The emerging role of miRNAs in epilepsy: From molecular signatures to diagnostic potential.

Epilepsy is a medical condition characterized by intermittent seizures accompanied by changes in consciousness. Epilepsy significantly impairs the daily functioning and overall well-being of affected individuals. Epilepsy is a chronic neurological disorder characterized by recurrent seizures resulting from various dysfunctions in brain activity. The molecular processes underlying changes in neuronal structure, impaired apoptotic responses in neurons, and disruption of regenerative pathways in glial cells in epilepsy remain unknown. MicroRNAs (miRNAs) play a crucial role in regulating apoptosis, autophagy, oxidative stress, neuroinflammation, and the body's regenerative and immune responses. miRNAs have been shown to influence many pathogenic processes in epilepsy including inflammatory responses, neuronal necrosis and apoptosis, dendritic growth, synaptic remodeling, and other processes related to the development of epilepsy. Therefore, the purpose of our current analysis was to determine the role of miRNAs in the etiology and progression of epilepsy. Furthermore, they have been examined for their potential application as biomarkers and therapeutic targets.

Quinazoline Based HSP90 Inhibitors: Synthesis, Modeling Study and ADME Calculations Towards Breast Cancer Targeting.

A new 2-thioquinazolinones series was designed and synthesized as HSP90 inhibitors based on the structure of hit compound VII obtained by virtual screening approach. Their in vitro anti-proliferative activity was evaluated against three human cancer cell lines rich in HSP90 namely; colorectal carcinoma (HCT-116), and cervical carcinoma (Hela), breast carcinoma (MCF-7). Compounds 5a, 5d, 5e and 9h showed a significant broad spectrum anti-proliferative activity against all tested cell lines. They were characterized by potent effect against breast cancer in particular with IC50 of 11.73, 8.56, 7.35 and 9.48 µM, respectively against Doxorubicin (IC50 4.17 µM). HSP90 ATPase activity inhibition assay were conducted where compound 5d exhibited the best IC50 with 1.58 µM compared to Tanespimycin (IC50 = 2.17 µM). Compounds 5a and 9h showed higher IC50 values of 3.21 and 3.41 µM, respectively. The effects of 5a, 5d and 9h on Her2 (a client proteins of HSP90) and HSP70 were evaluated in MCF-7 cells. All tested compounds were found to reduce Her2 protein expression levels and induce Hsp70 protein expression levels significantly, emphasizing that antibreast cancer effect is a consequence of HSP90 chaperone inhibition. Cell cycle analysis of MCF-7 cells treated with 5d showed cell cycle arrest at G2/M phase 38.89% and pro-apoptotic activity as indicated by annexin V-FITC staining by 22.42%. Molecular docking studies suggested mode of interaction to HSP90 via hydrogen bonding. ADME properties prediction of the active compounds suggested that they could be used as orally absorbed anticancer drug candidates.

Synthetic approaches, anticancer potential, HSP90 inhibition, multitarget evaluation, molecular modeling and apoptosis mechanistic study of thioquinazolinone skeleton: Promising antibreast cancer agent.

New series of compounds bearing 2-thioquinazolinone scaffold were designed, synthesized as HSP90 inhibitors. Anti-proliferative activity of the synthesized compounds was evaluated against HCT-116, Hela and MCF-7 cell lines and compound 5k was found to be the most active member of the entire study with IC50 of 4.47, 7.55 and 4.04 µM, respectively, compared to DOX (IC50 of 5.23, 5.57 and 4.17 µM, respectively). Most of the tested compounds revealed lower cytotoxicity against normal fibroblast cells WI-38. Compounds 5b, 5k and 8a showed potent HSP90 inhibitory activities with IC50 values in nanomolar range; 71.32, 25.07 and 56.78 nm, respectively, against Tanespimycin (IC50 of 86.45 nm). Their HSP90 inhibitory activities were confirmed by their down regulation of HSP90 client protein Her2 and up regulation of chaperone HSP70 levels. Compound 5k had shown potent multi-target inhibitory activities against EGFR, VEGFR-2 and Topoisomerase-2 with IC50 values in nanomolar range; 38.5, 126.95 and 25.85 nm, respectively. Compound 5k was further evaluated for cell cycle distribution and apoptosis induction on MCF-7 cells using flow cytometry. Compound 5k arrested the cell cycle on MCF-7 at a G2/M phase by 35.06% and induced apoptosis by 19.82%. Mechanistic evaluation of apoptosis induction was studied by following ways triggering mitochondrial apoptotic pathway through inducing ROS accumulation, increasing Bax/Bcl-2 ratio and activation of caspases 6, 7 and 9. Comparative molecular modeling study was performed between active and inactive HSP90 inhibitors. Docking studies into the active site of HSP90 N-terminal domain showed good agreement with the obtained biological results. ADMET analysis and parameters of Lipinski's rule of five were calculated where compound 5k had reasonable drug-likeness with acceptable physicochemical properties so it could be used as promising orally absorbed antibreast targeted therapy.

Design, synthesis and docking study of novel picolinamide derivatives as anticancer agents and VEGFR-2 inhibitors.

Two series of picolinamide derivatives bearing (thio)urea and dithiocarbamate moieties were designed and synthesized as VEGFR-2 kinase inhibitors. All the new compounds were screened for their cytotoxic activity against A549 cancer cell line and VEGFR-2 inhibitory activity. Compounds 7h, 9a and 9l showed potent inhibitory activity against VEGFR-2 kinase with IC50 values of 87, 27 and 94 nM, respectively in comparison to sorafenib (IC50 = 180 nM) as a reference. Compounds 7h, 9a and 9l were further screened for their antitumor activity against specific resistant human cancer cell lines from different origins (Panc-1, OVCAR-3, HT29 and 786-O cell lines) where compound 7h showed significant cell death in most of them. Multi-kinase inhibition assays were performed for the most potent VEGFR-2 inhibitors where compound 7h showed enhanced potency towards EGFR, HER-2, c-MET and MER kinases. Cell cycle analysis of A549 cells treated with 9a showed cell cycle arrest at G2/M phase and pro-apoptotic activity as indicated by annexin V-FITC staining.

Design and synthesis of 2-phenyl benzimidazole derivatives as VEGFR-2 inhibitors with anti-breast cancer activity.

Three new series of 2-phenyl benzimidazole-based derivatives were designed, synthesized, and evaluated for their in vitro cytotoxic activity against breast cancer (MCF-7) cell lines. Three compounds 8, 9, and 15 showed high cytotoxic activities, with IC50 values of 3.37, 6.30, and 5.84 µM, respectively, while they showed comparable cytotoxicity to the standard drug doxorubicin against human normal cells, including nontumorigenic breast epithelial cell line (MCF-10F), skin fibroblast cell line (BJ), and lung fibroblast cell line (MRC-5). Six of the synthesized compounds were screened against vascular endothelial growth factor receptor 2 (VEGFR-2) where compounds 8, 9, 12, and 15 exhibited an outstanding potency in comparison with sorafenib, with IC50 values of 6.7-8.9 nM. Molecular docking study assessed the good binding patterns of the most potent compounds with the reported conserved amino acids of VEGFR-2 active site.