A novel isatin Schiff based cerium complex: synthesis, characterization, antimicrobial activity and molecular docking studies.

In this work, a novel isatin-Schiff base L2 had been synthesized through a simple reaction between isatin and 2-amino-5-methylthio-1,3,4-thiadiazole. The produced Schiff base L2 was then subjected to a hydrothermal reaction with cerium chloride to produce the cerium (III)-Schiff base complex C2. Several spectroscopic methods, including mass spectra, FT-IR, elemental analysis, UV-vis, 13C-NMR, 1H-NMR, Thermogravimetric Analysis, HR-TEM, and FE-SEM/EDX, were used to completely characterize the produced L2 and C2. A computer simulation was performed using the MOE software program to find out the probable biological resistance of studied compounds against the proteins in some types of bacteria or fungi. To investigate the interaction between the ligand and its complex, we conducted molecular docking simulations using the molecular operating environment (MOE). The docking simulation findings revealed that the complex displayed greater efficacy and demonstrated a stronger affinity for Avr2 effector protein from the fungal plant pathogen Fusarium oxysporum (code 5OD4) than the original ligand. The antibacterial activity of the ligand and its Ce3+ complex were applied in vitro tests against different microorganism. The study showed that the complex was found to be more effective than the ligand.

Synthesis and Biological Evaluation of 2-Azolylmethylene-3-(2H)-benzofuranone Derivatives as Potent Monoamine Oxidases Inhibitors.

A series of 2-azolylmethylene-3-(2H)-benzofuranone derivatives, 2-indolylmethylene-3-(2H)-benzofuranone and 2-pyrrolylmethylene-3-(2H)-benzofuranone derivatives, were synthesized, and their monoamine oxidase (MAO) A and B inhibitory activities were evaluated. Compounds 1b, 3b, 6b, 7b, and 10b showed strong inhibitory activity against MAO-A, and compound 3b showed the highest potency and selectivity, with an IC50 value of 21 nM and a MAO-A selectivity index of 48. Compounds 3c, 4c, 9a, 9c, 10c, 11a, and 11c showed strong inhibitory activity against MAO-B, and compound 4c showed the highest potency and selectivity, with an IC50 value of 16 nM and a MAO-B selectivity index of >1100. Further analysis of these compounds indicated that compound 3b for MAO-A and compound 4c for MAO-B were competitive inhibitors, with Ki values of 10 and 6.1 nM, respectively. Furthermore, computational analyses, such as quantitative structure-activity relationship (QSAR) analysis of the 2-azolylmethylene-3-(2H)-benzofuranone derivatives conducting their pIC50 values with the Molecular Operating Environment (MOE) and Mordred, and molecular docking analysis using MOE-Dock supported that the 2-azolylmethylene-3-(2H)-benzofuranone derivatives are a privileged scaffold for the design and development of novel MAO inhibitors.

Utilization of Synthetic Near-Infrared Spectra via Generative Adversarial Network to Improve Wood Stiffness Prediction.

Near-infrared (NIR) spectroscopy is widely used as a nondestructive evaluation (NDE) tool for predicting wood properties. When deploying NIR models, one faces challenges in ensuring representative training data, which large datasets can mitigate but often at a significant cost. Machine learning and deep learning NIR models are at an even greater disadvantage because they typically require higher sample sizes for training. In this study, NIR spectra were collected to predict the modulus of elasticity (MOE) of southern pine lumber (training set = 573 samples, testing set = 145 samples). To account for the limited size of the training data, this study employed a generative adversarial network (GAN) to generate synthetic NIR spectra. The training dataset was fed into a GAN to generate 313, 573, and 1000 synthetic spectra. The original and enhanced datasets were used to train artificial neural networks (ANNs), convolutional neural networks (CNNs), and light gradient boosting machines (LGBMs) for MOE prediction. Overall, results showed that data augmentation using GAN improved the coefficient of determination (R2) by up to 7.02% and reduced the error of predictions by up to 4.29%. ANNs and CNNs benefited more from synthetic spectra than LGBMs, which only yielded slight improvement. All models showed optimal performance when 313 synthetic spectra were added to the original training data; further additions did not improve model performance because the quality of the datapoints generated by GAN beyond a certain threshold is poor, and one of the main reasons for this can be the size of the initial training data fed into the GAN. LGBMs showed superior performances than ANNs and CNNs on both the original and enhanced training datasets, which highlights the significance of selecting an appropriate machine learning or deep learning model for NIR spectral-data analysis. The results highlighted the positive impact of GAN on the predictive performance of models utilizing NIR spectroscopy as an NDE technique and monitoring tool for wood mechanical-property evaluation. Further studies should investigate the impact of the initial size of training data, the optimal number of generated synthetic spectra, and machine learning or deep learning models that could benefit more from data augmentation using GANs.

