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Cocoa Bioactive Compounds: Significance and Potential for the Maintenance of Skin Health


Abstract and Figures

Cocoa has a rich history in human use. Skin is prone to the development of several diseases, and the mechanisms in the pathogenesis of aged skin are still poorly understood. However, a growing body of evidence from clinical and bench research has begun to provide scientific validation for the use of cocoa-derived phytochemicals as an effective approach for skin protection. Although the specific molecular and cellular mechanisms of the beneficial actions of cocoa phytochemicals remain to be elucidated, this review will provide an overview of the current literature emphasizing potential cytoprotective pathways modulated by cocoa and its polyphenolic components. Moreover, we will summarize in vivo studies showing that bioactive compounds of cocoa may have a positive impact on skin health.
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Nutrients 2014, 6, 3202-3213; doi:10.3390/nu6083202
ISSN 2072-6643
Cocoa Bioactive Compounds: Significance and Potential for the
Maintenance of Skin Health
Giovanni Scapagnini 1,2,*, Sergio Davinelli 1,2, Laura Di Renzo 3, Antonino De Lorenzo 3,
Hector Hugo Olarte 4, Giuseppe Micali 5, Arrigo F. Cicero 6 and Salvador Gonzalez 7,8
1 Department of Medicine and Health Sciences, University of Molise, Campobasso 86100, Italy;
2 Inter-University Consortium “SannioTech”, Benevento 82030, Italy
3 Division of Human Nutrition, Department of Neuroscience, University of Rome Tor Vergata,
Rome 00173, Italy; E-Mails: (L.R.); (A.L.)
4 Casa Luker S.A., Bogotà DC, Colombia; E-Mail:
5 Dermatology Clinic, University of Catania, Catania 95123, Italy; E-Mail:
6 Department Medical and Surgical Sciences, University of Bologna, Bologna 40138, Italy;
7 Dermatology Service, Memorial Sloan-Kettering Cancer Center, New York, NY 10017, USA;
8 Dermatology Service, Ramon y Cajal Hospital, Madrid 28034, Spain
* Author to whom correspondence should be addressed; E-Mail:;
Tel.: +39-0874-404-774; Fax: +39-0874-404-2774.
Received: 19 May 2014; in revised form: 17 July 2014 / Accepted: 4 August 2014 /
Published: 11 August 2014
Abstract: Cocoa has a rich history in human use. Skin is prone to the development of
several diseases, and the mechanisms in the pathogenesis of aged skin are still poorly
understood. However, a growing body of evidence from clinical and bench research has
begun to provide scientific validation for the use of cocoa-derived phytochemicals as an
effective approach for skin protection. Although the specific molecular and cellular
mechanisms of the beneficial actions of cocoa phytochemicals remain to be elucidated, this
review will provide an overview of the current literature emphasizing potential
cytoprotective pathways modulated by cocoa and its polyphenolic components. Moreover,
we will summarize in vivo studies showing that bioactive compounds of cocoa may have a
positive impact on skin health.
Nutrients 2014, 6 3203
Keywords: cocoa; skin; health; phytochemicals; antioxidant; anti-inflammatory
1. Introduction
Seeds from Theobroma cacao L. (Sterculiaceae) are the base for the production of the most
important and widespread functional food in human history. The origin of cocoa dates back to more
than 3000 years ago, and it was used for nutritional and medicinal purposes by the Mayan and Aztec
civilizations [1]. Numerous reports have focused on various health-beneficial effects associated with
the consumption of cocoa products [2]. Although the cocoa plant contains an enormous range of
beneficial components, processing and manufacturing alters its content and bioactive moieties,
particularly during roasting, fermentation and drying, as well as with the use of analytical methods for
isolation, characterization and quantification of its bioactive compounds. For instance, the production
of cocoa liquor (a dark brown fluid obtained by grinding cocoa nibs), which is a combination of cocoa
butter and cocoa powder, involves the cleaning of the seeds followed by fermentation, drying and
roasting steps. The time and temperature conditions during the roasting process affect the flavor
characteristics and nutrient profile of the final product [3]. The liquor may then be processed with
alkali, also known as Dutch processing or Dutching, to increase the pH and improve palatability.
Furthermore, the alkalizing stage affects the chemical composition of the cocoa liquor [4]. The
chemical profile of roasted cocoa beans is complex, and the primary compounds that induce its
multiple beneficial functions are naturally occurring or process-derived flavonoids, theobromine and
magnesium. A summary of the manufacturing steps is shown in Figure 1. The term “cocoa
component” is intended to refer to a fraction derived from shell-free cocoa nib and includes chocolate
liquor, partially- or fully-defatted cocoa solids, cocoa extracts, cocoa butter and cocoa nib. The
potential health implications of biologically active substances present in cocoa components are well
documented. Many epidemiological studies associate cocoa and chocolate consumption to a reduced
risk of chronic diseases, and various health benefits of the cocoa compounds have been attributed to its
antioxidant and anti-inflammatory potency [5]. In particular, the bioactive constituents of cocoa
components exhibit pharmacologic effects in reducing inflammatory processes [6]. This is based on their
ability to downregulate pro-inflammatory cytokines and their downstream biochemical pathways [7].
In addition, according to Lee et al. [8] phenolic and flavonoid contents and total antioxidant capacities
of cocoa are higher than that of other phytochemical-rich foods. The antioxidant effects of the cocoa
components may influence insulin resistance, reduce the risk for diabetes or stimulate redox-sensitive
signaling pathways involved in the gene expression of endogenous antioxidant defenses [9]. Diet has
been recognized as an important modifier of health status, and dermal health can be greatly affected by
food composition. Although this is an emerging area of research and more robust findings are required,
it was reported that the consumption of cocoa rich in phytochemicals may help to maintain skin health
and confer photoprotection [10]. After a brief overview of typical phytochemicals present in cocoa, we
will review the beneficial impact of cocoa and chocolate consumption on human health with special
emphasis on skin physiology.
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Figure 1. Manufacturing processes of cocoa beans.
