Manf Enhances the Pyroptosis Inhibition of Bone Marrow-derived Mesenchymal Stem Cells to Relieve Cerebral Infarction Injury.

Cerebral infarction is a common disease characterized by high mortality, a narrow therapeutic window, and limited therapeutic options. Recently, cell therapy based on gene modification has brought a glimmer of hope to the treatment of cerebral infarction although the explicit underlying mechanism is beyond being well dissected. In the present study, we constructed an animal model of middle cerebral artery occlusion (MCAO), compared differentially expressed genes (DEGs) between the sham and MCAO groups by single-cell RNA sequencing (scRNA-seq) to explore the potential cell death-related pathways involved in cerebral infarction, and transfected Manf into BMSCs by lentivirus. Subsequently, we injected BMSCs (bone marrow-derived mesenchymal stem cells), Manf-modified BMSCs, or lentivirus encoding Manf into the brain. Their effects on MANF content, apoptosis, pyroptosis, infarct volume in the brain, and neurological function were evaluated after MCAO. We found that the DEGs upregulated in four major cell clusters after MCAO and were enriched with not only apoptosis, ferroptosis, and necroptosis but also with pyroptosis-related pathways. In addition, transfection of Manf into BMSCs significantly increased the expression and secretion of MANF in BMSCs; BMSCs, Manf-modified BMSCs, and Manf treatment all resulted in an increase in Manf content in the brain, a decrease in the expression of apoptosis- and pyroptosis-related molecules, a reduction in infarct volume, and an improvement in neurological function after MCAO. Moreover, Manf-modified BMSCs have the strongest therapeutic effect. Collectively, Manf-modified BMSCs ameliorate ischemic injury after cerebral infarction by repressing apoptosis- and pyroptosis-related molecules, which represents a new cell therapy strategy for cerebral infarction.

Identification of pyroptosis-related immune signature and drugs for ischemic stroke.

Background: Ischemic stroke (IS) is a common and serious neurological disease, and multiple pathways of cell apoptosis are implicated in its pathogenesis. Recently, extensive studies have indicated that pyroptosis is involved in various diseases, especially cerebrovascular diseases. However, the exact mechanism of interaction between pyroptosis and IS is scarcely understood. Thus, we aimed to investigate the impact of pyroptosis on IS-mediated systemic inflammation. Methods: First, the RNA regulation patterns mediated by 33 pyroptosis-related genes identified in 20 IS samples and 20 matched-control samples were systematically evaluated. Second, a series of bioinformatics algorithms were used to investigate the contribution of PRGs to IS pathogenesis. We determined three composition classifiers of PRGs which potentially distinguished healthy samples from IS samples according to the risk score using single-variable logistic regression, LASSO-Cox regression, and multivariable logistic regression analyses. Third, 20 IS patients were classified by unsupervised consistent cluster analysis in relation to pyroptosis. The association between pyroptosis and systemic inflammation characteristics was explored, which was inclusive of immune reaction gene sets, infiltrating immunocytes and human leukocyte antigen genes. Results: We identified that AIM2, SCAF11, and TNF can regulate immuno-inflammatory responses after strokes via the production of inflammatory factors and activation of the immune cells. Meanwhile, we identified distinct expression patterns mediated by pyroptosis and revealed their immune characteristics, differentially expressed genes, signaling pathways, and target drugs. Conclusion: Our findings lay a foundation for further research on pyroptosis and IS systemic inflammation, to improve IS prognosis and its responses to immunotherapy.

Plasma Concentration of Tumor Necrosis Factor-Stimulated Gene-6 as a Novel Diagnostic and 3-Month Prognostic Indicator in Non-Cardioembolic Acute Ischemic Stroke.