Incorporating Bioaccessibility into Inhalation Exposure Assessment of Emamectin Benzoate from Field Spraying.

The inhalation exposure of pesticide applicators and residents who live close to pesticide-treated fields is a worldwide concern in public health. Quantitative assessment of exposure to pesticide inhalation health risk highlights the need to accurately assess the bioaccessibility rather than the total content in ambient air. Herein, we developed an in vitro method to estimate the inhalation bioaccessibility of emamectin benzoate and validated its applicability using a rat plasma pharmacokinetic bioassay. Emamectin benzoate was extracted using the Gamble solution, with an optimized solid-to-liquid ratio (1/250), extraction time (24 h), and agitation (200 rpm), which obtained in vitro inhalation bioaccessibility consistent with its inhalation bioavailability in vivo (32.33%). The margin of exposure (MOE) was used to assess inhalation exposure risk. The inhalation unit exposures to emamectin benzoate of applicators and residents were 11.05-28.04 and 0.02-0.04 ng/m3, respectively, varying markedly according to the methods of application, e.g., formulations and nozzles. The inhalation risk assessment using present application methods appeared to be acceptable; however, the MOE of emamectin benzoate might be overestimated by 32% without considering inhalation bioaccessibility. Collectively, our findings contribute insights into the assessment of pesticide inhalation exposure based on bioaccessibility and provide guidance for the safe application of pesticides.

Screening and identification of potential MERS-CoV papain-like protease (PLpro) inhibitors; Steady-state kinetic and Molecular dynamic studies.

MERS-CoV belongs to the coronavirus group. Recent years have seen a rash of coronavirus epidemics. In June 2012, MERS-CoV was discovered in the Kingdom of Saudi Arabia, with 2,591 MERSA cases confirmed by lab tests by the end of August 2022 and 894 deaths at a case-fatality ratio (CFR) of 34.5% documented worldwide. Saudi Arabia reported the majority of these cases, with 2,184 cases and 813 deaths (CFR: 37.2%), necessitating a thorough understanding of the molecular machinery of MERS-CoV. To develop antiviral medicines, illustrative investigation of the protein in coronavirus subunits are required to increase our understanding of the subject. In this study, recombinant expression and purification of MERS-CoV (PLpro), a primary goal for the development of 22 new inhibitors, were completed using a high throughput screening methodology that employed fragment-based libraries in conjunction with structure-based virtual screening. Compounds 2, 7, and 20, showed significant biological activity. Moreover, a docking analysis revealed that the three compounds had favorable binding mood and binding free energy. Molecular dynamic simulation demonstrated the stability of compound 2 (2-((Benzimidazol-2-yl) thio)-1-arylethan-1-ones) the strongest inhibitory activity against the PLpro enzyme. In addition, disubstitutions at the meta and para locations are the only substitutions that may boost the inhibitory action against PLpro. Compound 2 was chosen as a MERS-CoV PLpro inhibitor after passing absorption, distribution, metabolism, and excretion studies; however, further investigations are required.

Lectins from plants and algae act as anti-viral against HIV, influenza and coronaviruses.

BACKGROUND: Carbohydrate-lectin interactions are extremely specific as the lectin is capable of recognising monomeric and oligomeric sugars in a reversible manner. It has been known for a long time that lectins have antibacterial, antifungal, and insecticidal activities. Recently, it has been reported that many lectins can prevent the virus growth by interacting with the viral envelop surface glycoprotein. Spike protein, which is found on the surface of some enveloped viruses, is heavily mannosylated and will have strong affinity for mannose specific lectins. According to the findings, lectins have a high binding affinity for the glycans of the SARS-CoV-2 spike glycoprotein, which contains N-glycosylation sites. As a result, various lectins are being researched and developed as anti-viral agents. RESULTS: According to our in silico studies, the amino acid residues Asn487, Tyr489, Gln493, Lys417, and Tyr505 of the receptor binding domain (RBD) of SARS-CoV-2 formed an interaction with the model lectin Lablab purpureus lectin. Similar interaction for SARS-CoV-2 spike protein was observed with Griffithsin lectin (algal source) as well. These observations demonstrate that lectins could be one of the potential molecules for neutralising coronavirus infection. CONCLUSION: This review focuses on anti-viral lectins isolated and characterized from plants and algae (last 5 years) and showed anti-viral properties against HIV, Influenza, and coronaviruses.

