Mechanistic insights into alkaloid-based inhibition of squalene epoxidase: A combined in silico and experimental approach for targeting cholesterol biosynthesis
International Journal of Biological Macromolecules,
Год журнала:
2025,
Номер
unknown, С. 140609 - 140609
Опубликована: Фев. 1, 2025
Язык: Английский
Associations between per-and polyfluoroalkyl substances (PFAS) and county-level cancer incidence between 2016 and 2021 and incident cancer burden attributable to PFAS in drinking water in the United States
Journal of Exposure Science & Environmental Epidemiology,
Год журнала:
2025,
Номер
unknown
Опубликована: Янв. 9, 2025
Abstract
Background
Exposure
to
per-
and
polyfluoroalkyl
substances
(PFAS)
has
been
linked
with
various
cancers.
Assessment
of
PFAS
in
drinking
water
cancers
can
help
inform
biomonitoring
prevention
efforts.
Objective
To
screen
for
incident
cancer
(2016–2021)
assess
associations
contamination
the
US.
Methods
We
obtained
county-level
age-adjusted
incidence
from
Surveillance,
Epidemiology,
End
Results
(SEER)
Program.
Data
on
levels
public
systems
were
Third
(UCMR3;
2013–2015)
Fifth
(UCMR5;
2023–2024)
Unregulated
Contaminant
Monitoring
Rule.
UCMR3
measured
PFOS,
PFOA,
PFNA,
PFHxS,
PFHpA,
PFBS.
UCMR5
expanded
measurements
include
PFBA,
PFHxA,
PFPeA,
PFPeS.
created
indicators
detection
and,
UCMR5,
concentrations
above
Maximum
Levels
(MCLs).
MCLs
PFOA
PFOS
are
4
ng/L,
PFNA
PFHxS
10
ng/L.
used
Poisson
regression
models
between
or
MCL
violation
incidence,
adjusting
potential
confounders.
estimated
number
attributable
cases.
was
associated
increased
digestive,
endocrine,
oral
cavity/pharynx,
respiratory
systems.
Incidence
rate
ratios
(IRRs)
ranged
1.02
1.33.
The
strongest
association
observed
PFBS
cavity/pharynx
(IRR:
1.33
[1.04,
1.71]).
Among
males,
urinary,
brain,
leukemia,
soft
tissues.
females,
thyroid,
tissue.
is
contribute
4626
[95%
CI:
1,377,
8046]
cases
per
year
based
data
6864
991,
12,804]
UCMR5.
Impact
statement
ecological
study
examined
two
waves
(2013–2015
2016
2021.
found
that
organ
system
including
lung,
digestive
system,
urinary
tissue,
thyroid.
Some
have
not
widely
studied
their
PFAS.
also
sex
differences
risks.
This
first
exposure
Язык: Английский
BRD1 deficiency affects SREBF1-related lipid metabolism through regulating H3K9ac/H3K9me3 transition to inhibit HCC progression
Cell Death and Disease,
Год журнала:
2025,
Номер
16(1)
Опубликована: Фев. 17, 2025
Abstract
BRD1
encodes
a
protein
containing
bromodomain,
which
is
an
essential
component
of
histone
acetyltransferase
(HAT)
complexes.
These
complexes
play
crucial
role
in
the
regulation
gene
transcription
and
modification
chromatin
structures.
The
aberrant
expression
frequently
observed
across
range
cancer
types,
including
hepatocellular
carcinomas
(HCC).
However,
precise
mechanisms
through
contributes
to
tumorigenesis,
especially
HCC,
remain
unclear.
In
our
investigation,
we
have
uncovered
novel
for
as
oncogene
implicated
lipid
metabolism
HCC
progression.
Specifically,
deficiency
impedes
proliferation
metastasis
cells
reducing
accumulation
droplets
cholesterol
levels.
This
effect
mediated
SREBF1-induced
downregulation
SCD1
cells.
Mechanistically,
ablation
disrupts
acetylation
level
H3K9,
culminating
subsequent
trimethylation
H3K9
(H3K9me3).
Notably,
H3K14ac
partially
colocalizes
with
H3K9me3
its
methyltransferase
SETDB1
from
double
labeling
both
at
SREBF1
promoter.
creation
repressive
environment,
ultimately
leading
HCC.
Furthermore,
combinatorial
use
inhibitor
simvastatin
augments
antitumor
efficacy
vivo.
