Biomolecules

43 pages, 4913 KiB

Open AccessArticle

MiRNA Profiles of Extracellular Vesicles Secreted by Mesenchymal Stromal Cells—Can They Predict Potential Off-Target Effects?

by Timo Z. Nazari-Shafti, Sebastian Neuber, Ana G. Duran, Vasileios Exarchos, Christien M. Beez, Heike Meyborg, Katrin Krüger, Petra Wolint, Johanna Buschmann, Roland Böni, Martina Seifert, Volkmar Falk and Maximilian Y. Emmert

Biomolecules 2020, 10(9), 1353; https://doi.org/10.3390/biom10091353 - 22 Sep 2020

Cited by 14 | Viewed by 3450

Abstract

The cardioprotective properties of extracellular vesicles (EVs) derived from mesenchymal stromal cells (MSCs) are currently being investigated in preclinical studies. Although microRNAs (miRNAs) encapsulated in EVs have been identified as one component responsible for the cardioprotective effect of MSCs, their potential off-target effects [...] Read more.

The cardioprotective properties of extracellular vesicles (EVs) derived from mesenchymal stromal cells (MSCs) are currently being investigated in preclinical studies. Although microRNAs (miRNAs) encapsulated in EVs have been identified as one component responsible for the cardioprotective effect of MSCs, their potential off-target effects have not been sufficiently characterized. In the present study, we aimed to investigate the miRNA profile of EVs isolated from MSCs that were derived from cord blood (CB) and adipose tissue (AT). The identified miRNAs were then compared to known targets from the literature to discover possible adverse effects prior to clinical use. Our data show that while many cardioprotective miRNAs such as miR-22-3p, miR-26a-5p, miR-29c-3p, and miR-125b-5p were present in CB- and AT-MSC-derived EVs, a large number of known oncogenic and tumor suppressor miRNAs such as miR-16-5p, miR-23a-3p, and miR-191-5p were also detected. These findings highlight the importance of quality assessment for therapeutically applied EV preparations. Full article

(This article belongs to the Special Issue Cell-Free Approaches and Therapeutic Biomolecules for Cardiac Regeneration)

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24 pages, 2946 KiB

Open AccessReview

A Great Catch for Investigating Inborn Errors of Metabolism—Insights Obtained from Zebrafish

by Maximilian Breuer and Shunmoogum A. Patten

Biomolecules 2020, 10(9), 1352; https://doi.org/10.3390/biom10091352 - 22 Sep 2020

Cited by 9 | Viewed by 6756

Abstract

Inborn errors of metabolism cause abnormal synthesis, recycling, or breakdown of amino acids, neurotransmitters, and other various metabolites. This aberrant homeostasis commonly causes the accumulation of toxic compounds or depletion of vital metabolites, which has detrimental consequences for the patients. Efficient and rapid [...] Read more.

Inborn errors of metabolism cause abnormal synthesis, recycling, or breakdown of amino acids, neurotransmitters, and other various metabolites. This aberrant homeostasis commonly causes the accumulation of toxic compounds or depletion of vital metabolites, which has detrimental consequences for the patients. Efficient and rapid intervention is often key to survival. Therefore, it requires useful animal models to understand the pathomechanisms and identify promising therapeutic drug targets. Zebrafish are an effective tool to investigate developmental mechanisms and understanding the pathophysiology of disorders. In the past decades, zebrafish have proven their efficiency for studying genetic disorders owing to the high degree of conservation between human and zebrafish genes. Subsequently, several rare inherited metabolic disorders have been successfully investigated in zebrafish revealing underlying mechanisms and identifying novel therapeutic targets, including methylmalonic acidemia, Gaucher’s disease, maple urine disorder, hyperammonemia, TRAPPC11-CDGs, and others. This review summarizes the recent impact zebrafish have made in the field of inborn errors of metabolism. Full article

(This article belongs to the Special Issue Zebrafish: A Model for the Study of Human Diseases)

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13 pages, 734 KiB

Open AccessReview

Arsenic Methyltransferase and Methylation of Inorganic Arsenic

by Nirmal K. Roy, Anthony Murphy and Max Costa

Biomolecules 2020, 10(9), 1351; https://doi.org/10.3390/biom10091351 - 22 Sep 2020

Cited by 34 | Viewed by 4909

Abstract

Arsenic occurs naturally in the environment, and exists predominantly as inorganic arsenite (As (III) and arsenate As (V)). Arsenic contamination of drinking water has long been recognized as a major global health concern. Arsenic exposure causes changes in skin color and lesions, and [...] Read more.

Arsenic occurs naturally in the environment, and exists predominantly as inorganic arsenite (As (III) and arsenate As (V)). Arsenic contamination of drinking water has long been recognized as a major global health concern. Arsenic exposure causes changes in skin color and lesions, and more severe health conditions such as black foot disease as well as various cancers originating in the lungs, skin, and bladder. In order to efficiently metabolize and excrete arsenic, it is methylated to monomethylarsonic and dimethylarsinic acid. One single enzyme, arsenic methyltransferase (AS3MT) is responsible for generating both metabolites. AS3MT has been purified from several mammalian and nonmammalian species, and its mRNA sequences were determined from amino acid sequences. With the advent of genome technology, mRNA sequences of AS3MT have been predicted from many species throughout the animal kingdom. Horizontal gene transfer had been postulated for this gene through phylogenetic studies, which suggests the importance of this gene in appropriately handling arsenic exposures in various organisms. An altered ability to methylate arsenic is dependent on specific single nucleotide polymorphisms (SNPs) in AS3MT. Reduced AS3MT activity resulting in poor metabolism of iAs has been shown to reduce expression of the tumor suppressor gene, p16, which is a potential pathway in arsenic carcinogenesis. Arsenic is also known to induce oxidative stress in cells. However, the presence of antioxidant response elements (AREs) in the promoter sequences of AS3MT in several species does not correlate with the ability to methylate arsenic. ARE elements are known to bind NRF2 and induce antioxidant enzymes to combat oxidative stress. NRF2 may be partly responsible for the biotransformation of iAs and the generation of methylated arsenic species via AS3MT. In this article, arsenic metabolism, excretion, and toxicity, a discussion of the AS3MT gene and its evolutionary history, and DNA methylation resulting from arsenic exposure have been reviewed. Full article

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16 pages, 3034 KiB

Open AccessReview

Emerging Roles for the INK4a/ARF (CDKN2A) Locus in Adipose Tissue: Implications for Obesity and Type 2 Diabetes

by Yasmina Kahoul, Frédérik Oger, Jessica Montaigne, Philippe Froguel, Christophe Breton and Jean-Sébastien Annicotte

Biomolecules 2020, 10(9), 1350; https://doi.org/10.3390/biom10091350 - 22 Sep 2020

Cited by 12 | Viewed by 3443

Abstract

Besides its role as a cell cycle and proliferation regulator, the INK4a/ARF (CDKN2A) locus and its associated pathways are thought to play additional functions in the control of energy homeostasis. Genome-wide association studies in humans and rodents have revealed that single [...] Read more.

