bluuebunny/crossref_metadata_2025 huggingface dataset:
A549 Cell-Covered Electrodes as a Sensing Element for Detection of Effects of Zn2+ Ions in a Solution
Authors: Eghbal Mina , Rozman Martin , Kononenko Veno , Hočevar Matej , Drobne Damjana
Published: October 2022

Electrochemical-based biosensors have the potential to be a fast, label-free, simple approach to detecting the effects of cytotoxic substances in liquid media. In the work presented here, a cell-based electrochemical biosensor was developed and evaluated to detect the cytotoxic effects of Zn2+ ions in a solution as a reference test chemical. A549 cells were attached to the surface of stainless-steel electrodes. After treatment with ZnCl2, the morphological changes of the cells and, ultimately, their death and detachment from the electrode surface as cytotoxic effects were detected through changes in the electrical signal. Electrochemical cell-based impedance spectroscopy (ECIS) measurements were conducted with cytotoxicity tests and microscopic observation to investigate the behavior of the A549 cells. As expected, the Zn2+ ions caused changes in cell confluency and spreading, which were checked by light microscopy, while the cell morphology and attachment pattern were explored by scanning electron microscopy (SEM). The ECIS measurements confirmed the ability of the biosensor to detect the effects of Zn2+ ions on A549 cells attached to the low-cost stainless-steel surfaces and its potential for use as an inexpensive detector for a broad range of chemicals and nanomaterials in their cytotoxic concentrations.
Plasma-Assisted Nanofabrication: The Potential and Challenges in Atomic Layer Deposition and Etching
Authors: Chiappim William , Neto Benedito Botan , Shiotani Michaela , Karnopp Júlia , Gonçalves Luan , Chaves João Pedro , Sobrinho Argemiro da Silva , Leitão Joaquim Pratas , Fraga Mariana , Pessoa Rodrigo
Published: October 2022

The growing need for increasingly miniaturized devices has placed high importance and demands on nanofabrication technologies with high-quality, low temperatures, and low-cost techniques. In the past few years, the development and recent advances in atomic layer deposition (ALD) processes boosted interest in their use in advanced electronic and nano/microelectromechanical systems (NEMS/MEMS) device manufacturing. In this context, non-thermal plasma (NTP) technology has been highlighted because it allowed the ALD technique to expand its process window and the fabrication of several nanomaterials at reduced temperatures, allowing thermosensitive substrates to be covered with good formability and uniformity. In this review article, we comprehensively describe how the NTP changed the ALD universe and expanded it in device fabrication for different applications. We also present an overview of the efforts and developed strategies to gather the NTP and ALD technologies with the consecutive formation of plasma-assisted ALD (PA-ALD) technique, which has been successfully applied in nanofabrication and surface modification. The advantages and limitations currently faced by this technique are presented and discussed. We conclude this review by showing the atomic layer etching (ALE) technique, another development of NTP and ALD junction that has gained more and more attention by allowing significant advancements in plasma-assisted nanofabrication.
Size-Dependent Buckling and Post-Buckling Analysis of the Functionally Graded Thin Plate Al–Cu Material Based on a Modified Couple Stress Theory
Authors: Tang Feixiang , Dong Fang , Guo Yuzheng , Shi Shaonan , Jiang Jize , Liu Sheng
Published: October 2022

Size-dependent functionally graded material thin plate buckling and post-buckling problems are considered using the framework of the MCST (Modified Couple Stress Theory). Based on modified couple stress theory and power law, the post-buckling deflection and critical buckling load of simply supported functionally graded material thin plate are derived using Hamilton’s minimum potential energy principle. The analysis compares the simulation results of linear buckling and nonlinear buckling. Innovatively, a power-law distribution with scale effects is considered. The influences of scale effect parameters l and power-law index parameters k on buckling displacement, load, and strain energy of plates have been investigated. In this article, it is found that the critical buckling displacement, critical buckling load, and buckling strain energy increase with increases in the power-law index parameters k. The membrane energy decreases as the power-law index parameter increases. If the upper and lower layers are swapped, the opposite result is obtained. In comparison, the scale effect parameter is more influential than the power-law exponent. The critical buckling displacement in the x-direction is not affected by scale effects. The critical buckling load, the membrane energy, and buckling strain energy increase as the scale effect parameter increases. Scale effects increase material stiffness compared with traditional theory, and the power-law index parameters affect FGM properties such as elastic modulus, Poisson’s ratio, density, etc. Both scale effects parameters and power-law index parameters have important effects on the mechanical behavior of materials.
Polystyrene Nanoplastics Induce Lung Injury via Activating Oxidative Stress: Molecular Insights from Bioinformatics Analysis
Authors: Zhang Tianyi , Yang Sheng , Ge Yiling , Wan Xin , Zhu Yuxin , Li Jie , Yin Lihong , Pu Yuepu , Liang Geyu
Published: October 2022

