Molecules

17 pages, 21039 KiB

Open AccessFeature PaperArticle

Evaluation of Self-Assembly Pathways to Control Crystallization-Driven Self-Assembly of a Semicrystalline P(VDF-co-HFP)-b-PEG-b-P(VDF-co-HFP) Triblock Copolymer

by Enrique Folgado, Matthias Mayor, Vincent Ladmiral and Mona Semsarilar

Molecules 2020, 25(17), 4033; https://doi.org/10.3390/molecules25174033 - 3 Sep 2020

Cited by 7 | Viewed by 3522

Abstract

To date, amphiphilic block copolymers (BCPs) containing poly(vinylidene fluoride-co-hexafluoropropene) (P(VDF-co-HFP)) copolymers are rare. At moderate content of HFP, this fluorocopolymer remains semicrystalline and is able to crystallize. Amphiphilic BCPs, containing a P(VDF-co-HFP) segment could, thus be appealing for the [...] Read more.

To date, amphiphilic block copolymers (BCPs) containing poly(vinylidene fluoride-co-hexafluoropropene) (P(VDF-co-HFP)) copolymers are rare. At moderate content of HFP, this fluorocopolymer remains semicrystalline and is able to crystallize. Amphiphilic BCPs, containing a P(VDF-co-HFP) segment could, thus be appealing for the preparation of self-assembled block copolymer morphologies through crystallization-driven self-assembly (CDSA) in selective solvents. Here the synthesis, characterization by ¹H and ¹⁹F NMR spectroscopies, GPC, TGA, DSC, and XRD; and the self-assembly behavior of a P(VDF-co-HFP)-b-PEG-b-P(VDF-co-HFP) triblock copolymer were studied. The well-defined ABA amphiphilic fluorinated triblock copolymer was self-assembled into nano-objects by varying a series of key parameters such as the solvent and the non -solvent, the self-assembly protocols, and the temperature. A large range of morphologies such as spherical, square, rectangular, fiber-like, and platelet structures with sizes ranging from a few nanometers to micrometers was obtained depending on the self-assembly protocols and solvents systems used. The temperature-induced crystallization-driven self-assembly (TI-CDSA) protocol allowed some control over the shape and size of some of the morphologies. Full article

(This article belongs to the Special Issue Organofluorine Chemistry)

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Normalized SEC chromatograms (viscometer detector) of P(VDF-co-HFP)-XA (black trace), PEGDA (red trace), P(VDF-co-HFP)-b-PEG-b-P(VDF-co-HFP) (blue trace), and chemical structure of the precursor polymers and final triblock copolymer. Full article ">Figure 2
TEM images of the P(VDF-co-HFP)-b-PEG-b-P(VDF-co-HFP) triblock copolymer aggregates formed by thin-film rehydration with water after one week in pure water. Images (a) and (b) show the aggregates at two different magnifications. Full article ">Figure 3
TEM images of self-assembled structures obtained by micellization of 1 mg mL−1 solutions of the P(VDF-co-HFP)-b-PEG-b-P(VDF-co-HFP) triblock copolymer in (a) DMF, (b) acetone, employing ethanol as a selective solvent for PEG; and (c) DMF, (d) acetone, employing water as the selective solvent for PEG. Final concentration of all samples = 0.14 mg mL−1, solvent: selective solvent final ratio = 1:6. Full article ">Figure 4
TEM images of self-assembled structures obtained by nanoprecipitation of 1 mg mL−1 solutions of the P(VDF-co-HFP)-b-PEG-b-P(VDF-co-HFP) triblock copolymer in: (a) DMF, (b) acetone, (c) THF, employing ethanol as the selective solvent for PEG and (d) DMF, (e) acetone, (f) THF, employing water as the selective solvent for PEG. Final concentration of all samples = 0.09 mg mL−1. Solvent: selective-solvent final ratio = 1:10. Full article ">Figure 5
TEM images of the self-assembled structures obtained after micellization and thermal annealing: Images (a–c) correspond to samples 3a, 3c, and 3d, respectively. Full article ">Figure 6
TEM images of self-assembled P(VDF-co-HFP)-b-PEG-b-P(VDF-co-HFP) triblock copolymer using nanoprecipitation in octanol from a 1 mg mL−1 THF solution: (a) Final concentration 0.1 mg mL−1. The solution was heated to 180 °C for 1 h and slowly cooled down to room temperature. Structures observed after: (b) 0 h, (c,d) 12 h, and (e,f) one week. Full article ">Scheme 1
Synthesis of P(VDF-co-HFP) copolymer by RAFT. Full article ">

27 pages, 1355 KiB

Open AccessReview

Ethiopian Medicinal Plants Traditionally Used for the Treatment of Cancer, Part 2: A Review on Cytotoxic, Antiproliferative, and Antitumor Phytochemicals, and Future Perspective

by Solomon Tesfaye, Kaleab Asres, Ermias Lulekal, Yonatan Alebachew, Eyael Tewelde, Mallika Kumarihamy and Ilias Muhammad

Molecules 2020, 25(17), 4032; https://doi.org/10.3390/molecules25174032 - 3 Sep 2020

Cited by 13 | Viewed by 5439

Abstract

This review provides an overview on the active phytochemical constituents of medicinal plants that are traditionally used to manage cancer in Ethiopia. A total of 119 articles published between 1968 and 2020 have been reviewed, using scientific search engines such as ScienceDirect, PubMed, [...] Read more.

This review provides an overview on the active phytochemical constituents of medicinal plants that are traditionally used to manage cancer in Ethiopia. A total of 119 articles published between 1968 and 2020 have been reviewed, using scientific search engines such as ScienceDirect, PubMed, and Google Scholar. Twenty-seven medicinal plant species that belong to eighteen families are documented along with their botanical sources, potential active constituents, and in vitro and in vivo activities against various cancer cells. The review is compiled and discusses the potential anticancer, antiproliferative, and cytotoxic agents based on the types of secondary metabolites, such as terpenoids, phenolic compounds, alkaloids, steroids, and lignans. Among the anticancer secondary metabolites reported in this review, only few have been isolated from plants that are originated and collected in Ethiopia, and the majority of compounds are reported from plants belonging to different areas of the world. Thus, based on the available bioactivity reports, extensive and more elaborate ethnopharmacology-based bioassay-guided studies have to be conducted on selected traditionally claimed Ethiopian anticancer plants, which inherited from a unique and diverse landscape, with the aim of opening a way forward to conduct anticancer drug discovery program. Full article

(This article belongs to the Special Issue Special Issue in Honor of Professor James D. McChesney on the Occasion of his 80th Birthday)

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31 pages, 5989 KiB

Open AccessReview

Peptidyl Fluoromethyl Ketones and Their Applications in Medicinal Chemistry

by Andrea Citarella and Nicola Micale

Molecules 2020, 25(17), 4031; https://doi.org/10.3390/molecules25174031 - 3 Sep 2020

Cited by 24 | Viewed by 5276

Abstract

Peptidyl fluoromethyl ketones occupy a pivotal role in the current scenario of synthetic chemistry, thanks to their numerous applications as inhibitors of hydrolytic enzymes. The insertion of one or more fluorine atoms adjacent to a C-terminal ketone moiety greatly modifies the physicochemical [...] Read more.

Peptidyl fluoromethyl ketones occupy a pivotal role in the current scenario of synthetic chemistry, thanks to their numerous applications as inhibitors of hydrolytic enzymes. The insertion of one or more fluorine atoms adjacent to a C-terminal ketone moiety greatly modifies the physicochemical properties of the overall substrate, especially by increasing the reactivity of this functionalized carbonyl group toward nucleophiles. The main application of these peptidyl α-fluorinated ketones in medicinal chemistry relies in their ability to strongly and selectively inhibit serine and cysteine proteases. These compounds can be used as probes to study the proteolytic activity of the aforementioned proteases and to elucidate their role in the insurgence and progress on several diseases. Likewise, if the fluorinated methyl ketone moiety is suitably connected to a peptidic backbone, it may confer to the resulting structure an excellent substrate peculiarity and the possibility of being recognized by a specific subclass of human or pathogenic proteases. Therefore, peptidyl fluoromethyl ketones are also currently highly exploited for the target-based design of compounds for the treatment of topical diseases such as various types of cancer and viral infections. Full article

(This article belongs to the Section Medicinal Chemistry)

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19 pages, 9056 KiB

Open AccessArticle

Construction of Molecular Model and Adsorption of Collectors on Bulianta Coal

by He Zhang, Peng Xi, Qiming Zhuo and Wenli Liu

Molecules 2020, 25(17), 4030; https://doi.org/10.3390/molecules25174030 - 3 Sep 2020

Cited by 17 | Viewed by 2979

Abstract

To study the effects of different oxygen functional groups on the quality of flotation clean low-rank coal, two kinds of collectors with different oxygen-containing functional groups, methyl laurate, and dodecanol, were selected and their flotation behaviors were investigated. The Bulianta coal was the [...] Read more.

To study the effects of different oxygen functional groups on the quality of flotation clean low-rank coal, two kinds of collectors with different oxygen-containing functional groups, methyl laurate, and dodecanol, were selected and their flotation behaviors were investigated. The Bulianta coal was the typical sub-bituminous coal in China, and the coal molecular model of which was constructed based on proximate analysis, ultimate analysis, ¹³C-NMR, and XPS. The chemical structure model of the coal molecule was optimized, and the periodic boundary condition was added via the method of molecular dynamics methods. The different combined systems formed by collectors, water, and a model surface of Bulianta coal have been studied using molecular dynamics simulation. The simulation results of dodecanol and methyl laurate on the surface of Bulianta coal show that dodecanol molecules are not evenly adsorbed on the surface of coal, and have higher adsorption capacity near carboxyl and hydroxyl groups, but less adsorption capacity near carbonyl and ether bonds. Methyl laurate can completely cover the oxygen-containing functional groups on the coal surface. Compared with dodecanol, methyl laurate can effectively improve the hydrophobicity of the Bulianta coal surface, which is consistent with the results of the XPS test and the flotation test. Full article

(This article belongs to the Special Issue Combined Quantum Mechanical and Molecular Mechanical Methods and Simulations II)

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13 pages, 1641 KiB

Open AccessArticle

On Viscous Flow in Glass-Forming Organic Liquids

by Michael I. Ojovan

Molecules 2020, 25(17), 4029; https://doi.org/10.3390/molecules25174029 - 3 Sep 2020

Cited by 9 | Viewed by 2792

Abstract

The two-exponential Sheffield equation of viscosity η(T) = A₁·T·[1 + A₂·exp(H_m/RT)]·[1 + C·exp(H_d/RT)], where A₁, A₂, H_m, C, and H_m are material-specific constants, is used to analyze the [...] Read more.

The two-exponential Sheffield equation of viscosity η(T) = A₁·T·[1 + A₂·exp(H_m/RT)]·[1 + C·exp(H_d/RT)], where A₁, A₂, H_m, C, and H_m are material-specific constants, is used to analyze the viscous flows of two glass-forming organic materials—salol and α-phenyl-o-cresol. It is demonstrated that the viscosity equation can be simplified to a four-parameter version: η(T) = A·T·exp(H_m/RT)]·[1 + C·exp(H_d/RT)]. The Sheffield model gives a correct description of viscosity, with two exact Arrhenius-type asymptotes below and above the glass transition temperature, whereas near the T_g it gives practically the same results as well-known and widely used viscosity equations. It is revealed that the constants of the Sheffield equation are not universal for all temperature ranges and may need to be updated for very high temperatures, where changes occur in melt properties leading to modifications of A and H_m for both salol and α-phenyl-o-cresol. Full article

(This article belongs to the Special Issue Physical Chemistry of Aqueous Solutions and Glass Forming Systems)

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35 pages, 3248 KiB

Open AccessReview

Interacting Quantum Atoms—A Review

by José Manuel Guevara-Vela, Evelio Francisco, Tomás Rocha-Rinza and Ángel Martín Pendás

Molecules 2020, 25(17), 4028; https://doi.org/10.3390/molecules25174028 - 3 Sep 2020

Cited by 74 | Viewed by 5216

Abstract

The aim of this review is threefold. On the one hand, we intend it to serve as a gentle introduction to the Interacting Quantum Atoms (IQA) methodology for those unfamiliar with it. Second, we expect it to act as an up-to-date reference of [...] Read more.

