bluuebunny/crossref_metadata_2025 huggingface dataset:
On the Role of Peripheral Sensory and Gut Mu Opioid Receptors: Peripheral Analgesia and Tolerance
Authors: Fürst Susanna , Zádori Zoltán S. , Zádor Ferenc , Király Kornél , Balogh Mihály , László Szilvia B. , Hutka Barbara , Mohammadzadeh Amir , Calabrese Chiara , Galambos Anna Rita , Riba Pál , Romualdi Patrizia , Benyhe Sándor , Timár Júlia , Schmidhammer Helmut , Spetea Mariana , Al-Khrasani Mahmoud
Published: May 2020

There is growing evidence on the role of peripheral µ-opioid receptors (MORs) in analgesia and analgesic tolerance. Opioid analgesics are the mainstay in the management of moderate to severe pain, and their efficacy in the alleviation of pain is well recognized. Unfortunately, chronic treatment with opioid analgesics induces central analgesic tolerance, thus limiting their clinical usefulness. Numerous molecular mechanisms, including receptor desensitization, G-protein decoupling, β-arrestin recruitment, and alterations in the expression of peripheral MORs and microbiota have been postulated to contribute to the development of opioid analgesic tolerance. However, these studies are largely focused on central opioid analgesia and tolerance. Accumulated literature supports that peripheral MORs mediate analgesia, but controversial results on the development of peripheral opioid receptors-mediated analgesic tolerance are reported. In this review, we offer evidence on the consequence of the activation of peripheral MORs in analgesia and analgesic tolerance, as well as approaches that enhance analgesic efficacy and decrease the development of tolerance to opioids at the peripheral sites. We have also addressed the advantages and drawbacks of the activation of peripheral MORs on the sensory neurons and gut (leading to dysbiosis) on the development of central and peripheral analgesic tolerance.
Preparation of 1-Hydroxy-2,5-hexanedione from HMF by the Combination of Commercial Pd/C and Acetic Acid
Authors: Yang Yanliang , Yang Dexi , Zhang Chi , Zheng Min , Duan Ying
Published: May 2020

The development of a simple and durable catalytic system for the production of chemicals from a high concentration of a substrate is important for biomass conversion. In this manuscript, 5-hydroxymethylfurfural (HMF) was converted to 1-hydroxy-2,5-hexanedione (HHD) using the combination of commercial Pd/C and acetic acid (AcOH) in water. The influence of temperature, H2 pressure, reaction time, catalyst amount and the concentration of AcOH and HMF on this transformation was investigated. A 68% yield of HHD was able to be obtained from HMF at a 13.6 wt% aqueous solution with a 98% conversion of HMF. The resinification of intermediates on the catalyst was characterized to be the main reason for the deactivation of Pd/C. The reusability of the used Pd/C was studied to find that most of the activity could be recovered by being washed in hot tetrahydrofuran.
Biological Activity of Some Aromatic Plants and Their Metabolites, with an Emphasis on Health-Promoting Properties
Authors: Kieliszek Marek , Edris Amr , Kot Anna Maria , Piwowarek Kamil
Published: May 2020

The biological activities of four aromatic plants, namely frankincense, myrrh, ginger, and turmeric, were reviewed in the current study. The volatile fraction (essential oil) as well as the nonvolatile fraction of these four plants showed different promising biological activities that are displayed in detail. These activities can include protection from and/or alleviation of some ailment, which is supported with different proposed mechanisms of action. This review aimed to finally help researchers to get a handle on the importance of considering these selected aromatic plants, which have not been thoroughly reviewed before, as a potential adjuvant to classical synthetic drugs to enhance their efficiency. Moreover, the results elicited in this review encourage the consumption of these medicinal plants as an integrated part of the diet to boost the body’s overall health based on scientific evidence.
Identification and Characterization of α-Glucosidase Inhibition Flavonol Glycosides from Jack Bean (Canavalia ensiformis (L.) DC
Authors: Sutedja Anita M. , Yanase Emiko , Batubara Irmanida , Fardiaz Dedi , Lioe Hanifah N.
Published: May 2020

Although the intake of jack bean (Canavalia ensiformis (L.) DC.), an underutilized tropical legume, can potentially decrease the risk of several chronic diseases, not much effort has been directed at profiling the polyphenolics contained therein. Hence, this work aimed to identify and quantify the dominant jack bean polyphenolics, which are believed to have antioxidant and other bioactivities. Four major compounds were detected and identified as kaempferol glycosides with three or four glycoside units. Their structures were established based on UV-visible, 1D, 2D NMR, and HR-ESI-MS analyses. Specifically, kaempferol 3-O-α-l-rhamnopyranosyl (1→6)- β-d-glucopyranosyl (1→2)-β-d-galactopyranosyl-7-O-[3-O-o-anisoyl]-α-l-rhamnopyranoside was detected for the first time, while the other three compounds have already been described in plants other than jack bean. This new compound was found to have a higher α-glucosidase inhibition activity compared to acarbose.
Verification of the Necessity of the Tolyl Group of PF-543 for Sphingosine Kinase 1 Inhibitory Activity
Authors: Kim Su Bin , Lee Taeho , Moon Hong Seop , Ki Sung Hwan , Oh Yoon Sin , Lee Joo-Youn , Kim Sang-Bum , Park Jeong-Eun , Kwon Yongseok , Kim Sanghee , Baek Dong Jae , Park Eun-Young
Published: May 2020

