bluuebunny/crossref_metadata_2025 huggingface dataset:
Essential Oil-Based Design and Development of Novel Anti-Candida Azoles Formulation
Authors: Hamdy Rania , Fayed Bahgat , Hamoda Alshaimaa M. , Rawas-Qalaji Mutasem , Haider Mohamed , Soliman Sameh S. M.
Published: April 2020

Candida is the most common fungal class, causing both superficial and invasive diseases in humans. Although Candida albicans is the most common cause of fungal infections in humans, C. auris is a new emergent serious pathogen causing complications similar to those of C. albicans. Both C. albicans and C. auris are associated with high mortality rates, mainly because of their multidrug-resistance patterns against most available antifungal drugs. Although several compounds were designed against C. albicans, very few or none were tested on C. auris. Therefore, it is urgent to develop novel effective antifungal drugs that can accommodate not only C. albicans, but also other Candida spp., particularly newly emergent one, including C. auris. Inspired by the significant broad-spectrum antifungal activities of the essential oil cuminaldehyde and the reported wide incorporation of azoles in the antifungal drugs, a series of compounds (UoST1-11) was designed and developed. The new compounds were designed to overcome the toxicity of the aldehyde group of cuminaldehyde and benefit from the antifungal selectivity of azoles. The new developed UoST compounds showed significant anti-Candida activities against both Candida species. The best candidate compound, UoST5, was further formulated into polymeric nanoparticles (NPs). The new formula, UoST5-NPs, showed similar activities to the nanoparticles-free drug, while providing only 25% release after 24 h, maintainng prolonged activity up to 48 h and affording no toxicity. In conclusion, new azole formulations with significantly enhanced activities against C. albicans and C. auris, while maintaining prolonged action and no toxicities at lower concentrations, were developed.
Effect of Instant Controlled Pressure-Drop on the Non-Nutritional Compounds of Seeds and Sprouts of Common Black Bean (Phaseolus vulgaris L.)
Authors: Cardador-Martínez Anaberta , Martínez-Tequitlalpan Yara , Gallardo-Velazquez Tzayhri , Sánchez-Chino Xariss M. , Martínez-Herrera Jorge , Corzo-Ríos Luis Jorge , Jiménez-Martínez Cristian
Published: April 2020

The common bean is an important caloric-protein food source. However, its nutritional value may be affected by the presence of non-nutritional compounds, which decrease the assimilation of some nutrients; however, at low concentrations, they show a beneficial effect. Germination and treatment by controlled pressure-drop (DIC, French acronym of Détente Instantanée Contrôlée) are methods that modify the concentration of these components. The objective of this work was to evaluate the change in the non-nutritional composition of bean seeds and sprouts by DIC treatment. The results show that with the germination, the concentration of phenolic and tannin compounds increased 99% and 73%, respectively, as well as the quantity of saponins (65.7%), while phytates and trypsin inhibitors decreased 26% and 42%, respectively. When applying the DIC treatment, the content of phytates (23–29%), saponins (44%) and oligosaccharides increased in bean sprouts and decreased phenolic compounds (4–14%), tannins (23% to 72%), and trypsin inhibitors (95.5%), according to the pressure and time conditions applied. This technology opens the way to new perspectives, especially to more effective use of legumes as a source of vegetable protein or bioactive compounds.
New Substituted Benzoylthiourea Derivatives: From Design to Antimicrobial Applications
Authors: Limban Carmen , Chifiriuc Mariana Carmen , Caproiu Miron Teodor , Dumitrascu Florea , Ferbinteanu Marilena , Pintilie Lucia , Stefaniu Amalia , Vlad Ilinca Margareta , Bleotu Coralia , Marutescu Luminita Gabriela , Nuta Diana Camelia
Published: April 2020

The increasing threat of antimicrobial resistance to all currently available therapeutic agents has urged the development of novel antimicrobials. In this context, a series of new benzoylthiourea derivatives substituted with one or more fluorine atoms and with the trifluoromethyl group have been tested, synthesized, and characterized by IR, NMR, CHNS and crystal X-ray diffraction. The molecular docking has provided information regarding the binding affinity and the orientation of the new compounds to Escherichia coli DNA gyrase B. The docking score predicted the antimicrobial activity of the studied compounds, especially against E. coli, which was further demonstrated experimentally against planktonic and biofilm embedded bacterial and fungal cells. The compounds bearing one fluorine atom on the phenyl ring have shown the best antibacterial effect, while those with three fluorine atoms exhibited the most intensive antifungal activity. All tested compounds exhibited antibiofilm activity, correlated with the trifluoromethyl substituent, most favorable in para position.
Green Tea Catechins Trigger Immediate-Early Genes in the Hippocampus and Prevent Cognitive Decline and Lifespan Shortening
Authors: Unno Keiko , Pervin Monira , Taguchi Kyoko , Konishi Tomokazu , Nakamura Yoriyuki
Published: April 2020

