International Journal of Molecular Sciences,
Год журнала:
2024,
Номер
25(24), С. 13496 - 13496
Опубликована: Дек. 17, 2024
Soluble
epoxide
hydrolase
(sEH)
is
a
bifunctional
enzyme
with
activity
in
the
C-terminal
domain
(C-EH)
and
lipid
phosphate
phosphatase
N-terminal
(N-phos).
The
C-EH
hydrolyzes
bioactive
epoxy
fatty
acids
such
as
epoxyeicosatrienoic
acid
(EET).
N-phos
phosphomonesters,
including
signaling
molecules
of
lysophosphatidic
(LPA).
Here,
we
report
that
are
reciprocally
regulated
by
their
respective
substrates.
Full-length
sEH
(sEH-FL)
showed
positive
cooperativity
toward
substrate
for
each
domain.
Similar
was
found
when
truncated
enzymes
having
only
C-
domains,
sEH-C
sEH-N,
respectively,
were
used,
suggesting
an
intra-domain
nature
cooperativity.
In
addition,
LPA
inhibited
sEH-FL
equally.
Similarly,
EET
activity.
Structural
kinetic
data
suggest
presence
allosteric
sites
enzyme,
which
share
binding
EET.
Thus,
two
activities
its
own
other
This
mechanism
may
explain
why
has
evolved
to
have
different
activities,
possibly
allows
balance
metabolism
lipids.
Proceedings of the National Academy of Sciences,
Год журнала:
2024,
Номер
121(7)
Опубликована: Фев. 8, 2024
Cancer
therapy,
including
immunotherapy,
is
inherently
limited
by
chronic
inflammation-induced
tumorigenesis
and
toxicity
within
the
tumor
microenvironment.
Thus,
stimulating
resolution
of
inflammation
may
enhance
immunotherapy
improve
immune
checkpoint
inhibition
(ICI).
As
epoxy-fatty
acids
(EpFAs)
are
degraded
enzyme
soluble
epoxide
hydrolase
(sEH),
sEH
increases
endogenous
EpFA
levels
to
promote
cancer-associated
inflammation.
Here,
we
demonstrate
that
systemic
treatment
with
ICI
induces
expression
in
multiple
murine
cancer
models.
Dietary
omega-3
polyunsaturated
fatty
acid
supplementation
pharmacologic
inhibition,
both
alone
combination,
significantly
anti-tumor
activity
these
Notably,
pharmacological
abrogation
pathway
or
combination
counter-regulates
an
ICI-induced
pro-inflammatory
pro-tumorigenic
cytokine
storm.
modulating
through
dietary
represent
a
unique
strategy
paradigm
therapies.
The
arachidonic
acid
(AA)
pathway
promotes
tumor
progression
by
modulating
the
complex
interactions
between
cancer
and
immune
cells
within
microenvironment.
In
this
Review,
we
summarize
knowledge
acquired
thus
far
concerning
intricate
mechanisms
through
which
eicosanoids
either
promote
or
suppress
antitumor
response.
addition,
will
discuss
impact
of
on
how
they
affect
responsiveness
to
immunotherapy,
as
well
potential
strategies
for
manipulating
AA
improve
anticancer
immunotherapy.
Understanding
molecular
pathways
underlying
role
played
its
metabolites
in
may
contribute
development
more
effective
immunotherapies.
International Journal of Molecular Sciences,
Год журнала:
2024,
Номер
25(10), С. 5408 - 5408
Опубликована: Май 15, 2024
Colorectal
cancer
(CRC)
is
one
of
the
most
prevalent
cancers
worldwide,
ranking
as
third
malignant.
The
incidence
CRC
has
been
increasing
with
time,
and
it
reported
that
Westernized
diet
lifestyle
play
a
significant
role
in
its
higher
rapid
progression.
intake
high
amounts
omega-6
(n
−
6)
PUFAs
low
levels
omega-3
3)
an
important
chronic
inflammation
progression,
which
could
be
associated
increase
prevalence.
Oxylipins
generated
from
are
bioactive
lipid
mediators
have
various
functions,
especially
proliferation.
Carcinogenesis
often
consequence
inflammation,
evidence
shown
particular
involvement
n
6
PUFA
arachidonic
acid-derived
oxylipins
CRC,
further
described
this
review.
A
deeper
understanding
metabolism
by
their
modifying
enzymes,
pathways,
corresponding
may
allow
us
to
identify
new
approaches
employ
oxylipin-associated
immunomodulation
enhance
immunotherapy
cancer.
This
paper
summarizes
identified
context
initiation,
development,
metastasis
CRC.
We
explore
chemo-prevention
strategies
involve
potential
therapeutics.
Frontiers in Pharmacology,
Год журнала:
2025,
Номер
16
Опубликована: Фев. 25, 2025
Blood
vessels
supply
oxygen,
nutrients
and
provide
gateways
for
immune
surveillance.
Since
this
network
nourishes
all
tissues,
vessel
abnormalities
contribute
to
many
diseases,
such
as
cancer.
