Molecules

16 pages, 4336 KiB

Open AccessReview

Molecular Interactions of Antibody Drugs Targeting PD-1, PD-L1, and CTLA-4 in Immuno-Oncology

by Hyun Tae Lee, Sang Hyung Lee and Yong-Seok Heo

Molecules 2019, 24(6), 1190; https://doi.org/10.3390/molecules24061190 - 26 Mar 2019

Cited by 193 | Viewed by 18043

Cancer cells can evade immune surveillance through the molecular interactions of immune checkpoint proteins, including programmed death 1 (PD-1), PD-L1, and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4). Since 2011, the FDA-approved antibody drugs ipilimumab (Yervoy^®), nivolumab (Opdivo^®), pembrolizumab (Keytruda [...] Read more.

Cancer cells can evade immune surveillance through the molecular interactions of immune checkpoint proteins, including programmed death 1 (PD-1), PD-L1, and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4). Since 2011, the FDA-approved antibody drugs ipilimumab (Yervoy^®), nivolumab (Opdivo^®), pembrolizumab (Keytruda^®), cemiplimab (Libtayo^®), atezolizumab (Tecentriq^®), durvalumab (Imfinzi^®), and avelumab (Bavencio^®), which block the immune checkpoint proteins, have brought about a significant breakthrough in the treatment of a wide range of cancers, as they can induce durable therapeutic responses. In recent years, crystal structures of the antibodies against PD-1, PD-L1, and CTLA-4 have been reported. In this review, we describe the latest structural studies of these monoclonal antibodies and their interactions with the immune checkpoint proteins. A comprehensive analysis of the interactions of these immune checkpoint blockers can provide a better understanding of their therapeutic mechanisms of action. The accumulation of these structural studies would provide a basis that is essential for the rational design of next-generation therapies in immuno-oncology. Full article

(This article belongs to the Special Issue Frontier of Protein Crystallography)

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16 pages, 2971 KiB

Open AccessArticle

Cardiac-Specific Cre Induces Age-Dependent Dilated Cardiomyopathy (DCM) in Mice

by Taha Rehmani, Maysoon Salih and Balwant S. Tuana

Molecules 2019, 24(6), 1189; https://doi.org/10.3390/molecules24061189 - 26 Mar 2019

Cited by 16 | Viewed by 6254

Abstract

The genetic modification of the mouse genome using the cre-lox system has been an invaluable tool in deciphering gene and protein function in a temporal and/or spatial manner. However, it has its pitfalls, as researchers have shown that the unregulated expression of cre [...] Read more.

The genetic modification of the mouse genome using the cre-lox system has been an invaluable tool in deciphering gene and protein function in a temporal and/or spatial manner. However, it has its pitfalls, as researchers have shown that the unregulated expression of cre recombinase can cause DNA damage, the consequences of which can be very detrimental to mouse health. Previously published literature on the most utilized cardiac-specific cre, αMHC-cre, mouse model exhibited a nonlethal hypertrophic cardiomyopathy (HCM) with aging. However, using the same αMHC-cre mice, we observed a cardiac pathology, resulting in complete lethality by 11 months of age. Echocardiography and histology revealed that the αMHC-cre mice were displaying symptoms of dilated cardiomyopathy (DCM) by seven months of age, which ultimately led to their demise in the absence of any HCM at any age. Molecular analysis showed that this phenotype was associated with the DNA damage response through the downregulation of activated p38 and increased expression of JNK, p53, and Bax, known inducers of myocyte death resulting in fibrosis. Our data urges strong caution when interpreting the phenotypic impact of gene responses using αMHC-cre mice, since a lethal DCM was induced by the cre driver in an age-dependent manner in this commonly utilized model system. Full article

(This article belongs to the Special Issue Cardiovascular Diseases Prevention and Therapy)

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10 pages, 610 KiB

Open AccessArticle

The Quality of DNA Isolated from Processed Food and Feed via Different Extraction Procedures

by Zora Piskata, Eliska Servusova, Vladimir Babak, Michaela Nesvadbova and Gabriela Borilova

Molecules 2019, 24(6), 1188; https://doi.org/10.3390/molecules24061188 - 26 Mar 2019

Cited by 59 | Viewed by 10513

Abstract

The extraction of DNA is a critical step for species identification by PCR analysis in processed food and feed products. In this study, eight DNA extraction procedures were compared—DNeasy Blood and Tissue Kit, DNeasy mericon Food Kit, chemagic DNA Tissue 10 Kit, Food [...] Read more.

The extraction of DNA is a critical step for species identification by PCR analysis in processed food and feed products. In this study, eight DNA extraction procedures were compared—DNeasy Blood and Tissue Kit, DNeasy mericon Food Kit, chemagic DNA Tissue 10 Kit, Food DNA Isolation Kit, UltraPrep Genomic DNA Food Mini Prep Kit, High Pure PCR Template Preparation Kit, phenol—chloroform extraction, and NucleoSpin Food—Using self-prepared samples from both raw and heat-processed and/or mechanically treated muscles and different types of meat products and pet food (pork, beef, and chicken). The yield, purity, and suitability of DNA for PCR amplification was evaluated. Additionally, comparisons between the effectiveness of various extraction methods were made with regard to price, and labor- and time-intensiveness. It was found that the DNeasy mericon Food Kit was the optimal choice for the extraction of DNA from raw muscle, heat-treated muscle, and homemade meat products from multiple and single species. Full article

(This article belongs to the Special Issue Recent Advances in Studies of Food and Beverages)

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13 pages, 1681 KiB

Open AccessArticle

Evaluation of Anti-Inflammatory Activities of a Triterpene β-Elemonic Acid in Frankincense In Vivo and In Vitro

by Yue Zhang, Ying-li Yu, Hua Tian, Ru-yu Bai, Ya-nan Bi, Xiao-mei Yuan, Li-kang Sun, Yan-ru Deng and Kun Zhou

Molecules 2019, 24(6), 1187; https://doi.org/10.3390/molecules24061187 - 26 Mar 2019

Cited by 16 | Viewed by 3661

Abstract

The purpose of this research was to extract and separate the compounds from frankincense, and then evaluate their anti-inflammatory effects. The isolated compound was a representative tetracyclic triterpenes of glycine structure according to ¹H-NMR and ¹³C-NMR spectra, which is β-elemonic acid [...] Read more.

The purpose of this research was to extract and separate the compounds from frankincense, and then evaluate their anti-inflammatory effects. The isolated compound was a representative tetracyclic triterpenes of glycine structure according to ¹H-NMR and ¹³C-NMR spectra, which is β-elemonic acid (β-EA). We determined the content of six different localities of frankincense; the average content of β-EA was 41.96 mg/g. The toxic effects of β-EA administration (400, 200, 100 mg/kg) for four weeks in Kunming (KM) mice were observed. Compared with the control group, the body weight of mice, the visceral coefficients and serum indicators in the β-EA groups showed no systematic variations. The anti-inflammatory effects of β-EA were evaluated in LPS-induced RAW264.7 cells, xylene-induced induced ear inflammation in mice, carrageenin-induced paw edema in mice, and cotton pellet induced granuloma formation in rats. β-EA inhibited overproduction of tumor necrosis factor-α(TNF-α), interleukin-6 (IL-6), monocyte chemotactic protein 1 (MCP-1), soluble TNF receptor 1 (sTNF R1), Eotaxin-2, Interleukin 10 (IL-10) and granulocyte colony-stimulating factor (GCSF) in the RAW264.7 cells. Intragastric administration with β-EA (300, 200, and 100 mg/kg in mice, and 210, 140, and 70 mg/kg in rats) all produced distinct anti-inflammatory effects in vivo in a dose-dependent manner. Following treatment with β-EA (300 mg/kg, i.g.), the NO level in mice ears and PGE2 in mice paws both decreased (p < 0.01). In conclusion, our study indicates that β-EA could be a potential anti-inflammatory agent for the treatment of inflammatory diseases. Full article

(This article belongs to the Section Natural Products Chemistry)

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16 pages, 1504 KiB

Open AccessArticle

Polyphenols and Alkaloids in Byproducts of Longan Fruits (Dimocarpus Longan Lour.) and Their Bioactivities

by Ya-Yuan Tang, Xue-Mei He, Jian Sun, Chang-Bao Li, Li Li, Jin-Feng Sheng, Ming Xin, Zhi-Chun Li, Feng-Jin Zheng, Guo-Ming Liu, Jie-Min Li and Dong-Ning Ling

Molecules 2019, 24(6), 1186; https://doi.org/10.3390/molecules24061186 - 26 Mar 2019

Cited by 67 | Viewed by 7312

Abstract

The longan industry produces a large amount of byproducts such as pericarp and seed, resulting in environmental pollution and resource wastage. The present study was performed to systematically evaluate functional components, i.e., polyphenols (phenolics and flavonoids) and alkaloids, in longan byproducts and their [...] Read more.

