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Mol. Nutr. Food Res. 61,7, 2017, 1600715 (1 of 12) 1600715
DOI 10.1002/mnfr.201600715
REVIEW
Whole grain oats, more than just a fiber: Role of unique
phytochemicals
Shengmin Sang1and YiFang Chu2
1Laboratory for Functional Foods and Human Health, Center for Excellence in Post-Harvest Technologies, North
Carolina Agricultural and Technical State University, North Carolina Research Campus, Kannapolis, NC, USA
2Quaker Oats Center of Excellence, PepsiCo R&D Nutrition, Barrington, IL, USA
Received: August 15, 2016
Revised: October 11, 2016
Accepted: December 30, 2016
Oats are a good source of soluble dietary fiber, especially -glucan, which has outstanding
functional and nutritional properties. -Glucan is considered to be the major active component
of oats because of its cholesterol-lowering and antidiabetic effects. However, the nutritional
benefits of oats appear to go beyond fiber to bioactive phytochemicals with strong antioxi-
dant and anti-inflammatory effects. In this review, we summarize current knowledge on the
chemistry, stability, bioavailability, and health effects of two unique phytochemicals in oats,
avenanthramides, and avenacosides A and B. We conclude that studies on the beneficial effects
of avenanthramides and avenacosides A and B are still in their infancy, and additional health
benefits of these unique oat components may yet be identified.
Keywords:
Avenacosides / Avenanthramides Health effect / Oats / Phytochemicals
1 Introduction
Cereal-based food products have been the basis of the human
diet for thousands of years, and contribute about 50% of di-
etary fiber intake in Western countries. Increased whole grain
consumption is inversely associated with the risk for devel-
oping certain diet-related disorders such as type 2 diabetes,
obesity, cancer, and cardiovascular disease [1,2]. Oats (Avena
sativa L.) have been cultivated for more than 2000 years in
various regions throughout the world. It is a multifunctional
crop considered to be nutritionally superior to many other
unfortified cereals. Oats are commonly consumed as whole
grains, which provide important nutrients such as proteins,
unsaturated fatty acids, vitamins, and minerals [3]. Numer-
ous laboratory and clinical studies have demonstrated that the
Correspondence: Dr. Shengmin Sang, Laboratory for Functional
Foods and Human Health, Center for Excellence in Post-Harvest
Technologies, North Carolina Agricultural and Technical State
University, North Carolina Research Campus, 500 Laureate Way,
Kannapolis, NC 28081, USA
E-mail: ssang@ncat.edu; shengminsang@yahoo.com
Abbreviations: AP-1, activator protein 1; AUC, area under the
curve; AVA, avenanthramide; dAA, 26-desglucoavenacoside A;
DPPH, 2,2-diphenyl-L-picrylhydrazyl; HAEC, human aortic en-
dothelial cell; HHT, hydroxycinnamoyl CoA:hydroxyanthranilate
N-hydroxycinnamoyl transferase; HO-1, heme oxygenase-1;
MAPK, mitogen-activated protein kinase; Nrf2, nuclear factor
erythroid-2 related factor 2; NF-B, nuclear factor-kappa B; SMC,
smooth muscle cell; UV, ultraviolet
consumption of oat-based products can lower serum choles-
terol levels, reduce glucose uptake, and decrease plasma in-
sulin response [3–6]. These nutritional benefits of oats have
attracted the attention of scientific researchers and the gen-
eral public. As a result, the food industry has increased its use
of oats as an ingredient in various food products, including
breakfast cereals, beverages, breads, and infant foods.
Oats are a good source of soluble dietary fiber, especially
-glucan, which has outstanding functional and nutritional
properties. -Glucan is considered to be the major active
component of oats because of its cholesterol-lowering and
antidiabetic effects [7]. However, oats supply more than just
fiber. This grain contains numerous bioactive phytochem-
icals, which are structurally diverse secondary metabolites
synthesized by plants [7]. For example, oats are a good source
of phenolic acids, flavonoids, carotenoids, vitamin E, and phy-
tosterols [7–9]. In addition, oats produce two unique types of
phytochemicals: avenanthramides (AVAs) [10] and steroidal
saponins [11]. In this review, we summarize current knowl-
edge on the chemistry and health effects of these two unique
phytochemicals.
2 Avenanthramides
2.1 Chemistry
AVAs are phenolic alkaloids found exclusively in oats among
the cereals. They are a type of phytoalexin that are produced
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1600715 (2 of 12) S. Sang and Y. F. Chu Mol. Nutr. Food Res. 61,7, 2017, 1600715
in response to pathogens [12]. The biosynthesis of AVAs re-
sults from the acylation of anthranilic acid and derivatives
by the CoA thioester of cinnamic acid catalyzed by hydrox-
ycinnamoyl CoA:hydroxyanthranilate N-hydroxycinnamoyl
transferase (HHT) [13]. These compounds are substituted
N-cinnamoylanthranilic acids consisting of anthranilic acid
and cinnamic acid moieties. The AVAs differ in the substitu-
tion pattern on the two moieties.
