Determination of the Effects of Prenatal Remdesivir Exposure on Placenta Morphology, Placental IgG Transfer, and Fetal Growth in a Humanized Mouse Model

Remdesivir (RDV) is an antiviral medication used most recently for the treatment of COVID-19. Although no adverse effects were observed on perinatal parameters in reproductive and development toxicology studies at doses up to four-fold clinical area under the curve (AUC) exposures, some researchers have reported that therapeutic levels of RDV may impair early embryogenesis, as observed by in vitro studies. In addition, the influence of prenatal RDV exposure on maternal IgG transfer in the placenta is still unknown. Administration of RDV in pregnant humanized mouse model (Tg32), which expresses the human Fc gamma receptor and transporter (FCGRT) gene, was used to further evaluate potential effects on IgG transfer and concurrent perinatal endpoints. Animals were dosed daily from gestational days (GDs) 10- 14 with 25 mg/kg RDV (GS-5734) via intravenous injection (n=3-5 per group). Concurrent vehicle control animals were dosed intravenously with 12% sulfobutyl ether- beta-cyclodextrin in water (pH3.5;NaOH/HCl). All animals were administered 2 mg/kg human IgG via intravenous injection on GD 14. Placentae and fetuses were collected from dams on GD 14, 15, 16, and 18 and evaluated using histopathology and qPCR for inflammation markers. No abnormal morphologies (necrosis/apoptosis) of placentae were observed between the concurrent control and RDVdosed groups. Additionally, no differences in maternal body weights were observed. There were no statistically significant differences in placenta weights. There were no statistically significant changes in pregnancy parameters (implantation sites and dead fetuses/litter) and fetal weights between the RDV-dosed group and concurrent controls at GD 14, 15, 16, and 18. No changes were observed in transcript levels of inflammation markers in the RDV-dosed group when compared to the concurrent control group. There was a slightly lower ratio of fetal IgG level to maternal IgG levels in the RDV-dosed group;however, no statistically significant differences were observed between the RDV-dosed group and concurrent controls on GD 14, 15, 16, and 18. Our results suggest that a daily dose of 25 mg/kg RDV on GDs 10-14 in humanized mice did not cause adverse effects on placenta and fetal development. (Funded by the Perinatal Health Center of Excellence: E0300201.).

COMPOSITION OF LIPOPHILIC COMPONENTS OF RHODODENDRON ADAMSAY ETHER EXTRACT AND ACTIVITY AGAINST SARS-COV-2 MAIN PROTEASE

The composition of the lipophilic components of the Adams rhododendron RhododendronadamsiiRehd. Acid and neutral components were identified using gas-liquid chromatography with mass spectrometric detection. Methyl tert-butyl ether (MTBE), which has all the advantages of diethyl ether, but is devoid of its disadvantages, was used as the raw material extractant. It does not form peroxides and does not create increased gas contamination due to its higher boiling point. As a result, comparison with databases identified triterpene, phenolcarboxylic and aliphatic acids with a chain length of 8 to 30 carbon atoms, including saturated, unsaturated and dibasic acids. More than 150 triterpene and aliphatic components of the unsaponifiable residue and acid fractions have been identified. Previously, unsaponifiable residues of lipophilic extracts were practically not studied. Only components of Rh.adamsiiand other species of the genus rhododendron essential oils have been studied in detail. For bioactivity testing, samples of the whole extract and its fractionation products were prepared. Some of the studied samples show inhibitory activity against the main protease of SARS-CoV-2. © 2022 Altai State University. All rights reserved.

Computational Study Reveals the Inhibitory Effects of Chemical Constituents from Azadirachta indica (Indian Neem) Against Delta and Omicron Variants of SARS-CoV-2