The longan industry produces a large amount of byproducts such as pericarp and seed, resulting in environmental pollution and resource wastage. The present study was performed to systematically evaluate functional components, i.e., polyphenols (phenolics and flavonoids) and alkaloids, in longan byproducts and their bioactivities, including antioxidant activities, nitrite scavenging activities in simulated gastric fluid and anti-hyperglycemic activities in vitro. Total phenolic and total flavonoid contents in pericarp were slightly higher than those in seeds, but seeds possessed higher alkaloid content than pericarp. Four polyphenolic substances, i.e., gallic acid, ethyl gallate, corilagin and ellagic acid, were identified and quantified using high-performance liquid chromatography. Among these polyphenolic components, corilagin was the major one in both pericarp and seed. Alkaloid extract in seed showed the highest DPPH radical scavenging activity and oxygen radical absorbance capacity. Nitrite scavenging activities were improved with extract concentration and reaction time increasing. Flavonoids in seed and alkaloids in pericarp had potential to be developed as anti-hyperglycemic agents. The research result was a good reference for exploring longan byproducts into various valuable health-care products. Full article

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20 pages, 2695 KiB

Open AccessArticle

Effect of Stereochemical Configuration on the Transport and Metabolism of Catechins from Green Tea across Caco-2 Monolayers

by Zeyi Ai, Shuyuan Liu, Fengfeng Qu, Haojie Zhang, Yuqiong Chen and Dejiang Ni

Molecules 2019, 24(6), 1185; https://doi.org/10.3390/molecules24061185 - 26 Mar 2019

Cited by 19 | Viewed by 4388

Abstract

The transcellular transport and metabolism of eight green tea catechins (GTCs) were studied in Caco-2 monolayers, with the aim of investigating the effect of cis–trans isomerism on the membrane permeability and biotransformation of GTCs. The results showed that the catechin stereochemistry significantly affects [...] Read more.

The transcellular transport and metabolism of eight green tea catechins (GTCs) were studied in Caco-2 monolayers, with the aim of investigating the effect of cis–trans isomerism on the membrane permeability and biotransformation of GTCs. The results showed that the catechin stereochemistry significantly affects the efflux transport rather than the absorption transport in the Caco-2 monolayers. The trans catechins showed a better transcellular permeability than their corresponding cis (epi) catechins in the efflux transport, as the efflux amount of trans catechins were all significantly higher than that of the cis (epi) catechins at each concentration and each time point tested. Moreover, the relative contents of the (+)-catechin (C)-O-sulfate, (+)-gallocatechin (GC)-O-sulfate, (−)-catechin gallate (CG)-O-sulfate, and (−)-gallocatechin gallate (GCG)-O-sulfate in the efflux transport were 2.67, 16.08, 50.48, and 31.54 times higher than that of the (−)-epicatechin (EC)-O-sulfate, (−)-epigallocatechin (EGC)-O-sulfate, (−)-epicatechin gallate (ECG)-O-sulfate, and (−)-epigallocatechin gallate (EGCG)-O-sulfate, respectively. It indicated that more metabolites were observed after the transcellular efflux of trans catechins. Furthermore, after two hours of incubation, the GTCs could significantly increase the expression of multidrug resistance-associated protein 2 (MRP2) and breast cancer-resistance protein (BCRP), and decrease the expression of P-glycoprotein in the Caco-2 cells. The regulation of GTCs on P-glycoprotein, MRP2, and BCRP could also be significantly influenced by the chemical and dimensional structure. In a conclusion, catechin stereochemistry significantly affects the transport and metabolism of GTCs when refluxed in the Caco-2 monolayers. Full article

(This article belongs to the Special Issue Catechins in Human Health)

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14 pages, 2912 KiB

Open AccessArticle

Hydrogen Gas Alleviates Chronic Intermittent Hypoxia-Induced Renal Injury through Reducing Iron Overload

by Peng Guan, Zhi-Min Sun, Li-Fei Luo, Ya-Shuo Zhao, Sheng-Chang Yang, Fu-Yang Yu, Na Wang and En-Sheng Ji

Molecules 2019, 24(6), 1184; https://doi.org/10.3390/molecules24061184 - 26 Mar 2019

Cited by 25 | Viewed by 4832

Abstract

Iron-induced oxidative stress has been found to be a central player in the pathogenesis of kidney injury. Recent studies have indicated H₂ can be used as a novel antioxidant to protect cells. The present study was designed to investigate the protective effects [...] Read more.

Iron-induced oxidative stress has been found to be a central player in the pathogenesis of kidney injury. Recent studies have indicated H₂ can be used as a novel antioxidant to protect cells. The present study was designed to investigate the protective effects of H₂ against chronic intermittent hypoxia (CIH)-induced renal injury and its correlation mechanism involved in iron metabolism. We found that CIH-induced renal iron overloaded along with increased apoptosis and oxidative stress. Iron accumulates mainly occurred in the proximal tubule epithelial cells of rats as showed by Perl’s stain. Moreover, we found that CIH could promote renal transferrin receptor and divalent metal transporter-1 expression, inhibit ceruloplasmin expression. Renal injury, apoptosis and oxidative stress induced by CIH were strikingly attenuated in H₂ treated rats. In conclusion, hydrogen may attenuate CIH-induced renal injury at least partially via inhibiting renal iron overload. Full article

(This article belongs to the Special Issue Chemistry and Pharmacology of Modulators of Oxidative Stress 2018)

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15 pages, 664 KiB

Open AccessArticle

Comparison of Volatile and Nonvolatile Compounds in Rice Fermented by Different Lactic Acid Bacteria

by Sang Mi Lee, Young Rim Hwang, Moon Seok Kim, Myung Sub Chung and Young-Suk Kim

Molecules 2019, 24(6), 1183; https://doi.org/10.3390/molecules24061183 - 26 Mar 2019

Cited by 23 | Viewed by 5386

Abstract

The production of rice-based beverages fermented by lactic acid bacteria (LAB) can increase the consumption of rice in the form of a dairy replacement. This study investigated volatile and nonvolatile components in rice fermented by 12 different LABs. Volatile compounds of fermented rice [...] Read more.