Besides its role as a cell cycle and proliferation regulator, the INK4a/ARF (CDKN2A) locus and its associated pathways are thought to play additional functions in the control of energy homeostasis. Genome-wide association studies in humans and rodents have revealed that single nucleotide polymorphisms in this locus are risk factors for obesity and related metabolic diseases including cardiovascular complications and type-2 diabetes (T2D). Recent studies showed that both p16^INK4a-CDK4-E2F1/pRB and p19^ARF-P53 (p14^ARF in humans) related pathways regulate adipose tissue (AT) physiology and adipocyte functions such as lipid storage, inflammation, oxidative activity, and cellular plasticity (browning). Targeting these metabolic pathways in AT emerged as a new putative therapy to alleviate the effects of obesity and prevent T2D. This review aims to provide an overview of the literature linking the INK4a/ARF locus with AT functions, focusing on its mechanisms of action in the regulation of energy homeostasis. Full article

(This article belongs to the Special Issue Deciphering alternative functions of the INK4a/ARF locus)

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23 pages, 5479 KiB

Open AccessArticle

G-Quadruplexes in the Archaea Domain

by Václav Brázda, Yu Luo, Martin Bartas, Patrik Kaura, Otilia Porubiaková, Jiří Šťastný, Petr Pečinka, Daniela Verga, Violette Da Cunha, Tomio S. Takahashi, Patrick Forterre, Hannu Myllykallio, Miroslav Fojta and Jean-Louis Mergny

Biomolecules 2020, 10(9), 1349; https://doi.org/10.3390/biom10091349 - 21 Sep 2020

Cited by 31 | Viewed by 4656

Abstract

The importance of unusual DNA structures in the regulation of basic cellular processes is an emerging field of research. Amongst local non-B DNA structures, G-quadruplexes (G4s) have gained in popularity during the last decade, and their presence and functional relevance at the DNA [...] Read more.

The importance of unusual DNA structures in the regulation of basic cellular processes is an emerging field of research. Amongst local non-B DNA structures, G-quadruplexes (G4s) have gained in popularity during the last decade, and their presence and functional relevance at the DNA and RNA level has been demonstrated in a number of viral, bacterial, and eukaryotic genomes, including humans. Here, we performed the first systematic search of G4-forming sequences in all archaeal genomes available in the NCBI database. In this article, we investigate the presence and locations of G-quadruplex forming sequences using the G4Hunter algorithm. G-quadruplex-prone sequences were identified in all archaeal species, with highly significant differences in frequency, from 0.037 to 15.31 potential quadruplex sequences per kb. While G4 forming sequences were extremely abundant in Hadesarchaea archeon (strikingly, more than 50% of the Hadesarchaea archaeon isolate WYZ-LMO6 genome is a potential part of a G4-motif), they were very rare in the Parvarchaeota phylum. The presence of G-quadruplex forming sequences does not follow a random distribution with an over-representation in non-coding RNA, suggesting possible roles for ncRNA regulation. These data illustrate the unique and non-random localization of G-quadruplexes in Archaea. Full article

(This article belongs to the Collection Archaea: Diversity, Metabolism and Molecular Biology)

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23 pages, 1442 KiB

Open AccessFeature PaperReview

Current Understanding of the Relationship of HDL Composition, Structure and Function to Their Cardioprotective Properties in Chronic Kidney Disease

by Gunther Marsche, Gunnar H. Heine, Julia T. Stadler and Michael Holzer

Biomolecules 2020, 10(9), 1348; https://doi.org/10.3390/biom10091348 - 21 Sep 2020

Cited by 25 | Viewed by 3903

Abstract

In the general population, the ability of high-density lipoproteins (HDLs) to promote cholesterol efflux is a predictor of cardiovascular events, independently of HDL cholesterol levels. Although patients with chronic kidney disease (CKD) have a high burden of cardiovascular morbidity and mortality, neither serum [...] Read more.

In the general population, the ability of high-density lipoproteins (HDLs) to promote cholesterol efflux is a predictor of cardiovascular events, independently of HDL cholesterol levels. Although patients with chronic kidney disease (CKD) have a high burden of cardiovascular morbidity and mortality, neither serum levels of HDL cholesterol, nor cholesterol efflux capacity associate with cardiovascular events. Important for the following discussion on the role of HDL in CKD is the notion that traditional atherosclerotic cardiovascular risk factors only partially account for this increased incidence of cardiovascular disease in CKD. As a potential explanation, across the spectrum of cardiovascular disease, the relative contribution of atherosclerotic cardiovascular disease becomes less important with advanced CKD. Impaired renal function directly affects the metabolism, composition and functionality of HDL particles. HDLs themselves are a heterogeneous population of particles with distinct sizes and protein composition, all of them affecting the functionality of HDL. Therefore, a more specific approach investigating the functional and compositional features of HDL subclasses might be a valuable strategy to decipher the potential link between HDL, cardiovascular disease and CKD. This review summarizes the current understanding of the relationship of HDL composition, metabolism and function to their cardio-protective properties in CKD, with a focus on CKD-induced changes in the HDL proteome and reverse cholesterol transport capacity. We also will highlight the gaps in the current knowledge regarding important aspects of HDL biology. Full article

(This article belongs to the Special Issue High-Density Lipoprotein (HDL): The Role of Reverse Cholesterol Transport in Human Health and Disease)

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15 pages, 2927 KiB

Open AccessCommunication

Identification of a Proanthocyanidin from Litchi Chinensis Sonn. Root with Anti-Tyrosinase and Antioxidant Activity

by Matthew Saive, Manon Genva, Thibaut Istasse, Michel Frederich, Chloé Maes and Marie-Laure Fauconnier

Biomolecules 2020, 10(9), 1347; https://doi.org/10.3390/biom10091347 - 21 Sep 2020

Cited by 6 | Viewed by 2738

Abstract

This work follows an ethnobotanical study that took place in the island of Mayotte (France), which pointed out the potential properties of Litchi chinensis Sonn. roots when used to enhance skin health and appearance. Through in vitro testing of a crude methanolic extract, [...] Read more.

This work follows an ethnobotanical study that took place in the island of Mayotte (France), which pointed out the potential properties of Litchi chinensis Sonn. roots when used to enhance skin health and appearance. Through in vitro testing of a crude methanolic extract, high anti-tyrosinase (skin whitening effect) and antioxidant activities (skin soothing effect) could be measured. HPLC successive bio-guided fractionation steps allowed the purification of one of the compounds responsible for the biological activities. The isolated compound was characterized by UV, IR, MS and 2D-NMR, revealing, for the first time in Litchi chinensis Sonn. roots, an A-type proanthocyanidin and thus revealing a consensus among the traditional use shown by the ethnobotanical study, in vitro biological activities and chemical characterization. Full article

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26 pages, 5875 KiB

Open AccessArticle

Recognition of Potential COVID-19 Drug Treatments through the Study of Existing Protein–Drug and Protein–Protein Structures: An Analysis of Kinetically Active Residues

by Ognjen Perišić

Biomolecules 2020, 10(9), 1346; https://doi.org/10.3390/biom10091346 - 21 Sep 2020

Cited by 10 | Viewed by 4591

Abstract

We report the results of our in silico study of approved drugs as potential treatments for COVID-19. The study is based on the analysis of normal modes of proteins. The drugs studied include chloroquine, ivermectin, remdesivir, sofosbuvir, boceprevir, and α-difluoromethylornithine (DMFO). We applied [...] Read more.

We report the results of our in silico study of approved drugs as potential treatments for COVID-19. The study is based on the analysis of normal modes of proteins. The drugs studied include chloroquine, ivermectin, remdesivir, sofosbuvir, boceprevir, and α-difluoromethylornithine (DMFO). We applied the tools we developed and standard tools used in the structural biology community. Our results indicate that small molecules selectively bind to stable, kinetically active residues and residues adjoining them on the surface of proteins and inside protein pockets, and that some prefer hydrophobic sites over other active sites. Our approach is not restricted to viruses and can facilitate rational drug design, as well as improve our understanding of molecular interactions, in general. Full article

(This article belongs to the Section Bioinformatics and Systems Biology)

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14 pages, 2438 KiB

Open AccessArticle

Lipophilic Cations Rescue the Growth of Yeast under the Conditions of Glycolysis Overflow

by Svyatoslav S. Sokolov, Ekaterina A. Smirnova, Olga V. Markova, Natalya A. Kireeva, Roman S. Kirsanov, Liudmila S. Khailova, Dmitry A. Knorre and Fedor F. Severin

Biomolecules 2020, 10(9), 1345; https://doi.org/10.3390/biom10091345 - 20 Sep 2020

Cited by 4 | Viewed by 3048

Abstract

Chemicals inducing a mild decrease in the ATP/ADP ratio are considered as caloric restriction mimetics as well as treatments against obesity. Screening for such chemicals in animal model systems requires a lot of time and labor. Here, we present a system for the [...] Read more.

