Identification of Potential Antiviral Inhibitors from Hydroxychloroquine and 1,2,4,5-Tetraoxanes Analogues and Investigation of the Mechanism of Action in SARS-CoV-2

This study aimed to identify potential inhibitors and investigate the mechanism of action on SARS-CoV-2 ACE2 receptors using a molecular modeling study and theoretical determination of biological activity. Hydroxychloroquine was used as a pivot structure and antimalarial analogues of 1,2,4,5 tetraoxanes were used for the construction and evaluation of pharmacophoric models. The pharmacophore-based virtual screening was performed on the Molport^® database (~7.9 million compounds) and obtained 313 structures. Additionally, a pharmacokinetic study was developed, obtaining 174 structures with 99% confidence for human intestinal absorption and penetration into the blood–brain barrier (BBB); posteriorly, a study of toxicological properties was realized. Toxicological predictions showed that the selected molecules do not present a risk of hepatotoxicity, carcinogenicity, mutagenicity, and skin irritation. Only 54 structures were selected for molecular docking studies, and five structures showed binding affinity (ΔG) values satisfactory for ACE2 receptors (PDB 6M0J), in which the molecule MolPort-007-913-111 had the best ΔG value of −8.540 Kcal/mol, followed by MolPort-002-693-933 with ΔG = −8.440 Kcal/mol. Theoretical determination of biological activity was realized for 54 structures, and five molecules showed potential protease inhibitors. Additionally, we investigated the Mpro receptor (6M0K) for the five structures via molecular docking, and we confirmed the possible interaction with the target. In parallel, we selected the TopsHits 9 with antiviral potential that evaluated synthetic accessibility for future synthesis studies and in vivo and in vitro tests.     

Tensile properties of cellulose fiber reinforced hydroxypropylcellulose films

The tensile properties of cross-linked and uncross-linked composite films (thickness ∼20–35 μm) prepared from Hydroxypropylcellulose (HPC) with incorporation of microcrystalline cellulose fibers (Avicel) were studied. The concentration of fibers in the composites ranged from 0 to 30 w/w% and cross-linked composites were obtained by the reaction of HPC-Avicel mixtures with 1,4-butyldiisocyanate. It was demonstrated that the inclusion of fibers in a HPC matrix produces composites with enhanced mechanical properties that are improved by cross-linking. Mechanical results seem to indicate that the elastic deformation of the cross-linked composites is predominantly dominated by the fiber content while the cross-linking affects mainly the plastic deformation. Maximum values of the Young's Modulus, yield stress and tensile stress were observed at 10 w/w% for the cross-linked and 20 w/w% for the uncross-linked composites. Furthermore cross-linked films with 10 w/w% of fibers present values of yield stress and tensile stress that are in average 15 to 20% higher than those obtained for uncross-linked composites with 20 w/w% of fibers. Studies in Polarizing Optical Microscopy and Atomic Force Microscopy (AFM) seem to indicate that tensile properties of these composites are correlated to the packing of fibers. For the concentration of the utilized cross-linking agent, and for a fiber content of 10 w/w%, an optimal packing of fibers throughout the matrix has been correlated to the minimal difference between the roughness parameters obtained by AFM analysis of the top and bottom surfaces of the films.     

Effect of crystallization rate on the formation of the polymorphs of solution cast poly(vinylidene fluoride)

A systematic study was carried out to investigate the effect of solvent type and temperature on the formation of the α and β phases from solution cast PVDF. Three solvents with different boiling points were used: N,N, dimethylformamide (DMF), N-methyl-2-pyrrolidone (NMP) and hexamethylphosphoramide (HMPA). Infrared spectroscopy (FTIR) and scanning electron microscopy (SEM) revealed that the type of phase formed depends on the crystallization rate of PVDF, which in turn is determined by the evaporation rate of the solvent. Low rates result predominantly in the trans-planar β phase, high rates predominantly in the trans-gauche α phase and intermediate rates in a mixture of these two phases, regardless of solvent and temperature used. Since evaporation rate of the solvent is intimately related to temperature, PVDF films can be obtained predominantly in either one of these phases, or a mixture of these, by an adequate choice of the evaporation temperature range for a given solvent. The possible solubility curves of the two polymorphs α and β of PVDF were sketched. The formation of different types of spherulites, associated with the two different PVDF polymorphs, could be verified by surface micrographs of the cast films.     

