bluuebunny/crossref_metadata_2025 huggingface dataset:
The Tuning of LIPSS Wettability during Laser Machining and through Post-Processing
Authors: Wood Michael J. , Servio Phillip , Kietzig Anne-Marie
Published: April 2021

In this work, we investigate the fabrication of stainless-steel substrates decorated with laser-induced periodic surface structures (LIPSS) of both hydrophilic and hydrophobic wettability through different post-processing manipulation. In carrying out these experiments, we have found that while a CO2-rich atmosphere during irradiation does not affect final wettability, residence in such an atmosphere after irradiation does indeed increase hydrophobicity. Contrarily, residence in a boiling water bath will instead lead to a hydrophilic surface. Further, our experiments show the importance of removing non-sintered nanoparticles and agglomerates after laser micromachining. If they are not removed, we demonstrate that the nanoparticle agglomerates themselves become hydrophobic, creating a Cassie air-trapping layer on the surface which presents with water contact angles of 180°. However, such a surface lacks robustness; the particles are removed with the contacting water. What is left behind are LIPSS which are integral to the surface and have largely been blocked from reacting with the surrounding atmosphere. The actual surface presents with a water contact angle of approximately 80°. Finally, we show that chemical reactions on these metallic surfaces decorated with only LIPSS are comparatively slower than the reactions on metals irradiated to have hierarchical roughness. This is shown to be an important consideration to achieve the highest degree of hydro-philicity/phobicity possible. For example, repeated contact with water from goniometric measurements over the first 30 days following laser micromachining is shown to reduce the ultimate wettability of the surface to approximately 65°, compared to 135° when the surface is left undisturbed for 30 days.
Bioactivation Treatment with Mixed Acid and Heat on Titanium Implants Fabricated by Selective Laser Melting Enhances Preosteoblast Cell Differentiation
Authors: Le Phuc Thi Minh , Shintani Seine A. , Takadama Hiroaki , Ito Morihiro , Kakutani Tatsuya , Kitagaki Hisashi , Terauchi Shuntaro , Ueno Takaaki , Nakano Hiroyuki , Nakajima Yoichiro , Inoue Kazuya , Matsushita Tomiharu , Yamaguchi Seiji
Published: April 2021

Selective laser melting (SLM) is a promising technology capable of producing individual characteristics with a high degree of surface roughness for implants. These surfaces can be modified so as to increase their osseointegration, bone generation and biocompatibility, features which are critical to their clinical success. In this study, we evaluated the effects on preosteoblast proliferation and differentiation of titanium metal (Ti) with a high degree of roughness (Ra = 5.4266 ± 1.282 µm) prepared by SLM (SLM-Ti) that was also subjected to surface bioactive treatment by mixed acid and heat (MAH). The results showed that the MAH treatment further increased the surface roughness, wettability and apatite formation capacity of SLM-Ti, features which are useful for cell attachment and bone bonding. Quantitative measurement of osteogenic-related gene expression by RT-PCR indicated that the MC3T3-E1 cells on the SLM-Ti MAH surface presented a stronger tendency towards osteogenic differentiation at the genetic level through significantly increased expression of Alp, Ocn, Runx2 and Opn. We conclude that bio-activated SLM-Ti enhanced preosteoblast differentiation. These findings suggest that the mixed acid and heat treatment on SLM-Ti is promising method for preparing the next generation of orthopedic and dental implants because of its apatite formation and cell differentiation capability.
Maternal Dietary Selenium Intake during Pregnancy and Neonatal Outcomes in the Norwegian Mother, Father, and Child Cohort Study
Authors: Modzelewska Dominika , Solé-Navais Pol , Brantsæter Anne Lise , Flatley Christopher , Elfvin Anders , Meltzer Helle Margrete , Sengpiel Verena , Barman Malin , Jacobsson Bo
Published: April 2021

Properly working antioxidant defence systems are important for fetal development. One of the nutrients with antioxidant activity is selenium. Increased maternal selenium intake has been associated with reduced risk for being small for gestational age and preterm delivery. Based on the Norwegian Mother, Father, and Child Cohort Study and the Medical Birth Registry of Norway, we investigated the association of maternal selenium intake from food and dietary supplements during the first half of pregnancy (n = 71,728 women) and selenium status in mid-pregnancy (n = 2628 women) with neonatal health, measured as two composite variables (neonatal morbidity/mortality and neonatal intervention). Low maternal dietary selenium intake (<30 µg/day) was associated with increased risk for neonatal morbidity/mortality (adjusted odds ratio (adjOR) 1.36, 95% confidence interval (95% CI) 1.08–1.69) and neonatal intervention (adjOR 1.16, 95% CI 1.01–1.34). Using continuous variables, there were no associations between maternal selenium intake (from diet or supplements) or whole-blood selenium concentration and neonatal outcome in the adjusted models. Our findings suggest that sufficient maternal dietary selenium intake is associated with neonatal outcome. Adhering to the dietary recommendations may help ensure an adequate supply of selenium for a healthy pregnancy and optimal fetal development.
Vitamin D Deficiency in Older Patients—Problems of Sarcopenia, Drug Interactions, Management in Deficiency
Authors: Kupisz-Urbańska Małgorzata , Płudowski Paweł , Marcinowska-Suchowierska Ewa
Published: April 2021

