bluuebunny/crossref_metadata_2025 huggingface dataset:
Zebrafish-Based Discovery of Antiseizure Compounds from the North Sea: Isoquinoline Alkaloids TMC-120A and TMC-120B
Authors: Copmans Daniëlle , Kildgaard Sara , Rasmussen Silas A. , Ślęzak Monika , Dirkx Nina , Partoens Michèle , Esguerra Camila V. , Crawford Alexander D. , Larsen Thomas O. , de Witte Peter A. M.
Published: October 2019

There is a high need for the development of new and improved antiseizure drugs (ASDs) to treat epilepsy. Despite the potential of marine natural products (MNPs), the EU marine biodiscovery consortium PharmaSea has made the only effort to date to perform ASD discovery based on large-scale screening of MNPs. To this end, the embryonic zebrafish photomotor response assay and the larval zebrafish pentylenetetrazole (PTZ) model were used to screen MNP extracts for neuroactivity and antiseizure activity, respectively. Here we report the identification of the two known isoquinoline alkaloids TMC-120A and TMC-120B as novel antiseizure compounds, which were isolated by bioactivity-guided purification from the marine-derived fungus Aspergillus insuetus. TMC-120A and TMC-120B were observed to significantly lower PTZ-induced seizures and epileptiform brain activity in the larval zebrafish PTZ seizure model. In addition, their structural analogues TMC-120C, penicisochroman G, and ustusorane B were isolated and also significantly lowered PTZ-induced seizures. Finally, TMC-120A and TMC-120B were investigated in a mouse model of drug-resistant focal seizures. Compound treatment significantly shortened the seizure duration, thereby confirming their antiseizure activity. These data underscore the possibility to translate findings in zebrafish to mice in the field of epilepsy and the potential of the marine environment for ASD discovery.
Premature Ejaculation: Aetiology and Treatment Strategies
Authors: Gillman Nicholas , Gillman Michael
Published: October 2019

Premature ejaculation (PE) is a highly prevalent male sexual dysfunction that is often neglected, presenting a currently unmet therapeutic need. The classification of PE has historically been varied and at times ambiguous, contributing to inaccurate prevalence estimates. This review uses the International Society for Sexual Medicine (ISSM) definition of PE, which includes reduced ejaculatory latency, lack of control and associated negative personal consequences. Patient assessment and management options differ depending on the classification of PE and it is the role of the clinician to appropriately classify patients and be aware of the correct management strategies. This review provides an overall background of PE in terms of classification and underlying physiology, patient assessment and management strategies along with the scientific rationale for treatment. Patients with lifelong and acquired PE are most likely to benefit from combination therapy of pharmacological treatment in the form of selective serotonin re-uptake inhibitor dapoxetine, psychosexual behavioural therapy and psychological therapy.
Advanced Heat Treatments and Complex Ferritic Structures for Bearing Steels
Authors: G. Caballero Francisca , Pujante Jaume , Sourmail Thomas , Rementeria Rosalia , De-Castro David , Dierickx Pierre , Ramírez Giselle , Sidoroff-Coicaud Christine , Valizadeh Moghaddam Pouria , Vuorinen Esa
Published: October 2019

Nanostructured bainitic steels exhibit an optimum strength/toughness combination as a consequence of their extremely fine structure. They have also demonstrated potential for wear-resistance applications. The aim of this work was to develop bearing steels by the multi-scale control of complex ferritic structures, designed using atomic transformation theory and processed by novel heat treatments. Based on the results, the new ball bearings outperformed conventional grades, approaching more expensive material options.
Process-Structure-Properties-Performance Modeling for Selective Laser Melting
Authors: Pinomaa Tatu , Yashchuk Ivan , Lindroos Matti , Andersson Tom , Provatas Nikolas , Laukkanen Anssi
Published: October 2019

Selective laser melting (SLM) is a promising manufacturing technique where the part design, from performance and properties process control and alloying, can be accelerated with integrated computational materials engineering (ICME). This paper demonstrates a process-structure-properties-performance modeling framework for SLM. For powder-bed scale melt pool modeling, we present a diffuse-interface multiphase computational fluid dynamics model which couples Navier–Stokes, Cahn–Hilliard, and heat-transfer equations. A computationally efficient large-scale heat-transfer model is used to describe the temperature evolution in larger volumes. Phase field modeling is used to demonstrate how epitaxial growth of Ti-6-4 can be interrupted with inoculants to obtain an equiaxed polycrystalline structure. These structures are enriched with a synthetic lath martensite substructure, and their micromechanical response are investigated with a crystal plasticity model. The fatigue performance of these structures are analyzed, with spherical porelike defects and high-aspect-ratio cracklike defects incorporated, and a cycle-amplitude fatigue graph is produced to quantify the fatigue behavior of the structures. The simulated fatigue life presents trends consistent with the literature in terms of high cycle and low cycle fatigue, and the role of defects in dominating the respective performance of the produced SLM structures. The proposed ICME workflow emphasizes the possibilities arising from the vast design space exploitable with respect to manufacturing systems, powders, respective alloy chemistries, and microstructures. By digitalizing the whole workflow and enabling a thorough and detailed virtual evaluation of the causal relationships, the promise of product-targeted materials and solutions for metal additive manufacturing becomes closer to practical engineering application.
The Effects of Various Metallic Surfaces on Cellular and Bacterial Adhesion
Authors: Shimabukuro Masaya , Ito Haruka , Tsutsumi Yusuke , Nozaki Kosuke , Chen Peng , Yamada Risa , Ashida Maki , Nagai Akiko , Hanawa Takao
Published: October 2019

