Epigenetic Mechanisms of Cardioprotection: Focus is on Activation of Sirtuins

Oxidative stress is a common sign of aging and cardiovascular disease (CVD), including atherosclerosis, heart failure, hypertension, diabetes mellitus and other diseases of the vascular system. In this regard, in recent years, researchers have shown increased interest in sirtuins (SIRTs) — stress adapters and epigenetic enzymes involved in cellular mechanisms for controlling age-related pathologies, cancer and CVD. Among sirtuins, of which there are seven in mammals (SIRT1-SIRT7), SIRT1 and SIRT6 possess the most cardioprotective, anti-inflammatory, atheroprotective and anti-aging properties. In this review, we present a comprehensive analysis of the latest developments in the field of cellular and molecular signaling pathways controlled by two post-translational modifiers — SIRT1 and SIRT6, which have proven their worth as tools to reduce inflammation and oxidative stress at the level of the cardiovascular system. A deeper understanding of the epigenetic mechanisms through which SIRT1 and SIRT6 exert their cardioprotective effect will have widespread implications and will accelerate the development of selective and effective pharmacological agents for modulating sirtuins for the prevention and treatment of CVD.

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Cellular Aging Characteristics and Their Association with Age-Related Disorders

Antioxidants ◽

10.3390/antiox9020094 ◽

2020 ◽

Vol 9 (2) ◽

pp. 94 ◽

Cited By ~ 8

Author(s):

Magdalena Rudzińska ◽

Alessandro Parodi ◽

Anastasia V. Balakireva ◽

Olga E. Chepikova ◽

Franco M. Venanzi ◽

...

Keyword(s):

Oxidative Stress ◽

Cellular Senescence ◽

Current Knowledge ◽

Cell Metabolism ◽

Critical Role ◽

Cellular Aging ◽

Molecular Signaling ◽

Age Related ◽

Organelle Communication ◽

Metabolic Dysfunctions

Different molecular signaling pathways, biological processes, and intercellular communication mechanisms control longevity and are affected during cellular senescence. Recent data have suggested that organelle communication, as well as genomic and metabolic dysfunctions, contribute to this phenomenon. Oxidative stress plays a critical role by inducing structural modifications to biological molecules while affecting their function and catabolism and eventually contributing to the onset of age-related dysfunctions. In this scenario, proteins are not adequately degraded and accumulate in the cell cytoplasm as toxic aggregates, increasing cell senescence progression. In particular, carbonylation, defined as a chemical reaction that covalently and irreversibly modifies proteins with carbonyl groups, is considered to be a significant indicator of protein oxidative stress and aging. Here, we emphasize the role and dysregulation of the molecular pathways controlling cell metabolism and proteostasis, the complexity of the mechanisms that occur during aging, and their association with various age-related disorders. The last segment of the review details current knowledge on protein carbonylation as a biomarker of cellular senescence in the development of diagnostics and therapeutics for age-related dysfunctions.

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Modulatory Effect of 2-(4-Hydroxyphenyl)amino-1,4-naphthoquinone on Endothelial Vasodilation in Rat Aorta

Oxidative Medicine and Cellular Longevity ◽

10.1155/2016/3939540 ◽

2016 ◽

Vol 2016 ◽

pp. 1-12 ◽

Cited By ~ 2

Author(s):

Javier Palacios ◽

Fredi Cifuentes ◽

Jaime A. Valderrama ◽

Julio Benites ◽

David Ríos ◽

...

