Research Square (Research Square),
Год журнала:
2023,
Номер
unknown
Опубликована: Окт. 3, 2023
Abstract
Background
NLRP3
inflammasome
activation
is
critical
for
neuroinflammation
in
microglia
during
postoperative
cognitive
dysfunction
(POCD)
induced
by
sevoflurane.
However,
the
molecular
mechanism
which
sevoflurane
activates
remains
unclear.
The
cGAS-
STING
pathway
an
evolutionarily
conserved
inflammatory
defense
mechanism.
role
of
cGAS-STING
sevoflurane-induced
inflammasome-dependent
and
underlying
mechanisms
require
further
investigation.
Methods
Prolonged
anesthesia
with
was
used
to
induce
mice.
passive
avoidance
test
Y-maze
were
assess
function.
We
then
cGAS
inhibitor
RU.521
investigate
whether
involved
mice
microglia.
To
sevoflurane-treated
microglia,
we
pre-treated
Mdivi-1
(a
DRP1
inhibitor),
CsA
mPTP
inhibitor)
or
VBIT-4
VDAC
inhibitor).
Results
found
that
prolonged
triggered
characterized
inflammasome.
Interestingly,
activated
hippocampus
receiving
While
blockade
attenuated
In
vitro
,
treatment
significantly
while
pre-treatment
robustly
inhibited
activation.
Mechanistically,
mitochondrial
fission
released
DNA
(mtDNA)
into
cytoplasm,
could
be
abolished
Mdivi-1.
Blocking
mtDNA
release
via
mPTP-VDAC
channel
cytosolic
escape
reduced
finally
inhibiting
Conclusion
this
study,
reported
a
novel
POCD.
Therefore,
regulating
targeting
may
provide
therapeutic
target
International Journal of Biological Sciences,
Год журнала:
2024,
Номер
20(5), С. 1927 - 1946
Опубликована: Янв. 1, 2024
The
activation
of
NLRP3
inflammasome
in
microglia
is
critical
for
neuroinflammation
during
postoperative
cognitive
dysfunction
(POCD)
induced
by
sevoflurane.However,
the
molecular
mechanism
which
sevoflurane
activates
remains
unclear.The
cGAS-STING
pathway
an
evolutionarily
conserved
inflammatory
defense
mechanism.The
role
sevoflurane-induced
inflammasome-dependent
and
underlying
mechanisms
require
further
investigation.We
found
that
prolonged
anesthesia
with
triggered
characterized
vivo.Interestingly,
was
activated
hippocampus
mice
receiving
sevoflurane.While
blockade
cGAS
RU.521
attenuated
mice.In
vitro,
we
treatment
significantly
microglia,
while
pre-treatment
robustly
inhibited
activation.Mechanistically,
mitochondrial
fission
released
DNA
(mtDNA)
into
cytoplasm,
could
be
abolished
Mdivi-1.Blocking
mtDNA
release
via
mPTP-VDAC
channel
inhibitor
cytosolic
escape
reduced
finally
inhibiting
activation.Therefore,
regulating
targeting
may
provide
a
novel
therapeutic
target
POCD.
CNS Neuroscience & Therapeutics,
Год журнала:
2025,
Номер
31(1)
Опубликована: Янв. 1, 2025
Communication
within
glial
cells
acts
as
a
pivotal
intermediary
factor
in
modulating
neuroimmune
pathology.
Meanwhile,
an
increasing
awareness
has
emerged
regarding
the
detrimental
role
of
and
neuroinflammation
morphine
tolerance
(MT).
This
study
investigated
influence
crosstalk
between
astrocyte
microglia
on
evolution
tolerance.
Sprague-Dawley
rats
were
intrathecally
treated
with
twice
daily
for
9
days
to
establish
morphine-tolerant
rat
model.
Tail-flick
latency
test
was
performed
identify
analgesic
effect
morphine.
The
microglia,
C3-C3aR
axis
elucidated
by
real-time
quantitative
polymerase
chain
reaction,
Western
blot,
immunofluorescence.
Chronic
treatment
notably
promoted
activation
upregulated
production
proinflammatory
mediators
(interleukin-1
alpha
(IL-1α),
tumor
necrosis
(TNFα),
complement
component
1q
(C1q)).
Simultaneously,
it
programed
astrocytes
pro-inflammatory
phenotype
(A1),
which
mainly
expresses
3
(C3)
serping1.
PLX3397
(a
colony-stimulating
1
receptor
(CSF1R)
inhibitor),
Compstain
C3
inhibitor)
SB290157(a
C3aR
antagonist)
could
reverse
above
pathological
process
alleviate
different
extents.
Our
findings
amplifier
microglia-astrocyte
crosstalk,
node
therapeutic
intervention
CNS Neuroscience & Therapeutics,
Год журнала:
2023,
Номер
29(11), С. 3588 - 3597
Опубликована: Июнь 2, 2023
We
investigated
the
mechanism,
whereby
tumor
necrosis
factor-like
ligand
1A
(TL1A)
mediates
A1
differentiation
of
astrocytes
in
postoperative
cognitive
dysfunction
(POCD).The
and
behavioral
abilities
mice
were
assessed
by
Morris
water
maze
open
field
tests,
while
levels
key
A2
astrocyte
factors
detected
RT-qPCR.
