bluuebunny/crossref_metadata_2025 huggingface dataset:
A Quantitative LC–MS/MS Method for the Detection of 16 Synthetic Cathinones and 10 Metabolites and Its Application to Suspicious Clinical and Forensic Urine Samples
Authors: Aldubayyan Abdulaziz , Castrignanò Erika , Elliott Simon , Abbate Vincenzo
Published: April 2022

Background: Synthetic cathinones currently represent one of the most predominant (sub)-classes of new psychoactive substance (NPS) in illicit drug markets. Despite the increased concerns caused by the constant introduction of new analogues, these drugs are not commonly assayed in routine drug testing procedures and may not be detected in standard screening procedures. This study presents a validated liquid chromatography–tandem mass spectrometry (LC–MS/MS) method for the detection and quantification of 16 synthetic cathinones and 10 metabolites in human urine. Methods: The method was validated for all analytes using published guidelines. The evaluated parameters achieved acceptable values according to the set criteria. Potential abuse of synthetic cathinones was investigated in suspicious urine samples from Saudi Arabia originating from workplace drug testing, pre-employment and Accident & Emergency (A&E). Such samples generated a presumptive positive immunoassay for amphetamine; however, they yielded a negative LC–MS/MS confirmation for this analyte, following the recommended cutoff values of Substance of Abuse and Mental Health Services Administration (SAMHSA) guidelines. Results: 5.8% of the analyzed samples were found to contain at least one target analyte, namely mephedrone and N-ethylpentylone, as well as their dihydro-metabolites. The results also revealed polydrug use with the synthetic cathinones being present together with other classical stimulant drugs. Conclusions: This is the first report of NPS use in Saudi Arabia with respect to designer stimulant drugs. Confirmatory urine analyses for suspicious stimulant use should extend beyond classical stimulants to cover a broad range of NPSs and their metabolites in order to report any otherwise potentially undetected/new analyte.
Using a Caenorhabditis elegans Parkinson’s Disease Model to Assess Disease Progression and Therapy Efficiency
Authors: Hughes Samantha , van Dop Maritza , Kolsters Nikki , van de Klashorst David , Pogosova Anastasia , Rijs Anouk M.
Published: April 2022

Despite Parkinson’s Disease (PD) being the second most common neurodegenerative disease, treatment options are limited. Consequently, there is an urgent need to identify and screen new therapeutic compounds that slow or reverse the pathology of PD. Unfortunately, few new therapeutics are being produced, partly due to the low throughput and/or poor predictability of the currently used model organisms and in vivo screening methods. Our objective was to develop a simple and affordable platform for drug screening utilizing the nematode Caenorhabditis elegans. The effect of Levodopa, the “Gold standard” of PD treatment, was explored in nematodes expressing the disease-causing α-synuclein protein. We focused on two key hallmarks of PD: plaque formation and mobility. Exposure to Levodopa ameliorated the mobility defect in C. elegans, similar to people living with PD who take the drug. Further, long-term Levodopa exposure was not detrimental to lifespan. This C. elegans-based method was used to screen a selection of small-molecule drugs for an impact on α-synuclein aggregation and mobility, identifying several promising compounds worthy of further investigation, most notably Ambroxol. The simple methodology means it can be adopted in many labs to pre-screen candidate compounds for a positive impact on disease progression.
An Albumin-Binding PSMA Ligand with Higher Tumor Accumulation for PET Imaging of Prostate Cancer
Authors: Ren Ya’nan , Liu Teli , Liu Chen , Guo Xiaoyi , Wang Feng , Zhu Hua , Yang Zhi
Published: April 2022

Prostate-specific membrane antigen (PSMA) is an ideal target for the diagnosis and treatment of prostate cancer. Due to the short half-life in blood, small molecules/peptides are rapidly cleared by the circulatory system. Prolonging the half-life of PSMA probes has been considered as an effective strategy to improve the tumor detection. Herein, we reported a 64Cu-labeled PSMA tracer conjugating with maleimidopropionic acid (MPA), 64Cu-PSMA-CM, which showed an excellent ability to detect PSMA-overexpressing tumors in delayed time. Cell experiments in PSMA-positive 22Rv1 cells, human serum albumin binding affinity, and micro-PET imaging studies in 22Rv1 model were performed to investigate the albumin binding capacity and PSMA specificity. Comparisons with 64Cu-PSMA-BCH were performed to explore the influence of MPA on the biological properties. 64Cu-PSMA-CM could be quickly prepared within 30 min. The uptake of 64Cu-PSMA-CM in 22Rv1 cells increased over time and it could bind to HSA with a high protein binding ratio (67.8 ± 1.5%). When compared to 64Cu-PSMA-BCH, 64Cu-PSMA-CM demonstrated higher and prolonged accumulation in 22Rv1 tumors, contributing to high tumor-to-organ ratios. These results showed that 64Cu-PSMA-CM was PSMA specific with a higher tumor uptake, which demonstrated that MPA is an optional strategy for improving the radioactivity concentration in PSMA-expressing tumors and for developing the ligands for PSMA radioligand therapy.
Phospholipid-Based Microemulsions for Cutaneous Imiquimod Delivery
Authors: Panoutsopoulou Eleni , Zbytovská Jarmila , Vávrová Kateřina , Paraskevopoulos Georgios
Published: April 2022

