Applied Sciences,
Journal Year:
2025,
Volume and Issue:
15(4), P. 1925 - 1925
Published: Feb. 13, 2025
Pioglitazone
(ACTOS)
is
a
thiazolidinedione
for
peroxisome
proliferator-activated
receptor
γ
(PPAR-γ)
that
has
been
well
established
the
second
or
third
line
treatment
of
type
2
diabetes
mellitus.
Beyond
effects
on
glucose
metabolism,
pioglitazone
displays
positive
lipid
blood
pressure,
endothelial
function,
bone
density,
and
apoptosis
cancer
cells.
In
fact,
according
to
in
vitro
experiments
preclinical
studies,
PPAR-γ
ligand
currently
considered
potential
target
both
chemoprevention
therapy.
ligands
are
known
inhibit
cell
proliferation
metastasis
through
terminal
differentiation
underexpression
inflammatory
mediators.
Despite
its
anticancer
properties,
was
withdrawn
by
national
medicine
agencies
France
Germany,
due
reports
increased
incidence
bladder
cancer.
These
were
associated
with
European
populations
undergoing
higher
doses
longer
durations
treatment.
this
review,
we
discuss
pharmacokinetics,
therapeutic
potential,
limitations
regarding
clinical
use
pioglitazone,
focus
ACS Omega,
Journal Year:
2025,
Volume and Issue:
unknown
Published: Feb. 17, 2025
Peroxisome
proliferator-activated
receptor
gamma
(PPARγ)
is
a
nuclear
whose
ligand-induced
conformational
changes,
primarily
driven
by
helix
12
(H12)
repositioning,
regulate
transcriptional
activity.
However,
the
precise
mechanism
remains
elusive.
In
this
study,
we
performed
classical
molecular
dynamics
(cMD)
simulations
of
PPARγ
ligand
binding
domain
(LBD)
in
complex
with
two
agonists
(BRL,
3EA),
partial
agonist
(GW0072),
and
an
antagonist
(EKP),
generating
3
μs
trajectories
for
each
system.
To
gain
deeper
insights,
integrated
machine
learning-assisted
clustering
MD
simulations,
revealing
favorable
trend
free
energy
(ΔG
b),
suggesting
enhanced
stability.
A
case
study
on
EKP
demonstrated
that,
despite
fitting
within
site,
it
failed
to
induce
rapid
LBD
or
H12
rearrangements
apo
agonist-induced
conformation.
Additionally,
investigated
apo-state
conformations
PPARγ-LBD
influenced
ligands,
utilizing
cMD
Gaussian
accelerated
(GaMD)
over
cumulative
6
(3
+
GaMD).
Key
residues
known
modulate
function
upon
mutation
were
analyzed,
confirmed
high
stability
both
ligand-bound
conformations.
Notably,
state,
specific
interacted
other
regions,
preventing
disorder
abrupt
transitions.
These
findings
guided
selection
collective
variables
(CVs)
well-tempered
metadynamics
(WT-MetaD)
which-in
apo-agonist
state-captured
shift
from
agonist-
antagonist-like
conformations,
consistent
resolved
X-ray
structures.
Overall,
computational
framework
provides
novel
insights
into
establishes
valuable
approach
rationally
assessing
effects
modulators
Cells,
Journal Year:
2025,
Volume and Issue:
14(7), P. 534 - 534
Published: April 2, 2025
Changes
in
skin
pigmentation,
like
hyperpigmentation
or
moles,
can
affect
appearance
and
social
life.
Unlike
locally
containable
malignant
melanomas
are
aggressive
spread
rapidly,
disproportionately
affecting
younger
individuals
with
a
high
potential
for
metastasis.
Research
has
shown
that
the
peroxisome
proliferator-activated
receptor
gamma
(PPAR-γ)
its
ligands
exhibit
protective
effects
against
melanoma.
As
transcription
factor,
PPAR-γ
is
crucial
functions
fatty
acid
storage
glucose
metabolism.
Activation
of
promotes
lipid
uptake
enhances
sensitivity
to
insulin.
In
many
cases,
it
also
inhibits
growth
cancer
cell
lines,
breast,
gastric,
lung,
prostate
cancer.
melanoma,
regulates
proliferation,
differentiation,
apoptosis,
survival.
During
tumorigenesis,
controls
metabolic
changes
immunogenicity
stromal
cells.
agonists
target
hypoxia-induced
angiogenesis
tumor
therapy,
but
their
on
tumors
be
suppressive
promotional,
depending
environment.
Published
data
show
PPAR-γ-targeting
agents
effective
specific
groups
patients,
further
studies
needed
understand
lesser-known
biological
address
existing
safety
concerns.
This
review
provides
summary
current
understanding
involvement
