Redox Biology,
Год журнала:
2024,
Номер
69, С. 103026 - 103026
Опубликована: Янв. 4, 2024
Dementia,
with
homocysteine
(Hcy)
as
an
important
risk
factor,
is
a
severe
public
health
problem
in
the
aging
society.
Betaine
serves
methyl
donor
and
plays
role
reducing
Hcy.
However,
effects
mechanisms
of
betaine
on
Hcy-induced
cognitive
impairment
remain
unclear.
Firstly,
SD
rats
were
injected
Hcy
(400
μg/kg)
through
vena
caudalis,
(2.5
%
w/v)
was
supplemented
via
drinking
water
for
14
days.
supplementation
could
attenuate
Y
maze
novel
object
recognition
tests
by
repairing
brain
injury.
Meanwhile,
microglial
activation
observed
to
be
inhibited
using
immunofluorescence
sholl
analysis.
Secondly,
HMC3
cells
treated
betaine,
which
found
decrease
ROS
level,
ameliorate
cell
membrane
rupture,
reduce
release
LDH,
IL-18
IL-1β,
damage
microglia
neurons.
Mechanistically,
alleviates
inhibiting
pyroptosis
expressions
NLRP3,
ASC,
pro-caspase-1,
cleaved-caspase-1,
GSDMD,
GSDMD-N,
IL-1β.
treatment
can
increase
SAM/SAH
ratio,
confirming
its
enhancement
methylation
capacity.
Furthermore,
enhance
N6-methyladenosine
(m6A)
modification
NLRP3
mRNA,
reduced
mRNA
stability
increasing
expression
m6A
reader
YTH
RNA
binding
protein
2
(YTHDF2).
Finally,
silencing
YTHDF2
reverse
inhibitory
effect
pyroptosis.
Our
data
demonstrated
that
attenuated
suppressing
NLRP3/caspase-1/GSDMD
pathway
m6A-YTHDF2-dependent
manner.
International Journal of Surgery,
Год журнала:
2024,
Номер
110(9), С. 5396 - 5408
Опубликована: Июнь 14, 2024
Background
Traumatic
brain
injury
(TBI)
is
a
common
complication
of
acute
and
severe
neurosurgery.
Remodeling
N6-methyladenosine
(m6A)
stabilization
may
be
an
attractive
treatment
option
for
neurological
dysfunction
after
TBI.
In
the
present
study,
authors
explored
epigenetic
methylation
RNA-mediated
NLRP3
inflammasome
activation
Methods
Neurological
dysfunction,
histopathology,
associated
molecules
were
examined
in
conditional
knockout
(CKO)
WTAP
[flox/flox,
Camk2a-cre]
,
flox/flox
pAAV-U6-shRNA-YTHDF1-transfected
mice.
Primary
neurons
used
vitro
to
further
explore
molecular
mechanisms
action
WTAP/YTHDF1
following
neural
damage.
Results
The
found
that
m6A
levels
upregulated
at
early
stage
TBI,
deletion
did
not
affect
function
but
promoted
functional
recovery
Conditional
suppressed
neuroinflammation
TBI
phase:
could
directly
act
on
mRNA,
regulate
mRNA
level,
promote
expression
neuronal
injury.
Further
investigation
YTH
domain
YTHDF1
bind
protein
expression.
mutation
or
silencing
improved
injury,
inhibited
Caspase-1
activation,
decreased
IL-1β
levels.
This
effect
was
mediated
via
suppression
translation,
which
also
reversed
stimulative
overexpression
inflammation.
Conclusions
Our
results
indicate
participates
damage
by
translation
m6A-YTHDF1-dependent
manner
WTAP/m6A/YTHDF1
downregulation
therapeutics
viable
promising
approach
preserving
can
provide
support
targeted
drug
development.
Aging,
Год журнала:
2024,
Номер
16(2), С. 1237 - 1248
Опубликована: Янв. 29, 2024
Diabetic
nephropathy
(DN)
is
one
of
the
most
serious
complications
in
diabetic
patients.
And
m6A
modifications
mediated
by
METTL3
are
involved
multiple
biological
processes.
However,
specific
function
and
mechanism
DN
remains
unclear.
model
mice
were
first
established
with
streptozotocin,
WISP1
expression
was
confirmed
qRT-PCR.
Then
influences
or/and
on
proliferation,
migration,
epithelial-mesenchymal
transition
(EMT)
fibrosis-related
proteins
high
glucose
(HG)-induced
HK2
cells
or
tested
through
CCK-8,
wound
healing,
western
blot.
We
revealed
that
highly
expressed
renal
tissues
HG-induced
cells.
Functionally,
silencing
could
weaken
EMT,
fibrosis
HG-treated
cells,
overexpression
induce
Additionally,
decrease
modification,
also
notably
suppress
functions
downregulating
WISP1.
Silencing
prevents
development
process
decreasing
modification
pattern.
Therefore,
we
suggest
METTL3/WISP1
axis
might
be
a
novel
therapeutic
target
for
DN.
