Peptidomimetic and Non- Peptidomimetic Derivatives as Possible SARS-CoV-2 Main Protease (Mpro) Inhibitors

To design novel inhibitors of the SARS-CoV-2 main protease (Mpro), we investigated the binding mode of the recently reported α-ketoamide inhibitors of this enzyme. Following, we utilized in-silico screening to identify 168 peptidomimetic and non-peptidomimetic compounds that are high probability Mpro binding candidates. The compounds were synthesized in 5 to 10 mg for initial screening for their potential inhibition of Mpro using Fluorescence Resonance Energy Transfer (FRET) assay. The study was conducted using the main protease, MBP-tagged (SARS-CoV-2) Assay Kit (BPS Bioscience, #79955-2), and the fluorescence due to enzymatic cleavage of substrate measured using BMG LABTECH CLARIOstar™, a fluorescent microplate reader, with an excited/emission wavelength of 360 nm/460 nm, respectively. The FRET assay showed 29 compounds to exhibit lower fluorescence compared to the positive control, indicating inhibitory activity, with three of the compounds exhibiting over 50% enzymatic inhibition. The assay average scores were plotted as dose inhibition curves using variable parameter nonlinear regression to calculate the IC50 values. To design more potent inhibitors, an in-silico molecular docking simulation using the SARS-CoV-2 Mpro crystal structure was conducted to investigate on a molecular level the key binding residues at the active site, as well as the possible binding modes and affinity of the lead inhibitors. Additionally, an in-silico study of the compounds\u27 molecular properties and physicochemical profiles was performed to predict their pharmacokinetic properties and assess their suitability as potential orally active drug candidates.https://scholarscompass.vcu.edu/gradposters/1139/thumbnail.jp

Surgical Approaches to Congenital Anomalies of Esophagus

With prevalence of about 1 in 3000 live births, pediatric surgeons commonly deal with esophageal abnormalities, which may provide substantial clinical complications. Surprisingly, the embryologic processes underlying esophageal atresia (EA) with or without tracheoesophageal fistula (TEF), one of the hallmark disease entities of pediatric surgery, have only lately been largely uncovered. When it comes to the treatment of congenital esophageal abnormalities, notably esophageal atresia and tracheoesophageal fistula, surgical methods are essential. In order to address the anatomical abnormalities and restore normal function, surgical correction is often necessary in the care of congenital esophageal anomalies, including esophageal atresia and tracheoesophageal fistula. In this review we are going to cover surgical approaches to repair those malformations, long-term outcomes, and latest developments in esophageal surgical approaches

Betaine and nano-emulsified vegetable oil supplementation for improving carcass and meat quality characteristics of broiler chickens under heat stress conditions

IntroductionThis research aimed to examine the effects of water-added betaine (BET) and/or nano-emulsified vegetable oil (MAGO) on carcass and meat quality characteristics of broilers raised under thermoneutral (TN) and heat stress (HS) conditions.MethodsOn day 21, 640 birds (Ross 308) were randomly assigned to one of two thermal conditions (thermoneutral 22 ± 1°C and heat stress 32 ± 1°C) each containing four treatment groups: Control, BET, MAGO, and a mixture of both (BETMAGO) in a 2 × 4 factorial arrangement (eight groups). Each group has eight replicates, with ten birds each. The birds' carcass and meat quality characteristics were evaluated at 35 days.Results and discussionThe dressing percentage, breast, leg, wing, heart, initial pH, color change, cooking loss (CL), water-holding capacity (WHC), shear force (SF), and texture profile with exception of springiness significantly affected by the treatments. The results showed that HS had negative effects on carcass weight and relative weights of the breast, spleen, and heart. Moreover, HS increased dressing percentage, wing, initial pH, final core temperature, initial lightness, WHC, and hardness. Significant differences in interactions between treatments and temperature were observed in the spleen, WHC, and SF.ConclusionWater supplemented with BET effectively improved carcass dressing percentage, breast weight, and meat quality in terms of water-holding capacity and tenderness under HS conditions. More studies on the use of BET and/or MAGO at different levels were recommended

Ceiba pentandra ethyl acetate extract improves doxorubicin antitumor outcomes against chemically induced liver cancer in rat model: a study supported by UHPLC-Q-TOF-MS/MS identification of the bioactive phytomolecules