Response of the Egg Parasitoids <Emphasis Type="Italic">Trissolcus basalis</Emphasis> and <Emphasis Type="Italic">Telenomus podisi</Emphasis> to Compounds from Defensive Secretions of Stink Bugs

We tested the hypotheses that host-searching behavior of the egg parasitoids Telenomus podisi and Trissolcus basalis may be differentially influenced by the different blends of volatiles released from the metathoracic glands of adult stink bug host species. We further studied whether such a differential response is due to different individual components of these glands and whether these responses reflect host preferences. Y-tube olfactometer bioassays were carried out with crude extracts of metathoracic glands of five different host species of neotropical stink bugs. Additionally, we tested the parasitoids’ responses to synthetic standards of individual compounds identified in these stink bug glands. Results showed that females of T. basalis and T. podisi responded differentially to crude gland extracts of the different species of host stink bugs and to the compounds tested. The parasitoid T. basalis showed a positive taxic behavior to Nezara viridula methathoracxic gland extracts of a host species preferred in the field, i.e., N. viridula. Furthermore, T. basalis responded positively to 4-oxo-(E)-2-hexenal and (E)-2-decenal, two components of N. viridula glandular secretion. Higher residence time, reduced linear velocity, and higher tortuosity in the arm of the olfactometer supplied with 4-oxo-(E)-2-hexenal showed that this compound modifies the kinetics of some traits of T. basalis walking pattern and suggests that it might stimulate the searching behavior of this parasitoid. The parasitoid T. podisi was attracted to crude gland extracts of the preferred host (Euschistus heros) and also to 4-oxo-(E)-2-hexenal. Additionally, this parasitoid responded positively to (E)-2-hexenal and to the hydrocarbon tridecane, both of which are defensive compounds released from the metathoracic glands by several stink bugs. The results indicate some degree of specialization in the response of two generalist parasitoid species toward defensive secretions of stink bugs.     

Effects of ultrasonication on the characteristics of emulsions and microparticles containing Indian clove essential oil

The effects of the emulsification method [either mechanical agitation or ultrasonication (US)] and proportion of gum arabic (GA)/maltodextrin (MD) on the characteristics of feed emulsions and microparticles containing Indian clove essential oil produced by spray drying were investigated. Emulsions produced using US were more stable with smaller droplets, lower polydispersity indexes, and higher viscosities. Increasing the proportion of GA resulted in an increased particle size. Powders produced by US exhibited a higher moisture content and hygroscopicity. The US improved oil retention, except for microparticles comprised GA. Powders with a higher proportion of MD exhibited smooth surfaces.     

Short-Chain Fatty Acid Receptors and Cardiovascular Function

Increasing experimental and clinical evidence points toward a very important role for the gut microbiome and its associated metabolism in human health and disease, including in cardiovascular disorders. Free fatty acids (FFAs) are metabolically produced and utilized as energy substrates during almost every biological process in the human body. Contrary to long- and medium-chain FFAs, which are mainly synthesized from dietary triglycerides, short-chain FFAs (SCFAs) derive from the gut microbiota-mediated fermentation of indigestible dietary fiber. Originally thought to serve only as energy sources, FFAs are now known to act as ligands for a specific group of cell surface receptors called FFA receptors (FFARs), thereby inducing intracellular signaling to exert a variety of cellular and tissue effects. All FFARs are G protein-coupled receptors (GPCRs) that play integral roles in the regulation of metabolism, immunity, inflammation, hormone/neurotransmitter secretion, etc. Four different FFAR types are known to date, with FFAR1 (formerly known as GPR40) and FFAR4 (formerly known as GPR120) mediating long- and medium-chain FFA actions, while FFAR3 (formerly GPR41) and FFAR2 (formerly GPR43) are essentially the SCFA receptors (SCFARs), responding to all SCFAs, including acetic acid, propionic acid, and butyric acid. As with various other organ systems/tissues, the important roles the SCFARs (FFAR2 and FFAR3) play in physiology and in various disorders of the cardiovascular system have been revealed over the last fifteen years. In this review, we discuss the cardiovascular implications of some key (patho)physiological functions of SCFAR signaling pathways, particularly those regulating the neurohormonal control of circulation and adipose tissue homeostasis. Wherever appropriate, we also highlight the potential of these receptors as therapeutic targets for cardiovascular disorders.     

