BCR-ABL Tyrosine Kinase Inhibitors as Candidates for the Treatment of COVID-19: Molecular Docking, Pharmacophore Modeling, ADMET Studies

The novel coronavirus pandemic (COVID-19) caused by SARS-CoV-2 has affected more than 53 million individuals worldwide. Currently, there is a dire need to develop or find potential drugs that can treat SARS-CoV-2 infection. One of the standard methods to accelerate drug discovery and development in pandemics is to screen currently available medications against the critical therapeutic targets to find potential therapeutic agents. The literature has pointed out to the 3CLpro and RdRp proteins as the most important proteins involved in viral replications. In the present study, we used an in-silico modeling approach to examine the affinity of six tyrosine kinases inhibitors (TKIs), Imatinib, Ponatinib, Nilotinib, Gefitinib, Erlotinib, and Dasatinibagainst the 3CLpro and RdRp by calculating the energy balance. The six tested TKIs had energy balance values of more than -7 Kcal/mol for both viral target proteins. Nilotinib and Ponatinib showed the highest affinity for 3CLpro (-8.32, -8.16, respectively) while Dasatinib, Ponatinib, and Imatinib presented the strongest binding toRdRp(-14.50, -10.57, -9.46, respectively). Based on these findings, we recommend future evaluations of TKIs for SARs-CoV-2 infection in-vitro and further testing in clinical trials

Extrato de Panax ginseng C.A. Meyer neutraliza o stress oxidativo em ratos alimentados com dieta contaminada com multi-micotoxinas

The current study was conducted to evaluate the protective effects of Panax ginseng extract (PGE)against the toxicity and oxidative stress in rats fed aflatoxin (AFs) and/or fumonisin (FB)-contaminateddiet. Eighty female Sprague-Dawley rats were divided into eight experimental groups included thecontrol group, the group treated orally with PGE (0.5 mg/kg b.w.) and the groups fed AFs (1.4 mg/kg diet) and/or FB (20 mg/kg b.w.) contaminated diet alone or plus PGE for 11 weeks. Blood, liverand kidney tissue samples were collected at the end of treatment period for biochemical andhistological studies. The results indicated that PGE increased super oxide dismutase (SOD) levelin liver; however, the other parameters were comparable to controls. Animals fed AFs and/or FBcontaminateddiet showed a significant increase in serum biochemical parameters and oxidativestress markers accompanied with a significant decrease in antioxidant parameters levels and asevere histological changes in the liver tissue. These changes were more pronounced in the groupfed AFs plus FB. PGE succeeded to induce a significant improvement in all biochemical parametersand the histological picture towards the control although it did not normalize them. It could beconcluded that PGE is a promise candidate against the exposure to multi-mycotoxins in food.O presente estudo foi conduzido para avaliar os efeitos protetores do extrato de Panax ginseng(PGE) contra a toxicidade e estresse oxidativo em ratos alimentados com aflatoxinas (AFs) e/oudieta contaminada por fumonisina (FB). Oitenta fêmeas de ratos Sprague-Dawley foram divididasem oito grupos experimentais, incluindo o grupo controle, o grupo tratado com PGE oralmente (0,5mg/kg de peso corporal) e os grupos alimentados com as dietas contaminadas de AFs (1,4 dieta mg/kg) e/ou FB (20 mg/kg de peso corporal) isoladas ou com mais PGE durante 11 semanas. Amostrasde sangue, do fígado e do tecido do rim foram recolhidas no final do período de tratamentopara estudos bioquímicos e histológicos. Os resultados indicaram que a PGE aumenta o nível desuperóxido dismutase (SOD) no fígado, no entanto, os outros parâmetros foram comparáveis aosdo grupo controle. Animais alimentados com dieta contaminada por AF e/ou FB mostraram umaumento significativo nos parâmetros bioquímicos séricos e marcadores de estresse oxidativo,acompanhados de uma diminuição significativa nos níveis de antioxidantes e nos parâmetros dealterações histológicas graves no tecido do fígado. Essas alterações foram mais pronunciadas nogrupo alimentado com AFs mais FB. PGE obteve sucesso quanto à introdução de uma melhoriasignificativa em todos os parâmetros bioquímicos e histológicos com relação ao grupo controle,embora não os tenha normalizado. Pode-se concluir que a PGE é uma promissora candidatacontra a exposição às multimicotoxinas em alimentos

