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Biomolecules, Volume 8, Issue 3 (September 2018)

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Open AccessArticle α-Tocopheryl Succinate-Based Polymeric Nanoparticles for the Treatment of Head and Neck Squamous Cell Carcinoma
Biomolecules 2018, 8(3), 97; https://doi.org/10.3390/biom8030097
Received: 27 July 2018 / Revised: 30 August 2018 / Accepted: 14 September 2018 / Published: 19 September 2018
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Abstract
The aim of this work is to study, in an in vitro head and neck squamous cell carcinomas model the anti-angiogenic and anti-migratory properties of self-assembled polymeric nanoparticles (NPs) with demonstrated selective anticancer activity. The NPs are based on α-tocopheryl succinate (α-TOS) encapsulated
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The aim of this work is to study, in an in vitro head and neck squamous cell carcinomas model the anti-angiogenic and anti-migratory properties of self-assembled polymeric nanoparticles (NPs) with demonstrated selective anticancer activity. The NPs are based on α-tocopheryl succinate (α-TOS) encapsulated in the hydrophobic core of the NPs. We analyzed the effect of the newly synthetized α-TOS-loaded NPs in proliferating endothelial cells and hypopharynx carcinoma squamous cells and measured markers of angiogenesis, apoptosis and reactive oxygen species (ROS). α-TOS-loaded NPs suppressed angiogenesis by inducing accumulation of ROS and inducing apoptosis of proliferating endothelial cells. These NPs also decrease the number and quality of capillary-like tubes in an in vitro three-dimensional (3D) experiment, decrease the production of the pro-angiogenic vascular endothelial growth factor and down-regulate the expression of its receptor. The anti-migratory efficacy of α-TOS is corroborated in hypopharynx carcinoma cells by decreasing the secretion of matrix metalloproteases 2 and 9 (MMP-2 and MMP-9) and inhibiting cell migration. These results confirm that α-TOS-based NPs not only present anticancer properties, but also antiangiogenic properties, therefore making them promising candidates for multi-active combinatorial anticancer therapy. Full article
(This article belongs to the Special Issue Nanoparticles for Cancer Therapy)
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Open AccessReview Mineralocorticoid Receptor and Aldosterone-Related Biomarkers of End-Organ Damage in Cardiometabolic Disease
Biomolecules 2018, 8(3), 96; https://doi.org/10.3390/biom8030096
Received: 3 August 2018 / Revised: 10 September 2018 / Accepted: 12 September 2018 / Published: 18 September 2018
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Abstract
The mineralocorticoid receptor (MR) was first identified as a blood pressure regulator, modulating renal sodium handling in response to its principal ligand aldosterone. The mineralocorticoid receptor is also expressed in many tissues other than the kidney, such as adipose tissue, heart and vasculature.
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The mineralocorticoid receptor (MR) was first identified as a blood pressure regulator, modulating renal sodium handling in response to its principal ligand aldosterone. The mineralocorticoid receptor is also expressed in many tissues other than the kidney, such as adipose tissue, heart and vasculature. Recent studies have shown that MR plays a relevant role in the control of cardiovascular and metabolic function, as well as in adipogenesis. Dysregulation of aldosterone/MR signaling represents an important cause of disease as high plasma levels of aldosterone are associated with hypertension, obesity and increased cardiovascular risk. Aldosterone displays powerful vascular effects and acts as a potent pro-fibrotic agent in cardiovascular remodeling. Mineralocorticoid receptor activation regulates genes involved in vascular and cardiac fibrosis, calcification and inflammation. This review focuses on the role of novel potential biomarkers related to aldosterone/MR system that could help identify cardiovascular and metabolic detrimental conditions, as a result of altered MR activation. Specifically, we discuss: (1) how MR signaling regulates the number and function of different subpopulations of circulating and intra-tissue immune cells; (2) the role of aldosterone/MR system in mediating cardiometabolic diseases induced by obesity; and (3) the role of several MR downstream molecules as novel potential biomarkers of cardiometabolic diseases, end-organ damage and rehabilitation outcome. Full article
(This article belongs to the Special Issue Biomolecules for Translational Approaches in Cardiology)
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Open AccessCommunication Lnc-EPB41-Protein Interactions Associated with Congenital Pouch Colon
Biomolecules 2018, 8(3), 95; https://doi.org/10.3390/biom8030095
Received: 21 August 2018 / Revised: 10 September 2018 / Accepted: 13 September 2018 / Published: 17 September 2018
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Abstract
Congenital Pouch Colon (CPC) is a rare anorectal anomaly common to northwestern India, specifically Rajasthan. Despite efforts to understand the clinical genetic makeup of CPC, no attempt on identifying non-coding RNAs was done. We have earlier reported CPC’s rare variants from whole exome
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Congenital Pouch Colon (CPC) is a rare anorectal anomaly common to northwestern India, specifically Rajasthan. Despite efforts to understand the clinical genetic makeup of CPC, no attempt on identifying non-coding RNAs was done. We have earlier reported CPC’s rare variants from whole exome sequencing (WES) across 18 affected samples in a total of 64 subjects. A Smith–Waterman algorithm was used to infer a couple of lncRNAs from WES samples of CPC with predictions from the Noncode database. Further screening and quantification using polymerase chain reaction (PCR), we ascertained interactions using Micro Scale Thermophoresis (MST). We report the role of lnc-EPB41-1-1 shown to be promiscuously interacting with KIF13A substantiating their role in regulation. Full article
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Open AccessReview Plasma Membrane Lipid Domains as Platforms for Vesicle Biogenesis and Shedding?