Senescence-accelerated mouse prone 10 (SAMP10) mice, after ingesting green tea catechins (GT-catechin, 60 mg/kg), were found to have suppressed aging-related decline in brain function. The dose dependence of brain function on GT-catechin indicated that intake of 1 mg/kg or more suppressed cognitive decline and a shortened lifespan. Mice that ingested 1 mg/kg GT-catechin had the longest median survival, but the dose was less effective at suppressing cognitive decline. The optimal dose for improving memory acquisition was 60 mg/kg, and memory retention was higher in mice that ingested 30 mg/kg or more. To elucidate the mechanism by which cognitive decline is suppressed by GT-catechin, changes in gene expression in the hippocampus of SAMP10 mice one month after ingesting GT-catechin were analyzed. The results show that the expression of immediate-early genes such as nuclear receptor subfamily 4 (Nr4a), FBJ osteosarcoma oncogene (Fos), early growth response 1 (Egr1), neuronal PAS domain protein 4 (Npas4), and cysteine-rich protein 61 (Cyr61) was significantly increased. These results suggest that GT-catechin suppresses age-related cognitive decline via increased expression of immediate-early genes that are involved in long-term changes in plasticity of synapses and neuronal circuits.
Synthesis and Biological Evaluation of Novel (thio)semicarbazone-Based Benzimidazoles as Antiviral Agents against Human Respiratory Viruses
Authors: Francesconi Valeria , Cichero Elena , Schenone Silvia , Naesens Lieve , Tonelli Michele
Published: April 2020

Respiratory RNA viruses are responsible for recurrent acute respiratory illnesses that still represent a major medical need. Previously we developed a large variety of benzimidazole derivatives able to inhibit these viruses. Herein, two series of (thio)semicarbazone- and hydrazone-based benzimidazoles have been explored, by derivatizing 5-acetyl benzimidazoles previously reported by us, thereby evaluating the influence of the modification on the antiviral activity. Compounds 6, 8, 16 and 17, bearing the 5-(thio)semicarbazone and 5-hydrazone functionalities in combination with the 2-benzyl ring on the benzimidazole core structure, acted as dual inhibitors of influenza A virus and human coronavirus. For respiratory syncytial virus (RSV), activity is limited to the 5-thiosemicarbazone (25) and 5-hydrazone (22) compounds carrying the 2-[(benzotriazol-1/2-yl)methyl]benzimidazole scaffold. These molecules proved to be the most effective antiviral agents, able to reach the potency profile of the licensed drug ribavirin. The molecular docking analysis explained the SAR of these compounds around their binding mode to the target RSV F protein, revealing the key contacts for further assessment. The herein-investigated benzimidazole-based derivatives may represent valuable hit compounds, deserving subsequent structural improvements towards more efficient antiviral agents for the treatment of pathologies caused by these human respiratory viruses.
Bifidobacterium animalis subsp. lactis A6 Alleviates Obesity Associated with Promoting Mitochondrial Biogenesis and Function of Adipose Tissue in Mice
Authors: Huo Yanxiong , Lu Xuhong , Wang Xiaoyu , Wang Xifan , Chen Lingli , Guo Huiyuan , Zhang Ming , Li Yixuan
Published: April 2020

Probiotics are widely known for their health benefits. Mitochondrial dysfunction is related to obesity. The aim of this study was to illuminate whether Bifidobacterium animalis subsp. lactis A6 (BAA6) could improve obesity due to increased mitochondrial biogenesis and function of adipose tissues. Four-week-old male C57BL/6 mice were fed with a high-fat diet (HFD) for 17 weeks. For the final eight weeks, the HFD group was divided into three groups including HFD, HFD with BAA6 (HFD + BAA6 group), and HFD with Akkermansia muciniphila (AKK) (HFD + AKK group as positive control). The composition of the microbiota, serum lipopolysaccharides (LPS), and mitochondrial biosynthesis and function of epididymal adipose tissues were measured. Compared with the HFD group, body weight, relative fat weight, the relative abundance of Oscillibacter and Bilophila, and serum LPS were significantly decreased in the HFD + BAA6 and HFD + AKK groups (p < 0.05). Furthermore, the addition of BAA6 and AKK increased the expression of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) (by 21.53- and 18.51-fold), estrogen-related receptor α (ERRα) (by 2.83- and 1.24-fold), and uncoupling protein-1 (UCP-1) (by 1.51- and 0.60-fold) in epididymal adipose tissues. Our results suggest that BAA6 could improve obesity associated with promoting mitochondrial biogenesis and function of adipose tissues in mice.
Analytical Detection of Sulfonamides and Organophosphorus Insecticide Residues in Fish in Taiwan
Authors: Chang Chung-Pei , Hou Po-Hsun , Yang Wei-Cheng , Wu Ching-Fen , Chang Chia-Chia , Tsai Ming-Yang , Tsai Hsiao-Pei , Lin Chien-Teng , Xue Yi-Jing , Wang Jiann-Hsiung , Chang Geng-Ruei
Published: April 2020

Exposure to residues of antibiotics (e.g., sulfonamides) and insecticides (e.g., organophosphorus insecticides) in aquacultured food can adversely affect humans and animals and thus affect public health globally. Here, using a validated method, we examined the levels of residues of 12 sulfonamides as well as 18 organophosphorus insecticides in aquacultured fish in Taiwan. A total of 52 fish samples (i.e., 20 tilapia, 16 milk fish, and 16 perch samples) were obtained from Taiwanese aquafarms from June 2018 to October 2019. We detected 0.02 and 0.03 mg/kg of sulfamethazine (a sulfonamide) in one tilapia and one milk fish, respectively, and 0.02, 0.05, and 0.03 mg/kg of chlorpyrifos (an organophosphorus insecticide) in one tilapia, one milk fish, and one perch, respectively; thus, among the samples, 3.85% and 5.77% contained sulfonamides and organophosphorus insecticide residues, respectively. Furthermore, we assessed human health risk based on the estimated daily intakes (EDIs) of these residues: EDIs of sulfonamide and organophosphorus insecticide residues were <1.0% of the acceptable daily intake recommended by the Joint Food and Agriculture Organization of the United Nations/World Health Organization Expert Committee on Food Additives. The risk of exposure to sulfonamide and organophosphorus insecticide residue by consuming aquacultured fish in Taiwan was thus negligible, signifying no immediate health risk related to the consumption of fish. Our findings can constitute a reference in efforts geared toward ensuring food safety and monitoring veterinary drug and insecticide residue levels in aquacultured organisms. Residue levels in fish must be continually monitored to further determine possible effects of these residues on human health.
Use of Thermal Black as Eco-Filler in Thermoplastic Composites and Hybrids for Injection Molding and 3D Printing Applications
Authors: Mihai Mihaela , Stoeffler Karen , Norton Edward
Published: April 2020

