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Molecules, Volume 24, Issue 8 (April-2 2019) – 196 articles

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Cover Story (view full-size image) Two highly selective triazole-containing peptidic polo-like kinase 1 (Plk1) polo-box domain [...] Read more.
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Open AccessArticle
Synthesis, Antibacterial Activities, Mode of Action and Acute Toxicity Studies of New Oxazolidinone-Fluoroquinolone Hybrids
Molecules 2019, 24(8), 1641; https://doi.org/10.3390/molecules24081641 - 25 Apr 2019
Cited by 1 | Viewed by 1122
Abstract
To combat bacterial resistance, a series of new oxazolidinone-fluoroquinolone hybrids have been synthesized and characterized. All synthetic hybrids were preliminarily evaluated for their in vitro antibacterial activities against 6 standard strains and 3 clinical isolates. The majority of hybrids displayed excellent activities against [...] Read more.
To combat bacterial resistance, a series of new oxazolidinone-fluoroquinolone hybrids have been synthesized and characterized. All synthetic hybrids were preliminarily evaluated for their in vitro antibacterial activities against 6 standard strains and 3 clinical isolates. The majority of hybrids displayed excellent activities against Gram-positive bacteria, but limited activities against Gram-negative bacteria. Hybrids OBP-4 and OBP-5 were found to be the most promising compounds. Further, in vitro antibacterial activities, mode of action and acute toxicity in mice of hybrids OBP-4 and OBP-5 were investigated. Hybrids OBP-4 and OBP-5 exhibited potent activities against Gram-positive bacteria, including drug-resistant strains. Correspondingly, studies on the mode of action of hybrids OBP-4 and OBP-5 indicated a strong inhibitory activity on protein synthesis by binding the active site of 50S subunit, but a weak inhibitory action on DNA synthesis. In addition, LD50 values of hybrids OBP-4 and OBP-5 in the acute oral toxicity were larger than 2000 mg/kg, suggesting a good safety profile. Full article
(This article belongs to the Section Medicinal Chemistry)
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Open AccessArticle
Microwave-Assisted Kabachnik–Fields Reaction with Amino Alcohols as the Amine Component
Molecules 2019, 24(8), 1640; https://doi.org/10.3390/molecules24081640 - 25 Apr 2019
Cited by 3 | Viewed by 749
Abstract
In this paper, the microwave (MW)-assisted catalyst-free and mostly solvent-free Kabachnik–Fields reaction of amino alcohols, paraformaldehyde, and various >P(O)H reagents (dialkyl phosphites, ethyl phenyl-H-phosphinate, and secondary phosphine oxides) is reported. The synthesis of N-2-hydroxyethyl-α-aminophosphonate derivatives was optimized in respect of [...] Read more.
In this paper, the microwave (MW)-assisted catalyst-free and mostly solvent-free Kabachnik–Fields reaction of amino alcohols, paraformaldehyde, and various >P(O)H reagents (dialkyl phosphites, ethyl phenyl-H-phosphinate, and secondary phosphine oxides) is reported. The synthesis of N-2-hydroxyethyl-α-aminophosphonate derivatives was optimized in respect of the temperature, the reaction time, and the molar ratio of the starting materials. A few by-products were also identified. N,N-Bis(phosphinoylmethyl)amines containing a hydroxyethyl group were also prepared by the double Kabachnik–Fields reaction of ethanolamine with an excess of paraformaldehyde and secondary phosphine oxides. The crystal structure of a 2-hydroxyethyl-α-aminophosphine oxide and a bis(phosphinoylmethyl)ethanolamine was studied by X-ray analysis. Full article
(This article belongs to the Special Issue Multicomponent Reactions)
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Open AccessReview
Modern Methods of Sample Preparation for the Analysis of Oxylipins in Biological Samples
Molecules 2019, 24(8), 1639; https://doi.org/10.3390/molecules24081639 - 25 Apr 2019
Cited by 9 | Viewed by 1264
Abstract
Oxylipins are potent lipid mediators derived from polyunsaturated fatty acids, which play important roles in various biological processes. Being important regulators and/or markers of a wide range of normal and pathological processes, oxylipins are becoming a popular subject of research; however, the low [...] Read more.
Oxylipins are potent lipid mediators derived from polyunsaturated fatty acids, which play important roles in various biological processes. Being important regulators and/or markers of a wide range of normal and pathological processes, oxylipins are becoming a popular subject of research; however, the low stability and often very low concentration of oxylipins in samples are a significant challenge for authors and continuous improvement is required in both the extraction and analysis techniques. In recent years, the study of oxylipins has been directly related to the development of new technological platforms based on mass spectrometry (LC–MS/MS and gas chromatography–mass spectrometry (GC–MS)/MS), as well as the improvement in methods for the extraction of oxylipins from biological samples. In this review, we systematize and compare information on sample preparation procedures, including solid-phase extraction, liquid–liquid extraction from different biological tissues. Full article
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Open AccessReview
Targeting Methyltransferases in Human Pathogenic Bacteria: Insights into Thymidylate Synthase (TS) and Flavin-Dependent TS (FDTS)
Molecules 2019, 24(8), 1638; https://doi.org/10.3390/molecules24081638 - 25 Apr 2019
Viewed by 863
Abstract
In cells, thymidylate synthases provide the only de novo source of 2′-deoxythymidine-5′-monophosphate (dTMP), required for DNA synthesis. The activity of these enzymes is pivotal for cell survival and proliferation. Two main families of thymidylate synthases have been identified in bacteria, folate-dependent thymidylate synthase [...] Read more.
In cells, thymidylate synthases provide the only de novo source of 2′-deoxythymidine-5′-monophosphate (dTMP), required for DNA synthesis. The activity of these enzymes is pivotal for cell survival and proliferation. Two main families of thymidylate synthases have been identified in bacteria, folate-dependent thymidylate synthase (TS) and flavin-dependent TS (FDTS). TS and FDTS are highly divergent enzymes, characterized by exclusive catalytic mechanisms, involving different sets of cofactors. TS and FDTS mechanisms of action have been recently revised, providing new perspectives for the development of antibacterial drugs targeting these enzymes. Nonetheless, some catalytic details still remain elusive. For bacterial TSs, half-site reactivity is still an open debate and the recent evidences are somehow controversial. Furthermore, different behaviors have been identified among bacterial TSs, compromising the definition of common mechanisms. Moreover, the redox reaction responsible for the regeneration of reduced flavin in FDTSs is not completely clarified. This review describes the recent advances in the structural and functional characterization of bacterial TSs and FDTSs and the current understanding of their mechanisms of action. Furthermore, the recent progresses in the development of inhibitors targeting TS and FDTS in human pathogenic bacteria are summarized. Full article
(This article belongs to the Section Chemical Biology)
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Open AccessArticle
Chemical Composition and Biological Activity of Five Essential Oils from the Ecuadorian Amazon Rain Forest
Molecules 2019, 24(8), 1637; https://doi.org/10.3390/molecules24081637 - 25 Apr 2019
Cited by 3 | Viewed by 1247
Abstract
The chemical composition and biological activity of essential oils isolated from the leaves of Siparuna aspera, Siparuna macrotepala, Piper leticianum, Piper augustum and the rhizome of Hedychium coronarium were evaluated. These species are used medicinally in different ways by the [...] Read more.
