Abstract
The
GDF15
protein,
a
member
of
the
TGF-β
superfamily,
is
stress-induced
multifunctional
protein
with
many
its
functions
associated
regulation
immune
system.
signaling
provides
defence
against
excessive
inflammation
induced
by
diverse
stresses
and
tissue
injuries.
Given
that
aging
process
low-grade
inflammatory
state,
called
inflammaging,
it
not
surprising
expression
gradually
increases
aging.
In
fact,
core
factor
secreted
senescent
cells,
state
senescence-associated
secretory
phenotype
(SASP).
Many
age-related
stresses,
e.g.,
mitochondrial
endoplasmic
reticulum
as
well
inflammatory,
metabolic,
oxidative
induce
GDF15.
Although
an
effective
anti-inflammatory
modulator,
there
robust
evidence
pro-aging
promoting
process.
only
modulator
but
also
potent
immunosuppressive
enhancer
in
chronic
states.
can
stimulate
responses
either
non-specifically
via
receptors
superfamily
or
specifically
through
GFRAL/HPA/glucocorticoid
pathway.
stimulates
network
activating
MDSCs,
Tregs,
M2
macrophages
triggering
inhibitory
checkpoint
cells.
Immunosuppressive
suppress
processes
they
evoke
detrimental
effects
aged
tissues,
such
cellular
senescence,
fibrosis,
atrophy/sarcopenia.
It
seems
survival
go
awry
persistent
thus
diseases.
Cancer & Metabolism,
Год журнала:
2025,
Номер
13(1)
Опубликована: Янв. 27, 2025
The
Warburg
effect,
characterized
by
the
shift
toward
aerobic
glycolysis,
is
closely
associated
with
onset
and
advancement
of
tumors,
including
multiple
myeloma
(MM).
Nevertheless,
specific
regulatory
mechanisms
glycolysis
in
MM
its
functional
role
remain
unclear.
In
this
study,
we
identified
that
growth
differentiation
factor
15
(GDF15)
a
glycolytic
regulator,
GDF15
highly
expressed
cells
patient
samples.
Through
gain-of-function
loss-of-function
experiments,
demonstrated
promotes
cell
proliferation
inhibits
apoptosis.
Moreover,
enhances
Warburg-like
metabolism
cells,
as
evidenced
increased
glucose
uptake,
lactate
production,
extracellular
acidification
rate,
while
reducing
oxidative
phosphorylation.
Importantly,
tumor-promoting
effects
are
fermentation-dependent.
Mechanistically,
was
found
to
promote
expression
key
genes,
particularly
transporter
GLUT1,
through
activation
TGFβ
signaling
pathway.
Pharmacological
inhibition
pathway
effectively
abrogated
oncogenic
activities
proliferation,
apoptosis,
fermentation.
vivo
experiments
using
subcutaneous
xenotransplanted
tumor
model
confirmed
knockdown
led
significant
reduction
growth,
overexpression
promoted
growth.
Overall,
our
study
provides
insights
into
molecular
underlying
pathogenesis
highlights
potential
targeting
GDF15-TGFβ
-glycolysis
axis
therapeutic
approach
for
future
interventions
MM.
Frontiers in Bioscience-Landmark,
Год журнала:
2025,
Номер
30(2)
Опубликована: Фев. 18, 2025
Background:
Heart
failure
with
preserved
ejection
fraction
(HFpEF)
is
a
systemic
syndrome
primarily
associated
fibrosis,
oxidative
stress,
inflammation,
and
cellular
apoptosis.
Growth
differentiation
factor
15
(GDF15),
biomarker
commonly
used
in
clinical
studies,
exhibits
protective
effects
on
the
myocardium.
Therefore,
focus
of
present
study
to
determine
mechanism
by
which
GDF15
protects
cardiac
function
HFpEF.
Methods:
We
conducted
functional
enrichment
analysis
protein-protein
interaction
network
genes
highly
expressed
HFpEF
but
lowly
normal
samples.
established
an
rat
model
feeding
rats
high-fat
diet
administering
N-omega-nitro-l-arginine-methyl
ester
(L-NAME)
their
drinking
water
silenced
tail
vein
injection
lentivirus
(L3110).