Thermal black (TB) is one of the purest and cleanest forms of carbon black (CB) commercially available. TB is manufactured by the decomposition of natural gas in the absence of oxygen while the common furnace CB is derived from the burning of organic oil. TB has a larger particle size, a lower surface area, and lower level of particle aggregation, while being the most eco-friendly grade among the CB family. This study is the first-time evaluation of TB as filler in composites and hybrids based on thermoplastics such as polypropylene (PP), polyamide 6 (PA6), polyphenylene sulfide (PPS), and acrylonitrile butadiene styrene (ABS). TB loadings in composites were varied from 1 up to 40 wt. % and, in hybrids, the TB was used in combination with carbon fibers (CFs) at total contents up to 20 wt. %. TB-containing composites and hybrids based on PA6 and ABS were also extruded in filaments, used in 3D printing, and the obtained 3D printed parts were characterized. TB provided a very high loadability in thermoplastics while preserving their viscosity and performance. TB can replace a fraction of expensive CFs in composites without important changes in the composites’ performance. The composites and hybrids exhibited electrical resistivity and good mechanical and thermal properties when compared to commercial compounds, while enabling significant cost savings. TB also showed to be an excellent coloring agent. TB proved to be an outstanding eco-filler for compounds to be used in injection molding and 3D printing technologies.
Cognitive Facilitation and Antioxidant Effects of an Essential Oil Mix on Scopolamine-Induced Amnesia in Rats: Molecular Modeling of In Vitro and In Vivo Approaches
Authors: Boiangiu Razvan Stefan , Brinza Ion , Hancianu Monica , Erdogan Orhan Ilkay , Eren Gokcen , Gündüz Elife , Ertas Halis , Hritcu Lucian , Cioanca Oana
Published: April 2020

The present study investigated the capability of an essential oil mix (MO: 1% and 3%) in ameliorating amnesia and brain oxidative stress in a rat model of scopolamine (Sco) and tried to explore the underlying mechanism. The MO was administered by inhalation to rats once daily for 21 days, while Sco (0.7 mg/kg) treatment was delivered 30 min before behavioral tests. Donepezil (DP: 5 mg/kg) was used as a positive reference drug. The cognitive-enhancing effects of the MO in the Sco rat model were assessed in the Y-maze, radial arm maze (RAM), and novel object recognition (NOR) tests. As identified by gas chromatography–mass spectrometry (GC–MS), the chemical composition of the MO is comprised by limonene (91.11%), followed by γ-terpinene (2.02%), β-myrcene (1.92%), β-pinene (1.76%), α-pinene (1.01%), sabinene (0.67%), linalool (0.55%), cymene (0.53%), and valencene (0.43%). Molecular interactions of limonene as the major compound in MO with the active site of butyrylcholinesterase (BChE) was explored via molecular docking experiments, and Van der Waals (vdW) contacts were observed between limonene and the active site residues SER198, HIS438, LEU286, VAL288, and PHE329. The brain oxidative status and acetylcholinesterase (AChE) and BChE inhibitory activities were also determined. MO reversed Sco-induced memory deficits and brain oxidative stress, along with cholinesterase inhibitory effects, which is an important mechanism in the anti-amnesia effect. Our present findings suggest that MO ameliorated memory impairment induced by Sco via restoration of the cholinergic system activity and brain antioxidant status.
Combined Pre- and Posttreatment of Paraoxon Exposure
Authors: Lorke Dietrich E , Nurulain Syed M , Hasan Mohamed Y , Kuča Kamil , Petroianu Georg A
Published: April 2020

Aims: Organophosphates (OPCs), useful agents as pesticides, also represent a serious health hazard. Standard therapy with atropine and established oxime-type enzyme reactivators is unsatisfactory. Experimental data indicate that superior therapeutic results can be obtained when reversible cholinesterase inhibitors are administered before OPC exposure. Comparing the protective efficacy of five such cholinesterase inhibitors (physostigmine, pyridostigmine, ranitidine, tacrine, or K-27), we observed best protection for the experimental oxime K-27. The present study was undertaken in order to determine if additional administration of K-27 immediately after OPC (paraoxon) exposure can improve the outcome. Methods: Therapeutic efficacy was assessed in rats by determining the relative risk of death (RR) by Cox survival analysis over a period of 48 h. Animals that received only pretreatment and paraoxon were compared with those that had received pretreatment and paraoxon followed by K-27 immediately after paraoxon exposure. Results: Best protection from paraoxon-induced mortality was observed after pretreatment with physostigmine (RR = 0.30) and K-27 (RR = 0.34). Both substances were significantly more efficacious than tacrine (RR = 0.67), ranitidine (RR = 0.72), and pyridostigmine (RR = 0.76), which were less efficacious but still significantly reduced the RR compared to the no-treatment group (paraoxon only). Additional administration of K-27 immediately after paraoxon exposure (posttreatment) did not further reduce mortality. Statistical analysis between pretreatment before paraoxon exposure alone and pretreatment plus K-27 posttreatment did not show any significant difference for any of the pretreatment regimens. Conclusions: Best outcome is achieved if physostigmine or K-27 are administered prophylactically before exposure to sublethal paraoxon dosages. Therapeutic outcome is not further improved by additional oxime therapy immediately thereafter.
Acorn Isotopic Composition: A New Promising Tool for Authenticity Maps of Montado’s High-Value Food Products
Authors: Alegria Carla , Antunes Cristina , Giovanetti Manuela , Abreu Marta , Máguas Cristina
Published: April 2020

