bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of Resveratrol in Prevention and Control of Cardiovascular Disorders and Cardiovascular Complications Related to COVID-19 Disease: Mode of Action and Approaches Explored to Increase Its Bioavailability
Authors: Gligorijević Nikola , Stanić-Vučinić Dragana , Radomirović Mirjana , Stojadinović Marija , Khulal Urmila , Nedić Olgica , Ćirković Veličković Tanja
Published: May 2021

Resveratrol is a phytoalexin produced by many plants as a defense mechanism against stress-inducing conditions. The richest dietary sources of resveratrol are berries and grapes, their juices and wines. Good bioavailability of resveratrol is not reflected in its high biological activity in vivo because of resveratrol isomerization and its poor solubility in aqueous solutions. Proteins, cyclodextrins and nanomaterials have been explored as innovative delivery vehicles for resveratrol to overcome this limitation. Numerous in vitro and in vivo studies demonstrated beneficial effects of resveratrol in cardiovascular diseases (CVD). Main beneficial effects of resveratrol intake are cardioprotective, anti-hypertensive, vasodilatory, anti-diabetic, and improvement of lipid status. As resveratrol can alleviate the numerous factors associated with CVD, it has potential as a functional supplement to reduce COVID-19 illness severity in patients displaying poor prognosis due to cardio-vascular complications. Resveratrol was shown to mitigate the major pathways involved in the pathogenesis of SARS-CoV-2 including regulation of the renin-angiotensin system and expression of angiotensin-converting enzyme 2, stimulation of immune system and downregulation of pro-inflammatory cytokine release. Therefore, several studies already have anticipated potential implementation of resveratrol in COVID-19 treatment. Regular intake of a resveratrol rich diet, or resveratrol-based complementary medicaments, may contribute to a healthier cardio-vascular system, prevention and control of CVD, including COVID-19 disease related complications of CVD.
The RNA-Binding Protein HuD Regulates Alternative Splicing and Alternative Polyadenylation in the Mouse Neocortex
Authors: Sena Rebecca M. , Twiss Jeffery L. , Gardiner Amy S. , Dell’Orco Michela , Linsenbardt David N. , Perrone-Bizzozero Nora I.
Published: May 2021

The neuronal Hu/ELAV-like proteins HuB, HuC and HuD are a class of RNA-binding proteins that are crucial for proper development and maintenance of the nervous system. These proteins bind to AU-rich elements (AREs) in the untranslated regions (3′-UTRs) of target mRNAs regulating mRNA stability, transport and translation. In addition to these cytoplasmic functions, Hu proteins have been implicated in alternative splicing and alternative polyadenylation in the nucleus. The purpose of this study was to identify transcriptome-wide effects of HuD deletion on both of these nuclear events using RNA sequencing data obtained from the neocortex of Elavl4–/– (HuD KO) mice. HuD KO affected alternative splicing of 310 genes, including 17 validated HuD targets such as Cbx3, Cspp1, Snap25 and Gria2. In addition, deletion of HuD affected polyadenylation of 53 genes, with the majority of significantly altered mRNAs shifting towards usage of proximal polyadenylation signals (PAS), resulting in shorter 3′-UTRs. None of these genes overlapped with those showing alternative splicing events. Overall, HuD KO had a greater effect on alternative splicing than polyadenylation, with many of the affected genes implicated in several neuronal functions and neuropsychiatric disorders.
Enthalpic and Liquid-Phase Adsorption Study of Toluene–Cyclohexane and Toluene–Hexane Binary Systems on Modified Activated Carbons
Authors: Hernández-Monje Diana , Giraldo Liliana , Moreno-Piraján Juan Carlos
Published: May 2021

The liquid-phase adsorption of toluene in cyclohexane and hexane solutions on modified activated carbons was evaluated; the energy involved in the interaction between these solutions and the solids was determined by immersion enthalpies of pure solvents and their mixtures, and the contribution of the system constituents was calculated by differential enthalpies. The thermal treatment generated modifications that favored adsorption and interaction with the evaluated solutions, since it increased the textural parameters and the basic character of the samples. Cyclohexane could create greater competition with the adsorption sites compared to hexane, but it favored the increase in adsorption capacities (0.416 to 1.026 mmol g−1) and the interactions with the solid evaluated through the immersion enthalpies. The immersion enthalpies of pure solvents (−16.36 to −112.7 J g−1) and mixtures (−25.65 to −104.34 J g−1) had exothermic behaviors that were decreasing due to the possible displacement of solvent molecules when increasing the solute concentration in the mixtures. The differential enthalpies for toluene were negative (−18.63 to −2.14 J), mainly due to the π–π interaction with the solid, while those of the solvent–solid component tended to be positive values (−4.25 to 55.97 J) due to the displacement of the solvent molecules by those of toluene.
Modulation of γ-Secretase Activity by a Carborane-Based Flurbiprofen Analogue
Authors: Saretz Stefan , Basset Gabriele , Useini Liridona , Laube Markus , Pietzsch Jens , Drača Dijana , Maksimović-Ivanić Danijela , Trambauer Johannes , Steiner Harald , Hey-Hawkins Evamarie
Published: May 2021