Vitamin D deficiency frequently occurs in older people, especially in individuals with comorbidity and polypharmacotherapy. In this group, low vitamin D plasma concentration is related to osteoporosis, osteomalacia, sarcopenia and myalgia. Vitamin D levels in humans is an effect of the joint interaction of all vitamin D metabolic pathways. Therefore, all factors interfering with individual metabolic stages may affect 25-hydroxyvitamin D plasma concentration. The known factors affecting vitamin D metabolism interfere with cytochrome CYP3A4 activity. There is another group of factors that impairs intestinal vitamin D absorption. The phenomenon of drugs and vitamin D interactions is observed first and foremost in patients with comorbidity. This is a typical situation, where the absence of “hard evidence” is not synonymous with the possible lack of adverse effects. Osteoporosis and sarcopenia (generalized and progressive decrease of skeletal muscle mass and strength) are some of the musculoskeletal consequences of hypovitaminosis D. These consequences are related to an increased risk of adverse outcomes, including bone fractures, physical disabilities, and a lower quality of life. This can lead not only to an increased risk of falls and fractures but is also one of the main causes of frailty syndrome in the aging population. Generally, Vitamin D plasma concentration is significantly lower in subjects with osteoporosis and muscle deterioration. In some observational and uncontrolled treatment studies, vitamin D supplementation resulted in a reduction of proximal myopathy and muscle pain. The most conclusive results were found in subjects with severe vitamin D deficiency and in patients avoiding large doses of vitamin D. However, the role of vitamin D in muscle pathologies is not clear and research has provided conflicting results. This is plausibly due to the heterogeneity of the subjects, vitamin D doses and environmental factors. This report presents data on some problems with vitamin D deficiency in the elderly population and the management of vitamin D deficiency D in successful or unsuccessful aging.
Small and Large Intestine (I): Malabsorption of Nutrients
Authors: Montoro-Huguet Miguel A. , Belloc Blanca , Domínguez-Cajal Manuel
Published: April 2021

Numerous disorders can alter the physiological mechanisms that guarantee proper digestion and absorption of nutrients (macro- and micronutrients), leading to a wide variety of symptoms and nutritional consequences. Malabsorption can be caused by many diseases of the small intestine, as well as by diseases of the pancreas, liver, biliary tract, and stomach. This article provides an overview of pathophysiologic mechanisms that lead to symptoms or complications of maldigestion (defined as the defective intraluminal hydrolysis of nutrients) or malabsorption (defined as defective mucosal absorption), as well as its clinical consequences, including both gastrointestinal symptoms and extraintestinal manifestations and/or laboratory abnormalities. The normal uptake of nutrients, vitamins, and minerals by the gastrointestinal tract (GI) requires several steps, each of which can be compromised in disease. This article will first describe the mechanisms that lead to poor assimilation of nutrients, and secondly discuss the symptoms and nutritional consequences of each specific disorder. The clinician must be aware that many malabsorptive disorders are manifested by subtle disorders, even without gastrointestinal symptoms (for example, anemia, osteoporosis, or infertility in celiac disease), so the index of suspicion must be high to recognize the underlying diseases in time.
Vanadium Decreases Hepcidin mRNA Gene Expression in STZ-Induced Diabetic Rats, Improving the Anemic State
Authors: Sánchez-González Cristina , Rivas-García Lorenzo , Rodríguez-Nogales Alba , Algieri Francesca , Gálvez Julio , Aranda Pilar , Montes-Bayón María , Llopis Juan
Published: April 2021

Diabetes is a disease with an inflammatory component that courses with an anemic state. Vanadium (V) is an antidiabetic agent that acts by stimulating insulin signaling. Hepcidin blocks the intestinal absorption of iron and the release of iron from its deposits. We aim to investigate the effect of V on hepcidin mRNA expression and its consequences on the hematological parameters in streptozotocin-induced diabetic Wistar rats. Control healthy rats, diabetic rats, and diabetic rats treated with 1 mgV/day were examined for five weeks. The mineral levels were measured in diet and serum samples. Hepcidin expression was quantified in liver samples. Inflammatory and hematological parameters were determined in serum or whole blood samples. The inflammatory status was higher in diabetic than in control rats, whereas the hematological parameters were lower in the diabetic rats than in the control rats. Hepcidin mRNA expression was significantly lower in the V-treated diabetic rats than in control and untreated diabetic rats. The inflammatory status remained at a similar level as the untreated diabetic group. However, the hematological profile improved after the V-treatment, reaching similar levels to those found in the control group. Serum iron level was higher in V-treated than in untreated diabetic rats. We conclude that V reduces gene expression of hepcidin in diabetic rats, improving the anemic state caused by diabetes.
Non-Celiac Gluten/Wheat Sensitivity: Clinical Characteristics and Microbiota and Mycobiota Composition by Response to the Gluten Challenge Test
Authors: Ponzo Valentina , Ferrocino Ilario , Goitre Ilaria , Pellegrini Marianna , Bruno Mauro , Astegiano Marco , Cadario Gianni , Castellana Eleonora , Bioletto Fabio , Corvaglia Maria Rita , Malfa Patrizia , Cocolin Luca , Ghigo Ezio , Bo Simona
Published: April 2021

