Myeloperoxidase-derived hypochlorous acid targets human airway epithelial plasmalogens liberating protein modifying electrophilic 2-chlorofatty aldehydes

Shakya, Shubha; Pyles, Kelly D.; Albert, Carolyn J.; Patel, Rakesh P.; McCommis, Kyle S.; Ford, David A.

doi:10.1016/j.redox.2022.102557

Cited by 6 publications

(6 citation statements)

References 57 publications

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“…2-ClFALD is produced when myeloperoxidase-derived HOCl or inhaled chlorine gas-derived HOCl targets the plasmalogen of neutrophils, endothelial cells or epithelial cells [3,9,17]. 2-ClFALD has been shown to accumulate in the lungs of chlorine gas-exposed mice, infarcted rat myocardium and human aorta [4,5,9].…”

Section: Discussionmentioning

confidence: 99%

“…Because previous data suggest that 2-ClHDyA modifies proteins in THP-1 cells, human endothelial cells (hCMEC/D3 and EA.hy926 cells), human lung microvascular endothelial cells (HLMVEC), human small airway epithelial cells and mouse HL-1 cardiomyocytes [10,15,17,18,25], we investigated if we could detect the subcellular localization of proteins modified by 2-ClHDyA in RAW 264.7 cells. We treated RAW 264.7 cells with 2-ClHDyA and used click chemistry to conjugate 2-ClHDyA with TAMRA fluorophore.…”

Section: Subcellular Localization Of 2-clhdyamentioning

confidence: 99%

“…Additionally, 2-ClHDA can modify proteins via Schiff base formation [10,16]. Recently, we identified proteins modified by 2-ClFALD without Schiff base stabilization in endothelial cells and epithelial cells [17,18]. 2-ClFALD has been shown to cause mitochondrial dysfunction, apoptosis via the activation of caspase 3 and an altered intracellular redox balance in brain microvascular endothelial cells (BMVEC) [10].…”

Section: Introductionmentioning

confidence: 99%

“…2-ClFALD has been shown to cause mitochondrial dysfunction, apoptosis via the activation of caspase 3 and an altered intracellular redox balance in brain microvascular endothelial cells (BMVEC) [10]. Additionally, 2-ClFALD elicits mitochondrial dysfunction in human small airway epithelial cells [17].…”

Section: Introductionmentioning

confidence: 99%

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Characterization of N-Acetyl Cysteine Adducts with Exogenous and Neutrophil-Derived 2-Chlorofatty Aldehyde

2023

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Hypochlorous acid is produced by leukocyte myeloperoxidase activity. 2-Chlorofatty aldehydes (2-ClFALDs) are formed when hypochlorous acid attacks the plasma membrane phospholipid plasmalogen molecular subclass and are thus produced following leukocyte activation as well as in the lungs of mice exposed to chlorine gas. The biological role of 2-ClFALD is largely unknown. Recently, we used an alkyne analog (2-ClHDyA) of the 2-ClFALD molecular species, 2-chlorohexadecanal (2-ClHDA), to identify proteins covalently modified by 2-ClHDyA in endothelial cells and epithelial cells. Here, we demonstrate that 2-ClHDA reduces the metabolic activity of RAW 264.7 cells in a dose-dependent manner. 2-ClHDyA localizes to the mitochondria, endoplasmic reticulum and Golgi in RAW 264.7 cells and modifies many proteins. The thiol-containing precursor of glutathione, N-acetyl cysteine (NAC), was shown to produce an adduct with 2-ClHDA with the loss of Cl− (HDA–NAC). This adduct was characterized in both positive and negative ion modes using LC-MS/MS and electrospray ionization. NAC treatment of neutrophils reduced the 2-ClFALD levels in PMA-stimulated cells with subsequent increases in HDA–NAC. NAC treatments reduced the 2-ClHDA-elicited loss of metabolic activity in RAW 264.7 cells as well as 2-ClHDA protein modification. These studies demonstrate that 2-ClFALD toxic effects can be reduced by NAC, which reduces protein modification.

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Section: Discussionmentioning

confidence: 99%

Section: Subcellular Localization Of 2-clhdyamentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Characterization of N-Acetyl Cysteine Adducts with Exogenous and Neutrophil-Derived 2-Chlorofatty Aldehyde

2023

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“…In living organisms, HOCl is an important ROS, mainly produced in the respiratory burst process of neutrophils (Elbim and Lizard, 2009;Güngör et al, 2009). A large body of research evidence shows that low concentrations of HOCl in organisms can regulate redox balance and resist the invasion of pathogens, while high concentrations of HOCl can cause oxidative damage to biologically active molecules (Goud et al, 2008;Guo et al, 2020;Shakya et al, 2023). For example, overexpression of HOCl can not only react with amnio, sulfhydryl, and thioethers groups to destroy the spatial structures of proteins and lead to protein inactivation but also react with nitrogen-containing bases to make nucleic acid lose the ability to assemble biological macromolecules (Dharmaraja, 2017).…”

Section: Introductionmentioning

confidence: 99%

Development of an activatable far-red fluorescent probe for rapid visualization of hypochlorous acid in live cells and mice with neuroinflammation

Mi,

Niu,

Chen

et al. 2024

Front. Chem.

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Recent investigations have suggested that abnormally elevated levels of HOCl may be tightly related to the severity of neuroinflammation. Although some successes have been achieved, fluorescent probes with far-red fluorescence emission and capable of detecting HOCl with high specificity in pure aqueous solution are still urgently needed. Herein, a responsive far-red fluorescent probe, DCI-H, has been constructed to monitor HOCl activity in vivo and in vitro. DCI-H could rapidly respond to HOCl within 120 s and had a low detection limit for HOCl of 1.5 nM. Importantly, physiologically common interfering species, except for HOCl, did not cause a change in the fluorescence intensity of DCI-HOCl at 655 nm. The results of confocal imaging demonstrated the ability of DCI-H to visualize endogenous HOCl produced by MPO-catalyzed H2O2/Cl− and LPS stimulation. With the assistance of DCI-H, upregulation of HOCl levels was observed in the mice model of LPS-induced neuroinflammation. Thus, we believed that DCI-H provided a valuable tool for HOCl detection and diagnosis of inflammation-related diseases.

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2-Chloro- and 2-Bromopalmitic acids inhibit mitochondrial function in airway epithelial cells

Ricart,

McCommis,

Ford

et al. 2025

Advances in Redox Research

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Myeloperoxidase-derived hypochlorous acid targets human airway epithelial plasmalogens liberating protein modifying electrophilic 2-chlorofatty aldehydes

Cited by 6 publications

References 57 publications

Characterization of N-Acetyl Cysteine Adducts with Exogenous and Neutrophil-Derived 2-Chlorofatty Aldehyde

Characterization of N-Acetyl Cysteine Adducts with Exogenous and Neutrophil-Derived 2-Chlorofatty Aldehyde

Development of an activatable far-red fluorescent probe for rapid visualization of hypochlorous acid in live cells and mice with neuroinflammation

2-Chloro- and 2-Bromopalmitic acids inhibit mitochondrial function in airway epithelial cells

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