Spermidine in health and disease

Science, Journal Year: 2018, Volume and Issue: 359(6374)

Published: Jan. 25, 2018

Having your longevity and eating too Although caloric restriction has clear benefits for maximizing health span life span, it is sufficiently unpleasant that few humans stick to it. Madeo et al. review evidence increased intake of the polyamine spermidine appears reproduce many healthful effects restriction, they explain its cellular actions, which include enhancement autophagy protein deacetylation. Spermidine found in foods such as wheat germ, soybeans, nuts, some fruits vegetables produced by microbiota. Increased uptake protective against cancer, metabolic disease, heart neurodegeneration. Science , this issue p. eaan2788

Language: Английский

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Thirty Years of HDAC Inhibitors: 2020 Insight and Hindsight

Journal of Medicinal Chemistry, Journal Year: 2020, Volume and Issue: 63(21), P. 12460 - 12484

Published: July 1, 2020

It is now 30 years since the first report of a potent zinc-dependent histone deacetylase (HDAC) inhibitor appeared. Since then, five HDAC inhibitors have received regulatory approval for cancer chemotherapy while many others are in clinical development oncology as well other therapeutic indications. This Perspective reviews biological and medicinal chemistry advances over past 3 decades with an emphasis on design selective that discriminate between 11 human isoforms.

Language: Английский

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A short guide to histone deacetylases including recent progress on class II enzymes

Experimental & Molecular Medicine, Journal Year: 2020, Volume and Issue: 52(2), P. 204 - 212

Published: Feb. 1, 2020

Abstract The interaction between histones and DNA is important for eukaryotic gene expression. A loose caused, example, by the neutralization of a positive charge on histone surface acetylation, induces less compact chromatin structure, resulting in feasible accessibility RNA polymerase increased In contrast, formation tight structure due to deacetylation lysine residues deacetylases enforces DNA, which minimizes chance polymerases contacting decreased Therefore, balance acetylation mediated acetylases (HATs) (HDACs) an issue transcription that has long been studied relation posttranslational modification. this review, current knowledge HDACs briefly described with emphasis recent progress research HDACs, especially class IIa HDACs.

Language: Английский

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Recent developments of HDAC inhibitors: Emerging indications and novel molecules

British Journal of Clinical Pharmacology, Journal Year: 2021, Volume and Issue: 87(12), P. 4577 - 4597

Published: May 10, 2021

The histone deacetylase (HDAC) enzymes, a class of epigenetic regulators, are historically well established as attractive therapeutic targets. During investigation trends within clinical trials, we have identified high number trials involving HDAC inhibitors, prompting us to further evaluate the current status this agents. In total, 32 agents with HDAC-inhibiting properties, which 29 were found interact enzymes their primary target. review, provide an overview drug development highlighting recent advances and analysis specific and, where applicable, chemical structures. We haematologic neoplasms continue represent majority indications for drugs; however, it is clear that there ongoing trend towards diversification. Therapies non-oncology including HIV infection, muscular dystrophies, inflammatory diseases neurodegenerative such Alzheimer's disease, frontotemporal dementia Friedreich's ataxia achieving promising progress. Combinatory regimens proving be useful improve responsiveness among FDA-approved agents; often results in increased treatment-related toxicities. This suggests indication field broadening through while several fields preclinical also promising.

Language: Английский

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Histone Deacetylases (HDACs): Evolution, Specificity, Role in Transcriptional Complexes, and Pharmacological Actionability

Genes, Journal Year: 2020, Volume and Issue: 11(5), P. 556 - 556

Published: May 15, 2020

Histone deacetylases (HDACs) are evolutionary conserved enzymes which operate by removing acetyl groups from histones and other protein regulatory factors, with functional consequences on chromatin remodeling gene expression profiles. We provide here a review the recent knowledge accrued zinc-dependent HDAC family across different species, tissues, human pathologies, specifically focusing role of inhibitors as anti-cancer agents. will investigate chemical specificity HDACs discuss their in interactome members chromatin-binding complexes.

