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Molecular Aspects of Medicine

Steven O'Reilly
Fibrosis is a common and important disease. It is a pathological state due to excessive scar formation mediated by an increase in activated fibroblasts that express alpha smooth muscle actin and copious amounts of extracellular matrix molecules. Epigenetics is an area of research that encompasses three main mechanisms: methylation, histone modifications to the tails of histones and also non-coding RNAs including long and short non-coding RNAs. These three mechanisms all seek to regulate gene expression without a change in the underlying DNA sequence...
October 6, 2016: Molecular Aspects of Medicine
Helene McNulty, J J Strain, Catherine F Hughes, Mary Ward
Hypertension is the leading risk factor contributing to mortality worldwide, primarily from cardiovascular disease (CVD), while effective treatment of hypertension is proven to reduce CVD events. Along with the well recognized nutrition and lifestyle determinants, genetic factors are implicated in the development and progression of hypertension. In recent years genome-wide association studies have identified a region near the gene encoding the folate-metabolizing enzyme methylenetetrahydrofolate reductase (MTHFR) among eight loci associated with blood pressure...
October 6, 2016: Molecular Aspects of Medicine
Hanah Rodriguez, Haloom Rafehi, Mrinal Bhave, Assam El-Osta
The regulation of gene expression in response to environmental and behavioural cues is critical for many biological processes. Histone tail modifications are dynamic and, as such, can regulate gene expression in response to extracellular conditions. Many of the enzymes involved in adding and removing these modifications require cofactors that are products of intermediary metabolism pathways, thus linking cellular metabolism to the regulation of gene expression. Furthermore, the expression and activity of such enzymes are influenced by the cellular concentrations of metabolic products...
September 30, 2016: Molecular Aspects of Medicine
Marlene Remely, Alexander G Haslberger
Dietary habits, lifestyle, medication, and food additives affect the composition and functions of the GI microbiota. Metabolic syndrome is already known to be associated with an aberrant gut microbiota affecting systemic low-grade inflammation, which is also outlined by differing epigenetic patterns. Thus, structural changes and compositional evaluation of gut microbial differences affecting epigenetic patterns in metabolic syndrome are of research interest. In the present review we focus on the disparities in the gut microbiota composition of metabolic syndrome and the resulting aberrant profile of bioactive microbial metabolites known to affect epigenetic modifications such as G-protein coupled receptors and inflammatory pathways...
September 23, 2016: Molecular Aspects of Medicine
Rongbao Zhao, Srinivas Aluri, I David Goldman
The proton-coupled folate transporter (PCFT-SLC46A1) is the mechanism by which folates are absorbed across the brush-border membrane of the small intestine. The transporter is also expressed in the choroid plexus and is required for transport of folates into the cerebrospinal fluid. Loss of PCFT function, as occurs in the autosomal recessive disorder "hereditary folate malabsorption" (HFM), results in a syndrome characterized by severe systemic and cerebral folate deficiency. Folate-receptor alpha (FRα) is expressed in the choroid plexus, and loss of function of this protein, as also occurs in an autosomal recessive disorder, results solely in "cerebral folate deficiency" (CFD), the designation for this disorder...
September 21, 2016: Molecular Aspects of Medicine
Xia Gao, Michael A Reid, Mei Kong, Jason W Locasale
Cancer cells have epigenetic alterations that are known to drive cancer progression. The reversibility of the epigenetic posttranslational modifications on chromatin and DNA renders targeting these modifications an attractive means for cancer therapy. Cellular epigenetic status interacts with cell metabolism, and we are now beginning to understand the nature of how this interaction occurs and the biological contexts that mediate its function. Given the tremendous interest in understanding and targeting metabolic reprogramming in cancer, this nexus also provides opportunities for exploring the liabilities of cancers...
September 9, 2016: Molecular Aspects of Medicine
Per Magne Ueland, Adrian McCann, Øivind Midttun, Arve Ulvik
The active form of vitamin B6, pyridoxal 5'-phosphate (PLP), serves as a co-factor in more than 150 enzymatic reactions. Plasma PLP has consistently been shown to be low in inflammatory conditions; there is a parallel reduction in liver PLP, but minor changes in in erythrocyte and muscle PLP and in functional vitamin B6 biomarkers. Plasma PLP also predicts the risk of chronic diseases like cardiovascular disease and some cancers, and is inversely associated with numerous inflammatory markers in clinical and population-based studies...
