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Fingolimod induces neuroprotective factors in human astrocytes

Overview of attention for article published in Journal of Neuroinflammation, September 2015
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Title
Fingolimod induces neuroprotective factors in human astrocytes
Published in
Journal of Neuroinflammation, September 2015
DOI 10.1186/s12974-015-0393-6
Pubmed ID
Authors

Franziska S. Hoffmann, Johann Hofereiter, Heike Rübsamen, Johannes Melms, Sigrid Schwarz, Hans Faber, Peter Weber, Benno Pütz, Verena Loleit, Frank Weber, Reinhard Hohlfeld, Edgar Meinl, Markus Krumbholz

Abstract

Fingolimod (FTY720) is the first sphingosine-1-phosphate (S1P) receptor modulator approved for the treatment of multiple sclerosis. The phosphorylated active metabolite FTY720-phosphate (FTY-P) interferes with lymphocyte trafficking. In addition, it accumulates in the CNS and reduces brain atrophy in multiple sclerosis (MS), and neuroprotective effects are hypothesized. Human primary astrocytes as well as human astrocytoma cells were stimulated with FTY-P or S1P. We analyzed gene expression by a genome-wide microarray and validated induced candidate genes by quantitative PCR (qPCR) and ELISA. To identify the S1P-receptor subtypes involved, we applied a membrane-impermeable S1P analog (dihydro-S1P), receptor subtype specific agonists and antagonists, as well as RNAi silencing. FTY-P induced leukemia inhibitory factor (LIF), interleukin 11 (IL11), and heparin-binding EGF-like growth factor (HBEGF) mRNA, as well as secretion of LIF and IL11 protein. In order to mimic an inflammatory milieu as observed in active MS lesions, we combined FTY-P application with tumor necrosis factor (TNF). In the presence of this key inflammatory cytokine, FTY-P synergistically induced LIF, HBEGF, and IL11 mRNA, as well as secretion of LIF and IL11 protein. TNF itself induced inflammatory, B-cell promoting, and antiviral factors (CXCL10, BAFF, MX1, and OAS2). Their induction was blocked by FTY-P. After continuous exposure of cells to FTY-P or S1P for up to 7 days, the extent of induction of neurotrophic factors and the suppression of TNF-induced inflammatory genes declined but was still detectable. The induction of neurotrophic factors was mediated via surface S1P receptors 1 (S1PR1) and 3 (S1PR3). We identified effects of FTY-P on astrocytes, namely induction of neurotrophic mediators (LIF, HBEGF, and IL11) and inhibition of TNF-induced inflammatory genes (CXCL10, BAFF, MX1, and OAS2). This supports the view that a part of the effects of fingolimod may be mediated via astrocytes.

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Mendeley readers

Mendeley readers

The data shown below were compiled from readership statistics for 87 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 87 100%

Demographic breakdown

Readers by professional status Count As %
Researcher 20 23%
Student > Ph. D. Student 15 17%
Student > Master 12 14%
Student > Bachelor 5 6%
Professor 5 6%
Other 14 16%
Unknown 16 18%
Readers by discipline Count As %
Neuroscience 17 20%
Medicine and Dentistry 16 18%
Biochemistry, Genetics and Molecular Biology 8 9%
Agricultural and Biological Sciences 7 8%
Pharmacology, Toxicology and Pharmaceutical Science 4 5%
Other 8 9%
Unknown 27 31%
Attention Score in Context

Attention Score in Context

This research output has an Altmetric Attention Score of 2. 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 23 June 2016.
All research outputs
#13,448,315
of 22,829,683 outputs
Outputs from Journal of Neuroinflammation
#1,447
of 2,635 outputs
Outputs of similar age
#129,558
of 274,274 outputs
Outputs of similar age from Journal of Neuroinflammation
#19
of 43 outputs
Altmetric has tracked 22,829,683 research outputs across all sources so far. This one is in the 39th percentile – i.e., 39% of other outputs scored the same or lower than it.
So far Altmetric has tracked 2,635 research outputs from this source. They typically receive more attention than average, with a mean Attention Score of 7.6. This one is in the 43rd percentile – i.e., 43% of its peers scored the same or lower than it.
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 274,274 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 51% of its contemporaries.
We're also able to compare this research output to 43 others from the same source and published within six weeks on either side of this one. This one is in the 48th percentile – i.e., 48% of its contemporaries scored the same or lower than it.