Biomolecules 2018, 8(3), 94; https://doi.org/10.3390/biom8030094
Received: 5 August 2018 / Revised: 3 September 2018 / Accepted: 4 September 2018 / Published: 14 September 2018
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Abstract
Extracellular vesicles (EVs) contribute to several pathophysiological processes and appear as emerging targets for disease diagnosis and therapy. However, successful translation from bench to bedside requires deeper understanding of EVs, in particular their diversity, composition, biogenesis and shedding mechanisms. In this review, we
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Extracellular vesicles (EVs) contribute to several pathophysiological processes and appear as emerging targets for disease diagnosis and therapy. However, successful translation from bench to bedside requires deeper understanding of EVs, in particular their diversity, composition, biogenesis and shedding mechanisms. In this review, we focus on plasma membrane-derived microvesicles (MVs), far less appreciated than exosomes. We integrate documented mechanisms involved in MV biogenesis and shedding, focusing on the red blood cell as a model. We then provide a perspective for the relevance of plasma membrane lipid composition and biophysical properties in microvesiculation on red blood cells but also platelets, immune and nervous cells as well as tumor cells. Although only a few data are available in this respect, most of them appear to converge to the idea that modulation of plasma membrane lipid content, transversal asymmetry and lateral heterogeneity in lipid domains may play a significant role in the vesiculation process. We suggest that lipid domains may represent platforms for inclusion/exclusion of membrane lipids and proteins into MVs and that MVs could originate from distinct domains during physiological processes and disease evolution. Full article
(This article belongs to the Special Issue Cellular Membrane Domains and Organization)
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Open AccessReview The Biology of Glial Cells and Their Complex Roles in Alzheimer’s Disease: New Opportunities in Therapy
Biomolecules 2018, 8(3), 93; https://doi.org/10.3390/biom8030093
Received: 6 August 2018 / Revised: 28 August 2018 / Accepted: 6 September 2018 / Published: 10 September 2018
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Abstract
Even though Alzheimer’s disease (AD) is of significant interest to the scientific community, its pathogenesis is very complicated and not well-understood. A great deal of progress has been made in AD research recently and with the advent of these new insights more therapeutic
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Even though Alzheimer’s disease (AD) is of significant interest to the scientific community, its pathogenesis is very complicated and not well-understood. A great deal of progress has been made in AD research recently and with the advent of these new insights more therapeutic benefits may be identified that could help patients around the world. Much of the research in AD thus far has been very neuron-oriented; however, recent studies suggest that glial cells, i.e., microglia, astrocytes, oligodendrocytes, and oligodendrocyte progenitor cells (NG2 glia), are linked to the pathogenesis of AD and may offer several potential therapeutic targets against AD. In addition to a number of other functions, glial cells are responsible for maintaining homeostasis (i.e., concentration of ions, neurotransmitters, etc.) within the central nervous system (CNS) and are crucial to the structural integrity of neurons. This review explores the: (i) role of glial cells in AD pathogenesis; (ii) complex functionalities of the components involved; and (iii) potential therapeutic targets that could eventually lead to a better quality of life for AD patients. Full article
Open AccessArticle On Molecular Descriptors of Carbon Nanocones
Biomolecules 2018, 8(3), 92; https://doi.org/10.3390/biom8030092
Received: 14 August 2018 / Revised: 31 August 2018 / Accepted: 31 August 2018 / Published: 7 September 2018
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Abstract
Many degree-based topological indices can be obtained from the closed-off M-polynomial of a carbon nanocone. These topological indices are numerical parameters that are associated with a structure and, in combination, determine the properties of the carbon nanocone. In this paper, we compute the
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Many degree-based topological indices can be obtained from the closed-off M-polynomial of a carbon nanocone. These topological indices are numerical parameters that are associated with a structure and, in combination, determine the properties of the carbon nanocone. In this paper, we compute the closed form of the M-polynomial of generalized carbon nanocone and recover many important degree-based topological indices. We use software Maple 2015 (Maplesoft, Waterloo, ON, Canada) to plot the surfaces and graphs associated with these nanocones, and relate the topological indices to the structure of these nanocones. Full article
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Open AccessArticle Stimulation of the Production of Prostaglandin E2 by Ethyl Gallate, a Natural Phenolic Compound Richly Contained in Longan
Biomolecules 2018, 8(3), 91; https://doi.org/10.3390/biom8030091
Received: 9 May 2018 / Revised: 1 July 2018 / Accepted: 3 July 2018 / Published: 6 September 2018
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Abstract
Ethyl gallate is a phenolic compound richly contained in Longan. In traditional Chinese medicine, Longan is widely known as a fruit with “hot” properties, with a tendency to promote inflammatory and certain other responses. The mechanism for its proinflammatory as well as health
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Ethyl gallate is a phenolic compound richly contained in Longan. In traditional Chinese medicine, Longan is widely known as a fruit with “hot” properties, with a tendency to promote inflammatory and certain other responses. The mechanism for its proinflammatory as well as health beneficial effects is poorly understood. Based on our earlier observation that certain natural phenolic compounds can serve as reducing cosubstrates for cyclooxygenases (COXs), we sought to test a hypothesis that ethyl gallate may activate the catalytic activity of the COX enzymes. Results from studies using cultured cells and animals show that ethyl gallate can activate the production of prostaglandin E2, a representative prostaglandin tested in this study. Computational analysis indicates that ethyl gallate can activate the peroxidase active sites of COX-1 and COX-2 by serving as a reducing cosubstrate. The effect of ethyl gallate is abrogated by galangin, which is known to bind to the same peroxidase active sites of COX-1 and COX-2 as a competitive inhibitor. The findings of this study offer support for a novel hypothesis that the proinflammatory as well as health beneficial effects of Longan may be partly attributable to the activation of COX-1 and COX-2 by ethyl gallate. Full article
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Open AccessArticle Numerical Simulation and FRAP Experiments Show That the Plasma Membrane Binding Protein PH-EFA6 Does Not Exhibit Anomalous Subdiffusion in Cells
Biomolecules 2018, 8(3), 90; https://doi.org/10.3390/biom8030090
Received: 18 July 2018 / Revised: 27 August 2018 / Accepted: 28 August 2018 / Published: 5 September 2018
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Abstract
