Therapeutic targets in fibrotic pathways

Chen, Bill B.

doi:10.1016/j.cyto.2016.09.008

Cited by 8 publications

(6 citation statements)

References 18 publications

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“…It is known that TGF-b1 increases the generation of free radicals such as reactive oxygen species and reactive nitrogen species in lung fibroblasts [41]. It has been reported that during BLM injury, TGF-b1 mRNA expression increases predominantly in various cells such as alveolar macrophages, fibroblasts, endothelial cells and mesothelial cells [42,43]. In accordance with these reports, the result of our study shows a pronounced expression of TGF-b1 in lung tissue sections of rats induced with BLM.…”

Section: Discussionsupporting

confidence: 91%

Regulation of Transforming Growth Factor‐β/Smad‐mediated Epithelial–Mesenchymal Transition by Celastrol Provides Protection against Bleomycin‐induced Pulmonary Fibrosis

Divya

Velavan

Sudhandiran

2018

Basic Clin Pharma Tox

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The respiratory disease pulmonary fibrosis (PF), which is characterized by scar formation throughout the lung, imposes a serious health burden. No effective drug without side effects has been proven to prevent this fatal lung disease. In this context, this study was undertaken to elucidate the protective effect of celastrol, a quinine methide pentacyclic triterpenoid from a Chinese medicinal plant 'thunder god vine' against bleomycin (BLM)-induced PF. We also attempted to study how the cytokine transforming growth factor-β (TGF-β) stimulates fibrosis through the induction of epithelial-mesenchymal transition (EMT) and the role of celastrol in regulating EMT. TGF-β (5 ng/ml) was administered to human alveolar epithelial adenocarcinoma A549 cells to induce fibrotic response in cells. Induction of EMT was analysed in cells through morphological analysis and expression of epithelial and mesenchymal markers by Western blotting. Bleomycin at a concentration of 3 U/Kg b.w was used to induce fibrosis in adult male rat lungs. Celastrol (5 mg/kg b.w) was given to rats twice a week after BLM administration for a period of 28 days. Western blot and immunofluorescence analyses were performed with lung tissue sample to find out the potential of celastrol in regulating EMT during the progression of fibrosis. TGF-β induces EMT in A549 cells as demonstrated by changes in epithelial cell morphology and expression of epithelial and mesenchymal marker proteins. The expressions of epithelial marker proteins E-cadherin and claudin were found to be reduced in the BLM-induced group of rats. Expression of mesenchymal markers, such as N-cadherin, snail, slug, vimentin and β-catenin, was enhanced in BLM-induced rat lungs. Celastrol reverts these cellular changes in rat lungs, and it was found that celastrol regulates EMT through the inhibition of heat shock protein 90 (HSP 90). Together, the results indicate that EMT is a crucial phenomenon for the progression of fibrosis, and celastrol provides protection against PF through the regulation of EMT.

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Section: Discussionsupporting

confidence: 91%

Regulation of Transforming Growth Factor‐β/Smad‐mediated Epithelial–Mesenchymal Transition by Celastrol Provides Protection against Bleomycin‐induced Pulmonary Fibrosis

Divya

Velavan

Sudhandiran

2018

Basic Clin Pharma Tox

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“…Analyses have indicated that the DCGs such as TGF-β, SMAD, MMP-2 and MMP-9 are mapped with different pathways related to stimulation, signaling cascades and pro-fibrotic protein expression. The role of these pathways was reported in early and late-onset ILDs pathogenesis ( 24 , 26 ). Pathways analyses of the DCGs have also suggested their significant involvement in the immune system (134 DCGs), innate immune system (91 DCGs), signal transduction (67 DCGs) and cytokine signaling (59 DCGs).…”

Section: Resultsmentioning

confidence: 98%

“…Outcomes of biological processes have shown that the maximum number of DCGs such as IL-4, IL-7, IL-8, IL-10 and CCL-ligands are mapped with defense response (90), response to external stimulus (84) and immune system process (74) ( Supplementary Figure S1C ). Identified cellular components for the majority of DCGs are extracellular region part (148), extracellular space (112) and few are from the intrinsic component of the membrane ( 24 ) ( Supplementary Figure S1B ). Results of molecular function have shown that the most of DCGs are mapped with cytokine activity ( 32 ), small molecule binding ( 12 ), chemokine receptor binding ( 11 ) and nucleoside binding ( 7 ) ( Supplementary Figure S1A ).…”

