Depolymerization of actin filaments by Cucurbitacin I through binding G-actin.

Cucurbitacins have high economic value as they are a major source of food and have pharmacological properties. Cucurbitacin I (CuI) is a plant-derived natural tetracyclic triterpenoid compound that shows an anticancer effect via inhibiting the JAK2-STAT3 signaling pathway. The actin cytoskeleton is the most abundant protein in cells and regulates critical events through reorganization in cells. In this study, it is aimed at determining the direct effect of CuI on actin dynamics. The fluorescence profile of G-actin in the presence of CuI (1-200 nM) shifted to a higher temperature, suggesting that G-actin binds CuI and that G-actin-CuI is more thermally stable than the ligand-free form. CuI dose-dependently inhibited the polymerization of F-actin in vitro and disrupted actin filaments in endothelial cells. Docking and MD simulations suggested that CuI binds to the binding site formed by residues I136, I175, D154, and A138 that are at the interface of monomers in F-actin. The migration ability of cells treated with CuI for 24 h was significantly lower than the control group (p < .001). This study reveals the molecular mechanisms of CuI in the regulation of actin dynamics by binding G-actin. More importantly, this study indicates a novel role of CuI as an actin-targeting drug by binding directly to G-actin and may contribute to the mode of action of CuI on anticancer activities.

The Inflammatory and Cytological Effect of Repeated Povidone-Iodine Application in Patients Receiving Intravitreal Injections.

OBJECTIVE: To investigate the effect of repeated povidone-iodine (PVI) application on the ocular surface parameters of patients who received intravitreal injections. MATERIALS AND METHODS: In this prospective study, 52 eyes of 52 patients with age-related macular degeneration who underwent unilateral intravitreal injection at least three times in the last 1 year (intravitreal injection [IVI] group), 52 fellow eyes with no previous intravitreal injection (NIVI group), and 51 eyes of 51 healthy subjects (control) were included. Tear break-up time (TBUT), the Schirmer test, the Oxford staining score, the Ocular Surface Disease Index questionnaire, conjunctival impression cytology, and tear inflammatory cytokine levels (interleukin [IL]-1ß and IL-6) were analyzed in all participants. RESULTS: The IVI group had lower TBUT and higher Oxford staining score than the NIVI and control groups ( P <0.05). No significant difference was found between the groups in the Schirmer test ( P =0.161). Conjunctival impression cytology analysis revealed that the IVI group had a significantly lower goblet cell count and significantly higher Nelson staging result than the NIVI and control groups ( P <0.05). As a result of tear cytokine analysis, although IVI and NIVI groups had higher IL-1ß and IL-6 levels than the control group ( P <0.05), there was no difference between NIVI and IVI groups ( P ≥0.05). CONCLUSIONS: Repeated PVI application caused cytotoxic injury to the ocular surface, resulting in goblet cell loss and squamous metaplasia of epithelial cells. As a result, the stability of the tear film layer was found to be impaired and ocular surface-related symptoms developed in patients.

Novel quinazoline-chromene hybrids as anticancer agents: Synthesis, biological activity, molecular docking, dynamics and ADME studies.

In this study, new quinazoline-chromene hybrid compounds were synthesized. The cytotoxic effects on cell viability of the hybrid compounds were tested against A549 human lung adenocarcinoma and BEAS-2B healthy bronchial epithelial cell lines in vitro. In addition, the ability of the active compounds to inhibit cell migration was tested. Molecular docking studies were performed to evaluate the ligand-protein interactions, and molecular dynamics simulations were performed to determine the interactions and stability of ligand-protein complexes. In silico absorption, distribution, metabolism, and excretion (ADME) studies were conducted to estimate the drug-likeness of the compounds. Compounds 4 (IC50 = 51.2 µM) and 5 (IC50 = 44.2 µM) were found to be the most active agents against A549 cells. They are found to be more selective against A549 cells than the reference drug doxorubicin. They also have the ability to significantly inhibit cell migration. They have the best docking scores against epidermal growth factor receptor (EGFR) (-11.300 and -11.226 kcal/mol) and vascular endothelial growth factor receptor 2 (VEGFR2) (-10.987 and -11.247 kcal/mol), respectively. In MD simulations, compounds 4 and 5 have strong hydrogen bond interactions above 80% of simulation times and showed a low ligand root mean square deviation (RMSD) around 2 Å. According to the ADME analysis, compounds 4 and 5 exhibit excellent drug-likeness and pharmacokinetic characteristics.