Health Benefits of Bioactive Compounds from the Genus Ilex, a Source of Traditional Caffeinated Beverages

Abstract

Tea and coffee are caffeinated beverages commonly consumed around the world in daily life. Tea from Camellia sinensis is widely available and is a good source of caffeine and other bioactive compounds (e.g., polyphenols and carotenoids). Other tea-like beverages, such as those from the genus Ilex, the large-leaved Kudingcha (Ilex latifolia Thunb and Ilex kudingcha C.J. Tseng), Yerba Mate (Ilex paraguariensis A. St.-Hil), Yaupon Holly (Ilex vomitoria), and Guayusa (Ilex guayusa Loes) are also traditional drinks, with lesser overall usage, but have attracted much recent attention and have been subjected to further study. This review summarizes the distribution, composition, and health benefits of caffeinated beverages from the genus Ilex. Plants of this genus mainly contain polyphenols and alkaloids, and show diverse health benefits, which, as well as supporting their further popularization as beverages, may also lead to potential applications in the pharmaceutical or nutraceutical industries.

Full text

nutrients
Review
Health Benefits of Bioactive Compounds from
the Genus Ilex, a Source of Traditional
Caffeinated Beverages
Ren-You Gan †, Dan Zhang †, Min Wang and Harold Corke *
Department of Food Science & Technology, School of Agriculture and Biology, Shanghai Jiao Tong University,
Shanghai 200240, China; renyougan@sjtu.edu.cn (R.-Y.G.); zhang.dan@sjtu.edu.cn (D.Z.);
wangmin799@outlook.com (M.W.)
*Correspondence: hcorke@sjtu.edu.cn or hcorke@yahoo.com; Tel.: +86-21-3420-6880
† These authors equally contributed to this paper.
Received: 10 October 2018; Accepted: 1 November 2018; Published: 5 November 2018


Abstract:
Tea and coffee are caffeinated beverages commonly consumed around the world in daily
life. Tea from Camellia sinensis is widely available and is a good source of caffeine and other bioactive
compounds (e.g., polyphenols and carotenoids). Other tea-like beverages, such as those from the
genus Ilex, the large-leaved Kudingcha (Ilex latifolia Thunb and Ilex kudingcha C.J. Tseng), Yerba Mate
(Ilex paraguariensis A. St.-Hil), Yaupon Holly (Ilex vomitoria), and Guayusa (Ilex guayusa Loes) are also
traditional drinks, with lesser overall usage, but have attracted much recent attention and have been
subjected to further study. This review summarizes the distribution, composition, and health benefits
of caffeinated beverages from the genus Ilex. Plants of this genus mainly contain polyphenols and
alkaloids, and show diverse health benefits, which, as well as supporting their further popularization
as beverages, may also lead to potential applications in the pharmaceutical or nutraceutical industries.
Keywords: kudingcha; yerba mate; yaupon holly; guayusa; caffeine; polyphenols
1. Introduction
Caffeine (1,3,7-trimethylxanthine) is a member of a group of compounds known as purine
alkaloids [
1
], occurs naturally in plants used to make beverages such as coffee and tea, and is
added in the formulation of many soft drinks. Caffeine is a well-known central nervous system
stimulant in humans. Tea from Camellia sinensis is the most popular non-alcoholic caffeine-containing
beverage, and has a long consumption history all over the world. Major chemical constituents
in tea are polyphenols, proteins, enzymes, caffeine, carbohydrates, and inorganics, which provide
health beneficial properties [
1
,
2
]. However, caffeinated tea-like beverages with somewhat comparable
chemical characteristics are also obtained from plants of the genus Ilex, mainly the large-leaved
Kudingcha, Yerba Mate, Yaupon tea, and Guayusa tea, which have been well studied in recent years.
The genus Ilex, comprising some 600 species, is widely distributed across most non-tropical parts of the
world. The best-known species in Western literature is the European or English Holly,
I. aquifolium L.
,
with its characteristic red drupes (berries) and leaves widely used in Christmas decorations.
Kudingcha has a long consumption history in China and its commercial products are commonly
found in the market. The large-leaved Kudingcha, including Ilex latifolia Thunb and Ilex kudingcha C.J.
Tseng, have been reported to show significant medicinal or bioactive properties such as antioxidant,
anti-inflammatory, anti-obesity, anti-cancer, modulation of gut microbiota, and antiproliferative
effects [
3
–
10
]. In addition, Yerba Mate produced from leaves of the tree Ilex paraguariensis is a
widely consumed beverage in South American countries such as Argentina, Brazil, Chile, Paraguay,
Nutrients 2018,10, 1682; doi:10.3390/nu10111682 www.mdpi.com/journal/nutrients