The aims of this observational “proof-of-concept” study were to analyze the clinical/psychological characteristics and gut microbiota/mycobiota composition of individuals with suspected non-celiac gluten/wheat sensitivity (NCGS/WS) according to responses to the double-blind-placebo-controlled (DBPC) crossover gluten challenge test. Fifty individuals with suspected NCGS/WS were subjected to the DBPC challenge test; anthropometric measurements, psychometric questionnaires, and fecal samples were collected. Twenty-seven (54%) participants were gluten responsive (NCGS), and 23 were placebo responsive, with an order effect. NCGS individuals displayed a significantly lower risk of eating disorders and a higher mental health score when compared to placebo-responsive participants, confirmed by multiple logistic regression analyses (OR = 0.87; 95% CI 0.76–0.98, p = 0.021, and OR = 1.30; 95% CI 1.06–1.59, p = 0.009, respectively). Principal coordinate analyses based on microbiota composition showed a separation by the DBPC response (p = 0.039). For Bacteroides (p = 0.05) and Parabacteroides (p = 0.007), the frequency of amplicon sequence variants was lower, and that for Blautia (p = 0.009) and Streptococcus (p = 0.004) was higher in NCGS individuals at multiple regression analyses. No difference in the mycobiota composition was detected between the groups. In conclusion, almost half of the individuals with suspected gluten sensitivity reported symptoms with placebo; they showed lower mental health scores, increased risk for eating disorders, and a different gut microbiota composition.
Perilla frutescens Extracts Enhance DNA Repair Response in UVB Damaged HaCaT Cells
Authors: Lee Hyuna , Park Eunmi
Published: April 2021

Physiological processes in skin are associated with exposure to UV light and are essential for skin maintenance and regeneration. Here, we investigated whether the leaf and callus extracts of Perilla frutescens (Perilla), a well-known Asian herb, affect DNA damage response and repair in skin and keratinocytes exposed to Untraviolet B (UVB) light. First, we examined the protective effects of Perilla leaf extracts in UVB damaged mouse skin in vivo. Second, we cultured calluses using plant tissue culture technology, from Perilla leaf explant and then examined the effects of the leaf and callus extracts of Perilla on UVB exposed keratinocytes. HaCaT cells treated with leaf and callus Perilla extracts exhibited antioxidant activities, smaller DNA fragment tails, and enhanced colony formation after UVB exposure. Interestingly, keratinocytes treated with the leaf and callus extracts of Perilla showed G1/S cell cycle arrest, reduced protein levels of cyclin D1, Cyclin Dependent Kinase 6 (CDK6), and γH2AX, and enhanced levels of phosphorylated checkpoint kinase 1 (pCHK1) following UVB exposure. These observations suggest that the leaf and callus extracts of Perilla are candidate nutraceuticals for the prevention of keratinocyte aging.
Adherence to Mediterranean Diet among Lebanese University Students
Authors: Karam Joanne , Bibiloni Maria del Mar , Serhan Mireille , Tur Josep A.
Published: April 2021

Scarce studies described eating habits and diet quality among university students in Lebanon. The aim of this study is to assess the rate of adherence to the Mediterranean diet (MedDiet) among Lebanese university students. A cross-sectional nutritional survey was carried out on 525 students (53% men, 18–25 years old) from the University of Balamand, Lebanon. Adherence to the MedDiet was assessed using a validated 14-item MedDiet adherence score. Mean adherence to the MedDiet was 7.96 (standard deviation 2.2), and it was adequate in 59% of participants. Adherence to the MedDiet was higher in older students and nonsmokers. Legumes, vegetables, fruits, and nuts were consumed according to the MedDiet standards among a minimum of 48.4% and a maximum of 69.5% of participants. Chicken, turkey, or rabbit was preferred by 66.9% of participants instead of beef, pork, hamburgers, or sausages; however, just 56.2% of participants showed adequate intake of red meat, hamburger, or meat products. Only 28.8% of them referred to an adequate intake of fish or shellfish. Most of the participants (86.3%) used olive oil as the main added fat, and 67.2% reported a low intake of butter and derivatives. Sofrito was also very usual among participants (79.6%). Only half of the studied sample reported an adequate intake of sweet or carbonated beverages and commercial sweets or pastries. Among the assessed sample, half the participants showed adequate adherence to the MedDiet; however, the mean of adherence among the sample is low.
Bulk-Fill Direct Restorative Materials: An In Vitro Assessment of Their Physio-Mechanical Properties
Authors: Yeo Hui Woon , Loo May Yeh , Alkhabaz Mariam , Li Kai Chun , Choi Joanne Jung Eun , Barazanchi Abdullah
Published: April 2021

Bulk-fill restorative material has gained popularity in clinical practice, due to their perceived timesaving aspect. Objective was to compare the properties of bulk-fill direct restorative materials. Filtek Z350 (CR), Filtek One Bulk Fill Restorative (BF), Fuji IX and EQUIA Forte (EF) were compared. Thirty specimens from each material were prepared according to ISO 4049 for three-point flexural strength. Elastic moduli and hardness (n = 20) were evaluated using nanoindentation. Depth of cure (DC) (n = 20) was measured for BF at three different depths (2, 3, 4 mm) and at two irradiation times (20 and 40 s). Wear testing was carried out for three different periods (3, 6, 12 month(s)). All specimens were stored in 37 °C water for 24 h prior to testing. Results were evaluated using one-way ANOVA followed by a post hoc Bonferroni test (p < 0.05). BF and CR showed a significantly higher flexural strength than other groups (p < 0.05), and the highest Weibull modulus was found in CR. BF showed sufficient DC with at least 85%, at all thicknesses. CR and BF also had a high level of translucency than EF and Fuji IX. Significant differences in flexural strength were found among all materials except between Fuji IX and EF. While all material tested are suitable for use clinically, BF and CR have superior properties than GIC based bulk-fill.
Tick Importin-α Is Implicated in the Interactome and Regulome of the Cofactor Subolesin
Authors: Artigas-Jerónimo Sara , Villar Margarita , Cabezas-Cruz Alejandro , Caignard Grégory , Vitour Damien , Richardson Jennifer , Lacour Sandrine , Attoui Houssam , Bell-Sakyi Lesley , Allain Eleonore , Nijhof Ard M. , Militzer Nina , Pinecki Socias Sophia , de la Fuente José
Published: April 2021