Background: Tumor necrosis factor-stimulated gene-6 (TSG-6) is a multifunctional, anti-inflammatory, and protective protein, while the association between TSG-6 and acute ischemic stroke (AIS) remains unclear in humans. This study aims to investigate the potential diagnostic and short-term prognosis predictive values of TSG-6 in non-cardioembolic AIS. Methods: A total of 134 non-cardioembolic AIS patients within 24 h after AIS onset and 40 control subjects were recruited. Using an AIS dataset from the Gene Expression Omnibus database and setting the median expression level of TNFAIP6 as the cutoff point, data were divided into TNFAIP6-high and TNFAIP6-low expression groups. Differently expressed genes (DEGs) were extracted to perform gene enrichment analysis and protein-protein interaction (PPI) network. Baseline data were analyzed in a four-group comparison plotted as plasma TSG-6 concentration median and 25th/75th percentiles. The correlative factors of 3-month outcome were evaluated by logistic regression. TSG-6 concentrations and TSG-6-to-interleukin-8 ratios were compared in a block design. A receiver-operating characteristic curve was used to analyze the detective value of TSG-6 and 3-month prognosis predictive values of TSG-6 and TSG-6-to-interleukin-8 ratio. Results: Non-cardioembolic AIS patients had significantly higher plasma TSG-6 levels than control subjects (P < 0.0001). The large-artery atherosclerosis group had significantly higher TSG-6 levels than the small-artery occlusion group (P = 0.0184). Seven hundred and eighty-two DEGs might be both AIS-related and TNFAIP6-correlated genes, and 17 targets were deemed AIS-related being closely relevant to TNFAIP6. Interleukin-8 was selected for further study. The National Institutes of Health Stroke Scale and the Acute Stroke Registry and Analysis of Lausanne scores at admission, lesion volume, neutrophil count, neutrophil-to-lymphocyte ratio, and interleukin-8 level were positively correlated with TSG-6 level, respectively (P < 0.0001). The unfavorable outcome group had meaningfully higher TSG-6 levels (P < 0.0001) and lower TSG-6-to-interleukin-8 ratios (P < 0.0001) than the favorable outcome group. After adjusting for confounding variables, elevated TSG-6 levels remained independently associated with 3-month poor prognosis of non-cardioembolic AIS (P = 0.017). In non-cardioembolic AIS, the cutoff values of TSG-6 concentration for detection and 3-month prognosis prediction and the TSG-6-to-interleukin-8 ratio for the 3-month prognosis prediction were 8.13 ng/ml [AUC, 0.774 (0.686-0.861); P < 0.0001], 10.21 ng/ml [AUC, 0.795 (0.702-0.887); P < 0.0001], and 1.505 [AUC, 0.873 (0.795-0.951); P < 0.0001]. Conclusions: Plasma TSG-6 concentration was a novel indicator for non-cardioembolic AIS diagnosis and 3-month prognosis. Elevated TSG-6-to-interleukin-8 ratio might suggest a 3-month favorable outcome.

Longitudinal metabolomics profiling of serum amino acids in rotenone-induced Parkinson's mouse model.

Recently, the detailed etiology and pathogenesis of Parkinson's disease (PD) have not been fully clarified yet. Increasing evidences suggested that the disturbance of peripheral branched-chain amino acids (BCAAs) metabolism can promote the occurrence and progression of neurodegenerative diseases through neuroinflammatory signaling. Although there are several studies on the metabolomics of PD, longitudinal study of metabolic pathways is still lacking. Therefore, the purpose of the present study was to determine the longitudinal alterations in serum amino acid profiles in PD mouse model. Gas chromatography-mass spectrometry (GC-MS) was applied to detect serum amino acid concentrations in C57BL/6 mice after 0, 3 and 4 weeks of oral administration with rotenone. Then the data were analysed by principal component analysis (PCA) and orthogonal projection to latent structures (OPLS) analysis. Finally, the correlations between different kinds of serum amino acids and behaviors in rotenone-treated mice were also explored. Compared with 0-week mice, the levels of L-isoleucine and L-leucine were down-regulated in 3-week and 4-week mice, especially in 4-week mice. Moreover, the comprehensive analysis showed that L-isoleucine and L-leucine were negatively correlated with pole-climbing time and positively correlated with fecal weight and water content of PD mice. These results not only suggested that L-isoleucine and L-leucine may be potential biomarkers, but also pointed out the possibility of treating PD by intervening in the circulating amino acids metabolism.

Alterations of gut microbiota and metabolome with Parkinson's disease.

