Molecules

19 pages, 1965 KiB

Open AccessArticle

Bioanalytical Method Development and Validation Study of Neuroprotective Extract of Kashmiri Saffron Using Ultra-Fast Liquid Chromatography-Tandem Mass Spectrometry (UFLC-MS/MS): In Vivo Pharmacokinetics of Apocarotenoids and Carotenoids

by Aboli Girme, Sandeep Pawar, Chetana Ghule, Sushant Shengule, Ganesh Saste, Arun Kumar Balasubramaniam, Amol Deshmukh and Lal Hingorani

Molecules 2021, 26(6), 1815; https://doi.org/10.3390/molecules26061815 - 23 Mar 2021

Cited by 14 | Viewed by 3957

Abstract

Kashmir saffron (Crocus sativus L.), also known as Indian saffron, is an important Asian medicinal plant with protective therapeutic applications in brain health. The main bioactive in Kashmir or Indian Saffron (KCS) and its extract (CSE) are apocarotenoids picrocrocin (PIC) and safranal [...] Read more.

Kashmir saffron (Crocus sativus L.), also known as Indian saffron, is an important Asian medicinal plant with protective therapeutic applications in brain health. The main bioactive in Kashmir or Indian Saffron (KCS) and its extract (CSE) are apocarotenoids picrocrocin (PIC) and safranal (SAF) with carotenoids, crocetin esters (crocins), and crocetins. The ultra-fast liquid chromatography(UFLC)- photodiode array standardization confirmed the presence of biomarkers PIC, trans-4-GG-crocin (T4C), trans-3-Gg-crocin (T3C), cis-4-GG-crocin (C4C), trans-2-gg-crocin (T2C), trans-crocetin (TCT), and SAF in CSE. This study’s objectives were to develop and validate a sensitive and rapid UFLC-tandem mass spectrometry method for PIC and SAF along T4C and TCT in rat plasma with internal standards (IS). The calibration curves were linear (R² > 0.990), with the lower limit of quantification (LLOQ) as 10 ng/mL. The UFLC-MS/MS assay-based precision (RSD, <15%) and accuracy (RE, −11.03–9.96) on analytical quality control (QC) levels were well within the acceptance criteria with excellent recoveries (91.18–106.86%) in plasma samples. The method was applied to investigate the in vivo pharmacokinetic parameters after oral administration of 40 mg/kg CSE in the rats (n = 6). The active metabolite TCT and T4C, PIC, SAF were quantified for the first time with T3C, C4C, T2C by this validated bioanalytical method, which will be useful for preclinical/clinical trials of CSE as a potential neuroprotective dietary supplement. Full article

(This article belongs to the Special Issue Crocus sativus L. Extract and Its Constituents: Chemistry, Pharmacology and Therapeutic Potential)

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Compounds of Kashmir saffron extract (CSE)-trans-4-gg-crocin (T4C); trans-3-Gg-crocin (T3C); trans-2gg-crocin (T2C); trans-crocetin (TCT); safranal (SAF); picrocrocin (PIC), and cis-4GG-crocin (C4C). Full article ">Figure 2
Possible mass fragmentation pattern and (m/z) values of precursor (Q1) and product (Q3) ions for T4C, T3C, T2C, C4C, TCT, IS2 (negative mode) and PIC, SAF, IS1 (positive mode) in the optimized ultra-fast liquid chromatography-tandem mass spectrometry (UFLC-MS/MS) based MRM conditions. Full article ">Figure 3
Typical MRM chromatograms of the seven components in rats: (A) blank plasma; (B) blank plasma sample spiked with standard mixtures and internal standard; (C) rat plasma samples collected after oral administration of the CSE. PIC, T4C, T3C, C4C, T2C, reserpine (IS1), TCT, SAF, chloramphenicol (IS2). Full article ">Figure 4
Mean plasma concentration-time curves of six constituents identified and quantified after oral administration of Kashmir saffron extract (CSE) at the dose of 40 mg/kg in rats (mean ± SEM, n = 6). PIC, T4C, TCT, T3C, C4C, and T2C. Full article ">

14 pages, 321 KiB

Open AccessReview

The Common Cichory (Cichorium intybus L.) as a Source of Extracts with Health-Promoting Properties—A Review

by Katarzyna Janda, Izabela Gutowska, Małgorzata Geszke-Moritz and Karolina Jakubczyk

Molecules 2021, 26(6), 1814; https://doi.org/10.3390/molecules26061814 - 23 Mar 2021

Cited by 63 | Viewed by 9227

Abstract

Natural products are gaining more interest recently, much of which focuses on those derived from medicinal plants. The common chicory (Cichorium intybus L.), of the Astraceae family, is a prime example of this trend. It has been proven to be a feasible [...] Read more.

Natural products are gaining more interest recently, much of which focuses on those derived from medicinal plants. The common chicory (Cichorium intybus L.), of the Astraceae family, is a prime example of this trend. It has been proven to be a feasible source of biologically relevant elements (K, Fe, Ca), vitamins (A, B₁, B₂, C) as well as bioactive compounds (inulin, sesquiterpene lactones, coumarin derivatives, cichoric acid, phenolic acids), which exert potent pro-health effects on the human organism. It displays choleretic and digestion-promoting, as well as appetite-increasing, anti-inflammatory and antibacterial action, all owing to its varied phytochemical composition. Hence, chicory is used most often to treat gastrointestinal disorders. Chicory was among the plants with potential against SARS-CoV-2, too. To this and other ends, roots, herb, flowers and leaves are used. Apart from its phytochemical applications, chicory is also used in gastronomy as a coffee substitute, food or drink additive. The aim of this paper is to present, in the light of the recent literature, the chemical composition and properties of chicory. Full article

(This article belongs to the Special Issue Plant Extracts: Biological and Pharmacological Activity—the Second Edition)

16 pages, 3307 KiB

Open AccessArticle

Selective Synthesis of N-Acylnortropane Derivatives in Palladium-Catalysed Aminocarbonylation

by László Kollár, Ádám Erdélyi, Haroon Rasheed and Attila Takács

Molecules 2021, 26(6), 1813; https://doi.org/10.3390/molecules26061813 - 23 Mar 2021

Cited by 5 | Viewed by 2716

Abstract

The aminocarbonylation of various alkenyl and (hetero)aryl iodides was carried out using tropane-based amines of biological importance, such as 8-azabicyclo[3.2.1]octan-3-one (nortropinone) and 3α-hydroxy-8-azabicyclo[3.2.1]octane (nortropine) as N-nucleophile. Using iodoalkenes, the two nucleophiles were selectively converted to the corresponding amide in the presence of [...] Read more.

The aminocarbonylation of various alkenyl and (hetero)aryl iodides was carried out using tropane-based amines of biological importance, such as 8-azabicyclo[3.2.1]octan-3-one (nortropinone) and 3α-hydroxy-8-azabicyclo[3.2.1]octane (nortropine) as N-nucleophile. Using iodoalkenes, the two nucleophiles were selectively converted to the corresponding amide in the presence of Pd(OAc)₂/2 PPh₃ catalysts. In the presence of several iodo(hetero)arenes, the application of the bidentate Xantphos was necessary to produce the target compounds selectively. The new carboxamides of varied structure, formed in palladium-catalyzed aminocarbonylation reactions, were isolated and fully characterized. In this way, a novel synthetic method has been developed for the producing of N-acylnortropane derivatives of biological importance. Full article

(This article belongs to the Special Issue Preparation of Heterocycles by Metal-Promoted Reactions)

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13 pages, 435 KiB

Open AccessArticle

Developing a Hazomalania voyronii Essential Oil Nanoemulsion for the Eco-Friendly Management of Tribolium confusum, Tribolium castaneum and Tenebrio molitor Larvae and Adults on Stored Wheat

by Nickolas G. Kavallieratos, Erifili P. Nika, Anna Skourti, Nikoletta Ntalli, Maria C. Boukouvala, Catherine T. Ntalaka, Filippo Maggi, Rianasoambolanoro Rakotosaona, Marco Cespi, Diego Romano Perinelli, Angelo Canale, Giulia Bonacucina and Giovanni Benelli

Molecules 2021, 26(6), 1812; https://doi.org/10.3390/molecules26061812 - 23 Mar 2021

Cited by 34 | Viewed by 3547

Abstract

Most insecticides commonly used in storage facilities are synthetic, an issue that generates concerns about food safety and public health. Therefore, the development of eco-friendly pest management tools is urgently needed. In the present study, a 6% (w/w) Hazomalania voyronii essential [...] Read more.

Most insecticides commonly used in storage facilities are synthetic, an issue that generates concerns about food safety and public health. Therefore, the development of eco-friendly pest management tools is urgently needed. In the present study, a 6% (w/w) Hazomalania voyronii essential oil-based nanoemulsion (HvNE) was developed and evaluated for managing Tribolium confusum, T. castaneum, and Tenebrio molitor, as an eco-friendly wheat protectant. Larval and adult mortality was evaluated after 4, 8, and 16 h, and 1, 2, 3, 4, 5, 6, and 7 days, testing two HvNE concentrations (500 ppm and 1000 ppm). T. confusum and T. castaneum adults and T. molitor larvae were tolerant to both concentrations of the HvNE, reaching 13.0%, 18.7%, and 10.3% mortality, respectively, at 1000 ppm after 7 days of exposure. However, testing HvNE at 1000 ppm, the mortality of T. confusum and T. castaneum larvae and T. molitor adults 7 days post-exposure reached 92.1%, 97.4%, and 100.0%, respectively. Overall, the HvNE can be considered as an effective adulticide or larvicide, depending on the target species. Our results highlight the potential of H. voyronii essential oil for developing green nanoinsecticides to be used in real-world conditions against key stored-product pests. Full article

(This article belongs to the Special Issue Insecticide, Acaricide, Repellent and Antimicrobial Development)

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16 pages, 4879 KiB

Open AccessArticle

Bioinformatic Analysis of Genome-Predicted Bat Cathelicidins

by José Manuel Pérez de la Lastra, Patricia Asensio-Calavia, Sergio González-Acosta, Victoria Baca-González and Antonio Morales-delaNuez

Molecules 2021, 26(6), 1811; https://doi.org/10.3390/molecules26061811 - 23 Mar 2021

Cited by 11 | Viewed by 3878

Abstract

Bats are unique in their potential to serve as reservoir hosts for intracellular pathogens. Recently, the impact of COVID-19 has relegated bats from biomedical darkness to the frontline of public health as bats are the natural reservoir of many viruses, including SARS-Cov-2. Many [...] Read more.

