Chemistry and health beneficial effects of Oolong Tea and theasinensins

Abstract

Among six major types of tea (white, green, oolong, yellow, black, and dark teas) from Camellia sinensis, oolong tea, a semi-fermented tea, with its own unique aroma and taste, has become a popular consumption as indicated by the increasing production. Representing the characteristic flavonoids of oolong tea, theasinensins are dimeric flavan-3-ols. Many recent studies have indicated that oolong tea and theasinensins possess several health benefit properties. We consider it significant and necessary to have a comprehensive review in the recent advances of oolong tea. Therefore, the aim of the present review is to provide a new perspective on oolong tea and its characteristic phytochemicals, theasinensins associated with health benefits, molecular action pathway, and chemical mechanism of theasinensin formation from scientific evidences available on the literature. Furthermore, the chemical characterization of the oxidation products and the model oxidation system to the chemical changes of theasinensins are also discussed.

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HOSTED BY
Food
Science
and
Human
Wellness
4
(2015)
133–146
Chemistry
and
health
beneficial
effects
of
oolong
tea
and
theasinensins
Monthana
Weerawatanakorn
a
,
Wei-Lun
Hung
b
,
Min-Hsiung
Pan
c
,
Shiming
Li
b
,
Daxiang
Li
d
,
Xiaochun
Wan
d
,
Chi-Tang
Ho
b,∗
a
Department
of
Agro-Industry,
Faculty
of
Agriculture,
Natural
Resources
and
Environment,
Naresuan
University,
Phitsanulok
65000,
Thailand
b
Department
of
Food
Science,
Rutgers
University,
65
Dudley
Road,
New
Brunswick,
NJ
08901,
USA
c
Institute
of
Food
Science
and
Technology,
National
Taiwan
University,
Taipei
10617,
Taiwan,
China
d
State
Key
Laboratory
of
Tea
Plant
Biology
and
Utilization,
Anhui
Agricultural
University,
130
West
Changjiang
Rd.,
Hefei
230036,
Anhui,
China
Received
28
September
2015;
received
in
revised
form
15
October
2015;
accepted
25
October
2015
Abstract
Among
six
major
types
of
tea
(white,
green,
oolong,
yellow,
black,
and
dark
teas)
from
Camellia
sinensis,
oolong
tea,
a
semi-fermented
tea,
with
its
own
unique
aroma
and
taste,
has
become
a
popular
consumption
as
indicated
by
the
increasing
production.
Representing
the
characteristic
flavonoids
of
oolong
tea,
theasinensins
are
dimeric
flavan-3-ols.
Many
recent
studies
have
indicated
that
oolong
tea
and
theasinensins
possess
several
health
benefit
properties.
We
consider
it
significant
and
necessary
to
have
a
comprehensive
review
in
the
recent
advances
of
oolong
tea.
Therefore,
the
aim
of
the
present
review
is
to
provide
a
new
perspective
on
oolong
tea
and
its
characteristic
phytochemicals,
theasinensins
associated
with
health
benefits,
molecular
action
pathway,
and
chemical
mechanism
of
theasinensin
formation
from
scientific
evidences
available
on
the
literature.
Furthermore,
the
chemical
characterization
of
the
oxidation
products
and
the
model
oxidation
system
to
the
chemical
changes
of
theasinensins
are
also
discussed.
©
2015
Beijing
Academy
of
Food
Sciences.
Production
and
hosting
by
Elsevier
B.V.
All
rights
reserved.
Abbreviations:
AGH,
alpha-glucosidase;
Akt,
protein
kinase
B
(PKB);
ALPHA-TOH,
alpha-tocopherol;
AMPK,
5

adenosine
monophosphate-
activated
protein
kinase;
CaMKK,
Ca(2+)/calmodulin-dependent
protein
kinase;
COX-2,
cyclooxygenase-2;
EC,
(−)-epicatechin;
ECG,
(−)-epicatechin-3-
gallate;
EGC,
(−)-epigallocatechin;
EGCG,
(−)-epigallocatechin
3-O-gallate;
EGFR,
epidermal
growth
factor
receptor;
ERK,
extracellular
signal-
regulated
protein
kinases;
HSV,
herpes
simplex
virus;
iNOS,
inducible
nitric
oxide
synthase;
IL-12
(p70),
interleukin-12;
MAPK,
mitogen-activated
protein
kinases;
MCP-1,
monocyte
chemoattractant
protein-1;
MIC,
mini-
mum
inhibitory
concentration;
MMP-2,
matrix
metalloproteinase-2;
MNIC,
maximum
non-inhibitory
concentration;
MRSA,
methicillin-resistant
Staphy-
lococcus
aureus;
2-NBDG,
2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-
deoxyglucose;
NF-␬B,
nuclear
factor
kappa-light-chain-enhancer
of
activated
B
cells;
NO,
nitric
oxide;
P13K,
phosphoinositide
3-kinase;
PGE2,
prostaglandin
E2;
TR,
thearubigin;
TF,
theaflavin;
TAK1,
transforming
growth
factor
beta-
activated
kinase
1;
TNF-alpha,
tumor
necrosis
factor
alpha;
Sp1,
transcription
factor
(specificity
protein
1);
SGLT1,
sodium-dependent
glucose
cotransporters
(sodium-glucose
linked
transporter);
SOD,
superoxide
dismutase.
∗
Corresponding
author
at:
Department
of
Food
Science,
Rutgers
University,
65
Dudley
Road,
New
Brunswick,
NJ
08901,
USA.
Tel.:
+1
848
932
5553.
E-mail
address:
ho@aesop.rutgers.edu
(C.-T.
Ho).
Peer
review
under
responsibility
of
Beijing
Academy
of
Food
Sciences.
1.
Introduction
Generally,
functional
foods
may
be
classified
into
three
cate-
gories:
food
to
which
a
component
has
been
added,
food
in
which
a
component
has
been
modified
in
nature
and/or
bioavailability,
and
conventional
food
containing
naturally
occurring
bioactive
substance
[1].
For
the
later
class,
tea
from
Camellia
sinensis
is
one
of
the
most
important
functional
foods
and
has
held
the
sec-
ond
most
popular
beverage
in
consumption
among
all
beverages
except
water
worldwide.
Tea
contains
over
4,000
chemicals
and
some
of
which
have
health
promoting
properties
[2].
Based
on
different
degree
of
fermentation
during
tea
pro-
cess,
tea
can
be
simplistically
divided
into
three
major
types:
green
(unfermented)
tea
produced
from
fresh
tea
leaves
and
enzymatic
oxidation
is
inhibited
using
steaming
or
pan-frying;
oolong
(partially-fermented)
tea
made
by
wilting
fresh
leaves
by
sun,
then
slightly
bruising;
and
black
(fully
fermented)
tea
made
by
crushing
tea
leaves
to
release
the
polyphenol
oxidase
and
peroxidase
for
fully
catalyzing
the
enzymatic
oxidation
and
polymerization
of
original
tea
catechins
[3–6].
Many
potential
health
promotion
properties
associated
with
these
three
types
of
tea
consumption
have
been
reported
[7,8].
Comparing
with
http://dx.doi.org/10.1016/j.fshw.2015.10.002
2213-4530/©
2015
Beijing
Academy
of
Food
Sciences.
Production
and
hosting
by
Elsevier
B.V.
All
rights
reserved.

134
M.
Weerawatanakorn
et
al.
/
Food
Science
and
Human
Wellness
4
(2015)
133–146
Table
1
Different
fermented
tea
and
catechin
contents.
Types
of
tea Fermentation
Total
catechins
(%
w/w)
Pu-erh
tea
Microbial
fermentation
6.07
±
018
Iron
Buddha
tea Semi-fermentation
7.49
±
0.22
Oolong
tea Semi-fermentation
8.05
±
0.18
Jasmine
tea
Less
fermentation
(reprocessed
from
loose
green
tea
scented
with
fresh
Jasmine
flower)
12.72
±
0.70
Lung
Chen
tea
Less
fermentation
14.57
±
1.08
Adapted
and
modified
from
Sajilata
et
al.
[5].
green
tea
having
only
monomeric
catechins,
i.e.
(−)-epicatechin
(EC),
(−)-epicatechin-3-gallate
(ECG),
(−)-epigallocatechin
(EGC),
and
(−)-epigallocatechin-3-gallate
(EGCG),
fully
fer-
mented
black
tea
and
semi-fermented
oolong
tea
contain
a
mixture
of
catechins
and
their
oxidized
polymeric
substances
such
as
theaflavins
and
thearubigins
[9].
Comparison
of
cate-
chin
contents
in
different
fermented
and
semi-fermented
teas
is
illustrated
in
Table
1.
Theaflavins
(TFs)
and
thearubigins
(TRs),
main
secondary
polyphenols
formed
during
fermentation
pro-
cess
by
enzymatic
oxidation,
have
been
extensively
studied
on
bioactivities
and
formation
mechanism.
The
orange
red
or
brown
color
and
astringent
taste
of
black
tea
infusion
is
attributed
to
TFs
as
TRs
contribute
to
rusty
color
and
richness
taste
[4,10].
There
are
four
major
TFs
in
black
tea
and
oolong
tea,
that
is,
theaflavin
(TF1),
theaflavin-3-gallate
(TF2a),
theaflavin-3

