Caveolae respond to acute oxidative stress through membrane lipid peroxidation, cytosolic release of CAVIN1, and downstream regulation of NRF2

2021 ◽  
Author(s):  
Yeping Wu ◽  
Ye-Wheen Lim ◽  
David Stroud ◽  
Nick Martel ◽  
Thomas Hall ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Lipid Peroxidation ◽  
Cultured Cells ◽  
Direct Interaction ◽  
Antioxidant Response ◽  
Membrane Lipid ◽  
Wound Response ◽  
Biological Functions ◽  
Structural Protein ◽  
Major Pathway

Abstract Caveolae have been linked to many biological functions, but their precise roles are unclear. Using quantitative whole cell proteomics of genome-edited cells, we show that the oxidative stress response is the major pathway dysregulated in cells lacking the key caveola structural protein, CAVIN1. CAVIN1 deletion compromised sensitivity to oxidative stress in cultured cells and in animals. Wound-induced accumulation of reactive oxygen species and apoptosis were suppressed in Cavin1-null zebrafish, negatively affecting regeneration. Oxidative stress triggered lipid peroxidation (LPO) and induced caveolar disassembly. The resulting release of CAVIN1 from caveolae allowed direct interaction between CAVIN1 and NRF2, a key regulator of the antioxidant response, facilitating NRF2 degradation. CAVIN1-null cells with impaired negative regulation of NRF2 showed resistance to LPO-induced ferroptosis. Thus, caveolae, via LPO and CAVIN1 release, maintain cellular susceptibility to oxidative stress-induced cell death demonstrating a crucial role for this enigmatic organelle in cellular homeostasis and wound response.

scholarly journals Caveolae, CAVIN1, and lipid peroxidation mediate the oxidative stress response

2021 ◽  
Author(s):  
Yeping Wu ◽  
Ye-Wheen Lim ◽  
David A Stroud ◽  
Nick Martel ◽  
Thomas E. Hall ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Lipid Peroxidation ◽  
Quantitative Proteomics ◽  
Cellular Response ◽  
Direct Interaction ◽  
Related Factor ◽  
The Novel ◽  
Biological Functions ◽  
Structural Protein ◽  
Mechanistic Studies

Caveolae have been linked to a number of biological functions but their precise roles are as yet unclear. Here we have undertaken an unbiased approach to characterize the cellular proteome regulated by the caveolar structural protein, CAVIN1, by utilizing genome-edited cells together with whole cell quantitative proteomics. Pathway analysis identified the cellular response to oxidative stress as the most significant effect of CAVIN1 loss. Functional experiments showed that sensitivity to oxidative stress was compromised in CAVIN1-null cells and zebrafish knockout lines. Mechanistic studies identified oxidative stress-triggered lipid peroxidation as the novel upstream mechanism for caveolar disassembly and release of CAVIN1. Disassembly of caveolae allows direct interaction of CAVIN1 and nuclear factor erythroid 2-related factor 2 (NRF2), a key antioxidant activator. This causes NRF2 sequestration and degradation in the cytosol, inhibiting its transcriptional function in the nucleus. Thus caveolae, via lipid peroxidation and CAVIN1 release, regulate cellular susceptibility to oxidative stress-induced ferroptosis.

scholarly journals The Effect of Nitrogen Fertilization and Fusarium culmorum Inoculation on the Biomarkers of Oxidative Stress in Wheat Flag Leaves

Poljoprivreda ◽  
2021 ◽  
Vol 27 (2) ◽  
pp. 15-24
Author(s):  
Magdalena Matić ◽  
◽  
Rosemary Vuković ◽  
Karolina Vrandečić ◽  
Ivna Štolfa Čamagajevac ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Hydrogen Peroxide ◽  
Lipid Peroxidation ◽  
Antioxidant Enzymes ◽  
Biotic Stress ◽  
Flag Leaf ◽  
Fusarium Culmorum ◽  
Antioxidant Response ◽  
The Impact ◽  
Biomarkers Of Oxidative Stress

