Cocoa, derived from the Theobroma cacao tree, has been widely used by industry as an ingredient in various food products, like chocolate, jams and jellies [1]. In addition to the food industry, cocoa has also been used as a raw material for cosmetic or pharmaceutical formulations, such as oils, hydratants and cocoa butter products. The wide applicability and interest in the use of cacao is due to its nutritional value, biological properties, stability and economic accessibility. Considering the nutritional aspect, cocoa has important dietary properties, constituting a natural source of macronutrients, as proteins and lipids, and micronutrients, as vitamins and minerals ^[2][3][2,3]. These nutrients are essential for the regulation of metabolism and the maintenance of the biological activities of the organism.

The cocoa fruit is elongated and grooved, supported by a woody peduncle, and has a shell composed of three parts: epicarp, mesocarp and endocarp. The structure of the cocoa bean contains the following components: proteins (12.92 g), fats (48.15–60.5 g, carbohydrates (9.23 g) and fibers (4.9 g). The main fatty acids are oleic (31–35 g), stearic (33–35 g), palmitic (25–28 g) and linoleic (2–3.5 g). Therefore, cocoa has a variety of minerals, including phosphorus, magnesium, copper, potassium and calcium ^[1][2][3][1,2,3], whereas the composition of cocoa and consequently the content/profile of its bioactive compounds can vary according to the genetic characteristics of the species, geographical factors, environmental conditions, maturation stage, cultivation and processing methods. Minerals play a fundamental role in several biological processes and some of them act as enzymatic cofactors in the synthesis of macromolecules ^[1][2][3][1,2,3]. Cocoa is also a source of fiber [4] and methylxanthines, such as theobromine, caffeine and theophylline ^[3][4][3,4]. The cocoa husk is particularly rich in fiber, which favors intestinal function, improves the lipid profile and contributes to cardiovascular health [4]. Furthermore, cocoa is one of the most abundant foods in flavonoids, which are bioactive compounds that exhibit biological properties of great interest for health [2]. Among them, flavonoids have considerable antioxidant, anti-inflammatory, antiallergic, antitumor, antimicrobial and antiviral potential [5].

Flavonoids are phytochemicals present in citrus fruits, berries, vegetables, legumes, cocoa, grains and beverages, like coffee, green tea and red wine [6]. These phytochemicals belong to the class of polyphenols and are classified into several subgroups according to the chemical composition of the carbon chain [7]. The main subgroups of dietary flavonoids are flavanols, flavones, flavonols, flavanones, anthocyanidins and isoflavones [7]. In cocoa, the main flavonoids present in the bean and husk belong to the flavanols subgroup, as epicatechins, catechins, and procyanidins [8]. Thus, flavanols largely contribute to the antioxidant effect of cocoa ^[1][2][4][8][1,2,4,8]. Procyanidins, in turn, are responsible for the astringent taste of cocoa, due to complexation with saliva proteins. Other subgroups of flavonoids are also part of the cocoa composition, such as anthocyanins, flavonols (quercetin, isoquercitin), flavones (luteolin, vitexin), and flavanones (naringenin) [2]. Flavonoids derived from cocoa have the ability to form insoluble complexes by binding with carbohydrates and proteins, and they can interfere with the metabolism of these macromolecule ^[4][8][4,8].

Several studies have reported that the consumption of cocoa can provide health benefits ^[2][3][4][2,3,4]. The internal and external structural part that forms the cocoa (husk, pulp, bean) are sources of macronutrients and micronutrients, such as carbohydrates, lipids, proteins, vitamins and mineral salts, which play a structural, functional and energetic biological role, as well as being rich in bioactive compounds, such as polyphenols and methylxanthines, which have potentially beneficial biological effects on health. The benefits from the use of cocoa are related to the biological properties of several active agents present in its composition, especially the flavonoids. The therapeutic action of flavonoids, in turn, is mainly attributed to their antioxidant and anti-inflammatory potential, considering that these properties are fundamental for the maintenance of tissue homeostasis ^{[9][10][11][12]}[10,11,12,13].

Flavonoids act by eliminating reactive oxygen species (ROS) and minimizing the formation of ROS, as well as reducing the synthesis of important inflammatory mediators, such as tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), interleukin-1 beta (IL-1β), cyclooxygenase-2 (COX- 2) and prostaglandin E2 (PGE2) ^[9][10][10,11]. Flavonoids also act by activating antioxidant enzymes and inhibiting enzymes involved with ROS production, as well as inhibiting the expression and synthesis of factors related to oxidative stress, as nitric oxide (NO) and nitric oxide synthase 2 inducible (iNOS) ^[11][12][12,13]. Neutralization and elimination of free radicals reduce toxicity and cellular oxidative damage, preventing deleterious changes in macromolecules, such as DNA ^[13][14]. Due to these properties, flavonoids and their metabolites may exert therapeutic potential, contributing to the prevention of cardiovascular, neurodegenerative, inflammatory and metabolic pathologies, like osteoarthritis and diabetes mellitus ^[7][9][14][7,10,15], in addition to sedentary and lifestyle-related diseases ^[13][14]. There is evidence in the literature that flavonoids may favor the reduction of plasmatic triglycerides and cholesterol levels and act by inhibiting tumor growth ^[15][16][16,17].

