Ischemic
stroke
(IS)
as
a
detrimental
neurological
disease
is
accompanied
by
oxidative-stress-induced
injury,
concurrent
inflammatory
response,
overactivated
brain
immune
microenvironment,
and
disruption
of
the
blood-brain
barrier
(BBB).
This
cascade
events
ultimately
leads
to
neuronal
death
significantly
impairs
recovery
function.
In
this
study,
we
presented
extracellular
vesicles
derived
from
gut
probiotic
Lactobacillus
reuteri
(LrEVs)
integrated
with
targeting,
reactive
oxygen
species
(ROS)
scavenging,
reduced
infiltration
cells
for
effective
multiple
therapeutic
interventions
IS.
LrEVs
inherited
peptidoglycan
(PGN)
specifically
targeted
upregulated
toll-like
receptor
2
(TLR2)
in
injured
region
ischemic
brain,
achieving
penetration
BBB
accumulation
brain.
meantime,
prevented
apoptosis
after
scavenging
ROS
overproduction
modulating
microglial
polarization
through
inhibition
MAPK
NF-κB
pathways.
Furthermore,
inhibited
aggregation
C-C
motif
chemokine
ligand
(CCL2),
peripheral
such
macrophages
neutrophils
into
tissue,
suppressed
impairment
BBB,
thereby
improving
microenvironment.
The
findings
provide
vesicle
that
combines
modulation
showcasing
potential
gut-probiotic-derived
treat
damage.
ACS Nano,
Год журнала:
2024,
Номер
18(4), С. 3260 - 3275
Опубликована: Янв. 16, 2024
The
ischemic
stroke
is
a
major
global
health
concern,
with
high
mortality
and
disability
rates.
Unfortunately,
there
dearth
of
effective
clinical
interventions
for
managing
poststroke
neuroinflammation
blood–brain
barrier
(BBB)
disruption
that
are
crucial
the
brain
injury
evolving
neurological
deficits.
By
leveraging
pathological
progression
an
stroke,
we
developed
M2
microglia-targeting
lipid
nanoparticle
(termed
MLNP)
approach
can
selectively
deliver
mRNA
encoding
phenotype-switching
interleukin-10
(mIL-10)
to
brain,
creating
beneficial
feedback
loop
drives
microglial
polarization
toward
protective
phenotypes
augments
homing
mIL-10-loaded
MLNPs
(mIL-10@MLNPs)
regions.
In
transient
middle
cerebral
artery
occlusion
(MCAO)
mouse
model
our
findings
demonstrate
intravenously
injected
mIL-10@MLNPs
induce
IL-10
production
enhance
microglia.
resulting
positive
reinforces
resolution
neuroinflammation,
restores
impaired
BBB,
prevents
neuronal
apoptosis
after
stroke.
Using
permanent
distal
MCAO
neuroprotective
effects
have
been
further
validated
by
attenuation
sensorimotor
cognitive
Furthermore,
mRNA-based
targeted
therapy
has
great
potential
extend
therapeutic
time
window
at
least
up
72
h
poststroke.
This
study
depicts
simple
versatile
LNP
platform
selective
delivery
therapeutics
lesions,
showcasing
promising
addressing
associated
conditions.
Journal of Neuroinflammation,
Год журнала:
2025,
Номер
22(1)
Опубликована: Фев. 7, 2025
Mitochondrial
dysfunction
is
a
pivotal
instigator
of
neuroinflammation,
with
mitochondrial
DNA
(mtDNA)
leakage
as
critical
intermediary.
This
review
delineates
the
intricate
pathways
leading
to
mtDNA
release,
which
include
membrane
permeabilization,
vesicular
trafficking,
disruption
homeostatic
regulation,
and
abnormalities
in
dynamics.
The
escaped
activates
cytosolic
sensors,
especially
cyclic
gmp-amp
synthase
(cGAS)
signalling
inflammasome,
initiating
neuroinflammatory
cascades
via
pathways,
exacerbating
spectrum
neurological
pathologies.
therapeutic
promise
targeting
discussed
detail,
underscoring
necessity
for
multifaceted
strategy
that
encompasses
preservation
homeostasis,
prevention
leakage,
reestablishment
dynamics,
inhibition
activation
sensors.
