Pharmacological Reviews,
Год журнала:
2024,
Номер
76(3), С. 454 - 499
Опубликована: Янв. 30, 2024
Steatotic
liver
disease
(SLD)
displays
a
dynamic
and
complex
phenotype.
Consequently,
the
metabolic
dysfunction-associated
steatotic
(MASLD)/metabolic
steatohepatitis
(MASH)
therapeutic
pipeline
is
expanding
rapidly
in
multiple
directions.
In
parallel,
non-invasive
tools
for
diagnosing
monitoring
responses
to
interventions
are
being
studied,
clinically
feasible
findings
explored
as
primary
outcomes
interventional
trials.
The
realization
that
distinct
subgroups
exist
under
umbrella
of
SLD
should
guide
more
precise
personalized
treatment
recommendations
facilitate
advancements
pharmacotherapeutics.
This
review
summarizes
recent
updates
pathophysiology-based
nomenclature
outlines
both
effective
pharmacotherapeutics
those
MASLD/MASH,
detailing
their
mode
action
current
status
phase
2
3
clinical
Of
extensive
arsenal
MASLD/MASH
pipeline,
several
have
been
rejected,
whereas
other,
mainly
monotherapy
options,
shown
only
marginal
benefits
now
tested
part
combination
therapies,
yet
others
still
development
monotherapies.
Although
successful
drug
candidate
(or
combinations)
remains
elusive,
such
approaches
will
ideally
target
MASH
fibrosis
while
improving
cardiometabolic
risk
factors.
Due
urgent
need
novel
strategies
potential
availability
safety
tolerability
data,
repurposing
existing
approved
drugs
an
appealing
option.
Finally,
it
essential
highlight
and,
by
extension,
MASLD
be
recognized
approached
systemic
affecting
organs,
with
vigorous
implementation
interdisciplinary
coordinated
plans.
Significance
Statement
SLD,
including,
among
others,
MASH,
considered
most
prevalent
chronic
condition
than
one-fourth
global
population.
aims
provide
information
regarding
pathophysiology,
diagnosis,
management
line
guidelines
Collectively,
hoped
provided
furthers
understanding
state
direct
implications
stimulates
additional
research
initiatives.
Signal Transduction and Targeted Therapy,
Год журнала:
2022,
Номер
7(1)
Опубликована: Дек. 16, 2022
Aging
is
a
gradual
and
irreversible
pathophysiological
process.
It
presents
with
declines
in
tissue
cell
functions
significant
increases
the
risks
of
various
aging-related
diseases,
including
neurodegenerative
cardiovascular
metabolic
musculoskeletal
immune
system
diseases.
Although
development
modern
medicine
has
promoted
human
health
greatly
extended
life
expectancy,
aging
society,
variety
chronic
diseases
have
gradually
become
most
important
causes
disability
death
elderly
individuals.
Current
research
on
focuses
elucidating
how
endogenous
exogenous
stresses
(such
as
genomic
instability,
telomere
dysfunction,
epigenetic
alterations,
loss
proteostasis,
compromise
autophagy,
mitochondrial
cellular
senescence,
stem
exhaustion,
altered
intercellular
communication,
deregulated
nutrient
sensing)
participate
regulation
aging.
Furthermore,
thorough
pathogenesis
to
identify
interventions
that
promote
longevity
caloric
restriction,
microbiota
transplantation,
nutritional
intervention)
clinical
treatment
methods
for
(depletion
senescent
cells,
therapy,
antioxidative
anti-inflammatory
treatments,
hormone
replacement
therapy)
could
decrease
incidence
turn
healthy
longevity.
Signal Transduction and Targeted Therapy,
Год журнала:
2022,
Номер
7(1)
Опубликована: Июнь 30, 2022
Fibrosis
is
characterized
by
the
excessive
extracellular
matrix
deposition
due
to
dysregulated
wound
and
connective
tissue
repair
response.
Multiple
organs
can
develop
fibrosis,
including
liver,
kidney,
heart,
lung.
such
as
liver
cirrhosis,
idiopathic
pulmonary
cystic
fibrosis
caused
substantial
disease
burden.
Persistent
abnormal
activation
of
myofibroblasts
mediated
various
signals,
transforming
growth
factor,
platelet-derived
fibroblast
growh
has
been
recongized
a
major
event
in
occurrence
progression
fibrosis.
Although
mechanisms
driving
organ-specific
have
not
fully
elucidated,
drugs
targeting
these
identified
aberrant
signals
achieved
potent
anti-fibrotic
efficacy
clinical
trials.
In
this
review,
we
briefly
introduce
aetiology
epidemiology
several
diseases,
kidney
cardiac
Then,
summarise
cells
(epithelial
cells,
endothelial
immune
fibroblasts)
their
interactions
addition,
also
focus
on
signaling
pathways
therapeutic
targets
that
regulate
myofibroblast
activation,
cross-linking,
metabolism,
inflammation
Finally,
discuss
based
This
review
provides
reference
for
further
research
mechanism,
drug
development,
Signal Transduction and Targeted Therapy,
Год журнала:
2022,
Номер
7(1)
Опубликована: Авг. 13, 2022
Non-alcohol-associated
fatty
liver/steatohepatitis
(NAFL/NASH)
has
become
the
leading
cause
of
liver
disease
worldwide.