The chemical composition and biological activity of essential oils isolated from the leaves of Siparuna aspera, Siparuna macrotepala, Piper leticianum, Piper augustum and the rhizome of Hedychium coronarium were evaluated. These species are used medicinally in different ways by the Amazonian communities that live near the Kutukú mountain range. Chemical studies revealed that the main components for the two Siparuna species were germacrene D, bicyclogermacrene, α-pinene, δ-cadinene, δ-elemene, α-copaene and β-caryophyllene; for the two Piper species β-caryophyllene, germacrene D, α-(E,E)-farnesene, β-elemene, bicyclogermacrene, δ-cadinene and for H. coronarium 1,8-cineole, β-pinene, α-pinene and α-terpineol. The antioxidant activity of all essential oils was evaluated by 1,1-diphenyl-2-picrylhydrazyl (DPPH), 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS), photochemiluminescence (PCL) quantitative assays, and DPPH and ABTS bioautographic profiles, with different results for each of them. Antimicrobial activity studies were carried out on three yeasts, six Gram positive and four Gram negative bacteria, by means of the disc diffusion method. The essential oil of H. coronarium showed the most relevant results on L. grayi, K. oxytoca and S. mutans, P. augustum and P. leticianum on S. mutans. An antibacterial bioautographic test for H. coronarium was also carried out and highlighted the potential activity of terpinen-4-ol and 1,8-cineole. Full article
(This article belongs to the Special Issue Biological Activities of Essential Oils)
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Open AccessReview
…Fell Upas Sits, the Hydra-Tree of Death , or the Phytotoxicity of Trees
Molecules 2019, 24(8), 1636; https://doi.org/10.3390/molecules24081636 - 25 Apr 2019
Cited by 3 | Viewed by 1010
Abstract
The use of natural products that can serve as natural herbicides and insecticides is a promising direction because of their greater safety for humans and environment. Secondary metabolites of plants that are toxic to plants and insects—allelochemicals—can be used as such products. Woody [...] Read more.
The use of natural products that can serve as natural herbicides and insecticides is a promising direction because of their greater safety for humans and environment. Secondary metabolites of plants that are toxic to plants and insects—allelochemicals—can be used as such products. Woody plants can produce allelochemicals, but they are studied much less than herbaceous species. Meanwhile, there is a problem of interaction of woody species with neighboring plants in the process of introduction or invasion, co-cultivation with agricultural crops (agroforestry) or in plantation forestry (multiclonal or multispecies plantations). This review describes woody plants with the greatest allelopathic potential, allelochemicals derived from them, and the prospects for their use as biopesticides. In addition, the achievement of and the prospects for the use of biotechnology methods in relation to the allelopathy of woody plants are presented and discussed. Full article
(This article belongs to the Special Issue Natural Products Acting as Insecticides or Herbicides)
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Open AccessArticle
The Effect of Concentration on the Cross-Linking and Gelling of Sodium Carbonate-Soluble Apple Pectins
Molecules 2019, 24(8), 1635; https://doi.org/10.3390/molecules24081635 - 25 Apr 2019
Cited by 1 | Viewed by 1818
Abstract
The cross-linking and gelation of low-methoxy pectins are basic processes commonly used in different industries. The aim of this research was to evaluate the cross-linking process of the sodium carbonate-soluble pectins (named DASP) extracted from apples, characterized by a low degree of methylesterification [...] Read more.
The cross-linking and gelation of low-methoxy pectins are basic processes commonly used in different industries. The aim of this research was to evaluate the cross-linking process of the sodium carbonate-soluble pectins (named DASP) extracted from apples, characterized by a low degree of methylesterification as a function of its concentration in water (CDASP). The cross-linking process was studied with a dynamic light scattering method, atomic force microscope (AFM), viscosity and pH measurements. An increase in CDASP above 0.01% resulted in a decrease in the aggregation index (AI) and the change of its sign from positive to negative. The value of AI = 0 occurred at CDASP = 0.33 ± 0.04% and indicated the formation of a pectin network. An increase in CDASP caused the changes in viscosity of pectin solutions and the nanostructure of pectins spin-coated on mica observed with AFM, which confirmed results obtained. The hydrogen bonds were involved in the cross-linking process. Full article
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Open AccessArticle
Synthesis of Ultrahigh Molecular Weight Polymers with Low PDIs by Polymerizations of 1-Decene, 1-Dodecene, and 1-Tetradecene by Cp*TiMe2(O-2,6-iPr2C6H3)–Borate Catalyst
Molecules 2019, 24(8), 1634; https://doi.org/10.3390/molecules24081634 - 25 Apr 2019
Cited by 1 | Viewed by 863
Abstract
Polymerizations of 1-decene (DC), 1-dodecene (DD), and 1-tetradecene (TD) by Cp*TiMe2(O-2,6-iPr2C6H3) (1)–[Ph3C][B(C6F5)4] (borate) catalyst have been explored in the presence of Al cocatalyst. [...] Read more.