Bats are unique in their potential to serve as reservoir hosts for intracellular pathogens. Recently, the impact of COVID-19 has relegated bats from biomedical darkness to the frontline of public health as bats are the natural reservoir of many viruses, including SARS-Cov-2. Many bat genomes have been sequenced recently, and sequences coding for antimicrobial peptides are available in the public databases. Here we provide a structural analysis of genome-predicted bat cathelicidins as components of their innate immunity. A total of 32 unique protein sequences were retrieved from the NCBI database. Interestingly, some bat species contained more than one cathelicidin. We examined the conserved cysteines within the cathelin-like domain and the peptide portion of each sequence and revealed phylogenetic relationships and structural dissimilarities. The antibacterial, antifungal, and antiviral activity of peptides was examined using bioinformatic tools. The peptides were modeled and subjected to docking analysis with the region binding domain (RBD) region of the SARS-CoV-2 Spike protein. The appearance of multiple forms of cathelicidins verifies the complex microbial challenges encountered by these species. Learning more about antiviral defenses of bats and how they drive virus evolution will help scientists to investigate the function of antimicrobial peptides in these species. Full article

(This article belongs to the Special Issue Discovering New Natural Compounds with Pharmacological or Biotechnological Applications)

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Figure 1
Multi-sequence alignments of the conserved cathelin region of bat cathelicidins using the default parameters of CLUSTALW (<a href="https://www.genome.jp/tools-bin/clustalw" target="_blank">https://www.genome.jp/tools-bin/clustalw</a>, accessed on: 10 January 2021). Gaps are inserted to optimize the alignment. Conserved cysteines are shaded and identical amino acids are indicated by asterisks, whereas those with high or low similarities are indicated by colons and dots, respectively. Full article ">Figure 2
Phylogenetic tree constructed from the multi-sequence alignments of the conserved cathelin region of bat cathelicidins. The tree was constructed using FastTree with default parameters. FastTree infers maximum-likelihood phylogenetic trees using the Neighbor Joining method and computes local support values with the Shimodaira-Hasegawa test. Full article ">Figure 3
Structure of an amphipathic helix. Yellow/green residues of the upper helical view are hydrophobic and form the hydrophobic face, whereas purple residues of the helix are polar residues and are located at the opposite face. This feature is typical of most antimicrobial peptides and allow them to interact with membranes (down). Full article ">Figure 4
Bioinformatic analysis of bat cathelicidins (part 1). Net charge, secondary structure, hydrophobicity of helixes, and interaction with membranes and SARS-CoV-2 region binding domain (RBD) of the Spike protein were computed. The analysis includes predictions of biological properties of the peptides, such as antibacterial, antifungal, antiviral, and hemolytic activities. Full article ">Figure 5
Bioinformatic analysis of bat cathelicidins (part 2). Net charge, secondary structure, hydrophobicity of helixes, interaction with membranes and with the SARS-CoV-2 region binding domain (RBD) of the Spike protein were computed. The analysis included predictions of biological properties of the peptides, such as antibacterial, antifungal, antiviral, and hemolytic activities. Full article ">Figure 6
Bioinformatic analysis of human cathelicidin peptide LL-37. Net charge, secondary structure, hydrophobicity of helixes, interaction with membranes and with the SARS-CoV-2 region binding domain (RBD) of the Spike protein were computed. The analysis included predictions of biological properties of the peptides; such as antibacterial, antifungal, antiviral and hemolytic activities. Full article ">

12 pages, 1354 KiB

Open AccessArticle

Relationships between the Content of Phenolic Compounds and the Antioxidant Activity of Polish Honey Varieties as a Tool for Botanical Discrimination

by Monika Kędzierska-Matysek, Małgorzata Stryjecka, Anna Teter, Piotr Skałecki, Piotr Domaradzki and Mariusz Florek

Molecules 2021, 26(6), 1810; https://doi.org/10.3390/molecules26061810 - 23 Mar 2021

Cited by 40 | Viewed by 3301

Abstract

The study compared the content of eight phenolic acids and four flavonoids and the antioxidant activity of six Polish varietal honeys. An attempt was also made to determine the correlations between the antioxidant parameters of the honeys and their polyphenol profile using principal [...] Read more.

The study compared the content of eight phenolic acids and four flavonoids and the antioxidant activity of six Polish varietal honeys. An attempt was also made to determine the correlations between the antioxidant parameters of the honeys and their polyphenol profile using principal component analysis. Total phenolic content (TPC), total flavonoid content (TFC), antioxidant activity (ABTS) and reduction capacity (FRAP) were determined spectrophotometrically, and the phenolic compounds were determined using high-performance liquid chromatography (HPLC). The buckwheat honeys showed the strongest antioxidant activity, most likely because they had the highest concentrations of total phenols, total flavonoids, p-hydroxybenzoic acid, caffeic acid, p-coumaric acid, vanillic acid and chrysin. The principal component analysis (PCA) of the data showed significant relationships between the botanic origin of the honey, the total content of phenolic compounds and flavonoids and the antioxidant activity of the six Polish varietal honeys. The strongest, significant correlations were shown for parameters of antioxidant activity and TPC, TFC, p-hydroxybenzoic acid, caffeic acid and p-coumaric acid. Analysis of four principal components (explaining 86.9% of the total variance), as a classification tool, confirmed the distinctiveness of the Polish honeys in terms of their antioxidant activity and content of phenolic compounds. Full article

(This article belongs to the Special Issue Bee Products Chemistry: Identification and Characterization of Natural Compound)

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18 pages, 7061 KiB

Open AccessArticle

A Novel Solid Nanocrystals Self-Stabilized Pickering Emulsion Prepared by Spray-Drying with Hydroxypropyl-β-cyclodextrin as Carriers

by Jifen Zhang, Yanhua Wang, Jirui Wang and Tao Yi

Molecules 2021, 26(6), 1809; https://doi.org/10.3390/molecules26061809 - 23 Mar 2021

Cited by 7 | Viewed by 3011

Abstract

A drug nanocrystals self-stabilized Pickering emulsion (NSSPE) with a unique composition and microstructure has been proven to significantly increase the bioavailability of poorly soluble drugs. This study aimed to develop a new solid NSSPE of puerarin preserving the original microstructure of NSSPE by [...] Read more.

A drug nanocrystals self-stabilized Pickering emulsion (NSSPE) with a unique composition and microstructure has been proven to significantly increase the bioavailability of poorly soluble drugs. This study aimed to develop a new solid NSSPE of puerarin preserving the original microstructure of NSSPE by spray-drying. A series of water-soluble solid carriers were compared and then Box-Behnken design was used to optimize the parameters of spray-drying. The drug release and stability of the optimized solid NSSPE in vitro were also investigated. The results showed that hydroxypropyl-β-cyclodextrin (HP-β-CD), rather than solid carriers commonly used in solidification of traditional Pickering emulsions, was suitable for the solid NSSPE to retain the original appearance and size of emulsion droplets after reconstitution. The amount of HP-β-CD had more influences on the solid NSSPE than the feed rate and the inlet air temperature. Fluorescence microscopy, confocal laser scanning microscopy and scanning electron microscopy showed that the reconstituted emulsion of the solid NSSPE prepared with HP-β-CD had the same core-shell structure with a core of oil and a shell of puerarin nanocrystals as the liquid NSSPE. The particle size of puerarin nanocrystal sand interfacial adsorption rate also did not change significantly. The cumulative amount of released puerarin from the solid NSSPE had no significant difference compared with the liquid NSSPE, which were both significantly higher than that of puerarin crude material. The solid NSSPE was stable for 3 months under the accelerated condition of 75% relative humidity and 40 °C. Thus, it is possible todevelop the solid NSSPE preserving the unique microstructure and the superior properties in vitro of the liquid NSSPE for poorly soluble drugs. Full article

(This article belongs to the Special Issue Nano-particulate Drug Delivery System: Current Status and Future Perspective)

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13 pages, 1196 KiB

Open AccessArticle

Concentration of Bioactive Phenolic Compounds in Olive Mill Wastewater by Direct Contact Membrane Distillation

by Rosa Tundis, Carmela Conidi, Monica R. Loizzo, Vincenzo Sicari, Rosa Romeo and Alfredo Cassano

Molecules 2021, 26(6), 1808; https://doi.org/10.3390/molecules26061808 - 23 Mar 2021

Cited by 31 | Viewed by 2683

Abstract

Olive mill wastewater (OMW), generated as a by-product of olive oil production, is considered one of the most polluting effluents produced by the agro-food industry, due to its high concentration of organic matter and nutrients. However, OMW is rich in several polyphenols, representing [...] Read more.

Olive mill wastewater (OMW), generated as a by-product of olive oil production, is considered one of the most polluting effluents produced by the agro-food industry, due to its high concentration of organic matter and nutrients. However, OMW is rich in several polyphenols, representing compounds with remarkable biological properties. This study aimed to analyze the chemical profile as well as the antioxidant and anti-obesity properties of concentrated fractions obtained from microfiltered OMW treated by direct contact membrane distillation (DCMD). Ultra-high performance liquid chromatography (UHPLC) analyses were applied to quantify some phenols selected as phytochemical markers. Moreover, α-Amylase, α-glucosidase, and lipase inhibitory activity were investigated together with the antioxidant activity by means of assays, namely β-carotene bleaching, 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulphonic) acid (ABTS) diammonium salts, 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay, and Ferric Reducing Activity Power (FRAP) tests. MD retentate—which has content of about five times greater of hydroxytyrosol and verbascoside and about 7 times greater of oleuropein than the feed—was more active as an antioxidant in all applied assays. Of interest is the result obtained in the DPPH test (an inhibitory concentration 50% (IC₅₀) of 9.8 μg/mL in comparison to the feed (IC₅₀ of 97.2 μg/mL)) and in the ABTS assay (an IC₅₀ of 0.4 μg/mL in comparison to the feed (IC₅₀ of 1.2 μg/mL)). Full article

(This article belongs to the Collection Advances in Food Chemistry)

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17 pages, 5767 KiB

Open AccessArticle

Spherical Al-MCM-41 Doped with Copper by Modified TIE Method as Effective Catalyst for Low-Temperature NH₃-SCR

by Aleksandra Jankowska, Andrzej Kowalczyk, Małgorzata Rutkowska, Marek Michalik and Lucjan Chmielarz

Molecules 2021, 26(6), 1807; https://doi.org/10.3390/molecules26061807 - 23 Mar 2021

Cited by 3 | Viewed by 2486

Abstract

Aluminum containing silica spherical MCM-41 was synthesized and modified with copper by the template ion-exchange method (TIE) and its modified version, including treatment of the samples with ammonia solution directly after template ion-exchange (TIE-NH₃). The obtained samples were characterized with respect [...] Read more.

Aluminum containing silica spherical MCM-41 was synthesized and modified with copper by the template ion-exchange method (TIE) and its modified version, including treatment of the samples with ammonia solution directly after template ion-exchange (TIE-NH₃). The obtained samples were characterized with respect to their chemical composition (ICP-OES), structure (XRD), texture (low temperature N₂ sorption), morphology (SEM-EDS), form and aggregation of deposited copper species (UV-vis DRS), reducibility of copper species (H₂-TPR), and surface acidity (NH₃-TPD). The deposition of copper by the TIE-NH₃ method resulted in much better dispersion of this metal on the MCM-41 surface comparing to copper introduced by TIE method. It was shown that such highly dispersed copper species, mainly monomeric Cu²⁺ cations, deposited on aluminum containing silica spheres of MCM-41, are significantly more catalytically effective in the NH₃-SCR process than analogous catalysts containing aggregated copper oxide species. The catalysts obtained by the TIE-NH₃ method effectively operated in much broader temperature and were less active in the side process of direct ammonia oxidation by oxygen. Full article

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

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17 pages, 3936 KiB

Open AccessArticle

Fractional Dynamics of HIV with Source Term for the Supply of New CD4⁺ T-Cells Depending on the Viral Load via Caputo–Fabrizio Derivative

by Zahir Shah, Rashid Jan, Poom Kumam, Wejdan Deebani and Meshal Shutaywi

Molecules 2021, 26(6), 1806; https://doi.org/10.3390/molecules26061806 - 23 Mar 2021

Cited by 40 | Viewed by 2622

Abstract

Human immunodeficiency virus (HIV) is a life life-threatening and serious infection caused by a virus that attacks

{CD 4}^{+}

T-cells, which fight against infections and make a person susceptible to other diseases. It is a global public health problem with no cure; [...] Read more.