During cultivation, wheat is exposed to several abiotic and/or biotic stress conditions that may adversely impact the wheat yield and quality. The impact of abiotic stress caused by nitrogen deficiency and biotic stress caused by phytopathogenic fungus Fusarium culmorum on biomarkers of oxidative stress in the flag leaf of nine winter wheat varieties (Ficko, U-1, Galloper, BC Mandica, BC Opsesija, Ingenio, Isengrain, Felix, and Bezostaya-1) was analyzed in this study. Hydrogen peroxide concentration and lipid peroxidation level were measured as indicators of oxidative stress, while the antioxidant response was determined by measuring the concentration of phenolic compounds and activities of antioxidant enzymes. Wheat variety and nitrogen treatment had a significant effect on all examined biomarkers of oxidative stress in the flag leaf, while the impact of Fusarium treatment was less pronounced. The most significant impact on the measured stress biomarkers had a low nitrogen level, which mainly increased hydrogen peroxide concentration and lipid peroxidation level and decreased activities of antioxidant enzymes in most varieties. The obtained results were discussed and compared with the previous study in which biochemical analyzes were performed on the wheat spike. There was no significant strong correlation between flag leaf and spike response in the measured parameters, which, in addition to the variety-specific response, also indicates a tissue-specific antioxidant response.

scholarly journals Multiple isoforms of mitochondrial glutathione S-transferases and their differential induction under oxidative stress

2002 ◽  
Vol 366 (1) ◽  
pp. 45-55 ◽  
Author(s):  
Haider RAZA ◽  
Marie-Anne ROBIN ◽  
Ji-kang FANG ◽  
Narayan G. AVADHANI
Keyword(s):  
Oxidative Stress ◽  
Lipid Peroxidation ◽  
Peptide Mapping ◽  
Mitochondrial Respiratory Chain ◽  
Immunoblot Analysis ◽  
Liver Mitochondria ◽  
Membrane Lipid ◽  
Dependent Manner ◽  
Mitochondrial Oxidative Stress ◽  
Mitochondrial Glutathione

The mitochondrial respiratory chain, which consumes approx. 85–90% of the oxygen utilized by cells, is a major source of reactive oxygen species (ROS). Mitochondrial genetic and biosynthetic systems are highly susceptible to ROS toxicity. Intramitochondrial glutathione (GSH) is a major defence against ROS. In the present study, we have investigated the nature of the glutathione S-transferase (GST) pool in mouse liver mitochondria, and have purified three distinct forms of GST: GSTA1-1 and GSTA4-4 of the Alpha family, and GSTM1-1 belonging to the Mu family. The mitochondrial localization of these multiple GSTs was confirmed using a combination of immunoblot analysis, protease protection assay, enzyme activity, N-terminal amino acid sequencing, peptide mapping and confocal immunofluorescence analysis. Additionally, exogenously added 4-hydroxynonenal (HNE), a reactive byproduct of lipid peroxidation, to COS cells differentially affected the cytosolic and mitochondrial GSH pools in a dose- and time-dependent manner. Our results show that HNE-mediated mitochondrial oxidative stress caused a decrease in the GSH pool, increased membrane lipid peroxidation, and increased levels of GSTs, glutathione peroxidase and Hsp70 (heat-shock protein 70). The HNE-induced oxidative stress persisted for longer in the mitochondrial compartment, where the recovery of GSH pool was slower than in the cytosolic compartment. Our study, for the first time, demonstrates the presence in mitochondria of multiple forms of GSTs that show molecular properties similar to those of their cytosolic counterparts. Our results suggest that mitochondrial GSTs may play an important role in defence against chemical and oxidative stress.

scholarly journals Ezetimibe Prevents Ischemia/Reperfusion-Induced Oxidative Stress and Up-Regulates Nrf2/ARE and UPR Signaling Pathways