Immunity Inflammation and Disease,
Год журнала:
2025,
Номер
13(1)
Опубликована: Янв. 1, 2025
ABSTRACT
Background
Recent
studies
show
that
N6‐methyladenosine
(m6A)
plays
an
important
role
in
the
pathogenesis
of
Alzheimer's
disease
(AD),
while
mechanisms
involved
were
studied
insufficiently.
Aims
The
present
study
aimed
to
explore
effect
human
insulin‐like
growth
factor
2
(IGF2)
mRNA
binding
proteins
(IGF2BP2),
one
m6A‐binding
on
progression
AD.
Materials
&
Methods
and
protein
expression
level
determined
using
RT‐qPCR
western
blot,
respectively.
MTT
assay
was
carried
out
evaluate
cell
viability.
content
ROS,
antioxidant
enzymes,
IL‐1β
pyroptosis,
as
well
m6A
contents
relative
commercial
kit.
AD
models
built
Aβ1‐42
‐stimulated
hippocampal
neuron
vitro
mice
vivo.
Results
Our
results
showed
IGF2BP2
significantly
upregulated
neuron.
inhibition
reversed
decreased
viability
increased
apoptosis
induced
by
Aβ1‐42.
siRNA
transfection
alleviated
pyroptosis
pyroptosis‐related
upregulation.
we
also
found
downregulated
NLRP3
through
methylation.
Furthermore,
overexpression
partly
‐induced
injury.
In
addition,
improved
cognitive
function
neuronal
injury
Conclusion
Knockdown
inhibit
damage
hippocampus
cells,
improve
m6A‐mediated
inflammasome.
Journal of Translational Medicine,
Год журнала:
2024,
Номер
22(1)
Опубликована: Янв. 5, 2024
Abstract
Background
(Pro)renin
receptor
(PRR)
is
highly
expressed
in
renal
tubules,
which
involved
physiological
and
pathological
processes.
However,
the
role
of
PRR,
tubular
epithelial
cells,
diabetic
kidney
disease
(DKD)
remain
largely
unknown.
Methods
In
this
study,
biopsies,
urine
samples,
public
RNA-seq
data
from
DKD
patients
were
used
to
assess
PRR
expression
cell
pyroptosis
cells.
The
regulation
by
was
investigated
situ
injection
adeno-associated
virus9
(AAV9)-shRNA
into
db/db
mice,
knockdown
or
overexpression
HK-2
To
reveal
underlined
mechanism,
interaction
with
potential
binding
proteins
explored
using
BioGrid
database.
Furthermore,
direct
dipeptidyl
peptidase
4
(DPP4),
a
pleiotropic
serine
increases
blood
glucose
degrading
incretins
under
conditions,
confirmed
co-immunoprecipitation
assay
immunostaining.
Results
Higher
found
tubules
positively
correlated
injuries
patients,
parallel
cells
pyroptosis.
Knockdown
kidneys
significantly
blunted
mice
injury
alleviating
resultant
interstitial
inflammation.
Moreover,
silencing
blocked
high
glucose-induced
pyroptosis,
whereas
enhanced
pyroptotic
death
Mechanistically,
selectively
bound
cysteine-enrich
region
C-terminal
DPP4
augmented
protein
abundance
DPP4,
leading
downstream
activation
JNK
signaling
suppression
SIRT3
FGFR1
signaling,
then
subsequently
mediated
death.
Conclusions
This
study
identified
significant
pathogenesis
DKD;
specifically,
promoted
via
highlighting
that
could
be
promising
therapeutic
target
DKD.
Abstract
Chronic
kidney
disease
(CKD)
is
a
global
health
burden,
with
ineffective
therapies
leading
to
increasing
morbidity
and
mortality.
Renal
interstitial
fibrosis
common
pathway
in
advanced
CKD,
resulting
function
structure
deterioration.
In
this
study,
we
investigate
the
role
of
FTO‐mediated
N6‐methyladenosine
(m6A)
its
downstream
targets
pathogenesis
renal
fibrosis.
M6A
modification,
prevalent
mRNA
internal
has
been
implicated
various
organ
processes.
We
use
mouse
model
unilateral
ureteral
obstruction
(UUO)
as
an
vivo
treated
tubular
epithelial
cells
(TECs)
transforming
growth
factor
(TGF)‐β1
vitro
models.
Our
findings
revealed
increased
FTO
expression
UUO
TGF‐β1‐treated
TECs.
By
modulating
through
heterozygous
mutation
mice
(FTO
+/−
)
small
interfering
RNA
(siRNA)
vitro,
observed
attenuation
TGF‐β1‐induced
epithelial–mesenchymal
transition
(EMT),
evidenced
by
decreased
fibronectin
N‐cadherin
accumulation
E‐cadherin
levels.
Silencing
significantly
improved
inflammation,
apoptosis,
inhibition
autophagy.
Further
transcriptomic
assays
identified
RUNX1
candidate
target
FTO.
Inhibiting
was
shown
counteract
UUO/TGF‐β1‐induced
elevation
vitro.
demonstrated
that
signaling
contributes
demethylating
improving
stability.
Finally,
PI3K/AKT
may
be
activated
FTO/RUNX1
axis
conclusion,
identifying
small‐molecule
compounds
could
offer
promising
therapeutic
strategies
for
treating