All over the world, societies are facing rapidly aging populations combined with a growing number of patients suffering from Alzheimer’s disease (AD). One focus in pharmaceutical research to address this issue is on the reduction of the longer amyloid-β (Aβ) fragments in the brain by modulation of γ-secretase, a membrane-bound protease. R-Flurbiprofen (tarenflurbil) was studied in this regard but failed to show significant improvement in AD patients in a phase 3 clinical trial. This was mainly attributed to its low ability to cross the blood–brain barrier (BBB). Here, we present the synthesis and in vitro evaluation of a racemic meta-carborane analogue of flurbiprofen. By introducing the carborane moiety, the hydrophobicity could be shifted into a more favourable range for the penetration of the blood–brain barrier, evident by a logD7.4 value of 2.0. Furthermore, our analogue retained γ-secretase modulator activity in comparison to racemic flurbiprofen in a cell-based assay. These findings demonstrate the potential of carboranes as phenyl mimetics also in AD research.
Cardiometabolic Risk Factors in Rosuvastatin-Treated Men with Mixed Dyslipidemia and Early-Onset Androgenic Alopecia
Authors: Krysiak Robert , Basiak Marcin , Okopień Bogusław
Published: May 2021

Men with early-onset androgenetic alopecia are characterized by hormonal profiles similar to those observed in women with polycystic ovary syndrome. The purpose of this research was to investigate levels of cardiometabolic risk factors in 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA)-treated men with early-onset androgenic alopecia. We studied two matched rosuvastatin-treated groups of men with mixed dyslipidemia: subjects with early-onset androgenic alopecia (group A) and subjects with normal hair growth (group B). Plasma lipids, glucose homeostasis markers, and levels of sex hormones, uric acid, hsCRP, homocysteine, fibrinogen, and 25-hydroxyvitamin D were measured before entering the study and six months later. Both groups differed in insulin sensitivity and levels of calculated bioavailable testosterone, dehydroepiandrosterone-sulfate, uric acid, hsCRP, fibrinogen, and 25-hydroxyvitamin D. Though observed in both study groups, treatment-induced reductions in total cholesterol, LDL cholesterol, hsCRP, and fibrinogen were more pronounced in group B than group A. Moreover, only in group A did rosuvastatin deteriorate insulin sensitivity, and only in group B did the drug affect uric acid, homocysteine, and 25-hydroxyvitamin D. The impact of rosuvastatin on cardiometabolic risk factors correlated with insulin sensitivity, calculated bioavailable testosterone, and dehydroepiandrosterone-sulfate. The obtained results suggest that men with early-onset androgenic alopecia may benefit to a lesser degree from rosuvastatin treatment than their peers.
Effects of Kynurenic Acid on the Rat Aorta Ischemia—Reperfusion Model: Pharmacological Characterization and Proteomic Profiling
Authors: Lima Viviane Soares Souza , Mariano Douglas Oscar Ceolin , Vigerelli Hugo , Janussi Sabrina Cardoso , Baptista Thayz Vanalli Lima , Claudino Mário Angelo , Pimenta Daniel Carvalho , Sciani Juliana Mozer
Published: May 2021

Kynurenic acid (KYNA) is derived from tryptophan, formed by the kynurenic pathway. KYNA is being widely studied as a biomarker for neurological and cardiovascular diseases, as it is found in ischemic conditions as a protective agent; however, little is known about its effect after ischemia-reperfusion in the vascular system. We induced ischemia for 30 min followed by 5 min reperfusion (I/R) in the rat aorta for KYNA evaluation using functional assays combined with proteomics. KYNA recovered the exacerbated contraction induced by phenylephrine and relaxation induced by acetylcholine or sodium nitroprussiate in the I/R aorta, with vessel responses returning to values observed without I/R. The functional recovery can be related to the antioxidant activity of KYNA, which may be acting on the endothelium-injury prevention, especially during reperfusion, and to proteins that regulate neurotransmission and cell repair/growth, expressed after the KYNA treatment. These proteins interacted in a network, confirming a protein profile expression for endothelium and neuron repair after I/R. Thus, the KYNA treatment had the ability to recover the functionality of injured ischemic-reperfusion aorta, by tissue repairing and control of neurotransmitter release, which reinforces its role in the post-ischemic condition, and can be useful in the treatment of such disease.
Two-Sided Antibacterial Cellulose Combining Probiotics and Silver Nanoparticles
Authors: Sabio Laura , Sosa Andrea , Delgado-López José M. , Dominguez-Vera José M.
Published: May 2021

The constant increase of antibiotic-resistant bacteria demands the design of novel antibiotic-free materials. The combination of antibacterials in a biocompatible biomaterial is a very promising strategy to treat infections caused by a broader spectrum of resistant pathogens. Here, we combined two antibacterials, silver nanoparticles (AgNPs) and living probiotics (Lactobacillus fermentum, Lf), using bacterial cellulose (BC) as scaffold. By controlling the loading of each antibacterial at opposite BC sides, we obtained a two-sided biomaterial (AgNP-BC-Lf) with a high density of alive and metabolically active probiotics on one surface and AgNPs on the opposite one, being probiotics well preserved from the killer effect of AgNPs. The resulting two-sided biomaterial was characterized by Field-Emission Scanning Electron Microscopy (FESEM) and Confocal Laser Scanning Microscopy (CLSM). The antibacterial capacity against Pseudomonas aeruginosa (PA), an opportunistic pathogen responsible for a broad range of skin infections, was also assessed by agar diffusion tests in pathogen-favorable media. Results showed an enhanced activity against PA when both antibacterials were combined into BC (AgNP-BC-Lf) with respect to BC containing only one of the antibacterials, BC-Lf or AgNP-BC. Therefore, AgNP-BC-Lf is an antibiotic-free biomaterial that can be useful for the therapy of topical bacterial infections.
Efficient Synthesis of a New Family of 2,6-Disulfanyl-9-selenabicyclo[3.3.1]nonanes
Authors: Musalov Maxim V. , Potapov Vladimir A. , Amosova Svetlana V.
Published: May 2021

