HSP47 and Its Involvement in Fibrotic Disorders

2019 ◽  
pp. 299-312
Author(s):  
Haiyan Chu ◽  
Li Jin ◽  
Jiucun Wang
Keyword(s):  
Fibrotic Disorders

Targets in Fibrotic Disorders

2008 ◽  
Vol 25 (10) ◽  
pp. 2413-2415
Author(s):  
R. J. Kok
Keyword(s):  
Fibrotic Disorders

scholarly journals A nutraceutical strategy for downregulating TGFβ signalling: prospects for prevention of fibrotic disorders, including post-COVID-19 pulmonary fibrosis

Open Heart ◽  
2021 ◽  
Vol 8 (1) ◽  
pp. e001663
Author(s):  
James J DiNicolantonio ◽  
Mark F McCarty ◽  
Jorge Barroso-Aranda ◽  
Simon Assanga ◽  
Lidianys Maria Lewis Lujan ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Tgfβ Signalling ◽  
Fibrotic Disorders

scholarly journals Naringenin: A Promising Therapeutic Agent against Organ Fibrosis

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Yanfei Du ◽  
Jun Ma ◽  
Yu Fan ◽  
Xinyu Wang ◽  
Shuzhan Zheng ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Transforming Growth Factor ◽  
Developed Countries ◽  
Mitogen Activated Protein Kinase ◽  
Drug Candidate ◽  
Wide Range ◽  
Fibrotic Disorders ◽  
Organ Fibrosis

Fibrosis is the final common pathology of most chronic diseases as seen in the heart, liver, lung, kidney, and skin and contributes to nearly half of death in the developed countries. Fibrosis, or scarring, is mainly characterized by the transdifferentiation of fibroblasts into myofibroblasts and the excessive accumulation of extracellular matrix (ECM) secreted by myofibroblasts. Despite immense efforts made in the field of organ fibrosis over the past decades and considerable understanding of the occurrence and development of fibrosis gained, there is still lack of an effective treatment for fibrotic diseases. Therefore, identifying a new therapeutic strategy against organ fibrosis is an unmet clinical need. Naringenin, a flavonoid that occurs naturally in citrus fruits, has been found to confer a wide range of pharmacological effects including antioxidant, anti-inflammatory, and anticancer benefits and thus potentially exerting preventive and curative effects on numerous diseases. In addition, emerging evidence has revealed that naringenin can prevent the pathogenesis of fibrosis in vivo and in vitro via the regulation of various pathways that involved signaling molecules such as transforming growth factor-β1/small mother against decapentaplegic protein 3 (TGF-β1/Smad3), mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt), sirtuin1 (SIRT1), nuclear factor-kappa B (NF-κB), or reactive oxygen species (ROS). Targeting these profibrotic pathways by naringenin could potentially become a novel therapeutic approach for the management of fibrotic disorders. In this review, we present a comprehensive summary of the antifibrotic roles of naringenin in vivo and in vitro and their underlying mechanisms of action. As a food derived compound, naringenin may serve as a promising drug candidate for the treatment of fibrotic disorders.

scholarly journals Targeting the DNM3OS / miR-199a~214 cluster for the treatment of fibroproliferative diseases

2018 ◽  
Author(s):  
G. Savary ◽  
M. Buscot ◽  
E. Dewaeles ◽  
S. Diazzi ◽  
N. Nottet ◽  
...  
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Mature Mirnas ◽  
Kidney Fibrosis ◽  
Downstream Effector ◽  
Non Coding Rna ◽  
Fibrotic Diseases ◽  
Fibrotic Disorders ◽  
Long Non Coding Rna ◽  
Lung And Kidney

AbstractGiven the paucity of effective treatments for fibrotic disorders, new insights into the deleterious mechanisms controlling fibroblast activation, the key cell type driving the fibrogenic process, are essential to develop new therapeutic strategies. Here, we identified the long non-coding RNA DNM3OS as a critical downstream effector of TGF-β-induced myofibroblast activation. Mechanistically, DNM3OS regulates this process in trans by giving rise to 3 distinct profibrotic mature miRNAs (i.e. miR-199a-5p/3p and miR-214-3p), which influence both SMAD and non-SMAD components of TGF-β signaling in a multifaceted way, through two modes of action consisting of either signal amplification or mediation. Finally, we provide preclinical evidence that interfering with DNM3OS function using distinct strategies not only prevents lung and kidney fibrosis but also improves established lung fibrosis, providing thus a novel paradigm for the treatment of refractory fibrotic diseases such as idiopathic pulmonary fibrosis.One Sentence SummaryThe DNM3OS lncRNA is a reservoir of fibromiRs with major functions in fibroblast response to TGF-β and represents a valuable therapeutic target for refractory fibrotic diseases such as idiopathic pulmonary fibrosis (IPF).

