Functional and Medicinal Properties of Caffeine-Based Common Beverages

FUNCTIONAL AND MEDICINAL PROPERTIES OF CAFFEINEBASED COMMON BEVERAGES

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Francine Carla Cadoná⁎, Grazielle Castagna Cezimbra Weis†,‡, Charles Elias Assmann†,§, Audrei de Oliveira Alves†,¶, Beatriz da Silva Rosa Bonadiman†,¶, Alencar Kolinski Machado‖, Marco Aurélio Echart Montano⁎, Ivana Beatrice Mânica da Cruz†,§,¶ ⁎

Graduate Program in Biosciences and Health, University of the West of Santa Catarina, Joaçaba, SC, Brazil †Biogenomics Laboratory, Federal University of Santa Maria, RS, Brazil ‡Graduate Program of Food Science and Technology, Federal University of Santa Maria, Santa Maria, RS, Brazil §Graduate Program in Biological Sciences: Toxicological Biochemistry, Federal University of Santa Maria, Santa Maria, RS, Brazil ¶Graduate Program of Pharmacology, Federal University of Santa Maria, Santa Maria, RS, Brazil ‖Franciscan University, Santa Maria, RS, Brazil

1.1  Coffee (Coffea arabica and Coffea canephora) 1.1.1  Coffee Chemical Constituents and Main Biological Activities Coffee was discovered in Ethiopia in the 6th century; later, it was taken to Arabia and subsequently to Europe around the 1500s. Coffee was transferred to Central and South America around the 1700s. The Brazilian culture of coffee began in 1727; nowadays, this country is considered the main coffee producer, promoting a huge social and economic impact (Yanagimoto et al., 2004) (Fig. 1.1). Coffee is considered an energetic and functional beverage, made from two main species (Coffea arabica and Coffea canephora). Coffea arabica has superior quality and aroma, representing ~70% of the

Caffeinated and cocoa based beverages. https://doi.org/10.1016/B978-0-12-815864-7.00001-5 © 2019 Elsevier Inc. All rights reserved.

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Fig. 1.1  Coffee drink (A) and coffee grain (B).

­production around the world, while Coffea canephora presents a more bitter taste than Coffea arabica and it is consumed mainly as instant coffee and in espresso blends, involved in “crema” formation (Crozier et al., 2012). Coffee intake represents a common habit; it is considered the most consumed beverage around the world. This fact is explained by coffee having a great aroma and taste as well as previous studies suggesting several health benefits of this plant due to the bioactive molecules present in its chemical matrix composition (Natella et al., 2002; Somoza et al., 2003; Okamura et al., 2005). In this sense, several chemical substances are present in coffee, including carbohydrates, lipids, vitamins, minerals, alkaloids, and phenolics compounds. However, the chemical composition of this plant depends on the coffee variety, culture weather, processing, roasting, and milling conditions (Crozier et al., 2012). Green coffee beans, before roasting, are composed of 6.5%–10% CGA, 1.2%–2.2% caffeine, 10%–16% lipids with special diterpenes (cafestol and kahweol), 0.7%– 1.0% trigonelline, 45%–52% carbohydrate, 11% protein, and 4.2%–4.4% minerals. However, roast coffee presents 2.7%–3.1% CA, 1.2%–2.4% caffeine, 23% melanoidins, 11%–17% lipids, 38%–42% carbohydrate, 10% protein, and 2.4%–2.5% aliphatic acids. These molecules are responsible for a special aroma, flavor, and color (Pan et  al., 2016a,b) (Table 1.1). Coffee has different micronutrients, such as magnesium, potassium, niacin, and vitamin E, that present a positive health effect (Higdon and Frei, 2006; Fig.  1.2). Moreover, the rich bioactive molecules present in the chemical matrix of coffee are associated with health benefits; including – Caffeine (1,3,7-trimethylxanthine): It is a purine alkaloid that acts by inhibiting the receptors of adenosine A1 and A2A, A2B, and A3 to stimulate neural activity and promote vasoconstriction. Neural

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Table 1.1  Main Biological Activities and Bioactive Molecules of Coffee (Coffea arabica) Biological activity

Antioxidant Antiinflammatory Antitumor

Neuroprotective

Chemical composition

Chlorogenic acid caffeine Lipids—cafestol and kahweol Trigonelline Carbohydrate Proteins Minerals

Fig. 1.2  Main biological properties of coffee.

Jung et al. (2017) Kempf et al. (2010), Akash et al. (2014), and Freedman (2012) Mut-Salud et al. (2016), Michaud et al. (2010), Jiang et al. (2013), and Liu et al. (2015) Davis et al. (2003), Smith (2002), Joghataie et al. (2004), and Arendash et al. (2006) Pan et al. (2016a,b)

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activity promotes an increase of adrenaline release by the adrenal gland and it results in increase of arterial pressure, respiratory capacity, and energetic metabolism. Moreover, caffeine increases dopamine levels, assuring better cognition capacity and pleasure sensation (Goel, 2017). – Chlorogenic acid (CGA): CGAs are five main groups of phenolic compounds and their isomers, formed mainly by the esterification of quinic acid with one of the following acids derived from hydroxycinnamic acids: caffeic acid, ferulic acid (FA), or ρ-cumaric acid (ρ-CoA). CGA is considered a remarkable antioxidant and antiinflammatory molecule, since it is able to scavenge free radicals (Crozier et al., 2012). – Cafestol and Kahweol: These molecules are diterpenes that have an important role in coffee quality and aroma. Cafestol and Kahwelol present antiinflammatory activity. Cafestol is able to reduce the cholesterol produced by inhibiting hydroxy methyl glutaryl coenzyme A reductase (HMG-CoA reductase), Lipoprotein lipase (LPL), and LDL receptors (B/E receptors) expression (Higdon and Frei, 2006). In this sense, Ross et al. (2000) performed a study involving 8000 Japanese and American men, who were investigated about coffee intake for 30 years. The findings suggested that consumption of coffee prevents Parkinson disease since the results showed 3–5 times lower incidence of this disease in men who consumed at least one cup of coffee regularly. Moreover, coffee intake is associated with lower suicide indices. This result was found in a study involving 43,599 men enrolled in the Health Professionals Follow-up Study (HPFS, 1988–2008), 73,820 women in the Nurses' Health Study (NHS, 1992–2008), and 91,005 women in the NHS II (1993–2007) (Lucas et al., 2014). Besides, the study of Hoffman et  al. (2006) reported the thermogenic effect of coffee, since this plant increases basal metabolism and consequently promotes weight loss. This effect is attributable to caffeine present in coffee, because this result is not found in decaffeinated coffee (Hoffman et al., 2006). Coffee is considered a remarkable antioxidant plant. Hori and collaborators analyzed the 8-deoxiguanosine levels, a DNA damage marker, in subjects who consumed daily two or more cups of coffee. The results showed that these subjects presented lower levels of DNA damage than others who did not consume coffee (Hori et al., 2014).

1.1.2  Antitumor Coffee Activity Coffee presents in its chemical matrix several bioactive molecules that are able to decrease cancer cell proliferation, inhibit angiogenesis and metastasis processes, and activate the apoptosis pathway (MutSalud et al., 2016).

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In this sense, Michaud et al. (2010) analyzed 33 cases of glioma and 245 cases of meningioma in nine countries. The analyses showed a direct association between 100 mL of coffee daily consumed and lower risk of glioma. This association was more frequently observed in men than in women (Michaud et al., 2010). Moreover, a metaanalysis involving 966,263 subjects and 59,018 cases of breast cancer suggested that coffee and caffeine decrease the risk of this disease in postmenopausal women. Breast cancer risk decreased around 2% for two cups of coffee and 1% for 200 mg per day of caffeine (Jiang et al., 2013). Another investigation performed by Liu et  al. (2015), involving 539,577 subjects and 34,105 cases of prostate cancer, suggested that coffee intake decreased the risk of this disease and advanced type of prostate cancer. Prostate cancer risk decreased 2.5% in individuals who consumed two cups of coffee daily (Liu et al., 2015). A study also investigated the coffee effect in lung cancer. A metaanalysis was performed with 8 cohort studies and 13 control cases involving 19,892 patients with lung cancer and 623,645 controls. However, the results were not conclusive since the findings can be confounded by tobacco smoking (Galarraga and Boffetta, 2016). Besides, 22 studies, 9 cohorts and 13 case-controls, involving 7631 cases and 1,019,693 controls significantly showed that coffee consumption reduced stomach cancer risk. The findings suggest an inverse relation between coffee intake and stomach cancer, since high coffee consumption was associated to lower stomach cancer risk (Xie et al., 2016). Moreover, another investigation was performed to analyze coffee intake and colorectal cancer. Five cohorts and nine case-control studies were identified, and a systematic review was performed with metaanalysis to verify coffee consumption and the colorectal cancer risk. The cohort results showed a strong inverse association only in women, while 3 case-controls showed a strong inverse association in men and women in both colon and rectal cancer. In the metaanalysis, high coffee consumption was not associated with colorectal cancer risk in cohort studies, while it was significantly associated with lower colon cancer and rectal cancer risk in case-control studies. Evidence was insufficient to conclude whether consumption and coffee increase or decrease the risk of colorectal cancer, indicating further investigations to clarify that (Akter et al., 2016). On the other hand, a study performed by Gan et al. (2017), which was a wide metaanalysis involving 2,046,575 participants and 22,629 patients with colorectal cancer in 19 cohort prospective studies showed that 7% decreased colon cancer risk in subjects who consumed four cups of coffee every day (Gan et al., 2017). Besides, 11 important studies including 2795 cases of hepatocellular carcinoma and 340,749 controls were investigated. A metaanalysis

