scholarly journals Is Ferroptosis a Key Component of the Process Leading to Multiorgan Damage in COVID-19?

Antioxidants ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 1677
Author(s):  
Anna Maria Fratta Pasini ◽  
Chiara Stranieri ◽  
Domenico Girelli ◽  
Fabiana Busti ◽  
Luciano Cominacini
Keyword(s):  
Reactive Oxygen Species ◽  
Fatty Acids ◽  
Cell Death ◽  
Cardiogenic Shock ◽  
Molecular Mechanisms ◽  
Lipid Peroxides ◽  
Oxygen Species ◽  
Intracellular Iron ◽  
Multiple Organs ◽  
Respiratory Pathology

Even though COVID-19 is mostly well-known for affecting respiratory pathology, it can also result in several extrapulmonary manifestations, leading to multiorgan damage. A recent reported case of SARS-CoV-2 myocarditis with cardiogenic shock showed a signature of myocardial and kidney ferroptosis, a novel, iron-dependent programmed cell death. The term ferroptosis was coined in the last decade to describe the form of cell death induced by the small molecule erastin. As a specific inducer of ferroptosis, erastin inhibits cystine-glutamate antiporter system Xc-, blocking transportation into the cytoplasm of cystine, a precursor of glutathione (GSH) in exchange with glutamate and the consequent malfunction of GPX4. Ferroptosis is also promoted by intracellular iron overload and by the iron-dependent accumulation of polyunsaturated fatty acids (PUFA)-derived lipid peroxides. Since depletion of GSH, inactivation of GPX4, altered iron metabolism, and upregulation of PUFA peroxidation by reactive oxygen species are peculiar signs of COVID-19, there is the possibility that SARS-CoV-2 may trigger ferroptosis in the cells of multiple organs, thus contributing to multiorgan damage. Here, we review the molecular mechanisms of ferroptosis and its possible relationship with SARS-CoV-2 infection and multiorgan damage. Finally, we analyze the potential interventions that may combat ferroptosis and, therefore, reduce multiorgan damage.

scholarly journals Elesclomol-induced increase of mitochondrial reactive oxygen species impairs glioblastoma stem-like cell survival and tumor growth

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Mariachiara Buccarelli ◽  
Quintino Giorgio D’Alessandris ◽  
Paola Matarrese ◽  
Cristiana Mollinari ◽  
Michele Signore ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Cell Death ◽  
Molecular Mechanisms ◽  
Reactive Oxygen ◽  
Strong Increase ◽  
Oxygen Species ◽  
Mitochondrial Reactive Oxygen Species

Abstract Background Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumor in adults, characterized by a poor prognosis mainly due to recurrence and therapeutic resistance. It has been widely demonstrated that glioblastoma stem-like cells (GSCs), a subpopulation of tumor cells endowed with stem-like properties is responsible for tumor maintenance and progression. Moreover, it has been demonstrated that GSCs contribute to GBM-associated neovascularization processes, through different mechanisms including the transdifferentiation into GSC-derived endothelial cells (GdECs). Methods In order to identify druggable cancer-related pathways in GBM, we assessed the effect of a selection of 349 compounds on both GSCs and GdECs and we selected elesclomol (STA-4783) as the most effective agent in inducing cell death on both GSC and GdEC lines tested. Results Elesclomol has been already described to be a potent oxidative stress inducer. In depth investigation of the molecular mechanisms underlying GSC and GdEC response to elesclomol, confirmed that this compound induces a strong increase in mitochondrial reactive oxygen species (ROS) in both GSCs and GdECs ultimately leading to a non-apoptotic copper-dependent cell death. Moreover, combined in vitro treatment with elesclomol and the alkylating agent temozolomide (TMZ) enhanced the cytotoxicity compared to TMZ alone. Finally, we used our experimental model of mouse brain xenografts to test the combination of elesclomol and TMZ and confirmed their efficacy in vivo. Conclusions Our results support further evaluation of therapeutics targeting oxidative stress such as elesclomol with the aim of satisfying the high unmet medical need in the management of GBM.

scholarly journals Bufalin Induces Reactive Oxygen Species Dependent Bax Translocation and Apoptosis in ASTC-a-1 Cells

