bluuebunny/crossref_metadata_2025 huggingface dataset:
Gut/Oral Bacteria Variability May Explain the High Efficacy of Green Tea in Rodent Tumor Inhibition and Its Absence in Humans
Authors: Adami Guy R. , Tangney Christy , Schwartz Joel L. , Dang Kim Chi
Published: October 2020

Consumption of green tea (GT) and GT polyphenols has prevented a range of cancers in rodents but has had mixed results in humans. Human subjects who drank GT for weeks showed changes in oral microbiome. However, GT-induced changes in RNA in oral epithelium were subject-specific, suggesting GT-induced changes of the oral epithelium occurred but differed across individuals. In contrast, studies in rodents consuming GT polyphenols revealed obvious changes in epithelial gene expression. GT polyphenols are poorly absorbed by digestive tract epithelium. Their metabolism by gut/oral microbial enzymes occurs and can alter absorption and function of these molecules and thus their bioactivity. This might explain the overall lack of consistency in oral epithelium RNA expression changes seen in human subjects who consumed GT. Each human has different gut/oral microbiomes, so they may have different levels of polyphenol-metabolizing bacteria. We speculate the similar gut/oral microbiomes in, for example, mice housed together are responsible for the minimal variance observed in tissue GT responses within a study. The consistency of the tissue response to GT within a rodent study eases the selection of a dose level that affects tumor rates. This leads to the theory that determination of optimal GT doses in a human requires knowledge about the gut/oral microbiome in that human.
Anti-Melanogenic Effects of Korean Red Ginseng Oil in an Ultraviolet B-Induced Hairless Mouse Model
Authors: Saba Evelyn , Kim Seung-Hyung , Lee Yuan Yee , Kim Hyun-Kyoung , Roh Seong-Soo , Kwak Yi-Seong , Park Chae-Kyu , Kim Sung-Dae , Rhee Man Hee
Published: October 2020

A ‘remedy for all’ natural product widely known in the Korean Peninsula is called Panax Ginseng Meyer. Globalization represents a persistent risk to the ozone layer, leading to bountiful amounts of Ultra-Violet B beams (UVB). The variety in human skin hues is ascribed to the characteristic color called Melanin. However, Melanin overproduction due to UVB beams promotes skin staining and tumorigenesis, a process called photo aging, which damages skin quality. To assess the effects of Korean Red Ginseng Oil (KGO) on photo aging, the murine melanoma cell lines B16/F10 were used in vitro and HRM-2 hairless mice exposed to UVB were studied in vivo. Our results revealed that KGO reduced tyrosinase activity and melanin production in B16/F10 cells along with the suppression of upstream factors involved in the melanin production pathway, both transcriptionally and transitionally. In the in vivo studies, KGO suppressed the expression of Matrix Metalloproteinase (MMP) and Interleukins along with a reduction of depth in wrinkle formation and reduced collagen degradation. Moreover, the feed intake and feed efficiency ratio that decreased as a result of UVB exposure was also improved by KGO treatment. In light of our results, we conclude that KGO can have considerable benefits due to its various properties of natural skin enhancement.
Potential Beneficial Effects of Extra Virgin Olive Oils Characterized by High Content in Minor Polar Compounds in Nephropathic Patients: A Pilot Study
Authors: Romani Annalisa , Bernini Roberta , Noce Annalisa , Urciuoli Silvia , Di Lauro Manuela , Pietroboni Zaitseva Anna , Marrone Giulia , Di Daniele Nicola
Published: October 2020

Extra virgin olive oil (EVOO) is a lipid food, which constitutes a pillar of the Mediterranean diet. A high number of scientific data have demonstrated that it exerts a variety of beneficial effects on human health due to its peculiar chemical composition including fatty acids (98–99%) and other active compounds even if found in a very low percentage (1–2%). Among them, minor polar compounds (MCPs), represented mainly by phenolic compounds, are relevant for their healthy properties, as stated by the European Food Safety Authority’s (EFSA) claims. In this paper, we described the results obtained from a pilot in vivo study, focused for the first time on the evaluation of the possible beneficial effects of two EVOOs on chronic kidney disease (CKD) patients after the consumption of 40 mL per day for 9 weeks. The selected EVOOs, traced in the production chain, and characterized by High-Performance Liquid Chromatography (HPLC-DAD-MS) analysis, resulted rich in MCPs and satisfied the EFSA’s claim for their content of hydroxytyrosol and derivatives. The results obtained by this in vivo study appear to highlight the potential beneficial role in CKD patients of these EVOOs and are promising for future studies.
Understanding the Factors Influencing Chitosan-Based Nanoparticles-Protein Corona Interaction and Drug Delivery Applications
Authors: Moraru Cristina , Mincea Manuela , Menghiu Gheorghita , Ostafe Vasile
Published: October 2020

