Nephrotoxicity is a critical adverse event that leads to discontinuation of kinase inhibitor (KI) treatment. Here we show, through meta-analyses of FDA Adverse Event Reporting System, that dasatinib is associated with high risk for glomerular toxicity that is uncoupled from hypertension, suggesting a direct link between dasatinib and podocytes. We further investigate the cellular effects of dasatinib and other comparable KIs with varying risks of nephrotoxicity. Dasatinib treated podocytes show significant changes in focal adhesions, actin cytoskeleton, and morphology that are not observed with other KIs. We use phosphoproteomics and kinome profiling to identify the molecular mechanisms of dasatinib-induced injury to the actin cytoskeleton, and atomic force microscopy to quantify impairment to cellular biomechanics. Furthermore, chronic administration of dasatinib in mice causes reversible glomerular dysfunction, loss of stress fibers, and foot process effacement. We conclude that dasatinib induces nephrotoxicity through altered podocyte actin cytoskeleton, leading to injurious cellular biomechanics.
Sepsis-induced brain injuries increase mortality, morbidity, cognitive impairment and lack of effective therapeutic treatment. Previous studies have suggested that metformin provides neuroprotective effects against ischemia, brain trauma and other brain damage, but whether metformin protects a septic brain remains unknown. Thus, the aim of this study is to investigate the possible effects and the mechanism of metformin against septic brain damage using the cecal ligation and puncture (CLP) model. Mice were randomly divided into five groups: the Sham group, CLP group, CLP+ Met group, CLP+ vehicle group and CLP+ Met+ LY group. The survival percentage and brain water content were examined, and the Morris water maze was conducted to determine the protective effect of metformin. Neuronal apoptosis in the cerebral cortex, striatum and hippocampus was examined using TUNEL assay and immunohistochemistry, and western blot was applied to measure the expression of p-Akt. The results indicate that metformin can increase survival percentage, decrease brain edema, preserve the blood-brain barrier (BBB) and improve cognitive function. Metformin also reduced the neuronal apoptosis induced by sepsis and increased the phosphorylation of Akt. However, the protective effect of metformin can be reversed by LY294002, a PI3K inhibitor. In summary, our results demonstrate that metformin can exert a neuroprotective effect by activating the PI3K/Akt signaling pathway.
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