scholarly journals Sirtuins: Molecular Traffic Lights in the Crossroad of Oxidative Stress, Chromatin Remodeling, and Transcription

2011 ◽  
Vol 2011 ◽  
pp. 1-17 ◽  
Author(s):  
Ramkumar Rajendran ◽  
Richa Garva ◽  
Marija Krstic-Demonacos ◽  
Constantinos Demonacos
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Transcriptional Regulation ◽  
Histone Deacetylases ◽  
Molecular Mechanisms ◽  
Biological Activities ◽  
Class Iii ◽  
Nonhistone Proteins ◽  
Traffic Lights ◽  
Major Mechanism

Transcription is regulated by acetylation/deacetylation reactions of histone and nonhistone proteins mediated by enzymes called KATs and HDACs, respectively. As a major mechanism of transcriptional regulation, protein acetylation is a key controller of physiological processes such as cell cycle, DNA damage response, metabolism, apoptosis, and autophagy. The deacetylase activity of class III histone deacetylases or sirtuins depends on the presence of NAD+(nicotinamide adenine dinucleotide), and therefore, their function is closely linked to cellular energy consumption. This activity of sirtuins connects the modulation of chromatin dynamics and transcriptional regulation under oxidative stress to cellular lifespan, glucose homeostasis, inflammation, and multiple aging-related diseases including cancer. Here we provide an overview of the recent developments in relation to the diverse biological activities associated with sirtuin enzymes and stress responsive transcription factors, DNA damage, and oxidative stress and relate the involvement of sirtuins in the regulation of these processes to oncogenesis. Since the majority of the molecular mechanisms implicated in these pathways have been described for Sirt1, this sirtuin family member is more extensively presented in this paper.

Oxidative-stress-induced epigenetic changes in chronic diabetic complications

2013 ◽  
Vol 91 (3) ◽  
pp. 213-220 ◽  
Author(s):  
Biao Feng ◽  
Michael Anthony Ruiz ◽  
Subrata Chakrabarti
Keyword(s):  
Oxidative Stress ◽  
Endothelial Cells ◽  
Protein Kinase ◽  
Diabetic Complications ◽  
Histone Deacetylases ◽  
Excision Repair ◽  
Mitogen Activated Protein Kinase ◽  
Signal Pathways ◽  
Epigenetic Changes ◽  
Class Iii

Oxidative stress plays an important role in the development and progression of chronic diabetic complications. Diabetes causes mitochondrial superoxide overproduction in the endothelial cells of both large and small vessels. This increased superoxide production causes the activation of several signal pathways involved in the pathogenesis of chronic complications. In particular, endothelial cells are major targets of glucose-induced oxidative damage in the target organs. Oxidative stress activates cellular signaling pathways and transcription factors in endothelial cells including protein kinase C (PKC), c-Jun-N-terminal kinase (JNK), p38 mitogen-activated protein kinase (MAPK), forkhead box O (FOXO), and nuclear factor kappa-B (NF-κB). Oxidative stress also causes DNA damage and activates DNA nucleotide excision repair enzymes including the excision repair cross complimenting 1(ERCC1), ERCC4, and poly(ADP-ribose) polymerase (PARP). Augmented production of histone acetyltransferase p300, and alterations of histone deacetylases, including class III deacetylases sirtuins, are also involved in this process. Recent research has found that small noncoding RNAs, like microRNA, are a new kind of regulator associated with chronic diabetic complications. There are extensive and complicated interactions and among these molecules. The purpose of this review is to demonstrate the role of oxidative stress in the development of diabetic complications in relation to epigenetic changes such as acetylation and microRNA alterations.

scholarly journals The Role of Sirtuins in Kidney Diseases

2020 ◽  
Vol 21 (18) ◽  
pp. 6686
Author(s):  
Yu Ah Hong ◽  
Ji Eun Kim ◽  
Minjee Jo ◽  
Gang-Jee Ko
Keyword(s):  
Histone Deacetylases ◽  
Energy Homeostasis ◽  
Molecular Mechanisms ◽  
Kidney Diseases ◽  
Expression Profiles ◽  
Kidney Injury ◽  
Class Iii ◽  
Cellular Functions ◽  
Wide Range