Human immunodeficiency virus (HIV) is a life life-threatening and serious infection caused by a virus that attacks

{CD 4}^{+}

T-cells, which fight against infections and make a person susceptible to other diseases. It is a global public health problem with no cure; therefore, it is highly important to study and understand the intricate phenomena of HIV. In this article, we focus on the numerical study of the path-tracking damped oscillatory behavior of a model for the HIV infection of

{CD 4}^{+}

T-cells. We formulate fractional dynamics of HIV with a source term for the supply of new CD4⁺ T-cells depending on the viral load via the Caputo–Fabrizio derivative. In the formulation of fractional HIV dynamics, we replaced the constant source term for the supply of new

{CD 4}^{+}

T-cells from the thymus with a variable source term depending on the concentration of the viral load, and introduced a term that describes the incidence of the HIV infection of

{CD 4}^{+}

T-cells. We present a novel numerical scheme for fractional view analysis of the proposed model to highlight the solution pathway of HIV. We inspect the periodic and chaotic behavior of HIV for the given values of input factors using numerical simulations. Full article

(This article belongs to the Special Issue Molecular Simulations and Mathematical Models in Adsorption and Interface Science)

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7 pages, 228 KiB

Open AccessEditorial

Advances in Chitin and Chitosan Science

by Massimiliano Fenice and Susanna Gorrasi

Molecules 2021, 26(6), 1805; https://doi.org/10.3390/molecules26061805 - 23 Mar 2021

Cited by 13 | Viewed by 2892

Abstract

Chitin is among the most abundant natural polysaccharides [...] Full article

(This article belongs to the Special Issue Advances in Chitin and Chitosan Science)

15 pages, 2131 KiB

Open AccessArticle

Identification and Quantification of Coumarins by UHPLC-MS in Arabidopsis thaliana Natural Populations

by Izabela Perkowska, Joanna Siwinska, Alexandre Olry, Jérémy Grosjean, Alain Hehn, Frédéric Bourgaud, Ewa Lojkowska and Anna Ihnatowicz

Molecules 2021, 26(6), 1804; https://doi.org/10.3390/molecules26061804 - 23 Mar 2021

Cited by 11 | Viewed by 3984

Abstract

Coumarins are phytochemicals occurring in the plant kingdom, which biosynthesis is induced under various stress factors. They belong to the wide class of specialized metabolites well known for their beneficial properties. Due to their high and wide biological activities, coumarins are important not [...] Read more.

Coumarins are phytochemicals occurring in the plant kingdom, which biosynthesis is induced under various stress factors. They belong to the wide class of specialized metabolites well known for their beneficial properties. Due to their high and wide biological activities, coumarins are important not only for the survival of plants in changing environmental conditions, but are of great importance in the pharmaceutical industry and are an active source for drug development. The identification of coumarins from natural sources has been reported for different plant species including a model plant Arabidopsis thaliana. In our previous work, we demonstrated a presence of naturally occurring intraspecies variation in the concentrations of scopoletin and its glycoside, scopolin, the major coumarins accumulating in Arabidopsis roots. Here, we expanded this work by examining a larger group of 28 Arabidopsis natural populations (called accessions) and by extracting and analysing coumarins from two different types of tissues–roots and leaves. In the current work, by quantifying the coumarin content in plant extracts with ultra-high-performance liquid chromatography coupled with a mass spectrometry analysis (UHPLC-MS), we detected a significant natural variation in the content of simple coumarins like scopoletin, umbelliferone and esculetin together with their glycosides: scopolin, skimmin and esculin, respectively. Increasing our knowledge of coumarin accumulation in Arabidopsis natural populations, might be beneficial for the future discovery of physiological mechanisms of action of various alleles involved in their biosynthesis. A better understanding of biosynthetic pathways of biologically active compounds is the prerequisite step in undertaking a metabolic engineering research. Full article

(This article belongs to the Special Issue Coumarin and Its Derivatives)

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Chemical structures of simple coumarins and their glycosides analysed in this work (<a href="http://www.chem-space.com" target="_blank">www.chem-space.com</a> (accessed on 20 January 2021)). Full article ">Figure 2
Heat maps based on the average (A) scopoletin and (B) scopolin concentration (µM/FW) in Arabidopsis tissue extracts from roots and leaves, without and after hydrolysis. The values used in the plots (<a href="https://app.displayr.com" target="_blank">https://app.displayr.com</a> (accessed on 20 January 2021)) are the mean of 3 biological replicates. The mean values and standard deviations (±SD) are gathered in the <a href="#app1-molecules-26-01804" class="html-app">supplementary materials (Table S1)</a>. Full article ">Figure 3
Heat maps based on the average (A) umbelliferone and (B) skimmin concentration (µM/ FW) in Arabidopsis tissue extracts from roots and leaves, without and after hydrolysis. The values used in the plots (<a href="https://app.displayr.com" target="_blank">https://app.displayr.com</a> (accessed on 20 January 2021)) are the mean of 3 biological replicates. The mean values and standard deviations (±SD) are gathered in the <a href="#app1-molecules-26-01804" class="html-app">supplementary materials (Table S2)</a>. Full article ">Figure 4
Heat maps based on the average (A) esculetin and (B) esculin concentration (µM/ FW) in Arabidopsis tissue extracts from roots and leaves, without and after hydrolysis. The values used in the plots (<a href="https://app.displayr.com" target="_blank">https://app.displayr.com</a> (accessed on 20 January 2021)) are the mean of 3 biological replicates. The mean values and standard deviations (±SD) are gathered in the <a href="#app1-molecules-26-01804" class="html-app">supplementary materials (Table S3)</a>. Full article ">Figure 5
(A) Principal component analysis (PCA) for 28 Arabidopsis accessions using the concentration of umbelliferone, scopoletin and their corresponding glycosides (skimmin and scopolin, respectively) in root samples without hydrolysis, and four geographic and climatic factors (maximal altitude [m], average winter minimal temperature [°C], average summer maximal temperature [°C] and average annual precipitation [mm]; <a href="#app1-molecules-26-01804" class="html-app">Table S4</a>). Factor coordinates are marked with arrows. Observations indicated by blue accession names represent European locations (n = 14), green represent Asian locations (n = 9), violet represent North American locations (n = 3) and red represent African locations (n = 2). The abbreviations indicate the accessions according to <a href="#molecules-26-01804-t002" class="html-table">Table 2</a>. Component one and two explain 49% of the point variability. (B) The Variables-PCA contribution plot shows the correlation of the variables used in PCA with the respective contribution of each factor (contrib) indicated with a colour gradient. (C) The scree plot/graph of variables demonstrate the percentage of variability explained by each dimension (PC). Principal Component 1 and 2 explain 27.1% and 21.9% of the variance respectively. Full article ">

13 pages, 2065 KiB

Open AccessArticle

Nanoproteomic Approach for Isolation and Identification of Potential Biomarkers in Human Urine from Adults with Normal Weight, Overweight and Obesity

by Sergio G. Hernandez-Leon, Jose Andre-i Sarabia Sainz, Gabriela Ramos-Clamont Montfort, José Ángel Huerta-Ocampo, Martha Nydia Ballesteros, Ana M. Guzman-Partida, María del Refugio Robles-Burgueño and Luz Vazquez-Moreno

Molecules 2021, 26(6), 1803; https://doi.org/10.3390/molecules26061803 - 23 Mar 2021

Cited by 3 | Viewed by 2378

Abstract

In this work, previously synthesized and characterized core-shell silica nanoparticles (FCSNP) functionalized with immobilized molecular bait, Cibacron blue, and a porous polymeric bis-acrylamide shell were incubated with pooled urine samples from adult women or men with normal weight, overweight or obesity for the [...] Read more.

In this work, previously synthesized and characterized core-shell silica nanoparticles (FCSNP) functionalized with immobilized molecular bait, Cibacron blue, and a porous polymeric bis-acrylamide shell were incubated with pooled urine samples from adult women or men with normal weight, overweight or obesity for the isolation of potential biomarkers. A total of 30 individuals (15 woman and 15 men) were included. FCSNP allowed the capture of a variety of low molecular weight (LMW) proteins as evidenced by mass spectrometry (MS) and the exclusion of high molecular weight (HMW) proteins (>34 kDa) as demonstrated by SDS-PAGE and 2D SDS-PAGE. A total of 36 proteins were successfully identified by MS and homology database searching against the Homo sapiens subset of the Swiss-Prot database. Identified proteins were grouped into different clusters according to their abundance patterns. Four proteins were found only in women and five only in men, whereas 27 proteins were in urine from both genders with different abundance patterns. Based on these results, this new approach represents an alternative tool for isolation and identification of urinary biomarkers. Full article

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SDS-PAGE analysis of the functionalized core-shell silica nanoparticles (FCSNP) elutions after incubation with urine from a healthy donor for 60 min. Lanes were loaded with 1 µg of protein and arranged as follows. Broad range molecular weight standards (lanes 1 and 10); BSA, 66 kDa, myoglobin, 17 kDa, and aprotinin, 6.5 kDa (lane 2); urine, without passing through FCSNP (lane 3); sample buffer (lanes 4, 6 and 8); elution with 50% isopropanol (lane 5). Simultaneous exclusion of high molecular weight proteins and capture of low molecular weight proteins ~34 kDa and smaller was achieved in elution with 50% methanol, one faded band ~30 kDa (lane 7) and ACN+NH4OH (lane 9). Full article ">Figure 2
2D SDS-PAGE analysis of the complete urine (from a healthy donor), not incubated with FCSNP (a) and ACN+NH4OH elution, final product of the incubation of urine (from same healthy donor) with the FCSNP (b). In <a href="#molecules-26-01803-f002" class="html-fig">Figure 2</a>a all proteins (high molecular weight (HMW) and low molecular weight (LMW) proteins) in urine are shown. Simultaneous exclusion of HMW and capture of LMW proteins (~34 kDa and smaller) of the FCSNP was achieved in the ACN+NH4OH elution (2B). Full article ">Figure 3
Heat map of the 36 proteins identified by LC-MS/MS. Columns represent groups of women (W-NW) or men (M-NW) with normal weight (controls), overweight (W-OW, M-OW) and obesity (W-OB, M-OB). Rows indicate individual identified proteins. Proteins not detected in any group/condition are indicated in gray. Increased and decreased protein abundance in the different groups compared to respective normal weight conditions are indicated in green or red, respectively. Protein names are indicated on the right side. Dashed blue boxes indicate protein clusters with similar abundance change patterns. Full article ">Figure 4
Basic Venn diagram. A total of 36 urine proteins were identified by LC-MS/MS analysis. Four proteins were only found in women and five only in men, whereas 27 proteins were found in both genders. Full article ">

16 pages, 1461 KiB

Open AccessArticle

Impact of High-Pressure Homogenization Parameters on Physicochemical Characteristics, Bioactive Compounds Content, and Antioxidant Capacity of Blackcurrant Juice

by Bartosz Kruszewski, Katarzyna Zawada and Piotr Karpiński

Molecules 2021, 26(6), 1802; https://doi.org/10.3390/molecules26061802 - 23 Mar 2021

Cited by 32 | Viewed by 3599

Abstract

High-pressure homogenization (HPH) is one of the food-processing methods being tested for use in food preservation as an alternative to pasteurization. The effects of the HPH process on food can vary depending on the process parameters used and product characteristics. The study aimed [...] Read more.

