Identification and validation of diagnostic biomarkers for temporal lobe epilepsy related to ferroptosis and potential therapeutic targets
Scientific Reports,
Год журнала:
2025,
Номер
15(1)
Опубликована: Фев. 10, 2025
Ferroptosis
pathway
activation
is
potentially
correlated
with
temporal
lobe
epilepsy
(TLE).
However,
the
diagnostic
significance
and
mechanism
of
ferroptosis-related
genes
(FRGs)
in
TLE
require
further
investigation.
A
comprehensive
analysis
GSE134697
dataset
from
Gene
Expression
Omnibus
(GEO)
database
using
Weighted
gene
co-expression
network
(WGCNA)
identified
3,212
differentially
expressed
(DEGs)
between
(TLE)
control
groups,
a
critical
focus
on
turquoise
module.
Through
intersection
DEGs
key
module
genes,
correlation
analyses
functional-related
(FRG),
protein-protein
interactions
(PPI),
least
absolute
shrinkage
selection
operator
(LASSO),
machine
learning
methods,
five
potential
biomarkers
ferroptosis
(CBS,
SHMT1,
RIN3,
QDPR,
PLPP4)
were
isolated.
nomogram
was
constructed
these
markers,
enrichment
revealed
their
links
to
T-cell
activation,
allograft
rejection,
glial
differentiation.
Variations
13
immune
cell
types
also
noted.
Upregulation
CBS,
PLPP4
confirmed
through
RT-qPCR
Western
blot
assays.
Additionally,
SHMT1-targeting
one
CBS-targeting
drugs
predicted
Drug-Gene
Interaction
Database
(DGIdb).
These
findings
provide
new
insights
into
pathogenesis
suggest
targets
for
future
research.
Язык: Английский
DMT1 ubiquitination by Nedd4 protects against ferroptosis after intracerebral hemorrhage
CNS Neuroscience & Therapeutics,
Год журнала:
2024,
Номер
30(4)
Опубликована: Апрель 1, 2024
Abstract
Objective
Neuronal
precursor
cells
expressed
developmentally
down‐regulated
4
(Nedd4)
are
believed
to
play
a
critical
role
in
promoting
the
degradation
of
substrate
proteins
and
involved
numerous
biological
processes.
However,
Nedd4
intracerebral
hemorrhage
(ICH)
remains
unknown.
This
study
aims
investigate
regulatory
ICH
model.
Methods
Male
C57BL/6J
mice
were
induced
with
ICH.
Subsequently,
levels
glutathione
peroxidase
(GPX4),
malondialdehyde
(MDA)
concentration,
iron
content,
mitochondrial
morphology,
as
well
expression
divalent
metal
transporter
1
(DMT1)
assessed
after
Furthermore,
impact
overexpression
was
evaluated
through
analyses
hematoma
area,
ferroptosis,
neurobehavioral
function.
The
mechanism
underlying
Nedd4‐mediated
DMT1
elecidated
using
immunoprecipitation
(IP)
Results
Upon
ICH,
level
brain
increased,
but
decreased
when
overexpressed
Lentivirus,
suggesting
negative
correlation
between
DMT1.
Additionally,
inhibited
it
found
that
can
interact
ubiquitinate
at
lysine
residues
6,
69,
277,
facilitating
Functional
analysis
indicated
alleviate
ferroptosis
promote
recovery
following
Conclusion
results
demonstrated
occurs
via
Nedd4/DMT1
pathway
during
potential
valuable
target
inhibit
for
treatment
Язык: Английский
The critical role of MLKL in hemorrhagic stroke and the therapeutic potential of its associated protein network
Frontiers in Cell and Developmental Biology,
Год журнала:
2025,
Номер
12
Опубликована: Янв. 20, 2025
Introduction
Mixed
Lineage
Kinase
Domain-Like
Protein
(MLKL),
as
the
executor
of
necroptosis
and
a
critical
factor
in
inflammation,
has
been
shown
to
be
associated
with
progression
hemorrhagic
stroke.
Studies
identified
MLKL
is
promoting
this
process,
suggesting
its
potential
therapeutic
target
mitigate
posthemorrhagic
stroke
damage.
However,
mechanisms
by
which
functions
process
intracerebral
hemorrhage
(ICH)-induced
damage
remain
unclear.
Methods
Here,
we
explored
correlation
between
pathological
ICH
patients
through
histopathological
staining
RT-qPCR.
Furthermore,
established
an
model
collagenase
IV
injection
WT
Mlkl
-/-
mice.