Sirtuins (SIRTs) are class III histone deacetylases (HDACs) that play important roles in aging and a wide range of cellular functions. Sirtuins are crucial to numerous biological processes, including proliferation, DNA repair, mitochondrial energy homeostasis, and antioxidant activity. Mammals have seven different sirtuins, SIRT1–7, and the diverse biological functions of each sirtuin are due to differences in subcellular localization, expression profiles, and cellular substrates. In this review, we summarize research advances into the role of sirtuins in the pathogenesis of various kidney diseases including acute kidney injury, diabetic kidney disease, renal fibrosis, and kidney aging along with the possible underlying molecular mechanisms. The available evidence indicates that sirtuins have great potential as novel therapeutic targets for the prevention and treatment of kidney diseases.

scholarly journals B cell Sirt1 deacetylates histone and non-histone proteins for epigenetic modulation of AID expression and the antibody response

2020 ◽  
Vol 6 (14) ◽  
pp. eaay2793 ◽  
Author(s):  
Huoqun Gan ◽  
Tian Shen ◽  
Daniel P. Chupp ◽  
Julia R. Taylor ◽  
Helia N. Sanchez ◽  
...  
Keyword(s):  
Antibody Response ◽  
B Cell ◽  
Histone Deacetylases ◽  
Somatic Hypermutation ◽  
Cytidine Deaminase ◽  
Dna Recombination ◽  
Sirtuin 1 ◽  
B Cell Differentiation ◽  
Class Iii ◽  
Nonhistone Proteins

Activation-induced cytidine deaminase (AID) mediates immunoglobulin class switch DNA recombination (CSR) and somatic hypermutation (SHM), critical processes for maturation of the antibody response. Epigenetic factors, such as histone deacetylases (HDACs), would underpin B cell differentiation stage–specific AID expression. Here, we showed that NAD+-dependent class III HDAC sirtuin 1 (Sirt1) is highly expressed in resting B cells and down-regulated by stimuli inducing AID. B cell Sirt1 down-regulation, deprivation of NAD+ cofactor, or genetic Sirt1 deletion reduced deacetylation of Aicda promoter histones, Dnmt1, and nuclear factor–κB (NF-κB) p65 and increased AID expression. This promoted class-switched and hypermutated T-dependent and T-independent antibody responses or led to generation of autoantibodies. Genetic Sirt1 overexpression, Sirt1 boost by NAD+, or allosteric Sirt1 enhancement by SRT1720 repressed AID expression and CSR/SHM. By deacetylating histone and nonhistone proteins (Dnmt1 and NF-κB p65), Sirt1 transduces metabolic cues into epigenetic changes to play an important B cell–intrinsic role in modulating antibody and autoantibody responses.

scholarly journals Histone methyltransferase SET8 is regulated by miR-192/215 and induces oncogene-induced senescence via p53-dependent DNA damage in human gastric carcinoma cells

2020 ◽  
Vol 11 (10) ◽  
Author(s):  
Xiaojing Zhang ◽  
Yin Peng ◽  
Yuan Yuan ◽  
Yuli Gao ◽  
Fan Hu ◽  
...  
Keyword(s):  
Dna Damage ◽  
Molecular Mechanisms ◽  
Biological Activities ◽  
Expression Profiles ◽  
Carcinoma Cells ◽  
Negative Regulator ◽  
Expression Change ◽  
Human Gastric Carcinoma Cells

Abstract Gastric cancer (GC) is the most common cancer throughout the world. Despite advances of the treatments, detailed oncogenic mechanisms are largely unknown. In our previous study, we investigated microRNA (miR) expression profiles in human GC using miR microarrays. We found miR-192/215 were upregulated in GC tissues. Then gene microarray was implemented to discover the targets of miR-192/215. We compared the expression profile of BGC823 cells transfected with miR-192/215 inhibitors, and HFE145 cells transfected with miR-192/-215 mimics, respectively. SET8 was identified as a proposed target based on the expression change of more than twofold. SET8 belongs to the SET domain-containing methyltransferase family and specifically catalyzes monomethylation of H4K20me. It is involved in diverse functions in tumorigenesis and metastasis. Therefore, we focused on the contributions of miR-192/215/SET8 axis to the development of GC. In this study, we observe that functionally, SET8 regulated by miR-192/215 is involved in GC-related biological activities. SET8 is also found to trigger oncogene-induced senescence (OIS) in GC in vivo and in vitro, which is dependent on the DDR (DNA damage response) and p53. Our findings reveal that SET8 functions as a negative regulator of metastasis via the OIS-signaling pathway. Taken together, we investigated the functional significance, molecular mechanisms, and clinical impact of miR-192/215/SET8/p53 in GC.