The effects of Ti, Nb, Ta, Zr, and Ag on cellular and bacterial adhesion were investigated in this study. Moreover, the relationships between surface compositions, metal ion release behaviors, and biological responses were examined. As a result, MC3T3-E1 cells and S. aureus were able to better attach to Ti and Zr rather than the Nb and Ta specimens. For the Ag specimen, the amount of Ag ions released into Hanks’ solution was the largest among all the specimens. Cellular and bacterial adhesion onto the Ag specimen was inhibited compared with the other specimens, because of Ag ion release. Alternatively, Nb and Ta specimens exhibited specific biological responses. Cellular adhesion on Nb and Ta specimens was similar to that on Ti, while bacterial adhesion on Nb and Ta specimens was inhibited compared with that on Ti. This study proved that Nb and Ta inhibited bacterial adhesion and exhibited no harmful effects on cellular adhesion. In addition, these results indicate that the passive layer on Nb and Ta plays a key role in the inhibition of bacterial adhesion.
Constitutive Equation of GH4169 Superalloy and Microstructure Evolution Simulation of Double-Open Multidirectional Forging
Authors: Jin Yongbo , Xue Hao , Yang Zheyi , Zhang Lili , Zhang Chunxiang , Wang Sirui , Luo Junting
Published: October 2019

This paper presented a double-open multidirectional forging with relatively few deformation passes and a uniform deformation. The constitutive equation and dynamic recrystallization model of the GH4169 superalloy were identified based on a thermal compression test and imported into Deform simulation software. The microstructure evolution law of GH4169 superalloy undergoing double-open multidirectional forging was simulated. The evolution of the recrystallization volume fraction and recrystallized grain size of the GH4169 superalloy during double-open multidirectional forging was obtained. Both higher temperatures and more passes were found to produce more complete recrystallization and smaller recrystallization grain size. At the maximum temperature studied, 1000 °C, with nine passes, the recrystallization volume fraction exceeded 95%, and the recrystallized grain size reached 3–5.5 µm.
Neuroprotective Effect of Cyperi rhizome against Corticosterone-Induced PC12 Cell Injury via Suppression of Ca2+ Overloading
Authors: Jia Hongmei , Liu Yang , Yu Meng , Shang Hai , Zhang Hongwu , Ma Liyan , Zhang Tao , Zou Zhongmei
Published: October 2019

Cyperi Rhizoma (CR) is a well-known functional food and traditional herbal medicine in Asian countries for the treatment of menstrual or emotional disturbances in women. Recent studies have shown the pharmacological effects of CR on neuronal diseases, such as Parkinson’s disease (PD) and depression. Thus, the neuroprotective effect of CR might play a vital role in exerting its effect. Here, corticosterone-induced PC12 cells were applied to screen the active fraction of CR and evaluate its neuroprotective effect. The results indicated that the fraction containing medium-polarity chemical constituents (CR-50E) displayed the best protection effect. CR-50E could increase the cell viability and reduce cell apoptosis through inhibiting oxidative stress and decreasing the lactate dehydrogenase LDH release induced by corticosterone. Further, the mechanism of action was explored by cell metabolomics. The result showed CR-50E mediated the sphingolipids metabolism of corticosterone-induced PC12 cells, which suggested inhibition of Ca2+ overloading may involve the protection of CR-50E against cell damage. The expression levels of three key proteins in calcium transport, including phospholipase A2 (PLA2), calcium/calmodulin independent protein kinase II (CaMK II), and caspase-3, confirmed the above result by Western blot. The findings suggest that CR-50E can suppress the disequilibrium of calcium homeostasis-mediated apoptosis by improving the abnormal sphingolipids metabolism as well as remedying the damage of the cell membrane.
Using Cerebral Metabolites to Guide Precision Medicine for Subarachnoid Hemorrhage: Lactate and Pyruvate
Authors: Zahra Kaneez , Gopal Neethu , Freeman William D. , Turnbull Marion T.
Published: October 2019

Subarachnoid hemorrhage (SAH) is one of the deadliest types of strokes with high rates of morbidity and permanent injury. Fluctuations in the levels of cerebral metabolites following SAH can be indicators of brain injury severity. Specifically, the changes in the levels of key metabolites involved in cellular metabolism, lactate and pyruvate, can be used as a biomarker for patient prognosis and tailor treatment to an individual’s needs. Here, clinical research is reviewed on the usefulness of cerebral lactate and pyruvate measurements as a predictive tool for SAH outcomes and their potential to guide a precision medicine approach to treatment.
Fabrication and Thermal Properties of Capric Acid/Calcinated Iron Tailings/Carbon Nanotubes Composite as Form-Stable Phase Change Materials for Thermal Energy Storage
Authors: Liu Peng , Gu Xiaobin , Zhang Zhikai , Shi Jianping , Rao Jun , Bian Liang
Published: October 2019

In this study, a novel form-stable phase change material (FSPCM) consisting of calcination iron tailings (CIT), capric acid (CA), and carbon nanotubes (CNT) was prepared using a simple direct melt impregnation method, and a series of tests have been carried out to investigate its properties. The leakage tests showed that CA can be retained in CIT with a mass fraction of about 20 wt.% without liquid leakage during the phase change process. Moreover, the morphology, chemical structure, and thermal properties of the fabricated composite samples were investigated. Scanning electron microscope (SEM) micrographs confirmed that CIT had a certain porous structure to confine CA in composites. According to the Fourier transformation infrared spectroscope (FTIR) results, the CA/CIT/CNT FSPCM had good chemical compatibility. The melting temperature and latent heat of CA/CIT/CNT by differential scanning calorimeter (DSC) were determined as 29.70 °C and 22.69 J/g, respectively, in which the mass fraction of CIT and CNT was about 80 wt.% and 5 wt.%, respectively. The thermal gravity analysis (TGA) revealed that the CA/CIT/CNT FSPCM showed excellent thermal stability above its working temperature. Furthermore, the melting and freezing time of CA/CIT/CNT FSPCM doped with 5 wt.% CNT reduced by 42.86% and 54.55% than those of pure CA, and it showed better heat transfer efficiency. Therefore, based on the above analyses, the prepared CA/CIT/CNT FSPCM is not only a promising candidate material for the application of thermal energy storage in buildings, but it also provides a new approach for recycling utilization of iron tailings.
Nano-Phase KNa(Si6Al2)O16 in Adularia: A New Member in the Alkali Feldspar Series with Ordered K–Na Distribution
Authors: Xu Huifang , Jin Shiyun , Lee Seungyeol , Hobbs Franklin
Published: October 2019

