bluuebunny/crossref_metadata_2025 huggingface dataset:
A Novel Approach to Unraveling the Apoptotic Potential of Rutin (Bioflavonoid) via Targeting Jab1 in Cervical Cancer Cells
Authors: Pandey Pratibha , Khan Fahad , Alzahrani Faisal Abdulrahman , Qari Huda A. , Oves Mohammad
Published: September 2021

Rutin has been well recognized for possessing numerous pharmacological and biological activities in several human cancer cells. This research has addressed the inhibitory potential of rutin against the Jab1 oncogene in SiHa cancer cells, which is known to inactivate various tumor suppressor proteins including p53 and p27. Further, the inhibitory efficacy of rutin via Jab1 expression modulation in cervical cancer has not been yet elucidated. Hence, we hypothesized that rutin could exhibit strong inhibitory efficacy against Jab1 and, thereby, induce significant growth arrest in SiHa cancer cells in a dose-dependent manner. In our study, the cytotoxic efficacy of rutin on the proliferation of a cervical cancer cell line (SiHa) was exhibited using MTT and LDH assays. The correlation between rutin and Jab1 mRNA expression was assessed by RT-PCR analysis and the associated events (a mechanism) with this downregulation were then explored via performing ROS assay, DAPI analysis, and expression analysis of apoptosis-associated signaling molecules such as Bax, Bcl-2, and Caspase-3 and -9 using qRT-PCR analysis. Results exhibit that rutin produces anticancer effects via inducing modulation in the expression of oncogenes as well as tumor suppressor genes. Further apoptosis induction, caspase activation, and ROS generation in rutin-treated SiHa cancer cells explain the cascade of events associated with Jab1 downregulation in SiHa cancer cells. Additionally, apoptosis induction was further confirmed by the FITC-Annexin V/PI double staining method. Altogether, our research supports the feasibility of developing rutin as one of the potent drug candidates in cervical cancer management via targeting one such crucial oncogene associated with cervical cancer progression.
Effect of Elicitation with (+)-Usnic Acid on Accumulation of Phenolic Acids and Flavonoids in Agitated Microshoots of Eryngium alpinum L.
Authors: Kikowska Małgorzata , Thiem Barbara , Jafernik Karolina , Klimek-Szczykutowicz Marta , Studzińska-Sroka Elżbieta , Ekiert Halina , Szopa Agnieszka
Published: September 2021

The present work was aimed at studying the potential of elicitation on the accumulation of phenolic compounds in in vitro shoot cultures of Eryngium alpinum L., a protected plant from the Apiaceae family. The study examined the influence of (+)-usnic acid on the biomass growth as well as on the biosynthesis of the desired flavonoids and phenolic acids in the cultured microshoots. The phenolic compound content was determined by HPLC-DAD. The flavonoid of the highest concentration was isoquercetin, and the phenolic acids of the highest amount were rosmarinic acid, caffeic acid and 3,4-dihydroxyphenylacetic acid, both in the non-elicited and elicited biomass. Isoquercetin accumulation was efficiently increased by a longer elicitation with a lower concentration of lichenic compound (107.17 ± 4.67 mg/100 g DW) or a shorter elicitation with a higher concentration of acid (127.54 ± 11.34 and 108.37 ± 12.1 mg/100 g DW). Rosmarinic acid production generally remained high in all elicited and non-elicited microshoots. The highest content of this acid was recorded at 24 h of elicitation with 3.125 µM usnic acid (512.69 ± 4.89 mg/100 g DW). The process of elicitation with (+)-usnic acid, a well-known lichenic compound with allelopathic nature, may therefore be an effective technique of enhancing phenolic compound accumulation in alpine eryngo microshoot biomass.
Sequential Injection Analysis for Automation and Evaluation of Drug Liberation Profiles: Clotrimazole Liberation Monitoring
Authors: Sklenářová Hana , Beran Marek , Novosvětská Lucie , Šmejkalová Daniela , Solich Petr
Published: September 2021

A fully automated sequential injection system was tested in terms of its application in liberation testing, and capabilities and limitations were discussed for clotrimazole liberation from three semisolid formulations. An evaluation based on kinetic profiles obtained in short and longer sampling intervals and steady-state flux values were applied as traditional methods. The obtained clotrimazole liberation profile was faster in the case of Delcore and slower for Clotrimazol AL and Canesten cream commercial formulations. The steady-state flux values for the tested formulations were 52 µg cm−2 h−1 for Canesten, 35 µg cm−2 h−1 for Clotrimazol AL, and 7.2 µg cm−2 h−1 for Delcore measured in 4 min sampling intervals. A simplified approach for the evaluation of the initial rate based on the gradient between the second and third sampling points was used for the first time and was found to correspond well with the results of the conventional methods. A comparison based on the ratio of the steady-state flux and the initial rate values for Canesten and Clotrimazol AL proved the similarity of the obtained results. The proposed alternative was successfully implemented for the comparison of short-term kinetic profiles. Consequently, a faster and simpler approach for dissolution/liberation testing can be used.
Analogue of Electromagnetically Induced Transparency in an All-Dielectric Double-Layer Metasurface Based on Bound States in the Continuum
Authors: He Fengyan , Liu Jianjun , Pan Guiming , Shu Fangzhou , Jing Xufeng , Hong Zhi
Published: September 2021

