bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of Hydrogen Annealing on Performances of BN-Based RRAM
Authors: Lee Doowon , Kim Hee-Dong
Published: May 2023

BN-based resistive random-access memory (RRAM) has emerged as a potential candidate for non-volatile memory (NVM) in aerospace applications, offering high thermal conductivity, excellent mechanical, and chemical stability, low power consumption, high density, and reliability. However, the presence of defects and trap states in BN-based RRAM can limit its performance and reliability in aerospace applications. As a result, higher set voltages of 1.4 and 1.23 V were obtained for non-annealed and nitrogen-annealed BN-based RRAM, respectively, but lower set voltages of 1.06 V were obtained for hydrogen-annealed BN-based RRAM. In addition, the hydrogen-annealed BN-based RRAM showed an on/off ratio of 100, which is 10 times higher than the non-annealed BN-based RRAM. We observed that the LRS changed to the HRS state before 10,000 s for both the non-annealed and nitrogen-annealed BN-based RRAMs. In contrast, the hydrogen-annealed BN-based RRAM showed excellent retention characteristics, with data retained up to 10,000 s.
Nanomaterial-Based Advanced Oxidation/Reduction Processes for the Degradation of PFAS
Authors: Cardoso Inês M. F. , Pinto da Silva Luís , Esteves da Silva Joaquim C. G.
Published: May 2023

This review focuses on a critical analysis of nanocatalysts for advanced reductive processes (ARPs) and oxidation processes (AOPs) designed for the degradation of poly/perfluoroalkyl substances (PFAS) in water. Ozone, ultraviolet and photocatalyzed ARPs and/or AOPs are the basic treatment technologies. Besides the review of the nanomaterials with greater potential as catalysts for advanced processes of PFAS in water, the perspectives for their future development, considering sustainability, are discussed. Moreover, a brief analysis of the current state of the art of ARPs and AOPs for the treatment of PFAS in water is presented.
Trends in Adherence to the Mediterranean Diet in Spanish Children and Adolescents across Two Decades
Authors: Herrera-Ramos Estefanía , Tomaino Laura , Sánchez-Villegas Almudena , Ribas-Barba Lourdes , Gómez Santiago F. , Wärnberg Julia , Osés Maddi , González-Gross Marcela , Gusi Narcis , Aznar Susana , Marín-Cascales Elena , González-Valeiro Miguel Ángel , Terrados Nicolás , Tur Josep A. , Segú Marta , Fitó Montserrat , Homs Clara , Benavente-Marín Juan Carlos , Labayen Idoia , Zapico Augusto G. , Sánchez-Gómez Jesús , Jiménez-Zazo Fabio , Alcaraz-Ramón Pedro Emilio , Sevilla-Sanchez Marta , Pulgar-Muñoz Susana , Bouzas Cristina , Sistac-Sorigué Clara , Schröder Helmut , Serra-Majem Lluis
Published: May 2023

Unhealthy dietary habits determined during childhood may represent a risk factor to many of the chronic non-communicable diseases (NCDs) in adulthood. Mediterranean Diet (MD) adherence in children and adolescents (8–16 years) living in Spain was investigated using the KIDMED questionnaire in a comparative analysis of two cross-sectional nationwide representative studies: enKid (1998–2000, n = 1001) and PASOS (2019–2020, n = 3540). Taking into account the educational level of pupils, as well as the characteristics of the place of living, a significant association was found between a KIDMED score ≥ 8 (optimal MD adherence) and primary education as well as residency in an area of <50,000 inhabitants, while living in the southern regions was associated with non-optimal MD adherence (p < 0.001). Participants of the 2019–2020 study showed an increase in the consumption of dairy products (31.1% increase), pasta/rice (15.4% increase), olive oil (16.9% increase), and nuts (9.7% increase), as well as a decreased sweets and candies intake (12.6% reduction). In contrast, a significantly lower MD adherence was found when comparing the 2019–2020 (mean ± SE: 6.9 ± 0.04) and the 1998–2000 study (7.37 ± 0.08); p < 0.001), due to less consumption of fish (20.3% reduction), pulse (19.4% reduction), and fruits (14.9% reduction), and an increased intake of commercial goods/pastries or fast-food intake (both 19.4% increase). The lowest adherence was recorded for adolescents also in the most recent study, where 10.9% of them presented a KIDMED score ≤ 3. This study shows that eating habits are deteriorating among Spanish children and adolescents. Such findings point out the urgency of undertaking strong measures to promote the consumption of healthy, sustainable, and non-ultra-processed food, such as those available in an MD, not only at a scientific and academic level, but also at a governmental one.
Yingyangbao Intervention Was Associated with the Improvement of Body Growth and Nutrition Status of Infants and Young Children in Poor Rural Areas of China: The Annual Comparison from 2012 to 2020
Authors: Wang Ou , Huang Jian , Huo Junsheng , Chen Di , Xu Yifan , Sun Jing
Published: May 2023

Yingyangbao (YYB) is a soy-based micronutrient-fortified powder used in the Nutrition Improvement Project on Children in Poor Areas of China. After the baseline study in 2012, YYB intervention gradually spread to 21 provinces in China. From 2015 to 2020, a secular trend study was carried out to evaluate the body growth and nutritional status of 6–23-month-old infants and young children (IYC) under YYB intervention. The aim of this research was to investigate whether YYB intervention was associated with the improvement of body growth and development in large populations from broad areas with national and multi-year survey results. The anthropometric data collected in the baseline study and cross-sectional surveys were compared, and the correlation between YYB intake amount and body growth were analyzed. Compared with the results of the baseline study, the 6–23-month-old IYC under YYB intervention showed a significant increase in body weight, body length and Z scores since 2015, and the stunting rate decreased from 9.7% in 2012 to 5.3% in 2020. Significantly positive correlations were observed between the YYB intake amount and the body growth indicators. Therefore, YYB intervention was associated with the improvement of body growth and nutrition status of Chinese IYC. In the future, long-term and continuous efforts are still needed to further reveal the health benefits of YYB in depth.
Umbelliferone Ameliorates Memory Impairment and Enhances Hippocampal Synaptic Plasticity in Scopolamine-Induced Rat Model
Authors: Choi Ga-Young , Kim Hyun-Bum , Cho Jae-Min , Sreelatha Inturu , Lee In-Seo , Kweon Hee-Seok , Sul Sehyun , Kim Sun Ae , Maeng Sungho , Park Ji-Ho
Published: May 2023