scholarly journals SIRT1 and Kidney Function

2015 ◽  
Vol 1 (4) ◽  
pp. 258-265 ◽  
Author(s):  
Yi Guan ◽  
Chuan-Ming Hao
Keyword(s):  
Histone Deacetylases ◽  
Acute Stress ◽  
Kidney Diseases ◽  
Kidney Injury ◽  
Renal Medulla ◽  
Cyst Formation ◽  
Renal Physiology ◽  
Dna Integrity ◽  
Class Iii ◽  
Nonhistone Proteins

Background: SIRT1 is a nicotinamide adenine dinucleotide-dependent deacetylase belonging to the class III histone deacetylases. Abundantly expressed in the kidney, especially in the renal medulla, SIRT1 is closely involved in renal physiology and pathology. Summary: SIRT1 targets both histone and nonhistone proteins, participates in many important signaling pathways and mediates the regulation of longevity, metabolic homeostasis, acute stress response and DNA integrity. With regard to the kidney, SIRT1 attenuates diabetic albuminuria, reduces blood pressure and related cardiovascular diseases, resists acute kidney injury, delays kidney fibrogenesis, promotes cyst formation and benefits renal ageing. Key Messages: This review summarizes the biology of SIRT1 and focuses on the latest studies concerning SIRT1 as a potential therapeutic target for kidney diseases.

scholarly journals Tellurite Promotes Stress Granules and Nuclear SG-Like Assembly in Response to Oxidative Stress and DNA Damage

2021 ◽  
Vol 9 ◽  
Author(s):  
Aracelly Gaete-Argel ◽  
Felipe Velásquez ◽  
Chantal L. Márquez ◽  
Barbara Rojas-Araya ◽  
Constanza Bueno-Nieto ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Molecular Mechanisms ◽  
Stress Granules ◽  
Cellular Stress Response ◽  
Industrial Manufacturing ◽  
The Past ◽  
Γh2ax Foci ◽  
Bona Fide ◽  
And Oxidative Stress

Tellurium oxyanion, tellurite (TeO3–2), is a highly toxic compound for many organisms. Its presence in the environment has increased over the past years due to industrial manufacturing processes and has been associated with adverse effects on human health. Although tellurite induces the phosphorylation of eIF2α, DNA damage and oxidative stress, the molecular mechanisms related to the cellular responses to tellurite-induced stress are poorly understood. In this work, we evaluated the ability of tellurite to induce phosphorylation of eIF2α, stress granules (SGs) assembly and their relationship with DNA damage in U2OS cells. We demonstrate that tellurite promotes the assembly of bona fide cytoplasmic SGs. Unexpectedly, tellurite also induces the assembly of nuclear SGs. Interestingly, we observed that the presence of tellurite-induced nuclear SGs correlates with γH2AX foci. However, although H2O2 also induce DNA damage, no nuclear SGs were observed. Our data show that tellurite promotes the assembly of cytoplasmic and nuclear SGs in response to oxidative stress and DNA damage, revealing a new aspect of cellular stress response mediated by the assembly of nuclear stress granules.

scholarly journals A Proteomic Approach to Uncover Neuroprotective Mechanisms of Oleocanthal against Oxidative Stress

2018 ◽  
Vol 19 (8) ◽  
pp. 2329 ◽  
Author(s):  
Laura Giusti ◽  
Cristina Angeloni ◽  
Maria Barbalace ◽  
Serena Lacerenza ◽  
Federica Ciregia ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Neurodegenerative Diseases ◽  
Olive Oil ◽  
Molecular Mechanisms ◽  
Biological Activities ◽  
Virgin Olive Oil ◽  
Extra Virgin Olive Oil ◽  
Neuroprotective Effects ◽  
Proteomic Approach ◽  
Mitochondrial Functions