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suggested an inverse association between coffee consumption and hepatocellular carcinoma risk; quantitative evidence indicates that higher consumption ensures greater protection (Bai et al., 2016). Furthermore, the antitumor coffee effect was revealed in pancreatic cancer. A metaanalysis involving 20 cohort studies indicated that high coffee consumption is associated with a lower pancreatic cancer risk. There was no significance for each increment of 1 cup of coffee on disease risk in nine studies (Ran et al., 2016). The same was found in the study performed by Liu et al. (2016) that investigated the antitumor effect of coffee in two case-control studies (846 melanoma patients and 843 controls) and five cohort studies (844,246 participants and 5737 melanomas). The results showed that caffeinated coffee decreases malignant melanoma risk, when comparing the highest intake with the lowest intake. There was a dose response relationship. Decaffeinated coffee did not interfere with the disease risk (Liu et al., 2016).

1.1.3 Neuromodulatory Coffee Effects Coffee is considered a remarkable neuromodulator beverage; for instance, it is widely used to increase the alert and cognitive state. Caffeine, the main bioactive molecule found in the chemical matrix of coffee, is responsible for this action. Caffeine acts by antagonizing the effects of adenosine, a brain chemical (neurotransmitter) that causes sleep. It can bind to adenosine receptors by blocking them. Thus, the inhibitory action of adenosine is prevented, and the effect of caffeine is consequently stimulating (Davis et al., 2003). However, caffeine consumption can adversely affect motor control and sleep quality, as well as cause irritability in individuals with anxiety disorders (Smith, 2002). Some authors have concluded that the efficacy of caffeine in relieving headaches induced by its deprivation (leading to cerebral vasodilation) reflects its vasoconstricting properties at the central level. In other types of headache, such as tension headaches, caffeine seems to play an active role in pain relief, being the dose-dependent effect (Baratloo et al., 2016). Moreover, coffee has been associated to Parkinson's disease prevention (Ascherio et  al., 2003; Sääksjärvi et  al., 2008). Parkinson’s disease is the second most common cause of neurodegenerative disturbance. This disease affects around 1%–3% of the subjects above 65 years (Ross et al., 2000). Parkinson's disease is directly associated with the elderly and it is more prevalent in men (Wooten, 2004). The neuropathologic disorders present in Parkinson’s involve dopaminergic neuron loss in the substantia nigra with subsequent depletion of the dopamine levels in the striatum. Consequently, severe loss of dopamine is associated with debilitating motor disorders associated

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with parkinsonism (Joghataie et  al., 2004). Several prospective and retrospective epidemiological studies have demonstrated an inverse relationship between coffee and caffeine consumption and the risk of developing Parkinson's disease (Ross et al., 2000; Prediger, 2010). The study performed by Ross et  al. (2000) suggested an inverse association between coffee consumption and the risk of developing Parkinson's disease, involving 8004 Japanese-American men over 30 years. In this study, the risk for Parkinson's disease was five times higher among men who reported not consuming coffee than among those who reported a daily intake of ~800 mL of coffee or seven small cups (Ross et al., 2000). In addition, coffee also has exhibited a neuroprotective effect against the development of Alzheimer's disease. However, the mechanism responsible for such protection is not clear yet. A study performed in animal nerve cell cultures suggests that adenosine A2A receptor antagonism protects nerve cells against β-amyloid ­protein-induced neurotoxicity. In another study, the daily intake of 1.5 mg of caffeine (equivalent to a daily human consumption of 500 mg) per mouse caused a decrease in the production of β-amyloid protein levels, protecting the cognitive ability of animals (Maia and De Mendonc, 2002; Dall’lgna et al., 2003; Arendash et al., 2006). Some authors reported that increased oxidative stress in the brain has a very important role in the development of Alzheimer's disease (Huang et al., 2016; Perry et al., 2002). In this sense, the bioactive molecules present in coffee, such as caffeine and CGAs, ensure a remarkable antioxidant activity, reducing oxidative stress by reactive oxygen species (ROSs) neutralization (You et al., 2011).

1.1.4  Coffee Drinking and Lower Risk of Suicide Coffee presents antidepressant-like activity since this beverage is able to increase dopamine levels and, consequently, able to cause pleasure sensation (Szopa et al., 2016). In this sense, coffee has been directly associated to lower risk of suicide (Higdon and Frei, 2006; Lucas et al., 2014). This association was evaluated in the study performed by Lucas et al. (2014), involving 43,599 men enrolled in the Health Professionals Follow-up Study (HPFS, 1988–2008), 73,820 women in the Nurses’ Health Study (NHS, 1992–2008), and 91,005 women in the NHS II (1993–2007). Consumption of caffeine, coffee, and decaffeinated coffee was evaluated for 4 years. Besides, deaths from suicide were determined by physician review of death certificates. The results suggested a direct association between caffeine intake and lower risk of suicide. Moreover, in a study performed for 10 years, involving more than 128,000 men and women participating in a California health, the

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f­ indings showed a lower risk of suicide in 13% for every cup of coffee consumed daily (Klatsky et al., 1993).

1.1.5  Antiinflammatory Coffee Effects The coffee chemical matrix is rich in bioactive molecules that present important biological activities, such as antiinflammatory and antioxidant (Jung et al., 2017). In this sense, coffee consumption promotes a lower risk of clinical conditions reducing inflammation and oxidative stress and increasing serum levels of antiinflammatory factors, such as adiponectin (Kempf et al., 2010; Wedick et al., 2011) and interleukins 4 and 10 (Akash et al., 2014). Consequently, regular coffee consumption is associated with reducing the development of some diseases involving with these processes, for instance, cardiovascular disease (Kleemola et  al., 2000), certain types of cancer, obesity (Greenberg et al., 2006), type 2 diabetes (Sartorelli et al., 2010; Ding et al., 2014), and metabolic syndrome (Shang et al., 2016). Moreover, moderate coffee consumption is able to increase longevity rates (Freedman, 2012). In addition, coffee has been associated with gene expression modulation involved in innate immune regulation. [Interferon gamma-­ induced protein 10; C-X-C motif chemokine 11; C-X-C motif chemokine 12; and chemokine (C-C motif) ligand 4.] This fact was observed by microarray gene expression, which suggested a direct association between regular coffee intake and the chemokine signaling pathway. A study reported that inflammatory genes were upregulated in native human macrophages by lipopolysaccharide (LPS) stimulation and downregulated by coffee treatment. These genes are associated with biological functions such as cell and leukocyte migration, suggesting the interference of coffee in the chemotactic response of activated macrophages, reducing leukocyte migration (Vissiennon et al., 2017). The potential bioactive molecules found in coffee that present antioxidant and antiinflammatory activity are caffeic acid and quinic acid-ester CGA (Yasuko et al., 1984). Previous investigations reported this effect by inhibiting phosphorylase kinase and protein kinase A and C (Nardini et al., 2000) as well as suppression of NF-κB and MAPKs (Feng et al., 2005). Moreover, a study showed that caffeic acid directly suppresses IL-1 receptor-associated kinase 1 and 4 (IRAK1 and IRAK4); these molecules are involved in downstream toll-like receptor 4 signaling, which promotes chemokine signaling (Yang et al., 2013). Furthermore, a study performed by Jung et al. (2017) analyzed the antiinflammatory effect of coffee extracts using lipopolysaccharidetreated RAW 264.7 macrophage cells. The gene expression decreased for the inflammatory markers tumor necrosis factor-alpha and ­interleukin-6 in cells exposed to coffee extract. Taking this into

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a­ ccount, these findings suggest that coffee has an antiinflammatory action, reducing inflammation markers in RAW 264.7 macrophage cells (Jung et al., 2017).