It is often overlooked that even food production is linked to the ecology of plants and animals. Living organisms respond to environmental short-and long-term variability: acknowledging this may help in the ultimate goal of valorizing a territory/product. We investigated acorns of the two main Quercus species of the Portuguese Montado, a main feed of the renown black Iberian pig. We tested their responses to an aridity gradient by morphological parameters and isotopic signature. Q. rotundifolia and Q. suber acorns did not differ morphologically, even if a higher variability in all parameters was observed in acorns of Q. suber. According to the site-specific Aridity Index, correlations are indicative to higher weight and length only in Q. suber acorns from more arid sites. As for isotopic composition, there were no differences in nitrogen or carbon (δ15N and δ13C) between the two species. However, combining the samples and testing for association with the Aridity Index, we found that more arid sites lead to a 15N enrichment. This result, combined with the positive correlation between AI and acorns length, support the use of acorns as a tool, their isoscapes of nitrogen being a stepping stone for the provenance of the black Iberian pig.
Formulation and Optimization of Nanoemulsions Using the Natural Surfactant Saponin from Quillaja Bark
Authors: Schreiner Tatiana B. , Santamaria-Echart Arantzazu , Ribeiro Andreia , Peres António M. , Dias Madalena M. , Pinho Simão P. , Barreiro Maria Filomena
Published: April 2020

Replacing synthetic surfactants by natural alternatives when formulating nanoemulsions has gained attention as a sustainable approach. In this context, nanoemulsions based on sweet almond oil and stabilized by saponin from Quillaja bark with glycerol as cosurfactant were prepared by the high-pressure homogenization method. The effects of oil/water (O/W) ratio, total surfactant amount, and saponin/glycerol ratio on their stability were analyzed. The formation and stabilization of the oil-in-water nanoemulsions were analyzed through the evaluation of stability over time, pH, zeta potential, and particle size distribution analysis. Moreover, a design of experiments was performed to assess the most suitable composition based on particle size and stability parameters. The prepared nanoemulsions are, in general, highly stable over time, showing zeta potential values lower than −40 mV, a slight acid behavior due to the character of the components, and particle size (in volume) in the range of 1.1 to 4.3 µm. Response surface methodology revealed that formulations using an O/W ratio of 10/90 and 1.5 wt% surfactant resulted in lower particle sizes and zeta potential, presenting higher stability. The use of glycerol did not positively affect the formulations, which reinforces the suitability of preparing highly stable nanoemulsions based on natural surfactants such as saponins.
Antiestrogenic Activity and Possible Mode of Action of Certain New Nonsteroidal Coumarin-4-acetamides
Authors: Almutairi Maha S. , Al Suwayyid Areej N. , Aldarwesh Amal , Aboulwafa Omaima M. , Attia Mohamed I.
Published: April 2020

The preparation of certain 2-(2-oxo-2H-chromen-4-yl)-N-substituted acetamides IIIa–h was planned as a step in the development of new modified nonsteroidal antiestrogens. The purity of target compounds IIIa–h was checked by thin-layer chromatography (TLC), and their structures were confirmed using various spectroscopic tools including IR, 1H-NMR, 13C-NMR, and MS spectroscopy. Viability tests were applied using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay to evaluate the cytotoxic effect of the synthesized compounds against two breast cancer cell lines, MCF-7 and MDA-MB-231. Compound IIIb proved the most active against MCF-7 cells, with an IC50 value of 0.32 μM. The results of an analysis of in vitro antiestrogenic activity indicated that only compound IIIb exhibited antiestrogenic activity; its IC50 value of 29.49 μM was about twice as potent as that of the reference compound, MIBP. The aromatase activity was evaluated for the synthesized target compounds IIIa–g and the intermediates Ib and IIa. A significant aromatase inhibition was observed for the intermediate Ib and compound IIIe, with IC50 values of 14.5 and 17.4 μM, respectively. Compound IIIb, namely 7-methoxy-4-(2-oxo-2-(piperidin-1-yl)ethyl)-2H-chromen-2-one, could be used as an antiestrogen and/or cytotoxic agent with selective activity against tumor cells.
Synthesis and Antimicrobial Activity of Phosphonopeptide Derivatives Incorporating Single and Dual Inhibitors
Authors: Ng Keng Tiong , Perry John D. , Marrs Emma C.L. , Orenga Sylvain , Anderson Rosaleen J. , Gray Mark
Published: April 2020