Alzheimer’s disease (AD) is a neurodegenerative disorder, characterized by memory loss and cognitive decline. Among the suggested pathogenic mechanisms of AD, the cholinergic hypothesis proposes that AD symptoms are a result of reduced synthesis of acetylcholine (ACh). A non-selective antagonist of the muscarinic ACh receptor, scopolamine (SCOP) induced cognitive impairment in rodents. Umbelliferone (UMB) is a Apiaceae-family-derived 7-hydeoxycoumarin known for its antioxidant, anti-tumor, anticancer, anti-inflammatory, antibacterial, antimicrobial, and antidiabetic properties. However, the effects of UMB on the electrophysiological and ultrastructure morphological aspects of learning and memory are still not well-established. Thus, we investigated the effect of UMB treatment on cognitive behaviors and used organotypic hippocampal slice cultures for long-term potentiation (LTP) and the hippocampal synaptic ultrastructure. A hippocampal tissue analysis revealed that UMB attenuated a SCOP-induced blockade of field excitatory post-synaptic potential (fEPSP) activity and ameliorated the impairment of LTP by the NMDA and AMPA receptor antagonists. UMB also enhanced the hippocampal synaptic vesicle density on the synaptic ultrastructure. Furthermore, behavioral tests on male SD rats (7–8 weeks old) using the Y-maze test, passive avoidance test (PA), and Morris water maze test (MWM) showed that UMB recovered learning and memory deficits by SCOP. These cognitive improvements were in association with the enhanced expression of BDNF, TrkB, and the pCREB/CREB ratio and the suppression of acetylcholinesterase activity. The current findings indicate that UMB may be an effective neuroprotective reagent applicable for improving learning and memory against AD.
Comparative Analysis of Fecal Microbiota in Vegetarians and Omnivores
Authors: Sun Changbao , Li Ang , Xu Cong , Ma Jiage , Wang Huan , Jiang Zhanmei , Hou Juncai
Published: May 2023

Diet has a significant impact on fecal microbiota, which in turn plays an important role in human health. To evaluate the impact of dietary habits on fecal microbiota, we investigated the fecal microbial composition in vegetarians and omnivores using 16S rRNA gene sequencing, and estimated the correlation between fecal microbiota, body mass and diet. The dietary data showed that vegetarians consumed more plant-based foods rich in dietary fiber, omnivores consumed more animal-based foods rich in fat and overweight and obese people consumed more high-energy foods. Compared to omnivores, vegetarians had greater richness and diversity in their fecal microbiota. The Firmicutes/Bacteroidetes ratio was lower and the Prevotella/Bacteroides ratio was higher in vegetarians. The meat intake correlated positively with the proportion of Bacteroides and negatively with the proportion of Prevotella. The composition and diversity in fecal microbiota in the normal weight group, overweight group and obesity group were similar to that of vegetarians and omnivores, respectively. This paper revealed the distinctive characteristics of fecal microbiota in vegetarians and omnivores. The omnivorous diet contained more fat, which reduced the fecal microbial diversity, and was more likely to lead to being overweight or obese.
Carotenoid Markers of Dietary Exposure and Nutritional Status
Authors: Olmedilla-Alonso Begoña
Published: May 2023

Carotenoids are lipophilic isoprenoid compounds synthesized by photosynthetic organisms and some non-photosynthethic prokaryotes and fungi [...]
In Vitro Screening for Probiotic Properties of Lactobacillus and Bifidobacterium Strains in Assays Relevant for Non-Alcoholic Fatty Liver Disease Prevention
Authors: Lopez-Escalera Silvia , Lund Mari L. , Hermes Gerben D. A. , Choi Béatrice S.-Y. , Sakamoto Kei , Wellejus Anja
Published: May 2023

