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Molecules, Volume 26, Issue 11 (June-1 2021) – 417 articles

Cover Story (view full-size image): After our deep immersion in the OPE world, we now firmly believe that the possibility of the modulation of their skeleton in terms of substitution, length, and as a consequence their photophysical properties, makes the class of oligophenylene ethynylenes be extremely promising for their future exploitation in the biological field. Furthermore, their tendency to aggregate in supramolecular structures gives OPEs extra gear for the modulation of their photophysical features and, as a logical consequence, of their applicability in the mentioned field. View this paper
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19 pages, 5082 KiB  
Article
Carbon Nanotube Fibers Decorated with MnO2 for Wire-Shaped Supercapacitor
by Luman Zhang, Xuan Zhang, Jian Wang, David Seveno, Jan Fransaer, Jean-Pierre Locquet and Jin Won Seo
Molecules 2021, 26(11), 3479; https://doi.org/10.3390/molecules26113479 - 7 Jun 2021
Cited by 26 | Viewed by 4322
Abstract
Fibers made from CNTs (CNT fibers) have the potential to form high-strength, lightweight materials with superior electrical conductivity. CNT fibers have attracted great attention in relation to various applications, in particular as conductive electrodes in energy applications, such as capacitors, lithium-ion batteries, and [...] Read more.
Fibers made from CNTs (CNT fibers) have the potential to form high-strength, lightweight materials with superior electrical conductivity. CNT fibers have attracted great attention in relation to various applications, in particular as conductive electrodes in energy applications, such as capacitors, lithium-ion batteries, and solar cells. Among these, wire-shaped supercapacitors demonstrate various advantages for use in lightweight and wearable electronics. However, making electrodes with uniform structures and desirable electrochemical performances still remains a challenge. In this study, dry-spun CNT fibers from CNT carpets were homogeneously loaded with MnO2 nanoflakes through the treatment of KMnO4. These functionalized fibers were systematically characterized in terms of their morphology, surface and mechanical properties, and electrochemical performance. The resulting MnO2–CNT fiber electrode showed high specific capacitance (231.3 F/g) in a Na2SO4 electrolyte, 23 times higher than the specific capacitance of the bare CNT fibers. The symmetric wire-shaped supercapacitor composed of CNT–MnO2 fiber electrodes and a PVA/H3PO4 electrolyte possesses an energy density of 86 nWh/cm and good cycling performance. Combined with its light weight and high flexibility, this CNT-based wire-shaped supercapacitor shows promise for applications in flexible and wearable energy storage devices. Full article
(This article belongs to the Special Issue Research on Nanostructured Materials)
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Figure 1

Figure 1
<p>Schematic diagram of the manufacturing method of the CNT–MnO<sub>2</sub> supercapacitors.</p> Full article ">Figure 2
<p>SEM images of (<b>a</b>) raw CNT fiber and (<b>b</b>) CNT–MnO<sub>2</sub> fiber (1, 12), (<b>c</b>) (10, 4), (<b>d</b>) (10, 8), and (<b>e</b>) (10, 12). (<b>f</b>) EDS pattern detected from CNT–MnO<sub>2</sub> fiber (10, 8). Scale bars equal 500 nm.</p> Full article ">Figure 3
<p>(<b>a</b>) ADF scanning TEM image of CNT–MnO<sub>2</sub> fiber (10, 8) showing that MnO<sub>2</sub> nanoflakes (bright contrast) were present along the CNT fiber. (<b>b</b>) High-resolution TEM image revealing that the size of the MnO<sub>2</sub> nanoflakes (some are marked by red circles) was approximately 2–3 nm.</p> Full article ">Figure 4
<p>Strength–strain curves of single fiber tensile test.</p> Full article ">Figure 5
<p>Raman spectra of (<b>a</b>) raw CNT fiber and (<b>b</b>) CNT–MnO<sub>2</sub> fibers (10, 4), (<b>c</b>) (10, 8), and (<b>d</b>) (10, 12).</p> Full article ">Figure 6
<p>XPS survey spectra of (<b>a</b>) CNT fiber (bottom) and CNT–MnO<sub>2</sub> fiber (top). High-resolution XPS spectra from CNT–MnO<sub>2</sub> fiber: (<b>b</b>) C 1 s and K 2p, (<b>c</b>) Mn 2p, and (<b>d</b>) Mn 3 s peaks. The splitting width of the doublet peaks in Mn 3 s was 4.7 eV.</p> Full article ">Figure 7
<p>Schematic representation of the three-electrode cell used to test the electrochemical performance of individual CNT–MnO<sub>2</sub> fibers.</p> Full article ">Figure 8
<p>Electrochemical characterization of CNT–MnO<sub>2</sub> fiber electrode (working electrode) in a three-electrode cell using 1M Na<sub>2</sub>SO<sub>4</sub> (aq) as electrolyte: (<b>a</b>) comparison of CV curves of raw CNT fiber and CNT–MnO<sub>2</sub> fiber (10, 8) electrodes; (<b>b</b>) CP curves of CNT–MnO<sub>2</sub> fiber (10, 8) electrode at various current densities; (<b>c</b>) specific capacitance for the CNT–MnO<sub>2</sub> fiber (10, 8) electrode and the deposited MnO<sub>2</sub> at different scan rates; (<b>d</b>) Nyquist plots of CNT fiber and CNT–MnO<sub>2</sub> fiber (10, 8) electrodes. (<b>e</b>,<b>f</b>) Deconvolutions of two contributions to the capacitance in CNT–MnO<sub>2</sub> fiber (10, 8): the diffusion-limited process (∝ν<sup>1/2</sup>, blank regions) and the surface-limited process (∝ν, shaded regions). (<b>e</b>) CV at 30 mV/s and (<b>f</b>) bar graph of the two contributions versus the scan rate ν.</p> Full article ">Figure 9
<p>Electrochemical characterization of the symmetric CNT–MnO<sub>2</sub> fiber supercapacitor using PVA/H<sub>3</sub>PO<sub>4</sub> polymer as the solid electrolyte: (<b>a</b>) photograph showing the flexibility of the wire-shaped supercapacitor, (<b>b</b>) CV curves of the CNT–MnO<sub>2</sub> fiber supercapacitor at various scan rates, (<b>c</b>) CP curves at different current densities, and (<b>d</b>) cycling performance of the supercapacitor at a current density of 1 A/g.</p> Full article ">Figure 10
<p>Ragone plots of length energy density versus length power density for the CNT–MnO<sub>2</sub> fiber supercapacitor fabricated in this work (black star); asymmetric supercapacitors based on pristine and MnO<sub>2</sub>-coated CNT fibers (grey triangle) [<a href="#B24-molecules-26-03479" class="html-bibr">24</a>]; and supercapacitors based on bare CNT fiber and CNT-OMC fibers (grey square) [<a href="#B1-molecules-26-03479" class="html-bibr">1</a>].</p> Full article ">
24 pages, 5634 KiB  
Review
What Can Electrochemical Methods Offer in Determining DNA–Drug Interactions?
by Sandra Ramotowska, Aleksandra Ciesielska and Mariusz Makowski
Molecules 2021, 26(11), 3478; https://doi.org/10.3390/molecules26113478 - 7 Jun 2021
Cited by 35 | Viewed by 5716
Abstract
The interactions of compounds with DNA have been studied since the recognition of the role of nucleic acid in organisms. The design of molecules which specifically interact with DNA sequences allows for the control of the gene expression. Determining the type and strength [...] Read more.
The interactions of compounds with DNA have been studied since the recognition of the role of nucleic acid in organisms. The design of molecules which specifically interact with DNA sequences allows for the control of the gene expression. Determining the type and strength of such interaction is an indispensable element of pharmaceutical studies. Cognition of the therapeutic action mechanisms is particularly important for designing new drugs. Owing to their sensitivity, simplicity, and low costs, electrochemical methods are increasingly used for this type of research. Compared to other techniques, they require a small number of samples and are characterized by a high reliability. These methods can provide information about the type of interaction and the binding strength, as well as the damage caused by biologically active molecules targeting the cellular DNA. This review paper summarizes the various electrochemical approaches used for the study of the interactions between pharmaceuticals and DNA. The main focus is on the papers from the last decade, with particular attention on the voltammetric techniques. The most preferred experimental approaches, the electrode materials and the new methods of modification are presented. The data on the detection ranges, the binding modes and the binding constant values of pharmaceuticals are summarized. Both the importance of the presented research and the importance of future prospects are discussed. Full article
(This article belongs to the Special Issue Anticancer Drug Discovery and Development)
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Figure 1

Figure 1
<p>Types of interactions between molecules and the DNA chain.</p> Full article ">Figure 2
<p>(<b>A</b>) Cyclic voltammogram of 2 × 10−4 M 1,5-ppz-AQ in an aqueous buffer at pH 7.4 in the absence (dashed line) and the presence (solid line) of 10–100 μM ct-DNA on the glassy carbon electrode. Scan rate: 100 mV s−1, temperature: 25 °C; (<b>B</b>) Cyclic voltammogram of 2 × 10−4 M ethidium bromide in aqueous buffer at pH 7.4 in the absence (dashed line) and the presence (solid line) of 10–100 μM ctDNA on the glassy carbon electrode. Scan rate: 100 mV s−1, temperature: 25 °C. Figure adapted from the reference [<a href="#B24-molecules-26-03478" class="html-bibr">24</a>] with permission from Elsevier.</p> Full article ">Figure 3
<p>(<b>A</b>) The plot of log [1-(I<sub>0</sub>/I)] versus log [1/DNA] used to calculate the binding constant of 1,5-ppz-AQ-ctDNA complex; (<b>B</b>) The plot of log [1-(I<sub>0</sub>/I)] versus log [1/DNA] used to calculate the binding constant of the ethidium bromide–ct-DNA complex. Figure adapted from the reference [<a href="#B24-molecules-26-03478" class="html-bibr">24</a>] with permission from Elsevier.</p> Full article ">Figure 4
<p>DP voltammograms, with no conditioning potential, in a 0.1 M acetate buffer with a pH of 4.5, with the dsDNA-electrochemical biosensor after: (<b>A</b>) (▬) 30 min in the buffer control experiment, and incubation in: 10 μM of danusertib during (•••) 15, (⁃⁃⁃) 30 and (<span style="color:red">▬</span>) 60 min, and (<b>B</b>) incubation in (▬) 5 μM and (<span style="color:red">▬</span>) 25 μM of danusertib during 30 min. Figure adapted from the reference [<a href="#B45-molecules-26-03478" class="html-bibr">45</a>] with permission from Elsevier.</p> Full article ">Figure 5
<p>DPV voltammograms of 10.0 μM DSB with increasing concentrations of DNA in an acetate buffer solution with a pH of 4.8. Insets: (<b>A</b>) C<sub>DNA</sub>−i<span class="html-italic"><sub>p</sub></span><sub>DSB</sub>; (<b>B</b>) C<sub>DNA</sub>−E<span class="html-italic"><sub>p</sub></span><sub>DSB</sub>; (<b>C</b>) <math display="inline"><semantics> <mrow> <mi>log</mi> <mfrac> <mrow> <msub> <mi>i</mi> <mrow> <mi>d</mi> <mi>r</mi> <mi>u</mi> <mi>g</mi> <mo>−</mo> <mi>D</mi> <mi>N</mi> <mi>A</mi> </mrow> </msub> </mrow> <mrow> <msub> <mi>i</mi> <mrow> <mi>d</mi> <mi>r</mi> <mi>u</mi> <mi>g</mi> </mrow> </msub> <mo>−</mo> <msub> <mi>i</mi> <mrow> <mi>d</mi> <mi>r</mi> <mi>u</mi> <mi>g</mi> <mo>−</mo> <mi>D</mi> <mi>N</mi> <mi>A</mi> </mrow> </msub> </mrow> </mfrac> <mo>−</mo> <mi>log</mi> <mfenced> <mrow> <mfrac> <mn>1</mn> <mrow> <mfenced close="]" open="["> <mrow> <mi>D</mi> <mi>N</mi> <mi>A</mi> </mrow> </mfenced> </mrow> </mfrac> </mrow> </mfenced> </mrow> </semantics></math>. Figure adapted from the reference [<a href="#B54-molecules-26-03478" class="html-bibr">54</a>] with permission from Elsevier.</p> Full article ">Figure 6
<p>(<b>A</b>) Schematic illustration of the formation of amino acids-Cu<sub>3</sub>(PO<sub>4</sub>)<sub>2</sub> hybrid NFs, (<b>B</b>) The representative scheme of the pretreatment of PGE (i), modification of NFs (ii), immobilization of DNA (iii) and DNR (iv), surface-confined interaction of DNR and ctdsDNA (vi). Figure adapted from the reference [<a href="#B53-molecules-26-03478" class="html-bibr">53</a>] with permission from Elsevier.</p> Full article ">Figure 7
<p>SEM image of (<b>A</b>) GNFs; (<b>B</b>) LNFs; (<b>C</b>) PGE; (<b>D</b>) GNFs-PGE; (<b>E</b>) LNFs-PGE ((<b>a</b>–<b>c</b>)—different resolutions) and EDX pattern (<b>d</b>). Figure adapted from the reference [<a href="#B52-molecules-26-03478" class="html-bibr">52</a>] with permission from Elsevier.</p> Full article ">Figure 8
<p>The experimental steps of the modification of LVN at the PGE surface, voltammetric determination of fsDNA and DNR using LVN-PGE and the voltammetric analysis of the biomolecular interaction between fsDNA and DNR at the LVN-PGE surface. Figure adapted from the reference [<a href="#B56-molecules-26-03478" class="html-bibr">56</a>] with permission from Elsevier.</p> Full article ">Figure 9
<p>Electrochemical characterization of the surface layer assembly. (<b>A</b>) CVs at a scan rate of 100 mVs<sup>−1</sup> and (<b>B</b>) The Nyquist diagrams of impedance recorded on (a) bare PGE, (b) PGE coated with poly(CTAB-MWCNTs), (c) 150 μg/mL dsDNA immobilized poly(CTAB-MWCNTs)/PGE in 0.1 M KCl solution containing 5.0 mM Fe(CN)<sub>6</sub> <sup>3−</sup>/<sup>4−</sup> (Inset represents the equivalent circuit model for fitted impedance data. R<sub>s</sub> is the solution resistance; R<sub>ct</sub> is the charge transfer resistance at the electrode/electrolyte interface; C is the constant phase element related to the space charge capacitance at the electrode/electrolyte interface; W is the Warburg element). Figure adapted from the reference [<a href="#B55-molecules-26-03478" class="html-bibr">55</a>] with permission from Elsevier.</p> Full article ">
19 pages, 5981 KiB  
Article
DFT Calculations of 1H NMR Chemical Shifts of Geometric Isomers of Conjugated Linolenic Acids, Hexadecatrienyl Pheromones, and Model Triene-Containing Compounds: Structures in Solution and Revision of NMR Assignments
by Themistoklis Venianakis, Christina Oikonomaki, Michael G. Siskos, Alexandra Primikyri and Ioannis P. Gerothanassis
Molecules 2021, 26(11), 3477; https://doi.org/10.3390/molecules26113477 - 7 Jun 2021
Cited by 9 | Viewed by 4664
Abstract
A DFT study of the 1H NMR chemical shifts, δ(1H), of geometric isomers of 18:3 conjugated linolenic acids (CLnAs), hexadecatrienyl pheromones, and model triene-containing compounds is presented, using standard functionals (B3LYP and PBE0) as well as corrections for dispersion interactions [...] Read more.
A DFT study of the 1H NMR chemical shifts, δ(1H), of geometric isomers of 18:3 conjugated linolenic acids (CLnAs), hexadecatrienyl pheromones, and model triene-containing compounds is presented, using standard functionals (B3LYP and PBE0) as well as corrections for dispersion interactions (B3LYP-D3, APFD, M06–2X and ωB97XD). The results are compared with literature experimental δ(1H) data in solution. The closely spaced “inside” olefinic protons are significantly more deshielded due to short-range through-space H…H steric interactions and appear close to or even beyond δ-values of aromatic systems. Several regularities of the computational δ(1H) of the olefinic protons of the conjugated double bonds are reproduced very accurately for the lowest-energy DFT-optimized single conformer for all functionals used and are in very good agreement with experimental δ(1H) in solution. Examples are provided of literature studies in which experimental resonance assignments deviate significantly from DFT predictions and, thus, should be revised. We conclude that DFT calculations of 1H chemical shifts of trienyl compounds are powerful tools (i) for the accurate prediction of δ(1H) even with less demanding functionals and basis sets; (ii) for the unequivocal identification of geometric isomerism of conjugated trienyl systems that occur in nature; (iii) for tackling complex problems of experimental resonance assignments due to extensive signal overlap; and (iv) for structure elucidation in solution. Full article
(This article belongs to the Special Issue Theme Issue in Honor of Professor Atta-Ur-Rahman, FRS)
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Graphical abstract

Graphical abstract
Full article ">Figure 1
<p>Chemical structures of three geometric isomers of the 18:3 ω-5 conjugated linolenic acid, four geometric isomers of the 16:3 ω-2 conjugated hexadecatrienyl acetate, and triene-containing model compounds investigated in the present work.</p> Full article ">Figure 2
<p>(<b>A</b>) Calculated, δ<sub>calc</sub>, <sup>1</sup>H NMR chemical shifts with CPCM of the olefinic protons vs. experimental, δ<sub>exp</sub>, chemical shifts using the same level of theory as geometry optimization for the model trienyl compounds (<span class="html-italic">Z</span>)-1,3,5-hexatriene, (<span class="html-italic">E</span>)-1,3,5-hexatriene, (<span class="html-italic">E,Z,E</span>)-2,4,6-octatriene, and (<span class="html-italic">E,E,E</span>)-2,4,6-octatriene. (<b>B</b>) The same as in (A), but the literature experimental values of δ(H (3,6)) = 5.83 ppm and δ(H (4,5)) = 6.50 ppm of (<span class="html-italic">E,Z,E</span>)-2,4,6-octatriene [<a href="#B23-molecules-26-03477" class="html-bibr">23</a>] have been reversed.</p> Full article ">Figure 2 Cont.