Ticks and tick-borne diseases (TBDs) represent a burden for human and animal health worldwide. Currently, vaccines constitute the safest and most effective approach to control ticks and TBDs. Subolesin (SUB) has been identified as a vaccine antigen for the control of tick infestations and pathogen infection and transmission. The characterization of the molecular function of SUB and the identification of tick proteins interacting with SUB may provide the basis for the discovery of novel antigens and for the rational design of novel anti-tick vaccines. In the present study, we used the yeast two-hybrid system (Y2H) as an unbiased approach to identify tick SUB-interacting proteins in an Ixodes ricinus cDNA library, and studied the possible role of SUB as a chromatin remodeler through direct interaction with histones. The Y2H screening identified Importin-α as a potential SUB-interacting protein, which was confirmed in vitro in a protein pull-down assay. The sub gene expression levels in tick midgut and fat body were significantly higher in unfed than fed female ticks, however, the importin-α expression levels did not vary between unfed and fed ticks but tended to be higher in the ovary when compared to those in other organs. The effect of importin-α RNAi was characterized in I. ricinus under artificial feeding conditions. Both sub and importin-α gene knockdown was observed in all tick tissues and, while tick weight was significantly lower in sub RNAi-treated ticks than in controls, importin-α RNAi did not affect tick feeding or oviposition, suggesting that SUB is able to exert its function in the absence of Importin-α. Furthermore, SUB was shown to physically interact with histone 4, which was corroborated by protein pull-down and western blot analysis. These results confirm that by interacting with numerous tick proteins, SUB is a key cofactor of the tick interactome and regulome. Further studies are needed to elucidate the nature of the SUB-Importin-α interaction and the biological processes and functional implications that this interaction may have.
The Major Constituent of Green Tea, Epigallocatechin-3-Gallate (EGCG), Inhibits the Growth of HPV18-Infected Keratinocytes by Stimulating Proteasomal Turnover of the E6 and E7 Oncoproteins
Authors: Yap Jason K. W. , Kehoe Sean T. , Woodman Ciaran B. J. , Dawson Christopher W.
Published: April 2021

Epigallocatechin-3-gallate (EGCG), the primary bioactive polyphenol in green tea, has been shown to inhibit the growth of human papilloma virus (HPV)-transformed keratinocytes. Here, we set out to examine the consequences of EGCG treatment on the growth of HPV18-immortalised foreskin keratinocytes (HFK-HPV18) and an authentic HPV18-positive vulvar intraepithelial neoplasia (VIN) clone, focusing on its ability to influence cell proliferation and differentiation and to impact on viral oncogene expression and virus replication. EGCG treatment was associated with degradation of the E6 and E7 oncoproteins and an upregulation of their associated tumour suppressor genes; consequently, keratinocyte proliferation was inhibited in both monolayer and organotypic raft culture. While EGCG exerted a profound effect on cell proliferation, it had little impact on keratinocyte differentiation. Expression of the late viral protein E4 was suppressed in the presence of EGCG, suggesting that EGCG was able to block productive viral replication in differentiating keratinocytes. Although EGCG did not alter the levels of E6 and E7 mRNA, it enhanced the turnover of the E6 and E7 proteins. The addition of MG132, a proteasome inhibitor, to EGCG-treated keratinocytes led to the accumulation of the E6/E7 proteins, showing that EGCG acts as an anti-viral, targeting the E6 and E7 proteins for proteasome-mediated degradation.
Isofuranodiene, a Natural Sesquiterpene Isolated from Wild Celery (Smyrnium olusatrum L.), Protects Rats against Acute Ischemic Stroke
Authors: Yousefi-Manesh Hasan , Dehpour Ahmad Reza , Shirooie Samira , Bagheri Fariba , Farrokhi Vida , Mousavi Seyyedeh Elaheh , Ricciutelli Massimo , Cappellacci Loredana , López Víctor , Maggi Filippo , Petrelli Riccardo
Published: April 2021

The myrrh-like furanosesquiterpene isofuranodiene (IFD) is the main constituent of wild celery (Smyrnium olusatrum L., Apiaceae), an overlooked vegetable that was cultivated during the Roman Empire. In the present study, we investigated the protective effects of IFD pre-treatment against oxidative stress and inflammatory response in an animal model of ischemic stroke. IFD was isolated by the crystallization of Smyrnium olusatrum essential oil, and its structure and purity were confirmed by NMR and HPLC analyses. Acute pre-treatment of IFD (10 mg/kg i.p.) significantly reduced the levels of the inflammatory cytokines IL-1β and TNF-α, the expression of pNF-κB/NF-κB, and the lipid peroxidation indicator MDA. Finally, IFD boosted a faster recovery and better scores in grid-walking and modified neurological severity scores (mNSS) tests. Taken together, these findings indicate IFD as a promising lead compound for the discovery of new treatments of brain ischemia.
Budget Impact Analysis of Biosimilar Products in Spain in the Period 2009–2019
Authors: García-Goñi Manuel , Río-Álvarez Isabel , Carcedo David , Villacampa Alba
Published: April 2021