Neurodegenerative diseases represent a heterogeneous group of disorders that share common features like abnormal protein aggregation, perturbed Ca2+ homeostasis, excitotoxicity, impairment of mitochondrial functions, apoptosis, inflammation, and oxidative stress. Despite recent advances in the research of biomarkers, early diagnosis, and pharmacotherapy, there are no treatments that can halt the progression of these age-associated neurodegenerative diseases. Numerous epidemiological studies indicate that long-term intake of a Mediterranean diet, characterized by a high consumption of extra virgin olive oil, correlates with better cognition in aged populations. Olive oil phenolic compounds have been demonstrated to have different biological activities like antioxidant, antithrombotic, and anti-inflammatory activities. Oleocanthal, a phenolic component of extra virgin olive oil, is getting more and more scientific attention due to its interesting biological activities. The aim of this research was to characterize the neuroprotective effects of oleocanthal against H2O2-induced oxidative stress in neuron-like SH-SY5Y cells. Moreover, protein expression profiling, combined with pathways analyses, was used to investigate the molecular events related to the protective effects. Oleocanthal was demonstrated to counteract oxidative stress, increasing cell viability, reducing reactive oxygen species (ROS) production, and increasing reduced glutathione (GSH) intracellular level. Proteomic analysis revealed that oleocanthal significantly modulates 19 proteins in the presence of H2O2. In particular, oleocanthal up-regulated proteins related to the proteasome, the chaperone heat shock protein 90, the glycolytic enzyme pyruvate kinase, and the antioxidant enzyme peroxiredoxin 1. Moreover, oleocanthal protection seems to be mediated by Akt activation. These data offer new insights into the molecular mechanisms behind oleocanthal protection against oxidative stress.

scholarly journals What makes a fertile sperm? Unique molecular attributes of stallion fertility

Reproduction ◽  
2019 ◽  
Vol 158 (4) ◽  
pp. R125-R137 ◽  
Author(s):  
Róisín A Griffin ◽  
Mark Baker ◽  
Robert John Aitken ◽  
Aleona Swegen ◽  
Zamira Gibb
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Breeding Season ◽  
Molecular Mechanisms ◽  
Relative Importance ◽  
Accurate Assessment ◽  
Functional Competence ◽  
Thoroughbred Horse ◽  
Livestock Species ◽  
Horse Breeding

Stallions experience lower per-cycle conception rates compared to other livestock species, largely because they are selected for breeding based on athletic prowess and not reproductive fitness. Mares are seasonal breeders, and pregnancies cannot be detected until 10–14 days post cover via transrectal ultrasonography. This means the detection of stallion fertility fluctuations is delayed by at least 2 weeks, which within the short breeding season employed by the thoroughbred horse breeding industry, can prove quite costly. For these reasons, there is increased demand for robust laboratory assays aimed at the accurate assessment of stallion fertility. This paper reviews our existing knowledge concerning the molecular mechanisms that underpin the functional competence of stallion spermatozoa, highlighting the relative importance of oxidative stress, DNA damage, sperm proteomics and RNA profile. We also consider the way in which fundamental improvements in our understanding of stallion sperm biology are informing the identification and development of possible biomarkers of fertility and thus avenues for the development of specific assays for fertility prediction.

scholarly journals Edaravone Ameliorates Depressive and Anxiety-like Behaviors via Sirt1/Nrf2/HO-1/Gpx4 Pathway

2021 ◽  
Author(s):  
Ruozhi Dang ◽  
Mingyang Wang ◽  
Xinhui Li ◽  
Haiyang Wang ◽  
Lanxiang Liu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Molecular Mechanisms ◽  
Biological Activities ◽  
Forced Swim Test ◽  
Preference Test ◽  
Antidepressant Activity ◽  
Tail Suspension Test ◽  
Free Radical Scavenger ◽  
Radical Scavenger ◽  
Nissl Staining