Chitosan is a polymer that is extensively used to prepare nanoparticles (NPs) with tailored properties for applications in many fields of human activities. Among them, targeted drug delivery, especially when cancer therapy is the main interest, is a major application of chitosan-based NPs. Due to its positive charges, chitosan is used to produce the core of the NPs or to cover NPs made from other types of polymers, both strategies aiming to protect the carried drug until NPs reach the target sites and to facilitate the uptake and drug delivery into these cells. A major challenge in the design of these chitosan-based NPs is the formation of a protein corona (PC) upon contact with biological fluids. The composition of the PC can, to some extent, be modulated depending on the size, shape, electrical charge and hydrophobic/hydrophilic characteristics of the NPs. According to the composition of the biological fluids that have to be crossed during the journey of the drug-loaded NPs towards the target cells, the surface of these particles can be changed by covering their core with various types of polymers or with functionalized polymers carrying some special molecules, that will preferentially adsorb some proteins in their PC. The PC’s composition may change by continuous processes of adsorption and desorption, depending on the affinity of these proteins for the chemical structure of the surface of NPs. Beside these, in designing the targeted drug delivery NPs one can take into account their toxicity, initiation of an immune response, participation (enhancement or inhibition) in certain metabolic pathways or chemical processes like reactive oxygen species, type of endocytosis of target cells, and many others. There are cases in which these processes seem to require antagonistic properties of nanoparticles. Products that show good behavior in cell cultures may lead to poor in vivo results, when the composition of the formed PC is totally different. This paper reviews the physico-chemical properties, cellular uptake and drug delivery applications of chitosan-based nanoparticles, specifying the factors that contribute to the success of the targeted drug delivery. Furthermore, we highlight the role of the protein corona formed around the NP in its intercellular fate.
Unravelling the Antifungal Effect of Red Thyme Oil (Thymus vulgaris L.) Compounds in Vapor Phase
Authors: Pinto Loris , Bonifacio Maria Addolorata , De Giglio Elvira , Cometa Stefania , Logrieco Antonio F. , Baruzzi Federico
Published: October 2020

The aim of this work was to evaluate the antifungal activity in vapor phase of thymol, p-cymene, and γ-terpinene, the red thyme essential oil compounds (RTOCs). The Minimum Inhibitory Concentration (MIC) of RTOCs was determined against postharvest spoilage fungi of the genera Botrytis, Penicillium, Alternaria, and Monilinia, by measuring the reduction of the fungal biomass after exposure for 72 h at 25 °C. Thymol showed the lowest MIC (7.0 µg/L), followed by γ-terpinene (28.4 µg/L) and p-cymene (40.0 µg/L). In the case of P. digitatum ITEM 9569, resistant to commercial RTO, a better evaluation of interactions among RTOCs was performed using the checkerboard assay and the calculation of the Fractional Inhibitory Concentration Index (FICI). During incubation, changes in the RTOCs concentration were measured by GC-MS analysis. A synergistic effect between thymol (0.013 ± 0.003 L/L) and γ-terpinene (0.990 ± 0.030 L/L) (FICI = 0.50) in binary combinations, and between p-cymene (0.700 ± 0.010 L/L) and γ-terpinene (0.290 ± 0.010 L/L) in presence of thymol (0.008 ± 0.001 L/L) (FICI = 0.19), in ternary combinations was found. The synergistic effect against the strain P. digitatum ITEM 9569 suggests that different combinations among RTOCs could be defined to control fungal strains causing different food spoilage phenomena.
Bioactive Flavonoid Glycosides and HPLC and UPLC Quantification of Commercial Astragali Complanati Semen
Authors: Kuo Jenny Chun-Ling , Zhang Li-Jie , Huang Hung-Tse , Liaw Chia-Ching , Lin Zhi-Hu , Liu Min , Kuo Yao-Haur
Published: October 2020

Eleven compounds, including nine known flavonoid glycosides (1–4, 6–8, and 10–11), one isoflavone glycoside (5), and a glansreginic acid (9), were isolated from the 80% ethanol extract of commercial Astragali Complanati Semen (ACS). All chemical structures were determined by spectroscopic analyses, including 1D and 2D NMR. Compounds 2, 4, 5, 6, 9, and 10 were isolated and identified from the title plant for the first time. Biological evaluation revealed that all the isolates showed promising anti-NO production, and 1, 2, 3, and 8 were more potent in antioxidant activity than vitamin E. The major peaks in the UPLC and HPLC profiles identified their chemical structures by comparing their retention time and UV spectra with those of the reference substances. Furthermore, nine of the eleven samples collected from North, Middle, and South regions of Taiwan possessed similar HPLC fingerprints and were identified as Astragali Complanati Semen, whereas the other two samples from southern Taiwan would be the adulterants due to the different fingerprinting patterns. In addition, an HPLC-UV method was employed to determine the content of target compound complanatuside (11) with good linear regression (R2 = 0.9998) for ACS in the Taiwanese market. Of the isolates, flavonol glycosides 1 and 3 were the major peaks in HPLC/UPLC, and showed more potent antioxidant and anti-NO production activities than that of 11, revealing that these compounds can be the available agents for the quality control of ACS.
Phytochemical Evaluation of Tinctures and Essential Oil Obtained from Satureja montana Herb
Authors: Hudz Nataliia , Makowicz Ewa , Shanaida Mariia , Białoń Marietta , Jasicka-Misiak Izabela , Yezerska Oksana , Svydenko Liudmyla , Wieczorek Piotr Paweł
Published: October 2020

Winter Savory (Satureja montana L.) has been used in traditional medicine and as a spice or natural food preservative in the Mediterranean region for centuries. In this paper, some technological and analytical aspects of the S. montana tinctures development and an evaluation of the essential oil composition are provided. The total phenolic and flavonoid contents and phenolic compounds profile analyzed spectrophotometrically and by high-performance thin-layer chromatography (HPTLC), respectively, were evaluated in the developed tinctures. The results showed that the tinctures prepared from the S. montana herb by maceration or remaceration are rich in polyphenols, and there is an influence of the technological factors (particle size and extraction mode) on the total phenolic and flavonoid contents. Caffeic, rosmarinic, and chlorogenic acids, (–)-catechin and rutin were identified in the tinctures using the HPTLC method. p-Thymol (81.79%) revealed by gas chromatography-mass spectrometry (GC-MS) was the predominant compound of the essential oil of this plant. Thus, the high contents of polyphenols and flavonoids in the developed tinctures and p-thymol among the volatile components of the S. montana essential oil could indicate the promising antioxidant and antimicrobial properties of these herbal preparations. The obtained results are a ground for the organization of the manufacture of the S. montana tincture and essential oil with the purpose of performing preclinical studies.
Copper-Catalyzed Trifluoromethylation of Alkoxypyridine Derivatives
Authors: Gyorfi Nandor , Farkas Emese , Nemet Norbert , Weber Csaba , Novak Zoltan , Kotschy Andras
Published: October 2020

