scholarly journals Epigenetic Targeting of Histone Deacetylases in Diagnostics and Treatment of Depression

2021 ◽  
Vol 22 (10) ◽  
pp. 5398
Author(s):  
Hyun-Sun Park ◽  
Jongmin Kim ◽  
Seong Hoon Ahn ◽  
Hong-Yeoul Ryu
Keyword(s):  
Histone Acetylation ◽  
Histone Deacetylases ◽  
Therapeutic Potential ◽  
Hdac Inhibitors ◽  
Diagnostic Biomarker ◽  
Acetylation Status ◽  
Treatment Of Depression ◽  
Current Therapies ◽  
Pharmacological Regulation ◽  
Clinical Strategy

Depression is a highly prevalent, disabling, and often chronic illness that places substantial burdens on patients, families, healthcare systems, and the economy. A substantial minority of patients are unresponsive to current therapies, so there is an urgent need to develop more broadly effective, accessible, and tolerable therapies. Pharmacological regulation of histone acetylation level has been investigated as one potential clinical strategy. Histone acetylation status is considered a potential diagnostic biomarker for depression, while inhibitors of histone deacetylases (HDACs) have garnered interest as novel therapeutics. This review describes recent advances in our knowledge of histone acetylation status in depression and the therapeutic potential of HDAC inhibitors.

NEW AND EMERGING HDAC INHIBITORS FOR THE TREATMENT OF DISEASES

INDIAN DRUGS ◽  
2014 ◽  
Vol 51 (06) ◽  
pp. 5-15
Author(s):  
S.S Mahajan ◽  
◽  
A Chavan
Keyword(s):  
Lupus Erythematosus ◽  
Histone Deacetylases ◽  
Therapeutic Potential ◽  
Cell Lymphoma ◽  
Human Cancer ◽  
Trichostatin A ◽  
Hdac Inhibitors ◽  
New Strategy ◽  
Us Fda

Histone deacetylases (HDACs) are critical in regulating gene expression and transcription. They also play a fundamental role in regulating cellular activities such as cell proliferation, survival and differentiation. Inhibition of histone deacetylases has generated many fascinating results including a new strategy in human cancer therapy. Suberoylanilide hydroxamic acid (SAHA) and romidepsin are the two drugs approved by US FDA for the treatment of cutaneous T-cell lymphoma. The HDAC inhibitors (HDACIs) like trichostatin A and SAHA are also emerging as new promising drugs for various conditions like rheumatoid arthritis, colitis, systemic lupus erythematosus and CNS disorders. This review, along with chemical classification of HDACIs, emphasizes on the therapeutic potential of various HDACIs against different diseases.

scholarly journals Targeting Histone Deacetylases: A Novel Approach in Parkinson’s Disease

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Sorabh Sharma ◽  
Rajeev Taliyan
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Transcriptional Activation ◽  
Histone Deacetylases ◽  
Therapeutic Potential ◽  
Hdac Inhibitors ◽  
Clinical Manifestations ◽  
Future Research

The worldwide prevalence of movement disorders is increasing day by day. Parkinson’s disease (PD) is the most common movement disorder. In general, the clinical manifestations of PD result from dysfunction of the basal ganglia. Although the exact underlying mechanisms leading to neural cell death in this disease remains unknown, the genetic causes are often established. Indeed, it is becoming increasingly evident that chromatin acetylation status can be impaired during the neurological disease conditions. The acetylation and deacetylation of histone proteins are carried out by opposing actions of histone acetyltransferases (HATs) and histone deacetylases (HDACs), respectively. In the recent past, studies with HDAC inhibitors result in beneficial effects in bothin vivoandin vitromodels of PD. Various clinical trials have also been initiated to investigate the possible therapeutic potential of HDAC inhibitors in patients suffering from PD. The possible mechanisms assigned for these neuroprotective actions of HDAC inhibitors involve transcriptional activation of neuronal survival genes and maintenance of histone acetylation homeostasis, both of which have been shown to be dysregulated in PD. In this review, the authors have discussed the putative role of HDAC inhibitors in PD and associated abnormalities and suggest new directions for future research in PD.

