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Oxidative stress, Nrf2 and keratin up-regulation associate with Mallory-Denk body formation in mouse erythropoietic protoporphyria.
[erythropoietic protoporphyria]
Mallory-
Denk
bodies
(
MDBs
)
are
hepatocyte
inclusions
commonly
seen
in
steatohepatitis
.
They
are
induced
in
mice
by
feeding
3
,
5
-
diethoxycarbonyl-
1
,
4
-
dihydrocollidine
(
DDC
)
for
12
weeks
,
which
also
causes
porphyrin
accumulation
.
Erythropoietic
protoporphyria
(
EPP
)
is
caused
by
mutations
in
ferrochelatase
(
fch
)
,
and
a
fraction
of
EPP
patients
develop
liver
disease
that
is
phenocopied
in
Fech
(
m
1
Pas
)
mutant
(
fch
/
fch
)
mice
,
which
have
an
inactivating
fch
mutation
.
fch
/
fch
mice
develop
spontaneous
MDBs
,
but
the
molecular
factors
involved
in
their
formation
and
whether
they
relate
to
DDC
-induced
MDBs
are
unknown
.
We
tested
the
hypothesis
that
fch
mutation
creates
a
molecular
milieu
that
mimics
experimental
drug-induced
MDBs
.
In
13
-
and
20
-
week
-old
fch
/
fch
mice
,
serum
alkaline
phosphatase
,
alanine
aminotransferase
,
and
bile
acids
were
increased
.
The
13
-
week
-old
fch
/
fch
mice
did
not
develop
histologically
evident
MDBs
but
manifested
biochemical
alterations
required
for
MDB
formation
,
including
increased
transglutaminase-
2
and
keratin
overexpression
,
with
a
greater
keratin
8
(
K
8
)
-
to
-
keratin
18
(
K
18
)
ratio
,
which
are
critical
for
drug-induced
MDB
formation
.
In
20
-
week
-old
fch
/
fch
mice
,
spontaneous
MDBs
were
readily
detected
histologically
and
biochemically
.
Short
-term
(
3
-
week
)
DDC
feeding
markedly
induced
MDB
formation
in
20
-
week
-old
fch
/
fch
mice
.
Under
basal
conditions
,
old
fch
/
fch
mice
had
significant
alterations
in
mitochondrial
oxidative-stress
markers
,
including
increased
protein
oxidation
,
decreased
proteasomal
activity
,
reduced
adenosine
triphosphate
content
,
and
Nrf
2
(
redox
sensitive
transcription
factor
)
up-regulation
.
Nrf
2
knockdown
in
HepG
2
cells
down-regulated
K
8
,
but
not
K
18
.
F
ch
/
fch
mice
develop
age-associated
spontaneous
MDBs
,
with
a
marked
propensity
for
rapid
MDB
formation
upon
exposure
to
DDC
,
and
therefore
provide
a
genetic
model
for
MDB
formation
.
Inclusion
formation
in
the
fch
/
fch
mice
involves
oxidative
stress
which
,
together
with
Nrf
2
-
mediated
increase
in
K
8
,
promotes
MDB
formation
.
Diseases
Validation
Diseases presenting
"old fch"
symptom
erythropoietic protoporphyria
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