High-pressure homogenization (HPH) is one of the food-processing methods being tested for use in food preservation as an alternative to pasteurization. The effects of the HPH process on food can vary depending on the process parameters used and product characteristics. The study aimed to investigate the effect of pressure, the number of passes, and the inlet temperature of HPH processing on the quality of cloudy blackcurrant juice as an example of food rich in bioactive compounds. For this purpose, the HPH treatment (pressure of 50, 150, and 220 MPa; one, three, and five passes; inlet temperature at 4 and 20 °C) and the pasteurization of the juice were performed. Titratable acidity, pH, turbidity, anthocyanin, vitamin C, and total phenolics content, as well as colour, and antioxidant activity were measured. Heat treatment significantly decreased the quality of the juice. For processing of the juice, the best were the combinations of the following: one pass, the inlet temperature of 4 °C, any of the used pressures (50, 150, and 220 MPa); and one pass, the inlet temperature of 20 °C, and the pressure of 150 MPa. Vitamin C and anthocyanin degradation have been reported during the HPH. The multiple passes of the juice through the machine were only beneficial in increasing the antioxidant capacity but negatively affected the colour stability. Full article

(This article belongs to the Special Issue Colorants Changes during Food Treatment and Processing)

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Nephelometric turbidity of cloudy blackcurrant juice treated with high-pressure homogenization, or pasteurization. The values with different superscript letters are significantly different (p < 0.05). Full article ">Figure 2
The total concentration of anthocyanins (mg/100 mL) determined in cloudy blackcurrant juice treated with high-pressure homogenization or pasteurization. Samples were labelled as level of pressure/number of passes/inlet temperature. (a) HPH samples with the inlet temperature of 4 °C and (b) HPH samples with the inlet temperature of 20 °C. The values with different superscript letters (a–g) are significantly different (p < 0.05). Statistics were performed separately for (a) and (b). Full article ">Figure 3
Total phenolic content (mg GAE/100 mL) determined in cloudy blackcurrant juice treated with high-pressure homogenization or pasteurization. Samples were labelled as level of pressure/number of passes/inlet temperature. (a) HPH samples with the inlet temperature of 4 °C; (b) HPH samples with the inlet temperature of 20 °C. The values with different superscript letters (a–e) are significantly different (p < 0.05). Statistics were performed separately for figure (a) and figure (b). Full article ">Figure 3 Cont.
Total phenolic content (mg GAE/100 mL) determined in cloudy blackcurrant juice treated with high-pressure homogenization or pasteurization. Samples were labelled as level of pressure/number of passes/inlet temperature. (a) HPH samples with the inlet temperature of 4 °C; (b) HPH samples with the inlet temperature of 20 °C. The values with different superscript letters (a–e) are significantly different (p < 0.05). Statistics were performed separately for figure (a) and figure (b). Full article ">Figure 4
Principal component analysis (PCA) analyses results. (a) Score plot, PC1 versus PC2 of all samples; (b) Score plot, PC1 versus PC2 of data from determinations used as variables. C–control sample/raw juice, P–pasteurized juice, and HPH samples were labelled as level of pressure/number of passes/inlet temperature. Full article ">

16 pages, 1959 KiB

Open AccessArticle

Physicochemical Characterization and Simulation of the Solid–Liquid Equilibrium Phase Diagram of Terpene-Based Eutectic Solvent Systems

by Maha M. Abdallah, Simon Müller, Andrés González de Castilla, Pavel Gurikov, Ana A. Matias, Maria do Rosário Bronze and Naiara Fernández

Molecules 2021, 26(6), 1801; https://doi.org/10.3390/molecules26061801 - 23 Mar 2021

Cited by 22 | Viewed by 5787

Abstract

The characterization of terpene-based eutectic solvent systems is performed to describe their solid–liquid phase transitions. Physical properties are measured experimentally and compared to computed correlations for deep eutectic solvents (DES) and the percentage relative error e_r for the density, surface tension, and [...] Read more.

The characterization of terpene-based eutectic solvent systems is performed to describe their solid–liquid phase transitions. Physical properties are measured experimentally and compared to computed correlations for deep eutectic solvents (DES) and the percentage relative error e_r for the density, surface tension, and refractive index is obtained. The thermodynamic parameters, including the degradation, glass transition and crystallization temperatures, are measured using DSC and TGA. Based on these data, the solid–liquid equilibrium phase diagrams are calculated for the ideal case and predictions are made using the semi-predictive UNIFAC and the predictive COSMO RS models, the latter with two different parametrization levels. For each system, the ideal, experimental, and predicted eutectic points are obtained. The deviation from ideality is observed experimentally and using the thermodynamic models for Thymol:Borneol and Thymol:Camphor. In contrast, a negative deviation is observed only experimentally for Menthol:Borneol and Menthol:Camphor. Moreover, the chemical interactions are analyzed using FTIR and ¹H-NMR to study the intermolecular hydrogen bonding in the systems. Full article

(This article belongs to the Special Issue Breakthrough Developments in Fundamental Studies and Applications of Deep Eutectic Systems)

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12 pages, 2347 KiB

Open AccessArticle

Polydopamine-Assisted Rapid One-Step Immobilization of L-Arginine in Capillary as Immobilized Chiral Ligands for Enantioseparation of Dansyl Amino Acids by Chiral Ligand Exchange Capillary Electrochromatography

by Yuanqi Gui, Baian Ji, Gaoyi Yi, Xiuju Li, Kailian Zhang and Qifeng Fu

Molecules 2021, 26(6), 1800; https://doi.org/10.3390/molecules26061800 - 23 Mar 2021

Cited by 6 | Viewed by 3144

Abstract

Herein, a novel L-arginine (L-Arg)-modified polydopamine (PDA)-coated capillary (PDA/L-Arg@capillary) was firstly fabricated via the basic amino-acid-induced PDA co-deposition strategy and employed to constitute a new chiral ligand exchange capillary electrochromatography (CLE-CEC) method for the high-performance enantioseparation of D,L-amino acids (D,L-AAs) with L-Arg as [...] Read more.

Herein, a novel L-arginine (L-Arg)-modified polydopamine (PDA)-coated capillary (PDA/L-Arg@capillary) was firstly fabricated via the basic amino-acid-induced PDA co-deposition strategy and employed to constitute a new chiral ligand exchange capillary electrochromatography (CLE-CEC) method for the high-performance enantioseparation of D,L-amino acids (D,L-AAs) with L-Arg as the immobilized chiral ligand coordinating with the central metal ion Zn(II) as running buffer. Assisted by hydrothermal treatment, the robust immobilization of L-Arg on the capillary inner wall could be facilely achieved within 1 h, prominently improving the synthesis efficiency and simplifying the preparation procedure. The successful preparation of PDA/L-Arg coatings in the capillary was systematically characterized and confirmed using several methods. In comparison with bare and PDA-functionalized capillaries, the enantioseparation capability of the presented CLE-CEC system was significantly enhanced. Eight D,L-AAs were completely separated and three pairs were partially separated under the optimal conditions. The prepared PDA/L-Arg@capillary showed good repeatability and stability. The potential mechanism of the greatly enhanced enantioseparation performance obtained by PDA/L-Arg@capillary was also explored. Moreover, the proposed method was further utilized for studying the enzyme kinetics of L-glutamic dehydrogenase, exhibiting its promising prospects in enzyme assays and other related applications. Full article

(This article belongs to the Special Issue Chiral Stationary Phases for Enantioseparations: Fundamentals, Preparation, Methods, Applications and Chiral Recognition Mechanisms)

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Figure 1
Schematic of the hydrothermal-assisted preparation of PDA/L-Arg@capillary. Full article ">Figure 2
FESEM images of the inner wall of bare capillary (A) and PDA/L-Arg@capillary (B) with different magnification (a. 1.50 k, b. 20.0 k, c. 50.0 k). Full article ">Figure 3
(a) FTIR spectra of dopamine (1), PDA (2), and PDA/L-Arg composite (3). (b) ATR-FTIR spectra of unmodified (1), PDA-coated (2), and PDA/L-Arg-coated quartz sheets (3). (c) The electroosmotic flow mobilities of bare column, PDA-coated column, and PDA/L-Arg@capillary at different buffer pH values ranging from 4.5 to 8.0. EOF marker, DMSO; Buffer, 100.0 mM boric acid, 10.0 mM ammonium acetate, 6.0 mM ZnSO4, 6.0 mM L-Arg; Capillary: 50 µm i.d. × 35 cm length (26.5 cm effective); sample injection pressure and time at 35 mbar and 5 s; 25 °C; voltage, −20 kV; UV detection at 214 nm. Full article ">Figure 4
Effects of buffer pH (a), Zn(II) concentration (b), and the concentration ratio of Zn(II) to L-Arg (c) on the resolution of Dns-D,L-AAs. Chiral ligand exchange capillary electrochromatography conditions, 100.0 mM boric acid, 10.0 mM ammonium acetate at different pH and concentrations of Zn(II) and L-Arg. Other conditions are the same as <a href="#molecules-26-01800-f003" class="html-fig">Figure 3</a>. Full article ">Figure 5
Electropherograms of Dns-D,L-Asp (a), Dns-D,L-Ser (b), and Dns-D,L-Ala (c) on bare, PDA-coated column, and PDA/L-Arg@capillary. Buffer pH at 8. Other CE experimental conditions are the same as <a href="#molecules-26-01800-f003" class="html-fig">Figure 3</a>. Full article ">Figure 6
The possible mechanism of the CLE-CEC enantioseparation process. Full article ">

17 pages, 3829 KiB

Open AccessArticle

Cyanide Hydratase Modification Using Computational Design and Docking Analysis for Improved Binding Affinity in Cyanide Detoxification

by Narges Malmir, Najaf Allahyari Fard, Yamkela Mgwatyu and Lukhanyo Mekuto

Molecules 2021, 26(6), 1799; https://doi.org/10.3390/molecules26061799 - 23 Mar 2021

Cited by 5 | Viewed by 2293

Abstract

Cyanide is a hazardous and detrimental chemical that causes the inactivation of the respiration system through the inactivation of cytochrome c oxidase. Because of the limitation in the number of cyanide-degrading enzymes, there is a great demand to design and introduce new enzymes [...] Read more.

Cyanide is a hazardous and detrimental chemical that causes the inactivation of the respiration system through the inactivation of cytochrome c oxidase. Because of the limitation in the number of cyanide-degrading enzymes, there is a great demand to design and introduce new enzymes with better functionality. This study developed an integrated method of protein-homology-modelling and ligand-docking protein-design approaches that reconstructs a better active site from cyanide hydratase (CHT) structure. Designing a mutant CHT (mCHT) can improve the CHT performance. A computational design procedure that focuses on mutation for constructing a new model of cyanide hydratase with better activity was used. In fact, this study predicted the three-dimensional (3D) structure of CHT for subsequent analysis. Inducing mutation on CHT of Trichoderma harzianum was performed and molecular docking was used to compare protein interaction with cyanide as a ligand in both CHT and mCHT. By combining multiple designed mutations, a significant improvement in docking for CHT was obtained. The results demonstrate computational capabilities for enhancing and accelerating enzyme activity. The result of sequence alignment and homology modeling show that catalytic triad (Cys-Glu-Lys) was conserved in CHT of Trichoderma harzianum. By inducing mutation in CHT structure, MolDock score enhanced from −18.1752 to −23.8575, thus the nucleophilic attack can occur rapidly by adding Cys in the catalytic cavity and the total charge of protein in pH 6.5 is increased from −6.0004 to −5.0004. Also, molecular dynamic simulation shows a stable protein-ligand complex model. These changes would help in the cyanide degradation process by mCHT. Full article

(This article belongs to the Special Issue Cyanide Chemistry)

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17 pages, 1550 KiB

Open AccessArticle

Potential Mitigation of Smoke Taint in Wines by Post-Harvest Ozone Treatment of Grapes

by Margherita Modesti, Colleen Szeto, Renata Ristic, WenWen Jiang, Julie Culbert, Keren Bindon, Cesare Catelli, Fabio Mencarelli, Pietro Tonutti and Kerry Wilkinson

Molecules 2021, 26(6), 1798; https://doi.org/10.3390/molecules26061798 - 23 Mar 2021

Cited by 16 | Viewed by 4371

Abstract

When bushfires occur near grape growing regions, vineyards can be exposed to smoke, and depending on the timing and duration of grapevine smoke exposure, fruit can become tainted. Smoke-derived volatile compounds, including volatile phenols, can impart unpleasant smoky, ashy characters to wines made [...] Read more.

