Evidence map›Paper›PMID 32933418›Full record

ArticleStroke2020

Inhibition of EZH2 (Enhancer of Zeste Homolog 2) Attenuates Neuroinflammation via H3k27me3/SOCS3/TRAF6/NF-κB (Trimethylation of Histone 3 Lysine 27/Suppressor of Cytokine Signaling 3/Tumor Necrosis Factor Receptor Family 6/Nuclear Factor-κB) in a Rat Model of Subarachnoid Hemorrhage.

Yujie Luo, Yuanjian Fang, Ruiqing Kang, Cameron Lenahan, Marcin Gamdzyk, Zeyu Zhang, Takeshi Okada, Jiping Tang, Sheng Chen, John H Zhang

Expression of concernErratum issuedOpen access · greenAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Stroke, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It carries an expression of concern. Cited by 40 papers, 2 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
40citing papers in PubMed, 2 pooled it
4.0field-weighted citation impact, top 5% 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

40 citing papers in PubMed, 2 syntheses or guidelines pooled it, 62 citations in OpenAlex.

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4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

10 authors at 3 institutions in 2 countries.

Yujie Luo *Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China (Y.L., Y.F., Z.Z., S.C.).
Yuanjian Fang *Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China (Y.L., Y.F., Z.Z., S.C.).
Ruiqing KangDepartment of Physiology and Pharmacology, School of Medicine, Loma Linda University, CA (R.K., C.L., M.G., T.O., J.T., J.H.Z.).
Cameron LenahanDepartment of Physiology and Pharmacology, School of Medicine, Loma Linda University, CA (R.K., C.L., M.G., T.O., J.T., J.H.Z.).
Marcin GamdzykDepartment of Physiology and Pharmacology, School of Medicine, Loma Linda University, CA (R.K., C.L., M.G., T.O., J.T., J.H.Z.).
Zeyu ZhangDepartment of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China (Y.L., Y.F., Z.Z., S.C.).
Takeshi OkadaDepartment of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China (Y.L., Y.F., Z.Z., S.C.).
Jiping TangDepartment of Physiology and Pharmacology, School of Medicine, Loma Linda University, CA (R.K., C.L., M.G., T.O., J.T., J.H.Z.).
Sheng ChenDepartment of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China (Y.L., Y.F., Z.Z., S.C.).
John H ZhangDepartment of Physiology and Pharmacology, School of Medicine, Loma Linda University, CA (R.K., C.L., M.G., T.O., J.T., J.H.Z.).
Second Affiliated Hospital of Zhejiang University · CNLoma Linda University · USNew Mexico State University · US

Funding

Vascular Biology Core FacilityP01NS082184 · NINDS · LOMA LINDA UNIVERSITY · PI PEARCE, WILLIAM J. · 2014 to 2018
$6.1M
Neurovascular Protection for Early Brain Injury after SAHR01NS081740 · NINDS · LOMA LINDA UNIVERSITY · PI ZHANG, JOHN H · 2013 to 2017
$1.6M
NINDS NIH HHS P01 NS082184NINDS NIH HHS R01 NS081740
6 · The paper itself

Abstract

background and purposeNeuroinflammation has been proven to play an important role in the pathogenesis of early brain injury after subarachnoid hemorrhage (SAH). EZH2 (enhancer of zeste homolog 2)-mediated H3K27Me3 (trimethylation of histone 3 lysine 27) has been recognized to play a critical role in multiple inflammatory diseases. However, there is still a lack of evidence to address the effect of EZH2 on the immune response of SAH. Therefore, the aim of this study was to determine the role of EZH2 in SAH-induced neuroinflammation and explore the effect of EZH2 inhibition with its specific inhibitor EPZ6438.

methodsThe endovascular perforation method was performed on rats to induce subarachnoid hemorrhage. EPZ6438, a specific EZH2 inhibitor, was administered intraperitoneally at 1 hour after SAH. SOCS3 (Suppressor of cytokine signaling 3) siRNA and H3K27me3 CRISPR were administered intracerebroventricularly at 48 hours before SAH to explore potential mechanisms. The SAH grade, short-term and long-term neurobehavioral tests, immunofluorescence staining, and western blots were performed after SAH.

resultsThe expression of EZH2 and H3K27me3 peaked at 24 hours after SAH. In addition, inhibition of EZH2 with EPZ6438 significantly improved neurological deficits both in short-term and long-term outcome studies. Moreover, EPZ6438 treatment significantly decreased the levels of EZH2, H3K27Me3, pathway-related proteins TRAF6 (TNF [tumor necrosis factor] receptor family 6), NF-κB (nuclear factor-κB) p65, proinflammatory cytokines TNF-α, IL (interleukin)-6, IL-1β, but increased the expression levels of SOCS3 and anti-inflammatory cytokine IL-10. Furthermore, administration of SOCS3 siRNA and H3k27me3-activating CRISPR partly abolished the neuroprotective effect of EPZ6438, which indicated that the neuroprotective effect of EPZ6438 acted, at least partly, through activation of SOCS3.

conclusionsIn summary, the inhibition of EZH2 by EPZ6438 attenuated neuroinflammation via H3K27me3/SOCS3/TRAF6/NF-κB signaling pathway after SAH in rats. By targeting EZH2, this study may provide an innovative method to ameliorate early brain injury after SAH.

Indexed as

AnimalsBenzamidesBiphenyl CompoundsBrainClustered Regularly Interspaced Short Palindromic RepeatsDisease Models, AnimalEnhancer of Zeste Homolog 2 ProteinHistone CodeHistonesInflammationMaleMicrogliaMorpholinesMorris Water Maze TestNeutrophil InfiltrationNF-kappa BBenzamidesBiphenyl CompoundsEnhancer of Zeste Homolog 2 ProteinEZH2 protein, ratHistonesMorpholinesNF-kappa BPyridonesRNA, Small InterferingSocs3 protein, ratSuppressor of Cytokine Signaling 3 ProteintazemetostatTNF Receptor-Associated Factor 6enhancer of zeste homolog 2inflammationneuroprotectionsubarachnoid hemorrhage

Identifiers

PMID32933418
PMCPMC7725431
OpenAlexW3087690315

What OpenQuestion holds

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Read underepoch 390

Registered trials

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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.