The efficient synthesis of a new family of 2,6-disulfanyl-9-selenabicyclo[3.3.1]nonanes in high yields has been developed based on 9-selenabicyclo[3.3.1]nonane-2,6-dithiolate anion generated from bis-isothiouronium salt of 2,6-dibromo-9-selenabicyclo[3.3.1]nonane. The derivatives of 2,6-disulfanyl-9-selenabicyclo[3.3.1]nonane containing alkyl, allyl and benzyl moieties have been prepared in 90–99% yields by nucleophilic substitution of 9-selenabicyclo[3.3.1]nonane-2,6-dithiolate anion with alkyl, allyl and benzyl halides. The reaction of nucleophilic addition of 9-selenabicyclo[3.3.1]nonane-2,6-dithiolate anion to alkyl propiolates afforded 2,6-di(vinylsulfanyl)-9-selenabicyclo[3.3.1]nonanes. The conditions for regio- and stereoselective addition of 9-selenabicyclo[3.3.1]nonane-2,6-dithiolate anion to a triple bond of alkyl propiolates have been found. To date, not a single representative of 2,6-disulfanyl-9-selenabicyclo[3.3.1]nonanes has been described in the literature.
Incorporation of Antibiotics into Solid Lipid Nanoparticles: A Promising Approach to Reduce Antibiotic Resistance Emergence
Authors: Arana Lide , Gallego Lucia , Alkorta Itziar
Published: May 2021

Antimicrobial resistance is one of the biggest threats to global health as current antibiotics are becoming useless against resistant infectious pathogens. Consequently, new antimicrobial strategies are urgently required. Drug delivery systems represent a potential solution to improve current antibiotic properties and reverse resistance mechanisms. Among different drug delivery systems, solid lipid nanoparticles represent a highly interesting option as they offer many advantages for nontoxic targeted drug delivery. Several publications have demonstrated the capacity of SLNs to significantly improve antibiotic characteristics increasing treatment efficiency. In this review article, antibiotic-loaded solid lipid nanoparticle-related works are analyzed to summarize all information associated with applying these new formulations to tackle the antibiotic resistance problem. The main antimicrobial resistance mechanisms and relevant solid lipid nanoparticle characteristics are presented to later discuss the potential of these nanoparticles to improve current antibiotic treatment characteristics and overcome antimicrobial resistance mechanisms. Moreover, solid lipid nanoparticles also offer new possibilities for other antimicrobial agents that cannot be administrated as free drugs. The advantages and disadvantages of these new formulations are also discussed in this review. Finally, given the progress of the studies carried out to date, future directions are discussed.
A Multiscale Investigation on the Thermal Transport in Polydimethylsiloxane Nanocomposites: Graphene vs. Borophene
Authors: Di Pierro Alessandro , Mortazavi Bohayra , Noori Hamidreza , Rabczuk Timon , Fina Alberto
Published: May 2021

Graphene and borophene are highly attractive two-dimensional materials with outstanding physical properties. In this study we employed combined atomistic continuum multi-scale modeling to explore the effective thermal conductivity of polymer nanocomposites made of polydimethylsiloxane (PDMS) polymer as the matrix and graphene and borophene as nanofillers. PDMS is a versatile polymer due to its chemical inertia, flexibility and a wide range of properties that can be tuned during synthesis. We first conducted classical Molecular Dynamics (MD) simulations to calculate the thermal conductance at the interfaces between graphene and PDMS and between borophene and PDMS. Acquired results confirm that the interfacial thermal conductance between nanosheets and polymer increases from the single-layer to multilayered nanosheets and finally converges, in the case of graphene, to about 30 MWm−2 K−1 and, for borophene, up to 33 MWm−2 K−1. The data provided by the atomistic simulations were then used in the Finite Element Method (FEM) simulations to evaluate the effective thermal conductivity of polymer nanocomposites at the continuum level. We explored the effects of nanofiller type, volume content, geometry aspect ratio and thickness on the nanocomposite effective thermal conductivity. As a very interesting finding, we found that borophene nanosheets, despite having almost two orders of magnitude lower thermal conductivity than graphene, can yield very close enhancement in the effective thermal conductivity in comparison with graphene, particularly for low volume content and small aspect ratios and thicknesses. We conclude that, for the polymer-based nanocomposites, significant improvement in the thermal conductivity can be reached by improving the bonding between the fillers and polymer, or in other words, by enhancing the thermal conductance at the interface. By taking into account the high electrical conductivity of borophene, our results suggest borophene nanosheets as promising nanofillers to simultaneously enhance the polymers’ thermal and electrical conductivity.
Gold Nanoparticles Prepared with Phyllanthus emblica Fruit Extract and Bifidobacterium animalis subsp. lactis Can Induce Apoptosis via Mitochondrial Impairment with Inhibition of Autophagy in the Human Gastric Carcinoma Cell Line AGS
Authors: Wang Rongbo , Xu Xingyue , Puja Aditi Mitra , Perumalsamy Haribalan , Balusamy Sri Renukadevi , Kim Hoon , Kim Yeon-Ju
Published: May 2021