Subsequently,
investigated
impact
knockout
on
behavioral
tests,
Western
blotting,
Finally,
performed
proteomic
analysis
via
LC-MS/MS
explore
interacting
proteins
ICH.
Results
We
found
that
highly
expressed
brain
tissue
positively
correlated
extent
injury.
alone
was
insufficient
fully
reverse
neuroinflammation
Although
limited
effect
alleviating
damage,
proteomics
results
indicate
can
changes
metabolism,
coagulation
pathways,
may
exert
effects
these
pathways.
Discussion
In
summary,
our
suggest
although
ICH,
single
Proteomic
indicates
co-targeting
protein
network
yield
better
outcomes
for
Язык: Английский
Tungsten-based polyoxometalate nanoclusters as ferroptosis inhibitors modulating S100A8/A9-mediated iron metabolism pathway for managing intracerebral haemorrhage
Journal of Nanobiotechnology,
Год журнала:
2025,
Номер
23(1)
Опубликована: Фев. 19, 2025
Intracerebral
haemorrhage
(ICH)
is
a
devastating
neurological
disorder
with
high
morbidity
and
mortality
rates,
largely
owing
to
the
lack
of
effective
therapeutic
strategies.
Growing
evidence
has
underscored
pivotal
role
ferroptosis
in
intracerebral
haemorrhage,
its
contribution
neuronal
death
exacerbation
brain
injury,
thus
establishing
it
as
crucial
target
for
intervention.
In
recent
years,
polyoxometalate
nanoclusters
(NCs)
have
been
applied
various
neurodegenerative
diseases,
demonstrating
neuroprotective
effects.
However,
their
impact
on
iron
content
function
following
ICH
yet
be
reported.
Here,
we
explored
potential
tungsten-based
(W-POM)
NCs
inhibitors
targeting
metabolic
pathway
mediated
by
S100A8/A9
treatment
ICH.
We
successfully
synthesized
ultra-small
reduced
W-POM
that
can
rapidly
cross
blood-brain
barrier
are
cleared
through
kidney.
vitro
experiments
demonstrated
exhibit
significant
stable
ROS
scavenging
activity
while
effectively
alleviating
overload
associated
damage.
vivo,
restored
metabolism
homeostasis,
suppressed
neuroinflammation
oxidative
stress,
ultimately
severe
damage
motor
deficits
mice.
Proteomic
combined
bioinformatic
analyses
identified
two
core
genes,
S100A8
S100A9,
most
intervention
Further
confirmed
act
modulating
toll-like
receptor
4/hepcidin/ferroportin
signaling
pathway,
thereby
regulating
reducing
secondary
injury.
This
study
pioneers
application
polyoxometalates
offering
novel
promising
approach
management
ferroptosis-related
injuries.
Язык: Английский
MK5 Regulates Microglial Activation and Neuroinflammation in Experimental Stroke Models
CNS Neuroscience & Therapeutics,
Год журнала:
2025,
Номер
31(4)
Опубликована: Апрель 1, 2025
ABSTRACT
Objective
Microglial
activation
plays
a
crucial
role
in
neuroinflammation
following
ischemic
stroke.
This
study
was
conducted
to
investigate
the
and
potential
mechanisms
of
MK5
within
microglial
cells
inflammatory
response
stroke
mice
vivo
vitro.
Methods
Microglia‐specific
conditional
knockout
(MK5
cKO)
their
control
f/f
)
were
subjected
middle
cerebral
artery
occlusion
(MCAO).
BV2
(a
mouse
cell
line)
transfected
with
small
interfering
RNA
(siRNA)
knock
down
levels
subsequently
exposed
oxygen–glucose
deprivation/reperfusion
(OGD/R)
simulate
conditions
Following
MCAO,
behavioral
tests
infarct
volume
measurements
conducted.
Levels
cytokines
markers
evaluated
using
qPCR
Western
blotting,
while
immunofluorescence
employed
observe
activation.
Additionally,
blotting
performed
assess
phosphorylation
HSP27
NF‐κB.
Results
Compared
group,
gene
microglia
significantly
exacerbated
neurological
deficits
increased
MCAO
mice.
The
loss
promoted
inflammation
by
upregulating
pro‐inflammatory
factors
downregulating
anti‐inflammatory
factors,
also
enhancing
both
OGD/R.
Furthermore,
reduced
NF‐κB
aforementioned
models.
Conclusion
critical
neuroinflammatory
regulating
NF‐κB,
positioning
it
as
target
for
treatment.
Язык: Английский