PLoS ONE,
Journal Year:
2022,
Volume and Issue:
17(11), P. e0278111 - e0278111
Published: Nov. 28, 2022
Dimethyl
fumarate
(DMF)
is
a
first-line
prodrug
for
the
treatment
of
relapsing-remitting
multiple
sclerosis
(RRMS)
that
completely
metabolized
to
monomethyl
(MMF),
active
metabolite,
before
reaching
systemic
circulation.
Its
metabolism
has
been
proposed
be
due
ubiquitous
esterases
in
intestines
and
other
tissues,
but
specific
enzymes
involved
are
unknown.
We
hypothesized
based
on
its
structure
extensive
presystemic
DMF
would
carboxylesterase
substrate
subject
interaction
with
alcohol.
sought
determine
enzymes(s)
responsible
MMF
effect
alcohol
disposition
by
conducting
metabolic
incubation
studies
human
recombinant
carboxylesterase-1
(CES1),
carboxylesterase-2
(CES2)
intestinal
microsomes
(HIM),
performing
follow-up
study
an
vivo
mouse
model.
The
vitro
demonstrated
was
only
CES1.
Consistent
studies,
pharmacokinetic
decreased
maximum
concentration
area-under-the-curve
plasma
brain
after
dosing
DMF.
conclude
may
markedly
decrease
exposure
metabolite
potentially
decreasing
effectiveness
RRMS.
International Journal of Molecular Sciences,
Journal Year:
2023,
Volume and Issue:
24(4), P. 3067 - 3067
Published: Feb. 4, 2023
Acute
liver
injury
(ALI)
is
a
globally
important
public
health
issue
that,
when
severe,
rapidly
progresses
to
acute
failure,
seriously
compromising
the
life
safety
of
patients.
The
pathogenesis
ALI
defined
by
massive
cell
death
in
liver,
which
triggers
cascade
immune
responses.
Studies
have
shown
that
aberrant
activation
nod-like
receptor
protein
3
(NLRP3)
inflammasome
plays
an
role
various
types
and
NLRP3
causes
programmed
(PCD),
these
effectors
can
turn
regulate
activation.
This
indicates
inextricably
linked
PCD.
In
this
review,
we
summarize
PCD
(APAP,
ischemia
reperfusion,
CCl4,
alcohol,
Con
A,
LPS/D-GalN
induced
ALI)
analyze
underlying
mechanisms
provide
references
for
future
relevant
studies.
Pharmacological Research,
Journal Year:
2023,
Volume and Issue:
189, P. 106697 - 106697
Published: Feb. 14, 2023
Necroptosis
has
been
implicated
in
various
inflammatory
diseases
including
tumor-necrosis
factor-α
(TNF-α)-induced
systemic
response
syndrome
(SIRS).
Dimethyl
fumarate
(DMF),
a
first-line
drug
for
treating
relapsing-remitting
multiple
sclerosis
(RRMS),
shown
to
be
effective
against
diseases.
However,
it
is
still
unclear
whether
DMF
can
inhibit
necroptosis
and
confer
protection
SIRS.
In
this
study,
we
found
that
significantly
inhibited
necroptotic
cell
death
macrophages
induced
by
different
stimulations.
Both
the
autophosphorylation
of
receptor-interacting
serine/threonine
kinase
1
(RIPK1)
RIPK3
downstream
phosphorylation
oligomerization
MLKL
were
robustly
suppressed
DMF.
Accompanying
suppression
signaling,
blocked
mitochondrial
reverse
electron
transport
(RET)
stimulation,
which
was
associated
with
its
electrophilic
property.
Several
well-known
anti-RET
reagents
also
markedly
activation
RIPK1-RIPK3-MLKL
axis
accompanied
decreased
necrotic
death,
indicating
critical
role
RET
signaling.
other
ubiquitination
RIPK1
RIPK3,
they
attenuated
formation
necrosome.
Moreover,
oral
administration
alleviated
severity
TNF-α-induced
SIRS
mice.
Consistent
this,
mitigated
cecal,
uterine,
lung
damage
diminished
RIPK3-MLKL
Collectively,
represents
new
inhibitor
suppresses
through
blocking
RET.
Our
study
highlights
DMF's
potential
therapeutic
applications
SIRS-associated
Frontiers in Immunology,
Journal Year:
2024,
Volume and Issue:
15
Published: Feb. 6, 2024
Macrophages
play
a
critical
role
in
innate
immunity,
with
approximately
90%
of
the
total
macrophage
population
human
body
residing
liver.
This
encompasses
both
resident
and
infiltrating
macrophages.
Recent
studies
highlight
pivotal
liver
macrophages
various
aspects
such
as
inflammation,
regeneration,
immune
regulation.
A
novel
pro-inflammatory
programmed
cell
death,
pyroptosis,
initially
identified
macrophages,
has
garnered
substantial
attention
since
its
discovery.
Studies
investigating
pyroptosis
inflammation
progression
have
particularly
centered
around
In
diseases,
plays
an
important
driving
inflammatory
response,
facilitating
fibrotic
process,
promoting
tumor
progression.
Notably,
cannot
be
understated.
review
primarily
focuses
on
diseases.
Additionally,
it
underscores
therapeutic
potential
inherent
targeting
pyroptosis.
