HbA1c Variability and the Risk of Dementia in Patients with Diabetes: A Meta-Analysis.

Background: Variability of HbA1c has been related to the incidence micro and macrovascular complications in patients with diabetes. However, the association between of visit-to-visit variability of HbA1c and risk of dementia has not been fully determined. A meta-analysis was performed to comprehensively evaluate the above association. Methods: Medline, Embase, and Web of Science databases were searched for longitudinal follow-up studies comparing the incidence of dementia in diabetic patients with higher or lower variability of HbA1c. A random-effect model incorporating the potential heterogeneity among the included studies were used to pool the results. Results: Five retrospective studies with 577592 diabetic patients were included, and 99% of them were with type 2 diabetes mellitus (T2DM). With a mean follow-up duration of 6.3 years, 31963 patients had newly diagnosed dementia. Pooled results showed that diabetic patients with higher HbA1c variability was associated with higher risk of dementia, as evidenced by studies with coefficient of variation (CV: hazard ratio (HR): 1.06; 95% confidence interval (CI): 1.003-1.120; p=0.04; I 2 = 47%) and standard deviation (SD : HR: 1.19; 95% CI: 1.06-1.32; p=0.002; I 2 = 0%) of HbA1c in continuous variables, and CV of HbA1c (HR: 1.18; 95% CI: 1.08-1.28; p < 0.001; I 2 = 31%) in categorized variables. Conclusions: Higher variability of HbA1c is associated with a higher incidence of dementia in patients with diabetes.

Interaction between SNCA gene polymorphisms and T2DM with Parkinson's disease.

AIMS: To investigate the association of several single nucleotide polymorphisms (SNPs) within alpha-synuclein (SNCA) gene and additional gene-environment interaction with Parkinson's disease (PD) risk. METHODS: Hardy-Weinberg equilibrium (HWE) is tested for controls using SNPstats (http://bioinfo.iconcologia.net/SNPstats). Logistic regression is used to calculate the ORs (95% CI) for relations between the four SNPs and PD risk. The generalized multifactor dimensionality reduction (GMDR) model is used to evaluate the synergy between gene and environment. RESULTS: A total of 1161 people were included in this study, including 386 cases of PD and 775 normal controls. In this study, the genotype frequency of the control group was consistent with HWE distribution. Rs356219-G allele frequency was 30.0% in patients and 19.8% in control group. The rs356221-T allele frequency was 29.7% in the patients and 20.8% in the control group. Rs356219-G and rs356221-T alleles were associated with increased PD risk, with adjusted ORs (95% CI) of 1.92 (1.28-2.52) and 1.52 (1.05-2.02), respectively. We also found no significant correlation between rs2301134 and rs2301135 and susceptibility to PD. The best gene-environment interaction models were determined by GMDR analysis, which shown a significant gene-T2DM interaction combinations, but the gene-alcohol drinking interaction combinations were all not significant. We also conducted stratified analysis for interaction effect using logistic regression. We found that T2DM patients with rs356221-AT/ TT genotype have the highest PD risk, compared to subjects with rs356219-AA genotype, OR (95%CI) = 2.67 (1.83-3.46). CONCLUSIONS: The rs356219-G and rs356221-T, gene-environment interaction between rs356221 and T2DM were all associated with increased PD risk.

Magnetic resonance imaging and risk factors for progression of lacunar infarct lesions in Chinese patients.

PURPOSE: The proportion of acute symptomatic lacunar infarction lesions that undergo cavitation and the factors influencing cavity formation are yet unclear, particularly in the Chinese population. Hence, we investigated changes in the diameter of acute lacunar infarction lesions and identified the risk factors for the progression of these lesions. METHODS: A total of 160 patients (mean age 66 years) with acute symptomatic lacunar infarction lesions underwent two magnetic resonance imaging (MRI) examinations: diffusion-weighted imaging (DWI) at onset (lesion diameter < 20 mm) and T2-weighted imaging/fluid-attenuated inversion recovery sequences at follow-up (median follow-up time 389 days). Lacunar infarction lesion progression was categorized as complete cavitation (lacune), partial cavitation, white matter lesion (WML), or disappearance of the lesion. The risk factors for cavity formation were evaluated. RESULTS: Upon follow-up MRI, lesions had changed to lacunes in 20 (12.5%) patients, partial cavitation in 23 (14.4%), WMLs in 97 (60.6%), and had disappeared in 20 (12.5%). Lacune formation was related to hypertension (P = 0.026); cavity (lacune and partial cavitation) formation was related to diabetes (P = 0.009) and diameter change (P = 0.015). CONCLUSIONS: Approximately a quarter of the acute symptomatic lacunar infarction lesions observed with follow-up MRI were cavitated. Hypertension was negatively associated with lacune formation; diabetes and diameter change were negatively associated with cavity formation.