Since the first biosimilar medicine, Omnitrope® (active substance somatropin) was approved in 2006, 53 biosimilars have been authorized in Spain. We estimate the budget impact of biosimilars in Spain from the perspective of the National Health System (NHS) over the period between 2009 and 2019. Drug acquisition costs considering commercial discounts at public procurement procedures (hospital tenders) and uptake data for both originator and biosimilar as actual units consumed by the NHS were the two variables considered. Two scenarios were compared: a scenario where no biosimilars are available and the biosimilar scenario where biosimilars are effectively marketed. All molecules exposed to biosimilar competition during this period were included in the analysis. The robustness of the model was tested by conducting multiple sensitivity analyses. From the payer perspective, it is estimated that the savings produced by the adoption of biosimilars would reach EUR 2306 million over 11 years corresponding to the cumulative savings from all biosimilars. Three molecules (infliximab, somatropin and epoetin) account for 60% of the savings. This study provides the first estimation of the financial impact of biosimilars in Spain, considering both the effect of discounts that manufacturers give to hospitals and the growing market share of biosimilars. We estimate that in our last year of data, 2019, the savings derived from the use of biosimilars relative total pharmaceutical spending in Spain is 3.92%. Although more research is needed, our evidence supports the case that biosimilars represent a great opportunity to the sustainability of the NHS through rationalizing pharmaceutical spending and that the full potential of biosimilar-savings has not been achieved yet, as there is a high variability in biosimilar uptake across autonomous regions.
The YfkO Nitroreductase from Bacillus Licheniformis on Gold-Coated Superparamagnetic Nanoparticles: Towards a Novel Directed Enzyme Prodrug Therapy Approach
Authors: Ball Patrick , Hobbs Robert , Anderson Simon , Thompson Emma , Gwenin Vanessa , Von Ruhland Christopher , Gwenin Christopher
Published: April 2021

The bacterial nitroreductase NfnB has been the focus of a great deal of research for its use in directed enzyme prodrug therapy in combination with the nitroreductase prodrug CB1954 with this combination of enzyme and prodrug even entering clinical trials. Despite some promising results, there are major limitations to this research, such as the fact that the lowest reported Km for this enzyme far exceeds the maximum dosage of CB1954. Due to these limitations, new enzymes are now being investigated for their potential use in directed enzyme prodrug therapy. One such enzyme that has proved promising is the YfkO nitroreductase from Bacillus Licheniformis. Upon investigation, the YfkO nitroreductase was shown to have a much lower Km (below the maximum dosage) than that of NfnB as well as the fact that when reacting with the prodrug it produces a much more favourable ratio of enzymatic products than NfnB, forming more of the desired 4-hydroxylamine derivative of CB1954.
Synthesis and Evaluation of Novel Norfloxacin Isonitrile 99mTc Complexes as Potential Bacterial Infection Imaging Agents
Authors: Fang Si’an , Jiang Yuhao , Xiao Di , Zhang Xuran , Gan Qianqian , Ruan Qing , Zhang Junbo
Published: April 2021

To develop potential technetium-99m single-photon emission computed tomography (SPECT) imaging agents for bacterial infection imaging, the novel norfloxacin isonitrile derivatives CN4NF and CN5NF were synthesized and radiolabeled with a [99mTc][Tc(I)]+ core to obtain [99mTc]Tc-CN4NF and [99mTc]Tc-CN5NF. These compounds were produced in high radiolabeling yields and showed hydrophilicity and good stability in vitro. The bacterial binding assay indicated that [99mTc]Tc-CN4NF and [99mTc]Tc-CN5NF were specific to bacteria. Compared with [99mTc]Tc-CN4NF, biodistribution studies of [99mTc]Tc-CN5NF showed a higher uptake in bacteria-infected tissues than in turpentine-induced abscesses, indicating that [99mTc]Tc-CN5NF could distinguish bacterial infection from sterile inflammation. In addition, [99mTc]Tc-CN5NF had higher abscess/blood and abscess/muscle ratios. SPECT image of [99mTc]Tc-CN5NF showed that there was a clear accumulation in the infection site, suggesting that it could be a potential bacterial infection imaging radiotracer.
Engineered Human Heavy-Chain Ferritin with Half-Life Extension and Tumor Targeting by PAS and RGDK Peptide Functionalization
Authors: Yin Shuang , Wang Yan , Zhang Bingyang , Qu Yiran , Liu Yongdong , Dai Sheng , Zhang Yao , Wang Yingli , Bi Jingxiu
Published: April 2021

Ferritin, one of the most investigated protein nanocages, is considered as a promising drug carrier because of its advantageous stability and safety. However, its short half-life and undesirable tumor targeting ability has limited its usage in tumor treatment. In this work, two types of functional peptides, half-life extension peptide PAS, and tumor targeting peptide RGDK (Arg-Gly-Asp-Lys), are inserted to human heavy-chain ferritin (HFn) at C-terminal through flexible linkers with two distinct enzyme cleavable sites. Structural characterizations show both HFn and engineered HFns can assemble into nanoparticles but with different apparent hydrodynamic volumes and molecular weights. RGDK peptide enhanced the internalization efficiency of HFn and showed a significant increase of growth inhibition against 4T1 cell line in vitro. Pharmacokinetic study in vivo demonstrates PAS peptides extended ferritin half-life about 4.9 times in Sprague Dawley rats. RGDK peptides greatly enhanced drug accumulation in the tumor site rather than in other organs in biodistribution analysis. Drug loaded PAS-RGDK functionalized HFns curbed tumor growth with significantly greater efficacies in comparison with drug loaded HFn.
Clarithromycin Solid Lipid Nanoparticles for Topical Ocular Therapy: Optimization, Evaluation and In Vivo Studies
Authors: Nair Anroop , Shah Jigar , Al-Dhubiab Bandar , Jacob Shery , Patel Snehal , Venugopala Katharigatta , Morsy Mohamed , Gupta Sumeet , Attimarad Mahesh , Sreeharsha Nagaraja , Shinu Pottathil
Published: April 2021