The trifluoromethylation of aromatic and heteroaromatic cores has attracted considerable interest in recent years due to its pharmacological relevance. We studied the extension of a simple copper-catalyzed trifluoromethylation protocol to alkoxy-substituted iodopyridines and their benzologs. The trifluoromethylation proceeded smoothly in all cases, and the desired compounds were isolated and characterized. In the trifluoromethylation of 3-iodo-4-methoxyquinoline, we observed a concomitant O-N methyl migration, resulting in the trifluoromethylated quinolone as a product. Overall, the described procedure should facilitate the broader use of copper-catalyzed trifluoromethylation in medicinal chemistry.
On a Magical Mystery Tour with 8-Bromo-Cyclic ADP-Ribose: From All-or-None Block to Nanojunctions and the Cell-Wide Web
Authors: Evans A. Mark
Published: October 2020

A plethora of cellular functions are controlled by calcium signals, that are greatly coordinated by calcium release from intracellular stores, the principal component of which is the sarco/endooplasmic reticulum (S/ER). In 1997 it was generally accepted that activation of various G protein-coupled receptors facilitated inositol-1,4,5-trisphosphate (IP3) production, activation of IP3 receptors and thus calcium release from S/ER. Adding to this, it was evident that S/ER resident ryanodine receptors (RyRs) could support two opposing cellular functions by delivering either highly localised calcium signals, such as calcium sparks, or by carrying propagating, global calcium waves. Coincidentally, it was reported that RyRs in mammalian cardiac myocytes might be regulated by a novel calcium mobilising messenger, cyclic adenosine diphosphate-ribose (cADPR), that had recently been discovered by HC Lee in sea urchin eggs. A reputedly selective and competitive cADPR antagonist, 8-bromo-cADPR, had been developed and was made available to us. We used 8-bromo-cADPR to further explore our observation that S/ER calcium release via RyRs could mediate two opposing functions, namely pulmonary artery dilation and constriction, in a manner seemingly independent of IP3Rs or calcium influx pathways. Importantly, the work of others had shown that, unlike skeletal and cardiac muscles, smooth muscles might express all three RyR subtypes. If this were the case in our experimental system and cADPR played a role, then 8-bromo-cADPR would surely block one of the opposing RyR-dependent functions identified, or the other, but certainly not both. The latter seemingly implausible scenario was confirmed. How could this be, do cells hold multiple, segregated SR stores that incorporate different RyR subtypes in receipt of spatially segregated signals carried by cADPR? The pharmacological profile of 8-bromo-cADPR action supported not only this, but also indicated that intracellular calcium signals were delivered across intracellular junctions formed by the S/ER. Not just one, at least two. This article retraces the steps along this journey, from the curious pharmacological profile of 8-bromo-cADPR to the discovery of the cell-wide web, a diverse network of cytoplasmic nanocourses demarcated by S/ER nanojunctions, which direct site-specific calcium flux and may thus coordinate the full panoply of cellular processes.
Two-Step One-Pot Reductive Amination of Furanic Aldehydes Using CuAlOx Catalyst in a Flow Reactor
Authors: Nuzhdin Alexey L. , Bukhtiyarova Marina V. , Bukhtiyarov Valerii I.
Published: October 2020

Aminomethylhydroxymethylfuran derivatives are well known compounds which are used in the pharmaceutical industry. Reductive amination of 5-hydroxymethylfurfural (HMF) derived from available non-edible lignocellulosic biomass is an attractive method for the synthesis of this class of compounds. In the present study, the synthesis of N-substituted 5-(hydroxymethyl)-2-furfuryl amines and 5-(acetoxymethyl)-2-furfuryl amines was performed by two-step process, which includes the condensation of furanic aldehydes (HMF and 5-acetoxymethylfurfural) with primary amines in methanol on the first step and the reduction of obtained imines with hydrogen in a flow reactor over CuAlOx catalyst derived from layered double hydroxide on the second step. This process does not require isolation and purification of intermediate imines and can be used to synthesize a number of aminomethylhydroxymethylfurans in good to excellent yield.
Current Status of Matrix-Assisted Laser Desorption/Ionization–Time-of-Flight Mass Spectrometry (MALDI-TOF MS) in Clinical Diagnostic Microbiology
Authors: Tsuchida Sachio , Umemura Hiroshi , Nakayama Tomohiro
Published: October 2020

