bluuebunny/crossref_metadata_2025 huggingface dataset:
Dietary Quality Indices in Early Pregnancy and Rate of Gestational Weight Gain among a Prospective Multi-Racial and Ethnic Cohort
Authors: Liu Emily F. , Zhu Yeyi , Ferrara Assiamira , Hedderson Monique M.
Published: February 2023

Meeting the Institute of Medicine (IOM) gestational weight gain (GWG) guidelines is associated with a reduced risk of adverse perinatal outcomes. Overall diet quality comprehensively assesses dietary components and accounts for interactions between them. While GWG is influenced by maternal diet, its association with overall diet quality—measured by various dietary quality indices—is not well-defined. We prospectively estimated the relationship between four established dietary quality indices and the risk of GWG rate above (excessive) or below (inadequate) IOM guidelines in a multi-racial and ethnic cohort of 2914 pregnant people from the Pregnancy Environment and Lifestyle Study (2014–2019). We assessed diet quality using the Healthy Eating Index 2010 (HEI-2010), alternate Mediterranean Diet (aMED), Dietary Approaches to Stop Hypertension (DASH), and Empirical Dietary Inflammatory Index (EDIP). Following the first trimester, 56% of the cohort had excessive GWG, and 14% had inadequate GWG. Poor diet quality (below the 75th percentile), measured by HEI-2010, was associated with a higher risk of excessive GWG in the second and third trimesters [RR = 1.03 (1.00, 1.06)]. Effect modification of this relationship by race and ethnicity and pre-pregnancy BMI was assessed. We found poor diet quality to be associated with elevated risk of excessive GWG among Black participants [RR = 1.14 (1.02, 1.28)] and White participants [RR 1.07 (1.01, 1.12)]. This was also the case for participants with pre-pregnancy BMI < 25.0 [RR 1.05 (1.00, 1.10)]. These results suggest that diet quality measured by the HEI-2010 is associated with excessive GWG, and the associations appear to be stronger among pregnant people without overweight or obesity and pregnant people who identify as Black or White race and ethnicity.
Inhibition of Enzymatic Acetylation-Mediated Resistance to Plazomicin by Silver Ions
Authors: Ngo David , Magaña Angel J. , Tran Tung , Sklenicka Jan , Phan Kimberly , Eykholt Brian , Jimenez Verónica , Ramirez María S. , Tolmasky Marcelo E.
Published: February 2023

Plazomicin is a recent U.S. Food and Drug Administration (FDA)-approved semisynthetic aminoglycoside. Its structure consists of a sisomicin scaffold modified by adding a 2(S)-hydroxy aminobutyryl group at the N1 position and a hydroxyethyl substituent at the 6′ position. These substitutions produced a molecule refractory to most aminoglycoside-modifying enzymes. The main enzyme within this group that recognizes plazomicin as substrate is the aminoglycoside 2′-N-acetyltransferase type Ia [AAC(2′)-Ia], which reduces the antibiotic’s potency. Designing formulations that combine an antimicrobial with an inhibitor of resistance is a recognized strategy to extend the useful life of existing antibiotics. We have recently found that several metal ions inhibit the enzymatic inactivation of numerous aminoglycosides mediated by the aminoglycoside 6′-N-acetyltransferase type Ib [AAC(6′)-Ib]. In particular, Ag+, which also enhances the effect of aminoglycosides by other mechanisms, is very effective in interfering with AAC(6′)-Ib-mediated resistance to amikacin. Here we report that silver acetate is a potent inhibitor of AAC(2′)-Ia-mediated acetylation of plazomicin in vitro, and it reduces resistance levels of Escherichia coli carrying aac(2′)-Ia. The resistance reversion assays produced equivalent results when the structural gene was expressed under the control of the natural or the blaTEM-1 promoters. The antibiotic effect of plazomicin in combination with silver was bactericidal, and the mix did not show significant toxicity to human embryonic kidney 293 (HEK293) cells.
Renin–Angiotensin System Antagonism Protects the Diabetic Heart from Ischemia/Reperfusion Injury in Variable Hyperglycemia Duration Settings by a Glucose Transporter Type 4-Mediated Pathway
Authors: Al-Kouh Aisha , Babiker Fawzi , Al-Bader Maie
Published: February 2023

Background: Diabetes mellitus (DM) is a risk factor for cardiovascular diseases, specifically, the ischemic heart diseases (IHD). The renin–angiotensin system (RAS) affects the heart directly and indirectly. However, its role in the protection of the heart against I/R injury is not completely understood. The aim of the current study was to evaluate the efficacy of the angiotensin-converting enzyme (ACE) inhibitor and Angiotensin II receptor (AT1R) blocker or a combination thereof in protection of the heart from I/R injury. Methods: Hearts isolated from adult male Wistar rats (n = 8) were subjected to high glucose levels; acute hyperglycemia or streptozotocin (STZ)-induced diabetes were used in this study. Hearts were subjected to I/R injury, treated with Captopril, an ACE inhibitor; Losartan, an AT1R antagonist; or a combination thereof. Hemodynamics data were measured using a suitable software for that purpose. Additionally, infarct size was evaluated using 2,3,5-Triphenyltetrazolium chloride (TTC) staining. The levels of apoptosis markers (caspase-3 and -8), antioxidant enzymes, superoxide dismutase (SOD) and catalase (CAT), nitric oxide synthase (eNOS), and glucose transporter type 4 (GLUT-4) protein levels were evaluated by Western blotting. Pro-inflammatory and anti-inflammatory cytokines levels were evaluated by enzyme-linked immunosorbent assay (ELISA). Results: Captopril and Losartan alone or in combination abolished the effect of I/R injury in hearts subjected to acute hyperglycemia or STZ-induced diabetes. There was a significant (p < 0.05) recovery in hemodynamics, infarct size, and apoptosis markers following the treatment with Captopril, Losartan, or their combination. Treatment with Captopril, Losartan, or their combination significantly (p < 0.05) reduced pro-inflammatory cytokines and increased GLUT-4 protein levels. Conclusions: The blockade of the RAS system protected the diabetic heart from I/R injury. This protection followed a pathway that utilizes GLUT-4 to decrease the apoptosis markers, pro-inflammatory cytokines, and to increase the anti-inflammatory cytokines. This protection seems to employ a pathway which is not involving ERK1/2 and eNOS.
Real-World Study on Vedolizumab Serum Concentration, Efficacy, and Safety after the Transition from Intravenous to Subcutaneous Vedolizumab in Inflammatory Bowel Disease Patients: Single-Center Experience
Authors: Oršić Frič Vlasta , Borzan Vladimir , Šahinović Ines , Borzan Andrej , Kurbel Sven
Published: February 2023

