The roles of epigenetic modifications in neurodegenerative diseases / 浙江大学学报·医学版

In neuronal system, epigenetic modifications are essential for neuronal development, the fate determination of neural stem cells and neuronal function. The dysfunction of epigenetic regulation is closely related to occurrence and development of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease. Abnormally elevated DNA methylation inhibits the expression of some DNA repair-related genes and affects the progression of Huntington's disease. In the brain of Alzheimer's disease patients, the levels of H3K27ac and H3K9ac histone modifications increased. In addition, the alteration of RNA methylation in animal models of Alzheimer's disease and Parkinson's disease showed discrepancy trends. Therefore, epigenetic modifications may serve as potential therapeutic targets for neurodegenerative diseases. Here, we summarize the recent progress of the roles of epigenetic modifications in neurodegenerative diseases.

Changes of functional brain networks and their relations with cognitive function in patients with end-stage renal disease / 中华神经医学杂志

Objective To investigate the change patterns of functional brain networks and their relations with cognitive function in patients with end-stage renal disease (ESRD).Methods Sixty-two patients with ESRD (ESRD group),admitted to our hospital from July 2018 to June 2019,and 36 age-,gender-,and education level-matched healthy controls (HC group) were enrolled.Mini-mental State Examination (MMSE),Montreal Cognitive Assessment (MoCA),Trail Making Test A (TMT-A),TMT-B and Symbol Digit Modalities Test (SDMT) were used to evaluate the cognitive function for all subjects.Resting-state functional magnetic resonance imaging data were acquired;after data preprocessing,the brain functional networks were constructed and the topological parameters were calculated.Statistical methods were used to compare the differences of cognitive function scores and topological parameters between the two groups,and to analyze the correlations between these topological parameters and cognitive function scores in the ESRD group.Results The MMSE,MoCA and SDMT scores of the ESRD group were significantly lower than those of the HC group (P＜0.05),and the ESRD group took significantly longer time to complete TMT-A and TMT-B than the HC group (P＜0.05).The ESRD group had significantly lower normalized clustering coefficient (γ),small-worldness (σ) and local efficiency (Elocal) values than the HC group (P＜0.05).Patients in the ESRD group exhibited significantly decreased nodal efficiency in the paralimbic-limbic network (including the bilateral insula,median cingulate and paracingulate gyri,hippocampus,parahippocampal gyrus,amygdala,temporal pole:superior temporal gyrus,and temporal pole:middle temporal gyrus),right heschl gyrus and left superior temporal gyrus,and exhibited significantly increased nodal efficiency in the visual network (including the right distal-shaped gyrus,bilateral wedge,and left superior and middle occipital gyrus) as compared with the HC group (P＜0.05).In the ESRD group,the area under the curve (AUC) ofγ and σ was positively correlated with MoCA scores (r=0.698,P=0.000;r=0.661,P=0.000),and the AUC of Elocal showed positive correlation with MMSE scores (r=0.407,P=0.003).Conclusion Abnormal topological organization of the functional brain networks is revealed in patients with ESRD,which affects the cognitive function of these patients.

Inter-hemisphere voxel-mirrored homotopic connectivity in patients with end-stage renal disease and its relation with cognitive function / 中华神经医学杂志

Objective To investigate the inter-hemispheric resting-state functional connectivity and its relation with cognitive function in patients with end-stage renal disease (ESRD) by using resting-state functional magnetic resonance imaging (rs-fMRI) based on voxel-mirrored homotopic connectivity (VMHC). Methods A total of 52 patients with ESRD (ESRD group), admitted to our hospital from July 2018 to January 2019, were enrolled; 36 age-, gender-, and education level-matched healthy controls (HCs group) were collected at the same time period. The cognitive function of all subjects was assessed by Mini Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Trail Making Test (TMT)-A, TMT-B and Symbol Digit Modalities Test (SDMT). The rs-fMRI and 3D-T1WI data were acquired from all subjects; after image preprocessing, VMHC values between brain hemispheres were calculated and the regions with significantly different VMHC values were obtained. The correlations between VMHC values in significant regions and cognitive scale scores were analyzed. Results MMSE, MoCA and SDMT scores of ESRD patients were significantly lower than those of the HCs group (P<0.05), and ESRD patients took longer time to complete TMT-A and TMT-B tests than the HCs group (P<0.05). As compared with that of the HCs group, significant decrease of VMHC values of ESRD patients was found in the hippocampus, lingual gyrus, superior temporal gyrus, caudate nucleus and anterior cingulate gyrus (P<0.01, AlphaSim correction); the VMHC values of the anterior cingulate gyrus and hippocampus were positively correlated with MMSE and MoCA scores (P<0. 05). Conclusion Significant abnormal inter-hemisphere functional connectivity is found in patients with ESRD, which is associated with cognitive function.

