Multi-objective optimization method for coil current waveform of transcranial magnetic stimulation.

Transcranial magnetic stimulation (TMS) has been proved to be effective in the treatment of many kinds of mental diseases. However, the clicking noise produced by the pulse current with large amplitude and short duration in the TMS coil may damage the hearing of patients. The heat produced by the high-frequency pulse current in the coil also reduces the efficiency of TMS equipment. A multi-objective waveform optimization method to improve heat and noise problems at the same time is presented. By analyzing the current waveforms of TMS, the relationship between the current and the vibration energy/Joule heating is established. Taking the Joule heating and the vibration energy as the optimization objectives, exceeding the same amount of neuronal membrane potential as the limiting condition, the Pareto fronts of different current models are obtained by applying the multi-objective particle swarm optimization algorithm (MOPSO). Therefore, the corresponding current waveforms are inversely deduced. A ringing suppression cTMS (RS-cTMS) proof-of-principle experimental platform is constructed. The feasibility of the proposed method is validated through experiments. The results show that the optimized current waveforms can greatly reduce the vibration and heating of the coil compared with the conventional full-sine, recified sine and half-sine waveforms, thus reducing the pulse noise and prolonging the using time of the equipment. The optimized diversified waveforms also provide a reference for the diversity of TMS.

Expression and Regulatory Network Analysis of BICC1 for Aged Sca-1-Positive Bone Narrow Mesenchymal Stem Cells.

Background: The impaired osteoblastic differentiation of bone marrow mesenchymal stem cells (BMSCs) is a major cause of bone remodeling imbalance and osteoporosis. The bicaudal C homologue 1 (BICC1) gene is a genetic regulator of bone mineral density (BMD) and promotes osteoblast differentiation. The purpose of this study is to explore the probable function of BICC1 in osteoporosis and osteogenic differentiation of aged BMSCs. Methods: We examined the GSE116925 microarray dataset obtained from the Gene Expression Omnibus (GEO) database. The GEO2R algorithm identified differentially expressed genes (DEGs) in Sca-1+ BMSCs from young (3 months old) and old (18 months old) mice. Then, to identify the most crucial genes, we used pathway enrichment analysis and a protein-protein interaction (PPI) network. Furthermore, starBase v2.0 was used to generate the regulatory networks between BICC1 and related competing endogenous RNAs (ceRNAs). NetworkAnalyst was used to construct TF-gene networks and TF-miRNA-gene networks of BICC1 and ceRNA. Furthermore, we investigated the Bicc1 expression in aged Sca-1-positive BMSCs. Result: We detected 923 DEGs and discovered that epidermal growth factor receptor (EGFR) was the top hub gene with a high degree of linkage. According to the findings of the PPI module analysis, EGFR was mostly engaged in cytokine signaling in immune system and inflammation-related signaling pathways. 282 ceRNAs were found to interact with the BICC1 gene. EGFR was not only identified as a hub gene but also as a BICC1-related ceRNA. Then, we predicted 11 common TF-genes and 7 miRNAs between BICC1 and EGFR. Finally, we found that BICC1 mRNA and EGFR mRNA were significantly overexpressed in aged Sca-1-positive BMSCs. Conclusion: As a genetic gene that affects bone mineral density, BICC1 may be a new target for clinical treatment of senile osteoporosis by influencing osteogenic differentiation of BMSCs through EGFR-related signaling. However, the application of the results requires support from more experimental data.

27-Hydroxycholesterol Alters Synaptic Structural and Functional Plasticity in Hippocampal Neuronal Cultures.

This study aimed to explore the neurotoxic effects of 27-hydroxycholesterol (27-OHC), a major circulating cholesterol active derivative in brain on synaptic structural and functional plasticity in primary hippocampal neurons. Newborn SD rat primary hippocampal neurons were treated with 0, 1, 3, 10, and 30 µM 27-OHC for 24 hours. MTT and CCK-8 assays were used to monitor the cell viability of neurons with different treatments. Neurite morphology was assessed by staining for microtubule-associated protein-2 (MAP2) and analyzed by immunofluorescence. Synaptic ultrastructure was evaluated by transmission electron microscopy. Real-time polymerase chain reaction and Western blot analyses were used to evaluate the expression of key synaptic proteins: synaptophysin (SYP), postsynaptic density protein-95 (PSD-95), synaptosomal-associated protein 25 (SNAP-25), growth-associated protein-43 (GAP-43), MAP2, and activity-regulated cytoskeleton-associated protein (Arc). Treatment with 27-OHC at various doses stimulated cell death and resulted in significant decreases in neurite number and length, alteration of synaptic ultrastructure, and downregulated expression of synaptic proteins in a dose-dependent manner. These results suggest that 27-OHC is deleterious for synaptic structural and functional plasticity, which may partially account for its neurotoxic effects.

27-Hydroxycholesterol regulates cholesterol synthesis and transport in C6 glioma cells.

