bluuebunny/crossref_metadata_2025 huggingface dataset:
Experimental Validation of MHC Class I and II Peptide-Based Potential Vaccine Candidates for Human Papilloma Virus Using Sprague-Dawly Models
Authors: Ismail Mehreen , Bai Baogang , Guo Jinlei , Bai Yuhui , Sajid Zureesha , Muhammad Syed Aun , Shaikh Rehan Sadiq
Published: February 2023

Human papilloma virus (HPV) causes cervical and many other cancers. Recent trend in vaccine design is shifted toward epitope-based developments that are more specific, safe, and easy to produce. In this study, we predicted eight immunogenic peptides of CD4+ and CD8+ T-lymphocytes (MHC class I and II as M1 and M2) including early proteins (E2 and E6), major (L1) and minor capsid protein (L2). Male and female Sprague Dawly rats in groups were immunized with each synthetic peptide. L1M1, L1M2, L2M1, and L2M2 induced significant immunogenic response compared to E2M1, E2M2, E6M1 and E6M2. We observed optimal titer of IgG antibodies (>1.25 g/L), interferon-γ (>64 ng/L), and granzyme-B (>40 pg/mL) compared to control at second booster dose (240 µg/500 µL). The induction of peptide-specific IgG antibodies in immunized rats indicates the T-cell dependent B-lymphocyte activation. A substantial CD4+ and CD8+ cell count was observed at 240 µg/500 µL. In male and female rats, CD8+ cell count for L1 and L2 peptide is 3000 and 3118, and CD4+ is 3369 and 3484 respectively compared to control. In conclusion, we demonstrated that L1M1, L1M2, L2M1, L2M2 are likely to contain potential epitopes for induction of immune responses supporting the feasibility of peptide-based vaccine development for HPV.
Biomimetic Liquid Metal–Elastomer Composited Foam with Adjustable Thermal Conductivity for Heat Control
Authors: Tang Hongyao , Lü Xiaozhou , Meng Xiangyu , Wang Hai , Bai Guanghui , Bao Weimin
Published: February 2023

The application of traditional materials with constant thermal conductivity in time-varying thermal environments poses great challenges due to their inability of adjusting thermal conductivity according to different requirements, for which reason materials with adjustable thermal conductivity have attracted much attention. However, certain limitations induced by those materials’ low softness or harsh adjustment conditions restrict them from being applied in heat dissipation and heat transfer scenarios. In this study, we report a biomimetic liquid metal–elastomer composited foam with adjustable thermal conductivity (B-LM-ECF). Inspired by the rationale of homeothermic animals regulating the thermal conductivity of their subcutaneous tissue, the prepared material adjusts its thermal conductivity via adjusting the volume proportion of liquid metal within it. The thermal conductivity of B-LM-ECF can be adjusted within the range of 0.11–8.4 W·m−1K−1. The adjustment factor η of B-LM-ECF is 76, which is defined as the ratio of the highest to the lowest thermal conductivity of the material. The material enabling reversible switching for itself from thermal insulation to heat dissipation. The prepared material exhibits 45 KPa of Young’s modulus with the maximum fracture tensile rate of 600%, facilitating better covering for thermal management objects. We selected a power lithium battery and a smartphone as specific thermal management objects to demonstrate its practical application in thermal management experiment.
GC-MS Determination of Undeclared Phthalate Esters in Commercial Fragrances: Occurrence, Profiles and Assessment of Carcinogenic and Non-Carcinogenic Risk Associated with Their Consumption among Adult Consumers
Authors: Mostafa Ahmed , Shaaban Heba
Published: February 2023

Phthalates are chemicals that are extensively used in the manufacturing of cosmetic products. The occurrence of phthalate esters in personal care products may pose adverse effects on consumers’ health. In this work, a simple, fast and reliable GC-MS method was developed and validated for concurrent determination of phthalate esters in fragrances. Simple procedures were employed for sample preparation and clean up. The recoveries achieved were in the range of 94.9% to 105.6% with RSD ≤ 4.06. The detection limits were in the range of 0.0010 to 0.0021 µg/mL. The GC-MS method was utilized to investigate the occurrence of phthalate esters in different brands of perfumes sold in the Saudi Arabian market. Diethyl phthalate was detected in all analyzed samples, with a maximum concentration of 5766 µg/mL, and di (2-ethylhexyl) phthalate was detected in the majority of the analyzed samples (95%), with a mean concentration of 55.9 µg/mL and a highest concentration of 377.7 µg/mL. Additionally, the exposure to phthalate esters due to the consumption of perfumes was investigated among the adult Saudi population for the first time. It was found that the systemic exposure dose, measured at mean concentrations, ranged from 4.59 × 10−4 to 4.29 × 10−2 (mg/kg/day) and from 5.00 × 10−4 to 4.68 × 10−2 (mg/kg/day) for male and female users, respectively. Moreover, the non-carcinogenic risk of the investigated phthalate esters and the carcinogenic risk of DEHP were also evaluated. The non-carcinogenic risk values of the detected phthalate esters were greater than 100, which indicates that exposure to these phthalate esters is unlikely to produce non-carcinogenic health effects to consumers. However, at maximum DEHP concentrations, the carcinogenic risk values were 5.49 × 10−5 for male users and 5.98 × 10−5 for female users, which indicates the possibility of DEHP to pose a carcinogenic health effect if present at high levels. Regular monitoring of undeclared chemicals such as phthalate esters in personal care products marketed in Saudi Arabia is extremely important to ensure consumers’ safety. To the best of the authors’ knowledge, this is the first study to assess the health risk associated with consumption of perfumes in Saudi Arabia.
The Structural Diversity and Biological Activity of Steroid Oximes
Authors: Gomes Ana R. , Pires Ana S. , Roleira Fernanda M. F. , Tavares-da-Silva Elisiário J.
Published: February 2023