Nutrients 2018,10, 1682 2 of 17
and Uruguay, and the average annual consumption reaches around 3 kg to 10 kg per person.
Yerba Mate tea has developed into a main alternative to coffee and black tea since it is characterized
as having various health benefits, such as antimicrobial, antioxidant, anti-obesity, anti-diabetic,
and cardiovascular protective effects [
11
–
18
]. Moreover, in the southeastern part of the United
States, Yaupon tea (Yaupon Holly, Ilex vomitoria) is prepared as a healthy beverage by Native
Americans [
19
]. The polyphenolics extracted from Yaupon Holly are free of catechin, and exhibit
antioxidant, anti-inflammatory, and chemo-preventive effects [
19
–
21
]. Compared to green tea,
processing and packaging have less effect on the degradation of polyphenolics in Yaupon Holly,
indicating an advantage for commercial products of Yaupon tea. Guayusa tea, commercially known as
Runa tea, is natively grown in the Amazon and has long been consumed by Amazonian indigenous
tribes [
22
,
23
]. Ilex guayusa tea contains high levels of phenolic compounds, a good dietary resource
with cellular antioxidant and anti-inflammatory properties [23,24].
Therefore, in order to provide a better understanding of Ilex-based caffeinated beverages,
the relevant literature from the last ten years was searched in Web of Science. The geographical
distributions of different Ilex species are summarized, followed by a discussion of their main bioactive
compounds, and finally we highlight the potential health benefits and related molecular mechanisms.
Since many Ilex species are already commonly consumed in the world, the information in this review
will help to provide a scientific structure to explain the health benefits of Ilex-based beverages,
which may encourage further development by the Ilex tea industry and lead to new products for
the public.
2. Distribution
Plants of the genus Ilex are distributed widely in various parts of the world (Table 1). Large-leaved
Kudingcha, an infusion made from evergreen trees of two species (I. kudingcha C.J. Tseng and I. latifolia
Thunb.), is a popular bitter-tasting infused tea found in China and other Southeastern Asian countries
(e.g., Singapore, Malaysia, and Vietnam) [
3
,
25
]. Yerba Mate tea, from a native South American holly
shrub, is mainly produced and consumed in South America [
26
,
27
]. A study from Marcelo et al.
reported that Yerba Mate could possibly be identified as to country of origin in South America by
elemental concentration and chemometrics [
28
]. Leaves of Yaupon Holly (Ilex vomitoria), from an
evergreen and caffeine-containing shrub native to the southeastern United States, was used to make a
healthy beverage by Amerindians and later European colonists [
19
,
29
]. Guayusa is made from leaves
of an evergreen tree native to South America and is grown in the Amazon. Guayusa has recently
gained more attention [22,23].
Table 1. Distribution of the most commonly consumed species of the genus Ilex.
Common Name Species Distribution References
Large-leaved Kudingcha
I. kudingcha C.J. Tseng China: Guangxi;
Guangdong; Hainan [3,25,30]
I. latifolia Thunb. China: Zhejiang; Jiangsu;
Fujian; Anhui; Hainan [3,6,7,10]
Yerba Mate Ilex paraguariensis A.
St.-Hil
South America: Argentina;
Brazil; Paraguay; Uruguay [26,27,31–33]
Yaupon Holly Ilex vomitoria Southeastern United States [19,21,29,34]
Guayusa Ilex guayusa Loes
South America: Argentina,
Southern of Brazil, Paraguay
and Uruguay
[22,24,35,36]

Nutrients 2018,10, 1682 3 of 17
3. Bioactive Compounds
Ilex genus plants are generally known to be rich in a wide variety of bioactive compounds,
mainly polyphenols and alkaloids, which play an essential role in their health benefits.
3.1. Polyphenols
3.1.1. Polyphenols in Large-Leaved Kudingcha
Structurally, polyphenols are a class of compounds composed of benzene rings bonded to one
or more hydroxyl groups. In previous published studies, different methods have been applied to
determine the phenolic composition in Kudingcha. For example, the use of tyrosinase biosensor,
Folin-Ciocalteu assay, high performance liquid chromatography (HPLC), HPLC-nuclear magnetic
resonance (NMR), ultra-high performance liquid chromatography (UHPLC), UHPLC-diode array
detector-linear ion trap-Orbitrap (UHPLC-DAD-LTQ-Orbitrap), liquid chromatography-photodiode
array detector-atmospheric pressure chemical ionization-mass spectrometry (LC-PDA–APCI-MS),
and the quantitative analysis of multiple components with a single marker (QAMS) methods were
reported [
3
,
24
,
25
,
30
,
37
]. Using these methods, polyphenols can be identified and quantified effectively.
The total polyphenolic content (TPC) in I. latifolia was 188 mg gallic acid equivalent (GAE)
per g dry plant material using the Folin–Ciocalteu method [
10
]. Caffeoylquinic acids (Figure 1)
and their derivatives are the main polyphenols in Kudingcha. Compounds such as ethyl caffeate,
3,4-di-O-caffeoylquinic acid methyl ester, 3,5-di-O-caffeoylquinic acid methyl ester, and chlorogenic
acid were identified in I. latifolia [
38
]. Chlorogenic acid (CGA), the ester of caffeic acid and
quinic acid, is known for its biological functionality. The CGA derivatives 3-O-caffeoylquinic
acid, 5-O-caffeoylquinic acid, 3,5-O-dicaffeoylquinic acid, and 4,5-O-dicaffeoylquinic acid have
been identified as major compounds in methanol and ether acetate extracts of I. kudingcha [
39
].
This was confirmed by Che et al., who detected a total of 68 CGA candidates belonging to
12 categories [
40
]. Our previous study also reported that isomers of mono- and di-caffeoylquinic acids
were the predominant compounds from Kudingcha genotypes of two Ilex species, and the average
amount of major CGAs from these Kudingcha of different origins was 97 mg/g [
25
]. Furthermore,
18 active components including polyphenols, such as hydroxycasein, protocatechuic acid, rutin,
neochlorogenic acid, chlorogenic acid, cryptochlorogenic acid, caffeic acid, and isochlorogenic acid,
were first determined in I. kudingcha by the QAMS method, which was efficiently applied for
simultaneous determination of different phenolic compounds [
30
]. Moreover, three caffeoylquinic
acids, including neochlorogenic, chlorogenic, and cryptochlorogenic acids, and three dicaffeoylquinic
acids, were identified as the main constituents in I. kudingcha [37].
3.1.2. Polyphenols in Yerba Mate
Polyphenols have been extracted from different parts of Yerba Mate, such as the whole plant,
leaves, and stems. Of these, the highest level of phenolic compounds was found in the leaf extract [
15
].
From chromatographic analyses, the TPC was determined as about 51 mg/g dry mass (DM) in
I. paraguariensis [
41
]. Moreover, determination of the TPC in Yerba Mate was performed by the
Folin-Ciocalteu method, where 111 samples from the Parana State in Brazil were characterized [
18
].
Additionally, 46 different polyphenols from four commercial Yerba Mate products have been quantified,
with hydroxycinnamic acid derivatives and flavonols accounting for 90% and 10% of the polyphenols
present. Of these, 3-caffeoylquinic (26.8% to 28.8%), 5-caffeoylquinic (21.1% to 22.4%), 4-caffeoylquinic
(12.6% to 14.2%), and 3,5-dicaffeoylquinic acids (9.5% to 11.3%) along with rutin (7.1% to 7.8%) were
found to be the predominant polyphenolic compounds. In conclusion, I. paraguariensis was shown to
be a good source of polyphenols [
18
,
27
]. Moreover, the content of lutein in aqueous extracts of Yerba
Mate varied in different commercial samples, giving further prospects for a role in risk reduction for
certain diseases [42].