The fluorescence recovery after photobleaching (FRAP) technique has been used for decades to measure movements of molecules in two-dimension (2D). Data obtained by FRAP experiments in cell plasma membranes are assumed to be described through a means of two parameters, a diffusion coefficient,
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The fluorescence recovery after photobleaching (FRAP) technique has been used for decades to measure movements of molecules in two-dimension (2D). Data obtained by FRAP experiments in cell plasma membranes are assumed to be described through a means of two parameters, a diffusion coefficient, D (as defined in a pure Brownian model) and a mobile fraction, M. Nevertheless, it has also been shown that recoveries can be nicely fit using anomalous subdiffusion. Fluorescence recovery after photobleaching (FRAP) at variable radii has been developed using the Brownian diffusion model to access geometrical characteristics of the surrounding landscape of the molecule. Here, we performed numerical simulations of continuous time random walk (CTRW) anomalous subdiffusion and interpreted them in the context of variable radii FRAP. These simulations were compared to experimental data obtained at variable radii on living cells using the pleckstrin homology (PH) domain of the membrane binding protein EFA6 (exchange factor for ARF6, a small G protein). This protein domain is an excellent candidate to explore the structure of the interface between cytosol and plasma membrane in cells. By direct comparison of our numerical simulations to the experiments, we show that this protein does not exhibit anomalous diffusion in baby hamster kidney (BHK) cells. The non Brownian PH-EFA6 dynamics observed here are more related to spatial heterogeneities such as cytoskeleton fence effects. Full article
(This article belongs to the Special Issue Cellular Membrane Domains and Organization)
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Open AccessArticle An Empirical Analysis of the Perceived Challenges and Benefits of Introducing Biosimilars in Bangladesh: A Paradigm Shift
Biomolecules 2018, 8(3), 89; https://doi.org/10.3390/biom8030089
Received: 13 July 2018 / Revised: 28 August 2018 / Accepted: 30 August 2018 / Published: 5 September 2018
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Abstract
The high demand for and resulting financial success of biopharmaceutical products over the last three decades have seen the door open for close copies of these biological products, also known as biosimilars. This paper seeks to collate all relevant published intelligence with acquired
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The high demand for and resulting financial success of biopharmaceutical products over the last three decades have seen the door open for close copies of these biological products, also known as biosimilars. This paper seeks to collate all relevant published intelligence with acquired survey data to assess the weight of available evidence that these products hold immense potential for the pharmaceutical industry in terms of their applications and benefits. Biosimilars also pose to be of great promise to the Bangladesh pharmaceutical industry, with the commitment of drastically reducing its dependence on foreign imports of biopharmaceutics to meet local demand. Our questionnaire based survey involved 100 Clinicians, 50 Industry Experts and 100 Academicians. The study found that majority of Industry Experts (72%) and Academicians (63%) shared a different concept of biosimilars opposed to majority of Clinicians (78%). Majority of Academicians (68%) and Industry Experts (61%) also shared a different belief from that of most Clinicians (61%) regarding the need for updating the existing regulatory guidelines. The study also showed that Clinicians (67%), Industry Experts (83%) and Academicians (80%) highlighted the benefit of lower costs of biosimilars. Furthermore, the quality data obtained from the survey results allowed us to evaluate and provide recommendations for stakeholders on the need for increased biosimilar awareness, pharmacovigilance and safety in Bangladesh. Full article
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Open AccessReview Ectopic Neo-Formed Intracellular Membranes in Escherichia coli: A Response to Membrane Protein-Induced Stress Involving Membrane Curvature and Domains
Biomolecules 2018, 8(3), 88; https://doi.org/10.3390/biom8030088
Received: 30 July 2018 / Revised: 31 August 2018 / Accepted: 31 August 2018 / Published: 4 September 2018
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Abstract
Bacterial cytoplasmic membrane stress induced by the overexpression of membrane proteins at high levels can lead to formation of ectopic intracellular membranes. In this review, we report the various observations of such membranes in Escherichia coli, compare their morphological and biochemical characterizations,
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Bacterial cytoplasmic membrane stress induced by the overexpression of membrane proteins at high levels can lead to formation of ectopic intracellular membranes. In this review, we report the various observations of such membranes in Escherichia coli, compare their morphological and biochemical characterizations, and we analyze the underlying molecular processes leading to their formation. Actually, these membranes display either vesicular or tubular structures, are separated or connected to the cytoplasmic membrane, present mono- or polydispersed sizes and shapes, and possess ordered or disordered arrangements. Moreover, their composition differs from that of the cytoplasmic membrane, with high amounts of the overexpressed membrane protein and altered lipid-to-protein ratio and cardiolipin content. These data reveal the importance of membrane domains, based on local specific lipid–protein and protein–protein interactions, with both being crucial for local membrane curvature generation, and they highlight the strong influence of protein structure. Indeed, whether the cylindrically or spherically curvature-active proteins are actively curvogenic or passively curvophilic, the underlying molecular scenarios are different and can be correlated with the morphological features of the neo-formed internal membranes. Delineating these molecular mechanisms is highly desirable for a better understanding of protein–lipid interactions within membrane domains, and for optimization of high-level membrane protein production in E. coli. Full article
(This article belongs to the Special Issue Cellular Membrane Domains and Organization)
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Open AccessArticle Assessment of the Quorum Sensing Inhibition Activity of a Non-Toxic Chitosan in an N-Acyl Homoserine Lactone (AHL)-Based Escherichia coli Biosensor
Biomolecules 2018, 8(3), 87; https://doi.org/10.3390/biom8030087
Received: 20 July 2018 / Revised: 21 August 2018 / Accepted: 27 August 2018 / Published: 4 September 2018
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Abstract
New approaches to deal with drug-resistant pathogenic bacteria are urgent. We studied the antibacterial effect of chitosans against an Escherichia coli quorum sensing biosensor reporter strain and selected a non-toxic chitosan to evaluate its quorum sensing (QS) inhibition activity and its effect on