AVAs were first purified from oat groats and hulls
by Collins, who assigned an alphabetic descriptor to
each AVA congener [14, 15]. Dimberg developed a more
systematic nomenclature, assigning the anthranilate deriva-
tives a number and the accompanying cinnamate deriva-
tives the following letters: c for caffeic acid, f for fer-
ulic acid, and p for p-coumaric acid [16]. Dimberg’s
alphanumeric nomenclature is used in this review. The an-
thranilic acid moiety consists of one anthranilic acid (1), 5-
hydroxyanthranilic acid (2), 5-hydroxy-4-methoxyanthranilic
acid (3), or 4-hydroxyanthranilic acid (4). The cinnamic acid
moiety consists of cinnamic acid (a), caffeic acid (c), ferulic
acid (f), p-coumaric acid (p), or sinapic acid [17–20]. The pre-
dominant AVAs found in oats are 2c, 2f, and 2p; however,
at least 25 different AVAs have been detected in oats, al-
though some of these have not been purified from oats and
are present in very low concentrations [15, 20, 21]. If the cin-
namic moiety consists of avenalumic acid derivatives [22],
which have an additional double bond compared with cin-
namic acid derivatives, a letter d is added to the name of the
AVA (e.g., 2cd,2f
d,and2p
d) (Fig. 1). In addition, we recently
purified a novel glucoside derivative of 2c and identified a
series of AVA-glucoside derivatives from oat products (un-
published data) (Fig. 1).
The total concentration of AVAs in oat grains reported in
the literature varies widely from 2 to 289 mg/kg [9,20,23–26].
Most of the AVAs present in oats are found in oat groats,
with the highest concentration in the bran. However, these
compounds are also present in the hulls and leaves [15, 27].
The concentration of AVAs in oat leaves ranges from 5 to 120
mg/kg, with large variations between cultivars and cultiva-
tion conditions, and especially high concentrations in leaves
treated with elicitors [27–29]. The AVA content in the oat
grain also varies according to cultivar, year, location, cul-
tivation conditions, and interactions between these factors
[23,25,26]. The AVA content is negatively affected by high ni-
trogen fertilization but does not differ between conventional
or organic cropping systems [9]. The level of AVA increases
throughout grain maturation [29].
Dimberg et al. examined the effects of long-term storage,
heat treatment, pH, and ultraviolet (UV) light on the stabil-
ity of oat AVAs (2c, 2f, and 2p) [24, 30]. The results showed
that long-term storage does not significantly affect AVA con-
centration [24]. In addition, the AVAs 2f and 2p and their
corresponding cinnamic acids, ferulic acid and p-coumaric
acid, do not appear to be sensitive to pH change at room
temperature over a 24-h period, although AVA 2f and ferulic
acid are less stable at higher temperatures at pH 7 and 12
[30]. In contrast, 2c and caffeic acid degrade completely in
an alkaline solution, and the instability of 2c and caffeic acid
is even more pronounced when pH-treated samples are also
heat treated [30]. Dimberg et al. found that UV irradiation
causes the trans–cis isomerization of cinnamic acids but not
AVAs [30], in contrast to Collins et al., who reported sim-
ilar isomerization of AVAs and cinnamic acids exposed to
UV light [15, 31]. Concentrations of AVAs were also studied
before and after processing in various food products contain-
ing oats (e.g., breads, muffins, fresh pasta, and macaroni)
[30]. The results showed that the concentration of total AVAs
(2c, 2p, and 2f) increased in all food products tested, pos-
sibly through de novo synthesis, release of insoluble bound
forms, increased extractability, or a combination of these fac-
tors. Bryngelsson and co-workers investigated the effects of
commercial hydrothermal processes (steaming, autoclaving,
and drum drying) on AVA concentrations in oats [32]. They
reported that 2p decreased during the processing of rolled
oats, whereas 2c and 2f levels remained stable. The AVAs 2c
and 2p decreased during the autoclaving of oat grains, and
all three AVAs decreased during the drum drying of milled
rolled oats. This loss of AVAs may be decreased by refinement
of the processing methods, such as lower temperature and
pH during heat treatment. Alternatively, these losses could
be offset by processing steps that increase the AVA levels in
the raw material. For centuries, cereal seeds have been ger-
minated after steeping in water to soften the kernel structure,
increase nutrient content, and decrease antinutritional com-
pounds. Bryngelsson et al. compared AVA concentrations
and enzyme activity of HHT in oats that were dry or steeped,
milled or unmilled, and raw or heat treated [13]. Their results
showed that steeping intact raw groats increased AVA con-
centrations in a time- and temperature-dependent manner,
with maximum concentrations observed after 10 h of steep-
ing at 20⬚C. In addition, AVA concentration and HHT activity
were positively correlated during the steeping of intact groats
at 8 and 20⬚C, suggesting that this increase in AVAs was due
to de novo synthesis. However, AVA levels also increased in
the steeped heat-treated oats, which lack HHT activity; this
increase may be due to the release of bound forms during
heat treatment.
2.2 Bioavailability and biotransformation
Few studies have evaluated the uptake of AVAs. In one study
[33], 0.25 g oat bran phenol-rich powder containing 0.63 mol
2p and 0.49 mol 2f was delivered to hamsters as a slurry via
stomach gavage, and blood was collected at 0, 20, 40, 60, 80,
and 120 min. Maximum plasma concentrations (Cmax)ofAVA
2p and 2f and the major phenolic acids in oats appeared at 40
min. Cmax values of 2p and 2f were 0.04 ±0.03 and 0.03 ±
0.02 mol/L, respectively; however, the apparent bioavailabil-
ity of the AVAs was only 5% of the least bioavailable phenolic
acid (vanillic acid) and 1.3% of the most bioavailable phenolic
acid (p-coumaric acid).
