraded
in the same extracts stored at 37 °C for the same period [37].
The stability of anthocyanins from various Ribes species was reported to depend on their
composition and storage conditions [24]. Anthocyanins in redcurrant berry extract have been shown
to be more stable at room temperature and in the presence of light than extracts from berries of golden
currant and gooseberry. After the storage of anthocyanin extracts under dark and cold conditions (+4
°C) for 84 days, up to 90% of redcurrant, 80% of gooseberry and golden currant, and up to 50% of
blackcurrant anthocyanins remained intact [24].
Thermal food processing negatively affects the nutritional value of anthocyanin-rich juices as it
results in anthocyanin degradation [38]. Thermal processing is responsible for the loss of up to 35%
of anthocyanins. Even short-term thermal treatment (5 s at 85 °C) resulted in a loss of 9% of
anthocyanins from strawberry juice, while pasteurization for 15 min resulted in a loss of 21% [39].
Boiling of red cabbage resulted in a loss of 41.2% of anthocyanins, while the anthocyanin
concentration remained the same after steaming or stir-frying. Possibly, as highly water-soluble
pigments, anthocyanins may be lost by leaching in the case of boiling [30].
Various anthocyanin stabilization methods are being developed. For instance, the improvement
of anthocyanin thermal stability by yeast mannoproteins at pH 7.0 has been studied. The complexes
were found to effectively protect anthocyanins from degradation during heating at 80 and 126 °C
[40]. Mixing of clarified acerola juice with montmorillonite resulted in 50% more anthocyanins,
regardless of time or pH changes [41]. Copigmentation is another natural tool that can be used to
enhance anthocyanin stability. The most studied copigments are phenolic acids such as
hydroxycinnamic and hydroxybenzoic acids [42]. Babaloo and Jamei [43] established that caffeic acid
provides more stability for anthocyanins than benzoic, tannic, and coumaric acids. Encapsulation
with polysaccharides, such as β-cyclodextrin, maltodextrin, or Arabic gum, is also important for the
stabilization of anthocyanins. The protective effect of β-cyclodextrin was evident for all blackberry
anthocyanins after thermal treatment at 90 °C for 2 h [44].
Novel techniques for phenolic compound isolation from natural products that avoid the
degradation of these compounds have been developed. Block freeze concentration has been
employed to extract anthocyanins from strawberries and enrich yogurt with the obtained
concentrated strawberry juice. As a result, yogurt with a high anthocyanin content and greater
antioxidant activity was produced; however, it had a short shelf life [45]. The foam mat drying
technique is now considered to be an effective dehydration method to produce powder from juices
Antioxidants 2020, 9, 819 4 of 16
or pulp. Only a small reduction in anthocyanins (7–9%) was observed after the storage of jambolana
juice powder produced by foam mat drying for 150 days [46]. When foam-mat freeze-drying was
used for powder production from blueberry juice, 80–100% of anthocyanins remained after
processing; the most stable was Cy3glc [47].
4. Bioavailability of Anthocyanins
The beneficial health effects of anthocyanins strongly depend on their bioavailability, as only a
small fraction of anthocyanins is absorbed by human body [48,49]. The concentration of anthocyanins
in the plasma reaches a maximum value within 0.5–2 h after the consumption of anthocyanin-rich
foods [50]. A low concentration of anthocyanins in plasma and urine has been observed in several
studies. Less than 2% of original anthocyanins may be found in the plasma or urine after
consumption; however, anthocyanins go through several transformations in the small and large
intestines; thus, only a small fraction of the anthocyanins remains nonmetabolized or catabolized [51].
Mueller et al. [52] stated that a complex mixture of anthocyanin metabolites in the plasma rather than
a single type of anthocyanins may cause beneficial effects in humans.
Gamel et al. [32] evaluated the absorption of anthocyanin metabolites after the consumption of
purple wheat crackers and bars. They established that the total concentration of anthocyanin
metabolites in urine peaked at 0–2 and 2–4 h, with 18–22 ng/mL excreted on average. For both
products, the total amount of accumulated anthocyanins reached 13 µg in 24 h, representing 0.19%.