One
of
the
potential
targets
Docosahexaenoic
Acid
(DHA)
in
cancer
is
suppressing
angiogenesis,
a
process
new
blood
formation
within
tumors.
In
addition,
aspirin
(ASA)
has
antineoplastic
effects
that
may
be
mediated,
at
least
part,
by
metabolites
derived
from
acetylated
COX-2.
We
aimed
determining
effect
DHA
well
its
using
vitro
vivo
models.
Endothelial
cell
(EC)
proliferation,
motility
capillary-like
tube
were
determined
MTT,
wound
healing,
Boyden
Matrigel
assays,
respectively.
angiogenesis
was
measured
sponge
model
mice.
The
biosynthesis
proresolving
lipid
mediators
ECs
LC-MS-MS.
DHA,
but
not
arachidonic
acid
(AA),
concentrations
consistent
with
those
reached
after
fish
oil
supplementation,
decreased
EC
migration
time-
concentration-dependent
manner.
Pretreatment
ASA
modulated
already
24
h,
while
both
longer
incubation
times
without
affecting
viability.
17-hydroxy-DHA
detected
upon
increased
amounts
observed
combined
treatment
ASA,
an
increase
associated
synergic
on
migration.
17(R)-hydroxy-DHA
(17R-HDHA),
metabolite
resulting
COX-2
activity
reduced
presence
17R-HDHA,
also
formation.
These
results
confirmed
where
17R-HDHA
or
downstream
17RResolvinD1
able
decrease
microvessels
density
model.
Overall,
we
demonstrated
ASA-dependent
acetylation
showed
antiangiogenic
effects,
possibly
conversion
hydroxylated
derivatives.
ABSTRACT
Background
and
Aims
Epoxide
hydrolase
2
(EPHX2)
regulates
lipid
signaling
across
various
metabolites
by
encoding
soluble
epoxide
hydrolase.
However,
its
mechanisms
implications
in
human
malignancies
remain
unknown.
This
research
aimed
to
detail
the
prognostic
landscape
of
EPHX2
pan‐cancer
explore
potential
relationship
with
immune
infiltration
tumor
microenvironment.
Methods
Herein,
multiple
bioinformatics
tools
were
used
comprehensively
evaluate
expression,
diagnostic,
significance
roles
microenvironment
cancers.
The
underlying
EPHX2‐associated
pathways
cancers
investigated
gene
set
variation
analysis
(GSVA).
TIDE,
GDSC,
CTRP
databases
applied
predict
response
immunotherapy
sensitivity
small
molecule
drugs.
Furthermore,
expression
was
also
validated
qPCR
experiments
cancer
cell
lines.
Results
Overall
results
revealed
significant
down‐regulation
mRNA
most
tumors.
Despite
high
predictive
cancers,
played
a
protective
or
detrimental
effect
distinct
types
proved
be
valuable
diagnostic
biomarker
range
types,
particularly
kidney
renal
clear
carcinoma,
cervical
squamous
endocervical
adenocarcinoma.
Genetic
alterations
33
tumors
investigated.
significantly
linked
infiltrations
(particularly
tumor‐associated
macrophages),
mutation
burden,
microsatellite
instability,
modulators,
immunotherapeutic
biomarkers.
Single‐cell
sequencing
GSVA
highlighted
relevance
regulating
cancer‐related
biological
processes,
including
cycle
apoptosis.
In
this
view,
targeting
EPHX2‐dependent
could
promising
therapeutic
strategy
for
immunotherapy.
Conclusion
may
serve
as
molecular
diagnosis
prognosis
become
novel
target
Journal of Biomolecular Structure and Dynamics,
Год журнала:
2025,
Номер
unknown, С. 1 - 12
Опубликована: Май 4, 2025
Parkinson's
disease
(PD)
is
a
prevalent
neurodegenerative
disorder
characterized
by
the
loss
of
dopaminergic
neurons
in
substantia
nigra
that
leads
to
bradykinesia
and
rest
tremors.
While
molecular
mechanisms
underlying
PD
are
not
fully
understood,
rising
evidence
shows
neuroinflammation
as
key
factor
neuron
damage.
The
soluble
epoxide
hydrolase
(sEH)
has
appeared
player
associated
with
which
represents
itself
promising
drug
target.
Here,
we
employed
structure-based
virtual
screening
methodology
using
repurposed
drugs
from
DrugBank
database
identify
high-affinity
potential
inhibitors
sEH.
Results
showed
two
hit
molecules,
Fluspirilene
Penfluridol,
demonstrated
appreciable
docking
specificity
toward
sEH
active
site.
These
molecules
exhibited
favorable
pharmacological
properties
formed
critical
interactions
residues
essential
for
activity.
Further,
all-atom
dynamics
(MD)
simulations
followed
principal
component
analysis
free
energy
landscape
were
carried
out
provide
deeper
insights
into
conformational
stability
interaction
complex
Penfluridol.
simulation
results
indicated
Penfluridol
contributed
stabilization
its
structure
throughout
MD
trajectories
500
ns.
findings
collectively
suggest
hold
development
inhibitors,
offer
therapeutic
implications
combating
other
conditions.
