The Histone Deacetylase Family: Structural Features and Application of Combined Computational Methods DOI Creative Commons
Antonio Curcio, Roberta Rocca, Stefano Alcaro

et al.

Pharmaceuticals, Journal Year: 2024, Volume and Issue: 17(5), P. 620 - 620

Published: May 10, 2024

Histone deacetylases (HDACs) are crucial in gene transcription, removing acetyl groups from histones. They also influence the deacetylation of non-histone proteins, contributing to regulation various biological processes. Thus, HDACs play pivotal roles diseases, including cancer, neurodegenerative disorders, and inflammatory conditions, highlighting their potential as therapeutic targets. This paper reviews structure function four classes human HDACs. While HDAC inhibitors currently available for treating hematological malignancies, numerous others undergoing clinical trials. However, non-selective toxicity necessitates ongoing research into safer more efficient class-selective or isoform-selective inhibitors. Computational methods have aided discovery with desired potency and/or selectivity. These include ligand-based approaches, such scaffold hopping, pharmacophore modeling, three-dimensional quantitative structure–activity relationships, structure-based virtual screening (molecular docking). Moreover, recent developments field molecular dynamics simulations, combined Poisson–Boltzmann/molecular mechanics generalized Born surface area techniques, improved prediction ligand binding affinity. In this review, we delve ways which these contributed designing identifying

Language: Английский

α-myosin heavy chain lactylation maintains sarcomeric structure and function and alleviates the development of heart failure DOI Creative Commons
Naijin Zhang,

Ying Zhang,

Jiaqi Xu

et al.

Cell Research, Journal Year: 2023, Volume and Issue: 33(9), P. 679 - 698

Published: July 13, 2023

The sarcomeric interaction of α-myosin heavy chain (α-MHC) with Titin is vital for cardiac structure and contraction. However, the mechanism regulating this in normal failing hearts remains unknown. Lactate a crucial energy substrate heart. Here, we identify that α-MHC undergoes lactylation on lysine 1897 to regulate Titin. We observed reduction K1897 mice patients heart failure. Loss K1897R knock-in reduces α-MHC-Titin leads impaired function. Furthermore, identified p300 Sirtuin 1 act as acyltransferase delactylase α-MHC, respectively. Decreasing lactate production by chemical or genetic manipulation lactylation, impairs worsens By contrast, upregulation concentration administering sodium inhibiting pivotal transporter cardiomyocytes can promote interaction, thereby alleviating In conclusion, dynamically regulated an important determinant overall Excessive efflux consumption may decrease intracellular level, which main cause reduced during myocardial injury. Our study reveals metabolism directly modulates function through lactate-dependent modification α-MHC.

Language: Английский

Citations

89
Cellular Senescence in Intervertebral Disc Aging and Degeneration: Molecular Mechanisms and Potential Therapeutic Opportunities DOI Creative Commons
Prashanta Silwal, Allison M. Nguyen-Thai,

Haneef Ahamed Mohammad

et al.

Biomolecules, Journal Year: 2023, Volume and Issue: 13(4), P. 686 - 686

Published: April 18, 2023

Closely associated with aging and age-related disorders, cellular senescence (CS) is the inability of cells to proliferate due accumulated unrepaired damage irreversible cell cycle arrest. Senescent are characterized by their senescence-associated secretory phenotype that overproduces inflammatory catabolic factors hamper normal tissue homeostasis. Chronic accumulation senescent thought be intervertebral disc degeneration (IDD) in an population. This IDD one largest age-dependent chronic often neurological dysfunctions such as, low back pain, radiculopathy, myelopathy. (SnCs) increase number aged, degenerated discs, have a causative role driving IDD. review summarizes current evidence supporting CS on onset progression The discussion includes molecular pathways involved as p53-p21CIP1, p16INK4a, NF-κB, MAPK, potential therapeutic value targeting these pathways. We propose several mechanisms including mechanical stress, oxidative genotoxic nutritional deprivation, stress. There still large knowledge gaps research, understanding which will provide opportunities develop interventions treat

Language: Английский

Citations

79
Sirtuins, resveratrol and the intertwining cellular pathways connecting them DOI
Anca Ungurianu, Anca Zanfirescu, Denisa Margină

et al.

Ageing Research Reviews, Journal Year: 2023, Volume and Issue: 88, P. 101936 - 101936

Published: April 26, 2023

Language: Английский

Citations

51
SIRT1 and SIRT6: The role in aging-related diseases DOI Creative Commons
Yuzi You, Wei Liang

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, Journal Year: 2023, Volume and Issue: 1869(7), P. 166815 - 166815

Published: July 26, 2023

Aging is characterized by progressive functional deterioration with increased risk of mortality. It a complex biological process driven multitude intertwined mechanisms such as DNA damage, chronic inflammation, and metabolic dysfunction. Sirtuins (SIRTs) are family NAD+-dependent enzymes that regulate fundamental functions from genomic stability lifespan to energy metabolism tumorigenesis. Of the seven mammalian SIRT isotypes (SIRT1-7), SIRT1 SIRT6 well-recognized for regulating signaling pathways related aging. Herein, we review protective role in aging-related diseases at molecular, cellular, tissue, whole-organism levels. We also discuss therapeutic potential modulators treatment these challenges thereof.

Language: Английский

Citations

46
Natural Phytochemicals as SIRT Activators—Focus on Potential Biochemical Mechanisms DOI Open Access
Michał Wiciński, Jakub Erdmann, Agnieszka Nowacka

et al.