Chemicals inducing a mild decrease in the ATP/ADP ratio are considered as caloric restriction mimetics as well as treatments against obesity. Screening for such chemicals in animal model systems requires a lot of time and labor. Here, we present a system for the rapid screening of non-toxic substances causing such a de-energization of cells. We looked for chemicals allowing the growth of yeast lacking trehalose phosphate synthase on a non-fermentable carbon source in the presence of glucose. Under such conditions, the cells cannot grow because the cellular phosphate is mostly being used to phosphorylate the sugars in upper glycolysis, while the biosynthesis of bisphosphoglycerate is blocked. We reasoned that by decreasing the ATP/ADP ratio, one might prevent the phosphorylation of the sugars and also boost bisphosphoglycerate synthesis by providing the substrate, i.e., inorganic phosphate. We confirmed that a complete inhibition of oxidative phosphorylation alleviates the block. As our system includes a non-fermentable carbon source, only the chemicals that did not cause a complete block of mitochondrial ATP synthesis allowed the initial depletion of glucose followed by respiratory growth. Using this system, we found two novel compounds, dodecylmethyl diphenylamine (FS1) and diethyl (tetradecyl) phenyl ammonium bromide (Kor105), which possess a mild membrane-depolarizing activity. Full article

(This article belongs to the Section Cellular Biochemistry)

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12 pages, 2496 KiB

Open AccessArticle

5-Hydroxytryptamine (5-HT) Positively Regulates Pigmentation via Inducing Melanoblast Specification and Melanin Synthesis in Zebrafish Embryos

by Li Liu, Min Zhong, Jing Dong, Minghan Chen, Jing Shang and Yunyun Yue

Biomolecules 2020, 10(9), 1344; https://doi.org/10.3390/biom10091344 - 19 Sep 2020

Cited by 11 | Viewed by 3721

Abstract

It has been reported that 5-hydroxytryptamine (5-HT) is related to melanogenesis in mice and melanoma cells. However, the underlying mechanisms of 5-HT in regulating pigmentation remains unknown. In this study, we aim to clarify the regulatory mechanism of 5-HT in the pigmentation of [...] Read more.

It has been reported that 5-hydroxytryptamine (5-HT) is related to melanogenesis in mice and melanoma cells. However, the underlying mechanisms of 5-HT in regulating pigmentation remains unknown. In this study, we aim to clarify the regulatory mechanism of 5-HT in the pigmentation of zebrafish embryos and B16F10 cells. Our results show that 5-HT induces the pigmentation of zebrafish embryos in a dosage-dependent manner at concentrations of 0.01–1 mM. Whole mount in situ hybridizations and qRT-PCR in zebrafish embryos indicate that the expression of neural crest cells marker gene sox10 is not changed in embryos treated with 5-HT compared to control group. The expression of mitfa, the marker gene of melanoblasts, is increased in the presence of 5-HT. Furthermore, 5-HT increased the expression of regeneration associated genes, namely kita, mitfa, and dct, after ablation of the melanogenic cells in zebrafish embryos. The experiments in B16F10 cells show that 5-HT promotes melanin synthesis by up-regulating the expression of key proteins MITF, TYR, TRP-1, and TRP-2. Especially, the small molecule inhibitor of PKA signaling, but not AKT and MAPK signaling, attenuates the up-regulation of MITF and TYR resulted from 5-HT induction in B16F10 cells. These results will help us to further understand the regulatory network of vertebrate pigmentation. Full article

(This article belongs to the Section Molecular Biology)

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12 pages, 1500 KiB

Open AccessArticle

Molecular Topology for the Discovery of New Broad-Spectrum Antibacterial Drugs

by Jose I. Bueso-Bordils, Pedro A. Alemán-López, Beatriz Suay-García, Rafael Martín-Algarra, Maria J. Duart, Antonio Falcó and Gerardo M. Antón-Fos

Biomolecules 2020, 10(9), 1343; https://doi.org/10.3390/biom10091343 - 19 Sep 2020

Cited by 3 | Viewed by 2038

Abstract

In this study, molecular topology was used to develop several discriminant equations capable of classifying compounds according to their antibacterial activity. Topological indices were used as structural descriptors and their relation to antibacterial activity was determined by applying linear discriminant analysis (LDA) on [...] Read more.

In this study, molecular topology was used to develop several discriminant equations capable of classifying compounds according to their antibacterial activity. Topological indices were used as structural descriptors and their relation to antibacterial activity was determined by applying linear discriminant analysis (LDA) on a group of quinolones and quinolone-like compounds. Four equations were constructed, named DF1, DF2, DF3, and DF4, all with good statistical parameters such as Fisher–Snedecor’s F (over 25 in all cases), Wilk’s lambda (below 0.36 in all cases) and percentage of correct classification (over 80% in all cases), which allows a reliable extrapolation prediction of antibacterial activity in any organic compound. From the four discriminant functions, it can be extracted that the presence of sp³ carbons, ramifications, and secondary amine groups in a molecule enhance antibacterial activity, whereas the presence of 5-member rings, sp² carbons, and sp² oxygens hinder it. The results obtained clearly reveal the high efficiency of combining molecular topology with LDA for the prediction of antibacterial activity. Full article

(This article belongs to the Special Issue Big Data Analysis in Biomolecular Research, Bioinformatics, and Systems Biology with Complex Networks and Multi-Label Machine Learning Models)

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11 pages, 2813 KiB

Open AccessArticle

Cryo-EM Structure of Heterologous Protein Complex Loaded Thermotoga Maritima Encapsulin Capsid

by Xiansong Xiong, Chen Sun, Frank S. Vago, Thomas Klose, Jiankang Zhu and Wen Jiang

Biomolecules 2020, 10(9), 1342; https://doi.org/10.3390/biom10091342 - 19 Sep 2020

Cited by 7 | Viewed by 3864

Abstract

Encapsulin is a class of nanocompartments that is unique in bacteria and archaea to confine enzymatic activities and sequester toxic reaction products. Here we present a 2.87 Å resolution cryo-EM structure of Thermotoga maritima encapsulin with heterologous protein complex loaded. It is the [...] Read more.

Encapsulin is a class of nanocompartments that is unique in bacteria and archaea to confine enzymatic activities and sequester toxic reaction products. Here we present a 2.87 Å resolution cryo-EM structure of Thermotoga maritima encapsulin with heterologous protein complex loaded. It is the first successful case of expressing encapsulin and heterologous cargo protein in the insect cell system. Although we failed to reconstruct the cargo protein complex structure due to the signal interference of the capsid shell, we were able to observe some unique features of the cargo-loaded encapsulin shell, for example, an extra density at the fivefold pore that has not been reported before. These results would lead to a more complete understanding of the encapsulin cargo assembly process of T. maritima. Full article

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22 pages, 3882 KiB

Open AccessArticle

Triapine Derivatives Act as Copper Delivery Vehicles to Induce Deadly Metal Overload in Cancer Cells

by Kateryna Ohui, Iryna Stepanenko, Iuliana Besleaga, Maria V. Babak, Radu Stafi, Denisa Darvasiova, Gerald Giester, Vivien Pósa, Eva A. Enyedy, Daniel Vegh, Peter Rapta, Wee Han Ang, Ana Popović-Bijelić and Vladimir B. Arion

Biomolecules 2020, 10(9), 1336; https://doi.org/10.3390/biom10091336 - 19 Sep 2020

Cited by 11 | Viewed by 4386

Abstract

Thiosemicarbazones continue to attract the interest of researchers as potential anticancer drugs. For example, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone, or triapine, is the most well-known representative of this class of compounds that has entered multiple phase I and II clinical trials. Two new triapine derivatives HL [...] Read more.