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New approaches to deal with drug-resistant pathogenic bacteria are urgent. We studied the antibacterial effect of chitosans against an Escherichia coli quorum sensing biosensor reporter strain and selected a non-toxic chitosan to evaluate its quorum sensing (QS) inhibition activity and its effect on bacterial aggregation. To this end, chitosans of varying degree of acetylation (DA) (12 to 69%) and molecular weight (Mw) (29 to 288 kDa) were studied. Only chitosans of low DA (~12%) inhibited bacterial growth, regardless of their Mw. A chitosan with medium degree of polymerization (named MDP) DA30, with experimental DA 42% and Mw 115 kDa was selected for further QS inhibition and scanning electron microscopy (SEM) imaging studies. MDP DA30 chitosan exhibited QS inhibition activity in an inverse dose-dependent manner (≤12.5 µg/mL). SEM images revealed that this chitosan, when added at low concentration (≤30.6 µg/mL), induced substantial bacterial aggregation, whereas at high concentration (234.3 µg/mL), it did not. Aggregation explains the QS inhibition activity as the consequence of retardation of the diffusion of N-acylated homoserine lactones (AHLs). Full article
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Open AccessArticle Cross-Sectional Associations between Homoarginine, Intermediate Phenotypes, and Atrial Fibrillation in the Community—The Gutenberg Health Study
Biomolecules 2018, 8(3), 86; https://doi.org/10.3390/biom8030086
Received: 11 July 2018 / Revised: 26 August 2018 / Accepted: 27 August 2018 / Published: 30 August 2018
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Abstract
Homoarginine has come into the focus of interest as a biomarker for cardiovascular disease. Atrial fibrillation (AF) causes a substantial increase in morbidity and mortality. Whether circulating homoarginine is associated with occurrence or persistence of AF and may serve as a new predictive
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Homoarginine has come into the focus of interest as a biomarker for cardiovascular disease. Atrial fibrillation (AF) causes a substantial increase in morbidity and mortality. Whether circulating homoarginine is associated with occurrence or persistence of AF and may serve as a new predictive biomarker remains unknown. We measured plasma levels of homoarginine in the population-based Gutenberg health study (3761 patients included, of them 51.7% males), mean age 55.6 ± 10.9 years-old. Associations between homoarginine and intermediate electrocardiographic and echocardiographic phenotypes and manifest AF were examined. Patients with AF (124 patients, of them 73.4% males) had a mean age 64.8 ± 8.6 years-old compared to a mean age of 55.3 ± 10.9 in the population without AF (p-value < 0.001) and showed a less beneficial risk factor profile. The median homoarginine levels in individuals with and without AF were 1.9 μmol/L (interquartile range (IQR) 1.5–2.5) and 2.0 μmol/L (IQR 1.5–2.5), respectively, p = 0.56. In multivariable-adjusted regression analyses homoarginine was not statistically significantly related to electrocardiographic variables. Among echocardiographic variables beta per standard deviation increase was −0.12 (95% confidence interval (CI) −0.23–(−0.02); p = 0.024) for left atrial area and −0.01 (95% CI −0.02–(−0.003); p = 0.013) for E/A ratio. The odds ratio between homoarginine and AF was 0.91 (95% CI 0.70–1.16; p = 0.45). In our large, population-based cross-sectional study, we did not find statistically significant correlations between lower homoarginine levels and occurrence or persistence of AF or most standard electrocardiographic phenotypes, but some moderate inverse associations with echocardiographic left atrial size and E/A. Homoarginine may not represent a strong biomarker to identify individuals at increased risk for AF. Further investigations will be needed to elucidate the role of homoarginine and cardiac function. Full article
(This article belongs to the Special Issue Biomolecules for Translational Approaches in Cardiology)
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Open AccessFeature PaperArticle Predicting Aromatic Amine Mutagenicity with Confidence: A Case Study Using Conformal Prediction
Biomolecules 2018, 8(3), 85; https://doi.org/10.3390/biom8030085
Received: 26 June 2018 / Revised: 16 August 2018 / Accepted: 21 August 2018 / Published: 29 August 2018
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Abstract
The occurrence of mutagenicity in primary aromatic amines has been investigated using conformal prediction. The results of the investigation show that it is possible to develop mathematically proven valid models using conformal prediction and that the existence of uncertain classes of prediction, such
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The occurrence of mutagenicity in primary aromatic amines has been investigated using conformal prediction. The results of the investigation show that it is possible to develop mathematically proven valid models using conformal prediction and that the existence of uncertain classes of prediction, such as both (both classes assigned to a compound) and empty (no class assigned to a compound), provides the user with additional information on how to use, further develop, and possibly improve future models. The study also indicates that the use of different sets of fingerprints results in models, for which the ability to discriminate varies with respect to the set level of acceptable errors. Full article
(This article belongs to the Special Issue Machine Learning for Molecular Modelling in Drug Design)
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Open AccessArticle YKL-40, Soluble IL-2 Receptor, Angiotensin Converting Enzyme and C-Reactive Protein: Comparison of Markers of Sarcoidosis Activity
Biomolecules 2018, 8(3), 84; https://doi.org/10.3390/biom8030084
Received: 30 June 2018 / Revised: 17 August 2018 / Accepted: 23 August 2018 / Published: 28 August 2018
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Abstract
The aims of this study were to describe the clinical, radiological and immunological features of a population of sarcoidosis patients and to analyse chitinase-3-like protein 1 (YKL-40), soluble interleukin-2 receptor (sIL-2R), neopterin concentrations and adenosine deaminase (ADA) activity in serum of these patients
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The aims of this study were to describe the clinical, radiological and immunological features of a population of sarcoidosis patients and to analyse chitinase-3-like protein 1 (YKL-40), soluble interleukin-2 receptor (sIL-2R), neopterin concentrations and adenosine deaminase (ADA) activity in serum of these patients in order to understand their potential as disease markers. Fifty-nine patients affected by chronic sarcoidosis, in active (20 patients) and inactive (39 patients) phase according to the clinical, radiological and laboratory criteria were studied. Serum YKL-40, sIL-2R, high-sensitive C-reactive protein (hs-CRP), neopterin levels and ADA activities were evaluated and compared with those of 25 healthy controls. Individuals with chronic sarcoidosis were significantly higher serum YKL-40, sIL-2R, neopterin, hs-CRP concentrations, angiotensin converting enzyme (ACE) and ADA activity than those of control subjects. Sarcoidosis patients in the active phase of the disease were significantly higher YKL-40, sIL-2R, hs-CRP levels and ACE activity than those in the inactive phase, while ADA activities and neopterin levels did not display any significant difference between the active and inactive disease groups. In comparison to the other parameters, as panel measurement of the serum YKL-40, sIL-2R, ACE and hs-CRP indicate a greater discrimination between active and inactive disease. The results indicate that serum YKL-40, sIL-2R, ACE and hs-CRP concentrations may be useful marker for monitoring sarcoidosis disease activity. Full article
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Open AccessReview Molecular Modeling Applied to Nucleic Acid-Based Molecule Development