Bound states in the continuum (BICs) have attracted much attention due to their infinite Q factor. However, the realization of the analogue of electromagnetically induced transparency (EIT) by near-field coupling with a dark BIC in metasurfaces remains challenging. Here, we propose and numerically demonstrate the realization of a high-quality factor EIT by the coupling of a bright electric dipole resonance and a dark toroidal dipole BIC in an all-dielectric double-layer metasurface. Thanks to the designed unique one-dimensional (D)–two-dimensional (2D) combination of the double-layer metasurface, the sensitivity of the EIT to the relative displacement between the two layer-structures is greatly reduced. Moreover, several designs for widely tunable EIT are proposed and discussed. We believe the proposed double-layer metasurface opens a new avenue for implementing BIC-based EIT with potential applications in filtering, sensing and other photonic devices.
Gradient Microstructure Design in Stainless Steel: A Strategy for Uniting Strength-Ductility Synergy and Corrosion Resistance
Authors: He Qiong , Wei Wei , Wang Ming-Sai , Guo Feng-Jiao , Zhai Yu , Wang Yan-Fei , Huang Chong-Xiang
Published: September 2021

Martensite transformation and grain refinement can make austenitic stainless steel stronger, but this comes at a dramatic loss of both ductility and corrosion resistance. Here we report a novel gradient structure in 301 stainless steel sheets, which enables an unprecedented combination of high strength, improved ductility and good corrosion resistance. After producing inter-layer microstructure gradient by surface mechanical attrition treatment, the sheet was annealed at high temperature for a short duration, during which partial reverse transformation occurred to form recrystallized austenitic nano-grains in the surface layer, i.e., introducing extra intra-layer heterogeneity. Such 3D microstructure heterogeneity activates inter-layer and inter-phase interactions during deformation, thereby producing back stress for high yield strength and hetero-deformation induced (HDI) hardening for high ductility. Importantly, the recrystallized austenitic nano-grains significantly ameliorates the corrosion resistance. These findings suggest an effective route for evading the strength–ductility and strength–corrosion tradeoffs in stainless steels simultaneously.
Simulation of Z-Shaped Graphene Geometric Diodes Using Particle-in-Cell Monte Carlo Method in the Quasi-Ballistic Regime
Authors: Stearns John , Moddel Garret
Published: September 2021

Geometric diodes are planar conductors patterned asymmetrically to provide electrical asymmetry, and they have exhibited high-frequency rectification in infrared rectennas. These devices function by ballistic or quasi-ballistic transport in which the transport characteristics are sensitive to the device geometry. Common methods for predicting device performance rely on the assumption of totally ballistic transport and neglect the effects of electron momentum relaxation. We present a particle-in-cell Monte Carlo simulation method that allows the prediction of the current–voltage characteristics of geometric diodes operating quasi-ballistically, with the mean-free-path length shorter than the critical device dimensions. With this simulation method, we analyze a new diode geometry made from graphene that shows an improvement in rectification capability over previous geometries. We find that the current rectification capability of a given geometry is optimized for a specific mean-free-path length, such that arbitrarily large mean-free-path lengths are not desirable. These results present a new avenue for understanding geometric effects in the quasi-ballistic regime and show that the relationship between device dimensions and the carrier mean-free-path length can be adjusted to optimize device performance.
Controlled Lattice Thermal Conductivity of Transparent Conductive Oxide Thin Film via Localized Vibration of Doping Atoms
Authors: Choi Young Joong , Lee Ho Yun , Kim Seohan , Song Pung Keun
Published: September 2021

Amorphization using impurity doping is a promising approach to improve the thermoelectric properties of tin-doped indium oxide (ITO) thin films. However, an abnormal phenomenon has been observed where an excessive concentration of doped atoms increases the lattice thermal conductivity (κl). To elucidate this paradox, we propose two hypotheses: (1) metal hydroxide formation due to the low bond enthalpy energy of O and metal atoms and (2) localized vibration due to excessive impurity doping. To verify these hypotheses, we doped ZnO and CeO2, which have low and high bond enthalpies with oxygen, respectively, into the ITO thin film. Regardless of the bond enthalpy energy, the κl values of the two thin films increased due to excessive doping. Fourier transform infrared spectroscopy was conducted to determine the metal hydroxide formation. There was no significant difference in wave absorbance originating from the OH stretching vibration. Therefore, the increase in κl due to the excessive doping was due to the formation of localized regions in the thin film. These results could be valuable for various applications using other transparent conductive oxides and guide the control of the properties of thin films.
Oxidative Desulfurization Catalyzed by Phosphotungstic Acid Supported on Hierarchical Porous Carbons
Authors: Wang Bao , Kang Lihua , Zhu Mingyuan
Published: September 2021

A hierarchical porous carbon material (HPC) with an ultra-high specific surface area was synthesized with sisal fiber (SF) as a precursor, and then H3PW12O40·24H2O (HPW) was immobilized on the support of SF-HPC by a simple impregnation method. A series characterization technology approved that the obtained SF-HPC had a high surface area of 3152.46 m2g−1 with micropores and macropores. HPW was well-dispersed on the surface of the SF-HPC support, which reduced the loading of HPW to as low as 5%. HPW/SF-HPW showed excellent catalytic performance for oxidative desulfurization, and the desulfurization rate reached almost 100% under the optimal reaction conditions. The desulfurization rate of HPW/SF-HPW could be maintained at above 94% after four recycles.
Dietary Lipids and Dyslipidemia in Chronic Kidney Disease
Authors: Kochan Zdzislaw , Szupryczynska Natalia , Malgorzewicz Sylwia , Karbowska Joanna
Published: September 2021

