bluuebunny/crossref_metadata_2025 huggingface dataset:
Transamination-Like Reaction Catalyzed by Leucine Dehydrogenase for Efficient Co-Synthesis of α-Amino Acids and α-Keto Acids
Authors: Mu Xiaoqing , Feng Xian , Wu Tao , Zhou Feng , Nie Yao , Xu Yan
Published: December 2021

α-Amino acids and α-keto acids are versatile building blocks for the synthesis of several commercially valuable products in the food, agricultural, and pharmaceutical industries. In this study, a novel transamination-like reaction catalyzed by leucine dehydrogenase was successfully constructed for the efficient enzymatic co-synthesis of α-amino acids and α-keto acids. In this reaction mode, the α-keto acid substrate was reduced and the α-amino acid substrate was oxidized simultaneously by the enzyme, without the need for an additional coenzyme regeneration system. The thermodynamically unfavorable oxidation reaction was driven by the reduction reaction. The efficiency of the biocatalytic reaction was evaluated using 12 different substrate combinations, and a significant variation was observed in substrate conversion, which was subsequently explained by the differences in enzyme kinetics parameters. The reaction with the selected model substrates 2-oxobutanoic acid and L-leucine reached 90.3% conversion with a high total turnover number of 9.0 × 106 under the optimal reaction conditions. Furthermore, complete conversion was achieved by adjusting the ratio of addition of the two substrates. The constructed reaction mode can be applied to other amino acid dehydrogenases in future studies to synthesize a wider range of valuable products.
Analytical Separation of Closantel Enantiomers by HPLC
Authors: Saleh Basma , Ding Tongyan , Wang Yuwei , Zheng Xiantong , Liu Rong , He Limin
Published: December 2021

Closantel is an antiparasitic drug marketed in a racemic form with one chiral center. It is meaningful to develop a method for separating and analyzing the closantel enantiomers. In this work, two enantiomeric separation methods of closantel were explored by normal-phase high-performance liquid chromatography. The influences of the chiral stationary phase (CSP) structure, the mobile phase composition, the nature and proportion of different mobile phase modifiers (alcohols and acids), and the column temperature on the enantiomeric separation of closantel were investigated in detail. The two enantiomers were successfully separated on the novel CSP of isopropyl derivatives of cyclofructan 6 and n-hexane-isopropanol-trifluoroacetic acid (97:3:0.1, v/v/v) as a mobile phase with a resolution (Rs) of about 2.48. The enantiomers were also well separated on the CSP of tris-carbamates of amylose with a higher Rs (about 3.79) when a mixture of n-hexane-isopropanol-trifluoroacetic acid (55:45:0.1, v/v/v) was used as mobile phase. Thus, the proposed separation methods can facilitate molecular pharmacological and biological research on closantel and its enantiomers.
A New Kid on the Block: Sacituzumab Govitecan for the Treatment of Breast Cancer and Other Solid Tumors
Authors: Pavone Giuliana , Motta Lucia , Martorana Federica , Motta Gianmarco , Vigneri Paolo
Published: December 2021

Human trophoblast cell-surface antigen-2 (Trop-2) is a membrane glycoprotein involved in cell proliferation and motility, frequently overexpressed in epithelial tumors. Thus, it represents an attractive target for anticancer therapies. Sacituzumab govitecan (SG) is a third-generation antibody-drug conjugate, consisting of an anti-Trop-2 monoclonal antibody (hRS7), a hydrolyzable linker, and a cytotoxin (SN38), which inhibits topoisomerase 1. Specific pharmacological features, such as the high antibody to payload ratio, the ultra-toxic nature of SN38, and the capacity to kill surrounding tumor cells (the bystander effect), make SG a very promising drug for cancer treatment. Indeed, unprecedented results have been observed with SG in patients with heavily pretreated advanced triple-negative breast cancer and urothelial carcinomas, and the drug has already received approval for these indications. These results are coupled with a manageable toxicity profile, with neutropenia and diarrhea as the most frequent adverse events, mainly of grades 1–2. While several trials are exploring SG activity in different tumor types and settings, potential biomarkers of response are under investigation. Among these, Trop-2 overexpression and the presence of BRCA1/2 mutations seem to be the most promising. We review the available literature concerning SG, with a focus on its toxicity spectrum and possible biomarkers of its response.
Moisture Absorption Effects on the Mechanical Properties of Sandwich Biocomposites with Cork Core and Flax/PLA Face Sheets
Authors: Dhakal Hom Nath , Jiang Chulin , Sit Moumita , Zhang Zhongyi , Khalfallah Moussa , Grossmann Erwan
Published: December 2021

