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Lin C, Hsu JL, Hsu YT, Fan KC, Wu SS, Lin MH, Guh JH, Yu CW. Design and synthesis of novel HDAC6 inhibitor dimer as HDAC6 degrader for cancer treatment by palladium catalysed dimerisation. J Enzyme Inhib Med Chem 2025; 40:2468355. [PMID: 40013582 PMCID: PMC11869342 DOI: 10.1080/14756366.2025.2468355] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Revised: 02/07/2025] [Accepted: 02/11/2025] [Indexed: 02/28/2025] Open
Abstract
The enigmatic histone deacetylase 6 (HDAC6) is one of a kind among its family. Recent reports revealed that HDAC6 CD1 exhibits E3 ligase activity. Inspired by these researches, we attempted to develop drugs targeting HDAC6 via novel mechanism. Herein, we report a palladium catalysed transformation and purification method for hydroxamic acid dimers, and series of HDAC6 inhibitor-based dimer showing outstanding biological activities and capability of inducing auto-degradation. Our proof-of-concept was highlighted with 2-amino benzamide-based HDAC6 inhibitor dimers that exhibit great HDAC6 inhibition activity (3.9-15.4 nM), good HDAC1/6 selectivity (95-577), and excellent cytotoxicity against human hormone-resistant prostate cancer (HRPC) PC-3 and non-small cell lung cancer (NSCLC) A549 cell lines (5.9-11.3 and 6.6-17.9 μM, respectively) while simultaneously inducing HDAC6 degradation. These dimers not only induce apoptosis and autophagy but also interfere with kinetochore attachment by the detection of BUBR1 phosphorylation at S670.
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Affiliation(s)
- Ching Lin
- School of Pharmacy, National Taiwan University, Taipei, ROC
| | - Jui-Ling Hsu
- School of Pharmacy, National Taiwan University, Taipei, ROC
- Department of Nursing, Chang Gung University of Science and Technology, Taoyuan City, ROC
- Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan City, ROC
| | - Yu-Tung Hsu
- School of Pharmacy, National Taiwan University, Taipei, ROC
| | - Kuo-Chen Fan
- School of Pharmacy, National Taiwan University, Taipei, ROC
| | - Sian-Siou Wu
- School of Pharmacy, National Taiwan University, Taipei, ROC
| | - Miao-Hsia Lin
- Department and Graduate Institute of Medical Microbiology, College of Medicine, National Taiwan University, Taipei, ROC
| | - Jih-Hwa Guh
- School of Pharmacy, National Taiwan University, Taipei, ROC
| | - Chao-Wu Yu
- School of Pharmacy, National Taiwan University, Taipei, ROC
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2
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Khallaf WAI, Taha AEAH, Ahmed AS, Hassan MIA, Abo-Youssef AM, Hemeida RAM. Sildenafil abrogates radiation-induced hepatotoxicity in animal model: The impact of NF-κB-p65, P53, Nrf2, and SIRT 1 pathway. Food Chem Toxicol 2025; 200:115373. [PMID: 40086583 DOI: 10.1016/j.fct.2025.115373] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2024] [Revised: 02/23/2025] [Accepted: 03/04/2025] [Indexed: 03/16/2025]
Abstract
Ionizing radiation has both beneficial and harmful effects on human health, prompting researchers to find ways to protect organs from its adverse impacts. Sildenafil (SIL) has gained attention in protective medicine due to its antioxidant, anti-inflammatory, and anti-apoptotic properties. AIM This study aimed to investigate SIL's protective mechanisms against radiation-induced liver damage. METHOD Forty adult male Wistar rats were divided into: control group, SIL group (2.5 mg/kg,p.o), irradiation group (rats were exposed to single shot at a dose of 10 Gy to induce liver damage), and SIL + irradiation group. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) were evaluated. Liver samples were used to evaluate oxidative stress indicators, reduced glutathione (GSH), malondialdehyde (MDA), nitric oxide(NO), Hepatic antioxidant nuclear factor erythroid 2-related factor 2(Nrf2), and apoptoticp53 upregulated modulator of apoptosis(P53) gene expression were determined by Western blot analysis. Immunohistochemical analysis for hepatic nuclear factor-kappa B (NF-κB) and silent information regulator-1(SIRT1) were performed along with histopathological examination. RESULTS SIL effectively diminished inflammation by reducing p-NF-κB-p65 and increasing Nrf2 and SIRT 1 expression. Additionally, SIL restrained apoptosis by reducing P53 protein expressions. Moreover, SIL significantly improved radiation-induced histopathological changes. SIGNIFICANCE SIL preventing hepatotoxicity associated with radiation exposure.
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Affiliation(s)
- Waleed A I Khallaf
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, 62514, Egypt
| | - Abd Elmoneim A H Taha
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut, 71524, Egypt.
| | - Ahmed S Ahmed
- Radiation Therapy and Nuclear Medicine Department, South Egypt Cancer Institute, Assiut University, Assiut, Egypt
| | - Mohamed I A Hassan
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut Branch, Assiut, 71524, Egypt
| | - Amira M Abo-Youssef
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, 62514, Egypt
| | - Ramadan A M Hemeida
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Deraya University, Minya, 61519, Egypt
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3
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Liang X, Yin S, Hu C, Tang D, Luo G, Liu Z. METTL14 Promotes Ischemic Stroke-induced Brain Injury by Stabilizing HDAC3 Expression in an m6A-IGF2BP3 Mechanism. Cell Biochem Biophys 2025; 83:1897-1907. [PMID: 39448421 DOI: 10.1007/s12013-024-01596-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/09/2024] [Indexed: 10/26/2024]
Abstract
N6-methyladenosine (m6A) modification is the most abundant post-transcriptional modification of mRNAs and has been identified to play critical roles in ischemic stroke (IS). Herein, this study aimed to investigate the function and mechanism of Methyltransferase-like 14 (METTL14) methylase in cerebral IS. Murine BV-2 microglial cell OGD/R models and rat middle cerebral artery occlusion (MCAO) models were established to mimic IS-induced neuronal damage in vitro and brain injury in vivo. Levels of METTL14, Histone Deacetylase 3 (HDAC3) and cGAS-STING axis-related proteins were detected using qRT-PCR or western blotting. Cell proliferation and inflammation were assessed by CCK-8 assay, EdU assay and ELISA. Flow cytometry detected microglia polarization. Cell pyroptosis was analyzed by detecting related-protein markers by western blotting. The m6A modification was determined by methylated RNA immunoprecipitation assay. Brain injury was analyzed by evaluating infarct volume and neurologic score. METTL14 levels were higher in OGD/R-induced microglial cells, primary microglia and infarct brain tissues of rat MCAO models. Functionally, METTL14 silencing reversed OGD/R-induced proliferation inhibition, inflammation and pyroptosis in microglial cells and primary microglia in vitro, and ameliorated cerebral ischemic injury in rat MCAO models. Mechanistically, METTL14 induced HDAC3 m6A modification in an IGF2BP3-dependent manner, and could activate cGAS-STING pathway through HDAC3. Moreover, HDAC3 overexpression reversed the neuroprotective effects of METTL14 silencing. METTL14 silencing reversed ischemic stroke-induced brain injury by inducing HDAC3 m6A modification in an IGF2BP3-dependent mechanism, recommending a novel insight for ameliorating cerebral ischemic stroke.
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Affiliation(s)
- Xuelin Liang
- The Medical Department of Neurology, Jinshan branch of Shanghai Sixth People's Hospital, Shanghai, China
| | - Songhe Yin
- The Medical Department of Neurology, Jinshan branch of Shanghai Sixth People's Hospital, Shanghai, China
| | - Canfang Hu
- The Medical Department of Neurology, Jinshan branch of Shanghai Sixth People's Hospital, Shanghai, China
| | - Dingzhong Tang
- The Medical Department of Neurology, Jinshan branch of Shanghai Sixth People's Hospital, Shanghai, China
| | - Guojun Luo
- The Medical Department of Neurology, Jinshan branch of Shanghai Sixth People's Hospital, Shanghai, China
| | - Zhen Liu
- The Medical Department of Neurology, Jinshan branch of Shanghai Sixth People's Hospital, Shanghai, China.
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Salyer LG, Wang Y, Ma X, Foryst-Ludwig A, Kintscher U, Chennappan S, Kontaridis MI, McKinsey TA. Modulating the Secretome of Fat to Treat Heart Failure. Circ Res 2025; 136:1363-1381. [PMID: 40403114 DOI: 10.1161/circresaha.125.325593] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2025] [Revised: 04/21/2025] [Accepted: 04/23/2025] [Indexed: 05/24/2025]
Abstract
Heart failure afflicts >6 million individuals in the United States alone and is associated with significant mortality (≈40% within 5 years of diagnosis) and cost (estimated to exceed $70 billion in the United States by 2030). Obesity is a major risk factor for the development of heart failure. The contribution of excess adipose tissue to heart failure pathogenesis is multifactorial. For example, adipose tissue-driven inflammation contributes to the development of other cardiometabolic comorbidities, such as hypertension, leading to left ventricular pressure overload and adverse remodeling of the heart. Adipose tissue also functions as an endocrine organ, and altered secretion of proteins, lipid mediators, metabolites, and small extracellular vesicles (collectively referred to as the secretome) from dysfunctional fat can lead to cardiac inflammation and oxidative stress, which drive changes in structure and function of the heart. In this review, we begin with an overview of current therapies for obesity and what is known about how they influence the heart. Then we focus on mechanisms by which fat communicates with the heart via secreted factors and highlight druggable nodes in this circuit that could be exploited to develop next-generation therapies for heart failure.
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Affiliation(s)
- Lorien G Salyer
- Division of Cardiology, Department of Medicine (L.G.S., T.A.M.), University of Colorado Anschutz Medical Campus, Aurora, CO
- Consortium for Fibrosis Research & Translation (L.G.S., T.A.M.), University of Colorado Anschutz Medical Campus, Aurora, CO
| | - Yajing Wang
- Department of Biomedical Engineering, University of Alabama at Birmingham, Birmingham, AL (Y.W.)
| | - Xinliang Ma
- Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA (X.M.)
| | - Anna Foryst-Ludwig
- Institute of Pharmacology, Max Rubner Center for Cardiovascular Metabolic Renal Research (MRC), Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Germany (A.F.-L., U.K.)
- DZHK (German Centre for Cardiovascular Research), Berlin, Germany (A.F.-L., U.K.)
| | - Ulrich Kintscher
- Institute of Pharmacology, Max Rubner Center for Cardiovascular Metabolic Renal Research (MRC), Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Germany (A.F.-L., U.K.)
- DZHK (German Centre for Cardiovascular Research), Berlin, Germany (A.F.-L., U.K.)
| | - Saravanakkumar Chennappan
- Department of Biomedical Research and Translational Medicine, Masonic Medical Research Institute, Utica, NY (S.C., M.I.K.)
| | - Maria I Kontaridis
- Department of Biomedical Research and Translational Medicine, Masonic Medical Research Institute, Utica, NY (S.C., M.I.K.)
- Division of Cardiology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA (M.I.K.)
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA (M.I.K.)
| | - Timothy A McKinsey
- Division of Cardiology, Department of Medicine (L.G.S., T.A.M.), University of Colorado Anschutz Medical Campus, Aurora, CO
- Consortium for Fibrosis Research & Translation (L.G.S., T.A.M.), University of Colorado Anschutz Medical Campus, Aurora, CO
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Hazra RS, Dutta D, Khan MRH, Tani S, Abdullah CS, Remex NS, Aishwarya R, Islam T, Yang Z, Mallik S, Bhuiyan MS, Choi Y, Quadir M. Mechanistic Underpinnings of Epigenetic Enzyme-Responsive Nanoparticles. ACS APPLIED BIO MATERIALS 2025; 8:3845-3857. [PMID: 40307668 DOI: 10.1021/acsabm.4c02007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/02/2025]
Abstract
Epigenetic enzyme-responsive nanoparticles (ERPs), which destabilize under the influence of histone deacetylase 8 (HDAC8), have been characterized in terms of their physicochemical, nanomechanical, and in vitro attributes. These nanoparticles were synthesized from amphiphilic block copolymers composed of poly(acetyl l-lysine) as the hydrophobic and poly(ethylene glycol) as the hydrophilic block. Upon optimizing the particle assembly process, we demonstrated that the nanoscale properties of ERPs, including hydrodynamic diameter (DH), size distribution, and stiffness, are selectively influenced by the HDAC8 enzyme. Using 1H NMR and circular dichroism spectroscopy, we identified that deacetylation of the lysine residues located within the hydrophobic block acts as a molecular driver for the enzyme-induced destabilization of ERPs. Comprehensive in vitro studies demonstrated that ERPs are biocompatible and noncytotoxic and can accumulate in perinuclear and several cellular organelles, including lysosomes and mitochondria. Collectively, this study attempts to establish the mechanistic background of ERP functions, providing the baseline for designing epigenetic-enzyme-sensitive nanoscale platforms.
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Affiliation(s)
- Raj Shankar Hazra
- Department of Coatings and Polymeric Materials, North Dakota State University, Fargo, North Dakota 58102, United States
| | - Debasmita Dutta
- Department of Coatings and Polymeric Materials, North Dakota State University, Fargo, North Dakota 58102, United States
| | - Md Rakib Hasan Khan
- Biomedical Engineering Program, North Dakota State University, Fargo, North Dakota 58102, United States
| | - Sakurako Tani
- Deapartment of Physics, North Dakota State University, Fargo, North Dakota 58102, United States
| | - Chowdhury S Abdullah
- Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71103, United States
| | - Naznin Sultana Remex
- Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71103, United States
| | - Richa Aishwarya
- Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71103, United States
| | - Tamjid Islam
- Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71103, United States
| | - Zhongyu Yang
- Department of Chemical and Biomedical Engineering, University of Misouri, Columbia, Missouri 65211, United States
| | - Sanku Mallik
- College of Pharmacy and Allied Health Professions, South Dakota State University, Brooking, South Dakota 57007, United States
| | - Md Shenuarin Bhuiyan
- Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71103, United States
- Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71103, United States
| | - Yongki Choi
- Deapartment of Physics, North Dakota State University, Fargo, North Dakota 58102, United States
| | - Mohiuddin Quadir
- Department of Coatings and Polymeric Materials, North Dakota State University, Fargo, North Dakota 58102, United States
- Biomedical Engineering Program, North Dakota State University, Fargo, North Dakota 58102, United States
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6
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Liu N, Li JX, Yuan DY, Su YN, Zhang P, Wang Q, Su XM, Li L, Li H, Chen S, He XJ. Essential angiosperm-specific subunits of HDA19 histone deacetylase complexes in Arabidopsis. EMBO J 2025:10.1038/s44318-025-00445-w. [PMID: 40295864 DOI: 10.1038/s44318-025-00445-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Revised: 02/14/2025] [Accepted: 03/31/2025] [Indexed: 04/30/2025] Open
Abstract
Although the Arabidopsis thaliana RPD3-type histone deacetylase HDA19 and its close homolog HDA6 participate in SIN3-type histone deacetylase complexes, they display distinct biological roles, with the reason for these differences being poorly understood. This study identifies three angiosperm-specific HDA19-interacting homologous proteins, termed HDIP1, HDIP2, and HDIP3 (HDIP1/2/3). These proteins interact with HDA19 and other conserved histone deacetylase complex components, leading to the formation of HDA19-containing SIN3-type complexes, while they are not involved in the formation of HDA6-containing complexes. While mutants of conserved SIN3-type complex components show phenotypes divergent from the hda19 mutant, the hdip1/2/3 mutant closely phenocopies the hda19 mutant with respect to development, abscisic acid response, and drought stress tolerance. Genomic and transcriptomic analyses indicate that HDIP1/2/3 and HDA19 co-occupy chromatin and jointly repress gene transcription, especially for stress-related genes. An α-helix motif within HDIP1 has the capacity to bind to nucleosomes and architectural DNA, and is required for its function in Arabidopsis plants. These findings suggest that the angiosperm SIN3-type complexes have evolved to include additional subunits for the precise regulation of histone deacetylation and gene transcription.