The progression of chronic kidney disease (CKD) leads to altered lipid metabolism. CKD patients exhibit high blood triglyceride (TG) levels, reduced concentrations and functionality of high-density lipoproteins (HDL), and elevated levels of atherogenic small, dense, low-density lipoproteins (sdLDL). Disorders of lipid metabolism and other metabolic disturbances place CKD patients at high risk for cardiovascular disease (CVD). Extensive evidence supports the cardioprotective effects of unsaturated fatty acids, including their beneficial effect on serum cholesterol and TG levels. Dietary lipids might therefore be especially important in the nutritional management of CKD. We review current dietary recommendations for fat intake by CKD patients and suggest potential nutritional interventions by emphasizing dietary lipids that might improve the blood lipid profile and reduce cardiovascular risk in CKD.
Dairy Consumption and 3-Year Risk of Type 2 Diabetes after Myocardial Infarction: A Prospective Analysis in the Alpha Omega Cohort
Authors: Jacobo Cejudo Maria G. , Cruijsen Esther , Heuser Christiane , Soedamah-Muthu Sabita S. , Voortman Trudy , Geleijnse Johanna M.
Published: September 2021

Population-based studies suggest a role for dairy, especially yogurt, in the prevention of type 2 diabetes (T2D). Whether dairy affects T2D risk after myocardial infarction (MI) is unknown. We examined associations of (types of) dairy with T2D incidence in drug-treated, post-MI patients from the Alpha Omega Cohort. The analysis included 3401 patients (80% men) aged 60–80 y who were free of T2D at baseline (2002–2006). Dairy intakes were assessed using a validated food-frequency questionnaire. Incident T2D was ascertained through self-reported physician diagnosis and/or medication use. Multivariable Cox models were used to calculate Hazard ratios (HRs) and 95% confidence intervals (CI) for T2D with dairy intake in categories and per 1-standard deviation (SD) increment. Most patients consumed dairy, and median intakes were 264 g/d for total dairy, 82 g/d for milk and 41 g/d for yogurt. During 40 months of follow-up (10,714 person-years), 186 patients developed T2D. After adjustment for confounders, including diet, HRs per 1-SD were 1.06 (95% CI 0.91–1.22) for total dairy, 1.02 (0.88–1.18) for milk and 1.04 (0.90–1.20) for yogurt. Associations were also absent for other dairy types and in dairy categories (all p-trend > 0.05). Our findings suggest no major role for dairy consumption in T2D prevention after MI.
Diet Beverage Intake during Lactation and Associations with Infant Outcomes in the Infant Feeding Practices Study II
Authors: Huang Qiushi , Murphy Jeanne , Smith Emily R. , Sylvetsky Allison C.
Published: September 2021

Consumption of diet beverages (DB) containing low-calorie sweeteners (LCS) is widespread in the United States. LCS are ingested by nursing infants upon maternal DB consumption, which may impact infants’ weight and health. This study aims to examine cross-sectional associations between infants’ LCS exposure via maternal DB intake during lactation and infants’ health outcomes. Six hundred and eighty-two mother–infant dyads at three months postpartum, from the Infant Feeding Practices Study II, 2005–2007, were included in the analysis. Maternal DB consumption during lactation was estimated using the serving size and frequency of DB consumption reported on the diet history questionnaire. Infants’ LCS exposure was estimated by multiplying maternal DB consumption and breastfeeding intensity. Infant outcomes included weight, weight-for-age and BMI-for-age z-scores, overweight, and gastrointestinal (GI) symptoms including diarrhea, reflux, and vomiting. Associations between infants’ LCS exposure and continuous and categorical outcomes were examined using linear and logistic regressions adjusting for confounders, respectively. Forty-three percent of lactating women reported DB consumption. While no significant associations were observed between infants’ LCS exposure and BMI-for-age or risk of overweight, infants’ LCS exposure was associated with a 2.78-fold increased risk of vomiting (95% confidence interval 1.05–7.34). Potential adverse effects of LCS exposure on GI symptoms require further study, and null findings on infant weight should be interpreted with caution, given the small sample size. Additional research is needed to inform recommendations for or against DB consumption during lactation.
Comparing Associations of Dietary Energy Density and Energy Intake, Macronutrients with Obesity in Patients with Type 2 Diabetes (JDDM 63)
Authors: Takeda Yasunaga , Fujihara Kazuya , Nedachi Rina , Ikeda Izumi , Morikawa Sakiko Yoshizawa , Hatta Mariko , Horikawa Chika , Kato Mitsutoshi , Kato Noriko , Yokoyama Hiroki , Kurihara Yoshio , Miyazawa Kazuhiro , Maegawa Hiroshi , Sone Hirohito
Published: September 2021

