Alzheimer’s
disease (AD) is one of the most challenging
diseases around the world with no effective clinical treatment. Previous
studies have suggested c-Jun N-terminal kinase 3 (JNK3) as an attractive
therapeutic target for AD. Herein, we report 3-substituted indolin-2-one
derivatives as the first isoform-selective JNK3 inhibitors by multistage
screening. In this study, comparative structure-based virtual screening
was performed, and J30-8 was identified with a half-maximal
inhibitory concentration of 40 nM, which exhibited over 2500-fold
isoform selectivity and marked kinome-wide selectivity. Further study
indicated that 1 μM J30-8 exhibited neuroprotective
activity in vitro so as to alleviate the spatial memory impairment
in vivo through reducing plaque burden and inhibiting the phosphorylation
of JNKs, Aβ precursor protein, and Tau protein. All of these
indicated J30-8 as proved isoform-selective JNK3 inhibitors
that might serve as a useful tool for further JNK3 studies with AD
as well as for the development of JNK3 inhibitors for the potential
treatment of neurodegenerative diseases.
This study aimed to investigate the transportation and absorption mechanism of La2(CO3)3 through the GI tract using in vitro and in vivo models. The results demonstrated that La2(CO3)3 can be dissolved in gastric fluids and precipitated into lanthanum phosphate (LaPO4) as the main transformed specie in intestinal fluid. Using Caco-2 cell monoculture and Caco-2/Raji B cell coculture models to simulate the intestinal epithelium and microfold (M) cells, it was found that the amount of lanthanum transported in Caco-2/ Raji B coculture model was significantly higher than that in Caco-2 monoculture model (about 50 times higher), indicating that M cells play an important role in the intestinal absorption of La2(CO3)3. Furthermore, oral administration of La2(CO3)3 to Balb/c mice demonstrated that lanthanum can be absorbed by both Peyer's patches (PPs) and non-PPs intestinal epithelium, with a higher amount of absorption in the PPs per unit weight. This finding further confirmed that the lanthanum absorption in GI tract could be mainly due to the contribution of M cells. Meanwhile, the administration of La2(CO3)3 caused a marked lanthanum accumulation in liver, accompanied by the activation of KCs. This study clarified how La2(CO3)3 is absorbed through the GI tract to enter the body and would be helpful to evaluate its potential biological consequences of accumulation in human beings.
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