Molecular Mechanisms Underlying Ca2+/Calmodulin-Dependent Protein Kinase Kinase Signal Transduction

Ca2+/calmodulin-dependent protein kinase kinase (CaMKK) is the activating kinase for multiple downstream kinases, including CaM-kinase I (CaMKI), CaM-kinase IV (CaMKIV), protein kinase B (PKB/Akt), and 5'AMP-kinase (AMPK), through the phosphorylation of their activation-loop Thr residues in response to increasing the intracellular Ca2+ concentration, as CaMKK itself is a Ca2+/CaM-dependent enzyme. The CaMKK-mediated kinase cascade plays important roles in a number of Ca2+-dependent pathways, such as neuronal morphogenesis and plasticity, transcriptional activation, autophagy, and metabolic regulation, as well as in pathophysiological pathways, including cancer progression, metabolic syndrome, and mental disorders. This review focuses on the molecular mechanism underlying CaMKK-mediated signal transduction in normal and pathophysiological conditions. We summarize the current knowledge of the structural, functional, and physiological properties of the regulatory kinase, CaMKK, and the development and application of its pharmacological inhibitors

Synthesis and bioactivities of halogen bearing phenolic chalcones and their corresponding bis Mannich bases.

Phenolic bis Mannich bases having the chemical structure of 1-[3,5-bis-aminomethyl-4-hydroxyphenyl]-3-(4-halogenophenyl)-2-propen-1-ones (1a-c, 2a-c, 3a-c) were synthesized (Numbers 1, 2, and 3 represent fluorine, chlorine, and bromine bearing compounds, respectively, while a, b, and c letters represent the compounds having piperidine, morpholine, and N-methyl piperazine) and their cytotoxic and carbonic anhydrase (CA, EC 4.2.1.1) enzyme inhibitory effects were evaluated. Lead compounds should possess both marked cytotoxic potencies and selective toxicity for tumors. To reflect this potency, PSE values of the compounds were calculated. According to PSE values, the compounds 2b and 3b may serve as lead molecules for further anticancer drug candidate developments. Although the compounds showed a low inhibition potency toward hCA I (25-43%) and hCA II (6-25%) isoforms at 10 μM concentration of inhibitor, the compounds were more selective (1.5-5.2 times) toward hCA I isoenzyme. It seems that the compounds need molecular modifications for the development of better CA inhibitors

Mechanical, antibacterial and bond strength properties of nano-titanium-enriched glass ionomer cement

The use of nanoparticles (NPs) has become a significant area of research in Dentistry. Objective The aim of this study was to investigate the physical, antibacterial activity and bond strength properties of conventional base, core build and restorative of glass ionomer cement (GIC) compared to GIC supplemented with titanium dioxide (TiO2) nanopowder at 3% and 5% (w/w). Material and Methods Vickers microhardness was estimated with diamond indenter. Compressive and flexural strengths were analyzed in a universal testing machine. Specimens were bonded to enamel and dentine, and tested for shear bond strength in a universal testing machine. Specimens were incubated with S. mutans suspension for evaluating antibacterial activity. Surface analysis of restorative conventional and modified GIC was performed with SEM and EDS. The analyses were carried out with Kolmogorov-Smirnov, ANOVA (post-hoc), Tukey test, Kruskal-Wallis, and Mann Whitney. Results Conventional GIC and GIC modified with TiO2 nanopowder for the base/liner cement and core build showed no differences for mechanical, antibacterial, and shear bond properties (p>;0.05). In contrast, the supplementation of TiO2 NPs to restorative GIC significantly improved Vickers microhardness (