The aim of this study was to evaluate the moisture absorption behaviour and its influence on the mechanical properties of newly developed sandwich biocomposites with flax fibre-reinforced poly-lactic acid (PLA) face sheets and soft cork as the core material. Three different types of sandwich biocomposite laminates comprised of different layup configurations, namely, non-woven flax/PLA (Sample A), non-woven flax/PLA and cork as core (Sample B) and non-woven flax/paper backing/PLA, cork as core (Sample C), were fabricated. In order to evaluate the influence of moisture ingress on the mechanical properties, the biocomposites were immersed in seawater for a period of 1200 h. The biocomposites (both dry and water immersed) were then subjected to tensile, flexural and low-velocity falling weight impact tests. It was observed from the experimental results that the moisture uptake significantly influenced the mechanical properties of the biocomposites. The presence of the cork and paper in sample C made it more susceptible to water absorption, reaching a value of 34.33%. The presence of cork in the core also has a considerable effect on the mechanical, as well as energy dissipation, behaviours. The results of sample A exhibited improved mechanical performance in both dry and wet conditions compared to samples B and C. Sample A exhibits 32.6% more tensile strength and 81.4% more flexural strength in dry conditions than that in sample C. The scanning electron microscopy (SEM) and X-ray micro-CT images revealed that the failure modes observed are a combination of matrix cracking, core crushing and face core debonding. The results from this study suggest that flax/PLA sandwich biocomposites can be used in various lightweight applications with improved environmental benefits.
Chemical Constituents from the Wild Atractylodes macrocephala Koidz and Acetylcholinesterase Inhibitory Activity Evaluation as Well as Molecular Docking Study
Authors: Zhu Qiannan , Lin Min , Zhuo Wanying , Li Yunzhi
Published: December 2021

Screening the lead compounds which could interact both with PAS and CAS of acetylcholinesterase (AChE) is an important trend in finding innovative drugs for Alzheimer’s disease (AD). In this paper, four sesquiterpenes, i.e., atractylenolide III (1), atractylenolide IV (2), 3-acetyl-atractylon (3) and β-eudesmol (4), were obtained from the wild Atractylode macrocephala grown in Qimen for the first time. Their structures were elucidated mainly by NMR spectroscopy. To screen the potential dual site inhibitors of AChE, the compounds 1, 2, 3, as well as a novel and rare bisesquiterpenoid lactone, biatractylenolide II (5), which was also obtained from the tilted plant in our previous investigation, were evaluated their AChE inhibitory activities by using Ellman’s colorimetric method. The results showed that biatractylenolide II displayed moderate inhibitory activity (IC50 = 19.61 ± 1.11 μg/mL) on AChE. A further molecular docking study revealed that biatractylenolide II can interact with both the peripheral anionic site (PAS) and the catalytic active site (CAS) of AChE. These data suggest that biatractylenolide II can be considered a new lead compound to research and develop more potential dual site inhibitors of AChE.
Case Studies in Game-Based Complex Learning
Authors: Miller Josh Aaron , Cooper Seth
Published: December 2021

Despite the prevalence of game-based learning (GBL), most applications of GBL focus on teaching routine skills that are easily teachable, drill-able, and testable. Much less work has examined complex cognitive skills such as computational thinking, and even fewer are projects that have demonstrated commercial or critical success with complex learning in game contexts. Yet, recent successes in the games industry have provided examples of success in game-based complex learning. This article represents a series of case studies on those successes. We interviewed game designers Zach Gage and Jack Schlesinger, creators of Good Sudoku, and Zach Barth, creator of Zachtronics games, using reflexive thematic analysis to thematize findings. We additionally conducted a close play of Duolingo following Bizzocchi and Tanenbaum’s adaptation of close reading. Several insights result from these case studies, including the practice of game design as instructional design, the use of constructionist environments, the tensions between formal education and informal learning, and the importance of entrepreneurialism. Specific recommendations for GBL designers are provided.
Pitch It Right: Using Prosodic Entrainment to Improve Robot-Assisted Foreign Language Learning in School-Aged Children
Authors: Molenaar Bo , Soliño Fernández Breixo , Polimeno Alessandra , Barakova Emilia , Chen Aoju
Published: December 2021

Robot-assisted language learning (RALL) is a promising application when employing social robots to help both children and adults acquire a language and is an increasingly widely studied area of child–robot interaction. By introducing prosodic entrainment, i.e., converging the robot’s pitch with that of the learner, the present study aimed to provide new insights into RALL as a facilitative method for interactive tutoring. It is hypothesized that pitch-level entrainment by a Nao robot during a word learning task in a foreign language will result in increased learning in school-aged children. The results indicate that entrainment has no significant effect on participants’ learning, contra the hypothesis. Research on the implementation of entrainment in the context of RALL is new. This study highlights constraints in currently available technologies for voice generation and methodological limitations that should be taken into account in future research.
Repetitive Transcranial Magnetic Stimulation for Major Depressive Disorder Comorbid with Huntington’s Disease: A Case Report
Authors: Noiseux Clémence , Miron Jean-Philippe , Desbeaumes Jodoin Véronique , Chu Tian Ren , Chouinard Sylvain , Lespérance Paul
Published: December 2021

Huntington’s disease (HD) is a rare genetic disorder resulting in progressive neurodegeneration leading to motor, cognitive and psychiatric symptoms. A high percentage of HD patients suffer from comorbid major depressive disorder (MDD). We are not aware of any literature on the use of repetitive transcranial magnetic stimulation (rTMS) for treating comorbid MDD in HD. We present the case of a 57-year-old man suffering from HD in which comorbid MDD was successfully treated with rTMS. Further work is required to better characterize the safety, tolerability and effectiveness of rTMS to treat comorbid MDD in HD.
From Denture to the Final Implant-Supported Prosthesis Using a Full-Digital Protocol: A Dental Technique
Authors: Todescan Francisco , Hayashi Marcos , Giugni Luiz , Bottino Marco , Tribst João
Published: December 2021

