scholarly journals NF-κB balances vascular regression and angiogenesis via chromatin remodeling and NFAT displacement

Blood ◽  
2010 ◽  
Vol 116 (3) ◽  
pp. 475-484 ◽  
Author(s):  
Arin B. Aurora ◽  
Dauren Biyashev ◽  
Yelena Mirochnik ◽  
Tetiana A. Zaichuk ◽  
Cristina Sánchez-Martinez ◽  
...  
Keyword(s):  
Histone Acetylation ◽  
Hdac Inhibitors ◽  
Nuclear Factor Κb ◽  
Angiogenic Switch ◽  
Histone Deacetylase 1 ◽  
Angiogenic Balance ◽  
Biphasic Effect ◽  
Apoptotic Pathways

Abstract Extracellular factors control the angiogenic switch in endothelial cells (ECs) via competing survival and apoptotic pathways. Previously, we showed that proangiogenic and antiangiogenic factors target the same signaling molecules, which thereby become pivots of angiogenic balance. Here we show that in remodeling endothelium (ECs and EC precursors) natural angiogenic inhibitors enhance nuclear factor-κB (NF-κB) DNA binding, which is critical for antiangiogenesis, and that blocking the NF-κB pathway abolishes multiple antiangiogenic events in vitro and in vivo. NF-κB induction by antiangiogenic molecules has a dual effect on transcription. NF-κB acts as an activator of proapoptotic FasL and as a repressor of prosurvival cFLIP. On the FasL promoter, NF-κB increases the recruitment of HAT p300 and acetylated histones H3 and H4. Conversely, on cFLIP promoter, NF-κB increases histone deacetylase 1 (HDAC1), decreases p300 and histone acetylation, and reduces the recruitment of NFAT, a transcription factor critical for cFLIP expression. Finally, we found a biphasic effect, when HDAC inhibitors (HDACi) were used to test the dependence of pigment epithelial-derived factor activity on histone acetylation. The cooperative effect seen at low doses switches to antagonistic as the concentrations increase. Our study defines an interactive transcriptional network underlying angiogenic balance and points to HDACi as tools to manipulate the angiogenic switch.

Modulation of granulocyte apoptosis can influence the resolution of inflammation

2007 ◽  
Vol 35 (2) ◽  
pp. 288-291 ◽  
Author(s):  
A.G. Rossi ◽  
J.M. Hallett ◽  
D.A. Sawatzky ◽  
M.M. Teixeira ◽  
C. Haslett
Keyword(s):  
Kinase Inhibitor ◽  
Nuclear Factor Κb ◽  
Mitogen Activated Protein Kinase ◽  
Apoptotic Cells ◽  
Resolution Of Inflammation ◽  
Mitogen Activated Protein ◽  
Apoptotic Pathways ◽  
Phosphoinositide 3 Kinase

Apoptosis of granulocytes and the subsequent clearance of apoptotic cells are important processes for the successful resolution of inflammation. Signalling pathways, including those involving NF-κB (nuclear factor κB), MAPK (mitogen-activated protein kinase) and PI3K (phosphoinositide 3-kinase) have been shown to be key regulators of inflammatory cell survival and apoptosis in vitro. In addition, manipulation of such pathways in vivo has indicated that they also play a role in the resolution of inflammation. Furthermore, manipulation of proteins directly involved in the control of apoptosis, such as Bcl-2 family members and caspases, can be targeted in vivo to influence inflammatory resolution. Recently, it has been shown that CDK (cyclin-dependent kinase) inhibitor drugs induce caspase-dependent human neutrophil apoptosis possibly by altering levels of the anti-apoptotic Bcl-2 family member, Mcl-1. Importantly, CDK inhibitor drugs augment the resolution of established ‘neutrophil-dominant’ inflammation by promoting apoptosis of neutrophils. Thus manipulation of apoptotic pathways, together with ensuring macrophage clearance of apoptotic cells, appears to be a viable pharmacological target for reducing established inflammation.

scholarly journals Differential regulation of DNA methylation versus histone acetylation in cardiomyocytes during HHcy in vitro and in vivo: an epigenetic mechanism

2014 ◽  
Vol 46 (7) ◽  
pp. 245-255 ◽  
Author(s):  
Pankaj Chaturvedi ◽  
Anuradha Kalani ◽  
Srikanth Givvimani ◽  
Pradip Kumar Kamat ◽  
Anastasia Familtseva ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Histone Acetylation ◽  
Dna Methyltransferase ◽  
Epigenetic Mechanism ◽  
Dependent Manner ◽  
Histone Deacetylase 1 ◽  
H3k9 Acetylation ◽  
Dose Dependent

