Frontiers in Pharmacology,
Год журнала:
2025,
Номер
15
Опубликована: Янв. 7, 2025
Acute
lung
injury
(ALI)
is
a
severe
condition
characterized
by
inflammation,
tissue
damage,
and
persistent
activation
of
the
cyclic
GMP-AMP
(cGAS)-stimulator
interferon
genes
(STING)
pathway,
which
exacerbates
production
pro-inflammatory
mediators
promotes
progression
ALI.
Specific
inhibition
this
pathway
has
been
shown
to
alleviate
ALI
symptoms.
Kaempferol-3-O-α-L-(4″-E-p-coumaroyl)-rhamnoside
(KAE),
an
active
compound
found
in
flowers
Angelica
acutiloba
Kitagawa,
exhibits
anti-inflammatory
antioxidant
properties.
This
study
aimed
investigate
molecular
mechanisms
through
KAE
regulates
cGAS-STING
context
was
induced
using
LPS.
Lung
damage
anti-inflammatory/antioxidant
effects
were
assessed
H&E
staining,
edema
index,
SOD,
MDA,
ELISA
assays.
NO
release
mitochondrial
membrane
potential
(MMP)
measured
JC-1
Griess
methods.
The
impact
on
PANoptosis
analyzed
flow
cytometry,
Western
blot,
immunofluorescence.
significantly
alleviated
lipopolysaccharide-induced
pulmonary
reducing
inflammatory
cell
infiltration,
alleviating
edema,
enhancing
capacity,
decreasing
levels
cytokines
mouse
tissues.
In
both
vitro
vivo
analyses,
downregulated
expression
key
components
including
cGAS,
STING,
p-TBK1,
nuclear
factor-κB.
also
reduced
assembly
PANoptosome,
thereby
attenuating
apoptosis,
necroptosis,
pyroptosis.
Additionally,
inhibited
cGAS
restoring
MMP,
cytosolic
DNA.
improve
inhibiting
DNA
suppressing
activation,
protecting
cells
from
PANoptosis.
Our
findings
provide
valuable
insights
for
development
application
novel
therapeutic
strategies
ABSTRACT
Programmed
cell
death,
including
necroptosis,
plays
a
critical
role
in
the
pathogenesis
of
cerebral
ischemia/reperfusion
injury
(CIRI).
Silent
information
regulator
1
(SIRT1)
has
been
identified
as
potential
therapeutic
target
for
CIRI,
yet
its
precise
regulating
necroptosis
remains
controversial.
Furthermore,
interaction
between
SIRT1
and
receptor‐interacting
protein
kinase
(RIP1)
this
context
is
not
fully
understood.
Sanpian
Decoction
(SPD),
classical
traditional
herbal
formula,
was
previously
shown
to
enhance
expression
our
studies.
Our
findings
demonstrated
that,
both
vivo
vitro,
CIRI
associated
with
decrease
levels
phosphorylated
dynamin‐related
(p‐DRP1)
at
Ser637,
alongside
an
increase
RIP1
other
necroptosis‐related
proteins.
Co‐immunoprecipitation
immunofluorescence
analyses
revealed
weakened
RIP1.
abnormal
mitochondrial
fission
dysfunction
were
mediated
through
phosphoglycerate
mutase
5–DRP1
pathway.
Notably,
SPD
treatment
improved
neurological
outcomes
reversed
these
pathological
changes
by
enhancing
SIRT1–RIP1
interaction.
In
conclusion,
study
suggests
that
promising
capable
inhibiting
mitigating
via
exhibits
activating
SIRT1,
thereby
attenuating
during
CIRI.
Heliyon,
Год журнала:
2024,
Номер
10(4), С. e26219 - e26219
Опубликована: Фев. 1, 2024
BackgroundEpilepsy
is
recognized
as
the
most
common
chronic
neurological
condition
among
children,
and
hippocampal
neuronal
cell
death
has
been
identified
a
crucial
factor
in
pathophysiological
processes
underlying
seizures.
In
recent
studies,
PANoptosis,
newly
characterized
form
of
death,
emerged
significant
contributor
to
development
various
disorders,
including
Alzheimer's
disease,
Parkinson's
amyotrophic
lateral
sclerosis.
PANoptosis
involves
simultaneous
activation
pyroptosis,
apoptosis,
necroptosis
within
same
population
cells.
However,
its
specific
role
context
seizures
remains
be
fully
elucidated.
Further
investigation
required
uncover
precise
involvement
pathogenesis
better
understand
potential
implications
for
targeted
therapeutic
approaches
epilepsy.MethodsIn
this
study,
gene
expression
data
hippocampus
following
administration
kainic
acid
(KA)
or
NaCl
was
obtained
from
Gene
Expression
Omnibus
(GEO)
database.
The
PANoptosis-related
set
compiled
GeneCards
database
previous
literature.
