Ferroptotic cell death triggered by conjugated linolenic acids is mediated by ACSL1
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ABSTRACT:
PROVIDER: PRJNA680497 | ENA |
REPOSITORIES: ENA
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Project description:Ferroptosis is associated with lipid hydroperoxides generated by oxidation of polyunsaturated acyl chains. Lipid hydroperoxides are reduced by glutathione peroxidase 4 (GPX4) and GPX4 inhibitors induce ferroptosis. However, the therapeutic potential of triggering ferroptosis in cancer cells with polyunsaturated fatty acids is unknown. We identified conjugated linoleates including α-eleostearic acid (αESA) as novel ferroptosis inducers. αESA did not alter GPX4 activity but was incorporated into cellular lipids and promoted lipid peroxidation and cell death in diverse cancer cell types. αESA-triggered death was mediated by acyl-CoA synthetase long-chain isoform 1, which promoted αESA incorporation into neutral lipids including triacylglycerols. Interfering with triacylglycerol biosynthesis suppressed ferroptosis triggered by αESA but not by GPX4 inhibition. Orally administered tung oil, naturally rich in αESA, limited tumor growth and metastasis with transcriptional changes consistent with ferroptosis. Overall, these findings illuminate a novel approach to ferroptosis, complementary to GPX4 inhibition, with therapeutic potential.
2021-02-08 | GSE162069 | GEO
Project description:Plant damage promotes the interaction of lipoxygenases (LOX) with fatty acids yielding 9-hydroperoxides, 13-hydroperoxides and complex arrays of oxylipins. The action of 13-LOX on linolenic acid enables production of 12-oxo-phytodienoic acid (12-OPDA) and its downstream products, termed jasmonates. As signals, jasmonates have related yet distinct roles in the regulation of plant resistance against insect and pathogen attack. A similar pathway involving 9-LOX activity on linolenic and linoleic acid leads to the 12-OPDA positional isomer, 10-oxo-11-phytodienoic acid (10-OPDA) and 10-oxo-11-phytoenoic acid (10-OPEA), respectively; however, physiological roles for 9-LOX cyclopentenones have remained unclear. In developing maize (Zea mays) leaves, southern leaf blight (Cochliobolus heterostrophus) infection results in dying necrotic tissue and the localized accumulation of 10-OPEA, 10-OPDA and a series of related 14- and 12-carbon metabolites, collectively termed ‘death acids’. 10-OPEA accumulation becomes wound-inducible within fungal-infected tissues and at physiologically relevant concentrations acts as a phytoalexin by suppressing the growth of fungi and herbivores including Aspergillus flavus, Fusarium verticillioides, and Helicoverpa zea. Unlike previously established maize phytoalexins, 10-OPEA and 10-OPDA display significant phytotoxicity. Both 12-OPDA and 10-OPEA promote the transcription of defense genes encoding glutathione S-transferases, cytochrome P450s, and pathogenesis-related proteins. In contrast, 10-OPEA only weakly promotes the accumulation of multiple protease inhibitor transcripts. Consistent with a role in dying tissue, 10-OPEA application promotes cysteine protease activation and cell death which is inhibited by overexpression of the cysteine protease inhibitor maize cystatin-9. Functions for 10-OPEA and associated death acids are consistent with specialized roles in local defense reactions. A total of 6 samples were analyzed, comprised of two treatments: 10-OPEA and DMSO carrier control (5%DMSO/0.1% Tween20 in H20), both in replicates of three.
2015-08-07 | E-GEOD-69659 | biostudies-arrayexpress
Project description: Not available
| S-EPMC8046803 | biostudies-literature
Project description:Plant damage promotes the interaction of lipoxygenases (LOX) with fatty acids yielding 9-hydroperoxides, 13-hydroperoxides and complex arrays of oxylipins. The action of 13-LOX on linolenic acid enables production of 12-oxo-phytodienoic acid (12-OPDA) and its downstream products, termed jasmonates. As signals, jasmonates have related yet distinct roles in the regulation of plant resistance against insect and pathogen attack. A similar pathway involving 9-LOX activity on linolenic and linoleic acid leads to the 12-OPDA positional isomer, 10-oxo-11-phytodienoic acid (10-OPDA) and 10-oxo-11-phytoenoic acid (10-OPEA), respectively; however, physiological roles for 9-LOX cyclopentenones have remained unclear. In developing maize (Zea mays) leaves, southern leaf blight (Cochliobolus heterostrophus) infection results in dying necrotic tissue and the localized accumulation of 10-OPEA, 10-OPDA and a series of related 14- and 12-carbon metabolites, collectively termed ‘death acids’. 10-OPEA accumulation becomes wound-inducible within fungal-infected tissues and at physiologically relevant concentrations acts as a phytoalexin by suppressing the growth of fungi and herbivores including Aspergillus flavus, Fusarium verticillioides, and Helicoverpa zea. Unlike previously established maize phytoalexins, 10-OPEA and 10-OPDA display significant phytotoxicity. Both 12-OPDA and 10-OPEA promote the transcription of defense genes encoding glutathione S-transferases, cytochrome P450s, and pathogenesis-related proteins. In contrast, 10-OPEA only weakly promotes the accumulation of multiple protease inhibitor transcripts. Consistent with a role in dying tissue, 10-OPEA application promotes cysteine protease activation and cell death which is inhibited by overexpression of the cysteine protease inhibitor maize cystatin-9. Functions for 10-OPEA and associated death acids are consistent with specialized roles in local defense reactions.
