Red clover (Trifolium pratense L.) extract inhibits ferroptotic cell death by modulating cellular iron homeostasis
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE221119 | GEO | 2023/12/01
REPOSITORIES: GEO
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Project description:Red clover (Trifolium pratense L.) extract inhibits ferroptotic cell death by modulating cellular iron homeostasis
| PRJNA913001 | ENA
Project description:One of the most critical axes for cell fate determination is how cells respond to excessive reactive oxygen species (ROS)-oxidative stress. Extensive lipid peroxidation commits cells to death via a distinct cell death paradigm termed ferroptosis. However, the molecular mechanism regulating cellular fates to distinct ROS remains incompletely understood. Through siRNA against human receptor-interacting protein kinases (RIPK) family members, we discovered that RIPK4 is crucial for oxidative stress and ferroptotic death. Upon ROS induction, RIPK4 is rapidly activated and the kinase activity of RIPK4 is indispensable to induce cell death. Specific ablation of RIPK4 in kidney proximal tubules protects mice from acute kidney injury induced by cisplatin and renal ischemia/reperfusion. RNA sequencing revealed the dramatically decreased expression of acyl-CoA synthetase medium-chain (ACSM) family members induced by cisplatin treatment which is compromised in RIPK4 deficient mice. Among these ACSM family members, suppression of ACSM1 strongly augments oxidative stress and ferroptotic cell death with induced expression of ACSL4, an important component for ferroptosis execution. Our lipidome analysis revealed that over-expression of ACSM1 leads to the accumulation of monounsaturated fatty acids (MUFAs), attenuation of polyunsaturated fatty acids (PUFAs) production, and thereby cellular resistance to ferroptosis. Hence, knock-down ACSM1 re-sensitizes RIPK4 KO cells to oxidative stress and ferroptotic death. In conclusion, RIPK4 is a key player involved in oxidative stress and ferroptotic death, which is potentially important for a broad spectrum of human pathologies. The link between RIPK4-ASCM1 axis to PUFAs and ferroptosis reveals a novel mechanism to oxidative stress induced necrosis and ferroptosis.
2024-09-04 | GSE276038 | GEO
Project description:Oxidative stress has been shown to induce cell death in a wide range of human diseases including cardiac ischemia/reperfusion injury, drug induced cardiotoxicity, and heart failure. However, the mechanism of cell death induced by oxidative stress remains incompletely understood. Here we provide new evidence that oxidative stress primarily induces ferroptosis, but not apoptosis, necroptosis, or mitochondria-mediated necrosis, in cardiomyocytes. Intriguingly, oxidative stress induced by organic oxidants such as tert-butyl hydroperoxide (tBHP) and cumene hydroperoxide (CHP), but not hydrogen peroxide (H2O2), promoted glutathione depletion and glutathione peroxidase 4 (GPX4) degradation in cardiomyocytes, leading to increased lipid peroxidation. Moreover, elevated oxidative stress is also linked to labile iron overload through downregulation of the transcription suppressor BTB and CNC homology 1 (Bach1), upregulation of heme oxygenase 1 (HO-1) expression, and enhanced iron release via heme degradation. Strikingly, oxidative stress also promoted HO-1 translocation to mitochondria, leading to mitochondrial iron overload and lipid reactive oxygen species (ROS) accumulation. Targeted inhibition of mitochondrial iron overload or ROS accumulation, by overexpressing mitochondrial ferritin (FTMT) or mitochondrial catalase (mCAT), respectively, markedly inhibited oxidative stress-induced ferroptosis. The levels of mitochondrial iron and lipid peroxides were also markedly increased in cardiomyocytes subjected to simulated ischemia and reperfusion (sI/R) or the chemotherapeutic agent doxorubicin (DOX). Overexpressing FTMT or mCAT effectively prevented cardiomyocyte death induced by sI/R or DOX. Taken together, oxidative stress induced by organic oxidants but not H2O2 primarily triggers ferroptotic cell death in cardiomyocyte through GPX4 and Bach1/HO-1 dependent mechanisms. Our results also reveal mitochondrial iron overload via HO-1 mitochondrial translocation as a key mechanism as well as a potential molecular target for oxidative stress-induced ferroptosis in cardiomyocytes.
| S-EPMC10509277 | biostudies-literature
Project description:To investigate ferroptosis-dependent changes in DNA methylation, a genome wide DNA methylation profiling of ferroptotic (RSL3-treated) multiple myeloma cells (MM1S & MM1R) was performed using the 850K MethylationEPIC BeadChip Array. The ferroptotic DNA methylation signature was compared to myeloma cells pre-treated with the ferroptosis inhibitor ferrostatin-1 (FRSL3), which served as a negative control. In total, three biological replicates per treatment per cell line were included.