Hepatocellular carcinoma (HCC) is a prevalent cancer worldwide. Late-stage detection, ineffective treatments, and tumor recurrence contribute to the low survival rate of the HCC. Conventional chemotherapeutic drugs, like doxorubicin (DOX), are associated with severe side effects, limited effectiveness, and tumor resistance. To improve therapeutic outcomes and minimize these drawbacks, combination therapy with natural drugs is being researched. Herein, we assessed the antitumor efficacy of Ceiba pentandra ethyl acetate extract alone and in combination with DOX against diethylnitrosamine (DENA)-induced HCC in rats. Our in vivo study significantly revealed improvement in the liver-function biochemical markers (ALT, AST, GGT, and ALP), the tumor marker (AFP-L3), and the histopathological features of the treated groups. A UHPLC-Q-TOF-MS/MS analysis of the Ceiba pentandra ethyl acetate extract enabled the identification of fifty phytomolecules. Among these are the dietary flavonoids known to have anticancer, anti-inflammatory, and antioxidant qualities: protocatechuic acid, procyanidin B2, epicatechin, rutin, quercitrin, quercetin, kaempferol, naringenin, and apigenin. Our findings highlight C. pentandra as an affordable source of phytochemicals with possible chemosensitizing effects, which could be an intriguing candidate for the development of liver cancer therapy, particularly in combination with chemotherapeutic drugs

Early mobilisation in critically ill COVID-19 patients: a subanalysis of the ESICM-initiated UNITE-COVID observational study

Background Early mobilisation (EM) is an intervention that may improve the outcome of critically ill patients. There is limited data on EM in COVID-19 patients and its use during the first pandemic wave. Methods This is a pre-planned subanalysis of the ESICM UNITE-COVID, an international multicenter observational study involving critically ill COVID-19 patients in the ICU between February 15th and May 15th, 2020. We analysed variables associated with the initiation of EM (within 72 h of ICU admission) and explored the impact of EM on mortality, ICU and hospital length of stay, as well as discharge location. Statistical analyses were done using (generalised) linear mixed-effect models and ANOVAs. Results Mobilisation data from 4190 patients from 280 ICUs in 45 countries were analysed. 1114 (26.6%) of these patients received mobilisation within 72 h after ICU admission; 3076 (73.4%) did not. In our analysis of factors associated with EM, mechanical ventilation at admission (OR 0.29; 95% CI 0.25, 0.35; p = 0.001), higher age (OR 0.99; 95% CI 0.98, 1.00; p ≤ 0.001), pre-existing asthma (OR 0.84; 95% CI 0.73, 0.98; p = 0.028), and pre-existing kidney disease (OR 0.84; 95% CI 0.71, 0.99; p = 0.036) were negatively associated with the initiation of EM. EM was associated with a higher chance of being discharged home (OR 1.31; 95% CI 1.08, 1.58; p = 0.007) but was not associated with length of stay in ICU (adj. difference 0.91 days; 95% CI − 0.47, 1.37, p = 0.34) and hospital (adj. difference 1.4 days; 95% CI − 0.62, 2.35, p = 0.24) or mortality (OR 0.88; 95% CI 0.7, 1.09, p = 0.24) when adjusted for covariates. Conclusions Our findings demonstrate that a quarter of COVID-19 patients received EM. There was no association found between EM in COVID-19 patients' ICU and hospital length of stay or mortality. However, EM in COVID-19 patients was associated with increased odds of being discharged home rather than to a care facility. Trial registration ClinicalTrials.gov: NCT04836065 (retrospectively registered April 8th 2021)

Competitive strategies and barriers to achieving competitive advantage : a study of two Saudi Arabian industries.