Imiquimod (IMQ) is a potent immune response modifier with antiviral and antitumor properties. IMQ’s low aqueous solubility and unsatisfactory cutaneous permeability limit its formulation into effective dosage forms. This work aimed to develop IMQ-loaded microemulsions (MEs) based on phospholipids and oleic acid to improve IMQ penetration into the epidermis. A pseudo-ternary phase diagram was constructed, and the microstructure of the formulations was examined by measuring the conductivity values. Selected MEs were characterized and studied for their ability to deliver IMQ into and through ex vivo human skin. ME1 with 1% IMQ (bicontinuous ME with Bingham rheology) delivered similar IMQ quantities to the human epidermis ex vivo as the commercial product while having a 5-fold lower IMQ dose. IMQ was not detected in the acceptor phase after the permeation experiment, suggesting a lower systemic absorption risk than the established product. Infrared spectroscopy of the stratum corneum revealed less ordered and less tightly packed lipids after ME1 application. The ME1-induced barrier disruption recovered within less than 5 h after the formulation removal, as detected by transepidermal water loss measurements. In conclusion, our findings demonstrate that phospholipid and oleic acid-based MEs could become a promising alternative for topical IMQ administration.
Radiopharmaceutical Labelling for Lung Ventilation/Perfusion PET/CT Imaging: A Review of Production and Optimization Processes for Clinical Use
Authors: Blanc-Béguin Frédérique , Hennebicq Simon , Robin Philippe , Tripier Raphaël , Salaün Pierre-Yves , Le Roux Pierre-Yves
Published: April 2022

Lung ventilation/perfusion (V/Q) positron emission tomography-computed tomography (PET/CT) is a promising imaging modality for regional lung function assessment. The same carrier molecules as a conventional V/Q scan (i.e., carbon nanoparticles for ventilation and macro aggregated albumin particles for perfusion) are used, but they are labeled with gallium-68 (68Ga) instead of technetium-99m (99mTc). For both radiopharmaceuticals, various production processes have been proposed. This article discusses the challenges associated with the transition from 99mTc- to 68Ga-labelled radiopharmaceuticals. The various production and optimization processes for both radiopharmaceuticals are reviewed and discussed for optimal clinical use.
Age-Related Decline of Male Fertility: Mitochondrial Dysfunction and the Antioxidant Interventions
Authors: Wang Jing-Jing , Wang Shu-Xia , Tehmina  , Feng Yan , Zhang Rui-Fen , Li Xin-Yue , Sun Qiong , Ding Jian
Published: April 2022

Mitochondria are structurally and functionally unique organelles in male gametes. Apparently, as the only organelles remaining in mature sperm, mitochondria not only produce adeno-sine triphosphate (ATP) through oxidative phosphorylation (OXPHOS) to support sperm mobility, but also play key roles in regulating reactive oxidation species (ROS) signaling, calcium homeostasis, steroid hormone biosynthesis, and apoptosis. Mitochondrial dysfunction is often associated with the aging process. Age-dependent alterations of the epididymis can cause alterations in sperm mitochondrial functioning. The resultant cellular defects in sperm have been implicated in male infertility. Among these, oxidative stress (OS) due to the overproduction of ROS in mitochondria may represent one of the major causes of these disorders. Excessive ROS can trigger DNA damage, disturb calcium homeostasis, impair OXPHOS, disrupt the integrity of the sperm lipid membrane, and induce apoptosis. Given these facts, scavenging ROS by antioxidants hold great potential in terms of finding promising therapeutic strategies to treat male infertility. Here, we summarize the progress made in understanding mitochondrial dysfunction, aging, and male infertility. The clinical potential of antioxidant interventions was also discussed.
Assessing the Oxidative State of the Skin by Combining Classical Tape Stripping with ORAC Assay
Authors: Alnemari Reem M. , Brüßler Jana , Keck Cornelia M.
Published: April 2022

The antioxidant barrier system of the skin acts as the main defence against environmental pro-oxidants. Impaired skin oxidative state is linked to unhealthy conditions such as skin autoimmune diseases and cancer. Thus, the evaluation of the overall oxidative state of the skin plays a key role in further understanding and prevention of these disorders. This study aims to present a novel ex vivo model to evaluate the skin oxidative state by the measurement of its antioxidant capacity (AOC). For this the ORAC assay was combined with classical tape stripping and infrared densitometry to evaluate the oxidative state of the stratum corneum (SC). Outcomes implied the suitability of the used model to determine the intrinsic antioxidant capacity (iAOC) of the skin. The average iAOC of untreated skin was determined as 140 ± 7.4 µM TE. Skin exposure to UV light for 1 h reduced the iAOC by about 17%, and exposure for 2 h decreased the iAOC by about 30%. Treatment with ascorbic acid (AA) increased the iAOC in a dose-dependent manner and reached an almost two-fold iAOC when 20% AA solution was applied on the skin. The application of coenzyme Q10 resulted in an increase in the iAOC at low doses but decreased the iAOC when doses > 1% were applied on the skin. The results show that the combination of classical tape stripping and ORAC assay is a cost-effective and versatile method to evaluate the skin oxidative state and the pro-oxidate and antioxidative effects of topical skin treatments on the iAOC of the skin. Therefore, the model can be considered to be a valuable tool in skin research.
Improved Database Filtering Technology Enables More Efficient Ab Initio Design of Potent Peptides against Ebola Viruses
Authors: Ripperda Thomas , Yu Yangsheng , Verma Atul , Klug Elizabeth , Thurman Michellie , Reid St Patrick , Wang Guangshun
Published: April 2022