Solid lipid nanoparticles (SLNs) are being extensively exploited as topical ocular carrier systems to enhance the bioavailability of drugs. This study investigated the prospects of drug-loaded SLNs to increase the ocular permeation and improve the therapeutic potential of clarithromycin in topical ocular therapy. SLNs were formulated by high-speed stirring and the ultra-sonication method. Solubility studies were carried out to select stearic acid as lipid former, Tween 80 as surfactant, and Transcutol P as cosurfactant. Clarithromycin-loaded SLN were optimized by fractional factorial screening and 32 full factorial designs. Optimized SLNs (CL10) were evaluated for stability, morphology, permeation, irritation, and ocular pharmacokinetics in rabbits. Fractional factorial screening design signifies that the sonication time and amount of lipid affect the SLN formulation. A 32 full factorial design established that both factors had significant influences on particle size, percent entrapment efficiency, and percent drug loading of SLNs. The release profile of SLNs (CL9) showed ~80% drug release in 8 h and followed Weibull model kinetics. Optimized SLNs (CL10) showed significantly higher permeation (30.45 μg/cm2/h; p < 0.0001) as compared to control (solution). CL10 showed spherical shape and good stability and was found non-irritant for ocular administration. Pharmacokinetics data demonstrated significant improvement of clarithromycin bioavailability (p < 0.0001) from CL10, as evidenced by a 150% increase in Cmax (~1066 ng/mL) and a 2.8-fold improvement in AUC (5736 ng h/mL) (p < 0.0001) as compared to control solution (Cmax; 655 ng/mL and AUC; 2067 ng h/mL). In summary, the data observed here demonstrate the potential of developed SLNs to improve the ocular permeation and enhance the therapeutic potential of clarithromycin, and hence could be a viable drug delivery approach to treat endophthalmitis.
Antidiabetic Flavonoids from Fruits of Morus alba Promoting Insulin-Stimulated Glucose Uptake via Akt and AMP-Activated Protein Kinase Activation in 3T3-L1 Adipocytes
Authors: Lim Sung Ho , Yu Jae Sik , Lee Ho Seon , Choi Chang-Ik , Kim Ki Hyun
Published: April 2021

Morus alba (Moraceae), known as white mulberry, has been used to treat fever, protect against liver damage, improve eyesight, and lower blood sugar levels in traditional oriental medicine. Few studies have been conducted on the antidiabetic compounds identified from M. alba and their underlying mechanisms of action. Consequently, in this study, the fruits of M. alba were investigated for potential antidiabetic natural products using 3T3-L1 adipocytes. Phytochemical analysis of the ethanolic extract of M. alba fruits, followed by high-performance liquid chromatography (HPLC), purification led to the isolation of two main compounds: rutin and quercetin-3-O-β-d-glucoside (Q3G). Long-term use of available drugs for treating type 2 diabetes ((T2D) is often accompanied by undesirable side effects, which have generated increased interest in the development of more effective and safer antidiabetic agents. Examination of the isolated compounds, rutin and Q3G, for antidiabetic or anti-obesity properties or both in 3T3-L1 adipocytes demonstrated that they both improved glucose uptake via Akt-mediated insulin signaling pathway or AMP-activated protein kinase (AMPK) activation in 3T3-L1 adipocytes. The compounds also showed a positive effect on lipid accumulation in adipocytes, suggesting that glucose uptake occurred through activation of the Akt and AMPK signaling pathway without inducing adipogenesis. Taken together, our findings suggest that rutin and Q3G in M. alba fruits have the potential to induce fewer side effects such as weight gain, and these active compounds could be potential therapeutic candidates for the management of T2D.
Dosing Accuracy of Oral Extemporaneous Suspensions of Antibiotics: Measuring Procedures and Administration Devices
Authors: Neves Inês , Auxtero Maria D.
Published: April 2021

Extemporaneous suspensions are often marketed with several administration devices that can be freely used by patients/caregivers. The homogeneity of suspensions requires shaking before use. Hence, it is crucial to assess the precision of all devices and the users’ awareness of the shaking procedure. This study was conducted at University Institute Egas Moniz with 40 pharmacy students who were asked to measure 2.5 and 5 mL of two extemporaneous azithromycin suspensions. Formulation A is marketed with a double-dosing spoon and oral syringe, whereas B includes a transparent dosing spoon. Both have a reconstitution cup. The user’s preference for administration devices, the degree of compliance with the ‘shake before use’ instruction and the accuracy of the manipulation were assessed. The double-dosing spoon was the preferred device. The “shake before use” instruction was overlooked by most volunteers. The average measured volumes obtained with the double-dosing spoon were significantly different from the ones obtained with the oral syringe (p < 0.001) and significantly lower than the reference dose (p < 0.001). The oral syringe originates significantly higher values than the reference dose (p < 0.001). The dosing spoons values were significantly different from each other (p < 0.001). Liquid medicines containing several administration devices may be a challenge since they are nonequivalent.
Resveratrol-Loaded Hydrogel Contact Lenses with Antioxidant and Antibiofilm Performance
Authors: Vivero-Lopez María , Muras Andrea , Silva Diana , Serro Ana Paula , Otero Ana , Concheiro Angel , Alvarez-Lorenzo Carmen
Published: April 2021