When bushfires occur near grape growing regions, vineyards can be exposed to smoke, and depending on the timing and duration of grapevine smoke exposure, fruit can become tainted. Smoke-derived volatile compounds, including volatile phenols, can impart unpleasant smoky, ashy characters to wines made from smoke-affected grapes, leading to substantial revenue losses where wines are perceivably tainted. This study investigated the potential for post-harvest ozone treatment of smoke-affected grapes to mitigate the intensity of smoke taint in wine. Merlot grapevines were exposed to smoke at ~7 days post-veraison and at harvest grapes were treated with 1 or 3 ppm of gaseous ozone (for 24 or 12 h, respectively), prior to winemaking. The concentrations of smoke taint marker compounds (i.e., free and glycosylated volatile phenols) were measured in grapes and wines to determine to what extent ozonation could mitigate the effects of grapevine exposure to smoke. The 24 h 1 ppm ozone treatment not only gave significantly lower volatile phenol and volatile phenol glycoside concentrations but also diminished the sensory perception of smoke taint in wine. Post-harvest smoke and ozone treatment of grapes suggests that ozone works more effectively when smoke-derived volatile phenols are in their free (aglycone) form, rather than glycosylated forms. Nevertheless, the collective results demonstrate the efficacy of post-harvest ozone treatment as a strategy for mitigation of smoke taint in wine. Full article

(This article belongs to the Special Issue Smoke Taint in Grapes and Wine)

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Sensory profiles of wines made from control and smoke-affected grapes, with and without post-harvest ozone treatment (at 1 ppm for 24 h or 3 ppm for 12 h); A = aroma; F = flavor; AT = aftertaste. Values are mean ratings of one blended wine per treatment, presented to 50 judges; * indicates statistical significance (p = 0.05, one-way ANOVA). Smoke exposure occurred at approximately 7 days post-veraison. Full article ">Figure 2
Concentrations (µg/L) of (a,b) guaiacol, (c,d) phenol and (e,f) syringol in smoke-affected grapes, with and without ozone treatment (at (a,c,e) 1 or (b,d,f) 3 ppm for 6, 12 or 24 h).Values are means of three replicates (n = 3). Different letters indicate statistical significance (p = 0.05, one-way ANOVA). Post-harvest smoke treatments were applied on consecutive days, but smoke density was lower on the second day of treatment due to increased wind. Full article ">Figure 3
Total tannin and anthocyanin concentrations (mg/g) in smoke-affected grapes, with and without post-harvest ozone treatment (at (a,b) 1 or (c,d) 3 ppm for 6, 12 or 24 h).Values are means of three replicates (n = 3). Different letters indicate statistical significance (p = 0.05, one-way ANOVA); ns = not significant. Post-harvest smoke treatments were applied on consecutive days, but smoke density was lower on the second day of treatment due to increased wind. Full article ">

26 pages, 1962 KiB

Open AccessReview

Nanotechnology in Wastewater Management: A New Paradigm Towards Wastewater Treatment

by Keerti Jain, Anand S. Patel, Vishwas P. Pardhi and Swaran Jeet Singh Flora

Molecules 2021, 26(6), 1797; https://doi.org/10.3390/molecules26061797 - 23 Mar 2021

Cited by 168 | Viewed by 15263

Abstract

Clean and safe water is a fundamental human need for multi-faceted development of society and a thriving economy. Brisk rises in populations, expanding industrialization, urbanization and extensive agriculture practices have resulted in the generation of wastewater which have not only made the water [...] Read more.

Clean and safe water is a fundamental human need for multi-faceted development of society and a thriving economy. Brisk rises in populations, expanding industrialization, urbanization and extensive agriculture practices have resulted in the generation of wastewater which have not only made the water dirty or polluted, but also deadly. Millions of people die every year due to diseases communicated through consumption of water contaminated by deleterious pathogens. Although various methods for wastewater treatment have been explored in the last few decades but their use is restrained by many limitations including use of chemicals, formation of disinfection by-products (DBPs), time consumption and expensiveness. Nanotechnology, manipulation of matter at a molecular or an atomic level to craft new structures, devices and systems having superior electronic, optical, magnetic, conductive and mechanical properties, is emerging as a promising technology, which has demonstrated remarkable feats in various fields including wastewater treatment. Nanomaterials encompass a high surface to volume ratio, a high sensitivity and reactivity, a high adsorption capacity, and ease of functionalization which makes them suitable for application in wastewater treatment. In this article we have reviewed the techniques being developed for wastewater treatment using nanotechnology based on adsorption and biosorption, nanofiltration, photocatalysis, disinfection and sensing technology. Furthermore, this review also highlights the fate of the nanomaterials in wastewater treatment as well as risks associated with their use. Full article

(This article belongs to the Special Issue Materials and Technologies Used in Wastewater Treatment)

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Various sources of wastewater. Full article ">Figure 2
Typical composition of sewage water. Full article ">Figure 3
Graphical representation of structure and absorption sites of graphene sheets (Reproduced with permission from [<a href="#B65-molecules-26-01797" class="html-bibr">65</a>]). Full article ">Figure 4
Graphical representation of (A) excitation of a nanophotocatalyst during the photocatalytic process; (B) photocatalytic treatment of polluted water and recovery of nanophotocatalyst (Reproduced with permission from [<a href="#B130-molecules-26-01797" class="html-bibr">130</a>]). Full article ">Figure 5
Schematic presentation of the different mechanisms of antimicrobial action of nanomaterials (Reproduced with permission from [<a href="#B161-molecules-26-01797" class="html-bibr">161</a>]). Full article ">Figure 6
Mechanisms of cell damage by NPs. (1) Physical damage of membranes. (2) Structural changes in cytoskeleton components. (3) Disturbance of transcription and oxidative damage of DNA. (4) Damage of mitochondria. (5) Disturbance of lysosome functioning. (6) Generation of reactive oxygen species. (7) Disturbance of membrane protein functions. (8) Synthesis of inflammatory factors and mediators (Reproduced with permission from [<a href="#B189-molecules-26-01797" class="html-bibr">189</a>]). Full article ">

12 pages, 2829 KiB

Open AccessArticle

Spectral and Texture Properties of Hydrophobic Aerogel Powders Obtained from Room Temperature Drying

by Dimitar Shandurkov, Petar Ignatov, Ivanka Spassova and Stoyan Gutzov

Molecules 2021, 26(6), 1796; https://doi.org/10.3390/molecules26061796 - 23 Mar 2021

Cited by 6 | Viewed by 2373

Abstract

Attenuated Total Reflectance Infrared (ATR-IR) spectroscopy and texture measurements based on nitrogen adsorption-desorption isotherms are combined to characterize silica aerogel granules with different degrees of hydrophobicity. The aerogels were prepared from tetraethoxysilane via a room temperature hydrolysis-gelation process, solvent exchange, hydrophobization, and drying [...] Read more.

Attenuated Total Reflectance Infrared (ATR-IR) spectroscopy and texture measurements based on nitrogen adsorption-desorption isotherms are combined to characterize silica aerogel granules with different degrees of hydrophobicity. The aerogels were prepared from tetraethoxysilane via a room temperature hydrolysis-gelation process, solvent exchange, hydrophobization, and drying at subcritical conditions. The dependencies between the texture properties, pore architectures, surface fractal dimensions, and degree of hydrophobicity of the samples are extracted from the ATR-IR spectra and the adsorption-desorption isotherms. The IR absorption in the region of the Si-O-Si and Si-OH vibrations is used for a description of the structural and chemical changes in aerogel powders connected with their surface hydrophobization. The Frenkel–Halsey–Hill (FHH) theory is applied to determine the surface fractal dimension of the powder species. Full article

(This article belongs to the Special Issue Sol-Gel Composites and Aerogels)

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Figure 1
Normalized ATR-IR spectra of the studied samples. Sample notations are the same as in <a href="#molecules-26-01796-t001" class="html-table">Table 1</a>: MJ0—α = 0; MJ2—α = 0.352; MJ4—α = 0.700; MJ6—α = 1.055 and MJ8—α = 1.407. The SiO2 represents bulk silica. Full article ">Figure 2
Spectral deconvolution of samples with a different hydrophobization degree: MJ0—hydrophilic silica, left; MJ4—α = 0.7, right. The appearance of the 1260 cm−1 band is indicative after the addition of the surface-modifying agent TMCS. Full article ">Figure 3
The relative area of the IR-bands band of samples in the region of the Si-O-Si and Si-OH vibrations. Full article ">Figure 4
Low-temperature nitrogen adsorption-desorption isotherm of silica samples having a different degree of hydrophobicity: 1—MJ0, α = 0; 2—MJ2, α = 0.352; 3—MJ4, α = 0.700; 4—MJ6, α = 1.055 and 5—MJ8, α = 1.407. Full article ">Figure 5
Pore size distribution of silica samples with different degrees of hydrophobicity: 1—MJ0, α = 0; 2—MJ2, α = 0.352; 3—MJ4, α = 0.7; 4—MJ6, α = 1.055 and 5—MJ8, α = 1.407. Full article ">Figure 6
Linear fit (red line) of the low pressure adsorption region of sample MJ4 with α = 0.7. Full article ">Figure 7
Sol-gel preparation procedure used in the present investigation. Compared to our recent published results, all steps are performed at room temperature and the solvent exchange is two times shorter. Full article ">

15 pages, 7938 KiB

Open AccessArticle

Hair Growth Promoting Activity of Cedrol Nanoemulsion in C57BL/6 Mice and Its Bioavailability

by Yaling Deng, Feixue Huang, Jiewen Wang, Yumeng Zhang, Yan Zhang, Guangyue Su and Yuqing Zhao

Molecules 2021, 26(6), 1795; https://doi.org/10.3390/molecules26061795 - 23 Mar 2021

Cited by 15 | Viewed by 4020

Abstract

As the main component of Platycladus orientalis, cedrol has known germinal activity. A range of cedrol formulations have been developed to prevent hair-loss, but compliance remains key issues. In this study, we prepared cedrol nanoemulsion (CE-NE) and determined the particle size and [...] Read more.