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Mol. Nutr. Food Res. 61,7, 2017, 1600715 (3 of 12) 1600715
Figure 1. Structures of the major oat avenanthramides and tranilast.
A study conducted by the same group evaluated the
pharmacokinetics of AVAs 2p, 2f, and 2c in humans after
consumption of an AVA-enriched mixture containing 154
mol/g 2p, 109 mol/g 2f, and 117 mol/g 2c [34]. This
AVA-enriched mixture (0.5 or 1.0 g) was given to six healthy
older adults (three men and three women) in skim milk. A
baseline blood sample was obtained, and blood samples were
collected at 15, 30, and 45 min and at 1, 2, 3, 5, and 10 h after
drinking the test beverage. The Cmax values of 2p, 2f, and 2c
were 166.7–1002.2, 49.3–153.5, and 29.6–328.1 mol/g, re-
spectively, after consuming the beverage containing 1.0 g of
the AVA-enriched mixture [34]. These Cmax values were 231%,
627%, and 115% larger, respectively, than after consumption
of the 0.5 g dose. The Cmax of 2p at both doses was at least
twofold larger than those of 2f and 2c. For all three AVAs,
the time at which Cmax was observed (tmax) was approximately
2 h, but the tmax of 2f was shorter (1.5 h) after consuming
the 1.0 g dose. For each AVA, there was no difference in the
plasma half-life (t1/2) between the two doses; however, there
were differences between the three AVAs after the 0.5 g dose,
with a longer t1/2 for 2f compared with 2p. For all three AVAs,
the area under the curve (AUC) after the 1.0 g dose was two-
to eightfold greater than the AUC after the 0.5 g dose, even
though the difference in dose was only onefold. The AUC
of 2p was more than twofold larger than that of 2f and 2c
after the 1.0 g dose, and more than sevenfold larger than 2f
after the 0.5 g dose. The relative bioavailabilities of the three
AVAs were estimated as the ratio of the AUC to the AVA
concentration in the test beverage. The bioavailability of 2p
was considerably higher than those of 2f and 2c (9.7, 4.4, and
4.2, respectively, after the 1.0 g dose, and 5.1, 1.0, and 3.8,
respectively, after the 0.5 g dose).
Koenig et al. evaluated the tissue distribution of AVAs in
rats after ingestion of a mixture containing 20 mg/kg body
weight of each of the three major AVAs (2c, 2f, and 2p) [35].
They analyzed AVA levels in plasma, liver, heart, and gas-
trocnemius at 0, 2, 4, and 12 h (n=6 at each time point)
and found that AVAs circulate in the blood before reaching
peripheral tissues, where they are differentially taken up by
the organs [35]. All three AVAs were detected mainly in their
phase II conjugated forms. Consistent with findings in ham-
sters and humans, 2p was the most bioavailable AVA in rat
plasma. However, concentration of 2f was highest in the liver
and heart, and the concentration of 2c was highest in muscle.
Peak plasma AVA concentrations occurred 1 h postgavage in
rats, 2 h after ingestion in humans, and 40 min after inges-
tion in hamsters in the studies of Chen et al. Overall, AVA
concentrations were considerably lower in muscle than in the
liver and heart up to 12 h postgavage.
Our recent publication on the metabolism of AVA 2c
in mice and by the human gut microbiome was the first
study on the biotransformation of AVAs [36]. Mice housed in
metabolic cages received AVA 2c (200 mg/kg) by oral gavage,
and urine and fecal samples were collected over 24 h and
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Figure 2. Major metabolic pathways of 2c.
analyzed by LC/MS. We found that 2c was extensively me-
tabolized in mice, with a total of eight metabolites (phase II
conjugated) detected in the urine. Only one major metabolite
(in its free form) was found in feces. Upon the elucidation
of the structures of these metabolites, three major metabolic
pathways were proposed (Fig. 2). Because of its catechol
structure, 2c is a substrate for catechol-O-methyltransferase
to generate the methylated metabolite 2f (M8). The C7–C8
double bonds of 2c and 2f can be reduced to generate
the metabolites DH-2c (M6) and DH-2f (M7). In addition,
cleavage of the amide bond is another major metabolic
pathway of 2c. For example, cleavage of its amide bond leads
to the formation of M1 and M3. Metabolites M1 and M5 are
generated by the cleavage of M6, and metabolites M1 and
M4 are generated by the cleavage of M7.
We also examined 2c metabolism by the highly complex
microbial ecosystem of the human colon, which contains
1012 microorganisms/g gut content [37]. Results of in vitro
fecal batch fermentation, using human fecal microbes
collected from six healthy individuals, showed that 2c was
progressively degraded by the microbes over 120 h. DH-2c
(M6), CA (M3), and DH-CA (M2) were identified as the
major microbial metabolites of 2c, indicating that human
fecal microbes are able to reduce the double bond and cleave
the amide bond of 2c. Another important finding was the
interindividual variability in 2c metabolism. For example,
the microbes of some subjects did not produce or produced
only low levels of the metabolite DH-2c, whereas the
microbes of other subjects almost completely metabolized
2c by 120 h, suggesting that an individual’s gut microbiota
composition plays a crucial role in the ability to metabolize
2c. Further mechanistic studies demonstrated that AVAs
are metabolized to the double bond reduced metabolites
mainly by gut microbiota rather than by liver and intestinal
microsomes and S9 fraction (unpublished data).
