Journal of Functional Foods 38 (2017) 308–320 Contents lists available at ScienceDirect Journal of Functional Foods journal homepage: www.elsevier.com/locate/jff Yerba mate: An overview of physiological effects in humans Liza Ghassan Riachi a, Carlos Alberto Bastos De Maria a,b,⇑ a b Nursing and Biosciences Postgraduation Program, Nursing School (PPGENFBIO – UNIRIO), Av. Pasteur 296, CEP 22290-240 Rio de Janeiro, Brazil Collective Health Department, Biomedical Institute, (UNIRIO), Brazil a r t i c l e i n f o a b s t r a c t Article history: Received 21 June 2017 Received in revised form 11 September 2017 Accepted 13 September 2017 This review aims to make an outline of the existing clinical studies from the past twenty years concerning to maté effects in human health. Physiological effects have been attributed to phenolics, methylxanthines and saponins. Antilipemic activity was more consistent than glycaemic control. Maté seems to protect low-density lipoprotein cholesterol (LDL-c) from oxidation in whole plasma. Results from isolated LDLc particles are contradictory. The antioxidant enzymatic complex was positively modulated, indicating that maté might help in the redox homeostasis maintenance. Most clinical trials did not find a significant positive effect of maté consumption on glycaemia. However, it seems that maté hypoglycaemic effect is more evident in type-2 diabetes mellitus subjects. Maté had no effect on anti-glycation in vivo. It has shown potential to increase energy expenditure and weight loss. Carcinogenicity is related to consumption temperature, not maté itself. Long-term randomized double-blind placebo-controlled studies are essential to provide more consistent data. Ó 2017 Elsevier Ltd. All rights reserved. Keywords: Ilex paraguariensis Human Oxidative stress Antioxidant enzymes Lipidaemic and glycaemic control Weight loss Contents 1. 2. 3. 4. 5. 6. 7. Introduction . . . . . . . . . . . . . . Phytochemicals. . . . . . . . . . . . Antioxidant defense . . . . . . . . Weight loss potential . . . . . . . Lipid and glycemic profile . . . Other physiological activities Final considerations . . . . . . . . Acknowledgements . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Introduction Yerba mate or maté (Ilex paraguariensis A. St.-Hil.) is a native plant from South American countries, such as Brazil, Argentina, Paraguay, and Uruguay. Maté is commonly sold in markets either as dried and green or dried and roasted ground leaves. The first is used to prepare tereré and chimarrão by adding cold and hot water, respectively, while maté tea is made through the infusion ⇑ Corresponding author at: Collective Health Department, Biomedical Institute, Federal University of Rio de Janeiro State (UNIRIO), Rua Frei Caneca 94, sala A-411, CEP 20211-040 Rio de Janeiro, Brazil. E-mail addresses: email@example.com (L.G. Riachi), firstname.lastname@example.org (C.A.B. De Maria). http://dx.doi.org/10.1016/j.jff.2017.09.020 1756-4646/Ó 2017 Elsevier Ltd. All rights reserved. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 308 309 309 313 314 317 318 318 318 of roasted leaves with boiling water. Maté is much appreciated worldwide for its bittersweet taste and aroma (Márquez et al., 2013). The daily consumption can vary between 1 and 6 L per person (Bastos, Oliveira, Matsumoto, Carvalho, & Ribeiro, 2007). Maté is known for having stimulant, anticonvulsant and neuroprotective effects on the central nervous system and this is mostly attributed to its high content of caffeine and phenolics (Bastos et al., 2007; Branco et al., 2013). It is an important source of bioactive compounds, such as phenolic acids, flavonoids, and saponins (Heck & de Mejia, 2007). The presence of these components aroused the interest of the scientific community on the physiological benefits of maté consumption. This is primarily related to the high antioxidant capacity of the plant. Biological molecules oxidation caused 309 L.G. Riachi, C.A.B. De Maria / Journal of Functional Foods 38 (2017) 308–320 by reactive oxygen and nitrogen species (ROS and RNS), would be responsible for several chronic pathologies (Lobo et al., 2010; Bracesco, Sanchez, Contreras, Menini, & Gugliucci, 2011). In vitro, ex vivo and animal model studies have demonstrated beneficial effects of maté on lipid, glucose and intrinsic antioxidant metabolism (Bracesco et al., 2011). Furthermore, phenolic components and metabolites from maté extract was found to decrease cancer cell viability and proliferation in human carcinoma cells (AmigoBenavent, Wang, Mateos, Sarriá, & Bravo, 2017). In the past twenty years, clinical trials have been exploiting the possibility to use maté in the prevention or as a complementary treatment of some diseases (Boaventura et al., 2015; Gugliucci, 1996; Kim, Oh, Kim, Chae, & Chae, 2015; Menini, Heck, Schulze, de Mejia, & Gugliucci, 2007; Petrilli et al., 2016). Given the increasing amount of clinical trials concerning maté, this review aims to discuss critically the existing research findings on human intervention trials and maté consumption. 2. Phytochemicals In general, phytochemicals content is susceptible to environmental conditions (e.g. soil, temperature, light intensity) and to genetic variability (Coelho et al., 2007; Heck, Schmalko, & De Mejia, 2008). Maté composition can also vary according to the processing (dried – green maté, or roasted) and brewing conditions (infusion or use of heated or cold water) used in the preparation of maté beverages (maté tea, chimarrão and tereré) (Bastos, Fornari, Queiroz, & Torres, 2006; da Silveira, Meinhart, Ballus, & Godoy, 2014; Isolabella et al., 2010; Meinhart et al., 2010). Since there was no distinction between all these variables in Table 1, the concentration of each compound may vary greatly. In addition, it was focused on works that used water as a solvent to reproduce as much as possible the extraction method commonly used and the amount of compounds that is theoretically consumed. The single exception was for saponins that required other solvents rather than water for extraction and quantification. Table 1 and Fig. 1 show the most important soluble components of maté aqueous extract. Maté is a natural source of phenolic compounds that is mainly represented by chlorogenic acids (e.g. caffeoylquinic, feruloylquinic and dicaffeoylquinic acids). If a high amount of maté is consumed daily the intake of caffeine could be close to that of coffee. A cup of coffee (150 mL) has between 75 mg and 330 mg of caffeine (0.5–2.2 mg mL–1 of caffeine) (Danhelova et al., 2012) while a serving volume of chimarrão (500 mL) has between 93 mg and 110 mg of caffeine. This value can be greater, considering that maté ingestion can be up to 6 L per day (Bastos et al., 2007). Maté also has considerable amounts of theobromine which contribute for total methylxanthines ingestion. Although some works reported the occurrence of theophylline, its presence is still controversial (Heck & de Mejia, 2007; Ribeiro et al., 2017). Maté has a small number of flavonoids that contribute to its overall antioxidant capacity. The most common flavonoids are quercetin and rutin. Identification of kaempferol is questionable since this compound is completely insoluble in water. Maté drinks have also triterpenic saponins formed with oleanolic and ursolic acids aglycones (Gnoatto, Schenkel, & Bassani, 2005; Heck & de Mejia, 2007). These compounds are responsible for both foaming formation and for the typical bitter taste in maté beverages. More recently, lutein was identified for the first time in tereré (2.83 lg 100 mL1) and chimarrão extracts (0.43–2.55 lg 100 mL1). This finding suggests maté as a potential source of this carotenoid (da Silveira et al., 2016). 3. Antioxidant defense Natural antioxidants are known to retard the oxidative damage caused by the unrestrained production of ROS and RNS. The oxidation of cell constituents and other components can lead to structural modification and consequently cause loss of their biological activity. This phenomenon is associated with the occurrence of several pathologies, such as cancer, cardiopathy, and diabetes (Bracesco et al., 2011). Maté has shown great antioxidant potential, mainly attributed to its phenolics. It has also been proven to be more efficient both in the reduction of AGE formation in vitro than green tea and in the prevention of protein nitration and cell death induced by peroxynitrite compared to green tea and red wine (Bixby, Spieler, Menini, & Gugliucci, 2005; Lunceford & Gugliucci, 2005). The reduction of AGE formation is particularly important for prevention of oxidative stress and diabetes complications. Anti-glycation capacity of two major phenolic compounds (caffeic and chlorogenic acids) and of a sapogenin (oleanolic acid) from maté was tested for the first time against AGE generation by methylglyoxal using two protein models (histone and bovine serum albumin model (BSA)) (Gugliucci, Bastos, Schulze, & Souza, 2009). Antiglycation effect of phenolics could be attributed to their Table 1 Bioactive compounds from maté aqueous extract (mg mL–1). Compound Amount* Phenolic acids 5-CQA 3- CQA 4- CQA 3- FQA 4- FQA 5- FQA 3,4- diCQA 3,5- diCQA 4,5- diCQA CA 51–388a,b,c,d,e 63.9–175.42b,c 35.2–136.08b,c 1.85b 0.95b 1.56b 14.3–27.5b,d 65.69–158.2b,c,d 37.79–256.8b,c,d 0.66–4.15a,b,d Compound Amount* Methylxanthines Caffeine Theobromine 187.58–220a,c,e 88.92c Flavonoids Quercetin-3-rhamnosylglucoside Quercetin-3-O-glucoside Kaempferol-3-O-glucoside Rutin 10.25c 9.33c 11.25c 43.40d Saponins** 352f Reference: a Bastos et al. (2006). b Marques and Farah (2009). c Peres et al. (2013). d da Silveira et al. (2016). e Bastos et al. (2005). f Gnoatto et al. (2005). * Lower and higher mean values of compounds from different studies with no distinction between maté preparations (maté tea, chimarrão, tereré). ** Total saponins expressed as ursolic acid. CQA: caffeoyl quinic acid; FQA: feruloyl quinic acid; diCQA: dicafeoyl quinic acid; CA: caffeic acid. 310 L.G. Riachi, C.A.B. De Maria / Journal of Functional Foods 38 (2017) 308–320 Fig. 1. Chemical structure of some maté phytochemicals. Fig. 2. Inhibition of AGEs formation through maté consumption. *Gugliucci et al. (2009) **Bains and Gugliucci (2017). capacity to inhibit or reduce the oxidation process. Caffeic acid (0.5 mmol L–1) was the most effective in inhibiting AGEs generation (> 95% in BSA and 41% in histone model, P < 0.0001), followed by chlorogenic acid (0.5 mmol L–1) (59% in BSA and 29% in histone model, P < 0.0001) and oleanolic acid (17% in histone and 24% in BSA model, 10 mmol L1). More recently, Bains and Gugliucci (2017) provided the first evidence for enteral formation of fructose-derived AGE and its inhibition by maté extract and chlorogenic and caffeic acids, under time, temperature, pH, and concentrations compatible with the digestive system lumen. AGEs from the reaction between free fructose and proteins in the intestinal lumen, after being absorbed would activate the AGE receptor inflammatory pathway (Bains & Gugliucci, 2017). Excessive consumption of free fructose has been associated with the occurrence of inflammatory disease (DeChristopher, Uribarri, & Tucker, 2015, 2016). It was observed in the study a time-dependent formation of AGE fluorescence at a time frame compatible with digestive process and in a concentration plausibly found in the intestines. Maté tea displayed great inhibition effect, reaching 83% at 50 ll mL–1 concentration (P < 0.001). AGE formation was inhibited by aminoguanidine, a standard antiglycation agent, in a dosedependent manner with an IC50 of 0.9 mM. Caffeic and chlorogenic acids were as potent as aminoguanidine (IC50 = 0.8 mM) displaying potent inhibition at concentrations compatible with those found in the intestinal lumen (Bains & Gugliucci, 