Proper maxillomandibular relationship registration can be clinically challenging during a digital workflow in full-arch rehabilitations. This dental technique requires the manufacturing and use of a hybrid surgical guide custom scanning device, indicated to be used during implant placement surgery, in addition to being used to simultaneously register the maxillomandibular relationship and transfer the implants’ 3D positioning, ensuring a fully digital workflow in full-arch implant-supported prosthesis rehabilitation. The sequence of steps presented here will allow dentists and dental technicians to conduct rehabilitations from denture to the final implant-supported prosthesis using a full-digital protocol, using a minimal quantity of intraoral devices and digital tools.
Assessment of the In Vitro Cytotoxicity Effects of the Leaf Methanol Extract of Crinum zeylanicum on Mouse Induced Pluripotent Stem Cells and Their Cardiomyocytes Derivatives
Authors: Ndjenda II Magloire Kanyou , Nguelefack-Mbuyo Elvine Pami , Hescheler Jürgen , Nguelefack Télesphore Benoît , Nguemo Filomain
Published: December 2021

Crinum zeylanicum (C. zeylanicum) is commonly used in African folk medicine to treat cardiovascular ailments. In the present study, we investigated the cytotoxic effect of the leaf methanol extract of C. zeylanicum (CZE) using mouse pluripotent stem cells (mPSCs). mPSCs and their cardiomyocytes (CMs) derivatives were exposed to CZE at different concentrations. Cell proliferation, differentiation capacity, and beating activity were assessed using xCELLigence system and microscopy for embryoid body (EB) morphology. Expression of markers associated with major cardiac cell types was examined by immunofluorescence and quantitative RT-PCR. Intracellular reactive oxygen species (ROS) levels were assessed by dichlorodihydrofluorescein diacetate staining. The results showed that the plant extract significantly reduced cell proliferation and viability in a concentration- and time-dependent manner. This was accompanied by a decrease in EB size and an increase in intracellular ROS. High concentrations of CZE decreased the expression of some important cardiac biomarkers. In addition, CZE treatment was associated with poor sarcomere structural organization of CMs and significantly decreased the amplitude and beating rate of CMs, without affecting CMs viability. These results indicate that CZE might be toxic at high concentrations in the embryonic stages of stem cells and could modulate the contracting activity of CMs.
Negligible Effect of Quercetin in the Pharmacokinetics of Sulfasalazine in Rats and Beagles: Metabolic Inactivation of the Interaction Potential of Quercetin with BCRP
Authors: Oh Ju-Hee , Kim Dokeun , Lee Haejun , Kim Gyeonghee , Park Taehoon , Kim Min Chang , Lee Young-Joo
Published: December 2021

Breast cancer resistance protein (BCRP) mediates pharmacokinetic drug interactions. This study evaluated the potential of quercetin to inhibit and induce BCRP in vitro and in vivo. The inhibition of BCRP was investigated for quercetin and its metabolites using BCRP/mBcrp1-overexpressing MDCKII cells by flow cytometry. The induction of BCRP was investigated in LS174T cells using quantitative PCR. The expression of rat BCRP in rat small intestine, liver, and kidney was also measured after multiple administrations of quercetin in rats (50, 100, and 250 mg/kg, seven days). The in vivo pharmacokinetic changes of sulfasalazine following single or multiple administration of quercetin in rats and beagles were investigated. Although the induction effect of quercetin on BCRP was observed in vitro, the in vivo expression of rat BCRP was not changed by multiple quercetin administrations. Oral administration of quercetin did not affect the plasma concentration or pharmacokinetic parameters of sulfasalazine, regardless of dose and dosing period in either rats or beagles. In addition, the inhibitory effect of quercetin metabolites on BCRP/mBcrp1 was not observed. These results suggest that the in vivo drug interaction caused by quercetin via BCRP was negligible, and it may be related to the metabolic inactivation of quercetin for the inhibition of BCRP.
Antimicrobial Photodynamic Therapy: Latest Developments with a Focus on Combinatory Strategies
Authors: Youf Raphaëlle , Müller Max , Balasini Ali , Thétiot Franck , Müller Mareike , Hascoët Alizé , Jonas Ulrich , Schönherr Holger , Lemercier Gilles , Montier Tristan , Le Gall Tony
Published: December 2021

Antimicrobial photodynamic therapy (aPDT) has become a fundamental tool in modern therapeutics, notably due to the expanding versatility of photosensitizers (PSs) and the numerous possibilities to combine aPDT with other antimicrobial treatments to combat localized infections. After revisiting the basic principles of aPDT, this review first highlights the current state of the art of curative or preventive aPDT applications with relevant clinical trials. In addition, the most recent developments in photochemistry and photophysics as well as advanced carrier systems in the context of aPDT are provided, with a focus on the latest generations of efficient and versatile PSs and the progress towards hybrid-multicomponent systems. In particular, deeper insight into combinatory aPDT approaches is afforded, involving non-radiative or other light-based modalities. Selected aPDT perspectives are outlined, pointing out new strategies to target and treat microorganisms. Finally, the review works out the evolution of the conceptually simple PDT methodology towards a much more sophisticated, integrated, and innovative technology as an important element of potent antimicrobial strategies.
The Effect of Capsule-in-Capsule Combinations on In Vivo Disintegration in Human Volunteers: A Combined Imaging and Salivary Tracer Study
Authors: Rump Adrian , Weiss Franziska N. , Schulz Louisa , Kromrey Marie-Luise , Scheuch Eberhard , Tzvetkov Mladen V. , White Tyler , Durkee Shane , Judge Kevin W. , Jannin Vincent , Bellamine Aouatef , Weitschies Werner , Grimm Michael
Published: December 2021