Polymerizations of 1-decene (DC), 1-dodecene (DD), and 1-tetradecene (TD) by Cp*TiMe2(O-2,6-iPr2C6H3) (1)–[Ph3C][B(C6F5)4] (borate) catalyst have been explored in the presence of Al cocatalyst. The polymerizations of DC and DD, in n-hexane containing a mixture of AliBu3 and Al(n-C8H17)3, proceeded with high catalytic activities in a quasi-living manner, affording high molecular weight polymers (activity 4120–5860 kg-poly(DC)/mol-Ti·h, Mn for poly(DC) = 7.04–7.82 × 105, after 20 min at −30 °C). The PDI (Mw/Mn) values in the resultant polymers decreased upon increasing the ratio of Al(n-C8H17)3/AliBu3 with decreasing the activities at −30 °C. The PDI values also became low when these polymerizations were conducted at low temperatures (−40 or −50 °C); high molecular weight poly(DD) with low PDI (Mn = 5.26 × 105, Mw/Mn = 1.16) was obtained at −50 °C. The TD polymerization using 1–borate–AliBu3 catalyst (conducted in n-hexane at −30 °C) afforded ultrahigh molecular weight poly(TD) (Mn = 1.02 × 106, Mw/Mn = 1.38), and the PDI values also decreased with increasing the Al(n-C8H17)3/AliBu3 ratio. Full article
(This article belongs to the Special Issue Well-Defined Metal Complex Catalysts for Olefin Polymerization)
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Open AccessArticle
Microfluidics-Based Fabrication of Cell-Laden Hydrogel Microfibers for Potential Applications in Tissue Engineering
Molecules 2019, 24(8), 1633; https://doi.org/10.3390/molecules24081633 - 25 Apr 2019
Cited by 3 | Viewed by 1013
Abstract
Fibrous hydrogel scaffolds have recently attracted increasing attention for tissue engineering applications. While a number of approaches have been proposed for fabricating microfibers, it remains difficult for current methods to produce materials that meet the essential requirements of being simple, flexible and bio-friendly. [...] Read more.
Fibrous hydrogel scaffolds have recently attracted increasing attention for tissue engineering applications. While a number of approaches have been proposed for fabricating microfibers, it remains difficult for current methods to produce materials that meet the essential requirements of being simple, flexible and bio-friendly. It is especially challenging to prepare cell-laden microfibers which have different structures to meet the needs of various applications using a simple device. In this study, we developed a facile two-flow microfluidic system, through which cell-laden hydrogel microfibers with various structures could be easily prepared in one step. Aiming to meet different tissue engineering needs, several types of microfibers with different structures, including single-layer, double-layer and hollow microfibers, have been prepared using an alginate-methacrylated gelatin composite hydrogel by merely changing the inner and outer fluids. Cell-laden single-layer microfibers were obtained by subsequently seeding mouse embryonic osteoblast precursor cells (MC3T3-E1) cells on the surface of the as-prepared microfibers. Cell-laden double-layer and hollow microfibers were prepared by directly encapsulating MC3T3-E1 cells or human umbilical vein endothelial cells (HUVECs) in the cores of microfibers upon their fabrication. Prominent proliferation of cells happened in all cell-laden single-layer, double-layer and hollow microfibers, implying potential applications for them in tissue engineering. Full article
(This article belongs to the Special Issue Supramolecular Gel)
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Open AccessArticle
New UHPLC-QqQ-MS/MS Method for the Rapid and Sensitive Analysis of Ascorbic and Dehydroascorbic Acids in Plant Foods
Molecules 2019, 24(8), 1632; https://doi.org/10.3390/molecules24081632 - 25 Apr 2019
Cited by 1 | Viewed by 976
Abstract
A new method using ultra high-performance liquid chromatography coupled with triple quadrupole mass spectrometry (UHPLC-QqQ-MS/MS) methodology was developed for the determination of ascorbic acid (AA) and dehydroascorbic acid (DHAA) contents in liquid and solid vegetable samples. The advantages of this method are speed, [...] Read more.
A new method using ultra high-performance liquid chromatography coupled with triple quadrupole mass spectrometry (UHPLC-QqQ-MS/MS) methodology was developed for the determination of ascorbic acid (AA) and dehydroascorbic acid (DHAA) contents in liquid and solid vegetable samples. The advantages of this method are speed, high sensitivity and practical application. In accordance with these advantages, the present method allows the simultaneous determination of AA and DHAA without previous reduction/derivatization of DHAA and without the use of internal standards in the samples. This is of high interest in routine analysis, providing a simpler sample preparation, as well as enhanced accuracy and robustness. Its validation included selectivity, sensitivity and linearity, precision and accuracy, matrix effect, and recovery. The results showed high selectivity and sensitivity, with calibration curves ranging from 10 to 500 ng mL−1 and from 50 to 500 ng mL−1 for AA and DHAA, respectively. Appropriate dilutions for each sample are necessary to avoid the matrix effect with accepted recoveries. Full article
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Open AccessArticle
Synthesis of Telmisartan Organotin(IV) Complexes and their use as Carbon Dioxide Capture Media
Molecules 2019, 24(8), 1631; https://doi.org/10.3390/molecules24081631 - 25 Apr 2019
Cited by 7 | Viewed by 760
Abstract
Novel, porous, highly aromatic organotin(IV) frameworks were successfully synthesized by the condensation of telmisartan and an appropriate tin(IV) chloride. The structures of the synthesized organotin(IV) complexes were elucidated by elemental analysis, 1H-, 13C-, and 119Sn-NMR, and FTIR spectroscopy. The surface [...] Read more.
Novel, porous, highly aromatic organotin(IV) frameworks were successfully synthesized by the condensation of telmisartan and an appropriate tin(IV) chloride. The structures of the synthesized organotin(IV) complexes were elucidated by elemental analysis, 1H-, 13C-, and 119Sn-NMR, and FTIR spectroscopy. The surface morphologies of the complexes were inspected by field emission scanning electron microscopy. The synthesized mesoporous organotin(IV) complexes have a Brunauer–Emmett–Teller (BET) surface area of 32.3–130.4 m2·g−1, pore volume of 0.046–0.162 cm3·g−1, and pore size of around 2.4 nm. The tin complexes containing a butyl substituent were more efficient as carbon dioxide storage media than the complexes containing a phenyl substituent. The dibutyltin(IV) complex had the highest BET surface area (SBET = 130.357 m2·g−1), the largest volume (0.162 cm3·g−1), and was the most efficient for carbon dioxide storage (7.1 wt%) at a controlled temperature (323 K) and pressure (50 bars). Full article
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Open AccessArticle
Identifying Reducing and Capping Sites of Protein-Encapsulated Gold Nanoclusters
Molecules 2019, 24(8), 1630; https://doi.org/10.3390/molecules24081630 - 25 Apr 2019
Cited by 2 | Viewed by 941
Abstract
The reducing and capping sites along with their local structure impact photo properties of the red bovine serum albumin-capped Au nanocluster (BSA-AuNC), however, they are hard to identify. We developped a workflow and relevant techniques using mass spectrometry (MS) to identify the reducing [...] Read more.
