Covalent adduct formation between the plasmalogen-derived modification product 2-chlorohexadecanal and phloretin

Üllen, Andreas; Nusshold, Christoph; Glasnov, Toma N.; Saf, Robert; Cantillo, David; Eibinger, Gerald; Reicher, Helga; Fauler, Günter; Bernhart, Eva; Hallström, Seth; Kogelnik, Nora; Zangger, Klaus; Kappe, C. Oliver; Malle, Ernst; Sattler, Wolfgang

doi:10.1016/j.bcp.2014.12.017

Cited by 9 publications

(8 citation statements)

References 57 publications

(83 reference statements)

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“…To determine whether PHL could cross the rat bloodbrain barrier (BBB), the level of PHL in the brain was determined by a liquid chromatography-tandem mass spectrometry (LC-MS/MS) following the intragastrical administration of 50 mg/kg PHL. We found that the peak level of PHL was detected in the brain at 60 min (Figure 1B), suggesting that PHL can cross the rat blood-brain barrier (BBB), which was consistent with a previous report in mice [25].…”

Section: Phl Attenuates the Cms-induced Depressive-like Behaviors In ...supporting

confidence: 92%

Phloretin decreases microglia-mediated synaptic engulfment to prevent chronic mild stress-induced depression-like behaviors in the mPFC

Li¹,

Liu²,

Xu³

et al. 2023

Theranostics

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Background: Stress is an important risk factor to induce psychiatric disorders such as depression. Phloretin (PHL), a natural dihydrochalcone compound, has been shown to exhibit anti-inflammatory and anti-oxidative effects. However, the impact of PHL on the depression and the underlying mechanism remain unclear. Methods: The animal behavior tests were used to determine the protective of PHL on the chronic mild stress (CMS)-induced depression-like behaviors. The Magnetic Resonance Imaging (MRI), electron microscopy analysis, fiber photometry, electrophysiology, and Structure Illumination Microscopy (SIM) were used to investigate the protective of PHL on the structural and functional impairments induced by CMS exposure in the mPFC. The RNA sequencing, western blot, reporter gene assay, and chromatin immunoprecipitation were adopted to investigate the mechanisms. Results: We showed that PHL efficiently prevented the CMS-induced depressive-like behaviors. Moreover, PHL not only attenuated the decrease of synapse losses but also improved the dendritic spine density and neuronal activity in the mPFC after CMS exposure. Furthermore, PHL remarkably inhibited the CMS-induced microglial activation and phagocytic activity in the mPFC. In addition, we demonstrated that PHL decreased the CMS-induced synapse losses by inhibiting the deposition of complement C3 deposition onto synapses and subsequent microglia-mediated synaptic engulfment. Finally, we revealed that PHL inhibited the NF-κB-C3 axis to display neuroprotective effects. Conclusions: Our results indicate that PHL represses the NF-κB-C3 axis and subsequent microglia-mediated synaptic engulfment to protect against CMS-induced depression in the mPFC.

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Section: Phl Attenuates the Cms-induced Depressive-like Behaviors In ...supporting

confidence: 92%

Phloretin decreases microglia-mediated synaptic engulfment to prevent chronic mild stress-induced depression-like behaviors in the mPFC

Li¹,

Liu²,

Xu³

et al. 2023

Theranostics

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“…Moreover, these fatty acid species have been detected as being free or esterified. Furthermore, emerging studies indicate unique biological effects of Cllipids in stimulating inflammation, promoting cell-death, and dysfunction in eNOS-signaling (19,21,23,(26)(27)(28)(29)(30), which are also all features of post-Cl 2 gas toxicity (4,15). Cl-lipids are predicted to be formed via direct reactions of Cl 2 gas with the vinyl ether bond in plasmalogens, leading us to hypothesize that these species may be mediators of post-Cl 2 gas toxicity.…”

Section: Measurement Of Glutathione Adducts Of 2-cl-pald and 2-cl-mentioning

confidence: 99%

Formation of chlorinated lipids post-chlorine gas exposure

Ford

Honavar

Albert

et al. 2016

Journal of Lipid Research

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“…2-ClFALD has been shown to accumulate in the lungs of chlorine gas-exposed mice, infarcted rat myocardium and human aorta [4,5,9]. 2-ClFALD has been shown to cause cytotoxicity in several cell lines [10][11][12]. It is likely that the 2-ClFALD modification of proteins is responsible for many of the biological properties of 2-ClFALD.…”

Section: Discussionmentioning

confidence: 99%

“…Myeloperoxidase-derived 2-ClFALD and 2-ClFA are suggested to be involved in endothelial dysfunction, neutrophil chemotaxis, NETosis and vascular tone [6][7][8][9]. Additionally, the Ford lab and other labs have shown that 2-ClFALD and 2-ClFA cause cell toxicity [10][11][12][13].…”

Section: Introductionmentioning

confidence: 99%

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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Covalent adduct formation between the plasmalogen-derived modification product 2-chlorohexadecanal and phloretin

Abstract: Graphical abstract

Cited by 9 publications

References 57 publications

Phloretin decreases microglia-mediated synaptic engulfment to prevent chronic mild stress-induced depression-like behaviors in the mPFC

Phloretin decreases microglia-mediated synaptic engulfment to prevent chronic mild stress-induced depression-like behaviors in the mPFC

Formation of chlorinated lipids post-chlorine gas exposure

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

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