Thiosemicarbazones continue to attract the interest of researchers as potential anticancer drugs. For example, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone, or triapine, is the most well-known representative of this class of compounds that has entered multiple phase I and II clinical trials. Two new triapine derivatives HL¹ and HL² were prepared by condensation reactions of 2-pyridinamidrazone and S-methylisothiosemicarbazidium chloride with 3-N-(tert-butyloxycarbonyl) amino-pyridine-2-carboxaldehyde, followed by a Boc-deprotection procedure. Subsequent reaction of HL¹ and HL² with CuCl₂·2H₂O in 1:1 molar ratio in methanol produced the complexes [Cu^II(HL¹)Cl₂]·H₂O (1·H₂O) and [Cu^II(HL²)Cl₂] (2). The reaction of HL² with Fe(NO₃)₃∙9H₂O in 2:1 molar ratio in the presence of triethylamine afforded the complex [Fe^III(L²)₂]NO₃∙0.75H₂O (3∙0.75H₂O), in which the isothiosemicarbazone acts as a tridentate monoanionic ligand. The crystal structures of HL¹, HL² and metal complexes 1 and 2 were determined by single crystal X-ray diffraction. The UV-Vis and EPR spectroelectrochemical measurements revealed that complexes 1 and 2 underwent irreversible reduction of Cu(II) with subsequent ligand release, while 3 showed an almost reversible electrochemical reduction in dimethyl sulfoxide (DMSO). Aqueous solution behaviour of HL¹ and 1, as well as of HL² and its complex 2, was monitored as well. Complexes 1−3 were tested against ovarian carcinoma cells, as well as noncancerous embryonic kidney cells, in comparison to respective free ligands, triapine and cisplatin. While the free ligands HL¹ and HL² were devoid of antiproliferative activity, their respective metal complexes showed remarkable antiproliferative activity in a micromolar concentration range. The activity was not related to the inhibition of ribonucleotide reductase (RNR) R2 protein, but rather to cancer cell homeostasis disturbance—leading to the disruption of cancer cell signalling. Full article

(This article belongs to the Section Molecular Biology)

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25 pages, 4764 KiB

Open AccessReview

Metabolic Diversity and Therapeutic Potential of Holarrhena pubescens: An Important Ethnomedicinal Plant

by Kulsoom Zahara, Sujogya Kumar Panda, Shasank Sekhar Swain and Walter Luyten

Biomolecules 2020, 10(9), 1341; https://doi.org/10.3390/biom10091341 - 18 Sep 2020

Cited by 12 | Viewed by 5231

Abstract

Holarrhena pubescens is an important medicinal plant of the Apocynaceae family that is widely distributed over the Indian subcontinent. The plant is extensively used in Ayurveda and other traditional medicinal systems without obvious adverse effects. Beside notable progress in the biological and phytochemical [...] Read more.

Holarrhena pubescens is an important medicinal plant of the Apocynaceae family that is widely distributed over the Indian subcontinent. The plant is extensively used in Ayurveda and other traditional medicinal systems without obvious adverse effects. Beside notable progress in the biological and phytochemical evaluation of this plant over the past few years, comprehensive reviews of H. pubescens are limited in scope. It has economic importance due to the extensive use of seeds as an antidiabetic. Furthermore, the plant is extensively reported in traditional uses among the natives of Asia and Africa, while scientifical validation for various ailments has not been studied either in vitro or in vivo. This review aims to summarize information on the pharmacology, traditional uses, active constituents, safety and toxicity of H. pubescens. Chemical analysis of H. pubescens extracts revealed the presence of several bioactive compounds, such as conessine, isoconnessine, conessimine, conimine, conessidine, conkurchicine, holarrhimine, conarrhimine, mokluangin A-D and antidysentericine. Overall, this review covers the ethnopharmacology, phytochemical composition, and pharmacological potential of H. pubescens, with a critical discussion of its toxicity, biological activities (in vitro and in vivo), the mechanism of action, as well as suggestions for further basic and clinical research. Full article

(This article belongs to the Collection Pharmacology of Medicinal Plants)

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25 pages, 4193 KiB

Open AccessArticle

Evaluation of the Adverse Effects of Chronic Exposure to Donepezil (An Acetylcholinesterase Inhibitor) in Adult Zebrafish by Behavioral and Biochemical Assessments

by Gilbert Audira, Nguyen Thi Ngoc Anh, Bui Thi Ngoc Hieu, Nemi Malhotra, Petrus Siregar, Omar Villalobos, Oliver B. Villaflores, Tzong-Rong Ger, Jong-Chin Huang, Kelvin H.-C. Chen and Chung-Der Hsiao

Biomolecules 2020, 10(9), 1340; https://doi.org/10.3390/biom10091340 - 18 Sep 2020

Cited by 12 | Viewed by 4942

Abstract

Donepezil (DPZ) is an acetylcholinesterase inhibitor used for the clinical treatment of mild cognitive impairment. However, DPZ has been reported to have adverse effects, including causing abnormal cardiac rhythm, insomnia, vomiting, and muscle cramps. However, the existence of these effects in subjects without [...] Read more.

Donepezil (DPZ) is an acetylcholinesterase inhibitor used for the clinical treatment of mild cognitive impairment. However, DPZ has been reported to have adverse effects, including causing abnormal cardiac rhythm, insomnia, vomiting, and muscle cramps. However, the existence of these effects in subjects without Dementia is unknown. In this study, we use zebrafish to conduct a deeper analysis of the potential adverse effects of DPZ on the short-term memory and behaviors of normal zebrafish by performing multiple behavioral and biochemical assays. Adult zebrafish were exposed to 1 ppm and 2.5 ppm of DPZ. From the results, DPZ caused a slight improvement in the short-term memory of zebrafish and induced significant elevation in aggressiveness, while the novel tank and shoaling tests revealed anxiolytic-like behavior to be caused by DPZ. Furthermore, zebrafish circadian locomotor activity displayed a higher reduction of locomotion and abnormal movement orientation in both low- and high-dose groups, compared to the control group. Biomarker assays revealed that these alterations were associated with an elevation of oxytocin and a reduction of cortisol levels in the brain. Moreover, the significant increases in reactive oxygen species (ROS) and malondialdehyde (MDA) levels in muscle tissue suggest DPZ exposure induced muscle tissue oxidative stress and muscle weakness, which may underlie the locomotor activity impairment. In conclusion, we show, for the first time, that chronic waterborne exposure to DPZ can severely induce adverse effects on normal zebrafish in a dose-dependent manner. These unexpected adverse effects on behavioral alteration should be carefully addressed in future studies considering DPZ conducted on zebrafish or other animals. Full article

(This article belongs to the Special Issue Cholinesterase Research)

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19 pages, 588 KiB

Open AccessReview

Pompe Disease: New Developments in an Old Lysosomal Storage Disorder

by Naresh K. Meena and Nina Raben

Biomolecules 2020, 10(9), 1339; https://doi.org/10.3390/biom10091339 - 18 Sep 2020

Cited by 51 | Viewed by 13242

Abstract

Pompe disease, also known as glycogen storage disease type II, is caused by the lack or deficiency of a single enzyme, lysosomal acid alpha-glucosidase, leading to severe cardiac and skeletal muscle myopathy due to progressive accumulation of glycogen. The discovery that acid alpha-glucosidase [...] Read more.