mA Regulates Neurogenesis and Neuronal Development by Modulating Histone Methyltransferase Ezh2 / 基因组蛋白质组与生物信息学报·英文版

N-methyladenosine (mA), catalyzed by the methyltransferase complex consisting of Mettl3 and Mettl14, is the most abundant RNA modification in mRNAs and participates in diverse biological processes. However, the roles and precise mechanisms of mA modification in regulating neuronal development and adult neurogenesis remain unclear. Here, we examined the function of Mettl3, the key component of the complex, in neuronal development and adult neurogenesis of mice. We found that the depletion of Mettl3 significantly reduced mA levels in adult neural stem cells (aNSCs) and inhibited the proliferation of aNSCs. Mettl3 depletion not only inhibited neuronal development and skewed the differentiation of aNSCs more toward glial lineage, but also affected the morphological maturation of newborn neurons in the adult brain. mA immunoprecipitation combined with deep sequencing (MeRIP-seq) revealed that mA was predominantly enriched in transcripts related to neurogenesis and neuronal development. Mechanistically, mA was present on the transcripts of histone methyltransferase Ezh2, and its reduction upon Mettl3 knockdown decreased both Ezh2 protein expression and consequent H3K27me3 levels. The defects of neurogenesis and neuronal development induced by Mettl3 depletion could be rescued by Ezh2 overexpression. Collectively, our results uncover a crosstalk between RNA and histone modifications and indicate that Mettl3-mediated mA modification plays an important role in regulating neurogenesis and neuronal development through modulating Ezh2.

Effects of aspirin and verapamil alone or in combination on mesenteric microcirculation of rats / 中国临床药理学与治疗学

AimTo study the effects of aspirin (Asp) and verapamil(Ver)alone or in combination on mesenteric microcirculation of rats. MethodsAcute microcirculation disturbance(AMD) was produced by highmolecular weight dextran(Mr 480, 000) 360 mg· kg-1 iv. Arteriol and venul blood flow velocity and diameter (ABFV, VBFV, AD, VD) and blood flow state(BFS) were observed by intravital microcirculation method. Results Asp 2.5, 5 mg · kg-i, Ver 0.3, 0.6 mg · kg-1,Asp+ Ver(1 + 0.15), (2. 5+ 0. 3) mg· kg-1 iv significant increase ABFV by 11.1%, 31.3%, 18.7%,19.5%, 26.5%, 37.3%, VBFV by 12.5%, 5.7%, 2.5%, 3.7%, 30%, 34.7%,AD by 4.3%, 17.9%, 31.5%, 35%, 20%, 38.1% and VDby 2.2%,4.2%, 25%, 31.5%,5.8%,23.5%espectively, and got a raise in the number of capillaries and a marked improvement of BFS. Asp + Ver(1+0.15, 2.5+0.3) mg · kg-1 iv could reverse AMD. Conclusion Asp is superior to Ver in the increase of BFV, but Ver is superior to Asp in expansion of blood vessel. Asp in combination with Ver produces marked synergistic action and protection againist AMD.

Isolation and culture of neural stem cells in ventral midbrain of a rat embryo / 中国康复理论与实践

@#ObjectiveTo establish a method of isolation and culture of neural stem cells(NSCs). MethodsTissues of ventral midbrain were isolated from a rat embryo,and the NSCs were cultured stimulated with basic fibroblast growth factor(bFGF)in vitro.The cells were identified by immunocytochemistry.ResultsNSCs proliferated into neurosphere in symmetric and non-symmetric cleavage ways,and differentiated into neuron, astroglia and oligodendrosyte. ConclusionsThe method has been established to isolate and culture the neural stem cells.

