Free Radical Biology and Medicine,
Год журнала:
2021,
Номер
164, С. 315 - 328
Опубликована: Янв. 12, 2021
Mice
deficient
in
the
antioxidant
enzyme
Cu/Zn-superoxide
dismutase
(Sod1-/-
or
Sod1KO
mice)
have
increased
oxidative
stress,
show
accelerated
aging
and
develop
spontaneous
hepatocellular
carcinoma
(HCC)
with
age.
Similar
to
humans,
HCC
development
mice
progresses
from
non-alcoholic
fatty
liver
disease
(NAFLD)
steatohepatitis
(NASH)
fibrosis,
which
eventually
HCC.
Oxidative
stress
plays
a
role
NAFLD
NASH
progression,
inflammation
is
main
mechanism
that
drives
progression
fibrosis.
Because
necroptosis
major
source
of
inflammation,
we
tested
hypothesis
fibrosis
mice.
Phosphorylation
MLKL
(P-MLKL),
well-accepted
marker
necroptosis,
expression
protein
were
significantly
livers
compared
wild
type
(WT)
indicating
necroptosis.
Similarly,
phosphorylation
RIPK3
levels
also
increased.
Markers
pro-inflammatory
M1
macrophages,
NLRP3
inflammasome,
transcript
cytokines
chemokines,
e.g.,
TNFα,
IL-6,
IL-1β,
Ccl2
are
associated
human
NASH,
Expression
enzymes
heat
shock
proteins,
markers
oncogenic
transcription
factor
STAT3
upregulated
autophagy
was
downregulated
Short
term
treatment
necrostatin-1s
(Nec-1s),
inhibitor,
reversed
these
conditions.
Our
data
for
first
time
necroptosis-mediated
contributes
mouse
model
aging,
exhibits
progressive
development.
Hepatology,
Год журнала:
2021,
Номер
74(4), С. 1884 - 1901
Опубликована: Май 11, 2021
Background
and
Aims
Animal
models
of
human
disease
are
a
key
component
translational
hepatology
research,
yet
there
is
no
consensus
on
which
model
optimal
for
NAFLD.
Approach
Results
We
generated
database
3,920
rodent
Study
designs
were
highly
heterogeneous,
therefore,
few
had
been
cited
more
than
once.
Analysis
genetic
supported
the
current
evidence
role
adipose
dysfunction
suggested
innate
immunity
in
progression
identified
that
high‐fat,
high‐fructose
diets
most
closely
recapitulate
phenotype
There
was
substantial
variability
nomenclature
animal
models:
terminology
specialist
needed.
More
broadly,
this
analysis
demonstrates
preclinical
study
design,
has
wider
implications
reproducibility
vivo
experiments
both
field
beyond.
Conclusions
This
systematic
provides
framework
phenotypic
assessment
NAFLD
highlights
need
increased
standardization
replication.
Molecular Therapy,
Год журнала:
2022,
Номер
30(6), С. 2342 - 2353
Опубликована: Фев. 19, 2022
Type
2
diabetes
mellitus
(DM2)
is
associated
closely
with
non-alcoholic
fatty
liver
disease
(NAFLD)
by
affecting
lipid
metabolism,
which
may
lead
to
steatohepatitis
(NASH),
fibrosis,
and
hepatocellular
carcinoma
(HCC).
N6-methyladenosine
(m6A)
RNA
methylation
an
important
epigenetic
regulation
for
gene
expression
related
HCC
development.
We
developed
a
new
NAFLD
model
oriented
from
DM2
mouse,
spontaneously
progressed
histological
features
of
NASH,
high
incidence.
By
sequencing,
protein
methylated
immunoprecipitation
(MeRIP)-qPCR
analysis,
we
found
that
enhanced
ACLY
SCD1
in
this
human
samples
was
due
excessive
m6A
modification,
but
not
elevation
mature
SREBP1.
Moreover,
targeting
METTL3/14
vitro
increases
level
as
well
triglyceride
cholesterol
production
accumulation
droplets.
sequencing
analysis
revealed
overexpressed
METTL14
binds
mRNA
alters
their
pattern.
Our
findings
demonstrate
mouse
provides
study
platform
DM2-related
reveals
unique
epitranscriptional
regulating
mechanism
metabolism
via
m6A-modified
SCD1.
Nature,
Год журнала:
2024,
Номер
626(7999), С. 635 - 642
Опубликована: Янв. 31, 2024
Abstract
Type
2
diabetes
mellitus
is
a
major
risk
factor
for
hepatocellular
carcinoma
(HCC).
Changes
in
extracellular
matrix
(ECM)
mechanics
contribute
to
cancer
development
1,2
,
and
increased
stiffness
known
promote
HCC
progression
cirrhotic
conditions
3,4
.
characterized
by
an
accumulation
of
advanced
glycation
end-products
(AGEs)
the
ECM;
however,
how
this
affects
non-cirrhotic
unclear.
Here
we
find
that,
patients
animal
models,
AGEs
changes
collagen
architecture
enhance
ECM
viscoelasticity,
with
greater
viscous
dissipation
faster
stress
relaxation,
but
not
stiffness.
High
viscoelasticity
combined
oncogenic
β-catenin
signalling
induction,
whereas
inhibiting
AGE
production,
reconstituting
clearance
receptor
AGER1
or
breaking
AGE-mediated
cross-links
reduces
growth.
Matrix
analysis
computational
modelling
demonstrate
that
lower
interconnectivity
AGE-bundled
matrix,
marked
shorter
fibre
length
heterogeneity,
enhances
viscoelasticity.
Mechanistically,
studies
3D
cell
cultures
show
enhanced
promotes
proliferation
invasion
through
integrin-β1–tensin-1–YAP
mechanotransductive
pathway.
These
results
reveal
structural
can
vivo,
independent
Liver
cancer
is
the
third
leading
cause
of
cancer-related
deaths
and
ranks
as
sixth
most
prevalent
type
globally.
NAFLD
or
metabolic
dysfunction-associated
steatotic
liver
disease,
its
more
severe
manifestation,
NASH
steatohepatitis
(MASH),
pose
a
significant
global
health
concern,
affecting
approximately
20%-25%
population.
The
increased
prevalence
disease
MASH
parallel
to
increasing
rates
obesity-associated
diseases,
including
2
diabetes,
insulin
resistance,
fatty
diseases.
can
progress
MASH-related
HCC
(MASH-HCC)
in
about
2%
cases
each
year,
influenced
by
various
factors
such
genetic
mutations,
carcinogen
exposure,
immune
microenvironment,
microbiome.
MASH-HCC
exhibits
distinct
molecular
characteristics
compared
other
causes
affects
both
men
women
equally.
management
early
intermediate-stage
typically
involves
surgery
locoregional
therapies,
while
advanced
treated
with
systemic
anti-angiogenic
therapies
checkpoint
inhibitors.
In
this
comprehensive
review,
we
consolidate
previous
research
findings
also
providing
current
insights
into
intricate
processes
underlying
development.
We
delve
MASH-HCC-associated
variations
somatic
progression
models,
multiomics
analysis,
immunological
microenvironmental
impacts,
discuss
targeted/combined
overcome
evasion
biomarkers
recognize
treatment
responders.
By
furthering
our
comprehension
mechanisms
MASH-HCC,
goal
catalyze
advancement
potent
strategies,
ultimately
enhanced
patient
outcomes.