In diagnostic microbiology, culture media are widely used for detection of pathogenic bacteria. Such media employ various ingredients to optimize detection of specific pathogens such as chromogenic enzyme substrates and selective inhibitors to reduce the presence of commensal bacteria. Despite this, it is rarely possible to inhibit the growth of all commensal bacteria, and thus pathogens can be overgrown and remain undetected. One approach to attempt to remedy this is the use of “suicide substrates” that can target specific bacterial enzymes and selectively inhibit unwanted bacterial species. With the purpose of identifying novel selective inhibitors, six novel phosphonopeptide derivatives based on d/l-fosfalin and β-chloro-l-alanine were synthesized and tested on 19 different strains of clinically relevant bacteria. Several compounds show potential as useful selective agents that could be exploited in the recovery of several bacterial pathogens including Salmonella, Pseudomonas aeruginosa, and Listeria.
5-Alkylamino-N-phenylpyrazine-2-carboxamides: Design, Preparation, and Antimycobacterial Evaluation
Authors: Ambrożkiewicz Weronika , Kučerová-Chlupáčová Marta , Janďourek Ondřej , Konečná Klára , Paterová Pavla , Bárta Pavel , Vinšová Jarmila , Doležal Martin , Zitko Jan
Published: April 2020

According to the World Health Organization, tuberculosis is still in the top ten causes of death from a single infectious agent, killing more than 1.7 million people worldwide each year. The rising resistance developed by Mycobacterium tuberculosis against currently used antituberculars is an imperative to develop new compounds with potential antimycobacterial activity. As a part of our continuous research on structural derivatives of the first-line antitubercular pyrazinamide, we have designed, prepared, and assessed the in vitro whole cell growth inhibition activity of forty-two novel 5-alkylamino-N-phenylpyrazine-2-carboxamides with various length of the alkylamino chain (propylamino to octylamino) and various simple substituents on the benzene ring. Final compounds were tested against Mycobacterium tuberculosis H37Ra and four other mycobacterial strains (M. aurum, M. smegmatis, M. kansasii, M. avium) in a modified Microplate Alamar Blue Assay. We identified several candidate molecules with micromolar MIC against M. tuberculosis H37Ra and low in vitro cytotoxicity in HepG2 cell line, for example, N-(4-hydroxyphenyl)-5-(pentylamino)pyrazine-2-carboxamide (3c, MIC = 3.91 µg/mL or 13.02 µM, SI > 38) and 5-(heptylamino)-N-(p-tolyl)pyrazine-2-carboxamide (4e, MIC = 0.78 µg/mL or 2.39 µM, SI > 20). In a complementary screening, we evaluated the in vitro activity against bacterial and fungal strains of clinical importance. We observed no antibacterial activity and sporadic antifungal activity against the Candida genus.
Purine and Purine Isostere Derivatives of Ferrocene: An Evaluation of ADME, Antitumor and Electrochemical Properties
Authors: Rep Valentina , Piškor Martina , Šimek Helena , Mišetić Petra , Grbčić Petra , Padovan Jasna , Gabelica Marković Vesna , Jadreško Dijana , Pavelić Krešimir , Kraljević Pavelić Sandra , Raić-Malić Silvana
Published: April 2020

Novel purine and purine isosteres containing a ferrocene motif and 4,1-disubstituted (11a−11c, 12a−12c, 13a−13c, 14a−14c, 15a−15c, 16a, 23a−23c, 24a−24c, 25a−25c) and 1,4-disubstituted (34a−34c and 35a−35c) 1,2,3-triazole rings were synthesized. The most potent cytotoxic effect on colorectal adenocarcinoma (SW620) was exerted by the 6-chloro-7-deazapurine 11c (IC50 = 9.07 µM), 6-chloropurine 13a (IC50 = 14.38 µM) and 15b (IC50 = 15.50 µM) ferrocenylalkyl derivatives. The N-9 isomer of 6-chloropurine 13a containing ferrocenylmethylene unit showed a favourable in vitro physicochemical and ADME properties including high solubility, moderate permeability and good metabolic stability in human liver microsomes.
Scaffold Hopping in Discovery of HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors: From CH(CN)-DABOs to CH(CN)-DAPYs
Authors: Li Ting-Ting , Pannecouque Christophe , De Clercq Erik , Zhuang Chun-Lin , Chen Fen-Er
Published: April 2020

Scaffold hopping is a frequently-used strategy in the development of non-nucleoside reverse transcriptase inhibitors. Herein, CH(CN)-DAPYs were designed by hopping the cyano-methylene linker of our previous published CH(CN)-DABOs onto the etravirine (ETR). Eighteen CH(CN)-DAPYs were synthesized and evaluated for their anti-HIV activity. Most compounds exhibited promising activity against wild-type (WT) HIV-1. Compounds B4 (EC50 = 6 nM) and B6 (EC50 = 8 nM) showed single-digit nanomolar potency against WT HIV-1. Moreover, these two compounds had EC50 values of 0.06 and 0.08 μM toward the K103N mutant, respectively, which were comparable to the reference efavirenz (EFV) (EC50 = 0.08 μM). The preliminary structure–activity relationship (SAR) indicated that introducing substitutions on C2 of the 4-cyanophenyl group could improve antiviral activity. Molecular docking predicted that the cyano-methylene linker was positioned into the hydrophobic cavity formed by Y181/Y188 and V179 residues.
Lecithin-Based Dermal Drug Delivery for Anti-Pigmentation Maize Ceramide
Authors: Kagotani Kazuhiro , Nakayama Hiroko , Zang Liqing , Fujimoto Yuki , Hayashi Akihito , Sono Ryoji , Nishimura Norihiro , Shimada Yasuhito
Published: April 2020

