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1.
Nat Chem Biol ; 17(4): 465-476, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33542532

RESUMO

Ferroptosis, triggered by discoordination of iron, thiols and lipids, leads to the accumulation of 15-hydroperoxy (Hp)-arachidonoyl-phosphatidylethanolamine (15-HpETE-PE), generated by complexes of 15-lipoxygenase (15-LOX) and a scaffold protein, phosphatidylethanolamine (PE)-binding protein (PEBP)1. As the Ca2+-independent phospholipase A2ß (iPLA2ß, PLA2G6 or PNPLA9 gene) can preferentially hydrolyze peroxidized phospholipids, it may eliminate the ferroptotic 15-HpETE-PE death signal. Here, we demonstrate that by hydrolyzing 15-HpETE-PE, iPLA2ß averts ferroptosis, whereas its genetic or pharmacological inactivation sensitizes cells to ferroptosis. Given that PLA2G6 mutations relate to neurodegeneration, we examined fibroblasts from a patient with a Parkinson's disease (PD)-associated mutation (fPDR747W) and found selectively decreased 15-HpETE-PE-hydrolyzing activity, 15-HpETE-PE accumulation and elevated sensitivity to ferroptosis. CRISPR-Cas9-engineered Pnpla9R748W/R748W mice exhibited progressive parkinsonian motor deficits and 15-HpETE-PE accumulation. Elevated 15-HpETE-PE levels were also detected in midbrains of rotenone-infused parkinsonian rats and α-synuclein-mutant SncaA53T mice, with decreased iPLA2ß expression and a PD-relevant phenotype. Thus, iPLA2ß is a new ferroptosis regulator, and its mutations may be implicated in PD pathogenesis.


Assuntos
Ferroptose/fisiologia , Fosfolipases A2 do Grupo VI/metabolismo , Animais , Araquidonato 15-Lipoxigenase/metabolismo , Modelos Animais de Doenças , Feminino , Fosfolipases A2 do Grupo VI/fisiologia , Humanos , Ferro/metabolismo , Leucotrienos/metabolismo , Metabolismo dos Lipídeos/fisiologia , Peróxidos Lipídicos/metabolismo , Lipídeos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Oxirredução , Doença de Parkinson/metabolismo , Proteína de Ligação a Fosfatidiletanolamina/metabolismo , Fosfolipases/metabolismo , Fosfolipídeos/metabolismo , Ratos , Ratos Endogâmicos Lew
2.
Mycotoxin Res ; 36(3): 287-299, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32076947

RESUMO

Deoxynivalenol (DON) is a type B trichothecenes that is widely contaminating human and animal foods, leading to several toxicological implications if ingested. Induction of oxidative stress and production of lipid peroxides were suggested to be the reasons for DON-induced cytotoxicity. However, detailed and comprehensive profiling of DON-related lipid hydroperoxides was not identified. Furthermore, the mechanisms behind DON-induced cytotoxicity and oxidative stress have received less attention. Zinc (Zn) is an essential element that has antioxidant activities; however, the protective effects of Zn against DON-induced adverse effects were not examined. Therefore, this study was undertaken to investigate DON-induced cytotoxicity and oxidative damage to human HepG2 cell lines. Furthermore, a quantitative estimation for the formed lipid hydroperoxides was conducted using LC-MS/MS. In addition, DON-induced transcriptomic changes on the inflammatory markers and antioxidant enzymes were quantitatively examined using qPCR. The protective effects of Zn against DON-induced cytotoxicity and oxidative stress, the formation of lipid hydroperoxides (LPOOH), and antioxidant status in HepG2 cells were investigated. Finally, the effects of DON and Zn on the Nrf2-Keap1 pathway were further explored. The achieved results indicated that DON caused significant cytotoxicity in HepG2 cells accompanied by significant oxidative damage and induction of the inflammatory markers. Identification of DON-related LPOOH revealed the formation of 22 LPOOH species including 14 phosphatidylcholine hydroperoxides, 5 triacylglycerol hydroperoxides, and 3 cholesteryl ester hydroperoxides. DON caused significant downregulation of Nrf2-regulated antioxidant enzymes. Zn administration led to significant protection of HepG2 cells against DON-induced adverse effects, probably via activation of the Nrf2-Keap1 pathway.


Assuntos
Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Peróxidos Lipídicos/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Tricotecenos/toxicidade , Zinco/farmacologia , Células Hep G2 , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Peróxidos Lipídicos/química , Fator 2 Relacionado a NF-E2/genética , Oxirredução/efeitos dos fármacos
3.
Nat Chem Biol ; 16(3): 278-290, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32080625

RESUMO

Ferroptotic death is the penalty for losing control over three processes-iron metabolism, lipid peroxidation and thiol regulation-that are common in the pro-inflammatory environment where professional phagocytes fulfill their functions and yet survive. We hypothesized that redox reprogramming of 15-lipoxygenase (15-LOX) during the generation of pro-ferroptotic signal 15-hydroperoxy-eicosa-tetra-enoyl-phosphatidylethanolamine (15-HpETE-PE) modulates ferroptotic endurance. Here, we have discovered that inducible nitric oxide synthase (iNOS)/NO•-enrichment of activated M1 (but not alternatively activated M2) macrophages/microglia modulates susceptibility to ferroptosis. Genetic or pharmacologic depletion/inactivation of iNOS confers sensitivity on M1 cells, whereas NO• donors empower resistance of M2 cells to ferroptosis. In vivo, M1 phagocytes, in comparison to M2 phagocytes, exert higher resistance to pharmacologically induced ferroptosis. This resistance is diminished in iNOS-deficient cells in the pro-inflammatory conditions of brain trauma or the tumour microenvironment. The nitroxygenation of eicosatetraenoyl (ETE)-PE intermediates and oxidatively truncated species by NO• donors and/or suppression of NO• production by iNOS inhibitors represent a novel redox mechanism of regulation of ferroptosis in pro-inflammatory conditions.


