bluuebunny/crossref_metadata_2025 huggingface dataset:
Australindolones, New Aminopyrimidine Substituted Indolone Alkaloids from an Antarctic Tunicate Synoicum sp.
Authors: Kokkaliari Sofia , Pham Kim , Shahbazi Nargess , Calcul Laurent , Wojtas Lukasz , Wilson Nerida G. , Crawford Alexander D. , Baker Bill J.
Published: March 2022

Five new alkaloids have been isolated from the lipophilic extract of the Antarctic tunicate Synoicum sp. Deep-sea specimens of Synoicum sp. were collected during a 2011 cruise of the R/V Nathanial B. Palmer to the southern Scotia Arc, Antarctica. Crude extracts from the invertebrates obtained during the cruise were screened in a zebrafish-based phenotypic assay. The Synoicum sp. extract induced embryonic dysmorphology characterized by axis truncation, leading to the isolation of aminopyrimidine substituted indolone (1–4) and indole (5–12) alkaloids. While the primary bioactivity tracked with previously reported meridianins A–G (5–11), further investigation resulted in the isolation and characterization of australindolones A–D (1–4) and the previously unreported meridianin H (12).
Current Trends and New Challenges in Marine Phycotoxins
Authors: Louzao Maria Carmen , Vilariño Natalia , Vale Carmen , Costas Celia , Cao Alejandro , Raposo-Garcia Sandra , Vieytes Mercedes R. , Botana Luis M.
Published: March 2022

Marine phycotoxins are a multiplicity of bioactive compounds which are produced by microalgae and bioaccumulate in the marine food web. Phycotoxins affect the ecosystem, pose a threat to human health, and have important economic effects on aquaculture and tourism worldwide. However, human health and food safety have been the primary concerns when considering the impacts of phycotoxins. Phycotoxins toxicity information, often used to set regulatory limits for these toxins in shellfish, lacks traceability of toxicity values highlighting the need for predefined toxicological criteria. Toxicity data together with adequate detection methods for monitoring procedures are crucial to protect human health. However, despite technological advances, there are still methodological uncertainties and high demand for universal phycotoxin detectors. This review focuses on these topics, including uncertainties of climate change, providing an overview of the current information as well as future perspectives.
Stimulating the Hematopoietic Effect of Simulated Digestive Product of Fucoidan from Sargassum fusiforme on Cyclophosphamide-Induced Hematopoietic Damage in Mice and Its Protective Mechanisms Based on Serum Lipidomics
Authors: Ma Wei-Ping , Yin Shi-Ning , Chen Jia-Peng , Geng Xi-Cheng , Liu Ming-Fei , Li Hai-Hua , Liu Ming , Liu Hong-Bing
Published: March 2022

Hematopoietic damage is a serious side effect of cytotoxic drugs, and agents promoting hematopoiesis are quite important for decreasing the death rate in cancer patients. In our previous work, we prepared the simulated digestive product of fucoidan from Sargassum fusiforme, DSFF, and found that DSFF could activate macrophages. However, more investigations are needed to further evaluate whether DSFF could promote hematopoiesis in the chemotherapy process. In this study, the protective effect of DSFF (1.8–7.2 mg/kg, i.p.) on cyclophosphamide-induced hematopoietic damage in mice and the underlying mechanisms were investigated. Our results show that DSFF could restore the numbers of white blood cells, neutrophils, and platelets in the peripheral blood, and could also retard bone marrow cell decrease in mice with cyclophosphamide-induced hematopoietic damage. UPLC/Q-Extraction Orbitrap/MS/MS-based lipidomics results reveal 16 potential lipid biomarkers in a serum that responded to hematopoietic damage in mice. Among them, PC (20:1/14:0) and SM (18:0/22:0) were the key lipid molecules through which DSFF exerted protective actions. In a validation experiment, DSFF (6.25–100 μg/mL) could also promote K562 cell proliferation and differentiation in vitro. The current findings indicated that DSFF could affect the blood cells and bone marrow cells in vivo and thus showed good potential and application value in alleviating the hematopoietic damage caused by cyclophosphamide.
Microstructures and Mechanical Properties of Steels and Alloys Subjected to Large-Strain Cold-to-Warm Deformation
Authors: Dolzhenko Anastasiia , Tikhonova Marina , Kaibyshev Rustam , Belyakov Andrey
Published: March 2022

The effect of large-strain cold-to-warm deformation on the microstructures and mechanical properties of various steels and alloys is critically reviewed. The review is mainly focused on the microstructure evolution, whereas the deformation textures are cursorily considered without detailed examination. The deformation microstructures are considered in a wide strain range, from early straining to severe deformations. Such an approach offers a clearer view of how the deformation mechanisms affect the structural changes leading to the final microstructures evolved in large strains. The general regularities of microstructure evolution are shown for different deformation methods, including conventional rolling/swaging and special techniques, such as equal channel angular pressing or torsion under high pressure. The microstructural changes during deformations under different processing conditions are considered as functions of total strain. Then, some important mutual relationships between the microstructural parameters, e.g., grain size vs. dislocation density, are revealed and discussed. Particular attention is paid to the mechanisms of microstructure evolution that are responsible for the grain refinement. The development of an ultrafine-grained microstructure during large strain deformation is considered in terms of continuous dynamic recrystallization. The regularities of the latter are discussed in comparison with conventional (discontinuous) dynamic recrystallization and grain subdivision (fragmentation) phenomenon. The structure–property relations are quantitatively represented for the structural strengthening, taking into account various mechanisms of dislocation retardation.
In-Situ Alloying of CoCrFeNiX High Entropy Alloys by Selective Laser Melting
Authors: Farquhar Lucy , Maddison George , Hardwick Liam , Livera Frances , Todd Iain , Goodall Russell
Published: March 2022

