BACKGROUND: Patients with non-small cell lung cancer (NSCLC) are susceptible to coronavirus disease-2019 (COVID-19), but current treatments are limited. Icariside II (IS), a flavonoid compound derived from the plant epimedin, showed anti-cancer,anti-inflammation and immunoregulation effects. The present study aimed to evaluate the possible effect and underlying mechanisms of IS on NSCLC patients with COVID-19 (NSCLC/COVID-19).
METHODS: NSCLC/COVID-19 targets were defined as the common targets of NSCLC (collected from The Cancer Genome Atlas database) and COVID-19 targets (collected from disease database of Genecards, OMIM, and NCBI). The correlations of NSCLC/COVID-19 targets and survival rates in patients with NSCLC were analyzed using the survival R package. Prognostic analyses were performed using univariate and multivariate Cox proportional hazards regression models. Furthermore, the targets in IS treatment of NSCLC/COVID-19 were defined as the overlapping targets of IS (predicted from drug database of TMSCP, HERBs, SwissTarget Prediction) and NSCLC/COVID-19 targets. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis of these treatment targets were performed aiming to understand the biological process, cellular component, molecular function and signaling pathway. The hub targets were analyzed by a protein-protein interaction network and the binding capacity with IS was characterized by molecular docking.
RESULTS: The hub targets for IS in the treatment of NSCLC/COVID-19 includes F2, SELE, MMP1, MMP2, AGTR1 and AGTR2, and the molecular docking results showed that the above target proteins had a good binding degree to IS. Network pharmacology showed that IS might affect the leucocytes migration, inflammation response and active oxygen species metabolic process, as well as regulate the interleukin-17, tumor necrosus factor and hypoxia-inducible factor-1 signaling pathway in NSCLC/COVID-19.
CONCLUSIONS: IS may enhance the therapeutic efficacy of current clinical anti-inflammatory and anti-cancer therapy to benefit patients with NSCLC combined with COVID-19.

Through molecular recognition, drugs can interact and complex with macromolecules circulating in the body. The serum albumin transport protein, found in several mammals, has several interaction sites where these molecules can be located. The drug sulfasalazine (SSZ) is known in the literature to complex at drug site 1 (DS1) in human serum (HSA) and bovine serum (BSA) proteins. This complexation can be studied using various spectroscopic techniques. With the techniques used in this work, absorption in the ultraviolet and visible regions (UV-Vis) and electronic circular dichroism (ECD), a significant difference was observed in the results involving HSA and BSA. The application of theoretical methodologies, such as TD-DFT and molecular docking, suggests that the conformation that SSZ assumes in DS1 of the two proteins is different, which exposes it to different amino acid residues and different hydrophobicities. This difference in conformation may be related to the location of DS1 where the drug interacts or to the possibility of SSZ moving in the BSA site, due to its larger size, and moving less freely in HSA.

The elucidation of the interaction mechanism between phospholipids and milk proteins within emulsions is pivotal for comprehending the properties of infant formula fat globules. In this study, multispectral methods and molecular docking were employed to explore the relationship between phosphatidylcholine (PC) and whey protein isolate (WPI). Observations indicate that the binding constant, alongside thermodynamic parameters, diminishes as temperature ascends, hinting at a predominantly static quenching mechanism. Predominantly, van der Waals forces and hydrogen bonds constitute the core interactions between WPI and PC. This assertion is further substantiated by Fourier transform infrared spectroscopy, which verifies PC\'s influence on WPI\'s secondary structure. A detailed assessment of thermodynamic parameters coupled with molecular docking reveals that PC predominantly adheres to specific sites within α-lactalbumin, β-lactoglobulin, and bovine serum albumin, propelled by a synergy of hydrophobic interactions, hydrogen bonding, and van der Waals forces, with binding energies noted at -5.59, -6.71, and -7.85 kcal/mol, respectively. An increment in PC concentration is observed to amplify the emulsification properties of WPI whilst concurrently diminishing the zeta potential. This study establishes a theoretical foundation for applying the PC-WPI interaction mechanism in food.

