E4 engages uPAR and enolase-1 and activates urokinase to exert antifibrotic effects

Sharma, Shailza; Watanabe, Tomoya; Nishimoto, Tetsuya; Takihara, Takahisa; Mlakar, Logan; Nguyen, Xinh-Xinh; Sanderson, Matthew; Su, Yeping; Chambers, Roger; Feghali‐Bostwick, Carol

doi:10.1172/jci.insight.144935

Cited by 13 publications

(7 citation statements)

References 45 publications

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“…Peptides designed with biomimicry in mind aim to convey activities akin to growth factors, receptor agonists, competitive binders, and protein antagonists. Alternatively, the identification of cleaved protein generation of in situ peptide neoepitopes [ 5 , 6 ] and intermediate peptide forms with elevated potency [ 7 ] as modes of eliciting beneficial actions has inspired investigations into the use of peptide neoepitopes and peptide intermediate forms as endogenous therapeutics. In this review, we collate recently identified peptide solutions that interact with and modulate key myofibroblast-promoting pathways, namely the TGF-β/Smad signaling pathways and the ECM/mechanotransduction pathways ( Figure 1 ).…”

Section: Introductionmentioning

confidence: 99%

Emergent Peptides of the Antifibrotic Arsenal: Taking Aim at Myofibroblast Promoting Pathways

Liu,

Zhang,

Wang

et al. 2023

Biomolecules

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Myofibroblasts are the principal effector cells driving fibrosis, and their accumulation in tissues is a fundamental feature of fibrosis. Essential pathways have been identified as being central to promoting myofibroblast differentiation, revealing multiple targets for intervention. Compared with large proteins and antibodies, peptide-based therapies have transpired to serve as biocompatible and cost-effective solutions to exert biomimicry, agonistic, and antagonistic activities with a high degree of targeting specificity and selectivity. In this review, we summarize emergent antifibrotic peptides and their utilization for the targeted prevention of myofibroblasts. We then highlight recent studies on peptide inhibitors of upstream pathogenic processes that drive the formation of profibrotic cell phenotypes. We also briefly discuss peptides from non-mammalian origins that show promise as antifibrotic therapeutics. Finally, we discuss the future perspectives of peptide design and development in targeting myofibroblasts to mitigate fibrosis.

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Section: Introductionmentioning

confidence: 99%

Emergent Peptides of the Antifibrotic Arsenal: Taking Aim at Myofibroblast Promoting Pathways

Liu,

Zhang,

Wang

et al. 2023

Biomolecules

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“…We previously reported that endostatin and a peptide from its carboxyl-terminal region decrease skin thickness in TGFβ1-treated skin as well as in bleomycin mouse models [ 20 ]. We also reported that the peptide is orally available and activates the urokinase pathway [ 24 , 39 ]. The peptide was modified and manufactured in plants as an Fc-fusion protein.…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, END55 decreased gene expression of pro-fibrotic markers while stimulating the secretion of matrix metalloproteases known to break down ECM components. The efficacy of END55 in reducing fibrosis is likely due to its multi-pronged effect targeting several different key pathways in fibrosis [ 20 , 39 ].…”

Section: Discussionmentioning

confidence: 99%

Ameliorating Fibrosis in Murine and Human Tissues with END55, an Endostatin-Derived Fusion Protein Made in Plants

et al. 2022

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Organ fibrosis, particularly of the lungs, causes significant morbidity and mortality. Effective treatments are needed to reduce the health burden. A fragment of the carboxyl-terminal end of collagen XVIII/endostatin reduces skin and lung fibrosis. This fragment was modified to facilitate its production in plants, which resulted in the recombinant fusion protein, END55. We found that expression of END55 had significant anti-fibrotic effects on the treatment and prevention of skin and lung fibrosis in a bleomycin mouse model. We validated these effects in a second mouse model of pulmonary fibrosis involving inducible, lung-targeted expression of transforming growth factor β1. END55 also exerted anti-fibrotic effects in human lung and skin tissues maintained in organ culture in which fibrosis was experimentally induced. The anti-fibrotic effect of END55 was mediated by a decrease in the expression of extracellular matrix genes and an increase in the levels of matrix-degrading enzymes. Finally, END55 reduced fibrosis in the lungs of patients with systemic sclerosis (SSc) and idiopathic pulmonary fibrosis (IPF) who underwent lung transplantation due to the severity of their lung disease, displaying efficacy in human tissues directly relevant to human disease. These findings demonstrate that END55 is an effective anti-fibrotic therapy in different organs.

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“…Enolase1 (ENO1) is a key enzyme in the glycolysis pathway, which catalyzes the reversible conversion of 2-phosphoglyceric acid to phosphoenolpyruvate during glycolysis. In addition, the expression of ENO1 in primary fibroblasts up-regulated the expression of pro-fibrotic genes, down-regulated the expression of MMP-1 and MMP-3 ( 104 ), and promoted the fibrosis phenotype in vivo and in vitro . After Serpina3c knockout, the ability of glycolysis and the expression of ENO1 increased in the myocardium of mice.…”

Section: Pathophysiological Roles Of Serpina3cmentioning

confidence: 99%

The versatile role of Serpina3c in physiological and pathological processes: a review of recent studies

Yang

Guo

2023

Front. Endocrinol.

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Murine Serpina3c belongs to the family of serine protease inhibitors (Serpins), clade “A” and its human homologue is SerpinA3. Serpina3c is involved in some physiological processes, including insulin secretion and adipogenesis. In the pathophysiological process, the deletion of Serpina3c leads to more severe metabolic disorders, such as aggravated non-alcoholic fatty liver disease (NAFLD), insulin resistance and obesity. In addition, Serpina3c can improve atherosclerosis and regulate cardiac remodeling after myocardial infarction. Many of these processes are directly or indirectly mediated by its inhibition of serine protease activity. Although its function has not been fully revealed, recent studies have shown its potential research value. Here, we aimed to summarize recent studies to provide a clearer view of the biological roles and the underlying mechanisms of Serpina3c.

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E4 engages uPAR and enolase-1 and activates urokinase to exert antifibrotic effects

Cited by 13 publications

References 45 publications

Emergent Peptides of the Antifibrotic Arsenal: Taking Aim at Myofibroblast Promoting Pathways

Emergent Peptides of the Antifibrotic Arsenal: Taking Aim at Myofibroblast Promoting Pathways

Ameliorating Fibrosis in Murine and Human Tissues with END55, an Endostatin-Derived Fusion Protein Made in Plants

The versatile role of Serpina3c in physiological and pathological processes: a review of recent studies

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