1.1.6  Coffee and Prevention of Type 2 Diabetes Mellitus Type 2 diabetes is a current global problem as it presents growing prevalence, complications, and mortality. Insulin resistance and pancreatic beta cell dysfunction that are presented in type 2 diabetes lead to hyperglycemia. This condition is associated with an increase of oxidative stress and activation of inflammatory pathways (Odegaard et al., 2016). Since coffee has antiinflammatory and antioxidant activities, this beverage has been associated with improving and avoiding type 2 diabetes development (Sartorelli et  al., 2010; Ding et  al., 2014). In this context, several recent studies show an inverse association between coffee intake and incidence of type 2 diabetes mellitus (T2DM) (Sartorelli et al., 2010). Data obtained in Finland, the country with the most consumption of coffee in the world, corroborate this fact (Pereira et al., 2006). A study performed by Yamaji et al. (2004) reported that daily consumption of ~150 mL of coffee promote lower levels of postprandial and fasting glucose (1.5% and 4.3% respectively). In addition, glucose resistance decreases with coffee consumption (Yamaji et al., 2004). Moreover, pieces of evidence indicated that coffee presents an antiobesogenic action since it is considered a thermogenic beverage (Hoffman et  al., 2006; Pimentel et  al., 2009). In this sense, Pimentel et al. (2009) reported greater weight loss in coffee consumers than in nonconsumers. Since obesity is a main factor in the development of T2DM, this is an important finding to control this dysfunction. Furthermore, coffee also influences the secretion of incretin hormones, such as glucagon-like peptide-1 (GLP-1) and glucose-­ dependent insulinotropic peptide (GIP), decreasing the absorption of glucose in the small intestine, activating anorexigenic peptides such as pro-opio-melanocortin and regulation of transcripts by cocaine and amphetamine (POMC/CART), and inhibiting orexigenic peptides as agouti-related protein and neuropeptide Y (AgRP/NPY) (Fujii et al., 2015). Several epidemiological investigations showed that total caffeine from coffee and other sources is associated with a decreased risk of T2DM and that this association takes place after regular coffee consumption (Yamaji et  al., 2004; Pimentel et  al., 2009; Sartorelli et  al., 2010). This effect is the stimulation of pancreatic secretion, basal

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e­ nergy metabolism, stimulation of lipid oxidation, mobilization of glycogen in muscle, and weight loss (Zhang et al., 2011). In addition, Yamauchi et al. (2010) reported that caffeine influences the metabolism of carbohydrates. Caffeine acts as an antagonist of A1 and A2A adenosine receptors by the inhibition of phosphodiesterases and the mobilization of calcium. Since adenosine is a neurotransmitter responsible for decreased cerebral activity, therefore caffeine increases in brain activity. Consequently, the gland is stimulated to release adrenaline, provoking stimulatory effects. A stimulation of the central and autonomic nervous system is observed, as is elevation of blood pressure, an increase in the metabolic rate, and an increase in diuresis. Adrenaline, one of the hormones involved in the stimulation of thermogenesis, inhibits glycogenesis and stimulates glycogenolysis and lipolysis. In addition, adrenaline promotes the formation of cyclic adenosine monophosphate (CAMP) in the cells, initiating a cascade of chemical reactions that lead to the activation of the enzyme phosphorylase, allowing the release of glucose residues, available for use as a power source. In lipolysis, caffeine inhibits phosphodiesterases, enzymes responsible for converting cAMP into adenosine monophosphate (AMP), which leads to the increase of cAMP in the tissues, leading to a greater stimulation of lipolysis. Triglycerides, stored in the adipocytes, are then degraded into fatty acids and glycerol, which can be used as a power source. Consequently, metabolism reduction is increased in the size and number of adipocytes, total body fat and, body weight loss (Yamauchi et al., 2010). Caffeine is commonly associated with risk of hypertension, heart disease, osteoporosis, or hypercholesterolemia. However, Pimentel et al. (2009) reported that with a moderate intake of caffeine (~400 mg/ day) this association is not verified (Pimentel et al., 2009).

1.2  Black Tea (Camellia sinensis) 1.2.1  Black Tea (Camellia sinensis), Main Characteristics and Chemical Matrix Tea is one of the oldest beverages consumed worldwide that also is an important contributing factor to economic parameters on the food and beverage trade (Dufresne and Farnworth, 2001; Luczaj and Skrzydlewska, 2005; Lahiry et al., 2010). Commonly, teas are intaken in three different forms, including nonfermented, semifermented, or fully fermented, that are obtained through specific processes of preparation (Malongane et al., 2017). China was the first country to introduce tea intake as a traditional medicine alternative (Camargo, 2011). Currently, different teas are consumed and produced in several countries; however, China is still the main one in terms of cultivation and

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Fig. 1.3  Black tea (A) and black tea powder (B).

trade (Engelhardt, 2013; Chang, 2015). Of all types of tea, those ones that are made from Camellia sinensis are the main ones (Malongane et al., 2017; Fig. 1.3). Camellia sinensis tea is a shrub-type perennial plant that belongs to the Theaceae family. This plant is originally from China but its consumption was widespread to India and Japan and lately to European countries and Russia. This tea plant can reach 3–4 m high and, usually, its leaves are used to prepare different teas (Camargo, 2011). Black tea is one of the most consumed teas made by Camellia sinensis leaves, corresponding to about 80%. However, apart from black tea it is possible to prepare other kinds of tea from this same tea plant, including green tea and white tea, for example. Actually, because of its biological properties, green tea intake is increasing, but currently it is also known that black tea has a lot of different positive effects on human cells, tissues, and organisms (Bhattacharya and Giri, 2013). The main difference between black tea and other types of Camellia sinensis tea is the way that their leaves are harvested and the method of preparation. The leaves used for black tea preparation are initially washed and dried for 1 day; then, they are wrapped and fermented for 6 h; a second drying step is performed later (Camargo, 2011; Engelhardt, 2013). All these processes are carried out to transform an integral part of natural leaves into a consumable product that is highly commercialized in several oriental countries and that is advancing in the Western market (Sharangi, 2009). Considering the chemical composition, it has already been described that Camellia sinensis’ leaves have lipids, carbohydrates, and proteins that are not present in the tea infusion (Camargo, 2011). On the other hand, there are several molecules present in its leaves as part of the chemical matrix, such as polyphenols, caffeine, theobromine, vitamin C, some metals, as well as fluoride ions, that are consumed by drinking its tea. These molecules when intaken

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could positively interact with some cells and induce positive effects (Barcirova, 2010). Despite the leaves’ fermentation, black tea presents significant levels of preserved polyphenols, as well as organic compounds and specific molecules known as theaflavins and thearubigins. Theaflavin 3-gallate, theaflavin 3′-gallate, and theaflavin 3,3′-gallate are the most important theoflavins found in black tea (Dufresne and Farnworth, 2001; Luczaj and Skrzydlewska, 2005; Lahiry et al., 2010). These molecules are responsible for the taste and color of black tea (Santos-Buelga and Scalbert, 2000; Ngure et  al., 2009). In addition, thearubigins are found in high amounts in black tea; however, their chemical structure is not completely understood (Haslam, 2003; Ngure et al., 2009). In addition, most of the biological properties related to black tea (Pinto, 2013; Senanayake, 2013), described further are associated with its chemical matrix composition (Table 1.2 and Fig. 1.4).

Table 1.2  Main Biological Activities and Bioactive Molecules of Black Tea (Camellia sinensis) Biological activity

Antioxidant

Antiinflammatory Antitumor Neuroprotective Chemical composition

Polyphenols Theaflavins and derivatives: Theaflavin 3-gallate

Salah et al. (1995), Zandi and Gordon (1999), Vinson and Dabbargh (1998), Wiseman et al. (1997), Chan et al. (2011), and Yang et al. (2008) Wu et al. (2012) and Bedran et al. (2015) Nomura et al. (2000), Sharma et al. (2017), Pan et al. (2017), and Charehsaz et al. (2017) Chaturvedi et al. (2016), Zhang et al. (2016), and Qi et al. (2017) Dufresne and Farnworth (2001) Luczaj and Skrzydlewska (2005) Lahiry et al. (2010)

Theaflavin 3′-gallate Theaflavin 3,3′-gallate Thearubigins Polyphenols Caffeine Theobromine Vitamins

Barcirova (2010)

Chapter 1  Functional and Medicinal Properties of Caffeine-Based Common Beverages   13

Mitochondrial function recovering in neurons associated to antioxidant effect

O2+ SOD

H2O2 2GSH

Fe++

CAT

Fe+++

OH

GPx

GR

+

GSSG

H2O

Antioxidant enzyme modulation Antiinflammatory effect through pathogenic agents elimination and proinflammatory cytokines control Tumor cells proliferation decreasing via promoter gen inhibition and cell cycle arresting Antioxidant capacity by free radicals and ROS scavenging

Fig. 1.4  Main biological properties of black tea.

1.3  Black Tea as a Significant Bioactive Compound 1.3.1  Antioxidant: The Main and More Explored Bioactive Property of Black Tea The oxidative metabolism is an important system linked to mitochondrial function (Malkus et  al., 2009; Streck et  al., 2013). Mitochondria are responsible for energy production via ATP synthesis through the mitochondrial electron transport chain (MTC) (Twig et  al., 2008; Santo-Domingo and Demaurex 2010; Atkin et  al., 2011; Rizzuto et  al., 2012; Liesa and Shirihai 2013). However, during ATP synthesis some electrons escape from the chain and they are able to reduce, especially, the molecular oxygen (O2)-producing superoxide radical (O•−). Fortunately, this reactive molecule is metabolized by the superoxide dismutase enzyme, releasing hydrogen peroxide (H2O2). Still inside the mitochondria, H2O2 is converted to O2 and H2O, or it can happen through catalase enzyme in the cytoplasmic space (Goldstein et al., 1993; Kirkinezos and Moraes 2001; Valko et al., 2007).