Ceramides have several well-known biological properties, including anti-pigmentation and anti-melanogenesis, which make them applicable for use in skincare products in cosmetics. However, the efficacy of ceramides is still limited. Dermal or transdermal drug delivery systems can enhance the anti-pigmentation properties of ceramides, although there is currently no systemic evaluation method for the efficacy of these systems. Here we prepared several types of lecithin-based emulsion of maize-derived glucosylceramide, determining PC70-ceramide (phosphatidylcholine-base) to be the safest and most effective anti-pigmentation agent using zebrafish larvae. We also demonstrated the efficacy of PC70 as a drug delivery system by showing that PC70-Nile Red (red fluorescence) promoted Nile Red accumulation in the larval bodies. In addition, PC70-ceramide suppressed melanin in mouse B16 melanoma cells compared to ceramide alone. In conclusion, we developed a lecithin-based dermal delivery method for ceramide using zebrafish larvae with implications for human clinical use.
Visible Light-Induced Homolytic Cleavage of Perfluoroalkyl Iodides Mediated by Phosphines
Authors: Bracker Mario , Helmecke Lucas , Kleinschmidt Martin , Czekelius Constantin , Marian Christel M.
Published: April 2020

In an effort to explain the experimentally observed variation of the photocatalytic activity of t Bu 3 P, n Bu 3 P and (MeO) 3 P in the blue-light regime [Helmecke et al., Org. Lett. 21 (2019) 7823], we have explored the absorption characteristics of several phosphine– and phosphite–IC 4 F 9 adducts by means of relativistic density functional theory and multireference configuration interaction methods. Based on the results of these computational and complementary experimental studies, we offer an explanation for the broad tailing of the absorption of t Bu 3 P-IC 4 F 9 and (MeO) 3 P-IC 4 F 9 into the visible-light region. Larger coordinate displacements of the ground and excited singlet potential energy wells in n Bu 3 P-IC 4 F 9 , in particular with regard to the P–I–C bending angle, reduce the Franck–Condon factors and thus the absorption probability compared to t Bu 3 P-IC 4 F 9 . Spectroscopic and computational evaluation of conformationally flexible and locked phosphites suggests that the reactivity of (MeO) 3 P may be the result of oxygen lone-pair participation and concomitant broadening of absorption. The proposed mechanism for the phosphine-catalyzed homolytic C–I cleavage of perfluorobutane iodide involves S1 ← S0 absorption of the adduct followed by intersystem crossing to the photochemically active T 1 state.
Ajmalicine and Reserpine: Indole Alkaloids as Multi-Target Directed Ligands Towards Factors Implicated in Alzheimer’s Disease
Authors: Kashyap Priya , Kalaiselvan Vivekanandan , Kumar Robin , Kumar Suresh
Published: April 2020

Alzheimer’s disease (AD) is a multifactorial disorder characterized by exponential loss of memory and cognitive deficit involving several disease modifying targets (amyloid beta, beta-secretase, monoaminoxidase-B, and cholinesterase). The present study explores multi-target directed ligand approach using secondary metabolite reserpine (RES) and ajmalicine (AJM) obtained from Rauwolfia serpentina roots. Novel LCMS and HPLC methods were developed for identification and quantification of reserpine and ajmalicine. In vitro enzyme inhibition assays were performed to evaluate anti-cholinesterase, β-site amyloid cleaving enzyme (BACE-1) inhibition and monoamine oxidase-B (MAO-B) inhibition, further analyzed with in silico analysis. Anti-amyloidogenic potential was studied using anti-aggregation studies along with TEM and circular dichroism (CD) analysis. In vitro neuroprotective potential against Aβ toxicity and anti-oxidative stress was demonstrated using PC12 cell cultures. Reserpine is a more potent dual cholinesterase inhibitor than ajmalicine (IC50 values of 1.7 μM (AChE) and 2.8 μM (BuChE)). The anti-aggregation activity of reserpine (68%) was more than ajmalicine (56%). Both compounds demonstrated neuroprotective activity against Aβ42 (92%) and H2O2 (93%) induced toxicity in PC12 cells against controls. Phytocompounds also inhibited MAO-B and BACE-1 enzymes in concentration dependent manner. Molecular docking studies indicated the strong binding of compounds to the catalytic site of targets. This novel study demonstrated that reserpine and ajmalicine as a multi-target directed ligand that have disease modifying potential for amelioration of AD.
The Automation Technique Lab-In-Syringe: A Practical Guide
Authors: Horstkotte Burkhard , Solich Petr
Published: April 2020

About eight years ago, a new automation approach and flow technique called “Lab-In-Syringe” was proposed. It was derived from previous flow techniques, all based on handling reagent and sample solutions in a flow manifold. To date Lab-In-Syringe has evidently gained the interest of researchers in many countries, with new modifications, operation modes, and technical improvements still popping up. It has proven to be a versatile tool for the automation of sample preparation, particularly, liquid-phase microextraction approaches. This article aims to assist newcomers to this technique in system planning and setup by overviewing the different options for configurations, limitations, and feasible operations. This includes syringe orientation, in-syringe stirring modes, in-syringe detection, additional inlets, and addable features. The authors give also a chronological overview of technical milestones and a critical explanation on the potentials and shortcomings of this technique, calculations of characteristics, and tips and tricks on method development. Moreover, a comprehensive overview of the different operation modes of Lab-In-Syringe automated sample pretreatment is given focusing on the technical aspects and challenges of the related operations. We further deal with possibilities on how to fabricate required or useful system components, in particular by 3D printing technology, with over 20 different elements exemplarily shown. Finally, a short discussion on shortcomings and required improvements is given.
Role of Indole Scaffolds as Pharmacophores in the Development of Anti-Lung Cancer Agents
Authors: Dhuguru Jyothi , Skouta Rachid
Published: April 2020

