scholarly journals Programmed Cell-Death by Ferroptosis: Antioxidants as Mitigators

2019 ◽  
Vol 20 (19) ◽  
pp. 4968 ◽  
Author(s):  
Kajarabille ◽  
Latunde-Dada
Keyword(s):  
Reactive Oxygen Species ◽  
Lipid Peroxidation ◽  
Cell Death ◽  
Membrane Lipids ◽  
Glutamate Transporter ◽  
Reactive Oxygen ◽  
Antioxidant Response ◽  
Heme Oxygenase 1 ◽  
Oxygen Species ◽  
Radical Trapping

Iron, the fourth most abundant element in the Earth’s crust, is vital in living organisms because of its diverse ligand-binding and electron-transfer properties. This ability of iron in the redox cycle as a ferrous ion enables it to react with H2O2, in the Fenton reaction, to produce a hydroxyl radical (•OH)—one of the reactive oxygen species (ROS) that cause deleterious oxidative damage to DNA, proteins, and membrane lipids. Ferroptosis is a non-apoptotic regulated cell death that is dependent on iron and reactive oxygen species (ROS) and is characterized by lipid peroxidation. It is triggered when the endogenous antioxidant status of the cell is compromised, leading to lipid ROS accumulation that is toxic and damaging to the membrane structure. Consequently, oxidative stress and the antioxidant levels of the cells are important modulators of lipid peroxidation that induce this novel form of cell death. Remedies capable of averting iron-dependent lipid peroxidation, therefore, are lipophilic antioxidants, including vitamin E, ferrostatin-1 (Fer-1), liproxstatin-1 (Lip-1) and possibly potent bioactive polyphenols. Moreover, most of the enzymes and proteins that cascade or interact in the pathway of ferroptosis such as a subunit of the cystine/glutamate transporter xc- (SLC7A11), glutathione peroxidase 4 (GPX4), and the glutamate–cysteine ligase (GCLC) iron metabolism genes transferrin receptor 1 (TfR1) ferroportin, (Fpn) heme oxygenase 1 (HO-1) and ferritin are regulated by the antioxidant response element of the transcription factor, Nrf2. These, as well as other radical trapping antioxidants (RTAs), are discussed in the current review.

scholarly journals OTUD1 deubiquitylase regulates NF-κB- and KEAP1-mediated inflammatory responses and reactive oxygen species-associated cell death pathways

2021 ◽  
Author(s):  
Daisuke Oikawa ◽  
Min Gi ◽  
Hidetaka Kosako ◽  
Kouhei Shimizu ◽  
Hirotaka Takahashi ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Cell Death ◽  
Stress Responses ◽  
Inflammatory Responses ◽  
Reactive Oxygen ◽  
Antioxidant Response ◽  
Oxygen Species ◽  
Ubiquitin Chain ◽  
Intrinsically Disordered ◽  
Cell Death Pathways

Deubiquitylating enzymes (DUBs) regulate numerous cellular functions by removing ubiquitin modifications. We examined the effects of 88 human DUBs on linear ubiquitin chain assembly complex (LUBAC)-induced NF-κB activation, and identified OTUD1 as a potent suppressor. OTUD1 regulates the canonical NF-κB pathway by hydrolysing K63-linked ubiquitin chains from NF-κB signalling factors, including LUBAC. OTUD1 negatively regulates the canonical NF-κB activation, apoptosis, and necroptosis, whereas OTUD1 upregulates the interferon (IFN) antiviral pathway. The N-terminal intrinsically disordered region of OTUD1, which contains an EGTE motif, is indispensable for KEAP1-binding and NF-κB suppression. OTUD1 is involved in the KEAP1-mediated antioxidant response and reactive oxygen species (ROS)-induced cell death, oxeiptosis. In Otud1-/--mice, inflammation, oxidative damage, and cell death were enhanced in inflammatory bowel disease, acute hepatitis, and sepsis models. Thus, OTUD1 is a crucial regulator for the inflammatory, innate immune, and oxidative stress responses and ROS-associated cell death pathways.

scholarly journals Antioxidant Activity of Selected Stilbenoid Derivatives in a Cellular Model System

Biomolecules ◽  
2019 ◽  
Vol 9 (9) ◽  
pp. 468 ◽  
Author(s):  
Treml ◽  
Leláková ◽  
Šmejkal ◽  
Paulíčková ◽  
Labuda ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Reactive Oxygen ◽  
Antioxidant Response ◽  
Heme Oxygenase 1 ◽  
Oxygen Species ◽  
Cellular Model ◽  
Ros Scavenging ◽  
Antioxidative Agents