(1) Background: Nanotechnology is being widely applied for anticancer strategies with few side effects. Nanoparticles (NPs) prepared from natural extracts are promising candidates for cancer treatment because of their unique physicochemical characteristics. This study aimed to prepare gold nanoparticles (AuNPs) from Phyllanthus emblica fruit extract (PEFE) using Bifidobacterium animalis subsp. lactis (B. lactis) and to evaluate their anticancer activity against the human gastric adenocarcinoma cell-line (AGS). (2) Methods: The safety of microbial biosynthesis AuNPs (PEFE-AuNPs) was assessed by evaluating the cytotoxicity. The anticancer activity of PEFE-AuNPs was investigated in AGS cells in terms of apoptosis and autophagy. (3) Results: PEFE-AuNPs exhibited significant cytotoxicity against AGS cells but not against normal cells. The apoptosis induced by PEFE-AuNPs in AGS cells was associated with PTEN-induced kinase 1 (PINK1)-Parkin mediated reduction of mitochondrial membrane potential and activation of intracellular signaling apoptosis pathways. The anticancer activity of PEFE-AuNPs was associated with induction of apoptosis through inhibition of autophagy, downregulation of LC3-II/LC3-I and Beclin-1 expression, and upregulation of p62 expression in AGS cells. (4) Conclusions: This study is the first to demonstrate the anticancer activity of PEFE-AuNPs against AGS cells. Our results provide a good starting point for the development of new anticancer products based on gold nanoparticles of P. emblica fruit extract.
25-Hydroxyvitamin D and Cardiorespiratory Fitness in Prepubertal Overweight and Obese Children
Authors: Villalba-Heredia Lorena , Comeras-Chueca Cristina , González-Agüero Alejandro , Domingo-del-Val Daniel , Calmarza Pilar , Vicente-Rodríguez Germán , Casajús José A. , Matute-Llorente Ángel
Published: May 2021

Childhood obesity has become a major global health problem. Vitamin D deficiency and poor cardiorespiratory fitness are highly prevalent in children with overweight or obesity, but little is known about their relationships. In this study, we aimed to analyze the relationship between serum 25-hydroxyvitamin D (25(OH)D) and cardiorespiratory fitness parameters in prepubertal obese and overweight children. A cross-sectional design with a sample of 57 prepubertal children, aged 9–11 years, with overweight or obesity was used. The fasting concentration of 25(OH)D was analyzed with a chemiluminescent microparticle immunoassay. Fat and lean body masses were determined by using DXA. Maximal oxygen uptake (VO2max) was measured with the maximal treadmill test. A total of 68.4% of the sample had sufficient levels of 25(OH)D. As expected, their cardiorespiratory fitness was poor compared with that of normal-weight children, but 60% of the group exceeded the median obesity-specific reference values. No differences were found between the sexes for relative VO2max or 25(OH)D levels. Moreover, no correlations were found between 25(OH)D and body composition or cardiorespiratory parameters for sex or vitamin D groups. Vitamin D status seems not to be directly related to body composition or cardiorespiratory fitness in prepubertal overweight or obese children.
Trends in Eating Habits and Body Weight Status, Perception Patterns and Management Practices among First-Year Students of Kaunas (Lithuania) Universities, 2000–2017
Authors: Kriaucioniene Vilma , Raskiliene Asta , Petrauskas Dalius , Petkeviciene Janina
Published: May 2021

Students’ transition from high school to university is accompanied by lifestyle changes. This study aimed to assess trends in students’ body weight status, perception, management practices and eating habits from 2000 to 2017. Three cross-sectional surveys were carried out among the first-year students of five Kaunas (Lithuania) universities in 2000, 2010 and 2017. The self-administered questionnaires were filled in during lectures. Altogether, 3275 students aged 20.0 (1.5) years participated in the survey. The prevalence of self-reported overweight increased among male students from 11.3% in 2000 to 24.3% in 2017 and female students from 5.2 to 9.6%. The intake frequency of fruits, vegetables and cereals increased, and red meat decreased. At a normal BMI, more female than male students perceived themselves as being ‘too fat’ (19.4% and 8.8% in 2017), while more male than female students perceived themselves as being ‘too thin’ (37.2% and 4.5% in 2017). More females than males were dissatisfied with their weight, worried about gaining weight and tried to lose weight. Weight-management practices were associated with body weight, self-perception, dissatisfaction, worries about weight gain and eating behaviours. Our study highlights the need for interventions to increase the accuracy of weight perception and to promote the appropriate weight-management methods, addressing gender differences.
Administration of Bifidobacterium breve Improves the Brain Function of Aβ1-42-Treated Mice via the Modulation of the Gut Microbiome
Authors: Zhu Guangsu , Zhao Jianxin , Zhang Hao , Chen Wei , Wang Gang
Published: May 2021

Psychobiotics are used to treat neurological disorders, including mild cognitive impairment (MCI) and Alzheimer’s disease (AD). However, the mechanisms underlying their neuroprotective effects remain unclear. Herein, we report that the administration of bifidobacteria in an AD mouse model improved behavioral abnormalities and modulated gut dysbiosis. Bifidobacterium breve CCFM1025 and WX treatment significantly improved synaptic plasticity and increased the concentrations of brain-derived neurotrophic factor (BDNF), fibronectin type III domain-containing protein 5 (FNDC5), and postsynaptic density protein 95 (PSD-95). Furthermore, the microbiome and metabolomic profiles of mice indicate that specific bacterial taxa and their metabolites correlate with AD-associated behaviors, suggesting that the gut–brain axis contributes to the pathophysiology of AD. Overall, these findings reveal that B. breve CCFM1025 and WX have beneficial effects on cognition via the modulation of the gut microbiome, and thus represent a novel probiotic dietary intervention for delaying the progression of AD.
Involving Parents in Promoting Healthy Energy Balance-Related Behaviors in Preschoolers: A Mixed Methods Impact and Process Evaluation of SuperFIT
Authors: Harms Lisa S. E. , Gerards Sanne M. P. L. , Kremers Stef P. J. , Bessems Kathelijne M. H. H. , van Luijk Carsten , Arslan Tülay , Mombers Femke M. , Gubbels Jessica S.
Published: May 2021