Inhibition of sugar-binding activity of Galectins-8 by thiogalactoside (TDG) attenuates secondary brain damage and improves long-term prognosis following intracerebral hemorrhage.

Galectins-8 (Gal-8), the tandem repeat sequences of the galectin family, can influence the pathophysiologic processes in neurological disorders. However, its effect on intracerebral hemorrhage and related mechanisms remains nebulous. Using collagenase VII-S-induced ICH in the left striatum of mice, we investigated the effects of Gal-8 on cellular and molecular immune inflammatory responses in hemorrhagic brain and evaluated the severity of short- and long-term brain injury. Our results showed that activated microglia in the periphery of hematoma in mice with intracerebral hemorrhage expressed Gal-8, while Gal-8 could regulate the expression of cytokines, such as HMGB-1 (P = 0.0032), TNF-α (P = 0.0158), and IL-10 (P = 0.0379). Inhibition of the glucose-binding activity of Gal-8 by thiogalactoside (TDG) significantly reduced the volume of cerebral hematoma (P = 0.0241) and hydrocephalus (P = 0.0112) during the acute phase of cerebral hemorrhage and improved the long-term prognosis. TDG can reduce acute-phase brain tissue injury and improve the prognosis by inhibiting the activation of immune-inflammatory cells in the periphery of hematoma and reducing the release of pro-inflammatory factors.

Value of white matter hyperintensity volume and total white matter volume for evaluating cognitive impairment in patients with cerebral small-vessel disease.

Background: White matter hyperintensities (WMH) are a key imaging feature of cerebral small-vessel disease (CSVD). However, there is a lack of standardized methods for determining WMH volume, and the value of total white matter (WM) volume in the assessment of cognitive impairment in patients with CSVD remains unknown. Objective: We aimed to explore the correlations of WMH volume and WM volume with cognitive dysfunction and its components in patients with CSVD. We also aimed to compare the value of the Fazekas score, WMH volume, and ratio of WMH volume to total WM volume in the assessment of cognitive dysfunction. Methods: The study included 99 patients with CSVD. Patients were categorized into following groups based on MoCA scores: patients with mild cognitive impairment and those without. Brain magnetic resonance images were processed to investigate differences in WMH and WM volumes between the groups. Logistic regression analysis was used to determine whether these two factors were independent risk factors for cognitive dysfunction. Correlation analysis was used to examine the relationships of WMH and WM volume with different types of cognitive impairment. Receiver operating characteristic curves were used to compare the effectiveness of the WMH score, WMH volume, and WMH to WM ratio for evaluating cognitive dysfunction. Results: There were significant differences in age, education level, WMH volume, and WM volume between the groups (P < 0.05). After adjusting for age and education, the multivariate logistic analysis indicated that both WMH volume and WM volume were independent risk factors for cognitive dysfunction. Correlation analysis indicated that WMH volume was mainly related to cognition involving the visual space and delayed recall. WM volume was not strongly associated with different types of cognitive dysfunction. The WMH to WM ratio was the strongest predictor, with an area under the curve value of 0.800 and a 95% confidence interval of 0.710-0.891. Conclusion: Increases in WMH volume may aggravate cognitive dysfunction in patients with CSVD, and a higher WM volume may reduce the effect of WMH volume on cognitive function to a certain extent. The ratio of WMH to total WM volume may reduce the impact of brain atrophy, allowing for more accurate evaluation of cognitive dysfunction in older adults with CSVD.

