Drugs and Targets in Fibrosis

Li, Xiaohua; Zhu, Lixin; Wang, Beibei; Yuan, Meifei; Zhu, Rong

doi:10.3389/fphar.2017.00855

Cited by 89 publications

(99 citation statements)

References 204 publications

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“…Pharmaceutical agents can be designed to prevent the progression of fibrosis and reverse steatohepatitis (8). Excessive ECM production by activated HSCs, portal myofibroblasts (MFs), and activated sinusoidal endothelial cells can be targeted in the development of antifibrotic agents (2).…”

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confidence: 99%

Glutamyl‐prolyl‐tRNA synthetase induces fibrotic extracellular matrix via both transcriptional and translational mechanisms

et al. 2018

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Fibrosis is characterized by the increased accumulation of extracellular matrix (ECM), which drives abnormal cell proliferation and progressive organ dysfunction in many inflammatory and metabolic diseases. Studies have shown that halofuginone, a racemic halogenated derivative, inhibits glutamyl‐prolyl‐transfer RNA‐synthetase (EPRS)‐mediated fibrosis. However, the mechanism by which this occurs is unclear. We explored the mechanistic aspects of how EPRS could develop liver fibrotic phenotypes in cells and animal models. Treatment with TGF‐β1 up‐regulated fibronectin and collagen I levels in LX2 hepatic stellate cells. This effect was inhibited in prolyl‐transfer RNA synthetase (PRS)‐suppressed LX2 cells. Using the promoter luciferase assay, TGF‐β1–mediated collagen I, α1 chain transcription and γ2 basal laminin transcription in LX2 cells were down‐regulated by EPRS suppression, suggesting that EPRS may play roles in ECM production at transcriptional levels. Furthermore, signal transducer and activator of transcription (STAT) signaling activation was involved in the effects of TGF‐β1 on ECM expression in a PRS‐dependent manner. This was mediated via a protein‐protein complex formation consisting of TGF‐β1 receptor, EPRS, Janus kinases, and STAT6. Additionally, ECM expression in fibrotic livers overlapped with EPRS expression along fibrotic septa regions and was positively correlated with STAT6 activation in carbon tetrachloride‐treated mice. This was less obvious in livers of Eprs−/+ mice. These findings suggest that, during fibrosis development, EPRS plays roles in nontranslational processes of ECM expression via intracellular signaling regulation upon TGF‐β1 stimulation.—Song, D.‐G., Kim, D., Jung, J. W., Nam, S. H., Kim, J. E., Kim, H.‐J., Kim, J. H., Lee, S.‐J., Pan, C.‐H., Kim, S., Lee, J. W. Glutamyl‐prolyl‐tRNA synthetase induces fibrotic extracellular matrix via both transcriptional and translational mechanisms. FASEB J. 33, 4341–4354 (2019). http://www.fasebj.org

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confidence: 99%

Glutamyl‐prolyl‐tRNA synthetase induces fibrotic extracellular matrix via both transcriptional and translational mechanisms

et al. 2018

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“…Hence. the activity of paquinimod, a novel anti-inflammatory compound initially developed against Systemic Lupus Erythematosus (SLE) that targets S100A9, one subunit of the S100A8/A9 complex, in liver, lung, heart and skin (37), was tested in vitro . The percentage of dead cells (propidium iodide positive cells) using flow cytometry analysis (FACS) was assessed on treatment of WT BMDMs with various drug concentrations of paquinimod.…”

Section: Resultsmentioning

confidence: 99%

S100A8/A9 modulates inflammatory collateral tissue damage during intraperitoneal origin systemic candidiasis

Shankar

Uwamahoro

Holmberg

et al. 2020

Preprint

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15Peritonitis is a leading cause of severe sepsis in surgical intensive care units, as 16 over 70% of patients diagnosed with peritonitis develop septic shock. A critical role of 17 65 non-mucosal fungal diseases among hospitalized patients in the developed world are 66Candida peritonitis, also referred to as intra-abdominal candidiasis (IAC). IAC is 67 challenging to diagnose and hence results in high mortality rates ranging from 25% -68

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“…Therefore, one strategy to stimulate regeneration after proximal amputation may be the exogenous administration of degradative enzymes, which can decrease ECM density and stiffness (Qu et al, 2018) and trigger cell proliferation and migration (Qu et al, 2017;Qu et al, 2015). Modulating early scar formation by targeting fibrotic signaling pathways (Li et al, 2017) may also give stem/progenitor cells an opportunity to expand and differentiate. Finally, spatiotemporal delivery of morphogenic signaling molecules by genetically modified cells and/or biomaterials may help direct and sustain the regenerative process Taghiyar et al, 2017;Qu et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic analysis of bone and fibrous tissue morphogenesis during digit tip regeneration in the adult mouse

Palte

Gontarz

et al. 2019

Preprint

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StatementMurine digit tip regeneration after distal amputation is orchestrated through a transient, limb-specific gene network by blastema cells. Proximal amputation activates an alternate transcriptional program that results in scar formation. AbstractHumans have limited regenerative potential of musculoskeletal tissues following limb or digit loss. The murine digit has been used to study mammalian regeneration, where stem/progenitor cells (the 'blastema') regrow the digit tip after distal, but not proximal, amputation. However, the molecular mechanisms responsible for this response remain to be determined. We hypothesized that regeneration is initiated and maintained by a gene regulatory network that recapitulates aspects of limb development, whereas a non-regenerative response exhibits fibrotic wound healing and minimal bone remodeling. To test these hypotheses, we evaluated the spatiotemporal formation of bone and fibrous tissues after level-dependent amputation of the murine terminal phalanx and quantified the transcriptome of the repair tissue. We show that digit regeneration is a level-dependent and spatiotemporally controlled process, with distal and proximal amputations showing significant differences in gene expression and tissue regrowth over time. Regeneration is characterized by the transient upregulation of genes that direct skeletal system development and limb morphogenesis, including distal Hox genes.

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Drugs and Targets in Fibrosis

Cited by 89 publications

References 204 publications

Glutamyl‐prolyl‐tRNA synthetase induces fibrotic extracellular matrix via both transcriptional and translational mechanisms

Glutamyl‐prolyl‐tRNA synthetase induces fibrotic extracellular matrix via both transcriptional and translational mechanisms

S100A8/A9 modulates inflammatory collateral tissue damage during intraperitoneal origin systemic candidiasis

Transcriptomic analysis of bone and fibrous tissue morphogenesis during digit tip regeneration in the adult mouse

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