Gut microbiota and amino acids that are one of their metabolites play important roles in the mechanism of pathology of Parkinson's disease (PD). It has been reported that the level of amino acids in vivo participate in neurodegeneration by regulating adaptive immune response, while the current researches on alteration of amino acids in gut microbiota are still insufficient. We hypothesized that alterations in gut microbiota might be accompanied by altered concentrations of amino acids, leading to the occurrence of PD. In this study, we collected stool samples from PD and healthy controls to analyse fecal microbiome and targeted metabolome by 16S ribosomal RNA (16S rRNA) gene sequencing and gas chromatography coupled to mass spectrometry (GC-MS). At the genus level, there was a greater abundance of Alistipes, Rikenellaceae_RC9_gut_group, Bifidobacterium, Parabacteroides, while Faecalibacterium was decreased in fecal samples from PD patients. Moreover, fecal branched chain amino acids (BCAAs) and aromatic amino acids concentrations were significantly reduced in PD patients compared to controls. Our study not only finds the abundance of certain gut microbiota in PD,but also reveals that it is related to BCAAs and aromatic amino acids. These findings are beneficial to identifying new therapeutic targets for PD by regulating diet and/or gut microbiota.

Integrated network analysis identifying potential novel drug candidates and targets for Parkinson's disease.

This study aimed to identify potential novel drug candidates and targets for Parkinson's disease. First, 970 genes that have been reported to be related to PD were collected from five databases, and functional enrichment analysis of these genes was conducted to investigate their potential mechanisms. Then, we collected drugs and related targets from DrugBank, narrowed the list by proximity scores and Inverted Gene Set Enrichment analysis of drug targets, and identified potential drug candidates for PD treatment. Finally, we compared the expression distribution of the candidate drug-target genes between the PD group and the control group in the public dataset with the largest sample size (GSE99039) in Gene Expression Omnibus. Ten drugs with an FDR < 0.1 and their corresponding targets were identified. Some target genes of the ten drugs significantly overlapped with PD-related genes or already known therapeutic targets for PD. Nine differentially expressed drug-target genes with p < 0.05 were screened. This work will facilitate further research into the possible efficacy of new drugs for PD and will provide valuable clues for drug design.

Inverse associations of outdoor activity and vitamin D intake with the risk of Parkinson's disease.

Early studies had suggested that vitamin D intake was inversely associated with neurodegenerative diseases, such as Alzheimer's disease and multiple sclerosis. However, the associations of vitamin D intake and outdoor activities with Parkinson's disease (PD) are still unclear, so this study is to evaluate these relationships from a case-control study in elderly Chinese. The study population involved 209 cases with new onsets of PD and 210 controls without neurodegenerative diseases. The data on dietary vitamin D and outdoor activities were collected using a food-frequency questionnaire and self-report questionnaire. Multivariable logistic regressions were used to examine the associations between dietary outdoor activities, vitamin D intake and PD. Adjustment was made for sex, age, smoking, alcohol use, education, and body mass index (BMI). Adjusted odds ratios (ORs) for PD in quartiles for outdoor physical activity were 1 (reference), 0.739 (0.413, 1.321), 0.501 (0.282, 0.891), and 0.437 (0.241, 0.795), respectively (P=0.002 for trend). Adjusted ORs for PD in quartiles for total vitamin D intake were 1 (reference), 0.647 (0.357, 1.170), 0.571 (0.318, 1.022), and 0.538 (0.301, 0.960), respectively (P=0.011 for trend). Our study suggested that outdoor activity and total vitamin D intake were inversely associated with PD, and outdoor activity seems to be more significantly associated with decreased risk for PD.

[A prevalence study on mild cognitive impairment among the elderly populations of Mongolian and Han nationalities in a pastoral area of Inner Mongolia].