High Entropy Alloys are a class of alloys which have been shown to largely exhibit stable microstructures, as well as frequently good mechanical properties, particularly when manufactured by additive manufacturing. Due to the large number of potential compositions that their multi-component nature introduces, high throughput alloy development methods are desirable to speed up the investigation of novel alloys. Here, we explore once such method, in-situ alloying during Additive Manufacture, where a powder of a certain pre-alloyed composition is mixed with the required composition of powder of an additional element, such that alloying takes place when powders are melted during the process. To test the effectiveness and capability of the approach, selective laser melting has been used to manufacture pre-alloyed CoCrFeNi, and also CoCrFeNiCu and CoCrFeNiTi alloys by combining pre-alloyed CoCrFeNi powder with elemental powders of Cu and Ti. Processing parameter variations are used to find the highest relative density for each alloy, and samples were then characterised for microstructure and phase composition. The CoCrFeNi alloy shows a single phase face centred cubic (FCC) microstructure, as found with other processing methods. The CoCrFeNiCu alloy has a two phase FCC microstructure with clear partitioning of the Cu, while the CoCrFeNiTi alloy has an FCC matrix phase with NiTi intermetallics and a hexagonal close packed (HCP) phase, as well as unmelted Ti particles. The microstructures therefore differ from those observed in the same alloys manufactured by other methods, mainly due to the presence of areas with higher concentrations than usually encountered of Cu and Ti respectively. Successful in-situ alloying in this process seems to be improved by the added elemental powder having a lower melting point than the base alloy, as well as a low inherent tendency to segregate. While not producing directly comparable microstructures however, the approach does seem to offer advantages for the rapid screening of alloys for AM processability, identifying, for example, extensive solid-state cracking in the CoCrFeNiTi alloy.
Contour Maps for Simultaneous Increase in Yield Strength and Elongation of Hot Extruded Aluminum Alloy 6082
Authors: Peruš Iztok , Kugler Goran , Malej Simon , Terčelj Milan
Published: March 2022

In this paper, the Conditional Average Estimator artificial neural network (CAE ANN) was used to analyze the influence of chemical composition in conjunction with selected process parameters on the yield strength and elongation of an extruded 6082 aluminum alloy (AA6082) profile. Analysis focused on the optimization of mechanical properties as a function of casting temperature, casting speed, addition rate of alloy wire, ram speed, extrusion ratio, and number of extrusion strands on one side, and different contents of chemical elements, i.e., Si, Mn, Mg, and Fe, on the other side. The obtained results revealed very complex non-linear relationships between all of these parameters. Using the proposed approach, it was possible to identify the combinations of chemical composition and process parameters as well as their values for a simultaneous increase of yield strength and elongation of extruded profiles. These results are a contribution of the presented study in comparison with published research results of similar studies in this field. Application of the proposed approach, either in the research and/or in industrial aluminum production, suggests a further increase in the relevant mechanical properties.
Association between Smoking and Urine Indole Levels Measured by a Commercialized Test
Authors: Mine Masataka , Masaki Nobuyuki , Toya Takumi , Namba Takayuki , Nagatomo Yuji , Takase Bonpei , Adachi Takeshi
Published: March 2022

Indoles are formed from dietary tryptophan by tryptophanase-positive bacterium. A few amounts of indole are excreted in the urine. On the other hand, cigarette smoke contains indoles, which could also change the urine indole levels. This study sought to elucidate the relationship between urine indole levels and smoking habits. A total of 273 healthy men (46 ± 6 years old) were enrolled in the study. Fasting urine and blood samples were obtained in the morning. The indole concentration was measured by a commercialized kit with a modified Kovac’s reagent. The relationship with smoking status was evaluated. The median value of the urine indole test was 29.2 mg/L (interquartile range; 19.6–40.8). The urine indole level was significantly elevated in the smoking subjects (non-smoking group, 28.9 (20.9–39.1) mg/L, n = 94; past-smoking group, 24.5 (15.7–35.5) mg/L, n = 108; current-smoking group, 34.3 (26.9–45.0) mg/L, n = 71). In the current-smoking group, urine indole levels correlated with the number of cigarettes per day (ρ = 0.224, p = 0.060). A multivariate regression test with stepwise method revealed that the factors relating to urine indole level were current smoking (yes 1/no 0) (standardized coefficient β = 0.173, p = 0.004), blood urea nitrogen (β = 0.152, p = 0.011), and triglyceride (β = −0.116, p = 0.051). The result suggests that smoking is associated with increased urine indole levels. The practical test might be used as a screening tool to identify the harmful effect of smoking.
Power Losses Models for Magnetic Cores: A Review
Authors: Rodriguez-Sotelo Daniela , Rodriguez-Licea Martin A. , Araujo-Vargas Ismael , Prado-Olivarez Juan , Barranco-Gutiérrez Alejandro-Israel , Perez-Pinal Francisco J.
Published: March 2022

In power electronics, magnetic components are fundamental, and, unfortunately, represent one of the greatest challenges for designers because they are some of the components that lead the opposition to miniaturization and the main source of losses (both electrical and thermal). The use of ferromagnetic materials as substitutes for ferrite, in the core of magnetic components, has been proposed as a solution to this problem, and with them, a new perspective and methodology in the calculation of power losses open the way to new design proposals and challenges to overcome. Achieving a core losses model that combines all the parameters (electric, magnetic, thermal) needed in power electronic applications is a challenge. The main objective of this work is to position the reader in state-of-the-art for core losses models. This last provides, in one source, tools and techniques to develop magnetic solutions towards miniaturization applications. Details about new proposals, materials used, design steps, software tools, and miniaturization examples are provided.
The Effects of Freeze-Thaw and UVC Radiation on Microbial Survivability in a Selected Mars-like Environment
Authors: Keaney Daniel , Lucey Brigid , Quinn Noreen , Finn Karen
Published: March 2022