The reducing and capping sites along with their local structure impact photo properties of the red bovine serum albumin-capped Au nanocluster (BSA-AuNC), however, they are hard to identify. We developped a workflow and relevant techniques using mass spectrometry (MS) to identify the reducing and capping sites of BSA-AuNCs involved in their formation and fluorescence. Digestion without disulfide cleavages yielded an Au core fraction exhibiting red fluorescence and [AunSm] ion signals and a non-core fraction exhibiting neither of them. The core fraction was identified to mainly be comprised of peptides containing cysteine residues. The fluorescence and [AunSm] signals were quenched by tris(2-carboxyethyl)phosphine, confirming that disulfide groups were required for nanocluster stabilization and fluorescence. By MS sequencing, the disulfide pairs, C75–C91/C90–C101 in domain IA, C315–C360/C359–C368 in domain IIB, and C513–C558/C557–C566 in domain IIIB, were identified to be main capping sites of red AuNCs. Peptides containing oxidized cysteines (sulfinic or cysteic acid) were identified as reducing sites mainly in the non-core fraction, suggesting that disulfide cleavages by oxidization and conformational changes contributed to the subsequent growth of nanoclusters at nearby intact disulfide pairs. This is the first report on precise identification of the reducing and capping sites of BSA-AuNCs. Full article
(This article belongs to the Special Issue Structure and Properties of Metal Nanoclusters)
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Open AccessReview
Encoded Library Technologies as Integrated Lead Finding Platforms for Drug Discovery
Molecules 2019, 24(8), 1629; https://doi.org/10.3390/molecules24081629 - 25 Apr 2019
Cited by 17 | Viewed by 2077
Abstract
The scope of targets investigated in pharmaceutical research is continuously moving into uncharted territory. Consequently, finding suitable chemical matter with current compound collections is proving increasingly difficult. Encoded library technologies enable the rapid exploration of large chemical space for the identification of ligands [...] Read more.
The scope of targets investigated in pharmaceutical research is continuously moving into uncharted territory. Consequently, finding suitable chemical matter with current compound collections is proving increasingly difficult. Encoded library technologies enable the rapid exploration of large chemical space for the identification of ligands for such targets. These binders facilitate drug discovery projects both as tools for target validation, structural elucidation and assay development as well as starting points for medicinal chemistry. Novartis internalized two complementing encoded library platforms to accelerate the initiation of its drug discovery programs. For the identification of low-molecular weight ligands, we apply DNA-encoded libraries. In addition, encoded peptide libraries are employed to identify cyclic peptides. This review discusses how we apply these two platforms in our research and why we consider it beneficial to run both pipelines in-house. Full article
(This article belongs to the Special Issue DNA-Encoded Chemical Libraries)
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Open AccessArticle
Protein Hydrolysate from Pterygoplichthys disjunctivus, Armoured Catfish, with High Antioxidant Activity
Molecules 2019, 24(8), 1628; https://doi.org/10.3390/molecules24081628 - 25 Apr 2019
Cited by 3 | Viewed by 1095
Abstract
Pterygoplichthys disjunctivus, locally named the armoured catfish, is a by-catch of tilapia fishing that accounts for up to 80% of total captured fish in the Adolfo Lopez Mateos dam, in Michoacán, México, affecting the economy of its surrounding communities. This invasive fish [...] Read more.
Pterygoplichthys disjunctivus, locally named the armoured catfish, is a by-catch of tilapia fishing that accounts for up to 80% of total captured fish in the Adolfo Lopez Mateos dam, in Michoacán, México, affecting the economy of its surrounding communities. This invasive fish is discarded by fishermen since native people do not consume it, partly due to its appearance, yet it is rich in protein. The aim of this study was to produce hydrolysates from armoured catfish using food-grade proteases (neutrases HT and PF and alcalase PAL) and investigate the processing conditions (pH and temperature) that lead to a high degree of hydrolysis, antioxidant activity, and Angiotensin I-Converting Enzyme (ACE) Inhibitory activity. No other similar research has been reported on this underutilized fish. The antioxidant activity was measured by three different methods, ABTS, FRAP and ORAC, with relevance to food and biological systems in order to obtain a more comprehensive assessment of the activity. In addition, the main peptide sequences were identified. All enzymes produced hydrolysates with high antioxidant activity. In particular, the protease HT led to the highest antioxidant activity according to the ABTS (174.68 μmol Trolox equivalent/g fish) and FRAP (7.59 mg ascorbic acid equivalent/g fish) methods and almost the same as PAL according to the ORAC method (51.43 μmol Trolox equivalent/g fish). Moreover, maximum activity was obtained at mild pH and temperature (7.5; 50 °C). Interestingly, the ORAC values obtained here were higher than others previously reported for fish hydrolysates and similar to those reported for fruits such as blueberries, apples and oranges. The peptide sequence IEE(E) was present in several peptides in both hydrolysates; this sequence may be partly responsible for the high antioxidant activity, particularly the one based on iron-reducing power. These findings will be relevant to the valorization of other fish/fish muscle discards and could contribute to the production of food supplements and nutraceuticals. Full article
(This article belongs to the Special Issue Bioactives from Bioprocessing: Sources and Production)
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Open AccessArticle
Topical Application of Cinnamaldehyde Promotes Faster Healing of Skin Wounds Infected with Pseudomonas aeruginosa
Molecules 2019, 24(8), 1627; https://doi.org/10.3390/molecules24081627 - 25 Apr 2019
Cited by 1 | Viewed by 1133
Abstract
Wound healing can be delayed following colonization and infection with the common bacterium Pseudomonas aeruginosa. While multiple therapies are used for their treatment, these are ineffective, expensive, and labour-intensive. Thus, there is an enormous unmet need for the treatment of infected wounds. [...] Read more.
Wound healing can be delayed following colonization and infection with the common bacterium Pseudomonas aeruginosa. While multiple therapies are used for their treatment, these are ineffective, expensive, and labour-intensive. Thus, there is an enormous unmet need for the treatment of infected wounds. Cinnamaldehyde, the major component of cinnamon oil, is well known for its antimicrobial properties. Herein, we investigated the effects of sub-inhibitory concentrations of cinnamaldehyde in the virulence of P. aeruginosa. We also assessed its healing potential in P. aeruginosa-infected mouse skin wounds and the mechanisms involved in this response. Sub-inhibitory concentrations of cinnamaldehyde reduced P. aeruginosa metabolic rate and its ability to form biofilm and to cause haemolysis. Daily topical application of cinnamaldehyde on P. aeruginosa-infected skin wounds reduced tissue bacterial load and promoted faster healing. Lower interleukin-17 (IL-17), vascular endothelial growth factor (VEGF) and nitric oxide levels were detected in cinnamaldehyde-treated wound samples. Blockage of transient receptor potential ankyrin 1, the pharmacological target of cinnamaldehyde, abrogated its healing activity and partially reversed the inhibitory actions of this compound on VEGF and IL-17 generation. We suggest that topical application of sub-inhibitory concentrations of cinnamaldehyde may represent an interesting approach to improve the healing of P. aeruginosa-infected skin wounds. Full article
(This article belongs to the Special Issue Antimicrobial Properties of Natural Products)
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Open AccessArticle
Calculation of the Isobaric Heat Capacities of the Liquid and Solid Phase of Organic Compounds at and around 298.15 K Based on Their “True” Molecular Volume
Molecules 2019, 24(8), 1626; https://doi.org/10.3390/molecules24081626 - 24 Apr 2019
Cited by 1 | Viewed by 873
Abstract
A universally applicable method for the prediction of the isobaric heat capacities of the liquid and solid phase of molecules at 298.15 K is presented, derived from their “true” volume. The molecules’ “true” volume in A3 is calculated on the basis of [...] Read more.
