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Differential Anti-inflammatory Activity of HDAC Inhibitors in Human Macrophages and Rat Arthritis

Overview of attention for article published in The Journal of Pharmacology and Experimental Therapeutics, December 2015
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  • Good Attention Score compared to outputs of the same age (69th percentile)
  • Above-average Attention Score compared to outputs of the same age and source (60th percentile)

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Title
Differential Anti-inflammatory Activity of HDAC Inhibitors in Human Macrophages and Rat Arthritis
Published in
The Journal of Pharmacology and Experimental Therapeutics, December 2015
DOI 10.1124/jpet.115.229328
Pubmed ID
Authors

Rink-Jan Lohman, Abishek Iyer, Thomas J. Fairlie, Adam Cotterell, Praveer Gupta, Robert C. Reid, David A. Vesey, Matthew J. Sweet, David P. Fairlie

Abstract

Vorinostat and other inhibitors of different histone deacetylase (HDAC) enzymes are currently being sought to modulate a variety of human conditions, including chronic inflammatory diseases. Some HDAC inhibitors are anti-inflammatory in rodent models of arthritis and colitis, usually at cytotoxic doses that may cause side effects. Here, we investigate the dose-dependent pro- and anti- inflammatory efficacy of two known inhibitors of multiple HDACs, Vorinostat and BML281, in human macrophages and in a rat model of collagen-induced arthritis by monitoring effects on disease progression, histopathology and immunohistochemistry. Both HDAC inhibitors differentially modulated lipopolysaccharide (LPS)-induced cytokine release from human macrophages, suppressing release of some inflammatory mediators (IL12p40, IL6) at low concentrations (< 3 µM) but amplifying production of others (TNF, IL1β) at higher concentrations (>3 µM). This trend translated in vivo to rat arthritis, with anti-inflammatory activity inversely correlating with dose. Both compounds were efficacious only at a low dose (1 mg.kg-1.day-1 s.c.), whereas a higher dose (5 mg.kg-1.day-1) showed no positive effects on reducing pathology, even showing signs of exacerbating disease. These striking effects suggest a smaller therapeutic window than previously reported for HDAC inhibition in experimental arthritis. The findings support new investigations into repurposing HDAC inhibitors for anti-inflammatory therapeutic applications. However, HDAC inhibitors should be reinvestigated at lower, rather than higher, doses for enhanced efficacy in chronic diseases that require long-term treatment, with careful management of efficacy and long-term safety. .

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Mendeley readers

Mendeley readers

The data shown below were compiled from readership statistics for 41 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
United Kingdom 1 2%
Unknown 40 98%

Demographic breakdown

Readers by professional status Count As %
Student > Bachelor 7 17%
Student > Ph. D. Student 7 17%
Researcher 7 17%
Student > Master 6 15%
Student > Doctoral Student 2 5%
Other 4 10%
Unknown 8 20%
Readers by discipline Count As %
Agricultural and Biological Sciences 7 17%
Pharmacology, Toxicology and Pharmaceutical Science 6 15%
Biochemistry, Genetics and Molecular Biology 5 12%
Medicine and Dentistry 4 10%
Immunology and Microbiology 4 10%
Other 5 12%
Unknown 10 24%
Attention Score in Context

Attention Score in Context

This research output has an Altmetric Attention Score of 4. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 09 August 2023.
All research outputs
#7,960,693
of 25,374,917 outputs
Outputs from The Journal of Pharmacology and Experimental Therapeutics
#1,704
of 5,548 outputs
Outputs of similar age
#114,536
of 394,835 outputs
Outputs of similar age from The Journal of Pharmacology and Experimental Therapeutics
#18
of 48 outputs
Altmetric has tracked 25,374,917 research outputs across all sources so far. This one has received more attention than most of these and is in the 67th percentile.
So far Altmetric has tracked 5,548 research outputs from this source. They typically receive a little more attention than average, with a mean Attention Score of 6.1. This one has gotten more attention than average, scoring higher than 68% of its peers.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 394,835 tracked outputs that were published within six weeks on either side of this one in any source. This one has gotten more attention than average, scoring higher than 69% of its contemporaries.
We're also able to compare this research output to 48 others from the same source and published within six weeks on either side of this one. This one has gotten more attention than average, scoring higher than 60% of its contemporaries.