scholarly journals Synthesis and Biological Evaluation of Novel Thiazolyl-Coumarin Derivatives as Potent Histone Deacetylase Inhibitors with Antifibrotic Activity

Molecules ◽  
2019 ◽  
Vol 24 (4) ◽  
pp. 739 ◽  
Author(s):  
Viviana Pardo-Jiménez ◽  
Patricio Navarrete-Encina ◽  
Guillermo Díaz-Araya
Keyword(s):  
Histone Deacetylases ◽  
Histone Deacetylase Inhibitors ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Hdac Inhibitors ◽  
Biological Evaluation ◽  
Neonatal Rat ◽  
Zinc Binding ◽  
Coumarin Derivatives

New histone deacetylases (HDAC) inhibitors with low toxicity to non-cancerous cells, are a prevalent issue at present because these enzymes are actively involved in fibrotic diseases. We designed and synthesized a novel series of thiazolyl-coumarins, substituted at position 6 (R = H, Br, OCH3), linked to classic zinc binding groups, such as hydroxamic and carboxylic acid moieties and alternative zinc binding groups such as disulfide and catechol. Their in vitro inhibitory activities against HDACs were evaluated. Disulfide and hydroxamic acid derivatives were the most potent ones. Assays with neonatal rat cardiac fibroblasts demonstrated low cytotoxic effects for all compounds. Regarding the parameters associated to cardiac fibrosis development, the compounds showed antiproliferative effects, and triggered a strong decrease on the expression levels of both α-SMA and procollagen I. In conclusion, the new thiazolyl-coumarin derivatives inhibit HDAC activity and decrease profibrotic effects on cardiac fibroblasts.

Abstract 220: miR-486 Mediates the Benefits of Exercise in Attenuating Cardiac Fibrosis

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Dongchao Lv ◽  
Yihua Bei ◽  
Qiulian Zhou ◽  
Qi Sun ◽  
Tianzhao Xu ◽  
...  
Keyword(s):  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Mrna Level ◽  
Neonatal Rat ◽  
Cardiac Growth ◽  
Non Coding Rnas ◽  
Exercise Induced ◽  
Proliferation Assays

MicroRNAs (miRNAs, miRs), a novel group of small non-coding RNAs, play important roles in cardiac fibrosis. Exercise-induced physiological cardiac growth is associated with hypertrophy and proliferation of cardiomyocytes. In addition, exercise has been shown to inhibit cardiac fibrosis. However, relative little is known about whether exercise could attenuating cardiac fibrosis via targeting miRNA. miR-486 is a muscle enriched miRNAs, however, its role in heart is relative unclear. The current study aimed to investigate the role of miR-486 in exercise-induced cardiac growth in a 3-week swimming training murine model as well as in the function of cardiac fibroblasts and production of extracellular matrix (ECM) using neonatal rat cardiac fibroblasts in primary culture. Our data showed that exercised mice displayed increased about three-fold expression of miR-486 in hearts as measured by microarray analysis and qRT-PCRs. EdU proliferation assays demonstrated that miR-486 mimics decreased (5.90%±0.57% vs 4.02%±0.27% in nc-mimics vs miR-486-mimics, respectively), while miR-486 inhibitor increased the proliferation of cardiac fibroblasts in vitro (5.87%±0.16% vs 9.60%±0.58% in nc-inhibitor vs miR-486-inhibitor, respectively). Although downregulation of miR-486 had no regulatory effect on α-sma and collagen-1 gene expression in cardiac fibroblasts, overexpression of miR-486 significantly reduced the mRNA level of α-sma (1.01±0.08 vs 0.28±0.04 in nc-mimics vs miR-486-mimics, respectively) and collagen-1(1.02±0.12 vs 0.58±0.09 in nc-mimics vs miR-486-mimics, respectively), indicative of attenuated activation of fibroblasts and reduced production of ECM. These data reveal that miR-486 is essentially involved in the proliferation and activation of cardiac fibroblasts, and might be a key regulator mediating the benefit of exercise in preventing cardiac fibrosis.

scholarly journals Histone Deacetylase Inhibitors as Therapeutic Interventions on Cervical Cancer Induced by Human Papillomavirus