The aim of this review is threefold. On the one hand, we intend it to serve as a gentle introduction to the Interacting Quantum Atoms (IQA) methodology for those unfamiliar with it. Second, we expect it to act as an up-to-date reference of recent developments related to IQA. Finally, we want it to highlight a non-exhaustive, yet representative set of showcase examples about how to use IQA to shed light in different chemical problems. To accomplish this, we start by providing a brief context to justify the development of IQA as a real space alternative to other existent energy partition schemes of the non-relativistic energy of molecules. We then introduce a self-contained algebraic derivation of the methodological IQA ecosystem as well as an overview of how these formulations vary with the level of theory employed to obtain the molecular wavefunction upon which the IQA procedure relies. Finally, we review the several applications of IQA as examined by different research groups worldwide to investigate a wide variety of chemical problems. Full article

(This article belongs to the Special Issue Electron Density Analysis Tools)

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Regions of definition of the <math display="inline"><semantics> <mrow> <msubsup> <mi>D</mi> <mrow> <msub> <mi>l</mi> <mn>1</mn> </msub> <msub> <mi>m</mi> <mn>1</mn> </msub> </mrow> <mrow> <msub> <mi>l</mi> <mn>2</mn> </msub> <msub> <mi>m</mi> <mn>2</mn> </msub> </mrow> </msubsup> <mrow> <mo stretchy="false">(</mo> <msub> <mi>r</mi> <mn>1</mn> </msub> <mo>,</mo> <msub> <mi>r</mi> <mn>2</mn> </msub> <mo>,</mo> <mi mathvariant="bold-italic">R</mi> <mo stretchy="false">)</mo> </mrow> </mrow> </semantics></math> function. Full article ">Figure 2
Biphenyl representations. Schematic (left) and non-overlapping topological atoms bounded by interatomic surfaces (right). Figure from reference [<a href="#B80-molecules-25-04028" class="html-bibr">80</a>]. Full article ">Figure 3
Interacting quantum atoms (IQA) allows for the individual changes in IQA interaction components accompanying the formation of the different hydrogen bonds. Figure from reference [<a href="#B98-molecules-25-04028" class="html-bibr">98</a>] shows systems with insaturations and intramolecular HBs (a,b), along with their non-conjugated counterparts (c,d). Figure reproduced by permission of the PCCP Owner Societies. Full article ">Figure 4
IQA energy partition of the FBr ⋯ NH<math display="inline"><semantics> <msub> <mrow/> <mn>3</mn> </msub> </semantics></math> complex. (Top) changes intra-atomic energies (red) and intermolecular interactions (classical and exchange terms in blue and green, respectively). (Bottom) Change in interatomic energies within each fragment upon complex formation. Figure reprinted (adapted) with permission from reference [<a href="#B98-molecules-25-04028" class="html-bibr">98</a>]. Copyright 2020 American Chemical Society. Full article ">Figure 5
Diagram representing the changes in the strength of the different bonds. The greens arrows represent bond strengthening/forming and while the red ones bond weakening/breaking. Figure taken from Reference [<a href="#B125-molecules-25-04028" class="html-bibr">125</a>]. Full article ">Figure 6
Atomic volume of one of the congested hydrogen atoms in tetra- cyclododecane at a H...H distance of 2.4 Å (top), the equilibrium distance of 1.831 Å (middle), and 0.5 Å (bottom). Figure taken from reference [<a href="#B141-molecules-25-04028" class="html-bibr">141</a>]. Full article ">Figure 7
Flowchart representing the different stages in the training (first four steps) and execution (DL_POLY) of the, detailing the programs involved and summaries of their tasks. Figure taken from reference [<a href="#B147-molecules-25-04028" class="html-bibr">147</a>]. Full article ">

12 pages, 2789 KiB

Open AccessArticle

IgY Targeting Bacterial Quorum-Sensing Molecules in Implant-Associated Infections

by Ulrike Dapunt, Birgit Prior, Christopher Oelkrug and Jan Philippe Kretzer

Molecules 2020, 25(17), 4027; https://doi.org/10.3390/molecules25174027 - 3 Sep 2020

Cited by 7 | Viewed by 3029

Abstract

Background: Implant-associated infections are still a major complication in the field of orthopedics. Bacteria can form biofilms on implant surfaces, making them more difficult to detect and treat. Since standard antibiotic therapy is often impaired in biofilm infections, particular interest is directed [...] Read more.

Background: Implant-associated infections are still a major complication in the field of orthopedics. Bacteria can form biofilms on implant surfaces, making them more difficult to detect and treat. Since standard antibiotic therapy is often impaired in biofilm infections, particular interest is directed towards finding treatment alternatives. Biofilm-formation is a well-organized process during which bacteria communicate via quorum-sensing molecules (QSM). The aim of this study was to inhibit bacterial communication by directing avian IgY against specific QSM. Methods: Chicken were immunized against the following QSM: (1) AtlE, a member of the autolysin family which mediates attachment to a surface in Staphylococcus epidermidis; (2) GroEL, the bacterial heat shock protein; (3) PIA (polysaccharide intercellular adhesion), which is essential for cell–cell adhesion in biofilms. Staphylococcus epidermidis biofilms were grown and inhibition of biofilm-formation by IgYs was evaluated. Additionally, human osteoblasts were cultivated and biocompatibility of IgYs was tested. Results: We were able to demonstrate that all IgYs reduced biofilm-formation, also without prior immunization. Therefore, the response was probably not specific with regard to the QSM. Osteoblasts were activated by all IgYs which was demonstrated by microscopy and an increased release of IL-8. Conclusions: In conclusion, avian IgY inhibits biofilm-formation, though the underlying mechanism is not yet clear. However, adverse effects on local tissue cells (osteoblasts) were also observed. Full article

(This article belongs to the Special Issue Novel Biologically Active Molecules, Biomaterials and Nanoparticles for the Microbial Biofilm Control in Human Medicine)

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69 pages, 6280 KiB

Open AccessReview

Review of Chromatographic Methods Coupled with Modern Detection Techniques Applied in the Therapeutic Drugs Monitoring (TDM)

by Tomasz Tuzimski and Anna Petruczynik

Molecules 2020, 25(17), 4026; https://doi.org/10.3390/molecules25174026 - 3 Sep 2020

Cited by 70 | Viewed by 9696

Abstract

Therapeutic drug monitoring (TDM) is a tool used to integrate pharmacokinetic and pharmacodynamics knowledge to optimize and personalize various drug therapies. The optimization of drug dosing may improve treatment outcomes, reduce toxicity, and reduce the risk of developing drug resistance. To adequately implement [...] Read more.

Therapeutic drug monitoring (TDM) is a tool used to integrate pharmacokinetic and pharmacodynamics knowledge to optimize and personalize various drug therapies. The optimization of drug dosing may improve treatment outcomes, reduce toxicity, and reduce the risk of developing drug resistance. To adequately implement TDM, accurate and precise analytical procedures are required. In clinical practice, blood is the most commonly used matrix for TDM; however, less invasive samples, such as dried blood spots or non-invasive saliva samples, are increasingly being used. The choice of sample preparation method, type of column packing, mobile phase composition, and detection method is important to ensure accurate drug measurement and to avoid interference from matrix effects and drug metabolites. Most of the reported procedures used liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) techniques due to its high selectivity and sensitivity. High-performance chromatography with ultraviolet detection (HPLC-UV) methods are also used when a simpler and more cost-effective methodology is desired for clinical monitoring. The application of high-performance chromatography with fluorescence detection (HPLC-FLD) with and without derivatization processes and high-performance chromatography with electrochemical detection (HPLC-ED) techniques for the analysis of various drugs in biological samples for TDM have been described less often. Before chromatographic analysis, samples were pretreated by various procedures—most often by protein precipitation, liquid–liquid extraction, and solid-phase extraction, rarely by microextraction by packed sorbent, dispersive liquid–liquid microextraction. The aim of this article is to review the recent literature (2010–2020) regarding the use of liquid chromatography with various detection techniques for TDM. Full article

(This article belongs to the Special Issue Theme Issue Honoring Professor Dr. Bogusław Buszewski on His 70th Birthday:"Separation Sciences & Related Techniques")

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25 pages, 8035 KiB

Open AccessFeature PaperArticle

Mechanistic Insights into the Chaperoning of Human Lysosomal-Galactosidase Activity: Highly Functionalized Aminocyclopentanes and C-5a-Substituted Derivatives of 4-epi-Isofagomine

by Patrick Weber, Martin Thonhofer, Summer Averill, Gideon J. Davies, Andres Gonzalez Santana, Philipp Müller, Seyed A. Nasseri, Wendy A. Offen, Bettina M. Pabst, Eduard Paschke, Michael Schalli, Ana Torvisco, Marion Tschernutter, Christina Tysoe, Werner Windischhofer, Stephen G. Withers, Andreas Wolfsgruber, Tanja M. Wrodnigg and Arnold E. Stütz

Molecules 2020, 25(17), 4025; https://doi.org/10.3390/molecules25174025 - 3 Sep 2020

Cited by 7 | Viewed by 3405

Abstract

Glycosidase inhibitors have shown great potential as pharmacological chaperones for lysosomal storage diseases. In light of this, a series of new cyclopentanoid β-galactosidase inhibitors were prepared and their inhibitory and pharmacological chaperoning activities determined and compared with those of lipophilic analogs of the [...] Read more.

Glycosidase inhibitors have shown great potential as pharmacological chaperones for lysosomal storage diseases. In light of this, a series of new cyclopentanoid β-galactosidase inhibitors were prepared and their inhibitory and pharmacological chaperoning activities determined and compared with those of lipophilic analogs of the potent β-d-galactosidase inhibitor 4-epi-isofagomine. Structure-activity relationships were investigated by X-ray crystallography as well as by alterations in the cyclopentane moiety such as deoxygenation and replacement by fluorine of a “strategic” hydroxyl group. New compounds have revealed highly promising activities with a range of β-galactosidase-compromised human cell lines and may serve as leads towards new pharmacological chaperones for G_M1-gangliosidosis and Morquio B disease. Full article

(This article belongs to the Special Issue Targeting Carbohydrate–Protein Interactions)

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21 pages, 6860 KiB

Open AccessArticle

Qualitative and Quantitative Study of Glycosphingolipids in Human Milk and Bovine Milk Using High Performance Liquid Chromatography–Data-Dependent Acquisition–Mass Spectrometry

by Lin Ma, Bertram Y. Fong, Alastair K. H. MacGibbon and Gillian Norris

Molecules 2020, 25(17), 4024; https://doi.org/10.3390/molecules25174024 - 3 Sep 2020

Cited by 11 | Viewed by 3008

Abstract

Cerebrosides (Crb; including glucosylceramide and galactosylceramide) and lactosylceramide (LacCer) are structurally complex lipids found in many eukaryotic cell membranes, where they play important roles in cell growth, apoptosis, cell recognition and signaling. They are also found in mammalian milk as part of the [...] Read more.