Alkali feldspars with diffuse reflections that violate C-centering symmetry were reported in Na-bearing adularia, orthoclase and microcline. TEM results indicate elongated nano-precipitates with intermediate composition of KNa(Si6Al2)O16 cause the diffuse reflections. Density functional theory (DFT) calculation indicates ordered distribution of K and Na atoms in the nano-phase with Pa symmetry. K and Na atoms are slightly off special positions for K atoms in the orthoclase structure. Formation of the intermediate nano-phase may lower the interface energy between the nano-phase and the host orthoclase. Previously reported P21/a symmetry was resulted from an artifact of overlapped diffraction spots from the nano-precipitates (Pa) and host orthoclase (C2/m). Adularia, orthoclase and microcline with the Pa nano-precipitates indicate very slow cooling of their host rocks at low temperature.
Competing Deformation Mechanisms in Periclase: Implications for Lower Mantle Anisotropy
Authors: Lin Feng , Couper Samantha , Jugle Mike , Miyagi Lowell
Published: October 2019

Seismic anisotropy is observed above the core-mantle boundary in regions of slab subduction and near the margins of Large Low Shear Velocity Provinces (LLSVPs). Ferropericlase is believed to be the second most abundant phase in the lower mantle. As it is rheologically weak, it may be a dominant source for anisotropy in the lowermost mantle. Understanding deformation mechanisms in ferropericlase over a range of pressure and temperature conditions is crucial to interpret seismic anisotropy. The effect of temperature on deformation mechanisms of ferropericlase has been established, but the effects of pressure are still controversial. With the aim to clarify and quantify the effect of pressure on deformation mechanisms, we perform room temperature compression experiments on polycrystalline periclase to 50 GPa. Lattice strains and texture development are modeled using the Elasto-ViscoPlastic Self Consistent method (EVPSC). Based on modeling results, we find that { 110 } ⟨ 1 1 ¯ 0 ⟩ slip is increasingly activated with higher pressure and is fully activated at ~50 GPa. Pressure and temperature have a competing effect on activities of dominant slip systems. An increasing { 100 } ⟨ 011 ⟩ : { 110 } ⟨ 1 1 ¯ 0 ⟩ ratio of slip activity is expected as material moves from cold subduction regions towards hot upwelling region adjacent to LLSVPs. This could explain observed seismic anisotropy in the circum-Pacific region that appears to weaken near margins of LLVSPs.
Synthesis of Trichodermin Derivatives and Their Antimicrobial and Cytotoxic Activities
Authors: Barúa Javier E. , de la Cruz Mercedes , de Pedro Nuria , Cautain Bastien , Hermosa Rosa , Cardoza Rosa E. , Gutiérrez Santiago , Monte Enrique , Vicente Francisca , Collado Isidro G.
Published: October 2019

Trichothecene mycotoxins are recognized as highly bioactive compounds that can be used in the design of new useful bioactive molecules. In Trichoderma brevicompactum, the first specific step in trichothecene biosynthesis is carried out by a terpene cyclase, trichodiene synthase, that catalyzes the conversion of farnesyl diphosphate to trichodiene and is encoded by the tri5 gene. Overexpression of tri5 resulted in increased levels of trichodermin, a trichothecene-type toxin, which is a valuable tool in preparing new molecules with a trichothecene skeleton. In this work, we developed the hemisynthesis of trichodermin and trichodermol derivatives in order to evaluate their antimicrobial and cytotoxic activities and to study the chemo-modulation of their bioactivity. Some derivatives with a short chain at the C-4 position displayed selective antimicrobial activity against Candida albicans and they showed MIC values similar to those displayed by trichodermin. It is important to highlight the cytotoxic selectivity observed for compounds 9, 13, and 15, which presented average IC50 values of 2 μg/mL and were cytotoxic against tumorigenic cell line MCF-7 (breast carcinoma) and not against Fa2N4 (non-tumoral immortalized human hepatocytes).
X-ray Photospectroscopy and Electronic Studies of Reactor Parameters on Photocatalytic Hydrogenation of Carbon Dioxide by Defect-Laden Indium Oxide Hydroxide Nanorods
Authors: Loh Joel Y. Y. , Kherani Nazir P.
Published: October 2019

In the study reported herein, glovebox-protected X-ray photoelectron spectroscopy (XPS) and in situ Hall charge carrier measurements provide new insights into the surface physical chemistry of gaseous H2, CO2, and H2+CO2 combined with nanostructured In2O(3−x)(OH)y nanorods, which ensue under photochemical and thermochemical operating conditions. Heterolytic dissociation of H2 in H2-only atmosphere appears to occur mainly under dark and ambient temperature conditions, while the greatest amount of OH shoulder expansion in H2+CO2 atmosphere appears to mainly occur under photoilluminated conditions. These results correlate with those of the Hall measurements, which show that the prevalence of homolytic over heterolytic dissociation at increasing temperatures leads to a steeper rate of increase in carrier concentrations; and that H2 adsorption is more prevalent than CO2 in H2+CO2 photoillumination conditions.
Enhanced Killing of Candida krusei by Polymorphonuclear Leucocytes in the Presence of Subinhibitory Concentrations of Melaleuca alternifolia and “Mentha of Pancalieri” Essential Oils
Authors: Tullio Vivian , Roana Janira , Scalas Daniela , Mandras Narcisa
Published: October 2019