A universally applicable method for the prediction of the isobaric heat capacities of the liquid and solid phase of molecules at 298.15 K is presented, derived from their “true” volume. The molecules’ “true” volume in A3 is calculated on the basis of their geometry-optimized structure and the Van-der-Waals radii of their constituting atoms by means of a fast numerical algorithm. Good linear correlations of the “true” volume of a large number of compounds encompassing all classes and sizes with their experimental liquid and solid heat capacities over a large range have been found, although noticeably distorted by intermolecular hydrogen-bond effects. To account for these effects, the total amount of 1303 compounds with known experimental liquid heat capacities has been subdivided into three subsets consisting of 1102 hydroxy-group-free compounds, 164 monoalcohols/monoacids, and 36 polyalcohols/polyacids. The standard deviations for Cp(liq,298) were 20.7 J/mol/K for the OH-free compunds, 22.91 J/mol/K for the monoalcohols/monoacids and 16.03 J/mol/K for the polyols/polyacids. Analogously, 797 compounds with known solid heat capacities have been separated into a subset of 555 OH-free compounds, 123 monoalcohols/monoacids and 119 polyols/polyacids. The standard deviations for Cp(sol,298) were calculated to 23.14 J/mol/K for the first, 21.62 J/mol/K for the second, and 19.75 J/mol/K for the last subset. A discussion of structural and intermolecular effects influencing the heat capacities as well as of some special classes, in particular hydrocarbons, ionic liquids, siloxanes and metallocenes, has been given. In addition, the present method has successfully been extended to enable the prediction of the temperature dependence of the solid and liquid heat capacities in the range between 250 and 350 K. Full article
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Open AccessArticle
Characterisation of the Convective Hot-Air Drying and Vacuum Microwave Drying of Cassia alata: Antioxidant Activity, Essential Oil Volatile Composition and Quality Studies
Molecules 2019, 24(8), 1625; https://doi.org/10.3390/molecules24081625 - 24 Apr 2019
Cited by 9 | Viewed by 810
Abstract
The preservation of active constituents in Cassia alata through the removal of moisture is crucial in producing a final product with high antioxidant activity. This study aims to determine the influences of various drying methods and drying conditions on the antioxidant activity, volatiles [...] Read more.
The preservation of active constituents in Cassia alata through the removal of moisture is crucial in producing a final product with high antioxidant activity. This study aims to determine the influences of various drying methods and drying conditions on the antioxidant activity, volatiles and phytosterols content of C. alata. The drying methods used were convective drying (CD) at 40 °C, 50 °C and 60 °C; freeze drying; vacuum microwave drying (VMD) at 6, 9 and 12 W/g; and two-stage convective pre-drying followed by vacuum microwave finish drying (CPD-VMFD) at 50 °C and 9 W/g. The drying kinetics of C. alata are best described by the thin-layer model (modified Page model). The highest antioxidant activity, TPC and volatile concentration were achieved with CD at 40 °C. GC–MS analysis identified the presence of 51 volatiles, which were mostly present in all samples but with quantitative variation. The dominant volatiles in fresh C. alata are 2-hexenal (60.28 mg 100 g−1 db), 1-hexanol (18.70 mg 100 g−1 db) and salicylic acid (15.05 mg 100 g−1 db). The concentration of phytosterols in fresh sample was 3647.48 mg 100 g−1 db, and the major phytosterols present in fresh and dried samples were β-sitosterol (1162.24 mg 100 g−1 db). CPD-VMFD was effective in ensuring the preservation of higher phytosterol content in comparison with CD at 50 °C. The final recommendation of a suitable drying method to dehydrate C. alata leaves is CD at 40 °C. Full article
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Open AccessArticle
Absolute Bioavailability, Tissue Distribution, and Excretion of Erinacine S in Hericium erinaceus Mycelia
Molecules 2019, 24(8), 1624; https://doi.org/10.3390/molecules24081624 - 24 Apr 2019
Cited by 2 | Viewed by 928
Abstract
Erinacine S, so far known to have been produced only in Hericium erinaceus mycelia, has just recently been discovered and is able to reduce amyloid plaque growth and improve neurogenesis in aged brain of rats. However, few investigations have been conducted on the [...] Read more.
Erinacine S, so far known to have been produced only in Hericium erinaceus mycelia, has just recently been discovered and is able to reduce amyloid plaque growth and improve neurogenesis in aged brain of rats. However, few investigations have been conducted on the absorption, distribution, and excretion study of Erinacine S. This study aimed to investigate the absolute bioavailability, tissue distribution, and excretion of Erinacine S in H. Erinaceus mycelia in eight-week old Sprague-Dawley rats. After oral administration and intravenous administration of 2.395 g/kg body weight of the H. erinaceus mycelia extract (equivalent to 50 mg/kg body weight Erinacine S) and 5 mg/kg of Erinacine S, respectively, the absolute bioavailability was estimated as 15.13%. In addition, Erinacine S was extensively distributed in organs such as brain, heart, lung, liver, kidney, stomach, small intestine, and large intestine. The maximum concentration of Erinacine S was observed in the stomach, 2 h after the oral administration of H. erinaceus mycelia extract, whereas the maximum amount of Erinacine S found in other tissues were seen after 8 h. Total amount of unconverted Erinacine S eliminated in feces and urine in 24 h was 0.1% of the oral dosage administrated. This study is the first to show that Erinacine S can penetrate the blood–brain barrier of rats and thus support the development of H. erinaceus mycelia, for the treatment of neurological diseases. Full article
(This article belongs to the Section Natural Products Chemistry)
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Open AccessArticle
Excellent Temperature-Control Based on Reversible Thermochromic Materials for Light-Driven Phase Change Materials System
Molecules 2019, 24(8), 1623; https://doi.org/10.3390/molecules24081623 - 24 Apr 2019
Cited by 2 | Viewed by 843
Abstract
Light-driven phase change materials (PCMs) have received significant attention due to their capacity to convert visible light into thermal energy, storing it as latent heat. However, continuous photo-thermal conversion can cause the PCMs to reach high thermal equilibrium temperatures after phase transition. In [...] Read more.
