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Phenolic
Compounds Class Compounds Role In Diabetic Complications References
Fisetin (Flavonol) Diabetic neuropathy modulation by improved motor nerve conduction velocity and reduced
inflammation in sciatic nerves by nuclear factor kappa B inhibition and nuclear erythroid 2-related
factor 2-positive modulation
[39]
Quercetin (Flavonol) Reduced pancreatic tissue MDA levels, serum nitric oxide concentrations, increased superoxide
dismutase, glutathione peroxidase, and catalase enzyme activation in pancreatic homogenates, and
preserved pancreatic β-cell integrity
[40]
Total green tea extract (Flavanol) Reduced fasting blood glucose level, increased total antioxidant capacity and thiol groups in blood [41]
Cocoa (Flavanol) Decreased fasting plasma glucose, glycosylated hemoglobin, and blood pressure levels [42]
Hesperidin (Flavanone) Attenuated streptozotocin-induced neurochemical alterations, increased norepinephrine,
dopamine, and serotonin levels, decreased MDA, increased reduced glutathione, and decreased
interleukin-6 in the brain
[43]
Genistein (Isoflavone) Reduced hyperglycemia, improved cognition by restoring acetylcholinesterase activity and ameliorated
neuroinflammation via decreasing tumor necrosis factor-alpha, interleukin-1β, and nitrites in brain
[44]
Cyanidin, delphinidin, petunidin,
peonidin, malvidin extract
(Anthocyanidins)
Reduced fasting plasma glucose and glycosylated hemoglobin levels, elevated serum adiponectin
and β-hydroxybutyrate concentrations, improved dyslipidemia, enhanced antioxidant capacity
measured in plasma
[45]
Cyanidin-3-glucoside, delphinidin-
3-glucoside, and petunidin-3-
glucoside extract (Anthocyanins)
Decreased fed blood glucose, triglycerides levels, enhanced glucose transporter-4 expression and
insulin receptor phosphorylation in heart and skeletal muscle, protected pancreatic tissue of
apoptosis through regulation of caspase-3, B-cell lymphoma protein 2-associated X, suppressed
MDA levels, and restored superoxide dismutase and catalase activities in serum
[46]
Cyanidin 3-rutinoside, cyanidin
3-glucoside, pelargonidin
3-glucoside and pelargonidin
3-rutinoside extract
(Anthocyanins)
Reduced fasting blood glucose, maintains insulin levels and β cell histology [47]
Delphinidin and cyanidin extract
(Anthocyanidins)
Decreased fasting blood glucose levels and improved glucose tolerance [48]
Cyanidin extract (Anthocyanidins) Inhibited intestinal α-glucosidase activity and decreased post-prandial glycemic response, delayed
absorption of carbohydrates
[49].
Table 6.3 (Continued)
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6.4 Nutraceutical Benefits of Polyphenols 119
Figure 6.2 Mechanisms for the antioxidant activity: (a) hydrogen atom transfer (HAT), (b) single electron
transfer (SET), and (c) transition metal chelation (TMC). Adapted from Ref [54].
Munin and Edwards-Lévy [1] mention the inhibition potential of PPH ROS-generating enzymes,
such as xanthine oxydase [56], cyclooxygenase, and lipoxygenase [57], by complexing the protein.
This process of PPH complexation is influenced by some protein characteristics such as [58–60]:
● Solubility
● Molecular mass
● Hydrodynamic volume
● Isoelectric point
● Amino-acid composition
Some PPH characteristics also affect their protein complexation ability such as [20, 61–63]:
● Molecular weight
● Chemical structure
● Conformational flexibility
● Water solubility
The physicochemical conditions of the mean properties (pH, solvent, temperature, ionic strength,
presence of organic molecules such as polysaccharides) must also be considered [64–67].
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6 Polyphenols in Food Products – Nutraceutical Applications
120
6.4.3 Against Degenerative Diseases
Neurodegenerative diseases are caused by the damage or loss of the expected function of neurons,
provoking misfunction in the cognitive functions, motor functions, or both. Many of these diseases
accomplish aging, despite the fact that the conditions are expected to appear throughout the life-
time. A continuous increase in dementia cases between 2005 and 2030, reaching approximately
50% of the aged population, is predicted [68, 69].
