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Phytochemicals as Potential Epidrugs in Type 2 Diabetes Mellitus.
Ramírez-Alarcón, K, Victoriano, M, Mardones, L, Villagran, M, Al-Harrasi, A, Al-Rawahi, A, Cruz-Martins, N, Sharifi-Rad, J, Martorell, M
Frontiers in endocrinology. 2021;:656978
Abstract
Type 2 diabetes Mellitus (T2DM) prevalence has significantly increased worldwide in recent years due to population age, obesity, and modern sedentary lifestyles. The projections estimate that 439 million people will be diabetic in 2030. T2DM is characterized by an impaired β-pancreatic cell function and insulin secretion, hyperglycemia and insulin resistance, and recently the epigenetic regulation of β-pancreatic cells differentiation has been underlined as being involved. It is currently known that several bioactive molecules, widely abundant in plants used as food or infusions, have a key role in histone modification and DNA methylation, and constituted potential epidrugs candidates against T2DM. In this sense, in this review the epigenetic mechanisms involved in T2DM and protein targets are reviewed, with special focus in studies addressing the potential use of phytochemicals as epidrugs that prevent and/or control T2DM in vivo and in vitro. As main findings, and although some controversial results have been found, bioactive molecules with epigenetic regulatory function, appear to be a potential replacement/complementary therapy of pharmacological hypoglycemic drugs, with minimal side effects. Indeed, natural epidrugs have shown to prevent or delay the T2DM development and the morbidity associated to dysfunction of blood vessels, eyes and kidneys due to sustained hyperglycemia in T2DM patients.
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Influence of the Bioactive Diet Components on the Gene Expression Regulation.
Mierziak, J, Kostyn, K, Boba, A, Czemplik, M, Kulma, A, Wojtasik, W
Nutrients. 2021;(11)
Abstract
Diet bioactive components, in the concept of nutrigenetics and nutrigenomics, consist of food constituents, which can transfer information from the external environment and influence gene expression in the cell and thus the function of the whole organism. It is crucial to regard food not only as the source of energy and basic nutriments, crucial for living and organism development, but also as the factor influencing health/disease, biochemical mechanisms, and activation of biochemical pathways. Bioactive components of the diet regulate gene expression through changes in the chromatin structure (including DNA methylation and histone modification), non-coding RNA, activation of transcription factors by signalling cascades, or direct ligand binding to the nuclear receptors. Analysis of interactions between diet components and human genome structure and gene activity is a modern approach that will help to better understand these relations and will allow designing dietary guidances, which can help maintain good health.
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GDF-15 as a Weight Watcher for Diabetic and Non-Diabetic People Treated With Metformin.
Ouyang, J, Isnard, S, Lin, J, Fombuena, B, Peng, X, Chen, Y, Routy, JP
Frontiers in endocrinology. 2020;:581839
Abstract
Weight gain and obesity are global health concerns contributing to morbidity with increased risks of cardiovascular disease, diabetes, liver steatohepatitis and cancer. Pharmacological therapies or bariatric surgery are often required for those who fail to adhere to diet and lifestyle modifications. Metformin, a widely used antidiabetic agent, seems to have a health benefit beyond its anti-hyperglycemic properties, with few side effects. Emerging evidence shows weight loss to be associated with metformin in both diabetic and non-diabetic individuals. Recently, the growth differentiation factor 15 (GDF-15), a member of the transforming growth factor beta superfamily, has been identified as a key mediator of metformin-induced weight loss. Metformin increases the secretion of GDF-15, which binds exclusively to glial cell-derived neurotrophic factor family receptor alpha-like (GFRAL). This gut-brain cytokine works as a prominent player in reducing food intake and body weight in health and disease, like anorexia nervosa and cancer. Herein, we critically review advances in the understanding of the weight-reducing effects of metformin via the GDF-15 pathway.
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4.
Diurnal Rhythmicity Programs of Microbiota and Transcriptional Oscillation of Circadian Regulator, NFIL3.
