scholarly journals Drugs Repurposed as Antiferroptosis Agents Suppress Organ Damage, Including AKI, by Functioning as Lipid Peroxyl Radical Scavengers

2019 ◽  
Vol 31 (2) ◽  
pp. 280-296 ◽  
Author(s):  
Eikan Mishima ◽  
Emiko Sato ◽  
Junya Ito ◽  
Ken-ichi Yamada ◽  
Chitose Suzuki ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Cell Death ◽  
Cytochrome P450 ◽  
Liver Injury ◽  
Peroxyl Radical ◽  
Organ Damage ◽  
Peroxyl Radicals ◽  
Radical Scavengers ◽  
Lipid Peroxyl Radicals ◽  
Elevated Lipid

BackgroundFerroptosis, nonapoptotic cell death mediated by free radical reactions and driven by the oxidative degradation of lipids, is a therapeutic target because of its role in organ damage, including AKI. Ferroptosis-causing radicals that are targeted by ferroptosis suppressors have not been unequivocally identified. Because certain cytochrome P450 substrate drugs can prevent lipid peroxidation via obscure mechanisms, we evaluated their antiferroptotic potential and used them to identify ferroptosis-causing radicals.MethodsUsing a cell-based assay, we screened cytochrome P450 substrate compounds to identify drugs with antiferroptotic activity and investigated the underlying mechanism. To evaluate radical-scavenging activity, we used electron paramagnetic resonance–spin trapping methods and a fluorescence probe for lipid radicals, NBD-Pen, that we had developed. We then assessed the therapeutic potency of these drugs in mouse models of cisplatin-induced AKI and LPS/galactosamine-induced liver injury.ResultsWe identified various US Food and Drug Administration–approved drugs and hormones that have antiferroptotic properties, including rifampicin, promethazine, omeprazole, indole-3-carbinol, carvedilol, propranolol, estradiol, and thyroid hormones. The antiferroptotic drug effects were closely associated with the scavenging of lipid peroxyl radicals but not significantly related to interactions with other radicals. The elevated lipid peroxyl radical levels were associated with ferroptosis onset, and known ferroptosis suppressors, such as ferrostatin-1, also functioned as lipid peroxyl radical scavengers. The drugs exerted antiferroptotic activities in various cell types, including tubules, podocytes, and renal fibroblasts. Moreover, in mice, the drugs ameliorated AKI and liver injury, with suppression of tissue lipid peroxidation and decreased cell death.ConclusionsAlthough elevated lipid peroxyl radical levels can trigger ferroptosis onset, some drugs that scavenge lipid peroxyl radicals can help control ferroptosis-related disorders, including AKI.

scholarly journals The mechanism of Fe2+-initiated lipid peroxidation in liposomes: the dual function of ferrous ions, the roles of the pre-existing lipid peroxides and the lipid peroxyl radical

2000 ◽  
Vol 352 (1) ◽  
pp. 27-36 ◽  
Author(s):  
Lixia TANG ◽  
Yong ZHANG ◽  
Zhongming QIAN ◽  
Xun SHEN
Keyword(s):  
Lipid Peroxidation ◽  
Latent Period ◽  
Time Lag ◽  
Lipid Peroxides ◽  
Peroxyl Radicals ◽  
Dual Function ◽  
Critical Ratio ◽  
Ferrous Ions ◽  
Liposomal System ◽  
Lipid Peroxyl Radicals

The mechanism of Fe2+-initiated lipid peroxidation in a liposomal system was studied. It was found that a second addition of ferrous ions within the latent period lengthened the time lag before lipid peroxidation started. The apparent time lag depended on the total dose of Fe2+ whenever the second dose of Fe2+ was added, which indicates that Fe2+ has a dual function: to initiate lipid peroxidation on one hand and suppress the species responsible for the initiation of the peroxidation on the other. When the pre-existing lipid peroxides (LOOH) were removed by incorporating triphenylphosphine into liposomes, Fe2+ could no longer initiate lipid peroxidation and the acceleration of Fe2+ oxidation by the liposomes disappeared. However, when extra LOOH were introduced into liposomes, both enhancement of the lipid peroxidation and shortening of the latent period were observed. When the scavenger of lipid peroxyl radicals (LOOP), N,N´-diphenyl-p-phenylene-diamine, was incorporated into liposomes, neither initiation of the lipid peroxidation nor acceleration of the Fe2+ oxidation could be detected. The results may suggest that both the pre-existing LOOH and LOOP are necessary for the initiation of lipid peroxidation. The latter comes initially from the decomposition of the pre-existing LOOH by Fe2+ and can be scavenged by its reaction with Fe2+. Only when Fe2+ is oxidized to such a degree that LOOP is no longer effectively suppressed does lipid peroxidation start. It seems that by taking the reactions of Fe2+ with LOOH and LOOP into account, the basic chemistry in lipid peroxidation can explain fairly well the controversial phenomena observed in Fe2+-initiated lipid peroxidation, such as the existence of a latent period, the critical ratio of Fe2+ to lipid and the required oxidation of Fe2+.

