Molecules

10 pages, 2487 KiB

Open AccessArticle

Multimode Robust Lasing in a Dye-Doped Polymer Layer Embedded in a Wedge-Shaped Cholesteric

by Tatevik M. Sarukhanyan, Hermine Gharagulyan, Mushegh S. Rafayelyan, Sergey S. Golik, Ashot H. Gevorgyan and Roman B. Alaverdyan

Molecules 2021, 26(19), 6089; https://doi.org/10.3390/molecules26196089 - 8 Oct 2021

Cited by 10 | Viewed by 2514

Abstract

Cholesteric liquid crystals (CLCs) with induced defects are one of the most prominent materials to realize compact, low-threshold and tunable coherent light sources. In this context, the investigation of optical properties of induced defect modes in such CLCs is of great interest. In [...] Read more.

Cholesteric liquid crystals (CLCs) with induced defects are one of the most prominent materials to realize compact, low-threshold and tunable coherent light sources. In this context, the investigation of optical properties of induced defect modes in such CLCs is of great interest. In particular, many studies have been devoted to the spectral control of the defect modes depending on their thickness, optical properties, distribution along the CLC, etc. In this paper, we investigate the lasing possibilities of a dye-doped polymer layer embedded in a wedge-shaped CLC. We show that multimode laser generation is possible due to the observed multiple defect modes in the PBG that enlarges the application range of the system. Furthermore, our simulations based on a Berreman 4 × 4 matrix approach for a wide range of CLC thickness show both periodic and continuous generation of defect modes along particular spectral lines inside the PBG. Such a robust spectral behaviour of induced defect modes is unique, and, to our knowledge, is not observed in similar CLC-based structures. Full article

(This article belongs to the Special Issue Liquid Crystals 2020)

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44 pages, 10855 KiB

Open AccessReview

Proceedings of Chemistry, Pharmacology, Pharmacokinetics and Synthesis of Biflavonoids

by Xinqian He, Fan Yang and Xin’an Huang

Molecules 2021, 26(19), 6088; https://doi.org/10.3390/molecules26196088 - 8 Oct 2021

Cited by 39 | Viewed by 4757

Abstract

Biflavonoids, composed of two monoflavonoid residues, occur naturally in angiosperms, bryophytes, ferns, and gymnosperms. More than 592 biflavonoids have been structurally elucidated, and they can be classified into two groups of C-C and C-linear fragments-C, based on whether the linker between the two [...] Read more.

Biflavonoids, composed of two monoflavonoid residues, occur naturally in angiosperms, bryophytes, ferns, and gymnosperms. More than 592 biflavonoids have been structurally elucidated, and they can be classified into two groups of C-C and C-linear fragments-C, based on whether the linker between the two residues contains an atom. As the linker can be established on two arbitrary rings from different residues, the C-C type contains various subtypes, as does the C-linear fragment-C type. Biflavonoids have a wide range of pharmacological activities, including anti-inflammatory, antioxidant, antibacterial, antiviral, antidiabetic, antitumor, and cytotoxic properties, and they can be applied in Alzheimer’s disease and Parkinson’s disease. This review mainly summarizes the distribution and chemistry of biflavonoids; additionally, their bioactivities, pharmacokinetics, and synthesis are discussed. Full article

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17 pages, 1377 KiB

Open AccessArticle

Is Phytomelatonin Complex Better Than Synthetic Melatonin? The Assessment of the Antiradical and Anti-Inflammatory Properties

by Wirginia Kukula-Koch, Dominik Szwajgier, Katarzyna Gaweł-Bęben, Marcelina Strzępek-Gomółka, Kazimierz Głowniak and Henry O. Meissner

Molecules 2021, 26(19), 6087; https://doi.org/10.3390/molecules26196087 - 8 Oct 2021

Cited by 11 | Viewed by 5963

Abstract

This work aims to assess the recently established anti-inflammatory and antioxidant potential of melatonin of plant origin extracted from the plant matrix as a phytomelatonin complex (PHT-MLT), and compare its activity with synthetic melatonin (SNT-MLT) when used on its own or with vitamin [...] Read more.

This work aims to assess the recently established anti-inflammatory and antioxidant potential of melatonin of plant origin extracted from the plant matrix as a phytomelatonin complex (PHT-MLT), and compare its activity with synthetic melatonin (SNT-MLT) when used on its own or with vitamin C. For this purpose, a COX-2 enzyme inhibitory activity test, an antiradical activity in vitro and on cell lines assays, was performed on both PHT-MLT and SNT-MLT products. COX-2 inhibitory activity of PHT-MLT was found to be ca. 6.5 times stronger than that of SNT-MLT (43.3% and 6.7% enzyme inhibition, equivalent to the activity of acetylsalicylic acid in conc. 30.3 ± 0.2 and 12.0 ± 0.3 mg/mL, respectively). Higher antiradical potential and COX-2 inhibitory properties of PHT-MLT could be explained by the presence of additional naturally occurring constituents in alfalfa, chlorella, and rice, which were clearly visible on the HPLC-ESI-QTOF-MS fingerprint. The antiradical properties of PHT-MLT determined in the DPPH test (IC₅₀ of 21.6 ± 1 mg of powder/mL) were found to originate from the presence of other metabolites in the 50% EtOH extract while SNT-MLT was found to be inactive under the applied testing conditions. However, the antioxidant studies on HaCaT keratinocytes stimulated with H₂O₂ revealed a noticeable activity in all samples. The presence of PHT-MLT (12.5, 25 and 50 µg/mL) and vitamin C (12.5, 25 and 50 µg/mL) in the H₂O₂-pretreated HaCaT keratinocytes protected the cells from generating reactive oxygen species. This observation confirms that MLT-containing samples affect the intracellular production of enzymes and neutralize the free radicals. Presented results indicated that MLT-containing products in combination with Vitamin C dosage are worth to be considered as a preventive alternative in the therapy of various diseases in the etiopathogenesis, of which radical and inflammatory mechanisms play an important role. Full article

(This article belongs to the Special Issue Natural Plant Substances—Structural and Application Aspects: A Theme Issue in Honor of Professor Wieslaw Oleszek)

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11 pages, 1543 KiB

Open AccessArticle

Cudraxanthone D Ameliorates Psoriasis-like Skin Inflammation in an Imiquimod-Induced Mouse Model via Inhibiting the Inflammatory Signaling Pathways

by Namkyung Kim, Soyoung Lee, Jinjoo Kang, Young-Ae Choi, Yong Hyun Jang, Gil-Saeng Jeong and Sang-Hyun Kim

Molecules 2021, 26(19), 6086; https://doi.org/10.3390/molecules26196086 - 8 Oct 2021

Cited by 12 | Viewed by 4185

Abstract

Psoriasis is a chronic inflammatory skin disease accompanied by excessive keratinocyte proliferation. Corticosteroids, vitamin D3 analogs, and calcineurin inhibitors, which are used to treat psoriasis, have diverse adverse effects, whereas natural products are popular due to their high efficiency and relatively low toxicity. [...] Read more.

Psoriasis is a chronic inflammatory skin disease accompanied by excessive keratinocyte proliferation. Corticosteroids, vitamin D3 analogs, and calcineurin inhibitors, which are used to treat psoriasis, have diverse adverse effects, whereas natural products are popular due to their high efficiency and relatively low toxicity. The roots of the Cudrania tricuspidata (C. tricuspidata) are known to have diverse pharmacological effects, among which the anti-inflammatory effect is reported as a potential therapeutic agent in skin cells. Nevertheless, its effectiveness against skin diseases, especially psoriasis, is not fully elucidated. Here, we investigated the effect of cudraxanthone D (CD), extracted from the roots the C. tricuspidata Bureau, on psoriasis using an imiquimod (IMQ)-induced mouse model and the tumor necrosis factor (TNF)-α/interferon (IFN)-γ-activated keratinocytes. IMQ was topically applied to the back skin of C57BL/6 mice for seven consecutive days, and the mice were orally administered with CD. This resulted in reduced psoriatic characteristics, such as the skin thickness and Psoriasis Area Severity Index score, and the infiltration of neutrophils in IMQ-induced skin. CD inhibited the serum levels of TNF-α, immunoglobulin G2a, and myeloperoxidase, and the expression of Th1/Th17 cells in splenocytes. In TNF-α/IFN-γ-activated keratinocytes, CD reduced the expressions of CCL17, IL-1β, IL-6, and IL-8 by inhibiting the phosphorylation of STAT1 and the nuclear translocation of NF-kB. Taken together, these results suggest that CD could be a potential drug candidate for the treatment of psoriasis. Full article

(This article belongs to the Special Issue Biological Activities of Traditional Medicinal Plants)

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Graphical abstract

Graphical abstract
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Effects of cudraxanthone D (CD) on psoriasis-like skin inflammation. (a) Skin thickness of mice measured 24 h after imiquimod (IMQ) or drug (CD or Dexa) application with a dial thickness gauge No. 7301. (b) Psoriasis Area Severity Index (PASI) accounting for scaling, erythema, and thickness were scored from 0 to 4 in IMQ-induced skin inflammation, and total PASI score at day 7. (c) Body weight during the experimental period was measured using a HKC65050 electronic balance for 7 consecutive days. (d) Representative micrographs of the skin were stained with hematoxylin and eosin (H&E). Magnification: 200×, scale bar: 50 μm. (e) Epidermal and dermal thickness. At 200× magnification, the epidermal and dermal thickening was analyzed with a stage micrometer. Each data point represents the mean ± SEM of two independent samples. * p < 0.05 compared to the IMQ-induced group only. IMQ: imiquimod, CD: cudraxanthone D, Dexa: dexamethasone. Full article ">Figure 2
Effects of CD on psoriasis-associated cytokines and chemokines in IMQ-induced skin. The mRNA expressions of IMQ-induced skin lesions were measured via quantitative polymerase chain reactions (qPCR) and normalized with GAPDH. Each data point represents the mean ± SEM of two independent samples. * p < 0.05 compared to the IMQ-induced group only. IMQ: imiquimod, CD: cudraxanthone D, Dexa: dexamethasone. Full article ">Figure 3
Effects of CD on serum immunoglobulin levels and infiltration of MPO-associated cells. After the in vivo experiments, the mice were sacrificed, after which their blood and skin were harvested. (a,b) The serum levels of tumor necrosis factor (TNF)-α, IgG2a, and MPO were measured via sandwich enzyme-linked immunosorbent assay (ELISA). Each data point represents the mean ± SEM of the two independent samples. * p < 0.05 compared to the IMQ-induced group only. (c) Tissue slides stained with immunohistochemistry (IHC) (for myeloperoxidase [MPO]). (d) The expressions of neutrophil markers in IMQ-induced skin lesions were measured by qPCR. Magnification: 200×, scale bar: 50 μm. MPO: myeloperoxidase, IMQ: imiquimod, CD: cudraxanthone D, Dexa: dexamethasone. Full article ">Figure 4
Effects of CD on the mRNA expression and secreted protein in activated keratinocytes with TNF-α/IFN-γ. (a) The expression levels of CCL17, IL-1β, IL-6, and IL-8 measured via qPCR. (b) Effects of CD on levels of secretory cytokine and chemokine measured by ELISA. (c) Translocation of NF-κB and phosphorylating of STAT1 were detected via Western blotting. The STAT1, β-actin, and lamin B1 bands were used as loading control. Each data point represents the mean ± SEM of three independent samples. * p < 0.05 compared with TNF-α/IFN-γ-stimulated group only. CD: cudraxanthone D, Dexa: dexamethasone. Full article ">

19 pages, 5903 KiB

Open AccessArticle

Development of Amino Acids Functionalized SBA-15 for the Improvement of Protein Adsorption

by Raquel Gutiérrez-Climente, Margaux Clavié, Jérémie Gouyon, Giang Ngo, Yoann Ladner, Pascal Etienne, Pascal Dumy, Pierre Martineau, Martine Pugnière, Catherine Perrin, Gilles Subra and Ahmad Mehdi

Molecules 2021, 26(19), 6085; https://doi.org/10.3390/molecules26196085 - 8 Oct 2021

Cited by 4 | Viewed by 2884

Abstract

Ordered mesoporous materials and their modification with multiple functional groups are of wide scientific interest for many applications involving interaction with biological systems and biomolecules (e.g., catalysis, separation, sensor design, nano-science or drug delivery). In particular, the immobilization of enzymes onto solid supports [...] Read more.

