ABSTRACT
Regarding the significance of SARS-CoV-2, scientists have shown considerable interest in developing effective drugs. Inhibitors for PLpro are the primary strategies for locating suitable COVID-19 drugs. Natural compounds comprise the majority of COVID-19 drugs. Due to limitations on the safety of clinical trials in cases of COVID, computational methods are typically utilized for inhibition studies. Whereas papain is highly similar to PLpro and is entirely safe, the current study aimed to examine several plant secondary metabolites to identify the most effective papain inhibitor and validate the results using molecular dynamics and docking. This simulation was conducted identically for PLpro and the optimal inhibitor. The results indicated that the experimental results are comparable to those obtained In-Silico, and the inhibition effects of Chlorogenic acid (CGA) on papain attained in the experiment were validated (IC50=0.54 mM). CGA as an inhibitor was located in the active site of PLpro and papain (total energy -2009410 and -456069 kJ/mol, respectively) at the desired location and distance. The study revealed that CGA and its derivatives are effective PLpro inhibitors against SARS-CoV-2.Communicated by Ramaswamy H. Sarma.
ABSTRACT
Doxorubicin is one of the most effective chemotherapeutic agents; however, it has various side effects, such as cardiotoxicity. Therefore, novel methods are needed to reduce its adverse effects. Quercetin is a natural flavonoid with many biological activities. Liposomes are lipid-based carriers widely used in medicine for drug delivery. In this study, liposomal doxorubicin with favorable characteristics was designed and synthesized by the thin-film method, and its physicochemical properties were investigated by different laboratory techniques. Then, the impact of the carrier, empty liposomes, free doxorubicin, liposomal doxorubicin, and quercetin were analyzed in animal models. To evaluate the interventions, measurements of cardiac enzymes, oxidative stress and antioxidant markers, and protein expression were performed, as well as histopathological studies. Additionally, cytotoxicity assay and cellular uptake were carried out on H9c2 cells. The mean size of the designed liposomes was 98.8 nm, and the encapsulation efficiency (EE%) was about 85%. The designed liposomes were anionic and pH-sensitive and had a controlled release pattern with excellent stability. Co-administration of liposomal doxorubicin with free quercetin to rats led to decreased weight loss, creatine kinase (CK-MB), lactate dehydrogenase (LDH), and malondialdehyde (MDA), while it increased the activity of glutathione peroxidase, catalase, and superoxide dismutase enzymes in their left ventricles. Additionally, it changed the expression of NOX1, Rac1, Rac1-GTP, SIRT3, and Bcl-2 proteins, and caused tissue injury and cell cytotoxicity. Our data showed that interventions can increase antioxidant capacity, reduce oxidative stress and apoptosis in heart tissue, and lead to fewer complications. Overall, the use of liposomal doxorubicin alone or the co-administration of free doxorubicin with free quercetin showed promising results.
ABSTRACT
Background: The truncation level of human airways is an influential factor in the analysis of respiratory flow in numerical simulations. Due to computational limitations and limited resolution of diagnostic medical imaging equipment, a truncated geometry of airways is always investigated. Objective: This study aimed to employ image-based geometries with zero generation and 5th-generation truncation levels and assess bronchial airways truncation's effect on tracheal airflow characteristics. Material and Methods: In this numerical study, computational fluid dynamics was employed to solve the respiratory flow in a realistic human airway model using the large eddy simulation technique coupling with the wall-adapting local eddy-viscosity (WALE) sub-grid scale model. The accuracy of numerical simulations was ensured by examining the large eddy simulation index of quality and Kolmogorov's K-5/3 law. Results: The turbulent kinetic energy along the trachea has increased abnormally in the geometry with the zero-generation truncation level, and more severe fluctuations occurred in the velocity field of this geometry, which increased the tendency of each point to rotate. Compared to the extended model, the airflow's more chaotic behavior prevented larger-scale vortices from forming in the geometry with the zero-generation truncation level. Larger-scale vortices in the extended model caused the primary flow passing next to the vortices to accelerate more intensely, increasing the wall shear stress peaks in this geometry. Conclusion: Eliminating the bronchial airways caused changes in tracheal airflow characteristics.
ABSTRACT
The objective of this study is to assess tracheobronchial flow features with the cartilaginous rings during a light exercising. Tracheobronchial is part of human's body airway system that carries oxygen-rich air to human's lungs as well as takes carbon dioxide out of the human's lungs. Consequently, evaluation of the flow structures in tracheobronchial is important to support diagnosis of tracheal disorders. Computational Fluid Dynamics (CFD) allows evaluating effectiveness of tracheal cartilage rings in human body under different configurations. This study utilizes Large Eddy Simulation (LES) to model an anatomically-based human large conducting airway model with and without cartilaginous rings at the breathing conditions at Reynolds number of 5,176 in trachea region. It is observed that small recirculating areas shaped between rings cavities. While these recirculating areas are decaying, similar to periodic 2D-hills, the cartilaginous rings contribute to the construction of a vortical flow structure in the main flow. The separated vortically-shaped zone creates a wake in the flow and passes inside of the next ring cavity and disturb its boundary layer. At last, the small recirculation flow impinges onto tracheal wall. The outcome of this impinge flow is a latitudinal rotating flow perpendicular to the main flow in a cavity between the two cartilaginous rings crest which appear and disappear within a hundredth of a second. Kelvin-Helmholtz instability is observed in trachea caused by shear flow created behind of interaction between these flow structures near to tracheal wavy wall and main flow. A comparison of the results between a smooth wall model named simplified model and a rough wall model named modified model shows that these structures do not exist in simplified model, which is common in modeling tracheobronchial flow. This study proposes to consider macro surface roughness to account for the separating and rotating instantaneous flow structures. Finally, solving trachea airflow with its cartilages can become one of major issues in measuring the validity and capability of solving flow in developing types of sub-grid scale models as a turbulence studies benchmark.