Chitinase-3 like-protein-1, matrix metalloproteinase -9 and positive intracranial arterial remodelling.

Introduction: Positive intracranial arterial remodelling is a dilated lesion of the large intracranial vessels; however, its pathogenesis is currently unknown. Some studies have identified chitinase-3 like-protein-1 (YKL-40) and matrix metalloproteinase (MMP)-9 as circulating inflammatory factors involved in positive vascular remodelling. Herein, we aimed to investigate the relationship between changes in serum YKL-40 and MMP-9 levels and positive intracranial arterial remodelling in patients with cerebral small vessel disease (CSVD). Methods: A total of 110 patients with CSVD were selected. Patients with brain arterial remodelling (BAR) scores >1 times the standard deviation were defined as the positive intracranial artery remodelling group (n = 21 cases), and those with BAR scores ≤1 times the standard deviation were defined as the non-positive intracranial artery remodelling group (n = 89 cases). Serum YKL-40 and MMP-9 levels were measured using an enzyme-linked immunosorbent assay kit. Factors influencing positive intracranial artery remodelling using binary logistic regression analysis and predictive value of YKL-40 and MMP-9 for positive intracranial arterial remodelling in patients with CSVD were assessed by a subject receiver operating characteristic curve. Results: Statistically significant differences in serum YKL-40 and MMP-9 levels were observed between the positive and non-positive remodelling groups (p < 0.05). The integrated indicator (OR = 9.410, 95% CI: 3.156 ~ 28.054, P<0.01) of YKL-40 and MMP-9 levels were independent risk factors for positive intracranial arterial remodelling. The integrated indicator (OR = 3.763, 95% CI: 1.884 ~ 7.517, p < 0.01) of YKL-40 and MMP-9 were independent risk factors for positive arterial remodelling in posterior circulation, but were not significantly associated with positive arterial remodelling in anterior circulation (p > 0.05). The area under the curve for YKL-40 and MMP-9 diagnostic positive remodelling was 0.778 (95% CI: 0.692-0.865, p < 0.01) and 0.736 (95% CI: 0.636-0.837, p < 0.01), respectively. Discussion: Elevated serum YKL-40 and MMP-9 levels are independent risk factors for positive intracranial arterial remodelling in patients with CSVD and may predict the presence of positive intracranial arterial remodelling, providing new ideas for the mechanism of its occurrence and development and the direction of treatment.

Outer membrane protein OMP76 of Riemerella anatipestifer contributes to complement evasion and virulence by binding to duck complement factor vitronectin.

Riemerella anatipestifer is an important bacterial pathogen in poultry. Pathogenic bacteria recruit host complement factors to resist the bactericidal effect of serum complement. Vitronectin (Vn) is a complementary regulatory protein that inhibits the formation of the membrane attack complex (MAC). Microbes use outer membrane proteins (OMPs) to hijack Vn for complement evasion. However, the mechanism by which R. anatipestifer achieves evasion is unclear. This study aimed to characterise OMPs of R. anatipestifer which interact with duck Vn (dVn) during complement evasion. Far-western assays and comparison of wild-type and mutant strains that were treated with dVn and duck serum demonstrated particularly strong binding of OMP76 to dVn. These data were confirmed with Escherichia coli strains expressing and not expressing OMP76. Combining tertiary structure analysis and homology modelling, truncated and knocked-out fragments of OMP76 showed that a cluster of critical amino acids in an extracellular loop of OMP76 mediate the interaction with dVn. Moreover, binding of dVn to R. anatipestifer inhibited MAC deposition on the bacterial surface thereby enhancing survival in duck serum. Virulence of the mutant strain ΔOMP76 was attenuated significantly relative to the wild-type strain. Furthermore, adhesion and invasion abilities of ΔOMP76 decreased, and histopathological changes showed that ΔOMP76 was less virulent in ducklings. Thus, OMP76 is a key virulence factor of R. anatipestifer. The identification of OMP76-mediated evasion of complement by recruitment of dVn contributes significantly to the understanding of the molecular mechanism by which R. anatipestifer escapes host innate immunity and provides a new target for the development of subunit vaccines.