Steroids and their derivatives have been the subject of extensive research among investigators due to their wide range of pharmacological properties, in which steroidal oximes are included. Oximes are a chemical group with the general formula R1R2C=N−OH and they exist as colorless crystals and are poorly soluble in water. Oximes can be easily obtained through the condensation of aldehydes or ketones with various amine derivatives, making them a very interesting chemical group in medicinal chemistry for the design of drugs as potential treatments for several diseases. In this review, we will focus on the different biological activities displayed by steroidal oximes such as anticancer, anti-inflammatory, antibacterial, antifungal and antiviral, among others, as well as their respective mechanisms of action. An overview of the chemistry of oximes will also be reported, and several steroidal oximes that are in clinical trials or already used as drugs are described. An extensive literature search was performed on three main databases—PubMed, Web of Science, and Google Scholar.
Study on the Influence of the Preparation Method of Konjac Glucomannan-Silica Aerogels on the Microstructure, Thermal Insulation, and Flame-Retardant Properties
Authors: Kuang Ying , Liu Puming , Yang Yichen , Wang Xiaosa , Liu Menglong , Wang Wei , Guo Tianlin , Xiao Man , Chen Kai , Jiang Fatang , Li Cao
Published: February 2023

Natural polysaccharides with high viscosity, good thermal stability, and biocompatibility can improve the mechanical properties of inorganic silica aerogels and enhance their application safety. However, the effects of the preparation methods of polysaccharide-silica aerogels on their microstructure and application properties have not been systematically studied. To better investigate the effect of the microstructure on the properties of aerogel materials, two aerogels with different structures were prepared using Konjac glucomannan (KGM) and tetraethoxysilane (TEOS) via physical blending (KTB) and co-precursor methods (KTC), respectively. The structural differences between the KTB and KTC aerogels were characterized, and the thermal insulation and fire-retardant properties were further investigated. The compressive strength of the KTC aerogels with a cross-linked interpenetrating network (IPN) structure was three times higher than that of the KTB aerogels, while their thermal conductivity was 1/3 of that of the KTB aerogels. The maximum limiting oxygen index (LOI) of the KTC aerogels was 1.4 times, the low peak heat release rate (PHRR) was reduced by 61.45%, and the lowest total heat release (THR) was reduced by 41.35% compared with the KTB aerogels. The results showed that the KTC aerogels with the IPN have better mechanical properties, thermal insulation, and fire-retardant properties than the simple physically blending KTB aerogels. This may be due to the stronger hydrogen-bonding interactions between KGM and silica molecules in the KTC aerogels under the unique forcing effect of the IPN, thus enhancing their structural stability and achieving complementary properties. This work will provide new ideas for the microstructure design of aerogels and the research of new thermal insulation and fire-retardant aerogels.
Electric Dipole Moments from Stark Effect in Supersonic Expansion: n-Propanol, n-Butanol, and n-Butyl Cyanide
Authors: Kisiel Zbigniew , Habdas Krzysztof
Published: February 2023

The orientation and magnitude of the molecular electric dipole moment are key properties relevant to topics ranging from the nature of intermolecular interactions to the quantitative analysis of complex gas-phase mixtures, such as chemistry in astrophysical environments. Stark effect measurements on rotational spectra have been the method of choice for isolated molecules but have become less common with the practical disappearance of Stark modulation spectrometers. Their role has been taken over by supersonic expansion measurements within a Fabry-Perot resonator cavity, which introduces specific technical problems that need to be overcome. Several of the adopted solutions are described and compared. Presently, we report precise electric dipole moment determinations for the two most stable conformers of the selected molecules of confirmed or potential astrophysical relevance: n-propanol, n-butanol, and n-butyl cyanide. All dipole moment components have been precisely determined at supersonic expansion conditions by employing specially designed Stark electrodes and a computer program for fitting the measured Stark shifts, inclusive of cases with resolved nuclear quadrupole hyperfine structure. The experimental values are compared with suitable quantum chemistry computations. It is found that, among the tested levels of computation, vibrationally averaged dipole moments are the closest to the observation and the molecular values are, as in the lighter molecules in the series, largely determined by the hydroxyl or nitrile groups.
Quantitative Structure Retention-Relationship Modeling: Towards an Innovative General-Purpose Strategy
Authors: Kumari Priyanka , Van Laethem Thomas , Hubert Philippe , Fillet Marianne , Sacré Pierre-Yves , Hubert Cédric
Published: February 2023