Assuntos
Ferroptose/fisiologia , Macrófagos/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Animais , Araquidonato 15-Lipoxigenase/metabolismo , Araquidonato 15-Lipoxigenase/fisiologia , Morte Celular , Feminino , Ferro/metabolismo , Ferro/fisiologia , Leucotrienos/metabolismo , Peroxidação de Lipídeos/fisiologia , Peróxidos Lipídicos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/metabolismo , Óxido Nítrico Sintase Tipo II/fisiologia , Oxirredução , Espécies Reativas de Oxigênio/metabolismo
4.
PLoS One ; 15(2): e0215113, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32107484

RESUMO

Reinforcement of the hydroperoxide-eliminating activity in the small and large intestines should prevent associated diseases. We previously isolated a lactic acid bacterium, Pediococcus pentosaceus Be1 that facilitates a 2-electron reduction of hydrogen peroxide to water. In this study, we successfully isolated an alternative lactic acid bacterium, Lactobacillus plantarum P1-2, that can efficiently reduce environmental alkyl hydroperoxides and fatty acid hydroperoxides to their corresponding hydroxyl derivatives through a 2-electron reduction. Each strain exhibited a wide concentration range with regard to the environmental reducing activity for each hydroperoxide. Given this, the two lactic acid bacteria were orally administered to an oxygen-sensitive short-lived nematode mutant, and this resulted in a significant expansion of its lifespan. This observation suggests that P. pentosaceus Be1 and L. plantarum P1-2 inhibit internal oxidative stress. To determine the specific organs involved in this response, we performed a similar experiment in rats, involving induced lipid peroxidation by iron-overloading. We observed that only L. plantarum P1-2 inhibited colonic mucosa lipid peroxidation in rats with induced oxidative stress.


Assuntos
Mucosa Intestinal/microbiologia , Lactobacillus plantarum/metabolismo , Peróxidos Lipídicos/metabolismo , Estresse Oxidativo , Animais , Caenorhabditis elegans , Mucosa Intestinal/metabolismo , Lactobacillus plantarum/patogenicidade , Masculino , Oxirredução , Ratos , Ratos Wistar
5.
Redox Biol ; 28: 101328, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31574461

RESUMO

Ferroptosis is a form of cell death primed by iron and lipid hydroperoxides and prevented by GPx4. Ferrostatin-1 (fer-1) inhibits ferroptosis much more efficiently than phenolic antioxidants. Previous studies on the antioxidant efficiency of fer-1 adopted kinetic tests where a diazo compound generates the hydroperoxyl radical scavenged by the antioxidant. However, this reaction, accounting for a chain breaking effect, is only minimally useful for the description of the inhibition of ferrous iron and lipid hydroperoxide dependent peroxidation. Scavenging lipid hydroperoxyl radicals, indeed, generates lipid hydroperoxides from which ferrous iron initiates a new peroxidative chain reaction. We show that when fer-1 inhibits peroxidation, initiated by iron and traces of lipid hydroperoxides in liposomes, the pattern of oxidized species produced from traces of pre-existing hydroperoxides is practically identical to that observed following exhaustive peroxidation in the absence of the antioxidant. This supported the notion that the anti-ferroptotic activity of fer-1 is actually due to the scavenging of initiating alkoxyl radicals produced, together with other rearrangement products, by ferrous iron from lipid hydroperoxides. Notably, fer-1 is not consumed while inhibiting iron dependent lipid peroxidation. The emerging concept is that it is ferrous iron itself that reduces fer-1 radical. This was supported by electroanalytical evidence that fer-1 forms a complex with iron and further confirmed in cells by fluorescence of calcein, indicating a decrease of labile iron in the presence of fer-1. The notion of such as pseudo-catalytic cycle of the ferrostatin-iron complex was also investigated by means of quantum mechanics calculations, which confirmed the reduction of an alkoxyl radical model by fer-1 and the reduction of fer-1 radical by ferrous iron. In summary, GPx4 and fer-1 in the presence of ferrous iron, produces, by distinct mechanism, the most relevant anti-ferroptotic effect, i.e the disappearance of initiating lipid hydroperoxides.