Non-alcoholic fatty liver disease (NAFLD) is a multifactorial metabolic disorder that poses health challenges worldwide and is expected to continue to rise dramatically. NAFLD is associated with metabolic syndrome, type 2 diabetes mellitus, and impaired gut health. Increased gut permeability, caused by disturbance of tight junction proteins, allows passage of damaging microbial components that, upon reaching the liver, have been proposed to trigger the release of inflammatory cytokines and generate cellular stress. A growing body of research has suggested the utilization of targeted probiotic supplements as a preventive therapy to improve gut barrier function and tight junctions. Furthermore, specific microbial interactions and metabolites induce the secretion of hormones such as GLP-1, resulting in beneficial effects on liver health. To increase the likelihood of finding beneficial probiotic strains, we set up a novel screening platform consisting of multiple in vitro and ex vivo assays for the screening of 42 bacterial strains. Analysis of transepithelial electrical resistance response via co-incubation of the 42 bacterial strains with human colonic cells (Caco-2) revealed improved barrier integrity. Then, strain-individual metabolome profiling was performed revealing species-specific clusters. GLP-1 secretion assay with intestinal secretin tumor cell line (STC-1) found at least seven of the strains tested capable of enhancing GLP-1 secretion in vitro. Gene expression profiling in human biopsy-derived intestinal organoids was performed using next generation sequencing transcriptomics post bacterial co-incubation. Here, different degrees of immunomodulation by the increase in certain cytokine and chemokine transcripts were found. Treatment of mouse primary hepatocytes with selected highly produced bacterial metabolites revealed that indole metabolites robustly inhibited de novo lipogenesis. Collectively, through our comprehensive bacterial screening pipeline, not previously ascribed strains from both Lactobacillus and Bifidobacterium genera were proposed as potential probiotics based on their ability to increase epithelial barrier integrity and immunity, promote GLP-1 secretion, and produce metabolites relevant to liver health.
Effects of a Mediterranean Diet Intervention on Maternal Stress, Well-Being, and Sleep Quality throughout Gestation—The IMPACT-BCN Trial
Authors: Casas Irene , Nakaki Ayako , Pascal Rosalia , Castro-Barquero Sara , Youssef Lina , Genero Mariona , Benitez Leticia , Larroya Marta , Boutet Maria Laura , Casu Giulia , Gomez-Gomez Alex , Pozo Oscar J. , Morilla Ivette , Martínez-Àran Anabel , Vieta Eduard , Gómez-Roig María Dolores , Casas Rosa , Estruch Ramon , Gratacos Eduard , Crispi Fàtima , Crovetto Francesca
Published: May 2023

Stress and anxiety are frequent occurrences among pregnant women. We aimed to evaluate the effects of a Mediterranean diet intervention during pregnancy on maternal stress, well-being, and sleep quality throughout gestation. In a randomized clinical trial, 1221 high-risk pregnant women were randomly allocated into three groups at 19–23 weeks’ gestation: a Mediterranean diet intervention, a Mindfulness-Based Stress Reduction program, or usual care. All women who provided self-reported life-style questionnaires to measure their anxiety (State Trait Anxiety Inventory (STAI), Perceived Stress Scale (PSS)), well-being (WHO Five Well Being Index (WHO-5)), and sleep quality (Pittsburgh sleep quality index (PSQI)) at enrollment and at the end of the intervention (34–36 weeks) were included. In a random subgroup of 106 women, the levels of cortisol and related metabolites were also measured. At the end of the intervention (34–36 weeks), participants in the Mediterranean diet group had significantly lower perceived stress and anxiety scores (PSS mean (SE) 15.9 (0.4) vs. 17.0 (0.4), p = 0.035; STAI-anxiety mean (SE) 13.6 (0.4) vs. 15.8 (0.5), p = 0.004) and better sleep quality (PSQI mean 7.0 ± 0.2 SE vs. 7.9 ± 0.2 SE, p = 0.001) compared to usual care. As compared to usual care, women in the Mediterranean diet group also had a more significant increase in their 24 h urinary cortisone/cortisol ratio during gestation (mean 1.7 ± SE 0.1 vs. 1.3 ± SE 0.1, p < 0.001). A Mediterranean diet intervention during pregnancy is associated with a significant reduction in maternal anxiety and stress, and improvements in sleep quality throughout gestation.
Impact of Dietary Fiber on Inflammation and Insulin Resistance in Older Patients: A Narrative Review
Authors: Niero Michele , Bartoli Giulio , De Colle Paolo , Scarcella Marialaura , Zanetti Michela
Published: May 2023

The beneficial impact of dietary fiber on the prevention and management of several chronic conditions associated with aging, including diabetes, neurodegenerative, cardiovascular diseases, and cancer, is well-known. High fiber intake has been associated with reduced inflammatory mediators counteracting the low-grade chronic inflammation typical of older age. In addition, dietary fiber improves postprandial glucose response and insulin resistance. In contrast, during acute diseases, its effects on insulin resistance and modulation of immune response are unclear. The aim of this narrative is to summarize the evidence for the potential impact of dietary fiber on inflammation and insulin resistance in older adults, with a particular focus on those acutely ill. Available evidence suggests that dietary fiber has the potential to counteract acute inflammation and to improve metabolic health. In addition, modulation of gut microbiota composition may contribute to improved immune function, particularly in the setting of aging-associated dysbiosis. This phenomenon has relevant implications in those acutely ill, in whom dysbiosis can be exacerbated. Our review leads to the conclusion that dietary interventions based on fiber manipulation could exploit its beneficial effects on inflammation and insulin resistance, if conducted from a precision nutrition perspective. This could also be true for the acutely ill patient, even though strong evidence is lacking.
Effect of Inhibiting Butyrylcholinesterase Activity Using Fractionated Coffee Extracts Digested In Vitro in Gastrointestinal Tract: Docking Simulation and Calorimetric and Studies
Authors: Grzelczyk Joanna , Szwajgier Dominik , Baranowska-Wójcik Ewa , Pérez-Sánchez Horacio , Carmena-Bargueño Miguel , Sosnowska Bożena , Budryn Grażyna
Published: May 2023

Butyrylcholinesterase (BChE) is a major enzyme from the alpha-glycoprotein family that catalyzes the hydrolysis of neurotransmitter acetylcholine (ACh), lowering the concentration of ACh in the nervous system, which could cause aggravation of Alzheimer’s disease (AD). In select pathological conditions, it is beneficial to reduce the activity of this enzyme. The aim of this study was to evaluate the degree of BChE inhibition by coffee extracts fractionated into mono- and diesters of caffeic acid/caffeine, digested in vitro in the gastrointestinal tract. The bioactive compounds from coffee showed high affinity for BchE, −30.23–−15.28 kJ/mol, and was the highest for the caffeine fraction from the green Arabica extract. The isolated fractions were highly effective in inhibiting BChE activity at all in vitro digestion phases. It has been shown that the fractionation of coffee extracts could be potentially used to obtain high prophylactic or even therapeutic effectiveness against AD.
Accounting Gut Microbiota as the Mediator of Beneficial Effects of Dietary (Poly)phenols on Skeletal Muscle in Aging
Authors: Ticinesi Andrea , Nouvenne Antonio , Cerundolo Nicoletta , Parise Alberto , Meschi Tiziana
Published: May 2023