2017). The inhibition of AGEs is shown in Fig. 2. Klein et al. (2011) did not find any significant decrease (P 0.05) in serum AGEs value from pre-diabetic individuals (n = 29) after maté tea consumption (roasted herb, 990 mL/d, 20 mg mL–1), dietary intervention or both treatments combined, after 60 days. Boaventura et al. (2013) also did not find any significant difference in the antioxidant capacity of serum (expressed in ferric ion reducing antioxidant power – FRAP) and AGE concentration of prediabetic and type-2 diabetic subjects after 60 days of maté tea (roasted herb) intake (990 mL, 20 mg mL–1). However, they could find a significant inverse correlation between AGE and GSH concentrations from type-2 diabetic subjects (R2 = 0.422; P = 0.035), indicating that some individuals may have a decrease in AGE concentration related to the enhancement of blood GSH after maté consumption. This statement is merely speculative since AGE concentration did not change significantly in the studied group. Highly reactive lipid peroxidation products can also undergo additional oxidation reactions generating carbonyl reactive species, which in turn, can undergo rearrangements, leading to AGEs generation L.G. Riachi, C.A.B. De Maria / Journal of Functional Foods 38 (2017) 308–320 (Ott et al., 2014). Thus, the control of lipid peroxidation is important in terms of glycation process. Although in vitro studies had demonstrated antiglycation properties of maté, in vivo crosssectional studies with pre-diabetic and type-2 diabetic subjects did not corroborate in vitro studies. The small number of clinical studies makes comparison of in vivo and in vitro data difficult. The great majority of clinical trials was focused on the field of lipid peroxidation, more specifically regarding the oxidation of LDL-c in plasma, which plays a key role in the onset of atherosclerosis (Kita et al., 2006; Steinberg & Witztum, 2010). A pioneering study demonstrated a strong antioxidant capacity of maté extract against LDL copper/H2O2-induced autoxidation, in a dosedependent manner, in vitro (Gugliucci & Stahl, 1995). Antioxidants from water extract inhibited the initiation and propagation (until 180 min) processes of isolated LDL-c particles, measured by diene conjugates and thiobarbituric acid-reactive substances (TBARS). This inhibition became apparent at concentrations of the extract as low as 7.5 lg mL–1. Modification of lysine and other residues in apolipoprotein B (apoB) by aldehydes formed as end products of unsaturated lipids oxidation was assessed by direct measurement of free amino groups, electrophoretic mobility, and fluorescence. Maté extract was able to suppress the appearance of Schiff-base induced fluorescence, the higher electrophoretic mobility and to reduce the modification of free amino groups thought products of peroxidation (Gugliucci & Stahl, 1995). After showing great antioxidant protection in vitro, questions have been raised about whether the same effects of maté on LDL-c could be reproduced in vivo. To test the hypothesis if maté protect LDL-c from aqueous environment in a similar way as vitamin C, Gugliucci (1996) examined the oxidability of LDL in whole plasma from 3 healthy volunteers before and after 1 h of maté intake (500 mL). Copper-induced oxidation of LDL-c in whole plasma measured by TBARS was inhibited after maté consumption. It was also observed a reduction in the appearance of Schiff bases in fluorescence analysis, in higher electrophoretic mobility and in the fragmentation of apoB. LDL-c was also isolated from the same participants before and after maté intake and submitted to copper-induced autoxidation, in order to determine whether maté protects isolated LDL-c from oxidation by conferring to it an intrinsic antioxidant capacity. Oxidation of isolated LDL-c was measured through diene conjugate formation. No significant differences were found between both preparations. It was suggested that maté prevents the oxidation of LDL-c from the aqueous environment without increasing the intrinsic antioxidant capacity of LDL-c particles (Gugliucci, 1996). da Silva, Neiva, Shirai, Terao, and Abdalla (2008) reported for the first time the potential of maté in enhancing resistance of isolated LDL-c from participants (n = 12) after 1 h of maté intake (500 mL, 50 mg mL–1) against an AAPH (2,20 -Azobis(2-amidinopropane) dihydrochloride)/CuCl2 induced-oxidation. They suggested that antioxidants from maté also might remain adhered to LDL-c particles. Oxidation progress was measured through the formation of cholesteryl-ester hydroperoxide (CE-OOH) and cholesterol oxides by chromatographic techniques. The susceptibility of isolated LDL-c to lipid peroxidation was significantly reduced (P < 0.05, 52% of inhibition of CE-OOH formation) after incubation (3 h) with copper ions. Accumulation of oxysterols in LDL-c particles was also inhibited after oxidation by copper or AAPH for 6 h (P < 0.05) after maté intake. In line with previous study (Gugliucci, 1996), LDL-c in the whole plasma was also less susceptible to oxidation when compared to control (P < 0.05). Differences regarding the contribution of maté antioxidants on the resistance of isolated LDL-c particles against oxidation, between both studies may be attributed to small number of volunteers in Gugliucci (1996) study when compared with da Silva et al. (2008). In the last study, inhibition of plasma lipid peroxidation in vitro with the absence or presence of maté extract, caffeic, chlorogenic, ferulic and vanillic acids was 311 tested. Maté extract had higher in vitro antioxidant activity than chlorogenic or caffeic acids, at the same phenol equivalent concentration, indicating a possible synergistic effect of maté constituents. It is important to emphasize that it was not clear which kind of maté (green or roasted) was used in these studies (da Silva et al., 2008; Gugliucci, 1996). In our opinion, difference in the maté composition related to processing condition could impact on its physiological activity. Matsumoto, Mendonça, Moura de Oliveira, Souza, and Markowicz Bastos (2009) analysed the effect of maté (roasted) on isolated LDL-c from healthy volunteers (n = 5) after acute (1 h) and prolonged tea intake (1 week) (500 mL, 0.01 g mL1). LDL-c was isolated before and after maté consumption and submitted to oxidation by copper (CuSO4), lipoxygenase and peroxynitrite (SIN-1). The formation of diene conjugates and structural modifications on LDL-c apoB after cupper-induced oxidation were evaluated. Maté prevented LDL apoB from structural modification after one week of daily consumption. Although it was observed an increased resistance of isolated LDL-c against copper-induced oxidation after prolonged tea intake (P < 0.05), there was no significant difference in diene conjugate formation when SIN-1 or lipoxygenase were used as oxidants. Protection of maté against LDL-c oxidation was attributed to its ability to chelate metal ions, rather than to scavenge nitrogen free radical species or inhibit lipoxygenase activity (Matsumoto, Mendonça, et al., 2009). Consumption of maté extract was also reported to influence the expression of antioxidant enzymes. Menini et al. (2007) tested for the first time the ability of maté to protect high-density lipoprotein cholesterol (HDL-c) from oxidation in vitro and to increase paraoxonase-1 (PON-1) activity in vivo. PON-1 is an oxidant enzyme associated with apolipoprotein A-1 (apoA-1) in HDL-c. It is related to HDL-c ability to protect LDL-c from oxidation. Maté aqueous extracts (2 mg mL–1–20 mg mL–1) conserved PON-1 activity and preserved apoA-1 structure from AAPH-induced oxidation of HDL-c. PON-1 activity also had a significant increase in all 4 volunteers after maté intake (500 mL) (10% ± 2% vs. 1% ± 2% for control group, P < 0.05) (Menini et al., 2007). Fernandes et al. (2012) analysed the potential of maté extracts in modulating gene expression and activity of paraoxonase-2 (PON-2) in monocytes and monocyte-derived macrophages (MDM), and PON-1 activity in plasma. Analyses were performed after acute (2 h, n = 20) and short-term (7 days, n = 15) consumption of chimarrão (green maté, 0.05 g mL–1, 500 mL/acute, 1 L/daily/7 d) and maté tea (roasted herb, 0.02 g mL–1, 500 mL/acute, 1 L/daily/7 d). Both green and roasted herbs significantly increased mRNA expression of PON-2 in monocytes after acute intake (P < 0.05) and significantly increased mRNA expression of PON-2 in MDM after short-term maté intake (P < 0.05). Both preparations significantly enhanced PON-2 activity in monocytes after acute maté ingestion (P = 0.05), but not after short-term intake. Green maté increased the arylesterase activity of PON-2, while roasted maté had a greater effect on the lactonase activity. These differences were reported to be due to the composition of both maté preparations (Fernandes et al., 2012). We suggest that this could be attributed to the presence of chlorogenic acid lactones in roasted maté. These lactones could be formed in maté in a similar manner as during the roasting process of coffee (Farah, de Paulis, Trugo, & Martin, 2005). Presence of chlorogenic acid lactones, in turn, would stimulate lactonase activity in PON-2. The acute and short-term ingestion of green and roasted maté also increased PON-1 activity in plasma (Fernandes et al., 2012), confirming previous finding (Menini et al., 2007). Fernandes et al. (2012) also investigated whether green or roasted maté and chlorogenic or caffeic acid could modulate the gene expression and activity of PON-2 in vitro, in THP-1 macrophages. Maté extracts and chlorogenic acid increased PON2 gene expression at concentrations of 1 and 3 mmol/L (P < 0.05), whereas higher concentrations (5 and 10 mmol/L) only 312 L.G. Riachi, C.A.B. De Maria / Journal of Functional Foods 38 (2017) 308–320 increased the enzyme activity. Caffeic acid had no effect on PON-2 gene expression but increased the enzyme activity. Matsumoto, Bastos, et al. (2009) demonstrated that consumption of maté tea may regulate the plasmatic antioxidant enzyme gene expression. After one week of maté tea intake (roasted herb, 500 mL, 0.01 g mL1), participants (n = 15) experienced a significant (P < 0.001) increase in gene expression of superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT). It was observed a significant decrease in TBARS level after one hour (decrease of 17%, p < 0.001) and one week (decrease of 37%, p < 0.001) of maté intake. Maté also protected plasma from copperinduced peroxidation. The lag time increased 69% after one hour (p < 0.05) and 91% after one week of maté ingestion (p < 0.05). The plasma total antioxidant status increased after one week. Arçari et al. (2011) analysed the effect of maté tea (200 mL, 0.012 g mL1, roasted herb) chronic consumption (60 days) on oxidative stress biomarkers and LDL-c oxidisability in normolipidaemic (n = 42) and hyperlipidaemic (n = 18) volunteers. Serum total antioxidant status and SOD activity from normolipidaemic and hyperlipidaemic volunteers significantly increased (P < 0.05), while H2O2induced DNA breakage significantly decreased (P < 0.05). They did not find any influence of maté intake on GPx activity. Maté also was unable to confer protection to isolated LDL particles against copper-induced oxidation in agreement with previous study (Gugliucci, 1996). The reduction of plasma lipid peroxidation products was only significant (P < 0.05) in the hyperlipidaemic group (Arçari et al., 2011). Boaventura et al. (2012) evaluated the longterm (90 days) effect of maté tea (roasted) intake (990 mL/daily, 20 mg mL–1) on antioxidant status of dyslipidaemic individuals (n = 74), with or without qualitative dietary intervention (groups: maté tea; dietary intervention, DI; and maté tea with dietary intervention, MD). Regardless of dietary intervention, maté