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Activation of the stress proteome as a mechanism for small molecule therapeutics.
[x-linked adrenoleukodystrophy]
Various
small
molecule
pharmacologic
agents
with
different
known
functions
produce
similar
outcomes
in
diverse
Mendelian
and
complex
disorders
,
suggesting
that
they
may
induce
common
cellular
effects
.
These
molecules
include
histone
deacetylase
inhibitors
,
4
-
phenylbutyrate
(
4
PBA
)
and
trichostatin
A
,
and
two
small
molecules
without
direct
histone
deacetylase
inhibitor
activity
,
hydroxyurea
(
HU
)
and
sulforaphane
.
In
some
cases
,
the
therapeutic
effects
of
histone
deacetylase
inhibitors
have
been
attributed
to
an
increase
in
expression
of
genes
related
to
the
disease-causing
gene
.
However
,
here
we
show
that
the
pharmacological
induction
of
mitochondrial
biogenesis
was
necessary
for
the
potentially
therapeutic
effects
of
4
PBA
or
HU
in
two
distinct
disease
models
,
X-
linked
adrenoleukodystrophy
and
sickle
cell
disease
.
We
hypothesized
that
a
common
cellular
response
to
these
four
molecules
is
induction
of
mitochondrial
biogenesis
and
peroxisome
proliferation
and
activation
of
the
stress
proteome
,
or
adaptive
cell
survival
response
.
Treatment
of
human
fibroblasts
with
these
four
agents
induced
mitochondrial
and
peroxisomal
biogenesis
as
monitored
by
flow
cytometry
,
immunofluorescence
and
/
or
western
analyses
.
In
treated
normal
human
fibroblasts
,
all
four
agents
induced
the
adaptive
cell
survival
response
:
heat
shock
,
unfolded
protein
,
autophagic
and
antioxidant
responses
and
the
c-jun
N-
terminal
kinase
pathway
,
at
the
transcriptional
and
translational
levels
.
Thus
,
activation
of
the
evolutionarily
conserved
stress
proteome
and
mitochondrial
biogenesis
may
be
a
common
cellular
response
to
such
small
molecule
therapy
and
a
common
basis
of
therapeutic
action
in
various
diseases
.
Modulation
of
this
novel
therapeutic
target
could
broaden
the
range
of
treatable
diseases
without
directly
targeting
the
causative
genetic
abnormalities
.
Diseases
Validation
Diseases presenting
"potentially therapeutic effects"
symptom
x-linked adrenoleukodystrophy
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