Overexpression of C9orf72 exacerbates Aß25­35­induced oxidative stress and apoptosis in PC12 cells.

Alzheimer's disease (AD) is the most common neurodegenerative disease and is manifested by memory loss and spatial disorientation. There is currently no effective treatment for AD. Abnormalities of the chromosome 9 open reading frame 72 (C9ORF72) gene have been associated with various neurodegenerative diseases. However, its intrinsic roles in AD remain to be elucidated. Here we found that Aß25­35 increased the expression of C9orf72 in PC12 cells at both mRNA and protein levels. In Aß25­35­treated PC12 cells, C9orf72 overexpression induced an abnormally condensed and fragmented nucleus and apoptosis, as well as significantly enhanced reactive oxygen species (ROS) levels. Mechanistically, an Aß25­35­induced decrease of superoxide dismutase activity was augmented by C9orf72 overexpression, which in contrast increased malondialdehyde content. Consistently, further apoptotic analysis revealed significant downregulation of Bcl­2 and Bcl­xL expression and enhanced cleavage of caspase­3 with Aß25­35 treatment, all of which were exacerbated by C9orf72 overexpression. In addition, tau phosphorylation, another hallmark of AD pathology, was induced by Aß25­35 and was remarkably enhanced by C9orf72 overexpression. Our data indicate that C9orf72 plays important roles in intracellular ROS signaling and Aß25­35­induced neuronal apoptosis in AD. These findings provide insights into C9orf72 function in the pathogenesis of many related neurodegenerative diseases and provide a basis for potential therapeutic interventions.

Relationship between heart rate variability and cognitive function in patients with enlarged perivascular space.

Objective: To explore the relationship between heart rate variability (HRV), the brain distribution of enlarged perivascular space (EPVS), and cognitive impairment in patients with EPVS. Materials and methods: The clinical and imaging data of 199 patients with EPVS were retrospectively analyzed. EPVS load in the basal ganglia (BG) and centrum semiovale (CS) regions were assessed using the Potter's method. Cognitive function was evaluated using the Montreal Cognitive Assessment Scale. A logistic regression model was used to analyze the relationship between HRV, the brain distribution of EPVS and cognitive function in patients with EPVS. A receiver operating characteristic curve was used to assess the predictive value of HRV for cognitive function in patients with EPVS. Results: Of the 199 patients, 27 and 42 presented with severe BG-EPVS and cognitive impairment, respectively. Significant differences were observed in the root mean square of successive differences of normal-normal (NN) intervals for period of interest (rMSSD), the percentage of adjacent NN intervals greater than 50 ms (PNN50), and the ratio of low-frequency power (LF) to high-frequency power (HF) between the mild and severe BG-EPVS groups (P < 0.05). Patients who presented with and without cognitive impairment differed significantly in the standard deviation of NN intervals (SDNN), rMSSD, PNN50, total power, LF, and LF/HF (P < 0.05). rMSSD (odds ratio [OR] 0.871, 95% confidence interval [CI] 0.768-0.988) and LF/HF (OR 3.854, 95% CI 1.196-12.419) were independent influencing factors of BG-EPVS, and rMSSD (OR 0.936, 95% CI 0.898-0.976) was an independent influencing factor of cognitive impairment in patients with EPVS. The optimal cut-off point was 0.312, with an area under the curve of 0.795 (95% CI 0.719-0.872) for predicting cognitive impairment in patients with EPVS by rMSSD. Conclusion: Reduced HRV is involved in the pathophysiological mechanisms of the formation and development of BG-EPVS and is associated with cognitive impairment in patients with EPVS, independent of CS-EPVS. For patients with HRV changes but without autonomic nervous system symptoms, positive intervention may slow the occurrence or progression of EPVS and cognitive impairment in patients with EPVS.

Responses of AM fungal abundance to the drivers of global climate change: A meta-analysis.