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Affiliation(s)
- Na Liu
- College of Life Sciences, Beijing Normal University, Beijing, China
- National Institute of Biological Sciences, Beijing, China
| | - Jia-Xin Li
- National Institute of Biological Sciences, Beijing, China
| | - Dan-Yang Yuan
- National Institute of Biological Sciences, Beijing, China
| | - Yin-Na Su
- National Institute of Biological Sciences, Beijing, China
| | - Pei Zhang
- School of Basic Medical Sciences, Tsinghua University, Beijing, China
| | - Qi Wang
- National Institute of Biological Sciences, Beijing, China
| | - Xiao-Min Su
- National Institute of Biological Sciences, Beijing, China
| | - Lin Li
- National Institute of Biological Sciences, Beijing, China
| | - Haitao Li
- School of Basic Medical Sciences, Tsinghua University, Beijing, China
| | - She Chen
- National Institute of Biological Sciences, Beijing, China
| | - Xin-Jian He
- National Institute of Biological Sciences, Beijing, China.
- Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing, China.
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Roa-Cordero MV, Arenas-Sepúlveda CA, Herrera-Plata MC, Leal-Pinto SM, Villota-Salazar NA, González-Prieto JM. Switching off the yeast-to-hyphae transition in Yarrowia lipolytica through histone deacetylase inhibitors. Res Microbiol 2025:104299. [PMID: 40306381 DOI: 10.1016/j.resmic.2025.104299] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Revised: 03/23/2025] [Accepted: 04/08/2025] [Indexed: 05/02/2025]
Abstract
Fungi can develop a variety of morphotypes to survive, colonize, adapt and prevail under different environmental conditions. In general, two morphological shapes encompass the others: yeast (unicellular) and hyphae (multicellular). Under specific conditions, some fungi can adopt these two cellular morphologies, and for this reason, they are called dimorphic. Histone acetylation and deacetylation are well-known important mechanisms of chromatin remodelling that control cell differentiation processes as dimorphism. The reactions involved are catalysed by histone acetyltransferases (HATs) and histone deacetylases (HDACs), respectively. In the present work, we used Yarrowia lipolytica as a dimorphic fungal model to investigate the effect of HDAC chemical inhibition on the growth and yeast-to-hyphae switch of fungi. For this purpose, we tested the compounds sodium butyrate (SB) and valproic acid (VPA) as epigenetic modulators. Our results indicated that Y. lipolytica tolerates high doses of these inhibitors due to its lipolytic nature. However, once the metabolic capability of the fungus is overcome, SB and VPA strongly suppress hyphal growth, suggesting that histone acetylation plays a pivotal role in the regulation of this process.
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Affiliation(s)
- Martha Viviana Roa-Cordero
- Universidad de Santander, Facultad de Ciencias Médicas y de la Salud, Instituto de Investigación Masira, 680006, Bucaramanga, Colombia.
| | | | - María Cristina Herrera-Plata
- Universidad de Santander, Facultad de Ciencias Exactas, Naturales y Agropecuarias, 680006, Bucaramanga, Colombia.
| | - Sandra Milena Leal-Pinto
- Universidad de Santander, Facultad de Ciencias Médicas y de la Salud, Instituto de Investigación Masira, 680006, Bucaramanga, Colombia.
| | - Nubia Andrea Villota-Salazar
- Biotecnología Vegetal, Centro de Biotecnología Genómica, Instituto Politécnico Nacional, Blvd. del Maestro. S/N esq. Elías Piña. Col. Narciso Mendoza, 88710, Reynosa, Tamaulipas, Mexico.
| | - Juan Manuel González-Prieto
- Biotecnología Vegetal, Centro de Biotecnología Genómica, Instituto Politécnico Nacional, Blvd. del Maestro. S/N esq. Elías Piña. Col. Narciso Mendoza, 88710, Reynosa, Tamaulipas, Mexico.
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8
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Na ES. Epigenetic Mechanisms of Obesity: Insights from Transgenic Animal Models. Life (Basel) 2025; 15:653. [PMID: 40283207 PMCID: PMC12028693 DOI: 10.3390/life15040653] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2025] [Revised: 04/11/2025] [Accepted: 04/14/2025] [Indexed: 04/29/2025] Open
Abstract
Obesity is a chronic disease with prevalence rates that have risen dramatically over the past four decades. This increase is not due to changes in the human genome but rather to environmental factors that promote maladaptive physiological responses. Emerging evidence suggests that external influences, such as high-fat diets, modify the epigenome-the interface between genes and the environment-leading to persistent alterations in energy homeostasis. This review explores the role of epigenetic mechanisms in obesity, emphasizing insights from transgenic animal models and clinical studies. Additionally, we discuss the evolution of obesity research from homeostatic to allostatic frameworks, highlighting key neuroendocrine regulators of energy balance.
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Affiliation(s)
- Elisa S Na
- School of Social Work, Psychology, & Philosophy, Texas Woman's University, Denton, TX 76209, USA
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9
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Pires GS, Tolomeu HV, Rodrigues DA, Lima LM, Fraga CAM, Pinheiro PDSM. Drug Discovery for Histone Deacetylase Inhibition: Past, Present and Future of Zinc-Binding Groups. Pharmaceuticals (Basel) 2025; 18:577. [PMID: 40284012 PMCID: PMC12030391 DOI: 10.3390/ph18040577] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2025] [Revised: 04/07/2025] [Accepted: 04/09/2025] [Indexed: 04/29/2025] Open
Abstract
Histone deacetylases (HDACs) are key regulators of gene expression, influencing chromatin remodeling and playing a crucial role in various physiological and pathological processes. Aberrant HDAC activity has been linked to cancer, neurodegenerative disorders, and inflammatory diseases, making these enzymes attractive therapeutic targets. HDAC inhibitors (HDACis) have gained significant attention, particularly those containing zinc-binding groups (ZBGs), which interact directly with the catalytic zinc ion in the enzyme's active site. The structural diversity of ZBGs profoundly impacts the potency, selectivity, and pharmacokinetics of HDACis. While hydroxamic acids remain the most widely used ZBGs, their limitations, such as metabolic instability and off-target effects, have driven the development of alternative scaffolds, including ortho-aminoanilides, mercaptoacetamides, alkylhydrazides, oxadiazoles, and more. This review explores the structural and mechanistic aspects of different ZBGs, their interactions with HDAC isoforms, and their influence on inhibitor selectivity. Advances in structure-based drug design have allowed the fine-tuning of HDACi pharmacophores, leading to more selective and efficacious compounds with improved drug-like properties. Understanding the nuances of ZBG interactions is essential for the rational design of next-generation HDACis, with potential applications in oncology, neuroprotection, and immunotherapy.
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Affiliation(s)
- Gustavo Salgado Pires
- Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio), Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Cidade Universitária, Rio de Janeiro 21941-902, Brazil; (G.S.P.); (H.V.T.); (L.M.L.)
- Programa de Pós-Graduação em Farmacologia e Química Medicinal (PPGFQM), Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Cidade Universitária, Rio de Janeiro 21941-902, Brazil
| | - Heber Victor Tolomeu
- Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio), Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Cidade Universitária, Rio de Janeiro 21941-902, Brazil; (G.S.P.); (H.V.T.); (L.M.L.)
| | - Daniel Alencar Rodrigues
- School of Pharmacy and Biomolecular Sciences (PBS), Royal College of Surgeons in Ireland, 1st Floor Ardilaun House Block B, 111 St Stephen’s Green, Dublin 2, Ireland;
| | - Lídia Moreira Lima
- Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio), Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Cidade Universitária, Rio de Janeiro 21941-902, Brazil; (G.S.P.); (H.V.T.); (L.M.L.)
- Programa de Pós-Graduação em Farmacologia e Química Medicinal (PPGFQM), Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Cidade Universitária, Rio de Janeiro 21941-902, Brazil
- Instituto Nacional de Ciência e Tecnologia de Fármacos e Medicamentos (INCT-INOFAR), Universidade Federal do Rio de Janeiro, Cidade Universitária, Rio de Janeiro 21941-902, Brazil
| | - Carlos Alberto Manssour Fraga
- Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio), Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Cidade Universitária, Rio de Janeiro 21941-902, Brazil; (G.S.P.); (H.V.T.); (L.M.L.)
- Programa de Pós-Graduação em Farmacologia e Química Medicinal (PPGFQM), Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Cidade Universitária, Rio de Janeiro 21941-902, Brazil
- Instituto Nacional de Ciência e Tecnologia de Fármacos e Medicamentos (INCT-INOFAR), Universidade Federal do Rio de Janeiro, Cidade Universitária, Rio de Janeiro 21941-902, Brazil
| | - Pedro de Sena Murteira Pinheiro
- Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio), Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Cidade Universitária, Rio de Janeiro 21941-902, Brazil; (G.S.P.); (H.V.T.); (L.M.L.)
- Programa de Pós-Graduação em Farmacologia e Química Medicinal (PPGFQM), Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Cidade Universitária, Rio de Janeiro 21941-902, Brazil
- Instituto Nacional de Ciência e Tecnologia de Fármacos e Medicamentos (INCT-INOFAR), Universidade Federal do Rio de Janeiro, Cidade Universitária, Rio de Janeiro 21941-902, Brazil
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10
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Lai R, Li H. Deacetylation mechanism of histone deacetylase 8: insights from QM/MM MP2 calculations. Phys Chem Chem Phys 2025; 27:7120-7138. [PMID: 40109193 DOI: 10.1039/d5cp00002e] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/22/2025]
Abstract
Understanding the catalytic mechanism of histone deacetylases can greatly benefit the development of targeted therapies that are safe and effective. Combined quantum mechanical and molecular mechanical (QM/MM) Møller-Plesset second-order perturbation theory (MP2) geometry optimizations are performed to investigate the catalytic mechanism of the deacetylation reaction of a tetrapeptide catalyzed by human Histone Deacetylase 8. A three-step catalytic mechanism is identified: the first step is the formation of a negatively charged tetrahedral intermediate via nucleophilic addition of the activated water to the amide C atom and a proton transfer from the water to His143; the second step is the formation of a neutral tetrahedral intermediate with an elongated amide C-N bond via a proton transfer from His143 to the amide N atom. The third step is the complete cleavage of the amide C-N bond, accompanied by a proton transfer from the newly formed carboxylic group of the neutral tetrahedral intermediate to His142. These three steps have similar computed energy barriers, with the second step having the highest calculated activation free energy of 19.6 kcal mol-1. When there is no potassium ion at site 1, the calculated activation free energy is 17.7 kcal mol-1. Both values are in good agreement with an experimental value of 17.5 kcal mol-1. Their difference implies that there would be a 25-fold increase in the enzyme's activity, in line with experiments. The solvent hydrogen-deuterium kinetic isotope effect was computed to be ∼3.8 for the second step in both cases. It is also found that the energy barriers are significantly and systematically higher on the QM/MM B3LYP and QM/MM B3LYP-D3 potential energy surfaces. In particular, the QM/MM B3LYP and B3LYP-D3 methods fail to predict the neutral tetrahedral intermediate and a meaningful transition state for the third step, leading to a two-step mechanism. With a sufficiently large basis set such as aug-cc-pVDZ, QM/MM M05-2X, M06-2X, M06, and MN15 methods can give results much closer to the QM/MM MP2 method. However, when a smaller basis set such as 6-31G* is used, these methods can lead to errors as large as 10 kcal mol-1 on the reaction pathway. These results highlight the importance of using accurate QM methods in the computational study of enzyme catalysis.
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Affiliation(s)
- Rui Lai
- College of Chemistry, Jilin University, Changchun, 130021, China.
| | - Hui Li
- Department of Chemistry, University of Nebraska-Lincoln, Lincoln, NE, 68588, USA.
- Nebraska Center for Materials and Nanoscience, University of Nebraska-Lincoln, Lincoln, NE, 68588, USA
- Center for Integrated Biomolecular Communication, University of Nebraska-Lincoln, Lincoln, NE 68588, USA
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11
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Stollmaier JG, Czarnecki BAR, Christianson DW. Mechanism-Based Inhibition of Histone Deacetylase 6 by a Selenocyanate Is Subject to Redox Modulation. J Am Chem Soc 2025; 147:6373-6377. [PMID: 39957581 PMCID: PMC11929974 DOI: 10.1021/jacs.5c00157] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/18/2025]
Abstract
Organoselenocyanates have attracted considerable attention in recent years due to their therapeutic potential and versatility in medicinal chemistry. Here, we report on the mechanism of inhibition by 5-phenylcarbamoylpentyl selenocyanide (SelSA-2), an analogue of the well-characterized histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA, a.k.a. Vorinostat). We show that histone deacetylases 6 and 10 promote selenocyanate hydrolysis to generate a selenolate anion, and we explore the redox chemistry of selenium as it modulates inhibitory activity through reversible formation of the diselenide. The 2.15 Å-resolution crystal structure of histone deacetylase 6 cocrystallized with SelSA-2 conclusively demonstrates that it is not the selenocyanate, but instead a zinc-bound selenolate anion, that is the active pharmacophore responsible for enzyme inhibition.
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Affiliation(s)
- Juana Goulart Stollmaier
- Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, 231 South 34 Street, Philadelphia, PA 19104-6323 USA
| | - Briana Abigail R. Czarnecki
- Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, 231 South 34 Street, Philadelphia, PA 19104-6323 USA
| | - David W. Christianson
- Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, 231 South 34 Street, Philadelphia, PA 19104-6323 USA
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12
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Du X, Yu W, Chen F, Jin X, Xue L, Zhang Y, Wu Q, Tong H. HDAC inhibitors and IBD: Charting new approaches in disease management. Int Immunopharmacol 2025; 148:114193. [PMID: 39892171 DOI: 10.1016/j.intimp.2025.114193] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2024] [Revised: 12/14/2024] [Accepted: 01/27/2025] [Indexed: 02/03/2025]
Abstract
Inflammatory bowel disease (IBD) represents a group of chronic inflammatory disorders of the gastrointestinal tract. Despite substantial advances in our understanding of IBD pathogenesis, the currently available therapeutic options remain limited in their efficacy and often come with significant side effects. Therefore, there is an urgent need to explore novel approaches for the management of IBD. One promising avenue of investigation revolves around the use of histone deacetylase (HDAC) inhibitors, which have garnered considerable attention for their potential in modulating gene expression and curbing inflammatory responses. This review emphasizes the pressing need for innovative drugs in the treatment of IBD, and drawing from a wealth of preclinical studies and clinical trials, we underscore the multifaceted roles and the therapeutic effects of HDAC inhibitors in IBD models and patients. This review aims to contribute significantly to the understanding of HDAC inhibitors' importance and prospects in the management of IBD, ultimately paving the way for improved therapeutic strategies in this challenging clinical landscape.
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Affiliation(s)
- Xueting Du
- College of Life and Environmental Science, Wenzhou University, Wenzhou 325000, China
| | - Weilai Yu
- Department of Gastroenterology, The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou 325200, China
| | - Fangyu Chen
- College of Life and Environmental Science, Wenzhou University, Wenzhou 325000, China
| | - Xiaosheng Jin
- Department of Gastroenterology, The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou 325200, China
| | - Liwei Xue
- Department of Gastroenterology, The Third Affiliated Hospital of Wenzhou Medical University, Wenzhou 325200, China
| | - Ya Zhang
- College of Life and Environmental Science, Wenzhou University, Wenzhou 325000, China; Hepatology Diagnosis and Treatment Center & Zhejiang Provincial Key Laboratory for Accurate Diagnosis and Treatment of Chronic Liver Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325035, China
| | - Qifang Wu
- College of Life and Environmental Science, Wenzhou University, Wenzhou 325000, China.
| | - Haibin Tong
- College of Life and Environmental Science, Wenzhou University, Wenzhou 325000, China.
