F1000Research,
Год журнала:
2023,
Номер
12, С. 230 - 230
Опубликована: Март 1, 2023
Background
Alzheimer's
disease
(AD)
is
a
neurological
condition
that
primarily
affects
older
people.
Currently
available
AD
drugs
are
associated
with
side
effects
and
there
need
to
develop
natural
from
plants.
Aquilaria
as
an
endangered
medicinal
plant
genus
(commonly
called
agarwood
plants)
various
products
of
spp.
including
resinous
heartwood,
leaves,
bark,
stem
have
been
widely
used
in
traditional
medicine
systems.
Research
on
plants
sparse
only
few
previous
studies
demonstrated
their
neuroprotective
properties
in
vitro.
Owing
the
presence
plethora
secondary
metabolites
plants,
it
imperative
not
protect
these
but
also
evaluate
bioactivity
phytochemicals.Methods
Computational
methods
such
AutoDock
Vina
molecular
dynamic
(MD)
simulations
were
employed
for
docking
41
selected
compounds
AD-related
targets.
Results
Conclusion
According
data,
three
aquilarisin,
aquilarisinin,
aquilarixanthone
showed
highest
binding
affinity
targets
compared
known
inhibitors.
MD
simulation
revealed
that,
compounds'
protein-ligand
complexes
remarkable
structural
stability
throughout
100
ns
simulation.
The
chemicals
aquilarixanthone,
pillion,
agarotetrol
consequently
suggested
some
found
hits
against
targets,
however,
additional
experimental
validation
required
establish
effectiveness.
Biomedicine & Pharmacotherapy,
Год журнала:
2020,
Номер
134, С. 111128 - 111128
Опубликована: Дек. 18, 2020
Phosphodiesterase
5
(PDE5)
is
one
of
the
most
well-studied
phosphodiesterases
(PDEs)
that
specifically
targets
cGMP
typically
generated
by
nitric
oxide
(NO)-mediated
activation
soluble
guanylyl
cyclase.
Given
crucial
role
through
this
cellular
signaling
pathway
in
a
variety
physiologically
processes,
pharmacological
inhibition
PDE5
has
been
demonstrated
to
have
several
therapeutic
applications
including
erectile
dysfunction
and
pulmonary
arterial
hypertension.
While
they
are
designed
inhibit
PDE5,
inhibitors
show
different
affinities
specificities
against
all
PDE
subtypes.
Additionally,
shown
induce
allosteric
structural
changes
protein.
These
mostly
attributed
their
chemical
structure
and,
therefore,
binding
interactions
with
catalytic
domains.
Therefore,
understanding
how
these
interact
basis
selectivity
critically
important
for
design
novel,
highly
selective
inhibitors.
Here,
we
review
its
function
regulated,
discuss
clinically
available
target
phosphodiesterase
5,
aiming
better
understand
bases
affinity
specificity.
We
also
indications
potential
repurposing
wider
range
clinical
applications.
Frontiers in Pharmacology,
Год журнала:
2023,
Номер
14
Опубликована: Июнь 2, 2023
Despite
extensive
research,
no
disease-modifying
therapeutic
option,
able
to
prevent,
cure
or
halt
the
progression
of
Alzheimer’s
disease
[AD],
is
currently
available.
AD,
a
devastating
neurodegenerative
pathology
leading
dementia
and
death,
characterized
by
two
pathological
hallmarks,
extracellular
deposits
amyloid
beta
(Aβ)
intraneuronal
neurofibrillary
tangles
(NFTs)
consisting
altered
hyperphosphorylated
tau
protein.
Both
have
been
widely
studied
pharmacologically
targeted
for
many
years,
without
significant
results.
In
2022,
positive
data
on
monoclonal
antibodies
targeting
Aβ,
donanemab
lecanemab,
followed
2023
FDA
accelerated
approval
lecanemab
publication
final
results
phase
III
Clarity
AD
study,
strengthened
hypothesis
causal
role
Aβ
in
pathogenesis
AD.
However,
magnitude
clinical
effect
elicited
drugs
limited,
suggesting
that
additional
mechanisms
may
contribute
disease.
Cumulative
studies
shown
inflammation
as
one
main
contributors
recognition
specific
neuroinflammation
synergic
with
NFTs
cascades.
The
present
review
provides
an
overview
investigational
are
trials.
Moreover,
their
action,
positioning
cascade
events
occur
brain
throughout
potential
benefit/limitation
strategy
discussed
highlighted
well.
addition,
latest
patent
requests
inflammation-targeting
therapeutics
be
developed
will
also
discussed.