2. Cocoa Bioactive Compounds and Minerals
2.1. Polyphenols
Plants provide abundant minerals and phytochemicals when presented as food. Cocoa is a widely
consumed food ingredient. Phytochemicals’ profile in cocoa beans varies for different cultivars and
among cocoa beans and cocoa-containing foods. However, cocoa is a rich source of polyphenolic
compounds with a high amount of flavonoids, specifically flavanols, also known as flavan-3-ols.
Polyphenols are secondary plant metabolites that are involved in plant defense against herbivores,
pathogens and ultraviolet (UV) damage [11]. More than 8000 phenolic structures are currently known,
and among them, over 4000 flavonoids have been identified [12–14]. The basic flavonoid skeleton
consists of 15 carbon atoms with two aromatic rings (Ring A and Ring B) connected by a three-carbon
bridge (Ring C). Flavonoids can be divided into different sub-groups, such as anthocyanins,
flavan-3-ols, flavones, flavanones and flavonols, according to hydroxylation pattern and variations in
the chromane ring (Ring C) [15]. Moreover, cocoa components are particularly rich in catechins, and
based on their structure, catechins are classified as flavan-3-ols. They mainly include monomeric ()
epicatechin and (+) catechin, as well as oligomeric and polymeric proanthocyanidin flavanols [5].
However, in smaller amounts, gallocatechin and epigallocatechin, have also been quantified [16]. The
procyanidins represent a dominant class of proanthocyanidins, and it was found that these naturally
occurring compounds are the main group responsible for the antioxidant activity of the cocoa
components [17]. The bitterness is primarily due to the high levels of flavanols, and they represent a
fundamental aspect of the organoleptic and palatability characteristics of chocolate [18]. More
importantly, flavanols may influence healing properties and offer a wide range of health benefits. For
Dried cocoa
and breaking
Cocoa liquor
Butter Cocoa cake
Cocoa powder
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instance, flavanol-rich cocoa consumption improves dermal blood flow, increases photoprotection and
contributes to the maintenance of skin health [19,20].
2.2. Theobromine
In addition to polyphenols, cocoa contains methylxanthine compounds, predominantly theobromine
and caffeine, but in lower amounts than those of theobromine [9]. The average contents of the
individual methylxanthines is dependent on the genotype of the cacao tree. Theobromine belongs to
the group of purine alkaloids, which can elicit various physiological effects, and they are synthesized
in a limited number of plant species, including tea, coffee and cacao [21]. The pharmacology and
toxicology of theobromine and other methylxanthines have been reviewed by Smit et al. [22,23]. Since
theobromine has been shown to possess high bioavailability and multiple biological activities, recent
cocoa intervention studies have been conducted on the ability of theobromine to increase serum HDL
cholesterol [24]. Furthermore, theobromine stimulates heart muscle, relaxes bronchial smooth muscles
in the lungs and plays an important role in the transmission of intracellular signals [25–27]. It is
noteworthy that theobromine has antioxidant activity, and several antioxidant compounds may be
effective treatments for depressive disorders [28]. Although new findings indicate that theobromine
does not influence mood, there is a growing body of literature indicating that theobromine and cocoa
flavanols, in isolation and in combination, may have measurable neurocognitive effects [29,30]. The
value of antioxidants in skin health is a controversial area, but several botanical agents, including
theobromine, can scavenge reactive oxygen species (ROS) generated in the skin as a consequence of
UV exposure, and they can interfere with signaling pathways altered in the skin as a consequence of
these ROS [31].
2.3. Minerals
The cocoa bean is an extremely rich source of many essential minerals, including magnesium,
copper, potassium and iron. As reviewed by Steinberg et al. [32], most of these minerals may affect
vascular health and function, improving cocoa’s nutritional effects. The predominant mineral found in
cocoa is magnesium, which catalyzes a multitude of biologic reactions, including protein synthesis and
energy production [32]. In addition, magnesium is an antiarrhythmic and hypotensive agent, and its
deficiency has been linked to the metabolic syndrome, insulin resistance and diabetes [33,34]. Dark
chocolate is also an important source of copper, and this mineral is required for processes, such as iron
transport, glucose metabolism, infant growth and brain development [18,35]. Moreover, cocoa and
cocoa products are rich in iron, but they are relatively low in potassium [9].
3. Molecular Mechanisms Relevant to Skin Health
In recent years, there has been a growing interest, supported by a large number of experimental and
epidemiological studies, for the beneficial effects of some phenolic substances, contained in commonly
used spices and herbs, in preventing various age-related pathologic conditions, ranging from cancer to
neurodegenerative diseases. Although the exact mechanisms by which polyphenols promote these
effects remain to be elucidated, several reports have shown their ability to stimulate a general
Nutrients 2014, 6 3206
xenobiotic response in the target cells, activating multiple defense genes, activating a number of
different molecular targets, impinging on several signaling pathways and showing pleiotropic activity
on cells and tissues. Cocoa polyphenols, mainly flavanols in both monomeric and oligomeric form,
have been shown to act as a strong antioxidants, having the potential to inhibit lipid peroxidation and
to effectively intercept and neutralize ROS. In this regard, cocoa flavanols have been demonstrated to
be more potent than other food polyphenols. The tricyclic structure of the flavonoids determines their
antioxidant effects; phenolic quinoid tautomerism and the delocalization of electrons over the aromatic
system scavenge ROS. These aromatic rings directly neutralize free radicals and chelate metals
(Fe2+ and Cu+) that enhance ROS. Due to the good bioavailability, cocoa intake increases serum
antioxidant capacity, protecting the endothelium from oxidative stress and endogenous ROS [36],
although contemporary milk assumption decreases this ability [37]. Beyond their ROS quencher
activity, cocoa polyphenols effects have been mostly associated with cocoa’s ability to interfere at
a molecular level with numerous cellular antioxidant pathways. They strongly inhibit enzymes
involved in ROS production. Enzymes inhibited by cocoa flavonoids include xanthene oxidase,
NADPH-oxidase, tyrosine kinases and protein kinases [38]. Furthermore, cocoa flavanols have been