Nutrients 2018,10, 1682 4 of 17
Nutrients 2018, 10, x FOR PEER REVIEW 4 of 18
Figure 1. The chemical structures of caffeoylquinic acids.
3.1.2. Polyphenols in Yerba Mate
Polyphenols have been extracted from different parts of Yerba Mate, such as the whole plant,
leaves, and stems. Of these, the highest level of phenolic compounds was found in the leaf extract
[15]. From chromatographic analyses, the TPC was determined as about 51 mg/g dry mass (DM) in I.
paraguariensis [41]. Moreover, determination of the TPC in Yerba Mate was performed by the Folin-
Ciocalteu method, where 111 samples from the Parana State in Brazil were characterized [18].
Additionally, 46 different polyphenols from four commercial Yerba Mate products have been
quantified, with hydroxycinnamic acid derivatives and flavonols accounting for 90% and 10% of the
polyphenols present. Of these, 3-caffeoylquinic (26.8% to 28.8%), 5-caffeoylquinic (21.1% to 22.4%),
4-caffeoylquinic (12.6% to 14.2%), and 3,5-dicaffeoylquinic acids (9.5% to 11.3%) along with rutin
(7.1% to 7.8%) were found to be the predominant polyphenolic compounds. In conclusion, I.
paraguariensis was shown to be a good source of polyphenols [18,27]. Moreover, the content of lutein
in aqueous extracts of Yerba Mate varied in different commercial samples, giving further prospects
for a role in risk reduction for certain diseases [42].
3.1.3. Polyphenols in Yaupon Holly
Recently, limited research has been carried out on Yaupon Holly (I. vomitoria). In infusions, eight
polyphenolic compounds were identified including mono-caffeoylquinic acids, di-caffeoylquinic
acids, and two flavonol glycosides (quercetin 3-rutinosides and kaempferol 3-rutinoside), where the
mono- and di-caffeoylquinic acids comprised 70% of the total polyphenolics [20]. Kim and Talcott
also determined the composition of diverse polyphenolic compounds in tea infusion of Yaupon Holly,
and found that 3-O-caffeoylquinic acid (chlorogenic acid), quercetin 3-rutinoside (rutin), 5-O-
caffeoylquinic acid (neochlorogenic acid), and 4-O-caffeoylquinic acid (cryptochlorogenic acid) were
the main phenolic compounds, with 423, 392, 318, and 125 mg/L rutin equivalents, respectively [21].
Figure 1. The chemical structures of caffeoylquinic acids.
3.1.3. Polyphenols in Yaupon Holly
Recently, limited research has been carried out on Yaupon Holly (I. vomitoria). In infusions,
eight polyphenolic compounds were identified including mono-caffeoylquinic acids, di-caffeoylquinic
acids, and two flavonol glycosides (quercetin 3-rutinosides and kaempferol 3-rutinoside), where the
mono- and di-caffeoylquinic acids comprised 70% of the total polyphenolics [
20
]. Kim and
Talcott also determined the composition of diverse polyphenolic compounds in tea infusion of
Yaupon Holly, and found that 3-O-caffeoylquinic acid (chlorogenic acid), quercetin 3-rutinoside
(rutin), 5-O-caffeoylquinic acid (neochlorogenic acid), and 4-O-caffeoylquinic acid (cryptochlorogenic
acid) were the main phenolic compounds, with 423, 392, 318, and 125 mg/L rutin equivalents,
respectively [21].
3.1.4. Polyphenols in Guayusa
I. guayusa teas showed high polyphenolic content totaling between 54 and 67 mg GAE/g DM,
and phenolic mono- and di-caffeoylquinic acid derivatives were the major compounds determined by
mass spectrometry [
23
]. Moreover, determination of TPC by the Slinkard and Singleton method showed
a very different content in green leaves and in processed Guayusa [
22
]. For green leaves, TPC was about
55 mg/g DM, with hydroxycinnamic acid derivatives as the major constituents. The levels of 5-O-CQA
(chlorogenic acid), 3,5-Dicaffeoylquinic acid (isochlorogenic acid), and 3-O-CQA (neochlorogenic acid)
were 24, 16, and 8 mg/g DM, respectively. Processing methods such as blanching and fermentation are
important factors affecting the TPC in Guayusa [
22
]. Kapp et al. reported that catechin, epicatechin,
epicatechin gallate, epigallocatechin, and epigallocatechin gallate (EGCG) were found in I. guayusa
leaves [
36
]. Other research showed that the major constituents of phenolics were hydroxycinnamic
acid, and chlorogenic acid was the main phenolic compound found in both young and old leaves of
Guayusa [24].