Assuntos
Cicloexilaminas/farmacologia , Ferroptose/efeitos dos fármacos , Fenilenodiaminas/farmacologia , Antioxidantes/farmacologia , Morte Celular/efeitos dos fármacos , Cromatografia Líquida , Cicloexilaminas/química , Teoria da Densidade Funcional , Relação Dose-Resposta a Droga , Ferroptose/genética , Hidrogênio/química , Peroxidação de Lipídeos/efeitos dos fármacos , Peróxidos Lipídicos/metabolismo , Lipidômica/métodos , Lipídeos/química , Modelos Moleculares , Estrutura Molecular , Oxirredução , Fenilenodiaminas/química , Espectrometria de Massas em Tandem
6.
J Sci Food Agric ; 100(5): 2074-2081, 2020 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-31875960

RESUMO

BACKGROUND: A mouse model in which diabetes mellitus was induced by low-dose streptozotocin (STZ) injection combined with a high-fat diet was used to study the effect of two water cress (Lepidium savitum) preparations. Diabetic mice were treated with dried cress powder or with water-soluble extracts (tested at two doses), together with proper control groups. The mice were evaluated after 4 weeks of continuous intervention for type 2 diabetic and associated markers. We determined blood glucose, body weight, total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL), high-density lipoprotein (HDL), serum insulin levels, and DNA integrity of hepatic cells. The concentrations of malondialdehyde (MDA) and lipid peroxide (LPO) and the activities of four enzymes that are part of the antioxidant defense system were determined in liver samples, as well as gene expression (by semi-quantitative reverse transcription polymerase chain reaction) and enzyme activity of IRS-1, IRS-2, PI3K, AKT-2, and GLUT4. RESULTS: After 4 weeks of intervention, the levels of TC, TG, and LDL cholesterol were significantly (P < 0.5) decreased and HDL cholesterol was significantly increased. Enzyme activities of liver superoxide dismutase, glutathione, glutathione peroxidase, and catalase were significantly increased, whereas MDA and LPO concentrations were significantly reduced. The transcription level of the five genes assessed was increased, with corresponding increases in protein expression. CONCLUSION: Oral uptake of garden cress can significantly reduce the blood glucose and improve the blood lipid metabolism of diabetic mice. Considerable improvements in the activity of antioxidant defense enzymes were observed in type 2 diabetic mice that improved the body's antioxidant emergency response. © 2019 Society of Chemical Industry.


Assuntos
Glicemia/metabolismo , Dieta Hiperlipídica , Lepidium sativum/química , Lipídeos/sangue , Animais , Antioxidantes/metabolismo , Catalase/metabolismo , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Fragmentação do DNA , Diabetes Mellitus Experimental/prevenção & controle , Regulação da Expressão Gênica , Transportador de Glucose Tipo 4/genética , Transportador de Glucose Tipo 4/metabolismo , Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Hemoglobina A Glicada/metabolismo , Hipoglicemiantes/farmacologia , Insulina/sangue , Proteínas Substratos do Receptor de Insulina/genética , Proteínas Substratos do Receptor de Insulina/metabolismo , Peróxidos Lipídicos/metabolismo , Masculino , Malondialdeído/metabolismo , Camundongos , Camundongos Endogâmicos ICR , Estresse Oxidativo/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Extratos Vegetais/farmacologia , Superóxido Dismutase/metabolismo , Triglicerídeos/sangue
7.
F1000Res ; 82019.
Artigo em Inglês | MEDLINE | ID: mdl-31814961

RESUMO

Muscle failure has been demonstrated in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Neurophysiological tools demonstrate the existence of both central and peripheral fatigue in these patients. Central fatigue is deduced from the reduced amplitude of myopotentials evoked by transcranial magnetic stimulation of the motor cortex as well as by the muscle response to interpolated twitches during sustained fatiguing efforts. An impaired muscle membrane conduction velocity assessed by the reduced amplitude and lengthened duration of myopotentials evoked by direct muscle stimulation is the defining feature of peripheral fatigue. Some patients with ME/CFS show an increased oxidative stress response to exercise. The formation of lipid hydroperoxides in the sarcolemma, which alters ionic fluxes, could explain the reduction of muscle membrane excitability and potassium outflow often measured in these patients. In patients with ME/CFS, the formation of heat shock proteins (HSPs) is also reduced. Because HSPs protect muscle cells against the deleterious effects of reactive oxygen species, the lack of their production could explain the augmented oxidative stress and the consecutive alterations of myopotentials which could open a way for future treatment of ME/CFS.


Assuntos
Síndrome de Fadiga Crônica/fisiopatologia , Doenças Musculares/fisiopatologia , Exercício Físico , Proteínas de Choque Térmico/metabolismo , Humanos , Peróxidos Lipídicos/metabolismo , Músculo Esquelético/fisiopatologia , Estresse Oxidativo , Potássio/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Estimulação Magnética Transcraniana
8.
Georgian Med News ; (295): 141-145, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31804217

RESUMO

Aim - to assess the effects of doxycycline on the state of lipid peroxidation processes and the activity of the antioxidant system. The study was performed on 144 rats of the WAG population weighing 200-250 g (6 rats in each group). Animals with thermal burns were injected with the test drug doxycycline, as well as reference drugs - thiotriazolin and methyluracil orally in starch suspensionafter thermal exposure and daily during the entire experiment period (28 days). Animals were removed from the experiment in accordance with the rules of bioethics on the 7th, 14th, 21st and 28th day. As a result of the research, the most intense influence of doxycycline on the processes of lipid peroxidation in the blood serum of rats was found - a decrease in DC activity by the end of the experiment (regardless of dose) and TBA-AP starting from the 14th day of observation reaching the value of intact rats (at a dose of 30 mg/kg). At the same time, an increase in the activity of enzymes of the antioxidant system was noted - the level of catalase from the 14th day (significantly higher than the control group regardless of dose) and the level of ceruloplasmin (from the second week of observation the indicator reached intact values ​​at a dose of 30 mg/kg). Reference drugs were inferior to doxycycline in their effectiveness. The data obtained may indicate the possibility of reducing the healing time of a thermal burn due to the suppression of excessive free radical oxidation activity and activation of antioxidant protection.