shown to upregulate antioxidant defenses by overexpressing highly protective inducible genes
involved in the cellular stress response, such as the activation of the nuclear factor erythroid 2-related
factor 2 (Nrf2) signaling pathway (Figure 2). Nrf2 is a conserved master regulator of cellular
antioxidant responses. Nrf2 belongs to the Cap’n’Collar family leucine zipper transcription factors and
regulates the expression of genes encoding anti-oxidant and detoxifying proteins, such as glutathione
S-transferase (GST), glutathione synthetase (GSS), heme oxygenase-1 (HO-1) and NAD(P)H:quinone
oxidoreductase. Among the genes activated by Nrf2, HO-1 has been the object of intensive studies for
its potential role in protecting several tissues against cell death [39]. Cocoa extract has been recently
shown to efficiently induce HO-1 expression through the activation of Nrf2 in mice and, by this, to
protect neurons against different challenges [40]. Flavonoids have a number of other properties that
may contribute to their protective and healing effects, including anti-inflammatory and antiplatelet
activity, immunoregulatory properties and beneficial effects on vascular endothelium. The epicatechin
content of cocoa is primarily responsible for its favorable impact on vascular endothelium, which is the
result of both acute and chronic upregulation of nitric oxide (NO) production [41]. NO synthesis is the
most investigated endothelial function in relation to cocoa over the past 10 years, and many authors
have reported that cocoa polyphenols significantly increase plasma concentrations of NO [42]. The
predominant mechanistic hypothesis is that cocoa components, in particular epicatechin, stimulate
endothelial nitric oxide synthases (eNOS) activity, inhibit arginase and NADPH oxidase, leading to
lower levels of superoxide and, hence, higher levels of NO. Although this is not the only mechanism
involved, a substantial increase in NO synthesis may account for flow-mediated dilation and lower
blood pressure following intervention treatments. Cocoa procyanidins are also potent inhibitors of
mitogen-activated protein kinase kinase (MEK) and membrane type-1 (MT1)-matrix metalloproteinase
(MMP). They subsequently inhibit the expression and activation of pro-MMP-2, as well as the
invasion and migration of human vascular smooth muscle cells (VSMCs) [43]. Both of these
mechanisms have a critical relevance, not only in flavanols cardioprotective effects, but also for their
potential use in cancer prevention and photoprotection. Ramiro et al. [44] studied the effects of a cocoa
extract on the secretion and RNA expression of various proinflammatory mediators by macrophages.
Nutrients 2014, 6 3207
Of these, monocyte chemoattractant protein (MCP)-1 and tumor necrosis factor (TNF)-α were
significantly and dose-dependently diminished by the extract. All cocoa flavonoids tested were capable
of reducing MCP-1 secretion after 6 h of LPS activation. The regulatory effects of cocoa flavanols on
nuclear factor-κB (NF-κB) activation have also been studied. ()-Epicatechin, (+)-catechin and their
dimeric forms were found to inhibit the NF-κB activation induced by phorbol esters in T-cells, with a
clear reduction of NF-κB-DNA binding activity that leads to a reduction in interleukin 2 (IL-2)
production. These effects were related to the direct interaction with the inhibitor of κB (IκB) to prevent
its phosphorylation, thereby preventing NF-κB activation [45].
Figure 2. Schematic presentation of the Nrf2 pathway. When oxidants, such as ROS, RNS
and dietary phytochemical compounds react with redox reactive cysteines in Keap1, Nrf2
will be released from Keap1, allowing Nrf2 to be translocated into the nucleus. In the
nucleus, Nrf2 dimerizes with Maf protein and bind to ARE, which is located in the
promoter of the phase II and antioxidative genes, triggering the transcription of
ARE-regulated genes. Nuclear factor erythroid 2-related factor 2 (Nrf2); Kelch-like
ECH-associated protein 1 (Keap1); musculoaponeurotic fibrosarcoma (Maf); antioxidant
response element (ARE); NAD(P)H:quinone oxidoreductase 1 (NQO1); glutathione
S-transferase (GST); glutathione peroxidase (GPX); heme oxygenase-1 (HO-1).
4. Role of Cocoa Polyphenols in the Skin: Anti-Aging Effects
Skin aging is a complex process that involves intrinsic and exogenous causes. Intrinsic skin aging is
inevitable, but exogenous aging is caused by exogenous harmful environments and can be, at least
partially, prevented. Photo-oxidative damage caused by solar UV light is the main cause of extrinsic
aging of the skin, a phenomenon known as photoaging. UV damage can be linked mostly to the
photochemical overproduction of ROS, which induces a complex molecular cascade able to activate
inflammation, to accelerate physiological aging and determining a typical dermal/epidermal
degeneration. ROS and reactive nitrosative species (RNS) generated by UV can damage critical
Oxidative and
(cocoa) phenolic
Antioxidant and
Phase II enzymes
Nutrients 2014, 6 3208
cellular components (DNA, proteins, lipids) and also affect the regulation of signaling molecules, such
as mitogen-activated protein kinases (MAPKs), inflammatory cytokines, as well as nuclear factor-kβ
(NF-κβ) and activator protein-1 (AP-1). Furthermore, photo-exposure induces the activation of the
enzymatic systems, e.g., lipoxygenase (LOX) and cyclooxygenase (COX), which are responsible for
the production of additional inflammatory mediators. It is also well established that cutaneous
exposure to UV radiation contributes to the development of skin cancers. Epidemiological, clinical and
pre-clinical studies have shown that solar UV radiation is the major etiological factor in the
development of cutaneous malignancy [46], including the non-melanoma skin cancers, which
represent the most common malignant neoplasms in humans [47]. Various animal models have been
employed to examine the anti-photocarcinogenic effects of plant polyphenols. The plant polyphenols
possess anti-inflammatory, immunomodulatory, antioxidant properties and DNA repair activities, and
they can be exploited for the prevention of a variety of skin disorders caused by excessive exposure to
solar UV light. In vitro and in vivo systems have both shown the protective effects of polyphenols on
the biochemical processes that are induced or mediated by UV radiation, suggesting that routine use of
natural polyphenols both topically and orally may provide effective protection against UV radiation,
and subsequent photoaging [48]. Cellular studies and results from oral treatment and topical
application studies in both animals and humans provide evidence that cocoa polyphenols, especially
those belonging to the flavanol family, can offer effective photoprotection. Furthermore, the
