European Medical Journal,
Год журнала:
2024,
Номер
unknown, С. 50 - 62
Опубликована: Сен. 12, 2024
Osteoarthritis
(OA)
is
a
chronic
condition
that
can
lead
to
pain,
disability,
and
loss
of
function.
There
are
currently
few
pharmacological
treatments,
none
disease
modifying.
It
important
identify
new
treatments
reduce
associated
morbidity,
as
well
high
costs
the
individual
society.
OA
pathogenesis
involves
cartilage,
synovium,
bone,
with
many
mediators
in
immune
system
implicated
this
process.
These
provide
several
targets
for
pharmacotherapy
be
divided
into
target
pain
or
disease-modifying
drugs
aim
maintain
joint.
Previous
trials
conducted
have
failed
either
meet
efficacy
safety
measures.
Notably,
anti-nerve
growth
factor
were
superior
placebo
had
adverse
events
subsequently
limited
their
usage.
The
paper
highlight
current
under
investigation
Phase
II
III
development.
This
review
searched
been
registered
on
clinicaltrials.gov
term
“osteoarthritis”
primary
completion
date
2021
after
III.
identified
252
studies,
52
which
included
screening
eligibility
checks,
then
categorised
targeting
inflammatory
pathways
osteoarthritis
drugs.
Two
further
papers
they
present
two
distinct
therapies
hand
OA.
results
showed
numerous
avenues
development,
promising
results,
provides
hope
global
burden
morbidity.
these
affordable
condition.
Cells,
Год журнала:
2024,
Номер
13(17), С. 1413 - 1413
Опубликована: Авг. 24, 2024
The
α-Klotho
protein
(hereafter
Klotho)
is
an
obligate
coreceptor
for
fibroblast
growth
factor
23
(FGF23).
It
produced
in
the
kidneys,
brain
and
other
sites.
Klotho
insufficiency
causes
hyperphosphatemia
anomalies.
Importantly,
it
associated
with
chronic
pathologies
(often
age-related)
that
have
inflammatory
component.
This
includes
atherosclerosis,
diabetes
Alzheimer's
disease.
Its
mode
of
action
these
diseases
not
well
understood,
but
inhibits
or
regulates
multiple
major
pathways.
has
a
membrane
form
soluble
(s-Klotho).
Cytosolic
postulated
characterized.
s-Klotho
endocrine
properties
are
incompletely
elucidated.
binds
to
FGF
receptor
1c
(FGFR1c)
widely
expressed
(including
endothelial
cells).
also
attaches
FGF23,
FGF23/Klotho
FGFRs.
Thus,
might
be
roaming
FGF23
coreceptor,
functions.
Notably,
(cell-bound
soluble)
counteracts
inflammation
appears
mitigate
related
aging
(inflammaging).
NF-κB
NLRP3
inflammasome.
inflammasome
requires
priming
by
produces
active
IL-1β,
pores
cell
death
(pyroptosis).
In
accord,
countered
injury
induced
toxins,
damage-associated
molecular
patterns
(DAMPs),
cytokines,
reactive
oxygen
species
(ROS).
blocks
TGF-β
Wnt
ligands,
which
lessens
fibrotic
Low
loss
muscle
mass
(sarcopenia),
as
occurs
diseases.
counters
inhibitory
effects
myostatin
on
muscle,
reduces
inflammation,
improves
repair
following
injury.
inhibition
factors
may
protective
diabetic
retinopathy
age-related
macular
degeneration
(AMD).
review
examines
functions
especially
potential
applications.
Journal of Medicinal Chemistry,
Год журнала:
2024,
Номер
67(17), С. 15711 - 15737
Опубликована: Авг. 22, 2024
The
NLRP3
inflammasome
is
a
multiprotein
complex
that
component
of
the
innate
immune
system,
involved
in
production
pro-inflammatory
cytokines.
Its
abnormal
activation
associated
with
many
inflammatory
diseases.
In
this
study,
we
designed
and
synthesized
series
inhibitors
based
on
pyridazine
scaffolds.
Among
them,
P33
exhibited
significant
inhibitory
effects
against
nigericin-induced
IL-1β
release
THP-1
cells,
BMDMs,
PBMCs,
IC50
values
2.7,
15.3,
2.9
nM,
respectively.
Mechanism
studies
indicated
directly
binds
to
protein
(KD
=
17.5
nM),
inhibiting
pyroptosis
by
suppressing
ASC
oligomerization
during
assembly.
Additionally,
displayed
excellent
pharmacokinetic
properties,
an
oral
bioavailability
62%.
vivo
efficacy
revealed
significantly
ameliorated
LPS-induced
septic
shock
MSU
crystal-induced
peritonitis
mice.