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13
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Liu X, Yang M, Ge F, Zhao J. Lysine acetylation in cyanobacteria: emerging mechanisms and functions. Biochem Soc Trans 2025; 53:BST20241037. [PMID: 39936403 DOI: 10.1042/bst20241037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2024] [Revised: 01/28/2025] [Accepted: 01/30/2025] [Indexed: 02/13/2025]
Abstract
Cyanobacteria are ancient and abundant photosynthetic prokaryotes that play crucial roles in global carbon and nitrogen cycles. They exist in a variety of environments and have been used extensively as model organisms for studies of photosynthesis and environmental adaptation. Lysine acetylation (Kac), a widespread and evolutionarily conserved protein posttranslational modification, is reversibly catalyzed by lysine acetyltransferases (KAT) and lysine deacetylases (KDACs). Over the past decade, a growing number of acetylated proteins have been identified in cyanobacteria, and Kac is increasingly recognized as having essential roles in many cellular processes, such as photosynthesis, energy metabolism, and stress responses. Recently, cGNAT2 and CddA were identified as KAT and KDAC in the model cyanobacterium Synechococcus sp. PCC 7002, respectively. The identified Kac regulatory enzymes provide novel insight into the mechanisms that globally regulate photosynthesis in cyanobacteria and potentially other photosynthetic organisms. This review summarizes recent progress in our understanding of the functions and mechanisms of lysine acetylation in Cyanobacteria. The challenges and future perspectives in this field are also discussed.
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Affiliation(s)
- Xin Liu
- School of Animal Science and Nutritional Engineering, Wuhan Polytechnic University, Wuhan, 430070, China
- State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China
| | - Mingkun Yang
- State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China
| | - Feng Ge
- State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China
| | - Jindong Zhao
- State Key Laboratory of Protein and Plant Genetic Engineering, College of Life Sciences, Peking University, Beijing 100871, China
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14
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Goulart Stollmaier J, Herbst-Gervasoni CJ, Christianson DW. Expression, purification, and crystallization of "humanized" Danio rerio histone deacetylase 10 "HDAC10", the eukaryotic polyamine deacetylase. Methods Enzymol 2025; 715:19-40. [PMID: 40382137 DOI: 10.1016/bs.mie.2025.01.074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/20/2025]
Abstract
The class IIb histone deacetylase HDAC10 is responsible for the deacetylation of intracellular polyamines, in particular N8-acetylspermidine. HDAC10 is emerging as an attractive target for drug design owing to its role as an inducer of autophagy, and high-resolution crystal structures enable structure-based drug design efforts. The only crystal structure available to date is that of HDAC10 from Danio rerio (zebrafish), but a construct containing the A24E and D94A substitutions yields an active site contour that more closely resembles that of human HDAC10. The use of this "humanized" construct has advanced our understanding of HDAC10-inhibitor structure-activity relationships. Here, we outline the preparation, purification, assay, and crystallization of humanized zebrafish HDAC10-inhibitor complexes. The plasmid containing the humanized zebrafish HDAC10 construct for heterologous expression in Escherichia coli is available through Addgene (#225542).
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Affiliation(s)
- Juana Goulart Stollmaier
- Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, PA, United States
| | - Corey J Herbst-Gervasoni
- Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, PA, United States
| | - David W Christianson
- Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, PA, United States.
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15
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Pan Q, Huang R, Xiao Q, Wu X, Jian B, Xiang Y, Gan L, Liu Z, Li Y, Gu T, Liu H. Inhibition of histone deacetylase in Arabidopsis root calli promotes de novo shoot organogenesis. FRONTIERS IN PLANT SCIENCE 2025; 15:1500573. [PMID: 39931333 PMCID: PMC11807735 DOI: 10.3389/fpls.2024.1500573] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Accepted: 11/25/2024] [Indexed: 02/13/2025]
Abstract
De novo organogenesis from somatic cells to the entire plant represents a remarkable biological phenomenon, but the underlying regulatory mechanism, particularly at the epigenetic level, remains obscure. In this work, we demonstrate the important role of histone deacetylases (HDACs) in shoot organogenesis. HDAC inhibition by trichostatin A (an HDAC inhibitor) at the callus induction stage promotes shoot formation in wounded roots and circumvents tissue wounding to initiate shoot regeneration in unwounded roots. This HDAC inhibition-mediated promotion of shoot organogenesis in wounded roots is associated with the concomitant upregulation of the wound signaling pathway (WOUND INDUCED DEDIFFERENTIATION 4, ENHANCER OF SHOOT REGENERATION1, ISOPENTENYLTRANSFERASE 5, CUP-SHAPED COTYLEDON 2 etc.) and the ARF-LBD pathway (AUXIN RESPONSE FACTOR 19, LATERAL ORGAN BOUNDARIES-DOMAIN 29, etc.) and the downregulation of auxin biosynthesis and reduced auxin content. Furthermore, inhibiting HDACs enhances the local enrichment of histone 3 lysine 9/lysine 14 acetylation at ISOPENTENYLTRANSFERASE 5, supporting the role of histone acetylation in its transcriptional regulation. On the other hand, the HDAC inhibition-associated activation of shoot organogenesis from unwounded roots is coupled with increased expression of the ARF-LBD pathway gene LATERAL ORGAN BOUNDARIES-DOMAIN 29 while bypassing the wound signaling or auxin biosynthetic genes. These findings provide novel insights into the regulatory mechanisms underlying de novo shoot organogenesis and lay a foundation for the improvement of plant transformation technologies.
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Affiliation(s)
- Qinwei Pan
- State Key Laboratory of Crop Genetics and Germplasm Enhancement, College of Horticulture, Nanjing Agricultural University, Nanjing, China
| | - Ruirui Huang
- State Key Laboratory of Crop Genetics and Germplasm Enhancement, College of Horticulture, Nanjing Agricultural University, Nanjing, China
| | - Qiong Xiao
- State Key Laboratory of Crop Genetics and Germplasm Enhancement, College of Horticulture, Nanjing Agricultural University, Nanjing, China
| | - Xuting Wu
- State Key Laboratory of Crop Genetics and Germplasm Enhancement, College of Horticulture, Nanjing Agricultural University, Nanjing, China
| | - Baoxia Jian
- State Key Laboratory of Crop Genetics and Germplasm Enhancement, College of Horticulture, Nanjing Agricultural University, Nanjing, China
| | - Yanan Xiang
- Laboratory of Plant Hormone, College of Life Sciences, Nanjing Agricultural University, Nanjing, China
| | - Lijun Gan
- Laboratory of Plant Hormone, College of Life Sciences, Nanjing Agricultural University, Nanjing, China
| | - Zongrang Liu
- USDA-ARS, Appalachian Fruit Research Station, Kearneysville, WV, United States
| | - Yi Li
- Department of Plant Science and Landscape Architecture, University of Connecticut, Storrs, CT, United States
| | - Tingting Gu
- State Key Laboratory of Crop Genetics and Germplasm Enhancement, College of Horticulture, Nanjing Agricultural University, Nanjing, China
| | - Huawei Liu
- State Key Laboratory of Crop Genetics and Germplasm Enhancement, College of Horticulture, Nanjing Agricultural University, Nanjing, China
- State Key Laboratory of Desert and Oasis Ecology, Key Laboratory of Ecological Safety and Sustainable Development in Arid Lands, Xinjiang Institute of Ecology and Geography, Chinese Academy of Sciences, Urumqi, China
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16
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Pan J, Chen S, Chen X, Song Y, Cheng H. Histone Modifications and DNA Methylation in Psoriasis: A Cellular Perspective. Clin Rev Allergy Immunol 2025; 68:6. [PMID: 39871086 DOI: 10.1007/s12016-024-09014-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/08/2024] [Indexed: 01/29/2025]
Abstract
In recent years, epigenetic modifications have attracted significant attention due to their unique regulatory mechanisms and profound biological implications. Acting as a bridge between environmental stimuli and changes in gene activity, they reshape gene expression patterns, providing organisms with regulatory mechanisms to respond to environmental changes. A growing body of evidence indicates that epigenetic regulation plays a crucial role in the pathogenesis and progression of psoriasis. A deeper understanding of these epigenetic mechanisms not only helps unveil the molecular mechanisms underlying the initiation and progression of psoriasis but may also provide new insights into diagnostic and therapeutic strategies. Given the unique roles and significant contributions of various cell types involved in the process of psoriasis, a thorough analysis of specific epigenetic patterns in different cell types becomes a key entry point for elucidating the mechanisms of disease development. Although epigenetic modifications encompass multiple complex layers, this review will focus on histone modifications and DNA methylation, describing how they function in different cell types and subsequently impact the pathophysiological processes of psoriasis. Finally, we will summarize the current problems in research concerning histone modifications and DNA methylation in psoriasis and discuss the clinical application prospects and challenges of targeting epigenetic modifications as therapeutic strategies for psoriasis.
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Affiliation(s)
- Jing Pan
- Department of Dermatology and Venereology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Siji Chen
- Department of Dermatology and Venereology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Xianzhen Chen
- Department of Dermatology and Venereology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yinjing Song
- Department of Dermatology and Venereology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
| | - Hao Cheng
- Department of Dermatology and Venereology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
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17
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Zhang Z, Su R, Liu J, Chen K, Wu C, Sun P, Sun T. Tubulin/HDAC dual-target inhibitors: Insights from design strategies, SARs, and therapeutic potential. Eur J Med Chem 2025; 281:117022. [PMID: 39500063 DOI: 10.1016/j.ejmech.2024.117022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Revised: 10/21/2024] [Accepted: 10/30/2024] [Indexed: 12/02/2024]
Abstract
Microtubules, one of the cytoskeletons in eukaryotic cells, maintain the proper operation of several cellular functions. Additionally, they are regulated by the acetylation of HDAC6 and SIRT2 which affects microtubule dynamics. Given the fact that tubulin and HDAC inhibitors play a synergistic effect in the treatment of many cancers, the development of tubulin/HDAC dual-target inhibitors is conducive to addressing multiple limitations including drug resistance, dose toxicity, and unpredictable pharmacokinetic properties. At present, tubulin/HDAC dual-target inhibitors have been obtained in three main ways: uncleavable linked pharmacophores, cleavable linked pharmacophores, and modification of single-target drugs. Their therapeutic efficacy has been verified in vivo and in vitro assays. In this article, we reviewed the research progress of tubulin/HDAC dual inhibitors from design strategies, SARs, and biological activities, which may provide help for the discovery of novel tubulin/HDAC dual inhibitors.
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Affiliation(s)
- Zhen Zhang
- Key Laboratory of Structure-Based Drug Design and Discovery, Shenyang Pharmaceutical University, Ministry of Education. Shenyang 110016, PR China
| | - Rui Su
- Key Laboratory of Structure-Based Drug Design and Discovery, Shenyang Pharmaceutical University, Ministry of Education. Shenyang 110016, PR China
| | - Junao Liu
- Key Laboratory of Structure-Based Drug Design and Discovery, Shenyang Pharmaceutical University, Ministry of Education. Shenyang 110016, PR China
| | - Keyu Chen
- Key Laboratory of Structure-Based Drug Design and Discovery, Shenyang Pharmaceutical University, Ministry of Education. Shenyang 110016, PR China
| | - Chengjun Wu
- Key Laboratory of Structure-Based Drug Design and Discovery, Shenyang Pharmaceutical University, Ministry of Education. Shenyang 110016, PR China.
| | - Pinghua Sun
- Key Laboratory of Structure-Based Drug Design and Discovery, Shenyang Pharmaceutical University, Ministry of Education. Shenyang 110016, PR China; Key Laboratory of Xinjiang Phytomedicine Resource and Utilization, Ministry of Education, School of Pharmacy, Shihezi University, Shihezi, 832003, PR China.
| | - Tiemin Sun
- Key Laboratory of Structure-Based Drug Design and Discovery, Shenyang Pharmaceutical University, Ministry of Education. Shenyang 110016, PR China.
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18
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Christianson DW, Stollmaier JG, Czarnecki BAR. Mechanism-Based Inhibition of Histone Deacetylase 6 by a Selenocyanate is Subject to Redox Modulation. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.01.04.631333. [PMID: 39803514 PMCID: PMC11722227 DOI: 10.1101/2025.01.04.631333] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/26/2025]
Abstract
Organoselenocyanates have attracted considerable attention in recent years due to their therapeutic potential and versatility in medicinal chemistry. Here, we report on the mechanism of inhibition by 5-phenylcarbamoylpentyl selenocyanide (SelSA-2), an analogue of the well-characterized histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA, a.k.a. Vorinostat). We show that histone deacetylases 6 and 10 can promote selenocyanate hydrolysis to generate a selenolate anion, and we explore the redox chemistry of selenium as it modulates inhibitory activity through reversible formation of the diselenide. The 2.15 Å-resolution crystal structure of histone deacetylase 6 cocrystallized with SelSA-2 conclusively demonstrates that it is not the selenocyanate, but instead the selenolate anion, that is the active pharmacophore responsible for enzyme inhibition.
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Affiliation(s)
- David W Christianson
- Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania, 19104-6323, United States
| | - Juana Goulart Stollmaier
- Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania, 19104-6323, United States
| | - Briana Abigail R Czarnecki
- Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania, 19104-6323, United States
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19
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Sanjuan-Badillo A, P. Martínez-Castilla L, García-Sandoval R, Ballester P, Ferrándiz C, Sanchez MDLP, García-Ponce B, Garay-Arroyo A, R. Álvarez-Buylla E. HDACs MADS-domain protein interaction: a case study of HDA15 and XAL1 in Arabidopsis thaliana. PLANT SIGNALING & BEHAVIOR 2024; 19:2353536. [PMID: 38771929 PMCID: PMC11110687 DOI: 10.1080/15592324.2024.2353536] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Accepted: 05/01/2024] [Indexed: 05/23/2024]
Abstract
Cellular behavior, cell differentiation and ontogenetic development in eukaryotes result from complex interactions between epigenetic and classic molecular genetic mechanisms, with many of these interactions still to be elucidated. Histone deacetylase enzymes (HDACs) promote the interaction of histones with DNA by compacting the nucleosome, thus causing transcriptional repression. MADS-domain transcription factors are highly conserved in eukaryotes and participate in controlling diverse developmental processes in animals and plants, as well as regulating stress responses in plants. In this work, we focused on finding out putative interactions of Arabidopsis thaliana HDACs and MADS-domain proteins using an evolutionary perspective combined with bioinformatics analyses and testing the more promising predicted interactions through classic molecular biology tools. Through bioinformatic analyses, we found similarities between HDACs proteins from different organisms, which allowed us to predict a putative protein-protein interaction between the Arabidopsis thaliana deacetylase HDA15 and the MADS-domain protein XAANTAL1 (XAL1). The results of two-hybrid and Bimolecular Fluorescence Complementation analysis demonstrated in vitro and in vivo HDA15-XAL1 interaction in the nucleus. Likely, this interaction might regulate developmental processes in plants as is the case for this type of interaction in animals.
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Affiliation(s)
- Andrea Sanjuan-Badillo
- Laboratorio de Genética Molecular, Epigenética, Desarrollo y Evolución de Plantas, Instituto de Ecología, Universidad Nacional Autónoma de México, Ciudad de México, México
- Programa de Doctorado en Ciencias Biomédicas, de la Universidad Nacional Autónoma de México, Ciudad de México, México
| | - León P. Martínez-Castilla
- Investigadoras e Investigadores por México, Grupo de Genómica y Dinámica Evolutiva de Microorganismos Emergentes, Consejo Nacional de Ciencia y Tecnología, Ciudad de México, México
| | | | - Patricia Ballester
- Instituto de Biología Molecular y Celular de Plantas, CSIC-UPV Universidad Politécnica de Valencia, Valencia, España
| | - Cristina Ferrándiz
- Instituto de Biología Molecular y Celular de Plantas, CSIC-UPV Universidad Politécnica de Valencia, Valencia, España
| | - Maria de la Paz Sanchez
- Laboratorio de Genética Molecular, Epigenética, Desarrollo y Evolución de Plantas, Instituto de Ecología, Universidad Nacional Autónoma de México, Ciudad de México, México
| | - Berenice García-Ponce
- Laboratorio de Genética Molecular, Epigenética, Desarrollo y Evolución de Plantas, Instituto de Ecología, Universidad Nacional Autónoma de México, Ciudad de México, México
| | - Adriana Garay-Arroyo
- Laboratorio de Genética Molecular, Epigenética, Desarrollo y Evolución de Plantas, Instituto de Ecología, Universidad Nacional Autónoma de México, Ciudad de México, México
| | - Elena R. Álvarez-Buylla
- Laboratorio de Genética Molecular, Epigenética, Desarrollo y Evolución de Plantas, Instituto de Ecología, Universidad Nacional Autónoma de México, Ciudad de México, México
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20
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Aparecida Dos Santos France F, Maeda DK, Rodrigues AB, Ono M, Lopes Nogueira Marchetti F, Marchetti MM, Faustino Martins AC, Gomes RDS, Rainho CA. Exploring fatty acids from royal jelly as a source of histone deacetylase inhibitors: from the hive to applications in human well-being and health. Epigenetics 2024; 19:2400423. [PMID: 39255363 PMCID: PMC11404605 DOI: 10.1080/15592294.2024.2400423] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2024] [Revised: 08/17/2024] [Accepted: 08/30/2024] [Indexed: 09/12/2024] Open
Abstract
A differential diet with royal jelly (RJ) during early larval development in honeybees shapes the phenotype, which is probably mediated by epigenetic regulation of gene expression. Evidence indicates that small molecules in RJ can modulate gene expression in mammalian cells, such as the fatty acid 10-hydroxy-2-decenoic acid (10-HDA), previously associated with the inhibition of histone deacetylase enzymes (HDACs). Therefore, we combined computational (molecular docking simulations) and experimental approaches for the screening of potential HDAC inhibitors (HDACi) among 32 RJ-derived fatty acids. Biochemical assays and gene expression analyses (Reverse Transcriptase - quantitative Polymerase Chain Reaction) were performed to evaluate the functional effects of the major RJ fatty acids, 10-HDA and 10-HDAA (10-hydroxy-decanoic acid), in two human cancer cell lines (HCT116 and MDA-MB-231). The molecular docking simulations indicate that these fatty acids might interact with class I HDACs, specifically with the catalytic domain of human HDAC2, likewise well-known HDAC inhibitors (HDACi) such as SAHA (suberoylanilide hydroxamic acid) and TSA (Trichostatin A). In addition, the combined treatment with 10-HDA and 10-HDAA inhibits the activity of human nuclear HDACs and leads to a slight increase in the expression of HDAC-coding genes in cancer cells. Our findings indicate that royal jelly fatty acids collectively contribute to HDAC inhibition and that 10-HDA and 10-HDAA are weak HDACi that facilitate the acetylation of lysine residues of chromatin, triggering an increase in gene expression levels in cancer cells.