antioxidant and anti-inflammatory properties of cocoa polyphenols may constitute the basis of the
possible antitumor promoting effects of these phytochemicals. A study conducted in rodents
has demonstrated that a high phenolic extraction from cocoa powder (containing 468 mg/g of
gallic acid-equivalent phenolics and 413 mg/g epicatechin-equivalent flavonoids) strongly inhibits
the induction of COX-2 expression, the activation of MAPKs and NF-κβ signaling in
12-O-tetradecanoylphorbol-13-acetate (TPA)-treated mouse skin [49]. In particular, oral administering
of cocoa polyphenols (4, 20, 40 and 200 mg/kg body weight) to mice 1 h prior to TPA exposure
(10 nmol) inhibited ear edema at 5 h in a dose-dependent manner. The levels of COX-2 expression
induced in mouse skin after 4-h treatment with topical TPA (10 nmol) was also diminished
significantly by pretreating with cocoa polyphenols (40 or 200 mg/kg) for 30 min [49]. A more recent
study has demonstrated that cocoa polyphenol extract effectively inhibited TNF-α-induced vascular
endothelial growth factor (VEGF) expression in mouse epidermal cells [50]. This effect has been
related to the ability of cocoa polyphenols to block TNF-α-induced activation of the nuclear
transcription factors, AP-1 and NF-κβ, which are key regulators of VEGF expression. Other studies
have explored the protective action of cocoa directly applied on the skin. The topical application of
cocoa polyphenols has been shown to positively affect several parameters of skin elasticity and skin
tonus, namely, glycosaminoglycans and collagen I, III and IV [51]. Moreover, topical application of
both cocoa extract titled in theobromine or pure theobromine have been shown to prevent UV-induced
wrinkle formation in hairless mice. Mice were exposed to solar simulated ultraviolet irradiation at a
dose of 13.0 J/cm2 (UVA) for 15 weeks, five times a week on weekdays. After the final irradiation,
histological and analytical studies showed that the topical application of cacao extracts or theobromine
markedly prevented photodamage, including wrinkle formation, dermal connective alteration and
collagen accumulation. The research also suggested that xanthine derivatives prevented neutrophil
infiltration caused by UV-irradiation, supporting a critical role for theobromine in the dermal
Nutrients 2014, 6 3209
protective action of cocoa [52]. In vivo human skin studies have also shown the strong
anti-inflammatory, antioxidant, photoprotective and chemopreventative effects of cocoa, after oral
consumption. In a double-blind clinical trial, two groups of women, with healthy and normal skin of
type II, consumed either a high flavanol (326 mg/day) or low flavanol (27 mg/day) cocoa powder
dissolved in 100 mL water for 12 weeks. Epicatechin (61 mg/day) and catechin (20 mg/day) were the
major flavanol monomers in the high flavanol drink, whereas the low flavanol drink contained 6.6 mg
epicatechin and 1.6 mg catechin as the daily dose. Dietary intervention with a cocoa beverage rich in
flavanols decreased the sensitivity of human skin toward UV light, which was determined by the
degree of erythema (reddening) following irradiation with a solar light simulator. Compared to
baseline, skin response was decreased by 15% after six weeks of intervention, and the decrease was
more pronounced, 25%, after 12 weeks. UV sensitivity did not change in the women that consumed
the cocoa beverage low in flavanols. Compared to the low flavanol product, the high flavanol cocoa
powder contained ~10× the amount of epicatechin and catechin, as well as total flavanols. The same
study has found an increase in cutaneous and subcutaneous blood flow in women supplemented for
12 weeks with a cocoa beverage rich in flavanols. At Week 12, blood flow increased ~100% at a 1-mm
depth and ~40% at a 7–8-mm depth compared with baseline [19]. Microcirculation is an important
factor for thermoregulation, nutrient and oxygen supply, and it affects skin condition and
appearance [53]. To better assess the activity of flavanol-rich cocoa acute consumption on dermal
blood flow, in a crossover study, 10 healthy women ingested a cocoa drink (100 mL) with a high
(329 mg) or a low (27 mg) content of flavanols. Dermal blood flow and oxygen saturation of
hemoglobin were examined by laser Doppler flowmetry and spectroscopically at a 1-mm skin depth at
t = 0, 1, 2, 4 and 6 h. At the same time points, plasma levels of total epicatechin (free compound plus
conjugates) were measured by means of HPLC. Subsequent to the intake of high flavanol cocoa,
dermal blood flow was significantly increased by 1.7-fold at t = 2 h, and oxygen saturation was
elevated 1.8-fold. No statistically significant changes were found upon the intake of low flavanol
cocoa. Maximum plasma levels of total epicatechin were observed 1 h after ingestion of the high
flavanol cocoa drink, 11.6 ± 7.4 nmol/L at baseline and 62.9 ± 35.8 nmol/L at 1 h [20]. The
relationship between dark chocolate consumption rich in flavanols and skin photoprotection has been
investigated in a double-blind in vivo study in 30 healthy subjects. Fifteen subjects each were
randomly assigned to either a high flavanol or low flavanol chocolate group and consumed a 20-g
portion of their allocated chocolate daily. The minimal erythema dose (MED) was assessed at baseline
and after 12 weeks under standardized conditions. In the high flavanol chocolate group, the mean
MED more than doubled after 12 weeks of chocolate consumption, while in the low flavanol chocolate
group, the MED remained without significant change. These results demonstrated that regular
consumption of a chocolate rich in flavanols confers significant photoprotection and can thus be
effective at protecting human skin from harmful UV effects [54]. Although more clinical evidence is
probably needed to better evaluate the clinical relevance of polyphenols in dermatology, the data
presented above clearly showed that cocoa components have important antioxidant, anti-inflammatory
and photoprotective functions on the skin. The ability of cocoa phytochemicals to modulate
critical biochemical functions through oral and topical formulations makes cocoa a promising
candidate for further dermatological applications, ranging from cosmetic wellness to the prevention
of carcinogenesis.
Nutrients 2014, 6 3210
5. Conclusions
Cocoa and cocoa products are important sources of phytocompounds with nutritional and
therapeutic value. A growing body of scientific evidence is becoming available to support that cocoa
components with antioxidants and anti-inflammatory activities contribute to endogenous
photoprotection and are crucial for the maintenance of skin health. However, several studies have
shown that the beneficial effects of cocoa vary among the wide range of cocoa and chocolate products.
