Oak Leaves as a New Potential Source for Functional Beverages: Their Antioxidant Capacity and Monomer Flavonoid Composition

OAK LEAVES AS A NEW POTENTIAL SOURCE FOR FUNCTIONAL BEVERAGES: THEIR ANTIOXIDANT CAPACITY AND MONOMER FLAVONOID COMPOSITION

11

Nuria Elizabeth Rocha-Guzmán*, Rubén Francisco GonzálezLaredo*, Blanca Denis Vázquez-Cabral*, Martha Rocío Moreno-Jiménez*, José Alberto Gallegos-Infante*, Claudia Ivette Gamboa-Gómez†, Ana Gabriela Flores-Rueda* *

Research Group on Functional Foods and Nutraceuticals, Department of Chemical and Biochemical Engineering, National Technological Institute of Mexico-Technological Institute of Durango, Durango, Mexico, †Biomedical Research Unit, Mexican Institute of Social Security, Durango, Mexico

11.1 Introduction It has been known for years that diet is of crucial importance as a risk factor for cardiovascular diseases. The consumption of foods integrated into the Mediterranean diet is associated with beneficial effects on health, since many nutrients and phytochemicals in these foods could be independently or jointly responsible for the apparent reduction in the risk of suffering from chronic diseases. Due to the modern pace of life, today one tends to neglect the consumption of fruits and vegetables; therefore, this has led to the development of nutraceuticals and functional beverages. Nutraceuticals are defined as dietary supplements obtained from one or more natural bioactive substances, usually existing in foods, but presented in a nonfood matrix. The main objective on the technology of functional foods and nutraceuticals is to develop products that endorse the intake of beneficial bioactive compounds and help to prevent the risk of suffering from certain illnesses such as cardiovascular diseases, among others. Functional and Medicinal Beverages. https://doi.org/10.1016/B978-0-12-816397-9.00011-X © 2019 Elsevier Inc. All rights reserved.

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382  Chapter 11  OAK LEAVES AS A NEW POTENTIAL SOURCE FOR FUNCTIONAL BEVERAGES

Phenolic compounds present in herbs, vegetables, and fruits are involved in various processes as a defense mechanism against biotic and abiotic stress. Flavonoids also play physiological roles in plants, for example, as promoters of the gene expression involved in the development of nodules, which is accomplished in nitrogen fixation. The flavonoids diversity represents a wide defense system against attack by herbivores and a protection system against genetic material damage caused by ultraviolet radiation. Polyphenols are easily oxidized and act as antioxidants and inhibitors of plant growth. They tend to accumulate as a shield in the outer layers of vegetables and capture up to 90% of UV radiation, preventing the harmful effects of these emissions in the internal tissues of the plant. Plants compete with each other to preserve their territory (i.e., allelopathy); in this competition are involved phenols such as salicylic acid, which are synthesized as toxic phytochemicals against the neighboring individuals, thereby preventing their spreading and development. At the level of microorganisms, plants defend against the attack of pathogens, synthesizing polyphenols such as phytoalexins, which generally are antimicrobial. Vegetal polyphenols (tannins) protect plants, generating flavors (mainly bitter) or textures, which are unpleasant for herbivores. As a group of secondary metabolites broadly distributed in natural products, polyphenols are in general considered health promoters as a result of their antioxidant activity. These compounds are abundant in leaves, barks, seed shells, and tree trunks, commonly as glycoside flavonoids. Among the major phytochemicals found in Quercus leaves are phenolic compounds. The non-timber forest products represent important economic, social, and cultural values, and are used for food, medicinal, and crafts, among others. According to the Food and Agriculture Organization (FAO, 1999), non-timber forest products refer to the “goods of biological origin other than wood, derived from forests and woodland outside the forest and specifically include roots, stems, bark, leaves, galls, flowers and fruits”. This definition excludes, consequently the production of wood chips, coal and wood, as well as tools, wood logs, and crafts made of wood. In particular, the foliage is a very abundant, useless, and worthless resource (Luna et al., 2003). Commonly the non-timber forest products give little or noncommercial value. However, these wastes can have any of the following applications: animal feed (Balentine et al., 1997), soil fertilization (Blanc, 1996), energy production and extraction (Cai and Harrison, 2000), and generation of useful materials for industrial (Cardona et al., 2013) or domestic use (Gonzalez and Gonzalez, 1992), and as a source of functional beverages. From the list, the first two uses have been applied without interruption in natural ecosystems. The third one was probably the original

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natural use by the early man to fight cold weather and predators, and to cook their food or make the first lasting ceramic containers. The fourth application has great importance today, by chemical and biochemical means to produce innovative value-added products such as nutraceuticals.

11.2  Quercus genus Oaks are the trees belonging to the family Fagaceae and to one of the most important genera worldwide: Quercus. This genus is found in almost all the temperate forests of the Northern hemisphere, as well as in some tropical and subtropical regions of the same; there are even some species in drier habitats, in Southeast Asia and Northeastern Africa. In the United States, oaks are located from Canada to Colombia, including Cuba. Two centers of diversity for the gender are recognized. The first is located in Southeast Asia with about 125 species (Valencia, 2004) and the second occurs in Mexico, particularly in mountainous regions, where they form an important part of temperate forests. The number of species in Mexico is unknown; some authors who study its distribution estimate them in 253 species and others calculate among 135–150 species. The forest resource is important in the ecology and economy of Mexico, especially in the state of Durango, where about 44% (5,402,825 ha) of the total area is covered by temperate forests of conifers, pine-oak (Pinus-Quercus), oak-pine, or oaks. Ethnobotanical reports mention that tea from some species of Quercus, in combination with other plants such as Solanum rostranum, show anticarcinogenic effects in patients with gastric cancer, when it is consumed as drinking water. Further investigations regarding antiinflammatory studies of aqueous oak extracts were performed by Gharzouli et al. (1999), who demonstrated cytoprotective properties of aqueous extracts from Quercus ilex root bark compared with aqueous extracts of Punica granatum and leaves of Artemisia herbaalba against the damage caused by ethanol in the stomach. This study was considered as a positive control of tannic acid protection, a compound documented along with other polyphenols such as quercetin and ellagic acid as capable of inhibiting the proton pump present in parietal cells, postulating this mechanism for the protection of the stomach against harmful agents. In this study, the presence of high concentrations of tannic acid in the aqueous extracts of Q. ilex and P. granatum was detected, whereas the leaves of A. herba-alba only presumed the presence of monomeric flavonoids. In the last decade, our research group has aimed to obtain and characterize new bioactive food ingredients and its application to the development of new functional foods, supported by the studies of bioavailability and biological