-gallate
(TF2b),
and
theaflavin-3,3

-digallate
(TF3)
[6,11,12].
Chemical
struc-
tures
of
various
types
of
tea
catechins
and
theaflavins
are
shown
in
Fig.
1.
Among
three
types
of
tea,
black
tea
is
the
most
popular
tea
produced
and
consumed
preferentially
in
the
United
State,
England,
and
other
Western
countries
with
78%
of
global
mar-
ket,
followed
by
20%
of
green
tea
consumed
primarily
in
Asian
and
Northern
African
countries,
and
about
2%
of
oolong
tea
consumed
mainly
in
Taiwan,
southern
China,
and
most
Eastern
countries
[13,14].
It
has
been
noted
that
production
and
con-
sumption
of
oolong
tea
worldwide
have
increased
over
the
past
decades.
For
example,
the
production
of
oolong
tea
in
China
from
2000
to
2014
had
been
nearly
doubled
and
increased
from
67.6
×
10
3
to
254
×
10
3
metric
tons
[15].
Catechin
prior
to
oolong
tea
is
oxidized
in
the
range
of
10–80%
during
processing
depending
on
the
demand
of
customers
[9,16].
The
taste
qual-
ity
of
oolong
tea
depends
on
several
properties,
such
as
smell
of
volatile
fragrance,
taste
sensation
of
sweetness,
umami,
and
intensity
of
astringency.
The
differentiation
of
green
tea,
black
tea
and
oolong
tea,
regardless
of
degree
of
fermentation,
is
also
depended
on
their
contents
of
free
amino
acids,
mainly
L
-theanine
and
several
natural
amino
acids
including
glutamic
acid,
asparagine,
serine,
alanine,
leucine,
and
isoleucine
[17].
Major
contents
of
oolong
tea
infusion
are
listed
in
Table
2,
which
has
two
categories:
monomeric
polyphenols
and
poly-
meric
substances.
Oolong
tea
have
been
demonstrated
to
possess
various
pharmacological
activities
such
as
antioxidant
activity
Fig.
1.
Chemical
structure
of
tea
catechins
(EC,
ECG,
EGCG,
EGC),
theaflavins,
and
theasinensins
A–E.
Table
2
Components
of
oolong
tea
beverage.
Compounds
Contents
(mg/100
mL)
Catechin
1.65
Gallocatechin
6.68
Epigallocatechin
16.14
Epicatechin
5.08
Catechin
gallate
0.6
Epicatechin
gallate 5.73
Epigallocatechin
gallate
25.73
Allocatechin
gallate
1.85
Gallic
acid
2.19
Caffeine
23.51
Polymerized
33.65
Total
polyphenols
99.32
Sajilata
et
al.
[5].

M.
Weerawatanakorn
et
al.
/
Food
Science
and
Human
Wellness
4
(2015)
133–146
135
by
reducing
oxidative
stress,
anti-cancer,
anti-obesity,
anti-
diabetes,
preventive
effect
of
atherosclerosis,
heart
disease,
hypertension,
anti-allergic
effect,
and
antiseptic
effects
[18–27].
However,
all
of
the
studies
were
applied
to
oolong
tea
extract,
not
single
characteristic
oolong
tea
polyphenols.
Until
1984,
a
new
group
of
polymeric
oxidized
flavan-3-ols
was
isolated
and
identified
from
oolong
tea
as
theasinensins
A,
B,
C,
and
later
in
1988
for
D,
E,
F
and
G,
have
been
confirmed
from
oolong
tea
by
the
Japanese
scientists
Nonaka
and
Hashimoto
[28–33].
As
a
matter
of
fact,
this
group
of
compounds
was
formerly
discov-
ered
by
Robert
in
1958
[34,35]
and
was
known
as
bisflavanol
A,
B,
and
C,
which
were
formed
by
coupling
of
EGCG
[36].
Based
on
the
literatures
listed
above,
theasinensins
were
implied
as
the
bioactive
flavonoids
in
oolong
tea.
2.
Theasinensins
–
structure
and
occurrence
Theasinensins
are
formed
from
catechin
dimerization
at
their
B-rings,
i.e.
two
catechin
B-rings
are
connected
through
C
C
bonds
[35,37]
.
The
major
tea
polyphenol
components
found
in
black
and
oolong
teas
are
shown
in
Fig.
1.
The
configuration
of
theasinensins
A,
B,
and
C
differ
from
that
of
theasinensins
D
and
E
in
which
the
biphenyl
bonds
of
theasinensins
A,
B,
and
C,
carrying
a
R-biphenyl
configuration,
whereas
theasinensins
D,
and
E
embed
with
S-biphenyl
bonds.
Hashimoto
et
al.
[33]
also
concluded
that
theasinensins
D
and
E
were
characterized
as
the
atropisomers/stereoisomers
of
theasinensin
A
and
C,
respec-
tively.
Theasinensin
A
and
D
are
the
dimers
of
EGCG
with
an
R-
and
an
S-biphenyl
bond,
respectively
[37].
Theasinensin
B
is
the
dimer
of
EGCG
and
EGC
and
theasinensin
C
is
the
dimer
of
EGC
[38].
Theasinensins,
mainly
exist
in
black
tea
and
oolong
tea
[39],
are
transformed
from
the
unstable
intermediate
produced
by
the
oxidation
of
original
catechins
in
tea
leaves
[28–33].
Among
tea
catechins
found
in
fresh
tea
leaves,
EGCG
is
the
dominant
catechin
(63%)
followed
by
EGC
(25%)
[5,40,41].
Therefore,
oxidation
of
EGC
and
EGCG,
two
pyrogallol-type
catechins,
is
important
during
fermentation
process.
Many
studies
had
been
focused
on
the
oxidation
of
these
two
catechins
to
understand
the
formation
of
theasinensins.
Several
studies
have
been
designed
to
clarify
the
underlying
mechanisms
of
theasinensin
formation
in
the
fermentation
process
including
a
model
system
to
mimic
catechin
oxidation
[33,35,37,42,43].
3.
Proposed
formation
mechanism
of
theasinensin
via
gallocatechin
dimerization
Hashimoto
et
al.
[42]
indicated
that
tea
catechins
are
easily
transformed
to
theasinensins
by
endogeneous
polyphenol
oxi-
dase
than
to
theaflavins
which
are
the
characteristic
flavonoids
in
black
tea.
This
finding
has
unequivocally
confirmed
that
theasi-
nensin
production
involved
in
the
enzymatic
oxidative
coupling
of
two
pyrogallol
rings
of
EGCG.
The
pyrogallol
rings
are
also
susceptible
to
be
oxidized
by
chemical
agents
[44].
There
are
different
pathways
toward
the
formation
of
theasinensins
and
theaflavins.
The
benzotropolone
core
of
TFs
is
formed
from
an
oxidative
condensation
reaction
between
a
catechol
moiety
of
EC
or
ECG
and
a
pyrogallol
moiety
of
EGC
or
EGCG
[42],
whereas
theasinensin
carrying
a
R-biphenyl
bond
is
generated
by
a
pyrogallol-type
B
rings
of
EGCG
and
EGC.
Once
the
fresh
tea
leaves
are
crushed
and
kneaded,
TFs
are
formed
in
the
leaves,
but
theasinensins
are
not
detected
in
this
step
[28,33].
The
formation
of
theasinensins
is
observed
in
heat-
ing
the
leaves
to
80
◦
C
[28,33,35].
Several
researches
who
tried
to
investigate
theasinensin
formation
pathway
initially
focused
on
characterizing
the
intermediates
and
later
known
that
they
were
heat
and
chemical
susceptible
intermediates.
The
struc-
ture
elucidation
from
derivatization
of
the
unstable
intermediates
has
concluded
that
they
are
quinone
dimers
of
EGC
and
EGCG
produced
by
these
two
catechin
quinone
monomers.
To
date,
one
of
the
intermediates
has
been
successfully
synthesized
by
an
enzymatic
oxidation
of
EGCG
and
named
dehydrotheasi-
nensin
A
with
a
pale
yellow
color
[37,43].
In
the
heating
and
drying
process
of
the
tea
leaves
at
the
final
stage
of
black
and
oolong
tea
manufacturing,
dehydrotheasinensin
A
undergoes
redox
dismutation
to
generate
theasinensin
A
and
its
atropisomer
[37,43].
The
production
of
unstable
dehydrotheasinensins
from
the
oxidation
of
pyrogallol-type
B-ring
catechins
is
the
most
important
reaction
in
theasinensin
formation.
Takana
et
al.
[38]
have
utilized
an
in
vitro
experiment
to
investigate
the
chemical
mechanism
of
theasinensin
formation
and
the
proposed
pathway
is
also
given
in
Fig.
2.
More
than
a
decade
ago,
the
oxidized
EGCG
and
EGC
as
theasinensin
quinones
were
trapped
for
the
first
time
with
o-phenylenediamine,
yielding
five
phenazine
derivatives
of
cat-
echin
dimer
quinones
[35].
The
result
was
also
the
first
evidence
supporting
the
formation
and
accumulation
of
catechin
dimer
quinones
in
tea
fermentation
process
and
proving
that
the
formation
mechanism
of
theasinensin
A
is
not
simply
pro-
duced
by
enzymatic
oxidation
of
EGCG,
the
main
catechin
in
fresh
tea
leaves.
These
theasinensin
quinones
are
unstable
and
decomposed
readily
in
particular
the
process
of
extract
solu-
tion
concentration
by
rotary
evaporator
[35].
Later,
Tanaka’s
team
also
suggested
that
the
addition
of
0.1%
trifluoroacetic
acid
(TFA)
in
the
mobile
phase
increased
the
stability
of
theasinensin
quinones
[37].
Tanaka
and
his
team
were
also
focused
on
the
chemical
examination
of
theasinensin
production
using
in
vitro
experi-
ments
to
mimic
black
tea
production
process
in
particular
on
the
fermentation
step.
EGCG
and
enzymes
from
homogeneous
pear
were
applied
at
room
temperature
for
2
h.
The
study
elu-
cidated
the
structure
of
dehydrotheasinensin
A
and
mechanism
of
theasinensin
formation,
and
successfully
obtained
dehydroth-
easinensin
A,
a
theasinensin
precursor
from
enzymatic
oxidation
of
EGCG.
The
results
also
revealed
that
dehydrotheasinensin
A
produced
from
coupling
of
EGCG
quinone
monomers
is
equiva-
lent
to
a
hydrated
ortho-quinone
of
the
theasinensin
A,
which
is
readily
converted
to
theasinensin
A
and
D
by
oxidation
reduc-
tion
dismutation.
Previous
studies
from
Takana
et
al.
[35,37]
suggested
that
several
chemical
reactions
involved
in
EGCG
oxidation
subsequently
produced
theasinensins
(A
and
D).
EGCG
was
initially
oxidized
to
the
ortho-quinone,
and
sub-
sequently
an
unstable
dimer,
theasinensin
quinone
was
formed
after
stereoselective
dimerization
(Fig.
2).
This
unique
quinone

