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Caffeic acid phenethyl ester induces adrenoleukodystrophy (Abcd2) gene in human X-ALD fibroblasts and inhibits the proinflammatory response in Abcd1/2 silenced mouse primary astrocytes.
[x-linked adrenoleukodystrophy]
X-
linked
adrenoleukodystrophy
(
X-
ALD
)
is
a
peroxisomal
disorder
caused
by
mutations
in
the
ABCD
1
gene
.
Accumulation
of
very
long
chain
fatty
acids
(
VLCFA
)
that
have
been
attributed
to
reduced
peroxisomal
VLCFA
β-oxidation
activity
are
the
hallmark
of
the
disease
.
Overexpression
of
ABCD
2
gene
,
the
closest
homolog
of
ABCD
1
,
has
been
shown
to
compensate
for
ABCD
1
,
thus
correcting
the
VLCFA
derangement
.
The
accumulation
of
VLCFA
leads
to
a
neuroinflammatory
disease
process
associated
with
demyelination
of
the
cerebral
white
matter
.
The
present
study
underlines
the
importance
of
caffeic
acid
phenethyl
ester
(
CAPE
)
in
inducing
the
expression
of
ABCD
2
(
ALDRP
)
,
and
normalizing
the
peroxisomal
β-oxidation
as
well
as
the
levels
of
saturated
and
monounsaturated
VLCFAs
in
cultured
human
skin
fibroblasts
of
X-
ALD
patients
.
The
expression
of
ELOVL
1
,
the
single
elongase
catalyzing
the
synthesis
of
both
saturated
VLCFA
(
C
2
6
:
0
)
and
mono-unsaturated
VLCFA
(
C
2
6
:
1
)
,
was
also
reduced
by
CAPE
treatment
.
Importantly
,
CAPE
upregulated
Abcd
2
expression
and
peroxisomal
β-oxidation
and
lowered
the
VLCFA
levels
in
Abcd
1
-
deficient
U
87
astrocytes
and
B
12
oligodendrocytes
.
In
addition
,
using
Abcd
1
/
Abcd
2
-
silenced
mouse
primary
astrocytes
we
examined
the
effects
of
CAPE
in
VLCFA-induced
inflammatory
response
.
CAPE
treatment
decreased
the
inflammatory
response
as
the
expression
of
inducible
nitric
oxide
synthase
,
inflammatory
cytokine
,
and
activation
of
NF-κB
in
Abcd
1
/
Abcd
2
-
silenced
mouse
primary
astrocytes
was
reduced
.
The
observations
indicate
that
CAPE
corrects
both
the
metabolic
disease
of
VLCFA
as
well
as
secondary
inflammatory
disease
;
therefore
,
it
may
be
a
potential
drug
candidate
to
be
tested
for
X-
ALD
therapy
in
humans
.
Diseases
Validation
Diseases presenting
"cultured human skin fibroblasts"
symptom
neonatal adrenoleukodystrophy
x-linked adrenoleukodystrophy
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