After
12
weeks
feeding,
echocardiographic
examinations
were
performed.
Following
euthanasia
rats,
blood
heart
tissue
samples
collected.
sections
stained
using
Masson’s
trichrome
terminal
deoxynucleotidyl
transferase-mediated
deoxyuridine
triphosphate
nick-end
labeling
(TUNEL)
staining
methods.
Western
blot
(WB)
was
employed
concentrations
relevant
proteins.
Results:
The
results
showed
that
compared
+
MOCK
group,
HFpEF+silencing
(siGDF15)
group
exhibited
more
severe
dysfunction,
significant
decreases
(p
<
0.05)
E/A
ratio
0.001).
WB
demonstrated
that,
HFpEF+siGDF15
increased
expression
fibrosis-associated
proteins,
including
collagen
I
0.01),
III
α-smooth
muscle
actin
(α-SMA)
0.01).
Additionally,
stress-associated
biomarkers
such
as
myeloperoxidase
(MPO)
0.01)
oxidized
low-density
lipoprotein
(ox-LDL)
inflammation-associated
biomarkers,
interleukin-1
beta
(IL-1β)
interleukin-6
(IL-6)
interleukin-8
(IL-8)
tumor
necrosis
α
(TNFα)
apoptosis-associated
like
cleaved
caspase-3
BCL2-associated
X
(BAX)
also
upregulated
group.
Conclusions:
Our
research
indicates
preserves
inhibiting
myocardial
reducing
cell
alleviating
suppressing
International Journal of Molecular Sciences,
Год журнала:
2024,
Номер
25(8), С. 4342 - 4342
Опубликована: Апрель 14, 2024
Acute
myeloid
leukemia
(AML)
is
a
hematological
malignancy
that
characterized
by
an
expansion
of
immature
precursors.
Despite
therapeutic
advances,
the
prognosis
AML
patients
remains
poor
and
there
need
for
evaluation
promising
candidates
to
treat
disease.
The
objective
this
study
was
evaluate
efficacy
duocarmycin
Stable
A
(DSA)
in
cells
vitro.
We
hypothesized
DSA
would
induce
DNA
damage
form
double-strand
breaks
(DSBs)
exert
cytotoxic
effects
on
within
picomolar
range.
Human
cell
lines
Molm-14
HL-60
were
used
perform
3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium
bromide
(MTT),
DSBs,
cycle,
5-ethynyl-2-deoxyuridine
(EdU),
colony
formation
unit
(CFU),
Annexin
V,
RNA
sequencing
other
assays
described
study.
Our
results
showed
induced
cycle
arrest
at
G2M
phase,
reduced
proliferation
increased
apoptosis
cells.
Additionally,
regulates
genes
are
associated
with
cellular
processes
such
as
repair,
checkpoint
apoptosis.
These
suggest
efficacious
therefore
potential
candidate
can
be
further
evaluated
treatment
AML.
Research Square (Research Square),
Год журнала:
2024,
Номер
unknown
Опубликована: Авг. 21, 2024
Abstract
Metastasis
is
a
major
challenge
for
colorectal
cancer
(CRC)
treatment.
Here,
we
uncovered
CENPF
may
be
involved
in
CRC
metastasis
through
bioinformatics
mining
and
small
interfering
RNA
(siRNA)
targeted
functional
screening.
We
observed
expression
was
preferentially
increased
tissues
compared
to
adjacent
normal
tissues.
More
importantly,
multicenter
cohort
study
identified
upregulated
significantly
correlated
with
poor
survival
CRC.
Knockdown
of
inhibited
cell
invasion
vitro
vivo.
Intriguingly,
found
undergoes
degradation
via
the
ubiquitination-proteasome
pathway.
Mechanistically,
that
USP4
interacted
stabilized
deubiquitination.
Furthermore,
USP4-mediated
upregulation
critical
regulators
Examination
clinical
samples
confirmed
positively
correlates
protein
expression,
but
not
mRNA
transcript
levels.
Taken
together,
this
describes
novel
USP4-CENPF
signaling
axis
which
crucial
metastasis,
potentially
serving
as
therapeutic
target
promising
prognostic
biomarker