The stilbenoids, a group of naturally occurring phenolic compounds, are found in a variety of plants, including some berries that are used as food or for medicinal purposes. They are known to be beneficial for human health as anti-inflammatory, chemopreventive, and antioxidative agents. We have investigated a group of 19 stilbenoid substances in vitro using a cellular model of THP-1 macrophage-like cells and pyocyanin-induced oxidative stress to evaluate their antioxidant or pro-oxidant properties. Then we have determined any effects that they might have on the expression of the enzymes catalase, glutathione peroxidase, and heme oxygenase-1, and their effects on the activation of Nrf2. The experimental results showed that these stilbenoids could affect the formation of reactive oxygen species in a cellular model, producing either an antioxidative or pro-oxidative effect, depending on the structure pinostilbene (2) worked as a pro-oxidant and also decreased expression of catalase in the cell culture. Piceatannol (4) had shown reactive oxygen species (ROS) scavenging activity, whereas isorhapontigenin (18) had a mild direct antioxidant effect and activated Nrf2-antioxidant response element (ARE) system and elevated expression of Nrf2 and catalase. Their effects shown on cells in vitro warrant their further study in vivo.

scholarly journals Cystine and Methionine Deficiency Promotes Ferroptosis by Inducing B-Cell Translocation Gene 1

Antioxidants ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 1543
Author(s):  
Il-Je Cho ◽  
Doyeon Kim ◽  
Eun-Ok Kim ◽  
Kyung-Hwan Jegal ◽  
Jae-Kwang Kim ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Lipid Peroxidation ◽  
Cell Death ◽  
Transcription Factor ◽  
Stress Response ◽  
B Cell ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Integrated Stress Response ◽  
Methionine Deficiency

Ferroptosis is a type of programmed necrosis triggered by iron-dependent lipid peroxidation. We investigated the role of B-cell translocation gene 1 (BTG1) in cystine and methionine deficiency (CST/Met (–))-mediated cell death. CST/Met (–) depleted reduced and oxidized glutathione in hepatocyte-derived cells, increased prostaglandin-endoperoxide synthase 2 expression, and promoted reactive oxygen species accumulation and lipid peroxidation, as well as necrotic cell death. CST/Met (–)-mediated cell death and lipid peroxidation was specifically inhibited by pretreatment with ferroptosis inhibitors. In parallel with cell death, CST/Met (–) blocked global protein translation and increased the expression of genes associated with the integrated stress response. Moreover, CST/Met (–) significantly induced BTG1 expression. Using a BTG1 promoter-harboring reporter gene and siRNA, activating transcription factor 4 (ATF4) was identified as an essential transcription factor for CST/Met (–)-mediated BTG1 induction. Although knockout of BTG1 in human HAP1 cells did not affect the accumulation of reactive oxygen species induced by CST/Met (–), BTG1 knockout significantly decreased the induction of genes associated with the integrated stress response, and reduced lipid peroxidation and cell death in response to CST/Met (–). The results demonstrate that CST/Met (–) induces ferroptosis by activating ATF4-dependent BTG1 induction.

scholarly journals Reactive Oxygen Species-Induced Lipid Peroxidation in Apoptosis, Autophagy, and Ferroptosis

2019 ◽  
Vol 2019 ◽  
pp. 1-13 ◽  
Author(s):  
Lian-Jiu Su ◽  
Jia-Hao Zhang ◽  
Hernando Gomez ◽  
Raghavan Murugan ◽  
Xing Hong ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Lipid Peroxidation ◽  
Cell Death ◽  
Critical Role ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Chain Reactions ◽  
Know How ◽  
Different Types ◽  
Highly Evolved

Reactive oxygen species- (ROS-) induced lipid peroxidation plays a critical role in cell death including apoptosis, autophagy, and ferroptosis. This fundamental and conserved mechanism is based on an excess of ROS which attacks biomembranes, propagates lipid peroxidation chain reactions, and subsequently induces different types of cell death. A highly evolved sophisticated antioxidant system exists that acts to protect the cells from oxidative damage. In this review, we discussed how ROS propagate lipid peroxidation chain reactions and how the products of lipid peroxidation initiate apoptosis and autophagy in current models. We also discussed the mechanism of lipid peroxidation during ferroptosis, and we summarized lipid peroxidation in pathological conditions of critical illness. We aim to bring a more global and integrative sight to know how different ROS-induced lipid peroxidation occurs among apoptosis, autophagy, and ferroptosis.

scholarly journals Lysosomal Destabilizing Drug Siramesine and the Dual Tyrosine Kinase Inhibitor Lapatinib Induce a Synergistic Ferroptosis through Reduced Heme Oxygenase-1 (HO-1) Levels