<p>(<b>A</b>) Calculated, δ<sub>calc</sub>, <sup>1</sup>H NMR chemical shifts with CPCM of the olefinic protons vs. experimental, δ<sub>exp</sub>, chemical shifts using the same level of theory as geometry optimization for the model trienyl compounds (<span class="html-italic">Z</span>)-1,3,5-hexatriene, (<span class="html-italic">E</span>)-1,3,5-hexatriene, (<span class="html-italic">E,Z,E</span>)-2,4,6-octatriene, and (<span class="html-italic">E,E,E</span>)-2,4,6-octatriene. (<b>B</b>) The same as in (A), but the literature experimental values of δ(H (3,6)) = 5.83 ppm and δ(H (4,5)) = 6.50 ppm of (<span class="html-italic">E,Z,E</span>)-2,4,6-octatriene [<a href="#B23-molecules-26-03477" class="html-bibr">23</a>] have been reversed.</p> Full article ">Figure 3
<p>Effect of the variation in the torsion angle φ (C<sub>1</sub>C<sub>2</sub>C<sub>3</sub>C<sub>4</sub>) of (<span class="html-italic">Z</span>)-1,3,5-hexatriene, with energy minimization at the B3LYP/6–31+G(d) level, on the electronic energy Δ<span class="html-italic">E</span> (kcal/mol) (characteristic Δ<span class="html-italic">G</span> values are also shown) (<b>A</b>), and δ<sub>calc</sub>(<sup>1</sup>H) data of the olefinic protons (at the GIAO/B3LYP/6–311+G(2d,p) level with CPCM in CHCl<sub>3</sub>) (<b>B</b>). The experimental chemical shift values are denoted with the horizontal dotted lines.</p> Full article ">Figure 4
<p>Effect of variation in the torsion angle φ<sub>1</sub>(C<sub>2</sub>C<sub>3</sub>C<sub>4</sub>C<sub>5</sub>) of (<span class="html-italic">E</span>,<span class="html-italic">Z,E</span>)-2,4,6-octatriene, with energy minimization at the B3LYP/6–31+G(d) level, on the electronic energy Δ<span class="html-italic">E</span> (kcal/mol) (characteristic Δ<span class="html-italic">G</span> values are also shown) (<b>A</b>) and on the olefinic δ<sub>calc</sub>(<sup>1</sup>H) data (at the GIAO/B3LYP/6–311+G(2d,p) level with CPCM in CHCl<sub>3</sub>) (<b>B</b>). The experimental chemical shift values are denoted with the horizontal dotted lines.</p> Full article ">Figure 5
<p>Effect of variation in the torsion angle φ<sub>2</sub>(C<sub>1</sub>C<sub>2</sub>C<sub>3</sub>C<sub>4</sub>) of (<span class="html-italic">E</span>)-1,3,5-hexatriene, with energy minimization at the B3LYP/6–31+G(d) level, on the electronic energy Δ<span class="html-italic">E</span> (kcal/mol) (characteristic Δ<span class="html-italic">G</span> values are also shown) (<b>A</b>) and on the olefinic δ<sub>calc</sub>(<sup>1</sup>H) data (at the GIAO/B3LYP/6–311+G(2d,p) level with CPCM in CHCl<sub>3</sub>) (<b>B</b>). The experimental chemical shift values are denoted with the horizontal dotted lines.</p> Full article ">Figure 6
<p>Effect of variation in the torsion angle φ<sub>3</sub> (C<sub>2</sub>C<sub>3</sub>C<sub>4</sub>C<sub>5</sub>) of (<span class="html-italic">E</span>,<span class="html-italic">E,E</span>)-2,4,6-octatriene, with energy minimization at the B3LYP/6–31+G(d) level, on the electronic energy Δ<span class="html-italic">E</span> (kcal/mol) (characteristic Δ<span class="html-italic">G</span> values are also shown) (<b>A</b>) and on δ<sub>calc</sub>(<sup>1</sup>H) data of the olefinic protons (at the GIAO/B3LYP/6–311+G(2d,p) level of theory with CPCM in CCl<sub>4</sub>) (<b>B</b>). The experimental chemical shift values are denoted with the horizontal dotted lines.</p> Full article ">Figure 7
<p>Structures of various conformers (<b>A</b>–<b>E</b>) of the β-eleostearic acid (9<span class="html-italic">E</span>,11<span class="html-italic">E</span>,13<span class="html-italic">E</span>-isomer) with energy minimization in the gas phase at the B3LYP/6–31+G(d) level of theory. Δ<span class="html-italic">G</span> values (kcal·mol<sup>−1</sup>) and % populations of conformers (<b>A</b>–<b>E</b>) are shown in <a href="#molecules-26-03477-t002" class="html-table">Table 2</a>.</p> Full article ">Figure 8
<p>Definition of various conformations of the allylic carbon C8 of β-eleostearic acid (9<span class="html-italic">E</span>,11<span class="html-italic">E</span>,13<span class="html-italic">E</span> isomer).</p> Full article ">Figure 9
<p>(<b>A</b>) Calculated, δ<sub>calc</sub>, <sup>1</sup>H NMR chemical shifts of the olefinic protons at the GIAO/B3LYP/6–311+G(2d,p) level with CPCM) vs. experimental, δ<sub>exp</sub>, chemical shifts with energy minimization using B3LYP/6–31+G(d) and APFD/6–31+G(d) for <span class="html-italic">(Z</span>)-1,3,5-hexatriene, (<span class="html-italic">E</span>)-1,3,5-hexatriene, (<span class="html-italic">E,Z,E</span>)-2,4,6-octatriene, (<span class="html-italic">E,E,E</span>)-2,4,6-octatriene, α-oleostearic acid (9<span class="html-italic">Z</span>, 11<span class="html-italic">E</span>, 13<span class="html-italic">E</span>), <span class="html-italic">β</span>-oleostearic acid (9<span class="html-italic">E</span>, 11<span class="html-italic">E</span>, 13<span class="html-italic">E</span>), punicic acid (9<span class="html-italic">Z</span>, 11<span class="html-italic">E</span>, 13<span class="html-italic">Z</span>), and (10<span class="html-italic">E</span>, 12<span class="html-italic">E</span>, 14<span class="html-italic">Z</span>)-, (10<span class="html-italic">E</span>,12<span class="html-italic">Z</span>,14<span class="html-italic">Z</span>)-, (10<span class="html-italic">Z</span>, 12<span class="html-italic">Z</span>, 14<span class="html-italic">E</span>)-, and (10<span class="html-italic">Z</span>, 12<span class="html-italic">E</span>, 14<span class="html-italic">E</span>)-hexatrienyl acetates. (<b>B</b>) The same as in (<b>A</b>); however, the literature experimental chemical shift data (δ<sub>exp</sub>) of the compounds shown in <a href="#app1-molecules-26-03477" class="html-app">Figure S14</a> have been revised.</p> Full article ">
13 pages, 2198 KiB  
Article
Investigation of Antifungal Mechanisms of Thymol in the Human Fungal Pathogen, Cryptococcus neoformans
by Kwang-Woo Jung, Moon-Soo Chung, Hyoung-Woo Bai, Byung-Yeoup Chung and Sungbeom Lee
Molecules 2021, 26(11), 3476; https://doi.org/10.3390/molecules26113476 - 7 Jun 2021
Cited by 16 | Viewed by 3622
Abstract
Due to lifespan extension and changes in global climate, the increase in mycoses caused by primary and opportunistic fungal pathogens is now a global concern. Despite increasing attention, limited options are available for the treatment of systematic and invasive mycoses, owing to the [...] Read more.
Due to lifespan extension and changes in global climate, the increase in mycoses caused by primary and opportunistic fungal pathogens is now a global concern. Despite increasing attention, limited options are available for the treatment of systematic and invasive mycoses, owing to the evolutionary similarity between humans and fungi. Although plants produce a diversity of chemicals to protect themselves from pathogens, the molecular targets and modes of action of these plant-derived chemicals have not been well characterized. Using a reverse genetics approach, the present study revealed that thymol, a monoterpene alcohol from Thymus vulgaris L., (Lamiaceae), exhibits antifungal activity against Cryptococcus neoformans by regulating multiple signaling pathways including calcineurin, unfolded protein response, and HOG (high-osmolarity glycerol) MAPK (mitogen-activated protein kinase) pathways. Thymol treatment reduced the intracellular concentration of Ca2+ by controlling the expression levels of calcium transporter genes in a calcineurin-dependent manner. We demonstrated that thymol decreased N-glycosylation by regulating the expression levels of genes involved in glycan-mediated post-translational modifications. Furthermore, thymol treatment reduced endogenous ergosterol content by decreasing the expression of ergosterol biosynthesis genes in a HOG MAPK pathway-dependent manner. Collectively, this study sheds light on the antifungal mechanisms of thymol against C. neoformans. Full article
(This article belongs to the Special Issue Biomolecules from Essential Oil Bearing Plants: Biological and Industrial Applications)
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Graphical abstract

Graphical abstract
Full article ">Figure 1
<p>The calcineurin pathway is required for thymol resistance. (<b>A</b>) Growth inhibition of <span class="html-italic">C. neoformans</span> signaling mutants to monoterpenoid compounds that originate from thyme oil, including thymol, <span class="html-italic">p</span>-cymene, and carvacrol. (<b>B</b>,<b>C</b>) Expression levels of genes involved in calcium transport were determined using quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis with cDNA synthesized from total RNA isolated from the WT (H99) strain (<b>B</b>) and the indicated strains (<b>C</b>) treated with thymol (1 mM) during the indicated time-points. (<b>D</b>) Relative levels of intracellular Ca<sup>2+</sup> concentration in the WT and <span class="html-italic">cna1</span>Δ mutant upon thymol treatment. The fold differences of target genes were statistically analyzed using the Bonferroni’s multiple comparison test and relative Ca<sup>2+</sup> intensity was statistically analyzed using the Bonferroni’s selected comparison test performed with Prism software (* <span class="html-italic">p</span> &lt; 0.05, ** <span class="html-italic">p</span> &lt; 0.01, *** <span class="html-italic">p</span> &lt; 0.001, and NS non-significant).</p> Full article ">Figure 2
<p>Calcineurin pathway is involved in thymol resistance in a Crz1-independent manner. (<b>A</b>) Phosphorylation of Crz1 in response to thymol. Total proteins were extracted from Crz1-FLAG strains treated with or without thymol (1 mM) for 2 h. The electrophoretic mobility of Crz1 was monitored using an anti-FLAG antibody. Anti-Hog1 polyclonal antibody was used as a loading control. (<b>B</b>) Crz1 was found to be not involved in thymol resistance in <span class="html-italic">C. neoformans</span>. The overnight-cultured <span class="html-italic">C. neoformans</span> strains were serially diluted and spotted onto a yeast-peptone-dextrose (YPD) plate containing the indicated concentration of thymol. Cells were further incubated at 30 °C and photographed daily for 3 days.</p> Full article ">Figure 3
<p>Thymol induces ER stress through reduction of protein glycosylation. (<b>A</b>) RT-PCR analysis of <span class="html-italic">HXL1</span> splicing upon thymol treatment. <span class="html-italic">HXL1<sup>us</sup></span> and <span class="html-italic">HXL1<sup>s</sup></span> indicate the unspliced and spliced versions of <span class="html-italic">HXL1</span>, respectively. (<b>B</b>) Ire1 controls thymol resistance in an Hxl1-independent manner. (<b>C</b>) Quantitative RT-PCR analysis of UPR downstream genes upon thymol treatment. Fold difference in the expression of the target genes was statistically analyzed using the Bonferroni’s multiple comparison test performed with Prism software (* <span class="html-italic">p</span> &lt; 0.05, ** <span class="html-italic">p</span> &lt; 0.01, and *** <span class="html-italic">p</span> &lt; 0.001). (<b>D</b>) The glycosylation level of Cpy1 was reduced upon thymol treatment. TM is used as an inhibitor of protein glycosylation. Anti-Hog1 polyclonal antibody was used as a loading control. (<b>E</b>) The overlapping roles in thymol resistance between calcineurin and UPR pathways. TM, tunicamycin.</p> Full article ">Figure 4
<p>Thymol decreased cellular ergosterol content in a Hog1-dependent manner. (<b>A</b>) Thymol induced Hog1 dephosphorylation. Hog1 phosphorylation was detected using an anti-dually phosphorylated p38 antibody. Hog1 polyclonal antibody was used as a loading control. (<b>B</b>) Expression levels of gene involved in ergosterol biosynthesis reduced upon thymol treatment. cDNA was synthesized from total RNA obtained from the <span class="html-italic">C. neoformans</span> wild-type (H99) strain treated with or without thymol. For statistical analysis, the Bonferroni’s multiple comparison test was performed using Prism software. (<b>C</b>) Change in cellular ergosterol measurement in the WT and <span class="html-italic">hog1</span>Δ mutant, in the presence or absence of thymol. Relative ergosterol contents were calculated with 5α-cholestan-3β-ol as an internal control. For statistical analysis, experiments with three independent biological samples were executed. Error bars indicate S.E.M. Asterisks indicate statistical significance of difference (* <span class="html-italic">p</span> &lt; 0.05, ** <span class="html-italic">p</span> &lt; 0.01, *** <span class="html-italic">p</span> &lt; 0.001, and NS non-significant). AU, arbitrary unit.</p> Full article ">Figure 5
<p>The redundant role of HOG and calcineurin pathways in thymol resistance. (<b>A</b>,<b>B</b>) Overnight-cultured cells were serially diluted (1 to 10<sup>4</sup>) and spotted onto YPD media containing the indicated concentration of thymol with and without sorbitol (0.05 or 0.25 M). The cells were further incubated at 30 °C for 4 days and photographed daily.</p> Full article ">Figure 6
<p>The suggested antifungal mechanism of thymol in <span class="html-italic">C. neoformans</span>. Thymol induced Hog1-dephosphorylation, thereby decreasing ergosterol biosynthesis. Thymol resulted in intracellular calcium imbalance by regulation of calcium transporter genes in calcineurin-dependent and -independent manners. Furthermore, thymol affects protein glycosylation by controlling expressions of genes encoding <span class="html-italic">O</span>-glycosylation and <span class="html-italic">N</span>-glycosylation.</p> Full article ">
18 pages, 4019 KiB  
Article
Unveiling Putative Functions of Mucus Proteins and Their Tryptic Peptides in Seven Gastropod Species Using Comparative Proteomics and Machine Learning-Based Bioinformatics Predictions
by Viroj Tachapuripunya, Sittiruk Roytrakul, Pramote Chumnanpuen and Teerasak E-kobon
Molecules 2021, 26(11), 3475; https://doi.org/10.3390/molecules26113475 - 7 Jun 2021
Cited by 20 | Viewed by 4511
Abstract
Gastropods are among the most diverse animals. Gastropod mucus contains several glycoproteins and peptides that vary by species and habitat. Some bioactive peptides from gastropod mucus were identified only in a few species. Therefore, using biochemical, mass spectrometric, and bioinformatics approaches, this study [...] Read more.