Cerebrosides (Crb; including glucosylceramide and galactosylceramide) and lactosylceramide (LacCer) are structurally complex lipids found in many eukaryotic cell membranes, where they play important roles in cell growth, apoptosis, cell recognition and signaling. They are also found in mammalian milk as part of the milk fat globule membrane (MFGM), making milk an important dietary component for the rapidly growing infant. This study reports the development of a robust analytical method for the identification and characterization of 44 Crb and 23 LacCer molecular species in milk, using high performance liquid chromatography–tandem mass spectrometry in data-dependent acquisition mode. For the first time, it also compares the distributions of these species in human and bovine milks, a commercial MFGM-enriched dairy ingredient (MFGM Lipid 100) and commercial standards purified from bovine milk. A method for quantifying Crb and LacCer in milk using mass spectrometry in neutral loss scan mode was developed and validated for human milk, bovine milk and MFGM Lipid 100. Human milk was found to contain approximately 9.9–17.4 µg Crb/mL and 1.3–3.0 µg LacCer/mL, whereas bovine milk (pooled milk from a Friesian herd) contained 9.8–12.0 and 14.3–16.2 µg/mL of these lipids, respectively. The process used to produce MFGM Lipid 100 was shown to have enriched these components to 448 and 1036 µg/g, respectively. No significant changes in the concentrations of both Crb and LacCer were observed during lactation. Full article

(This article belongs to the Special Issue Analytical Methods in Milk and Dairy Products: Focus on Functional Compounds)

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23 pages, 8252 KiB

Open AccessFeature PaperArticle

Spatial Metagenomics of Three Geothermal Sites in Pisciarelli Hot Spring Focusing on the Biochemical Resources of the Microbial Consortia

by Roberta Iacono, Beatrice Cobucci-Ponzano, Federica De Lise, Nicola Curci, Luisa Maurelli, Marco Moracci and Andrea Strazzulli

Molecules 2020, 25(17), 4023; https://doi.org/10.3390/molecules25174023 - 3 Sep 2020

Cited by 13 | Viewed by 3633

Abstract

Terrestrial hot springs are of great interest to the general public and to scientists alike due to their unique and extreme conditions. These have been sought out by geochemists, astrobiologists, and microbiologists around the globe who are interested in their chemical properties, which [...] Read more.

Terrestrial hot springs are of great interest to the general public and to scientists alike due to their unique and extreme conditions. These have been sought out by geochemists, astrobiologists, and microbiologists around the globe who are interested in their chemical properties, which provide a strong selective pressure on local microorganisms. Drivers of microbial community composition in these springs include temperature, pH, in-situ chemistry, and biogeography. Microbes in these communities have evolved strategies to thrive in these conditions by converting hot spring chemicals and organic matter into cellular energy. Following our previous metagenomic analysis of Pisciarelli hot springs (Naples, Italy), we report here the comparative metagenomic study of three novel sites, formed in Pisciarelli as result of recent geothermal activity. This study adds comprehensive information about phylogenetic diversity within Pisciarelli hot springs by peeking into possible mechanisms of adaptation to biogeochemical cycles, and high applicative potential of the entire set of genes involved in the carbohydrate metabolism in this environment (CAZome). This site is an excellent model for the study of biodiversity on Earth and biosignature identification, and for the study of the origin and limits of life. Full article

(This article belongs to the Special Issue From Molecules to Origin of Life: The Astrobiology Network)

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18 pages, 3659 KiB

Open AccessFeature PaperArticle

Colorimetry of Luminescent Lanthanide Complexes

by Julien Andres and Anne-Sophie Chauvin

Molecules 2020, 25(17), 4022; https://doi.org/10.3390/molecules25174022 - 3 Sep 2020

Cited by 9 | Viewed by 3596

Abstract

Europium, terbium, dysprosium, and samarium are the main trivalent lanthanide ions emitting in the visible spectrum. In this work, the potential of these ions for colorimetric applications and colour reproduction was studied. The conversion of spectral data to colour coordinates was undertaken for [...] Read more.

Europium, terbium, dysprosium, and samarium are the main trivalent lanthanide ions emitting in the visible spectrum. In this work, the potential of these ions for colorimetric applications and colour reproduction was studied. The conversion of spectral data to colour coordinates was undertaken for three sets of Ln complexes composed of different ligands. We showed that Eu is the most sensitive of the visible Ln ions, regarding ligand-induced colour shifts, due to its hypersensitive transition. Further investigation on the spectral bandwidth of the emission detector, on the wavelengths’ accuracy, on the instrumental correction function, and on the use of incorrect intensity units confirm that the instrumental correction function is the most important spectrophotometric parameter to take into account in order to produce accurate colour values. Finally, we established and discussed the entire colour range (gamut) that can be generated by combining a red-emitting Eu complex with a green-emitting Tb complex and a blue fluorescent compound. The importance of choosing a proper white point is demonstrated. The potential of using different sets of complexes with different spectral fingerprints in order to obtain metameric colours suitable for anti-counterfeiting is also highlighted. This work answers many questions that could arise during a colorimetric analysis of luminescent probes. Full article

(This article belongs to the Special Issue Luminescent Lanthanide Complexes)

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Full article ">Figure 1
Spectral data in normalised counts per second (measured) and final cropped relative spectral irradiances (processed) for the 3 series of complexes. Full article ">Figure 2
Chromaticity diagrams CIE-xy (a) and CIE 1976 UCS (b) of the 3 series of Ln complexes (circle = dipic, square = Lc2, diamond = do3a) with the blue fluorescent colours of [Lu2(Lc2)3], D65 and E illuminants and the Planckian locus showing the colours of black body radiations from 1000 K to ∞. Full article ">Figure 3
(a) Simulated relative spectral irradiances for broadened Ln spectra (Gaussian function with σ = 10 nm) and (b) corresponding colours (crosses) compared to the colours obtained from the original spectrum shown in <a href="#molecules-25-04022-f001" class="html-fig">Figure 1</a> (squares). Full article ">Figure 4
Miscalibration effects on the UCS of the [Ln2(Lc2)3] series for unapplied instrumental correction function (red circles), wavelength shifts of ±2.5 nm (magenta triangles), and spectral data in normalised photon counts (blue diamonds) compared to the correct values (black squares). Full article ">Figure 5
(a–c) Relative spectral irradiances of the tested R, G, and B primaries and (d) resulting (1; 1; 1) white points on the UCS insert for the N white points of the dipic (circle), Lc2 (square), and do3a (diamond) series. Full article ">Figure 6
CIELAB projection of the full 3-D gamuts onto the a*b* plane for different white points (N, E, D65) of the dipic series. Full article ">Figure 7
(a) CIELAB projection of the full 3-D gamuts (sRGB —, dipic ·····, Lc2 – – –, do3a – · – ·) onto the a*b* plane for the three series of Ln complexes with primaries combining to a D65 white point, and (b) corresponding hue cuts in CIELCh (cylindrical representation of CIELAB). Full article ">Figure 7 Cont.
(a) CIELAB projection of the full 3-D gamuts (sRGB —, dipic ·····, Lc2 – – –, do3a – · – ·) onto the a*b* plane for the three series of Ln complexes with primaries combining to a D65 white point, and (b) corresponding hue cuts in CIELCh (cylindrical representation of CIELAB). Full article ">Figure 8
(a) Overlapping gamuts of the dipic and Lc2 sets with the white points matched to have the same luminance Y and to have the same chromaticity as a D65 illuminant. (b) Corresponding white relative spectral irradiances where all the primaries of the Lc2 set were scaled by a factor of 0.6989 in order to match the luminance of the dipic white spectrum. Full article ">Scheme 1
Structure of dipicolinic acid (H2dipic) of the helicate ligand (H2Lc2) and of the do3a ligand (H3do3a-c) forming 1:3, 2:3, and 1:1 (Ln/L) complexes with a D3h, D3, and C4v symmetry around the Ln ion, respectively (Δ enantiomer shown). Full article ">

10 pages, 4056 KiB

Open AccessArticle

Enhancing the Performance of Dye Sensitized Solar Cells Using Silver Nanoparticles Modified Photoanode

by Faizah Saadmim, Taseen Forhad, Ahmed Sikder, William Ghann, Meser M. Ali, Viji Sitther, A. J. Saleh Ahammad, Md. Abdus Subhan and Jamal Uddin

Molecules 2020, 25(17), 4021; https://doi.org/10.3390/molecules25174021 - 3 Sep 2020

Cited by 26 | Viewed by 4217

Abstract

In this study, silver nanoparticles were synthesized, characterized, and applied to a dye-sensitized solar cell (DSSC) to enhance the efficiency of solar cells. The synthesized silver nanoparticles were characterized with UV–Vis spectroscopy, dynamic light scattering, transmission electron microscopy, and field emission scanning electron [...] Read more.

In this study, silver nanoparticles were synthesized, characterized, and applied to a dye-sensitized solar cell (DSSC) to enhance the efficiency of solar cells. The synthesized silver nanoparticles were characterized with UV–Vis spectroscopy, dynamic light scattering, transmission electron microscopy, and field emission scanning electron microscopy. The silver nanoparticles infused titanium dioxide film was also characterized by Fourier transform infrared and Raman spectroscopy. The performance of DSSC fabricated with silver nanoparticle-modified photoanode was compared with that of a control group. The current and voltage characteristics of the devices as well as the electrochemical impedance measurements were also carried out to assess the performance of the fabricated solar cells. The solar-to-electric efficiency of silver nanoparticles based DSSC was 1.76%, which is quite remarkable compared to the 0.98% realized for DSSC fabricated without silver nanoparticles. Full article

(This article belongs to the Special Issue Photosensitizer: Design, Characteriazation and Application)

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14 pages, 1932 KiB

Open AccessFeature PaperArticle

Unveiling the Differential Antioxidant Activity of Maslinic Acid in Murine Melanoma Cells and in Rat Embryonic Healthy Cells Following Treatment with Hydrogen Peroxide

by Khalida Mokhtari, Amalia Pérez-Jiménez, Leticia García-Salguero, José A. Lupiáñez and Eva E. Rufino-Palomares

Molecules 2020, 25(17), 4020; https://doi.org/10.3390/molecules25174020 - 3 Sep 2020

Cited by 22 | Viewed by 2716

Abstract

Maslinic acid (MA) is a natural triterpene from Olea europaea L. with multiple biological properties. The aim of the present study was to examine MA’s effect on cell viability (by the MTT assay), reactive oxygen species (ROS levels, by flow cytometry) and key [...] Read more.