(1) Background: Increasing evidence reveals that airborne plastic particles will continue to degrade into nanoplastics which are then inhaled by humans, causing injury to the respiratory system with controversial molecular mechanisms. (2) Methods: We used polystyrene nanoplastics (PS-NPs) as the representative pollutants to explore the inhalation toxicology of nanoplastics and identified the potential mechanism through high-throughput sequencing. (3) Results: PS-NPs inhibited cell viability in a dose-dependent manner and 0 μg/cm2, 7.5 μg/cm2 and 30 μg/cm2 PS-NP-treated groups were selected for RNA-seq. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis suggested that lung injuries caused by PS-NPs were mediated via redox imbalance, which was verified by reactive oxygen species (ROS) staining. Additionally, we obtained ten key transcription factors (TFs) governing differentially expressed genes (DEGs), nine of which were involved in the regulation of oxidative stress. An oxidative stress-associated TF-mRNA regulatory network was constructed on account of the findings above. Further joint analysis with animal experiment data from the GEO database identified a crucial oxidative stress-related molecule, TNFRSF12A. qRT-PCR was performed to confirm the results of RNA-seq. (4) Conclusions: Our study indicates the potential role of oxidative stress in the mechanism of nanoplastics-induced lung injuries, with several key genes being promising targets to analyze in future investigations.
In Vivo Evaluation of DMSA-Coated Magnetic Nanoparticle Toxicity and Biodistribution in Rats: A Long-Term Follow-Up
Authors: Paulini Fernanda , Marangon Aline R. M. , Azevedo Carolina L. , Brito Juliana L. M. , Lemos Marcelle S. , Sousa Marcelo H. , Veiga-Souza Fabiane H. , Souza Paulo E. N. , Lucci Carolina M. , Azevedo Ricardo B.
Published: October 2022

This work presents a long-term follow-up (300 days) of rats after a single intravenous injection of DMSA-coated magnetite nanoparticles (DMSA-MNP). The animals were systematically evaluated by hematological, biochemical, and ultrasound examinations, monitoring the same animal over time. In addition, oxidative stress evaluation, DMSA-MNP biodistribution, computerized tomography for ex vivo organs, and histopathology analysis were performed at the end of the experiment period. Overall, DMSA-MNP administration did not cause serious damage to the rats’ health over the course of 300 days post-administration. All animals presented hematological parameters within the normal limits, and no alterations on serum creatinine, urea, ALT, and AST were related to DMSA-MNP administration. Liver and spleen showed no important alterations in any of the examinations. The kidneys of treated animals displayed intermittent pelvis dilation at ultrasound analysis, but without damage to the organ parenchyma after 300 days. The lungs of treated animals presented a light interalveolar septal thickening, but the animals did not present any clinical respiratory symptom. Nanoparticles were not detected in the vital organs of treated animals 300 days after administration. This work represents the first assessment of the long-term effects of DMSA-MNP and goes a step further on the safety of its use for biomedical applications.
Effect of Covalent Organic Frameworks Containing Different Groups on Properties of Sulfonated Poly(ether ether ketone) Matrix Proton Exchange Membranes
Authors: Meng Xiaoyu , Lv Yinan , Ding Lei , Peng Luman , Peng Qiwang , Cong Chuanbo , Ye Haimu , Zhou Qiong
Published: October 2022

The rich −SO3H groups enable sulfonated poly (ether ether ketone) (SPEEK) to possess excellent proton conductivities in proton exchange membrane (PEM), but cause excessive water absorption, resulting in the decline of dimensional stability. It is a challenge to resolve the conflict between conductivity and stability. Owing to its unique structural designability, covalent organic frameworks (COFs) have been used to regulate the performances of PEMs. The authors propose the use of COFs with acidic and basic groups for meeting the requirements of proton conductivity and dimensional stability. Herein, COFs containing different groups (sulfoacid, pyridine, and both) were uniformly dispersed into the SPEEK matrix by in situ synthesis, and the effects on the properties of SPEEK matrix PEMs were revealed. The sulfoacid group significantly improves proton conductivities. At 60 °C, under 95% RH, the conductivity of the SPEEK/TpPa−SO3H-20 composite membrane was 443.6 mS·cm−1, which was 3.3 times that of the pristine SPEEK membrane. The pyridine group reduced the swelling ratio at 50 °C from 220.7% to 2.4%, indicating an enhancement in dimensional stability. Combining the benefits of sulfoacid and pyridine groups, SPEEK/TpPa−(SO3H-Py) composite membrane has a conductivity of 360.3 mS·cm−1 at 60 °C and 95% RH, which is 1.86 times that of SPEEK, and its swelling ratio is 11.8%, about 1/20 of that of SPEEK membrane. The method of in situ combination and regulation of groups open up a way for the development of SPEEK/COFs composite PEMs.
Layered Double Hydroxides for Photo(electro)catalytic Applications: A Mini Review
Authors: Li Cheng , Jing Huihua , Wu Zhong , Jiang Denghui
Published: October 2022

Chemical energy conversion strategies by photocatalysis and electrocatalysis are promising approaches to alleviating our energy shortages and environmental issues. Due to the 2D layer structure, adjustable composition, unique thermal decomposition and memory properties, abundant surface hydroxyl, and low cost, layered double hydroxides (LDHs) have attracted extensive attention in electrocatalysis, photocatalysis, and photoelectrocatalysis. This review summarizes the main structural characteristics of LDHs, including tunable composition, thermal decomposition and memory properties, delaminated layer, and surface hydroxyl. Next, the influences of the structural characteristics on the photo(electro)catalytic process are briefly introduced to understand the structure–performance correlations of LDHs materials. Recent progress and advances of LDHs in photocatalysis and photoelectrocatalysis applications are summarized. Finally, the challenges and future development of LDHs are prospected from the aspect of structural design and exploring structure-activity relationships in the photo(electro)catalysis applications.
Reduced Consumption of Sugar-Sweetened Beverages Is Associated with Lower Body Mass Index Z-Score Gain among Chinese Schoolchildren
Authors: Wang Chenchen , Chen Yijia , Hong Xin , Xu Hao , Zhou Hairong , Wang Weiwei , Zhou Nan , Zhao Jinkou
Published: October 2022