To investigate the association between dietary energy density (DED) and obesity in people with type 2 diabetes mellitus. Moreover, we compared the strength of the associations of DED with intake of energy and macronutrients in terms of obesity as well as nutritional factors that have long been used for medical nutritional therapy. Cross-sectionally investigated were 1615 outpatients with type 2 diabetes who attended 26 clinics nationwide with diabetes specialists. Odds ratios (ORs) were calculated for the association between obesity and DED, energy, and macronutrients by quintile categories and a 1 SD increment with adjustment for potential confounders. β coefficients were calculated for the association between body mass index (BMI) and each nutritional factor by 1 SD increments in nutritional values. Multi-adjusted OR for obesity between extreme quintiles of DED was 2.99 (95% confidence interval (95% CI): 2.01–3.12). Conversely, the ORs did not differ significantly according to the quintiles of other nutrient factors. Multi-adjusted β coefficient of BMI per 1 SD according to DED was far higher than those of other nutrient factors (β coefficient 0.65, 95% CI: 0.41–0.88). These findings indicated that DED in persons with type 2 diabetes was positively associated with BMI and the prevalence of obesity. DED was also much more potently associated with obesity and BMI than nutritional indicators such as intake of energy or macronutrients.
Propolis and Its Gastroprotective Effects on NSAID-Induced Gastric Ulcer Disease: A Systematic Review
Authors: Ruiz-Hurtado Porfirio Alonso , Garduño-Siciliano Leticia , Domínguez-Verano Pilar , Balderas-Cordero Daniela , Gorgua-Jiménez Gustavo , Canales-Álvarez Octavio , Canales-Martínez María Margarita , Rodríguez-Monroy Marco Aurelio
Published: September 2021

Gastric ulcer disease induced by the consumption of NSAIDs is a major public health problem. The therapy used for its treatment causes adverse effects in the patient. Propolis is a natural product that has been used for the treatments of different diseases around the world. Nevertheless, there is little information about the activity of propolis in gastric ulcers caused by treatment with NSAIDs. Therefore, this review evaluates and compares the gastroprotective potential of propolis and its function against NSAID-induced gastric ulcers, for which a systematic search was carried out in the PubMed and ScienceDirect databases. The main criteria were articles that report the gastroprotective activity of propolis against the damage produced by NSAIDs in the gastric mucosa. Gastroprotection was related to the antioxidant, antisecretory, and cytoprotective effects, as well as the phenolic compounds present in the chemical composition of propolis. However, most of the studies used different doses of NSAIDs and propolis and evaluated different parameters. Propolis has proven to be a good alternative for the treatment of gastric ulcer disease. However, future studies should be carried out to identify the compounds responsible for these effects and to determine their potential use in people.
Alcohol and Cancer: Epidemiology and Biological Mechanisms
Authors: Rumgay Harriet , Murphy Neil , Ferrari Pietro , Soerjomataram Isabelle
Published: September 2021

Approximately 4% of cancers worldwide are caused by alcohol consumption. Drinking alcohol increases the risk of several cancer types, including cancers of the upper aerodigestive tract, liver, colorectum, and breast. In this review, we summarise the epidemiological evidence on alcohol and cancer risk and the mechanistic evidence of alcohol-mediated carcinogenesis. There are several mechanistic pathways by which the consumption of alcohol, as ethanol, is known to cause cancer, though some are still not fully understood. Ethanol’s metabolite acetaldehyde can cause DNA damage and block DNA synthesis and repair, whilst both ethanol and acetaldehyde can disrupt DNA methylation. Ethanol can also induce inflammation and oxidative stress leading to lipid peroxidation and further DNA damage. One-carbon metabolism and folate levels are also impaired by ethanol. Other known mechanisms are discussed. Further understanding of the carcinogenic properties of alcohol and its metabolites will inform future research, but there is already a need for comprehensive alcohol control and cancer prevention strategies to reduce the burden of cancer attributable to alcohol.
Exposure to SARS-CoV-2 in Hospital Environment: Working in a COVID-19 Ward Is a Risk Factor for Infection
Authors: Kapuczinski Abeline , de Terwangne Christophe , De Keukeleire Steven , Goffard Jean-Christophe , Sorgente Antonio , Place Sammy , De Cubber Michael
Published: September 2021

Aims. Health care workers (HCWs) are at risk of acquiring the Severe Acute Respiratory Syndrome Coronavirus 2 Infection (SARS-CoV-2). The aim of the study is to determine the SARS-CoV-2 positivity rates during the first epidemiologic peak among HCWs of a south Belgian hospital and to identify risks factors for infection. Methods. All hospital staff who worked during the first epidemiological peak were asked to answer a questionnaire regarding demographical data, function, type of working unit, type of contact with patients, eventual symptomatology, and the positivity of reverse transcription-polymerase chain reaction (RT-PCR) testing or immunoassay. Results. A total of 235 questionnaires were collected; 90 (38%) HCWs tested positive for SARS-CoV-2 from either RT-PCR or immunoassay testing. The positivity rate of HCWs between wards was statistically different (p = 0.004) and was higher in COVID-19 wards than Intensive Care Unit (ICU) and Emergency Department (ED). A total of 114 (49%) HCWs presented SARS-CoV-2-compatible symptomatology; 79 (88%) were positive on either RT-PCR or immunoassay testing; 74 (37%) HCWs were unable to work during the studied period; 5 were hospitalized. No deaths were reported. Multivariate logistic regression modeling showed that having symptoms was highly associated with test positivity (OR 23.3, CI 11.1, 53.1, p-value < 0.001). Working in a COVID-19 ward against working in ICU or ED was also predictive of positivity among HCWs (OR 3.25, CI 1.50, 7.28, p-value = 0.003). Discussion and Conclusions. This study shows a higher positivity rate compared to already reported positivity rates among HCWs. Reported differences in positivity rates depend on many factors, such as local crisis intensity, screening strategy, training in use of self-protective equipment, and study selection bias. HCWs working in COVID-19 wards, in comparison to ED and ICU, seemed at greater risk of being infected in this study. This could be explained by the disparity of HCWs’ experience in handling self-protective equipment and knowledge in infection prevention. Hence, care should be taken in proper training for less-experienced HCWs during hospital epidemics. The latter could increase HCWs’ protection and consequently decrease work absenteeism, ensuring enhanced continuity of patient care during hospital crisis. Rapid quarantine of symptomatic HCWs could reduce contamination rates, as having symptoms was highly associated with test positivity in this study.
Chemical Composition and Antimicrobial Activity of a New Olive Pomace Functional Ingredient
Authors: Nunes Maria Antónia , Palmeira Josman Dantas , Melo Diana , Machado Susana , Lobo Joana Correia , Costa Anabela Sílvia Guedes , Alves Rita Carneiro , Ferreira Helena , Oliveira Maria Beatriz Prior Pinto
Published: September 2021