136
M.
Weerawatanakorn
et
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/
Food
Science
and
Human
Wellness
4
(2015)
133–146
Fig.
2.
Possible
formation
mechanism
of
theasinensin.
was
equivalent
to
dehydrotheasinensin
A,
generated
by
both
enzymatic
and
non-enzymatic
reaction
[28,33,35,37,43,45,46].
To
further
understand
the
chemical
mechanism
of
theasinensin
formation,
many
studies
had
concentrated
on
the
enzymatic
oxi-
dation
of
catechins
such
as
EGCG
oxidation.
However,
several
studies
also
focused
on
the
non-enzymatic
oxidation
of
cate-
chins.
The
non-enzymatic
oxidation
of
EGCG
providing
theasi-
nensin
quinones
can
be
developed
from
not
only
chemical
oxidation
with
either
potassium
ferricyanide
or
copper
salts,
but
also
autoxidation
in
a
phosphate
buffer
(pH
7.4
or
6.8)
in
which
the
oxidized
product
is
unstable
even
at
a
neutral
pH
[37].
Therefore,
it
can
be
implied
that
the
production
of
theasinensin
A
and
D
derived
from
dehydrotheasinensin
A
during
black
tea
and
oolong
tea
manufacturing
may
possi-
bly
be
a
non-enzymatic
process
which
occurs
spontaneously
when
tea
leaves
are
heated
and
dried.
Shii
further
showed
that
non-enzymatic
oxidation
of
EGCG
by
copper
salts
with
the
optimum
pH
of
4–5
at
room
temperature
yielded
dehy-
drotheasinensin
A
and
the
product
increased
with
the
elevated
temperature
[43].
Initial
oxidation
reaction
was
carried
out
at
room
temperature
and
elevated
temperature
increased
byprod-
uct
generation.
The
difference
between
enzymatic
oxidation
in
tea
leaves
and
in
vitro
chemical
oxidation
by
copper
salt
is
that
catechol-type
catechins
prefer
to
enzyme
catalyzed
oxida-
tion,
such
as
EC
and
ECG,
whereas
pyrogallol-type
catechins,
such
as
EGC
and
EGCG,
are
less
reactive
[43,45].
By
enzy-
matic
oxidation
(banana
homogenate)
of
catechin,
EGC
was
oxidized
to
the
corresponding
catechin
quinone
but
the
reac-
tion
was
accelerated
in
presence
of
ECG.
The
oxidation
of
ECG
was
much
faster
than
EGC
due
to
its
higher
redox
potential
than
pyrogallol-type
catechin
(EGCG,
EGC)
[35,43].
Technically,
the
catechol-type
catechins
were
not
chemically
oxidized
by
cup-
per
salt.
Therefore,
the
chemical
oxidation
of
catechins
does
not
yield
theaflavins
which
are
generated
from
the
oxidative
couplings
between
the
quinones
produced
from
catechol-type
and
pyrogallol-type
catechins
[47–49].
Enzymatic
oxidation
of
EGC
generates
a
new
quinone
dimer
with
a
hydrated
cyclohexenetrione
structure,
which
may
be
equivalent
to
dehydrotheasinensin
C
whereas
theasinensins
C
and
E
were
produced
through
oxidation–reduction
dismutation
[39].
In
addition,
the
enzymes
isolated
from
pear
homogenates
catalyzed
the
oxidation
of
EGC
at
the
pyrogallol
B-ring,
yielding
predominantly
unstable
quinone
products
known
as
dehydrotheasinensin
C
trapped
with
o-phenylenediamine
[45].
Non-enzymatic
coupling
reaction
of
dehydrotheasinensin
C
was
subsequently
occurred
to
give
theasinensins
A
and
C
[37,38,45,46].
From
commercial
back
tea,
an
interesting
derivative
of
theasi-
nensin,
N-ethylpyrrolidinonyl
theasinensin
has
been
isolated
and
identified
[44,50].
Tea
leaves
contain
an
amino
acid
named
L-theanine
(N
5
-ethy-L-glutamine)
accounting
for
over
50%
of
the
total
amino
acids.
Consequently,
the
catechin
quinones
gen-
erated
from
the
beginning
of
tea
process
maybe
react
with
L-theanine
to
generate
theanine
Strecker
aldehyde
[51,52]
as
demonstrated
in
Fig.
3.
The
Strecker
aldehyde
of
theanine
subse-
quently
reacts
with
theasinensin
to
yield
N-ethylpyrrolidinonyl
theasinensin.
In
addition,
the
reduction
of
dehydrotheasinensin
A
to
yield
theasinensin
derived
from
several
paths.
The
formation
of
theasi-
nensins
through
several
chemical
reactions
was
involved
in
EGCG
oxidation
[35,37,43]
.
Dehydrotheasinensin
A
could
be
reduced
by
the
reductants
such
as
ascorbic
acid
or
sulfur
contain-
ing
compounds
at
room
temperature
and
subsequently
forming
theasinensin
A
[37].
It
is
also
known
that
reduction
of
dehydroth-
easinensin
A
with
2-mercaptoethanol
afforded
theasinensin
A
only.
Stereoselective
formation
of
dehydrotheasinensin
A
from
EGCG
created
a
chiral
center
at
the
benzylic
position
of
the
pyro-
gallol
ring
[46,53].
Unstable
dehydrotheasinensin
A
was
rapidly
degraded
by
heating
alone
or
heating
with
ascorbic
acid,
higher