DUX4 Transcript Knockdown with Antisense 2'-O-Methoxyethyl Gapmers for the Treatment of Facioscapulohumeral Muscular Dystrophy.

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant disorder characterized by a progressive, asymmetric weakening of muscles, starting with those in the upper body. It is caused by aberrant expression of the double homeobox protein 4 gene (DUX4) in skeletal muscle. FSHD is currently incurable. We propose to develop a therapy for FSHD using antisense 2'-O-methoxyethyl (2'-MOE) gapmers, to knock down DUX4 mRNA expression. Using immortalized patient-derived muscle cells and local intramuscular injections in the FLExDUX4 FSHD mouse model, we showed that our designed 2'-MOE gapmers significantly reduced DUX4 transcript levels in vitro and in vivo, respectively. Furthermore, in vitro, we observed significantly reduced expression of DUX4-activated downstream targets, restoration of FSHD signature genes by RNA sequencing, significant improvements in myotube morphology, and minimal off-target activity. This work facilitates the development of a promising candidate therapy for FSHD and lays down the foundation for in vivo systemic treatment studies.

Synthesis of novel antioxidant and antitumor 5-aminopyrazole derivatives, 2D/3D QSAR, and molecular docking.

5-Aminopyrazole serves as a vital precursor for several biologically active pyrazoloazines, including pyrazolopyridine, pyrazolopyrimidine, and pyrazolotriazine, as well as Schiff bases, thiourea, and phthalimide derivatives. In this study, we structurally characterized novel pyrazole derivatives by spectral IR, 1H and 13C NMR, and MASS spectroscopy. We also evaluated antioxidant activity of various derivatives using ABTS and DPPH methods and cytotoxicity in the hepatocellular carcinoma Hep-G2 cells by SRB assay. The most potent antitumor molecules were 5-aminopyrazole derivative 3, chloroacetanilide derivative 8, maleimide derivative 10a, pyrazolopyrimidine 16, and enamine 19, with IC50 values of 41, 3.6, 37, 24.4, and 17.7 µM, respectively. Complementary computational studies predicted QSAR and bioactivity of these molecules. Interestingly, the most effective compounds were also predicted to be kinase inhibitors; in addition, molecular docking with liver receptors (3MBG, 4XCU, and 4G9C) predicted promising interactions.

Synthesis and Antimicrobial Activity Screening of Piperazines Bearing N,N'-Bis(1,3,4-thiadiazole) Moiety as Probable Enoyl-ACP Reductase Inhibitors.

A new N,N'-disubstituted piperazine conjugated with 1,3,4-thiadiazole and 1,2,4-triazole was prepared and the chemical structures were identified by IR, NMR and elemental analysis. All the prepared compounds were tested for their antimicrobial activity. The antimicrobial results indicated that the tested compounds showed significant antibacterial activity against gram-negative strains, especially E. coli, relative to gram-positive bacteria. Docking analysis was performed to support the biological results; binding modes with the active site of enoyl reductase amino acids from E. coli showed very good scores, ranging from -6.1090 to -9.6184 kcal/mol. Correlation analysis was performed for the inhibition zone (nm) and the docking score.

Strategic job market-guided development of pharmacy bachelor's curriculum and its importance in maintaining the profession viability in the Middle Eastern countries: Colleges of pharmacy in the UAE as a model.