consumption significantly increased (P < 0.05) serum antioxidant capacity (FRAP levels). The GSH blood concentration had a significant increase (P < 0.05) in subjects from all groups, with a maximum increase of 21.7% in maté tea group. Only subjects from maté tea group had a significant decrease (P < 0.05) in LDL-c concentration. However, there were no significant changes in serum lipid hydroperoxides (LOOH), protein carbonyl, and PON-1 activity values. Unlike previous findings (Fernandes et al., 2012; Menini et al., 2007) it was not observed any significant change in PON-1 activity after prolonged maté tea ingestion (Boaventura et al., 2012). However, a significant increase (23%) in PON-1 activity was found in 50% of the participants, suggesting a potential protection against cardiovascular disease in these individuals. In our opinion, this suggestion is quite speculative because it was based on results of a selected population. LOOH concentration had a positive correlation with LDL cholesterol levels for individuals in maté tea (r = 0.337, P < 0.005); and MD group (r = 0.241, P < 0.04). LOOH serum level in maté tea group was inversely correlated to HDL-c concentration (r = 0.309, P = 0.009) and PON-1 activity was found to be positively associated with HDL cholesterol levels in participants in the MD group (r = 0.263, P = 0.016) (Boaventura et al., 2012). Boaventura et al. (2015) evaluated the effect of acute intake (1 h, 200 mL) of a freeze concentrated maté infusion (CM), in relation to traditional one (TM, 200 mL, 0.03 g mL–1) on antioxidant and peroxidation parameters of healthy subjects (n = 31). Concentration of phenolics and methylxanthines were from three to seven times higher in CM. The acute intake of CM significantly (P < 0.05) increased the activity of CAT (28.7%), SOD (21.3%), and GPx (9.6%), and increased the level of GSH (8.8%) and serum antioxidant capacity (FRAP) (7.5%), while TM promoted a significant increase only in GSH values (8.3%). The serum levels of LOOH did not change after consumption of both maté infusions. It was found a significant positive association between GPx activity with GSH (r = 0.36; P = 0.04), CAT (r = 0.38; P = 0.03), and SOD (r = 0.46; P = 0.01) parameters after CM consumption. In addition, a significant and negative association was observed between LOOH and FRAP values (r = 0.38; P = 0.03). In a randomized controlled cross-over study it was analysed the effect of roasted maté tea (600 mL, 5 mg mL1) on recovery of muscle strength and blood oxidative stress biomarkers in physically active subjects (n = 12) after eccentric exercise (24, 48 and 72 h) (Panza et al., 2016). Although not influencing in muscle strength at all-time points, maté treatment significantly improved (P < 0.05) the rate of strength recovery (8.6%) over 24 h after eccentric exercise. The concentration of total phenolic compounds in plasma was significantly (P < 0.05) higher after maté intake when compared to control, but it was significantly (P < 0.05) decreased at 72 h after exercise in both treatments. GSH blood level was significantly enhanced in maté group and remained significantly higher than control after exercise. In agreement with previous studies (Boaventura et al., 2012, 2015) no significant changes were found in serum LOOH level (Panza et al., 2016). A summary of the findings on oxidative stress and glycemic and lipid parameters and the enzymatic antioxidant system is shown in Table 2. Table 2 Effect of maté on biochemical parameters related to oxidative stress in humans. Analysed parameters with significant changes Lipid and glycidic parameters AGE concentration Plasma lipid peroxidation (+) Resistance of isolatedLDL to oxidation Serum level of lipid hydroperoxides –da Silva et al. (2008)–Gugliucci (1996)–Matsumoto, Mendonça, et al. (2009)–Matsumoto, Bastos, et al. (2009) –da Silva et al. (2008)–Matsumoto, Mendonça et al. (2009) –Boaventura et al. (2013) Antioxidant enzyme complex PON-1 activity PON–2 activity PON–2 gene expression SOD activity SOD gene expression GSH concentration GSH activity GPx activity GPx gene expression CAT activity CAT gene expression –Fernandes et al. (2012)–Menini et al. (2007) –Fernandes et al. (2012) –Fernandes et al. (2012) –Arçari et al. (2011)–Boaventura et al. (2015) –Matsumoto, Bastos et al. (2009) –Boaventura et al. (2012)–Boaventura et al. (2013)–Panza et al. (2016) –Boaventura et al. (2015) –Arçari et al. (2011) –Matsumoto, Bastos et al. (2009) –Boaventura et al. (2015) –Matsumoto, Bastos et al. (2009) (–) –Boaventura et al. (2013)–Klein et al. (2011) –Petrilli et al. (2016) –Arçari et al. (2011)–Gugliucci (1996) –Boaventura et al. (2012)–Boaventura et al. (2015)–Panza et al. (2016) –Boaventura et al. (2012) (+): study that found significant change in the analysed parameters; (–) study that did not find any significant change in the analysed parameter; AGE: advanced glycation end products; PON-1: paraoxonase-1; PON-2: paraoxonase-2; SOD: superoxide dismutase; GSH: glutathione; GPx: glutathione peroxidase; CAT: catalase. L.G. Riachi, C.A.B. De Maria / Journal of Functional Foods 38 (2017) 308–320 In contrast, Petrilli et al. (2016) did not find any effect of maté on plasma lipid peroxidation. In our opinion, this conflicting result is probably because they recruited HIV/AIDS subjects submitted to antiretroviral therapy. This treatment can lead to pronounced alteration in lipid metabolism. The capacity of maté to protect isolated LDL-c from oxidation is still controversial. The fact that maté aqueous extract does not enhance the intrinsic antioxidant capacity of LDL-c does not mean that maté itself does not have the potential for this. Non-exhaustive water extraction (home extraction) does not extract or extract in small quantities more apolar compounds that could confer this activity. Therefore, ethanolic or acetanolic extracts could increase the resistance of isolated LDL-c to oxidation. Conflicting results regarding LOOH levels could be related to health status of recruited volunteers. While Boaventura et al. (2015) recruited healthy volunteers, Boaventura et al. (2013) worked with pre-diabetic and type-2 diabetes mellitus (T2DM) subjects. The effect of maté could be more easily observed in subjects with altered glucose metabolism, because the production of lipid reactive species may already be increased in these individuals. Although the results with PON-1 are controversial, in general maté has positively affected the human antioxidant enzyme complex. Although different studies have shown an antiglycation effect of maté in vitro, it was not possible to confirm this ability in vivo. Further studies should be conducted to assess whether the effect is reproduced in humans. 4. Weight loss potential The knowledge on maté compounds with thermogenic potential led to research of the plant in the field of weight loss. In the past 20 years, only a few clinical studies were conducted to investigate the potential of maté in enhancing energy expenditure, increasing satiety, reducing appetite and body fat composition (Alkhatib, 2014; Andersen & Fogh, 2001; Jung & Hur, 2016; Kim, Ko, Storni, Song, & Cho, 2012; Kim et al., 2015; Martinet, Hostettmann, & Schutz, 1999; Oliveira et al., 2016). The thermogenic effect of maté was tested in humans for the first time in a double-blind placebocontrolled study using indirect calorimetry for 3 h at rest, after the ingestion of 5 capsules of maté (1.5 g of dry extract) or placebo (Martinet et al., 1999). Other plant preparations were tested, such as Paullinia cupana, Ephedra sinica, Garcinia Cambogia, Camellia thea, Cynara scolymus, Iris versicolor, Corylus avellana, Crithmum maritimum, Fucus versiculosus, Phytolacca decandra and Laminara digitate. From all preparations, only maté significantly decreased the respiratory coefficient (P = 0.0043) when compared to placebo, indicating an enhancement in the proportion of fat oxidized. Maté also showed the advantage of not influencing in blood pressure and heart response (Martinet et al., 1999). A pilot study analysed the energy expenditure of healthy adults 1 h after intake of maté aqueous extract (500 mL, 0.01 g mL–1) or placebo (500 mL of water) (Oliveira et al., 2016). Energy expenditure was measured during 30 min through indirect calorimetry. It was observed a significant (P < 0.05) increase in energy expenditure (125 kcal, 7.7%) when compared to control group (Oliveira et al., 2016). Alkhatib (2014) analysed for the first time the thermogenic effect of maté using different exercise intensities. Subjects ingested two capsules containing 500 mg of maté (standardized with 1.5% of caffeine) or placebo and rested during 1 h before performing incremental exercise. Maté ingestion improved fatty acid oxidation (FAO) and reduced carbohydrates oxidation (CHO) over a wide range of exercise intensities when compared to placebo (P < 0.001). These effects were particularly predominant in light and moderate exercises intensities, which are often prescribed for weight loss, disease prevention and improving endurance performance (Alkhatib, 2014). It is established that in this range of exercise intensity FAO is the main 313 fuel source for energy expenditure (30–70%), while CHO predominates at heavy exercise intensities (Alkhatib, 2014; Brooks & Mercier, 1994). Although in both conditions FAO was increased similarly as a function of power output, higher FAO was found at exercise intensities below 70% of the peak of oxygen uptake. Maté increased energy expenditure derived from FAO by 24% when compared to placebo during exercise, without negatively affecting the maximal performance. These findings indicate maté as a promoter of fat metabolism and suggest a glycogen sparing potential for exercise performance (Alkhatib, 2014). When compared to other thermogenic supplements with high caffeine content (350 mg) (Outlaw et al., 2013), maté supplement displayed similar results (an increase of FAO and energy expenditure) with a much lower content of the compound (80 mg). Thus, it was suggested that other constituents of maté, rather than caffeine itself, could have thermogenic properties (Alkhatib, 2014). Indeed, chlorogenic acid has been shown to inhibit cAMP phosphodiesterase and indirectly increase the fatty acid oxidation (Bruckbauer & Zemel, 2014; Stohs & Badmaev, 2016). Another possible indirect mechanism was through the inhibition of pancreatic lipase with a consequent reduction of lipid absorption and weight loss (Narita, Iwai, Fukunaga, & Nakagiri, 2012; Stohs & Badmaev, 2016). In another study, a treatment with rutin significantly reduced adiposity and increased energy expenditure in genetically obese mice and in those with diet-induced obesity (Yuan et al., 2017). This was attributed to rutin potential in increasing the number of mitochondria and uncoupling protein 1 (UCP1) activity in brown adipose tissue (Yuan et al., 2017). In a study with mice, lutein was also able to stimulate the expression of mitochondrial UCP1 of brown adipocytes, in a dose-dependent manner (Serra, Bonet, Puigserver, Oliver, & Palou, 1999; Stohs & Badmaev, 2016). Activation of UCP1 is involved with uncoupling of the respiratory chain in mitochondria, leading to a rapid fatty acid oxidation with a low rate of adenosine triphosphate (ATP) production and high ATP utilization and heat energy release. This process is recognized as the main event leading to thermogenesis (Stohs & Badmaev, 2016). Thermogenic effect through uncoupling protein was also observed in rodent models after the administration of maté extracts (Arçari et al., 2009; Pang, Choi, & Park, 2008). The intake of maté (previously extracted with 15% ethanol) augmented the expression of both UCP2 and UCP3 in visceral adipose tissue of rats that were submitted to a high-fat diet (Pang et al., 2008). These