Nutrients 2018,10, 1682 5 of 17
Overall, caffeoylquinic acids and their derivatives are the main phenolic compounds in the genus
Ilex, which are summarized in Table 2.
Table 2. Main phenolic compounds in the genus Ilex.
Tea Name Species Main Polyphenols Reference
Large-leaved Kudingcha
Ilex kudingcha C. J. Tseng
Neochlorogenic acid
[30,37]
Chlorogenic acid
Cryptochlorogenic acid
Protocatechuic acid
[37]
Caffeic acid
Isochlorogenic acid
Rutin
I.latifolia
Caffeic acid derivatives [3]
Ethyl caffeate
[5]
3,4-di-O-caffeoylquinic
acid methyl ester
3,5-di-O-caffeoylquinic
acid methyl ester
Chlorogenic acid
Yerba Mate Ilex paraguariensis A.
St.-Hil
Hydroxycinnamic acid
derivatives
[18]
Flavonols
3-caffeoylquinic acid
5-caffeoylquinic acid
4-caffeoylquinic acid
3, 5-dicaffeoylquinic acid
Rutin
Yaupon holly I.vomitoria
Rutin [20,21]
Chlorogenic acid
[21]
Neochlorogenic acid
Cryptochlorogenic acid
Guayusa I.guayusa
Chlorogenic acid [22,24]
Isochlorogenic acid [22]
Neochlorogenic acid
3.2. Alkaloids
3.2.1. Alkaloids in Large-Leaved Kudingcha
Alkaloids are a class of naturally occurring compounds that mostly contain basic nitrogen atoms,
showing a wide range of physiological and pharmacological effects. Methylxanthines, mainly caffeine
and theobromine (Figure 2), are the main alkaloids in large-leaved kudingcha. However, alkaloid
content is relatively low. It was reported that the content of total methylxanthines was around 7% to
9%, of which caffeine accounted for 3% to 6%, while theobromines made up only 0.1% [1].
3.2.2. Alkaloids in Yerba Mate
Methylxanthines are alkaloids naturally present in Yerba Mate, mainly comprising caffeine and
theobromine [
18
,
27
,
31
]. It was reported that near infrared spectroscopy analysis could be applied to
predict the total methylxanthine content in Yerba Mate. The total amount of methylxanthine in 25
samples of Yerba Mate ranged from 3.69 to 12.7 mg/g, with concentrations of caffeine and theobromine
as 0.001 to 10.1 and 0.02 to 5.03 mg/g, respectively [
31
]. To quantify theobromine and caffeine in
I. paraguariensis
extracts, quality by design (QbD) models and UHPLC were optimized and applied,
and indicated good future potential for application of this methodology [
32
]. In another study of