Parental involvement is an essential component of obesity prevention interventions for children. The present study provides a process and impact evaluation of the family component of SuperFIT. SuperFIT is a comprehensive, integrated intervention approach aiming to improve energy balance-related behaviors (EBRBs) of young children (2–4 years). A mixed methods design combined in-depth interviews with parents (n = 15) and implementers (n = 3) with questionnaire data on nutritional and physical activity-related parenting practices (CFPQ and PPAPP), the physical home environment (EPAO_SR) (n = 41), and intervention appreciation (n = 19). Results were structured using the concepts of reach, adoption, implementation, and perceived impact. Findings indicated that the families reached were mostly those that were already interested in the topic. Participants of the intervention appreciated the information received and the on-the-spot guidance on their child’s behavior. Having fun was considered a success factor within the intervention. Parents expressed the additional need for peer-to-peer discussion. SuperFIT increased awareness and understanding of parents’ own behavior. Parents made no changes in daily life routines or the physical home environment. Translating knowledge and learned strategies into behavior at home has yet to be achieved. To optimize impact, intervention developers should find the right balance between accessibility, content, and intensity of interventions for parents.
The Association between Maternal Stress and Glucocorticoid Rhythmicity in Human Milk
Authors: Romijn Michelle , van Tilburg Luca J. L. , Hollanders Jonneke J. , van der Voorn Bibian , de Goede Paul , Dolman Koert M. , Heijboer Annemieke C. , Broekman Birit F. P. , Rotteveel Joost , Finken Martijn J. J.
Published: May 2021

Background: Chronic stress is often accompanied by alterations in the diurnal rhythm of hypothalamus–pituitary–adrenal activity. However, there are limited data on the diurnal rhythmicity of breast milk glucocorticoids (GCs) among women with psychological distress. We compared mothers who sought consultation at an expertise center for pregnant women with an increased risk of psychological distress with control mothers for GC diurnal rhythmicity in milk and saliva obtained at the same time. Methods: We included 19 mothers who sought consultation at the psychiatry–obstetric–pediatric (POP) outpatient clinic and 44 control mothers. One month postpartum, mothers collected on average eight paired milk and saliva samples during a 24 h period. GC levels were measured using liquid chromatography–tandem mass spectrometry. GC rhythmicity parameters were determined with specialized software. Results: For both milk and saliva, no group differences regarding GC rhythms were found. Milk cortisol area under the curve with respect to the ground was lower in the POP group than in the control group (p = 0.02). GC levels in human milk and saliva were highly correlated within each group (p < 0.001). Conclusion: Although there were no differences between groups in GC rhythmicity, the total amount of milk cortisol was lower in the POP group. Long-term follow-up is needed to address the impact of vertical transmission of breast milk GCs.
Salmonella enterica Serovar Minnesota Biofilms, Susceptibility to Biocides, and Molecular Characterization
Authors: de Melo Roberta Torres , dos Reis Cardoso Taciano , Peres Phelipe Augusto Borba Martins , Braz Raquelline Figueiredo , Monteiro Guilherme Paz , Rossi Daise Aparecida
Published: May 2021

The presence of virulence genes, phylogenetic relationships, biofilm formation index (BFI), and ultrastructure in S. Minnesota at different temperatures (4, 25, and 36 °C) were analyzed. In addition, the ability of biocidal agents (chlorhexidine1%, sodium hypochlorite 1%, and peracetic acid 0.8%) to inhibit biofilms formed by 20 strains isolated from broiler slaughter plants from two Brazilian companies in 2009, 2010, and 2014 was determined. The presence of specific genes was evaluated by PCR and phylogeny between strains by pulsed-field gel electrophoresis. The BFI was determined using tryptone soy broth with 5% of chicken juice, and its structure was observed by scanning electron microscopy. The presence of specific genes indicated that S. Minnesota has the potential to cause disease in humans, adapting to adverse conditions. Temperatures of 25 and 36 °C favored biofilm formation, although at 4 °C, there was still biomass that could contaminate the final product. Tolerance to all biocides was identified in 12/20 (60%), representing a real risk of adaptation mechanisms development, especially regarding to resistance to sodium hypochlorite. Phylogenetic analysis indicated cross-contamination and spread among companies, which was probably related to biofilms formation. Results show the necessity of attention to this serovar considering its resistance to sodium hypochlorite, including the need for rigorous control, adopting low temperatures to prevent biofilms formation in the poultry industry.
Kinsenoside Alleviates 17α-Ethinylestradiol-Induced Cholestatic Liver Injury in Rats by Inhibiting Inflammatory Responses and Regulating FXR-Mediated Bile Acid Homeostasis
Authors: Ming Jiaxiong , Xu Qianqian , Gao Limin , Deng Yanfang , Yin Jie , Zhou Qun , Tong Qingyi , Zhang Yonghui
Published: May 2021