The mechanisms of homocysteine-mediated cardiac threats are poorly understood. Homocysteine, being the precursor to S-adenosyl methionine (a methyl donor) through methionine, is indirectly involved in methylation phenomena for DNA, RNA, and protein. We reported previously that cardiac-specific deletion of N-methyl-d-aspartate receptor-1 (NMDAR1) ameliorates homocysteine-posed cardiac threats, and in this study, we aim to explore the role of NMDAR1 in epigenetic mechanisms of heart failure, using cardiomyocytes during hyperhomocysteinemia (HHcy). High homocysteine levels activate NMDAR1, which consequently leads to abnormal DNA methylation vs. histone acetylation through modulation of DNA methyltransferase 1 (DNMT1), HDAC1, miRNAs, and MMP9 in cardiomyocytes. HL-1 cardiomyocytes cultured in Claycomb media were treated with 100 μM homocysteine in a dose-dependent manner. NMDAR1 antagonist (MK801) was added in the absence and presence of homocysteine at 10 μM in a dose-dependent manner. The expression of DNMT1, histone deacetylase 1 (HDAC1), NMDAR1, microRNA (miR)-133a, and miR-499 was assessed by real-time PCR as well as Western blotting. Methylation and acetylation levels were determined by checking 5′-methylcytosine DNA methylation and chromatin immunoprecipitation. Hyperhomocysteinemic mouse models (CBS+/−) were used to confirm the results in vivo. In HHcy, the expression of NMDAR1, DNMT1, and matrix metalloproteinase 9 increased with increase in H3K9 acetylation, while HDAC1, miR-133a, and miR-499 decreased in cardiomyocytes. Similar results were obtained in heart tissue of CBS+/− mouse. High homocysteine levels instigate cardiovascular remodeling through NMDAR1, miR-133a, miR-499, and DNMT1. A decrease in HDAC1 and an increase in H3K9 acetylation and DNA methylation are suggestive of chromatin remodeling in HHcy.

Epigenetics in Neurodegenerative Diseases: The Role of Histone Deacetylases

2019 ◽  
Vol 18 (1) ◽  
pp. 11-18 ◽  
Author(s):  
Sorabh Sharma ◽  
K.C. Sarathlal ◽  
Rajeev Taliyan
Keyword(s):  
Neurodegenerative Diseases ◽  
Histone Acetylation ◽  
Histone Deacetylases ◽  
Hdac Inhibitors ◽  
Beneficial Effects ◽  
In Vivo Animal Models ◽  
Preclinical And Clinical Studies

Background & Objective: Imbalance in histone acetylation levels and consequently the dysfunction in transcription are associated with a wide variety of neurodegenerative diseases. Histone proteins acetylation and deacetylation is carried out by two opposite acting enzymes, histone acetyltransferases and histone deacetylases (HDACs), respectively. In-vitro and in-vivo animal models of neurodegenerative diseases and post mortem brains of patients have been reported overexpressed level of HDACs. In recent past numerous studies have indicated that HDAC inhibitors (HDACIs) might be a promising class of therapeutic agents for treating these devastating diseases. HDACs being a part of repressive complexes, the outcome of their inhibition has been attributed to enhanced gene expression due to heightened histone acetylation. Beneficial effects of HDACIs has been explored both in preclinical and clinical studies of these diseases. Thus, their screening as future therapeutics for neurodegenerative diseases has been widely explored. Conclusion: In this review, we focus on the putative role of HDACs in neurodegeneration and further discuss their potential as a new therapeutic avenue for treating neurodegenerative diseases.

scholarly journals The capability of reprogramming the male chromatin after fertilization is dependent on the quality of oocyte maturation

Reproduction ◽  
2005 ◽  
Vol 130 (1) ◽  
pp. 29-39 ◽  
Author(s):  
Luisa Gioia ◽  
Barbara Barboni ◽  
Maura Turriani ◽  
Giulia Capacchietti ◽  
Maria Gabriella Pistilli ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Histone Acetylation ◽  
Hdac Inhibitors ◽  
Germinal Vesicle ◽  
Fertilization Rate ◽  
Sperm Nucleus ◽  
Sperm Chromatin ◽  
Germinal Vesicle Breakdown