September 1, 2016: Molecular Aspects of Medicine
Frederico Alisson-Silva, Kunio Kawanishi, Ajit Varki
One of the most consistent epidemiological associations between diet and human disease risk is the impact of red meat consumption (beef, pork, and lamb, particularly in processed forms). While risk estimates vary, associations are reported with all-cause mortality, colorectal and other carcinomas, atherosclerotic cardiovascular disease, type II diabetes, and possibly other inflammatory processes. There are many proposed explanations for these associations, some long discussed in the literature. Attempts to explain the effects of red meat consumption have invoked various red meat-associated agents, including saturated fat, high salt intake, Trimethylamine-N-oxide (TMAO) generation by microbiota, and environmental pollutants contaminating red meat, none of which are specific for red meat...
October 2016: Molecular Aspects of Medicine
Mariko Taniguchi-Ikeda, Ichiro Morioka, Kazumoto Iijima, Tatsushi Toda
α-Dystroglycanopathy, an autosomal recessive disease, is associated with the development of a variety of diseases, including muscular dystrophy. In humans, α-dystroglycanopathy includes various types of congenital muscular dystrophy such as Fukuyama type congenital muscular dystrophy (FCMD), muscle eye brain disease (MEB), and the Walker Warburg syndrome (WWS), and types of limb girdle muscular dystrophy 2I (LGMD2I). α-Dystroglycanopathy share a common etiology, since it is invariably caused by gene mutations that are associated with the O-mannose glycosylation pathway of α-dystroglycan (α-DG)...
October 2016: Molecular Aspects of Medicine
Chrissa A Dwyer, Jeffrey D Esko
Idiopathic autism spectrum disorders (ASDs) are neurodevelopmental disorders with unknown etiology. An estimated 1:68 children in the U.S. are diagnosed with ASDs, making these disorders a substantial public health issue. Recent advances in genome sequencing have identified numerous genetic variants across the ASD patient population. Many genetic variants identified occur in genes that encode glycosylated extracellular proteins (proteoglycans or glycoproteins) or enzymes involved in glycosylation (glycosyltransferases and sulfotransferases)...
October 2016: Molecular Aspects of Medicine
Poh-Choo Pang, Stuart M Haslam, Anne Dell, Gary F Clark
No abstract text is available yet for this article.
October 2016: Molecular Aspects of Medicine
Partha S Banerjee, Olof Lagerlöf, Gerald W Hart
O-GlcNAcylation, a dynamic nutrient and stress sensitive post-translational modification, occurs on myriad proteins in the cell nucleus, cytoplasm and mitochondria. O-GlcNAcylation serves as a nutrient sensor to regulate signaling, transcription, translation, cell division, metabolism, and stress sensitivity in all cells. Aberrant protein O-GlcNAcylation plays a critical role both in the development, as well as in the progression of a variety of age related diseases. O-GlcNAcylation underlies the etiology of diabetes, and changes in specific protein O-GlcNAc levels and sites are responsible for insulin expression and sensitivity and glucose toxicity...
October 2016: Molecular Aspects of Medicine
Tadashi Suzuki
N-glycans on glycoproteins serve as one of the most important co- and post-translational modifications of proteins, and it has been well established that they play pivotal roles in controlling the physicochemical and/or physiological properties of the carrier proteins. The biosynthetic/processing pathways for N-glycans have been well characterized in mammalian cells. There are, however, issues that remain to be clarified concerning aspects of their degradation. While the molecular mechanism of the lysosomal degradation for N-glycoproteins has been well studied in relation to genetic disorders, which are collectively referred to as lysosomal storage disorders, evidence exists to suggest that there are also "non-lysosomal" degradation processes, which are now known to occur widely in eukaryotic cells...
October 2016: Molecular Aspects of Medicine
Larissa Krasnova, Chi-Huey Wong
Glycosylation of lipids and proteins is not encoded by genes directly and depends on many factors including the origin of cell-lines, differential expression of carbohydrate enzymes and availability of substrates, as well as environmental conditions. Individual cells from different tissues produce each glycoprotein as heterogeneous mixtures of glycoforms with distinct biological activities in response to different conditions and disease states. As the result, the study of glycosylation could not rely purely on biochemical methods; instead it requires a multidisciplinary approach utilizing a variety of methods including genetic manipulation and glycosylation pathway engineering, structural and functional proteomic analysis, chemical and enzymatic synthesis, development of glycosylation probes and glycan microarrays...