The aim of this study was to evaluate the influence of tea tree oil (TTO) and “Mentha of Pancalieri” essential oil (MPP) on intracellular killing of Candida krusei, often resistant to conventional drugs, by polymorphonuclear leucocytes (PMNs). Intracellular killing was investigated by incubating yeasts and PMNs with essential oils (EOs) at 1/4 and 1/8 × MIC (Minimal Inhibitory Concentration), in comparison with anidulafungin, used as a reference drug. Killing values were expressed as Survival Index (SI) values. The cytotoxicity of EOs was evaluated by 3-[4,-5-dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay. Both EOs were more efficaceous at 1/8 × MIC than 1/4 × MIC, with killing values higher than observed in EO-free systems and in presence of anidulafungin, indicating that the decreasing concentrations did not cause lower candidacidal activity. This better activity at 1/8 × MIC is probably due to the EOs’ toxicity at 1/4 × MIC, suggesting that at higher concentrations EOs might interfere with PMNs functionality. TTO and MPP at 1/8 × MIC significantly increased intracellular killing by PMNs through their direct action on the yeasts (both EOs) or on phagocytic cells (MPP), suggesting a positive interaction between EOs and PMNs to eradicate intracellular C. krusei. These data showed a promising potential application of TTO and “Mentha of Pancalieri” EO as natural adjuvants in C. krusei infection management.
Various Patterns of Composition and Accumulation of Steroids and Triterpenoids in Cuticular Waxes from Screened Ericaceae and Caprifoliaceae Berries during Fruit Development
Authors: Dashbaldan Soyol , Becker Rafał , Pączkowski Cezary , Szakiel Anna
Published: October 2019

Cuticular waxes are primarily composed of two classes of lipids: compounds derived from very-long-chain fatty acids and isoprenoids, particularly triterpenoids and steroids. Isoprenoids can occur in cuticular waxes in high amounts, dominating the mixture of aliphatic long-chain hydrocarbons, while in other plants they are found in trace concentrations. Triterpenoids occurring in fruit cuticular waxes are of interest due to their potential role in the protection against biotic stresses, including pathogen infections, and their impact on the mechanical toughness of the fruit surface, maintaining fruit integrity, and post-harvest quality. The aim of the present study was the determination of the changes in the triterpenoid profile of the fruit cuticular waxes of four plant species bearing edible berries: Vaccinium myrtillus, V. vitis-idaea, and Arbutus unedo of the Ericaceae and the edible honeysuckle Lonicera caerulea of the Caprifoliaceae. Triterpenoids were identified and quantified by GC-MS/FID (gas chromatography-mass spectrometry/flame ionization detection) at three different phenological stages: young berries, berries at the onset of ripening, and mature berries. During fruit development and maturation, the triterpenoid content in cuticular waxes displayed species-specific patterns of changes. The steroid content seemed to be directly correlated with the developmental stage, with a very typical point of transition between growth and ripening being observed in all the fruit analyzed in this study.
Inhibitory Effect of Oat Bran Ethanol Extract on Survival and Gemcitabine Resistance of Pancreatic Cancer Cells
Authors: Kim Myoungjae , Mun Jeong-Geon , Lee Hyun Jin , Son So-Ri , Lee Mi-Ja , Kee Ji-Ye
Published: October 2019

Pancreatic cancer (PC) is one of the most aggressive malignancies in the world. Gemcitabine (Gem), a nucleoside pyrimidine analogue, is a first-line chemotherapeutic drug for PC, but the tumor response rate of Gem is very low and resistance to Gem has emerged as a major problem in the treatment of PC. Oat bran, used as animal and human food, has been found to be beneficial to health. In this study, effects of oat bran ethanol extract (OBE) on PC cells and Gem-resistant PC cells were investigated in vitro. OBE decreased cell survival and colony forming ability of PC cells, without any cytotoxicity on the normal pancreatic cells. Flow cytometry analysis and TUNEL assay showed that the OBE reduced G1/S phase transition and induced death in PC cells through AMPK activation and downregulation of JNK. Additionally, OBE could overcome Gem resistance through reduction in RRM1/2 expression and showed synergistic effect by combinatorial treatment with Gem on Gem-resistant PC cells. Additionally, LC-MS data showed that avenacoside A was a component of OBE. Thus, this study elucidated the anti-proliferative effect of OBE and synergistic effect of OBE with Gem on PC cells and Gem-resistant cells.
Molecular Structures and Spectral Properties of Natural Indigo and Indirubin: Experimental and DFT Studies
Authors: Ju Zixin , Sun Jie , Liu Yanping
Published: October 2019

This paper presents a comparative study on natural indigo and indirubin in terms of molecular structures and spectral properties by using both computational and experimental methods. The spectral properties were analyzed with Fourier transform infrared (FTIR), Raman, UV-Visible, and fluorescence techniques. The density functional theory (DFT) method with B3LYP using 6-311G(d,p) basis set was utilized to obtain their optimized geometric structures and calculate the molecular electrostatic potential, frontier molecular orbitals, FTIR, and Raman spectra. The single-excitation configuration interaction (CIS), time-dependent density functional theory (TD-DFT), and polarization continuum model (PCM) were used to optimize the excited state structure and calculate the UV-Visible absorption and fluorescence spectra of the two molecules at B3LYP/6-311G(d,p) level. The results showed that all computational spectra agreed well with the experimental results. It was found that the same vibrational mode presents a lower frequency in indigo than that in indirubin. The frontier molecular orbital analysis demonstrated that the UV-Visible absorption and fluorescence bands of indigo and indirubin are mainly derived from π → π* transition. The results also implied that the indigo molecule is more conjugated and planar than indirubin, thereby exhibiting a longer maximum absorption wavelength and stronger fluorescence peak.
Synthesis of the C3 and C1 Constitutional Isomers of Trifluorosubphthalocyanine and Their Fluorescence within MDA-MB-231 Breast Tumor Cells
Authors: L. Calandrino Rosemarie , J. McAuliffe Katherine , E. Dolmage Lauren , R. Trivedi Evan
Published: October 2019