This study focuses on how organisations achieve and sustain competitive advantage and the possible barriers to this advantage. It first deals with a theoretical framework by examining related literature on developing a better understanding of competitive advantage and generic strategies, as well as the important aspects that may affect a firm's achievement and the sustainability of its competitive advantage. This study extends the strategic management literature on competitive advantage and generic strategies mainly based on Porter's (1980, 1985) work. In particular, instead of the two generic strategies (differentiation and cost leadership) put forward by Porter, four competitive strategies are developed. These are (1) price leadership, (2) low cost differentiation, (3) imitation and (4) differentiation. Barriers to competitive advantage are conceptionalised in terms of "strategic coherence" model, which has three aspects. Competitive strategies require internal consistency referred to as 'competitive coherence'. In addition, 'organisational coherence' needs to be built, involving the structure of internal and external elements affecting an organisation's ability to achieve its competitive advantage. The creation of this structure is not automatic. The difficulties increase with growing dynamism and complexity of the environment in which an organisation is operating. While competitive and organisational coherence might exist accidentally, the third aspect developed in this study is called 'cognitive coherence'. The lack of coherence in one or more of these aspects is a barrier to a firm achieving and sustaining its competitive advantage. Secondly, this study reports empirical evidence on the validity of the theoretical framework. This study takes the case of two different industries (petrochemical and food) in Saudi Arabia. Results indicate that all four competitive strategies are possible and statistically defined. In addition, high-performing firms, in both industries, have more strategic coherence than lower performing firms. The results suggest that high-performing firms are able not only to achieve their competitive advantage but also to sustain it over time. Moreover, in each industry, firms with different competitive strategies have different barriers to achieving their competitive advantage. These results are consistent with those found in the existing literature, lending support to the view that western strategy models seem to be applicable to developing countries such as Saudi Arabia

New Megastigmane and Polyphenolic Components of Henna Leaves and Their Tumor-Specific Cytotoxicity on Human Oral Squamous Carcinoma Cell Lines

Polyphenols have a variety of phenolic hydroxyl and carbonyl functionalities that enable them to scavenge many oxidants, thereby preserving the human redox balance and preventing a number of oxidative stress-related chronic degenerative diseases. In our ongoing investigation of polyphenol-rich plants in search of novel molecules, we resumed the investigation of Lawsonia inermis L. (Lythraceae) or henna, a popular ancient plant with aesthetic and therapeutic benefits. The leaves’ 70% aq acetone extract was fractionated on a Diaion HP-20 column with different ratios of H2O/an organic solvent. Multistep gel chromatographic fractionation and HPLC purification of the Diaion 75% aq MeOH and MeOH fractions led to a new compound (1) along with tannin-related metabolites, benzoic acid (2), benzyl 6′-O-galloyl-β-D-glucopyranoside (3), and ellagic acid (4), which are first isolated from henna. Repeating the procedures on the Diaion 50% aq MeOH eluate led to the first-time isolation of two O-glucosidic ellagitannins, heterophylliin A (5), and gemin D (6), in addition to four known C-glycosidic ellagitannins, lythracin D (7), pedunculagin (8), flosin B (9), and lagerstroemin (10). The compound structures were determined through intensive spectroscopic investigations, including HRESIMS, 1D (1H and 13C) and 2D (1H–1H COSY, HSQC, HMBC, and NOESY) NMR, UV, [α]D, and CD experiments. The new structure of 1 was determined to be a megastigmane glucoside gallate; its biosynthesis from gallic acid and a β-ionone, a degradative product of the common metabolite β-carotin, was highlighted. Cytotoxicity investigations of the abundant ellagitannins revealed that lythracin D2 (7) and pedunculagin (8) are obviously more cytotoxic (tumor specificity = 2.3 and 2.8, respectively) toward oral squamous cell carcinoma cell lines (HSC-2, HSC-4, and Ca9-22) than normal human oral cells (HGF, HPC, and HPLF). In summary, Lawsonia inermis is a rich source of anti-oral cancer ellagitannins. Also, the several discovered polyphenolics highlighted here emphasize the numerous biological benefits of henna and encourage further clinical studies to profit from their antioxidant properties against oxidative stress-related disorders

Effect of water supplementation of Magic oil at different growing periods on growth performance, carcass traits, blood biochemistry, and ileal histomorphology of broiler chickens

ABSTRACT: Natural antibiotic substitutes have recently been used as growth promoters and to combat pathogens. Therefore, this study aimed to assess the effects of adding Magic oil (nano-emulsified plant oil) at different growing periods on growth performance, histomorphology of the ileum, carcass traits, and blood biochemistry of broiler chickens. A total of 432-day-old Ross 308 chicks were randomly assigned to 1 of 6 water supplementation treatment groups based on growing periods, with 4 groups of Magic oil programs compared to probiotic (Albovit) as a positive control and nonsupplemented group as a negative control, with 9 replicates each with 8 birds (4♂ and 4♀). The periods of adding Magic oil Magic oil were 35, 20, 23, and 19 d for T1, T2, T3, and T4, respectively. Birds’ performance was evaluated during 0 to 4, 4 to 14, 21 to 30, 30 to 35, and overall days old. Carcass parameters, blood chemistry, and ileal histomorphology were examined on d 35. The findings showed that birds in the T4 group of the Magic oil supplementation program (from 1 to 4 and 21 to 35 d of age) consumed 1.82% and 4.20% more food, gained 3.08% and 6.21% more, and converted feed to meat 1.39% and 2.07% more than Albovit and negative control, respectively, during the experiment (1–35). Magic oil particularly T1 (Magic oil is supplemented throughout the growing period) and T4 programs improved intestinal histology compared to the negative control. There were no changes (P > 0.05) between treatments in carcass parameters and blood biochemistry. In conclusion, water supplementation with Magic oil for broilers improves intestinal morphometrics and growth performance similar to or better than probiotic, especially during brooding and overall periods. Further studies are needed to evaluate the effect of adding both nano-emulsified plant oil and probiotics on different parameters

