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e
s
s
c
h
a
r
a
c
t
e
r
i
z
e
d
by
h
i
g
h
r
e
a
c
t
i
v
e
o
xy
g
e
n
s
up
e
r
f
a
m
il
y
(
R
O
S
)
a
n
d
i
nf
l
a
mm
a
t
o
r
y
r
e
a
c
t
i
o
n
[
8
]
.
All
o
x
a
n
i
s
a
d
i
a
b
e
t
o
ge
ni
c
c
o
m
po
un
d
t
h
a
t
de
s
t
r
o
y
s
pa
n
c
r
e
a
t
i
c
i
s
l
e
t
c
e
l
l
s
s
o
t
h
a
t
i
ns
u
l
i
n
pr
o
duc
t
i
o
n
i
s
re
duc
e
d
a
n
d
hy
pe
r
g
ly
c
e
mi
a
o
c
c
ur
s
[
9
]
.
I
n
t
r
a
pe
r
i
t
on
e
a
l
a
ll
o
x
a
n
i
nduc
t
i
o
n
h
a
s
b
e
e
n
s
h
o
wn
t
o
c
a
us
e
da
m
a
ge
t
o
pa
n
c
r
e
a
t
i
c
i
s
l
e
t
c
e
l
l
s
a
n
d
t
he
i
nc
i
d
e
n
c
e
o
f
hy
pe
r
g
l
y
c
e
mi
a
pr
e
c
e
de
d
by
e
l
e
v
a
t
e
d
l
e
v
e
l
s
o
f
R
OS
a
n
d
M
D
A
a
n
d
f
o
l
l
o
w
e
d
by
a
n
i
n
f
l
a
m
m
a
t
o
r
y
r
e
a
c
t
i
o
n
[
10,
11
]
.
R
OS
a
n
d
NO
S
due
t
o
e
x
po
s
ur
e
to
a
l
l
o
x
a
n
s
p
ur
l
i
p
i
d
m
e
m
br
a
n
e
pe
r
o
xi
da
t
i
o
n
a
n
d
o
xi
da
t
i
o
n
r
e
a
c
t
i
o
ns
i
n
pr
o
t
e
i
n
s
a
n
d
DN
A
[
4,
11,
12
]
.
P
a
n
c
r
e
a
t
i
c
i
s
l
e
t
c
e
ll
de
s
t
r
uc
t
i
o
n
due
t
o
e
x
po
s
ur
e
to
a
l
l
o
x
a
n
i
s
c
h
a
r
a
c
t
e
r
i
z
e
d
by
ge
ne
t
i
c
da
m
a
ge
(
DN
A
)
a
n
d
e
l
e
va
t
e
d
M
D
A
l
e
v
e
l
s
[
13
-
15
]
.
P
53
ge
ne
p
l
a
y
s
a
n
im
po
r
t
a
n
t
r
o
l
e
i
n
m
o
du
l
a
t
i
n
g
t
h
e
e
f
f
e
c
t
o
f
e
l
e
v
a
t
e
d
i
n
t
r
a
c
e
l
l
u
l
a
r
R
OS
o
r
NO
S
l
e
v
e
l
s
,
r
e
pa
i
r
i
n
g
g
e
n
e
t
i
c
da
m
a
ge
a
n
d
r
e
gu
l
a
t
i
n
g
th
e
b
a
l
a
nc
e
o
f
i
n
f
l
a
mm
a
t
or
y
r
e
s
po
ns
e
s
[
12,
16,
17
]
.
P
53
pr
ot
e
i
n
p
l
a
y
s
a
r
o
l
e
i
n
s
t
i
m
u
l
a
t
i
n
g
a
po
pto
s
i
s
i
n
c
e
l
l
s
u
n
d
e
r
go
i
n
g
ge
n
e
t
i
c
s
t
r
e
s
s
due
to
o
xi
da
t
i
v
e
s
t
r
e
s
s
a
n
d
i
nh
i
b
i
t
i
n
g
t
he
i
nf
l
a
mm
a
t
o
r
y
r
e
a
c
t
i
o
n
t
h
r
o
ugh
s
uppr
e
s
s
i
o
n
o
f
pr
o
-
i
nf
l
a
mm
a
t
o
r
y
t
r
a
n
s
c
r
i
pt
i
o
n
f
a
c
to
r
NF
-
ka
ppa
B
.
Un
de
r
n
o
r
m
a
l
c
o
n
d
i
t
i
o
n
s
,
t
h
e
p53
ge
ne
i
s
i
na
c
t
i
v
e
.
P
53
ge
ne
i
s
a
c
t
i
v
a
t
e
d
by
t
h
e
pr
e
s
e
n
c
e
o
f
o
xi
da
t
i
v
e
s
t
r
e
s
s
o
r
ge
n
e
t
i
c
da
m
a
g
e
.
[
18,
19
]
.
S
e
v
e
r
a
l
s
t
ud
i
e
s
h
a
v
e
pr
o
v
e
n
t
h
a
t
B
l
a
c
k
c
u
mi
n
(
N
i
ge
ll
a
s
a
t
i
v
a
L
.