Nutrients, Journal Year: 2023, Volume and Issue: 15(16), P. 3578 - 3578

Published: Aug. 14, 2023

Sirtuins are a family of proteins with enzymatic activity. There seven mammalian sirtuins (SIRT1-SIRT7) that found in different cellular compartments. They part crucial pathways and regulated by many factors, such as chemicals, environmental stress, phytochemicals. Several vitro vivo studies have presented their involvement anti-inflammatory, antioxidant, antiapoptotic processes. Recent findings imply phytochemicals resveratrol, curcumin, quercetin, fisetin, berberine, kaempferol may regulate the activity sirtuins. Resveratrol mainly activates SIRT1 indirectly AMPK. Curcumin influences SIRT3, but its is broad, cells affected. Quercetin modulates SIRT1, which triggers antioxidant responses. Fisetin, through regulation, modifies lipid metabolism anti-inflammatory Berberine has wide spectrum effects significant impact on signaling pathways. Finally, induction. This review aims to summarize recent properties modulation sirtuin activity, particular focus biochemical aspects.

Language: Английский

Citations

44
O-GlcNAcylation in cancer development and immunotherapy DOI

Xue-Fen He,

Xiaoli Hu,

Gao-Jing Wen

et al.

Cancer Letters, Journal Year: 2023, Volume and Issue: 566, P. 216258 - 216258

Published: June 4, 2023

Language: Английский

Citations

42
Epigenetics-targeted drugs: current paradigms and future challenges DOI Creative Commons

Wanlin Dai,

Xinbo Qiao, Yuanyuan Fang

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Nov. 26, 2024

Epigenetics governs a chromatin state regulatory system through five key mechanisms: DNA modification, histone RNA remodeling, and non-coding regulation. These mechanisms their associated enzymes convey genetic information independently of base sequences, playing essential roles in organismal development homeostasis. Conversely, disruptions epigenetic landscapes critically influence the pathogenesis various human diseases. This understanding has laid robust theoretical groundwork for developing drugs that target epigenetics-modifying pathological conditions. Over past two decades, growing array small molecule targeting such as methyltransferase, deacetylase, isocitrate dehydrogenase, enhancer zeste homolog 2, have been thoroughly investigated implemented therapeutic options, particularly oncology. Additionally, numerous epigenetics-targeted are undergoing clinical trials, offering promising prospects benefits. review delineates epigenetics physiological contexts underscores pioneering studies on discovery implementation drugs. include inhibitors, agonists, degraders, multitarget agents, aiming to identify practical challenges avenues future research. Ultimately, this aims deepen epigenetics-oriented strategies further application settings.

Language: Английский

Citations

24
Research progress on Sirtuins (SIRTs) family modulators DOI Open Access
Mingkai Chen,

Junfei Tan,

Zihan Jin

et al.

Biomedicine & Pharmacotherapy, Journal Year: 2024, Volume and Issue: 174, P. 116481 - 116481

Published: March 24, 2024

Sirtuins (SIRTs) represent a class of nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylases that exert crucial role in cellular signal transduction and various biological processes. The mammalian sirtuins family encompasses SIRT1 to SIRT7, exhibiting therapeutic potential counteracting aging, modulating metabolism, responding oxidative stress, inhibiting tumors, improving microenvironment. These enzymes are intricately linked the occurrence treatment diverse pathological conditions, including cancer, autoimmune diseases, cardiovascular disorders. Given significance histone modification gene expression chromatin structure, maintaining equilibrium is imperative for disease prevention health restoration. Mounting evidence suggests modulators SIRTs play treating diseases physiological balance. This review delves into molecular structure regulatory functions family, reviews classification historical evolution modulators, offers systematic overview existing modulation strategies, elucidates mechanisms (agonists inhibitors) their clinical applications. article concludes by summarizing challenges encountered modulator research offering insights future directions.

Language: Английский

Citations

19
Crossing epigenetic frontiers: the intersection of novel histone modifications and diseases DOI Creative Commons

Weiyi Yao,

Xinting Hu,

Xin Wang

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Sept. 16, 2024

Abstract Histone post-translational modifications (HPTMs), as one of the core mechanisms epigenetic regulation, are garnering increasing attention due to their close association with onset and progression diseases potential targeted therapeutic agents. Advances in high-throughput molecular tools abundance bioinformatics data have led discovery novel HPTMs which similarly affect gene expression, metabolism, chromatin structure. Furthermore, a growing body research has demonstrated that histone also play crucial roles development various diseases, including cancers, cardiovascular infectious psychiatric disorders, reproductive system diseases. This review defines nine modifications: lactylation, citrullination, crotonylation, succinylation, SUMOylation, propionylation, butyrylation, 2-hydroxyisobutyrylation, 2-hydroxybutyrylation. It comprehensively introduces modification processes these HPTMs, transcription, replication, DNA repair recombination, structure, well involvement promoting occurrence clinical applications targets biomarkers. Moreover, this provides detailed overview HPTM inhibitors targeting emerging strategies treatment multiple while offering insights into future prospects challenges. Additionally, we briefly introduce techniques field research.

Language: Английский

Citations

18
Sirtuins in kidney health and disease DOI
Luca Perico, Giuseppe Remuzzi, Ariela Benigni

et al.

Nature Reviews Nephrology, Journal Year: 2024, Volume and Issue: 20(5), P. 313 - 329

Published: Feb. 6, 2024

Language: Английский

Citations

17