The rapid mutations of viruses such as SARS-CoV-2 require vaccine updates and the development of novel antiviral drugs. This article presents an improved database filtering technology for a more effective design of novel antiviral agents. Different from the previous approach, where the most probable parameters were obtained stepwise from the antimicrobial peptide database, we found it possible to accelerate the design process by deriving multiple parameters in a single step during the peptide amino acid analysis. The resulting peptide DFTavP1 displays the ability to inhibit Ebola virus. A deviation from the most probable peptide parameters reduces antiviral activity. The designed peptides appear to block viral entry. In addition, the amino acid signature provides a clue to peptide engineering to gain cell selectivity. Like human cathelicidin LL-37, our engineered peptide DDIP1 inhibits both Ebola and SARS-CoV-2 viruses. These peptides, with broad antiviral activity, may selectively disrupt viral envelopes and offer the lasting efficacy required to treat various RNA viruses, including their emerging mutants.
Impairment of Glucose Metabolism and Suppression of Stemness in MCF-7/SC Human Breast Cancer Stem Cells by Nootkatone
Authors: Nguyen Yen Thi-Kim , To Ngoc Bao , Truong Vi Nguyen-Phuong , Kim Hee Young , Ediriweera Meran Keshawa , Lim Yoongho , Cho Somi Kim
Published: April 2022

Targeting cancer stem cell metabolism has emerged as a promising therapeutic strategy for cancer treatment. Breast cancer stem cells (BCSCs) exert distinct metabolism machinery, which plays a major role in radiation and multidrug resistance. Therefore, exploring the mechanisms involved in energy utilization of BCSCs could improve the effectiveness of therapeutic strategies aimed at their elimination. This study was conducted to clarify the glucose metabolism machinery and the function of nootkatone, a bioactive component of grapefruit, in regulating glucose metabolism and stemness characteristics in human breast carcinoma MCF-7 stem cells (MCF-7SCs). In vivo experiments, transcriptomic analysis, seahorse XF analysis, MTT assay, Western blotting, mammosphere formation, wound healing, invasion assay, flow cytometric analysis, reverse transcription-quantitative polymerase chain reaction, and in silico docking experiments were performed. MCF-7SCs showed a greater tumorigenic capacity and distinct gene profile with enrichment of the genes involved in stemness and glycolysis signaling pathways compared to parental MCF-7 cells, indicating that MCF-7SCs use glycolysis rather than oxidative phosphorylation (OXPHOS) for their energy supply. Nootkatone impaired glucose metabolism through AMPK activation and reduced the stemness characteristics of MCF-7SCs. In silico docking analysis demonstrated that nootkatone efficiently bound to the active site of AMPK. Therefore, this study indicates that regulation of glucose metabolism through AMPK activation could be an attractive target for BCSCs.
Exosomes Derived from Dental Pulp Stem Cells Show Different Angiogenic and Osteogenic Properties in Relation to the Age of the Donor
Authors: Brunello Giulia , Zanotti Federica , Trentini Martina , Zanolla Ilaria , Pishavar Elham , Favero Vittorio , Favero Riccardo , Favero Lorenzo , Bressan Eriberto , Bonora Massimo , Sivolella Stefano , Zavan Barbara
Published: April 2022

Craniofacial tissue reconstruction still represents a challenge in regenerative medicine. Mesenchymal stem cell (MSC)-based tissue engineering strategies have been introduced to enhance bone tissue repair. However, the risk of related complications is limiting their usage. To overcome these drawbacks, exosomes (EXOs) derived from MSCs have been recently proposed as a cell-free alternative to MSCs to direct tissue regeneration. It was hypothesized that there is a correlation between the biological properties of exosomes derived from the dental pulp and the age of the donor. The aim of the study was to investigate the effect of EXOs derived from dental pulp stem cells of permanent teeth (old donor group) or exfoliated deciduous teeth (young donor group) on MSCs cultured in vitro. Proliferation potential was evaluated by doubling time, and commitment ability by gene expression and biochemical quantification for tissue-specific factors. Results showed a well-defined proliferative influence for the younger donor aged group. Similarly, a higher commitment ability was detected in the young group. In conclusion, EXOs could be employed to promote bone regeneration, likely playing an important role in neo-angiogenesis in early healing phases.
Hard, Soft, and Hard-and-Soft Drug Delivery Carriers Based on CaCO3 and Alginate Biomaterials: Synthesis, Properties, Pharmaceutical Applications
Authors: Huang Yanqi , Cao Lin , Parakhonskiy Bogdan V. , Skirtach Andre G.
Published: April 2022

Because free therapeutic drug molecules often have adverse effects on normal tissues, deliver scanty drug concentrations and exhibit a potentially low efficacy at pathological sites, various drug carriers have been developed for preclinical and clinical trials. Their physicochemical and toxicological properties are the subject of extensive research. Inorganic calcium carbonate particles are promising candidates as drug delivery carriers owning to their hardness, porous internal structure, high surface area, distinctive pH-sensitivity, low degradability, etc, while soft organic alginate hydrogels are also widely used because of their special advantages such as a high hydration, bio-adhesiveness, and non-antigenicity. Here, we review these two distinct substances as well as hybrid structures encompassing both types of carriers. Methods of their synthesis, fundamental properties and mechanisms of formation, and their respective applications are described. Furthermore, we summarize and compare similarities versus differences taking into account unique advantages and disadvantages of these drug delivery carriers. Moreover, rational combination of both carrier types due to their performance complementarity (yin-&yang properties: in general, yin is referred to for definiteness as hard, and yang is broadly taken as soft) is proposed to be used in the so-called hybrid carriers endowing them with even more advanced properties envisioned to be attractive for designing new drug delivery systems.
Preformulation Studies of Ezetimibe-Simvastatin Solid Dispersions in the Development of Fixed-Dose Combinations
Authors: Górniak Agata , Złocińska Adrianna , Trojan Mateusz , Pęcak Adrianna , Karolewicz Bożena
Published: April 2022