Ordered mesoporous materials and their modification with multiple functional groups are of wide scientific interest for many applications involving interaction with biological systems and biomolecules (e.g., catalysis, separation, sensor design, nano-science or drug delivery). In particular, the immobilization of enzymes onto solid supports is highly attractive for industry and synthetic chemistry, as it allows the development of stable and cheap biocatalysts. In this context, we developed novel silylated amino acid derivatives (Si-AA-NH₂) that have been immobilized onto SBA-15 materials in biocompatible conditions avoiding the use of toxic catalyst, solvents or reagents. The resulting amino acid-functionalized materials (SBA-15@AA) were characterized by XRD, TGA, EA, Zeta potential, nitrogen sorption and FT-IR. Differences of the physical properties (e.g., charges) were observed while the structural ones remained unchanged. The adsorption of the enzyme lysozyme (Lyz) onto the resulting functionalized SBA-15@AA materials was evaluated at different pHs. The presence of different functional groups compared with bare SBA-15 showed better adsorption results, for example, 79.6 nmol of Lyz adsorbed per m² of SBA-15@Tyr compared with the 44.9 nmol/m² of the bare SBA-15. Full article

(This article belongs to the Special Issue 25th Anniversary of Molecules—Recent Advances in Applied Chemistry)

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21 pages, 3307 KiB

Open AccessArticle

Antioxidant and Anti-Inflammatory Effects of Peganum harmala Extracts: An In Vitro and In Vivo Study

by Malik Waseem Abbas, Mazhar Hussain, Muhammad Qamar, Sajed Ali, Zahid Shafiq, Polrat Wilairatana and Mohammad S. Mubarak

Molecules 2021, 26(19), 6084; https://doi.org/10.3390/molecules26196084 - 8 Oct 2021

Cited by 41 | Viewed by 7248

Abstract

Peganum harmala (P. harmala) belongs to the family Zygophyllaceae, and is utilized in the traditional medicinal systems of Pakistan, China, Morocco, Algeria, and Spain to treat several chronic health disorders. The aim of the present study was to identify the [...] Read more.

Peganum harmala (P. harmala) belongs to the family Zygophyllaceae, and is utilized in the traditional medicinal systems of Pakistan, China, Morocco, Algeria, and Spain to treat several chronic health disorders. The aim of the present study was to identify the chemical constituents and to evaluate the antioxidant, anti-inflammatory, and toxicity effects of P. harmala extracts both in vitro and in vivo. Sequential crude extracts including 100% dichloromethane, 100% methanol, and 70% aqueous methanol were obtained and their antioxidant and anti-inflammatory effects evaluated both in vitro and in vivo. The anti-inflammatory effect of the extract was investigated using the carrageenan-induced paw edema method in mice, whereas the toxicity of the most active extract was evaluated using an acute and subacute toxicity rat model. In addition, we have used the bioassay-guided approach to obtain potent fractions, using solvent–solvent partitioning and reversed phase high performance liquid chromatography from active crude extracts; identification and quantification of compounds from the active fractions was achieved using electrospray ionization mass spectrometry and high performance liquid chromatography techniques. Results revealed that the 100% methanol extract of P. harmala exhibits significant in vitro antioxidant activity in DPPH assay with an IC₅₀ of 49 µg/mL as compared to the standard quercetin with an IC₅₀ of 25.4 µg/mL. The same extract exhibited 63.0% inhibition against serum albumin denaturation as compared to 97% inhibition by the standard diclofenac sodium in an in vitro anti-inflammatory assay, and in vivo anti-inflammatory against carrageenan-induced paw edema (75.14% inhibition) as compared to 86.1% inhibition caused by the standard indomethacin. Furthermore, this extract was not toxic during a 14 day trial of acute toxicity when given at a dose of 3 g/kg, indicating that the lethal dose (LD₅₀) of P. harmala methanol extract was greater than 3 g/kg. P. harmala methanolic fraction 2 obtained using bioassay-guided fractionation showed the presence of quinic acid, peganine, harmol, harmaline, and harmine, confirmed by electrospray ionization mass spectrometry and quantified using external standards on high performance liquid chromatography. Taken all together, the current investigation further confirms the antioxidant, anti-inflammatory, and safety aspects of P. harmala, which justifies its use in folk medicine. Full article

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

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16 pages, 4012 KiB

Open AccessReview

Molecular Design in Practice: A Review of Selected Projects in a French Research Institute That Illustrates the Link between Chemical Biology and Medicinal Chemistry

by Benoit Deprez, Damien Bosc, Julie Charton, Cyril Couturier, Rebecca Deprez-Poulain, Marion Flipo, Florence Leroux, Baptiste Villemagne and Nicolas Willand

Molecules 2021, 26(19), 6083; https://doi.org/10.3390/molecules26196083 - 8 Oct 2021

Cited by 2 | Viewed by 3251

Abstract

Chemical biology and drug discovery are two scientific activities that pursue different goals but complement each other. The former is an interventional science that aims at understanding living systems through the modulation of its molecular components with compounds designed for this purpose. The [...] Read more.

Chemical biology and drug discovery are two scientific activities that pursue different goals but complement each other. The former is an interventional science that aims at understanding living systems through the modulation of its molecular components with compounds designed for this purpose. The latter is the art of designing drug candidates, i.e., molecules that act on selected molecular components of human beings and display, as a candidate treatment, the best reachable risk benefit ratio. In chemical biology, the compound is the means to understand biology, whereas in drug discovery, the compound is the goal. The toolbox they share includes biological and chemical analytic technologies, cell and whole-body imaging, and exploring the chemical space through state-of-the-art design and synthesis tools. In this article, we examine several tools shared by drug discovery and chemical biology through selected examples taken from research projects conducted in our institute in the last decade. These examples illustrate the design of chemical probes and tools to identify and validate new targets, to quantify target engagement in vitro and in vivo, to discover hits and to optimize pharmacokinetic properties with the control of compound concentration both spatially and temporally in the various biophases of a biological system. Full article

(This article belongs to the Special Issue The Chemical Biology Research in France)

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(A) Ethionamide bioactivation pathways: EthA and EthA2 are triggered by the inhibition of mycobacterial transcription factors EthR and EthR2 with small molecules BDM41906, BDM71339, and SMARt-420; (B) structure of the clinical candidate BVL-GSK098. Full article ">Figure 2
Target engagement using CETSA and CETSA-aRPPA. (A) Principle of CETSA and measurement of ΔTagg of protein and ITDRF; (B) detection methods: 1. Immunofluorescent staining with a target-directed antibody and high-content imaging; 2. Western blot using immunofluorescent staining; 3. Dual-antibody detection of the folded target protein and antibody proximity detection systems based on, for example, Bioluminescence or fluorescence; 4. enzyme fragment complementation (EFC) system where a small fragment tag (e.g., 42 amino acid of β-galactosidase; or 14 amino acid Hibit fragment of nanoluciferase) is tagged to the target of interest, and compound-mediated target stabilization is subsequently detected by the addition of the enzyme acceptor (EA) fragment (e.g., rest of β-galactosidase or NanoLuc) and luminescence reporter; 5. CETSA-aRPPA uses immunostaining detection (dotblot format) and acoustic reverse phase protein array. CETSA-aRPPA combines a high throughput, low quantity of material, and advantageously no need for target tagging, in comparison to other detection methods. Full article ">Figure 3
High-throughput screening cascades for the discovery of metalloprotease inhibitors. (A) Ebselen is the most active IDE inhibitor. It is a reversible covalent inhibitor that impairs the open–close conformational shift of IDE and the entry of the substrates; (B) screening a focused library of acidic compounds allowed the discovery of the first activator of ERAP2 among a family of inhibitors. Full article ">Figure 4
(A) Principle of kinetic target-guided synthesis (KTGS) with the example of the in situ click chemistry strategy. A pool of azides and alkynes are presented to the protein of interest, which stabilizes a pair of affine reagents in reacting configuration (close proximity and proper orientation of their compatible reactive moieties). The protein accelerates the irreversible reaction of these two reagents to afford the final 1,2,3-triazole ligand; (B) KTGS by EthR using a multicomponent strategy from one azide and 60 diverse alkynes leading to BDM14950 that traps a new “open-gate” conformation; (C) KTGS by IDE using an orthogonal multicomponent strategy from two azides and 90 diverse alkynes leading to 66 hits including the best in vivo active IDE inhibitor BDM44768 that shifts IDE conformer ensemble toward closed conformations. Full article ">Figure 5
Fragment-based drug design (FBDD) approaches used to identify hits in three different anti-infectious drug discovery programs. (A) Enrichment of the library with 3D-fragments; (B) structures of three optimized inhibitors of mycobacterial proteins EthR2, MabA and EthR. Full article ">Figure 6
Chimeric TGR5 agonists with fine-tuned pharmacokinetic behavior. For the ionic kinetophores (top), compounds with gut-restricted exposure were obtained. In the case of mPEG kinetophores (bottom), depending on the length of the PEG moiety tethered on the pharmacophore, either systemic or gut-restricted compounds were obtained. Full article ">Figure 7
Use of pharmacokinetic studies to provide toolbox for optimization: the case of hydroxamic acids. CES: carboxylesterases, LogP: partition coefficient; HBD: count of hydrogen-bond donors. Full article ">Figure 8
Rat model of perioperative cardiac injury. Panel (A): in blue and pink: plots of the fold change of respectively RevErb and Bmal1 gene expressions relative to ZT0, in green and brown: plots of the fold change of respectively RevErb and p21 proteins relative to ZT0. In red: plot of the plasma concentration of the RevErb antagonist. ZT means Zeitgeber Time. ZT0 is set at the beginning of the light phase. Five bolus injections of the antagonist provide an exposure profile matching the target protein expression. Panels (B) and (C): effects of the pharmacological pulse with the RevErb antagonist antedrug: increase of Bmal1 target gene (Panel (B)), and reduction in the infarct size (Panel (C)); ** p < 0.01 and * p < 0.05 vs SHA. Full article ">

18 pages, 6509 KiB

Open AccessArticle

Study on Nuclear Magnetic Resonance Logging T₂ Spectrum Shape Correction of Sandstone Reservoirs in Oil-Based Mud Wells

by Jianmeng Sun, Jun Cai, Ping Feng, Fujing Sun, Jun Li, Jing Lu and Weichao Yan

Molecules 2021, 26(19), 6082; https://doi.org/10.3390/molecules26196082 - 8 Oct 2021

Cited by 8 | Viewed by 2879

Abstract

The oil-based mud filtrate will invade the formation under the overbalanced pressure during drilling operations. As a result, alterations will occur to the nuclear magnetic resonance (NMR) response characteristics of the original formation, causing the relaxation time of the NMR T₂ spectrum [...] Read more.

