Phytotherapy Research,
Journal Year:
2024,
Volume and Issue:
38(5), P. 2496 - 2517
Published: March 6, 2024
Abstract
We
investigated
the
mechanism
by
which
quercetin
preserves
mitochondrial
quality
control
(MQC)
in
cardiomyocytes
subjected
to
ischemia–reperfusion
stress.
An
enzyme‐linked
immunosorbent
assay
was
employed
vivo
experiments
assess
myocardial
injury
markers,
measure
transcript
levels
of
SIRT5/DNAPK‐cs/MLKL
during
various
time
intervals
ischemia–reperfusion,
and
observe
structural
changes
using
transmission
electron
microscopy.
In
vitro
investigations,
adenovirus
transfection
establish
a
gene‐modified
model
DNA‐PKcs,
primary
were
obtained
from
mouse
with
modified
SIRT5
gene.
Reverse
transcription
polymerase
chain
reaction,
laser
confocal
microscopy,
immunofluorescence
localization,
JC‐1
fluorescence
assay,
Seahorse
energy
analysis,
other
assays
applied
corroborate
regulatory
influence
on
MQC
network
after
ischemia–reperfusion.
demonstrated
that
caused
structure
myocardium.
It
seen
had
beneficial
effect
tissue,
providing
protection.
As
process
continued,
DNA‐PKcs/SIRT5/MLKL
transcripts
also
found
change.
investigations
revealed
mitigated
cardiomyocyte
oxidative
stress
through
regulated
mitophagy
kinetics
sustain
optimal
metabolism
levels.
Quercetin,
desuccinylation,
modulated
stability
together
they
“mitophagy‐unfolded
protein
response.”
This
preserved
integrity
membrane
genome,
dynamics,
metabolism.
Quercetin
may
operate
synergistically
oversee
regulation
unfolded
response
DNA‐PKcs‐SIRT5
interaction.
Abstract
Background
Septic
cardiomyopathy
(SCM),
a
common
cardiovascular
comorbidity
of
sepsis,
has
emerged
among
the
leading
causes
death
in
patients
with
sepsis.
SCM’s
pathogenesis
is
strongly
affected
by
mitochondrial
metabolic
dysregulation
and
immune
infiltration
disorder.
However,
specific
mechanisms
their
intricate
interactions
SCM
remain
unclear.
This
study
employed
bioinformatics
analysis
drug
discovery
approaches
to
identify
regulatory
molecules,
distinct
functions,
underlying
metabolism
microenvironment,
along
potential
interventional
strategies
SCM.
Methods
GSE79962,
GSE171546,
GSE167363
datasets
were
obtained
from
Gene
Expression
Omnibus
(GEO)
database.
Differentially
expressed
genes
(DEGs)
module
identified
using
Limma
Weighted
Correlation
Network
Analysis
(WGCNA),
followed
functional
enrichment
analysis.
Machine
learning
algorithms,
including
support
vector
machine–recursive
feature
elimination
(SVM–RFE),
least
absolute
shrinkage
selection
operator
(LASSO)
regression,
random
forest,
used
screen
mitochondria-related
hub
for
early
diagnosis
Subsequently,
nomogram
was
developed
based
on
six
genes.
The
immunological
landscape
evaluated
single-sample
gene
set
(ssGSEA).
We
also
explored
expression
pattern
distribution
mitochondria/inflammation-related
pathways
UMAP
plots
single-cell
dataset.
Potential
drugs
Drug
Signatures
Database
(DSigDB).
In
vivo
vitro
experiments
performed
validate
pathogenetic
mechanism
therapeutic
efficacy
candidate
drugs.
Results
Six
DEGs
[MitoDEGs;
translocase
inner
membrane
domain-containing
1
(TIMMDC1),
ribosomal
protein
S31
(MRPS31),
F-box
only
7
(FBXO7),
phosphatidylglycerophosphate
synthase
(PGS1),
LYR
motif
containing
(LYRM7),
chaperone
BCS1
(BCS1L)]
identified.
diagnostic
model
demonstrated
high
reliability
validity
both
training
validation
sets.
microenvironment
differed
between
control
groups.
Spearman
correlation
revealed
that
MitoDEGs
significantly
associated
cells.
Upregulated
showed
remarkably
naive/memory
B
cell,
CD14
+
monocyte,
plasma
cell
subgroup,
evidenced
plot.
varied
across
subgroups
individuals.
Metformin
predicted
be
most
promising
highest
combined
score.
Its
restoring
function
suppressing
inflammatory
responses
been
validated.
Conclusions
presents
comprehensive
SCM,
providing
novel
direction
medical
intervention
International Journal of Biological Sciences,
Journal Year:
2024,
Volume and Issue:
20(11), P. 4458 - 4475
Published: Jan. 1, 2024
This
study
investigated
the
mechanism
by
which
NR4A1
regulates
mitochondrial
fission
factor
(Mff)-related
and
FUN14
domain
1
(FUNDC1)-mediated
mitophagy
following
cardiac
ischemia-reperfusion
injury(I/R).