Although there are no treatments beyond the attenuation of symptoms, many neurodegenerative
diseases share common mechanisms of neuroinflammation and oxidative stress [70–72] against
which PPHs are known to have activity. There is consensus that diet, both in the form of natural or
processed foods and in the form of supplements, plays an important role in neuroprotection [73,
74]. Resveratrol (Table 6.1), which attenuate neuron degradation [75, 76], has been investigated for
its antioxidative properties and has been prescribed as a supplement against neurodegenerative
conditions with low adverse effects [77]. PPHs, such as flavonoids, can reach the brain [78], and
epigallocatechin gallate (EGCG) has been proven to be able to significantly cross the human blood–
brain barrier and protect cortical neurons from oxidative stress induced apoptosis [79].
The accumulation of free radicals in the tissues of the central nervous system, as well as the pres-
ence of high levels of metal ions (mainly iron), have been recognized as the main etiological cause
of Parkinson’s disease (PD) [55], Alzheimer’s diseases (AD), and Huntington’s chorea [80–82]. A
correlation between basal ganglia ferritin iron content and the occurrence of AD has been described
[83, 84]. The content of Fe(III) and hydroxyl radicals in degenerating zones of the brain is probably
because of Fenton reactions [85–87].
6.5 Isolation Methods of Polyphenols from Food Products
Isolating PPHs from plants may be difficult; phenolic compounds can be found in plant matrices
in two forms, extractable polyphenols (EEPs) and non-extractable polyphenols (NEPs), or bound
polyphenols [20]. EEPs do not interact with other plant macromolecules and can be easily extracted
after plant tissue disruption, and NEPs can be found crosslinked to cellulose, pectin, hemicellu-
lose, lignin, and rod-shaped structural proteins [88], or entrapped within the food matrix [89].
NEPs cannot usually be extracted with water or mixtures with the most common organic solvents,
which makes the use of classic chromatographic techniques impractical. In this scenario, alterna-
tive methods, such as high-speed counter current chromatography and microwave-assisted extrac-
tion, may be feasible.
6.5.1 Chromatographic Methods
A chromatographic technique with great applicability in the isolation of PPHs is high-speed coun-
ter current chromatography (HSCCC) based on continuous liquid–liquid partitioning, which elim-
inates irreversible adsorption on solid supports [90]. Partitioning of the solute between two
non-mixable solvents (stationary and mobile phases) is achieved through hydrodynamic motion in
a rotating coiled tube [91].
This technique combines the absorption of two liquid solvents, intensified by constant agitation,
with different interactions between the solute and mobile and stationary phases [92]. The solvents
are selected such that:
● the settling time should be less than 30 s;
● the analytes should be stable and soluble in the chosen system;
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6.5 Isolation Methods of Polyphenols from Food Products 121
● partition coefficients K should range from 0.5 to 2.0, and the separation factor α (α = K
2
/K
1
, K
2
> K
1
) for any two components should exceed 1.5;
● the two-phase system should feature similar volumes in both phases.
The combination of two-phase solvent systems for HSCCC usually employs the following classical
systems [93]: n-heptane–ethyl acetate–methanol–water (Arizona family), n-heptane–acetonitrile–
n-butanol–water (HBAWat family), chloroform–methanol–water (ChMWat family), and n-hex-
ane–ethyl acetate–methanol–water (HEMWat family). The choice will depend on the polarity and
distribution constants of the components.
To illustrate the use of chromatographic methods in general (in HSCCC in particular) in the
isolation of PPHs, we present two case studies [90]:
Case study 1:
One study was the application of HSCCC to the separation and purification of three phenolic
acids (neochlorogenic acid, chlorogenic acid, and 3,5-O-dicaffeoylquinic acid; see Table 6.1)
and two Sorbus pohuashanensis Hedl. flavonoids (SPF). This isolation was performed under
optimal conditions (ethyl acetate–n-butanol–water 3.5:1.5:5) at a ratio of n-hexane–ethyl ac-
etate–methanol–water of 1:3:1:3.5, and the purification yields were > 95%. Further conditions
were tested by other researchers, with similar separation performances, such as the isola-
tion of three caffeic acids and two new cinnamic acids using n-hexane–ethyl acetate–metha-
nol–0.5% aqueous acetic acid 1:3:1:4 [94], as well as the isolation of two phenolic acids from
white grape skin extract by HSCCC using n-hexane–ethyl acetate–water at a 1:50:50 ratio for
> 90% yield [95].
