HIF-1α/BNIP3 mediated endoplasmic reticulum degradation via autophagy protects against ischemia reperfusion-induced acute kidney injury.

Endoplasmic reticulum (ER) degradation via autophagy is a process that maintains ER homeostasis when cells are in a state of stress and is associated with many diseases; however, the role of hypoxia inducible factor-1α (HIF-1α)-mediated ER degradation and the related regulatory pathway in acute kidney injury (AKI) still needs to be further established. In the present study, an in vivo AKI model was induced in mice via the ischemia‒reperfusion (IR) method. The results revealed that HIF-1α and BNIP3 were increased, and autophagy and ER degradation were activated in the kidneys of AKI mice, whereas HIF-1α knockout significantly inhibited BNIP3, autophagy and ER degradation, accompanied by aggravated kidney injury. Overexpression of HIF-1α in vitro significantly increased BNIP3, autophagy and ER degradation, whereas inhibition of BNIP3 significantly reversed the effects of HIF-1α. In addition, the in vitro inhibition of autophagy with chloroquine significantly reversed the effects of HIF-1α on cell apoptosis. Moreover, selectively overexpressing BNIP3 on the ER membrane significantly increased ER degradation via autophagy and decreased cell apoptosis in vitro. These data indicate that HIF-1α/BNIP3-mediated ER degradation via autophagy in tubular cells protects against IR-induced AKI.

Design, synthesis and biological evaluation of Nrf2 modulators for the treatment of glioblastoma multiforme.

Glioblastoma multiforme (GBM) is a prevalent primary brain tumor. However, no specific therapeutic drug has been developed for it. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a crucial transcription factor involved in the cellular response to oxidative stress. Numerous studies have demonstrated that Nrf2 plays a pivotal role in GBM angiogenesis, and inhibiting Nrf2 can significantly enhance patient prognosis. Using virtual screening technology, we examined our in-house library and identified pinosylvin as a potential compound with high activity. Pinosylvin exhibited robust hydrogen bond and Π-Π interaction with Nrf2. Cell experiments revealed that pinosylvin effectively reduced the proliferation of U87 tumor cells by regulating Nrf2 and demonstrated greater inhibitory activity than temozolomide. Consequently, we believe that this study will offer valuable guidance for the future development of highly efficient therapeutic drugs for GBM.