As the main component of Platycladus orientalis, cedrol has known germinal activity. A range of cedrol formulations have been developed to prevent hair-loss, but compliance remains key issues. In this study, we prepared cedrol nanoemulsion (CE-NE) and determined the particle size and PDI (polydispersion coefficient), investigated the hair growth activity and studied the bioavailability in vitro and in vivo. Results showed that the average particle size of CE-NE is 14.26 ± 0.16 nm, and the PDI value is 0.086 ± 0.019. In vitro drug release investigation and drug release kinetics analysis showed release profile of CE from nanoparticles demonstrates the preferred partition of CE in buffer pH 4.0, the release profile of CE-NE showed a first-order kinetics reaching around 36.7% after 6 h at 37 °C. We artificially depilated the back hair of C57BL/6 mice and compared the efficacy of a designed cedrol nanoemulsion to an existing ointment group. The hair follicles were imaged and quantified using a digital photomicrograph. The results showed that compared with the ointment, CE-NE had positive effects on hair growth, improved drug solubility. Compared with the ointment and 2% minoxidil groups, 50 mg/mL CE-NE led to more robust hair growth. Pharmacokinetics analysis showed that the AUC_0–t of CE-NE was 4-fold higher than that of the ointment group, confirming that the bioavailability of the nanoemulsion was greater than that of the ointment. CE-NE also significantly reduced the hair growth time of model mice and significantly increased the growth rate of hair follicles. In conclusion, these data suggest that the nanoemulsion significantly improved the pharmacokinetic properties and hair growth effects cedrol, enhancing its efficacy in vitro and in vivo. Full article

(This article belongs to the Special Issue State-of-the-Art Analytical Technologies for Natural Products)

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14 pages, 2385 KiB

Open AccessReview

Basic Principles in the Design of Spider Silk Fibers

by José Pérez-Rigueiro, Manuel Elices, Gustavo R. Plaza and Gustavo V. Guinea

Molecules 2021, 26(6), 1794; https://doi.org/10.3390/molecules26061794 - 23 Mar 2021

Cited by 20 | Viewed by 3575

Abstract

The prominence of spider silk as a hallmark in biomimetics relies not only on its unrivalled mechanical properties, but also on how these properties are the result of a set of original design principles. In this sense, the study of spider silk summarizes [...] Read more.

The prominence of spider silk as a hallmark in biomimetics relies not only on its unrivalled mechanical properties, but also on how these properties are the result of a set of original design principles. In this sense, the study of spider silk summarizes most of the main topics relevant to the field and, consequently, offers a nice example on how these topics could be considered in other biomimetic systems. This review is intended to present a selection of some of the essential design principles that underlie the singular microstructure of major ampullate gland silk, as well as to show how the interplay between them leads to the outstanding tensile behavior of spider silk. Following this rationale, the mechanical behavior of the material is analyzed in detail and connected with its main microstructural features, specifically with those derived from the semicrystalline organization of the fibers. Establishing the relationship between mechanical properties and microstructure in spider silk not only offers a vivid image of the paths explored by nature in the search for high performance materials, but is also a valuable guide for the development of new artificial fibers inspired in their natural counterparts. Full article

(This article belongs to the Special Issue Frontiers in Silk Science-How Silks/Biomimetic Polymers Solve Specific Challenges?)

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Figure 1
Characteristic tensile properties of spider silk expressed as true stress vs. true strain curves. (a) Tensile properties of spider silk spun by Argiope trifasciata spiders. FS: forcibly silked, NS: naturally spun, MS: maximum supercontracted. (b) Tensile properties of maximum supercontracted (MS) spider silk fibers spun by Argiope argentata spiders. The experimental details may be found in the corresponding references by the authors cited in the main text. Full article ">Figure 2
(a) Comparison of true stress-true strain curves of fibers spun by different spiders species of the Entelegynae suborder after being subjected to maximum supercontraction (MS curves). (b) Definition of the α* parameter by displacing the true stress-true strain curves of the maximum supercontracted fibers along the true strain axis (X-axis) so that it concurs with the Argiope aurantia MS curve used as reference at high values of true strain. The experimental details may be found in the corresponding references by the authors cited in the main text. Full article ">Figure 3
(a) X ray diffraction patterns of individual spider silk fibers of selected representatives of the Entelegynae suborder after being subjected to maximum supercontraction. (b) Relationship between the extent of supercontraction and the orientation of the nanocrystals with respect to the macroscopic axis of the fiber (measured as the full width at half maximum (FWHM) of the diffraction spot along the azimuthal direction) for the different species. (c) Relationship between the extent of supercontraction and the crystallinity of the fibers for the different species. The experimental details may be found in the corresponding references by the authors cited in the main text. Full article ">Figure 3 Cont.
(a) X ray diffraction patterns of individual spider silk fibers of selected representatives of the Entelegynae suborder after being subjected to maximum supercontraction. (b) Relationship between the extent of supercontraction and the orientation of the nanocrystals with respect to the macroscopic axis of the fiber (measured as the full width at half maximum (FWHM) of the diffraction spot along the azimuthal direction) for the different species. (c) Relationship between the extent of supercontraction and the crystallinity of the fibers for the different species. The experimental details may be found in the corresponding references by the authors cited in the main text. Full article ">Figure 4
(a) X ray diffraction patterns obtained from individual Argiope trifasciata spider silk fibers subjected to different values of stretching from the maximum supercontracted state. The approximate value of the corresponding alignment parameter is indicated on an MS curve. (b) Evolution of the orientation of the nanocrystals with increasing values of the alignment parameter. (c) Evolution of the crystallinity of the fibers with increasing values of the alignment parameter. (d) Evolution of the size of the nanocrystals along three independent spatial directions as a function of the alignment parameter. The experimental details may be found in the corresponding references by the authors cited in the main text. Full article ">Figure 5
(a) X ray diffraction patterns obtained from individual Argiope trifasciata flagelliform (or viscid) spider silk fibers subjected to different values of stretching from the maximum supercontracted state. The approximate value of the corresponding alignment parameter is indicated on an MS curve. (b) Evolution of the orientation of the nanocrystals with increasing values of the alignment parameter. (c) Evolution of the crystallinity of the fibers with increasing values of the alignment parameter. (d) Evolution of the size of the nanocrystals as a function of the alignment parameter. The experimental details may be found in the corresponding references by the authors cited in the main text. Full article ">Figure 6
Scheme of the proposed deformation micromechanisms of the Entelegynae major ampullate gland silk fibers. The hydrogen bonds are stretched in the elastic regime (a) and begin to break upon reaching the yield stress (b). The breaking of the initial network of hydrogen bonds is followed by the rotation of the polyalanine β-nanocrytals that tends to get oriented with the macroscopic axis of the fiber (c) When the maximum possible orientation of the polyalanine β-nanocrystals is attained, polyproline II nanocrystals start to form at the ends of the β-nanocrystals (d). Full article ">

24 pages, 4778 KiB

Open AccessArticle

Quantum Chemical Microsolvation by Automated Water Placement

by Miguel Steiner, Tanja Holzknecht, Michael Schauperl and Maren Podewitz

Molecules 2021, 26(6), 1793; https://doi.org/10.3390/molecules26061793 - 23 Mar 2021

Cited by 19 | Viewed by 5410

Abstract

We developed a quantitative approach to quantum chemical microsolvation. Key in our methodology is the automatic placement of individual solvent molecules based on the free energy solvation thermodynamics derived from molecular dynamics (MD) simulations and grid inhomogeneous solvation theory (GIST). This protocol enabled [...] Read more.

We developed a quantitative approach to quantum chemical microsolvation. Key in our methodology is the automatic placement of individual solvent molecules based on the free energy solvation thermodynamics derived from molecular dynamics (MD) simulations and grid inhomogeneous solvation theory (GIST). This protocol enabled us to rigorously define the number, position, and orientation of individual solvent molecules and to determine their interaction with the solute based on physical quantities. The generated solute–solvent clusters served as an input for subsequent quantum chemical investigations. We showcased the applicability, scope, and limitations of this computational approach for a number of small molecules, including urea, 2-aminobenzothiazole, (+)-syn-benzotriborneol, benzoic acid, and helicene. Our results show excellent agreement with the available ab initio molecular dynamics data and experimental results. Full article

(This article belongs to the Special Issue Describing Bulk Phase Effects with Ab Initio Methods)

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Graphical abstract

27 pages, 26944 KiB

Open AccessReview

PET Diagnostic Molecules Utilizing Multimeric Cyclic RGD Peptide Analogs for Imaging Integrin α_vβ₃ Receptors

by Christos Liolios, Christos Sachpekidis, Antonios Kolocouris, Antonia Dimitrakopoulou-Strauss and Penelope Bouziotis

Molecules 2021, 26(6), 1792; https://doi.org/10.3390/molecules26061792 - 22 Mar 2021

Cited by 31 | Viewed by 4652

Abstract

Multimeric ligands consisting of multiple pharmacophores connected to a single backbone have been widely investigated for diagnostic and therapeutic applications. In this review, we summarize recent developments regarding multimeric radioligands targeting integrin α_vβ₃ receptors on cancer cells for molecular imaging [...] Read more.

Multimeric ligands consisting of multiple pharmacophores connected to a single backbone have been widely investigated for diagnostic and therapeutic applications. In this review, we summarize recent developments regarding multimeric radioligands targeting integrin α_vβ₃ receptors on cancer cells for molecular imaging and diagnostic applications using positron emission tomography (PET). Integrin α_vβ₃ receptors are glycoproteins expressed on the cell surface, which have a significant role in tumor angiogenesis. They act as receptors for several extracellular matrix proteins exposing the tripeptide sequence arginine-glycine-aspartic (RGD). Cyclic RDG peptidic ligands c(RGD) have been developed for integrin α_vβ₃ tumor-targeting positron emission tomography (PET) diagnosis. Several c(RGD) pharmacophores, connected with the linker and conjugated to a chelator or precursor for radiolabeling with different PET radionuclides (¹⁸F, ⁶⁴Cu, and ⁶⁸Ga), have resulted in multimeric ligands superior to c(RGD) monomers. The binding avidity, pharmacodynamic, and PET imaging properties of these multimeric c(RGD) radioligands, in relation to their structural characteristics are analyzed and discussed. Furthermore, specific examples from preclinical studies and clinical investigations are included. Full article

(This article belongs to the Special Issue Radiopharmaceuticals for PET Imaging - Issue B)

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17 pages, 1622 KiB

Open AccessArticle

A Novel Dual Drug Approach That Combines Ivermectin and Dihydromyricetin (DHM) to Reduce Alcohol Drinking and Preference in Mice

by Joshua Silva, Eileen Carry, Chen Xue, Jifeng Zhang, Jing Liang, Jacques Y. Roberge and Daryl L. Davies

Molecules 2021, 26(6), 1791; https://doi.org/10.3390/molecules26061791 - 22 Mar 2021

Cited by 8 | Viewed by 3352

Abstract

Alcohol use disorder (AUD) affects over 18 million people in the US. Unfortunately, pharmacotherapies available for AUD have limited clinical success and are under prescribed. Previously, we established that avermectin compounds (ivermectin [IVM] and moxidectin) reduce alcohol (ethanol/EtOH) consumption in mice, but these [...] Read more.