Maslinic acid (MA) is a natural triterpene from Olea europaea L. with multiple biological properties. The aim of the present study was to examine MA’s effect on cell viability (by the MTT assay), reactive oxygen species (ROS levels, by flow cytometry) and key antioxidant enzyme activities (by spectrophotometry) in murine skin melanoma (B16F10) cells compared to those on healthy cells (A10). MA induced cytotoxic effects in cancer cells (IC₅₀ 42 µM), whereas no effect was found in A10 cells treated with MA (up to 210 µM). In order to produce a stress situation in cells, 0.15 mM H₂O₂ was added. Under stressful conditions, MA protected both cell lines against oxidative damage, decreasing intracellular ROS, which were higher in B16F10 than in A10 cells. The treatment with H₂O₂ and without MA produced different responses in antioxidant enzyme activities depending on the cell line. In A10 cells, all the enzymes were up-regulated, but in B16F10 cells, only superoxide dismutase, glutathione S-transferase and glutathione peroxidase increased their activities. MA restored the enzyme activities to levels similar to those in the control group in both cell lines, highlighting that in A10 cells, the highest MA doses induced values lower than control. Overall, these findings demonstrate the great antioxidant capacity of MA. Full article

(This article belongs to the Special Issue Anticancer Properties of Natural and Derivative Products)

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Schedule chemical structure of maslinic acid from pomace olive (Olea europaea L.) (PubChem). Full article ">Figure 2
Cytotoxicity curves of maslinic acid (MA) for B16F10 murine melanoma cells (A) and A10 rat embryonic healthy cells (B) and of hydrogen peroxide (H2O2) for B16F10 murine melanoma cells (C) and A10 rat embryonic healthy cells (D). Cell proliferation was determined by the MTT assay. Values are expressed as means ± SEM (n = 9). Full article ">Figure 3
Positive fluorescent Rh123 on B16F10 cells (A) and A10 cells (B) with (+) or without (−) H2O2 and MA treatment at different doses: IC50/4, IC50/2, IC50 and 2·IC50 (10.6, 21.6, 42.3 and 84.6 μM, respectively). Values are expressed as means ± SEM (n = 9). Different letters indicate significant differences (p < 0.05). Full article ">Figure 4
Effect of different maslinic acid doses—IC50/4, IC50/2, IC50 and 2·IC50 (10.6, 21.6, 42.3 and 84.6 μM, respectively)—on the specific activity of superoxide dismutase (SOD) in cancer cells, B16F10 (A), and normal cells, A10 (B), and glutathione S-transferase (GST) in cancer cells, B16F10 (C), and normal cells, A10 (D), subjected to the presence of hydrogen peroxide. Symbols (+) and (−) indicate the presence or absence of incubation with H2O2, respectively. Enzyme activities (U or mU × mg protein−1) are expressed as means ± SEM (n = 9). Different letters indicate significant differences (p < 0.05). Full article ">Figure 5
Effect of different maslinic acid doses—IC50/4, IC50/2, IC50 and 2·IC50 (10.6, 21.6, 42.3 and 84.6 μM, respectively)—on the specific activity of catalase (CAT) in cancer cells, B16F10 (A), and normal cells, A10 (B), and glucose 6-phosphate dehydrogenase (G6PDH) in cancer cells, B16F10 (C), and normal cells, A10 (D), subjected to the presence of hydrogen peroxide. Symbols (+) and (−) indicate the presence or absence of incubation with H2O2, respectively. Enzyme activities (U or mU × mg protein−1) are expressed as means ± SEM (n = 9). Different letters indicate significant differences (p < 0.05). Full article ">Figure 6
Effect of different maslinic acid doses—IC50/4, IC50/2, IC50 and 2·IC50 (10.6, 21.6, 42.3 and 84.6 μM, respectively)—on the specific activity of glutathione peroxidase (GPX) in cancer cells, B16F10 (A), and normal cells, A10 (B), and glutathione reductase (GR) in cancer cells, B16F10 (C), and normal cells, A10 (D), subjected to the presence of hydrogen peroxide. Symbols (+) and (−) indicate the presence or absence of incubation with H2O2, respectively. Enzyme activity (mU × mg protein−1) is expressed as means ± SEM (n = 9). Different letters indicate significant differences (p < 0.05) Full article ">

29 pages, 1454 KiB

Open AccessReview

A Review of the Ethnomedicinal Uses, Biological Activities, and Triterpenoids of Euphorbia Species

by Douglas Kemboi, Xolani Peter, Moses Langat and Jacqueline Tembu

Molecules 2020, 25(17), 4019; https://doi.org/10.3390/molecules25174019 - 3 Sep 2020

Cited by 62 | Viewed by 6988

Abstract

The genus Euphorbia is one of the largest genera in the spurge family, with diversity in range, distribution, and morphology. The plant species in this genus are widely used in traditional medicine for the treatment of diseases, ranging from respirational infections, body and [...] Read more.

The genus Euphorbia is one of the largest genera in the spurge family, with diversity in range, distribution, and morphology. The plant species in this genus are widely used in traditional medicine for the treatment of diseases, ranging from respirational infections, body and skin irritations, digestion complaints, inflammatory infections, body pain, microbial illness, snake or scorpion bites, pregnancy, as well as sensory disorders. Their successes have been attributed to the presence of diverse phytochemicals like polycyclic and macrocyclic diterpenes with various pharmacological properties. As a result, Euphorbia diterpenes are of interest to chemists and biochemists with regard to drug discovery from natural products due to their diverse therapeutic applications as well as their great structural diversity. Other chemical constituents such as triterpenoids have also been reported to possess various pharmacological properties, thus supporting the traditional uses of the Euphorbia species. These triterpenoids can provide potential leads that can be developed into pharmaceutical compounds for a wide range of medicinal applications. However, there are scattered scientific reports about the anticancer activities of these constituents. Harnessing such information could provide a database of bioactive pharmacopeia or targeted scaffolds for drug discovery. Therefore, this review presents an updated and comprehensive summary of the ethnomedicinal uses, phytochemistry, and the anticancer activities of the triterpenoids of Euphorbia species. Most of the reported triterpenoids in this review belong to tirucallane, cycloartanes, lupane, oleanane, ursane, and taraxane subclass. Their anticancer activities varied distinctly with the majority of them exhibiting significant cytotoxic and anticancer activities in vitro. It is, therefore, envisaged that the report on Euphorbia triterpenoids with interesting anticancer activities will form a database of potential leads or scaffolds that could be advanced into the clinical trials with regard to drug discovery. Full article

(This article belongs to the Special Issue Bioactive Compounds from Natural Sources (2020, 2021))

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20 pages, 2624 KiB

Open AccessArticle

In Silico, In Vitro, and In Vivo Antitumor and Anti-Inflammatory Evaluation of a Standardized Alkaloid-Enriched Fraction Obtained from Boehmeria caudata Sw. Aerial Parts

by Paula P. de Paiva, Julia H. B. Nunes, Fabiana R. Nonato, Ana L. T. G. Ruiz, Rafael R. T. Zafred, Ilza M. O. Sousa, Márcia Y. Okubo, Daniel F. Kawano, Paula A. Monteiro, Mary A. Foglio and João E. Carvalho

Molecules 2020, 25(17), 4018; https://doi.org/10.3390/molecules25174018 - 3 Sep 2020

Cited by 2 | Viewed by 2620

Abstract

In the context of the cancer-inflammation relationship and the use of natural products as potential antitumor and anti-inflammatory agents, the alkaloid-enriched fraction of Boehmeriacaudata (BcAEF) aerial parts was evaluated. In vitro antiproliferative studies with human tumor cell lines showed high activity at [...] Read more.

In the context of the cancer-inflammation relationship and the use of natural products as potential antitumor and anti-inflammatory agents, the alkaloid-enriched fraction of Boehmeriacaudata (BcAEF) aerial parts was evaluated. In vitro antiproliferative studies with human tumor cell lines showed high activity at low concentrations. Further investigation on NCI-H460 cells showed an irreversible effect on cell proliferation, with cell cycle arrest at G2/M phase and programmed cell death induction. Molecular docking studies of four alkaloids identified in BcAEF with colchicine’s binding site on β-tubulin were performed, suggesting (−)-C (15R)-hydroxycryptopleurine as the main inductor of the observed mitotic death. In vivo studies showed that BcAEF was able to reduce Ehrlich tumor volume progression by 30 to 40%. Checking myeloperoxidase activity, BcAEF reduced neutrophils migration towards the tumor. The in vivo anti-inflammatory activity was evaluated by chemically induced edema models. In croton oil-induced ear edema and carrageenan (CG)-induced paw edema models, BcAEF reduced edema around 70 to 80% together with inhibition of activation and/or migration of neutrophils to the inflammatory area. All together the results presented herein show BcAEF as a potent antitumor agent combining antiproliferative and anti-inflammatory properties, which could be further explored in (pre)clinical studies. Full article

(This article belongs to the Special Issue Current Trends in the Analysis of Medicinal Plants)

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Antiproliferative profiles of paclitaxel (0.025 to 25 µg mL−1), vincristine (0.025 to 25 µg mL−1), colchicine (0.25 to 250 µg mL−1), and BcAEF (0.25 to 250 µg mL−1) after 48h-exposition over a panel of tumor cell lines. Human tumor cell lines: U251 (glioblatoma); MCF-7 (breast, adenocarcinoma); NCI-ADR/RES (multidrug resistant ovarian adenocarcinoma); 786-0 (kidney, adenocarcinoma); NCI-H460 (lung, large cells carcinoma); PC-3 (prostate, adenocarcinoma); OVCAR-3 (ovarian, adenocarcinoma); HT29 (colon, adenocarcinoma); K562 (chronic myeloid leukemia). For colchicine the PC-3 cell line is not presented due to an experimental error. Full article ">Figure 2
Inhibitory effects of BcAEF on NCI-H460 cell proliferation and cell cycle. (A) Percentage of colonies in the colony formation assay of untreated cells (control) and cells treated with 0.0025 and 0.025 µg mL−1 of BcAEF. (B) Influence on NCI-H460 cell cycle. NCI-H460 cells were treated for 30 h with 0.25 µM of colchicine (positive control), 0.0025 and 0.025 µg mL−1 of BcAEF. Statistical analysis: two-way ANOVA followed by Bonferroni test (*** p < 0.001, relative to untreated cells-control). (C) Histograms of cell cycle analysis (cell count vs. DNA content, Guava Cell Cycle module) of (1) untreated cells—control, (2) 0.25 µM of colchicine, (3) 0.0025 µg mL−1 and (4) 0.025 µg mL−1 of BcAEF over NCI-H460 cells (30 h), showing cell population in G1, S and G2/M phases. Full article ">Figure 3
Superposition between the crystallographic pose of colchicine (yellow) at the corresponding binding site in the β-tubulin monomer (PDB ID: 4O2B) [<a href="#B8-molecules-25-04018" class="html-bibr">8</a>] and the docking poses of the alkaloids R-boehmeriasin A (green), R-boehmeriasin B (purple), R-cryptopleurine (light blue) and (−)-C (15R)-hydroxycryptopleurine (red). Full article ">Figure 4
Programmed cell death effects of BcAEF on NCI-H460 cells. (A) Influence of BcAEF on phosphatidylserine externalization of NCI-H460 after 36 h of treatment. NCI-H460 cells were treated for 36 h with 0.025, 0.25 and 2.5 µg mL−1 of BcAEF. (B) Influence of BcAEF on caspases activation of NCI-H460 after 48 h of treatment. NCI-H460 cells were treated for 48 h with 0.025, 0.25 and 2.5 µg mL−1 of BcAEF. Statistical analysis for PS externalization and caspases activation: two-way ANOVA followed by Bonferroni test (** p < 0.01 and *** p < 0.001, relative to untreated cells - control). (C) Dot-plot graphics of cell distribution after using Annexin-V and 7-AAD dyes over NCI-H460 cells treated for 36 h (Guava Nexin Module): (1) untreated cells (control), (2) 0.025 µg mL−1, (3) 0.25 µg mL−1 and (4) 2.5 µg mL−1 of BcAEF. (D) Dot-plot graphics of cell distribution after using SR-VAD-FMK and 7-AAD dyes over NCI-H460 cells treated for 48 h (Guava MultiCaspase module): (5) untreated cells (control), (6) 0.025 µg mL−1, (7) 0.25 µg mL−1 and (8) 2.5 µg mL−1 of BcAEF. Full article ">Figure 5
Antitumor and anti-inflammatory effects of BcAEF on Ehrlich solid tumor model and CG-induced paw edema model. (A) Mean tumor volume variation (%) in the Ehrlich solid tumor paw model during 15 days of treatment with vehicle (negative control), positive controls, and BcAEF. (B) Myeloperoxidase (MPO) activity expressed as O.D (optical density) per milligram of paw tissue with (vehicle group, positive controls and BcAEF) or without (satellite group) Ehrlich’s solid tumor. (C) Variation of mice body weight during 15 days of experiment of Ehrlich’s solid tumor in the paw. (D) CG-induced paw edema represented by edema variation (%). Results were expressed as mean ± standard error. Groups = vehicle (negative control), doxorubicin (positive control), piroxicam (positive control), BcAEF (3, 10, and 30 mg/kg), satellite (without inoculation of tumor cells and without treatment) and a group treated with the higher dose of BcAEF (30 mg/kg), in which tumor cells were not inoculated. Legend: i.p. intraperitoneal; o.a. oral administration. Statistical analysis: * p < 0.05, ** p < 0.01 and *** p < 0.001, statistically significant difference in relation to the vehicle group (two-way ANOVA followed by Bonferroni test). Full article ">Figure 6
Anti-inflammatory effect of BcAEF evaluated on croton oil-induced ear edema. (A,C) Results are expressed as the mean ± standard error media; weight difference (mg) = weight differences of equal portions obtained from the treated and untreated ears of the animals from each experimental group. (B,D) Tissue sample evaluated: ear fragment after exposure to croton oil; myeloperoxidase activity expressed as O.D. (optical density) per ear milligram. Groups: negative control (vehicle = acetone 70% to group with application topic or 10 mL kg−1 of the PBS pH 7 + tween 80 5% to group with oral treatment), positive control (dexamethasone), and experimental group (BcAEF: alkaloid enriched fraction extracted from the aerial parts of Boehmeria caudata Sw). Legend: t.a. topic application; o.a. oral administration. Statistical analysis: * p < 0.05, ** p < 0.01 and *** p < 0.001, significant difference by statistical means according to vehicle group. a: p < 0.001, b: p < 0.01, c: p < 0.05, significant difference by statistical means according to satellite group (one-way ANOVA followed by Tukey test). Full article ">