2011 ◽  
Vol 2011 ◽  
pp. 1-12 ◽  
Author(s):  
Lei Sun ◽  
Tongsheng Chen ◽  
Xiaoping Wang ◽  
Yun Chen ◽  
Xunbin Wei
Keyword(s):  
Reactive Oxygen Species ◽  
Cell Death ◽  
Molecular Mechanisms ◽  
Caspase 3 ◽  
Temporal Dynamics ◽  
Reactive Oxygen ◽  
Ros Generation ◽  
Ros Production ◽  
Oxygen Species ◽  
Induced Apoptosis

Bufalin has been shown to induce cancer cell death through apoptotic pathways. However, the molecular mechanisms are not well understood. In this study, we used the confocal fluorescence microscopy (CFM) to monitor the spatio-temporal dynamics of reactive oxygen species (ROS) production, Bax translocation and caspase-3 activation during bufalin-induced apoptosis in living human lung adenocarcinoma (ASTC-a-1) cells. Bufalin induced ROS production and apoptotic cell death, demonstrated by Hoechst 33258 staining as well as flow cytometry analysis. Bax redistributed from cytosol to mitochondria from 12 to 48 h after bufalin treatment in living cells expressed with green fluorescent protein Bax. Treatment with the antioxidantN-acetyl-cysteine (NAC), a ROS scavenger, inhibited ROS generation and Bax translocation and led to a significant protection against bufalin-induced apoptosis. Our results also revealed that bufalin induced a prominent increase of caspase-3 activation blocked potently by NAC. Taken together, bufalin induced ROS-mediated Bax translocation, mitochondrial permeability transition and caspase-3 activation, implying that bufalin induced apoptosis via ROS-dependent mitochondrial death pathway in ASTC-a-1 cells.

Regulation of necroptosis signaling and cell death by reactive oxygen species

2016 ◽  
Vol 397 (7) ◽  
pp. 657-660 ◽  
Author(s):  
Simone Fulda
Keyword(s):  
Reactive Oxygen Species ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Signaling Pathways ◽  
Posttranslational Modifications ◽  
Molecular Mechanisms ◽  
Reactive Oxygen ◽  
Alternative Form ◽  
Oxygen Species

Abstract Necroptosis has recently been identified as an alternative form of programmed cell death that is characterized by defined molecular mechanisms. Reactive oxygen species (ROS) are involved in the regulation of numerous signaling pathways, as they are highly reactive and can cause (ir)reversible posttranslational modifications. While the role of ROS in other modes of cell death has been extensively studied, its impact on necroptotic signaling and cell death is far less clear. The current minireview discusses the evidence for and against a role of ROS in necroptosis.

scholarly journals Prevention of 7-Ketocholesterol-Induced Overproduction of Reactive Oxygen Species, Mitochondrial Dysfunction and Cell Death with Major Nutrients (Polyphenols, ω3 and ω9 Unsaturated Fatty Acids) of the Mediterranean Diet on N2a Neuronal Cells

Molecules ◽  
2020 ◽  
Vol 25 (10) ◽  
pp. 2296 ◽  
Author(s):  
Aline Yammine ◽  
Thomas Nury ◽  
Anne Vejux ◽  
Norbert Latruffe ◽  
Dominique Vervandier-Fasseur ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Fatty Acids ◽  
Flow Cytometry ◽  
Cell Death ◽  
Mediterranean Diet ◽  
Unsaturated Fatty Acids ◽  
Neuronal Cells ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
The Mediterranean

The brain, which is a cholesterol-rich organ, can be subject to oxidative stress in a variety of pathophysiological conditions, age-related diseases and some rare pathologies. This can lead to the formation of 7-ketocholesterol (7KC), a toxic derivative of cholesterol mainly produced by auto-oxidation. So, preventing the neuronal toxicity of 7KC is an important issue to avoid brain damage. As there are numerous data in favor of the prevention of neurodegeneration by the Mediterranean diet, this study aimed to evaluate the potential of a series of polyphenols (resveratrol, RSV; quercetin, QCT; and apigenin, API) as well as ω3 and ω9 unsaturated fatty acids (α-linolenic acid, ALA; eicosapentaenoic acid, EPA; docosahexaenoic acid, DHA, and oleic acid, OA) widely present in this diet, to prevent 7KC (50 µM)-induced dysfunction of N2a neuronal cells. When polyphenols and fatty acids were used at non-toxic concentrations (polyphenols: ≤6.25 µM; fatty acids: ≤25 µM) as defined by the fluorescein diacetate assay, they greatly reduce 7KC-induced toxicity. The cytoprotective effects observed with polyphenols and fatty acids were comparable to those of α-tocopherol (400 µM) used as a reference. These polyphenols and fatty acids attenuate the overproduction of reactive oxygen species and the 7KC-induced drop in mitochondrial transmembrane potential (ΔΨm) measured by flow cytometry after dihydroethidium and DiOC6(3) staining, respectively. Moreover, the studied polyphenols and fatty acids reduced plasma membrane permeability considered as a criterion for cell death measured by flow cytometry after propidium iodide staining. Our data show that polyphenols (RSV, QCT and API) as well as ω3 and ω9 unsaturated fatty acids (ALA, EPA, DHA and OA) are potent cytoprotective agents against 7KC-induced neurotoxicity in N2a cells. Their cytoprotective effects could partly explain the benefits of the Mediterranean diet on human health, particularly in the prevention of neurodegenerative diseases.

