5-Lipoxygenase Inhibition Protects Retinal Pigment Epithelium from Sodium Iodate-Induced Ferroptosis and Prevents Retinal Degeneration

Lee, Jong‐Jer; Chang-Chien, Guo-Ping; Lin, Shing-Jong; Hsiao, Yu‐Ting; Ke, Mu-Chan; Chen, Alexander; Lin, Tay-Jyi

doi:10.1155/2022/1792894

Cited by 28 publications

(21 citation statements)

References 46 publications

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“…Yet, why do tumor cells restrict 5-LO expression and activity during proliferation when the nutrient and oxygen demand is adequately addressed? This is probably due to the fact that reactive oxygen species generated during LT formation are a threat to cellular survival as they can covalently bind to nucleic acids or proteins ( Hankin et al, 2003 ; Zhu et al, 2006 ) or induce cell death ( Liu et al, 2015 ; Lee et al, 2022 ; Wu et al, 2022 ). Furthermore, the release of 5-LO products with chemoattractant properties such as LTB 4 and 5-oxo-ETE might interfere with the tumors’ immune evasive tactic.…”

Section: Discussionmentioning

confidence: 99%

“…5-LO is a dioxygenase that inserts molecular oxygen into the membrane-derived PUFA arachidonic acid (ARA) resulting in the formation of LTA 4 , which is then further converted to LTB 4 and the cysteinyl LTs by LTA 4 hydrolase (LTA 4 H) and LTC 4 synthase (LTC 4 S), respectively ( Peters-Golden & Henderson, 2007 ). As reactive oxygen species accumulate during the enzymatic reaction, active 5-LO represents a threat to healthy cells ( Harrison & Murphy, 1995; Cho et al, 2011 ) because 5-LO products such as LTA 4 and fatty acid hydroperoxides can form DNA adducts ( Hankin et al, 2003 ; Zhu et al, 2006 ) and signal ferroptosis ( Liu et al, 2015 ; Lee et al, 2022 ; Wu et al, 2022 ). Accordingly, highly active 5-LO is only expressed in short-lived immune cells such as granulocytes.…”

Section: Introductionmentioning

confidence: 99%

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Three-dimensional growth reveals fine-tuning of 5-lipoxygenase by proliferative pathways in cancer

et al. 2023

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The leukotriene (LT) pathway is positively correlated with the progression of solid malignancies, but the factors that control the expression of 5-lipoxygenase (5-LO), the central enzyme in LT biosynthesis, in tumors are poorly understood. Here, we report that 5-LO along with other members of the LT pathway is up-regulated in multicellular colon tumor spheroids. This up-regulation was inversely correlated with cell proliferation and activation of PI3K/mTORC-2– and MEK-1/ERK-dependent pathways. Furthermore, we found thatE2F1and its target geneMYBL2were involved in the repression of 5-LO during cell proliferation. Importantly, we found that this PI3K/mTORC-2– and MEK-1/ERK-dependent suppression of 5-LO is also existent in tumor cells from other origins, suggesting that this mechanism is widely applicable to other tumor entities. Our data show that tumor cells fine-tune 5-LO and LT biosynthesis in response to environmental changes repressing the enzyme during proliferation while making use of the enzyme under cell stress conditions, implying that tumor-derived 5-LO plays a role in the manipulation of the tumor stroma to quickly restore cell proliferation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Three-dimensional growth reveals fine-tuning of 5-lipoxygenase by proliferative pathways in cancer

et al. 2023

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“…Reactive oxygen species (ROS) are produced in the process of aerobic metabolism, including the superoxide anion (O 2 − ), hydrogen peroxide (H 2 O 2 ), and hydroxyl radicals (OH·) (Schieber & Chandel, 2014). Both the buildup of ROS and the impairment of defensive systems result in oxidative stress, which leads to cell apoptosis and disruptions in lipid metabolism (Lee et al, 2022). The fundamental process of cytotoxicity by alcohol is oxidative stress.…”

Section: Resultsmentioning

confidence: 99%

γ‐Glutamylcysteine alleviates ethanol‐induced hepatotoxicity via suppressing oxidative stress, apoptosis, and inflammation