scholarly journals The MicroRNA miR-155 Is Essential in Fibrosis

2019 ◽  
Vol 5 (1) ◽  
pp. 23 ◽  
Author(s):  
Mousa Eissa ◽  
Carol Artlett
Keyword(s):  
Collagen Synthesis ◽  
Regulation Of Gene Expression ◽  
Viable Option ◽  
Adaptive Immune ◽  
Biological Interest ◽  
Integral Role ◽  
Fibrotic Disorders ◽  
Adaptive Immune Systems ◽  
Tgf Β1

The function of microRNAs (miRNAs) during fibrosis and the downstream regulation of gene expression by these miRNAs have become of great biological interest. miR-155 is consistently upregulated in fibrotic disorders, and its ablation downregulates collagen synthesis. Studies demonstrate the integral role of miR-155 in fibrosis, as it mediates TGF-β1 signaling to drive collagen synthesis. In this review, we summarize recent findings on the association between miR-155 and fibrotic disorders. We discuss the cross-signaling between macrophages and fibroblasts that orchestrates the upregulation of collagen synthesis mediated by miR-155. As miR-155 is involved in the activation of the innate and adaptive immune systems, specific targeting of miR-155 in pathologic cells that make excessive collagen could be a viable option before the depletion of miR-155 becomes an attractive antifibrotic approach.

scholarly journals P0710DUAL GPR40/GPR84 FATTY ACID RECEPTOR DELETION IMPROVES ADENINE-INDUCED RENAL INJURY IN MICE

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Véronique Cheff ◽  
Amelie Blais ◽  
Chet Holterman ◽  
Richard Hébert ◽  
Chris Kennedy ◽  
...  
Keyword(s):  
Weight Loss ◽  
Fatty Acid ◽  
Kidney Diseases ◽  
Functional Decline ◽  
Fractional Excretion ◽  
Clinical Settings ◽  
Double Knockout ◽  
Renal Hypertrophy ◽  
Sustained Weight Loss ◽  
Fibrotic Disorders

Abstract Background and Aims Fatty acid receptors have recently been implicated in the progression of fibrotic disorders. GPR40 deletion predisposes to AKI and CKD-induced fibrosis, while deletion of the pro-inflammatory GPR84 receptor was beneficial in this context. PBI-4050, a novel therapeutic compound with excellent safety and efficacy profiles in both experimental and clinical settings, is a dual GPR40 agonist and GPR84 antagonist. In this study, we sought to determine which of these receptors had a predominant effect in adenine-induced CKD. Method Ten-week-old male GPR40/84 double knockout mice (40/84ko) and age/strain matched WT C57BL/6 mice were subjected to a regular or adenine-supplemented diet (0.25%) for 4 weeks (n=10 per group). Plasma samples were collected on a weekly basis for hematocrit assessment. At endpoint, mice were placed in metabolic cages for 24 hours for urine collection. Plasma minerals and electrolytes, urinalysis and a comprehensive blood count were performed at endpoint. Results Adenine feeding led to early and sustained weight-loss, which was significantly worse in WT mice compared to 40/84ko mice. At day 14, Hct was significantly decreased in adenine-fed WT mice, while unaffected in the 40/84ko group. Adenine-induced reductions in hemoglobin and red blood cells counts were also greatly improved in 40/84ko mice. Adenine-feeding led to increased circulating neutrophils and decreased lymphocyte in WT mice, which was not seen in 40/84ko mice. Importantly, renal function assessed by plasma creatinine, urea and creatinine-clearance and renal hypertrophy were significantly improved in Ad-fed 40/84ko mice. Moreover, fractional excretion for sodium, potassium and calcium were increased by adenine-feeding in WT, but not in 40/84ko mice. Conclusion Overall, the loss of both GPR40 and GPR84 led to major improvements in several key renal functional abnormalities associated with adenine-induced CKD including weight-loss, anemia and renal functional decline. These studies, along with our previous work highlight the potential of targeting fatty-acid GPCR’s, notably GPR84, for the treatment of inflammation/fibrosis related kidney diseases.

scholarly journals Transforming Growth Factor-β Signaling in Fibrotic Diseases and Cancer-Associated Fibroblasts

Biomolecules ◽  
2020 ◽  
Vol 10 (12) ◽  
pp. 1666
Author(s):  
Xueke Shi ◽  
Christian D. Young ◽  
Hongmei Zhou ◽  
Xiao-Jing Wang
Keyword(s):  
Growth Factor ◽  
Cancer Progression ◽  
Immune Cells ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Cell Types ◽  
Cancer Associated Fibroblasts ◽  
The Matrix ◽  
Fibrotic Diseases ◽  
Fibrotic Disorders