PF-543, the most potent sphingosine kinase (SK) inhibitor, does not demonstrate effective anticancer activity in some cancer cells, unlike other known SK1 inhibitors. PF-543 has a non-lipid structure with a unique toluene backbone; however, the importance of this structure remains unclear. Therefore, the purpose of this study was to investigate changes in SK inhibitory and anticancer activities and to explore the role of the tolyl group structure of PF-543 through various modifications. We transformed the methyl group of PF-543 into hydrogen, fluorine, and hydroxy. PF-543 derivatives in which the methyl group was substituted by hydrogen and fluorine (compound 5) demonstrated SK1 inhibitory and anticancer activities similar to PF-543. Moreover, we performed molecular modeling studies of PF-543 and compound 5. To assess the metabolic stability of PF-543 and compound 5, we determined their degree of degradation using the liver microsomes of four different animal species (human, dog, rat, and mouse). However, both PF-543 and compound 5 showed poor microsomal stability. Therefore, for the medical applications of PF-543, the structural modifications of its other parts may be necessary. Our results provide important information for the design of additional PF-543 analogs.
Natural Nitrogenous Sesquiterpenoids and Their Bioactivity: A Review
Authors: Chen De-Li , Wang Bo-Wen , Sun Zhao-Cui , Yang Jun-Shan , Xu Xu-Dong , Ma Guo-Xu
Published: May 2020

Nitrogenous sesquiterpenoids fromnatural sourcesare rare, so unsurprisingly neither the potentially valuable bioactivity nor thebroad structural diversity of nitrogenous sesquiterpenoids has been reviewed before. This report covers the progressduring the decade from 2010 to February 2020 on the isolation, identification, and bioactivity of 391 nitrogen-containing natural sesquiterpenes from terrestrial plant, marine organisms, and microorganisms. This complete and in-depth reviewshouldbe helpful for discovering and developing new drugs of medicinal valuerelated to natural nitrogenous sesquiterpenoids.
Synthesis and Properties of NitroHPHAC: The First Example of Substitution Reaction on HPHAC
Authors: Sasaki Yoshiki , Takase Masayoshi , Mori Shigeki , Uno Hidemitsu
Published: May 2020

Hexapyrrolohexaazacoronene (HPHAC) is one of the N-containing polycyclic aromatic hydrocarbons in which six pyrroles are fused circularly around a benzene. Despite the recent development of HPHAC analogues, there is no report on direct introduction of functional groups into the HPHAC skeleton. This work reports the first example of nitration reaction of decaethylHPHAC. The structures of nitrodecaethylHPHAC including neutral and two oxidized species (radical cation and dication), intramolecular charge transfer (ICT) character, and global aromaticity of the dication are discussed.
A Deep-Learning Approach toward Rational Molecular Docking Protocol Selection
Authors: Jiménez-Luna José , Cuzzolin Alberto , Bolcato Giovanni , Sturlese Mattia , Moro Stefano
Published: May 2020

While a plethora of different protein–ligand docking protocols have been developed over the past twenty years, their performances greatly depend on the provided input protein–ligand pair. In this study, we developed a machine-learning model that uses a combination of convolutional and fully connected neural networks for the task of predicting the performance of several popular docking protocols given a protein structure and a small compound. We also rigorously evaluated the performance of our model using a widely available database of protein–ligand complexes and different types of data splits. We further open-source all code related to this study so that potential users can make informed selections on which protocol is best suited for their particular protein–ligand pair.
Theoretical and Experimental Investigations of Large Stokes Shift Fluorophores Based on a Quinoline Scaffold
Authors: Czaplińska Barbara , Malarz Katarzyna , Mrozek-Wilczkiewicz Anna , Slodek Aneta , Korzec Mateusz , Musiol Robert
Published: May 2020

A series of novel styrylquinolines with the benzylidene imine moiety were synthesized and spectroscopically characterized for their applicability in cellular staining. The spectroscopic study revealed absorption in the ultraviolet–visible region (360–380 nm) and emission that covered the blue-green range of the light (above 500 nm). The fluorescence quantum yields were also determined, which amounted to 0.079 in the best-case scenario. The structural features that are behind these values are also discussed. An analysis of the spectroscopic properties and the theoretical calculations indicated the charge-transfer character of an emission, which was additionally evaluated using the Lippert–Mataga equation. Changes in geometry in the ground and excited states, which had a significant influence on the emission process, are also discussed. Additionally, the capability of the newly synthesized compounds for cellular staining was also investigated. These small molecules could effectively penetrate through the cellular membrane. Analyses of the images that were obtained with several of the tested styrylquinolines indicated their accumulation in organelles such as the mitochondria and the endoplasmic reticulum.
Pretreatment with Warfarin Attenuates the Development of Ischemia/Reperfusion-Induced Acute Pancreatitis in Rats
Authors: Maduzia Dawid , Ceranowicz Piotr , Cieszkowski Jakub , Gałązka Krystyna , Kuśnierz-Cabala Beata , Warzecha Zygmunt
Published: May 2020

In acute pancreatitis (AP), pancreatic damage leads to local vascular injury, manifesting as endothelial damage and activation, increased vascular permeability, leukocyte rolling, sticking and transmigration to pancreatic tissue as well as activation of coagulation. Previous studies have shown that pretreatment with heparin or acenocoumarol inhibits the development of AP. The aim of the present study was to check the impact of pretreatment with warfarin, an oral vitamin K antagonist, on the development of ischemia/reperfusion-induced AP in rats. AP was induced by pancreatic ischemia followed by reperfusion of the gland. Warfarin (90, 180 or 270 µg/kg/dose) or vehicle were administered intragastrically once a day for 7 days before induction of AP. The effect of warfarin on the severity of AP was assessed 6 h after pancreatic reperfusion. The assessment included histological, functional, and biochemical analyses. Pretreatment with warfarin given at a dose of 90 or 180 µg/kg/dose increased the international normalized ratio and reduced morphological signs of pancreatic damage such as pancreatic edema, vacuolization of acinar cells, necrosis and the number of hemorrhages. These effects were accompanied by an improvement of pancreatic blood flow and a decrease in serum level amylase, lipase, pro-inflammatory interleukin-1β and plasma level of D-dimer. In contrast, pretreatment with warfarin given at a dose of 270 µg/kg/dose led to an increase in severity of pancreatic damage and biochemical indicators of AP. In addition, this dose of warfarin resulted in deaths in some animals. Pretreatment with low doses of warfarin inhibits the development of AP induced by pancreatic ischemia followed by reperfusion.
Resolving DNA Damage: Epigenetic Regulation of DNA Repair
Authors: Karakaidos Panagiotis , Karagiannis Dimitris , Rampias Theodoros
Published: May 2020