The purpose of this study was to determine survivability of Escherichia coli, Deinococcus radiodurans and Paraburkholderia fungorum under Mars-simulated conditions for freeze-thawing (−80 °C to +30 °C) and UV exposure alone and in combination. E. coli ATCC 25922, D. radiodurans and P. fungorum remained viable following 20 successive freeze-thaw cycles, exhibiting viabilities of 2.3%, 96% and 72.6%, respectively. E. coli ATCC 9079 was non-recoverable by cycle 9. When exposed to UV irradiation, cells withstood doses of 870 J/m2 (E. coli ATCC 25922), 200 J/m2 (E. coli ATCC 9079), 50,760 J/m2 (D. radiodurans) and 44,415 J/m2 (P. fungorum). Data suggests P. fungorum is highly UV-resistant. Combined freeze-thawing with UV irradiation showed freezing increased UV resistance in E. coli ATCC 25922, E. coli DSM 9079 and D. radiodurans by 6-fold, 30-fold and 1.2-fold, respectively. Conversely, freezing caused P. fungorum to exhibit a 1.75-fold increase in UV susceptibility. Strain-dependent experimentation demonstrated that freezing increases UV resistance and prolongs survival. These findings suggest that exposure to short wavelength UV rays (254 nm) and temperature cycles resembling the daily fluctuating conditions on Mars do not significantly affect survival of D. radiodurans, P. fungorum and E. coli ATCC 25922 following 20 days of exposure.
Plasmid-Mediated Quinolone Resistance (PMQR) in Two Clinical Strains of Salmonella enterica Serovar Corvallis
Authors: Vázquez Xenia , Fernández Javier , Hernáez Silvia , Rodicio Rosaura , Rodicio Maria Rosario
Published: March 2022

Non-typhoid serovars of Salmonella enterica are one of the main causes of bacterial food-borne infections worldwide. For the treatment of severe cases of salmonellosis in adults, fluoroquinolones are amongst the drugs of choice. They are categorized by the World Health Organization (WHO) as “critically important with highest priority in human medicine”. In the present study, two clinical S. enterica serovar Corvallis isolates (HUA 5/18 and HUA 6/18) from a Spanish hospital, selected on the basis of fluoroquinolone resistance, were characterized. The MICs of ciprofloxacin, determined by E-test, were 0.5 and 0.75 µg/mL for HUA 5/18 and HUA 6/18, respectively, and both were also resistant to pefloxacin but susceptible to nalidixic acid. Whole genome sequencing (WGS) of the isolates was performed with Illumina platform, and different bioinformatics tools were used for sequence analysis. The two isolates belonged to ST1541, and had the Thr57Ser substitution in the ParC protein which is also found in ciprofloxacin susceptible isolates. However, they harbored identical ColE plasmids of 10 kb carrying the qnrS1 gene. In these plasmids, the gene was flanked by defective versions of IS2-like and ISKra4-like insertion sequences. HUA 5/18 and HUA 6/18 were also phenotypically resistant to streptomycin, sulfonamides and tetracycline, with the responsible genes: strA, strB, sul2 and tet(A) genes, being located on a IncQ1 plasmid. ColE plasmids with the qnrS1 gene are widely spread among multiple serovars of S. enterica from different samples and countries. These mobilizable plasmids are playing an important role in the worldwide spread of qnrS1. Thus, their detection in hospitals is a cause of concern which deserves further attention.
Avian Louse Flies and Their Trypanosomes: New Vectors, New Lineages and Host–Parasite Associations
Authors: Santolíková Anežka , Brzoňová Jana , Čepička Ivan , Svobodová Milena
Published: March 2022

Louse flies (Hippoboscidae) are permanent ectoparasites of birds and mammals. They have a cosmopolitan distribution with more than 200 described species. The aim of this study was to reveal host–vector–parasite associations between louse flies, birds, and trypanosomes. A total of 567 louse fly specimens belonging to 7 species were collected from birds at several localities in Czechia, including the rare species Ornithophila metallica and Ornithoica turdi. There was a significant difference in the occurrence of Ornithomya avicularia and Ornithomya fringillina on bird hosts according to their migratory status, O. fringillina being found more frequently on long-distance migrants. Trypanosomes were found in four species, namely, Ornithomya avicularia, O. fringillina, O. biloba, and Ornithoica turdi; the later three species are identified in this paper as natural trypanosome vectors for the first time. The prevalence of trypanosomes ranged between 5 and 19%, the highest being in O. biloba and the lowest being in O. fringillina. Phylogenetic analysis of the SSU rRNA gene revealed that a vast majority of trypanosomes from hippoboscids belong to the avian T. corvi/culicavium group B. Four new lineages were revealed in group B, with louse flies being probable vectors for some of these trypanosome lineages. We also confirmed the transcontinental distribution of several trypanosome lineages. Our results show that hippoboscids of several genera are probable vectors of avian trypanosomes.
Evaluation of UV-C Radiation Efficiency in the Decontamination of Inanimate Surfaces and Personal Protective Equipment Contaminated with Phage ϕ6
Authors: Bartolomeu Maria , Braz Márcia , Costa Pedro , Duarte João , Pereira Carla , Almeida Adelaide
Published: March 2022