proteins are homologs of UCP1 and are also capable of uncoupling mitochondrial respiration (Pang et al., 2008). The ingestion of roasted maté extract by obese mice also increased mRNA levels of PGC-1a and UCP1 in brown adipose tissue. PGC-1a seems to stimulate mitochondrial biogenesis and respiration in muscle by inducing the expression of UCPs (Arçari et al., 2009). Maté has been combined with other plant preparations and used as a constituent of commercial formulas to help losing weight. A plant formulation (YGD capsule) containing maté (112 mg of leave extract), guarana (Paullinia cupana – 95 mg of seeds extract) and damiana (Turnera diffusa var. aphrodisiaca, 36 mg of leave extract) was able to slow gastric emptying time over placebo, promote weight loss in overweight subjects (n = 48) after 45 days of YGD intake (3 capsules daily) in a double-blind study, and helped to maintain weight (n = 22) after 12 month in an uncontrolled maintenance treatment (Andersen & Fogh, 2001). However, in the study, it was not considered the energy intake and the physical activity of the participants. In another study, YGD promoted reduction of food and energy intake after breakfast and lunch, but the lowest intake was observed when YGD was combined with inulin fibre (Harrold et al., 2013). A formulation made with active ingredients of maté, guarana, and damiana (ZotrimÒ) has shown satiety effect in different consumer survey tests, in which participants self-reported feeling of fullness and weight loss (Ruxton, 314 L.G. Riachi, C.A.B. De Maria / Journal of Functional Foods 38 (2017) 308–320 2004; Ruxton, Hinton, & Evans, 2005; Ruxton, Kirkwood, McMillan, St John, & Evans, 2007). Problems concerning the studies included the use of self-reported data that could lead to bias and absence of diet and physical activity control. A supplement known as MeltdownÒ is a formulation with maté extract and other ingredients, such as synephrine, caffeine, phenylethylamine, yohimbine and other stimulants of b-adrenergic receptors. Placebo-controlled studies have shown positive effects regarding MeltdownÒ administration, such as enhancement of respiratory exchange ratio, fat oxidation, increase in energy expenditure, and increase in catecholamine secretion and lipolysis markers in blood (Bloomer, Canale, et al., 2009; Bloomer, Fisher-Wellman, et al., 2009; Hoffman et al., 2009; Jitomir et al., 2008; Rashti et al., 2009). However, the supplement had the adverse effect of increasing the heart rate and blood pressure. A product containing maté extract, caffeine, guarana, green tea, L-carnitine, L-tartrate, pantothenic acid, chromium picolinate and other substances (Dyma-BurnÒ Xtreme) also was effective in increasing resting energy expenditure in a double-blind placebo study (Outlaw et al., 2013). Other product available as FitMiss BurnTM combining a mix of ingredients (i.e. maté extract, green tea, caffeine, guarana seed extract) increased resting metabolic rate over time in a double-blind placebo study. Nevertheless, the supplement promoted slight elevations in blood pressure (Campbell et al., 2016). Analysis of several herb preparations with anti-obesity potential in combination has the limitation of not identifying which ingredient effectively contributed to the observed effects. Therefore, results obtained with maté in a mixture of other herb preparations and substances does not necessarily reflect maté activity per se. The effect of maté on body composition in a double-blind placebo-controlled study was assessed for the first time in overweight subjects (n = 46) with administration of 1200 mg of green maté during 6 weeks under controlled energy intake (1500 kcal/daily) and physical activity (Kim et al., 2012). Participants from maté group had a significant (P < 0.05) reduction in the body fat percentage (0.3%) and body fat mass (0.5 kg), while the placebo group had an increase in both measurements (0.6% and 0.2 kg, respectively). They did not observe any significant change in weight, body mass index (BMI), lean body mass and waist circumference. In other study, supplementation with maté (3000 mg) in a 12-week period by obese subjects (n =15) also led to a significant decrease in body fat mass (P = 0.036) and body fat percentage (P = 0.030) when compared to placebo (n = 15) (Kim et al., 2015). It was also observed a significant reduction of the waist-hip ratio (P = 0.004). However, the study lacked in monitoring the energy intake and the physical activity of participants. More recently (Jung & Hur, 2016), the effect of maté on body weight and on fat content was investigated in obese women after 6 weeks of supplementation. Maté group (n = 17) ingested four capsules daily (3000 mg of green maté extract), while control group (n = 16) consumed placebo. Volunteers were instructed to reduce their daily caloric intake by 500 kcal per day and maintain their normal amount of physical activity throughout the study. There was no difference in energy intake from baseline until the end of the study between both groups. After 6 weeks, it was observed a significant reduction in trunk fat (P = 0.03), which comprehends the fat that is distributed in the abdomen and includes visceral and subcutaneous fat (1.24 ± 1.72% in the maté group; +0.16 ± 1.70% in the control group). However, there was no significant reduction in weight, BMI and hip circumference between groups (Jung & Hur, 2016). In a clinical study, normolipidaemic (n = 15), dyslipidaemic (n = 57) and hypercholesterolemic subjects under long-term statin therapy consumed green (50 mg mL–1) or roasted maté (20 mg mL–1) infusions (900 mL/d) in a 40-days period. In general, none of the maté infusions were effective in reducing the body weight of participants, except for dyslipidaemic individuals who had a slight (0.5 kg) but significant decrease (P = 0.02) in body weight after 40 days of maté intake (De Morais et al., 2009). Since there was no significant change in energy intake during the study, the decrease in body weight might be due to changes in physical activity practice. In other study, T2DM subjects (n = 29) and pre-diabetes (n = 29) consumed maté tea (roasted herb, 990 mL/d, 20 mg mL–1), undertook dietary intervention (DI) or both (maté tea + DI) for 60 days. T2DM subjects did not show significant variations in body weight, BMI, abdominal circumference and blood pressure. However, pre-diabetic subjects in maté tea group had a significant reduction (P < 0.05) in body weight (baseline, 73.2 ± 3.1 kg versus 71.6 ± 13.5 kg), BMI (baseline, 29.4 ± 4.0 kg/m2 versus 28.7 ± 3.4 kg/m2) and in systolic (baseline, 137.6 ± 23.6 mmHg versus 130.3 ± 19.7 mmHg) and diastolic (baseline, 80.5 ± 7.5 mmHg versus 76.1 ± 7.7 mmHg) blood pressure (Klein et al., 2011). Since it is difficult to maintain a daily dietary record, the energy consumption is generally assessed through a 24 h dietary recall or a dietary record of selected days, at baseline and at different time-points. Thus, discrepancies in results also could be related to the daily variation of energy intake between participants. 5. Lipid and glycemic profile Animal studies have shown a glycemic-control capacity and a lipid-lowering effect of maté (Bravo et al., 2014; De Resende et al., 2015; Pang et al., 2008; Pereira et al., 2012). In a study with obese rats under high-fat diet administration, the consumption of maté extract significantly (P < 0.05) lowered blood and hepatic lipid, glucose and insulin levels (Pang et al., 2008). Pereira et al. (2012) demonstrated that butanolic (n-BuOH) and ethanolic (EtOAc) maté extracts (200 mg kg–1, P < 0.001) and green (200 mg mL–1, P < 0.001) and roasted (200 mg mL–1, P < 0.01) maté infusions improved significantly the oral glucose tolerance curve of normal rats with induced hyperglycaemia. Additionally, they observed an induced insulin secretion after the acute treatment with n-BuOH or EtOAc extracts in hyperglycaemic rats. Since n-BuOH and EtOAc extracts and green maté infusion improved the oral glucose tolerance curve but did not influence on glucoselowering in diabetic rats, they suggested that the hypoglycemic mechanism involves insulin-secretagogue compounds. Since catechin and chlorogenic acid were found in high amount in n-BuOH and green maté extracts, they assumed that these compounds are the probable secretagogues (Pereira et al., 2012). It is important to emphasize that the catechins content found in the study was higher than is normally found in maté beverages, reaching values from three to six times greater than chlorogenic acid. In our opinion, the hypoglycemic effect above-mentioned also could be attributed to an incretin-secretagogue compound. Incretins are well known to modulate the amount of insulin secreted after food intake (Kim & Egan, 2008). In a previous study, chlorogenic acid treatment in rats resulted in beneficial effects on blood glucose response, with modifications in incretin levels (Tunnicliffe, Eller, Reimer, Hittel, & Shearer, 2011). Thus, maté compounds might also regulate the insulin secretion through this mechanism. Hypothetical mechanisms of insulin secretion through maté consumption are shown in Fig. 3. In a study with db/db mice, chlorogenic acid decreased fasting blood glucose in the glucose tolerance test (Ong, Hsu, & Tan, 2012), reinforcing the hypothesis that chlorogenic acid might contribute to the hypoglycemic effect of maté extract found in the study of Pereira et al. (2012). Moreover, Ong et al. (2012) demonstrated for the first time that chlorogenic acid stimulates a glucose transport in skeletal muscle through the activation of 5ꞌ adenosine monophosphate-activated protein kinase (AMPK). In another L.G. Riachi, C.A.B. De Maria / Journal of Functional Foods 38 (2017) 308–320 315 Fig. 3. Hypothetical mechanism of insulin secretion through maté consumption. (A) hypothetical mechanism 1 (Pereira et al., 2012): maté polyphenols stimulates insulin secretion in pancreas. (B) hypothetical mechanism 2 (suggested by the authors): maté polyphenols stimulate the secretion of incretins in small intestine, which, in turn stimulates insulin secretion in pancreas. study, gallic acid has shown to induce the glucose transporter 4 (GLUT4) translocation and glucose uptake activity in 3T3-L1 cells (Vishnu Prasad, Anjana, Banerji, and Gopalakrishnapillai, 2010). Furthermore, caffeic and cinnamic acids increased glucose uptake in insulin-resistant mouse hepatocytes (Huang, Shen, & Wu, 2009). These findings indicate that chlorogenic acid appears to be an important contributor to the hypoglycemic effect of maté in rats. Although animal studies have found a hypoglycemic effect related to maté consumption, evidence in humans is still insufficient. In an experimental study, normoglycemic subjects (n = 12) ingested sumac (1 g or 2 g), Turkish coffee (60 mL) or maté tea (100 or 200 mL) to test the effect on postprandial glycemic response to a Lebanese carbohydrate-rich food (mankoucheh) (Kahale, Tranchant, Pakzad, & Farhat, 2015). The glycemic response to mankoucheh meal (blood glucose concentration at all times) did not differ with the ingestion of tested items. Aside from a true lack of effect of the three constituents tested, the authors attributed the absence of a statistically significant difference among the glycemic responses to the different meals to some possible factors: the relative low dose used of each constituent, the individual variation, and the fact that mankoucheh is a medium glycemic index (GI) meal, producing a lower overall glycemic response in comparison with high-GI foods (Kahale et al., 2015). As shown in Table 3, regardless of the distinctions between each study, the majority of clinical trials still did not find a significant positive effect of maté consumption on the blood glucose concentration in noninstitutionalized subjects (Arçari et al., 2011; Jung & Hur, 2016; Kahale et al., 2015; Kim et al., 2012), with the exception of two studies (Boaventura et al., 2013; Klein et al., 2011). In the pilot study from Klein et al. (2011) T2DM subjects (n = 29) and prediabetes (n = 29) consumed maté tea with or without dietetic counselling (maté tea + DI) or only undertook DI for 60 days to test their effect on the glycemic and lipid profile. Only T2DM participants from maté tea group had their levels of fasting plasma glucose and HbA1c significantly decreased (glucose reduction of 25.0 mg dL–1/17%, when compared with baseline after 60 days, P < 0.05; HbA1c level decreased 0.85% after 20 and 60 days, P < 0.05), while no significant change was observed in T2DM subjects from maté tea + DI and DI group and pre-diabetics from all groups. In general, the nutritional counselling performed with or without maté tea intake did not promote a significant improvement in the glycemic control of T2DM subjects. Additionally, in prediabetic subjects, maté consumption with or without nutrition counselling did not promote a reduction in fasting plasma glucose, although it was detected a significant and temporary decrease in HbA1c levels. Although the study from Klein et al. (2011) showed a significant reduction in glucose level of diabetic subjects after maté intake, some results were inconsistent. For instance, subjects from maté tea group but not from maté tea + DI group had their fasting plasma blood glucose level decreased. The authors attributed the presence of inconsistencies in results to a small number of individuals and to differences in dietary intake. Boaventura et al. (2013) analysed the glycemic profile of T2DM (n =11) and prediabetic (n = 11) subjects after 60 days of maté tea intake. T2DM subjects had a significant reduction (P < 0.05) in plasma glucose (146.39 ± 19.49 mg dL–1 vs. 135.50 ± 16.75 mg dL–1) and HbA1c after 60 days when compared to baseline, while in pre-diabetic subjects maté intake did not promote a decrease in plasma glucose, but significantly lowered the HbA1c concentration after 40 days of treatment. This result agrees partially with Klein et al. (2011) that observed a significant reduction in blood glucose in diabetic subjects, but not in pre-diabetics. It seems that maté hypoglycemic effect is more evident when the concentration of glucose in the blood is higher. Our research group investigated for the first time the effect of roasted maté infusion administration (14 days) on blood glucose of institutionalized patients with traumatic brain injury (TBI) (n: maté group = 4, control = 4) (Ribeiro et al., 2017). The glycemic control in these subjects is of utmost importance since the stress-induced hyperglycaemia is associated with higher mortality after TBI event in non-diabetic patients. Although the mean glycemic levels were not significant (P < 0.05) between maté and control group, the first had a lower mean glycaemia. Throughout the study, the four non-treated patients received a total lente insulin of 4IU, 32 IU, 2 IU and 34 IU, while two matétreated patients received 6 IU and 8 IU of lente insulin, due to isolated harmful hyperglycaemia episodes. Two maté-treated patients did not receive insulin therapy because their blood glucose remained stable throughout the study. Despite the limitation of having a small number of volunteers in the study, these preliminary results suggest that maté may assist in harmful hyperglycaemia management and thus decrease the insulin administration in TBI patients. The potential of maté to act as a lipid-lowering agent in humans is more consistent than as a hypoglycemic agent in terms of numbers of clinical trials and positive results. It is important to emphasize though that despite some studies have found beneficial effects of maté on lipid profile (Boaventura et al., 2012; De Morais et al., 2009; Klein et al., 2011; Messina et al., 2015; Yu et al., 2015), others did not find significant changes (Arçari et al., 2011; Jung & 316 L.G. Riachi, C.A.B. De Maria / Journal of Functional Foods 38 (2017) 308–320 Table 3 Effect of maté consumption on human lipid and glycaemic profile. Subjects/Intervention Duration Lipid/glycidic parameters analysed There were sgfnt. changes? In which parameter? Traumatic brain injury patients ingested maté tea (roasted herb) 2/day (7 g, 300 mL–1 each) via nasoenteric feeding tube/orally (n: maté = 4, control = 4)1 Overweight subjects took maté tablets (3 g/daily, n = 17) or placebo (n = 16)2 HIV-infected subjects (n = 92) consumed maté tea, placebo-maté, dark chocolate or placebo-chocolate3 Obese subjects consumed maté capsules (3 g/daily, n = 15) or placebo (n = 15)4 14 days Glucose No n/a 6 weeks TC, glucose No n/a 60 days No n/a No n/a Subjects with high blood viscosity (n = 142) ingested maté tea (16 mg mL–1, 1500 mL/daily, n = 71) or placebo tea (n = 71)5 Dyslipidemic subjects consumed different amounts of maté infusion (100 mg mL–1): 500 mL/daily, n = 74 or 1 L/daily, n = 476 Normoglycemics (n = 12) ingested a carbohydrate-rich food (mankoucheh) with sumac, Turkish coffee or maté tea (100 or 200 mL, 25 mg mL–1) to test the postprandial glycaemic response7 Pré-diabetic (n = 11) and type-2 diabetic (n = 11) subjects (T2 DM) ingested maté tea (roasted herb, 990 mL, 20 mg mL–1, daily)8 Overweigh subjects ingested green maté capsule (3g/d, n = 24) or placebo (n = 22)9 Dyslipidaemics (n = 74) ingested maté tea (roasted herb, 990 mL/d, 20 mg mL-1) with or without DI or only undertook DI10 Normolipidaemics (n = 42) and hyperlipidaemics (n = 18) ingested maté tea (roasted leaves, 0.012 g mL–1)11 6 weeks Lipid profile (not specified) TC, free fatty acid, triglycerides, HDL-c, LDL-c TC, LDL-c, HDL-c, triglycerides Yes LDL-c, triglycerides and TC: ; and HDL-c " in maté group (P < 0.05). 12 weeks TC, LDL-c, HDL-c, triglycerides Yes TC and LDL-c: ; in both groups (P < 0.001) 1 day Glucose No n/a 60 days Glucose, HbA1c Yes Glucose: ; in T2 DM. HbA1c: ; in T2 DM after 60d, and ;in pré-diabetics after 40d (P < 0.05). 6 weeks TC, triglycerides, HDLc, glucose TC, LDL-c, HDL-c nonHDL-c, triglycerides No n/a Yes LDL-c: ; only in maté group (P < 0.05) No n/a T2DM subjects (n = 29) and pre-diabetics (n = 29) ingested maté tea (roasted herb, 990 mL/d, 20 mg mL–1) with (MT + DI) or without DI (MT) or only undertook DI12 60 days TC, LDL-c, VLDL-c, HDL-c, triglycerides, glucose TC, LDL-c, HDL-c, nonHDL, triglycerides, glucose, HbA1c Yes Normolipidaemics (n = 15), dyslipidaemics (n = 57) and hypercholesterolemics under long-term statin therapy ingested 990 mL of green (50 mg mL–1) or roasted maté (20 mg mL–1) infusions daily13 40 days TC, LDL-c, HDL-c, nonHDL, triglycerides, apoB-100, apoB-100/ apoA-1 Yes LDL-c, glycaemia and HbA1c: ; in T2DM from MT group (P < 0.05). LDL-c (P < 0.05), non-HDL (P <0.05), triglycerides (P < 0.01) and HbA1c (P = 0.01): ; in pre-diabetics from MT + DI group. HbA1c (P = 0.01): ; pre-diabetics from MT group. LDL-c: ; in normolipidaemics (both infusions) (p < 0.01). TC, LDL-c, non-HDL, apo B-100 (after 20d) and apo B-100/apo A-1 (after 20d) (P < 0.01): ; in dyslipidaemics (both infusions). LDL-c: ; and HDL-c " (P < 0.05) in hypercholesterolemics (roasted herb) 12 weeks 90 days 60 days Sgfnt: significant; DI: dietary intervention; TC: total cholesterol; LDL-c: low-density lipoprotein cholesterol; HDL-c: High-density lipoprotein cholesterol; HbA1c: haemoglobin A1c; ApoB-100: Apolipoprotein B-100; apoA-1: Apolipoprotein A-1. Ref.: Reference. 1 Ribeiro et al. (2017). 2 Jung and Hur (2016). 3 Petrilli et al. (2016). 4 Kim et al. (2015). 5 Yu et al. (2015). 6 Messina et al. (2015). 7 Kahale et al. (2015). 8 Boaventura et al. (2013). 9 Kim et al. (2012). 10 Boaventura et al. (2012). 11 Arçari et al. (2011). 12 Klein et al. (2011). 13 De Morais et al. (2009). Hur, 2016; Kim et al., 2012, 2015; Petrilli et al., 2016). In the study of Jung and Hur (2016) blood cholesterol levels decreased in maté group (n = 17) in relation to control group (n = 16), but values did not differ significantly (P < 0.05) after 6 weeks (maté group: 11.65 ± 31.78 mg dL–1, control group: 12.63 ± 27.24 mg dL–1). Petrilli et al. (2016) did not find a significant increase in HDL-c level after maté intake when compared with baseline. Kim et al. (2015) observed a decrease in free fatty acid after maté capsules intake (n = 15), although the difference from placebo group (n = 15) was not significant (P < 0.05) after 12 weeks (maté group: 443.5 ± 169.7 lEq L–1; control: 575.3 ± 220.1 lEq L–1). Kim et al. (2012) did not find significant differences (P < 0.05) in the levels of cholesterol, triacylglycerol and HDL-c between participants who consumed maté capsules (n = 24) and placebo (n = 22), but the mean cholesterol level in maté group was lower than in placebo (172.3 mg dL–1 vs. 183.2 mg dL–1; P = 0.09). Arçari et al. (2011) did not observe a significant (P < 0.05) lipid profile improvement of hyperlipidaemic (n = 18) and normolipidaemic (n = 42) subjects after maté tea intake for 60 days. De Morais et al. (2009) was the first clinical trial to demonstrate a cholesterol- and lipoprotein- L.G. Riachi, C.A.B. De Maria / Journal of Functional Foods 38 (2017) 308–320 lowering property of maté infusion in humans. In the study, the consumption of green or roasted maté tea by normolipidaemic (n = 15) and dyslipidaemic subjects (n = 57) significantly improved serum lipid parameters after 40 days of treatment. The results from both green and roasted maté consumption were undistinguished because both infusions had a similar hypocholesterolemic effect. In normolipidaemic participants the level of LDL-c and LDL-c/ HDL-c ratio had a significant reduction (P < 0.05) after 20 days (LDL-c: 8.7% or 9.9 mg dL–1; LDL-c/HDL-c ratio: 16%) and 40 days (LDL-c: 7.3% or 8.3 mg dL–1; LDL-c/HDL-c ratio: 10%), when compared with baseline. In dyslipidaemic subjects, intake of maté for 20 and 40 days reduced levels of total cholesterol by 3.5 and 4.6% (8.1 and 10.7 mg dL–1, P < 0.01), LDL-c by 8.1 and 8.6% (12.9 and 13.7 mg dL–1, P < 0.001), non-HDL by 5.4 and 6.5% (10.1 and 12 mg dL–1, P < 0.05), and LDL-c/HDL-c ratio by 12.1 and 11.2% (P < 0.01), respectively when compared with baseline. After 20 days HDL-c increased by 4.4% (2.1 mg dL–1) (P < 0.01), apoB-100 reduced by 6% (P < 0.05) and apoB/apoA-1 ratio lowered by 6.4% (P < 0.05). In normolipidaemic individuals, the HDL-c level had a similar increase but was it was not statistically significant, probably because of the small number of participants. The mechanism by which maté may increase HDL-C level is not clear. Since it was not found a significant increase in apoA-1 level after maté ingestion, it was suggested that HDL-c synthesis may not play a role in the observed HDL-c enhancement (De Morais et al., 2009). In our opinion, maté may inhibit the removal of HDL apoA-1 subfactor by inhibiting hepatocyte HDL catabolism receptor. Previous study suggested that niacin, by inhibiting the hepatocyte surface expression of b-chain adenosine triphosphate synthase (a recently reported HDL-apo A-I holoparticle receptor), inhibits the removal of HDL-apo A-I (Kamanna & Kashyap, 2008). The inhibition of the HDL apoA-1 subfraction catabolism would increase circulant levels of the lipoprotein favoring cholesterol reverse transport (De Maria & Moreira, 2011). In addition, roasted maté tea intake provided a further LDL-c reduction in subjects undergoing statin therapy (n = 30) (simvastatin – 10 mg/daily; atorvastatin – 20 mg/daily; or lovastatin – 40 mg/daily). Their LDL-c level reduced by 10.0% (13.5mg dL–1), from 135.4 ± 15.1 to 121.9 ± 13.0 mg dL–1 (P < 0.01) after 20 days and by 13.1% (17.7 mg dL–1) after 40 days (P < 0.05). The synergistic effect of maté with statin was explained based on a dual cholesterol inhibition, that is, blocking intestinal