M.
Weerawatanakorn
et
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/
Food
Science
and
Human
Wellness
4
(2015)
133–146
137
Fig.
3.
Proposed
route
for
the
formation
of
N-ethylpyrrolidinonyl
theasinensin
A
[44,50].
pH,
and
theasinensin
A
subsequently
was
formed
[37,43].
Even
so,
the
reducing
agent
such
as
2-mercaptoethanol
had
lower
yield
of
theasinensin
A
compared
to
ascorbic
acid
[43].
On
the
other
hand,
the
reduction
of
dehydrotheasinensin
A
occurred
at
80
◦
C
and
thermodynamically
underwent
the
oxidation–reduction
dis-
mutation
to
yield
theasinensin
A.
Theasinensin
D
also
was
produced
as
it
is
probably
isomerized
at
an
elevated
temperature
during
heating
and
drying
in
black
tea
manufacturing.
Further-
more,
theasinensin
quinones
were
gradually
decomposed
to
a
mixture
of
theasinensin
A
and
D
in
a
pH
6.8
phosphate
buffer
at
20
◦
C
[37].
Taken
together,
it
is
clear
that
the
products
from
enzymatic
oxidation
of
tea
catechins
both
in
oolong
and
black
tea
process
can
be
classified
into
two
major
oxidation
routes
[4,35,38,42,46]:
the
condensation
with
coexisting
epicatechin
forming
theaflavins
[47,48]
and
oxidative
dimerization
of
two
gallo
moiety
and
reduction
yielding
epigallocatechin
dimers,
such
as
theasinensins
and
oolongtheanins
[28,33].
4.
Potential
bioactive
compounds
Evidence
from
experimental
and
clinical
studies
has
indi-
cated
that
tea
exerts
antioxidative,
anti-inflammatory,
cancer
prevention
and
vasodilating
effects
among
others
[54].
Epi-
demiological
studies,
both
in
vitro
and
in
vivo,
have
indicated
that
tea
consumption
is
positively
associated
with
reduced
risk
of
chronic
diseases,
causing
60%
global
death
such
as
coro-
nary
heart
disease,
stroke
and
cancer
[54–58].
One
of
the
health
benefits
of
tea
polyphenols
is
generally
attributed
to
its
potent
antioxidant
property.
Act
as
free
radical
scavengers,
tea
polyphenols
may
remove
endogenously
superoxide,
per-
oxyl,
and
hydroxyl
radicals
[22,59,60].
Tea
polyphenols
and
their
metabolites
also
possess
antibacterial
properties
against
pathogenic
bacteria
such
as
Clostridium
perfringen,
Clostridium
difficile,
Escherichia
Coli,
Salmonella,
and
Pseudomonas
and
enhance
probiotics
such
as
Bifidobacterium
and
Lactobacillus
species,
which
improve
the
intestinal
microbial
balance
[61,62].
The
study
on
bioactivities
of
oolong
tea
and
its
characteristic
compounds,
theasinesins
on
health
promotion
property
in
the
literature
is
still
limited
compared
to
that
of
black
and
green
teas.
Several
studies
have
revealed
that
oolong
tea
and
theasi-
nensins
have
biological
activities
such
as
antioxidative
effects
against
lipid
peroxidation,
anti-inflammatory
activity,
antibacte-
rial
properties
and
anti-obesity.
Herein,
we
summarize
the
health
benefits
of
oolong
tea
and
theasinensins
in
Tables
3
and
4.
4.1.
Antioxidant
activities
of
oolong
tea
and
theasinensins
The
FRAP
(ferric
reducing/antioxidant
power)
assay
has
tested
that
antioxidant
value
of
oolong
tea
ranged
between
233
and
532
␮mol/g
[63].
In
an
in
vivo
study,
modest
tran-
sient
increase
in
human
plasma
antioxidant
capacity
was
noticed
upon
oolong
tea
consumption
[22].
It
is
observed
that
oolong
tea
reduced
oxidative
stress,
especially
oxidative
DNA
damage
[22].
Furthermore,
human
studies
on
athletes
showed
that
oolong
tea
ingestion
significantly
reduced
plasma
malondialdehyde
lev-
els
in
rest
and
post-exhaustive
exercise
athletes,
as
well
as

138
M.
Weerawatanakorn
et
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/
Food
Science
and
Human
Wellness
4
(2015)
133–146
Table
3
Health
benefits
and
proposed
molecular
mechanisms
of
theasinensins.
Bioactivity Experimental
model
Compound
tested/control
Mechanism/biomarker
Ref.
In
vitro In
vivo
Antioxidant
activity
Ferric
thiocyanate
assay
Theasinensins
A–E/alpha-tocopherol
Decreasing
lipid
peroxidation
[64]
Anti-
inflammation
LPS-activated
murine
macrophage
RAW264.7
cells
Theasinensins
A–E Reducing
gene
expression
of
cyclooxygenase-2
(COX-2)
and
PGE
2
[68]
LPS-activated
murine
macrophage
RAW264.7
cells
(a
genome-wide
microarray)
Theasinensin
A
22,050
genes
of
inflammatory
and
immune
response
[69]
LPS-activated
murine
macrophage
RAW264.7
Mouse
paw
edema
model
Theasinensin
A
Reducing
the
production
of
NO/iNOS,
IL-12
(p70),
TNF-␣,
and
MCP-1
[70]
Anti-cancer
Human
fibrosarcoma
HT1080
cells
Theasinensin
D
Suppressing
invasion
by
reducing
Gelatinase/Type
IV
Collagenases
(MMP-2
and
-9)
activities
[84]
Human
histolytic
lymphoma
(U937)
cell
line
and
acute
T
cell
leukemia
(Jurkat)
cell
line
Theasinensin
A
Inducing
DNA
fragmentation,
and
caspase
activation
[85]
Hypoglycemic
effect
KKAy
mice
and
Sprague-Dawley
rats
Theasinensin
A
Regulation
of
serum
glucose,
lipid
serum,
hepatic
fatty
acid
synthase
activity
[9]
Rat
skeletal
muscle
cells
Theasinensin
A
and
B
Increasing
glucose
uptake
[90]
Alpha-glucosidase
from
rat
intestinal
acetone
powder
Catechin,
theaflavin,
theasinensin
A
Increasing
alpha-glucosidase
(AGH)
inhibitory
activity
[89]
Anti-microbial
effect
MRSA
(strains
OM48,
505,584,
and
623)
Theasinensin
A
and
EGCG
Increasing
antibiotic
resistance
[103]
HSV-1
and
HSV-2
Theasinensin
A,
theaflavin,
and
EGCG
Enhancing
protein
aggregation
[108]
NBDG;
2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxyglucose:
herpes
simplex
virus
(HSV)
MRSA;
methicillin-resistant
Staphylococcus
aureus.
resting
levels
of
superoxide
dismutase
activity,
suggesting
that
the
decrease
of
oxidative
stress
is
resulted
from
reduction
of
the
lipid
peroxidation
level
and
its
free
radical
scavenging
activity
[25].
Hashimoto
reported
that
the
antioxidant
activ-
ity
evaluated
by
the
5-day
lipid
peroxidation
of
theasinensins
A–E
were
ranged
from
9
to
13%
compared
to
3
and
17%
for
BHA
and
alpha-tocopherol,
respectively.
The
result
suggests
that
the
inhibitory
activity
on
lipid
oxidation
of
theasinensins
A–E
were
lower
than
BHA
(the
synthetic
antioxidant),
but
higher
than
alpha-tocopherol
[64].
Among
theasinensin
isomers,
theasinensin
C
has
the
highest
ability
against
lipid
oxidation
inhibition.
Until
now,
there
is
no
data
reported
concerning
on
bio-antioxidative
effect
of
oolong
tea
or
theasinensin
on
the
antioxidant
defense
systems.
4.2.
Anti-inflammatory
effect
Previous
studies
have
indicated
that
ethanol
extract
of
oolong
tea
was
profoundly
increased
adiponectin
gene
expression
in
epididymal
fat,
consistent
with
an
anti-inflammatory
effect,
and
angiogenesis
during
adipose
tissue
expansion
[65].
The
increase
of
blood
vessel
formation
in
adipose
tissue
contributes
to
their
anti-inflammatory
effects
by
maintaining
adipocyte
perfusion
[65]
.
This
finding
is
consistent
with
the
pro-angiogenic
activity
of
oolong
tea
ethanol
extract
during
adipose
tissue
expansion
mediating
protective
effects
on
metabolism
and
inflammation,
although
this
finding
is
in
contrast
to
the
traditional
concept
that
inhibition
of
angiogenesis
results
in
weight
loss
[65,66].
In
addition,
ethanol
extract
of
oolong
tea
decreased
the
con-
centration
of
monocyte
chemoattractant
protein-1
(MCP-1)
in
serum.
The
reduction
of
plasma
MCP-1
also
explains
the
anti-
inflammatory
effect
of
oolong
tea
polyphenol
since
MCP-1
is
a
small
cytokine
recruiting
monocytes,
memory
T
cells,
and
dendritic
cells
to
the
site
of
injury
[67].
The
anti-inflammatory
activity
of
oolong
tea
might
be
due
to
flavonoids
such
as
cate-
chins,
theaflavins
and
theasinensins
[68].
There
are
some
reports
on
the
anti-inflammatory
properties
of
theasinensins.
Results
from
the
first
molecular
basis
of
the
anti-inflammatory
proper-
ties
of
oolong
tea
theasinensins
showed
that
theasinensin
A
and
D
exhibited
better
activities
in
reducing
LSP-stimulated
COX-2
and
PGE
2
production
than
theasinensins
B,
C
and
E.
Structure
analysis
of
theasinensins
A
and
D
with
two
galloyl
moieties
and
theasinensins
C
and
E
without
galloyl
moieties,
showed
that
the
galloyl
moiety
played
an
important
role
on
anti-inflammatory
effects
of
oolong
tea
theasinensins.
Molecular
mechanisms
of
anti-inflammatory
property
of
oolong
tea
theasinensins
demon-
strated
that
the
down-regulation
of
TAK1-mediated
NF-␬B
and
MAPK
signaling
pathway
might
be
involved
in
the
inhibition
of
COX-2
expression
by
theasinensin
A
[68].
Recently,
in
clari-
fying
the
molecular
mechanism
of
anti-inflammatory
effects
of

