Journal of Medicinal Chemistry,
Journal Year:
2024,
Volume and Issue:
67(6), P. 4889 - 4903
Published: March 15, 2024
Directly
blocking
the
Keap1–Nrf2
pathway
is
a
promising
strategy
for
mitigation
of
acute
lung
injury
(ALI).
Peptide
inhibitors
have
been
reported
to
high
Keap1
binding
affinity.
However,
these
showed
weak
activity
in
cells
and/or
animals.
In
this
study,
we
designed
series
linear
peptides
from
an
Nrf2-based
9-mer
Ac-LDEETGEFL-NH2.
To
improve
cellular
activity,
further
cyclic
based
on
crystal
complex
with
peptide.
Among
them,
ZC9
targeting
better
affinity
(KD2
=
51
nM).
Specifically,
it
exhibited
acceptable
water
solubility
(>38
mg/mL),
cell
permeability,
and
metabolic
stability
(serum
t1/2
>
24
h).
vitro
LPS-induced
oxidative
damages
ALI
model,
significant
dose–response
reversal
without
apparent
toxicity.
conclusion,
our
results
suggested
as
lead
peptide
clinical
treatment.
International Journal of Biological Sciences,
Journal Year:
2022,
Volume and Issue:
18(5), P. 2075 - 2090
Published: Jan. 1, 2022
Ferroptosis
and
neuroinflammation
play
crucial
roles
in
Alzheimer's
disease
(AD)
pathophysiology.
Forsythoside
A
(FA),
the
main
constituent
of
Forsythia
suspensa
(Thunb.)
Vahl.,
possesses
anti-inflammatory,
antibacterial,
antioxidant,
neuroprotective
properties.
The
present
study
aimed
to
investigate
potential
role
FA
AD
neuropathology
using
male
APP/PS1
double
transgenic
mice,
Aβ1-42-exposed
N2a
cells,
erastin-stimulated
HT22
LPS-induced
BV2
cells.
treatment
significantly
improved
mitochondrial
function
inhibited
lipid
peroxidation
In
LPS-stimulated
decreased
formation
pro-inflammatory
factors
IL-6,
IL-1β,
NO.
ameliorated
memory
cognitive
impairments
suppressed
Aβ
deposition
p-tau
levels
brain.
Analyses
proteomics,
immunohistochemistry,
ELISA,
western
blot
revealed
that
augmented
dopaminergic
signaling,
iron
peroxidation,
prevented
activation
IKK/IκB/NF-κB
reduced
secretion
factors,
promoted
production
anti-inflammatory
exerted
anti-ferroptosis
anti-neuroinflammatory
effects
Nrf2/GPX4
axis
played
a
key
these
effects.
Collectively,
results
demonstrate
protective
highlight
its
therapeutic
as
drug
component
for
treatment.
Frontiers in Cell and Developmental Biology,
Journal Year:
2022,
Volume and Issue:
9
Published: Feb. 2, 2022
Nrf2
and
NF-κB
are
important
regulators
of
the
response
to
oxidative
stress
inflammation
in
body.
Previous
pharmacological
genetic
studies
have
confirmed
crosstalk
between
two.
The
deficiency
elevates
expression
NF-κB,
leading
increased
production
inflammatory
factors,
while
can
affect
downstream
target
genes
by
regulating
transcription
activity
Nrf2.
At
same
time,
many
therapeutic
drug-induced
organ
toxicities,
including
hepatotoxicity,
nephrotoxicity,
cardiotoxicity,
pulmonary
toxicity,
dermal
neurotoxicity,
received
increasing
attention
from
researchers
clinical
practice.
Drug-induced
injury
destroy
body
function,
reduce
patients’
quality
life,
even
threaten
lives
patients.
Therefore,
it
is
urgent
find
protective
drugs
ameliorate
injury.
There
substantial
evidence
that
medications
alleviate
toxicity
modulating
both
signaling
pathways.
Thus,
has
become
increasingly
explore
mechanism
toxicity.