The production of rice-based beverages fermented by lactic acid bacteria (LAB) can increase the consumption of rice in the form of a dairy replacement. This study investigated volatile and nonvolatile components in rice fermented by 12 different LABs. Volatile compounds of fermented rice samples were analyzed using gas chromatography-mass spectrometry (GC-MS) combined with solid-phase microextraction (SPME), while nonvolatile compounds were determined using gas chromatography-time-of-flight/mass spectrometry (GC-TOF/MS) after derivatization. The 47 identified volatile compounds included acids, aldehydes, esters, furan derivatives, ketones, alcohols, benzene and benzene derivatives, hydrocarbons, and terpenes, while the 37 identified nonvolatile components included amino acids, organic acids, and carbohydrates. The profiles of volatile and nonvolatile components generally differed significantly between obligatorily homofermentative/facultatively heterofermentative LAB and obligatorily heterofermentative LAB. The rice sample fermented by Lactobacillus sakei (RTCL16) was clearly differentiated from the other samples on principal component analysis (PCA) plots. The results of PCA revealed that the rice samples fermented by LABs could be distinguished according to microbial strains. Full article

(This article belongs to the Special Issue Instrumental Analysis for Volatile Odorants and Flavours)

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18 pages, 749 KiB

Open AccessReview

A Critical Review of Phenolic Compounds Extracted from the Bark of Woody Vascular Plants and Their Potential Biological Activity

by Corneliu Tanase, Sanda Coșarcă and Daniela-Lucia Muntean

Molecules 2019, 24(6), 1182; https://doi.org/10.3390/molecules24061182 - 26 Mar 2019

Cited by 197 | Viewed by 10468

Abstract

Polyphenols are one of the largest and most widespread groups of secondary metabolites in the plants world. These compounds are of particular interest due to their occurrence and the properties they possess. The main sources of phenolic compounds are fruits and vegetables, but [...] Read more.

Polyphenols are one of the largest and most widespread groups of secondary metabolites in the plants world. These compounds are of particular interest due to their occurrence and the properties they possess. The main sources of phenolic compounds are fruits and vegetables, but lately, more and more studies refer to woody vascular plants, especially to bark, as an important source of phenolic compounds with a potential biological effect. This study aims to bring together information on the phenolic compounds present in the bark of woody vascular plants by discussing extraction methods, the chemical composition of the extracts and potential biological effects. The literature data used in this paper were collected via PubMed (2004–2019). Search terms were: bark, rhytidome, woody vascular plant, polyphenols, phenolic compounds, biologic activity, antioxidant, immunostimulatory, antimutagenic, antibacterial, anti-inflammatory, and antitumoral. This paper intends to highlight the fact that the polyphenolic extracts obtained from the bark of woody vascular plants represent sources of bioactive compounds with antioxidant, immunostimulatory, antimutagenic, antibacterial properties, etc. Future research directions should be directed towards identification and isolation of bioactive compounds. Consequently, biologically active compounds obtained from the bark of woody plants could be exploited on an industrial scale. Full article

(This article belongs to the Collection Phenolic Compounds from Plants: Chemistry, Analysis and Biological Activity)

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19 pages, 5318 KiB

Open AccessArticle

Deep Learning for Validating and Estimating Resolution of Cryo-Electron Microscopy Density Maps ^†

by Todor Kirilov Avramov, Dan Vyenielo, Josue Gomez-Blanco, Swathi Adinarayanan, Javier Vargas and Dong Si

Molecules 2019, 24(6), 1181; https://doi.org/10.3390/molecules24061181 - 26 Mar 2019

Cited by 22 | Viewed by 7218

Abstract

Cryo-electron microscopy (cryo-EM) is becoming the imaging method of choice for determining protein structures. Many atomic structures have been resolved based on an exponentially growing number of published three-dimensional (3D) high resolution cryo-EM density maps. However, the resolution value claimed for the reconstructed [...] Read more.

Cryo-electron microscopy (cryo-EM) is becoming the imaging method of choice for determining protein structures. Many atomic structures have been resolved based on an exponentially growing number of published three-dimensional (3D) high resolution cryo-EM density maps. However, the resolution value claimed for the reconstructed 3D density map has been the topic of scientific debate for many years. The Fourier Shell Correlation (FSC) is the currently accepted cryo-EM resolution measure, but it can be subjective, manipulated, and has its own limitations. In this study, we first propose supervised deep learning methods to extract representative 3D features at high, medium and low resolutions from simulated protein density maps and build classification models that objectively validate resolutions of experimental 3D cryo-EM maps. Specifically, we build classification models based on dense artificial neural network (DNN) and 3D convolutional neural network (3D CNN) architectures. The trained models can classify a given 3D cryo-EM density map into one of three resolution levels: high, medium, low. The preliminary DNN and 3D CNN models achieved 92.73% accuracy and 99.75% accuracy on simulated test maps, respectively. Applying the DNN and 3D CNN models to thirty experimental cryo-EM maps achieved an agreement of 60.0% and 56.7%, respectively, with the author published resolution value of the density maps. We further augment these previous techniques and present preliminary results of a 3D U-Net model for local resolution classification. The model was trained to perform voxel-wise classification of 3D cryo-EM density maps into one of ten resolution classes, instead of a single global resolution value. The U-Net model achieved 88.3% and 94.7% accuracy when evaluated on experimental maps with local resolutions determined by MonoRes and ResMap methods, respectively. Our results suggest deep learning can potentially improve the resolution evaluation process of experimental cryo-EM maps. Full article

(This article belongs to the Special Issue Selected Papers from the 11th Computational Structural Bioinformatics Workshop (CSBW-2018))

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13 pages, 1131 KiB

Open AccessArticle

Oligonucleotide–Palladacycle Conjugates as Splice-Correcting Agents

by Madhuri Hande, Osama Saher, Karin E. Lundin, C. I. Edvard Smith, Rula Zain and Tuomas Lönnberg

Molecules 2019, 24(6), 1180; https://doi.org/10.3390/molecules24061180 - 26 Mar 2019

Cited by 10 | Viewed by 5114

Abstract

2’-O-Methylribo phosphorothioate oligonucleotides incorporating cyclopalladated benzylamine conjugate groups at their 5’-termini have been prepared and their ability to hybridize with a designated target sequence was assessed by conventional UV melting experiments. The oligonucleotides were further examined in splice-switching experiments in human [...] Read more.

2’-O-Methylribo phosphorothioate oligonucleotides incorporating cyclopalladated benzylamine conjugate groups at their 5’-termini have been prepared and their ability to hybridize with a designated target sequence was assessed by conventional UV melting experiments. The oligonucleotides were further examined in splice-switching experiments in human cervical cancer (HeLa Luc/705), human liver (HuH7_705), and human osteosarcoma (U-2 OS_705) reporter cell lines. Melting temperatures of duplexes formed by the modified oligonucleotides were approximately 5 °C lower than melting temperatures of the respective unmodified duplexes. The cyclopalladated oligonucleotides functioned as splice-correcting agents in the HeLa Luc/705 cell line somewhat more efficiently than their unmodified counterparts. Furthermore, the introduction of this chemical modification did not induce toxicity in cells. These results demonstrate the feasibility of using covalently metalated oligonucleotides as therapeutic agents. Full article

(This article belongs to the Special Issue Molecular Tools for Nucleic Acid Manipulation for Biological Intervention)

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13 pages, 2500 KiB

Open AccessArticle

Enhanced Liver Targeting of Camptothecin via Conjugation with Deoxycholic Acid

by Linxia Xiao, Endian Yu, Hanlin Yue and Qingyong Li

Molecules 2019, 24(6), 1179; https://doi.org/10.3390/molecules24061179 - 26 Mar 2019

Cited by 27 | Viewed by 3831

Abstract

Camptothecin (CPT) shows potent anticancer activity through inhibition of topoisomerase I. However, its water insolubility and severe toxicity limit its clinical application. Coupling with bile acid moieties is a promising method for liver-targeted drug delivery, which takes advantage of the bile acid receptors [...] Read more.