Assuntos
Antioxidantes , Queimaduras , Peróxidos Lipídicos , Metaloproteinases da Matriz , Animais , Antibacterianos/farmacologia , Antioxidantes/farmacologia , Queimaduras/tratamento farmacológico , Queimaduras/metabolismo , Doxiciclina/farmacologia , Peroxidação de Lipídeos , Peróxidos Lipídicos/metabolismo , Metaloproteinases da Matriz/metabolismo , Oxirredução , Cicatrização
9.
Cell Death Dis ; 10(12): 902, 2019 11 28.
Artigo em Inglês | MEDLINE | ID: mdl-31780644

RESUMO

The incidence of melanoma is increasing over the years with a still poor prognosis and the lack of a cure able to guarantee an adequate survival of patients. Although the new immuno-based coupled to target therapeutic strategy is encouraging, the appearance of targeted/cross-resistance and/or side effects such as autoimmune disorders could limit its clinical use. Alternative therapeutic strategies are therefore urgently needed to efficiently kill melanoma cells. Ferroptosis induction and execution were evaluated in metastasis-derived wild-type and oncogenic BRAF melanoma cells, and the process responsible for the resistance has been dissected at molecular level. Although efficiently induced in all cells, in an oncogenic BRAF- and ER stress-independent way, most cells were resistant to ferroptosis execution. At molecular level we found that: resistant cells efficiently activate NRF2 which in turn upregulates the early ferroptotic marker CHAC1, in an ER stress-independent manner, and the aldo-keto reductases AKR1C1 ÷ 3 which degrades the 12/15-LOX-generated lipid peroxides thus resulting in ferroptotic cell death resistance. However, inhibiting AKRs activity/expression completely resensitizes resistant melanoma cells to ferroptosis execution. Finally, we found that the ferroptotic susceptibility associated with the differentiation of melanoma cells cannot be applied to metastatic-derived cells, due to the EMT-associated gene expression reprogramming process. However, we identified SCL7A11 as a valuable marker to predict the susceptibility of metastatic melanoma cells to ferroptosis. Our results identify the use of pro-ferroptotic drugs coupled to AKRs inhibitors as a new valuable strategy to efficiently kill human skin melanoma cells.


Assuntos
Aldo-Ceto Redutases/metabolismo , Estresse do Retículo Endoplasmático , Ferroptose , Melanoma/enzimologia , Melanoma/patologia , Aldo-Ceto Redutases/antagonistas & inibidores , Araquidonato 15-Lipoxigenase/metabolismo , Biomarcadores Tumorais/metabolismo , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Ferroptose/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Peróxidos Lipídicos/metabolismo , Melanoma/genética , Fator 2 Relacionado a NF-E2/metabolismo , Metástase Neoplásica , Oncogenes , Piperazinas/farmacologia , Proteínas Proto-Oncogênicas B-raf/metabolismo , Regulação para Cima/efeitos dos fármacos , gama-Glutamilciclotransferase/metabolismo
10.
Chem Biol Interact ; 314: 108847, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31610155

RESUMO

Lead (Pb) is one of the toxic heavy metals that have several toxicological implications including cytotoxicities and oxidative stress. The release of reactive oxygen species (ROS) usually initiates lipid peroxidation and resulting in inflammation and tissue injury. However, the detailed identification of the Pb-produced lipid hydroperoxides has received little attention. Furthermore, the mechanisms behind such effects are less informed. Therefore, this study firstly investigated Pb-produced lipid hydroperoxides in human HepG2 cells using LC/MS. The effects of Pb on the antioxidant enzymes were additionally examined using qPCR and their dependent activities. As a protection trial, the ameliorative effects of rosmarinic (RMA) and ascorbic (ASA) acids on Pb-induced cytotoxicity and oxidative stress and their regulatory effects on Nrf2/Keap1 pathway were investigated. The achieved results confirmed cytotoxicity and oxidative damage of Pb on HepG2 cells. In addition, 20 lipid hydroperoxides (LOOH) were identified including 11 phosphatidylcholine hydroperoxides (PCOOH), 5 triacylglycerol hydroperoxides (TGOOH) and 4 cholesteryl ester hydroperoxides (CEOOH). The most dominant LOOH species were PCOOH 34:2, PCOOH 34:3, PCOOH 38:7, TGOOH 60:14, TGOOH 60:15, CEOOH 18:3 and CEOOH 20:4. Pb significantly downregulated Nrf2-regulated antioxidant enzymes at both the pretranscriptional and functional levels. Co-exposure of HepG2 cells to RMA and ASA significantly reduced Pb-produced adverse outcomes. This protection occurred via activation Nrf2-Keap1 antioxidant pathway.