Light-driven phase change materials (PCMs) have received significant attention due to their capacity to convert visible light into thermal energy, storing it as latent heat. However, continuous photo-thermal conversion can cause the PCMs to reach high thermal equilibrium temperatures after phase transition. In our study, a novel light-driven phase change material system with temperature-control properties was constructed using a thermochromic compound. Thermochromic phase change materials (TC-PCMs) were prepared by introducing 2-anilino-6-dibutylamino-3-methylfluoran (ODB-2) and bisphenol A (BPA) into 1-hexadecanol (1-HD) in various proportions. Photo-thermal conversion performance was investigated with solar radiation (low power of 0.09 W/cm2) and a xenon lamp (at a high power of 0.14 W/cm2). The TC-PCMs showed a low equilibrium temperature due to variations in absorbance. Specifically, the temperature of TC-PCM180 (ODB-2, bisphenol A and 1-HD ratio 1:2:180) could stabilize at 54 °C approximately. TC-PCMs exhibited reversibility and repeatability after 20 irradiation and cooling cycles. Full article
(This article belongs to the Special Issue Phase Change Materials)
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Open AccessReview
Fused in Sarcoma: Properties, Self-Assembly and Correlation with Neurodegenerative Diseases
Molecules 2019, 24(8), 1622; https://doi.org/10.3390/molecules24081622 - 24 Apr 2019
Cited by 7 | Viewed by 1194
Abstract
Fused in sarcoma (FUS) is a DNA/RNA binding protein that is involved in RNA metabolism and DNA repair. Numerous reports have demonstrated by pathological and genetic analysis that FUS is associated with a variety of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal [...] Read more.
Fused in sarcoma (FUS) is a DNA/RNA binding protein that is involved in RNA metabolism and DNA repair. Numerous reports have demonstrated by pathological and genetic analysis that FUS is associated with a variety of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), and polyglutamine diseases. Traditionally, the fibrillar aggregation of FUS was considered to be the cause of those diseases, especially via its prion-like domains (PrLDs), which are rich in glutamine and asparagine residues. Lately, a nonfibrillar self-assembling phenomenon, liquid–liquid phase separation (LLPS), was observed in FUS, and studies of its functions, mechanism, and mutual transformation with pathogenic amyloid have been emerging. This review summarizes recent studies on FUS self-assembling, including both aggregation and LLPS as well as their relationship with the pathology of ALS, FTLD, and other neurodegenerative diseases. Full article
(This article belongs to the Special Issue Recent Advances in Self-Assembled Peptides)
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Open AccessArticle
Synthesis and Novel Purification Process of PANI and PANI/AgNPs Composite
Molecules 2019, 24(8), 1621; https://doi.org/10.3390/molecules24081621 - 24 Apr 2019
Cited by 4 | Viewed by 807
Abstract
In this work, polyaniline (PANI) is synthesized via oxidative polymerization of aniline and purified using organic solvents where the emeraldine phase is isolated by employing a phase separation system. The above contributes to the increase in the percentage yield compared to previous works [...] Read more.
In this work, polyaniline (PANI) is synthesized via oxidative polymerization of aniline and purified using organic solvents where the emeraldine phase is isolated by employing a phase separation system. The above contributes to the increase in the percentage yield compared to previous works and the possibility of being used as a single phase. In addition, the PANI/AgNPs composite is prepared in situ at the polymerization of aniline, adding silver nitrate and glycine to create the AgNPs inside the PANI matrix by controlling the pH, temperature, time of reaction and incorporating a new purification technique. Full article
(This article belongs to the Section Organic Chemistry)
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Open AccessReview
Coumarins and P450s, Studies Reported to-Date
Molecules 2019, 24(8), 1620; https://doi.org/10.3390/molecules24081620 - 24 Apr 2019
Cited by 6 | Viewed by 891
Abstract
Cytochrome P450 enzymes (CYPs) are important phase I enzymes involved in the metabolism of endogenous and xenobiotic compounds mainly through mono-oxygenation reactions into more polar and easier to excrete species. In addition to their role in detoxification, they play important roles in the [...] Read more.
Cytochrome P450 enzymes (CYPs) are important phase I enzymes involved in the metabolism of endogenous and xenobiotic compounds mainly through mono-oxygenation reactions into more polar and easier to excrete species. In addition to their role in detoxification, they play important roles in the biosynthesis of endogenous compounds and the bioactivation of xenobiotics. Coumarins, phytochemicals abundant in food and commonly used in fragrances and cosmetics, have been shown to interact with P450 enzymes as substrates and/or inhibitors. In this review, these interactions and their significance in pharmacology and toxicology are discussed in detail. Full article
(This article belongs to the Special Issue Coumarins and Coumarin Derivatives: From Chemistry to Drug)
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Open AccessArticle
Interaction of Arsenic Species with Organic Ligands: Competitive Removal from Water by Coagulation-Flocculation-Sedimentation (C/F/S)
Molecules 2019, 24(8), 1619; https://doi.org/10.3390/molecules24081619 - 24 Apr 2019
Cited by 3 | Viewed by 786
Abstract
The co-occurrence of arsenic (As) and organic ligands in water bodies has raised environmental concerns due to their toxicity and adverse effects on human health. The present study aims to elucidate the influences of hydrophobic/hydrophilic organic ligands, such as humic acid (HA) and [...] Read more.