384  Chapter 11  OAK LEAVES AS A NEW POTENTIAL SOURCE FOR FUNCTIONAL BEVERAGES

activity. In this way, it is sought to increase the scientific evidence on the healthy properties of these new foods or functional beverages. In particular, and focusing on the study of oak, it has been determined its potential as a source of high value-added by-products, characterizing its antioxidant capacity (Gamboa-Gómez et al., 2013) and potential as an anticarcinogenic agent (Rocha-Guzmán et  al., 2009; Moreno-Jiménez et  al., 2015). The anti-topoisomerase activity of herbal infusions from Quercus species has been identified in in vitro models using mutated yeasts and antimicrobial activities toward enteric pathogens (Sánchez-Burgos et  al., 2013). Additional studies have explored alternatives for the production of food products based on phenolic compounds from oak that have demonstrated an antihypertensive potential, particularly when the species of study is Quercus resinosa (Rivas-Arreola et al., 2010). Recently, a significant gastroprotective potential has been demonstrated in human gastric-intestinal cellular models (Sánchez-Burgos et al., 2013). Mexico has a great diversity of edible plants from which it can be obtained herbal infusions with apparent protective potential against several pathophysiologies. One of these sources is the leaves from oak trees (Quercus spp.), also known as tea trees. The oaks belong to the family Fagaceae, Quercus genus. They are deciduous trees and shrubs with leaves of varying size irregularly shaped fruit and acorns. The oaks are associated with pines and firs; they show affinity for diverse soils and temperate climates of mountainous areas. The oak is distributed in the mountainous regions of the state of Durango, Sonora, Chihuahua, Coahuila, Veracruz to Chiapas, and Mexico, forming large forests with pines at elevations ranging from 1100 to 2800 m. The 44% of total area of the state of Durango consists of oak-pine forests, which have a large number of registered species and varieties of oaks. In Durango, there are 39 known species of the Quercus genus, of which about 20 are white oaks with representative species like Q. resinosa, Quercus grisea, Quercus laeta, and Quercus rugose, and the rest are red oaks, including Quercus sideroxyla, Quercus durifolia, Quercus eduardii, etc. Based on the botanical characteristics, different oak species can be classified into two mayor groups or botanical orders: Erythrobalanus (black or red oaks) and Leucobalanus (white oaks). The distinctive anatomical difference between these two groups is the presence of tyloses in white oak cells and its absence in the red oak. Oaks are some of the more notable floristic components in various temperate and tropical communities worldwide. Particularly, they are part of distinctive shrubs, bushes, and plant tree populations, which are distinctive of the mountainous and forest areas of Mexico. Many studies on the utilization of oaks mainly highlight their timber use due to their physical, mechanical, and anatomical properties; while this use is widely recognized, its nonwoody utilization has been little

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valued, although in several ethnic communities in Mexico the production and processing of ethnomedicinal products or foodstuffs are part of their culture (Luna et al., 2003). In Mexico, there are a many oak species that are used for nonwoody purposes, among which are: Q. eduardii, Q. sideroxyla, Q. durifolia, Q. resinosa, Q. laeta, and Quercus obtusata. These species have been used by different ethnic groups such as Tarahumara, Tepehuano, Purepecha, and Mixteco for medicinal, nutritional, and forage purposes.

11.3  Beverages From Quercus It has been shown that tea (Camellia sinensis) and herbal infusions have multiple physiological effects due to the presence of polyphenols, in addition to the evidence of the biological potential associated with antiinflammatory, gastroprotective, and anticarcinogenic activities. It is noteworthy that the tea is a drink obtained from the leaves of the plant C. sinensis, whereas an herbal infusion is obtained from aerial parts of trees or herbs that have been poured in hot water for a while. They are popular due their aroma, antioxidant properties, therapeutic applications, and folkloric traditions. Specifically, an infusion is considered such as a beverage obtained from the parts of aromatic herbs or plants, which have been placed in boiling water and allow steeping for short time before drinking (Ordoudi et al., 2015). In particular cases, decoction are used to extract vegetal principles from hard materials such as barks, roots, seeds, or wood, which are boiled for at least 10 min and then let it still for several hours. In recent years, the interest and consumption of these beverages has increased considerably among the Mexican population and expected to remain in expansion toward 2018. According to Euromonitor (www.euromonitor.com), forecasted sales in Mexico for 2018 estimate a 39% growth in this sector compared to 2014. Consequently, several research groups have explored natural products used in folk and traditional medicine for the production of beverages with beneficial potential. Mexico has a great diversity of edible plants from which herbal infusions with apparent medicinal or nutraceutical properties can be prepared. However, such properties have not been systematically and scientifically proven in vitro or in vivo, and so there is limited information about them. The use of herbal infusions as antioxidant nutraceuticals in traditional medicine in Mexico is a common practice (Figueroa-Pérez et al., 2014). Although the active components in most cases are unknown, the evaluation of pharmacological effects of crude extracts from herbal teas, natural product screening, and discovery of new biologically active compounds are goals for the scientific community and technological challenges for the pharmaceutical companies.

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In recent decades, several research groups have explored natural sources used in folk and traditional medicine for the manufacture of beverages with potential health benefits. Some functional beverages have transcended their sources to become everyday products in more than one continent. The development of functional beverages from defoliation products of oak (Quercus spp.) may mitigate consumers thirst, but also contain phytochemicals that provide health-protective effects, is considered as an innovative area with high value added. Oak leaf infusions used by local ethnic groups as a refreshing drink, contains high amounts of polyphenols. Luna et al. (2003) indicate that the species Q. obtusata is used by the Mixteco for medicinal purposes and food, Q. sideroxyla used by Tepehuanos for food purposes, Q. durifolia used by Totonacos and Tepehuas for food purposes, and Q. eduardii is used for medicinal purposes. The use of herbal infusions is very popular due its aroma, antioxidant properties, and therapeutic applications. We have studied the acceptability of waste or pruning leaf infusions of different Quercus species, finding that oaks with more flavonoid content have lower acceptability (Rocha-Guzmán et al., 2012). This phenomenon is due to astringency, where polyphenols bind the proline-rich proteins of saliva in the mouth, resulting in a soluble precipitate. This stimulation also affects the rheological properties of saliva, leading to friction and reducing its lubricity. Additionally, tannins are compounds that have the ability to form complexes with proteins, polysaccharides, nucleic acids, steroids, alkaloids, and saponins. They present astringency (i.e., harsh taste that dries out the mucous membranes of mouth), vasoconstrictive, and antiinflammatory activities and can be used in the preventive treatment of various diseases such as cardiovascular disease, cancer, and other degenerative diseases. Based on their chemical origin, tannins are classified into two groups: hydrolysable tannins and condensed tannins. Hydrolysable tannins are polymers of phenolic acids (gallic and ellagic acid) bonded on a glucose backbone. Condensed tannins or proanthocyanidins are polymers of catechin and flavan-3-ols. It has been reported in Quercus species the presence of hydrolysable tannins such as vescalagin and castalagin (García-Villalba et  al., 2017). Individual hydrolysable tannins, proanthocyanidins, ­flavonoid glycosides, and simple phenolics were reported by Yarnes et al. (2008), who demonstrated that the phenolic composition varies seasonally in Q. grisea and their hybrids.

11.3.1  Infusions of Quercus Typical polyphenols in oak leaves decoctions include catechin, quercetin, kaempferol, naringin, naringenin, and ellagic acid (RivasArreola et  al., 2010; Gamboa-Gómez et  al., 2017). Particularly, our

Chapter 11  OAK LEAVES AS A NEW POTENTIAL SOURCE FOR FUNCTIONAL BEVERAGES   387

research group has explored the presence of flavonoid monomers, quantifying them through the monitoring of multiple reactions by mass spectrometry, determining the presence of rutin, quercetin glucuronide, kaempferol 3-O-glucoside, and phloridzin, among other compounds. Phloridzin is a dihydrochalcone glycoside recognized for its astringent properties and antidiabetic effects. This compound was detected at higher concentrations in white oak species, particularly in Q. resinosa (1.003 ± 0.116 μg/mL). It is remarkable to mention that gallocatechin content present in Quercus convallata (25.22 ± 2.38 mg/L) was an order of magnitude greater than Q. resinosa (6.36 ± 1.61 mg/L) and Quercus arizonica (5.52 ± 1.20 mg/L) (Table 11.1). Gallocatechin has been identified by Ko et  al. (2009) as a compound that may decrease the osteoclastogenesis at a concentration of 20 μM even as its gallocatechin gallate ester derivate. Another compound present in oak infusions is (+)-catechin, which is 1.92 times more abundant in Q. resinosa than in Q. sideroxyla, while in the species Q. convallata and Q. arizonica is 87% and 85% even lower than­ Q. resinosa, respectively. It is important to note that these compounds must be conjugated (glucuronidated or sulfated) to be bioavailable and bioactive. However, we can find them in nature as glucuronidated compounds, such as quercetin glucuronide. This compound occurrence was significantly detected in Q. sideroxyla (10.07 ± 1.03 μg/mL), with 83% higher than Q. resinosa and 81% higher than Q. laeta. Other glycosylated flavonoids were found in the herbal infusions. First, rutin was present in the following order: Q. sideroxyla > Q. resinosa >  Q. durifolia > Q. arizonica > Q. grisea, and not detected in Q. convallata and Q. eduardii. Kaempferol 3-O-glucoside was detected abundantly in Q. resinosa (8.34 ± 0.13 μg/mL) and Q. grisea (4.62 ± 0.26 μg/ mL). Finally, Q. resinosa was the only species where naringenin was detected; this flavanone has been reported with antioxidant, estrogenic, and anticarcinogenic properties. Dai et al. (2015) indicate that seasonal metabolic regulation affects the biochemical pathways of biosynthesis of flavan-3-ols and flavonols, significantly influencing the phenolic composition of C. sinensis. These investigators have reported the presence of 11 flavan-3-ols, 8 catechin dimers, 18 flavonols and flavonol/flavone glycosides, 5 amino acids, 12 phenolic acids, 3 nucleosides, 2 organic acids, 2 ­lipids, and 6 carbohydrates. In our oak leaves studies, the presence of 7 ­flavan-3-ols, 2 flavonols, 18 flavonol/flavanone glycosides, 1 flavanone, 1 flavone, and 4 other unknown compounds were reported (Table 11.2). Polymerization of polyhydroxy-flavan-3-ol units such as (+)-catechin and (−)-epicatechin (EC) or their gallate esters produce oligomers and polymers called proanthocyanidins (often recognized just as procyanidins), in this context, the presence of 4 procyanidin dimers in infusions was also reported. From the polyphenolic profile