Two active pharmaceutical ingredients (APIs) with limited solubility, simvastatin and ezetimibe, prepared as a drug-drug solid dispersion (SD) was evaluated for physicochemical, microstructural, and aqueous dissolution properties. The simvastatin-ezetimibe SD was prepared using the co-grinding method in a wide range of weight fractions and differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD) were used to perform the phase composition analysis. DSC studies confirmed that simvastatin and ezetimibe form a simple eutectic phase equilibrium diagram. Analysis of Fourier transform infrared spectroscopy (FTIR) studies excluded strong interactions between the APIs. Our investigations have revealed that all studied dispersions are characterized by substantially improved ezetimibe dissolution regardless of simvastatin content, and are best when the composition oscillates near the eutectic point. Data obtained in our studies provide an opportunity for the development of well-formulated, ezetimibe-simvastatin fixed-dose combinations (for hypercholesterolemia treatment) with reduced ezetimibe dosages based on its dissolution improvement.
A Pharmacometric Model to Predict Chemotherapy-Induced Myelosuppression and Associated Risk Factors in Non-Small Cell Lung Cancer
Authors: Park Kyemyung , Kim Yukyung , Son Mijeong , Chae Dongwoo , Park Kyungsoo
Published: April 2022

Chemotherapy often induces severe neutropenia due to the myelosuppressive effect. While predictive pharmacokinetic (PK)/pharmacodynamic (PD) models of absolute neutrophil count (ANC) after anticancer drug administrations have been developed, their deployments to routine clinics have been limited due to the unavailability of PK data and sparseness of PD (or ANC) data. Here, we sought to develop a model describing temporal changes of ANC in non-small cell lung cancer patients receiving (i) combined chemotherapy of paclitaxel and cisplatin and (ii) granulocyte colony stimulating factor (G-CSF) treatment when needed, under such limited circumstances. Maturation of myelocytes into blood neutrophils was described by transit compartments with negative feedback. The K-PD model was employed for drug effects with drug concentration unavailable and the constant model for G-CSF effects. The fitted model exhibited reasonable goodness of fit and parameter estimates. Covariate analyses revealed that ANC decreased in those without diabetes mellitus and female patients. Using the final model obtained, an R Shiny web-based application was developed, which can visualize predicted ANC profiles and associated risk of severe neutropenia for a new patient. Our model and application can be used as a supportive tool to identify patients at the risk of grade 4 neutropenia early and suggest dose reduction.
Physiologically Based Pharmacokinetic (PBPK) Modeling of Clopidogrel and Its Four Relevant Metabolites for CYP2B6, CYP2C8, CYP2C19, and CYP3A4 Drug–Drug–Gene Interaction Predictions
Authors: Loer Helena Leonie Hanae , Türk Denise , Gómez-Mantilla José David , Selzer Dominik , Lehr Thorsten
Published: April 2022

The antiplatelet agent clopidogrel is listed by the FDA as a strong clinical index inhibitor of cytochrome P450 (CYP) 2C8 and weak clinical inhibitor of CYP2B6. Moreover, clopidogrel is a substrate of—among others—CYP2C19 and CYP3A4. This work presents the development of a whole-body physiologically based pharmacokinetic (PBPK) model of clopidogrel including the relevant metabolites, clopidogrel carboxylic acid, clopidogrel acyl glucuronide, 2-oxo-clopidogrel, and the active thiol metabolite, with subsequent application for drug–gene interaction (DGI) and drug–drug interaction (DDI) predictions. Model building was performed in PK-Sim® using 66 plasma concentration-time profiles of clopidogrel and its metabolites. The comprehensive parent-metabolite model covers biotransformation via carboxylesterase (CES) 1, CES2, CYP2C19, CYP3A4, and uridine 5′-diphospho-glucuronosyltransferase 2B7. Moreover, CYP2C19 was incorporated for normal, intermediate, and poor metabolizer phenotypes. Good predictive performance of the model was demonstrated for the DGI involving CYP2C19, with 17/19 predicted DGI AUClast and 19/19 predicted DGI Cmax ratios within 2-fold of their observed values. Furthermore, DDIs involving bupropion, omeprazole, montelukast, pioglitazone, repaglinide, and rifampicin showed 13/13 predicted DDI AUClast and 13/13 predicted DDI Cmax ratios within 2-fold of their observed ratios. After publication, the model will be made publicly accessible in the Open Systems Pharmacology repository.
Prunus armeniaca Gum-Alginate Polymeric Microspheres to Enhance the Bioavailability of Tramadol Hydrochloride: Formulation and Evaluation
Authors: Noureen Shazia , Noreen Sobia , Ghumman Shazia Akram , Batool Fozia , Hameed Huma , Hasan Sara , Noreen Fozia , Elsherif Mervat A. , Bukhari Syed Nasir Abbas
Published: April 2022

