bioRxiv (Cold Spring Harbor Laboratory),
Journal Year:
2024,
Volume and Issue:
unknown
Published: June 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,
Journal Year:
2024,
Volume and Issue:
26(6), P. 481 - 481
Published: May 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,
Journal Year:
2025,
Volume and Issue:
20(1)
Published: Feb. 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
Biomedicine & Pharmacotherapy,
Journal Year:
2024,
Volume and Issue:
175, P. 116681 - 116681
Published: May 4, 2024
GCN1
is
a
highly
conserved
protein
present
widely
across
eukaryotes.
As
an
upstream
activator
of
kinase
GCN2,
plays
pivotal
role
in
integrated
stress
responses,
such
as
amino
acid
starvation
and
oxidative
stress.
Through
interaction
with
facilitates
the
activation
thus
initiating
downstream
signaling
cascades
response
to
cellular
stressors.
In
these
contexts,
GCN2
necessitates
presence
action
GCN1.
Notably,
also
operates
ribosome
collision
sensor,
contributing
significantly
translation
quality
control
pathway.
These
discoveries
offer
valuable
insights
into
responses
internal
stresses,
vital
for
maintaining
homeostasis.
Additionally,
exhibits
ability
regulate
cell
cycle
suppress
inflammation,
among
other
processes,
independently
GCN2.
Our
review
outlines
structural
characteristics
biological
functions
GCN1,
shedding
light
on
its
significant
involvement
onset
progression
various
cancer
non-cancer
diseases.
work
underscores
context
drug
therapeutic
effects,
hinting
at
potential
promising
target.
Furthermore,
our
delves
deep
functional
mechanisms
innovative
avenues
diagnosis
treatment
diseases
future.
The
exploration
GCN1's
multifaceted
roles
not
only
enhances
understanding
but
paves
way
novel
interventions.
ongoing
quest
unveil
additional
holds
promise
further
enriching
comprehension
mode
action.
Antioxidants,
Journal Year:
2024,
Volume and Issue:
13(7), P. 820 - 820
Published: July 8, 2024
Dietary
restriction
(DR)
protocols
frequently
employ
intermittent
fasting.
Following
a
period
of
fasting,
meal
consumption
increases
lipogenic
gene
expression,
including
that
NADPH-generating
enzymes
fuel
lipogenesis
in
white
adipose
tissue
(WAT)
through
the
induction
transcriptional
regulators
SREBP-1c
and
CHREBP.
knockout
mice,
unlike
controls,
did
not
show
an
extended
lifespan
on
DR
diet.
WAT
cytoplasmic
NADPH
is
generated
by
both
malic
enzyme
1
(ME1)
pentose
phosphate
pathway
(PPP),
while
liver
primarily
synthesized
folate
cycle
provided
one-carbon
units
serine
catabolism.
During
daily
fasting
diet,
fatty
acids
are
released
from
transported
to
peripheral
tissues,
where
they
used
for
beta-oxidation
phospholipid
lipid
droplet
synthesis,
monounsaturated
(MUFAs)
may
activate
Nrf1
inhibit
ferroptosis
promote
longevity.
Decreased
PPP
stimulated
browning
protected
high-fat
high
levels
macrophages
linked
obesity.
But
oscillations
[NADPH]/[NADP+]
feeding
cycles
play
important
role
maintaining
metabolic
plasticity
drive
Studies
measuring
malate/pyruvate
as
proxy
[NADPH]/[NADP+],
well
studies
using
fluorescent
biosensors
expressed
animal
models
monitor
changes
needed
during
ad
libitum
diets
determine
associated
with
bioRxiv (Cold Spring Harbor Laboratory),
Journal Year:
2025,
Volume and Issue:
unknown
Published: April 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.