Antioxidants ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 349 ◽  
Author(s):  
Denise Peserico ◽  
Chiara Stranieri ◽  
Ulisse Garbin ◽  
Chiara Mozzini C ◽  
Elisa Danese ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Cultured Cells ◽  
Ischemia Reperfusion ◽  
Cholesterol Absorption ◽  
Antioxidant Response ◽  
Related Factor ◽  
Cellular Models ◽  
Compound C ◽  
Cholesterol Absorption Inhibitor

Background: While reperfusion is crucial for survival after an episode of ischemia, it also causes oxidative stress. Nuclear factor-E2-related factor 2 (Nrf2) and unfolded protein response (UPR) are protective against oxidative stress and endoplasmic reticulum (ER) stress. Ezetimibe, a cholesterol absorption inhibitor, has been shown to activate the AMP-activated protein kinase (AMPK)/Nrf2 pathway. In this study we evaluated whether Ezetimibe affects oxidative stress and Nrf2 and UPR gene expression in cellular models of ischemia-reperfusion (IR). Methods: Cultured cells were subjected to simulated IR with or without Ezetimibe. Results: IR significantly increased reactive oxygen species (ROS) production and the percentage of apoptotic cells without the up-regulation of Nrf2, of the related antioxidant response element (ARE) gene expression or of the pro-survival UPR activating transcription factor 6 (ATF6) gene, whereas it significantly increased the pro-apoptotic CCAAT-enhancer-binding protein homologous protein (CHOP). Ezetimibe significantly decreased the cellular ROS formation and apoptosis induced by IR. These effects were paralleled by the up-regulation of Nrf2/ARE and ATF6 gene expression and by a down-regulation of CHOP. We also found that Nrf2 activation was dependent on AMPK, since Compound C, a pan inhibitor of p-AMPK, blunted the activation of Nrf2. Conclusions: Ezetimibe counteracts IR-induced oxidative stress and induces Nrf2 and UPR pathway activation.

scholarly journals Micronuclei in Bone Marrow and Liver in relation to Hepatic Metabolism and Antioxidant Response due to Coexposure to Chloroform, Dichloromethane, and Toluene in the Rat Model

2014 ◽  
Vol 2014 ◽  
pp. 1-13 ◽  
Author(s):  
Javier Belmont-Díaz ◽  
Ana Paulina López-Gordillo ◽  
Eunice Molina Garduño ◽  
Luis Serrano-García ◽  
Elvia Coballase-Urrutia ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Bone Marrow ◽  
Oxidative Metabolism ◽  
Micronucleus Test ◽  
Direct Interaction ◽  
Hepatic Metabolism ◽  
Antioxidant Response ◽  
Oxidative Stress Biomarkers ◽  
Metabolism Enzymes ◽  
Electrophilic Metabolites

Genotoxicity in cells may occur in different ways, direct interaction, production of electrophilic metabolites, and secondary genotoxicity via oxidative stress. Chloroform, dichloromethane, and toluene are primarily metabolized in liver by CYP2E1, producing reactive electrophilic metabolites, and may also produce oxidative stress via the uncoupled CYP2E1 catalytic cycle. Additionally, GSTT1 also participates in dichloromethane activation. Despite the oxidative metabolism of these compounds and the production of oxidative adducts, their genotoxicity in the bone marrow micronucleus test is unclear. The objective of this work was to analyze whether the oxidative metabolism induced by the coexposure to these compounds would account for increased micronucleus frequency. We used an approach including the analysis of phase I, phase II, and antioxidant enzymes, oxidative stress biomarkers, and micronuclei in bone marrow (MNPCE) and hepatocytes (MNHEP). Rats were administered different doses of an artificial mixture of CLF/DCM/TOL, under two regimes. After one administration MNPCE frequency increased in correlation with induced GSTT1 activity and no oxidative stress occurred. Conversely, after three-day treatments oxidative stress was observed, without genotoxicity. The effects observed indicate that MNPCE by the coexposure to these VOCs could be increased via inducing the activity of metabolism enzymes.

scholarly journals Role of Membrane Lipid Peroxidation, Enzymatic and Non-enzymatic Antioxidative Systems in the Development of Chilling Injury in Japanese Plums