2.3 Bioactivities with implication for health
2.3.1 Antioxidant effects
Numerous clinical and preclinical studies have demonstrated
the antioxidant properties of AVAs (Fig. 3). The previously
mentioned study by Chen et al. [32] found that consuming
skimmilkcontaining1gofanAVA-enrichedmixturesignif-
icantly increased plasma levels of reduced glutathione at 15
min (21% over baseline) and increased the AUC of reduced
glutathione [34]. Another randomized study of 120 healthy
individuals who consumed oat AVA capsules (3.12 mg) or
placebo daily for 1 month showed significant differences in
plasma lipid peroxide levels and antioxidant status [38]. In
individuals taking the AVA supplements, levels of serum
superoxide dismutase increased by 8.4%, levels of reduced
glutathione increased by 17.9%, and malondialdehyde levels
decreased by 28.1%. In a more recent study, subjects ate two
cookies made from oat flour daily for 8 weeks. Those who
consumed cookies containing 9.2 mg AVAs showed signifi-
cantly higher total plasma antioxidant capacity and erythro-
cyte superoxide dismutase activity compared to subjects in
the control group, whose consumption of AVAs was 23-fold
lower [39].
A study investigating the antioxidant activity of AVAs also
found that rats fed AVAs (0.1 g/kg for 50 days) had higher
superoxide dismutase activity in the deep portion of the vas-
tus lateralis muscle, liver, and kidney and higher glutathione
peroxidase activity in the heart and deep portion of the vastus
lateralis muscle compared to control animals [40]. In addi-
tion, AVAs lower the levels of exercise-induced reactive oxy-
gen species [40,41]. In mice, injection of an AVA-rich extract
reverses D-galactose-induced oxidative stress by upregulating
gene expression and activity of antioxidant enzymes (e.g.,
superoxide dismutase) [42]. In addition, AVAs act synergisti-
cally with vitamin C to protect against low-density lipoprotein
oxidation in hamsters and humans [33].
Results of in vitro studies showed that the antioxidant
capacity of AVA 2f is approximately 20% greater than that
of ␣-tocopherol, as assessed by oxygen consumption in a
linoleic acid system [20,43]. The antioxidant activities of AVA
2c, 2f, and 2p were also determined by testing their abil-
ity to inhibit -carotene bleaching and react with the free
radical 2,2-diphenyl-L-picrylhydrazyl (DPPH) [44]. Each AVA
exhibited antioxidant activity in both in vitro assays, with 2c
showing the strongest antioxidant capacity of the three com-
pounds. A structure–antioxidant activity relationship study
found that synthetic AVAs containing caffeic or sinapic
acid were more effective antioxidants than those containing
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Figure 3. Bioactivities of
avenanthramides.
ferulic or p-coumaric acid [18]. In addition, a recent study in-
vestigated the antioxidant capacities of 2c, 2f, and 2p against
peroxyl radicals, hydroxyl radicals, superoxide anions, singlet
oxygen, and peroxynitrite [43]. This study also found that 2c
had the highest total antioxidant capacity of the three AVAs,
although the antioxidant activity against specific reactive oxy-
gen species varied.
Despite evidence from in vivo and in vitro studies demon-
strating the strong antioxidant capacity of AVAs, the underly-
ing mechanisms for these effects are largely unknown. One
potential mechanism is related to the number and positions
of hydroxyl groups on the anthranilic acid and cinnamic acid
moieties. Previous in vitro studies demonstrated that the trap-
ping of reactive species accounts for the ability of AVAs to
combat oxidative stress [43, 45, 46]. One study evaluated the
antioxidant activities of AVAs and the drug tranilast (Fig. 1),
which is structurally similar to AVAs but has no hydroxyl
groups [45]. Tranilast showed no antioxidant activity in the
DPPH assay or the ferric reducing antioxidant potential as-
say, suggesting that the hydroxyl groups of AVAs are involved
in free radical trapping. The particularly strong antioxidant
capacity of AVA 2c appears to be due to the ortho-hydroxyl
group on the cinnamic acid moiety [43–46]. However, the an-
thranilic acid moiety might be as important as the cinnamic
acid moiety for antioxidant activity [45,46]. Fagerlund and co-
workers found that conjugation across the amide bond of the
AVAs was also important for trapping DPPH, although this
feature is less important than the hydroxyl groups on the two
aromatic rings [46].
Our recent study suggested a novel mechanism by which
AVAs activate cellular defense pathways against oxidative
stress that involves the ␣,β-unsaturated carbonyl moiety
[47]. The transcription factor nuclear factor erythroid-2 re-
lated factor 2 (Nrf2) regulates the expression of molecules
that protect against oxidative and electrophilic stress [48].
