Evidence map›Paper›PMID 26712011›Full record

ArticleProceedings of the National Academy of Sciences of the United States of America2016

Systematic study of constitutive cyclooxygenase-2 expression: Role of NF-κB and NFAT transcriptional pathways.

Nicholas S Kirkby, Melissa V Chan, Anne K Zaiss, Eliana Garcia-Vaz, Jing Jiao, Lisa M Berglund, Elena F Verdu, Blerina Ahmetaj-Shala, John L Wallace, Harvey R Herschman and 2 more

Registry-linked trialOpen access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT04765644 (Arginine Supplementation to Improve Cardiovascular and Endothelial Function After NSAID Treatment), which is not on this map. Cited by 77 papers, 2 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
77citing papers in PubMed, 2 pooled it
11.0field-weighted citation impact, top 1% 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.

NCT04765644 phase4completednot on this mapstarted 2021, after this paper: background citation

Arginine Supplementation to Improve Cardiovascular and Endothelial Function After NSAID Treatment (ASCENT)

TypeinterventionalSponsorImperial College LondonRan2021 to 2022Enrolled44ConditionsHealthyArmsCelecoxib, Placebo, L-arginine + placebo, L-arginine + celecoxib
3 · Its place in the literature

Who cites it

77 citing papers in PubMed, 2 syntheses or guidelines pooled it, 168 citations in OpenAlex.

  1. Pooled it
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  14. Mechanisms of prostatic inflammation-mediated male lower urinary tract symptoms.American journal of clinical and experimental urology · 2025
    Review
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  20. Protective Effect of the Phycobiliproteins fromPlants (Basel, Switzerland) · 2023
    Article

17 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

12 authors at 6 institutions in 4 countries.

Nicholas S KirkbyCardiothoracic Pharmacology, Vascular Biology, National Heart and Lung Institute, Imperial College London, London SW3 6LY, United Kingdom; n.kirkby@imperial.ac.uk j.a.mitchell@ic.ac.uk.
Melissa V ChanTranslational Medicine and Therapeutics, The William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary, University of London, London EC1M 6BQ, United Kingdom; Farmcombe Family Institute of Digestive Health, McMaster University, Hamilton, ON L8S 4K1, Canada;
Anne K ZaissDepartment of Medical and Molecular Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095-1570;
Eliana Garcia-VazDepartment of Clinical Sciences in Malmo, Lund University, Malmo SE-205 02, Sweden;
Jing JiaoDepartment of Medical and Molecular Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095-1570;
Lisa M BerglundDepartment of Clinical Sciences in Malmo, Lund University, Malmo SE-205 02, Sweden;
Elena F VerduFarmcombe Family Institute of Digestive Health, McMaster University, Hamilton, ON L8S 4K1, Canada;
Blerina Ahmetaj-ShalaCardiothoracic Pharmacology, Vascular Biology, National Heart and Lung Institute, Imperial College London, London SW3 6LY, United Kingdom;
John L WallaceFarmcombe Family Institute of Digestive Health, McMaster University, Hamilton, ON L8S 4K1, Canada; Antibe Therapeutics Inc., Toronto, ON M5R 1B2, Canada.
Harvey R HerschmanDepartment of Medical and Molecular Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095-1570;
Maria F GomezDepartment of Clinical Sciences in Malmo, Lund University, Malmo SE-205 02, Sweden;
Jane A MitchellCardiothoracic Pharmacology, Vascular Biology, National Heart and Lung Institute, Imperial College London, London SW3 6LY, United Kingdom; n.kirkby@imperial.ac.uk j.a.mitchell@ic.ac.uk.
Imperial College London · GBLund University · SEUniversity of California, Los Angeles · USMcMaster University · CAPopulation Health Research Institute · CAWilliam Harvey Research Institute · GB

Funding

Women's CancersP30CA016042 · NCI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI Samuel Wheeler French · 1985 to 2026
$134.5M
Transductionally Redirected /Transcriptionally RestricteP50CA086306 · NCI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI HERSCHMAN, HARVEY R. · 2000 to 2014
$29.0M
British Heart Foundation FS/16/1/31699NCI NIH HHS P30 CA016042NCI NIH HHS P50 CA086306Wellcome TrustWellcome Trust 0852551Z108/Z
6 · The paper itself

Abstract

Cyclooxygenase-2 (COX-2) is an inducible enzyme that drives inflammation and is the therapeutic target for widely used nonsteroidal antiinflammatory drugs (NSAIDs). However, COX-2 is also constitutively expressed, in the absence of overt inflammation, with a specific tissue distribution that includes the kidney, gastrointestinal tract, brain, and thymus. Constitutive COX-2 expression is therapeutically important because NSAIDs cause cardiovascular and renal side effects in otherwise healthy individuals. These side effects are now of major concern globally. However, the pathways driving constitutive COX-2 expression remain poorly understood. Here we show that in the kidney and other sites, constitutive COX-2 expression is a sterile response, independent of commensal microorganisms and not associated with activity of the inflammatory transcription factor NF-κB. Instead, COX-2 expression in the kidney but not other regions colocalized with nuclear factor of activated T cells (NFAT) transcription factor activity and was sensitive to inhibition of calcineurin-dependent NFAT activation. However, calcineurin/NFAT regulation did not contribute to constitutive expression elsewhere or to inflammatory COX-2 induction at any site. These data address the mechanisms driving constitutive COX-2 and suggest that by targeting transcription it may be possible to develop antiinflammatory therapies that spare the constitutive expression necessary for normal homeostatic functions, including those important to the cardiovascular-renal system.

Indexed as

Signal TransductionTranscription, GeneticAnimalsCyclooxygenase 2CyclosporineCytokinesFemaleGene Expression Regulation, EnzymologicGerm-Free LifeKidneyLipopolysaccharidesLuciferasesMaleMice, Inbred C57BLNFATC Transcription FactorsNF-kappa BCyclooxygenase 2CyclosporineCytokinesLipopolysaccharidesLuciferasesNFATC Transcription FactorsNF-kappa BRNA, Messengercardiovascularcyclooxygenasenonsteroidal antiinflammatory drugsprostacyclinVioxx

Identifiers

PMID26712011
PMCPMC4720301
OpenAlexW2213746779

What OpenQuestion holds

Textmetadata
Read underepoch 390

Registered trials

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.