Controlling the time point and site of the release of active ingredients within the gastrointestinal tract after administration of oral delivery systems is still a challenge. In this study, the effect of the combination of small capsules (size 3) and large capsules (size 00) on the disintegration site and time was investigated using magnetic resonance imaging (MRI) in combination with a salivary tracer technique. As capsule shells, Vcaps® HPMC capsules, Vcaps® Plus HPMC capsules, gelatin and DRcaps® designed release capsules were used. The three HPMC-based capsules (Vcaps®, Vcaps® Plus and DRcaps® capsules) were tested as single capsules; furthermore, seven DUOCAP® capsule-in-capsule combinations were tested in a 10-way crossover open-label study in six healthy volunteers. The capsules contained iron oxide and hibiscus tea powder as tracers for visualization in MRI, and two different caffeine species (natural caffeine and 13C3) to follow caffeine release and absorption as measured by salivary levels. Results showed that the timing and location of disintegration in the gastrointestinal tract can be measured and differed when using different combinations of capsule shells. Increased variability among the six subjects was observed in most of the capsule combinations. The lowest variability in gastrointestinal localization of disintegration was observed for the DUOCAP® capsule-in-capsule configuration using a DRcaps® designed release capsule within a DRcaps® designed release outer capsule. In this combination, the inner DRcaps® designed release capsule always opened reliably after reaching the ileum. Thus, this combination enables targeted delivery to the distal small intestine. Among the single capsules tested, Vcaps® Plus HPMC capsules showed the fastest and most consistent disintegration.
Immunotherapy for Triple-Negative Breast Cancer
Authors: Cao Yifeng , Chen Chuyang , Tao Yi , Lin Weifeng , Wang Ping
Published: December 2021

Triple-negative breast cancer (TNBC) is characterized by extensive tumor heterogeneity at both the pathologic and molecular levels, particularly accelerated aggressiveness, and terrible metastasis. It is responsible for the increased mortality of breast cancer patients. Due to the negative expression of estrogen receptors, progesterone receptors, and human epidermal growth factor receptor 2, the progress of targeted therapy has been hindered. Higher immune response in TNBCs than for other breast cancer types makes immunotherapy suitable for TNBC therapy. At present, promising treatments in immunotherapy of TNBC include immune checkpoints (ICs) blockade therapy, adoptive T-cell immunotherapy, and tumor vaccine immunotherapy. In addition, nanomedicines exhibit great potential in cancer therapy through the enhanced permeability and retention (EPR) effect. Immunotherapy-involved combination therapy may exert synergistic effects by combining with other treatments, such as traditional chemotherapy and new treatments, including photodynamic therapy (PTT), photodynamic therapy (PDT), and sonodynamic therapy (SDT). This review focuses on introducing the principles and latest development as well as progress in using nanocarriers as drug-delivery systems for the immunotherapy of TNBC.
Anti-Irritant Strategy against Retinol Based on the Genetic Analysis of Korean Population: A Genetically Guided Top–Down Approach
Authors: Kang Seongsu , Kim Kyunghoe , Jun Seung-Hyun , Lee Seonju , Kim Juhyun , Shin Joong-Gon , Kim Yunkwan , Kim Mina , Park Sun-Gyoo , Kang Nae-Gyu
Published: December 2021

Retinol, one of the most powerful cosmetic materials for anti-aging supported by a solid scientific background, exhibits a wide range of type and severity of irritation while showing limited user compliance. The lack of understanding of the mechanism of retinol-induced irritation has been the main hurdle in the development of anti-irritation strategies. Here, we identified 30 genetic markers related to the susceptibility to retinol-induced irritation in the Korean population. Based on the genetic analysis, a novel formula against retinol-induced irritation was developed, which mitigated the molecular pathogenesis—as indicated by the genetic markers—of the retinol-induced irritation. In human tests, this formula effectively decreased retinol-induced irritation. Furthermore, a polygenic risk score model for irritation was constructed and validated. Our comprehensive approach for the analysis of retinol-induced irritation will not only aid the development of anti-irritation strategies to ensure higher user compliance but also contribute to improving the current knowledge about the biological effects of retinoids.
An Update to Dialysis-Based Drug Release Testing—Data Analysis and Validation Using the Pharma Test Dispersion Releaser
Authors: Mast Marc-Phillip , Modh Harshvardhan , Knoll Julian , Fecioru Elena , Wacker Matthias G.
Published: December 2021