Little is known about how the change from intravenous to subcutaneous vedolizumab in a real-life setting in inflammatory bowel disease patients on stable maintenance therapy affects clinical outcomes. We compared the data on vedolizumab serum trough concentration, efficacy, and safety prior to and six months after the switch from intravenous to subcutaneous vedolizumab. In total, 24 patients, 13 with ulcerative colitis (UC) and 11 with Crohn’s disease (CD), were included. Mean serum trough concentration of intravenous vedolizumab was significantly lower than mean serum trough concentration of subcutaneous vedolizumab (p = 0.002). There was no significant difference between C-reactive protein levels, fecal calprotectin levels or clinical scores (Harvey–Bradshaw index or Partial Mayo score) prior to transition to subcutaneous vedolizumab and after 6 months. In four (16.7%) patients, two CD and two UC, therapy was discontinued during the follow-up period with a median of 5 months (minimum–maximum: 4–6). In all patients, therapy was discontinued due to loss of response. In total, 13 adverse events were reported by 11 patients, and the most common adverse event was COVID-19. No serious adverse events were reported. In conclusion, subcutaneous vedolizumab has shown to be effective and safe in patients on previously established maintenance therapy with intravenous vedolizumab.
Synthetic Methodologies and Therapeutic Potential of Indole-3-Carbinol (I3C) and Its Derivatives
Authors: Centofanti Federica , Buono Alessandro , Verboni Michele , Tomino Carlo , Lucarini Simone , Duranti Andrea , Pandolfi Pier Paolo , Novelli Giuseppe
Published: February 2023

Indole-3-carbinol (I3C) is a natural product contained in vegetables belonging to the Brassicaceae family and has been studied in recent decades for its biological and pharmacological properties. Herein, we will analyze: (1) the biosynthetic processes and synthetic procedures through which I3C and its main derivatives have been obtained; (2) the characteristics that lead to believe that both I3C and its derivatives are responsible for several important activities—in particular, antitumor and antiviral, through insights concerning in vitro assays and in vivo tests; (3) the mechanisms of action of the most important compounds considered; (4) the potential social impact that the enhancement of the discussed molecules can have in the prevention and treatment of the pathologies’ examined field—first of all, those related to respiratory tract disorders and cancer.
The Use of Calcium Phosphate-Based Starter Pellets for the Preparation of Sprinkle IR MUPS Formulation of Rosuvastatin Calcium
Authors: Cal Krzysztof , Mikolaszek Barbara , Hess Tobias , Papaioannou Markos , Lenik Joanna , Ciosek-Skibińska Patrycja , Wall Helene , Paszkowska Jadwiga , Romanova Svitlana , Garbacz Grzegorz , Zakowiecki Daniel
Published: February 2023

Sprinkle formulations represent an interesting concept of medicinal products aimed at the steadily growing population of patients suffering from swallowing difficulties (dysphagia). In the present work, immediate-release sprinkle MUPS (multiple-unit pellet system) containing rosuvastatin calcium as a model drug substance was successfully developed. The formulation was prepared by drug layering technique using novel calcium phosphate-based starting pellets (PharSQ® Spheres CM) of three different particle sizes. The study showed that the developed multiparticulates were characterized by uniform distribution of coating layers thickness, as well as fast dissolution rate (more than 85% of rosuvastatin calcium dissolved within 30 min, as required by the relevant USP/NF monograph). Rosuvastatin calcium, like other statins, has a bitter, unpleasant taste. Investigations conducted with an electronic tongue suggested that the developed formulation achieved the desired taste-masking efficiency. The effect was found to be particle size-dependent, improving as the size of the multiparticulates increased.
Chemokine Receptors—Structure-Based Virtual Screening Assisted by Machine Learning
Authors: Dragan Paulina , Merski Matthew , Wiśniewski Szymon , Sanmukh Swapnil Ganesh , Latek Dorota
Published: February 2023