M.
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/
Food
Science
and
Human
Wellness
4
(2015)
133–146
139
Table
4
Health
benefits
of
oolong
tea.
Bioactivity
Experiment
model
Compound
tested/control
Mechanism/biomarker
Ref.
In
vitro
In
vivo
Antioxidant
activity
Lipoxygenase
inhibition
activity
Fraction
compound
from
oolong
tea
[114]
FRAP
assay Tea
infusion
(green,
oolong
and
black
tea)
Antioxidant
power [63]
Human
plasma
Consumption
oolong
tea
infusion
Reducing
oxidative
DNA
damage
[22]
Athletes
before
and
after
exhaustive
exercise
Daily
consumption
of
oolong
infusion
for
30
days
Normalizing
the
cholesterol
profiles,
reducing
lipid
peroxidation
level,
and
superoxide
dismutase
activity
[25]
Anti-inflammation
Mice
Crude
ethanol
extract
of
oolong
tea
Reducing
MCP-1
plasma
concentration
[65]
Anti-obesity
Mice
Crude
ethanol
extract
of
oolong
tea
Reducing
MCP-1
gene
expression
[65]
High-fat
diet-induced
obese
mice
Oolong
tea
Fat
cells
and
a
cell-free
system
consisting
of
lipid
droplets
and
hormone-sensitive
lipase
[72]
Rats
Oolong,
black,
pu-erh,
and
green
teas
leaves
Reducing
plasma
lipid
Increasing
plasma
enzyme
SOD
Weight
ratios
of
liver
to
epididylmal
adipose
tissue
[74]
Fifty-four
polyphenols
isolated
from
tea
leaves
Oolonghomobisflavans
A
and
B
Elevating
pancreatic
lipase
activity
[73]
Anti-cancer
Salmonella/microsome
reverse
mutation
assay
(Salmonella
typhimurium
TA98
and
TA100)
Tea
water
extract
(green,
oolong,
pouchong,
and
black
teas)
Anti-mutagenicity
[19]
Salmonella/microsome
reverse
mutation
assay
(Salmonella
typhimurium
TA98
and
TA100)
Tea
water
extracts
(green,
pouchong,
oolong
and
black
tea)
Anti-mutagenicity
[79]
Male
F344
rats
induced
by
diethylnitrosamine
(rat
model
is
in
vivo
study)
Tea
extract
(black
and
oolong
tea/tea
catechins)
Suppressing
hepatocarcinogenesis
[19]
Salmonella/microsome
reverse
mutation
assay
(Salmonella
typhimuriumTA100,
TA98
and
TA97)
Tea
water
extracts
(green,
pouchong,
oolong
and
black
tea/EGCG,
gallic
acid
and
caffeine)
Anti-mutagenic
activities
[78]
AH109A
rat
ascites
hepatoma
cell
line
Tea
water
extracts
(green,
oolong
and
black
tea/catechin,
theaflavins)
Preventing
proliferation
and
invasion
of
AH109A
cells
[21]
Male
Donryu
rats
Tea
water
extracts
(green,
oolong
and
black
tea/catechin,
theaflavins)
Inducing
apoptosis,
and
cell
cycle
arrest
[81]
Human
stomach
cancer
KATO
III
cells
Oolong
tea
extract
Apoptosis
by
fragmentation
of
DNA
to
oligonucleosomal
sized
fragments
[82]
Salmonella/microsome
reverse
mutation
assay
(Salmonella
typhimurium
TA1535/pSK
1002)
Tea
methanol
extract
(green,
pouchong,
oolong
and
black
tea)
Anti-genotoxic
abilities
(suppressive
effects
against
umu
gene
expression)
[80]
Hypoglycemic
effect
Adult
female
frogs
(Xenopus
laeVis)
Tea
extract
by
hot
normal
frog
Ringer
Solution
(green,
oolong,
and
black
tea)
Inhibition
of
SGLT1
Response
[86]
Rat
epididymal
adipocytes
Tea
infusion
(green,
oolong,
and
black
tea)
Enhancing
insulin-activity
[87]

140
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/
Food
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and
Human
Wellness
4
(2015)
133–146
Table
4
(Continued)
Bioactivity
Experiment
model
Compound
tested/control
Mechanism/biomarker
Ref.
In
vitro
In
vivo
10
men
and
10
women
(average
age
61.2
years,
duration
of
diabetes
4.8
years)
1500
ml
of
oolong
tea
per
day
(tea
bags)
for
10
weeks
Decreasing
plasma
glucose
and
fructosamine
[88]
Prevention
of
Heart
Disease
Male
Sprague-Dawley
rats
Tea
solutions
for
9
weeks
(green,
Jasmine,
Iron
Buddha,
oolong
and
Pu
erh
tea)
Decreasing
serum
and
liver
lipids
[101]
12
healthy
men
Water
plus
caffeine
and
oolong
tea
Increasing
EE
and
fat
oxidation
[100]
12
patients
with
previous
myocardial
infarction
and
10
patients
with
stable
angina
pectoris
Medication
during
their
additional
oolong
tea
for
1
month
Decreasing
plasma
adiponectin,
glucose
and
hemoglobin
A1c
levels
[97]
12
healthy
university
students,
3
males
and
9
females
The
polymerized-polyphenol
extract
from
oolong
tea
as
beverage
for
10
days
Increasing
fecal
lipid
excretion
[98]
12
healthy
Japanese
females Oolong
tea
and
green
tea Increasing
energy
expenditure
and
resting
energy
expenditure
[99]
711
men
and
796
women
without
hypertensive
history
Epidemiology
study
(tea
consumption)
Anti-hypertension
[94]
Anti-microbial
effect
Streptococcus
sobrinus
6715
Oolong
tea
extract
and
its
polymeric
polyphenols
Inhibition
of
GTase
[105]
Pathogen
Aqueous
tea
extract
(green
and
oolong
tea)
catechin,
theasinensin
A,
theaflavin
Increasing
MNIC
and
MIC
[20]
Bacillus
subtilis,
Escherichia
coli,
Proteus
vulgaris,
Pseudomonas
fluorescens,
Salmonella
sp.
and
Staphylococcus
aureus
Dry
tea
extract
(green,
oolong,
and
black
tea)
Decrease
of
growth
and
survival
[104]
S.
mutans
MT8148R
and
Streptococcus
sobrinus
6715
Methanol
extract
of
oolong
tea
Antibacterial
activity
[106]
Superoxide
dismutase
(SOD);
minimum
inhibitory
concentration
(MIC);
maximum
non-inhibitory
concentration
(MNIC);
energy
expenditure
(EE);
glucosyl
transferase
(GTase).
theasinensin
A,
gene
expression
profiling
in
macrophage-like
cells
treated
with
theasinensin
A
through
a
genome-wide
DNA
microarray
were
used
to
detect
the
changes
of
22,050
genes
involving
inflammatory
and
immune
response.
The
changes
of
1382
genes
suggested
that
theasinensin
A
has
exerted
anti-
inflammatory
effects
by
regulating
the
relevant
expression
networks
of
chemokines,
interleukins,
and
interferons
[69].
Recently,
an
in
vitro
study
on
anti-inflammatory
activity
of
theasinensin
A
by
LPS-activated
macrophages
indicated
that
the
levels
of
pro-inflammatory
mediators
including
inducible
nitric
oxide
synthase
(iNOS),
nitric
oxide
(NO),
interleukin-12
(IL-12)
(p70),
tumor
necrosis
factor
alpha
(TNF-␣),
and
MCP-1
were
significantly
reduced
by
theasinensin
A.
Cellular
signaling
pathway
of
this
study
uncovers
that
theasinensin
A
downregu-
lated
MAPK/ERK
kinase
(MEK)-extracellular
signal-regulated
kinase
(ERK)
signaling
through
directly
binding
to
MEK-ERK
for
the
inhibitory
action.
The
in
vivo
study
also
demonstrates
that
the
theasinensin
A
suppressed
the
production
of
IL-12
(p70),
TNF-␣,
and
MCP-1
and
attenuated
mouse
paw
edema
induced
by
LPS
[70].
4.3.
Anti-obesity
Nowadays
obesity
has
emerged
as
a
major
health
concerning
problem
and
a
risk
factor
of
metabolic
disorders.
Functional
foods
affecting
energy
metabolism
and
fat
partitioning
may
be
helpful
adjuncts
to
a
dietary
approach
to
weight
control.
The
mechanism
of
anti-obesity
effects
of
tea
catechins,
espe-
cially
EGCG
and
theaflavins,
appear
to
be
related
to
modulation
of
energy
balance,
endocrine
systems,
food
intake,
lipid
and
carbohydrate
metabolism,
and
activities
of
different
cell
types
including
fat,
liver,
muscle
and
␤-pancreatic
cells
[7,27].
Tea
catechins
inhibit
lipogenesis
through
down-regulation
of
gene
expression
of
fatty
acid
syntheses
in
the
nucleus,
resulting
in
the
down-regulation
of
EGFR/P13K/Akt/Sp1
signal
transduc-
tion
pathways,
and
stimulation
of
cell
energy
expenditure
in
the
mitochondria
[27,69].
One
of
the
mechanisms
on
fat
reduc-
tion
by
oolong
tea
is
the
inhibition
of
pancreatic
lipase
activity.
A
mouse
study
suggested
that
inhibition
of
digestive
lipase
activity
can
significantly
affect
dietary
lipid
absorption
and
increase
lipid
excretion
into
the
feces
[71].
Another
study
was

