ACS Applied Polymer Materials,
Год журнала:
2024,
Номер
6(16), С. 9859 - 9865
Опубликована: Авг. 13, 2024
In
classical
reversible
addition
fragmentation
chain
transfer
(RAFT)
polymerization,
the
use
of
sulfur-containing
reagents
is
required,
which
inevitably
causes
some
pollution
to
environment.
From
perspective
green
chemistry,
nontoxic
and
harmless
reactants
does
not
pollute
environment
builds
environmentally
friendly
biosensors.
this
study,
we
proposed
a
sulfur-free
RAFT
electrochemical
biosensor
without
transition
metal
or
sulfur
catalyst
using
protein
kinase
A
(PKA)
as
model
analyte.
sensing
process,
peptide
consisting
kinase-specific
recognition
sequence
was
designed.
The
can
be
attached
negatively
charged
surface
an
APTMS-modified
indium
tin
oxide
(ITO)
electrode
(APTMS/ITO)
via
amide
reaction.
When
PKA
present,
substrate
phosphorylated,
then
immediately
coordinated
with
Zr4+.
Then,
Zr4+
used
linker
adsorb
carboxyl-modified
hollow
gold
nanoparticles
(HAuNPs)
surface.
SH-β-CD@2-NH2-Ada
inclusion
complex
conjugated
HAuNPs
Au–S,
immersed
into
polymerization
solution
catalytic
(CCTP)
RAFT,
resulting
in
increased
signal.
platform
offers
advantages
simplicity,
ease
handling,
enhanced
phosphorylation,
thanks
emulsion
need
for
modification
immobilization
processes.
Also,
method
friendly,
promises
promising
results,
represents
major
advance
development
macromolecular
preparation.
Basically,
no
toxic
dangerous
chemical
are
entire
biomolecular
detection
process.
Moreover,
given
pivotal
role
cell
lysate
inhibition
activity,
demonstrates
prospects
kinase-related
bioanalysis
clinical
biomedicine.
Signal Transduction and Targeted Therapy,
Год журнала:
2024,
Номер
9(1)
Опубликована: Авг. 23, 2024
Abstract
Alzheimer’s
disease
(AD)
stands
as
the
predominant
form
of
dementia,
presenting
significant
and
escalating
global
challenges.
Its
etiology
is
intricate
diverse,
stemming
from
a
combination
factors
such
aging,
genetics,
environment.
Our
current
understanding
AD
pathologies
involves
various
hypotheses,
cholinergic,
amyloid,
tau
protein,
inflammatory,
oxidative
stress,
metal
ion,
glutamate
excitotoxicity,
microbiota-gut-brain
axis,
abnormal
autophagy.
Nonetheless,
unraveling
interplay
among
these
pathological
aspects
pinpointing
primary
initiators
require
further
elucidation
validation.
In
past
decades,
most
clinical
drugs
have
been
discontinued
due
to
limited
effectiveness
or
adverse
effects.
Presently,
available
primarily
offer
symptomatic
relief
often
accompanied
by
undesirable
side
However,
recent
approvals
aducanumab
(
1
)
lecanemab
2
Food
Drug
Administration
(FDA)
present
potential
in
disrease-modifying
Nevertheless,
long-term
efficacy
safety
need
Consequently,
quest
for
safer
more
effective
persists
formidable
pressing
task.
This
review
discusses
pathogenesis,
advances
diagnostic
biomarkers,
latest
updates
trials,
emerging
technologies
drug
development.
We
highlight
progress
discovery
selective
inhibitors,
dual-target
allosteric
modulators,
covalent
proteolysis-targeting
chimeras
(PROTACs),
protein-protein
interaction
(PPI)
modulators.
goal
provide
insights
into
prospective
development
application
novel
drugs.
ACS Pharmacology & Translational Science,
Год журнала:
2025,
Номер
8(3), С. 654 - 672
Опубликована: Фев. 10, 2025
Dysregulation
of
correct
protein
tau
homeostasis
represents
the
seed
for
development
several
devastating
central
nervous
system
disorders,
known
as
tauopathies,
that
affect
millions
people
worldwide.
Despite
massive
public
and
private
support
to
research
funding,
these
diseases
still
represent
unmet
medical
needs.
In
fact,
tau-targeting
tools
developed
date
have
failed
translate
into
clinic.
Recently,
taking
advantage
modes
nature
uses
mediate
flow
information
in
cells,
researchers
a
new
class
molecules,
called
proximity-inducing
modulators,
which
exploit
spatial
proximity
modulate
function(s)
redirect
cellular
processes.
this
perspective,
after
brief
discussion
about
classic
approaches,
we
will
discuss
different
classes
modulators
so
far
highlight
applications
protein's
function
tau-induced
toxicity.
Translational Neurodegeneration,
Год журнала:
2024,
Номер
13(1)
Опубликована: Янв. 9, 2024
Alzheimer's
disease
(AD)
is
the
most
prevalent
form
of
dementia
in
elderly
and
represents
a
major
clinical
challenge
ageing
society.
Neuropathological
hallmarks
AD
include
neurofibrillary
tangles
composed
hyperphosphorylated
tau,
senile
plaques
derived
from
deposition
amyloid-β
(Aβ)
peptides,
brain
atrophy
induced
by
neuronal
loss,
synaptic
dysfunctions.
Death-associated
protein
kinase
1
(DAPK1)
ubiquitously
expressed
central
nervous
system.
Dysregulation
DAPK1
has
been
shown
to
contribute
various
neurological
diseases
including
AD,
ischemic
stroke
Parkinson's
(PD).
We
have
established
an
upstream
effect
on
Aβ
tau
pathologies
apoptosis
through
kinase-mediated
phosphorylation,
supporting
causal
role
pathophysiology
AD.
