Aspidin PB, a novel natural anti-fibrotic compound, inhibited fibrogenesis in TGF-β1-stimulated keloid fibroblasts via PI-3K/Akt and Smad signaling pathways

Ren-gang, Song; Li, Gaofeng; Liu, Shirong

doi:10.1016/j.cbi.2015.06.005

Cited by 22 publications

(19 citation statements)

References 42 publications

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“…TGFβ1 is known to influence cell migration through MMP regulation (52) and its effect on single cell motility is thought to require synergy with the EGFR family of tyrosine kinase receptors (53,54), such as ErbB2 (55)(56)(57). Both ErbB2 and TGFβ also independently activate PI3K/Akt (58,59) and MAPK/ Erk (60,61) pathways, which are regulators of migration and are both known to be dysregulated in keloid disease (62,63).…”

Section: Discussionmentioning

confidence: 99%

A Role for Neuregulin-1 in Promoting Keloid Fibroblast Migration via ErbB2-mediated Signaling

Jumper¹,

Hodgkinson²,

Paus³

2017

Acta Derm Venerol

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Keloid disease is a fibroproliferative tumour characterised by aggressive local invasion, evident from a clinically and histologically active migrating margin. During combined laser capture microdissection and microarray analysis-based in situ gene expression profiling, we identified upregulation of the polypeptide growth factor neuregulin-1 (NRG1) and ErbB2 oncogene in keloid margin dermis, leading to the hypothesis that NRG1 contributed to keloid margin migration through ErbB2-mediated signalling. The aim of this study was to probe this hypothesis through functional in vitro studies. Exogenous NRG1 addition to keloid and normal skin fibroblasts altered cytokine expression profiles, significantly increased in vitro migration and keloid fibroblast Src and protein tyrosine kinase 2 (PTK2/FAK) gene expression. ErbB2 siRNA knockdown attenuated both keloid fibroblast migration and Src/PTK2 expression, which were not recovered following NRG1 administration, suggesting the NRG1/ErbB2/Src/PTK2 signaling pathway may be a novel regulator of keloid fibroblast migration, and representing a potential new therapeutic target.

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Section: Discussionmentioning

confidence: 99%

A Role for Neuregulin-1 in Promoting Keloid Fibroblast Migration via ErbB2-mediated Signaling

Jumper¹,

Hodgkinson²,

Paus³

2017

Acta Derm Venerol

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“…As shown in previous studies, AMPK, MAPK and PI3K-Akt signalling pathways stimulated by TGF-β/Smad actively participate in keloid formation [30,31,32,33]. As mentioned above, CTGF functions as a typical downstream mediator of the TGF-β/Smad signalling pathway in keloids [12].…”

Section: Resultsmentioning

confidence: 79%

Adiponectin Is Involved in Connective Tissue Growth Factor-Induced Proliferation, Migration and Overproduction of the Extracellular Matrix in Keloid Fibroblasts