Gastropods are among the most diverse animals. Gastropod mucus contains several glycoproteins and peptides that vary by species and habitat. Some bioactive peptides from gastropod mucus were identified only in a few species. Therefore, using biochemical, mass spectrometric, and bioinformatics approaches, this study aimed to comprehensively identify putative bioactive peptides from the mucus proteomes of seven commonly found or commercially valuable gastropods. The mucus was collected in triplicate samples, and the proteins were separated by 1D-SDS-PAGE before tryptic digestion and peptide identification by nano LC-MS/MS. The mucus peptides were subsequently compared with R scripts. A total of 2818 different peptides constituting 1634 proteins from the mucus samples were identified, and 1218 of these peptides (43%) were core peptides found in the mucus of all examined species. Clustering and correspondence analyses of 1600 variable peptides showed unique mucous peptide patterns for each species. The high-throughput k-nearest neighbor and random forest-based prediction programs were developed with more than 95% averaged accuracy and could identify 11 functional categories of putative bioactive peptides and 268 peptides (9.5%) with at least five to seven bioactive properties. Antihypertensive, drug-delivering, and antiparasitic peptides were predominant. These peptides provide an understanding of gastropod mucus, and the putative bioactive peptides are expected to be experimentally validated for further medical, pharmaceutical, and cosmetic applications. Full article
(This article belongs to the Special Issue The Machine Learning Applications in the Discovery of New Bioactive Molecules)
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<p>Mucus samples from seven gastropod species separated on 1D-SDS polyacrylamide gels. The gels were stained with Coomassie brilliant blue (<b>A</b>) and silver nitrate (<b>B</b>). By lane: 1, MW = protein molecular marker; 2, AF = <span class="html-italic">Achatina fulica</span>; 3, PC = <span class="html-italic">Pomacea canaliculata</span>; 4, CS = <span class="html-italic">Cryptozona siamensis</span>; 5, SS = <span class="html-italic">Semperula siamensis</span>; 6, HD = <span class="html-italic">Hemiplecta distincta</span>; 7, CF = <span class="html-italic">Cyclophorus fulguratus</span>; and 8, and HP = <span class="html-italic">Helix pomatia</span>.</p> Full article ">Figure 2
<p>Comparative proteomes and peptides of mucus from seven gastropod species. (<b>A</b>) Number of protein bands of the mucus proteins from seven gastropod species separated by 1D-SDS-PAGE and stained by Coomassie brilliant blue (blue) and silver nitrate (red) as counted by the GelAnalyzer program. The number of protein bands is shown on the <span class="html-italic">x</span>-axis. The gastropod species are shown on the <span class="html-italic">y</span>-axis. (<b>B</b>) Functional annotation terms of the mucus proteome in three Gene Ontology categories (<span class="html-italic">y</span>-axis) biological process (BP), molecular function (MF), and cellular component (CC). The <span class="html-italic">x</span>-axis represents the number of proteins. (<b>C</b>) The number of different peptides identified in the mucus of seven gastropod species. These peptide data were obtained from the mass spectrometric analysis. The number of peptides is shown on the <span class="html-italic">x</span>-axis. AF = <span class="html-italic">Achatina fulica</span>; PC = <span class="html-italic">Pomacea canaliculata</span>; CS = <span class="html-italic">Cryptozona siamensis</span>; SS = <span class="html-italic">Semperula siamensis</span>; HD = <span class="html-italic">Hemiplecta distincta</span>; CF = <span class="html-italic">Cyclophorus fulguratus</span>; and HP = <span class="html-italic">Helix pomatia</span>.</p> Full article ">Figure 3
<p>Clustering of peptides identified in the mucus of seven gastropod species. The peptides were clustered according to their presence (<b>A</b>), relative abundance (<b>B</b>), molecular mass (<b>C</b>), number of amino acids or length (<b>D</b>), hydrophobicity score (<b>E</b>), numbers of positively charged amino acids (<b>F</b>), and negatively charged amino acids (<b>G</b>). Columns represent gastropod species, and rows represent peptides. AF = <span class="html-italic">Achatina fulica</span>; PC = <span class="html-italic">Pomacea canaliculata</span>; CS = <span class="html-italic">Cryptozona siamensis</span>; SS = <span class="html-italic">Semperula siamensis</span>; HD = <span class="html-italic">Hemiplecta distincta</span>; CF = <span class="html-italic">Cyclophorus fulguratus</span>; and HP = <span class="html-italic">Helix pomatia</span>.</p> Full article ">Figure 4
<p>Correspondence analysis of 28 patterns of variable peptides in the mucus of seven gastropod species. Blue squares in the heatmap (<b>A</b>) indicate the presence of the peptide, and white squares indicate the absence of a peptide. The sizes of the red circles in the balloon plot (<b>B</b>) indicate the number of peptides within each pattern. The biplot (<b>C</b>) shows global patterns of the variable peptides (blue circles) and the gastropod species (triangles) according to the first two dimensions (Dim1 and Dim2). Colors of the square cosine scores indicate the gastropod species. The scores for the first five dimensions (Dim1 to Dim5) are shown in (<b>D</b>), and the sizes of the green circles represent the score level. AF = <span class="html-italic">Achatina fulica</span>; PC = <span class="html-italic">Pomacea canaliculata</span>; CS = <span class="html-italic">Cryptozona siamensis</span>; SS = <span class="html-italic">Semperula siamensis</span>; HD = <span class="html-italic">Hemiplecta distincta</span>; CF = <span class="html-italic">Cyclophorus fulguratus</span>; and HP = <span class="html-italic">Helix pomatia</span>.</p> Full article ">Figure 5
<p>Prediction of 20 bioactive properties from the mucous peptides of seven gastropod species. The predictions were based on two machine-learning algorithms (k-nearest neighbor and random forest). (<b>A</b>) The prediction results show peptides that were predicted by either method in light blue, whereas those predicted by both methods are colored in dark blue. (<b>B</b>) Distribution of the bioactive peptides across seven gastropod species. Sizes of the red circles represent the number of peptides. (<b>C</b>) Number of the bioactive peptides classified by the properties are presented in the same order as the properties in (A). (<b>D</b>) Number of bioactive peptides (indicated by numbers on top of the bars) that had multiple bioactive properties (from one to seven). AP: antiparasitic, DD: drug-delivering, AC: anticancer, AV: antiviral, CC: cell-communicating, TH: tumor-homing, AF: antifungal, AI: anti-inflammatory, CP: cell-penetrating, AB: antibacterial, Abi: antibiofilm, QS: quorum-sensing, and AH: antihypertensive properties. The abbreviations of the gastropod species are the same as those presented in <a href="#molecules-26-03475-f004" class="html-fig">Figure 4</a>.</p> Full article ">
11 pages, 1800 KiB  
Article
Monitoring the Reaction of the Body State to Antibiotic Treatment against Helicobacter pylori via Infrared Spectroscopy: A Case Study
by Kiran Sankar Maiti and Alexander Apolonski
Molecules 2021, 26(11), 3474; https://doi.org/10.3390/molecules26113474 - 7 Jun 2021
Cited by 12 | Viewed by 2462
Abstract
The current understanding of deviations of human microbiota caused by antibiotic treatment is poor. In an attempt to improve it, a proof-of-principle spectroscopic study of the breath of one volunteer affected by a course of antibiotics for Helicobacter pylori eradication was performed. Fourier [...] Read more.
The current understanding of deviations of human microbiota caused by antibiotic treatment is poor. In an attempt to improve it, a proof-of-principle spectroscopic study of the breath of one volunteer affected by a course of antibiotics for Helicobacter pylori eradication was performed. Fourier transform spectroscopy enabled searching for the absorption spectral structures sensitive to the treatment in the entire mid-infrared region. Two spectral ranges were found where the corresponding structures strongly correlated with the beginning and end of the treatment. The structures were identified as methyl ester of butyric acid and ethyl ester of pyruvic acid. Both acids generated by bacteria in the gut are involved in fundamental processes of human metabolism. Being confirmed by other studies, measurement of the methyl butyrate deviation could be a promising way for monitoring acute gastritis and anti-Helicobacter pylori antibiotic treatment. Full article
(This article belongs to the Special Issue Recent Advances in Volatile Organic Compound Analysis as Diagnostic Biomarkers)
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<p>Absorbance variation (proportional to the concentration variation) of three spectral structures centered at 2972 cm<sup>−1</sup>, 1170 cm<sup>−1</sup> (<b>left</b>), and 1130 cm<sup>ß1</sup> (<b>right</b>) caused by QAC. The lines connecting the data points are used for better visibility. Vertical dash lines show the start of the QAC course (left line), the end of the antibiotic course (middle line) and the end of the probiotic course. The corresponding bars indicate the same: orange horizontal bar shows the antibiotic treatment in frame of QAC whereas blue bar—Omnibiotic 10 course taken in parallel to QAC. Absorbances at −62 and 58 days at the plots correspond to the steady state level of the corresponding VOC. Data points corresponding to dates earlier than −60 and longer than 60 days were collected and used only for analysis; they are not presented here in order to improve the visibility of the plots.</p> Full article ">Figure 2
<p>Variation of the absorbance centered at 2972 cm<sup>−1</sup> during a period of 3.5 years, with the peak related to accute gastritis and QAC. Inset: the recovering dynamics via QAC.</p> Full article ">Figure 3
<p>(<b>a</b>) Breath absorption spectra at 1130 cm<sup>−1</sup> together with the ethyl pyruvate spectrum (red) taken from [<a href="#B27-molecules-26-03474" class="html-bibr">27</a>] as the best fitting candidate, and at 1170 cm<sup>−1</sup> together with the methyl butyrate [<a href="#B27-molecules-26-03474" class="html-bibr">27</a>] (grey). The spectra correspond to day “−2” (the first elevated points on the left plot of <a href="#molecules-26-03474-f001" class="html-fig">Figure 1</a>). Noisy signals are caused by the presence of residual water. (<b>b</b>) The difference (red) between the inflammation (day “0”, turquoise blue) and normal state (day “10 February 2018”, gray). Sharp spikes in the turquoise blue and gray curves belong to methane. (<b>c</b>) Differential (see text) breath absorption spectrum taken during the antibiotic treatment together with the measured methyl butyrate absorption spectrum as the best fitting candidate (red).</p> Full article ">Figure 4
<p>Orange curve: measured absorption spectrum of methyl butyrate; blue curve: result of numerical calculation (see <a href="#sec3dot4-molecules-26-03474" class="html-sec">Section 3.4</a>). Inset: 3D structure of methyl butyrate. Green arrows show the movement of atoms in the complex vibration linked to the peak at 1170 cm<sup>−1</sup>. Red balls: oxygen, large grey balls: carbon, small grey pins: hydrogen.</p> Full article ">
20 pages, 39435 KiB  
Article
Role of Organic and Eco-Friendly Inhibitors on the Corrosion Mitigation of Steel in Acidic Environments—A State-of-Art Review
by Hyun-Min Yang
Molecules 2021, 26(11), 3473; https://doi.org/10.3390/molecules26113473 - 7 Jun 2021
Cited by 70 | Viewed by 6037
Abstract
Steel has versatile application in chemical, structure and construction industries owing to its mechanical properties. However, it is susceptible to corrosion in acid environments. Thus, it requires to protect the steel from corrosion. Different types of corrosion resistance steel, coatings and inhibitors are [...] Read more.
Steel has versatile application in chemical, structure and construction industries owing to its mechanical properties. However, it is susceptible to corrosion in acid environments. Thus, it requires to protect the steel from corrosion. Different types of corrosion resistance steel, coatings and inhibitors are developed to mitigate the corrosion, but, inhibitor is the best remedies to control the corrosion of steel in acid condition. Moreover, organic and green inhibitors used in acid condition for descaling, acid pickling, pipelines, boiler tubes and oil-wells. Organic inhibitors reduce the dissolution of steel in acid but, it is hazardous, expensive and needs expertise to synthesize the inhibitor. Therefore, there is utmost required to study and compile the latest research about the eco-friendly corrosion inhibitors, which showed more than 90% corrosion inhibition efficiency. In the present study, I have reviewed the state-of-arts, and compile the latest development in organic and eco-friendly corrosion inhibitor used in acid environment as well as suggested about the future scope and role of green inhibitor for sustainable society, which is economical, less hazardous and readily available from the natural sources. Full article
(This article belongs to the Special Issue Ecofriendly Inhibitor to Mitigate the Corrosion of Metals and Alloys)
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<p>Adsorption action of inhibitor on steel surface.</p> Full article ">Figure 2
<p>Schematic of a boiler [<a href="#B59-molecules-26-03473" class="html-bibr">59</a>].</p> Full article ">Figure 3
<p>Variation of inhibition efficiency with immersion time of UMOD for N-80 steel in 15% boiling HCl from weight loss measurements [<a href="#B70-molecules-26-03473" class="html-bibr">70</a>].</p> Full article ">Figure 4
<p>Micrographs of mild steel after immersion in 2 M HCl solution in the presence of 400 ppm of the inhibitor [<a href="#B72-molecules-26-03473" class="html-bibr">72</a>].</p> Full article ">Figure 5
<p>SEM of mild steel (<b>a</b>) after polishing, (<b>b</b>) after immersion in 1.0 mol·L<sup>−1</sup> HCl and (<b>c</b>) after immersion in 1.0 mol·L<sup>−1</sup> HCl + 0.04% Na-CMC [<a href="#B75-molecules-26-03473" class="html-bibr">75</a>].</p> Full article ">Figure 6
<p>Relationship between inhibition efficiency (IE) and BAP concentration in 1.0 M H<sub>2</sub>SO<sub>4</sub> [<a href="#B76-molecules-26-03473" class="html-bibr">76</a>].</p> Full article ">Figure 7
<p>Dependence of the inhibition efficiency values (IE%) obtained from weight loss, polarization, impedance and EFM methods recorded for a LCS in 4.0 M H<sub>2</sub>SO<sub>4</sub> solutions containing different concentrations of KI alone, AD alone and various concentrations of AD in presence of 0.0005 and 0.001 M KI [<a href="#B81-molecules-26-03473" class="html-bibr">81</a>].</p> Full article ">Figure 8
<p>Variation of the protection efficiency with (<b>a</b>) the logarithmic concentrations of the inhibitors in 1.0 M H<sub>2</sub>SO<sub>4</sub> at 30 °C and (<b>b</b>) temperatures at concentration 5 × 10<sup>−4</sup> M inhibitors [<a href="#B82-molecules-26-03473" class="html-bibr">82</a>].</p> Full article ">Figure 9
<p>Corrosion protection mechanism of Guar gum in 1 M H<sub>2</sub>SO<sub>4</sub> solution [<a href="#B83-molecules-26-03473" class="html-bibr">83</a>].</p> Full article ">Figure 10
<p>Optical micrographs showing (<b>a</b>) pitting (without inhibitor) and (<b>b</b>) adsorbed layer by 4% EDA on carbon steel surface in 16% petroleum water [<a href="#B135-molecules-26-03473" class="html-bibr">135</a>].</p> Full article ">Figure 11
<p>Scanning electron micrographs for: (<b>a</b>) polished mild steel, (<b>b</b>) mild steel in 20% formic acid and (<b>c</b>) mild steel in 20% formic acid +100 ppm APT [<a href="#B139-molecules-26-03473" class="html-bibr">139</a>].</p> Full article ">
11 pages, 2513 KiB  
Article
Development of a Promising Method for Producing Oligomeric Mixture of Branched Alkylene Guanidines to Improve Substance Quality and Evaluate Their Antiviral Activity against SARS-CoV-2
by Denis O. Shatalov, Stanislav A. Kedik, Ivan S. Ivanov, Anna V. Aydakova, Diana A. Akhmedova, Dmitrii S. Minenkov, Sergei V. Beliakov, Alexander Herbst, Lasse Greiner, Liubov I. Kozlovskaya and Viktor P. Volok
Molecules 2021, 26(11), 3472; https://doi.org/10.3390/molecules26113472 - 7 Jun 2021
Cited by 3 | Viewed by 2430
Abstract
This paper reports the synthesis of branched alkylene guanidines using microfluidic technologies. We describe the preparation of guanidine derivatives at lower temperatures, and with significantly less time than that required in the previously applicable method. Furthermore, the use of microfluidics allows the attainment [...] Read more.
This paper reports the synthesis of branched alkylene guanidines using microfluidic technologies. We describe the preparation of guanidine derivatives at lower temperatures, and with significantly less time than that required in the previously applicable method. Furthermore, the use of microfluidics allows the attainment of high-purity products with a low residual monomer content, which can expand the range of applications of this class of compounds. For all the samples obtained, the molecular-weight characteristics are calculated, based on which the optimal condensation conditions are established. Additionally, in this work, the antiviral activity of the alkylene guanidine salt against the SARS-CoV-2 virus is confirmed. Full article
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<p>This is a figure. Schemes follow the same formatting. 1—GH and HMDA aqueous solution; 2—medium-pressure syringe pump module; 3—PC; 4—microreactor; 5—cyclone; 6—flask-receiver of ammonia; 7—rotary evaporator.</p> Full article ">Figure 2
<p>Typical <sup>13</sup>C-NMR spectrum of OHMG-HC.</p> Full article ">Figure 3
<p><sup>13</sup>C-NMR spectra of the obtained samples.</p> Full article ">Figure 4
<p>Approximations of Mn (L, h) and z (L, h) based on batches 2, 4, 5 and 6. (<b>a</b>) z as functions of L and h; (<b>b</b>) Mn, as functions of L and h; (<b>c</b>) Overlay plots of Mn and z, as functions of L and h.</p> Full article ">Figure 5
<p>NMR spectrum after optimization.</p> Full article ">Figure 6
<p>ESI-TOF mass spectrum after optimization.</p> Full article ">
13 pages, 2205 KiB  
Article
Photoinduced DNA Cleavage and Photocytotoxic of Phenanthroline-Based Ligand Ruthenium Compounds
by Xia Hu, Ning-Yi Liu, Yuan-Qing Deng, Shan Wang, Ting Liu and Xue-Wen Liu
Molecules 2021, 26(11), 3471; https://doi.org/10.3390/molecules26113471 - 7 Jun 2021
Cited by 6 | Viewed by 2496
Abstract
The photophysical and biological properties of two new phenanthroline-based ligand ruthenium complexes were investigated in detail. Their DNA interaction modes were determined to be the intercalation mode using spectra titration and viscosity measurements. Under irradiation, obvious photo-reduced DNA cleavages were observed in the [...] Read more.
The photophysical and biological properties of two new phenanthroline-based ligand ruthenium complexes were investigated in detail. Their DNA interaction modes were determined to be the intercalation mode using spectra titration and viscosity measurements. Under irradiation, obvious photo-reduced DNA cleavages were observed in the two complexes via singlet oxygen generation. Furthermore, complex 2 showed higher DNA affinity, photocleavage activity, and singlet oxygen quantum yields than complex 1. The two complexes showed no toxicity towards tumor cells (HeLa, A549, and A375) in the dark. However, obvious photocytotoxicities were observed in the two complexes. Complex 2 exhibited large PIs (phototherapeutic indices) (ca. 400) towards HeLa cells. The study suggests that these complexes may act as DNA intercalators, DNA photocleavers, and photocytotoxic agents. Full article
(This article belongs to the Special Issue Application of Nucleic Acid Probe in Analysis and Detection)
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<p>Absorption spectra of <b>1</b> (<b>A</b>) and <b>2</b> (<b>B</b>) (20 μM) incubating various concentrations of ct-DNA. Inset: plots of (<span class="html-italic">ε</span><sub>a</sub> − <span class="html-italic">ε</span><sub>f</sub>)<span class="html-italic">/</span>(<span class="html-italic">ε</span><sub>b</sub> − <span class="html-italic">ε</span><sub>f</sub>) vs. DNA.</p> Full article ">Figure 2
<p>Comparison of DNA (0.25 mM) viscosity of the compounds. [Ru]/[DNA] = 0, 0.04, 0.06, 0.08, 0.1.</p> Full article ">Figure 3
<p>Luminescence spectra of complex <b>1</b> (<b>A</b>) and <b>2</b> (<b>B</b>) (5 μM) with various concentrations of ct-DNA in a tris buffer.</p> Full article ">Figure 4
<p>Luminescence quenching curves of two complexes (5 μM) without or with DNA (400 μM) at various concentrations of [Fe(CN)<sub>6</sub>]<sup>4−</sup>.</p> Full article ">Figure 5
<p>Photoinduced cleavage of pBR322 DNA (0.1 μg) by complex <b>1</b> (<b>a</b>) and <b>2</b> (<b>b</b>) (20 μM) after 2 h irradiation. Lane 0: DNA only, no hv; lane 1: DNA + Ru(20 μM), no hv; lane 2–5: DNA + Ru, hv.</p> Full article ">Figure 6
<p>Photoinduced cleavage of pBR322 DNA incubating different scavengers after 2 h irradiation for <b>1</b> (<b>a</b>) and <b>2</b> (<b>b</b>) (30 μM).</p> Full article ">Figure 7
<p>Fluorescence spectra of the DPBF (20 μM) mixed with <b>1</b> (<b>A</b>) or <b>2</b> (<b>B</b>) (20 μM) in methanol.</p> Full article ">Figure 8
<p>Cell viabilities of A549 cells pretreated with various concentrations of complexes <b>1</b> and <b>2</b> for 12 h and irradiated at 450 nm, for 10 min (6 mW/cm<sup>2</sup>).</p> Full article ">Scheme 1
<p>Synthesis of pni, complexes <b>1</b> and <b>2</b>.</p> Full article ">
10 pages, 792 KiB  
Article
Application of an LC–MS/MS Method for the Simultaneous Quantification of Homovanillic Acid and Vanillylmandelic Acid for the Diagnosis and Follow-Up of Neuroblastoma in 357 Patients
by Narae Hwang, Eunbin Chong, Hyeonju Oh, Hee Won Cho, Ji Won Lee, Ki Woong Sung and Soo-Youn Lee
Molecules 2021, 26(11), 3470; https://doi.org/10.3390/molecules26113470 - 7 Jun 2021
Cited by 15 | Viewed by 3664
Abstract
Homovanillic acid (HVA) and vanillylmandelic acid (VMA) are end-stage metabolites of catecholamine and are clinical biomarkers for the diagnosis of neuroblastoma. For the first time in Korea, we implemented and validated a liquid chromatography tandem mass spectrometry (LC–MS/MS) assay to measure urinary concentrations [...] Read more.