Collectively,
findings
underscore
critical
regulator
SREBF1-associated
participant
progression
distinct
epigenetic
regulatory
mechanism.
discoveries
further
suggest
promising
therapeutic
approach
treatment
Язык: Английский
Lipid Metabolism and Immune Response in Hepatocellular Carcinoma: Interplay Driving Tumor Progression
Опубликована: Апрель 4, 2025
With
the
rising
incidence
of
metabolic
dysfunction-associated
steatotic
liver
disease
(MASLD),
it
has
become
a
significant
risk
factor
for
hepatocellular
carcinoma
(HCC).
This
review
focuses
on
roles
lipid
metabolism
aberrations
and
reprogramming
in
HCC
development.
We
begin
with
brief
overview
relevant
lipids
to
HCC,
including
fatty
acyls,
glycerolipids,
glycerophospholipids
sterol
lipids,
discuss
particularly
how
associated
its
promotes
chemoresistance
HCC.
then
explore
heterogeneity
distribution
across
different
stages
includes
intra-tissue
spatial
histological
structure
zonated
regions
liver,
interpatient
tumor
at
various
degrees
resolutions,
from
single
cell
bulk
tissue
levels.
Next,
we
describe
plasticity
MASLD
advent
immunotherapy
also
examine
relationship
between
anti-tumor
immunity
Finally,
address
challenges
future
perspectives
targeting
as
dual
approach
improve
treatment.
Язык: Английский
Multidimensional insights into squalene epoxidase drug development: in vitro mechanisms, in silico modeling, and in vivo implications
Expert Opinion on Therapeutic Targets,
Год журнала:
2025,
Номер
unknown
Опубликована: Апрель 30, 2025
Squalene
epoxidase
(SQLE)
is
a
pivotal
enzyme
in
sterol
biosynthesis,
catalyzing
the
conversion
of
squalene
to
2,3-oxidosqualene.
Beyond
its
core
role
cholesterol
homeostasis,
SQLE
implicated
cancer,
hypercholesterolemia,
and
fungal
infections,
positioning
it
as
valuable
therapeutic
target.
We
conducted
comprehensive
literature
search
across
primary
databases
gather
vitro,
silico,
vivo
evidence
on
SQLE.
This
review
explores
enzyme's
structural
functional
features,
including
substrate
specificity
catalytic
mechanisms,
examines
inhibitor
interactions.
Computational
methods
predict
-
dynamics,
guiding
drug
design,
while
investigations
clarify
SQLE's
metabolic
disorders
tumorigenesis.
Challenges
include
resistance
study
discrepancies,
but
emerging
technologies,
such
cryo-electron
microscopy
CRISPR
editing,
offer
new
avenues
for
deeper
exploration.
an
underexplored
yet
promising
target,
with
particular
relevance
oxidative
stress,
ferroptosis,
gut
microbiota
research.
Overcoming
current
barriers
through
advanced
technologies
multidisciplinary
strategies
could
propel
SQLE-targeted
treatments
into
clinical
practice,
supporting
precision
medicine
broader
translational
applications.
Язык: Английский
GDF15: Immunomodulatory Role in Hepatocellular Carcinoma Pathogenesis and Therapeutic Implications
Journal of Hepatocellular Carcinoma,
Год журнала:
2024,
Номер
Volume 11, С. 1171 - 1183
Опубликована: Июнь 1, 2024
Abstract:
Hepatocellular
carcinoma
(HCC)
is
the
third
leading
cause
of
cancer-related
deaths
globally
and
sixth
most
common
cancer
worldwide.
Evidence
shows
that
growth
differentiation
factor
15
(GDF15)
contributes
to
hepatocarcinogenesis
through
various
mechanisms.
This
paper
reviews
latest
insights
into
role
GDF15
in
development
HCC,
its
immune
microenvironment
molecular
mechanisms
metabolic
dysfunction
associated
steatohepatitis
(MASH)
fatty
liver
disease
(MAFLD)-related
HCC.
Additionally,
as
a
serum
biomarker
for
diagnostic
prognostic
value
HCC
summarized.
The
article
elaborates
on
immunological
effects
GDF15,
elucidating
hepatic
stellate
cells
(HSCs),
fibrosis,
well
metastasis
tumor
angiogenesis,
interactions
with
anticancer
drugs.
Based
impact
response
future
research
should
identify
signaling
pathways,
affected
cells,
interactions.
Clinical
studies
correlating
levels
patient
outcomes
can
aid
personalized
treatment.
exploring
GDF15-targeted
therapies
immunotherapies
could
improve
anti-tumor
responses
outcomes.
Keywords:
15,
hepatocellular
carcinoma,
suppression,
immunotherapy
Язык: Английский