)
c
a
n
l
o
we
r
bl
o
o
d
gl
uc
o
s
e
l
e
v
e
l
s
[
20
]
.
T
hy
m
o
qu
i
n
o
ne
i
s
i
de
n
t
i
f
i
e
d
a
s
a
m
a
j
o
r
c
o
m
po
n
e
n
t
(
o
v
e
r
50%
)
o
f
bl
a
c
k
c
u
mi
n
s
e
e
d
e
s
s
e
n
t
i
a
l
o
i
l
,
o
r
B
C
S
O
[
21
]
.
T
hy
m
o
qu
i
n
o
n
e
pr
o
v
e
d
t
o
h
a
v
e
a
n
e
f
f
e
c
t
a
s
a
n
a
n
t
i
o
xi
d
a
n
t
a
n
d
i
mm
u
n
o
m
o
du
l
a
t
o
r
[
22
-
24
]
.
I
t
pe
r
f
o
r
m
s
i
t
s
a
c
t
i
vi
t
y
a
s
a
n
a
n
t
i
o
xi
da
n
t
by
m
e
a
n
s
o
f
a
hy
dr
o
ge
n
do
n
o
r
to
f
r
e
e
r
a
d
i
c
a
l
s
[
23
]
.
H
i
g
h
lev
e
l
s
o
f
t
i
m
o
xy
ge
n
i
n
B
C
S
O
a
r
e
e
x
pe
c
t
e
d
to
a
c
t
a
s
a
n
t
i
o
xi
da
n
t
s
a
n
d
c
a
n
pr
e
v
e
n
t
c
e
l
l
da
m
a
ge
i
nduc
e
d
by
a
l
l
o
x
a
n
.
B
a
s
e
d
o
n
pr
e
vi
o
u
s
s
t
ud
i
e
s
,
i
t
i
s
e
vi
de
n
t
t
h
a
t
B
C
S
O
m
a
y
i
nc
r
e
a
s
e
p53
e
x
pr
e
s
s
i
o
n
i
n
t
h
e
li
ve
r
t
i
s
s
ue
o
f
a
l
l
o
x
a
n
-
i
nduc
e
d
r
a
t
s
[
25
]
.
W
e
hy
po
t
h
e
s
i
z
e
t
ha
t
t
hy
mo
qui
n
o
n
e
c
a
n
pr
e
v
e
n
t
pa
n
c
r
e
a
t
i
c
c
e
ll
da
m
a
ge
,
pr
e
v
e
n
t
hy
pe
r
g
ly
c
e
mi
a
,
a
n
d
i
nc
r
e
a
s
e
p53
e
x
pr
e
s
s
i
o
n
.
T
hi
s
s
t
udy
a
im
s
t
o
de
t
e
r
m
i
ne
t
h
e
e
f
f
e
c
t
o
f
B
C
S
O
o
n
M
a
l
o
n
d
i
a
l
de
hy
de
l
e
ve
l
s
i
n
a
ll
o
x
a
n
-
i
nduc
e
d
S
pr
a
gue
da
w
l
e
y
r
a
t
s
.
2.
RE
S
E
AR
CH
M
E
T
HO
D
2
.
1.
To
ol
s
an
d
M
a
t
e
r
ial
s
T
hi
s
r
e
s
e
a
r
c
h
i
s
a
n
e
x
pe
r
im
e
n
t
a
l
r
e
s
e
a
r
c
h
w
i
t
h
P
r
e
t
e
s
t
a
n
d
P
o
s
tt
e
s
t
C
o
n
tr
o
l
D
e
s
i
g
n
.
T
hi
s
s
t
ud
y
us
e
s
s
pe
c
t
r
o
ph
oto
m
e
t
e
r
(
UV
-
1201V
S
hi
m
a
dz
u)
,
a
n
a
ly
t
i
c
a
l
b
a
l
a
n
c
e
(
A
d
v
e
n
t
ur
e
r
)
f
o
r
we
i
g
hi
ng
s
a
m
p
les
,
s
pu
i
t
i
n
j
e
c
t
i
o
n
(
T
e
r
u
m
o
)
,
o
r
a
l
m
o
us
e
s
o
n
de
,
c
a
p
i
ll
a
r
y
p
i
pe
,
m
e
a
s
ur
i
ng
c
up
(
p
y
r
e
x
)
,
m
o
r
t
a
r
s
t
a
m
pe
r
,
E
ppe
n
do
r
f
,
m
o
us
e
c
a
ge
(
p
y
r
e
x
)
,
f
u
nn
e
l
(
p
y
r
e
x
)
,
f
l
a
c
o
n
,
b
e
a
k
e
r
(
p
y
r
e
x
)
,
a
n
d
t
e
s
t
t
ub
e
(
p
y
r
e
x
)
.
