Melatonin-mediated cGAS-STING signal in senescent macrophages promote TNBC chemotherapy resistance and drive the SASP
Journal of Biological Chemistry,
Год журнала:
2025,
Номер
unknown, С. 108438 - 108438
Опубликована: Март 1, 2025
The
build-up
of
senescent
cells
in
tissues
is
a
key
indicator
aging,
associated
with
negative
prognosis
and
therapy
resistance.
Despite
immune
dysfunction
related
to
also
known
as
immunosenescence,
recognized
factor
this
process,
the
exact
mechanisms
are
still
unclear.
In
study,
we
reported
that
melatonin
deficiency
accelerated
macrophage
senescence
triple-negative
breast
cancer
(TNBC),
whereas,
could
defend
macrophages
against
through
Nfatc1-Trim26-cgas-Sting
pathway.
Mechanistically,
enhanced
nuclear
translocation
Nfatc1
elevated
Trim26
transcription
levels.
Trim26,
functioning
an
E3
ligase,
ubiquitinates
cgas,
thereby
inhibiting
activation
cgas-Sing
pathway
consequently
preventing
cell
senescence.
Conversely,
induced
cgas-Sting
promote
aging.
Our
results
show
inhibited
improved
chemotherapy
responsiveness,
further
enhancement
when
combined
cgas
inhibitor
(G150).
Overall,
our
findings
indicated
protects
from
suggesting
its
therapeutic
potential
for
enhancing
response.
Язык: Английский
Mammalian Ste20-like kinase 1 regulates AMPK to mitigate the progression of non-alcoholic fatty liver disease
European journal of medical research,
Год журнала:
2025,
Номер
30(1)
Опубликована: Апрель 17, 2025
Abstract
Background
Non-alcoholic
steatohepatitis
(NASH)
progression
is
strongly
associated
with
deteriorating
hepatic
function,
primarily
driven
by
free
cholesterol
(FC)
accumulation-induced
lipotoxicity.
Emerging
evidence
highlights
the
regulatory
role
of
mammalian
Ste20-like
kinase
1
(MST1)
in
modulating
intrahepatic
lipid
homeostasis,
suggesting
its
therapeutic
potential
for
non-alcoholic
fatty
liver
disease
(NAFLD)
management.
This
investigation
seeks
to
elucidate
pathophysiological
mechanisms
through
which
MST1
modulates
NASH
progression.
Methods
The
experimental
design
employed
two
murine
genetic
models—wild-type
(WT)
controls
and
MST1-knockout
(MST1-KO)
specimens—subjected
a
nutritionally
modified
Western
diet
(WD)
enriched
saturated
fats,
simple
carbohydrates,
dietary
induce
pathogenesis.
Lentiviral
transduction
techniques
facilitated
targeted
overexpression
WT
animals
maintained
on
this
regimen.
Parallel
vitro
investigations
utilized
HepG2
hepatocyte
cultures
exposed
acid
(FFA)
cocktails
comprising
palmitic
oleic
acids,
coupled
CRISPR-mediated
suppression
complementary
gain-of-function
manipulations
delineate
molecular
mechanisms.
Results
triggers
sterol
biosynthesis
activation,
resulting
pathological
FC
overload
concurrent
transcriptional
suppression.
Genetic
ablation
amplifies
retention
potentiates
histopathological
inflammation,
while
reconstitution
mitigates
steatotic
deposition
attenuates
inflammatory
cascades.
Mechanistic
profiling
revealed
MST1-mediated
AMPKα
phosphorylation
at
Thr172,
suppresses
cholesterogenic
enzyme
expression
via
element-binding
transcription
factor
2
(SREBP2)
axis
modulation.
cascade
demonstrates
dose-dependent
inhibition
HMGCR
activity,
resolving
FC-induced
hepatotoxicity.
Crucially,
orchestrates
AMPK/SREBP2
crosstalk
maintain
knockout
models
exhibiting
67%
elevated
SREBP2
nuclear
translocation
compared
controls.
Conclusions
involving
AMPK
emerges
as
promising
modality
metabolism.
It
significant
arresting
cascades
extracellular
matrix
remodeling
characteristic
studies
confirm
that
effectively
de
novo
lipogenesis
enhancing
efflux
capacity,
thereby
establishing
dual-target
strategy
against
both
metabolic
dysfunction
fibrotic
transformation
preclinical
models.
Язык: Английский
Lycopene mitigates atrazine-induced hypothalamic neural stem cell senescence by modulating the integrated stress response pathway
Phytomedicine,
Год журнала:
2024,
Номер
135, С. 156114 - 156114
Опубликована: Сен. 30, 2024
Язык: Английский
Rab8a Is a Key Target That Melatonin Prevents Lipid Disorder from Atrazine
Journal of Agricultural and Food Chemistry,
Год журнала:
2024,
Номер
72(42), С. 23511 - 23519
Опубликована: Окт. 9, 2024
Atrazine
(ATZ),
a
widely
used
herbicide,
disrupts
mitochondrial
function
and
lipid
metabolism
in
the
liver.
Melatonin
(MLT),
naturally
synthesized
hormone,
combats
dysfunction
alleviates
toxicity.
However,
mechanisms
behind
ATZ-induced
toxicity
protective
effects
of
MLT
remain
unexplored.
Mice
were
randomly
assigned
to
four
groups:
control
(Con),
5
mg/kg
MLT,
170
ATZ,
cotreatment
group
receiving
ATZ
with
(ATZ+MLT).
Additionally,
we
analyzed
Rab8a
on
mRNA
proteins
related
disrupted
by
AML12
cells.
In
conclusion,
induced
stress
fatty
acid
mouse
hepatocytes
Exogenous
restores
levels,
regulating
utilization
mitochondria
function.
