I
nte
rna
t
io
na
l J
o
urna
l o
f
Adv
a
nces in Applie
d Science
s
(
I
J
AAS)
Vo
l.
14
,
No
.
3
,
Sep
tem
b
er
20
25
,
p
p
.
9
66
~
9
74
I
SS
N:
2252
-
8
8
1
4
,
DOI
:
1
0
.
1
1
5
9
1
/ijaas
.
v
14
.
i
3
.
pp
9
66
-
9
74
966
J
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ur
na
l ho
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e
:
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ttp
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Thera
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ervi
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an
in vitro
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on H
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Adi P
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c
h
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o
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a
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p
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g
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n
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it
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La
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e
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s.
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rv
ica
l
c
a
n
c
e
r
is
o
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e
o
f
th
e
m
o
st
c
o
m
m
o
n
ty
p
e
s
o
f
c
a
n
c
e
r
in
w
o
m
e
n
,
wh
ich
is
o
fte
n
c
a
u
se
d
b
y
h
u
m
a
n
p
a
p
il
l
o
m
a
v
i
ru
s
(HPV)
in
fe
c
ti
o
n
.
Alt
h
o
u
g
h
c
h
e
m
o
th
e
ra
p
y
t
h
e
ra
p
y
is
o
n
e
o
f
t
h
e
m
a
in
m
e
th
o
d
s
in
c
a
n
c
e
r
trea
tme
n
t,
th
is
a
p
p
r
o
a
c
h
o
ften
c
a
u
se
s
sid
e
e
ffe
c
ts
a
n
d
d
ru
g
re
sista
n
c
e
.
ALA,
wh
ich
is
o
n
e
o
f
t
h
e
m
a
in
c
o
m
p
o
n
e
n
ts
o
f
S
a
c
h
a
In
c
h
i
o
il
,
is
k
n
o
w
n
t
o
h
a
v
e
a
n
ti
o
x
id
a
n
t
a
n
d
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i
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c
a
n
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e
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a
c
ti
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it
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t
h
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y
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a
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In
c
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a
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a
ly
z
e
d
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c
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m
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ra
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h
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h
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g
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re
so
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t
io
n
m
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ss
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e
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tro
m
e
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(LC
-
HRMS
)
fo
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i
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e
n
ti
fica
ti
o
n
o
f
it
s
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c
ti
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o
m
p
o
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n
ts
.
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t
o
to
x
ic
a
ss
a
y
s
we
re
p
e
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rm
e
d
u
sin
g
t
h
e
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TT
m
e
th
o
d
o
n
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La
c
e
ll
s,
wh
ich
sh
o
we
d
th
a
t
ALA
sig
n
ifi
c
a
n
tl
y
i
n
h
i
b
it
e
d
c
a
n
c
e
r
c
e
ll
v
iab
il
it
y
a
t
lo
w
c
o
n
c
e
n
trat
io
n
s,
with
lo
w
IC
50
v
a
l
u
e
s
c
o
m
p
a
re
d
to
t
h
e
p
o
siti
v
e
c
o
n
tr
o
l
c
o
m
p
o
u
n
d
c
is
p
latin
.
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e
se
re
su
lt
s
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g
g
e
st
t
h
a
t
ALA
h
a
s
p
o
ten
ti
a
l
a
s
a
n
e
ffe
c
ti
v
e
a
n
ti
-
can
c
e
r
a
g
e
n
t
a
g
a
in
st
c
e
rv
ica
l
c
a
n
c
e
r
c
e
ll
s.
Th
is
stu
d
y
c
o
n
c
lu
d
e
s
t
h
a
t
ALA
fr
o
m
S
a
c
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In
c
h
i
o
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l
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n
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n
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te
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ffe
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ti
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e
c
e
rv
ica
l
c
a
n
c
e
r
th
e
ra
p
y
.
K
ey
w
o
r
d
s
:
Alp
h
a
-
lin
o
len
ic
ac
id
C
er
v
ic
al
ca
n
ce
r
HeL
a
ce
lls
I
n
vitr
o
s
tu
d
y
Sach
a
I
n
ch
i
o
il
T
h
is i
s
a
n
o
p
e
n
a
c
c
e
ss
a
rticle
u
n
d
e
r th
e
CC B
Y
-
SA
li
c
e
n
se
.
C
o
r
r
e
s
p
o
nd
ing
A
uth
o
r
:
Ad
i Per
m
ad
i
Dep
ar
tm
en
t o
f
C
h
em
ical
E
n
g
i
n
ee
r
in
g
,
Facu
lty
o
f
I
n
d
u
s
tr
ial
T
ec
h
n
o
lo
g
y
,
Un
i
v
er
s
itas
Ah
m
ad
Dah
lan
R
in
g
r
o
ad
Selatan
,
T
am
a
n
an
,
B
an
g
u
n
tap
an
,
B
an
tu
l,
I
n
d
o
n
es
ia
E
m
ail: a
d
i.p
er
m
ad
i@
ch
e.
u
a
d
.
ac
.
id
.
1.
I
NT
RO
D
UCT
I
O
N
C
er
v
ical
ca
n
ce
r
r
em
ain
s
o
n
e
o
f
th
e
m
o
s
t
p
r
ev
alen
t
m
alig
n
an
cies
af
f
ec
tin
g
wo
m
en
g
lo
b
ally
,
with
o
v
er
6
0
4
,
0
0
0
n
ew
ca
s
es
an
d
3
1
1
,
0
0
0
d
ea
th
s
r
ep
o
r
ted
a
n
n
u
ally
[
1
]
,
[
2
]
.
T
h
e
r
e
ar
e
3
1
1
,
3
6
5
ce
r
v
ical
ca
n
ce
r
d
ea
th
s
an
d
5
6
9
,
8
4
7
n
ew
ca
s
e
s
p
er
y
ea
r
.
T
h
e
p
r
im
ar
y
r
is
k
f
ac
to
r
is
th
e
h
u
m
an
p
ap
illo
m
av
ir
u
s
(
HPV)
,
an
d
p
r
o
lo
n
g
ed
h
ig
h
-
r
is
k
HPV
in
f
e
ctio
n
h
as
b
ee
n
lin
k
e
d
to
ce
r
v
ic
al
ca
n
ce
r
.
Sex
u
al
co
n
tact
ca
n
s
p
r
ea
d
HPV,
wh
ich
h
as
b
ee
n
im
p
l
icate
d
in
9
9
%
o
f
ca
s
es
o
f
ce
r
v
ical
s
q
u
a
m
o
u
s
ce
ll
ca
n
ce
r
[
3
]
,
[
4
]
.
HPV
in
f
ec
tio
n
,
esp
ec
ially
h
ig
h
-
r
is
k
s
u
b
ty
p
es
s
u
ch
as
H
PV
1
6
an
d
1
8
,
is
r
eq
u
ir
ed
to
ca
u
s
e
ce
r
v
ical
n
eo
p
lasi
a,
alth
o
u
g
h
HPV
in
f
ec
tio
n
alo
n
e
is
n
o
t
s
u
f
f
icien
t
to
ca
u
s
e
ca
n
ce
r
[
5
]
.
T
h
er
e
ar
e
u
p
to
2
2
5
d
if
f
er
e
n
t
v
a
r
ieties
o
f
HPVs
,
a
d
iv
er
s
e
co
llectio
n
o
f
d
o
u
b
le
-
s
tr
an
d
e
d
DNA
v
ir
u
s
es,
an
d
n
ew
t
y
p
es
ar
e
c
o
n
s
tan
tly
b
ein
g
d
is
co
v
er
ed
[
6
]
.
HPV
in
f
ec
tio
n
is
s
tr
o
n
g
ly
ass
o
ciate
d
with
t
h
e
d
ev
elo
p
m
en
t
o
f
ce
r
v
ical
ca
n
ce
r
,
esp
ec
ially
h
ig
h
-
r
is
k
HPV
ty
p
es
s
u
ch
as
1
6
,
1
8
,
3
1
,
3
3
,
an
d
4
5
,
wh
i
ch
ar
e
f
o
u
n
d
in
ap
p
r
o
x
im
ately
9
7
%
o
f
ce
r
v
ical
ca
n
ce
r
p
atien
ts
[
1
]
.
