Despite the high efficacy and safety of arsenic trioxide (ATO) in treating acute promyelocytic leukemia (APL) and eradicating APL leukemia-initiating cells (LICs), the mechanism underlying its selective cytotoxicity remains elusive. We have recently demonstrated that APL cells undergo a novel cell death program, termed ETosis, through autophagy. However, the role of ETosis in ATO-induced APL LIC eradication remains unclear. For this study, we evaluated the effects of ATO on ETosis and the contributions of drug-induced ETosis to APL LIC eradication. In NB4 cells, ATO primarily increased ETosis at moderate concentrations (0.5–0.75 μM) and stimulated apoptosis at higher doses (1.0–2.0 μM). Furthermore, ATO induced ETosis through mammalian target of rapamycin (mTOR)-dependent autophagy, which was partially regulated by reactive oxygen species. Additionally, rapamycin-enhanced ATO-induced ETosis in NB4 cells and APL cells from newly diagnosed and relapsed patients. In contrast, rapamycin had no effect on apoptosis in these cells. We also noted that PML/RARA oncoprotein was effectively cleared with this combination. Intriguingly, activation of autophagy with rapamycin-enhanced APL LIC eradication clearance by ATO in vitro and in a xenograft APL model, while inhibition of autophagy spared clonogenic cells. Our current results show that ATO exerts antileukemic effects at least partially through ETosis and targets LICs primarily through ETosis. Addition of drugs that target the ETotic pathway could be a promising therapeutic strategy to further eradicate LICs and reduce relapse.

Objective To investigate the expression of HOX transcript antisense RNA (HOTAIR) in cardiac tissues and plasma of patients with congenital heart diseases (CHDs). Methods qRT-PCR was used to detect the expression of HOTAIR in right atrial appendage tissues of 16 patients with CHDs and 14 patients with rheumatic valvular heart diseases (RVHDs), as well as in plasma of 36 normal people and 90 patients with CHDs including 36 cases of ASD, 23 cases of VSD, and 31 cases of PDA. Besides, the proteins interacting with HOTAIR were obtained from databases. Results The HOTAIR expression in cardiac tissues of CHDs group was significantly higher than that of the RVHDs group (P < 0.01). Compared with the control group, the expression of plasma HOTAIR in the ASD group, the VSD group, and the PDA group was all remarkably upregulated (P < 0.01), whereas there was no relationship between HOTAIR and pulmonary arterial hypertension and defects size. Databases show that HOTAIR is associated with polycomb repressive complex 2 (PRC2) which contributes to heart development. Conclusion The levels of HOTAIR were increased in cardiac tissues and plasma of patients with CHDs. HOTAIR is a potential novel diagnostic biomarker in patients with CHDs.

The cytoskeleton serves an important role in maintaining cellular morphology and function, and it is a substrate of calpain during myocardial ischemia/reperfusion (I/R) injury (MIRI). Calpain may be activated by endoplasmic reticulum (ER) stress during MIRI. The activation of peroxisome proliferator-activated receptor α (PPARα) may inhibit ischemia/reperfusion damage by regulating stress reactions. The present study aimed to determine whether the activation of PPARα protects against MIRI-induced cytoskeletal degradation, and investigated the underlying mechanism involved. Wistar rats were pretreated with or without fenofibrate and subjected to left anterior descending coronary artery ligation for 45 min, followed by 120 min of reperfusion. Calpain activity and the expression of PPARα, desmin and ER stress parameters were evaluated. Electrocardiography was performed and cardiac function was evaluated. The ultrastructure was observed under transmission electron microscopy. I/R significantly induced damage to the cytoskeleton in cardiomyocytes and cardiac dysfunction, all of which were improved by PPARα activation. In addition, I/R increased ER stress and calpain activity, which were significantly decreased in fenofibrate-pretreated rat heart tissue. The results suggested that PPARα activation may exert a protective effect against I/R in the myocardium, at least in part via ER stress inhibition. Suppression of ER stress may be an effective therapeutic target for protecting the I/R myocardium.

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