Advancing
our
understanding
complex
interplay
between
neuroinflammation
imperative
developing
precision
interventions
disorders.
Cardiovascular Diabetology,
Год журнала:
2024,
Номер
23(1)
Опубликована: Фев. 29, 2024
Abstract
Type-2
diabetes
(T2D)
worsens
stroke
recovery,
amplifying
post-stroke
disabilities.
Currently,
there
are
no
therapies
targeting
this
important
clinical
problem.
Sodium-glucose
cotransporter
2
inhibitors
(SGLT2i)
potent
anti-diabetic
drugs
that
also
efficiently
reduce
cardiovascular
death
and
heart
failure.
In
addition,
SGLT2i
facilitate
several
processes
implicated
in
recovery.
However,
the
potential
efficacy
of
to
improve
recovery
T2D
has
not
been
investigated.
Therefore,
we
determined
whether
a
intervention
with
Empagliflozin
could
mice.
was
induced
C57BL6J
mice
by
8
months
high-fat
diet
feeding.
Hereafter,
animals
were
subjected
transient
middle
cerebral
artery
occlusion
treated
vehicle
or
SGLTi
(10
mg/kg/day)
starting
from
3
days
after
stroke.
A
similar
study
non
diabetic
conducted.
Stroke
assessed
using
forepaw
grip
strength
test.
To
identify
mechanisms
involved
Empagliflozin-mediated
effects,
metabolic
parameters
assessed.
Additionally,
neuronal
survival,
neuroinflammation,
neurogenesis
vascularization
analyzed
immunohistochemistry/quantitative
microscopy.
significantly
improved
but
non-diabetic
Improvement
functional
associated
lowered
glycemia,
increased
serum
levels
fibroblast
growth
factor-21
(FGF-21),
normalization
T2D-induced
aberration
parenchymal
pericyte
density.
The
global
T2D-epidemic
fact
is
major
risk
factor
for
drastically
increasing
number
people
need
efficacious
Our
data
provide
strong
incentive
use
treatment
sequelae
T2D.
ACS Nano,
Год журнала:
2024,
Номер
18(14), С. 9895 - 9916
Опубликована: Март 27, 2024
Restoration
of
blood-brain
barrier
(BBB)
dysfunction,
which
drives
worse
outcomes
ischemic
stroke,
is
a
potential
target
for
therapeutic
opportunities,
whereas
sealed
BBB
blocks
the
therapeutics
entrance
into
brain,
making
protection
strategy
paradoxical.
Post
hypoxia/hypoglycemia
provokes
up-regulation
transmembrane
glucose
transporters
and
iron
due
to
multiple
metabolic
disorders,
especially
in
brain
endothelial
cells.
Herein,
we
develop
myricetin
oligomer-derived
nanostructure
doped
with
Ce
bypass
cointermediated
by
such
as
1
(GLUT1),
sodium/glucose
cotransporters
(SGLT1),
transferrin(Tf)
reporter
(TfR).
Moreover,
it
exhibits
restoration
capacity
regulating
expression
tight
junctions
(TJs)
through
activation
protective
autophagy.
The
oligomers
scaffold
not
only
acts
targeting
moiety
but
prominent
active
entity
that
inherits
all
diverse
pharmacological
activities
myricetin.
suppression
oxidative
damage,
M1
microglia
activation,
inflammatory
factors
makes
multitasking
nanoagent
single
component
scaffold,
domain
curative
components.
EMBO Molecular Medicine,
Год журнала:
2025,
Номер
unknown
Опубликована: Фев. 28, 2025
Abstract
As
a
common
and
severe
cerebrovascular
disease,
ischemic
stroke
casts
significant
shadow
over
global
health.
Unfortunately,
the
mechanisms
regulating
neuronal
death
in
affected
areas
remain
largely
unclear.
Here,
we
found
that
deletion
of
deubiquitinating
enzyme
Otubain-2
(OTUB2)
significantly
alleviated
ischemia-induced
cerebral
infarction
neurological
deficits,
accompanied
by
reduction
loss,
glial
activation,
neuroinflammation.
OTUB2
was
predominantly
expressed
neurons
its
decreased
receptor-interacting
protein
kinase
3
(RIPK3)-mediated
necroptosis.
Moreover,
increased
RIPK3
abundance
inhibiting
proteasomal
degradation
RIPK3.