Nutrients 2018,10, 1682 6 of 17
samples of Yerba Mate methylxanthines were quantified by HPLC–DAD, with caffeine consistently
higher in content than theobromine. Overall, Yerba Mate, with the total methylxanthines ranging from
8.2 to 10.2 mg/g, can be regarded as a moderate source of these purine alkaloids [18].
Nutrients 2018, 10, x FOR PEER REVIEW 6 of 18
around 7% to 9%, of which caffeine accounted for 3% to 6%, while theobromines made up only 0.1%
[1].
Figure 2. The chemical structures of main alkaloids in the genus Ilex.
3.2.2. Alkaloids in Yerba Mate
Methylxanthines are alkaloids naturally present in Yerba Mate, mainly comprising caffeine and
theobromine [18,27,31]. It was reported that near infrared spectroscopy analysis could be applied to
predict the total methylxanthine content in Yerba Mate. The total amount of methylxanthine in 25
samples of Yerba Mate ranged from 3.69 to 12.7 mg/g, with concentrations of caffeine and
theobromine as 0.001 to 10.1 and 0.02 to 5.03 mg/g, respectively [31]. To quantify theobromine and
caffeine in I. paraguariensis extracts, quality by design (QbD) models and UHPLC were optimized and
applied, and indicated good future potential for application of this methodology [32]. In another
study of samples of Yerba Mate methylxanthines were quantified by HPLC–DAD, with caffeine
consistently higher in content than theobromine. Overall, Yerba Mate, with the total methylxanthines
ranging from 8.2 to 10.2 mg/g, can be regarded as a moderate source of these purine alkaloids [18].
3.2.3. Alkaloids in Yaupon Holly
To identify residues of caffeinated beverages, three xanthines theobromine, theophylline, and
caffeine (Figure 2) are commonly used as standards. It was found that Yaupon beverages contained
all three, but their concentrations were significantly different between wild and domesticated types
[34]. Moreover, the caffeine content in dioecious Yaupon Holly was 0% to 1.91% of dry weight, with
the level strongly affected by nitrogen fertilizer but not by gender [19,29]. In another study, caffeine
was undetectable by HPLC in Yaupon Holly leaves [43].
3.2.4. Alkaloids in Guayusa
The tea of I. guayusa, prepared by steeping leaves in boiling water, is consumed by Amazonian
families and has a high caffeine content [23]. Kapp et al. found that the extract of Guayusa contained
several secondary metabolites, such as caffeine and theobromine, at 36 and 0.3 mg/mL, respectively
[36]. Extracts from I. guayusa have also been shown to contain caffeine [23].
4. Health Benefits
Some of the physiological effects of caffeinated beverages from Ilex are potentially beneficial for
human health (Figure 3). Here, we further discuss the actions and related mechanisms of these
potential benefits from different Ilex species.
Figure 2. The chemical structures of main alkaloids in the genus Ilex.
3.2.3. Alkaloids in Yaupon Holly
To identify residues of caffeinated beverages, three xanthines theobromine, theophylline,
and caffeine (Figure 2) are commonly used as standards. It was found that Yaupon beverages contained
all three, but their concentrations were significantly different between wild and domesticated types [
34
].
Moreover, the caffeine content in dioecious Yaupon Holly was 0% to 1.91% of dry weight, with the
level strongly affected by nitrogen fertilizer but not by gender [
19
,
29
]. In another study, caffeine was
undetectable by HPLC in Yaupon Holly leaves [43].
3.2.4. Alkaloids in Guayusa
The tea of I. guayusa, prepared by steeping leaves in boiling water, is consumed by Amazonian
families and has a high caffeine content [
23
]. Kapp et al. found that the extract of Guayusa
contained several secondary metabolites, such as caffeine and theobromine, at 36 and 0.3 mg/mL,
respectively [36]. Extracts from I. guayusa have also been shown to contain caffeine [23].
4. Health Benefits
Some of the physiological effects of caffeinated beverages from Ilex are potentially beneficial
for human health (Figure 3). Here, we further discuss the actions and related mechanisms of these
potential benefits from different Ilex species.
Nutrients 2018, 10, x FOR PEER REVIEW 7 of 18
Figure 3. The health benefits of caffeinated beverages from the genus Ilex.
4.1. Antioxidant Activity
Consumption of herbal teas prepared from I. paraguariensis, I. vomitoria, I. kudingcha, and I.
guayusa have been reported to exhibit high reducing power, 2,2-diphenyl-1-picrylhydrazyl (DPPH)
scavenging and lipid peroxidation inhibition activities, thus relieving oxidative damage [44]. Based
on the in vitro ferric-reducing antioxidant power (FRAP) assay, one extracted alkaloid constituent
from I. latifolia had high reducing power [5]. Our previous study also found that the methanol extracts
of six Kudingcha genotypes of the genus Ilex had relatively high in vitro antioxidant activity based
on different antioxidant assays [25]. I. guayusa tea aqueous extracts (1 g/mL) prepared by conventional
means protected 70% to 80% Caco-2 cells from oxidative damage [23], and prevented lipid
peroxidation and DNA oxidative damage induced by ultraviolet radiation [45]. Similar antioxidant
ability was also found in vivo and in human studies. Pereira et al. found that giving a gavage of Mate
tea (20 mg/kg BW/day) to female Wistar rats minimized oxidative stress induced by hormonal
changes during perimenopause [46]. Moreover, the impaired endogenous antioxidant defense
system in the host could also be recovered by these widely consumed non-alcoholic beverages. As
reported, the long-term ingestion of Mate tea (1 L/day) contributed to the increase in ferric-reducing
antioxidant potential in dyslipidemic subjects [44], as well as the increased glutathione (GSH)
concentration and decreased serum lipid hydroperoxides (LOOH) levels in type 2 diabetic mellitus
(T2DM) subjects [47]. In addition, the acute consumption of freeze concentrated Yerba Mate infusion
(100 mL) also enhanced the activities of antioxidant enzymes in healthy individuals, including
catalase (CAT, 28.7%), superoxide dismutase (SOD, 21.3%), and glutathione peroxidase (GPx, 9.6%)
in blood samples [48].
It is widely accepted that the counteraction on oxidative stress is mainly attributable to the
existing phenolic compounds, especially chlorogenic acids (like mono- and dicaffeoylquinic acids) as
well as flavonols [49,50], since in vitro antioxidant capacity has been confirmed to be positively
correlated with their concentrations [13,51]. In order to better retain the contents and stability of
health-beneficial antioxidants in Ilex teas, more attention should be paid to the adjustment of
industrial processing methods and the improvement of packaging methods [22,52].
Figure 3. The health benefits of caffeinated beverages from the genus Ilex.