The oil-based mud filtrate will invade the formation under the overbalanced pressure during drilling operations. As a result, alterations will occur to the nuclear magnetic resonance (NMR) response characteristics of the original formation, causing the relaxation time of the NMR T₂ spectrum of the free fluid part to move towards a slower relaxation time. Consequently, the subsequent interpretation and petrophysical evaluation will be heavily impacted. Therefore, the actual measured T₂ spectrum needs to be corrected for invasion. For this reason, considering the low-porosity and low-permeability of sandstone gas formations in the East China Sea as the research object, a new method to correct the incorrect shape of the NMR logging T₂ spectrum was proposed in three main steps. First, the differences in the morphology of the NMR logging T₂ spectrum between oil-based mud wells and water-based mud wells in adjacent wells were analyzed based on the NMR relaxation mechanism. Second, rocks were divided into four categories according to the pore structure, and the NMR logging T₂ spectrum was extracted using the multidimensional matrix method to establish the T₂ spectrum of water-based mud wells and oil-based mud wells. Finally, the correctness of the method was verified by two T₂ spectrum correction examples of oil-based mud wells in the study area. The results show that the corrected NMR T₂ spectrum eliminates the influence of oil-based mud filtrate and improves the accuracy of NMR logging for calculating permeability. Full article

(This article belongs to the Special Issue Practical Applications of NMR to Solve Real-World Problems)

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Schematic diagram of mud invasion process. Full article ">Figure 2
Gas reservoir volume model and theoretical NMR T2 spectrum diagram. (a) Volume model of gas-bearing reservoirs in undisturbed formations and theoretical distribution of the nuclear magnetic T2 spectrum. (b) Volume model of gas-bearing reservoirs in water-based mud wells and theoretical distribution of the nuclear magnetic T2 spectrum. (c) Volume model of gas-bearing reservoirs in oil-based mud wells and theoretical distribution of the nuclear magnetic T2 spectrum. Full article ">Figure 3
NMR logging response in different mud environments: (a) Water-based mud well A; (b) Oil-based mud well B. Full article ">Figure 4
Casting sheet images of four types of rocks: (a) Type I (Φ = 13.9%, K = 269 mD); (b) Type II (Φ = 10.6%, K = 17.1 mD); (c) Type Ⅲ (Φ = 10.4%, K = 4.9 mD); (d) Type Ⅳ (Φ = 9.7%, K = 0.45 mD). Full article ">Figure 5
Pore-throat size distributions of four types of rocks. Full article ">Figure 6
Comparisons of T2 spectrum of four types of rocks in different mud environments: (a) Type I; (b) Type II; (c) Type III; (d) Type IV. Full article ">Figure 7
A field example of correcting the invasion of oil-based mud to field NMR logging in well B. In the first track, the displayed curves are gamma-ray (GR), borehole diameter (CAL), and bit diameter (BIT). The second track is the depth. The third is resistivity curve. The acoustic transit time log (AC), the density log (DEN), compensated neutron log (CNL) are shown in the fourth track. The fifth track is the initial measured T2 spectrum of NMR logging before correction (Initial T2 spectrum). The T2 spectrum of nuclear magnetic resonance logging (Corrected T2 spectrum) under the condition of water-based mud corrected by the method proposed in this study is displayed in the sixth track. The NMR calculated porosity (NMR-por) and core analysis porosity (Core-por) are shown in the seventh track and have good consistency. The Corrected SDR permeability is calculated permeability from the corrected T2 spectrum by using Schlumberger-doll-Research (SDR) model, and the Initial SDR permeability is estimated permeability from the Initial T2 spectrum by using the SDR model, the Core-permeability is derived permeability from core analysis. The ninth track is the permeability calculated by using the traditional porosity-permeability relationship (Fitted permeability). Good consistency of estimated permeability from the Corrected T2 spectrum with core derived permeability illustrates the reliability of the proposed method. Full article ">Figure 8
A field example of correcting the invasion of oil-based mud to field NMR logging in well C. In the first track, the displayed curves are gamma ray (GR), borehole diameter (CAL), and bit diameter (BIT). The second track is the depth. The third is resistivity curve. The acoustic transit time log (AC), the density log (DEN), compensated neutron log (CNL) are shown in the fourth track. The fifth track is the initial measured T2 spectrum of NMR logging before correction (Initial T2 spectrum). The T2 spectrum of nuclear magnetic resonance logging (Corrected T2 spectrum) under the condition of water-based mud corrected by the method proposed in this study is displayed in the sixth track. The NMR calculated porosity (NMR-por) and core analysis porosity (Core-por) are shown in the seventh track and have good consistency. The Corrected SDR permeability is calculated permeability from the corrected T2 spectrum by using Schlumberger-doll-Research (SDR) model, and the Initial SDR permeability is estimated permeability from the Initial T2 spectrum by using SDR model, the Core-permeability is derived permeability from core analysis. The ninth track is the permeability calculated by using the traditional porosity-permeability relationship (Fitted permeability). Good consistency of estimated permeability from Corrected T2 spectrum with core derived permeability illustrates the reliability of the proposed method. Full article ">Figure 9
Comparison of permeability calculated by various methods and core analysis results. Full article ">Figure 10
Workflow of the T2 spectrum shape correction method for NMR logging under oil-based mud conditions. Full article ">

16 pages, 5193 KiB

Open AccessArticle

The Antimicrobial Activities of Silver Nanoparticles from Aqueous Extract of Grape Seeds against Pathogenic Bacteria and Fungi

by Fatimah Al-Otibi, Shahad K. Alkhudhair, Raedah I. Alharbi, Abdulaziz A. Al-Askar, Reem M. Aljowaie and Sameha Al-Shehri

Molecules 2021, 26(19), 6081; https://doi.org/10.3390/molecules26196081 - 8 Oct 2021

Cited by 27 | Viewed by 3568

Abstract

Grape seed extract (GSE) is a natural source of polyphenolic compounds and secondary metabolites, which have been tested for their possible antimicrobial activities. In the current study, we tested the antibacterial and antifungal activities of aqueous GSE and the biosynthesized silver nanoparticles loaded [...] Read more.

Grape seed extract (GSE) is a natural source of polyphenolic compounds and secondary metabolites, which have been tested for their possible antimicrobial activities. In the current study, we tested the antibacterial and antifungal activities of aqueous GSE and the biosynthesized silver nanoparticles loaded with GSE (GSE-AgNPs) against different pathogens. The biosynthesized GSE-AgNPs were assessed by UV spectroscopy, dynamic light scattering (DLS), field emission scanning electron microscopy (FE-SEM), transmission electron microscopy (TEM), Fourier-transform infrared spectroscopy (FTIR), and gas chromatography/mass spectrometry (GC/MS). The antimicrobial activities were assessed against different bacterial and fungal species. DLS analysis showed that GSE-AgNPs had a Z-Average of 91.89 nm while UV spectroscopy showed that GSE-AgNPs had the highest absorbance at a wavelength of ~415 nm. FTIR analysis revealed that both of GSE and GSE-AgNPs consisted of different functional groups, such as hydroxyl, alkenes, alkyne, and aromatic rings. Both FE-SEM and TEM showed that GSE-AgNPs had larger sizes and rough surfaces than GSE and AgNO₃. The results showed significant antimicrobial activities of GSE-AgNPs against all tested species, unlike GSE, which had weaker and limited effects. More studies are needed to investigate the other antimicrobial activities of GSE. Full article

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Physical biosynthesis of GSE-AgNPs. GSE-AgNPs were prepared by boiling with an aqueous solution of AgNO3 (1 mM), which turned it from light-yellow into brownish-yellow. (A) GSE, (B) GSE-AgNPs. Full article ">Figure 2
Analysis of the physical properties of GSE-AgNPs. The morphological analysis of the biosynthesised GSE-AgNPs showed their ability to induce higher SPR by UV excitation through either (A) UV spectroscopy, or (B) the size distribution curve by Zetasizer; three preparations of GSE-AgNPs, at the same concentrations, were used to confirm the results of DLS. Full article ">Figure 3
The FE-SEM imaging of GSE-AgNPs. A total of 8 μL were loaded on the 200 mesh grids with a carbon support film of JEOL JEM-2100 microscope. JEM-2100 optic system with 15 kV was used to capture the SEM images at the magnification powers of 20,000× (right) and 50,000× (left). Full article ">Figure 4
The TEM imaging of GSE-AgNPs. JEM-1011 transmission electron microscope was used to investigate the crystalline structure of (A) GSE, (B) GSE-AgNPs, and (C) AgNO3. The diameter sizes of the tested materials were measured by ImageJ software. Full article ">Figure 5
FTIR analysis. Nicolet 6700 FTIR Spectrometer was used to identify the functional groups in (A) GSE and (B) GSE-AgNPs at the range of 500–4000 cm−1. Full article ">Figure 6
The antibacterial activity of aqueous GSE and the biosynthesized GSE-AgNPs. The bacterial growth was detected by measuring the inhibition zone using the agar disk-diffusion method by the Mueller–Hinton Agar. The plates were treated with (A) Milli-Q water as control, (B) GSE extract (100%, 50%, & 10%), (C) 0.2 mL AgNO3, or (D) 0.2 mL GSE-AgNPs. The zone of inhibition was measured after seven days ImageJ at the scale of 2.61 pixels/mm. Full article ">Figure 7
The antifungal activity of aqueous GSE and the biosynthesized GSE-AgNPs. The mycelial growth was measured by the agar well diffusion method using potato dextrose agar (PDA) media. The plates were treated with either (A) Milli-Q water as control, (B) GSE extract (100%), (C) 0.2 mL AgNO3, or (D) 0.2 mL GSE-AgNPs. The mycelial growth measuring of the colony diameter after seven days. The mycelial growth was measured by ImageJ at the scale of 2.61 pixels/mm. Full article ">

16 pages, 2543 KiB

Open AccessReview

Analytical Ultracentrifugation as a Matrix-Free Probe for the Study of Kinase Related Cellular and Bacterial Membrane Proteins and Glycans

by Stephen E. Harding

Molecules 2021, 26(19), 6080; https://doi.org/10.3390/molecules26196080 - 8 Oct 2021

Cited by 2 | Viewed by 2807

Abstract

Analytical ultracentrifugation is a versatile approach for analysing the molecular mass, molecular integrity (degradation/aggregation), oligomeric state and association/dissociation constants for self-association, and assay of ligand binding of kinase related membrane proteins and glycans. It has the great property of being matrix free—providing separation [...] Read more.

Analytical ultracentrifugation is a versatile approach for analysing the molecular mass, molecular integrity (degradation/aggregation), oligomeric state and association/dissociation constants for self-association, and assay of ligand binding of kinase related membrane proteins and glycans. It has the great property of being matrix free—providing separation and analysis of macromolecular species without the need of a separation matrix or membrane or immobilisation onto a surface. This short review—designed for the non-hydrodynamic expert—examines the potential of modern sedimentation velocity and sedimentation equilibrium and the challenges posed for these molecules particularly those which have significant cytoplasmic or extracellular domains in addition to the transmembrane region. These different regions can generate different optimal requirements in terms of choice of the appropriate solvent (aqueous/detergent). We compare how analytical ultracentrifugation has contributed to our understanding of two kinase related cellular or bacterial protein/glycan systems (i) the membrane erythrocyte band 3 protein system—studied in aqueous and detergent based solvent systems—and (ii) what it has contributed so far to our understanding of the enterococcal VanS, the glycan ligand vancomycin and interactions of vancomycin with mucins from the gastrointestinal tract. Full article

(This article belongs to the Section Bioorganic Chemistry)

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12 pages, 14096 KiB

Open AccessArticle

In Vitro Analyses of Spinach-Derived Opioid Peptides, Rubiscolins: Receptor Selectivity and Intracellular Activities through G Protein- and β-Arrestin-Mediated Pathways

by Yusuke Karasawa, Kanako Miyano, Hideaki Fujii, Takaaki Mizuguchi, Yui Kuroda, Miki Nonaka, Akane Komatsu, Kaori Ohshima, Masahiro Yamaguchi, Keisuke Yamaguchi, Masako Iseki, Yasuhito Uezono and Masakazu Hayashida

Molecules 2021, 26(19), 6079; https://doi.org/10.3390/molecules26196079 - 8 Oct 2021

Cited by 13 | Viewed by 3770

Abstract

Activated opioid receptors transmit internal signals through two major pathways: the G-protein-mediated pathway, which exerts analgesia, and the β-arrestin-mediated pathway, which leads to unfavorable side effects. Hence, G-protein-biased opioid agonists are preferable as opioid analgesics. Rubiscolins, the spinach-derived naturally occurring opioid peptides, are [...] Read more.