absorption by maté and decreasing endogenous biosynthesis by statins and maté phenolics (De Morais et al., 2009). Indeed, caffeic acid lowered plasma triglyceride and cholesterol concentrations and efficiently inhibited liver cholesterol biosynthesis in mice under diet-induced hyperlipidaemia (Liao, Ou, Wu, & Wang, 2013). Khan, Baboota, Ali, Narang, and Narang (2016), used chlorogenic acid in a nanostructured lipid carrier (NLC) aiming to develop an optimized oral NCL atorvastatin formulation and observed a highly significant (P < 0.01) reduction in cholesterol and triglyceride value when compared with ATORVAÒ tablets in a pharmacodynamic study with rats. Saponins from maté inhibited the passive diffusion of cholic acid through dialysis membranes (Ferreira, Vázquez, Güntner, & Moyna, 1997). This was attributed to the formation of large macromolecular mixed micelles between cholic acid and maté saponins, which could increase sterols excretion (Ferreira et al., 1997). In the study of Klein et al. (2011) maté consumption also promoted beneficial effects on lipid profile of T2DM and pre-diabetic subjects after maté tea consumption and/or dietary intervention (maté tea, maté tea + DI, or DI). In general, nutritional counselling performed with or without maté tea intake did not promote a significant improvement in the lipid parameters of T2DM subjects. In pre-diabetics when maté was combined with dietary counselling, the hypolipidaemic effect was greater. After 60 days of treatment, there were a reduction in total lipids (19 mg dL–1), LDL-c 317 (11 mg dL–1), non-HDL-c (21.5 mg dL–1) and triglycerides (53 mg dL–1) levels. In this case, it was suggested that the decrease in LDL-c and non-HDL-c levels was due to a reduction in total fat intake (23%), particularly saturated fatty acid (36%) and cholesterol (28%), and the concomitant enhancement of fibre consumption (35%). The results were conflicting since maté had not effect in the lipid profile of diabetic subjects from maté tea + DI group and on pre-diabetic subjects from maté tea group (Klein et al., 2011). Boaventura et al. (2012) also analysed the effect of maté tea with or without dietary intervention (maté tea, maté tea + DI or DI) on the lipid profile of dyslipidaemic subjects (n = 74) for 90 days. The single significant improvement found was in participants from maté tea group, which had a significant reduction in LDL-c level, when compared with baseline level (160.2 ± 5.7 mg dL–1 vs. 150.1 ± 4.8 dL–1, P < 0.05). These results also were conflicting since lipid parameters in dyslipidaemic subjects from maté tea + DI and DI group did not change. In another study, Messina et al. (2015) analysed the lipid-lowering potential of different amounts of maté infusion in dyslipidaemic subjects for 12 weeks (group 1 consumed 500 mL/daily, n = 74 and group 2 consumed 1L/daily, n = 47; 100 mg mL–1). Both amounts of maté infusion were effective in decreasing LDL-c (group 1: 151.35 ± 21.39 mg dL–1 vs. 133.52 ± 27.61 mg dL–1, P < 0.001; group 2: 148.16 ± 19.77 mg dL–1 vs. 129.98 ± 23.73 mg dL–1, P < 0.001) and total cholesterol levels (group 1: 231.28 ± 27.29 mg dL–1 vs. 209.70 ± 31.08 mg dL–1, P < 0.001; group 2: 223.08 ± 24.01 mg dL–1 vs. 201.26 ± 26.33 mg dL–1, P < 0.001). Maté consumption also showed to be beneficial in lipid profile of subjects with high blood viscosity (Yu et al., 2015). Blood lipid levels play a role in erythrocyte aggregation both by altering membrane phospholipids and by influencing plasma factors that regulate blood cell-blood cell interactions. Maté intake significantly increased HDL-c (P < 0.00) and reduced LDL-c, triglycerides and total cholesterol levels (P < 0.00) of subjects with high blood viscosity (n = 71) after 6 weeks. In fact, blood lipid profile of maté tea drinkers was significantly improved to levels exhibited by control patients unaffected by irregularities in microcirculation or blood viscosity. 6. Other physiological activities For a long time, case-control studies have been associating maté consumption with the occurrence of cancer (Deneo-Pellegrini et al., 2013; Szymańska et al., 2010; Vassallo et al., 1985). They have suggested a strong association between maté drinking and cancer of the upper gastrointestinal tract. However, residual confounding by alcohol drinking and tobacco smoking could not be excluded entirely (IARC., 1991). The association could be due to the composition of the beverage, the temperature at which it is consumed or both, as the analysed studies were conducted in populations that consume hot maté (IARC, 1991). Additionally, no studies were available on a population that consumes cold maté. Therefore, IARC from World Health Organization (WHO) concluded that maté is not classifiable as to its carcinogenicity to humans, but hot maté drinking is probably carcinogenic to humans (IARC, 1991). Recently, a working group convened by IARC evaluated the carcinogenicity of drinking coffee, mate, and very hot beverages (Loomis et al., 2016). It was suggested that drinking very hot beverages (above 65 °C), including very hot maté, is one probable cause of oesophageal cancer and classified this behaviour as probably carcinogenic to humans. On the other hand, cold maté did not have carcinogenic effects in experiments on animals or in epidemiological studies, thus drinking maté at temperatures that are not very hot was not classifiable as to its carcinogenicity to humans. Consequently, temperature, and not maté itself, appears to be responsible for the carcinogenic effect (Loomis et al., 2016). 318 L.G. Riachi, C.A.B. De Maria / Journal of Functional Foods 38 (2017) 308–320 Recently, evidence of a protective effect of maté drinking on the risk of breast cancer was found (Ronco, Stefani, Mendoza, Deneo-Pellegrini, et al., 2016; Ronco, Stefani, Mendoza, Vazquez, et al., 2016). In a case-control study high consumption of maté was inversely associated with breast cancer risk (odds ratio = 0.40, 95% confidence interval: 0.26–0.57, P < 0.001) (Ronco, Stefani, Mendoza, Deneo-Pellegrini, et al., 2016). Another study suggested a favourable combination regarding breast cancer risk when high maté intake is associated with high consumption of tea and even a stronger positive effect when it is combined with a high antioxidant diet (Ronco, Stefani, Mendoza, Vazquez, et al., 2016). Case-control and cross-sectional studies have been showing a beneficial effect of maté intake in relation to different issues. A cross-sectional study associated maté consumption with higher bone mineral density in postmenopausal women, suggesting a protective effect of chronic maté consumption on bone mass (Conforti, Gallo, & Saraví, 2012). Maté drinking showed a positive correlation with density of both lumbar spine (P < 0.0001) and femoral neck (P = 0.0028) (Conforti et al., 2012). A case-control study found an inverse association between maté drinking and Parkinson’s disease (odds ratio 0.64, 95% confidence interval: 0.54–0.76, P = 0.00001), suggesting a possible protective effect of maté on the expression, development, and progression of the disease (Gatto, Melcon, Parisi, Bartoloni, & Gonzalez, 2015). Regarding the safety of maté consumption during pregnancy, a preliminary case-control study did not find harmful effect of maté drinking on intrauterine growth or duration of pregnancy (Santos, Matijasevich, & Valle, 2005). It was suggested that the amount of maté regularly consumed during pregnancy in South Brazil is probably safe for the foetus. Clinical studies reported other effects of maté, different from what was previously investigated, demonstrating new possible applications. In a double-blind placebo-controlled study, maté significantly (P < 0.05) improved parameters of blood viscosity and microcirculation of subjects with high blood viscosity. Maté played a role in the regulation of various indexes of hemorheology, nailfold microcirculation, and the platelet aggregating factors 6-ketoPGF1a and TXB2, showing a potential in reducing the incidence of risk factors attributed to cardiovascular disease (Yu et al., 2015). Petrilli et al. (2016) analysed the effect of maté tea intake (3g) on HIV-infected subjects for 60 days but they did not find any change in oxidative or inflammatory parameters (highsensitivity C-reactive protein, fibrinogen, white blood cell profile and lipid peroxidation). A pioneering study done by our group (Ribeiro et al., 2017) analysed the effect of short-term (14 days) consumption of roasted maté on blood total creatine phosphokinase (CPK) level in institutionalized patients with traumatic brain injury (TBI) (n: maté group = 4, control = 4). Elevated levels of total CPK, creatinine, and urea are prognostic markers of rhabdomyolysis, a severe complication in TBI patients that leads to death. Nontreated patients did not have significant decrease (P < 0.05) in total CPK values and one not-treated patient was diagnosed with rhabdomyolysis. Maté-treated patients had a significant decrease (P < 0.05) in total CPK values. Principal components analysis data and Person’s correlation test indicated a correlation between maté consumption and lower levels of total CPK in TBI patients. Although several beneficial associations regarding maté consumption were reported, the results should be interpreted with caution. The small number of studies and their limitations create the necessity of more investigation. 7. Final considerations In general, maté showed a beneficial effect on human health. Conflicting results might be attributed to the type of herb, variations in processing and preparation methods, environmental variables, and experimental design, including interpersonal variations. In addition to the above-mentioned limitations, other factors, such as small sample size and lack of longitudinal clinical trials may have masked the effect of maté on human parameters analysed in the studies. These factors might be responsible for controversial results regarding PON-1 activity, LDL-c oxidation and glycemic and lipid controls in humans. Maté showed an antioxidative activity on LDL-c in whole plasma, but results from the isolated LDL-c particles are inconclusive. Further, future studies should address the influence of maté on oxidized LDL-c particles and LDL-c size. Although different studies had shown an antiglycation effect of maté in vitro, it was not possible to confirm this ability in vivo. In most studies maté was not able to control efficiently the glycaemia. Favourable results only were found in T2DM subjects. The influence of maté on stimulation of incretin secretion and/or insulin liberation is an interesting topic for future research. Despite the limitations, it was observed a positive effect of maté on human antioxidant enzymatic complex. There is a unanimous tendency of maté in helping to restore human redox balance on the short-term. It would be interesting to analyse if this effect is sustained for a long period of time (eg. 5 years). Maté supplementation showed a positive effect on energy expenditure and in the reduction of body fat in humans, with additional advantage of all treatments being well tolerated. Although maté has been pointed out as a potential thermogenic, the supplement still should be used with caution until more clinical controlled studies prove its efficacy and safety. Considering to the carcinogenicity of maté beverages, temperature, and not maté itself, appears to be responsible for the carcinogenic effect. Despite the existing studies, the amount of controlled clinical trials is still scarce. Therefore, assessment of long-term randomized double-blind placebo-controlled studies with more consistent sampling will provide a better understanding of the effects of maté on human health. Furthermore, compounds from different maté extracts should be properly identified and