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This metabolism is physiological in the same time that free radicals and reactive oxygen species (ROS) are necessary for some intra and extracellular signaling (Gough and Cotter 2011; Rupérez et al., 2014). However, there are some situations where the free radical and ROS production exceed the endogenous antioxidant enzyme amount. In this sense, an imbalance called oxidative stress is established (Kirkinezos and Moraes 2001; Valko et al., 2007). As a consequence of oxidative stress, cells can suffer several damages such as lipid peroxidation, protein oxidation, and DNA damage, completely losing cellular homeostasis (Rupérez et al., 2014). In addition, several research studies worldwide have shown that oxidative metabolism imbalance could be found in subjects with some chronic nontransmissible diseases as part of their pathophysiology, such as cancer (Da Costa et al., 2012) diabetes, and heart diseases (Valko et  al., 2007), as well as neuropsychiatric illness (Wang et  al., 2009; Andreazza et al., 2010; Brown et al., 2014). In this sense, numerous studies have been performed to find alternatives of treatment that could recover this imbalance and prevent its damages. Studies with natural products are in highlight in this field of interest. It is due to the chemical matrix of these functional foods or beverages, for example, black tea (Pinto 2013; Senanayake, 2013). Camellia sinensis is a tea plant strongly known for its antioxidant properties. According to Salah et  al. (1995) and Zandi and Gordon (1999), the extract of black tea leaves has antioxidant capacity mainly due to the presence of flavonoids acting as free radical scavengers. In addition, Vinson and Dabbargh (1998) have already reported that polyphenols found in black tea have antioxidant properties. In addition, Wiseman et al. (1997) also showed black tea’s antioxidant ability and its cellular protective effects since it was able to reduce lipid peroxidation under black tea exposure. In an experimental study, Chan et al. (2011) evaluated the antioxidant capacity of different teas made from Camellia sinensis (green, black, and herbal teas). It was shown that green tea has higher antioxidant capacity compared to all of them, followed by black tea, and finally herbal tea. The authors emphasize that it is in accordance with the way that each tea is made, since theoretically green tea has more conserved molecules, such as epigallocatech gallate (EGCG) than black tea, for example. On the other hand, this study also described that black tea’s antioxidant capacity is strongly related to functional molecules that are part of this plant, corroborating previous publications reinforcing the aspect that natural products with biological capacities, as black tea, owe their properties to the chemical matrix. More recently, Yang et  al. (2008) showed the ability of theaflavins and their gallate esters against oxidative damage induced in the HPF-1 cell line, acting as an antioxidant agent through free radical ­scavenging. Moreover, Qi et al. (2017) showed through an in vitro study

Chapter 1  Functional and Medicinal Properties of Caffeine-Based Common Beverages   15

that ­polyphenols from different teas, including black tea, are able to protect neurons from an oxidative exposure and recover mitochondrial dysfunction by an antioxidant mechanism controlling both protein and gene expression of cellular metabolism. In addition, Khanum et al. (2017) showed that different types of black tea present antioxidant effects by free radical scavenging activity and this response was proportional to the number of polyphenols present in each infusion. In this sense, black tea and/or its main compounds could be great alternatives for research development about new alternatives of therapy or even prevention of several chronic diseases related to oxidative metabolism imbalance, such as diabetes, cancer, and neuropsychiatric illness, previously commented upon in this section.

1.3.2 Upstream Pathways of Black Tea Controlling Inflammatory Activation The immune system is a complex and very important organization responsible for an organism’s protection against pathogenic agents, such as bacteria, viruses, and parasites (Medzhitov 2008; Cruvinel et al., 2010). The immunological response is linked to inflammatory activation since it is made by cellular and protein mediators, leukocytes, and cytokines, respectively (Cruvinel et al., 2010; Rabolli et al., 2016). In addition, it is already known that the inflammatory response can be activated by sterile agents released by tissues that are under stressor agents, damaging the cells. Cellular-released molecules include ATP, for example (Takeuchi and Akira, 2010; Chen and Nuñez, 2010), and some current publications have described that excessive EROs also could activate the inflammatory cascade through inflammasome protein complex formation (Zhou et al., 2011; Kim et al., 2016). Despite the importance of the inflammatory response, it must be controlled. After harmful agent elimination, both cellular and protein mediators must be attenuated and returned to basal physiological conditions (Bettelli et al., 2006; Ivanov et al., 2006; O’Connell et al., 2010). However, there are different chronic diseases where the inflammatory response is continuous and persistent, characterizing chronic inflammatory activation, mediated mainly by cytokines (Basha et al., 2016). In this sense, important efforts have targeted at this field of understanding. Similar to antioxidant capacity, the antiinflammatory effect is one of the most explored effects of black tea. There are many interesting studies developed in this field that indicate the black tea beverage as a potential antiinflammatory agent, specially associating this characteristic with atherosclerosis and heart-protection properties (Da Silva, 2013; Hayat et al., 2015). Wu et  al. (2012), in an in  vivo experimental evaluation, extracted theoflavins from black tea. In this study, rats were cigarette i­nhalation-induction exposed and concomitantly treated with

16  Chapter 1  Functional and Medicinal Properties of Caffeine-Based Common Beverages

t­heaflavins. While rats from the cigarette inhalation positive control group presented high mucous secretion, the animals treated with theaflavins from black tea showed inhibition of airway mucous hypersecretion. The authors suggest that this significant effect is due to the antiinflammatory effect induced by theaflavin exposure. More recently, Bedran et al. (2015) through an experimental model showed that black tea extract is capable of causing antibacterial activity against pathogens causing periodontal infection as well as it was able to attenuate the secretion of interleukin (IL-8) in oral cells, suggesting that this extract has not only antimicrobial activity but also antiinflammatory ability that could be used as a tool against oral infections and inflammation. In this sense, black tea or its main compounds could be potent alternatives for antiinflammatory pharmacological research targeting drug development against chronic inflammation.

1.3.3  Black Tea as a Preventive and Potential Natural Therapy Alternative for Cancer Cancer is be a chronic disease associated with aging due to loss of cellular repair capacity and cumulative DNA damages. However, different cancer types have been found increasingly in young subjects. In this sense, currently it is reported that cancer is a genetic multifactorial disease with several known causes and consequences that lead to its classification as a huge global public-health problem (Torre et al., 2015). It is already known that there are many agents able to induce cancer development, such as chemical substances, radiation, virus, by activation of proto-oncogenes causing loss or gain of function specially related to intense cellular proliferation, apoptosis resistance, and cell cycle impairment (Balkwill and Mantovani, 2012; Kidane et al., 2014). In addition, some studies have described the relationship between cancer development and oxidative stress, as well as immune system dysfunction (Da Costa et al., 2012). Then, substances or compounds capable of avoiding or treating these conditions with reduced side effects have been the focus of cancer therapy research (Cadoná et  al., 2017). Again, natural products are in the limelight because of their positive biological effects for more than 50 years (Newman and Cragg, 2016) and black tea is one of these functional beverages that have been evaluated for antitumor ability. In an experimental study performed by Nomura et al. (2000) it was shown that theaflavins from black tea are able to inhibit ultraviolet B-induced AP1 activation. AP1 is a cancer promotor that is activated under radiation exposure, being related to skin cancer development and progression. According to Sharma et al. (2017), tea polyphenols could prevent ultraviolet damage in skin cells since there is some

Chapter 1  Functional and Medicinal Properties of Caffeine-Based Common Beverages   17

research showing this potential: Nichols and Katiyar (2010) and Sang et al. (2011), for example. Despite chemotherapy side effects, another huge problem about cancer therapy is tumor cell chemotherapy resistance (Cadoná et al., 2017). An example of this situation is found in some cases of ovarian cancer. Traditional pharmacological ovarian cancer therapy is based on cisplatin chemotherapeutic. Pan et al. (2017) performed an in vitro experimental study where cisplatin-resistant ovarian cancer cells were exposed to different concentrations of theaflavin-3/3′-gallate, found in high concentrations in black tea infusion. This molecule was able to decrease cellular proliferation, showing the inhibitory effect of cellular cisplatin resistance through apoptosis induction and cell cycle arrest. Moreover, Charehsaz et al. (2017) showed that black tea presents antimutagenic and anticlastogenic effects through in vitro and in vivo assays and its activities were again associated with theaflavins and thearubigins levels that were capable of modulating TA98 and TA100 genes. In addition, Mbuthia et al. (2017) also demonstrated the antitumor action of Camellia sinensis infusions; moreover, the authors also proved that this plant has the capacity to ameliorate metastatic breast cancer. In this regard, it is clear that black tea or even similar teas have antitumor potential and could be used as natural alternatives of cancer prevention.