To help halt the global spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), appropriate disinfection techniques are required. Over the last years, the interest in Ultraviolet-C (UV-C) radiation as a method to disinfect inanimate surfaces and personal protective equipment (PPE) has increased, mainly to efficiently disinfect and prevent SARS-CoV-2 from spreading and allow for the safe reuse of said equipment. The bacteriophage ϕ6 (or simply phage ϕ6) is an RNA virus with a phospholipid envelope and is commonly used in environmental studies as a surrogate for human RNA-enveloped viruses, including SARS-CoV-2. The present study investigated the use of two new UV irradiation systems ((2)2.4W and (8)5.5W)) constituted by conventional mercury UV-C lamps with a strong emission peak at ~254 nm to potentially inactivate phage ϕ6 on different surfaces (glass, plastic, stainless steel, and wood) and personal protective equipment, PPE, (surgical and filtering facepiece 2, FFP2, masks, a clear acetate visor, and disposable protective clothing). The results showed that both UV-C systems were effective in inactivating phage ϕ6, but the UV-C sterilizing chamber (8)5.5W had the best disinfection performance on the tested surfaces. The inactivation effectiveness is material-dependent on all surfaces, reaching the detection limit of the method at different times (between 60 and 240 s of irradiation). The glass surface needed less time to reduce the virus (30 s) when compared with plastic, stainless, and wood surfaces (60 s). The virus inactivation was more effective in the disposable surgical and FFP2 masks (60 and 120 s, respectively) than in the disposable vest and clear acetate visor (240 s). Overall, this study suggests that UV-C lamps with peak emission at ~254 nm could provide rapid, efficient, and sustainable sanitization procedures to different materials and surfaces. However, dosage and irradiation time are important parameters to be considered during their implementation as a tool in the fight against human coronaviruses, namely against SARS-CoV-2.
Development of Backfill Concrete Including Coal Gangue and Metakaolin and Prediction of Compressive Strength by Extreme Learning Machine
Authors: Jin Jiaxu , Yuan Shihao , Lv Zhiqiang , Sun Qi
Published: March 2022

The main aim of this investigation is to develop backfill concrete including coal gangue and metakaolin to reduce solid waste. For this purpose, a total of 30 concrete mixtures were designed by the inclusion of 0%, 25%, 50%, 75% and 100% coal gangue as coarse aggregates and 0%, 10% and 20% metakaolin as binder at 0.55 and 0.45 water to cement ratios. The compressive strength was tested after 3, 7 and 28 days for a total of 90 samples. Meanwhile, the influences of coal gangue and metakaolin on the elastic modulus, ultrasonic pulse velocity, rebound number and open porosity were explored. Then, the relationship between physical and mechanical properties was revealed by design code expressions and empirical models. Furthermore, an extreme learning machine was developed to predict compressive strength by concrete mixtures. The results show that the inclusion of coal gangue results in a poor performance in physical and mechanical properties of concrete. However, the drawbacks of concrete containing coal gangue can be compensated by metakaolin. The predicted results of design code expressions and empirical models are closed to the experiment results, with a 10% error. In addition, the findings reveal that the extreme learning machine offers significant potential to predict the compressive strength of concrete with high precision.
Phytochemical Characterization of Rhus coriaria L. Extracts by Headspace Solid-Phase Micro Extraction Gas Chromatography, Comprehensive Two-Dimensional Liquid Chromatography, and Antioxidant Activity Evaluation
Authors: Arena Katia , Trovato Emanuela , Cacciola Francesco , Spagnuolo Ludovica , Pannucci Elisa , Guarnaccia Paolo , Santi Luca , Dugo Paola , Mondello Luigi , Dugo Laura
Published: March 2022

Rhus coriaria L. (Anacardiaceae), commonly known as sumac, has been used since ancient times for many different applications, and nowadays is used mostly as a spice obtained from its in the Mediterranean and the Middle ground fruits and employed for flavoring and garnishing food, predominantly Eastern regions. Traditionally, sumac has been also used in popular medicine for the treatment of many ailments including hemorrhoids, wound healing, diarrhea, ulcers, and eye inflammation. Sumac drupes are indeed rich in various classes of phytochemicals including organic acids, flavonoids, tannins, and others, which are responsible of their powerful antioxidant capacity, from which treatment of many common diseases such as cardiovascular disease, diabetes, and cancer could benefit. In this work we evaluated the influence of fruit ripeness, conservation, and processing. To this aim, a phytochemical characterization of six different samples of Rhus coriaria L. was carried out. Specifically, headspace solid-phase micro extraction gas chromatography coupled to mass spectrometry and comprehensive two-dimensional liquid chromatography coupled to photodiode array and mass spectrometry detection, were employed. A total of 263 volatile compounds, including terpene hydrocarbons, acids, and aldehydes, as well as 83 polyphenolic compounds, mainly gallic acid derivatives, were positively identified. All samples showed a significant antioxidant activity by means of oxygen radical absorbance capacity, in line with their polyphenolic content and composition. Such findings set a solid ground to support the utilization of this plant as an attractive target for novel nutraceutical approaches and for drug discovery.
Anthraquinones from the Aerial Parts of Rubia cordifolia with Their NO Inhibitory and Antibacterial Activities
Authors: Luo Han , Qin Wei , Zhang Hong , Ren Fu-Cai , Fang Wen-Tao , Kong Qing-Hua , Yang Liu , Zhang Jian-Mei , Fang Cheng-Wu , Hu Jiang-Miao , Liu Shou-Jin
Published: March 2022