Olive pomace, an olive oil processing byproduct, can be upcycled and meet the current demand for natural and sustainable food ingredients. In this work, a patented process was used to obtain a functional ingredient from different olive pomaces. The nutritional, chemical and antioxidant profiles, as well as the antimicrobial activity against S. aureus, E. coli and C. albicans, were investigated for the first time. The amount of phenolics ranged between 3.1 and 3.8 g gallic acid eq./100 g in all samples and flavonoids between 2.0 and 3.2 g catechin eq/100 g. No significant differences were found regarding the antioxidant activity. The total fat varied between 5 and 11%, α-tocopherol being the major vitamer and oleic acid the main fatty acid. The protein and ash contents were 1–4% and 10–17%, respectively. The functional ingredient with a higher hydroxytyrosol content (220 mg/100 g) also presented the best minimal inhibitory concentration against the tested bacteria. No activity against C. albicans was verified. This new functional ingredient presents the potential to be used as a natural preservative or as a nutritional profile enhancer. Moreover, it can be an advantageous ingredient in food products, since it comprises specific lipid and hydrophilic bioactive compounds usually not present in other plant extracts.
Chemoreversal Agents from Taiwanofungus Genus and Their More Potent Methyl Derivatives Targeting Signal Transducer and Activator of Transcription 3 (STAT3) Phosphorylation
Authors: Yu Ko-Hua , Hung Chin-Chuan , Wu Tian-Shung , Chen Chin-Fu , Wu I-Ting , Kuo Ping-Chung , Lam Sio-Hong , Hung Hsin-Yi
Published: September 2021

Multidrug resistance (MDR), for which the mechanisms are not yet fully clear, is one of the major obstacles to cancer treatment. In recent years, signal transducer and activator of transcription 3 (STAT3) were found to be one of the important MDR mechanism pathways. Based on the previous research, zhankuic acid A, B, and C were found to have collateral sensitivity effects on MDR cancer cells, and MDR inhibitory activity of zhankuic acid methyl ester was found to be better than that of its acid. Therefore, we executed a systematic examination of the structure–activity relationship of zhankuic acid methyl ester derivatives to collateral sensitivity in MDR cancer cells. The results showed that compound 12 is the best in terms of chemoreversal activity, where the reversal fold was 692, and the IC50 value of paclitaxel combined with 10 μM compound 12 treatment was 1.69 nM in MDR KBvin cells. Among all the derivatives, methyl ester compounds were found to be better than their acids, and a detailed discussion of the structure–activity relationships of all of the derivatives is provided in this work. In addition, compounds 8, 12, and 26 were shown to influence the activation of STAT3 in KBvin cells, accounting for part of their chemoreversal effects. Our results may provide a new combined therapy with paclitaxel to treat multidrug-resistant cancers and provide a new therapy option for patients.
Antifungal Activity of Extracts, Fractions, and Constituents from Coccoloba cowellii Leaves
Authors: Méndez Daniel , Escalona-Arranz Julio C. , Pérez Enrique Molina , Foubert Kenn , Matheeussen An , Tuenter Emmy , Cuypers Ann , Cos Paul , Pieters Luc
Published: September 2021

Coccoloba cowellii Britton (Polygonaceae, order Caryophyllales) is an endemic and critically endangered plant species that only grows in the municipality of Camagüey, a province of Cuba. A preliminary investigation of its total methanolic extract led to the discovery of promising antifungal activity. In this study, a bioassay-guided fractionation allowed the isolation of quercetin and four methoxyflavonoids: 3-O-methylquercetin, myricetin 3,3′,4′-trimethyl ether, 6-methoxymyricetin 3,4′-dimethyl ether, and 6-methoxymyricetin 3,3′,4′-trimethyl ether. The leaf extract, fractions, and compounds were tested against various fungi and showed strong in vitro antifungal activity against Cryptococcus neoformans and various Candida spp. with no cytotoxicity (CC50 > 64.0 µg/mL) on MRC-5 SV2 cells, determined by a resazurin assay. A Candida albicans SC5314 antibiofilm assay indicated that the antifungal activity of C. cowellii extracts and constituents is mainly targeted to planktonic cells. The total methanolic extract showed higher and broader activity compared with the fractions and mixture of compounds.
Testing the Stability of Drug Resistance on Cryopreserved, Gene-Engineered Human Induced Pluripotent Stem Cells
Authors: Khan Dilaware , Nickel Ann-Christin , Jeising Sebastian , Uhlmann Constanze , Muhammad Sajjad , Hänggi Daniel , Fischer Igor , Kahlert Ulf Dietrich
Published: September 2021

