Thymoquinone Loaded Topical Nanoemulgel for Wound Healing: Formulation Design and In-Vivo Evaluation

Thymoquinone is a natural bioactive with significant therapeutic activity against multiple ailments including wound healing. The poor aqueous solubility and low skin permeability limit its therapeutic efficacy. The present investigation aimed to improve the biopharmaceutical attributes of thymoquinone to enhance its topical efficacy in wound healing. A nanoemulsion-based hydrogel system was designed and characterized as a nanotechnology-mediated drug delivery approach to improve the therapeutic efficacy of thymoquinone, utilizing a high-energy emulsification technique. The black seed oil, as a natural home of thymoquinone, was utilized to improve the drug loading capacity of the developed nanoemulsion system and reduced the oil droplet size to <100 nm through ultrasonication. The influence of formulation composition, and the ultrasonication process conditions, were investigated on the mean globule size and polydispersity index of the generated nanoemulsion. Irrespective of surfactant/co-surfactant ratio and % concentration of surfactant/co-surfactant mixture, the ultrasonication time had a significant (p < 0.05) influence on the mean droplet size and polydispersity index of the generated nanoemulsion. The developed nanoemulgel system of thymoquinone demonstrated the pseudoplastic behavior with thixotropic properties, and this behavior is desirable for topical application. The nanoemulgel system of thymoquinone exhibited significant enhancement (p < 0.05) in skin penetrability and deposition characteristics after topical administration compared to the conventional hydrogel system. The developed nanoemulgel system of thymoquinone exhibited quicker and early healing in wounded Wistar rats compared to the conventional hydrogel of thymoquinone, while showing comparable healing efficacy with respect to marketed silver sulfadiazine (1%) cream. Furthermore, histopathology analysis of animals treated with a developed formulation system demonstrated the formation of the thick epidermal layer, papillary dermis along with the presence of extensive and organized collagen fibers in newly healed tissues. The outcome of this investigation signifies that topical delivery of thymoquinone through nanoemulgel system is a promising candidate which accelerates the process of wound healing in preclinical study.     

A Comprehensive In Silico Study of New Metabolites from Heteroxenia fuscescens with SARS-CoV-2 Inhibitory Activity

Chemical investigation of the total extract of the Egyptian soft coral Heteroxenia fuscescens, led to the isolation of eight compounds, including two new metabolites, sesquiterpene fusceterpene A (1) and a sterol fuscesterol A (4), along with six known compounds. The structures of 1–8 were elucidated via intensive studies of their 1D, 2D-NMR, and HR-MS analyses, as well as a comparison of their spectral data with those mentioned in the literature. Subsequent comprehensive in-silico-based investigations against almost all viral proteins, including those of the new variants, e.g., Omicron, revealed the most probable target for these isolated compounds, which was found to be M^pro. Additionally, the dynamic modes of interaction of the putatively active compounds were highlighted, depending on 50-ns-long MDS. In conclusion, the structural information provided in the current investigation highlights the antiviral potential of H. fuscescens metabolites with 3β,5α,6β-trihydroxy steroids with different nuclei against SARS-CoV-2, including newly widespread variants.     

QSAR,Molecular Docking,MD Simulation and MMGBSA Calculations Approaches to Recognize Concealed Pharmacophoric Features Requisite for the Optimization of ALK Tyrosine Kinase Inhibitors as Anticancer Leads

ALK tyrosine kinase ALK TK is an important target in the development of anticancer drugs. In the present work, we have performed a QSAR analysis on a dataset of 224 molecules in order to quickly predict anticancer activity on query compounds. Double cross validation assigns an upward plunge to the genetic algorithm–multi linear regression (GA-MLR) based on robust univariate and multivariate QSAR models with high statistical performance reflected in various parameters like, fitting parameters; R² = 0.69–0.87, F = 403.46–292.11, etc., internal validation parameters; Q²_LOO = 0.69–0.86, Q²_LMO = 0.69–0.86, CCC_cv = 0.82–0.93, etc., or external validation parameters Q²_F1 = 0.64–0.82, Q²_F2 = 0.63–0.82, Q²_F3 = 0.65–0.81, R²_ext = 0.65–0.83 including RMSE_tr < RMSE_cv. The present QSAR evaluation successfully identified certain distinct structural features responsible for ALK TK inhibitory potency, such as planar Nitrogen within four bonds from the Nitrogen atom, Fluorine atom within five bonds beside the non-ring Oxygen atom, lipophilic atoms within two bonds from the ring Carbon atoms. Molecular docking, MD simulation, and MMGBSA computation results are in consensus with and complementary to the QSAR evaluations. As a result, the current study assists medicinal chemists in prioritizing compounds for experimental detection of anticancer activity, as well as their optimization towards more potent ALK tyrosine kinase inhibitor.     

