The dual role of FSP1 in programmed cell death: resisting ferroptosis in the cell membrane and promoting necroptosis in the nucleus of THP-1 cells.

BACKGROUND: Acute monocytic leukemia-M5 (AML-M5) remains a challenging disease due to its high morbidity and poor prognosis. In addition to the evidence mentioned earlier, several studies have shown that programmed cell death (PCD) serves a critical function in treatment of AML-M5. However, the role and relationship between ferroptosis and necroptosis in AML-M5 remains unclear. METHODS: THP-1 cells were mainly treated with Erastin and IMP-366. The changes of ferroptosis and necroptosis levels were detected by CCK-8, western blot, quantitative real-time PCR, and electron microscopy. Flow cytometry was applied to detect the ROS and lipid ROS levels. MDA, 4-HNE, GSH and GSSG were assessed by ELISA kits. Intracellular distribution of FSP1 was studied by immunofluorescent staining and western blot. RESULTS: The addition of the myristoylation inhibitor IMP-366 to erastin-treated acute monocytic leukemia cell line THP-1 cell not only resulted in greater susceptibility to ferroptosis characterized by lipid peroxidation, glutathione (GSH) depletion and mitochondrial shrinkage, as the FSP1 position on membrane was inhibited, but also increased p-RIPK1 and p-MLKL protein expression, as well as a decrease in caspase-8 expression, and triggered the characteristic necroptosis phenomena, including cytoplasmic translucency, mitochondrial swelling, membranous fractures by FSP1 migration into the nucleus via binding importin α2. It is interesting to note that ferroptosis inhibitor fer-1 reversed necroptosis. CONCLUSION: We demonstrated that inhibition of myristoylation by IMP-366 is capable of switching ferroptosis and ferroptosis-dependent necroptosis in THP-1 cells. In these findings, FSP1-mediated ferroptosis and necroptosis are described as alternative mechanisms of PCD of THP-1 cells, providing potential therapeutic strategies and targets for AML-M5.

The suppression of hyperlipid diet-induced ferroptosis of vascular smooth muscle cells protests against atherosclerosis independent of p53/SCL7A11/GPX4 axis.

Ferroptosis as a novel programmed cell death that involves metabolic dysfunction due to iron-dependent excessive lipid peroxidation has been implicated in atherosclerosis (AS) development characterized by disrupted lipid metabolism, but the atherogenic role of ferroptosis in vascular smooth muscle cells (VSMCs), which are principal components of atherosclerotic plaque fibrous cap, remains unclear. The aim of this study was to determine the effects of ferroptosis on AS induced by lipid overload, and the effects of that on VSMCs ferroptosis. We found intraperitoneal injection of Fer-1, a ferroptosis inhibitor, ameliorated obviously high-fat diet-induced high plasma levels of triglycerides, total cholesterol, low-density lipoprotein, glucose and atherosclerotic lesions in ApoE-/- mice. Moreover, in vivo and in vitro, Fer-1 reduced the iron accumulation of atherosclerotic lesions through affecting the expression of TFR1, FTH, and FTL in VSMCs. Interestingly, Fer-1 did augment nuclear factor E2-related factor 2/ferroptosis suppressor protein 1 to enhance endogenous resistance to lipid peroxidation, but not classic p53/SCL7A11/GPX4. Those observations indicated inhibition of VSMCs ferroptosis can improve AS lesions independent of p53/SLC7A11/GPX4, which preliminarily revealed the potential mechanism of ferroptosis in aortic VSMCs on AS and provided new therapeutic strategies and targets for AS.

Focus on ferroptosis, pyroptosis, apoptosis and autophagy of vascular endothelial cells to the strategic targets for the treatment of atherosclerosis.

Vascular endothelial cells (VECs), which are lined up in the inner surface of blood vessels, are in direct contact with the metabolite-related endogenous danger signals in the circulatory system. Moreover, VECs death impairs vasodilation and increases endothelium-dependent permeability, which is strongly correlated with the development of atherosclerosis (AS). Among several forms of cell death, regulatory death of endothelial cells frequently occurs in AS, mainly including ferroptosis, pyroptosis, apoptosis and autophagy. In this review, we summarize regulatory factors and signaling mechanisms of regulatory death in endothelial cells, discussing their effects in the context of the atherosclerotic procession.

Assessment of renal pathophysiological processes and protective effect of quercetin on contrast-induced acute kidney injury in type 1 diabetic mice using diffusion tensor imaging.