Sarcopenia, the age-related loss of muscle mass and function increasing the risk of disability and adverse outcomes in older people, is substantially influenced by dietary habits. Several studies from animal models of aging and muscle wasting indicate that the intake of specific polyphenol compounds can be associated with myoprotective effects, and improvements in muscle strength and performance. Such findings have also been confirmed in a smaller number of human studies. However, in the gut lumen, dietary polyphenols undergo extensive biotransformation by gut microbiota into a wide range of bioactive compounds, which substantially contribute to bioactivity on skeletal muscle. Thus, the beneficial effects of polyphenols may consistently vary across individuals, depending on the composition and metabolic functionality of gut bacterial communities. The understanding of such variability has recently been improved. For example, resveratrol and urolithin interaction with the microbiota can produce different biological effects according to the microbiota metabotype. In older individuals, the gut microbiota is frequently characterized by dysbiosis, overrepresentation of opportunistic pathogens, and increased inter-individual variability, which may contribute to increasing the variability of biological actions of phenolic compounds at the skeletal muscle level. These interactions should be taken into great consideration for designing effective nutritional strategies to counteract sarcopenia.
Testing the Anticancer Effect of Matcha Using Zebrafish as an Animal Model
Authors: Sokary Sara , Zakaria Zain , Bawadi Hiba , Al-Asmakh Maha
Published: May 2023

Cancer is the second leading cause of death worldwide, and triple-negative breast cancer (TNBC) patients show the poorest prognosis and survival and the highest metastasis prevalence among all breast cancer subtypes. Matcha has recently been associated with multiple health benefits, and in vitro studies showed the potential effect of matcha in inhibiting cancer development and metastasis. We aimed to determine the safe, non-toxic dose of matcha suitable for zebrafish and to investigate the anticancer effect of matcha on the metastasis and growth of human TBNC cells using a zebrafish xenograft model. Wild-type AB zebrafish were used to conduct multiple general toxicity assessments, including developmental, neuromuscular, and cardiovascular toxicities. The safe, non-toxic concentration of matcha was determined to be 50 µg/mL and 100 µg/mL. Afterward, the zebrafish xenograft model was successfully established for MDA-MB-468 and MDA-MB-231 TNBC cells. The tumor size and metastasis of the injected cancer cells were traced through CM-Dil red fluorescent dye. Upon exposure to matcha at the safe doses, MDA-MB-231 and MDA-MB-468 showed a trend toward reduction in tumor size in a dose-dependent manner, indicated by quantified fluorescence. Matcha also visibly suppressed metastasis of cancer cells in the zebrafish body. Our results point to a potential dose-dependent anticancer effect of matcha on TNBC cells; however, more extended observation periods after xenotransplantation are required to confirm the long-term anticancer effect of matcha on tumor growth and metastasis.
Bacterial Pathogens Causing Pneumonia Post Hematopoietic Stem Cell Transplant: The Chronic GVHD Population
Authors: Chaaban Said , Zimmer Andrea , Bhatt Vijaya Raj , Schmidt Cynthia , Sadikot Ruxana T.
Published: May 2023

Allogeneic stem cell transplantation is a lifesaving treatment for many malignancies. Post-transplant patients may suffer from graft versus host disease in the acute and/or the chronic form(s). Post-transplantation immune deficiency due to a variety of factors is a major cause of morbidity and mortality. Furthermore, immunosuppression can lead to alterations in host factors that predisposes these patients to infections. Although patients who receive stem cell transplant are at an increased risk of opportunistic pathogens, which include fungi and viruses, bacterial infections remain the most common cause of morbidity. Here, we review bacterial pathogens that lead to pneumonias specifically in the chronic GVHD population.
Thermal Tolerance Data and Molecular Identification Are Useful for the Diagnosis, Control and Modeling of Diseases Caused by Thielaviopsis paradoxa
Authors: Azeez Abiodun Abeeb , Esiegbuya Daniel Ofeoritse , Jaber Emad , Ren Wenzi , Lateef Adebola Azeez , Ojieabu Amarachi , Asiegbu Fred O.
Published: May 2023

Several economically important diseases of forest trees and agricultural crops in many parts of the world have been linked to the ascomycete fungal pathogen Thielaviopsis paradoxa. This study compared the growth rate of 41 isolates of T. paradoxa sourced from different hosts and two countries (Nigeria and Papua New Guinea (PNG)) under six temperature levels (22 °C, 25 °C, 30 °C, 32 °C, 34 °C and 35 °C). Phylogenetic relationships were obtained from the analysis of their nuclear ribosomal DNA internal transcribed sequence (ITS) data. While all the isolates from PNG and few from Nigeria grew optimally between 22 °C and 32 °C, the majority had their highest growth rate (2.9 cm/day) between 25 °C and 32 °C. Growth performances were generally low between 34 °C and 35 °C; no isolate from the sugar cane grew at these high temperatures. The oil palm isolate DA029 was the most resilient, with the highest growth rate (0.97 cm/day) at 35 °C. Phylogenetic analysis delineated five clusters: a very large clade which accommodates the majority (30 Nigerian and 3 PNG oil palm isolates) and four small clades containing two members each. To a large extent, the clustering pattern failed to address the temperature–isolate relationship observed. However, only the four small clades represent isolates with similar temperature tolerances. It is most likely that wider and robust analyses with more diverse isolates and genetic markers will provide better insight on thermal resilience of T. paradoxa. Additionally, future research to establish relationships between vegetative growth at different temperatures and of different pathogenicity and disease epidemiology merits being explored. The results might provide useful information for the formulation of effective management and control strategies against the pathogen, especially in this era of climate change.
Plasmodium falciparum Chloroquine-pfcrt Resistant Haplotypes in Brazilian Endemic Areas Four Decades after CQ Withdrawn
Authors: de Abreu-Fernandes Rebecca , Almeida-de-Oliveira Natália Ketrin , Gama Bianca Ervatti , Gomes Larissa Rodrigues , De Lavigne Mello Aline Rosa , Queiroz Lucas Tavares de , Barros Jacqueline de Aguiar , Alecrim Maria das Graças Costa , Medeiros de Souza Rodrigo , Pratt-Riccio Lilian Rose , Brasil Patrícia , Daniel-Ribeiro Cláudio Tadeu , Ferreira-da-Cruz Maria de Fátima
Published: May 2023