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 HDAC Inhibitors: Therapeutic Potential in Fibrosis-Associated Human Diseases

2019 ◽  
Vol 20 (6) ◽  
pp. 1329 ◽  
Author(s):  
Somy Yoon ◽  
Gaeun Kang ◽  
Gwang Eom
Keyword(s):  
Extracellular Matrix ◽  
Animal Models ◽  
Histone Deacetylases ◽  
Cardiac Fibrosis ◽  
Therapeutic Potential ◽  
Hdac Inhibitors ◽  
Human Diseases ◽  
Normal Organ ◽  
Surgical Failure ◽  
Functional Relevance

Fibrosis is characterized by excessive deposition of the extracellular matrix and develops because of fibroblast differentiation during the process of inflammation. Various cytokines stimulate resident fibroblasts, which differentiate into myofibroblasts. Myofibroblasts actively synthesize an excessive amount of extracellular matrix, which indicates pathologic fibrosis. Although initial fibrosis is a physiologic response, the accumulated fibrous material causes failure of normal organ function. Cardiac fibrosis interferes with proper diastole, whereas pulmonary fibrosis results in chronic hypoxia; liver cirrhosis induces portal hypertension, and overgrowth of fibroblasts in the conjunctiva is a major cause of glaucoma surgical failure. Recently, several reports have clearly demonstrated the functional relevance of certain types of histone deacetylases (HDACs) in various kinds of fibrosis and the successful alleviation of the condition in animal models using HDAC inhibitors. In this review, we discuss the therapeutic potential of HDAC inhibitors in fibrosis-associated human diseases using results obtained from animal models.

Trichostatin A inducesTrypanosoma cruzihistone and tubulin acetylation: effects on cell division and microtubule cytoskeleton remodelling

Parasitology ◽  
2018 ◽  
Vol 146 (4) ◽  
pp. 543-552 ◽  
Author(s):  
Jean de Oliveira Santos ◽  
Aline Araujo Zuma ◽  
Francisca Nathalia de Luna Vitorino ◽  
Julia Pinheiro Chagas da Cunha ◽  
Wanderley de Souza ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Histone Acetylation ◽  
Histone Deacetylases ◽  
Cell Biology ◽  
Trichostatin A ◽  
Hdac Inhibitors ◽  
Health Concern ◽  
Microtubule Cytoskeleton ◽  
Chromatin Compaction ◽  
Tubulin Acetylation

AbstractTrypanosoma cruzi, the causative agent of Chagas disease, is a public health concern in Latin America. Epigenetic events, such as histone acetylation, affect DNA topology, replication and gene expression. Histone deacetylases (HDACs) are involved in chromatin compaction and post-translational modifications of cytoplasmic proteins, such as tubulin. HDAC inhibitors, like trichostatin A (TSA), inhibit tumour cell proliferation and promotes ultrastructural modifications. In the present study, TSA effects on cell proliferation, viability, cell cycle and ultrastructure were evaluated, as well as on histone acetylation and tubulin expression of theT. cruziepimastigote form. Protozoa proliferation and viability were reduced after treatment with TSA. Quantitative proteomic analyses revealed an increase in histone acetylation after 72 h of TSA treatment. Surprisingly, results obtained by different microscopy methodologies indicate that TSA does not affect chromatin compaction, but alters microtubule cytoskeleton dynamics and impair kDNA segregation, generating polynucleated cells with atypical morphology. Confocal fluorescence microscopy and flow cytometry assays indicated that treated cell microtubules were more intensely acetylated. Increases in tubulin acetylation may be directly related to the higher number of parasites in the G2/M phase after TSA treatment. Taken together, these results suggest that deacetylase inhibitors represent excellent tools for understanding trypanosomatid cell biology.

scholarly journals Induction of histone deacetylases (HDACs) in human abdominal aortic aneurysm: therapeutic potential of HDAC inhibitors

2016 ◽  
Vol 9 (5) ◽  
pp. 541-552 ◽  
Author(s):  
María Galán ◽  
Saray Varona ◽  
Mar Orriols ◽  
José Antonio Rodríguez ◽  
Silvia Aguiló ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Histone Deacetylases ◽  
Therapeutic Potential ◽  
Hdac Inhibitors ◽  
Abdominal Aortic

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.