Lung cancer is the leading cause of death in men and women worldwide, affecting millions of people. Between the two types of lung cancers, non-small cell lung cancer (NSCLC) is more common than small cell lung cancer (SCLC). Besides surgery and radiotherapy, chemotherapy is the most important method of treatment for lung cancer. Indole scaffold is considered one of the most privileged scaffolds in heterocyclic chemistry. Indole may serve as an effective probe for the development of new drug candidates against challenging diseases, including lung cancer. In this review, we will focus on discussing the existing indole based pharmacophores in the clinical and pre-clinical stages of development against lung cancer, along with the synthesis of some of the selected anti-lung cancer drugs. Moreover, the basic mechanism of action underlying indole based anti-lung cancer treatment, such as protein kinase inhibition, histone deacetylase inhibition, DNA topoisomerase inhibition, and tubulin inhibition will also be discussed.
Antiproliferative and Antimetastatic Effects of Praeruptorin C on Human Non–Small Cell Lung Cancer through Inactivating ERK/CTSD Signalling Pathways
Authors: Liu Chien-Ming , Shen Huan-Ting , Lin Yi-An , Yu Yung-Luen , Chen Yong-Syuan , Liu Chung-Jung , Hsieh Yi-Hsien
Published: April 2020

Praeruptorin C (PC) reportedly has beneficial effects in terms of antiinflammation, antihypertension, and antiplatelet aggregation, and it potentially has anticancer activity. However, the effect of PC on human non–small cell lung cancer (NSCLC) is largely unknown. Compared with the effects of praeruptorin A and praeruptorin B, we observed that PC significantly suppressed cell proliferation, colony formation, wound closure, and migration and invasion of NSCLC cells. It induced cell cycle arrest in the G0/G1 phase, downregulated cyclin D1 protein, and upregulated p21 protein. PC also significantly reduced the expression of cathepsin D (CTSD). In addition, the phosphorylation/activation of the ERK1/2 signalling pathway was significantly suppressed in PC-treated NSCLC cells. Cotreatment with PC and U0126 synergistically inhibited CTSD expression, cell migration, and cell invasion, which suggests that the ERK1/2 signalling pathway is involved in the downregulation of CTSD expression and invasion activity of NSCLC cells by PC. These findings are the first to demonstrate the inhibitory effects of PC in NSCLC progression. Therefore, PC may represent a novel strategy for treating NSCLC.
A Global Model for the Estimation of Speeds of Sound in Deep Eutectic Solvents
Authors: Peyrovedin Hamed , Haghbakhsh Reza , Duarte Ana Rita C. , Raeissi Sona
Published: April 2020

Deep eutectic solvents (DESs) are newly introduced green solvents that have attracted much attention regarding fundamentals and applications. Of the problems along the way of replacing a common solvent by a DES, is the lack of information on the thermophysical properties of DESs. This is even more accentuated by considering the dramatically growing number of DESs, being made by the combination of vast numbers of the constituting substances, and at their various molar ratios. The speed of sound is among the properties that can be used to estimate other important thermodynamic properties. In this work, a global and accurate model is proposed and used to estimate the speed of sound in 39 different DESs. This is the first general speed of sound model for DESs. The model does not require any thermodynamic properties other than the critical properties of the DESs, which are themselves calculated by group contribution methods, and in doing so, make the proposed method entirely independent of any experimental data as input. The results indicated that the average absolute relative deviation percentages (AARD%) of this model for 420 experimental data is only 5.4%. Accordingly, based on the achieved results, the proposed model can be used to predict the speeds of sound of DESs.
The Analysis of Lead Phytotoxicity in Seeds Using CO2 Laser Photoacoustic Spectroscopy
Authors: Popa Cristina , Bratu Ana Maria , Petrus Mioara , Bacalum Mihaela
Published: April 2020

Lead (Pb) is the most prevalent heavy metal pollutant in the natural environment. Pb is not a fundamental element for plants, but they absorb it when it is present in their environment, having no known physiological activity. The aim of our research was to evaluate the efficacy of laser photoacoustic spectroscopy as a tool to monitor changes induced by Pb in plant respiration by highlighting two molecular markers (C2H4 and CO2). To better understand Pb phytotoxicity, we monitored the plantlets evolution as well as the morphology of the root cells. Firstly, we showed that the treatment hinders the plantlet’s development. Furthermore, using laser photoacoustic spectroscopy, we found a decrease in the concentration of C2H4 and CO2 vapors measured in the respiration of treated plants. Finally, fluorescence microscopy results showed that in Pb treated plantlets, the cell roots morphology is clearly altered as compared with the untreated ones. All the results are well correlated and can help further in understanding Pb phytotoxicity.
Use of Lead Isotopic Ratios as Geographical Tracer for Lambrusco PDO Wines
Authors: Lancellotti Lisa , Sighinolfi Simona , Marchetti Andrea , Tassi Lorenzo
Published: April 2020

In this study, the lead isotope signature was tested with the aim to verify its potential as geographic tracer for wine production and particularly for the Lambrusco PDO wines of the province of Modena (Italy). A solid phase extraction procedure, for separating lead from the investigated matrices, soil and wine, was optimized. Furthermore, different mathematical models, based on an exponential law and internal or external correction approach, were evaluated for the correction of instrumental mass dependent fractionation. The optimized analytical procedure yielded isotopic ratio data relative to the lead NIST 981 standard, 208Pb/206Pb = 2.16664 and 207Pb/206Pb = 0.914645, in good agreement both with the tabulated values and with the most recent literature data. Measured isotope ratio data highlight the contribute of multiple lead sources in bottled wine but different from the one present in soils.
Self-Avoiding Random Walks as a Model to Study Athermal Linear Polymers under Extreme Plate Confinement
Authors: Parreño Oscar , Ramos Pablo Miguel , Karayiannis Nikos Ch. , Laso Manuel
Published: April 2020