Assuntos
Antioxidantes/metabolismo , Ácido Ascórbico/química , Cinamatos/química , Depsídeos/química , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Chumbo/química , Fator 2 Relacionado a NF-E2/metabolismo , Ácido Ascórbico/farmacologia , Cromatografia Líquida de Alta Pressão , Cinamatos/farmacologia , Depsídeos/farmacologia , Regulação para Baixo/efeitos dos fármacos , Células Hep G2 , Humanos , Chumbo/toxicidade , Peróxidos Lipídicos/análise , Peróxidos Lipídicos/metabolismo , Espectrometria de Massas , NAD(P)H Desidrogenase (Quinona)/genética , NAD(P)H Desidrogenase (Quinona)/metabolismo , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Superóxido Dismutase-1/genética , Superóxido Dismutase-1/metabolismo
11.
Nature ; 575(7784): 688-692, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31634900

RESUMO

Ferroptosis is a form of regulated cell death that is caused by the iron-dependent peroxidation of lipids1,2. The glutathione-dependent lipid hydroperoxidase glutathione peroxidase 4 (GPX4) prevents ferroptosis by converting lipid hydroperoxides into non-toxic lipid alcohols3,4. Ferroptosis has previously been implicated in the cell death that underlies several degenerative conditions2, and induction of ferroptosis by the inhibition of GPX4 has emerged as a therapeutic strategy to trigger cancer cell death5. However, sensitivity to GPX4 inhibitors varies greatly across cancer cell lines6, which suggests that additional factors govern resistance to ferroptosis. Here, using a synthetic lethal CRISPR-Cas9 screen, we identify ferroptosis suppressor protein 1 (FSP1) (previously known as apoptosis-inducing factor mitochondrial 2 (AIFM2)) as a potent ferroptosis-resistance factor. Our data indicate that myristoylation recruits FSP1 to the plasma membrane where it functions as an oxidoreductase that reduces coenzyme Q10 (CoQ) (also known as ubiquinone-10), which acts as a lipophilic radical-trapping antioxidant that halts the propagation of lipid peroxides. We further find that FSP1 expression positively correlates with ferroptosis resistance across hundreds of cancer cell lines, and that FSP1 mediates resistance to ferroptosis in lung cancer cells in culture and in mouse tumour xenografts. Thus, our data identify FSP1 as a key component of a non-mitochondrial CoQ antioxidant system that acts in parallel to the canonical glutathione-based GPX4 pathway. These findings define a ferroptosis suppression pathway and indicate that pharmacological inhibition of FSP1 may provide an effective strategy to sensitize cancer cells to ferroptosis-inducing chemotherapeutic agents.


Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Ferroptose/genética , Proteínas Mitocondriais/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Ubiquinona/análogos & derivados , Animais , Proteínas Reguladoras de Apoptose/genética , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Regulação Enzimológica da Expressão Gênica , Xenoenxertos , Humanos , Peróxidos Lipídicos/metabolismo , Masculino , Camundongos , Camundongos SCID , Proteínas Mitocondriais/genética , Ubiquinona/metabolismo
12.
J Am Chem Soc ; 141(45): 18301-18307, 2019 11 13.
Artigo em Inglês | MEDLINE | ID: mdl-31644876

RESUMO

Ferroptosis, a new form of regulated cell death, results from the iron-dependent accumulation of lipid peroxides that are associated with reactive oxygen species. However, it remains unclear how hydroxyl radical (•OH) and cellular microenvironments such as viscosity alter in this process. Herein, we characterize for the first time the changing behavior of •OH and cytoplasmic viscosity during ferroptosis using a dual-functional fluorescence probe (H-V) that is designed via the molecular rotor strategy and the unique aromatic hydroxylation of •OH. Probe H-V shows completely separate spectral responses to •OH and viscosity with high sensitivity and selectivity, thereby achieving the detection of •OH and viscosity in two independent channels without spectral cross-interference. With the probe we find that ferroptosis is accompanied by significant •OH generation and cytoplasmic viscosity increase. Most notably, the raised •OH comprises the majority of the total reactive oxygen species in ferroptosis. H-V is biocompatible, ready to prepare, and may be expected to be used in the study of viscosity and •OH detection in more biosystems.


