Suppression of fibrogenic gene expression and liver fibrosis using a synthetic prostacyclin agonist

Xu, Qing; Sakai, Katsuya; Tambo, Chikako; Sakai, Yoshiki; Matsumoto, Kunio

doi:10.2220/biomedres.34.241

Cited by 3 publications

(4 citation statements)

References 39 publications

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“…Treatment with synthetic prostacyclin agonist decreased the expressions of TGF β in liver fibrosis [42]. Prostacyclin also significantly suppressed the increase of TGF β expression and Smad2/3 phosphorylation in kidney [58].…”

Section: Discussionmentioning

confidence: 91%

“…Beraprost, one common prostacyclin analogue, selectively inhibits proliferation in a dose-dependent manner in murine primary pulmonary arterial smooth muscle cells [41]. ONO-1301, a synthetic prostacyclin agonist, suppressed myofibroblast expansion and liver fibrosis in CCl 4 -induced mice [42]. ONO-1301 also improved airway remodeling induced by ovalbumin in mice [43], but little is known about the role of prostacyclin in myocardial fibrosis.…”

Section: Discussionmentioning

confidence: 99%

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Prostacyclin Analogue Beraprost Inhibits Cardiac Fibroblast Proliferation Depending on Prostacyclin Receptor Activation through a TGF β-Smad Signal Pathway

et al. 2014

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Previous studies showed that prostacyclin inhibited fibrosis. However, both receptors of prostacyclin, prostacyclin receptor (IP) and peroxisome proliferator-activated receptor (PPAR), are abundant in cardiac fibroblasts. Here we investigated which receptor was vital in the anti-fibrosis effect of prostacyclin. In addition, the possible mechanism involved in protective effects of prostacyclin against cardiac fibrosis was also studied. We found that beraprost, a prostacyclin analogue, inhibited angiotensin II (Ang II)-induced neonatal rat cardiac fibroblast proliferation in a concentration-dependent and time-dependent manner. Beraprost also suppressed Ang II-induced collagen I mRNA expression and protein synthesis in cardiac fibroblasts. After IP expression was knocked down by siRNA, Ang II-induced proliferation and collagen I synthesis could no longer be rescued by beraprost. However, treating cells with different specific inhibitors of PPAR subtypes prior to beraprost and Ang II stimulation, all of the above attenuating effects of beraprost were still available. Moreover, beraprost significantly blocked transforming growth factor β (TGF β) expression as well as Smad2 phosphorylation and reduced Smad-DNA binding activity. Beraprost also increased phosphorylation of cAMP response element binding protein (CREB) at Ser133 in the nucleus. Co-immunoprecipitation analysis revealed that beraprost increased CREB but decreased Smad2 binding to CREB-binding protein (CBP) in nucleus. In conclusion, beraprost inhibits cardiac fibroblast proliferation by activating IP and suppressing TGF β-Smad signal pathway.

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Prostacyclin Analogue Beraprost Inhibits Cardiac Fibroblast Proliferation Depending on Prostacyclin Receptor Activation through a TGF β-Smad Signal Pathway

et al. 2014

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“…[ 21 ] This activity may contribute to a general antifibrotic mode of action for ONO‐1301. [ 22,23 ] Moreover, ONO‐1301 was the only compound that triggered the expression of MMP1 and VEGFA , thereby indirectly performing as a small molecule “VEGF mimetic” on primary human fibroblasts. High VEGF levels typically accelerate and improve skin healing by angiogenesis that re‐establishes microcirculation and rescues tissue perfusion in damaged tissue.…”

Section: Resultsmentioning

confidence: 99%

Growth factor mimetics for skin regeneration: In vitro profiling of primary human fibroblasts and keratinocytes