Experimental study of the treatment of Xingusheng(XGS) Capsule on the femoral head necrosis in mouse and rat / 中国康复理论与实践

@#ObjectiveTo study the effect of XGS Capsule on the femoral head necrosis in mouse and rat. MethodsThe animal model of femoral head necrosis was caused with tretinoin per os. The free locomotive activity, bone density and pathological changed were observed. ResultsIn the model mouse, the free locomotive activity decreased significantly(P<0.01). In the model rat, the density and weight of the bone also decreased(P<0.01). The defects of cartilage, disorders of ossification and dead bone were observed in the femoral head joint. After treatment with XGS Capsule for 5 weeks, these pathological changes significantly improved. Conclusions XGS Capsule was effective in treating the femoral head necrosis.

Survival and differentiation of transplanted neural stem cells in the brain of MPTP-induced Parkinson's disease model mice / 中国康复理论与实践

@#ObjectiveTo determine survival and differentiation of cultured neural stem cells (NSCs) into viable and functional neurons upon transplantation into the brain of MPTP-induced Parkinson's Disease (PD) mode micel.MethodsMice model of PD was established with intraperitoneal (i.p.) injections of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP,40mg/kg) twice interspersed by 16 hr. Tissues isolated from an embryonic rat midbrain were cultured in clonal density. After labeled with 5-bromo-2′-deoxyuridine (BrdU), the NSCs were transplanted into the uni- or bilateral striatum of PD mice. Tyrosine hydroxylase (TH) immunofluorescence was used to evaluate the toxicity of MPTP on the neural cells in the substantia nigra. Immunohistochemistry and laser confocal were used to detect the survival and differentiation of transplanted NSCs.ResultsTH positive neural cells were significantly reduced in the substantia nigra after MPTP injection. Immunohistology showed that the uni-or bilateral transplanted NSCs could survive in the brains of PD model mice.Some transplanted NSCs could properly differentiate into targeted TH positive neural cells in vivo.ConclusionsThe transplanted multipotent NSCs could survive, differentiate into functional dopamine neurons in the brains of PD model mice.

Effects of β-Amyloid peptide on neurogenesis in brain hippocampus of mice and interfering effect of traditional Chinese medicine / 中国康复理论与实践

@#ObjectiveTo observe the changes of neurogenesis in the hippocampus of Alzheimer's model mice and the effect of traditional Chinese medicine Nao Fu Cong. MethodsAlzheimer's type dementia of mice was induced by Aβ25-35 icv.Space learning and memorial ability were tested with Morris Water Maze.The activity of NMDA and M receptor were measured with radio-ligand of MK-801 and QNB.Neurogenesis was observed with the BrdU immunohitochemistry.ResultsSpace learning and memorial ability significantly decreased(P<0.05),MK-801 binding increased and QNB binding decreased (P<0.001),BrdU positive cells decreased in hippocampus(P<0.05).After given drugs for 2 weeks,the mentioned changes were improved significantly(P<0.05,P<0.001,P<0.05).ConclusionsThe toxic effect of Aβ25-35 was involved with the inhibitory action of neurogenesis.Promoting the neurogenesis may be one of the mechanism of traditional Chinese medicine to treat the neurodegenerative diseases.

Effects of neural stem cells transplantation on the behavior of Parkinson's disease mice / 中国康复理论与实践

@#ObjectiveTo observe the effects of neural stem cells transplantation on the behavioral deficits of Parkinson's disease mice.MethodsSpontaneous movement,Morris Water Maze and Rotarod were adopted to evaluate the behavioral changes.ResultsCompared with the control,the time of spontaneous movement was decreased,the latency of Water Maze was lengthened,and the time of Rotarod was shortened in the Parkinson's disease(PD) mice. These deficits were improved 2,4 and 8 weeks after unilateral and bilateral transplantation of neural stem cells.ConclusionsThe transplantation of neural stem cells can improve the behavioral deficits in the PD mice.