Activation of the Akt/mTOR signaling pathway:a potential response to long-term neuronal loss in the hippocampus after sepsis

Survivors of sepsis may suffer chronic cognitive impairment as a long-term sequela. However, the precise mechanisms of cognitive dys- function after sepsis are not well understood. We employed the cecal ligation-and-puncture-induced septic mouse model. We observed elevated phosphorylation of Akt, mammalian target of rapamycin （roTOR） and p70S6K on days 14 and 60, progressive neuronal loss in the cornu ammonis 1 region, and abnormal neuronal morphology in the hippocampus in the sepsis mouse model, These findings indicate that changes in neuronal morphology and number in the hippocampus after sepsis were associated with strong activation of the Akt/mTOR sig- naling pathway, and may reflect a ＂self-rescuing＂ feedback response to neuronal loss after sepsis.

Phosphorylated p70S6K in urothelial carcinoma of the tumor recurrence noninvasive low-grade bladder： correlation with

We investigated whether inhibiting phosphorylated p70S6K （p-p70S6K） suppresses the proliferation and growth of noninvasive low-grade urothelial carcinoma （LG-URCa） in vitro and whether p-p70S6K can serve as a predictive biomarker for the recurrence of noninvasive LG-URCa of the bladder in patients. We constructed a tissue microarray （TMA） for 95 LG-URCa and 35 benign urothelium samples and performed immunohistochemical staining for p-p70S6K and p-4E-BP1. A Cox regression model was used to investigate the predictive factors for recurrence of LG-URCa. We investigated the dose-dependent antiproliferative effect of rapamycin, its antiproliferative effect and the growth-inhibition effect of p70S6K siRNA transfection in RT4 and 253J cell lines. The pT1 staged group （P 〈 0.05; hazard ratio （HR）, 2.415） and the high p-p70S6K staining group （P 〈 0.05; HR, 2.249） were independent factors for predicting recurrence. Rapamycin inhibited RT4 and 253J cell proliferation in a dose-dependent manner （r = -0.850, P 〈 0.001 in RT4 cells; r = -0.835, P 〈 0.001 in 253J cells）. RT4 and 253J cell proliferation and growth were inhibited by the transfection of p70S6K siRNA and rapamycin, respectively （P 〈 0.05）. Transfection of p70S6K siRNA resulted in inhibitory effects on cell proliferation and growth that were similar to those of rapamycin. Our results suggest that inhibiting p70S6K phosphorylation is important to prevent recurrence and that p70S6K phosphorylation can be used as a molecular biomarker to predict recurrence of certain LG-URCa of the bladder.