The present experiments compared the ability of pig oocytes matured eitherin vivoorin vitroto structurally reorganize the penetrated sperm chromatin into male pronucleus (PN) and to carry out, in parallel, the epigenetic processes of global chromatin methylation and acetylation, 12–14 h afterin vitrofertilization (IVF). In addition, PN distribution of histone deacetylase (HDAC), a major enzyme interfacing DNA methylation and histone acetylation, was investigated. The ability of the oocyte to operate an efficient block to polyspermy was markedly affected by maturation. The monospermic fertilization rate was significantly higher forin vivothan forin vitromatured (IVM) oocytes(P< 0.01) which, furthermore, showed a reduced ability to transform the chromatin of penetrated sperm into male PN(P< 0.01). Indirect immunofluorescence analysis of global DNA methylation, histone acetylation and HDAC distribution (HDAC-1, -2 and -3), carried out in monospermic zygotes that reached the late PN stage, showed that IVM oocytes also had a reduced epigenetic competence. In fact, while in about 80% ofin vivomatured and IVF oocytes the male PN underwent a process of active demethylation and showed a condition of histone H4 hyperacetylation, only 40% of IVM/IVF zygotes displayed a similar PN remodelling asymmetry. Oocytes that carried out the first part of maturationin vivo(up to germinal vesicle breakdown; GVBD) and then completed the processin vitro, displayed the same PN asymmetry as oocytes matured entirelyin vivo. A crucial role of HDAC in the establishment of PN acetylation asymmetry seems to be confirmed by the use of HDAC inhibitors as well as by the abnormal distribution of the enzyme between the two PN in IVM zygotes. Collectively, these data demonstrated that some pig IVM oocytes fail to acquire full remodelling competence which is independent from their ooplasmic ability to morphologically reorganize the sperm nucleus into PN.

scholarly journals HDAC inhibitors as antifibrotic drugs in cardiac and pulmonary fibrosis

2019 ◽  
Vol 10 ◽  
pp. 204062231986269 ◽  
Author(s):  
Xing Lyu ◽  
Min Hu ◽  
Jieting Peng ◽  
Xiangyu Zhang ◽  
Yan Y Sanders
Keyword(s):  
Pulmonary Fibrosis ◽  
Histone Acetylation ◽  
Histone Deacetylases ◽  
Wound Repair ◽  
Hdac Inhibitors ◽  
Scar Tissue ◽  
Nonhistone Proteins ◽  
Fibrotic Diseases

Fibrosis usually results from dysregulated wound repair and is characterized by excessive scar tissue. It is a complex process with unclear mechanisms. Accumulating evidence indicates that epigenetic alterations, including histone acetylation, play a pivotal role in this process. Histone acetylation is governed by histone acetyltransferases (HATs) and histone deacetylases (HDACs). HDACs are enzymes that remove the acetyl groups from both histone and nonhistone proteins. Aberrant HDAC activities are observed in fibrotic diseases, including cardiac and pulmonary fibrosis. HDAC inhibitors (HDACIs) are molecules that block HDAC functions. HDACIs have been studied extensively in a variety of tumors. Currently, there are four HDACIs approved by the US Food and Drug Administration for cancer treatment yet none for fibrotic diseases. Emerging evidence from in vitro and in vivo preclinical studies has presented beneficial effects of HDACIs in preventing or reversing fibrogenesis. In this review, we summarize the latest findings of the roles of HDACs in the pathogenesis of cardiac and pulmonary fibrosis and highlight the potential applications of HDACIs in these two fibrotic diseases.

Inhibition of Histone Deacetylation: A Strategy for Tumor Radiosensitization

2007 ◽  
Vol 25 (26) ◽  
pp. 4051-4056 ◽  
Author(s):  
Kevin Camphausen ◽  
Philip J. Tofilon
Keyword(s):  
Histone Acetylation ◽  
Histone Deacetylases ◽  
Hdac Inhibitors ◽  
Human Tumor ◽  
Chemotherapeutic Agents ◽  
Histone Deacetylation ◽  
Hdac Activity ◽  
Two Parameters

Recently, strategies to enhance tumor radiosensitivity have begun to focus on targeting the molecules and processes that regulate cellular radioresponse. A molecular target that has begun to receive considerable attention is histone acetylation. Histone acetylation is determined by the dynamic interaction of two families of enzymes: histone acetylases and histone deacetylases (HDACs). Histone acetylation plays a role in regulating chromatin structure and gene expression—two parameters that have long been considered determinants of radioresponse. As a means of modifying histone acetylation status, considerable effort has been put into the development of inhibitors of HDAC activity. This has led to the generation of a relatively large number of structurally diverse compounds that can inhibit HDAC activity resulting in histone hyperacetylation. Many of the newer HDAC inhibitor compounds have been designed with better bioavailability or pharmacology than the first-generation compounds. Whereas a number of these second-generation HDAC inhibitors have antitumor activity in preclinical cancer models when delivered as single agents, early clinical data demonstrate only cytostasis when used as monotherapy. However, recent preclinical studies have indicated that HDAC inhibitors from structurally diverse classes can enhance both the in vitro and in vivo radiosensitivity of human tumor cell lines generated from a spectrum of solid tumors. HDAC inhibitors are in clinical trials as single modalities, in combination with chemotherapeutic agents, and recently, in combination with radiotherapy.