Assuntos
Citoplasma/metabolismo , Ferroptose/fisiologia , Corantes Fluorescentes/química , Radical Hidroxila/metabolismo , Linhagem Celular Tumoral , Citoplasma/química , Ferroptose/efeitos dos fármacos , Glutationa/metabolismo , Humanos , Gotículas Lipídicas/metabolismo , Peróxidos Lipídicos/metabolismo , Microscopia Confocal , Microscopia de Fluorescência , Piperazinas/farmacologia , Viscosidade
13.
Biogerontology ; 20(5): 711-722, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31363871

RESUMO

Despite its rare occurrence, humans and animals have been prone to getting fast developing severe hypobaric hypoxia. Understanding the redox homeostasis related response of an aging heart to this type of hypoxia are crucially important, since the metabolism of myocardial tissue depends on the redox status of proteins. Rodents can tolerate hypoxic stress better than human subjects. This study was aimed at investigating the effects of fast developing severe hypobaric hypoxia on redox status biomarkers; such as, advanced oxidation protein products (AOPP), lipid hydroperoxides (LHPs), protein carbonyl groups (PCO), protein thiol groups (P-SH), and total thiol groups (T-SH) on the myocardial left ventricles of young and aged Wistar rats. The rats were gradually ascended and exposed to an 8000-meter hypobaric hypoxia. While AOPP levels showed no difference, the TSH and PSH concentrations decreased, and the PCO and LHP increased in both of the hypoxic groups than the controls. The TSH and PSH were lower, and AOPP, PCO and LHP were found to be higher in the elderly hypoxic groups than in the young ones. The significant outcome of the study represents that an 8000-meter hypobaric hypoxia could be considered as a severe hypoxic stress, but not life-treating for the rats and would affect both the young and aged left ventricles similarly in respect to impaired redox status. However, if the percentage increases are taken into consideration, it seems that the higher rate of protein oxidation occurs in young hearts; meanwhile aged hearts are more prone to T-SH oxidation.


Assuntos
Produtos da Oxidação Avançada de Proteínas/metabolismo , Senescência Celular/fisiologia , Ventrículos do Coração , Homeostase , Hipóxia/metabolismo , Peróxidos Lipídicos/metabolismo , Miocárdio/metabolismo , Oxirredução , Animais , Pressão Atmosférica , Biomarcadores/metabolismo , Ventrículos do Coração/metabolismo , Ventrículos do Coração/patologia , Peroxidação de Lipídeos , Tamanho do Órgão , Condicionamento Físico Animal , Carbonilação Proteica , Ratos
14.
Plant J ; 100(3): 536-548, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31306517

RESUMO

In auxin-stimulated roots, production of reactive oxygen species (ROS) via the hormone-induced activation of respiratory burst oxidase homologous NADPH oxidases facilitates lateral root (LR) formation. In this study, in order to verify that ROS can modulate auxin signaling, we examined the involvement of the lipid peroxide-derived agents known as reactive carbonyl species (RCS) in LR formation. When auxin was added to Arabidopsis thaliana roots, the levels of RCS, for example acrolein, 4-hydroxynonenal and crotonaldehyde, were increased prior to LR formation. Addition of the carbonyl scavenger carnosine suppressed auxin-induced LR formation. Addition of RCS to the roots induced the expression of the auxin-responsive DR5 promoter and the TIR1, IAA14, ARF7, LBD16 and PUCHI genes and facilitated LR formation without increasing the endogenous auxin level. DR5 and LBD16 were activated in the LR primordia. The auxin signaling-deficient mutants arf7 arf19 and slr-1 did not respond - and tir1 afb2 appeared to show a poor response - to RCS. When given to the roots RCS promoted the disappearance of the AXR3NT-GUS fusion protein, i.e. the degradation of the auxin/indole-3-acetic acid protein, as did auxin. These results indicate that the auxin-induced production of ROS and their downstream products RCS modulate the auxin signaling pathway in a feed-forward manner. RCS are key agents that connect the ROS signaling and the auxin signaling pathways.


Assuntos
Arabidopsis/fisiologia , Radicais Livres/metabolismo , Ácidos Indolacéticos/metabolismo , Reguladores de Crescimento de Planta/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Arabidopsis/genética , Arabidopsis/crescimento & desenvolvimento , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Genes Reporter , Peróxidos Lipídicos/metabolismo , Oxilipinas/metabolismo , Raízes de Plantas/genética , Raízes de Plantas/crescimento & desenvolvimento , Raízes de Plantas/fisiologia , Regiões Promotoras Genéticas/genética , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo
15.
ACS Appl Mater Interfaces ; 11(33): 29655-29666, 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31359759

RESUMO

Ferroptosis is an iron-dependent cell death pathway that can eradicate certain apoptosis-insensitive cancer cells. The ferroptosis-inducing molecules are tailored lipid peroxides whose efficacy is compromised in hypoxic solid tumor and lack of tumor selectivity. It has been demonstrated that ascorbate (Asc) in pharmacological concentrations can selectively kill cancer cells via accumulating hydrogen peroxide (H2O2) only in tumor extracellular fluids. It was hypothesized that Asc-induced, selective enrichment of H2O2 in tumor coupled with Fe3+ codelivery could simultaneously address the above two problems via boosting the levels of hydroxyl radicals and oxygen in the tumor site to ease peroxidation initiation and propagation, respectively. The aim of this work was to synergize the action of Asc with lipid-coated calcium phosphate (CaP) hybrid nanocarrier that can concurrently load polar Fe3+ and nonpolar RSL3, a ferroptosis inducer with the mechanism of inhibiting lipid peroxide repair enzyme (GPX4). The hybrid nanocarriers showed accelerated cargo release at acidic conditions (pH 5.0). The combinational approach (Asc plus nanocarrier) produced significantly elevated levels of hydroxyl radicals, lipid peroxides, and depleted glutathione under hypoxia, which was accompanied with the strong cytotoxicity (IC50 = 1.2 ± 0.2 µM) in the model 4 T1 cells. In the 4 T1 tumor-bearing xenograft mouse model, the intravenous nanocarrier delivery plus intraperitoneal Asc administration resulted in a superior antitumor performance in terms of tumor suppression, which did not produce supplementary adverse effects to the healthy organs. This work provides a novel approach to enhance the potency of ferroptotic nanomedicine against solid tumors without inducing additional side effects.