To examine whether reducing sugar-sweetened beverage (SSB) consumption is associated with reduced body mass index z-score gain among Chinese schoolchildren in Nanjing, China, a randomized controlled trial (RCT) was conducted in four selected primary schools from September 2019 to September 2020. Students in the third grade in the Intervention Group received school-based and home-based interventions for two consecutive semesters to reduce SSB consumption, while two schools in the Control Group did not receive any interventions. Weight changes were expressed as body mass index (BMI) z-scores as standard deviations of the BMI distribution per age and sex group. Changes in SSB consumption before and after the interventions were categorized into Level-Up if it increased, Level-Same if it was maintained and Level-Down if it decreased. Multivariable linear regression models were used to explore the association of different levels of changes in SSB consumption pre- and post-intervention with the BMI z-score. Among 1633 participants who completed the trial, the mean age at baseline was 9.36 years (±0.48 SD).The median baseline BMI z-score was −0.24 (25th percentile −0.72; 75th percentile 0.58). After the intervention, the median BMI z-score increased by 0.06 (−0.17~0.37) in the Intervention Group and by 0.14 (−0.08~0.41) in the Control Group (p < 0.001). A higher increase in BMI was found in the Control Group than in the Intervention Group (1.20 vs. 0.94) during the 12-month period. Among participants whose parents’ educational attainment was above 9 years, the median BMI z-score increased by 0.07 (−0.17~0.37) in the Intervention Group and by 0.16 (−0.06~0.41) in the Control Group (p < 0.001). In a linear regression analysis adjusted for potential confounders, the BMI z-score decreased by 0.057 more in Level-Down than in Level-Up (95% CI: −0.103 to −0.012, p = 0.014). These results indicate that the decreased consumption of SSBs might have reduced the prevalence of overweight in schoolchildren in China, especially in students whose parents had high educational levels.
Two Gold Kiwifruit Daily for Effective Treatment of Constipation in Adults—A Randomized Clinical Trial
Authors: Bayer Simone B. , Heenan Phoebe , Frampton Chris , Wall Catherine L. , Drummond Lynley N. , Roy Nicole C. , Gearry Richard B.
Published: October 2022

Chronic constipation is highly prevalent worldwide and may be managed with two green or three gold kiwifruit daily. It is unknown whether a smaller standard serve of gold kiwifruit (two daily) is as effective in constipation management. The study aimed to improve chronic constipation with two gold kiwifruit and psyllium in lieu of a placebo daily over four weeks. Adult participants (18–65 years) with functional constipation (FC, n = 11), constipation-predominant irritable bowel syndrome (IBS-C, n = 13), and healthy controls (n = 32) were block-randomized to the treatment order: gold kiwifruit (2/day) or psyllium (fiber-matched, 7.5 g/day) for four weeks, followed by four weeks washout before crossover. Outcomes included alterations of Gastrointestinal Symptom Rating Scale (GSRS) domains and weekly complete spontaneous bowel movements (CSBM) as part of a larger study. Both interventions reduced GSRS constipation domain scores in all subjects compared to baseline values (p = 0.004). All participants reported significantly more weekly CSBM (p = 0.014). Two gold kiwifruit decreased straining (p = 0.021). Two gold kiwifruit daily are as effective as fiber-matched psyllium in treating constipation in adults and should be considered as a treatment option.
Royal Jelly: Beneficial Properties and Synergistic Effects with Chemotherapeutic Drugs with Particular Emphasis in Anticancer Strategies
Authors: Salama Suzy , Shou Qiyang , Abd El-Wahed Aida A. , Elias Nizar , Xiao Jianbo , Swillam Ahmed , Umair Muhammad , Guo Zhiming , Daglia Maria , Wang Kai , Khalifa Shaden A. M. , El-Seedi Hesham R.
Published: October 2022

Cancer is one of the major causes of death globally. Currently, various methods are used to treat cancer, including radiotherapy, surgery, and chemotherapy, all of which have serious adverse effects. A healthy lifestyle, especially a nutritional diet, plays a critical role in the treatment and prevention of many disorders, including cancer. The above notion, plus the trend in going back to nature, encourages consumers and the food industry to invest more in food products and to find potential candidates that can maintain human health. One of these agents, and a very notable food agent, is royal jelly (RJ), known to be produced by the hypopharyngeal and mandibular salivary glands of young nurse honeybees. RJ contains bioactive substances, such as carbohydrates, protein, lipids, peptides, mineral salts and polyphenols which contribute to the appreciated biological and pharmacological activities. Antioxidant, anticancer, anti-inflammatory, antidiabetic, and antibacterial impacts are among the well-recognized benefits. The combination of RJ or its constituents with anticancer drugs has synergistic effects on cancer disorders, enhancing the drug’s effectiveness or reducing its side effects. The purpose of the present review is to emphasize the possible interactions between chemotherapy and RJ, or its components, in treating cancer illnesses.
Ethanol Extract of Licorice Alleviates HFD-Induced Liver Fat Accumulation in Association with Modulation of Gut Microbiota and Intestinal Metabolites in Obesity Mice
Authors: Liu Fei , Tang Xin , Mao Bingyong , Zhang Qiuxiang , Zhao Jianxin , Cui Shumao , Chen Wei
Published: October 2022