2015-08-07 | GSE69659 | GEO
Project description:Normalized relative abundance measurement of amine-conjugated deoxycholic acids in B. fragilis P207 cultures in triplicate. All using positive ionization.
2023-10-04 | MSV000093039 | MassIVE
Project description:Ferroptosis is a form of regulated cell death driven by lipid peroxidation of polyunsaturated fatty acids (PUFAs). Endogenous PUFAs are nonconjugated PUFAs and their peroxidation proceeds via the hydrogen-atom transfer (HAT) mechanism. We previously reported that lipids with conjugated double bonds undergo lipid peroxidation mostly via a different mechanism, peroxyl radical addition (PRA), and were much more readily oxidizable than nonconjugated ones. In this study, we aim to elucidate the effects of various unsaturated lipids in sensitizing ferroptosis. 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 showed that conjugated linolenic acid (CLA 18:3) could act as a ferroptosis inducer by itself and conjugated linoleic acid (CLA 18:2) was more potent in sensitizing cells to RSL3-induced cell death than any 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. Furthermore, 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.
2023-04-17 | GSE224249 | GEO
Project description:A collection of cultured fecal samples exposed to microbialy conjugated bile acids and bile acid controls.
2021-02-16 | MSV000086889 | GNPS
Project description:<p>Gut microbes have been recognized to convert the human bile acids by deconjugation, dehydroxylation, dehydrogenation and epimerization of the cholesterol core, but the ability to re-conjugate them with amino acids as an additional conversion has only been recently described. These new bile acids are known as microbially conjugated bile acids (MCBAs). The aim of this study was evaluating the MCBAs diversity produced by the gut microbiota through a metabolomics approach. In this study, fresh fecal samples from healthy donors were evaluated to explore the re-conjugation of chenodeoxycholic and 3-oxo-chenodeoxycholic acids by the human gut microbiota. No significant differences were found between the conversion trend of both BAs incubations. The <em>in vitro</em> results showed a clear trend to first accumulate the epimer isoursochenodeoxycholic acid, and the dehydroxylated lithocholic acid derivatives in samples incubated with chenodeoxycholic and 3-oxo-chenodeoxycholic acid. Also showed a strong trend for the production of microbially conjugated dehydroxylated bile acids, instead of chenodeoxycholic backbone conjugates. Different molecules and isomers of microbial conjugates with valine and leucine were also identified and confirmed by MS/MS. These results document the gut microbiota capability to produce esters of MCBAs on hydroxyls of the sterol backbone in addition to amides at the C24 acyl site. This study opens a new perspective to study the BAs diversity produced by the human gut microbiota.</p>
2024-01-16 | MTBLS4140 | MetaboLights
Project description:Plant cellular damage promotes the interaction of lipoxygenases (LOX) with free fatty acids to yield 9- and 13-hydroperoxides which are further metabolized into diverse oxylipins. The enzymatic action of 13-LOX on linolenic acid enables production of 12-oxo-phytodienoic acid (12-OPDA) and its downstream products, jointly known as jasmonates. As signals, jasmonates have related yet distinct roles in the regulation of plant resistance against insect and pathogen attack. An additional and conceptually parallel pathway involving 9-LOX activity on linoleic acid leads to the production of 10-oxo-11-phytoenoic acid (10-OPEA). Despite structural similarity to jasmonates, physiological roles for 10-OPEA have remained unclear. Both 12-OPDA and 10-OPEA equally promote the transcription of numerous defense genes encoding glutathione S-transferases, cytochrome P450s, and pathogenesis-related proteins; however, 10-OPEA activity diverges in the context of reduced protease inhibitor transcript accumulation. To identify additional differential responses, we subsequently performed whole transcriptome analyses using RNAseq. These comparisons provide a platform for further examination of plant response specificity to the cyclopentenone 10-OPEA. A total of 12 samples were analyzed, comprised of two treatments (10-OPEA and 12-OPDA) and a DMSO carrier control (5%DMSO/0.1%Tween 20 in H20), all in replicates of four.
2015-08-13 | E-GEOD-68589 | biostudies-arrayexpress
Project description:Plant cellular damage promotes the interaction of lipoxygenases (LOX) with free fatty acids to yield 9- and 13-hydroperoxides which are further metabolized into diverse oxylipins. The enzymatic action of 13-LOX on linolenic acid enables production of 12-oxo-phytodienoic acid (12-OPDA) and its downstream products, jointly known as jasmonates. As signals, jasmonates have related yet distinct roles in the regulation of plant resistance against insect and pathogen attack. An additional and conceptually parallel pathway involving 9-LOX activity on linoleic acid leads to the production of 10-oxo-11-phytoenoic acid (10-OPEA). Despite structural similarity to jasmonates, physiological roles for 10-OPEA have remained unclear. Both 12-OPDA and 10-OPEA equally promote the transcription of numerous defense genes encoding glutathione S-transferases, cytochrome P450s, and pathogenesis-related proteins; however, 10-OPEA activity diverges in the context of reduced protease inhibitor transcript accumulation. To identify additional differential responses, we subsequently performed whole transcriptome analyses using RNAseq. These comparisons provide a platform for further examination of plant response specificity to the cyclopentenone 10-OPEA.
2015-08-13 | GSE68589 | GEO