Reversed-Phase Liquid Chromatography (RPLC) is a common liquid chromatographic mode used for the control of pharmaceutical compounds during their drug life cycle. Nevertheless, determining the optimal chromatographic conditions that enable this separation is time consuming and requires a lot of lab work. Quantitative Structure Retention Relationship models (QSRR) are helpful for doing this job with minimal time and cost expenditures by predicting retention times of known compounds without performing experiments. In the current work, several QSRR models were built and compared for their adequacy in predicting the retention times. The regression models were based on a combination of linear and non-linear algorithms such as Multiple Linear Regression, Support Vector Regression, Least Absolute Shrinkage and Selection Operator, Random Forest, and Gradient Boosted Regression. Models were built for five pH conditions, i.e., at pH 2.7, 3.5, 6.5, and 8.0. In the end, the model predictions were combined using stacking and the performances of all models were compared. The k-nearest neighbor-based application domain filter was established to assess the reliability of the prediction for further compound prioritization. Altogether, this study can be insightful for analytical chemists working with RPLC to begin with the computational prediction modeling such as QSRR to predict the separation of small molecules.
A Novel 5-Chloro-N-phenyl-1H-indole-2-carboxamide Derivative as Brain-Type Glycogen Phosphorylase Inhibitor: Validation of Target PYGB
Authors: Huang Yatao , Li Shuai , Wang Youde , Yan Zhiwei , Guo Yachun , Zhang Liying
Published: February 2023

Brain-type glycogen phosphorylase (PYGB) inhibitors are recognized as prospective drugs for treating ischemic brain injury. We previously reported compound 1 as a novel glycogen phosphorylase inhibitor with brain-protective properties. In this study, we validated whether PYGB could be used as the therapeutic target for hypoxic-ischemic diseases and investigated whether compound 1 exerts a protective effect against astrocyte hypoxia/reoxygenation (H/R) injury by targeting PYGB. A gene-silencing strategy was initially applied to downregulate PYGB proteins in mouse astrocytes, which was followed by a series of cellular experiments with compound 1. Next, we compared relevant indicators that could prove the protective effect of compound 1 on brain injury, finding that after PYGB knockdown, compound 1 could not obviously alleviate astrocytes H/R injury, as evidenced by cell viability, which was not significantly improved, and lactate dehydrogenase (LDH) leakage rate, intracellular glucose content, and post-ischemic reactive oxygen species (ROS) level, which were not remarkably reduced. At the same time, cellular energy metabolism did not improve, and the degree of extracellular acidification was not downregulated after administration of compound 1 after PYGB knockdown. In addition, it could neither significantly increase the level of mitochondrial aerobic energy metabolism nor inhibit the expression of apoptosis-associated proteins. The above results indicate that compound 1 could target PYGB to exert its protective effect against cellular H/R injury in mouse astrocytes. Simultaneously, we further demonstrated that PYGB could be an efficient therapeutic target for ischemic-hypoxic diseases. This study provides a new reference for further in-depth study of the action mechanism of the efficacy of compound 1.
A Non-Conventional Platinum Drug against a Non-Small Cell Lung Cancer Line
Authors: Silva Jéssica D. , Marques Joana , Santos Inês P. , Batista de Carvalho Ana L. M. , Martins Clara B. , Laginha Raquel C. , Batista de Carvalho Luís A. E. , Marques Maria Paula M.
Published: February 2023

A dinuclear Pt(II) complex with putrescine as bridging polyamine ligand ([Pt2Put2(NH3)4]Cl4) was synthesized and assessed as to its potential anticancer activity against a human non-small cell lung cancer line (A549), as well as towards non-cancer cells (BEAS-2B). This effect was evaluated through in vitro cytotoxicity assays (MTT and SRB) coupled to microFTIR and microRaman spectroscopies, the former delivering information on growth-inhibiting and cytotoxic abilities while the latter provided very specific information on the metabolic impact of the metal agent (at the sub-cellular level). Regarding cancer cells, a major impact of [Pt2Put2(NH3)4]Cl4 was evidenced on cellular proteins and lipids, as compared to DNA, particularly via the Amide I and Amide II signals. The effect of the chelate on non-malignant cells was lower than on malignant ones, evidencing a promising low toxicity towards healthy cells.
Iodine-Modified Ag NPs for Highly Sensitive SERS Detection of Deltamethrin Residues on Surfaces
Authors: Hu Zhangmei , Peng Dandan , Xing Feiyue , Wen Xiang , Xie Kun , Xu Xuemei , Zhang Hui , Wei Feifei , Zheng Xiaoke , Fan Meikun
Published: February 2023

It is essential to estimate the indoor pesticides/insecticides exposure risk since reports show that 80% of human exposure to pesticides occurs indoors. As one of the three major contamination sources, surface collected pesticides contributed significantly to this risk. Here, a highly sensitive liquid freestanding membrane (FSM) SERS method based on iodide modified silver nanoparticles (Ag NPs) was developed for quantitative detection of insecticide deltamethrin (DM) residues in solution phase samples and on surfaces with good accuracy and high sensitivity. The DM SERS spectrum from 500 to 2500 cm−1 resembled the normal Raman counterpart of solid DM. Similar bands at 563, 1000, 1165, 1207, 1735, and 2253 cm−1 were observed as in the literature. For the quantitative analysis, the strongest peak at 1000 cm−1 that was assigned to the stretching mode of the benzene ring and the deformation mode of C-C was selected. The peak intensity at 1000 cm−1 and the concentration of DM showed excellent linearity from 39 to 5000 ppb with a regression equation I = 649.428 + 1.327 C (correlation coefficient R2 = 0.991). The limit of detection (LOD) of the DM was found to be as low as 11 ppb. Statistical comparison between the proposed and the HPLC methods for the analysis of insecticide deltamethrin (DM) residues in solution phase samples showed no significant difference. DM residue analysis on the surface was mimicked by dropping DM pesticide on the glass surface. It is found that DM exhibited high residue levels up to one week after exposure. This proposed SERS method could find application in the household pesticide residues analysis.
Determination of 3′-Sialyllactose in Edible Bird’s Nests and the Effect of Stewing Conditions on the 3′-Sialyllactose Content of Edible Bird’s Nest Products
Authors: Zhang Xiaojiang , Liang Ruifang , Bai Weijuan , Xiao Yue’e , Liu Xuncai , Fan Qunyan , Guo Baozhong
Published: February 2023