As a traditional Chinese medicine, licorice is often used in functional foods for its health benefits. However, the role of gut microbiota in the efficacy of licorice has not yet been fully elucidated. We hypothesized that the involvement of intestinal flora may be a key link in licorice ethanol extract (LEE)-induced health benefits. The aim of this study was to investigate whether LEE improves hepatic lipid accumulation in obese mice fed a high-fat diet (HFD) and whether the gut microbiota plays a key role in LEE treatment. Male C57BL/6J mice were fed HFD for liver fat accumulation and then treated with LEE. The same experiments were later performed using pseudo-sterile mice to verify the importance of gut flora. Supplementation with LEE improved the obesity profile, lipid profile and liver fat accumulation in HFD mice. In addition, LEE treatment improved intestinal flora dysbiosis caused by HFD in mice, as evidenced by a decrease in the percentage of Firmicutes/Bacteroidetes and an increase in the abundance of known anti-obesity-related bacteria. However, LEE failed to exhibit a therapeutic effect in pseudo-sterile mice. The results of the cellular assay showed that glycyrrhetic acid (GA), the main conversion product of glycyrrhizin (GL), was more effective in reducing fat accumulation and intracellular TG content in hepatocytes compared to GL. In conclusion, our data suggest that LEE attenuates obesity and hepatic fat accumulation in HFD mice, which may be associated with modulating the composition of gut microbiota and the conversion of LLE by the intestinal flora.
A Novel Approach to Managing a COVID-19 Outbreak at a Farm in Outer Regional Victoria, Australia
Authors: Kabwe Mwila , Dittmer Jennifer L. , Oxford Jaimee , Eyres Catina , Thomas Ancara , Mahony Andrew , Bolam Bruce
Published: October 2022

The coronavirus disease (COVID-19) has been established as a major occupational health and safety issue that compounds pre-existing socioeconomic inequalities such as access to basic health services. This is exacerbated in migrant farmworkers who are an essential workforce in maintaining food supply across the country. An outbreak occurred in a remote part of Victoria with limited access to healthcare resources. Existing relationships allowed the Loddon Mallee Public Health Unit to quickly engage farm management and local pathology services and provide cultural and language support. After contact-tracing and comprehensive clinical review, rather than isolate positive cases, those who were asymptomatic and willing to work continued to do so whilst negative workers were in quarantine. Outbreak management and public health actions were quickly implemented even when the nationwide state-testing and contact-tracing systems were experiencing significant strain due to the rapid escalation in case numbers. Despite a large outbreak (68/74 workers), the management of the outbreak allowed asymptomatic cases to perform their work so farm productivity remained uninterrupted. Cases’ health status was closely monitored, with no adverse outcomes in a high-risk population. COVID-19 negative workers safely quarantined away from positive cases until the closure of the outbreak.
Evaluation of the Multiple Tissue Factors in the Cartilage of Primary and Secondary Rhinoplasty in Cleft Lip and Palate Patients
Authors: Buile Dace , Pilmane Mara , Akota Ilze
Published: October 2022

Cleft lip and palate (CLP) is one of the craniofacial defects. The objective of this study was to identify the differences in appearance between the tissue factors in cartilage of CLP patients after primary and secondary rhinoplasty. Immunohistochemistry was performed with MMP-2, MMP-8, MMP-9, TIMP-2, IL-1α, IL-10, bFGF, and TGFβ1. The quantification of the structures was performed using a semi-quantitative census method. MMP-2, -9, IL-1a, and bFGF demonstrated higher number of positive cells in patients, while the number of MMP-8, IL-1a, -10 and TGFβ1 cells was higher or equal in the control subjects. The only statistically significant difference between CLP-operated patients was found in the TIMP-2 group, where the primary CLP patient group had a higher number of TIMP-2 positive chondrocytes than the secondary CLP patient group (U = 53.5; p = 0.021). The median value of the primary CLP group was ++ number of TIMP-2 positive chondrocytes compared to +++ in the secondary CLP group. No statistically significant difference was found between primary and secondary rhinoplasty patients for other tissue factors. Commonly, the rich expression of different tissue factors suggests a stimulation of higher elasticity in cleft affected cartilage. The statistically significant TIMP-2 elevation in primary operated cartilage indicates an impact of the selective tissue remodeling for hard tissue.
A Review of the Biological Activity of Amidrazone Derivatives
Authors: Paprocka Renata , Wiese-Szadkowska Małgorzata , Kosmalski Tomasz , Frisch Daria , Ratajczak Magdalena , Modzelewska-Banachiewicz Bożena , Studzińska Renata
Published: October 2022

Amidrazones are widely used in chemical synthesis, industry and agriculture. We compiled some of the most important findings on the biological activities of amidrazones described in the years 2010–2022. The data were obtained using the ScienceDirect, Reaxys and Google Scholar search engines with keywords (amidrazone, carbohydrazonamide, carboximidohydrazide, aminoguanidine) and structure strategies. Compounds with significant biological activities were included in the review. The described structures derived from amidrazones include: amidrazone derivatives; aminoguanidine derivatives; complexes obtained using amidrazones as ligands; and some cyclic compounds obtained from amidrazones and/or containing an amidrazone moiety in their structures. This review includes chapters based on compound activities, including: tuberculostatic, antibacterial, antifungal, antiparasitic, antiviral, anti-inflammatory, cytoprotective, and antitumor compounds, as well as furin and acetylocholinesterase inhibitors. Detailed information on the compounds tested in vivo, along the mechanisms of action and toxicity of the selected amidrazone derivatives, are described. We describe examples of compounds that have a chance of becoming drugs due to promising preclinical or clinical research, as well as old drugs with new therapeutic targets (repositioning) which have the potential to be used in the treatment of other diseases. The described examples prove that amidrazone derivatives are a potential source of new therapeutic substances and deserve further research.
Stability of Inhaled Ciprofloxacin-Loaded Poly(2-ethyl-2-oxazoline) Nanoparticle Dry Powder Inhaler Formulation in High Stressed Conditions
Authors: Sabuj Mohammad Zaidur Rahman , Rashid Md Abdur , Dargaville Tim R. , Islam Nazrul
Published: October 2022