T
h
e
i
ngr
e
d
i
e
n
t
s
us
e
d
a
r
e
bl
a
c
k
c
u
mi
n
s
e
e
ds
(
P
T
M
e
ga
Agu
n
g
S
e
t
i
a
)
,
vi
t
a
mi
n
C
f
r
o
m
I
P
I
t
a
bl
e
t
s
,
s
im
va
s
t
a
t
i
n
10
m
g
g
e
n
e
r
i
c
t
a
bl
e
t
s
(
S
OH
O)
,
DM
S
O
(
di
m
e
t
hyl
s
u
l
f
o
xi
d
e
)
,
a
l
l
o
x
a
n
m
o
n
o
hy
dr
a
t
e
(
S
i
g
m
a
)
,
a
q
ua
de
s
t
,
h
e
pa
r
i
n
(
a
n
t
i
c
o
a
gu
l
a
n
t
)
,
T
B
A
r
e
a
ge
n
t
s
,
p53
m
o
n
o
c
l
o
n
a
l
a
n
t
i
b
o
d
i
e
s
,
s
e
c
o
n
da
r
y
a
n
t
i
b
o
d
y
a
n
d
im
m
u
n
o
hi
s
t
o
c
h
e
m
i
c
a
l
t
i
s
s
ue
d
y
e
s
i
.
e
.
DA
B
.
T
h
e
e
x
pe
r
i
m
e
n
t
a
l
a
nim
a
l
s
us
e
d
a
r
e
49
S
pr
a
gue
Da
w
l
e
y
m
a
l
e
r
a
t
s
a
ge
d
30
da
y
s
we
i
g
hi
ng
f
r
o
m
150
t
o
300
gr
a
m
s
o
b
t
a
i
ne
d
f
r
o
m
t
h
e
Na
t
i
o
n
a
l
F
o
o
d
a
n
d
Dr
ug
T
e
s
t
C
e
n
t
e
r
o
f
Anim
a
l
L
a
b
o
r
a
to
r
y
o
f
E
x
p
e
r
i
m
e
n
t
s
,
B
P
OM
R
I
J
a
ka
r
t
a
.
T
h
e
a
nim
a
l
s
a
r
e
d
i
vi
d
e
d
i
n
t
o
7
gr
o
ups
.
.
T
h
e
s
t
udy
pr
o
to
c
o
l
wa
s
r
e
vi
e
we
d
a
n
d
r
e
c
e
i
ve
d
a
l
e
t
t
e
r
o
f
e
t
hi
c
a
l
c
l
e
a
r
a
nc
e
f
r
o
m
t
h
e
r
e
s
e
a
r
c
h
e
t
hi
c
s
c
o
m
mi
t
t
e
e
o
f
L
P
P
T
UG
M
n
o
222
/K
E
C
-
L
P
P
T
/I
I
I
/
2015.
2
.
2
.
Re
s
e
ar
c
h
p
r
oc
e
d
u
r
e
2.
2.
1.
T
r
e
at
m
e
n
t
an
d
I
n
d
u
c
t
ion
of
A
l
l
o
x
an
A
t
ot
a
l
o
f
49
S
D
r
a
t
s
a
ge
d
3
we
e
ks
we
r
e
r
a
n
do
m
ly
d
i
vi
d
e
d
i
n
t
o
s
e
v
e
n
gr
o
ups
a
n
d
qua
r
a
n
t
i
n
e
d
f
o
r
7
da
y
s
pr
i
o
r
to
t
h
e
tr
e
a
t
m
e
n
t
.
T
h
e
7
gr
o
ups
we
r
e
:
Gr
o
up
I
,
t
h
e
n
o
r
m
a
l
c
o
n
t
r
o
l
gr
o
up
r
e
c
e
i
vi
ng
s
t
a
n
da
r
d
f
e
e
d
i
ng
a
n
d
dr
i
n
k
i
ng
;
Gr
o
up
I
I
,
t
h
e
n
e
ga
t
i
v
e
c
o
n
t
r
o
l
gr
o
u
p
r
e
c
e
i
vi
ng
a
l
l
o
xa
n;
Gr
o
up
I
I
I
&
I
V,
t
h
e
tr
e
a
t
m
e
nt
g
r
o
ups
,
r
e
c
e
i
vi
ng
B
C
S
O
w
i
t
h
a
do
s
e
o
f
6.
9
m
g/
K
gB
W
(
B
C
S
O6.
8)
a
n
d
68
m
g/
K
gB
W
(
B
C
S
O68
gr
o
up)
;
Gr
oup
V,
t
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3.
RE
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A
ND
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CU
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ON
3.
1.
T
h
e
B
l
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Gl
u
c
os
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L
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l
All
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6.
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d
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r
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l
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Gl
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s
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G
r
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l
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f
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n
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mg/
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77.88±3.38
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A
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310.42±35.52
A
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A
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S
O
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W
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A
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A
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it
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mi
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6
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80.13±18.61
D
M
S
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l
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nt
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81.33±3.57
81.33±3.56
81.33±3.55
T
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s
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t
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s
h
o
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[
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2.
B
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M
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d
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d
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All
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(
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