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Protein aggregation has been proved to be a pathological basis accounting for neuronal death caused by either transient global ischemia or oxygen glucose deprivation (OGD), and inhibition of protein aggregation is emerging as a potential strategy of preventing brain damage. Trehalose was found to inhibit protein aggregation caused by neurodegenerative diseases via induction of autophagy, whereas its effect is still elusive on ischemia-induced protein aggregation. In this study, we investigated this issue by using rat model of transient global ischemia and SH-SY5Y model of OGD. We found that pretreatment with trehalose inhibited transient global ischemia-induced neuronal death in the hippocampus CA1 neurons and OGD-induced death in SH-SY5Y cells, which was associated with inhibition of the formation of ubiquitin-labeled protein aggregates and preservation of proteasome activity. In vitro study showed that the protection of trehalose against OGD-induced cell death and protein aggregation in SH-SY5Y cells was reversed when proteasome activity was inhibited by MG-132. Further studies revealed that trehalose prevented OGD-induced reduction of proteasome activity via suppression of both oxidative stress and endoplasmic reticulum stress. Particularly, our results showed that trehalose inhibited OGD-induced autophagy. Therefore, we demonstrated that proteasome dysfunction contributed to protein aggregation caused by ischemic insults and trehalose prevented protein aggregation via preservation of proteasome activity, not via induction of autophagy.

Gliomas are malignant primary brain tumors with high morbidity. This tumor has a feature of resistance to chemotherapy and radiotherapy and the underlying mechanism is not yet clear. Autophagy is an evolutionarily conserved process of cytoplasm and cellular organelle in lysosome degradation. Under poor conditions, cells use autophagy to recycle cellular components to sustain metabolism and to prevent the accumulation of damaged, toxic proteins and organelles. More and more recent experimental results suggest that autophagy allows tumor cells survive gene therapy, chemotherapy or nutrient deficient environment. Therefore, we propose the hypothesis that autophagy may be one of the factors influencing on malignant glioma's resistance to therapy. Although there is not yet reaching an agreement about the effects of autophagy on tumor cells survival and death and much more studies are needed to prove the effects of autophagy on malignant gliomas, it gives us a new direction to investigate the mechanism underlying therapy resistance of malignant gliomas.

RSL3 is a type of small molecular compound which can inactivate glutathione peroxidase 4 (GPX4) and induce ferroptosis, but its role in glioma cell death remains unclear. In this study, we found RSL3 inhibited the viabilities of glioma cells and induced glioma cell death in a dose-dependent manner. In vitro studies revealed that RSL3-induced cell death was accompanied with the changes of autophagy-associated protein levels and was alleviated by pretreatment of 3-Methyladenine, bafilomycin A1 and knockdown of ATG5 with siRNA. The ATP and pyruvate content as well as the protein levels of HKII, PFKP, PKM2 were decreased in cells treated by RSL3, indicating that RSL3 induced glycolysis dysfunction in glioma cells. Moreover, supplement of exterior sodium pyruvate, which was a final product of glycolysis, not only inhibited the changes of autophagy-associated protein levels caused by RSL3, but also prevented RSL3-induced cell death. In vivo data suggested that the inhibitory effect of RSL3 on the growth of glioma cells was associated with glycolysis dysfunction and autophagy activation. Taken together, RSL3 induced autophagic cell death in glioma cells via causing glycolysis dysfunction. • RSL3 inhibited glioma cellular viabilities and induced glioma cell death. • RSL3 activated autophagy in glioma cells in vivo and in vitro. • RSL3 induced glycolysis dysfunction in glioma cells in vivo and in vitro. • Supplement of pyruvate prevented RSL3-induced autophagic cell death. [ABSTRACT FROM AUTHOR]