Alcohol use disorder (AUD) affects over 18 million people in the US. Unfortunately, pharmacotherapies available for AUD have limited clinical success and are under prescribed. Previously, we established that avermectin compounds (ivermectin [IVM] and moxidectin) reduce alcohol (ethanol/EtOH) consumption in mice, but these effects are limited by P-glycoprotein (Pgp/ABCB1) efflux. The current study tested the hypothesis that dihydromyricetin (DHM), a natural product suggested to inhibit Pgp, will enhance IVM potency as measured by changes in EtOH consumption. Using a within-subjects study design and two-bottle choice study, we tested the combination of DHM (10 mg/kg; i.p.) and IVM (0.5–2.5 mg/kg; i.p.) on EtOH intake and preference in male and female C57BL/6J mice. We also conducted molecular modeling studies of DHM with the nucleotide-binding domain of human Pgp that identified key binding residues associated with Pgp inhibition. We found that DHM increased the potency of IVM in reducing EtOH consumption, resulting in significant effects at the 1.0 mg/kg dose. This combination supports our hypothesis that inhibiting Pgp improves the potency of IVM in reducing EtOH consumption. Collectively, we demonstrate the feasibility of this novel combinatorial approach in reducing EtOH consumption and illustrate the utility of DHM in a novel combinatorial approach. Full article

(This article belongs to the Special Issue Natural Products: Therapeutic Properties and Beyond)

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Figure 1
Randomized within-subjects drug treatment layout for behavioral analysis. Male and female C57BL/6J mice were separated into four cohorts and treated randomly each week with incremental doses of IVM as either (1) IVM dose control (red), (2) IVM + DHM (green), (3) Saline control (blue), and (4) DHM control (black). Full article ">Figure 2
DHM (10 mg/kg) combined with IVM reduces the dosing necessary to significantly decrease EtOH consumption and 10E preference in male C57BL/6J mice over a period of 24 h. (A) IVM (1.0–2.5 mg/kg) combined with DHM (10 mg/kg) significantly reduced EtOH intake relative to saline treatment (Ctl), with 1.0–2.0 mg/kg IVM and DHM showing significant effects compared to IVM doses alone. (B) IVM (1.0–2.0 mg/kg) combined with DHM significantly reduces 10E preference in comparison to IVM controls. IVM (1.0–2.0 mg/kg) and DHM (10 mg/kg) significantly reduced 10E preference relative to saline values. Ctl = saline; DHM = dihydromyricetin; IVM = ivermectin. * p < 0.05 vs. Ctl values, † p < 0.05 vs. corresponding IVM dose control, and # p < 0.05 vs. DHM control; n = 48/group for DHM and saline groups; n = 8/group for IVM and IVM + DHM groups. All values are shown as averages ± SEM. 2-way ANOVA followed by Bonferroni’s multiple comparisons. Full article ">Figure 3
DHM (10 mg/kg) combined with IVM significantly reduces the dosing for EtOH consumption and 10E preference in female C57BL/6J mice over a period of 24 h. (A) IVM (1.0–2.5 mg/kg) combined with DHM (10 mg/kg) significantly reduced EtOH intake relative to saline treatment (Ctl), with 1.0–2.0 mg/kg IVM and DHM showing significant effects compared to IVM doses alone. (B) IVM (1.0–2.0 mg/kg) combined with DHM significantly reduces 10E preference in comparison to IVM controls. IVM (1.0–2.0 mg/kg) and DHM (10 mg/kg) significantly reduced 10E preference relative to saline values. Ctl = saline; DHM = dihydromyricetin; IVM = ivermectin. * p < 0.05 vs. Ctl values, † p < 0.05 vs. corresponding IVM dose control, and # p < 0.05 vs. DHM control; n = 48/group for DHM and saline groups; n = 8/group for IVM and IVM + DHM groups. All values are shown as averages ± SEM. 2-way ANOVA followed by Bonferroni’s multiple comparisons. Full article ">Figure 4
DHM (10 mg/kg) combined with IVM significantly reduces the dosing for EtOH consumption and 10E preference over 24 h in male and female C57BL/6J mice with no sex-specific differences. (A) DHM combined with IVM (1.0–2.5 mg/kg) significantly reduced EtOH consumption 24 h post-treatment with no sex-specific differences between normalized consumption values. Similarly, (B) DHM combined with IVM (1.0–2.5 mg/kg) significantly reduced 10E preference 24 h post-treatment with no sex-specific differences between normalized consumption values. IVM = ivermectin; DHM = dihydromyricetin; Baseline = day 0 values presented in <a href="#molecules-26-01791-f001" class="html-fig">Figure 1</a> and <a href="#molecules-26-01791-f003" class="html-fig">Figure 3</a> for males and females, respectively. * p < 0.05 vs. sex-matched baseline values (n = 48/group for DHM and saline controls; n = 8/group for IVM and IVM + DHM groups). All values are shown as averages ± SEM. 2-way ANOVA followed by Bonferroni’s multiple comparisons. Full article ">Figure 5
(A) Chemical structures of taxifolin (a potent Pgp ATPase inhibitor) and DHM, depicting variation only at the 5′ position of ring B. (B) Overlay of lowest binding energy conformations of taxifolin (green) and DHM (yellow) in NBD1 of human Pgp (PDB: 6C0V), depicting near-perfect overlap. Full article ">Figure 6
Lowest energy binding conformation of DHM (yellow) in NBD1 of human Pgp (PDB:6C0V). Atoms are displayed in the following colors: oxygen (red), nitrogen (blue), hydrogen (white), and carbon (grey, except DHM). Hydrogen bonds and distances are displayed in green. As depicted, in the lowest binding energy conformation, the 2-hydrogen and 3-carbonyl of DHM form hydrogen bond interactions with Gln1175 and Arg905 residues, respectively. Full article ">

8 pages, 4731 KiB

Open AccessArticle

Improved Diazo-Transfer Reaction for DNA-Encoded Chemistry and Its Potential Application for Macrocyclic DEL-Libraries

by Selahattin Ede, Mandy Schenk, Donald Bierer, Hilmar Weinmann and Keith Graham

Molecules 2021, 26(6), 1790; https://doi.org/10.3390/molecules26061790 - 22 Mar 2021

Cited by 8 | Viewed by 3073

Abstract

DNA-encoded libraries (DEL) are increasingly being used to identify new starting points for medicinal chemistry in drug discovery. Herein, we discuss the development of methods that allow the conversion of both primary amines and anilines, attached to DNA, to their corresponding azides in [...] Read more.

DNA-encoded libraries (DEL) are increasingly being used to identify new starting points for medicinal chemistry in drug discovery. Herein, we discuss the development of methods that allow the conversion of both primary amines and anilines, attached to DNA, to their corresponding azides in excellent yields. The scope of these diazo-transfer reactions was investigated, and a proof-of-concept has been devised to allow for the synthesis of macrocycles on DNA. Full article

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Graphical abstract
Full article ">Scheme 1
Aliphatic and aromatic amines attached to DNA for reaction optimization studies. Full article ">Scheme 2
Route for synthesizing macrocyclic DNA-encoded libraries. (i) ISA.H2SO4, CuSO4.5H2O, K2CO3, water, room temperature (RT); (ii) Cu(OAc)2. H2O, sodium L-ascorbate, tris(benzyltriazolylmethyl)amine (TBTA), dimethylformamide (DMF), phosphate buffer pH 7, RT. Blue circles highlight the different amino acids conjugated to the DNA, and grey circles highlight the subsequent amino acid. (i) a) Fmoc-Pra-OH, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methyl-morpholinium chloride (DMT-MM), DMF, borate buffer pH 9.5, RT; b) 10% piperidine in water, RT; c) Fmoc-amino acid (blue circle), DMT-MM, DMF, borate buffer pH 9.5, RT; d) 10% piperidine in water, RT; e) Fmoc-amino acid (grey circle), DMT-MM, DMF, borate buffer pH 9.5, RT; f) 10% piperidine in water, RT; (ii) ISA.H2SO4, CuSO4.5H2O, K2CO3, water, RT; (iii) Cu(OAc)2.H2O, sodium L-ascorbate, TBTA, DMF, phosphate buffer pH 7, RT; (iv) 14, DMT-MM, DMF, borate buffer pH 9.5, RT. Full article ">Scheme 3
Off-DNA Confirmation of Key Transformations. (i) ISA.H2SO4, CuSO4.5H2O, K2CO3, water, RT; (ii) Cu(OAc)2.H2O, sodium L-ascorbate, TBTA, DMF, phosphate buffer pH 7, RT. Grey circle highlights the different amino acid used. Full article ">

19 pages, 4158 KiB

Open AccessArticle

Needle Trap Device-GC-MS for Characterization of Lung Diseases Based on Breath VOC Profiles

by Fernanda Monedeiro, Maciej Monedeiro-Milanowski, Ileana-Andreea Ratiu, Beata Brożek, Tomasz Ligor and Bogusław Buszewski

Molecules 2021, 26(6), 1789; https://doi.org/10.3390/molecules26061789 - 22 Mar 2021

Cited by 29 | Viewed by 3947

Abstract

Volatile organic compounds (VOCs) have been assessed in breath samples as possible indicators of diseases. The present study aimed to quantify 29 VOCs (previously reported as potential biomarkers of lung diseases) in breath samples collected from controls and individuals with lung cancer, chronic [...] Read more.

Volatile organic compounds (VOCs) have been assessed in breath samples as possible indicators of diseases. The present study aimed to quantify 29 VOCs (previously reported as potential biomarkers of lung diseases) in breath samples collected from controls and individuals with lung cancer, chronic obstructive pulmonary disease and asthma. Besides that, global VOC profiles were investigated. A needle trap device (NTD) was used as pre-concentration technique, associated to gas chromatography-mass spectrometry (GC-MS) analysis. Univariate and multivariate approaches were applied to assess VOC distributions according to the studied diseases. Limits of quantitation ranged from 0.003 to 6.21 ppbv and calculated relative standard deviations did not exceed 10%. At least 15 of the quantified targets presented themselves as discriminating features. A random forest (RF) method was performed in order to classify enrolled conditions according to VOCs’ latent patterns, considering VOCs responses in global profiles. The developed model was based on 12 discriminating features and provided overall balanced accuracy of 85.7%. Ultimately, multinomial logistic regression (MLR) analysis was conducted using the concentration of the nine most discriminative targets (2-propanol, 3-methylpentane, (E)-ocimene, limonene, m-cymene, benzonitrile, undecane, terpineol, phenol) as input and provided an average overall accuracy of 95.5% for multiclass prediction. Full article

(This article belongs to the Special Issue Recent Advances in Volatile Organic Compound Analysis as Diagnostic Biomarkers)

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Figure 1
(a) VOCs distribution according to main chemical classes, in profiles belonging to the different studied groups, the contoured box displays the total number of compounds found in each group; (b) Similarity matrix displaying number and percentage of overlapping VOCs in the acquired profiles. Full article ">Figure 2
PCA plots using as input (a) VOCs’ responses in global profile analysis, (b) responses of the targets quantified in the samples (triangles = control samples; squares = positive samples). Full article ">Figure 3
(a) Volcano plot displaying the most discriminating features, in terms of fold change (x-axis) and statistical relevance (y-axis), in which the dashed line represents the point of y-axis in which p = 0.01; (b) Graph of distribution of number of all compounds assigned as discriminating features, according to disease and chemical class (significance criteria: p ≤ 0.05). Full article ">Figure 4
(a) Variable importance plot in terms of mean decrease Gini (node purity), obtained in the first training of RF model. Diamonds refer to VOCs selected for generation of the final classificatory model; (b) ROC curves based on RF’s final model output regarding the test set, using a panel of 12 VOCs; (c) Example decision tree produced by RF analysis, in which obtained accuracy was 81% (AS = asthma, CA = lung cancer, COPD = chronic obstructive pulmonary disease, H = healthy). Full article ">Figure 5
Plot of −(log 10) of p values when applying Mann-Whitney test for specific classes: (a) lung cancer, (b) COPD or (c) asthma, against all other conditions. Dashed line represents where p ≤ 0.05. Variables represented by triangle shape icon were those included in MLR final model. Full article ">Figure 6
ROC curves generated from fitted values (train set) created by MLR model, labelling (a) healthy, (b) lung cancer, (c) COPD and (d) asthma as the state variables; (e) ROC curves generated from predictions computed by the MLR model for the test set. Colored numerals refer to values of AUC obtained for each depicted curve. Full article ">

11 pages, 22767 KiB

Open AccessArticle

Solution and Solid State Studies of Urea Derivatives of DITIPIRAM Acting as Powerful Anion Receptors

by Patryk Niedbała, Kajetan Dąbrowa, Agnieszka Cholewiak-Janusz and Janusz Jurczak

Molecules 2021, 26(6), 1788; https://doi.org/10.3390/molecules26061788 - 22 Mar 2021

Cited by 1 | Viewed by 2087

Abstract

Herein, we present the synthesis and anion binding studies of a family of homologous molecular receptors 4–7 based on a DITIPIRAM (8-propyldithieno-[3,2-b:2′,3′-e]-pyridine-3,5-di-amine) platform decorated with various urea para-phenyl substituents (NO₂, F, CF₃, and Me). Solution, X-ray, [...] Read more.

