International Journal of Molecular Sciences,
Journal Year:
2022,
Volume and Issue:
23(21), P. 13538 - 13538
Published: Nov. 4, 2022
Sphingosine
1-phosphate
(S1P)
is
a
bioactive
sphingolipid,
noteworthy
for
its
involvement
both
in
the
modulation
of
various
biological
processes
and
development
many
diseases.
S1P
signaling
can
be
either
pro
or
anti-inflammatory,
sphingosine
kinase
(SphK)-S1P-S1P
receptor
(S1PR)
axis
factor
accelerating
growth
several
cells,
including
endometriotic
cells
fibrosis.
Gynecologic
disorders,
endometriosis,
adenomyosis,
uterine
fibroids
are
characterized
by
inflammation
metabolism
have
been
shown
to
dysregulated
those
disorders
they
likely
implicated
their
pathogenesis
pathophysiology.
Enzymes
responsible
inactivating
most
affected
dysregulation
balanced
levels,
thus
causing
accumulation
sphingolipids
within
these
tissues.
The
present
review
highlights
past
latest
evidence
on
role
played
pathways
common
gynecologic
(GDs).
Furthermore,
it
discusses
potential
future
approaches
regulation
this
pathway
that
could
represent
an
innovative
promising
therapeutical
target,
also
ovarian
cancer
treatment.
Nature Reviews Drug Discovery,
Journal Year:
2023,
Volume and Issue:
22(4), P. 317 - 335
Published: Feb. 13, 2023
For
decades,
preclinical
toxicology
was
essentially
a
descriptive
discipline
in
which
treatment-related
effects
were
carefully
reported
and
used
as
basis
to
calculate
safety
margins
for
drug
candidates.
In
recent
years,
however,
technological
advances
have
increasingly
enabled
researchers
gain
insights
into
toxicity
mechanisms,
supporting
greater
understanding
of
species
relevance
translatability
humans,
prediction
events,
mitigation
side
development
biomarkers.
Consequently,
investigative
(or
mechanistic)
has
been
gaining
momentum
is
now
key
capability
the
pharmaceutical
industry.
Here,
we
provide
an
overview
current
status
field
using
case
studies
discuss
potential
impact
ongoing
developments,
based
on
survey
toxicologists
from
14
European-based
medium-sized
large
companies.
Investigative
tools
strategies
are
companies
reduce
safety-related
attrition
development.
This
Perspective
article
summarizes
goals
toxicology,
highlights
approaches
discusses
selected
emerging
technologies
that
improve
safety-testing
paradigm.
International Journal of Molecular Sciences,
Journal Year:
2021,
Volume and Issue:
22(16), P. 8370 - 8370
Published: Aug. 4, 2021
The
disruption
of
blood-brain
barrier
(BBB)
for
multiple
sclerosis
(MS)
pathogenesis
has
a
double
effect:
early
on
during
the
onset
immune
attack
and
later
CNS
self-sustained
'inside-out'
demyelination
neurodegeneration
processes.
This
review
presents
characteristics
BBB
malfunction
in
MS
but
mostly
highlights
current
developments
regarding
impairment
neurovascular
unit
(NVU)
metabolic
mitochondrial
dysfunctions
BBB's
endothelial
cells.
hypoxic
hypothesis
is
largely
studied
agreed
upon
recently
pathologic
processes
MS.
Hypoxia
might
be
produced
per
se
by
NVU
or
secondary
to
mitochondria
dysfunction.
We
present
three
different
related
terms
that
denominate
ongoing
neurodegenerative
process
progressive
forms
are
indirectly
disruption:
progression
independent
relapses,
no
evidence
disease
activity
smoldering
silent
progression.
Dimethyl
fumarate
(DMF),
modulators
S1P
receptor,
cladribine
laquinimode
DMTs
able
cross
exhibit
beneficial
direct
effects
with
very
mechanisms
action,
providing
hope
combined
therapy
effective
treating
Detailed
action
these
described
also
illustrated
dedicated
images.
With
increasing
knowledge
about
involvement
pathology,
become
therapeutic
target
not
only
make
it
impenetrable
against
activated
cells
allow
molecules
have
neuroprotective
effect
reaching
cell
inside
CNS.
Cureus,
Journal Year:
2023,
Volume and Issue:
unknown
Published: Jan. 2, 2023
Multiple
sclerosis
(MS)
is
an
immune-inflammatory
disease
that
attacks
and
damages
myelinated
axons
in
the
central
nervous
system
(CNS)
causes
nontraumatic
neurological
impairment
young
people.
Historically,
Lidwina
of
Schiedam
documented
first
MS
case.
After
that,
Augustus
d'Este
wrote
for
years
about
how
his
symptoms
worsened.
Age,
sex,
genetics,
environment,
smoking,
injuries,
infections,
including
herpes
simplex
rabies,
are
risk
factors
MS.
According
to
epidemiology,
average
age
onset
between
20
40
years.
more
prevalent
women
common
Europe
America.
As
diagnostic
methods
criteria
change,
people
with
may
be
discovered
at
earlier
stages
disease.
therapy
has
advanced
dramatically
due
breakthroughs
our
knowledge
disease's
etiology
progression.