Language: Английский

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The Roles of Histone Deacetylases and Their Inhibitors in Cancer Therapy

Frontiers in Cell and Developmental Biology, Journal Year: 2020, Volume and Issue: 8

Published: Sept. 29, 2020

Genetic mutations and abnormal gene regulation are key mechanisms underlying tumorigenesis. Nucleosomes, which consist of DNA wrapped around histone cores, represent the basic units chromatin. The fifth amino group (Nε) lysine residues is a common site for post-translational modifications (PTMs), these, acetylation second most common. Histone modulated by acetyltransferases (HATs) deacetylases (HDACs), involved in expression. Over past two decades, numerous studies characterizing HDACs HDAC inhibitors (HDACi) have provided novel exciting insights concerning their biological potential anti-cancer treatments. In this review, we detail diverse structures functions, including transcriptional regulation, metabolism, angiogenesis, damage response, cell cycle, apoptosis, protein degradation, immunity other several physiological processes. We also highlight avenues to use HDACi as novel, precision cancer

Language: Английский

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Anticancer Therapy with HDAC Inhibitors: Mechanism-Based Combination Strategies and Future Perspectives

Cancers, Journal Year: 2021, Volume and Issue: 13(4), P. 634 - 634

Published: Feb. 5, 2021

The increasing knowledge of molecular drivers tumorigenesis has fueled targeted cancer therapies based on specific inhibitors. Beyond “classic” oncogene inhibitors, epigenetic therapy is an emerging field. Epigenetic alterations can occur at any time during progression, altering the structure chromatin, accessibility for transcription factors and thus genes. They rely post-translational histone modifications, particularly acetylation lysine residues, are determined by inverse action acetyltransferases (HATs) deacetylases (HDACs). Importantly, HDACs often aberrantly overexpressed, predominantly leading to transcriptional repression tumor suppressor Thus, deacetylase inhibitors (HDACis) powerful drugs, with some already approved certain hematological cancers. Albeit HDACis show activity in solid tumors as well, further refinement development novel drugs needed. This review describes capability influence various pathways and, this knowledge, gives a comprehensive overview preclinical clinical studies tumors. A particular focus placed strategies achieving higher efficacy combination therapies, including phosphoinositide 3-kinase (PI3K)-EGFR hormone- or immunotherapy. also includes new bifunctional well approaches HDAC degradation via PROteolysis-TArgeting Chimeras (PROTACs).

Language: Английский

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Understanding the Function of Mammalian Sirtuins and Protein Lysine Acylation

Annual Review of Biochemistry, Journal Year: 2021, Volume and Issue: 90(1), P. 245 - 285

Published: April 13, 2021

Protein lysine acetylation is an important posttranslational modification that regulates numerous biological processes. Targeting regulatory factors, such as acetyltransferases, deacetylases, and acetyl-lysine recognition domains, has been shown to have potential for treating human diseases, including cancer neurological diseases. Over the past decade, many other acyl-lysine modifications, succinylation, crotonylation, long-chain fatty acylation, also investigated interesting functions. Here, we provide overview of functions different modifications in mammals. We focus on it well characterized, principles learned from are useful understanding acylations. pay special attention sirtuins, given study sirtuins provided a great deal information about acylation. emphasize regulation illustrate their enables cells respond various signals stresses.

Language: Английский

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Therapeutic targets for cardiac fibrosis: from old school to next-gen

Journal of Clinical Investigation, Journal Year: 2022, Volume and Issue: 132(5)

Published: Feb. 28, 2022

Cardiovascular diseases remain the leading cause of death worldwide, with pathological fibrotic remodeling mediated by activated cardiac myofibroblasts representing a unifying theme across etiologies. Despite profound contributions myocardial fibrosis to dysfunction and heart failure, there currently exist limited clinical interventions that effectively target fibroblast its role in tissue deposition. Exploration novel strategies designed mitigate or reverse myofibroblast activation will likely yield powerful therapeutic approaches for treatment multiple heart, including failure preserved reduced ejection fraction, acute coronary syndrome, cardiovascular disease linked type 2 diabetes. In this Review, we provide an overview classical regulators highlight emerging, next-generation epigenetic regulatory targets have potential revolutionize expanding patient population.

Language: Английский

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Mechanisms of spermidine-induced autophagy and geroprotection

Nature Aging, Journal Year: 2022, Volume and Issue: 2(12), P. 1112 - 1129

Published: Dec. 22, 2022

Language: Английский

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