Vitamin D Inhibits the Early Aggregation of α-Synuclein and Modulates Exocytosis Revealed by Electrochemical Measurements.

Alpha-synuclein (α-Syn) localizes at presynaptic terminal and modulates synaptic functions. Increasing evidence demonstrate that α-Syn oligomers, forming at the early of aggregation, are cytotoxic and is thus related to brain neurodegenerative diseases. Herein, we find that vitamin D (VD) can reduce neurocytotoxicity. The reduced neurocytotoxicity might be attributed to the less amount of large-sized α-Syn oligomers inhibited by VD, measured by electrochemical collision at single particle level, which are not observable with traditionally ensembled method. Single-cell amperometry (SCA) results show that VD can recover the amount of neurotransmitter release during exocytosis induced by α-Syn oligomers, further verifying the neuroprotection of VD. Our study reveals the neuroprotective role of VD through inhibiting α-Syn aggregation, which is envisioned to be of great importance in treatment and prevention of the neurodegenerative diseases.

Theaflavins alleviate sevoflurane-induced neurocytotoxicity via Nrf2 signaling pathway.

Aim: Sevoflurane could induce apoptosis of rat hippocampal neurons, while theaflavins (TFs) have antioxidant and anti-inflammatory properties. This study aims to explore whether TFs could alleviate sevoflurane-induced neuronal cell injury.Materials and methods: Cells were treated by concentration gradient of sevoflurane and TFs. Cell viability, level of reactive oxygen species (ROS) and apoptosis rate were determined by cell counting kit-8 (CCK-8) and flow cytometry, respectively. Quantitative PCR (qPCR) and western blot were performed to determine mRNA and protein expressions.Results: TFs promoted viability of cells under the treatment of sevoflurane, while it suppressed apoptosis and down-regulated ROS level in a concentration-dependent manner. TFs could also down-regulate expression levels of caspase-3 and caspase-9 and cytosol and intranuclear nuclear factor E2-related factor 2 (Nrf2) in rat hippocampal nerve cells, while it up-regulated those of heme oxygenase 1 (HO-1), NADPH quinine oxidoreductase 1 (NQO1), glutamate cysteine ligase (GCL) and peroxiredoxin 1 (Prx1).Conclusions: Our study suggests that TFs exert protective effects on sevoflurane-induced neurocytotoxicity and therefore could be used as a potential drug for treatment of neuronal injury.

Increasing anti-Aß-induced neurotoxicity ability of Antrodia camphorata-fermented product with deep ocean water supplementary.

BACKGROUND: Antrodia camphorata is proven to probably inhibit the neurotoxicity of amyloid ß-peptide (Aß), known as a risk factor toward the development of Alzheimer's disease. Deep ocean water (DOW), drawn from an ocean depth of more than 200 m, has proven to stimulate the growth and metabolite biosynthesis of fungi owing to its rich minerals and trace elements. Based on these advantages of DOW, this study used statistical response surface methodology (RSM) to investigate the effects of DOW on the growth and anti-Aß-induced neurocytotoxicity ability of A. camphorata. RESULTS: The results showed that DOW was useful for increasing the biomass of A. camphorata and enhancing its neuroprotective capability. The anti-Aß40-induced neurocytotoxicity ability of filtrate was increased via raising the mycelium-secreted components. Furthermore, the anti-Aß40-induced neurocytotoxicity ability of mycelium was also increased by the DOW-stimulated intracellular antioxidants. Using 80% DOW concentration, initial pH 3.3 and 20% inoculum size as the optimal culture conditions of A. camphorata significantly stimulated the biomass and mycelium-mediated Aß40-induced cell viability from 302 ± 14 mg per 100 mL and 49.2 ± 2.2% to 452 ± 33 mg per 100 mL and 65.0 ± 7.4% respectively. CONCLUSION: This study indicated that DOW could be used as a promising supplementary for the production of A. camphorata secondary metabolites with strong antioxidant activity to protect neuron cells from damage based on Aß stimulation cytotoxicity. © 2016 Society of Chemical Industry.

In vitro and in silico assessment of GPER-dependent neurocytotoxicity of emerging bisphenols.

To rapidly assess the toxicity of bisphenols (BPs) via the activation of G protein-coupled estrogen receptor (GPER), eight BPs action on GPER were evaluated by molecular docking and molecular dynamics (MD) simulation and then confirmed with IMR-32 cells. The target BPs significantly promoted the production of reactive oxygen species (ROS), reduced cell viability, activated the expression of apoptosis-related proteins and increased the apoptosis rate of IMR-32 cells. Intracellular Ca2+ level increased significantly after the treatments with bisphenol A (BPA), bisphenol E (BPE), bisphenol C (BPC) and bisphenol AP (BPAP), suggesting the activation of GPER. Moreover, the stable binding conformations between GPER and BPA, BPE, BPC and BPAP and their dynamic changes of GPER-BPs via MD simulation also suggest that these BPs may activate GPER. The interaction between bisphenol G/bisphenol P/bisphenol PH and GPER are weak, which is consistent with their low GPER activity in vitro. Notably, after the pretreatment of GPER antagonist, Ca2+ accumulation and ROS production induced by BPA, BPE, BPC and BPAP in IMR-32 cells were attenuated. Overall, MD simulation and in vitro results mutually verified the activation of GPER by BPs, and MD simulation can rapidly evaluate the neurocytotoxicity of BPs.