Arbuscular mycorrhizal fungi (AMF), playing critical roles in carbon cycling, are vulnerable to climate change. However, the responses of AM fungal abundance to climate change are unclear. A global-scale meta-analysis was conducted to investigate the response patterns of AM fungal abundance to warming, elevated CO2 concentration (eCO2), and N addition. Both warming and eCO2 significantly stimulated AM fungal abundance by 18.6% (95%CI: 5.9%-32.8%) and 21.4% (15.1%-28.1%) on a global scale, respectively. However, the response ratios (RR) of AM fungal abundance decreased with the degree of warming while increased with the degree of eCO2. Furthermore, in warming experiments, as long as the warming exceeded 4 °C, its effects on AM fungal abundance changed from positive to negative regardless of the experimental durations, methods, periods, and ecosystem types. The effects of N addition on AM fungal abundance are -5.4% (-10.6%-0.2%), and related to the nitrogen fertilizer input rate and ecosystem type. The RR of AM fungal abundance is negative in grasslands and farmlands when the degree of N addition exceeds 33.85 and 67.64 kg N ha-1 yr-1, respectively; however, N addition decreases AM fungal abundance in forests only when the degree of N addition exceeds 871.31 kg N ha-1 yr-1. The above results provide an insight into predicting ecological functions of AM fungal abundance under global changes.

Curcumin slows the progression of Alzheimer's disease by modulating mitochondrial stress responses via JMJD3-H3K27me3-BDNF axis.

Disturbance of mitochondrial proteins by amyloid beta-protein (Aß) that associates with mitochondrial stress responses (MSR) is one of the pathological mechanisms of Alzheimer's disease (AD). This study tried to explore whether the axis of Jumonji domain-containing protein 3 (JMJD3)-trimethylated lysine 27 on histone H3 (H3K27me3)-brain derived neurotrophic factor (BDNF) is involved in the regulation of MSR which in turn intervenes in the process of AD, and whether curcumin (CUR) has a protective role against AD by influencing this axis, aiming to provide insights into AD treatment. AD mouse models presented a significant aggregation of Aß, with conspicuous pathological changes in brain tissues and an increase in neuronal apoptosis. Moreover, the mRNA and protein levels of JMJD3 and BDNF were down-regulated, H3K27me3 methylation levels were increased, and the MSR markers (ClpP, HSP6, HSP-60, and ATFS-1) showed abnormal alterations. In in-vitro cellular models of AD, up-regulation of either JMJD3 or BDNF up-regulated BDNF levels, down-regulated H3K27me3 methylation levels, mitigated abnormalities of MSR markers and Aß aggregation, and increased cell proliferation and inhibited apoptosis. JMJD3 was confirmed to regulate Aß and MSR via BDNF. In addition, CUR was confirmed to modulate JMJD3-H3K27me3-BDNF axis. Furthermore, moderate and high doses of CUR could improve the morphology and histopathology of the brain, inhibit Aß aggregation and cell apoptosis, and maintain MSR balance at least partly by modulating the JMJD3-H3K27me3-BDNF axis. To sum up, moderate and high doses of CUR regulate the progression of AD via MSR JMJD3-H3K27me3-BDNF axis.

The telomere length of peripheral blood cells is associated with the risk of ischemic stroke in Han population of northern China.

BACKGROUND: Telomere length is closely related to the onset and prognosis of ischemic stroke. This study was to investigate the relationship between telomere length and the incidence of ischemic stroke in Han population of northern China. METHODS: In the present study, 152 patients with ischemic stroke were selected as the case group, and 152 healthy persons were used as the control group. Detection of telomere length was done by real-time polymerase chain reaction after extraction of genomic DNA from peripheral venous blood. RESULTS: Our results showed that the telomere length of the patients in the case group was significantly lower than that of the control group (Z = -11.843, P < .0001). Further analysis found that the telomere length of the control group was inversely correlated with age (r = -0.234, P = .004), and the telomere length and homocysteine (HCY) were inversely correlated in the case group (r = -0.176, P = .03), especially in women (r = -0.357, P = .024). Multivariate regression analysis showed that telomere length was a protective factor for ischemic stroke (odds ratio [OR] 95% confidence interval [95% CI] = 0.748 [0.681-0.823], ß = -0.29, P < .0001). The receiver operating characteristic curve showed that telomere length was a good diagnostic biomarker of ischemic stroke (area under the curve: 0.894, sensitivity: 84.7%, specificity: 93.4%). CONCLUSION: Our results indicate that shorter telomere length has some connection with the risk of ischemic stroke in the northern Chinese Han population. Telomere length might serve as a potential candidate biomarker for ischemic stroke. This requires a large sample to be further verified.