19 pages, 3261 KiB

Open AccessReview

PET Radiotracers for CNS-Adrenergic Receptors: Developments and Perspectives

by Santosh Reddy Alluri, Sung Won Kim, Nora D. Volkow and Kun-Eek Kil

Molecules 2020, 25(17), 4017; https://doi.org/10.3390/molecules25174017 - 3 Sep 2020

Cited by 4 | Viewed by 3691

Abstract

Epinephrine (E) and norepinephrine (NE) play diverse roles in our body’s physiology. In addition to their role in the peripheral nervous system (PNS), E/NE systems including their receptors are critical to the central nervous system (CNS) and to mental health. Various antipsychotics, antidepressants, [...] Read more.

Epinephrine (E) and norepinephrine (NE) play diverse roles in our body’s physiology. In addition to their role in the peripheral nervous system (PNS), E/NE systems including their receptors are critical to the central nervous system (CNS) and to mental health. Various antipsychotics, antidepressants, and psychostimulants exert their influence partially through different subtypes of adrenergic receptors (ARs). Despite the potential of pharmacological applications and long history of research related to E/NE systems, research efforts to identify the roles of ARs in the human brain taking advantage of imaging have been limited by the lack of subtype specific ligands for ARs and brain penetrability issues. This review provides an overview of the development of positron emission tomography (PET) radiotracers for in vivo imaging of AR system in the brain. Full article

(This article belongs to the Special Issue Radiolabeled Compounds for Diagnosis and Treatment of Cancer)

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20 pages, 2666 KiB

Open AccessArticle

Targeting the Initiator Protease of the Classical Pathway of Complement Using Fragment-Based Drug Discovery

by Blake R. Rushing, Denise L. Rohlik, Sourav Roy, D. Andrew Skaff and Brandon L. Garcia

Molecules 2020, 25(17), 4016; https://doi.org/10.3390/molecules25174016 - 3 Sep 2020

Cited by 7 | Viewed by 3447

Abstract

The initiating protease of the complement classical pathway, C1r, represents an upstream and pathway-specific intervention point for complement-related autoimmune and inflammatory diseases. Yet, C1r-targeted therapeutic development is currently underrepresented relative to other complement targets. In this study, we developed a fragment-based drug discovery [...] Read more.

The initiating protease of the complement classical pathway, C1r, represents an upstream and pathway-specific intervention point for complement-related autoimmune and inflammatory diseases. Yet, C1r-targeted therapeutic development is currently underrepresented relative to other complement targets. In this study, we developed a fragment-based drug discovery approach using surface plasmon resonance (SPR) and molecular modeling to identify and characterize novel C1r-binding small-molecule fragments. SPR was used to screen a 2000-compound fragment library for binding to human C1r. This led to the identification of 24 compounds that bound C1r with equilibrium dissociation constants ranging between 160–1700 µM. Two fragments, termed CMP-1611 and CMP-1696, directly inhibited classical pathway-specific complement activation in a dose-dependent manner. CMP-1611 was selective for classical pathway inhibition, while CMP-1696 also blocked the lectin pathway but not the alternative pathway. Direct binding experiments mapped the CMP-1696 binding site to the serine protease domain of C1r and molecular docking and molecular dynamics studies, combined with C1r autoactivation assays, suggest that CMP-1696 binds within the C1r active site. The group of structurally distinct fragments identified here, along with the structure–activity relationship profiling of two lead fragments, form the basis for future development of novel high-affinity C1r-binding, classical pathway-specific, small-molecule complement inhibitors. Full article

(This article belongs to the Special Issue Deep Learning for Molecular Structure Modelling)

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Figure 1
(A) Complement is activated by three canonical pathways known as the classical pathway (CP), lectin pathway (LP), or alternative pathway (AP). Activation of the classical pathway is controlled by the C1 complex (i.e., C1qC1r2C1s2). The pattern recognition protein C1q binds to target surfaces resulting in the autoactivation of the zymogen C1r proteases (shown here as ‘Pro-C1r’) into C1r enzymes, which then proteolytically cleave and activate C1s within the C1 complex. The lectin pathway is activated by lectin pathway-specific pattern recognition proteins in complex with mannan-binding associated serine proteases (MASPs), while the alternative pathway is constitutively activated at low levels by a spontaneous hydrolytic event known as tick-over. Both the classical and lectin pathways converge at the cleavage of C2 and C4 to generate the classical/lectin pathway C3 convertases, C4b2b. Alternative pathway activation results in the formation of C3 convertases in the form of C3bBb. C3 convertases cleave the central molecule of the cascade, C3, into C3a and C3b, resulting in an amplification loop that produces increasing quantities of surface bound C3b. At high surface concentrations of C3b, C3 convertases bind an additional C3b molecule, resulting in a switch of substrate specificity to C5. Cleavage of C5 by these C5 convertases (i.e., C4b2bC3b and C3bBbC3b) results in the release of the anaphylatoxin C5a and the formation of the pore-like lytic structure called the membrane attack complex (i.e., C5b–C9). (B) Fragment-based drug discovery schematic. Full article ">Figure 2
Direct binding of compounds to full-length C1r by SPR. A 2000-compound library was screened at 500 µM final compound concentration for solubility in SPR buffer and for non-specific binding to a blank sensor chip surface (i.e., ‘clean screen’). A total of 1619 compounds were soluble and exhibited low non-specific binding capacity in our SPR assay system. The ability of each of these compounds to bind directly to C1r was measured by injecting a 500 µM final compound concentration over immobilized full-length C1r. A molecular weight corrected theoretical maximal binding response (Rmax) for each compound was calculated and compounds that exhibited superstoichiometric binding (i.e., > 2 × Rmax) were eliminated from further consideration. In total, 95 compounds exhibited ≥ 60% Rmax (green circles). Full article ">Figure 3
Dose-dependent binding of full-length C1r by selected hit compounds. Dose-dependent C1r binding for 24 compounds was measured by injecting a two-fold variable concentration series of each compound ranging from 7.8 to 500 µM. Steady-state affinities were calculated from the resulting sensorgrams. A representative set of sensorgrams are shown along with the associated steady-state KD values. The corresponding steady-state fits are shown in <a href="#app1-molecules-25-04016" class="html-app">Figure S1</a>. KD values are reported as the mean ± S.D. calculated from three independent injection series. Full article ">Figure 4
Inhibition of the classical pathway by selected hit compounds. All 24 hit fragments were tested for their ability to block C4 activation in an ELISA-based assay under conditions specific for the classical pathway. Each compound was tested in triplicate at a single concentration of 500 µM. Positive hits (four in total) were defined as any compound that significantly reduced C4b deposition relative to a non-binding control compound (CMP-685), as judged by an unpaired t-test (* p < 0.05). Full article ">Figure 5
Selectivity and mechanistic analysis of CMP-1611 and CMP-1696. (A) Chemical structure of CMP-1611. (B) Chemical structure of CMP-1696. (C) Dose-dependent inhibition by CMP-1611 and CMP-1696 in a classical pathway-specific ELISA. Data were fit with GraphPad Prism using non-linear regression with a log(inhibitor) vs. response model. For CMP-1611, an IC50 value of 660 µM with an associated 95% confidence interval of (560–790 µM, n = 9) was calculated. For CMP-1696, an IC50 value of 520 µM with an associated 95% confidence interval of (410–680 µM, n = 7) was calculated. The CMP-778 inhibitory response could not be fit to a dose–response inhibition model. (D) Complement pathway selectivity of CMP-1611 and CMP-1696. Compounds were assessed for their ability to inhibit activation of complement via the lectin and alternative pathways using single doses of 500 µM compound in triplicate. To ensure only lectin pathway activation, 2% (v/v) C1q-depleted serum (CompTech) was used and mannan was used as the activator. To match serum sources and amounts for this assay, the classical pathway assays were repeated here using serum from CompTech at 2% (v/v) final concentration. Alternative pathway activation assays were performed using 20% (v/v) serum (CompTech), alternative pathway buffers, and C3b detection (see Methods and Materials for details). CMP-1611 had no effect on the lectin or alternative pathway, whereas CMP-1696 blocked lectin but not alternative pathway activation. (E) C1r, C1r-CUB1, and C1r-CCP2-SP, were immobilized on an SPR sensor chip and binding responses for 500 µM CMP-1611 and CMP-1696 or 10 µM Futhan were each injected in duplicate over all surfaces. Binding responses were corrected for the molecular weight of each analyte and the immobilization level and molecular weight of each surface ligand. Measures of statistical significance in (D) were obtained by comparison of vehicle control using an unpaired t-test (* p < 0.05). Full article ">Figure 6
CMP-1696 structure activity relationship. (A) CMP-1696 was redocked onto C1r-CCP2-SP (PDB: 1MD8, grey surface representation) and the top nine scored poses are shown. All CMP-1696 poses dock into the S1 subsite (cyan) near the catalytic triad (blue). (B) C1r autoactivation assay. C1r proenzyme undergoes time-dependent autoactivation at 37 °C. Autoactivation was measured using a synthetic substrate for C1r enzyme. The reaction progress of vehicle control (dashed line) or in the presence of 10 mM CMP-1696 (solid line) was monitored for 1 h. (C) Molecular dynamics (MD) simulations of CMP-1696/C1r-CCP2-SP. Root mean square deviation (RMSD) in nm for each of the CMP-1696 poses measured over the 10 ns molecular dynamics simulation. (D) MM/PBSA energy calculations for each pose in the 10 ns MD simulations indicate that pose 1 is the most energetically favorable. (E) Hydrogen bonding interactions at the start of the MD simulation are shown as dashed lines. (F) A 50 ns MD simulation (Video S1) was carried out for pose 1 and MM/PBSA was used to calculate total energy. Subcategorized energy contributions are also shown where vDW is van der Waals forces and SASA is solvent-accessible surface area. Full article ">

16 pages, 1335 KiB

Open AccessArticle

Free Amino Acids in Three Pleurotus Species Cultivated on Agricultural and Agro-Industrial By-Products

by Dimitra Tagkouli, Andriana Kaliora, Georgios Bekiaris, Georgios Koutrotsios, Margarita Christea, Georgios I. Zervakis and Nick Kalogeropoulos

Molecules 2020, 25(17), 4015; https://doi.org/10.3390/molecules25174015 - 2 Sep 2020

Cited by 22 | Viewed by 3223

Abstract

Previous studies have demonstrated the feasibility of employing by-products of the olive and wine sectors for the production of Pleurotus mushrooms with enhanced functionalities. In this work we investigated the influence of endogenous and exogenous factors on free amino acids (FAAs) profile of [...] Read more.