Chemokines modulate the immune response by regulating the migration of immune cells. They are also known to participate in such processes as cell–cell adhesion, allograft rejection, and angiogenesis. Chemokines interact with two different subfamilies of G protein-coupled receptors: conventional chemokine receptors and atypical chemokine receptors. Here, we focused on the former one which has been linked to many inflammatory diseases, including: multiple sclerosis, asthma, nephritis, and rheumatoid arthritis. Available crystal and cryo-EM structures and homology models of six chemokine receptors (CCR1 to CCR6) were described and tested in terms of their usefulness in structure-based drug design. As a result of structure-based virtual screening for CCR2 and CCR3, several new active compounds were proposed. Known inhibitors of CCR1 to CCR6, acquired from ChEMBL, were used as training sets for two machine learning algorithms in ligand-based drug design. Performance of LightGBM was compared with a sequential Keras/TensorFlow model of neural network for these diverse datasets. A combination of structure-based virtual screening with machine learning allowed to propose several active ligands for CCR2 and CCR3 with two distinct compounds predicted as CCR3 actives by all three tested methods: Glide, Keras/TensorFlow NN, and LightGBM. In addition, the performance of these three methods in the prediction of the CCR2/CCR3 receptor subtype selectivity was assessed.
Perceived Usability of Tablet Crushers: Comparison of Devices by People with and without Limited Hand Functions
Authors: Lee Su Vin , Aplin Tammy , Sefidani Forough Aida , Steadman Kathryn J.
Published: February 2023

Tablet crushing is a common practice used by patients and their carers, mainly to facilitate swallowing. Various tablet-crushing devices with different designs are currently available on the market. This study aimed to compare the usability of different tablet-crushing devices in people with and without limited hand functions. The hand function of 100 adults recruited from the general community (40 of whom self-reported a limited hand function) was assessed using the hand and finger function subscale of the Arthritis Impact Measurement Scale version 2. The hand strength was measured using a dynamometer. Participants crushed tablets using 11 crushing devices and completed a Rapid Assessment of Product Usability and Universal Design questionnaire for each device. Hand-held twist-action crushers with an ergonomic grip received the highest usability scores among both groups, irrespective of the cost (p < 0.05). Crushers with bags were scored lower by those with limited hand functions, although the score improved if the device was automatic. Preferences regarding electronic crushers significantly changed once the cost was revealed. Economical twist-action crushers with ergonomic grips and without bags or cups were the most favoured crushers.
Correlation between Antimicrobial Resistance and the Hospital-Wide Diverse Use of Broad-Spectrum Antibiotics by the Antimicrobial Stewardship Program in Japan
Authors: Ueda Takashi , Takesue Yoshio , Nakajima Kazuhiko , Ichiki Kaoru , Ishikawa Kaori , Yamada Kumiko , Tsuchida Toshie , Otani Naruhito , Takahashi Yoshiko , Ishihara Mika , Takubo Shingo , Iijima Kosuke , Ikeuchi Hiroki , Uchino Motoi , Kimura Takeshi
Published: February 2023

Increased antibiotic use and antibiotic homogeneity cause selective pressure. This study investigated the correlation between antibiotic diversity and antimicrobial resistance (AMR) in Gram-negative organisms. The days of therapy/100 patient-days (DOT) for four broad-spectrum antibiotic classes were evaluated for 2015–2022. The antibiotic heterogeneity index (AHI) for the equal use of four classes (25%) and the modified AHI for the equal use of three classes (30%), excluding fluoroquinolones (10%), were measured (target: 1.0). Quarterly antibiotic use markers and the resistance rates against ≥2 anti-Pseudomonas antibiotics were compared. The DOT value was 9.94, and the relative DOT were 34.8% for carbapenems, 32.1% for piperacillin/tazobactam, 24.3% for fourth generation cephalosporins/ceftazidime/aztreonam, and 8.9% for fluoroquinolones. Although no correlation was found between the total DOT and the resistance rate for any bacterium, a significant negative correlation was found between the heterogeneity indices and resistance rates for Pseudomonas aeruginosa and Klebsiella pneumoniae. The significant cutoffs that discriminate the risk of resistance were 0.756 for the AHI and 0.889 for the modified AHI for K. pneumoniae. Antibiotic diversity is more important in preventing AMR than overall antibiotic use. The ideal ratio of broad-spectrum antibiotics should be studied for diversified use to prevent AMR.
Integrating In Vitro Biopharmaceutics into Physiologically Based Biopharmaceutic Model (PBBM) to Predict Food Effect of BCS IV Zwitterionic Drug (GSK3640254)
Authors: Stamatopoulos Konstantinos , Ferrini Paola , Nguyen Dung , Zhang Ying , Butler James M. , Hall Jon , Mistry Nena
Published: February 2023

A strategy followed to integrate in vitro solubility and permeability data into a PBBM model to predict the food effect of a BCS IV zwitterionic drug (GSK3640254) observed in clinical studies is described. The PBBM model was developed, qualified and verified using clinical data of an immediate release (IR)-tablet (10–320 mg) obtained in healthy volunteers under fasted and fed conditions. The solubility of GSK3640254 was a function of its ionization state, the media composition and pH, whereas its permeability determined using MDCK cell lines was enhanced by the presence of mixed micelles. In vitro data alongside PBBM modelling suggested that the positive food effect observed in the clinical studies was attributed to micelle-mediated enhanced solubility and permeability. The biorelevant media containing oleic acid and cholesterol in fasted and fed levels enabled the model to appropriately capture the magnitude of the food effect. Thus, by using Simcyp® v20 software, the PBBM model accurately predicted the results of the food effect and predicted data were within a two-fold error with 70% being within 1.25-fold. The developed model strategy can be effectively adopted to increase the confidence of using PBBM models to predict the food effect of BCS class IV drugs.
Extracellular Vesicles of Probiotics: Shedding Light on the Biological Activity and Future Applications
Authors: Krzyżek Paweł , Marinacci Beatrice , Vitale Irene , Grande Rossella
Published: February 2023

