Epigenetic Modifications in Fibrotic Diseases: Implications for Pathogenesis and Pharmacological Targets

Yao, Hongwei; Li, Jun

doi:10.1124/jpet.114.219816

Cited by 32 publications

(28 citation statements)

References 203 publications

(166 reference statements)

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“…Epithelial-mesenchymal transition (EMT) is a key event playing a critical role in the development of lung fibrotic disease4. Repetitive alveolar epithelial cell injury followed by the formation of fibroblastic foci could lead to an excessive deposition of ECM, which causes scarring and architectural distortion of the lung as well as irreversible loss of lung function56.…”

mentioning

confidence: 99%

Nrf2 inhibits epithelial-mesenchymal transition by suppressing snail expression during pulmonary fibrosis

Zhou

Cui

et al. 2016

Sci Rep

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Epithelial-mesenchymal transition (EMT) is a phenotype conversion that plays a critical role in the development of pulmonary fibrosis (PF). It is known that snail could regulate the progression of EMT. Nuclear factor erythroid 2 related factor 2 (Nrf2), a key regulator of antioxidant defense system, protects cells against oxidative stress. However, it is not known whether Nrf2 regulates snail thereby modulating the development of PF. Here, bleomycin (BLM) was intratracheally injected into both Nrf2-knockout (Nrf2−/−) and wild-type mice to compare the development of PF. Rat type II alveolar epithelial cells (RLE-6TN) were treated with a specific Nrf2 activator sulforaphane, or transfected with Nrf2 and snail siRNAs to determine their effects on transforming growth factor β1 (TGF-β1)-induced EMT. We found that BLM-induced EMT and lung fibrosis were more severe in Nrf2−/− mice compared to wild-type mice. In vitro, sulforaphane treatment attenuated TGF-β1-induced EMT, accompanied by the down-regulation of snail. Inversely, silencing Nrf2 by siRNA enhanced TGF-β1-induced EMT along with increased expression of snail. Interestingly, when snail was silenced by siRNA, sulforaphane treatment was unable to reduce the progression of EMT in RLE-6TN cells. These findings suggest that Nrf2 attenuates EMT and fibrosis process by regulating the expression of snail in PF.

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confidence: 99%

Nrf2 inhibits epithelial-mesenchymal transition by suppressing snail expression during pulmonary fibrosis

Zhou

Cui

et al. 2016

Sci Rep

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“…MicroRNAs are integrated into a large family of genomically encoded noncoding RNAs (ncRNAs) and play a critical role in controlling cancer cell proliferation, apoptosis and invasion, and tumor initiation and progression (Kasinski and Slack, 2011;Bader, 2012), as well as drug disposition (Yu, 2009;Ingelman-Sundberg et al, 2013) and pathogenesis of other diseases (Yao and Li, 2015). MicroRNA (miRNA or miR) biologic functions contribute to the development of novel anticancer treatments, and several miRNA-based therapies are under or moving toward clinical trials.…”

Section: Introductionmentioning

confidence: 99%

Bioengineering Novel Chimeric microRNA-34a for Prodrug Cancer Therapy: High-Yield Expression and Purification, and Structural and Functional Characterization

Wang

Chen

et al. 2015

J Pharmacol Exp Ther

140

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Development of anticancer treatments based on microRNA (miRNA/miR) such as miR-34a replacement therapy is limited to the use of synthetic RNAs with artificial modifications. Herein, we present a new approach to a high-yield and large-scale biosynthesis, in Escherichia coli using transfer RNA (tRNA) scaffold, of chimeric miR-34a agent, which may act as a prodrug for anticancer therapy. The recombinant tRNA fusion pre-miR34a (tRNA/mir-34a) was quickly purified to a high degree of homogeneity (.98%) using anion-exchange fast protein liquid chromatography, whose primary sequence and post-transcriptional modifications were directly characterized by mass spectrometric analyses. Chimeric tRNA/mir-34a showed a favorable cellular stability while it was degradable by several ribonucleases. Deep sequencing and quantitative real-time polymerase chain reaction studies revealed that tRNA-carried pre-miR-34a was precisely processed to mature miR-34a within human carcinoma cells, and the same tRNA fragments were produced from tRNA/ mir-34a and the control tRNA scaffold (tRNA/MSA). Consequently, tRNA/mir-34a inhibited the proliferation of various types of human carcinoma cells in a dose-dependent manner and to a much greater degree than the control tRNA/MSA, which was mechanistically attributable to the reduction of miR-34a target genes. Furthermore, tRNA/mir-34a significantly suppressed the growth of human non-small-cell lung cancer A549 and hepatocarcinoma HepG2 xenograft tumors in mice, compared with the same dose of tRNA/MSA. In addition, recombinant tRNA/mir-34a had no or minimal effect on blood chemistry and interleukin-6 level in mouse models, suggesting that recombinant RNAs were well tolerated. These findings provoke a conversation on producing biologic miRNAs to perform miRNA actions, and point toward a new direction in developing miRNAbased therapies.