Currently, a wide variety of complex non-oral dosage forms are entering the global healthcare market. Although many assays have been described in recent research, harmonized procedures and standards for testing their in vitro performance remain widely unexplored. Among others, dialysis-based techniques such as the Pharma Test Dispersion Releaser are developed for testing the release of drugs from nanoparticles, liposomes, or extracellular vesicle preparations. Here, we provide advanced strategies and practical advice for the development and validation of dialysis-based techniques, including documentation, analysis, and interpretation of the raw data. For this purpose, key parameters of the release assay, including the hydrodynamics in the device at different stirring rates, the selectivity for particles and molecules, as well as the effect of excipients on drug permeation were investigated. At the highest stirring rate, a more than twofold increase in the membrane permeation rate (from 0.99 × 10−3 to 2.17 × 10−3 cm2/h) was observed. Additionally, we designed a novel computer model to identify important quality parameters of the dialysis experiment and to calculate error-corrected release profiles. Two hydrophilic creams of diclofenac, Voltaren® Emulgel, and Olfen® gel, were tested and provide first-hand evidence of the robustness of the assay in the presence of semisolid dosage forms.
Vehicles for Drug Delivery and Cosmetic Moisturizers: Review and Comparison
Authors: Barnes Tanya M. , Mijaljica Dalibor , Townley Joshua P. , Spada Fabrizio , Harrison Ian P.
Published: December 2021

Many dermatological conditions, such as eczema and psoriasis, are treated with topical therapeutic products. Instead of applying the active drug directly onto the skin, it is combined with a vehicle to aid in its delivery across the stratum corneum (SC) and into deeper regions of the skin, namely the epidermis and dermis. Absorption into the systemic circulation is minimized. Topical vehicles are also used as cosmetic moisturizers (often termed emollient therapy) to ameliorate dry skin, which is a cornerstone of the management of various dermatological conditions, including xerosis, eczema, psoriasis, and aging. The most common topical vehicles include ointments, creams, gels, and lotions, among others. It is crucial that topical vehicles are chosen based upon the size and properties (wet/dry, mucous/non-mucous, healthy/diseased) of the skin to be treated in order to optimize application and contact of the product with the skin, as this can have profound impacts on potency, efficacy, and patient compliance. This review examines common topical vehicles used for drug delivery and cosmetic moisturizers, including their formulation, advantages and disadvantages, and effects on the skin. The unique rules imposed by governing regulatory bodies in Australia and around the world, in terms of topical product claims, are also briefly examined.
Antimicrobial Activities of Propolis in Poloxamer Based Topical Gels
Authors: An Seong-Hyeon , Ban Eunmi , Chung In-Young , Cho You-Hee , Kim Aeri
Published: December 2021

Propolis contains a group of compounds with various activities. However, their low solubility is a drawback for the development of pharmaceutical formulations. In this study, poloxamers as a solubilizer and gelling agent were evaluated to develop a topical antimicrobial formulation of propolis. The effects of poloxamer type and concentration on the propolis solubility, release rate, and antimicrobial activities were investigated. Staphylococcus aureus (S. aureus) and Candida albicans (C. albicans) were the representative bacteria and fungi, respectively. At 5%, poloxamer 407 (P407) and poloxamer 188 (P188) enhanced the propolis solubility by 2.86 and 2.06 folds, respectively; at 10%, they were 2.81 and 2.59 folds, respectively. The micelle size in the P188 formulation increased in the presence of propolis, whereas there was no change in the P407 formulation. Release rates of propolis decreased with the P188 concentration increase, which was attributed to viscosity increase. Both P188 and P407 formulations showed antimicrobial activity against S. aureus in a time-kill kinetics assay. However, only the P188 formulation reduced the cell’s numbers significantly against C. albicans, compared to the control. We speculate that P188 mixed micelles were more effective in releasing free active compounds to exhibit anti-microbial activity compared to the P407 micelles encapsulating the hydrophobic compounds in their cores. Propolis in P188 formulation is proposed as a potential topical antimicrobial agent based on its activity against both S. aureus and C. albicans.
PEG-Modified tert-Octylcalix[8]arenes as Drug Delivery Nanocarriers of Silibinin
Authors: Budurova Desislava , Momekova Denitsa , Momekov Georgi , Shestakova Pavletta , Penchev Hristo , Rangelov Stanislav
Published: December 2021

The hepatoprotective properties of silibinin, as well its therapeutic potential as an anticancer and chemo-preventive agent, have failed to progress towards clinical development and commercialization due to this material’s unfavorable pharmacokinetics and physicochemical properties, low aqueous solubility, and chemical instability. The present contribution is focused on the feasibility of using PEGylated calixarene, in particular polyoxyethylene-derivatized tert-octylcalix[8]arene, to prepare various platforms for the delivery of silibinin, such as inclusion complexes and supramolecular aggregates thereof. The inclusion complex is characterized by various instrumental methods. At concentrations exceeding the critical micellization concentration of PEGylated calixarene, the tremendous solubility increment of silibinin is attributed to the additional solubilization and hydrophobic non-covalent interactions of the drug with supramolecular aggregates. PEG-modified tert-octylcalix[8]arenes, used as drug delivery carriers for silibinin, were additionally investigated for cytotoxicity against human tumor cell lines.
Interaction of Supramolecular Congo Red and Congo Red-Doxorubicin Complexes with Proteins for Drug Carrier Design
Authors: Jagusiak Anna , Chłopaś Katarzyna , Zemanek Grzegorz , Kościk Izabela , Roterman Irena
Published: December 2021