T
h
e
p
en
to
s
e
p
h
o
s
p
h
ate
p
ath
way
(
PP
P)
ca
n
b
e
ab
n
o
r
m
ally
ac
tiv
ate
d
b
y
HPV
in
f
ec
tio
n
;
PP
P
p
lay
s
an
im
p
o
r
tan
t
r
o
le
in
th
e
d
ev
elo
p
m
e
n
t a
n
d
p
r
o
g
r
ess
io
n
o
f
ce
r
v
ical
ca
n
ce
r
[
7
]
.
Giv
en
th
ese
lim
itatio
n
s
,
th
er
e
is
a
g
r
o
win
g
n
ee
d
f
o
r
alter
n
ativ
e
th
er
ap
eu
tic
ag
e
n
ts
th
at
ar
e
s
af
er
,
m
o
r
e
e
f
f
ec
tiv
e,
an
d
d
e
r
iv
ed
f
r
o
m
n
atu
r
al
s
o
u
r
ce
s
.
O
n
e
p
r
o
m
is
in
g
ca
n
d
i
d
ate
is
Sach
a
I
n
ch
i
,
also
k
n
o
wn
as
P
lu
ke
n
etia
vo
lu
b
ilis
L.
,
an
Am
az
o
n
ian
p
lan
t
k
n
o
w
n
f
o
r
its
h
ig
h
co
n
ten
t
o
f
p
o
ly
u
n
s
atu
r
ated
f
atty
ac
id
s
,
Evaluation Warning : The document was created with Spire.PDF for Python.
I
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v
Ap
p
l Sci
I
SS
N:
2252
-
8
8
1
4
Th
era
p
eu
tic
p
o
ten
tia
l
o
f a
lp
h
a
-
lin
o
len
ic
a
cid
fr
o
m
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a
ch
a
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h
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l c
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(
A
d
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967
p
ar
ticu
lar
ly
alp
h
a
-
lin
o
len
ic
a
cid
(
AL
A)
[
8
]
,
[
9
]
.
L
in
o
le
n
ic
ac
id
(
L
A)
h
as
b
ee
n
s
h
o
wn
to
ex
er
t
an
ti
-
ca
n
ce
r
p
r
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p
er
ties
th
r
o
u
g
h
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ar
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s
m
ec
h
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is
m
s
,
in
clu
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th
e
i
n
d
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ctio
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o
f
ap
o
p
to
s
is
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in
h
ib
i
tio
n
o
f
ca
n
ce
r
ce
ll
p
r
o
life
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atio
n
,
an
d
en
h
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m
en
t o
f
th
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t
o
to
x
ic
ef
f
ec
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o
f
ch
em
o
th
er
ap
e
u
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ts
[
1
0
]
,
[
1
1
]
.
S
e
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o
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[
1
2
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[
1
3
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.
S
a
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.
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g
h
l
y
v
a
l
u
e
d
f
o
r
i
t
s
h
i
g
h
n
u
t
r
i
t
i
o
n
a
l
c
o
n
t
e
n
t
.
T
h
e
o
i
l
c
o
n
t
a
i
n
s
5
2
%
LA
a
n
d
3
4
%
LA
,
a
t
o
t
a
l
o
f
8
5
%
e
s
s
e
n
t
ia
l
f
a
t
t
y
a
c
i
d
s
[
1
4
]
.
T
h
i
s
o
i
l
is
o
b
t
a
in
e
d
t
h
r
o
u
g
h
c
o
l
d
p
r
e
s
s
i
n
g
a
n
d
i
s
k
n
o
w
n
f
o
r
i
t
s
m
o
i
s
t
u
r
i
zi
n
g
e
f
f
e
c
t
o
n
t
h
e
s
k
i
n
.
I
t
i
s
li
g
h
t
a
n
d
g
o
o
d
f
o
r
d
r
y
s
k
i
n
,
c
o
m
p
a
r
a
b
l
e
t
o
o
l
i
v
e
o
i
l
[
1
5
]
.
S
a
c
h
a
I
n
c
h
i
h
a
s
p
h
y
t
o
c
h
e
m
i
c
al
s
t
h
a
t
m
a
y
f
u
n
c
t
i
o
n
as
a
n
a
n
t
i
-
c
a
n
c
e
r
.
T
h
e
o
il
f
r
o
m
S
a
c
h
a
I
n
c
h
i
s
e
e
d
s
c
o
n
t
a
i
n
s
p
h
e
n
o
l
i
c
c
o
m
p
o
u
n
d
s
a
n
d
a
n
t
i
o
x
i
d
a
n
t
s
t
h
at
m
a
y
h
e
l
p
p
r
e
v
e
n
t
a
n
d
t
r
e
a
t
c
a
n
c
e
r
.
I
n
a
d
d
i
t
i
o
n
,
t
h
e
p
h
e
n
o
l
i
c
c
o
m
p
o
u
n
d
s
a
n
d
p
h
y
t
o
s
t
e
r
o
l
s
in
S
a
c
h
a
I
n
c
h
i
s
e
e
d
s
h
a
v
e
a
ls
o
b
e
e
n
e
v
a
l
u
a
t
e
d
f
o
r
t
h
e
i
r
a
n
t
i
o
x
i
d
a
n
t
a
c
t
i
v
i
t
y
,
w
h
ic
h
i
s
i
m
p
o
r
t
a
n
t
f
o
r
f
i
g
h
t
i
n
g
o
x
i
d
a
t
i
v
e
s
t
r
ess
o
f
t
e
n
a
s
s
o
c
i
at
e
d
wi
t
h
c
a
n
c
e
r
[
1
6
]
.
A
L
A
,
w
i
t
h
t
h
e
c
h
e
m
i
c
a
l
f
o
r
m
u
l
a
C
1
8
H
3
0
O
2
,
h
as
s
e
v
e
r
a
l
b
e
n
e
f
i
t
s
i
n
c
a
n
c
e
r
t
r
e
at
m
e
n
t
.
I
t
is
k
n
o
w
n
t
h
a
t
AL
A
r
e
d
u
c
es
t
u
m
o
r
c
e
l
l
v
i
a
b
i
li
t
y
a
n
d
p
r
o
l
i
f
e
r
a
t
i
o
n
a
n
d
i
n
c
r
e
a
s
es
a
p
o
p
t
o
s
i
s
i
n
v
a
r
i
o
u
s
t
y
p
es
o
f
ca
n
c
e
r
c
e
l
ls
,
i
n
c
l
u
d
i
n
g
n
e
u
r
o
b
la
s
t
o
m
a
a
n
d
b
r
e
a
s
t
c
a
n
c
e
r
.
I
n
a
d
d
i
t
i
o
n
,
w
h
e
n
A
L
A
i
s
c
o
m
b
i
n
e
d
wi
t
h
c
h
e
m
o
t
h
e
r
a
p
y
o
r
r
a
d
i
o
t
h
e
r
a
p
y
(
R
T
)
ag
e
n
t
s
,
it
e
x
h
i
b
i
ts
a
s
y
n
e
r
g
i
s
ti
c
e
f
f
e
c
t
,
w
h
i
c
h
e
n
h
a
n
c
e
s
t
h
e
c
y
t
o
t
o
x
i
c
e
f
f
e
ct
o
f
t
h
e
tr
e
a
t
m
e
n
t
.
A
L
A
al
s
o
f
u
n
c
t
i
o
n
s
a
s
a
r
a
d
i
o
s
e
n
s
i
ti
z
e
r
,
i
n
c
r
e
a
s
i
n
g
c
el
l
s
e
n
s
it
i
v
it
y
[
1
6
]
.
A
L
A
i
s
r
e
p
o
r
t
e
d
t
o
h
a
v
e
c
a
r
d
i
o
v
a
s
c
u
l
a
r
p
r
o
t
e
ct
i
o
n
,
n
e
u
r
o
n
p
r
o
t
e
c
t
i
o
n
,
a
n
t
i
-
c
a
n
c
e
r
,
a
n
t
i
-
o
s
t
e
o
p
o
r
o
s
i
s
,
a
n
t
i
-
i
n
f
l
a
m
m
at
o
r
y
,
a
n
d
a
n
t
i
o
x
id
a
n
t
e
f
f
e
c
ts
.
A
L
A
h
as
t
h
e
a
b
i
l
it
y
t
o
c
o
n
t
r
o
l
t
h
e
n
o
s
i
g
n
a
l
r
e
l
e
as
e
a
n
d
l
i
p
i
d
p
e
r
o
x
i
d
a
t
i
o
n
i
n
t
u
m
o
r
t
h
e
r
a
p
y
.
