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.

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.

scholarly journals Viewpoint: Mechanisms of Action and Therapeutic Potential of Neurohormetic Phytochemicals

Dose-Response ◽  
2007 ◽  
Vol 5 (3) ◽  
pp. dose-response.0 ◽  
Author(s):  
Mark. P. Mattson ◽  
Tae Gen Son ◽  
Simonetta Camandola
Keyword(s):  
Animal Models ◽  
Neurodegenerative Disorders ◽  
Histone Deacetylases ◽  
Therapeutic Potential ◽  
Antioxidant Properties ◽  
Disease Process ◽  
Antioxidant Response ◽  
Mechanisms Of Action ◽  
Cellular Stress Response ◽  
Vegetables And Fruits

The nervous system is of fundamental importance in the adaptive (hormesis) responses of organisms to all types of stress, including environmental “toxins”. Phytochemicals present in vegetables and fruits are believed to reduce the risk of several major diseases including cardiovascular disease, cancers and neurodegenerative disorders. Although antioxidant properties have been suggested as the basis of health benefits of phytochemicals, emerging findings suggest a quite different mechanism of action. Many phytochemicals normally function as toxins that protect the plants against insects and other damaging organisms. However, at the relatively low doses consumed by humans and other mammals these same “toxic” phytochemicals activate adaptive cellular stress response pathways that can protect the cells against a variety of adverse conditions. Recent findings have elucidated hormetic mechanisms of action of phytochemicals (e.g., resveratrol, curcumin, sulforaphanes and catechins) using cell culture and animal models of neurological disorders. Examples of hormesis pathways activated by phytochemicals include the transcription factor Nrf-2 which activates genes controlled by the antioxidant response element, and histone deacetylases of the sirtuin family and FOXO transcription factors. Such hormetic pathways stimulate the production of antioxidant enzymes, protein chaperones and neurotrophic factors. In several cases neurohormetic phytochemicals have been shown to suppress the disease process in animal models relevant to neurodegenerative disorders such as Alzheimer's and Parkinson's diseaess, and can also improve outcome following a stroke. We are currently screening a panel of biopesticides in order to establish hormetic doses, neuroprotective efficacy, mechanisms of action and therapeutic potential as dietary supplements.

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.

scholarly journals Regulation of Chemokines and Cytokines by Histone Deacetylases and an Update on Histone Decetylase Inhibitors in Human Diseases

2019 ◽  
Vol 20 (5) ◽  
pp. 1110 ◽  
Author(s):  
Himavanth Gatla ◽  
Nethaji Muniraj ◽  
Prashanth Thevkar ◽  
Siddhartha Yavvari ◽  
Sahithi Sukhavasi ◽  
...  
Keyword(s):  
Histone Deacetylases ◽  
Viral Infections ◽  
Kidney Diseases ◽  
Hdac Inhibitors ◽  
Cardiovascular Complications ◽  
Human Diseases ◽  
Wide Range ◽  
Hematological Cancers ◽  
Anti Tumor Activity

Histone acetyltransferases (HATs) and histone deacetylases (HDACs) counteract with each other to regulate gene expression by altering chromatin structure. Aberrant HDAC activity was reported in many human diseases including wide range of cancers, viral infections, cardiovascular complications, auto-immune diseases and kidney diseases. HDAC inhibitors are small molecules designed to block the malignant activity of HDACs. Chemokines and cytokines control inflammation, immunological and other key biological processes and are shown to be involved in various malignancies. Various HDACs and HDAC inhibitors were reported to regulate chemokines and cytokines. Even though HDAC inhibitors have remarkable anti-tumor activity in hematological cancers, they are not effective in treating many diseases and many patients relapse after treatment. However, the role of HDACs and cytokines in regulating these diseases still remain unclear. Therefore, understanding exact mechanisms and effector functions of HDACs are urgently needed to selectively inhibit them and to establish better a platform to combat various malignancies. In this review, we address regulation of chemokines and cytokines by HDACs and HDAC inhibitors and update on HDAC inhibitors in human diseases.

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.

scholarly journals Cardiac Fibroblast to Myofibroblast Phenotype Conversion—An Unexploited Therapeutic Target

2019 ◽  
Vol 6 (3) ◽  
pp. 28 ◽  
Author(s):  
Czubryt
Keyword(s):  
Extracellular Matrix ◽  
Cardiac Fibrosis ◽  
Therapeutic Potential ◽  
Contractile Activity ◽  
Cardiac Fibroblasts ◽  
Critical Event ◽  
Organ Function ◽  
Myofibroblast Phenotype ◽  
Extracellular Matrix Components ◽  
Contraction And Relaxation

Fibrosis occurs when the synthesis of extracellular matrix outpaces its degradation, and over time can negatively impact tissue and organ function. In the case of cardiac fibrosis, contraction and relaxation of the heart can be impaired to the point of precipitating heart failure, while at the same time fibrosis can result in arrhythmias due to altered electrical properties of the myocardium. The critical event in the evolution of cardiac fibrosis is the phenotype conversion of cardiac fibroblasts to their overly-active counterparts, myofibroblasts: cells demarked by their expression of novel markers such as periostin, by their gain of contractile activity, and by their pronounced and prolonged increase in the production of extracellular matrix components such as collagens. The phenotype change is dramatic, and can be triggered by many stimuli, including mechanical force, inflammatory cytokines, and growth factors. This review will explore fibroblast to myofibroblast transition mechanisms and will consider the therapeutic potential of targeting this process as a means to arrest or even reverse cardiac fibrosis.

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 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.

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.

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