Mass spectrometry (MS), a core technology for proteomics and metabolomics, is currently being developed for clinical applications. The identification of microorganisms in clinical samples using matrix-assisted laser desorption/ionization–time-of-flight mass spectrometry (MALDI-TOF MS) is a representative MS-based proteomics application that is relevant to daily clinical practice. This technology has the advantages of convenience, speed, and accuracy when compared with conventional biochemical methods. MALDI-TOF MS can shorten the time used for microbial identification by about 1 day in routine workflows. Sample preparation from microbial colonies has been improved, increasing the accuracy and speed of identification. MALDI-TOF MS is also used for testing blood, cerebrospinal fluid, and urine, because it can directly identify the microorganisms in these liquid samples without prior culture or subculture. Thus, MALDI-TOF MS has the potential to improve patient prognosis and decrease the length of hospitalization and is therefore currently considered an essential tool in clinical microbiology. Furthermore, MALDI-TOF MS is currently being combined with other technologies, such as flow cytometry, to expand the scope of clinical applications.
Self-Perception and Training Perceptions on Teacher Digital Competence (TDC) in Spanish and French University Students
Authors: Ortega-Sánchez Delfín , Gómez-Trigueros Isabel María , Trestini Marc , Pérez-González Carlos
Published: October 2020

The purpose of this research is, on the one hand, to analyze the self-perception of future teachers of childhood education and primary education, and those studying for a master’s degree in secondary education teacher training on their Teacher Digital Competence (TDC), as well as the potential influence of gender, country and university institution of origin in their representations. On the other hand, it seeks to analyze the perception of future teachers on the TDC of their university trainers (formative perception). In accordance with these aims, a quantitative methodology of a non-experimental nature and of a prospective cross-sectional ex post facto approach has been used. A total of 428 students from two Spanish universities and from a French university agreed to participate in the research. The results report a positive and differential self-perception by gender of the TDC acquired and unfavorable perceptions of the digital competences of their teachers. These results confirm the need to improve the technological-manipulative and didactic training of university teachers, and to adapt the teaching competences to the demands of the Information and Communication Society (ICS) and to the guidelines of the Common Digital Competence Framework.
Graphene Flakes for Electronic Applications: DC Plasma Jet-Assisted Synthesis
Authors: Antonova Irina V. , Shavelkina Marina B. , Ivanov Artem I. , Soots Regina A. , Ivanov Peter P. , Bocharov Alexey N.
Published: October 2020

The possibility of graphene synthesis (the bottom-up approach) in plasma and the effective control of the morphology and electrical properties of graphene-based layers were demonstrated. Graphene flakes were grown in a plasma jet generated by a direct current plasma torch with helium and argon as the plasma-forming gases. In the case of argon plasma, the synthesized graphene flakes were relatively thick (2–6 nm) and non-conductive. In helium plasma, for the first time, graphene with a predominance of monolayer flakes and high conductivity was grown in a significant amount using an industrial plasma torch. One-dimensional (1D) flow modeling shows that the helium plasma is a less charged environment providing the formation of thinner graphene flakes with low defect density. These flakes might be used for a water-based suspension of the graphene with PEDOT:PSS (poly(3,4-ethylenedioxythiophene): polystyrene sulfonate) composite to create the structures employing the 2D printing technologies. Good structural quality, low layer resistance, and good mechanical strength combined with the ability to obtain a large amount of the graphene powder, and to control the parameters of the synthesized particles make this material promising for various applications and, above all, for sensors and other devices for flexible electronics and the Internet of things ecosystem.
Synthesis of Mo2C by Thermal Decomposition of Molybdenum Blue Nanoparticles
Authors: Gavrilova Natalia , Dyakonov Victor , Myachina Maria , Nazarov Victor , Skudin Valery
Published: October 2020

In recent years, the development of methods for the synthesis of Mo2C for catalytic application has become especially important. In this work a series of Mo2C samples was synthesized by thermal decomposition of molybdenum blue xerogels obtained using ascorbic acid. The influence of the molar ratio reducing agent/Mo [R]/[Mo] on morphology, phase composition and characteristics of the porous structure of Mo2C has been established. The developed synthesis method allows the synthesis to be carried out in an inert atmosphere and does not require a carburization step. The resulting molybdenum carbide has a mesoporous structure with a narrow pore size distribution and a predominant pore size of 4 nm.
Adherence to a Mediterranean Diet and Thyroid Function in Obesity: A Cross-Sectional Apulian Survey
Authors: Zupo Roberta , Castellana Fabio , Panza Francesco , Lampignano Luisa , Murro Isanna , Di Noia Carmen , Triggiani Vincenzo , Giannelli Gianluigi , Sardone Rodolfo , De Pergola Giovanni
Published: October 2020

Much research suggests that Mediterranean eating habits and lifestyle contribute to counteract the risk of chronic diseases while promoting longevity, but little information is available on the effects of the Mediterranean diet (Med-Diet) on thyroid function, particularly among overweight/obese subjects. Nevertheless, consistent data reported a slight increase in serum levels of the thyroid-stimulating hormone (TSH) and a higher rate of conversion of thyroxine (T4) to triiodothyronine (T3) in obesity. This cross-sectional study was aimed at investigating the relationship between adherence to the Med-Diet and circulating thyroid hormones in a cohort of overweight/obese subjects from Apulia (Southern Italy). Methods: We studied 324 consecutive outpatient subjects (228 women and 96 men, age range 14–72 years) taking no drug therapy and showing normal levels of thyroid hormones, but complicated by overweight and obesity (body mass index (BMI) ≥ 25 Kg/m2). The PREDIMED (PREvención con DIeta MEDiterránea) questionnaire was cross-sectionally administered to assess the adherence to the Med-Diet, and hormonal, metabolic, and routine laboratory parameters were collected. Results: Higher adherence to Med-Diet was found to be inversely related to free T3 (p < 0.01) and T4 (p < 0.01) serum levels. Considering each item in the PREDIMED questionnaire, people consuming at least four spoonfuls of extra-virgin olive oil (EVOO) per day, as well as those consuming at least two servings of vegetables per day, had lower free T3 levels (p 0.033 and p 0.021, respectively). Furthermore, consuming at least four spoonfuls of EVOO per day was found to be associated to lower free T4 serum concentrations (p 0.011). Multinomial logistic regression models, performed on tertiles of thyroid hormones to further investigate the relationship with Med-Diet, corroborated the significance only for free T4. Conclusion: Increased adherence to the Med-Diet was independently associated to a slightly reduced thyroid function, but still within the reference range for free T3 and T4 serum levels. This first finding in this field opens up a research line on any underlying biological interplay.
Understanding the Reactivity of Trimethylsilyldiazoalkanes Participating in [3+2] Cycloaddition Reactions towards Diethylfumarate with a Molecular Electron Density Theory Perspective
Authors: Domingo Luis , Acharjee Nivedita , Mohammad-Salim Haydar
Published: October 2020