A significant difference between male and female participants was also observed: males excreted 17.1 µg,
while females excreted 11.6 µg of anthocyanin metabolites in a 24-h period. Krga and Milenkovic [53]
conducted a comprehensive analysis of 20 studies on the anthocyanin concentration in human plasma
after the ingestion of food, extracts, and drinks. They found that anthocyanin adsorption was the
fastest after drinking red wine and red grape juice. The maximum concentration in the plasma was
reached in 0.3 and 0.5 h, respectively, while the maximum concentration of anthocyanins from
blueberry powder was reached in 4 h. Interestingly, the maximum anthocyanin concentration in
plasma varied from 1.4 to 591.7 nM and did not depend on the administered dose, which was possibly
due to differences in the anthocyanin composition in various foods. Recently, a human pilot study
was performed by Röhrig and colleagues [54] on five healthy male volunteers who were consuming
anthocyanin-rich blackcurrant extract. They studied the kinetics of the dominant anthocyanins—
Dp3rut and Cy3rut—in plasma and urine after the consumption of blackcurrant extract. The peak
concentrations of both anthocyanins in plasma were reached within 2 h after consumption. The
maximum concentrations were 8.6 ± 5.8 nmol/L for Dp3rut and 9.8 ± 3.1 nmol/L for Cy3rut, which
later gradually decreased. Similarly, urinary excretion rates of both studied anthocyanins peaked
within 02 h of ingestion and reached 20.0 ± 2.6 nmol/h (Dp3rut) and 21.2 ± 3.8 nmol/h (Cy3rut). The
total excreted amount was calculated: 0.040% (Dp3rut) and 0.048% (Cy3rut) of the ingested doses. In
addition, after consumption of the anthocyanin-rich extract, the concentration of the main metabolite,
protocatechuic acid, increased significantly [54].
In humans, anthocyanins consumed with food may be digested in the gastrointestinal tract,
absorbed into the blood, and later metabolized [55]. Some studies have stated that minute amounts
of anthocyanins are absorbed in the small intestine. The majority of ingested anthocyanins reach the
large intestine where they are metabolized [56] and where structural modifications (deglycolysation,
degradation, hydroxylation, etc.) take place due to the changing physiological conditions.
Anthocyanins can also be further modified by various enzymes in the small intestine before entering
the bloodstream [57]. Twenty-two metabolites of Cy3glc were identified using an isotopic approach
[58]. Among them, phloroglucinaldehyde, 3,4-dihydroxybenzaldehyde, and hydroxybenzoic acid
were found to be produced as phase I metabolites, while the phase II metabolites identified were
mainly glucuronidated and methylated cyanidins. Colonic anthocyanin metabolites included
hydroxybenzoic acid, hippuric acid, phenylpropenoic acid, ferulic acid, and phase II protocatechuic
acid conjugates [58–60]. Bresciani and colleagues [61] analyzed the catabolism of anthocyanin-rich
elderberry extract with different gut microbial strains in vitro and established that their metabolic
pathways were different. Some common metabolites were found among all studied strains; however,
Antioxidants 2020, 9, 819 5 of 16
each of them had several phenolic metabolites produced specifically by that strain. These in vitro
results could provide new knowledge of the variability in anthocyanin metabolism in different
organisms. After absorption, the fast transport of anthocyanins and their metabolites to the liver,
heart, lungs, brain, and kidneys may be observed [55,62].
Sandoval-Ramírez and colleagues [63] summarized studies on the anthocyanin concentration in
various animal tissues and stated that in short-term experiments, after a single dose of bilberry
extract, the highest concentration of cyanidin-3-O-glucoside (40.46 pmol/g) was found in the brain
after 0.25 min [62]. In addition, Cy3glc was identified in other tissues, such as the gastrointestinal
tract (8 × 105 pmol/g), lungs (5.19 × 104 pmol/g), and prostate (4 × 104 pmol/g), with peak
concentrations occurring at different times after a single oral dose of the extract [63,64]. In long-term
studies, the highest concentration of Mv3glc (4.43 pmol/g) was established in the brains of pigs, while
the concentration of Pt3glc reached 6.66 pmol/g [63]. Cy3ara from tart cherry was identified in the
hearts, brains, livers, kidneys, and bladders of Wistar rats; however, its concentration was low and
ranged from 2.28 × 104 to 1.16 × 103 pmol/g [65]. In general, Cy3glcand its metabolites are the most
abundant anthocyanins in animal tissues, and Cy3glcmay be one of the most promising bioactive
molecules for human health [63]. It is also worth noting that care is needed to avoid artefacts when
studying and evaluating antioxidant effects of bioavailable anthocyanins in model organisms and the
human body, as findings can depend on the chosen marker, the sensitivity of method to detect ROS
and to measure oxidative damage, or even on the changes in plasma urate concentrations [66]). It is
not the aim of the present review to analyze the suitability of methods to evaluate the antioxidant
activity of anthocyanins; thus, for the complexity of the matter, one could consult several excellent
reviews[66–70].