Keyword(s):

Oxidative Stress ◽

Calcium Release ◽

Vascular Dysfunction ◽

Rat Aorta ◽

Cellular Mechanisms ◽

No Donor ◽

Pharmacological Agents ◽

Naphthoquinone Derivative ◽

Low Cytotoxicity ◽

Endothelium Damage

The vascular endothelium plays an essential role in the control of the blood flow. Pharmacological agents like quinone (menadione) at various doses modulate this process in a variety of ways. In this study,Q7, a 2-phenylamino-1,4-naphthoquinone derivative, significantly increased oxidative stress and induced vascular dysfunction at concentrations that were not cytotoxic to endothelial or vascular smooth muscle cells.Q7reduced nitric oxide (NO) levels and endothelial vasodilation to acetylcholine in rat aorta. It also blunted the calcium release from intracellular stores by increasing the phenylephrine-induced vasoconstriction when CaCl2was added to a calcium-free medium but did not affect the influx of calcium from extracellular space.Q7increased the vasoconstriction to BaCl2(10−3 M), an inward rectifying K+channels blocker, and blocked the vasodilation to KCl (10−2 M) in aortic rings precontracted with BaCl2. This was recovered with sodium nitroprusside (10−8 M), a NO donor. In conclusion,Q7induced vasoconstriction was through a modulation of cellular mechanisms involving calcium fluxes through K+channels, and oxidative stress induced endothelium damage. These findings contribute to the characterization of new quinone derivatives with low cytotoxicity able to pharmacologically modulate vasodilation.

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Protective Effects and Molecular Signaling of n-3 Fatty Acids on Oxidative Stress and Inflammation in Retinal Diseases

Antioxidants ◽

10.3390/antiox9100920 ◽

2020 ◽

Vol 9 (10) ◽

pp. 920

Author(s):

Ayana Suzumura ◽

Ryo Terao ◽

Hiroki Kaneko

Keyword(s):

Oxidative Stress ◽

Fatty Acids ◽

Essential Fatty Acids ◽

Age Related Macular Degeneration ◽

Therapeutic Effects ◽

Retinal Diseases ◽

Protective Effects ◽

Molecular Signaling ◽

Age Related ◽

Membrane Components

Oxidative stress and inflammation play crucial roles in the development and progression of retinal diseases. Retinal damage by various etiologies can result in retinopathy of prematurity (ROP), diabetic retinopathy (DR), and age-related macular degeneration (AMD). n-3 fatty acids are essential fatty acids and are necessary for homeostasis. They are important retinal membrane components and are involved in energy storage. n-3 fatty acids also have antioxidant and anti-inflammatory properties, and their suppressive effects against ROP, DR, and AMD have been previously evaluated. α-linolenic acid (ALA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and their metabolites have been shown to alleviate retinal oxidative stress and inflammation involving various biological signaling pathways. In this review, we summarize the current understanding of the n-3 fatty acids effects on the mechanisms of these retinal diseases and how they exert their therapeutic effects, focusing on ALA, EPA, DHA, and their metabolites. This knowledge may provide new remedial strategies for n-3 fatty acids in the prevention and treatment of retinal diseases associated with oxidative stress and inflammation.

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Aldosterone and the cardiovascular system: a dangerous association

Hormone Molecular Biology and Clinical Investigation ◽

10.1515/hmbci.2010.057 ◽

2010 ◽

Vol 4 (2) ◽

Author(s):

Victoria Cachofeiro ◽

Natalia López-Andrés ◽

Maria Miana ◽

Beatriz Martín-Fernández ◽

Natalia de las Heras ◽

...

Keyword(s):