Background: The newly emerged delta and omicron variants of severe acute respiratory syn-drome coronavirus (SARS-CoV-2) have affected millions of individuals globally with increased transmis-sible and infectivity rates. Although, numerous vaccines are available or under clinical trials to combat the SARS-CoV-2 and its variant, still, a therapeutic agent is awaited. Objective(s): The present work is focused on rigorous screening of chemical constituents of Azadirachta indica (A. indica) against delta and omicron variants of SARS-CoV-2 via inhibition of S-glycoprotein. Method(s): Total, 10 compounds of A. indica were subjected to molecular docking and pharmacophore modeling studies against the S-glycoprotein of delta and omicron variants of SARS-CoV-2. Furthermore, homology modeling was performed for omicron S-glycoprotein with the help of SWISS-MODEL and aligned by PyMOL software. Later on, the residues of protein were verified in the allowed region via Ramachandran plot. In addition, our docking results have also been validated by MMGBSA binding free energy calculations. Result(s): Our computed study demonstrated that nimbolinin B12-methyl ether and nimbidinin showed promising docking scores (>-6.0) as compared to docking scores (< 6.0) of reference drug 'camostat' against S-glycoproteins of both delta and omicron variants. Redocking by using MMGBSA calculation also reveals that both these compounds can effectively bind within the pockets of said protein receptors Conclusion(s): Nimbolinin B12-methyl ether and nimbidinin have potent anti-SARS-CoV activity against delta and omicron variants and thus, A. indica might be a useful source for developing novel anti-SARS-CoV-2 therapeutic agents.Copyright © 2022 Bentham Science Publishers.

The Potential of Stilbene Compounds to Inhibit Mpro Protease as a Natural Treatment Strategy for Coronavirus Disease-2019.

COVID-19 disease has had a global impact on human health with increased levels of morbidity and mortality. There is an unmet need to design and produce effective antivirals to treat COVID-19. This study aimed to explore the potential ability of natural stilbenes to inhibit the Mpro protease, an acute respiratory syndrome coronavirus-2 (SARS-CoV-2) enzyme involved in viral replication. The binding affinities of stilbene compounds against Mpro were scrutinized using molecular docking, prime molecular mechanics-generalized Born surface area (MM-GBSA) energy calculations, and molecular dynamic simulations. Seven stilbene molecules were docked with Mpro and compared with GC376 and N3, antivirals with demonstrated efficacy against Mpro. Ligand binding efficiencies and polar and non-polar interactions between stilbene compounds and Mpro were analyzed. The binding affinities of astringin, isorhapontin, and piceatannol were -9.319, -8.166, and -6.291 kcal/mol, respectively, and higher than either GC376 or N3 at -6.976 and -6.345 kcal/mol, respectively. Prime MM-GBSA revealed that these stilbene compounds exhibited useful ligand efficacy and binding affinity to Mpro. Molecular dynamic simulation studies of astringin, isorhapontin, and piceatannol showed their stability at 300 K throughout the simulation time. Collectively, these results suggest that stilbenes such as astringin, isorhapontin, and piceatannol could provide useful natural inhibitors of Mpro and thereby act as novel treatments to limit SARS-CoV-2 replication.

COMPOSITION OF LIPOPHILIC COMPONENTS OF RHODODENDRON ADAMSAY ETHER EXTRACT AND ACTIVITY AGAINST SARS-COV-2 MAIN PROTEASE

The composition of the lipophilic components of the Adams rhododendron RhododendronadamsiiRehd. Acid and neutral components were identified using gas-liquid chromatography with mass spectrometric detection. Methyl tert-butyl ether (MTBE), which has all the advantages of diethyl ether, but is devoid of its disadvantages, was used as the raw material extractant. It does not form peroxides and does not create increased gas contamination due to its higher boiling point. As a result, comparison with databases identified triterpene, phenolcarboxylic and aliphatic acids with a chain length of 8 to 30 carbon atoms, including saturated, unsaturated and dibasic acids. More than 150 triterpene and aliphatic components of the unsaponifiable residue and acid fractions have been identified. Previously, unsaponifiable residues of lipophilic extracts were practically not studied. Only components of Rh.adamsiiand other species of the genus rhododendron essential oils have been studied in detail. For bioactivity testing, samples of the whole extract and its fractionation products were prepared. Some of the studied samples show inhibitory activity against the main protease of SARS-CoV-2. © 2022 Altai State University. All rights reserved.