quantified to better understand their contribution to the expected physiological effects. If positive and consistent results are confirmed over time, maté could be recognized as a functional food. Acknowledgements This work was supported by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Capes) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). References Alkhatib, A. (2014). Yerba Maté (Illex Paraguariensis) ingestion augments fat oxidation and energy expenditure during exercise at various submaximal intensities. Nutrition & Metabolism, 11(1), 42. Amigo-Benavent, M., Wang, S., Mateos, R., Sarriá, B., & Bravo, L. (2017). Antiproliferative and cytotoxic effects of green coffee and yerba mate extracts, their main hydroxycinnamic acids, methylxanthine and metabolites in different human cell lines. Food and Chemical Toxicology, 106, 125–138. Andersen, T., & Fogh, J. (2001). Weight loss and delayed gastric emptying following a South American herbal preparation in overweight patients. Journal of Human Nutrition & Dietetics, 14(3), 243–250. Arçari, D. P., Bartchewsky, W., dos Santos, T. W., Oliveira, K. A., Funck, A., Pedrazzoli, J., ... Ribeiro, M. L. (2009). Antiobesity effects of yerba maté Extract (Ilex paraguariensis) in High-fat Diet–induced Obese Mice. Obesity, 17(12), 2127–2133. Arçari, D. P., Porto, V. B., Rodrigues, E. R. V., Martins, F., De Lima, R. J., Sawaya, A. C. F., ... Carvalho, P. de O. (2011). Effect of mate tea (Ilex paraguariensis) supplementation on oxidative stress biomarkers and LDL oxidisability in normo- and hyperlipidaemic humans. Journal of Functional Foods, 3, 190–197. Bains, Y., & Gugliucci, A. (2017). Ilex paraguariensis and its main component chlorogenic acid inhibit fructose formation of advanced glycation endproducts with amino acids at conditions compatible with those in the digestive system. Fitoterapia, 117, 6–10. L.G. Riachi, C.A.B. De Maria / Journal of Functional Foods 38 (2017) 308–320 Bastos, D. H. M., Fornari, A. C., Queiroz, Y. S., Soares, R. A. M., & Torres, E. A. F. S. (2005). The chlorogenic acid and caffeine content of yerba maté (Ilex paraguariensis) beverages. Acta Farmaceutica Bonaerense, 24(1), 91–95. Bastos, D. H. M., Fornari, A. C., Queiroz, Y. S., & Torres, E. A. F. S. (2006). Bioactive Compounds Content of Chimarrão Infusions Related to the Moisture of Yerba Maté (Ilex Paraguariensis) Leaves. Brazilian Archives of Biology and Technology, 49(3), 399–404. Bastos, D. H. M., Oliveira, D. M., Matsumoto, R. L. T., Carvalho, P. O., & Ribeiro, M. L. (2007). Yerba maté: Pharmacological properties, research and biotechnology. Medicinal and Aromatic Plant Science and Biotechnology, 1(1), 37–46. Bixby, M., Spieler, L., Menini, T., & Gugliucci, A. (2005). Ilex paraguariensis extracts are potent inhibitors of nitrosative stress: A comparative study with green tea and wines using a protein nitration model and mammalian cell cytotoxicity. Life Sciences, 77(3), 345–358. Bloomer, R. J., Canale, R. E., Blankenship, M. M., Hammond, K. G., Fisher-Wellman, K. H., & Schilling, B. K. (2009). Effect of the dietary supplement Meltdown on catecholamine secretion, markers of lipolysis, and metabolic rate in men and women: a randomized, placebo controlled, cross-over study. Lipids in Health and Disease, 8(1), 32. Bloomer, R. J., Fisher-Wellman, K. H., Hammond, K. G., Schilling, B. K., Weber, A. A., & Cole, B. J. (2009). Dietary supplement increases plasma norepinephrine, lipolysis, and metabolic rate in resistance trained men. Journal of the International Society of Sports Nutrition, 6(1), 4. Boaventura, B. C. B., da Silva, E. L., Liu, R. H., Prudêncio, E. S., Di Pietro, P. F., Becker, A. M., ... Amboni, R. D. de M. C. (2015). Effect of yerba mate (Ilex paraguariensis A St. Hil.) infusion obtained by freeze concentration technology on antioxidant status of healthy individuals. LWT – Food Science and Technology, 62(2), 948–954. Boaventura, B. C. B., Di Pietro, P. F., Klein, G. A., Stefanuto, A., de Morais, E. C., de Andrade, F., ... da Silva, E. L. (2013). Antioxidant potential of mate tea (Ilex paraguariensis) in type 2 diabetic mellitus and pre-diabetic individuals. Journal of Functional Foods, 5(3), 1057–1064. Boaventura, B. C. B., Di Pietro, P. F., Stefanuto, A., Klein, G. A., de Morais, E. C., de Andrade, F., ... da Silva, E. L. (2012). Association of mate tea (Ilex paraguariensis) intake and dietary intervention and effects on oxidative stress biomarkers of dyslipidemic subjects. Nutrition, 28(6), 657–664. Bracesco, N., Sanchez, A. G., Contreras, V., Menini, T., & Gugliucci, A. (2011). Recent advances on Ilex paraguariensis research: Minireview. Journal of Ethnopharmacology, 136(3), 378–384. Bravo, L., Mateos, R., Sarriá, B., Baeza, G., Lecumberri, E., & Ramos, S. (2014). Hypocholesterolaemic and antioxidant effects of yerba mate (Ilex paraguariensis) in high-cholesterol fed rats. Fitoterapia, 92, 219–229. Brooks, G. A., & Mercier, J. (1994). Balance of carbohydrate and lipid utilization during exercise: the ‘‘crossover” concept. J Appl Physiol 1985, 76(6), 2253–2261. Bruckbauer, A., & Zemel, M. B. (2014). Synergistic effects of polyphenols and methylxanthines with leucine on AMPK/Sirtuin-mediated metabolism in muscle cells and adipocytes. PLoS ONE, 9(2). Campbell, B. I., Zito, G., Colquhoun, R., Martinez, N., Kendall, K., Buchanan, L., ... Pingel, A. (2016). The effects of a single-dose thermogenic supplement on resting metabolic rate and hemodynamic variables in healthy females – a randomized, double-blind, placebo-controlled, cross-over trial. Journal of the International Society of Sports Nutrition, 13(1), 13. Coelho, G. C., Rachwal, M. F. G., Dedecek, R. a., Curcio, G. R., Nietsche, K., & Schenkel, E. P. (2007). Effect of light intensity on methylxanthine contents of Ilex paraguariensis A. St. Hil. Biochemical Systematics and Ecology, 35(2), 75–80. Conforti, A. S., Gallo, M. E., & Saraví, F. D. (2012). Yerba Mate (Ilex paraguariensis) consumption is associated with higher bone mineral density in postmenopausal women. Bone, 50(1), 9–13. da Silva, E. L., Neiva, T. J. C., Shirai, M., Terao, J., & Abdalla, D. S. P. (2008). Acute ingestion of yerba mate infusion (Ilex paraguariensis) inhibits plasma and lipoprotein oxidation. Food Research International, 41(10), 973–979. da Silveira, T. F. F., Meinhart, A. D., Ballus, C. A., & Godoy, H. T. (2014). The effect of the duration of infusion, temperature, and water volume on the rutin content in the preparation of mate tea beverages: An optimization study. Food Research International, 60, 241–245. da Silveira, T. F. F., Meinhart, A. D., Coutinho, J. P., de Souza, T. C. L., Cunha, E. C. E., & de Moraes, M. R. (2016). Content of lutein in aqueous extracts of yerba mate (Ilex paraguariensis St. Hil). Food Research International, 82, 165–171. Danhelova, H., Hradecky, J., Prinosilova, S., Cajka, T., Riddellova, K., Vaclavik, L., & Hajslova, J. (2012). Rapid analysis of caffeine in various coffee samples employing direct analysis in real-time ionization-high-resolution mass spectrometry. Analytical and Bioanalytical Chemistry, 403(10), 2883–2889. De Maria, C. A. B., & Moreira, R. F. A. (2011). A intrigante bioquímica da niacina – uma revisão crítica. Quimica Nova. http://dx.doi.org/10.1590/S010040422011001000007. De Morais, E. C., Stefanuto, A., Klein, G. a., Boaventura, B. C. B., de Andrade, F., Wazlawik, E., ... da Silva, E. L. (2009). Consumption of yerba mate (Ilex paraguariensis) improves serum lipid parameters in healthy dyslipidemic subjects and provides an additional LDL-cholesterol reduction in individuals on statin therapy. Journal of Agricultural and Food Chemistry, 57(18), 8316–8324. De Resende, P. E., Kaiser, S., Pittol, V., Hoefel, A. L., D’Agostini Silva, R., Vieira Marques, C., ... Ortega, G. G. (2015). Influence of crude extract and bioactive fractions of Ilex paraguariensis A. St. Hil. (yerba mate) on the Wistar rat lipid metabolism. Journal of Functional Foods, 15, 440–451. 319 DeChristopher, L. R., Uribarri, J., & Tucker, K. L. (2015). Intake of high fructose corn syrup sweetened soft drinks is associated with prevalent chronic bronchitis in U.S. Adults, ages 20–55 y. Nutrition Journal, 14(1), 107. DeChristopher, L. R., Uribarri, J., & Tucker, K. L. (2016). Intake of high-fructose corn syrup sweetened soft drinks, fruit drinks and apple juice is associated with prevalent arthritis in US adults, aged 20–30 years. Nutrition & Diabetes, 6(3), e199. Deneo-Pellegrini, H., De Stefani, E., Boffetta, P., Ronco, A. L., Acosta, G., Correa, P., & Mendilaharsu, M. (2013). Maté consumption and risk of oral cancer: Casecontrol study in Uruguay. Head and Neck, 35(8), 1091–1095. dos Branco, C. dos S., Scola, G., Rodrigues, A. D., Cesio, V., Laprovitera, M., Heinzen, H., ... Salvador, M. (2013). Anticonvulsant, neuroprotective and behavioral effects of organic and conventional yerba mate (Ilex paraguariensis St. Hil.) on pentylenetetrazol-induced seizures in Wistar rats. Brain Research Bulletin, 92, 60–68. Farah, A., de Paulis, T., Trugo, L. C., & Martin, P. R. (2005). Effect of roasting on the formation of chlorogenic acid lactones in coffee. Journal of Agricultural and Food Chemistry, 53(5), 1505–1513. Fernandes, E. S., Machado, M. D. O., Becker, A. M., de Andrade, F., Maraschin, M., & da Silva, E. L. (2012). Yerba mate (Ilex paraguariensis) enhances the gene modulation and activity of paraoxonase-2: In vitro and in vivo studies. Nutrition, 28(11–12), 1157–1164. Ferreira, F., Vázquez, A., Güntner, C., & Moyna, P. (1997). Inhibition of the passive diffusion of cholic acid by the Ilex paraguariensis St. Hil. saponins. Phytotherapy Research, 11(1), 79–81. Gatto, E. M., Melcon, C., Parisi, V. L., Bartoloni, L., & Gonzalez, C. D. (2015). Inverse association between yerba mate consumption and idiopathic Parkinson’s disease. A case–control study. Journal of the Neurological Sciences, 356(1–2), 163–167. Gnoatto, S. C. B., Schenkel, E. P., & Bassani, V. L. (2005). HPLC method to assay total saponins in Ilex paraguariensis aqueous extract. Journal of the Brazilian Chemical Society, 16(4), 723–726. Gugliucci, A. (1996). Antioxidant effects of Ilex Paraguariensis: Induction of decreased oxidability of human LDL in vivo. Biochemical and Biophysical Research Communications, 344(224), 338–344. Gugliucci, A., Bastos, D. H. M., Schulze, J., & Souza, M. F. F. (2009). Caffeic and chlorogenic acids in Ilex paraguariensis extracts are the main inhibitors of AGE generation by methylglyoxal in model proteins. Fitoterapia, 80, 339–344. Gugliucci, A., & Stahl, A. J. (1995). Low density lipoprotein oxidation is inhibited by extracts of Ilex paraguariensis. Biochemistry and Molecular Biology International, 35(1), 47–56. Harrold, J. A., Hughes, G. M., O’Shiel, K., Quinn, E., Boyland, E. J., Williams, N. J., & Halford, J. C. G. (2013). Acute effects of a herb extract formulation and inulin fibre on appetite, energy intake and food choice. Appetite, 62, 84–90. Heck, C. I., & de Mejia, E. G. (2007). Yerba Mate Tea (Ilex paraguariensis): a comprehensive review on chemistry, health implications, and technological considerations. Journal of Food Science, 72(9), 138–151. Heck, C. I., Schmalko, M., & De Mejia, E. G. (2008). Effect of growing and drying conditions on the phenolic composition of mate teas (Ilex paraguariensis). Journal of Agricultural and Food Chemistry, 56(18), 8394–8403. Hoffman, J. R., Kang, J., Ratamess, N. A., Rashti, S. L., Tranchina, C. P., & Faigenbaum, A. D. (2009). Thermogenic effect of an acute ingestion of a weight loss supplement. Journal of the International Society of Sports Nutrition, 6(1), 1. Huang, D.-W., Shen, S.-C., & Wu, J. S.