A Molecular Electron Density Theory (MEDT) study is presented here for [3+2] cycloaddition (32CA) reactions of three trimethylsilyldiazoalkanes with diethyl fumarate. The presence of silicon bonded to the carbon of these silyldiazoalkanes changes its structure and reactivity from a pseudomonoradical to that of a zwitterionic one. A one-step mechanism is predicted for these polar zw-type 32CA reactions with activation enthalpies in CCl4 between 8.0 and 19.7 kcal·mol−1 at the MPWB1K (PCM)/6-311G(d,p) level of theory. The negative reaction Gibbs energies between −3.1 and −13.2 kcal·mole−1 in CCl4 suggests exergonic character, making the reactions irreversible. Analysis of the sequential changes in the bonding pattern along the reaction paths characterizes these zw-type 32CA reactions. The increase in nucleophilic character of the trimethylsilyldiazoalkanes makes these 32CA reactions more polar. Consequently, the activation enthalpies are decreased and the TSs require less energy cost. Non-covalent interactions at the TSs account for the stereoselectivity found in these 32CA reactions involving the bulky trimethylsilyl group.
Immunological Perspective for Ebola Virus Infection and Various Treatment Measures Taken to Fight the Disease
Authors: Jain Sahil , Khaiboullina Svetlana F. , Baranwal Manoj
Published: October 2020

Ebolaviruses, discovered in 1976, belongs to the Filoviridae family, which also includes Marburg and Lloviu viruses. They are negative-stranded RNA viruses with six known species identified to date. Ebola virus (EBOV) is a member of Zaire ebolavirus species and can cause the Ebola virus disease (EVD), an emerging zoonotic disease that results in homeostatic imbalance and multi-organ failure. There are three EBOV outbreaks documented in the last six years resulting in significant morbidity (>32,000 cases) and mortality (>13,500 deaths). The potential factors contributing to the high infectivity of this virus include multiple entry mechanisms, susceptibility of the host cells, employment of multiple immune evasion mechanisms and rapid person-to-person transmission. EBOV infection leads to cytokine storm, disseminated intravascular coagulation, host T cell apoptosis as well as cell mediated and humoral immune response. In this review, a concise recap of cell types targeted by EBOV and EVD symptoms followed by detailed run-through of host innate and adaptive immune responses, virus-driven regulation and their combined effects contributing to the disease pathogenesis has been presented. At last, the vaccine and drug development initiatives as well as challenges related to the management of infection have been discussed.
Nanoemulsion Stabilized by Safe Surfactin from Bacillus subtilis as a Multifunctional, Custom-Designed Smart Delivery System
Authors: Lewińska Agnieszka , Domżał-Kędzia Marta , Jaromin Anna , Łukaszewicz Marcin
Published: October 2020

The developing field of bio-nanotechnology aims to advance colloidal research via the introduction of multifunctional nanoparticles to augment the dermal effectiveness of active substances. Self-emulsifying drug delivery systems (SEDDS)—isotropic mixtures of oils, surfactants, solvents and co-solvents or surfactants—are attracting interest in the cosmeceutical field. As part of this study, SEDDS systems containing vitamin C or vitamin E and curcumin were developed, whereby the bioavailability of the active compounds increased by enhancing their permeability to deeper layers of the skin. A composition consisting of 50% surfactin from Bacillus subtilis, 30% Transcutol and 20% oil phase was designed to encapsulate the active substances, i.e., vitamin C or vitamin E and curcumin, contained in the oil phase. The developed carriers were characterized by average particle sizes of 69–183 nm. The formulations with the vitamins were found to be physically and chemically stable for 6 months. Transdermal tests were carried out, showing that the carriers enable the transport of active substances deep into the skin, stopping at the dermis border. The formulations with vitamin C and vitamin E reduced the discoloration, the vascular lesions, and the depth of the wrinkles on the tested skin, which can be useful in cosmetics in the treatment of problem skin, including capillary and sensitive skin.
Production of Itraconazole Nanocrystal-Based Polymeric Film Formulations for Immediate Drug Release
Authors: Karagianni Anna , Peltonen Leena
Published: October 2020