OBJECTIVE: To understand the epidemiological characteristics and distribution of mild cognitive impairment (MCI) in elderly populations from Mongolian and Han nationalities living in the pastoral areas of Inner Mongolia Autonomous Region of China. METHODS: According to the MCI clinical diagnostic criteria from Diagnostic and Statistical Manual of Mental Disorders 4th revised edition (DSM-IV) by American Psychiatric Association, the individuals under study were at the age of 55 or over, with Mongolian or Han ethnicities and living in the pastoral area of Inner Mongolia. RESULTS: The crude MCI morbidity rates of Mongolian and Han of the study populations in the pastoral area of Inner Mongolia Autonomous Region of China was 19.48% (1782/9146) and the standardization morbidity was 18.98%. The crude MCI morbidity rates of both Mongolian and Han ethnicities were 17.46% (the standardization morbidity was 16.99%) and 20.60% (the standardization morbidity was 19.98%), respectively. There showed a significant positive correlation between the crude morbidities and age, also significantly increasing with the latter. In the Mongolian population, the morbidity increased from 12.17% at the age 55-59 to 27.78% at 85 while in the Han population, the morbidity increased from 15.50% at the age 55-59 to 23.53% at 85. In both the populations of Mongolian and Han, there was a statistically difference found between the morbidities of MCI (χ2=13.229, P=0.000). The morbidity was higher in Hans than in the Mongolians. However, there was no statistically significant difference noticed between the morbidities of MCI in the Mongolian males and females (χ2=2.376, P=0.123). There was statistically significant difference found between the morbidities of MCI in the Han males and females, with females having higher risk than males (χ2=24.470, P=0.000). CONCLUSION: The morbidity of MCI in the elderly Mongolian and Han populations from the pastoral area of Inner Mongolia Autonomous Region of China was considered to be quite high and correlated to age and gender.

IL-6-174 G/C and -572 C/G polymorphisms and risk of Alzheimer's disease.

Associations between interleukin 6 (IL-6) polymorphisms and Alzheimer's disease (AD) remain controversial and ambiguous. The aim of this meta-analysis is to explore more precise estimations for the relationship between IL-6-174 G/C and -572 C/G polymorphisms and risk for AD. Electronic searches for all publications in databases PubMed and EMBASE were conducted on the associations between IL-6 polymorphisms and risk for AD until January 2012. Odds ratio (OR) and 95% confidence intervals (CIs) were calculated using fixed and random effects models. Twenty-seven studies were included with a total of 19,135 individuals, involving 6,632 AD patients and 12,503 controls. For IL-6-174 G/C polymorphism, the combined results showed significant differences in recessive model (CC vs. CG+GG: OR = 0.65, 95%CI = 0.52-0.82). As regards IL-6-572 C/G polymorphism, significant associations were shown in dominant model (CG+GG vs. CC: OR= 0.73, 95% CI = 0.62-0.86) and in additive model (GG vs. CC, OR= 0.66, 95% CI = 0.46-0.96). In conclusion, genotype CC of IL-6-174 G/C and genotype GG plus GC of IL-6-572 C/G could decrease the risk of AD.

Increased levels of IL-23 and osteopontin in serum and cerebrospinal fluid of multiple sclerosis patients.

Osteopontin (OPN) and interleukin-23 (IL-23) are pro-inflammatory cytokines proposed to play central roles to the development of multiple sclerosis (MS). The aim of this study was to evaluate levels of OPN, IL-23 and other inflammatory cytokines and investigate their relationships in serum and cerebrospinal fluid (CSF) in patients with MS. Fifty one MS patients and 48 patients with non-inflammatory neurological diseases (NIND) were recruited from clinic. The levels of OPN, IL-23, IL-17, IL-6, and tumor necrosis factor-alpha (TNF-alpha) in serum and CSF were determined in each participant. Compared with NIND group, MS patients had significantly elevated levels of OPN, IL-23, IL-17 and TNF-alpha in CSF, and elevated levels of IL-23, IL-17 and TNF-alpha in serum (All P<0.001). In MS patients, OPN and IL-23 were positively correlated with IL-17 (r=0.302, P=0.019; r=0.417, P=0.001, respectively); and IL-23 was positively correlated with EDSS (r=0.329, P=0.019). Both OPN and IL-23 may play pivotal role in development of MS and might be specific markers and therapeutic targets for MS.

Expression of δNp73 in hippocampus of APP/PS1 transgenic mice following GFP-BMSCs transplantation.

OBJECTIVE: To study the effect of hippocampal bone marrow stromal cells (GFP-BMSCs) transplantation on spatial memory and DeltaNp73 expression in APP/PS1 transgenic mice. METHODS: Twelve APP/PS1 transgenic mice randomly received either 10 µl GFP-BMSCs suspension in medium (GFP-BMSCs transplantation group) or 10 µl complete medium (sham-operated group). Learning and memory function of mice in both groups were observed and tested in Morris water maze experiment at 2 weeks after surgery. Senile plaques and DeltaNp73 protein in hippocampuses were determined by immunohistochemistry and western blot at 3 weeks after surgery, respectively. RESULTS: APP/PS1 mice treated with BMSCs performed significantly better on the water maze test than those in sham-operated group (P<0·05). Immunohistochemistry showed that GFP-BMSCs distributed uniformly and the number of Alzheimer's senile plaques reduced after transplantation. Western blot showed that quantified DeltaNp73 protein expression was significantly higher in BMSCs transplantation group when compared with sham-operated group (P<0·01). CONCLUSIONS: Our results suggest that BMSCs transplatation could retard Alzheimer's disease (AD) like pathology and upregulate DeltaNp73 expression in hippocampuses of APP/PS1 transgenic mice. GFP-BMSCs transplantation will be a potential treatment for AD.