Metal tetrapyrrole macrocycles such as porphyrins and chlorins are ubiquitous in nature. Synthetic analogs, including phthalocyanines, have found applications in medicine, particularly as photosensitizers for photodynamic therapy and as fluorescent imaging probes. Tripyrrolic macrocycles, called subphthalocyanines (SPcs) with a smaller boron atom at their core, have similar potential as optical agents. We have recently reported a series of mixed fluorinated SPcs with varying aromaticity, showing that electronic absorption and emission are synthetically tunable across the far visible region, and that the inclusion of 4–12 peripheral fluorine atoms results in strong fluorescence within MDA-MB-231 breast tumor cells. Further probing this system, we report herein the synthesis and characterization of boron trifluorosubphthalocyanine chloride (F3SPc). The constitutional isomers F3SPc(C3) and F3SPc(C1) are readily separable by chromatography, and their identity and purity have been confirmed by 1H NMR, 19F NMR, HR APCI-MS, and HPLC. Unsurprisingly, these structurally similar F3SPcs have identical electronic absorption (λmax = 557 nm; tetrahydrofuran (THF)) and emission (λem = 574 nm; Φf = 0.27–0.28; THF). Strong fluorescence from MDA-MB-231 breast tumor cells was observed following treatment with F3SPc(C3) and F3SPc(C1) (50 µM F3SPc, 15 min), further highlighting the importance of even a limited number of peripheral fluorine atoms for this type of application.
An Amphiphilic Pyridinoyl-hydrazone Probe for Colorimetric and Fluorescence pH Sensing
Authors: Diana Rosita , Panunzi Barbara , Tuzi Angela , Piotto Stefano , Concilio Simona , Caruso Ugo
Published: October 2019

A new pH sensor based on a substituted aroylhydrazide with a flexible side chain and a terminal trimethyl ammonium group (PHA+) was designed and synthesized. The terminal quaternary ammonium guarantees excellent solubility in water. At the same time, the probe is very soluble in hydrophobic envirornments. The pyridinoyl-hydrazone moiety acts as the pH-sensitive fluorophore/chromophore probe. Extensive physicochemical characterization has been performed on the bromide salt PHABr. DFT calculations, based on single-crystal X-ray data, permitted to rationalize the optical behavior. Molecular dynamics simulations permitted to clarify the mode of interaction with lipid membrane. The ability of the probe to change color and fluorescence in response to different pH and media of different polarity has been investigated. PHABr shows a remarkable pH-dependent behavior in both absorption and fluorescence spectra with high sensitivity and strong on-off switch effect at neutral pH, perceptible even to the naked eye.
Multimerization through Pegylation Improves Pharmacokinetic Properties of scFv Fragments of GD2-Specific Antibodies
Authors: Kholodenko Irina V. , Kalinovsky Daniel V. , Svirshchevskaya Elena V. , Doronin Igor I. , Konovalova Maria V. , Kibardin Alexey V. , Shamanskaya Tatyana V. , Larin Sergey S. , Deyev Sergey M. , Kholodenko Roman V.
Published: October 2019

Antigen-binding fragments of antibodies specific to the tumor-associated ganglioside GD2 are well poised to play a substantial role in modern GD2-targeted cancer therapies, however, rapid elimination from the body and reduced affinity compared to full-length antibodies limit their therapeutic potential. In this study, scFv fragments of GD2-specific antibodies 14.18 were produced in a mammalian expression system that specifically bind to ganglioside GD2, followed by site-directed pegylation to generate mono-, di-, and tetra-scFv fragments. Fractionated pegylated dimers and tetramers of scFv fragments showed significant increase of the binding to GD2 which was not accompanied by cross-reactivity with other gangliosides. Pegylated multimeric di-scFvs and tetra-scFvs exhibited cytotoxic effects in GD2-positive tumor cells, while their circulation time in blood significantly increased compared with monomeric antibody fragments. We also demonstrated a more efficient tumor uptake of the multimers in a syngeneic GD2-positive mouse cancer model. The findings of this study provide the rationale for improving therapeutic characteristics of GD2-specific antibody fragments by multimerization and propose a strategy to generate such molecules. On the basis of multimeric antibody fragments, bispecific antibodies and conjugates with cytotoxic drugs or radioactive isotopes may be developed that will possess improved pharmacokinetic and pharmacodynamic properties.
Analysis of Nitraria Tangutourum Bobr-Derived Fatty Acids with HPLC-FLD-Coupled Online Mass Spectrometry
Authors: Hu Na , Ouyang Jian , Dong Qi , Wang Honglun
Published: October 2019