Biomolecules 2018, 8(3), 83; https://doi.org/10.3390/biom8030083
Received: 31 July 2018 / Revised: 12 August 2018 / Accepted: 16 August 2018 / Published: 27 August 2018
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Abstract
Molecular modeling by means of docking and molecular dynamics (MD) has become an integral part of early drug discovery projects, enabling the screening and enrichment of large libraries of small molecules. In the past decades, special emphasis was drawn to nucleic acid (NA)-based
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Molecular modeling by means of docking and molecular dynamics (MD) has become an integral part of early drug discovery projects, enabling the screening and enrichment of large libraries of small molecules. In the past decades, special emphasis was drawn to nucleic acid (NA)-based molecules in the fields of therapy, diagnosis, and drug delivery. Research has increased dramatically with the advent of the SELEX (systematic evolution of ligands by exponential enrichment) technique, which results in single-stranded DNA or RNA sequences that bind with high affinity and specificity to their targets. Herein, we discuss the role and contribution of docking and MD to the development and optimization of new nucleic acid-based molecules. This review focuses on the different approaches currently available for molecular modeling applied to NA interaction with proteins. We discuss topics ranging from structure prediction to docking and MD, highlighting their main advantages and limitations and the influence of flexibility on their calculations. Full article
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Open AccessArticle Recombinant Fusion Protein Joining E Protein Domain III of Tick-Borne Encephalitis Virus and HSP70 of Yersinia pseudotuberculosis as an Antigen for the TI-Complexes
Biomolecules 2018, 8(3), 82; https://doi.org/10.3390/biom8030082
Received: 4 July 2018 / Revised: 15 August 2018 / Accepted: 20 August 2018 / Published: 25 August 2018
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Abstract
Domain III (DIII) of the tick-borne encephalitis virus (TBEV) protein E contains epitopes, which induce antibodies capable of neutralizing the virus. To enhance the immunogenicity of this protein, which has a low molecular weight, the aim of the present work was to express,
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Domain III (DIII) of the tick-borne encephalitis virus (TBEV) protein E contains epitopes, which induce antibodies capable of neutralizing the virus. To enhance the immunogenicity of this protein, which has a low molecular weight, the aim of the present work was to express, isolate, and characterize a chimeric protein based on the fusion of the bacterial chaperone HSP70 of Yersinia pseudotuberculosis and EIII (DIII + stem) as a prospective antigen for an adjuvanted delivery system, the tubular immunostimulating complex (TI-complex). The chimeric construction was obtained using pET-40b(+) vector by ligating the respective genes. The resulting plasmid was transformed into DE3 cells for the heterologous expression of the chimeric protein, which was purified by immobilized metal affinity chromatography (IMAC). ELISA, differential scanning calorimetry, intrinsic fluorescence, and computational analysis were applied for the characterization of the immunogenicity and conformation of the chimeric protein. Mice immunization showed that the chimeric protein induced twice the number of anti-EIII antibodies in comparison with EIII alone. In turn, the incorporation of the HSP70/EIII chimeric protein in the TI-complex resulted in a twofold increase in its immunogenicity. The formation of this vaccine construction was accompanied by significant conformational changes in the chimeric protein. Using HSP70 in the content of the chimeric protein represents an efficient means for presenting the main antigenic domain of the TBEV envelope protein to the immune system, whereas the incorporation of this chimeric protein into the TI-complex further contributes to the development of a stronger immune response against the TBEV infection. Full article
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Open AccessArticle Crystal Structure of the Human tRNA Guanine Transglycosylase Catalytic Subunit QTRT1
Biomolecules 2018, 8(3), 81; https://doi.org/10.3390/biom8030081
Received: 24 July 2018 / Revised: 20 August 2018 / Accepted: 20 August 2018 / Published: 24 August 2018
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Abstract
RNA modifications have been implicated in diverse and important roles in all kingdoms of life with over 100 of them present on tRNAs. A prominent modification at the wobble base of four tRNAs is the 7-deaza-guanine derivative queuine which substitutes the guanine at
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RNA modifications have been implicated in diverse and important roles in all kingdoms of life with over 100 of them present on tRNAs. A prominent modification at the wobble base of four tRNAs is the 7-deaza-guanine derivative queuine which substitutes the guanine at position 34. This exchange is catalyzed by members of the enzyme class of tRNA guanine transglycosylases (TGTs). These enzymes incorporate guanine substituents into tRNAAsp, tRNAAsn tRNAHis, and tRNATyr in all kingdoms of life. In contrast to the homodimeric bacterial TGT, the active eukaryotic TGT is a heterodimer in solution, comprised of a catalytic QTRT1 subunit and a noncatalytic QTRT2 subunit. Bacterial TGT enzymes, that incorporate a queuine precursor, have been identified or proposed as virulence factors for infections by pathogens in humans and therefore are valuable targets for drug design. To date no structure of a eukaryotic catalytic subunit is reported, and differences to its bacterial counterpart have to be deducted from sequence analysis and models. Here we report the first crystal structure of a eukaryotic QTRT1 subunit and compare it to known structures of the bacterial TGT and murine QTRT2. Furthermore, we were able to determine the crystal structure of QTRT1 in complex with the queuine substrate. Full article
(This article belongs to the collection RNA Modifications)
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Open AccessReview Research Progress on the Relationship between Atherosclerosis and Inflammation
Biomolecules 2018, 8(3), 80; https://doi.org/10.3390/biom8030080
Received: 14 June 2018 / Revised: 3 August 2018 / Accepted: 17 August 2018 / Published: 23 August 2018
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Atherosclerosis is a chronic inflammatory disease; unstable atherosclerotic plaque rupture, vascular stenosis, or occlusion caused by platelet aggregation and thrombosis lead to acute cardiovascular disease. Atherosclerosis-related inflammation is mediated by proinflammatory cytokines, inflammatory signaling pathways, bioactive lipids, and adhesion molecules. This review discusses
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Atherosclerosis is a chronic inflammatory disease; unstable atherosclerotic plaque rupture, vascular stenosis, or occlusion caused by platelet aggregation and thrombosis lead to acute cardiovascular disease. Atherosclerosis-related inflammation is mediated by proinflammatory cytokines, inflammatory signaling pathways, bioactive lipids, and adhesion molecules. This review discusses the effects of inflammation and the systemic inflammatory signaling pathway on atherosclerosis, the role of related signaling pathways in inflammation, the formation of atherosclerosis plaques, and the prospects of treating atherosclerosis by inhibiting inflammation. Full article