Epigenetic research has rapidly evolved into a dynamic field of genome biology. Chromatin regulation has been proved to be an essential aspect for all genomic processes, including DNA repair. Chromatin structure is modified by enzymes and factors that deposit, erase, and interact with epigenetic marks such as DNA and histone modifications, as well as by complexes that remodel nucleosomes. In this review we discuss recent advances on how the chromatin state is modulated during this multi-step process of damage recognition, signaling, and repair. Moreover, we examine how chromatin is regulated when different pathways of DNA repair are utilized. Furthermore, we review additional modes of regulation of DNA repair, such as through the role of global and localized chromatin states in maintaining expression of DNA repair genes, as well as through the activity of epigenetic enzymes on non-nucleosome substrates. Finally, we discuss current and future applications of the mechanistic interplays between chromatin regulation and DNA repair in the context cancer treatment.
Insights on the Extraction Performance of Alkanediols and Glycerol: Using Juglans regia L. Leaves as a Source of Bioactive Compounds
Authors: Vieira Vanessa , Calhelha Ricardo C. , Barros Lillian , Coutinho João A. P. , C. F. R. Ferreira Isabel , Ferreira Olga
Published: May 2020

Glycerol and alkanediols are being studied as alternative solvents to extract phytochemicals from plant material, often as hydrogen bond donors in deep eutectic solvents (DESs). Many of those alcohols are liquid at room temperature, yet studies of their use as extraction solvents are scarce. In this work, glycerol and a series of alkanediols (1,2-ethanediol, 1,2-propanediol, 1,3-propanediol, 1,3-butanediol, 1,2-pentanediol, 1,5-pentanediol, and 1,2-hexanediol) were studied for the extraction of phenolic compounds from Juglans regia L. leaves, a rich source of this class of bioactive compounds. The extraction yield was quantified, and the bioactivity of both extracts and pure solvents was evaluated by measuring the anti-inflammatory and cytotoxic activities. The solvents showing the best combined results were 1,2 and 1,3-propanediol, as their extracts presented a high amount of phenolic compounds, close to the results of ethanol, and similar cytotoxicity against cervical carcinoma cells, with no impact on non-tumor porcine liver cells in the studied concentration range. On the other hand, none of the extracts (and solvents) presented anti-inflammatory activity. Overall, the results obtained in this work contribute to the study of alternative solvents that could potentially be used also as formulation media, highlighting the importance of walnut leaves as a source of bioactive compounds.
Molecular Spectroscopic Markers of Abnormal Protein Aggregation
Authors: Wilkosz Natalia , Czaja Michał , Seweryn Sara , Skirlińska-Nosek Katarzyna , Szymonski Marek , Lipiec Ewelina , Sofińska Kamila
Published: May 2020

Abnormal protein aggregation has been intensively studied for over 40 years and broadly discussed in the literature due to its significant role in neurodegenerative diseases etiology. Structural reorganization and conformational changes of the secondary structure upon the aggregation determine aggregation pathways and cytotoxicity of the aggregates, and therefore, numerous analytical techniques are employed for a deep investigation into the secondary structure of abnormal protein aggregates. Molecular spectroscopies, including Raman and infrared ones, are routinely applied in such studies. Recently, the nanoscale spatial resolution of tip-enhanced Raman and infrared nanospectroscopies, as well as the high sensitivity of the surface-enhanced Raman spectroscopy, have brought new insights into our knowledge of abnormal protein aggregation. In this review, we order and summarize all nano- and micro-spectroscopic marker bands related to abnormal aggregation. Each part presents the physical principles of each particular spectroscopic technique listed above and a concise description of all spectral markers detected with these techniques in the spectra of neurodegenerative proteins and their model systems. Finally, a section concerning the application of multivariate data analysis for extraction of the spectral marker bands is included.
New Methyl Threonolactones and Pyroglutamates of Spilanthes acmella (L.) L. and Their Bone Formation Activities
Authors: Widyowati Retno , Sulistyowaty Melanny Ika , Uyen Nguyen Hoang , Sugimoto Sachiko , Yamano Yoshi , Otsuka Hideaki , Matsunami Katsuyoshi
Published: May 2020

In our continuing research for bioactive constituents from natural resources, a new methyl threonolactone glucopyranoside (1), a new methyl threonolactone fructofuranoside (2), 2 new pyroglutamates (3 and 4), and 10 known compounds (5–14) were isolated from the whole plant of Spilanthes acmella (L.) L. The structures of these compounds were determined based on various spectroscopic and chemical analyses. All of the isolated compounds were evaluated on bone formation parameters, such as ALP (alkaline phosphatase) and mineralization stimulatory activities of MC3T3-E1 cell lines. The results showed that the new compound, 1,3-butanediol 3-pyroglutamate (4), 2-deoxy-d-ribono-1,4-lactone (6), methyl pyroglutamate (7), ampelopsisionoside (10), icariside B1 (11), and benzyl α-l-arabinopyranosyl-(1→6)-β-d-glucopyranoside (12) stimulated both ALP and mineralization activities.
Application of Super Absorbent Polymer and Plant Mucilage Improved Essential Oil Quantity and Quality of Ocimum basilicum var. Keshkeni Luvelou
Authors: Beigi Somaye , Azizi Majid , Iriti Marcello
Published: May 2020