The Middle East has high youth population; however, it is challenged by uncertain economic situation. Higher education plays a crucial role in the development of nations by equipping generations with the knowledge and skill through cumulative curriculum development. Like other professions, pharmacy is a dynamic field of study where continuous improvements are required to keep the viability of the profession and endow future generations with up to date skills. This article describes a strategy for pharmacy curriculum development considering four layers. The strategy starts from the understanding of the current situation in a university, looking into national, international accreditations and job market. The strategy covers development from program to subject's level. The strategy is applied to pharmacy programs in the UAE. Upon analysis, several recommendations were obtained for curriculum improvements. At individual university level, there is a need to work on clinical oriented topics in the curriculum to fit with international accreditation and country's vision. Details on this can be taken form deeper analysis of job market and stakeholders in the UAE. On the national level, unifications of total credit hours for the degree across universities needs to be envisaged with limits on contact experiential hours. The strategy has the potential of extrapolating to other Middle Eastern countries.

Xylem biomechanics, water storage, and density within roots and shoots of an angiosperm tree species.

Xylem is a complex tissue that forms the bulk of tree bodies and has several functions, including to conduct water, store water and nutrients, and biomechanically support the plant body. We examined how xylem functional traits varied at different positions within 9-year-old Populus balsamifera subsp. trichocarpa. Whole trees were excavated, and xylem samples were collected at 1-m increments along the main root-to-shoot axis of six trees, from root tip to shoot tip. We examined biomechanical and water-storage traits of the xylem, including using a non-invasive imaging technique to examine water content within long, intact branches (high-resolution computed tomography; microCT). Xylem density, strength, and stiffness were greater in shoots than roots. Along the main root-to-shoot axis, xylem strength and stiffness were greatest at shoot tips, and the tissue became linearly weaker and less stiff down the plant and through the root. Roots had greater water storage with lower biomechanical support, and shoots had biomechanically stronger and stiffer xylem with lower water storage. These findings support trade-offs among xylem functions between roots and shoots. Understanding how xylem functions differ throughout tree bodies is important in understanding whole-tree functioning and how terrestrial plants endure numerous environmental challenges over decades of growth.

Synthesis and biological evaluation of 3-styrylchromone derivatives as selective monoamine oxidase B inhibitors.

A series of 3-styrylchromone derivatives was synthesized and evaluated for monoamine oxidase (MAO) A and B inhibitory activities. Most of all derivatives inhibited MAO-B selectively, except compound 21. Compound 19, which had a methoxy group at R2 on the chromone ring and chlorine at R4 on phenyl ring, potently inhibited MAO-B, with an IC50 value of 2.2 nM. Compound 1 showed the highest MAO-B selectivity, with a selectivity index of >3700. Further analysis of these compounds indicated that compounds 1 and 19 were reversible and mixed-type MAO-B inhibitors, suggesting that their mode of action may be through tight-binding inhibition to MAO-B. Quantitative structure-activity relationship (QSAR) analyses of the 3-styrylchromone derivatives were conducted using their pIC50 values, through Molecular Operating Environment (MOE) and Dragon. There were 1796 descriptors of MAO-B inhibitory activity, which showed significant correlations (P < 0.05). Further investigation of the 3-styrylchromone structures as useful scaffolds was performed through three-dimensional-QSAR studies using AutoGPA, which is based on the molecular field analysis algorithm using MOE. The MAO-B inhibitory activity model constructed using pIC50 value index exhibited a determination coefficients (R2) of 0.972 and a Leave-One-Out cross-validated determination coefficients (Q2) of 0.914. These data suggest that the 3-styrylchromone derivatives assessed herein may be suitable for the design and development of novel MAO inhibitors.

Synthesis, characterization, antibacterial evaluation, 2D-QSAR modeling and molecular docking studies for benzocaine derivatives.

Possible application of incorporating a well-known drug (benzocaine) with cyanoacetamide function to get a powerful synthon ethyl 4-cyanoacetamido benzoate. This synthetic intermediate was used as a precursor for the synthesis of triazine, pyridone, thiazolidinone, thiazole and thiophene scaffolds containing the benzocaine core. Facile coupling, Michael addition, condensation and nucleophilic attack reactions were used to synthesize our targets. The structural features of the synthesized scaffolds were characterized using IR, 1H NMR, 13C NMR and mass spectroscopy. The antibacterial activities against Gram-positive (Staphylococcus aureus, Bacillus subtilis) and Gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa) were evaluated using ampicillin as a reference drug. DNA/methyl-green colorimetric assay of the DNA-binding compounds was also performed. Theoretical studies of the newly synthesized compounds based on molecular docking and QSAR study were conducted. The molecular docking studies were screened by MOE software for the more potent antibacterial agent 28b and each native ligand against four of S. aureus proteins 1jij, 2xct, 2w9s and 3t07.

