Acta Pharmaceutica Sinica B,
Journal Year:
2024,
Volume and Issue:
15(2), P. 892 - 908
Published: Dec. 2, 2024
Stearoyl-coenzyme
A
desaturase
1
(SCD1)
catalyzes
the
rate-limiting
step
of
de
novo
lipogenesis
and
modulates
lipid
homeostasis.
Although
numerous
SCD1
inhibitors
were
tested
for
treating
metabolic
disorders
both
in
preclinical
clinic
studies,
tissue-specific
roles
modulating
obesity-associated
determining
pharmacological
effect
chemical
inhibition
remain
unclear.
Here
a
novel
role
intestinal
was
uncovered.
Intestinal
found
to
be
induced
during
obesity
progression
humans
mice.
Intestine-specific,
but
not
liver-specific,
deficiency
reduced
hepatic
steatosis.
A939572,
an
SCD1-specific
inhibitor,
ameliorated
steatosis
dependent
on
intestinal,
hepatic,
SCD1.
Mechanistically,
impeded
obesity-induced
oxidative
stress
through
its
function
inducing
metallothionein
epithelial
cells.
These
results
suggest
that
could
viable
target
underlies
treatment
disorders.
Pharmacological Reviews,
Journal Year:
2024,
Volume and Issue:
77(1), P. 100002 - 100002
Published: Sept. 20, 2024
The
history
of
anti-obesity
pharmacotherapies
is
marked
by
disappointments,
often
entangled
with
societal
pressure
promoting
weight
loss
and
the
conviction
that
excess
body
signifies
a
lack
willpower.
However,
categories
emerging
generate
hope
to
reduce
obesity
rates.
This
systematic
review
phase
2
3
trials
in
adults
overweight/obesity
investigates
effect
novel
pharmacotherapies,
compared
placebo/control
or
Food
Drug
Administration-approved
medication,
through
searching
Medline,
Embase,
ClinicalTrials.gov
(2012-2024).
We
identified
53
trials,
36
drugs
combinations
thereof
four
withdrawn
terminated
trials.
Oral
semaglutide
50
mg
only
medication
has
completed
trial.
There
are
14
ongoing
on
glucagon-like
peptide-1
(GLP-1)
receptor
agonists
(RAs)
(ecnoglutide,
orforglipron,
TG103),
GLP-1
RA/amylin
agonist
(CagriSema),
GLP-1/glucagon
RAs
(mazdutide,
survodutide),
GLP-1/glucose-dependent
insulinotropic
polypeptide
glucagon
RA
(retatrutide),
dapagliflozin,
combination
sibutramine/topiramate.
Completed
incretin-based
therapies
showed
mean
percent
7.4-24.2%.
Almost
half
undergoing
were
incretin
analogs.
drug
pipeline
expanding
rapidly,
most
promising
results
reported
Data
mortality
obesity-related
complications,
such
as
cardio-renal-metabolic
events,
needed.
Moreover,
long-term
follow-up
data
safety
efficacy
maintenance
along
studies
focused
under-represented
populations,
cost-effectiveness
assessments,
availability,
needed
bridge
care
gap
for
patients
obesity.
Significance
Statement
Obesity
epidemic
21st
century.
Except
newer
injectable
medications,
suboptimal
have
been
available
clinician's
armamentarium.
alternatives
agents
populate
therapeutic
pipeline.
identifies
state
mechanism
action
having
clinical
information
provided
herein
furthers
understanding
management,
implying
direct
implications
stimulating
research
initiatives.
GeroScience,
Journal Year:
2024,
Volume and Issue:
unknown
Published: Oct. 8, 2024
Abstract
The
incidence
of
colorectal
cancer
(CRC)
has
been
steadily
rising,
and
obesity
identified
as
a
significant
risk
factor.
Numerous
studies
suggest
strong
correlation
between
excess
body
weight
increased
CRC,
but
comprehensive
quantification
through
pooled
analysis
remains
limited.
This
study
aims
to
systematically
review
meta-analyze
the
existing
literature
evaluate
association
CRC
risk,
considering
variations
across
sex
designs.