The oxysterol 27-Hydroxycholesterol (27-OHC) is a major cholesterol metabolite that can cross the blood brain barrier (BBB) from peripheral circulation to the brain. Currently, the role of 27-OHC on cholesterol homeostasis in astrocytes and the underlying mechanisms are not defined. Since all brain cholesterol is essentially synthesized in brain itself and astrocytes as net producers of cholesterol are essential for normal brain function, here we investigated the effects of 27-OHC on cholesterol synthesis and transport in C6 glioma cells. C6 cells were treated with 5, 10 and 20µM 27-OHC for 24h and the cell viability and apoptosis, the cholesterol levels and metabolism-related mediators, genes and proteins were subsequently assessed using cell-counting kit (CCK)-8, Amplex red, ELISA, real-time PCR and Western blot, respectively. We found that 27-OHC decreased cholesterol levels by down-regulating the expression of sterol-regulated element binding protein-1 (SREBP-1a), 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CR) and low density lipoprotein receptor (LDLR) and promoted cholesterol transport by up-regulating the expression of peroxisome proliferator-activated receptors-γ (PPAR-γ), liver X receptor-α (LXR-α), ATP-binding cassette transporter protein family member A1 (ABCA1) and apolipoprotein E (ApoE)genes. Our results suggested that 27-OHC may represent a sensitive modulator of cholesterol metabolism disorder by suppressing cholesterol synthesis and stimulating cholesterol transport in astrocytes.

Genistein Inhibits Aß25-35-Induced Synaptic Toxicity and Regulates CaMKII/CREB Pathway in SH-SY5Y Cells.

Genistein (Gen), as a functional food in human diet, has shown many beneficial effects on neurodegenerative diseases such as Alzheimer's disease (AD). But the neuroprotective mechanism of Gen is not clear. Because synaptic failure is considered as the earliest phase in the pathogenesis of AD, we try to validate our hypothesis that synapse may be one target of Gen on protecting neurons. In this study, SH-SY5Y cells were pre-incubated with or without Gen for 2 h followed by the incubation with Aß25-35 (25 µmol/L) for another 24 h. Flow cytometry, Western Blots, and RT-PCR analysis were used to test the synaptic factors. The data showed that Gen pre-treatment could reverse the Aß25-35-induced down-regulation of synaptophysin and postsynaptic marker postsynaptic density-95. In addition, the down-regulation of NR1 and NR2B induced by Aß25-35 which are subunits of N-methyl-D-aspartate receptor also could be antagonized by pre-treatment of Gen. Moreover, the factors of CaMKII/CREB signaling pathway were detected. The results showed that mRNA and protein expressions of (Ca(2+))/calmodulin(CaM), CaMKII/pCaMKII, and CREB/pCREB were significantly down-regulated by Aß25-35, but they were all restored by the pre-treatment of Gen. Furthermore, Gen also maintained the intracellular Ca(2+) concentration which was disturbed by Aß25-35. In conclusion, these results suggested that Gen could protect synaptic dysfunction induced by Aß, and the mechanism might be associated with the regulation of synaptic markers and Ca(2+) level through activating CaM/CaMK/CREB signaling pathway.

The effect of soybean isoflavone on the dysregulation of NMDA receptor signaling pathway induced by ß-amyloid peptides 1-42 in rats.

Synaptic damage is the key factor of cognitive impairment. The purpose of this study was to understand the effect of soybean isoflavone (SIF) on synaptic damage induced by ß-amyloid peptide 1-42 (Aß1-42) in rats. Adult male Wistar rats were randomly divided into control, Aß1-42, SIF, and SIF + Aß1-42 (SIF pretreatment) groups according to body weight. SIF was treated orally by gavage in SIF and SIF + Aß1-42 groups. After 14 days pretreatment with SIF or vehicle, Aß1-42 was injected into the lateral cerebral ventricle of rats in Aß1-42 and SIF + Aß1-42 groups using miniosmotic pump. The level of Aß1-42 and the expression of N-methyl-D-aspartic-acid receptor (NMDAR) were observed by immunohistochemistry. Reverse transcriptase polymerase chain reaction was used to detect the mRNA levels of NMDAR, calmodulin (CaM), calcium/CaM-dependent protein kinase II (CaMKII), cAMP-response element binding protein (CREB), and brain-derived neurotrophic factor (BDNF). The results showed that Aß1-42 down-regulated mRNA and protein expression of the NR1 and NR2B subunits of NMDAR, SIF pretreatment could reverse these changes. The mRNA expression of CaM, CaMKII, CREB, and BDNF were down-regulated by Aß1-42, but they were all regulated by SIF pretreatment. These results suggest that SIF pretreatment could antagonize the neuron damage in rats induced by Aß1-42, and its mechanism might be associated with the NMDA receptor and CaM/CaMKII/CREB/BDNF signaling pathway, which are the synaptic plasticity-related molecules.

The oxysterol 27-hydroxycholesterol increases oxidative stress and regulate Nrf2 signaling pathway in astrocyte cells.