Virtual screening to identify potent sepiapterin reductase inhibitors.

Sepiapterin reductase has been identified as a potential drug target for neuropathic and inflammatory pain. Virtual screening was executed against a publicly available x-ray crystal structure of sepiapterin reductase. A set of structurally diverse and potent sepiapterin reductase inhibitors was identified. This set of compounds with favorable ligand efficiency and lipophilic efficiency are tractable for further optimization. An SAR follow-up library was synthesized based on one of the virtual screening hits exploring SAR.

Estimation of acrylamide exposure in Italian schoolchildren consuming a canteen menu: health concern in three age groups.

Acrylamide (AA) is a food process contaminant with carcinogenic and genotoxic properties that is formed in thermally treated foods, especially carbohydrate-rich. Dietary exposure to AA, due to school canteen foods, was estimated in schoolchildren aged 3-13 years by combining the AA concentration in foods with the amount and frequency of food consumption. Potato products and bakery products presented the highest mean levels of AA (841 and 244 µg/kg, respectively) followed by meat (222 µg/kg) and egg products (151 µg/kg). The mean total AA intake was estimated at 2.16 µg/kg bw/d, with the highest percentages provided by potato products (34.5%), meat products (26.1%) and bread (24.5%). The calculated margins of exposure (MOEs) for the average AA exposure (84 and 212 for the benchmark dose lower confidence limits (BMDL) of 0.17 and 0.43 mg/kg bw/d) suggest that there is a health concern with respect to students eating in school canteens.

Membrane Repair Deficit in Facioscapulohumeral Muscular Dystrophy.

Deficits in plasma membrane repair have been identified in dysferlinopathy and Duchenne Muscular Dystrophy, and contribute to progressive myopathy. Although Facioscapulohumeral Muscular Dystrophy (FSHD) shares clinicopathological features with these muscular dystrophies, it is unknown if FSHD is characterized by plasma membrane repair deficits. Therefore, we exposed immortalized human FSHD myoblasts, immortalized myoblasts from unaffected siblings, and myofibers from a murine model of FSHD (FLExDUX4) to focal, pulsed laser ablation of the sarcolemma. Repair kinetics and success were determined from the accumulation of intracellular FM1-43 dye post-injury. We subsequently treated FSHD myoblasts with a DUX4-targeting antisense oligonucleotide (AON) to reduce DUX4 expression, and with the antioxidant Trolox to determine the role of DUX4 expression and oxidative stress in membrane repair. Compared to unaffected myoblasts, FSHD myoblasts demonstrate poor repair and a greater percentage of cells that failed to repair, which was mitigated by AON and Trolox treatments. Similar repair deficits were identified in FLExDUX4 myofibers. This is the first study to identify plasma membrane repair deficits in myoblasts from individuals with FSHD, and in myofibers from a murine model of FSHD. Our results suggest that DUX4 expression and oxidative stress may be important targets for future membrane-repair therapies.

Optimization of the Production Factors of Boards Obtained from Arundo donax L. Fibers Without Added Adhesives.

The main objective of this work was to further analyze the optimization of the production factors of Arundo donax L. fiberboards obtained without adhesives. The production of boards derived from Arundo donax L. without added adhesives and with high mechanical performance has already been demonstrated. This present study explored a modification in the production process through a final curing thermal treatment (final heat treatment, FHT). Since pressing time is an influential factor in the production cost, it is expected that curing allows a reduction of this time. This study compared the results obtained by three panel-production alternatives: long pressing time (tp) without curing and long and short tp with FHT. Of the two factors analyzed, pressing pressure (Pp) was the most important production factor in both the modulus of elasticity (MOE) and modulus of rupture (MOR), while curing was the most important factor for the internal bond (IB). The study shows that a FHT facilitates the distribution of lignin and a possible improvement in the quantity and quality of bonds between lignin and cellulosic fibers. As a consequence, it improves the IB, produces boards with more homogeneous physical and mechanical properties and thereby makes them more hydrophobic. The curing thermal treatment allows high performance panels to be obtained in a manner which is more ecological, quicker, and cheaper.