Under basal conditions, Nrf2 is continuously degraded by
the 26S proteasome via Kelch-like ECH-associated protein 1
mediated ubiquitination. However, in response to oxidative
and electrophilic stress, Nrf2 detaches from Kelch-like ECH-
associated protein 1, migrates to the nucleus, and binds to
the antioxidant response element sequence to activate tran-
scription of genes encoding cytoprotective and detoxifying
enzymes such as heme oxygenase-1 (HO-1) [49–51]. The ␣,β-
unsaturated carbonyl groups of AVAs act as Michael acceptors
for nucleophilic attack. Therefore, we hypothesized that AVAs
are able to activate the Nrf2 defense system against oxidative
stress. This hypothesis was supported by our observations
that AVAs significantly increase HO-1 expression in HK-2
cells in a dose- and time-dependent manner, and this upreg-
ulation of HO-1 expression is mediated by Nrf2 translocation
and reactive oxygen species. Pretreatment with the kinase in-
hibitors PD98059, LY294002, and SB202190 does not inhibit
AVA-induced HO-1 expression, suggesting that this effect
is not mediated by phosphoinositide 3-kinase or mitogen-
activated protein kinase (MAPK). Moreover, hydrogenation
of the double bond of the ␣,β-unsaturated carbonyl moiety
completely blocks AVA-induced HO-1 expression, indicating
that the ␣,β-unsaturated carbonyl moiety is important for
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antioxidant activity and that the hydroxyl groups are not in-
volved in the activation of the Nrf2 pathway. Taken together,
these results show that both the hydroxyl groups and the
␣,β-unsaturated carbonyl moiety are crucial for the antioxi-
dant properties of AVAs, and they act directly or indirectly to
scavenge reactive oxygen species.
2.3.2 Anti-inflammatory effects
The AVAs are also thought to exert anti-inflammatory activ-
ities, as demonstrated by in vitro and in vivo studies. In a
randomized double-blind trial [39], women aged 50–80 years
consumed two cookies made up of oat flour containing either
9.2 mg AVAs or 0.4 mg AVAs (control) daily for 8 weeks.
Before and after the 8-week dietary regimen, inflammation
and antioxidant status was evaluated after exercise (down-
hill walking on a treadmill). Blood samples were collected
at rest, 24 h after exercise, and 48 h after exercise. The re-
sults showed that the AVA supplementation (9.2 mg) signif-
icantly decreased the systemic inflammatory response of the
women, as assessed by neutrophil respiratory burst at 24 h
and C-reactive protein level at 48 h. AVA supplementation
also suppressed proinflammatory cytokine production, as as-
sessed by plasma IL-1concentration and mononuclear cell
nuclear factor-kappa B (NF-B) binding. In a similar study
[52], the same authors evaluated the effect of AVA supple-
mentation on the systemic inflammatory response of younger
women (18–30 years old) after exercise (downhill running
on a treadmill). The results showed significantly decreased
neutrophil respiratory burst, NFB activation, plasma IL-6
concentration, and erythrocyte glutathione peroxidase activ-
ity and increased reduced glutathione levels. Thus, long-term
AVA supplementation appears to be a useful dietary strategy
to reduce inflammation after demanding physical exercise in
both younger and older women.
Modulation of the inflammatory response by AVAs ap-
pears to be mediated through interaction with molecular and
signaling pathways in cells. Liu et al. investigated the anti-
inflammatory and antiatherogenic effects of oat AVAs in the
human aortic endothelial cell (HAEC) culture system. Prein-
cubation of HAECs with a mixture of AVAs extracted from
oats (20 or 40 mg/mL) for 24 h significantly suppressed IL-
l-stimulated expression of intracellular adhesion molecule-
l, vascular cell adhesion molecule-1, and E-selectin, thereby
decreasing the production of inflammatory cytokines and
chemokines such as IL-6, IL-8, and monocyte chemoattrac-
tant protein 1 [53]. Further mechanistic studies suggested
that the decrease in expression of proinflammatory endothe-
lial cytokines was mediated, at least in part, by inhibiting
NF-B activation (blocking phosphorylation of IKK and IB)
and suppressing proteasome activity [54]. Furthermore, AVAs
inhibited NF-B-dependent gene expression induced by TNF
receptor associated factor-2 and factor-6 and NF-B-inducing
kinase but did not inhibit the binding of NF-B to DNA [54].
2.3.3 Antiatherosclerosis effects
Besides the anti-inflammatory effects, AVAs appears to pre-
vent atherosclerosis by inhibiting the proliferation of smooth
muscle cells (SMCs) and modulating nitric oxide production.
Under healthy conditions, vascular SMCs are maintained in
a quiescent and contractile state scattered within the inti-
mal extracellular matrix [55, 56]. In injured blood vessels or
in chronic vascular inflammation, SMCs switch to a more
synthetic phenotype and then activate, proliferate, and mi-
grate into the intima, resulting in thickening of the arterial
wall [55–57]. In an in vitro study, treatment with 40, 80, or
120 M AVA 2c significantly inhibited serum-induced SMC
proliferation by 41, 62, and 73%, respectively [55]. The mech-
anism underlying this effect involves G1 cell cycle arrest, with
AVA 2c acting on multiple steps upstream of pRb, inhibiting
cyclin D1 expression, and upregulating the cell cycle regula-
tory protein p21cip1 [56]. In addition, AVA 2c significantly
and dose-dependently increases nitric oxide production and
mRNA levels of endothelial nitric oxide synthase in both vas-
cular SMCs and HAECs [55].
