Dietary Supplementation With Acer truncatum Oil Promotes Remyelination in a Mouse Model of Multiple Sclerosis.

Background: Multiple sclerosis is a chronic demyelinating disease of uncertain etiology. Traditional treatment methods produce more adverse effects. Epidemiological and clinical treatment findings showed that unknown environmental factors contribute to the etiology of MS and that diet is a commonly assumed factor. Despite the huge interest in diet expressed by people with MS and the potential role diet plays in MS, very little data is available on the role of diet in MS pathogenesis and MS course, in particular, studies on fats and MS. The oil of Acer truncatum is potential as a resource to be exploited in the treatment of some neurodegenerative diseases. Objective: Here, we investigated the underlying influences of Acer truncatum oil on the stimulation of remyelination in a cuprizone mouse model of demyelination. Methods: Cuprizone (0.2% in chow) was used to establish a mouse model of demyelination. Acer truncatum oil was administrated to mice during remyelination. Following techniques were used: behavioral test, histochemistry, fluorescent immunohistochemistry, transmission electron microscope. Results: Mice exposed to cuprizone for 6 weeks showed schizophrenia-like behavioral changes, the increased exploration of the center in the open field test (OFT), increased entries into the open arms of the elevated plus-maze, as well as demyelination in the corpus callosum. After cuprizone withdrawal, the diet therapy was initiated with supplementation of Acer truncatum oil for 2 weeks. As expected, myelin repair was greatly enhanced in the demyelinated regions with increased mature oligodendrocytes (CC1) and myelin basic protein (MBP). More importantly, the supplementation with Acer truncatum oil in the diet reduced the schizophrenia-like behavior in the open field test (OFT) and the elevated plus-maze compared to the cuprizone recovery group. The results revealed that the diet supplementation with Acer truncatum oil improved behavioral abnormalities, oligodendrocyte maturation, and remyelination in the cuprizone model during recovery. Conclusion: Diet supplementation with Acer truncatum oil attenuates demyelination induced by cuprizone, indicating that Acer truncatum oil is a novel therapeutic diet in demyelinating diseases.

Pathogenicity analysis of variations and prenatal diagnosis in a hereditary coagulation factor XIII deficiency family.

OBJECTIVES: Prenatal diagnosis (PND) procedure is urgent to be established for timely management and fatal consequence prevention of factor XIII deficiency (FXIIID), and variations data among Chinese are very scanty. We aimed to find a novel mutation among Chinese and establish a rapid and precise PND procedure with pathogenicity analysis to contribute to the prevention of postpartum hemorrhage in pregnant women and central nervous system bleeding in newborns. METHODS: FXIIID was diagnosed by qualitative and quantitative tests of clot solubility test and enzyme-linked immunosorbent assay, respectively. Variations were detected by direct sequencing of F13A and F13B genes in the pedigree and the unborn fetus. Pathogenicity assessment of variations was based on American College of Medical Genetics and Genomics Guidelines. RESULTS: Ten variants in the F13A gene including a novel missense mutation in exon 10, a nonsense mutation in exon 4, a missense mutation in exon 12, 2 missense mutations in exon 14, 3 polymorphisms in intron 10, 2 polymorphisms in intron 14 were detected. Two variants in the F13B gene including a polymorphism in 3'UTR and a synonymous mutation were detected. The compound heterozygous mutations of the nonsense mutation and a novel missense mutation of the F13A gene caused the deficiency in proband, and the fetus which was evaluated to be unaffected by PND was born successfully and the results were verified by follow-up visits. DISCUSSION: We first established the PND procedure with pathogenicity assessment in FXIIID patients. The F13A gene mutations' spectrum of the Chinese Han population was enriched.

Combined effect of nerve growth factor and brain­derived neurotrophic factor on neuronal differentiation of neural stem cells and the potential molecular mechanisms.

Neural stem cells (NSCs) are important pluripotent stem cells, which have potential applications in cell replacement therapy. Brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) have been demonstrated to exert a marked impact on the proliferation and differentiation of NSCs. The effects of NGF, BDNF, and BDNF combined with NGF on NSC neuronal differentiation and the possible mechanisms for these effects were investigated in this study. An adherent monolayer culture was employed to obtain highly homogeneous NSCs. The cells were divided into four groups: Control, NGF, BDNF and combination (BDNF + NGF) groups. Neuron differentiation was examined using immunocytochemistry and phospho-extracellular signal-regulated kinase (p­ERK) levels were analyzed using western blotting. Reverse transcription polymerase chain reaction was used to measure the mRNA expression levels of the HES1, HES5, MASH1, NGN1 and NeuroD transcription factors at different time intervals following neurotrophin-induced differentiation. NGF and BDNF were observed to induce NSC neuronal differentiation, and ß-tubulin III-positive cells and p-ERK expression levels were highest in the NGF + BDNF combination group at all time points. The proportion of ß-tubulin Ⅲ-positive neurons in each group was associated with the expression levels of MASH1, NGN1 and NeuroD in the group. In conclusion, BDNF combined with NGF significantly improved NSC neuronal differentiation, which may provide support for the practical application of NSCs in neurodegenerative diseases.

Elevated glycogen synthase kinase-3 activity in Fragile X mice: key metabolic regulator with evidence for treatment potential.

Significant advances have been made in understanding the underlying defects of and developing potential treatments for Fragile X syndrome (FXS), the most common heritable mental retardation. It has been shown that neuronal metabotropic glutamate receptor 5 (mGluR5)-mediated signaling is affected in FX animal models, with consequent alterations in activity-dependent protein translation and synaptic spine functionality. We demonstrate here that a central metabolic regulatory enzyme, glycogen synthase kinase-3 (GSK3) is present in a form indicating elevated activity in several regions of the FX mouse brain. Furthermore, we show that selective GSK3 inhibitors, as well as lithium, are able to revert mutant phenotypes of the FX mouse. Lithium, in particular, remained effective with chronic administration, although its effects were reversible even when given from birth. The combination of an mGluR5 antagonist and GSK3 inhibitors was not additive. Instead, it was discovered that mGluR5 signaling and GSK3 activation in the FX mouse are coordinately elevated, with inhibition of mGluR5 leading to inhibition of GSK3. These findings raise the possibility that GSK3 is a fundamental and central component of FXS pathology, with a substantial treatment potential.

Prolonged epileptiform discharges induced by altered group I metabotropic glutamate receptor-mediated synaptic responses in hippocampal slices of a fragile X mouse model.

Mutations in FMR1, which encodes the fragile X mental retardation protein (FMRP), are the cause of fragile X syndrome (FXS), an X-linked mental retardation disorder. Inactivation of the mouse gene Fmr1 confers a number of FXS-like phenotypes including an enhanced susceptibility to epileptogenesis during development. We find that in a FXS mouse model, in which the function of FMRP is suppressed, synaptically released glutamate induced prolonged epileptiform discharges resulting from enhanced group I metabotropic glutamate receptor (mGluR)-mediated responses in hippocampal slices. The induction of the group I mGluR-mediated, prolonged epileptiform discharges was inhibited in preparations that were pretreated with inhibitors of ERK1/2 (extracellular signal-regulated kinase 1/2) phosphorylation or of mRNA translation, and their maintenance was suppressed by group I mGluR antagonists. The results suggest that FMRP plays a key role in the control of signaling at the recurrent glutamatergic synapses in the hippocampus. The absence of this control causes the synaptically activated group I mGluRs to elicit translation-dependent epileptogenic activities.