This study explores the impact of juglone on cucumber (Cucumis sativus cv. Beith Alpha), scrutinizing its effects on seed germination, growth, and the polyphenol oxidase (PPO) enzyme\'s activity and gene expression. Employing concentrations ranging from 0.01 to 0.5 mM, we found juglone\'s effects to be concentration-dependent. At lower concentrations (0.01 and 0.1 mM), juglone promoted root and shoot growth along with germination, whereas higher concentrations (0.25 and 0.5 mM) exerted inhibitory effects, delineating a threshold for its allelopathic influence. Notably, PPO activity surged, especially at 0.5 mM in roots, hinting at oxidative stress involvement. Real-time PCR unveiled that juglone modulates PPO gene expression in cotyledons, peaking at 0.1 mM and diminishing at elevated levels. Correlation analyses elucidated a positive link between juglone-induced root growth and cotyledon PPO gene expression but a negative correlation with heightened root enzyme activity. Additionally, germination percentage inversely correlated with root PPO activity, while PPO activities positively associated with dopa and catechol substrates in both roots and cotyledons. Molecular docking studies revealed juglone\'s selective interactions with PPO\'s B chain, suggesting regulatory impacts. Protein interaction assessments highlighted juglone\'s influence on amino acid metabolism, and molecular dynamics indicated juglone\'s stronger, more stable binding to PPO, inferring potential alterations in enzyme function and stability. Conclusively, our findings elucidate juglone\'s dose-dependent physiological and biochemical shifts in cucumber plants, offering insights into its role in plant growth, stress response, and metabolic modulation.

Drying is an important stage used to improve the quality of white tea (WT). However, the effect of the drying temperature on the key taste compounds in WT remains unclear. In this study, targeted metabolomics, molecular docking, and a simulated reaction were used to investigate the transformation mechanism of flavonoid glycosides (FGs) in WT during drying at 60, 80, and 100 °C and its impact on taste. There were 45 differential FGs in WT at three drying temperatures. Compared with the withering samples for 48 h, the total FGs contents at three drying temperatures showed a decreasing trend, with quercetin-3-O-galactoside and kaempferol-3-O-glucoside showing the most degradation. These results were confirmed via a simulated drying reaction of FGs standards. Drying at 80 and 100 °C contributed to the formation of flavonoid-C-glycosides, but only trace amounts of these compounds were observed. In addition, nine key taste FGs were selected using dose-over-threshold values. These FGs regulated the taste of WT, mainly by binding to taste receptors via hydrogen bond, hydrophobic and electrostatic interactions. Finally, the taste acceptability of WT dried at 60 °C was found to be the highest, as this method could properly reduce the contents of FGs, weaken the bitterness and astringency, and retain the sweet and umami taste. This study revealed for the first time the transformation mechanism of sensory-active FGs affected by drying temperature, which provides a novel perspective for the analysis of the formation mechanism of the unique flavor of WT and the optimization of this process.

BACKGROUND: Existing researches confirmed that β amyloid (Aβ) has a high affinity for the α7 nicotinic acetylcholine receptor (α7nAChR), associating closely to Alzheimer\'s disease. The majority of related studies focused on the experimental reports on the neuroprotective role of Aβ fragment (Aβx), however, with a lack of investigation into the most suitable binding region and mechanism of action between Aβ fragment and α7nAChR. In the study, we employed four Aβ1-42 fragments Aβx, Aβ1-16, Aβ10-16, Aβ12-28, and Aβ30-42, of which the first three were confirmed to play neuroprotective roles upon directly binding, to interact with α7nAChR.
METHODS: The protein-ligand docking server of CABS-DOCK was employed to obtain the α7nAChR-Aβx complexes. Only the top α7nAChR-Aβx complexes were used to perform all-atom GROMACS dynamics simulation in combination with Charmm36 force field, by which α7nAChR-Aβx interactions\' dynamic behavior and specific locations of these different Aβx fragments were identified. MM-PBSA calculations were also done to estimate the binding free energies and the different contributions from the residues in the Aβx. Two distinct results for the first three and fourth Aβx fragments in binding site, strength, key residue, and orientation, account for why the fourth fails to play a neuroprotective role at the molecular level.

Inhibitors of monoamine oxidases (MAOs) are of interest for the treatment of neurodegenerative disorders and other human pathologies. In this frame, the present work describes different synthetic strategies to obtain MAO inhibitors via the coupling of the aminocoumarin core with arylsulfonyl chlorides followed by copper azide-alkyne cycloaddition, leading to coumarin-sulfonamide-nitroindazolyl-triazole hybrids. The nitration position on the coumarin moiety was confirmed through nuclear magnetic resonance spectroscopy and molecular electron density theory in order to elucidate the molecular mechanism and selectivity of the electrophilic aromatic substitution reaction. The coumarin derivatives were evaluated for their inhibitory potency against monoamine oxidases and cholinesterases. Molecular docking calculations provided a rational binding mode of the best compounds in the series with MAO A and B. The work identified hybrids 14a-c as novel MAO inhibitors, with a selective action against isoform B, of potential interest to combat neurological diseases.