It is generally believed that -glucan is responsible for the
cholesterol-lowering effect of oats. A recent human study in-
dicated that AVAs may also play a role in lowering plasma
cholesterol levels [38]. Daily supplementation with oat AVA
capsules (3.12 mg daily) for 1 month significantly decreased
total cholesterol by 11.1%, triglycerides by 28.1%, and low-
density lipoprotein cholesterol by 15.1% in 120 healthy sub-
jects (P<0.05).
2.3.4 Anticancer effects
Among the few in vitro studies that have evaluated the an-
ticancer effects of AVAs, Guo et al. reported that AVA 2c
dose-dependently inhibited proliferation of HT-29, HCT-116,
and LS-174 human colon cancer cell lines at concentrations
of 40–160 M [58]. To determine whether 2c metabolites re-
tain the biological effects of 2c, we compared the ability of
2c and its major metabolites (DH-2c, 2f, DH-2f, caffeic acid,
and 5-hydroxyanthranilic acid) to inhibit the growth of the
human colon cancer cell lines HCT-116 and HT-29 [36]. Com-
pared with 2c, the double bond reduced metabolite DH-2c was
more effective at inhibiting growth and triggering apoptosis
in human colon cancer cells, indicating that 2c continues to
be pharmacologically effective after being metabolized. Us-
ing cervical cancer HeLa cells stably transfected with a Wnt
signaling reporter, 2p was identified as a chemopreventive
compound. AVA 2p modulates upstream events in -catenin-
mediated transcription of the Wnt target gene c-Myc, inhibits
proliferation of HeLa cells, and increases -catenin degrada-
tion in the cytosol in a concentration-dependent manner [59].
Similarly, dihydroavenanthramide D (DH-1p), a synthetic
analogue of AVAs, inhibits human breast cancer cell invasion
by suppressing tetradecanoyl phorbol acetate induced matrix
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metallopeptidase 9 expression and blocking the MAPK/NF-
B and MAPK/AP-1 signaling pathways [60].
2.3.5 Anti-itch effects
Colloidal oatmeal is widely used as a topical treatment for skin
conditions such as atopic dermatitis and allergic or irritant
contact dermatitis. In a mouse model of chemically induced
pruritus, AVAs were shown to mediate the anti-itch effect
of oats, likely through their anti-inflammatory effects [61].
Compared with control mice, which scratched 79.2 times per
30 min on average, mice treated with AVAs (3 ppm) showed
a 40.7% decrease in scratching (47.0 scratches per 30 min
on average) [61]. Topical application of AVAs (2–3 ppm) sig-
nificantly decreased ear edema in the oxazolone model of
contact hypersensitivity [61]. The mean ear weights of AVA-
treated mice (6.24 mg, 2 ppm AVA; 3.58 mg, 3 ppm AVA)
were considerably lower than that of control mice (10.93 mg).
Topical application of AVAs also inhibited neurogenic inflam-
mation, as demonstrated by a 31.58% and 46.09% decrease
in resiniferatoxin-induced ear edema by 2 and 3 ppm AVA,
respectively [61]. In addition, the anti-inflammatory effects
of AVAs may suppress the secondary inflammation due to
scratching in atopic dermatitis and eczema. Furthermore,
the chemical structures of AVAs are similar to that of the
drug tranilast, which has antihistamine activity [62], suggest-
ing that the anti-itch properties of AVAs may be related to the
inhibition of histamine signaling. The synthetic analogue of
AVAs, DH-1p, also reduces histamine-related reactions such
as itching, redness, and wheals [63–65].
3 Avenacosides
3.1 Chemistry
Saponins play a role in plant defense and are widely dis-
tributed in the plant kingdom [66]. Although cereals are gen-
erally deficient in these secondary metabolites, oats contain
two types of saponins (avenacins and avenacosides), which
are synthesized by different biosynthetic pathways [67, 68].
Avenacins are triterpenoid saponins that are stored mainly in
roots, where they inhibit pathogens such as Gaeumannomyces
graminis [67, 68]. This family consists of four structurally re-
lated compounds: avenacins A-1, A-2, B-1, and B-2 (Fig. 4).
Avenacin A-1 is the most abundant of these saponins, com-
prising approximately 70% of the total avenacin content. Ave-
nacins A-1 and B-1 are esterified with N-methyl anthranilic
acid, whereas avenacins A-2 and B-2 are esterified with ben-
zoic acid (Fig. 4). The aglycone backbone of avenacins A-1 and
A-2 is the derivative of that of the B-1 and B-2 (hydroxylated
at C-4) (Fig. 4).
