Molecular Metabolism,
Год журнала:
2023,
Номер
76, С. 101794 - 101794
Опубликована: Авг. 20, 2023
Despite
great
advances
in
obesity
therapeutics
recent
years,
there
is
still
a
need
to
identify
additional
therapeutic
targets
for
the
treatment
of
this
disease.
We
previously
discovered
signature
genes,
including
Chloride
intracellular
channel
1
(Clic1),
whose
expression
was
associated
with
drug-induced
weight
gain,
and
these
studies,
we
assess
effect
Clic1
inhibition
on
food
intake
body
mice.
studied
impact
mouse
models
binge-eating,
diet-induced
obese
mice
genetic
(Magel2
KO
mice)
weight.
knockout
ate
significantly
less
had
lower
than
WT
littermates
when
either
fed
chow
or
high
fat
diet.
Furthermore,
pharmacological
resulted
suppression
promoted
highly
efficacious
loss.
also
reduced
binge-eating
hyperphagic
Magel2
observed
that
chronic
significant
change
subcellular
localization
an
increased
ratio
membrane
state.
These
observations
provide
novel
strategy
block
translocation
as
potential
mechanism
reduce
studies
attribute
role
driver
overconsumption.
In
summary,
have
identified
hypothalamic
plays
key
intake,
providing
target
treat
overconsumption
root
cause
modern
obesity.
Aging and Disease,
Год журнала:
2024,
Номер
unknown
Опубликована: Янв. 1, 2024
The
blood-brain
barrier
(BBB)
plays
a
critical
role
in
maintaining
ion
and
fluid
homeostasis,
essential
for
brain
metabolism
neuronal
function.
Regulation
of
nutrient,
water,
transport
across
the
BBB
is
tightly
controlled
by
specialized
transporters
channels
located
within
its
unique
cellular
components.
These
dynamic
processes
not
only
influence
BBB’s
structure
but
also
impact
vital
signaling
mechanisms,
optimal
Disruption
ion,
pH,
balance
at
associated
with
pathology
has
been
implicated
various
neurological
conditions,
including
stroke,
epilepsy,
trauma,
neurodegenerative
diseases
such
as
Alzheimer’s
disease
(AD).
However,
knowledge
gaps
exist
regarding
dysregulation
on
function
dementias.
Several
factors
contribute
to
this
gap:
complex
nature
these
historical
research
focus
mechanisms
technical
challenges
studying
in
vivo
models
lack
efficient
vitro
dementia
models.
This
review
provides
an
overview
current
roles
poses
specific
questions:
1)
How
are
expression
activity
key
altered
AD
vascular
(VaD);
2)
Do
changes
dysfunction
progression;
3)
Can
restoring
mitigate
improve
clinical
outcomes.
Addressing
will
provide
greater
insight
into
disorders.
Pharmacological Research,
Год журнала:
2023,
Номер
189, С. 106698 - 106698
Опубликована: Фев. 14, 2023
Despite
recent
advances
in
understanding
the
causes
of
epilepsy,
especially
genetic,
comprehending
biological
mechanisms
that
lead
to
epileptic
phenotype
remains
difficult.
A
paradigmatic
case
is
constituted
by
epilepsies
caused
altered
neuronal
nicotinic
acetylcholine
receptors
(nAChRs),
which
exert
complex
physiological
functions
mature
as
well
developing
brain.
The
ascending
cholinergic
projections
potent
control
forebrain
excitability,
and
wide
evidence
implicates
nAChR
dysregulation
both
cause
effect
epileptiform
activity.
First,
tonic-clonic
seizures
are
triggered
administration
high
doses
agonists,
whereas
non-convulsive
have
kindling
effects.
Second,
sleep-related
epilepsy
can
be
mutations
on
genes
encoding
subunits
widely
expressed
(CHRNA4,
CHRNB2,
CHRNA2).
Third,
animal
models
acquired
time-dependent
alterations
innervation
observed
following
repeated
seizures.
Heteromeric
nAChRs
central
players
epileptogenesis.
Evidence
for
autosomal
dominant
hypermotor
(ADSHE).
Studies
ADSHE-linked
expression
systems
suggest
epileptogenic
process
promoted
overactive
receptors.
Investigation
ADSHE
indicates
mutant
lifelong
hyperexcitability
altering
i)
function
GABAergic
populations
neocortex
thalamus,
ii)
synaptic
architecture
during
synaptogenesis.
Understanding
balance
effects
adult
networks
essential
plan
rational
therapy
at
different
ages.
Combining
this
knowledge
with
a
deeper
functional
pharmacological
properties
individual
will
advance
precision
personalized
medicine
nAChR-dependent
epilepsy.
Abstract
Epilepsy
and
autism
often
co‐occur
in
genetic
developmental
epileptic
encephalopathies
(DEEs),
but
their
underlying
neurobiological
processes
remain
poorly
understood,
complicating
treatment.
Advances
molecular
genetics
understanding
the
neurodevelopmental
pathogenesis
of
epilepsy–autism
phenotype
may
lead
to
mechanism‐based
treatments
for
children
with
DEEs
autism.