Contact lenses (CLs) are prone to biofilm formation, which may cause severe ocular infections. Since the use of antibiotics is associated with resistance concerns, here, two alternative strategies were evaluated to endow CLs with antibiofilm features: copolymerization with the antifouling monomer 2-methacryloyloxyethyl phosphorylcholine (MPC) and loading of the antioxidant resveratrol with known antibacterial activity. MPC has, so far, been used to increase water retention on the CL surface (Proclear® 1 day CLs). Both poly(hydroxyethyl methacrylate) (HEMA) and silicone hydrogels were prepared with MPC covering a wide range of concentrations (from 0 to 101 mM). All hydrogels showed physical properties adequate for CLs and successfully passed the hen’s egg-chorioallantoic membrane (HET-CAM) test. Silicone hydrogels had stronger affinity for resveratrol, with higher loading and a slower release rate. Ex vivo cornea and sclera permeability tests revealed that resveratrol released from the hydrogels readily accumulated in both tissues but did not cross through. The antibiofilm tests against Pseudomonas aeruginosa and Staphylococcus aureus evidenced that, in general, resveratrol decreased biofilm formation, which correlated with its concentration-dependent antibacterial capability. Preferential adsorption of lysozyme, compared to albumin, might also contribute to the antimicrobial activity. In addition, importantly, the loading of resveratrol in the hydrogels preserved the antioxidant activity, even against photodegradation. Overall, the designed hydrogels can host therapeutically relevant amounts of resveratrol to be sustainedly released on the eye, providing antibiofilm and antioxidant performance.
Development of Epirubicin-Loaded Biocompatible Polymer PLA–PEG–PLA Nanoparticles: Synthesis, Characterization, Stability, and In Vitro Anticancerous Assessment
Authors: Massadeh Salam , Almohammed Iman , Barhoush Eman , Omer Mustafa , Aldhawi Nouf , Almalik Abdulaziz , Alaamery Manal
Published: April 2021

Epirubicin (EPI) is an anti-cancerous chemotherapeutic drug that is an effective epimer of doxorubicin with less cardiotoxicity. Although EPI has fewer side effects than its analog, doxorubicin, this study aims to develop EPI nanoparticles as an improved formula of the conventional treatment of EPI in its free form. Methods: In this study, EPI-loaded polymeric nanoparticles (EPI-NPs) were prepared by the double emulsion method using a biocompatible poly (lactide) poly (ethylene glycol) poly(lactide) (PLA–PEG–PLA) polymer. The physicochemical properties of the EPI-NPs were determined by dynamic light scattering (DLS), transmission electron microscopy (TEM), differential scanning calorimetry (DSC), entrapment efficiency and stability studies. The effect of EPI-NPs on cancer cells was determined by high throughput imaging and flow cytometry. Results: The synthesis process resulted in monodisperse EPI-NPs with a size of 166.93 ± 1.40 nm and an elevated encapsulation efficiency (EE) of 88.3%. In addition, TEM images revealed the spherical uniformness of EPI-NPs with no aggregation, while the cellular studies presented the effect of EPI-NPs on MCF-7 cells’ viability; after 96 h of treatment, the MCF-7 cells presented considerable apoptotic activity. The stability study showed that the EPI-NPs remained stable at room temperature at physiological pH for over 30 days. Conclusion: EPI-NPs were successfully encapsulated within a highly stable biocompatible polymer with minimal loss of the drug. The used polymer has low cytotoxicity and EPI-NPs induced apoptosis in estrogen-positive cell line, making them a promising, safe treatment for cancer with less adverse side effects.
Effect of Printing Parameters on Dimensional Error, Surface Roughness and Porosity of FFF Printed Parts with Grid Structure
Authors: Buj-Corral Irene , Bagheri Ali , Sivatte-Adroer Maurici
Published: April 2021

Extrusion printing processes allow for manufacturing complex shapes in a relatively cheap way with low-cost machines. The present study analyzes the effect of printing parameters on dimensional error, roughness, and porosity of printed PLA parts obtained with grid structure. Parts are obtained by means of the fused filament fabrication (FFF) process. Four variables are chosen: Layer height, temperature, speed, and flow rate. A two-level full factorial design with a central point is used to define the experimental tests. Dimensional error and porosity are measured with a profile projector, while roughness is measured with a contact roughness meter. Mathematical regression models are found for each response, and multi-objective optimization is carried out by means of the desirability function. Dimensional error and roughness depend mainly on layer height and flow rate, while porosity depends on layer height and printing speed. Multi-objective optimization shows that recommended values for the variables are layer height 0.05 mm, temperature 195 ºC, speed 50 mm/min, and flow rate 0.93, when dimensional error and roughness are to be minimized, and porosity requires a target value of 60%. The present study will help to select appropriate printing parameters for printing porous structures such as those found in prostheses, by means of extrusion processes.
Sensorized Robotic Skin Based on Piezoresistive Sensor Fiber Composites Produced with Injection Molding of Liquid Silicone
Authors: Georgopoulou Antonia , Michel Silvain , Clemens Frank
Published: April 2021

Soft robotics and flexible electronics are rising in popularity and can be used in many applications. However, there is still a need for processing routes that allow the upscaling in production for functional soft robotic parts in an industrial scale. In this study, injection molding of liquid silicone is suggested as a fabrication method for sensorized robotic skin based on sensor fiber composites. Sensor fibers based on thermoplastic elastomers with two different shore hardness (50A and 70A) are combined with different silicone materials. A mathematical model is used to predict the mechanical load transfer from the silicone matrix to the fiber and shows that the matrix of the lowest shore hardness should not be combined with the stiffer fiber. The sensor fiber composites are fixed on a 3D printed robotic finger. The sensorized robotic skin based on the composite with the 50A fiber in combination with pre-straining gives good sensor performance as well as a large elasticity. It is proposed that a miss-match in the mechanical properties between fiber sensor and matrix should be avoided in order to achieve low drift and relaxation. These findings can be used as guidelines for material selection for future sensor integrated soft robotic systems.
Plasticized Polymer Blend Electrolyte Based on Chitosan for Energy Storage Application: Structural, Circuit Modeling, Morphological and Electrochemical Properties
Authors: Hamsan M. H. , Nofal Muaffaq M. , Aziz Shujahadeen B. , Brza M. A. , Dannoun Elham M. A. , Murad Ary R. , Kadir M. F. Z. , Muzakir S. K.
Published: April 2021