Gyrophoric acid (GA), a lichen secondary metabolite, has attracted more attention during the last years because of its potential biological effects. Until now, its effect in vivo has not yet been demonstrated. The aim of our study was to evaluate the basic physicochemical and pharmacokinetic properties of GA, which are directly associated with its biological activities. The stability of the GA in various pH was assessed by conducting repeated UV-VIS spectral measurements. Microsomal stability in rat liver microsomes was performed using Ultra-Performance LC/MS. Binding to human serum albumin (HSA) was assessed using synchronous fluorescence spectra, and molecular docking analysis was used to reveal the binding site of GA to HSA. In the in vivo experiment, 24 Sprague-Dawley rats (Velaz, Únetice, Czech Republic) were used. The animals were divided as follows. The first group (n = 6) included healthy males as control intact rats (♂INT), and the second group (n = 6) included healthy females as controls (♀INT). Groups three and four (♂GA/n = 6 and ♀GA/n = 6) consisted of animals with daily administered GA (10 mg/kg body weight) in an ethanol-water solution per os for a one-month period. We found that GA remained stable under various pH and temperature conditions. It bonded to human serum albumin with the binding constant 1.788 × 106 dm3mol-1 to reach the target tissue via this mechanism. In vivo, GA did not influence body mass gain, food, or fluid intake during the experiment. No liver toxicity was observed. However, GA increased the rearing frequency in behavioral tests (p < 0.01) and center crossings in the elevated plus-maze (p < 0.01 and p < 0.001, respectively). In addition, the time spent in the open arm was prolonged (p < 0.01 and p < 0.001, respectively). Notably, GA was able to pass through the blood-brain barrier, indicating its ability to permeate into the brain and to stimulate neurogenesis in the hilus and subgranular zone of the hippocampus. These observations highlight the potential role of GA in influencing brain function and neurogenesis.

UNASSIGNED: Vector-borne infectious diseases contribute significantly to global mortality, with over 700,000 annual deaths, and malaria alone accounts for more than 400,000 of these fatalities. Anopheles gambiae, a prominent mosquito species, serves as a primary vector for transmitting malaria to humans. To address this issue, researchers have identified the D1-like dopamine receptor (DAR), specifically DOP2, as a promising target for developing new insecticides.
METHODS: The three-dimensional structure of DOP2 from A. gambiae was unavailable; in-silico approach was used to model and validate DOP2 structure. The Discovery Studio 2021 program was used to identify potential binding sites on DOP2. Virtual screening of 235 anti-parasitic compounds was performed against DOP2 using PyRx 0.8.
RESULTS: The screening demonstrated strong binding and interactions with active site residues of DOP2 for five compounds: Diclazuril, Kaempferol, Deracoxib, Clindamycin, and Diaveridine. These compounds exhibited higher binding affinity values compared to the control (Asenapine). In addition, the predicted physiochemical properties for these compounds were within acceptable ranges and there were no violations in drug-likeness properties.
UNASSIGNED: These compounds show promise as potential new insecticides targeting A. gambiae mosquito by inhibiting the DOP2 protein. However, additional experimental validation is required to optimize their efficacy as DOP2 inhibitors.

FOXM1, a proto-oncogenic transcription factor, plays a critical role in cancer development and treatment resistance in cancers, particularly in breast cancer. Thus, this study aimed to identify potential FOXM1 inhibitors through computational screening of drug databases, followed by in vitro validation of their inhibitory activity against breast cancer cells. In silico studies involved pharmacophore modeling using the FOXM1 inhibitor, FDI-6, followed by virtual screening of DrugBank and Selleckchem databases. The selected drugs were prepared for molecular docking, and the crystal structure of FOXM1 was pre-processed for docking simulations. In vitro studies included MTT assays to assess cytotoxicity, and Western blot analysis to evaluate protein expression levels. Our study identified Pantoprazole and Rabeprazole as potential FOXM1 inhibitors through in silico screening and molecular docking. Molecular dynamics simulations confirmed stable interactions of these drugs with FOXM1. In vitro experiments showed both Pantoprazole and Rabeprazole exhibited strong FOXM1 inhibition at effective concentrations and that showed inhibition of cell proliferation. Rabeprazole showed the inhibitor activity at 10 µM in BT-20 and MCF-7 cell lines. Pantoprazole exhibited FOXM1 inhibition at 30 µM and in BT-20 cells and at 70 µM in MCF-7 cells, respectively. Our current study provides the first evidence that Rabeprazole and Pantoprazole can bind to FOXM1 and inhibit its activity and downstream signaling, including eEF2K and pEF2, in breast cancer cells. These findings indicate that rabeprazole and pantoprazole inhibit FOXM1 and breast cancer cell proliferation, and they can be used for FOXM1-targeted therapy in breast or other cancers driven by FOXM1.