(1) Background: Malaria is a public health problem worldwide. Despite global efforts to control it, antimalarial drug resistance remains a great challenge. In 2009, our team identified, for the first time in Brazil, chloroquine (CQ)-susceptible Plasmodium falciparum parasites in isolates from the Brazilian Amazon. The present study extends those observations to include survey samples from 2010 to 2018 from the Amazonas and Acre states for the purpose of tracking pfcrt molecular changes in P. falciparum parasites. (2) Objective: to investigate SNPs in the P. falciparum gene associated with chemoresistance to CQ (pfcrt). (3) Methods: Sixty-six P. falciparum samples from the Amazonas and Acre states were collected from 2010 to 2018 in patients diagnosed at the Reference Research Center for Treatment and Diagnosis of Malaria (CPD-Mal/Fiocruz), FMT-HVD and Acre Health Units. These samples were subjected to PCR and DNA Sanger sequencing to identify mutations in pfcrt (C72S, M74I, N75E, and K76T). (4) Results: Of the 66 P. falciparum samples genotyped for pfcrt, 94% carried CQ-resistant genotypes and only 4 showed a CQ pfcrt sensitive-wild type genotype, i.e., 1 from Barcelos and 3 from Manaus. (5) Conclusion: CQ-resistant P. falciparum populations are fixed, and thus, CQ cannot be reintroduced in malaria falciparum therapy.
Identification of the Hepatic Metabolites of Flumazenil and their Kinetic Application in Neuroimaging
Authors: Chen Wei-Hsi , Chiu Chuang-Hsin , Farn Shiou-Shiow , Cheng Kai-Hung , Huang Yuan-Ruei , Lee Shih-Ying , Fang Yao-Ching , Lin Yu-Hua , Chang Kang-Wei
Published: May 2023

Studies of the neurobiological causes of anxiety disorders have suggested that the γ-aminobutyric acid (GABA) system increases synaptic concentrations and enhances the affinity of GABAA (type A) receptors for benzodiazepine ligands. Flumazenil antagonizes the benzodiazepine-binding site of the GABA/benzodiazepine receptor (BZR) complex in the central nervous system (CNS). The investigation of flumazenil metabolites using liquid chromatography (LC)-tandem mass spectrometry will provide a complete understanding of the in vivo metabolism of flumazenil and accelerate radiopharmaceutical inspection and registration. The main goal of this study was to investigate the use of reversed-phase high performance liquid chromatography (PR-HPLC), coupled with electrospray ionization triple-quadrupole tandem mass spectrometry (ESI-QqQ MS), to identify flumazenil and its metabolites in the hepatic matrix. Carrier-free nucleophilic fluorination with an automatic synthesizer for [18F]flumazenil, combined with nano-positron emission tomography (NanoPET)/computed tomography (CT) imaging, was used to predict the biodistribution in normal rats. The study showed that 50% of the flumazenil was biotransformed by the rat liver homogenate in 60 min, whereas one metabolite (M1) was a methyl transesterification product of flumazenil. In the rat liver microsomal system, two metabolites were identified (M2 and M3), as their carboxylic acid and hydroxylated ethyl ester forms between 10 and 120 min, respectively. A total of 10–30 min post-injection of [18F]flumazenil showed an immediate decreased in the distribution ratio observed in the plasma. Nevertheless, a higher ratio of the complete [18F]flumazenil compound could be used for subsequent animal studies. [18F] According to in vivo nanoPET/CT imaging and ex vivo biodistribution assays, flumazenil also showed significant effects on GABAA receptor availability in the amygdala, prefrontal cortex, cortex, and hippocampus in the rat brain, indicating the formation of metabolites. We reported the completion of the biotransformation of flumazenil by the hepatic system, as well as [18F]flumazenil’s potential as an ideal ligand and PET agent for the determination of the GABAA/BZR complex for multiplex neurological syndromes at the clinical stage.
Antibody-Loaded Nanoplatforms for Colorectal Cancer Diagnosis and Treatment: An Update
Authors: Djermane Rania , Nieto Celia , Vega Milena A. , del Valle Eva M. Martín
Published: May 2023