Homovanillic acid (HVA) and vanillylmandelic acid (VMA) are end-stage metabolites of catecholamine and are clinical biomarkers for the diagnosis of neuroblastoma. For the first time in Korea, we implemented and validated a liquid chromatography tandem mass spectrometry (LC–MS/MS) assay to measure urinary concentrations of HVA and VMA according to Clinical and Laboratory Standards Institute guidelines. Our LC–MS/MS assay with minimal sample preparation was validated for linearity, lower limit of detection (LOD), lower limit of quantification (LLOQ), precision, accuracy, extraction recovery, carryover, matrix effect, and method comparison. A total of 1209 measurements was performed to measure HVA and VMA in spot urine between October 2019 and September 2020. The relationship between the two urinary markers, HVA and VMA, was analyzed and exhibited high agreement (89.1% agreement, kappa’s k = 0.6) and a strong correlation (Pearson’s r = 0.73). To our knowledge, this is the first study to utilize LC–MS/MS for simultaneous quantitation of spot urinary HVA and VMA and analyze the clinical application of both markers on a large scale for neuroblastoma patients. Full article
(This article belongs to the Special Issue Application of LC–MS/MS to Biochemistry)
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<p>Relationship between 1209 VMA and HVA concentrations in 357 patients.</p> Full article ">Figure 2
<p>Representative LC–MS/MS chromatograms of blank urine spiked with HVA (10 μg/mL), VMA (10 μg/mL), and their internal standards (HVA-d<sub>5</sub> and VMA-d<sub>3</sub>, 5 μg/mL).</p> Full article ">
9 pages, 1873 KiB  
Article
Impact of Crystal Habit on the Dissolution Rate and In Vivo Pharmacokinetics of Sorafenib Tosylate
by Chi Uyen Phan, Jie Shen, Kaxi Yu, Jianming Mao and Guping Tang
Molecules 2021, 26(11), 3469; https://doi.org/10.3390/molecules26113469 - 7 Jun 2021
Cited by 15 | Viewed by 3537
Abstract
The dissolution rate is the rate-limiting step for Biopharmaceutics Classification System (BCS) class II drugs to enhance their in vivo pharmacokinetic behaviors. There are some factors affecting the dissolution rate, such as polymorphism, particle size, and crystal habit. In this study, to improve [...] Read more.
The dissolution rate is the rate-limiting step for Biopharmaceutics Classification System (BCS) class II drugs to enhance their in vivo pharmacokinetic behaviors. There are some factors affecting the dissolution rate, such as polymorphism, particle size, and crystal habit. In this study, to improve the dissolution rate and enhance the in vivo pharmacokinetics of sorafenib tosylate (Sor-Tos), a BCS class II drug, two crystal habits of Sor-Tos were prepared. A plate-shaped crystal habit (ST-A) and a needle-shaped crystal habit (ST-B) were harvested by recrystallization from acetone (ACN) and n-butanol (BuOH), respectively. The surface chemistry of the two crystal habits was determined by powder X-ray diffraction (PXRD) data, molecular modeling, and face indexation analysis, and confirmed by X-ray photoelectron spectroscopy (XPS) data. The results showed that ST-B had a larger hydrophilic surface than ST-A, and subsequently a higher dissolution rate and a substantial enhancement of the in vivo pharmacokinetic performance of ST-B. Full article
(This article belongs to the Collection Poorly Soluble Drugs)
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Full article ">Figure 1
<p>Molecular structure of sorafenib tosylate.</p> Full article ">Figure 2
<p>Compound micrographs of the crystal habit of Sor-Tos crystals grown from (<b>a</b>) acetone and (<b>b</b>) n-butanol.</p> Full article ">Figure 3
<p>Overlay of PXRD patterns of ST-A, ST-B, and calculated ST.</p> Full article ">Figure 4
<p>Face indexation data of (<b>a</b>) ST-A and (<b>b</b>) ST-B.</p> Full article ">Figure 5
<p>(<b>a</b>) LP analysis of Sor-Tos, moving from orange to blue on the scale, indicates increasing hydrophilic potential. (<b>b</b>) The corresponding molecular structure of Sor-Tos. The hydrophilic and hydrophobic moieties of Sor-Tos are shown in light blue and orange circles, respectively.</p> Full article ">Figure 6
<p>Molecular surface packing visualized along with the surface chemistry of (<b>a</b>) the (100) and (-100) as well as (<b>b</b>) (001) and (00-1) facets.</p> Full article ">Figure 7
<p>Dissolution rates of ST-A and ST-B in (<b>a</b>) water, (<b>b</b>) gastric juice pH 1.2 acid solution, and (<b>c</b>) in vivo pharmacokinetic profiles of ST-A and ST-B.</p> Full article ">
12 pages, 2313 KiB  
Article
Understanding the Effects of Crosslinking and Reinforcement Agents on the Performance and Durability of Biopolymer Films for Cultural Heritage Protection
by Giulia Infurna, Giuseppe Cavallaro, Giuseppe Lazzara, Stefana Milioto and Nadka Tzankova Dintcheva
Molecules 2021, 26(11), 3468; https://doi.org/10.3390/molecules26113468 - 7 Jun 2021
Cited by 13 | Viewed by 2877
Abstract
In the last two decades, the naturally occurring polysaccharides, such as chitosan and pectin, have gained great attention having potential applications in different sectors, from biomedical to new generation packaging. Currently, the chitosan and pectic have been proposed as suitable materials also for [...] Read more.
In the last two decades, the naturally occurring polysaccharides, such as chitosan and pectin, have gained great attention having potential applications in different sectors, from biomedical to new generation packaging. Currently, the chitosan and pectic have been proposed as suitable materials also for the formulation of films and coatings for cultural heritage protection, as well as packaging films. Therefore, the formulation of biopolymer films, considering only naturally occurring polymers and additives, is a current challenging trend. This work reports on the formulation of chitosan (CS), pectin (PC), and chitosan:pectin (CS:PC) films, also containing natural crosslinking and reinforcement agents, such as citric acid (CA) and halloysite nanotubes (HNT), through the solvent casting technique. The produced films are characterized through water contact angle measurements, infrared and UV–visible spectroscopy and tensile test, while the durability of the CS:PC films is evaluated subjecting the film to accelerated UVB exposure and monitoring the photo-oxidation degradation in time though infrared spectroscopy. All obtained results suggest that both crosslinking and reinforcement agents have beneficial effects on the wettability, rigidity, and photo-oxidation resistance of biopolymer films. Therefore, these biopolymer films, also containing naturally occurring additives, have good properties and performance and they are suitable as coverage films for cultural heritage protection. Full article
(This article belongs to the Special Issue Investigation of Polymer Nanocomposites' Performance)
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Graphical abstract
Full article ">Figure 1
<p>Frame of water contact angle (WCA) immediately after drop deposition on the biopolymer films surface.</p> Full article ">Figure 2
<p>Main mechanical properties of all investigated samples.</p> Full article ">Figure 3
<p>UV–visible spectra of biopolymer films containing citric acid (CA) or halloysite nanotubes (HNT) in which the matrix is (<b>a</b>) chitosan, CS, (<b>b</b>) pectin, PC, (<b>c</b>) chitosan:pectin blend, CS:PC.</p> Full article ">Figure 4
<p>FT-IR spectra of biopolymer films containing citric acid (CA) or halloysite nanotubes (HNT) in different matrices: (<b>a</b>) chitosan, CS, (<b>b</b>) pectin, PC, (<b>c</b>) chitosan:pectin blend, CS:PC; (<b>d</b>) ATR-FTIR spectrum of neat CA.</p> Full article ">Figure 4 Cont.
<p>FT-IR spectra of biopolymer films containing citric acid (CA) or halloysite nanotubes (HNT) in different matrices: (<b>a</b>) chitosan, CS, (<b>b</b>) pectin, PC, (<b>c</b>) chitosan:pectin blend, CS:PC; (<b>d</b>) ATR-FTIR spectrum of neat CA.</p> Full article ">Figure 5
<p>FTIR spectra at different exposure time of (<b>a</b>) CS:PC, (<b>b</b>) CS:PC/CA and (<b>c</b>) CS:PC/HNT films.</p> Full article ">Figure 6
<p>Variation of (<b>a</b>) &gt;C=O (~1630 cm<sup>−1</sup>) and (<b>b</b>) NH bending (~1530 cm<sup>−1</sup>) for CS:PC, CS:PC/CA and CS:PC/HNT films.</p> Full article ">
13 pages, 38609 KiB  
Article
Paclitaxel-Loaded Magnetic Nanoparticles Based on Biotinylated N-Palmitoyl Chitosan: Synthesis, Characterization and Preliminary In Vitro Studies
by Vlad Constantin Ursachi, Gianina Dodi, Alina Gabriela Rusu, Cosmin Teodor Mihai, Liliana Verestiuc and Vera Balan
Molecules 2021, 26(11), 3467; https://doi.org/10.3390/molecules26113467 - 7 Jun 2021
Cited by 11 | Viewed by 3041
Abstract
A considerable interest in cancer research is represented by the development of magnetic nanoparticles based on biofunctionalized polymers for controlled-release systems of hydrophobic chemotherapeutic drugs targeted only to the tumor sites, without affecting normal cells. The objective of the paper is to present [...] Read more.
A considerable interest in cancer research is represented by the development of magnetic nanoparticles based on biofunctionalized polymers for controlled-release systems of hydrophobic chemotherapeutic drugs targeted only to the tumor sites, without affecting normal cells. The objective of the paper is to present the synthesis and in vitro evaluation of the nanocomposites that include a magnetic core able to direct the systems to the target, a polymeric surface shell that provides stabilization and multi-functionality, a chemotherapeutic agent, Paclitaxel (PTX), and a biotin tumor recognition layer. To our best knowledge, there are no studies concerning development of magnetic nanoparticles obtained by partial oxidation, based on biotinylated N-palmitoyl chitosan loaded with PTX. The structure, external morphology, size distribution, colloidal and magnetic properties analyses confirmed the formation of well-defined crystalline magnetite conjugates, with broad distribution, relatively high saturation magnetization and irregular shape. Even if the ability of the nanoparticles to release the drug in 72 h was demonstrated, further complex in vitro and in vivo studies will be performed in order to validate the magnetic nanoparticles as PTX delivery system. Full article
(This article belongs to the Special Issue Multifunctional magnetic hybrid nanomaterials for biomedical applications: Paving the Old, Opening the way for the New)
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<p>Schematic diagram of the composite magnetic nanoparticles synthesis.</p> Full article ">Figure 2
<p>TEM micrographs of PTX-MN nanoparticles.</p> Full article ">Figure 3
<p>FTIR spectra of PTX, drug-free MN nanoparticles and PTX-MN nanoparticles.</p> Full article ">Figure 4
<p>DTG (<b>A</b>) and TG (<b>B</b>) curves of PTX, PTX-MN nanoparticles and drug-free MN nanoparticles.</p> Full article ">Figure 5
<p>XRD diffractograms of Mg-NaOl and PTX-MN.</p> Full article ">Figure 6
<p>Magnetization curve of PTX-MN.</p> Full article ">Figure 7
<p>CytoViva hyperspectral microscopy data: (<b>A</b>) PTX-MN spectrum, filtered against drug-free nanoparticles spectrum (inset); (<b>B</b>) PTX-MN mapping; and (<b>C</b>) MDA-MB-231 cells in the presence of PTX-MN.</p> Full article ">Figure 8
<p>In vitro drug release of PTX-MN.</p> Full article ">Figure 9
<p>Biodegradation data of PTX-MN and MN.</p> Full article ">Figure 10
<p>Cellular viability-MTT assay on MCF-7 and MDA-MB-231 cell lines of MN (<b>A</b>) and PTX-MN nanoparticles (<b>B</b>).</p> Full article ">
25 pages, 9165 KiB  
Article
Design, Synthesis, Biological Evaluation and Silico Prediction of Novel Sinomenine Derivatives
by Shoujie Li, Mingjie Gao, Xin Nian, Liyu Zhang, Jinjie Li, Dongmei Cui, Chen Zhang and Changqi Zhao
Molecules 2021, 26(11), 3466; https://doi.org/10.3390/molecules26113466 - 7 Jun 2021
Cited by 8 | Viewed by 2846
Abstract
Sinomenine is a morphinan alkaloid with a variety of biological activities. Its derivatives have shown significant cytotoxic activity against different cancer cell lines in many studies. In this study, two series of sinomenine derivatives were designed and synthesized by modifying the active positions [...] Read more.
Sinomenine is a morphinan alkaloid with a variety of biological activities. Its derivatives have shown significant cytotoxic activity against different cancer cell lines in many studies. In this study, two series of sinomenine derivatives were designed and synthesized by modifying the active positions C1 and C4 on the A ring of sinomenine. Twenty-three compounds were synthesized and characterized by spectroscopy (IR, 1H-NMR, 13C-NMR, and HRMS). They were further evaluated for their cytotoxic activity against five cancer cell lines, MCF-7, Hela, HepG2, SW480 and A549, and a normal cell line, Hek293, using MTT and CCK8 methods. The chlorine-containing compounds exhibited significant cytotoxic activity compared to the nucleus structure of sinomenine. Furthermore, we searched for cancer-related core targets and verified their interaction with derivatives through molecular docking. The chlorine-containing compounds 5g, 5i, 5j, 6a, 6d, 6e, and 6g exhibited the best against four core targets AKT1, EGFR, HARS and KARS. The molecular docking results were consistent with the cytotoxic results. Overall, results indicate that chlorine-containing derivatives might be a promising lead for the development of new anticancer agents. Full article
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<p>The structures of sionmenine, morphine and codeine.</p> Full article ">Figure 2
<p>Anticancer activity of compounds <b>5a</b>–<b>5k</b> against MCF-7, Hela, and HepG2 cell lines at 2, 20, and 200 μM concentrations. (<b>A</b>) Human breast cancer cell lines, (<b>B</b>) human cervical cancer cells lines, (<b>C</b>) human hepatocellular carcinoma cell lines.</p> Full article ">Figure 2 Cont.
<p>Anticancer activity of compounds <b>5a</b>–<b>5k</b> against MCF-7, Hela, and HepG2 cell lines at 2, 20, and 200 μM concentrations. (<b>A</b>) Human breast cancer cell lines, (<b>B</b>) human cervical cancer cells lines, (<b>C</b>) human hepatocellular carcinoma cell lines.</p> Full article ">Figure 3
<p>Heat map representation of the primary cytotoxic effects of novel sinomenine derivatives on different cell lines (concentration = 2.5 and 25 μM; incubation time = 60 h).</p> Full article ">Figure 4
<p>The number of genes collected in each database and the total number of genes after duplicates removed for each cancer cell.</p> Full article ">Figure 5
<p>Five cancer disease-related protein interaction networks constructed by Cytoscape. Each network has 10 nodes with the top 10 degrees. (<b>A</b>) Breast cancer-related genes, (<b>B</b>) cervical cancer-related genes, (<b>C</b>) hepatocellular cancer-related genes, (<b>D)</b> colonic cancer-related genes, and (<b>E</b>) lung adenocarcinoma-related genes.</p> Full article ">Figure 6
<p>Gene ontology terms of top 10 targets of five cancer diseases (<span class="html-italic">p</span>-value &lt; 0.05). BP, MF, and CC represent Biological Process, Molecular Function, and Cellular Component groups of GO, respectively. (<b>A</b>) Breast cancer, (<b>B</b>) cervical cancer, (<b>C</b>) hepatocellular cancer, (<b>D</b>) colonic cancer, and (<b>E</b>) lung adenocarcinoma.</p> Full article ">Figure 7
<p>Bubble plot of KEGG pathway enrichment analysis of the genes related to the five cancer diseases. Bubble plot: letters on the left are KEGG names, numbers on the bottom are the proportions of genes, sizes of the circles indicate the numbers of enriched genes, and colors reflect <span class="html-italic">p</span>-values. The redder the colors are, the more enriched the genes, and the smaller the <span class="html-italic">p</span> values. (<span class="html-italic">p</span> is normalized according to −log10). (<b>A</b>) Breast cancer, (<b>B</b>) cervical cancer, (<b>C</b>) hepatocellular cancer, (<b>D</b>) colonic cancer and (<b>E</b>) lung adenocarcinoma.</p> Full article ">Figure 8
<p>The total energy of molecular docking between compounds <b>5a</b>–<b>5k</b> and 11 potential targets.</p> Full article ">Figure 9
<p>The total energy of molecular docking between compounds <b>6a</b>–<b>6l</b> and 13 potential targets.</p> Full article ">Figure 10
<p>The binding pose of the selected ligands. (<b>A</b>) <b>5g</b> docked into the binding cavity of the protein AKT1; (<b>B</b>) <b>5j</b> docked into the binding cavity of the protein EGFR; (<b>C</b>) <b>5i</b> docked into the binding cavity of the protein HRAS; (<b>D</b>) <b>5g</b> docked into the binding cavity of the protein HRAS.</p> Full article ">Figure 11
<p>The binding pose of the selected ligands. (<b>A</b>) <b>6e</b> docked into the binding cavity of the protein AKT1; (<b>B</b>) <b>6d</b> docked into the binding cavity of the protein EGFR; (<b>C</b>) <b>6a</b> docked into the binding cavity of the protein HRAS; (<b>D</b>) <b>6e</b> docked into the binding cavity of the protein HRAS; (<b>E</b>) <b>6g</b> docked into the binding cavity of the protein HRAS; (<b>F</b>) <b>6a</b> docked into the binding cavity of the protein KRAS. The ligand is represented by orange sticks. The active site residues are shown as blue sticks. The main atoms involving hydrogen bonds are indicated by blue lines. The main atoms involving hydrophobic bonds are indicated by grey dashes. The main atoms involving halogen bonds are indicated by green lines. The main atoms involving salt bridges are indicated by yellow dotted lines. The main atoms involving π-stacking are indicated by green dotted lines. The key residues participating in hydrogen bonds and hydrophobic interactions are labeled.</p> Full article ">Scheme 1
<p>Synthetic scheme of compounds <b>2</b>–<b>6</b> (R′ = Compound <b>4</b>, the red gradient circle represents the ester substitution R.)</p> Full article ">
13 pages, 2305 KiB  
Article
Biochemical Studies in Perfundates and Homogenates of Isolated Porcine Kidneys after Flushing with Zinc or Zinc–Prolactin Modified Preservation Solution Using a Static Cold Storage Technique
by Aneta Ostróżka-Cieślik, Barbara Dolińska and Florian Ryszka
Molecules 2021, 26(11), 3465; https://doi.org/10.3390/molecules26113465 - 7 Jun 2021
Cited by 4 | Viewed by 2687
Abstract
Zinc is an effective anti-inflammatory and antioxidant trace element. The aim of this study was to analyse the protective effect of zinc and zinc–prolactin systems as additives of preservation solutions in the prevention of nephron damage caused during ischemia. The study used a [...] Read more.