Did COVID-19 Pandemic Influence the Ether Cryptocurrency Market? Perception and Analysis

In recent days, DeFi tokens have gained popularity as an investment option in the pandemic period and has gained a significant amount of investment. Cryptocurrency trading is a type of DeFi that has gained a lot of attention in the global market. The value of such currencies is increasing on a daily basis and peaked during the pandemic. One of these significant cryptocurrencies is the ether cryptocurrency, which ranks second only to the bitcoin cryptocurrency in terms of the value of a single coin. The ARIMA model will be used to forecast the price of ether. In this paper, an hourly forecast and a short term period forecast are performed. The forecast clearly shows that the ARIMA model performed better on log transformed data than on the original data. It's also evident that COVID-19 pandemic has also aided the growth of ethereum when compared to previous year. © 2022 IEEE.

Antimicrobial V-Shaped Copper(II) Pentaiodide: Insights to Bonding Pattern and Susceptibility.

Antimicrobial resistance (AMR) is a major concern for the survival of mankind. COVID-19 accelerated another silent pandemic of AMR through the uncontrolled use of antibiotics and biocides. New generations of antimicrobial agents are needed to combat resistant pathogens. Crown ethers can be used as models for drug action because they are similar to antibiotics. Iodine is a well-known microbicide but is characterized by instability and short-term effectivity. Iodine can be stabilized in the form of polyiodides that have a rich topology but are dependent on their immediate surroundings. In addition, copper has been successfully used since the beginning of history as a biocidal agent. We, therefore, combined iodine and copper with the highly selective crown ether 1,4,7,10-tetraoxacyclododecane (12-crown-4). The morphology and composition of the new pentaiodide [Cu(12-crown-4)2]I5 was investigated. Its antimicrobial activities against a selection of 10 pathogens were studied. It was found that C. albicans WDCM 00054 is highly susceptible to [Cu(12-crown-4)2]I5. Additionally, the compound has good to intermediate antimicrobial activity against Gram-positive and Gram-negative bacilli. The chain-like pentaiodide structure is V-shaped and consists of iodine molecules with very short covalent bonds connected to triiodides by halogen bonding. The single crystal structure is arranged across the lattice fringes in the form of ribbons or honeycombs. The susceptibility of microorganisms towards polyiodides depends on polyiodide bonding patterns with halogen-, covalent-, and non-covalent bonding.

Are cryptocurrencies safe havens during the COVID-19 pandemic? A threshold regression perspective with pandemic-related benchmarks

The paper employs a threshold regression framework conditioned by two COVID-19 related proxies, to investigate whether Bitcoin and Ether exhibit short-term safe haven or diversifier features for stock and bond markets. Both cryptocurrencies fulfil a diversifier role for the responsible investments represented by sustainable stock market indices, a safe haven role for major bond markets and a mixed role for a selection of representative stock market indices. Furthermore, in times characterized by an increasing number of COVID-19 daily cases or deaths the statistical relationship between both cryptocurrencies and the main financial market determinants weakens.

A review on ethnomedicinal and phytopharmacological potential of traditionally wild and endemic plant Berberis tinctoria Lesch

Introduction: Berberis tinctoria an evergreen shrub, endemic and predominantly found at a higher altitude of the Nilgiri Biosphere Reserve, India. This leaf and fruit are edible, which are also used in homeopathic remedies for countless illnesses. Objectives: B. tinctoria with diverse ethnomedicinal uses was focused in the prevailing study to detailed the phytochemical and pharmacological properties for further imminent research in this species. Materials and methods: Published data in this review were all gathered from the online bibliographical databases: PubMed, Elsevier, Scopus, Google Scholar, Web of Science, and local ethnic community peoples of Kurumba and Toda. Results: B. tinctoria was used as a Ayurvedic and homeopathy medicine by the tribal communities. The previous findings of B. tinctoria were used for skin diseases, wound healing, inflammatory, menorrhagia, diarrhea, jaundice, and a snakebites. The phytochemical studies revealed that secondary metabolites, antioxidants, and antimicrobial activity as a result of major alkaloid isoforms of berberine, berbamine, jatrorrhizine, etc. Conclusion: B. tinctoria is an important plant due to the presence of bioactive phytochemicals, especially berberine protoberberine group of benzylisoquinoline. As a result of its diverse ethnopharmacological importance, as well as numerous commercial products and novel bioactive compounds yet to be discovered for future drug discovery and development.