Our
findings
showed
that
damage
regulation
was
positively
correlated
with
pathological
pan-apoptosis
of
myocardial
cell
mitochondria.
Compared
wild-type
mice
(WT),
NR4A1-knockout
exhibited
resistance
to
injury
fission,
characterized
activation.
Results
increased
expression
level,
activating
mediated
Mff
restoring
phenotype
FUNDC1.
The
inactivation
FUNDC1
phosphorylation
could
not
mediate
normalization
in
a
timely
manner,
leading
an
excessive
stress
response
unfolded
proteins
imbalance
homeostasis.
process
disrupted
quality
control
network,
accumulation
damaged
mitochondria
activation
pan-apoptotic
programs.
data
indicate
is
novel
critical
target
I/R
exertsand
negative
regulatory
effects
Mff-mediated
mito-fission
inhibiting
FUNDC1-mediated
mitophagy.
Targeting
crosstalk
balance
between
NR4A1-Mff-FUNDC1
potential
approach
for
treating
I/R.
Biomedicine & Pharmacotherapy,
Journal Year:
2023,
Volume and Issue:
159, P. 114171 - 114171
Published: Jan. 13, 2023
Mitochondrial
dysfunction
is
the
main
cause
of
damage
to
pathological
mechanism
ischemic
cardiomyopathy.
In
addition,
mitochondrial
can
also
affect
homeostasis
cardiomyocytes
or
endothelial
cell
dysfunction,
leading
a
vicious
cycle
oxidative
stress.
And
an
important
basis
for
cardiomyopathy
and
reperfusion
injury
after
myocardial
infarction
end-stage
coronary
heart
disease.
Therefore,
mitochondria
be
used
as
therapeutic
targets
against
ischemia
injury,
regulation
morphology,
function
structure
key
way
targeting
quality
control
mechanisms.
includes
mechanisms
such
mitophagy,
dynamics
(mitochondrial
fusion/fission),
biosynthesis,
unfolded
protein
responses.
Among
them,
increase
fragmentation
caused
by
fission
initial
factor.
The
protective
fusion
strengthen
interaction
synthesis
paired
promote
biosynthesis.
hypoxia,
formation
fragments,
fragmented
lead
damaged
DNA
production,
which
biosynthesis
insufficient
ATP
ROS.
Burst
growth
loss
membrane
potential.
This
eventually
leads
accumulation
mitochondria.
Then,
under
leadership
complete
degradation
process
through
transport
morphologically
structurally
lysosomes
degradation.
But
once
increases,
may
activate
pathway
cardiomyocyte
death.
Although
laboratory
studies
have
found
that
variety
mitochondrial-targeted
drugs
reduce
protect
cardiomyocytes,
there
are
still
few
successfully
passed
clinical
trials.
this
review,
we
describe
role
MQS
in
ischemia/hypoxia-induced
physiopathology
elucidate
relevant
further
explained
advantages
natural
products
improving
protecting
cells
from
perspective
pharmacological
mechanism,
its
related
Potential
targeted
therapies
improve
ischemia/hypoxia
discussed,
aiming
accelerate
development
cardioprotective
dysfunction.
International Journal of Biological Sciences,
Journal Year:
2023,
Volume and Issue:
19(13), P. 4327 - 4339
Published: Jan. 1, 2023
Sirtuin-3
(Sirt3)
deacetylates
several
mitochondrial
proteins
implicated
into
cerebral
ischemia/reperfusion
(I/R)
injury.
The
unfolded
protein
response
(UPRmt)
favors
proteostasis
during
various
stressors.
Here,
we
used
Sirt3
transgenic
mice
and
a
transient
middle
artery
occlusion
model
to
evaluate
the
molecular
basis
of
on
UPRmt
brain
post-ischemic
dysfunction.
present
study
illustrated
that
abundance
was
suppressed
in
after
ischemic
abnormalities.
Overexpression
vivo
infarction
size
attenuated
neuroinflammation
I/R
overexpression
restored
neural
viability
by
reducing
ROS
synthesis,
maintaining
potential
improving
adenosine
triphosphate
synthesis.
protected
neuronal
mitochondria
against
malfunction
via
eliciting
forkhead
box
O3
(Foxo3)/sphingosine
kinase
1
(Sphk1)
pathway.
Inhibiting
either
or
Foxo3/Sphk1
pathway
relieved
favorable
influence
function
behavior.
In
contrast,
Sphk1
sufficient
reduce
size,
attenuate
neuroinflammation,
sustain
prevent
abnormalities
post-ischemia
Thus,
protects
homeostasis,
Sirt3/Foxo3/Sphk1
is
promosing
therapeutic
candidate
for
stroke.