Various mechanisms have been proposed to explain the possible benefits of cocoa consumption on
human health, but a clear molecular mechanism is still lacking. Although clinical data provide critical
evidence of the health value of cocoa, the main cellular processes and signaling pathways involved in
the detoxification of reactive species and the removal of pro-inflammatory mediators are significantly
underestimated. Moreover, since cocoa contains a mixture of bioactive components, further studies are
needed to determine the possible synergistic interaction between them. For several reasons, cocoa-
derived phytochemicals are receiving increasing interest from consumers and food manufacturers, but
the bioavailability, the kinetics of absorption and the bioactivity are not well-established. Pertaining to
skin health, cocoa components have been utilized in diseases, such as skin cancer, psoriasis, acne and
wound healing. It is noteworthy that is has been shown that cocoa has great potential not only for the
treatments of skin diseases, but also for their prevention. In particular, antioxidants found in cocoa
protect the skin from the inside by neutralizing oxidative stress, a major factor of dermal structure
deterioration and premature skin aging. In conclusion, multiple lines of evidence support the role of
cocoa in the promotion of human health, but a full understanding of the mechanisms of action of
cocoa-derived phytochemicals as modulators of cell signaling is the key to evaluate the efficiency of
these potent biomolecules as anti-aging agents.
Author Contributions
Scapagnini, G.; Davinelli, S. and Gonzalez, S. wrote the paper. Micali, G. and Gonzalez, S.
contributed to dermatological aspects. De Lorenzo, A.; Renzo, L.; Olarte, H. and Cicero, A.
contributed to nutritional aspects. Scapagnini, G.; Davinelli, S. and Olarte, H. contributed to molecular
biology aspects. Micali, G.; De Lorenzo, A.; Renzo, L. and Cicero, A. contributed to the conclusions
and reading the manuscript.
Conflict of Interest
The authors declare no conflict of interest.
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... Pertaining to skin health, cocoa components have been utilized in diseases, such as skin cancer, psoriasis, acne, and wound healing. Cocoa has great potential not only for the treatments of skin diseases, but also for their prevention [30]. ...
... Consequently, natural moisturizers may be used in moisturizing cosmetic formulations and also as adjuvant therapy for the treatment of atopic dermatitis and other dry skin conditions. Canoderm cream 5% (coconut oil, emulsifying wax, hydrogenated canola oil, propylene glycol, carbomer, dimethicone, hard paraffin, glycerol polymetacrylate, propyl-and methyl parahydroxybenzoate, sodium lactate solution, lactic acid, glyceryl stearate, polyoxyethylene stearate, purified water) 26 week maintenance period the relative risk of recurrence reduced by 53% in 22 moisturized patients, and the risk of relapse was reduced to around one-third of the risk of no treatment Median time to relapse for patients treated with moisturizer was more than 180 days (duration of the study) compared with 30 days for the no-treatment group. 68% of the patients treated with the moisturizer and 32% of the untreated patients remained free from eczema during the observation period. ...
Effective management of dry skin conditions involves the treatment of a defective skin barrier. Moisturizers enhance and preserve the smoothness of the skin in patients with dry skin conditions as well as those with healthy skin. Many ingredients of moisturizers have the potential to cause irritant and allergic contact dermatitis; therefore, it is necessary for clinicians to be aware of such potential allergens to manage and advise their patients’ accordingly. Moisturizers free of paraben, mineral oil, alcohol and ingredients from animal origin (PAMA) have an advantage since they don’t cause sensitivity, allergy or dermatitis. This review will help dermatologists understand the need and benefits of low allergen containing moisturizers.
... They characterized 33 flavan-3-ol derivatives (including procyanidins), flavonols (including quercetin), and N-phenylpropenoyl-L-amino acids (Cádiz-Gurrea et al., 2014). Many articles have reported the potential health benefit of cacao, such as acts as antioxidant, increases cell apoptosis in human lung carcinoma (Bauer et al., 2016), diminishes the risk of cardiovascular diseases, increases the immune system, antiinflammation, and anti-cancer (Andújar et al., 2012), and helps to protect skin from UV damage (anti-aging effects) (Scapagnini et al., 2014). Moreover, in 2012, EFSA published a report permitting a claim that cocoa flavanols positively contribute to maintaining normal endothelium-dependent vasodilation. ...
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Cacao is attractive for its flavor and taste and its beneficial effects. Therefore, this commodity is promising to be developed as a functional food. Many studies reported the bioactive compounds in cacao beans and their health benefits. However, to attain desirable flavor and taste, the curing process of cacao beans is a common practice, in which fermentation is one of the processes. Despite its significance, fermentation also alters the bioactive components in cacao beans. To develop a functional food rich in bioactive compounds, measuring the bioactive contents of treated and untreated cacao beans is desired. For that reason, in this study, the analysis of total polyphenol, flavonoid, catechin, and epicatechin, as well as the radical scavenging activity of fermented cacao beans, was performed. The study revealed that fermentation negatively affected all parameters. Cacao beans fermentation up to 96 h resulted in the loss of 54% of total polyphenol, 77% of total flavonoid, and 56% of radical scavenging activity. Determination of the flavan-3-ol components, catechin, and epicatechin, revealed that they were reduced as the fermentation occurred.
... In the nucleus, NRF-2 is dimerized to the Maf protein and bound to the ARE, and the ARE is located in the promoter of phase II, anti-oxidative gene, triggering the transcription of the ARE-regulated gene. Phase II enzyme such as NQO1, GSTpi, GPX, catalase, and HO-1 is expressed through a series of processes, which has an anti-oxidative effect [39][40][41]. ...
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Dermal papilla cells (DPCs) are a rich source of nutrients and secrete multiple growth factors that can affect hair growth. As oxidative stress leads to hair loss in humans, it is considered to be one of the factors that can impair the function of DPCs. Herb-derived phytochemicals exhibit potent antioxidant activities; therefore, this study investigated whether a set of essential oils (lavender, lemongrass, rosemary, and chamomile oils) promote the hair-growth activity of DPCs. Intracellular reactive oxygen species (ROS) increased markedly in ultraviolet B-irradiated DPCs (50 mJ/cm2) and were efficiently blocked by essential oils. Essential oils upregulated the mRNA and protein levels of phase II enzymes (detoxifying and antioxidant), including heme oxygenase-1, NAD(P)H quinone oxidoreductase-1, and glutathione S-transferase pi. They also upregulated and activated nuclear factor E2-related factor 2, an essential transcription factor for phase II enzymes. Regarding biomarkers for hair growth, essential oils significantly increased vascular endothelial cell growth factor and insulin-like growth factor-1 mRNA levels. In conclusion, phytochemicals in essential oils enhance hair growth through ROS-scavenging activity in DPCs.