Sialyllactose is an acidic oligosaccharide that has an immune-protective effect against pathogens and contributes to developing the immune system and intestinal microbes. In this study, a method for the determination of 3′-sialyllactose by high-performance liquid chromatography tandem mass spectrometry was established. The sample was treated with 0.1% formic acid methanol solution, and the gradient elution was performed with 0.05% formic acid water and 0.1% formic acid acetonitrile. The hydrophilic liquid chromatographic column was used for separation. The results showed that the linearity was good in the concentration range of 1~160 μg/L. The limit of detection (LOD) and the limit of quantification (LOQ) of the method were 0.3 μg/kg and 1.0 μg/kg, the recovery range was 91.6%~98.4%, and the relative standard deviation (RSD) was 1.5%~2.2%. This method is fast and sensitive. In addition, the 3′-sialyllactose content in edible bird’s nest products produced by different processes was studied. It was found that within the tested range, 3′-sialyllactose in edible bird’s nest products increased with the intensity of stewing and increased with the addition of sugar. In short, the results provided a new method for detecting the nutritional value of edible bird’s nests, as well as a new direction for improving the nutritional value of edible bird’s nest products.
An Eco-Benign Biomimetic Approach for the Synthesis of Ni/ZnO Nanocomposite: Photocatalytic and Antioxidant Activities
Authors: Alhar Munirah Sulaiman Othman , Muhammad Dost , Tahir Kamran , Zaki Magdi E. A. , Urooj Muniba , Nazir Sadia , Albalawi Karma , Al-Shehri Hamza S. , Saleh Ebraheem Abdu Musad , Khan Afaq Ullah
Published: February 2023

With the increasing demand for wastewater treatment and multidrug resistance among pathogens, it was necessary to develop an efficient catalyst with enhanced photocatalytic and antibacterial applications. The present study proposes a facile and green strategy for synthesizing zinc oxide (ZnO) decorated nickel (Ni) nanomaterials. The synthesized Ni/ZnO nanocomposite displays a high crystallinity and spherical morphology, which was systematically characterized by XRD, SEM, FT-IR, UV-visible spectroscopy, EDX, HRTEM, and XPS techniques. In addition, the bacteriological tests indicated that Ni/ZnO nanocomposite exhibits potent antibacterial activity against human pathogens, i.e., Pseudomonas aeruginosa (P. aeruginosa), Staphylococcus aureus (S. aureus), and Escherichia coli (E. coli). The inhibition zone observed in light and dark conditions for E. coli was 16 (±0.3) mm and 8 (±0.4) mm, respectively, which confirms the high efficacy of the nanocomposite in the presence of light compared to dark conditions. The detailed inhibition mechanism of said bacterium and damage were also studied through fluorescence spectroscopy and SEM analysis, respectively. Evaluation of antioxidant activity based on free radical scavenging activity revealed that the Ni/ZnO nanocomposite effectively scavenges DPPH. In the photocatalytic performance, the Ni/ZnO nanocomposite exhibited a remarkable degradation ability under the optimized condition, which was attributed to their controllable size, high surface area, and exceptional morphology. Good selectivity, high photodegradation, and antibacterial activities and satisfactory hemolytic behavior of the as-prepared nanocomposite make them able to become a potential candidate for superior biological performance and environmental remediation.
Application of Polypyrrole-Based Electrochemical Biosensor for the Early Diagnosis of Colorectal Cancer
Authors: Zhang Xindan , Tan Xiao , Wang Ping , Qin Jieling
Published: February 2023

Although colorectal cancer (CRC) is easy to treat surgically and can be combined with postoperative chemotherapy, its five-year survival rate is still not optimistic. Therefore, developing sensitive, efficient, and compliant detection technology is essential to diagnose CRC at an early stage, providing more opportunities for effective treatment and intervention. Currently, the widely used clinical CRC detection methods include endoscopy, stool examination, imaging modalities, and tumor biomarker detection; among them, blood biomarkers, a noninvasive strategy for CRC screening, have shown significant potential for early diagnosis, prediction, prognosis, and staging of cancer. As shown by recent studies, electrochemical biosensors have attracted extensive attention for the detection of blood biomarkers because of their advantages of being cost-effective and having sound sensitivity, good versatility, high selectivity, and a fast response. Among these, nano-conductive polymer materials, especially the conductive polymer polypyrrole (PPy), have been broadly applied to improve sensing performance due to their excellent electrical properties and the flexibility of their surface properties, as well as their easy preparation and functionalization and good biocompatibility. This review mainly discusses the characteristics of PPy-based biosensors, their synthetic methods, and their application for the detection of CRC biomarkers. Finally, the opportunities and challenges related to the use of PPy-based sensors for diagnosing CRC are also discussed.
Topical Application of Linezolid–Loaded Chitosan Nanoparticles for the Treatment of Eye Infections
Authors: Alkholief Musaed , Kalam Mohd Abul , Alshememry Abdullah K. , Ali Raisuddin , Alhudaithi Sulaiman S. , Alsaleh Nasser B. , Raish Mohammad , Alshamsan Aws
Published: February 2023

