KEAP1‐NRF2/HO‐1 Pathway Promotes Ferroptosis and Neuronal Injury in Schizophrenia
Brain and Behavior,
Год журнала:
2025,
Номер
15(3)
Опубликована: Фев. 28, 2025
ABSTRACT
Background
This
study
investigates
the
role
of
KEAP1‐NRF2/HO‐1
signaling
pathway
in
inducing
ferroptosis
and
contributing
to
neuronal
damage
schizophrenia.
Methods
We
retrieved
schizophrenia‐related
data
ferroptosis‐related
genes
from
RNA
microarray
dataset
GSE27383
FerrDB
database,
respectively.
Bioinformatics
identified
KEAP1
as
a
downregulated
gene,
which
was
validated
using
qRT‐PCR
Western
blot.
assessed
intracellular
Fe
2
⁺
content,
MDA
levels,
GSH,
GPX4
prefrontal
cortex
peripheral
blood
mononuclear
cells
(PBMCs)
patients
with
Cortical
interneurons
(cINs)
were
generated
human‐induced
pluripotent
stem
(hiPSCs)
schizophrenia
used
explore
alterations
during
neurodevelopment.
In
addition,
overexpression
induced
cINs
via
transfection
pcDNA
KEAP1.
The
Fe⁺
oxidative
stress
indicators,
lipid
peroxidation,
inflammatory
cytokines
measured
after
transfection.
To
investigate
molecular
mechanisms,
KI696—a
high‐affinity
probe
that
disrupts
KEAP1–NRF2
interaction—was
applied,
changes
stress,
peroxidation
(C11‐BODIPY
staining),
iron
metabolism,
pathways
evaluated.
Results
Patients
exhibited
underexpression
KEAP1,
key
regulator
ferroptosis,
along
elevated
levels
increased
concentrations,
indicating
enhanced
stress.
Reduced
activity
GSH
also
observed,
suggesting
an
susceptibility
ferroptosis.
further
this,
derived
hiPSCs
studied.
These
showed
decreased
expression.
Overexpression
led
reduction
concentrations
damage,
highlighting
KEAP1's
regulatory
treatment
KI696
significant
related
antioxidant
defenses,
inflammation.
Conclusion
Our
findings
indicate
contributes
injury
Язык: Английский
Molecular and Functional Analysis of TLR 1, 2 and 6 in Peripheral Blood Monocytes of Patients with Schizophrenia: A Pilot Study
International Journal of Molecular Sciences,
Год журнала:
2025,
Номер
26(3), С. 926 - 926
Опубликована: Янв. 23, 2025
Schizophrenia
(SZ)
is
a
chronic
disabling
mental
disorder
with
high
heritability,
and
several
immune-regulating
genes
have
been
implicated
in
its
pathophysiology
In
this
study,
we
investigated
the
expression
of
Toll-like
receptors
(TLRs)
1,
2,
6
peripheral
blood
monocytes
from
SZ
patients
healthy
control
subjects
(HCSs)
Mexican
population,
focusing
on
specific
SZ-associated
gene
variants.
Gene
expressions
were
assessed
by
qPCR,
protein
was
measured
using
flow
cytometry.
The
secretory
profiles
MALP2-stimulated
evaluated
through
immunoproteomic
arrays.
Our
results
indicate
that
carrying
rs4833093/TLR1
GG
genotype
exhibited
significantly
lower
TLR1
compared
to
TT
carriers.
Notably,
HCSs
showed
markedly
higher
expression,
while
all
reduced
levels
regardless
genotype.
Furthermore,
displayed
altered
secretion
upon
TLR
stimulation,
significant
elevations
IL-18,
uPAR,
angiopoietin-2,
serpin
E1,
alongside
reductions
MCP-1,
IL-17A,
IL-24,
MIF,
myeloperoxidase
HCSs.
These
findings
suggest
dysfunctional
TLR-mediated
innate
immune
response
SZ.