Activated opioid receptors transmit internal signals through two major pathways: the G-protein-mediated pathway, which exerts analgesia, and the β-arrestin-mediated pathway, which leads to unfavorable side effects. Hence, G-protein-biased opioid agonists are preferable as opioid analgesics. Rubiscolins, the spinach-derived naturally occurring opioid peptides, are selective δ opioid receptor agonists, and their p.o. administration exhibits antinociceptive effects. Although the potency and effect of rubiscolins as G-protein-biased molecules are partially confirmed, their in vitro profiles remain unclear. We, therefore, evaluated the properties of rubiscolins, in detail, through several analyses, including the CellKey^TM assay, cADDis^® cAMP assay, and PathHunter^® β-arrestin recruitment assay, using cells stably expressing µ, δ, κ, or µ/δ heteromer opioid receptors. In the CellKey^TM assay, rubiscolins showed selective agonistic effects for δ opioid receptor and little agonistic or antagonistic effects for µ and κ opioid receptors. Furthermore, rubiscolins were found to be G-protein-biased δ opioid receptor agonists based on the results obtained in cADDis^® cAMP and PathHunter^® β-arrestin recruitment assays. Finally, we found, for the first time, that they are also partially agonistic for the µ/δ dimers. In conclusion, rubiscolins could serve as attractive seeds, as δ opioid receptor-specific agonists, for the development of novel opioid analgesics with reduced side effects. 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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Molecular structures of rubiscolins. Full article ">Figure 2
Effect of rubiscolins on MOR, DOR, and KOR, observed using the CellKeyTM system. The cells expressing MOR (A), DOR (B), and KOR (C) were treated with each compound (10−11–10−5 M), and changes in impedance (ΔZiec) were measured using the CellKeyTM system. Concentration–response curves were prepared by calculating ΔZiec relative to the data obtained for each positive control: 10−5 M DAMGO for MOR (A), 10−5 M SNC-80 for DOR (B), and 10−5 M U-50488H for KOR (C). All data points are presented as means ± S.E.M. for three independent experiments (n = 3–5). Full article ">Figure 3
Evaluation of antagonistic effects induced by rubiscolins combined with positive control for MOR or KOR, observed using the CellKeyTM system. The cells expressing MOR (A) and KOR (B) were treated with each positive control alone or in combination with rubiscolin-5, rubiscolin-6, or 10−5 concentration of each negative control (10−11–10−5 M), and changes in impedance (ΔZiec) were measured using the CellKeyTM system. Concentration–response curves were prepared by calculating ΔZiec relative to the data obtained for each positive control: 10−5 M DAMGO for MOR (A) and 10−5 M U-50488H for KOR (B). All data points are presented as means ± S.E.M. for three independent experiments (n = 3–4). Full article ">Figure 4
Changes in intracellular cAMP levels induced by rubiscolin-5, rubiscolin-6, and opioid compounds. Cells expressing MOR (A), DOR (B), or KOR (C) were treated with the listed compounds (10−11–10−5 M), and intracellular cAMP levels were measured with the cADDis® cAMP assay. Concentration–response curves were prepared by calculating cAMP levels relative to the data obtained with 10−5 M DAMGO for MOR (A), 10−5 M SNC-80 for DOR (B), and 10−5 M U-50488H for KOR (C). Data are presented as means ± S.E.M. for three independent experiments (n = 3–5). Full article ">Figure 5
Levels of β-arrestin recruitment through OR induced by rubiscolin-5, rubiscolin-6, and opioid compounds. PathHunter® β-arrestin assay was performed in cells expressing MOR (A), DOR (B), and KOR (C) by treating with each compound (10−11–10−5 M). Concentration–response curves were prepared by calculating intracellular β-arrestin levels relative to the data obtained for each positive control: 10−5 M DAMGO for MOR (A), 10−5 M SNC-80 for DOR (B), and 10−6 M of U-50488H for KOR (C). All data points are presented as means ± S.E.M. for three independent experiments (n = 3–6). Full article ">Figure 6
Changes in intracellular cAMP levels induced by rubiscolin-5, rubiscolin-6, and opioid compounds. Cells expressing MOR (A), DOR (B), or MOR/DOR (C) were treated with the listed compounds (10−11–10−5 M), and the intracellular cAMP levels were measured with the cADDis® cAMP assay. Concentration–response curves were prepared by calculating cAMP levels relative to the data obtained with 10−5 M DAMGO for MOR (A), 10−5 M SNC-80 for DOR (B), and 10−5 M ML335 for MOR/DOR (C). Data are presented as means ± S.E.M. for three independent experiments (n = 6–8). Full article ">

21 pages, 5012 KiB

Open AccessReview

Revisiting Therapeutic Strategies for H. pylori Treatment in the Context of Antibiotic Resistance: Focus on Alternative and Complementary Therapies

by Ioana Alexandra Cardos, Dana Carmen Zaha, Rakesh K. Sindhu and Simona Cavalu

Molecules 2021, 26(19), 6078; https://doi.org/10.3390/molecules26196078 - 8 Oct 2021

Cited by 33 | Viewed by 7522

Abstract

The prevalence of Helicobacter pylori infection remains significant worldwide and it depends on many factors: gender, age, socio-economic status, geographic area, diet, and lifestyle. All successful infectious diseases treatments use antibiotic-susceptibility testing, but this strategy is not currently practical for H. pylori and [...] Read more.

The prevalence of Helicobacter pylori infection remains significant worldwide and it depends on many factors: gender, age, socio-economic status, geographic area, diet, and lifestyle. All successful infectious diseases treatments use antibiotic-susceptibility testing, but this strategy is not currently practical for H. pylori and the usual cure rates of H. pylori are lower than other bacterial infections. Actually, there is no treatment that ensures complete eradication of this pathogen. In the context of an alarming increase in resistance to antibiotics (especially to clarithromycin and metronidazole), alternative and complementary options and strategies are taken into consideration. As the success of antibacterial therapy depends not only on the susceptibility to given drugs, but also on the specific doses, formulations, use of adjuvants, treatment duration, and reinfection rates, this review discusses the current therapies for H. pylori treatment along with their advantages and limitations. As an alternative option, this work offers an extensively referenced approach on natural medicines against H. pylori, including the significance of nanotechnology in developing new strategies for treatment of H. pylori infection. Full article

(This article belongs to the Special Issue Role of Polyphenols and Other Phytochemicals in Prevention and Therapy of Civilization Diseases)

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33 pages, 41004 KiB

Open AccessReview

In Vitro Studies on Therapeutic Effects of Cannabidiol in Neural Cells: Neurons, Glia, and Neural Stem Cells

by Jungnam Kim, Hyunwoo Choi, Eunhye K. Kang, Gil Yong Ji, Youjeong Kim and Insung S. Choi

Molecules 2021, 26(19), 6077; https://doi.org/10.3390/molecules26196077 - 8 Oct 2021

Cited by 15 | Viewed by 6274

Abstract

(‒)-Cannabidiol (CBD) is one of the major phytocannabinoids extracted from the Cannabis genus. Its non-psychoactiveness and therapeutic potential, partly along with some anecdotal—if not scientific or clinical—evidence on the prevention and treatment of neurological diseases, have led researchers to investigate the biochemical actions [...] Read more.

(‒)-Cannabidiol (CBD) is one of the major phytocannabinoids extracted from the Cannabis genus. Its non-psychoactiveness and therapeutic potential, partly along with some anecdotal—if not scientific or clinical—evidence on the prevention and treatment of neurological diseases, have led researchers to investigate the biochemical actions of CBD on neural cells. This review summarizes the previously reported mechanistic studies of the CBD actions on primary neural cells at the in vitro cell-culture level. The neural cells are classified into neurons, microglia, astrocytes, oligodendrocytes, and neural stem cells, and the CBD effects on each cell type are described. After brief introduction on CBD and in vitro studies of CBD actions on neural cells, the neuroprotective capability of CBD on primary neurons with the suggested operating actions is discussed, followed by the reported CBD actions on glia and the CBD-induced regeneration from neural stem cells. A summary section gives a general overview of the biochemical actions of CBD on neural cells, with a future perspective. This review will provide a basic and fundamental, but crucial, insight on the mechanistic understanding of CBD actions on neural cells in the brain, at the molecular level, and the therapeutic potential of CBD in the prevention and treatment of neurological diseases, although to date, there seem to have been relatively limited research activities and reports on the cell culture-level, in vitro studies of CBD effects on primary neural cells. Full article

(This article belongs to the Special Issue The Chemistry of Essential Oils)

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15 pages, 729 KiB

Open AccessReview

Probiotics Regulate Gut Microbiota: An Effective Method to Improve Immunity

by Xinzhou Wang, Peng Zhang and Xin Zhang

Molecules 2021, 26(19), 6076; https://doi.org/10.3390/molecules26196076 - 8 Oct 2021

Cited by 209 | Viewed by 16354

Abstract

Probiotics are beneficial active microorganisms that colonize the human intestines and change the composition of the flora in particular parts of the host. Recently, the use of probiotics to regulate intestinal flora to improve host immunity has received widespread attention. Recent evidence has [...] Read more.

Probiotics are beneficial active microorganisms that colonize the human intestines and change the composition of the flora in particular parts of the host. Recently, the use of probiotics to regulate intestinal flora to improve host immunity has received widespread attention. Recent evidence has shown that probiotics play significant roles in gut microbiota composition, which can inhibit the colonization of pathogenic bacteria in the intestine, help the host build a healthy intestinal mucosa protective layer, and enhance the host immune system. Based on the close relationship between the gut microbiota and human immunity, it has become an extremely effective way to improve human immunity by regulating the gut microbiome with probiotics. In this review, we discussed the influence of probiotics on the gut microbiota and human immunity, and the relationship between immunity, probiotics, gut microbiota, and life quality. We further emphasized the regulation of gut microflora through probiotics, thereby enhancing human immunity and improving people’s lives. Full article

(This article belongs to the Section Natural Products Chemistry)

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20 pages, 2981 KiB

Open AccessReview

Recent Advances and Applications of Plant-Based Bioactive Saponins in Colloidal Multiphase Food Systems

by Mengyue Xu, Zhili Wan and Xiaoquan Yang

Molecules 2021, 26(19), 6075; https://doi.org/10.3390/molecules26196075 - 8 Oct 2021

Cited by 14 | Viewed by 4129

Abstract

The naturally occurring saponins exhibit remarkable interfacial activity and also possess many biological activities linking to human health benefits, which make them particularly attractive as bifunctional building blocks for formulation of colloidal multiphase food systems. This review focuses on two commonly used food-grade [...] Read more.