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Affiliation(s)
| | - Debora Kazumi Maeda
- Department of Chemical and Biological Sciences, Institute of Biosciences of Botucatu, São Paulo State University (UNESP), Botucatu, SP, Brazil
| | - Ana Beatriz Rodrigues
- Department of Chemical and Biological Sciences, Institute of Biosciences of Botucatu, São Paulo State University (UNESP), Botucatu, SP, Brazil
| | - Mai Ono
- Department of Chemical and Biological Sciences, Institute of Biosciences of Botucatu, São Paulo State University (UNESP), Botucatu, SP, Brazil
| | - Franciele Lopes Nogueira Marchetti
- Department of Chemical and Biological Sciences, Institute of Biosciences of Botucatu, São Paulo State University (UNESP), Botucatu, SP, Brazil
| | - Marcos Martins Marchetti
- Department of Chemical and Biological Sciences, Institute of Biosciences of Botucatu, São Paulo State University (UNESP), Botucatu, SP, Brazil
| | | | | | - Cláudia Aparecida Rainho
- Department of Chemical and Biological Sciences, Institute of Biosciences of Botucatu, São Paulo State University (UNESP), Botucatu, SP, Brazil
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21
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Xu Z, Ye C, Wang X, Kong R, Chen Z, Shi J, Chen X, Liu S. Design and synthesis of triazolopyridine derivatives as potent JAK/HDAC dual inhibitors with broad-spectrum antiproliferative activity. J Enzyme Inhib Med Chem 2024; 39:2409771. [PMID: 39377432 PMCID: PMC11463018 DOI: 10.1080/14756366.2024.2409771] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Revised: 09/05/2024] [Accepted: 09/23/2024] [Indexed: 10/09/2024] Open
Abstract
A series of triazolopyridine-based dual JAK/HDAC inhibitors were rationally designed and synthesised by merging different pharmacophores into one molecule. All triazolopyridine derivatives exhibited potent inhibitory activities against both targets and the best compound 4-(((5-(benzo[d][1, 3]dioxol-5-yl)-[1, 2, 4]triazolo[1, 5-a]pyridin-2-yl)amino)methyl)-N-hydroxybenzamide (19) was dug out. 19 was proved to be a pan-HDAC and JAK1/2 dual inhibitor and displayed high cytotoxicity against two cancer cell lines MDA-MB-231 and RPMI-8226 with IC50 values in submicromolar range. Docking simulation revealed that 19 fitted well into the active sites of HDAC and JAK proteins. Moreover, 19 exhibited better metabolic stability in vitro than SAHA. Our study demonstrated that compound 19 was a promising candidate for further preclinical studies.
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Affiliation(s)
- Zhengshui Xu
- Department of Thoracic Surgery, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, P. R. China
- Key Laboratory of Surgery Critical Care and Life Support, Ministry of Education, Xi’an Jiaotong University, Xi’an, Shaanxi, P. R. China
| | - Changchun Ye
- Department of General Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, P. R. China
| | - Xingjie Wang
- Department of General Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, P. R. China
| | - Ranran Kong
- Department of Thoracic Surgery, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, P. R. China
| | - Zilu Chen
- Department of General Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, P. R. China
- Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA
| | - Jing Shi
- Department of Respiratory and Endocrinology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, P. R. China
| | - Xin Chen
- Shaanxi Key Labotory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University, Yangling, P. R. China
| | - Shiyuan Liu
- Department of Thoracic Surgery, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, P. R. China
- Key Laboratory of Surgery Critical Care and Life Support, Ministry of Education, Xi’an Jiaotong University, Xi’an, Shaanxi, P. R. China
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22
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Raouf YS, Moreno-Yruela C. Slow-Binding and Covalent HDAC Inhibition: A New Paradigm? JACS AU 2024; 4:4148-4161. [PMID: 39610753 PMCID: PMC11600154 DOI: 10.1021/jacsau.4c00828] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Revised: 10/21/2024] [Accepted: 10/23/2024] [Indexed: 11/30/2024]
Abstract
The dysregulated post-translational modification of proteins is an established hallmark of human disease. Through Zn2+-dependent hydrolysis of acyl-lysine modifications, histone deacetylases (HDACs) are key regulators of disease-implicated signaling pathways and tractable drug targets in the clinic. Early targeting of this family of 11 enzymes (HDAC1-11) afforded a first generation of broadly acting inhibitors with medicinal applications in oncology, specifically in cutaneous and peripheral T-cell lymphomas and in multiple myeloma. However, first-generation HDAC inhibitors are often associated with weak-to-modest patient benefits, dose-limited efficacies, pharmacokinetic liabilities, and recurring clinical toxicities. Alternative inhibitor design to target single enzymes and avoid toxic Zn2+-binding moieties have not overcome these limitations. Instead, recent literature has seen a shift toward noncanonical mechanistic approaches focused on slow-binding and covalent inhibition. Such compounds hold the potential of improving the pharmacokinetic and pharmacodynamic profiles of HDAC inhibitors through the extension of the drug-target residence time. This perspective aims to capture this emerging paradigm and discuss its potential to improve the preclinical/clinical outlook of HDAC inhibitors in the coming years.
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Affiliation(s)
- Yasir S. Raouf
- Department
of Chemistry, United Arab Emirates University, P.O. Box No. 15551 Al Ain, UAE
| | - Carlos Moreno-Yruela
- Laboratory
of Chemistry and Biophysics of Macromolecules (LCBM), Institute of
Chemical Sciences and Engineering (ISIC), School of Basic Sciences, École Polytechnique Fédérale
de Lausanne (EPFL), CH-1015 Lausanne, Switzerland
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23
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Hu W, Shen J, Zhou C, Tai Z, Zhu Q, Chen Z, Huang Y, Sheng C. Discovery of Janus Kinase and Histone Deacetylase Dual Inhibitors as a New Strategy to Treat Psoriasis. J Med Chem 2024; 67:19267-19281. [PMID: 39415349 DOI: 10.1021/acs.jmedchem.4c01681] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2024]
Abstract
Psoriasis is a common, chronic, recurrent, and inflammatory skin disease, which causes physical and psychological problems in patients and lacks effective and economic therapeutics. Herein, we designed Janus kinase (JAK) and histone deacetylase (HDAC) dual inhibitors as a new strategy for the treatment of psoriasis. In particular, compound 11i was identified with excellent inhibitory activity toward JAKs (JAK2 IC50 = 0.49 nM) and HDACs (HDAC6 IC50 = 12 nM). Moreover, it exhibited potent activities in inhibiting the proliferation of TNF-α-induced HaCAT cells and the production of nitric oxide. Importantly, compound 11i significantly ameliorated psoriasis-like skin lesions in an imiquimod-induced murine model with low toxicity, which was superior to JAK inhibitor momelotinib, HDAC inhibitor vorinostat, and their combination. This work provided a proof-of-concept for JAK/HDAC dual inhibitors as a promising strategy for the treatment of psoriasis.
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Affiliation(s)
- Weijie Hu
- School of Pharmaceutical Sciences, Wenzhou Medical University, Chashan Road, Wenzhou 325035, Zhejiang, People's Republic of China
| | - Jing Shen
- The Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), School of Pharmacy, Second Military Medical University (Naval Medical University), 325 Guohe Road, Shanghai 200433, People's Republic of China
| | - Chenchen Zhou
- The Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), School of Pharmacy, Second Military Medical University (Naval Medical University), 325 Guohe Road, Shanghai 200433, People's Republic of China
| | - Zongguang Tai
- Shanghai Skin Disease Hospital, School of Medicine, Tongji University, 1278 Baode Road, Shanghai 200443, People's Republic of China
| | - Quangang Zhu
- Shanghai Skin Disease Hospital, School of Medicine, Tongji University, 1278 Baode Road, Shanghai 200443, People's Republic of China
| | - Zhongjian Chen
- Shanghai Skin Disease Hospital, School of Medicine, Tongji University, 1278 Baode Road, Shanghai 200443, People's Republic of China
| | - Yahui Huang
- The Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), School of Pharmacy, Second Military Medical University (Naval Medical University), 325 Guohe Road, Shanghai 200433, People's Republic of China
| | - Chunquan Sheng
- School of Pharmaceutical Sciences, Wenzhou Medical University, Chashan Road, Wenzhou 325035, Zhejiang, People's Republic of China
- The Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), School of Pharmacy, Second Military Medical University (Naval Medical University), 325 Guohe Road, Shanghai 200433, People's Republic of China
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24
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Debbarma M, Sarkar K, Sil SK. Dissecting the epigenetic orchestra of HDAC isoforms in breast cancer development: a review. Med Oncol 2024; 42:1. [PMID: 39532757 DOI: 10.1007/s12032-024-02553-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Accepted: 10/29/2024] [Indexed: 11/16/2024]
Abstract
Epigenetic modulators have recently emerged as potential targets in cancer therapy. Breast cancer, the second leading cause of cancer-related deaths among women globally and the most common cancer in India, continues to have a low survival rate despite available treatments. This underscores the urgent need for more effective therapeutic strategies. Histone deacetylases (HDACs), a prominent class of epigenetic modulators, are frequently overexpressed in various cancers, including breast cancer, making them and their downstream pathways, a focus of current research, aiming to develop more effective and less invasive treatments that could help overcome chemoresistance and enhance patient outcomes. Despite the growing body of evidences, a comprehensive and consolidated review on molecular intricacy behind the HDAC-mediated epigenetic regulation of breast cancer is conspicuously absent. Therefore, this review aims to open doors for future research by exploring the evolving role of HDACs, their molecular mechanisms, and their potential as therapeutic targets in breast cancer treatment.
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Affiliation(s)
- Maria Debbarma
- Molecular Genetics & Cancer Biology Laboratory, Department of Human Physiology, Tripura University, Suryamaninagar, Tripura, 799022, India
| | - Kakali Sarkar
- Molecular Genetics & Cancer Biology Laboratory, Department of Human Physiology, Tripura University, Suryamaninagar, Tripura, 799022, India
| | - Samir Kumar Sil
- Molecular Genetics & Cancer Biology Laboratory, Department of Human Physiology, Tripura University, Suryamaninagar, Tripura, 799022, India.
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25
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Yue Z, Zhang Y, Zhang W, Zheng N, Wen J, Ren L, Rong X, Bai L, Wang R, Zhao S, Liu E, Wang W. Kaempferol alleviates myocardial ischemia injury by reducing oxidative stress via the HDAC3-mediated Nrf2 signaling pathway. J Adv Res 2024:S2090-1232(24)00491-0. [PMID: 39505146 DOI: 10.1016/j.jare.2024.10.037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2024] [Revised: 10/18/2024] [Accepted: 10/30/2024] [Indexed: 11/08/2024] Open
Abstract
INTRODUCTION Kaempferol (KAE) is a flavonoid found in various plants. Recent studies showed that high dietary intake of KAE was associated with a lower risk of myocardial infarction; however, the cardioprotective mechanism of KAE remains unknown. OBJECTIVES To determine the effect of KAE on cardiac injury in isoproterenol (ISO)-induced rats and cobalt chloride (CoCl2)-treated cardiomyocytes, and the underlying mechanisms. METHODS Male rats were pretreated with different doses of KAE for 14 days, and then injected with ISO to induce myocardial ischemia injury. We also established a model of myocardial cell injury using rat H9c2 cardiomyocytes stimulated with CoCl2. RESULTS We found that KAE pretreatment significantly alleviated myocardial injury and improved cardiac function in ISO-injected rats. In addition, KAE reduced oxidative stress in rats with myocardial ischemia by decreasing malondialdehyde concentration and increasing superoxide dismutase activity, and protection of the myocardial mitochondrial structure. KAE also attenuated CoCl2-induced injuryof H9c2 cardiomyocytes via suppression ofoxidative stress. With regard to the mechanism, we found that KAE down-regulated HDAC3 expression and up-regulated Nrf2 expression in ISO-induced rats and CoCl2-stimulated cardiomyocytes. Incubation of cardiomyocytes with HDAC3-selective inhibitor RGFP966 augmented the protective effect of KAE and reduced oxidative stress. By contrast, HDAC3 overexpression by adenovirus attenuated the effect of KAE on oxidative stress compared with KAE treatment group. HDAC3 also regulated Nrf2 expression in the cardiomyocytes with RGFP966 or an adenovirus overexpressing HDAC3; but Nrf2 inhibition reduced the effect of KAE on ROS generation in CoCl2-induced cardiomyocytes. Immunoprecipitation assay showed that HDAC3 interacted with Nrf2 in cardiomyocytes. Further studies found that KAE increased the acetylation level of Nrf2, while HDAC3 overexpression decreased the acetylation of Nrf2 compared with KAE treatment group. CONCLUSION Our data show that KAE ameliorates cardiac injury by reducing oxidative stress via the HDAC3-mediated Nrf2 signaling pathway in cardiomyocytes.
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Affiliation(s)
- Zejun Yue
- Institute of Cardiovascular Science, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an 710061, China; Laboratory Animal Center, Xi'an Jiaotong University, Xi'an 710061, China
| | - Yirong Zhang
- Institute of Cardiovascular Science, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an 710061, China; Laboratory Animal Center, Xi'an Jiaotong University, Xi'an 710061, China
| | - Wei Zhang
- Department of Cardiovascular Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China
| | - Nanbo Zheng
- Department of Pharmacology, Xi'an Jiaotong University Health Science Center, Xi'an 710061, China
| | - Jiazheng Wen
- Institute of Cardiovascular Science, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an 710061, China; Laboratory Animal Center, Xi'an Jiaotong University, Xi'an 710061, China
| | - Lingxuan Ren
- Department of Pharmacology, Xi'an Jiaotong University Health Science Center, Xi'an 710061, China
| | - Xiaoyu Rong
- Institute of Cardiovascular Science, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an 710061, China; Laboratory Animal Center, Xi'an Jiaotong University, Xi'an 710061, China
| | - Liang Bai
- Institute of Cardiovascular Science, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an 710061, China; Laboratory Animal Center, Xi'an Jiaotong University, Xi'an 710061, China
| | - Rong Wang
- Institute of Cardiovascular Science, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an 710061, China; Laboratory Animal Center, Xi'an Jiaotong University, Xi'an 710061, China
| | - Sihai Zhao
- Institute of Cardiovascular Science, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an 710061, China; Laboratory Animal Center, Xi'an Jiaotong University, Xi'an 710061, China
| | - Enqi Liu
- Institute of Cardiovascular Science, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an 710061, China; Laboratory Animal Center, Xi'an Jiaotong University, Xi'an 710061, China
| | - Weirong Wang
- Institute of Cardiovascular Science, Translational Medicine Institute, Xi'an Jiaotong University Health Science Center, Xi'an 710061, China; Laboratory Animal Center, Xi'an Jiaotong University, Xi'an 710061, China.