Zinc is an effective anti-inflammatory and antioxidant trace element. The aim of this study was to analyse the protective effect of zinc and zinc–prolactin systems as additives of preservation solutions in the prevention of nephron damage caused during ischemia. The study used a model for storing isolated porcine kidneys in Biolasol®. The solution was modified with the addition of Zn at a dose of 1 µg/L and Zn: 1 µg/L with prolactin (PRL): 0.1 µg/L. After 2 h and 48 h of storage, the levels of alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, sodium, potassium, creatinine and total protein were determined. Zinc added to the Biolasol® composition at a dose of 1 µg/L showed minor effectiveness in the protection of nephrons. In turn, Zn2+ added to Biolasol + PRL (PRL: 0.1 µg/L) acted as a prolactin inhibitor. We do not recommend the addition of Zn(II) (1 µg/L) and Zn(II) (1 µg/L) + PRL (0.1 µg/L) to the Biolasol solution. Full article
(This article belongs to the Special Issue Bioactive Compounds and Antioxidant Activity of Extracts from Different Natural Plants)
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<p>ALT activity in the collected perfusates and reperfusates in model of storing isolated porcine kidneys. The values are expressed as mean ± SEM. Data were analysed by one-way ANOVA and Bonferroni post hoc tests; n = 10; * <span class="html-italic">p</span> &lt; 0.05; ** <span class="html-italic">p</span> &lt; 0.01 compared to the control group (Biolasol).</p> Full article ">Figure 2
<p>AST activity in the collected perfusates and reperfusates in model of storing isolated porcine kidneys. The values are expressed as mean ± SEM. Data were analysed by one-way ANOVA and Bonferroni post hoc tests; n = 10; * <span class="html-italic">p</span> &lt; 0.05; ** <span class="html-italic">p</span> &lt; 0.01 compared to the control group (Biolasol).</p> Full article ">Figure 3
<p>LDH activity in the collected perfusates and reperfusates in model of storing isolated porcine kidneys. The values are expressed as mean ± SEM. Data were analysed by one-way ANOVA and Bonferroni post hoc tests; n = 10; * <span class="html-italic">p</span> &lt; 0.05; ** <span class="html-italic">p</span> &lt; 0.01 compared to the control group (Biolasol).</p> Full article ">Figure 4
<p>Sodium concentrations in the collected perfusates and reperfusates in model of storing isolated porcine kidneys. The values are expressed as mean ± SEM. Data were analysed by one-way ANOVA and Bonferroni post hoc tests; n = 10; * <span class="html-italic">p</span> &lt; 0.05; ** <span class="html-italic">p</span> &lt; 0.01 compared to the control group (Biolasol).</p> Full article ">Figure 5
<p>Potassium concentrations in the collected perfusates and reperfusates in model of storing isolated porcine kidneys. The values are expressed as mean ± SEM. Data were analysed by one-way ANOVA and Bonferroni post hoc tests; n = 10; * <span class="html-italic">p</span> &lt; 0.05 compared to the control group (Biolasol).</p> Full article ">Figure 6
<p>Activity of biochemical markers in the kidney homogenates in model of storing isolated porcine kidneys. The values are expressed as mean ± SEM. Data were analysed by one-way ANOVA and Bonferroni post hoc tests; n = 10; * <span class="html-italic">p</span> &lt; 0.05; ** <span class="html-italic">p</span> &lt; 0.01 compared to the control group (Biolasol).</p> Full article ">Figure 7
<p>Creatinine and protein concentrations in the kidney homogenates in model of storing isolated porcine kidneys. The values are expressed as mean ± SEM. Data were analysed by one-way ANOVA and Bonferroni post hoc tests; n = 10; * <span class="html-italic">p</span> &lt; 0.05; ** <span class="html-italic">p</span> &lt; 0.01 compared to the control group (Biolasol).</p> Full article ">
6 pages, 951 KiB  
Communication
Pyrrolizidine-Derived Alkaloids: Highly Toxic Components in the Seeds of Crotalaria cleomifolia Used in Popular Beverages in Madagascar
by Anjaramampionona Henintsoa Duvale Solofomalala, Clara Fredeline Rajemiarimoelisoa, Randriamampianina Lovarintsoa Judicael, Hanitra Ranjana Randrianarivo, Danielle Aurore Doll Rakoto, Victor Louis Jeannoda and Ahcène Boumendjel
Molecules 2021, 26(11), 3464; https://doi.org/10.3390/molecules26113464 - 7 Jun 2021
Cited by 5 | Viewed by 2396
Abstract
Seeds of Crotalaria cleomifolia (Fabaceae) are consumed in Madagascar in preparation of popular beverages. The investigation of extracts from the seeds of this species revealed the presence of high amounts of alkaloids from which two pyrrolizidine-derived alkaloids were isolated. One of them was [...] Read more.
Seeds of Crotalaria cleomifolia (Fabaceae) are consumed in Madagascar in preparation of popular beverages. The investigation of extracts from the seeds of this species revealed the presence of high amounts of alkaloids from which two pyrrolizidine-derived alkaloids were isolated. One of them was fully characterized by spectroscopic and spectrometric methods, which was found to be usaramine. Owing to the high toxicity of these alkaloids, issuing a strong warning among populations consuming the seeds of Crotalaria cleomifolia must be considered. Full article
(This article belongs to the Collection Bioactive Compounds)
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<p><span class="html-italic">Crotalaria cleomifolia</span>. From left to right—aerial part, leaves, flowers, and pods.</p> Full article ">Figure 2
<p>Structure of compound <b>1</b> (usaramine), retrosine, integerrimine, and senecionine.</p> Full article ">Figure 3
<p>Scaffolds involved in the biosynthesis of macrocyclic pyrrolizidine-derived alkaloids. The stars (*) indicate that both enantiomers may exist. The carbon–carbon double bond of necic acid can be found in the <span class="html-italic">Z</span> and <span class="html-italic">E</span> configuration.</p> Full article ">
55 pages, 3546 KiB  
Review
Emergent Approaches to Efficient and Sustainable Polyhydroxyalkanoate Production
by Dattatray K. Bedade, Cody B. Edson and Richard A. Gross
Molecules 2021, 26(11), 3463; https://doi.org/10.3390/molecules26113463 - 7 Jun 2021
Cited by 35 | Viewed by 8406
Abstract
Petroleum-derived plastics dominate currently used plastic materials. These plastics are derived from finite fossil carbon sources and were not designed for recycling or biodegradation. With the ever-increasing quantities of plastic wastes entering landfills and polluting our environment, there is an urgent need for [...] Read more.
Petroleum-derived plastics dominate currently used plastic materials. These plastics are derived from finite fossil carbon sources and were not designed for recycling or biodegradation. With the ever-increasing quantities of plastic wastes entering landfills and polluting our environment, there is an urgent need for fundamental change. One component to that change is developing cost-effective plastics derived from readily renewable resources that offer chemical or biological recycling and can be designed to have properties that not only allow the replacement of current plastics but also offer new application opportunities. Polyhydroxyalkanoates (PHAs) remain a promising candidate for commodity bioplastic production, despite the many decades of efforts by academicians and industrial scientists that have not yet achieved that goal. This article focuses on defining obstacles and solutions to overcome cost-performance metrics that are not sufficiently competitive with current commodity thermoplastics. To that end, this review describes various process innovations that build on fed-batch and semi-continuous modes of operation as well as methods that lead to high cell density cultivations. Also, we discuss work to move from costly to lower cost substrates such as lignocellulose-derived hydrolysates, metabolic engineering of organisms that provide higher substrate conversion rates, the potential of halophiles to provide low-cost platforms in non-sterile environments for PHA formation, and work that uses mixed culture strategies to overcome obstacles of using waste substrates. We also describe historical problems and potential solutions to downstream processing for PHA isolation that, along with feedstock costs, have been an Achilles heel towards the realization of cost-efficient processes. Finally, future directions for efficient PHA production and relevant structural variations are discussed. Full article
(This article belongs to the Special Issue Natural Polymers and Biopolymers III)
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<p>Polyhydroxyalkanoates with short chain-length repeat units (Scl-PHA) monomers include 3-hydroxybutyrate (3HB) and 3-hydroxyvalerate (3HV). Mcl-PHA monomers include 3-hydroxyhexanoate (3HHx), 3-hydroxyoctanoate (3HO), 3-hydroxydecanoate (3HD), and 3-hydroxydodecanoate (3-HDD). PHA granules accumulate within the cytoplasm of the bacteria cell.</p> Full article ">Figure 2
<p>Metabolic routes for PHA biosynthesis.</p> Full article ">Figure 3
<p>Using renewable, low-cost carbon sources such as energy crops or waste streams in combination with optimized fermentation strategies supports high yielding PHA production processes. The PHA polymers are processed and manufactured into consumer plastics that will biodegrade when disposed. The cycle begins again when biodegradation products of PHA plastics are consumed during photosynthesis or are recovered in waste streams from composting facilities.</p> Full article ">Figure 4
<p>Process regimes for PHA fermentative synthesis.</p> Full article ">Figure 5
<p>Genetic engineering strategies to improve bacterial strains for PHA production. PHA producing strains can be improved to convert various carbon substrates into PHAs via gene insertion or deletion. PHA synthase genes from PHA producing strains are often inserted in non-PHA producing strains. Using different strains of bacteria facilitates PHA production under conditions that are not suitable for naturally producing PHA strains.</p> Full article ">Figure 6
<p>The use of mixed microbial consortia (MMC) for PHA production.</p> Full article ">Figure 7
<p>Sustainable sources and conversion of feedstocks for PHA production. Provided within the dashed area is a simplified representation of the conversion of waste oils (lipids) to PHAs. The waste lipid is hydrolyzed to yield substrates for fermentation: fatty acids and glycerol. The substrates are purified prior to use in fermentations. Recovered waste biomass can be recycled as a carbon source for future fermentations.</p> Full article ">Figure 8
<p>Key areas of PHA production to optimize to obtain high-yields of PHA. To compete with petroleum-based plastics whilst remaining as environmentally friendly as possible, PHA production requires constant innovation and optimization in four major areas. The cyclic arrows illustrate that any modification to one of the four categories will affect the following stage of production. The strategies presented herein have been proposed due to the published success regarding improved PHA production yields or PHA properties.</p> Full article ">
12 pages, 1413 KiB  
Article
Chemical Composition of Volatile Compounds in Apis mellifera Propolis from the Northeast Region of Pará State, Brazil
by Mozaniel Santana de Oliveira, Jorddy Neves Cruz, Oberdan Oliveira Ferreira, Daniel Santiago Pereira, Natanael Santiago Pereira, Marcos Enê Chaves Oliveira, Giorgio Cristino Venturieri, Giselle Maria Skelding Pinheiro Guilhon, Antônio Pedro da Silva Souza Filho and Eloisa Helena de Aguiar Andrade
Molecules 2021, 26(11), 3462; https://doi.org/10.3390/molecules26113462 - 7 Jun 2021
Cited by 23 | Viewed by 3880
Abstract
Propolis is a balsamic product obtained from vegetable resins by exotic Africanized bees Apis mellifera L., transported and processed by them, originating from the activity that explores and maintains these individuals. Because of its vegetable and natural origins, propolis is a complex mixture [...] Read more.
Propolis is a balsamic product obtained from vegetable resins by exotic Africanized bees Apis mellifera L., transported and processed by them, originating from the activity that explores and maintains these individuals. Because of its vegetable and natural origins, propolis is a complex mixture of different compound classes; among them are the volatile compounds present in the aroma. In this sense, in the present study we evaluated the volatile fraction of propolis present in the aroma obtained by distillation and simultaneous extraction, and its chemical composition was determined using coupled gas chromatography, mass spectrometry, and flame ionization detection. The majority of compounds were sesquiterpene and hydrocarbons, comprising 8.2–22.19% α-copaene and 6.2–21.7% β-caryophyllene, with additional compounds identified in greater concentrations. Multivariate analysis showed that samples collected from one region may have different chemical compositions, which may be related to the location of the resin’s production. This may be related to other bee products. Full article
(This article belongs to the Special Issue Essential Oils 2021)
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Full article ">Figure 1
<p>Biplot (principal component analysis) from the analysis of volatile compound classes identified in the aromas of seven samples of bee propolis from <span class="html-italic">Apis mellifera</span>.</p> Full article ">Figure 2
<p>Dendrogram presenting the relational similarity of the volatile compound classes identified in the aromas of seven bee propolis samples from <span class="html-italic">Apis mellifera</span>.</p> Full article ">Figure 3
<p>Biplot (PCA) from the analysis of volatile compounds identified in the aromas of seven samples of bee propolis from <span class="html-italic">Apis mellifera</span>.</p> Full article ">Figure 4
<p>Dendrogram representing the relational similarity of the volatile compounds identified in the aromas of seven bee propolis samples from <span class="html-italic">Apis mellifera</span>.</p> Full article ">
12 pages, 2082 KiB  
Article
Targeting SARS-CoV-2 Polymerase with New Nucleoside Analogues
by Vasiliki Daikopoulou, Panagiotis Apostolou, Sofia Mourati, Ioanna Vlachou, Maria Gougousi and Ioannis Papasotiriou
Molecules 2021, 26(11), 3461; https://doi.org/10.3390/molecules26113461 - 7 Jun 2021
Cited by 9 | Viewed by 3974
Abstract
Despite the fact that COVID-19 vaccines are already available on the market, there have not been any effective FDA-approved drugs to treat this disease. There are several already known drugs that through drug repositioning have shown an inhibitory activity against SARS-CoV-2 RNA-dependent RNA [...] Read more.
Despite the fact that COVID-19 vaccines are already available on the market, there have not been any effective FDA-approved drugs to treat this disease. There are several already known drugs that through drug repositioning have shown an inhibitory activity against SARS-CoV-2 RNA-dependent RNA polymerase. These drugs are included in the family of nucleoside analogues. In our efforts, we synthesized a group of new nucleoside analogues, which are modified at the sugar moiety that is replaced by a quinazoline entity. Different nucleobase derivatives are used in order to increase the inhibition. Five new nucleoside analogues were evaluated with in vitro assays for targeting polymerase of SARS-CoV-2. Full article
(This article belongs to the Section Medicinal Chemistry)
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Full article ">Figure 1
<p>Remdesivir (<b>1</b>), Sofosbuvir (<b>2</b>) and Ribavirin (<b>3</b>).</p> Full article ">Figure 2
<p>Areas for modification on nucleoside analogues.</p> Full article ">Figure 3
<p>Replacement of sugar moiety with a quinazoline moiety for synthesis of new nucleoside analogues.</p> Full article ">Figure 4
<p>Synthesis of nucleoside analogues <b>6</b>–<b>8</b>. Reagents and conditions: (a) sodium hydroxide solution (2% NaOH), r.t. 4 h, (b) for compound <b>6</b>, adenine, cesium carbonate (Cs<sub>2</sub>CO<sub>3</sub>), silica gel, inert atmosphere, 130 °C, 3.5 h, (c) for compound <b>7</b>, <span class="html-italic">N</span>-acetyl guanine, cesium carbonate (Cs<sub>2</sub>CO<sub>3</sub>), silica gel, inert atmosphere, 130 °C, 24 h, (d) for compound <b>8</b>, <span class="html-italic">N</span>-acetyl cytosine, cesium carbonate (Cs<sub>2</sub>CO<sub>3</sub>), silica gel, inert atmosphere, 130 °C, 24 h.</p> Full article ">Figure 5
<p>Deprotection of compound <b>8</b>. Reagents and conditions: (a) methylamine solution (40%), 65 °C, 24 h.</p> Full article ">Figure 6
<p>Synthesis of compound <b>14</b>. Reagents and conditions: (a) urea, 150 °C, 7 h, (b) POCl<sub>3</sub>, N, <span class="html-italic">N</span>-dimethylaniline, 110 °C, 7 h, (c) sodium hydroxide solution (NaOH 2%), 60 °C, 6 h, (d) adenine, cesium carbonate (Cs<sub>2</sub>CO<sub>3</sub>), silica gel, inert atmosphere, 130 °C, 24 h.</p> Full article ">Figure 7
<p>Phosphorylation of compound <b>6</b>. Reagents and conditions: (a) phosphorus pentachloride (P<sub>2</sub>O<sub>5</sub>), tetrabutylammonium bromide (TBAB), hydrogen peroxide solution (30% H<sub>2</sub>O<sub>2</sub>), CH<sub>3</sub>CN/H<sub>2</sub>O, 0 °C, 5 h.</p> Full article ">Figure 8
<p>In-vitro assay using NSP12 polymerase and different adenine nucleoside inhibitors.</p> Full article ">Figure 9
<p>In-vitro assay using NSP12 polymerase and different adenine, guanine and cytosine nucleoside inhibitors.</p> Full article ">
9 pages, 2235 KiB  
Article
The Investigation on Ultrafast Pulse Formation in a Tm–Ho-Codoped Mode-Locking Fiber Oscillator
by Jingcheng Shang, Yizhou Liu, Shengzhi Zhao, Yuefeng Zhao, Yuzhi Song, Tao Li and Tianli Feng
Molecules 2021, 26(11), 3460; https://doi.org/10.3390/molecules26113460 - 7 Jun 2021
Cited by 6 | Viewed by 3746
Abstract
We experimentally investigate the formation of various pulses from a thulium–holmium (Tm–Ho)-codoped nonlinear polarization rotation (NPR) mode-locking fiber oscillator. The ultrafast fiber oscillator can simultaneously operate in the noise-like and soliton mode-locking regimes with two different emission wavelengths located around 1947 and 2010 [...] Read more.