WITHDRAWN: Effects of traditional Chinese medicine Fuzhisan on PP1 expression in the hippocampus of SAMP8 mice.

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Effects of Chinese herbal medicine Fuzhisan on autologous neural stem cells in the brain of SAMP-8 mice.

Fuzhisan (FZS), a Chinese herbal complex prescription, has been used in the treatment of Alzheimer's disease (AD) for more than 16 years. However the underlying mechanism remains to be explored. The effects of the aqueous extract of FZS on the cognitive functions of the aged mice and the pharmacological basis for its therapeutic efficacy were investigated. The results showed that FZS improved impaired cognitive ability of aged SAMP-8 mice. FZS (2.4, 4.8 g/kg/d) increased hippocampal neurogenesis and the long-term survival of BrdU-labeled cells without affecting the proportion of BrdU-positive neurons and glial cells. FZS also increased the number of BrdU-positive cells in the subventricular zone (SVZ) of the lateral ventricles of 8-month-old SAMP-8 mice. These studies suggest that FZS upregulates neurogenesis by increasing proliferation of neural progenitor cells and prolonging survival of the newborn cells in the hippocampal DG. FZS may be beneficial for the treatment of senile dementia, especially Alzheimer's disease.

Inhibition of glycogen synthase kinase-3ß by Angelica sinensis extract decreases ß-amyloid-induced neurotoxicity and tau phosphorylation in cultured cortical neurons.

Increasing evidence has shown that ß-amyloid (Aß) induces hyperphosphorylation of tau and contributes to Aß toxicity. Recently, tau hyperphosphorylation by glycogen synthase kinase-3ß (GSK-3ß) activation has been emphasized as one of the pathogenic mechanisms of Alzheimer's disease (AD). The phosphoinositide 3 kinase (PI3K)/Akt pathway is known as an upstream element of GSK-3ß. The inhibitory control of GSK-3ß, via the PI3K/Akt pathway, is an important mechanism of cell survival. In the present study, we investigated the neuroprotective effects of Angelica sinensis (AS), a traditional Chinese herbal medicine, against Aß(1-42) toxicity in cultured cortical neurons and also the potential involvement of PI3K/Akt/GSK-3ß signal pathway. We revealed that AS extract significantly attenuated Aß(1-42) -induced neurotoxicity and tau hyperphosphorylation at multiple AD-related sites in a dose-dependent manner. Simultaneously, it increased the levels of phospho-Ser(473) -Akt and down-regulated GSK-3ß activity by PI3K activation. The neuroprotective effects of AS extract against Aß(1-42) -induced neurotoxicity and tau hyperphosphorylation were blocked by LY294002 (10 µM), a PI3K inhibitor. In addition, AS extract reversed the Aß(1-42) -induced decrease in phosphorylation cyclic AMP response element binding protein (CREB), which could be blocked by the PI3K inhibitor. These results suggest that AS-mediated neuroprotection against Aß toxicity is likely mediated by the PI3K/Akt/GSK-3ß signal pathway.

Fuzhisan, a Chinese herbal medicine, inhibits beta-amyloid-induced neurotoxicity and tau phosphorylation through calpain/Cdk5 pathway in cultured cortical neurons.