Pompe disease, also known as glycogen storage disease type II, is caused by the lack or deficiency of a single enzyme, lysosomal acid alpha-glucosidase, leading to severe cardiac and skeletal muscle myopathy due to progressive accumulation of glycogen. The discovery that acid alpha-glucosidase resides in the lysosome gave rise to the concept of lysosomal storage diseases, and Pompe disease became the first among many monogenic diseases caused by loss of lysosomal enzyme activities. The only disease-specific treatment available for Pompe disease patients is enzyme replacement therapy (ERT) which aims to halt the natural course of the illness. Both the success and limitations of ERT provided novel insights in the pathophysiology of the disease and motivated the scientific community to develop the next generation of therapies that have already progressed to the clinic. Full article

(This article belongs to the Special Issue Lysosomal Storage Disorders: Molecular Basis and Therapeutic Approaches)

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30 pages, 3017 KiB

Open AccessFeature PaperArticle

Production of Aromatic Compounds by Catalytic Depolymerization of Technical and Downstream Biorefinery Lignins

by Alfonso Cornejo, Fernando Bimbela, Rui Moreira, Karina Hablich, Íñigo García-Yoldi, Maitane Maisterra, António Portugal, Luis M. Gandía and Víctor Martínez-Merino

Biomolecules 2020, 10(9), 1338; https://doi.org/10.3390/biom10091338 - 18 Sep 2020

Cited by 12 | Viewed by 3509

Abstract

Lignocellulosic materials are promising alternatives to non-renewable fossil sources when producing aromatic compounds. Lignins from Populus salicaceae. Pinus radiata and Pinus pinaster from industrial wastes and biorefinery effluents were isolated and characterized. Lignin was depolymerized using homogenous (NaOH) and heterogeneous (Ni-, Cu- [...] Read more.

Lignocellulosic materials are promising alternatives to non-renewable fossil sources when producing aromatic compounds. Lignins from Populus salicaceae. Pinus radiata and Pinus pinaster from industrial wastes and biorefinery effluents were isolated and characterized. Lignin was depolymerized using homogenous (NaOH) and heterogeneous (Ni-, Cu- or Ni-Cu-hydrotalcites) base catalysis and catalytic hydrogenolysis using Ru/C. When homogeneous base catalyzed depolymerization (BCD) and Ru/C hydrogenolysis were combined on poplar lignin, the aromatics amount was ca. 11 wt.%. Monomer distributions changed depending on the feedstock and the reaction conditions. Aqueous NaOH produced cleavage of the alkyl side chain that was preserved when using modified hydrotalcite catalysts or Ru/C-catalyzed hydrogenolysis in ethanol. Depolymerization using hydrotalcite catalysts in ethanol produced monomers bearing carbonyl groups on the alkyl side chain. The analysis of the reaction mixtures was done by size exclusion chromatography (SEC) and diffusion ordered nuclear magnetic resonance spectroscopy (DOSY NMR). ³¹P NMR and heteronuclear single quantum coherence spectroscopy (HSQC) were also used in this study. The content in poly-(hydroxy)-aromatic ethers in the reaction mixtures decreased upon thermal treatments in ethanol. It was concluded that thermo-solvolysis is key in lignin depolymerization, and that the synergistic effect of Ni and Cu provided monomers with oxidized alkyl side chains. Full article

(This article belongs to the Special Issue Biomolecules from Plant Residues)

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14 pages, 18129 KiB

Open AccessFeature PaperArticle

The Cytokine IL-1β and Piperine Complex Surveyed by Experimental and Computational Molecular Biophysics

by Gabriel Zazeri, Ana Paula Ribeiro Povinelli, Marcelo de Freitas Lima and Marinônio Lopes Cornélio

Biomolecules 2020, 10(9), 1337; https://doi.org/10.3390/biom10091337 - 18 Sep 2020

Cited by 7 | Viewed by 2404

Abstract

The bioactive piperine, a compound found in some pepper species, has been widely studied because of its therapeutic properties that include the inhibition of an important inflammation pathway triggered by interleukin-1 beta (IL-1β). However, investigation into the molecular interactions between IL-1β and piperine [...] Read more.

The bioactive piperine, a compound found in some pepper species, has been widely studied because of its therapeutic properties that include the inhibition of an important inflammation pathway triggered by interleukin-1 beta (IL-1β). However, investigation into the molecular interactions between IL-1β and piperine is not reported in the literature. Here, we present for the first time the characterisation of the complex formed by IL-1β and piperine through experimental and computational molecular biophysical analyses. Fluorescence spectroscopy unveiled the presence of one binding site for piperine with an affinity constant of 14.3 × 10⁴ M⁻¹ at 298 K. The thermodynamic analysis indicated that the interaction with IL-1β was spontaneous (∆G = −25 kJ/mol) and, when split into enthalpic and entropic contributions, the latter was more significant. Circular dichroism spectroscopy showed that piperine did not affect IL-1β secondary structure (~2%) and therefore its stability. The set of experimental data parameterized the computational biophysical approach. Through molecular docking, the binding site micro-environment was revealed to be composed mostly by non-polar amino acids. Furthermore, molecular dynamics, along with umbrella sampling, are in agreement with the thermodynamic parameters obtained by fluorescence assays and showed that large protein movements are not present in IL-1β, corroborating the circular dichroism data. Full article

(This article belongs to the Special Issue Enzymatic Inhibitors from Natural Sources: A Huge Collection of New Potential Drugs)

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11 pages, 7212 KiB

Open AccessArticle

Natural Compounds Modulate Drug Transporter Mediated Oral Cancer Treatment

by Hsiang Yang, Yu-Ching Wei, Wan-Chun Li, Hsin-Yung Chen, Hung-Ying Lin, Chun-Pin Chiang and Hsin-Ming Chen

Biomolecules 2020, 10(9), 1335; https://doi.org/10.3390/biom10091335 - 17 Sep 2020

Cited by 9 | Viewed by 2724

Abstract

Oral cancer (OC) is a serious health problem. Surgery is the best method to treat the disease but might reduce the quality of life of patients. Photodynamic therapy (PDT) may enhance quality of life but with some limitations. Therefore, the development of a [...] Read more.