Fatty acids (FAs) are basic components in plants. The pharmacological significance of FAs has attracted attentions of nutritionists and pharmaceutists. Sensitive and accurate detection of FAs is of great importance. In the present study, a pre-column derivatization and online mass spectrometry-based qualitative and quantitative analysis of FAs was developed. Nineteen main FAs were derivatized by 2-(7-methyl-1H-pyrazolo-[3,4-b]quinoline-1-yl)ethyl-4-methyl benzenesulfonate (NMP) and separated on reversed-phase Hypersil BDS C8 column with gradient elution. All FAs showed excellent linear responses with correlation coefficients more than 0.9996. The method obtained LOQs between 0.93 ng/mL and 5.64 ng/mL. FA derivatives were identified by both retention time and protonated molecular ion corresponding to m/z [M + H]+. A comparative study based on FA contents in peel and pulp, seeds and leaves of Nitraria tangutourum Bobr (NTB) from different geographical origins was performed with the established method. Results indicated that NTB were rich in FAs, and the types and contents of FAs varied among tissues. On the other hand, the same tissue of NTB from different geographical areas differed in the content, but not in type, of FAs.
Metabolomic Approach for Discrimination of Cultivation Age and Ripening Stage in Ginseng Berry Using Gas Chromatography-Mass Spectrometry
Authors: Park Seong-Eun , Seo Seung-Ho , Kim Eun-Ju , Park Dae-Hun , Park Kyung-Mok , Cho Seung-Sik , Son Hong-Seok
Published: October 2019

The purpose of this study was to analyze metabolic differences of ginseng berries according to cultivation age and ripening stage using gas chromatography-mass spectrometry (GC-MS)-based metabolomics method. Ginseng berries were harvested every week during five different ripening stages of three-year-old and four-year-old ginseng. Using identified metabolites, a random forest machine learning approach was applied to obtain predictive models for the classification of cultivation age or ripening stage. Principal component analysis (PCA) score plot showed a clear separation by ripening stage, indicating that continuous metabolic changes occurred until the fifth ripening stage. Three-year-old ginseng berries had higher levels of valine, glutamic acid, and tryptophan, but lower levels of lactic acid and galactose than four-year-old ginseng berries at fully ripened stage. Metabolic pathways affected by different cultivation age were involved in amino acid metabolism pathways. A random forest machine learning approach extracted some important metabolites for predicting cultivation age or ripening stage with low error rate. This study demonstrates that different cultivation ages or ripening stages of ginseng berry can be successfully discriminated using a GC-MS-based metabolomic approach together with random forest analysis.
Heterocycles in Medicinal Chemistry
Authors: Jampilek Josef
Published: October 2019

Heteroatoms constitute a very common fragment of a number of active pharmaceutical ingredients as well as excipients; from the point of view of significance, it is all the same if these are isosterically/bioisosterically replaced carbons/carbon substructures in aliphatic structures or real heterocycles [...]
Natural Occurrence, Bioactivity and Biosynthesis of Elaiophylin Analogues
Authors: Gui Min , Zhang Meng-xue , Wu Wen-hui , Sun Peng
Published: October 2019

Elaiophylins belong to a special family of 16-membered macrodiolides with C2-symmetry. They have exhibited remarkable biological activities, such as antimicrobial, anthelmintic, anticancer, immunosuppressive, anti-inflammatory, antiviral, and α-glucosidase inhibitory activities. A member of elaiophylins, efomycin M, is as a specific small molecule inhibitor of selectin in preclinical trial for the treatment of psoriasis, ischemia-reperfusion, and allergy. The biosynthetic investigation of elaiophylins has uncovered a unique thioesterase, which is responsible for the formation of C2-symmetric diolide. We herein summarize the natural occurrence, bioactivity, and biosynthesis of elaiophylins covering the literatures from 1959 to 2019. Hopefully, this review will inspire further research interests of these compounds and encourage the discovery of new analogues by metabolic engineering or genome mining.
Intracellular Environment Improvement of Mycobacterium neoaurum for Enhancing Androst-1,4-Diene-3,17-Dione Production by Manipulating NADH and Reactive Oxygen Species Levels
Authors: Shao Minglong , Zhao Youxi , Liu Yu , Yang Taowei , Xu Meijuan , Zhang Xian , Rao Zhiming
Published: October 2019

As one of the most significant steroid hormone precursors, androst-1,4-diene-3,17-dione (ADD) could be used to synthesize many valuable hormone drugs. The microbial transformation of sterols to ADD has received extensive attention in recent years. In a previous study, Mycobacterium neoaurum JC-12 was isolated and converted sterols to the major product, ADD. In this work, we enhanced ADD yield by improving the cell intracellular environment. First, we introduced a nicotinamide adenine dinucleotide (NADH) oxidase from Bacillus subtilis to balance the intracellular NAD+ availability in order to strengthen the ADD yield. Then, the catalase gene from M. neoaurum was also over-expressed to simultaneously scavenge the generated H2O2 and eliminate its toxic effects on cell growth and sterol transformation. Finally, using a 5 L fermentor, the recombinant strain JC-12yodC-katA produced 9.66 g/L ADD, which increased by 80% when compared with the parent strain. This work shows a promising way to increase the sterol transformation efficiency by regulating the intracellular environment.
Development and Validation of a Reporter-Cell-Line-Based Bioassay for Therapeutic Soluble gp130-Fc
Authors: Yu Lei , Jia Chuncui , Yao Wenrong , Pei Dening , Qin Xi , Rao Chunming , Wang Junzhi
Published: October 2019