Oxidative Stress ◽

Cardiovascular System ◽

Vascular System ◽

Heart Function ◽

Ionic Channels ◽

Pressure Control ◽

System A ◽

Activation Of Transcription ◽

Patients With Heart Failure

AbstractInitial studies have focussed on the actions of aldosterone in renal electrolyte handling and, as a consequence, blood pressure control. More recently, attention has primarily been focussed on its actions on the heart and vascular system, where it is locally produced. Aldosterone by binding mineralocorticoid receptors causes oxidative stress, fibrosis and triggers an inflammatory response in the cardiovascular system. All these effects could be underlying the role of aldo-sterone on cardiac and vascular remodelling associated with different pathological situations. At the vascular level, aldo-sterone affects endothelial function because administration of aldosterone to rats impaired endothelium-dependent relaxations. In addition, the administration of mineralocorticoid receptor antagonists ameliorates endothelium-dependent relaxation in models of both hypertension and atherosclerosis, and in patients with heart failure. Several mechanisms can participate in this effect, including production of vasoconstrictor factors and a reduction in nitric oxide levels. This reduction can involve both a decrease in its production as well as an increase in its degradation by reactive oxygen species. Aldosterone can produce oxidative stress by the activation of transcription factors such as the NF-κB system, which can also trigger an inflammatory process through the production of different cytokines. At cardiac level, high levels of aldosterone can also adversely impact heart function by producing cardiac hypertrophy, diastolic dysfunction and electrical remodelling through changes in ionic channels. All these effects can explain the beneficial effect of mineralocorticoid blockade in the cardiovascular system.

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Curcumin Ameliorates the Cd-Induced Anxiety-like Behavior in Mice by Regulating Oxidative Stress and Neuro-Inflammatory Proteins in the Prefrontal Cortex Region of the Brain

Antioxidants ◽

10.3390/antiox10111710 ◽

2021 ◽

Vol 10 (11) ◽

pp. 1710

Author(s):

Dhondup Namgyal ◽

Sher Ali ◽

Muhammad Delwar Hussain ◽

Mohsin Kazi ◽

Ajaz Ahmad ◽

...

Keyword(s):

Oxidative Stress ◽

Working Memory ◽

Prefrontal Cortex ◽

Neurodegenerative Diseases ◽

Spatial Working Memory ◽

Cellular Mechanisms ◽

Behavioral Impairment ◽

Age Related ◽

The Brain ◽

And Oxidative Stress

Age-related neurodegenerative diseases and vascular dementia are major challenges to the modern health care system. Most neurodegenerative diseases are associated with impaired spatial working memory and anxiety-like behavior. Thus, it is important to understand the underlying cellular mechanisms of neurodegenerative diseases in different regions of the brain to develop an effective therapeutic approach. In our previous research paper, we have reported the ameliorative effect of curcumin in Cd-induced hippocampal neurodegeneration. However, recently many researchers had reported the important role of the prefrontal cortex in higher cognitive functions. Therefore, to look into the cellular mechanism of curcumin protection against Cd-induced prefrontal cortex neurotoxicity, we investigated spatial working memory, anxiety-like behavior and analyzed prefrontal cortex inflammatory markers (IL-6, IL-10, and TNFα), antioxidant enzymes (SOD, GSH, and CAT), and pro-oxidant MDA level. Further, we conducted histological studies of the prefrontal cortex in Swiss albino mice exposed to cadmium (2.5 mg/kg). We observed that curcumin treatment improved the spatial working memory and anxiety-like behavior of mice through reduction of prefrontal cortex neuroinflammation and oxidative stress as well as increasing the number of viable prefrontal cortex neuronal cells. Our result suggests that environmental heavy metal cadmium can induce behavioral impairment in mice through prefrontal cortex cellular inflammation and oxidative stress. We found that curcumin has a potential therapeutic property to mitigate these behavioral and biochemical impairments induced by cadmium.

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Age-Related Macular Degeneration: New Paradigms for Treatment and Management of AMD

Oxidative Medicine and Cellular Longevity ◽

10.1155/2018/8374647 ◽

2018 ◽

Vol 2018 ◽

pp. 1-14 ◽

Cited By ~ 52

Author(s):

Luis Fernando Hernández-Zimbrón ◽

Ruben Zamora-Alvarado ◽

Lenin Ochoa-De la Paz ◽

Raul Velez-Montoya ◽

Edgar Zenteno ◽

...