The present study aimed to identify the composition of the aerial parts of Rubia cordifolia L. A chemical investigation on the EtOAc extracts from the aerial parts of Rubia cordifolia resulted in the isolation of four new anthraquinones, namely Cordifoquinone A–D (1–4), along with 16 known anthraquinones. Their structures were elucidated on the basis of NMR and HR-ESIMS data. All isolates were assessed for their inhibitory effects on NO production in LPS-stimulated RAW 264.7 macrophage cells. Compounds 1, 3 and 10 exhibited significant inhibitory activities with IC50 values of 14.05, 23.48 and 29.23 μmol·L−1, respectively. Their antibacterial activities of four bacteria, Escherichia coli (ATCC 25922), Staphylococcus aureus subsp. aureus (ATCC 29213), Salmonella enterica subsp. enterica (ATCC 14028) and Pseudomonas aeruginosa (ATCC 27853), were also evaluated. Our results indicated that the antibacterial activity of these compounds is inactive.
Investigation of Different Winemaking Protocols to Mitigate Smoke Taint Character in Wine
Authors: Oberholster Anita , Wen Yan , Dominguez Suarez Sandra , Erdmann Jesse , Cauduro Girardello Raul , Rumbaugh Arran , Neupane Bishnu , Brenneman Charles , Cantu Annegret , Heymann Hildegarde
Published: March 2022

There is an increase in the levels of volatile phenols in wine made with smoke-impacted grapes. These compounds are present in wood smoke resulting from the pyrolysis (thermal decomposition) of lignin and at high levels give overpowering smoky and ashy characters to a wine. This research aimed to compare all the suggested wine mitigation strategies that evolved from prior research using smoke-impacted grapes under identical winemaking conditions except for the parameter under investigation. Cabernet Sauvignon grapes were received from three areas with varying amounts of smoke exposure in Northern California. Gas chromatography combined with mass spectrometry (GC-MS) and descriptive analyses were performed to correlate the volatile phenol composition to smoke taint characteristics. The winemaking variables investigated were the use of different fermentation yeasts, oak additions, and fermentation temperatures. Among other attributes, smokiness and ashy aftertaste were significantly different among the wines, showing a clear difference between the wines made from smoke-impacted fruit and the control wines made from non-impacted fruit. Findings indicate that mitigation strategies during red wine fermentation have a limited impact on the extraction of smoke-taint markers and the expression of smoke-taint sensory characteristics.
Efficacy and Limitations of Chemically Diverse Small-Molecule Enzyme-Inhibitors against the Synergistic Coagulotoxic Activities of Bitis Viper Venoms
Authors: Youngman Nicholas J. , Lewin Matthew R. , Carter Rebecca , Naude Arno , Fry Bryan G.
Published: March 2022

Snakebite remains a significant public health burden globally, disproportionately affecting low-income and impoverished regions of the world. Recently, researchers have begun to focus on the use of small-molecule inhibitors as potential candidates for the neutralisation of key snake venom toxins and as potential field therapies. Bitis vipers represent some of the most medically important as well as frequently encountered snake species in Africa, with a number of species possessing anticoagulant phospholipase A2 (PLA2) toxins that prevent the prothrombinase complex from inducing clot formation. Additionally, species within the genus are known to exert pseudo-procoagulant activity, whereby kallikrein enzymatic toxins cleave fibrinogen to form a weak fibrin clot that rapidly degrades, thereby depleting fibrinogen levels and contributing to the net anticoagulant state. Utilising well-validated coagulation assays measuring time until clot formation, this study addresses the in vitro efficacy of three small molecule enzyme inhibitors (marimastat, prinomastat and varespladib) in neutralising these aforementioned activities. The PLA2 inhibitor varespladib showed the greatest efficacy for the neutralisation of PLA2-driven anticoagulant venom activity, with the metalloproteinase inhibitors prinomastat and marimastat both showing low and highly variable degrees of cross-neutralisation with PLA2 anticoagulant toxicity. However, none of the inhibitors showed efficacy in neutralising the pseudo-procoagulant venom activity exerted by the venom of B. caudalis. Our results highlight the complex nature of snake venoms, for which single-compound treatments will not be universally effective, but combinations might prove highly effective. Despite the limitations of these inhibitors with regards to in vitro kallikrein enzyme pseudo-procoagulant venom activity, our results further support the growing body of literature indicating the potential use of small molecule inhibitors to enhance first-aid treatment of snakebite envenoming, particularly in cases where hospital and thus antivenom treatment is either unavailable or far away.
Occurrence of Mycosporine-like Amino Acids (MAAs) from the Bloom-Forming Cyanobacteria Aphanizomenon Strains
Authors: Zhang Hang , Jiang Yongguang , Zhou Chi , Chen Youxin , Yu Gongliang , Zheng Liping , Guan Honglin , Li Renhui
Published: March 2022

Mycosporine-like amino acids (MAAs) are widespread in various microbes and protect them against harsh environments. Here, four different Aphanizomenon species were isolated from severely eutrophic waterbodies, Lake Dianchi and the Guanqiao fishpond. Morphological characters and molecular phylogenetic analysis verified that the CHAB5919, 5921, and 5926 strains belonged to the Aphanizomenon flos-aquae clade while Guanqiao01 belonged to the Aphanizomenon gracile clade. Full wavelength scanning proved that there was obvious maximal absorption at 334 nm through purified methanol extraction, and these substances were further analyzed by HPLC and UPLC-MS-MS. The results showed that two kinds of MAAs were discovered in the cultured Aphanizomenon strains. One molecular weight was 333.28 and the other was 347.25, and the daughter fragment patterns were in accordance with the previously articles reported shinorine and porphyra-334 ion characters. The concentration of the MAAs was calibrated from semi-prepared MAAs standards from dry cells of Microcystis aeruginosa PCC7806 algal powder, and the purity of shinorine and porphyra-334 were 90.2% and 85.4%, respectively. The average concentrations of shinorine and porphyra-334 were 0.307–0.385 µg/mg and 0.111–0.136 µg/mg in Aphanizomenon flos-aquae species, respectively. And there was only one kind of MAAs (shinorine) in Aphanizomenon gracile species.,with a content of 0.003–0.049 µg/mg dry weight among all Aphanizomenon gracile strains. The shinorine concentration in Aphanizomenon flos-aquae was higher than that in Aphanizomenon gracile strains. The total MAAs production can be ranked as Aphanizomenon flos-aquae > Aphanizomenon gracile.
(−)-Naringenin 4′,7-dimethyl Ether Isolated from Nardostachys jatamansi Relieves Pain through Inhibition of Multiple Channels
Authors: Gu Ru-Rong , Meng Xian-Hua , Zhang Yin , Xu Hai-Yan , Zhan Li , Gao Zhao-Bing , Yang Jun-Li , Zheng Yue-Ming
Published: March 2022