In
this
review,
we
summarize
current
knowledge
about
how
involved
pathological
changes
hyperphosphorylation,
deposition,
cell
death
degeneration.
The
underlying
molecular
mechanisms
dysregulation
are
discussed.
also
review
recent
progress
regarding
development
novel
modulators
their
potential
applications
intervention.
These
findings
substantiate
as
therapeutic
target
for
multifunctional
disease-modifying
treatments
other
disorders.
Journal of Alzheimer s Disease,
Год журнала:
2025,
Номер
unknown
Опубликована: Янв. 15, 2025
Background
Extracellular
signal-regulated
kinase
1
(ERK1)
belongs
to
mitogen-activated
protein
kinases,
which
are
essential
for
memory
formation,
cognitive
function,
and
synaptic
plasticity.
During
Alzheimer's
disease
(AD),
ERK1
phosphorylates
tau
at
15
phosphorylation
sites,
leading
the
formation
of
neurofibrillary
tangles.
The
overactivation
in
microglia
promotes
release
pro-inflammatory
cytokines,
results
neuroinflammation.
Additionally,
elevated
oxidative
stress
during
AD
stimulates
pathway,
neuronal
loss.
Objective
Because
signaling
plays
a
significant
role
phosphorylation,
targeting
may
be
therapeutically
beneficial
by
either
preventing
excessive
activation
pathway
or
altering
its
enhance
neuroprotective
effects
AD.
Methods
This
study
employed
structure-based
virtual
screening
phytoconstituents
from
IMPPAT
library.
Subsequently,
in-depth
docking
molecular
dynamics
(MD)
simulation
studies
were
implemented
identify
potential
inhibitors
with
desirable
pharmacological
properties.
Results
Silandrin
Hydroxytuberosone
found
higher
affinity
specificity
than
control
molecule
Tizaterkib.
These
compounds
specifically
bind
substrate
binding
pocket
interact
crucial
residues.
Finally,
elucidated
evaluated
using
an
all-atom
MD
analyze
structural
dynamics,
compactness,
hydrogen
bond
principal
component
analysis,
free
energy
landscape.
Conclusions
suggested
that
can
further
exploited
as
lead
molecules
therapeutic
development
against
ERK1-mediated
Alzheimer s & Dementia,
Год журнала:
2025,
Номер
21(2)
Опубликована: Фев. 1, 2025
Abstract
INTRODUCTION
MicroRNA
(miRNA)
activity
is
increasingly
appreciated
as
a
key
regulator
of
pathophysiologic
pathways
in
Alzheimer's
disease
(AD).
However,
the
role
miRNAs
during
progression
AD,
including
resilience
and
prodromal
syndromes
such
mild
cognitive
impairment
(MCI),
remains
underexplored.
METHODS
We
performed
miRNA‐sequencing
on
samples
posterior
cingulate
cortex
(PCC)
obtained
post
mortem
from
Rush
Religious
Orders
Study
participants
diagnosed
ante
with
no
(NCI),
MCI,
or
AD.
NCI
subjects
were
subdivided
low
pathology
(Braak
stage
I/II)
high
III/IV),
suggestive
resilience.
Bioinformatics
approaches
included
differential
expression,
messenger
RNA
(mRNA)
target
prediction,
interactome
modeling,
functional
enrichment,
AD
risk
modeling.
RESULTS
identified
specific
miRNA
groups,
mRNA
targets,
signaling
distinguishing
resilience,
neuropsychological
test
performance,
neuropathological
burden,
risk.
DISCUSSION
These
findings
highlight
potential
harnessing
to
manipulate
disease‐modifying
implications
for
precision
medicine.
Highlights
(MiRNA)
dysregulation
well‐established
feature
Novel
also
distinguish
putative
MiRNAs
correlate
performance
burden.
Select
are
associated
age
significant
covariate.
MiRNA
include
insulin,
prolactin,
kinases,
neurite
plasticity.
JBIC Journal of Biological Inorganic Chemistry,
Год журнала:
2025,
Номер
unknown
Опубликована: Март 22, 2025
Abstract
Alzheimer's
disease
(AD)
is
a
progressive
neurodegenerative
disorder
characterized
by
brain
aggregates
of
amyloid-β
(Aβ)
plaques
and
Tau
tangles.
Despite
extensive
research,
effective
therapy
for
AD
remains
elusive.
Polyoxometalates
(POMs),
class
inorganic
compounds
with
diverse
chemical
structures
properties,
are
emerging
as
potential
candidates
treatment
due
to
their
ability
target
key
molecular
players
implicated
in
pathogenesis,
such
Aβ,
acetylcholinesterase
(AChE)
butyryl
(BChE).
Here,
we
use
docking
predict
the
binding
pose
affinities
POMs
10
top
targets
associated
AD.
First,
validate
our
method
replicating
experimentally
known
Aβ
(Δ
G
=
–
9.67
kcal/mol),
AChE
9.39
kcal/mol)
BChE
10.86
kcal/mol).
Then,
using
this
method,
show
that
POM
can
also
bind
β-secretase
1
(BACE1,
Δ
10.14
presenilin
(PSEN1,
10.65
2
(PSEN2,
7.94
Amyloid
Precursor
Protein
(APP,
7.26
Apolipoprotein
E
(APOE4,
10.05
Microtubule-Associated
(MAPT,
5.28
depending
on
phosphorylation,
α-synuclein
(SNCA,
7.64
Through
binding,
offer
mitigate
APP
cleavage,
oligomer
neurotoxicity,
aggregation,
thereby
attenuating
progression.
Overall,
study
represents
powerful
tool
discovery
POM-based
therapeutics
AD,
facilitating
development
novel
treatments
Graphical
abstract