Table 11.1  Monomers of flavonoid concentration (mg/L) present in six herbal infusions of oak (Quercus spp.) Compound

Rt (min)

[M-H]− m/z

MS/MS transitions

Q.r.

Q.a. a

Q.c a

Q.s. c

b

Q.d.

Q.e.

1

Gallocatechin

2.56

305

164, 125

6.369

5.521

25.227

0.811

nd

nd

2 3 4 5 6 7 8 9 10 11

Catechin Epicatechin Gallocatechin gallate Rutin Quercetin glucuronide Epicatechin gallate Kaempferol-3-O-glucoside Naringin Phloridzin dehydrate Naringenin

4.46 5.18 5.32 6.30 6.61 6.73 7.35 7.65 8.17 9.33

289 289 457 609 477 441 447 579 471 271

203, 109 162, 125 305, 169, 125 300, 271 301, 151 289, 169 285 271, 151 435, 273, 167 151, 119, 107

48.244a nd 0.069a 2.550a 1.736a 0.504a 8.341a 0.035a 1.003a 0.68a

6.147c nd 0.022a 1.376c 1.932a 0.102c nd 0.011a 0.966a nd

6.895c 1.813 a 0.144b nd 0.598b 0.056b 1.029c 0.034a 0.812a nd

25.114d nd 0.015a 5.713d 10.079c 0.120c 1.755c 0.038a 0.211c nd

3.128e nd 0.011a 2.388a 0.015b 0.019b 0.780d 0.031a 0.077d nd

0.111b nd 0.041a nd 0.399b 0.021b 0.052e 0.029a nd nd

Q.r., Quercus resinosa; Q.a., Quercus arizonica; Q.c., Quercus convallata; Q.s., Quercus sideroxyla; Q.d., Quercus durifolia; Q.e., Quercus eduardii. nd means not detected. Data are expressed as the mean of triplicate samples. Different literals in rows mean statistical difference between samples (Tukey, P ≤.05).

Chapter 11  OAK LEAVES AS A NEW POTENTIAL SOURCE FOR FUNCTIONAL BEVERAGES   389

Table 11.2  Qualitative Analysis of Flavonoids Present in Leaves of Six Oak Species (Quercus spp.) No.

Phenolic Compounds

Rt (min)

[M-H]− m/z

1 2 3 4 5 6 7 8

2.164 3.92 4.12 5.77 5.85 5.96 6.51 6.97

577 305 577 577 493 479 457 593

9

Procyanidin dimer (epi) gallocatechin Procyanidin dimer Procyanidin dimer Myricetin glucuronide Myricetin glucoside (epi) gallocatechin gallate Kaempferol-3-O-coumaroyl glucoside Unknown

7.08

609

10

Unknown

7.19

609

11 12 13

Kaempferol-3-O-glycoside Isorhamnetin 3-O-glucoside Kaempferol-3-O-malonyl glucoside Kaempferol rhamnoside Quercetin-3-O-rutinoside

7.35 7.47 7.80

447 477 533

8.04 8.15

431 609

14 15

16

Quercetin-3-O-rutinoside isomer

8.32

609

17

8.59

593

8.75 8.76

285 593

20

Kaempferol-3-O-coumaroyl glucoside isomer Luteolin p-coumaroyl kaempferol glucoside Unknown

8.97

593

21 22 23

Unknown Naringin isomer Unknown

9.08 9.13 9.18

593 579 609

18 19

MS/MS transitions 457, 441, 305, 289 164 425, 407, 289 425, 407, 289 317 359, 317, 270 305, 169, 125 533, 507, 489, 477, 301, 285 593, 533, 507, 489, 479, 477 593, 533, 507, 489, 479, 477 285 314 489, 469, 433, 301, 285, 271 285 593, 533, 489, 477, 463, 431, 317, 301, 285 593, 533, 489, 477, 463, 431, 317, 301, 285 533, 507, 489, 477, 301, 285 241, 217, 175 477, 461, 447, 431, 317, 285 533, 507, 489, 477, 285 479, 461, 447, 317 271, 151 593, 477, 461, 447

Species Qr, Qr, Qa, Qc, Qs, Qe Qr, Qa, Qc, Qs, Qd, Qe Qr, Qa, Qs, Qa, Qc, Qe Qr, Qa, Qc, Qs, Qr, Qa, Qc, Qs, Qd Qa, Qs, Qe Qr, Qa, Qc, Qr, Qa, Qc, Qr, Qa, Qc, Qs, Qr, Qa, Qc, Qa, Qc, Qs, Qe

Qr, Qa, Qc, Qs, Qd, Qe

Qr, Qa, Qc, Qs, Qd, Qe Qd, Qe Qr, Qa, Qc, Qs, Qd, Qe Qr, Qa, Qc, Qs, Qd, Qe Qs, Qe Qr, Qc, Qd, Qe Qr, Qc, Qs, Qe

Qr, Quercus resinosa; Ql, Quercus arizonica; Qo, Quercus convallata; Qs, Quercus sideroxyla; Qd, Quercus durifolia; Qe, Quercus eduardii.

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mentioned, 5 flavan 3-ols, 2 flavonols, 5 flavonol/flavanone glycosides, and 1 flavanone were quantified (Table 11.1). Flavonols, flavonols/flavones glycosides, and procyanidins are important tea pigments that have been described with relevant antioxidant activity; it is attributed to them the biological response associated with the consumption of herbal infusions of these species by some ethnic and mestizo communities of Mexico, which is a part of its traditional culture.

11.3.2  Kombucha Analogues Based on this background, preliminary studies on fermentation of infusions from oak leaves (Q. resinosa) with the Kombucha consortium have been carried out. With this process, it has been demonstrated that antioxidant capacity and the sensorial acceptability are improved, decreasing the characteristic astringency of these herbal infusions (Vázquez-Cabral et al., 2014). This section aims to highlight the bioactive ingredients present in oak decoctions as well as the compositional changes in flavonoid monomers resulting from the action of the Kombucha microbiome; one of the possible use of the acetic acid bacteria present in the consortium, is the metabolism of bioactive compounds. In our research group, preliminary studies of low-molecular metabolite profiles of fermented products have been carried out, using Kombucha as a model, without addressing bioactive compound conjugation studies yet. Kombucha tea is a sour drink that is produced by the fermentation of black tea and sugar by a symbiotic association of bacteria and yeasts that form the “Chinese Tea Mushroom” or Kombucha Fungus. Black tea and white sugar have proved to be the traditional and best substrates for the preparation of Kombucha tea, although there are also studies where green tea has been used. Bacteria and yeasts present in Kombucha form a powerful symbiosis capable of inhibiting the growth of potential contaminating bacteria (Balentine et al., 1997; Liu et al., 1996). The main bacteria found in the tea fungus are: Acetobacter xylinum (Balentine et al., 1997), Acetobacter xylinoides and Bacterium gluconicum (Reiss, 1994), and Acetobacter aceti and Acetobacter pasteurianus (Liu et  al., 1996). Yeasts identified as Schizosaccharomyces pombe, Saccharomycodes ludwigii, Kloeckera apiculata, Saccharomyces cerevisiae, Zygosaccharomyces bailii, Brettanomyces bruxellensis, Brettanomyces lambicus, B. custersii, Candida, and Pichia species (Balentine et  al., 1997; Liu et  al., 1996; Mayser et al., 1995) have been also identified in the tea fungus. During the fermentation process, the invertase hydrolyzes sucrose to glucose and fructose, producing ethanol as a metabolite (Reiss, 1994; Sievers et al., 1995). Yeasts selectively take fructose primarily for the production of ethanol. The available glucose is used by bacteria that