Camptothecin (CPT) shows potent anticancer activity through inhibition of topoisomerase I. However, its water insolubility and severe toxicity limit its clinical application. Coupling with bile acid moieties is a promising method for liver-targeted drug delivery, which takes advantage of the bile acid receptors on hepatocytes. In this study, we evaluated the potential liver targeting and stability of a deoxycholic acid-CPT conjugate (G2). The competitive inhibition of antitumor activity experiment based on bile acid transporters was performed using the MTT method. The effects of deoxycholic acid on uptake of G2 and CPT were assessed in 2D and 3D HepG2 cell models. The stability of G2 and CPT was evaluated in vitro (in simulated gastric fluid, simulated intestinal fluid, and fresh rat plasma). Finally, biodistribution of G2 and CPT was investigated in Kunming mice following oral administration. The results showed that deoxycholic acid pretreatment could significantly reduce the antitumor activity and cellular uptake of G2 in HepG2 cells, but had no distinct effects on CPT. Meanwhile, G2 exhibited better stability compared with CPT. More importantly, biodistribution study in mice demonstrated that the liver targeting index of G2 increased 1.67-fold than that of CPT. Overall, the study suggests that conjugation with deoxycholic acid is a feasible method to achieve liver targeting delivery of CPT. Full article

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15 pages, 2529 KiB

Open AccessArticle

A Novel Modified Electrode for Detection of the Food Colorant Sunset Yellow Based on Nanohybrid of MnO₂ Nanorods-Decorated Electrochemically Reduced Graphene Oxide

by Ziyu Ding, Peihong Deng, Yiyong Wu, Yaling Tian, Guangli Li, Jun Liu and Quanguo He

Molecules 2019, 24(6), 1178; https://doi.org/10.3390/molecules24061178 - 25 Mar 2019

Cited by 63 | Viewed by 4292

Abstract

The nanohybrid of electrochemically-reduced graphene oxide (ERGO) nanosheets decorated with MnO₂ nanorods (MnO₂ NRs) was modified on the surface of a glassy carbon electrode (GCE). Controlled potential reduction was applied for the reduction of graphene oxide (GO). The characterization was performed [...] Read more.

The nanohybrid of electrochemically-reduced graphene oxide (ERGO) nanosheets decorated with MnO₂ nanorods (MnO₂ NRs) was modified on the surface of a glassy carbon electrode (GCE). Controlled potential reduction was applied for the reduction of graphene oxide (GO). The characterization was performed by scanning electron microscopy, X-ray diffraction and cyclic voltammetry. Compared with the poor electrochemical response at bare GCE, a well-defined oxidation peak of sunset yellow (SY) was observed at the MnO₂ NRs-ERGO/GCE, which was attributed to the high accumulation efficiency as well as considerable electrocatalytic activity of ERGO and MnO₂ NRs on the electrode surface. The experimental parameters for SY detection were optimized in detail. Under the optimized experiment conditions, the MnO₂ NRs-ERGO/GCE showed good linear response to SY in concentration range of 0.01–2.0 μM, 2.0–10.0 μM and 10.0–100.0 μM with a detection limit of 2.0 nM. This developed method was applied for SY detection in soft drinks with satisfied detected results. Full article

(This article belongs to the Special Issue Analysis of Residues in Food and Environment)

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21 pages, 4117 KiB

Open AccessArticle

Neuroprotective Effects of an Aqueous Extract of Forsythia viridissima and Its Major Constituents on Oxaliplatin-Induced Peripheral Neuropathy

by Jin-Mu Yi, Sarah Shin, No Soo Kim and Ok-Sun Bang

Molecules 2019, 24(6), 1177; https://doi.org/10.3390/molecules24061177 - 25 Mar 2019

Cited by 21 | Viewed by 4186

Abstract

The dried fruits of Forsythia viridissima have been prescribed to relive fever, pain, vomiting, and nausea in traditional medicine. Oxaliplatin (LOHP) is used to treat advanced colorectal cancer; however, it frequently induces peripheral neuropathies. This study was done to evaluate the neuroprotective effects [...] Read more.

The dried fruits of Forsythia viridissima have been prescribed to relive fever, pain, vomiting, and nausea in traditional medicine. Oxaliplatin (LOHP) is used to treat advanced colorectal cancer; however, it frequently induces peripheral neuropathies. This study was done to evaluate the neuroprotective effects of an aqueous extract of Forsythia viridissima fruits (EFVF) and its major constituents. Chemical constituents from EFVF were characterized and quantified with the UHPLC-diode array detector method, and three major constituents were identified as arctiin, matairesinol, and arctigenin. The in vitro cytotoxicity was measured by the Ez-cytox viability assay, and the in vivo neuroprotection activity was evaluated by a von Frey test in two rodent animal models that were administered LOHP. EFVF significantly alleviated the LOHP-induced mechanical hypersensitivity in the induction model. EFVF also prevented the induction of mechanical hyperalgesia by LOHP in the pre- and co-treatment of LOHP and EFVF. Consistently, EFVF exerted protective effects against LOHP-induced neurotoxicity as well as inhibited neurite outgrowths in PC12 and dorsal root ganglion cells. Among the major components of EFVF, arctigenin and matairesinol exerted protective effects against LOHP-induced neurotoxicity. Therefore, EFVF may be useful for relieving or preventing LOHP-induced peripheral neuropathy in cancer patients undergoing chemotherapy with LOHP. Full article

(This article belongs to the Special Issue Natural Product Pharmacology and Medicinal Chemistry)

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20 pages, 4127 KiB

Open AccessArticle

Highly Linear Polyethylenes Achieved Using Thermo-Stable and Efficient Cobalt Precatalysts Bearing Carbocyclic-Fused NNN-Pincer Ligand

by Jingjing Guo, Zheng Wang, Wenjuan Zhang, Ivan I. Oleynik, Arumugam Vignesh, Irina V. Oleynik, Xinquan Hu, Yang Sun and Wen-Hua Sun

Molecules 2019, 24(6), 1176; https://doi.org/10.3390/molecules24061176 - 25 Mar 2019

Cited by 30 | Viewed by 4035

Abstract

Six examples of 2-(1-arylimino)ethyl-9-arylimino-5,6,7,8-tetrahydrocycloheptapyridine-cobalt(II) chloride complexes, [2-(1-ArN)C₂H₃-9-ArN-5,6,7,8-C₅H₈C₅H₃N]CoCl₂, (Ar = 2-(C₅H₉)-6-MeC₆H₃ Co1, 2-(C₆H₁₁)-6-MeC₆H₃ Co2, [...] Read more.

Six examples of 2-(1-arylimino)ethyl-9-arylimino-5,6,7,8-tetrahydrocycloheptapyridine-cobalt(II) chloride complexes, [2-(1-ArN)C₂H₃-9-ArN-5,6,7,8-C₅H₈C₅H₃N]CoCl₂, (Ar = 2-(C₅H₉)-6-MeC₆H₃ Co1, 2-(C₆H₁₁)-6-MeC₆H₃ Co2, 2-(C₈H₁₅)-6-MeC₆H₃ Co3, 2-(C₅H₉)-4,6-Me₂C₆H₂ Co4, 2-(C₆H₁₁)-4,6-Me₂C₆H₂ Co5, and 2-(C₈H₁₅)-4,6-Me₂C₆H₂ Co6), were synthesized by the direct reaction of the corresponding ortho-cycloalkyl substituted carbocyclic-fused bis(arylimino)pyridines (L1–L6) and cobalt(II) chloride in ethanol with good yields. All the synthesized ligands (L1–L6) and their corresponding cobalt complexes (Co1–Co6) were fully characterized by FT-IR, ¹H/¹³C-NMR spectroscopy and elemental analysis. The crystal structure of Co2 and Co3 revealed that the ring puckering of both the ortho-cyclohexyl/cyclooctyl substituents and the one pyridine-fused seven-membered ring; a square-based pyramidal geometry is conferred around the metal center. On treatment with either methylaluminoxane (MAO) or modified methylaluminoxane (MMAO), all the six complexes showed high activities (up to 4.09 × 10⁶ g of PE mol⁻¹ (Co) h⁻¹) toward ethylene polymerization at temperatures between 20 °C and 70 °C with the catalytic activities correlating with the type of ortho-cycloalkyl substituent: Cyclopentyl (Co1 and Co4) > cyclohexyl (Co2 and Co5) > cyclooctyl (Co3 and Co6) for either R = H or Me and afforded strictly linear polyethylene (T_m > 130 °C). The narrow unimodal distributions of the resulting polymers are consistent with single-site active species for the precatalyst. Furthermore, compared to the previously reported cobalt analogues, the titled precatalysts exhibited good thermo-stability (up to 70 °C) and possessed longer lifetime along with a higher molecular weight of PE (M_w: 9.2~25.3 kg mol⁻¹). Full article

(This article belongs to the Special Issue Well-Defined Metal Complex Catalysts for Olefin Polymerization)

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22 pages, 2557 KiB

Open AccessArticle

Design and Synthesis of New Quinoxaline Derivatives as Anticancer Agents and Apoptotic Inducers

by Aliya M. S. El Newahie, Yassin M. Nissan, Nasser S. M. Ismail, Dalal A. Abou El Ella, Sohair M. Khojah and Khaled A.M. Abouzid

Molecules 2019, 24(6), 1175; https://doi.org/10.3390/molecules24061175 - 25 Mar 2019

Cited by 50 | Viewed by 6876

Abstract

The quinoxaline scaffold is a promising platform for the discovery of active chemotherapeutic agents. Three series of quinoxaline derivatives were synthesized and biologically evaluated against three tumor cell lines (HCT116 human colon carcinoma, HepG2, liver hepatocellular carcinoma and MCF-7, human breast adenocarcinoma cell [...] Read more.