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26
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Graf LG, Moreno-Yruela C, Qin C, Schulze S, Palm GJ, Schmöker O, Wang N, Hocking DM, Jebeli L, Girbardt B, Berndt L, Dörre B, Weis DM, Janetzky M, Albrecht D, Zühlke D, Sievers S, Strugnell RA, Olsen CA, Hofmann K, Lammers M. Distribution and diversity of classical deacylases in bacteria. Nat Commun 2024; 15:9496. [PMID: 39489725 PMCID: PMC11532494 DOI: 10.1038/s41467-024-53903-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Accepted: 10/25/2024] [Indexed: 11/05/2024] Open
Abstract
Classical Zn2+-dependent deac(et)ylases play fundamental regulatory roles in life and are well characterized in eukaryotes regarding their structures, substrates and physiological roles. In bacteria, however, classical deacylases are less well understood. We construct a Generalized Profile (GP) and identify thousands of uncharacterized classical deacylases in bacteria, which are grouped into five clusters. Systematic structural and functional characterization of representative enzymes from each cluster reveal high functional diversity, including polyamine deacylases and protein deacylases with various acyl-chain type preferences. These data are supported by multiple crystal structures of enzymes from different clusters. Through this extensive analysis, we define the structural requirements of substrate selectivity, and discovered bacterial de-D-/L-lactylases and long-chain deacylases. Importantly, bacterial deacylases are inhibited by archetypal HDAC inhibitors, as supported by co-crystal structures with the inhibitors SAHA and TSA, and setting the ground for drug repurposing strategies to fight bacterial infections. Thus, we provide a systematic structure-function analysis of classical deacylases in bacteria and reveal the basis of substrate specificity, acyl-chain preference and inhibition.
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Affiliation(s)
- Leonie G Graf
- Department Synthetic and Structural Biochemistry, Institute of Biochemistry, University of Greifswald, Greifswald, Germany
| | - Carlos Moreno-Yruela
- Center for Biopharmaceuticals & Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Institute of Chemical Sciences and Engineering (ISIC), School of Basic Sciences (SB), EPFL, Lausanne, Switzerland
| | - Chuan Qin
- Department Synthetic and Structural Biochemistry, Institute of Biochemistry, University of Greifswald, Greifswald, Germany
| | - Sabrina Schulze
- Department Synthetic and Structural Biochemistry, Institute of Biochemistry, University of Greifswald, Greifswald, Germany
| | - Gottfried J Palm
- Department Synthetic and Structural Biochemistry, Institute of Biochemistry, University of Greifswald, Greifswald, Germany
| | - Ole Schmöker
- Department Synthetic and Structural Biochemistry, Institute of Biochemistry, University of Greifswald, Greifswald, Germany
| | - Nancy Wang
- Peter Doherty Institute for Infection and Immunity, Department of Microbiology and Immunology, The University of Melbourne, Melbourne, VIC, Australia
| | - Dianna M Hocking
- Peter Doherty Institute for Infection and Immunity, Department of Microbiology and Immunology, The University of Melbourne, Melbourne, VIC, Australia
| | - Leila Jebeli
- Peter Doherty Institute for Infection and Immunity, Department of Microbiology and Immunology, The University of Melbourne, Melbourne, VIC, Australia
| | - Britta Girbardt
- Department Synthetic and Structural Biochemistry, Institute of Biochemistry, University of Greifswald, Greifswald, Germany
| | - Leona Berndt
- Department Synthetic and Structural Biochemistry, Institute of Biochemistry, University of Greifswald, Greifswald, Germany
| | - Babett Dörre
- Department Synthetic and Structural Biochemistry, Institute of Biochemistry, University of Greifswald, Greifswald, Germany
| | - Daniel M Weis
- Department Synthetic and Structural Biochemistry, Institute of Biochemistry, University of Greifswald, Greifswald, Germany
| | - Markus Janetzky
- Department Synthetic and Structural Biochemistry, Institute of Biochemistry, University of Greifswald, Greifswald, Germany
| | - Dirk Albrecht
- Department of Microbial Physiology and Molecular Biology, Institute of Microbiology, University of Greifswald, Greifswald, Germany
| | - Daniela Zühlke
- Department of Microbial Physiology and Molecular Biology, Institute of Microbiology, University of Greifswald, Greifswald, Germany
| | - Susanne Sievers
- Department of Microbial Physiology and Molecular Biology, Institute of Microbiology, University of Greifswald, Greifswald, Germany
| | - Richard A Strugnell
- Peter Doherty Institute for Infection and Immunity, Department of Microbiology and Immunology, The University of Melbourne, Melbourne, VIC, Australia
| | - Christian A Olsen
- Center for Biopharmaceuticals & Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Kay Hofmann
- Institute for Genetics, University of Cologne, Cologne, Germany
| | - Michael Lammers
- Department Synthetic and Structural Biochemistry, Institute of Biochemistry, University of Greifswald, Greifswald, Germany.
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27
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Ray P, Sedigh A, Confeld M, Alhalhooly L, Iduoku K, Casanola-Martin GM, Pham-The H, Rasulev B, Choi Y, Yang Z, Mallik S, Quadir M. Design and evaluation of nanoscale materials with programmed responsivity towards epigenetic enzymes. J Mater Chem B 2024; 12:9905-9920. [PMID: 39021201 DOI: 10.1039/d4tb00514g] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/20/2024]
Abstract
Self-assembled materials capable of modulating their assembly properties in response to specific enzymes play a pivotal role in advancing 'intelligent' encapsulation platforms for biotechnological applications. Here, we introduce a previously unreported class of synthetic nanomaterials that programmatically interact with histone deacetylase (HDAC) as the triggering stimulus for disassembly. These nanomaterials consist of co-polypeptides comprising poly(acetyl L-lysine) and poly(ethylene glycol) blocks. Under neutral pH conditions, they self-assemble into particles. The hydrodynamic diameters of particles were typically withing the range of 108-190 nm, depending on degree of acetylation of the hydrophobic block. However, their stability is compromised upon exposure to HDACs, depending on enzyme concentration and exposure time. Our investigation, utilizing HDAC8 as the model enzyme, revealed that the primary mechanism behind disassembly involves a decrease in amphiphilicity within the block copolymer due to the deacetylation of lysine residues within the particles' hydrophobic domains. To elucidate the response mechanism, we encapsulated a fluorescent dye within these nanoparticles. Upon incubation with HDAC, the nanoparticle structure collapsed, leading to controlled release of the dye over time. Notably, this release was not triggered by denatured HDAC8, other proteolytic enzymes like trypsin, or the co-presence of HDAC8 and its inhibitor. We also demonstrated the biocompatibility and cellular effects of these materials in the context of drug delivery in different types of anticancer cell lines, such as MIA PaCa-2, PANC-1, cancer like stem cells (CSCs), and non-cancerous HPNE cells. We observed that the release of a model drug (such as a STAT3 pathway inhibitor, Napabucasin) can be loaded into these nanoparticles, with >90% of the dosage can be released over 3 h under the influence of HDAC8 enzyme in a controlled fashion. Further, we conducted a comprehensive computational study to unveil the possible interaction mechanism between enzymes and particles. By drawing parallels to the mechanism of naturally occurring histone proteins, this research represents a pioneering step toward developing functional materials capable of harnessing the activity of epigenetic enzymes such as HDACs.
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Affiliation(s)
- Priyanka Ray
- Department of Coatings and Polymeric Materials, North Dakota State University, Fargo, ND 58102, USA.
| | - Abbas Sedigh
- Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND 58102, USA
| | - Matthew Confeld
- Deapartment of Physics, North Dakota State University, Fargo, ND 58102, USA
| | - Lina Alhalhooly
- Department of Chemistry and Biochemistry, North Dakota State University, Fargo, ND 58102, USA
| | - Kweeni Iduoku
- Department of Coatings and Polymeric Materials, North Dakota State University, Fargo, ND 58102, USA.
| | - Gerardo M Casanola-Martin
- Department of Coatings and Polymeric Materials, North Dakota State University, Fargo, ND 58102, USA.
| | - Hai Pham-The
- University of Science and Technology of Hanoi, Vietnam Academy of Science and Technology, 18 Hoang Quoc Viet, Cau Giay, Hanoi 10000, Vietnam
| | - Bakhtiyor Rasulev
- Department of Coatings and Polymeric Materials, North Dakota State University, Fargo, ND 58102, USA.
| | - Yongki Choi
- Department of Chemistry and Biochemistry, North Dakota State University, Fargo, ND 58102, USA
| | - Zhongyu Yang
- Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND 58102, USA
| | - Sanku Mallik
- Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND 58102, USA
| | - Mohiuddin Quadir
- Department of Coatings and Polymeric Materials, North Dakota State University, Fargo, ND 58102, USA.
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28
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Kujawowicz K, Mirończuk-Chodakowska I, Witkowska AM. Sirtuin 1 as a potential biomarker of undernutrition in the elderly: a narrative review. Crit Rev Food Sci Nutr 2024; 64:9532-9553. [PMID: 37229564 DOI: 10.1080/10408398.2023.2214208] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/27/2023]
Abstract
Undernutrition and inflammatory processes are predictors of early mortality in the elderly and require a rapid and accurate diagnosis. Currently, there are laboratory markers for assessing nutritional status, but new markers are still being sought. Recent studies suggest that sirtuin 1 (SIRT1) has the potential to be a marker for undernutrition. This article summarizes available studies on the association of SIRT1 and undernutrition in older people. Possible associations between SIRT1 and the aging process, inflammation, and undernutrition in the elderly have been described. The literature suggests that low SIRT1 levels in the blood of older people may not be associated with physiological aging processes, but with an increased risk of severe undernutrition associated with inflammation and systemic metabolic changes.
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Affiliation(s)
- Karolina Kujawowicz
- Department of Food Biotechnology, Medical University of Bialystok, Bialystok, Poland
| | | | - Anna Maria Witkowska
- Department of Food Biotechnology, Medical University of Bialystok, Bialystok, Poland
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29
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Sang C, Li X, Liu J, Chen Z, Xia M, Yu M, Yu W. Reversible acetylation of HDAC8 regulates cell cycle. EMBO Rep 2024; 25:3925-3943. [PMID: 39043961 PMCID: PMC11387496 DOI: 10.1038/s44319-024-00210-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Revised: 05/28/2024] [Accepted: 07/05/2024] [Indexed: 07/25/2024] Open
Abstract
HDAC8, a member of class I HDACs, plays a pivotal role in cell cycle regulation by deacetylating the cohesin subunit SMC3. While cyclins and CDKs are well-established cell cycle regulators, our knowledge of other regulators remains limited. Here we reveal the acetylation of K202 in HDAC8 as a key cell cycle regulator responsive to stress. K202 acetylation in HDAC8, primarily catalyzed by Tip60, restricts HDAC8 activity, leading to increased SMC3 acetylation and cell cycle arrest. Furthermore, cells expressing the mutant form of HDAC8 mimicking K202 acetylation display significant alterations in gene expression, potentially linked to changes in 3D genome structure, including enhanced chromatid loop interactions. K202 acetylation impairs cell cycle progression by disrupting the expression of cell cycle-related genes and sister chromatid cohesion, resulting in G2/M phase arrest. These findings indicate the reversible acetylation of HDAC8 as a cell cycle regulator, expanding our understanding of stress-responsive cell cycle dynamics.
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Affiliation(s)
- Chaowei Sang
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, 200438, Shanghai, China
| | - Xuedong Li
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, 200438, Shanghai, China
| | - Jingxuan Liu
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, 200438, Shanghai, China
| | - Ziyin Chen
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, 200438, Shanghai, China
| | - Minhui Xia
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, 200438, Shanghai, China
| | - Miao Yu
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, 200438, Shanghai, China
| | - Wei Yu
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, 200438, Shanghai, China.
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30
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Fang J, Shu S, Dong H, Yue X, Piao J, Li S, Hong L, Cheng XW. Histone deacetylase 6 controls cardiac fibrosis and remodelling through the modulation of TGF-β1/Smad2/3 signalling in post-infarction mice. J Cell Mol Med 2024; 28:e70063. [PMID: 39232846 PMCID: PMC11374528 DOI: 10.1111/jcmm.70063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Revised: 08/19/2024] [Accepted: 08/22/2024] [Indexed: 09/06/2024] Open
Abstract
Histone deacetylase 6 (HDAC6) belongs to the class IIb group of the histone deacetylase family, which participates in remodelling of various tissues. Herein, we sought to examine the potential regulation of HDAC6 in cardiac remodelling post-infarction. Experimental myocardial infarction (MI) was created in HDAC6-deficient (HDAC6-/-) mice and wild-type (HADC6+/+) by left coronary artery ligation. At days 0 and 14 post-MI, we evaluated cardiac function, morphology and molecular endpoints of repair and remodelling. At day 14 after surgery, the ischemic myocardium had increased levels of HADC6 gene and protein of post-MI mice compared to the non-ischemic myocardium of control mice. As compared with HDAC6-/--MI mice, HADC6 deletion markedly improved infarct size and cardiac fibrosis as well as impaired left ventricular ejection fraction and left ventricular fraction shortening. At the molecular levels, HDAC6-/- resulted in a significant reduction in the levels of the transforming growth factor-beta 1 (TGF-β1), phosphor-Smad-2/3, collagen I and collagen III proteins and/or in the ischemic cardiac tissues. All of these beneficial effects were reproduced by a pharmacological inhibition of HADC6 in vivo. In vitro, hypoxic stress increased the expressions of HADC6 and collagen I and III gene; these alterations were significantly prevented by the HADC6 silencing and TubA loading. These findings indicated that HADC6 deficiency resists ischemic injury by a reduction of TGF-β1/Smad2/3 signalling activation, leading to decreased extracellular matrix production, which reduces cardiac fibrosis and dysfunction, providing a potential molecular target in the treatment of patients with MI.
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Affiliation(s)
- Junqiao Fang
- Department of Cardiology and Hypertension, Jilin Provincial Key Laboratory of Stress and Cardiovascular DiseaseYanbian University HospitalYanjiJilinChina
- Department of Cardiology, The Wuxi Fifth People's HospitalThe Fifth Affiliated Hospital of Jiangnan UniversityWuxiJiangshuChina
| | - Shangzhi Shu
- Department of CardiologyThe First Hospital of Jilin UniversityChangchunJilinChina
| | - Hui Dong
- Department of Physiology and Pathophysiology, College of MedicineYanbian UniversityYanjinJilinChina
| | - Xueling Yue
- Department of Cardiology and Hypertension, Jilin Provincial Key Laboratory of Stress and Cardiovascular DiseaseYanbian University HospitalYanjiJilinChina
| | - Jinshun Piao
- Department of Cardiology and Hypertension, Jilin Provincial Key Laboratory of Stress and Cardiovascular DiseaseYanbian University HospitalYanjiJilinChina
- Department of Cardiology, The Wuxi Fifth People's HospitalThe Fifth Affiliated Hospital of Jiangnan UniversityWuxiJiangshuChina
| | - Shuyan Li
- Department of CardiologyThe First Hospital of Jilin UniversityChangchunJilinChina
| | - Lan Hong
- Department of Physiology and Pathophysiology, College of MedicineYanbian UniversityYanjinJilinChina
| | - Xian Wu Cheng
- Department of Cardiology and Hypertension, Jilin Provincial Key Laboratory of Stress and Cardiovascular DiseaseYanbian University HospitalYanjiJilinChina
- Key Laboratory of Natural Medicines of the Changbai Mountain, Ministry of EducationYanbian UniversityYanjiJilinChina
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31
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Asmamaw MD, He A, Zhang LR, Liu HM, Gao Y. Histone deacetylase complexes: Structure, regulation and function. Biochim Biophys Acta Rev Cancer 2024; 1879:189150. [PMID: 38971208 DOI: 10.1016/j.bbcan.2024.189150] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Revised: 06/07/2024] [Accepted: 07/01/2024] [Indexed: 07/08/2024]
Abstract
Histone deacetylases (HDACs) are key epigenetic regulators, and transcriptional complexes with deacetylase function are among the epigenetic corepressor complexes in the nucleus that target the epigenome. HDAC-bearing corepressor complexes such as the Sin3 complex, NuRD complex, CoREST complex, and SMRT/NCoR complex are common in biological systems. These complexes activate the otherwise inactive HDACs in a solitary state. HDAC complexes play vital roles in the regulation of key biological processes such as transcription, replication, and DNA repair. Moreover, deregulated HDAC complex function is implicated in human diseases including cancer. Therapeutic strategies targeting HDAC complexes are being sought actively. Thus, illustration of the nature and composition of HDAC complexes is vital to understanding the molecular basis of their functions under physiologic and pathologic conditions, and for designing targeted therapies. This review presents key aspects of large multiprotein HDAC-bearing complexes including their structure, function, regulatory mechanisms, implication in disease development, and role in therapeutics.