At present, colorectal cancer (CRC) is the second deadliest type of cancer, partly because a high percentage of cases are diagnosed at advanced stages when tumors have already metastasized. Thus, there is an urgent need to develop novel diagnostic systems that allow early detection as well as new therapeutic systems that are more specific than those currently available. In this context, nanotechnology plays a very important role in the development of targeted platforms. In recent decades, many types of nanomaterials with advantageous properties have been used for nano-oncology applications and have been loaded with different types of targeted agents, capable of recognizing tumor cells or biomarkers. Indeed, among the different types of targeted agents, the most widely used are monoclonal antibodies, as the administration of many of them is already approved by the main drug regulatory agencies for the treatment of several types of cancer, including CRC. In this way, this review comprehensively discusses the main drawbacks of the conventional screening technologies and treatment for CRC, and it presents recent advances in the application of antibody-loaded nanoplatforms for CRC detection, therapy or theranostics applications.
Combination of Drug Delivery Properties of PAMAM Dendrimers and Cytotoxicity of Platinum(IV) Complexes—A More Selective Anticancer Treatment?
Authors: Lerchbammer-Kreith Yvonne , Hejl Michaela , Vician Petra , Jakupec Michael A. , Berger Walter , Galanski Mathea S. , Keppler Bernhard K.
Published: May 2023

Based on their drug delivery properties and activity against tumors, we combined PAMAM dendrimers with various platinum(IV) complexes in order to provide an improved approach of anticancer treatment. Platinum(IV) complexes were linked to terminal NH2 moieties of PAMAM dendrimers of generation 2 (G2) and 4 (G4) via amide bonds. Conjugates were characterized by 1H and 195Pt NMR spectroscopy, ICP-MS and in representative cases by pseudo-2D diffusion-ordered NMR spectroscopy. Additionally, the reduction behavior of conjugates in comparison to corresponding platinum(IV) complexes was investigated, showing a faster reduction of conjugates. Cytotoxicity was evaluated via the MTT assay in human cell lines (A549, CH1/PA-1, SW480), revealing IC50 values in the low micromolar to high picomolar range. The synergistic combination of PAMAM dendrimers and platinum(IV) complexes resulted in up to 200 times increased cytotoxic activity of conjugates in consideration of the loaded platinum(IV) units compared to their platinum(IV) counterparts. The lowest IC50 value of 780 ± 260 pM in the CH1/PA-1 cancer cell line was detected for an oxaliplatin-based G4 PAMAM dendrimer conjugate. Finally, in vivo experiments of a cisplatin-based G4 PAMAM dendrimer conjugate were performed based on the best toxicological profile. A maximum tumor growth inhibition effect of 65.6% compared to 47.6% for cisplatin was observed as well as a trend of prolonged animal survival.
Antinociceptive Action of Thymoquinone-Loaded Liposomes in an In Vivo Model of Tendinopathy
Authors: Micheli Laura , Di Cesare Mannelli Lorenzo , Mosti Elena , Ghelardini Carla , Bilia Anna Rita , Bergonzi Maria Camilla
Published: May 2023

Tendinopathies represent about 45% of musculoskeletal lesions and they are a big burden in clinics characterized by activity-related pain, focal tendon tenderness and intra-tendinous imaging changes. Many approaches have been proposed for tendinopathies’ management (e.g., nonsteroidal anti-inflammatory drugs, corticosteroids, eccentric exercises, laser therapy), unfortunately with very little support of efficacy or serious side effects, thus making the identification of new treatments fundamental. The aim of the study was to test the protective and pain reliever effect of thymoquinone (TQ)-loaded formulations in a rat model of tendinopathy induced by carrageenan intra-tendon injection (20 µL of carrageenan 0.8% on day 1). Conventional (LP-TQ) and hyaluronic acid (HA)-coated TQ liposomes (HA-LP-TQ) were characterized and subjected to in vitro release and stability studies at 4 °C. Then, TQ and liposomes were peri-tendon injected (20 µL) on days 1, 3, 5, 7 and 10 to evaluate their antinociceptive profile using mechanical noxious and non-noxious stimuli (paw pressure and von Frey tests), spontaneous pain (incapacitance test) and motor alterations (Rota rod test). Liposomes containing 2 mg/mL of TQ and covered with HA (HA-LP-TQ2) reduced the development of spontaneous nociception and hypersensitivity for a long-lasting effect more than the other formulations. The anti-hypersensitivity effect matched with the histopathological evaluation. In conclusion, the use of TQ encapsulated in HA-LP liposomes is suggested as a new treatment for tendinopathies.
Curcumin Enhances the Abscopal Effect in Mice with Colorectal Cancer by Acting as an Immunomodulator
Authors: Shih Kuang-Chung , Chan Hui-Wen , Wu Chun-Yi , Chuang Hui-Yen
Published: May 2023

Radiotherapy (RT) is an effective cancer treatment. The abscopal effect, referring to the unexpected shrinkage observed in non-irradiated tumors after radiation therapy, is thought to be mediated by systemic immune activation. However, it has low incidence and is unpredictable. Here, RT was combined with curcumin to investigate how curcumin affects RT-induced abscopal effects in mice with bilateral CT26 colorectal tumors. Indium 111-labeled DOTA-anti-OX40 mAb was synthesized to detect the activated T cell accumulations in primary and secondary tumors correlating with the changes in protein expressions and tumor growth to understand the overall effects of the combination of RT and curcumin. The combination treatment caused the most significant tumor suppression in both primary and secondary tumors, accompanied by the highest 111In-DOTA-OX40 mAb tumor accumulations. The combination treatment elevated expressions of proapoptotic proteins (Bax and cleaved caspase-3) and proinflammatory proteins (granzyme B, IL-6, and IL-1β) in both primary and secondary tumors. Based on the biodistribution of 111In-DOTA-OX40 mAb, tumor growth inhibition, and anti-tumor protein expression, our findings suggest that curcumin could act as an immune booster to augment RT-induced anti-tumor and abscopal effects effectively.
Metal-Organic Framework-Based Nanomedicines for the Treatment of Intracellular Bacterial Infections
Authors: Qi Xiaoli , Shen Ningfei , Al Othman Aya , Mezentsev Alexandre , Permyakova Anastasia , Yu Zhihao , Lepoitevin Mathilde , Serre Christian , Durymanov Mikhail
Published: May 2023