Cholestasis is an important predisposing factor of liver diseases, such as hepatocyte necrosis, liver fibrosis and primary biliary cirrhosis. In this study, we aimed to investigate the effects of Kinsenoside (KD), a natural active ingredient of Anoectochilus roxburghii, on estrogen-induced cholestatic liver injury in Sprague-Dawley rats and the underlying mechanism. The rats were randomly divided into six groups: control group, model group, low-dose KD group (50 mg/kg body weight, KD-L), medium-dose KD group (100 mg/kg body weight, KD-M), high-dose KD group (200 mg/kg body weight, KD-H) and ursodeoxycholic acid group (40 mg/kg body weight, UDCA). 17α-Ethinylestradiol (EE) was used to establish an experimental animal model of estrogen-induced cholestasis (EIC). The results demonstrated that KD alleviated liver pathologic damage, serum biochemical status and inhibited hepatocellular microstructure disorder and bile duct hyperplasia in EE-induced cholestatic rats. Mechanically, KD alleviated EE-induced cholestatic liver injury by inhibiting inflammatory responses and regulating bile acid homeostasis. Concretely, KD reduced the expression of IL-1β and IL-6 by inhibiting NF-κB p65 to suppress EE-mediated inflammation in rat liver. KD enhanced the expression of FXR and inhibited EE-mediated reduction of FXR in vitro and in vivo. It was the potential mechanism that KD mitigates cholestasis by increasing efflux and inhibiting uptake of bile acids via FXR-mediated induction of bile salt export pump (BSEP) and reduction of Na+-dependent taurocholate cotransport peptide (NTCP) to maintain bile acid homeostasis. Moreover, KD repressed the bile acid synthesis through reducing the expression of synthetic enzyme (CYP7A1), thereby normalizing the expression of metabolic enzyme (SULT2A1) of bile acid. In conclusion, our results revealed that KD may be an effective drug candidate for the treatment of cholestasis.
Combinations of Freeze-Dried Amorphous Vardenafil Hydrochloride with Saccharides as a Way to Enhance Dissolution Rate and Permeability
Authors: Wiergowska Gabriela , Ludowicz Dominika , Wdowiak Kamil , Miklaszewski Andrzej , Lewandowska Kornelia , Cielecka-Piontek Judyta
Published: May 2021

To improve physicochemical properties of vardenafil hydrochloride (VAR), its amorphous form and combinations with excipients—hydroxypropyl methylcellulose (HPMC) and β-cyclodextrin (β-CD)—were prepared. The impact of the modification on physicochemical properties was estimated by comparing amorphous mixtures of VAR to their crystalline form. The amorphous form of VAR was obtained as a result of the freeze-drying process. Confirmation of the identity of the amorphous dispersion of VAR was obtained through the use of comprehensive analysis techniques—X-ray powder diffraction (PXRD) and differential scanning calorimetry (DSC), supported by FT-IR (Fourier-transform infrared spectroscopy) coupled with density functional theory (DFT) calculations. The amorphous mixtures of VAR increased its apparent solubility compared to the crystalline form. Moreover, a nearly 1.3-fold increase of amorphous VAR permeability through membranes simulating gastrointestinal epithelium as a consequence of the changes of apparent solubility (Papp crystalline VAR = 6.83 × 10−6 cm/s vs. Papp amorphous VAR = 8.75 × 10−6 cm/s) was observed, especially for its combinations with β-CD in the ratio of 1:5—more than 1.5-fold increase (Papp amorphous VAR = 8.75 × 10−6 cm/s vs. Papp amorphous VAR:β-CD 1:5 = 13.43 × 10−6 cm/s). The stability of the amorphous VAR was confirmed for 7 months. The HPMC and β-CD are effective modifiers of its apparent solubility and permeation through membranes simulating gastrointestinal epithelium, suggesting a possibility of a stronger pharmacological effect.
Tenofovir, Another Inexpensive, Well-Known and Widely Available Old Drug Repurposed for SARS-COV-2 Infection
Authors: Zanella Isabella , Zizioli Daniela , Castelli Francesco , Quiros-Roldan Eugenia
Published: May 2021

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is spreading worldwide with different clinical manifestations. Age and comorbidities may explain severity in critical cases and people living with human immunodeficiency virus (HIV) might be at particularly high risk for severe progression. Nonetheless, current data, although sometimes contradictory, do not confirm higher morbidity, risk of more severe COVID-19 or higher mortality in HIV-infected people with complete access to antiretroviral therapy (ART). A possible protective role of ART has been hypothesized to explain these observations. Anti-viral drugs used to treat HIV infection have been repurposed for COVID-19 treatment; this is also based on previous studies on severe acute respiratory syndrome virus (SARS-CoV) and Middle East respiratory syndrome virus (MERS-CoV). Among them, lopinavir/ritonavir, an inhibitor of viral protease, was extensively used early in the pandemic but it was soon abandoned due to lack of effectiveness in clinical trials. However, remdesivir, a nucleotide analog that acts as reverse-transcriptase inhibitor, which was tested early during the pandemic because of its wide range of antiviral activity against several RNA viruses and its safety profile, is currently the only antiviral medication approved for COVID-19. Tenofovir, another nucleotide analog used extensively for HIV treatment and pre-exposure prophylaxis (PrEP), has also been hypothesized as effective in COVID-19. No data on tenofovir’s efficacy in coronavirus infections other than COVID-19 are currently available, although information relating to SARS-CoV-2 infection is starting to come out. Here, we review the currently available evidence on tenofovir’s efficacy against SARS-CoV-2.
Stability and In Vitro Aerodynamic Studies of Inhalation Powders Containing Ciprofloxacin Hydrochloride Applying Different DPI Capsule Types
Authors: Benke Edit , Varga Patrícia , Szabó-Révész Piroska , Ambrus Rita
Published: May 2021