In
this
review,
we
summarize
potential
molecular
mechanisms
pathways
effects
on
adverse
toxic
reactions
look
forward
finding
Frontiers in Aging,
Journal Year:
2022,
Volume and Issue:
3
Published: July 12, 2022
The
α-Klotho
protein
(henceforth
denoted
Klotho)
has
antiaging
properties,
as
first
observed
in
mice
homozygous
for
a
hypomorphic
Klotho
gene
(kl/kl).
These
have
shortened
lifespan,
stunted
growth,
renal
disease,
hyperphosphatemia,
hypercalcemia,
vascular
calcification,
cardiac
hypertrophy,
hypertension,
pulmonary
cognitive
impairment,
multi-organ
atrophy
and
fibrosis.
Overexpression
of
opposite
effects,
extending
lifespan.
In
humans,
levels
decline
with
age,
chronic
kidney
diabetes,
Alzheimer's
disease
other
conditions.
Low
correlate
an
increase
the
death
rate
from
all
causes.
acts
either
obligate
coreceptor
fibroblast
growth
factor
23
(FGF23),
or
soluble
pleiotropic
endocrine
hormone
(s-Klotho).
It
is
mainly
produced
kidneys,
but
also
brain,
pancreas
tissues.
On
tubular-cell
membranes,
it
associates
FGF
receptors
to
bind
FGF23.
Produced
bones,
FGF23
regulates
excretion
phosphate
(phosphaturic
effect)
vitamin
D
metabolism.
Lack
results
hyperphosphatemia
hypervitaminosis
D.
With
human
function
often
deteriorates,
lowering
levels.
This
appears
promote
age-related
pathology.
Remarkably,
inhibits
four
pathways
that
been
linked
aging
various
ways:
Transforming
β
(TGF-β),
insulin-like
1
(IGF-1),
Wnt
NF-κB.
can
induce
cellular
senescence,
apoptosis,
inflammation,
immune
dysfunction,
fibrosis
neoplasia.
Furthermore,
increases
cell-protective
antioxidant
enzymes
through
Nrf2
FoxO.
accord,
preclinical
therapy
ameliorated
renal,
cardiovascular,
diabetes-related
neurodegenerative
diseases,
well
cancer.
s-Klotho
injection
was
effective,
requires
further
investigation.
Several
drugs
enhance
circulating
levels,
some
cross
blood-brain
barrier
potentially
act
brain.
clinical
trials,
increased
noted
renin-angiotensin
system
inhibitors
(losartan,
valsartan),
statin
(fluvastatin),
mTOR
(rapamycin,
everolimus),
pentoxifylline.
work,
antidiabetic
(metformin,
GLP-1-based,
GABA,
PPAR-γ
agonists)
enhanced
Klotho.
traditional
medicines
and/or
nutraceuticals
rodents,
including
astaxanthin,
curcumin,
ginseng,
ligustilide
resveratrol.
Notably,
exercise
sport
activity
review
addresses
molecular,
physiological
therapeutic
aspects
Antioxidants,
Journal Year:
2023,
Volume and Issue:
12(2), P. 280 - 280
Published: Jan. 27, 2023
Neurological
and
neurodegenerative
diseases,
particularly
those
related
to
aging,
are
on
the
rise,
but
drug
therapies
rarely
curative.
Functional
disorders
organic
degeneration
of
nervous
tissue
often
have
complex
causes,
in
which
phenomena
oxidative
stress,
inflammation
cytotoxicity
intertwined.
For
these
reasons,
search
for
natural
substances
that
can
slow
down
or
counteract
pathologies
has
increased
rapidly
over
last
two
decades.
In
this
paper,
studies
neuroprotective
effects
flavonoids
(especially
most
widely
used,
hesperidin
quercetin)
animal
models
depression,
neurotoxicity,
Alzheimer’s
disease
(AD)
Parkinson’s
reviewed.
The
literature
topics
amounts
a
few
hundred
publications
vitro
vivo
(notably
rodents)
provides
us
with
very
detailed
picture
action
mechanisms
targets
substances.