5. Biological Effects Related to the Antioxidant Activity of Anthocyanins—In Vivo Studies in
Model Organisms
5.1. Neuroprotection
At the animal level, oral administration of anthocyanin-rich berry extract of Vaccinium myrtillis
L. (100 mg/kg for 7 days) has been shown to suppress psychological stress-induced cerebral oxidative
stress and dopamine abnormalities in distressed mice [71]. Anthocyanins extracted from black
soybeans have also been demonstrated to reverse D-galactose- or lipopolysaccharide (LPS)-induced
oxidative stress, neuroinflammation, and neurodegeneration in adult murine models [72–74].
Likewise, the same anthocyanins were shown to reduce elevation of the ROS level and consequent
oxidative stress induced by the amyloid beta oligomer (Aβ 1-42) through stimulating the intracellular
antioxidant system (the transcription factor E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1)
pathways). These anthocyanins also prevented apoptosis and neurodegeneration by suppressing the
apoptotic and neurodegenerative markers in the amyloid precursor protein/presenilin-1 (APP/PS1)
mouse model of Alzheimer’s disease (AD) [75].
Positive findings have also been reported by Qin et al. [76] in Cy3glc-treated (10 mg/kg for 30 days)
rats injected with Aβ 1-42, which showed an attenuation of Aβ- and oxidative stress-induced GSK-
3β hyperactivation and hyperphosphorylation of the tau protein. These findings are in agreement
with a study in which rats were injected with Aβ 1-42 bilaterally into the hippocampal CA1 area in
order to produce an animal model of AD [77]. It was observed that the memory impairment was
reduced in rats that received 80 mg/kg of Lycium ruthenicum Murr. anthocyanin-rich extract in
comparison to other AD model rats. Moreover, the anthocyanin extract enhanced the activities of
total SOD and catalase and increased the glutathione concentration in serum and brain tissues.
Chen et al. [78] also confirmed that Lycium ruthenicum Murr. anthocyanins can exert
neuroprotective effects in D-galactose (D-gal)-treated rats. Anthocyanins reduce the level of receptor
for advanced glycation end products (RAGE), suppress oxidative stress, and reduce levels of
inflammation markers such as nuclear factor kappa B (NF-κB), interleukin-1-β (IL-1β),
cyclooxygenase-2 (COX-2), and tumor necrosis factor-α (TNF-α), among others. Sustained levels of
antioxidant enzymes (SOD and catalase), a decreased concentration of the lipid peroxidation product
malondialdehyde, and significantly decreased expression of aging-associated monoamine oxidase-B
Antioxidants 2020, 9, 819 6 of 16
in D-gal-treated mice were also demonstrated after the administration (30 mg/kg and 60 mg/kg) of
black rice anthocyanins [79]. Anthocyanins from fruits of Aronia melanocarpa (Michx.) Elliot (30
mg/kg) retained the levels of total SOD and glutathione peroxidase and inhibited the excessive
accumulation of inflammatory cytokines in the brain tissue of D-gal-treated mice [80]. Furthermore,
recently, a study using a model of streptozotocin-induced dementia of sporadic AD [81] proposed
that pretreatment with a commercial anthocyanin extract from grape skins (200 mg/kg for 25 days)
can prevent behavioral alterations and protect against the changes in ROS and antioxidant enzyme
(SOD, catalase, and glutathione peroxidase) levels.