The quinoxaline scaffold is a promising platform for the discovery of active chemotherapeutic agents. Three series of quinoxaline derivatives were synthesized and biologically evaluated against three tumor cell lines (HCT116 human colon carcinoma, HepG2, liver hepatocellular carcinoma and MCF-7, human breast adenocarcinoma cell line), in addition to VEGFR-2 enzyme inhibition activity. Compounds VIId, VIIIa, VIIIc, VIIIe and XVa exhibited promising activity against the tested cell lines and weak activity against VEGFR-2. Compound VIIIc induced a significant disruption in the cell cycle profile and cell cycle arrest at the G2/M phase boundary. In further assays, the cytotoxic effect of the highly active compounds was determined using a normal Caucasian fibroblast-like fetal lung cell line (WI-38). Compound VIIIc could be considered as a lead compound that merits further optimization and development as an anti-cancer and an apoptotic inducing candidate against the HCT116 cell line. Full article

(This article belongs to the Section Medicinal Chemistry)

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9 pages, 1666 KiB

Open AccessCommunication

Halogen-Substituted Triazolethioacetamides as a Potent Skeleton for the Development of Metallo-β-Lactamase Inhibitors

by Yilin Zhang, Yong Yan, Lufan Liang, Jie Feng, Xuejun Wang, Li Li and Kewu Yang

Molecules 2019, 24(6), 1174; https://doi.org/10.3390/molecules24061174 - 25 Mar 2019

Cited by 9 | Viewed by 3213

Abstract

Metallo-β-lactamases (MβLs) are the target enzymes of β-lactam antibiotic resistance, and there are no effective inhibitors against MβLs available for clinic so far. In this study, thirteen halogen-substituted triazolethioacetamides were designed and synthesized as a potent skeleton of MβLs inhibitors. All the compounds [...] Read more.

Metallo-β-lactamases (MβLs) are the target enzymes of β-lactam antibiotic resistance, and there are no effective inhibitors against MβLs available for clinic so far. In this study, thirteen halogen-substituted triazolethioacetamides were designed and synthesized as a potent skeleton of MβLs inhibitors. All the compounds displayed inhibitory activity against ImiS with an IC₅₀ value range of 0.032–15.64 μM except 7. The chlorine substituted compounds (1, 2 and 3) inhibited NDM-1 with an IC₅₀ value of less than 0.96 μM, and the fluorine substituted 12 and 13 inhibited VIM-2 with IC₅₀ values of 38.9 and 2.8 μM, respectively. However, none of the triazolethioacetamides exhibited activity against L1 at inhibitor concentrations of up to 1 mM. Enzyme inhibition kinetics revealed that 9 and 13 are mixed inhibitors for ImiS with K_i values of 0.074 and 0.27μM using imipenem as the substrate. Docking studies showed that 1 and 9, which have the highest inhibitory activity against ImiS, fit the binding site of CphA as a replacement of ImiS via stable interactions between the triazole group bridging ASP120 and hydroxyl group bridging ASN233. Full article

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16 pages, 5768 KiB

Open AccessArticle

Synthesis, Evaluation, and Mechanism Study of New Tepotinib Derivatives as Antiproliferative Agents

by Niu-niu Zhang, Bai-jiao An, Yan Zhou, Xing-shu Li and Ming Yan

Molecules 2019, 24(6), 1173; https://doi.org/10.3390/molecules24061173 - 25 Mar 2019

Cited by 5 | Viewed by 5889

Abstract

Inspired by the potent inhibition activity of the c-Met (mesenchymal−epithelial transition factor) inhibitor Tepotinib, a series of new Tepotinib derivatives were synthesized and evaluated for their ability to act as antiproliferative agents to find the leading compounds with good activity and limited side [...] Read more.

Inspired by the potent inhibition activity of the c-Met (mesenchymal−epithelial transition factor) inhibitor Tepotinib, a series of new Tepotinib derivatives were synthesized and evaluated for their ability to act as antiproliferative agents to find the leading compounds with good activity and limited side effects. Among them, compound 31e exhibited potent antiproliferative activity (IC₅₀ (50% inhibitory concentration) = 0.026 μΜ) against hepatic carcinoma 97H (human liver cancer cell) cells and, importantly, had very low inhibitory activity against normal cells. A mechanism study demonstrated that 31e induced G1 phase (First growth phase or G indicating gap) arrest, inhibited the phosphorylation of c-Met and its downstream signaling component, Akt (Protein Kinase B), and also inhibited the migration of hepatic carcinoma 97H cells. Full article

(This article belongs to the Collection Efficient Pharmaceutical and Chemical Approaches for Anticancer Therapy: Design, Preliminary Evaluations, and Further Developments)

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16 pages, 1248 KiB

Open AccessArticle

Speciation of Chromium in Alkaline Soil Extracts by an Ion-Pair Reversed Phase HPLC-ICP MS Method

by Barbara Leśniewska and Beata Godlewska-Żyłkiewicz

Molecules 2019, 24(6), 1172; https://doi.org/10.3390/molecules24061172 - 25 Mar 2019

Cited by 16 | Viewed by 4295

Abstract

The aim of this work was to study by a hyphenated HPLC-ICP MS technique the chromium species released during alkaline extraction of various soils collected from a contaminated area of an old tannery. An ultrasound-assisted extraction procedure using 0.1 mol L⁻¹ Na [...] Read more.

The aim of this work was to study by a hyphenated HPLC-ICP MS technique the chromium species released during alkaline extraction of various soils collected from a contaminated area of an old tannery. An ultrasound-assisted extraction procedure using 0.1 mol L⁻¹ Na₂CO₃ solution was developed for the release of chromium species from the soil. The chromium species in the soil extracts were separated on a C₈ column using EDTA and TBAH solution as a mobile phase. The use of an ICP-QQQ MS spectrometer in tandem mass configuration (MS/MS) combined with an octopole reaction system (ORS³) pressurized with helium allows one to eliminate spectral interferences during Cr determination in the soil extracts. The detection limit of the procedure was 0.08 µg L⁻¹ for Cr(III) and 0.09 µg L⁻¹ for Cr(VI) species. The trueness of the IP RP HPLC-ICP MS method was proved by an analysis of CRM 041 and CRM 060. The advantage of the proposed method is the analysis of soil extracts without their preliminary neutralization, which limits the losses of Cr(VI) due to the reduction process. The analysed soils mainly contained chromium in immobile forms (94.6–98.5% of the total Cr content). In all alkaline soil extracts mostly the Cr(VI) form was found, but in the extract of organic soils Cr(III) was also present. This arose from the reduction of Cr(VI) species by organic matter (humic acids) and Fe(II). The amount of formed Cr(III) species was dependent on the type of soil (content of organic matter, Mn and Fe) and its moistness. For the first time, the presence of neutral and non-polar chromium fractions in the soil extracts was also demonstrated. It was found that reliable speciation analysis results could be obtained for mineral soils. Full article

(This article belongs to the Special Issue Trends in Environmental Analytical Chemistry)

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16 pages, 1116 KiB

Open AccessArticle

Two Approaches for Evaluating the Effects of Galangin on the Activities and mRNA Expression of Seven CYP450

by Yin-Ling Ma, Feng Zhao, Jin-Tuo Yin, Cai-Juan Liang, Xiao-Li Niu, Zhi-Hong Qiu and Lan-Tong Zhang

Molecules 2019, 24(6), 1171; https://doi.org/10.3390/molecules24061171 - 25 Mar 2019

Cited by 24 | Viewed by 4108

Abstract

Galangin is a marker compound of honey and Alpinia officinarum Hance that exhibits great potential for anti-microbial, anti-diabetic, anti-obesity, anti-tumour and anti-inflammatory applications. Galangin is frequently consumed in combination with common clinical drugs. Here, we evaluated the effects of galangin on cytochrome P450 [...] Read more.