In order to improve the solubility properties of BCS class II drug itraconazole, fast dissolving oral polymeric film formulations based on itraconazole nanocrystals were produced. Drug nanocrystals were manufactured by the wet pearl milling technique. In polymeric film formulations, hydroxypropyl methyl cellulose (HPMC) was used as a film forming polymer, and glycerin was used as a plasticizer. For nanocrystal suspensions and film formulations, thorough physicochemical characterization was performed, including particle sizing and size deviation, film appearance, weight variation, thickness, folding endurance, drug content uniformity, disintegration time, and dissolution profile. After milling, the nanoparticles were 369 nm in size with a PI value of 0.20. Nanoparticles were stable and after redispersion from film formulations, the particle size remained almost the same (330 nm and PI 0.16). The produced films were flexible, homogeneous, fast disintegrating, and drug release rate from both the nanosuspension and film formulations showed immediate release behavior. Based on the study, the film casting method for production of itraconazole nanocrystal based immediate release formulations is a good option for improved solubility.
Encapsulation of a Ru(II) Polypyridyl Complex into Polylactide Nanoparticles for Antimicrobial Photodynamic Therapy
Authors: Soliman Nancy , Sol Vincent , Ouk Tan-Sothea , Thomas Christophe M. , Gasser Gilles
Published: October 2020

Antimicrobial photodynamic therapy (aPDT) also known as photodynamic inactivation (PDI) is a promising strategy to eradicate pathogenic microorganisms such as Gram-positive and Gram-negative bacteria. This therapy relies on the use of a molecule called photosensitizer capable of generating, from molecular oxygen, reactive oxygen species including singlet oxygen under light irradiation to induce bacteria inactivation. Ru(II) polypyridyl complexes can be considered as potential photosensitizers for aPDT/PDI. However, to allow efficient treatment, they must be able to penetrate bacteria. This can be promoted by using nanoparticles. In this work, ruthenium-polylactide (RuPLA) nanoconjugates with different tacticities and molecular weights were prepared from a Ru(II) polypyridyl complex, RuOH. Narrowly-dispersed nanoparticles with high ruthenium loadings (up to 53%) and an intensity-average diameter < 300 nm were obtained by nanoprecipitation, as characterized by dynamic light scattering (DLS). Their phototoxicity effect was evaluated on four bacterial strains (Staphylococcus aureus, Staphylococcus epidermidis, Escherichia coli and Pseudomonas aeruginosa) and compared to the parent compound RuOH. RuOH and the nanoparticles were found to be non-active towards Gram-negative bacterial strains. However, depending on the tacticity and molecular weight of the RuPLA nanoconjugates, differences in photobactericidal activity on Gram-positive bacterial strains have been evidenced whereas RuOH remained non active.
Targeting the Choroid Plexuses for Protein Drug Delivery
Authors: Bryniarski Mark A. , Ren Tianjing , Rizvi Abbas R. , Snyder Anthony M. , Morris Marilyn E.
Published: October 2020

Delivery of therapeutic agents to the central nervous system is challenged by the barriers in place to regulate brain homeostasis. This is especially true for protein therapeutics. Targeting the barrier formed by the choroid plexuses at the interfaces of the systemic circulation and ventricular system may be a surrogate brain delivery strategy to circumvent the blood-brain barrier. Heterogenous cell populations located at the choroid plexuses provide diverse functions in regulating the exchange of material within the ventricular space. Receptor-mediated transcytosis may be a promising mechanism to deliver protein therapeutics across the tight junctions formed by choroid plexus epithelial cells. However, cerebrospinal fluid flow and other barriers formed by ependymal cells and perivascular spaces should also be considered for evaluation of protein therapeutic disposition. Various preclinical methods have been applied to delineate protein transport across the choroid plexuses, including imaging strategies, ventriculocisternal perfusions, and primary choroid plexus epithelial cell models. When used in combination with simultaneous measures of cerebrospinal fluid dynamics, they can yield important insight into pharmacokinetic properties within the brain. This review aims to provide an overview of the choroid plexuses and ventricular system to address their function as a barrier to pharmaceutical interventions and relevance for central nervous system drug delivery of protein therapeutics. Protein therapeutics targeting the ventricular system may provide new approaches in treating central nervous system diseases.
Carbohydrate Immune Adjuvants in Subunit Vaccines
Authors: Bashiri Sahra , Koirala Prashamsa , Toth Istvan , Skwarczynski Mariusz
Published: October 2020

Modern subunit vaccines are composed of antigens and a delivery system and/or adjuvant (immune stimulator) that triggers the desired immune responses. Adjuvants mimic pathogen-associated molecular patterns (PAMPs) that are typically associated with infections. Carbohydrates displayed on the surface of pathogens are often recognized as PAMPs by receptors on antigen-presenting cells (APCs). Consequently, carbohydrates and their analogues have been used as adjuvants and delivery systems to promote antigen transport to APCs. Carbohydrates are biocompatible, usually nontoxic, biodegradable, and some are mucoadhesive. As such, carbohydrates and their derivatives have been intensively explored for the development of new adjuvants. This review assesses the immunological functions of carbohydrate ligands and their ability to enhance systemic and mucosal immune responses against co-administered antigens. The role of carbohydrate-based adjuvants/delivery systems in the development of subunit vaccines is discussed in detail.
Silver (I) N-Heterocyclic Carbenes Carbosilane Dendritic Systems and Their Imidazolium-Terminated Analogues as Antibacterial Agents: Study of Their Mode of Action
Authors: Rodríguez-Prieto Tamara , Popp Philipp F. , Copa-Patiño José Luis , Mata F. Javier de la , Cano Jesús , Mascher Thorsten , Gómez Rafael
Published: October 2020