2021 ◽  
Vol 8 ◽  
Author(s):  
Natália Lourenço de Freitas ◽  
Maria Gabriela Deberaldini ◽  
Diana Gomes ◽  
Aline Renata Pavan ◽  
Ângela Sousa ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Histone Deacetylases ◽  
Histone Deacetylase Inhibitors ◽  
Hdac Inhibitors ◽  
Human Papillomaviruses ◽  
Therapeutic Interventions ◽  
Cellular Targets

The role of epigenetic modifications on the carcinogenesis process has received a lot of attention in the last years. Among those, histone acetylation is a process regulated by histone deacetylases (HDAC) and histone acetyltransferases (HAT), and it plays an important role in epigenetic regulation, allowing the control of the gene expression. HDAC inhibitors (HDACi) induce cancer cell cycle arrest, differentiation, and cell death and reduce angiogenesis and other cellular events. Human papillomaviruses (HPVs) are small, non-enveloped double-stranded DNA viruses. They are major human carcinogens, being intricately linked to the development of cancer in 4.5% of the patients diagnosed with cancer worldwide. Long-term infection of high-risk (HR) HPV types, mainly HPV16 and HPV18, is one of the major risk factors responsible for promoting cervical cancer development. In vitro and in vivo assays have demonstrated that HDACi could be a promising therapy to HPV-related cervical cancer. Regardless of some controversial studies, the therapy with HDACi could target several cellular targets which HR-HPV oncoproteins could be able to deregulate. This review article describes the role of HDACi as a possible intervention in cervical cancer treatment induced by HPV, highlighting the main advances reached in the last years and providing insights for further investigations regarding those agents against cervical cancer.

Synthesis and biological evaluation of thiophene-based hydroxamate derivatives as HDACis with antitumor activities

2020 ◽  
Vol 12 (8) ◽  
pp. 655-672 ◽  
Author(s):  
Feifei Yang ◽  
Lina Han ◽  
Na Zhao ◽  
Yang Yang ◽  
Di Ge ◽  
...  
Keyword(s):  
Anticancer Agents ◽  
Histone Deacetylases ◽  
Hdac Inhibitors ◽  
Xenograft Model ◽  
Biological Evaluation ◽  
Anticancer Activities ◽  
Antitumor Activities ◽  
Cancer Treatments

Aim:   Histone deacetylases (HDACs) are one of the validated targets for cancer treatments. In our previous work, we designed a series of bis-substituted aromatic amide HDAC inhibitors (HDACis), among which compounds 7 and 8 showed promising anticancer effects. However, the low solubilities prevented their subsequent developments. We developed additional thiophene-based hydroxamate HDACis in order to improve their physicochemical properties. Materials & methods: In vitro biological evaluations of these analogs revealed potent antiproliferative and antimigrated activities. More importantly, compound 10h exhibited excellent in vivo antitumor activities in MDA-MB-231 xenograft model mice. Furthermore, 10h showed better anticancer activities and drug-like properties than 7. Results & conclusion: Our results proved that thiophene-based hydroxamate HDACis can serve as a promising framework for developing potential anticancer agents.

Abstract 298: Flavin Containing Monooxygenase 2 in Cardiac Fibrosis

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Xinyang Hu ◽  
Cheng Ni
Keyword(s):  
Cardiac Fibrosis ◽  
Nuclear Translocation ◽  
Heart Function ◽  
Cardiac Fibroblasts ◽  
Neonatal Rat ◽  
Critical Determinant ◽  
Ubiquitin Protein Ligase ◽  
Over Expression ◽  
First Time