Combinations of polymers can improve the functional properties of microspheres to achieve desired therapeutic goals. Hence, the present study aimed to formulate Prunus armeniaca gum (PAG) and sodium alginate microsphere for sustained drug release. Blended and coated microspheres were prepared using the ionotropic gelation technique. The effect of polymer concentration variation was studied on the structural and functional properties of formulated microspheres. FTIR, XRD, and thermal analysis were performed to characterize the microspheres. All the formulations were well-formed spherical beads having an average diameter from 579.23 ± 07.09 to 657.67 ± 08.74 μm. Microspheres entrapped drugs within the range 65.86 ± 0.26–83.74 ± 0.79%. The pH-dependent swelling index of coated formulations was higher than blended. FTIR spectra confirmed the presence of characteristic peaks of entrapped Tramadol hydrochloride showing no drug-polymer interaction. In vitro drug release profile showed sustained release following the Korsmeyer-Peppas kinetic model with an R2 value of 0.9803–0.9966. An acute toxicology study employing the oral route in Swiss albino mice showed no signs of toxicity. It can be inferred from these results that blending PAG with sodium alginate can enhance the stability of alginate microspheres and improve its drug release profile by prolonging the release time.
Nanotheranostics for Image-Guided Cancer Treatment
Authors: Dennahy Isabel S. , Han Zheng , MacCuaig William M. , Chalfant Hunter M. , Condacse Anna , Hagood Jordan M. , Claros-Sorto Juan C. , Razaq Wajeeha , Holter-Chakrabarty Jennifer , Squires Ronald , Edil Barish H. , Jain Ajay , McNally Lacey R.
Published: April 2022

Image-guided nanotheranostics have the potential to represent a new paradigm in the treatment of cancer. Recent developments in modern imaging and nanoparticle design offer an answer to many of the issues associated with conventional chemotherapy, including their indiscriminate side effects and susceptibility to drug resistance. Imaging is one of the tools best poised to enable tailoring of cancer therapies. The field of image-guided nanotheranostics has the potential to harness the precision of modern imaging techniques and use this to direct, dictate, and follow site-specific drug delivery, all of which can be used to further tailor cancer therapies on both the individual and population level. The use of image-guided drug delivery has exploded in preclinical and clinical trials although the clinical translation is incipient. This review will focus on traditional mechanisms of targeted drug delivery in cancer, including the use of molecular targeting, as well as the foundations of designing nanotheranostics, with a focus on current clinical applications of nanotheranostics in cancer. A variety of specially engineered and targeted drug carriers, along with strategies of labeling nanoparticles to endow detectability in different imaging modalities will be reviewed. It will also introduce newer concepts of image-guided drug delivery, which may circumvent many of the issues seen with other techniques. Finally, we will review the current barriers to clinical translation of image-guided nanotheranostics and how these may be overcome.
Improved Efficiency of Pomegranate Seed Oil Administrated Nasally
Authors: Natsheh Hiba , Touitou Elka
Published: April 2022

Pomegranate seed oil (PSO) is currently administrated orally as a food supplement for improving memory. However, the efficiency of the oral dosage forms for such purposes is low, mainly due to the blood brain barrier impeding a good delivery to brain. In this work, we designed and characterized a PSO phospholipid oily gel for nasal administration. We tested the performance of the new PSO delivery system in animal models for impaired memory and locomotor activity. The experimental results indicated a statistically significant improvement (p < 0.05) of more than 1.5 fold in the behavior of animals treated nasally, in comparison to those treated with orally administrated oil. Furthermore, in multiphoton microscopy and near infrared imaging studies, the nasal administration of fluorescent probes, fluorescein isothiocyanate (FITC), and indocyanine green (ICG) incorporated in the PSO system showed enhanced delivery to the brain. Results of the histopathologic examination of the nasal cavity and mucosa, as carried out by a pathologist, indicated the safety of the PSO phospholipid oily gel. In conclusion, the results of this work encourage further investigation of the phospholipid oily gel composition as a new way of PSO administration.
Elucidating Pathway and Anesthetic Mechanism of Action of Clove Oil Nanoformulations in Fish
Authors: Kheawfu Kantaporn , Pikulkaew Surachai , Wellendorph Petrine , Jørgensen Louise von Gersdorff , Rades Thomas , Müllertz Anette , Okonogi Siriporn
Published: April 2022

Clove oil (CO), an essential oil of Syzygium aromaticum, has been reported as an anesthetic for many fish species. However, its insoluble properties require a suitable delivery system for its application. In the present study, nanoformulations of CO as a nanoemulsion (CO-NE), a self-microemulsifying drug-delivery system (CO-SMEDDS), and a self-nanoemulsifying drug-delivery system (CO-SNEDDS) were prepared for delivering CO. Zebrafish were used as a fish model to investigate oil pathways. The result shows fluorescence spots of fluorescence-labeled CO accumulate on the gills, skin, and brain. All CO nanoformulations significantly increased penetration flux compared to CO ethanolic solution. Investigation of the anesthetic mechanism of action using a rat brain γ-aminobutyric acid subtype A (GABAA) receptor-binding test demonstrates that CO and its major compound, eugenol, modulate [3H]muscimol binding. CO-NE exhibited a concentration-dependent binding activity with an EC50 value of 175 µg/mL, significantly higher than CO solution in dimethyl sulfoxide. In conclusion, CO enters the fish through the skin and gills. The anesthetic mechanism of action of CO is based on modulation of [3H] muscimol binding to GABAA receptors. Among three nanoformulations tested, CO-NE is the most effective at increasing permeability and enhancing the receptor-binding activity of the oil.
Single-Step Self-Assembly of Zein–Honey–Chitosan Nanoparticles for Hydrophilic Drug Incorporation by Flash Nanoprecipitation
Authors: Loureiro Jorge , Miguel Sónia P. , Seabra Inês J. , Ribeiro Maximiano P. , Coutinho Paula
Published: April 2022