-B. (2009). Effects of caffeic acid and cinnamic acid on glucose uptake in insulin-resistant mouse hepatocytes. Journal of Agricultural and Food Chemistry, 57(17), 7687–7692. IARC. (1991). Coffee, tea, mate, methylxanthines and methylglyoxal. In IARC Monographs on the evaluation of carcinogenic risks to humans (pp. 1–513). Isolabella, S., Cogoi, L., López, P., Anesini, C., Ferraro, G., & Filip, R. (2010). Study of the bioactive compounds variation during yerba mate (Ilex paraguariensis) processing. Food Chemistry, 122(3), 695–699. Jitomir, J., Nassar, E., Culbertson, J., Moreillon, J., Buford, T., Hudson, G., ... Willoughby, D. S. (2008). The acute effects of the thermogenic supplement Meltdown on energy expenditure, fat oxidation, and hemodynamic responses in young, healthy males. Journal of the International Society of Sports Nutrition, 5 (1), 23. Jung, J.-H., & Hur, Y.-I. (2016). The Effect of Maté Extract on Body Weight and Fat Reduction in Obese Women: A Randomized Placebo-controlled Clinical Trial. The Korean Journal of Obesity, 25(4), 197–206. Kahale, K. H., Tranchant, C., Pakzad, S., & Farhat, A. G. (2015). Effect of sumac spice, Turkish cofee and yerba mate tea on the postprandial glycemic response to Lebanese mankoucheh. Nutrition & Food Science, 45(3), 433–447. Kamanna, V. S., & Kashyap, M. L. (2008). Mechanism of action of niacin. The American Journal of Cardiology, 101(8), S20–S26. Khan, S., Baboota, S., Ali, J., Narang, R. S., & Narang, J. K. (2016). Chlorogenic acid stabilized nanostructured lipid carriers (NLC) of atorvastatin: Formulation, design and in vivo evaluation. Drug Development and Industrial Pharmacy, 42(2), 209–220. Kim, W., & Egan, J. M. (2008). The role of incretins in glucose homeostasis and diabetes treatment. Pharmacological Reviews, 60(4), 470–512. Kim, H. J., Ko, J., Storni, C., Song, H. J., & Cho, Y. G. (2012). Effect of green mate in overweight volunteers: A randomized placebo-controlled human study. Journal of Functional Foods, 4(1), 287–293. Kim, S.-Y., Oh, M.-R., Kim, M.-G., Chae, H.-J., & Chae, S.-W. (2015). Anti-obesity effects of Yerba Mate (Ilex Paraguariensis): a randomized, double-blind, 320 L.G. Riachi, C.A.B. De Maria / Journal of Functional Foods 38 (2017) 308–320 placebo-controlled clinical trial. BMC Complementary and Alternative Medicine, 15(1), 338. Kita, T., Kume, N., Minami, M., Hayashida, K., Murayama, T., Sano, H., ... Yokode, M. (2006). Role of oxidized LDL in atherosclerosis. Annals of the New York Academy of Sciences, 947(1), 199–206. Klein, G. A., Stefanuto, A., Boaventura, B. C. B., Morais, E. C., Cavalcante, L. S., Andrade, F., ... Silva, E. (2011). Mate tea (Ilex paraguariensis) improves glycemic and lipid profiles of type 2 diabetes and pre-diabetes individuals: a pilot study. Journal of the American College of Nutrition, 30(5), 320–332. Liao, C.-C., Ou, T.-T., Wu, C.-H., & Wang, C.-J. (2013). Prevention of diet-induced hyperlipidemia and obesity by caffeic acid in C57BL/6 mice through regulation of hepatic lipogenesis gene expression. Journal of Agricultural and Food Chemistry, 61(46), 11082–11088. Lobo, V., Patil, A., Phatak, A., & Chandra, N. (2010). Free radicals, antioxidants and functional foods: Impact on human health. Pharmacognosy Review, 4(8), 118–126. Loomis, D., Guyton, K. Z., Grosse, Y., Lauby-Secretan, B., El Ghissassi, F., Bouvard, V., ... Straif, K. (2016). Carcinogenicity of drinking coffee, mate, and very hot beverages. Lancet Oncol., 17(7), 877–878. Lunceford, N., & Gugliucci, A. (2005). Ilex paraguariensis extracts inhibit AGE formation more efficiently than green tea. Fitoterapia, 76(5), 419–427. Marques, V., & Farah, A. (2009). Chlorogenic acids and related compounds in medicinal plants and infusions. Food Chemistry, 113(4), 1370–1376. Márquez, V., Martínez, N., Guerra, M., Fariña, L., Boido, E., & Dellacassa, E. (2013). Characterization of aroma-impact compounds in yerba mate (Ilex paraguariensis) using GC–olfactometry and GC–MS. Food Research International, 53(2), 808–815. Martinet, A., Hostettmann, K., & Schutz, Y. (1999). Thermogenic effects of commercially available plant preparations aimed at treating human obesity. Phytomedicine, 6(4), 231–238. Matsumoto, R. L. T., Bastos, D. H. M., Mendonça, S., Nunes, V. S., Bartchewsky, W., Ribeiro, M. L., & de Oliveira Carvalho, P. (2009). Effects of mate tea (Ilex paraguariensis) ingestion on mRNA expression of antioxidant enzymes, lipid peroxidation, and total antioxidant status in healthy young women. Journal of Agricultural and Food Chemistry, 57(5), 1775–1780. Matsumoto, R. L. T., Mendonça, S., Moura de Oliveira, D., Souza, M. F., & Markowicz Bastos, D. H. (2009). Effects of maté tea intake on ex vivo LDL peroxidation induced by three different pathways. Nutrients, 1(1), 18–29. Meinhart, A. D., Bizzotto, C. S., Ballus, C. A., Rybka, A. C. P., Sobrinho, M. R., CerroQuintana, R. S., ... Godoy, H. T. (2010). Methylxanthines and phenolics content extracted during the consumption of mate (Ilex paraguariensis St. Hil) beverages. Journal of Agricultural and Food Chemistry, 58(4), 2188–2193. Menini, T., Heck, C., Schulze, J., de Mejia, E., & Gugliucci, A. (2007). Protective action of Ilex paraguariensis extract against free radical inactivation of paraoxonase-1 in high-density lipoprotein. Planta Medica, 73(11), 1141–1147. Messina, D., Soto, C., Méndez, A., Corte, C., Kemnitz, M., Avena, V., ... Elizalde, R. P. (2015). Efecto hipolipemiante del consumo de mate en individuos dislipidémicos. Nutricion Hospitalaria, 31(5), 2131–2139. Narita, Y., Iwai, K., Fukunaga, T., & Nakagiri, O. (2012). Inhibitory activity of chlorogenic acids in decaffeinated green coffee beans against porcine pancreas lipase and effect of a decaffeinated green coffee bean extract on an emulsion of olive oil. Bioscience, Biotechnology, and Biochemistry, 76(12), 2329–2331. Oliveira, E. P. de., Torezan, G. A., Gonçalves, L. deS., Corrente, J. E., McLellan, K. C. P., ... Burini, R. C. (2016). O consumo agudo de erva mate aumenta o gasto energético de homens jovens saudáveis: um estudo piloto. Revista Brasileira de Obesidade, Nutrição E Emagrecimento, 10(59), 242–249. Ong, K. W., Hsu, A., & Tan, B. K. H. (2012). Chlorogenic acid stimulates glucose transport in skeletal muscle via AMPK activation: a contributor to the beneficial effects of coffee on diabetes. PLoS ONE, 7(3), e32718. Ott, C., Jacobs, K., Haucke, E., Navarrete Santos, A., Grune, T., & Simm, A. (2014). Role of advanced glycation end products in cellular signaling. Redox Biology, 2, 411–429. Outlaw, J., Wilborn, C., Smith, A., Urbina, S., Hayward, S., Foster, C., ... Taylor, L. (2013). Effects of ingestion of a commercially available thermogenic dietary supplement on resting energy expenditure, mood state and cardiovascular measures. Journal of the International Society of Sports Nutrition, 10(1), 25. Pang, J., Choi, Y., & Park, T. (2008). Ilex paraguariensis extract ameliorates obesity induced by high-fat diet: Potential role of AMPK in the visceral adipose tissue. Archives of Biochemistry and Biophysics, 476(2), 178–185. Panza, V. P., Diefenthaeler, F., Tamborindeguy, A. C., Camargo, C. deQ., de Moura, B. M., Brunetta, H. S., ... da Silva, E. L. (2016). Effects of mate tea consumption on muscle strength and oxidative stress markers after eccentric exercise. British Journal of Nutrition, 115(8), 1370–1378. Pereira, D. F., Kappel, V. D., Cazarolli, L. H., Boligon, a. a., Athayde, M. L., ... Silva, F. R. M. B. (2012). Influence of the traditional Brazilian drink Ilex paraguariensis tea on glucose homeostasis. Phytomedicine : International Journal of Phytotherapy and Phytopharmacology, 19(10), 868–877. Peres, R. G., Tonin, F. G., Tavares, M. F. M., & Rodriguez-Amaya, D. B. (2013). HPLCDAD-ESI/MS identification and quantification of phenolic compounds in Ilex paraguariensis beverages and on-line evaluation of individual antioxidant activity. Molecules, 18(4), 3859–3871. Petrilli, A., Souza, S., Teixeira, A., Pontilho, P., Souza, J., Luzia, L., & Rondó, P. (2016). Effect of chocolate and yerba mate phenolic compounds on inflammatory and oxidative biomarkers in HIV/AIDS individuals. Nutrients, 8(5), 132. Rashti, S. L., Ratamess, N. A., Kang, J., Faigenbaum, A. D., Chilakos, A., & Hoffman, J. R. (2009). Thermogenic effect of meltdown RTDTM energy drink in young healthy women: a double blind, cross-over design study. Lipids in Health and Disease, 8 (1), 57. Ribeiro, M. C., Santos, Â., Riachi, L. G., Rodrigues, A. C. B., Coelho, G. C., Marcellini, P. S., ... de Maria, C. A. B. (2017). The effects of roasted yerba mate (Ilex paraguariensis A. ST. Hil.) consumption on glycemia and total serum creatine phosphokinase in patients with traumatic brain injury. Journal of Functional Foods, 28, 240–245. Ronco, A. L., Stefani, E. De, Mendoza, B., Deneo-Pellegrini, H., Vazquez, A., & Abbona, E. (2016). Mate intake and risk of breast cancer in Uruguay: A case-control study. Asian Pacific Journal of Cancer Prevention: APJCP, 17(3), 1453–1461. Ronco, A. L., Stefani, E. De, Mendoza, B., Vazquez, A., Abbona, E., Sanchez, G., & Rosa, A. De (2016). Mate and tea intake, Dietary antioxidants and risk of breast cancer: A case-control study. Asian Pacific Journal of Cancer Prevention: APJCP, 17 (6), 2923–2933. Ruxton, C. H. S. (2004). Efficacy of Zotrim: A herbal weight loss preparation. Nutrition & Food Science, 34(1), 25–28. Ruxton, C. H. S., Hinton, F., & Evans, C. E. L. (2005). Effects of an over-the-counter herbal weight management product (ZotrimÒ) on weight and waist circumference in a sample of overweight women: a consumer study. Nutrition & Food Science, 35(5), 303–314. Ruxton, C. H. S., Kirkwood, L., McMillan, B., St John, D., & Evans, C. E. L. (2007). Effectiveness of a herbal supplement (ZotrimTM) for weight management. British Food Journal, 109(6), 416–428. Santos, I. S., Matijasevich, A., & Valle, N. C. J. (2005). Mate drinking during pregnancy and risk of preterm and small for gestational age birth. The Journal of Nutrition, 135(5), 1120–1123. Serra, F., Bonet, M. L., Puigserver, P., Oliver, J., & Palou, A. (1999). Stimulation of uncoupling protein 1 expression in brown adipocytes by naturally occurring carotenoids. International Journal of Obesity, 23(6), 650–655. http://dx.doi.org/ 10.1038/sj.ijo.0800897. Steinberg, D., & Witztum, J. L. (2010). Oxidized low-density lipoprotein and atherosclerosis. Arteriosclerosis, Thrombosis, and Vascular Biology, 30(12), 2311–2316. Stohs, S. J., & Badmaev, V. (2016). A review of natural stimulant and non-stimulant thermogenic agents. Phytotherapy Research, 30(5), 732–740. Szymańska, K., Matos, E., Hung, R. J., Wünsch-Filho, V., Eluf-Neto, J., Menezes, A., ... Boffetta, P. (2010). Drinking of maté and the risk of cancers of the upper aerodigestive tract in Latin America: a case-control study. Cancer Causes & Control: CCC, 21(11), 1799–1806. Tunnicliffe, J. M., Eller, K. L., Reimer, R. A., Hittel, D. S., & Shearer, J. (2011). Chlorogenic acid differentially affects postprandial glucose and glucosedependent insulinotropic polypeptide response in rats. Applied Physiology, Nutrition and Metabolism, 36(5), 650–659. Vassallo, A., Correa, P., De Stéfani, E., Cendán, M., Zavala, D., Chen, V., ... DeneoPellegrini, H. (1985). Esophageal cancer in Uruguay: a case-control study. Journal of the National Cancer Institute, 75(6), 1005–1009. Vishnu Prasad, C. N., Anjana, T., Banerji, A., & Gopalakrishnapillai, A. (2010). Gallic acid induces GLUT4 translocation and glucose uptake activity in 3T3-L1 cells. FEBS Letters, 584(3), 531–536. Yu, S., Yue, S. W., Liu, Z., Zhang, T., Xiang, N., & Fu, H. (2015). Yerba mate (Ilex paraguariensis) improves microcirculation of volunteers with high blood viscosity: A randomized, double-blind, placebo-controlled trial. Experimental Gerontology, 62, 14–22. Yuan, X., Wei, G., You, Y., Huang, Y., Lee, H. J., Dong, M., ... Ellipsis Jin, W. (2017). Rutin ameliorates obesity through brown fat activation. The FASEB Journal, 31 (1), 333–345.