2012 ◽  
Vol 137 (6) ◽  
pp. 473-481 ◽  
Author(s):  
Sukhvinder Pal Singh ◽  
Zora Singh
Keyword(s):  
Oxidative Stress ◽  
Lipid Peroxidation ◽  
Cold Storage ◽  
Chilling Injury ◽  
Membrane Lipid ◽  
Enzymatic Antioxidants ◽  
Membrane Lipid Peroxidation ◽  
Stress Theory ◽  
Antioxidative Systems ◽  
Duration Of Storage

Chilling injury (CI) is a major postharvest constraint in the long-term cold storage, transportation, and distribution of japanese plums (Prunus salicina). The aim of the work was to explain the development and severity of CI in japanese plums based on the oxidative stress theory following time course analysis of enzymatic and non-enzymatic antioxidants. Changes in membrane lipid peroxidation and enzymatic and non-enzymatic antioxidative systems in japanese plum cultivar Blackamber were determined at weekly intervals during 5 weeks of cold storage at 0 °C and at 2-day intervals during poststorage simulated shelf conditions (21 ± 1 °C) for 8 days after each week of cold storage. Fruit respiration and ethylene production rates showed typical climacteric patterns after removal from cold storage and these rates were relatively high after 4 and 5 weeks compared with 0 to 3 weeks of storage. The CI symptoms first appeared after 3 weeks of cold storage after fruit had been transferred to simulated shelf conditions. The incidence and severity of CI intensified with increasing storage duration. The extent of lipid peroxidation indicated by concentration of thiobarbituric acid-reactive substances and membrane damage manifested as electrolyte leakage increased with increasing duration of storage and subsequent simulated shelf conditions. Membrane lipid peroxidation exhibited positive correlation with the severity of CI. Activities of primary antioxidant enzymes and the enzymes involved in the ascorbate–glutathione cycle were determined to explain the levels of reduced and oxidized forms of cellular redox buffers, ascorbate and glutathione. In response to chilling stress, antioxidative protection systems operated efficiently during the first 3 weeks of cold storage, but extended storage resulted in loss of ability to ameliorate increasing levels of oxidative stress. In this study, the comprehensive analyses of various metabolites and antioxidative systems explain the series of events involved in development of CI in japanese plums in support of the oxidative stress theory.

scholarly journals Palm oil extracts protected against cadmium chloride poisoning via inhibition of oxidative stress in rats

2022 ◽  
Vol 46 (1) ◽  
Author(s):  
Patrick Chukwuyenum Ichipi-Ifukor ◽  
Samuel Ogheneovo Asagba ◽  
Chibueze Nwose ◽  
Joseph Chukwufumnanya Mordi ◽  
John Chukwuma Oyem
Keyword(s):  
Oxidative Stress ◽  
Lipid Peroxidation ◽  
Superoxide Dismutase ◽  
Palm Oil ◽  
Underlying Mechanism ◽  
Antioxidant Response ◽  
High Dose ◽  
Stress Indicators ◽  
Cadmium Poisoning ◽  
Oxidative Stress Indicators

Abstract Background The probable mechanism of an earlier reported capacity of palm oil extracts to confer protection against high dose cadmium poisoning in rats was reported in this study. Similar experimental design earlier reported by us was retained. Rats therefore were sacrificed at intervals of twelve; twenty four and forty eight hours post CdCl2 insult. Results Oxidative stress and antioxidant status (malondialdehyde, superoxide dismutase, catalase and glutathione) were assessed in tissues (liver, kidney, heart, brain, muscle) and serum. Oxidative stress indicators showed a significantly (p < 0.05) increased lipid peroxidation and alterations in antioxidant defence systems occasioned by drop in catalase and superoxide dismutase enzymes (serum, liver, heart, brain and kidneys) of the rats. Also observed were significant (p < 0.05) reduction in the non-enzymatic antioxidant reduced glutathione over time. Pre-administration of rats with the crude palm oil and its extracts modulated cadmium mediated depletion of the antioxidant capacities of rats acutely exposed to cadmium and rising lipid peroxidation profile. Conclusions Regulation of stress and antioxidant response was the underlying mechanism by which the extracts conferred protection against high dose cadmium insult thus suggesting its potential as a viable therapeutic target against its deleterious effects. Graphical Abstract

scholarly journals Iron mobilization from myocardial cells by 3-hydroxypyridin-4-one chelators: studies in rat heart cells in culture