Metal-organic frameworks (MOFs) are a highly versatile class of ordered porous materials, which hold great promise for different biomedical applications, including antibacterial therapy. In light of the antibacterial effects, these nanomaterials can be attractive for several reasons. First, MOFs exhibit a high loading capacity for numerous antibacterial drugs, including antibiotics, photosensitizers, and/or photothermal molecules. The inherent micro- or meso-porosity of MOF structures enables their use as nanocarriers for simultaneous encapsulation of multiple drugs resulting in a combined therapeutic effect. In addition to being encapsulated into an MOF’s pores, antibacterial agents can sometimes be directly incorporated into an MOF skeleton as organic linkers. Next, MOFs contain coordinated metal ions in their structure. Incorporation of Fe2/3+, Cu2+, Zn2+, Co2+, and Ag+ can significantly increase the innate cytotoxicity of these materials for bacteria and cause a synergistic effect. Finally, abundance of functional groups enables modifying the external surface of MOF particles with stealth coating and ligand moieties for improved drug delivery. To date, there are a number of MOF-based nanomedicines available for the treatment of bacterial infections. This review is focused on biomedical consideration of MOF nano-formulations designed for the therapy of intracellular infections such as Staphylococcus aureus, Mycobacterium tuberculosis, and Chlamydia trachomatis. Increasing knowledge about the ability of MOF nanoparticles to accumulate in a pathogen intracellular niche in the host cells provides an excellent opportunity to use MOF-based nanomedicines for the eradication of persistent infections. Here, we discuss advantages and current limitations of MOFs, their clinical significance, and their prospects for the treatment of the mentioned infections.
Comparative Study of Selected Excipients’ Influence on Carvedilol Release from Hypromellose Matrix Tablets
Authors: Ojsteršek Tadej , Hudovornik Grega , Vrečer Franc
Published: May 2023

Solid dosage forms based on hypromellose (HPMC) with prolonged/extended drug release are very important from the research and industrial viewpoint. In the present research, the influence of selected excipients on carvedilol release performance from HPMC-based matrix tablets was studied. A comprehensive group of selected excipients was used within the same experimental setup, including different grades of excipients. Compression mixtures were directly compressed using constant compression speed and main compression force. LOESS modelling was used for a detailed comparison of carvedilol release profiles via estimating burst release, lag time, and times at which a certain % of carvedilol was released from the tablets. The overall similarity between obtained carvedilol release profiles was estimated using the bootstrapped similarity factor (f2). In the group of water-soluble carvedilol release modifying excipients, which produced relatively fast carvedilol release profiles, POLYOXᵀᴹ WSR N-80 and Polyglykol® 8000 P demonstrated the best carvedilol release control, and in the group of water-insoluble carvedilol release modifying excipients, which produced relatively slow carvedilol release profiles, AVICEL® PH-102 and AVICEL® PH-200 performed best.
Exploring the Solid-State Landscape of Carbamazepine during Dehydration: A Low Frequency Raman Spectroscopy Perspective
Authors: Remoto Peter III J. G. , Bērziņš Kārlis , Fraser-Miller Sara J. , Korter Timothy M. , Rades Thomas , Rantanen Jukka , Gordon Keith C.
Published: May 2023

The solid-state landscape of carbamazepine during its dehydration was explored using Raman spectroscopy in the low- (−300 to −15, 15 to 300) and mid- (300 to 1800 cm−1) frequency spectral regions. Carbamazepine dihydrate and forms I, III, and IV were also characterized using density functional theory with periodic boundary conditions and showed good agreement with experimental Raman spectra with mean average deviations less than 10 cm−1. The dehydration of carbamazepine dihydrate was examined under different temperatures (40, 45, 50, 55, and 60 °C). Principal component analysis and multivariate curve resolution were used to explore the transformation pathways of different solid-state forms during the dehydration of carbamazepine dihydrate. The low-frequency Raman domain was able to detect the rapid growth and subsequent decline of carbamazepine form IV, which was not as effectively observed by mid-frequency Raman spectroscopy. These results showcased the potential benefits of low-frequency Raman spectroscopy for pharmaceutical process monitoring and control.
Lung Inflammation Resolution by RvD1 and RvD2 in a Receptor-Dependent Manner
Authors: Gao Jin , Su Yujie , Wang Zhenjia
Published: May 2023

Inflammation resolution is an active process via specialized pro-resolving mediators (SPMs) to fight invading microbes and repair tissue injury. RvD1 and RvD2 are SPMs produced from DHA during inflammation responses and show a benefit in treating inflammation disorders, but it is not completely understood how they act on vasculature and immune cells in the lung to promote inflammation resolution programs. Here, we studied how RvD1 and RvD2 regulated the interactions between endothelial cells and neutrophils in vitro and in vivo. In an acute lung inflammation (ALI) mouse model, we found that RvD1 and RvD2 resolved lung inflammation via their receptors (ALX/GPR32 or GPR18) and enhanced the macrophage phagocytosis of apoptotic neutrophils, which may be the molecular mechanism of lung inflammation resolution. Interestingly, we observed the higher potency of RvD1 over RvD2, which may be associated with unique downstream signaling pathways. Together, our studies suggest that the targeted delivery of these SPMs into inflammatory sites may be novel strategies with which to treat a wide range of inflammatory diseases.
Novel Perspectives on the Design and Development of a Long-Acting Subcutaneous Raltegravir Injection for Treatment of HIV—In Vitro and In Vivo Evaluation
Authors: Abd-Ellah Heba S. , Mudududdla Ramesh , Carter Glen P. , Baell Jonathan B.
Published: May 2023