1.3.4 Neuroprotective Effect of Black Tea is Associated With Mitochondrial Function Recovery Neuropsychiatric and neurodegenerative diseases have affected many patients worldwide (Murray and Lopez, 1996). Currently, the most intriguing aspect of these illnesses is that we still do not have a complete understanding of their pathophysiology and progressing characteristics (Judd et al., 2008; Emsley et al., 2013). However, there are some research studies showing that individuals with neuropsychiatric illnesses, such as bipolar disorder, schizophrenia, and major depression, as well as neurodegenerative illness, including Alzheimer’s diseases, present oxidative imbalance and/or chronic inflammatory activation (Andreazza et al., 2007, 2013). The oxidative stress found in neurons and in the peripheral blood of subjects with neuronal illness is associated with a mitochondrial dysfunction in the electron transport chain, specifically at complex I or IV. This mitochondrial impairment decreases ATP synthesis while increasing free radical and EROs production, followed by cellular homeostasis loss. On the other hand, the inflammatory activation in these subjects happens through cytokine gene and protein overexpression. In addition, some studies have demonstrated that there is a relationship between mitochondrial dysfunction and inflammatory chronic activation

18  Chapter 1  Functional and Medicinal Properties of Caffeine-Based Common Beverages

in these subjects that happens through NLRP3 inflammasome overexpression and protein complex formation (Zhou et al., 2011; Kim et al., 2016). Then, mitochondrial recovery at neurons with any neuronal disease has been the theme of scientific speculation looking forward to find new methods that could improve imbalanced cellular. In 2006, Chaturvedi et al., published one of the first papers showing the neuroprotective modulation of black tea through an in  vivo evaluation. The authors performed a Parkinson’s disease model using 6-hydroxydopamine. Black tea extract was shown to be proficient to modulate rat behavioral parameters as well as recover enzymatic and oxidative metabolism conditions compared to negative control accessed via ex vivo experiments. Zhang et al. (2016), in an experimental research with PC12 cells, proved that theaflavin monomers from black tea present neuroprotective effects against oxidative stress-induced apoptosis. In this research, the authors showed that theaflavins at 10 μM are able to protect neuronal cells against H2O2 apoptosis induction by positive modulations of pro- and antiapoptotic gene expression, also increasing SOD and CAT antioxidant enzyme activity, while decreasing total level of ROS and lipid peroxidation. In addition, Qi et  al. (2017) proved that tea polyphenols can ameliorate redox parameters and mitochondrial dysfunction of neurons via Bmal1, a circadian key protein. All these findings suggest that black tea has significant neuroprotective effects, especially under induced damage neuronal conditions mainly through a mitochondrial effect as well as antioxidant capacity. The set of information about black tea and its chemical matrix strongly suggests that this kind of beverage has several bioactive effects, characterizing it as a functional natural product, which has been the theme of different investigations. In addition, all these biological capacities appear to be associated with the chemical composition of black tea, especially theaflavins that are specific molecules found in black tea. However, more experimental and scientific evaluations are needed to elucidate some aspects that are not completely clear yet as well as to demonstrate the mechanism by which all functions occur.

1.4  Green Tea (Camellia sinensis) 1.4.1 Green Tea Chemical Constituents and Main Biological Activities Green tea, made from Camellia sinensis (Kuntze, Theaceae), is a famous herb, and its extract has been extensively used in the traditional Chinese medicinal system. All true tea comes from a single species of plant, Camellia sinensis, including black, green, oolong, and white tea (Cooper, 2012; Saeed et al., 2017). Green tea may be consumed in the form of a brewed beverage or capsular extract. In some countries, tea is

Chapter 1  Functional and Medicinal Properties of Caffeine-Based Common Beverages   19

Fig. 1.5  Green tea (A) and green tea powder (B).

used as a dietary supplement. Successful tea cultivation requires moist, humid climates provided most ideally by the slopes of Northern India, Sri Lanka, Tibet, and Southern China. This type of tea is consumed predominantly in China, Japan, India, and a number of countries in North Africa and the Middle East (Cooper, 2012; Qadir, 2017; Fig. 1.5). After water, green tea is the most popular flavored and healthy beverage in the world (Jiang et  al., 2013; Chuang et  al., 2017). Different varieties of green tea are available. The main differences between the varieties are due to harvesting time, production procedures, and horticulture (Qadir, 2017). Unlike black tea, which is fermented, green tea is produced in a nonfermented process. After the leaves are picked, they may or may not undergo some processes, which determine whether or not the tea will be green, white, oolong, or black (Cooper, 2012). Archeological evidence actually predates this legend and suggests that tea was first consumed during the early Paleolithic period (about 5000 years ago) (Cooper, 2012). Many people today are taking advantage of the benefits of green tea, which has been used as both a beverage and a medicine historically in most of Asia, China, Japan, Vietnam, Korea, and Thailand. Asians have used green tea to control bleeding, heal wounds, regulate body temperature and blood sugar, and promote digestion (Nakachi et al., 1998; Qadir, 2017). Studies show that the main constituents of green tea are catechin (C), epicatechin (EC), epigallocatechin (EGC), epicatechingallate (ECG), epigallocatechin gallate (EGCG), gallic acid (GA), caffeine, gallocatechin gallate (GCG), theaflavin (TF); theaflavin-3-gallate (TF-3-G), and theaflavin-30-gallate (TF-30-G) (Kao et  al., 2000; Chuang Zhu et al., 2017). Green tea also contains carotenoids; tannins (flavonols); theophylline; theobromine; fats; wax; saponins; essential oils; carotene; vitamins C, A, B1, B12, K, and P; fluoride; iron; magnesium; calcium; strontium; nickel; and copper (Suzuki et  al., 2009; Chuang Zhu et al., 2017).

20  Chapter 1  Functional and Medicinal Properties of Caffeine-Based Common Beverages

EGCG, the main flavonoid in green tea and the most abundant of all the catechins, receives the most attention because it is the main ingredient providing the health benefits of green tea (Zhong et  al., 2001; Qadir, 2017). Green tea has a strong antioxidant property by acting through multiple mechanisms, including free radical scavenging, metal sequestration, and against lipid peroxidation (Fraga et al., 2010; Chuang Zhu et al., 2017; Table 1.3 and Fig. 1.6).

Table 1.3  Main Biological Activities and Bioactive Molecules of Green Tea (Camellia sinensis) Biological activity

Antitumor

Neuroprotective Against diabetes and cardiovascular diseases

Chemical composition

Against age-related macular degeneration Catechin Epicatechin Epigallocatechin Epicatechingallate Epigallocatechin gallate Gallic acid Caffeine Gallocatechingallate Theaflavin and derivatives: Theaflavin-3-gallate Theaflavin-30-gallate Carotenoids Tannins—flavonols Theophylline Theobromine Saponins, essential oils, carotene, and vitamins Minerals

Yang et al. (2009), Yuan (2013), Yiannakopoulou (2014), Rathore and Wang (2012), Rathore et al. (2012), Zeng et al. (2014), Zhou et al. (2014), Cerezo-Guisado et al. (2015), Khan et al. (2009), Connors et al. (2012), and Wang et al. (2014, 2015) Fuso (2013), Nicolia et al. (2015), Mandel et al. (2008), Weinreb et al. (2004), Pinto et al. (2015), and Schimidt et al. (2017) Fraga et al. (2010), Del Rio et al. (2013), Galleano et al. (2013), Abdulkhaleq et al. (2017), Chen et al. (2015), and Grassi et al. (2008) Pan et al. (2016a,b) Kao et al. (2000) and Chuang Zhu et al. (2017)

Suzuki et al. (2009) and Chuang Zhu et al. (2017)

Chapter 1  Functional and Medicinal Properties of Caffeine-Based Common Beverages   21

Fig. 1.6  Main biological properties of green tea.

