Overexpressing SIRT6 can Attenuate the Injury of Intracerebral Hemorrhage by Down-Regulating NF-kB.

Sirtuin-6 (SIRT6), a member of the sirtuins family of NAD ( +) dependent deacetylases, has been shown to have beneficial effects in ischemic stroke. However, the role of SIRT6 in intracerebral haemorrhage (ICH) has not reported. We observed that SIRT6 expression was down-regulated in human ICH patients and down-regulated in ICH-induced rat cortical neurons. We subsequently found that SIRT6 overexpression reduced brain tissue damage and increased neuronal survival in the ICH model of rats and hemin-induced cortical neurons. Our further study found that overexpression of SIRT6 can reduce inflammatory response by down-regulating the expression of NF-kB and thus promote the recovery of neurological function in ICH animals. In conclusion, SIRT6 can inhibit the expression of NF-kB and plays a neuroprotective role in ICH by inhibiting the NF-kB-mediated inflammatory response.SIRT6 could be a novel therapeutic target for ICH.

Transcranial direct-current stimulation protects against cerebral ischemia-reperfusion injury through regulating Cezanne-dependent signaling.

Transcranial direct-current stimulation (tDCS) is proved safe and shows therapeutic effect in cerebral ischemic stroke in clinical trials. But the underlying molecular mechanisms remain unclear. Here we show that tDCS treatment reduces the infarct volume after rat cerebral ischemia-reperfusion (I/R) injury and results in functional improvement of stroke animals. At the cellular and molecular level, tDCS suppresses I/R-induced upregulation of Cezanne in the ischemic neurons. Cezanne inhibition confers neuroprotection after rat I/R and oxygen glucose deprivation (OGD) in the cortical neuronal cultures. Inhibiting Cezanne increases the level of SIRT6 that is downregulated in the ischemic neurons. Suppressing SIRT6 blocks Cezanne inhibition-induced neuroprotective effect and overexpressing SIRT6 attenuates OGD-induced neuronal death. We further show that downregulating Cezanne reduces DNA double-strand break (DSB) through upregulation of SIRT6 in OGD-insulted neurons. Together, this study suggests that Cezanne-dependent SIRT6-DNA DSB signaling pathway may mediate the neuroprotective effect of tDCS in ischemic neurons.

ACSL4 suppresses glioma cells proliferation via activating ferroptosis.

Acyl­CoA synthetase long­chain family member 4 (ACSL4) is a member of the long chain family of acyl­CoA synthetase proteins, which have recently been shown to serve an important role in ferroptosis. Previous studies have suggested that ferroptosis is involved in the occurrence of glioma; however, the role of ACSL4 in glioma remains unknown. In the present study, a reduction of ferroptosis in human glioma tissues and glioma cells was observed. Subsequently, it was demonstrated that the expression of ACSL4 was also downregulated in human glioma tissues and cells. A ferroptosis inhibitor and inducer were used to investigate the effects of ferroptosis on viability. The results showed that promoting ferroptosis inhibited the proliferation of glioma cells, and that the use of inducers had the reverse effect. Therefore, it was hypothesized that the reduction in ACSL4 expression may have been involved in ferroptosis and proliferation in glioma. Overexpression of ACSL4 decreased expression of glutathione peroxidase 4 and increased the levels of ferroptotic markers, including 5­hydroxyeicosatetraenoic (HETE), 12­HETE and 15­HETE. Additionally, ACSL4 overexpression resulted in an increase in lactate dehydrogenase release and a reduction in cell viability. The opposite results were observed when ACSL4 was silenced. These findings suggest that ACSL4 regulates ferroptosis and proliferation of glioma cells. To further investigate the mechanism underlying ACSL4­mediated regulation of proliferation in glioma cells, cells were treated with small interfering (si)­ACSL4 and sorafenib, a ferroptosis inducer. sorafenib attenuated the ability of siRNA­mediated silencing of ACSL4, thus improving cell viability. These results demonstrate that ACSL4 protects glioma cells and exerts anti­proliferative effects by activating a ferroptosis pathway and highlight the pivotal role of ferroptosis regulation by ACSL4 in its protective effects on glioma. Therefore, ACSL4 may serve as a novel therapeutic target for the treatment of glioma.