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Tobias M Seibt, Bettina Proneth, Marcus Conrad
Ferroptosis is a non-apoptotic form of cell death characterized by iron-dependent lipid peroxidation and metabolic constraints. Dependence on NADPH/H+, polyunsaturated fatty acid metabolism, and the mevalonate and glutaminolysis metabolic pathways have been implicated in this novel form of regulated necrotic cell death. Genetic studies performed in cells and mice established the selenoenzyme glutathione peroxidase (GPX4) as the key regulator of this form of cell death. Besides these genetic models, the identification of a series of small molecule ferroptosis-specific inhibitors and inducers have not only helped in the delineation of the molecular underpinnings of ferroptosis but they might also prove highly beneficial when tipping the balance between cell death inhibition and induction in the context of degenerative diseases and cancer, respectively...
September 13, 2018: Free Radical Biology & Medicine
D A Stoyanovsky, Y Y Tyurina, I Shrivastava, I Bahar, V A Tyurin, O Protchenko, S Jadhav, S B Bolevich, A V Kozlov, Y A Vladimirov, A A Shvedova, C C Philpott, H Bayir, V E Kagan
Duality of iron as an essential cofactor of many enzymatic metabolic processes and as a catalyst of poorly controlled redox-cycling reactions defines its possible biological beneficial and hazardous role in the body. In this review, we discuss these two "faces" of iron in a newly conceptualized program of regulated cell death, ferroptosis. Ferroptosis is a genetically programmed iron-dependent form of regulated cell death driven by enhanced lipid peroxidation and insufficient capacity of thiol-dependent mechanisms (glutathione peroxidase 4, GPX4) to eliminate hydroperoxy-lipids...
September 11, 2018: Free Radical Biology & Medicine
Kui Liu, Meng Jin, Li Xiao, Huiguo Liu, Shuang Wei
Introduction: Glutathione peroxidases (GPxs) constitutes an enzyme family which has the ability to reduce free hydrogen peroxide to water and lipid hydroperoxides to their corresponding alcohols, and its main biological roles are to protect organisms from oxidative stress-induced damage. GPxs include eight members in different tissues of the body, and they play essential roles in carcinogenesis. However, the prognostic value of individual GPx in non-small cell lung cancer (NSCLC) remains elusive...
2018: Cancer Management and Research
A Arangasamy, Renu Balkrishan Sharma, K Hemalatha, M Venkata Krishnaiah, S Selvaraju, G Pushpa Rani, B K Binsila, N M Soren, I J Reddy, J P Ravindra, Raghavendra Bhatta
The antioxidant properties and the protective role of organic zinc (Zn) and copper (Cu) in white blood cells (WBCs) and spermatozoa were analyzed through quantification of superoxide dismutase 1 (SOD1), catalase (CAT), glutathione peroxidase 4 (GPx4) and nuclear factor erythroid 2-like 2 (NFE2L2) and correlations were determined with sperm functional characteristics in Osmanabadi bucks. Bucks (aged 5 months; n = 40) were divided into ten groups, and the dietary treatments comprised of a control and nine treatment groups as follows: organic Zn as Zn 20, Zn 40 and Zn 60, organic Cu as Cu 12...
October 2018: Animal Reproduction Science
Ewa Strauss, Jolanta Tomczak, Ryszard Staniszewski, Grzegorz Oszkinis
BACKGROUND: Little is known on the role of selenoprotein genes in cardiovascular disease. This study examines the associations of the SEPP1, SELENOS, TXNRD1, TXNRD2, GPX4, and SOD2 polymorphisms and selenoprotein P (SeP) and thioredoxin concentrations with the development of abdominal aortic aneurysm (AAA) and aortoiliac occlusive disease (AOID), as well as their influence on cardiac phenotype. METHODS: 564 patients with AAA, 400 patients with AIOD, and 543 controls were enrolled and characterized for coronary artery disease, myocardial infarction, and systolic heart failure (HF) occurrence...
2018: PloS One
Csilla Pelyhe, Benjámin Kövesi, Erika Zándoki, Balázs Kovács, Márta Erdélyi, Szabina Kulcsár, Miklós Mézes, Krisztián Balogh
Co-occurrence of mycotoxin contamination of feeds is a frequent problem, therefore the purpose of this study was to evaluate the combined effect of T-2 toxin and deoxynivalenol (DON) on lipid peroxidation, parameters and regulation of the glutathione redox system in broiler chickens in a sub-chronic (7 day) study. The applied doses were: low mix: 0.23 mg T-2 toxin and 4.96 mg DON/kg feed; medium mix: 1.21 mg T-2 toxin and 12.38 mg DON/kg feed; and high mix: 2.42 T-2 toxin and 24.86 mg DON/kg feed...
August 29, 2018: Toxicon: Official Journal of the International Society on Toxinology
Jia-Rui Wu, Qing-Zhang Tuo, Peng Lei
Ferroptosis is a recently defined form of cell death with the involvement of iron and reactive oxygen species (ROS), which is distinct from apoptosis, autophagy and other forms of cell death. Emerging evidence suggested that iron accumulation and lipid peroxidation can be discovered in various neurological diseases, accompanied with reduction of glutathione (GSH) and glutathione peroxidase 4 (GPX4). In addition, ferroptotic inhibitors have been shown to protect neurons, and recover the cognitive function in disease animal models...