Linezolid (LZ) loaded chitosan–nanoparticles (CSNPs) was developed by the ionic–gelation method using Tripolyphosphate–sodium as a crosslinker for topical application for the treatment of bacterial eye infections. Particles were characterized by Zeta–Sizer (Malvern Nano–series). TEM was used for structural morphology. Encapsulation and drug loading were estimated by measuring the unencapsulated drug. In-vitro drug release in STF (pH 7) was performed through a dialysis membrane. Storage stability of LZ–CSNPs was checked at 25 °C and 40 °C for six months. The antimicrobial potency of NPs was evaluated on different Gram–positive strains. Ocular irritation and pharmacokinetic studies were completed in rabbits. Ex-vivo transcorneal permeation of the drug was determined through the rabbit cornea. Ionic interaction among the oppositely charged functional groups of CS and TPP generated the CSNPs. The weight ratio at 3:1, wt/wt (CS/TPP) with 21.7 mg of LZ produced optimal NPs (213.7 nm with 0.387 of PDI and +23.1 mV of ZP) with 71% and 11.2% encapsulation and drug loading, respectively. Around 76.7% of LZ was released from LZ–AqS within 1 h, while 79.8% of LZ was released from CSNPs at 12 h and 90% at 24 h. The sustained drug release property of CSNPS was evaluated by applying kinetic models. The linearity in the release profile suggested that the release of LZ from CSNPs followed the Higuchi–Matrix model. LZ–CSNPs have shown 1.4 to 1.6-times improved antibacterial activity against the used bacterial strains. The LZ–CSNPs were “minimally–irritating” to rabbit eyes and exhibited 4.4-times increased transcorneal permeation of LZ than from LZ–AqS. Around 3-, 1.2- and 3.1-times improved Tmax, Cmax, and AUC0–24 h, respectively were found for LZ–CSNPs during the ocular pharmacokinetic study. AqS has shown 3.1-times faster clearance of LZ. Conclusively, LZ–CSNPs could offer a better alternative for the prolonged delivery of LZ for the treatment of bacterial infections in the eyes.
The Magnesium Status and Suggested Reference Ranges of Plasma Magnesium, Calcium, and Calcium/Magnesium Ratio in Chinese Adults over 45 Years Old
Authors: Yang Jingxin , Cao Yang , Shan Xiaoyun , Zhang Huidi , Feng Jie , Lu Jiaxi , Yang Lichen
Published: February 2023

Magnesium (Mg) is an essential nutrient that participates in various enzymatic reactions and regulates important biological functions. The distribution and reference ranges in China have not been reported in populations more than 45 years old. This study aimed to assess the magnesium status and determine the reference values of plasma Mg, Ca, and Ca/Mg ratios for China’s population more than 45 years old. A total of 2101 people were randomly selected from the China Nutrition and Health surveillance (CNHS) (2015–2017), considering the regional types and monitoring points. Then, 337 healthy individuals were further selected by a series of strict inclusion criteria to explore the reference range. The plasma magnesium and calcium were tested by inductively coupled plasma mass spectrometry (ICP-MS). The suggested reference values for plasma Mg, Ca, and Ca/Mg ratios were 0.75–1.14 mmol/L, 2.17–3.64 mmol/L, and 2.36–3.66, respectively. Taking 0.75 mmol/L as the lower cut-off limit, the prevalence of Mg deficiency was 6.66%, and the average level of plasma magnesium was 0.88 mmol/L for populations older than 45 years in China. In conclusion, this study provides the magnesium status and reference ranges for plasma Mg, Ca, and Ca/Mg ratio for Chinese people over 45 years old. The results of the recommended reference ranges in this study were very similar to our published results in women of reproductive age. Thus, the reference range of plasma magnesium in different populations in China was further improved.
Caloric Restriction (CR) Plus High-Nitrate Beetroot Juice Does Not Amplify CR-Induced Metabolic Adaptation and Improves Vascular and Cognitive Functions in Overweight Adults: A 14-Day Pilot Randomised Trial
Authors: Alharbi Mushari , Chiurazzi Martina , Nasti Gilda , Muscariello Espedita , Mastantuono Teresa , Koechl Christina , Stephan Blossom CM , Shannon Oliver M , Colantuoni Antonio , Siervo Mario
Published: February 2023

Caloric restriction (CR) and dietary nitrate supplementation are nutritional interventions with pleiotropic physiological functions. This pilot study investigates the combined effects of CR and nitrate-rich beetroot juice (BRJ) on metabolic, vascular, and cognitive functions in overweight and obese middle-aged and older adults. This was a two-arm, parallel randomized clinical trial including 29 participants allocated to CR + BRJ (n = 15) or CR alone (n = 14) for 14 days. Body composition, resting energy expenditure (REE), and hand-grip strength were measured. Resting blood pressure (BP) and microvascular endothelial function were measured, and Trail-Making Test A and B were used to assess cognitive function. Salivary nitrate and nitrite, and urinary nitrate and 8-isoprostane concentrations were measured. Changes in body composition, REE, and systolic and diastolic BP were similar between the two interventions (p > 0.05). The CR + BRJ intervention produced greater changes in average microvascular flux (p = 0.03), NO-dependent endothelial activity (p = 0.02), and TMT-B cognitive scores (p = 0.012) compared to CR alone. Changes in urinary 8-isoprostane were greater in the CR + BRJ group (p = 0.02), and they were inversely associated with changes in average microvascular flux (r = −0.53, p = 0.003). These preliminary findings suggest that greater effects on vascular and cognitive functions could be achieved by combining CR with dietary nitrate supplementation.
Hereditary Hemorrhagic Telangiectasia in Pediatric Age: Focus on Genetics and Diagnosis
Authors: Danesino Cesare , Cantarini Claudia , Olivieri Carla
Published: February 2023