Keyword(s):

Oxidative Stress ◽

Macular Degeneration ◽

Vision Loss ◽

Age Related Macular Degeneration ◽

Related Factor ◽

Visual Disability ◽

Cellular Mechanisms ◽

Cell Dysfunction ◽

Age Related ◽

Endothelial Growth Factor

Age-related macular degeneration (AMD) is a well-characterized and extensively studied disease. It is currently considered the leading cause of visual disability among patients over 60 years. The hallmark of early AMD is the formation of drusen, pigmentary changes at the macula, and mild to moderate vision loss. There are two forms of AMD: the “dry” and the “wet” form that is less frequent but is responsible for 90% of acute blindness due to AMD. Risk factors have been associated with AMD progression, and they are taking relevance to understand how AMD develops: (1) advanced age and the exposition to environmental factors inducing high levels of oxidative stress damaging the macula and (2) this damage, which causes inflammation inducing a vicious cycle, altogether causing central vision loss. There is neither a cure nor treatment to prevent AMD. However, there are some treatments available for the wet form of AMD. This article will review some molecular and cellular mechanisms associated with the onset of AMD focusing on feasible treatments for each related factor in the development of this pathology such as vascular endothelial growth factor, oxidative stress, failure of the clearance of proteins and organelles, and glial cell dysfunction in AMD.

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Phosphatidylcholine Extends Lifespan via DAF-16 and Reduces Amyloid-Beta-Induced Toxicity in Caenorhabditis elegans

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/2860642 ◽

2019 ◽

Vol 2019 ◽

pp. 1-14 ◽

Cited By ~ 4

Author(s):

So-Hyeon Kim ◽

Bo-Kyoung Kim ◽

Suhyeon Park ◽

Sang-Kyu Park

Keyword(s):

Oxidative Stress ◽

Amyloid Beta ◽

Dietary Intervention ◽

Disease Model ◽

Cellular Membrane ◽

Cellular Mechanisms ◽

Hormetic Effect ◽

Age Related ◽

Significant Difference

Phosphatidylcholine is one of the major phospholipids comprising cellular membrane and is known to have several health-promoting activities, including the improvement of brain function and liver repair. In this paper, we examine the in vivo effect of dietary supplementation with phosphatidylcholine on the response to environmental stressors and aging in C. elegans. Treatment with phosphatidylcholine significantly increased the survival of worms under oxidative stress conditions. However, there was no significant difference in response to stresses caused by heat shock or ultraviolet irradiation. Oxidative stress is believed to be one of the major causal factors of aging. Then, we examined the effect of phosphatidylcholine on lifespan and age-related physiological changes. Phosphatidylcholine showed a lifespan-extending effect and a reduction in fertility, possibly as a tradeoff for long lifespan. Age-related decline of motility was also significantly delayed by supplementation with phosphatidylcholine. Interestingly, the expressions of well-known longevity-assuring genes, hsp-16.2 and sod-3, were significantly upregulated by dietary intervention with phosphatidylcholine. DAF-16, a transcription factor modulating stress response genes, was accumulated in the nucleus by phosphatidylcholine treatment. Increase of the ROS level with phosphatidylcholine suggests that the antioxidant and lifespan-extending effects are due to the hormetic effect of phosphatidylcholine. Phosphatidylcholine also showed a protective effect against amyloid beta-induced toxicity in Alzheimer’s disease model animals. Experiments with long-lived mutants revealed that the lifespan-extending effect of phosphatidylcholine specifically overlapped with that of reduced insulin/IGF-1-like signaling and required DAF-16. These findings showed the antioxidant and antiaging activities of phosphatidylcholine for the first time in vivo. Further studies focusing on the identification of underlying cellular mechanisms involved in the antiaging effect will increase the possibility of using phosphatidylcholine for the development of antiaging therapeutics.