Case study 2:
Another study was the application of HSCCC to the separation and purification of four stil-
benes from the roots of Cabernet Sauvignon wine (Vitis vinifera). A one-step HSCCC using
chloroform–methanol–n-butanol–water 4:3:0.05:2 provided the isolation of trans-resvera-
trol, δ-viniferin, ε-viniferin, and trans-vitisin B according to their NMR spectra and LC-MS [94].
Trans-vitisin B was obtained with a purity of 78.37%, and the purities of the other species ex-
ceeded 90%. Other solvent systems (such as chloroform–methanol–water, cyclohexane ethyl
acetate–methanol–water, and ethyl acetate–ethanol–water) have also been used in the sepa-
ration of resveratrol derivatives and their glucosides [90, 96].
6.5.2 Solvent extraction
The occurrence of NEPs and EEPs in plant-based food has been investigated, and some studies
suggest that NEPs are even more abundant than EEPs in many plant foods [6, 97], although con-
ventional solvent extraction methods are most applicable to EEPs [98].
Although the extraction of PPHs with conventional organic solvents (often mixed with some
water) is the most common method, it hast some disadvantages [99]:
● It may create hazardous effects that cause health issues.
● Contamination with residues of the solvents may also remain in the final products, requiring
additional time-consuming purification steps.
● By using pure organic solvents, very polar phenolic acids (benzoic, cinnamic acids) cannot be
extracted completely, requiring aqueous mixtures.
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6 Polyphenols in Food Products – Nutraceutical Applications
122
Concerning the polarity of the solvent, methanol has been suggested to be more efficient in the
extraction of lower molecular weight PPHs, while aqueous acetone extracts higher molecular
weight flavanols more efficiently [100, 101].
Temperature is an important parameter in extraction. Conventional extraction is typically car-
ried out at temperatures ranging from 20°C to 50°C, and temperatures greater than 70°C can cause
anthocyanin degradation. Modern extraction methods may be useful to help overcome these
drawbacks.
6.5.3 Microwave-assisted Extraction
Classical solvent extraction methods have the disadvantages of being time and solvent consuming.
In this scenario, alternative techniques emerge, such as supercritical fluid extraction, microwave-
assisted extraction (MAE), pressurized microwave-assisted extraction (PMAE), and Soxhlet sol-
vent extraction [102].
In the comparison of the efficiency of PPH extraction from a Clinacanthus nutans Lindau medic-
inal plant with and without microwave pre-treatment, the pre-treatment resulted in a considerable
increase in the extraction yield and a significantly faster extraction [103].
PPH extraction from bamboo shoots with microwave irradiation was approximately eight-fold
greater than that obtained with conventional extraction, and the use of microwaves guaranteed a
drastic reduction in extraction time [104].
6.6 Nanodelivery Systems for Polyphenol Nutraceutical Applications
6.6.1 Encapsulation
Microencapsulation can be defined as the process of packaging substances in various aggregation
states (solids, liquids, gases) within sealed capsules capable of delivering its content at controlled
rates under specific conditions [5, 105]. Several formulations can be used to package the substances
that will be slowly released in the body in a controlled manner such as sugars, gums, proteins,
natural and modified polysaccharides, lipids, and synthetic polymers [106, 107].
The compounds are incorporated in a capsule of approximately 5–300 microns in diameter
[108]. The technique for the capsule formation involves the formation of a wall around the mate-
rial so leakage does not occur and undesired materials are kept out. Figure 6.3 illustrates the vari-
ous technologies for encapsulation: spray drying, coacervation, liposomes, inclusion,
co-crystallization, nanoparticles (more properly discussed in the next topic), freeze drying, yeast
encapsulation, and emulsion.
(a) Spray drying
Figure 6.3 Illustration of the characteristics of encapsulated polyphenolic capsules produced by various
encapsulation processes. Reproduced, by permission (Elsevier License), from Ref [5].