Abstract Background: The inflammation and oxidative stress (OS) have been considered crucial components of the pathogenesis of depression. Edaravone (EDA), a free radical scavenger, processes strong biological activities including antioxidant, anti-inflammatory and neuroprotective properties. However, its role and potential molecular mechanisms in depression remain unclear. The present study aimed to investigate the antidepressant activity of EDA and its underlying mechanisms.Methods: A chronic social defeat stress (CSDS) depression model was performed to explore whether EDA could produce antidepressant effects. C57BL/6J mice were intraperitoneally injected with EDA or Vehicle daily for 10 days. Behaviors tests were then carried out to examine depressive, anxiety-like and cognitive behaviors including social interaction (SI) test, sucrose preference test (SPT), open field test (OFT), elevated plus maze (EPM), novel object recognition (NOR), tail suspension test (TST) and forced swim test (FST). Hippocampal and medial prefrontal cortex (mPFC) tissues were collected for Nissl staining, immunofluorescence, targeted energy metabolomics analysis, measurement of MDA, SOD, GSH and transmission electron microscopy (TEM). Western blotting (WB) and quantitative real time polymerase chain reaction (qRT-PCR) detected the Sirt1/Nrf2/HO-1/Gpx4 signaling pathway. Knockdown experiments were performed to determine the effects of Gpx4 on CSDS mice with EDA treatment by an adeno-associated virus (AAV) vector containing miRNAi(GPX4)-EGFP infusion.Results: The administrated of EDA dramatically ameliorated CSDS-induced depressive and anxiety-like behaviors. Additionally, EDA notably attenuated neuronal loss, microglial activation, astrocyte dysfunction, oxidative stress damage and energy metabolism in the hippocampus (Hip) and mPFC of CSDS-induced mice. Further examination indicated that the application of EDA after the CSDS model significantly increased the protein expressions of Sirt1, Nrf2, HO-1 and Gpx4 in the Hip. In addition, Gpx4 knockdown in CSDS mice abolished EDA-generated efficacy on depressive and anxiety-like behaviors.Conclusion: These findings suggest that EDA possesses potent antidepressant and anxiolytic properties through Sirt1/Nrf2/HO-1/Gpx4 axis and Gpx4-mediated ferroptosis may play a key role in this effect.

scholarly journals Neddylation Regulates Class IIa and III Histone Deacetylases to Mediate Myoblast Differentiation

2021 ◽  
Vol 22 (17) ◽  
pp. 9509
Author(s):  
Hongyi Zhou ◽  
Huabo Su ◽  
Weiqin Chen
Keyword(s):  
Transcriptional Activation ◽  
Nuclear Export ◽  
Histone Deacetylases ◽  
Molecular Mechanisms ◽  
Myogenic Differentiation ◽  
The Body ◽  
Muscle Disease ◽  
Sirtuin 1 ◽  
Myoblast Differentiation ◽  
Class Iii

As the largest tissue in the body, skeletal muscle has multiple functions in movement and energy metabolism. Skeletal myogenesis is controlled by a transcriptional cascade including a set of muscle regulatory factors (MRFs) that includes Myogenic Differentiation 1 (MYOD1), Myocyte Enhancer Factor 2 (MEF2), and Myogenin (MYOG), which direct the fusion of myogenic myoblasts into multinucleated myotubes. Neddylation is a posttranslational modification that covalently conjugates ubiquitin-like NEDD8 (neural precursor cell expressed, developmentally downregulated 8) to protein targets. Inhibition of neddylation impairs muscle differentiation; however, the underlying molecular mechanisms remain less explored. Here, we report that neddylation is temporally regulated during myoblast differentiation. Inhibition of neddylation through pharmacological blockade using MLN4924 (Pevonedistat) or genetic deletion of NEDD8 Activating Enzyme E1 Subunit 1 (NAE1), a subunit of the E1 neddylation-activating enzyme, blocks terminal myoblast differentiation partially through repressing MYOG expression. Mechanistically, we found that neddylation deficiency enhances the mRNA and protein expressions of class IIa histone deacetylases 4 and 5 (HDAC4 and 5) and prevents the downregulation and nuclear export of class III HDAC (NAD-Dependent Protein Deacetylase Sirtuin-1, SIRT1), all of which have been shown to repress MYOD1-mediated MYOG transcriptional activation. Together, our findings for the first time identify the crucial role of neddylation in mediating class IIa and III HDAC co-repressors to control myogenic program and provide new insights into the mechanisms of muscle disease and regeneration.

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