August 25, 2018: Journal of Molecular Neuroscience: MN
Bettina Proneth, Marcus Conrad
Ferroptosis is a non-apoptotic form of cell death characterized by overwhelming iron-dependent lipid peroxidation, which contributes to a number of pathologies, most notably tissue ischemia/reperfusion injury, neurodegeneration and cancer. Cysteine availability, glutathione biosynthesis, polyunsaturated fatty acid metabolism and modulation of the phospholipidome are the key events of this necrotic cell death pathway. Non-enzymatic and enzymatic lipoxygenase (LOX)-mediated lipid peroxidation of lipid bilayers is efficiently counteracted by the glutathione (GSH)/glutathione peroxidase 4 (GPX4) axis...
August 6, 2018: Cell Death and Differentiation
Tine Iskov Kopp, Malene Outzen, Anja Olsen, Ulla Vogel, Gitte Ravn-Haren
Background: Selenium is an essential trace element and is suggested to play a role in the etiology of a number of chronic diseases. Genetic variation in genes encoding selenoproteins, such as selenoprotein P and the glutathione peroxidases, may affect selenium status and, thus, individual susceptibility to some chronic diseases. In the present study, we aimed to (1) investigate the effect of mussel and fish intake on glutathione peroxidase enzyme activity and (2) examine whether single nucleotide polymorphisms in the GPX1 , GPX4 , and SELENOP genes modify the effect of mussel and fish intake for 26 weeks on whole blood selenium, plasma selenoprotein P concentrations, and erythrocyte GPX enzyme activity in a randomized intervention trial in Denmark...
2018: Genes & Nutrition
Jiayong Tang, Aihua He, Hui Yan, Gang Jia, Guangmang Liu, Xiaoling Chen, Jingyi Cai, Gang Tian, Haiying Shang, Hua Zhao
This study was conducted to profile the selenoprotein encoding genes or proteins in mouse C2C12 cells and integrate their roles in the skeletal cell damage induced by heat stress (HS). Cells were cultured at 37.0 °C or 41.5 °C for 4, 6 or 8 days. The mRNA expression of 24 selenoprotein encoding genes and abundance of 5 selenoproteins were investigated. HS suppressed myogenic differentiation and impaired the development of muscle myotubes. HS down-regulated (P < 0.01) mRNA abundance of MYOD and MYOGENIN, and decreased (P < 0...
July 13, 2018: Scientific Reports
Ashley J Russo, Vijay A K Rathinam
Glutathione peroxidase 4 (GPX4) is an antioxidant enzyme that protects cells from lipid peroxidation. In this issue of Cell Host & Microbe, Kang et al. (2018) report that GPX4 is a negative regulator of the pyroptotic cell death pathway and plays an important role in inhibiting lethal inflammation associated with sepsis.
July 11, 2018: Cell Host & Microbe
Shahnawaz Kumbhar, Alam Z Khan, Fahmida Parveen, Zaheer A Nizamani, Farman A Siyal, Mohamed E Abd El-Hack, Fang Gan, Yunhuan Liu, Muhammad Hamid, Sonia A Nido, Kehe Huang
The study was carried out to investigate the effect of dietary selenium (Se) and vitamin E (VE) supplementation on mRNA level of heat shock proteins, selenoproteins, and antioxidant enzyme activities in the breast meat of broilers under summer heat stress conditions. A total of 200 male broilers (Ross 308) of 1 day age were randomly separated into 4 groups in a complete randomized design and were given a basal diet (Control, 0.08 mg Se/kg diet) or basal diet supplemented with VE (250 mg/kg VE), sodium selenite (0...
July 10, 2018: AMB Express
Yun Sun, Yingfeng Zheng, Chunxiao Wang, Yizhi Liu
Glutathione (GSH) protects against oxidative damage in many tissues, including retinal pigment epithelium (RPE). Oxidative stress-mediated senescence and death of RPE and subsequent death of photoreceptors have been observed in age-related macular degeneration (AMD). Although the consequences of GSH depletion have been described previously, questions remain regarding the molecular mechanisms. We herein examined the downstream effects of GSH depletion on stress-induced premature senescence (SIPS) and cell death in human RPE cells...
July 9, 2018: Cell Death & Disease
Silvia Codenotti, Maura Poli, Michela Asperti, Daniela Zizioli, Francesco Marampon, Alessandro Fanzani
PURPOSE: Ferroptosis is a programmed form of iron-dependent cell death caused by lipid hydroperoxide accumulation, which can be prevented by glutathione peroxidase 4 (GPx4) activity. Here we investigated the effects of ferroptosis inducers called erastin and RSL3, which act by glutathione depletion and GPx4 inactivation, respectively, on muscle-derived cell lines of embryonal and alveolar rhabdomyosarcoma (RMS), and mouse normal skeletal C2C12 myoblasts. METHODS: Myogenic lines were exposed to stepwise increasing concentrations of ferroptosis inducers either alone or in combination with iron supplementation, iron chelating agents (bathophenanthrolinedisulfonic acid, BPS), antioxidant molecules (glutathione, N-acetylcysteine), lipid peroxidation inhibitors (ferrostatin-1), and chemotherapeutic agents (doxorubicin and actinomycin D)...
