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1.
An Overview of Epigenetics in Obesity: The Role of Lifestyle and Therapeutic Interventions.
Mahmoud, AM
International journal of molecular sciences. 2022;(3)
Abstract
Obesity has become a global epidemic that has a negative impact on population health and the economy of nations. Genetic predispositions have been demonstrated to have a substantial role in the unbalanced energy metabolism seen in obesity. However, these genetic variations cannot entirely explain the massive growth in obesity over the last few decades. Accumulating evidence suggests that modern lifestyle characteristics such as the intake of energy-dense foods, adopting sedentary behavior, or exposure to environmental factors such as industrial endocrine disruptors all contribute to the rising obesity epidemic. Recent advances in the study of DNA and its alterations have considerably increased our understanding of the function of epigenetics in regulating energy metabolism and expenditure in obesity and metabolic diseases. These epigenetic modifications influence how DNA is transcribed without altering its sequence. They are dynamic, reflecting the interplay between the body and its surroundings. Notably, these epigenetic changes are reversible, making them appealing targets for therapeutic and corrective interventions. In this review, I discuss how these epigenetic modifications contribute to the disordered energy metabolism in obesity and to what degree lifestyle and weight reduction strategies and pharmacological drugs can restore energy balance by restoring normal epigenetic profiles.
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2.
COVID-19 Is a Multi-Organ Aggressor: Epigenetic and Clinical Marks.
Kgatle, MM, Lawal, IO, Mashabela, G, Boshomane, TMG, Koatale, PC, Mahasha, PW, Ndlovu, H, Vorster, M, Rodrigues, HG, Zeevaart, JR, et al
Frontiers in immunology. 2021;:752380
Abstract
The progression of coronavirus disease 2019 (COVID-19), resulting from a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, may be influenced by both genetic and environmental factors. Several viruses hijack the host genome machinery for their own advantage and survival, and similar phenomena might occur upon SARS-CoV-2 infection. Severe cases of COVID-19 may be driven by metabolic and epigenetic driven mechanisms, including DNA methylation and histone/chromatin alterations. These epigenetic phenomena may respond to enhanced viral replication and mediate persistent long-term infection and clinical phenotypes associated with severe COVID-19 cases and fatalities. Understanding the epigenetic events involved, and their clinical significance, may provide novel insights valuable for the therapeutic control and management of the COVID-19 pandemic. This review highlights different epigenetic marks potentially associated with COVID-19 development, clinical manifestation, and progression.
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3.
The potential role of m6A RNA methylation in diabetic retinopathy.
Kumari, N, Karmakar, A, Ahamad Khan, MM, Ganesan, SK
Experimental eye research. 2021;:108616
Abstract
Diabetic retinopathy (DR), a major microvascular complication of diabetes, affects most diabetic individuals and has become the leading cause of vision loss. Metabolic memory associated with diabetes retains the risk of disease occurrence even after the termination of glycemic insult. Further, various limitations associated with its current diagnostic and treatment strategies like unavailability of early diagnostic and treatment methods, variation in treatment response from patient to patient, and cost-effectiveness have driven the need to find alternative solutions. Post-transcriptional epigenetic modification of RNA mainly, N6-methyladenosine (m6A), is an emerging concept in the scientific community. It has an indispensable effect in various physiological and pathological conditions. m6A mediates its effect through the various reader, writer, and eraser proteins. Recent studies have shown the impact of m6A RNA modification on various disease conditions, including diabetes, but its role in diabetic retinopathy is still unclear. However, change in m6A levels has been observed in various prime aggravators of DR pathogenesis, such as inflammation, oxidative stress, and angiogenesis. Further, various non-coding RNAs like microRNA, lncRNA, and circRNA are also associated with DR, and m6A has been shown to affect all these non-coding RNAs. This review is concerned with the possible mechanisms through which alteration in m6A modification of RNA can participate in the DR progression and pathogenesis and its expected role in metabolic memory phenomena.
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4.
Epigenetic Therapies for Heart Failure: Current Insights and Future Potential.