These
include
decrease
enzymes
produce
reactive
oxygen
ferroptosis,
inhibition
mono-amine
oxidases,
stimulation
Nrf2/ARE
system,
induction
brain-derived
neurotrophic
factor
production
and,
case
AD,
prevention
amyloid-beta
aggregation.
neuroinflammatory
processes
been
documented
as
cytokine
formation
(mainly
TNF-alpha
IL-1beta)
by
microglia
astrocytes,
modulating
number
regulatory
proteins
such
Nf-kB
NLRP3/inflammasome.
Although
clinical
trials
humans
still
scarce,
preclinical
allow
consider
hesperidin,
quercetin,
other
interesting
safe
dietary
molecules
be
further
investigated
complementary
treatments
order
prevent
diseases
moderate
their
deleterious
effects.
Signal Transduction and Targeted Therapy,
Journal Year:
2023,
Volume and Issue:
8(1)
Published: Dec. 10, 2023
Abstract
Ferroptosis,
a
unique
modality
of
cell
death
with
mechanistic
and
morphological
differences
from
other
modes,
plays
pivotal
role
in
regulating
tumorigenesis
offers
new
opportunity
for
modulating
anticancer
drug
resistance.
Aberrant
epigenetic
modifications
posttranslational
(PTMs)
promote
resistance,
cancer
progression,
metastasis.
Accumulating
studies
indicate
that
can
transcriptionally
translationally
determine
vulnerability
to
ferroptosis
functions
as
driver
nervous
system
diseases
(NSDs),
cardiovascular
(CVDs),
liver
diseases,
lung
kidney
diseases.
In
this
review,
we
first
summarize
the
core
molecular
mechanisms
ferroptosis.
Then,
roles
processes,
including
histone
PTMs,
DNA
methylation,
noncoding
RNA
regulation
such
phosphorylation,
ubiquitination,
SUMOylation,
acetylation,
ADP-ribosylation,
are
concisely
discussed.
The
PTMs
genesis
cancers,
NSD,
CVDs,
well
application
PTM
modulators
therapy
these
then
discussed
detail.
Elucidating
mediated
by
will
facilitate
development
promising
combination
therapeutic
regimens
containing
or
PTM-targeting
agents
inducers
be
used
overcome
chemotherapeutic
resistance
could
prevent
addition,
highlight
potential
approaches
chemoresistance
halt
Signal Transduction and Targeted Therapy,
Journal Year:
2024,
Volume and Issue:
9(1)
Published: Oct. 14, 2024
Iron,
an
essential
mineral
in
the
body,
is
involved
numerous
physiological
processes,
making
maintenance
of
iron
homeostasis
crucial
for
overall
health.
Both
overload
and
deficiency
can
cause
various
disorders
human
diseases.
Ferroptosis,
a
form
cell
death
dependent
on
iron,
characterized
by
extensive
peroxidation
lipids.
Unlike
other
kinds
classical
unprogrammed
death,
ferroptosis
primarily
linked
to
disruptions
metabolism,
lipid
peroxidation,
antioxidant
system
imbalance.
Ferroptosis
regulated
through
transcription,
translation,
post-translational
modifications,
which
affect
cellular
sensitivity
ferroptosis.
Over
past
decade
or
so,
diseases
have
been
as
part
their
etiology,
including
cancers,
metabolic
disorders,
autoimmune
diseases,
central
nervous
cardiovascular
musculoskeletal
Ferroptosis-related
proteins
become
attractive
targets
many
major
that
are
currently
incurable,
some
regulators
shown
therapeutic
effects
clinical
trials
although
further
validation
potential
needed.
Therefore,
in-depth
analysis
its
molecular
mechanisms
may
offer
additional
strategies
prevention
treatment.
In
this
review,
we
discuss
significance
contribution
etiology
development
along
with
evidence
supporting
targeting
approach.
Importantly,
evaluate
recent
promising
interventions,
providing
guidance
future
targeted
treatment
therapies
against