Hereditary Hemorrhagic Telangiectasia (HHT) or Rendu–Osler–Weber Syndrome (ROW) is an autosomal dominant vascular disease, with an estimated prevalence of 1:5000. Genes associated with HHT are ACVRL1, ENG, SMAD4, and GDF2, all encoding for proteins involved in the TGFβ/BMPs signaling pathway. The clinical diagnosis of HHT is made according to the “Curaçao Criteria,” based on the main features of the disease: recurrent and spontaneous epistaxis, muco-cutaneous telangiectases, arteriovenous malformations in the lungs, liver, and brain, and familiarity. Since the clinical signs of HHT can be misinterpreted, and the primary symptom of HHT, epistaxis, is common in the general population, the disease is underdiagnosed. Although HHT exhibits a complete penetrance after the age of 40, young subjects may also present symptoms of the disease and are at risk of severe complications. Here we review the literature reporting data from clinical, diagnostic, and molecular studies on the HHT pediatric population.
Photocaging of Pyridinylimidazole-Based Covalent JNK3 Inhibitors Affords Spatiotemporal Control of the Binding Affinity in Live Cells
Authors: Hoffelner Beate Sandra , Andreev Stanislav , Plank Nicole , Koch Pierre
Published: February 2023

The concept of photocaging represents a promising approach to acquire spatiotemporal control over molecular bioactivity. To apply this strategy to pyridinylimidazole-based covalent JNK3 inhibitors, we used acrylamido-N-(4-((4-(4-(4-fluorophenyl)-1-methyl-2-(methylthio)-1H-imidazol-5-yl)pyridin-2-yl)amino)phenyl)benzamide (1) as a lead compound to design novel covalent inhibitors of JNK3 by modifying the amide bond moiety in the linker. The newly synthesized inhibitors demonstrated IC50 values in the low double-digit nanomolar range in a radiometric kinase assay. They were further characterized in a NanoBRETTM intracellular JNK3 assay, where covalent engagement of the target enzyme was confirmed by compound washout experiments and a loss in binding affinity for a newly generated JNK3(C154A)-NLuc mutant. The most potent compound of the series, N-(3-acrylamidophenyl)-4-((4-(4-(4-fluorophenyl)-1-methyl-2-(methylthio)-1H-imidazol-5-yl)pyridin-2-yl)amino)benzamide (13), was equipped with a photolabile protecting group leading to a nearly 10-fold decrease in intracellular JNK3 binding affinity, which was fully recovered by UV irradiation at a wavelength of 365 nm within 8 min. Our results highlight that photocaged covalent inhibitors can serve as a pharmacological tool to control JNK3 activity in live cells with light.
Oral Wound Healing Potential of Polygoni Cuspidati Rhizoma et Radix Decoction—In Vitro Study
Authors: Hadzik Jakub , Choromańska Anna , Karolewicz Bożena , Matkowski Adam , Dominiak Marzena , Złocińska Adrianna , Nawrot-Hadzik Izabela
Published: February 2023

Polygoni Cuspidati Rhizoma et Radix (syn. rhizomes of Reynoutria japonica Houtt.) is a pharmacopoeial raw material in Europe and China. In traditional medicine, one of the applications for Reynoutria japonica rhizomes is wound healing. In a recent in vitro study, we demonstrated that ethanol and acetone extracts from this herbal drug have the potential to heal oral gum wounds. However, considering that a majority of herbal medicines have been traditionally administered as water decoctions, in the present study, a decoction of Reynoutria japonica rhizomes was prepared and detailed tests to determine its in vitro gingival wound healing activity were conducted. We used the primary human gingival fibroblasts (HGF) incubated with a decoction to determine cell viability (MTT assay), cell proliferation (the confocal laser scanning microscope—CLSM), and cell migration (wound healing assay). Moreover, the collagen type III expression was examined using immunocytochemical staining. The studied decoction was qualitatively and quantitatively characterized using the validated HPLC/DAD/ESI-HR-QTOF-MS method. The Folin–Ciocalteu assay was used to determine the total phenols and tannins content. Additionally, HPLC-RI analysis of decoction and the previously obtained ethanol and acetone extracts was used to determine the composition of saccharides. Low concentration (from 50 to 1000 µg/mL) of decoction after 24 h incubation caused a significant increase in HGF cell viability. No cytotoxic effect was observed at any tested concentration (up to 2000 µg/mL). The lowest active concentration of decoction (50 µg/mL) was selected for further experiments. It significantly stimulated human gingival fibroblasts to proliferate, migrate, and increase the synthesis of collagen III. Phytochemical analysis showed significantly fewer polyphenols in the decoction than in the ethanol and acetone extracts tested earlier. In contrast, high levels of polysaccharides were observed. In our opinion, they may have a significant effect on the oral wound healing parameters analyzed in vitro. The results obtained encourage the use of this raw material in its traditional, safe form—decoction.
Semi-Synthetic Dihydrotestosterone Derivatives Modulate Inherent Multidrug Resistance and Sensitize Colon Cancer Cells to Chemotherapy
Authors: Nagy Ferenc István , Adamecz Dóra Izabella , Baji Ádám , Kiricsi Ágnes , Huliák Ildikó , Rónavári Andrea , Kónya Zoltán , Frank Éva , Gopisetty Mohana Krishna , Kiricsi Mónika
Published: February 2023