Galangin is a marker compound of honey and Alpinia officinarum Hance that exhibits great potential for anti-microbial, anti-diabetic, anti-obesity, anti-tumour and anti-inflammatory applications. Galangin is frequently consumed in combination with common clinical drugs. Here, we evaluated the effects of galangin on cytochrome P450 (CYP)-mediated metabolism, using two different approaches, to predict drug–drug interactions. Male Sprague Dawley rats were administered galangin daily for 8 weeks. A “cocktail-probes” approach was employed to evaluate the activities of different CYP450 enzymes. Blood samples of seven probe drugs were analysed using liquid chromatography-tandem mass spectrometry in positive and negative electrospray-ionisation modes. Pharmacokinetic parameters were calculated to identify statistical differences. CYP mRNA-expression levels were investigated in real-time quantitative polymerase chain reaction experiments. The galangin-treated group showed significantly decreased AUC_0–∞ and C_max values for CYP1A2, and CYP2B3. The galangin-treated group showed significantly increased AUC_0–∞ and C_max values for CYP2C13 and CYP3A1. No significant influences were observed in the pharmacokinetic profiles of CYP2C11, CYP2D4 and CYP2E1. The mRNA-expression results were consistent with the pharmacokinetic results. Thus, CYP450 enzyme activities may be altered by long-term galangin administration, suggesting galangin to be a promising candidate molecule for enhancing oral drug bioavailability and chemoprevention and reversing multidrug resistance. Full article

(This article belongs to the Special Issue Method Development and Validation in Food and Pharmaceutical Analysis)

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11 pages, 2221 KiB

Open AccessArticle

Antineuroinflammatory Activities and Neurotoxicological Assessment of Curcumin Loaded Solid Lipid Nanoparticles on LPS-Stimulated BV-2 Microglia Cell Models

by Palanivel Ganesan, Byungwook Kim, Prakash Ramalingam, Govindarajan Karthivashan, Vishnu Revuri, Shinyoung Park, Joon Soo Kim, Young Tag Ko and Dong-Kug Choi

Molecules 2019, 24(6), 1170; https://doi.org/10.3390/molecules24061170 - 25 Mar 2019

Cited by 36 | Viewed by 6571

Abstract

Curcumin, which is a potential antineuroinflammatory and neuroprotective compound, exhibits poor bioavailability in brain cells due to its difficulty in crossing the blood–brain barrier and its rapid metabolism during circulation, which decreases its efficacy in treating chronic neuroinflammatory diseases in the central nervous [...] Read more.

Curcumin, which is a potential antineuroinflammatory and neuroprotective compound, exhibits poor bioavailability in brain cells due to its difficulty in crossing the blood–brain barrier and its rapid metabolism during circulation, which decreases its efficacy in treating chronic neuroinflammatory diseases in the central nervous system. The bioavailability and potential of curcumin can be improved by using a nanodelivery system, which includes solid lipid nanoparticles. Curcumin-loaded solid lipid nanoparticles (SLCN) were efficiently developed to have a particle size of about 86 nm and do not exhibit any toxicity in the endothelial brain cells. Furthermore, the curcumin-loaded solid lipid nanoparticles (SLCN) were studied to assess their efficacy in BV-2 microglial cells against LPS-induced neuroinflammation. The SLCN showed a higher inhibition of nitric oxide (NO) production compared to conventional curcumin in a dose-dependent manner. Similarly, the mRNA and proinflammatory cytokine levels were also reduced in a dose-dependent manner when compared to those with free curcumin. Thus, SLCN could be a potential delivery system for curcumin to treat microglia-mediated neuroinflammation. Full article

(This article belongs to the Special Issue Role of Natural Compounds in Inflammation and Inflammatory-Related Diseases)

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14 pages, 2073 KiB

Open AccessArticle

Density Functional Theory Investigations on the Mechanism of Formation of Pa(V) Ion in Hydrous Solutions

by Jun Ma, Chuting Yang, Jun Han, Jie Yu, Sheng Hu, Haizhu Yu and Xinggui Long

Molecules 2019, 24(6), 1169; https://doi.org/10.3390/molecules24061169 - 25 Mar 2019

Cited by 2 | Viewed by 2943

Abstract

Due to the enormous threat of protactinium to the environment and human health, its disposal and chemistry have long been important topics in nuclear science. [PaO(H₂O)₆]³⁺ is proposed as the predominant species in hydrous and acidic solutions, but [...] Read more.

Due to the enormous threat of protactinium to the environment and human health, its disposal and chemistry have long been important topics in nuclear science. [PaO(H₂O)₆]³⁺ is proposed as the predominant species in hydrous and acidic solutions, but little is known about its formation mechanism. In this study, density functional theory (DFT) calculations demonstrate a water coordination-proton transfer-water dissociation mechanism for the formation of PaO³⁺ in hydrous solutions. First, Pa(V) ion preferentially forms hydrated complexes with a coordination number of 10. Through hydrogen bonding, water molecules in the second coordination sphere easily capture two protons on the same coordinated H₂O ligand to form [PaO(H₂O)₉]³⁺. Water dissociation then occurs to generate the final [PaO(H₂O)₆]³⁺, which is the thermodynamic product of Pa(V) in hydrous solutions. Full article

(This article belongs to the Section Computational and Theoretical Chemistry)

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13 pages, 2926 KiB

Open AccessArticle

Anti-Fatigue Activity of Aqueous Extracts of Sonchus arvensis L. in Exercise Trained Mice

by Tian Yuan, Di Wu, Keyu Sun, Xintong Tan, Jia Wang, Tong Zhao, Bo Ren, Beita Zhao, Zhigang Liu and Xuebo Liu

Molecules 2019, 24(6), 1168; https://doi.org/10.3390/molecules24061168 - 25 Mar 2019

Cited by 31 | Viewed by 6178

Abstract

Sonchus arvensis L. is a nutritious vegetable and herbal medicine that is consumed worldwide. The aim of this study was to evaluate the anti-fatigue effects and underlying effects of aqueous extract of Sonchus arvensis L. (SA). Male C57BL/6 mice from four groups designated [...] Read more.