Antiretrovirals (ARVs) are a highly effective therapy for treatment and prevention of HIV infection, when administered as prescribed. However, adherence to lifelong ARV regimens poses a considerable challenge and places HIV patients at risk. Long-acting ARV injections may improve patient adherence as well as maintaining long-term continuous drug exposure, resulting in improved pharmacodynamics. In the present work, we explored the aminoalkoxycarbonyloxymethyl (amino-AOCOM) ether prodrug concept as a potential approach to long-acting ARV injections. As a proof of concept, we synthesised model compounds containing the 4-carboxy-2-methyl Tokyo Green (CTG) fluorophore and assessed their stability under pH and temperature conditions that mimic those found in the subcutaneous (SC) tissue. Among them, probe 21 displayed very slow fluorophore release under SC-like conditions (98% of the fluorophore released over 15 d). Compound 25, a prodrug of the ARV agent raltegravir (RAL), was subsequently prepared and evaluated using the same conditions. This compound showed an excellent in vitro release profile, with a half-life (t½) of 19.3 d and 82% of RAL released over 45 d. In mice, 25 extended the half-life of unmodified RAL by 4.2-fold (t½ = 3.18 h), providing initial proof of concept of the ability of amino-AOCOM prodrugs to extend drug lifetimes in vivo. Although this effect was not as pronounced as seen in vitro—presumably due to enzymatic degradation and rapid clearance of the prodrug in vivo—the present results nevertheless pave the way for development of more metabolically stable prodrugs, to facilitate long-acting delivery of ARVs.
Potential Barriers to the Implementation of Computer-Based Simulation in Pharmacy Education: A Systematic Review
Authors: Gharib Ahmed M. , Peterson Gregory M. , Bindoff Ivan K. , Salahudeen Mohammed S.
Published: May 2023

Computer-based simulation (CBS) is an interactive pedagogical training method that has seen increased interest, especially in recent years. There is some evidence that CBS in pharmacy education is not as widely adopted compared to other healthcare disciplines. Pharmacy education literature to date has not specifically discussed the potential barriers which may cause this uptake challenge. In this systematic narrative review, we attempted to explore and discuss potential barriers that may impact the integration of CBS in pharmacy practice education and provide our suggestions to overcome them. We searched five major databases and used the AACODS checklist for grey literature assessment. We identified 42 studies and four grey literature reports, published between 1 January 2000 and 31 August 2022, which met the inclusion criteria. Then, the specific approach of Braun and Clarke for thematic analysis was followed. The majority of the included articles were from Europe, North America, and Australasia. Although none of the included articles had a specific focus on barriers to implementation, thematic analysis was used to extract and discuss several potential barriers, such as resistance to change, cost, time, usability of software, meeting accreditation standards, motivating and engaging students, faculty experience, and curriculum constraints. Ad- dressing academic, process, and cultural barriers can be considered the first step in providing guidance for future implementation research for CBS in pharmacy education. The analysis suggests that to effectively overcome any possible barriers to implementing CBS, different stakeholders must engage in careful planning, collaboration, and investment in resources and training. The review indicates that additional research is required to offer evidence-based approach and strategies to prevent overwhelming or disengaging users from either learning or teaching process. It also guides further research into exploring potential barriers in different institutional cultures and regions.
Long-Wave Infrared Polarization-Based Airborne Marine Oil Spill Detection and Identification Technology
Authors: Sun Hongyu , Ma Lianji , Fu Qiang , Li Yingchao , Shi Haodong , Liu Zhuang , Liu Jianan , Wang Jiayu , Jiang Huilin
Published: May 2023

In this paper, infrared polarization detection information acquisition technology is proposed, and the polarization characteristics of oil spills are modeled and studied. A set of long-wave infrared polarization detection equipment for oil spills is designed and built, and modeling research on oil spill polarization characteristics is carried out to accurately detect and identify oil spill types and for the faster processing of oil spill events. Oil spill accuracy is increased by defining the polarization maintenance method of the polarization optical system and reducing the polarization measurement error brought on by the imaging system. As a result, a higher than 3% contrast exists between the polarization degree image and the corrected infrared intensity image. Outdoor tests using oil, palm oil, crude oil, gasoline, and diesel oil spill types are carried out in a controlled environment to collect data on the polarization of various oil species. According to the findings, each oil species’ infrared polarization contrast with seawater is typically greater than its infrared intensity contrast. However, the polarization data of saltwater, diesel, and palm oil, which are difficult to identify in intensity data, show a noticeable difference, further proving the viability of utilizing polarization to discern oil spills.
Subwavelength-Scale 3D Broadband Unidirectional Waveguides Based on Surface Magnetoplasmons at Terahertz Frequencies
Authors: Bao Han , You Yun , Shen Linfang , Shen Qian
Published: May 2023

Unidirectional electromagnetic modes have significant potential for routing electromagnetic radiation and are highly desirable for various applications, such as isolators, splitters, and switches. In this study, we theoretically investigate surface magnetoplasmons (SMPs) in a four-layer structure consisting of a perfect magnetic conductor (PMC)–semiconductor–dielectric–metal, which exhibits complete unidirectional propagation. We extend this structure to a 3D model by decreasing the width of the PMC-semiconductor part to an appropriate value and demonstrate that the SMPs in the proposed 3D waveguide retain complete unidirectional propagation. Our findings indicate that the unidirectional SMPs are robust to backscattering caused by surface roughness and defects. Moreover, the proposed 3D waveguide can be efficiently coupled to conventional microstrip line waveguides. Our results (based on the numerical method) demonstrate that SMPs based on semiconductors offer a promising approach to creating devices with new functionalities in the terahertz regime below the diffraction limit.