Largazole, a Novel Cyclic Peptide Histone Deacetylase Inhibitor, Demonstrates Anti-MM Effects Alone and Increases the Anti-MM Effects of Bortezomib.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4925-4925
Author(s):  
Zhi-Wei Li ◽  
Mengyin Hu ◽  
Crystal Leung ◽  
Jeffrey A Steinberg ◽  
Jing Shen ◽  
...  
Keyword(s):  
Histone Acetylation ◽  
Histone Deacetylase ◽  
Cell Lines ◽  
Cyclic Peptide ◽  
Hdac Inhibitors ◽  
In Vitro Studies ◽  
Normal Peripheral Blood ◽  
Anti Cancer

Abstract Abstract 4925 Multiple myeloma (MM) remains an incurable malignancy. Therefore, there is a need for the development of new agents to improve the survival for these patients. Histone acetylation, which is controlled by the balanced activities between histone acetyltransferase (HAT) and histone deacetylase (HDAC), is a major epigenetic modification that contributes to tumorigenesis. Through inhibition of HDAC activity, HDAC inhibitors (HDACis) increase acetylation levels of histones as well as other tumor suppressor gene products; and, therefore, are potential anti-cancer agents. Based on the structures, currently available HDAC inhibitors can be divided into four groups, including hydroxamates, cyclic peptides, aliphatic acids, and benzamides. Largazole is a novel member of the cyclic peptide family of HDACis some of which have shown anti-cancer effects in preclinical studies and early clinical trials including for patients with MM especially when used in combination with the proteasome inhibitor bortezomib. In this study, we have explored the potential anti-MM activity of largazole alone and in combination with bortezomib in preclinical in vitro studies. As demonstrated using the MTS assay, this HDACi inhibits the growth of cells from the MM cell lines RPMI8226, U266 and MM1S with an IC50 of approximately 0.2 μM in all three cell lines. In addition, largazole also induces apoptotic death of MM cells as determined with Annexin V staining followed by flow cytometric analysis. Largazole was also shown to induce histone acetylation in MM cells as determined with Western blot analysis using an antibody against acetyl-histone H4. Furthermore, the combination of this HDACi and bortezomib demonstrated synergistic anti-MM effects in these cell lines. Importantly, treatment of mice with largazole shows excellent tolerability at doses that produce concentrations in vivo that are higher than those shown to produce anti-MM effects in our in vitro studies. Thus, largazole may be a potential new agent for the treatment of MM alone and in combination with bortezomib. Currently, we are evaluating the cytotoxic effects of largazole on normal peripheral blood and bone marrow mononuclear cells in vitro and in vivo using our severe combined immunodeficiency mouse models of human myeloma alone as well as in combination with several other drugs including bortezomib used in the treatment of MM. Updated results from these ongoing studies will be presented at the meeting. Disclosures Berenson: Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding, Speakers Bureau.

scholarly journals Functional Interplay between Histone Demethylase and Deacetylase Enzymes

2006 ◽  
Vol 26 (17) ◽  
pp. 6395-6402 ◽  
Author(s):  
Min Gyu Lee ◽  
Christopher Wynder ◽  
Daniel A. Bochar ◽  
Mohamed-Ali Hakimi ◽  
Neil Cooch ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Anticancer Agents ◽  
Hdac Inhibitors ◽  
Ectopic Expression ◽  
Histone Demethylase ◽  
Functional Connection ◽  
Histone Deacetylase 1 ◽  
In Vivo Analysis

ABSTRACT Histone deacetylase (HDAC) inhibitors are a promising class of anticancer agents for the treatment of solid and hematological malignancies. The precise mechanism by which HDAC inhibitors mediate their effects on tumor cell growth, differentiation, and/or apoptosis is the subject of intense research. Previously we described a family of multiprotein complexes that contain histone deacetylase 1/2 (HDAC1/2) and the histone demethylase BHC110 (LSD1). Here we show that HDAC inhibitors diminish histone H3 lysine 4 (H3K4) demethylation by BHC110 in vitro. In vivo analysis revealed an increased H3K4 methylation concomitant with inhibition of nucleosomal deacetylation by HDAC inhibitors. Reconstitution of recombinant complexes revealed a functional connection between HDAC1 and BHC110 only when nucleosomal substrates were used. Importantly, while the enzymatic activity of BHC110 is required to achieve optimal deacetylation in vitro, in vivo analysis following ectopic expression of an enzymatically dead mutant of BHC110 (K661A) confirmed the functional cross talk between the demethylase and deacetylase enzymes. Our studies not only reveal an intimate link between the histone demethylase and deacetylase enzymes but also identify histone demethylation as a secondary target of HDAC inhibitors.