Kubo, M
Frontiers in immunology. 2020;:552188
Abstract
Circadian rhythms are a very exquisite mechanism to influence on transcriptional levels and physiological activities of various molecules that affect cell metabolic pathways. Long-term alteration of circadian rhythms increases the risk of cardiovascular diseases, hypertension, hypertriglyceridemia, and metabolic syndrome. A drastic change in dietary patterns can affect synchronizing the circadian clock within the metabolic system. Therefore, the interaction between the host and the bacterial community colonizing the mammalian gastrointestinal tract has a great impact on the circadian clock in diurnal programs. Here, we propose that the microbiota regulates body composition through the transcriptional oscillation of circadian regulators. The transcriptional regulator, NFIL3 (also called E4BP4) is a good example. Compositional change of the commensal bacteria influences the rhythmic expression of NFIL3 in the epithelium, which subsequently controls obesity and insulin resistance. Therefore, control of circadian regulators would be a promising therapeutic target for metabolic diseases.
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5.
RNA regulons are essential in intestinal homeostasis.
Parham, LR, Williams, PA, Chatterji, P, Whelan, KA, Hamilton, KE
American journal of physiology. Gastrointestinal and liver physiology. 2019;(1):G197-G204
Abstract
Intestinal epithelial cells are among the most rapidly proliferating cell types in the human body. There are several different subtypes of epithelial cells, each with unique functional roles in responding to the ever-changing environment. The epithelium's ability for rapid and customized responses to environmental changes requires multitiered levels of gene regulation. An emerging paradigm in gastrointestinal epithelial cells is the regulation of functionally related mRNA families, or regulons, via RNA-binding proteins (RBPs). RBPs represent a rapid and efficient mechanism to regulate gene expression and cell function. In this review, we will provide an overview of intestinal epithelial RBPs and how they contribute specifically to intestinal epithelial stem cell dynamics. In addition, we will highlight key gaps in knowledge in the global understanding of RBPs in gastrointestinal physiology as an opportunity for future studies.
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6.
Phosphorylation and Signal Transduction Pathways in Translational Control.
Proud, CG
Cold Spring Harbor perspectives in biology. 2019;(7)
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Abstract
Protein synthesis, including the translation of specific messenger RNAs (mRNAs), is regulated by extracellular stimuli such as hormones and by the levels of certain nutrients within cells. This control involves several well-understood signaling pathways and protein kinases, which regulate the phosphorylation of proteins that control the translational machinery. These pathways include the mechanistic target of rapamycin complex 1 (mTORC1), its downstream effectors, and the mitogen-activated protein (MAP) kinase (extracellular ligand-regulated kinase [ERK]) signaling pathway. This review describes the regulatory mechanisms that control translation initiation and elongation factors, in particular the effects of phosphorylation on their interactions or activities. It also discusses current knowledge concerning the impact of these control systems on the translation of specific mRNAs or subsets of mRNAs, both in physiological processes and in diseases such as cancer.
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Bromodomains in Protozoan Parasites: Evolution, Function, and Opportunities for Drug Development.
Jeffers, V, Yang, C, Huang, S, Sullivan, WJ
Microbiology and molecular biology reviews : MMBR. 2017;(1)
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Abstract
Parasitic infections remain one of the most pressing global health concerns of our day, affecting billions of people and producing unsustainable economic burdens. The rise of drug-resistant parasites has created an urgent need to study their biology in hopes of uncovering new potential drug targets. It has been established that disrupting gene expression by interfering with lysine acetylation is detrimental to survival of apicomplexan (Toxoplasma gondii and Plasmodium spp.) and kinetoplastid (Leishmania spp. and Trypanosoma spp.) parasites. As "readers" of lysine acetylation, bromodomain proteins have emerged as key gene expression regulators and a promising new class of drug target. Here we review recent studies that demonstrate the essential roles played by bromodomain-containing proteins in parasite viability, invasion, and stage switching and present work showing the efficacy of bromodomain inhibitors as novel antiparasitic agents. In addition, we performed a phylogenetic analysis of bromodomain proteins in representative pathogens, some of which possess unique features that may be specific to parasite processes and useful in future drug development.