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make up the Kombucha microbiome in two main ways: the catalase present in the system transforms the glucose to the glucono-∂-lactone metabolite (Balentine et al., 1997), which is spontaneously isomerized to gluconic acid and (Blanc, 1996) glucose is oxidized by the action of the enzyme UDP-glucose-dehydrogenase to the UDP-glucuronic metabolite, which is hydrolyzed for the release of glucuronic acid. An alternative route is the action of UDP-glucuronosyl transferase, which can transfer the oxidized sugar to xenobiotics such as flavonoids releasing UDP and yielding glucuronidated compounds, presumably with greater bioavailability and bioactivity. It has been reported that the product at the seventh day of fermentation has optimal sensorial characteristics and that letting fermentation for more days makes Kombucha tea acidic and unpleasant. The fermentation temperature significantly influences the kinetics of substrate consumption and product formation; some authors found that the optimum temperature is 28°C. In addition, it has been established that the composition of the fermented tea depends on the consortium (Reiss, 1994; Blanc, 1996) and on the aggregate inoculum concentration. With regard to sucrose, a concentration of 50 g of sucrose/L has been reported to give an optimum balance of ethanol and lactic acid concentrations; the use of any other type of sugar (lactose, glucose, or fructose) may have a different influence on the formation of these metabolites, although the effect on taste is small (Reiss, 1994). The taste of Kombucha tea changes from fruity, subtly bitter and frothy after a few days of fermentation to a vinegary flavor, resulting from a prolonged incubation period (Reiss, 1994; Blanc, 1996). To obtain a pleasant drink, the fermentation must end when the titratable acidity is among 4–4.5 g/L. The biogenesis of sucrose at the early stages of the fermentation process has not been reported yet, however, it appears in the system at the first 48 h. This biogenesis can be attributed to the metabolic activity of Gluconoacetobacter xylinum, present in the consortium and responsible for static cultures of the formation of a cellulose biofilm (Nguyen et al., 2008), in which cells whose metabolism is aerobic are embedded. Particularly in the oak-kombucha system, the presence of the bacteria G. xylinum, Gluconoacetobacter liquefaciens, and Acetobacter aceti has been identified in the biofilm formed. In addition, yeasts of the species Candida apicola, Kluyveromyces delbruckii, and Torulospora marxianus have been identified. It should be mentioned that it is necessary to carry out a study on the population dynamics of the system to determine how the phytochemical composition influences the development of the members of the consortium, as well as to study the composition of the consortium in the beverage. The oxidation of the polyphenols of tea during the fermentation leads to the depolymerization of proanthocyanidins with the

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consequent release of catechins, theaflavins, and theaflavinic acid. Jabalayan et al. (2008) found that the content of total phenolic compounds in black tea increases progressively, in a way dependent on the time of fermentation. These bioactive compounds have been termed as high-level antioxidants because of their ability to trap free radicals and reactive oxygen species (ROS). Specifically, in fermented beverages formulated with Q. resinosa decoction this behavior was not detected, since the monomers of flavonoids decreased as a result of the action of the kombucha consortium. Vázquez-Cabral et al. (2014) postulated that compounds such as flavanols and ellagitannin monomers decreased their abundance when this species of oak was used as substrate for the Kombucha consortium, associating this reduction with the increase of acceptability of the developed products. However, when changes in the profile of flavonoid monomers have been explored in other white oak species (Q. arizonica and Q. convallata) and compared against red oak species (Q. sideroxyla, Q. durifolia, and Q. eduardii), in general an increase of this group of phenolic compounds is detected (Fig. 11.1). The trend in consumer preference for products based on decoctions of oak-fermented beverages with the Kombucha consortium shows that the formulations prepared with Q. convallata presented high acceptability by panelists (Fig. 11.2) as reported by Rocha-Guzmán et al. (2012) for the decoctions of leaves of Q. resinosa, Q. sideroxyla, Q. durifolia, and Q. eduardii.

11.4  Biological Effects of Oak Beverages Plant extracts with antioxidant activity, including tea, have been proposed for the treatment of various physiopathologies. Flavonoids and other polyphenols found in some of these extracts have been considered in many studies as potent antioxidants. In this sense, there is increasing interest in learning about their role played in diet, to understand their mechanisms of action in vivo and especially their beneficial effects on health. The ability of some plant foods for reducing disease risk has been associated at least in part to the presence of nonnutrient secondary metabolites (phytochemicals), which have proven to exert a wide range of biological activities. These phytochemicals have a low potency as bioactive compounds when compared with drugs. However, if they are consumed regularly and in significant quantities as part of the diet, they may have a significant long-term physiological effect, so they can be considered as alternate, more effective, and less toxic therapeutic alternatives for treating diverse physiological disorders. Polyphenols are common constituents in plant foods and the main antioxidants in our diet. The main sources of polyphenols in the diet

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Fig. 11.1  Profile of flavonoid monomers identified by LC-ESI-MS/MS through monitoring of multiple reactions in decoctions and fermented beverages of three white oak and three red oak species (Quercus spp.)

Fig. 11.2  Consumer preference of fermented beverages of three white oak and three red oak species (Quercus spp.)

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are fruits and beverages. As antioxidants, polyphenols may protect cell constituents against oxidative damage and therefore, limit the risk against various degenerative diseases associated with oxidative stress. Phenolic compounds are widely distributed in the plant kingdom and are located in all plants and therefore, can be located basically in all food groups. Benefits attributable to this type of beverages are due to its high content of ellagitannins and flavonoids, which exert their action through the induction of antioxidant enzymes and the scavenging of ROS, among other mechanisms. However, these phytochemicals are involved in the astringency of the products. The ellagitannins, flavonoids, and other polyphenols found in some of these sources have been considered in many biological studies. In this regard, there is increasing interest in understanding the biological activity of these phenolic compounds and the role they play in the diet to understand its mechanism of action in vivo and especially its beneficial effects on health (Kancheva and Kasaikina, 2013). Currently, the functional beverage industry is a very successful field from the economic point of view and because of its impact on health and wellness has being labeled as an “alternative medicine” at the same level of herbal remedies and acupuncture, which still are considered as unconventional medicine therapies. The term botanical medicine has been related with phytochemicals, in such form that there is some confusion between nutraceuticals, dietary supplements, and pharmaceuticals, thus the area of nutraceuticals has received special attention by the FDA (US Food and Drug Administration, 1999). These terms are in addition to those associated with other constituents with biological activity but different origin such as zoochemicals (chocolate, conjugated linoleic, and n-3 fatty acids), fungochemicals (β-glucans, lentinan, schizophyllan, and other compounds in mushrooms), bacteriochemicals (equol, butyrate, and other compounds formed from gastrointestinal flora fermentation) (Xie et al., 2013). In the last decade, the potential of oak decoctions in different biological models has been explored. The genotoxicity of Q. resinosa leaves decoctions was evaluated on HeLa cells as well as its underlying mechanism by the single-cell electrophoresis assay (comet assay), demonstrating that phytochemical compounds present in extracts obtained from their decoctions increase the oxidative process and other damage to DNA in transformed human cells (Rocha-Guzmán et  al., 2009). This has led us to postulate that defoliation products of this specie (Q. resinosa) may serve as a potential source of phenolic compounds with anticancer activity. Additional studies have shown that oak beverages have anticarcinogenic (Moreno-Jiménez et  al., 2015), antioxidant (Rocha-Guzmán et  al., 2012), antimicrobial (SánchezBurgos et  al., 2013), antiinflammatory (Vázquez-Cabral et  al., 2017),