Zein- and chitosan-based nanoparticles have been described as promising carrier systems for food, biomedical and pharmaceutical applications. However, the manufacture of size-controlled zein and chitosan particles is challenging. In this study, an adapted anti-solvent nanoprecipitation method was developed. The effects of the concentration of zein and chitosan and the pH of the collection solution on the properties of the zein–honey–chitosan nanoparticles were investigated. Flash nanoprecipitation was demonstrated as a rapid, scalable, single-step method to achieve the self-assembly of zein–honey–chitosan nanoparticles. The nanoparticles size was tuned by varying certain formulation parameters, including the total concentration and ratio of the polymers. The zein–honey–chitosan nanoparticles’ hydrodynamic diameter was below 200 nm and the particles were stable for 30 days. Vitamin C was used as a hydrophilic model substance and efficiently encapsulated into these nanoparticles. This study opens a promising pathway for one-step producing zein–honey–chitosan nanoparticles by flash nanoprecipitation for hydrophilic compounds’ encapsulation.
Preparation, Characterization, and Evaluation of Breviscapine Nanosuspension and Its Freeze-Dried Powder
Authors: Zhang Ting , Li Xixi , Xu Juewen , Shao Jingbao , Ding Meihong , Shi Senlin
Published: April 2022

As a biopharmaceutics classification system (BCS) class IV drug, breviscapine (Bre) has low solubility in water, poor chemical stability, a short biological half-life and rapid removal from plasma. This paper prepared a Bre nanosuspension (Bre-NS) by an ultrasound-assisted anti-solvent precipitation method. Characterization of Bre-NS was studied using a Box–Behnken design concerning drug concentration in DMSO, an anti-solvent-to-solvent ratio, and sonication time. Under the optimized conditions of 170 mg/mL for the drug concentration, a 1:60 solvent-to-anti-solvent ratio, and a 9 min sonication time, the particle size of Bre-NS was 303.7 ± 7.3 nm, the polydispersity index was 0.178 ± 0.015, and the zeta potential was −31.10 ± 0.26 mV. Combined with the results from differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and Fourier transform-infrared spectroscopy (FT-IR), the findings indicated that the crystal form and chemical structure of Bre-NS did not change during the entire process. The optimized formulation displayed good stability, increased solubility, and better in vitro release. Therefore, the results of this study can be a reference for the delivery system design of insoluble active components and effective parts in traditional Chinese medicine.
The Lean Six Sigma Define, Measure, Analyze, Implement, Control (LSS DMAIC) Framework: An Innovative Strategy for Quality Improvement of Pharmacist Vaccine Recommendations in Community Pharmacy
Authors: Hohmeier Kenneth C. , Renfro Chelsea , Loomis Benjamin , Alexander Connor E. , Patel Urvi , Cheramie Matthew , Cernasev Alina , Hagemann Tracy , Chiu Chi-Yang , Chisholm-Burns Marie A. , Gatwood Justin D.
Published: April 2022

Community pharmacies represent a highly accessible and convenient setting for vaccination. However, setting-specific barriers exist which contribute to suboptimal vaccination rates, particularly for pneumococcal vaccinations. One proven quality improvement framework growing in use within healthcare settings is Lean Six Sigma (LSS). This paper describes the application of the LSS framework in select locations of a national pharmacy chain. The implementation of a training program for improved recommendation techniques to promote higher rates of pneumococcal vaccinations in high-risk adult populations is also addressed. A mixed-methods approach including pre/post quasi-experimental design and in-depth key informant interviews was used.
Fixed-Dose Factor Eight Inhibitor Bypassing Activity (FEIBA) in the Management of Warfarin-Associated Coagulopathies
Authors: Ibarra Francisco , Cruz Mallory , Ford Matthew , Wu Meng-Jou
Published: April 2022

This retrospective review evaluated our institutions’ practice of administering low fixed-dose FEIBA (high (1000 units) or low dose (500 units) for an INR ≥ 5 or <5, respectively) for the management of warfarin-associated coagulopathies. The primary outcome was the percentage of patients who had a post-FEIBA INR ≤ 1.5. In the total population, 55.6% (10/18) of patients achieved a post-FEIBA INR ≤ 1.5. In the subgroup analysis, significantly more patients in the low dose FEIBA group achieved a post-FEIBA INR ≤ 1.5 compared to the high dose FEIBA group (71.4% vs. 45.5%, respectively, p < 0.001). In the post hoc analysis, there was a significant difference in the number of patients who achieved a post-FEIBA INR ≤ 1.5 when comparing those who received high dose FEIBA with a baseline INR 5–9.9 to those who received high dose FEIBA with a baseline INR ≥ 10 (60% vs. 33.3%, respectively, p < 0.001). The existing literature and our findings suggest that patients who present with lower baseline INR values and receive additional reversal agents are more likely to meet post-reversal INR goals. Current low fixed-dose protocols may be oversimplified and may need to be revised to provide larger fixed-doses.
Scarcity, Justice, and Health Crisis Leadership
Authors: Häyry Matti
Published: April 2022