Open AccessReview Role of the HPRG Component of Striated Muscle AMP Deaminase in the Stability and Cellular Behaviour of the Enzyme
Biomolecules 2018, 8(3), 79; https://doi.org/10.3390/biom8030079
Received: 19 July 2018 / Revised: 13 August 2018 / Accepted: 20 August 2018 / Published: 23 August 2018
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Abstract
Multiple muscle-specific isoforms of the Zn2+ metalloenzyme AMP deaminase (AMPD) have been identified based on their biochemical and genetic differences. Our previous observations suggested that the metal binding protein histidine-proline-rich glycoprotein (HPRG) participates in the assembly and maintenance of skeletal muscle AMP
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Multiple muscle-specific isoforms of the Zn2+ metalloenzyme AMP deaminase (AMPD) have been identified based on their biochemical and genetic differences. Our previous observations suggested that the metal binding protein histidine-proline-rich glycoprotein (HPRG) participates in the assembly and maintenance of skeletal muscle AMP deaminase (AMPD1) by acting as a zinc chaperone. The evidence of a role of millimolar-strength phosphate in stabilizing the AMPD-HPRG complex of both AMPD1 and cardiac AMP deaminase (AMPD3) is suggestive of a physiological mutual dependence between the two subunit components with regard to the stability of the two isoforms of striated muscle AMPD. The observed influence of the HPRG content on the catalytic behavior of the two enzymes further strengthens this hypothesis. Based on the preferential localization of HPRG at the sarcomeric I-band and on the presence of a Zn2+ binding motif in the N-terminal regions of fast TnT and of the AMPD1 catalytic subunit, we advance the hypothesis that the Zn binding properties of HPRG could promote the association of AMPD1 to the thin filament. Full article
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Open AccessArticle Multi-Spectroscopic and Theoretical Analysis on the Interaction between Human Serum Albumin and a Capsaicin Derivative—RPF101
Biomolecules 2018, 8(3), 78; https://doi.org/10.3390/biom8030078
Received: 14 July 2018 / Revised: 13 August 2018 / Accepted: 16 August 2018 / Published: 23 August 2018
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Abstract
The interaction between the main carrier of endogenous and exogenous compounds in the human bloodstream (human serum albumin, HSA) and a potential anticancer compound (the capsaicin analogue RPF101) was investigated by spectroscopic techniques (circular dichroism, steady-state, time-resolved, and synchronous fluorescence), zeta potential,
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The interaction between the main carrier of endogenous and exogenous compounds in the human bloodstream (human serum albumin, HSA) and a potential anticancer compound (the capsaicin analogue RPF101) was investigated by spectroscopic techniques (circular dichroism, steady-state, time-resolved, and synchronous fluorescence), zeta potential, and computational method (molecular docking). Steady-state and time-resolved fluorescence experiments indicated an association in the ground state between HSA:RPF101. The interaction is moderate, spontaneous (ΔG° < 0), and entropically driven (ΔS° = 0.573 ± 0.069 kJ/molK). This association does not perturb significantly the potential surface of the protein, as well as the secondary structure of the albumin and the microenvironment around tyrosine and tryptophan residues. Competitive binding studies indicated Sudlow’s site I as the main protein pocket and molecular docking results suggested hydrogen bonding and hydrophobic interactions as the main binding forces. Full article
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Open AccessReview Membrane Active Peptides and Their Biophysical Characterization
Biomolecules 2018, 8(3), 77; https://doi.org/10.3390/biom8030077
Received: 29 June 2018 / Revised: 8 August 2018 / Accepted: 13 August 2018 / Published: 22 August 2018
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Abstract
In the last 20 years, an increasing number of studies have been reported on membrane active peptides. These peptides exert their biological activity by interacting with the cell membrane, either to disrupt it and lead to cell lysis or to translocate through it
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In the last 20 years, an increasing number of studies have been reported on membrane active peptides. These peptides exert their biological activity by interacting with the cell membrane, either to disrupt it and lead to cell lysis or to translocate through it to deliver cargos into the cell and reach their target. Membrane active peptides are attractive alternatives to currently used pharmaceuticals and the number of antimicrobial peptides (AMPs) and peptides designed for drug and gene delivery in the drug pipeline is increasing. Here, we focus on two most prominent classes of membrane active peptides; AMPs and cell-penetrating peptides (CPPs). Antimicrobial peptides are a group of membrane active peptides that disrupt the membrane integrity or inhibit the cellular functions of bacteria, virus, and fungi. Cell penetrating peptides are another group of membrane active peptides that mainly function as cargo-carriers even though they may also show antimicrobial activity. Biophysical techniques shed light on peptide–membrane interactions at higher resolution due to the advances in optics, image processing, and computational resources. Structural investigation of membrane active peptides in the presence of the membrane provides important clues on the effect of the membrane environment on peptide conformations. Live imaging techniques allow examination of peptide action at a single cell or single molecule level. In addition to these experimental biophysical techniques, molecular dynamics simulations provide clues on the peptide–lipid interactions and dynamics of the cell entry process at atomic detail. In this review, we summarize the recent advances in experimental and computational investigation of membrane active peptides with particular emphasis on two amphipathic membrane active peptides, the AMP melittin and the CPP pVEC. Full article
(This article belongs to the Special Issue Cell Penetrating Peptides)
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Open AccessArticle Testosterone Levels and Type 2 Diabetes—No Correlation with Age, Differential Predictive Value in Men and Women
Biomolecules 2018, 8(3), 76; https://doi.org/10.3390/biom8030076
Received: 8 June 2018 / Revised: 3 August 2018 / Accepted: 13 August 2018 / Published: 20 August 2018
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Abstract
Most studies reporting on the association of circulating testosterone levels with type 2 diabetes in men are of cross-sectional design. Reports on the relevance of altered testosterone levels in women are scarce. Here, we evaluate the role of low serum testosterone levels for
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Most studies reporting on the association of circulating testosterone levels with type 2 diabetes in men are of cross-sectional design. Reports on the relevance of altered testosterone levels in women are scarce. Here, we evaluate the role of low serum testosterone levels for incident diabetes in men and women in a population setting of 7706 subjects (3896 females). During a mean follow up time of 13.8 years, 7.8% developed type 2 diabetes. Significant correlations of testosterone with high density lipoprotein (HDL)-cholesterol (R = 0.21, p < 0.001), body-mass-index (R = −0.23, p < 0.001), and waist-to-hip-ratio (R = −0.21, p < 0.001) were found in men. No correlation was found with age in men; in women, the correlation was negligible (R = 0.04, p = 0.012). In men, low testosterone levels predicted high risk of type 2 diabetes, while in women this relationship was opposite. Men with low testosterone levels showed increased risk of future diabetes (hazard ratio (HR) 2.66, 95% confidence interval (CI) 1.91–3.72, p < 0.001 in basic model; HR 1.56 95%, CI 1.10–2.21, p = 0.003). In women, low testosterone levels indicated lower risk with (HR 0.53, 95% CI 0.37–0.77, p = 0.003), while the association lost significance in the fully adjusted model (HR 0.72, 95% CI 0.49–1.05, p = 0.09). Low levels of testosterone predicted future diabetes in men. A borderline opposite association was found in women. Full article