I
n
ad
d
i
t
i
o
n
,
A
L
A
c
a
n
a
c
t
i
v
at
e
t
h
e
m
i
t
o
g
e
n
-
a
c
ti
v
a
t
e
d
p
r
o
t
e
i
n
k
i
n
a
s
e
(
MA
PK
)
s
i
g
n
al
in
g
p
a
t
h
w
a
y
,
w
h
i
c
h
c
a
u
s
e
s
m
it
o
c
h
o
n
d
r
i
a
l
d
a
m
a
g
e
i
n
c
a
n
c
e
r
c
ell
s
[
1
7
]
.
I
n
r
esear
ch
o
n
ce
r
v
ical
ca
n
ce
r
,
HeL
a
ce
lls
ar
e
u
s
ed
.
I
n
th
is
s
tu
d
y
,
HeL
a
ce
lls
wer
e
u
s
ed
to
s
tu
d
y
th
e
p
o
ten
tial
m
ec
h
an
is
m
o
f
5
,
6
,
7
,
an
d
4'
-
tetr
am
eth
o
x
y
f
l
av
o
n
e
ag
ain
s
t
ca
n
ce
r
ce
lls
;
th
is
s
tu
d
y
s
p
ec
if
ically
co
n
ce
n
tr
ated
o
n
its
in
h
ib
ito
r
y
ef
f
ec
ts
th
r
o
u
g
h
v
ar
io
u
s
s
ig
n
a
lin
g
p
at
h
way
s
[
1
8
]
.
W
h
en
ex
p
o
s
ed
to
n
o
n
s
en
s
e
-
m
ed
iated
m
R
NA
d
ec
a
y
(
NM
D)
an
d
m
o
u
s
e
d
o
u
b
le
m
in
u
te
2
h
o
m
o
lo
g
(
MD
M2
)
i
n
h
ib
ito
r
s
,
HeL
a
c
ells
s
h
o
we
d
s
ig
n
if
ican
t
s
y
n
er
g
is
tic
ef
f
ec
ts
.
HeL
a
ce
lls
d
ied
,
an
d
th
e
ce
ll
cy
cle
s
to
p
p
ed
with
th
is
tr
ea
tm
en
t
[
1
9
]
.
Sach
a
I
n
ch
i
s
ee
d
o
il
h
as
an
ti
-
ca
n
ce
r
ac
tiv
ity
,
ac
co
r
d
in
g
to
r
esear
ch
.
E
x
v
ivo
,
a
Sach
a
I
n
ch
i
o
il
-
b
ased
d
iet
(
1
g
/
k
g
b
o
d
y
weig
h
t
d
aily
f
o
r
f
o
u
r
we
ek
s
)
r
ed
u
ce
d
tu
m
o
r
m
ass
an
d
tu
m
o
r
ce
ll
p
r
o
life
r
atio
n
in
tu
m
o
r
-
b
ea
r
in
g
W
alk
er
2
5
6
m
ice.
I
n
ad
d
itio
n
,
p
lasma
lev
els
o
f
g
ly
ce
m
ia,
tr
ig
ly
ce
r
id
es,
an
d
in
f
lam
m
at
o
r
y
cy
t
o
k
i
n
es
d
ec
r
ea
s
ed
,
an
d
l
ip
o
p
er
o
x
id
atio
n
in
c
r
ea
s
ed
in
W
alk
er
2
5
6
tu
m
o
r
tis
s
u
es.
Ad
d
itio
n
al
r
esear
ch
u
s
ed
1
,
2
-
d
i
m
eth
y
lh
y
d
r
az
in
e
to
in
d
u
ce
co
lo
n
ca
n
ce
r
in
Sp
r
ag
u
e
-
Daw
ley
an
d
W
is
tar
r
ats.
T
h
e
r
esu
lts
s
h
o
wed
th
at
th
e
g
r
o
u
p
o
f
r
ats
g
iv
en
Sach
a
I
n
c
h
i
s
ee
d
o
il
at
a
d
o
s
e
o
f
1
5
0
μ
L
/(
k
g
-
da
y
)
s
h
o
wed
a
1
2
.
5
%
in
cr
ea
s
e
in
th
e
n
u
m
b
er
o
f
in
d
iv
id
u
als
p
r
o
tecte
d
f
r
o
m
tu
m
o
r
in
d
u
ctio
n
[
2
0
]
,
[
2
1
]
.
T
h
is
s
tu
d
y
was
co
n
d
u
cted
u
s
in
g
th
e
MT
T
a
s
s
ay
m
eth
o
d
.
MT
T
ass
ay
is
a
m
eth
o
d
u
s
ed
to
ass
ess
th
e
cy
to
to
x
icity
o
f
f
r
ee
d
r
u
g
s
an
d
d
r
u
g
co
m
b
i
n
atio
n
s
ag
ain
s
t H
eL
a
ce
lls
[
2
2
]
.
MT
T
is
co
n
v
er
ted
t
o
a
co
lo
r
f
u
l,
in
s
o
lu
b
le
f
o
r
m
az
an
in
s
id
e
th
e
ce
lls
.
T
h
r
o
u
g
h
th
e
u
s
e
o
f
an
en
z
y
m
e
-
lin
k
e
d
im
m
u
n
o
s
o
r
b
en
t
ass
ay
(
E
L
I
SA
)
r
ea
d
er
t
o
m
ea
s
u
r
e
th
e
o
p
tica
l
d
en
s
ity
o
f
th
e
f
o
r
m
az
an
p
r
o
d
u
ct
at
4
9
5
n
m
,
th
is
p
r
o
ce
d
u
r
e
en
a
b
les th
e
q
u
a
n
tific
atio
n
o
f
liv
e
ce
lls
in
m
u
lti
-
well
m
icr
o
p
lates
[
2
3
]
,
[
2
4
]
.
T
h
is
s
tu
d
y
test
s
p
u
r
e
AL
A
is
o
lated
f
r
o
m
Sach
a
I
n
c
h
i
o
il
ag
ain
s
t
HeL
a
ce
r
v
ical
-
ca
n
ce
r
ce
lls
.
Un
lik
e
p
r
io
r
wo
r
k
th
at
u
s
ed
cr
u
d
e
ex
t
r
ac
ts
,
we
ev
alu
ate
th
e
p
u
r
if
ied
f
atty
ac
id
its
elf
,
f
in
d
in
g
th
at
it
s
I
C
₅₀
is
lo
wer
th
an
cisp
latin
’
s
,
m
ar
k
in
g
it
as
th
e
m
o
r
e
p
o
ten
t
ag
en
t.
W
e
also
c
o
m
p
ar
e
AL
A
f
r
o
m
two
o
il
s
o
u
r
ce
s
,
co
n
v
en
tio
n
al
p
lan
ts
v
s
.
th
o
s
e
g
r
o
w
n
with
s
h
r
im
p
-
waste
f
er
tili
ze
r
,
an
an
g
le
n
o
t
y
et
r
e
p
o
r
ted
.
T
h
e
r
esu
lts
p
r
o
v
id
e
a
n
ea
r
l
y
f
o
u
n
d
atio
n
f
o
r
s
af
er
,
s
u
s
tain
ab
le
n
atu
r
al
ad
ju
v
an
ts
in
ce
r
v
ical
ca
n
ce
r
th
er
a
p
y
.
2.
RE
S
E
ARCH
M
E
T
H
O
D
T
h
e
MT
T
ass
ay
u
s
in
g
HeL
a
ce
lls
in
clu
d
es
a
n
u
m
b
er
o
f
im
p
o
r
tan
t
s
tep
s
.
I
t
b
eg
in
s
with
ce
ll
an
aly
s
is
an
d
s
ep
ar
atio
n
an
d
en
d
s
with
an
ass
ay
u
s
in
g
th
e
MT
T
m
eth
o
d
to
ev
a
lu
ate
v
iab
ilit
y
.
T
o
d
eter
m
in
e
th
e
m
etab
o
lic
ac
tiv
ity
o
f
th
e
ce
ll
s
,
th
e
p
r
o
ce
d
u
r
e
in
v
o
l
v
es
th
e
s
ep
ar
atio
n
an
d
em
b
ed
d
in
g
o
f
ce
lls
in
a
9
6
-
well
p
late,
in
cu
b
atio
n
with
MT
T
r
e
ag
en
t,
an
d
m
ea
s
u
r
em
e
n
t o
f
a
b
s
o
r
b
an
ce
r
esu
lts
.
2
.
1
.
