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Statements

Subject Item
n2:RIV%2F00216208%3A11110%2F14%3A10284362%21RIV15-MSM-11110___
rdf:type
skos:Concept n17:Vysledek
rdfs:seeAlso
http://dx.doi.org/10.1136/annrheumdis-2012-203095
dcterms:description
Objectives Targeted therapies for systemic sclerosis (SSc) and other fibrotic diseases are not yet available. We evaluated the efficacy of heat shock protein 90 (Hsp90) inhibition as a novel approach to inhibition of aberrant transforming growth factor (TGF)-beta signalling and for the treatment of fibrosis in preclinical models of SSc. Methods Expression of Hsp90 was quantified by quantitative PCR, western blot and immunohistochemistry. The effects of Hsp90 inhibition were analysed in cultured fibroblasts, in bleomycin-induced dermal fibrosis, in tight-skin (Tsk-1) mice and in mice overexpressing a constitutively active TGF-beta receptor I (T beta RI). Results Expression of Hsp90 beta was increased in SSc skin and in murine models of SSc in a TGF-beta-dependent manner. Inhibition of Hsp90 by 17-dimethylaminoethylamino-17-demethoxy-geldanamycin (17-DMAG) inhibited canonical TGF-beta signalling and completely prevented the stimulatory effects of TGF-beta on collagen synthesis and myofibroblast differentiation. Treatment with 17-DMAG decreased the activation of canonical TGF-beta signalling in murine models of SSc and exerted potent antifibrotic effects in bleomycin-induced dermal fibrosis, in Tsk-1 mice and in mice overexpressing a constitutively active T beta RI. Dermal thickness, number of myofibroblasts and hydroxyproline content were all significantly reduced on treatment with 17-DMAG. No toxic effects were observed with 17-DMAG at antifibrotic doses. Conclusions Hsp90 is upregulated in SSc and is critical for TGF-beta signalling. Pharmacological inhibition of Hsp90 effectively blocks the profibrotic effects of TGF-beta in cultured fibroblasts and in different preclinical models of SSc. These results have translational implications, as several Hsp90 inhibitors are in clinical trials for other indications. Objectives Targeted therapies for systemic sclerosis (SSc) and other fibrotic diseases are not yet available. We evaluated the efficacy of heat shock protein 90 (Hsp90) inhibition as a novel approach to inhibition of aberrant transforming growth factor (TGF)-beta signalling and for the treatment of fibrosis in preclinical models of SSc. Methods Expression of Hsp90 was quantified by quantitative PCR, western blot and immunohistochemistry. The effects of Hsp90 inhibition were analysed in cultured fibroblasts, in bleomycin-induced dermal fibrosis, in tight-skin (Tsk-1) mice and in mice overexpressing a constitutively active TGF-beta receptor I (T beta RI). Results Expression of Hsp90 beta was increased in SSc skin and in murine models of SSc in a TGF-beta-dependent manner. Inhibition of Hsp90 by 17-dimethylaminoethylamino-17-demethoxy-geldanamycin (17-DMAG) inhibited canonical TGF-beta signalling and completely prevented the stimulatory effects of TGF-beta on collagen synthesis and myofibroblast differentiation. Treatment with 17-DMAG decreased the activation of canonical TGF-beta signalling in murine models of SSc and exerted potent antifibrotic effects in bleomycin-induced dermal fibrosis, in Tsk-1 mice and in mice overexpressing a constitutively active T beta RI. Dermal thickness, number of myofibroblasts and hydroxyproline content were all significantly reduced on treatment with 17-DMAG. No toxic effects were observed with 17-DMAG at antifibrotic doses. Conclusions Hsp90 is upregulated in SSc and is critical for TGF-beta signalling. Pharmacological inhibition of Hsp90 effectively blocks the profibrotic effects of TGF-beta in cultured fibroblasts and in different preclinical models of SSc. These results have translational implications, as several Hsp90 inhibitors are in clinical trials for other indications.
dcterms:title
Heat shock protein 90 (Hsp90) inhibition targets canonical TGF-beta signalling to prevent fibrosis Heat shock protein 90 (Hsp90) inhibition targets canonical TGF-beta signalling to prevent fibrosis
skos:prefLabel
Heat shock protein 90 (Hsp90) inhibition targets canonical TGF-beta signalling to prevent fibrosis Heat shock protein 90 (Hsp90) inhibition targets canonical TGF-beta signalling to prevent fibrosis
skos:notation
RIV/00216208:11110/14:10284362!RIV15-MSM-11110___
n3:aktivita
n11:S
n3:aktivity
S
n3:cisloPeriodika
6
n3:dodaniDat
n7:2015
n3:domaciTvurceVysledku
n6:1793845 n6:2286041 n6:2072890
n3:druhVysledku
n12:J
n3:duvernostUdaju
n14:S
n3:entitaPredkladatele
n8:predkladatel
n3:idSjednocenehoVysledku
18875
n3:idVysledku
RIV/00216208:11110/14:10284362
n3:jazykVysledku
n4:eng
n3:klicovaSlova
Hsp90; fibrosis; systemic sclerosis
n3:klicoveSlovo
n10:systemic%20sclerosis n10:Hsp90 n10:fibrosis
n3:kodStatuVydavatele
GB - Spojené království Velké Británie a Severního Irska
n3:kontrolniKodProRIV
[6FC164475937]
n3:nazevZdroje
Annals of the Rheumatic Diseases
n3:obor
n5:FE
n3:pocetDomacichTvurcuVysledku
3
n3:pocetTvurcuVysledku
10
n3:rokUplatneniVysledku
n7:2014
n3:svazekPeriodika
73
n3:tvurceVysledku
Schett, G. Tomčík, Michal Distler, J. Distler, J. H. Šenolt, Ladislav Zerr, P. Palumbo-Zerr, K. Avouac, J. Bečvář, Radim Pitkowski, J.
n3:wos
000335362100048
s:issn
0003-4967
s:numberOfPages
8
n19:doi
10.1136/annrheumdis-2012-203095
n15:organizacniJednotka
11110