Notably,
targeting
does
not
significantly
affect
but
prevents
disorders
hepatocytes.
Язык: Английский
Parkin‐TLR4‐NLRP3 Axis Directs Melatonin to Alleviate Atrazine‐Induced Immune Impairment in Splenic Macrophages
Journal of Pineal Research,
Год журнала:
2024,
Номер
76(8)
Опубликована: Ноя. 1, 2024
ABSTRACT
Atrazine
(ATR)
is
a
widespread
environmental
herbicide
that
seriously
affects
agricultural
work
and
human
safety.
Melatonin
(MLT)
as
an
endogenous
neuroendocrine
hormone
widely
found
in
animals
plants,
which
have
antioxidant
anti‐inflammatory
effects.
Pink1/Parkin‐mediated
mitophagy
keeps
normal
physiological
processes
by
degrading
damaged
mitochondria
cells.
Therefore,
we
investigated
the
potential
role
mechanism
of
MLT
ATR‐induced
toxic
injury
spleen.
The
results
showed
alleviated
unclear
boundary
between
white
pulp
red
It
also
shown
ATR
resulted
swollen
mitochondria,
partial
extinction
mitochondrial
membranes
cristae,
increased
under
action
MLT.
reactive
oxygen
species
(ROS)
activates
Pink1/Parkin
pathway,
guides
development
then
causes
activation
TLR4/NF‐κB
inflammatory
pathway.
Meanwhile,
these
damages
further
exacerbated
production
NLRP3
inflammasomes,
leading
to
spleen
necrosis.
Interestingly,
changes
were
improved
after
treatment.
Collectively,
alleviates
immune
impairment
splenic
macrophages
via
regulating
Parkin‐TLR4‐NLRP3
axis
elucidates
effect
melatonin
on
provides
novel
perspective
Язык: Английский
A New Insight into the Mechanism of Atrazine-Induced Neurotoxicity: Triggering Neural Stem Cell Senescence by Activating Integrated Stress Response Pathway
Research,
Год журнала:
2024,
Номер
7
Опубликована: Янв. 1, 2024
Atrazine
(AT),
a
widely
utilized
chemical
herbicide,
causes
widespread
contamination
of
agricultural
water
bodies.
Recently,
exposure
to
AT
has
been
linked
the
development
age-related
neurodegenerative
diseases
(NDs),
suggesting
its
neurotoxicity
potential.
As
an
endocrine
disruptor,
targets
hypothalamus,
crucial
part
neuroendocrine
system.
However,
toxicological
mechanism
hypothalamus
and
correlation
with
ND
remain
unexplored.
Our
results
indicated
that
caused
significant
morphological
structural
damage
leading
loss
mature
intact
neurons
microglial
activation.
Furthermore,
hypothalamic
neural
stem
cells
(HtNSCs)
were
recruited
areas
neuronal
by
AT.
Through
in
vivo
vitro
experiments,
we
clarified
outcomes
AT-induced
HtNSC
recruitment
alongside
mature/intact
neurons.
Mechanistically,
induces
senescence
these
HtNSCs
activating
integrated
stress
response
signaling.
This
consequently
hinders
repair
damaged
inhibiting
proliferation
differentiation.
Overall,
our
findings
underscore
pivotal
role
pathway
damage.
Additionally,
present
study
offers
novel
perspectives
understand
mechanisms
provides
preliminary
evidence
linking
NDs.
Язык: Английский
Metasilicate-based alkaline mineral water improves the growth performance of weaned piglets by maintaining gut-liver axis homeostasis through microbiota-mediated secondary bile acid pathway
Animal nutrition,
Год журнала:
2024,
Номер
20, С. 95 - 109
Опубликована: Ноя. 2, 2024
Weaning
stress
causes
substantial
economic
loss
in
the
swine
industry.
Moreover,
weaning-induced
intestinal
barrier
damage
and
dysfunction
of
gut-liver
axis
are
associated
with
reduced
growth
performance
piglets.
Metasilicate-based
alkaline
mineral
water
(AMW)
has
shown
potential
therapeutic
effects
on
gastrointestinal
disorders;
however,
mechanisms
involved
their
overall
have
not
been
explored.
Here,
sodium
metasilicate
(SMS)
was
used
to
prepare
metasilicate-based
AMW
(basal
+
500
mg/L
SMS).
A
total
240
newly
weaned
piglets
were
allocated
Control
SMS
groups
(6
replicate
pens
per
group
20
pen)
for
a
15-day
trial
period.
Histopathological
evaluations
conducted
using
hematoxylin
eosin
staining.
To
analyze
composition
gut
microbiota,
16S
rRNA
PacBio
SMRT
Gene
Full-Length
Sequencing
performed.
Western
blotting
immunofluorescence
employed
assess
protein
expression
levels.
Our
results
indicated
that
effectively
alleviated
colonic
or
liver
morphological
injury
inflammatory
response,
as
well
cholesterol
metabolism
disorders.
Further
analysis
showed
promoted
deoxycholic
acid
(DCA)
biosynthesis
by
increasing
abundance
Lactobacillus_delbrueckii
colon
(P
<
0.001).
This
consequently
improved
through
DCA-secondary
bile
(SBA)
receptors
(SBAR)-nuclear
factor-kappaB
(NF-κB)/NOD-like
receptor
family
pyrin
domain-containing
3
(NLRP3)
pathways.
Growth
parameters,
including
final
body
weight
=
0.034)
average
daily
gain
0.001),
significantly
higher
than
those
group.
Therefore,
maintains
homeostasis
regulating
microbiota-mediated
SBA-SBAR
pathway
under
weaning
stress.
research
provides
new
strategy
mitigating
stress-induced
Язык: Английский