Human induced pluripotent stem cells (hiPSCs) have emerged as a powerful tool for in vitro modelling of diseases with broad application in drug development or toxicology testing. These assays usually require large quantities of hiPSC, which can entail long-term storage via cryopreservation of the same cell charges. However, it is essential that cryopreservation does not oppose durable changes on the cells. In this project, we characterize one parameter of functionality of one that is well established in the field, in a different research context, an applied hiPSC line (iPS11), namely their resistance to a medium size library of chemo interventions (>160 drugs). We demonstrate that cells, before and after cryopreservation, do not change their relative overall drug response phenotypes, as defined by identification of the top 20 interventions causing dose-dependent reduction of cell growth. Importantly, also frozen cells that are exogenously enforced for stable overexpression of oncogenes myelocytomatosis (cMYC) or tumor protein 53 mutation (TP53R175H), respectively, are not changed in their relative top 20 drugs response compared to their non-frozen counterparts. Taken together, our results support iPSCs as a reliable in vitro platform for in vitro pharmacology, further raising hopes that this technology supports biomarker-associated drug development. Given the general debate on ethical and economic problems associated with the reproducibly crisis in biomedicine, our results may be of interest to a wider audience beyond stem cell research.
Development of a Robust Control Strategy for Fixed-Dose Combination Bilayer Tablets with Integrated Quality by Design, Statistical, and Process Analytical Technology Approach
Authors: Chun Myung-Hee , Kim Ji Yeon , Park Eun-Seok , Choi Du Hyung
Published: September 2021

Control strategy and quality by design (QbD) are widely used to develop pharmaceutical products and improve drug quality; however, studies on fixed-dose combination (FDC) bilayer tablets are limited. In this study, the bilayer tablet consisted of high-dose metformin HCl in a sustained-release layer and low-dose dapagliflozin l-proline in an immediate-release layer. The formulation and process of each layer were optimized using the QbD approach. A d-optimal mixture design and response surface design were applied to optimize critical material attributes and critical process parameters, respectively. The robust design space was developed using Monte Carlo simulations by evaluating the risk of uncertainty in the model predictions. Multivariate analysis showed that there were significant correlations among impeller speed, massing time, granule bulk density, and dissolution in the metformin HCl layer, and among roller pressure, ribbon density, and dissolution in the dapagliflozin l-proline layer. Process analytical technology (PAT) was used with in–line transmittance near-infrared spectroscopy to confirm the bulk and ribbon densities of the optimized bilayer tablet. Moreover, the in vitro drug release and in vivo pharmacokinetic studies showed that the optimized test drug was bioequivalent to the reference drug. This study suggested that integrated QbD, statistical, and PAT approaches can develop a robust control strategy for FDC bilayer tablets by implementing real-time release testing based on the relationships among various variables.
Dry Powder Inhalers in the Digitalization Era: Current Status and Future Perspectives
Authors: Xiroudaki Styliani , Schoubben Aurélie , Giovagnoli Stefano , Rekkas Dimitrios M.
Published: September 2021

During the last decades, the term “drug delivery systems” (DDSs) has almost fully replaced previously used terms, such as “dosage forms”, in an attempt to emphasize the importance of the drug carrier in ensuring the claimed safety and effectiveness of the product. However, particularly in the case of delivery devices, the term “system”, which by definition implies a profound knowledge of each single part and their interactions, is not always fully justified when using the DDS term. Within this context, dry powder inhalers (DPIs), as systems to deliver drugs via inhalation to the lungs, require a deep understanding of the complex formulation–device–patient interplay. As of now and despite the progress made in particle engineering and devices design, DPIs’ clinical performance is limited by variable patients’ breathing patterns. To circumvent this pitfall, next-generation DPIs should ideally adapt to the different respiratory capacity of individuals across age, health conditions, and other related factors. In this context, the recent wave of digitalization in the health care and industrial sectors may drive DPI technology towards addressing a personalized device–formulation–patient liaison. In this review, evolving technologies are explored and analyzed to outline the progress made as well as the gaps to fill to align novel DPIs technologies with the systems theory approach.
Modelling Photoionisations in Tautomeric DNA Nucleobase Derivatives 7H-Adenine and 7H-Guanine: Ultrafast Decay and Photostability
Authors: Segarra-Martí Javier , Nouri Sara M. , Bearpark Michael J.
Published: September 2021

The study of radiation effects in DNA is a multidisciplinary endeavour, connecting the physical, chemical and biological sciences. Despite being mostly filtered by the ozone layer, sunlight radiation is still expected to (photo)ionise DNA in sizeable yields, triggering an electron removal process and the formation of potentially reactive cationic species. In this manuscript, photoionisation decay channels of important DNA tautomeric derivatives, 7H-adenine and 7H-guanine, are characterised with accurate CASSCF/XMS-CASPT2 theoretical methods. These simulation techniques place the onset of ionisation for 7H-adenine and 7H-guanine on average at 8.98 and 8.43 eV, in line with recorded experimental evidence when available. Cationic excited state decays are analysed next, uncovering effective barrierless deactivation routes for both species that are expected to decay to their (cationic) ground state on ultrafast timescales. Conical intersection topographies reveal that these photoionisation processes are facilitated by sloped single-path crossings, known to foster photostability, and which are predicted to enable the (VUV) photo-protection mechanisms present in these DNA tautomeric species.
A Traceable DNA-Replicon Derived Vector to Speed Up Gene Editing in Potato: Interrupting Genes Related to Undesirable Postharvest Tuber Traits as an Example
Authors: Acha Giovana , Vergara Ricardo , Muñoz Marisol , Mora Roxana , Aguirre Carlos , Muñoz Manuel , Kalazich Julio , Prieto Humberto
Published: September 2021