The COVID-19 pandemic has created or revealed scarcities in many domains: medical, civic, economic, and ideological. Responses to these are analyzed in the framework of a map of justice and an imperative of openness. The main argument is that whatever the view of justice chosen by public health authorities, they should be able and willing to disclose it to the citizens. Objections are considered and qualifications added, but the general conclusion is that in liberal democracies, truth-telling by those in power, although politically hazardous, would be ethically advisable.
Special Issue on “Visible Light Communication (VLC)”
Authors: Chen Chen
Published: April 2022

Due to its appealing advantages, including abundant and unregulated spectrum resources, no electromagnetic interference (EMI) radiation and high security, visible light communication (VLC) using light-emitting diodes (LEDs) or laser diodes (LDs) has been envisioned as one of the key enabling technologies for 6G and Internet of Things (IoT) systems [...]
Short-Reach MCF-Based Systems Employing KK Receivers and Feedforward Neural Networks for ICXT Mitigation
Authors: Piedade Derick , Alves Tiago , Brandão Tomás
Published: April 2022

This paper proposes and evaluates the use of machine learning (ML) techniques for mitigating the effect of the random inter-core crosstalk (ICXT) on 256 Gb/s short-reach systems employing weakly coupled multicore fiber (MCF) and Kramers–Kronig (KK) receivers. The performance improvement provided by the k-means clustering, k nearest neighbor (KNN) and feedforward neural network (FNN) techniques are assessed and compared with the system performance obtained without employing ML. The FNN proves to significantly improve the system performance by mitigating the impact of the ICXT on the received signal. This is achieved by employing only 10 neurons in the hidden layer and four input features for the training phase. It has been shown that k-means or KNN techniques do not provide performance improvement compared to the system without using ML. These conclusions are valid for direct detection MCF-based short-reach systems with the product between the skew (relative time delay between cores) and the symbol rate much lower than one (skew×symbol rate≪1). By employing the proposed FNN, the bit error rate (BER) always stood below 10−1.8 on all the time fractions under analysis (compared with 100 out of 626 occurrences above the BER threshold when ML was not used). For the BER threshold of 10−1.8 and compared with the standard system operating without employing ML techniques, the system operating with the proposed FNN shows a received optical power improvement of almost 3 dB.
Two-Dimensional Ultrafast X-ray Imager for Inertial Confinement Fusion Diagnosis
Authors: Cai Houzhi , Lin Kaixuan , Luo Qiuyan , Wang Dong , Huang Junkun , Xu Kangjing , Luo Longjie , Liu Jinyuan
Published: April 2022

A two-dimensional ultrafast X-ray imager (UXI) composed of a time-dilation device, an electron-beam imaging unit, a gated microchannel plate (MCP) framing tube, and a pulser was developed. The time-dilation device extends the time spread of the electron signal generated by the pulsed photocathode (PC), and the electron-beam imaging unit images the electron pulse from PC to MCP. Finally, the gated MCP framing tube samples the dilated electron pulse. The time resolution and image size of the UXI were measured with an X-ray generated by a terawatt laser targeting device. When a driving pulse with a 2 V/ps slope is applied to the PC, the measured time resolution is 21 ps, and the image size is 12 mm × 3.9 mm. Furthermore, the image size varies with the time resolution. The results show that as the time resolution improves, the image size decreases. The use of two opposite-transmission PC driving pulses could improve the image size. Moreover, the measured UXI spatial resolution is 5 lp/mm, and the spatial resolution will be worse with the increasing off-axis distance.
Application of Adaptive Optics in Ophthalmology
Authors: Liu Lixin , Wu Zhaoqing , Qi Meijie , Li Yanru , Zhang Meiling , Liao Dingying , Gao Peng
Published: April 2022

The eye, the photoreceptive organ used to perceive the external environment, is of great importance to humans. It has been proven that some diseases in humans are accompanied by fundus changes; therefore, the health status of people may be interpreted from retinal images. However, the human eye is not a perfect refractive system for the existence of ocular aberrations. These aberrations not only affect the ability of human visual discrimination and recognition, but restrict the observation of the fine structures of human eye and reduce the possibility of exploring the mechanisms of eye disease. Adaptive optics (AO) is a technique that corrects optical wavefront aberrations. Once integrated into ophthalmoscopes, AO enables retinal imaging at the cellular level. This paper illustrates the principle of AO in correcting wavefront aberrations in human eyes, and then reviews the applications and advances of AO in ophthalmology, including the adaptive optics fundus camera (AO-FC), the adaptive optics scanning laser ophthalmoscope (AO-SLO), the adaptive optics optical coherence tomography (AO-OCT), and their combined multimodal imaging technologies. The future development trend of AO in ophthalmology is also prospected.
u-Channel Color Transparency Observables
Authors: Huber Garth M. , Li Wenliang B. , Cosyn Wim , Pire Bernard
Published: April 2022

The paper proposes to study the onset of color transparency in hard exclusive reactions in the backward regime. Guided by the encouraging Jefferson Laboratory (JLab) results on backward π and ω electroproduction data at moderate virtuality Q2, which may be interpreted as the signal of an early scaling regime, where the scattering amplitude factorizes in a hard coefficient function convoluted with nucleon to meson transition distribution amplitudes, the study shows that investigations of these channels on nuclear targets opens a new opportunity to test the appearance of nuclear color transparency for a fast-moving nucleon.
Contact and Fumigant Activities of Citrus aurantium Essential Oil against the Stable Fly Stomoxys calcitrans (Diptera: Muscidae)
Authors: Changbunjong Tanasak , Boonmasawai Sookruetai , Sungpradit Sivapong , Weluwanarak Thekhawet , Leesombun Arpron
Published: April 2022