(−)-Naringenin 4′,7-dimethyl ether ((−)-NRG-DM) was isolated for the first time by our lab from Nardostachys jatamansi DC, a traditional medicinal plant frequently used to attenuate pain in Asia. As a natural derivative of analgesic, the current study was designed to test the potential analgesic activity of (−)-NRG-DM and its implicated mechanism. The analgesic activity of (−)-NRG-DM was assessed in a formalin-induced mouse inflammatory pain model and mustard oil-induced mouse colorectal pain model, in which the mice were intraperitoneally administrated with vehicle or (−)-NRG-DM (30 or 50 mg/kg) (n = 10 for each group). Our data showed that (−)-NRG-DM can dose dependently (30~50 mg/kg) relieve the pain behaviors. Notably, (−)-NRG-DM did not affect motor coordination in mice evaluated by the rotarod test, in which the animals were intraperitoneally injected with vehicle or (−)-NRG-DM (100, 200, or 400 mg/kg) (n = 10 for each group). In acutely isolated mouse dorsal root ganglion neurons, (−)-NRG-DM (1~30 μM) potently dampened the stimulated firing, reduced the action potential threshold and amplitude. In addition, the neuronal delayed rectifier potassium currents (IK) and voltage-gated sodium currents (INa) were significantly suppressed. Consistently, (−)-NRG-DM dramatically inhibited heterologously expressed Kv2.1 and Nav1.8 channels which represent the major components of the endogenous IK and INa. A pharmacokinetic study revealed the plasma concentration of (−)-NRG-DM is around 7 µM, which was higher than the effective concentrations for the IK and INa. Taken together, our study showed that (−)-NRG-DM is a potential analgesic candidate with inhibition of multiple neuronal channels (mediating IK and INa).
Virtual Screening of Natural Chemical Databases to Search for Potential ACE2 Inhibitors
Authors: Yao Huiping
Published: March 2022

The angiotensin-converting enzyme II (ACE2) is a multifunctional protein in both health and disease conditions, which serves as a counterregulatory component of RAS function in a cardioprotective role. ACE2 modulation may also have relevance to ovarian cancer, diabetes, acute lung injury, fibrotic diseases, etc. Furthermore, since the outbreak of the coronavirus disease in 2019 (COVID-19), ACE2 has been recognized as the host receptor of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The receptor binding domain of the SARS-CoV-2 S-protein has a strong interaction with ACE2, so ACE2 may be a potent drug target to prevent the virus from invading host cells for anti-COVID-19 drug discovery. In this study, structure- and property-based virtual screening methods were combined to filter natural product databases from ChemDiv, TargetMol, and InterBioScreen to find potential ACE2 inhibitors. The binding affinity between protein and ligands was predicted using both Glide SP and XP scoring functions and the MM-GBSA method. ADME properties were also calculated to evaluate chemical drug-likeness. Then, molecular dynamics (MD) simulations were performed to further explore the binding modes between the highest-potential compounds and ACE2. Results showed that the compounds 154-23-4 and STOCK1N-07141 possess potential ACE2 inhibition activities and deserve further study.
First Experimental Quantitative Charge Density Studies of Advanced Intermediate of Vitamin D Analogues
Authors: Wanat Monika , Malinska Maura , Kutner Andrzej , Woźniak Krzysztof
Published: March 2022

Vitamins D are a group of fat-soluble secosteroids which play a regulatory role in the functioning of most cells. Rational design of new vitamin D analogs, of increased therapeutic potency and lowered calcemic side effects, requires high-resolution initial structures and a deep understanding of interactions with the molecular targets. In this paper, using quantum crystallography, we present the first determination of the experimental quantitative charge density of an advanced intermediate of vitamin D analogues as well as a reconstruction of the theoretical electron density of final vitamin D analogues. Application of these methods allows for topological and electrostatic interaction energy analysis. We showed that the A-ring chair conformation has a significant influence on the topological properties of vitamin D compounds. Moreover, the interactions between the CD-ring and side-chain additionally stabilize the crystal structure. These results are supported by our theoretical calculations and previous biological studies.
Botanically-Derived Δ9-Tetrahydrocannabinol and Cannabidiol, and Their 1:1 Combination, Modulate Toll-like Receptor 3 and 4 Signalling in Immune Cells from People with Multiple Sclerosis
Authors: Fitzpatrick John-Mark , Hackett Becky , Costelloe Lisa , Hind William , Downer Eric J.
Published: March 2022