Notably, purified anthocyanins and anthocyanidins have also been found to exert
neuroprotective activities. For instance, pre-treatment with pelargonidin (Pg) (20 mg/kg) significantly
suppressed the formation of thiobarbituric acid reactive substances, indicating reduced lipid
peroxidation in 6-hydroxydopamine-lesioned rats (an experimental model or Parkinson’s disease)
[82]. Furthermore, orally consumed Cy3glc (2 mg/kg) reduced brain superoxide levels, infarct size,
and improved neurological functions, thus revealing a neuroprotective effect in the cerebral artery
occlusion model of ischemia in mice [83]. A recent report [84] also showed that an intravenous
injection of Cy3gal and Cy3glc (0.025 mg/kg and 0.05 mg/kg), but not Cy3rut, in rats protected against
ischemia-induced caspase-3 activation and necrotic cell death, as well as reducing the infarct size in
the cerebral cortex and cerebellum. In contrast, 0.025 mg/kg of Pg3glc had no effect of the activity of
caspase-3 but reduced the infarct size. The effects of anthocyanins have been found to correlate with
the cytochrome c reducing capacity, and Pg3glc has been shown to have the smallest effect among
tested anthocyanins. Thus, authors have proposed that under certain conditions, such as ischemic
brain damage, the reducing properties rather than antioxidant properties of anthocyanins might be
important in providing neuroprotection.
5.2. Cardioprotection
Since it is known that bilberries and blackcurrant berries are rich in anthocyanins, Brader et al.
[85] investigated the effects of a berry-enriched diet (5 g of berry powder containing 172 mg of
anthocyanins per day) on lipid profiles and other biomarkers in Zucker diabetic fatty rats. The results
after eight weeks of supplementation demonstrated reduced levels of total and LDL-cholesterol,
which was partly due to the altered expression of hepatic liver X receptor-α. Using an in vivo model
of coronary occlusion and reperfusion, another study showed that the infarct size was reduced in the
hearts of rats that received a long-term purple maize anthocyanin-enriched diet (with Cy and Pg
glycosides as the main components) [86]. The authors proposed that the observed cardioprotection
could be associated with increased myocardial glutathione levels and thus an improved endogenous
cardiac antioxidant defense system. Moreover, Ziberna et al. [87] demonstrated that bilberry
anthocyanins could exert concentration-dependent responses on whole rat hearts under ischemia–
reperfusion (I-R) conditions. Thus, at low concentrations (0.01–1 mg/L, expressed as Cy3glc
equivalents), the extent of I-R injury was significantly reduced, whereas at 5–50 mg/L, anthocyanins
showed cardiotoxic activity despite having an intracellular antioxidant capability that increased in a
concentration-dependent manner.
In addition, recent evidence from an LPS-induced myocardial injury model in mice [88] showed
that pure anthocyanins such as Cy3glc could restore the activity of the mitochondrial electron
transport chain (namely, the activity of complexes I and II) and thus significantly attenuate ROS
production. Furthermore, the anthocyanins ameliorated cardiac injury, cell death, and improved
cardiac function. It is worth noting that Cy3glc also suppressed the expression of endotoxin-induced
pro-inflammatory cytokines and the level of protein nitration while elevating the intracellular level
of reduced glutathione.
In general, these observations suggest that the cardioprotective activities of anthocyanins may
not be solely attributed to their antioxidant properties; therefore, a broader view should be
implemented [18,87,89,90].
5.3. Hepatoprotection
Antioxidants 2020, 9, 819 7 of 16
The liver plays an important role in the metabolic elimination of drugs and toxic compounds
known to cause injury and reduce the function of the liver. Arjinajarn et al. [91] observed that rice
bran extract (250–1000 mg/kg) rich in Cy3glc and Pn3glc (13.24 and 5.33 mg/g of crude extract,
respectively) significantly prevented gentamicin-induced intoxication of the liver. It has been shown
that an anthocyanin-rich extract significantly reduced the hepatic malondialdehyde level (a
biomarker for oxidized lipids), increased expression of the antioxidant enzyme SOD, and prevented
elevation of levels of liver injury markers, namely alanine and aspartate aminotransferase. These
effects were related to the suppression of both the oxidative pathway regulated by the transcription
factor Nrf2 and the inflammatory pathway regulated by NF-κB. The authors proposed that Cy3glc,
the major anthocyanin in this extract, is responsible for these antioxidant and anti-inflammatory
properties [91]. Moreover, Hou et al. found that black rice bran extract, which is rich in anthocyanins
(mainly Cy3glc and Pn3glc), protected mice liver intoxicated with carbon tetrachloride (CCl4) [87]. It
was found that mice treated with black rice extract (200–800 mg/kg) showed increased SOD and
glutathione peroxidase activities and increased levels of reduced glutathione as compared with a
CCl4-intoxicated model group [92]. Similar results about the protective effects of blueberry
anthocyanin extract (anthocyanin content up to 25%) on CC14-induced liver injury in mice in vivo
were presented by [93]. The extract had reduced concentrations of alanine aminotransferase,
aspartate aminotransferase, and malondialdehyde in a dose-dependent manner, while the activities
of SOD, catalase, and glutathione reductase increased [93]. Blackberry fruit extract was similarly
shown to attenuate lipid peroxidation and to recover the activity of antioxidant enzymes in CC14-
treated rats [94]. Recently, Sun et al. observed that anthocyanins from blueberry (100 mg/kg and 200 mg/kg
per day) protected mouse liver from CCl4-induced hepatic fibrosis [95]. It was detected that blueberry
anthocyanins reduced ROS generation and tissue oxidative damage, decreased inflammation, and
suppressed the activity of hepatic stellate cells. Interestingly, the activity of mitochondrial electron
transport chain complexes I and II was also restored after treatment with anthocyanins [95].