Assuntos
Antineoplásicos/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Fosfatos de Cálcio , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Ferroptose/efeitos dos fármacos , Glutationa/metabolismo , Humanos , Peróxido de Hidrogênio/metabolismo , Peróxidos Lipídicos/química , Peróxidos Lipídicos/metabolismo , Camundongos , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Eur J Pharm Biopharm ; 142: 1-7, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31176725

RESUMO

Recent studies using 3D scaffolds have emphasized the importance of the surrounding stroma on chemoresistance in drug efficacy screenings. Since 15-lipoxygenase (15-LOX) metabolites reduced growth of breast, colon, prostate, lung and leukemia cancer cells in 2D cell culture, we were intrigued by the direct comparison of 15-LOX metabolite efficacy in 2D and 3D culture including a stroma equivalent. Herein, we studied the effects of 15-LOX metabolites 13-HpOTrE, 13-HpODE, and 15-HpETE on cutaneous squamous cell carcinoma cells. All metabolites reduced the viability of cancer cells in 2D culture below 10% at 100 µM of each substance. 13-HpOTrE, being the most active agent with respect to cytotoxicity and apoptosis was selected for further experiments. Other than with the 2D culture, we did not obverse cell death, neither from lactate dehydrogenase release, nor from morphology when applying 13-HpOTrE onto the surface of the 3D tumor constructs for one week. Next, we investigated the protein expression of peroxisome proliferator activated receptor gamma, for which the ligand is 13-HpOTrE, and Bcl-2 protein, an apoptosis regulator, but did not find any change following 13-HpOTrE administration. However, 13-HpOTrE treatment reduced the release of interleukin-6, bringing it closer to the level of tumor-free constructs. In conclusion, 13-HpOTrE reduces viability of skin cancer cells in 2D cultures only but modulates inflammatory cytokine levels in the corresponding 3D tumor constructs, too. These studies highlight the need for screening of anticancer drugs employing 3D tumors and including tumor microenvironment in the screening process to increase the low success rate of clinical trials in oncology.


Assuntos
Anti-Inflamatórios/farmacologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Araquidonato 15-Lipoxigenase/metabolismo , Leucotrienos/metabolismo , Ácidos Linoleicos/metabolismo , Peróxidos Lipídicos/metabolismo , Microambiente Tumoral/efeitos dos fármacos , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/metabolismo
17.
Am J Physiol Heart Circ Physiol ; 317(1): H156-H163, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31050558

RESUMO

Cell death is an important component of the pathophysiology of any disease. Myocardial disease is no exception. Understanding how and why cells die, particularly in the heart where cardiomyocyte regeneration is limited at best, becomes a critical area of study. Ferroptosis is a recently described form of nonapoptotic cell death. It is an iron-mediated form of cell death that occurs because of accumulation of lipid peroxidation products. Reactive oxygen species and iron-mediated phospholipid peroxidation is a hallmark of ferroptosis. To date, ferroptosis has been shown to be involved in cell death associated with Alzheimer's disease, Huntington's disease, cancer, Parkinson's disease, and kidney degradation. Myocardial reperfusion injury is characterized by iron deposition as well as reactive oxygen species production. These conditions, therefore, favor the induction of ferroptosis. Currently there is no available treatment for reperfusion injury, which accounts for up to 50% of the final infarct size. This review will summarize the evidence that ferroptosis can induce cardiomyocyte death following reperfusion injury and the potential for this knowledge to open new therapeutic approaches for myocardial ischemia-reperfusion injury.


Assuntos
Ferroptose , Ferro/metabolismo , Peroxidação de Lipídeos , Peróxidos Lipídicos/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Miócitos Cardíacos/metabolismo , Fosfolipídeos/metabolismo , Animais , Humanos , Traumatismo por Reperfusão Miocárdica/patologia , Miócitos Cardíacos/patologia , Oxirredução , Transdução de Sinais
18.
Environ Pollut ; 252(Pt A): 51-61, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31146238

RESUMO

Melatonin (Mel) serves as an important signalling molecule in various aspects of stress tolerance in plants. However, the function of Mel in pesticide metabolism remains unknown. Here, selecting the widely used fungicide carbendazim (MBC) as the model, we found that exogenous Mel had the ability to alleviate pesticide phytotoxicity and residues in tomato as well as in some other vegetables. Additionally, overexpression of the Mel biosynthetic gene caffeic acid O-methyltransferase 1 (COMT1) significantly enhanced the capacity of the tomato to reduce MBC phytotoxicity and residue. This outcome was mainly because of the Mel-induced antioxidant capability, as well as the key detoxification process. Indeed, levels of reactive oxygen species (ROS) and lipid peroxides significantly decreased after applying exogenous Mel or overexpressing COMT1, which resulted from direct ROS scavenging, and increased Mel levels significantly enhanced antioxidant enzymatic activity. More importantly, Mel activated the ascorbate-glutathione cycle to participate in glutathione S-transferase-mediated pesticide detoxification. A grafting experiment showed that rootstocks from COMT1 transgenic plants increased the Mel accumulation of wild-type scions, resulting in MBC metabolism in the scions. To our knowledge, this is the first report providing evidence of Mel-induced pesticide metabolism, which provides a novel approach for minimizing pesticide residues in crops by exploiting plant self-detoxification mechanisms.


