Frontiers in Aging Neuroscience,
Год журнала:
2021,
Номер
13
Опубликована: Июнь 24, 2021
While
the
central
nervous
system
compromises
2%
of
our
body
weight,
it
harbors
up
to
25%
body's
cholesterol.
Cholesterol
levels
in
brain
are
tightly
regulated
for
physiological
function,
but
mounting
evidence
indicates
that
excessive
cholesterol
accumulates
Alzheimer's
disease
(AD),
where
may
drive
AD-associated
pathological
changes.
This
seems
especially
relevant
late-onset
AD,
as
several
major
genetic
risk
factors
functionally
associated
with
metabolism.
In
this
review
we
discuss
different
systems
maintain
metabolism
healthy
brain,
and
how
dysregulation
these
processes
can
lead,
or
contribute
to,
disease.
We
will
also
AD-risk
genes
might
impact
downstream
AD
pathology.
Finally,
address
outstanding
questions
field
recent
technical
advances
CRISPR/Cas9-gene
editing
induced
pluripotent
stem
cell
(iPSC)-technology
aid
study
problems.
Antioxidants,
Год журнала:
2020,
Номер
9(8), С. 743 - 743
Опубликована: Авг. 13, 2020
Neurodegenerative
disorders,
such
as
Alzheimer’s
disease,
are
a
global
public
health
burden
with
poorly
understood
aetiology.
Neuroinflammation
and
oxidative
stress
(OS)
undoubtedly
hallmarks
of
neurodegeneration,
contributing
to
disease
progression.
Protein
aggregation
neuronal
damage
result
in
the
activation
disease-associated
microglia
(DAM)
via
damage-associated
molecular
patterns
(DAMPs).
DAM
facilitate
persistent
inflammation
reactive
oxygen
species
(ROS)
generation.
However,
mechanisms
linking
OS
have
not
been
well-defined;
thus
targeting
these
cells
for
clinical
benefit
has
possible.
In
microglia,
ROS
generated
primarily
by
NADPH
oxidase
2
(NOX2)
NOX2
is
associated
DAMP
signalling,
amyloid
plaque
deposition,
especially
cerebrovasculature.
Additionally,
originating
from
both
NOX
mitochondria
may
act
second
messengers
propagate
immune
activation;
intracellular
signalling
underlie
excessive
OS.
Targeting
key
kinases
inflammatory
response
could
cease
promote
tissue
repair.
Expression
antioxidant
proteins
dehydrogenase
1
(NQO1),
promoted
transcription
factor
Nrf2,
which
functions
control
limit
Lipid
droplet
accumulating
(LDAM)
also
represent
double-edged
sword
neurodegenerative
sequestering
peroxidised
lipids
non-pathological
ageing
but
becoming
dysregulated
pro-inflammatory
disease.
We
suggest
that
future
studies
should
focus
on
targeted
manipulation
understand
driving
inflammatory-related
activation.
Finally,
we
discuss
recent
evidence
therapeutic
target
identification
be
unbiased
founded
relevant
pathophysiological
assays
discovery
translatable
anti-inflammatory
therapeutics.
Signal Transduction and Targeted Therapy,
Год журнала:
2022,
Номер
7(1)
Опубликована: Сен. 1, 2022
Abstract
The
current
understanding
of
lactate
extends
from
its
origins
as
a
byproduct
glycolysis
to
role
in
tumor
metabolism,
identified
by
studies
on
the
Warburg
effect.
shuttle
hypothesis
suggests
that
plays
an
important
bridging
signaling
molecule
coordinates
among
different
cells,
organs
and
tissues.
Lactylation
is
posttranslational
modification
initially
reported
Professor
Yingming
Zhao’s
research
group
2019.
Subsequent
confirmed
lactylation
vital
component
function
involved
proliferation,
neural
excitation,
inflammation
other
biological
processes.
An
indispensable
substance
for
various
physiological
cellular
functions,
regulatory
aspects
energy
metabolism
signal
transduction.
Therefore,
comprehensive
review
summary
presented
clarify
disease
provide
reference
direction
future
research.