Napoli, C, Bontempo, P, Palmieri, V, Coscioni, E, Maiello, C, Donatelli, F, Benincasa, G
Vascular health and risk management. 2021;:247-254
Abstract
Despite the current reductionist approach providing an optimal indication for diagnosis and treatment of patients with heart failure with reduced ejection fraction (HFrEF), there are no standard pharmacological therapies for heart failure with preserved ejection fraction (HFpEF). Although in its infancy in cardiovascular diseases, the epigenetic-based therapy ("epidrugs") is capturing the interest of physician community. In fact, an increasing number of controlled clinical trials is evaluating the putative beneficial effects of: 1) direct epigenetic-oriented drugs, eg, apabetalone, and 2) repurposed drugs with a possible indirect epigenetic interference, eg, metformin, statins, sodium glucose transporter inhibitors 2 (SGLT2i), and omega 3 polyunsaturated fatty acids (PUFAs) in both HFrEF and HFpEF, separately. Apabetalone is the first and unique direct epidrug tested in cardiovascular patients to date, and the BETonMACE trial has reported a reduction in first HF hospitalization (any EF value) and cardiovascular death in patients with type 2 diabetes and recent acute coronary syndrome, suggesting a possible role in secondary prevention. Patients with HFpEF seem to benefit from supplementation to the standard therapy with statins, metformin, and SGLT2i owing to their ability in reducing mortality. In contrast, the vasodilator hydralazine, with or without isosorbide dinitrate, did not provide beneficial effects. In HFrEF, metformin and SGLT2i could reduce the risk of incident HF and mortality in affected patients whereas clinical trials based on statins provided mixed results. Furthermore, PUFAs diet supplementation was significantly associated with reduced cardiovascular risk in both HFpEF and HFrEF. Future large trials will reveal whether direct and indirect epitherapy will remain a work in progress or become a useful way to customize the therapy in the real-world management of HFpEF and HFrEF. Our goal is to discuss the recent advancement in the epitherapy as a possible way to improve personalized therapy of HF.
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5.
New promising developments for potential therapeutic applications of high-dose ascorbate as an anticancer drug.
Testa, U, Pelosi, E, Castelli, G
Hematology/oncology and stem cell therapy. 2021;(3):179-191
Abstract
Vitamin C (ascorbate) is an essential dietary requirement, with fundamental redox, anti-oxidant functions at physiologic concentrations. Vitamin C is a cofactor for Fe2+ and 2-oxoglutarate-dependent dioxygenases, englobing large families of enzymes, including also epigenetic regulators of DNA and histone methylation. Importantly, vitamin C is involved in the control of the activity of TET (ten-eleven translocation) enzymes, key epigenetic regulators. For this spectrum of activities, often involving pathways deregulated in cancer cells, vitamin C possesses some pharmacologic activities that can be exploited in anticancer therapy. In particular, the capacity of pharmacological doses of vitamin C to target redox imbalance and to rescue deregulated epigenetic program observed in some cancer cells represents a consistent therapeutic potentiality. Several recent studies have identified some cancer subsets that could benefit from the pharmacological activities of vitamin C. The identification of these potentially responsive patients will help to carefully define controlled clinical trials aiming to evaluate the anticancer activity of Vitamin C.
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6.
Model-based robustness and bistability analysis for methylation-based, epigenetic memory systems.
Klingel, V, Kirch, J, Ullrich, T, Weirich, S, Jeltsch, A, Radde, NE
The FEBS journal. 2021;(19):5692-5707
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Abstract
In recent years, epigenetic memory systems have been developed based on DNA methylation and positive feedback systems. Achieving a robust design for these systems is generally a challenging and multifactorial task. We developed and validated a novel mathematical model to describe methylation-based epigenetic memory systems that capture switching dynamics of methylation levels and methyltransferase amounts induced by different inputs. A bifurcation analysis shows that the system operates in the bistable range, but in its current setup is not robust to changes in parameters. An expansion of the model captures heterogeneity of cell populations by accounting for distributed cell division rates. Simulations predict that the system is highly sensitive to variations in temperature, which affects cell division and the efficiency of the zinc finger repressor. A moderate decrease in temperature leads to a highly heterogeneous response to input signals and bistability on a single-cell level. The predictions of our model were confirmed by flow cytometry experiments conducted in this study. Overall, the results of our study give insights into the functional mechanisms of methylation-based memory systems and demonstrate that the switching dynamics can be highly sensitive to experimental conditions.
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7.
ABA and Bud Dormancy in Perennials: Current Knowledge and Future Perspective.