The innate immune response to bacterial and viral molecules involves the coordinated production of cytokines, chemokines, and type I interferons (IFNs), which is orchestrated by toll-like receptors (TLRs). TLRs, and their intracellular signalling intermediates, are closely associated with multiple sclerosis (MS) pathogenesis. Recent data from our laboratory reported that the plant-derived cannabinoids, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), regulate viral and bacterial inflammatory signalling pathways controlled by TLR3 and TLR4 in macrophages. The aim of this study was to assess the impact of THC and CBD, when delivered in isolation and in combination (1:1), on TLR3- and TLR4-dependent signalling in peripheral blood mononuclear cells (PBMCs) from people with MS (pwMS; n = 21) and healthy controls (HCs; n = 26). We employed the use of poly(I:C) and lipopolysaccharide (LPS) to induce viral TLR3 and bacterial TLR4 signalling, and PBMCs were pre-exposed to plant-derived highly purified THC (10 μM), CBD (10 μM), or a combination of both phytocannabinoids (1:1 ratio, 10:10 μM), prior to LPS/poly(I:C) exposure. TLR3 stimulation promoted the protein expression of the chemokine CXCL10 and the type I IFN-β in PBMCs from both cohorts. THC and CBD (delivered in 1:1 combination at 10 μM) attenuated TLR3-induced CXCL10 and IFN-β protein expression in PBMCs from pwMS and HCs, and this effect was not seen consistently when THC and CBD were delivered alone. In terms of LPS, TLR4 activation promoted TNF-α expression in PBMCs from both cohorts, and, interestingly, CBD when delivered alone at 10 μM, and in combination with THC (in 1:1 combination at 10 μM), exacerbated TLR4-induced TNF-α protein expression in PBMCs from pwMS and HCs. THC and CBD displayed no evidence of toxicity in primary PBMCs. No significant alteration in the relative expression of TLR3 and TLR4 mRNA, or components of the endocannabinoid system, including the cannabinoid receptor CB1 (encoded by CNR1 gene) and CB2 (encoded by CNR2 gene), and endocannabinoid metabolising enzymes, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MGLL), was determined in PBMCs from pwMS versus HCs. Given their role in inflammation, TLRs are clinical targets, and data herein identify CBD and THC as TLR3 and TLR4 modulating drugs in primary immune cells in vitro. This offers insight on the cellular target(s) of phytocannabinoids in targeting inflammation in the context of MS.
Aziridine Ring Opening as Regio- and Stereoselective Access to C-Glycosyl-Aminoethyl Sulfide Derivatives
Authors: Tracz Aleksandra , Malinowska Martyna , Leśniak Stanisław , Zawisza Anna
Published: March 2022

A short synthetic route to stereoselective access to C-glycosyl-aminoethyl sulfide derivatives has been developed through the reaction of tributhyltin derivatives of glycals with aziridinecarboaldehyde and the regioselective ring opening of a chiral aziridine with thiophenol. The absolute configurations of the resulting diastereoisomers were determined by 1H NMR spectroscopy.
Methyl Jasmonate Activates the 2C Methyl-D-erithrytol 2,4-cyclodiphosphate Synthase Gene and Stimulates Tanshinone Accumulation in Salvia miltiorrhiza Solid Callus Cultures
Authors: Szymczyk Piotr , Szymańska Grażyna , Kuźma Łukasz , Jeleń Agnieszka , Balcerczak Ewa
Published: March 2022

The present study characterizes the 5′ regulatory region of the SmMEC gene. The isolated fragment is 1559 bp long and consists of a promoter, 5′UTR and 31 nucleotide 5′ fragments of the CDS region. In silico bioinformatic analysis found that the promoter region contains repetitions of many potential cis-active elements. Cis-active elements associated with the response to methyl jasmonate (MeJa) were identified in the SmMEC gene promoter. Co-expression studies combined with earlier transcriptomic research suggest the significant role of MeJa in SmMEC gene regulation. These findings were in line with the results of the RT-PCR test showing SmMEC gene expression induction after 72 h of MeJa treatment. Biphasic total tanshinone accumulation was observed following treatment of S. miltiorrhiza solid callus cultures with 50–500 μM methyl jasmonate, with peaks observed after 10–20 and 50–60 days. An early peak of total tanshinone concentration (0.08%) occurred after 20 days of 100 μM MeJa induction, and a second, much lower one, was observed after 50 days of 50 μM MeJa stimulation (0.04%). The dominant tanshinones were cryptotanshinone (CT) and dihydrotanshinone (DHT). To better understand the inducing effect of MeJa treatment on tanshinone biosynthesis, a search was performed for methyl jasmonate-responsive cis-active motifs in the available sequences of gene proximal promoters associated with terpenoid precursor biosynthesis. The results indicate that MeJa has the potential to induce a significant proportion of the presented genes, which is in line with available transcriptomic and RT-PCR data.
Folate Conjugated Polyethylene Glycol Probe for Tumor-Targeted Drug Delivery of 5-Fluorouracil
Authors: Sarwar Shabnam , Abdul Qadir Muhammad , Alharthy Rima D. , Ahmed Mahmood , Ahmad Saghir , Vanmeert Michiel , Mirza Muhammad Usman , Hameed Abdul
Published: March 2022