Blood ◽  
1991 ◽  
Vol 77 (9) ◽  
pp. 2049-2053 ◽  
Author(s):  
C Hershko ◽  
G Link ◽  
A Pinson ◽  
HH Peter ◽  
P Dobbin ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Direct Interaction ◽  
Iron Chelator ◽  
Membrane Lipid ◽  
Molar Ratio ◽  
Heart Cells ◽  
Lipid Solubility ◽  
Myocardial Cells ◽  
Iron Mobilization ◽  
Cells In Culture

The ability of 3-hydroxypyridin-4-ones (CP), a family of bidentate orally effective iron chelators, to remove iron and to prevent iron- induced lipid peroxidation was studied in beating rat myocardial cells in culture. The iron (III) binding constant (log beta 3) of all CP compounds is 36, but their lipophilicity may be modified by altering the length of the R2 substituent on the ring nitrogen. There was a direct relation between lipid solubility and chelating efficiency. Although at high concentrations all CP compounds were more effective in iron mobilization than deferoxamine, the opposite was true for low concentrations. Further studies with 1,2-diethyl-3-hydroxypyridin-4-one (CP94), the most effective CP compound, have shown that iron mobilization is completed within 6 hours, that effective mobilization requires a drug: iron molar ratio exceeding 3:1 permitting the formation of a hexadentate complex, and that the beneficial effects of iron mobilization are manifested in a marked reduction in membrane lipid peroxidation as indicated by cellular malonaldehyde content. Our study represents the first demonstration of a direct interaction between myocardial cells and an orally effective iron chelator, and underlines the need for high molar concentrations for achieving an optimal therapeutic effect.

scholarly journals Palm oil extracts’ protected against cadmium chloride poisoning via inhibition of oxidative stress in rats”

2021 ◽  
Author(s):  
Patrick Chukwuyenum ICHIPI-IFUKOR ◽  
Samuel Ogheneovo ASAGBA ◽  
Chibueze NWOSE ◽  
Joseph Chukwufumnanya MORDI ◽  
John Chukwuma OYEM
Keyword(s):  
Oxidative Stress ◽  
Lipid Peroxidation ◽  
Superoxide Dismutase ◽  
Palm Oil ◽  
Underlying Mechanism ◽  
Antioxidant Response ◽  
High Dose ◽  
Stress Indicators ◽  
Cadmium Poisoning ◽  
Oxidative Stress Indicators

Abstract Background: The probable mechanism of an earlier reported capacity of palm oil extracts to confer protection against high dose cadmium poisoning in rats was reported in this study. Similar experimental design earlier reported by us was retained. Rats therefore were sacrificed at intervals of twelve; twenty four and forty eight hours post CdCl2 insult. Results: Oxidative stress and antioxidant status (malondialdehyde, superoxide dismutase, catalase and glutathione) were assessed in tissues (liver, kidney, heart, brain, muscle) and serum. Oxidative stress indicators showed a significantly (p<0.05) increased lipid peroxidation and alterations in antioxidant defence systems occasioned by drop in catalase and superoxide dismutase enzymes (serum, liver, heart, brain and kidneys) of the rats. Also observed were significant (p<0.05) reduction in the non-enzymatic antioxidant reduced glutathione over time. Pre-administration of rats with the crude palm oil and its extracts modulated cadmium mediated depletion of the antioxidant capacities of rats acutely exposed to cadmium and rising lipid peroxidation profile. Conclusions: Regulation of stress and antioxidant response was the underlying mechanism by which the extracts conferred protection against high dose cadmium insult thus suggesting its potential as a viable therapeutic target against its deleterious effects.

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