Oxy-Polybrominated Diphenyl Ethers from the Indonesian Marine Sponge,Lamellodysidea herbacea: X-ray,SAR, and Computational Studies

Polybrominated diphenyl ether (PBDE) compounds, derived from marine organisms, originate from symbiosis between marine sponges and cyanobacteria or bacteria. PBDEs have broad biological spectra; therefore, we analyzed structure and activity relationships of PBDEs to determine their potential as anticancer or antibacterial lead structures, through reactions and computational studies. Six known PBDEs (1–6) were isolated from the sponge, Lamellodysdiea herbacea; ¹³C NMR data for compound 6 are reported for the first time and their assignments are confirmed by their theoretical ¹³C NMR chemical shifts (RMSE < 4.0 ppm). Methylation and acetylation of 1 (2, 3, 4, 5-tetrabromo-6-(3′, 5′-dibromo-2′-hydroxyphenoxy) phenol) at the phenol functional group gave seven molecules (7–13), of which 10, 12, and 13 were new. New crystal structures for 8 and 9 are also reported. Debromination carried out on 1 produced nine compounds (1, 2, 14, 16–18, 20, 23, and 26) of which 18 was new. Debromination product 16 showed a significant IC₅₀ 8.65 ± 1.11; 8.11 ± 1.43 µM against human embryonic kidney (HEK293T) cells. Compounds 1 and 16 exhibited antibacterial activity against Gram-positive Staphylococcus aureus and Gram-negative Klebsiella pneumoniae with MID 0.078 µg/disk. The number of four bromine atoms and two phenol functional groups are important for antibacterial activity (S. aureus and K. pneumoniae) and cytotoxicity (HEK293T). The result was supported by analysis of frontier molecular orbitals (FMOs). We also propose possible products of acetylation and debromination using analysis of FMOs and electrostatic charges and we confirm the experimental result.     

Derivations and generating degrees in the ring of arithmetical functions

In this paper we study a family of derivations in the ring of arithmetical functions of several variables over an integral domain, and compute the generating degrees of the ring of arithmetical functions over the kernel of these derivations.     

Velocity Distributions of Copper and Lithium Atoms Sputtered from a Cu/Li Alloy Measured with Laser Induced Fluorescence

To test its applicability as wall material for nuclear fusion experiments, a copper based binary alloy containing 17 at.% of lithium has been bombarded with a monoenergetic mass-analyzed 6 keV argon ion beam at target temperatures close to room temperature. The velocity distributions of both constituents have been measured by means of laser induced fluorescence. Mean surface binding energies of 2.2 eV for the Li component and 2.4 eV for the Cu component have been derived from the experimental data, while 3.5 eV are obtained for a pure copper target. A comparison of the energies indicates only a moderate lithium enrichment in the first few atomic surface layers of the alloy under irradiation. Furthermore, mean transport velocities of the sputtered particles have been calculated.     

Synthesis and characterization of 5-(arylazo)thiobarbituric acids and their complexes

Summary S-(Arylazo)thiobarbituric acids and their complexes, derived from cobalt(II), nicke(II) and copper(II) were characterized by elemental analyses and spectral measurements. The¹H n.m.r. and i.r. spectra show the ligands to be in the keto-thione form. The strength of the intramolecular hydrogen-bonding is influenced by the electronic requirements of the aryl ring substituents.     

Saturation of the photon-drag voltage at high CO2 laser intensities

p-Type Ge is investigated as a photon-drag detector for high-power pulsed CO₂ laser, using 3-samples of different dimensions and resistivities. Nonlinear behaviour of the photon-drag effect is observed. This phenomena could be accounted for by taking into consideration the decrease of absorption and the increase of resistivity instantaneously at the moment of interaction, rather than the effect of multireflection. The observed saturation at intensities higher than 30 MW/cm₂ could be due to multireflection since its role increases at high intensities. Using the quantum mechanical model with the above considerations it was possible to obtain good agreement to the measured results.     

Kinetics of ion-exchange on montmorillonite clays

The kinetics for the exchange of Li⁺, K⁺, Rb⁺, and Cs⁺ for Na⁺ as the exchangeable cation on bentonite and montmorillonite K10 and KSF have been studied using conductimetric stoppedflow. Dilute aqueous suspensions of the clays, of particle sizes of a few micrometers, were used, so that diffusion was fast and the rate-determining step was the substitution of one cation by another on the lattice surface. The kinetics were treated in terms of relaxation from equilibrium. Relaxation times ranged from 100 to 250 ms, and forward rate constants from 30 to 500 M^?1 s^?1. The reactions had very low activation enthalpies (7–25 kJ mol^?1) and were only slow enough to be studied by the stopped-flow technique because of the large negative entropies of activation (?120 to ?170 J K^?1 mol^?1). © 1993 John Wiley & Sons, Inc.