The Triptryium wilfordii derivative celastrol has anti-fibrotic effects in systemic sclerosis
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ABSTRACT:
PROVIDER: PRJNA940081 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23674700.fastq.gz | Fastqsanger.gz | |||
| SRR23674701.fastq.gz | Fastqsanger.gz | |||
| SRR23674702.fastq.gz | Fastqsanger.gz | |||
| SRR23674703.fastq.gz | Fastqsanger.gz | |||
| SRR23674704.fastq.gz | Fastqsanger.gz |
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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
Project description:The Triptryium wilfordii derivative celastrol has anti-fibrotic effects in systemic sclerosis [Spatial Transcriptomics]
| PRJNA941340 | ENA
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 | GSE226375 | GEO
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 | GSE226374 | GEO
Project description:The Triptryium wilfordii derivative celastrol has anti-fibrotic effects in systemic sclerosis [In vivo bulk RNA-seq]
| PRJNA940093 | ENA
Project description:The Triptryium wilfordii derivative celastrol has anti-fibrotic effects in systemic sclerosis [in vitro bulk RNA-seq]
| PRJNA940092 | ENA
Project description:This SuperSeries is composed of the SubSeries listed below.
2023-11-01 | GSE226376 | GEO
Project description:<p><em>Tripterygium wilfordii</em> is a vine used in Traditional Chinese Medicine (TCM) from the family Celastraceae. The active ingredient celastrol is a friedelane-type pentacyclic triterpenoid, with a putative role as an anti-tumor, immunosuppression, and obesity agent. Here we reported a reference genome assembly of <em>T. wilfordii</em> with high-quality annotation by using a hybrid sequencing strategy, which obtained a 340.12 Mb total genome size, a contig N50 reaching 3.09 Mb, 31593 structure genes, and the repeat percentage was 44.31%. Comparative evolutional analyses showed that <em>T. wilfordii</em> diverged from species of Malpighiales about 102.4 million years ago. In addition, we successfully anchored 91.02% sequences into 23 pseudochromosomes using Hi-C technology and the super-scaffold N50 reached 13.03 Mb. Based on integration of genome, transcriptome and metabolite analyses, as well as in vivo and in vitro enzyme assays of the two CYP450 genes, <em>TwCYP712K1</em> and <em>TwCYP712K2</em> the second biosynthesis step of celastrol was investigated and elucidated. Syntenic analysis revealed that <em>TwCYP712K1</em> and <em>TwCYP712K2</em> derived from a common ancestor. These results have provided insights into further investigating pathways for celastrol and valuable information to aid the conservation of resources and helped us reveal the evolution of Celastrales.</p>
2021-02-24 | MTBLS1080 | MetaboLights
Project description:As a terpenoids natural product isolated from the plant Thunder God Vine, Celastrol is widely studied for its pharmacological activities, including anti-tumor activities. However, the clinical application of Celastrol is strictly limited due to its severe side effects. Without identification and validation of the target protein of Celastrol, it is difficult to determine whether its anti-tumor activities and side effects are due to inhibition of the same protein. Using a new computational tool we have developed for target discovery, peroxiredoxin I (PRDX1) was identified as the ROS-manipulating target protein of Celastrol. High-resolution crystal structure revealed the unique binding mode of Celastrol with PRDX1, via covalent reaction to the catalytic Cys-173 residue of PRDX1. New derivative compound named 19-048 with improved potency against PRDX1 and selectivity towards PRDX2~PRDX6 were synthesized. Both Celastrol and compound 19-048 effectively suppressed the proliferation of colorectal cancer cells. While these anti-tumor efficacy was significantly diminished on xenograft nude mice bearing PRDX1 knock-down colorectal cancer cells. Several downstream genes of p53 were dramatically up-regulated in the presence of Celastrol and compound 19-048. Our findings reveal that the side effects of Celastrol could be reduced via structural modification, and PRDX1 inhibition is promising for the treatment of colorectal cancer.
2022-12-31 | GSE198630 | GEO