Evidence map›Paper›PMID 25751721›Full record

ArticleInternational journal of molecular sciences2015

Methemoglobin is an endogenous toll-like receptor 4 ligand-relevance to subarachnoid hemorrhage.

Min Seong Kwon, Seung Kyoon Woo, David B Kurland, Sung Hwan Yoon, Andre F Palmer, Uddyalok Banerjee, Sana Iqbal, Svetlana Ivanova, Volodymyr Gerzanich, J Marc Simard

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

Article in International journal of molecular sciences, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 83 papers, 3 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
83citing papers in PubMed, 3 pooled it
4.7field-weighted citation impact, top 4% 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

83 citing papers in PubMed, 3 syntheses or guidelines pooled it, 117 citations in OpenAlex.

  1. Pooled it
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  4. Toll like receptor 4 (TLR4) in neuroinflammation: From acute hemorrhagic stroke to chronic neurodegeneration.Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism · 2026
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23 more citing papers are in PubMed but not listed here.

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

10 authors at 2 institutions in 1 country.

Min Seong KwonDepartment of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA. mskwon@smail.umaryland.edu.
Seung Kyoon WooDepartment of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA. skwoo@smail.umaryland.edu.
David B KurlandDepartment of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA. kurland.davidb@gmail.com.
Sung Hwan YoonDepartment of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201, USA. syoon@rx.umaryland.edu.
Andre F PalmerWilliam G. Lowrie Department of Chemical and Biomolecular Engineering, the Ohio State University, Columbus, OH 43210, USA. palmer.351@osu.edu.
Uddyalok BanerjeeWilliam G. Lowrie Department of Chemical and Biomolecular Engineering, the Ohio State University, Columbus, OH 43210, USA. banerjee.49@osu.edu.
Sana IqbalDepartment of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA. sveta0652@yahoo.com.
Svetlana IvanovaDepartment of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA. sveta0652@yahoo.com.
Volodymyr GerzanichDepartment of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA. vgerzanich@smail.umaryland.edu.
J Marc SimardDepartment of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA. msimard@smail.umaryland.edu.
University of Maryland, Baltimore · USThe Ohio State University · US

Funding

Sulfonylurea receptor 1 (SUR1)- A novel therapeutic target in ischemic strokeR01HL082517 · NHLBI · UNIVERSITY OF MARYLAND BALTIMORE · PI SIMARD, J. MARC · 2006 to 2021
$5.6M
Pathological role of the SUR1-regulated NC(Ca-ATP) channel in cortex after subaraR01NS061808 · NINDS · UNIVERSITY OF MARYLAND BALTIMORE · PI SIMARD, J. MARC · 2009 to 2013
$1.6M
Attenuating the Oxidative and Myocardial Toxicity of Polymerized HemoglobinsR56HL123015 · NHLBI · OHIO STATE UNIVERSITY · PI CABRALES, PEDRO, PALMER, ANDRE FRANCIS · 2014 to 2014
$400k
NHLBI NIH HHS HL082517NHLBI NIH HHS R01 HL082517NHLBI NIH HHS R56 HL123015NHLBI NIH HHS R56HL123015NINDS NIH HHS NS061808NINDS NIH HHS R01 NS061808
6 · The paper itself

Abstract

Neuroinflammation is a well-recognized consequence of subarachnoid hemorrhage (SAH), and may be responsible for important complications of SAH. Signaling by Toll-like receptor 4 (TLR4)-mediated nuclear factor κB (NFκB) in microglia plays a critical role in neuronal damage after SAH. Three molecules derived from erythrocyte breakdown have been postulated to be endogenous TLR4 ligands: methemoglobin (metHgb), heme and hemin. However, poor water solubility of heme and hemin, and lipopolysaccharide (LPS) contamination have confounded our understanding of these molecules as endogenous TLR4 ligands. We used a 5-step process to obtain highly purified LPS-free metHgb, as confirmed by Fourier Transform Ion Cyclotron Resonance mass spectrometry and by the Limulus amebocyte lysate assay. Using this preparation, we show that metHgb is a TLR4 ligand at physiologically relevant concentrations. metHgb caused time- and dose-dependent secretion of the proinflammatory cytokine, tumor necrosis factor α (TNFα), from microglial and macrophage cell lines, with secretion inhibited by siRNA directed against TLR4, by the TLR4-specific inhibitors, Rs-LPS and TAK-242, and by anti-CD14 antibodies. Injection of purified LPS-free metHgb into the rat subarachnoid space induced microglial activation and TNFα upregulation. Together, our findings support the hypothesis that, following SAH, metHgb in the subarachnoid space can promote widespread TLR4-mediated neuroinflammation.

Indexed as

AnimalsCattleCell LineHippocampusInflammationLigandsMacrophagesMethemoglobinMiceMicrogliaRatsRNA InterferenceRNA, Small InterferingSubarachnoid HemorrhageSulfonamidesToll-Like Receptor 4ethyl 6-(N-(2-chloro-4-fluorophenyl)sulfamoyl)cyclohex-1-ene-1-carboxylateLigandsMethemoglobinRela protein, ratRNA, Small InterferingSulfonamidesToll-Like Receptor 4Transcription Factor RelATumor Necrosis Factor-alpha

Identifiers

PMID25751721
PMCPMC4394463
OpenAlexW2035576485

What OpenQuestion holds

Textmetadata
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.