2021-11-08 | GSE184576 | GEO
Project description:Ferroptosis is a form of regulated cell death characterized by iron-dependent lipid peroxidation. While ferroptosis has been identified as a mechanism for suppressing cancer, its overall physiological significance remains poorly understood. Recent studies have revealed that labile iron and lipid peroxides are released from ferroptotic cells, leading to the propagation of ferroptosis through lipid peroxidation. However, other specific effects of secreted factors derived from ferroptotic cells remain unclear. We constructed a model cell system capable of inducing ferroptosis by re-expressing the transcription factor BACH1, a potent inducer of ferroptosis, in immortalized mouse embryonic fibroblasts (iMEFs). We investigated the impact of the secreted factors from ferroptotic cells with the iMEFs. As a result, we observed that the administration of supernatant media from ferroptotic iMEFs activated proliferation of hepatoma cells and suppressed cellular senescence-like features. This suggested that ferroptotic MEFs secrete anti-senescent substances. Transcriptome analysis of ferroptotic MEFs revealed an increase in the secretion of longevity factor FGF21 in a BACH1-dependent manner. Furthermore, the anti-senescent effects of the supernatant media from these ferroptotic cells were canceled by the knockout of Fgf21. Totally, it is suggested that BACH1 promotes ferroptosis in fibroblasts and contributes to the suppression of cellular senescence in neighboring cells by inducing FGF21 secretion from fibroblasts. It was also discovered that BACH1 not only activates indirectly the transcription of FGF21 by enhancing ferroptotic stress but also increases FGF21 protein level by suppressing the selective autophagic degradation of FGF21 through the transcriptional repression for Sqstm1 and Lamp2a. This represents a dual mechanism of FGF21 upregulation mediated by BACH1, suggesting that BACH1 is a potent inducer of FGF21 expression. It was also found that the BACH1-ferroptosis-FGF21 axis can suppress obesity of mice under high fat diet or short lifespan of progeria mice, closely associated phenotypes with aging. The inhibition of these aging-related phenotypes is considered to be a novel physiological significance of ferroptosis, and BACH1 is considered to function as a longevity gene by promoting ferroptotsis and subsequent FGF21 expression.
2024-06-11 | GSE238147 | GEO
Project description:Gallic acid (GA) is a natural anti-cancer compound that can be found in many food sources, including edible mushrooms, fruits, and vegetables. Studies generally attribute the anti-cancer activity of GA to the induction of apoptosis. Here, we reported that GA activated iron-dependent cell death mechanisms with apoptotic, ferroptotic, and necroptotic features. Our time-lapse live-cell microscopy study demonstrated that GA could induce coexistence of multiple types of cell death pathways, including apoptosis characterized by mitochondrial cytochrome c release and caspase-3 activation, ferroptosis characterized by lipid peroxidation, and necroptosis characterized by the loss of plasma membrane integrity. This GA-induced cell death could be completely suppressed by exposure to an iron chelator deferoxamine, indicating that it is an iron-dependent cell death process. Importantly, MLKL (mixed lineage kinase domain-like protein) inhibitor necrosulfonamide exerted a synergistic effect by increasing the sensitivity of cancer cells to GA. Taken together, our results provide new mechanistic insights, and also suggest new strategies to enhance the efficacy of this natural anti-cancer compound by identifying the agents that can promote or suppress the GA-induced cell death process.
| S-EPMC6783835 | biostudies-other
Project description:Necrosis is commonly found in various solid tumors and predicts worse outcome. Chronic ischemia can initiate tumor necrosis, but how the damaged tissue further expands is unclear. Previous studies found that neutrophils associate with necrosis and could contribute to necrosis development in glioblastoma (GBM) by transferring myeloperoxidase (MPO)-containing granules into tumor cells and inducing tumor cell ferroptosis. How the neutrophilic granule transfer occurs is unknown. Here, through an unbiased small molecule screen, we found that statins can inhibit neutrophil-induced tumor cell death by blocking the neutrophilic content transfer into tumor cells. Surprisingly, we found that neutrophils are engulfed by tumor cells before they are fragmented and release the MPO-containing contents in tumor cells. This process involves LC3-associated phagocytosis (LAP) and can be blocked by inhibiting the Vps34-UVRAG-containing PI3K complex. Inhibition of MPO or depletion of Vps34 in an orthotopic xenograft GBM mouse model reduced necrosis formation and allowed tumor-bearing mice to survive longer. Therefore, this study revealed that the neutrophilic granule transfer involves LAP-mediated neutrophil internalization, which then triggers tumor ferroptotic cell death in glioblastoma. Blocking this process may improve prognosis of GBM.
2024-04-29 | GSE263766 | GEO
Project description:The objective is to understand how the transcriptome of dendritic cells changes after the uptake of ferroptotic cells.
2022-06-02 | GSE205069 | GEO
Project description:Transcriptomes analysis of the petals from a red-flowered white clover mutant (red flowers) and its shade-treated counterpart (white flowers) grown under shaded conditions was performed using high-throughput sequencing. We obtained 121,626,564 and 130,577,944 clean reads in red-flowered mutant and treated counterpart, respectively. Of these clean reads, we respectively gained 125,350 and 99,638 unigene sequencces in two groups. As a result, a total of 157,964 unigenes were obtained with an average length of 728 bp and a median length of 1346 bp. These findings provideed insights into the expression profiles in red-flowered white clover mutant, and deepened our understanding of flower pigmentation in white clower.
2018-12-04 | GSE101059 | GEO
Project description:LC3-associated phagocytosis of neutrophils trigger tumor ferroptotic cell death in glioblastoma
| PRJNA1099203 | ENA