scholarly journals Nitric Oxide Reaction with Lipid Peroxyl Radicals Spares α-Tocopherol during Lipid Peroxidation

2000 ◽  
Vol 275 (15) ◽  
pp. 10812-10818 ◽  
Author(s):  
Homero Rubbo ◽  
Rafael Radi ◽  
Daniel Anselmi ◽  
Marion Kirk ◽  
Stephen Barnes ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Lipid Peroxidation ◽  
Peroxyl Radicals ◽  
Lipid Peroxyl Radicals

scholarly journals Promethazine inhibits the formation of aldehydic products of lipid peroxidation but not covalent binding resulting from the exposure of rat liver fractions to CCl4

1989 ◽  
Vol 264 (2) ◽  
pp. 527-532 ◽  
Author(s):  
G Poli ◽  
K H Cheeseman ◽  
F Biasi ◽  
E Chiarpotto ◽  
M U Dianzani ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Free Radical ◽  
Covalent Binding ◽  
Antioxidant Properties ◽  
Radical Scavenging ◽  
Isolated Hepatocytes ◽  
Peroxyl Radicals ◽  
Liver Necrosis ◽  
Lipid Peroxyl Radicals ◽  
Carbonyl Products

Promethazine is known to have protective activity in relation to CCl4-induced liver necrosis. This hepatoprotective property has been investigated with regard to the free radical scavenging and antioxidant properties of promethazine using isolated hepatocytes and microsomal suspensions. CCl4 is activated in both systems to free radical metabolites that bind covalently to lipid and protein, and initiate lipid peroxidation. A large number of carbonyl products is produced during CCl4-induced lipid peroxidation; promethazine strongly inhibits the production of all classes of carbonyl compounds in both microsomal suspensions and isolated hepatocytes. In contrast, promethazine is a very weak inhibitor of the covalent binding of metabolites of CCl4. We conclude that promethazine acts by scavenging the trichloromethylperoxyl radical and lipid peroxyl radicals, and is a weak scavenger of the trichloromethyl radical. These data, when considered together with the hepatoprotective effects of promethazine, suggest that lipid peroxidation is of relatively more importance than covalent binding in the pathogenesis of CCl4-induced liver necrosis.

Markedly Enhanced Cytochrome P450 2E1 Induction and Lipid Peroxidation Is Associated with Severe Liver Injury in Fish Oil-Ethanol-Fed Rats

1994 ◽  
Vol 18 (5) ◽  
pp. 1280-1285 ◽  
Author(s):  
Arnin A. Nanji ◽  
Shuping Zhao ◽  
S. M. Hossein Sadrzadeh ◽  
Andrew J. Dannenberg ◽  
Steven R. Tahan ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Cytochrome P450 ◽  
Liver Injury ◽  
Fish Oil ◽  
Cytochrome P450 2E1 ◽  
Severe Liver

Nitric Oxide Inhibition of Lipid Peroxidation:  Kinetics of Reaction with Lipid Peroxyl Radicals and Comparison with α-Tocopherol†

Biochemistry ◽  
1997 ◽  
Vol 36 (49) ◽  
pp. 15216-15223 ◽  
Author(s):  
Valerie B. O'Donnell ◽  
Phillip H. Chumley ◽  
Neil Hogg ◽  
Allison Bloodsworth ◽  
Victor M. Darley-Usmar ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Lipid Peroxidation ◽  
Peroxyl Radicals ◽  
Nitric Oxide Inhibition ◽  
Kinetics Of Reaction ◽  
Lipid Peroxyl Radicals ◽  
Kinetics Of ◽  
Oxide Inhibition

scholarly journals Metabolic Regulation of Ferroptosis in Cancer

Biology ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 83
Author(s):  
Min Ji Kim ◽  
Greg Jiho Yun ◽  
Sung Eun Kim
Keyword(s):  
Lipid Peroxidation ◽  
Cell Death ◽  
Lipid Metabolism ◽  
Metabolic Pathways ◽  
Metabolic Regulation ◽  
Organ Damage ◽  
Cell Death Mechanism ◽  
Therapeutic Uses ◽  
Unique Cell ◽  
Excessive Accumulation

Ferroptosis is a unique cell death mechanism that is executed by the excessive accumulation of lipid peroxidation in cells. The relevance of ferroptosis in multiple human diseases such as neurodegeneration, organ damage, and cancer is becoming increasingly evident. As ferroptosis is deeply intertwined with metabolic pathways such as iron, cyst(e)ine, glutathione, and lipid metabolism, a better understanding of how ferroptosis is regulated by these pathways will enable the precise utilization or prevention of ferroptosis for therapeutic uses. In this review, we present an update of the mechanisms underlying diverse metabolic pathways that can regulate ferroptosis in cancer.

scholarly journals 7-Dehydrocholesterol is an endogenous suppressor of ferroptosis

2021 ◽  
Author(s):  
Jose Pedro Friedmann Angeli ◽  
Florencio Porto Freitas ◽  
Palina Nepachalovich ◽  
Lohans Puentes ◽  
Omkar Zilka ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Cell Death ◽  
Cancer Cells ◽  
Survival Function ◽  
Peroxyl Radicals ◽  
Metabolic Adaptation ◽  
Compelling Evidence ◽  
Intrinsic Mechanism ◽  
A Cell ◽  
Developing Neurons