The naturally occurring saponins exhibit remarkable interfacial activity and also possess many biological activities linking to human health benefits, which make them particularly attractive as bifunctional building blocks for formulation of colloidal multiphase food systems. This review focuses on two commonly used food-grade saponins, Quillaja saponins (QS) and glycyrrhizic acid (GA), with the aim of clarifying the relationship between the structural features of saponin molecules and their subsequent self-assembly and interfacial properties. The recent applications of these two saponins in various colloidal multiphase systems, including liquid emulsions, gel emulsions, aqueous foams and complex emulsion foams, are then discussed. A particular emphasis is on the unique use of GA and GA nanofibrils as sole stabilizers for fabricating various multiphase food systems with many advanced qualities including simplicity, ultrastability, stimulability, structural viscoelasticity and processability. These natural saponin and saponin-based colloids are expected to be used as sustainable, plant-based ingredients for designing future foods, cosmetics and pharmaceuticals. Full article

(This article belongs to the Special Issue Saponin-Rich Plant Extracts: Properties and Application)

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Graphical abstract

Graphical abstract
Full article ">Figure 1
Molecular structures of three monodesmosidic saponins, glycyrrhizic acid (a), escin (b) and tea saponin (c), and bidesmosidic saponin Quillaja saponin (d). Full article ">Figure 2
(a) Schematic illustration of the fibrillar self-assembly of glycyrrhizic acid (GA) molecules in water, forming GA nanofibrils and hydrogels, and of the formation of thermoresponsive gel emulsions by the multilayer adsorption of GA nanofibrils at the oil–water interface and the assembly of fibrillar hydrogel network in the continuous phase after cooling. (b) PLM (left) and optical microscopy (right) images of the reconstituted emulsions with 0.25 wt% GA nanofibrils from the gel emulsions stabilized by 4 wt% GA nanofibrils. The radiant halo with a Maltese cross in PLM image reveals the multilayer fibril shell structure of the droplets. (c) Photograph and PLM image of the gel emulsion with 60 wt% olive oil prepared using 4 wt% GA nanofibrils. Images were reproduced with permission from [<a href="#B33-molecules-26-06075" class="html-bibr">33</a>]. Full article ">Figure 3
Schematic illustration of the mechanism for programmed release of hydrophobic cargoes from the multicompartment microdroplets stabilized by Quillaja saponin (QS)-coated nanodroplets. Images were reproduced with permission from [<a href="#B87-molecules-26-06075" class="html-bibr">87</a>]. Full article ">Figure 4
(a) Photographs of the gel emulsions (60 wt% olive oil, 2–4 wt% GA nanofibrils) with the shape of alphabets using a plastic syringe after cooling the extruded warm emulsions at room temperature (25 °C) for 1 min. (b,c) CLSM images of gel emulsions with 60 wt% olive oil prepared using 4 wt% GA nanofibrils. The sample was prepared with the oil dyed with Nile Red (b) and the GA fibrillar network dyed with ThT (c), respectively. (d,e) SEM images of 4 wt% GA nanofibril gel emulsion with 40 wt% hexane as oil phase. The sample was prepared at air-drying condition. Images were reproduced with permission from [<a href="#B33-molecules-26-06075" class="html-bibr">33</a>,<a href="#B34-molecules-26-06075" class="html-bibr">34</a>]. Full article ">Figure 5
(a) Photographs of initial aqueous foam stabilized by 8 wt% GA nanofibrils, obtained by cooling in an ice bath (2 °C), made with cylindrical and annular molds. (b,c) Environmental SEM images of this initial wet foam. (d) FTIR spectra collected from this foam in D2O and (e) FTIR image (right) and the corresponding bright field image (left) of this foam, obtained by plotting the reflectance at 3400 cm−1 (associated with hydrogen bonding); colors qualitatively indicate the strength gradients of hydrogen bonds from low (blue) to high (red), showing the strong interfibrillar hydrogen bonding in the continuous phase as well as around the bubble surfaces. Images were reproduced with permission from [<a href="#B35-molecules-26-06075" class="html-bibr">35</a>]. Full article ">Figure 6
(a) Photographs showing the temperature-switchable process for complex emulsion foams containing 10 and 20 wt% oils stabilized by 4 wt% GA nanofibrils. Stable emulsion foams can again be obtained after homogenizing and aerating the mixtures (c) at 80 °C followed by cooling in an ice bath. (b–d) PLM images of the above samples with 20 wt% oil during the temperature-switchable process. Inset PLM image shows the jamming of the oil droplets in the liquid channels as well as around the bubbles. Images were reproduced with permission from [<a href="#B36-molecules-26-06075" class="html-bibr">36</a>]. Full article ">

16 pages, 2847 KiB

Open AccessArticle

Aspergillus oryzae-Fermented Wheat Peptone Enhances the Potential of Proliferation and Hydration of Human Keratinocytes through Activation of p44/42 MAPK

by Kyung Man Hahm, See-Hyoung Park, Sae Woong Oh, Ji Hye Kim, Hyun Sook Yeom, Hye Ja Lee, Seoyeon Yang, Jae Youl Cho, Jin Oh Park and Jongsung Lee

Molecules 2021, 26(19), 6074; https://doi.org/10.3390/molecules26196074 - 8 Oct 2021

Cited by 4 | Viewed by 2914

Abstract

Identifying materials contributing to skin hydration, essential for normal skin homeostasis, has recently gained increased research interest. In this study, we investigated the potential benefits and mechanisms of action of Aspergillus oryzae-fermented wheat peptone (AFWP) on the proliferation and hydration of human [...] Read more.

Identifying materials contributing to skin hydration, essential for normal skin homeostasis, has recently gained increased research interest. In this study, we investigated the potential benefits and mechanisms of action of Aspergillus oryzae-fermented wheat peptone (AFWP) on the proliferation and hydration of human skin keratinocytes, through in vitro experiments using HaCaT cell lines. The findings revealed that compared to unfermented wheat peptone, AFWP exhibited an improved amino acid composition, significantly (p < 0.05) higher DPPH scavenging capability and cell proliferation activity, and reduced lipopolysaccharide-induced NO production in RAW 264.7 cells. Furthermore, we separated AFWP into eleven fractions, each ≤2 kDa; of these, fraction 4 (AFW4) demonstrated the highest efficacy in the cell proliferation assay and was found to be the key component responsible for the cell proliferation potential and antioxidant properties of AFWP. Additionally, AFW4 increased the expression of genes encoding natural moisturizing factors, including filaggrin, transglutaminase-1, and hyaluronic acid synthase 1–3. Furthermore, AFW4 activated p44/42 MAPK, but not JNK and p38 MAPK, whereas PD98059, a p44/42 MAPK inhibitor, attenuated the beneficial effects of AFW4 on the skin, suggesting that the effects of AFW4 are mediated via p44/42 MAPK activation. Finally, in clinical studies, AFW4 treatment resulted in increased skin hydration and reduced trans-epidermal water loss compared with a placebo group. Collectively, these data provide evidence that AFW4 could be used as a potential therapeutic agent to improve skin barrier damage induced by external stresses. Full article

(This article belongs to the Special Issue Natural Products for Cosmetic Applications)

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23 pages, 9337 KiB

Open AccessArticle

Cissus subtetragona Planch. Ameliorates Inflammatory Responses in LPS-induced Macrophages, HCl/EtOH-induced Gastritis, and LPS-induced Lung Injury via Attenuation of Src and TAK1

by Laily Rahmawati, Nur Aziz, Jieun Oh, Yo Han Hong, Byoung Young Woo, Yong Deog Hong, Philaxay Manilack, Phetlasy Souladeth, Ji Hwa Jung, Woo Shin Lee, Mi Jeong Jeon, Taewoo Kim, Mohammad Amjad Hossain, Jinwhoa Yum, Jong-Hoon Kim and Jae Youl Cho

Molecules 2021, 26(19), 6073; https://doi.org/10.3390/molecules26196073 - 8 Oct 2021

Cited by 13 | Viewed by 3326

Abstract

Several Cissus species have been used and reported to possess medicinal benefits. However, the anti-inflammatory mechanisms of Cissus subtetragona have not been described. In this study, we examined the potential anti-inflammatory effects of C. subtetragona ethanol extract (Cs-EE) in vitro and in vivo, [...] Read more.

Several Cissus species have been used and reported to possess medicinal benefits. However, the anti-inflammatory mechanisms of Cissus subtetragona have not been described. In this study, we examined the potential anti-inflammatory effects of C. subtetragona ethanol extract (Cs-EE) in vitro and in vivo, and investigated its molecular mechanism as well as its flavonoid content. Lipopolysaccharide (LPS)-induced macrophage-like RAW264.7 cells and primary macrophages as well as LPS-induced acute lung injury (ALI) and HCl/EtOH-induced acute gastritis mouse models were utilized. Luciferase assays, immunoblotting analyses, overexpression strategies, and cellular thermal shift assay (CETSA) were performed to identify the molecular mechanisms and targets of Cs-EE. Cs-EE concentration-dependently reduced the secretion of NO and PGE₂, inhibited the expression of inflammation-related cytokines in LPS-induced RAW264.7 cells, and decreased NF-κB- and AP-1-luciferase activity. Subsequently, we determined that Cs-EE decreased the phosphorylation events of NF-κB and AP-1 pathways. Cs-EE treatment also significantly ameliorated the inflammatory symptoms of HCl/EtOH-induced acute gastritis and LPS-induced ALI mouse models. Overexpression of HA-Src and HA-TAK1 along with CETSA experiments validated that inhibited inflammatory responses are the outcome of attenuation of Src and TAK1 activation. Taken together, these findings suggest that Cs-EE could be utilized as an anti-inflammatory remedy especially targeting against gastritis and acute lung injury by attenuating the activities of Src and TAK1. Full article

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

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9 pages, 2430 KiB

Open AccessArticle

A Galactosidase-Activatable Fluorescent Probe for Detection of Bacteria Based on BODIPY

by Xi Chen, Yu-Cong Liu, Jing-Jing Cui, Fang-Ying Wu and Qiang Xiao

Molecules 2021, 26(19), 6072; https://doi.org/10.3390/molecules26196072 - 8 Oct 2021

Cited by 7 | Viewed by 2800

Abstract

Pathogenic E. coli infection is one of the most widespread foodborne diseases, so the development of sensitive, reliable and easy operating detection tests is a key issue for food safety. Identifying bacteria with a fluorescent medium is more sensitive and faster than using [...] Read more.

Pathogenic E. coli infection is one of the most widespread foodborne diseases, so the development of sensitive, reliable and easy operating detection tests is a key issue for food safety. Identifying bacteria with a fluorescent medium is more sensitive and faster than using chromogenic media. This study designed and synthesized a β-galactosidase-activatable fluorescent probe BOD-Gal for the sensitive detection of E. coli. It employed a biocompatible and photostable 4,4-difluoro-3a,4a-diaza-s-indancene (BODIPY) as the fluorophore to form a β-O-glycosidic bond with galactose, allowing the BOD-Gal to show significant on-off fluorescent signals for in vitro and in vivo bacterial detection. This work shows the potential for the use of a BODIPY based enzyme substrate for pathogen detection. Full article

(This article belongs to the Special Issue Women in Bioorganic Chemistry)

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Fluorescence and absorption changes of BOD-Gal to β-Gal (8 U) in DMSO/PBS solution (PBS / DMSO = 49:1 v:v, pH = 7.4). “-” indicated the absence of β-Gal, “+” indicated the presence of β-Gal. (a) Fluorescence changes, λex = 470 nm. (b) Absorption changes. (c) Time dependence of fluorescence spectra (0–45 min, λex = 470 nm). Inset: Curve of fluorescence intensity versus time. (d) Fluorescence changes of BOD-Gal to different concentration of β-Gal (0 U–12 U), λex = 470 nm. Inset: The relationship between I516 nm and the β-Gal concentration. Full article ">Figure 2
The selectivity of BOD-Gal for β-Gal. (a) Fluorescence spectra of BOD-Gal to various analytes in an aqueous system (PBS/DMSO = 49:1 v:v; pH = 7.4, 37 °C) with β-Gal (8U), Cys (1 mM), DTT (1 mM), GSH (1 mM), Hcy (1 mM), NaClO (1 mM), NADPH (1 mM), NaHS (1 mM), lysozyme (1 kU), Vc (1 mM), cellulose (1 kU), trypsin (1 kU), H2O2 (1 mM) and Na2S2O3 (1 mM), λex = 470 nm. (b) Corresponding fluorescence intensity. Full article ">Figure 3
The calculated energy levels of acceptor and donor (a) before and (b) after hydrolysis reaction according to the theory of the PET mechanism-based on DFT at the B3LYP/6-31 G*(d, p) level. Full article ">Figure 4
Standard plate count method (SPC) assay of E. coli was treated in the presence of BOD-Gal (0–200 μM) incubated for 8 h. Full article ">Figure 5
Comparison of different substrates on plate. (a) Painting β-Gal and (b) Inoculating E. coli (ATCC 25922) on the plate containing BOD-Gal. (c) Inoculating E. coli on the plate containing X-Gal (267 μg/mL). UV irradiation was achieved using a hand-held UV lamp, X-Gal staining appearance was in the ambient light condition. Full article ">Scheme 1
Synthesis Bod-Gal and the proposed sensing mechanism for E. coli (ATCC 25922). Full article ">

11 pages, 3103 KiB

Open AccessArticle

Awn Stem-Derived High-Activity Free-Metal Porous Carbon for Oxidation Reduction

by Qingyun Zhao, Shikai Wen and Junhua Hou

Molecules 2021, 26(19), 6071; https://doi.org/10.3390/molecules26196071 - 8 Oct 2021

Viewed by 1647

Abstract

Designing oxygen reduction reaction (ORR) catalysts with excellent performance has far-reaching significance. In this work, a high-activity biomass free-metal carbon catalyst with N and S co-doped was successfully prepared by using the KOH activated awn stem powder as the precursor with organic matter [...] Read more.