M.
Weerawatanakorn
et
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/
Food
Science
and
Human
Wellness
4
(2015)
133–146
141
also
demonstrated
that
the
oolong
tea
water
extract
enhanced
noradrenaline-induced
lipolysis
and
inhibited
pancreatic
lipase
activity,
resulting
in
anti-obesity
effects.
This
might
be
par-
tially
due
to
the
effects
of
caffeine
or
some
other
bioactive
compounds
in
oolong
tea
[72].
The
homobisflavans
A
and
B,
typical
compounds
in
oolong
tea,
exhibit
more
potent
inhibitory
activities
against
pancreatic
lipase
with
IC50
values
of
0.048,
and
0.108
␮mol/L,
respectively,
than
EGCG
with
IC
50
val-
ues
of
0.349
␮mol/L.
The
data
hinted
that
galloyl
moieties
in
the
molecule
were
crucial
for
pancreatic
lipase
inhibition
[73].
Supplementation
with
oolong
tea
leaves
reduced
body
weights
and
plasma
triacylglycerol,
cholesterol
and
LDL-cholesterol
of
rats.
Pu-erh
tea
and
oolong
tea
can
significantly
decrease
the
levels
of
triacylglycerol
more
significantly
than
green
tea
and
black
tea.
In
addition,
superoxide
dismutase
activity
(SOD)
was
increased
and
the
relative
weight
ratios
of
liver
to
epi-
didylmal
adipose
tissue
reduced
by
oolong
tea.
This
study
also
suggested
that
oolong
tea
was
more
effective
on
their
growth
suppressive
and
hypolipidemic
effects
as
compared
to
green
tea
[74]
.
Scientific
evidence
has
revealed
the
role
of
MCP-1
gene
expression
in
the
etiologies
of
obesity-
and
diabetes-related
diseases
[75].
Plasma
concentration
of
MCP-1
is
positively
asso-
ciated
with
obesity
[67].
A
recent
study
shows
that
the
ethanol
extract
of
oolong
tea
polyphenol
caused
weight
loss
in
mice
fed
with
an
high-fat
diet,
and
decreased
plasma
MCP-1
protein
as
well
as
its
gene
expression
in
mesenteric
fat
and
epididymal
fat
[65].
4.4.
Anti-cancer
Among
the
biological
activities
of
tea
polyphenols,
the
cancer-chemopreventive
effects
in
various
animal
models
have
been
intensively
investigated
[76].
Many
studies
have
reported
that
the
anti-cancer
effect
of
oolong
tea
mostly
focused
on
catechins.
However,
some
studies
paid
much
attention
to
eval-
uate
the
anti-cancer
effects
of
theasinensins.
It
is
well
known
that
inflammation
plays
a
key
role
in
the
initiation
and/or
pro-
gression
of
multiple
types
of
cancers,
including
liver,
bladder
and
gastric
cancers
by
inducing
oxidative
stress
and
promot-
ing
cell
growth
[77].
As
mentioned
above,
oolong
tea
extract
exhibits
a
higher
anti-inflammatory
activity
than
green
tea
and
black
tea
extracts
[65].
The
anti-cancer
activity
of
oolong
tea
may
be
originated
from
its
antioxidant
and
anti-inflammatory
activities.
The
mutagenic
effects
of
carcinogens
such
as
heterocyclic
amines
are
reduced
by
oolong
tea
extracts.
In
Salmonella
reverse
mutation
assay
(Ames
test),
Yen
and
Chen
[18]
indicated
that
the
greater
anti-mutagenic
effect
was
found
in
oolong
tea
than
in
green
tea
and
black
tea
and
some
anti-mutagenic
substances
might
be
formed
during
manufacturing
processes
of
tea.
Ames
test
with
bacterium
Salmonella
typhimurium
has
confirmed
anti-
mutagenic
activities
of
EGCG,
GC,
and
caffeine
from
green
tea
[78].
Furthermore,
oolong
tea
extract
remarkably
inhibited
the
mutagenicity
of
2-amino-3-methylimidazo(4,5-f)quinoline
(IQ),
3-amino-l,4-dimethyl-5/H-pyrido-(4,3-b)indole
(Trp-P-
1),
2-amino-6-methyl-dipyrido(l,2-a:3

,2

-d)imidazole
(Glu-P-
1),
benzo[a]pyrene
(B[a]P)
and
aflatoxin
B,
(AFB,)
and
the
inhibitory
effect
was
associated
with
the
contents
of
cate-
chins
and
ascorbic
acid
[79]
.
Oolong
tea
extract
possessed
the
highest
anti-mutagenic
activity
against
several
mutagens,
including
four
nitroarenes,
two
nitro
compounds
and
one
alkylating
agent
(1-nitropyrene
(1-NP),
2-nitropyrene
(2-NF),
3-nitropyrene
(3-NF)
and
2,4-dinitrophenol
(DNP)
among
the
different
teas
[79].
In
addition,
oolong
tea
extracts
have
a
chemopreventive
action
against
hepatocarcinogenesis.
Different
concentrations
of
oolong
tea
extract
(0.05
or
0.1%)
signifi-
cantly
decreased
the
number
and
area
of
diethylnitrosamine-
and
phenobarbital-induced
preneoplastic
glutathione
S-transferase
placental
form-positive
foci
in
the
liver
of
rats
[19].
Oolong
tea
extracts
also
inhibited
the
formation
of
reactive
oxygen
species
(ROS)
and
induced
cytochromes
P450
1A1,
1A2,
and
2B1,
and
glucuronosyl
transferase,
leading
to
glucuronide,
which
is
an
important
mechanism
in
biological
detoxification
system
[76].
Therefore,
one
of
the
anti-carcinogenetic
mecha-
nisms
of
oolong
tea
may
be
involved
in
regulation
of
catalytic
activities
of
the
P450
enzymes
and
glucuronosyl
transferase
[7,76].
Besides
the
anti-inflammatory
effects,
anti-genotoxic
and
anti-mutagenic
properties
of
oolong
tea
also
contribute
to
its
chemopreventive
effect.
Zhang
et
al.
[21,81]
suggested
that
the
chemopreventive
mechanism
of
oolong
tea
might
be
attributed
to
its
bioactivities
against
the
invasion
and
proliferation
of
can-
cer
cells
(AH109A)
through
the
loss
of
cell
viability,
apoptosis,
and
cell
cycle
arrest
at
the
G1
phase
in
a
rat
hepatoma
cell
line
(AH109A)
and
murine
B16
melanoma
cells.
Furthermore,
the
oolong
tea
extract
inhibited
the
growth
of
human
stomach
cancer
KATO
III
cells
by
the
induction
of
apoptosis
[82].
Saeki
et
al.
[83]
has
confirmed
that
a
pyrogallol
type
structure
in
the
B-ring
of
catechin
induced
apoptosis
of
cancer
cells
compared
with
the
catechins
without
a
pyrogallol-type.
In
1999,
an
in
vitro
study
showed
that
comparing
with
ECG
and
EGCG,
theasinensin
D
and
theaflavin-3,3

-digallate
exhibited
a
weak
invasion
inhibitory
effect
determined
by
the
suppression
of
the
gelatin
degradation
mediated
through
matrix
metalloproteinase
(MMP)
[84].
However,
using
human
his-
tolytic
lymphoma
(U937)
cell
line
and
acute
T
cell
leukemia
(Jurkat)
cell
line,
the
study
demonstrates
that
theasinensin
A
from
oolong
tea
induced
the
process
of
cell
death
through
the
release
of
cytochrome
c
and
activation
of
caspase-9
and
caspase-
3
[85].
Their
results
also
suggested
that
a
linear
and
specific
activation
cascade
between
caspase-9
and
caspase-3
in
response
to
cytochrome
c
released
from
mitochondrial
and
apoptosis
by
activation
of
the
caspases,
leading
to
the
process
of
cell
death
[85].
4.5.
Hypoglycemic
effect
Hyperglycemia
is
the
major
cause
of
diabetic
angiopathy.
The
Na
+
-dependent
glucose
cotransporter
(SGLT1)
in
jejunum
transports
glucose
into
epithelial
cells.
The
inhibition
of
glucose
uptake
via
SGLT1
in
the
small
intestine
may
prevent
hyper-
glycemia
[86].
Aqueous
extracts
of
green,
oolong,
and
black
tea
failed
to
exhibit
effects
on
SGLT1
response
compared
with
tea
catechins.
Black,
green,
and
oolong
teas
as
tea
beverages
had