We experimentally investigate the formation of various pulses from a thulium–holmium (Tm–Ho)-codoped nonlinear polarization rotation (NPR) mode-locking fiber oscillator. The ultrafast fiber oscillator can simultaneously operate in the noise-like and soliton mode-locking regimes with two different emission wavelengths located around 1947 and 2010 nm, which are believed to be induced from the laser transition of Tm3+ and Ho3+ ions respectively. When the noise-like pulse (NLP) and soliton pulse (SP) co-exist inside the laser oscillator, a maximum output power of 295 mW is achieved with a pulse repetition rate of 19.85-MHz, corresponding to a total single pulse energy of 14.86 nJ. By adjusting the wave plates, the fiber oscillator could also deliver the dual-NLPs or dual-SPs at dual wavelengths, or single NLP and single SP at one wavelength. The highest 61-order harmonic soliton pulse and 33.4-nJ-NLP are also realized respectively with proper design of the fiber cavity. Full article
(This article belongs to the Special Issue Advances in Lasers and Optoelectronics)
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Figure 1
<p>The typical pulse shapes and spectral profiles for conventional soliton (<b>a</b>), dissipative soliton (<b>b</b>), dissipative soliton resonance (DSR) (<b>c</b>), noise-like pulse (NLP) (<b>d</b>), bunched solitons (<b>e</b>), and soliton rains (<b>f</b>).</p> Full article ">Figure 2
<p>(<b>a</b>) Output power versus pump power. cw: continuous wave, QML: Q-switched mode-locking, ML: mode-locking. (<b>b</b>) Output laser spectrum in the NLP and SP coexisted mode-locking regime. Inset: typical mode-locking pulse train at the time scale of 20 μs. (<b>c</b>) The radio frequency spectral at the scanning ranges of 1.5 MHz. Inset: 2 GHz. (<b>d</b>) The pulse auto-correlation traces under different pump powers, P: pump power.</p> Full article ">Figure 3
<p>(<b>a</b>) The initial spectrum (gray line) and filtered spectrum (blue line). (<b>b</b>) The SP trains at the time scales of 2 and 20 μs. (<b>c</b>) The RF spectrum of SP at the scanning ranges of 1.3 MHz and 2 GHz (inset). (<b>d</b>) The SP auto-correlation trace. Inset: the SP auto-correlation trace fitted by the sech<sup>2</sup> function.</p> Full article ">Figure 4
<p>The output spectrum under different average output powers evolutions at the maximum pump power. The number marks the central wavelength of the emission spectrum. Single wavelength for single SP (<b>a</b>), (<b>b</b>) and single NLP (<b>f</b>), dual-wavelengths for dual-SPs (<b>c</b>) and dual-NLPs (<b>e</b>), and the coexisted SP and NLP (<b>d</b>).</p> Full article ">Figure 5
<p>(<b>a</b>) The emission spectra under different pump powers. (<b>b</b>) The measured autocorrelation traces under different pump powers. Inset: the SP auto-correlation trace fitted by the sech<sup>2</sup> function at 61-order HML regime. The RF spectra of the 61-order soliton (<b>c</b>) and the NLP (<b>d</b>) at the scanning range of 26.1 MHz and 1.8 MHz. HML: harmonic mode-locking.</p> Full article ">Figure 6
<p>(<b>a</b>) The absorption and emission cross section of Tm<sup>3+</sup> and Ho<sup>3+</sup>. (<b>b</b>) The simplified energy diagram of Tm–Ho-codoped gain fiber pumped at 1560 nm. ET: energy transition, ME: multi-phonon emission.</p> Full article ">Figure 7
<p>Schematic diagram of the Tm–Ho-codoped fiber oscillator. FLA: fiber laser amplifier; PI-ISO: polarization-independent isolator; WDM: wavelength division multiplex; THDF: Tm–Ho-codoped fiber; SMF: single-mode-fiber; PBS: polarization beam splitter; λ/2: half-wave plate; λ/4: quarter-wave plate.</p> Full article ">
47 pages, 13471 KiB  
Review
Bisindole Alkaloids from the Alstonia Species: Recent Isolation, Bioactivity, Biosynthesis, and Synthesis
by Kamal P. Pandey, Md Toufiqur Rahman and James M. Cook
Molecules 2021, 26(11), 3459; https://doi.org/10.3390/molecules26113459 - 7 Jun 2021
Cited by 17 | Viewed by 5082
Abstract
Bisindoles are structurally complex dimers and are intriguing targets for partial and total synthesis. They exhibit stronger biological activity than their corresponding monomeric units. Alkaloids, including those containing C-19 methyl-substitution in their monomeric units, their synthetic derivatives, and their mismatched pairs can be [...] Read more.
Bisindoles are structurally complex dimers and are intriguing targets for partial and total synthesis. They exhibit stronger biological activity than their corresponding monomeric units. Alkaloids, including those containing C-19 methyl-substitution in their monomeric units, their synthetic derivatives, and their mismatched pairs can be attractive targets for synthesis and may unlock better drug targets. We herein discuss the isolation of bisindoles from various Alstonia species, their bioactivity, putative biosynthesis, and synthesis. The total synthesis of macralstonidine, macralstonine, O-acetylmacralstonine, and dispegatrine, as well as the partial synthesis of alstonisidine, villalstonine, and macrocarpamine are also discussed in this review. The completion of the total synthesis of pleiocarpamine by Sato et al. completes the formal synthesis of the latter two bisindoles. Full article
(This article belongs to the Special Issue Alkaloids in Future Drug Discovery)
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<p>Proposed biogenetic pathway to (+)-angustilongine G <b>8</b> and (+)-angustilongine H <b>9</b>.</p> Full article ">Figure 2
<p>Proposed biogenetic pathway to (−)-angustilongine E <b>6</b>, (−)-angustilongine F <b>7</b>, and (+)-angustilongine J <b>10</b>.</p> Full article ">Figure 3
<p>Putative biogenetic pathway to (-)-lumusidines A–D (<b>14</b>–<b>17</b>).</p> Full article ">Figure 4
<p>Putative biogenetic pathway to lumutinines A–D (<b>16</b>–<b>19</b>).</p> Full article ">Figure 5
<p>Possible alternative mechanism of bisindole formation via a Friedel–Crafts alkylation process for (+)-macralstonine <b>24</b> and (+)-lumutinine A <b>18</b>, respectively, as representative examples.</p> Full article ">Figure 6
<p>Pyrolysis of (-)-macrocarpamine <b>31</b> and macrosalhine <b>75</b> to generate key olefin <b>33</b>.</p> Full article ">Figure 7
<p>Abbreviated chemical and biosynthetic relations among the sarpagine/macroline/ajmaline family of alkaloids.</p> Full article ">Figure 8
<p>Representative examples of C-19 methyl-substituted monomeric sarpagine/macroline-related alkaloids from <span class="html-italic">Alstonia</span> species and their bioactivity.</p> Full article ">Figure 9
<p>Examples of C-19 methylated alkaloids synthesized employing the general strategy developed herein.</p> Full article ">Scheme 1
<p>Synthesis of <span class="html-italic">rac</span>-pleiocarpamine <b>32</b> and 16-<span class="html-italic">ep</span>i-pleiocarpamine <b>85</b> by Sato et al.</p> Full article ">Scheme 2
<p>An improved total synthesis of (-)-alstophylline <b>28</b> using modified Wacker (Pd II) conditions.</p> Full article ">Scheme 3
<p>Enantiospecific total synthesis of (-)-anhydromacrosalhine-methine <b>33</b> via the asymmetric Pictet–Spengler reaction.</p> Full article ">Scheme 4
<p>Improved synthesis of (+)-macroline <b>5</b>.</p> Full article ">Scheme 5
<p>Stereoselective total synthesis of macroline <b>5</b> and alstomicine <b>123</b>.</p> Full article ">Scheme 6
<p>Enantiomeric total synthesis of (+)-majvinine <b>128</b> and (+)-<span class="html-italic">N</span><sub>a</sub>-methylsarpagine <b>124</b>.</p> Full article ">Scheme 7
<p>Biomimetic partial synthesis of (-)-alstonisidine <b>3</b>.</p> Full article ">Scheme 8
<p>Biomimetic partial synthesis of (+)-dispegatrine <b>131</b> by oxidative phenolic coupling by Yu et al. [<a href="#B86-molecules-26-03459" class="html-bibr">86</a>].</p> Full article ">Scheme 9
<p>The biomimetic total synthesis of the natural P(<span class="html-italic">S</span>)-atropodiastereomer of (+)-dispegatrine <b>131</b>.</p> Full article ">Scheme 10
<p>Biomimetic total synthesis of macralstonidine <b>23</b> by the condensation of macroline <b>5</b> with <span class="html-italic">N</span><sub>a</sub>-methyl sarpagine <b>124</b> via two possible mechanisms.</p> Full article ">Scheme 11
<p>The biomimetic total synthesis of macralstonine <b>24</b>, and <span class="html-italic">O</span>-acetylmacralstonine <b>25</b>.</p> Full article ">Scheme 12
<p>Partial synthesis of (-)-macrocarpamine <b>31</b>.</p> Full article ">Scheme 13
<p>Biomimetic partial synthesis of (+)-villalstonine <b>43</b>.</p> Full article ">Scheme 14
<p>Intramolecular cyclization of macroline <b>5</b> into dihydroalstonerine <b>105</b>.</p> Full article ">Scheme 15
<p>Improved partial synthesis of (+)-villalstonine <b>43</b>.</p> Full article ">Scheme 16
<p>Improved general strategy toward the tetracyclic ketone intermediates of C-19 methyl-substituted alkaloids.</p> Full article ">Scheme 17
<p>Access to both natural and unnatural enantiomers of C-19 methyl-substituted sarpagine/macroline indole alkaloids from the same chiral tryptophan.</p> Full article ">
18 pages, 2414 KiB  
Review
Epigenetic and Transcriptional Control of the Opioid Prodynorphine Gene: In-Depth Analysis in the Human Brain
by Olga Nosova, Igor Bazov, Victor Karpyak, Mathias Hallberg and Georgy Bakalkin
Molecules 2021, 26(11), 3458; https://doi.org/10.3390/molecules26113458 - 7 Jun 2021
Cited by 4 | Viewed by 3553
Abstract
Neuropeptides serve as neurohormones and local paracrine regulators that control neural networks regulating behavior, endocrine system and sensorimotor functions. Their expression is characterized by exceptionally restricted profiles. Circuit-specific and adaptive expression of neuropeptide genes may be defined by transcriptional and epigenetic mechanisms controlled [...] Read more.
Neuropeptides serve as neurohormones and local paracrine regulators that control neural networks regulating behavior, endocrine system and sensorimotor functions. Their expression is characterized by exceptionally restricted profiles. Circuit-specific and adaptive expression of neuropeptide genes may be defined by transcriptional and epigenetic mechanisms controlled by cell type and subtype sequence-specific transcription factors, insulators and silencers. The opioid peptide dynorphins play a critical role in neurological and psychiatric disorders, pain processing and stress, while their mutations cause profound neurodegeneration in the human brain. In this review, we focus on the prodynorphin gene as a model for the in-depth epigenetic and transcriptional analysis of expression of the neuropeptide genes. Prodynorphin studies may provide a framework for analysis of mechanisms relevant for regulation of neuropeptide genes in normal and pathological human brain. Full article
(This article belongs to the Special Issue Opioids and Their Receptors: Present and Emerging Concepts in Opioid Drug Discovery II)
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<p>Human <span class="html-italic">PDYN</span> gene (modified screenshot from UCSC Genome Browser). (<b>a</b>) Gene structure. (<b>b</b>) Promoter <span class="html-italic">PDYN</span> region with VNTR and TSSs. Conservation across vertebrates. (<b>c</b>) Canonical <span class="html-italic">PDYN</span> mRNAs and transcripts initiated in exon 4. Their conservation across vertebrates. Non-coding sequences are shown by thin <span class="html-italic">dark blue</span> line; coding sequences by thick <span class="html-italic">dark blue</span> line; dynorphin peptides-encoding sequences by <span class="html-italic">yellow</span>. CN, caudate nucleus; NAc, nucleus accumbens; Put, putamen. Modified from [<a href="#B41-molecules-26-03458" class="html-bibr">41</a>].</p> Full article ">Figure 2
<p><span class="html-italic">PDYN</span> mRNAs coding for the full-length (FL, (<b>a</b>)) and truncated proteins (<b>b</b>). (<b>a</b>) Transcripts encoding FL-PDYN protein. The dominant FL1-<span class="html-italic">PDYN</span> and shorter transcripts including FL2-<span class="html-italic">PDYN</span> and <span class="html-italic">GTEx1-3</span> and testis-specific <span class="html-italic">Taf</span> I and <span class="html-italic">Taf</span> II transcripts differ in the first and second exons, and in TSS. (<b>b</b>) PDYN mRNAs encoding truncated PDYN proteins including alternatively spliced Sp1, Sp2, ΔSP-PDYN and ΔSP/NLS-PDYN transcripts, and transcripts initiated within the coding part of exon 4 (T1 and T2). Signal peptide is truncated in both ΔSP- and ΔSP/NLS-PDYN. Putative nuclear localization signal (NLS) is located in the dynorphin domain. Curved arrows show initiation of translation. Modified from [<a href="#B46-molecules-26-03458" class="html-bibr">46</a>].</p> Full article ">Figure 3
<p>Structure of ΔSP-<span class="html-italic">PDYN</span> mRNA and protein, <span class="html-italic">PDYN</span> pathogenic mutations causing SCA23, and nuclear localization of ∆SP-PDYN protein. (<b>a</b>) ΔSP<span class="html-italic">-PDYN</span> encode ΔSP-PDYN protein with truncated signal peptide. Sequences of opioid peptides α-neoendorphin (α-NE), dynorphin A (Dyn A), dynorphinB (Dyn B), and big dynorphin (Big Dyn) are shown in yellow. Pathogenic mutations form a mutational hot spot that is localized within the pathogenic big dynorphin sequence with dynorphin A as a core. (<b>b</b>,<b>c</b>) PDYN immunoreactivity (red) in the nuclei (green) of neurons in the human caudate nucleus. (<b>d</b>) Double labeling (yellow) of neuronal nuclei (arrows) in 3D confocal reconstruction projections. Scale bar, 20 μm. Modified from [<a href="#B46-molecules-26-03458" class="html-bibr">46</a>].</p> Full article ">Figure 4
<p>Locus of human <span class="html-italic">PDYN</span> with targets for transcription factors. (<b>a</b>) Genomic organization showing <span class="html-italic">PDYN</span>, the antisense <span class="html-italic">AK090681</span> transcript and transcription factor targets deposited on UCSC Genome Browser. (<b>b</b>) Verified and putative transcription factor binding elements, promoter VNTR, CpG islands 1 and 2 (CGI 1 and CGI 2), <span class="html-italic">PDYN</span> pathogenic mutations causing neurodegeneration, and DNase I hypersensitivity sequence (DHS), and CpG-SNPs association with alcoholism. Thin <span class="html-italic">light blue</span> line shows non-coding RNA, thick <span class="html-italic">dark blue</span> line coding region, vertical <span class="html-italic">yellow</span> lines dynorphin sequences. Modified from [<a href="#B41-molecules-26-03458" class="html-bibr">41</a>].</p> Full article ">Figure 5
<p>Model for epigenetic and transcriptional regulation of neuronal <span class="html-italic">PDYN</span> transcription. In neurons, USF2 binds to E-box in the promoter CGI that is hypomethylated and enriched in 5-hydroxymethylcytosine (5-hmC). In glia, the CGI is hypermethylated. DMR2 and DMR1/CGI exhibit methylation patterns that are opposite between them and between neurons and glia for each of them. In non-neuronal cells, DMR2 may be targeted by methylation-sensitive transcriptional repressor such as DREAM, while in neurons by a methylation-dependent transcriptional activator. In glia, the DMR1/CGI may be wrapped in a nucleosome, that prevents transcriptional initiation. These mechanisms may underlie contrasting <span class="html-italic">PDYN</span> expression in neurons and glia. Modified from [<a href="#B79-molecules-26-03458" class="html-bibr">79</a>].</p> Full article ">Figure 6
<p>The CpG-SNP hypothesis. (<b>a</b>) Genetic, epigenetic and environmental factors are mechanistically integrated at CpG-SNPs that may be methylated and hydroxymethylated at the C-allele. Two alleles and three cytosine epialleles may differentially affect gene transcription and thereby differently contribute to deasease predisposition [<a href="#B89-molecules-26-03458" class="html-bibr">89</a>]. (<b>b</b>) <span class="html-italic">PDYN</span> SNPs variants associated with alcoholism are shown in <span class="html-italic">blue</span> while those forming CpGs in <span class="html-italic">red</span>. (<b>c</b>) T-allele-binding factor (Ta-BF) has high affinity for the T and methylated C alleles of the 3′-UTR CpG-SNP but not to unmethylated C allele. The high affinity interaction may be a basis for transcriptional activation by this DNA-binding protein.</p> Full article ">Figure 7
<p>Correlation of USF2 and PDYN (<b>a</b>,<b>b</b>), and their co-localization (<b>c</b>–<b>e</b>) in the human dlPFC. (<b>a</b>,<b>b</b>) The estimated effect with 95% confidence interval. Immunoreactivity of (<b>c</b>) PDYN, and (<b>d</b>) USF2 in the cytoplasm and nuclei of the layer V neurons, respectively. (<b>e</b>) Double labeling of PDYN and USF2 in the same neuron. Scale bars, 50 μm (<b>c</b>,<b>d</b>); and 25 μm (<b>e</b>). Modified from [<a href="#B79-molecules-26-03458" class="html-bibr">79</a>].</p> Full article ">
18 pages, 2122 KiB  
Review
Influencing Factors on the Physicochemical Characteristics of Tea Polysaccharides
by Ting Hu, Peng Wu, Jianfeng Zhan, Weixin Wang, Junfeng Shen, Chi-Tang Ho and Shiming Li
Molecules 2021, 26(11), 3457; https://doi.org/10.3390/molecules26113457 - 7 Jun 2021
Cited by 20 | Viewed by 3343
Abstract
Tea polysaccharides (TPSs) are one of the main bioactive constituents of tea with various biological activities such as hypoglycemic effect, antioxidant, antitumor, and immunomodulatory. The bioactivities of TPSs are directly associated with their structures such as chemical composition, molecular weight, glycosidic linkages, and [...] Read more.