Designing oxygen reduction reaction (ORR) catalysts with excellent performance has far-reaching significance. In this work, a high-activity biomass free-metal carbon catalyst with N and S co-doped was successfully prepared by using the KOH activated awn stem powder as the precursor with organic matter pore-forming doping technology, which is named TAAS. The content of pyridine nitrogen groups accounts for up to 36% of the total nitrogen content, and a rich pore structure is formed on the surface and inside, which are considered as the potential active centers of ORR. The results show that the specific surface area of TAAS reaches 191.04 m²/g, which effectively increases the active sites of the catalyst, and the initial potential and half slope potential are as high as 0.90 and 0.76 V vs. RHE, respectively. This study provides a low-cost, environmentally friendly and feasible strategy for the conversion of low-value agricultural and forestry wastes into high value-added products to promote sustainable development of energy and the environment. Full article

(This article belongs to the Special Issue Novel Carbon Nanomaterials: Preparation and Photoelectric Properties)

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SEM images of AS (a), AAS (b) and TAAS (c). TEM images of AS (d), AAS (e) and TAAS (f). High-resolution XPS spectrum for the C 1s (g), O 1s (h) and S 2p (i) peaks of AS, AAS and TAAS. Full article ">Figure 2
N2 adsorption-desorption isotherms (a) and corresponding pore size distribution diagrams (b) of AS, AAS and TAAS. XRD patterns (c) and Raman spectra (d) of all catalysts. Full article ">Figure 3
FT-IR diagram of AS, AAS and TAAS (a). XPS spectrum (b), high-resolution XPS spectrum of N 1s (c) and 3D bar graphs of the relative content of nitrogen species on the surface of AS, AAS and TAAS (d). Full article ">Figure 4
CV curves (a) of all catalysts in O2 or N2-saturated 0.1 M KOH solution at room temperature and the scanning rate of 50 mV/s. The LSV curves of AS, AAS and TAAS at the electrode rotation rate of 1600 rpm and the scanning rate of 10 mV/s (b). The LSV curve (c) of TAAS at different speeds from 400 to 2500 rpm coincide with the K-L diagram (d) of TAAS from 0.2 to 0.6 V. The RRDE linear sweep voltammogram of TAAS and 20 wt% Pt/C in O2-saturated 0.1 M KOH at the electrode rotation rate and the scanning rate are 1600 rpm and 5 mV/s, respectively (e). Electron transfer number n (up) and H2O2 yield (down) calculated from the RRDE measurement results of TAAS and 20 wt% Pt/C (f). Full article ">Figure 5
Tafel slope curve spectrum (a) and electrochemical impedance (EIS) spectrum (b) of AS, AAS and TAAS. Full article ">Figure 6
The stability curve of TAAS and 20 wt% Pt/C in O2-saturated 0.1 M KOH solution, RDE rotation rate of 1600 rpm, 15,000 s stability curve (a) and the methanol tolerance performance curve measured by current-time chronoamperometry (b). Full article ">

2 pages, 382 KiB

Open AccessCorrection

Correction: Khan et al. Anticancer Function and ROS-Mediated Multi-Targeting Anticancer Mechanisms of Copper (II) 2-hydroxy-1-naphthaldehyde Complexes. Molecules 2019, 24, 2544

by Muhammad Hamid Khan, Meiling Cai, Jungang Deng, Ping Yu, Hong Liang and Feng Yang

Molecules 2021, 26(19), 6070; https://doi.org/10.3390/molecules26196070 - 8 Oct 2021

Cited by 1 | Viewed by 1550

Abstract

Due to the previous incorrect characterization of compound C1, the authors wish to make the following corrections to this paper [...] Full article

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14 pages, 1096 KiB

Open AccessArticle

Comparing Dimerization Free Energies and Binding Modes of Small Aromatic Molecules with Different Force Fields

by Ilias Patmanidis, Riccardo Alessandri, Alex H. de Vries and Siewert J. Marrink

Molecules 2021, 26(19), 6069; https://doi.org/10.3390/molecules26196069 - 7 Oct 2021

Cited by 3 | Viewed by 2811

Abstract

Dimerization free energies are fundamental quantities that describe the strength of interaction of different molecules. Obtaining accurate experimental values for small molecules and disentangling the conformations that contribute most to the binding can be extremely difficult, due to the size of the systems [...] Read more.

Dimerization free energies are fundamental quantities that describe the strength of interaction of different molecules. Obtaining accurate experimental values for small molecules and disentangling the conformations that contribute most to the binding can be extremely difficult, due to the size of the systems and the small energy differences. In many cases, one has to resort to computational methods to calculate such properties. In this work, we used molecular dynamics simulations in conjunction with metadynamics to calculate the free energy of dimerization of small aromatic rings, and compared three models from popular online servers for atomistic force fields, namely G54a7, CHARMM36 and OPLS. We show that, regardless of the force field, the profiles for the dimerization free energy of these compounds are very similar. However, significant care needs to be taken when studying larger molecules, since the deviations from the trends increase with the size of the molecules, resulting in force field dependent preferred stacking modes; for example, in the cases of pyrene and tetracene. Our results provide a useful background study for using topology builders to model systems which rely on stacking of aromatic moieties, and are relevant in areas ranging from drug design to supramolecular assembly. Full article

(This article belongs to the Special Issue Molecular Dynamics Simulations: Advances and Applications)

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List of the molecules with their chemical structure considered in this work. The black line connects the center of geometry (COG) of the molecules and together with the black vectors represent the dihedral angle for the relative orientation of the dimers. The red vector denotes the normal of the plane for each molecule. The dihedral between the two black vectors and the angle between the red vectors, together with the COG distance, were used as collective variables (CV) for the calculation and presentation of the FES profiles. Full article ">Figure 2
FES for the dimerization of benzene as a function of the distance and the torsional angle. The results for each force field are presented in each row. The plots on the left correspond to the FES based on the general setup and the plots on the right to the default parameters of each force field (see Methods). Full article ">Figure 3
FES for the dimerization of benzene as a function of the distance and the angle between the normal of benzene planes. The results for each force field are presented in each row. The plots on the left correspond to the FES based on the general setup and the plots on the right to the default parameters of each force field. Full article ">Figure 4
Statistical error of the FES calculations as a function of the block size. The solid lines correspond to the error analysis of the original biased simulation, whereas the dashed lines correspond to the reweighted profiles. Full article ">Figure 5
Binding energy at the lowest point of each molecule’s dimerization FES for different force fields. All simulations were performed with the general setup. The error bars correspond to the average error calculated from block analysis. Full article ">Figure 6
FES for the dimerization of pyrene as a function of the distance and the torsional angle (left) and the distance and the angle between the normal of aromatic planes (right). Full article ">Figure 7
FES for the dimerization of tetracene as a function of the distance and the torsional angle (left) and the distance and the angle between the normal of aromatic planes (right). Full article ">

12 pages, 2465 KiB

Open AccessArticle

Natural Polyphenols Inhibit the Dimerization of the SARS-CoV-2 Main Protease: The Case of Fortunellin and Its Structural Analogs

by Athanasios A. Panagiotopoulos, Ioannis Karakasiliotis, Danai-Maria Kotzampasi, Marios Dimitriou, George Sourvinos, Marilena Kampa, Stergios Pirintsos, Elias Castanas and Vangelis Daskalakis

Molecules 2021, 26(19), 6068; https://doi.org/10.3390/molecules26196068 - 7 Oct 2021

Cited by 13 | Viewed by 3218

Abstract

3CL-Pro is the SARS-CoV-2 main protease (MPro). It acts as a homodimer to cleave the large polyprotein 1ab transcript into proteins that are necessary for viral growth and replication. 3CL-Pro has been one of the most studied SARS-CoV-2 proteins and a main target [...] Read more.

3CL-Pro is the SARS-CoV-2 main protease (MPro). It acts as a homodimer to cleave the large polyprotein 1ab transcript into proteins that are necessary for viral growth and replication. 3CL-Pro has been one of the most studied SARS-CoV-2 proteins and a main target of therapeutics. A number of drug candidates have been reported, including natural products. Here, we employ elaborate computational methods to explore the dimerization of the 3CL-Pro protein, and we formulate a computational context to identify potential inhibitors of this process. We report that fortunellin (acacetin 7-O-neohesperidoside), a natural flavonoid O-glycoside, and its structural analogs are potent inhibitors of 3CL-Pro dimerization, inhibiting viral plaque formation in vitro. We thus propose a novel basis for the search of pharmaceuticals as well as dietary supplements in the fight against SARS-CoV-2 and COVID-19. Full article

(This article belongs to the Special Issue Biomolecules from Essential Oil Bearing Plants: Biological and Industrial Applications)

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(A). The molecular structure of fortunellin. (B). The interaction of fortunellin with the 3CL-Pro monomer. Fortunellin is shown in green, the interacting amino acids are shown in yellow, and the dimerization interacting amino acids are shown in blue. (C). The free energy surfaces (FES) from the PTmetaD-WTE-enhanced sampling runs. Three minima of the 3CL-Pro homodimer dynamics are identified at the blue regions (C1, C2, and C3) on the CV–1/CV–2 phase space. (D). The identified states of 3CL-Pro in the absence of fortunellin within CV–1/CV–2 phase space. (E). The identified states of 3CL-Pro in the presence of fortunellin within the refined CV–1/CV–2 phase space. The C1–C3 minima are indicated on the D–E graphs based on the comparison with <a href="#molecules-26-06068-f001" class="html-fig">Figure 1</a>A. (F,G). The transition times between the C1 and C3 minima are calculated in the absence (F) and in the presence (G) of fortunellin. Full article ">Figure 2
Effect of point mutations on the conformation of 3CL-Pro monomer. The crystal structure of 3CL-Pro (pdb code: 6YB7) is shown (white ribbon), while the middle structure of the mutated protein, along a 100 ns MD analysis, is shown in red. In (A), the structure of the unliganded protein is presented, while in (B), the bound structure of the protein is shown. Fortunellin is presented in ball-and-sticks while the dimerization interface of the protein is shown within a dotted circle. Full article ">Figure 3
Effect of fortunellin on plaque formation of VERO cells. (A). SARS-CoV-2-infected VERO cells were cultured for 48 h in the absence (Control-DMSO) or the presence of different concentrations of fortunellin, as indicated. The figure presents typical microphotography for each condition repeated three times, in triplicate. The white areas in each microphotograph (acquired with an inverted phase-contrast microscope) are indicative of infected/dead cells. (B). Quantitation of the plaques in each condition obtained with the Fiji (ImageJ2) program. Mean ± SE of three independent assays in triplicate. (C). Non-denatured Western blot of 3CL-Pro in SARS-CoV-2 Vero E6-infected cells treated or not (Control) with 10−6 M fortunellin. Molecular markers are also presented, and the areas of the gel used for the densitometric analysis of dimerized and monomeric 3CL-Pro are denoted by red boxes. Three separate experiments are presented. (D). Densitometric ratio of monomeric/dimerized 3CL-Pro in non-treated and treated cells in the three experiments is shown. (E). Normalized differences in the monomeric/dimerized 3CL-Pro densitometric ratios between treated and untreated cells. Full article ">

11 pages, 2545 KiB

Open AccessArticle

Formation of Copper Oxide Nanotextures on Porous Calcium Carbonate Templates for Water Treatment

by Mahmud Diab, Karam Shreteh, Michael Volokh and Taleb Mokari

Molecules 2021, 26(19), 6067; https://doi.org/10.3390/molecules26196067 - 7 Oct 2021

Cited by 3 | Viewed by 4787

Abstract

The necessity of providing clean water sources increases the demand to develop catalytic systems for water treatment. Good pollutants adsorbers are a key ingredient, and CuO is one of the candidate materials for this task. Among the different approaches for CuO synthesis, precipitation [...] Read more.