Sonchus arvensis L. is a nutritious vegetable and herbal medicine that is consumed worldwide. The aim of this study was to evaluate the anti-fatigue effects and underlying effects of aqueous extract of Sonchus arvensis L. (SA). Male C57BL/6 mice from four groups designated vehicle, exercise, exercise with low dose (250 mg/kg) or high dose of SA (500 mg/kg), were trained by swimming exercise and orally administrated with SA every other day for 28 days. The anti-fatigue activity was determined by exhaustive swimming test, as well as the muscle structure, levels of blood hemoglobin, and metabolites including lactate and urea nitrogen. SA alleviated mice fatigue behaviors by eliminating metabolites, while improving muscle structure and hemoglobin levels. Moreover, SA enhanced glycogen synthesis of liver but not muscle via increasing GCK and PEPCK gene expressions. Importantly, SA improved antioxidant enzymes expression and activities in both liver and muscle, which was possibly related to its primary components polysaccharides and the antioxidant components including chlorogenic acid, luteolin, and chicoric acid. Taken together, the anti-fatigue effects of SA could be partly explained by its antioxidant activity and mediating effects on glycogen synthesis and metabolites elimination. Therefore, SA could be a potential nutraceutical for improving exercise performance and alleviating physical fatigue. Full article

(This article belongs to the Special Issue Natural Products Used as Foods and Food Ingredients)

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17 pages, 1861 KiB

Open AccessReview

Contributions of Mass Spectrometry to the Identification of Low Molecular Weight Molecules Able to Reduce the Toxicity of Amyloid-β Peptide to Cell Cultures and Transgenic Mouse Models of Alzheimer’s Disease

by Raluca Ştefănescu, Gabriela Dumitriṭa Stanciu, Andrei Luca, Ioana Cezara Caba, Bogdan Ionel Tamba and Cosmin Teodor Mihai

Molecules 2019, 24(6), 1167; https://doi.org/10.3390/molecules24061167 - 24 Mar 2019

Cited by 24 | Viewed by 8887

Abstract

Alzheimer’s Disease affects approximately 33 million people worldwide and is characterized by progressive loss of memory at the cognitive level. The formation of toxic amyloid oligomers, extracellular amyloid plaques and amyloid angiopathy in brain by amyloid beta peptides are considered a part of [...] Read more.

Alzheimer’s Disease affects approximately 33 million people worldwide and is characterized by progressive loss of memory at the cognitive level. The formation of toxic amyloid oligomers, extracellular amyloid plaques and amyloid angiopathy in brain by amyloid beta peptides are considered a part of the identified mechanism involved in disease pathogenesis. The optimal treatment approach leads toward finding a chemical compound able to form a noncovalent complex with the amyloid peptide thus blocking the process of amyloid aggregation. This direction gained an increasing interest lately, many studies demonstrating that mass spectrometry is a valuable method useful for the identification and characterization of such molecules able to interact with amyloid peptides. In the present review we aim to identify in the scientific literature low molecular weight chemical compounds for which there is mass spectrometric evidence of noncovalent complex formation with amyloid peptides and also there are toxicity reduction results which verify the effects of these compounds on amyloid beta toxicity towards cell cultures and transgenic mouse models developing Alzheimer’s Disease. Full article

(This article belongs to the Special Issue Mass Spectroscopy in Chemical Biology)

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12 pages, 845 KiB

Open AccessArticle

Determination of Urinary Pterins by Capillary Electrophoresis Coupled with LED-Induced Fluorescence Detector

by Wojciech Grochocki, Magdalena Buszewska-Forajta, Szymon Macioszek and Michał J. Markuszewski

Molecules 2019, 24(6), 1166; https://doi.org/10.3390/molecules24061166 - 24 Mar 2019

Cited by 9 | Viewed by 3673

Abstract

Urinary pterins have been found as potential biomarkers in many pathophysiological conditions including inflammation, viral infections, and cancer. However, pterins determination in biological samples is difficult due to their degradation under exposure to air, light, and heat. Besides, they occur at shallow concentration [...] Read more.

Urinary pterins have been found as potential biomarkers in many pathophysiological conditions including inflammation, viral infections, and cancer. However, pterins determination in biological samples is difficult due to their degradation under exposure to air, light, and heat. Besides, they occur at shallow concentration levels, and thus, standard UV detectors cannot be used without additional sample preconcentration. On the other hand, ultra-sensitive laser-induced fluorescence (LIF) detection can be used since pterins exhibit native fluorescence. The main factor that limits an everyday use of LIF detectors is its high price. Here, an alternative detector, i.e., light-emitted diode induced fluorescence (LEDIF) detector, was evaluated for the determination of pterins in urine samples after capillary electrophoresis (CE) separation. An optimized method was validated in terms of linearity range, limit of detection (LOD), limit of quantification (LOQ), intra- and interday precision and accuracy, sample stability in the autosampler, and sample stability during the freezing/thawing cycle. The obtained LOD (0.1 µM) and LOQ (0.3 µM) values were three-order of magnitude lower compared to UV detector, and two orders of magnitude higher compared to previously reported house-built LIF detector. The applicability of the validated method was demonstrated in the analysis of urine samples from healthy individuals and cancer patients. Full article

(This article belongs to the Special Issue Analysis of Xenobiotics and their Residues in Food, Biological and Environmental Samples by Chromatographic Techniques Coupled with Modern Detection Techniques (DAD, FLD, MS, MS/MS))

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19 pages, 2396 KiB

Open AccessArticle

Bactericidal and Anti-Biofilm Activity of Ethanol Extracts Derived from Selected Medicinal Plants against Streptococcus pyogenes

by Niluni M. Wijesundara and H. P. Vasantha Rupasinghe

Molecules 2019, 24(6), 1165; https://doi.org/10.3390/molecules24061165 - 24 Mar 2019

Cited by 32 | Viewed by 8107

Abstract

Background: There is a growing interest in medicinal plants which have been traditionally used for the treatment of human infections. This study assessed 14 ethanol extracts (EEs) on bacterial growth and biofilm formation of Streptococcus pyogenes. Methods: Constituent major phytochemicals in the [...] Read more.

Background: There is a growing interest in medicinal plants which have been traditionally used for the treatment of human infections. This study assessed 14 ethanol extracts (EEs) on bacterial growth and biofilm formation of Streptococcus pyogenes. Methods: Constituent major phytochemicals in the extracts were identified using ultra performance liquid chromatography-electrospray ionization-tandem mass spectrometry (UPLC-ESI-MS/MS). Micro-broth dilution and time-kill assays were used to determine antibacterial activities. Anti-biofilm activities were studied using MTT assay, and morphology of biofilms was observed by scanning electron microscopy (SEM). Transmission electron microscopy (TEM) was employed to visualize the ultra-cross section structure of bacteria treated with efficacious extracts. Results: Licorice root, purple coneflower flower, purple coneflower stem, sage leaves and slippery elm inner bark EEs were the most effective, with minimum inhibitory concentrations (MIC) and minimum bactericidal concentrations (MBC) of 62.5 μg/mL and 125 μg/mL, respectively. The minimum biofilm inhibitory concentration (MBIC) of extracts ranged from 31.5–250 μg/mL. Morphological changes were observed in treated biofilms compared to the untreated. The four most effective extracts exhibited the ability to induce degradation of bacterial cell wall and disintegration of the plasma membrane. Conclusion: We suggest that EEs of sage leaf and purple coneflower flower are promising candidates to be further investigated for developing alternative natural therapies for the management of streptococcal pharyngitis. Full article

(This article belongs to the Special Issue Recent Advances in Food Chemistry and Microbiology in Relation to Health)

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18 pages, 4772 KiB

Open AccessArticle

Synthesis of AMPSA Polymeric Derivatives Monitored by Electrical Conductivity and Evaluation of Thermosensitive Properties of Resulting Microspheres

by Agnieszka Gola, Magdalena Sacharczuk and Witold Musiał

Molecules 2019, 24(6), 1164; https://doi.org/10.3390/molecules24061164 - 23 Mar 2019

Cited by 7 | Viewed by 3211

Abstract

Four stimuli-responsive polymers of N-isopropylacrylamide (NIPA) and 2-acrylamido-2-methyl-1-propanesulfonic acid (AMPSA) and crosslinked derivatives by N,N′-methylene bisacrylamide (MBA) were synthesized: PNA, PAMPSA, PNAM, PAMPSAM. The effect of the cross-linker and methyl sulphonic acid (-CH₃-SO₃H) group on particle size, [...] Read more.