In this study, the stability of ciprofloxacin (CIP)-loaded poly(2-ethyl-2-oxazoline) (PEtOx) nanoparticles (NPs) was investigated at normal and high stressed conditions. The blank NPs were used to understand the intrinsic physicochemical properties of the polymer NPs under these storage conditions. The formulated NPs were prepared by a coassembly reaction and dried by lyophilization. The powder NPs were stored at controlled room temperature (25 °C) with normal relative humidity (RH) (43%) and high temperature (40 °C) and RH (75%). The stored samples were analyzed by determining the particle sizes, morphology, solid-state properties, thermal behavior, drug-polymer interactions, and aerosol performances over six months. The chemical stability of the formulations was determined by X-ray diffraction, attenuated total refection-Fourier transform infrared (ATR-FTIR), and high-performance liquid chromatography (HPLC) over six months under both conditions. The particle size of the blank PEtOx NPs significantly (p < 0.05) increased from 195.4 nm to 202.7 nm after 3 months at 40 °C/75% RH due to the moisture absorption from high RH; however, no significant increase was observed afterward. On the other hand, the sizes of CIP-loaded PEtOx NPs significantly (p < 0.05) reduced from 200.2 nm to 126.3 nm after 6 months at 40 °C/75% RH. In addition, the scanning electron microscopy (SEM) images revealed that the surfaces of CIP-loaded PEtOx NPs become smoother after 3 months of storage due to the decay of surface drugs compared to the freshly prepared NPs. However, transmission electron microscopy (TEM) images could not provide much information on drug decay from the nanoparticle’s surfaces. The fine particle fraction (FPF) of CIP-loaded PEtOx NPs dropped significantly (p < 0.05) after three months at 25 °C/43% RH and 40 °C/75% RH conditions. The reduced FPF of CIP-loaded PEtOx NPs occurred due to the drug decay from the polymeric surface and blank PEtOx NPs due to the aggregations of the NPs at high temperatures and RH. Although the aerosolization properties of the prepared CIP-loaded PEtOx NPs were reduced, all formulations were chemically stable in the experimental conditions.
Factors Associated with Aspirin Resistance in Hong Kong Chinese Patients with Stable Coronary Heart Disease Using the Multiplate® Analyzer and Serum Thromboxane B2
Authors: Zeng Weiwei , Chu Tanya T. W. , Chow Elaine Y. K. , Hu Miao , Fok Benny S. P. , Chan Juliana C. N. , Yan Bryan P. Y. , Tomlinson Brian
Published: October 2022

Introduction: Aspirin resistance may be associated with various conditions. We measured serum thromboxane B2 (TXB2) and platelet function using the Multiplate® Analyzer with arachidonic acid (ASPI) in patients on long term aspirin therapy to identify aspirin resistance and associated factors. Materials and Methods: Chinese patients with stable coronary heart disease had samples for serum TXB2 and ASPI measurement taken before and 1 h after taking a morning dose of 80 mg aspirin. Results: In 266 patients with mean age 66.6 ± 10.7 years, 17% were female and 55% were current or previous smokers. TXB2 and ASPI measurements were significantly higher before the dose than at 1 h post dose, with 46% of subjects having high ASPI values (AUC > 300 AU*min) pre dose compared with 27% at 1 h post dose. TXB2 and ASPI measures of platelet aggregation showed weak correlations, which were only significant before the dose (r = 0.219, p = 0.001). Increased ASPI measurements were associated with white blood cell (WBC) count, haematocrit, platelet count and heart rate at 24 h post dose but only with WBC count, smoking history and heart rate at 1 h post dose. Diabetes was not associated with reduced platelet response to aspirin. The WBC count associated with aspirin resistance was over 6.55 × 109/L by receiver operating characteristic analysis. Conclusions: The antiplatelet response to aspirin was reduced in a large proportion of patients. Patients with higher WBC count within the normal range appear to be at increased risk of aspirin resistance. Higher or more frequent doses of aspirin may be needed in many patients.
Drug–Drug Interaction Study to Evaluate the Pharmacokinetics, Safety, and Tolerability of Ipatasertib in Combination with Darolutamide in Patients with Advanced Prostate Cancer
Authors: Sutaria Dhruvitkumar S. , Rasuo Grozdana , Harris Adam , Johnson Ryan , Miles Dale , Gallo Jorge Daniel , Sane Rucha
Published: October 2022

Ipatasertib is a selective, small molecule Akt inhibitor that is currently being developed for the treatment of metastatic castration-resistant prostate cancer. Darolutamide is an androgen receptor (AR) inhibitor that is approved for the treatment of non-metastatic castration-resistant prostate cancer. Ipatasertib is metabolized by CYP3A4 to form a less active metabolite M1 (G-037720). Ipatasertib is also a weak time-dependent CYP3A4 inhibitor. Darolutamide is a mild CYP3A4 inducer and is metabolized into an active keto-darolutamide metabolite via CYP3A4. In this Phase 1b open-label, single sequence crossover study, ipatasertib pharmacokinetics safety and tolerability were evaluated in combination with darolutamide in metastatic castration-resistant prostate cancer (n = 15 patients). Specifically, the effect of 600 mg BID of darolutamide on 400 mg QD ipatasertib was evaluated in this study. Based on pharmacokinetic analysis, a mild reduction in ipatasertib AUC0–24 h,ss and Cmax,ss exposures was observed (~8% and ~21%, respectively) when administered in combination with darolutamide, which is considered not clinically meaningful. M1 exposures were similar with and without darolutamide administration. Darolutamide and keto-darolutamide exposures in combination with ipatasertib were similar to previously reported exposures for single agent darolutamide. Overall, the combination appears to be well-tolerated in the metastatic castration-resistant prostate cancer indication with very few AEs.
Dermal Delivery of Diclofenac Sodium—In Vitro and In Vivo Studies
Authors: Iliopoulos Fotis , Goh Choon Fu , Haque Tasnuva , Rahma Annisa , Lane Majella E.
Published: October 2022