Soluble glycoprotein 130 kDa (sgp130)-Fc fusion protein, an innovative therapeutic bio-macromolecular drug specifically targeting IL-6 trans-signaling, proved to have good potential for application in the treatment of chronic inflammatory diseases. A simple and quick bioassay for sgp130-Fc was developed in this study. First, a stable reporter cell line was obtained by transfecting CHO-K1 cells with a sis-inducible element (SIE)-driving luciferase reporter gene (CHO/SIE-Luc). Sgp130-Fc could inhibit the expression of luciferase induced by IL-6/sIL-6Rα complex, and the dose–response curve fitted the four-parameter logistic model, with 50% inhibitive concentration (IC50) being about 500 ng/mL and detection range between 40 and 5000 ng/mL. Both the intra-assay and inter-assay coefficient of variation (CV) were below 10.0%, and the accuracy estimates ranged from 94.1% to 106.2%. The assay indicated a good linearity (R² = 0.99) in the range of 50% to 150% of optimized initial concentration. No significant difference was found between the test results of new assay and BAF3/gp130 proliferation assay (unpaired t test, p = 0.4960, n = 6). The dose-response effect and copy number of the luciferase gene was basically unchanged after long-term culture (up to passage 60), demonstrating the stability of CHO/SIE-Luc cells. These results suggested that the new reporter assay was suited to routine potency determination of therapeutic sgp130-Fc.
Catalyst-Free Synthesis of Polysubstituted 5-Acylamino-1,3-Thiazoles via Hantzsch Cyclization of α-Chloroglycinates
Authors: Tomassetti Mara , Lupidi Gabriele , Piermattei Pamela , Rossi Federico V. , Lillini Samuele , Bianchini Gianluca , Aramini Andrea , Ciufolini Marco A. , Marcantoni Enrico
Published: October 2019

A catalyst-free heterocyclization reaction of α-chloroglycinates with thiobenzamides or thioureas leading to 2,4-disubstituted-5-acylamino-1,3-thiazoles has been developed. The methodology provides straightforward access to valuable building blocks for pharmaceutically relevant compounds.
(3β,16α)-3,16-Dihydroxypregn-5-en-20-one from the Twigs of Euonymus alatus (Thunb.) Sieb. Exerts Anti-Inflammatory Effects in LPS-Stimulated RAW-264.7 Macrophages
Authors: Lee Seulah , Lee Dahae , Baek Su Cheol , Jo Mun Seok , Kang Ki Sung , Kim Ki Hyun
Published: October 2019

To discover new pharmacologically active natural products, here, we performed the phytochemical analysis of a Korean medicinal plant. Euonymus alatus (Thunb.) Sieb. is a traditional medicinal plant that has been used as a remedy for various diseases in Asian countries. In particular, the cork cambium on the twigs of E. alatus has been used to treat dysmenorrhea, tumors, diabetes, and wound. Phytochemical analysis of the methanolic extract of E. alatus twigs led to the isolation of a sterol, which was identified as (3β,16α)-3,16-dihydroxypregn-5-en-20-one (1) by 1D and 2D nuclear magnetic resonance (NMR) spectroscopy and high-resolution electrospray ionization mass spectrometry. The stereochemistry of 1 was established with nuclear Overhauser effect spectroscopy (NOESY) analysis and comparison of electronic circular dichroism (ECD) data. To the best of our knowledge, the isolation of compound 1 from nature is first reported here, as well as the complete and revised NMR data assignment of 1. In lipopolysaccharide (LPS)-stimulated RAW-264.7 macrophages, compound 1 significantly inhibited nitric oxide (NO) production at an IC50 value of 12.54 ± 0.05 μM as well as the protein expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Moreover, the pre-treatment with compound 1 attenuated the LPS-induced phosphorylation of nuclear factor kappa B (NF-κB) p65 through the inhibition of the phosphorylation of IκB kinase alpha (IKKα), IKKβ, and inhibitor of kappa B alpha (IκBα). Compound 1 also inhibited the LPS-induced phosphorylation of p38, c-Jun NH2-terminal kinase (JNK), and extracellular signal-regulated kinase (ERK). Taken together, compound 1 may serve as an anti-inflammatory constituent of E. alatus twigs and its anti-inflammatory property is thought to be associated with the inhibition of NO production via suppression of iNOS and COX-2 expression through inhibition of IKKα/β, I-κBα and NF-κB p65 activation and downregulation of p38, JNK, and ERK mitogen-activated protein kinase signal pathways in RAW 264.7 macrophages. These findings also provide experimental evidence that compound 1 identified from E. alatus twigs could be a candidate for an anti-inflammatory agent.
Antileukemic Activity of Twig Components of Caucasian Beech in Turkey
Authors: Shida Wataru , Tateishi Hiroshi , Tahara Yurika , Fujita Mikako , Husham Majeed Alsaadi Doaa , Watanabe Masato , Koga Ryoko , Radwan Mohamed O. , Ciftci Halil I. , Gezici Sevgi , Kurauchi Yuki , Katsuki Hiroshi , Otsuka Masami , Sugimura Koji , Wada Mikiyo , Sekeroglu Nazim , Watanabe Takashi
Published: October 2019

Despite the development of a range of anti-cancer agents, cancer diagnoses are still increasing in number, remaining a leading cause of death. Anticancer drug treatment is particularly important for leukemia. We screened Turkish plants and found the unique antileukemic activity of twig components in Turkish Caucasian beech, selectively inducing apoptosis in leukemia cells. This effect is unique among some kinds of beeches, presumably related to oxidative stress. This study would lead to effective use of discarded material, i.e., twig of beech, and a new anti-leukemic drug based on large tree.
Essential Oil from Pinus Koraiensis Pinecones Inhibits Gastric Cancer Cells via the HIPPO/YAP Signaling Pathway
Authors: Zhang Yandong , Xin Chao , Qiu Junqiang , Wang Zhenyu
Published: October 2019