In potato (Solanum tuberosum L.), protoplast techniques are limited to a few genotypes; thus, the use of regular regeneration procedures of multicellular explants causes us to face complexities associated to CRISPR/Cas9 gene editing efficiency and final identification of individuals. Geminivirus-based replicons contained in T-DNAs could provide an improvement to these procedures considering their cargo capability. We built a Bean yellow dwarf virus-derived replicon vector, pGEF-U, that expresses all the editing reagents under a multi-guide RNA condition, and the Green Fluorescent Protein (GFP) marker gene. Agrobacterium-mediated gene transfer experiments were carried out on ‘Yagana-INIA’, a relevant local variety with no previous regeneration protocol. Assays showed that pGEF-U had GFP transient expression for up to 10 days post-infiltration when leaf explants were used. A dedicated potato genome analysis tool allowed for the design of guide RNA pairs to induce double cuts of genes associated to enzymatic browning (StPPO1 and 2) and to cold-induced sweetening (StvacINV1 and StBAM1). Monitoring GFP at 7 days post-infiltration, explants led to vector validation as well as to selection for regeneration (34.3% of starting explants). Plant sets were evaluated for the targeted deletion, showing individuals edited for StPPO1 and StBAM1 genes (1 and 4 lines, respectively), although with a transgenic condition. While no targeted deletion was seen in StvacINV1 and StPPO2 plant sets, stable GFP-expressing calli were chosen for analysis; we observed different repair alternatives, ranging from the expected loss of large gene fragments to those showing punctual insertions/deletions at both cut sites or incomplete repairs along the target region. Results validate pGEF-U for gene editing coupled to regular regeneration protocols, and both targeted deletion and single site editings encourage further characterization of the set of plants already generated.
Transition from Seeds to Seedlings: Hormonal and Epigenetic Aspects
Authors: Smolikova Galina , Strygina Ksenia , Krylova Ekaterina , Leonova Tatiana , Frolov Andrej , Khlestkina Elena , Medvedev Sergei
Published: September 2021

Transition from seed to seedling is one of the critical developmental steps, dramatically affecting plant growth and viability. Before plants enter the vegetative phase of their ontogenesis, massive rearrangements of signaling pathways and switching of gene expression programs are required. This results in suppression of the genes controlling seed maturation and activation of those involved in regulation of vegetative growth. At the level of hormonal regulation, these events are controlled by the balance of abscisic acid and gibberellins, although ethylene, auxins, brassinosteroids, cytokinins, and jasmonates are also involved. The key players include the members of the LAFL network—the transcription factors LEAFY COTYLEDON1 and 2 (LEC 1 and 2), ABSCISIC ACID INSENSITIVE3 (ABI3), and FUSCA3 (FUS3), as well as DELAY OF GERMINATION1 (DOG1). They are the negative regulators of seed germination and need to be suppressed before seedling development can be initiated. This repressive signal is mediated by chromatin remodeling complexes—POLYCOMB REPRESSIVE COMPLEX 1 and 2 (PRC1 and PRC2), as well as PICKLE (PKL) and PICKLE-RELATED2 (PKR2) proteins. Finally, epigenetic methylation of cytosine residues in DNA, histone post-translational modifications, and post-transcriptional downregulation of seed maturation genes with miRNA are discussed. Here, we summarize recent updates in the study of hormonal and epigenetic switches involved in regulation of the transition from seed germination to the post-germination stage.
Finite Element Analysis for Biodegradable Dissolving Microneedle Materials on Skin Puncture and Mechanical Performance Evaluation
Authors: Yan Qinying , Weng Jiaqi , Shen Shulin , Wang Yan , Fang Min , Zheng Gensuo , Yang Qingliang , Yang Gensheng
Published: September 2021

In this study, a micro-molding technology was used to prepare the microneedles (MNs), while a texture analyzer was used to measure its Young’s modulus, Poisson’s ratio and compression breaking force, to evaluate whether the MNs can penetrate the skin. The effects of different materials were characterized by their ability to withstand stresses using the Structural Mechanics Module of COMSOL Multiphysics. Carboxymethylcellulose (CMC) was chosen as the needle formulation material with varying quantities of polyvinyl pyrrolidone (PVP), polyvinyl alcohol (PVA) and hyaluronic acid (HA) to adjust the viscosity, brittleness, hardness and solubility of the material. The results of both the experimental tests and the predictions indicated that the hardest tip material had a solids content of 15% (w/w ) with a 1:2 (w/w) CMC: HA ratio. Furthermore, it was shown that a solid content of 10% (w/w) with a 1:5 (w/w) CMC: PVA ratio is suitable for making patches. The correlation between the mechanical properties and the different materials was found using the simulation analysis as well as the force required for different dissolving microneedles (DMNs) to penetrate the skin, which significantly promoted the research progress of microneedle transdermal drug delivery.
Biomimetic Wax Interfaces Facilitating Rehealable Polymer Composites
Authors: Kuo Ching-Te , Chen Chien-Chin
Published: September 2021

