Leukemia is a fatal hematopoietic disorder with a poor prognosis. Drug resistance is inevitable after the long-term use of chemotherapeutic agents. Liproxstatin-1, commonly known as a ferroptosis inhibitor, has never been reported to have anticancer effects. In the present study, the antileukemic role of liproxstatin-1 in K562 leukemia cells was investigated. Liproxstatin-1 inhibited K562 cell proliferation in a dose-and time-dependent manner. RNA sequencing revealed several pathways that were affected by liproxstatin-1, such as the G1/S transition of the mitotic cell cycle and extrinsic or intrinsic apoptotic signaling pathways. The results of flow cytometry indicated that liproxstatin-1 arrests the cell cycle at the G1 phase, and even at the G2/M phase. p21 WAF1/CIP1 , a cyclin-dependent kinase inhibitor, was upregulated. It was also determined that liproxstatin-1 induced BAX and TNF-α expression, which was accompanied by cleavage of caspase-3 and PARP. The caspase-3-specific inhibitor z-DEVD-FMK rescued some of the apoptotic cells. Interestingly, K562 cells were characterized by swelling and plasma membrane rupture when treated with a high concentration of liproxstatin-1, which was inconsistent with the typical apoptotic appearance. Thus, it was hypothesized that apoptosis-mediated pyroptosis occurs during liproxstatin-1-induced cell death. The expression of the hallmark of pyroptosis, the cleaved N-terminal GSDME, increased. Additionally, it was observed that endoplasmic reticulum stress and autophagy were involved in liproxstatin-1-induced cell death. Collectively, liproxstatin-1 induced cell cycle arrest, apoptosis, and caspase-3/GSDME-dependent secondary pyroptosis in K562 leukemia cells, which provides new hope for the treatment of leukemia.
Background Early exercise for acute deep venous thrombosis (DVT) improves the patient’s symptoms and does not increase the risk of pulmonary embolism. However, information about its effect on thrombus resolution is limited. The aim of this study was to investigate the role of resistance exercise (RE) in thrombus resolution and recanalization and determine its underlying mechanisms. Methods Ninety-six C57BL/6 J mice were randomly divided into four groups: Control group (C, n = 24); DVT group (D, n = 24); RE + DVT group (ED, n = 24); and inhibitor + RE + DVT group (IED, n = 24). A DVT model was induced by stenosis of the inferior vena cava (IVC). After undergoing IVC ultrasound within 24 h post-operation to confirm DVT formation, mice without thrombosis were excluded. Other mice were sacrificed and specimens were obtained 14 or 28 days after operation. Thrombus-containing IVC was weighed, and the thrombus area and recanalization rate were calculated using HE staining. Masson’s trichrome staining was used to analyze the collagen content. RT-PCR and ELISA were performed to examine IL-6, TNF-α, IL-10, and VEGF expression levels. SIRT1 expression was assessed using immunohistochemistry staining and RT-PCR. VEGF-A protein expression and CD-31-positive microvascular density (MVD) in the thrombus were observed using immunohistochemistry. Results RE did not increase the incidence of pulmonary embolism. It reduced the weight and size of the thrombus and the collagen content. Conversely, it increased the recanalization rate. It also decreased the levels of the pro-inflammatory factors IL-6 and TNF-α and increased the expression levels of the anti-inflammatory factor IL-10. RE enhanced VEGF and SIRT1 expression levels and increased the MVD in the thrombosis area. After EX527 (SIRT1 inhibitor) was applied, the positive effects of exercise were suppressed. Conclusions RE can inhibit inflammatory responses, reduce collagen deposition, and increase angiogenesis in DVT mice, thereby promoting thrombus resolution and recanalization. Its underlying mechanism may be associated with the upregulation of SIRT1 expression.
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