The disturbance in cholesterol metabolism has been considered as a cause of alzheimer's disease (AD), which dues to the oxidative damage and cell apoptosis in the brain. We aimed to investigate the toxicity and mechanism of AD-like pathology caused by cholesterol oxidation metabolite 27-hydroxycholesterol (27-OHC) in astrocyte cells. C6 cells were treated with 0, 5, 10, 20 µM 27-OHC for 24 h (h). The cell viability was monitored by using methyl thiazolyl tetrazolium test, generation of reactive oxygen species (ROS) was measured by using 2', 7'-dichlorodihydrofluorescein diacetate fluorescent probe under flow cytometry. The concentrations of 8-hydroxyl deoxyguanosine, the anti-oxidative enzymes such as total superoxide dismutase (tSOD), reduced glutathione (rGSH) and glutathione peroxidase (GSH-Px) were tested by using enzyme-linked immunosorbent assay and enzymic method, respectively. The gene and protein expression of nuclear factor E2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), NAD(P)H dehydrogenase quinone 1 (NQO1) and γ-glutamylcysteine synthetase (γ-GCS) in C6 cells were detected by quantitative western blot analysis and real-time PCR analysis. Moreover, the Nrf2 expressions in both of the cytoplasm and nucleus were detected with western blot analysis, and the localization of Nrf2 was performed by immunocytochemistry and confocal microscopy. 27-OHC increased the levels of ROS and decreased the levels of tSOD, rGSH, GSH-Px in C6 cells dose-dependently. In addition, 27-OHC down regulated the expressions of Nrf2, HO-1, NQO1 and γ-GCS at both of gene and protein levels, while Nrf2 expression in the cytoplasm showed decreased trend after incubated for 24 h with 27-OHC. The cholesterol metabolite 27-OHC is toxic to C6 cells and contributed to oxidative damage via regulating the Nrf2 signaling pathway. Our results suggest that 27-OHC may represent a common pathogenic factor in AD.

Soy isoflavone antagonizes the oxidative cerebrovascular injury induced by ß-amyloid peptides 1-42 in rats.

Numerous evidences have shown that the antioxidative properties of soy isoflavone (SIF) have beneficial effects on prophylaxis of neurodegeneration, however, the mechanism is still not fully illustrated. As cerebrovascular dysfunction could initiate a cascade of events leading to pathogenesis of Alzheimer's disease, we tried to investigate whether SIF could protect the cerebrovascular system due to antagonizing oxidative damage induced by Aß1-42 in present study. In addition, NF-E2-related factor 2 (Nrf2) signaling pathways in the cerebrovascular tissue of Wistar rats were investigated to identify the potential cerebrovascular protective targets of SIF. Research results showed that SIF reduced the excessive production of nitrotyrosine in cerebrovascular tissue induced by Aß1-42, and maintained redox homeostasis by increasing the level of GSH and GSH/GSSG. Moreover, SIF could alleviate the down-regulation of Nrf2, γ-glutamylcysteine synthetase, Heme oxygenase-1 expressions in cerebrovascular tissue induced by Aß1-42 and suppress the increase of Kelch like ECH protein-1 (Keap1). These data suggested that SIF might reduce the cerebrovascular oxidative damage induced by Aß1-42 through regulating the Nrf2 signaling pathway. The mechanisms of SIF modulating the potential target Nrf2 might be associated with Keap1 expression.

Soybean isoflavone ameliorates ß-amyloid 1-42-induced learning and memory deficit in rats by protecting synaptic structure and function.

This research aims to investigate whether soybean isoflavone (SIF) could alleviate the learning and memory deficit induced by ß-amyloid peptides 1-42 (Aß 1-42) by protecting the synapses of rats. Adult male Wistar rats were randomly allocated to the following groups: (1) control group; (2) Aß 1-42 group; (3) SIF group; (4) SIF + Aß 1-42 group (SIF pretreatment group) according to body weight. The 80 mg/kg/day of SIF was administered orally by gavage to the rats in SIF and SIF+Aß 1-42 groups. Aß 1-42 was injected into the lateral cerebral ventricle of rats in Aß 1-42 and SIF+Aß 1-42 groups. The ability of learning and memory, ultramicrostructure of hippocampal synapses, and expression of synaptic related proteins were investigated. The Morris water maze results showed the escape latency and total distance were decreased in the rats of SIF pretreatment group compared to the rats in Aß1-42 group. Furthermore, SIF pretreatment could alleviate the synaptic structural damage and antagonize the down-regulation expressions of below proteins induced by Aß1-42: (1) mRNA and protein of the synaptophysin and postsynaptic density protein 95 (PSD-95); (2) protein of calmodulin (CaM), Ca(2+) /calmodulin-dependent protein kinase II (CaMK II), and cAMP response element binding protein (CREB); (3) phosphorylation levels of CaMK II and CREB (pCAMK II, pCREB). These results suggested that SIF pretreatment could ameliorate the impairment of learning and memory ability in rats induced by Aß 1-42, and its mechanism might be associated with the protection of synaptic plasticity by improving the synaptic structure and regulating the synaptic related proteins.