Plasmalogenic Lipid Analogs as Platelet-Activating Factor Antagonists: A Potential Novel Class of Anti-inflammatory Compounds.

Plasmalogens and Platelet-Activating Factor (PAF) are both bioactive ether phospholipids. Whereas plasmalogens are recognized for their important antioxidant function and modulatory role in cell membrane structure and dynamics, PAF is a potent pro-inflammatory lipid mediator known to have messenger functions in cell signaling and inflammatory response. The relationship between these two types of lipids has been rarely studied in terms of their metabolic interconversion and reciprocal modulation of the pro-inflammation/anti-inflammation balance. The vinyl-ether bonded plasmalogen lipid can be the lipid sources for the precursor of the biosynthesis of ether-bonded PAF. In this opinion paper, we suggest a potential role of plasmalogenic analogs of PAF as modulators and PAF antagonists (anti-PAF). We discuss that the metabolic interconversion of these two lipid kinds may be explored towards the development of efficient preventive and relief strategies against PAF-mediated pro-inflammation. We propose that plasmalogen analogs, acting as anti-PAF, may be considered as a new class of bioactive anti-inflammatory drugs. Despite of the scarcity of available experimental data, the competition between PAF and its natural plasmalogenic analogs for binding to the PAF receptor (PAF-R) can be proposed as a mechanistic model and potential therapeutic perspective against multiple inflammatory diseases (e.g., cardiovascular and neurodegenerative disorders, diabetes, cancers, and various manifestations in coronavirus infections such as COVID-19).

Development of a tandem mass spectrometric method for the quantitation of dexamethasone levels

BACKGROUND AND AIM: Dexamethasone is one of the most potent glucocorticoid. It is used in the various medical conditions such as multiple sclerosis, allergies, inflammation, asthma, dermatitis and shock. Recently, dexamethasone has been found to be beneficial in patients with COVID-19 pneumonia requiring supplemental oxygen or mechanical ventilation. It can cause serious adverse effects such as adrenal suppression, hyperglycemia, and cardiac arrhythmia. Therefore, monitoring of dexamethasone levels is important. Our aim in this study is to develop an LC-MS/MS method for dexamethasone. METHODS: Dexamethasone was detected with ABSciex API 3200 tandem mass spectrometery in positive electrospray ionization mode. The selected ion transitions for dexamethasone and internal standard were m/z 289.5/97.3 and m/z 339.1/113.2, respectively. Briefly, 100 μL of internal standard (17-hydroxyprogesterone-d8) and 4 mL of diethylether were added to 250 μL of sample, and vortexed for 1 minute, then centrifuged at 4000 g for 10 minutes. The supernatant was taken into tubes and evaporated at 40 °C under nitrogen gas. The residues were dissolved in 200 μL of methanol:water (1:1, v/v%) and 25 μL was injected. RESULTS: The calibration curve was linear between 1.95 and 2000 ng/mL (r2>0.99). The limit of quantitation for dexamethasone was 1.95 ng/mL. Total run time was 5 minutes. Intra- and inter-assay imprecision values were less than 9%. The mean extraction recovery was 92.8%, and the matrix effect ranged from 3.6% to 9.8%. CONCLUSIONS: A sensitive and reproducible tandem mass spectrometry method was developed for dexamethasone. The method can be used in the analysis of dexamethasone.

Exhaust Emissions from a Hybrid City Bus Fuelled by Conventional and Oxygenated Fuel

City buses are one of the main means of public transport in cities. As they move in a limited and densely populated area and are intensively exploited, it is particularly important that they are environmentally friendly. There are many ways to reduce emissions from city buses, including the use of hybrid propulsion. Another way is to use low-emission fuels. This article presents the results of the emission tests of an 18 m articulated city bus with a serial hybrid drive fuelled comparatively by conventional diesel fuel and oxygenated fuel containing 10% v/v of triethylene glycol dimethyl ether (TEGDME). The emission tests were carried out during the actual operation of the bus on a route in Poznań (Poland) and over the SORT cycles. The obtained test results were compared also with the results obtained for a conventional bus. The reduction in emissions of some exhaust components was found when the hybrid bus was fuelled with oxygenated fuel during its actual operation on the bus route. There was a reduction in CO emissions by ~50% and NOx emissions by ~10%. Almost identical levels of PM and HC emissions and smoke opacity were observed for both fuels. In the SORT cycles, the differences in the emissions obtained for both types of fuel were small. In general, for the hybrid bus, a lower influence of oxygenated fuel on emissions was recorded than for the conventional bus.