Tea polysaccharides (TPSs) are one of the main bioactive constituents of tea with various biological activities such as hypoglycemic effect, antioxidant, antitumor, and immunomodulatory. The bioactivities of TPSs are directly associated with their structures such as chemical composition, molecular weight, glycosidic linkages, and conformation among others. To study the relationship between the structures of TPSs and their bioactivities, it is essential to elucidate the structure of TPSs, particularly the fine structures. Due to the vast variation nature of monosaccharide units and their connections, the structure of TPSs is extremely complex, which is also affected by several major factors including tea species, processing technologies of tea and isolation methods of TPSs. As a result of the complexity, there are few studies on their fine structures and chain conformation. In the present review, we aim to provide a detailed summary of the multiple factors influencing the characteristics of TPS chemical structures such as variations of tea species, degree of fermentation, and preparation methods among others as well as their applications. The main aspects of understanding the structural difference of TPSs and influencing factors are to assist the study of the structure and bioactivity relationship and ultimately, to control the production of the targeted TPSs with the most desired biological activity. Full article
(This article belongs to the Special Issue Food Polysaccharides: Structure, Properties and Application)
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Full article ">Figure 1
<p>General structure of TPSs.</p> Full article ">Figure 2
<p>A schematic diagram of extraction and purification of TPSs.</p> Full article ">
23 pages, 3711 KiB  
Article
Epilobium angustifolium L. Extracts as Valuable Ingredients in Cosmetic and Dermatological Products
by Anna Nowak, Martyna Zagórska-Dziok, Paula Ossowicz-Rupniewska, Edyta Makuch, Wiktoria Duchnik, Łukasz Kucharski, Urszula Adamiak-Giera, Piotr Prowans, Norbert Czapla, Piotr Bargiel, Jan Petriczko, Marta Markowska and Adam Klimowicz
Molecules 2021, 26(11), 3456; https://doi.org/10.3390/molecules26113456 - 7 Jun 2021
Cited by 27 | Viewed by 5886
Abstract
Epilobium angustifolium L. is a popular and well-known medicinal plant. In this study, an attempt to evaluate the possibility of using this plant in preparations for the care and treatment of skin diseases was made. The antioxidant, antiaging and anti-inflammatory properties of ethanolic [...] Read more.
Epilobium angustifolium L. is a popular and well-known medicinal plant. In this study, an attempt to evaluate the possibility of using this plant in preparations for the care and treatment of skin diseases was made. The antioxidant, antiaging and anti-inflammatory properties of ethanolic extracts from Epilobium angustifolium (FEE) were assessed. Qualitative and quantitative evaluation of extracts chemically composition was performed by gas chromatography with mass spectrometry (GC-MS) and high-performance liquid chromatography (HPLC). The total polyphenol content (TPC) of biologically active compounds, such as the total content of polyphenols (TPC), flavonoids (TFC), and assimilation pigments, as well as selected phenolic acids, was assessed. FEE was evaluated for their anti-inflammatory and antiaging properties, achieving 68% inhibition of lipoxygenase activity, 60% of collagenase and 49% of elastase. FEE also showed high antioxidant activity, reaching to 87% of free radical scavenging using 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 59% using 2,2′-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS). Additionally, in vitro penetration studies were performed using two vehicles, i.e., a hydrogel and an emulsion containing FEE. These studies showed that the active ingredients contained in FEE penetrate through human skin and accumulate in it. The obtained results indicate that E. angustifolium may be an interesting plant material to be applied as a component of cosmetic and dermatological preparations with antiaging and anti-inflammatory properties. Full article
(This article belongs to the Special Issue Natural Products and Skin Diseases)
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Full article ">Figure 1
<p>GC-MS chromatogram of the ethanolic extracts of <span class="html-italic">E. angustifolium</span> (FEE).</p> Full article ">Figure 2
<p>Chromatogram of phenolic acid identified in the ethanol extracts from <span class="html-italic">E. angustifolium</span> (FEE): GA—gallic acid; 3,4-DHB—3,4-dihydroxybenzoic acid, 4-HB—4-hydroxybenzoic acid, 3-HB—3-hydroxybenzoic acid, ChA—chlorogenic acid, and CA—caffeic acid.</p> Full article ">Figure 3
<p>Kinetics of the antioxidant activity changes in the DPPH solutions in the presence of various concentrations of ethanolic extracts from <span class="html-italic">E. angustifolium</span> (FEE). Values are the mean of three replicate determinations (<span class="html-italic">n</span> = 3). Different letters—values are significantly different, α &lt; 0.05.</p> Full article ">Figure 4
<p>Kinetics of the antioxidant activity changes in the ABTS solutions in the presence of various concentrations of ethanolic extracts from <span class="html-italic">E. angustifolium</span> (FEE). Values are the mean of three replicate determinations (<span class="html-italic">n</span> = 3). Different letters—values are significantly different, α &lt; 0.05.</p> Full article ">Figure 5
<p>Influence of ethanolic extracts from <span class="html-italic">E. angustifolium</span> (FEE) on the elastase and collagenase inhibitions. SPCK for elastase and 1,10-phenanthroline for collagenase were used as the control inhibitors. Data are the mean ± SD of three independent experiments, each of which consisted of two replicates per treatment group. Vertical lines represent the standard deviation. Different letters—values are significantly different, α &lt; 0.05.</p> Full article ">Figure 6
<p>Influence of ethanolic extracts from <span class="html-italic">E. angustifolium</span> (FEE) on lipoxygenase inhibition. Quercetin was used as a control inhibitor. Data are the mean ± SD of three independent experiments, each of which consisted of two replicates per treatment group. Vertical lines represent the standard deviation. Different letters—values are significantly different, α &lt; 0.05.</p> Full article ">Figure 7
<p>Effect of ethanolic extracts from <span class="html-italic">E. angustifolium</span> (FEE) on the inhibition of protein (BSA) denaturation. Acetylsalicylic acid (aspirin) was used as a control inhibitor. Data are the mean ± SD of three independent experiments, each consisting of three replicates per treatment group. Vertical lines represent the standard deviation. Different letters—values are significantly different, α &lt; 0.05.</p> Full article ">Figure 8
<p>The cumulative mass of phenolic acids in the acceptor fluid during the 24-h penetration after the application of dry ethanolic extracts from <span class="html-italic">E. angustifolium</span> (FEE) in two vehicles. Vertical lines represent the standard deviation, <span class="html-italic">n</span> = 3.</p> Full article ">Figure 9
<p>The content of phenolic acids in the solution obtained after the skin extraction collected after 24-h penetration. Vertical lines represent the standard deviation, <span class="html-italic">n</span> = 3. Different letters—values are significantly different, α &lt; 0.05.</p> Full article ">Figure 10
<p>The hydrogel end emulsions with the dry extracts from <span class="html-italic">E. angustifolium</span> FEE.</p> Full article ">
13 pages, 2156 KiB  
Article
Amino Acid Profile and Biological Properties of Silk Cocoon as Affected by Water and Enzyme Extraction
by Chuleeporn Bungthong, Colin Wrigley, Thanathat Sonteera and Sirithon Siriamornpun
Molecules 2021, 26(11), 3455; https://doi.org/10.3390/molecules26113455 - 7 Jun 2021
Cited by 8 | Viewed by 3664
Abstract
We compared the efficacy for protein extraction of water versus enzymatic extraction. The amino-acid composition, inhibitory activity against enzymes α-amylase and α-glucosidase, and anti-glycation activities of silk protein extract (SPE) were determined. We used water extraction (100 °C, six hours) and protease-enzymatic extraction. [...] Read more.
We compared the efficacy for protein extraction of water versus enzymatic extraction. The amino-acid composition, inhibitory activity against enzymes α-amylase and α-glucosidase, and anti-glycation activities of silk protein extract (SPE) were determined. We used water extraction (100 °C, six hours) and protease-enzymatic extraction. The microstructure of silk fibers was obviously different after extraction. The results showed that enzymatic extraction gave the greater values of protein content, amino acids, total phenolic content (TPC), and total flavonoid content (TFC), as well as all biological activities parameters tested, but it also provided a more bitter taste in the extract—contributing amino acids of 51% (arginine, phenylalanine, histidine, valine, tryptophan, isoleucine, and leucine) and less sweet and umami taste contributing amino acids than did water extraction, which could be more suitable to be used as concentrated nutraceuticals. Full article
(This article belongs to the Special Issue Natural Products in Asia)
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Graphical abstract

Graphical abstract
Full article ">Figure 1
<p>Appearance and microstructure of silk fiber. (<b>A</b>) Control treatment that was immersed in water only and without heating, (<b>B</b>) water extraction and (<b>C</b>) enzymatic extraction, using scanning electron micrographs (SEM; ×200 and ×1200).</p> Full article ">Figure 2
<p>The effect of extraction method on the contribution of amino acids to the taste of SPE.</p> Full article ">Figure 3
<p>The effect of extraction method on total phenolic (TPC) and total flavonoid (TFC) contents of SPE. Values are expressed as mean ± standard deviation (<span class="html-italic">n</span> = 3). Means with different letters on different bars were significantly different among treatments at <span class="html-italic">p</span> &lt; 0.05.</p> Full article ">Figure 4
<p>The effect of extraction method on DPPH radical-scavenging activity, ABTS<sup>+•</sup> assay, and FRAP assay of SPE. Values are expressed as mean ± standard deviation (<span class="html-italic">n</span> = 3). Means with different letters on different bars were significantly different among treatments at <span class="html-italic">p</span> &lt; 0.05.</p> Full article ">Figure 5
<p>The effect of extraction method on inhibitory activity against enzyme α-amylase and α-glucosidase and antiglycation activities of SPE. Values are expressed as mean ± standard deviation (<span class="html-italic">n</span> = 3). Means with different letters on different bars were significantly different among treatments at <span class="html-italic">p</span> &lt; 0.05.</p> Full article ">
17 pages, 5280 KiB  
Article
Quality by Design for Development, Optimization and Characterization of Brucine Ethosomal Gel for Skin Cancer Delivery
by Tamer A. Ismail, Tamer M. Shehata, Dalia I. Mohamed, Heba S. Elsewedy and Wafaa E. Soliman
Molecules 2021, 26(11), 3454; https://doi.org/10.3390/molecules26113454 - 7 Jun 2021
Cited by 38 | Viewed by 3662
Abstract
Natural products have been extensively used for treating a wide variety of disorders. In recent times, Brucine (BRU) as one of the natural medications extracted from seeds of nux vomica, was investigated for its anticancer activity. As far as we know, this is [...] Read more.
Natural products have been extensively used for treating a wide variety of disorders. In recent times, Brucine (BRU) as one of the natural medications extracted from seeds of nux vomica, was investigated for its anticancer activity. As far as we know, this is the first study on BRU anticancer activity against skin cancer. Thus, the rational of this work was implemented to develop, optimize and characterize the anticancer activity of BRU loaded ethosomal gel. Basically, thin film hydration method was used to formulate BRU ethosomal preparations, by means of Central composite design (CCD), which were operated to construct (32) factorial design. Two independent variables were designated (phospholipid percentage and ethanol percentage) with three responses (vesicular size, encapsulation efficiency and flux). Based on the desirability function, one formula was selected and incorporated into HPMC gel base to develop BRU loaded ethosomal gel. The fabricated gel was assessed for all physical characterization. In-vitro release investigation, ex-vivo permeation and MTT calorimetric assay were performed. BRU loaded ethosomal gel exhibited acceptable values for the characterization parameters which stand proper for topical application. In-vitro release investigation was efficiently prolonged for 6 h. The flux from BRU loaded ethosome was enhanced screening optimum SSTF value. Finally, in-vitro cytotoxicity study proved that BRU loaded ethosomal gel significantly improved the anticancer activity of the drug against A375 human melanoma cell lines. Substantially, the investigation proposed a strong motivation for further study of the lately developed BRU loaded ethosomal gel as a prospective therapeutic strategy for melanoma treatment. Full article
(This article belongs to the Special Issue Preparation, Characterization, and Effect of Lipid Nanoparticles Used in Different Application Fields II)
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<p>(<b>A</b>) 2D contour graph, (<b>B</b>) 3D response surface plot demonstrating the influence of independent variables (X<sub>1</sub>) and (X<sub>2</sub>) on ethosome vesicular size (Y<sub>1</sub>) and (<b>C</b>) linear correlation plot between actual and predicted values for response (Y<sub>1</sub>).</p> Full article ">Figure 2
<p>(<b>A</b>) 2D contour graph, (<b>B</b>) 3D response surface plot demonstrating the influence of independent variables (X<sub>1</sub>) and (X<sub>2</sub>) on encapsulation efficiency (Y<sub>2</sub>) and (<b>C</b>) linear correlation plot between actual and predicted values for response (Y<sub>2</sub>).</p> Full article ">Figure 3
<p>(<b>A</b>) 2D contour graph, (<b>B</b>) 3D response surface plot demonstrating the influence of independent variables (X<sub>1</sub>) and (X<sub>2</sub>) on the flux (Y<sub>3</sub>) and (<b>C</b>) linear correlation plot between actual and predicted values for response (Y<sub>3</sub>).</p> Full article ">Figure 4
<p>(<b>A</b>) Optimization plot screening the effect of different variables X<sub>1</sub> and X<sub>2</sub> on overall desirability and (<b>B</b>) overlay plot of the desired responses for the optimal region of ethosome formulation.</p> Full article ">Figure 5
<p>(<b>A</b>) Vesicular size distribution curve (<b>B</b>) Zeta potential of optimized BRU loaded ethosome.</p> Full article ">Figure 6
<p>Scanning electron microscopy of BRU loaded ethosomal gel formulation.</p> Full article ">Figure 7
<p>Profile of In vitro release experiment from BRU preparations at 37 °C. Data are expressed as the mean ± SD (<span class="html-italic">n</span> = 3). * <span class="html-italic">p</span> &lt; 0.05 comparable to BRU suspension, ● <span class="html-italic">p</span> &lt; 0.05 comparable to BRU loaded gel and + <span class="html-italic">p</span> &lt; 0.05 comparable to BRU loaded ethosome.</p> Full article ">Figure 8
<p>Outline skin permeation study of BRU from developed formulations. Data are expressed as mean ± SD (<span class="html-italic">n</span> = 3). * <span class="html-italic">p</span> &lt; 0.05 comparable to BRU suspension, ● <span class="html-italic">p</span> &lt; 0.05 comparable to BRU loaded gel and + <span class="html-italic">p</span> &lt; 0.05 comparable to BRU loaded ethosomal gel.</p> Full article ">Figure 9
<p>In-vitro cytotoxicity study of BRU suspension. Blank ethosome and BRU loaded ethosomal gel against A 375 cell line for 48 h. Data are expressed as mean ± SD (<span class="html-italic">n</span> = 3). * <span class="html-italic">p</span> &lt; 0.05 comparable to control, # <span class="html-italic">p</span> &lt; 0.05 comparable to blank ethosome and <span>$</span> <span class="html-italic">p</span> &lt; 0.05 comparable to BRU suspension.</p> Full article ">
26 pages, 2931 KiB  
Review
Pharmacological Activities of Aminophenoxazinones
by Jesús G. Zorrilla, Carlos Rial, Daniel Cabrera, José M. G. Molinillo, Rosa M. Varela and Francisco A. Macías
Molecules 2021, 26(11), 3453; https://doi.org/10.3390/molecules26113453 - 7 Jun 2021
Cited by 10 | Viewed by 4466
Abstract
Aminophenoxazinones are degradation products resulting from the metabolism of different plant species, which comprise a family of natural products well known for their pharmacological activities. This review provides an overview of the pharmacological properties and applications proved by these compounds and their structural [...] Read more.