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Affiliation(s)
- Moges Dessale Asmamaw
- Department of Pharmacology, School of Basic Medical Sciences, State Key Laboratory for Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou, Henan Province 450001, China
| | - Ang He
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Drug Discovery and Development, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan Province 450001, China
| | - Li-Rong Zhang
- Department of Pharmacology, School of Basic Medical Sciences, State Key Laboratory for Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou, Henan Province 450001, China.
| | - Hong-Min Liu
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Drug Discovery and Development, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan Province 450001, China.
| | - Ya Gao
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, Key Laboratory of Henan Province for Drug Quality and Evaluation, Institute of Drug Discovery and Development, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan Province 450001, China.
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Phull AR, Arain SQ, Majid A, Fatima H, Ahmed M, Kim SJ. Oxidative stress-mediated epigenetic remodeling, metastatic progression and cell signaling in cancer. ONCOLOGIE 2024; 26:493-507. [DOI: 10.1515/oncologie-2024-0157] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/16/2024]
Abstract
Abstract
Cancer is a serious public health issue and cases are rising at a high rate around the world. Altered production of reactive oxygen species (ROS) causes oxidative stress (OS) which plays a vital role in cancer development by disrupting signaling pathways and genomic integrity in the cellular microenvironment. In this study, we reviewed the regulation of noncoding RNAs, histone modifications, and DNA methylation which OS is involved in. These mechanisms promote cancer growth, metastasis, and resistance to chemotherapeutic agents. There is significant potential to improve patient outcomes through the development of customized medications and interventions that precisely address the role of OS in the onset and progression of cancer. Redox-modulating drugs, antioxidant-based therapies, and measures to restore regular cellular activity and OS-modulated signaling pathways are some examples of these strategies. One other hypothesis rationalizes the cancer-suppressing effect of OS, which acts as a two-edged condition that warns against the use of antioxidants for cancer treatment and management. The present study was executed to review the impact of OS on epigenetic machinery, the evolution of metastatic cancer, and how OS mediates cellular signaling. Along with, insights into the potential of targeting OS-mediated mechanisms for cancer therapy.
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Affiliation(s)
- Abdul-Rehman Phull
- Department of Biochemistry , 66858 Shah Abdul Latif University , Khairpur , Sindh , Pakistan
| | - Sadia Qamar Arain
- Department of Biochemistry , 66858 Shah Abdul Latif University , Khairpur , Sindh , Pakistan
| | - Abdul Majid
- Department of Biochemistry , 66858 Shah Abdul Latif University , Khairpur , Sindh , Pakistan
| | - Humaira Fatima
- Department of Pharmacy , Quaid-i-Azam University , Islamabad , Pakistan
| | - Madiha Ahmed
- Shifa College of Pharmaceutical Sciences , Shifa Tameer-e-Millat University , Islamabad , Pakistan
| | - Song-Ja Kim
- Department of Biological Sciences, College of Natural Sciences , Kongju National University , Gongju , South Korea
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Ming S, Zhang S, Xing J, Yang G, Zeng L, Wang J, Chu B. Alphaherpesvirus manipulates retinoic acid metabolism for optimal replication. iScience 2024; 27:110144. [PMID: 38989466 PMCID: PMC11233922 DOI: 10.1016/j.isci.2024.110144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Revised: 04/29/2024] [Accepted: 05/27/2024] [Indexed: 07/12/2024] Open
Abstract
Retinoic acid (RA), derived from retinol (ROL), is integral to cell growth, differentiation, and organogenesis. It is known that RA can inhibit herpes simplex virus (HSV) replication, but the interactions between alphaherpesviruses and RA metabolism are unclear. Our present study revealed that alphaherpesvirus (HSV-1 and Pseudorabies virus, PRV) infections suppressed RA synthesis from ROL by activating P53, which increased retinol reductase 3 (DHRS3) expression-an enzyme that converts retinaldehyde back to ROL. This process depended on the virus-triggered DNA damage response, the degradation of class I histone deacetylases, and the subsequent hyperacetylation of histones H3 and H4. Counteracting DHRS3 or P53 enabled higher RA synthesis and reduced viral growth. RA enhanced antiviral defenses by promoting ABCA1- and ABCG1-mediated lipid efflux. Treatment with the retinoic acid receptor (RAR) agonist palovarotene protected mice from HSV-1 infection, thus providing a potential therapeutic strategy against viral infections.
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Affiliation(s)
- Shengli Ming
- College of Veterinary Medicine, Henan Agricultural University, Zhengzhou 450046, Henan Province, China
- Key Laboratory of Animal Biochemistry and Nutrition, Ministry of Agriculture and Rural Affairs, Zhengzhou, Henan Province 450046, China
- Key Laboratory of Animal Growth and Development of Henan Province, Henan Agricultural University, Zhengzhou 450046, Henan Province, China
| | - Shijun Zhang
- College of Veterinary Medicine, Henan Agricultural University, Zhengzhou 450046, Henan Province, China
- Key Laboratory of Animal Biochemistry and Nutrition, Ministry of Agriculture and Rural Affairs, Zhengzhou, Henan Province 450046, China
- Key Laboratory of Animal Growth and Development of Henan Province, Henan Agricultural University, Zhengzhou 450046, Henan Province, China
| | - Jiayou Xing
- College of Veterinary Medicine, Henan Agricultural University, Zhengzhou 450046, Henan Province, China
- Key Laboratory of Animal Biochemistry and Nutrition, Ministry of Agriculture and Rural Affairs, Zhengzhou, Henan Province 450046, China
- Key Laboratory of Animal Growth and Development of Henan Province, Henan Agricultural University, Zhengzhou 450046, Henan Province, China
| | - Guoyu Yang
- Key Laboratory of Animal Biochemistry and Nutrition, Ministry of Agriculture and Rural Affairs, Zhengzhou, Henan Province 450046, China
- Key Laboratory of Animal Growth and Development of Henan Province, Henan Agricultural University, Zhengzhou 450046, Henan Province, China
- International Joint Research Center of National Animal Immunology, Henan Agricultural University, Zhengzhou 450046, Henan Province, China
| | - Lei Zeng
- College of Veterinary Medicine, Henan Agricultural University, Zhengzhou 450046, Henan Province, China
- Key Laboratory of Animal Biochemistry and Nutrition, Ministry of Agriculture and Rural Affairs, Zhengzhou, Henan Province 450046, China
- Key Laboratory of Animal Growth and Development of Henan Province, Henan Agricultural University, Zhengzhou 450046, Henan Province, China
| | - Jiang Wang
- College of Veterinary Medicine, Henan Agricultural University, Zhengzhou 450046, Henan Province, China
- Key Laboratory of Animal Biochemistry and Nutrition, Ministry of Agriculture and Rural Affairs, Zhengzhou, Henan Province 450046, China
- Key Laboratory of Animal Growth and Development of Henan Province, Henan Agricultural University, Zhengzhou 450046, Henan Province, China
- Ministry of Education Key Laboratory for Animal Pathogens and Biosafety, Zhengzhou 450046, Henan Province, China
| | - Beibei Chu
- College of Veterinary Medicine, Henan Agricultural University, Zhengzhou 450046, Henan Province, China
- Key Laboratory of Animal Biochemistry and Nutrition, Ministry of Agriculture and Rural Affairs, Zhengzhou, Henan Province 450046, China
- Key Laboratory of Animal Growth and Development of Henan Province, Henan Agricultural University, Zhengzhou 450046, Henan Province, China
- International Joint Research Center of National Animal Immunology, Henan Agricultural University, Zhengzhou 450046, Henan Province, China
- Ministry of Education Key Laboratory for Animal Pathogens and Biosafety, Zhengzhou 450046, Henan Province, China
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Maciejewski K, Giers M, Oleksiewicz U, Czerwinska P. The Epigenetic Modifiers HDAC2 and HDAC7 Inversely Associate with Cancer Stemness and Immunity in Solid Tumors. Int J Mol Sci 2024; 25:7841. [PMID: 39063083 PMCID: PMC11277355 DOI: 10.3390/ijms25147841] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Revised: 07/07/2024] [Accepted: 07/13/2024] [Indexed: 07/28/2024] Open
Abstract
Dysregulation of histone deacetylases (HDACs) is closely associated with cancer development and progression. Here, we comprehensively analyzed the association between all HDAC family members and several clinicopathological and molecular traits of solid tumors across 22 distinct tumor types, focusing primarily on cancer stemness and immunity. To this end, we used publicly available TCGA data and several bioinformatic tools (i.e., GEPIA2, TISIDB, GSCA, Enrichr, GSEA). Our analyses revealed that class I and class II HDAC proteins are associated with distinct cancer phenotypes. The transcriptomic profiling indicated that class I HDAC members, including HDAC2, are positively associated with cancer stemness, while class IIA HDAC proteins, represented by HDAC7, show a negative correlation to cancer stem cell-like phenotypes in solid tumors. In contrast to tumors with high amounts of HDAC7 proteins, the transcriptome signatures of HDAC2-overexpressing cancers are significantly enriched with biological terms previously determined as stemness-associated genes. Moreover, high HDAC2-expressing tumors are depleted with immune-related processes, and HDAC2 expression correlates with tumor immunosuppressive microenvironments. On the contrary, HDAC7 upregulation is significantly associated with enhanced immune responses, followed by enriched infiltration of CD4+ and CD8+ T cells. This is the first comprehensive report demonstrating robust and versatile associations between specific HDAC family members, cancer dedifferentiation, and anti-tumor immune statuses in solid tumors.
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Affiliation(s)
- Kacper Maciejewski
- Undergraduate Research Group “Biobase”, Poznan University of Medical Sciences, 61-701 Poznan, Poland; (K.M.); (M.G.)
| | - Marek Giers
- Undergraduate Research Group “Biobase”, Poznan University of Medical Sciences, 61-701 Poznan, Poland; (K.M.); (M.G.)
| | - Urszula Oleksiewicz
- Department of Cancer Immunology, Poznan University of Medical Sciences, 61-866 Poznan, Poland
- Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, 61-866 Poznan, Poland
| | - Patrycja Czerwinska
- Undergraduate Research Group “Biobase”, Poznan University of Medical Sciences, 61-701 Poznan, Poland; (K.M.); (M.G.)
- Department of Cancer Immunology, Poznan University of Medical Sciences, 61-866 Poznan, Poland
- Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, 61-866 Poznan, Poland
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35
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Rizo J, Encarnación-Guevara S. Bacterial protein acetylation: mechanisms, functions, and methods for study. Front Cell Infect Microbiol 2024; 14:1408947. [PMID: 39027134 PMCID: PMC11254643 DOI: 10.3389/fcimb.2024.1408947] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2024] [Accepted: 06/03/2024] [Indexed: 07/20/2024] Open
Abstract
Lysine acetylation is an evolutionarily conserved protein modification that changes protein functions and plays an essential role in many cellular processes, such as central metabolism, transcriptional regulation, chemotaxis, and pathogen virulence. It can alter DNA binding, enzymatic activity, protein-protein interactions, protein stability, or protein localization. In prokaryotes, lysine acetylation occurs non-enzymatically and by the action of lysine acetyltransferases (KAT). In enzymatic acetylation, KAT transfers the acetyl group from acetyl-CoA (AcCoA) to the lysine side chain. In contrast, acetyl phosphate (AcP) is the acetyl donor of chemical acetylation. Regardless of the acetylation type, the removal of acetyl groups from acetyl lysines occurs only enzymatically by lysine deacetylases (KDAC). KATs are grouped into three main superfamilies based on their catalytic domain sequences and biochemical characteristics of catalysis. Specifically, members of the GNAT are found in eukaryotes and prokaryotes and have a core structural domain architecture. These enzymes can acetylate small molecules, metabolites, peptides, and proteins. This review presents current knowledge of acetylation mechanisms and functional implications in bacterial metabolism, pathogenicity, stress response, translation, and the emerging topic of protein acetylation in the gut microbiome. Additionally, the methods used to elucidate the biological significance of acetylation in bacteria, such as relative quantification and stoichiometry quantification, and the genetic code expansion tool (CGE), are reviewed.
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Affiliation(s)
| | - Sergio Encarnación-Guevara
- Laboratorio de Proteómica, Centro de Ciencias Genómicas, Universidad Nacional Autónoma de México, Cuernavaca, Mexico
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36
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Yamauchi Y, Shimizu E, Duncan HF. Dynamic Alterations in Acetylation and Modulation of Histone Deacetylase Expression Evident in the Dentine-Pulp Complex during Dentinogenesis. Int J Mol Sci 2024; 25:6569. [PMID: 38928274 PMCID: PMC11203584 DOI: 10.3390/ijms25126569] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Revised: 06/07/2024] [Accepted: 06/12/2024] [Indexed: 06/28/2024] Open
Abstract
Epigenetic modulation, including histone modification, alters gene expression and controls cell fate. Histone deacetylases (HDACs) are identified as important regulators of dental pulp cell (DPC) mineralisation processes. Currently, there is a paucity of information regarding the nature of histone modification and HDAC expression in the dentine-pulp complex during dentinogenesis. The aim of this study was to investigate post-translational histone modulation and HDAC expression during DPC mineralisation and the expression of Class I/II HDACs during tooth development and in adult teeth. HDAC expression (isoforms -1 to -6) was analysed in mineralising primary rat DPCs using qRT-PCR and Western blot with mass spectrometry being used to analyse post-translational histone modifications. Maxillary molar teeth from postnatal and adult rats were analysed using immunohistochemical (IHC) staining for HDACs (1-6). HDAC-1, -2, and -4 protein expression increased until days 7 and 11, but decreased at days 14 and 21, while other HDAC expression increased continuously for 21 days. The Class II mineralisation-associated HDAC-4 was strongly expressed in postnatal sample odontoblasts and DPCs, but weakly in adult teeth, while other Class II HDACs (-5, -6) were relatively strongly expressed in postnatal DPCs and adult odontoblasts. Among Class I HDACs, HDAC-1 showed high expression in postnatal teeth, notably in ameloblasts and odontoblasts. HDAC-2 and -3 had extremely low expression in the rat dentine-pulp complex. Significant increases in acetylation were noted during DPC mineralisation processes, while trimethylation H3K9 and H3K27 marks decreased, and the HDAC-inhibitor suberoylanilide hydroxamic acid (SAHA) enhanced H3K27me3. These results highlight a dynamic alteration in histone acetylation during mineralisation and indicate the relevance of Class II HDAC expression in tooth development and regenerative processes.
