Inflammatory
gut
disorders,
including
inflammatory
bowel
disease
(IBD),
can
be
impacted
by
dietary,
environmental,
and
genetic
factors.
While
the
incidence
of
IBD
is
increasing
worldwide,
we
still
lack
a
complete
understanding
gene-by-environment
interactions
underlying
inflammation
IBD.
Here,
profiled
colon
transcriptome
52
BXD
mouse
strains
fed
with
chow
or
high-fat
diet
(HFD)
identified
subset
that
exhibit
an
IBD-like
signature
on
HFD,
indicating
interplay
genetics
significantly
affect
intestinal
inflammation.
Using
gene
co-expression
analyses,
modules
are
enriched
for
IBD-dysregulated
genes
found
these
IBD-related
share
cis
-regulatory
elements
responsive
to
STAT2,
SMAD3
,
REL
transcription
We
used
module
quantitative
trait
locus
analyses
identify
loci
associated
expression
modules.
Through
prioritization
scheme
involving
systems
in
integration
external
human
datasets,
Muc4
Epha6
as
top
candidates
mediating
differences
HFD-driven
This
work
provides
insights
into
contribution
risk
identifies
two
candidate
genes,
MUC4
EPHA6
may
mediate
susceptibility
humans.
Type
2
diabetes
mellitus
(T2DM)
represents
one
of
the
fastest
growing
epidemic
metabolic
disorders
worldwide
and
is
a
strong
contributor
for
broad
range
comorbidities,
including
vascular,
visual,
neurological,
kidney,
liver
diseases.
Moreover,
recent
data
suggest
mutual
interplay
between
T2DM
Corona
Virus
Disease
2019
(COVID-19).
characterized
by
insulin
resistance
(IR)
pancreatic
β
cell
dysfunction.
Pioneering
discoveries
throughout
past
few
decades
have
established
notable
links
signaling
pathways
pathogenesis
therapy.
Importantly,
number
substantially
control
advancement
core
pathological
changes
in
T2DM,
IR
dysfunction,
as
well
additional
pathogenic
disturbances.
Accordingly,
an
improved
understanding
these
sheds
light
on
tractable
targets
strategies
developing
repurposing
critical
therapies
to
treat
its
complications.
In
this
review,
we
provide
brief
overview
history
pathways,
offer
systematic
update
role
mechanism
key
underlying
onset,
development,
progression
T2DM.
content,
also
summarize
current
therapeutic
drugs/agents
associated
with
treatment
complications,
discuss
some
implications
directions
future
field.
Quantitative
traits
are
often
complex
because
of
the
contribution
many
loci,
with
further
complexity
added
by
environmental
factors.
In
medical
research,
systems
genetics
is
a
powerful
approach
for
study
traits,
as
it
integrates
intermediate
phenotypes,
such
RNA,
protein,
and
metabolite
levels,
to
understand
molecular
physiological
phenotypes
linking
discrete
DNA
sequence
variation
clinical
traits.
The
primary
purpose
this
review
describe
some
resources
tools
in
humans
rodent
models,
so
that
researchers
areas
biology
medicine
can
make
use
data.
Proceedings of the National Academy of Sciences,
Год журнала:
2024,
Номер
121(47)
Опубликована: Ноя. 12, 2024
The
gut
microbiota
has
a
significant
impact
on
the
development
and
function
of
intestinal
epithelial
cells
(IECs)
by
modifying
bile
acid
(BA)
metabolites.
Recently,
specific
microbiome-derived
BAs,
such
as
7-oxo-deoxycholic
(7-oxo-DCA)
isodeoxycholic
(isoDCA),
have
been
identified
to
be
shifted
inversely
in
colitis
hepatic
liver
diseases.
Although
responsible
microbes
identified,
metabolites’
effects
IECs
remain
largely
unclear.
We
found
that
although
high-fat
diet
treatment
mice
elevated
both
7-oxo-DCA
isoDCA
levels,
during
tumorigenesis,
levels
rise
while
decrease.
Interestingly,
promotes
cancer
cell
growth,
suppresses
it.
Moreover,
whereas
inhibits
proliferation
stem
organoids
derived
from
WT
APC
Min/+
mice,
well
patient-derived
colon
organoids.
administered
with
heightened
permeability
increased
tumor
burden,
protected
barrier
reduced
loads.
Both
BAs
reshape
BA
pool
microbiome.
Mechanistically,
we
natural
antagonist
Farnesoid
X
Receptor
(FXR)
downregulate
FXR
signaling,
opposed
isoDCA,
which
is
potent
agonist
upregulate
signaling.
In
conclusion,
unveiled
opposing
roles
promote
or
inhibit
respectively.
Manipulating
BA–FXR
axis
initiation
progression
holds
great
promise
for
developing
innovative
diagnostic
therapeutic
approaches
colorectal
cancer.
Communications Biology,
Год журнала:
2024,
Номер
7(1)
Опубликована: Май 27, 2024
Abstract
Bile
acids
(BAs)
play
important
pathophysiological
roles
in
both
humans
and
mammalian
animals.
Laboratory
rats
mice
are
widely
used
animal
models
for
assessing
pharmacological
effects
their
underlying
molecular
mechanisms.