One of the major factors limiting the production of medicinal plants in arid and semi-arid areas is water deficit or drought stress. One-third of the land in the world is arid and semi-arid and is inhabited by nearly 4 × 108 people. Ocimum basilicum (sweet basil) is a valuable medicinal plant that is sensitive to water deficit, and water shortage negatively affects sweet basil yield and quality. Water availability in the root zone of basil could ameliorate the negative effects of water shortage. To the best of our knowledge, although the effects of hydrophilic polymers (HPs) have been studied in different agricultural crops, the effects of HP application in medicinal plants have not been previously investigated. This investigation was conducted to explore the effects on water use efficiency when using Stockosorb® (STS) and psyllium seed mucilage (PSM) as hydrophilic polymers (HPs) and the effects of these HPs on essential oil quality, quantity, and yield. The research was set up in a factorial experiment on the basis of completely randomized block design with three replications. We used two HPs, STS (industrial) and PSM (herbal), with two methods of application (mixed with soil, mixed with soil + root) at four concentrations (0%, 0.1%, 0.2%, and 0.3% (w/w)). Results showed that the STS and PSM significantly increased the dry herb yield (both shoot and root) in comparison to the control, and the improving effect was higher when these HPs were mixed with soil + root. The highest dry herb yield (6.74 and 3.68 g/plant for shoot and root, respectively) was detected in the PSM at 0.1% mixed with soil + root. There was not any significant difference in dry herb yield among PSM (0.1%), PSM (0.2%), and STS (0.2%) when mixed with soil + root. Soil application of PSM and soil + root application of STS at a concentration of 0.3% increased the Essential Oil (EO) content almost three-fold in comparison to the control (0.5% and 0.52% to 0.18% v/w, respectively). The maximum essential oil yield was recorded in plants treated with STS (0.2% in) or PSM (0.1%) by soil + root application (0.21 and 0.19 mL/plant, respectively). PSM at concentrations of 0.1% and 0.2% (mixed with soil + root) showed the highest water use efficiency (1.91 and 1.82 g dry weight (DW)/L H2O, respectively). STS mixed with soil also significantly improved water use efficiency (WUE) in comparison to the control. The application of these HPs improved the quality of sweet basil essential oil by increasing the linalool and decreasing the eugenol, epi-α-cadinol, and trans-α-bergamotene content.
Interaction of Reactive-Dye Chromophores and DEG on Ink-Jet Printing Performance
Authors: Zhang Liyuan , Fang Kuanjun , Zhou Hua
Published: May 2020

Digital inkjet printing has been widely used in textile industry. The quality of dye solutions and ink-jet droplets limits the ink-jet printing performance, which is very important for obtaining high-quality ink-jet printing images on fabrics. In this paper, we introduced diethylene glycol (DEG) into the dye solutions of Reactive Blue 49 and Reactive Orange 13, respectively, and investigated the interaction between dye chromophores and DEG molecules. Results indicated that the dye chromophores were featured in the aggregation. Adding DEG into the dye solution could effectively disaggregate clusters of reactive dyes, and eliminate satellite ink droplets, thus improving the resolution of the ink-jet printing image on fabrics. Under the same DEG concentration, the disaggregation effect was more obvious in Orange 13 than in Reactive Blue 49. Higher DEG concentration was required in Reactive Orange 13 solution for creating complete and stable ink drops. The surface tension and viscosity of the dye solutions were measured, and printing performance on cotton fabrics was evaluated. The interaction mechanism between dye chromophores and DEG molecules was also investigated. Results from this work are useful for high-quality ink-jet printing images on fabrics.
Development, Optimization, and Comparison of Different Sample Pre-Treatments for Simultaneous Determination of Vitamin E and Vitamin K in Vegetables
Authors: Aresta Antonella , Milani Gualtiero , Clodoveo Maria Lisa , Franchini Carlo , Cotugno Pietro , Radojcic Redovnikovic Ivana , Quinto Maurizio , Corbo Filomena , Zambonin Carlo
Published: May 2020

The absence of vitamin E from the diet can lead to cardiovascular disease, cancer, cataracts, and premature aging. Vitamin K deficiency can lead to bleeding disorders. These fat-soluble vitamins are important nutritional factors that can be determined in different methods in vegetables. In this work, the simultaneous determination of α-tocopherol, α-tocopheryl acetate, phylloquinone, and menaquinone-4 by gas chromatography–mass spectrometry (GC–MS) has been optimized using both direct injection and solid phase microextraction (SPME). Three different sample pre-treatment approaches based on: (A) solid–liquid–liquid–liquid extraction (SLE–LLE), (B) SLE, and (C) SPME were then applied to extract the target analytes from vegetables samples using menaquinone as internal standard. All the procedures allowed the determination of the target analytes in onion, carrot, celery, and curly kale samples. Similar results were obtained with the three different approaches, even if the one based on SPME offers the best performance, together with a reduced use of solvent, time consumption, and experimental complexity, which makes it the preferable option for industrial applications.
Development of Resistance to Endoplasmic Reticulum Stress-Inducing Agents in Mouse Leukemic L1210 Cells
Authors: Cagala Martin , Pavlikova Lucia , Seres Mario , Kadlecikova Karolina , Breier Albert , Sulova Zdena
Published: May 2020