Oral cancer (OC) is a serious health problem. Surgery is the best method to treat the disease but might reduce the quality of life of patients. Photodynamic therapy (PDT) may enhance quality of life but with some limitations. Therefore, the development of a new strategy to facilitate PDT effectiveness has become crucial. ATP-binding cassette G2 (ABCG2) is a membrane protein-associated drug resistance and stemness in cancers. Here, we examined whether ABCG2 plays an important role in regulating the treatment efficacy of PDT and whether ABCG2 inhibition by natural compounds can promote the effect of PDT in OC cells. Several head and neck cancer cells were utilized in this study. OECM1 and SAS cells were selected to investigate the relationship between ABCG2 expression and protoporphyrin IX (PpIX) accumulation. Western blot analysis, flow cytometry analysis, and survival probability were performed to determine PDT efficacy and cellular stemness upon treatment of different dietary compounds, including epigallocatechin gallate (EGCG) and curcumin. In this study, we found that ABCG2 expression varied in OC cells. Hypoglycemic culture for SAS cells enhanced ABCG2 expression as higher ABCG2 expression was associated with lower PpIX accumulation and cellular stemness in OC cells. In contrast, suppression of ABCG2 expression by curcumin and tea polyphenol EGCG led to greater PpIX accumulation and enhanced PDT treatment efficiency in OC cells. In conclusion, ABCG2 plays an important role in regulating the effect of PDT. Change in glucose concentration and treatment with natural compounds modulated ABCG2 expression, resulting in altered PDT efficacy for OC cells. These modulations raise a potential new treatment strategy for early-stage OCs. Full article

(This article belongs to the Special Issue Application and Mechanism of Natural Compounds in Dentistry)

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25 pages, 26408 KiB

Open AccessArticle

Automatic Quantification of Cardiomyocyte Dimensions and Connexin 43 Lateralization in Fluorescence Images

by Antoni Oliver-Gelabert, Laura García-Mendívil, José María Vallejo-Gil, Pedro Carlos Fresneda-Roldán, Katarína Andelová, Javier Fañanás-Mastral, Manuel Vázquez-Sancho, Marta Matamala-Adell, Fernando Sorribas-Berjón, Carlos Ballester-Cuenca, Narcisa Tribulova, Laura Ordovás, Emiliano Raúl Diez and Esther Pueyo

Biomolecules 2020, 10(9), 1334; https://doi.org/10.3390/biom10091334 - 17 Sep 2020

Cited by 6 | Viewed by 3929

Abstract

Cardiomyocytes’ geometry and connexin 43 (CX43) amount and distribution are structural features that play a pivotal role in electrical conduction. Their quantitative assessment is of high interest in the study of arrhythmias, but it is usually hampered by the lack of automatic tools. [...] Read more.

Cardiomyocytes’ geometry and connexin 43 (CX43) amount and distribution are structural features that play a pivotal role in electrical conduction. Their quantitative assessment is of high interest in the study of arrhythmias, but it is usually hampered by the lack of automatic tools. In this work, we propose a software algorithm (Myocyte Automatic Retrieval and Tissue Analyzer, MARTA) to automatically detect myocytes from fluorescent microscopy images of cardiac tissue, measure their morphological features and evaluate the expression of CX43 and its degree of lateralization. The proposed software is based on the generation of cell masks, contouring of individual cells, enclosing of cells in minimum area rectangles and splitting of these rectangles into end-to-end and middle compartments to estimate CX43 lateral-to-total ratio. Application to human ventricular tissue images shows that mean differences between automatic and manual methods in terms of cardiomyocyte length and width are below 4

μ

m. The percentage of lateral CX43 also agrees between automatic and manual evaluation, with the interquartile range approximately covering from 3% to 30% in both cases. MARTA is not limited by fiber orientation and has an optimized speed by using contour filtering, which makes it run hundreds of times faster than a trained expert. Developed for CX43 studies in the left ventricle, MARTA is a flexible tool applicable to morphometric and lateralization studies of other markers in any heart chamber or even skeletal muscle. This open-access software is available online. Full article

(This article belongs to the Special Issue Connexins, Innexins, and Pannexins: From Biology to Clinical Targets)

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25 pages, 4138 KiB

Open AccessReview

Mulinane- and Azorellane-Type Diterpenoids: A Systematic Review of Their Biosynthesis, Chemistry, and Pharmacology

by Angel de Jesús Dzul-Beh, Andrés Humberto Uc-Cachón, Jorge Bórquez, Luis A. Loyola, Luis Manuel Peña-Rodríguez and Gloria María Molina-Salinas

Biomolecules 2020, 10(9), 1333; https://doi.org/10.3390/biom10091333 - 17 Sep 2020

Cited by 6 | Viewed by 2835

Abstract

Mulinane- and azorellane-type diterpenoids have unique tricyclic fused five-, six-, and seven-membered systems and a wide range of biological properties, including antimicrobial, antiprotozoal, spermicidal, gastroprotective, and anti-inflammatory, among others. These secondary metabolites are exclusive constituents of medicinal plants belonging to the Azorella, [...] Read more.

Mulinane- and azorellane-type diterpenoids have unique tricyclic fused five-, six-, and seven-membered systems and a wide range of biological properties, including antimicrobial, antiprotozoal, spermicidal, gastroprotective, and anti-inflammatory, among others. These secondary metabolites are exclusive constituents of medicinal plants belonging to the Azorella, Laretia, and Mulinum genera. In the last 30 years, more than 95 mulinanes and azorellanes have been reported, 49 of them being natural products, 4 synthetics, and the rest semisynthetic and biotransformed derivatives. This systematic review highlights the biosynthetic origin, the chemistry, and the pharmacological activities of this remarkably interesting group of diterpenoids. Full article

(This article belongs to the Section Chemical Biology)

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25 pages, 3302 KiB

Open AccessReview

Rescue of Hepatic Phospholipid Remodeling Defect in iPLA₂β-Null Mice Attenuates Obese but Not Non-Obese Fatty Liver

by Walee Chamulitrat, Chutima Jansakun, Huili Li and Gerhard Liebisch

Biomolecules 2020, 10(9), 1332; https://doi.org/10.3390/biom10091332 - 17 Sep 2020

Cited by 8 | Viewed by 3541

Abstract

Polymorphisms of group VIA calcium-independent phospholipase A2 (iPLA₂β or PLA2G6) are positively associated with adiposity, blood lipids, and Type-2 diabetes. The ubiquitously expressed iPLA₂β catalyzes the hydrolysis of phospholipids (PLs) to generate a fatty acid and a lysoPL. We [...] Read more.

Polymorphisms of group VIA calcium-independent phospholipase A2 (iPLA₂β or PLA2G6) are positively associated with adiposity, blood lipids, and Type-2 diabetes. The ubiquitously expressed iPLA₂β catalyzes the hydrolysis of phospholipids (PLs) to generate a fatty acid and a lysoPL. We studied the role of iPLA₂β on PL metabolism in non-alcoholic fatty liver disease (NAFLD). By using global deletion iPLA₂β-null mice, we investigated three NAFLD mouse models; genetic Ob/Ob and long-term high-fat-diet (HFD) feeding (representing obese NAFLD) as well as feeding with methionine- and choline-deficient (MCD) diet (representing non-obese NAFLD). A decrease of hepatic PLs containing monounsaturated- and polyunsaturated fatty acids and a decrease of the ratio between PLs and cholesterol esters were observed in all three NAFLD models. iPLA₂β deficiency rescued these decreases in obese, but not in non-obese, NAFLD models. iPLA₂β deficiency elicited protection against fatty liver and obesity in the order of Ob/Ob › HFD » MCD. Liver inflammation was not protected in HFD NAFLD, and that liver fibrosis was even exaggerated in non-obese MCD model. Thus, the rescue of hepatic PL remodeling defect observed in iPLA₂β-null mice was critical for the protection against NAFLD and obesity. However, iPLA₂β deletion in specific cell types such as macrophages may render liver inflammation and fibrosis, independent of steatosis protection. Full article

(This article belongs to the Special Issue Phospholipases: From Structure to Biological Function)

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20 pages, 1085 KiB

Open AccessFeature PaperReview

Targeting Receptors on Cancer Cells with Protein Toxins

by Antonella Antignani, Eric Chun Hei Ho, Maria Teresa Bilotta, Rong Qiu, Robert Sarnvosky and David J. FitzGerald

Biomolecules 2020, 10(9), 1331; https://doi.org/10.3390/biom10091331 - 17 Sep 2020

Cited by 20 | Viewed by 4486

Abstract

Cancer cells frequently upregulate surface receptors that promote growth and survival. These receptors constitute valid targets for intervention. One strategy involves the delivery of toxic payloads with the goal of killing those cancer cells with high receptor levels. Delivery can be accomplished by [...] Read more.