Nutrients 2018,10, 1682 7 of 17
4.1. Antioxidant Activity
Consumption of herbal teas prepared from I. paraguariensis,I. vomitoria,I. kudingcha, and
I. guayusa
have been reported to exhibit high reducing power, 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging
and lipid peroxidation inhibition activities, thus relieving oxidative damage [
44
]. Based on the
in vitro
ferric-reducing antioxidant power (FRAP) assay, one extracted alkaloid constituent from I. latifolia
had high reducing power [
5
]. Our previous study also found that the methanol extracts of six
Kudingcha genotypes of the genus Ilex had relatively high
in vitro
antioxidant activity based on
different antioxidant assays [
25
]. I. guayusa tea aqueous extracts (1 g/mL) prepared by conventional
means protected 70% to 80% Caco-2 cells from oxidative damage [
23
], and prevented lipid peroxidation
and DNA oxidative damage induced by ultraviolet radiation [
45
]. Similar antioxidant ability was
also found
in vivo
and in human studies. Pereira et al. found that giving a gavage of Mate tea
(
20 mg/kg BW/day
) to female Wistar rats minimized oxidative stress induced by hormonal changes
during perimenopause [
46
]. Moreover, the impaired endogenous antioxidant defense system in the
host could also be recovered by these widely consumed non-alcoholic beverages. As reported, the
long-term ingestion of Mate tea (1 L/day) contributed to the increase in ferric-reducing antioxidant
potential in dyslipidemic subjects [
44
], as well as the increased glutathione (GSH) concentration and
decreased serum lipid hydroperoxides (LOOH) levels in type 2 diabetic mellitus (T2DM) subjects [
47
].
In addition, the acute consumption of freeze concentrated Yerba Mate infusion (100 mL) also
enhanced the activities of antioxidant enzymes in healthy individuals, including catalase (CAT, 28.7%),
superoxide dismutase (SOD, 21.3%), and glutathione peroxidase (GPx, 9.6%) in blood samples [48].
It is widely accepted that the counteraction on oxidative stress is mainly attributable to the existing
phenolic compounds, especially chlorogenic acids (like mono- and dicaffeoylquinic acids) as well as
flavonols [
49
,
50
], since
in vitro
antioxidant capacity has been confirmed to be positively correlated
with their concentrations [
13
,
51
]. In order to better retain the contents and stability of health-beneficial
antioxidants in Ilex teas, more attention should be paid to the adjustment of industrial processing
methods and the improvement of packaging methods [22,52].
4.2. Anti-Inflammatory Activity
The inflammatory response is usually accompanied by the activation of macrophages, neutrophils,
and various released inflammatory cytokines, such as tumor necrosis factor-
α
(TNF-
α
), interleukin
(IL)-1
β
, -6, and -12, triggering histological damage to specific tissues. Reduction of the exudate
concentration, reestablishment of the balance between pro- and anti-inflammatory cytokines (IL-4 and
-10), and suppression of the pro-inflammatory enzyme activity are considered to be major therapeutic
targets in inflammation treatment.
High anti-inflammatory effects were observed in RAW 264.7 cells treated with I. latifolia ethanol
extract (50
µ
g/mL), coupled with reduced nitric oxide (NO) production, which could dilate small blood
vessels and increase the infiltration of pro-inflammatory mediators [
5
,
10
]. Similarly, a 10% to 30% NO
inhibition rate was also reported in I. guayusa aqueous extracts (1 g/mL) treatment [
23
]. In addition,
several animal experiments also reported the anti-inflammatory effects of these tea-like beverages.
For instance, I. kudingcha C. J. Tseng methanol extracts (KME) administration upregulated the mRNA
expression of inducible nitric oxide synthase (iNOS) and reduced the formation of pro-inflammatory
factors like TNF-
α
, IL-1
β
, and IL-6 in dextran sulfate sodium (DSS)-induced ulcerative colitis (UC)
mice [
53
]. Besides, I. paraguariensis has been reported to show anti-inflammatory effects in various
animal models, such as pleurisy in mice [
54
], cigarette smoke-induced acute lung inflammation in
mice [
55
], obesity-related inflammation in rats [
56
,
57
], azoxymethane-induced inflammation in a rat
colon [
58
], and acute edema in a mouse model [
59
] at concentrations ranging from 150 mg/kg to
250 mg/kg. The anti-inflammatory mechanism of Yerba Mate was reported to inhibit the NF-
κ
B
signaling pathway through restraining the phosphorylation of upstream I
κ
B-
α
and GSK-3
β
, leading
to blocking downstream iNOS and cyclooxygenase-2 (COX-2) expression, and the secretion of
inflammatory cytokines [
56
,
58
]. However, the anti-inflammatory effects observed in several animal

Nutrients 2018,10, 1682 8 of 17
models have not been reported in human studies. Preliminary evidence has shown that Yerba Mate
consumption (3 g Yerba Mate diluted in 200 mL water once a day for sixty days) did not alter the
inflammatory parameters like high-sensitivity C-reactive protein (hs-CRP), fibrinogen, and HDL-C
levels in 92 HIV/AIDS-positive individuals. The discrepancy between basic research and clinical cases
could be due to the amount of beverage offered, the concentration of bioactive compounds in Mate tea,
and the metabolic conditions of specific populations [60].
4.3. Antibacterial Activity
Compared to tea from Camellia sinensis, research on the antibacterial properties of Yerba Mate is
relatively limited [
27
]. The antibacterial effects of Yerba Mate have been reported for Escherichia (E.) coli,
Salmonella typhimurium,Listeria monocytogenes,Staphylococcus (S.) aureus, and even methicillin-resistant
S. aureus (MRSA), with the antibacterial concentration ranging from 40
µ
g/mL to 7.4 mg/mL,
and the inhibitory effects seemingly better on gram-positive bacteria than gram-negative bacteria [
61
].
Commonly, higher concentrations are required when applied to food systems due to the interaction
of antibacterial substances with food components like proteins and lipids. Burris et al. found that
the concentration of lyophilized aqueous extract of Yerba Mate in apple juice (40 mg/mL) was
eight-fold higher than that in a medium (5 mg/mL) for equivalent bacterial inactivation [
62
]. A similar
conclusion was also reached for ground beef, where the anti-MRSA concentration of Mate tea increased
dose-dependently with increase of fat content [63].
Although the composition of Yerba Mate extract is relatively clear, conflicting results are shown
with regards to the identification of bioactive compounds responsible for antimicrobial activity.
Apart from the generally believed phenolic compounds [
64
], 3,4-dihydroxybenzaldehyde could
significantly inhibit MRSA growth even at the lowest concentration of 100
µ
g/mL [
65
]. Besides,
macromolecules like protein, occupying about 26% of Yerba Mate, might be responsible for the
antibacterial activity since dialyzed aqueous extracts have also shown inhibitory effects on E. coli and
S. aureus [
62
]. The antibacterial mechanism has been much less investigated, and it was pointed out
that the tea extract of I. paraguariensis had a destructive effect on the central carbon metabolism and
energy production pathways, as well as cell membrane integrity [
66
]. Overall, it is still unclear whether
the ingredients that have important antibacterial properties are completely identified and whether
they have synergistic or additive antibacterial effects.
4.4. Lipid-Reducing Activity
Several
in vitro
,
in vivo
, and human studies have reported the lipid-lowering benefits of the
extract of I. paraguariensis. The inhibited accumulation of triglycerides in HepG2 cells and attenuated
blood lipid levels were demonstrated in I. latifolia aqueous extracts [
7
,
67
]. Besides, N-butanolic fraction
(n-BFIP), a standardized fraction rich in phenolic compounds derived from Yerba Mate was also
shown to reduce triglycerides (TG) and low-density lipoprotein cholesterol (LDL-C) in high-fat-diet
induced (HFD) rats by 30% and 26%, respectively [
68
]. This was consistent with the conclusion
that polyphenols and methylxanthines in Yerba Mate showed higher lipid-reducing activity than
saponins [
69
]. In addition, the lipid-reducing effect of Yerba Mate extract was proven to be effective
not only in animal models, such as hyperlipidemic hamster model [
70
], rats [
68
], and rabbits [
69
],
but also in humans. Dyslipidemic and normolipidemic subjects supplemented with 50 g (330 mL
infusion and 3 times/day) Yerba Mate had about 10% reduction in lipid parameters (LDL-C and
TG) [
71
,
72
]. In addition, it was reported that heavy drinkers of I. paraguariensis beverage (>1 L/day)
had lower total cholesterol, LDL-C, and fasting glucose, but interestingly, their body weight was higher,
compared with moderate drinkers [
73
]. This low-lipids high-body-weight paradox observed in the
population of heavy drinkers of I. paraguariensis beverages could be due to the induced hypoglycemia
and compensatory higher intake of refined carbohydrates, since their consumption of carbohydrates
was higher than moderate drinkers [73].