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6.6 Nanodelivery Systems for Polyphenol Nutraceutical Applications 123
(b) Coacervation
(c) Liposomes
(d) Inclusion
(e) Co-crystallization
(f) Nanoparticles
(g) Freeze drying
(h) Yeast
encapsulation
(i) Emulsion
Oil phase
Emulsifying agent
Water soluble
polyphenols in
water phase
Water phase
Emulsifying a
gent
Oil soluble
polyphenols in
water phase
Figure 6.3 (Cont’d)
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6 Polyphenols in Food Products – Nutraceutical Applications
124
According to Desai and Park [109], spray drying (Figure 6.3a) is a technique comprising soaking
a mass of material that will encapsulate the sample with water, and subsequent drying of the
agglomerate. Modified starch, maltodextrin, gum, or other materials can be used as the wall mate-
rials, which are homogenized with the core materials. The mixture is subject to spray drying and
is atomized with a nozzle or spinning wheel, and the water is evaporated by hot air. Coacervation
(Figure 6.3b) involves the separation of a liquid phase of the coating material from a polymeric
solution followed by the coating of that phase as a uniform layer around the suspended core parti-
cles. The overall process involves the following steps:
● Formation of a three-immiscible chemical phase
● Deposition of the coating
● Solidification of the coating
The use of liposomes (Figure 6.3c) as a vehicle for transporting vaccines, hormones, enzymes, and
vitamins throughout the body is well known [110]. Liposomes comprise one or more layers of
phospholipids capable of encapsulating the exogen compound in a hydrophilic environment. This
delivery method has some advantages such that liposomes are non-toxic, stable, and permeable,
and their properties can be manipulated by varying the size (from 25 nm to several microns in
diameter) and type of lipid chains used [106].
The most common phospholipid is phosphatidyl choline, which is insoluble in water and can be
isolated from soy or egg yolk. The liposomes are formed from the mixture of solvents, such as 2:1
chloroform–methanol, and the subsequent decrease in the volume of solvent, followed by the dis-
persion of the film of lipids/solvent in an aqueous phase. The liposomes are then recovered from
the water phase [111]. The liposomes are susceptible to oxidizing, metal chelating, and tempera-
ture-driven degradation. Fang et al. [112] described how (+)-catechin and (−)-epicatechin may be
entrapped in liposomes with similar encapsulation levels and release rates.
The inclusion technique includes using oligosaccharide cages (Figure 6.3d), the most common
example being cyclodextrins (CDs). Inclusion is a low-cost method and is well known in its kinetic
and thermodynamic aspects. CDs are naturally occurring cyclic oligosaccharides (with six, seven,
or eight glucose residues linked by
α
(1–4) glycosidic bonds in a cylindrically shaped structure)
derived from starch. The most common form that is applied as an inclusion system is
β
-cyclodex-
trin. The cylinder structure has non-polar interactions in the inner surface and polar interactions
outside [113]. Many works describing the inclusion of PPHs are available such as morin and
quercetin in
α
- and
β
-CDs [114] and resveratrol in
β
-CD [115].
Co-crystallization (Figure 6.3e) involves the formation of an irregular porous matrix assembling
two or more active ingredients from an original perfect crystal [5, 116]. This encapsulation method
improves solubility, wettability, homogeneity, dispersibility, hydration, anticaking, stability, and
flowability of the encapsulated moiety [117]. The core materials in liquid form can be converted to
a dry powdered form without additional drying [109].
Nanospheres and nanocapsules are a common name for encapsulation by nanoparticles (Figure
6.3f). While nanospheres have a type of structure, such that the active compounds enclosed are
either adsorbed on the surface of the sphere or encapsulated in its interior, these compounds are
confined in a cavity constituted by an internal liquid core contained by a polymeric membrane
[118]. A possible application of this technology to PPHs is the encapsulation of quercetin with lipid
nanocapsules by mixing through heating soy bean lecithin, surfactant, NaCl, and distilled water to
form a water/oil (W/O) emulsion. The addition of distilled water forms O/W nanocapsules [119].
The freeze drying (Figure 6.3g) process (better known as lyophilization) involves the drastic
reduction in pressure and the addition of a minimum amount of heat necessary for the evaporation
of the solvent. This procedure prevents the use of severe heating that can cause the sample to
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6.6 Nanodelivery Systems for Polyphenol Nutraceutical Applications 125
decompose. As a result, core materials homogenize in matrix solutions and usually yield amor-
phous materials [120]. Despite being a safe and efficient method, one of the setbacks is the long
drying time (approximately 20 hours).
The use of yeast cells (Saccharomyces cerevisiae) as wall material encapsulating the bioactive
material has been proven to be low cost and high volume [121]. Yeast encapsulation (Figure 6.3h)
allows the exogen substances to be delivery through the cell wall and membrane via passive migra-
tion. The cell wall still protects liquid active ingredients inside the matrix against deleterious fac-
tors such as evaporation, extrusion, oxidation, and light [122].