M
a
t
er
ia
ls
T
h
is
s
tu
d
y
u
s
ed
two
Sach
a
I
n
ch
i
o
il
s
am
p
les.
“Sac
h
i”
o
il
was
p
r
ess
ed
f
r
o
m
n
u
ts
g
r
o
wn
in
B
atan
g
,
C
en
tr
al
J
av
a:
1
0
0
g
o
f
d
r
ie
d
,
s
h
elled
b
ea
n
s
wer
e
m
ec
h
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ically
p
r
ess
ed
at
6
0
°C
,
allo
wed
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s
ettle
f
o
r
2
-
3
d
ay
s
,
a
n
d
y
ield
ed
ab
o
u
t
1
0
0
m
L
o
f
cr
u
d
e
o
il.
“Ali”
o
i
l,
s
u
p
p
lied
b
y
C
V
.
I
n
o
v
asi
An
ak
Neg
er
i
in
W
est
J
av
a
s
er
v
ed
as th
e
s
o
u
r
ce
f
o
r
i
s
o
latin
g
AL
A.
2
.
2
.
P
r
o
ce
du
re
s
2
.
2
.
1
.
L
iqu
id chro
m
a
t
o
g
ra
p
hy
-
hig
h r
eso
lutio
n m
a
s
s
s
pec
t
ro
m
et
r
y
a
s
s
a
y
T
h
e
an
aly
s
is
m
eth
o
d
u
s
es
liq
u
id
ch
r
o
m
at
o
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r
a
p
h
y
-
h
ig
h
r
eso
l
u
tio
n
m
ass
s
p
ec
tr
o
m
e
tr
y
(
L
C
-
HR
MS)
t
o
id
en
tify
an
d
c
h
ar
ac
ter
ize
AL
A
in
Sach
a
I
n
ch
i
o
il
with
a
h
ig
h
d
eg
r
ee
o
f
ac
cu
r
ac
y
,
all
o
win
g
d
etec
tio
n
o
f
Evaluation Warning : The document was created with Spire.PDF for Python.
I
SS
N
:
2
2
5
2
-
8
8
1
4
I
n
t J Ad
v
Ap
p
l Sci
,
Vo
l.
14
,
No
.
3
,
Sep
tem
b
er
20
25
:
966
-
9
7
4
968
co
m
p
o
u
n
d
s
in
lo
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c
o
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ce
n
tr
ati
o
n
s
as
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e
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b
etwe
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u
ctu
r
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o
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er
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.
L
C
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ich
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s
es
T
h
er
m
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Scien
tifi
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s
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q
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UHPL
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ar
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m
p
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ic'
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ad
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o
le
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itra
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Hig
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R
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tio
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s
s
Sp
ec
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o
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eter
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i
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er
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m
an
ce
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id
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r
o
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ato
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ap
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u
s
in
g
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m
o
Scien
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'
s
Acc
u
co
r
e™
Ph
en
y
l
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y
l
co
l
u
m
n
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T
h
e
m
o
b
ile
p
h
ases
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r
e
m
ass
s
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ec
tr
o
m
etr
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-
g
r
ad
e
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r
co
n
tain
in
g
0
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1
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f
o
r
m
ic
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id
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A)
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n
d
MS
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g
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ad
e
m
et
h
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o
l
co
n
tain
in
g
0
.
1
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f
o
r
m
ic
ac
id
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B
)
,
ap
p
lied
u
n
d
e
r
a
g
r
ad
ien
t
elu
tio
n
p
r
o
g
r
am
at
a
f
lo
w
r
ate
o
f
0
.
3
m
L
/m
in
.
T
h
e
g
r
a
d
ien
t
was
in
itiated
at
5
%
B
,
in
cr
ea
s
ed
lin
ea
r
ly
to
9
0
%
with
in
1
6
m
in
,
h
eld
f
o
r
4
m
in
,
a
n
d
th
e
n
r
etu
r
n
ed
t
o
th
e
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itial
co
n
d
iti
o
n
(
5
%
B
)
b
y
2
5
m
in
.
T
h
e
i
n
jectio
n
v
o
lu
m
e
was
3
µL
.
Ma
s
s
s
p
ec
tr
o
m
etr
ic
d
etec
tio
n
was
p
er
f
o
r
m
e
d
u
s
in
g
elec
tr
o
s
p
r
ay
io
n
izatio
n
(
E
SI
)
in
p
o
s
itiv
e
io
n
m
o
d
e,
with
a
ca
p
illar
y
v
o
ltag
e
o
f
3
.
3
0
k
V,
a
ca
p
illar
y
tem
p
e
r
a
tu
r
e
o
f
3
2
0
°
C
,
an
d
a
s
ca
n
r
an
g
e
o
f
6
6
.
7
–
1
0
0
0
m
/z.
T
h
is
co
m
b
in
atio
n
o
f
u
ltra
-
h
ig
h
-
p
er
f
o
r
m
a
n
ce
liq
u
id
ch
r
o
m
ato
g
r
ap
h
y
an
d
h
ig
h
-
r
es
o
lu
tio
n
Or
b
itra
p
m
ass
s
p
ec
tr
o
m
etr
y
en
a
b
led
h
ig
h
s
en
s
itiv
ity
,
ac
cu
r
ate
m
ass
m
e
asu
r
em
en
t,
an
d
co
m
p
r
e
h
en
s
iv
e
ch
ar
ac
ter
izatio
n
o
f
b
o
th
tar
g
et
co
m
p
o
u
n
d
s
an
d
co
m
p
lex
m
eta
b
o
lites
.
2
.
2
.
2
.
I
s
o
la
t
io
n o
f
a
lph
a
-
lin
o
lenic
a
cid
T
h
e
s
tu
d
y
u
s
es
f
lash
ch
r
o
m
a
to
g
r
ap
h
y
to
is
o
late
alp
h
a
-
lin
o
len
at
e
f
r
o
m
a
lar
g
e
s
am
p
le
o
f
1
.
2
g
,
an
aly
zin
g
it
in
an
8
:2
r
atio
.
T
h
e
s
am
p
le
is
d
is
s
o
lv
ed
in
ch
lo
r
o
f
o
r
m
f
o
r
1
5
m
in
u
tes,
an
d
p
u
r
if
icatio
n
is
p
er
f
o
r
m
ed
u
s
in
g
f
lash
ch
r
o
m
ato
g
r
ap
h
y
C
-
8
5
0
.
T
h
e
f
las
h
ch
r
o
m
ato
g
r
a
p
h
y
co
lu
m
n
is
ch
ar
ac
ter
ized
b
y
a
s
tatio
n
an
d
eq
u
ilib
r
atio
n
.
Sach
a
I
n
ch
i
o
il
s
am
p
les
wer
e
ex
tr
ac
ted
u
s
in
g
th
e
c
o
ld
-
p
r
ess
in
g
m
eth
o
d
,
th
e
n
p
u
r
if
ied
b
y
liq
u
id
-
liq
u
id
e
x
tr
a
ctio
n
u
s
in
g
n
-
h
ex
an
e
s
o
lv
en
t.
L
C
-
HR
MS
an
aly
s
i
s
was
p
er
f
o
r
m
ed
u
s
in
g
a
C
1
8
co
lu
m
n
(
1
0
0
m
m
×
2
.
1
m
m
,
1
.
7
µm
)
with
a
tem
p
er
atu
r
e
o
f
4
0
°C
,
a
f
l
o
w
r
ate
o
f
0
.
3
m
L
/
m
in
,
an
d
a
m
o
b
ile
p
h
ase
o
f
0
.
1
%
f
o
r
m
ic
ac
id
i
n
wate
r
:
m
eth
an
o
l
(
3
0
:7
0
v
/
v
)
.
Dete
ctio
n
was
p
er
f
o
r
m
ed
at
a
wav
elen
g
th
o
f
2
1
5
n
m
,
with
p
o
s
itiv
e
io
n
elec
tr
o
s
p
r
ay
io
n
izatio
n
(
E
SI+
)
m
o
d
e
to
id
en
tif
y
th
e
s
p
ec
if
ic
m
/z
o
f
AL
A
.
2
.
2
.
3
.
Culture
H
eLa
ce
lls
T
h
e
MT
T
ass
ay
in
v
o
lv
es
u
s
in
g
HeL
a
ce
lls
th
at
r
ea
ch
7
0
-
8
0
%
co
n
f
lu
en
ce
i
n
a
7
5
cm
2
t
-
f
lask
.