142
M.
Weerawatanakorn
et
al.
/
Food
Science
and
Human
Wellness
4
(2015)
133–146
shown
to
increase
insulin
activity
by
a
minimum
of
15-fold
in
an
epididymal
fat
cell
assay
[87].
Oolong
tea
extract
can
reduce
plasma
glucose
and
have
a
complicated
impact
on
antioxidant
systems
in
diabetic
rats
[7,87].
Oolong
tea
is
an
effective
adjunct
to
oral
hypoglycemic
agents
in
the
treatment
of
type
2
diabetes.
An
in
vivo
study
with
respect
to
type
2
diabetes
subjects
indicated
that
oolong
tea
remarkably
reduced
concentrations
of
plasma
glucose
from
229
to
162.2
mg/dL
and
fructosamine
(from
409.9
to
323.3
␮mol/L)
[88]
.
This
study
also
strongly
supports
the
concept
of
combination
therapy
because
the
ingestion
of
oral
anti-hyperglycemic
agents
and
oolong
tea
simultaneously
was
more
effective
in
lowering
plasma
glucose
than
taking
the
drugs
alone
[88].
Theasinensins
might
play
a
key
role
in
anti-hyperglycemic
activity
of
oolong
tea.
Theasinensin
A
induces
antihy-
perglycemic
responses
in
diabetic
mice
and
shows
hypo-
triacylglycerolemic
effect
in
rats
by
suppressing
intestinal
fat
absorption
[89].
Miyata
indicated
that
feeding
male
KK-Ay
mice
with
diets
containing
0.1%
theasinensin
A
for
6
weeks
reduced
serum
glucose
levels
by
greater
than
30%
and
feed-
ing
rats
with
diets
containing
0.2%
theasinensin
A
for
4
weeks
had
higher
fecal
fat
excretion
and
33%
lower
hepatic
tria-
cylglycerol
without
the
effect
on
hepatic
fatty
acid
synthase
activity
[10].
High
fecal
excretion
of
fatty
acid
is
associ-
ated
with
the
inhibition
of
pancreatic
lipase
by
theasinensin
A
[89].
The
result
suggested
that
it
might
be
due
to
sup-
pression
of
postprandial
hypertriacylglycerolemia,
theasinensin
A
inhibited
glucose
production
in
the
intestine
through
sup-
pression
of
␣-glucosidase
activity.
Theasinensin
A
inhibited
␣-glucosidase
(AGH)
activity
(IC50
of
142
␮mol/L
for
malt-
ase
and
286
␮mol/L
for
sucrase)
evaluated
by
an
immobilized
AGH
assay
system
and
thus
provides
a
substantially
useful
pre-
diction
of
the
in
vivo
suppression
of
glucose
absorption
[89].
Qiu
et
al.
[90]
proposed
the
mechanism
of
anti-hyperglycemic
activity
of
theasinensins
A
and
B
using
rat
skeletal
muscle
cells
(L6
myotubes).
Theasinensins
A
and
B
were
found
to
promote
GLUT4
translocation
to
the
plasma
membrane
in
L6
myotubes
through
the
CaMKK/AMPK
signaling
pathway,
but
not
through
the
PI3K/Akt
pathway.
Moreover,
theasinensin
A
is
more
effective
in
stimulating
2-NBDG
(2-(N-(7-nitrobenz-2-oxa-
1,3-diazol-4-yl)amino)-2-deoxyglucose;
a
fluorescent
glucose
analog)
uptake
than
theasinensin
B,
which
is
as
potent
as
EGCG,
suggesting
that
the
number
of
galloyl
moieties
may
be
asso-
ciated
with
the
promotion
of
2-NBDG
uptake
in
cells
[90].
GLUT4
plays
a
pivotal
role
in
regulating
insulin-stimulated
glucose
transport
predominantly
in
muscle
of
skeleton,
car-
diac
and
adipose
tissue
[91].
Glucose
uptake
by
muscle
and
fat
cells
is
regulated
by
modulating
the
number
of
GLU4
on
cell
surface.
Promoting
glucose
uptake
or
improv-
ing
insulin
resistance
by
increasing
GLUT4
translocation
to
the
plasma
membrane
via
the
AMP-activated
protein
kinase
(AMPK)
pathway
raises
the
possibility
to
prevent
hyper-
glycemia.
The
effects
of
theasinensins
A
and
B
on
regulation
of
GLUT4
are
differs
from
that
of
EGCG
that
involved
in
stimulating
the
phosphatidylinositol
3-kinase
(PI3K)/Akt
pathway
in
skeletal
muscle
to
improve
insulin
sensitivity
[90]
.
4.6.
Prevention
of
atherosclerosis,
heart
disease,
and
hypertension
High
blood
pressure
affects
millions
of
people
globally
[92]
and
it
is
associated
with
atherosclerosis
and
plaque
build-up
in
the
arteries,
both
of
which
are
considered
as
main
cardiovascu-
lar
risk
factors
[93].
The
prevention
of
atherosclerosis
can
also
reduce
the
risk
of
developing
hypertension
and
heart
disease.
An
epidemiology
study
has
shown
that
people
with
habitual
and
moderate
oolong
tea
consumption,
such
as
120
ml/day
or
more
for
a
year
period,
significantly
reduced
the
risk
of
developing
hypertension
in
Taiwan
[94].
Not
only
the
level
but
also
the
particle
size
of
low-density
lipoprotein
(LDL)
is
the
major
risk
factor
in
the
early
develop-
ment
of
coronary
heart
disease
(CAD)
[95,96].
Small
particle
size
of
LDL
is
considered
as
a
great
risk
factor
for
CAD
[97].
Oolong
tea
increased
plasma
adiponectin
levels
and
LDL
particle
size
in
CAD
patients
and
decreased
hemoglobin
A1c
(HbA1c).
Therefore,
oolong
tea
may
have
beneficial
effects
on
the
progression
of
atherosclerosis
in
patients
with
CAD.
As
mentioned
earlier,
oolong
tea
decreased
levels
of
triglyceride
in
Sprague-Dawley
rats
and
lowered
the
relative
weight
ratios
of
liver
to
epididylmal
adipose
tissues
[74].
The
result
also
showed
that
oolong
tea
was
more
effective
in
suppressing
the
growth
of
adipose
tissues
as
compared
to
green
tea
[74].
In
addition,
oolong
tea
may
inhibit
the
oxidized-LDL
cholesterol,
which
is
a
risk
factor
for
atherosclerosis
and
heart
disease,
and
reduced
the
formation
of
8-hydroxydeoxyguanosine,
a
marker
of
oxidative
DNA
damage
[76].
There
is
an
affiliation
between
the
ingestion
of
dietary
lipid
and
some
diseases
such
as
obesity
and
cardiovascular
diseases.
Hence
reduction
of
lipid
intake
is
a
logical
nutritional
inter-
vention
strategy.
Moreover,
the
more
energy
expenditure
means
less
accumulation
of
lipid,
which
can
decrease
the
incidence
of
atherosclerosis
and
heart
disease.
To
absorb
dietary
lipids,
the
lipid
digestion
by
pancreatic
lipase
is
a
key
step.
Inhibi-
tion
of
digestive
lipase
activity
significantly
affects
dietary
lipid
absorption,
leading
to
increase
lipid
excretion
into
the
feces
[71].
Thus,
it
is
a
possible
strategy
responsible
for
the
prevention
of
atherosclerosis
and
heart
disease.
Polyphenol-enriched
oolong
tea
extract
increased
lipid
excretion
into
feces
in
subjects
with
high
fat
diet,
and
polymerized-polyphenol
extract
from
oolong
tea
appears
to
increase
cholesterol
excretion
into
feces
[98].
Fur-
thermore,
the
consumption
of
oolong
tea
in
healthy
women
leads
to
the
increase
of
energy
expenditure
(EE)
and
this
effect
is
higher
than
that
of
green
tea
[99].
The
same
trend
of
the
effect
of
oolong
tea
on
energy
expenditure
was
reported
in
Japanese
subjects
[99]
and
the
result
showed
that
oolong
tea
stimulates
fat
oxidation.
Therefore,
the
consumption
of
oolong
tea
increased
metabolic
rate
and
fat
oxidation,
potential
beneficial
effect
on
an
individual’s
ability
to
maintain
a
lower
body
fat
content,
associated
with
lower
risk
of
atherosclerosis
and
hypertension
[100].
Oolong
tea
decreased
atherogenic
index
and
increased
HDL-total
cholesterol
ratio
in
hypercholesterolemia
rats
[101].
However,
there
is
still
no
report
of
the
bioactivity
of
theasi-
nensins
on
prevention
of
atherosclerosis
and
heart
disease
in
the
literature.