Pinecone is a traditional folk herb, which has been used in China for many years. In this paper, the essential oil from Pinus koraiensis pinecones (PEO) was obtained by hydrodistillation and 41 compounds were identified by gas chromatography–mass spectrometry (GC-MS), mainly including α-Pinene (40.91%), Limonene (24.82%), and β-Pinene (7.04%). The purpose of this study was to investigate the anti-tumor activity of PEO on MGC-803 cells and its mechanism. Anti-tumor experiments in vitro showed PEO could significantly inhibit the proliferation and migration of MGC-803 cells, and it also could arrest the cell cycle in the G2/M phase, decrease the mitochondrial membrane potential, and induce apoptosis. Finally, the effects of PEO on genes expression on MGC-803 cells were analyzed by RNA sequencing, and results showed that after treatment with PEO, 100 genes were up-regulated, and 57 genes were down-regulated. According to the KEGG pathway and GSEA, FAT4, STK3, LATS2, YAP1, and AJUBA were down-regulated, which were related to HIPPO signaling pathway. Real-time PCR and western blot further confirmed the results of RNA sequencing. These results indicated that PEO may exert anti-tumor activity via the HIPPO/YAP signaling pathway. The anti-tumor mechanism of this oil can be further studied, which is important for the development of anti-tumor drugs.
Erratum: Hong, E., et al. Toll-Like Receptor-Mediated Recognition of Nucleic Acid Nanoparticles (NANPs) in Human Primary Blood Cells. Molecules 2019, 24, 1094
Authors: Hong Enping , Halman Justin R. , Shah Ankit , Cedrone Edward , Truong Nguyen , Afonin Kirill A. , Dobrovolskaia Marina A.
Published: October 2019

The Molecules Editorial Office wishes to make the following erratum to this paper [...]
Novel Hit Compounds as Putative Antifungals: The Case of Aspergillus fumigatus
Authors: Kritsi Eftichia , Matsoukas Minos-Timotheos , Potamitis Constantinos , Detsi Anastasia , Ivanov Marija , Sokovic Marina , Zoumpoulakis Panagiotis
Published: October 2019

The prevalence of invasive fungal infections has been dramatically increased as the size of the immunocompromised population worldwide has grown. Aspergillus fumigatus is characterized as one of the most widespread and ubiquitous fungal pathogens. Among antifungal drugs, azoles have been the most widely used category for the treatment of fungal infections. However, increasingly, azole-resistant strains constitute a major problem to be faced. Towards this direction, our study focused on the identification of compounds bearing novel structural motifs which may evolve as a new class of antifungals. To fulfil this scope, a combination of in silico techniques and in vitro assays were implemented. Specifically, a ligand-based pharmacophore model was created and served as a 3D search query to screen the ZINC chemical database. Additionally, molecular docking and molecular dynamics simulations were used to improve the reliability and accuracy of virtual screening results. In total, eight compounds, bearing completely different chemical scaffolds from the commercially available azoles, were proposed and their antifungal activity was evaluated using in vitro assays. Results indicated that all tested compounds exhibit antifungal activity, especially compounds 1, 2, and 4, which presented the most promising minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) values and, therefore, could be subjected to further hit to lead optimization.
Synthesis of Enantiomerically Pure N-Boc-Protected 1,2,3-Triaminopropylphosphonates and 1,2-Diamino-3-Hydroxypropylphosphonates
Authors: Trocha Aleksandra , Piotrowska Dorota G. , Głowacka Iwona E.
Published: October 2019

All possible isomers of 1,2,3-tri(N-tert-butoxycarbonylamino)propylphosphonate 6 were synthesized from the respective diethyl [N-(1-phenylethyl)]-1-benzylamino-2,3-epiiminopropylphosphonates 5 via opening the aziridine ring with trimethylsilyl azide (TMSN3) followed by hydrogenolysis in the presence of di-tert-butyl dicarbonate (Boc2O). [N-(1-phenylethyl)]-1-benzylamino-2,3-epiiminopropylphosphonates (1R,2R,1′S)-5a and (1S,2S,1′R)-5c were smoothly transformed into diethyl 3-acetoxy-1-benzylamino-2-[N-(1-phenylethyl)amino]propylphosphonates (1R,2R,1′S)-9a and (1S,2S,1′R)-9c, respectively by the opening of the aziridine ring with acetic acid. Transformations of [N-(1-phenylethyl)]-1-benzylamino-2,3-epiiminopropylphosphonates (1S,2R,1′S)-5b and (1R,2S,1′R)-5d into diethyl 3-acetoxy-1-benzylamino-2-[(1-phenylethyl)amino]propylphosphonates (1S,2R,1′S)-9b and (1R,2S,1′R)-9d were accompanied by the formation of ethyl {1-(N-benzylacetamido)-3-hydroxy-2-[(1-phenylethyl)amino]propyl}phosphonate (1S,2R,1′S)-10b and (1R,2S,1′R)-10d and 3-(N-benzylacetamido)-4-[N-(1-phenylethyl)]amino-1,2-oxaphospholane (3S,4R,1′S)-11b and (3R,4S,1′R)-11d as side products. Diethyl (1R,2R)-, (1S,2S)-, (1S,2R)- and (1R,2S)-3-acetoxy-1,2-di(N-tert-butoxycarbonylamino)propylphosphonates 7a–7d were obtained from the respective 3-acetoxy-1-benzylamino-2-[N-(1-phenylethyl)amino]propylphosphonates 9a–9d by hydrogenolysis in the presence of Boc2O.
A Mechanistic Study on the Tautomerism of H-Phosphonates, H-Phosphinates and Secondary Phosphine Oxides
Authors: Vincze Daniella , Ábrányi-Balogh Péter , Bagi Péter , Keglevich György
Published: October 2019

H-phosphonates, H-phosphinates and secondary phosphine oxides may be preligands, and are important building blocks in the synthesis of pharmaceuticals, pesticides, and P-ligands. The prototropic tautomerism influenced by substituent effects plays an important role in the reactivity of these species. The main goal of our research was to study the tautomerism of the >P(O)H reagents by means of computational investigations applying several DFT methods at different levels. We focused on the effect of implicit solvents, and on explaining the observed trends with physical chemical molecular descriptors. In addition, multiple reaction pathways incorporating three P-molecules were elucidated for the mechanism of the interconversion.