This
offers
systematic
overview
homeostasis
roles
pathological
processes,
well
effects
diseases,
particularly
cancer.
Redox Biology,
Год журнала:
2020,
Номер
35, С. 101454 - 101454
Опубликована: Фев. 9, 2020
Mistakenly
thought
to
be
the
consequence
of
oxygen
lack
in
contracting
skeletal
muscle
we
now
know
that
L-enantiomer
lactate
anion
is
formed
under
fully
aerobic
conditions
and
utilized
continuously
diverse
cells,
tissues,
organs
at
whole-body
level.
By
shuttling
between
producer
(driver)
consumer
(recipient)
cells
fulfills
least
three
purposes:
1]
a
major
energy
source
for
mitochondrial
respiration;
2]
gluconeogenic
precursor;
3]
signaling
molecule.
Working
by
mass
action,
cell
redox
regulation,
allosteric
binding,
reprogramming
chromatin
lactylation
lysine
residues
on
histones,
has
influences
substrate
partitioning.
The
physiological
range
tissue
[lactate]
0.5-20
mM
cellular
Lactate/Pyruvate
ratio
(L/P)
can
from
10
>500;
these
changes
during
exercise
other
stress-strain
responses
dwarf
metabolic
signals
magnitude
span.
Hence,
dynamics
have
rapid
short-
long-term
effects
control
systems.
inhibiting
lipolysis
adipose
via
HCAR-1,
fatty
acid
uptake
malonyl-CoA
CPT1,
controls
Repeated
exposure
regular
results
expression
regulatory
enzymes
glycolysis
respiration.
Lactate
fulcrum
regulation
vivo.
Molecules,
Год журнала:
2018,
Номер
23(8), С. 1941 - 1941
Опубликована: Авг. 3, 2018
Cancer
cells
possess
remarkable
abilities
to
adapt
adverse
environmental
conditions.
Their
survival
during
severe
nutrient
and
oxidative
stress
depends
on
their
capacity
acquire
extracellular
lipids
the
plasticity
of
mechanisms
for
intracellular
lipid
synthesis,
mobilisation,
recycling.
Lipid
droplets,
cytosolic
fat
storage
organelles
present
in
most
from
yeast
men,
are
emerging
as
major
regulators
metabolism,
trafficking,
signalling
various
tissues
exposed
stress.
biogenesis
is
induced
by
they
accumulate
cancers.
droplets
act
switches
that
coordinate
trafficking
consumption
different
purposes
cell,
such
energy
production,
protection
against
or
membrane
rapid
cell
growth.
They
sequester
toxic
lipids,
fatty
acids,
cholesterol
ceramides,
thereby
preventing
lipotoxic
damage
engage
a
complex
relationship
with
autophagy.
Here,
we
focus
stress-induced
droplet
biogenesis;
roles
nutrient,
lipotoxic,
stress;
between
The
recently
discovered
principles
biology
can
improve
our
understanding
govern
cancer
adaptability
resilience
We
generated
a
library
of
~1000
Drosophila
stocks
in
which
we
inserted
construct
the
intron
genes
allowing
expression
GAL4
under
control
endogenous
promoters
while
arresting
transcription
with
polyadenylation
signal
3'
GAL4.
This
allows
numerous
applications.
First,
~90%
insertions
essential
cause
severe
loss-of-function
phenotype,
an
effective
way
to
mutagenize
genes.
Interestingly,
12/14
chromosomes
engineered
through
CRISPR
do
not
carry
second-site
lethal
mutations.
Second,
26/36
(70%)
tested
are
rescued
single
UAS-cDNA
construct.
Third,
phenotypes
associated
many
can
be
reverted
by
excision
UAS-flippase.
Fourth,
driven
UAS-GFP/RFP
reports
tissue
and
cell-type
specificity
gene
high
sensitivity.
report
hundreds
previously
reported.
Finally,
cassettes
replaced
GFP
or
any
DNA.
These
comprise
powerful
resource
for
assessing
function.