Flavonoids can also have a considerable neuroprotective effect, contributing to the preservation of nervous tissue. The antioxidant and anti-inflammatory potential of flavonoids contributes to this protective effect, considering that cellular oxidative stress and increased levels of inflammatory mediators alter tissue homeostasis, favoring nerve cell apoptosis, axonal degeneration and demyelination ^{[17][18][19][20]}[18,19,20,21]. These molecular and tissue alterations, in turn, are frequently associated with the development of neurodegenerative diseases ^[18][19][21][19,20,22]. Flavonoids also act on bone cell metabolism, favoring the expression of factors that induce bone formation and inhibiting the expression of factors involved in matrix resorption ^{[22][23][24][25]}[23,24,25,26]. The anti-inflammatory action of flavonoids contributes to minimize bone resorption by inhibiting the synthesis of inflammatory mediators ^[22][25][23,26]. The antioxidant and antiapoptotic potential of flavonoids, in turn, favor the survival of bone cells and contribute to the maintenance of tissue homeostasis ^[25][26]. Some flavonoids are even considered phytoestrogens, such as isoflavones. By stimulating osteogenesis, phytoestrogens exert an anabolic effect, contributing to the preservation of tissue structure and to the increase of bone mineral density ^[24][25].

In addition to flavonoids, cocoa has several other bioactive molecules (vitamins, mineral salts, methylxanthines, fibers, proteins and fatty acids) that, together, act beneficially on the different tissues of the organism. Studies report that bioactive agents in cocoa can act to reduce the risk of vascular and blood pressure alterations, coronary heart disease, stroke, cerebral oxidative stress, cognitive impairment and neurodegenerative disorders ^[2][4][13][2,4,14]. Thus, there are reports in the literature that cocoa may have a beneficial impact on cognitive functions ^[2][4][2,4], contributing to the prevention of neurodegenerative diseases and conditions resulting from aging [4]. A beneficial effect of these bioactive agents on inflammatory, immunological and metabolic diseases has also been suggested ^[2][13][26][2,14,27]. The bioactive compounds in cocoa, especially flavonoids and their metabolites, also exert an important prebiotic effect, favoring the growth of beneficial bacteria to the detriment of pathogenic ones ^[27][28]. This modulatory effect on the composition of the microbiota favors intestinal health and reduces the risk of various diseases ^[27][28].

With regard to bone, there is little evidence in the literature about the effects of cocoa consumption on this tissue. A clinical study conducted with women aged 70 to 85 years to investigate the effect of chocolate consumption on bone density and strength did not find a positive association between the frequency of chocolate consumption and an improvement in the evaluated bone parameters. This study considered the frequency of chocolate consumption, as rarely (<1 time/week), moderate (1–6 times/week) and daily (≥1 time/day). Daily consumption of chocolate (1 time/day), when compared to 1 time/week, showed a 3.1% lower body bone density ^[28][29]. Clough and colleagues (2017) showed that theobromine, one of the bioactive components of cocoa, is a xanthine alkaloid found in cocoa and cocoa-derived products, e.g., chocolate, and favors the osteogenic potential of bone marrow mesenchymal stem cells human in vitro ^[29][30]. In this study, the progeny of rats treated with theobromine during pregnancy and lactation, and that received theobromine for a period of time after weaning, showed greater body mass and more accelerated bone development. Microtomographic analysis of the trabecular structures of the tibia showed that the group treated with theobromine presented a considerable increase in the number of trabeculae and a reduction in the trabecular separation compared to the untreated group; however, between the groups, there was no expressive difference in the trabecular thickness. Taken together, the in vitro and in vivo data from this study pointed to a potential effect of theobromine on bone tissue ^[29][30].

The nutritional importance and beneficial effects of cocoa consumption on health were highlighted in a recent literature review [3]. This review compiled several studies that investigated the effects of cocoa on general health, considering different types of diseases or clinical conditions. This comprehensive study of the literature reported that there is a significant association between cocoa intake, in the form of chocolate, and reduced risk of coronary heart disease, estimating that this association can reduce the risk of developing cardiovascular disease and stroke in 37% and 29%, respectively. Some studies reported that the consumption of products containing cocoa can have a vasoprotective effect, improving endothelial function. Other studies have observed a beneficial effect of flavonoids present in chocolate on blood pressure, especially in hypertensive individuals.

Few epidemiological studies have compared dark chocolate with milk chocolate. It is not clear what the ideal amount of chocolate is, given the lack of uniformity in dosing in randomized trials. Most studies performed do not specify the exact type or amount of chocolate used in individual studies. Generally, positive effects on cardiovascular health are seen with a higher percentage of cocoa. Clinical studies also reported that there was an improvement in cognitive functions by the use of cocoa or cocoa-derived products. Additionally, some studies have investigated the effects of cocoa consumption on cancer, but these data are not yet conclusive. Research should advance to expand knowledge about the mechanisms of action and the biological effects of cocoa on health [3].

Figure 1 summarizes the main properties and biological effects of cocoa (pulp, cocoa beans and husk) on health.