Horinouchi

Oostendorp

Schade

et al. 2021

Archiv der Pharmazie

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Small molecules have gained considerable interest in regenerative medicine, as they can effectively modulate cell fates in a spatiotemporal controllable fashion. A continuous challenge in the field represents genuine mimicry or activation of growth factor signaling with small molecules. Here, we selected and profiled three compounds for their capacity to directly or indirectly activate endogenous FGF‐2, VEGF, or SHH signaling events in the context of skin regeneration. Phenotypic and functional analysis of primary skin fibroblasts and keratinocytes revealed unique, cell‐specific activity profiles for the FGF‐2 mimetic SUN11602 and the putative VEGF mimetic ONO‐1301. Whereas SUN11602 exclusively stimulated keratinocyte differentiation, ONO‐1301 mainly affected the proliferation and migration behavior of fibroblasts. In each skin cell type, both compounds selectively enhanced the expression of MMP1 and VEGFA. A combined small molecule FGF‐2/VEGF mimicry may not only improve angiogenesis‐related microcirculation but also reduce early fibrosis while facilitating wound remodeling at later stages. SUN11602 and ONO‐1301 represent valuable tools for improving the management of difficult‐to‐heal wounds, particularly for the design and development of small molecule‐functionalized, next‐generation, engineered skin substitutes.

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“…Xu et al [95] reported in 2011 that intermittent oral administration of ONO-1301, not SR product, ameliorated CCl4-induced acute hepatic injury in mice partly via up-regulation of HGF. The same group reported in 2013 that ONO-1301SR was effective in treating CCl4-induced inflammatory chronic liver fibrosis in mice [96]. Inflammation plays a key role in clinical and pathological progression of chronic pancreatitis.…”

Section: Ono-1301/ono-1301sr Treatment For Extracardiac Pathologiesmentioning

confidence: 99%

A sustained-release drug-delivery system of synthetic prostacyclin agonist, ONO-1301SR: a new reagent to enhance cardiac tissue salvage and/or regeneration in the damaged heart

et al. 2015

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Cardiac failure is a major cause of mortality and morbidity worldwide, since the standard treatment for cardiac failure in the clinical practice is chiefly to focus on removal of insults against the heart or minimisation of additional factors to exacerbate cardiac failure, but not on regeneration of the damaged cardiac tissue. A synthetic prostacyclin agonist, ONO-1301, has been developed as a long-acting drug for acute and chronic pathologies related to regional ischaemia, inflammation and/or interstitial fibrosis by pre-clinical studies. In addition, poly-lactic co-glycolic acid-polymerised form of ONO-1301, ONO-1301SR, was generated to achieve a further sustained release of this drug into the targeted region. This unique reagent has been shown to act on fibroblasts, vascular smooth muscle cells and endothelial cells in the tissue via the prostaglandin IP receptor to exert paracrinal release of multiple protective factors, such as hepatocyte growth factor, vascular endothelial growth factor or stromal cell-derived factor-1, into the adjacent damaged tissue, which is salvaged and/or regenerated as a result. Our laboratory developed a new surgical approach to treat acute and chronic cardiac failure using a variety of animal models, in which ONO-1301SR is directly placed over the cardiac surface to maximise the therapeutic effects and minimise the systemic complications. This review summarises basic and pre-clinical information of ONO-1301 and ONO-1301SR as a new reagent to enhance tissue salvage and/or regeneration, with a particular focus on the therapeutic effects on acute and chronic cardiac failure and underlying mechanisms, to explore a potential in launching the clinical study.

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Suppression of fibrogenic gene expression and liver fibrosis using a synthetic prostacyclin agonist

Cited by 3 publications

References 39 publications

Prostacyclin Analogue Beraprost Inhibits Cardiac Fibroblast Proliferation Depending on Prostacyclin Receptor Activation through a TGF β-Smad Signal Pathway

Prostacyclin Analogue Beraprost Inhibits Cardiac Fibroblast Proliferation Depending on Prostacyclin Receptor Activation through a TGF β-Smad Signal Pathway

Growth factor mimetics for skin regeneration: In vitro profiling of primary human fibroblasts and keratinocytes

A sustained-release drug-delivery system of synthetic prostacyclin agonist, ONO-1301SR: a new reagent to enhance cardiac tissue salvage and/or regeneration in the damaged heart

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