Cancer cells frequently upregulate surface receptors that promote growth and survival. These receptors constitute valid targets for intervention. One strategy involves the delivery of toxic payloads with the goal of killing those cancer cells with high receptor levels. Delivery can be accomplished by attaching a toxic payload to either a receptor-binding antibody or a receptor-binding ligand. Generally, the cell-binding domain of the toxin is replaced with a ligand or antibody that dictates a new binding specificity. The advantage of this “immunotoxin” approach lies in the potency of these chimeric molecules for killing cancer cells. However, receptor expression on normal tissue represents a significant obstacle to therapeutic intervention. Full article

(This article belongs to the Special Issue Immunotoxins: From Design to Clinical Application)

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17 pages, 18386 KiB

Open AccessArticle

Allosteric Inhibition of Adenylyl Cyclase Type 5 by G-Protein: A Molecular Dynamics Study

by Elisa Frezza, Tina-Méryl Amans and Juliette Martin

Biomolecules 2020, 10(9), 1330; https://doi.org/10.3390/biom10091330 - 17 Sep 2020

Cited by 6 | Viewed by 2720

Abstract

Adenylyl cyclases (ACs) have a crucial role in many signal transduction pathways, in particular in the intricate control of cyclic AMP (cAMP) generation from adenosine triphosphate (ATP). Using homology models developed from existing structural data and docking experiments, we have carried out all-atom, [...] Read more.

Adenylyl cyclases (ACs) have a crucial role in many signal transduction pathways, in particular in the intricate control of cyclic AMP (cAMP) generation from adenosine triphosphate (ATP). Using homology models developed from existing structural data and docking experiments, we have carried out all-atom, microsecond-scale molecular dynamics simulations on the AC5 isoform of adenylyl cyclase bound to the inhibitory G-protein subunit Gαi in the presence and in the absence of ATP. The results show that Gαi has significant effects on the structure and flexibility of adenylyl cyclase, as observed earlier for the binding of ATP and Gsα. New data on Gαi bound to the C1 domain of AC5 help explain how Gαi inhibits enzyme activity and obtain insight on its regulation. Simulations also suggest a crucial role of ATP in the regulation of the stimulation and inhibition of AC5. Full article

(This article belongs to the Section Molecular Structure and Dynamics)

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13 pages, 2608 KiB

Open AccessFeature PaperArticle

The Receptor Tyrosine Kinase TrkA Is Increased and Targetable in HER2-Positive Breast Cancer

by Nathan Griffin, Mark Marsland, Severine Roselli, Christopher Oldmeadow, John Attia, Marjorie M. Walker, Hubert Hondermarck and Sam Faulkner

Biomolecules 2020, 10(9), 1329; https://doi.org/10.3390/biom10091329 - 17 Sep 2020

Cited by 9 | Viewed by 3029

Abstract

The tyrosine kinase receptor A (NTRK1/TrkA) is increasingly regarded as a therapeutic target in oncology. In breast cancer, TrkA contributes to metastasis but the clinicopathological significance remains unclear. In this study, TrkA expression was assessed via immunohistochemistry of 158 invasive ductal carcinomas (IDC), [...] Read more.

The tyrosine kinase receptor A (NTRK1/TrkA) is increasingly regarded as a therapeutic target in oncology. In breast cancer, TrkA contributes to metastasis but the clinicopathological significance remains unclear. In this study, TrkA expression was assessed via immunohistochemistry of 158 invasive ductal carcinomas (IDC), 158 invasive lobular carcinomas (ILC) and 50 ductal carcinomas in situ (DCIS). TrkA was expressed in cancer epithelial and myoepithelial cells, with higher levels of TrkA positively associated with IDC (39% of cases) (p < 0.0001). Interestingly, TrkA was significantly increased in tumours expressing the human epidermal growth factor receptor-2 (HER2), with expression in 49% of HER2-positive compared to 25% of HER2-negative tumours (p = 0.0027). A panel of breast cancer cells were used to confirm TrkA protein expression, demonstrating higher levels of TrkA (total and phosphorylated) in HER2-positive cell lines. Functional investigations using four different HER2-positive breast cancer cell lines indicated that the Trk tyrosine kinase inhibitor GNF-5837 reduced cell viability, through decreased phospho-TrkA (Tyr490) and downstream AKT (Ser473) activation, but did not display synergy with Herceptin. Overall, these data highlight a relationship between the tyrosine kinase receptors TrkA and HER2 and suggest the potential of TrkA as a novel or adjunct target for HER2-positive breast tumours. Full article

(This article belongs to the Special Issue Protein Phosphorylation in Cancer: Unraveling the Signaling Pathways)

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10 pages, 1140 KiB

Open AccessArticle

Oxygen: The Rate-Limiting Factor for Episodic Memory Performance, Even in Healthy Young Individuals

by Gil Suzin, Tom Halpert Frolinger, Dror Yogev, Amir Hadanny, Merav Catalogna, Yuri Rassovsky and Shai Efrati

Biomolecules 2020, 10(9), 1328; https://doi.org/10.3390/biom10091328 - 17 Sep 2020

Cited by 3 | Viewed by 4142

Abstract

Cognition is a crucial element of human functionality. Like any other physical capability, cognition is both enabled and limited by tissue biology. The aim of this study was to investigate whether oxygen is a rate-limiting factor for any of the main cognitive domains [...] Read more.

Cognition is a crucial element of human functionality. Like any other physical capability, cognition is both enabled and limited by tissue biology. The aim of this study was to investigate whether oxygen is a rate-limiting factor for any of the main cognitive domains in healthy young individuals. Fifty-six subjects were randomly assigned to either increased oxygen supply using hyperbaric oxygen (two atmospheres of 100% oxygen) or to a “sham” treatment (a simulation of increased pressure in a chamber with normal air). While in the chamber, participants went through a battery of tests evaluating the major cognitive domains including information processing speed, episodic memory, working memory, cognitive flexibility, and attention. The results demonstrated that from all evaluated cognitive domains, a statistically significant improvement was found in the episodic memory of the hyper-oxygenized group. The hyper-oxygenized group demonstrated a better learning curve and a higher resilience to interference. To conclude, oxygen delivery is a rate-limiting factor for memory function even in healthy young individuals under normal conditions. Understanding the biological limitations of our cognitive functions is important for future development of interventional tools that can be used in daily clinical practice. Full article

(This article belongs to the Special Issue Oxygen Therapy)

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35 pages, 1893 KiB

Open AccessReview

Extracellular Vesicles as Nanotherapeutics for Parkinson’s Disease

by Loredana Leggio, Greta Paternò, Silvia Vivarelli, Francesca L’Episcopo, Cataldo Tirolo, Gabriele Raciti, Fabrizio Pappalardo, Carmela Giachino, Salvatore Caniglia, Maria Francesca Serapide, Bianca Marchetti and Nunzio Iraci

Biomolecules 2020, 10(9), 1327; https://doi.org/10.3390/biom10091327 - 16 Sep 2020

Cited by 20 | Viewed by 5648

Abstract

Extracellular vesicles (EVs) are naturally occurring membranous structures secreted by normal and diseased cells, and carrying a wide range of bioactive molecules. In the central nervous system (CNS), EVs are important in both homeostasis and pathology. Through receptor–ligand interactions, direct fusion, or endocytosis, [...] Read more.