(This article belongs to the Special Issue Biomolecules for Translational Approaches in Cardiology)
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Open AccessEssay Bach Goes to Town
Biomolecules 2018, 8(3), 75; https://doi.org/10.3390/biom8030075
Received: 13 August 2018 / Accepted: 17 August 2018 / Published: 20 August 2018
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Abstract
Donald A. Tomalia is one of the pioneers in the field of dendrimers, who is still active at the age of 80 years-old. The present contribution is a journey through his scientific contributions from the early beginning until his discovery of the poly(amidoamine),
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Donald A. Tomalia is one of the pioneers in the field of dendrimers, who is still active at the age of 80 years-old. The present contribution is a journey through his scientific contributions from the early beginning until his discovery of the poly(amidoamine), (PAMAM)-dendrimers. Full article
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Open AccessArticle Novel DNA Methylation Sites Influence GPR15 Expression in Relation to Smoking
Biomolecules 2018, 8(3), 74; https://doi.org/10.3390/biom8030074
Received: 16 July 2018 / Revised: 6 August 2018 / Accepted: 9 August 2018 / Published: 20 August 2018
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Abstract
Smoking is a major risk factor for cardiovascular diseases and has been implicated in the regulation of the G protein-coupled receptor 15 (GPR15) by affecting CpG methylation. The G protein-coupled receptor 15 is involved in angiogenesis and inflammation. An effect on GPR15 gene
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Smoking is a major risk factor for cardiovascular diseases and has been implicated in the regulation of the G protein-coupled receptor 15 (GPR15) by affecting CpG methylation. The G protein-coupled receptor 15 is involved in angiogenesis and inflammation. An effect on GPR15 gene regulation has been shown for the CpG site CpG3.98251294. We aimed to analyze the effect of smoking on GPR15 expression and methylation sites spanning the GPR15 locus. DNA methylation of nine GPR15 CpG sites was measured in leukocytes from 1291 population-based individuals using the EpiTYPER. Monocytic GPR15 expression was measured by qPCR at baseline and five-years follow up. GPR15 gene expression was upregulated in smokers (beta (ß) = −2.699, p-value (p) = 1.02 × 10−77) and strongly correlated with smoking exposure (ß = −0.063, p = 2.95 × 10−34). Smoking cessation within five years reduced GPR15 expression about 19% (p = 9.65 × 10−5) with decreasing GPR15 expression over time (ß = 0.031, p = 3.81 × 10−6). Additionally, three novel CpG sites within GPR15 affected by smoking were identified. For CpG3.98251047, DNA methylation increased steadily after smoking cessation (ß = 0.123, p = 1.67 × 10−3) and strongly correlated with changes in GPR15 expression (ß = 0.036, p = 4.86 × 10−5). Three novel GPR15 CpG sites were identified in relation to smoking and GPR15 expression. Our results provide novel insights in the regulation of GPR15, which possibly linked smoking to inflammation and disease progression. Full article
(This article belongs to the Special Issue Biomolecules for Translational Approaches in Cardiology)
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Open AccessArticle Membrane Permeabilities of Ascorbic Acid and Ascorbate
Biomolecules 2018, 8(3), 73; https://doi.org/10.3390/biom8030073
Received: 31 July 2018 / Revised: 10 August 2018 / Accepted: 13 August 2018 / Published: 17 August 2018
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Abstract
Vitamin C (VC)—a collective term for the different oxidation and protonation forms of ascorbic acid (AscH)—is an essential micronutrient that serves as (i) a potent antioxidant and (ii) a cofactor of a manifold of enzymatic processes. Its role in health is related to
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Vitamin C (VC)—a collective term for the different oxidation and protonation forms of ascorbic acid (AscH)—is an essential micronutrient that serves as (i) a potent antioxidant and (ii) a cofactor of a manifold of enzymatic processes. Its role in health is related to redox balance maintenance, which is altered in diseases such as obesity, cancer, neurodegenerative diseases, hypertension, and autoimmune diseases. Despite its importance, VC uptake has been poorly investigated. Available literature values for the passive membrane permeability P of lipid bilayers for AscH scatter by about 10 orders of magnitude. Here, we show by voltage clamp that P of AscH’s anionic form (ascorbate Asc ) is negligible. To cross the membrane, Asc picks up a proton in the membrane vicinity and releases it on the other side of the membrane. This leads to a near-membrane pH drop that was visualized by scanning pH microelectrodes. The AscH concentration dependent pH profiles indicated P   =   1.1   ±   0.1   ×   10 8   cm / s . Thus, AscH’s P is comparable to that of sorbitol and much lower than that of other weak acids like acetic acid or salicylic acid. The observation suggests that the capacity of the passive transcellular transport pathway across the lipid matrix does not suffice to ensure the required VC intake from the gastrointestinal tract. Full article
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Open AccessArticle Intrinsic Iron Release Is Associated with Lower Mortality in Patients with Stable Coronary Artery Disease—First Report on the Prospective Relevance of Intrinsic Iron Release
Biomolecules 2018, 8(3), 72; https://doi.org/10.3390/biom8030072
Received: 9 July 2018 / Revised: 3 August 2018 / Accepted: 3 August 2018 / Published: 9 August 2018
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Intrinsic iron release is discussed to have favorable effects in coronary artery disease (CAD). The aim of this study was to evaluate the prognostic relevance of intrinsic iron release in patients with CAD. Intrinsic iron release was based on a definition including hepcidin
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Intrinsic iron release is discussed to have favorable effects in coronary artery disease (CAD). The aim of this study was to evaluate the prognostic relevance of intrinsic iron release in patients with CAD. Intrinsic iron release was based on a definition including hepcidin and soluble transferrin receptor (sTfR). In a cohort of 811 patients with angiographically documented CAD levels of hepcidin and sTfR were measured at baseline. Systemic body iron release was defined as low levels of hepcidin (<24 ng/mL) and high levels of sTfR (≥2 mg/L). A commercially available ELISA (DRG) was used for measurements of serum hepcidin. Serum sTfR was determined by using an automated immunoassay (). Cardiovascular mortality was the main outcome measure. The criteria of intrinsic iron release were fulfilled in 32.6% of all patients. Significantly lower cardiovascular mortality rates were observed in CAD patients with systemic iron release. After adjustment for body mass index, smoking status, hypertension, diabetes, dyslipidemia, sex, and age, the hazard ratio for future cardiovascular death was 0.41. After an additional adjustment for surrogates of the size of myocardial necrosis (troponin I), anemia (hemoglobin), and cardiac function and heart failure severity (N-terminal pro B-type natriuretic peptide), this association did not change (Hazard ratio 0.37 (95% confidence interval 0.14–0.99), p = 0.047). In conclusion, significantly lower cardiovascular mortality rates were observed in CAD patients with intrinsic iron release shown during follow-up. Full article