Mechanistically,
removed
K48-linked
polyubiquitin
chains
from
through
active
site
C51.
Importantly,
pharmacological
inhibition
brain
injury
mice
reduced
oxygen-glucose
deprivation-induced
human
organoids.
These
results
demonstrate
critically
regulates
potentiating
necroptosis,
suggesting
may
become
potential
therapeutic
approach
for
treating
stroke.
Immunosenescence
refers
to
the
multifaceted
and
profound
alterations
in
immune
system
brought
about
by
aging,
exerting
complex
influences
on
pathophysiological
processes
of
diseases
that
manifest
upon
it.
Using
a
combination
single-cell
RNA
sequencing,
cytometry
time
flight,
various
immunological
assays,
we
investigated
characteristics
immunosenescence
peripheral
blood
aged
mice
its
impact
cerebral
environment
after
ischemic
stroke.
Our
results
revealed
some
features
immunosenescence.
We
observed
an
increase
neutrophil
counts,
concurrent
with
accelerated
characterized
altered
expression
aging-associated
markers
like
CD62L
consequential
changes
neutrophil-mediated
functions.
Monocytes/macrophages
exhibited
enhanced
antigen-presentation
capabilities.
T
cell
profiles
shifted
from
naive
effector
or
memory
states,
specific
rise
helper
1
cells
17
subpopulations
increased
regulatory
activation
CD4
cells.
Furthermore,
CD8
marked
Klra
decreased
while
subpopulation
exhausted-like
expanded,
retaining
potent
immunostimulatory
proinflammatory
Critically,
these
inherent
disparities
not
only
persisted
but
were
further
amplified
within
hemispheres
following
In
summary,
our
comprehensive
insights
into
key
attributes
provide
vital
theoretical
foundation
for
understanding
strokes
also
other
age-associated
diseases.
Clinical and Translational Medicine,
Год журнала:
2024,
Номер
14(5)
Опубликована: Май 1, 2024
Abstract
Cerebrovascular
diseases
(CVDs)
are
a
major
threat
to
global
health.
Elucidation
of
the
molecular
mechanisms
underlying
pathology
CVDs
is
critical
for
development
efficacious
preventative
and
therapeutic
approaches.
Accumulating
studies
have
highlighted
significance
ubiquitin‐modifying
enzymes
(UMEs)
in
regulation
CVDs.
UMEs
group
that
orchestrate
ubiquitination,
post‐translational
modification
tightly
involved
Functionally,
regulate
multiple
pathological
processes
ischemic
hemorrhagic
stroke,
moyamoya
disease,
atherosclerosis.
Considering
important
roles
CVDs,
they
may
become
novel
druggable
targets
these
diseases.
Besides,
techniques
applying
UMEs,
such
as
proteolysis‐targeting
chimera
deubiquitinase‐targeting
chimera,
also
revolutionize
therapy
future.
Science Bulletin,
Год журнала:
2024,
Номер
69(22), С. 3618 - 3632
Опубликована: Сен. 20, 2024
Brain
diseases,
mainly
including
acute
brain
injuries,
neurodegenerative
and
mental
disorders,
have
posed
a
significant
threat
to
human
health
worldwide.
Due
the
limited
regenerative
capability
existence
of
blood-brain
barrier,
was
previously
thought
be
separated
from
rest
body.
Currently,
various
cross-talks
between
central
nervous
system
peripheral
organs
been
widely
described,
brain-gut
axis,
brain-liver
brain-skeletal
muscle
brain-bone
axis.
Moreover,
several
lines
evidence
indicate
that
leveraging
systemic
biology
intervention
approaches,
but
not
lifestyle
interventions,
exercise,
diet,
blood
administration,
immune
responses,
demonstrated
influence
on
progress
prognosis
diseases.
The
advancement
innovative
proteomic
transcriptomic
technologies
has
enriched
our
understanding
nuanced
interplay
An
array
novel
or
underappreciated
blood-derived
factors
identified
play
pivotal
roles
in
mediating
these
communications.
In
this
review,
we
provide
comprehensive
summary
blood-to-brain
communication
following
Special
attention
is
given
instrumental
role
signals,
positing
them
as
contributors
complex
process
insights
presented
here
aim
bridge
current
knowledge
gaps
inspire
therapeutic
strategies
for