Identification of a bacteriocin and its cognate immunity factor expressed by Moraxella catarrhalis

<p>Abstract</p> <p>Background</p> <p>Bacteriocins are antimicrobial proteins and peptides ribosomally synthesized by some bacteria which can effect both intraspecies and interspecies killing.</p> <p>Results</p> <p><it>Moraxella catarrhalis </it>strain E22 containing plasmid pLQ510 was shown to inhibit the growth of <it>M. catarrhalis </it>strain O35E. Two genes (<it>mcbA </it>and <it>mcbB</it>) in pLQ510 encoded proteins predicted to be involved in the secretion of a bacteriocin. Immediately downstream from these two genes, a very short ORF (<it>mcbC</it>) encoded a protein which had some homology to double-glycine bacteriocins produced by other bacteria. A second very short ORF (<it>mcbI</it>) immediately downstream from <it>mcbC </it>encoded a protein which had no significant similarity to other proteins in the databases. Cloning and expression of the <it>mcbI </it>gene in <it>M. catarrhalis </it>O35E indicated that this gene encoded the cognate immunity factor. Reverse transcriptase-PCR was used to show that the <it>mcbA</it>, <it>mcbB</it>, <it>mcbC</it>, and <it>mcbI </it>ORFs were transcriptionally linked. This four-gene cluster was subsequently shown to be present in the chromosome of several <it>M. catarrhalis </it>strains including O12E. Inactivation of the <it>mcbA</it>, <it>mcbB</it>, or <it>mcbC </it>ORFs in <it>M. catarrhalis </it>O12E eliminated the ability of this strain to inhibit the growth of <it>M. catarrhalis </it>O35E. In co-culture experiments involving a <it>M. catarrhalis </it>strain containing the <it>mcbABCI </it>locus and one which lacked this locus, the former strain became the predominant member of the culture after overnight growth in broth.</p> <p>Conclusion</p> <p>This is the first description of a bacteriocin and its cognate immunity factor produced by <it>M. catarrhalis</it>. The killing activity of the McbC protein raises the possibility that it might serve to lyse other <it>M. catarrhalis </it>strains that lack the <it>mcbABCI </it>locus, thereby making their DNA available for lateral gene transfer.</p

Potential impact of iron oxide conjugated nano-fertilizer on growth, flowering and isozyme expression in Gardenia jasminoides

Nano-fertilizers protect the soil from the excessive addition of traditional fertilizers, enhancing the efficiency of the elements and diminishing the number of additive fertilizers. The effect of Fe2O3NPs-Boron (Fe2O3NPs-B), and Fe2O3 NP-Humic Acid (Fe2O3NPs-HA) at 100, 150 and 250 ppm, Fe2O3, and control (without any iron fertilizers) on the vegetative growth, flowering, photosynthetic pigments, nutrient element content and isozymes activity (peroxidase, superoxide dismutase and polyphenol oxide) of Gardenia jasminoides plants was investigated. Gamma-rays at 25 kGy were conducted for the promising synthesis of Fe2O3NPs-B, and Fe2O3NPs-HA. The experiment was carried out under greenhouse conditions during two successive seasons. The results stated that Fe2O3NPs-B and Fe2O3NPs-HA at the highest concentration (250 ppm) had a significant positive effect in all vegetative characteristics, photosynthetic pigments, nutrient element content and isozymes activity. Fe2O3NPs-HA showed the optimal result in all morphological and biochemical characteristics. The highest activity of enzymes appeared in the treated plants with Fe2O3 NPs-B followed by Fe2O3 NPs-HA at 250 ppm. The advantage nano-fertilizer usage may be summarized as saving the soil from the unreasonable accumulation of classic fertilizers, improving the use efficiency of parts and reducing the number of different fertilizers as a consequence of their increased surface area and their nano-size