Cardiac fibrosis is associated with clinical outcome in patients with heart failing. There is no information concerning whether flavin containing monooxygenase 2 (FMO2) is involved in the fibrotic response. Here, we demonstrate that FMO2 is consistently down-regulated after myocardial infarction (MI) in rats, non-human primates and patients with chronic MI. Furthermore, FMO2 knockdown or knockout results in significantly increased cardiac fibrosis accompanied with impaired heart function in rats. Compensation of non-myocyte FMO2 using the strategy of miR133a/1a TS aided lentivirus inhibits the cardiac fibrosis and restores the deteriorated cardiac function following MI in rats. In vitro studies showed FMO2 expression in neonatal rat cardiac fibroblasts (NRCFs) is dramatically decreased after treatment of TGF-β. FMO2 deficiency in CFs isolated from FMO2-/- rats induces augmented collagen deposition, fibroblast-myofibroblast transdifferentiation and increased phosphorylated SMAD2/3. However, overexpression of FMO2 in NRCFs or CFs from MI patients suppresses this exact process. Mechanistically, we demonstrate using mass spectrometry that FMO2 combines with cytochrome p450 superfamily 2J3 (CYP2J3) at the ubiquitination site of the latter one after TGF-β stimulation, and then blocks the CYP2J3 ubiquitination. The accumulated CYP2J3 expression induces the up-regulation and nuclear translocation of SMURF2, the E3 ubiquitin-protein ligase specifically degrades phosphorylated SMAD2/3, through a negative feedback as another substrate of SMURF2, in addition, FMO2 can competitively exploit CYP2J3 from SMURF2, thus in turn promotes nuclear translocation of SMURF2 to degrade phosphorylated SMAD2/3. Furthermore, in non-human primate MI model, delivery of non-myocyte FMO2 over-expression lentivirus significantly decreases the cardiac fibrosis and improves heart function. In summary, our study demonstrates for the first time that FMO2 is a critical determinant of cardiac fibrosis by interfering TGF-β/SMAD2/3 and provides a novel potential target for treating cardiac fibrosis.

Identification of novel small-molecule histone deacetylase inhibitors by medium-throughput screening using a fluorigenic assay

2008 ◽  
Vol 413 (1) ◽  
pp. 143-150 ◽  
Author(s):  
Dennis Wegener ◽  
Christian Hildmann ◽  
Daniel Riester ◽  
Andreas Schober ◽  
Franz-Josef Meyer-Almes ◽  
...  
Keyword(s):  
Gene Expression ◽  
Histone Deacetylases ◽  
Histone Deacetylase Inhibitors ◽  
Cell Metabolism ◽  
Hdac Inhibitors ◽  
Tumour Suppressor Genes ◽  
Histone H4 ◽  
Histone H4 Acetylation

HDACs (histone deacetylases) are considered to be among the most important enzymes that regulate gene expression in eukaryotic cells. In general, increased levels of histone acetylation are associated with increased transcriptional activity, whereas decreased levels are linked to repression of gene expression. HDACs associate with a number of cellular oncogenes and tumour-suppressor genes, leading to an aberrant recruitment of HDAC activity, which results in changes of gene expression, impaired differentiation and excessive proliferation of tumour cells. Therefore HDAC inhibitors are efficient anti-proliferative agents in both in vitro and in vivo pre-clinical models of cancer, making them promising anticancer therapeutics. In the present paper, we present the results of a medium-throughput screening programme aiming at the identification of novel HDAC inhibitors using HDAH (HDAC-like amidohydrolase) from Bordetella or Alcaligenes strain FB188 as a model enzyme. Within a library of 3719 compounds, several new classes of HDAC inhibitor were identified. Among these hit compounds, there were also potent inhibitors of eukaryotic HDACs, as demonstrated by an increase in histone H4 acetylation, accompanied by a decrease in tumour cell metabolism in both SHEP neuroblastoma and T24 bladder carcinoma cells. In conclusion, screening of a compound library using FB188 HDAH as model enzyme identified several promising new lead structures for further development.

scholarly journals 6- and 8-Prenylnaringenin, Novel Natural Histone Deacetylase Inhibitors Found in Hops, Exert Antitumor Activity on Melanoma Cells

2018 ◽  
Vol 51 (2) ◽  
pp. 543-556 ◽  
Author(s):  
Sascha Venturelli ◽  
Heike Niessner ◽  
Tobias Sinnberg ◽  
Alexander Berger ◽  
Markus Burkard ◽  
...  
Keyword(s):  
In Silico ◽  
Histone Deacetylases ◽  
Histone Deacetylase Inhibitors ◽  
Cellular Proliferation ◽  
Hdac Inhibitors ◽  
Binding Pocket ◽  
Zinc Ion ◽  
Melanoma Cells ◽  
The Impact

