Outlining In Vitro and In Silico Cholinesterase Inhibitory Activity of Twenty-Four Natural Products of Various Chemical Classes: Smilagenin,Kokusaginine, and Methyl Rosmarinate as Emboldening Inhibitors

Cholinesterase (ChE) inhibition is an important treatment strategy for Alzheimer’s disease (AD) as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are involved in the pathology of AD. In the current work, ChE inhibitory potential of twenty-four natural products from different chemical classes (i.e., diosgenin, hecogenin, rockogenin, smilagenin, tigogenin, astrasieversianins II and X, astragalosides I, IV, and VI, cyclocanthosides E and G, macrophyllosaponins A-D, kokusaginin, lamiide, forsythoside B, verbascoside, alyssonoside, ipolamide, methyl rosmarinate, and luteolin-7-O-glucuronide) was examined using ELISA microtiter assay. Among them, only smilagenin and kokusaginine displayed inhibitory action against AChE (IC₅₀ = 43.29 ± 1.38 and 70.24 ± 2.87 µg/mL, respectively). BChE was inhibited by only methyl rosmarinate and kokusaginine (IC₅₀ = 41.46 ± 2.83 and 61.40 ± 3.67 µg/mL, respectively). IC₅₀ values for galantamine as the reference drug were 1.33 ± 0.11 µg/mL for AChE and 52.31 ± 3.04 µg/mL for BChE. Molecular docking experiments showed that the orientation of smilagenin and kokusaginine was mainly driven by the interactions with the peripheral anionic site (PAS) comprising residues of hAChE, while kokusaginine and methyl rosmarinate were able to access deeper into the active gorge in hBChE. Our data indicate that similagenin, kokusaginine, and methyl rosmarinate could be hit compounds for designing novel anti-Alzheimer agents.     

Cycloartocarpin Inhibits Migration through the Suppression of Epithelial-to-Mesenchymal Transition and FAK/AKT Signaling in Non-Small-Cell Lung Cancer Cells

Lung cancer metastasis is a multifaceted process that accounts for 90% of cancer deaths. According to several studies, the epithelial–mesenchymal transition (EMT) plays an essential role in lung cancer metastasis. Therefore, this study aimed to investigate the potential pharmacological effect of cycloartocarpin on the suppression of metastasis-related behaviors and EMT. An MTT assay was used to examine cell viability. Cell migration was determined using a wound healing assay. Anchorage-independent cell growth was also performed. Western blot analysis was used to identify the key signaling proteins involved in the regulation of EMT and migration. The results found that non-toxic concentrations of cycloartocarpin (10–20 μM) effectively suppressed cell migration and attenuated anchorage-independent growth in H292, A549, and H460 cells. Interestingly, these effects were consistent with the findings of Western blot analysis, which revealed that the level of phosphorylated focal adhesion kinase (p-FAK), phosphorylated ATP-dependent tyrosine kinase (p-AKT), and cell division cycle 42 (Cdc42) were significantly reduced, resulting in the inhibition of the EMT process, as evidenced by decreased N-cadherin, vimentin, and slug expression. Taken together, the results suggest that cycloartocarpin inhibits EMT by suppressing the FAK/AKT signaling pathway, which is involved in Cdc42 attenuation. Our findings demonstrated that cycloartocarpin has antimetastatic potential for further research and development in lung cancer therapy.     

Interactions of Apigenin and Safranal with the 5HT1A and 5HT2A Receptors and Behavioral Effects in Depression and Anxiety: A Molecular Docking,Lipid-Mediated Molecular Dynamics,and In Vivo Analysis

Background: The current study utilizes in silico molecular docking/molecular dynamics to evaluate the binding affinity of apigenin and safranal with 5HT1AR/5HT2AR, followed by assessment of in vivo effects of these compounds on depressive and anxious behavior. Methods: The docking between apigenin and safranal and the 5HT1A and 5HT2A receptors was performed utilizing AutoDock Vina software, while MD and protein-lipid molecular dynamics simulations were executed by AMBER16 software. For in vivo analysis, healthy control (HC), disease control (DC), fluoxetine-, and apigenin-safranal-treated rats were tested for changes in depression and anxiety using the forced swim test (FST) and the elevated plus-maze test (EPMT), respectively. Results: The binding affinity estimations identified the superior interacting capacity of apigenin over safranal for 5HT1A/5HT2A receptors over 200 ns MD simulations. Both compounds exhibit oral bioavailability and absorbance. In the rodent model, there was a significant increase in the overall mobility time in the FST, while in the EPMT, there was a decrease in latency and an increase in the number of entries for the treated and HC rats compared with the DC rats, suggesting a reduction in depressive/anxiety symptoms after treatment. Conclusions: Our analyses suggest apigenin and safranal as prospective medication options to treat depression and anxiety.