Transforming growth factor-β (TGF-β) signaling is essential in embryo development and maintaining normal homeostasis. Extensive evidence shows that TGF-β activation acts on several cell types, including epithelial cells, fibroblasts, and immune cells, to form a pro-fibrotic environment, ultimately leading to fibrotic diseases. TGF-β is stored in the matrix in a latent form; once activated, it promotes a fibroblast to myofibroblast transition and regulates extracellular matrix (ECM) formation and remodeling in fibrosis. TGF-β signaling can also promote cancer progression through its effects on the tumor microenvironment. In cancer, TGF-β contributes to the generation of cancer-associated fibroblasts (CAFs) that have different molecular and cellular properties from activated or fibrotic fibroblasts. CAFs promote tumor progression and chronic tumor fibrosis via TGF-β signaling. Fibrosis and CAF-mediated cancer progression share several common traits and are closely related. In this review, we consider how TGF-β promotes fibrosis and CAF-mediated cancer progression. We also discuss recent evidence suggesting TGF-β inhibition as a defense against fibrotic disorders or CAF-mediated cancer progression to highlight the potential implications of TGF-β-targeted therapies for fibrosis and cancer.

scholarly journals Identifying collagen VI as a target of fibrotic diseases regulated by CREBBP/EP300

2020 ◽  
Vol 117 (34) ◽  
pp. 20753-20763 ◽  
Author(s):  
Lynn M. Williams ◽  
Fiona E. McCann ◽  
Marisa A. Cabrita ◽  
Thomas Layton ◽  
Adam Cribbs ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Association Studies ◽  
Genomic Analysis ◽  
Genome Wide Association Studies ◽  
Proteomic Profiling ◽  
Collagen Vi ◽  
Genome Wide ◽  
Fibrotic Diseases ◽  
Fibrotic Disorders ◽  
Fibrotic Disorder

Fibrotic diseases remain a major cause of morbidity and mortality, yet there are few effective therapies. The underlying pathology of all fibrotic conditions is the activity of myofibroblasts. Using cells from freshly excised disease tissue from patients with Dupuytren’s disease (DD), a localized fibrotic disorder of the palm, we sought to identify new therapeutic targets for fibrotic disease. We hypothesized that the persistent activity of myofibroblasts in fibrotic diseases might involve epigenetic modifications. Using a validated genetics-led target prioritization algorithm (Pi) of genome wide association studies (GWAS) data and a broad screen of epigenetic inhibitors, we found that the acetyltransferase CREBBP/EP300 is a major regulator of contractility and extracellular matrix production via control of H3K27 acetylation at the profibrotic genes,ACTA2andCOL1A1. Genomic analysis revealed that EP300 is highly enriched at enhancers associated with genes involved in multiple profibrotic pathways, and broad transcriptomic and proteomic profiling of CREBBP/EP300 inhibition by the chemical probe SGC-CBP30 identified collagen VI (Col VI) as a prominent downstream regulator of myofibroblast activity. Targeted Col VI knockdown results in significant decrease in profibrotic functions, including myofibroblast contractile force, extracellular matrix (ECM) production, chemotaxis, and wound healing. Further evidence for Col VI as a major determinant of fibrosis is its abundant expression within Dupuytren’s nodules and also in the fibrotic foci of idiopathic pulmonary fibrosis (IPF). Thus, Col VI may represent a tractable therapeutic target across a range of fibrotic disorders.

scholarly journals Decorin Interacts with Connective Tissue Growth Factor (CTGF)/CCN2 by LRR12 Inhibiting Its Biological Activity

2011 ◽  
Vol 286 (27) ◽  
pp. 24242-24252 ◽  
Author(s):  
Cecilia Vial ◽  
Jaime Gutiérrez ◽  
Cristian Santander ◽  
Daniel Cabrera ◽  
Enrique Brandan
Keyword(s):  
Biological Activity ◽  
Growth Factor ◽  
Connective Tissue ◽  
Connective Tissue Growth Factor ◽  
Core Protein ◽  
Tissue Growth ◽  
Collagen Iii ◽  
Fibrotic Disorders ◽  
Leucine Rich Repeats

Fibrotic disorders are the end point of many chronic diseases in different tissues, where an accumulation of the extracellular matrix occurs, mainly because of the action of the connective tissue growth factor (CTGF/CCN2). Little is known about how this growth factor activity is regulated. We found that decorin null myoblasts are more sensitive to CTGF than wild type myoblasts, as evaluated by the accumulation of fibronectin or collagen III. Decorin added exogenously negatively regulated CTGF pro-fibrotic activity and the induction of actin stress fibers. Using co-immunoprecipitation and in vitro interaction assays, decorin and CTGF were shown to interact in a saturable manner with a Kd of 4.4 nm. This interaction requires the core protein of decorin. Experiments using the deletion mutant decorin indicated that the leucine-rich repeats (LRR) 10–12 are important for the interaction with CTGF and the negative regulation of the cytokine activity, moreover, a peptide derived from the LRR12 was able to inhibit CTGF-decorin complex formation and CTGF activity. Finally, we showed that CTGF specifically induced the synthesis of decorin, suggesting a mechanism of autoregulation. These results suggest that decorin interacts with CTGF and regulates its biological activity.

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