In the case of capsule-based dry powder inhalation systems (DPIs), the selection of the appropriate capsule is important. The use of gelatin, gelatin-PEG, and HPMC capsules has become widespread in marketed capsule-based DPIs. We aimed to perform a stability test according to the ICH guideline in the above-mentioned three capsule types. The results of the novel combined formulated microcomposite were more favorable than those of the carrier-free formulation for all capsule types. The use of HPMC capsules results in the greatest stability and thus the best in vitro aerodynamic results for both DPI powders after six months. This can be explained by the fact that the residual solvent content (RSC) of the capsules differs. Under the applied conditions the RSC of the HPMC capsule decreased the least and remained within the optimal range, thus becoming less fragmented, which was reflected in the RSC, structure and morphology of the particles, as well as in the in vitro aerodynamic results (there was a difference of approximately 10% in the lung deposition results). During pharmaceutical dosage form developments, emphasis should be placed in the case of DPIs on determining which capsule type will be used for specific formulations.
One and Two-Step In Vitro-In Vivo Correlations Based on USP IV Dynamic Dissolution Applied to Four Sodium Montelukast Products
Authors: Prieto-Escolar Mercedes , Torrado Juan J. , Álvarez Covadonga , Ruiz-Picazo Alejandro , Simón-Vázquez Marta , Govantes Carlos , Frias Jesús , García-Arieta Alfredo , Gonzalez-Alvarez Isabel , Bermejo Marival
Published: May 2021

Montelukast is a weak acid drug characterized by its low solubility in the range of pH 1.2 to 4.5, which may lead to dissolution-limited absorption. The aim of this paper is to develop an in vivo predictive dissolution method for montelukast and to check its performance by establishing a level-A in vitro-in vivo correlation (IVIVC). During the development of a generic film-coated tablet formulation, two clinical trials were done with three different experimental formulations to achieve a similar formulation to the reference one. A dissolution test procedure with a flow-through cell (USP IV) was used to predict the in vivo absorption behavior. The method proposed is based on a flow rate of 5 mL/min and changes of pH mediums from 1.2 to 4.5 and then to 6.8 with standard pharmacopoeia buffers. In order to improve the dissolution of montelukast, sodium dodecyl sulfate was added to the 4.5 and 6.8 pH mediums. Dissolution profiles in from the new method were used to develop a level-A IVIVC. One-step level-A IVIVC was developed from dissolution profiles and fractions absorbed obtained by the Loo–Riegelman method. Time scaling with Levy’s plot was necessary to achieve a linear IVIVC. One-step differential equation-based IVIVC was also developed with a time-scaling function. The developed method showed similar results to a previously proposed biopredictive method for montelukast, and the added value showed the ability to discriminate among different release rates in vitro, matching the in vivo clinical bioequivalence results.
How to Achieve High Encapsulation Efficiencies for Macromolecular and Sensitive APIs in Liposomes
Authors: Ullmann Kirsten , Leneweit Gero , Nirschl Hermann
Published: May 2021

This research highlights the capacity of a newly introduced centrifugation process to form liposomes from water-in-fluorocarbon nano-emulsions stabilized with phospholipids to incorporate macromolecular and sensitive active pharmaceutical ingredients (API). The encapsulation efficiency of the produced liposomes, incorporating fluorescein-sodium, bovine serum albumin and fluorecein isothiocyanate dextran as model APIs, is determined by applying Vivaspin® centrifugation filtration and quantified by UV-Vis spectroscopy. It was found that higher densities of the fluorocarbons used as the hydrophobic phase enable a higher encapsulation efficiency and that an efficiency of up to 98% is possible depending on the used phospholipid. Among the engineering aspects of the process, a comparison between different membrane substances was performed. Efficiency increases with a higher phospholipid concentration but decreases with the addition of cholesterol. Due to the higher bending modulus, liposome formation is slowed down by cholesterol during liposome closure leading to a greater leakage of the model API. The encapsulation of bovine serum albumin and dextran, both investigated under different osmotic conditions, shows that an efflux negatively affects the encapsulation efficiency while an influx increases the stability. Overall, the process shows the potential for a very high encapsulation efficiency for macromolecules and future pharmaceutical applications.
Improvement of a 1D Population Balance Model for Twin-Screw Wet Granulation by Using Identifiability Analysis
Authors: Barrera Jiménez Ana Alejandra , Van Hauwermeiren Daan , Peeters Michiel , De Beer Thomas , Nopens Ingmar
Published: May 2021

Recently, the pharmaceutical industry has undergone changes in the production of solid oral dosages from traditional inefficient and expensive batch production to continuous manufacturing. The latest advancements include increased use of continuous twin-screw wet granulation and application of advanced modeling tools such as Population Balance Models (PBMs). However, improved understanding of the physical process within the granulator and improvement of current population balance models are necessary for the continuous production process to be successful in practice. In this study, an existing compartmental one-dimensional PBM of a twin-screw granulation process was improved by altering the original aggregation kernel in the wetting zone as a result of an identifiability analysis. In addition, a strategy was successfully applied to reduce the number of model parameters to be calibrated in both the wetting zone and kneading zones. It was found that the new aggregation kernel in the wetting zone is capable of reproducing the particle size distribution that is experimentally observed at different process conditions as well as different types of formulations, varying in hydrophilicity and API concentration. Finally, it was observed that model parameters could be linked not only to the material properties but also to the liquid to solid ratio, paving the way to create a generic PBM to predict the particle size distribution of a new formulation.
Twenty Years of Research on Cyclodextrin Conjugates with PAMAM Dendrimers
Authors: Arima Hidetoshi
Published: May 2021