Previously, we reported the use of confocal Raman spectroscopy (CRS) as a novel non-invasive approach to determine drug disposition in the skin in vivo. Results obtained by CRS were found to correlate with data from the well-established in vitro permeation test (IVPT) model using human epidermis. However, these studies used simple vehicles comprising single solvents and binary or ternary solvent mixtures; to date, the utility of CRS for monitoring dermal absorption following application of complex marketed formulations has not been examined. In the present work, skin delivery of diclofenac sodium (DFNa) from two topical dermatological drug products, namely Diclac® Lipogel 10 mg/g and Primofenac® Emulsion gel 1%, was determined by IVPT and in vivo by both CRS and tape stripping (TS) methodologies under similar experimental conditions. The in vivo data were evaluated against the in vitro findings, and a direct comparison between CRS and TS was performed. Results from all methodologies showed that Diclac promoted significantly greater DFNa delivery to the skin (p < 0.05). The cumulative amounts of DFNa which permeated at 24 h in vitro for Diclac (86.5 ± 9.4 µg/cm2) were 3.6-fold greater than the corresponding amounts found for Primofenac (24.4 ± 2.7 µg/cm2). Additionally, total skin uptake of DFNa in vivo, estimated by the area under the depth profiles curves (AUC), or the signal intensity of the drug detected in the upper stratum corneum (SC) (4 µm) ranged from 3.5 to 3.6-fold greater for Diclac than for Primofenac. The shape of the distribution profiles and the depth of DFNa penetration to the SC estimated by CRS and TS were similar for the two methods. However, TS data indicated a 4.7-fold greater efficacy of Diclac relative to Primofenac, with corresponding total amounts of drug penetrated, 94.1 ± 22.6 µg and 20.2 ± 7.0 µg. The findings demonstrate that CRS is a methodology that is capable of distinguishing skin delivery of DFNa from different formulations. The results support the use of this approach for non-invasive evaluation of topical products in vivo. Future studies will examine additional formulations with more complex compositions and will use a wider range of drugs with different physicochemical properties. The non-invasive nature of CRS coupled with the ability to monitor drug permeation in real time offer significant advantages for testing and development of topical dermatological products.
Lactoferrin Binding to SARS-CoV-2 Spike Glycoprotein Blocks Pseudoviral Entry and Relieves Iron Protein Dysregulation in Several In Vitro Models
Authors: Cutone Antimo , Rosa Luigi , Bonaccorsi di Patti Maria Carmela , Iacovelli Federico , Conte Maria Pia , Ianiro Giusi , Romeo Alice , Campione Elena , Bianchi Luca , Valenti Piera , Falconi Mattia , Musci Giovanni
Published: October 2022

SARS-CoV-2 causes COVID-19, a predominantly pulmonary disease characterized by a burst of pro-inflammatory cytokines and an increase in free iron. The viral glycoprotein Spike mediates fusion to the host cell membrane, but its role as a virulence factor is largely unknown. Recently, the antiviral activity of lactoferrin against SARS-CoV-2 was demonstrated in vitro and shown to occur via binding to cell surface receptors, and its putative interaction with Spike was suggested by in silico analyses. We investigated the anti-SARS-CoV-2 activity of bovine and human lactoferrins in epithelial and macrophagic cells using a Spike-decorated pseudovirus. Lactoferrin inhibited pseudoviral fusion and counteracted the deleterious effects of Spike on iron and inflammatory homeostasis by restoring basal levels of iron-handling proteins and of proinflammatory cytokines IL-1β and IL-6. Using pull-down assays, we experimentally proved for the first time that lactoferrin binds to Spike, immediately suggesting a mechanism for the observed effects. The contribution of transferrin receptor 1 to Spike-mediated cell fusion was also experimentally demonstrated. In silico analyses showed that lactoferrin interacts with transferrin receptor 1, suggesting a multifaceted mechanism of action for lactoferrin. Our results give hope for the use of bovine lactoferrin, already available as a nutraceutical, as an adjuvant to standard therapies in COVID-19.
A Comparative Analysis of the Wound Healing-Related Heterogeneity of Adipose-Derived Stem Cells Donors
Authors: Ren Guoqiang , Peng Qiuyue , Emmersen Jeppe , Zachar Vladimir , Fink Trine , Porsborg Simone
Published: October 2022

Adipose-derived Stem cells (ASCs) are on the verge of being available for large clinical trials in wound healing. However, for developing advanced therapy medicinal products (ATMPs), potency assays mimicking the mode of action are required to control the product consistency of the cells. Thus, greater effort should go into the design of product assays. Therefore, we analyzed three ASC-based ATMPs from three different donors with respect to their surface markers, tri-lineage differentiation, proliferation, colony-forming unit capacity, and effect on fibroblast proliferation and migration, endothelial proliferation, migration, and angiogenesis. Furthermore, the transcriptome of all three cell products was analyzed through RNA-sequencing. Even though all products met the criteria by the International Society for Cell and Gene Therapy and the International Federation for Adipose Therapeutics and Science, we found one product to be consistently superior to others when exploring their potency in the wound healing specific assays. Our results indicate that certain regulatory genes associated with extracellular matrix and angiogenesis could be used as markers of a superior ASC donor from which to use ASCs to treat chronic wounds. Having a panel of assays capable of predicting the potency of the product would ensure the patient receives the most potent product for a specific indication, which is paramount for successful patient treatment and acceptance from the healthcare system.
Understanding the Multidimensional Effects of Polymorphism, Particle Size and Processing for D-Mannitol Powders
Authors: Mareczek Lena , Riehl Carolin , Harms Meike , Reichl Stephan
Published: October 2022

