scholarly journals Inhibiting HDAC3 (Histone Deacetylase 3) Aberration and the Resultant Nrf2 (Nuclear Factor Erythroid-Derived 2-Related Factor-2) Repression Mitigates Pulmonary Fibrosis

Author(s):  
Fang Chen ◽  
Qi Gao ◽  
Lijun Zhang ◽  
Yibing Ding ◽  
Hongwei Wang ◽  
...  

Pulmonary fibrosis is a common cause of pulmonary hypertension and its development is associated with aberrant HDAC (histone deacetylase) activities and altered fibrogenic gene expressions; however, whether the epigenetic alterations causally affect pulmonary fibrosis remains poorly understood. Here, we report that HDAC3 aberration and the resultant inhibition of Nrf2 (nuclear factor erythroid-derived 2-related factor-2), a master transcription factor of antioxidative stress, contribute significantly to pulmonary fibrogenesis. HDAC3 is preferentially upregulated with concomitant Nrf2 suppression in fibrotic lungs of both idiopathic pulmonary fibrosis patients and bleomycin-treated mice. Genetic knockout of HDAC3 or Nrf2 inversely resisted or exacerbated the fibrotic pathologies, respectively, suggesting that they are crucial regulators of pulmonary fibrosis with opposite functions. Intriguingly, a HDAC3-selective inhibitor RGFP966 effectively reduced the Nrf2 suppression and normalized the fibrosis and adverse expressions of major fibrogenic proteins, Nrf2 downstream antioxidant enzymes and inflammatory cytokines. Nrf2 promoter contains a putative binding motif for FOXM1 (Forkhead box M1), a profibrotic transcriptional factor. HDAC3 and FOXM1 inducibly bound to Nrf2 promoter locus containing the motif in lung tissues of bleomycin mice, accompanied by reduced local histone3 acetylation, which were relieved by RGFP966. In cultured lung cells, RGFP966 blockage of the Nrf2 suppression was partially attenuated by a FOXM1 inhibitor or when the FOXM1 motif was mutated; while in Nrf2 knockout mice, the antifibrotic effects of RGFP966 were largely reduced. Thus, HDAC3 aberration and its suppression of Nrf2 plays important roles in pulmonary fibrogenesis and strategies targeting HDAC3/Nrf2 axis by HDAC3 inhibition might potentially benefit patients with idiopathic pulmonary fibrosis and the related pulmonary fibrotic disorders.

2013 ◽  
Vol 18 (1) ◽  
pp. 66-79 ◽  
Author(s):  
Elise Artaud-Macari ◽  
Delphine Goven ◽  
Stéphanie Brayer ◽  
Akila Hamimi ◽  
Valérie Besnard ◽  
...  

2018 ◽  
Author(s):  
G. Savary ◽  
M. Buscot ◽  
E. Dewaeles ◽  
S. Diazzi ◽  
N. Nottet ◽  
...  

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).


2021 ◽  
Vol 18 (6) ◽  
pp. 1173-1177
Author(s):  
Prasetyastuti ◽  
Rahmah Dara Ayunda ◽  
Sunarti

Purpose: To investigate the effect of 7-hydroxy-2-(4-hydroxy-3-methoxyphenyl)-chromen-4-one isolated from mahogany (Swietenia macrophylla King) seeds on atherogenic index, expressions of nuclear factor erythroid 2-related factor 2 (Nrf2) and expression of the glutathione peroxidase (GPx) genes in hyperlipidemic rats. Methods: A total of 25 rats male aged 8 weeks and weighing an average of 200 g were used. They were divided into five groups as follows: (I) normal (N), (II) hyperlipidemic (HL), (III) hyperlipidemic rats treated with simvastatin (HL+SV), (IV and V) hyperlipidemic rats treated with 30 or 90mg, respectively, of 7-hydroxy-2-(4-hydroxy-3-methoxyphenyl)-chromen-4-one per 200 g body weight per day for 4 weeks. Atherogenic index (AI) was calculated from the levels of triglyceride (TG) and high-density lipoprotein (HDL) while Nrf2 and GPx gene expressions were determined by quantitative real-time polymerase chain reaction (qRT-PCR). Results: Two different doses of 7-hydroxy-2-(4-hydroxy-3-methoxyphenyl)-chromen-4-one in hyperlipidemic rats significantly reduced their atherogenic index (p < 0.05). Nrf2 and GPx expression levels were lower than (p > 0.05) those of hyperlipidemic group. Conclusion: Seven-hydroxy-2-(4-hydroxy-3-methoxyphenyl)-chromen-4-one reduces the atherogenic index and expression levels of Nrf2 and GPx genes in hyperlipidemic rats. Thus, this compound has potential as an antihyperlipidemic agent


Antioxidants ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 1064
Author(s):  
Alessandro G. Fois ◽  
Elisabetta Sotgiu ◽  
Valentina Scano ◽  
Silvia Negri ◽  
Sabrina Mellino ◽  
...  