M.
Weerawatanakorn
et
al.
/
Food
Science
and
Human
Wellness
4
(2015)
133–146
143
4.7.
Antiseptic
effects
Oxacillin
(methicillin)-resistant
Staphylococcus
aureus
(MRSA)
caused
infection
is
a
problem
in
health
care
institutions
in
the
United
States
and
worldwide,
especially
for
intensive
care
unit
patients
[102].
This
type
of
bacteria
is
resistant
to
a
num-
ber
of
widely
used
antibiotics,
so
MRSA
infections
can
be
more
difficult
to
cure
than
other
bacterial
infections.
Aqueous
extract
of
oolong
tea
inhibits
various
pathogens
including
Staphylo-
coccus
aureus
(a
methicillin-resistant
strain).
A
previous
study
indicated
that
theasinensin
A
has
the
maximum
non-inhibitory
concentration
at
130–180
mg/mL.
Hatano
et
al.
[103]
found
that
theasinensin
A
suppressed
the
oxacillin
resistance
of
MRSA
and
the
minimum
inhibition
concentration
(MICs)
of
oxacillin
decreased
from
64
to
4
␮g/mL.
It
decreased
the
MICs
of
other
␤-lactam
including
penicillin
G,
ampicillin,
and
streptomycin,
antibiotics
for
MRSA
strain
[104].
Pathogenesis
is
closely
associated
with
the
ability
to
synthesize
water-insoluble
glucans
from
sucrose
by
gluco-
syltransferases
(GTases)
and
to
release
acids
from
various
fermentable
sugars
[105]
.
Oolong
tea
extract
can
decrease
the
cellular
surface
hydrophobicity
of
almost
all
the
oral
strepto-
coccus
and
inhibit
bacterial
adherence
to
the
tooth
surfaces,
as
well
as
reduce
the
growth
rate
and
the
rate
of
acid
production
of
mutant
streptococci
[104].
Oolong
tea
extract
and
its
puri-
fied
polymeric
polyphenols
identified
as
dehydro-dicatechin
A
exhibit
the
inhibition
of
glucosyltransferase
(GTase)
of
mutans
streptococci,
Streptococcus
sobrinus
6715.
As
the
degree
of
polymerization
of
catechin
increased,
GTase
was
inhibited
more
effectively
[105].
Furthermore,
antibacterial
activity
of
oolong
tea
extract
on
oral
streptococci,
including
Streptococcus
mutans
and
S.
sobrinus
has
been
confirmed
by
Sasaki’s
study
who
reported
that
the
oolong
tea
extract
have
antibacterial
activity
against
all
of
the
oral
streptococci
examined,
with
the
high-
est
activity
against
S.
mutans
MT8148R
in
which
the
activity
was
attributed
to
a
monomeric
polyphenol-rich
fraction.
The
results
also
suggested
that
the
antibacterial
activity
of
oolong
tea
extract
was
resulted
from
a
synergistic
effect
of
monomeric
polyphenols,
which
can
easily
bind
to
proteins
[106].
Besides,
theasinensin
A
weakening
virus
has
been
reported.
For
exam-
ple,
herpes
simplex
virus
(HSV),
both
HSV-1
and
HSV-2,
is
the
leading
cause
of
genital
ulcers
in
the
developed
world
[107].
Theasinensin
A
caused
aggregation
of
HSV-1
glycoprotein
B
(gB)
and
the
effect
is
faster
than
EGCG
suggesting
that
dimers
may
inhibit
the
function
of
viral
proteins.
This
effect
is
sim-
ilar
to
EGCG,
on
herpes
simplex
virus
(HSV)
infectivity.
As
microbicide
agents
against
HSV,
theasinensin
A
appears
to
have
excellent
potential
at
acidic
and
neutral
pHs
[108].
5.
Bioavailability
Theasinensins
have
been
reported
to
have
many
biologi-
cal
properties
closely
associated
with
the
antihyperglycemic,
anti-obesity,
anticancer,
anti-inflammatory,
antibacterial
activ-
ity.
Usually,
biological
properties
of
polyphenols
are
associated
with
their
bioavailability
[109].
Tea
polyphenols
are
biologically
regarded
as
xenobiotics
that
will
be
extensively
metabolized
for
elimination
from
the
body
[110].
Metabolism
of
tea
polyphenols
can
be
affected
by
interaction
with
other
dietary
ingredients,
sol-
ubility,
molecular
transformations,
different
cellular
transporters
and
the
action
of
gut
microbiota,
interindividual
variations
[110]
.
The
Caco-2
cell
monolayers,
derived
from
human
colon
carcinoma,
have
been
widely
used
as
an
in
vitro
intestinal
absorp-
tion
model
for
studying
permeability
and
transport
of
drugs
[111,112].
It
represents
morphologically
the
enterocytes
of
the
small
intestine
and
exhibits
brush-border
characteristics
at
the
apical
side
[112].
Qiu
et
al.
[112]
illustrated
the
in
vivo
and
in
vitro
absorption
of
theasinensins
A
and
B
and
evaluated
their
transport
pathway
across
intestinal
membrane.
The
rat
study
showed
that
a
sin-
gle
oral
administration
of
theasinensins
demonstrated
the
intact
absorption
of
theasinensins
into
the
blood
system,
which
was
estimated
to
be
a
greater
than
10-fold
lower
absorption
amount
than
EGCG.
The
in
vitro
absorption
study
indicated
that
theasi-
nensins
can
be
transported
across
Caco-2
cell
monolayers,
while
their
permeability
coefficients
were
also
>10-fold
lower
than
those
of
EGCG
and
EGC.
In
addition,
theasinensins
were
trans-
ported
across
Caco-2
cells
in
a
tight
junction
(TJ)
paracellular
diffusion
pathway
which
is
the
same
route
as
EGCG
[112].
6.
Future
studies
of
theasinensin
We
have
known
that
the
concentration
of
theasinensin
A
is
higher
than
theasinensin
D
in
black
tea
[44].
Hashimoto
et
al.
[42]
also
found
that
the
concentration
of
theasinensin
A
is
higher
than
theasinensin
B
in
fermented
tea
leaves.
The
average
contents
of
theasinensins
in
green
tea
and
oolong
tea
are
0.05%
and
0.65%,
respectively
[36,113].
Data
on
the
content
of
theasi-
nensins
in
black
or
oolong
tea
are
still
scarce.
Comparison
of
each
isoform
of
theasinensins
between
black
tea
and
oolong
tea
is
necessary.
Many
work
are
needed
to
clarify
pharmacokinetics
and
bioactivity
of
theasinensins
both
in
vivo
and
in
vitro
model.
Despite
there
are
studies
reporting
the
potential
health
benefits
of
theasinensins,
the
potential
biological
activities
of
their
metabo-
lites
(conjugates
or
microbial)
is
poorly
understood.
Finally,
it
is
also
important
to
highlight
that
no
studies
regarding
the
mech-
anism
of
theasinensins
(A–E)
on
obesity
and
other
bioactivity
such
as
hypertension
and
atherosclerosis
associated
with
heart
disease
prevention.
7.
Conclusion
In
summary,
oolong
tea
and
its
characteristic
compounds
theasinensins
have
been
reviewed
for
chemical
formation
mechanism
of
theasinensins
and
their
corresponding
biolog-
ical
property
and
potential
action
pathway,
specifically,
the
bioactivity
of
oolong
tea
and
theasinensins
and
their
struc-
tural
information.
These
studies
clearly
indicated
the
various
bioactivities
on
health
benefit
of
oolong
tea
coming
from
theasi-
nensins.
Regardless
of
the
polymolecular
nature
of
oolong
tea
extract,
the
results
shown
in
the
published
literatures
implicated
a
relationship
between
oolong
tea
and
theasinensins
and
their
biological
properties.
A
better
knowledge
of
bioavailability
of
theasinensins
is
required.
It
is
foreseeable
that
theasinensins

144
M.
Weerawatanakorn
et
al.
/
Food
Science
and
Human
Wellness
4
(2015)
133–146
may
become
a
promising
class
of
health
products
against
the
development
of
many
diseases.
Conflict
of
interest
The
authors
have
no
conflicts
of
interest
to
declare.
Acknowledgments
This
study
was
made
possible
by
Naresuan
University,
Phisanulok,
Thailand
under
the
International
Research
Univer-
sity
(IRU)
program
and
Anhui
Major
Demonstration
Project
for
Leading
Talent
Team
on
Tea
Chemistry
and
Health,
Anhui
Department
of
Education,
Hefei,
China.
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