However,
substantial
physiological
differences
exist
BA
composition
between
murine
rodents.
Here,
we
comprehensively
compare
profiles,
including
primary
secondary
BAs,
along
with
amino
acid
conjugates,
sulfated
metabolites
serum,
urine,
feces
two
We
further
analyze
the
capabilities
gut
microbial
transform
BAs
among
three
species
sex-dependent
variations
within
each
species.
As
a
result,
undergo
amidation
predominately
glycine
taurine
but
primarily
unamidated
rats.
sulfation
is
unique
characteristic
humans,
whereas
perform
multiple
hydroxylations
during
synthesis
metabolism.
For
transformed
capabilities,
comparable
to
those
of
rats,
stronger
than
deconjugation
7α-dehydroxylation,
while
weak
or
oxidation
epimerization.
Such
enhance
our
understanding
divergent
experimental
outcomes
observed
rodents,
necessitating
caution
when
translating
findings
from
these
rodent
humans.
In
response
to
energy
and
nutrient
shortage,
the
liver
triggers
several
catabolic
processes
promote
survival.
Despite
recent
progress,
precise
molecular
mechanisms
regulating
hepatic
adaptation
fasting
remain
incompletely
characterized.
Here,
we
report
identification
of
hydroxysteroid
dehydrogenase–like
2
(HSDL2)
as
a
mitochondrial
protein
highly
induced
by
fasting.
We
show
that
activation
PGC1α-PPARα
inhibition
PI3K-mTORC1
axis
stimulate
HSDL2
expression
in
hepatocytes.
found
depletion
decreases
cholesterol
conversion
bile
acids
(BAs)
impairs
FXR
activity.
knockdown
also
reduces
respiration,
fatty
acid
oxidation,
TCA
cycle
Bioinformatics
analyses
revealed
Hsdl2
positively
associates
with
postprandial
excursion
various
BA
species
mice.
liver-specific
affects
metabolism
circulating
levels
upon
refeeding.
Overall,
our
identifies
fasting-induced
links
nutritional
signals
BAs
homeostasis.
Human Molecular Genetics,
Год журнала:
2025,
Номер
unknown
Опубликована: Янв. 8, 2025
Abstract
Constitutively
active
mutants
of
BRAF
cause
cardio-facio-cutaneous
(CFC)
syndrome,
characterized
by
growth
and
developmental
defects,
cardiac
malformations,
facial
features,
cutaneous
manifestations,
mental
retardation.
An
animal
model
human
CFC
the
systemic
BrafQ241R/+
mutant
mouse,
has
been
reported
to
exhibit
multiple
syndrome-like
phenotypes.
In
this
study,
we
analyzed
effects
Braf
mutations
on
neural
function,
separately
from
their
processes.
To
end,
generated
mice
expressing
BRAFQ241R
specifically
in
mature
excitatory
neurons
(n-BrafQ241R/+).
We
found
no
retardation
or
malformations
n-BrafQ241R/+
mice,
indicating
normal
development.
Behavioral
analysis
revealed
that
exhibited
reduced
home
cage
activity
learning
disability,
which
were
similar
those
mice.
The
form
ERK
was
increased
hippocampus
whereas
basal
synaptic
transmission
plasticity
hippocampal
Schaffer
collateral-CA1
synapses
seems
be
normal.
Transcriptome
tissue
significant
changes
expression
genes
involved
regulation
RAS/mitogen-activated
protein
kinase
(MAPK)
signaling
pathway,
function
memory
formation.
These
data
suggest
neuronal
dysfunction
observed
mouse
is
due
disruption
homeostasis
RAS/MAPK
pathway
activated
after
maturation,
rather
than
abnormal
development
brain.
A
mechanism
may
possible
syndrome.
Frontiers in Oncology,
Год журнала:
2022,
Номер
12
Опубликована: Дек. 22, 2022
Chemoresistance
is
a
major
barrier
in
the
treatment
of
colorectal
cancer
(CRC)
and
many
other
cancers.
ENO1
has
been
associated
with
various
biological
characteristics
CRC.
This
study
aimed
to
investigate
function
regulating
5-Fluorouracil
(5-FU)
resistance
CRC.ENO1
level
120
pairs
tumor
tissues
adjacent
normal
was
examined
by
immunohistochemistry,
correlation
between
expression
prognosis
explored
survival
analysis.
Its
role
potential
mechanisms
5-FU
CRC
were
studied
Western
blotting,
MTT
assay,
colony
formation
assay
transwell
invasion
assay.
Murine
xenograft
implied
verify
results
vivo.Our
indicated
that
elevated
poor
patient
prognosis.
High
levels
detected
as
significant
influencing
factor
for
overall
survival.
Furthermore,
found
have
increased
drug-resistant
cells
(HCT116/5-FU
SW620/5-FU)
constructed
increasing
concentrations
5-FU.
Knockdown
markedly
drug
susceptibility
inhibited
proliferation
migration
ability
HCT116/5-FU
SW620/5-FU
cells.
It
down-regulation
epithelial-mesenchymal
transformation
(EMT)
signaling
process.
Finally,
murine
verified
depletion
alleviated
resistance.This
identified
regulated
via
EMT
pathway
may
be
novel
target
prevention
5-FUresistant