For many decades, the proper functioning of the human body has become a leading scientific topic. In the course of numerous experiments, a striking impact of probiotics on the human body has been documented, including maintaining the physiological balance of endogenous microorganisms, regulating the functioning of the immune system, enhancing the digestive properties of the host, and preventing or alleviating the course of many diseases. Recent research, especially from the last decade, shows that this health-benefiting activity of probiotics is largely conditioned by the production of extracellular vesicles. Although the importance of extracellular vesicles in the virulence of many live-threatening pathogens is widely described in the literature, much less is known with respect to the health-promoting effect of extracellular vesicles secreted by non-pathogenic microorganisms, including probiotics. Based on this, in the current review article, we decided to collect the latest literature data on the health-inducing properties of extracellular vesicles secreted by probiotics. The characteristics of probiotics’ extracellular vesicles will be extended by the description of their physicochemical properties and the proteome in connection with the biological activities exhibited by these structures.
Impact of Omalizumab in Patients with Severe Uncontrolled Asthma and Possible Predictive Biomarkers of Response: A Real-Life Study
Authors: Rojo-Tolosa Susana , González-Gutiérrez María Victoria , Sánchez-Martínez José Antonio , Jiménez-Gálvez Gonzalo , Pineda-Lancheros Laura Elena , Gálvez-Navas José María , Jiménez-Morales Alberto , Pérez-Ramírez Cristina , Morales-García Concepción
Published: February 2023

Most patients with asthma can control their symptoms with a basic standard of medical care and with maintenance and rescue medication. However, between 5% and 10% of asthmatics worldwide do not achieve control of their symptoms and have recurrent exacerbations and respiratory difficulties. The objective of the study was the real-life evaluation of the clinical improvement of patients with severe eosinophilic asthma treated with omalizumab, together with the search for biomarkers associated with the response. An observational retrospective cohort study was conducted that included patients with severe uncontrolled allergic asthma being treated with omalizumab. Three types of response were evaluated: lower use of oral corticosteroids, improvement in lung function, and reduction in exacerbations. A total of 110 patients under treatment with omalizumab were included, with a mean age of 48 ± 16 years. After 12 months had elapsed, significant reductions were found in the number of exacerbations, use of oral cortico-steroids and doses of inhaled corticosteroids (p < 0.001). Lung function and asthma control improved significantly (p < 0.001; p = 0.004) and eosinophil levels were significantly reduced (p = 0.004). Low scores in the Asthma Control Test were associated with the oral corticosteroid-saving effect; lower previous FEV1 levels and absence of chronic obstructive pulmonary disease (COPD) were related to improvement in lung function, and prior FEV1 values higher than 80% and absence of gastroesophageal reflux disease (GERD) with a reduction in exacerbations. The results of this study confirm the clinical benefit obtained after the introduction of omalizumab and the possible predictive biomarkers of response to the treatment.
Dendritic Polymers in Tissue Engineering: Contributions of PAMAM, PPI PEG and PEI to Injury Restoration and Bioactive Scaffold Evolution
Authors: Arkas Michael , Vardavoulias Michail , Kythreoti Georgia , Giannakoudakis Dimitrios A.
Published: February 2023

The capability of radially polymerized bio-dendrimers and hyperbranched polymers for medical applications is well established. Perhaps the most important implementations are those that involve interactions with the regenerative mechanisms of cells. In general, they are non-toxic or exhibit very low toxicity. Thus, they allow unhindered and, in many cases, faster cell proliferation, a property that renders them ideal materials for tissue engineering scaffolds. Their resemblance to proteins permits the synthesis of derivatives that mimic collagen and elastin or are capable of biomimetic hydroxy apatite production. Due to their distinctive architecture (core, internal branches, terminal groups), dendritic polymers may play many roles. The internal cavities may host cell differentiation genes and antimicrobial protection drugs. Suitable terminal groups may modify the surface chemistry of cells and modulate the external membrane charge promoting cell adhesion and tissue assembly. They may also induce polymer cross-linking for healing implementation in the eyes, skin, and internal organ wounds. The review highlights all the different categories of hard and soft tissues that may be remediated with their contribution. The reader will also be exposed to the incorporation of methods for establishment of biomaterials, functionalization strategies, and the synthetic paths for organizing assemblies from biocompatible building blocks and natural metabolites.
Multimeric RGD-Based Strategies for Selective Drug Delivery to Tumor Tissues
Authors: Cossu Jordan , Thoreau Fabien , Boturyn Didier
Published: February 2023

RGD peptides have received a lot of attention over the two last decades, in particular to improve tumor therapy through the targeting of the αVβ3 integrin receptor. This review focuses on the molecular design of multimeric RGD compounds, as well as the design of suitable linkers for drug delivery. Many examples of RGD–drug conjugates have been developed, and we show the importance of RGD constructs to enhance binding affinity to tumor cells, as well as their drug uptake. Further, we also highlight the use of RGD peptides as theranostic systems, promising tools offering dual modality, such as tumor diagnosis and therapy. In conclusion, we address the challenging issues, as well as ongoing and future development, in comparison with large molecules, such as monoclonal antibodies.
Rapidly Dissolving Microneedles for the Delivery of Steroid-Loaded Nanoparticles Intended for the Treatment of Inflammatory Skin Diseases
Authors: Dawud Hala , Abu Ammar Aiman Abu
Published: February 2023