Role of calcium and magnesium on dramatic physiological and anatomical responses in tomato plants

Minerals are the fundamental source of nutrients for plant functions such as photosynthesis, ATP currency, cellular respiration, metabolic activities, defense mechanisms, and tolerance to biotic and abiotic stressors. Minerals are the most significant component of plant nutrition and applying these minerals supplements can increase fruit output. The study’s main aim was to make agricultural farming easier by foliar applying newly created nutrients like Lebosol-calcium and Magnesium. The four treatments: To (Control), T1 (Lebosol-Mg-Plus, 3 ml/L), T2 (Lebosol-Ca-Forte, 3 ml/L), and T3 (Lebosol-Mg-Plus and Lebosol-Ca-Forte, 3 ml/L) was applied as foliar spray to the seedlings of tomato. It was found that T3 substantially enhanced tomato’s morphological features and yield. The treatment T3 significantly increased total soluble protein, chlorophyll content, and antioxidant enzyme activity. Furthermore, the foliar application of T3 considerably improved phenolic and ascorbic acid contents. The general anatomical features of the leaf, stem, and roots of tomato were qualitatively affected by the treatments. Application of Lebosol-Ca provided the highest total thickness of lamina, number of vessel elements, total phloem area, chlorenchyma layer, total area of vessel elements, xylem ratio, and increased palisade layer thickness, vessel diameter. Furthermore, T3 treatment showed a diverse impact on the internal structure of tomato organs, with palisade and spongy parenchyma growing to maximum values and vessel diameters expanding. T3 had also posed remarkable alterations in morpho-physiological, biochemical, and anatomical aspects in tested plants

Dihydrophenazine:a multifunctional new weapon that kills multidrug-resistant Acinetobacter baumannii and restores carbapenem and oxidative stress susceptibilities

AimsThe current work aims to fully characterize a new antimicrobial agent against Acinetobacter baumannii, which continues to represent a growing threat to healthcare settings worldwide. With minimal treatment options due to the extensive spread of resistance to almost all the available antimicrobials, the hunt for new antimicrobial agents is a high priority. Methods and resultsAn Egyptian soil-derived bacterium strain NHM-077B proved to be a promising source for a new antimicrobial agent. Bioguided fractionation of the culture supernatants of NHM-077B followed by chemical structure elucidation identified the active antimicrobial agent as 1-hydroxy phenazine. Chemical synthesis yielded more derivatives, including dihydrophenazine (DHP), which proved to be the most potent against A. baumannii, yet it exhibited a safe cytotoxicity profile against human skin fibroblasts. Proteomics analysis of the cells treated with DHP revealed multiple proteins with altered expression that could be correlated to the observed phenotypes and potential mechanism of the antimicrobial action of DHP. DHP is a multi-pronged agent that affects membrane integrity, increases susceptibility to oxidative stress, interferes with amino acids/protein synthesis, and modulates virulence-related proteins. Interestingly, DHP in sub-inhibitory concentrations resensitizes the highly virulent carbapenem-resistant A. baumannii strain AB5075 to carbapenems providing great hope in regaining some of the benefits of this important class of antibiotics. ConclusionsThis work underscores the potential of DHP as a promising new agent with multifunctional roles as both a classical and non-conventional antimicrobial agent that is urgently needed.<br/

Improving fodder yields and nutritive value of some forage grasses as animal feeds through intercropping with Egyptian Clover (trifolium alexandrinum l.)