1.4.2 Green Tea and Cancer One of the most studied beneficial aspects of green tea regarding human health is the case of cancer. Cancer is one of the leading causes of death in the world. It is characterized by the uncontrolled growth of cells in the affected body part where it begins, essentially as a result of mutations that occur in genes that are involved either in cell survival and proliferation, which basically give the cancer cell immortality, or these alterations can affect genes that are implicated in DNA repair, for example. The incidence of new cancer cases is dramatically increasing worldwide in the past decades, especially in the Western world, and modern treatments still deal with a lot of side effects, which give space to studies involving dietary factors as chemopreventive agents or assistants in the case of cancer management. It is well known that dietary components can considerably influence human cancer risk and many of those compounds have been reported to have anticancer or cancer-preventive activities. Green tea has been widely investigated for its protective roles, especially against cancer development. Many studies using several animal models have addressed the inhibitory activities of isolated green tea polyphenols and/or green tea extract against tumorigenesis at diverse organ sites (Yang et  al., 2009). Mechanisms of action of tea polyphenols,

22  Chapter 1  Functional and Medicinal Properties of Caffeine-Based Common Beverages

­ articularly EGCG, have been broadly explored for numerous cancer p types in vitro and in vivo, such as breast, prostate, lung, and colon cancers (Yuan, 2013). Several studies have postulated that especially catechins, found in high amounts in green tea, could modulate breast cell carcinogenesis (Yiannakopoulou, 2014). These results were found based on in vitro studies in which immortalized human MCF10A breast epithelial cells were exposed to very small concentrations of environmental carcinogens to induce carcinogenesis. Further, these cells were also treated with green tea catechins at physiologically levels and it was shown that these phytochemicals were able to suppress chronically induced cellular carcinogenesis due to a combination of biological activities, such as blockage of DNA damage, cell proliferation, and carcinogen-induced ROS elevation (Rathore and Wang, 2012; Rathore et al., 2012). Isolated EGCG, the major component of green tea, was shown to increase cell death and inhibit cell proliferation of breast cancer cells in vitro (Zeng et al., 2014). In addition, EGCG modulation of microRNA (miRNA) seems to play a key role in the inhibition of tobacco ­carcinogen-induced lung tumors in  vivo, suggesting that miRNA-­ mediated regulation is involved in the major aspects of the anticancer activity of EGCG in mice (Zhou et al., 2014). EGCG could potentially be used as a chemotherapeutic agent for colon cancer treatment: EGCG induced cancer cell death by inhibiting Akt, ERK1/2, or alternative p38MAPK activity in vitro (Cerezo-Guisado et al., 2015). There are also some literature data available especially in the past decade, regarding both in  vivo and in  vitro approaches that investigated the effect of green tea or EGCG on DNA methylation and gene expression of enzymes involved in epigenetic modifications such as DNA methyltransferase 1 (DNMT1), suggesting that green tea and its constituents could be exerting their biological effects, such as anticancer activity, through epigenetic modulations (Henning et  al., 2013). The inhibition of growth factor signaling pathways, modification of epigenetic factors, and modulation of oxidative stress for green tea was also observed in animal models of prostate cancer, showing some encouraging chemopreventive effects of green tea and its catechins against prostate cancer (Khan et al., 2009; Connors et al., 2012). Green tea and its main constituents have shown some positive effects as adjuvants in cancer therapy (Fujiki et al., 2015). Currently, despite many treatment efforts, multidrug resistance is still one of the major challenges concerning cancer management. To overcome this issue, there is a growing interest in the use of combinations of natural products to target multiple mechanisms concomitantly. In fact, an increase in anticarcinogenic action was observed when quercetin and green tea were combined in a prostate cancer xenograft mouse model

Chapter 1  Functional and Medicinal Properties of Caffeine-Based Common Beverages   23

(Wang et al., 2014). Another study, performed with castration-resistant prostate cancer cells, showed that green tea and quercetin were able to sensitize and, consequently, enhance the chemotherapeutic effect of docetaxel on those cells through multiple mechanisms including the downregulation of chemoresistance-related proteins (Wang et al., 2015). Taking this information into account, the use of green tea or its isolated compounds could alleviate the deleterious side effects of conventional cancer therapies as well as increase their action through additive or synergistic effects (Lecumberri et al., 2013). Despite the many encouraging results towards the use of green tea and its main phytochemicals for chemopreventive purposes, still further investigations need to be performed in order to clarify the proposed mechanisms of action for each cancer type (Lambert, 2013).

1.4.3 Neuroprotective Effects of Green Tea Neurodegenerative diseases represent nowadays a heavy burden for public health worldwide in the sense of socioeconomic costs, once they affect an individual’s functioning and result in disabilities or limit activities, increasing the necessity for medical and personal care. Alzheimer’s and Parkinson’s diseases, among various others, exemplify a difficult challenge in terms of health promotion and disease prevention. In this scenario, many efforts come from the scientific community to discover the underlying mechanisms of these disorders and so new treatment strategies (Alonso et  al., 2011). Increasing evidence suggests that actually environmental factors, such as dietary habits could interfere with neurodegenerative processes through, for example, epigenetic regulation of genes and DNA methylation (Fuso, 2013; Nicolia et al., 2015). Green tea is among the most traditional beverages consumed around the world. Although not every country has the habit of consuming it, other functional beverages, such as black tea, coffee, and yerba mate, are ingested by the population and present very similar basal chemical matrices, rich in catechins and polyphenols. Taking this into consideration, some studies came up with the idea that dietary elements like green tea could be beneficial for the prevention of some neurodegenerative diseases (Mandel et  al., 2008; Weinreb et al., 2004). In a recent study, green tea and its main catechins, EC, and EGCG, were shown to protect against a Parkinson’s disease model in rats. The results indicated that both had the capacity of reverting behavioral changes induced by the Parkinson’s disease model and showed an overall neuroprotective effect by increasing locomotor activity, cognitive functions, and antidepressive outcomes of the disease (Pinto et al., 2015).

24  Chapter 1  Functional and Medicinal Properties of Caffeine-Based Common Beverages

More recently, another investigation explored the neuroprotective effects of green, red, and black tea in an Alzheimer-like rat model. Green and red tea were effective in avoiding memory deficits in an Alzheimer-like model, but green tea also avoided oxidative stress and damage in the hippocampus. However, green tea was more effective in rats with Alzheimer-induced disease than red and black teas (Schimidt et al., 2017).

1.4.4 Green Tea, Diabetes, and Cardiovascular Diseases Diabetes mellitus (DM) is currently one of the main public health challenges, because the number of people with this disorder has more than doubled worldwide in the past three decades. In this sense, there are a lot of concerns about DM, as the cases of T2DM and prediabetes are increasing dramatically among children, adolescents, and younger adults (Chen et al., 2012). Studies show that 90% of diabetes cases belong to T2DM, a chronic metabolic disorder characterized by insulin resistance and high blood glucose levels (hyperglycemia) (WHO, 2000; Kahn et al., 2006). Green tea and its main constituents, such as EC, are being suggested to improve insulin resistance. In fact, some studies suggested the beneficial effects of EC consumption, proposing various cellular mechanisms including insulin-sensitivity adjustment (Fraga et  al., 2010). In addition, EC showed to be helpful to decrease blood pressure. By reducing both insulin resistance and blood pressure, the consumption of EC-containing foods could help to prevent the onset of T2DM and many cardiovascular diseases (Del Rio et al., 2013; Galleano et  al., 2013; Abdulkhaleq et  al., 2017). However, the development of cardiovascular diseases due to insulin sensitivity (as an independent risk factor) is still under debate (Chen et  al., 2015). Nevertheless, EC consumption is indicated to decrease systolic blood pressure and EC-rich green tea was shown to exhibit in vivo antiplatelet effect, a ­cardiovascular-associated risk factor, as determined in a murine model and human subjects (Grassi et al., 2008; Del Rio et al., 2013; Abdulkhaleq et al., 2017).

1.4.5 Green Tea and Age-related Macular Degeneration Aging can cause several age-related disorders such as age-related macular degeneration (AMD). In fact, AMD is the most common cause of visual loss among elderly people in developed countries. The number of AMD cases increases considerably because of aging, affecting about 8.5% to 27.9% of the population more than 75 years

Chapter 1  Functional and Medicinal Properties of Caffeine-Based Common Beverages   25

of age (Soubrane et  al., 2002; Torres et  al., 2009). The incidence of this pathology has dramatically increased in the past decades, about 30%–40%, despite other ophthalmic diseases such as glaucoma and cataracts, reaching the same population range, having shown a reduction in their records (Evans and Wormald, 1996; Torres et al., 2009). Estimates show that by 2020, about 196 million people will be affected worldwide, coming to an estimated number of 288 million people by 2040 (Torres et al., 2009; Wong et al., 2014; Marazita et al., 2016). Some studies suggest that oxidative stress, arising from the excessive production or inefficient neutralization of ROS, caused, for example, due to the exposure to environment factors, could exert a great influence on the retinal pigment epithelium (RPE) and so, to the pathophysiology of AMD (Datta et al., 2017). Green tea is known for its many beneficial biological properties, due to the presence of many constituents with high antioxidant capacity, for example, catechins. In this sense, the effect of green tea consumption and visual impairment in the elderly was analyzed by an epidemiological study performed by Pan et al. (2016a,b). Data obtained from this investigation with 4579 older adults (>60 years) living in a rural community in Eastern China have shown lower occurrence of visual impairment associated with the intake of three or more glasses of green tea per day. These results demonstrate that green tea could be a powerful ally in the prevention of ocular diseases, such as AMD, promoting a better quality of life for elderly people.