The co-occurrence of arsenic (As) and organic ligands in water bodies has raised environmental concerns due to their toxicity and adverse effects on human health. The present study aims to elucidate the influences of hydrophobic/hydrophilic organic ligands, such as humic acid (HA) and salicylic acid (SA), on the interactive behavior of As species in water. Moreover, the competitive removal behaviors of As(III, V) species and total organic carbon (TOC) were systematically investigated by coagulation-flocculation-sedimentation (C/F/S) under various aqueous matrices. The results showed the stronger binding affinity of As(V) than As(III) species, with a higher complexation ability of hydrophobic ligands than hydrophilic. The media containing hydrophilic ligands require smaller ferric chloride (FC) doses to achieve the higher As(III, V) removal, while the optimum FC dose required for As(III) removal was found to be higher than that for As(V). Moreover, hydrophobic ligands showed higher TOC removal than hydrophilic ligands. The pronounced adverse effect of a higher concentration of hydrophobic ligands on the removal efficiencies of As(V) and TOC was observed. The adsorption of As(V) on Fe precipitates was better fitted with the Langmuir model but the Freundlich isotherm was more suitable for As(III) in the presence of hydrophilic SA. Moreover, TOC removal was substantially decreased in the As(V) system as compared to the As(III) system due to the dissolution of Fe precipitates at higher As(V) concentrations. The results of FC composite flocs demonstrated that the combined effect of oxidation, charge neutralization and adsorption played an important role in the removal of both toxicants during the C/F/S process. In summary, the findings of the present study provide insights into the fate, mobility and competitive removal behavior of As(III, V) species and organic ligands in the water treatment process. Full article
(This article belongs to the Special Issue Advanced Materials and Technologies for Wastewater Treatment)
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Open AccessArticle
Discovery of Potent and Selective Halogen-Substituted Imidazole-Thiosemicarbazides for Inhibition of Toxoplasma gondii Growth In Vitro via Structure-Based Design
Molecules 2019, 24(8), 1618; https://doi.org/10.3390/molecules24081618 - 24 Apr 2019
Cited by 2 | Viewed by 805
Abstract
Employing a simple synthetic protocol, a series of highly effective halogen-substituted imidazole-thiosemicarbazides with anti-Toxoplasma gondii effects against the RH tachyzoites, much better than sulfadiazine, were obtained (IC50s 10.30—113.45 µg/mL vs. ~2721.45 µg/mL). The most potent of them, 12, 13, and 15, [...] Read more.
Employing a simple synthetic protocol, a series of highly effective halogen-substituted imidazole-thiosemicarbazides with anti-Toxoplasma gondii effects against the RH tachyzoites, much better than sulfadiazine, were obtained (IC50s 10.30—113.45 µg/mL vs. ~2721.45 µg/mL). The most potent of them, 12, 13, and 15, blocked the in vitro proliferation of T. gondii more potently than trimethoprim (IC50 12.13 µg/mL), as well. The results of lipophilicity studies collectively suggest that logP would be a rate-limiting factor for the anti-Toxoplasma activity of this class of compounds. Full article
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Open AccessArticle
The Anticonvulsant Effects of Baldrinal on Pilocarpine-Induced convulsion in Adult Male Mice
Molecules 2019, 24(8), 1617; https://doi.org/10.3390/molecules24081617 - 24 Apr 2019
Cited by 1 | Viewed by 703
Abstract
Epilepsy is a prevalent neurological disorder that was reported to affect about 56 million people in the world. Approximately one-third of the epileptic patients that suffer from seizures do not receive effective medical treatment. The aim of this study was to determine the [...] Read more.
Epilepsy is a prevalent neurological disorder that was reported to affect about 56 million people in the world. Approximately one-third of the epileptic patients that suffer from seizures do not receive effective medical treatment. The aim of this study was to determine the potential anticonvulsant activities of Baldrinal (BAL) with a mouse model of pilocarpine (PILO)-induced epilepsy. The mice were treated with different doses of BAL or sodium valproate prior to PILO injection. Spontaneous and evoked seizures were evaluated from EEG recordings, and their severity was tested by the Racine scale. In addition, the brain tissues were analyzed for histological changes, and the in situ levels of glutamic acid (Glu) and gamma-aminobutyric acid (GABA) were also measured. Activation of astrocytes in the hippocampus was measured. PILO-treated mice showed a significant increase in Glu levels, which was restored by BAL. In addition, BAL treatment also reduced the rate of seizures in the epileptic mice, and ameliorated the increased levels of NMDAR1, BDNF, IL-1β and TNF-α. Taken together, BAL has a potential antiepileptic effect, which may be mediated by reducing the inflammatory response in the PILO-induced brain and restoring the balance of GABAergic and glutamatergic neurons. Full article
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Open AccessArticle
Volatile Organic Compound and Fatty Acid Profile of Milk from Cows and Buffaloes Fed Mycorrhizal or Nonmycorrhizal Ensiled Forage
Molecules 2019, 24(8), 1616; https://doi.org/10.3390/molecules24081616 - 24 Apr 2019
Cited by 3 | Viewed by 734
Abstract
Seed inoculation of forage crops by arbuscular mycorrhizal fungi (AMF) generally results in higher profitability, but also modifies the chemical composition of silage in terms of increased biomass, protein, and dry matter. Raw milk aroma is affected by the type of feed. This [...] Read more.
Seed inoculation of forage crops by arbuscular mycorrhizal fungi (AMF) generally results in higher profitability, but also modifies the chemical composition of silage in terms of increased biomass, protein, and dry matter. Raw milk aroma is affected by the type of feed. This work investigated the influence of ensiled forage obtained by seed inoculation with AMF on the volatile fractions and fatty acid composition of milk. Two experiments were carried out: in the first, buffaloes were fed maize silage, and in the second, cows were fed sorghum silage. The volatile fractions of milk were quantified by headspace solid-phase micro-extraction (HS-SPME), combined with gas chromatography–mass spectrometry (GC-MS), and fatty acids by gas chromatography (GC). The ensiled forage obtained with AMF increased saturated fatty acids (SFAs), and decreased monounsaturated fatty acids (MUFAs) and polyunsaturated fatty acids (PUFAs) in both experiments. The volatile fraction in milk samples obtained from bovines fed mycorrhizal ensiled forage showed an increase of free fatty acids and ketones, responsible for cheesy and fruity odors. Aldehydes, responsible for green and grassy notes, increased only in the milk from buffaloes fed ensiled maize. Our results suggest that inoculation of maize and sorghum seed with AMF, combined with a low rate of fertilizers, leads to ensiled forage that could slightly affect the FA profile and odor quality of milk. Full article
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Open AccessArticle
Chemical Composition, Antimicrobial and Antiparasitic Screening of the Essential Oil from Phania matricarioides (Spreng.) Griseb.
Molecules 2019, 24(8), 1615; https://doi.org/10.3390/molecules24081615 - 24 Apr 2019
Cited by 2 | Viewed by 980
Abstract
Essential oils (EOs) have gained increasing attention due to their pharmacological effectiveness, and they also constitute some of the most popular natural products. In this study, we present the chemical characterization of the EO from Phania matricarioides and the in vitro activity/selectivity against [...] Read more.
