Using Sprague-Dawley rats and rat
PC12 cells treated with sodium
fluoride (NaF), we investigated the effects of SIK2-CRTC1 signaling
on the neurobehavioral toxicity induced by fluoride. The in
vivo results demonstrated that NaF treatment induced anxiety-
and depression-like behaviors in juvenile rats, resulting in histological
and ultrastructural abnormalities in the rat hippocampus and medial
prefrontal cortex. Moreover, NaF exposure induced neuronal loss and
excessive apoptosis. We also found that NaF elevated the expression
of SIK2 and reduced the expression of CRTC1, brain-derived neurotrophic
factor (BDNF), and VGF. The in vitro results showed
that NaF suppressed cell viability, induced SIK2-CRTC1 signaling dysfunction,
and caused excessive apoptosis in PC12 cells. Notably, targeted knockout
of SIK2 with SIK2-siRNA or blocking of SIK2-CRTC1 signaling with 7,8-dihydroxyflavone
(7,8-DHF) (as well as venlafaxine) can reduce apoptosis and increase
cell viability in vitro. These findings suggest that
neuronal death resulting from abnormal SIK2-CRTC1 signaling contributes
to neurobehavioral toxicity induced by fluoride.
Fluorosis is a serious global public health problem. Interestingly, so far, there is no specific drug treatment for the treatment of fluorosis. In this paper, the potential mechanisms of 35 ferroptosis-related genes in U87 glial cells exposed to fluoride were explored by bioinformatics methods. Significantly, these genes are involved in oxidative stress, ferroptosis, and decanoate CoA ligase activity. Ten pivotal genes were found by the Maximal Clique Centrality (MCC) algorithm. Furthermore, according to the Connectivity Map (CMap) and the Comparative Toxicogenomics Database (CTD), 10 possible drugs for fluorosis were predicted and screened, and a drug target ferroptosis-related gene network was constructed. Molecular docking was used to study the interaction between small molecule compounds and target proteins. Molecular dynamics (MD) simulation results show that the structure of the Celestrol–HMOX1 composite is stable and the docking effect is the best. In general, Celastrol and LDN-193189 may target ferroptosis-related genes to alleviate the symptoms of fluorosis, which may be effective candidate drugs for the treatment of fluorosis.
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