Drug delivery through the skin has immense advantages compared to other routes of administration and offers an optimal way to treat inflammatory skin diseases, where corticosteroids are the cornerstone of topical therapy. Still, their therapeutic efficiency is limited due to inadequate skin permeability, potential side effects, and reduced patient compliance. To overcome these drawbacks, we propose a drug delivery system consisting of dexamethasone (DEX)-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) incorporated in sodium alginate (SA) microneedles (MNs) as a minimally invasive dosage form for controlled drug release. Drug-loaded PLGA NPs were prepared by a nanoprecipitation method with a high encapsulation yield. They exhibited a controlled release pattern over 120 h. A modified vacuum-deposition micromolding method was used to load the obtained DEX-NPs into the tips of dissolving MNs. The NP-MNs showed improved insertion capabilities into the skin-simulant parafilm model and enhanced mechanical strength when tested against different static forces compared to their counterparts (SA-MNs). The results of an MN dissolution study following application to ex vivo chicken skin and agarose gel indicate that the NP-loaded segments of MNs dissolve within 15 s, in which the NPs are released into the skin. Taken together, the incorporation of DEX-NPs into SA-MNs could be a promising approach to bypass the limitations of conventional topical treatment of skin diseases, allowing for self-administration, increased patient compliance, and controlled drug release.
Development of a Clioquinol Nanocarrier as a New, Promising Option for the Treatment of Dermatomycosis
Authors: Jacobus Berlitz Simone , Reginatto Paula , Machado Gabriella da Rosa Monte , Fuentefria Alexandre Meneghello , Morisso Fernando Dal Pont , Contri Renata Vidor , Külkamp-Guerreiro Irene Clemes
Published: February 2023

Dermatomycosis is a common fungal infection, and its treatment is limited by few antifungal agents. Clioquinol (CQ) is an antiparasitic agent that has been studied for new uses, such as antifungal and antiviral applications. CQ was incorporated into a lipid-based nanocarrier as a new, promising option for dermatomycosis. This study aimed to develop a CQ-loaded lipid-based nanocarrier for cutaneous application and to evaluate its antifungal activity. CQ-loaded nanoformulation (LBN-CQ) was developed using the ultrasonication method, and the particle size, polydispersity index (PDI), pH, zeta potential, and drug content were monitored for 45 days. To evaluate antifungal activity, broth microdilution and a time-kill assay were performed. LBN-CQ presented a particle size of 91 ± 3 nm and PDI of 0.102 ± 0.009. The zeta potential and pH values were −9.7 ± 2.0 mV and 6.0 ± 0.1, respectively. The drug content was 96.4 ± 2.3%, and the encapsulation efficiency was 98.4%. LBN-CQ was able to reduce the minimum inhibitory concentration (MIC) in a 2-fold or 4-fold manner in most of the tested strains. Additionally, LBN-CQ presented stable fungistatic action that was not concentration- or time-dependent. In conclusion, the developed CQ-loaded nanocarrier is a promising treatment for skin fungal infections and a promising candidate for future randomized clinical trials.
Lipid-DNA Nanoparticles as Drug-Delivery Vehicles for the Treatment of Retinal Diseases
Authors: Schnichels Sven , Simmang David , Löscher Marina , Herrmann Andreas , de Vries Jan Willem , Spitzer Martin S. , Hurst José
Published: February 2023

Retinal eye diseases are the leading cause of blindness in the Western world. Up to date, the only efficient treatment for many retinal diseases consists of invasive intravitreal injections of highly concentrated drugs. Despite the fact that these injections are unpleasant for the patients, they potentially cause serious side effects, e.g., infections, bleeding within the eye or retinal detachment, especially when performed on a monthly basis, thus decreasing the injection frequency and lowering the desired drug dose. Therefore, a sustained released at the region of interest with a sustained release is desired. Recently, novel lipid-DNA nanoparticles (NPs) were shown to be an efficient drug delivery platform to the anterior segment of the eye. In this study, we investigated the distribution and tropism of the NPs when applied intravitreally, as a potential medication carrier to the posterior part of the eye. This technology is perfectly suited for the delivery of low molecular weight drugs to the back of the eye, which so far is greatly hindered by fast diffusion rates of the free drugs in the vitreous body and their intrinsically low retainability in ocular tissue. Excellent biodistribution, adherence and presence for up to five days was found for the different tested nanoparticles ex vivo and in vivo. In conclusion, our lipid-DNA based nanocarrier system was able to reach the retina within minutes and penetrate the retina providing potentially safe and long-term carrier systems for small molecules or nucleotide-based therapies.
Hydroxychloroquine Enhances Cytotoxic Properties of Extracellular Vesicles and Extracellular Vesicle–Mimetic Nanovesicles Loaded with Chemotherapeutics
Authors: Brezgin Sergey , Kostyusheva Anastasiya , Ponomareva Natalia , Bayurova Ekaterina , Kondrashova Alla , Frolova Anastasia , Slatinskaya Olga , Fatkhutdinova Landysh , Maksimov Georgy , Zyuzin Mikhail , Gordeychuk Ilya , Lukashev Alexander , Makarov Sergey , Ivanov Alexander , Zamyatnin Andrey A. , Chulanov Vladimir , Parodi Alessandro , Kostyushev Dmitry
Published: February 2023