NASH,
an
advanced
form
NAFL,
can
be
progressive
and
more
susceptible
to
developing
cirrhosis
hepatocellular
carcinoma.
Currently,
lifestyle
interventions
are
most
essential
effective
strategies
for
preventing
controlling
NAFL
without
development
fibrosis.
While
there
still
limited
appropriate
drugs
specifically
treat
NAFL/NASH,
growing
progress
is
being
seen
in
elucidating
pathogenesis
identifying
therapeutic
targets.
In
this
review,
we
discussed
recent
developments
etiology
prospective
targets,
as
well
pharmacological
candidates
pre/clinical
trials
patents,
with
a
focus
on
diabetes,
hepatic
lipid
metabolism,
inflammation,
Importantly,
evidence
elucidates
that
disruption
gut-liver
axis
microbe-derived
metabolites
drive
NAFL/NASH.
Extracellular
vesicles
(EVs)
act
signaling
mediator,
resulting
accumulation,
macrophage
stellate
cell
activation,
further
promoting
inflammation
fibrosis
progression
during
Targeting
gut
microbiota
or
EVs
may
serve
new
treatment
Finally,
other
mechanisms,
such
therapy
genetic
approaches,
also
have
enormous
potential.
Incorporating
different
mechanisms
personalized
medicine
improve
efficacy
better
benefit
patients
Journal of Internal Medicine,
Год журнала:
2022,
Номер
292(2), С. 190 - 204
Опубликована: Июль 7, 2022
Abstract
Non‐alcoholic
fatty
liver
disease
(NAFLD)
comprises
a
wide
spectrum
of
pathologies
ranging
from
non‐alcoholic
(NAFL),
characterized
by
simple
steatosis
without
inflammation,
to
steatohepatitis
(NASH),
the
accompanied
inflammation
and
hepatocyte
ballooning,
which
can
lead
advanced
fibrosis,
cirrhosis
hepatocellular
carcinoma.
Apart
lifestyle
modifications
such
as
weight
loss,
Mediterranean
diet
physical
activity,
only
few
NAFLD‐specific
pharmacological
treatment
options
Vitamin
E
Pioglitazone
are
considered
current
international
guidelines.
However,
recently
randomized
controlled
trials
with
GLP‐1
agonists,
FXR
PPAR
ligands
well
other
agents
have
been
published
may
expand
therapeutic
armamentarium
for
NAFLD
in
near
future.
Finally,
knowledge
about
treating
complications
end‐stage
due
NASH
becomes
an
increasingly
important
cornerstone
broad
NAFLD.
In
this
review,
we
summarize
currently
available
future
patients
that
help
internal
medicine
specialists
treat
complete
clinical
highly
prevalent
disease.
Frontiers in Endocrinology,
Год журнала:
2023,
Номер
13
Опубликована: Янв. 16, 2023
Non-alcoholic
fatty
liver
disease
(NAFLD)
is
a
series
of
diseases,
involving
excessive
lipid
deposition
in
the
and
often
accompanied
by
obesity,
diabetes,
dyslipidemia,
abnormal
blood
pressure,
other
metabolic
disorders.
In
order
to
more
accurately
reflect
its
pathogenesis,
an
international
consensus
renamed
NAFLD
2020
as
(dysfunction)
associated
with
(MAFLD).
The
changes
diet
lifestyle
are
recognized
non-drug
treatment
strategies;
however,
due
complex
pathogenesis
NAFLD,
current
drug
therapies
mainly
focused
on
pathogenic
factors,
key
links
related
disorders
targets.
There
still
lack
specific
drugs.
clinical
studies,
common
treatments
include
regulation
glucose
metabolism
protect
anti-inflammation.
based
enterohepatic
axis,
targeting
gut
microbiota,
gradually
emerging,
various
new
metabolism-regulating
drugs
also
under
development.
Therefore,
this
review
article
has
comprehensively
discussed
research
advancements
recent
years.
Cholestatic
and
non-alcoholic
fatty
liver
disease
(NAFLD)
share
several
key
pathophysiological
mechanisms
which
can
be
targeted
by
novel
therapeutic
concepts
that
are
currently
developed
for
both
areas.
Nuclear
receptors
(NRs)
ligand-activated
transcriptional
regulators
of
metabolic
processes
including
hepatic
lipid
glucose
metabolism,
energy
expenditure
bile
acid
(BA)
homoeostasis,
as
well
inflammation,
fibrosis
cellular
proliferation.
Dysregulation
these
contributes
to
the
pathogenesis
progression
cholestatic
disease,
placing
NRs
at
forefront
approaches.
This
includes
BA
activated
such
farnesoid-X
receptor
(FXR)
peroxisome
proliferator-activated
receptors,
respectively,
high
affinity
ligands
targeting
specific
or
multiple
isoforms
have
been
developed.
Moreover,
liver-specific
thyroid
hormone
beta
1
complete
spectrum
available
NR-targeted
drugs.
Apart
from
FXR
ligands,
signalling
mimetics
FXR-activated
fibroblast
growth
factor
19,
modulation
their
enterohepatic
circulation
through
uptake
inhibitors
in
hepatocytes
enterocytes,
derivatives
undergoing
cholehepatic
shunting
(instead
circulation).
Other
approaches
more
directly
target
inflammation
and/or
critical
events
progression.
Combination
strategies
synergistically
disturbances,
may
ultimately
necessary
successful
treatment
complex
multifactorial
disorders.