Spherical dendrimers and dendrons containing silver(I) N-heterocyclic carbenes (Ag(I)-NHC) and additionally bow-tie metal-free dendritic systems were synthesized in a simple and straightforward synthetic procedure and subsequently characterized. The antibacterial activity was evaluated, and in parallel, a comparative study with the cationic analogue precursors was performed to explore the effect of silver ions in the dendritic structure. Other parameters, such as topology, generation, and hydrophobicity, of the imidazole substituents were also studied. All these dendritic systems presented antibacterial activity against three different bacterial strains, two Gram-positive (Staphylococcus aureus and Bacillus subtilis) and one Gram-negative (Escherichia coli). Several assays were conducted to elucidate their mechanism of action against Bacillus subtilis, by using bacterial biosensors or specific probes and fluorescent proteins sensitive to changes in the cell membrane potential. These studies are specially focused on the role of the polyvalence of our systems containing silver atoms, which may provoke interesting effects in the mode of action.
An Updated Review of Macro, Micro, and Nanostructured Hydrogels for Biomedical and Pharmaceutical Applications
Authors: Lima Caroline S. A. de , Balogh Tatiana S. , Varca Justine P. R. O. , Varca Gustavo H. C. , Lugão Ademar B. , A. Camacho-Cruz Luis , Bucio Emilio , Kadlubowski Slawomir S.
Published: October 2020

Hydrogels are materials with wide applications in several fields, including the biomedical and pharmaceutical industries. Their properties such as the capacity of absorbing great amounts of aqueous solutions without losing shape and mechanical properties, as well as loading drugs of different nature, including hydrophobic ones and biomolecules, give an idea of their versatility and promising demand. As they have been explored in a great number of studies for years, many routes of synthesis have been developed, especially for chemical/permanent hydrogels. In the same way, stimuli-responsive hydrogels, also known as intelligent materials, have been explored too, enhancing the regulation of properties such as targeting and drug release. By controlling the particle size, hydrogel on the micro- and nanoscale have been studied likewise and have increased, even more, the possibilities for applications of the so-called XXI century materials. In this paper, we aimed to produce an overview of the recent studies concerning methods of synthesis, biomedical, and pharmaceutical applications of macro-, micro, and nanogels.
Physiologically-Based Pharmacokinetic/Pharmacodynamic Model of MBQ-167 to Predict Tumor Growth Inhibition in Mice
Authors: Reig-López Javier , Maldonado María del Mar , Merino-Sanjuan Matilde , Cruz-Collazo Ailed M. , Ruiz-Calderón Jean F. , Mangas-Sanjuán Victor , Dharmawardhane Suranganie , Duconge Jorge
Published: October 2020

MBQ-167 is a dual inhibitor of the Rho GTPases Rac and Cdc42 that has shown promising results as an anti-cancer therapeutic at the preclinical stage. This drug has been tested in vitro and in vivo in metastatic breast cancer mouse models. The aim of this study is to develop a physiologically based pharmacokinetic/pharmacodynamic (PBPK-PD) model of MBQ-167 to predict tumor growth inhibition following intraperitoneal (IP) administration in mice bearing Triple Negative and HER2+ mammary tumors. PBPK and Simeoni tumor growth inhibition (TGI) models were developed using the Simcyp V19 Animal Simulator. Our developed PBPK framework adequately describes the time course of MBQ-167 in each of the mouse tissues (e.g., lungs, heart, liver, kidneys, spleen, plasma) and tumor, since the predicted results were consistent with the experimental data. The developed PBPK-PD model successfully predicts tumor shrinkage in HER2+ and triple-negative breast tumors after the intraperitoneal administration of 1 and 10 mg/kg body weight (BW) dose level of MBQ-167 three times a week. The findings from this study suggest that MBQ-167 has a higher net effect and potency inhibiting Triple Negative mammary tumor growth compared to HER2+ and that liver metabolism is the major route of elimination of this drug.
Simple Method to Measure the Aerodynamic Size Distribution of Porous Particles Generated on Lyophilizate for Dry Powder Inhalation
Authors: Miyamoto Kahori , Taga Hiroaki , Akita Tomomi , Yamashita Chikamasa
Published: October 2020

Recently, statistical techniques such as design of experiments are being applied for efficient optimization of oral formulations. To use these statistical techniques for inhalation formulations, efficient methods for rapid determination of the aerodynamic particle size distribution of many samples are needed. Therefore, we aimed to develop a simple method to measure aerodynamic particle size distribution that closely agrees with the results of inhalation characteristic tests. We added attachments for dispersion to the aerodynamic particle sizer (APS) so that formulations could be dispersed under the same condition as for multi-stage liquid impinger (MSLI) measurement. Then, we examined the correlation between MSLI and APS using lyophilizate for dry powder inhalation formulations that generate porous particles just on inhalation. It is difficult to obtain the accurate aerodynamic particle size distribution of porous particles by APS because the particle density is difficult to estimate accurately. However, there was a significant correlation between MSLI and APS when the particle density settings for APS measurement was calculated by a conversion factor based on the result of MSLI. The APS with dispersion attachments and this conversion factor can measure a number of samples in a short time, thereby enabling more efficient optimization of dry powder inhalers.
Preclinical Evaluation of the GRPR-Targeting Antagonist RM26 Conjugated to the Albumin-Binding Domain for GRPR-Targeting Therapy of Cancer
Authors: Abouzayed Ayman , Tano Hanna , Nagy Ábel , Rinne Sara S. , Wadeea Fadya , Kumar Sharmishtaa , Westerlund Kristina , Tolmachev Vladimir , Eriksson Karlström Amelie , Orlova Anna
Published: October 2020