Essential oils (EOs) have gained increasing attention due to their pharmacological effectiveness, and they also constitute some of the most popular natural products. In this study, we present the chemical characterization of the EO from Phania matricarioides and the in vitro activity/selectivity against a wide panel of bacteria, fungi and parasitic protozoa. Forty-five compounds were identified in the studied EO, of which lavandulyl acetate (40.1%) and thymyl isobutyrate (13.9%) were the major components. The EO did not inhibit bacterial or fungal growth at the maximum concentration tested (64 µg/mL), although it displayed activity on all evaluated protozoa (IC50 values ranging from 2.2 to 56.6 µg/mL). In parallel, the EO demonstrated a noteworthy cytotoxic activity against peritoneal macrophages (CC50 values of 28.0 µg/mL). The most sensitive microorganism was Trypanosoma cruzi, which had a superior activity (IC50 = 2.2 µg/mL) and selectivity (SI = 13) in respect to other parasitic protozoa and the reference drug (p < 0.05). Further in vivo studies are needed to evaluate the potential use of this EO and the main compounds as antitrypanosomal agents. To our knowledge, this is the first report of chemical characterization and antimicrobial assessment of the EO from P. matricarioides. Full article
(This article belongs to the Special Issue Drug Discovery for Neglected Diseases)
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Open AccessArticle
Carpesium divaricatum Sieb. & Zucc. Revisited: Newly Identified Constituents from Aerial Parts of the Plant and Their Possible Contribution to the Biological Activity of the Plant
Molecules 2019, 24(8), 1614; https://doi.org/10.3390/molecules24081614 - 24 Apr 2019
Cited by 1 | Viewed by 1017
Abstract
Carpesium divaricatum Sieb. & Zucc. has a long history of use as both a medicinal and a food plant. However, except for terpenoids, its chemical constituents have remained poorly investigated. The composition of hydroalcoholic extract from aerial parts of C. divaricatum was analyzed [...] Read more.
Carpesium divaricatum Sieb. & Zucc. has a long history of use as both a medicinal and a food plant. However, except for terpenoids, its chemical constituents have remained poorly investigated. The composition of hydroalcoholic extract from aerial parts of C. divaricatum was analyzed by HPLC-DAD-MSn, revealing the presence of numerous caffeic acid derivatives that were formerly unknown constituents of the plant. In all, 17 compounds, including commonly found chlorogenic acids and rarely occurring butyryl and methylbutyryl tricaffeoylhexaric acids, were tentatively identified. Fractionation of lipophilic extract from cultivated shoots led to the isolation of 12-oxo-phytodienoic acid (12-OPDA), which is a newly identified constituent of the plant. The compound, at concentrations of 0.5, 1.0, and 2.5 μM, significantly reduced IL-8, IL-1β, TNFα, and CCL2 excretion by lipopolysaccharide (LPS)-stimulated human neutrophils. Reactive oxygen species (ROS) production induced by f-MLP was also significantly diminished in the neutrophils pretreated by 12-OPDA. The newly identified constituents of the plant seem to be partly responsible for its pharmacological activity and elevate the value of C. divaricatum as a potential functional food. Full article
(This article belongs to the Section Natural Products Chemistry)
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Open AccessArticle
Conformational Dynamics of the RNA G-Quadruplex and its Effect on Translation Efficiency
Molecules 2019, 24(8), 1613; https://doi.org/10.3390/molecules24081613 - 24 Apr 2019
Cited by 1 | Viewed by 1051
Abstract
During translation, intracellular mRNA folds co-transcriptionally and must refold following the passage of ribosome. The mRNAs can be entrapped in metastable structures during these folding events. In the present study, we evaluated the conformational dynamics of the kinetically favored, metastable, and hairpin-like structure, [...] Read more.
During translation, intracellular mRNA folds co-transcriptionally and must refold following the passage of ribosome. The mRNAs can be entrapped in metastable structures during these folding events. In the present study, we evaluated the conformational dynamics of the kinetically favored, metastable, and hairpin-like structure, which disturbs the thermodynamically favored G-quadruplex structure, and its effect on co-transcriptional translation in prokaryotic cells. We found that nascent mRNA forms a metastable hairpin-like structure during co-transcriptional folding instead of the G-quadruplex structure. When the translation progressed co-transcriptionally before the metastable hairpin-like structure transition to the G-quadruplex, function of the G-quadruplex as a roadblock of the ribosome was sequestered. This suggested that kinetically formed RNA structures had a dominant effect on gene expression in prokaryotes. The results of this study indicate that it is critical to consider the conformational dynamics of RNA-folding to understand the contributions of the mRNA structures in controlling gene expression. Full article
(This article belongs to the Special Issue G-quadruplex and Microorganisms) Printed Edition available
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Open AccessArticle
[18F]Fluoroethyltriazolyl Monocyclam Derivatives as Imaging Probes for the Chemokine Receptor CXCR4
Molecules 2019, 24(8), 1612; https://doi.org/10.3390/molecules24081612 - 24 Apr 2019
Cited by 2 | Viewed by 803
Abstract
Determining chemokine receptor CXCR4 expression is significant in multiple diseases due to its role in promoting inflammation, cell migration and tumorigenesis. [68Ga]Pentixafor is a promising ligand for imaging CXCR4 expression in multiple tumor types, but its utility is limited by the [...] Read more.
Determining chemokine receptor CXCR4 expression is significant in multiple diseases due to its role in promoting inflammation, cell migration and tumorigenesis. [68Ga]Pentixafor is a promising ligand for imaging CXCR4 expression in multiple tumor types, but its utility is limited by the physical properties of 68Ga. We screened a library of >200 fluorine-containing structural derivatives of AMD-3465 to identify promising candidates for in vivo imaging of CXCR4 expression by positron emission tomography (PET). Compounds containing fluoroethyltriazoles consistently achieved higher docking scores. Six of these higher scoring compounds were radiolabeled by click chemistry and evaluated in PC3-CXCR4 cells and BALB/c mice bearing bilateral PC3-WT and PC3-CXCR4 xenograft tumors. The apparent CXCR4 affinity of the ligands was relatively low, but tumor uptake was CXCR4-specific. The tumor uptake of [18F]RPS-534 (7.2 ± 0.3 %ID/g) and [18F]RPS-547 (3.1 ± 0.5 %ID/g) at 1 h p.i. was highest, leading to high tumor-to-blood, tumor-to-muscle, and tumor-to-lung ratios. Total cell-associated activity better predicted in vivo tumor uptake than did the docking score or apparent CXCR4 affinity. By this metric, and on the basis of their high yielding radiosynthesis, high tumor uptake, and good contrast to background, [18F]RPS-547, and especially [18F]RPS-534, are promising 18F-labeled candidates for imaging CXCR4 expression. Full article
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