Background/Aims: Prenylnaringenins are natural prenylflavonoids with anticancer properties. However, the underlying mechanisms have not been elucidated yet. Here we report a novel mode of action of 6- and 8-prenylnaringenin (PN) on human melanoma cells: Inhibition of cellular histone deacetylases (HDACs). Methods: We performed in silico and in vitro analyses using 6-PN or 8-PN to study a possible interaction of 6-PN or 8-PN with HDAC as well as Western blot and FACS analyses, real-time cell proliferation and cell viability assays to assess the impact of 6-PN and 8-PN on human metastatic melanoma cells. Results: In silico, 6-PN and 8-PN fit into the binding pocket of HDAC2, 4, 7 and 8, binding to the zinc ion of their catalytic center that is essential for enzymatic activity. In vitro, 100 µmol/L of 6-PN or 8-PN inhibited all 11 conserved human HDAC of class I, II and IV. In clinical oncology HDAC inhibitors are currently investigated as new anticancer compounds. In line, treatment of SK-MEL-28 cells with 6-PN or 8-PN induced a hyperacetylation of histone complex H3 within 2 h. Further, 6-PN or 8-PN mediated a prominent, dose-dependent reduction of cellular proliferation and viability of SK-MEL-28 and BLM melanoma cells. This effect was apoptosis-independent and accompanied by down-regulation of mTOR-specific pS6 protein via pERK/pP90 in SK-MEL-28 cells. Conclusion: The identification of a broad inhibitory capacity of 6-PN and 8-PN for HDAC enzymes with antiproliferative effects on melanoma cells opens the perspective for clinical application as novel anti-melanoma drugs and the usage as innovative lead structures for chemical modification to enhance pharmacology or inhibitory activities.

Abstract 304: Estrogen Plays a Protective Role in Advanced Heart Failure by Suppressing Cardiac Fibrosis Associated Genes via miR129 Induction

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Salil Sharma ◽  
Andrea Iorga ◽  
Harnek Singh ◽  
Jingyaun Li ◽  
Mansoureh Eghbali
Keyword(s):  
Heart Failure ◽  
Target Genes ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Pressure Overload ◽  
Neonatal Rat ◽  
Fibroblast Proliferation ◽  
Short Term ◽  
Short Term Treatment

We have previously shown that short term treatment of estrogen(E2) can rescue advance heart failure(HF) and decreases associated fibrosis. We hypothesized that E2 can reduce fibrosis by regulating the levels of specific microRNAs including miR129-5p(miR129) through ERβ mediated mechanism. We used transaortic constriction to induce HF in male mice, and once the ejection fraction (EF) reached ~30%, one group of animals was sacrificed (HF), and the other group received 17b-estradiol via a subcutaneous pellet implant (0.012mg/pellet, n=16) (E2) for 10 days. Sham-operated mice served as CTRL. Serial echocardiography was performed to monitor cardiac structure and function. Short-term E2 treatment rescued pressure overload-induced decompensated HF in mice by restoring the EF from 33.17±1.12% to 53.05±1.29 (p <0.001, n=16). E2 decreased both interstitial and perivascular fibrosis in HF. Microarray analysis comparing HF with E2 revealed ~70 microRNAs including miR129 regulated by E2. qPCR validation revealed that E2 treatment upregulates miR129 by 2 folds compared to HF restoring it to CTRL levels. Treatment of HF with ERβ agonist (DPN), but not ERα agonist (PPT) resulted in the upregulation of miR129 indicating the E2 mediated induction of miR129 is mediated through ERβ. In vitro, angiotensin II treatment significantly downregulated miR129 expression in neonatal rat fibroblasts (NRVF) which was restored by E2 and DPN but not by E2+ERβ antagonist (PHPT) further confirming the role of ERβ in regulating miR129. In vitro, OE of miR129 in both neonatal and adult rat cardiac fibroblasts (ARVF) resulted in significant downregulation of transcripts of many in-silico predicted pro-fibrotic target genes including EGFR, RUNX, GREM1, COL2A, PDGFA, PDGFRA and the transcription factor SOX4. OE of miR129 in fibroblasts also resulted in downregulation of EGFR protein. Gain of miR129 prevented the transition of fibroblasts to myofibroblasts in both NRVF and ARVF and inhibited fibroblast proliferation in vitro. In conclusion, E2 treatment during HF induces miR129 likely through ERβ. MiR129 represses fibrosis by targeting key genes associated with cardiac fibrosis, inhibits fibroblast proliferation and fibroblast to myofibroblast transition.

