In vitro biological activity of Salvia fruticosa Mill. infusion against amyloid ß-peptide-induced toxicity and inhibition of GSK-3ß, CK-1δ, and BACE-1 enzymes relevant to Alzheimer's disease.

Salvia species have been traditionally used to improve cognition and have been proved to be a potential natural treatment for Alzheimer's disease. Salvia fruticosa Mill. (Turkish sage or Greek sage) demonstrated to have anticholinergic effects in vitro. The aim of this study was to understand the mechanism underlying the neuroprotective effects of S. fruticosa infusion and its representative compound rosmarinic acid, which was detected by LC-DAD-ESI-MS/MS. The protective effects of the S. fruticosa infusion (SFINF) and its major substance rosmarinic acid (RA) on amyloid beta 1-42 -induced cytotoxicity on SH-SY5Y cells together with p-GSK-3ß activation were investigated. Their in vitro inhibitory effects against glycogen synthase kinase 3ß, ß-secretase, and casein kinase 1δ enzymes were also evaluated. The results showed that treatment with the all tested concentrations, SFINF significantly decreased Aß 1-42-induced cytotoxicity and exhibited promising in vitro glycogen synthase kinase 3ß inhibitory activity below 10 µg/mL (IC50 6.52 ± 1.14 µg/mL), in addition to ß-secretase inhibition (IC50 86 ± 2.9 µg/mL) and casein kinase 1δ inhibition (IC50 121.57 ± 4.00). The SFINF (100 µg/mL and 250 µg/mL) also activated the expression of p-GSK-3ß in amyloid beta 1-42 treated SH-SY5Y cells. The outcomes of this study demonstrated that the S. fruticosa infusion possessed activity to prevent amyloid beta 1-42 -induced neurotoxicity and provided proof that its mechanism may involve regulation of p-GSK-3ß protein.

Famotidine has a neuroprotective effect on MK-801 induced toxicity via the Akt/GSK-3ß/ß-catenin signaling pathway in the SH-SY5Y cell line.

Schizophrenia cannot be treated sufficiently with existing antipsychotic drugs. Taken into account that increased Glycogen Synthase Kinase 3 Beta (GSK-3ß) activity is associated with schizophrenia pathophysiology and certain antipsychotics can be able to decrease GSK3ß activity, inhibition of GSK-3ß activity could be a novel approach for the treatment of schizophrenia. In the present study MK-801, a widely used chemical for the in vivo/in vitro modeling of schizophrenia was selected to evoke a detrimental effect on cellular survival via GSK3ß and related proteins. A limited number of studies have reported the curative effects of famotidine, an antiulcer drug, in schizophrenic patients. To the best of our knowledge, no study investigated the molecular mechanism of the beneficial effect of famotidine in the patients. A recent study based on computerized drug modeling software (docking) indicated that famotidine might inhibit the GSK3ß activity due to its chemical structure independent from histaminergic receptors. In this study, we aimed to investigate the effects of famotidine on the Akt/GSK-3ß/ß-catenin signaling pathway on SH-SY5Y neuroblastoma cells in the presence of MK-801. We investigated the effects of famotidine, olanzapine (an antipsychotic drug), and SB 415286 (specific GSK-3ß inhibitor), on the basal cellular survival and MK-801 induced neuronal death beside of Akt/GSK-3ß/ß-catenin protein and gene expressions in SH-SY5Y cells. Cell viability, protein and gene expressions were determined by the real-time cell analysis (xCELLigence) system, western blotting and real-time polymerase chain reactions (Rt-PCR), respectively. Our findings suggested that MK-801 administration decreased cell survival probably via the increasing GSK-3ß gene expression and activity in the SH-SY5Y cells. Pre-treatments with famotidine, olanzapine, and SB 415286 prevented MK-801 induced cell death via inhibitory effects on the MK-801 induced GSK-3ß activity. Overall, the present results suggest that famotidine has a neuroprotective effect against MK-801 via modulation of the Akt/GSK-3ß/ß-catenin signaling pathway, an important mechanism in schizophrenia neurobiology.

Vildagliptine protects SH-SY5Y human neuron-like cells from Aß 1-42 induced toxicity, in vitro.

The amyloid ß (Aß) toxic fibrils is thought to play a central role in the onset and progression of Alzheimer's disease (AD) because of it is a main formation of senile plaques. Diabetic patients are more vulnerable to caught Alzheimer's disease. Vildagliptine, a novel anti diabetic agent, has been reported to exert protective effects on AD rat models in restricted study. We aimed to investigate any protective effects of vildagliptine against Aß fibrils on SH-SY5Y cell line. Vildagliptine decreased PSEN1 and PSEN2 mRNA levels which enroll Aß production. In addition, vildagliptin was downregulated caspase-3 and caspase-9 expression levels which were evoked by Aß. Also we confirmed cellular viability with real time cell analyzer and MTT assay. Our data exposed that vildagliptine has lowering effect on GSK3ß and Tau phosphorylation. However we did not get protective effect of vildagliptine against Aß toxicity on mitochondrial membrane potential. These results indicate that vildagliptine exerts a protective effect against Aß by decreasing apoptosis related proteins, lowering GSK3ß and Tau phosphorylation levels in addition to expression of PSEN1 and PSEN2 mRNA downregulation effect.

Real-time Analysis of Impedance Alterations by the Effects of Vanadium Pentoxide on Several Carcinoma Cell Lines.

OBJECTIVES: Vanadium compounds have various pharmacologic effects and all available evidence reveals that the effects of vanadium compounds depend on many factors, mainly on the type of cells and dose. The proapoptotic or antiapoptotic effect of vanadium compounds depends strongly on the cell type. MATERIALS AND METHODS: In this study, the effects of vanadium pentoxide (V2O5) were investigated using several tumor cell lines: a colorectal cancer cell line (Colo-205), a human breast adenocarcinoma cell line (MCF-7), and a normal human fibroblast cell line. Five different concentrations of V2O5 between 25-200 µM were applied on the cells and xCELLigence real-time cell analysis was conducted to evaluate the impedance alterations. This study is the first to show V2O5's effects on Colo-205 and MCF-7 and human fibroblast cell lines in a real-time manner. RESULTS: In the Colo-205 cell line, cell index (CI) alterations decreased slightly at 25 µM and 50 µM, and increased at 100 µM, 150 µM and 200 µM concentrations. In the MCF-7 cell line, CI alterations increased at all concentrations compared with the untreated control. However, in the healthy fibroblast cell line, the CI alterations decreased at all concentrations compared with the untreated control, which limits the use of V2O5 for its cytotoxic effect in vivo. CONCLUSION: The combination of conventional anticancer drugs can be used to increase the effectiveness and reduce the adverse effects of these drugs considering stages of cancer and cancer type. Our results suggest that V2O5 has disparate effects on several cancer cells at different concentrations.