Liu

Lü

Zhang

et al. 2022

Journal of Food Biochemistry

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Alcohol abuse is a major cause of alcoholic liver disease (ALD) and can result in fibrosis and cirrhosis. γ-glutamylcysteine (γ-GC) is a precursor of glutathione (GSH) with antioxidant and anti-inflammatory properties. Our research aimed to explore the protective impact of γ-GC on ALD and its potential mechanisms of efficiency in vitro and in vivo. L02 cells were pretreated with γ-GC (20, 40, and 80 μM) for 2 h and exposed to ethanol for 24 h. Cell viability, apoptosis, oxidative stress, and inflammatory levels were measured. The expression of protein cleaved caspase-3 and cleaved PARP and flow cytometry results indicated that γ-GC decreases apoptosis on L02 cells after ethanol treatment. Moreover, γ-GC also attenuated oxidative stress and mitochondrial damage in hepatocytes caused by ethanol via increasing cellular GSH, SOD activity, and mitochondrial membrane potential. In vivo experiments, γ-GC effectively reduced the AST, ALT, and TG levels in mice. The inflammation of ALD was alleviated by γ-GC both in vivo and in vitro. Additionally, histopathological examination demonstrated that γ-GC treatment lessened lipid droplet formation and inflammatory damage. In conclusion, these results showed that γ-GC has anti-inflammatory and anti-apoptotic effects on ALD because it could help hepatocytes maintain sufficient GSH levels to combat the excess reactive oxygen species (ROS) generated during ethanol metabolism. Practical applicationsAlcohol intake is the fifth highest risk factor for premature death and disability among all risk variables. However, few medicines are both safe and effective for the treatment of ALD. As a direct precursor of GSH, γ-GC has a broad variety of potential antioxidant and anti-inflammatory applications for the treatment of numerous medical conditions. In conclusion, these results showed that γ-GC could protect cells from ALD via suppressing oxidative stress, alleviating inflammation, and preventing apoptosis.

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“…In our study, TNFα upregulated arachidonic acid, an ω-6 polyunsaturated fatty acid, which serves as a precursor to a cascade of pro-inflammatory eicosanoids, including prostaglandins and thromboxanes catalyzed by cyclooxygenase-1 and -2 enzymes, and leukotrienes catalyzed by the 5-lipoxygenase enzyme [ 33 ]. Arachidonic acid has been found to reduce the phagocytic capacity of RPE [ 34 ], and inhibition of 5-lipoxygenase protects RPE from sodium-iodate-induced degeneration [ 35 ]. TNFα can directly stimulate arachidonic acid in neutrophils, perpetuating the inflammatory cascade [ 36 ].…”

Section: Discussionmentioning

confidence: 99%

Divergent Metabolomic Signatures of TGFβ2 and TNFα in the Induction of Retinal Epithelial-Mesenchymal Transition

Saint‐Geniez

Kim

et al. 2023

Metabolites

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Epithelial-mesenchymal transition (EMT) is a dedifferentiation program in which polarized, differentiated epithelial cells lose their cell-cell adhesions and transform into matrix-producing mesenchymal cells. EMT of retinal pigment epithelial (RPE) cells plays a crucial role in many retinal diseases, including age-related macular degeneration, proliferative vitreoretinopathy, and diabetic retinopathy. This dynamic process requires complex metabolic reprogramming to accommodate the demands of this dramatic cellular transformation. Both transforming growth factor-beta 2 (TGFβ2) and tumor necrosis factor-alpha (TNFα) have the capacity to induce EMT in RPE cells; however, little is known about their impact on the RPE metabolome. Untargeted metabolomics using high-resolution mass spectrometry was performed to reveal the metabolomic signatures of cellular and secreted metabolites of primary human fetal RPE cells treated with either TGFβ2 or TNFα for 5 days. A total of 638 metabolites were detected in both samples; 188 were annotated as primary metabolites. Metabolomics profiling showed distinct metabolomic signatures associated with TGFβ2 and TNFα treatment. Enrichment pathway network analysis revealed alterations in the pentose phosphate pathway, galactose metabolism, nucleotide and pyrimidine metabolism, purine metabolism, and arginine and proline metabolism in TNFα-treated cells compared to untreated control cells, whereas TGFβ2 treatment induced perturbations in fatty acid biosynthesis metabolism, the linoleic acid pathway, and the Notch signaling pathway. These results provide a broad metabolic understanding of the bioenergetic rewiring processes governing TGFβ2- and TNFα-dependent induction of EMT. Elucidating the contributions of TGFβ2 and TNFα and their mechanistic differences in promoting EMT of RPE will enable the identification of novel biomarkers for diagnosis, management, and tailored drug development for retinal fibrotic diseases.

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5-Lipoxygenase Inhibition Protects Retinal Pigment Epithelium from Sodium Iodate-Induced Ferroptosis and Prevents Retinal Degeneration

Cited by 28 publications

References 46 publications

Three-dimensional growth reveals fine-tuning of 5-lipoxygenase by proliferative pathways in cancer

Three-dimensional growth reveals fine-tuning of 5-lipoxygenase by proliferative pathways in cancer

γ‐Glutamylcysteine alleviates ethanol‐induced hepatotoxicity via suppressing oxidative stress, apoptosis, and inflammation

Divergent Metabolomic Signatures of TGFβ2 and TNFα in the Induction of Retinal Epithelial-Mesenchymal Transition

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