An Overview of HDAC Inhibitors and their Synthetic Routes

2019 ◽  
Vol 19 (12) ◽  
pp. 1005-1040 ◽  
Author(s):  
Xiaopeng Peng ◽  
Guochao Liao ◽  
Pinghua Sun ◽  
Zhiqiang Yu ◽  
Jianjun Chen
Keyword(s):  
Histone Acetylation ◽  
Histone Deacetylases ◽  
Histone Deacetylase Inhibitors ◽  
Cell Cycle Control ◽  
Hdac Inhibitors ◽  
Cancer Therapeutics ◽  
Cellular Processes ◽  
Chaperone Function ◽  
Damage Repair ◽  
Synthetic Routes

Epigenetics play a key role in the origin, development and metastasis of cancer. Epigenetic processes include DNA methylation, histone acetylation, histone methylation, and histone phosphorylation, among which, histone acetylation is the most common one that plays important roles in the regulation of normal cellular processes, and is controlled by histone deacetylases (HDACs) and histone acetyltransferases (HATs). HDACs are involved in the regulation of many key cellular processes, such as DNA damage repair, cell cycle control, autophagy, metabolism, senescence and chaperone function, and can lead to oncogene activation. As a result, HDACs are considered to be an excellent target for anti-cancer therapeutics like histone deacetylase inhibitors (HDACi) which have attracted much attention in the last decade. A wide-ranging knowledge of the role of HDACs in tumorigenesis, and of the action of HDACi, has been achieved. The primary purpose of this paper is to summarize recent HDAC inhibitors and the synthetic routes as well as to discuss the direction for the future development of new HDAC inhibitors.

scholarly journals A Comparative Study of Target Engagement Assays for HDAC1 Inhibitor Profiling

2019 ◽  
Vol 25 (3) ◽  
pp. 253-264
Author(s):  
Rosita R. Asawa ◽  
Alexey Zakharov ◽  
Taylor Niehoff ◽  
Ata Chitsaz ◽  
Ajit Jadhav ◽  
...  
Keyword(s):  
High Throughput ◽  
Histone Deacetylases ◽  
Therapeutic Potential ◽  
Hdac Inhibitors ◽  
Therapeutic Action ◽  
Target Engagement ◽  
Cell Type ◽  
Cellular Environment ◽  
Highly Sensitive ◽  
Cell Type Specific

Histone deacetylases (HDACs) are epigenetic modulators linked to diseases including cancer and neurodegeneration. Given their therapeutic potential, highly sensitive biochemical and cell-based profiling technologies have been developed to discover small-molecule HDAC inhibitors. Ultimately, the therapeutic action of these inhibitors is dependent on a physical engagement with their intended targets in cellular and tissue environments. Confirming target engagement in the cellular environment is particularly relevant for HDACs since they function as part of cell type-specific multiprotein complexes. Here we implemented two recently developed high-throughput target engagement technologies, NanoBRET and SplitLuc CETSA, to profile 349 compounds in the Epigenetic-Focused collection for HDAC1 binding. We found that the two HDAC1 target engagement assays correlated well with each other and with orthogonal activity-based assays, in particular those carried out in cellular environments rather than with isolated HDAC proteins. The assays detected a majority of the previously described HDAC1 inhibitors in the collection and, importantly, triaged HDAC inhibitors known to target other HDACs.

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