Luo

Liu

et al. 2017

IJMS

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Adiponectin, an adipocyte-derived hormone, exerts pleiotropic biological effects on metabolism, inflammation, vascular homeostasis, apoptosis and immunity. Recently, adiponectin has been suggested to attenuate the progression of human dermal fibrosis. Connective tissue growth factor (CTGF) is induced in keloids and is thought to be participated in the formation of keloid fibrosis. However, the roles played by adiponectin in keloids remain unclear. In this study, we explored the effects of adiponectin on CTGF-induced cell proliferation, migration and the deposition of extracellular matrix (ECM) and their associated intracellular signalling pathways in keloid fibroblasts (KFs). We also explored possible mechanisms of keloid pathogenesis. Primary fibroblast cultures were established from foreskin biopsies and skin biopsies from patients with keloids. The expression of adiponectin and adiponectin receptors (adipoRs) was evaluated by reverse transcription-PCR (RT-PCR), quantitative real-time RT-PCR, immunofluorescence staining, and immunohistochemical analysis. Next, KFs and normal dermal fibroblasts (NFs) were treated with CTGF in the presence or absence of adiponectin. A cell counting kit-8 (CCK-8) and the Transwell assay were used to examine cell proliferation and migration. The level of the collagen I, fibronectin (FN) and α-smooth muscle actin (α-SMA) mRNAs and proteins were determined by quantitative real-time RT-PCR and western blotting. The effects of RNA interference (RNAi) targeting the adipoR genes were detected. Phosphorylation of adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK), mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3 kinase-protein kinase (PI3K-Akt) were examined by western blotting to further investigate the signalling pathways. Furthermore, inhibitors of signal transduction pathways were investigated. The expression levels of adiponectin and adipoRs were significantly decreased in keloids compared with those in normal skin tissue. Adiponectin suppressed the CTGF-induced KFs, but not NFs, proliferation, migration and ECM production. Moreover, adiponectin inhibited the phosphorylation of AMPK, p38 and extracellular-regulated kinase (ERK), but not that of Jun N-terminal kinase (JNK) or Akt, in CTGF-treated KFs. The activity of adiponectin-mediated signalling pathways was attenuated by small interfering RNAs (siRNAs) targeting adipoR1 (but not siRNAs targeting adipoR2, T-cadherin or calreticulin), AMPK (Compound C), p38 (SB203580) inhibitors, and mitogen-activated protein kinase kinase (MEK) inhibitor (PD98059). Based on our results, adiponectin suppresses CTGF-induced KFs proliferation, migration and ECM overproduction. One of the underlying mechanisms is the activation of the adipoR1, AMPK, p38, and ERK signalling pathways. Therefore, adiponectin may play an important role in the progression of keloids, suggesting a potential novel target for keloid treatment.

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“…Pathway analysis also revealed that 11 pathways corresponded to downregulated transcripts and that the most enriched network was metabolic pathways (TDC, 49.2%), which comprised 30 target genes (Figure 3(d)). Many of these pathways are reported to be associated with keloid, including the gene category focal adhesion pathway [15], TGF- β signaling pathway [16–18], mitogen-activated protein kinase (MAPK) pathway [19], and gap junction pathway [20, 21]. …”

Section: Resultsmentioning

confidence: 99%

Expression Profile of Long Noncoding RNAs in Human Earlobe Keloids: A Microarray Analysis

Guo

Yan

et al. 2016

BioMed Research International

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Background. Long noncoding RNAs (lncRNAs) play key roles in a wide range of biological processes and their deregulation results in human disease, including keloids. Earlobe keloid is a type of pathological skin scar, and the molecular pathogenesis of this disease remains largely unknown. Methods. In this study, microarray analysis was used to determine the expression profiles of lncRNAs and mRNAs between 3 pairs of earlobe keloid and normal specimens. Gene Ontology (GO) categories and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed to identify the main functions of the differentially expressed genes and earlobe keloid-related pathways. Results. A total of 2068 lncRNAs and 1511 mRNAs were differentially expressed between earlobe keloid and normal tissues. Among them, 1290 lncRNAs and 1092 mRNAs were upregulated, and 778 lncRNAs and 419 mRNAs were downregulated. Pathway analysis revealed that 24 pathways were correlated to the upregulated transcripts, while 11 pathways were associated with the downregulated transcripts. Conclusion. We characterized the expression profiles of lncRNA and mRNA in earlobe keloids and suggest that lncRNAs may serve as diagnostic biomarkers for the therapy of earlobe keloid.

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Aspidin PB, a novel natural anti-fibrotic compound, inhibited fibrogenesis in TGF-β1-stimulated keloid fibroblasts via PI-3K/Akt and Smad signaling pathways

Cited by 22 publications

References 42 publications

A Role for Neuregulin-1 in Promoting Keloid Fibroblast Migration via ErbB2-mediated Signaling

A Role for Neuregulin-1 in Promoting Keloid Fibroblast Migration via ErbB2-mediated Signaling

Adiponectin Is Involved in Connective Tissue Growth Factor-Induced Proliferation, Migration and Overproduction of the Extracellular Matrix in Keloid Fibroblasts

Expression Profile of Long Noncoding RNAs in Human Earlobe Keloids: A Microarray Analysis

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