Purpose: To investigate the renal pathophysiological processes and protective effect of quercetin on contrast-induced acute kidney injury (CI-AKI) in mice with type 1 diabetic mellitus(DM) using diffusion tensor imaging(DTI).Methods: Mice with DM were divided into two groups. In the diabetic + contrast medium(DCA) group, the changes of the mice kidneys were monitored at 1, 24, 48, and 72 h after the injection of iodixanol(4gI/kg). The mice in the diabetic + contrast medium + quercetin(DCA + QE) group were orally given different concentrations of quercetin for seven days before injection of iodixanol. In vitro experiments, renal tubular epithelial (HK-2) cells exposed to high glucose conditions were treated with various quercetin concentrations before treatment with iodixanol(250 mgI/mL).Results: DTI-derived mean diffusivity(MD) and fractional anisotropy(FA) values can be used to evaluate CI-AKI effectively. Quercetin significantly increased the expression of Sirt 1 and reduced oxidative stress by increasing Nrf 2/HO-1/SOD1. The antiapoptotic effect of quercetin on CI-AKI was revealed by decreasing proteins level and by reducing the number of apoptosis-positive cells. In addition, flow cytometry indicated quercetin-mediated inhibition of M1 macrophage polarization in the CI-AKI.Conclusions: DTI will be an effective noninvasive tool in diagnosing CI-AKI. Quercetin attenuates CI-AKI on the basis of DM through anti-oxidative stress, apoptosis, and inflammation.

CXCL13-neutralizing Antibody Alleviate Chronic Skeletal Muscle Degeneration in a Mouse Model.

INTRODUCTION: Skeletal muscle degeneration is a common effect of chronic muscle injuries, including fibrosis and fatty infiltration, which is the replacement of preexisting parenchymal tissue by extracellular matrix proteins and abnormal invasive growth of fibroblasts and adipocytes. METHOD: This remodeling limits muscle function and strength, eventually leading to reduced quality of life for those affected. Chemokines play a major role in the regulation of immunocyte migration, inflammation, and tissue remodeling and are implicated in various fibrotic and degenerative diseases. In this study, we aimed to investigate the role of the B-cell chemokine CXCL13 in the gastrocnemius muscle of the Achilles tendon rupture model mouse. We hypothesize that CXCL13 may promote fibrosis and aggravate skeletal muscle degeneration. We performed RNA sequencing and bioinformatics analysis of gastrocnemius muscle from normal and model mice to identify differentially expressed genes and signal pathways related to skeletal muscle degeneration and fibrosis. RESULTS: Our results show that CXCL13 is highly expressed in chronically degenerating skeletal muscle. Furthermore, CXCL13-neutralising antibodies with therapeutic potential were observed to inhibit fibrosis and adipogenesis in vivo and in vitro. CONCLUSION: Our study reveals the underlying therapeutic implications of CXCL13 inhibition for clinical intervention in skeletal muscle degeneration, thereby improving patient prognosis.

P53: A Key Target in the Development of Osteoarthritis.

Osteoarthritis (OA), a chronic degenerative disease characterized mainly by damage to the articular cartilage, is increasingly relevant to the pathological processes of senescence, apoptosis, autophagy, proliferation, and differentiation of chondrocytes. Clinical strategies for osteoarthritis can only improve symptoms and even along with side effects due to age, sex, disease, and other factors. Therefore, there is an urgent need to identify new ideas and targets for current clinical treatment. The tumor suppressor gene p53, which has been identified as a potential target for tumor therapeutic intervention, is responsible for the direct induction of the pathological processes involved in OA modulation. Consequently, deciphering the characteristics of p53 in chondrocytes is essential for investigating OA pathogenesis due to p53 regulation in an array of signaling pathways. This review highlights the effects of p53 on senescence, apoptosis, and autophagy of chondrocytes and its role in the development of OA. It also elucidates the underlying mechanism of p53 regulation in OA, which may help provide a novel strategies for the clinical treatment of OA.

Exosome is a Fancy Mobile Sower of Ferroptosis.

Exosomes, nano-sized small extracellular vesicles, have been shown to serve as mediators between intercellular communications by transferring bioactive molecules, such as non-coding RNA, proteins, and lipids from secretory to recipient cells, modulating a variety of physiological and pathophysiological processes. Recent studies have gradually demonstrated that altered exosome charges may represent a key mechanism driving the pathological process of ferroptosis. This review summarizes the potential mechanisms and signal pathways relevant to ferroptosis and then discusses the roles of exosome in ferroptosis. As well as transporting iron, exosomes may also indirectly convey factors related to ferroptosis. Furthermore, ferroptosis may be transmitted to adjacent cells through exosomes, resulting in cascading effects. It is expected that further research on exosomes will be conducted to explore their potential in ferroptosis and will lead to the creation of new therapeutic avenues for clinical diseases.

Ferroptosis: the potential value target in atherosclerosis.

In advanced atherosclerosis (AS), defective function-induced cell death leads to the formation of the characteristic necrotic core and vulnerable plaque. The forms and mechanisms of cell death in AS have recently been elucidated. Among them, ferroptosis, an iron-dependent form of necrosis that is characterized by oxidative damage to phospholipids, promotes AS by accelerating endothelial dysfunction in lipid peroxidation. Moreover, disordered intracellular iron causes damage to macrophages, vascular smooth muscle cells (VSMCs), vascular endothelial cells (VECs), and affects many risk factors or pathologic processes of AS such as disturbances in lipid peroxidation, oxidative stress, inflammation, and dyslipidemia. However, the mechanisms through which ferroptosis initiates the development and progression of AS have not been established. This review explains the possible correlations between AS and ferroptosis, and provides a reliable theoretical basis for future studies on its mechanism.