October 2016: Molecular Aspects of Medicine
Motoko Takahashi, Yasuhiko Kizuka, Kazuaki Ohtsubo, Jianguo Gu, Naoyuki Taniguchi
Most of membrane molecules including cell surface receptors and secreted proteins including ligands are glycoproteins and glycolipids. Therefore, identifying the functional significance of glycans is crucial for developing an understanding of cell signaling and subsequent physiological and pathological cellular events. In particular, the function of N-glycans associated with cell surface receptors has been extensively studied since they are directly involved in controlling cellular functions. In this review, we focus on the roles of glycosyltransferases that are involved in the modification of N-glycans and their target proteins such as epidermal growth factor receptor (EGFR), ErbB3, transforming growth factor β (TGF-β) receptor, T-cell receptors (TCR), β-site APP cleaving enzyme (BACE1), glucose transporter 2 (GLUT2), E-cadherin, and α5β1 integrin in relation to diseases and epithelial-mesenchymal transition (EMT) process...
October 2016: Molecular Aspects of Medicine
Ian Loke, Daniel Kolarich, Nicolle H Packer, Morten Thaysen-Andersen
Proteins are frequently modified by complex carbohydrates (glycans) that play central roles in maintaining the structural and functional integrity of cells and tissues in humans and lower organisms. Mannose forms an essential building block of protein glycosylation, and its functional involvement as components of larger and diverse α-mannosidic glycoepitopes in important intra- and intercellular glycoimmunological processes is gaining recognition. With a focus on the mannose-rich asparagine (N-linked) glycosylation type, this review summarises the increasing volume of literature covering human and non-human protein mannosylation, including their structures, biosynthesis and spatiotemporal expression...
October 2016: Molecular Aspects of Medicine
Javier Angulo, Mariam El Assar, Leocadio Rodríguez-Mañas
Frailty is a functional status that precedes disability and is characterized by decreased functional reserve and increased vulnerability. In addition to disability, the frailty phenotype predicts falls, institutionalization, hospitalization and mortality. Frailty is the consequence of the interaction between the aging process and some chronic diseases and conditions that compromise functional systems and finally produce sarcopenia. Many of the clinical manifestations of frailty are explained by sarcopenia which is closely related to poor physical performance...
August 2016: Molecular Aspects of Medicine
Jose Viña, Francisco Jose Tarazona-Santabalbina, Pilar Pérez-Ros, Francisco Miguel Martínez-Arnau, Consuelo Borras, Gloria Olaso-Gonzalez, Andrea Salvador-Pascual, Mari Carmen Gomez-Cabrera
Frailty is associated with loss of functional reserve as well as with the prediction of adverse events in the old population. The traditional criteria of frailty are based on five physical determinations described in the Cardiovascular Health Study. We propose that biological and genetic markers of frailty should be used to increase the predictive capacity of the established clinical indeces. In recent times, research for biological markers of frailty has gained impetus. Finding a biological markers with diagnostic and prognostic capacity would be a major milestone to identify frailty risk, and also pre-frailty status...
August 2016: Molecular Aspects of Medicine
Malcolm J Jackson
Physical frailty in the elderly is driven by loss of muscle mass and function and hence preventing this is the key to reduction in age-related physical frailty. Our current understanding of the key areas in which ROS contribute to age-related deficits in muscle is through increased oxidative damage to cell constituents and/or through induction of defective redox signalling. Recent data have argued against a primary role for ROS as a regulator of longevity, but studies have persistently indicated that aspects of the aging phenotype and age-related disorders may be mediated by ROS...
August 2016: Molecular Aspects of Medicine
Rachel Raynes, Laura C D Pomatto, Kelvin J A Davies
The proteasome is a ubiquitous and highly plastic multi-subunit protease with multi-catalytic activity that is conserved in all eukaryotes. The most widely known function of the proteasome is protein degradation through the 26S ubiquitin-proteasome system, responsible for the vast majority of protein degradation during homeostasis. However, the proteasome also plays an important role in adaptive immune responses and adaptation to oxidative stress. The unbound 20S proteasome, the core common to all proteasome conformations, is the main protease responsible for degrading oxidized proteins...
August 2016: Molecular Aspects of Medicine
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