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Affiliation(s)
- Yukako Yamauchi
- Division of Restorative Dentistry & Periodontology, Dublin Dental University Hospital, Trinity College Dublin, Lincoln Place, D02 F859 Dublin, Ireland;
| | - Emi Shimizu
- Department of Oral Biology, Rutgers School of Dental Medicine, Newark, NJ 07103, USA;
| | - Henry F. Duncan
- Division of Restorative Dentistry & Periodontology, Dublin Dental University Hospital, Trinity College Dublin, Lincoln Place, D02 F859 Dublin, Ireland;
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Umar M, Rehman Y, Ambreen S, Mumtaz SM, Shaququzzaman M, Alam MM, Ali R. Innovative approaches to Alzheimer's therapy: Harnessing the power of heterocycles, oxidative stress management, and nanomaterial drug delivery system. Ageing Res Rev 2024; 97:102298. [PMID: 38604453 DOI: 10.1016/j.arr.2024.102298] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Revised: 03/10/2024] [Accepted: 04/05/2024] [Indexed: 04/13/2024]
Abstract
Alzheimer's disease (AD) presents a complex pathology involving amyloidogenic proteolysis, neuroinflammation, mitochondrial dysfunction, and cholinergic deficits. Oxidative stress exacerbates AD progression through pathways like macromolecular peroxidation, mitochondrial dysfunction, and metal ion redox potential alteration linked to amyloid-beta (Aβ). Despite limited approved medications, heterocyclic compounds have emerged as promising candidates in AD drug discovery. This review highlights recent advancements in synthetic heterocyclic compounds targeting oxidative stress, mitochondrial dysfunction, and neuroinflammation in AD. Additionally, it explores the potential of nanomaterial-based drug delivery systems to overcome challenges in AD treatment. Nanoparticles with heterocyclic scaffolds, like polysorbate 80-coated PLGA and Resveratrol-loaded nano-selenium, show improved brain transport and efficacy. Micellar CAPE and Melatonin-loaded nano-capsules exhibit enhanced antioxidant properties, while a tetra hydroacridine derivative (CHDA) combined with nano-radiogold particles demonstrates promising acetylcholinesterase inhibition without toxicity. This comprehensive review underscores the potential of nanotechnology-driven drug delivery for optimizing the therapeutic outcomes of novel synthetic heterocyclic compounds in AD management. Furthermore, the inclusion of various promising heterocyclic compounds with detailed ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) data provides valuable insights for planning the development of novel drug delivery treatments for AD.
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Affiliation(s)
- Mohammad Umar
- Department of Pharmaceutical Chemistry, Delhi Pharmaceutical Sciences and Research University, Pushp Vihar, New Delhi 110017, India
| | - Yasir Rehman
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, Hamdard Nagar, New Delhi 110062, India
| | - Subiya Ambreen
- Department of Pharmaceutical Chemistry, Delhi Pharmaceutical Sciences and Research University, Pushp Vihar, New Delhi 110017, India
| | - Sayed Md Mumtaz
- Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, Hamdard Nagar, New Delhi 110062, India
| | - Mohd Shaququzzaman
- Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research, Jamia Hamdard, Hamdard Nagar, New Delhi 110062, India
| | - Mohammad Mumtaz Alam
- Department of Pharmaceutical Chemistry, School of Pharmaceutical Education and Research, Jamia Hamdard, Hamdard Nagar, New Delhi 110062, India
| | - Ruhi Ali
- Department of Pharmaceutical Chemistry, Delhi Pharmaceutical Sciences and Research University, Pushp Vihar, New Delhi 110017, India.
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Zhang D, Dong X, Li X, Yang Y, Li H, Hong Y, Yang G, Kong X, Wang X, Ma X. Moxibustion ameliorates chronic inflammatory visceral pain via spinal circRNA-miRNA-mRNA networks: a central mechanism study. Mol Brain 2024; 17:23. [PMID: 38750560 PMCID: PMC11097453 DOI: 10.1186/s13041-024-01093-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Accepted: 04/22/2024] [Indexed: 05/18/2024] Open
Abstract
This study aimed to unveil the central mechanism of moxibustion treating chronic inflammatory visceral pain (CIVP) from the angle of circRNA-miRNA-mRNA networks in the spinal cord. The rat CIVP model was established using a mixture of 5% (w/v) 2,4,6-trinitrobenzene sulfonic acid and 50% ethanol at a volume ratio of 2:1 via enema. Rats in the moxibustion group received herb-partitioned moxibustion at Tianshu (ST25, bilateral) and Qihai (CV6) points. The abdominal withdrawal reflex (AWR), mechanical withdrawal threshold (MWT), and thermal withdrawal latency (TWL) were adopted for pain behavior observation and pain sensitivity assessment. The circRNA, miRNA, and mRNA expression profiles were detected using the high-throughput sequencing technique. Relevant databases and bioinformatics analysis methods were used to screen for differentially expressed (DE) RNAs and build a circRNA-miRNA-mRNA (competing endogenous RNA) ceRNA regulatory network. The real-time quantitative PCR was employed to verify the sequencing result. CIVP rat models had a significantly higher AWR and lower TWL and MWT than normal rats. Between normal and model rats, there were 103 DE-circRNAs, 16 DE-miRNAs, and 397 DE-mRNAs in the spinal cord. Compared with the model group, the moxibustion group had a lower AWR and higher TWL and MWT; between these two groups, there were 118 DE-circRNAs, 15 DE-miRNAs, and 804 DE-mRNAs in the spinal cord. Two ceRNA networks were chosen to be verified. As a result, moxibustion's analgesic effect on visceral pain in CIVP rats may be associated with regulating the circRNA_02767/rno-miR-483-3p/Gfap network in the spinal cord and improving central sensitization.
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Affiliation(s)
- Dan Zhang
- Laboratory of Acupuncture-Moxibustion and Immunology, Shanghai Research Institute of Acupuncture and Meridian, Shanghai University of Traditional Chinese Medicine, Shanghai, 200030, China
| | - Xiaoqing Dong
- Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200437, China
- Department of Acupuncture and Moxibustion, Xi'an Hospital of Encephalopathy, Shaanxi University of Chinese Medicine, Shaanxi, 710032, China
| | - Xiaoying Li
- Department of Acupuncture and Moxibustion, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200071, China
| | - Yanting Yang
- Laboratory of Acupuncture-Moxibustion and Immunology, Shanghai Research Institute of Acupuncture and Meridian, Shanghai University of Traditional Chinese Medicine, Shanghai, 200030, China
| | - Hongna Li
- Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200437, China
| | - Yue Hong
- Laboratory of Acupuncture-Moxibustion and Immunology, Shanghai Research Institute of Acupuncture and Meridian, Shanghai University of Traditional Chinese Medicine, Shanghai, 200030, China
| | - Guang Yang
- Laboratory of Acupuncture-Moxibustion and Immunology, Shanghai Research Institute of Acupuncture and Meridian, Shanghai University of Traditional Chinese Medicine, Shanghai, 200030, China
| | - Xiehe Kong
- Laboratory of Acupuncture-Moxibustion and Immunology, Shanghai Research Institute of Acupuncture and Meridian, Shanghai University of Traditional Chinese Medicine, Shanghai, 200030, China
| | - Xuejun Wang
- Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200437, China.
- Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, Shanghai, 200031, China.
| | - Xiaopeng Ma
- Laboratory of Acupuncture-Moxibustion and Immunology, Shanghai Research Institute of Acupuncture and Meridian, Shanghai University of Traditional Chinese Medicine, Shanghai, 200030, China.
- Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200437, China.
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Thi HV, Ngo AD, Chu DT. Epigenetic regulation in ovarian cancer. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2024; 387:77-98. [PMID: 39179349 DOI: 10.1016/bs.ircmb.2024.03.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/26/2024]
Abstract
Ovarian cancer is one of the diseases that have the highest mortality rate for women, especially women over 50 years old. In the future, incidence and mortality rates are predicted to extend in countries with low HDI. Instability in the structure and function of genetic factors has long been known as a cause of cancer, including ovarian cancer. Besides understanding gene mutations, epigenetic alterations have emerged as another aspect leading to the pathogenesis of ovarian neoplasm. The development and progression of this fatal disease have been found to be associated with abnormalities of epigenetic regulation. DNA methylation, histone modification, and non-coding RNAs-based gene silencing are processes of interest in developing ovarian carcinoma and are also new targets for cancer detection or treatment.
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Affiliation(s)
- Hue Vu Thi
- Center for Biomedicine and Community Health, International School, Vietnam National University, Hanoi, Vietnam; Faculty of Applied Sciences, International School, Vietnam National University, Hanoi, Vietnam
| | - Anh-Dao Ngo
- Center for Biomedicine and Community Health, International School, Vietnam National University, Hanoi, Vietnam
| | - Dinh-Toi Chu
- Center for Biomedicine and Community Health, International School, Vietnam National University, Hanoi, Vietnam; Faculty of Applied Sciences, International School, Vietnam National University, Hanoi, Vietnam.
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Zhang Y, Zhao Y, Wang Y, Li J, Huang Y, Lyu F, Wang Y, Wei P, Yuan Y, Fu Y, Gao Y. Microglial histone deacetylase 2 is dispensable for functional and histological outcomes in a mouse model of traumatic brain injury. J Cereb Blood Flow Metab 2024; 44:817-835. [PMID: 38069842 PMCID: PMC11197137 DOI: 10.1177/0271678x231197173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Revised: 08/08/2023] [Accepted: 08/08/2023] [Indexed: 04/26/2024]
Abstract
The Class-I histone deacetylases (HDACs) mediate microglial inflammation and neurological dysfunction after traumatic brain injury (TBI). However, whether the individual Class-I HDACs play an indispensable role in TBI pathogenesis remains elusive. HDAC2 has been shown to upregulate pro-inflammatory genes in myeloid cells under brain injuries such as intracerebral hemorrhage, thereby worsening outcomes. Thus, we hypothesized that HDAC2 drives microglia toward a pro-inflammatory neurotoxic phenotype in a murine model of controlled cortical impact (CCI). Our results revealed that HDAC2 expression was highly induced in CD16/CD32+ pro-inflammatory microglia 3 and 7d after TBI. Surprisingly, microglia-targeted HDAC2 knockout (HDAC2 miKO) mice failed to demonstrate a beneficial phenotype after CCI/TBI compared to their wild-type (WT) littermates. HDAC2 miKO mice exhibited comparable levels of grey and white matter injury, efferocytosis, and sensorimotor and cognitive deficits after CCI/TBI as WT mice. RNA sequencing of isolated microglia 3d after CCI/TBI indicated the elevation of a panel of pro-inflammatory cytokines/chemokines in HDAC2 miKO mice over WT mice, and flow cytometry showed further elevated brain infiltration of neutrophils and B cells in HDAC2 miKO mice. Together, this study does not support a detrimental role for HDAC2 in microglial responses after TBI and calls for investigation into alternative mechanisms.
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Affiliation(s)
- Yue Zhang
- State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, and Institutes of Brain Science, Fudan University, Shanghai, China
| | - Yongfang Zhao
- State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, and Institutes of Brain Science, Fudan University, Shanghai, China
| | - Yana Wang
- State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, and Institutes of Brain Science, Fudan University, Shanghai, China
| | - Jiaying Li
- State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, and Institutes of Brain Science, Fudan University, Shanghai, China
| | - Yichen Huang
- State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, and Institutes of Brain Science, Fudan University, Shanghai, China
| | - Fan Lyu
- State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, and Institutes of Brain Science, Fudan University, Shanghai, China
| | - Yangfan Wang
- State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, and Institutes of Brain Science, Fudan University, Shanghai, China
| | - Pengju Wei
- State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, and Institutes of Brain Science, Fudan University, Shanghai, China
| | - Yiwen Yuan
- State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, and Institutes of Brain Science, Fudan University, Shanghai, China
| | - Yi Fu
- Department of Neurology & Institute of Neurology, Rui Jin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yanqin Gao
- State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, and Institutes of Brain Science, Fudan University, Shanghai, China
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Mansour MA, AboulMagd AM, Abbas SH, Abdel-Aziz M, Abdel-Rahman HM. Quinazoline-chalcone hybrids as HDAC/EGFR dual inhibitors: Design, synthesis, mechanistic, and in-silico studies of potential anticancer activity against multiple myeloma. Arch Pharm (Weinheim) 2024; 357:e2300626. [PMID: 38297894 DOI: 10.1002/ardp.202300626] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2023] [Revised: 01/02/2024] [Accepted: 01/05/2024] [Indexed: 02/02/2024]
Abstract
Two new series of quinazoline-chalcone hybrids were designed, synthesized as histone deacetylase (HDAC)/epidermal growth factor receptor (EGFR) dual inhibitors, and screened in vitro against the NCI 60 human cancer cell line panel. The most potent derivative, compound 5e bearing a 3,4,5-trimethoxyphenyl chalcone moiety, showed the most effective growth inhibition value against the panel of NCI 60 human cancer cell lines. Thus, it was selected for further investigation for NCI 5 log doses. Interestingly, this trimethoxy-substituted analog inhibited the proliferation of Roswell Park Memorial Institute (RPMI)-8226 cells by 96%, at 10 µM with IC50 = 9.09 ± 0.34 µM and selectivity index = 7.19 against normal blood cells. To confirm the selectivity of this compound, it was evaluated against a panel of tyrosine kinase enzymes. Mechanistically, it successfully and selectively inhibited HDAC6, HDAC8, and EGFR with IC50 = 0.41 ± 0.015, 0.61 ± 0.027, and 0.09 ± 0.004 µM, respectively. Furthermore, the selected derivative induced apoptosis via the mitochondrial apoptotic pathway by raising the Bax/Bcl-2 ratio and activating caspases 3, 7, and 9. Also, the flow cytometry analysis of RPMI-8226 cells showed that the trimethoxy-substituted analog produced cell cycle arrest in the G1 and S phases at 55.82%. Finally, an in silico study was performed to explore the binding interaction of the most active compound within the zinc-containing binding site of HDAC6 and HDAC8.
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Affiliation(s)
- Mostafa A Mansour
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, Nahda University in Beni-Suef (NUB), Beni-Suef, Egypt
| | - Asmaa M AboulMagd
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, Nahda University in Beni-Suef (NUB), Beni-Suef, Egypt
| | - Samar H Abbas
- Medicinal Chemistry Department, Faculty of Pharmacy, Minia University, Minia, Egypt
| | - Mohamed Abdel-Aziz
- Medicinal Chemistry Department, Faculty of Pharmacy, Minia University, Minia, Egypt
| | - Hamdy M Abdel-Rahman
- Medicinal Chemistry Department, Faculty of Pharmacy, Assiut University, Assiut, Egypt
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, Badr University in Assiut (BUA), Assiut, Egypt
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Zhang L, Xie F, Zhang F, Lu B. The potential roles of exosomes in pathological cardiomyocyte hypertrophy mechanisms and therapy: A review. Medicine (Baltimore) 2024; 103:e37994. [PMID: 38669371 PMCID: PMC11049793 DOI: 10.1097/md.0000000000037994] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2024] [Accepted: 03/29/2024] [Indexed: 04/28/2024] Open
Abstract
Pathological cardiac hypertrophy, characterized by the enlargement of cardiac muscle cells, leads to serious cardiac conditions and stands as a major global health issue. Exosomes, comprising small lipid bilayer vesicles, are produced by various cell types and found in numerous bodily fluids. They play a pivotal role in intercellular communication by transferring bioactive cargos to recipient cells or activating signaling pathways in target cells. Exosomes from cardiomyocytes, endothelial cells, fibroblasts, and stem cells are key in regulating processes like cardiac hypertrophy, cardiomyocyte survival, apoptosis, fibrosis, and angiogenesis within the context of cardiovascular diseases. This review delves into exosomes' roles in pathological cardiac hypertrophy, first elucidating their impact on cell communication and signaling pathways. It then advances to discuss how exosomes affect key hypertrophic processes, including metabolism, fibrosis, oxidative stress, and angiogenesis. The review culminates by evaluating the potential of exosomes as biomarkers and their significance in targeted therapeutic strategies, thus emphasizing their critical role in the pathophysiology and management of cardiac hypertrophy.
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Affiliation(s)
- Lijun Zhang
- Department of Cardiovascular Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Fang Xie
- Department of Cardiovascular Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Fengmei Zhang
- Department of Cardiovascular Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Beiyao Lu
- Department of Cardiovascular Surgery, West China Hospital, Sichuan University, Chengdu, China
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Shi J, Wang J, Wang X, Qu C, Ye C, Li X, Chen X, Xu Z. Design, synthesis and antiproliferative evaluation of tetrahydro-β-carboline histone deacetylase inhibitors bearing an aliphatic chain linker. RSC Adv 2024; 14:12762-12771. [PMID: 38645526 PMCID: PMC11027041 DOI: 10.1039/d4ra01672f] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Accepted: 04/03/2024] [Indexed: 04/23/2024] Open
Abstract
The use of histone deacetylase inhibitors (HDACis) is an effective approach for cancer treatment. In this work, a series of hydroxamic acid-based HDACis with a tetrahydro-β-carboline core and aliphatic linker have been designed and synthesized. The optimal compound 13d potently inhibited HDAC1 and showed good antiproliferative activity against different tumor cell lines in vitro. Molecular docking of 13d was conducted to rationalize the high binding affinity for HDAC1. Therefore, this work provides a new structure design for HDAC inhibitors and also offers a promising treatment for solid tumors.