Medicinal Research Reviews,
Год журнала:
2024,
Номер
44(4), С. 1404 - 1445
Опубликована: Янв. 27, 2024
Neurodegenerative
diseases
(NDs)
cause
progressive
loss
of
neuron
structure
and
ultimately
lead
to
neuronal
cell
death.
Since
the
available
drugs
show
only
limited
symptomatic
relief,
NDs
are
currently
considered
as
incurable.
This
review
will
illustrate
principal
roles
signaling
systems
cyclic
adenosine
guanosine
3',5'-monophosphates
(cAMP
cGMP)
in
functions,
summarize
expression/activity
changes
associated
enzymes
ND
patients,
including
cyclases,
protein
kinases,
phosphodiesterases
(PDEs).
As
sole
hydrolyzing
cAMP
cGMP,
PDEs
logical
targets
for
modification
neurodegeneration.
We
focus
on
PDE
inhibitors
their
potentials
disease-modifying
therapeutics
treatment
Alzheimer's
disease,
Parkinson's
Huntington's
disease.
For
overlapped
but
distinct
contributions
cGMP
NDs,
we
hypothesize
that
dual
inhibitors,
which
simultaneously
regulate
both
pathways,
may
have
complementary
synergistic
effects
modifying
neurodegeneration
thus
represent
a
new
direction
discovery
drugs.
International Journal of Molecular Sciences,
Год журнала:
2021,
Номер
22(18), С. 9794 - 9794
Опубликована: Сен. 10, 2021
Proteins
dynamically
contribute
towards
maintaining
cellular
homeostasis.
Posttranslational
modification
regulates
the
function
of
target
proteins
through
their
immediate
activation,
sudden
inhibition,
or
permanent
degradation.
Among
numerous
protein
modifications,
nitrosation
and
its
functional
relevance
have
emerged.
Nitrosation
generally
initiates
nitric
oxide
(NO)
production
in
association
with
NO
synthase.
is
conjugated
to
free
thiol
cysteine
side
chain
(S-nitrosylation)
propagated
via
transnitrosylation
mechanism.
S-nitrosylation
a
signaling
pathway
frequently
involved
physiologic
regulation.
forms
peroxynitrite
excessive
oxidation
conditions
induces
tyrosine
nitration,
which
quite
stable
considered
irreversible.
Two
main
reducing
systems
are
attributed
denitrosylation:
glutathione
thioredoxin
(TRX).
Glutathione
captures
from
S-nitrosylated
S-nitrosoglutathione
(GSNO).
The
intracellular
system
catalyzes
GSNO
into
GSH
again.
TRX
can
remove
NO-like
break
down
disulfide
bridge.
Although
usually
beneficial
basal
context,
cumulative
stress
chronic
inflammation
oxidative
insult
produces
large
amount
NO,
atypical
nitrosation.
Herein,
we
(1)
provide
brief
introduction
denitrosylation
processes,
(2)
discuss
nitrosation-associated
human
diseases,
(3)
possible
strategy
therapeutic
applications.
Frontiers in Aging Neuroscience,
Год журнала:
2022,
Номер
14
Опубликована: Окт. 4, 2022
Alzheimer’s
disease
(AD)
is
the
most
common
form
of
dementia
and
ranked
as
6th
leading
cause
death
in
US.
The
prevalence
AD
steadily
increasing
expected
cases
USA
14.8
million
by
2050.
Neuroinflammation
gradual
neurodegeneration
occurs
disease.
However,
existing
medications
has
limitation
to
completely
abolish,
delay,
or
prevent
progression.
Phosphodiesterases
(PDEs)
are
large
family
enzymes
hydrolyze
3’-phosphodiester
links
cyclic
adenosine
monophosphate
(cAMP)
guanosine
(cGMP)
signal-transduction
pathways
for
generation
5’-cyclic
nucleotides.
It
plays
vital
role
orchestrate
several
pharmacological
activities
proper
cell
functioning
regulating
levels
cAMP
cGMP.
Several
evidence
suggested
that
abnormal
signaling
linked
cognitive
problems
neurodegenerative
disorders
like
AD.
Therefore,
PDE
become
a
widely
accepted
multipotential
therapeutic
target
diseases.
Notably,
modulation
cAMP/cGMP
phytonutrients
huge
potential
management
Natural
compounds
have
been
known
inhibit
phosphodiesterase
targeting
key
cGMP
synthesis
pathway,
however,
mechanism
action
their
efficacy
not
explored
extensively.
Currently,
few
inhibitors
such
Vinpocetine
Nicergoline
used
treatment
central
nervous
system
(CNS)
disorders.
Considering
flavonoids
PDE,
this
review
discussed
natural
with
inhibitory
activity
related
dementia.