Four new variants of L1210 cells resistant to endoplasmic reticulum (ER) stressors, tunicamycin (STun), thapsigargin (SThap), bortezomib (SBor), and MG-132 (SMG-132), were developed via an 18-month periodic cultivation in culture medium with a gradual increase in substance concentration. Multidrug resistance was generated for STun (to tunicamycin, bortezomib and MG-132), SThap (to tunicamycin, thapsigargin and MG-132), SBor (to bortezomib and MG-132), and SMG-132 (to bortezomib and MG-132). These cells were compared to the original L1210 cells and another two variants, which expressed P-gp due to induction with vincristine or transfection with the gene encoding P-gp, in terms of the following properties: sensitivity to either vincristine or the ER stressors listed above, proliferative activity, expression of resistance markers and proteins involved in the ER stress response, and proteasome activity. The resistance of the new cell variants to ER stressors was accompanied by a decreased proliferation rate and increased proteasome activity. The most consistent change in protein expression was the elevation of GRP78/BiP at the mRNA and protein levels in all resistant variants of L1210 cells. In conclusion, the mechanisms of resistance to these stressors have certain common features, but there are also specific differences.
Reliable Ultra Trace Analysis of Cd, U and Zn Concentrations in Greenland Snow and Ice by Using Ultraclean Methods for Contamination Control
Authors: Han Changhee , Hwang Heejin , Kang Jung-Ho , Hong Sang-Bum , Han Yeongcheol , Lee Khanghyun , Hur Soon Do , Hong Sungmin
Published: May 2020

This study presents ultraclean procedures used in the challenging task of determining trace elements at or below the pg/g concentration level encountered in Greenland snow and ice. In order to validate these ultraclean procedures, recent snowfall and Holocene ice from northwest Greenland were analyzed for Cd, U, and Zn concentrations. The total procedural blanks brought through the entire measurement procedure proved to be negligible, compared to trace element concentrations, measured in snow and ice samples. This validates the overall practicality of the proposed ultraclean procedures, thereby ensuring the reliable measurements of ultra-trace analysis. A comparison between our study and published data shows that improper procedures employed throughout all stages, from field sampling to analysis to elevate the concentrations by several orders of magnitude, relative to the reliable concentration ranges. The risk of contamination exposure for selected trace elements appears to increase in the order of U < As ≤ Pb < Cd < Zn. Reliable measurements of Cd, U, and Zn concentrations in snow and ice allowed us to interpret the data in terms of seasonal variations in the inputs of crustal and anthropogenic sources to Greenland ice sheet.
Discovery of New Apoptosis-Inducing Agents for Breast Cancer Based on Ethyl 2-Amino-4,5,6,7-Tetra Hydrobenzo[b]Thiophene-3-Carboxylate: Synthesis, In Vitro, and In Vivo Activity Evaluation
Authors: Gad Emad M. , Nafie Mohamed S. , Eltamany Elsayed H. , Hammad Magdy S. A. G. , Barakat Assem , Boraei Ahmed T. A.
Published: May 2020

A multicomponent synthesis was empolyed for the synthesis of ethyl 2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate 1. An interesting cyclization was obtained when the amino-ester 1 reacted with ethyl isothiocyanate to give the benzo[4,5]thieno[2,3-d][1,3]thiazin-4-one 3. Acylation of the amino-ester 1 with chloroacetyl chloride in DCM and Et3N afforded the acylated ester 4. The amino-ester 1 was cyclized to benzo[4,5]thieno[2,3-d]pyrimidin-4(3H)-one 8, which was reacted with some alkylating agents leading to alkylation at nitrogen 9–13. Hydrazide 14 was utilized as a synthon for the synthesis of the derivatives 15–19. Chloro-thieno[2,3-d]pyrimidine 20 was synthesized and reacted with the hydrazine hydrate to afford the hydrazino derivative 21, which was used as a scaffold for getting the derivatives 22–28. Nucleophilic substitution reactions were used for getting the compounds 29–35 from chloro-thieno[2,3-d]pyrimidine 20. In the way of anticancer therapeutics development, the requisite compounds were assessed for their cytotoxicity in vitro against MCF-7 and HepG-2 cancer cell lines. Twelve compounds showed an interesting antiproliferative potential with IC50 from 23.2 to 95.9 µM. The flow cytometric analysis results showed that hit 4 induces the apoptosis in MCF-7 cells with a significant 26.86% reduction in cell viability. The in vivo study revealed a significant decrease in the solid tumor mass (26.6%) upon treatment with compound 4. Moreover, in silico study as an agonist for inhibitors of JAK2 and prediction study determined their binding energies and predicted their physicochemical properties and drug-likeness scores.
Five New Pregnane Glycosides from Gymnema sylvestre and Their α-Glucosidase and α-Amylase Inhibitory Activities
Authors: Kiem Phan Van , Yen Duong Thi Hai , Hung Nguyen Van , Nhiem Nguyen Xuan , Tai Bui Huu , Trang Do Thi , Yen Pham Hai , Ngoc Tran Minh , Minh Chau Van , Park SeonJu , Lee Jae Hyuk , Kim Sun Yeou , Kim Seung Hyun
Published: May 2020

Gymnema sylvestre, a medicinal plant, has been used in Indian ayurvedic traditional medicine for the treatment of diabetes. Phytochemical investigation of Gymnema sylvestre led to the isolation of five new pregnane glycosides, gymsylosides A–E (1–5) and four known oleanane saponins, 3β-O-β-D-glucopyranosyl (1→6)-β-D-glucopyranosyl oleanolic acid 28-O-β-D-glucopyranosyl ester (6), gymnemoside-W1 (7), 3β-O-β-D-xylopyranosyl-(1→6)-β-D- glucopyranosyl-(1→6)-β-D-glucopyranosyl oleanolic acid 28-O-β-D-glucopyranosyl ester (8), and alternoside XIX (9). Their structures were identified based on spectroscopic evidence and comparison with those reported in the literature. All compounds were evaluated for their α-glucosidase and α-amylase inhibitory activities. Compounds 2–4 showed significant α-amylase inhibitory activity, with IC50 values ranging from 113.0 to 176.2 µM.
The Interaction of Hydrogen with the van der Waals Crystal γ-InSe
Authors: Felton James , Blundo Elena , Ling Sanliang , Glover Joseph , Kudrynskyi Zakhar R. , Makarovsky Oleg , Kovalyuk Zakhar D. , Besley Elena , Walker Gavin , Polimeni Antonio , Patané Amalia
Published: May 2020