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Affiliation(s)
- Jing Shi
- Department of Thoracic Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University Xi'an Shaanxi 710004 China +86-029-87679000
- Department of Respiratory and Endocrinology, The Second Affiliated Hospital of Xi'an Jiaotong University Xi'an 710004 Shaanxi China
| | - Jiayun Wang
- Shaanxi Key Labotory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University Yangling 712100 China +86-029-87092335
| | - Xingjie Wang
- Department of General Surgery, The First Affiliated Hospital of Xi'an Jiaotong University Xi'an 710061 Shaanxi China
| | - Chao Qu
- Department of General Surgery, The First Affiliated Hospital of Xi'an Jiaotong University Xi'an 710061 Shaanxi China
| | - Changchun Ye
- Department of General Surgery, The First Affiliated Hospital of Xi'an Jiaotong University Xi'an 710061 Shaanxi China
| | - Xiuli Li
- Department of Respiratory and Endocrinology, The Second Affiliated Hospital of Xi'an Jiaotong University Xi'an 710004 Shaanxi China
| | - Xin Chen
- Shaanxi Key Labotory of Natural Products & Chemical Biology, College of Chemistry & Pharmacy, Northwest A&F University Yangling 712100 China +86-029-87092335
| | - Zhengshui Xu
- Department of Thoracic Surgery, The Second Affiliated Hospital of Xi'an Jiaotong University Xi'an Shaanxi 710004 China +86-029-87679000
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Christianson DW. Chemical Versatility in Catalysis and Inhibition of the Class IIb Histone Deacetylases. Acc Chem Res 2024; 57:1135-1148. [PMID: 38530703 PMCID: PMC11021156 DOI: 10.1021/acs.accounts.3c00801] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/28/2024]
Abstract
The zinc-dependent histone deacetylases (HDACs 1-11) belong to the arginase-deacetylase superfamily of proteins, members of which share a common α/β fold and catalytic metal binding site. While several HDACs play a role in epigenetic regulation by catalyzing acetyllysine hydrolysis in histone proteins, the biological activities of HDACs extend far beyond histones. HDACs also deacetylate nonhistone proteins in the nucleus as well as the cytosol to regulate myriad cellular processes. The substrate pool is even more diverse in that certain HDACs can hydrolyze other covalent modifications. For example, HDAC6 is also a lysine decrotonylase, and HDAC11 is a lysine-fatty acid deacylase. Surprisingly, HDAC10 is not a lysine deacetylase but instead is a polyamine deacetylase. Thus, the HDACs are biologically and chemically versatile catalysts as they regulate the function of diverse protein and nonprotein substrates throughout the cell.Owing to their critical regulatory functions, HDACs serve as prominent targets for drug design. At present, four HDAC inhibitors are FDA-approved for cancer chemotherapy. However, these inhibitors are active against multiple HDAC isozymes, and a lack of selectivity is thought to contribute to undesirable side effects. Current medicinal chemistry campaigns focus on the development of isozyme-selective inhibitors, and many such studies largely focus on HDAC6 and HDAC10. HDAC6 is a target for therapeutic intervention due to its cellular role as a tubulin deacetylase and tau deacetylase, and selective inhibitors are being studied in cancer chemotherapy and the treatment of peripheral neuropathy. Crystal structures of enzyme-inhibitor complexes reveal how various features of inhibitor design, such as zinc-coordinating groups, bifurcated capping groups, and aromatic fluorination patterns, contribute to affinity and isozyme selectivity. The polyamine deacetylase HDAC10 is also an emerging target for cancer chemotherapy. Crystal structures of intact substrates trapped in the HDAC10 active site reveal the molecular basis of strikingly narrow substrate specificity for N8-acetylspermidine hydrolysis. Active site features responsible for substrate specificity have been successfully exploited in the design of potent and selective inhibitors.In this Account, I review the structural chemistry and inhibition of HDACs, highlighting recent X-ray crystallographic and functional studies of HDAC6 and HDAC10 in my laboratory. These studies have yielded fascinating snapshots of catalysis as well as novel chemical transformations involving bound inhibitors. The zinc-bound water molecule in the HDAC active site is the catalytic nucleophile in the deacetylation reaction, but this activated water molecule can also react with inhibitor C═O or C═N groups to yield unanticipated reaction products that bind exceptionally tightly. Versatile active site chemistry unleashes the full inhibitory potential of such compounds, and X-ray crystallography allows us to view this chemistry in action.
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Affiliation(s)
- David W. Christianson
- Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania, 19104-6323, USA
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Xiong S, Song K, Xiang H, Luo G. Dual-target inhibitors based on ERα: Novel therapeutic approaches for endocrine resistant breast cancer. Eur J Med Chem 2024; 270:116393. [PMID: 38588626 DOI: 10.1016/j.ejmech.2024.116393] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Revised: 04/04/2024] [Accepted: 04/04/2024] [Indexed: 04/10/2024]
Abstract
Estrogen receptor alpha (ERα), a nuclear transcription factor, is a well-validated therapeutic target for more than 70% of all breast cancers (BCs). Antagonizing ERα either by selective estrogen receptor modulators (SERMs) or selective estrogen receptor degraders (SERDs) forms the foundation of endocrine therapy and has achieved great success in the treatment of ERα positive (ERα+) BCs. Unfortunately, despite initial effectiveness, endocrine resistance eventually emerges in up to 30% of ERα+ BC patients and remains a significant medical challenge. Several mechanisms implicated in endocrine resistance have been extensively studied, including aberrantly activated growth factor receptors and downstream signaling pathways. Hence, the crosstalk between ERα and another oncogenic signaling has led to surge of interest to develop combination therapies and dual-target single agents. This review briefly introduces the synergisms between ERα and another anticancer target and summarizes the recent advances of ERα-based dual-targeting inhibitors from a medicinal chemistry perspective. Accordingly, their rational design strategies, structure-activity relationships (SARs) and biological activities are also dissected to provide some perspectives on future directions for ERα-based dual target drug discovery in BC therapy.
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Affiliation(s)
- Shuangshuang Xiong
- Jiangsu Key Laboratory of Drug Design and Optimization, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Ke Song
- Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China
| | - Hua Xiang
- Jiangsu Key Laboratory of Drug Design and Optimization, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
| | - Guoshun Luo
- Jiangsu Key Laboratory of Drug Design and Optimization, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
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de Sena Murteira Pinheiro P, Franco LS, Montagnoli TL, Fraga CAM. Molecular hybridization: a powerful tool for multitarget drug discovery. Expert Opin Drug Discov 2024; 19:451-470. [PMID: 38456452 DOI: 10.1080/17460441.2024.2322990] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Accepted: 02/21/2024] [Indexed: 03/09/2024]
Abstract
INTRODUCTION The current drug discovery paradigm of 'one drug, multiple targets' has gained attention from both the academic medicinal chemistry community and the pharmaceutical industry. This is in response to the urgent need for effective agents to treat multifactorial chronic diseases. The molecular hybridization strategy is a useful tool that has been widely explored, particularly in the last two decades, for the design of multi-target drugs. AREAS COVERED This review examines the current state of molecular hybridization in guiding the discovery of multitarget small molecules. The article discusses the design strategies and target selection for a multitarget polypharmacology approach to treat various diseases, including cancer, Alzheimer's disease, cardiac arrhythmia, endometriosis, and inflammatory diseases. EXPERT OPINION Although the examples discussed highlight the importance of molecular hybridization for the discovery of multitarget bioactive compounds, it is notorious that the literature has focused on specific classes of targets. This may be due to a deep understanding of the pharmacophore features required for target binding, making targets such as histone deacetylases and cholinesterases frequent starting points. However, it is important to encourage the scientific community to explore diverse combinations of targets using the molecular hybridization strategy.
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Affiliation(s)
- Pedro de Sena Murteira Pinheiro
- Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio), Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Lucas Silva Franco
- Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio), Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Tadeu Lima Montagnoli
- Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio), Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
- Programa de Pós-Graduação em Farmacologia e Química Medicinal, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Carlos Alberto Manssour Fraga
- Laboratório de Avaliação e Síntese de Substâncias Bioativas (LASSBio), Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
- Programa de Pós-Graduação em Farmacologia e Química Medicinal, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
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Zhou G, Liu Y, Wu H, Zhang D, Yang Q, Li Y. Research Progress on Histone Deacetylases Regulating Programmed Cell Death in Atherosclerosis. J Cardiovasc Transl Res 2024; 17:308-321. [PMID: 37821683 DOI: 10.1007/s12265-023-10444-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2023] [Accepted: 09/28/2023] [Indexed: 10/13/2023]
Abstract
Histone deacetylases (HDACs) are epigenetic modifying enzyme that is closely related to chromatin structure and gene transcription, and numerous studies have found that HDACs play an important regulatory role in atherosclerosis disease. Apoptosis, autophagy and programmed necrosis as the three typical programmed cell death modalities that can lead to cell loss and are closely related to the developmental process of atherosclerosis. In recent years, accumulating evidence has shown that the programmed cell death mediated by HDACs is increasingly important in the pathophysiology of atherosclerosis. This paper first gives a brief overview of HDACs, the mechanism of programmed cell death, and their role in atherosclerosis, and then further elaborates on the role and mechanism of HDACs in regulating apoptosis, autophagy, and programmed necrosis in atherosclerosis, respectively, to provide new effective measures and theoretical basis for the prevention and treatment of atherosclerosis.
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Affiliation(s)
- Gang Zhou
- Institute of Cardiovascular Disease, China Three Gorges University, Yichang, 443003, China
- Department of Central Experimental Laboratory, Yichang Central People's Hospital, Yichang, 443003, China
- HuBei Clinical Research Center for Ischemic Cardiovascular Disease, Yichang, 443003, China
| | - Yanfang Liu
- Institute of Cardiovascular Disease, China Three Gorges University, Yichang, 443003, China
- Department of Central Experimental Laboratory, Yichang Central People's Hospital, Yichang, 443003, China
- HuBei Clinical Research Center for Ischemic Cardiovascular Disease, Yichang, 443003, China
| | - Hui Wu
- Institute of Cardiovascular Disease, China Three Gorges University, Yichang, 443003, China.
- HuBei Clinical Research Center for Ischemic Cardiovascular Disease, Yichang, 443003, China.
- Department of Cardiology, Yichang Central People's Hospital, Yiling Road 183, Yichang, 443003, Hubei, China.
| | - Dong Zhang
- Institute of Cardiovascular Disease, China Three Gorges University, Yichang, 443003, China
- Department of Central Experimental Laboratory, Yichang Central People's Hospital, Yichang, 443003, China
- HuBei Clinical Research Center for Ischemic Cardiovascular Disease, Yichang, 443003, China
| | - Qingzhuo Yang
- Institute of Cardiovascular Disease, China Three Gorges University, Yichang, 443003, China
- Department of Central Experimental Laboratory, Yichang Central People's Hospital, Yichang, 443003, China
- HuBei Clinical Research Center for Ischemic Cardiovascular Disease, Yichang, 443003, China
| | - Yi Li
- Institute of Cardiovascular Disease, China Three Gorges University, Yichang, 443003, China
- Department of Central Experimental Laboratory, Yichang Central People's Hospital, Yichang, 443003, China
- HuBei Clinical Research Center for Ischemic Cardiovascular Disease, Yichang, 443003, China
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Ray P, Sedigh A, Confeld M, Alhalhooly L, Iduoku K, Casanola-Martin GM, Pham-The H, Rasulev B, Choi Y, Yang Z, Mallik S, Quadir M. Design and Evaluation of Nanoscale Materials with Programmed Responsivity towards Epigenetic Enzymes. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.03.26.585429. [PMID: 38586020 PMCID: PMC10996597 DOI: 10.1101/2024.03.26.585429] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/09/2024]
Abstract
Self-assembled materials capable of modulating their assembly properties in response to specific enzymes play a pivotal role in advancing 'intelligent' encapsulation platforms for biotechnological applications. Here, we introduce a previously unreported class of synthetic nanomaterials that programmatically interact with histone deacetylase (HDAC) as the triggering stimulus for disassembly. These nanomaterials consist of co-polypeptides comprising poly (acetyl L-lysine) and poly(ethylene glycol) blocks. Under neutral pH conditions, they self-assemble into particles. However, their stability is compromised upon exposure to HDACs, depending on enzyme concentration and exposure time. Our investigation, utilizing HDAC8 as the model enzyme, revealed that the primary mechanism behind disassembly involves a decrease in amphiphilicity within the block copolymer due to the deacetylation of lysine residues within the particles' hydrophobic domains. To elucidate the response mechanism, we encapsulated a fluorescent dye within these nanoparticles. Upon incubation with HDAC, the nanoparticle structure collapsed, leading to controlled release of the dye over time. Notably, this release was not triggered by denatured HDAC8, other proteolytic enzymes like trypsin, or the co-presence of HDAC8 and its inhibitor. We further demonstrated the biocompatibility and cellular effects of these materials and conducted a comprehensive computational study to unveil the possible interaction mechanism between enzymes and particles. By drawing parallels to the mechanism of naturally occurring histone proteins, this research represents a pioneering step toward developing functional materials capable of harnessing the activity of epigenetic enzymes such as HDACs.
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Gan Q, Fan C. Orthogonal Translation for Site-Specific Installation of Post-translational Modifications. Chem Rev 2024; 124:2805-2838. [PMID: 38373737 PMCID: PMC11230630 DOI: 10.1021/acs.chemrev.3c00850] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/21/2024]
Abstract
Post-translational modifications (PTMs) endow proteins with new properties to respond to environmental changes or growth needs. With the development of advanced proteomics techniques, hundreds of distinct types of PTMs have been observed in a wide range of proteins from bacteria, archaea, and eukarya. To identify the roles of these PTMs, scientists have applied various approaches. However, high dynamics, low stoichiometry, and crosstalk between PTMs make it almost impossible to obtain homogeneously modified proteins for characterization of the site-specific effect of individual PTM on target proteins. To solve this problem, the genetic code expansion (GCE) strategy has been introduced into the field of PTM studies. Instead of modifying proteins after translation, GCE incorporates modified amino acids into proteins during translation, thus generating site-specifically modified proteins at target positions. In this review, we summarize the development of GCE systems for orthogonal translation for site-specific installation of PTMs.
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Affiliation(s)
- Qinglei Gan
- Department of Chemistry and Biochemistry, University of Arkansas, Fayetteville, Arkansas 72701, United States
| | - Chenguang Fan
- Department of Chemistry and Biochemistry, University of Arkansas, Fayetteville, Arkansas 72701, United States
- Cell and Molecular Biology Program, University of Arkansas, Fayetteville, Arkansas 72701, United States
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50
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König B, Hansen FK. 2-(Difluoromethyl)-1,3,4-oxadiazoles: The Future of Selective Histone Deacetylase 6 Modulation? ACS Pharmacol Transl Sci 2024; 7:899-903. [PMID: 38481687 PMCID: PMC10928878 DOI: 10.1021/acsptsci.4c00031] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2024] [Indexed: 02/23/2025]
Abstract
Histone deacetylase 6 (HDAC6) is an important target for the treatment of oncological and non-oncological diseases. Established HDAC6 inhibitors feature a hydroxamic acid as a zinc-binding group (ZBG) and thus possess mutagenic and genotoxic potential. Recently, the 2-(difluoromethyl)-1,3,4-oxadiazole (DFMO) group emerged as a novel ZBG. In this Viewpoint, we summarize the discovery of the mode of action of DFMOs. Additionally, we discuss opportunities and challenges in the journey toward the clinical development of DFMO-based drugs for the treatment of HDAC6-driven diseases.
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Affiliation(s)
- Beate König
- Department of Pharmaceutical
and Cell Biological Chemistry, Pharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany
| | - Finn K. Hansen
- Department of Pharmaceutical
and Cell Biological Chemistry, Pharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany
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