1.5  Yerba Mate (Ilex paraguariensis) 1.5.1  Yerba Mate Chemical Constituents and Main Biological Activities Ilex paraguariensis is a plant localized in South America, belonging to the Aquifoliaceae family. It is a dioecious evergreen tree, which can grow to a height of up to 8–15 m. The 8-cm long olive-green leaves are perennial, alternate, coriaceous, obovate with slightly crenate dentate margins and obtuse apex, and have a wedge-shaped base. The petioles are up to 15 mm long. The flowering stage occurs during the spring season, producing small, unisexual flowers with four white petals. In some tropical or subtropical species, the number of petals may be five, six, or seven. These may be clustered in groups of 1–15 flowers that appear in the axils of the leaves. The fruits are red-colored berries containing four to five seeds (Bracesco et al., 2011; Fig. 1.7). Starting with yerba leaves, a powder is produced from which a nonalcoholic beverage with very regional characteristics, called “chimarrão” in the south of Brazil, “tereré” in Paraguay, and “mate” in Argentina and Uruguay is originated. This drink is consumed by the

26  Chapter 1  Functional and Medicinal Properties of Caffeine-Based Common Beverages

Fig. 1.7  Yerba mate tea (A) and chimarrão mate tea (B).

population in these countries, with huge cultural, economic, and social importance (Mejia et  al., 2010). Besides, it is used as an energy source, to improve energy for daily activities and as a therapeutic agent due to its pharmacologic properties (Bracesco et al., 2011). The production process of yerba mate involves the harvest of the older leaves of I. paraguariensis, which are dried over a fire, milled, stored, and packed for their commercialization. The industrialization process involves the stages of harvesting, roasting, drying, milling, aging, and final preparation. Especially in the first stages of processing, the leaves could suffer important alterations in the profile and concentration of bioactive compounds, which could modify the biological activities of yerba (Isolabella et al., 2010). The interest on yerba mate has increased mainly because of its phytochemistry composition and biological activities (Cardozo Junior and Morand, 2016). The chemical composition of I. paraguariensis includes several constituents that may be responsible for the numerous recognized biological and pharmacological activities. The compounds found in high quantities are purine alkaloids (methylxanthines such as caffeine and theophylline), polyphenols (CGAs and its derivatives), saponins, and flavonoids (Heck and De Mejia, 2007; Bracesco et al., 2011). The alkaloids, specially methylxanthines, such as caffeine and theobromine (Meinhart et al., 2010) are responsible for the stimulant activity of yerba mate on the brain and increasing the utilization of fat as an energy source (Silva et al., 2011). The saponins found in yerba mate are responsible for the decrease of cholesterol (Ferreira et al., 1997). The phenolic compounds, responsible for the antioxidant activity of yerba mate, are the major constituents and more studied in this plant. These compounds are secondary metabolites, normally involved in defense against UV radiation or aggression of pathogens (Manach et al., 2004). The polyphenol levels in I. paraguariensis extracts are higher than those of green

Chapter 1  Functional and Medicinal Properties of Caffeine-Based Common Beverages   27

tea and parallel to those of red wines (Gugliucci et al., 2009). The phenolics are present, mostly in the form of phenolic acids, as CGAs and flavonoids (Bravo et al., 2007). In a study in 2009, Marques identified esters of CGA in samples of green and toasted yerba mate such as 5-cafeoilquinic, 4-cafeoilquinic, 3-cafeoilquinic, 3,5-dicafeoilquinic, 3,4-dicafeoilquinic, and 4,5-dicafeoilquinic acids. Although the phenolic compounds are being present in the aqueous extract of yerba mate, the bioavailability of these compounds is unknown. In this way, some studies have verified the action of CGAs present in coffee in humans and, due to the similarity with those found in both, extrapolated the action for yerba mate (Monteiro et al., 2007; Duarte and Farah, 2011). The intrinsic activity is low, and they could be absorbed in the intestines or be quickly metabolized and excreted (Manach et al., 2004). When they are absorbed, the phenolics are conjugated in the small intestine and, after this, in the liver, in a process that includes methylation, sulfatation, and glucuronidation (Scalbert and Williamson, 2000; Manach et al., 2004). The bioavailability is variable between phenolics. The metabolites present in blood, results of digestion are, most of the time, different from the intact compounds (Manach et al., 2005). Oliveira et al. (2016) evaluated the metabolization of CGAs from yerba mate in rats and verified that a little parcel of these compounds was sent to the bloodstream; and the cafeoilquinic and dicafeoilquinic acids of yerba mate are absorbed by cells of the gastrointestinal tract, and could be active in these tissues. Besides that, cafeoilquinic acid and intact metabolites of yerba are presents in stomach, small and large intestine, liver, kidneys, muscles, plasma, and urine. Monteiro et  al. (2007) investigated the CGAs bioavailability after the acute consumption of coffee and found six intact types in the plasma, among them being 3-cafeoilquinic acid, 4-cafeoilquinic acid, 5-cafeoilquinic acid, 3,5-dicafeoilquinic acid, 3,4-dicafeoilquinic acid, and 4,5-dicafeoilquinic acid. The authors also observed that urine is not an excretion route for intact CGAs. Although the bioavailability and the effects of each of the I. paraguariensis compounds in plasma and tissues have not yet been clarified in the literature, several biological properties are reported. Among them are antioxidant and antiinflammatory (Miranda et  al., 2008; Berté et  al., 2011; Borges et  al., 2013), regulation of adipogenesis (Arçari et al., 2013), weight reduction and antiobesity properties (Arçari et al., 2009, 2011a; Borges et al., 2013), and reduction of blood lipid levels and atherosclerosis risk factors (Mosimann et  al., 2006; Gao et al., 2013). Some studies have demonstrated significant biological effects in traditional medicine for the treatment of arthritis, rheumatism, and other inflammatory diseases, headache, hypertension,

28  Chapter 1  Functional and Medicinal Properties of Caffeine-Based Common Beverages

hepatic, and digestive disorders (Mosimann et al., 2006), and research has demonstrated its benefits for cardiovascular health (Balzan et al., 2013; Table 1.4 and Fig. 1.8).

1.5.2 Effects of Yerba Mate Extracts on Obesity, Diabetes, and Cardiovascular Health I. paraguariensis has been studied due to its potential beneficial effects on obesity, diabetes, and cardiovascular health, mainly for regulation of oxidative markers and lipid metabolism.

Table 1.4  Main Biological Activities and Bioactive Molecules of Yerba Mate (Ilex paraguariensis) Biological activity

Against obesity, diabetes, and cardiovascular diseases

Antiinflammatory Antitumor

Neuroprotective

Chemical composition

Caffeine Theophylline Saponins Flavonoids Polyphenols—chlorogenic acids and derivatives: 5-cafeoilquinic acid 4-Cafeoilquini acid 3-Cafeoilquinic acid 3,5-Dicafeoilquinic acid 3,4-Dicafeoilquinic acid 4,5-Dicafeoilquinic acid

Yu et al. (2015), Menini et al. (2007), Gugliucci and Bastos (2009), Kim et al. (2015), Gao et al. (2013), Arçari et al. (2011b, 2013), Fujii et al. (2014), Kang et al. (2012), Lima et al. (2014), and Boaventura et al. (2013) Puangpraphant and Mejía (2009), Schubert et al. (2007), Luz et al. (2016), and Carmo et al. (2013) Bracesco et al. (2003), Miranda et al. (2008), Ronco et al. (2016, 2017), and de Mejía et al. (2010) Milioli et al. (2007), Reis et al. (2014), Branco et al. (2013), Colpo et al. (2007), Prediger et al. (2008), Vignes et al. (2006), and Park et al. (2010) Heck and De Mejia (2007) Bracesco et al. (2011) Meinhart et al. (2010) Manach et al. (2004) Marques and Farah (2009) and Bravo et al. (2007)

Chapter 1  Functional and Medicinal Properties of Caffeine-Based Common Beverages   29

Fig. 1.8  Main biological properties of yerba mate.

Yerba mate plays a role in the regulation of several indices of haemorheology, nailfold microcirculation, and platelet aggregating factors (Yu et al., 2015). Studies with I. paraguariensis uncovered a strong protection of ex  vivo human low-density lipoprotein (LDL) from oxidation as well as protection of paraoxonase activity regarding high-density lipoprotein (HDL) (Menini et al., 2007; Gugliucci and Bastos, 2009). Paraoxonase 1 (PON1) is an antioxidant enzyme carried by HDL, which has an atheroprotective effect (Menini et al., 2007; Gugliucci and Bastos, 2009). Besides this, yerba mate may modulate positively the mRNA expression and activity of paraoxonase 2 (PON-2), an intracellular antioxidant enzyme, in monocytes and macrophages, protecting against oxidative stress and the formation of foam cells (Fernandes et al., 2012). Kim et  al. (2015) conducted a randomized, double-blind, ­placebo-controlled trial with obese Korean subjects. For 12 weeks, the subjects were daily supplemented with capsules of yerba mate. The results showed significant decreases in body fat mass, percent body fat, and the waist-hip ratio in the supplemented group compared to the placebo group, suggesting an antiobesogenic effect of I. paraguariensis. In vivo and ex vivo studies reported decreased serum lipid levels in the hyperlipidemic hamster model (Gao et al., 2013) and humans supplemented with yerba mate aqueous extract (Arçari et al., 2011b).