Avenacosides are nuatigenin-type steroid glycosides that
accumulate mainly in the leaves and grain [69, 70]. The
presence of avenacosides A and B, the two primary oat
avenacosides, in oat grains and leaves was first reported by
Tschesche et al. [71]. Their structures were established by
stepwise enzymatic degradation, hydrolysis of the perme-
thylated glycosides, and mass spectrometry as nuatigenin
3-O-{␣-L-rhamnopyranosyl-(1→4)-[β-D-glucopyranosyl-
(1→2)]-β-D-glucopyranoside}-26-O-β-D-glucopyranoside,
and nuatigenin 3-O-{␣-L-rhamnopyranosyl-(1→4)-[β-D-
glucopyranosyl-(1→3)-β-D-glucopyranosyl-(1→2)]-β-D-
glucopyranoside}-26-O-β-D-glucopyranoside, respectively. In
2011, Pecio and co-workers revised their structures, as shown
in Fig. 4, based on detailed 1-dimensional and 2-dimensional
nuclear magnetic resonance (NMR) analysis [71]. Avenaco-
sides A and B are glycosylated at C-3, with a trisaccharide (one
rhamnose and two glucose units) in the case of avenacoside
A, and a tetrasaccharide (one rhamnose and three glucose
units) in the case of avenacoside B; both are glycosylated at
C-26 with a glucose unit. The O-β-glucosidic bond at C-26
can be easily hydrolyzed by a special β-glucosidase (i.e.,
avenacosidase) to yield 26-deglucoavenacosides [72]. Besides,
avenacosides A [73] and B [74], 26-desglucoavenacosides A
(26-DGA) and B (26-DGB) [75, 76], avenacoside C [77], and
the sulfated avenacoside A [70] have also been detected in
oats (Fig. 4).
As part of our efforts to complete the chemical profile of oat
bran, five steroidal saponins were isolated by means of chro-
matographic methods, including silica gel and DiaionHP-20
chromatography [78]. Their structures were identified as ave-
nacosides A–D and chamaedroside E2(Fig. 4) by analyzing
their MS and NMR spectra. Among the five purified com-
pounds, avenacoside D is a new steroidal saponin with one
more glucose residue than avenacoside B at C-3 of the agly-
cone moiety. Chamaedroside E2was first identified as a com-
ponent of Veronica chamaedrys L., and we are the first to report
its presence in oats along with its full NMR assignment. Based
on the ionization and fragmentation patterns of the five pu-
rified compounds, we searched for minor steroidal saponins
in oat extract. Eleven compounds were detected, and their
structures were tentatively identified based on the analysis
of tandem mass spectra (MSn,n=2–3), as reported in our
recent article [78]. These saponins share the same aglycone
(nuatigenin) but vary according to sugar linkages or number
of sugar residues.
The avenacoside content in plants is influenced by species,
cultivar, plant part, physiological age, and geographic en-
vironment [67]. Few studies have compared saponin con-
tent across oat varieties. In an early study, Onning and co-
workers measured the levels of avenacosides A and B in
16 Scandinavian oat varieties using HPLC with UV detec-
tion at 200 nm [79]. The saponin content differed signifi-
cantly between cultivars, ranging from 200 to 500 mg/kg
with a mean of 400 mg/kg (dry matter basis). The avena-
coside A content was two to four times higher than the
avenacoside B content in these oat cultivars with mean val-
ues of 290 and 110 mg/kg, respectively. Because of the lack
of chromophores of oat saponins, the UV detection below
215 nm is not very specific or sensitive. Therefore, Pecio and
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1600715 (8 of 12) S. Sang and Y. F. Chu Mol. Nutr. Food Res. 61,7, 2017, 1600715
Figure 4. Structures of the major oat saponins.
co-workers developed a more sensitive ultraperformance
LC/MS method to quantify the levels of avenacosides A and
B and 26-desglucoavenacoside A (dAA) in 16 Polish oat culti-
vars [80]. The mean values of avenacosides A and B and dAA
were 360, 300, and 23.6 mg/kg in the grains, and 12, 10, and
3.1 mg/kg in the husks, respectively. The dAA concentration
was much lower than avenacoside A and B concentrations
in both grains and husks. Avenacoside A represented 41.9–
60.6% of the total saponin content in grains and 37.1–57.5%
in husks, whereas avenacoside B represented 35.8–55.2% of
the total saponin content in grains and 13.8–49.0% in husks.
Processing can also affect the saponin content in oat prod-
ucts. Onning and co-workers evaluated the effects of pH,
stainless steel, and iron on the stability of avenacosides A and
B during heat processing [81]. The avenacosides were stable at
room temperature for 24 h and when heated to 100⬚Cfor3h
at pH 4–7. However, heating at 140⬚C, especially at pH 4, led
to partial degradation. The rate of breakdown was the same
for avenacosides A and B, and the reduction was about 50%
after 3 h at pH 4. The decrease in the amount of avenacoside
A after heating at 140⬚C for 3 h at pH 5, 6, and 7 was 19, 12,
and 13%, respectively. Iron and stainless steel dramatically
increased the rate of degradation at pH 4–6. Desrhamnoave-
nacosides A and B were identified as the major degradation
products of avenacosides A and B, respectively. We developed
an HPLC-MS method to analyze avenacosides in 15 different
commercial oat products including three oat bran products,
six oatmeal products, and six cold oat cereals [78]. In all 15
products, avenacoside A content was three to six times higher
than avenacoside B content. Saponin content differed signif-
icantly between the oat products, ranging from 37.9 to 377.5
mg/kg for avenacoside A and 11.7 to 89.2 mg/kg for avenaco-
side B. In general, concentrations of these compounds were
much lower in cold oat cereal than in oat bran or oatmeal.