2019 ◽  
Vol 2019 ◽  
pp. 1-14 ◽  
Author(s):  
Gloria E. Villalpando-Rodriguez ◽  
Anna R. Blankstein ◽  
Carmen Konzelman ◽  
Spencer B. Gibson
Keyword(s):  
Reactive Oxygen Species ◽  
Lipid Peroxidation ◽  
Cell Death ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Heme Oxygenase ◽  
Kinase Inhibitor ◽  
Heme Oxygenase 1 ◽  
Oxygen Species ◽  
Lysosomotropic Agent

Ferroptosis is an iron-dependent type of cell death distinct from apoptosis or necrosis characterized by accumulation of reactive oxygen species. The combination of siramesine, a lysosomotropic agent, and lapatinib, a dual tyrosine kinase inhibitor (TKI), synergistically induced cell death in breast cancer cells mediated by ferroptosis. In this study, we showed that this combination of siramesine and lapatinib induces synergistic cell death in glioma cell line U87 and lung adenocarcinoma cell line A549. This cell death was characterized by the increase in iron content, reactive oxygen species (ROS) production, and lipid peroxidation accumulation after 24 hours of treatment. Moreover, iron chelator DFO and ferrostatin-1, a ferroptosis inhibitor, significantly reduced cell death. The mechanism underlying the activation of the ferroptotic pathway involves lysosomal permeabilization and increase in reactive iron levels in these cells. In addition, the downregulation of heme oxygenase-1 (HO-1) protein occurred. Overexpression of HO-1 resulted in reduction of ROS and lipid peroxidation production and cell death. Furthermore, knocking down of HO-1 combined with siramesine treatment resulted in increased cell death. Finally, we found that the inhibition of the proteasome system rescued HO-1 expression levels. Our results suggest that the induction of ferroptosis by combining a lysosomotropic agent and a tyrosine kinase inhibitor is mediated by iron release from lysosomes and HO-1 degradation by the proteasome system.

scholarly journals 4-Hydroxychalcone Induces Cell Death via Oxidative Stress in MYCN-Amplified Human Neuroblastoma Cells

2019 ◽  
Vol 2019 ◽  
pp. 1-16 ◽  
Author(s):  
Amnah M. Alshangiti ◽  
Eszter Tuboly ◽  
Shane V. Hegarty ◽  
Cathal M. McCarthy ◽  
Aideen M. Sullivan ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Cell Death ◽  
Cytotoxic Effect ◽  
Neuroblastoma Cells ◽  
Reactive Oxygen ◽  
Prognostic Indicator ◽  
Oxygen Species ◽  
Human Neuroblastoma Cells ◽  
Human Neuroblastoma

Neuroblastoma is an embryonal malignancy that arises from cells of sympathoadrenal lineage during the development of the nervous system. It is the most common pediatric extracranial solid tumor and is responsible for 15% of childhood deaths from cancer. Fifty percent of cases are diagnosed as high-risk metastatic disease with a low overall 5-year survival rate. More than half of patients experience disease recurrence that can be refractory to treatment. Amplification of the MYCN gene is an important prognostic indicator that is associated with rapid disease progression and a poor prognosis, highlighting the need for new therapeutic approaches. In recent years, there has been an increasing focus on identifying anticancer properties of naturally occurring chalcones, which are secondary metabolites with variable phenolic structures. Here, we report that 4-hydroxychalcone is a potent cytotoxin for MYCN-amplified IMR-32 and SK-N-BE (2) neuroblastoma cells, when compared to non-MYCN-amplified SH-SY5Y neuroblastoma cells and to the non-neuroblastoma human embryonic kidney cell line, HEK293t. Moreover, 4-hydroxychalcone treatment significantly decreased cellular levels of the antioxidant glutathione and increased cellular reactive oxygen species. In addition, 4-hydroxychalcone treatment led to impairments in mitochondrial respiratory function, compared to controls. In support of this, the cytotoxic effect of 4-hydroxychalcone was prevented by co-treatment with either the antioxidant N-acetyl-L-cysteine, a pharmacological inhibitor of oxidative stress-induced cell death (IM-54) or the mitochondrial reactive oxygen species scavenger, Mito-TEMPO. When combined with the anticancer drugs cisplatin or doxorubicin, 4-hydroxychalcone led to greater reductions in cell viability than was induced by either anti-cancer agent alone. In summary, this study identifies a cytotoxic effect of 4-hydroxychalcone in MYCN-amplified human neuroblastoma cells, which rationalizes its further study in the development of new therapies for pediatric neuroblastoma.

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