T
h
e
ce
lls
ar
e
wash
ed
,
in
c
u
b
ated
i
n
a
3
7
°
C
,
5
%
C
O
2
in
c
u
b
ato
r
,
an
d
th
e
n
tr
an
s
f
e
r
r
ed
to
a
c
en
tr
if
u
g
atio
n
tu
b
e.
C
o
m
p
lete
m
ed
ia
is
ad
d
ed
,
an
d
th
e
ce
lls
ar
e
s
ep
ar
ated
an
d
s
u
b
cu
ltu
r
e
d
in
9
6
-
well
p
lates.
T
h
e
r
em
ain
in
g
ce
lls
ar
e
th
en
s
u
b
c
u
ltu
r
ed
in
7
5
c
m
2
t
-
f
lask
s
.
HeL
a
ce
lls
wer
e
s
ee
d
ed
in
9
6
-
well
p
lates
u
s
in
g
1
0
0
μ
L
o
f
ce
lls
,
a
5
tim
es
d
ilu
tio
n
,
a
n
d
2
,
0
0
0
,
0
0
0
ce
lls
p
er
well.
On
e
p
late
was
u
s
ed
to
test
th
r
ee
co
m
p
o
u
n
d
s
an
d
a
p
o
s
itiv
e
co
n
tr
o
l,
cisp
latin
,
a
n
d
ce
lls
wer
e
in
cu
b
ated
o
v
e
r
n
ig
h
t i
n
a
3
7
°
C
,
5
% C
O
2
in
cu
b
ato
r
.
2.
2
.
4
.
M
T
T
a
s
s
a
y
cy
t
o
t
o
x
icit
y
t
est
T
h
e
s
ee
d
ed
ce
lls
wer
e
o
b
s
er
v
ed
f
o
r
co
n
f
lu
e
n
cy
,
an
d
if
9
0
%
co
n
f
lu
en
cy
was
r
ea
ch
ed
,
th
ey
wer
e
r
ea
d
y
f
o
r
th
e
MT
T
ass
ay
.
T
h
r
ee
test
co
m
p
o
u
n
d
s
(
Sach
i,
Al
i,
an
d
AL
A)
wer
e
v
a
r
ied
in
co
n
ce
n
tr
atio
n
u
s
in
g
s
tr
atif
ied
d
ilu
tio
n
in
Fig
u
r
e
1
.
Ali
an
d
S
ac
h
i
wer
e
u
s
ed
as
a
co
n
tr
o
l,
wh
ile
A
L
A
was
u
s
ed
a
s
a
p
o
s
itiv
e
co
n
tr
o
l.
T
h
e
9
6
-
well
p
late
was
in
cu
b
at
ed
with
MT
T
s
o
lu
tio
n
d
is
s
o
lv
ed
in
b
asal
m
ed
ia
f
o
r
4
h
o
u
r
s
,
f
o
llo
wed
b
y
th
e
ad
d
itio
n
o
f
test
s
am
p
les.
Fo
r
m
az
an
cr
y
s
tals
wer
e
o
b
s
er
v
ed
af
ter
4
h
o
u
r
s
,
an
d
d
i
s
s
o
lv
ed
with
2
0
%
s
o
d
iu
m
d
o
d
ec
y
l
s
u
lf
ate
(
SDS
)
s
to
p
r
ea
ctio
n
s
o
lu
tio
n
.
Af
ter
2
4
,
4
8
,
a
n
d
7
2
h
o
u
r
s
o
f
tr
ea
tm
en
t
with
AL
A,
1
0
µL
o
f
MT
T
s
o
lu
tio
n
(
5
m
g
/m
L
in
p
h
o
s
p
h
ate
-
b
u
f
f
er
ed
s
alin
e
(
PB
S)
)
was
ad
d
e
d
to
ea
ch
we
ll
an
d
i
n
cu
b
ate
d
f
o
r
4
h
o
u
r
s
at
3
7
°C
.
T
h
e
m
e
d
iu
m
was
r
em
o
v
ed
,
an
d
1
0
0
µL
d
im
eth
y
l
s
u
lf
o
x
id
e
(
DM
SO)
was
ad
d
ed
t
o
d
is
s
o
lv
e
th
e
f
o
r
m
az
an
f
o
r
m
ed
.
Ab
s
o
r
b
an
ce
was
m
ea
s
u
r
e
d
u
s
in
g
an
E
L
I
SA
r
ea
d
er
at
a
wav
elen
g
th
o
f
5
7
0
n
m
with
a
r
ef
er
en
ce
f
ilter
o
f
6
3
0
n
m
.
Fig
u
r
e
1
.
Dilu
tio
n
p
r
o
ce
s
s
o
f
test
co
m
p
o
u
n
d
f
o
r
MT
T
ass
ay
3.
RE
SU
L
T
S AN
D
D
I
SCU
SS
I
O
N
T
h
is
s
tu
d
y
u
tili
ze
d
AL
A
i
s
o
lated
f
r
o
m
Sach
a
I
n
ch
i
o
il
B
,
wh
er
e
th
e
Sach
a
I
n
ch
i
p
lan
ts
wer
e
f
er
tili
ze
d
u
s
in
g
s
h
r
im
p
waste
.
I
n
co
n
tr
ast,
Sach
a
I
n
c
h
i
o
i
l
A
was
o
b
tain
ed
f
r
o
m
p
la
n
ts
cu
ltiv
ated
u
s
in
g
co
n
v
en
tio
n
al
f
e
r
tili
za
tio
n
m
et
h
o
d
s
.
T
h
e
c
o
m
p
ar
is
o
n
b
etwe
e
n
th
ese
two
cu
ltiv
atio
n
s
y
s
tem
s
aim
ed
to
ev
alu
ate
Evaluation Warning : The document was created with Spire.PDF for Python.
I
n
t J Ad
v
Ap
p
l Sci
I
SS
N:
2252
-
8
8
1
4
Th
era
p
eu
tic
p
o
ten
tia
l
o
f a
lp
h
a
-
lin
o
len
ic
a
cid
fr
o
m
S
a
ch
a
I
n
c
h
i o
il in
ce
r
vica
l c
a
n
ce
r
:
…
(
A
d
i P
erma
d
i
)
969
th
e
p
o
ten
tial
ef
f
ec
t
o
f
o
r
g
an
ic
s
h
r
im
p
waste
f
er
tili
ze
r
o
n
o
il
q
u
ality
.
T
h
is
d
is
tin
ctio
n
p
r
o
v
id
es
v
a
lu
ab
le
in
s
ig
h
t
in
to
s
u
s
tain
ab
le
ag
r
icu
ltu
r
al
p
r
ac
tices a
n
d
th
eir
im
p
ac
t o
n
b
io
ac
tiv
e
co
m
p
o
u
n
d
p
r
o
d
u
ctio
n
.
3
.
1
.
Co
m
po
un
d identif
ica
t
io
n in
Sa
cha
I
nc
hi
o
il
T
h
e
L
C
-
HR
MS
an
aly
s
i
s
o
f
Sach
a
I
n
ch
i
o
il
s
am
p
le
B
(
cu
ltiv
ated
with
s
h
r
im
p
waste
f
er
tili
ze
r
)
id
en
tifie
d
2
6
ac
tiv
e
co
m
p
o
u
n
d
s
,
in
clu
d
in
g
AL
A,
d
ig
ly
ce
r
i
d
es
,
m
an
d
en
o
l
,
an
d
o
th
er
b
io
ac
tiv
e
lip
id
s
.
AL
A,
with
a
r
eten
tio
n
tim
e
o
f
1
4
.
4
9
4
m
in
u
tes an
d
a
m
o
lecu
lar
f
o
r
m
u
la
o
f
C
18
H
30
O
2
,
was c
o
n
f
ir
m
ed
as th
e
d
o
m
in
an
t
an
ti
-
ca
n
ce
r
co
m
p
o
u
n
d
in
T
ab
l
e
1
.
T
h
ese
f
in
d
in
g
s
ar
e
co
n
s
is
ten
t
with
p
r
io
r
s
tu
d
ies
s
h
o
win
g
Sach
a
I
n
ch
i
’
s
r
ich
u
n
s
atu
r
ated
f
atty
ac
id
p
r
o
f
ile
an
d
an
tio
x
id
an
t
p
o
ten
tial.