3.2 Bioactivities with implication for health
Apart from their important role in plant defense, saponins
have received considerable attention for their potential as
cholesterol-lowering agents [82–85]. For example, Onning
and Asp used rodent models to investigate whether avena-
cosides contributed to the cholesterol-lowering effects of oats
[86]. Gerbils and rats fed high-cholesterol diets were treated
with avenacosides (0, 0.35, or 0.7 g/kg diet) for 21 and 19 days,
respectively. Compared with controls, the animals consum-
ing oat avenacosides showed significantly higher high-density
lipoprotein cholesterol levels and significantly lower liver
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Mol. Nutr. Food Res. 61,7, 2017, 1600715 (9 of 12) 1600715
cholesterol levels. No significant differences were observed
according to avenacoside dose (0.35 or 0.7 g/kg diet) regard-
ing total plasma cholesterol, high-density lipoprotein choles-
terol, and plasma triacylglycerol levels. However, plasma tri-
acylglycerols was significantly lower in rats given the higher
dose.
Onning and co-workers studied the effects of oat saponins
on nutrient absorption in the gut [87,88]. The treatment with
2 mg/mL avenacosides (1.7 mg avenacoside A and 0.3 mg
avenacoside B) inhibited maltase, trehalase, and lactase ac-
tivity in vitro and significantly increased starch hydrolysis by
␣-amylase. However, 1 mg/mL avenacosides (0.696 g avena-
coside A and 0.135 g avenacoside B per gram dry matter)
had no effect on the active transport of glucose. Avenaco-
side treatment significantly increased passive transport of the
macromolecule ovalbumin in both the proximal and the dis-
tal small intestine and appeared to increase permeability of
small marker molecules (mannitol and [51Cr]EDTA). These
in vitro effects were not observed after treatment with a crude
oat extract in either study.
The O-β-glucosidic bond at C-26 can be easily hydrolyzed
by a special β-glucosidase (avenacosidase) to yield bioac-
tive 26-deglucoavenacosides [72]. 26-Desglucoavenacosides A
and B have been shown to inhibit the phytopathogenic fun-
gus Stagonospora avenae [89], and 26-desglucoavenacoside B
strongly inhibits the fungus Pyrenophora mycelia [8]. In addi-
tion, 26-desglucoavenacosides A and B show hemolytic and
antibiotic activity [90]. The sugar moieties at C-3 are essen-
tial for the antimicrobial effects of 26-deglucoavenacosides
[89], and these saponins can be detoxified via sequential hy-
drolysis of the sugar units at C-3 by ␣-rhamnosidase and
β-glucosidase, which are secreted by pathogenic fungi [89].
The immunoregulatory and anticancer activities of avena-
cosides have also been reported. In an in vitro model, 3 and
10 g/mL avenacoside A decreased intracellular IL-2 produc-
tion in activated T lymphocytes by 23 and 32%, respectively
[91]. In our recent study [78], we demonstrated that avena-
cosides A and B inhibit growth in human colon cancer cells.
Both avenacosides showed weak activity in the cell lines tested
(HCT-116 and HT-29); however, avenacoside B was more po-
tent than A in both cell lines with an IC50 of 175.3 Min
HCT-116 cells.
4 Conclusions and perspectives
The nutritional benefits of oats appear to go beyond fiber
to bioactive compounds with strong antioxidant and anti-
inflammatory effects, suggesting that consuming oats may
help prevent chronic diseases such as cancer and cardiovas-
cular disease. However, studies on the beneficial effects of
AVAs are still in their infancy, and additional health benefits
of AVAs may yet be identified. Similarly, few studies have
assessed the bioactivity of avenacosides A and B, indicating
the need for more research in this area.
Increased consumption of whole grain oats has been in-
versely associated with the risk for developing diet-related dis-
orders including type 2 diabetes, cancer, and cardiovascular
diseases [5, 92–94]. However, the results of epidemiological
studies have not been consistent because of the lack of tools
able to accurately assess dietary intake and internal dosage.
For example, food frequency questionnaires and 24-h food
recalls, the two methods used most often in epidemiological
studies to assess dietary intake, cannot accurately measure
the amounts of specific foods consumed. Besides food intake,
other factors must be considered including the levels of the
bioactive components, which are influenced by factors such as
plant cultivar, processing methods, and storage. Interindivid-
ual genetic differences also hamper the ability to determine
the relationship between the intake of specific foods and the
risk of chronic diseases. For example, the same compound
can be metabolized and absorbed differently in individuals
with different genetic backgrounds. Interindividual variation
of the gut microbiota adds another layer of complexity.
To better understand the beneficial health effects of whole
grains, biomarkers for their exposure and effects are needed.
The AVAs and avenacosides A and B are unique components
of oats. Therefore, these compounds and their metabolites
may be useful as markers of whole grain oat intake and in-
terindividual genetic differences.
PepsiCo, Inc. provided funding for the work. Y.C. is an em-
ployee of PepsiCo, Inc., which manufactures oatmeal products
under the brand name Quaker Oats R. The views expressed in
this article are those of the authors and do not necessarily reflect
the opinion or policies of PepsiCo, Inc.
The authors have declared no conflict of interest.
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