Therefore,
efficacy
treatment
medications
increased
exponentially.
Management
goals
include
reducing
lesion
activity
avoiding
secondary
Current
approaches
focus
on
managing
acute
episodes,
relieving
symptoms,
biological
activity.
Disease-modifying
drugs
such
as
fingolimod,
interferon-beta,
natalizumab,
dimethyl
fumarate
most
widely
used
treatments
For
proof
safety
these
medications,
investigations
real
world
necessary.
Frontiers in Immunology,
Journal Year:
2023,
Volume and Issue:
14
Published: May 16, 2023
Inflammatory
demyelinating
diseases
(IDDs)
are
among
the
main
causes
of
inflammatory
and
neurodegenerative
injury
central
nervous
system
(CNS)
in
young
adult
patients.
Of
these,
multiple
sclerosis
(MS)
is
most
frequent
studied,
as
it
affects
about
a
million
people
USA
alone.
The
understanding
mechanisms
underlying
their
pathology
has
been
advancing,
although
there
still
no
highly
effective
disease-modifying
treatments
for
progressive
symptoms
disability
late
stages
disease.
Among
these
mechanisms,
action
glial
cells
upon
lesion
regeneration
become
prominent
research
topic,
helped
not
only
by
discovery
glia
targets
autoantibodies,
but
also
role
on
CNS
homeostasis
neuroinflammation.
In
present
article,
we
discuss
participation
IDDs,
well
association
with
demyelination
synaptic
dysfunction
throughout
course
disease
experimental
models,
focus
MS
phenotypes.
Further,
involvement
microglia
astrocytes
formation
organization,
remyelination,
induction
pruning
through
different
signaling
pathways.
We
argue
that
evidence
several
glia-mediated
supports
viable
therapy
development.
International Journal of Molecular Sciences,
Journal Year:
2025,
Volume and Issue:
26(8), P. 3585 - 3585
Published: April 10, 2025
Microglia
and
macrophages
are
critical
mediators
of
immune
responses
in
the
central
nervous
system.
Their
roles
range
from
homeostatic
maintenance
to
pathogenesis
autoimmune
demyelinating
diseases
such
as
multiple
sclerosis
neuromyelitis
optica
spectrum
disorder.
This
review
explores
origins
microglia
macrophages,
well
their
mechanisms
activation,
interactions
with
other
neural
cells,
contributions
disease
progression
repair
processes.
It
also
highlights
translational
relevance
insights
gained
animal
models
therapeutic
potential
targeting
microglial
macrophage
activity
Molecules,
Journal Year:
2023,
Volume and Issue:
28(13), P. 5041 - 5041
Published: June 28, 2023
Oxime
ethers
are
a
class
of
compounds
containing
the
>C=N-O-R
moiety.
The
presence
this
moiety
affects
biological
activity
compounds.
In
review,
structures
oxime
with
specific
have
been
collected
and
presented,
bactericidal,
fungicidal,
antidepressant,
anticancer
herbicidal
activities,
among
others,
described.
review
includes
both
those
substances
that
currently
used
as
drugs
(e.g.,
fluvoxamine,
mayzent,
ridogrel,
oxiconazole),
well
non-drug
for
which
various
studies
conducted.
To
best
our
knowledge,
is
first
such
authors
hope
will
inspire
scientists
to
take
greater
interest
in
group
compounds,
it
constitutes
an
interesting
research
area.
Proceedings of the National Academy of Sciences,
Journal Year:
2024,
Volume and Issue:
121(8)
Published: Feb. 12, 2024
Physics-based
simulation
methods
can
grant
atomistic
insights
into
the
molecular
origin
of
function
biomolecules.
However,
potential
such
approaches
has
been
hindered
by
their
low
efficiency,
including
in
design
selective
agonists
where
simulations
myriad
protein–ligand
combinations
are
necessary.
Here,
we
describe
an
automated
input-free
path
searching
protocol
that
offers
(within
14
d
using
Graphics
Processing
Unit
servers)
a
minimum
free
energy
(MFEP)
defined
high-dimension
configurational
space
for
activating
sphingosine-1-phosphate
receptors
(S1PRs)
arbitrary
ligands.
The
distributions
along
MFEP
four
distinct
ligands
and
three
S1PRs
reached
remarkable
agreement
with
Bioluminescence
Resonance
Energy
Transfer
(BRET)
measurements
G-protein
dissociation.
In
particular,
revealed
transition
state
structures
pointed
out
toward
two
S1PR3
residues
F263/I284,
dictate
preference
existing
CBP307
BAF312
on
S1PR1/5.
Swapping
these
between
S1PR1
reversed
response
to
BRET
assays.
These
results
inspired
us
improved
both
strong
polar
head
bulky
hydrophobic
tail
higher
selectivity
S1PR1.
Through
merely
silico
iterations,
our
tool
predicted
unique
compound
scaffold.
assays
confirmed
chiral
forms
activate
at
nanomolar
concentration,
1
2
orders
magnitude
less
than
those
S1PR3/5.
Collectively,
signify
promise
approach
fine
agonist
G-protein-coupled
receptors.