Lipid aldehyde hydrophobicity affects apo-SOD1 modification and aggregation

Dantas, Lucas S.; Viviani, Lucas G.; Inague, Alex; Piccirillo, Erika; Rezende, Leandro de; Ronsein, Graziella Eliza; Augusto, Ohára; Medeiros, Marisa Helena Gennari de; Amaral, Antônia Tavares do; Miyamoto, Sayuri

doi:10.1016/j.freeradbiomed.2020.05.011

Cited by 17 publications

(11 citation statements)

References 73 publications

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“…Indeed, reactions between proteins and 2-t-octenal were previously reported to result in significant losses of histidine and lysine residues (98,99). In addition, 2,4-tt-nonadienal can modify the protein side chains, leading to substantial protein structural alterations and aggregations (100). In the context of ferroptosis, significant protein modifications by lipid-derived electrophiles were detected in HT-1080 cells treated with RSL3 (101).…”

Section: Discussionmentioning

confidence: 99%

Differential contributions of distinct free radical peroxidation mechanisms to the induction of ferroptosis

Zhang

Hooper

et al. 2022

Preprint

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Ferroptosis is a form of regulated cell death driven by lipid peroxidation of polyunsaturated fatty acids (PUFAs). Lipid peroxidation can propagate through either hydrogen-atom transfer (HAT) or peroxyl radical addition (PRA) mechanism. However, the contribution of the PRA mechanism to the induction of ferroptosis has not been studied. In this study, we aim to elucidate the relationship between the reactivity and mechanisms of lipid peroxidation and ferroptosis induction. We found that while some peroxidation-reactive lipids, such as 7-dehydrocholesterol, vitamins D3 and A, and coenzyme Q10, suppress ferroptosis, both nonconjugated and conjugated PUFAs enhanced cell death induced by RSL3, a ferroptosis inducer. Importantly, we found that conjugated polyunsaturated fatty acids (PUFAs), including conjugated linolenic acid (CLA 18:3) and conjugated linoleic acid (CLA 18:2) can induce or potentiate ferroptosis much more potently than nonconjugated PUFAs. We next sought to elucidate the mechanism underlying the different ferroptosis-inducing potency of conjugated and nonconjugated PUFAs. Lipidomics revealed that conjugated and nonconjugated PUFAs are incorporated into distinct cellular lipid species. The different peroxidation mechanisms predict the formation of higher levels of reactive electrophilic aldehydes from conjugated PUFAs than nonconjugated PUFAs, which was confirmed by aldehyde-trapping and mass spectrometry. RNA sequencing revealed that protein processing in the endoplasmic reticulum and proteasome are among the most significantly upregulated pathways in cells treated with CLA 18:3, suggesting increased ER stress and activation of unfolded protein response. Significantly, using click chemistry, we observed increased protein adduction by oxidized lipids in cells treated with an alkynylated CLA 18:2 probe. These results suggest that protein damage by lipid electrophiles is a key step in ferroptosis.

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Section: Discussionmentioning

confidence: 99%

Differential contributions of distinct free radical peroxidation mechanisms to the induction of ferroptosis

Zhang

Hooper

et al. 2022

Preprint

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“…Nrf2, as a dominant regulator of the antioxidant response, exists in multiple tissues and protects against oxidation and inflammation [ 29 ]. Keap1, acting as a major inhibitory regulator of Nrf2, can bind to Nrf2 and cause it to carry out proteasomal degradation [ 30 ]. Therefore, to further reveal whether the antioxidant effect of K3O was mediated by the Nrf2-Keap1 signaling pathway, the Nrf2 and Keap1 mRNA expression levels were investigated.…”

Section: Discussionmentioning

confidence: 99%

Kaempferol-3-O-Glucuronide Ameliorates Non-Alcoholic Steatohepatitis in High-Cholesterol-Diet-Induced Larval Zebrafish and HepG2 Cell Models via Regulating Oxidation Stress

