Therapeutic approaches to organ fibrosis

Franklin, T. J.

doi:10.1016/s1357-2725(96)00121-5

Cited by 115 publications

(73 citation statements)

References 46 publications

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“…The potential role of CTGF in fibrotic renal disease has been extensively reviewed [67][68][69]. At the moment, CTGF, in contrast to TGF-β, seems to lack the anti-proliferative effects on epithelial cells, and no data is yet available showing the involvement of CTGF in immunoregulatory actions [68,70]. If it indeed turns out that CTGF is specifically involved in TGF-β-induced fibrosis routing, it would make CTGF an attractive therapeutic target in renal disease.…”

Section: Connective Tissue Growth Factormentioning

confidence: 99%

“…For instance, Franklin has extensively elaborated on the use of agents in organ fibrosis, which could target components that are involved in posttranslational processing events of the formation of fibrillar collagens in the ECM [70]. For example, prolyl 4-hydroxylase is an enzyme required for inter-and intra-chain cross-linking of collagen, and is thereby essential for forming stable collagen helices deposited in the ECM.…”

Section: Other Ecm-related Targetsmentioning

confidence: 99%

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ECM homeostasis in renal diseases: a genomic approach

Eikmans

Baelde

Heer

et al. 2003

The Journal of Pathology

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Chronic renal disease is in general histologically accompanied by a vast amount of scar tissue, ie glomerulosclerosis and interstitial fibrosis. Scarring results from excessive accumulation of extracellular matrix (ECM) components, a process driven by a plethora of cytokines and growth factors. Studies in experimental renal disease which target these regulators using gene therapy limit or prevent the development of scarring. This review focuses specifically on the role of transforming growth factor-beta, platelet-derived growth factor, connective tissue growth factor, hepatocyte growth factor, and epidermal growth factor. The results obtained in animal models hold promise for molecular intervention strategies in human renal disease. Microarray technology allows large-scale gene expression profiling in kidney tissue to identify common molecular pathways in a step towards discovery of new drug targets. Molecular techniques are expected to be used for diagnostic and prognostic purposes in nephrological practice to supplement renal biopsy. Several studies already show that molecular techniques might be of use in routine diagnostic practice. Improvement of diagnosis and prediction of outcome in renal patients might lead to more efficient and earlier therapeutic intervention.

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Section: Connective Tissue Growth Factormentioning

confidence: 99%

Section: Other Ecm-related Targetsmentioning

confidence: 99%

ECM homeostasis in renal diseases: a genomic approach

Eikmans

Baelde

Heer

et al. 2003

The Journal of Pathology

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“…[6] Inhibitors of the collagen prolyl hydroxylases have also been evaluated as potential therapeutics for the treatment of liver fibrosis. [7,8] The discovery of the JmjC domain histone demethylases, and the suggestions that some of them are potential therapeutic targets for cancer treatment, [9] Figure 1). [10][11][12][13] Compounds which catalyse the ejection of a structural Zn(II) ion from the JMJD2 demethylases have also been reported ( Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Histone Demethylases by 4‐Carboxy‐2,2′‐Bipyridyl Compounds

et al. 2011

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# These authors contributed equally to this work. Keywordsepigenetics; histone demethylase; bipyridyl; enzyme inhibitors; 2-oxoglutarate In eukaryotes, nuclear DNA is packaged into chromatin by binding to histones and associated factors. Covalent modifications to histone tails are associated with specific transcriptional states of the associated DNA. Acetylation of lysine side-chains normally correlates with transcriptional activation, while deacetylation leads to transcriptional silencing. The regulatory roles of methylation of lysine and arginine residues appear to be more complex. Methylation of certain lysine residues is associated with active transcription, while methylation of others is associated with silencing and heterochromatin formation. Each methylation 'mark' is placed, removed and 'interpreted' in a site-specific manner by histone methyltransferases, demethylases and methyl-binding domains, respectively. The biological functions of the individual enzymes are largely undefined, and are the focus of current investigations (for review see [1,2] The JmjC histone demethylases are 2-oxoglutarate (2OG) dependent oxygenases that catalyse N ε -lysyl demethylation via hydroxylation of the methyl group in a 2-oxoglutarate and Fe(II)-dependent manner (Scheme 1). Human 2OG oxygenases catalyse a range of reactions, including hydroxylation of amino acids, DNA and small molecules, and demethylation of proteins and DNA. [3] 2OG oxygenases show promise as therapeutic targets. An inhibitor of γ-butyrobetaine hydroxylase (BBOX) is used for the treatment of cardiovascular disease [4,5] and inhibitors of the hypoxia inducible factor (HIF) prolyl hydroxylases are in clinical trials for the treatment of anaemia. [6] Inhibitors of the collagen prolyl hydroxylases have also been evaluated as potential therapeutics for the treatment of liver fibrosis. [7,8] The discovery of the JmjC domain histone demethylases, and the suggestions that some of them are potential therapeutic targets for cancer treatment, [9] Figure 1). [10][11][12][13] Compounds which catalyse the ejection of a structural Zn(II) ion from the JMJD2 demethylases have also been reported ( Figure 1). [14] In a study describing various template inhibitors of the JmjC demethylases, we found that 2,2′-bipyridyl compounds with at least one 4-carboxylate group inhibit the histone demethylase JMJD2E. [11] A related series of compounds, 5,5′-dicarboxylate-2,2′-bipyridyls, is reported to inhibit the collagen prolyl-4-hydroxylases. [15] 2,2′-Bipyridine and bipyridyl compounds have also been used as inhibitors of the HIF hydroxylases. [16] Although it is likely that in some cases the enzyme inhibition effects of bipyridyl compounds result from metal chelation in solution, they also have the potential to inhibit via active site binding, as is the case for some 2OG oxygenases; however, to date there is no structural information on their mechanism of action. Here we report structure-activity relationship studies and analyses on bipyridyl inhibitors of JMJD2E.The bipyridyl com...

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“…Inhibition of prolyl-4-hydroxylase alters extracellular matrix (ECM) deposition at a post-translational level (40), and the absence of hydroxylation of pro-collagen results in the accumulation of the newly formed collagen in the endoplasmic reticulum, with local degradation and decreased secretion to the interstitium. Similarly, PHI treatment decreases interstitial collagen accumulation and ameliorates clinical cirrhosis in an experimental model of liver fibrosis (41).…”

Section: Discussionmentioning

confidence: 99%