It has been shown that ß-amyloid (Aß) induced hyperphosphorylation of tau is implicated in the pathogenesis of Alzheimer's disease (AD), and deregulation of cyclin-dependent kinase 5 (Cdk5) activity is involved in the abnormal tau phosphorylation. The cleavage of neuron-specific Cdk5 activator, p35, to p25, mediated by calpain and calcium, deregulates Cdk5 activity and promotes neurodegeneration. Fuzhisan (FZS), a Chinese herbal complex prescription that has been used for the treatment of AD for over 15 years, is known to enhance the cognitive ability in AD patients. In this study, we investigated the neuroprotective effects and potential molecular mechanisms of FZS against Aß(25-35)-induced toxicity in cultured cortical neurons. We revealed that FZS attenuated Aß(25-35)-induced neurotoxicity in a dose-dependent manner. FZS inhibited Aß(25-35)-induced activation of Cdk5 and decreased tau hyperphosphorylation although it did not directly inhibit Cdk5. In addition, FZS also blocked Aß(25-35)-induced calcium influx, calpain activation and decreased cleavage of p35 to p25.

Implication of phosphatidylinositol-3 kinase/Akt/glycogen synthase kinase-3ß pathway in ginsenoside Rb1's attenuation of beta-amyloid-induced neurotoxicity and tau phosphorylation.

Ginseng has long been used to alleviate many ailments, particularly those associated with aging and memory deterioration. In the present study we aimed to investigate the neuroprotective effects of ginsenoside Rb1, against Aß(1-42) toxicity in cultured cortical neurons and also the potential involvement of PI3K/Akt/GSK-3ß signal pathway. Cortical neurons were pre-treated with ginsenoside Rb1 (20, 40, 100 µM) or LiCl (1, 5, 10 mM) for 24 h, and then were co-treated with 20 µM Aß(1-42) for 12 h. In some experiments to evaluate the mechanism of Rb1 action, a PI3K inhibitor (LY294002 10 µM) was co-administered with Rb1 for the 24-h pretreatment. We revealed that Rb1 significantly attenuated Aß(1-42)-induced neurotoxicity and tau hyperphosphorylation at multiple AD-related sites in a dose-dependent manner. Simultaneously, it increased the levels of phospho-Ser(473)-Akt and down-regulated GSK-3ß activity by PI3K activation. The neuroprotective effects of Rb1 against Aß(1-42)-induced neurotoxicity and tau hyperphosphorylation were blocked by LY294002 (10 µM), a PI3K inhibitor. In addition, Rb1 reversed the Aß(1-42)-induced decrease in phosphorylation cyclic AMP response element binding (CREB) protein, which could also be blocked by the PI3K inhibitor. All these findings suggest that Rb1 may represent a potential treatment strategy for Alzheimer's disease.

An epidemiological study of Alzheimer's disease in elderly Mongolian and Han populations living in rural areas of Inner Mongolia.

BACKGROUND AND AIMS: This study investigated the current status and distribution of Alzheimer's disease (AD) among Mongolian and Han individuals who were at least 55 years old and living in rural areas of Inner Mongolia. This study sought to provide basic epidemiological data to better understand and treat Alzheimer's disease. METHODS: Individuals with AD who were at least 55 old and living in one of 27 communities and two settlements in Mongolia, took part in an AD epidemiological survey from June 2008 to June 2009. Stratified, multistage random-cluster sampling was used to analyze data. The first level of random-cluster sampling consisted of data collected from questionnaires and home-visit interviews of individuals living in four Qi (a county level administration region in Mongolia) and in one city in the Xilin Guole League. Data from individuals in four district offices and ten towns from the first level random-cluster formed the second level of random-cluster sampling. RESULTS: The final sample for this epidemiological investigation consisted of 9266 individuals. Analyses revealed that the prevalence rate of AD was 4.79% (SD=4.71%) in the combined Mongolian and Han populations of individuals at least 55 years old and living in rural areas of Inner Mongolia. The individual AD prevalence rates in the Mongolian and Han populations were 4.63% (SD=4.84%) and 4.89% (SD=4.60%), respectively. The AD prevalence rate for women was higher than for men (p<0.05). The AD prevalence rate for individuals aged 65 and older in the two combined populations was 8.06% (SD=8.55%); the rate in the Mongolian population was 7.81% (SD=8.38%) and 8.18% (SD=8.57%) in the Han population. Gender and age were risk factors for the development of AD (p<0.05) in both populations. CONCLUSIONS: 1) There was no significant difference in the AD prevalence rate between the Mongolian and Han populations consisting of individuals aged 55 and older, living in rural areas of Inner Mongolia. However, the AD prevalence rates in these populations were higher than the national average. 2) Gender and age were risk factors for the development of AD in the Mongolian and Han populations.