September 2018: Journal of Cancer Research and Clinical Oncology
Rui Kang, Ling Zeng, Shan Zhu, Yangchun Xie, Jiao Liu, Qirong Wen, Lizhi Cao, Min Xie, Qitao Ran, Guido Kroemer, Haichao Wang, Timothy R Billiar, Jianxin Jiang, Daolin Tang
Sepsis is a life-threatening condition caused by pathogen infection and associated with pyroptosis. Pyroptosis occurs upon activation of proinflammatory caspases and their subsequent cleavage of gasdermin D (GSDMD), resulting in GSDMD N-terminal fragments that form membrane pores to induce cell lysis. Here, we show that antioxidant defense enzyme glutathione peroxidase 4 (GPX4) and its ability to decrease lipid peroxidation, negatively regulate macrophage pyroptosis, and septic lethality in mice. Conditional Gpx4 knockout in myeloid lineage cells increases lipid peroxidation-dependent caspase-11 activation and GSDMD cleavage...
July 11, 2018: Cell Host & Microbe
Caitlin W Brown, John J Amante, Arthur M Mercurio
Ferroptosis is an iron-dependent form of programmed cell death characterized by the accumulation of lipid-targeting reactive oxygen species that kill cells by damaging their plasma membrane. The lipid repair enzyme GSH peroxidase 4 (GPX4) protects against this oxidative damage and enables cells to resist ferroptosis. Recent work has revealed that matrix-detached carcinoma cells can be susceptible to ferroptosis and that they can evade this fate through the signaling properties of the α6β4 integrin, which sustains GPX4 expression...
August 17, 2018: Journal of Biological Chemistry
Hui Zhao, Flora S Kalish, Ronald J Wong, David K Stevenson
PROBLEM: Uterine and placental macrophages play critical roles in maintaining a normal pregnancy. The majority of these macrophages are believed to be alternatively activated macrophages (M2). METHOD OF STUDY: Mouse bone marrow cells were differentiated into macrophages and polarized to M2 in vitro by treatment with IL-4 [M2a] or IL-10 [M2c] and M1 with LPS/IFN-γ as controls. Macrophage subtypes were confirmed by surface markers and characterized by gene expression profiles...
June 22, 2018: American Journal of Reproductive Immunology: AJRI
Adauto Tsutomu Ikejiri, Frederico Somaio Neto, Paulo Roberto Bertoletto, José Carlos Chaves, Alexandre Key WakateTeruya, Cândida Aparecida Leite Kassuya, Murched Omar Taha, Djalma José Fagundes
PURPOSE: To evaluate the effect of hyperbaric oxygenation (HBO) on the expression of the genes antioxidant glutathione peroxidase 4 (Gpx4) and lactoperoxidase (Lpo) in the lung of mice subjected to intestinal ischemia and reperfusion (IIR). METHODS: Control group (CG) in which were subjected to anesthesia, laparotomy and observation for 120 minutes; an ischemia and reperfusion group (IRG) subjected to anesthesia, laparotomy, small bowel ischemia for 60 minutes and reperfusion for 60 minutes; and three groups treated with HBO during ischemia (HBOG + I), during reperfusion (HBOG + R) and during ischemia and reperfusion (HBOG + IR)...
May 2018: Acta Cirúrgica Brasileira
Michael J Kerins, John Milligan, James A Wohlschlegel, Aikseng Ooi
Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a hereditary cancer syndrome characterized by inactivation of the Krebs cycle enzyme fumarate hydratase (FH). HLRCC patients are at high risk of developing kidney cancer of type 2 papillary morphology that is refractory to current radiotherapy, immunotherapy and chemotherapy. Hence, an effective therapy for this deadly form of cancer is urgently needed. Here, we show that FH inactivation (FH-/- ) proves synthetic lethal with inducers of ferroptosis, an iron-dependent and nonapoptotic form of cell death...
September 2018: Cancer Science
Jin Wang, Qi-Fan Zeng, Hui Wang, Wei Chen, Yong-Qing Zeng
Ultimate pH (pHu ) is a major determinant factor of meat quality. In this study, we investigated the effects of pHu on the muscle antioxidant capacity, and the relationship between pHu and muscle antioxidant capacity of pigs. A total of 137 pigs from three pig breeds with the same feeding condition were slaughtered and used to measure the pHu , superoxide dismutase (SOD), glutathione peroxidase (GSH-PX), total antioxidant capacity (T-AOC), and malondialdehyde (MDA) content, and gene expression of SOD1 and GPX4...
September 2018: Animal Science Journal, Nihon Chikusan Gakkaihō
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