Multidrug resistance (MDR) is a serious hurdle to successful cancer therapy. Here, we examined the efficiency of novel semi-synthetic dihydrotestosterone derivatives, more specifically androstano-arylpyrimidines in inhibiting the efflux activity of ATP-binding cassette (ABC) transporters and sensitizing inherently MDR colon cancer cells to various chemotherapy drugs. Using the Rhodamine123 accumulation assay, we evaluated the efflux activity of cancer cells following treatments with androstano-arylpyrimidines. We found that acetylated compounds were capable of attenuating the membrane efflux of inherently MDR cells; however, deacetylated counterparts were ineffective. To delineate the possible molecular mechanisms underlying these unique activities of androstano-arylpyrimidines, the degree of apoptosis induction was assessed by AnnexinV-based assays, both upon the individual as well as by steroid and chemotherapy agent combination treatments. Five dihydrotestosterone derivatives applied in combination with Doxorubicin or Epirubicin triggered massive apoptosis in MDR cells, and these combinations were more efficient than chemotherapy drugs together with Verapamil. Furthermore, our results revealed that androstano-arylpyrimidines induced significant endoplasmic reticulum stress (ER stress) but did not notably modulate ABC transporter expression. Therefore, ER stress triggered by acetylated androstano-arylpyrimidines is probably involved in the mechanism of efflux pump inhibition and drug sensitization which can be targeted in future drug developments to defeat inherently multidrug-resistant cancer.
Irisin Role in Chondrocyte 3D Culture Differentiation and Its Possible Applications
Authors: Posa Francesca , Zerlotin Roberta , Ariano Anastasia , Cosola Michele Di , Colaianni Graziana , Fazio Aldo Di , Colucci Silvia , Grano Maria , Mori Giorgio
Published: February 2023

Irisin is a recently discovered cytokine, better known as an exercise-induced myokine, produced primarily in skeletal muscle tissue as a response to exercise. Although the skeleton was initially identified as the main target of Irisin, its action is also proving effective in many other tissues. Physical activity determines a series of beneficial effects on health, including the possibility of counteracting the damage that is caused by arthritis to the cartilage of people suffering from osteoarthritis. Nevertheless, up to now, the studies that have taken into consideration the possible involvement of Irisin on the well-being of cartilage tissue are particularly limited. In this study, we postulated that the protective effect of physical activity on cartilage tissue may depend on the paracrine action of Irisin secreted during exercise; therefore, we analyzed the effects of Irisin, in vitro, on chondrogenic differentiation. To achieve this goal, three-dimensional cultures of commercially available human articular chondrocytes (HACs) were treated with the molecule under study. Our results revealed new crosstalk mechanisms between muscle and cartilage tissue. Furthermore, the confirmation of Irisin ability to induce chondrogenic differentiation could favor the development of exercise-mimetic drugs, with application relevance for patients who cannot perform physical activity.
Adalimumab Serum Concentrations, Clinical and Endoscopic Disease Activity in Crohn’s Disease: A Cross-Sectional Multicentric Latin American Study
Authors: de Souza Letícia Rodrigues , Magro Daniela Oliveira , Teixeira Fábio Vieira , Parra Rogério Serafim , Miranda Eron Fábio , Féres Omar , Saad-Hossne Rogério , Soares Prates Herrerias Giedre , Nisihara Renato Mitsunori , Coy Claudio Saddy Rodrigues , Sassaki Ligia Yukie , Kotze Paulo Gustavo
Published: February 2023

Despite some variability in ideal serum Adalimumab (ADA) concentrations, there is increasing evidence that higher concentrations of anti-TNF-α agents can be associated with sustained efficacy, and low or undetectable levels may lead to loss of response. This study aims to correlate serum ADA concentrations with clinical and endoscopic activity in patients with Crohn’s disease (CD). A cross-sectional and multicentric study was performed with patients with CD, who used ADA for at least 24 weeks. Patients were allocated into groups according to the presence of clinical or endoscopic disease activity. Serum ADA concentrations were measured and compared between groups. Overall, 89 patients were included. A total of 27 patients had clinically active CD and 62 were in clinical remission. Forty patients had endoscopic disease activity and 49 were in endoscopic remission. The mean serum ADA concentration was 10.2 μg/mL in patients with clinically active CD and 14.3 μg/mL in patients in clinical remission (p = 0.395). The mean serum ADA concentration in patients with endoscopic activity was 11.3 μg/mL as compared to 14.5 μg/mL in those with endoscopic remission (p = 0.566). There was no difference between serum ADA concentrations regarding clinical or endoscopic activity in CD, as compared to patients in remission
Properties and Bioapplications of Amphiphilic Janus Dendrimers: A Review
Authors: Căta Adina , Ienașcu Ioana Maria Carmen , Ştefănuț Mariana Nela , Roșu Dan , Pop Oana-Raluca
Published: February 2023

Amphiphilic Janus dendrimers are arrangements containing both hydrophilic and hydrophobic units, capable of forming ordered aggregates by intermolecular noncovalent interactions between the dendrimer units. Compared to conventional dendrimers, these molecular self-assemblies possess particular and effective attributes i.e., the presence of different terminal groups, essential to design new elaborated materials. The present review will focus on the pharmaceutical and biomedical application of amphiphilic Janus dendrimers. Important information for the development of novel optimized pharmaceutical formulations, such as structural classification, synthetic pathways, properties and applications, will offer the complete characterization of this type of Janus dendrimers. This work will constitute an up-to-date background for dendrimer specialists involved in designing amphiphilic Janus dendrimer-based nanomaterials for future innovations in this promising field.
Exosome-Based Carrier for RNA Delivery: Progress and Challenges
Authors: Lu Yicheng , Huang Wei , Li Meng , Zheng Aiping
Published: February 2023