It is also known that liver inflammation and an excessive accumulation of lipids play critical
roles in the pathogenesis of alcoholic liver diseases. Accordingly, in a recent study, Cy3glc extracted
from Lonicera caerulea L. was shown to exert a hepatoprotective effect on alcoholic steatohepatitis in
mice [96]. Zuo et al. detected substantial decreases in serum aminotransferases and triglycerides and
found increased albumin levels after treatment. In addition, anthocyanidins significantly suppressed
the expression of SREBP1 (a transcription factor involved in lipogenesis) and enhanced the
phosphorylation of AMPK as compared with chronic ethanol administration. Cy-3-g suppressed
inflammasome activation, thereby preventing activated macrophages from producing pro-inflammation
cytokines [96]. Moreover, another study demonstrated that a phenolic fraction of Lonicera caerulea L.
ameliorated inflammation and lipid peroxidation by upregulating Nrf2 and SOD and
downregulating the transcription factor forkhead box protein O1 and HO-1 in a mouse model of
nonalcoholic steatohepatitis (NASH) induced by a high-fat diet in combination with CCl4 [97]. Prokop
et al. also showed in vivo that a blue grain bread wheat-based diet (genotype UC66049, containing
121 mg of Cy3glc per kg of wheat) increased the activity of the microsomal xenobiotic-metabolizing
system cytochrome P450 by 20–50% in rats after 72 days of intake. In addition, an anthocyanin-rich
diet significantly increased the antioxidant power of plasma as shown by a FRAP assay and the level
of total –SH groups in plasma when compared with the control [98].
5.4. Nephroprotective Effects
Anthocyanins are considered to be a functional food factor and to play an important role in the
prevention of kidney diseases. For example, a recent study [99] investigated the effects of
anthocyanin-rich bilberry extract (200 mg/kg daily) on the antioxidant status of animals intoxicated
with CCl4. Rats received the extract orally for 7 days, and on the last day, a single dose of CCl4 was
intraperitoneal (i.p.) injected. It was found that pretreatment with the anthocyanin-rich extract
resulted in a significant reduction in pro-oxidative (H2O2, oxidized glutathione, xanthine oxidase)
and pro-inflammatory markers (myeloperoxidase, nitric oxide, and TNF-α), and a substantial
increase of antioxidant enzyme levels (catalase, SOD, glutathione peroxidase, and S-transferase).
Antioxidants 2020, 9, 819 8 of 16
Moreover, the anthocyanins significantly reduced the degree of damage to the proximal and distal
tubules in the kidney cortex [99].
Positive findings have also been reported by another study [100]. It showed that the
administration of Malva sylvestris L. extract (200 or 400 mg/kg) rich in anthocyanins reduced the renal
toxicity induced by gentamicin and thus led to (i) an improvement in kidney function, (ii) a decrease
in the expression levels of pro-inflammatory markers (TNF-α), (iii) a reduction in oxidative stress
(levels of malondialdehyde and total antioxidant capacity), and (iv) a decrease in tissue injuries.