Several
genes,
including
newly
reported
PPFIA3
,
MYCBP2
DHX9
TMEM63B
RELN
are
linked
various
disorders,
intellectual
disabilities,
autistic
features.
These
findings
underscore
clinical
heterogeneity
suggest
diverse
mechanisms
influenced
by
genetic,
epigenetic,
environmental
factors.
Mechanisms
linking
epilepsy
include
γ‐aminobutyric
acidergic
(GABAergic)
signaling
dysregulation,
synaptic
plasticity,
disrupted
functional
connectivity,
neuroinflammatory
responses.
GABA
system
abnormalities,
critical
inhibitory
neurotransmission,
contribute
both
conditions.
Dysregulation
mechanistic
target
rapamycin
(mTOR)
pathway
neuroinflammation
also
pivotal,
affecting
seizure
generation,
drug
resistance,
neuropsychiatric
comorbidities.
Abnormal
function
connectivity
further
phenotype.
New
treatment
options
targeting
specific
emerging.
Genetic
variants
potassium
channel
genes
like
KCNQ2
KCNT1
frequent
causes
early
onset
DEEs.
Personalized
retigabine
quinidine
have
been
explored
heterogeneous
Efforts
ongoing
develop
more
effective
KCNQ
activators
blockers.
SCN1A
variants,
particularly
Dravet
syndrome,
show
potential
symptoms
low‐dose
clonazepam,
fenfluramine,
cannabidiol,
although
human
trials
yet
consistently
replicate
animal
model
successes.
Early
intervention
before
age
3
years,
‐
tuberous
sclerosis
complex‐related
DEEs,
is
crucial.
Additionally,
mTOR
shows
promise
control
managing
epilepsy‐associated
Understanding
distinct
spectrum
disorder
implementing
behavioral
interventions
essential
improving
outcomes.
Despite
advances,
significant
challenges
persist
diagnosing
treating
DEE‐associated
phenotypes.
Future
should
adopt
precision
health
approaches
improve
Neurobiology of Disease,
Год журнала:
2023,
Номер
180, С. 106102 - 106102
Опубликована: Март 26, 2023
Epilepsy
is
based
on
abnormal
neuronal
activities
that
have
historically
been
suggested
to
arise
from
an
excess
of
excitation
and
a
defect
inhibition,
or
in
other
words
excessive
glutamatergic
drive
not
balanced
by
GABAergic
activity.
More
recent
data
however
indicate
signaling
defective
at
focal
seizure
onset
may
even
be
actively
involved
generation
providing
excitatory
inputs.
Recordings
interneurons
revealed
they
are
active
initiation
their
selective
time-controlled
activation
using
optogenetics
triggers
seizures
more
general
context
increased
excitability.
Moreover,
appears
mandatory
many
models.
The
main
pro-ictogenic
effect
the
depolarizing
action
GABAA
conductance
which
occur
when
activity
causes
Cl-
accumulation
neurons.
This
process
combine
with
background
dysregulation
Cl-,
well
described
epileptic
tissues.
equilibrium
maintained
(Na+)/K+/Cl-
co-transporters,
can
therefore
favor
effects
GABA.
In
addition,
these
co-transporters
further
contribute
this
as
mediate
K+
outflow
together
extrusion,
responsible
for
extracellular
space
subsequent
increase
local
role
obvious
but
its
complex
dynamics
balance
between
flux
polarity
excitability
still
remain
established,
especially
tissues
where
receptors
ion
regulators
disrupted
rather
plays
2
faces
Janus
role.
The Journal of Physiological Sciences,
Год журнала:
2023,
Номер
73(1)
Опубликована: Ноя. 15, 2023
Physiological
roles
of
Cl-,
a
major
anion
in
the
body,
are
not
well
known
compared
with
those
cations.
This
review
article
introduces:
(1)
Cl-
bodily
and
cellular
functions;
(2)
range
cytosolic
concentration
([Cl-]c);
(3)
whether
[Cl-]c
could
change
cell
volume
under
an
isosmotic
condition;
(4)
conditions
where
multiple
transporters
channels
contribute
to
influx
efflux
state;
(5)
be
large
enough
act
as
signals;
(6)
effects
on
cytoskeletal
tubulin
polymerization
through
inhibition
GTPase
activity
polymerization-dependent
biological
activity;
(7)
proliferation;
(8)
Cl--regulatory
mechanisms
ciliary
motility;
(9)
sweet/umami
taste
receptors;
(10)
with-no-lysine
kinase
(WNK);
(11)
regulation
epithelial
Na+
transport;
(12)
relationship
between
H+
body
functions.
Biochemical Pharmacology,
Год журнала:
2024,
Номер
228, С. 116481 - 116481
Опубликована: Авг. 13, 2024
Depression
is
among
the
most
common
psychiatric
illnesses,
which
imposes
a
major
socioeconomic
burden
on
patients,
caregivers,
and
public
health
system.
Treatment
with
classical
antidepressants
(e.g.
tricyclic
selective
serotonine
reuptake
inhibitors),
primarily
affect
monoaminergic
systems
has
several
limitations,
such
as
delayed
onset
of
action
moderate
efficacy
in
relatively
large
proportion
depressed
patients.