(This article belongs to the Special Issue Biomolecules for Translational Approaches in Cardiology)
Open AccessArticle On Eccentricity-Based Topological Indices Study of a Class of Porphyrin-Cored Dendrimers
Biomolecules 2018, 8(3), 71; https://doi.org/10.3390/biom8030071
Received: 11 June 2018 / Revised: 29 July 2018 / Accepted: 1 August 2018 / Published: 7 August 2018
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Abstract
It is revealed from the previous studies that there is a strong relation between the chemical characteristic of a chemical compound and its molecular structure. Topological indices defined on the molecular structure of biomolecules can help to gain a better understanding of their
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It is revealed from the previous studies that there is a strong relation between the chemical characteristic of a chemical compound and its molecular structure. Topological indices defined on the molecular structure of biomolecules can help to gain a better understanding of their physical features and biological activities. Eccentricity connectivity indices are distance-based molecular structure descriptors that have been used for the mathematical modeling of biological activities of diverse nature. As the porphyrin has photofunctional properties, such as a large absorption cross-section, fluorescence emission, and photosensitizing properties, due to these properties, porphyrin dendrimers can be used as photofunctional nanodevices. In this paper, we compute the exact formulae of different versions of eccentric connectivity index and their corresponding polynomials for a class of porphyrin-cored dendrimers. The results obtained can be used in computer-aided molecular design methods applied to pharmaceutical engineering. Full article
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Open AccessArticle Functional Annotation of Caenorhabditis elegans Genes by Analysis of Gene Co-Expression Networks
Biomolecules 2018, 8(3), 70; https://doi.org/10.3390/biom8030070
Received: 3 July 2018 / Revised: 30 July 2018 / Accepted: 1 August 2018 / Published: 3 August 2018
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Abstract
Caenorhabditis elegans (C. elegans) is a well-characterized metazoan, whose transcriptome has been profiled in different tissues, development stages, or other conditions. Large-scale transcriptomes can be reused for gene function annotation through systematic analysis of gene co-expression relationships. We collected 2101 microarray
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Caenorhabditis elegans (C. elegans) is a well-characterized metazoan, whose transcriptome has been profiled in different tissues, development stages, or other conditions. Large-scale transcriptomes can be reused for gene function annotation through systematic analysis of gene co-expression relationships. We collected 2101 microarray data from National Center for Biotechnology Information Gene Expression Omnibus (NCBI GEO), and identified 48 modules of co-expressed genes that correspond to tissues, development stages, and other experimental conditions. These modules provide an overview of the transcriptional organizations that may work under different conditions. By analyzing higher-order module networks, we found that nucleus and plasma membrane modules are more connected than other intracellular modules. Module-based gene function annotation may help to extend the candidate cuticle gene list. A comparison with other published data validates the credibility of our result. Our findings provide a new source for future gene discovery in C. elegans. Full article
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Open AccessReview The Role of Calcium in Inflammation-Associated Bone Resorption
Biomolecules 2018, 8(3), 69; https://doi.org/10.3390/biom8030069
Received: 28 June 2018 / Revised: 25 July 2018 / Accepted: 27 July 2018 / Published: 1 August 2018
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Abstract
The aim of this mini-review is to discuss the role of calcium in the process of cytokine-mediated bone resorption in an effort to understand the role circulating calcium may play in the resorption of bone. The liberation of calcium and possibly phosphorus and
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The aim of this mini-review is to discuss the role of calcium in the process of cytokine-mediated bone resorption in an effort to understand the role circulating calcium may play in the resorption of bone. The liberation of calcium and possibly phosphorus and magnesium by bone resorption may sustain and intensify the inflammatory response. We used a burn injury setting in humans and a burn injury model in animals in order to examine the effects on the bone of the systemic inflammatory response and identified the parathyroid calcium-sensing receptor as the mediator of increasing bone resorption, hence higher interleukin (IL)-1 production, and decreasing bone resorption, hence the lowering of circulating ionized calcium concentration. Thus, extracellular calcium, by means of the parathyroid calcium-sensing receptor, is able to modulate inflammation-mediated resorption. Full article
(This article belongs to the Special Issue Key Biomolecules in Bone Resorption)
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Open AccessArticle Cytotoxicity of Different Concentrations of Three Root Canal Sealers on Human Mesenchymal Stem Cells
Biomolecules 2018, 8(3), 68; https://doi.org/10.3390/biom8030068
Received: 12 July 2018 / Revised: 27 July 2018 / Accepted: 30 July 2018 / Published: 1 August 2018
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This study assessed the dose-dependent effect on the cytotoxicity of BioRoot RCS (BR) and Endosequence BC (BC) sealers in human bone marrow mesenchymal stem cells (hMSCs) compared to those of the AH Plus sealer. Cells were exposed to different dilutions of extracts from
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This study assessed the dose-dependent effect on the cytotoxicity of BioRoot RCS (BR) and Endosequence BC (BC) sealers in human bone marrow mesenchymal stem cells (hMSCs) compared to those of the AH Plus sealer. Cells were exposed to different dilutions of extracts from freshly prepared sealers (1:2, 1:8, 1:32). Unexposed cells acted as the negative control. Cytotoxicity was evaluated by an alamar blue assay. Cell morphology was analyzed by using scanning electron microscopy after exposure to the different sealers’ extracts. Statistical analysis was performed using a one-way analysis of variance and the Bonferroni post hoc test (p < 0.05). The cytotoxicities of BC and BR were less than that of AH Plus. In the presence of 1:2 BR, the cell proliferation was significantly lower than the control. At 1:8 and 1:32 concentrations, both the tricalcium silicate sealers led to similar cellular proliferation. Cells in BC and BR sealers’ extracts spread better than those in AH Plus extract. Full article
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