Monte Carlo (MC) simulations, built around chain-connectivity-altering moves and a wall-displacement algorithm, allow us to simulate freely-jointed chains of tangent hard spheres of uniform size under extreme confinement. The latter is realized through the presence of two impenetrable, flat, and parallel plates. Extreme conditions correspond to the case where the distance between the plates approaches the monomer size. An analysis of the local structure, based on the characteristic crystallographic element (CCE) norm, detects crystal nucleation and growth at packing densities well below the ones observed in bulk analogs. In a second step, we map the confined polymer chains into self-avoiding random walks (SAWs) on restricted lattices. We study all realizations of the cubic crystal system: simple, body centered, and face centered cubic crystals. For a given chain size (SAW length), lattice type, origin of SAW, and level of confinement, we enumerate all possible SAWs (equivalently all chain conformations) and calculate the size distribution. Results for intermediate SAW lengths are used to predict the behavior of long, fully entangled chains through growth formulas. The SAW analysis will allow us to determine the corresponding configurational entropy, as it is the driving force for the observed phase transition and the determining factor for the thermodynamic stability of the corresponding crystal morphologies.
Securing MQTT by Blockchain-Based OTP Authentication
Authors: Buccafurri Francesco , De Angelis Vincenzo , Nardone Roberto
Published: April 2020

The Internet of Things is constantly capturing interest from modern applications, changing our everyday life and empowering industrial applications. Interaction and the collaboration among smart devices offer new challenges to security since they conflict with economic and energy consumption requirement constraints. On the other hand, the lack of security measures could negatively impact the concrete adoption of this paradigm. This paper focuses on the Message Queuing Telemetry Transport (MQTT) protocol, widely adopted in the Internet of Things. This protocol does not implement natively secure authentication mechanisms, which are demanded to developers. Hence, this paper proposes a novel OTP (one-time password)-authentication schema for MQTT, which uses the Ethereum blockchain to implement a second-factor out-of-band channel. The proposal enables the authentication of both local and remote devices preserving user privacy and guaranteeing trust and accountability via Ethereum smart contracts.
Uncertainty Quantification in Machine Learning Modeling for Multi-Step Time Series Forecasting: Example of Recurrent Neural Networks in Discharge Simulations
Authors: Song Tianyu , Ding Wei , Liu Haixing , Wu Jian , Zhou Huicheng , Chu Jinggang
Published: April 2020

As a revolutionary tool leading to substantial changes across many areas, Machine Learning (ML) techniques have obtained growing attention in the field of hydrology due to their potentials to forecast time series. Moreover, a subfield of ML, Deep Learning (DL) is more concerned with datasets, algorithms and layered structures. Despite numerous applications of novel ML/DL techniques in discharge simulation, the uncertainty involved in ML/DL modeling has not drawn much attention, although it is an important issue. In this study, a framework is proposed to quantify uncertainty contributions of the sample set, ML approach, ML architecture and their interactions to multi-step time-series forecasting based on the analysis of variance (ANOVA) theory. Then a discharge simulation, using Recurrent Neural Networks (RNNs), is taken as an example. Long Short-Term Memory (LSTM) network, a state-of-the-art DL approach, was selected due to its outstanding performance in time-series forecasting, and compared with simple RNN. Besides, novel discharge forecasting architecture is designed by combining the expertise of hydrology and stacked DL structure, and compared with conventional design. Taking hourly discharge simulations of Anhe (China) catchment as a case study, we constructed five sample sets, chose two RNN approaches and designed two ML architectures. The results indicate that none of the investigated uncertainty sources are negligible and the influence of uncertainty sources varies with lead-times and discharges. LSTM demonstrates its superiority in discharge simulations, and the ML architecture is as important as the ML approach. In addition, some of the uncertainty is attributable to interactions rather than individual modeling components. The proposed framework can both reveal uncertainty quantification in ML/DL modeling and provide references for ML approach evaluation and architecture design in discharge simulations. It indicates uncertainty quantification is an indispensable task for a successful application of ML/DL.
Study on the Ecological Operation and Watershed Management of Urban Rivers in Northern China
Authors: Deng Guangyi , Yao Xiaohan , Jiang Haibo , Cao Yingyue , Wen Yang , Wang Wenjia , Zhao She , He Chunguang
Published: April 2020

Small- and medium-sized rivers are facing a serious degradation of ecological function in water resource-scarce regions of Northern China. Reservoir ecological operation can restore the damaged river ecological environment. Research on reservoir ecological operation and watershed management of urban rivers is limited in cold regions of middle and high latitudes. In this paper, the urban section of the Yitong River was selected as the research object in Changchun, Northern China. The total ecological water demand and reservoir operation water (79.35 × 106 m3 and 15.52 × 106 m3, respectively) were calculated by the ecological water demand method, and a reservoir operation scheme was established to restore the ecological function of the urban section of the river. To examine the scientific basis and rationality of the operation scheme, the water quality of the river and physical habitat after carrying out the scheme were simulated by the MIKE 11 one-dimensional hydrodynamic-water quality model and the Physical Habitat Simulation Model (PHABSIM). The results indicate that the implementation of the operation scheme can improve the ecological environment of the urban section of the Yitong River. A reform scheme was proposed for the management of the Yitong River Basin based on the problems in the process of carrying out the operation schemes, including clarifying department responsibility, improving laws and regulations, strengthening service management, and enhancing public participation.