Previous studies have demonstrated the feasibility of employing by-products of the olive and wine sectors for the production of Pleurotus mushrooms with enhanced functionalities. In this work we investigated the influence of endogenous and exogenous factors on free amino acids (FAAs) profile of Pleurotus ostreatus, P. eryngii and P. nebrodensis mushrooms produced on wheat straw (WS), alone or mixed with grape marc (GM), and on by-products of the olive industry (OL). Overall, 22 FAAs were determined in substrates and mushrooms, including all the essential amino acids, the neurotransmitter γ-aminobutyric acid (GABA) and ornithine. On a dry weight (dw) basis, total FAAs ranged from 17.37 mg/g in P. nebrodensis to 130.12 mg/g in P. ostreatus samples, with alanine, leucine, glutamine, valine and serine predominating. Similar distribution patterns were followed by the monosodium glutamate (MSG)-like, sweet and bitter FAAs. Significant differences in FAAs level were observed among the species examined and among the cultivation substrates used. Principal Component Analysis (PCA) performed on the entire FAAs profile of six Pleurotus strains, clearly separated P. ostreatus from P. eryngii and P. nebrodensis, in accordance to their phylogenetic affinity. This is the first report of FAAs in P. nebrodensis. Full article

(This article belongs to the Special Issue Mushrooms:The Versatile Roles)

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Figure 1
Total and individual groups of free amino acids in Pleurotus mushrooms, compared by species in each substrate. (A) Total Amino Acids, (B) Essential Amino Acids, (C) Branched Chain Amino Acids; (D) Monosodium Glutamate (MSG)-like Amino Acids, (E) Bitter Taste Amino Acids, (F) Sweet Taste Amino Acids. Lack of letters in common denotes statistically significant differences in comparisons among species in each substrate by Duncan’s multiple comparison test at p < 0.05. Essential amino acids, Thr + Val + Met + Ile + Leu + Phe + Lys + His+ Trp; BCAA Branched chain amino acids, Val + Ile + Leu; MSG-like, monosodium glutamate-like, Asp + Glu; Bitter, Val + Met + Ile + Leu + Phe + His + Trp; Sweet, Thr + Ser + Gly + Ala + Pro. Full article ">Figure 2
(a) Score plot of PCA (PC1 vs. PC2) for the discrimination among Pleurotus species (P. os, P. ostreatus; P. er, P. eryngii; P. nb, P. nebrodensis); (b) Plot with the loadings of the amino acids related to the discrimination among Pleurotus species. Full article ">Figure 2 Cont.
(a) Score plot of PCA (PC1 vs. PC2) for the discrimination among Pleurotus species (P. os, P. ostreatus; P. er, P. eryngii; P. nb, P. nebrodensis); (b) Plot with the loadings of the amino acids related to the discrimination among Pleurotus species. Full article ">

17 pages, 14683 KiB

Open AccessFeature PaperReview

Methods of Purification and Application Procedures of Alpha1 Antitrypsin: A Long-Lasting History

by Simona Viglio, Paolo Iadarola, Maura D’Amato and Jan Stolk

Molecules 2020, 25(17), 4014; https://doi.org/10.3390/molecules25174014 - 2 Sep 2020

Cited by 8 | Viewed by 9515

Abstract

The aim of the present report is to review the literature addressing the methods developed for the purification of alpha1-antitrypsin (AAT) from the 1950s to the present. AAT is a glycoprotein whose main function is to protect tissues from human neutrophil elastase (HNE) [...] Read more.

The aim of the present report is to review the literature addressing the methods developed for the purification of alpha1-antitrypsin (AAT) from the 1950s to the present. AAT is a glycoprotein whose main function is to protect tissues from human neutrophil elastase (HNE) and other proteases released by neutrophils during an inflammatory state. The lack of this inhibitor in human serum is responsible for the onset of alpha1-antitrypsin deficiency (AATD), which is a severe genetic disorder that affects lungs in adults and for which there is currently no cure. Being used, under special circumstances, as a medical treatment of AATD in the so-called “replacement” therapy (consisting in the intravenous infusion of the missing protein), AAT is a molecule with a lot of therapeutic importance. For this reason, interest in AAT purification from human plasma or its production in a recombinant version has grown considerably in recent years. This article retraces all technological advances that allowed the manufacturers to move from a few micrograms of partially purified AAT to several grams of highly purified protein. Moreover, the chronic augmentation and maintenance therapy in individuals with emphysema due to congenital AAT deficiency (current applications in the clinical setting) is also presented. Full article

(This article belongs to the Special Issue The Optimized Production, Purification, Characterization and Application of Proteins/Enzymes)

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16 pages, 1961 KiB

Open AccessCommunication

Proteinoid Nanocapsules as Drug Delivery System for Improving Antipsychotic Activity of Risperidone

by Liroy Lugasi, Igor Grinberg, Rivka Sabag, Ravit Madar, Haim Einat and Shlomo Margel

Molecules 2020, 25(17), 4013; https://doi.org/10.3390/molecules25174013 - 2 Sep 2020

Cited by 9 | Viewed by 3022

Abstract

Risperidone (RSP) is an atypical antipsychotic drug widely used to treat schizophrenia and bipolar disorder. Nanoparticles (NPs) are being developed as in vivo targeted drug delivery systems, which cross the blood-brain barrier and improve pharmacokinetics and drug effectiveness. Here, biodegradable proteinoids were synthesized [...] Read more.

Risperidone (RSP) is an atypical antipsychotic drug widely used to treat schizophrenia and bipolar disorder. Nanoparticles (NPs) are being developed as in vivo targeted drug delivery systems, which cross the blood-brain barrier and improve pharmacokinetics and drug effectiveness. Here, biodegradable proteinoids were synthesized by thermal step-growth polymerization from the amino acids l-glutamic acid, l-phenylalanine and l-histidine and poly (l-lactic acid). Proteinoid NPs containing RSP were then formed by self-assembly, overcoming the insolubility of the drug in water, followed by PEGylation (poly ethylene glycol (PEG) conjugation to increase the stability of the NPs in the aqueous continuous phase. These NPs are biodegradable owing to their peptide and ester moieties. They were characterized in terms of diameter, size distribution, drug loading, and long-term storage. Behavioral studies on mice found enhanced antipsychotic activity compared to free RSP. Full article

(This article belongs to the Special Issue Nanotechnology-Drug Delivery Systems)

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37 pages, 5184 KiB

Open AccessReview

Overview of Radiolabeled Somatostatin Analogs for Cancer Imaging and Therapy

by Romain Eychenne, Christelle Bouvry, Mickael Bourgeois, Pascal Loyer, Eric Benoist and Nicolas Lepareur

Molecules 2020, 25(17), 4012; https://doi.org/10.3390/molecules25174012 - 2 Sep 2020

Cited by 73 | Viewed by 11054

Abstract

Identified in 1973, somatostatin (SST) is a cyclic hormone peptide with a short biological half-life. Somatostatin receptors (SSTRs) are widely expressed in the whole body, with five subtypes described. The interaction between SST and its receptors leads to the internalization of the ligand–receptor [...] Read more.

Identified in 1973, somatostatin (SST) is a cyclic hormone peptide with a short biological half-life. Somatostatin receptors (SSTRs) are widely expressed in the whole body, with five subtypes described. The interaction between SST and its receptors leads to the internalization of the ligand–receptor complex and triggers different cellular signaling pathways. Interestingly, the expression of SSTRs is significantly enhanced in many solid tumors, especially gastro-entero-pancreatic neuroendocrine tumors (GEP-NET). Thus, somatostatin analogs (SSAs) have been developed to improve the stability of the endogenous ligand and so extend its half-life. Radiolabeled analogs have been developed with several radioelements such as indium-111, technetium-99 m, and recently gallium-68, fluorine-18, and copper-64, to visualize the distribution of receptor overexpression in tumors. Internal metabolic radiotherapy is also used as a therapeutic strategy (e.g., using yttrium-90, lutetium-177, and actinium-225). With some radiopharmaceuticals now used in clinical practice, somatostatin analogs developed for imaging and therapy are an example of the concept of personalized medicine with a theranostic approach. Here, we review the development of these analogs, from the well-established and authorized ones to the most recently developed radiotracers, which have better pharmacokinetic properties and demonstrate increased efficacy and safety, as well as the search for new clinical indications. Full article

(This article belongs to the Special Issue Radiolabeled Compounds for Diagnosis and Treatment of Cancer)

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17 pages, 3186 KiB

Open AccessArticle

Development of a Molecular Snail Xenomonitoring Assay to Detect Schistosoma haematobium and Schistosoma bovis Infections in their Bulinus Snail Hosts

by Tom Pennance, John Archer, Elena Birgitta Lugli, Penny Rostron, Felix Llanwarne, Said Mohammed Ali, Amour Khamis Amour, Khamis Rashid Suleiman, Sarah Li, David Rollinson, Jo Cable, Stefanie Knopp, Fiona Allan, Shaali Makame Ame and Bonnie Lee Webster

Molecules 2020, 25(17), 4011; https://doi.org/10.3390/molecules25174011 - 2 Sep 2020

Cited by 18 | Viewed by 4357

Abstract

Schistosomiasis, a neglected tropical disease of medical and veterinary importance, transmitted through specific freshwater snail intermediate hosts, is targeted for elimination in several endemic regions in sub-Saharan Africa. Multi-disciplinary methods are required for both human and environmental diagnostics to certify schistosomiasis elimination when [...] Read more.