The relevance of the polymorphic form, particle size, and processing of mannitol for the mechanical properties of solid oral dosage forms was examined. Thus, particle and powder properties of spray granulated β D-mannitol, β D-mannitol, and δ D-mannitol were assessed in this study with regards to their manufacturability. D-mannitol is a commonly used excipient in pharmaceutical formulations, especially in oral solid dosage forms, and can be crystallized as three polymorphic forms, of which β is the thermodynamically most stable form and δ is a kinetically stabilized polymorph. A systematic analysis of the powders as starting materials and their respective roller compacted granules is presented to elucidate the multidimensional effects of powder and granules characteristics such as polymorphic form, particle size, and preprocessing on the resulting tablets’ mechanical properties. In direct compression and after roller compaction, δ polymorph displayed superior tableting properties over β mannitol, but was outperformed by spray granulated β mannitol. This could be primarily correlated to the higher specific surface area, leading to higher bonding area and more interparticle bonds within the tablet. Hence, it was shown that surface characteristics and preprocessing can prevail over the impact of polymorphism on manufacturability for oral solid dosage forms.
Development of Biocompatible Ciprofloxacin–Gold Nanoparticle Coated Sutures for Surgical Site Infections
Authors: Sampathi Sunitha , Tiriya Pankaj , Dodoala Sujatha , Junnuthula Vijayabhaskarreddy , Dyawanapelly Sathish
Published: October 2022

Surgical site infections (SSIs) are mainly observed after surgeries that use biomaterials. The aim of this present work was to develop ciprofloxacin hydrochloride (CPH)-loaded gold nanoparticles. These ciprofloxacin–gold nanoparticles were coated onto a sterile surgical suture using an adsorption technique, followed by rigidization via ionotropic crosslinking using sodium alginate. Furthermore, UV-visible spectroscopy, infrared spectroscopy, and scanning electron microscopy were used to characterize the samples. The particle size of the nanoparticles was 126.2 ± 13.35 nm with a polydispersity index of 0.134 ± 0.03, indicating nanosize formation with a monodispersed system. As per the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines, stability studies were performed for 30 days under the following conditions: 2–8 °C, 25 ± 2 °C/60 ± 5% RH, and 40 ± 2 °C/75 ± 5% RH. For both Gram-negative and Gram-positive bacteria, the drug-coupled nanoparticle-laden sutures showed a twofold higher zone of inhibition compared with plain drug-coated sutures. In vitro drug release studies showed a prolonged release of up to 180 h. Hemolysis and histopathology studies displayed these sutures’ acceptable biocompatibility with the healing of tissue in Albino Swiss mice. The results depict that the use of antibiotic-coated sutures for preventing surgical site infection for a long duration could be a viable clinical option.
Development of Heterocyclic PPAR Ligands for Potential Therapeutic Applications
Authors: Virendra Sharma Arvind , Kumar Ankur , Chawla Pooja A. , Mamidi Narsimha
Published: October 2022

The family of nuclear peroxisome proliferator-activated receptors (PPARα, PPARβ/δ, and PPARγ) is a set of ligand-activated transcription factors that regulate different functions in the body. Whereas activation of PPARα is known to reduce the levels of circulating triglycerides and regulate energy homeostasis, the activation of PPARγ brings about insulin sensitization and increases the metabolism of glucose. On the other hand, PPARβ when activated increases the metabolism of fatty acids. Further, these PPARs have been claimed to be utilized in various metabolic, neurological, and inflammatory diseases, neurodegenerative disorders, fertility or reproduction, pain, and obesity. A series of different heterocyclic scaffolds have been synthesized and evaluated for their ability to act as PPAR agonists. This review is a compilation of efforts on the part of medicinal chemists around the world to find novel compounds that may act as PPAR ligands along with patents in regards to PPAR ligands. The structure–activity relationship, as well as docking studies, have been documented to better understand the mechanistic investigations of various compounds, which will eventually aid in the design and development of new PPAR ligands. From the results of the structural activity relationship through the pharmacological and in silico evaluation the potency of heterocycles as PPAR ligands can be described in terms of their hydrogen bonding, hydrophobic interactions, and other interactions with PPAR.
Biologic Disease-Modifying Antirheumatic Drugs for Preventing Radiographic Progression in Psoriatic Arthritis: A Systematic Review and Network Meta-Analysis
Authors: Wang Szu-Hsuan , Yu Chia-Ling , Wang Tzu-Yu , Yang Chung-Han , Chi Ching-Chi
Published: October 2022