The emergence of the hydrogen economy requires development in the storage, generation and sensing of hydrogen. The indium selenide ( γ -InSe) van der Waals (vdW) crystal shows promise for technologies in all three of these areas. For these applications to be realised, the fundamental interactions of InSe with hydrogen must be understood. Here, we present a comprehensive experimental and theoretical study on the interaction of γ -InSe with hydrogen. It is shown that hydrogenation of γ -InSe by a Kaufman ion source results in a marked quenching of the room temperature photoluminescence signal and a modification of the vibrational modes of γ -InSe, which are modelled by density functional theory simulations. Our experimental and theoretical studies indicate that hydrogen is incorporated into the crystal preferentially in its atomic form. This behaviour is qualitatively different from that observed in other vdW crystals, such as transition metal dichalcogenides, where molecular hydrogen is intercalated in the vdW gaps of the crystal, leading to the formation of “bubbles” for hydrogen storage.
Combined Effect of Nitrofurantoin and Plant Surfactant on Bacteria Phospholipid Membrane
Authors: Rojewska Monika , Smułek Wojciech , Prochaska Krystyna , Kaczorek Ewa
Published: May 2020

Due to the increasing use of antibiotics, measures are being taken to improve their removal from the natural environment. The support of biodegradation with natural surfactants that increase the bioavailability of impurities for microorganisms that degrade them, raises questions about their effect on bacterial cells. In this paper we present analysis of the interaction of nitrofurantoin (NFT) and saponins from the Saponaria officinalis on the environmental bacteria membrane and the model phospholipid membrane mimicking it. A wide perspective of the process is provided with the Langmuir monolayer technique and membrane permeability test with bacteria. The obtained results showed that above critical micelle concentration (CMC), saponin molecules are incorporated into the POPE monolayer, but the NFT impact was ambiguous. What is more, differences in membrane permeability between the cells exposed to NFT in comparison to that of the non-exposed cells were observed above 1.0 CMC for Achromobacter sp. KW1 or above 0.5 CMC for Pseudomonas sp. MChB. In both cases, NFT presence lowered the membrane permeability. Moreover, the Congo red adhesion to the cell membrane also decreased in the presence of a high concentration of surfactants and NFT. The results suggest that saponins are incorporated into the bacteria membrane, but their sugar hydrophilic part remains outside, which modifies the adsorption properties of the cell surface as well as the membrane permeability.
Augmenting Printed School Atlases with Thematic 3D Maps
Authors: Schnürer Raimund , Dind Cédric , Schalcher Stefan , Tschudi Pascal , Hurni Lorenz
Published: May 2020

Digitalization in schools requires a rethinking of teaching materials and methods in all subjects. This upheaval also concerns traditional print media, like school atlases used in geography classes. In this work, we examine the cartographic technological feasibility of extending a printed school atlas with digital content by augmented reality (AR). While previous research rather focused on topographic three-dimensional (3D) maps, our prototypical application for Android tablets complements map sheets of the Swiss World Atlas with thematically related data. We follow a natural marker approach using the AR engine Vuforia and the game engine Unity. We compare two workflows to insert geo-data, being correctly aligned with the map images, into the game engine. Next, the imported data are transformed into partly animated 3D visualizations, such as a dot distribution map, curved lines, pie chart billboards, stacked cuboids, extruded bars, and polygons. Additionally, we implemented legends, elements for temporal and thematic navigation, a screen capture function, and a touch-based feature query for the user interface. We evaluated our prototype in a usability experiment, which showed that secondary school students are as effective, interested, and sustainable with printed as with augmented maps when solving geographic tasks.
Genome-Wide Technologies to Study RNA–Chromatin Interactions
Authors: Kato Masaki , Carninci Piero
Published: May 2020

An increasing number of studies have revealed that long non-coding RNAs (lncRNAs) play important roles in gene regulation and nuclear organization. Although the mechanisms are still largely unknown, many lncRNAs have been shown to interact with chromatin. Thus, one approach to understanding the function of these lncRNAs is to identify their sites of genomic interaction. Hybridization capture methods using oligonucleotide probes have been used for years to study chromatin-associated RNA. Recently, several groups have developed novel methods based on proximity ligation to investigate RNA–chromatin interactions at a genome-wide scale. This review discusses these technologies and highlights their advantages and disadvantages for the consideration of potential users.
Chitosan Film Containing Mansoa hirsuta Fraction for Wound Healing
Authors: Rodrigues Pereira Joquebede , Suassuna Bezerra Gabriela , Alves Furtado Allanny , de Carvalho Thaís Gomes , Costa da Silva Valéria , Lins Bispo Monteiro Amanda , Bernardo Guerra Gerlane Coelho , de Araújo Júnior Raimundo Fernandes , Sant’Ana Antônio Euzébio Goulart , Fernandes-Pedrosa Matheus de Freitas , de Melo Silva Daniel , Pereira de Azevedo Eduardo , Sarmento Silva Tania Maria , Araújo Moura Lemos Telma Maria , Neves de Lima Ádley Antonini
Published: May 2020