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“…Given (i) the limited positive results of decitabine treatment on renal fibrosis in the current experiment, (ii) the overall limited amount of positive publications on nucleoside analogues as a treatment strategy for fibrosis, and (iii) the severity of adverse effects (e.g., weight loss) of this compound (even for relative short-term treatments), the administration of nucleoside analogues as such seems unsuitable as a first-line treatment in CKD. Evaluating the efficacy of precisely targeted DNA-demethylation strategies would therefore be invaluable to fully reveal the putative therapeutic potential of DNA-demethylation in targeting development or progression of renal fibrosis [47] .…”

Section: Discussionmentioning

confidence: 99%

Untargeted DNA-Demethylation Therapy Neither Prevents Nor Attenuates Ischemia-Reperfusion-Induced Renal Fibrosis

Vervaet

Moonen²,

Godderis³

et al. 2017

Nephron

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Background: Current treatment options for chronic kidney disease (CKD) are limited and their focus is on slowing its progression by addressing comorbidities. Fibrosis, the common histopathological process in CKD, is a major therapeutic research target. In CKD, fibroblasts are terminally activated due to alterations in their DNA-methylation pattern, particularly hypermethylation. Preventing the copying of pathological DNA-methylation patterns in proliferating fibroblasts could be a new effective therapeutic strategy for treating CKD. Methods: To evaluate the therapeutic effect of short-term treatment with the DNA-methyltransferase (DNMT)-inhibitor decitabine on fibrosis (either developing or already established), male C57Bl/6 mice underwent warm unilateral ischemia-reperfusion injury. Respectively 3 days, 3 and 6 weeks after surgery, decitabine treatment (0.25 mg/kg) was initiated for 10 days after which animals were followed up to 12 weeks after ischemia. The efficacy of therapy on fibrosis was evaluated by collagen I and tgfβ gene expression and histological quantification of collagen I staining. In addition, the effect of decitabine treatment on tubular injury (Kim-1, Ngal), inflammation (TNFa, IL6), DNA-methyltransferases (Dnmt1, 3a, and 3b), and global methylation status was determined. Results: Following ischemia there was a significant increase in fibrotic, injury, and inflammatory markers as well as an increase of the various dnmts. Although decitabine treatment transiently increased renal injury and had a moderately decreasing effect on dnmt expression and on global DNA-methylation upon immediate treatment, none of the treatment regimens succeeded in preventing, attenuating, or diminishing fibrosis in the long run. Conclusion: Administration of untargeted nucleoside analogues seems unsuitable as a first-line treatment option in developing or established CKD.

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Epigenetic Modifications in Fibrotic Diseases: Implications for Pathogenesis and Pharmacological Targets

Cited by 32 publications

References 203 publications

Nrf2 inhibits epithelial-mesenchymal transition by suppressing snail expression during pulmonary fibrosis

Nrf2 inhibits epithelial-mesenchymal transition by suppressing snail expression during pulmonary fibrosis

Bioengineering Novel Chimeric microRNA-34a for Prodrug Cancer Therapy: High-Yield Expression and Purification, and Structural and Functional Characterization

Untargeted DNA-Demethylation Therapy Neither Prevents Nor Attenuates Ischemia-Reperfusion-Induced Renal Fibrosis

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