An emulsion (Figure 6.3i) as an encapsulation system has at least two immiscible liquids, such
as oil (O) and water (W), with one of the liquids being dispersed as small spherical droplets into the
other one [123]. There are several combinations of solvents dispersed in a drop-like pattern such
as an oil-in-water (O/W) emulsion (oil droplets dispersed in an aqueous phase), water-in-oil (W/O)
emulsion (water droplets dispersed in an oil phase), and more complex systems like oil-in-water-
in-oil (O/W/O) or water-in-oil-in-water (W/O/W) emulsions [124]. An example of a W/O emul-
sion applied to PPHs is the mixing of caffeic acid and Fe (III) as an antioxidant system [125].
6.6.2 Protein–Polyphenol Conjugates
The use of protein–polyphenol conjugates (PPCs) as a delivery system is interesting because the
conjugation of proteins and non-polar PPHs intensify the hydrophobicity and emulsifying proper-
ties of the modified proteins [112]. The proteins and non-polar PPH conjugates exhibit good anti-
oxidant emulsification at the O/W interface [126–128]. The interactions that govern the formation
of conjugates between protein and PPHs are generally reversible, weak, and non-covalent in nature
[129, 130]. PPHs are hydrogen bond donors, capable of interacting with the C=O groups of pro-
teins, as well as with OH and NH
2
groups [131, 132]. Hydrophobic interactions also occur between
non-polar PPHs and hydrophobic amino acids such as leucine, glycine, methionine, alanine, phe-
nylalanine, and tryptophan [133]. Ionic interactions with charged groups are also common [89].
Irreversible covalent interactions between PPHs and proteins are less common because they are
subject to factors that allow the formation of free radicals [134]. PPHs can be oxidized under alka-
line conditions (pH 9.0) in the presence of oxygen to form semiquinone radicals capable of reacting
with nucleophilic protein residues such as methionine, lysine, tryptophan, and cysteine, establish-
ing covalent bonds [38, 135].
The stability of the conjugates depends on some physical–chemical and structural factors.
Temperature affects the strength of hydrophobic interactions and intermolecular hydrogen bonds.
However, an excessive increase in temperature can cause protein denaturation and have an
adverse effect on conjugate stability, as described by Suryaprakash et al. [136], concerning the
interaction strength decrease at 10°C –45°C for caffeic acid with lysine, tryptophan, and tyrosine
residues of proteins isolated from some sunflower seeds. pH is another relevant factor that must be
considered given that PPCs can be formed within a pH of 4.0–10.0 via either covalent or non-
covalent interactions, where protein dissociation occurs at pH < 7.0 [137, 138].
Quan et al. [134] also mentions the nature of the PPH and the protein as an important factor the
affects the stability of the PPCs. The molecular diversity of the PPHs as depicted in Table 6.1 allows
different patterns of binding. Further effects have been described such as the molecular size [139],
species from which the protein was isolated [140], and the number of OH groups of the PPH [141].
The surface properties of proteins, related to the amino acid composition, hydrophobicity, and isoe-
lectric point, also affect the binding affinity of proteins with PPHs [137]. Depending on these character-
istics, the interaction sites are more or less exposed to bind to the PPHs. Evidence of this behavior is the
fact that unfolded proteins present more intense interactions than globular and compact proteins [132].
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6 Polyphenols in Food Products – Nutraceutical Applications
126
6.7 Conclusion and Future Perspectives
The study of PPHs introduces perspectives on their nutraceutical applications attributed to the
wide spectrum of activities and the availability in the most vegetables. Despite the accumulated
knowledge on the nature, occurrence, and applications of these compounds, some challenges
remain, such as the improvement of methods for the isolation of non-extractable PPHs, as well as
the particular pharmacology of the bound PPHs that may differ substantially from their extracta-
ble counterparts.
Research on delivery methods, notably those that employ nanostructures and the formation of
conjugates between PPHs and proteins, still promise advances. In this context, studies involving
computational chemistry, capable of characterizing the interactions that govern the formation of
these systems, are a constant stimulus to academic curiosity and the demand for new products.
New approaches include molecular docking, molecular dynamics simulation, and hybrid method
calculations of PPHs with β-lactoglobulin, a phenomenon that influences their antioxidant proper-
ties [142].
Finally, it is important to pursuit electrochemical studies employing techniques, such as cyclic
voltammetry, to accomplish the antioxidant and radical formation feasibility of PPHs related to
their influence on other conditions, including diabetes and cancer.
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