Abstract Ferroptosis is a form of cell death that has received considerable attention not only as a means to eradicate defined tumour entities but also because it provides unforeseen insights into the metabolic adaptation exploited by tumours to counteract phospholipid oxidation. Here, we identify a pro-ferroptotic activity of 7-dehydrocholesterol reductase (DHCR7) and an unexpected pro-survival function of its substrate, 7-dehydrocholesterol (7-DHC). Although previous studies suggested that high levels of 7-DHC are cytotoxic to developing neurons and favour lipid peroxidation, we now demonstrate that 7-DHC accumulation confers a robust pro-survival function in cancer cells. 7-DHC, due to its far superior reactivity towards peroxyl radicals, is shown here to effectively shield (phospho)lipids from autoxidation and subsequent fragmentation. We further demonstrate in a subset of ferroptosis-sensitive Burkitt lymphomas - where DHCR7 mutations have been reported - that the accumulation of 7-DHC is sufficient to suppress the basal sensitivity of cells toward ferroptosis, thereby translating into an unexpected growth advantage. Conclusively, our findings provide compelling evidence of a yet-unrecognised anti-ferroptotic activity of 7-DHC as a cell-intrinsic mechanism that could be exploited by cancer cells to escape ferroptosis.

scholarly journals Esophageal Cancer Stem-like Cells Resist Ferroptosis-Induced Cell Death by Active Hsp27-GPX4 Pathway

Biomolecules ◽  
2021 ◽  
Vol 12 (1) ◽  
pp. 48
Author(s):  
Chen-Chi Liu ◽  
Hsin-Hsien Li ◽  
Jiun-Han Lin ◽  
Ming-Chen Chiang ◽  
Tien-Wei Hsu ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Cell Death ◽  
Esophageal Cancer ◽  
Cancer Cells ◽  
Squamous Carcinoma ◽  
Protective Mechanism ◽  
Intracellular Iron ◽  
Regulatory Pathways ◽  
Squamous Carcinoma Cells ◽  
Elevated Lipid

Cancer stem cells (CSCs), a subpopulation of cancer cells responsible for tumor initiation and treatment failure, are more susceptible to ferroptosis-inducing agents than bulk cancer cells. However, regulatory pathways controlling ferroptosis, which can selectively induce CSC death, are not fully understood. Here, we demonstrate that the CSCs of esophageal squamous carcinoma cells enriched by spheroid culture have increased intracellular iron levels and lipid peroxidation, thereby increasing exposure to several products of lipid peroxidation, such as MDA and 4-HNE. However, CSCs do not reduce cell viability until glutathione is depleted by erastin treatment. Mechanistic studies revealed that damage from elevated lipid peroxidation is avoided through the activation of Hsp27, which upregulates GPX4 and thereby rescues CSCs from ferroptosis-induced cell death. Our results also revealed a correlation between phospho-Hsp27 and GPX4 expression levels and poor prognosis in patients with esophageal cancer. Together, these data indicate that targeting Hsp27 or GPX4 to block this intrinsic protective mechanism against ferroptosis is a potential treatment strategy for eradicating CSC in esophageal squamous cell carcinoma.

Changes in lipid peroxidation during pregnancy and after delivery in rats: effect of pinealectomy

Reproduction ◽  
2000 ◽  
pp. 143-149 ◽  
Author(s):  
RM Sainz ◽  
RJ Reiter ◽  
JC Mayo ◽  
J Cabrera ◽  
DX Tan ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Lipid Peroxidation ◽  
Oxidative Damage ◽  
Energy Demand ◽  
Physiological State ◽  
High Energy ◽  
Free Radical Scavengers ◽  
Radical Scavengers ◽  
Oxygen Requirement ◽  
Pregnant Rats

Pregnancy is a physiological state accompanied by a high energy demand of many bodily functions and an increased oxygen requirement. Because of the increased intake and utilization of oxygen, increased levels of oxidative stress would be expected. In the present study, the degree of lipid peroxidation was examined in different tissues from non-pregnant and pregnant rats after the delivery of their young. Melatonin and other indole metabolites are known to be direct free radical scavengers and indirect antioxidants. Thus the effect of pinealectomy at 1 month before pregnancy on the accumulation of lipid damage was investigated in non-pregnant and pregnant rats after the delivery of their young. Malonaldehyde and 4-hydroxyalkenal concentrations were measured in the lung, uterus, liver, brain, kidney, thymus and spleen from intact and pinealectomized pregnant rats soon after birth of their young and at 14 and 21 days after delivery. The same parameters were also evaluated in intact and pinealectomized non-pregnant rats. Shortly after delivery, lipid oxidative damage was increased in lung, uterus, brain, kidney and thymus of the mothers. No differences were detected in liver and spleen. Pinealectomy enhanced this effect in the uterus and lung. It is concluded that during pregnancy high levels of oxidative stress induce an increase in oxidative damage to lipids, which in some cases is inhibited by the antioxidative actions of pineal indoles.

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