Herein, we present the synthesis and anion binding studies of a family of homologous molecular receptors 4–7 based on a DITIPIRAM (8-propyldithieno-[3,2-b:2′,3′-e]-pyridine-3,5-di-amine) platform decorated with various urea para-phenyl substituents (NO₂, F, CF₃, and Me). Solution, X-ray, and DFT studies reveal that the presented host–guest system offers a convergent array of four urea NH hydrogen bond donors to anions allowing the formation of remarkably stable complexes with carboxylates (acetate, benzoate) and chloride anions in solution, even in competitive solvent mixtures such as DMSO-d₆/H₂O 99.5/0.5 (v/v) and DMSO-d₃/MeOH-d₃ 9:1 (v/v). The most effective derivatives among the series turned out to be receptors 5 and 6 containing electron-withdrawing F- and -CF₃para-substituents, respectively. Full article

(This article belongs to the Special Issue Structural Changes in Supramolecular Complexes)

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Figure 1
Structure of the 8-propyldithieno [3,2-b:2′,3′-e]pyridine-3,5-diamine (DITIPIRAM) platform. Full article ">Figure 2
Structures of receptors 2 and 3. Full article ">Figure 3
Representative comparison of chemical shift changes (Δδ) for urea protons NH(2/2′) (a) and NH(3/3′) (b) upon addition of TBA+X– (Cl−, PhCO2−, MeCO2−) to the solution of 6 in DMSO-d6 + 0.5% H2O (closed symbols) and DMSO-d6 + 10% CD3OH (open symbols); fitted binding isotherms (gray lines). Full article ">Figure 4
X-ray structures of 6@(DMSO∙H2O) solvate (a,c) and the 6@(Cl)TBA anionic complex (b,d). Non-acidic protons and disorder were omitted for clarity; the hydrogen bonds are shown as dashed blue lines. For hydrogen bond lengths (a–d), see the inset table in <a href="#molecules-26-01788-f005" class="html-fig">Figure 5</a>. Full article ">Figure 5
Geometrical descriptors of the binding pocket of the DITIPIRAM-based receptor 6 (a), superposition of crystal structures of 6∙(DMSO∙H2O) solvate (colored in blue) and 6∙TBACl (colored in green) (b). Full article ">Figure 6
Superposition of DFT-calculated structures of receptors 2−7 and their complexes with chloride, acetate, and benzoate exemplifies the high preorganization of the DITIPIRAM moiety (a) and average values of geometrical parameters describing anion complexes (b); see <a href="#molecules-26-01788-f005" class="html-fig">Figure 5</a>a for labels. Full article ">Scheme 1
Synthesis of acyclic receptors 4–7 varying in para-substituent (R) on the aryl rings. Full article ">

19 pages, 959 KiB

Open AccessReview

The Evolving Role of Microsampling in Therapeutic Drug Monitoring of Monoclonal Antibodies in Inflammatory Diseases

by Panagiotis-Dimitrios Mingas, Jurij Zdovc, Iztok Grabnar and Tomaž Vovk

Molecules 2021, 26(6), 1787; https://doi.org/10.3390/molecules26061787 - 22 Mar 2021

Cited by 7 | Viewed by 3518

Abstract

Monoclonal antibodies (mAbs) have been extensively developed over the past few years, for the treatment of various inflammatory diseases. They are large molecules characterized by complex pharmacokinetic and pharmacodynamic properties. Therapeutic drug monitoring (TDM) is routinely implemented in the therapy with mAbs, to [...] Read more.

Monoclonal antibodies (mAbs) have been extensively developed over the past few years, for the treatment of various inflammatory diseases. They are large molecules characterized by complex pharmacokinetic and pharmacodynamic properties. Therapeutic drug monitoring (TDM) is routinely implemented in the therapy with mAbs, to monitor patients’ treatment response and to further guide dose adjustments. Serum has been the matrix of choice in the TDM of mAbs and its sampling requires the visit of the patients to laboratories that are not always easily accessible. Therefore, dried blood spots (DBS) and various microsampling techniques have been suggested as an alternative. DBS is a sampling technique in which capillary blood is deposited on a special filter paper. It is a relatively simple procedure, and the patients can perform the home-sampling. The convenience it offers has enabled its use in the quantification of small-molecule drugs, whilst in the recent years, studies aimed to develop microsampling methods that will facilitate the TDM of mAbs. Nevertheless, hematocrit still remains an obstacle that hinders a more widespread implementation of DBS in clinical practice. The introduction of novel analytical techniques and contemporary microsampling devices can be considered the steppingstone to the attempts made addressing this issue. Full article

(This article belongs to the Special Issue Bioanalysis and Biological Matrix Sampling)

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10 pages, 2231 KiB

Open AccessArticle

Spermidine Prevents Ethanol and Lipopolysaccharide-Induced Hepatic Injury in Mice

by Raghabendra Adhikari, Ruchi Shah, Karina Reyes-Gordillo, Jaime Arellanes-Robledo, Ying Cheng, Joseph Ibrahim and Pamela L. Tuma

Molecules 2021, 26(6), 1786; https://doi.org/10.3390/molecules26061786 - 22 Mar 2021

Cited by 12 | Viewed by 4009

Abstract

To date, there is no effective treatment for alcoholic liver disease, despite its prevalence world-wide. Because alcohol consumption is associated with oxidative stress-induced liver injury and pro-inflammatory responses, naturally occurring antioxidants and/or anti-inflammatories may be potential therapeutics. Spermidine is an abundant, ubiquitous polyamine [...] Read more.

To date, there is no effective treatment for alcoholic liver disease, despite its prevalence world-wide. Because alcohol consumption is associated with oxidative stress-induced liver injury and pro-inflammatory responses, naturally occurring antioxidants and/or anti-inflammatories may be potential therapeutics. Spermidine is an abundant, ubiquitous polyamine that has been found to display strong antioxidant and anti-inflammatory properties. To further investigate whether spermidine is an effective intervention for alcohol-induced liver disease, we examined its hepatoprotective properties using a two-hit, chronic ethanol and acute lipopolysaccharide (LPS)-induced mouse model of liver injury. We determined that spermidine administration prevented ethanol and LPS-induced increases in liver injury using plasma ALT as a readout. Furthermore, histological analysis of tissue from control and treated animals revealed that the pathology associated with ethanol and LPS treatment was prevented in mice additionally treated with spermidine. As predicted, spermidine also prevented ethanol and LPS-induced oxidative stress by decreasing the levels of both reactive oxygen species (ROS) and lipid peroxidation. We further determined that spermidine treatment prevented the nuclear translocation of nuclear factor κB (NFκB) by blocking the phosphorylation of the inhibitory protein, IκB, thereby preventing expression of pro-inflammatory cytokines. Finally, by measuring expression of known markers of hepatic stellate cell activation and monitoring collagen deposition, we observed that spermidine also prevented alcohol and LPS-induced hepatic fibrosis. Together, our results indicate that spermidine is an antioxidant thereby conferring anti-inflammatory and anti-fibrotic effects associated with alcoholic liver injury. Full article

(This article belongs to the Special Issue The Therapeutic Potential of Naturally Occurring Compounds in Counteracting Oxidative Stress and Inflammation: From Basic Science to Therapy)

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Figure 1
Spermidine prevents ethanol and LPS-induced liver injury. Thick (4–6 µm) sections from mouse livers treated in the absence (control) or presence of ethanol (EtOH), LPS and/or spermidine (SPN) as indicated were stained with hematoxylin and eosin using routine procedures (A–D). Arrows indicate lipid droplets (B,C) and areas of inflammatory cell infiltration (C) that are absent in sections from control (A) or spermidine-treated mice (D). Bar = 100 µm. (E) Plasma levels of ALT were determined in control or treated mice as indicated. For each experimental condition, four mice were anlayzed (n = 4). The values in E represent the means of triplicate experiments ± SE. Full article ">Figure 2
Spermidine prevents ethanol and LPS-induced oxidative stress. The levels of ROS were determined fluorometrically in livers from mice treated in the absence (control) or presence of ethanol (EtOH), LPS and/or spermidine (SPN) as indicated (A). Total 4-HNE protein adducts (B). Molecular weight markers are indicated on the left of the immunoblot in kDa. Densitometric comparison of the immunoreactive species was performed to determine relative levels of expression. Values were normalized to total β-actin levels and are plotted as fold-increase relative to control (C). A representative immunoblot is shown in (B). For each experimental condition, four mice were analyzed (n = 4). The values in (A,C) represent the means of triplicate experiments ± SE. Full article ">Figure 3
Spermidine prevents ethanol and LPS-induced NFκB nuclear translocation, IκB activation by phosphorylation and pro-inflammatory cytokine expression. Nuclear (A) and cytosolic (B) fractions were isolated from livers of mice treated in the absence (control) or presence of ethanol (EtOH), LPS and/or spermidine (SPN) as indicated and immunoblotted for NFκB. Representative immunoblots from both fractions are shown. Densitometric comparison analysis of the immunoreactive species was performed and normalized to Lamin B1 levels (for the nuclear fractions) or β-actin (for the cytosolic fractions). The relative distributions were determined and plotted as fold-increase over control. (C) Total protein isolated from control or treated mice was immunoblotted for total and phosphorylated IκB (pIκB). The ratio of phospho-IκB vs. total IκB was calculated from densitometric analysis of immunoreactive species. Representative immunoblots are shown. Values are plotted as fold-change. Total mRNA isolated from livers of control or treated mice was processed for qRT-PCR to determine expression levels of TNFα (D), IL1β (E) or IL6 (F). For each experimental condition, four mice were analyzed (n = 4). The values are means of triplicate experiments ± SE. Full article ">Figure 4
Spermidine prevents ethanol and LPS-induced expression of markers of hepatic stellate cell activation and fibrogenesis. Whole homogenates were prepared from livers of mice treated in the absence (control) or presence of ethanol (EtOH), LPS and/or spermidine (SPN) as indicated and immunoblotted with antibodies specific to αSMA (A), PDGF-βR (B) or fibronectin (FN) (C). Densitometric comparison of the immunoreactive species was performed to determine relative levels of expression. Values were normalized to total β-actin levels and are plotted as fold-increase. Representative immunoblots are shown for each marker. For each experimental condition, four mice were analyzed (n = 4). The values represent means of triplicate experiments ± SE. Full article ">Figure 5
Spermidine prevents ethanol and and LPS-collagen deposition. Thick (4–6 µm) sections from mouse livers treated in the absence (control) or presence of ethanol (EtOH), LPS and/or spermidine (SPN) as indicated were stained with Sirius red to monitor collagen deposition (A–D). Labeling was only observed in sections from mice treated with ethanol alone or additionally treated with LPS (B,C). Bar = 100 µm Total hydroxyproline was detected colorimetrically from control or treated mice as an additional indicator of collagen deposition (E). For each experimental condition, four mice were analyzed (n = 4). Values are plotted as µg hydroxyproline detected per mg of liver. The values in E are means of triplicate experiments ± SE. Full article ">

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Molecules, Volume 26, Issue 6 (March-2 2021) – 319 articles

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