bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2024,
Номер
unknown
Опубликована: Июнь 10, 2024
Abstract
Diffuse
midline
gliomas
(DMGs)
are
lethal
primary
brain
tumors
in
children.
The
imipridones
ONC201
and
ONC206
induce
mitochondrial
dysfunction
have
emerged
as
promising
therapies
for
DMG
patients.
However,
efficacy
monotherapy
is
limited,
identifying
a
need
strategies
that
enhance
response.
Another
hurdle
the
lack
of
biomarkers
report
on
drug-target
engagement
at
an
early
timepoint
after
treatment
onset.
Here,
using
1
H-magnetic
resonance
spectroscopy,
which
non-invasive
method
quantifying
metabolite
pool
sizes,
we
show
accumulation
ψ-aminobutyric
acid
(GABA)
metabolic
biomarker
can
be
detected
within
week
treatment,
when
anatomical
alterations
absent,
mice
bearing
orthotopic
xenografts.
Mechanistically,
activate
protease
ClpP
upregulate
stress-responsive
transcription
factor
ATF4.
ATF4,
turn,
upregulates
glutamate
decarboxylase,
synthesizes
GABA,
downregulates
ABAT
,
degrades
leading
to
GABA
cells
tumors.
Functionally,
secreted
by
imipridone-treated
acts
autocrine
manner
via
GABAB
receptor
expression
superoxide
dismutase
(SOD1),
mitigates
imipridone-induced
oxidative
stress
and,
thereby,
curbs
apoptosis.
Importantly,
blocking
signaling
clinical
stage
antagonist
SGS-742
exacerbates
synergistically
induces
apoptosis
combination
with
tumor
Collectively,
identify
unique
adaptation
leveraged
assessment
therapy.
Clinical
translation
our
studies
has
potential
enable
precision
therapy
imaging
One
Sentence
Summary
Imipridones
diffuse
gliomas,
effect
imaging.
Entropy,
Год журнала:
2024,
Номер
26(6), С. 481 - 481
Опубликована: Май 31, 2024
Many
studies
on
memory
emphasize
the
material
substrate
and
mechanisms
by
which
data
can
be
stored
reliably
read
out.
Here,
I
focus
complementary
aspects:
need
for
agents
to
dynamically
reinterpret
modify
memories
suit
their
ever-changing
selves
environment.
Using
examples
from
developmental
biology,
evolution,
synthetic
bioengineering,
in
addition
neuroscience,
propose
that
a
perspective
as
preserving
salience,
not
fidelity,
is
applicable
many
phenomena
scales
cells
societies.
Continuous
commitment
creative,
adaptive
confabulation,
molecular
behavioral
levels,
answer
persistence
paradox
it
applies
individuals
whole
lineages.
also
speculate
substrate-independent,
processual
view
of
life
mind
suggests
memories,
patterns
excitable
medium
cognitive
systems,
could
seen
active
sense-making
process.
explore
diverse
set
embodied
perspectives—nested
who
interpret
each
other’s
own
past
messages
actions
best
they
(polycomputation).
This
synthesis
unifying
symmetries
across
disciplines,
relevance
research
programs
Diverse
Intelligence
engineering
novel
minds.
Molecular Neurodegeneration,
Год журнала:
2025,
Номер
20(1)
Опубликована: Фев. 19, 2025
Abstract
The
integrated
stress
response
(ISR)
is
a
conserved
network
in
eukaryotic
cells
that
mediates
adaptive
responses
to
diverse
stressors.
ISR
pathway
ensures
cell
survival
and
homeostasis
by
regulating
protein
synthesis
internal
or
external
stresses.
In
recent
years,
the
has
emerged
as
an
important
regulator
of
central
nervous
system
(CNS)
development,
pathology.
Dysregulation
signaling
been
linked
several
neurodegenerative
diseases.