MicroRNA-129-5p alleviates nerve injury and inflammatory response of Alzheimer's disease via downregulating SOX6.

There is growing evidence of the position of microRNAs (miRs) in Alzheimer's disease (AD), thus our objective was to discuss the impact of miR-129-5p regulating nerve injury and inflammatory response in AD rats by modulating SOX6 expression. The AD rat model was established by injecting Aß25-35 into the brain. The pathological changes, ultrastructure, number of neurons, cell degeneration and apoptosis of hippocampal tissue were observed in vivo. MiR-129-5p, SOX6, IL-1ß, TNF-α, Bcl-2 and Bax expression in serum and hippocampal tissues were detected by ELISA, RT-qPCR or western blot analysis. The successfully modeled hippocampal neuronal cells of AD were transfected with miR-129-5p mimic, SOX6-siRNA or their controls to figure out their roles in proliferation, apoptosis and inflammatory reaction in vitro. Low expression of SOX6 and high expression of miR-129-5p in vivo of rats would shorten the escape latent period and increase the times of crossing platforms, alleviate the pathological injury, inhibit neuronal apoptosis and reduce the inflammatory reaction. Up-regulation of miR-129-5p and down-regulation of SOX6 promoted proliferation, suppressed apoptosis and degraded the inflammatory reaction of neuronal cells in vitro. Up-regulation of SOX6 reversed the expression of miR-129-5p to reduce the damage and inflammatory response of the cell model of AD. Our study presents that up-regulation of miR-129-5p or down-regulation of SOX6 can reduce nerve injury and inflammatory response in rats with AD. Thus, miR-129-5p may be a potential candidate for the treatment of AD.

MicroRNA-128 knockout inhibits the development of Alzheimer's disease by targeting PPARγ in mouse models.

Alzheimer's disease (AD) is a great threat for the health and life of elderly people. MicroRNA-128 (miR-128) has been reported to be abnormally expressed in the brain of AD patients and associated with the pathogenesis of AD. Our study aimed to have a deep insight into the roles and molecular basis of miR-128 in the development and progression of AD. The cognitive ability and exploratory behaviors were assessed by morris water maze and open-field tests, respectively. The concentrations of amyloid-ß (Aß) 40, Aß 42, tumor necrosis factor (TNF)-α, interleukin (IL)-1ß and IL-10 and activity of ß-secretase and α-secretase were determined by corresponding ELISA commercial kits. RT-qPCR assay was performed to detect miR-128 level and the mRNA expression of peroxisome proliferator-activated receptor gamma (PPARγ), ionized calcium-binding adaptor molecule 1 (Iba1) and glial fibrillary acidic protein (GFAP). Western blot assay was conducted to determine protein expression of PPARγ, amyloid precursor protein (APP), ß-APP cleaving enzyme (BACE1), sAPPα and sAPPß. The effect of miR-128 and PPARγ on amyloid plaque formation was assessed by immunohistochemistry assay. PPARγ mean optical density was determined by immunofluorescence assay. The interaction between miR-128 and PPARγ were validated by bioinformatics analysis and luciferase reporter assay. We found AD mice showed AD-like performance and an increased cerebral cortex Aß production. MiR-128 expression was upregulated and PPARγ expression was downregulated in cerebral cortex of AD mice. Moreover, PPARγ was a target of miR-128. Additionally, miR-128 knockout or PPARγ upregulation inhibited AD-like performances, amyloid plaque formation, Aß generation, APP amyloidogenic processing and inflammatory responses in AD mice, while these effects of miR-128 knockout were abrogated by PPARγ inhibitor. The results indicated MiR-128 knockout weakened AD-like performances, and reduced Aß production and inflammatory responses by targeting PPARγ in AD mice.