Язык: Английский
Association between the COX-2 rs689466 polymorphism and antipsychotic treatment: Impact on HDL cholesterol changes in clozapine-treated psychosis patients
Prostaglandins Leukotrienes and Essential Fatty Acids,
Год журнала:
2025,
Номер
unknown, С. 102665 - 102665
Опубликована: Янв. 1, 2025
Язык: Английский
What Remains to Be Discovered in Schizophrenia Therapeutics: Contributions by Advancing the Molecular Mechanisms of Drugs for Psychosis and Schizophrenia
Biomolecules,
Год журнала:
2024,
Номер
14(8), С. 906 - 906
Опубликована: Июль 25, 2024
Schizophrenia
is
a
frequently
debilitating
and
complex
mental
disorder
affecting
approximately
1%
of
the
global
population,
characterized
by
symptoms
such
as
hallucinations,
delusions,
disorganized
thoughts
behaviors,
cognitive
dysfunction,
negative
symptoms.
Traditional
treatment
has
centered
on
postsynaptic
dopamine
antagonists,
commonly
known
antipsychotic
drugs,
which
aim
to
alleviate
improve
functioning
quality
life.
Despite
availability
these
medications,
significant
challenges
remain
in
schizophrenia
therapeutics,
including
incomplete
symptom
relief,
resistance,
medication
side
effects.
This
opinion
article
explores
advancements
treatment,
emphasizing
molecular
mechanisms,
novel
drug
targets,
innovative
delivery
methods.
One
promising
approach
strategies
that
target
neural
networks
circuits
rather
than
single
neurotransmitters,
acknowledging
complexity
brain
region
interconnections
involved
schizophrenia.
Another
development
biased
agonists,
selectively
activate
specific
signaling
pathways
downstream
receptors,
offering
potential
for
more
precise
pharmacological
interventions
with
fewer
The
concept
polypharmacy,
where
targets
multiple
pathways,
exemplified
KarXT,
combining
xanomeline
trospium
address
both
psychosis
dysfunction.
represents
comprehensive
strategy
potentially
improving
outcomes
patients.
In
conclusion,
advancing
understanding
exploring
therapeutic
hold
promise
addressing
unmet
needs
aiming
effective
tailored
interventions.
Future
research
should
focus
approaches
achieve
better
clinical
functional
level
life
individuals
Язык: Английский
Editorial: Reviews in psychiatry 2023: schizophrenia
Frontiers in Psychiatry,
Год журнала:
2024,
Номер
15
Опубликована: Июль 4, 2024
Keywords:
schizophrenia,
biomarkers,
therapeutic
targets,
systematic
reviews,
psychosocial
functioning,
psychological
therapy,
symptom
domains,
pharmacological
therapy
Язык: Английский
Effects of positive mGlu5 modulation on D2 signaling and nicotine-conditioned place preference: Mechanisms of epigenetic inheritance in a transgenerational model of drug abuse vulnerability in psychosis
Journal of Psychopharmacology,
Год журнала:
2024,
Номер
unknown
Опубликована: Окт. 27, 2024
Background:
The
metabotropic
glutamate
type
5
(mGlu5)
receptor
has
emerged
as
a
potential
target
for
the
treatment
of
psychosis
that
is
suggested
to
have
greater
efficacy
than
antipsychotic
medications
are
currently
utilized.
Aims:
This
study
sought
elucidate
mechanisms
therapeutic
action
associated
with
modulation
mGlu5
in
disordered
system
marked
by
dopamine
dysfunction.
We
further
explored
epigenetic
contributing
heritable
transmission
psychosis-like
phenotype
novel
model
drug
abuse
vulnerability
psychosis.
Methods:
F1
generation
male
and
female
Sprague-Dawley
rats
were
offspring
two
neonatal
quinpirole-treated
(QQ)
or
saline-treated
(SS)
animals
tested
on
nicotine-conditioned
place
preference
(CPP).
Regulators
G
protein
signaling
9
(RGS9)
β-arrestin
2
(βA2),
which
mediate
(DA)
D
signaling,
measured
nucleus
accumbens
shell,
prelimbic
infralimbic
cortices.
Reduced
Representation
Bisulfite
Sequencing
(RRBS)
was
used
analyze
cytosine
methylation
these
brain
regions.
Results:
Pretreatment
mGlu5-positive
allosteric
modulator
3-Cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide
(CDPPB)
20
min
prior
conditioning
trials
blocked
enhanced
nicotine
CPP
mitigated
aberrant
protein-dependent
-independent
QQ
animals.
RRBS
analysis
revealed
region-specific
changes
several
pathways,
including
addiction,
synapses,
neural
connectivity.
Conclusions:
These
results
reveal
an
important
mechanism
CDPPB
DAD
signaling.
Results
additionally
DNA
heritability,
validating
current
useful
tool
comorbid
use.
Язык: Английский