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antihypertensive (Rivas-Arreola et  al., 2010), and antihyperglycemic effects (Gamboa-Gómez et al., 2017) among other biological activities. Most in vitro biological activities have been performed using the aglycone or free forms of polyphenols. In nature, however, flavonoids are conjugated with sugars, which may affect the antioxidant properties of the compounds. In addition, recent studies have demonstrated the limited bioavailability of most polyphenols and the role of conjugated species such as glucosides or glucuronides in absorption and circulating forms in the body. Although deglycosylation is likely to occur either pre or post-uptake of foods, the metabolism of these compounds in vivo, lead to a neoconjugation of one or more hydroxyl groups with sulfate and glucuronic acid. The antioxidant properties of polyphenols are generally associated with the presence of phenolic groups with ortho-dihydroxy patterns. The nature and position of these functional groups and their substitution will affect subsequent biological activities and the possibly reduction or suppression of the activities detected in the aglycone forms (Marvarin and Azerad, 2011). Glucuronidation is the main conjugation reaction that is catalyzed by different isoforms of UDP glucuronosyl transferase. In mammals, these enzymes are located mainly in the endoplasmic reticulum and participate in the elimination of many endogenous compounds and xenobiotics because the main substrates of these isoforms are amines, hydroxylated compounds, and carboxylic acids (Kaivosaari et  al., 2011). Some studies indicate that sources rich in flavonoids subjected to fermentation may have an impact on the bioavailability of these phytochemicals (Cardona et  al., 2013; Espín et al., 2017; Williamson and Clifford, 2017). Hutchins et al. (1995) and Slavin et al. (1998) documented that cooked soybeans subjected to fermentation to make tempeh (i.e., using Rhizopus oligosporus) increase the bioavailability of flavones when compared to unfermented soybeans. In this context, the absorption of phenolic compounds from food matrices will depend on their physicochemical properties such as molecule size, configuration, lipophilicity, solubility, and pKa (Hollman, 2004). Conjugation of xenobiotics with glucuronic acid or sulfate is commonly known as detoxification routes. These routes result in increased solubility and molecular weight of the compound, necessarily excreted in the bile. The ingested glycosides are subjected to hydrolysis in the intestine by the colonic flora and the endogenous enzymes producing aglycones. In the enterocyte, the aglycones are then glucuronidated and can pass through the basolateral membrane of the enterocyte and thus into the vascular system and systemic circulation, or can be transferred back into the luminal compartment by P-glycoprotein or multiresistance proteins drugs (Yang et al., 2017). On the other hand, untransformed aglycones can undergo glucuronidation by hepatic

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microsomes. The total intake of a polyphenol is, therefore, a complex interaction between the biochemistry of the polyphenol glycoside, the metabolism of its aglycones, and the rate of transport of each form. However, it is recognized that the major part of the flavonoids circulating in blood is the conjugated form either glucuronidated or sulfated. Most flavonoids, except for catechins, are usually present in the diet as β-glycosides. Glycosides are considered very hydrophilic to be absorbed by passive diffusion into the small intestine, therefore, only their aglycones can be absorbed. Previous studies have shown that some carbohydrates of polyphenols are hydrolyzed by floridzin lactase hydrolase (LPH), a β-glycosidase that is found outside the small intestine membrane (Yasuda et  al., 2015). The substrate specificity of the LPH enzyme varies significantly in a wide range of flavonols, flavones, flavanones, isoflavones, and anthocyanins (glycosides, galactosides, arabinosides, xylosides, rhamnosides, and galactosides). Only some glycosides are efficiently hydrolyzed by LPH, more or less independent of the aglycone type in the glycoside (Islam et al., 2014). Glycosides that are not substrates for this enzyme will be transported to the colon, where the bacteria are able to hydrolyze flavonoid glycosides, but at the same time, the liberated flavonoid aglycones will be degraded (Valentová et al., 2014). Because the absorption capacity of the colon is much lower than that of the small intestine, only marginal absorption of these glycosides is to be expected. For the above, in the metabolism of polyphenols, two compartments are considered. The first compartment consists of tissues such as the small intestine, liver, and kidneys. The colon is the second compartment. Flavonoids are just partially absorbed in the small intestine and then with the secreted bile reach the colon along with the nonabsorbed flavonoids. In the first compartment, mainly the small intestine and liver, the biotransformation enzymes act on flavonoids and their metabolites of the colon (Fernandes et al., 2014). The kidney also contains enzymes capable of biotransforming the flavonoids. Among the metabolites formed in the colon has been reported the conjugation of the polar hydroxyl groups with glucuronic acid, sulfate, or glycine. In addition, O-methylation by the enzyme catechol-Omethyltransferase plays an important role in the inactivation of the catechol fraction, that is, the two adjacent (ortho) aromatic hydroxyl groups, flavonoids, and their metabolites of the colon (Kiss and Soares-da-Silva, 2014). Conjugation reactions are very efficient in humans, with important proportions of flavonoids in plasma and urine being conjugated, and present not only as flavonoid aglycones. Some authors have identified circulating plasma conjugates for polyphenols, mainly glucuronides of isoflavones, catechins, flavanones, and anthocyanins (Felgines et al., 2003). Catechins appear to take a separate position in the efficiency of conjugation and this is in function of the catechin type ranging from

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10% to 80%. The conjugation of phenolic acids and other metabolites of the colon from flavonoids also seem to occur less efficiently, with conjugation rates ranging from 13% to 100%, depending on the type of phenolic acid. In the colon, the microorganisms degrade the flavonoid molecule in the course of which the oxygen from the containing heterocyclic ring is taken apart. Subsequent degradation products, of course, can be absorbed because they are found in urine and plasma (Espín et al., 2017). These may include a variety of hydroxylated carboxylic acids. The total intake of a polyphenol is, therefore, a complex interaction between the biochemistry of the polyphenol glycoside, the metabolism of its aglycones, and the rate of transport of each form. However, it is recognized that the major part of the flavonoids circulating in the blood are either their glucuronidated or sulfated conjugated forms. However, not enough is known about glucuronosyl flavonoids present in food sources because is postulated that they can also enter the intestine through the biliary tract after metabolism in the liver (i.e., enterohepatic circulation). Although the mechanism is most likely to be disrupted by the β-glucuronidase enzyme in the colon prior to the absorption of its aglycone forms, which can then be re-glucuronidated by the action of UDP-glucuronosyltransferase in the small intestine or in the liver. It is necessary to delve into the elucidation of the potential role and the intrinsic activity of different conjugated forms of polyphenols. In vitro experiments using flavonoids aglycones or glycosidic conjugates have been carried out by Lotito et  al. (2011) demonstrating that the glucuronation or sulfation of quercetin affects its documented inhibitory effect on the expression of adhesion molecules, while methylation retains its anti-inflammatory activity. However, this type of cell-culture research requires careful considerations of absorption and bioavailability for its proper interpretation, since experiments carried out by the same research group have demonstrated that methylated EGCG inhibits dose-dependent expression induced by tumor necrosis factoralpha (TNF-α) of intercelular adhesion molecule (ICAM)-1, but no other adhesion molecules, while EGCG was ineffective for this purpose. It is important to keep in mind that the biological activities of metabolites cannot be predicted or extrapolated from their dietary forms. Therefore, the study of biological responses to physiologically relevant forms at systemic circulating concentrations is critical for an appropriate assessment of the beneficial health potential of dietary flavonoids. In addition, it is necessary to consider that the in vitro studies of aglycones and glycosidic compounds are not relevant when extrapolated to humans since there are no enzymes in the organism that will participate in the bioconversion of these metabolites. Such investigations should be taken only as approximations.