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In the first study, besides this reduction, it was observed that yerba mate treatment increased antioxidant enzyme activity, improved LPL and hepatic lipase activities in serum and liver, and modulated the expression levels of genes involved in lipid oxidation and lipogenesis. In the same way, Arçari et al. (2011b) showed that after 60 days, the yerba mate extract was able to decrease lipid peroxidation products and increase serum total antioxidant status and enzymatic activity of superoxide dismutase (Cu-Zn SOD) for both groups supplemented with yerba mate tea. Aqueous extracts of yerba mate and its major bioactive compounds could modulate adipogenesis and obesity. Arçari et al. (2013) demonstrated that yerba mate extract downregulated the expression of genes that regulate adipogenesis, such as Creb-1 and C/EBPa, and upregulated the expression of genes related to the inhibition of adipogenesis, including Dlk1, Gata2, Gata3, Klf2, Lrp5, Pparc2, Sfrp1, Tcf7l2, Wnt10b, and Wnt3a. In the same way, Pimentel et al. (2013) showed that yerba mate extract intake blunted the pro-inflammatory effects of diet-induced obesity in rats by reducing the phosphorylation of hypothalamic IKK and NFκBp65 expression and increasing the protein levels of IκBα, the expression of adiponectin receptor-1, and consequently the amount of IRS-2. Fujii et al. (2014) reported that treatment of I. paraguariensis dried aqueous extract in male Wistar rats fed with high-fat diet (HFD) reduced body weight gain and total blood cholesterol in comparison to the nontreated group. Besides, yerba mate tea decreased the ratio between phosphorylated and total kinase inhibitor of kB (IKK), increased the ratio of phosphorylated total form of protein kinase B (AKT), and reduced NF-kB phosphorylation in the liver of the HFD group, suggesting a beneficial role of I. paraguariensis in improving metabolic dysfunctions induced by a HFD. In  vivo research showed that I. paraguariensis has positive effects on metabolic alterations, a consequence of obesity, including reductions in serum cholesterol, serum triglycerides, and glucose concentrations (Kang et al., 2012; Lima et al., 2014). Important effects of I. paraguariensis have been reported in diabetes due to increase in the erythrocyte antioxidant glutathione peroxidase (GSH) and a decrease of serum lipid peroxidation, glycemia, and the HbA1c gene in prediabetic subjects (Boaventura et al., 2013). The increase of total antioxidant levels as well as antioxidant enzyme gene expression by yerba mate extract suggests that regular consumption could improve antioxidant defenses by multiple mechanisms, not only by increasing circulating bioactive compounds, but by upregulation of cellular enzymatic machinery to counter oxidative stress.

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1.5.3 Effects of Yerba Mate Extracts on Inflammation In traditional medicine, I. paraguariensisis is used to treat many diseases including inflammatory-related diseases. However, the mechanism and the compounds involved in this effect are not yet known precisely. Some studies reported that the combination of quercetin and saponins of yerba mate resulted in synergistic interaction inhibiting both nitric oxide and prostaglandin 2 (PGE2) production (Puangpraphant and Mejía, 2009; Schubert et al., 2007). In a study performed by Luz et  al. (2016), the antiinflammatory property of I. paraguariensis (crude extract—CE) and its related fractions—buthanolic (BF) and aqueous residue (ARF)—and its major compounds caffeine (CAF), rutin (RUT), and CGA were tested in an in vivo model of pleurisy. All the fractions were able to reduce leukocyte migration, concentration of myeloperoxidase (MPO), adenosine desaminase (ADA) activities, and nitric oxide levels. Moreover, I. paraguariensis also inhibited the release of Th1/Th17 pro-inflammatory cytokines, while increasing IL-10 production and improving the histological architecture of inflamed lungs. In addition, its major compounds decreased p65 NF-κB phosphorylation. On the same hand, Carmo et al. (2013) investigated the effects of yerba mate consumption on the hematological response and the production of inflammatory and antiinflammatory interleukins by bone marrow cells from Wistar rats fed with HFD. The data showed that yerba mate reduced pro-inflammatory interleukines IL-1α, IL-6, and TNF-α production by the cells. Similar results were found with macrophages of rats submitted to HFD and HFD plus yerba mate (Borges et al., 2013).

1.5.4 Effects of Yerba Mate Extracts on Mutagenesis Conversely, many studies in cell culture models as well as in animals seem to converge to show an antimutagenic and DNA-protecting effect for I. paraguariensis extracts and its major components CGA, rutin, and quercetin (Bracesco et al., 2003; Miranda et al., 2008). The regular ingestion of yerba mate tea increased the resistance of DNA to hydrogen peroxide-induced DNA strand breaks and improved DNA repair after hydrogen peroxide challenge in liver cells, independently of the dose ingested. These results suggest that yerba mate could protect against DNA damage and enhance DNA repair activity. Protection may be attributed to the antioxidant activity of the yerba mate bioactive compounds CGA, rutin, and quercetin (Bracesco et al., 2003; Miranda et al., 2008).

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In recent case-control studies, strong inverse associations between high “mate” intake and breast cancer were reported (Ronco et  al., 2016, 2017). Besides this, an in  vitro study showed that yerba mate tea inhibited 50% of net growth of human colorectal adenocarcinoma cells CaCo-2 and HT-29 when compared with the CCD-33Co normal colon fibroblast cell line. Yerba mate inhibited in  vitro colon cancer cell proliferation possibly mediated via pro-oxidant activities; therefore, it represents a potential source of chemopreventive agents (de Mejía et al., 2010). However, some epidemiological studies indicate that there is an association between hot water mate consumption and oropharyngeal and esophagus cancers (Loria et  al., 2009; Dasanayake et  al., 2010; Stefani et al., 2011). The effects may be related mainly to the temperature of the infusion (Ramirez-Mares et  al., 2004). At the same time, high levels of carcinogenic polycyclic aromatic hydrocarbons (PAH) have been found in yerba mate tea due to the manufacturing process of leaves (drying) using firewood (Kamangar et al., 2008; Dasanayake et al., 2010; Golozar et al., 2012).

1.5.5 Effects of Yerba Mate Extracts on Neurological Health Although I. paraguariensis preparations are traditionally and widely used as stimulating beverages, many neuropharmacological properties are reported such as antiparkinsonian-like (Milioli et  al., 2007), antidepressant-like (Reis et al., 2014), anticonvulsant (Branco et  al., 2013), neuroprotection of memory impairment (Colpo et  al., 2007), and cognitive enhancer (Prediger et al., 2008). The renowned effects of I. paraguariensis are mainly attributed to the levels of caffeine in this plant species, this substance being described as anxiogenic (El Yacoubi et al., 2000), although it appears contradictory that a beverage containing caffeine, a stimulant compound, would have anxiolytic-like features. In this regard, studies demonstrated that the known stimulant plant Panax ginseng promoted an anxiolytic-like effect attributed to saponin constituents (Carr et al., 2006). Plant extracts comprise hundreds of substances and it is possible that compounds as flavonoids (Herrera-Ruiz et al., 2008) and saponins (Wei et  al., 2007) could be responsible for the anxiolytic activity of I. paraguariensis, surpassing the anxiogenic effect of caffeine. In addition, the polyphenol (-)-EGCG present in I. paraguariensis was described as an anxiolytic molecule and is able to antagonize the anxiogenic effect of caffeine (Vignes et al., 2006; Park et al., 2010).

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1.6 Conclusion Many functional and medicinal beverages have been studied to treat several diseases. Coffee (Coffea arabica), black/green tea (Camellia sinensis), and yerba mate (Ilex paraguariensis) are remarkable functional and medicinal beverages, since they present many bioactive molecules in their chemical matrix. Previous studies reported that these plants present several biological activities. For instance, caffeine is able to decrease the production of β-amyloid protein levels and increase dopamine levels. Moreover, it presents anticancer activity by stimulating the apoptosis pathway, antioxidant activity by reducing oxidative stress, insulin sensitivity adjustment, and modulates the immune system. In addition, black and green tea are considerate remarkable antioxidant plants by neutralizing EROs, as well as they present anticancer activity, antiplatelet effect, insulin sensitivity adjustment and avoid memory deficits, oxidative stress, and damage in the hippocampus. In addition, yerba mate avoids memory deficits, acts as an antidepressant and anticonvulsant, inhibits nitric oxide, prostaglandin 2 (PGE2), and pro-inflammatory cytokines production, decreases LDL, increases HDL and antioxidant enzymes, protects against DNA damage and enhances DNA repair activity, as well as downregulates the expression of genes that modulate adipogenesis. Therefore, the frequent intake of these functional beverages can contribute to a healthier life.

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Further Reading Cruvinel, W.M., Mesquita, J.R.D., Araujo, J., Salmazi, K., Kallas, E., Rabolli, V., Lison, D., Huaux, F., 2015. The complex cascade of cellular events governing inflammasome activation and IL-1β processing in response to inhaled particles. Part. Fibre Toxicol. 13, 40.

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