The present study aimed to evaluate the potential of improving the feeding value of Egyptian clover (EC), ryegrass (R), triticale (T), barley (B), and oats (O) monoculture, or Egyptian clover mixed with ryegrass (EC+R), oats (EC+O), barely (EC+B), and triticale (EC+T) at 75:25% seeding rate, respectively, during two successive winter seasons of 2018/19 and 2019/20. Harvesting of plots was carried out at 5 cm stubble height after 60, 100, and 140 days from sowing. The in vitro nutritive value and ruminal fermentation of the monoculture and intercropping containing EC were evaluated. Green forage yield of EC was higher than other plants with about 160% of fresh forage compared with T, O, or EC+T intercropping. The highest crude protein (CP) concentration was noted in EC, while the lowest (p < 0.001) concentration was observed in T, which had the highest fiber fractions content. Ryegrass had the highest net in vitro gas production (GP), while EC+R had the lowest GP (p < 0.05). The EC increased dry matter and organic matter degradability. EC and R reduced protozoal count, while total volatile fatty acids (VFA), acetate, and propionate were increased with B and EC+T intercropping (p < 0.05). Overall, intercropping of EC with grass of triticale or ryegrass at mixing rates of 75:25% resulted in improving fresh and dry forage yields. The legume–grass intercropping improved the protozoa count partitioning factor as an index of microbial protein synthesis and total VFA concentration

Effects of thermocouple electrical insulation on the measurement of surface temperature

Analytical, numerical and experimental analyses have been performed to investigate the effects of thermocouple wire electrical insulation on the temperature measurement of a reference surface. Two diameters of type K thermocouple, 80 μm and 200 μm, with different exposed wire lengths (0 mm, 5 mm, 10 mm, 15 mm and 20 mm) were used to measure various surface temperatures (4 °C, 8 °C, 15 °C, 25 °C and 35 °C). Measurements were made with the thermocouple in direct contact with the surface, with wires extending vertically and exposed to natural convection. Analytical results of the thermocouple wire with insulation confirm that there is no specific value for the critical radius and the rate of heat flux around the thermocouple wire continuously increases with the wire diameter even when this is larger than the critical radius. Numerical simulation using COMSOL Multiphysics software also confirms that there is negligible thermal effect from the electrical insulation. Moreover, the experimental results agree well with those obtained by both the analytical and numerical methods and further confirm that the diameter of the thermocouple has an impact on the temperature measurement

Glycation marker glucosepane increases with the progression of osteoarthritis and correlates with morphological and functional changes of cartilage in vivo

Background: Changes of serum concentrations of glycated, oxidized, and nitrated amino acids and hydroxyproline and anticyclic citrullinated peptide antibody status combined by machine learning techniques in algorithms have recently been found to provide improved diagnosis and typing of early-stage arthritis of the knee, including osteoarthritis (OA), in patients. The association of glycated, oxidized, and nitrated amino acids released from the joint with development and progression of knee OA is unknown. We studied this in an OA animal model as well as interleukin-1β-activated human chondrocytes in vitro and translated key findings to patients with OA. Methods: Sixty male 3-week-old Dunkin-Hartley guinea pigs were studied. Separate groups of 12 animals were killed at age 4, 12, 20, 28 and 36 weeks, and histological severity of knee OA was evaluated, and cartilage rheological properties were assessed. Human chondrocytes cultured in multilayers were treated for 10 days with interleukin-1β. Human patients with early and advanced OA and healthy controls were recruited, blood samples were collected, and serum or plasma was prepared. Serum, plasma, and culture medium were analyzed for glycated, oxidized, and nitrated amino acids. Results: Severity of OA increased progressively in guinea pigs with age. Glycated, oxidized, and nitrated amino acids were increased markedly at week 36, with glucosepane and dityrosine increasing progressively from weeks 20 and 28, respectively. Glucosepane correlated positively with OA histological severity (r = 0.58, p < 0.0001) and instantaneous modulus (r = 0.52–0.56; p < 0.0001), oxidation free adducts correlated positively with OA severity (p < 0.0009–0.0062), and hydroxyproline correlated positively with cartilage thickness (p < 0.0003–0.003). Interleukin-1β increased the release of glycated and nitrated amino acids from chondrocytes in vitro. In clinical translation, plasma glucosepane was increased 38% in early-stage OA (p < 0.05) and sixfold in patients with advanced OA (p < 0.001) compared with healthy controls. Conclusions: These studies further advance the prospective role of glycated, oxidized, and nitrated amino acids as serum biomarkers in diagnostic algorithms for early-stage detection of OA and other arthritic disease. Plasma glucosepane, reported here for the first time to our knowledge, may improve early-stage diagnosis and progression of clinical OA