Similar beneficial effects of the bilberry diet (100 mg/kg daily) on the levels of serum
malondialdehyde, catalase, and advanced oxidation protein products were demonstrated in a rat
model of gentamicin-induced nephrotoxicity, and the effects correlated well with the antioxidant
activity (assessed in vivo and in vitro) as well as with high anthocyanin levels [101]. It is worth noting
that anthocyanin-rich fruits of Panax ginseng Meyer have also been shown to attenuate cisplatin-induced
elevations in blood urea nitrogen and creatinine levels as well as the prevalence of histopathological
injuries in mice [102]. The positive outcomes are related to reduced levels of malondialdehyde, HO-1,
cytochrome P450 E1, 4-hydroxynonenal, TNF-α, and IL-1β, as well as concomitantly increased levels
of reduced glutathione, catalase, and SOD.
In addition, Lee et al. [103] recently revealed that intravenously administered pure Pg (0.4 mg/kg)
could modulate renal function in a mouse model of sepsis. Treatment with Pg reduced renal tissue
injury, plasma nitrite and nitrate production, and TNF-α, IL-6, myeloperoxidase, and
malondialdehyde levels. The total glutathione content as well as the activity of antioxidant enzymes
such as SOD, glutathione peroxidase, and catalase in kidney tissues were also found to be restored
after Pg injection.
6. Biological Effects Related to the Antioxidant Activity of Anthocyanins—In Vivo Studies in
Humans
Epidemiological and clinical studies suggest that an anthocyanin-enriched diet may lower levels
of certain oxidative stress biomarkers in humans, and this could be associated with reduced risk of
cognitive decline and the development of neurodegenerative and cardiovascular diseases, as well as
having sustained hepatic function and kidney protecting activities [12,104–115].
6.1. Antioxidant and Anti-Atherosclerogenic Effects
A randomized clinical trial [116] evaluated the effects of a standardized maqui berry (Aristotelia
chilensis (Mol.) Stuntz) extract (containing 162 mg of anthocyanins) on products of lipid peroxidation
in healthy, overweight, and smoker adults. The results suggested that supplementation with the
extract can be related to a limited term (max for 40 days) reduction in oxidized low-density
lipoprotein (LDL) levels and a decrease in urinary F2-isoprostanes. Another study [117] concluded
that the acute consumption of anthocyanin-rich red Vitis labrusca L. grape juices could be related to
decreased levels of thiobarbituric acid reactive substances and lipid peroxides in the serum of healthy
subjects. It has also been demonstrated that regular (for 30 days) anthocyanin-rich sour cherry
consumption could suppress the formation of ROS by circulating phagocytes and decrease the risk
of systemic imbalance between oxidants and antioxidants [118]. It is worth noting that a portion (300 g) of
blueberries, the dietary source of anthocyanins provided to young volunteers involved in a
randomized cross-over study, significantly reduced H2O2-induced DNA damage in blood
mononuclear cells [119]. In another human pilot intervention study, the consumption of anthocyanin-
rich bilberry (Vaccinium myrtillius L.) pomace extract was found to modulate transcription factor E2-
related factor 2 (Nrf2)-dependent gene expression in peripheral blood mononuclear cells [120].
A single-blind randomized placebo-controlled intervention trial, which lasted for 8 weeks and
involved 72 unmedicated subjects, revealed that the administration of various berries (including
bilberries, chokeberries, and blackcurrants) increased both the concentration of high-density
lipoprotein (HDL) cholesterol and the plasma antioxidant capacity [121]. Higher dietary anthocyanin
and flavan-3-ol intake was associated with anti-inflammatory effects in 2375 Framingham Heart
Study Offspring Cohort participants [122]. Interestingly, the consumption of 300 mL of red wine (a
Antioxidants 2020, 9, 819 9 of 16
total dose of anthocyanins was 304 µM, which was the highest amount among detected compounds)
with a meal was shown to prevent the postprandial increases in plasma lipid hydroperoxides and
cholesterol oxidation products and therefore protect against a potential pro-atherosclerogenic effect
[123]. Similar findings were obtained in a randomized cross-over trial, which concluded that a
moderate consumption of red wine decreases erythrocyte SOD activity [124]. In another randomized
double-blind trial, 150 subjects with hypercholesterolemia consumed a purified anthocyanin mixture
derived from bilberries and blackcurrants (320 mg/d) for 24 weeks [125]. It was found that
anthocyanin consumption significantly decreased the levels of inflammatory biomarkers (C-reactive
protein, soluble vascular cell adhesion molecule-1, and plasma IL-1β) and increased the HDL
cholesterol level. Recently, it was shown that a daily intake of 150 g of anthocyanin-rich blueberries
resulted in clinically relevant improvements in endothelial function and systemic arterial stiffness,
which was probably due to the improved nitric oxide bioactivity and HDL status [126].