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The bioavailability of catechins differs markedly among the group of proanthocyanidins. It is highly documented that unconjugated EGCG is the most abundantly detected form in plasma, with a proportion between 77% and 90% of what is consumed. The other catechins are highly conjugated with glucuronic acid and/or sulfate groups (Rahman et al., 2006). For detailed kinetic analyzes of the bioconversion of bioactive compounds requires the use of sensitive analytical measurements such as liquid chromatography coupled to mass spectrometry (HPLC-MS). The most accurate approach also contemplates the use of glucuronidated metabolite standards. However, the number of commercially available glucuronidated standards is limited. The preparation of glucuronides presents significant challenges to the existing glucuronidation methods. Several methods have been described for obtaining these conjugates involving chemical and chemo-enzymatic methods, extraction from plants, isolation of blood or urine after consumption of flavonoids or enzymatic synthesis with crude microsomal preparations or purified glucuronosyltransferases.

11.4.1  Antiinflammatory Effect Numerous natural and synthetic molecules have been studied in order to find more specific therapeutic strategies with fewer side effects. Among the natural molecules with a proven effect on cardiovascular diseases are phenolic compounds, since their intake is associated in human and animal experiments with the decrease in: dyslipidemia and atherosclerosis (Balentine et al., 1997), endothelial dysfunction and hypertension (Blanc, 1996), platelet activation and thrombosis (Cai & Harrison, 2000), and the inflammatory processes associated with the induction and establishment of cardiovascular diseases (Cardona et al., 2013). In order to study the glucuronidation of various flavonoid substrates present in sources rich in these compounds such as oak leaves, the use of the Chinese Kombucha consortium as enzymatic machinery for the conjugation of these bioactive compounds can be postulated as a promising strategy. Studies conducted by Vázquez-Cabral et al. (2017) indicate that flavonols such as quercetin, myricetin, and kaempferol are glucuronidated by the action of the kombucha consortium, and that these metabolites are effective antioxidant and anti-inflammatory agents in human macrophages.

11.4.2  Anticarcinogenic Activity There is increasing interest in the role of different sources of phytochemicals in health and disease. One referent source for that is tea. The tea produced from the C. sinensis plant is after water, the most

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widely consumed beverage in the world. Among the teas consumed in the world, green tea is the most studied for its health benefits, including its chemopreventive efficacy. Epidemiological studies suggest that regular consumption of tea reduces cancer risk. Although tea has several components, the interest has been focused mainly on the polyphenols, especially those found in green tea. The green tea polyphenols include (−)-epigallocatechin gallate (EGCG), (−)-epigallocatechin (EGC), (−)-epicatechin gallate (ECG), and (−)-EC. There is an increasing evidence of the antiinflammatory effects of green tea polyphenols, which is possibly mediated by its antioxidant properties. Yang et al. (1998) examined the effects of oral administration of a mixture of green tea polyphenols in the expression of TNF-α in a rodent model, injecting intraperitoneally 40 mg/kg of lipopolysaccharide (LPS), and measuring after 90 min the serum levels of TNF-α. They found that green tea polyphenols dramatically decreased the levels of TNF-α in serum and concluded that green tea polyphenols block gene expression and TNF-α protein production by inhibiting the activation of nuclear factor kappa B (NF-kβ) factor, suggesting that green tea polyphenols reduce inflammatory responses by attenuation of that factor. Moreover, Jia and Han (2000) investigated the chemopreventive effects of green tea and tea pigments in a model of colorectal carcinogenesis induced by 1,2-dimethylhydrazine (DMH), administering 2% green tea for 16 and 32 weeks. The results showed that the carcinogen DMH increased the labeling index of proliferating cell nuclear antigen (PCNA) in the intestinal mucosa and the expression of ras-p21. By contrast, in the groups treated with 2% green tea the labeling index of PCNA and ras-p21 expression were significantly reduced, compared with the positive control group at the end of the experiment. These results coincided with the significant reduction in the formation of aberrant cryptic pits (AFC) and colorectal cancer induced by DMH. However, the mechanisms of the effects of tea in colorectal-induced carcinogenesis have not been fully elucidated. Anticancer effects of polyphenols are well documented in animal models. We have investigated the effect of chemopreventive oak herbal infusions of different species in the development of a model of colon cancer induced by DMH in Sprague–Dawley rats. Several parameters were determined weekly, including body weight, food consumption, and survival rate, being the initial weight of rats 80–95 g gaining a final weight of 440–495 g after 26 weeks, while the consumption of food at the end of the experiment was 22–31 g. The determinations of body weight and food consumption are important parameters in a cancer model, because they are indicators of the animal development in the presence of any treatment. In this regard, it was found that the carcinogen did not significantly affect the growth of animals, as their weight is

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very similar to the negative control. Polyphenols, when administered to rats or mice before, during or after administration of a carcinogen or implantation of a human cancer cell line, often exert a protective effect and induce a reduction in the number of tumors or growth (MorenoJiménez et al., 2015). As expected in this research, infusion administration from the different oak species as drinking water was assessed, showing no negative effect on the growth of experimental animals. However, there were differences in the consumption of tea associated with the samples astringency due to the high phenolic content in Q. resinosa, which was the least accepted by the experimental animals. Moreover, it was observed that the rats receiving infusions of Q. resinosa at different concentrations had a higher weight gain during the experimental period, compared with the negative control and DMH groups, but this difference was not statistically significant. These effects have been observed in various body sites, including the mouth, stomach, duodenum, colon, liver, lung, breast, or skin. Thus, various polyphenols such as quercetin, catechins, isoflavones, lignans, flavanones, ellagic acid, and polyphenols from red wine, resveratrol, or curcumin have shown protective effects in these models in vivo. Due to the diversity and complexity of natural mixtures of phenolic compounds in herbal extracts, it is quite difficult to characterize and measure each compound or compare their antioxidant activities, since the results vary depending on the measurement method. However, this study showed that the herbal oak teas have high antioxidant capacity and can be used as a viable alternative source for its high content of natural antioxidants. The administration of infusions of any oak species protected against the formation of colon tumors without affecting the body weight and food consumption in treated animals. It is suggested that the observed effect is mainly due to the diversity of polyphenol compounds contained in oak infusions. The administration of infusions from oak samples as Q. durifolia protected against the dysplasia observed in the control group with DMH. However, it is still difficult to assess the impact of individual constituents by the anticancer effects observed like in this study in vivo. The chemopreventive mechanism by which the polyphenols act against colon cancer is unclear, although the induction of apoptosis is suggested as a possible chemopreventive mechanism. Since polyphenols present in this source are important because of their biological properties. These sources have proven to exhibit antimicrobial activity against some pathogens (Sánchez-Burgos et  al., 2013), anticarcinogenic, and antioxidant potential (Moreno-Jiménez et  al., 2015). The epigallocatechin-3-gallate is the major phenolic compound in green tea, bearing the most important biological activity attributable to this infusion. In general, the chemical components

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present in polar extracts from herbal infusions are phenolic compounds, specifically flavonoids and triterpene alcohols. Exploration on the antioxidant activity of herbal teas from different oak species has shown an outstanding activity. Infusions from oak species like Q. sideroxyla, Q. durifolia, and Q. eduardii have not even reached the activity levels of infusions from Q. resinosa, which capacity for scavenging ROS and inhibiting peroxidation of lipid molecules, outstands some commercial brands of green and black teas (Rocha-Guzmán et al., 2012). This suggests that species normally used for food could be used for alternate purposes as nutraceuticals, which would be of great importance as it is currently seeking to increase the consumption of foods that have not only nutrition but also proven beneficial effects to health. Rocha-Guzmán et al. (2009) determined the antioxidant capacity of aqueous extracts of leaves from Q. resinosa and the induction of apoptosis in vitro in HeLa cells, finding that the infusions have a high antioxidant capacity and induce apoptosis, which is associated with its phenolic content. In addition, some studies indicate that extracts of Q. durifolia have higher scavenging capacity for DPPH radicals than the flavanol catechin. This has suggested that species that normally has being used for food or timber purposes could now be also considered as nutraceutical sources. Anti-topoisomerase activity has been demonstrated in the vitro models using mutated yeasts and antimicrobial activities toward enteric pathogens (Sánchez-Burgos et al., 2013). Additional studies have explored alternatives for the elaboration of food products based on phenolic compounds from oaks that have revealed a high antihypertensive potential.