Targeted immunotherapy has expanded to simultaneous delivery of drugs, including chemotherapeutics. The aim of the presented research is to design a new drug carrier system. Systems based on the use of proteins as natural components of the body offer the chance to boost safety and efficacy of targeted drug delivery and excess drug removal. Congo red (CR) type supramolecular, self-assembled ribbon-like structures (SRLS) were previously shown to interact with some proteins, including albumin and antibodies complexed with antigen. CR can intercalate some chemotherapeutics including doxorubicin (Dox). The goal of this work was to describe the CR-Dox complexes, to analyze their interaction with some proteins, and to explain the mechanism of this interaction. In the present experiments, a model system composed of heated immunoglobulin light chain Lλ capable of CR binding was used. Heat aggregated immunoglobulins (HAI) and albumin were chosen as another model system. The results of experiments employing methods such as gel filtration chromatography and dynamic light scattering confirmed the formation of the CR-Dox complex of large size and properties different from the free CR structures. Electrophoresis and chromatography experiments have shown the binding of free CR to heated Lλ while CR-Dox mixed structures were not capable of forming such complexes. HAI was able to bind both free CR and CR-Dox complexes. Albumin also bound both CR and its complex with Dox. Additionally, we observed that albumin-bound CR-Dox complexes were transferred from albumin to HAI upon addition of HAI. DLS analyses showed that interaction of CR with Dox distinctly increased the hydrodynamic diameter of CR-Dox compared with a free CR supramolecular structure. To our knowledge, individual small proteins such as Lλ may bind upon heating a few molecules of Congo red tape penetrating protein body due to the relatively low cohesion of the dye micelle. If, however, the compactness is high (in the case of, e.g., CR-Dox) large ribbon-like, micellar structures appear. They do not divide easily into smaller portions and cannot attach to proteins where there is no room for binding large ligands. Such binding is, however, possible by albumin which is biologically adapted to form complexes with different large ligands and by tightly packed immune complexes and heat aggregated immunoglobulin-specific protein complex structures of even higher affinity for Congo red than albumin. The CR clouds formed around them also bind the CR-Dox complexes. The presented research is essential in the search for optimum solutions for SRLS application in immuno-targeting therapeutic strategies, especially with the use of chemotherapeutics.
The Very First Modification of Pleuromutilin and Lefamulin by Photoinitiated Radical Addition Reactions—Synthesis and Antibacterial Studies
Authors: Thai Le Son , Páll Dávid , Rőth Erzsébet , Tran Tuyen , Debreczeni Nóra , Bege Miklós , Bereczki Ilona , Ostorházi Eszter , Milánkovits Márton , Herczegh Pál , Borbás Anikó , Csávás Magdolna
Published: December 2021

Pleuromutilin is a fungal diterpene natural product with antimicrobial properties, semisynthetic derivatives of which are used in veterinary and human medicine. The development of bacterial resistance to pleuromutilins is known to be very slow, which makes the tricyclic diterpene skeleton of pleuromutilin a very attractive starting structure for the development of new antibiotic derivatives that are unlikely to induce resistance. Here, we report the very first synthetic modifications of pleuromutilin and lefamulin at alkene position C19–C20, by two different photoinduced addition reactions, the radical thiol-ene coupling reaction, and the atom transfer radical additions (ATRAs) of perfluoroalkyl iodides. Pleuromutilin were modified with the addition of several alkyl- and aryl-thiols, thiol-containing amino acids and nucleoside and carbohydrate thiols, as well as perfluoroalkylated side chains. The antibacterial properties of the novel semisynthetic pleuromutilin derivatives were investigated on a panel of bacterial strains, including susceptible and multiresistant pathogens and normal flora members. We have identified some novel semisynthetic pleuromutilin and lefamulin derivatives with promising antimicrobial properties.
Oromucosal Alginate Films with Zein Nanoparticles as a Novel Delivery System for Digoxin
Authors: Rodrigues Daniela A. , Miguel Sónia P. , Loureiro Jorge , Ribeiro Maximiano , Roque Fátima , Coutinho Paula
Published: December 2021

Digoxin is a hydrophobic drug used for the treatment of heart failure that possesses a narrow therapeutic index, which raises safety concerns for toxicity. This is of utmost relevance in specific populations, such as the elderly. This study aimed to demonstrate the potential of the sodium alginate films as buccal drug delivery system containing zein nanoparticles incorporated with digoxin to reduce the number of doses, facilitating the administration with a quick onset of action. The film was prepared using the solvent casting method, whereas nanoparticles by the nanoprecipitation method. The nanoparticles incorporated with digoxin (0.25 mg/mL) exhibited a mean size of 87.20 ± 0.88 nm, a polydispersity index of 0.23 ± 0.00, and a zeta potential of 21.23 ± 0.07 mV. Digoxin was successfully encapsulated into zein nanoparticles with an encapsulation efficiency of 91% (±0.00). Films with/without glycerol and with different concentrations of ethanol were produced. The sodium alginate (SA) films with 10% ethanol demonstrated good performance for swelling (maximum of 1474%) and mechanical properties, with a mean tensile strength of 0.40 ± 0.04 MPa and an elongation at break of 27.85% (±0.58), compatible with drug delivery application into the buccal mucosa. The current study suggests that SA films with digoxin-loaded zein nanoparticles can be an effective alternative to the dosage forms available on the market for digoxin administration.
Screening for Optimal Liposome Preparation Conditions by Using Dual Centrifugation and Time-Resolved Fluorescence Measurements
Authors: Koehler Jonas K. , Schnur Johannes , Heerklotz Heiko , Massing Ulrich
Published: December 2021