6.2. Hepatoprotective Benefits
Nonalcoholic fatty liver disease (NAFLD), defined by excessive lipid accumulation in the liver,
is the hepatic manifestation of insulin resistance and metabolic syndrome. NAFLD encompasses a
wide spectrum of liver diseases ranging from simple uncomplicated steatosis to steatohepatitis,
cirrhosis, and hepatocellular carcinoma [106]. Zhang et al. [127] reported that anthocyanins extracted
from bilberry and blackcurrant (320 mg/day) and administered for 12 weeks ameliorated liver injury
in patients with NAFLD. It was observed that a so-called “anthocyanin group” exhibited significant
decreases in the plasma alanine aminotransferase, cytokeratin-18 M30 fragment, and
myeloperoxidase levels. It was also found that consumption of Myrica rubra Sieb. and Zucc. juice (250 mL
for 4 weeks) protected young adults (18–25 years old) against NAFLD by improving the plasma
antioxidant status and inhibiting the inflammatory and apoptotic responses involved in this disease [128].
6.3. Nephroprotection
In another study, red fruit juice (40% red grape juice, 20% blackberry juice, 15% sour cherry juice,
15% blackcurrant juice, and 10% elderberry juice) with high polyphenol and anthocyanin contents
was tested for its preventive potential in hemodialysis patients [129]. For this purpose, 21 subjects
consumed 200 mL/day of juice according to the following protocols: 3-week run-in; 4-week juice
uptake; 3-week wash-out. The results revealed a significant decrease in DNA oxidation damage and
protein and lipid peroxidation and an increase in the reduced glutathione level; the effects were
attributed to the high anthocyanin and polyphenol contents of the juice [129]. Another study [130]
demonstrated that the regular consumption of concentrated red grape juice by hemodialysis patients
could be associated with the reduced neutrophil NADPH oxidase activity and plasma concentrations
of oxidized LDL and inflammatory biomarkers.
7. Concluding Remarks
In conclusion, anthocyanins are valuable biomolecules with a broad variety of biological effects
on human health, and we suggest adding more anthocyanin rich fruits, vegetables, and their products
to the daily diet. Numerous studies indicate that bilberry, blackcurrant, elderberry, and other berries
have the highest total concentrations of anthocyanins; therefore, the consumption of fresh berries and
their processed products may have greater beneficial effects on humans. Various anthocyanin
stabilization methods have been developed e.g., copigmentation with other phenolic acids,
encapsulation with polysaccharides, block freeze concentration, and powder production using the
foam mat drying technique. All of them enable anthocyanins to be preserved during processing, thus
increasing their bioavailability and delivery to target tissues in the human body. However, long-term
studies on the impacts of anthocyanin-rich product consumption on human health are still rare.
Further studies could focus on the identification and tracking of individual anthocyanin metabolites
and on the determination of the exact dosage and delivery platforms sustaining the antioxidant
Antioxidants 2020, 9, 819 10 of 16
properties of anthocyanins in vivo. In addition, as an alternative to natural sources, synthesis of the
most bioactive anthocyanins in bioreactors should be considered.
Author Contributions: Original idea and conceptualization V.S. and J.L., original draft preparation V.B., V.S.,
I.M., S.T., R.B. and J.L., review and editing V.B., I.M. and J.L. All authors have read and agreed to the published
version of the manuscript.
Funding: This research was funded by the Research Council of Lithuania (V.B., V.S. and J.L.; No. SVE-11-008).
J.L. was supported by the COST Action FA0602 «Bioactive food components, mitochondrial function and
health». J.L. and S.T. are supported by the program «2014-2020 Investment of EU Funds in Lithuania: Intellect.
Common Scientific and Business Projects» (project No J05-LVPA--K-03-0117).
Conflicts of Interest: The authors declare no conflict of interest.
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