Hypoxia enhances stimulating effect of amyloid beta peptide (25-35) for interleukin 17 and T helper lymphocyte subtype 17 upregulation in cultured peripheral blood mononuclear cells.

Th17 has been demonstrated to have a key role in several autoimmune diseases. The present study was carried out to investigate changes in IL-17 and Th17 in cultured PBMC in response to Abeta peptide (25-35) and hypoxic stimulation in vitro. PBMC were collected from adult healthy donors and cultured in normal and anaerobic conditions (hypoxia 1, 3, 6, 12, 24 hr). Each group of cells was stimulated with Abeta peptide (25-35; 3, 10 nmol/ml). ELISA was used to examine IL-17A concentrations in the supernatants, and flow cytometry for the numbers of IL-17A secreting CD4 positive Th17 lymphocytes. Statistically significant increases in IL-17A and Th17 concentrations were found in groups with 10 nmol/ml Abeta (25-35) and more than three hr anaerobic culture. IL-17A and Th17 concentrations in anaerobic groups increased gradually with time and peaked at six hr. Compared with other groups, the highest concentrations were found in those treated with 10 nmol/ml Abeta and cultured for six hr (P < 0.001). This study provides the first report that IL-17A and Th17 lymphocytes are possibly involved in the immune pathogenesis caused by Abeta peptide (25-35). Hypoxia may enhance this response independently of time.

Serum C-reactive protein even at very low (<1.0 mg/l) concentration is associated with physical performance in a community-based elderly population aged 70 years and over.

BACKGROUND: Although several studies have reported that C-reactive protein (CRP) is associated with physical performance, few studies have evaluated the relationships between CRP and physical performance among subjects who had a very low range of CRP. Therefore, it is still unclear whether a lower CRP is favorably associated with physical performance even within a very low range. OBJECTIVE: The aim of this study was to investigate the relationships between CRP and physical performance among a Japanese population with a low serum CRP concentration (CRP <1.0 mg/l). METHODS: We designed a cross-sectional survey for 775 persons aged 70 years and older living in Japan. High-sensitivity CRP was measured using a nephelometric method. The subjects whose serum CRP concentrations were higher than 10.0 mg/l were excluded. Physical performance was assessed using a 10-meter maximum walk test, leg extension power, and a timed 'up and go' test. RESULTS: The median value (interquartile range) of CRP was 0.55 (0.29-1.20) mg/l. After adjustment for potential confounding factors, an inverse relation of CRP with the 10-meter maximum walk test and leg power was observed in all subjects (p for trend = 0.10 and 0.04, respectively). For subjects who had a CRP <1.0 mg/l, these inverse relations were unchanged (p for trend = 0.03 and 0.02, respectively). CONCLUSIONS: Serum CRP concentration is favorably related to physical performance, even within a very low range in a community-based elderly population aged 70 years and over. The findings suggest that maintaining as low CRP levels as possible may potentially maintain better physical performance.

Beta-fibrinogen promoter -455 G/A (HaeIII) polymorphism prediction of plasma fibrinogen but not of ischemic cerebrovascular disease.

OBJECTIVE: The -455 G/A (HaeIII) polymorphism of beta-fibrinogen gene influences levels of plasma fibrinogen. We further investigated whether it influences the risk of ischemic cerebrovascular disease. METHODS: We accumulated 134 acute ischemic cerebrovascular disease (ICVD) cases and compared their -455 G/A status with a control group (n = 166). The beta-fibrinogen gene -455 G/A polymorphism was analyzed for all subjects by PCR-RFLP with the restrictive enzyme HaeIII. RESULTS: Plasma fibrinogen was higher in AA homozygous participants (341 mg/dL) than in participants carrying the G allele: GA (290 mg/dL), GG (298 mg/dL) in the control group. Plasma fibrinogen was also higher in AA homozygous patients (353 mg/dL) than in cases carrying the G allele: GA (287 mg/dL), GG (302 mg/dL) in the ICVD group. However, there was no significant association between beta-fibrinogen gene -455 G/A polymorphism and ICVD group. CONCLUSIONS: Although a small effect cannot be excluded, beta-fibrinogen gene -455 G/A polymorphism is an independent predictor of plasma fibrinogen, but not of ischemic cerebrovascular disease.