T
h
i
s
co
m
p
o
u
n
d
s
h
o
wed
a
r
eten
tio
n
tim
e,
wh
ic
h
is
th
e
tim
e
r
eq
u
ir
ed
t
o
p
ass
th
r
o
u
g
h
th
e
ch
r
o
m
ato
g
r
ap
h
y
co
lu
m
n
,
o
f
1
4
.
4
9
2
.
T
h
ese
r
esu
lts
co
n
f
ir
m
e
d
th
at
AL
A
(
C
18
H
30
O
2
)
was
s
u
cc
ess
f
u
lly
id
en
tifie
d
in
th
e
Sach
a
I
n
c
h
i
o
i
l sam
p
le.
T
ab
le
1
.
An
aly
s
is
r
esu
lts
o
f
an
ti
-
ca
n
ce
r
co
m
p
o
u
n
d
s
in
Sach
a
I
n
ch
i
o
il
S
t
r
u
c
t
u
r
e
N
a
me
F
o
r
mu
l
a
R
e
t
e
n
t
i
o
n
t
i
m
e
(
mi
n
)
P
e
r
c
e
n
t
a
g
e
(
%)
A
LA
C
18
H
30
O
2
14
.
494
4
.
4
5
2
DG
(
1
8
:
2
(
9
Z,
1
2
Z)
/
1
8
:
3
(
9
Z.
1
2
Z,
1
5
Z)
/
0
:
0
)
C
39
H
66
O
5
19
.
657
20
.
09
1
,
2
-
D
i
l
i
n
o
l
e
o
y
l
-
sn
-
g
l
y
c
e
r
o
l
C
39
H
68
O
5
20
.
202
15
.
48
M
a
n
d
e
n
o
l
C
20
H
36
O
2
14
.
977
11
.
8
Tr
e
h
a
l
o
se
-
6,
6
-
d
i
b
e
h
e
n
a
t
e
C
56
H
106
O
13
21
.
15
6
.
5
3
3
3
-
[
(
1
5
Z,
1
9
Z)
-
1
1
,
1
2
-
d
i
h
y
d
r
o
x
y
-
1
5
,
19
-
d
o
c
t
r
i
a
c
o
n
t
a
d
i
e
n
-
1
-
y1]
-
5
-
me
t
h
y
l
-
2
(
5
H
)
-
f
u
r
a
n
o
n
e
C
37
H
66
O
4
20
.
416
5
.
7
9
2
1
-
o
l
e
o
y
l
-
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-
l
i
n
o
l
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l
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g
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y
c
e
r
o
l
C
39
H
70
O
5
20
.
726
5
.
7
0
1
(
2
2
R
,
2
3
R
,
2
4
S
)
-
22
,
23
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d
i
h
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d
r
o
x
y
e
r
g
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st
-
4
-
en
-
3
-
o
n
e
C
28
H
46
O
3
18
.
5
3
.
7
8
7
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a
mi
n
o
-
1
,
3
,
4
-
o
c
t
a
d
e
c
a
n
e
t
r
i
o
l
C
18
H
39
NO
3
9
.
9
3
3
3
.
5
4
8
1
-
(
9
Z
-
h
e
x
a
d
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e
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o
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l
)
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(
9
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o
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a
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e
r
o
l
C
37
H
66
O
5
19
.
97
1
.
2
5
5
3
.
2
.
I
s
o
la
t
io
n
o
f
a
lph
a
-
lin
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nic a
cid
T
o
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,
t
h
i
n
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la
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a
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p
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(
T
L
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w
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c
o
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c
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c
o
m
p
o
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n
d
s
e
p
a
r
a
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.
F
i
g
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2
s
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r
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b
io
a
s
s
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y
t
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t
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g
.
T
h
e
Evaluation Warning : The document was created with Spire.PDF for Python.
I
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I
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t J Ad
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Ap
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,
Vo
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14
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No
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3
,
Sep
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b
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20
25
:
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[
2
4
]
,
[
2
5
]
.
T
h
e
T
L
C
an
aly
s
is
r
ev
ea
ls
m
u
ltip
le
co
m
p
o
n
en
ts
in
Sach
a
I
n
ch
i
o
il,
in
clu
d
in
g
AL
A
(
Fig
u
r
e
3
(
a)
)
.
T
h
e
s
ep
ar
atio
n
p
r
o
f
ile
o
f
t
h
e
co
m
p
o
u
n
d
was
co
n
f
ir
m
e
d
u
s
in
g
T
L
C
an
d
f
las
h
c
h
r
o
m
ato
g
r
ap
h
y
,
as
p
r
esen
ted
in
Fig
u
r
e
3
.
T
h
e
T
L
C
r
esu
lt
(
Fig
u
r
e
3
(
a
)
)
s
h
o
ws
d
is
tin
ct
s
p
o
ts
in
d
icatin
g
t
h
e
p
r
esen
ce
o
f
th
e
tar
g
et
co
m
p
o
u
n
d
,
wh
ile
th
e
f
lash
ch
r
o
m
ato
g
r
ap
h
y
p
r
o
f
ile
(
Fig
u
r
e
3
(
b
)
)
d
em
o
n
s
tr
ates su
cc
ess
f
u
l iso
latio
n
with
a
clea
r
f
r
ac
tio
n
p
atter
n
.
Prio
r
to
p
u
r
if
icatio
n
,
th
e
o
il
s
am
p
le
u
n
d
er
g
o
es
1
5
m
in
u
te
s
s
o
n
icatio
n
to
en
h
an
ce
s
ep
ar
atio
n
ef
f
icien
cy
.
T
h
e
p
u
r
if
ied
f
r
ac
tio
n
s
ar
e
th
en
v
alid
at
ed
b
y
T
L
C
,
co
n
f
ir
m
in
g
th
e
s
u
cc
ess
f
u
l iso
latio
n
o
f
tar
g
et
co
m
p
o
u
n
d
s
.
AL
A
was
th
e
co
m
p
o
u
n
d
f
o
u
n
d
in
th
e
f
l
ash
ch
r
o
m
ato
g
r
ap
h
y
an
d
T
L
C
r
esu
lts
,
in
d
icatin
g
th
at
th
e
s
ep
a
r
atio
n
an
d
an
aly
s
i
s
p
r
o
ce
s
s
p
er
f
o
r
m
e
d
s
u
cc
ess
f
u
lly
id
en
tifie
d
th
e
m
ain
co
m
p
o
n
en
t
o
f
t
h
e
s
am
p
le.
T
h
e
s
im
ilar
r
esu
lts
f
o
r
b
o
th
m
eth
o
d
s
in
d
icate
th
at
th
e
s
ep
ar
atio
n
m
eth
o
d
u
s
ed
was
well
o
p
tim
ized
an
d
s
en
s
iti
v
e
an
d
s
elec
tiv
e
en
o
u
g
h
to
f
in
d
AL
A.
(
a)
(
b
)
Fig
u
r
e
2
.
Pro
f
ilin
g
with
(
a
)
T
L
C
an
d
(
b
)
T
L
C
r
esu
lts
(
a)
(
b
)
Fig
u
r
e
3
.
R
esu
lt o
f
(
a
)
T
L
C
an
d
(
b
)
f
lash
ch
r
o
m
ato
g
r
ap
h
y
3
.
3
.
M
T
T
a
s
s
a
y
us
ing
H
eLa
ce
lls
T
h
e
MT
T
cy
to
to
x
icity
test
o
n
HeL
a
ce
lls
r
ev
ea
led
p
r
o
n
o
u
n
ce
d
d
if
f
er
en
ce
s
in
p
o
ten
c
y
am
o
n
g
th
e
s
am
p
les.
C
is
p
latin
,
th
e
p
o
s
itiv
e
co
n
tr
o
l,
s
h
ar
p
ly
r
e
d
u
ce
d
c
ell
v
iab
ilit
y
a
b
o
v
e
3
1
p
p
m
,
y
ield
in
g
an
I
C
₅₀
o
f
1
6
.
7
p
p
m
.
I
n
co
n
tr
ast,
Sach
a
I
n
ch
i
o
il
m
ain
tain
ed
h
ig
h
v
iab
ilit
y
ac
r
o
s
s
th
e
test
ed
d
o
s
e
s
,
with
an
I
C
₅₀
o
f
2
2
5
.
9
p
p
m
,
in
d
icatin
g
wea
k
c
y
to
to
x
icity
.
Ali
o
il,
h
o
we
v
er
,
lo
wer
ed
v
iab
ilit
y
e
v
en
at
lo
w
co
n
ce
n
tr
atio
n
s
a
n
d
p
r
o
d
u
ce
d
an
I
C
₅₀
o
f
1
6
.