Aminophenoxazinones are degradation products resulting from the metabolism of different plant species, which comprise a family of natural products well known for their pharmacological activities. This review provides an overview of the pharmacological properties and applications proved by these compounds and their structural derivatives during 2000–2021. The bibliography was selected according to our purpose from the references obtained in a SciFinder database search for the Phx-3 structure (the base molecule of the aminophenoxazinones). Compounds Phx-1 and Phx-3 are among the most studied, especially as anticancer drugs for the treatment of gastric and colon cancer, glioblastoma and melanoma, among others types of relevant cancers. The main information available in the literature about their mechanisms is also described. Similarly, antibacterial, antifungal, antiviral and antiparasitic activities are presented, including species related directly or indirectly to significant diseases. Therefore, we present diverse compounds based on aminophenoxazinones with high potential as drugs, considering their levels of activity and few adverse effects. Full article
(This article belongs to the Special Issue Current Advances in Medicinal Phytochemistry—A Themed Issue in Honour of Professor Simon Gibbons)
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<p>Prominent benzoxazinones and some of their degradation products.</p> Full article ">Figure 2
<p>Phenoxazine and aminophenoxazinone structures, and some molecules of their different derivatives, like the drug actinomycin D.</p> Full article ">Figure 3
<p>Most studied aminophenoxazinones: 2-amino-4,4<span class="html-italic">α</span>-dihydro-4<span class="html-italic">α</span>,7-dimethyl-3<span class="html-italic">H</span>-phenoxazin-3-one (Phx-1), 3-amino-1,4<span class="html-italic">α</span>-dihydro-4<span class="html-italic">α</span>,8-dimethyl-2<span class="html-italic">H</span>-phenoxazin-2-one (Phx-2) and 2-aminophenoxazine-3-one (Phx-3).</p> Full article ">Figure 4
<p>Structure of <span class="html-italic">N</span>-(2-hydroxyphenyl)-2-phenazinamine (NHP).</p> Full article ">Figure 5
<p>Inhibition of cell growth and induction of apoptosis after treating LN229 cell line with Phx-3. Source: Che et al. [<a href="#B70-molecules-26-03453" class="html-bibr">70</a>] by permission from Spandidos Publications Ltd.</p> Full article ">Figure 6
<p>Effect of Phx-3 on the body weight of mice transplanted with B16 cells (○: Phx-3 △: positive control ■: negative control). Source: Miyano-Kurosaki et al. [<a href="#B51-molecules-26-03453" class="html-bibr">51</a>] by permission from <span class="html-italic">Biol. Pharm. Bull</span>.</p> Full article ">Figure 7
<p>Changes in the pHi of MCF-7 cells treated with different concentrations of Phx-3 Source: reproduced from Che et al. [<a href="#B57-molecules-26-03453" class="html-bibr">57</a>] with permission from <span class="html-italic">Proc. Japan Acad. Ser. B</span>.</p> Full article ">Figure 8
<p>Proapoptotic effects of Phx-3 on (<b>A</b>) MCF-7 and (<b>B</b>) A431 cells. Reproduced from Che et al. [<a href="#B57-molecules-26-03453" class="html-bibr">57</a>] with permission of <span class="html-italic">Proc. Japan Acad., Ser. B.</span> * <span class="html-italic">p</span> &lt; 0.01, ** <span class="html-italic">p</span> &lt; 0.001.</p> Full article ">Figure 9
<p>Structures of indole, the anticancer drug vincristine and the most active indole derivatives.</p> Full article ">Figure 10
<p>Structure of the pyridophenoxazinone derivatives conjugated to L-lysine.</p> Full article ">Figure 11
<p>Compound <b>8</b> and derivatives obtained by arylation using boronic acids (<b>9</b>–<b>12</b>) or by amination using anilines (<b>13</b>–<b>15</b>).</p> Full article ">Figure 12
<p>Phenoxazin derivatives with antibacterial (<b>16</b>) and antimalarial (<b>17</b> and <b>18</b>) activity.</p> Full article ">Figure 13
<p>Compounds that have exhibited some interesting potential to treat <span class="html-italic">L. major</span> infections.</p> Full article ">Scheme 1
<p>General degradation process of benzoxazinones.</p> Full article ">
14 pages, 1270 KiB  
Article
Untargeted Phytochemical Profile, Antioxidant Capacity and Enzyme Inhibitory Activity of Cultivated and Wild Lupin Seeds from Tunisia
by Amna Ben Hassine, Gabriele Rocchetti, Leilei Zhang, Biancamaria Senizza, Gökhan Zengin, Mohamad Fawzi Mahomoodally, Mossadok Ben-Attia, Youssef Rouphael, Luigi Lucini and Safia El-Bok
Molecules 2021, 26(11), 3452; https://doi.org/10.3390/molecules26113452 - 7 Jun 2021
Cited by 12 | Viewed by 2897
Abstract
Lupin seeds can represent a valuable source of phenolics and other antioxidant compounds. In this work, a comprehensive analysis of the phytochemical profile was performed on seeds from three Lupinus species, including one cultivar (Lupinus albus) and two wild accessions ( [...] Read more.
Lupin seeds can represent a valuable source of phenolics and other antioxidant compounds. In this work, a comprehensive analysis of the phytochemical profile was performed on seeds from three Lupinus species, including one cultivar (Lupinus albus) and two wild accessions (Lupinus cossentinii and Lupinus luteus), collected from the northern region of Tunisia. Untargeted metabolomic profiling allowed to identify 249 compounds, with a great abundance of phenolics and alkaloids. In this regard, the species L. cossentinii showed the highest phenolic content, being 6.54 mg/g DW, followed by L. luteus (1.60 mg/g DW) and L. albus (1.14 mg/g DW). The in vitro antioxidant capacity measured by the ABTS assay on seed extracts ranged from 4.67 to 17.58 mg trolox equivalents (TE)/g, recording the highest values for L. albus and the lowest for L. luteus. The DPPH radical scavenging activity ranged from 0.39 to 3.50 mg TE/g. FRAP values varied between 4.11 and 5.75 mg TE/g. CUPRAC values for lupin seeds ranged from 7.20 to 8.95 mg TE/g, recording the highest for L. cossentinii. The results of phosphomolybdenum assay and metal chelation showed similarity between the three species of Lupinus. The acetylcholinesterase (AChE) inhibition activity was detected in each methanolic extract analyzed with similar results. Regarding the butyrylcholinesterase (BChE) enzyme, it was weakly inhibited by the Lupinus extracts; in particular, the highest activity values were recorded for L. albus (1.74 mg GALAE/g). Overall, our results showed that L. cossentinii was the most abundant source of polyphenols, consisting mainly in tyrosol equivalents (5.82 mg/g DW). Finally, significant correlations were outlined between the phenolic compounds and the in vitro biological activity measured, particularly when considering flavones, phenolic acids and lower-molecular-weight phenolics. Full article
(This article belongs to the Special Issue Integration between Food Chemistry and Health in Focus)
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<p>Non-averaged unsupervised hierarchical clustering of the phenolic profiles of <span class="html-italic">Lupinus albus</span>, <span class="html-italic">luteus</span> and <span class="html-italic">cossentinii</span> (similarity: Euclidean; linkage rule: Ward). The compounds’ intensity was used to build up a heat map, on the basis of which the clusters were generated. LA: <span class="html-italic">L. albus;</span> LL: <span class="html-italic">L. luteus;</span> LC: <span class="html-italic">L. cossentinii</span>.</p> Full article ">Figure 2
<p>Orthogonal projection to latent structures discriminant analysis (OPLS-DA) built considering the phytochemical profile (from UHPLC-QTOF) of different seeds of the three Lupinus species.</p> Full article ">
11 pages, 3113 KiB  
Article
MWCNT Decorated Rich N-Doped Porous Carbon with Tunable Porosity for CO2 Capture
by Yuanjie Xiong, Yuan Wang, Housheng Jiang and Shaojun Yuan
Molecules 2021, 26(11), 3451; https://doi.org/10.3390/molecules26113451 - 7 Jun 2021
Cited by 16 | Viewed by 3378
Abstract
Designing of porous carbon system for CO2 uptake has attracted a plenty of interest due to the ever-increasing concerns about climate change and global warming. Herein, a novel N rich porous carbon is prepared by in-situ chemical oxidation polyaniline (PANI) on a [...] Read more.
Designing of porous carbon system for CO2 uptake has attracted a plenty of interest due to the ever-increasing concerns about climate change and global warming. Herein, a novel N rich porous carbon is prepared by in-situ chemical oxidation polyaniline (PANI) on a surface of multi-walled carbon nanotubes (MWCNTs), and then activated with KOH. The porosity of such carbon materials can be tuned by rational introduction of MWCNTs, adjusting the amount of KOH, and controlling the pyrolysis temperature. The obtained M/P-0.1-600-2 adsorbent possesses a high surface area of 1017 m2 g−1 and a high N content of 3.11 at%. Such M/P-0.1-600-2 adsorbent delivers an enhanced CO2 capture capability of 2.63 mmol g−1 at 298.15 K and five bars, which is 14 times higher than that of pristine MWCNTs (0.18 mmol g−1). In addition, such M/P-0.1-600-2 adsorbent performs with a good stability, with almost no decay in a successive five adsorption-desorption cycles. Full article
(This article belongs to the Special Issue Nano Environmental Materials)
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<p>Characteristics of M/P-0.1-600-2, M/P-0.1, PANI, and MWCNT samples: (<b>a</b>) FTIR spectra, (<b>b</b>) XRD patterns, (<b>c</b>) Raman spectra, and (<b>d</b>) TGA curves.</p> Full article ">Figure 2
<p>SEM images of (<b>a</b>–<b>c</b>) M/P-0.1 and (<b>d</b>–<b>f</b>) M/P-0.1-600-2 at different magnifications. TEM images of (<b>g</b>–i) M/P-0.1 and (<b>j</b>–<b>l</b>) M/P-0.1-600-2 at different magnifications.</p> Full article ">Figure 3
<p>XPS spectra of M/P-0.1: (<b>a</b>) wide scan, (<b>b</b>) C 1s, and (<b>c</b>) N 1s regions. XPS spectra of M/P-0.1-600-2: (<b>d</b>) wide scan, (<b>e</b>) C 1s, and (<b>f</b>) N 1s regions.</p> Full article ">Figure 4
<p>(<b>a</b>) N<sub>2</sub> adsorption-desorption isotherms of M/P-0.1-600-2, M/P-0.1, PANI, and MWCNT samples. (<b>b</b>) Corresponding pore size distribution profiles.</p> Full article ">Figure 5
<p>(<b>a</b>) The CO<sub>2</sub> adsorption capacity comparison of M/P-0.1-600-2 and MWCNTs absorbents. (<b>b</b>) Redlich–Peterson-fitted adsorption isotherms of M/P-0.1-600-2 at various temperatures. (<b>c</b>) Adsorption kinetics of CO<sub>2</sub> on M/P-0.1-600-2. (<b>d</b>) Regeneration performance of A-TDP-12 on CO<sub>2</sub> adsorption.</p> Full article ">Scheme 1
<p>Schematic representation showing the synthetic route of M/P: (<b>a</b>) Preparation of M/P composites by in-situ oxidative polymerization, (<b>b</b>) freeze drying M/P composites, (<b>c</b>) mixture of M/P composites and KOH, and (<b>d</b>) high temperature activation of M/P composites.</p> Full article ">
19 pages, 4850 KiB  
Article
Enhanced Oral Absorption of Icaritin by Using Mixed Polymeric Micelles Prepared with a Creative Acid-Base Shift Method
by Cheng Tang, Xiaoming Chen, Hua Yao, Haiyan Yin, Xiaoping Ma, Mingji Jin, Xin Lu, Quntao Wang, Kun Meng and Qipeng Yuan
Molecules 2021, 26(11), 3450; https://doi.org/10.3390/molecules26113450 - 6 Jun 2021
Cited by 16 | Viewed by 3052
Abstract
The purpose of this study was to develop mixed polymeric micelles with high drug loading capacity to improve the oral bioavailability of icaritin with Soluplus® and Poloxamer 407 using a creative acid-base shift (ABS) method, which exhibits the advantages of exclusion of [...] Read more.
The purpose of this study was to develop mixed polymeric micelles with high drug loading capacity to improve the oral bioavailability of icaritin with Soluplus® and Poloxamer 407 using a creative acid-base shift (ABS) method, which exhibits the advantages of exclusion of organic solvents, high drug loading and ease of scaling-up. The feasibility of the ABS method was successfully demonstrated by studies of icaritin-loaded polymeric micelles (IPMs). The prepared IPMs were characterized to have a spherical shape with a size of 72.74 ± 0.51 nm, and 13.18% drug loading content. In vitro release tests confirmed the faster release of icaritin from IPMs compared to an oil suspension. Furthermore, bioavailability of icaritin in IPMs in beagle dogs displayed a 14.9-fold increase when compared with the oil suspension. Transcellular transport studies of IPMs across Caco-2 cell monolayers confirmed that the IPMs were endocytosed in their intact forms through macropinocytosis, clathrin-, and caveolae-mediated pathways. In conclusion, the results suggested that the mixed micelles of Soluplus® and Poloxamer 407 could be a feasible drug delivery system to enhance oral bioavailability of icaritin, and the ABS method might be a promising technology for the preparation of polymeric micelles to encapsulate poorly water-soluble weakly acidic and alkaline drugs. Full article
(This article belongs to the Special Issue Advances on Pharmaceutical Nanotechnology at the Interface with Biological Barriers)
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<p>Plot of the absorbance at 366 nm as a function of log(1/<span class="html-italic">C</span>) for the mixture of Soluplus<sup>®</sup> /P407 in the mass ratio of 2:1 in aqueous solution. CMC, critical micelle concentration; P407, poloxamer 407.</p> Full article ">Figure 2
<p><sup>1</sup>H-NMR of icaritin in DMSO-<span class="html-italic">d</span><sub>6</sub> (<b>A</b>), IPMs in DMSO-<span class="html-italic">d</span><sub>6</sub> (<b>B</b>) and in D<sub>2</sub>O (<b>C</b>), and blank micelles in DMSO-<span class="html-italic">d</span><sub>6</sub> (<b>D</b>) and in D<sub>2</sub>O (<b>E</b>). (<b>F</b>) The HPLC chromatograms of raw icaritin and the loaded icaritin in the micelles. DMSO, dimethylsulfoxide; HPLC, high performance liquid chromatography; IPMs, icaritin-loaded polymeric micelles; P407, poloxamer 407.</p> Full article ">Figure 3
<p>(<b>A</b>) Photographs of IPMs solutions containing 3.6 mg/mL icaritin (left) and 20 mg/mL icaritin (right). (<b>B</b>) The SEM images of IPMs. (<b>C</b>) Size distribution and (<b>D</b>) Zeta potential of IPMs. (<b>E</b>) The X-ray powder diffractogram of raw icaritin, blank micelles, physical mixture of icaritin and polymers, and IPMs. IPMs, icaritin-loaded polymeric micelles; SEM, scanning electron microscope.</p> Full article ">Figure 4
<p>Changes in particle size (<b>A</b>,<b>D</b>), PDI (<b>B</b>,<b>E</b>) and LC (<b>C</b>,<b>F</b>) of IPMs with temperature (<b>A</b>–<b>C</b>) and physiological conditions (<b>D</b>–<b>F</b>). LC, drug loading content; IPMs, icaritin-loaded polymeric micelles; PDI, polydispersity index.</p> Full article ">Figure 5
<p>In vitro release profiles of IPMs (<b>A</b>) and oil suspension (<b>B</b>) in SGF (<b>C</b>) and SIF (<b>D</b>) at 37 °C (<span class="html-italic">n</span> = 3). IPMs, icaritin-loaded polymeric micelles; SGF, simulated gastric fluid; SIF, simulated intestinal fluid.</p> Full article ">Figure 6
<p>Mean plasma concentration of icaritin versus time profiles following a single injection of icaritin solution at a dose of 2 mg/kg (<b>A</b>), and oral administration of IPMs and oil suspensions at a dose of 20 mg/kg (<b>B</b>) to beagle dogs. IPMs, icaritin-loaded polymeric micelles.</p> Full article ">Figure 7
<p>(<b>A</b>) Fluorescence emission spectra of FRET micelles at an excitation wavelength of 635 nm. Fluorescence emission spectra of apical medium (<b>B</b>) and basolateral medium (<b>C</b>) collected after 4 h of transcellular transport of FRET micelles across Caco-2 cell monolayers at an excitation wavelength of 635 nm. TEM images of apical medium (<b>D</b>) and basolateral medium (<b>E</b>) collected after 4 h of transport of FRET micelles across Caco-2 cell monolayers. (<b>F</b>) The influence of various endocytosis inhibitors on the transcytosis of IPMs across Caco-2 cell monolayers (<span class="html-italic">n</span> = 3). ** <span class="html-italic">p</span> &lt; 0.01 and *** <span class="html-italic">p</span> &lt; 0.001 compared to the control. CMZ, Chlorpromazine hydrochloride; FRET, Forster Resonance Energy Transfer; M<span class="html-italic">β</span>CD, methyl-<span class="html-italic">β</span>-cyclodextrin; TEM, transmission electron microscope.</p> Full article ">Scheme 1
<p>Structure of icaritin (<b>A</b>), diosmin (<b>B</b>), ibuprofen (<b>C</b>) and remdesivir (<b>D</b>).</p> Full article ">Scheme 2
<p>An illustration of the different techniques to prepare polymeric micelles. (<b>A</b>) Thin film hydration method, (<b>B</b>) dialysis method, (<b>C</b>) simple equilibrium method, (<b>D</b>) oil in water emulsion method and (<b>E</b>) ABS method. ABS: acid-base shift.</p> Full article ">Scheme 3
<p>A schematic illustration of the ABS method to prepare polymeric micelles (<b>A</b>) and the experimental process (<b>B</b>). ABS, acid-base shift.</p> Full article ">Scheme 4
<p>Schematic illustration of the self-assembly for icaritin-loaded Soluplus<sup>®</sup> micelles (<b>A</b>) and icaritin-loaded Soluplus<sup>®</sup>/P407 micelles (<b>B</b>) in aqueous medium. P407, poloxamer 407.</p> Full article ">
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