11.4.3  Oxidative Stress and Their Effect in Endothelial Dysfunction The accumulation of evidence suggests that oxidative stress alters endothelial functions, including vasomotor tone modulation. Oxidation of nitric oxide (NO) by superoxide anion and other ROS appears to occur in conditions such as hypertension, hypercholesterolemia, diabetes, and cigarette smoking. The decrease in NO bioavailability associated with these traditional risk factors may be partly explained by why they predispose to atherosclerosis (Cai and Harrison, 2000). Antioxidant capacity is related to the presence of compounds capable of protecting biological molecules. The antioxidant properties of polyphenols have been extensively studied, but it has become accepted that the mechanisms of action of polyphenols are more extensive than just the modulation of oxidative stress. An important parameter that is involved in oxidative stress is the presence of ROS, which are the

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genesis of chronic degenerative diseases. It is well known that ROS react readily with biological constituents, damaging molecules such as proteins, lipids, and nucleic acids. Thus, ROS can regulate the cellular damage function via modulation of the redox state of subcellular constituents. Oxygen radical absorbance capacity (ORAC) assay was used to quantify the antioxidant capacity comparing the response of several oaks infusions to an antioxidant standard curve generated with Trolox. The relative ORAC value determined in this study indicated that the red oaks antioxidant capacity is higher than the white species response. Overall, results of this study enabled us to hypothesize that substances in beverages showing a lower value in the ORAC assay are associated with a lower abundance of chlorogenic acid, which is present at higher concentrations in red species (Table 11.3). A nonradical ROS include peroxynitrite (ONOO–), which results from the interaction of NO (NO•) and the superoxide anion. The radical NO• participates in the pathogenesis of many metabolic disorders, including cardiovascular diseases, since it is synthesized by different cells as a result of stimulation of pro-inflammatory cytokines. Quantification of NO• is difficult because of their low concentrations and therefore, its stable metabolites nitrite and nitrate are quantified. Therefore, in this research, the ability of phytochemicals from herbal beverages to compete with O2 to oxidize to NO•, which was generated from sodium nitroprusside and indirectly monitored by production nitrites was determined. According to the determination of the inhi-

Table 11.3  Antioxidant potential of three white oak and three red oak species (Quercus spp.) Species

IC50 NO•

ORAC

IC50 inhibition of deoxy-d-ribose degradation

Q. resinosa Q. laeta Q. obtusata Q. sideroxyla Q. durifolia Q. eduardii

15.30 ± 0.15a 12.98 ± 0.34c 12.91 ± 0.34c 9.40 ± 0.93d 10.96 ± 0.38d 7.40 ± 0.46e

25.83 ± 4.33a 37.10 ± 0.28c 33.82 ± 0.00bc 45.41 ± 0.83d 44.62 ± 0.14d 40.64 ± 2.40bd

3.70 ± 0.07a 4.52 ± 0.03c 4.97 ± 0.18d 4.24 ± 0.23ce 3.59 ± 0.21f 4.04 ± 0.19ae

Inhibition of lipid peroxidation (50 μL of reactant) 41.49 ± 0.11a 12.21 ± 0.80c 13.21 ± 4.99c 19.50 ± 1.36de 19.33 ± 0.79de 21.15 ± 3.81e

Data are expressed as the mean value ± standard deviation of triplicate samples; different literals in columns represent significant difference between samples (Tukey, P < .05). The response is expressed in μM Trolox equivalents for ORAC, μg of NO•, mg to inhibition of deoxy-d-ribose degradation and inhibition of lipid peroxidation in percentage.

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bition of the oxidation of NO•, it was possible to establish that red species have a better response to prevent this phenomenon (Table 11.3) with a high correlation to chlorogenic acid (R2 = 0.991), gallic acid (R2 = 0.812), and 3,4 di-hydroxybenzoic acid contents (R2 = 0.801); while the highest correlation observed in white species was associated with the gallic acid content (R2 = 0.938). It is important to know the ability of some compounds to inhibit the oxidation of NO• in vitro because it provides an estimation about the benefits offered by each type of beverages. The bioactive metabolites when present in excess lead to the evaluation of other markers from oxidative stress associated with lipid peroxidation, such as malondialdehyde or other unsaturated aldehydes. These free radicals are mediators of cytotoxicity and lipid peroxidation associated with chronic diseases such as atherosclerosis and inflammation; in addition, can react with DNA causing irreversible changes in the genome. Contrary to studies with ROS and nitrogen species, it was found by exploring the effect of infusion to inhibit lipid peroxidation and degradation of deoxy-d-ribose, where both assays are based on the Fenton reaction. It was detected that Q. resinosa species showed the greatest protective effect (44.49%) for inhibiting lipid peroxidation. Red species inhibited only at a 20% level, while the white species Q. laeta and Q. obtusata showed the least protective response. Furthermore, Q. resinosa and Q. grisea have shown the major protection inhibiting deoxy-d-ribose degradation. In these responses, it should be considered that the antioxidant capacity of phenolic compounds depends on their structure, which gives them the ability to chelate metal ions, elements present in this assay and prevent the generation of free radicals via delocalization of electrons. It considers that herbal tea drinks are complex in composition, where not only polyphenol compounds participate in antioxidant activities, but also the presence of other phytochemical compounds may contribute in this response. Endothelial dysfunction is the major event in the development of hypertension, atherosclerosis, and heart attack, despite the normal or increased production of NO by the endothelium. ROS contribute to vascular dysfunction and remodeling through oxidative damage. In human hypertension, an increase in the production of superoxide anion (O2−) and H2O2, a decrease in the synthesis of NO and bioavailability of antioxidants has been found. As a consequence of oxidative stress, the vascular bioavailability of NO, the most important endogenous vasodilator, is reduced. It has been proposed that in hypertension and hypercholesterolemia, the decrease in NO bioavailability is associated with an increase in the expression of the O2− anion, which reacts with NO for peroxynitrite formation, decreasing its bioavailability (Urao et al., 2013). Dietary supplementation with flavonols has shown a decrease in systolic blood pressure in individuals with a high

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cardiometabolic risk phenotype and a decrease in plasma concentrations of oxidized low-density lipoprotein (oxLDL) (Dower et al., 2015). Potential vascular sources of O2− are endothelial nitric oxide synthase (eNOS), xanthine oxidase, and NAD(P)H oxidase. eNOS and NAD(P)H oxidase are involved in the production of O2− in different models of hypertension, while xanthine oxidase is included in the production of O2− in hypercholesterolemia. Additional sources of ROS include cytochrome P450, cyclooxygenase (COX), and lipoxygenase (LOX). Taking into account the possible deleterious effects of ROS, it is likely that antioxidant protection mechanisms have evolved to limit production and release. In this way, the defense system includes antioxidant enzymes such as superoxide dismutase, catalase and glutathione peroxidase and a number of nonenzymatic antioxidants and small proteins including glutathione (GSH), vitamins (A, E, and C), carotenoids, and polyphenols (Carocho and Ferreira, 2013). Considering that increased oxidative stress plays a key role in the pathogenesis of endothelial dysfunction, it would be expected that the administration of exogenous antioxidants is a reasonable therapeutic strategy for the treatment of this disorder. Antioxidant supplementation has been shown to reverse endothelial dysfunction in the coronary and peripheral arteries of patients with cardiovascular risk factors and/or atherosclerosis. In addition, the positive effects of the consumption of these compounds have been associated in the case of atherosclerosis to a decrease in the oxidation of LDL via the inhibition of LOX and attenuation of the oxidative stress; also in decrease of inflammation by inhibition of leukocyte adhesion, myeloperoxidase and decrease in inducible NO synthase (iNOS) and COX-2 expressions. In the case of the polyphenols effect on hypertension, it is associated with vasodilator properties, inhibition of NADPH oxidase and recovery of NO levels due to inhibition of O2− anion.