Time
series
analysis
performed
analyze
temporal
patterns
genes.
variation
(GSVA),
ontology
(GO),
Kyoto
encyclopedia
genes
genomes
(KEGG)
were
employed
explore
biological
mechanisms
Weighted
co-expression
network
(WGCNA)
differential
utilized
identify
pivotal
modules
associated
with
To
validate
genes,
Western
blotting
quantitative
real-time
polymerase
chain
reaction
(qRT-PCR)
assays
conducted.
These
experimental
validations
human
blood
samples,
animal
models,
models
verify
their
relevance
epilepsy.ResultsThe
GSVA
study
demonstrated
that
have
distinguish
between
control
group
KA-induced
epileptic
mice.
This
suggests
these
are
significantly
altered
response
epilepsy.
Furthermore,
blue
module
being
highly
phenotypes.
consists
exhibit
correlated
specifically
related
Within
module,
10
further
biomarker
include
MLKL,
IRF1,
RIPK1,
GSDMD,
CASP1,
CASP8,
ZBP1,
CASP6,
PYCARD,
IL18.
likely
play
critical
roles
pathophysiology
epilepsy
could
serve
biomarkers
diagnosing
monitoring
condition.ConclusionIn
conclusion,
our
may
closely
novel
which
provides
insights
into
helps
Biomedicine & Pharmacotherapy,
Год журнала:
2024,
Номер
174, С. 116500 - 116500
Опубликована: Март 30, 2024
Chrysin
is
a
natural
flavonoid
with
powerful
neuroprotective
capacity.
Cerebral
ischemia/reperfusion
injury
(CIRI)
associated
oxidative
stress
and
ferroptosis.
Hypoxia-inducible
factor
1α
(HIF-1α)
ceruloplasmin
(CP)
are
the
critical
targets
for
oxidation
reactions
iron
transport.
But
regulatory
mechanism
between
them
still
unclear.
Transient
middle
cerebral
artery
occlusion
(tMCAO)
model
in
rats
oxygen
glucose
deprivation/re-oxygenation
(OGD/R)
PC12
cells
were
applied.
Pathological
tissue
staining
biochemical
kit
used
to
evaluate
effect
of
chrysin.
The
relationship
HIF-1α
CP
was
verified
by
transcriptomics,
qRT-PCR
Western
blot.
In
CIRI,
HIF-1α/CP
loop
discovered
be
pathway
CIRI
led
activation
nuclear
translocation
HIF-1α,
which
promoted
transcription
translation,
downstream
Inhibition
had
opposite
on
ferroptosis
regulation.
Overexpression
increased
expression
nevertheless,
inhibited
alleviated
CIRI.
Silencing
elevation
nucleus
aggravated
Mechanistically,
chrysin
restrained
translocation,
thereby
inhibiting
turn
reduced
mitigated
Our
results
highlight
restrains
through
loop.
Journal of Chemical Neuroanatomy,
Год журнала:
2024,
Номер
136, С. 102387 - 102387
Опубликована: Янв. 3, 2024
The
pathogenesis
of
brain
ischemic/reperfusion
(I/R)
insult
is
characterized
by
neuronal
loss
due
to
excessive
oxidative
stress
responses.
Ferroptosis,
a
form
cell
death,
can
be
triggered
when
the
balance
between
antioxidants
and
pro-oxidants
in
cells
disrupted.
Ozone,
natural
bioactive
molecule
with
antioxidant/anti-apoptotic
pro-autophagic
properties,
has
been
shown
enhance
antioxidant
system's
capacity
ameliorate
stress.
However,
its
role
ferroptosis
remains
unclear.
Therefore,
we
investigated
functions
possible
mechanisms
ozone
cerebral
I/R-induced
ferroptotic
death.
A
ischemia-reperfusion
injury
model
was
induced
Sprague-Dawley
(SD)
rats
pre-treated
ozone.
Intraperitoneal
administration
NRF2
inhibitor
ML385,
SLC7A11
Erastin,
GPX4
RSL3
performed
one
hour
prior
establishment.
Our
results
showed
that
preconditioning
mitigated
damage
caused
I/R,
reduced
severity
neurological
deficits,
lowered
infarct
volume
middle
artery
occlusion
(MCAO)
rats,
decreased
infarcts.
Transmission
electron
microscopy,
immunofluorescence,
Western
blotting
indicated
following
MCAO-induced
damage.
MCAO
resulted
morphological
mitochondria,
increased
lipid
peroxidation
accumulation,
elevated
malondialdehyde
(MDA)
production.
Furthermore,
levels
FTH1
(negative
regulators
ferroptosis)
ACSL4
(a
positive
regulator
ferroptosis).
Ozone
demonstrated
neuroprotective
effect
increasing
nuclear
translocation
expression
GPX4.
Treatment
significantly
reversed
preconditioning's
protective
on
ferroptosis.
findings
treatment
attenuates
ischemia/reperfusion
rat
via
NRF2/SLC7A11/GPX4
pathway,
providing
theoretical
basis
for
ozone's
potential
use
as
therapy
prevent
ischemic
stroke.