scholarly journals Transcriptome profiling of kenaf (Hibiscus cannabinus L.) under plumbic stress conditions implies the involvement of NAC transcription factors regulating reactive oxygen species-dependent programmed cell death

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e8733
Author(s):  
Xia An ◽  
Jie Chen ◽  
Guanrong Jin
Keyword(s):  
Reactive Oxygen Species ◽  
Heavy Metal ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Molecular Mechanisms ◽  
De Novo ◽  
Reactive Oxygen ◽  
Hibiscus Cannabinus ◽  
Differentially Expressed ◽  
Oxygen Species

Heavy metal contamination of soils has become a serious global issue, and bioremediation has been proposed as a potential solution. Kenaf (Hibiscus cannabinus L.) is a fast growing, non-woody multipurpose annual plant that is suitable for removing excess heavy metals from soils. However, there has been relatively little research on the kenaf molecular mechanisms induced in response to an exposure to heavy metal stress. Thus, whole kenaf seedlings grown under control (normal) and stress (plumbic treatment) conditions were sampled for transcriptome sequencing. Unigenes generated through the de novo assembly of clean reads were functionally annotated based on seven databases. Transcription factor (TF)-coding genes were predicted and the physiological traits of the seedlings were analyzed. A total of 44.57 Gb high-quality sequencing data were obtained, which were assembled into 136,854 unigenes. These unigenes included 1,697 that were regarded as differentially expressed genes (DEGs). A GO enrichment analysis of the DEGs indicated that many of them are related to catalytic activities. Moreover, the DEGs appeared to suggest that numerous KEGG pathways are suppressed (e.g., the photosynthesis-involving pathways) or enhanced (like the flavonoid metabolism pathways) in response to Pb stress. Of the 2,066 predicted TF-coding genes, only 55 were differentially expressed between the control and stressed samples. Further analyses suggested that the plumbic stress treatment induced reactive oxygen species-dependent programmed cell death in the kenaf plants via a process that may be regulated by the differentially expressed NAC TF genes.

scholarly journals ROS-mediated autophagy increases intracellular iron levels and ferroptosis by ferritin and transferrin receptor regulation

2019 ◽  
Vol 10 (11) ◽  
Author(s):  
Eunhee Park ◽  
Su Wol Chung
Keyword(s):  
Reactive Oxygen Species ◽  
Lipid Peroxidation ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Transferrin Receptor ◽  
Receptor Regulation ◽  
Oxygen Species ◽  
Wild Type ◽  
Intracellular Iron ◽  
Transferrin Receptor 1

Abstract Ferroptosis is a novel form of programmed cell death in which the accumulation of intracellular iron promotes lipid peroxidation, leading to cell death. Recently, the induction of autophagy has been suggested during ferroptosis. However, this relationship between autophagy and ferroptosis is still controversial and the autophagy-inducing mediator remains unknown. In this study, we confirmed that autophagy is indeed induced by the ferroptosis inducer erastin. Furthermore, we show that autophagy leads to iron-dependent ferroptosis by degradation of ferritin and induction of transferrin receptor 1 (TfR1) expression, using wild-type and autophagy-deficient cells, BECN1+/− and LC3B−/−. Consistently, autophagy deficiency caused depletion of intracellular iron and reduced lipid peroxidation, resulting in cell survival during erastin-induced ferroptosis. We further identified that autophagy was triggered by erastin-induced reactive oxygen species (ROS) in ferroptosis. These data provide evidence that ROS-induced autophagy is a key regulator of ferritin degradation and TfR1 expression during ferroptosis. Our study thus contributes toward our understanding of the ferroptotic processes and also helps resolve some of the controversies associated with this phenomenon.

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