Chitosan films entrapped with the Mansoa hirsuta fraction (CMHF) was developed as a new dressing for wound care. The chromatographic profile of the M. hirsuta fraction (MHF) was evaluated by ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry, and the results showed that MHF is rich in acid triterpenes. Physicochemical characterization of the films prepared using the solvent casting method was performed by Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), thermogravimetry (TGA), differential scanning calorimetry (DCS), scanning electron microscopy (SEM), atomic force microscopy (AFM), and mechanical properties. CMHF exhibited characteristic bands of both chitosan and MHF, revealing a physical mixture of both. CMHF presented an amorphous nature, thermostability, and dispersion of MHF in the chitosan matrix, resulting in a rough structure. Incorporation of M. hirsuta fraction into chitosan matrix favorably enhanced the mechanical performance and films thickness. The in vivo wound treatment with CMHF for seven days showed a characteristic area of advanced healing, re-epithelization, cell proliferation, and collagen formation. Furthermore, wound closure reached 100% contraction after 10 days of treatment with modulation of interleukins. The incorporation of M. hirsuta fraction into chitosan films was advantageous and showed great potential for stimulating wound repair and regeneration.
Validation of Pharmacological Protocols for Targeted Inhibition of Canalicular MRP2 Activity in Hepatocytes Using [99mTc]mebrofenin Imaging in Rats
Authors: Marie Solène , Hernández-Lozano Irene , Breuil Louise , Saba Wadad , Novell Anthony , Gennisson Jean-Luc , Langer Oliver , Truillet Charles , Tournier Nicolas
Published: May 2020

The multidrug resistance-associated protein 2 (MRP2) mediates the biliary excretion of drugs and metabolites. [99mTc]mebrofenin may be employed as a probe for hepatic MRP2 activity because its biliary excretion is predominantly mediated by this transporter. As the liver uptake of [99mTc]mebrofenin depends on organic anion-transporting polypeptide (OATP) activity, a safe protocol for targeted inhibition of hepatic MRP2 is needed to study the intrinsic role of each transporter system. Diltiazem (DTZ) and cyclosporin A (CsA) were first confirmed to be potent MRP2 inhibitors in vitro. Dynamic acquisitions were performed in rats (n = 5–6 per group) to assess the kinetics of [99mTc]mebrofenin in the liver, intestine and heart-blood pool after increasing doses of inhibitors. Their impact on hepatic blood flow was assessed using Doppler ultrasound (n = 4). DTZ (s.c., 10 mg/kg) and low-dose CsA (i.v., 0.01 mg/kg) selectively decreased the transfer of [99mTc]mebrofenin from the liver to the bile (k3). Higher doses of DTZ and CsA did not further decrease k3 but dose-dependently decreased the uptake (k1) and backflux (k2) rate constants between blood and liver. High dose of DTZ (i.v., 3 mg/kg) but not CsA (i.v., 5 mg/kg) significantly decreased the blood flow in the portal vein and hepatic artery. Targeted pharmacological inhibition of hepatic MRP2 activity can be achieved in vivo without impacting OATP activity and liver blood flow. Clinical studies are warranted to validate [99mTc]mebrofenin in combination with low-dose CsA as a novel substrate/inhibitor pair to untangle the role of OATP and MRP2 activity in liver diseases.
Engineering Sub-Cellular Targeting Strategies to Enhance Safe Cytosolic Silica Particle Dissolution in Cells
Authors: Iturrioz-Rodríguez Nerea , Correa-Duarte Miguel Ángel , Valiente Rafael , Fanarraga Mónica L.
Published: May 2020

Mesoporous silica particles (MSP) are major candidates for drug delivery systems due to their versatile, safe, and controllable nature. Understanding their intracellular route and biodegradation process is a challenge, especially when considering their use in neuronal repair. Here, we characterize the spatiotemporal intracellular destination and degradation pathways of MSP upon endocytosis by HeLa cells and NSC-34 motor neurons using confocal and electron microscopy imaging together with inductively-coupled plasma optical emission spectroscopy analysis. We demonstrate how MSP are captured by receptor-mediated endocytosis and are temporarily stored in endo-lysosomes before being finally exocytosed. We also illustrate how particles are often re-endocytosed after undergoing surface erosion extracellularly. On the other hand, silica particles engineered to target the cytosol with a carbon nanotube coating, are safely dissolved intracellularly in a time scale of hours. These studies provide fundamental clues for programming the sub-cellular fate of MSP and reveal critical aspects to improve delivery strategies and to favor MSP safe elimination. We also demonstrate how the cytosol is significantly more corrosive than lysosomes for MSP and show how their biodegradation is fully biocompatible, thus, validating their use as nanocarriers for nervous system cells, including motor neurons.
Design of Polymeric Nanocapsules for Intranasal Vaccination against Mycobacterium Tuberculosis: Influence of the Polymeric Shell and Antigen Positioning
Authors: Diego-González Lara , Crecente-Campo José , Paul Matthew John , Singh Mahavir , Reljic Rajko , Alonso María José , González-Fernández África , Simón-Vázquez Rosana
Published: May 2020