Nutrients 2018,10, 1682 9 of 17
For the lipid-reducing molecular mechanism, triterpenoid saponins (200 mg/kg/day) derived
from I. latifolia was reported to lower lipids by the inhibition of sterol regulatory element-binding
proteins (SREBPs) via enhancing AMP-activated protein kinase (AMPK) phosphorylation in a
non-alcoholic fatty liver disease mouse model [
74
,
75
]. In addition, Yerba Mate aqueous extract was
reported to improve plasma lipid profile both
in vitro
(3T3-L1 cells model) and
in vivo
(mice model),
probably by inhibiting adipogenesis via downregulating the expression of adipogenesis related genes
(Creb-1 and C/EBPα) [76].
4.5. Regulation of Gut Microbiota
More recently, growing attention has been paid to the effect of tea beverages on gut microbiota.
Enhanced probiotic colonization was observed in a broiler chicken model fed with ground Yerba
Mate leaf supplement (0.55% inclusion rate) [
77
]. Moreover, Ilex kudingcha extract (400 mg/kg)
was demonstrated to change the diet-disrupted gut microbiota composition to normal state and
increase their diversity in HFD-fed mice [
78
]. It was reported that polyphenols from I. latifolia
played a critical role in establishing the structure of gut microbiota, since dietary polyphenols,
especially dicaffeoylquinic acids (diCQAs), exhibited low bioavailability in the upper digestive tract,
and reached the colon with an intact form and interacted with the colonic microbiota, contributing
to the amelioration of the intestinal flora [
79
]. In addition, Xie et al. reported that diCQAs from
Kudingcha enhanced the diversity of intestinal microbiota
in vitro
and promoted the generation of
short-chain fatty acids (SCFAs) through gut microbiota, which in turn provided nutrients and energy
for the optimization of gut microbial profile [
9
]. Therefore, the interaction between tea consumption
and intestinal microbes can further improve the microbial colonization and promote human health.
4.6. Anti-Cancer Activity
Although epidemiological studies have reported a correlation between Mate tea consumption and
esophageal cancer, it is most likely due to confounding factors, such as high consumption temperature
rather than the carcinogenic constituents present [
80
,
81
], since any beverages with temperature above
65
◦
C are “likely carcinogenic to humans” [
82
]. In fact, the cytotoxic action against diverse cancer
cells, such as breast cancer, oral cancer, nasopharyngeal carcinoma, and colon adenocarcinoma cells,
was reported in Yaupon Holly leaves [
20
], Kudingcha extracts [
5
], and Yerba Mate extracts [
83
,
84
],
which were tested with concentrations ranging from 10
µ
g/mL to 1000
µ
g/mL, and could not only
inhibit the viability and proliferation of cancer cells, but also prevent metastasis and promote apoptosis
of cancer cells. The presence of characteristic ingredients, mainly chlorogenic acid derivatives, may be
responsible for the anti-cancer effects of Ilex Kudingcha [39].
Several studies also elucidated the anti-cancer molecular mechanisms. It was reported that
caffeoylquinic acids in Ilex tea extracts were able to activate the pro-apoptotic factors caspase-3 and
caspase-9 in TCA8113 cancer cells, and caspase-8 and caspase-3 in HT-29 human colon cancer cells,
accompanied with the decreased expression of the inflammatory mediator NF-
κ
B, which regulates
cell proliferation, anti-apoptosis, and cell metastasis [
6
,
85
]. Overall, induction of cancer cell apoptosis
and suppression of chronic inflammation could be two main mechanisms of the anti-cancer activity of
Ilex tea.
4.7. Cardiovascular Protective Activity
Research on cardiovascular protection is limited, and only reported for I. paraguariensis and
I. kudingcha. Kudingcha extract showed ameliorative effects on blood vessel contractility and blood
flow in both rats and rabbits [
3
]. Kudingcha polysaccharides were also reported to have a protective
effect against vascular dysfunction in high fructose-fed mice [
86
]. Yerba Mate consumption had
great potential for reducing intermediate factors for cardiovascular diseases in both animal and
human interventional studies [
87
]. In addition, improved blood viscosity and microcirculation were
observed in 142 subjects supplemented with Yerba Mate tea (5 g/day) [
88
]. Moreover, reduced

