Specific epigenetic regulators serve as potential therapeutic targets in idiopathic pulmonary fibrosis

Sehgal, Manas; Jakhete, Sharayu; Manekar, Amruta; Sasikumar, Satish

doi:10.1016/j.heliyon.2022.e09773

Cited by 11 publications

(10 citation statements)

References 280 publications

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“…Activating the coagulation cascade and resulting abnormal vascular remodeling are part of the attempt to repair damaged capillaries by leaking proteins such as fibrin and fibronectin into interstitial and alveolar spaces [ 21 ]. The fibrotic process is thus still influenced by neoangiogenesis [ 22 ]. The repeated stimulation of type II alveolar epithelial cells (AEC2) has been shown to primarily damage these cells [ 23 ].…”

Section: Discussionmentioning

confidence: 99%

The Effects of Interstitial Lung Diseases on Alveolar Extracellular Vesicles Profile: A Multicenter Study

d’Alessandro

Gangi

Soccio

et al. 2023

IJMS

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Diagnosis of interstitial lung diseases (ILD) is difficult to perform. Extracellular vesicles (EVs) facilitate cell-to-cell communication, and they are released by a variety of cells. Our goal aimed to investigate EV markers in bronchoalveolar lavage (BAL) from idiopathic pulmonary fibrosis (IPF), sarcoidosis and hypersensitivity pneumonitis (HP) cohorts. ILD patients followed at Siena, Barcelona and Foggia University Hospitals were enrolled. BAL supernatants were used to isolate the EVs. They were characterized by flow cytometry assay through MACSPlex Exsome KIT. The majority of alveolar EV markers were related to the fibrotic damage. CD56, CD105, CD142, CD31 and CD49e were exclusively expressed by alveolar samples from IPF patients, while HP showed only CD86 and CD24. Some EV markers were common between HP and sarcoidosis (CD11c, CD1c, CD209, CD4, CD40, CD44, CD8). Principal component analysis distinguished the three groups based on EV markers with total variance of 60.08%. This study has demonstrated the validity of the flow cytometric method to phenotype and characterize EV surface markers in BAL samples. The two granulomatous diseases, sarcoidosis and HP, cohorts shared alveolar EV markers not revealed in IPF patients. Our findings demonstrated the viability of the alveolar compartment allowing identification of lung-specific markers for IPF and HP.

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Section: Discussionmentioning

confidence: 99%

The Effects of Interstitial Lung Diseases on Alveolar Extracellular Vesicles Profile: A Multicenter Study

d’Alessandro

Gangi

Soccio

et al. 2023

IJMS

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“…Yield 81% (white solid); R f (ethyl acetate) 0.44; mp 153−155 °C; [α] D +12.0 (c 1.00, CHCl 3 ); 1 H NMR (400 MHz, CDCl 3 ) δ 8.12−8.01 (m, 3H), 7.50 (d, J = 7.6 Hz, 2H), 7.41 (d, J = 7.9 Hz, 2H), 7.33−7.27 (m, 3H), 7.24 (d, J = 5.7 Hz, 2H), 6.92 (d, J = 7.9 Hz, 2H), 5.12 (s, 2H), 5.04 (d, J = 14. 7 ( (32). To a stirred solution of 4-aminophenol (31) (200 mg, 1.83 mmol) in DMF (5 mL), Boc-OSu (394 mg, 1.83 mmol) was added at room temperature.…”

Section: ■ Conclusionmentioning

confidence: 99%

“…31 Specifically, numerous studies have indicated that TGF-β signaling and HDACs can regulate the expression of profibrotic and antifibrotic genes in alveolar epithelial cells, fibroblasts, and myofibroblasts, which are highly important cell types involved in IPF development and progression. 32 Accordingly, Sanders and co-workers employed a murine model of bleomycin-induced pulmonary fibrosis, where mice that were treated with vorinostat ameliorated lung fibrosis and improved lung function compared to the group treated solely with bleomycin. 33 In addition, FDA-approved HDAC inhibitor romidepsin has been demonstrated to inhibit bleomycininduced pulmonary fibrosis in vivo, supporting a potential use of HDAC inhibitors in IPF.…”