Tuberculosis (TB) is the leading cause of death from a single infectious microorganism and Bacillus Calmette Guerin (BCG), the only authorized vaccine, does not confer protection against pulmonary TB. Based on the hypothesis that mucosal protection could help to prevent the infection at the site of entrance, the objective of this work was to develop an intranasal vaccine against Mycobacterium tuberculosis (Mtb), the microorganism that causes TB. Our approach consisted of the use of polymeric nanocapsules (NCs) with an oily core and a polymer shell made of chitosan (CS) or inulin/polyarginine (INU/pArg). The immunostimulant Imiquimod, a Toll-like receptor-7 (TLR-7) agonist, was encapsulated in the oily core and a fusion protein, formed by two antigens of Mtb, was absorbed either onto the NC surface (CS:Ag and INU:pArg:Ag) or between two polymer layers (INU:Ag:pArg) in order to assess the influence of the antigen positioning on the immune response. Although CS NCs were more immunostimulant than the INU/pArg NCs in vitro, the in vivo experiments showed that INU:pArg:Ag NCs were the only prototype inducing an adequate immunoglobulin A (IgA) response. Moreover, a previous immunization with BCG increased the immune response for CS NCs but, conversely, decreased for INU/pArg NCs. Further optimization of the antigen and the vaccination regime could provide an efficacious vaccine, using the INU:pArg:Ag NC prototype as nanocarrier.
Effects of Decomplexation Rates on Ternary Gene Complex Transfection with α-Poly(l-Lysine) or ε-Poly(l-Lysine) as a Decomplexation Controller in An Easy-To-Transfect Cell or A Hard-To-Transfect Cell
Authors: Kim Kyoungnam , Ryu Kitae , Cho Hana , Shim Min Suk , Cho Yong-Yeon , Lee Joo Young , Lee Hye Suk , Kang Han Chang
Published: May 2020

The tight binding of pDNA with a cationic polymer is the crucial requirement that prevents DNA degradation from undesired DNase attack to safely deliver the pDNA to its target site. However, cationic polymer-mediated strong gene holding limits pDNA dissociation from the gene complex, resulting in a reduction in transfection efficiency. In this study, to control the decomplexation rate of pDNA from the gene complex in a hard-to-transfect cell or an easy-to-transfect cell, either α-poly(l-lysine) (APL) or ε-poly(l-lysine) (EPL) was incorporated into branched polyethylenimine (bPEI)-based nanocomplexes (NCs). Compared to bPEI/pDNA NCs, the addition of APL or EPL formed smaller bPEI-APL/pDNA NCs with similar zeta potentials or larger bPEI-EPL/pDNA NCs with reduced zeta potentials, respectively, due to the different characteristics of the primary amines in the two poly(l-lysine)s (PLs). Interestingly, although both bPEI-APL/pDNA NCs and bPEI-EPL/pDNA NCs showed similar pDNA compactness to bPEI/pDNA NCs, the addition of APL or EPL resulted in slower or faster pDNA release, respectively, from the bPEI-PL/pDNA NCs than from the bPEI/pDNA NCs. bPEI-EPL/pDNA NCs with a decomplexation enhancer (i.e., EPL) improved the transfection efficiency (TE) in both a hard-to-transfect HepG2 cell and an easy-to-transfect HEK293 cell. However, although a decomplexation inhibitor (i.e., APL) reduced the TE of bPEI-APL/pDNA NCs in both cells, the degree of reduction in the TE could be compensated by PL-mediated enhanced nuclear delivery, particularly in HepG2 cells but not HEK293 cells, because both PLs facilitate nuclear localization of the gene complex per its cellular uptake. In conclusion, a decomplexation rate controller could be a potential factor to establish a high TE and design clinically available gene complex systems.
In Vitro Skin Retention of Crisaborole after Topical Application
Authors: Fantini Adriana , Demurtas Anna , Nicoli Sara , Padula Cristina , Pescina Silvia , Santi Patrizia
Published: May 2020

Crisaborole, a nonsteroidal phosphodiesterase 4 inhibitor, represents the first nonsteroidal medication approved for the treatment of atopic dermatitis in over a decade. In this work, crisaborole skin permeation and retention was studied in vitro from a 2% ointment using porcine skin as barrier. Crisaborole was also characterized in terms of thermal behavior, solubility, and logP. Control experiments were performed also on tape stripped skin to clarify the role of stratum corneum in drug partitioning and permeation across the skin. The results obtained indicate that crisaborole accumulates into the skin in considerable amounts after application of a topical lipophilic ointment. Crisaborole shows more affinity for the dermis compared to the epidermis despite its relatively high value of partition coefficient; stratum corneum analysis revealed a low affinity of the drug for this skin layer. Skin penetration across hair follicles or sebaceous glands can be a reason for the high dermis retention and is worth further investigation. The comparison with data obtained from a solution in acetonitrile suggests that the formulation plays a certain role in determining the relative distribution of crisaborole in the skin layers and in the receptor compartment.
Enhancement in Oral Absorption of Ceftriaxone by Highly Functionalized Magnetic Iron Oxide Nanoparticles
Authors: Kawish Muhammad , Elhissi Abdelbary , Jabri Tooba , Muhammad Iqbal Kanwal , Zahid Hina , Shah Muhammad Raza
Published: May 2020

The present study aims at the development, characterization, biocompatibility investigation and oral bioavailability evaluation of ceftriaxone (CFT)-loaded N′-methacryloylisonicotinohydrazide (MIH)-functionalized magnetic nanoparticles (CFT-MIH-MNPs). Atomic force microscopy (AFM) and dynamic light scattering (DLS) showed that the developed CFT loaded MIH-MNPs are spherical, with a measured hydrodynamic size of 184.0 ± 2.7 nm and negative zeta potential values (–20.2 ± 0.4 mV). Fourier transformed infrared spectroscopic (FTIR) analysis revealed interactions between the nanocarrier and the drug. Nanoparticles showed high drug entrapment efficiency (EE) of 79.4% ±1.5%, and the drug was released gradually in vitro and showed prolonged in vitro stability using simulated gastrointestinal tract (GIT) fluids. The formulations were found to be highly biocompatible (up to 100 µg/mL) and hemocompatible (up to 1.0 mg/mL). Using an albino rabbit model, the formulation showed a significant enhancement in drug plasma concentration up to 14.4 ± 1.8 µg/mL in comparison with its control (2.0 ± 0.6 µg/mL). Overall, the developed CFT-MIH-MNPs formulation was promising for provision of high drug entrapment, gradual drug release and suitability for enhancing the oral delivery of CFT.