1
p
p
m
,
n
ea
r
ly
m
atch
in
g
cisp
latin
’
s
ef
f
ec
t.
T
h
e
m
o
s
t
p
o
wer
f
u
l
r
esp
o
n
s
e
ca
m
e
f
r
o
m
p
u
r
if
ied
AL
A:
test
ed
o
v
er
a
m
u
ch
n
ar
r
o
wer
co
n
ce
n
tr
atio
n
r
an
g
e,
it
p
r
o
d
u
ce
d
th
e
g
r
ea
test
in
h
ib
itio
n
,
with
an
ex
ce
p
tio
n
ally
lo
w
I
C
₅₀
(
~9
×1
0
⁻²⁶
p
p
m
)
,
u
n
d
e
r
s
co
r
in
g
its
s
u
p
er
io
r
p
o
ten
tial a
s
an
an
ti
-
ca
n
ce
r
ag
en
t.
T
h
ese
r
esu
lts
co
llectiv
ely
s
u
p
p
o
r
t
th
e
p
o
ten
tial
o
f
AL
A
as
a
s
tr
o
n
g
an
ti
-
ca
n
ce
r
ag
e
n
t
w
ith
h
ig
h
er
ef
f
ec
tiv
en
ess
at
lo
wer
co
n
ce
n
t
r
atio
n
s
co
m
p
ar
e
d
to
b
o
th
c
r
u
d
e
o
il
s
am
p
les
an
d
s
tan
d
ar
d
ch
em
o
th
er
ap
y
ag
en
ts
.
Fig
u
r
e
4
s
h
o
ws
th
e
v
is
u
al
d
if
f
er
en
ce
s
in
ce
ll
v
iab
ilit
y
tr
en
d
s
af
f
ir
m
th
e
r
elativ
e
cy
to
t
o
x
ic
s
tr
en
g
th
o
f
ea
ch
Evaluation Warning : The document was created with Spire.PDF for Python.
I
n
t J Ad
v
Ap
p
l Sci
I
SS
N:
2252
-
8
8
1
4
Th
era
p
eu
tic
p
o
ten
tia
l
o
f a
lp
h
a
-
lin
o
len
ic
a
cid
fr
o
m
S
a
ch
a
I
n
c
h
i o
il in
ce
r
vica
l c
a
n
ce
r
:
…
(
A
d
i P
erma
d
i
)
971
test
ed
co
m
p
o
u
n
d
.
Fig
u
r
e
4
(
a)
s
h
o
ws
th
e
co
m
p
ar
ativ
e
cy
t
o
to
x
icity
o
f
c
is
p
latin
,
Fig
u
r
e
4
(
b
)
s
h
o
ws
th
e
Sach
i
,
Fig
u
r
e
4
(
c)
s
h
o
ws
th
e
Ali,
a
n
d
Fig
u
r
e
4
(
d
)
s
h
o
ws
th
e
A
L
A
o
n
HeL
a
ce
lls
.
T
h
e
MT
T
ass
ay
elu
ate
s
th
e
cy
to
to
x
icity
o
f
AL
A,
Sach
a
I
n
ch
i
o
il
s
am
p
le
A
(
Sach
i
)
,
an
d
s
am
p
le
B
(
Ali)
o
n
He
L
a
ce
lls
.
T
h
e
r
esu
lts
s
h
o
wed
cisp
latin
h
ad
th
e
lo
west
I
C
50
(
1
6
,
7
3
p
p
m
)
,
in
d
ic
atin
g
s
tr
o
n
g
cy
t
o
to
x
icity
.
Sa
m
p
le
S
ac
h
i
h
ad
th
e
h
ig
h
est
I
C
50
(
2
2
5
.
9
p
p
m
)
,
s
h
o
win
g
th
e
wea
k
est
c
y
to
t
o
x
icity
ef
f
ec
t,
wh
ile
s
am
p
le
Ali
(
I
C
50
:
1
6
.
1
0
p
p
m
)
a
n
d
AL
A
(
I
C
50
:
9
.
5
5
7
e+
0
2
)
s
h
o
w
ed
s
tr
o
n
g
er
in
h
ib
itio
n
at
lo
we
r
co
n
ce
n
tr
atio
n
s
,
with
co
n
ce
n
tr
atio
n
s
,
with
AL
A
b
ein
g
th
e
m
o
s
t
p
o
ten
t.
T
h
ese
f
in
d
in
g
s
s
u
g
g
est
AL
A
is
a
p
r
o
m
is
in
g
an
ti
-
ca
n
ce
r
c
o
m
p
o
u
n
d
d
u
e
to
its
h
ig
h
ef
f
icac
y
at
m
in
im
al
c
o
n
ce
n
tr
at
io
n
s
.
Do
s
e
-
d
ep
en
d
e
n
t
cy
to
t
o
x
icity
s
h
o
ws
in
b
a
r
ch
a
r
ts
in
Fig
u
r
e
4
(
a)
cisp
latin
(
c
o
n
tr
o
l)
–
IC
50
=1
6
.
7
3
p
p
m
,
Fig
u
r
e
4
(
b
)
Sach
i
–
IC
50
=2
2
5
.
9
p
p
m
,
Fig
u
r
e
4
(
c
)
Ali
–
IC
50
=1
6
.
1
0
p
p
m
,
an
d
Fig
u
r
e
4
(
d
)
lin
o
len
ic
ac
id
–
IC
50
=9
.
5
5
7
e+
0
2
p
p
m
.
Data
ar
e
p
r
esen
ted
as
m
ea
n
s
tan
d
ar
d
d
ev
iatio
n
(
SD)
,
with
d
ec
r
ea
s
i
n
g
ce
ll
v
iab
ilit
y
as
co
n
ce
n
tr
atio
n
in
c
r
ea
s
es
.
T
h
e
I
C
50
v
alu
es
in
d
icate
th
e
co
n
ce
n
tr
atio
n
r
eq
u
i
r
ed
to
in
h
ib
it
5
0
%
o
f
ce
ll
v
iab
ilit
y
.
AL
A
h
as
a
lar
g
e
in
h
ib
ito
r
y
ef
f
ec
t
d
esp
ite
its
s
m
aller
co
n
ce
n
tr
atio
n
r
an
g
e
,
as
s
h
o
wn
b
y
th
e
I
C
50
v
alu
e
in
Fig
u
r
e
4
,
wh
ich
is
v
er
y
s
m
all.
T
h
is
v
alu
e
in
d
icate
s
th
at
e
v
e
n
at
lo
w
c
o
n
ce
n
tr
ati
o
n
s
,
AL
A
is
v
er
y
ef
f
ec
tiv
e
i
n
in
h
ib
itin
g
ca
n
ce
r
ce
ll g
r
o
wth
.
T
h
e
r
esu
lts
o
f
th
e
ce
ll v
iab
ilit
y
test
an
d
I
C
50
in
d
icate
th
at
A
L
A
h
as
th
e
p
o
ten
tial
to
b
e
a
v
e
r
y
s
tr
o
n
g
an
ti
-
ca
n
ce
r
ag
en
t.
(
a)
(
b
)
(
c)
(
d
)
Fig
u
r
e
4
.
E
f
f
ec
t o
f
d
if
f
e
r
en
t c
o
m
p
o
u
n
d
s
o
n
ce
ll
v
iab
ilit
y
o
f
(
a)
co
m
p
a
r
ativ
e
cy
to
to
x
icity
o
f
,
(
b
)
Sach
i
,
(
c)
Ali,
an
d
(
d
)
AL
A
o
n
HeL
a
ce
lls
Prio
r
to
th
e
MT
T
ass
ay
,
ce
ll
cu
ltu
r
e
o
f
h
elica
l
ce
lls
was
c
ar
r
ied
o
u
t
to
e
n
s
u
r
e
th
at
th
e
ce
lls
c
o
u
ld
g
r
o
w
an
d
d
e
v
e
lo
p
o
p
tim
ally
i
n
an
a
p
p
r
o
p
r
iate
cu
ltu
r
e
en
v
ir
o
n
m
en
t
,
as
s
h
o
wn
in
Fig
u
r
e
5
.
I
n
th
e
co
n
d
itio
n
o
f
h
elica
l
ce
lls
b
ef
o
r
e
s
ee
d
in
g
,
as
s
h
o
wn
in
Fig
u
r
e
5
(
a)
.
