Evidence map›Paper›PMID 25576489›Full record

ArticleBiochemical pharmacology2015

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

Andreas Üllen, Christoph Nusshold, Toma Glasnov, Robert Saf, David Cantillo, Gerald Eibinger, Helga Reicher, Günter Fauler, Eva Bernhart, Seth Hallstrom and 5 more

Open access · hybridAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Biochemical pharmacology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.

0numbers the graph read from it
0cells of the map it votes in
5citing papers in PubMed
0.3field-weighted citation impact, top 41% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

5 citing papers in PubMed, 9 citations in OpenAlex.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

15 authors at 3 institutions in 1 country.

Andreas ÜllenInstitute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria.
Christoph NussholdInstitute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria.
Toma GlasnovChristian Doppler Laboratory for Flow Chemistry, Institute of Chemistry, University of Graz, Graz, Austria.
Robert SafInstitute of Chemistry and Technology of Materials, Graz University of Technology, Graz, Austria.
David CantilloInstitute of Chemistry, University of Graz, Graz, Austria.
Gerald EibingerInstitute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria.
Helga ReicherInstitute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria.
Günter FaulerClinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria.
Eva BernhartInstitute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria.
Seth HallstromInstitute of Physiological Chemistry, Medical University of Graz, Graz, Austria.
Nora KogelnikInstitute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria.
Klaus ZanggerInstitute of Chemistry, University of Graz, Graz, Austria.
C Oliver KappeInstitute of Chemistry, University of Graz, Graz, Austria.
Ernst MalleInstitute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria.
Wolfgang SattlerInstitute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria. Electronic address: wolfgang.sattler@medunigraz.at.
Medical University of Graz · ATUniversity of Graz · ATGraz University of Technology · AT

Funding

Austrian Science Fund FWF F 3007
6 · The paper itself

Abstract

Hypochlorous acid added as reagent or generated by the myeloperoxidase (MPO)-H2O2-Cl(-) system oxidatively modifies brain ether-phospholipids (plasmalogens). This reaction generates a sn2-acyl-lysophospholipid and chlorinated fatty aldehydes. 2-Chlorohexadecanal (2-ClHDA), a prototypic member of chlorinated long-chain fatty aldehydes, has potent neurotoxic potential by inflicting blood-brain barrier (BBB) damage. During earlier studies we could show that the dihydrochalcone-type polyphenol phloretin attenuated 2-ClHDA-induced BBB dysfunction. To clarify the underlying mechanism(s) we now investigated the possibility of covalent adduct formation between 2-ClHDA and phloretin. Coincubation of 2-ClHDA and phloretin in phosphatidylcholine liposomes revealed a half-life of 2-ClHDA of approx. 120min, decaying at a rate of 5.9×10(-3)min(-1). NMR studies and enthalpy calculations suggested that 2-ClHDA-phloretin adduct formation occurs via electrophilic aromatic substitution followed by hemiacetal formation on the A-ring of phloretin. Adduct characterization by high-resolution mass spectroscopy confirmed these results. In contrast to 2-ClHDA, the covalent 2-ClHDA-phloretin adduct was without adverse effects on MTT reduction (an indicator for metabolic activity), cellular adenine nucleotide content, and barrier function of brain microvascular endothelial cells (BMVEC). Of note, 2-ClHDA-phloretin adduct formation was also observed in BMVEC cultures. Intraperitoneal application and subsequent GC-MS analysis of brain lipid extracts revealed that phloretin is able to penetrate the BBB of C57BL/6J mice. Data of the present study indicate that phloretin scavenges 2-ClHDA, thereby attenuating 2-ClHDA-mediated brain endothelial cell dysfunction. We here identify a detoxification pathway for a prototypic chlorinated fatty aldehyde (generated via the MPO axis) that compromises BBB function in vitro and in vivo.

Indexed as

AldehydesAnimalsBlood-Brain BarrierCells, CulturedEndothelium, VascularMaleMiceMice, Inbred C57BLPhloretinPlasmalogensSheepSwine2-chlorohexadecanalAldehydesPhloretinPlasmalogensBlood–brain barrierChlorinated fatty aldehydeMyeloperoxidaseNeuroinflammationPlasmalogens

Identifiers

PMID25576489
PMCPMC4321883
OpenAlexW2015190034

What OpenQuestion holds

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LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.