Plant Kunitz Inhibitors and Their Interaction with Proteases: Current and Potential Pharmacological Targets

The action of proteases can be controlled by several mechanisms, including regulation through gene expression; post-translational modifications, such as glycosylation; zymogen activation; targeting specific compartments, such as lysosomes and mitochondria; and blocking proteolysis using endogenous inhibitors. Protease inhibitors are important molecules to be explored for the control of proteolytic processes in organisms because of their ability to act on several proteases. In this context, plants synthesize numerous proteins that contribute to protection against attacks by microorganisms (fungi and bacteria) and/or invertebrates (insects and nematodes) through the inhibition of proteases in these organisms. These proteins are widely distributed in the plant kingdom, and are present in higher concentrations in legume seeds (compared to other organs and other botanical families), motivating studies on their inhibitory effects in various organisms, including humans. In most cases, the biological roles of these proteins have been assigned based mostly on their in vitro action, as is the case with enzyme inhibitors. This review highlights the structural evolution, function, and wide variety of effects of plant Kunitz protease inhibitors, and their potential for pharmaceutical application based on their interactions with different proteases.     

Improving food security through agricultural research and development in Timor-Leste: a country emerging from conflict

Timor-Leste is a small, poor and predominantly-agricultural nation of less than 1 million people. Most families suffer from chronic food insecurity practising food rationing 1–6 months of the year. The small size of Timor-Leste, its recent birth as a nation and conflict history, together with little previous research on staple crops make it a unique crucible to test the effect of a major post-conflict initiative of agriculture research on national food security. Research started in 2000 with the introduction of germplasm of staple crops (maize, peanut, rice, cassava and sweet potato). Replicated trials confirmed by extensive evaluation in farmer-managed trials revealed significant yield advantages over the local cultivar in maize of 53%, in peanut of 31%, in rice of 23% and in sweet potato of 80%, accompanied by improvements in size and eating quality. Cultivars of maize (2), peanut (1), rice (1) and sweet potato (3) were released in 2007. One year later an early adoption study of 544 farmers involved in on-farm trials showed that 73% had re-grown new cultivars. Cultivar adoption not only increased household food security but often produced surpluses for sale in the market—sometimes for the first time. The project is planning to increase seed production and dissemination to move from a highly positive pilot-scale impact in six Districts to impact food security nationally.     

Photocatalytic degradation of oxytetracycline using TiO2 under natural and simulated solar radiation

The main objective of the present study was to assess the photocatalytic degradation over TiO₂ of an aqueous solution containing 20 mg L⁻¹ of the antibiotic Oxytetracycline (OTC) using simulated solar radiation, seconded by a solar radiation experiment carried out in a pilot plant equipped with Compound Parabolic Collectors (CPCs) under the optimal conditions found in preliminary lab-scale experiments. These comprehended a set of 1 L aqueous experiments with TiO₂ loads ranging from 0.1 to 0.5 g L⁻¹ starting from different initial pH values. These experiments were carried out in a Solarbox equipped with a 1000 W Xe-OP lamp. OTC degradation was followed by HPLC-DAD, while its mineralization was followed by the removal of Total Organic Carbon.Results suggested that 0.5 g L⁻¹ of TiO₂ with no initial pH adjustment (pH ∼ 4.4) was the best combination for the removal of both OTC (100% after 40 min of irradiation; 7.5 kJ L⁻¹ of UV dose) and TOC (>90% after 180 min of irradiation; 38.3 kJ L⁻¹ of UV dose). Under these conditions, the BOD₅/COD ratio rose from almost 0 to nearly 0.5, showing a remarkable improvement in biodegradability, while inhibition percentage of bioluminescence of Vibrio fischeri after 15 min of exposition measured by Microtox® decreased significantly from 35% down to 7%. A scheme of the OTC degradation pathway is proposed, based on the results obtained from this particular experiment.The solar photocatalytic experiment done under the same conditions was carried out in a solar pilot plant equipped with CPCs. OTC and TOC removal was followed as a function of accumulated UV energy entering the reactor. Results showed a 100% OTC and almost 80% TOC removal with 1.8 kJ L⁻¹ and 11.3 kJ L⁻¹ of photo treatment energy, respectively.