The necessity of providing clean water sources increases the demand to develop catalytic systems for water treatment. Good pollutants adsorbers are a key ingredient, and CuO is one of the candidate materials for this task. Among the different approaches for CuO synthesis, precipitation out of aqueous solutions is a leading candidate due to the facile synthesis, high yield, sustainability, and the reported shape control by adjustment of the counter anions. We harness this effect to investigate the formation of copper oxide-based 3D structures. Specifically, the counter anion (chloride, nitrate, and acetate) affects the formation of copper-based hydroxides and the final structure following their conversion into copper oxide nanostructures over porous templates. The formation of a 3D structure is obtained when copper chloride or nitrate reacts with a Sorites scaffold (marine-based calcium carbonate template) without external hydroxide addition. The transformation into copper oxides occurs after calcination or reduction of the obtained Cu₂(OH)₃X (X = Cl⁻ or NO₃⁻) while preserving the porous morphology. Finally, the formed Sorites@CuO structure is examined for water treatment to remove heavy metal cations and degrade organic contaminant molecules. Full article

(This article belongs to the Special Issue Development of Novel Porous Materials)

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Optical images of the Sorites before (a) and after (b) reacting with CuCl2 to form a 3D structure of copper-based hydroxide. Full article ">Figure 2
Optical and scanning electron microscopy (SEM) images of the Sorites 3D structure before (left column, a–d) and after reacting with three different copper salts (the subsequent columns from left to right): CuCl2 (e–h), Cu(NO3)2 (i–l), and Cu(ac)2 (m–p). (a,e,i,m) optical images, SEM top-view images, and SEM cross-section images (d,h,l,p). Full article ">Figure 3
X-ray diffraction patterns of the 3D structures after reacting Sorites with different copper salts. (a) Sorites@Cu2Cl(OH)3, (b) Sorites@Cu2(OH)3(NO3), and (c) Sorites decorated with Cu(ac)2 hydrate. The blue and red bars in the XRD panels correspond to the rhombohedral Mg0.1Ca0.9CO3 and the coated material, respectively. Full article ">Figure 4
Structural characterization of the 3D structure after converting the hydroxide shell to an oxide. (a,d) The optical images, (b,e) SEM images, and (c,f) XRD patterns of Sorites@CuO and Sorites@Cu2O, respectively. The black, blue, and red stick patterns in the XRD panels correspond to the rhombohedral Mg0.1Ca0.9CO3, rhombohedral CaCO3, and the coated materials, respectively. Full article ">Figure 5
The performance of Sorites@CuO in water purification processes. (a) Different concentrations of Pb2+ (blue bars) and Cd2+ (red bars) were removed from the water by the Sorites@CuO 3D structure. The inset shows the concentrations of the Pb2+ and Cd2+ before and after removal using a logarithmic scale. (b) MB dye molecule degradation using Sorites@CuO. Complete degradation (blue) is achieved when the dye is mixed with both H2O2 and Sorites@CuO; two control conditions: degradation experiment (black) where the dye is mixed with H2O2 only; adsorption experiment (red) where the dye is mixed with Sorites@CuO only. Full article ">Figure 6
Purification and pretreatment processes of Sorites: (a) sifting and washing, (b) chemical pretreatment. Full article ">

21 pages, 25807 KiB

Open AccessArticle

New 4-Aminoproline-Based Small Molecule Cyclopeptidomimetics as Potential Modulators of α₄β₁ Integrin

by Andrea Sartori, Kelly Bugatti, Elisabetta Portioli, Monica Baiula, Irene Casamassima, Agostino Bruno, Francesca Bianchini, Claudio Curti, Franca Zanardi and Lucia Battistini

Molecules 2021, 26(19), 6066; https://doi.org/10.3390/molecules26196066 - 7 Oct 2021

Cited by 3 | Viewed by 2925

Abstract

Integrin α₄β₁ belongs to the leukocyte integrin family and represents a therapeutic target of relevant interest given its primary role in mediating inflammation, autoimmune pathologies and cancer-related diseases. The focus of the present work is the design, synthesis and characterization [...] Read more.

Integrin α₄β₁ belongs to the leukocyte integrin family and represents a therapeutic target of relevant interest given its primary role in mediating inflammation, autoimmune pathologies and cancer-related diseases. The focus of the present work is the design, synthesis and characterization of new peptidomimetic compounds that are potentially able to recognize α₄β₁ integrin and interfere with its function. To this aim, a collection of seven new cyclic peptidomimetics possessing both a 4-aminoproline (Amp) core scaffold grafted onto key α₄β₁-recognizing sequences and the (2-methylphenyl)ureido-phenylacetyl (MPUPA) appendage, was designed, with the support of molecular modeling studies. The new compounds were synthesized through SPPS procedures followed by in-solution cyclization maneuvers. The biological evaluation of the new cyclic ligands in cell adhesion assays on Jurkat cells revealed promising submicromolar agonist activity in one compound, namely, the c[Amp(MPUPA)Val-Asp-Leu] cyclopeptide. Further investigations will be necessary to complete the characterization of this class of compounds. Full article

(This article belongs to the Special Issue Women in Bioorganic Chemistry)

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11 pages, 4113 KiB

Open AccessArticle

Preparation of Hop Estrogen-Active Material for Production of Food Supplements

by Marcel Karabín, Tereza Haimannová, Kristýna Fialová, Lukáš Jelínek and Pavel Dostálek

Molecules 2021, 26(19), 6065; https://doi.org/10.3390/molecules26196065 - 7 Oct 2021

Cited by 5 | Viewed by 2931

Abstract

In recent years, the interest in the health-promoting effects of hop prenylflavonoids, especially its estrogenic effects, has grown. Unfortunately, one of the most potent phytoestrogens identified so far, 8-prenylnaringenin, is only a minor component of hops, so its isolation from hop materials for [...] Read more.

In recent years, the interest in the health-promoting effects of hop prenylflavonoids, especially its estrogenic effects, has grown. Unfortunately, one of the most potent phytoestrogens identified so far, 8-prenylnaringenin, is only a minor component of hops, so its isolation from hop materials for the production of estrogenically active food supplements has proved to be problematic. The aim of this study was to optimize the conditions (e.g., temperature, the length of the process and the amount of the catalyst) to produce 8-prenylnaringenin-rich material by the magnesium oxide-catalyzed thermal isomerization of desmethylxanthohumol. Under these optimized conditions, the yield of 8-prenylnaringenin was 29 mg per 100 gDW of product, corresponding to a >70% increase in its content relative to the starting material. This process may be applied in the production of functional foods or food supplements rich in 8-prenylnaringenin, which may then be utilized in therapeutic agents to help alleviate the symptoms of menopausal disorders. Full article

(This article belongs to the Special Issue Natural Product-Inspired Molecules: From Weed to Remedy)

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13 pages, 2462 KiB

Open AccessArticle

HPTLC and ATR/FTIR Characterization of Antioxidants in Different Rosemary Extracts

by Snezana Agatonovic-Kustrin, Ksenia S. Balyklova, Vladimir Gegechkori and David W. Morton

Molecules 2021, 26(19), 6064; https://doi.org/10.3390/molecules26196064 - 7 Oct 2021

Cited by 19 | Viewed by 3669

Abstract

The effect of spontaneous fermentation by lactic acid bacteria on the extraction yield of bioactive compounds and antioxidant activity from rosemary leaf extracts was investigated using high-performance thin-layer chromatography (HPTLC). Brining and spontaneous fermentation with lactic acid bacteria more than doubled extraction of [...] Read more.

The effect of spontaneous fermentation by lactic acid bacteria on the extraction yield of bioactive compounds and antioxidant activity from rosemary leaf extracts was investigated using high-performance thin-layer chromatography (HPTLC). Brining and spontaneous fermentation with lactic acid bacteria more than doubled extraction of polyphenolics and antioxidants from the rosemary leaves. The results show that lactic acid fermentation enhances antioxidant activity in extracts by increasing the total phenolic content but does not increase extraction of phytosterols. Increased extraction of phenolic oxidants during fermentation assisted extraction, results from the in situ generated natural eutectic solvent from the plant sample. ATR-FTIR spectra from the bioactive bands suggests that this increased antioxidant activity is associated with increased extraction of rosmarinic acid, depolymerised lignin, abietane diterpenoids and 15-hydroxy-7-oxodehydroabietic acid. Full article

(This article belongs to the Special Issue Chromatographic Science of Natural Products II)

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Figure 1
HPTLC fingerprints of (a) unfermented extract, (b) fermented extract from fresh leaves, (c) fermented extract from dried leaves, and (d) standards. Track 1, white light; track 2, UV 254 nm; track 3, UV 366 nm; track 4, DPPH· assay; track 5, with ferric chloride; track 6, with anisaldehyde/sulfuric acid under white light; track 7, with anisaldehyde/sulfuric acid under UV 366 nm; track 8, caffeic acid standard with ferric chloride; track 9, rosmarinic acid standard with ferric chloride; track 10, β-sitosterol standard with anisaldehyde/sulfuric acid. Full article ">Figure 2
Superimposed ATR-FTIR spectra of: (a) compound from a band at RF = 0.10 (black line) and rosmarinic acid; (b) compound from a band at RF = 0.37 (black line), lignin and caffeic acid; (c) compound from a band at RF = 0.53 (black line) and carnosic acid; (d) compound from a band at RF = 0.83 (black line) and abietic acid. Full article ">Figure 3
Comparisons of the DPPH· extract bioautograms. Full article ">Figure 4
The chemical structures of: (a) rosmarinic acid methyl ester, (b) carnosic acid, (c) abietic acid, (d) sagerinic acid, (e) salvianolic acid A, and (f) lithospermic acids. Full article ">

13 pages, 300 KiB

Open AccessArticle

Changes in the Folate Content and Fatty Acid Profile in Fermented Milk Produced with Different Starter Cultures during Storage

by Marta Czarnowska-Kujawska and Beata Paszczyk

Molecules 2021, 26(19), 6063; https://doi.org/10.3390/molecules26196063 - 7 Oct 2021

Cited by 13 | Viewed by 3559

Abstract

The application of bacterial cultures in food fermentation is a novel strategy to increase the “natural” levels of bioactive compounds. The unique ability of lactic acid bacteria (LAB) to produce folate, B vitamins, and conjugated linolenic acid cis9trans11 C18:2 (CLA) [...] Read more.