... Oleic acid, for instance, is an important constituent of Copoazú seeds and has been demonstrated to induce a faster wound closure (Cardoso et al., 2004). According to Scapagnini et al. (2014), the lipids present in different kinds of butter such as Theobroma cacao benefit skin health through skin elasticity improvement and dry skin relief also plays an outstanding role in the proinflammatory cytokines downregulation, resulting in the anti-inflammatory effect. For this consideration, a topical application of Theobroma grandiflorum butter (a close relative of T. cacao) based on its triglycerides and fatty acids and the unsaponifiable matter would increase dermal antioxidant capacity and protects the epidermis from oxidative stress and exogenous ROS. ...
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Copoazú seed butter [Theobroma grandiflorum (Wild ex Spreng) K. Schum] is a rich source of fatty acids and polyphenols, active substances with high antioxidant and moisturizing activities with potential applications in the cosmetic industry. Some studies have demonstrated that sun-induced skin damage is partially mediated by oxidative pathways; in fact, there is evidence for the photoprotective roles of antioxidants. We have developed a stable emulgel-type cosmetic formulation using Copoazú seed butter at different concentrations of 5, 10, and 20% and examined the antioxidant activity and the effect of Copoazú seed butter emulgels against UV-induced epidermal damage in mice to verify its use for topical photoprotective products. The antioxidant activity expressed as EC50 values varied from 8.47 ± 0.013 mg/ml to 4.53 ± 0.046 mg/ml for Copoazú seed butter emulgels. In vitro sun protection factor (SPF) assessment showed that Copoazú seed butter emulgel at 20% has the highest SPF of 11.67 ± 0.001, which is acceptable for the sunscreen products development, and these results were corroborated by the in vivo results since the mice were irradiated with UV light and treated with Copoazú seed emulgels and showed minor damage or significantly reduced the severity of the damage and were comparable with the standard photo-protector. The results showed that Copoazú seed butter is a promising compound for photoprotective formulations.
... 20 Theobromine can scavenge reactive oxygen species (ROS) produced in the skin after UV exposure. 21,22 Nicotinamide is also widely used as a cosmetic skin care ingredient for its whitening, antiaging, and skin barrier building properties. 23,24 The list was further extended to comprise 4aminopyridine, which is also known to enhance the release of presynaptic acetylcholine and increase the force of muscle contractions, thus behaving as an antagonist of the neuromuscular blockade effects of antibiotics. ...
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The possibility of obtaining cocrystals of kojic acid with organic coformers has been investigated by both computational and experimental approaches. Cocrystallization attempts have been carried out with about 50 coformers, in different stoichiometric ratios, by solution, slurry, and mechanochemical methods. Cocrystals were obtained with 3-hydroxybenzoic acid, imidazole, 4-pyridone, DABCO, and urotropine, while piperazine yielded a salt with the kojiate anion; cocrystallization with theophylline and 4-aminopyridine resulted in stoichiometric crystalline complexes that could not be described with certainty as cocrystals or salts. In the cases of panthenol, nicotinamide, urea, and salicylic acid the eutectic systems with kojic acid were investigated via differential scanning calorimetry. In all other preparations the resulting materials were constituted of a mixture of the reactants. All compounds were investigated by powder X-ray diffraction; the five cocrystals and the salt were fully characterized via single crystal X-ray diffraction. The stability of the cocrystals and the intermolecular interactions in all characterized compounds have been investigated by computational methods based on the electronic structure and pairwise energy calculations, respectively.
... TPC may improve health through its physiological effects. Furthermore, it has a key role in protecting the human body from chronic disease [11]. Researchers are looking into its potential use in the treatment and prevention of cancer, heart disease, and other illnesses. ...
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An optimum condition of the drying process can minimize nutrient losses and maximize the shelf life of food products. Thus, this study is aimed at developing an optimized system for the process conditions to determine the total phenolic content (TPC) of oven-dried papaya slices. The response surface method and central composite design were used to design the experiment, and it was found that the drying conditions had a significant impact on the total phenolic content of papaya slices. TPC was determined in relation to their interactions with the independent variables that include time, temperature, sample thickness, and stage of ripeness. The optimum drying conditions are those with the maximum content of TPC. In order to fit the experimental data, a quadratic polynomial model is created for the output variable, and an analysis of variance is carried out to determine whether or not the model is compatible to determine the optimal drying conditions. Time (10 h), temperature (62.02°C), thickness (9.75 mm) and stages (ripe) were found to be the optimal drying conditions. It was found that temperature had more effect on the amount of TPC than other factors. The numerical findings showed a good agreement with experimental data, with R 2 = 0.9237 . It is hoped that the findings will make a contribution to the process of drying food.
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Nutritional intervention plays a significant role in controlling the progression of chronic diseases and improving therapeutic outcomes. Food functional factors are bioactive compounds found in foods that can regulate body's physiological functions and support health by regulating enzyme activity and metabolic pathways. However, many food functional factors face significant challenges in terms of their bioavailability, stability, and solubility. Furthermore, individual differences in genetics, metabolism, lifestyle, and environmental factors can significantly influence nutrient requirements and intake. Therefore, personalized nutritional intervention and precise delivery based on individual characteristics are necessary to achieve precision nutrition. Steady‐state targeted delivery systems have emerged as a promising approach to improving the precise nutritional interventions for chronic diseases. In this review, we explore the latest progress in the steady‐state targeted delivery of food functional components for precision nutrition. We discuss the challenges and opportunities associated with these systems as well as their potential applications in managing chronic diseases and improving health outcomes. The review highlights the significant role that steady‐state targeted delivery systems can play in advancing precision nutrition and thus promoting better health for individuals.