Binding Studies of AICAR and Human Serum Albumin by Spectroscopic, Theoretical, and Computational Methodologies.

The interactions of small molecule drugs with plasma serum albumin are important because of the influence of such interactions on the pharmacokinetics of these therapeutic agents. 5-Aminoimidazole-4-carboxamide ribonucleoside (AICAR) is one such drug candidate that has recently gained attention for its promising clinical applications as an anti-cancer agent. This study sheds light upon key aspects of AICAR's pharmacokinetics, which are not well understood. We performed in-depth experimental and computational binding analyses of AICAR with human serum albumin (HSA) under simulated biochemical conditions, using ligand-dependent fluorescence sensitivity of HSA. This allowed us to characterize the strength and modes of binding, mechanism of fluorescence quenching, validation of FRET, and intermolecular interactions for the AICAR-HSA complexes. We determined that AICAR and HSA form two stable low-energy complexes, leading to conformational changes and quenching of protein fluorescence. Stern-Volmer analysis of the fluorescence data also revealed a collision-independent static mechanism for fluorescence quenching upon formation of the AICAR-HSA complex. Ligand-competitive displacement experiments, using known site-specific ligands for HSA's binding sites (I, II, and III) suggest that AICAR is capable of binding to both HSA site I (warfarin binding site, subdomain IIA) and site II (flufenamic acid binding site, subdomain IIIA). Computational molecular docking experiments corroborated these site-competitive experiments, revealing key hydrogen bonding interactions involved in stabilization of both AICAR-HSA complexes, reaffirming that AICAR binds to both site I and site II.

Essential and xenobiotic elements in cottage cheese from the Slovak market with a consumer risk assessment.

The examination of various elements in the milk products is very important in the food sector in respect of food quality and safety. The aim of this study was to determine the concentrations of calcium (Ca), cobalt (Co), cadmium (Cd), copper (Cu), chromium (Cr), iron (Fe), mercury (Hg), potassium (K), magnesium (Mg), sodium (Na), nickel (Ni), phosphorus (P), lead (Pb) and zinc (Zn) in white cottage cheese or cottage cheese supplemented with various additives (white, lacto-free, chive, tzatziki, mustard + onion, chili, active protein) available on the market of Slovakia. All essential elements were within the reference range. Cottage cheese enriched with tzatziki showed higher amount of Cu, Fe, K, and Zn. Mustard + onion cheese contained high values of Ca, Co, Mg, and Ni. In white cottage cheese high amount of Cr, Mn, and P was measured. The content of xenobiotic metals was below permitted limit. The contribution to PTWI (Provisional tolerable weekly intake) suggested very low dietary exposure to heavy metals as Cd, Hg, and Pb as well as other metals (Cu, Ni, and Zn) in cottage cheese. Numerous correlations between concentrations were observed. MOE (Margin of Exposure) evaluation denoted that average consumption of cottage cheese does not pose any high cardiovascular and nephrotoxicity threat.

[Analysis and Health Risk Assessment of Cadmium and Arsenic in Japanese, Vietnamese, and Indonesian Rice].

Herein, we quantified the concentrations of cadmium (Cd) and arsenic (As) in 63 milled rice (Oryza sativa L.) cultivated in Japan, Vietnam, and Indonesia. We estimated the daily intake of Cd and As by adults and children consuming this rice by inductively coupled plasma-mass spectrometer (ICP-MS). Cd and As were detected in all milled rice samples. No significant differences were observed in Cd concentrations between Japanese (50th percentile concentration: 0.036 mg/kg), Vietnamese (0.035 mg/kg), and Indonesian rice (0.022 mg/kg). However, As concentrations in Vietnamese rice (50th percentile concentration: 0.142 mg/kg) were significantly higher than those in Japanese (0.101 mg/kg, p<0.001) and Indonesian rice (0.038 mg/kg, p<0.0001). Target hazard quotients (THQs) were then calculated to evaluate the non-carcinogenic health risk from ingestion of individual heavy metals (Cd and As) by rice consumption. Results revealed that THQs of individual heavy metals for Japanese, Vietnamese, and Indonesian adults and children consuming this rice were all less than one, suggesting that no health risk is associated with the intake of a single heavy metal via rice consumption.