A targeted delivery system is primarily intended to carry a potent anticancer drug to specific tumor sites within the bodily tissues. In the present study, a carrier system has been designed using folic acid (FA), bis-amine polyethylene glycol (PEG), and an anticancer drug, 5-fluorouracil (5-FU). FA and PEG were joined via an amide bond, and the resulting FA-PEG-NH2 was coupled to 5-FU producing folate-polyethylene glycol conjugated 5-fluorouracil (FA-PEG-5-FU). Spectroscopic techniques (UV-Vis, 1HNMR, FTIR, and HPLC) were used for the characterization of products. Prodrug (FA-PEG-5-FU) was analyzed for drug release profile (in vitro) up to 10 days and compared to a standard anticancer drug (5-FU). Folate conjugate was also analyzed to study its folate receptors (FR) mediated transport and in vitro cytotoxicity assays using HeLa cancer cells/Vero cells, respectively, and antitumor activity in tumor-bearing mice models. Folate conjugate showed steady drug release patterns and improved uptake in the HeLa cancer cells than Vero cells. Folate conjugate treated mice group showed smaller tumor volumes; specifically after the 15th day post-treatment, tumor sizes were decreased significantly compared to the standard drug group (5-FU). Molecular docking findings demonstrated importance of Trp138, Trp140, and Lys136 in the stabilization of flexible loop flanking the active site. The folic acid conjugated probe has shown the potential of targeted drug delivery and sustained release of anticancer drug to tumor lesions with intact antitumor efficacy.
Sustainability in Skin Care: Incorporation of Avocado Peel Extracts in Topical Formulations
Authors: Ferreira Sara M. , Falé Zizina , Santos Lúcia
Published: March 2022

The avocado peel is an agro-industrial by-product that has exhibited a massive increase in its production in the last few years. The reuse and valorisation of this by-product are essential since its disposal raises environmental concerns. In the present study, ethanolic extracts of avocado peels of the Hass variety were obtained, for three extraction times (1.5 h, 3 h and 4 h) and analysed for their antioxidant and antibacterial properties. Antioxidant evaluations of the extracts revealed that the extraction time of 1.5 h exhibited the best results amongst the three, with a DPPH inhibition percentage of 93.92 ± 1.29 and an IC50 percentage, the necessary concentration of the extract to inhibit 50% of DPPH, of 37.30 ± 1.00. The antibacterial capacity of the extracts was evaluated and it was revealed that they were able to inhibit the growth and development of bacteria of the Staphylococcus family. The obtained extract was incorporated in two types of cosmetic formulations (oil-in-water and water-in-oil) and their stability was evaluated and compared with formulations containing synthetic preservatives (BHT and phenoxyethanol). The results of the stability evaluation suggest that the avocado peel extract has the potential to be incorporated in both types of emulsions, acting as an antioxidant and antibacterial agent, proving it to be a viable option to reduce/replace the use of synthetic preservatives. Furthermore, the avocado peel extract proved to be more effective and stable in oil-in-water emulsions. These results highlight the possibility of obtaining sustainable cosmetics, significantly reducing the negative impacts on the environment by the incorporation of extracts sourced from the avocado peel, an interesting source of phenolic compounds, an abundant and low-cost by-product.
Significant Roles of Notch O-Glycosylation in Cancer
Authors: Wang Weiwei , Okajima Tetsuya , Takeuchi Hideyuki
Published: March 2022

Notch signaling, which was initially identified in Drosophila wing morphogenesis, plays pivotal roles in cell development and differentiation. Optimal Notch pathway activity is essential for normal development and dysregulation of Notch signaling leads to various human diseases, including many types of cancers. In hematopoietic cancers, such as T-cell acute lymphoblastic leukemia, Notch plays an oncogenic role, while in acute myeloid leukemia, it has a tumor-suppressive role. In solid tumors, such as hepatocellular carcinoma and medulloblastoma, Notch may have either an oncogenic or tumor-suppressive role, depending on the context. Aberrant expression of Notch receptors or ligands can alter the ligand-dependent Notch signaling and changes in trafficking can lead to ligand-independent signaling. Defects in any of the two signaling pathways can lead to tumorigenesis and tumor progression. Strikingly, O-glycosylation is one such process that modulates ligand–receptor binding and trafficking. Three types of O-linked modifications on the extracellular epidermal growth factor-like (EGF) repeats of Notch receptors are observed, namely O-glucosylation, O-fucosylation, and O-N-acetylglucosamine (GlcNAc) modifications. In addition, O-GalNAc mucin-type O-glycosylation outside the EGF repeats also appears to occur in Notch receptors. In this review, we first briefly summarize the basics of Notch signaling, describe the latest information on O-glycosylation of Notch receptors classified on a structural basis, and finally describe the regulation of Notch signaling by O-glycosylation in cancer.
Development and Optimization of Methylcellulose-Based Nanoemulgel Loaded with Nigella sativa Oil for Oral Health Management: Quadratic Model Approach
Authors: Sultan Muhammad H. , Javed Shamama , Madkhali Osama Ali , Alam Mohammad Intakhab , Almoshari Yosif , Bakkari Mohammad Ali , Sivadasan Durgaramani , Salawi Ahmad , Jabeen Ameena , Ahsan Waquar
Published: March 2022

The present study aimed to develop a local dental nanoemulgel formulation of Nigella sativa oil (NSO) for the treatment of periodontal diseases. NSO purchased from a local market was characterized using a GC–MS technique. A nanoemulsion containing NSO was prepared and incorporated into a methylcellulose gel base to develop the nanoemulgel formulation. The developed formulation was optimized using a Box–Behnken statistical design (quadratic model) with 17 runs. The effects of independent factors, such as water, oil, and polymer concentrations, were studied on two dependent responses, pH and viscosity. The optimized formulation was further evaluated for droplet size, drug release, stability, and antimicrobial efficacy. The developed formulation had a pH of 7.37, viscosity of 2343 cp, and droplet size of 342 ± 36.6 nm. Sustained release of the drug from the gel for up to 8 h was observed, which followed Higuchi release kinetics with non-Fickian diffusion. The developed nanoemulgel formulation showed improved antimicrobial activity compared to the plain NSO. Given the increasing emergence of periodontal diseases and antimicrobial resistance, an effective formulation based on a natural antibacterial agent is warranted as a dental therapeutic agent.