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Sulfated Alginates as Heparin Analogues: A Review of Chemical and Functional Properties.
Arlov, Ø, Skjåk-Bræk, G
Molecules (Basel, Switzerland). 2017;(5)
Abstract
Heparin is widely recognized for its potent anticoagulating effects, but has an additional wide range of biological properties due to its high negative charge and heterogeneous molecular structure. This heterogeneity has been one of the factors in motivating the exploration of functional analogues with a more predictable modification pattern and monosaccharide sequence, that can aid in elucidating structure-function relationships and further be structurally customized to fine-tune physical and biological properties toward novel therapeutic applications and biomaterials. Alginates have been of great interest in biomedicine due to their inherent biocompatibility, gentle gelling conditions, and structural versatility from chemo-enzymatic engineering, but display limited interactions with cells and biomolecules that are characteristic of heparin and the other glycosaminoglycans (GAGs) of the extracellular environment. Here, we review the chemistry and physical and biological properties of sulfated alginates as structural and functional heparin analogues, and discuss how they may be utilized in applications where the use of heparin and other sulfated GAGs is challenging and limited.
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"Omics" in Human Colostrum and Mature Milk: Looking to Old Data with New Eyes.
Bardanzellu, F, Fanos, V, Reali, A
Nutrients. 2017;(8)
Abstract
Human Milk (HM) is the best source for newborn nutrition until at least six months; it exerts anti-inflammatory and anti-infective functions, promotes immune system formation and supports organ development. Breastfeeding could also protect from obesity, diabetes and cardiovascular disease. Furthermore, human colostrum (HC) presents a peculiar role in newborn support as a protective effect against allergic and chronic diseases, in addition to long-term metabolic benefits. In this review, we discuss the recent literature regarding "omics" technologies and growth factors (GF) in HC and the effects of pasteurization on its composition. Our aim was to provide new evidence in terms of transcriptomics, proteomics, metabolomics, and microbiomics, also in relation to maternal metabolic diseases and/or fetal anomalies and to underline the functions of GF. Since HC results are so precious, particularly for the vulnerable pre-terms category, we also discuss the importance of HM pasteurization to ensure donated HC even to neonates whose mothers are unable to provide. To the best of our knowledge, this is the first review analyzing in detail the molecular pattern, microbiota, bioactive factors, and dynamic profile of HC, finding clinical correlations of such mediators with their possible in vivo effects and with the consequent impact on neonatal outcomes.
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Genomic Determinants of Vitamin D-Regulated Gene Expression.
Pike, JW, Meyer, MB, Benkusky, NA, Lee, SM, St John, H, Carlson, A, Onal, M, Shamsuzzaman, S
Vitamins and hormones. 2016;:21-44
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Abstract
Insight into mechanisms that link the actions of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) to the regulation of gene expression has evolved extensively since the initial discovery of a nuclear protein known as the vitamin D receptor (VDR). Perhaps most important was the molecular cloning of this receptor which enabled its inclusion within the nuclear receptor gene family and further studies of both its structure and regulatory function. Current studies are now refocused on the vitamin D hormone's action at the genome, where VDR together with other transcription factors coordinates the recruitment of chromatin active coregulatory complexes that participate directly in the modification of gene output. These studies highlight the role of chromatin in the expression of genes and the dynamic impact of the epigenetic landscape that contextualizes individual gene loci thus influencing the VDR's transcriptional actions. In this chapter, we summarize advances made over the past few years in understanding vitamin D action on a genome-wide scale, focusing on overarching principles that have emerged at this level. Of particular significance is the finding that dynamic changes that occur to the genome during cellular differentiation at both genetic and epigenetic levels profoundly alter the ability of 1,25(OH)2D3 and its receptor to regulate gene expression. We address the broad impact of differentiation on specific epigenetic histone modifications that occur across the genome and the ability of the VDR to influence this activity at selected gene loci as well. These studies advance our understanding of not only vitamin D action but also of the complex and dynamic role played by the genome itself as a major determinant of VDR activity.