11.4.3.1  Role of the Renin-Angiotensin System in Cardiovascular Inflammation Angiotensin II (Ang II) the main inducer of renin-angiotensin system (RAS) is a potent vasoactive peptide that exerts pro-inflammatory effects on the vasculature by inducing integrin, cytokines and growth mediators and profibrotics through the activation of REDOX-sensitive pathways and transcription factors. In experimental models of atherosclerosis and hypertension, the inhibition of NF-kB prevents expression induced by Ang II of interleukin (IL)-6, vascular cell adhesion molecule (VCAM)-1, and monocyte chemotactic protein (MCP)-1. In smooth muscle cells (SCM) in atherosclerotic lesions, the peptide increases IL-8 expression by inducing NF-kB activation, as well as adhesion and migration proteins. In macrophages and SMC of atherosclerotic plaques, Ang II also increases MCP-1 which is the main

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regulator of T lymphocyte recruitment and is highly expressed in atherosclerotic lesions. Other mechanisms involved in hypertrophy and hyperplasia in SMC are through the AT-1 and epidermal growth factor (EGF) receptors, platelet-derived growth factor (PDGF), and insulin-like growth factor (IGF). Inflammatory biomarkers are systemic predictors of low-grade inflammation and risk of cardiovascular disease. Several mediators of inflammation, including C-reactive protein, myeloperoxidase, IL-1, IL-6, IL-8, TNF-α, adhesion molecules (VCAM, ICAM, E and P selectin), CD40 ligand are cardiovascular disease markers. Considering the proinflammatory effects of Ang II, agents that interfere with different RAS components such as angiotensin converting enzyme (ACE) inhibitors represent therapeutic tools for reducing vascular inflammation. RAS antagonists reduce inflammation, oxidative stress, and vascular remodeling in hypertension beyond blood pressure dropping and have improved the cardiovascular protection compared to some other antihypertensive agents, especially in populations of patients with diabetes or renal damage (Pacurari et al., 2014). This raises important questions and challenges in the study of biological mechanisms of phytochemicals present in oak infusions, associating them with their redox potential. The RAS is a known factor of vascular fluid homeostasis and blood pressure regulation. In this system, Ang II produces a large number of physiological consequences, including effects in the inflammatory response, acting as a proinflammatory mediator, furthermore generating ROS with cellular damage and inflammation. Phytochemicals present in oak infusions, particularly from Q. resinosa show antihypertensive effect by inhibiting the RAS more efficiently than prescription drugs such as Captopril (Rivas-Arreola et al., 2010). Recent studies including Q. resinosa, Q. sideroxyla, and Q. eduardii among another oak species have shown that fermentation with the Kombucha consortium affects enzyme activity. Particularly, the fermentation process of infusions of species such as Q. resinosa, Q, arizonica and Q. durifolia increases the effectiveness of the metabolites to inhibit the activity of the angiotensin-converting enzyme. On the other hand, the fermented products prepared with the species Q. convallata and Q. sideroxyla lose effectiveness in their response, while Q. eduardii does not show significant changes when comparing the infusion with the fermented product (Fig. 11.3).

11.5 Conclusions To recapitulate, polyphenols have moderate potency as bioactive compounds and low availability compared to drugs, but when ingested regularly and in significant amounts they can have physiological effects perceptible in the medium and long term. Among the various groups of polyphenols, there are proanthocyanidins, ellagitannins,

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Fig. 11.3  Effect of infusions (0.1 mg/mL) and fermented beverages of three white oak and three red oak species (Quercus spp.) in the inhibition of angiotensin converting enzyme (ACE). Data are expressed as the mean value ± standard deviation of triplicate samples.

and flavonols as the main constituents of oak infusions, which is a sufficient reason for the study of this natural resource. Polyphenols are the reducing agents in such a way that they can stabilize free radicals, participate in the regeneration of other antioxidants as vitamins, and protect cellular constituents against oxidative damage. Flavonoids, widely studied for their protective effects on atherosclerosis and certain types of cancer, are mainly present as β-glycosides, which influences the efficacy of its absorption that is believed to occur in the small intestine or in the large intestine after bacterial deconjugation. Glycosylation influences the chemical, physical, and biological properties of polyphenols. For glycosidic flavonoids, the removal of sugar by the action of glycosidases and consequent hydrophilic separation induces passive diffusion through the intestinal microvilli of the aglycone moieties. Dietary polyphenols are substrates of ß-glucosidases, UDP-glucuronosyltransferases, or catechol-O-methyl transferase in the small intestine, as well as various Phase I and II enzymes in the liver. The formation of conjugates may alter the biological properties of the circulating metabolites. In contrast, administration of drugs can saturate metabolic pathways when administered in concentrated form and at high doses, while polyphenols in functional foods or beverages presumably would not saturate metabolic pathways and circulating species, which should be expected as conjugated compounds. Focusing on the bioconversion of flavan-3-ols and flavonols, two of the subclasses of flavonoids associated with human health, conjuga-

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tion reactions (methylation, sulfation, and glucuronidation) can occur in enterocytes, while methylation and other reactions of bioconversion are performed in liver cells. Flavanols such as (−)-EC are frequently acylated especially by gallic acid. The resulting galloyl substitutions apparently do not affect the partition coefficients of the compounds and their bioavailability as dramatically glycosidation does. In general, it is difficult to detect traces of non-metabolized flavonoids in plasma or urine, with the exception of (−)-epigallocatechin3-O-gallate (EGCG) and (−)-epicatechin 3-O-gallate (ECG) compounds found in green tea. In investigations conducted by our research group, it has been demonstrated their presence in infusions of herbal teas and the same metabolites have been detected in plasma without metabolizing. Flavan-3-ol apparently passes through biological membranes and is absorbed without deconjugation or hydrolysis. Thus, when consuming (+)-catechin, the percentage in plasma varies from 0.2% to 2% of the total amount ingested; after 30 min, it is detected in plasma as unconjugated catechin and after 120 min as methylated catechin. After 8 h, 40% of catechin is detected in urine as their methylated, sulfated, and glucuronidated derivatives. This flavan-3-ol does not alter the endogenous antioxidant levels and its bioconversion results in the presence of the vanillic, 4-hydroxybenzoic, 3,4-dihydrobenzoic, and 3-methoxy-4-hydroxyhippuric phenolic acids. The antioxidant activity in vivo associated with the consumption of flavonoids is relevant due to the effect attributed to the consumption of products rich in this type of compounds. Among the mechanisms involved there are those associated with a decrease in the oxidative stress. They are direct entrapment of free radicals (i.e., antioxidant action in the strict sense of the word), interaction with metals (i.e., iron and copper chelation), and inhibition of ROS-producing enzymes, in particular xanthine oxidase, nicotinamide adenine dinucleotide phosphate (NADHP) oxidase, and LOX. However, it is not only antioxidant mechanisms that flavonoids can exert in vivo, in their action are involved other types of mechanisms associated with a reduction in the expression of inflammatory molecules. Studies conducted in patients and animals have explored the hemodynamic effect of acute and chronic administrations of food or beverage preparations rich in polyphenols, especially grape, wine, tea, or chocolate extracts, determining that endothelial vasodilation is improved after ingestion. Additional activities of polyphenols are associated with the effect on inhibition of iNOS and COX-2 expression and inhibition of leukocyte activation, in addition to mechanisms involving inhibition of platelet aggregation and direct vasodilator action (Mladěnka et al., 2010). Thus, the clinical relevance of the effects of endothelium-dependent polyphenols will be influenced by their

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systemic availability. Thus, intestinal absorption and metabolism of plant polyphenols such as those from Quercus species are a limiting step in the rate of protective effects of this class of compounds. Consequently, in  vitro effects should always be confronted with in vivo experiments and even with clinical trials before the protective properties assigned to plant polyphenols can be clearly established in cardiovascular diseases.

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