Because of their high biocompatibility, biological barrier negotiation, and functionalization properties, biological nanoparticles have been actively investigated for many medical applications. Biological nanoparticles, including natural extracellular vesicles (EVs) and synthetic extracellular vesicle–mimetic nanovesicles (EMNVs), represent novel drug delivery vehicles that can accommodate different payloads. In this study, we investigated the physical, biological, and delivery properties of EVs and EMNVs and analyzed their ability to deliver the chemotherapeutic drug doxorubicin. EMNVs and EVs exhibit similar properties, but EMNVs are more effectively internalized, while EVs show higher intracellular doxorubicin release activity. In addition, these nanotherapeutics were investigated in combination with the FDA-approved drug hydroxychloroquine (HCQ). We demonstrate that HCQ-induced lysosome destabilization and could significantly increase nanoparticle internalization, doxorubicin release, and cytotoxicity. Altogether, these data demonstrate that, from the delivery standpoint in vitro, the internalization of EMNVs and EVs and their payload release were slightly different and both nanotherapeutics had comparable cytotoxic performance. However, the synthesis of EMNVs was significantly faster and cost-effective. In addition, we highlight the benefits of combining biological nanoparticles with the lysosome-destabilizing agent HCQ that increased both the internalization and the cytotoxic properties of the particles.
Development and Optimisation of Inhalable EGCG Nano-Liposomes as a Potential Treatment for Pulmonary Arterial Hypertension by Implementation of the Design of Experiments Approach
Authors: Haddad Fatma , Mohammed Nura , Gopalan R. C. , Ayoub Yousef Al , Nasim Md Talat , Assi K. H.
Published: February 2023

Epigallocatechin gallate (EGCG), the main ingredient in green tea, holds promise as a potential treatment for pulmonary arterial hypertension (PAH). However, EGCG has many drawbacks, including stability issues, low bioavailability, and a short half-life. Therefore, the purpose of this research was to develop and optimize an inhalable EGCG nano-liposome formulation aiming to overcome EGCG’s drawbacks by applying a design of experiments strategy. The aerodynamic behaviour of the optimum formulation was determined using the next-generation impactor (NGI), and its effects on the TGF-β pathway were determined using a cell-based reporter assay. The newly formulated inhalable EGCG liposome had an average liposome size of 105 nm, a polydispersity index (PDI) of 0.18, a zeta potential of −25.5 mV, an encapsulation efficiency of 90.5%, and a PDI after one month of 0.19. These results are in complete agreement with the predicted values of the model. Its aerodynamic properties were as follows: the mass median aerodynamic diameter (MMAD) was 4.41 µm, the fine particle fraction (FPF) was 53.46%, and the percentage of particles equal to or less than 3 µm was 34.3%. This demonstrates that the novel EGCG liposome has all the properties required to be inhalable, and it is expected to be deposited deeply in the lung. The TGFβ pathway is activated in PAH lungs, and the optimum EGCG nano-liposome inhibits TGFβ signalling in cell-based studies and thus holds promise as a potential treatment for PAH.
The Fate of Sulfur Radical Cation of N-Acetyl-Methionine: Deprotonation vs. Decarboxylation
Authors: Grzyb Katarzyna , Sehrawat Vidhi , Pedzinski Tomasz
Published: February 2023

In the present study, we investigated the photooxidation of the biomimetic model of C-terminal methionine, N-Acetyl-Methionine (N-Ac-Met), sensitized by a 3-Carboxybenzophenone (3CB) excited triplet in neutral and basic aqueous solutions. The short-lived transient species that formed in the reaction were identified and quantified by laser flash photolysis and the final stable products were analyzed using liquid chromatography coupled with high-resolution mass spectrometry (LC-MS) and tandem mass spectrometry (MSMS). Based on these complementary methods, it was possible to calculate the quantum yields of both competing reactions, and the deprotonation was found to be favored over decarboxylation (for neutral pH: ϕ-H = 0.23 vs. ϕ-CO2 = 0.09, for basic pH: ϕ-H = 0.23 vs. ϕ-CO2 = 0.05). Findings on such a model system, which can possibly mimic the complex protein environment, are important in understanding complicated biological systems, for example, the studied compound, N-Ac-Met, can, to some extent, mimic the methionine in the C-terminal domain of β-amyloid, which is thought to be connected with the pathogenesis of Alzheimer’s disease.
Enzymatically-Crosslinked Gelatin Hydrogels with Nanostructured Architecture and Self-Healing Performance for Potential Use as Wound Dressings
Authors: Rusu Alina Gabriela , Nita Loredana Elena , Simionescu Natalia , Ghilan Alina , Chiriac Aurica P. , Mititelu-Tartau Liliana
Published: February 2023

Development of natural protein-based hydrogels with self-healing performance and tunable physical properties has attracted increased attention owing to their wide potential not only in the pharmaceutical field, but also in wounds management. This work reports the development of a versatile hydrogel based on enzymatically-crosslinked gelatin and nanogels loaded with amoxicillin (Amox), an antibiotic used in wound infections. The transglutaminase (TGase)-crosslinked hydrogels and encapsulating nanogels were formed rapidly through enzymatic crosslinking and self-assembly interactions in mild conditions. The nanogels formed through the self-assemble of maleoyl-chitosan (MAC5) and polyaspartic acid (PAS) may have positive influence on the self-healing capacity and drug distribution within the hydrogel network through the interactions established between gelatin and gel-like nanocarriers. The physicochemical properties of the enzymatically-crosslinked hydrogels, such as internal structure, swelling and degradation behavior, were studied. In addition, the Amox release studies indicated a rapid release when the pH of the medium decreased, which represents a favorable characteristic for use in the healing of infected wounds. It was further observed through the in vitro and in vivo biocompatibility assays that the optimized scaffolds have great potential to be used as wound dressings.
Noise Evaluation of Coated Polymer Gears
Authors: Polanec Brigita , Glodež Srečko , Belšak Aleš
Published: February 2023