Action of trichostatin A on Alzheimer's disease-like pathological changes in SH-SY5Y neuroblastoma cells.

The histone deacetylase inhibitor, trichostatin A, is used to treat Alzheimer's disease and can improve learning and memory but its underlying mechanism of action is unknown. To determine whether the therapeutic effect of trichostatin A on Alzheimer's disease is associated with the nuclear factor erythroid 2-related factor 2 (Nrf2) and Kelch-like epichlorohydrin-related protein-1 (Keap1) signaling pathway, amyloid ß-peptide 25-35 (Aß25-35) was used to induce Alzheimer's disease-like pathological changes in SH-SY5Y neuroblastoma cells. Cells were then treated with trichostatin A. The effects of trichostatin A on the expression of Keap1 and Nrf2 were detected by real-time quantitative polymerase chain reaction, western blot assays and immunofluorescence. Total antioxidant capacity and autophagy activity were evaluated by total antioxidant capacity assay kit and light chain 3-I/II levels, respectively. We found that trichostatin A increased cell viability and Nrf2 expression, and decreased Keap1 expression in SH-SY5Y cells. Furthermore, trichostatin A increased the expression of Nrf2-related target genes, such as superoxide dismutase, NAD(P)H quinone dehydrogenase 1 and glutathione S-transferase, thereby increasing the total antioxidant capacity of SH-SY5Y cells and inhibiting amyloid ß-peptide-induced autophagy. Knockdown of Keap1 in SH-SY5Y cells further increased trichostatin A-induced Nrf2 expression. These results indicate that the therapeutic effect of trichostatin A on Alzheimer's disease is associated with the Keap1-Nrf2 pathway. The mechanism for this action may be that trichostatin A increases cell viability and the antioxidant capacity of SH-SY5Y cells by alleviating Keap1-mediated inhibition Nrf2 signaling, thereby alleviating amyloid ß-peptide-induced cell damage.

Anatomical, animal, and cellular evidence for Zika-induced pathogenesis of fetal microcephaly.

Several recent articles published by Brain and Development in 2016 demonstrated some rare, but innovative, genetic mechanisms for microcephaly. This concise mini-review presented another novel pathogenic mechanism for microcephaly, which has actually been a worldwide medical challenge since the World Health Organization (WHO) defined the outbreak of the Zika virus (ZIKV) as an International Public Health Emergency on 1 Feb, 2016. As a recent noteworthy clinical phenomenon, the ZIKV outbreak was accompanied by a dramatically increased number of microcephalus fetuses. However, no direct evidence supporting the suspected pathogenic effects of ZIKV on fetal microcephaly was shown previously before 2016. Herein, we evaluated the most important human pathological, animal developmental, and neuro-cytotoxic findings released in 2016, and highlighted the original experimental evidence that strengthens the potential link between ZIKV and the high incidence of microcephaly in new-born babies. Because killing mosquitoes via insecticides is currently the only effective way to suppress ZIKV-induced disorders, the animal and cellular models described in this mini-review are very beneficial to anti-ZIKV drug development and vaccine assessment.

Role of oxidative stress and DNA hydroxymethylation in the neurotoxicity of fine particulate matter.

Epidemiological studies have implicated fine particulate matter (PM2.5) as a risk factor for neurodegenerative diseases and neurodevelopmental disorders. However, the underlying molecular mechanisms and the influences of different components remain largely elusive. Here, we extended our previous work to investigate the role of oxidative stress and DNA hydroxymethylation in neuronal pathology of PM2.5. We found PM2.5 and its extracts (water-soluble extracts, organic extracts and carbon core component) differentially caused cell cycle arrest, cell apoptosis and the cell proliferation inhibition in neuronal cells. These effects were mechanistically related to each other and oxidative stress, suggesting PM2.5 and toxic compounds adsorbed on the particles may cause different types of brain damages. In addition, PM2.5 and its organic extracts increased global DNA hydroxymethylation and gene-specific DNA hydroxymethylation of neuronal genes, and subsequently interfered with their mRNA expression. The impairments in neuronal progression characterized with decreased length of neurite and reduced mRNA expression of neuronal markers and synaptic markers. The blocking effects of antioxidants demonstrated the involvement of oxidative stress-mediated hydroxymethylation abnormalities in PM2.5-induced defects in neurite outgrowth and synapse formation. Our results first revealed the role of oxidative stress-mediated abnormal DNA hydroxymethylation in neuronal impairments of PM2.5, and thoroughly evaluated the neurocytotoxicity of different components.