The application of bacterial cultures in food fermentation is a novel strategy to increase the “natural” levels of bioactive compounds. The unique ability of lactic acid bacteria (LAB) to produce folate, B vitamins, and conjugated linolenic acid cis9trans11 C18:2 (CLA) during cold storage up to 21 days was studied. Although some species of LAB can produce folates and other important nutrients, little is known about the production ability of yogurt starter cultures. Pasteurized milk samples were inoculated with four different combinations of commercially available yogurt vaccines, including starter cultures of Bifidobacterium bifidum. Both the type of vaccine and the time of storage at 8 °C had a significant effect on the folate and CLA contents in the tested fermented milks. The highest folate content (105.4 µg/kg) was found in fresh fermented milk inoculated with Lactobacillus delbrueckii, Streptococcus thermophilus, and Bifidobacterium bifidum. Only the mix of Lactobacillus delbrueckii subsp. bulgaricus, Streptococcus thermophilus, and Bifidobacterium bifidum showed potential (59% increase) to synthesize folate during seven days of storage. A significant increase in the content of CLA, when compared to fresh fermented milk, was observed during cold storage for up to 21 days in products enriched with Bifidobacterium bifidum. Full article

(This article belongs to the Special Issue Health Promoting Compounds in Milk and Dairy Products)

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14 pages, 4519 KiB

Open AccessArticle

l-Arginine Improves Solubility and ANTI SARS-CoV-2 Mpro Activity of Rutin but Not the Antiviral Activity in Cells

by Luca Sancineto, Carmine Ostacolo, David Ortega-Alarcon, Ana Jimenez-Alesanco, Laura Ceballos-Laita, Sonia Vega, Olga Abian, Adrian Velazquez-Campoy, Silvia Moretti, Agnieszka Dabrowska, Pawel Botwina, Aleksandra Synowiec, Anna Kula-Pacurar, Krzysztof Pyrc, Nunzio Iraci and Claudio Santi

Molecules 2021, 26(19), 6062; https://doi.org/10.3390/molecules26196062 - 7 Oct 2021

Cited by 6 | Viewed by 4708

Abstract

The COVID-19 pandemic outbreak prompts an urgent need for efficient therapeutics, and repurposing of known drugs has been extensively used in an attempt to get to anti-SARS-CoV-2 agents in the shortest possible time. The glycoside rutin shows manifold pharmacological activities and, despite its [...] Read more.

The COVID-19 pandemic outbreak prompts an urgent need for efficient therapeutics, and repurposing of known drugs has been extensively used in an attempt to get to anti-SARS-CoV-2 agents in the shortest possible time. The glycoside rutin shows manifold pharmacological activities and, despite its use being limited by its poor solubility in water, it is the active principle of many pharmaceutical preparations. We herein report our in silico and experimental investigations of rutin as a SARS-CoV-2 Mpro inhibitor and of its water solubility improvement obtained by mixing it with l-arginine. Tests of the rutin/l-arginine mixture in a cellular model of SARS-CoV-2 infection highlighted that the mixture still suffers from unfavorable pharmacokinetic properties, but nonetheless, the results of this study suggest that rutin might be a good starting point for hit optimization. Full article

(This article belongs to the Special Issue Chasing New Therapeutics for COVID-19: Target Identification and Validation, Medicinal Chemistry and Drug Discovery Efforts)

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Figure 1
Structures of rutin (1), quercetin (2), and l-arginine (3). Full article ">Figure 2
Jaguar-predicted pKa values for the three acidic hydroxyl groups of the quercetin moiety. R represents the rutin glycon. Full article ">Figure 3
REST MD trajectories clustering of i1-4 rutin/l-arginine. The structure nearest to the centroid for each highly populated cluster (>100 members) is represented in sticks and colored according to the following scheme: i1—magenta, i2—yellow, i3—green, i4—cyan. Full article ">Figure 4
Inhibition curve for RutinArg against Mpro. (a) Time evolution of the substrate fluorescence as a function of time. The observed FRET diminishes as the substrate is hydrolyzed by Mpro, reflecting the spatial separation of the donor-acceptor FRET couple. As the RutinArg concentration increases (arrow), the activity of Mpro, quantitated as the initial slope of each trace, decreases. (b) Inhibition curve obtained by plotting the activity percentage of Mpro, calculated as the ratio of the initial slope at each RutinArg concentration by that corresponding to no compound added (control), as a function of the RutinArg concentration. The non-linear least-squares analysis of the data considering a ligand-depletion model provided an estimation of the inhibition constant Ki. When the enzyme concentration and the ligand depletion are not accounted for, the effective inhibition concentration IC50 is estimated. Full article ">Figure 5
Docking pose of 1 into SARS-CoV-2 Mpro active site. (a) 1 is shown in orange sticks; the molecular surface of Mpro is colored according to the binding sites S1 (yellow), S1′ (green), S2 (cyan) and S4 (magenta). (b) 1 is represented in magenta sticks and SARS-CoV-2 Mpro in cyan cartoons and sticks; dashed lines represent h-bonds (in yellow) and π-π stacking interactions (in green). Experimental bound conformation of 4 (PDB 7L11) [<a href="#B40-molecules-26-06062" class="html-bibr">40</a>] is shown in white sticks for reference in both panels. These figures were made using open source PyMOL v. 1.8.4.0. Full article ">Figure 6
Results summary of rutin/Mpro MD simulations. (a) Rutin/Mpro interaction diagram. Only interaction detected for at least 36 ns out of 120 ns of simulation time are shown. (b) Root mean square fluctuations of rutin atoms during 120 ns of MD simulation. Full article ">

19 pages, 41272 KiB

Open AccessArticle

Simulation of the Interactions of Arginine with Wild-Type GALT Enzyme and the Classic Galactosemia-Related Mutant p.Q188R by a Computational Approach

by Anna Verdino, Gaetano D’Urso, Carmen Tammone, Bernardina Scafuri, Lucrezia Catapano and Anna Marabotti

Molecules 2021, 26(19), 6061; https://doi.org/10.3390/molecules26196061 - 7 Oct 2021

Cited by 2 | Viewed by 2627

Abstract

Classic galactosemia is an inborn error of metabolism associated with mutations that impair the activity and the stability of galactose-1-phosphate uridylyltransferase (GALT), catalyzing the third step in galactose metabolism. To date, no treatments (including dietary galactose deprivation) are able to prevent or alleviate [...] Read more.

Classic galactosemia is an inborn error of metabolism associated with mutations that impair the activity and the stability of galactose-1-phosphate uridylyltransferase (GALT), catalyzing the third step in galactose metabolism. To date, no treatments (including dietary galactose deprivation) are able to prevent or alleviate the long-term complications affecting galactosemic patients. Evidence that arginine is able to improve the activity of the human enzyme expressed in a prokaryotic model of classic galactosemia has induced researchers to suppose that this amino acid could act as a pharmacochaperone, but no effects were detected in four galactosemic patients treated with this amino acid. Given that no molecular characterizations of the possible effects of arginine on GALT have been performed, and given that the samples of patients treated with arginine are extremely limited for drawing definitive conclusions at the clinical level, we performed computational simulations in order to predict the interactions (if any) between this amino acid and the enzyme. Our results do not support the possibility that arginine could function as a pharmacochaperone for GALT, but information obtained by this study could be useful for identifying, in the future, possible pharmacochaperones for this enzyme. Full article

(This article belongs to the Special Issue Computational Methods for Drug Discovery and Design II)

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Figure 1
Structure of the model of the homodimeric GALT enzyme carrying the mutation p.Gln188Arg. Chain A is in blue; chain B, in orange. The residues of the two active sites are represented in stick form and colored in magenta, with the mutant residue in black. Galactose-1-phosphate (G1P) is in green, and 5,6-dihydrouridine-5’-monophosphate (H2U) is in cyan. Zn ions are represented as yellow spheres. The surface of the central cavity of the enzyme is represented in grey. Full article ">Figure 2
Interactions of arginine in the active site with enzyme and ligands. (a) wtGALT + arginine; (b) p.Gln188Arg + arginine; (c) wtGALT + G1P + arginine; (d) p.Gln188Arg + G1P + arginine; (e) wtGALT + H2U + arginine; (f) p.Gln188Arg + H2U + arginine. Gray background indicates interactions that persisted for more than 50% of the simulation time. Gray dashed lines indicate H-bonds. Red dashed lines indicate interactions between the ligands. Full article ">Figure 3
Representative results of DSSP analysis for simulations with arginine in the active site. (a) wtGALT + arginine; (b) p.Gln188Arg + arginine; (c) wtGALT + G1P + arginine; (d) p.Gln188Arg + G1P + arginine; (e) wtGALT + H2U + arginine; (f) p.Gln188Arg + H2U + arginine. Full article ">Figure 4
Representative results of RMSF analysis for simulations with arginine in the active site. (a) wtGALT + arginine; (b) p.Gln188Arg + arginine; (c) wtGALT + G1P + arginine; (d) p.Gln188Arg + G1P + arginine; (e) wtGALT + H2U + arginine; (f) p.Gln188Arg + H2U + arginine. Blue lines represent RMSF fluctuation of chain A; red lines, that of chain B. Full article ">Figure 5
Interactions of arginine in the central cavity with enzyme and ligands. (a) Interactions of arginine in the simulation wtGALT + arginine; (b) Interactions of arginine in the simulation p.Gln188Arg + arginine; (c) Interactions of arginine (top) and of the substrates in the two active sites (bottom) in the simulation wtGALT + G1P + H2U + arginine; (d) Interactions of arginine (top) and of the substrates in the two active sites (bottom) in the simulation p.Gln188Arg + G1P + H2U + arginine. Gray background indicates interactions that persisted for more than 50% of the simulation time. Gray dashed lines indicate H-bonds. Red dashed lines indicate interactions between the ligands. Full article ">Figure 6
DSSP analysis for simulations with arginine in the central cavity. (a) wtGALT + arginine; (b) p.Gln188Arg + arginine; (c) wtGALT + G1P + H2U + arginine; (d) p.Gln188Arg + G1P + H2U + arginine. Full article ">Figure 7
RMSF analysis. Simulations with arginine in the central cavity. (a) wtGALT + arginine; (b) p.Gln188Arg + arginine; (c) wtGALT + G1P + H2U + arginine; (d) p.Gln188Arg + G1P + H2U + arginine. Blue lines represent RMSF fluctuation of chain A; red lines, that of chain B. Full article ">Scheme 1
Leloir pathway of galactose metabolism. The enzymes catalyzing the different steps are galactose mutarotase (GALM), galactokinase 1 (GALK), galactose-1-phosphate uridylyltransferase (GALT) and UDP-galactose 4-epimerase (GALE). Different forms of galactosemia derive from the impairment of each enzyme, as represented in the scheme. Full article ">

16 pages, 1266 KiB

Open AccessReview

Heavy Metals and Human Health: Possible Exposure Pathways and the Competition for Protein Binding Sites

by Danuta Witkowska, Joanna Słowik and Karolina Chilicka

Molecules 2021, 26(19), 6060; https://doi.org/10.3390/molecules26196060 - 7 Oct 2021

Cited by 256 | Viewed by 20431

Abstract

Heavy metals enter the human body through the gastrointestinal tract, skin, or via inhalation. Toxic metals have proven to be a major threat to human health, mostly because of their ability to cause membrane and DNA damage, and to perturb protein function and [...] Read more.

Heavy metals enter the human body through the gastrointestinal tract, skin, or via inhalation. Toxic metals have proven to be a major threat to human health, mostly because of their ability to cause membrane and DNA damage, and to perturb protein function and enzyme activity. These metals disturb native proteins’ functions by binding to free thiols or other functional groups, catalyzing the oxidation of amino acid side chains, perturbing protein folding, and/or displacing essential metal ions in enzymes. The review shows the physiological and biochemical effects of selected toxic metals interactions with proteins and enzymes. As environmental contamination by heavy metals is one of the most significant global problems, some detoxification strategies are also mentioned. Full article

(This article belongs to the Special Issue Protein Interactions—on the Frontier of Biochemistry and Biophysics)

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Molecules, Volume 26, Issue 19 (October-1 2021) – 365 articles

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