Four stimuli-responsive polymers of N-isopropylacrylamide (NIPA) and 2-acrylamido-2-methyl-1-propanesulfonic acid (AMPSA) and crosslinked derivatives by N,N′-methylene bisacrylamide (MBA) were synthesized: PNA, PAMPSA, PNAM, PAMPSAM. The effect of the cross-linker and methyl sulphonic acid (-CH₃-SO₃H) group on particle size, aggregation and volume phase transition temperature (VPTT) was investigated. Polymeric particles were synthesized via the surfactant free precipitation polymerization (SFPP) at 70 °C in the presence of cationic initiator 2,2′-azobis[2-methylpropionamidine] dihydrochloride (AMP) system. Chemical composition and morphology of investigated samples were evaluated using ATR-FTIR spectroscopy, ¹H-NMR spectrometry and SEM-EDS techniques. The hydrodynamic diameters (HD), zeta potential (ZP), and polydispersity index (PDI) in aqueous dispersions were assessed by dynamic light scattering (DLS) between 18–42 °C. HD values at 18 °C for PNA, PAMPSA, PNAM, PAMPSAM polymers were approx. 32, 730, 715, 665 nm, and ZP values were −1.36, −0.01, 8.90, −0.09 mV, respectively. The VPTT range was observed between 29 and 41 °C. PDI’s for PNA and PNAM were low and varied between 0.276 and 0.460, and between 0.119 and 0.056, respectively. PAMPSA and PAMPSAM were characterized by higher PDI in the range 0.728–0.959 and 0.658–0.836, respectively. The results confirmed the thermal sensitivity of the synthesized polymers and indicated a significant polydispersity and aggregation tendency of the resulting molecules. The conductivity results were applied for the interpretation of the polymerization process. Full article

(This article belongs to the Special Issue Stimuli-Responsive Polymeric Materials)

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8 pages, 2088 KiB

Open AccessArticle

Non-Isothermal Sublimation Kinetics of 2,4,6-Trinitrotoluene (TNT) Nanofilms

by Walid M. Hikal and Brandon L. Weeks

Molecules 2019, 24(6), 1163; https://doi.org/10.3390/molecules24061163 - 23 Mar 2019

Cited by 2 | Viewed by 2932

Abstract

Non-isothermal sublimation kinetics of low-volatile materials is more favorable over isothermal data when time is a crucial factor to be considered, especially in the subject of detecting explosives. In this article, we report on the in-situ measurements of the sublimation activation energy for [...] Read more.

Non-isothermal sublimation kinetics of low-volatile materials is more favorable over isothermal data when time is a crucial factor to be considered, especially in the subject of detecting explosives. In this article, we report on the in-situ measurements of the sublimation activation energy for 2,4,6-trinitrotoluene (TNT) continuous nanofilms in air using rising-temperature UV-Vis absorbance spectroscopy at different heating rates. The TNT films were prepared by the spin coating deposition technique. For the first time, the most widely used procedure to determine sublimation rates using thermogravimetry analysis (TGA) and differential scanning calorimetry (DSC) was followed in this work using UV-Vis absorbance spectroscopy. The sublimation kinetics were analyzed using three well-established calculating techniques. The non-isothermal based activation energy values using the Ozawa, Flynn–Wall, and Kissinger models were 105.9 ± 1.4 kJ mol⁻¹, 102.1 ± 2.7 kJ mol⁻¹, and 105.8 ± 1.6 kJ mol⁻¹, respectively. The calculated activation energy agreed well with our previously reported isothermally-measured value for TNT nanofilms using UV-Vis absorbance spectroscopy. The results show that the well-established non-isothermal analytical techniques can be successfully applied at a nanoscale to determine sublimation kinetics using absorbance spectroscopy. Full article

(This article belongs to the Special Issue Thermal Analysis Kinetics for Understanding Materials Behavior)

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19 pages, 2939 KiB

Open AccessArticle

Discovery of 2-Substituted 3-Arylquinoline Derivatives as Potential Anti-Inflammatory Agents Through Inhibition of LPS-Induced Inflammatory Responses in Macrophages

by Cheng-Yao Yang, Yung-Li Hung, Kai-Wei Tang, Shu-Chi Wang, Chih-Hua Tseng, Cherng-Chyi Tzeng, Po-Len Liu, Chia-Yang Li and Yeh-Long Chen

Molecules 2019, 24(6), 1162; https://doi.org/10.3390/molecules24061162 - 23 Mar 2019

Cited by 17 | Viewed by 3587

Abstract

We describe herein the preparation of certain 2-substituted 3-arylquinoline derivatives and the evaluation of their anti-inflammatory effects in LPS-activated murine J774A.1 macrophage cells. Among these newly synthesized 2-substituted 3-arylquinoline derivatives, 2-(4-methoxy- benzoyl)-3-(3,4,5-trimethoxyphenyl)quinoline (18a) and 2-(4-fluorobenzoyl)-3-(3,4,5-trimethoxy- phenyl)quinoline (18b) are two [...] Read more.

We describe herein the preparation of certain 2-substituted 3-arylquinoline derivatives and the evaluation of their anti-inflammatory effects in LPS-activated murine J774A.1 macrophage cells. Among these newly synthesized 2-substituted 3-arylquinoline derivatives, 2-(4-methoxy- benzoyl)-3-(3,4,5-trimethoxyphenyl)quinoline (18a) and 2-(4-fluorobenzoyl)-3-(3,4,5-trimethoxy- phenyl)quinoline (18b) are two of the most active compounds which can inhibit the production of NO at non-cytotoxic concentrations. Our results have also indicated that compounds 18a and 18b significantly decrease the secretion of pro-inflammatory cytokines (TNF-á and IL-6), inhibit the expression of iNOS, suppress the phosphorylation of MAPKs, and attenuate the activity of NF-êB by LPS-activated macrophages. Through molecular docking analysis, we found that 18b could fit into the middle of the TNF-á dimer and form hydrophobic interactions with Leu55, Leu57 chain A and B, Tyr59, Val123 chain B and D, Ile 155. These results suggest that both 18a and 18b are potential lead compounds in inhibiting LPS-induced inflammatory responses. Further structural optimization to discover novel anti-inflammatory agents is ongoing. Full article

(This article belongs to the Section Medicinal Chemistry)

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12 pages, 502 KiB

Open AccessArticle

Antibacterial and Biofilm Inhibitory Activity of Medicinal Plant Essential Oils Against Escherichia coli Isolated from UTI Patients

by Rihab Lagha, Fethi Ben Abdallah, Badriah Osama AL-Sarhan and Yassin Al-Sodany

Molecules 2019, 24(6), 1161; https://doi.org/10.3390/molecules24061161 - 23 Mar 2019

Cited by 87 | Viewed by 10005

Abstract

Urinary tract infections (UTIs), caused by Escherichia coli 80% to 85% of the time, are one of the most important causes of morbidity and health care spending affecting persons of all ages. These infections lead to many difficult problems, especially increasing resistance to [...] Read more.

Urinary tract infections (UTIs), caused by Escherichia coli 80% to 85% of the time, are one of the most important causes of morbidity and health care spending affecting persons of all ages. These infections lead to many difficult problems, especially increasing resistance to antibiotic drugs. Bacterial biofilms play an important role in UTIs, responsible for persistent infections leading to recurrences and relapses. In this study, we have investigated the antibacterial activity of five medicinal plant essential oils against UTIs caused by E. coli using disc diffusion and minimal inhibition concentration (MIC) methods. In addition, biofilm inhibitory action of oils was realized by crystal violet. Gas chromatography–mass spectrometry (GC–MS) analysis showed a variability between oils in terms of compound numbers as well as their percentages. Antibacterial activity was observed only in cases of Origanum majorana, Thymus zygis and Rosmarinus officinalis, while Juniperus communis and Zingiber officinale did not showed any effect towards E. coli isolates. T. zygis essential oil demonstrated the highest antibacterial activity against E. coli isolates, followed by O. majorana and R. officinalis. Further, oils showed high biofilm inhibitory action with a percentage of inhibition that ranged from 14.94% to 94.75%. R. officinalis oil had the highest antibiofilm activity followed by T. zygis and O. majorana. Accordingly, tested oils showed very effective antibacterial and antibiofilm activities against E. coli UTIs and can be considered as good alternative for antibiotics substitution. Full article

(This article belongs to the Special Issue Antimicrobial Properties of Natural Products)

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