Chitosan (CS)-dextran (DN) biopolymer electrolytes doped with ammonium iodide (NH4I) and plasticized with glycerol (GL), then dispersed with Zn(II)-metal complex were fabricated for energy device application. The CS:DN:NH4I:Zn(II)-complex was plasticized with various amounts of GL and the impact of used metal complex and GL on the properties of the formed electrolyte were investigated.The electrochemical impedance spectroscopy (EIS) measurements have shown that the highest conductivity for the plasticized system was 3.44 × 10−4 S/cm. From the x-ray diffraction (XRD) measurements, the plasticized electrolyte with minimum degree of crystallinity has shown the maximum conductivity. The effect of (GL) plasticizer on the film morphology was studied using FESEM. It has been confirmed via transference number analysis (TNM) that the transport mechanism in the prepared electrolyte is predominantly ionic in nature with a high transference number of ion (ti)of 0.983. From a linear sweep voltammetry (LSV) study, the electrolyte was found to be electrochemically constant as the voltage sweeps linearly up to 1.25 V. The cyclic voltammetry (CV) curve covered most of the area of the current–potential plot with no redox peaks and the sweep rate was found to be affecting the capacitance. The electric double-layer capacitor (EDLC) has shown a great performance of specific capacitance (108.3 F/g), ESR(47.8 ohm), energy density (12.2 W/kg) and power density (1743.4 W/kg) for complete 100 cycles at a current density of 0.5 mA cm−2.
Active Biodegradable Films Based on Sweet Lime Peel Residue and Its Effect on Quality of Fish Fillets
Authors: Arafat Yasir , Altemimi Ammar , Pratap-Singh Anubhav , Badwaik Laxmikant S.
Published: April 2021

Residual sweet lime peels after the extraction of essential oil by solvent free microwave extraction were used for developing biodegradable film. Glycerol as a plasticizer, soya lecithin as an emulsifier and sweet lime essential oil (0, 1, 2 and 3%) as an active agent was employed. Developed films were analyzed for their mechanical, barrier and antimicrobial properties. The films (with 3% essential oil) which reported highest antimicrobial property against E. coli (24.24 ± 2.69 mm) were wrapped on fish fillet and stored at the refrigerated condition for 12 days. The quality of fish fillets was evaluated every 4 days and compared with polyethylene wrapped and control fish fillets. The active film wrapped sample showed less surface microbial count (3.28 ± 0.16 log cfu/cm2) compared to polyethylene wrapped sample. The hardness values were increased during storage and cohesiveness and springiness of all wrapped samples decreased from day 0 to day 12.
Fabrication of Poly(Ethylene-glycol 1,4-Cyclohexane Dimethylene-Isosorbide-Terephthalate) Electrospun Nanofiber Mats for Potential Infiltration of Fibroblast Cells
Authors: El-Ghazali Sofia , Khatri Muzamil , Mehdi Mujahid , Kharaghani Davood , Tamada Yasushi , Katagiri Anna , Kobayashi Shunichi , Kim Ick Soo
Published: April 2021

Recently, bio-based electrospun nanofiber mats (ENMs) have gained substantial attention for preparing polymer-based biomaterials intended for use in cell culture. Herein, we prepared poly(ethylene-glycol 1,4-Cyclohexane dimethylene-isosorbide-terephthalate) (PEICT) ENMs using the electrospinning technique. Cell adhesion and cell viability of PEICT ENMs were checked by fibroblast cell culture. Field emission electron microscope (FE-SEM) image showed a randomly interconnected fiber network, smooth morphology, and cell adhesion on PEICT ENM. Fibroblasts were cultured in an adopted cell culturing environment on the surface of PEICT ENMs to confirm their biocompatibility and cell viability. Additionally, the chemical structure of PEICT ENM was checked under Fourier-transform infrared (FTIR) spectroscopy and the results were supported by -ray photoelectron (XPS) spectroscopy. The water contact angle (WCA) test showed the hydrophobic behavior of PEICT ENMs in parallel to good fibroblast cell adhesion. Hence, the results confirmed that PEICT ENMs can be potentially utilized as a biomaterial.
Synthesis of an Addition-Crosslinkable, Silicon-Modified Polyolefin via Reactive Extrusion Monitored by In-Line Raman Spectroscopy
Authors: Ulitzsch Steffen , Bäuerle Tim , Stefanakis Mona , Brecht Marc , Chassé Thomas , Lorenz Günter , Kandelbauer Andreas
Published: April 2021

We present the modification of ethylene-propylene rubber (EPM) with vinyltetra-methydisiloxane (VTMDS) via reactive extrusion to create a new silicone-based material with the potential for high-performance applications in the automotive, industrial and biomedical sectors. The radical-initiated modification is achieved with a peroxide catalyst starting the grafting reaction. The preparation process of the VTMDS-grafted EPM was systematically investigated using process analytical technology (in-line Raman spectroscopy) and the statistical design of experiments (DoE). By applying an orthogonal factorial array based on a face-centered central composite experimental design, the identification, quantification and mathematical modeling of the effects of the process factors on the grafting result were undertaken. Based on response surface models, process windows were defined that yield high grafting degrees and good grafting efficiency in terms of grafting agent utilization. To control the grafting process in terms of grafting degree and grafting efficiency, the chemical changes taking place during the modification procedure in the extruder were observed in real-time using a spectroscopic in-line Raman probe which was directly inserted into the extruder. Successful grafting of the EPM was validated in the final product by 1H-NMR and FTIR spectroscopy.