Section: ■ Introductionmentioning

confidence: 99%

“…Because HDACs are critical epigenetic modulators of gene expression, they have also been evaluated for treating parasitic diseases including malaria. , As aberrant HDAC activities are observed in fibrotic diseases, including pulmonary and cardiac fibrosis, HDAC inhibitors may prevent or reverse fibrogenesis. , Class I and class II HDACs also mediate fibrogenesis, and HDAC inhibitors may be useful in treating the orphan disease idiopathic pulmonary fibrosis (IPF) . Specifically, numerous studies have indicated that TGF-β signaling and HDACs can regulate the expression of profibrotic and antifibrotic genes in alveolar epithelial cells, fibroblasts, and myofibroblasts, which are highly important cell types involved in IPF development and progression . Accordingly, Sanders and co-workers employed a murine model of bleomycin-induced pulmonary fibrosis, where mice that were treated with vorinostat ameliorated lung fibrosis and improved lung function compared to the group treated solely with bleomycin .…”

Section: Introductionmentioning

confidence: 99%

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N-(2-Aminophenyl)-benzamide Inhibitors of Class I HDAC Enzymes with Antiproliferative and Antifibrotic Activity

Gerokonstantis,

Mantzourani,

Gkikas

et al. 2023

J. Med. Chem.

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Inhibitors of histone deacetylases (HDACs) have received special attention as novel anticancer agents. Among various types of synthetic inhibitors, benzamides constitute an important class, and one is an approved drug (chidamide). Here, we present a novel class of HDAC inhibitors containing the N-(2-aminophenyl)-benzamide functionality as the zinc-binding group linked to various cap groups, including the amino acids pyroglutamic acid and proline. We have identified benzamides that inhibit HADC1 and HDAC2 at nanomolar concentrations, with antiproliferative activity at micromolar concentrations against A549 and SF268 cancer cell lines. Docking studies shed light on the mode of binding of benzamide inhibitors to HDAC1, whereas cellular analysis revealed downregulated expression of EGFR mRNA and protein. Two benzamides were investigated in a mouse model of bleomycin-induced pulmonary fibrosis, and both showed efficacy on a preventative dosing schedule. N-(2-Aminophenyl)-benzamide inhibitors of class I HDACs might lead to new approaches for treating fibrotic disorders.

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“…Epigenetics is defined as heritable changes in gene expression that are influenced by endogenous and exogenous factors without alterations in the nucleotide sequence [ 29 , 30 ]. The main epigenetic mechanisms included DNA methylation, histone modifications, and non-coding RNAs (ncRNAs) such as microRNAs (miRNAs) and RNA modification [ 31 , 32 ] and dysregulated epigenetic modifications are well recognized player in the development of PF [ 33 , 34 , 35 , 36 , 37 , 38 ].…”

Section: Introductionmentioning

confidence: 99%

High-Fat Diet Related Lung Fibrosis-Epigenetic Regulation Matters

et al. 2023

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Pulmonary fibrosis (PF) is an interstitial lung disease characterized by the destruction of the pulmonary parenchyma caused by excessive extracellular matrix deposition. Despite the well-known etiological factors such as senescence, aberrant epithelial cell and fibroblast activation, and chronic inflammation, PF has recently been recognized as a metabolic disease and abnormal lipid signature was observed both in serum and bronchoalveolar lavage fluid (BALF) of PF patients and mice PF model. Clinically, observational studies suggest a significant link between high-fat diet (HFD) and PF as manifested by high intake of saturated fatty acids (SFAs) and meat increases the risk of PF and mice lung fibrosis. However, the possible mechanisms between HFD and PF remain unclear. In the current review we emphasize the diversity effects of the epigenetic dysregulation induced by HFD on the fibrotic factors such as epithelial cell injury, abnormal fibroblast activation and chronic inflammation. Finally, we discuss the potential ways for patients to improve their conditions and emphasize the prospect of targeted therapy based on epigenetic regulation for scientific researchers or drug developers.

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Specific epigenetic regulators serve as potential therapeutic targets in idiopathic pulmonary fibrosis

Cited by 11 publications

References 280 publications

The Effects of Interstitial Lung Diseases on Alveolar Extracellular Vesicles Profile: A Multicenter Study

The Effects of Interstitial Lung Diseases on Alveolar Extracellular Vesicles Profile: A Multicenter Study

N-(2-Aminophenyl)-benzamide Inhibitors of Class I HDAC Enzymes with Antiproliferative and Antifibrotic Activity

High-Fat Diet Related Lung Fibrosis-Epigenetic Regulation Matters

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