A comprehensive experimental investigation of the noise evaluation of coated spur polymer gears made of POM was performed in this study. The three Physical Vapour Deposition (PVD) coatings investigated were aluminium (Al), chromium (Cr), and chromium nitrite (CrN). The gears were tested on an in-house-developed testing machine under a torque of 20 Nm and at a rotational speed of 1000 rpm. The noise measurements were performed with the tested gear pair on the testing device with a sound-proof acoustic foam used for the acoustic sound-proof insulation. The sound signal was analysed in time, frequency, and time–frequency domains and typical phenomena were identified in the signal. Experimental results showed that the noise level was higher for polymer gears with different coatings if compared to the polymer gears without coatings. With sound analysis in the time–frequency domain, precise degradation of the coatings could be noticed. In future studies, it would be appropriate to use a new method for signal analysis, e.g., high-order statistics and hybrid technique.
Full Optoelectronic Simulation of Lead-Free Perovskite/Organic Tandem Solar Cells
Authors: Salem Marwa S. , Shaker Ahmed , Abouelatta Mohamed , Saeed Ahmed
Published: February 2023

Organic and perovskite semiconductor materials are considered an interesting combination thanks to their similar processing technologies and band gap tunability. Here, we present the design and analysis of perovskite/organic tandem solar cells (TSCs) by using a full optoelectronic simulator (SETFOS). A wide band gap lead-free ASnI2Br perovskite top subcell is utilized in conjunction with a narrow band gap DPPEZnP-TBO:PC61BM heterojunction organic bottom subcell to form the tandem configuration. The top and bottom cells were designed according to previous experimental work keeping the same materials and physical parameters. The calibration of the two cells regarding simulation and experimental data shows very good agreement, implying the validation of the simulation process. Accordingly, the two cells are combined to develop a 2T tandem cell. Further, upon optimizing the thickness of the front and rear subcells, a current matching condition is satisfied for which the proposed perovskite/organic TSC achieves an efficiency of 13.32%, Jsc of 13.74 mA/cm2, and Voc of 1.486 V. On the other hand, when optimizing the tandem by utilizing full optoelectronic simulation, the tandem shows a higher efficiency of about 14%, although it achieves a decreased Jsc of 12.27 mA/cm2. The study shows that the efficiency can be further improved when concurrently optimizing the various tandem layers by global optimization routines. Furthermore, the impact of defects is demonstrated to highlight other possible routes to improve efficiency. The current simulation study can provide a physical understanding and potential directions for further efficiency improvement for lead-free perovskite/organic TSC.
Influence of Surface Discharge on Resin Degradation in Decay-like Fracture of Composite Insulators
Authors: Wang Qian , Bao Weining , Gao Yanfeng , Liu Shuqi , Liu Shuming , Zuo Zhou , Wu Chao , Liang Xidong
Published: February 2023

Composite insulators have gradually become the preferred approach for electrical insulation in power systems, especially in polluted areas. Composite insulators consist of three main components: the shed, rod, and end fitting. Insulators withstand mechanical stresses via rods that are composed of glass-fiber-reinforced epoxy (GFRE). However, regardless of the high tensile strength of GFRE rods, in real-life operation, abnormal fractures have frequently been reported all over the world, which substantially increase the risk of major accidents in power systems. Fractural accidents mainly consist of brittle and decay-like fractures, which exhibit rather different morphologies at the cross sections. Brittle fracture has been effectively eliminated, while the mechanism of decay-like fracture has still not been clearly revealed. In this study, surface discharge tests were applied to investigate the discharge influence on the degradation of GFRE. The test successfully simulated the composition variation of the rods in real-life composite insulators with decay-like fractures. Moreover, it confirmed that the distinction between the characteristics of brittle fracture and decay-like fracture stems from epoxy degradation due to hydrolysis and carbonization. In addition, the respective influences of the resin type, glass fiber type, and acid liquid immersion on the degradation process were probed, and the degradation mechanism proposed in this research was verified. Based on the results, measures for preventing the development of decay-like fractures in real-life operations were determined.
Chitin-Glucan Complex Hydrogels: Physical-Chemical Characterization, Stability, In Vitro Drug Permeation, and Biological Assessment in Primary Cells
Authors: Araújo Diana , Rodrigues Thomas , Roma-Rodrigues Catarina , Alves Vítor D. , Fernandes Alexandra R. , Freitas Filomena
Published: February 2023