These
results
indicate
has
great
potential
for
further
development
as
candidate
treating
inflammasome-mediated
The
α-Klotho
protein
(hereafter
Klotho)
is
an
obligate
coreceptor
for
fibroblast
growth
factor
23
(FGF23).
It
produced
in
the
kidneys,
brain
and
other
sites.
Klotho
insufficiency
causes
hyperphosphatemia
anomalies.
Importantly,
it
associated
with
chronic
pathologies
(often
age-related)
that
have
inflammatory
component.
This
includes
atherosclerosis,
diabetes
Alzheimer’s
disease.
Its
mode
of
action
these
diseases
not
well
understood,
but
inhibits
or
regulates
multiple
major
pathways.
has
a
membrane
form,
soluble
form
(s-Klotho).
Cytosolic
postulated
characterized.
s-Klotho
endocrine
properties
are
incompletely
elucidated.
binds
to
FGF
receptor
1c
(FGFR1c)
widely
expressed
(including
endothelial
cells).
also
attaches
FGF23,
FGF23/Klotho
FGFRs.
Thus,
might
be
roaming
FGF23
coreceptor,
functions.
Notably,
(cell-bound
soluble)
counteracts
inflammation,
appears
mitigate
related
aging
(inflammaging).
NF-κB
NLRP3
inflammasome.
inflammasome
requires
priming
by
NF-κB,
produces
active
IL-1β,
pores
cell
death
(pyroptosis).
In
accord,
countered
inflammation
injury
induced
toxins,
damage-associated
molecular
patterns
(DAMPs),
cytokines,
reactive
oxygen
species
(ROS).
blocks
TGF-β
Wnt
ligands,
which
lessens
fibrotic
Low
loss
muscle
mass
(sarcopenia),
as
occurs
diseases.
counters
inhibitory
effects
myostatin
on
muscle,
reduces
improves
repair
following
injury.
Inhibition
factors
may
protective
diabetic
retinopathy
age-related
macular
degeneration
(AMD).
review
examines
functions
especially
potential
applications.
Journal of Medicinal Chemistry,
Год журнала:
2024,
Номер
67(19), С. 17833 - 17854
Опубликована: Сен. 20, 2024
The
NLRP3
inflammasome
plays
a
central
role
in
the
pathogenesis
of
various
intractable
human
diseases,
making
it
an
urgent
target
for
therapeutic
intervention.
Here,
we
report
development
SN3-1,
novel
orally
potent
inhibitor,
designed
through
lead
compound
strategy
centered
on
deep-learning-based
molecular
generative
models.
Our
enables
rapid
fragment
enumeration
and
takes
into
account
synthetic
accessibility
compounds,
thereby
significantly
enhancing
optimization
compounds
facilitating
discovery
inhibitors.
X-ray
crystallography
provided
insights
SN3-1
inhibitory
mechanism.
has
shown
favorable
safety
profile
both
acute
chronic
toxicity
assessments
exhibits
robust
pharmacokinetic
properties.
Furthermore,
demonstrated
significant
efficacy
disease
models
characterized
by
activation.
This
study
introduces
candidate
developing
inhibitors
expands
repertoire
tools
available
Journal of Neuroinflammation,
Год журнала:
2025,
Номер
22(1)
Опубликована: Май 17, 2025
Parkinson's
disease
(PD)
is
characterized
by
dopaminergic
neuron
loss,
neuroinflammation,
and
motor
dysfunction.
PD
a
multifactorial
disease,
with
neuroinflammation
driven
NLRP3
inflammasome
activation
representing
an
important
component
of
its
pathological
progression.
Therefore,
we
aimed
to
evaluate
the
therapeutic
potential
rebamipide
(Mucosta®),
clinically
approved
anti-inflammatory
agent,
in
targeting
inflammasome.
Specifically,
examined
effects
on
preservation,
deficits
using
BV2
microglia
cells
1-methyl-4-phenyl-1,
2,
3,
6-tetrahydropyridine
(MPTP)-induced
mouse
model.
Rebamipide
alleviated
microglial
downstream
suppressing
NLRP3-NEK7
interaction,
resulting
protection
MPTP-induced
downregulated
IL-1β
levels
treated
α-synuclein
MPP+.
Molecular
docking
analysis
revealed
high
binding
affinity
between
interaction
interface.
Surface
plasmon
resonance
confirmed
direct
NLRP3,
notable
kinetic
affinity,
supporting
role
as
novel
inhibitor.
significantly
levels,
activation,
loss
MPTP
model
disrupting
activation.
preserved
dopamine
striatum
improved
deficits,
including
bradykinesia
coordination.
The
neuroprotective
were
neutralized
knockout
mice,
confirming
dependency
action
NLRP3.
Considering
established
clinical
use,
this
study
supports
repurposing
for
treating
other
inflammasome-driven
neuroinflammatory
diseases.