Dual centrifugation (DC) is a novel in-vial homogenization technique for the preparation of liposomes in small batch sizes under gentle and sterile conditions which allows encapsulation efficiencies (EE) for water soluble compounds of >50%. Since liposome size, size distribution (PDI), and EE depend on the lipid concentration used in the DC process, a screening method to find optimal lipid concentrations for a defined lipid composition was developed. Four lipid mixtures consisting of cholesterol, hydrogenated or non-hydrogenated egg PC, and/or PEG-DSPE were screened and suitable concentration ranges could be identified for optimal DC homogenization. In addition to the very fast and parallel liposome preparation of up to 40 samples, the screening process was further accelerated by the finding that DC generates homogeneously mixed liposomes from a macroscopic lipid mixture without the need to initially prepare a molecularly mixed lipid film from an organic solution of all components. This much simpler procedure even works for cholesterol containing lipid blends, which could be explained by a nano-milling of the cholesterol crystals during DC homogenization. Furthermore, EE determination was performed by time-resolved fluorescence measurements of calcein-loaded liposomes without removing the non-entrapped calcein. The new strategy allows the rapid characterization of a certain lipid composition for the preparation of liposomes within a working day.
Pleiotropic Effects of Statins: New Therapeutic Approaches to Chronic, Recurrent Infection by Staphylococcus aureus
Authors: Evans Melissa D. , McDowell Susan A.
Published: December 2021

An emergent approach to bacterial infection is the use of host rather than bacterial-directed strategies. This approach has the potential to improve efficacy in especially challenging infection settings, including chronic, recurrent infection due to intracellular pathogens. For nearly two decades, the pleiotropic effects of statin drugs have been examined for therapeutic usefulness beyond the treatment of hypercholesterolemia. Interest originated after retrospective studies reported decreases in the risk of death due to bacteremia or sepsis for those on a statin regimen. Although subsequent clinical trials have yielded mixed results and earlier findings have been questioned for biased study design, in vitro and in vivo studies have provided clear evidence of protective mechanisms that include immunomodulatory effects and the inhibition of host cell invasion. Ultimately, the benefits of statins in an infection setting appear to require attention to the underlying host response and to the timing of the dosage. From this examination of statin efficacy, additional novel host-directed strategies may produce adjunctive therapeutic approaches for the treatment of infection where traditional antimicrobial therapy continues to yield poor outcomes. This review focuses on the opportunistic pathogen, Staphylococcus aureus, as a proof of principle in examining the promise and limitations of statins in recalcitrant infection.
Monitoring the Effect of Transdermal Drug Delivery Patches on the Skin Using Terahertz Sensing
Authors: Lindley-Hatcher Hannah , Wang Jiarui , Hernandez-Serrano Arturo I. , Hardwicke Joseph , Nurumbetov Gabit , Haddleton David M. , Pickwell-MacPherson Emma
Published: December 2021

Water content of the skin is an important parameter for controlling the penetration rate of chemicals through the skin barrier; therefore, for transdermal patches designed for drug delivery to be successful, the effects of the patches on the water content of the skin must be understood. Terahertz (THz) spectroscopy is a technique which is being increasingly investigated for biomedical applications due to its high sensitivity to water content and non-ionizing nature. In this study, we used THz measurements of the skin (in vivo) to observe the effect of partially and fully occlusive skin patches on the THz response of the skin after the patches had been applied for 24 h. We were able to observe an increase in the water content of the skin following the application of the patches and to identify that the skin remained hyper-hydrated for four hours after the removal of the fully occlusive patches. Herein, we show that THz spectroscopy has potential for increasing the understanding of how transdermal patches affect the skin, how long the skin takes to recover following patch removal, and what implications these factors might have for how transdermal drug patches are designed and used.
Er-Doped Tapered Fiber Amplifier for High Peak Power Sub-ns Pulse Amplification
Authors: Khudyakov Maksim M. , Levchenko Andrei E. , Velmiskin Vladimir V. , Bobkov Konstantin K. , Aleshkina Svetlana S. , Bubnov Mikhail M. , Yashkov Mikhail V. , Gur’yanov Aleksei N. , Kotov Leonid V. , Likhachev Mikhail E.
Published: December 2021

A tapered Er-doped fiber amplifier for high peak power pulses amplification has been developed and tested. The core diameter changed from 15.8 µm (mode field diameter (MFD) 14.5 µm) to 93 µm (MFD 40 µm) along 3.7 m maintaining single-mode performance at 1555 nm (according to the S2-method, the part of the power of high-order modes does not exceed 1.5%). The amplification of 0.9 ns pulses with spectral width below 0.04 nm up to a peak power above 200 kW (limited by self-phase modulation) with a slope pump-to-signal conversion efficiency of 15.6% was demonstrated.
Experimental Certification of Quantum Entanglement Based on the Classical Complementary Correlations of Two-Qubit States
Authors: Bian Zhi-Hao , Wu Hui
Published: December 2021