Recently, the number of gene and oligonucleotide drugs are increasing. Of various drug delivery systems (DDSs) for gene and oligonucleotide drugs, few examples of the clinical application of polymer as drug carriers are known, despite development of the novel polymers has been progressing. Cyclodextrin (CD) conjugates with starburst polyamidoamine (PAMAM) dendrimer (CDEs), as a new type of polymer-based carriers, were first published in 2001. After that, galactose-, lactose-, mannose-, fucose-, folate-, and polyethyleneglycol (PEG)-appended CDEs have been prepared for passive and active targeting for gene, oligonucleotide, and low-molecular-weight drugs. PEG-appended CDE formed polypsuedorotaxanes with α-CD and γ-CD, which are useful for a sustained release system of gene and oligonucleotide drugs. Interestingly, CDEs were found to have anti-inflammatory effects and anti-amyloid effects themselves, which have potential as active pharmaceutical ingredients. Most recently, CDE is reported to be a useful Cas9-RNA ribonucleoproteins (Cas9 RNP) carrier that induces genome editing in the neuron and brain. In this review, the history and progression of CDEs are overviewed.
Precise Optical Modulation and Its Application to Optoelectronic Device Measurement
Authors: Kawanishi Tetsuya
Published: May 2021

Optoelectronic devices which play important roles in high-speed optical fiber networks can offer effective measurement methods for optoelectronic devices including optical modulators and photodetectors. Precise optical signal modulation is required for measurement applications. This paper focuses on high-speed and precise optical modulation devices and their application to device measurement. Optical modulators using electro-optic effect offers precise control of lightwaves for wideband signals. As examples, this paper describes frequency response measurement of photodetectors using high-precision amplitude modulation and wavelength domain measurement of optical filters using fast optical frequency sweep. Precise and high-speed modulation can be achieved by active trimming which compensates device structure imbalance due to fabrication error, where preciseness can be described by on-off extinction ratio. A Mach-Zehnder modulator with sub Mach-Zehnder interferometors can offer high extinction-ratio optical intensity modulation, which can be used for precise optoelectronic frequency response measurement. Precise modulation would be also useful for multi-level modulation schemes. To investigate impact of finite extinction ratio on optical modulation, duobinary modulation with small signal operation was demonstrated. For optical frequency domain analysis, single sideband modulation, which shifts optical frequency, can be used for generation of stimulus signals. Rapid measurement of optical filters was performed by using an optical sweeper consisting of an integrated Mach-Zehnder modulator for optical frequency control and an arbitrary waveform generator for generation of a source frequency chirp signal.
Dispersion Optimization of Silicon Nitride Waveguides for Efficient Four-Wave Mixing
Authors: Hong Yaping , Hong Yixiao , Hong Jianxun , Lu Guo-Wei
Published: May 2021

Silicon nitride waveguides have emerged as an excellent platform for photonic applications, including nonlinear optical signal processing, owing to their relatively high Kerr nonlinearity, negligible two photon absorption, and wide transparent bandwidth. In this paper, we propose an effective approach using 3D finite element method to optimize the dispersion characteristics of silicon nitride waveguides for four-wave mixing (FWM) applications. Numerical studies show that a flat and low dispersion profile can be achieved in a silicon nitride waveguide with the optimized dimensions. Near-zero dispersion of 1.16 ps/km/nm and 0.97 ps/km/nm at a wavelength of 1550 nm are obtained for plasma-enhanced chemical vapor deposition (PECVD) and low-pressure chemical vapor deposition (LPCVD) silicon nitride waveguides, respectively. The fabricated micro-ring resonator with the optimized dimensions exhibits near-zero dispersion of −0.04 to −0.1 ps/m/nm over a wavelength range of 130 nm which agrees with the numerical simulation results. FWM results show that near-zero phase mismatch and high conversion efficiencies larger than −12 dB using a low pump power of 0.5 W in a 13-cm long silicon nitride waveguide are achieved.
Influence of the Manufacturing Method on the Adhesion of Candida albicans and Streptococcus mutans to Oral Splint Resins
Authors: Schubert Andrea , Bürgers Ralf , Baum Franziska , Kurbad Oliver , Wassmann Torsten
Published: May 2021

Microbial adhesion to oral splints may lead to oral diseases such as candidiasis, periodontitis or caries. The present in vitro study aimed to assess the effect of novel computer-aided design/computer-aided manufacturing (CAD/CAM) and conventional manufacturing on Candida albicans and Streptococcus mutans adhesion to oral splint resins. Standardized specimens of four 3D-printed, two milled, one thermoformed and one pressed splint resin were assessed for surface roughness by widefield confocal microscopy and for surface free energy by contact angle measurements. Specimens were incubated with C. albicans or S. mutans for two hours; a luminometric ATP assay was performed for the quantification of fungal and bacterial adhesion. Both one-way ANOVA with Tukey post hoc testing and Pearson correlation analysis were performed (p < 0.05) in order to relate manufacturing methods, surface roughness and surface free energy to microbial adhesion. Three-dimensional printing and milling were associated with increased adhesion of C. albicans compared to conventional thermoforming and pressing, while the S. mutans adhesion was not affected. Surface roughness and surface free energy showed no significant correlation with microbial adhesion. Increased fungal adhesion to oral splints manufactured by 3D printing or milling may be relevant for medically compromised patients with an enhanced risk for developing candidiasis.