Chitin-glucan complex (CGC) hydrogels were fabricated by coagulation of the biopolymer from an aqueous alkaline solution, and their morphology, swelling behavior, mechanical, rheological, and biological properties were studied. In addition, their in vitro drug loading/release ability and permeation through mimic-skin artificial membranes (Strat-M) were assessed. The CGC hydrogels prepared from 4 and 6 wt% CGC suspensions (Na51*4 and Na51*6 hydrogels, respectively) had polymer contents of 2.40 ± 0.15 and 3.09 ± 0.22 wt%, respectively, and displayed a highly porous microstructure, characterized by compressive moduli of 39.36 and 47.30 kPa and storage moduli of 523.20 and 7012.25 Pa, respectively. Both hydrogels had a spontaneous and almost immediate swelling in aqueous media, and a high-water retention capacity (>80%), after 30 min incubation at 37 °C. Nevertheless, the Na51*4 hydrogels had higher fatigue resistance and slightly higher-water retention capacity. These hydrogels were loaded with caffeine, ibuprofen, diclofenac, or salicylic acid, reaching entrapment efficiency values ranging between 13.11 ± 0.49% for caffeine, and 15.15 ± 1.54% for salicylic acid. Similar release profiles in PBS were observed for all tested APIs, comprising an initial fast release followed by a steady slower release. In vitro permeation experiments through Strat-M membranes using Franz diffusion cells showed considerably higher permeation fluxes for caffeine (33.09 µg/cm2/h) and salicylic acid (19.53 µg/cm2/h), compared to ibuprofen sodium and diclofenac sodium (4.26 and 0.44 µg/cm2/h, respectively). Analysis in normal human dermal fibroblasts revealed that CGC hydrogels have no major effects on the viability, migration ability, and morphology of the cells. Given their demonstrated features, CGC hydrogels are very promising structures, displaying tunable physical properties, which support their future development into novel transdermal drug delivery platforms.
Olive Industry Solid Waste-Based Biosorbent: Synthesis and Application in Wastewater Purification
Authors: Salahat Angham , Hamed Othman , Deghles Abdalhadi , Azzaoui Khalil , Qrareya Hisham , Assali Mohyeddin , Mansour Waseem , Jodeh Shehdeh , Hacıosmanoğlu Gül Gülenay , Can Zehra Semra , Hammouti Belkheir , Nandiyanto Asep Bayu Dani , Ayerdi-Gotor Alicia , Rhazi Larbi
Published: February 2023

In this work, we present a process for converting olive industry solid waste (OISW) into a value-added material with ionic receptors for use in the removal of toxic metal ions from wastewater. This 3D polymer is a promising adsorbent for large-scale application, since it is a low-cost material made from agricultural waste and showed exceptional performance. The synthesis of the network polymer involved the carboxymethylation of OISW and curing of the carboxymethylated OISW at an elevated temperature to promote the formation of ester linkages between OISW’s components. FT-IR, atomic force microscopy, and thermal analysis were performed on the crosslinked product. The adsorption efficiency of the crosslinked carboxymethylated OISW toward Pb(II), Cu(II), and other toxic metal ions present in sewage was evaluated as a function of adsorbent dose, temperature, pH, time, and initial metal ion. The percentage removal of about 20 metal ions present in a sewage sample collected from a sewer plant located in the Palestinian Territories was determined. The adsorption efficiency did not drop even after six cycles of use. The kinetic study showed that the adsorption process follows the Langmuir isotherm model and the second-order adsorption rate. The experimental Qe values of 13.91 and 13.71 mg/g were obtained for Pb(II) and Cu(II) removal, respectively. The thermodynamic results confirm the spontaneous metal bonding to the receptor sites of the crosslinked carboxymethylated OISW.
A Novel Design Method of an Evolutionary Mold Cooling Channel Using Biomimetic Engineering
Authors: Choi Jae Hyuk , Gim Jinsu , Rhee Byungohk
Published: February 2023

In this study, an evolutionary cooling channel, a new methodology for designing a conformal cooling channel, was proposed. This methodology was devised by imitating the way that a plant’s roots grow towards a nutrient-rich location. Additionally, Murray’s law was applied to increase the cooling efficiency through minimizing the pressure loss of the cooling water inside the cooling channel. The proposed method was applied to the specimen shape to verify the concept, and it was confirmed that efficient cooling was achieved by applying it to the headlamp lens cover part of an actual vehicle. When this methodology was applied, the temperature deviation of the part could be improved by about 46% in just third generations, and the pressure loss could be reduced by about 10 times or more compared to the result of applying the straight-line cooling channel.
Engineering Polypropylene–Calcium Sulfate (Anhydrite II) Composites: The Key Role of Zinc Ionomers via Reactive Extrusion
Authors: Murariu Marius , Paint Yoann , Murariu Oltea , Laoutid Fouad , Dubois Philippe
Published: February 2023

Polypropylene (PP) is one of the most versatile polymers widely used in packaging, textiles, automotive, and electrical applications. Melt blending of PP with micro- and/or nano-fillers is a common approach for obtaining specific end-use characteristics and major enhancements of properties. The study aims to develop high-performance composites by filling PP with CaSO4 β-anhydrite II (AII) issued from natural gypsum. The effects of the addition of up to 40 wt.% AII into PP matrix have been deeply evaluated in terms of morphology, mechanical and thermal properties. The PP–AII composites (without any modifier) as produced with internal mixers showed enhanced thermal stability and stiffness. At high filler loadings (40% AII), there was a significant decrease in tensile strength and impact resistance; therefore, custom formulations with special reactive modifiers/compatibilizers (PP functionalized/grafted with maleic anhydride (PP-g-MA) and zinc diacrylate (ZnDA)) were developed. The study revealed that the addition of only 2% ZnDA (able to induce ionomeric character) leads to PP–AII composites characterized by improved kinetics of crystallization, remarkable thermal stability, and enhanced mechanical properties, i.e., high tensile strength, rigidity, and even rise in impact resistance. The formation of Zn ionomers and dynamic ionic crosslinks, finer dispersion of AII microparticles, and better compatibility within the polyolefinic matrix allow us to explain the recorded increase in properties. Interestingly, the PP–AII composites also exhibited significant improvements in the elastic behavior under dynamic mechanical stress and of the heat deflection temperature (HDT), thus paving the way for engineering applications. Larger experimental trials have been conducted to produce the most promising composite materials by reactive extrusion (REx) on twin-screw extruders, while evaluating their performances through various methods of analysis and processing.