Deng

Weng

et al. 2021

Life

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NAFLD (non-alcoholic fatty liver disease) is one of the most prominent liver diseases in the world. As a metabolic-related disease, the development of NAFLD is closely associated with various degrees of lipid accumulation, oxidation, inflammation, and fibrosis. Ilex chinensis Sims is a form of traditional Chinese medicine which is used to treat bronchitis, burns, pneumonia, ulceration, and chilblains. Kaempferol-3-O-glucuronide (K3O) is a natural chemical present in Ilex chinensis Sims. This study was designed to investigate the antioxidative, fat metabolism-regulating, and anti-inflammatory potential of K3O. A high-cholesterol diet (HCD) was used to establish steatosis in larval zebrafish, whereby 1mM free fatty acid (FFA) was used to induce lipid accumulation in HepG2 cells, while H2O2 was used to induce oxidative stress in HepG2. The results of this experiment showed that K3O reduced lipid accumulation and the level of reactive oxygen species (ROS) both in vivo (K3O, 40μM) and in vitro (K3O, 20μM). Additionally, K3O (40μM) reduced neutrophil aggregation in vivo. K3O (20μM) also decreased the level of malondialdehyde (MDA) and significantly increased the level of glutathione peroxidase (GSH-px) in both the HCD-induced larval zebrafish model and H2O2-exposed HepG2 cells. In the mechanism study, keap1, nrf2, tnf-α, and il-6 mRNA were all significantly reversed by K3O (20μM) in zebrafish. Changes in Keap1 and Nrf2 mRNA expression were also detected in H2O2-exposed HepG2 cells after they were treated with K3O (20μM). In conclusion, K3O exhibited a reduction in oxidative stress and lipid peroxidation, and this may be related to the Nrf2/Keap1 pathway in the NAFLD larval zebrafish model.

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“…The combination of the two conjugated functional groups of 4-HNE, the carbonyl group (-C =0), and a double bond (C2/C3, -C=C-) facilitates the reaction of 4-HNE with biological molecules (including lipids, nucleic acids, and proteins) [ 39 ]. A mass spectrometry-based proteomic analysis of oxidative stress found that the electrophilic double bond and nucleophilic amino acid residues on proteins enable 4-HNE to form Michael adducts with lysine (Lys) [ 40 ], histidine (His) [ 41 ], and cysteine (Cys) [ 42 ] residues to increase the molecular masses of these amino acids by 156 Da (the molecular mass of HNE), or form Schiff-base adducts with its aldehyde group and Lys to an increase in the mass by 138 Da (Schiff-base formation with a net loss of water) [ 43 , 44 ]. Moreover, the research of proteomic analysis of in vitro histone carbonylation sites showed that Schiff-base modification is labile and reversible, while that of Michael adducts are stable and non-reversible [ 45 ].…”

Section: 4-hydroxy-2-nonenalmentioning

confidence: 99%

Oxidative Stress and 4-hydroxy-2-nonenal (4-HNE): Implications in the Pathogenesis and Treatment of Aging-related Diseases

Zhao

et al. 2022

Journal of Immunology Research

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Oxidative stress plays an important role in the development of aging-related diseases by accelerating the lipid peroxidation of polyunsaturated fatty acids in the cell membrane, resulting in the production of aldehydes, such as malondialdehyde and 4-hydroxy-2-nonenal (4-HNE) and other toxic substances. The compound 4-HNE forms adducts with DNA or proteins, disrupting many cell signaling pathways including the regulation of apoptosis signal transduction pathways. The binding of proteins to 4-HNE (4-HNE-protein) acts as an important marker of lipid peroxidation, and its increasing concentration in brain tissues and fluids because of aging, ultimately gives rise to some hallmark disorders, such as neurodegenerative diseases (Alzheimer’s and Parkinson’s diseases), ophthalmic diseases (dry eye, macular degeneration), hearing loss, and cancer. This review aims to describe the physiological origin of 4-HNE, elucidate its toxicity in aging-related diseases, and discuss the detoxifying effect of aldehyde dehydrogenase and glutathione in 4-HNE-driven aging-related diseases.

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Lipid aldehyde hydrophobicity affects apo-SOD1 modification and aggregation

Cited by 17 publications

References 73 publications

Differential contributions of distinct free radical peroxidation mechanisms to the induction of ferroptosis

Differential contributions of distinct free radical peroxidation mechanisms to the induction of ferroptosis

Kaempferol-3-O-Glucuronide Ameliorates Non-Alcoholic Steatohepatitis in High-Cholesterol-Diet-Induced Larval Zebrafish and HepG2 Cell Models via Regulating Oxidation Stress

Oxidative Stress and 4-hydroxy-2-nonenal (4-HNE): Implications in the Pathogenesis and Treatment of Aging-related Diseases

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