Introduction: In vitro evidence suggests that pirfenidone and nintedanib, approved agents for the treatment of idiopathic pulmonary fibrosis (IPF), exert anti-inflammatory and anti-oxidant effects. We aimed to investigate such effects in vivo in IPF patients. Methods: Systemic circulating markers of oxidative stress [nuclear factor erythroid 2–related factor 2 (Nrf2), thiobarbituric acid- reactive substances (TBARS), homocysteine (Hcy), cysteine (Cys), asymmetric dimethylarginine (ADMA) and ADMA/Arginine ratio, glutathione (GSH), plasma protein –SH (PSH), and taurine (Tau)] and inflammation [Kynurenine (Kyn), Tryptophan (Trp) and Kyn/Trp ratio] were measured at baseline and after 24-week treatment in 18 IPF patients (10 treated with pirfenidone and 8 with nintedanib) and in 18 age- and sex-matched healthy controls. Results: Compared to controls, IPF patients had significantly lower concentrations of reduced blood GSH (457 ± 73 µmol/L vs 880 ± 212 µmol/L, p < 0.001) and plasma PSH (4.24 ± 0.95 µmol/g prot vs 5.28 ± 1.35 µmol/g prot, p = 0.012). Pirfenidone treatment significantly decreased the Kyn/Trp ratio (0.030 ± 0.011 baseline vs 0.025 ± 0.010 post-treatment, p = 0.048) whilst nintedanib treatment significantly increased blood GSH (486 ± 70 μmol/L vs 723 ± 194 μmol/L, p = 0.006) and reduced ADMA concentrations (0.501 ± 0.094 vs. 0.468 ± 0.071 μmol/L, p = 0.024). Conclusion: pirfenidone and nintedanib exert beneficial effects on specific markers of oxidative stress and inflammation in IPF patients.


1990 ◽  
Vol 10 (12) ◽  
pp. 6283-6289
Author(s):  
M Nonaka ◽  
Z M Huang

Complement factor B, a serine protease playing a pivotal role in alternative pathway activation, is an acute-phase plasma protein. Previous studies have revealed that interleukin-1 (IL-1) mediates, at least in part, the acute-phase induction of factor B expression and that the IL-1-responsive element resides in the region between -553 and -478 relative to the transcription initiation site of the mouse factor B gene. In this paper, we demonstrate a specific binding site for a nuclear factor of human hepatoma HepG2 cells in this region of the factor B gene, using gel shift and methylation interference analysis. The nucleotide sequence of the binding site is closely similar to the NF kappa B or H2TF1 binding motif. The binding activity of HepG2 showed very similar specificity to that of NF kappa B or H2TF1, as shown by a competition binding assay, and was induced by IL-1 alpha treatment. A synthetic oligonucleotide corresponding to this binding site, as well as a similar sequence found in another class III complement C4 gene, conferred IL-1 responsiveness on the minimal factor B promoter. In contrast, a mutated oligonucleotide that could not bind to the HepG2 nuclear factor did not confer IL-1 responsiveness. These results suggest that IL-1 induces factor B expression via NF kappa B or a closely related factor in hepatocyte nuclei.


1990 ◽  
Vol 10 (12) ◽  
pp. 6283-6289 ◽  
Author(s):  
M Nonaka ◽  
Z M Huang

Complement factor B, a serine protease playing a pivotal role in alternative pathway activation, is an acute-phase plasma protein. Previous studies have revealed that interleukin-1 (IL-1) mediates, at least in part, the acute-phase induction of factor B expression and that the IL-1-responsive element resides in the region between -553 and -478 relative to the transcription initiation site of the mouse factor B gene. In this paper, we demonstrate a specific binding site for a nuclear factor of human hepatoma HepG2 cells in this region of the factor B gene, using gel shift and methylation interference analysis. The nucleotide sequence of the binding site is closely similar to the NF kappa B or H2TF1 binding motif. The binding activity of HepG2 showed very similar specificity to that of NF kappa B or H2TF1, as shown by a competition binding assay, and was induced by IL-1 alpha treatment. A synthetic oligonucleotide corresponding to this binding site, as well as a similar sequence found in another class III complement C4 gene, conferred IL-1 responsiveness on the minimal factor B promoter. In contrast, a mutated oligonucleotide that could not bind to the HepG2 nuclear factor did not confer IL-1 responsiveness. These results suggest that IL-1 induces factor B expression via NF kappa B or a closely related factor in hepatocyte nuclei.


2019 ◽  
Vol 30 (15) ◽  
pp. 1831-1848 ◽  
Author(s):  
Lin An ◽  
Li-Ying Peng ◽  
Ning-Yuan Sun ◽  
Yi-Lin Yang ◽  
Xiao-Wei Zhang ◽  
...  

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