Dimethyl fumarate modulates the dystrophic disease program following short-term treatment
JCI Insight,
Journal Year:
2023,
Volume and Issue:
8(21)
Published: Sept. 26, 2023
New
medicines
are
urgently
required
to
treat
the
fatal
neuromuscular
disease
Duchenne
muscular
dystrophy
(DMD).
Dimethyl
fumarate
(DMF)
is
a
potent
immunomodulatory
small
molecule
nuclear
erythroid
2-related
factor
2
activator
with
current
clinical
utility
in
treatment
of
multiple
sclerosis
and
psoriasis
that
could
be
effective
for
DMD
rapidly
translatable.
Here,
we
tested
weeks
daily
100
mg/kg
DMF
versus
5
standard-care
prednisone
(PRED)
juvenile
mdx
mice
early
symptomatic
DMD.
Both
drugs
modulated
seed
genes
driving
program
improved
force
production
fast-twitch
muscle.
However,
only
showed
pro-mitochondrial
effects,
protected
contracting
muscles
from
fatigue,
histopathology,
augmented
clinically
compatible
muscle
function
tests.
may
more
selective
modulator
than
PRED,
warranting
follow-up
longitudinal
studies
evaluate
disease-modifying
impact.
Language: Английский
Moderate-term dimethyl fumarate treatment reduces pathology of dystrophic skeletal and cardiac muscle in a mouse model
bioRxiv (Cold Spring Harbor Laboratory),
Journal Year:
2024,
Volume and Issue:
unknown
Published: July 17, 2024
Abstract
In
Duchenne
muscular
dystrophy
(DMD),
corticosteroids
significantly
slow
disease
progression
and
have
been
used
as
a
standard
of
care
tool
for
more
than
30
years.
However,
also
impart
side
effects
severe
enough
to
preclude
use
in
some
patients.
There
remains
an
unmet
need
new
therapeutics
that
target
the
flow-on
pathogenic
mechanisms
DMD
with
favourable
side-effect
profile.
We
previously
demonstrated
short-term
treatment
dual-purpose
anti-inflammatory,
anti-oxidative
dimethyl
fumarate
(DMF),
drug
indication
established
safety
data
Multiple
Sclerosis,
selectively
modulates
(
mdx
)
immunology
frequently
corticosteroid,
prednisone
(PRED).
Here,
we
assess
effect
moderate-term
DMF
over
5
weeks
typically
mild
mouse
model
aggravated
using
exercise.
show
like
PRED,
maintains
anti-inflammatory
action
but
additional
anti-fibrotic
anti-lipogenic
on
muscle
use.
This
study
supports
our
previous
work
highlighting
possible
repurposing
candidate
DMD,
especially
patients
who
cannot
tolerate
chronic
corticosteroid
treatment.
Language: Английский
Diagnosis of ADSSL1 Mutation-Induced Myopathy Through Electrophysiology and Genetic Tools
Journal of Electrodiagnosis and Neuromuscular Diseases,
Journal Year:
2024,
Volume and Issue:
26(2), P. 35 - 39
Published: Aug. 29, 2024
Mutations
in
the
adenylosuccinate
synthase
1
(ADSSL1)
gene,
resulting
deficiency,
are
a
rare
genetic
anomaly
characterized
by
muscular
weakness,
elevated
serum
creatine
kinase
levels,
and
pathological
muscle
findings.
However,
these
clinical
symptoms
similar
to
those
observed
many
other
myopathies,
increasing
risk
of
misdiagnosis.
In
an
era
rapidly
expanding
knowledge,
authors
sought
verify
diagnostic
utility
electromyography
for
disorders.
Through
combined
electrophysiological
studies,
patient
initially
thought
have
Becker’s
dystrophy
was
conclusively
diagnosed
with
ADSSL1
mutagenic
myopathy.
This
case
underscores
importance
re-evaluating
diseases
that
do
not
follow
typical
progression
traditional
especially
light
recent
advancements.
Language: Английский
Anaplerotic filling in heart failure: a review of mechanism and potential therapeutics
Cardiovascular Research,
Journal Year:
2024,
Volume and Issue:
unknown
Published: Nov. 21, 2024
Abstract
Heart
failure
(HF)
is
a
complex
syndrome
and
leading
cause
of
mortality
worldwide.
While
current
medical
treatment
based
on
known
pathophysiology
effective
for
many
patients,
the
underlying
cellular
mechanisms
are
poorly
understood.
Energy
deficiency
characteristic
HF,
marked
by
alterations
in
metabolism.
Within
tricarboxylic
acid
cycle,
anaplerosis
emerges
as
an
essential
metabolic
process
responsible
replenishing
lost
intermediates,
thereby
playing
crucial
role
sustaining
energy
metabolism
consequently
cardiac
function.
Alterations
commonly
observed
demonstrating
potential
therapeutic
intervention.
This
review
discusses
recent
advances
understanding
anaplerotic
adaptations
that
occur
HF.
We
also
explore
therapeutics
can
directly
modulate
or
likely
to
confer
cardioprotective
effects
through
anaplerosis,
which
could
potentially
be
implemented
rescue
failing
heart.
Language: Английский
Adenylosuccinic Acid Is a Non-Toxic Small Molecule In Vitro and In Vivo
Cara A. Timpani,
No information about this author
Lorna Rasmussen,
No information about this author
Emma Rybalka
No information about this author
et al.
Pharmaceuticals,
Journal Year:
2023,
Volume and Issue:
16(10), P. 1458 - 1458
Published: Oct. 13, 2023
Adenylosuccinic
acid
(ASA)
is
a
small
molecule
dicarboxylate
that
could
be
strong
clinical
development
candidate
for
inherited
myopathies
involving
dysregulated
purine
nucleotide
metabolism.
Currently,
there
are
no
published
pharmacokinetic/dynamic
or
toxicology
data
available,
although
10-year
trial
on
Duchenne
muscular
dystrophy
patients
suggests
it
chronically
safe
drug.
In
this
study,
we
tested
the
toxicity
of
ASA
to
cultured
myoblasts
in
vitro
and
its
acute
systemic
mice.
non-toxic
with
an
LD
Language: Английский
Adenylosuccinic Acid Is a Non-Toxic Small Molecule In Vitro and In Vivo
Cara A. Timpani,
No information about this author
Lorna Rasmussen,
No information about this author
Emma Rybalka
No information about this author
et al.
Published: Sept. 7, 2023
Adenylosuccinic
acid
(ASA)
is
a
small
molecule
dicarboxylate
that
could
be
strong
clinical
development
candidate
for
inherited
myopathies
involving
dysregulated
purine
nucleotide
metabo-lism.
Currently,
there
are
no
published
pharmacokinetic/dynamic
or
toxicology
data
available,
albeit
10-year
trial
in
Duchenne
muscular
dystrophy
patients
suggests
chronically
safe
drug.
In
this
study,
we
tested
the
toxicity
of
ASA
to
cultured
myoblasts
vitro
and
acute
systemic
mice.
non-toxic
with
an
LD50>
5000mg/kg.
Some
background
necrotic
foci
liver,
kidney
gastrointestinal
tract
were
shown
likely
incidental
but
warrant
follow-up
sub-/chronic
oral
exposure
studies.
Language: Английский