In the last few decades, RNA-based drugs have emerged as a promising candidate to specifically target and modulate disease-relevant genes to cure genetic defects. The key to applying RNA therapy in clinical trials is developing safe and effective delivery systems. Exosomes have been exploited as a promising vehicle for drug delivery due to their nanoscale size, high stability, high biocompatibility, and low immunogenicity. We reviewed and summarized the progress in the strategy and application of exosome-mediated RNA therapy. The challenges of exosomes as a carrier for RNA drug delivery are also elucidated in this article. RNA molecules can be loaded into exosomes and then delivered to targeted cells or tissues via various biochemical or physical approaches. So far, exosome-mediated RNA therapy has shown potential in the treatment of cancer, central nervous system disorders, COVID-19, and other diseases. To further exploit the potential of exosomes for RNA delivery, more efforts should be made to overcome both technological and logistic problems.
A Review of Protein- and Peptide-Based Chemical Conjugates: Past, Present, and Future
Authors: Holz Emily , Darwish Martine , Tesar Devin B. , Shatz-Binder Whitney
Published: February 2023

Over the past few decades, the complexity of molecular entities being advanced for therapeutic purposes has continued to evolve. A main propellent fueling innovation is the perpetual mandate within the pharmaceutical industry to meet the needs of novel disease areas and/or delivery challenges. As new mechanisms of action are uncovered, and as our understanding of existing mechanisms grows, the properties that are required and/or leveraged to enable therapeutic development continue to expand. One rapidly evolving area of interest is that of chemically enhanced peptide and protein therapeutics. While a variety of conjugate molecules such as antibody–drug conjugates, peptide/protein–PEG conjugates, and protein conjugate vaccines are already well established, others, such as antibody–oligonucleotide conjugates and peptide/protein conjugates using non-PEG polymers, are newer to clinical development. This review will evaluate the current development landscape of protein-based chemical conjugates with special attention to considerations such as modulation of pharmacokinetics, safety/tolerability, and entry into difficult to access targets, as well as bioavailability. Furthermore, for the purpose of this review, the types of molecules discussed are divided into two categories: (1) therapeutics that are enhanced by protein or peptide bioconjugation, and (2) protein and peptide therapeutics that require chemical modifications. Overall, the breadth of novel peptide- or protein-based therapeutics moving through the pipeline each year supports a path forward for the pursuit of even more complex therapeutic strategies.
Regulatory Requirements for the Development of Second-Entry Semisolid Topical Products in the European Union
Authors: García-Arieta Alfredo , Gordon John , Gwaza Luther , Merino Virginia , Mangas-Sanjuan Víctor
Published: February 2023

The development of second-entry topical products is hampered by several factors. The excipient composition should be similar to the reference product because excipients may also contribute to efficacy. Conventional pharmacokinetic bioequivalence studies were not considered acceptable because drug concentrations are measured downstream after the site of action. There was no agreed methodology to characterize the microstructure of semisolids, and waivers of therapeutic equivalence studies with clinical endpoints were not possible. Only the vasoconstrictor assay for corticosteroids was accepted as a surrogate. This paper describes the implementation of the European Union’s stepwise approach for locally acting products to cutaneous products, discusses the equivalence requirements of the EMA Draft Guideline on the Quality and Equivalence of Topical Products, and compares them with the US Food and Drug Administration recommendations. Step 1 includes the possibility of waivers for simple formulations based on in vitro data only (Q1 + Q2 + Q3 + IVRT). Step 2 includes step 1 requirements plus a kinetic study (TS/IVPT/PKBE) to compare the local availability of complex formulations. Step 3 refers to clinical studies with pharmacodynamic/clinical endpoints. As excipients may affect the local tolerability and efficacy of the products, the similarity of excipient composition is required in all steps, except where clinical endpoints are compared.
Promnesic, Anxiolytic and Antioxidant Effects of Glaucosciadium cordifolium (Boiss.) Burtt & Davis Essential Oil in a Zebrafish Model of Cognitive Impairment
Authors: Boiangiu Razvan Stefan , Bagci Eyup , Dumitru Gabriela , Hritcu Lucian , Todirascu-Ciornea Elena
Published: February 2023

The purpose of this study was to investigate the effect of Glaucosciadium cordifolium essential oil (GCEO, 25 and 150 µL/L) on anxiety and learning and memory impairment induced by scopolamine (SCOP) in zebrafish. The chemical composition was analyzed by GC-MS, and the results showed that the highest content was limonene followed by α- and β-pinene, p-cymene and α-phellandrene. The dementia model was induced by SCOP (100 µM), whereas GCEO and galantamine (GAL, 1 mg/L) were delivered to the SCOP-induced model. It was found that GCEO significantly improved memory impairment and anxiety-like response induced by SCOP through the Y-maze, novel object recognition (NOR) test, and novel tank diving tests (NTT). Biochemical analyses showed that GCEO reduced SCOP-induced oxidative damage. Additionally, the cholinergic system activity was improved in the SCOP-induced model by decreasing the acetylcholinesterase (AChE) activity following the exposure to GCEO. It was clear that as a mixture, GCEO displays positive action in improving memory impairment through restoring cholinergic dysfunction and brain antioxidant status.