Production of Extracellular Lipase by Bacillus halotolerans from Oil-Contaminated Soil in a Pilot-Scale Submerged Bioreactor

Microbial lipases are the biocatalyst of choice for the present and future because of their characteristics, including their ability to remain active as an enzyme throughout a broad pH, temperature, and substrate range. The goal of the current investigation was to find novel sources of substrates and isolates from soil contaminated by oil for the synthesis of lipase. On tributyrin media, 10 lipolytic bacterial strains that were isolated from oil-contaminated soil were grown. Using the zone of clearance, it was possible to identify the isolates with the highest activity. Following phylogenetic tree analysis, molecular characterization of the 16S rRNA sequence of the bacterial isolates revealed that it was Bacillus halotolerans (VSH 09). The enzyme was purified to near homogeneity. The enzyme activity was found to be optimum at a pH of 7.0 and a temperature of 35 °C. While Ni2+ and Cu2+ had no effect, the presence of Mg2+ and Ca2+ exhibited the highest levels of enzyme activity. At 1%, tributyrin as a substrate exhibited its highest level of activity. The molecular weight, as determined by SDS-PAGE, was found to be 38 kDa. The kinetics of the enzyme were found to be 41.66 and 9.37 mg/mL for Vmax and Km, respectively. The high yield of lipase produced by this method suggests that it holds potential for production on a large scale and could be used for various biotechnological applications

Chemical Composition and Antioxidant, Antimicrobial, and Anti-Inflammatory Properties of Origanum compactum Benth Essential Oils from Two Regions: In Vitro and In Vivo Evidence and In Silico Molecular Investigations

The purposes of this investigatory study were to determine the chemical composition of the essential oils (EOs) of Origanum compactum from two Moroccan regions (Boulemane and Taounate), as well as the evaluation of their biological effects. Determining EOs’ chemical composition was performed by a gas chromatography–mass spectrophotometer (GC-MS). The antioxidant activity of EOs was evaluated using free radical scavenging ability (DPPH method), fluorescence recovery after photobleaching (FRAP), and lipid peroxidation inhibition assays. The anti-inflammatory effect was assessed in vitro using the 5-lipoxygenase (5-LOX) inhibition test and in vivo using the carrageenan-induced paw edema model. Finally, the antibacterial effect was evaluated against several strains using the disk-diffusion assay and the micro-dilution method. The chemical constituent of O. compactum EO (OCEO) from the Boulemane zone is dominated by carvacrol (45.80%), thymol (18.86%), and α-pinene (13.43%). However, OCEO from the Taounate zone is rich in 3-carene (19.56%), thymol (12.98%), and o-cymene (11.16%). OCEO from Taounate showed higher antioxidant activity than EO from Boulemane. Nevertheless, EO from Boulemane considerably inhibited 5-LOX (IC50 = 0.68 ± 0.02 µg/mL) compared to EO from Taounate (IC50 = 1.33 ± 0.01 µg/mL). A similar result was obtained for tyrosinase inhibition with Boulemane EO and Taounate EO, which gave IC50s of 27.51 ± 0.03 μg/mL and 41.83 ± 0.01 μg/mL, respectively. The in vivo anti-inflammatory test showed promising effects; both EOs inhibit and reduce inflammation in mice. For antibacterial activity, both EOs were found to be significantly active against all strains tested in the disk-diffusion test, but O. compactum EO from the Boulemane region showed the highest activity. Minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) for O. compactum EO from the Boulemane region ranged from 0.06 to 0.25% (v/v) and from 0.15 to 0.21% (v/v) for O. compactum from the Taounate region. The MBC/MIC index revealed that both EOs exhibited remarkable bactericidal effects