International Journal of Molecular Sciences,
Journal Year:
2024,
Volume and Issue:
25(8), P. 4537 - 4537
Published: April 20, 2024
NLRP3
(NOD-,
LRR-,
and
pyrin
domain-containing
protein
3)
is
an
intracellular
complex
that
upon
external
stimuli
or
contact
with
specific
ligands,
recruits
other
components,
forming
the
inflammasome.
The
inflammasome
mainly
mediates
pyroptosis,
a
highly
inflammatory
mode
of
regulated
cell
death,
as
well
IL-18
IL-1β
production.
Acute
chronic
liver
diseases
are
characterized
by
massive
influx
pro-inflammatory
enriched
in
reactive
oxygen
species
(ROS)
damage-associated
molecular
patterns
(DAMPs)
promote
assemblage
activation
As
major
cause
cytokine
storm,
exacerbates
diseases,
even
though
it
might
exert
protective
effects
regards
to
hepatitis
C
B
virus
infection
(HCV
HBV).
Here,
we
summarize
current
knowledge
concerning
function
both
acute
disease
post
transplant
setting,
focusing
on
mechanisms
involved
activity.
Frontiers in Immunology,
Journal Year:
2024,
Volume and Issue:
15
Published: March 20, 2024
Macrophages
are
highly
plastic
cells
ubiquitous
in
various
tissues,
where
they
perform
diverse
functions.
They
participate
the
response
to
pathogen
invasion
and
inflammation
resolution
following
immune
response,
as
well
maintenance
of
homeostasis
proper
tissue
generally
considered
long-lived
with
relatively
strong
resistance
numerous
cytotoxic
factors.
On
other
hand,
their
death
seems
be
one
principal
mechanisms
by
which
macrophages
physiological
functions
or
can
contribute
development
certain
diseases.
In
this
review,
we
scrutinize
three
distinct
pro-inflammatory
programmed
cell
pathways
-
pyroptosis,
necroptosis,
ferroptosis
occurring
under
specific
circumstances,
explain
how
these
appear
undergo
dynamic
yet
not
always
final
changes
before
ultimately
dying.
We
achieve
that
examining
interconnectivity
types,
seem
create
a
coordinated
flexible
system
responding
microenvironment.
Finally,
discuss
complexity
consequences
pyroptotic,
necroptotic,
ferroptotic
pathway
induction
two
pathological
conditions
atherosclerosis
cancer.
summarize
damage-associated
molecular
patterns
(DAMPs)
along
microenvironmental
factors,
macrophage
polarization
states,
associated
general
outcomes,
such
comprehensive
look
at
correlations
may
point
out
methodologies
potential
therapeutic
approaches.
Journal of Gastroenterology and Hepatology,
Journal Year:
2025,
Volume and Issue:
unknown
Published: Jan. 11, 2025
ABSTRACT
Background
The
mechanism
underlying
chronic
drug‐induced
liver
injury
(DILI)
remains
unclear.
Immune
activation
is
a
common
feature
of
DILI
progression
and
closely
associated
with
metabolism.
We
explored
the
immunometabolic
profile
potential
progression.
Methods
Plasma
peripheral
blood
mononuclear
cells
from
patients
were
analyzed
using
multiplex
immunoassays
untargeted
metabolomics
to
reveal
their
profile.
effects
mechanisms
DILI‐related
metabolite
on
acute
or
induced
by
LPS
CCl
4
in
mice
investigated.
Results
Patients
exhibited
elevated
plasma
IL‐6,
IL‐12p70,
IL‐15
reduced
IL‐10
levels.
percentage
IL‐12
+
monocytes
was
higher,
while
that
CD206
monocytes,
Th2,
Treg,
CD4
T
lower
compared
those
DILI.
identified
most
significantly
increased
cis‐aconitic
acid
(CAA).
Administration
CAA
can
attenuate
promote
spontaneous
resolution
fibrosis
live
.
protective
against
inhibition
hepatic
macrophage
infiltration
polarization,
which
achieved
inhibiting
secretion
neutrophil‐derived
IL‐33
subsequent
phosphorylation
GATA3.
Conclusions
CAA,
DILI,
protects
polarization
through
suppression
IL‐33/GATA3
pathway,
suggesting
may
serve
as
target
for
regulating
tissue
repair
injury.
Frontiers in Cell and Developmental Biology,
Journal Year:
2025,
Volume and Issue:
13
Published: Jan. 23, 2025
Pyroptosis,
a
form
of
programmed
cell
death
induced
by
inflammasome
with
mechanism
distinct
from
that
apoptosis,
occurs
via
one
the
three
pathway
types:
classical,
non-classical,
and
granzyme
A/B-dependent
pyroptosis
pathways.
Pyroptosis
is
implicated
in
various
diseases,
notably
exhibiting
dual
role
liver
diseases.
It
facilitates
clearance
damaged
hepatocytes,
preventing
secondary
injury,
triggers
immune
responses
to
eliminate
pathogens
cells.
Conversely,
excessive
intensifies
inflammatory
responses,
exacerbates
hepatocyte
damage
promotes
activation
proliferation
hepatic
stellate
cells,
accelerating
fibrosis.
Furthermore,
sustaining
an
state,
impacts
survival
cancer
This
review
comprehensively
summarizes
diseases
its
therapeutic
strategies,
offering
new
theoretical
foundations
practical
guidance
for
treating