First Fluorescent Acetylspermidine Deacetylation Assay for HDAC10 Identifies Inhibitors of Neuroblastoma Cell Colony Growth That Increase Lysosome Accumulation

2020 ◽  
Author(s):  
Daniel Herp ◽  
Johannes Ridinger ◽  
Dina Robaa ◽  
Stephen A. Shinsky ◽  
Karin Schmidtkunz ◽  
...  
Keyword(s):  
Histone Deacetylases ◽  
High Throughput Screening ◽  
Neuroblastoma Cell ◽  
Hdac Inhibitors ◽  
Anticancer Therapy ◽  
Colony Growth ◽  
Autophagic Flux ◽  
Enzymatic Conversion ◽  
Lysine Deacetylase

Histone deacetylases (HDACs) are important epigenetic regulators involved in many diseases, esp. cancer. First HDAC inhibitors have been approved for anticancer therapy and many are in clinical trials. Among the 11 zinc-dependent HDACs, HDAC10 has received relatively little attention by drug discovery campaigns, despite its involvement e.g. in the pathogenesis of neuroblastoma. This is due in part to a lack of robust enzymatic conversion assays. In contrast to the protein lysine deacetylase and deacylase activity of the other HDAC subtypes, it has recently been shown that HDAC10 has strong preferences for deacetylation of oligoamine substrates like spermine or spermidine. Hence, it also termed a polyamine deacetylase (PDAC). Here, we present the first fluorescent enzymatic conversion assay for HDAC10 using an aminocoumarin labelled acetyl spermidine derivative to measure its PDAC activity, which is suitable for high-throughput screening. Using this assay, we identified potent inhibitors of HDAC10 mediated spermidine deacetylation in-vitro. Among those are potent inhibitors of neuroblastoma colony growth in culture that show accumulation of lysosomes, implicating disturbance of autophagic flux.

scholarly journals Up-Regulating Relaxin Expression by G-Quadruplex Interactive Ligand to Achieve Antifibrotic Action

Endocrinology ◽  
2012 ◽  
Vol 153 (8) ◽  
pp. 3692-3700 ◽  
Author(s):  
Hui-Ping Gu ◽  
Sen Lin ◽  
Ming Xu ◽  
Hai-Yi Yu ◽  
Xiao-Jun Du ◽  
...  
Keyword(s):  
Rna Polymerase Ii ◽  
Cardiac Fibrosis ◽  
Cardiac Fibroblasts ◽  
Heart Diseases ◽  
Gene Promoter ◽  
Binding Motif ◽  
Endogenous Expression ◽  
G Quadruplex

Myocardial fibrosis is a key pathological change in a variety of heart diseases contributing to the development of heart failure, arrhythmias, and sudden death. Recent studies have shown that relaxin prevents and reverses cardiac fibrosis. Endogenous expression of relaxin was elevated in the setting of heart disease; the extent of such up-regulation, however, is insufficient to exert compensatory actions, and the mechanism regulating relaxin expression is poorly defined. In the rat relaxin-1 (RLN1, Chr1) gene promoter region we found presence of repeated guanine (G)-rich sequences, which allowed formation and stabilization of G-quadruplexes with the addition of a G-quadruplex interactive ligand berberine. The G-rich sequences and the G-quadruplexes were localized adjacent to the binding motif of signal transducer and activator of transcription (STAT)3, which negatively regulates relaxin expression. Thus, we hypothesized that the formation and stabilization of G-quadruplexes by berberine could influence relaxin expression. We found that berberine-induced formation of G-quadruplexes did increase relaxin gene expression measured at mRNA and protein levels. Formation of G-quadruplexes significantly reduced STAT3 binding to the promoter of relaxin gene. This was associated with consequent increase in the binding of RNA polymerase II and STAT5a to relaxin gene promoter. In cardiac fibroblasts and rats treated with angiotensin II, berberine was found to suppress fibroblast activation, collagen synthesis, and extent of cardiac fibrosis through up-regulating relaxin. The antifibrotic action of berberine in vitro and in vivo was similar to that by exogenous relaxin. Our findings document a novel therapeutic strategy for fibrosis through up-regulating expression of endogenous relaxin.

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