Discovery and validation of Ferroptosis-related molecular patterns and immune characteristics in Alzheimer's disease.

Background: To date, the pathogenesis of Alzheimer's disease is still not fully elucidated. Much evidence suggests that Ferroptosis plays a crucial role in the pathogenesis of AD, but little is known about its molecular immunological mechanisms. Therefore, this study aims to comprehensively analyse and explore the molecular mechanisms and immunological features of Ferroptosis-related genes in the pathogenesis of AD. Materials and methods: We obtained the brain tissue dataset for AD from the GEO database and downloaded the Ferroptosis-related gene set from FerrDb for analysis. The most relevant Hub genes for AD were obtained using two machine learning algorithms (Least absolute shrinkage and selection operator (LASSO) and multiple support vector machine recursive feature elimination (mSVM-RFE)). The study of the Hub gene was divided into two parts. In the first part, AD patients were genotyped by unsupervised cluster analysis, and the different clusters' immune characteristics were analysed. A PCA approach was used to quantify the FRGscore. In the second part: we elucidate the biological functions involved in the Hub genes and their role in the immune microenvironment by integrating algorithms (GSEA, GSVA and CIBERSORT). Analysis of Hub gene-based drug regulatory networks and mRNA-miRNA-lncRNA regulatory networks using Cytoscape. Hub genes were further analysed using logistic regression models. Results: Based on two machine learning algorithms, we obtained a total of 10 Hub genes. Unsupervised clustering successfully identified two different clusters, and immune infiltration analysis showed a significantly higher degree of immune infiltration in type A than in type B, indicating that type A may be at the peak of AD neuroinflammation. Secondly, a Hub gene-based Gene-Drug regulatory network and a ceRNA regulatory network were successfully constructed. Finally, a logistic regression algorithm-based AD diagnosis model and Nomogram diagram were developed. Conclusion: Our study provides new insights into the role of Ferroptosis-related molecular patterns and immune mechanisms in AD, as well as providing a theoretical basis for the addition of diagnostic markers for AD.

Electron-Transfer-Enhanced Cation-Cation Interactions in Homo- and Heterobimetallic Actinide Complexes: A Relativistic Density Functional Theory Study.

To provide deep insight into cation-cation interactions (CCIs) involving hexavalent actinyl species that are major components in spent nuclear fuel and pose important implications for the effective removal of radiotoxic pollutants in the environment, a series of homo- and heterobimetallic actinide complexes supported by cyclopentadienyl (Cp) and polypyrrolic macrocycle (H4L) ligands were systematically investigated using relativistic density functional theory. The metal sort in both parts of (THF)(H2L)(OAnVIO) and (An')IIICp3 from U to Np to Pu, as well as the substituent bonding to Cp from electron-donating Me to H to electron-withdrawing Cl, SiH3, and SiMe3, was changed. Over 0.70 electrons are unraveled to transfer from the electron-rich UIII to the electron-deficient AnVI of the actinyl moiety, leading to a more stable AnV-UIV isomer; in contrast, uranylneptunium and uranylplutonium complexes behave as electron-resonance structures between VI-III and V-IV. These were further corroborated by geometrical and electronic structures. The energies of CCIs (i.e., Oexo-An' bonds) were calculated to be -19.6 to -41.2 kcal/mol, affording those of OUO-Np (-23.9 kcal/mol) and OUO-Pu (-19.6 kcal/mol) with less electron transfer (ET) right at the low limit. Topological analyses of the electron density at the Oexo-An' bond critical points demonstrate that the CCIs are ET or dative bonds in nature. A positive correlation has been built between the CCIs' strength and corresponding ET amount. It is concluded that the CCIs of Oexo-An' are driven by the electrostatic attraction between the actinyl oxo atom (negative) and the actinide ion (positive) and enhanced by their ET. Finally, experimental syntheses of (THF)(H2L)(OUVIO)(An')IIICp3 (An' = U and Np) were well reproduced by thermodynamic calculations that yielded negative free energies in a tetrahydrofuran solution but a positive one for their uranylplutonium analogue, which was synthetically inaccessible. So, our thermodynamics would provide implications for the synthetic possibility of other theoretically designed bimetallic actinide complexes.

Astemizole protects against human umbilical vein endothelial cell injury induced by hydrogen peroxide via the p53 signaling pathway.

Astemizole has gained attention as an antineoplastic drug that targets important ion channels. The present study aimed to investigate the protective effects of astemizole against hydrogen peroxide (H2O2)­induced oxidative damage to human umbilical vein endothelial cells (HUVECs). HUVECs were pretreated with astemizole (0.5 and 1 µM) for 12 h, then exposed to H2O2 (200 µM) for 12 h. Cell viability was measured using the MTT assay. The levels of malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH­Px), reactive oxygen species (ROS) and apoptotic percentage were determined. Additionally, the protein expression of p53, p21Cip1/Waf1 and p16INK4a was measured by western blot analysis The results demonstrated that astemizole (0.5­1 µM) was able to significantly restore the viability of HUVECs under oxidative stress and scavenge intracellular ROS induced by H2O2. Astemizole also suppressed the production of lipid peroxides, such as MDA, and restored the activities of endogenous antioxidants, including SOD and GSH­Px, indicating that cell apoptosis may be inhibited. In addition, astemizole significantly increased p53, p21Cip1/Waf1 and p16INK4a protein expression. In conclusion, astemizole effectively protected endothelial cells against oxidative stress induced by H2O2, a function that may involve ROS/p53/p21Cip1/Waf1/ p16INK4a signaling pathways. The present study therefore served as a preliminary investigation into the ROS­protective effects of astemizole, and may pave the way for future studies into the development of this compound as a novel therapy for atherosclerosis.

Na7CrCuW11O39.16H2O induces apoptosis in human ovarian cancer SKOV3 cells through the p38 signaling pathway.

Ovarian carcinoma is a common malignant disease worldwide with a poor therapeutic response. The present study investigated the effects of Na7CrCuW11O39.16H2O (CrCuW11) on ovarian cancer cell growth and investigated the mechanisms underlying its actions. The effects of CrCuW11 on cell viability and apoptosis were measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay, acridine orange/ethidium bromide staining and electron microscopy in human ovarian cancer SKOV3 cells. The expression of bcl-2-like protein 4 (Bax), B-cell lymphoma 2 (Bcl-2), cytochrome c, phosphorylated (p)-p38 and p38 was determined by western blot analysis. Caspase-3 activity was measured by caspase-3 activity kit. CrCuW11 concentrations of 1.87×10-3 mol. l-1 at 12 h reduced viability induced apoptosis in SKOV3 cells in a concentration-and time-dependent manner. Forced expression of CrCuW11 upregulated the expression of certain proteins (Bax, cytochrome c, and p-p38), and downregulated Bcl-2 protein expression. Furthermore, CrCuW11 also enhanced caspase-3 activity. The p38 inhibitor SB203580 was able to inhibit the activity of CrCuW11. Caspase-3 and p38 signaling pathways were associated with CrCuW11-regulated multiple targets involved in SKOV3 cell proliferation. Therefore, the results of the present study indicated that CrCuW11 may be used as a novel clinical drug for the treatment of ovarian cancer.