T
h
e
ce
lls
ar
e
n
u
m
er
o
u
s
an
d
s
ca
tter
ed
all
o
v
er
th
e
s
u
r
f
ac
e
with
a
r
o
u
n
d
o
r
o
v
al
s
h
ap
e
ty
p
ical
o
f
He
L
a
ce
lls
,
in
d
icatin
g
th
at
th
ey
ar
e
h
ea
lth
y
an
d
h
av
e
n
o
t
ex
p
er
ien
ce
d
f
u
ll
attac
h
m
en
t
to
th
e
cu
ltu
r
e
m
ed
iu
m
.
T
h
e
n
,
th
e
s
ee
d
in
g
p
r
o
ce
s
s
is
ca
r
r
ied
o
u
t
o
n
HeL
a
ce
lls
in
Fig
u
r
e
5
(
b
)
,
an
d
it
ca
n
b
e
s
ee
n
th
at
th
e
ce
lls
b
eg
in
to
ad
ap
t
an
d
ad
h
er
e
to
th
e
cu
lt
u
r
e
m
e
d
iu
m
.
Af
t
er
cu
ltu
r
e,
HeL
a
ce
lls
wer
e
test
ed
b
y
ad
d
in
g
test
p
ar
am
eter
s
o
r
s
am
p
les.
Fig
u
r
e
5
(
a)
is
a
n
o
r
m
al
HeL
a
ce
ll
with
o
u
t
an
y
tr
ea
tm
en
t.
Fig
u
r
e
6
s
h
o
ws
th
e
HeL
a
ce
lls
with
ad
d
itio
n
o
f
Sach
i
an
d
Ali
.
Fig
u
r
e
6
(
a
)
is
an
im
ag
e
o
f
H
eL
a
ce
lls
to
wh
ich
th
e
Sach
i
s
am
p
le
was
ad
d
ed
,
s
h
o
win
g
th
at
th
e
ce
ll
d
is
tr
ib
u
tio
n
an
d
m
o
r
p
h
o
lo
g
y
r
em
ain
ed
th
e
s
am
e
as
th
e
u
n
tr
ea
ted
HeL
a
ce
lls
.
T
h
er
e
wer
e
n
o
s
ig
n
if
ican
t
ch
an
g
es
in
s
h
ap
e
o
r
s
ig
n
s
o
f
ce
ll
d
am
ag
e,
s
u
ch
as
ab
n
o
r
m
al
r
o
u
n
d
in
g
o
r
cl
u
s
ter
in
g
,
wh
ich
ar
e
in
d
icativ
e
o
f
to
x
ic
ef
f
ec
ts
.
T
h
e
Sach
i
ca
n
b
e
co
n
s
id
er
ed
s
af
e
f
o
r
HeL
a
ce
lls
u
n
d
er
th
e
co
n
d
itio
n
s
test
ed
b
ec
au
s
e
n
o
s
ig
n
if
ican
t
cy
to
to
x
icity
o
r
ad
v
er
s
e
ef
f
e
cts
o
n
ce
ll
v
iab
ilit
y
,
p
r
o
life
r
atio
n
,
o
r
m
o
r
p
h
o
lo
g
y
wer
e
o
b
s
er
v
ed
d
u
r
i
n
g
th
e
e
x
p
e
r
im
en
tal
p
er
io
d
,
as sh
o
wn
in
F
ig
u
r
e
6
.
Fig
u
r
e
6
(
a)
s
h
o
ws
th
at
S
ac
h
i
A
o
il
h
as
n
o
to
x
ic
ef
f
ec
t
o
n
HeL
a
ce
ll
s
,
as
th
e
ce
lls
r
em
ain
v
iab
le
an
d
m
ai
n
tain
th
eir
s
tr
u
ctu
r
e
well.
HeL
a
ce
lls
s
h
o
w
s
ig
n
s
o
f
ce
ll
d
ea
th
o
r
d
a
m
ag
e
af
ter
tr
ea
tm
en
t
with
Sach
i
,
as
s
h
o
wn
in
Fig
u
r
e
6
(
b
)
.
T
h
e
ab
s
en
ce
o
f
n
ee
d
le
cr
y
s
tal
f
o
r
m
atio
n
s
u
g
g
es
ts
cy
to
to
x
icity
,
ca
u
s
in
g
a
d
ec
r
ea
s
e
in
ce
ll
d
en
s
ity
an
d
em
p
t
y
ar
ea
s
ar
o
u
n
d
d
am
a
g
ed
ce
lls
,
af
f
ec
tin
g
c
ell
d
ev
elo
p
m
en
t a
n
d
s
u
r
v
iv
al.
Fig
u
r
e
7
s
h
o
ws
th
e
MT
T
ass
a
y
r
esu
lts
r
ev
ea
l
g
r
ad
atio
n
s
o
f
c
o
lo
r
f
o
r
cisp
latin
,
Sach
i
,
Ali
,
an
d
AL
A
o
n
HeL
a
ce
lls
,
with
cisp
latin
s
h
o
win
g
th
e
p
alest
co
lo
r
(
in
d
i
ca
tin
g
h
ig
h
ce
ll
d
ea
th
)
,
wh
ile
AL
A
ex
h
ib
its
th
e
Evaluation Warning : The document was created with Spire.PDF for Python.
I
SS
N
:
2
2
5
2
-
8
8
1
4
I
n
t J Ad
v
Ap
p
l Sci
,
Vo
l.
14
,
No
.
3
,
Sep
tem
b
er
20
25
:
966
-
9
7
4
972
m
o
s
t
in
ten
s
e
p
u
r
p
le
(
s
u
g
g
esti
n
g
lo
wer
cy
to
to
x
icity
)
.
Pre
v
i
o
u
s
s
tu
d
ies
in
d
icate
th
at
AL
A
in
h
ib
its
HeL
a
ce
ll
g
r
o
wth
b
y
u
p
to
5
4
.
3
%
th
r
o
u
g
h
ap
o
p
t
o
s
is
an
d
ce
ll
cy
cle
ar
r
est,
m
ed
iated
b
y
in
cr
ea
s
ed
p
r
o
-
ap
o
p
to
tic
p
r
o
tein
ex
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ase
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(
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u
r
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5
.
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d
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6
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DATA AV
AI
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AB
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a
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d
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,
[
AP]
,
u
p
o
n
r
ea
s
o
n
ab
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r
eq
u
est.
RE
F
E
R
E
NC
E
S
[
1
]
L.
L
i
a
n
d
Y
.
S
u
,
“
M
e
d
i
a
t
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o
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f
f
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:
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sec
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[
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S
.
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a
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a
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.
,
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f
f
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ma
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x
p
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ss
e
d
g
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3
(
l
n
c
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EG
3
)
o
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t
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[
3
]
S
.
M
a
s
o
o
d
,
A
.
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.
K
u
s
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w
a
h
,
A
.
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.
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,
K
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v
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,
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M
.
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a
n
e
r
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e
e
,
“
‘
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Ep
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[
4
]
M
.
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n
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b
a
o
,
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e
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Adi
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s
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m
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sin
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0
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tere
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a
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m
a
ste
r’s
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ITB)
in
2
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a
n
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Do
c
to
r
o
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Ch
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m
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h
.
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fro
m
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ti
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i
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.
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c
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t
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t
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p
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d
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a
d
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c
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d
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tia
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m
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g
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g
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m
a
d
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h
lan
Un
i
v
e
rsity
with
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stro
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a
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o
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h
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n
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.
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h
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a
s
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c
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c
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s
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p
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v
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e
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ir
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ip
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rth
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s fo
r
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.
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h
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c
a
n
b
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c
o
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tac
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t
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m
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:
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e
b
m
a
il
.
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a
d
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a
c
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d
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h
a
m
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trep
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r
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n
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in
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o
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to
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w
h
o
h
a
s
p
ro
v
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n
h
ims
e
lf
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v
a
rio
u
s
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d
u
str
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c
to
rs.
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sk
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b
u
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m
a
n
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s
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s b
ra
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fiel
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s o
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lt
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c
o
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o
d
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ra
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s,
a
s
we
ll
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s
a
g
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re
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v
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k
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c
c
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in
c
re
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ti
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n
d
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s m
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trep
re
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d
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ra
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AS
P
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TRI),
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l
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e
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.
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ies
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c
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n
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c
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tac
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t
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m
a
il
:
m
u
h
.
a
li
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k
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a
r@g
m
a
il
.
c
o
m
.
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