The targeting of gastrin-releasing peptide receptors (GRPR) was recently proposed for targeted therapy, e.g., radiotherapy. Multiple and frequent injections of peptide-based therapeutic agents would be required due to rapid blood clearance. By conjugation of the GRPR antagonist RM26 (D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2) to an ABD (albumin-binding domain), we aimed to extend the blood circulation of peptides. The synthesized conjugate DOTA-ABD-RM26 was labelled with indium-111 and evaluated in vitro and in vivo. The labelled conjugate was stable in PBS and retained specificity and its antagonistic function against GRPR. The half-maximal inhibitory concentration (IC50) of natIn-DOTA-ABD-RM26 in the presence of human serum albumin was 49 ± 5 nM. [111In]In-DOTA-ABD-RM26 had a significantly longer residence time in blood and in tumors (without a significant decrease of up to 144 h pi) than the parental RM26 peptide. We conclude that the ABD-RM26 conjugate can be used for GRPR-targeted therapy and delivery of cytotoxic drugs. However, the undesirable elevated activity uptake in kidneys abolishes its use for radionuclide therapy. This proof-of-principle study justified further optimization of the molecular design of the ABD-RM26 conjugate.
Enhanced Lymphatic Delivery of Methotrexate Using W/O/W Nanoemulsion: In Vitro Characterization and Pharmacokinetic Study
Authors: Jang Ji-Hun , Jeong Seung-Hyun , Lee Yong-Bok
Published: October 2020

Methotrexate, which is widely used in the treatment of cancer and immune-related diseases, has limitations in use because of its low bioavailability, short half-life, and tissue toxicity. Thus, in this study, a nano-sized water-in-oil-in-water (W/O/W) double emulsion containing methotrexate was prepared to enhance its lymphatic delivery and bioavailability. Based on the results from solubility testing and a pseudo-ternary diagram study, olive oil as the oil, Labrasol as a surfactant, and ethanol as a co-surfactant, were selected as the optimal components for the nanoemulsion. The prepared nanoemulsion was evaluated for size, zeta potential, encapsulation efficiency, pH, morphology, and in vitro release profiles. Furthermore, pharmacokinetics and lymphatic targeting efficiency were assessed after oral and intravenous administration of methotrexate-loaded nanoemulsion to rats. Mean droplet size, zeta potential, encapsulation efficiency, and pH of formulated nanoemulsion were 173.77 ± 5.76 nm, −35.63 ± 0.78 mV, 90.37 ± 0.96%, and 4.07 ± 0.03, respectively. In vitro release profile of the formulation indicated a higher dissolution and faster rate of methotrexate than that of free drug. The prepared nanoemulsion showed significant increases in maximum plasma concentration, area under the plasma concentration-time curve, half-life, oral bioavailability, and lymphatic targeting efficiency in both oral and intravenous administration. Therefore, our research proposes a methotrexate-loaded nanoemulsion as a good candidate for enhancing targeted lymphatic delivery of methotrexate.
Conjugation of Native-Like HIV-1 Envelope Trimers onto Liposomes Using EDC/Sulfo-NHS Chemistry: Requirements and Limitations
Authors: Suleiman Ehsan , Mayer Julia , Lehner Elisabeth , Kohlhauser Bianca , Katholnig Alexandra , Batzoni Mirjam , Damm Dominik , Temchura Vladimir , Wagner Andreas , Überla Klaus , Vorauer-Uhl Karola
Published: October 2020

The display of native-like human immunodeficiency virus type 1 envelope (HIV-1 Env) trimers on liposomes has gained wide attention over the last few years. Currently, available methods have enabled the preparation of Env-liposome conjugates of unprecedented quality. However, these protocols require the Env trimer to be tagged and/or to carry a specific functional group. For this reason, we have investigated N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide/N-Hydroxysulfosuccinimide (EDC/Sulfo-NHS) chemistry for its potential to covalently conjugate tag-free, non-functionalized native-like Env trimers onto the surface of carboxyl-functionalized liposomes. The preservation of the liposome’s physical integrity and the immunogen’s conformation required a fine-tuned two-step approach based on the controlled use of β-mercaptoethanol. The display of Env trimers was strictly limited to activated liposomes of positive charge, i.e., liposomes with a positive zeta potential that carry amine-reactive Sulfo-NHS esters on their surface. In agreement with that, conjugation was found to be highly ionic strength- and pH-dependent. Overall, we have identified electrostatic pre-concentration (i.e., close proximity between negatively charged Env trimers and positively charged liposomes established through electrostatic attraction) to be crucial for conjugation reactions to proceed. The present study highlights the requirements and limitations of potentially scalable EDC/Sulfo-NHS-based approaches and represents a solid basis for further research into the controlled conjugation of tag-free, non-functionalized native-like Env trimers on the surface of liposomes, and other nanoparticles.
Extracellular Vesicle-Based Nucleic Acid Delivery: Current Advances and Future Perspectives in Cancer Therapeutic Strategies
Authors: Massaro Crescenzo , Sgueglia Giulia , Frattolillo Victoria , Baglio S. Rubina , Altucci Lucia , Dell'Aversana Carmela
Published: October 2020

Extracellular vesicles (EVs) are sophisticated and sensitive messengers released by cells to communicate with and influence distant and neighboring cells via selective transfer of bioactive content, including protein lipids and nucleic acids. EVs have therefore attracted broad interest as new and refined potential therapeutic systems in many diseases, including cancer, due to their low immunogenicity, non-toxicity, and elevated bioavailability. They might serve as safe and effective vehicles for the transport of therapeutic molecules to specific tissues and cells. In this review, we focus on EVs as a vehicle for gene therapy in cancer. We describe recent developments in EV engineering to achieve efficient intracellular delivery of cancer therapeutics and avoid off-target effects, to provide an overview of the potential applications of EV-mediated gene therapy and the most promising biomedical advances.