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The field of nutrigenomics studies the interaction between nutrition and genetics, and how certain dietary patterns can impact gene expression and overall health. The Mediterranean diet (MedDiet), characterized by a high intake of fruits, vegetables, whole grains, and healthy fats, has been linked to better cardiovascular health (CVH) outcomes. This review summarizes the current state of research on the effects of nutrigenomics and MedDiet on cardiovascular health. Results suggest that MedDiet, through its impact on gene expression, can positively influence CVH markers such as blood pressure, lipid profile, and inflammation. However, more research is needed to fully understand the complex interactions between genetics, nutrition, and CVH, and to determine the optimal dietary patterns for individualized care. The aim of this scientific review is to evaluate the current evidence on the effects of nutrigenomics and MedDiet on cardiovascular health. The review summarizes the available studies that have investigated the relationship between nutrition, genetics, and cardiovascular health, and explores the mechanisms by which certain dietary patterns can impact CVH outcomes. The review focuses on the effects of MedDiet, a dietary pattern that is rich in whole foods and healthy fats, and its potential to positively influence CVH through its impact on gene expression. The review highlights the limitations of current research and the need for further studies to fully understand the complex interplay between nutrition, genetics, and cardiovascular health.
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The physiological and morphological aspects of skin suffer from frequent change. Numerous internal and external factors have direct impact on inducing various skin problems like inflammation, aging, cancer, oxidative stress, hyperpigmentation etc. The use of plant polyphenols as a photo-ecting agent is gaining popularity nowadays. Polyphenols are known to enhance endogenic antioxidant system of skin thereby preventing various skin diseases. The biological activity of plant polyphenols is dependent on their physicochemical properties for overcoming the epidermal barriers to reach the specific receptor. Several evidences have reported the vital role polyphenols in mitigating adverse skin problems and reverting back the healthy skin condition. The interest in plant derived skin care products is emerging due to the changing notion of people to shift their focus towards use of plant-based products. The present review draws an attention to uncover the protective role of polyphenols in prevention of various skin problems. Several in vitro and in vivo studies have been summarized that claims the efficacious nature of plant extract having dermatological significance.
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Recent reports on cocoa are appealing in that a food commonly consumed for pure pleasure might also bring tangible benefits for human health. Cocoa consumption is correlated with reduced health risks of cardiovascular diseases, hypertension, atherosclerosis, and cancer, and the health-promoting effects of cocoa are mediated by cocoa-driven phytochemicals. Cocoa is rich in procyanidins, theobromine, (-)-epicatechin, catechins, and caffeine. Among the phytochemicals present in consumed cocoa, theobromine is most available in human plasma, followed by caffeine, (-)-epicatechin, catechin, and procyanidins. It has been reported that cocoa phytochemicals specifically modulate or interact with specific molecular targets linked to the pathogenesis of chronic human diseases, including cardiovascular diseases, cancer, neurodegenerative diseases, obesity, diabetes, and skin aging. This review summarizes comprehensive recent findings on the beneficial actions of cocoa-driven phytochemicals in molecular mechanisms of human health.
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Background: Evidence from clinical studies has suggested that cocoa may increase high-density lipoprotein (HDL)-cholesterol concentrations. However, it is unclear whether this effect is attributable to flavonoids or theobromine, both of which are major cocoa components. Objectives: We investigated whether pure theobromine increases serum HDL cholesterol and whether there is an interaction effect between theobromine and cocoa. Design: The study had a 2-center, double-blind, randomized, placebo-controlled, full factorial parallel design. After a 2-wk run-in period, 152 healthy men and women (aged 40-70 y) were randomly allocated to consume one 200-mL drink/d for 4 wk that contained 1) cocoa, which naturally provided 150 mg theobromine and 325 mg flavonoids [cocoa intervention (CC)], 2) 850 mg pure theobromine [theobromine intervention (TB)], 3) cocoa and added theobromine, which provided 1000 mg theobromine and 325 mg flavonoids [theobromine and cocoa intervention (TB+CC)], or 4) neither cocoa nor theobromine (placebo). Blood lipids and apolipoproteins were measured at the start and end of interventions. Results: In a 2-factor analysis, there was a significant main effect of the TB (P < 0.0001) but not CC (P = 0.1288) on HDL cholesterol but no significant interaction (P = 0.3735). The TB increased HDL-cholesterol concentrations by 0.16 mmol/L (P < 0.0001). Furthermore, there was a significant main effect of the TB on increasing apolipoprotein A-I (P < 0.0001) and decreasing apolipoprotein B and LDL-cholesterol concentrations (P < 0.02). Conclusions: Theobromine independently increased serum HDL-cholesterol concentrations by 0.16 mmol/L. The lack of significant cocoa and interaction effects suggested that theobromine may be the main ingredient responsible for the HDL cholesterol-raising effect. This trial was registered at as NCT01481389.
Dietary polyphenols show a great diversity of structures, ranging from rather simple molecules (monomers and oligomers) to polymers. Higher-molecular-weight structures (with molecular weights of > 500) are usually designated as tannins, which refers to their ability to interact with proteins. Among them, condensed tannins (proanthocyanidins) are particularly important because of their wide distribution in plants and their contributions to major food qualities. All phenolic compounds are highly unstable and rapidly transformed into various reaction products when the plant cells are damaged (for instance, during food processing), thus adding to the complexity of dietary polyphenol composition. The polyphenol composition of plant-derived foods and beverages depends on that of the raw material used but also on the extraction process and subsequent biochemical and chemical reactions of plant polyphenols. The occurrence of specific tannin-like compounds (ie, thearubigins and theaflavins) arising from enzymatic oxidation is well documented in black tea. Various chemical reactions involving anthocyanins and/or flavanols have been demonstrated to occur during red wine aging. Current knowledge regarding the reaction mechanisms involved in some of these processes and the structures of the resulting products is reviewed. Their effects on organoleptic and nutritional quality are also discussed.