In-vitro- und In-vivo-Wirkung von Schilddrüsenhormon auf das Wachstum von Neuroblastomzellen

1990 ◽  
Vol 29 (03) ◽  
pp. 120-124
Author(s):  
R. P. Baum ◽  
E. Rohrbach ◽  
G. Hör ◽  
B. Kornhuber ◽  
E. Busse
Keyword(s):  
Cell Differentiation ◽  
Neuroblastoma Cells ◽  
Control Group ◽  
Initial Value ◽  
Initial Rise ◽  
Biphasic Effect ◽  
Contrast Microscopy ◽  
Morphological Sign

The effect of triiodothyronine (T3) on the differentiation of cultured neuroblastoma (NB) cells was studied after 9 days of treatment with a dose of 10-4 M/106 cells per day. Using phase contrast microscopy, 30-50% of NB cells showed formation of neurites as a morphological sign of cellular differentiation. The initial rise of the mitosis rate was followed by a plateau. Changes in cyclic nucleotide content, in the triphosphates and in the activity of the enzyme ornithine decarboxylase (ODC) were assessed in 2 human and 2 murine cell lines to serve as biochemical parameters of the cell differentiation induced by T3. Whereas the cAMP level increased significantly (3 to 7 fold compared with its initial value), the cGMP value dropped to 30 to 50% of that of the control group. ATP and GTP increased about 200%, the ODC showed a decrease of about 50%. The present studies show a biphasic effect of T3 on neuroblastoma cells: the initial rise of mitotic activity is followed by increased cell differentiation starting from day 4 of the treatment.

scholarly journals Pharmacodynamic, pharmacokinetic, and phase 1a study of bisthianostat, a novel histone deacetylase inhibitor, for the treatment of relapsed or refractory multiple myeloma

2021 ◽  
Author(s):  
Yu-bo Zhou ◽  
Yang-ming Zhang ◽  
Hong-hui Huang ◽  
Li-jing Shen ◽  
Xiao-feng Han ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Drug Targets ◽  
Single Agent ◽  
Hdac Inhibitors ◽  
Preclinical Study ◽  
Parp Cleavage ◽  
Rpmi 8226 ◽  
Ongoing Phase

AbstractHDAC inhibitors (HDACis) have been intensively studied for their roles and potential as drug targets in T-cell lymphomas and other hematologic malignancies. Bisthianostat is a novel bisthiazole-based pan-HDACi evolved from natural HDACi largazole. Here, we report the preclinical study of bisthianostat alone and in combination with bortezomib in the treatment of multiple myeloma (MM), as well as preliminary first-in-human findings from an ongoing phase 1a study. Bisthianostat dose dependently induced acetylation of tubulin and H3 and increased PARP cleavage and apoptosis in RPMI-8226 cells. In RPMI-8226 and MM.1S cell xenograft mouse models, oral administration of bisthianostat (50, 75, 100 mg·kg-1·d-1, bid) for 18 days dose dependently inhibited tumor growth. Furthermore, bisthianostat in combination with bortezomib displayed synergistic antitumor effect against RPMI-8226 and MM.1S cell in vitro and in vivo. Preclinical pharmacokinetic study showed bisthianostat was quickly absorbed with moderate oral bioavailability (F% = 16.9%–35.5%). Bisthianostat tended to distribute in blood with Vss value of 0.31 L/kg. This distribution parameter might be beneficial to treat hematologic neoplasms such as MM with few side effects. In an ongoing phase 1a study, bisthianostat treatment was well tolerated and no grade 3/4 nonhematological adverse events (AEs) had occurred together with good pharmacokinetics profiles in eight patients with relapsed or refractory MM (R/R MM). The overall single-agent efficacy was modest, stable disease (SD) was identified in four (50%) patients at the end of first dosing cycle (day 28). These preliminary in-patient results suggest that bisthianostat is a promising HDACi drug with a comparable safety window in R/R MM, supporting for its further phase 1b clinical trial in combination with traditional MM therapies.

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