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Vitamin D: a Review of its Effects on Epigenetics and Gene Regulation

Folia Medica ◽

10.3897/folmed.62.e50204. ◽

2020 ◽

Vol 62 (4) ◽

pp. 662-667

Author(s):

Violeta Snegarova ◽

Darina Naydenova

Keyword(s):

Oxidative Stress ◽

Vitamin D ◽

Gene Regulation ◽

English Language ◽

Inflammatory Diseases ◽

Cost Effective ◽

Hypovitaminosis D ◽

Epigenetic Mechanisms ◽

Medical Subject Headings ◽

Age Related

Vitamin D is a secosteroid hormone with known beneficial effects on several body systems other than the musculoskeletal system. Both 25 dihydroxy vitamin D [25(OH)2D] and its active hormonal form, 1,25-dihydroxyvitamin D [1,25(OH)2D] are essential for hu-man physiological functions, including damping down inflammation and the excessive intracellular oxidative stresses. In the present study we set out to review all available literature on vitamin D and the role it plays in epigenetics and gene regulation. We searched the PubMed/Medline electronic database for studies published in the English language up to January 2020. The Medical Subject Headings (MeSH) database was searched with the keywords ‘vitamin D’, ‘DNA methylation’, ‘nutritional supplements’, ‘epigenome’ and ‘pregnancy’. Observational studies, supplementation studies, and meta-analyses dealing with the effect of vitamin D on epigenetics and gene regula-tion were included in the review. The obtained information from the databases such as PubMed, Google Scholar, and ResearchGate was analysed and summarized. We found that hypovitaminosis D increases the incidence and severity of several age-related common diseases such as the oxidative stress-associated metabolic disorders. These include obesity, insulin resistance, type 2 diabetes, hypertension, pregnancy complications, memory disorders, osteoporosis, autoimmune diseases, certain cancers, and systemic inflammatory diseases. New understandings of vitamin D-related advances in metabolomics, transcriptomics, epigenetics, in relation to its ability to control oxidative stress in conjunc-tion with micronutrients, vitamins, and antioxidants, following normalization of serum 25(OH)D and tissue 1,25(OH)2D concentra-tions, are likely to promise better cost-effective clinical outcomes in humans. There is a strong reciprocity between the vitamin D system and epigenetic mechanisms. The vitamin D system is, on the one hand regu-lated by epigenetic mechanisms and, on the other hand, is involved in regulating epigenetic events.

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The Polymorphisms with Cataract Susceptibility Impair the EPHA2 Receptor Stability and Its Cytoprotective Function

Journal of Ophthalmology ◽

10.1155/2015/401894 ◽

2015 ◽

Vol 2015 ◽

pp. 1-9 ◽

Cited By ~ 3

Author(s):

Jin Yang ◽

Dan Li ◽

Qi Fan ◽

Lei Cai ◽

Xiaodi Qiu ◽

...

Keyword(s):

Oxidative Stress ◽

Epithelial Cells ◽

Lens Epithelial Cells ◽

Missense Mutations ◽

Nucleotide Polymorphisms ◽

Cellular Mechanisms ◽

Downstream Signaling ◽

Functional Polymorphisms ◽

Age Related ◽

Induced Apoptosis

Despite accumulating evidence revealing susceptibility genes for age-related cataract, its pathophysiology leading to visual impairment at the cellular and molecular level remains poorly understood. Recent bioinformatic studies uncovered the association of two single nucleotide polymorphisms in human EPHA2, rs2291806 and rs1058371, with age-related cataract. Here we investigated the role of EPHA2 in counteracting oxidative stress-induced apoptosis of lens epithelial cells. The cataract-associated missense mutations resulted in the destabilization of EPHA2 receptor without altering the mRNA transcription. The cytoprotective and antiapoptotic function of EPHA2 in lens epithelial cells was abolished by the functional polymorphisms. Furthermore, our results suggest that the downstream signaling of activated EPHA2 promotes the antioxidative capacity of lens epithelial cells to eradicate the overproduction of reactive oxygen species. In contrast, the overexpression of EPHA2 with nonsynonymous mutations in the lens epithelial cells offered limited antioxidative protection against oxidative stress. Thus, our study not only sheds the light on the potential cytoprotective function of EPHA2 signaling in lens but also provides the cellular mechanisms underlying the pathogenesis of age-related cataract.

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