Alzheimer’s disease (AD) is an irreversible neurodegenerative
disorder. Currently, there are no available treatments that can effectively
stop or reverse the progression of the disease, and existing therapeutics
can only alleviate the symptoms. Thus, it remains urgent to develop
effective early-stage AD diagnostic methods. In recent years, the
search for near-infrared fluorescent (NIRF) probes of AD hallmarks
has become a promising research field. In this Review, we will focus
on small-molecule NIRF probes used to detect β-amyloid, tau
proteins, and reactive oxygen species in vivo during
the past 4 years. We believe that some new directions we raise herein
will benefit the future development of NIRF probes in the field of
AD research.
Concomitant inhibition of PARP and PI3K pathways has
been recognized
as a promising strategy for cancer therapy, which may expand the clinical
utility of PARP inhibitors. Herein, we report the discovery of dual
PARP/PI3K inhibitors that merge the pharmacophores of PARP and PI3K
inhibitors. Among them, compound 15 stands out as the
most promising candidate with potent inhibitory activities against
both PARP-1/2 and PI3Kα/δ with pIC50 values
greater than 8. Compound 15 displayed superior antiproliferative
profiles against both BRCA-deficient and BRCA-proficient cancer cells
in cellular assays. The prominent synergistic effects produced by
the concomitant inhibition of the two targets were elucidated by comprehensive
biochemical and cellular mechanistic studies. In vivo, 15 showed more efficacious antitumor activity than the corresponding
drug combination (Olaparib + BKM120) in the MDA-MB-468 xenograft model
with a tumor growth inhibitory rate of 73.4% without causing observable
toxic effects. All of the results indicate that 15, a
first potent dual PARP/PI3K inhibitor, is a highly effective anticancer
compound.
Aggregation of amyloid β-peptide (Aβ) is closely related to the pathology of Alzheimer's disease (AD). In this pathology, the beginning stage is characterized by excessive accumulation of Aβ monomers due to imbalanced Aβ in the process of clearance. The Aβ peptide exists in many forms such as soluble and insoluble Aβ species, both of which coexist during the progression of AD and contribute to AD pathology. Thus, probes capable of monitoring all Aβ species are highly desirable. While there are several fluorescent probes for detecting insoluble Aβ, it is still challenging to monitor all Aβ forms by using probes. Here, we describe a near-infrared fluorescent chemical probe, termed AD-1, developed through complexation of curcumin analogues with a stabilizer, which has good photophysical properties and shows high binding to all Aβ species in solution tests. Furthermore, AD-1 exhibited good blood−brain barrier penetrating ability and low cytotoxicity. More importantly, it was successfully applied to 4-month-young APP/PS1 mice imaging noninvasively.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.