Furthermore,
depression
highly
heterogeneus,
its
different
subtypes,
including
post-partum
depression,
involve
distinct
neurobiology,
warranting
differential
approach
to
pharmacotherapy.
Given
these
shortcomings,
need
for
novel
that
are
superior
faster
fully
justified.
The
development
market
introduction
rapid-acting
accelerated
recent
years.
Some
new
act
through
GABAergic
In
this
review,
we
discuss
discovery,
efficacy,
limitations
treatment
classic
antidepressants.
We
provide
detailed
discussion
neurotransmission,
special
focus
GABA
Cells,
Год журнала:
2023,
Номер
12(3), С. 442 - 442
Опубликована: Янв. 29, 2023
The
brain's
ability
to
strengthen
or
weaken
synaptic
connections
is
often
termed
plasticity.
It
has
been
shown
function
in
brain
remodeling
following
different
types
of
damage
(e.g.,
drugs
abuse,
alcohol
use
disorders,
neurodegenerative
diseases,
and
inflammatory
conditions).
Although
plasticity
mechanisms
have
extensively
studied,
how
neural
can
influence
neurobehavioral
abnormalities
disorders
(AUDs)
far
from
being
completely
understood.
Alcohol
during
pregnancy
its
harmful
effects
on
the
developing
offspring
are
major
public
health,
social,
economic
challenges.
significant
attribute
prenatal
exposure
central
nervous
system
(CNS),
causing
a
range
structural,
functional,
behavioral
impairments,
collectively
called
fetal
spectrum
disorder
(FASD).
FASD
limited,
emerging
evidence
suggests
that
pathogenesis
involves
altering
set
molecules
involved
neurotransmission,
myelination,
neuroinflammation.
These
studies
identify
several
immediate
long-lasting
changes
using
many
molecular
approaches
essential
for
cognitive
function.
Therefore,
they
offer
potential
targets
observed
FASD.
In
this
review,
we
discuss
substantial
research
progress
aspects
shed
light
mechanism
dysfunction
Increasing
our
understanding
will
significantly
advance
knowledge
could
provide
basis
finding
novel
therapeutic
innovative
treatment
strategies.
Current Issues in Molecular Biology,
Год журнала:
2024,
Номер
46(3), С. 1851 - 1864
Опубликована: Фев. 28, 2024
Autism
spectrum
disorder
(ASD)
is
thought
to
result
from
susceptibility
genotypes
and
environmental
risk
factors.
The
offspring
of
women
who
experience
pregnancy
infection
have
an
increased
for
autism.
Maternal
immune
activation
(MIA)
in
pregnant
animals
produces
with
autistic
behaviors,
making
MIA
a
useful
model
However,
how
causes
behaviors
not
fully
understood.
Here,
we
show
that
NKCC1
critical
mediating
offspring.
We
confirmed
induced
by
poly(I:C)
during
leads
further
demonstrated
showed
significant
microglia
activation,
excessive
dendritic
spines,
narrow
postsynaptic
density
(PSD)
their
prefrontal
cortex
(PFC).
Then,
discovered
these
abnormalities
may
be
caused
overexpression
offspring’s
PFCs.
Finally,
ameliorated
the
using
PFC
microinjection
inhibitor
bumetanide
(BTN)
Our
findings
shed
new
light
on
pathological
mechanisms
autism
infection.
Brain Sciences,
Год журнала:
2024,
Номер
14(3), С. 290 - 290
Опубликована: Март 19, 2024
Neuroinflammation
contributes
to
the
pathophysiology
of
major
depressive
disorder
(MDD)
by
inducing
neuronal
excitability
via
dysregulation
microglial
brain-derived
neurotrophic
factor
(BDNF),
Na-K-Cl
cotransporter-1
(NKCC1),
and
K-Cl
cotransporter-2
(KCC2)
due
activation
BDNF-tropomyosin
receptor
kinase
B
(TrkB)
signaling.
Allosteric
modulation
α7
nAChRs
has
not
been
investigated
on
BDNF,
KCC2,
NKCC1
during
LPS-induced
depressive-like
behavior.
Therefore,
we
examined
effects
PNU120596,
an
nAChR
positive
allosteric
modulator,
expression
in
hippocampus
prefrontal
cortex
using
Western
blot
analysis,
immunofluorescence
assay,
real-time
polymerase
chain
reaction.
The
ANA12,
a
TrkB
antagonist,
cognitive
deficit
behaviors
were
determined
Y-maze,
tail
suspension
test
(TST),
forced
swim
(FST).
Pharmacological
interactions
between
PNU120596
ANA12
also
examined.
Experiments
conducted
male
C57BL/6J
mice.
LPS
administration
(1
mg/kg)
resulted
increased
BDNF
NKCC1/KCC2
ratio
decreased
KCC2
cortex.
pretreatment
(4
attenuated
increase
reduction
these
brain
regions.
In
addition,
(0.25
or
0.50
reduced
measured
spontaneous
alternation
Y-maze
immobility
duration
TST
FST.
Coadministration
prevented
behaviors.
Overall,
behavior
likely
decreasing
targeting