Intriguingly,
while
acute
provide
neuroprotection
through
activation
mechanisms,
prolonged
can
promote
neurodegeneration
misfolding,
oxidative
stress,
mitochondrial
dysfunction.
Understanding
molecular
mechanisms
dynamics
diseases
aids
development
effective
therapies.
Here,
we
will
timely
review
on
cellular
We
highlight
current
knowledge
dual
role
plays
protective
disease
worsening
discuss
advances
therapeutic
approaches
have
developed
target
activity
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2025,
Номер
unknown
Опубликована: Апрель 23, 2025
Abstract
Pulmonary
veno-occlusive
disease
(PVOD)
is
a
rare
and
severe
subtype
of
pulmonary
arterial
hypertension,
marked
by
progressive
remodeling
small
arteries
veins
with
no
therapies.
Using
mitomycin
C
(MMC)-induced
rat
model,
we
previously
demonstrated
that
protein
kinase
R
(PKR)-mediated
integrated
stress
response
(ISR)
drives
endothelial
dysfunction
vascular
remodeling.
To
determine
if
PKR
the
sole
mediator
ISR
pathogenesis,
treated
control
(Ctrl)
knockout
(KO)
mice
same
dose
MMC.
Consistent
data,
Ctrl
displayed
activation,
remodeling,
hypertension
after
MMC
treatment,
while
KO
showed
none
these
phenotypes.
Proteomic
analysis
revealed
MMC-mediated
activation
attenuates
synthesis
in
but
not
mice.
These
findings
underscore
significance
PKR-dependent
subsequent
perturbation
proteostasis
as
central
mechanisms
driving
PVOD
pathogenesis
identifying
promising
therapeutic
target.
Metabolites,
Год журнала:
2025,
Номер
15(5), С. 307 - 307
Опубликована: Май 5, 2025
Background:
Parkinson’s
disorder
(PD)
affects
around
1:500
individuals
and
is
associated
with
enlarged
ventricles
symptoms
of
normal
pressure
hydrocephalus
(NPH).
These
features
suggest
disrupted
cerebrospinal
fluid
(CSF)
dynamics
folate
metabolism.
With
L-DOPA
treatment
showing
diminishing
benefits
over
time,
there
an
urgent
need
to
investigate
upstream
metabolic
disruptions,
including
tetrahydrobiopterin
(BH4)
pathways,
in
post-mortem
CSF
brain
tissue
understand
their
roles
PD
pathogenesis.
Methods:
from
20
patients
(mean
age
84
years;
55%
male;
disease
duration
10–30
years)
controls
82
50%
male)
were
analysed.
Western
Dot
Blots
measured
proteins
metabolites,
spectroscopic
assays
assessed
enzyme
activities,
BH4
Neopterin
levels
using
ELISA,
hydrogen
peroxide,
used
as
a
proxy
for
reactive
oxygen
species,
calcium
quantified
horseradish
peroxidase
flame
photometry
assays,
respectively.
ClinVar
genetic
data
analysed
variants
genes
encoding
key
enzymes.
Statistical
significance
was
unpaired
t-tests
(p
<
0.05).
Results:
All
enzymes
significantly
reduced
compared
0.01)
except
methyltetrahydrofolate
reductase
(MTHFR),
which
elevated
0.0001).
Enzymes
functional
control
but
undetectable
tyrosine
hydroxylase
(TH).
0.0001,
p
0.001)
or
unchanged
tissue.
Peroxide
increased
both
0.0001)
selectively
inhibiting
TH.
Calcium
40%
higher
than
No
pathogenic
found
searches,
suggesting
the
observed
deficiencies
are
physiological.
Conclusions:
We
identified
significant
disruptions
pathways
PD,
deficiencies,
oxidative
stress
dysregulation
pointing
choroid
plexus
dysfunction.
findings
highlight
players
cerebral
metabolism
promote
further
exploration
these
therapeutic
targets
address
dopaminergic
dysfunction
ventricular
enlargement
PD.
