DNA methylation landscape reveals GNAS as a decitabine-responsive marker in patients with acute myeloid leukemia

Background: The demethylation agent decitabine (DAC) is a pivotal non-intensive alternative treatment for acute myeloid leukemia (AML). However, patient responses to DAC are highly variable, and predictive biomarkers are warranted. Herein, the DNA methylation landscape of patients treated with a DAC-based combination regimen was compared with that of patients treated with standard chemotherapy to develop a molecular approach for predicting clinical response to DAC. Methods: Twenty-five non-M3 AML patients were enrolled and subjected to DNA methylation sequencing and profiling to identify differentially methylated regions (DMRs) and genes of interest. Moreover, the effects of a DAC-based regimen on apoptosis and gene expression were explored using Kasumi-1 and K562 cells. Results: Overall, we identified 541 DMRs that were specifically responsive to DAC, among which 172 DMRs showed hypomethylation patterns upon treatment and were aligned with the promoter regions of 182 genes. In particular, GNAS was identified as a critical DAC-responsive gene, with in vitro GNAS downregulation leading to reduced cell apoptosis induced by DAC and cytarabine combo treatment. Conclusions: We found that GNAS is a DAC-sensitive gene in AML and may serve as a prognostic biomarker to assess the responsiveness of patients with AML to DAC-based therapy

DHPA Protects SH-SY5Y Cells from Oxidative Stress-Induced Apoptosis via Mitochondria Apoptosis and the Keap1/Nrf2/HO-1 Signaling Pathway

Oxidative stress in the brain is highly related to the pathogenesis of Alzheimer’s disease (AD). It could be induced by the overproduction of reactive oxygen species (ROS), produced by the amyloid beta (Aβ) peptide and excess copper (Cu) in senile plaques and cellular species, such as ascorbic acid (AA) and O2. In this study, the protective effect of 5-hydroxy-7-(4′-hydroxy-3′-methoxyphenyl)-1-phenyl-3-heptanone (DHPA) on Aβ(1–42)/Cu2+/AA mixture-treated SH-SY5Y cells was investigated via in vitro and in silico studies. The results showed that DHPA could inhibit Aβ/Cu2+/AA-induced SH-SY5Y apoptosis, OH· production, intracellular ROS accumulation, and malondialdehyde (MDA) production. Further research demonstrated that DHPA could decrease the ratio of Bax/Bcl-2 and repress the increase of mitochondrial membrane potential (MMP) of SH-SY5Y cells, to further suppress the activation of caspase-3, and inhibit cell apoptosis. Meanwhile, DHPA could inhibit the Aβ/Cu2+/AA-induced phosphorylation of Erk1/2 and P38 in SH-SY5Y cells, and increase the expression of P-AKT. Furthermore, DHPA could bind to Keap1 to promote the separation of Nrf2 to Keap1 and activate the Keap1/Nrf2/HO-1 signaling pathway to increase the expression of heme oxygenase-1 (HO-1), quinone oxidoreductase-1 (NQO1), glutathione (GSH), and superoxide dismutase (SOD). Thus, our results demonstrated that DHPA could inhibit Aβ/Cu2+/AA-induced SH-SY5Y apoptosis via scavenging OH·, inhibit mitochondria apoptosis, and activate the Keap1/Nrf2/HO-1 signaling pathway

Author Correction: EpCAM-dependent extracellular vesicles from intestinal epithelial cells maintain intestinal tract immune balance

An amendment to this paper has been published and can be accessed via a link at the top of the paper