Nutrients 2018,10, 1682 10 of 17
cardiovascular diseases were observed in 95 postmenopausal women consuming more than 1 L/day
of mate infusion [
89
]. Thus, Ilex tea has great potential to be used as a preventive or therapeutic
ingredient against cardiovascular diseases.
4.8. Anti-Obesity Activity
In recent years, reports have shown that caffeinated beverages from the genus Ilex, including
Yerba Mate and Kudingcha, can reduce body weight and have great potential to be developed
into anti-obesity drugs [
78
]. I. latifolia (0.33% aqueous extract was added to the HFD) showed
protective effects against HFD-induced body weight gain in mice, accompanied by decreased adipocyte
lipid accumulation and suppressed expression of lipogenic genes in the liver [
90
]. Furthermore,
adipocyte size, adipocyte differentiation, and fat accumulation were also suppressed in obese rats
after treatment with I. paraguariensis aqueous solution [
91
–
94
]. In addition to direct impact on
adipogenesis, the anti-obesity effects of Mate extract were correlated with decreased appetite [
95
].
Hussein et al.
found that chronic administration of Yerba Mate (50 mg/kg) induced elevated levels
of the satiety markers glucagon-like peptide 1 (GLP-1) and leptin in high-fat diet-fed mice, leading
to appetite-suppression and reduced food intake, thus decreasing body weight (BW) and body mass
index [96].
Besides, the anti-obesity activity of Yerba Mate beverages has been validated in clinical trials.
A randomized double-blind trial conducted by Kim et al. showed that body fat mass was significantly
reduced in obese subjects supplemented with oral Yerba Mate capsules (3 g/day) for twelve weeks [
97
].
In addition, acute intake of Yerba Mate was confirmed to augment energy expenditure in healthy
people [
98
], and it was interesting that a higher increase in energy expenditure could be induced
by ingesting Yerba Mate at cold temperatures (e.g., 3
◦
C) rather than hot temperatures (e.g., 55
◦
C),
without exerting negative impacts on the cardiovascular system [
99
]. Thus Yerba Mate appears to have
great potential to be developed into an anti-obesity functional food.
4.9. Anti-Diabetic Activity
Increasing
in vitro
and
in vivo
studies support I. latifolia as an effective way to control postprandial
hyperglycemia. Kudingcha aqueous extracts (6 mg/mL) could decrease 36% and 50% of the
Na
+
-dependent and Na
+
-independent glucose absorption by Caco-2 cells
in vitro
, respectively [
100
].
In addition, blood glucose levels in the epinephrine hyperglycemia rat models also returned to normal
levels under treatment with 5 or 10 g/kg Kudingcha extracts [
3
]. This result was in agreement
with another
in vivo
study that oral administration of Yerba Mate (100 mg/kg) aqueous extract for
seven weeks decreased blood glucose levels and improved insulin sensitivity in Tsumura Suzuki
obese diabetic (TSOD) mice, thus reducing the risk of hyperglycemia [
97
]. The caffeoylquinic acid
(CQA) derivatives derived from I. latifolia were further confirmed to play an important role in
producing these effects, by means of binding to
α
-glucosidase via stable hydrogen bonding and
hydrophobic interaction, thus reducing blood sugar levels [
8
]. In addition, clinical trials demonstrated
the possibility of I. paraguariensis beverages for the prevention of diabetes complication, since long-term
I. paraguariensis consumption (1 L/day, sixty days) improved glycemic profile and pre-diabetes related
conditions (oxidative stress and dyslipidemia) in T2DM and pre-diabetic individuals [
47
]. Therefore,
the consumption of herbal teas prepared from Ilex species is likely to be beneficial for the treatment
of diabetes.
4.10. Neuroprotective Activity
The caffeinated beverages from the genus Ilex also show neuroprotective activity [
101
].
For instance, the exposure of cortical neurons to I. latifolia (1–100
µ
g/mL) was reported to inhibit
neuronal death induced by glutamate, hypoxia, and amyloid
β
protein (A
β
) through suppressing the
pathway of apoptosis [
102
,
103
]. Additionally,
in vivo
experiments also demonstrated that I. latifolia
supplement (25 to 200 mg/kg) significantly inhibited A
β
(25–35)-induced memory impairment in mice

Nutrients 2018,10, 1682 11 of 17
and ischemia-induced neurological deficits in rats in a dose-dependent manner [
103
,
104
]. Clinical
results further revealed its potential to inhibit the development of Parkinson’s disease [105].
4.11. Other Health Benefits
In addition to the health benefits mentioned above, Yerba Mate was also reported to improve
bone mineral density in postmenopausal women and accelerated the healing of the alveolar socket in
rats after tooth extraction [106,107]
5. Conclusions
In conclusion, this review summarized the distribution and chemical composition of the
caffeinated beverages from the genus Ilex, including the large-leaved Kudingcha, Yerba Mate,
Yaupon Holly, and Guayusa, along with their potential health benefits, including antioxidant,
anti-inflammatory, antibacterial, lipid-reducing, regulation of gut microbiota, anti-cancer,
cardiovascular protective, anti-obesity, anti-diabetic, neuroprotection, etc. However, the genus Ilex
contains about 600 species, most of which still lack detailed investigation. In the future, intensive
bioprospecting of the whole range of genetic resources is sure to reveal interesting and useful new
compounds and new sources of high levels of known compounds. In addition, further research
should aim at designing controlled clinical trials to investigate the effects of long-term consumption of
well-characterized Ilex-based beverages on human health.
Author Contributions:
Conceptualization, R.-Y.G. and H.C.; writing—original draft preparation, D.Z. and M.W.;
writing—review and editing, R.-Y.G. and H.C.; supervision, H.C.; funding acquisition, R.-Y.G. and H.C.
Funding:
This study was supported by the National Key R&D Program of China (2017YFC1600100), the Shanghai
Pujiang Talent Plan (No. 18PJ1404600), the Shanghai Basic and Key Program (No. 18JC1410800), and the Shanghai
Agricultural Science and Technology Key Program (18391900600).
Conflicts of Interest: The authors declare no conflict of interest.
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