A
systematic
search
was
conducted
in
PubMed,
Cochrane
Central
Register
Controlled
Trials
(CENTRAL),
Web
Science
identify
randomized
controlled
trials
human
clinical
from
1992
2024.
Statistical
performed
using
https://metaanalysisonline.com
web
application
random
effects
model
estimate
hazard
rates
(HR).
Forest
plots,
funnel
Z-score
plots
were
utilized
visualize
results.
We
52
14
case–control
studies,
encompassing
total
83,251,050
236,877
subjects,
respectively.
indicated
that
significantly
prevalence
(HR
=
1.36,
95%
CI
1.24–1.48,
p
<
0.01).
effect
consistent
sexes,
with
HRs
1.57
(95%
1.38–1.78,
0.01)
for
males
1.25
1.14–1.38,
females.
Case–control
specifically
showed
an
effect,
marginal
significance
only
1.27,
0.98–1.65,
0.07).
plot
need
additional
group.
heterogeneity
observed
all
four
settings.
meta-analysis
provides
robust
evidence
is
factor
cancer,
overall
rate
indicating
36%
risk.
pronounced
both
showing
slightly
higher
compared
Although
weaker
association,
trend
supports
link
CRC.
These
results
underscore
importance
public
health
interventions
aimed
at
reducing
potentially
lower
cancer.
Gut,
Journal Year:
2024,
Volume and Issue:
unknown, P. gutjnl - 334023
Published: Nov. 26, 2024
Clinically
effective
pharmacological
treatment(s)
for
metabolic
dysfunction-associated
steatotic
liver
disease
(MASLD)
and
its
progressive
form
steatohepatitis
(MASH)
represent
a
largely
unmet
need
in
medicine.
Since
glucagon-like
peptide-1
receptor
agonists
(GLP-1RAs)
have
been
licensed
the
treatment
of
type
2
diabetes
mellitus
obesity,
they
were
one
first
drug
classes
to
be
examined
individuals
with
MASLD/MASH.
Successful
phase
randomised
clinical
trials
these
agents
resulted
progression
3
(principally
testing
long-term
efficacy
subcutaneous
semaglutide).
Over
last
few
years,
addition
GLP-1RAs,
newer
glucose-dependent
insulinotropic
peptide
and/or
glucagon
agonist
functions
tested,
increasing
evidence
from
histological
improvements
MASLD/MASH,
as
well
benefits
on
MASLD-related
extrahepatic
complications.
Based
this
background
evidence,
single,
dual
or
triple
incretin
are
becoming
an
attractive
promising
option
MASLD
MASH,
particularly
coexisting
obesity
mellitus.
In
narrative
review,
we
examine
rapidly
expanding
body
supporting
role
incretin-based
pharmacotherapies
delaying
reversing
MASH
progression.
We
also
discuss
biology
incretins
putative
hepatoprotective
mechanisms
managing
MASH.
Journal of the American Chemical Society,
Journal Year:
2025,
Volume and Issue:
unknown
Published: Jan. 30, 2025
Modular
chemical
postmodification
of
peptides
is
a
promising
strategy
that
supports
the
optimization
and
innovation
hit
peptide
therapeutics
by
enabling
rapid
derivatization.
However,
current
methods
are
primarily
limited
to
traditional
bio-orthogonal
strategies
ligation
techniques,
which
require
preintroduction
non-natural
amino
acids
impose
fixed
limit
diversity.
Here,
we
developed
Tyrosine-1,2,3-Triazine
Ligation
(YTL)
strategy,
constructs
novel
linkages
(pyridine
pyrimidine)
through
"one-pot,
two-step"
process
combining
SNAr
IEDDA
reactions,
promoting
modular
post
modification
Tyr-containing
peptides.
After
optimizing
YTL
establishing
standard
procedures,
successfully
applied
it
solid-phase
various
biorelated
peptides,
such
as
synthesis
dual-mode
imaging
probes
long-acting
GLP-1
analogs.
As
proof
concept,
library
384
amphipathic
was
constructed
using
based
on
96-well
microfiltration
plates.
modifications
were
then
performed
screened
template
tripeptide
RYR,
leading
generation
20
derivatives.
The
antibacterial
activity
these
derivatives
systematically
characterized,
identifying
Z8
potential
candidate.