Schistosomiasis, a neglected tropical disease of medical and veterinary importance, transmitted through specific freshwater snail intermediate hosts, is targeted for elimination in several endemic regions in sub-Saharan Africa. Multi-disciplinary methods are required for both human and environmental diagnostics to certify schistosomiasis elimination when eventually reached. Molecular xenomonitoring protocols, a DNA-based detection method for screening disease vectors, have been developed and trialed for parasites transmitted by hematophagous insects, such as filarial worms and trypanosomes, yet few have been extensively trialed or proven reliable for the intermediate host snails transmitting schistosomes. Here, previously published universal and Schistosoma-specific internal transcribed spacer (ITS) rDNA primers were adapted into a triplex PCR primer assay that allowed for simple, robust, and rapid detection of Schistosoma haematobium and Schistosoma bovis in Bulinus snails. We showed this two-step protocol could sensitively detect DNA of a single larval schistosome from experimentally infected snails and demonstrate its functionality for detecting S. haematobium infections in wild-caught snails from Zanzibar. Such surveillance tools are a necessity for succeeding in and certifying the 2030 control and elimination goals set by the World Health Organization. Full article

(This article belongs to the Special Issue Biomarkers for Early Detection of Neglected Tropical Diseases (NTDs): Discovery, Validation and POC (Point-of-Care) Devices Implementation)

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Singleplex (A); ETTS2 + ETTS1) and multiplex (B); multiplex ETTS2 + ETTS1 + ITS2_Schisto_F, (C); ETTS2 + ETTS1 + ITS2_Schisto_R) PCRs on laboratory-bred Bulinus wrighti (B.w.) and Schistosoma haematobium (S.h.) gDNA separately (1; B.w., 2; S.h.) and combined (3; B.w. + S.h.). When B.w. and S.h. DNA was combined (A3, B3, C3), two amplicons were produced by the ETTS1 + ETTS2 primers, a larger snail amplicon (Sn) (~1200 bp) and a smaller Schistosoma amplicon (T) (~1000), with the additional Schistosoma-specific primers producing either a 538 bp (B3; ITS2_Schisto_F) or 835 bp (C3; ITS2_Schisto_R) amplicon (S). A larger amplicon (A) (~1400–1600 bp) was also observed to be amplified in some reactions, and this was thought to be a PCR artifact or additional primer targets in the Schistosoma gDNA. L1 = HyperLadder I (Bioline, London, UK). -ve = negative, no template control. ITS = internal transcribed spacer. Full article ">Figure 2
Multiplex ITS xenomonitoring assay trial at 55 °C (A) and 60 °C (B). Includes gDNA of Bulinus wrighti of both BioSprint (Lane 1 and 5) and DNeasy extractions (Lane 2 and 6) and gDNA of Schistosoma haematobium (Lane 3 and 5) and S. bovis (Lane 4 and 6). Combinations of B. wrighti and S. haematobium (Lane 5) or S. bovis (Lane 6) gDNA shown. Sn = snail amplicon, T = trematode amplicon, S = Schistosoma amplicon, and A = non-specific amplicon or artifact. L1 = HyperLadder I. L2 = HyperLadder IV (Bioline, London, UK). -ve = negative, no template control. Full article ">Figure 3
Gel showing the secondary singleplex ITS xenomonitoring (SIX) PCR for 1) Schistosoma haematobium gDNA; 2) S. bovis gDNA; 3) S. haematobium + B. wrighti gDNA; 4) S. bovis + B. wrighti gDNA. -ve = non-template negative control. L1 = HyperLadder I (Bioline, London, UK). Full article ">Figure 4
Sensitivity tests of ITS1-2-F PCR performed with serial dilutions of Schistosoma haematobium and S. bovis gDNA in the presence of Bulinus wrighti gDNA. L1 = HyperLadder I. L2 = HyperLadder IV (Bioline, London, UK). Full article ">Figure 5
Experimental infections of Bulinus truncatus with Schistosoma haematobium (1–24), field-collected B. globosus infected with Euclinostomum sp. (Euc.) and field-collected B. nasutus shedding Echinostoma sp. cercariae (Ech.). The S. haematobium DNA amplicon was present (+ve) in 13 of the 23 non-patent snails (11 at 24 h post-exposure, and two at 11 weeks post-exposure), highlighted by the arrow. Lane 24 = B. truncatus sample that was shedding S. haematobium cercariae 11 weeks after exposure. The positive control (+ve) is a mix of B. wrighti and S. haematobium control gDNA. L1: HyperLadder I, L2: HyperLadder IV (Bioline, London, UK). Full article ">Figure 6
Gel images for the multiplex ITS xenomonitoring (MIX) PCR amplicons for 94 non-patent Bulinus globosus collected from Wambaa, Pemba, United Republic of Tanzania. The text under each amplicon denotes the outcome of the Schistosoma sp. targeted sequencing where relevant (i.e., presence of 538 bp amplicon), which resulted in either S. haematobium (S.h.) or sequencing failure (F). The presence of a trematode band without the presence of the Schistosoma band indicated a non-Schistosoma trematode infection (Tr.). Other non-specific bands, in this case, larger bands (NA), were also observed in these snail populations, which did not amplify with the secondary SIX PCR. x = sample failure with no control amplicon. Arrows highlight the presence of the ~1000 bp trematode band when present (n = 8). B. globosus with a patent S. haematobium infection (Cham10.1 see [<a href="#B6-molecules-25-04011" class="html-bibr">6</a>]) was run as a positive control (+ve) and also represented the amplicon profile obtained for the seven patent B. globosus snails (five and two with S. bovis and S. haematobium infections, respectively (see <a href="#sec2dot4-molecules-25-04011" class="html-sec">Section 2.4</a>). -ve = the non-template negative control. L1—HyperLadder IV (Bioline, London, UK). Full article ">Figure 7
Primer annealing positions flanking and internal to the ITS1 + 2 rDNA targets. Primer positions were mapped to Schistosoma haematobium and S. bovis ITS1 + 2 reference data [<a href="#B59-molecules-25-04011" class="html-bibr">59</a>] and to a Bulinus globosus and B. nasutus DNA reference (Pennance et al., unpublished data). For Schistosoma DNA, the primer combinations produced two fragments; 1) ETTS2–ETTS1 (1005 bp) and either 2) ITS2_Schisto_F-ETTS1 (538 bp) or 3) ITS2_Schisto_R-ETTS2 (835 bp). For Bulinus DNA, the primer combinations produced one fragment, ranging in size between 1232 and 1263 due to interspecies variation. For Schistosoma species identification, four SNPs were present at bp positions 90, 145, 195, and 265 in the ITS2 rDNA region, allowing differentiation of S. haematobium and S. bovis following ITS2 sequencing. Full article ">

10 pages, 1266 KiB

Open AccessArticle

A Lanosteryl Triterpene (RA-3) Exhibits Antihyperuricemic and Nephroprotective Effects in Rats

by Nomadlozi Blessings Hlophe, Andrew Rowland Opoku, Foluso Oluwagbemiga Osunsanmi, Trayana Georgieva Djarova-Daniels, Oladipupo Adejumobi Lawal and Rebamang Anthony Mosa

Molecules 2020, 25(17), 4010; https://doi.org/10.3390/molecules25174010 - 2 Sep 2020

Cited by 6 | Viewed by 2516

Abstract

Considering the global health threat posed by kidney disease burden, a search for new nephroprotective drugs from our local flora could prove a powerful strategy to respond to this health threat. In this study we investigated the antihyperuricemic and nephroprotective potential of RA-3, [...] Read more.

Considering the global health threat posed by kidney disease burden, a search for new nephroprotective drugs from our local flora could prove a powerful strategy to respond to this health threat. In this study we investigated the antihyperuricemic and nephroprotective potential of RA-3, a plant-derived lanosteryl triterpene. The antihyperuricemic and nephroprotective effect of RA-3 was investigated using the adenine and gentamicin induced hyperuricemic and nephrotoxicity rat model. Following the induction of hyperuricemia and nephrotoxicity, the experimental model rats (Sprague Dawley) were orally administered with RA-3 at 50 and 100 mg/kg body weight, respectively, daily for 14 days. Treatment of the experimental rats with RA-3, especially at 100 mg/kg, effectively lowered the serum renal dysfunction (blood urea nitrogen and creatinine) and hyperuricemic (uric acid and xanthine oxidase) biomarkers. These were accompanied by increased antioxidant status with decrease in malondialdehyde content. A much improved histomorphological structure of the kidney tissues was also observed in the triterpene treated groups when compared to the model control group. It is evident that RA-3 possesses the antihyperuricemic and nephroprotective properties, which could be vital for prevention and amelioration of kidney disease. Full article

(This article belongs to the Special Issue Biological and Pharmacological Activity of Plant Natural Compounds)

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Methyl-3β-hydroxylanosta-9,24-dien-21-oate (RA-3), a lanosteryl triterpene from P. longifolia. Full article ">Figure 2
Effect of RA-3 on serum levels of creatinine (a), blood urea nitrogen (BUN) (b), and angiotensin converting enzyme (ACE) (c). Data were expressed as mean ± SD (n = 5), * p < 0.05 vs. MC group. NC—normal control, MC—model control, Allo—allopurinol. Full article ">Figure 3
Effect of RA-3 on the serum levels of uric acid (a), xanthine oxidase (XO) (b) and interleukin-6 (IL-6) (c). Data were expressed as mean ± SD (n = 5), * p < 0.05 vs. MC group. NC—normal control, MC—model control, Allo—allopurinol. Full article ">Figure 4
Photomicrographs of the kidney sections of the rats. (i) Section of kidney from normal group, showing normal kidney architecture with intact glomerulus (black arrow) and renal tubules (black triangle); (ii) section from model control group, showing glomerular congestion, dilated renal tubules, and epithelial degeneration (red arrow), (iii) section from group treated with allopurinol, showing minimal improved renal architecture; (iv) section from group treated with RA-3 (50 mg/kg), showing regeneration of epithelium, (v) section from group treated with RA-3 (100 mg/kg), showing improved renal architecture characterized by epithelial regeneration and reduced glomerular congestion. The indicator size for each image is 14X-200 µm (H&E). Full article ">

32 pages, 4896 KiB

Open AccessArticle

Synthesis of Potential Haptens with Morphine Skeleton and Determination of Protonation Constants

by István Köteles, Károly Mazák, Gergő Tóth, Boglárka Tűz and Sándor Hosztafi

Molecules 2020, 25(17), 4009; https://doi.org/10.3390/molecules25174009 - 2 Sep 2020

Cited by 7 | Viewed by 5165

Abstract

Vaccination could be a promising alternative warfare against drug addiction and abuse. For this purpose, so-called haptens can be used. These molecules alone do not induce the activation of the immune system, this occurs only when they are attached to an immunogenic carrier [...] Read more.

Vaccination could be a promising alternative warfare against drug addiction and abuse. For this purpose, so-called haptens can be used. These molecules alone do not induce the activation of the immune system, this occurs only when they are attached to an immunogenic carrier protein. Hence obtaining a free amino or carboxylic group during the structural transformation is an important part of the synthesis. Namely, these groups can be used to form the requisite peptide bond between the hapten and the carrier protein. Focusing on this basic principle, six nor-morphine compounds were treated with ethyl acrylate and ethyl bromoacetate, while the prepared esters were hydrolyzed to obtain the N-carboxymethyl- and N-carboxyethyl-normorphine derivatives which are considered as potential haptens. The next step was the coupling phase with glycine ethyl ester, but the reactions did not work or the work-up process was not accomplishable. As an alternative route, the normorphine-compounds were N-alkylated with N-(chloroacetyl)glycine ethyl ester. These products were hydrolyzed in alkaline media and after the work-up process all of the derivatives contained the free carboxylic group of the glycine side chain. The acid-base properties of these molecules are characterized in detail. In the N-carboxyalkyl derivatives, the basicity of the amino and phenolate site is within an order of magnitude. In the glycine derivatives the basicity of the amino group is significantly decreased compared to the parent compounds (i.e., morphine, oxymorphone) because of the electron withdrawing amide group. The protonation state of the carboxylate group significantly influences the basicity of the amino group. All of the glycine ester and the glycine carboxylic acid derivatives are currently under biological tests. Full article

(This article belongs to the Special Issue ECSOC-23)

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27 pages, 3272 KiB

Open AccessReview

Sunlight-Operated TiO₂-Based Photocatalysts

by Irene Barba-Nieto, Uriel Caudillo-Flores, Marcos Fernández-García and Anna Kubacka

Molecules 2020, 25(17), 4008; https://doi.org/10.3390/molecules25174008 - 2 Sep 2020

Cited by 27 | Viewed by 3790

Abstract

Photo-catalysis is a research field with broad applications in terms of potential technological applications related to energy production and managing, environmental protection, and chemical synthesis fields. A global goal, common to all of these fields, is to generate photo-catalytic materials able to use [...] Read more.