The stable fly, Stomoxys calcitrans (L.), is a cosmopolitan hematophagous fly of medical and veterinary importance. It is widely considered a major livestock pest that can cause significant economic losses. This study aimed to evaluate the insecticidal activity of Citrus aurantium (L.) essential oil against S. calcitrans based on contact and fumigant toxicity tests. Chemical analysis by gas chromatography-mass spectrometry of the essential oil showed the dominance (93.79%) of limonene in the total essential oil composition. Furthermore, the insecticidal test results showed that the mortality of flies increased with concentration and time within 24 h of exposure. In the contact toxicity test, the median lethal dose was 105.88 µg/fly, while the 90% lethal dose was 499.25 µg/fly. As for the fumigant toxicity test, the median lethal concentration was 13.06 mg/L air, and the 90% lethal concentration was 43.13 mg/L air. These results indicate that C. aurantium essential oil exhibits insecticidal activity against S. calcitrans. Therefore, it can be used as an alternative to synthetic insecticides for achieving stable fly control.
The Valorization of Spent Coffee Ground Extract as a Prospective Insecticidal Agent against Some Main Key Pests of Phaseolus vulgaris in the Laboratory and Field
Authors: Hussein Hany , Abouamer Waleed , Ali Hatem , Elkhadragy Manal , Yehia Hany , Farouk Amr
Published: April 2022

The exploitation of massive amounts of food and agro-waste represents a severe social, economic, and environmental issue. Under the growing demand for food products that are free of toxic synthetic insecticides, a methanolic extract of spent coffee grounds (SCGs), which represent the main byproduct of coffee production, was applied in the current study as a bioinsecticide against the main pests of the green bean: Spodoptera littoralis, Agrotis ipsilon, Bemisia tabaci, Empoasca fabae, and Aphis craccivora. A deterrent assay, contact bioassay, and lethal concentration analysis were performed to reveal the repellent, antifeedant, and oviposition deterrent effects. Parallel to the above-mentioned bioassays, the phytochemical composition of the methanolic SCG extract was investigated via a high-performance liquid chromatography (HPLC) analysis. Fourteen phenolic acids and five flavonoids, in addition to caffeine (alkaloid), were identified in the extract. Cinnamic, rosmarinic, and gallic acids were the predominant phenolics, while apigenin-7-glucoside was the main flavonoid, followed by naringin, catechin, and epicatechin. The extract of SCGs showed an insecticidal effect, with a mortality between 27.5 and 76% compared to the control (7.4%) and based on the concentration of the extract used. In the same trend, the oviposition efficiency revealed different batches of laid eggs (0.67, 2.33, 7.33, and 8.67 batches/jar) for 100, 50, and 25% of the SCG extract and the control. Finally, the major components of the SCG extract were docked into the insecticide acetylcholinesterase enzyme to explore their potential for inhibition, where apigenin-7-glucoside showed a higher binding affinity, followed by catechin, compared to the control (lannate). The obtained findings could be a starting point for developing novel bioinsecticides from SCGs.
Diazotrophic Bacteria Is an Alternative Strategy for Increasing Grain Biofortification, Yield and Zinc Use Efficiency of Maize
Authors: Jalal Arshad , Oliveira Carlos Eduardo da Silva , Fernandes Henrique Benetasse , Galindo Fernando Shintate , Silva Edson Cabral da , Fernandes Guilherme Carlos , Nogueira Thiago Assis Rodrigues , De Carvalho Pedro Henrique Gomes , Balbino Vinícius Rodrigues , Lima Bruno Horschut de , Teixeira Filho Marcelo Carvalho Minhoto
Published: April 2022

Biofortification of cereal crops with zinc and diazotrophic bacteria is a sustainable solution to nutrient deficiency and hidden hunger. The inoculation of staple grain crops such as maize is increased with reducing productivity losses while improving nutrition and use efficiency under climatic extremes and weathered soils of tropical savannah. Therefore, objectives of our study were to evaluate the influence of seed inoculation with diazotrophic bacteria (No inoculation–Control, Azospirillum brasilense, Bacillus subtilis, and Pseudomonas fluorescens) together with residual effect of soil Zn (absence and presence) on growth, yield, Zn nutrition, Zn use efficiencies, and intake of maize in 2019 and 2020 cropping seasons. The inoculation of B. subtilis increased hundred grain mass and yield (14.5 and 17%), while P. fluorescens under residual Zn fertilization has improved shoot and grain Zn concentration in shoot (29.5 and 30.5%). and grain (25.5 and 26.2%), while improving Zn accumulation in shoot (33.8 and 35%) and grain (37.2 and 42%) of maize. The estimated Zn intake in maize was also increased with A. brasilense inoculation and residual Zn application. The Zn use efficiencies including Zn use efficiency, agro-physiological, and utilization efficiency was increased with B. subtilis, while applied Zn recovery was increased with A. brasilense inoculations under residual Zn fertilization. Zinc use efficiency was increased by 93.3 and 397% with inoculation of B. subtilis regardless of Zn application. Therefore, inoculation with B. subtilis and P. fluorescens along residual Zn fertilization is considered the most effective and sustainable strategy for agronomic biofortification of maize under harsh tropical conditions of Brazil.