Epicuticular wax, the first protective film for numerous ground plant species, is crucial for modulating the evolution in plants. Since the waxy film is inherently thermoresponsive, many efforts focus on engineering materials for water/oil proofing, delivery, and collection, as well as microactuators by mimicking such film nature. Nonetheless, relatively fewer works address the mechanism of how the underlying substrates direct the reconstruction of waxy films while their temperature approaches the melting point. Here, we presented a strategy in which distinct frameworks of molten wax films could be examined among various substrates. Both “waxphobic” and “waxphilic” traits were first unveiled and could be achieved by the hydrophilic (water contact angle (WCA) = 42~82°) and hydrophobic (WCA = 109°) substrates, respectively. A theoretical model, based on experimental results, fluidic dynamics, and balance of surface energy, was developed to elucidate the above findings. Moreover, we demonstrated the above biomimetic epicuticular surface (BeSurface) can be applied for rewritable paper, erasable coding, and rehealable electronics without manual repairing. Remarkably, the healing time can be reduced down to 30 s, and the cycled folding test can be continued up to 500 times. All the new findings present the potentials of the BeSurface to improve the study of rehealable materials.
Impact Toughness of Hybrid Carbon Fiber-PLA/ABS Laminar Composite Produced through Fused Filament Fabrication
Authors: Ahmed Hafiz , Hussain Ghulam , Gohar Sohail , Ali Aaqib , Alkahtani Mohammed
Published: September 2021

Nowadays, the components of carbon fiber-reinforced polymer composites (an important material) are directly produced with 3D printing technology, especially Fused Filament Fabrication (FFF). However, such components suffer from poor toughness. The main aim of this research is to overcome this drawback by introducing an idea of laying down a high toughness material on the 3D-printed carbon fiber-reinforced polymer composite sheet, thereby making a hybrid composite of laminar structure. To ascertain this idea, in the present study, a carbon-reinforced Polylactic Acid (C-PLA) composite sheet was initially 3D printed through FFF technology, which was then laid upon with the Acrylonitrile Butadiene Styrene (ABS), named as C-PLA/ABS hybrid laminar composite, in an attempt to increase its impact toughness. The hybrid composite was fabricated by varying different 3D printing parameters and was then subjected to impact testing. The results revealed that toughness increased by employing higher layer thickness and clad ratio, while it decreased by increasing the fill density, but remained unaffected due to any change in the raster angle. The highest impact toughness (23,465.6 kJ/m2) was achieved when fabrication was performed employing layer thickness of 0.5 mm, clad ratio of 1, fill density of 40%. As a result of laying up ABS sheet on C-PLA sheet, the toughness of resulting structure increased greatly (280 to 365%) as compared to the equivalent C-PLA structure, as expected. Two different types of distinct failures were observed during impact testing. In type A, both laminates fractured simultaneously without any delamination as a hammer hit the sample. In type B, the failure initiated with fracturing of C-PLA sheet followed by interfacial delamination at the boundary walls. The SEM analysis of fractured surfaces revealed two types of pores in the C-PLA lamina, while only one type in the ABS lamina. Further, there was no interlayer cracking in the C-PLA lamina contrary to the ABS lamina, thereby indicating greater interlayer adhesion in the C-PLA lamina.
Proton Exchange Membrane Fuel Cells (PEMFCs): Advances and Challenges
Authors: Tellez-Cruz Miriam M. , Escorihuela Jorge , Solorza-Feria Omar , Compañ Vicente
Published: September 2021

The study of the electrochemical catalyst conversion of renewable electricity and carbon oxides into chemical fuels attracts a great deal of attention by different researchers. The main role of this process is in mitigating the worldwide energy crisis through a closed technological carbon cycle, where chemical fuels, such as hydrogen, are stored and reconverted to electricity via electrochemical reaction processes in fuel cells. The scientific community focuses its efforts on the development of high-performance polymeric membranes together with nanomaterials with high catalytic activity and stability in order to reduce the platinum group metal applied as a cathode to build stacks of proton exchange membrane fuel cells (PEMFCs) to work at low and moderate temperatures. The design of new conductive membranes and nanoparticles (NPs) whose morphology directly affects their catalytic properties is of utmost importance. Nanoparticle morphologies, like cubes, octahedrons, icosahedrons, bipyramids, plates, and polyhedrons, among others, are widely studied for catalysis applications. The recent progress around the high catalytic activity has focused on the stabilizing agents and their potential impact on nanomaterial synthesis to induce changes in the morphology of NPs.
A Methodology to Predict and Optimize Ease of Assembly for Injected Parts in a Family-Mold System
Authors: Huang Chao-Tsai , Lin Tsai-Wen , Jong Wen-Ren , Chen Shia-Chung
Published: September 2021

In this study, the assembly behavior for two injected components made by a family mold system were investigated. Specifically, a feasible method was proposed to evaluate the characteristic length of two components within a family mold system using numerical simulation and experimental validation. Results show that as the packing pressure increases, the product index (characteristic length) becomes worse. This tendency was consistent for both the simulation prediction and experimental observation. However, for the same operation condition setting through a basic test, there were some differences in the product index between the simulation prediction and experimental observation. Specifically, the product index difference of the experimental observation was 1.65 times over that of the simulation prediction. To realize that difference between simulation and experiment, a driving force index (DFI) based on the injection pressure history curve was proposed. Through the DFI investigation, the internal driving force of the experimental system was shown to be 1.59 times over that of the simulation. The DFI was further used as the basis for machine calibration. Furthermore, after finishing machine calibration, the integrated CAE and DOE (called CAE-DOE) strategy can optimize the ease of assembly up to 20%. The result was validated by experimental observation.