ArticleProceedings of the National Academy of Sciences of the United States of America2014
Lysine deacetylase inhibition prevents diabetes by chromatin-independent immunoregulation and β-cell protection.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 70 citations in OpenAlex.
- Article
- Macrophages: friend or foe in diabetes pathogenesis and therapy.Frontiers in immunology · 2025Review
- The impact of site-specific DNA methylation inHeliyon · 2024Article
- Exploring histone deacetylases in type 2 diabetes mellitus: pathophysiological insights and therapeutic avenues.Clinical epigenetics · 2024Review
- Chromatin modifiers in human disease: from functional roles to regulatory mechanisms.Molecular biomedicine · 2024Review
- Autoimmune disease: a view of epigenetics and therapeutic targeting.Frontiers in immunology · 2024Review
- Epigenetic regulation in metabolic diseases: mechanisms and advances in clinical study.Signal transduction and targeted therapy · 2023Review
- Epigenetic modifications in pancreas development, diabetes, and therapeutics.Medicinal research reviews · 2022Review
- Proinflammatory Cytokines Perturb Mouse and Human Pancreatic Islet Circadian Rhythmicity and Induce Uncoordinated β-Cell Clock Gene Expression via Nitric Oxide, Lysine Deacetylases, and Immunoproteasomal Activity.International journal of molecular sciences · 2020Article
- Reading between the (Genetic) Lines: How Epigenetics is Unlocking Novel Therapies for Type 1 Diabetes.Cells · 2020Review
- Enhancer of Zeste Homolog 2 (EZH2) Mediates Glucolipotoxicity-Induced Apoptosis in β-Cells.International journal of molecular sciences · 2020Article
- "High Treg" Inflammations Promote (Most) Non-Hematologic Cancers While "Low Treg" Inflammations Promote Lymphoid Cancers.Journal of inflammation research · 2020Article
- Protein acetylation derepresses Serotonin Synthesis to potentiate Pancreatic Beta-Cell Function through HDAC1-PKA-Tph1 signaling.Theranostics · 2020Article
- Targeting innate immune mediators in type 1 and type 2 diabetes.Nature reviews. Immunology · 2019Review
- The discovery of novel HDAC3 inhibitors via virtual screening and in vitro bioassay.Journal of enzyme inhibition and medicinal chemistry · 2018Article
- Histones and heart failure in diabetes.Cellular and molecular life sciences : CMLS · 2018Review
- Article
- MicroRNAs and histone deacetylase inhibition-mediated protection against inflammatory β-cell damage.PloS one · 2018Article
- Review
- The immunoproteasome is induced by cytokines and regulates apoptosis in human islets.The Journal of endocrinology · 2017Article
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Authors and funding
21 authors at 8 institutions in 7 countries.
Funding
Abstract
Type 1 diabetes is due to destruction of pancreatic β-cells. Lysine deacetylase inhibitors (KDACi) protect β-cells from inflammatory destruction in vitro and are promising immunomodulators. Here we demonstrate that the clinically well-tolerated KDACi vorinostat and givinostat revert diabetes in the nonobese diabetic (NOD) mouse model of type 1 diabetes and counteract inflammatory target cell damage by a mechanism of action consistent with transcription factor--rather than global chromatin--hyperacetylation. Weaning NOD mice received low doses of vorinostat and givinostat in their drinking water until 100-120 d of age. Diabetes incidence was reduced by 38% and 45%, respectively, there was a 15% increase in the percentage of islets without infiltration, and pancreatic insulin content increased by 200%. Vorinostat treatment increased the frequency of functional regulatory T-cell subsets and their transcription factors Gata3 and FoxP3 in parallel to a decrease in inflammatory dendritic cell subsets and their cytokines IL-6, IL-12, and TNF-α. KDACi also inhibited LPS-induced Cox-2 expression in peritoneal macrophages from C57BL/6 and NOD mice. In insulin-producing β-cells, givinostat did not upregulate expression of the anti-inflammatory genes Socs1-3 or sirtuin-1 but reduced levels of IL-1β + IFN-γ-induced proinflammatory Il1a, Il1b, Tnfα, Fas, Cxcl2, and reduced cytokine-induced ERK phosphorylation. Further, NF-κB genomic iNos promoter binding was reduced by 50%, and NF-κB-dependent mRNA expression was blocked. These effects were associated with NF-κB subunit p65 hyperacetylation. Taken together, these data provide a rationale for clinical trials of safety and efficacy of KDACi in patients with autoimmune disease such as type 1 diabetes.
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