Tregs depletion aggravates activation of astrocytes by modulating IL-10/GXP4 following cerebral infarction.

Background: Tregs plays a critical role in the development of secondary injuries in diseases. Accumulating evidence suggests an association between ischemic stroke and renal dysfunction; however, the underlying mechanisms remain unclear. This study aimed to investigate the potential of Tregs in inhibiting the activation of astrocytes after focal cerebral infarction. Methods: This study aimed to investigate the renal consequences of focal cerebral ischemia by subjecting a mouse model to transient middle cerebral artery occlusion (tMCAO). Subsequently, we assessed renal fibrosis, renal ferroptosis, Treg infiltration, astrocyte activation, as well as the expression levels of active GPX4, FSP1, IL-10, IL-6, and IL-2 after a 2-week period. Results: In the tMCAO mouse model, depletion of tregs protected against activation of astrocyte and significantly decreased FSP1, IL-6, IL-2, and NLRP3 expression levels, while partially reversing the changes in Tregs. Mechanistically, tregs depletion attenuates renal fibrosis by modulating IL-10/GPX4 following cerebral infarction. Conclusion: Tregs depletion attenuates renal fibrosis by modulating IL-10/GPX4 following cerebral infarction.

Feedback autophagy activation as a key resistance factor of Ku-0060648 in colorectal cancer cells.

The current study evaluated the potential anti-colorectal cancer (CRC) activity by Ku-0060648, a novel DNA-PKcs and PI3K duel inhibitor. In both CRC cell lines (HCT-116 and HT-29) and primary human colon cancer cells, Ku-0060648 exposure at nM concentrations efficiently inhibited cell proliferation. Meanwhile, Ku-0060648 provoked apoptosis in CRC cells. Ku-0060648 was yet ineffective to the normal colon epithelial cells. Ku-0060648 blocked PI3K-AKT-mTOR cascade and in-activated DNA-PKcs in CRC cells. Intriguingly, Ku-0060648 treatment induced feedback autophagy activation in HCT-116 cells. On the other hand, pharmacological autophagy inhibitors (3-methyladenine or chloroquine) or silencing key autophagy proteins (Beclin-1 or ATG-7) dramatically potentiated Ku-0060648-induced HCT-116 cell apoptosis. Together, these results suggest that feedback autophagy activation is a key resistance factor of Ku-0060648 in CRC cells, and autophagy inhibition sensitizes Ku-0060648-induced anti-CRC activity.