Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Phenotypic drug screening in a human fibrosis model identified a novel class of antifibrotic therapeutics

ABSTRACT: Fibrogenic processes instigate fatal chronic diseases leading to organ failure and death. Underlying biological processes involve induced massive deposition of extracellular matrix (ECM) by aberrant fibroblasts. We subjected diseased primary human lung fibroblasts to an advanced 3D phenotypic high-content assay and screened a library of FDA/EMA approved small molecules for inhibiting ECM deposition. Fibrotic Pattern Detection by Artificial Intelligence (FANTAIL) identified Tranilast as an effective inhibitor, however, by structure-activity relationship studies we found N-(2-butoxyphenyl)-3-(phenyl)acrylamides (N23Ps) as a novel and highly potent compound class. N23Ps suppressed myofibroblast transdifferentiation, ECM deposition, cellular contractility, and altered cell shapes, thus advocating a unique mode of action. Mechanistically, transcriptomics identified SMAD (de)ubiquitination/Smurf2 as a potential therapeutic target network. Antifibrotic activity of N23Ps was verified by proteomics in a human ex vivo tissue fibrosis disease model, suppressing profibrotic markers SERPINE1/PAI1 and CXCL8/IL8. Conclusively, these data suggest N23Ps as a novel class of highly potent compounds with implications for inhibiting organ fibrosis in patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE141905 | GEO | 2021/09/13

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Dynamic multi-omics and mechanistic modeling approach uncovers novel mechanisms of kidney fibrosis progression

Project description:Kidney fibrosis, characterized by excessive extracellular matrix (ECM) deposition, is a progressive disease that, despite affecting 10% of the population, lacks specific treatments and suitable biomarkers. Aimed at unraveling disease mechanisms and identifying potential therapeutic targets, this study presents a comprehensive, time-resolved multi-omics analysis of kidney fibrosis using an in vitro model system based on human kidney PDGFRβ+ mesenchymal cells. Using computational network modeling we integrated transcriptomics, proteomics, phosphoproteomics, and secretomics with imaging of the extracellular matrix (ECM). We quantified over 14,000 biomolecules across seven time points following TGF-β stimulation, revealing distinct temporal patterns in the expression and activity of known and potential novel renal fibrosis markers and modulators. The resulting time-resolved multi-omic network models allowed us to propose mechanisms related to fibrosis progression through early transcriptional reprogramming. Using siRNA knockdowns and phenotypic assays, we validated predictions and elucidated regulatory mechanisms underlying kidney fibrosis. Notably, we demonstrate that several early-activated transcription factors, including FLI1 and E2F1, act as negative regulators of collagen deposition and propose underlying molecular mechanisms. This work advances our understanding of the pathogenesis of kidney fibrosis and provides a valuable resource for the organ fibrosis research community.

2024-11-07 | E-MTAB-14521 | biostudies-arrayexpress

SOX9 regulated matrix proteins are increased in patients serum and correlate with severity of liver fibrosis

Project description:Extracellular matrix (ECM) deposition and resultant scar play a major role in the pathogenesis and progression of liver fibrosis. Identifying core regulators of ECM deposition may lead to urgently needed diagnostic and therapetic strategies for the disease. The transcription factor Sex determining region Y box 9 (SOX9) is actively involved in scar formation and its prevalence in patients with liver fibrosis predicts progression. In this study, transcriptomic approaches of Sox9-abrogated myofibroblasts identified >30% of genes regulated by SOX9 relate to the ECM.

2019-07-01 | E-MTAB-7298 | biostudies-arrayexpress

Integrin beta-1 (Itgb1) in profibrotic myofibroblasts

Project description:Fibrosis due to extracellular matrix (ECM) secretion from myofibroblasts complicates many chronic liver diseases causing scarring and organ failure. Integrin-dependent interaction with scar ECM promotes profibrotic features. This microarray study was performed to clarify the role of integrin beta-1 (Itgb1) in profibrotic myofibroblasts.

2016-08-18 | E-MTAB-4810 | biostudies-arrayexpress

SOX9 regulates NAV3 to control cytoskeletal and mechanical properties of profibrotic myofibroblasts during renal fibrosis

Project description:Fibrosis is a common pathway in the progression of chronic kidney disease. Extracellular matrix deposition from myofibroblasts causes scarring, tissue stiffness and organ failure. This submission studies the role of Sex determining region Y-box 9 (SOX9) in kidney fibrosis.

2020-02-06 | E-MTAB-8429 | biostudies-arrayexpress

RNAseq of livers of mice fed high fat high sugar diet and either untreated or treated with curcumin liposomes or calcitriol liposomes

Project description:Non-alcoholic fatty liver disease (NAFLD) is a common complication of obesity, where insulin resistance and hepatocyte fat deposition may progress to steatohepatitis (NASH) and fibrosis/ cirrhosis. NASH has no approved treatment. Consequent upon hepatic fat deposition, NF-κB activation in hepatic myeloid cells mediates inflammation and NASH progression. We delivered micro-doses of liposome-encapsulated lipophilic NF-κB inhibitors, curcumin or 1,25-dihydroxy-vitamin D3 (calcitriol), to the pro-fibrogenic inflammatory liver macrophages and dendritic cells (DCs) in diet-induced NASH. After i.v. administration, liver was the primary organ targeted. MHC class-II+ hepatic DCs taking up liposomes in mice and human were F4/80+ and CD14+ respectively, were lipid-laden and expressed pro-inflammatory genes. Curcumin or calcitriol liposomes suppressed hepatic inflammation, fibrosis and fat accumulation, and reduced insulin resistance associated with suppression of immune activation, cell cycle and collagen deposition pathways in vivo. Thus, hepatic inflammatory DCs passively targeted with liposomes encapsulating lipophilic NF-κB inhibitors are beneficial in NASH.