Assuntos
Benzimidazóis/metabolismo , Carbamatos/metabolismo , Fungicidas Industriais/metabolismo , Inativação Metabólica/fisiologia , Lycopersicon esculentum/metabolismo , Melatonina/metabolismo , Metiltransferases/metabolismo , Benzimidazóis/toxicidade , Carbamatos/toxicidade , Fungicidas Industriais/toxicidade , Glutationa Transferase/metabolismo , Peróxidos Lipídicos/metabolismo , Melatonina/biossíntese , Metiltransferases/biossíntese , Plantas Geneticamente Modificadas/metabolismo , Espécies Reativas de Oxigênio/metabolismo
19.
Microbiome ; 7(1): 72, 2019 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-31060614

RESUMO

BACKGROUND: The World Health Organization classified processed and red meat consumption as "carcinogenic" and "probably carcinogenic", respectively, to humans. Haem iron from meat plays a role in the promotion of colorectal cancer in rodent models, in association with enhanced luminal lipoperoxidation and subsequent formation of aldehydes. Here, we investigated the short-term effects of this haem-induced lipoperoxidation on mucosal and luminal gut homeostasis including microbiome in F344 male rats fed with a haem-enriched diet (1.5 µmol/g) 14-21 days. RESULTS: Changes in permeability, inflammation, and genotoxicity observed in the mucosal colonic barrier correlated with luminal haem and lipoperoxidation markers. Trapping of luminal haem-induced aldehydes normalised cellular genotoxicity, permeability, and ROS formation on a colon epithelial cell line. Addition of calcium carbonate (2%) to the haem-enriched diet allowed the luminal haem to be trapped in vivo and counteracted these haem-induced physiological traits. Similar covariations of faecal metabolites and bacterial taxa according to haem-induced lipoperoxidation were identified. CONCLUSIONS: This integrated approach provides an overview of haem-induced modulations of the main actors in the colonic barrier. All alterations were closely linked to haem-induced lipoperoxidation, which is associated with red meat-induced colorectal cancer risk.


Assuntos
Aldeídos/metabolismo , Colo/metabolismo , Heme/administração & dosagem , Mucosa Intestinal/metabolismo , Ferro/metabolismo , Microbiota , Animais , Heme/metabolismo , Homeostase , Inflamação , Peróxidos Lipídicos/metabolismo , Masculino , Testes de Mutagenicidade , Ratos , Ratos Endogâmicos F344
20.
Lipids Health Dis ; 18(1): 125, 2019 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-31138221

RESUMO

BACKGROUND: Exercise has proved effective in attenuating the unfavourable response normally associated with postprandial hypertriglyceridemia (PHTG) and accompanying oxidative stress. Yet, the acute effects of prior exercise and PHTG on DNA damage remains unknown. The purpose of this study was to examine if walking alters PHTG-induced oxidative damage and the interrelated inflammatory mechanisms. METHODS: Twelve apparently healthy, recreationally active, male participants (22.4 ± 4.1 years; 179.2 ± 6 cm; 84.2 ± 14.7 kg; 51.3 ± 8.6 ml·kg- 1·min- 1) completed a randomised, crossover study consisting of two trials: (1) a high-fat meal alone (resting control) or (2) a high-fat meal immediately following 1 h of moderate exercise (65% maximal heart rate). Venous blood samples were collected at baseline, immediately post-exercise or rest, as well as at 2, 4 and 6 h post-meal. Biomarkers of oxidative damage (DNA single-strand breaks, lipid peroxidation and free radical metabolism) and inflammation were determined using conventional biochemistry techniques. RESULTS: DNA damage, lipid peroxidation, free radical metabolism and triglycerides increased postprandially (main effect for time, p < 0.05), regardless of completing 1 h of preceding moderate intensity exercise. Plasma antioxidants (α-tocopherol and γ-tocopherol) also mobilised in response to the high-fat meal (main effect for time, p < 0.05), but no changes were detected for retinol-binding protein-4. CONCLUSION: The ingestion of a high fat meal induces postprandial oxidative stress, inflammation and a rise in DNA damage that remains unaltered by one hour of preceding exercise.


Assuntos
Vasos Sanguíneos/patologia , Dano ao DNA , Exercício Físico/fisiologia , Hipertrigliceridemia/sangue , Inflamação/sangue , Linfócitos/patologia , Período Pós-Prandial , Antioxidantes/metabolismo , Biomarcadores/metabolismo , Sedimentação Sanguínea , Quebras de DNA de Cadeia Simples , Humanos , Peróxidos Lipídicos/metabolismo , Masculino , Solubilidade , Adulto Jovem
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