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The Triptryium wilfordii derivative celastrol has anti-fibrotic effects in systemic sclerosis

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE226376 | GEO | 2023/11/01

REPOSITORIES: GEO

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The Triptryium wilfordii derivative celastrol has anti-fibrotic effects in systemic sclerosis [Spatial Transcriptomics]

Project description:Objectives: Scleroderma (systemic sclerosis, SSc), as a prototypic inflammation-driven fibrotic disease, possesses connective tissue lesions populated with persistently activated myofibroblasts maintained by an mechanotranductive/pro-adhesive signaling loop. Drugs targeting this pathway are therefore of likely therapeutic benefit. The mechanosensitive transcriptional co-activator, yes activated protein-1 (YAP1), is activated in SSc fibroblasts. The terpenoid celastrol has recently been identified as a YAP1 inhibitor: however, if celastrol can alleviate SSc fibrosis is unknown. Methods: Human dermal fibroblasts from healthy individuals and patients with diffuse cutaneous SSc were treated with or without transforming growth factor b1 (TGFb1) in the presence or absence of celastrol. C57BL6J mice were subjected to the inflammatory-driven bleomycin-induced model of skin SSc, in the presence or absence of celastrol. RNA expression was assessed using RNAseq, real-time polymerase chain reaction and spatial transcriptomic analyses. Protein expression was determined using Western blot and enzyme-linked immunosorbent assay. Fibrosis was monitored by hematoxylin and eosin and trichrome staining, and indirect immunofluorescence analysis. Results: In dermal fibroblasts, celastrol impaired the ability of TGFβ1 to induce an SSc-like pattern of gene expression, including the induction of cellular communication network factor 2 (CCN2), collagen I and TGFβ1 protein. Celastrol alleviated the persistent fibrotic phenotype of dermal fibroblasts cultured from lesions of SSc patients. In the bleomycin-induced model of SSc dermatopathology, celastrol inhibited fibrosis and blocked nuclear localization of YAP in myofibroblasts. Conclusion: Our data are consistent with the hypothesis that compounds, such as celastrol, that antagonize the YAP pathway may be potential treatments for SSc skin fibrosis.

2023-11-01 | GSE226760 | GEO

The Triptryium wilfordii derivative celastrol has anti-fibrotic effects in systemic sclerosis [In vivo bulk RNA-seq]

2023-11-01 | GSE226375 | GEO

The Triptryium wilfordii derivative celastrol has anti-fibrotic effects in systemic sclerosis [in vitro bulk RNA-seq]

2023-11-01 | GSE226374 | GEO

Multi-tissue functional genomic study of systemic sclerosis

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2016-01-12 | E-GEOD-76809 | biostudies-arrayexpress

Multi-tissue functional genomic study of systemic sclerosis

Project description:This SuperSeries is composed of the SubSeries listed below.

2016-01-12 | GSE76809 | GEO