Autoclavable, Breathable, and Waterproof Membranes Tailored by Ternary Nanofibers for Reusable Medical Protective Applications

The COVID-19 created severe shortages of prevention materials and supplies, and the reuse of medical protective clothing is ongoing worldwide. However, it has remained a significant challenge to realize the reusability of the current medical protective clothing. We reported a scalable strategy to create autoclavable ternary electrospun nanofibrous membranes (TENMs) by introducing the elastomer polyurethane (PU) and low-surface-energy fluorinated polyurethane (FPU) into poly(ether sulfone) (PES) fibers via electrospinning. The advantage of this design was that we could balance the waterproof-breathable function and the thermostable performance of the membrane by controlling the PES/PU/FPU mass ratio. The resulting TENMs showed excellent performances of a high moisture transmission rate of 8.3 kg m-2 day-1, a high hydrostatic pressure of 82.56 kPa, a high bacteria retention rate of 99.99%, a high aerosol retention rate of 99.99%, and autoclave sterilization-invariant to 10 cycles. The successful preparation of the material can lead to the reuse of medical protective clothing in the foreseeable future. © 2021 American Chemical Society.

In search of SARS CoV-2 replication inhibitors: Virtual screening, molecular dynamics simulations and ADMET analysis.

Severe acute respiratory syndrome has relapsed recently as novel coronavirus causing a life threat to the entire world in the absence of an effective therapy. To hamper the replication of the deadly SARS CoV-2 inside the host cells, systematic in silico virtual screening of total 267,324 ligands from Asinex EliteSynergy and BioDesign libraries has been performed using AutoDock Vina against RdRp. The molecular modeling studies revealed the identification of twenty-one macrocyclic hits (2-22) with better binding energy than remdesivir (1), marketed SARS CoV-2 inhibitor. Further, the analysis using rules for drug-likeness and their ADMET profile revealed the candidature of these hits due to superior oral bioavailability and druggability. Further, the MD simulation studies of top two hits (2 and 3) performed using GROMACS 2020.1 for 10 ns revealed their stability into the docked complexes. These results provide an important breakthrough in the design of macrocyclic hits as SARS CoV-2 RNA replicase inhibitor.

Antimicrobial Hexaaquacopper(II) Complexes with Novel Polyiodide Chains.

The non-toxic inorganic antimicrobial agents iodine (I2) and copper (Cu) are interesting alternatives for biocidal applications. Iodine is broad-spectrum antimicrobial agent but its use is overshadowed by compound instability, uncontrolled iodine release and short-term effectiveness. These disadvantages can be reduced by forming complex-stabilized, polymeric polyiodides. In a facile, in-vitro synthesis we prepared the copper-pentaiodide complex [Cu(H2O)6(12-crown-4)5]I6 · 2I2, investigated its structure and antimicrobial properties. The chemical structure of the compound has been verified. We used agar well and disc-diffusion method assays against nine microbial reference strains in comparison to common antibiotics. The stable complex revealed excellent inhibition zones against C. albicans WDCM 00054, and strong antibacterial activities against several pathogens. [Cu(H2O)6(12-crown-4)5]I6 · 2I2 is a strong antimicrobial agent with an interesting crystal structure consisting of complexes located on an inversion center and surrounded by six 12-crown-4 molecules forming a cationic substructure. The six 12-crown-4 molecules form hydrogen bonds with the central Cu(H2O)6. The anionic substructure is a halogen bonded polymer which is formed by formal I5- repetition units. The topology of this chain-type polyiodide is unique. The I5- repetition units can be understood as a triodide anion connected to two iodine molecules.

In silico Exploration of Interactions Between Potential COVID-19 Antiviral Treatments and the Pore of the hERG Potassium Channel-A Drug Antitarget.