The prevention of joint deformity is among the most important treatment goals of psoriatic arthritis. Some biologics disease-modifying antirheumatic drugs (bDMARDs) have been demonstrated to be effective for both the skin and joints, as well as for slowing radiographic progression. However, there has been a lack of direct comparisons of bDMARDs. To evaluate the comparative effects of bDMARDs in preventing radiographic progression in psoriatic arthritis, we conducted a systematic review and network meta-analysis. On March 7 2022, a search for relevant randomized trials was conducted on MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials. Our outcomes included radiographic non-progression, a mean change in the total radiographic score, and adverse events leading to discontinuation (DAE) at week 24. We included 11 trials on 10 bDMARDs, involving 4010 participants. Most bDMARDs were more effective than placebos in achieving radiographic non-progression, including adalimumab (odds ratio (OR) 4.7, 95% confidence interval (CI) 2.66–8.29), etanercept (OR 4.19, 95% CI 1.65–10.61), certolizumab pegol (OR 2.83, 95% CI 1.55–5.2), secukinumab 300 mg (OR 2.63, CI 1.62–4.27), infliximab (OR 2.54, CI 1.13–5.69), ixekizumab (OR 2.22, 95% CI 1.06–4.65), golimumab (OR 2.21, 95% CI 1.24–3.93), and abatacept (OR 1.54, 95% CI 1.03–2.28). A significant reduction in the total radiographic score was found in infliximab (standardized mean difference (SMD) −0.59, 95% CI −0.87, −0.3), etanercept (SMD −0.51, 95% CI −0.78, −0.23), adalimumab (SMD −0.45, 95% CI −0.64, −0.26), ixekizumab (SMD −0.37, 95% CI −0.62, −0.12), secukinumab 300 mg (SMD −0.33, 95% CI −0.50, −0.15), golimumab (SMD −0.33, 95% CI −0.58, −0.09), secukinumab 150 mg (SMD −0.25, 95% CI −0.43, −0.07), certolizumab pegol (SMD −0.23, 95% CI −0.44, −0.03), and ustekinumab (SMD −0.19, 95% CI −0.35, −0.33). No significant differences in DAE were detected between bDMARDs. In conclusion, anti-tumor necrosis factor agents (adalimumab, infliximab, and etanercept) may be preferred for treating psoriatic arthritis for their superiority in preventing radiographic progression.
Acoustically Driven Cell-Based Microrobots for Targeted Tumor Therapy
Authors: Cao Hiep Xuan , Nguyen Van Du , Jung Daewon , Choi Eunpyo , Kim Chang-Sei , Park Jong-Oh , Kang Byungjeon
Published: October 2022

Targeted drug delivery using microrobots manipulated by an external actuator has significant potential to be a practical approach for wireless delivery of therapeutic agents to the targeted tumor. This work aimed to develop a novel acoustic manipulation system and macrophage-based microrobots (Macbots) for a study in targeted tumor therapy. The Macbots containing superparamagnetic iron oxide nanoparticles (SPIONs) can serve as drug carriers. Under an acoustic field, a microrobot cluster of the Macbots is manipulated by following a predefined trajectory and can reach the target with a different contact angle. As a fundamental validation, we investigated an in vitro experiment for targeted tumor therapy. The microrobot cluster could be manipulated to any point in the 4 × 4 × 4 mm region of interest with a position error of less than 300 μm. Furthermore, the microrobot could rotate in the O-XY plane with an angle step of 45 degrees without limitation of total angle. Finally, we verified that the Macbots could penetrate a 3D tumor spheroid that mimics an in vivo solid tumor. The outcome of this study suggests that the Macbots manipulated by acoustic actuators have potential applications for targeted tumor therapy.
Laser Microperforation Assisted Drug-Elution from Biodegradable Films
Authors: Abdurashitov Arkady S. , Proshin Pavel I. , Sindeeva Olga A. , Sukhorukov Gleb B.
Published: October 2022

In a modern high-tech medicine, drug-eluting polymer coatings are actively used to solve a wide range of problems, including the prevention of post-surgery infection, inflammatory, restenosis, thrombosis and many other implant-associated complications. For major assumptions, the drug elution mechanism is considered mainly to be driven by the degradation of the polymer matrix. This process is very environmentally dependent, unpredictable and often leads to a non-linear drug release kinetic. In the present work, we demonstrate how the laser microperforation of cargo-loaded biodegradable films could be used as a tool to achieve zero-order release kinetics with different elution rates. The effects of the laser-induced hole’s diameter (10, 18, 22, 24 µm) and their density (0, 1, 2, 4 per sample) on release kinetic are studied. The linear dynamics of elution was measured for all perforation densities. Release rates were estimated to be 0.018 ± 0.01 µg/day, 0.211 ± 0.08 µg/day, 0.681 ± 0.1 µg/day and 1.19 ± 0.12 µg/day for groups with 0, 1, 2, 4 microperforations, respectively. The role of biodegradation of the polymer matrix is reduced only to the decomposition of the film over time with no major influence on elution rates.
Guidelines for Assessing and Enhancing the Organizational Vitality of Pharmacy Educational Programs: A Call to Action!
Authors: Malhotra Ashim , Hughes Jeremy , Fuentes David G.
Published: October 2022

Organizational vitality encompasses organizational mission and identity, organizational purpose and values, and employee engagement, cohesiveness, anxiety, and information sharing. Using the organizational vitality framework consisting of the following five pillars: (1) human, (2) knowledge, (3) intellectual, (4) financial capital, and (5) market value, we propose a reflection guide and specific calls to action for academic leaders including deans, department chairs, assistant/associate deans, and others within pharmacy and healthcare education systems. Our overall aim is to provide a blueprint for academic leaders to assess and enhance the organizational health, vitality, resiliency, and sustainability of their pharmacy educational programs using an established organizational vitality framework. This guide can help academic leaders at all levels to reflect on their organization’s vitality and use the steps outlined here to renew conversations about faculty life, identities as leaders, the global pharmacy Academy’s core mission and values, and the pursuit of work-life harmony in the context of their pharmacy schools’ organizational vitality. All leaders within pharmacy educational programs should identify and embrace a holistic and guided framework that emphasizes organizational vitality.