Study on the relationship between livin expression and osteosarcoma.

OBJECTIVE: The aim of this meta-analysis was to analysis the expression of livin in human osteosarcoma. METHODS: We searched the Pubmed, Science Direct, Embase and Web of Science, CNKI, Wanfang and VIP for relevant original studies. Statistical analysis was performed by Stata 11.0 software. RESULTS: Our study indicated that livin expressed in the osteosarcoma tissue was significantly higher than the control group (OR = 18.814, P c = 0.000, 95% CI: 10.973-32.257), and the positive expression of livin was correlated with the size of osteosarcoma tumor and Enncking staging (OR = 4.832, 95% CI: 2.198-10.621; OR = 4.851, 95% CI: 3.053-7.709, respectively). CONCLUSION: Livin was highly expressed in osteosarcoma, and osteosarcoma Enncking staging and tumor size were positively correlated, both may be involved in the occurrence and development of osteosarcoma, and be closely related to the prognosis of osteosarcoma patients.

SPK1-transfected UCMSC has better therapeutic activity than UCMSC in the treatment of experimental autoimmune encephalomyelitis model of Multiple sclerosis.

Multiple Sclerosis (MS), is a chronic inflammatory autoimmune disorder of the central nervous system that leads to chronic demyelination with axonal damage and neuronal loss. Mesenchymal stem cells (MSCs) represent a promising therapeutic approach for MS. In the current study, we investigated the effects of MSCs derived from the human umbilical cord (UCMSC) transfected by sphingosine kinase 1 (SPK1) gene. All the results showed that transplantation of UCMSCs gene modified by SPK1 (UCMSC-SPK1) dramatically reduce the severity of neurological deficits of the experimental autoimmune encephalomyelitis (EAE) mice, paralleling by reductions in demyelination, axonal loss, and astrogliosis. UCMSC-SPK1 transplantation also could inhibit the development of natural killer (NK) responses in the spleen of EAE mice, and increase the ratio of CD4+ CD25+ FoxP3+ (Treg) T cells. Furthermore, we described that a shift in the cytokine response from Th1/Th17 to Th2 was an underlying mechanism that suppressed CNS autoimmunity. UCMSCs transfected by SPK1 gene potentially offer a novel mode for the treatment of MS, and the specific mechanism of SPK1 in treating MS/EAE.

Ethyl pyruvate protects PC12 cells from oxygen-glucose deprivation: A potential role in ischemic cerebrovascular disease.

The protective potential of ethyl pyruvate (EP) on neuron has been investigated previously. This study was intended to investigate the effects of EP on the severity of oxygen-glucose deprivation (OGD)-induced injury in neural-like PC12 cells. PC12 cells were exposed to OGD condition with or without EP treatment. Then, cell viability, apoptosis, and the expressions of neurotrophic factors were detected. Further, Sprague-Dawley rats were intravenously administered with 5mg/kg EP for 14 days post-middle cerebral artery occlusion (MCAO). The effects of EP on the infarct volumes and neurological functions of MCAO rats were then assessed. Result showed that EP alleviated OGD-diminished cells viability, OGD-induced apoptosis, and OGD-reduced expressions of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF) and Nestin in PC-12 cells. EP blocked OGD-activated the Notch1 and nuclear factor Kappa B (NF-κB) signaling pathways in PC12 cells. Besides, in vivo data demonstrated that EP treatment decreased infarct volume and mNSS score, and increased the time spent on the rota-rod apparatus of MCAO rats. To conclude, EP protected neural-like PC12 cells from cerebral ischemia-reperfusion injury by suppressing apoptosis and promoting neural restoration. Notch1 and NF-κB pathway might implicated in the functions of EP on neuron.

Interaction between PPAR γ and SORL1 gene with Late-Onset Alzheimer's disease in Chinese Han Population.