Background: In the absence of SARS-CoV-2 specific antiviral treatments, various repurposed pharmaceutical approaches are under investigation for the treatment of COVID-19. Antiviral drugs considered for this condition include atazanavir, remdesivir, lopinavir-ritonavir, and favipiravir. Whilst the combination of lopinavir and ritonavir has been previously linked to prolongation of the QTc interval on the ECG and risk of torsades de pointes arrhythmia, less is known in this regard about atazanavir, remdesivir, and favipiravir. Unwanted abnormalities of drug-induced QTc prolongation by diverse drugs are commonly mediated by a single cardiac anti-target, the hERG potassium channel. This computational modeling study was undertaken in order to explore the ability of these five drugs to interact with known determinants of drug binding to the hERG channel pore. Methods: Atazanavir, remdesivir, ritonavir, lopinavir and favipiravir were docked to in silico models of the pore domain of hERG, derived from cryo-EM structures of hERG and the closely related EAG channel. Results: Atazanavir was readily accommodated in the open hERG channel pore in proximity to the S6 Y652 and F656 residues, consistent with published experimental data implicating these aromatic residues in atazanavir binding to the channel. Lopinavir, ritonavir, and remdesivir were also accommodated in the open channel, making contacts in a model-dependent fashion with S6 aromatic residues and with residues at the base of the selectivity filter/pore helix. The ability of remdesivir (at 30 µM) to inhibit the channel was confirmed using patch-clamp recording. None of these four drugs could be accommodated in the closed channel structure. Favipiravir, a much smaller molecule, was able to fit within the closed channel and could adopt multiple binding poses in the open channel, but with few simultaneous interactions with key binding residues. Only favipiravir and remdesivir showed the potential to interact with lateral pockets below the selectivity filter of the channel. Conclusions: All the antiviral drugs studied here can, in principle, interact with components of the hERG potassium channel canonical binding site, but are likely to differ in their ability to access lateral binding pockets. Favipiravir's small size and relatively paucity of simultaneous interactions may confer reduced hERG liability compared to the other drugs. Experimental structure-function studies are now warranted to validate these observations.

Hydroxychloroquine and QTc prolongation in patients with COVID-19: A systematic review and meta-analysis.

BACKGROUND: Among many drugs that hold potential in COVID-19 pandemic, chloroquine (CQ), and its derivative hydroxychloroquine (HCQ) have generated unusual interest. With increasing usage, there has been growing concern about the prolongation of QTc interval and Torsades de Pointes (TdP) with HCQ, especially in combination with azithromycin. AIMS: This meta-analysis is planned to study the risk of QTc prolongation and Torsades de pointes (TdP) by a well-defined criterion for HCQ, CQ alone, and in combination with Azithromycin in patients with COVID-19. METHODS: A comprehensive literature search was made in two databases (PubMed, Embase). Three outcomes explored in the included studies were frequency of QTc > 500 ms (ms) or ΔQTc > 60 ms (Outcome 1), frequency of QTc > 500 ms (Outcome 2) and frequency of TdP (Outcome 3). Random effects method with inverse variance approach was used for computation of pooled summary and risk ratio. RESULTS: A total of 13 studies comprising of 2138 patients were included in the final analysis. The pooled prevalence of outcome 1, outcome 2 and outcome 3 for HCQ, CQ with or without Azithromycin were 10.18% (5.59-17.82%, I2 - 92%), 10.22% (6.01-16.85%, I2 - 79%), and 0.72% (0.34-1.51, I2 - 0%) respectively. The prevalence of outcome 2 in subgroup analysis for HCQ and HCQ + Azithromycin was 7.25% (3.22-15.52, I2 - 59%) and 8.61% (4.52-15.79, I2 - 76%), respectively. The risk ratio (RR) for outcome 1 and outcome 2 between HCQ + Azithromycin and HCQ was 1.22 (0.77-1.93, I2 - 0%) & 1.51 (0.79-2.87, I2 - 13%), respectively and was not significant. Heterogeneity was noted statistically as well clinically (regimen types, patient numbers, study design, and outcome definition). CONCLUSION: The use of HCQ/CQ is associated with a high prevalence of QTc prolongation. However, it is not associated with a high risk of TdP.