Extracellular vesicles (EVs) are naturally occurring membranous structures secreted by normal and diseased cells, and carrying a wide range of bioactive molecules. In the central nervous system (CNS), EVs are important in both homeostasis and pathology. Through receptor–ligand interactions, direct fusion, or endocytosis, EVs interact with their target cells. Accumulating evidence indicates that EVs play crucial roles in the pathogenesis of many neurodegenerative disorders (NDs), including Parkinson′s disease (PD). PD is the second most common ND, characterized by the progressive loss of dopaminergic (DAergic) neurons within the Substantia Nigra pars compacta (SNpc). In PD, EVs are secreted by both neurons and glial cells, with either beneficial or detrimental effects, via a complex program of cell-to-cell communication. The functions of EVs in PD range from their etiopathogenetic relevance to their use as diagnostic tools and innovative carriers of therapeutics. Because they can cross the blood–brain barrier, EVs can be engineered to deliver bioactive molecules (e.g., small interfering RNAs, catalase) within the CNS. This review summarizes the latest findings regarding the role played by EVs in PD etiology, diagnosis, prognosis, and therapy, with a particular focus on their use as novel PD nanotherapeutics. Full article

(This article belongs to the Special Issue Potential Molecular Targets for Disease—Modifying Therapeutic Strategies in Parkinson’s Disease)

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17 pages, 12871 KiB

Open AccessArticle

Isolation of Cysteine-Rich Peptides from Citrullus colocynthis

by Behzad Shahin-Kaleybar, Ali Niazi, Alireza Afsharifar, Ghorbanali Nematzadeh, Reza Yousefi, Bernhard Retzl, Roland Hellinger, Edin Muratspahić and Christian W. Gruber

Biomolecules 2020, 10(9), 1326; https://doi.org/10.3390/biom10091326 - 16 Sep 2020

Cited by 5 | Viewed by 3988

Abstract

The plant Citrullus colocynthis, a member of the squash (Cucurbitaceae) family, has a long history in traditional medicine. Based on the ancient knowledge about the healing properties of herbal preparations, plant-derived small molecules, e.g., salicylic acid, or quinine, have been integral to [...] Read more.

The plant Citrullus colocynthis, a member of the squash (Cucurbitaceae) family, has a long history in traditional medicine. Based on the ancient knowledge about the healing properties of herbal preparations, plant-derived small molecules, e.g., salicylic acid, or quinine, have been integral to modern drug discovery. Additionally, many plant families, such as Cucurbitaceae, are known as a rich source for cysteine-rich peptides, which are gaining importance as valuable pharmaceuticals. In this study, we characterized the C. colocynthis peptidome using chemical modification of cysteine residues, and mass shift analysis via matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry. We identified the presence of at least 23 cysteine-rich peptides in this plant, and eight novel peptides, named citcol-1 to -8, with a molecular weight between ~3650 and 4160 Da, were purified using reversed-phase high performance liquid chromatography (HPLC), and their amino acid sequences were determined by de novo assignment of b- and y-ion series of proteolytic peptide fragments. In silico analysis of citcol peptides revealed a high sequence similarity to trypsin inhibitor peptides from Cucumis sativus, Momordica cochinchinensis, Momordica macrophylla and Momordica sphaeroidea. Using genome/transcriptome mining it was possible to identify precursor sequences of this peptide family in related Cucurbitaceae species that cluster into trypsin inhibitor and antimicrobial peptides. Based on our analysis, the presence or absence of a crucial Arg/Lys residue at the putative P1 position may be used to classify these common cysteine-rich peptides by functional properties. Despite sequence homology and the common classification into the inhibitor cysteine knot family, these peptides appear to have diverse and additional bioactivities yet to be revealed. Full article

(This article belongs to the Special Issue Enzymatic Inhibitors from Natural Sources: A Huge Collection of New Potential Drugs)

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26 pages, 5039 KiB

Open AccessFeature PaperArticle

Regulation of Poly(ADP-Ribose) Polymerase 1 Activity by Y-Box-Binding Protein 1

by Konstantin N. Naumenko, Mariya V. Sukhanova, Loic Hamon, Tatyana A. Kurgina, Elizaveta E. Alemasova, Mikhail M. Kutuzov, David Pastré and Olga I. Lavrik

Biomolecules 2020, 10(9), 1325; https://doi.org/10.3390/biom10091325 - 16 Sep 2020

Cited by 19 | Viewed by 3034

Abstract

Y-box-binding protein 1 (YB-1) is a multifunctional positively charged protein that interacts with DNA or RNA and poly(ADP-ribose) (PAR). YB-1 is poly(ADP-ribosyl)ated and stimulates poly(ADP-ribose) polymerase 1 (PARP1) activity. Here, we studied the mechanism of YB-1-dependent PAR synthesis by PARP1 in vitro using [...] Read more.

Y-box-binding protein 1 (YB-1) is a multifunctional positively charged protein that interacts with DNA or RNA and poly(ADP-ribose) (PAR). YB-1 is poly(ADP-ribosyl)ated and stimulates poly(ADP-ribose) polymerase 1 (PARP1) activity. Here, we studied the mechanism of YB-1-dependent PAR synthesis by PARP1 in vitro using biochemical and atomic force microscopy assays. PAR synthesis activity of PARP1 is known to be facilitated by co-factors such as Mg²⁺. However, in contrast to an Mg²⁺-dependent reaction, the activation of PARP1 by YB-1 is accompanied by overall up-regulation of protein PARylation and shortening of the PAR polymer. Therefore, YB-1 and cation co-factors stimulated PAR synthesis in divergent ways. PARP1 autoPARylation in the presence of YB-1 as well as trans-PARylation of YB-1 are greatly affected by the type of damaged DNA, suggesting that PARP1 activation depends on the formation of a PARP1–YB-1–DNA ternary complex. An unstructured C-terminal part of YB-1 involved in an interaction with PAR behaves similarly to full-length YB-1, indicating that both DNA and PAR binding are involved in the stimulation of PARP1 activity by YB-1. Thus, YB-1 is likely linked to the regulation of PARylation events in cells via an interaction with PAR and damaged DNA. Full article

(This article belongs to the Special Issue DNA Damage Response)

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18 pages, 510 KiB

Open AccessReview

Inflammation in Obesity-Related Complications in Children: The Protective Effect of Diet and Its Potential Role as a Therapeutic Agent

by Valeria Calcaterra, Corrado Regalbuto, Debora Porri, Gloria Pelizzo, Emanuela Mazzon, Federica Vinci, Gianvincenzo Zuccotti, Valentina Fabiano and Hellas Cena

Biomolecules 2020, 10(9), 1324; https://doi.org/10.3390/biom10091324 - 16 Sep 2020

Cited by 43 | Viewed by 4984

Abstract

Obesity is a growing health problem in both children and adults, impairing physical and mental state and impacting health care system costs in both developed and developing countries. It is well-known that individuals with excessive weight gain frequently develop obesity-related complications, which are [...] Read more.

Obesity is a growing health problem in both children and adults, impairing physical and mental state and impacting health care system costs in both developed and developing countries. It is well-known that individuals with excessive weight gain frequently develop obesity-related complications, which are mainly known as Non-Communicable Diseases (NCDs), including cardiovascular disease, type 2 diabetes mellitus, metabolic syndrome, non-alcoholic fatty liver disease, hypertension, hyperlipidemia and many other risk factors proven to be associated with chronic inflammation, causing disability and reduced life expectancy. This review aims to present and discuss complications related to inflammation in pediatric obesity, the critical role of nutrition and diet in obesity-comorbidity prevention and treatment, and the impact of lifestyle. Appropriate early dietary intervention for the management of pediatric overweight and obesity is recommended for overall healthy growth and prevention of comorbidities in adulthood. Full article

(This article belongs to the Special Issue Therapeutic or Preventive Potential of Dietary Compounds in the Inflammatory Response)

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