The NLRP3 inflammasome is a critical
component of innate immunity,
which defends internal and external threats. However, inappropriate
activation of the NLRP3 inflammasome induces various human diseases.
In this study, we discovered and synthesized a series of tetrahydroquinoline
inhibitors of NLRP3 inflammasome. Among these analogues, compound 6 exhibited optimal NLRP3 inhibitory activity. In
vitro studies indicated that compound 6 directly
bound to the NACHT domain of NLRP3 but not to protein pyrin domain
(PYD) or LRR domain, inhibited NLRP3 ATPase activity, and blocked
ASC oligomerization, thereby inhibiting NLRP3 inflammasome assembly
and activation. Compound 6 specifically inhibited the
NLRP3 inflammasome activation, but had no effect on the activation
of NLRC4 or AIM2 inflammasomes. Furthermore, in the dextran sulfate
sodium (DSS)-induced colitis mouse model, compound 6 exhibited
significant anti-inflammatory activity through inhibiting NLRP3 inflammasome in vivo. Therefore, our study provides a potent NLRP3 inflammasome
inhibitor, which deserves further structural optimization as a novel
therapeutic candidate for NLRP3-driven diseases.
Lung cancers are the leading cause of cancer deaths worldwide and pose a grave threat to human life and health. Non-small cell lung cancer (NSCLC) is the most frequent malignancy occupying 80% of all lung cancer subtypes. Except for other mutations (
e.g
.,
KRAS
G12V/D
) that are also vital for the occurrence,
KRAS
G12C
gene mutation is a significant driving force of NSCLC, with a prevalence of approximately 14% of all NSCLC patients. However, there are only a few therapeutic drugs targeting KRAS
G12C
mutations currently. Here, we synthesized hydrocarbon-stapled peptide
3
that was much shorter and more stable with modest KRAS
G12C
binding affinity and the same anti-tumor effect based on the
α
-helical peptide mimic SAH-SOS1
A
. The stapled peptide
3
effectively induced G2/M arrest and apoptosis, inhibiting cell growth in KRAS-mutated lung cancer cells
via
disrupting the KRAS-mediated RAF/MEK/ERK signaling, which was verified from the perspective of genomics and proteomics. Peptide
3
also exhibited strong anti-trypsin and anti-chymotrypsin abilities, as well as good plasma stability and human liver microsomal metabolic stability. Overall, peptide
3
retains the equivalent anti-tumor activity of SAH-SOS1
A
but with improved stability and affinity, superior to SAH-SOS1
A
. Our work offers a structural optimization approach of KRAS
G12C
peptide inhibitors for cancer therapy.
1,2,4-Oxadiazole derivatives, a class
of Nrf2-ARE activators, exert
an extensive therapeutic effect on inflammation, cancer, neurodegeneration,
and microbial infection. Among these analogues, DDO-7263 is the most potent Nrf2 activator and used as the core structure
for bioactive probes to explore the precise mechanism. In this work,
we obtained compound 7, a mimic of DDO-7263, and biotin-labeled and fluorescein-based probes, which exhibited
homologous biological activities to DDO-7263, including
activating Nrf2 and its downstream target genes, anti-oxidative stress,
and anti-inflammatory effects. Affinity chromatography and mass analysis
techniques revealed Rpn6 as the potential target protein regulating
the Nrf2 signaling pathway. In vitro affinity experiments further
confirmed that DDO-7263 upregulated Nrf2 through binding
to Rpn6 to block the assembly of 26S proteasome and the subsequent
degradation of ubiquitinated Nrf2. These results indicated that Rpn6
is a promising candidate target to activate the Nrf2 pathway for protecting
cells and tissues from oxidative, electrophilic, and exogenous microbial
stimulation.
It is counterintuitive that chemical reactions can be accelerated by freezing, but this amazing phenomenon was discovered as early as the 1960s. In frozen systems, the increase in reaction rate is caused by various mechanisms and the freeze concentration effect is the main reason for the observed acceleration. Some accelerated reactions have great application value in the chemistry synthesis and environmental fields; at the same time, certain reactions accelerated at low temperature during the storage of food, medicine, and biological products should cause concern. The study of reactions accelerated by freezing will overturn common sense and provide a new strategy for researchers in the chemistry field. In this review, we mainly introduce various mechanisms for accelerating reactions induced by freezing and summarize a variety of accelerated cryochemical reactions and their applications.
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