Erianin induces ferroptosis in GSCs via REST/LRSAM1 mediated SLC40A1 ubiquitination to overcome TMZ resistance.

In recent studies, erianin, a natural product isolated from Dendrobium chrysotoxum Lindl, has exhibited notable anticancer properties. Ferroptosis, a novel form of programmed cell death, holds potential as a strategy to overcome Temozolomide (TMZ) resistance in glioma by inducing ferroptosis in TMZ-resistant glioma cells. Here, utilizing various phenotyping experiments, including cell counting kit-8 (CCK-8) assays, EdU assays, transwell assays, neurosphere formation assays and extreme limiting dilution (ELDA) assays, we demonstrated that erianin exerts its anticancer activity on both TMZ sensitive and TMZ-resistant glioma stem cells (GSCs). Furthermore, we made an exciting discovery that erianin enhances TMZ sensitivity in TMZ-resistant GSCs. Subsequently, we demonstrated that erianin induced ferroptosis in TMZ-resistant GSCs and enhances TMZ sensitivity through inducing ferroptosis, which was confirmed by intracellular measurements of ROS, GSH, and MDA, as well as through the use of BODIPY (581/591) C11 and transmission electron microscopy. Conversely, the ferroptosis inhibitor ferrostatin-1 (Fer-1) blocked the effects of erianin. The underlying mechanism of ferroptosis induced by erianin was further explored through co-immunoprecipitation (Co-IP) assays, ubiquitination assays, protein stability assessments, chromatin immunoprecipitation (ChIP) assays and luciferase reporter gene assays. We found that erianin specifically targets REST, inhibiting its transcriptional repression function without altering its expression levels. Consequently, this suppression of REST's role leads to an upregulation of LRSAM1 expression. In turn, LRSAM1 ubiquitinates and degrades SLC40A1, a protein that inhibits ferroptosis by exporting ferrous ions. By downregulating SLC40A1, erianin ultimately induces ferroptosis in TMZ-resistant GSCs. Taken together, our research demonstrates that the natural product erianin inhibits the malignant phenotype of GSCs and increases the sensitivity of TMZ in TMZ-resistant GSCs by inducing ferroptosis. These findings suggest erianin as a prospective compound for the treatment of TMZ-resistant glioma.

Correlations of serum cystatin C, lipids with intracranial aneurysm rupture / 国际脑血管病杂志

Objective:To investigate the correlation between serum cystatin C (CysC), blood lipids and the risk of intracranial aneurysm (IA) rupture.Methods:Patients with saccular IA admitted to the First Affiliated Hospital of Xinjiang Medical University from December 2017 to May 2019 were enrolled retrospectively. The patients were divided into the ruptured group and the unruptured group. The correlation between CysC, lipids and IA rupture was identified by univariate and multivariate logistic regression analyses. Results:A total of 392 patients were enrolled, including 143 (36.5%) males and 249 (63.5%) females. Two hundred and seventy-eight patients (70.9%) were ruptured IAs, 114 (29.1%) were unruptured IAs. Univariate analysis showed that triglyceride (1.26±0.94 mmol/L vs. 2.12±1.45 mmol/L; t=5.872, P<0.001), apolipoprotein A-Ⅰ (0.95±0.29 g/L vs. 1.08±0.34 g/L; t=3.744, P<0.001 ), CysC (0.63±0.20 mg/L vs. 0.80±0.48 mg/L; t=3.650, P<0.001) level, and the proportions of hypertension (46.8% vs. 61.4%; χ2=6.938, P=0.008), hyperlipidemia (19.4% vs. 48.2%; χ2=32.493, P<0.001) and aneurysm diameter >7 mm (24.4% vs. 41.2%; χ2=11.504, P<0.001) of the ruptured group were significantly lower than those of the unruptured group, while the level of apolipoprotein B was significantly higher than that of the unruptured group (1.07±0.29 g/L vs. 0.99±0.30 g/L; t=2.417, P=0.016). Multivariate logistic regression analysis showed that aneurysm diameter ≤7 mm (odds ratio [ OR] 2.281, 95% confidence interval [ CI] 1.342-3.876; P=0.002), and the serum levels of triacylglycerol ( OR 0.484, 95% CI 0.333-0.705; P<0.001), apolipoprotein A-Ⅰ ( OR 0.248, 95% CI 0.105-0.587; P=0.002) and CysC ( OR 0.130, 95% CI 0.038-0.444; P=0.001) were significantly independently correlated with the risk of IA rupture. Conclusions:CysC, apolipoprotein A-Ⅰ and triacylglycerol are protective markers for IA rupture, and aneurysm diameter ≤7 mmis associated with IA rupture.