2020-01-22 | GSE94593 | GEO

RNAseq of liver dendritic cells targeted with empty liposomes or curcumin liposomes

2020-01-22 | GSE94592 | GEO

Enhanced Collagen Secretion in Epithelial Cancer Cells is associated with L1CAM Deficiency

Project description:Collagen, a critical component of the tumor microenvironment (TME), significantly influences cancer-associated fibrosis, tissue stiffness, immune response, and metastasis. Pancreatic ductal adenocarcinoma (PDAC) is characterized by excessive collagen deposition, and effective therapies remain limited. Our research challenges conventional understanding by highlighting the remarkable ability of specific tumor epithelial populations, particularly those with low levels of L1 cell adhesion molecule (L1CAM) expression (L1low), to actively modulate collagen dynamics within the TME. Transcriptome analysis of PDAC cells with varying L1 expression reveals shifts in collagen-related pathways, with heightened expression of collagen 17A1 (COL17A1) in L1low cells. Alongside, L1low cells exhibit enhanced migratory capacity. In an orthotopic mouse model, L1low cancer cells demonstrate increased collagen deposition, resistance to gemcitabine treatment, and an elevated propensity for liver metastases. Treatment with Tranilast, an anti-fibrotic drug, significantly reduces tumor volume and collagen deposition while enhancing L1 expression. This, in turn, mitigates tumor invasiveness and suppresses metastases formation. Overall, our study uncovers a novel role for L1CAM in PDAC aggressiveness and fibrosis, revealing a new epithelial population capable of collagen secretion and challenging the traditional notion that this function is solely attributed to stromal cells.

2024-06-11 | GSE268948 | GEO

Single-cell RNA-sequencing reveals profibrotic roles of distinct epithelial and mesenchymal lineages in pulmonary fibrosis

Project description:Pulmonary fibrosis (PF) is a form of chronic lung disease characterized by progressive destruction of normal alveolar gas-exchange surfaces and accumulation of extracellular matrix (ECM). In order to comprehensively define the cell types, mechanisms and mediators driving ECM deposition and fibrotic remodeling in lungs with pulmonary fibrosis, we performed single-cell RNA-sequencing (scRNA-seq) of single-cell suspensions generated from non-fibrotic control and PF lungs. Analysis of over 114,000 cells from 20 PF and 10 control lungs identified 31 distinct cell types. We identified multiple distinct lineages directly contribute to ECM expansion, including a novel HAS1hi fibroblast subtype and a previously undescribed KRT5-/KRT17+, collagen and ECM-producing epithelial cell population that was highly enriched in PF lungs. Together these data provide high-resolution insights into the basic mechanisms of pulmonary fibrosis, and indicate a direct profibrotic role of the lung epithelium in PF pathogenesis.

2019-09-05 | GSE135893 | GEO

TMEM43 as a Promising Target for Ameliorating Organ Fibrosis and Identification of two FDA-approved Anti-fibrosis Drugs

Project description:Fibrosis, characterized by the abnormal deposition of extracellular matrix, can cause organ dysfunction and mortality. However, research on the mechanisms of fibrosis, especially that focusing on the identification of drug targets, is currently still lacking. This study is the first to reveal that a small molecule (YTB-8) derived from the natural β-carboline alkaloid flazin has potent protective effects against renal fibrosis in vitro and in vivo. The cellular target of YTB-8, a nuclear and endoplasmic reticulum membrane protein known as transmembrane protein 43 (TMEM43), was identified by activity-based protein profiling (ABPP) strategy in a renal fibrosis model. YTB-8 was found to interact with amino acids Arg312 and Leu382 of TMEM43 and exert anti-renal fibrosis effects by suppressing the NF-κB and TGF-β/Smad signaling pathways. Utilization of simulated TMEM43 and its pocket structure for virtual screening, followed by in vitro and in vivo detection, led to us identifying two FDA-approved drugs, drospirenone and adapalene, with anti-renal fibrosis efficacy. TMEM43 was also found to be the target of YTB-8 in its alleviation of lung, liver, and skin fibrosis in vitro, verifying the value of TMEM43 as a general target for new-generation drug design relating to organ fibrosis. Collectively, these findings revealed TMEM43 to be a promising universal cellular target for organ fibrosis intervention.

2023-10-20 | PXD046296 |

Redundant effects of Pirfenidone against fibroblast activation and severe fibrotic lung disease

Project description:Idiopathic Pulmonary Fibrosis (IPF) is a progressive chronic lung disease characterized by excess deposition of extracellular matrix (ECM) proteins in the lung. TGFα is a is a ligand for the epidermal growth factor receptor, and found elevated in several fibrotic lung diseases including IPF. Notably, lung-specific overexpression of TGFα alone in adult mice can cause progressive and extensive adventitial and subpleural fibrosis similar to IPF. Pirfenidone, an FDA approved drug has been shown to improve the decline in lung function in IPF patients. However, the mechanism of action of pirfenidone largely unknown. In the current study, we investigated the effects of pirfenidone using a mouse model of TGFα-induced pulmonary fibrosis and fibroblasts isolated from IPF lungs. Total lung transcriptome analysis suggest a significant overlap in dysregulated gene transcripts between TGFα model and IPF. In vivo studies demonstrate a significant improvement in lung function with pirfenidone therapy compared to vehicle-treated TGFα mice on Dox for six wks. However, pirfenidone treatment did not affect fibroproliferation, myofibroblast transformation, and ECM deposition during TGFα-induced pulmonary fibrosis. In summary, pirfenidone treatment improved lung function but had a limited or no effect on the expression of collagen, ECM genes, fibroproliferation and migration of lung-resident fibroblasts.

2022-06-01 | GSE199034 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data