A systematic review was conducted to evaluate whether chocolate or its constituents were capable of influencing cognitive function and/or mood. Studies investigating potentially psychoactive fractions of chocolate were also included. Eight studies (in six articles) met the inclusion criteria for assessment of chocolate or its components on mood, of which five showed either an improvement in mood state or an attenuation of negative mood. Regarding cognitive function, eight studies (in six articles) met the criteria for inclusion, of which three revealed clear evidence of cognitive enhancement (following cocoa flavanols and methylxanthine). Two studies failed to demonstrate behavioral benefits but did identify significant alterations in brain activation patterns. It is unclear whether the effects of chocolate on mood are due to the orosensory characteristics of chocolate or to the pharmacological actions of chocolate constituents. Two studies have reported acute cognitive effects of supplementation with cocoa polyphenols. Further exploration of the effect of chocolate on cognitive facilitation is recommended, along with substantiation of functional brain changes associated with the components of cocoa.
Like caffeine, theobromine crosses the blood-brain barrier and binds to adenosine receptors, suggesting it might share caffeine's beneficial effects on mood and vigilance. Therefore, the purpose of this study was to assess the effect of theobromine doses commonly found in foods on mood and vigilance parameters sensitive to caffeine. Caffeine was tested as a positive control. Twenty-four men (age, 23 [3] years) completed 6 double-blind trials during which they consumed experimental beverages, assessed their mood using standardized self-report questionnaires, and completed a 2-hour visual vigilance task. Three experimental doses (100, 200, and 400 mg theobromine) were delivered in a cocoa-based beverage; 3 matched control treatments (0 mg theobromine, 400 mg theobromine, and 100 mg caffeine) were delivered in a non-cocoa beverage. Mean salivary concentrations of theobromine exhibited significant dose-dependent differences (400 mg trials > 200 mg trial > 100 mg trial > 0 mg trials; P < 0.005). At every dose tested, theobromine failed to consistently affect mood state or vigilance (P > 0.05), but 100-mg caffeine significantly decreased lethargy/fatigue and increased vigor (P = 0.006 and 0.011, respectively). These findings indicate theobromine does not influence mood and vigilance when administered in nutritionally relevant doses, despite sharing many of caffeine's structural characteristics.
Cocoa is a dry, powdered, nonfat component product prepared from the seeds of the Theobroma cacao L. tree and is a common ingredient of many food products, particularly chocolate. Nutritionally, cocoa contains biologically active substances that may affect human health: flavonoids (epicatechin and oligomeric procyanidins), theobromine, and magnesium. Theobromine and epicatechin are absorbed efficiently in the small intestine, and the nature of their conjugates and metabolites are now known. Oligomeric procyanidins are poorly absorbed in the small intestine, but catabolites are very efficiently absorbed after microbial biotransformation in the colon. A significant number of studies, using in vitro and in vivo approaches, on the effects of cocoa and its constituent flavonoids have been conducted. Most human intervention studies have been performed on cocoa as an ingredient, whereas many in vitro studies have been performed on individual components. Approximately 70 human intervention studies have been carried out on cocoa and cocoa-containing products over the past 12 years, with a variety of endpoints. These studies indicate that the most robust biomarkers affected are endothelial function, blood pressure, and cholesterol level. Mechanistically, supporting evidence shows that epicatechin affects nitric oxide synthesis and breakdown (via inhibition of nicotinamide adenine dinucleotide phosphate oxidase) and the substrate arginine (via inhibition of arginase), among other targets. Evidence further supports cocoa as a biologically active ingredient with potential benefits on biomarkers related to cardiovascular disease. However, the calorie and sugar content of chocolate and its contribution to the total diet should be taken into account in intervention studies. Expected final online publication date for the Annual Review of Nutrition Volume 33 is July 17, 2013. Please see for revised estimates.
Cocoa is a food ingredient that is important for the contribution of flavor to foods but is also associated with potential health benefits. The chemistry thought to be responsible for its cardiovascular health benefits is the flavanol (flavan-3-ol) antioxidants. Evidence from the literature indicates that natural cocoas are high in flavanols, but when the cocoa is processed with alkali, also known as Dutch processing or Dutching, the flavanols are substantially reduced. This paper provides a survey of the physical and chemical composition of representative natural cocoas and lightly, medium, and heavily alkalized cocoas. As part of the survey, both brown/black and red/brown alkali-processed cocoas were measured. Natural cocoa powders have an extractable pH of 5.3−5.8. Alkalized cocoa powders were grouped into lightly treated (pH 6.50−7.20), medium-treated (pH 7.21−7.60), and heavily treated (pH 7.61 and higher). The natural, nonalkalized powders had the highest ORAC and total polyphenols and flavanols (including procyanidins). These chemical measurements showed a linear decrease as the extractable pH of the cocoa powder increased. Likewise, the flavanol monomers, oligomers, and polymers all showed a linear decrease with increasing pH of the final cocoa powder. When brown/black cocoa powders were compared to red cocoa powders, similar decreases in flavanols were observed with increased alkalization. The average total flavanol contents were 34.6 ± 6.8 mg/g for the natural cocoas, 13.8 ± 7.3 mg/g for the lightly processed cocoas, 7.8 ± 4.0 mg/g for the medium processed cocoas, and 3.9 ± 1.8 mg/g for the heavily processed cocoa powders. The observed linear and predictable impact of alkalization on flavanol content is discussed with respect to other reports in the literature as well as what implications it may have on diet and food manufacturing.Keywords: Alkalization; Dutching; flavanols; flavan-3-ols; procyanidins; antioxidants; cocoa powder; cacao
Background Cocoa beans fresh from the tree are exceptionally rich in flavanols. Unfortunately, during conventional chocolate making, this high antioxidant capacity is greatly reduced due to manufacturing processes. Aim To evaluate the photoprotective potential of chocolate consumption, comparing a conventional dark chocolate to a specially produced chocolate with preserved high flavanol (HF) levels. Methods A double-blind in vivo study in 30 healthy subjects was conducted. Fifteen subjects each were randomly assigned to either a HF or low flavanol (LF) chocolate group and consumed a 20 g portion of their allocated chocolate daily. The minimal erythema dose (MED) was assessed at baseline and after 12 weeks under standardized conditions. Results In the HF chocolate group the mean MED more than doubled after 12 weeks of chocolate consumption, while in the LF chocolate group, the MED remained without significant change. Conclusions Our study demonstrated that regular consumption of a chocolate rich in flavanols confers significant photoprotection and can thus be effective at protecting human skin from harmful UV effects. Conventional chocolate has no such effect.