Photo-catalysis is a research field with broad applications in terms of potential technological applications related to energy production and managing, environmental protection, and chemical synthesis fields. A global goal, common to all of these fields, is to generate photo-catalytic materials able to use a renewable energy source such as the sun. As most active photocatalysts such as titanium oxides are essentially UV absorbers, they need to be upgraded in order to achieve the fruitful use of the whole solar spectrum, from UV to infrared wavelengths. A lot of different strategies have been pursued to reach this goal. Here, we selected representative examples of the most successful ones. We mainly highlighted doping and composite systems as those with higher potential in this quest. For each of these two approaches, we highlight the different possibilities explored in the literature. For doping of the main photocatalysts, we consider the use of metal and non-metals oriented to modify the band gap energy as well as to create specific localized electronic states. We also described selected cases of using up-conversion doping cations. For composite systems, we described the use of binary and ternary systems. In addition to a main photo-catalyst, these systems contain low band gap, up-conversion or plasmonic semiconductors, plasmonic and non-plasmonic metals and polymers. Full article

(This article belongs to the Section Inorganic Chemistry)

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11 pages, 2010 KiB

Open AccessArticle

Semi-Synthetic Approach Leading to 8-Prenylnaringenin and 6-Prenylnaringenin: Optimization of the Microwave-Assisted Demethylation of Xanthohumol Using Design of Experiments

by Corinna Urmann and Herbert Riepl

Molecules 2020, 25(17), 4007; https://doi.org/10.3390/molecules25174007 - 2 Sep 2020

Cited by 6 | Viewed by 3707

Abstract

The isomers 8-prenylnaringenin and 6-prenylnaringenin, both secondary metabolites occurring in hops, show interesting biological effects, like estrogen-like, cytotoxic, or neuro regenerative activities. Accordingly, abundant sources for this special flavonoids are needed. Extraction is not recommended due to the very low amounts present in [...] Read more.

The isomers 8-prenylnaringenin and 6-prenylnaringenin, both secondary metabolites occurring in hops, show interesting biological effects, like estrogen-like, cytotoxic, or neuro regenerative activities. Accordingly, abundant sources for this special flavonoids are needed. Extraction is not recommended due to the very low amounts present in plants and different synthesis approaches are characterized by modest yields, multiple steps, the use of expensive chemicals, or an elaborate synthesis. An easy synthesis strategy is the demethylation of xanthohumol, which is available due to hop extraction industry, using lithium chloride and dimethylformamide, but byproducts and low yield did not make this feasible until now. In this study, the demethylation of xanthohumol to 8-prenylnaringenin and 6-prenylnaringenin is described the first time and this reaction was optimized using Design of Experiment and microwave irradiation. With the optimized conditions—temperature 198 °C, 55 eq. lithium chloride, and a reaction time of 9 min, a final yield of 76% of both prenylated flavonoids is reached. Full article

(This article belongs to the Section Natural Products Chemistry)

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14 pages, 3073 KiB

Open AccessArticle

Comprehensive Metabolome Analysis of Fermented Aqueous Extracts of Viscum album L. by Liquid Chromatography−High Resolution Tandem Mass Spectrometry

by Evelyn Peñaloza, Carla Holandino, Claudia Scherr, Paula I. P. de Araujo, Ricardo M. Borges, Konrad Urech, Stephan Baumgartner and Rafael Garrett

Molecules 2020, 25(17), 4006; https://doi.org/10.3390/molecules25174006 - 2 Sep 2020

Cited by 33 | Viewed by 4175

Abstract

Fermented aqueous extracts of Viscum album L. are widely used for cancer treatment in complementary medicine. The high molecular weight compounds viscotoxins and lectins are considered to be the main active substances in the extracts. However, a vast number of small molecules (≤1500 [...] Read more.

Fermented aqueous extracts of Viscum album L. are widely used for cancer treatment in complementary medicine. The high molecular weight compounds viscotoxins and lectins are considered to be the main active substances in the extracts. However, a vast number of small molecules (≤1500 Da) is also expected to be present, and few studies have investigated their identities. In this study, a comprehensive metabolome analysis of samples of fermented aqueous extracts of V. album from two host tree species (Malus domestica and Pinus sylvestris), both prepared by two pharmaceutical manufacturing processes, was performed by liquid chromatography−high resolution tandem mass spectrometry (LC-HRMS/MS). A total of 212 metabolites were putatively annotated, including primary metabolites (e.g., amino acids, organic acids, etc.) and secondary metabolites (mostly phenolic compounds). A clear separation between V. album samples according to the host tree species, but not due to manufacturing processes, was observed by principal component analysis. The biomarkers responsible for this discrimination were assessed by partial least squares−discriminant analysis. Because V. album extracts from different host trees have different clinical applications, the present work highlights the possibility of characterizing the metabolome for identification and traceability of V. album fermented aqueous extracts. Full article

(This article belongs to the Special Issue Current Trends in the Analysis of Medicinal Plants)

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Metabolites in the fermented aqueous extracts of V. album putatively annotated by LC-HRMS/MS according to the ionization mode and chemical group. Full article ">Figure 2
Typical LC-HRMS chromatograms of fermented aqueous extracts of V. album from the two host trees (M. domestica and P. sylvestris) and manufacturing processes (APVAE and VAE) in positive (ESI+) and negative (ESI-) electrospray ionization modes. Abbreviations: ISCM: M. domestica/APVAE, HGM: M. domestica/VAE, ISCP: P. sylvestris/APVAE; HGP: P. sylvestris/VAE. Full article ">Figure 3
PCA (A,B) and PLS-DA (C,D) score plots from data of V. album fermented aqueous extracts analyzed by LC-ESI(±)-HRMS. Abbreviations: QC: pooled quality control samples, ISCM: M. domestica/APVAE, HGM: M. domestica/VAE, ISCP: P. sylvestris/APVAE; HGP: P. sylvestris/VAE. Full article ">Figure 4
Box plot graphs of annotated metabolites responsible for the discrimination of P. sylvestris group from M. domestica in the PLS-DA model. Abbreviations: ISCM: M. domestica/APVAE, HGM: M. domestica/VAE, ISCP: P. sylvestris/APVAE; HGP: P. sylvestris/VAE. Tukey’s multiple comparison test was performed for significant difference. * p < 0.05; ** p < 0.01; *** p < 0.001; **** p < 0.0001. Full article ">Figure 5
Box plot graphs of annotated metabolites responsible for the discrimination of M. domestica group from P. sylvestris in the PLS-DA model. Abbreviations: ISCM: M. domestica/APVAE, HGM: M. domestica/VAE, ISCP: P. sylvestris/APVAE; HGM: P. sylvestris/VAE. Tukey’s multiple comparison test was performed for significant difference. * p < 0.05; ** p < 0.01; *** p < 0.001; **** p < 0.0001. n.s. (not significant): p > 0.05. Full article ">Figure 6
Nodes from the molecular network related to flavonoid structures obtained from fermented aqueous extracts of V. album. Full article ">Figure 7
Nodes from the molecular network highlighting the compounds with high loading value in PLS-DA analysis and their distribution across different sample groups of fermented aqueous extracts of V. album. Full article ">

20 pages, 5091 KiB

Open AccessReview

Memantine Derivatives as Multitarget Agents in Alzheimer’s Disease

by Giambattista Marotta, Filippo Basagni, Michela Rosini and Anna Minarini

Molecules 2020, 25(17), 4005; https://doi.org/10.3390/molecules25174005 - 2 Sep 2020

Cited by 30 | Viewed by 5884

Abstract

Memantine (3,5-dimethyladamantan-1-amine) is an orally active, noncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonist approved for treatment of moderate-to-severe Alzheimer’s disease (AD), a neurodegenerative condition characterized by a progressive cognitive decline. Unfortunately, memantine as well as the other class of drugs licensed for AD treatment acting [...] Read more.

Memantine (3,5-dimethyladamantan-1-amine) is an orally active, noncompetitive N-methyl-D-aspartate receptor (NMDAR) antagonist approved for treatment of moderate-to-severe Alzheimer’s disease (AD), a neurodegenerative condition characterized by a progressive cognitive decline. Unfortunately, memantine as well as the other class of drugs licensed for AD treatment acting as acetylcholinesterase inhibitors (AChEIs), provide only symptomatic relief. Thus, the urgent need in AD drug development is for disease-modifying therapies that may require approaching targets from more than one path at once or multiple targets simultaneously. Indeed, increasing evidence suggests that the modulation of a single neurotransmitter system represents a reductive approach to face the complexity of AD. Memantine is viewed as a privileged NMDAR-directed structure, and therefore, represents the driving motif in the design of a variety of multi-target directed ligands (MTDLs). In this review, we present selected examples of small molecules recently designed as MTDLs to contrast AD, by combining in a single entity the amantadine core of memantine with the pharmacophoric features of known neuroprotectants, such as antioxidant agents, AChEIs and Aβ-aggregation inhibitors. Full article

(This article belongs to the Special Issue Multitarget Ligands)

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14 pages, 4308 KiB

Open AccessArticle

Quercitrin Stimulates Hair Growth with Enhanced Expression of Growth Factors via Activation of MAPK/CREB Signaling Pathway

by Jaeyoon Kim, Soon Re Kim, Yun-Ho Choi, Jae young Shin, Chang Deok Kim, Nae-Gyu Kang, Byung Cheol Park and Sanghwa Lee

Molecules 2020, 25(17), 4004; https://doi.org/10.3390/molecules25174004 - 2 Sep 2020

Cited by 29 | Viewed by 6573

Abstract

The present study aimed to investigate the molecular mechanism of quercitrin, a major constituent of Hottuynia cordata extract, for its hair growth stimulating activities in cultured human dermal papilla cells (hDPCs). Quercitrin enhanced the cell viability and cellular energy metabolism in cultured hDPCs [...] Read more.

The present study aimed to investigate the molecular mechanism of quercitrin, a major constituent of Hottuynia cordata extract, for its hair growth stimulating activities in cultured human dermal papilla cells (hDPCs). Quercitrin enhanced the cell viability and cellular energy metabolism in cultured hDPCs by stimulating the production of NAD(P)H and mitochondrial membrane potential (ΔΨ). The expression of Bcl2, an essential marker for anagen hair follicle and cell survival, was increased by quercitrin treatment. Quercitrin also increased the cell proliferation marker Ki67. The expression of growth factors—such as bFGF, KGF, PDGF-AA, and VEGF—were increased by quercitrin both in mRNA and protein levels. In addition, quercitrin was found to increase the phosphorylation of Akt, Erk, and CREB in cultured hDPCs, while inhibitors of MAPKs reversed the effects of quercitrin. Finally, quercitrin stimulated hair shaft growth in cultured human hair follicles. Our data obtained from present study are in line with those previously reported and demonstrate that quercitrin is (one of) the active compound(s) of Hottuynia cordata extract which showed hair growth promoting effects. It is strongly suggested that the hair growth stimulating activity of quercitrin was exerted by enhancing the cellular energy metabolism, increasing the production of growth factors via activation of MAPK/CREB signaling pathway. Full article

(This article belongs to the Section Medicinal Chemistry)

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