Immunohistochemical
(IHC)
staining
was
used
to
examine
expression
GFAP,
western
blot
assay
related
proteins,
enzyme-linked
immunosorbent
(ELISA)
detect
inflammatory
cytokines.The
results
showed
that
TL1A
could
promote
progression
mice.
Astrocytes
differentiated
into
phenotype,
unobvious
changes
noted
biomarkers.
Knockout
NLRP3
or
intervention
with
inhibitor
inhibit
effect
TL1A,
improving
suppressing
differentiation.Our
demonstrate
plays
an
important
role
POCD
mice,
which
promotes
through
NLRP3,
thereby
exacerbating
dysfunction.
BMC Anesthesiology,
Год журнала:
2025,
Номер
25(1)
Опубликована: Фев. 6, 2025
Postoperative
cognitive
dysfunction
(POCD)
represents
a
post-surgical
complication
that
features
progressive
impairment
and
memory
loss,
often
occurring
in
elderly
patients.
This
study
aimed
to
investigate
the
potential
biological
mechanisms
underlying
POCD.
Male
C57BL/6
mice
(2
17
months
old)
were
randomly
assigned
surgery
or
control
groups.
The
group
underwent
laparotomy
under
1.5%
isoflurane
anesthesia,
while
controls
received
no
intervention.
Cognitive
function
was
assessed
7–10
days
post-surgery
using
open
field,
Y-maze,
novel
object
recognition
tests.
Hippocampal
mRNA
expression
analyzed
Encyclopedia
of
Genes
Genomes
(KEGG)
Gene
Ontology
(GO)
enrichment.
A
competing
endogenous
RNA
(ceRNA)
network
constructed
microRNA
(miRNA)
target
prediction
databases
(miRanda,
miRTarbase,
miRcode)
sequencing
results.
Key
findings
validated
by
RT-qPCR
immunofluorescence.
Connectivity
Map
(CMap)
database
queried
predict
POCD
treatments.
Aging
significantly
affected
mice's
spontaneous
activity
field
test
(F1,
28
=
8.933,
P
<
0.01)
proportion
time
spent
center
area
5.387,
0.05).
Surgery
reduced
rate
alternations
Y-maze
16.94,
0.001)
index
6.839,
0.05)
aging
mice,
but
had
effect
on
young
mice.
Transcriptome
analysis
revealed
downregulated
multiple
neurogenesis-related
genes
hippocampus.
Doublecortin
(DCX)
immunofluorescence
staining
confirmed
hippocampal
neurogenesis
which
further
decreased
after
surgery.
We
identified
several
key
lncRNAs
miRNAs
implicated
regulation.
Additionally,
drugs
predicted
as
therapeutic
candidates
for
treatment.
Both
have
complex
effects
transcriptome
significant
decrease
may
be
reason
increased
susceptibility
regulatory
lncRNAs,
miRNAs,
provide
targets
prevention
CNS Neuroscience & Therapeutics,
Год журнала:
2024,
Номер
30(10)
Опубликована: Окт. 1, 2024
Abstract
Aim
The
aim
of
this
study
is
to
explore
the
key
mechanisms
perioperative
neurocognitive
dysfunction
(PND)
after
anesthesia/surgery
(A/S)
by
screening
hub
genes.
Methods
Transcriptome
sequencing
was
conducted
on
hippocampal
samples
obtained
from
18‐month‐old
C57BL/6
mice
assigned
control
(Ctrl)
and
A/S
groups.
functionality
differentially
expressed
genes
(DEGs)
investigated
using
Metascape.
Hub
associated
with
changes
between
two
groups
were
screened
combining
weighted
gene
coexpression
network
analysis
within
CytoHubba.
Reverse
transcription
PCR
western
blotting
used
validate
in
mRNA
protein
expression,
respectively.
NLRP3
inflammasome
activation
detected
ELISA.
Tauroursodeoxycholic
acid
(TUDCA),
an
inhibitor
endoplasmic
reticulum
(ER)
stress,
administrated
preoperatively
its
effects
occurrence
PND.
Immunofluorescence
performed
evaluate
astrocytes
microglia
hippocampus,
hippocampus‐dependent
learning
memory
assessed
behavioral
experiments.
Results
In
total,
521
DEGs
These
significantly
enriched
biological
processes
related
metabolic
their
regulation.
Four
(
Hspa5
,
Igf1r
Sfpq
Xbp1
)
identified.
Animal
experiments
have
shown
that
group
exhibited
cognitive
impairments
accompanied
increased
ER
inflammasome.
Conclusions
Inhibiting
stress
alleviated
impairment
mice;
particularly,
induced
results
neuroinflammation.
Moreover,
preoperative
administration
TUDCA
inhibited
activation,