Quantum entanglement is one of the essential resources in quantum information processing. It is of importance to verify whether a quantum state is entangled. At present, a typical quantum certification focused on the classical correlations has attracted widespread attention. Here, we experimentally investigate the relation between quantum entanglement and the classical complementary correlations based on the mutual information, Pearson correlation coefficient and mutual predictability of two-qubit states. Our experimental results show the classical correlations for complementary properties have strong resolution capability to verify entanglement for two qubit pure states and Werner states. We find that the resolution capability has great performance improvement when the eigenstates of the measurement observables constitute a complete set of mutually unbiased bases. For Werner states in particular, the classical complementary correlations based on the Pearson correlation coefficient and mutual predictability can provide the ultimate bounds to certify entanglement.
Comparison of Two- and Three-Beam Interference Pattern Generation in Structured Illumination Microscopy
Authors: Liao Jiuling , Liu Lina , Chen Tingai , Xia Xianyuan , Li Hui , Zheng Wei
Published: December 2021

Structured illumination microscopy (SIM) provides wide-field optical sectioning in the focal plane by modulating the imaging information using fringe pattern illumination. For generating the fringe pattern illumination, a digital micro-mirror device (DMD) is commonly used due to its flexibility and fast refresh rate. However, the benefit of different pattern generation, for example, the two-beam interference mode and the three-beam interference mode, has not been clearly investigated. In this study, we systematically analyze the optical sectioning provided by the two-beam inference mode and the three-beam interference mode of DMD. The theoretical analysis and imaging results show that the two-beam interference mode is suitable for fast imaging of the superficial dynamic target due to reduced number of phase shifts needed to form the image, and the three-beam interference mode is ideal for imaging three-dimensional volume due to its superior optical sectioning by the improved modulation of the illumination patterns. These results, we believe, will provide better guidance for the use of DMD for SIM imaging and also for the choice of beam patterns in SIM application in the future.
An Optical Tweezers-Based Single-Cell Manipulation and Detection Platform for Probing Real-Time Cancer Cell Chemotaxis and Response to Tyrosine Kinase Inhibitor PD153035
Authors: Peng Pei-Wen , Yang Jen-Chang , Colley Mamadi M.S , Yang Tzu-Sen
Published: December 2021

We presented an approach to address cancer cell chemotaxis and response to tyrosine kinase inhibitor PD153035 at the single-cell level. We applied an optical tweezer system together with the platform at the single-cell level to manipulate an epidermal growth factor (EGF)-coated bead positioned close to the filopodia to locally stimulate HT29 cells, the human colon cancer cell line overexpressing the EGF receptor (EGFR). To address cancer cell chemotaxis, a single-cell movement model was also proposed to quantify the propagation speed at the leading and trailing edges of the cell along the chemosensing axis. This study focused on three perspectives: probing the chemosensing process mediated by EGF/EGFR signaling, investigating the mode of locomotion during the EGF-coated bead stimulation, and quantifying the effect of PD153035 on the EGF–EGFR transport pathway. The results showed that the filopodial actin filament is a sensory system for EGF detection. In addition, HT29 cells may use the filopodial actin filament to distinguish the presence or absence of the chemoattractant EGF. Furthermore, we demonstrated the high selectivity of PD153035 for EGFR and the reversibility of binding to EGFR. We anticipate that the proposed single-cell method could be applied to construct a rapid screening method for the detection and therapeutic evaluation of many types of cancer during chemotaxis.
An Improved Analytical Model of a Spectrometer for Optical Coherence Tomography
Authors: Sherstnev Evgeny P. , Shilyagin Pavel A. , Terpelov Dmitry A. , Gelikonov Valentin M. , Gelikonov Grigory V.
Published: December 2021

We present an improved analytical model of a spectrometer for optical coherence tomography (OCT), which more accurately describes the OCT in-depth sensitivity fall-off. The model considers the intrinsic spectral resolution of the dispersive element and the influence of additional components (inequidistance-correcting prism). The model is validated by experimental data obtained both from other studies and our own experiments. The influence of the frequency response of the CCD electrical circuit and the analog-to-digital converter to the OCT signal fall-off was also detected and was shown to be significant in some cases.
Investigation of Shielding Effects on Picosecond Laser-Induced Copper Plasma Characteristics under Different Focusing Distances
Authors: Chen Linyu , Deng Hu , Xiong Zhonggang , Guo Jin , Liu Quancheng , Li Guilin , Shang Liping
Published: December 2021

In traditional laser-induced breakdown spectroscopy (LIBS) applications, the line intensity and analysis capability are susceptible to plasma shielding. To investigate the shielding effects on the characteristics of Cu plasma in air, a ~120-picosecond laser with a wavelength of 1064 nm was employed to produce plasma. The plasma temperature and electron density were calculated under the condition of local thermal equilibrium (LTE) and optically thin, while the relationships between the line intensity, plasma temperature and electron density were analyzed. Moreover, the LTE condition was validated by the McWhirter relation, plasma relaxation time and diffusion length, and the optically thin condition was observed through the variation in line intensity. The results indicated that when the focal point was below the target surface, the plasma shielding was the weakest, and the highest line intensity could be obtained. In addition, there was a positive correlation between the increased plasma temperature and the degree of shielding effect. When the focal point was above the target surface, the high-irradiance pulse directly broke down the free air and produced a shock wave. Under the high pressure of the over-heated shock wave, the line intensity, plasma temperature and electron density increased again. This study provides an important insight into the experiments and applications of picosecond LIBS.