Section: Resultsmentioning

confidence: 99%

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ILDgenDB: integrated genetic knowledge resource for interstitial lung diseases (ILDs)

et al. 2018

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Interstitial lung diseases (ILDs) are a diverse group of ∼200 acute and chronic pulmonary disorders that are characterized by variable amounts of inflammation, fibrosis and architectural distortion with substantial morbidity and mortality. Inaccurate and delayed diagnoses increase the risk, especially in developing countries. Studies have indicated the significant roles of genetic elements in ILDs pathogenesis. Therefore, the first genetic knowledge resource, ILDgenDB, has been developed with an objective to provide ILDs genetic data and their integrated analyses for the better understanding of disease pathogenesis and identification of diagnostics-based biomarkers. This resource contains literature-curated disease candidate genes (DCGs) enriched with various regulatory elements that have been generated using an integrated bioinformatics workflow of databases searches, literature-mining and DCGs–microRNA (miRNAs)–single nucleotide polymorphisms (SNPs) association analyses. To provide statistical significance to disease-gene association, ILD-specificity index and hypergeomatric test scores were also incorporated. Association analyses of miRNAs, SNPs and pathways responsible for the pathogenesis of different sub-classes of ILDs were also incorporated. Manually verified 299 DCGs and their significant associations with 1932 SNPs, 2966 miRNAs and 9170 miR-polymorphisms were also provided. Furthermore, 216 literature-mined and proposed biomarkers were identified. The ILDgenDB resource provides user-friendly browsing and extensive query-based information retrieval systems. Additionally, this resource also facilitates graphical view of predicted DCGs–SNPs/miRNAs and literature associated DCGs–ILDs interactions for each ILD to facilitate efficient data interpretation. Outcomes of analyses suggested the significant involvement of immune system and defense mechanisms in ILDs pathogenesis. This resource may potentially facilitate genetic-based disease monitoring and diagnosis.Database URL: http://14.139.240.55/ildgendb/index.php

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“…Since E3 ligases responsible for targeting most proteins have not been identified the first step will be to catalog the E3 ligases responsible for controlling protein expression in relevant cell populations in the lung. Once achieved, the next step will be to develop small molecules capable of augmenting or inhibiting the activity of specific E3 ligases, like has recently been done for specific E3 ligases in the cancer field [83, 84, 85]. Alternatively, one could also develop small molecules that bind preferentially to specific substrates or to their ancillary proteins rather than to an E3 ligase.…”

Section: Proteasome Dysfunction In Ipfmentioning

confidence: 99%

Fine-tuning the ubiquitin-proteasome system to treat pulmonary fibrosis

Roque

Summer

Romero

2018

Connective Tissue Research

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Idiopathic pulmonary fibrosis is an extremely aggressive lung disease that develops almost exclusively in older individuals, carries a very poor prognosis, and lacks any truly effective therapies. The current conceptual model is that IPF develops because of an age-related decline in the ability of the lung epithelium to regenerate after injury, largely due to death or senescence of epithelial progenitor cells in the distal airways. This loss of regenerative capacity is thought to initiate a chronic and ineffective wound healing response, characterized by persistent, low-grade lung inflammation and sustained production of collagen and other extracellular matrix materials. Despite recent advances in our understanding of IPF pathobiology, there remains a pressing need to further delineate underlying mechanisms to develop more effective therapies for this disease. In this review, we build the case that many of the manifestations of IPF result from a failure of cells to effectively manage their proteome. We propose that epithelial progenitor cells, as well as immune cells and fibroblasts become functionally impaired, at least in part, because of an accumulation or a loss in the expression of various crucial proteins. Further, we propose that central to this defect is the dysregulation of the ubiquitin proteasome system, which is the major protein degradation system in eukaryotic cells. Lastly, borrowing concepts from other fields, we discuss how targeting the UPS system could be employed as a novel treatment for IPF and perhaps for other fibrotic lung diseases as well.

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Therapeutic targets in fibrotic pathways

Cited by 8 publications

References 18 publications

Regulation of Transforming Growth Factor‐β/Smad‐mediated Epithelial–Mesenchymal Transition by Celastrol Provides Protection against Bleomycin‐induced Pulmonary Fibrosis

Regulation of Transforming Growth Factor‐β/Smad‐mediated Epithelial–Mesenchymal Transition by Celastrol Provides Protection against Bleomycin‐induced Pulmonary Fibrosis

ILDgenDB: integrated genetic knowledge resource for interstitial lung diseases (ILDs)

Fine-tuning the ubiquitin-proteasome system to treat pulmonary fibrosis

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