AIMS: To investigate the impact of sortilin-related receptor 1 gene 1 (SORL1) and peroxisome proliferator activated receptor gamma (PPAR G) gene single nucleotide polymorphisms (SNPs), gene- gene and gene- environment interactions and haplotype on late-onset Alzheimer's disease (LOAD) risk. METHODS: Hardy-Weinberg equilibrium (HWE), haplotype analysis and pairwise linkage disequilibrium (LD) analysis were investigated by using SNPStats (available online at http://bioinfo.iconcologia.net/SNPstats). Logistic regression was performed to investigate association between SNPs and LOAD. Generalized multifactor dimensionality reduction (GMDR) was used to investigate the interaction among gene- gene and gene- environment interaction. RESULTS: Logistic regression analysis showed that LOAD risk was significantly higher in carriers of the A allele of rs1784933 polymorphism than those with GG (GA+ AA versus GG), adjusted OR (95%CI) = 1.63(1.27-1.98), and higher in carriers of G allele of the rs1805192 polymorphism than those with CC (CG+ GG versus CC), adjusted OR (95%CI) = 1.70 (1.25-2.27). GMDR analysis suggested a significant two-locus model (p = 0.0010) involving rs1784933 and rs1805192, and a significant two-locus model (p = 0.0100) involving rs1784933 and alcohol drinking. Haplotype containing the rs1784933- A and rs689021- C alleles were associated with a statistically increased LOAD risk (OR = 1.86, 95%CI = 1.37- 2.52, p < 0.001). CONCLUSIONS: We conclude that rs1784933 and rs1805192 minor alleles, gene- gene interaction between rs1784933 and rs1805192, gene- environment interaction between rs1784933 and alcohol drinking, and haplotype containing the rs1784933- A and rs689021- C alleles are all associated with increased LOAD risk.

Intravenous administration of adipose tissue-derived stem cells enhances nerve healing and promotes BDNF expression via the TrkB signaling in a rat stroke model.

Previous studies have shown the beneficial effects of adipose-derived stem cells (ADSCs) transplantation in stroke. However, the molecular mechanism by which transplanted ADSCs promote nerve healing is not yet elucidated. In order to make clear the molecular mechanism for the neuroprotective effects of ADSCs and investigate roles of the BDNF-TrkB signaling in neuroprotection of ADSCs, we, therefore, examined the neurological function, brain water content, and the protein expression in middle cerebral artery occlusion (MCAO) rats with or without ADSCs transplantation. ADSCs were transplanted intravenously into rats at 30 minutes after MCAO. K252a, an inhibitor of TrkB, was administered into rats by intraventricular and brain stereotaxic injection. Modified neurological severity score tests were performed to measure behavioral outcomes. The results showed that ADSCs significantly alleviated neurological deficits and reduced brain water content in MCAO rats. The protein expression levels of BDNF and TrkB significantly increased in the cortex of MCAO rats with ADSCs treatment. However, K252a administration reversed the ADSCs-induced elevation of BDNF, TrkB, and Bcl-2 and reduction of Bax protein in MCAO rats. ADSCs promote BDNF expression via the TrkB signaling and improve functional neurological recovery in stroke rats.

Effects of caffeic acid on learning deficits in a model of Alzheimer's disease.

Caffeic acid is a type of phenolic acid and organic acid. It is found in food (such as tomatoes, carrots, strawberries, blueberries and wheat), beverages (such as wine, tea, coffee and apple juice) as well as Chinese herbal medicines. In the present study, we examined the effects of caffeic acid on learning deficits in a rat model of Alzheimer's disease (AD). The rats were randomly divided into three groups: i) control group, ii) AD model group and iii) caffeic acid group. Caffeic acid significantly rescued learning deficits and increased cognitive function in the rats with AD as demonstrated by the Morris water maze task. Furthermore, caffeic acid administration resulted in a significant decrease in acetylcholinesterase activity and nitrite generation in the rats with AD compared with the AD model group. Furthermore, caffeic acid suppressed oxidative stress, inflammation, nuclear factor­κB­p65 protein expression and caspase­3 activity as well as regulating the protein expression of p53 and phosphorylated (p-)p38 MAPK expression in the rats with AD. These experimental results indicate that the beneficial effects of caffeic acid on learning deficits in a model of AD were due to the suppression of oxidative stress and inflammation through the p38 MAPK signaling pathway.