Pan, W, Liang, J, Sui, J, Li, J, Liu, C, Xin, Y, Zhang, Y, Wang, S, Zhao, Y, Zhang, J, et al
Genes. 2021;(10)
Abstract
Bud dormancy is an evolved trait that confers adaptation to harsh environments, and affects flower differentiation, crop yield and vegetative growth in perennials. ABA is a stress hormone and a major regulator of dormancy. Although the physiology of bud dormancy is complex, several advancements have been achieved in this field recently by using genetics, omics and bioinformatics methods. Here, we review the current knowledge on the role of ABA and environmental signals, as well as the interplay of other hormones and sucrose, in the regulation of this process. We also discuss emerging potential mechanisms in this physiological process, including epigenetic regulation.
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The Relationship between Cadmium Toxicity and the Modulation of Epigenetic Traits in Plants.
Niekerk, LA, Carelse, MF, Bakare, OO, Mavumengwana, V, Keyster, M, Gokul, A
International journal of molecular sciences. 2021;(13)
Abstract
Elevated concentrations of heavy metals such as cadmium (Cd) have a negative impact on staple crop production due to their ability to elicit cytotoxic and genotoxic effects on plants. In order to understand the relationship between Cd stress and plants in an effort to improve Cd tolerance, studies have identified genetic mechanisms which could be important for conferring stress tolerance. In recent years epigenetic studies have garnered much attention and hold great potential in both improving the understanding of Cd stress in plants as well as revealing candidate mechanisms for future work. This review describes some of the main epigenetic mechanisms involved in Cd stress responses. We summarize recent literature and data pertaining to chromatin remodeling, DNA methylation, histone acetylation and miRNAs in order to understand the role these epigenetic traits play in cadmium tolerance. The review aims to provide the framework for future studies where these epigenetic traits may be used in plant breeding and molecular studies in order to improve Cd tolerance.
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9.
Role of Phytonutrients in Nutrigenetics and Nutrigenomics Perspective in Curing Breast Cancer.
Bhattacharya, T, Dutta, S, Akter, R, Rahman, MH, Karthika, C, Nagaswarupa, HP, Murthy, HCA, Fratila, O, Brata, R, Bungau, S
Biomolecules. 2021;(8)
Abstract
Breast cancer (BC) is one of the most common type of cancer and an important contributor to female mortality. Several genes and epigenetic modifications are involved in the development and progression of BC. Research in phytochemistry, nutrigenomics, and nutrigenetics has provided strong evidence that certain phytonutrients are able to modulate gene expression at transcriptional and post-transcriptional levels. Such phytonutrients may also be beneficial to prevent and treat BC. In this review, we will focus on the nutrigenomic effects of various phytochemicals including polyphenols, phytosterols, terpenoids, alkaloids, and other compounds from different sources. Overall, these phytonutrients are found to inhibit BC cell proliferation, differentiation, invasion, metastasis, angiogenesis, and induce apoptotic cell death by targeting various molecular pathways. They also alter epigenetic mechanisms and enhance the chemosensitivity and radiosensitivity of cancer cells. Such phytochemicals may be used for the effective management of BC patients in the clinical setting in the future. The present article aims to summarize the specific molecular pathways involved in the genetic effects of phytochemicals in BC.
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10.
High-resolution targeted bisulfite sequencing reveals blood cell type-specific DNA methylation patterns in IL13 and ORMDL3.
Söderhäll, C, Reinius, LE, Salmenperä, P, Gentile, M, Acevedo, N, Konradsen, JR, Nordlund, B, Hedlin, G, Scheynius, A, Myllykangas, S, et al
Clinical epigenetics. 2021;(1):106
Abstract
BACKGROUND Methylation of DNA at CpG sites is an epigenetic modification and a potential modifier of disease risk, possibly mediating environmental effects. Currently, DNA methylation is commonly assessed using specific microarrays that sample methylation at a few % of all methylated sites. METHODS To understand if significant information on methylation can be added by a more comprehensive analysis of methylation, we set up a quantitative method, bisulfite oligonucleotide-selective sequencing (Bs-OS-seq), and compared the data with microarray-derived methylation data. We assessed methylation at two asthma-associated genes, IL13 and ORMDL3, in blood samples collected from children with and without asthma and fractionated white blood cell types from healthy adult controls. RESULTS Our results show that Bs-OS-seq can uncover vast amounts of methylation variation not detected by commonly used array methods. We found that high-density methylation information from even one gene can delineate the main white blood cell lineages. CONCLUSIONS We conclude that high-resolution methylation studies can yield clinically important information at selected specific loci missed by array-based methods, with potential implications for future studies of methylation-disease associations.